Innovation in interventional cardiology

Abstract

Introduction and objectives: Patients with a low post-percutaneous coronary intervention (PCI) fractional flow reserve (FFR) are at a higher risk for future adverse cardiac events. The objective of the current study was to assess specific patient and procedural predictors of post-PCI FFR.

Methods: The FFR-SEARCH study is a prospective single-center registry of 1000 consecutive all-comer patients who underwent FFR measurements after an angiographically successful PCI with a dedicated microcatheter. Mixed effects models were used to search for independent predictors of post-PCI FFR.

Results: The mean post-PCI distal coronary pressure divided by the aortic pressure (Pd/Pa) was 0.96 ± 0.04 and the mean post-PCI FFR, 0.91 ± 0.07. After adjusting for the independent predictors of post-PCI FFR, the left anterior descending coronary artery as the measured vessel was the strongest predictor of post-PCI FFR (adjusted β = -0.063; 95%CI, -0.070 to -0.056; P < .0001) followed by the postprocedural minimum lumen diameter (adjusted β = 0.039; 95%CI, 0.015-0.065; P = .002). Additionally, male sex, in-stent restenosis, chronic total coronary occlusions, and pre- and post-dilatation were negatively associated with postprocedural FFR. Conversely, type A lesions, thrombus-containing lesions, postprocedural percent stenosis, and stent diameter were positively associated with postprocedural FFR. The R2 for the complete model was 53%.

Conclusions: Multiple independent patient and vessel related predictors of postprocedural FFR were identified, including sex, the left anterior descending coronary artery as the measured vessel, and postprocedural minimum lumen diameter.

keywords: Percutaneous coronary intervention. Post-PCI FFR. Predictors.

RESUMEN

Introducción y objetivos: Los pacientes con una reserva fraccional de flujo (FFR) posintervención coronaria percutánea (ICP) baja tienen mayor riesgo de futuros eventos cardiacos adversos. El objetivo del presente estudio fue evaluar predictores específicos de pacientes y procedimientos de FFR tras una ICP.

Métodos: El estudio FFR-SEARCH es un registro prospectivo de un solo centro que incluyó 1.000 pacientes consecutivos que se sometieron a una evaluación de la FFR tras una ICP con éxito angiográfico utilizando un microcatéter específico. Se utilizaron modelos de efectos mixtos para buscar predictores independientes de FFR tras la ICP.

Resultados: La media de presión distal dividida entre la presión aórtica tras la ICP fue de 0,96 ± 0,04, y la media de la FFR tras la ICP fue de 0,91 ± 0,07. Tras ajustar por predictores independientes de FFR tras la ICP, la arteria descendente anterior izquierda como vaso medido fue el predictor más fuerte (β ajustado = −0,063; IC95%, −0,070 a −0,056; p < 0,0001), seguida del diámetro luminal mínimo posprocedimiento (β ajustado = 0,039; IC95%, 0,015 a 0,065; p = 0,002). Además, el sexo masculino, la reestenosis del stent, las oclusiones totales crónicas y la pre- y posdilatación se correlacionaron negativamente con la FFR posprocedimiento. Por el contrario, las lesiones de tipo A, las lesiones con trombos, el porcentaje de estenosis posprocedimiento y el diámetro del stent se correlacionaron positivamente con la FFR posprocedimiento. El R2 para el modelo completo fue del 53%.

Conclusiones: Se identificaron diversos predictores independientes relacionados con los pacientes y con los vasos para la FFR posprocedimiento, incluyendo el sexo, la arteria descendente anterior izquierda como vaso medido y el diámetro luminal mínimo posprocedimiento.

Palabras clave: Intervención coronaria percutánea. FFR post-ICP. Predictores.

Abbreviations: FFR: fractional flow reserve. LAD: left anterior descending coronary artery. MLD: minimum luminal diameter. PCI: percutaneous coronary intervention.

INTRODUCTION

The limitations of an accurate assessment of the hemodynamic significance of coronary artery lesions through angiographic guidance alone are well-known.1 Instead, the fractional flow reserve (FFR) has proven to be a useful technique to address the coronary physiology and the hemodynamic significance of coronary segments before and after performing an intervention.2-4 Also, measuring FFR post-stenting has proven to be a strong and independent predictor of major adverse cardiovascular events at the 2-year follow-up.3-5

While FFR primarily takes into account the relative luminal narrowing and the amount of viable myocardium perfused by a specific vessel, several factors have been shown to impact the FFR values prior to performing a percutaneous coronary intervention (PCI). Therefore, longer lesion length, high syntax scores, calcifications, and tortuosity are associated with significantly lower FFR values. Conversely, the presence of microvascular dysfunction, chronic kidney disease and female gender have been associated with higher FFR values.6-11

At the present time, there is lack of data on independent predictors of post-PCI FFR. Therefore, the objective of the present study was to assess the patient and procedural characteristics associated with low post-PCI FFR in an all-comer patient population.

METHODS

The FFR-SEARCH study is a prospective single-center registry that assessed the routine distal pressure divided by the aortic pressure (Pd/Pa) and FFR values of all consecutive patients after an angiographically successful PCI. The primary endpoint was to study the impact of post-PCI FFR on the rate of major adverse cardiovascular event at the 2-year follow-up. Accordingly, no further actions were taken to improve post-PCI FFR. The study was performed in full compliance with the Declaration of Helsinki. The study protocol was approved by the local ethics committee. All patients gave their written informed consent to undergo the procedure. Also, anonymous datasets for research purposes were used in compliance with the Dutch Medical Research Act. A total of 1512 patients treated between March 2016 and May 2017 at the Erasmus Medical Center were eligible to enter our study. A total of 504 of these patients were excluded due to hemodynamic instability (156), a rather small distal outflow (129), the operator’s decision not to proceed with post-PCI hemodynamic assessment (148) or other reasons (79). A total of 1000 patients were included in the study. The microcatheter could not cross the treated lesion in 28 patients, technical issues with the catheter prevented post-PCI assessments in 11 patients, and in 2 patients the post-PCI FFR measurements had to be aborted prematurely due to adenosine intolerance. This left 959 patients whose post-PCI FFR values were measured in at least 1 angiographically successfully treated lesion.

Quantitative coronary angiography

The preprocedural lesion type was defined according to the ACC/AHA guidelines12 and divided into 4 categories: A, B1, B2, and C. Comprehensive quantitative coronary angiography analyses were performed pre- and post-stent implantation in all the treated lesions. An angiographic view with minimal foreshortening of the lesion and minimal overlapping with other vessels was selected. Similar angiographic views were used pre- and post-stent implantation. Measurements included pre- and postprocedural percent diameter stenosis, reference vessel diameter, lesion length, and minimum luminal diameter (MLD). In case of a total occlusion in patients presenting with ST-segment elevation myocardial infarction (STEMI) or chronic total coronary occlusion (CTO), the MLD was considered zero and the percent diameter stenosis, 100%. The reference vessel diameter and the lesion length were measured from the first angiographic view with restored flow. All measurements were taken using CAAS for Windows, version 2.11.2 (Pie Medical Imaging, The Netherlands).

Fractional flow reserve measurements

All FFR measurements were acquired using the Navvus RXi system (ACIST Medical Systems, United States), a dedicated FFR microcatheter with optical pressure sensor technology.13,14 Measurements were performed after an intracoronary bolus of nitrates (200 µg). The catheter was advanced while mounted over the previously used guidewire approximately 20 mm distal to the most distal border of the stent. The FFR was defined as the mean distal coronary artery pressure divided by the mean aortic pressure during maximum hyperemia achieved by the continuous IV infusion of adenosine at a rate of 140 µg/kg/min via the antecubital vein. In this study no vessels were assessed using intracoronary adenosine.

Statistical analysis

At baseline, the categorical variables were expressed as counts (percentage) and the continuous ones as mean ± standard deviation. To assess the independent predictors of post-PCI FFR, all the patient and vessel characteristics were primarily assessed through an univariate test using a mixed effects model (LME-model) with a random effect for the patients and a fixed effect for the post-PCI FFR. All variables were subsequently inserted in a multivariate LME-model using the enter method that resulted in all the significant independent predictors of post-PCI FFR values. A forest plot was developed to depict all variables with the corresponding 95% confidence intervals (95%CI). Beta (β) values show the average increase or decrease of the FFR values in the case of dichotomous variables or the increment per unit increase in the case of continuous variables. Statistical analyses were performed using the statistical software package R (version 3.5.1, packages: Hmisc, lme4 and nlme, RStudio Team, United States).

RESULTS

Demographic characteristics

The mean age was 64.6 ± 11.8 years and 72.5% were males. In 959 patients, at least, 1 lesion was measured with an overall 1165 successfully treated and measured lesions. The patient demographics and baseline characteristics are shown on table 1. Up to 70% of the patients presented with an acute coronary syndrome, and 18% had confirmed thrombus as seen on the angiography. Intravascular imaging modalities were used in 9.6% of the patients to guide the procedure. Overall, 1.4 ± 0.6 lesions were treated per patient and in 1.2 ± 0.5 lesions per patient the post-PCI FFR was successfully assessed. The average overall stent length per vessel was 29 mm ± 17 mm with an average stent diameter of 3.2 mm ± 0.5 mm.

Table 1. Baseline patient and vessel characteristics

Variable Total FFR-SEARCH registry
Patient characteristics (n = 1000)
Age 64.6 ± 11.8
Sex, male 725 (73)
Hypertension 515 (52)
Hypercholesterolemia 451 (45)
Diabetes 191 (19)
Smoking history 499 (50)
Previous stroke 77 (8)
Peripheral arterial disease 76 (8)
Previous myocardial infarction 203 (20)
Previous PCI 264 (26)
Previous CABG 57 (6)
Indication for PCI
 Stable angina 304 (30)
 NSTEMI 367 (37)
 STEMI 329 (33)
Vessel characteristics (n = 1165)
Lesion type
 A 125 (11)
 B1 233 (20)
 B2 379 (33)
 C 428 (37)
LAD 593 (51)
Bifurcation 138 (12)
Calcified 402 (35)
In-stent restenosis 39 (3)
Thrombus 214 (18)
Stent thrombosis 14 (1)
Ostial 97 (8)
CTO 42 (4)
Stenosis pre procedural 69 ± 22
Reference diameter pre procedural (mm) 2.6 ± 0.6
Length pre procedural (cm) 21 ± 11
MLD pre (mm) 0.9 ± 0.6
Predilatation 769 (66)
Postdilatation 691 (59)
Stenosis post procedural 44 ± 13
Reference diameter post procedural (mm) 2.7 ± 0.5
Length post procedural (cm) 24 ± 13
MLD post procedural (mm) 2.6 ± 0.5
Number of stents 1.4 ± 0.6
Stent length (cm) 29 ± 17
Stent diameter (mm) 3.2 ± 0.5
Mean post-PCI Pd/Pa 0.96 ± 0.04
Mean post-PCI FFR 0.91 ± 0.07

CABG, coronary artery bypass graft; CTO, chronic total coronary occlusion; FFR, fractional flow reserve; LAD, left anterior descending artery; MLD, minimum luminal diameter; NSTEMI, non-ST segment elevation acute myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; Pd/Pa, ratio of mean distal coronary artery pressure to mean aortic pressure; Values are expressed as mean ± standard deviation or no. (%).

The mean post-PCI FFR was 0.91 ± 0.07 and 7.7% of vessels had a post-PCI FFR ≤ 0.80. In the LME-model and after adjusting for independent predictors of post-PCI FFR, the left anterior descending coronary artery (LAD) as the measured vessel was the strongest predictor of post-PCI FFR (adjusted β = -0.063; 95%CI, -0.070 to -0.056; P < .0001) followed by the postprocedural MLD (adjusted β = 0.039; 95%CI, 0.015-0.065]; P = .002). Additionally, male sex, in-stent restenosis, CTO, and pre- and post-dilatation were negatively correlated with postprocedural FFR. Conversely, type A lesions, thrombus-containing lesions, postprocedural percent diameter stenosis, and stent diameter were positively correlated with postprocedural FFR. The R2 for the entire model was 53%. Figure 1 shows all significant and non-significant adjusted predictors included in the LME-model. Table 2 shows all adjusted and unadjusted predictors with corresponding β values and 95%CI. The most important predictors are shown on figure 2.

Figure 1. Forest plot of independent predictors of post-PCI FFR. Adjusted beta values with 95% confidence intervals. Triangles indicate significant predictors while circles are indicative of non-significant predictors in the multivariate generalized mixed model to predict post-PCI FFR. ACS, acute coronary syndrome; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; LAD, left anterior descending coronary artery; CTO, chronic total coronary occlusion; MLD, minimum lumen diameter.

Table 2. Predictors for post-PCI FFR

Variable Unadjusted Adjusted
P β(95%CI) P β(95%CI)
Patient characteristics
Male sex .214 -0.006 (-0.015 – 0.003) .001 -0.013 (-0.021 – -0.005)
Age (per 10 years) .976 0.000 (-0.03 – 0.03) .724 0.001 (-0.002 – 0.003)
Hypertension .013 -0.010 (-0.018 – -0.002) .610 0.002 (-0.006 – 0.010)
Hypercholesterolemia < .001 -0.019 (-0.027 – -0.011) .287 -0.004 (-0.012 – 0.004)
Diabetes < .001 0.018 (0.008 – 0.042) .081 -0.008 (-0.017 – 0.001)
Smoking history .007 0.020 (0.010 – 0.019) .054 0.007 (-0.0001 – 0.014)
Previous stroke .831 -0.002 (-0.017 – 0.013) .342 0.006 (-0.0007 – 0.019)
Peripheral arterial disease .022 -0.017 (-0.032 – -0.003) .460 -0.005 (-0.018 – 0.008)
Previous myocardial infarction .002 -0.016 (-0.026 – -0.006) .137 -0.008 (-0.019 – 0.003)
Previous PCI < .001 -0.016 (-0.025 – -0.007) .569 -0.032 (-0.014 – 0.008)
Previous CABG .896 -0.001 (-0.019 – 0.017) .166 -0.011 (-0.014 – 0.004)
Indication for PCI
 Stable angina < .001 -0.025 (-0.034 – -0.016) .563 -0.002 (-0.011 – 0.005)
 STEMI < .001 0.032 (0.025 – 0.041) .171 0.006 (-0.003 – 0.015)
Vessel characteristics
Lesion type
 A <.001 0.022 (0.009 – 0.035) .040 0.012 (0.0005 – 0.023)
 C .045 -0.008 (-0.016 – -0.0002) .172 -0.006 (-0.014 – 0.002)
LAD <.001 -0.070 ( -0.077 – -0.064) <.001 -0.063 (-0.070 – -0.056)
Bifurcation < .001 -0.024 (-0.036 – - 0.012) .883 0.001 (-0.010 – 0.011)
Calcified < .001 -0.025 (-0.033 – -0.017) .409 -0.003 (-0.011 – 0.005)
In-stent restenosis .006 -0.031 (-0.053 – -0.009) .007 -0.029 (-0.051 – -0.008)
Thrombus < .001 0.031 (0.021 – 0.042) .026 0.012 (-0.001 – 0.023)
Stent thrombosis .920 0.002 (-0.034 – 0.038) .362 0.019 (-0.022 – 0.060)
Ostial .181 -0.010 (-0.024 – 0.005) .165 -0.010 (-0.024 – 0.004)
CTO .002 -0.034 (-0.056 – -0.013) .036 -0.027 (-0.053 – -0.002)
Stenosis pre procedural (per 10%) <.001 0.007 (0.005 – 0.009) .105 0.004 (-0.0009 – 0.009)
Reference diameter pre procedural (mm) <.001 0.030 (0.023 – 0.037) .704 0.002 (-0.008 – 0.011)
Length pre procedural (cm) .900 -0.00002 (-0.004 – 0.003) .101 0.004 (0.0008 – 0.009)
MLD pre procedural (mm) <.001 -0.015 (-0.022 – -0.008) .638 0.004 (-0.014 – 0.023)
Predilatation <.001 -0.019 (-.027 – -0.011) .002 -0.012 (-0.020 – -0.005)
Postdilatation <.001 0.027 (-0.035 – -0.019) .015 -0.009 (-0.016 – -0.002)
Stenosis post procedural (per 10%) .077 0.003 (-0.0003 – 0.006) .029 0.01 (0.0007 – 0.01)
Reference diameter post procedural (mm) <.001 0.035 (0.027 – 0.042) .067 -0.022 (-0.045 – 0.002)
Length post procedural (cm) .312 -0.002 (-0.005 – 0.001) .086 0.001 (-0.0007 – 0.001)
MLD post procedural (mm) <.001 0.032 (0.024 – 0.040) .002 0.039 (0.015 – 0.063)
Number of stents <.001 -0.012 (-0.018 – -0.006) .620 -0.002 (-0.012 – 0.007)
Stent length (cm) <.001 0.019 (0.009 – 0.041) .286 -0.003 (-0.009 – 0.002)
Stent diameter (mm) <.001 0.033 (0.025 – 0.042) .026 0.012 (0.001 – 0.022)

Beta (β) values are indicative of the average increase or decrease of the FFR values in cases of dichotomous variables or the increment per unit increase in cases of continuous variables. 95%CI, 95% confidence interval; CABG, coronary artery bypass graft; CTO, chronic total coronary occlusion; FFR, fractional flow reserve; LAD, left anterior descending coronary artery; MLD, minimum lumen diameter; STEMI, ST-segment elevation myocardial infarction.

Figure 2. Forest plot of most important predictors of post-PCI FFR. Adjusted beta values with 95% confidence intervals. The figure includes all significant predictors from the multivariate generalized mixed model predicting post-PCI FFR except for categorical variables with beta values < 0.02. LAD, left anterior descending coronary artery; CTO, chronic total coronary occlusion; MLD, minimum lumen diameter.

DISCUSSION

This study is the largest report to this day of predictors of post-PCI FFR. Based on data derived from the FFR-SEARCH registry, we could identify several patient and procedural predictors of post-PCI FFR. These predictors will bring more in-depth interpretations of post-PCI FFR values to be able to identify correctly which vessels are prone to future events. At first, male gender appeared to be negatively correlated with postprocedural FFR. This finding is consistent with the findings of former studies that focused on the impact of gender on pre-PCI FFR measurements.6,11,15,16 Compared to females, males are known to have a lower prevalence of microvascular dysfunction.8,17 The concept of FFR is based on drug-induced maximal hyperemia to minimize microvascular resistance. Microvascular dysfunction may hamper this vasodilator response and consequently result in a dampened flow response and high FFR.15 Subsequently, on average, males have larger myocardial masses and myocardial perfusion territories compared to females.18,19 The importance of the latter is illustrated by the second and strongest predictor of post-PCI FFR in this study, the FFR measurements in the LAD. FFR values are associated with the myocardial mass and the outflow territory of the measured vessel. As such, the LAD—the vessel with the largest perfusion area—has previously been associated with lower pre- and postprocedural FFR values.20-22

The diameters of the stents implanted in the RCA are larger, on average, but the outflow territory of the LAD is even larger.23 This discrepancy between luminal dimensions and myocardial mass may explain why the optimal improvement of the FFR measurements in the LAD is difficult to achieve.23

Thirdly, larger stent diameters and larger post-PCI MLDs were associated with higher post-PCI FFR values. However, higher postprocedural percent stenosis was also associated with higher post-PCI FFR values. While these findings may seem contradictory, post procedural percent stenosis was not associated with post-PCI physiology in the DEFINE PCI study either.24

In the intravascular ultrasound substudy of the FFR-SEARCH registry, van Zandvoort et al. showed that evident signs of residual luminal narrowing including focal lesions, underexpansion, and malapposition were present in a significant amount of vessels with post-PCI FFR values ≤ 0.85. These findings were not readily apparent on the comprehensive quantitative coronary angiography.25 Percent diameter stenosis was 20% in the cohort of patients with post-PCI FFR values ≤ 0.85 and > 0.85.26

Together with the latter predictors of post-PCI FFR we identified several others. A dedicated analysis of 26 CTOs recently showed that postprocedural FFR values are typically low initially; however they seem to increase at the 4-month follow-up. The initially low post-PCI FFR values is thought to be due to the microvascular dysfunction of the recently opened vessel, a phenomenon that improves after several months.27 In-stent restenosis and pre- and postdilatation were associated with lower post-PCI FFR values. A finding that is consistent with former studies that showed that, in general, complex lesions are associated with lower post-PCI FFR values.20,21,26,28

Also, it was interesting to see the impact of clinical presentation on post-PCI FFR values in the study population in which most patients presented with acute coronary syndrome. Contrary to former studies that questioned the validity of invasive hyperemic physiological indices in patients with acute coronary syndrome, we could not confirm the impact of clinical presentation on post-PCI FFR values. However, the identification of a thrombus, that often occurs after a ruptured plaque in patients with acute coronary syndrome, was associated with significantly higher FFR values. Despite the restoration of epicardial flow by the PCI, a relatively large number of patients with STEMI have abnormal myocardial perfusion at the end of the procedure.29 This phenomenon is thought to be related to microvascular obstruction due to distal embolization (reperfusion injury) and tissue inflammation due to myocyte necrosis.30,31 The latter may explain the significantly higher post-PCI FFR values reported in patients presenting with thrombus-containing lesions compared to those without such lesions. Conversely, our findings also show that in patients without thrombus-containing lesions the post-PCI FFR may be a valuable diagnostic tool for the identification of patients at a high risk of future adverse cardiac events.

Limitations

This study was conducted with the Navvus microcatheter, a dedicated rapid exchange microcatheter with a mean diameter of 0.022 in that proved its utility in a slight but significant underestimation of the FFR compared to conventional 0.014 in pressure guidewires.32 That is why we cannot directly extrapolate the current findings to wire-based FFR devices.14 Based on the study protocol, no further action was taken in the presence of low post-PCI FFR values. The Target FFR and FFR REACT studies (NCT03259815 and NTR6711) will provide further information on post-PCI FFR and the potential of further actions to improve post-PCI FFR and clinical outcomes.33,34 These studies should also focus on the trade-off of potential benefits and harm when performing additional interventions in order to improve the final FFR values.

CONCLUSIONS

In this substudy of the FFR-SEARCH registry, the largest real-world post-PCI FFR registry conducted to this day, we identified sex, LAD vessels, postprocedural MLD, and several other independent predictors of postprocedural FFR.

CONFLICTS OF INTEREST

L.J.C. van Zandvoort received institutional research support from Acist medical Inc. J. Daemen received institutional research support from Pie Medical, ACIST Medical Inc., PulseCath, Medtronic, Boston Scientific, Abbott Vascular, Pie Medical and speaker and consultancy fees from PulseCath, Medtronic, ReCor Medical, ACIST Medical Inc. and Pie Medical. The remaining authors declared no conflicts of interest.

WHAT IS KNOWN ABOUT THE TOPIC?

  • – FFR has proven to be a useful technique to address coronary physiology and the hemodynamic significance of coronary segments pre- and post-intervention.
  • – Also, the FFR post-stenting has proven to be a strong and independent predictor of major adverse cardiovascular events at the 2-year follow-up.
  • – Unfortunately, at present, there is lack of data on independent predictors of post PCI FFR.

WHAT DOES THIS STUDY ADD?

  • – This study is the largest report to this day on predictors of post-PCI FFR.
  • – Based on data from the FFR-SEARCH registry, we could identify several patient and procedural predictors of post-PCI FFR.
  • – The main predictors included sex, LAD vessels, and postprocedural lumen dimensions. These predictors will help us interpret post-PCI FFR values and identify correctly the vessels that are prone to future events.

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29. Stone GW, Webb J, Cox DA, et al. Distal microcirculatory protection during percutaneous coronary intervention in acute ST-segment elevation myocardial infarction:a randomized controlled trial. JAMA. 2005;293:1063-1072.

30. Shah NR, Al-Lamee R, Davies J. Fractional flow reserve in acute coronary syndromes:A review. Int J Cardiol Heart Vasc. 2014;5:20-25.

31. Cuculi F, De Maria GL, Meier P, et al. Impact of microvascular obstruction on the assessment of coronary flow reserve, index of microcirculatory resistance, and fractional flow reserve after ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2014;64:1894-904.

32. Pouillot C, Fournier S, Glasenapp J, et al. Pressure wire versus microcatheter for FFR measurement:a head-to-head comparison. EuroIntervention. 2018;13:e1850-e1856.

33. van Zandvoort LJC, Masdjedi K, Tovar Forero MN, et al. Fractional flow reserve guided percutaneous coronary intervention optimization directed by high-definition intravascular ultrasound versus standard of care:Rationale and study design of the prospective randomized FFR-REACT trial. Am Heart J. 2019;213:66-72.

34. Collison D, McClure JD, Berry C, Oldroyd KG. A randomized controlled trial of a physiology-guided percutaneous coronary intervention optimization strategy:Rationale and design of the TARGET FFR study. Clin Cardiol. 2020;43:414-422.

Corresponding author: Department of Cardiology, Room Rg-628, Erasmus University Medical Center, P.O. Box 2040. 3000 CA Rotterdam, The Netherlands.


E-mail address: (J. Daemen).

https://doi.org/10.24875/RECICE.M20000155

ABSTRACT

Introduction and objectives: To analyze if there is an association between certain structural variables of the treating centres (availability of cardiac surgery and an intensive care unit [CICU] led by cardiologists) and the volume of procedures performed that may be impacting the results of surgical (SAVR) or transcatheter (TAVI) aortic valve treatment.

Methods: Retrospective and observational study of all patients discharged from hospitals from the Spanish National Health System who underwent a SAVR or a TAVI procedure. The source of the data was the administrative minimum basic data set. The outcome variables analyzed were in-hospital mortality, length of stay (both of them risk-adjusted), and presence of complications. As structural variables for the centers studied we used the availability of cardiac surgeries and CICU.

Results: A total of 2055 TAVI and 15 146 SAVR episodes were identified. The adjustment models for in-hospital mortality showed good discrimination (AUC for the SAVR and TAVI model: 0.84; 95%CI, 0.82-0.85) and calibration (P < .001). The model median odds ratio was 1.73, indicative of a high inter-hospital variability. High-volume hospitals, with cardiac surgery services, and CICU-capable centers had the lowest risk-adjusted mortality rate in both procedures.

Conclusions: A consistent association is observed between the structural characteristics of the treating centers and the results of aortic valve management both surgical and transcatheter. Also, the availability of a CICU could be a relevant factor in the outcomes of these procedures.

Keywords: TAVI. Volume. Results. Aortic stenosis. Surgery.

RESUMEN

Introducción y objetivos: Analizar la asociación entre algunas variables estructurales de los centros tratantes (disponibilidad de cirugía cardiaca y de unidad de cuidados intensivos cardiológicos [UCIC]), así como su volumen de procedimientos, con los resultados del reemplazo quirúrgico de válvula aórtica (RQVA) o transcatéter (TAVI).

Métodos: Estudio observacional retrospectivo de todos los pacientes dados de alta en los hospitales del Sistema Nacional de Salud español a quienes se realizó un procedimiento RQVA o TAVI en los años 2014 y 2015. La fuente de los datos fue el Conjunto Mínimo Básico de Datos. Las variables de resultados analizadas fueron la mortalidad intrahospitalaria, la duración de la estancia (ambas ajustadas por el riesgo) y la presencia de complicaciones. La disponibilidad de cirugía cardiaca y la disponibilidad de UCIC se utilizaron como variables estructurales de los centros.

Resultados: Se analizaron 2.055 TAVI y 15.146 RQVA. Los modelos de ajuste para la mortalidad intrahospitalaria mostraron una buena discriminación (área bajo la curva ROC para el modelo conjunto de TAVI y RQVA: 0,84; IC95%, 0,82-0,85) y calibración (p < 0,001). La odds ratio mediana del modelo fue de 1,73, lo que señala una elevada variabilidad interhospitalaria. Los hospitales con mayor volumen de actividad, con servicio de cirugía cardiaca y dotados de UCIC muestran menor mortalidad ajustada al riesgo en ambos procedimientos.

Conclusiones: Se observa una asociación consistente entre las características estructurales de los centros tratantes y los resultados del reemplazo valvular aórtico, tanto quirúrgico como transcatéter. Además, la disponibilidad de UCIC podría ser un factor relevante en los resultados de dichos procedimientos.

Palabras clave: TAVI. Volumen. Resultados. Estenosis aórtica. Cirugía.

Abbreviations RA-SMR: risk-adjusted standardized mortality ratio. RA-LOSR: risk-adjusted length of stay ratio. MBD: minimum basic dataset. SAVR: surgical aortic valve replacement. TAVI: transcatheter aortic valve implantation.

INTRODUCTION

Severe aortic stenosis is a common disease in our setting and has high morbidity and mortality rate. Its basic treatment is valve replacement.1 Over the last 2 decades, transcatheter aortic valve implantation (TAVI) has joined the traditional surgical aortic valve replacement (SAVR).2

Data are clear on the association between results and certain characteristics of the centers. The fact that has been most described in the medical literature is that, regarding mortality and complications, better results are obtained in those centers that reach the activity threshold (per center and per operator) for certain processes and procedures,3-7 including coronary artery bypass graft (CABG)5,8 and primary angioplasty.9-11 Regarding TAVI, the association between volume and results has been reported in hospitals in the United States.12-14 In Germany, this association is less obvious.15 In Spain, the association between volume and results has also been reported for CABG.16

There are fewer studies that analyze the structural characteristics of the centers and their association with the characteristics of the healthcare systems of every country and the results obtained. In Spain, Bertomeu et al.17 found a lower mortality rate in patients with acute myocardial infarction (AMI) in high-volume centers with higher complexity. Worner et al.18 described a lower mortality rate in the management of AMI in hospitals with cardiac surgery and intensive care unit (CICU) capabilities. Rodríguez-Padial et al.19 found better results in the management of AMI in hospitals serving large communities. The association between CICU availability and better results has also been reported in our setting for the management of cardiogenic shock due to ST-segment elevation myocardial infarction.20

Our objective was to analyze the structural variables of the treating centers (availability of CICU), the volume of procedures performed and their association with results obtained after aortic valve replacement (whether through TAVI or SAVR).

METHODS

Population and sources of data

This is an observational and retrospective study of all the patients discharged from the hospitals of the Spanish National Healthcare System who underwent a SAVR o a TAVI procedure. The source of data was the minimum basic dataset (MBD) of the Spanish National Healthcare System of 2014 and 2015 (the only years available with a specific code for TAVI in the MBD). The clinical results of the patients transferred were assigned to the centers from which they were eventually discharged. Whenever the same episode was treated through TAVI and SAVR, it was considered as a TAVI treated episode and SAVR as a TAVI related complication. The main result variables were in-hospital mortality, length of the hospital stay, and in-hospital complications. The codes used for the complications seen are shown on table 1 of the supplementary data.

Table 1. Differences in the profile of patients and in the results of transcatheter aortic valve implantation based on the structural characteristics of each center (2014-2015)

Type 3 hospitals Type 4 hospitals
Non-CICU CICU Non-CICU CICU P
Number of episodes 85 25 865 1064
Age 81.3 ± 5.9 82.4 ± 2.5 80.6 ± 6.9 80.8 ± 6.8 .408
Sex 54.1 44 52.1 50.4 .705
Charlson index 7.6 ± 1.5 7.2 ± 1.8 7.1 ± 1.6 7.3 ± 1.7 .022
Cardiogenic shock 1.2 0.0 0.8 1.1 .854
Previous percutaneous transluminal coronary angioplasty 12.9 24.0 20.6 15.7 .02
Infectious endocarditis 0.0 0.0 0.1 0.2 .952
CABG in the episode 0.0 0.0 0.5 0.3 .836
Percutaneous transluminal coronary angioplasty in the episode 2.4 0.0 3.7 5.4 .155
Previous CABG in the episode 3.5 8.0 9.1 7.9 .311
Cancer, metastatic cancer, and acute leukemia (CC8_14) 3.5 4.0 3.2 5.0 .293
Protein-calorie malnutrition (CC21) 0.0 0.0 0.5 0.3 .836
Morbid obesity: other endocrine/metabolic/nutritional disorders (CC22_25_26) 50.6 64.0 55.1 48.1 .011
Vascular or circulatory disease (CC27_32) 5.9 0.0 3.1 5.1 .103
Other gastrointestinal disorders (CC38) 16.5 8.0 10.6 11.3 .404
Dementia or other specific cerebral disorders (CC51_53) 1.2 0.0 1.4 2.4 .307
Hemiparesis, paraplegia, paralysis, functional disability (CC70_74_103_104_189_190) 0.0 0.0 1.2 2.0 .27
Congestive heart failure (CC85) 43.5 44.0 28.8 32.0 .014
Acute myocardial infarction (CC86) 1.2 0.0 0.7 0.9 .878
Unstable angina and other acute ischemic heart diseases (CC87) 0.0 0.0 0.9 0.6 .634
Angina; acute myocardial infarction (CC88) 3.5 12.0 2.4 2.7 .036
Hypertension (CC95) 43.5 56.0 58.6 51.9 .005
Stroke (CC99_100) 2.4 0.0 1.3 0.8 .492
Vascular or circulatory disease (CC106_109) 17.6 28.0 18.6 21.6 .267
Chronic obstructive pulmonary disease (CC111) 9.4 24.0 13.4 12.7 .277
Pneumonia (CC114_116) 1.2 0.0 1.2 2.3 .259
Kidney dialysis (CC134) 2.4 0.0 0.3 0.8 .139
Kidney damage (CC135_140) 36.5 24.0 23.9 27.8 .04
Pressure ulcers or chronic skin ulcer (CC157_160) 1.2 4.0 0.5 0.3 .031
Chronic skin ulcer except for pressure ulcers (CC161) 0.0 0.0 0.6 0.0 .078
Diabetes mellitus or diabetic complications except for proliferative retinopathy (CC17_19_123) 34.1 32.0 34.7 32.9 .868

CABG, coronary artery bypass graft; CC, Condition Categories;25 CICU, cardiac surgery and intensive care unit.

Note: 16 episodes could not be identified into any of the 4 groups of hospitals.

Data are expressed as no. (%) or mean ± standard deviation.

Hospital structural variables

To analyze the possible correlation between the hospital structural variables and the results of aortic valve implantation both the volume of procedures performed and the cardiovascular resources available were studied. Hospitals were classified based on the availability of cardiology related resources and according to the RECALCAR criteria21 (table 2 of the supplementary data). Regarding this study, to analyze the inter-hospital differences, only those with cath lab capabilities without (type 3) and with cardiac surgery (type 4) were included. The availability of CICU based on a survey previously conducted by the Spanish Society of Cardiology was also included.22 The characteristics to consider the presence of a CICU were: a) a comprehensive capacity to manage patients in critical condition including invasive mechanical ventilation, and b) the administrative adhesion of the CICU to the cardiology unit.

Table 2. Differences in the profile of patients and in the results of surgical aortic valve replacement based on the structural characteristics of each center (2014-2015)

Hospitales tipo 4
Non-CICU CICU P
Number of episodes 6456 7523
Age 69.3 ± 11.2 69.6 ± 11.3 .053
Sex 41.7 41.8 .823
Charlson index 6.5 ± 1.8 6.5 ± 1.9 .885
Cardiogenic shock 2.0 1.3 .001
Previous percutaneous transluminal coronary angioplasty 4.9 3.9 .004
Infectious endocarditis 1.5 1.4 .507
CABG in the episode 18.9 18.9 .894
Percutaneous transluminal coronary angioplasty in the episode 0.5 0.8 .116
Previous CABG in the episode 2.4 3.5 < .001
Cancer, metastatic cancer, and acute leukemia (CC8_14) 2.0 2.6 .023
Protein-calorie malnutrition (CC21) 0.6 0.2 < .001
Morbid obesity: other endocrine/metabolic/nutritional disorders (CC22_25_26) 49.7 49.5 .789
Vascular or circulatory disease (CC27_32) 4.1 3.7 .209
Other gastrointestinal disorders (CC38) 7.0 8.2 .006
Dementia or other specific cerebral disorders (CC51_53) 0.8 0.8 .666
Hemiparesis, paraplegia, paralysis, functional disability (CC70_74_103_104_189_190) 1.7 1.7 .737
Congestive heart failure (CC85) 19.2 24.1 < .001
Acute myocardial infarction (CC86) 1.4 1.4 .670
Unstable angina and other acute ischemic heart diseases (CC87) 1.7 1.6 .528
Angina; acute myocardial infarction (CC88) 1.2 1.4 .242
Hypertension (CC95) 55.6 53.5 .015
Stroke (CC99_100) 1.7 2.0 .140
Vascular or circulatory disease (CC106_109) 19.7 21.1 .034
Chronic obstructive pulmonary disease (CC111) 7.7 7.7 .893
Pneumonia (CC114_116) 1.9 2.1 .309
Kidney dialysis (CC134) 0.3 0.4 .857
Kidney damage (CC135_140) 18.9 18.5 .576
Pressure ulcers or chronic skin ulcer (CC157_160) 0.8 0.5 .058
Chronic skin ulcer except for pressure ulcers (CC161) 0.2 0.2 .707
Diabetes mellitus or diabetic complications except for proliferative retinopathy (CC17_19_123) 25.3 23.3 .007

CABG, coronary artery bypass graft; CC, Condition Categories;25 CICU, cardiac surgery and intensive care unit.

Note: 1167 episodes could not be identified in any of the 2 groups of hospitals.

Data are expressed as no. (%) or mean ± standard deviation. Only statistically significant factors with OR > 1 are shown.

Statistical analysis

The risk adjustment models were specified based on the Centers for Medicare and Medicaid Services (CMS) methodology. Regarding CABG, the variables included in the 30-day mortality model were considered as independent variables.23 Also, certain variables anticipated by the Society of Thoracic Surgeons score for aortic valve replacement—and that can be identified in the MBD24—were included too. Finally, the CMS model was adjusted to the data structure of the MBD after gathering secondary diagnoses based on clinical categories.25 The multilevel logistics regression models were also adjusted.26,27 Only statistically significant comorbidities and odds ratio (OR) > 1.0 were considered for the adjustment model.

Based on specified models the risk-adjusted standardized mortality ratio (RA-SMR) was estimated.28 To adjust the length of the hospital stay, the Poisson regression model was used including the year of hospital discharge, the sex of the patient, and the degree of severity of groups related by refined diagnosis as risk factors. The expected length of the hospital stay was obtained from the individual predictions of the adjusted model. Also, the risk-adjusted length of stay ratio (RA-LOSR) was estimated as the coefficient between the length of the stay observed and the length of the stay expected.

To distinguish between high and low-volume hospitals (based on the number of episodes treated), a group clustering algorithm was used. To that end, the mathematical model used was developed with two thirds of the database and validated with the remaining third. The algorithm ranked as high-volume centers for TAVI those that performed ≥ 46 procedures, and as high-volume centers for SAVR those that performed ≥ 240 procedures during the study 2 year-period (2014-2015).

Quantitative variables were expressed as means ± standard deviations and the qualitative ones as frequencies and percentages. The correlation among the quantitative variables was analyzed using Pearson correlation coefficient. For comparison purposes, the Student t test for 2 samples and the analysis of variance (ANOVA) were used with correction of the level of significance using the Bonferroni method for ≥ 3 groups. Comparisons among the different categorical variables were conducted using the chi-square test or Fisher’s exact test.

All comparisons were bilateral, and differences were considered statistically significant with P values < .05. Statistical analyses were conducted using the STATA 13 and SPSS v21.0 software package.

RESULTS

A total of 2055 TAVIs and 15146 SAVRs were performed. Back in 2014 a total of 812 TAVIs were performed in 47 centers and in 2015 the number went up to 1243 in 53 centers.

The differences seen in the profile of the patients who underwent TAVI and SAVR are shown on table 1 and table 2, respectively, based on the type of hospital where procedures were performed. No statistically significant differences regarding age and sex were seen in patients who underwent TAVI in any of the 4 groups. Still, comorbidity was significantly higher (higher Charlson index and higher incidence of heart failure) in patients treated in type 3 non-CICU hospitals.

Regarding patients who underwent SAVR, by definition in type 4 hospitals, no statistically significant differences were seen regarding age, sex or presence of comorbidities among patients treated with and without CICU except for a higher prevalence of cardiogenic shock and previous percutaneous coronary interventions in non-CICU hospitals (2.0% vs 1.3%, P < .001; and 4.9% vs 3.9%, P = .004, respectively) (table 2).

The in-hospital mortality adjustment model for surgical aortic valve replacement showed good discrimination capabilities (area under the ROC curve, 0.84; 95% confidence interval [95%CI], 0.82-0.85) and calibration (P < .001). The model median odds ratio was 1.73, indicative of a high inter-hospital variability.

The SAVR specific in-hospital mortality adjustment model also showed excellent discrimination and calibration capabilities too (area under the ROC curve, 0.84; 95%CI, 0.83-0.84; calibration, P < .001) that were slightly lower for the TAVI specific adjustment model (area under the ROC curve, 0.79; 95%CI, 0.74-0.84; calibration, P < .001).

Characteristics of the treating center and TAVI results

Type 4 hospitals had a significantly lower RA-SMR compared to type 3 hospitals (4.04 ± 0.98 vs 4.47 ± 0.79). No statistically significant differences were seen on the RA-LOSR (0.99 ± 0.81 vs 1.07 ± 0.81; P = .278). The presence of a CICU was associated with a slightly lower, but sill statistically significant, RA-SMR (4.03 ± 0.87 vs 4.1 ± 1.07; P < .001). The correlation between CICU and a lower RA-SMR was also found in type 4 (4.03 ± 0.88 vs 4.05 ± 1.08; P < .001) and type 3 hospitals (4.09 ± 0.06 vs 4.59 ± 0.87; P < .001) (table 3).

Table 3. Differences in the results of transcatheter aortic valve implantation based on the characteristics each center (2014-2015)

Type 3 hospitals Type 4 hospitals P
Non-CICU CICU Non-CICU CICU
Acute myocardial infarction 1.2 0.0 0.7 0.9 .878
Implantation of permanent pacemaker 17.6 16.0 13.2 15.0 .536
Postoperative stroke 1.2 0.0 1.0 0.6 .624
Prosthetic heart valve complications 3.53 0.00 1.85 4.32 .002
Postoperative shock 0.00 0.00 0.58 1.79 .017
Postoperative kidney damage 1.2 0.0 2.5 2.4 .743
Hemorrhage or hematoma complicating the procedure 16.5 32.0 10.5 13.7 .003
Accidental puncture or laceration during the procedure 3.5 0.0 3.2 4.0 .600
Postoperative infection 1.2 0.0 0.6 1.7 .145
Sepsis 0.0 0.0 0.8 0.8 .819
Vascular surgery during admission 2.4 4.0 5.0 5.7 .542
RA-LOSR 1.10 ± 0.87 0.97 ± 0.47 0.98 ± 0.77 1.00 ± 0.85 .581
RA-SMR 4.59 ± 0.87 4.09 ± 0.06 4.05 ± 1.08 4.03 ± 0.88 < .001

CICU, cardiac surgery and intensive care unit; RA-LOSR, risk-adjusted length of stay ratio; RA-SMR, risk-adjusted standardized mortality ratio.

Data are expressed as no. (%) or mean ± standard deviation.

CICU capable type 4 hospitals had a higher incidence of postoperative shock (1.8% vs 0.6%; P = .017), the same incidence of sepsis (0.8% vs 0.8%; P < .819), and a lower RA-SMR (4.03 ± 0.88 vs 4.05 ± 1.08; P < .001) compared to non-CICU hospitals.

Regarding the volume of procedures performed by the hospitals, the median of TAVI per year was 11 [2-36 for low-volume centers and 33 [9-67] for high-volume hospitals. The RA-SMR was lower in high-volume hospitals (3.95 ± 1.08 vs 4.26 ± 0.72; P < .001) (table 4 and figure 1). The mean adjusted stay did not show any differences between CICU capable and non-CICU hospitals (1.00 ± 0.85 vs 0.98 ± 0.77; P = .581). In general, regarding the crude complication rates, TAVI did not show any statistically significant differences between high and low-volume hospitals (table 4).

Table 4. Differences in the results of transcatheter aortic valve implantation based on the volume of cases of each center (2014-2015)

Low-volume centers High-volume centers P
Acute myocardial infarction 0.63 0.95 .311
Implantation of permanent pacemaker 14.21 14.36 .489
Postoperative stroke 0.91 0.71 .402
Prosthetic heart valve complications 2.92 4.86 .366
Postoperative shock 1.46 1.33 .172
Postoperative kidney damage 2.54 2.29 .412
Hemorrhage or hematoma complicating the procedure 13.60 12.15 .188
Accidental puncture or laceration during the procedure 2.72 4.18 .054
Postoperative infection 1.30 1.10 .424
Sepsis 1.17 0.55 .105
Vascular surgery during admission 4.15 5.92 .049
RA-LOSR 0.992 ± 0.655 1.008 ± 0.787 .237
RA-SMR 4.26 ± 0.72 3.95 ± 1.08 < .001

RA-LOSR, risk-adjusted length of stay ratio; RA-SMR, risk-adjusted standardized mortality ratio.

Data are expressed as no. (%) or mean ± standard deviation.

Figure 1. In-hospital mortality adjusted comparison for transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR). Note that, regarding SAVR, in low-volume centers with CICU only 1 center was excluded. CICU, cardiac surgery and intensive care unit; RA-LOSR, risk-adjusted length of stay ratio; RA-SMR, risk-adjusted standardized mortality ratio.

Characteristics of the treating center and SAVR results

The presence of a CICU turned out to be a protective factor for in-hospital mortality in these patients (OR, 0.79; 95%CI, 0.67-0.93; P = .005). However, the different RA-SMRs seen among various centers with and without CICU capabilities did not show statistically significant differences (5.91 ± 1.49 with CICU vs 5.94 ± 1.72 without it; P = .335) (figure 1). The same thing happened with the RA-LOSR. CICU capable type 4 hospitals had a higher incidence of postoperative shock (2.2% vs 1.3%; P = .024) but a lower incidence of sepsis (1.1% vs 2.3%; P < .001) (table 5).

Table 5. Differences in the results of surgical aortic valve replacement based on the characteristics of each center (2014-2015)

Type 4 hospitals P
Non-CICU CICU
Acute myocardial infarction 1.4 1.4 .67
Implantation of permanent pacemaker 4.0 4.5 .138
Postoperative stroke 1.1 1.3 .305
Prosthetic heart valve complications 2.5 1.1 .729
Postoperative shock 1.3 2.2 .024
Postoperative kidney damage 6.9 6.1 .038
Hemorrhage or hematoma complicating the procedure 6.2 6.3 .767
Accidental puncture or laceration during the procedure 1.0 0.8 .095
Postoperative infection 1.8 2.2 .132
Sepsis 2.3 1.1 < .001
Vascular surgery during admission 2.7 3.1 .166
RA-LOSR 1.00 ± 0.68 0.99 ± 0.67 .770
RA-SMR 5.91 ± 1.49 5.94 ± 1.72 .335

CICU, cardiac surgery and intensive care unit; RA-LOSR, risk-adjusted length of stay ratio; RA-SMR, risk-adjusted standardized mortality ratio.

Data are expressed as no. (%) or mean ± standard deviation.

In relation to the volume of procedures performed, the RA-SMR was lower in high-volume hospitals (5.89 ± 1.54 vs 6.27 ± 2.02; P < .001) (table 6) without any statistically significant differences with respect to the RA-LOSR (0.99 ± 0.73 vs 1.06 ± 0.75; P = .463). No statistically significant differences were seen between high and low-volume hospitals in the crude complication rates (table 6).

Table 6. Differences in the results of surgical aortic valve replacement based on the volume of cases of each center (2014-2015)

Low-volume centers High-volume centers P
Acute myocardial infarction 1.81 1.37 .066
Implantation of permanent pacemaker 3.75 4.32 .117
Postoperative stroke 0.93 1.22 .117
Prosthetic heart valve complications 1.54 1.14 .072
Postoperative shock 2.26 2.44 .320
Postoperative kidney damage 6.63 6.67 .462
Hemorrhage or hematoma complicating the procedure 5.95 6.35 .279
Accidental puncture or laceration during the procedure 0.82 0.88 .445
Postoperative infection 1.57 2.04 .112
Sepsis 1.46 1.69 .269
Vascular surgery during admission 2.22 2.93 .055
RA-LOSR 1.06 ± 0.75 0.99 ± 0.73 .463
RA-SMR 6.27 ± 2.02 5.89 ± 1.54 < .001

CICU, cardiac surgery and intensive care unit; RA-LOSR, risk-adjusted length of stay ratio; RA-SMR, risk-adjusted standardized mortality ratio.

Data are expressed as no. (%) or mean ± standard deviation.

Association between TAVI and SAVR results

In type 4 hospitals, no statistically significant linear correlations were found between the RA-SMRs of TAVI and those of SAVR (r = 0.21; P = .14). Similarly, the SAVR high-volume variable had a non-statistically significant protective effect when it was introduced in the risk-adjustment model of TAVI related in-hospital mortality (OR, 0.73; 95%CI, 0.33-1.62). The 17 hospitals (1134 episodes identified) that shared the TAVI and SAVR high-volume feature had a TAVI related RA-SMR that was significantly lower compared to centers with the TAVI and SAVR low-volume feature (4 ± 1.1 vs 4.5 ± 0.7; P < .001). A single center (80 episodes) with a high-volume of TAVI and a low-volume of SAVR had the lowest TAVI related RA-SMR of all (2.8 ± 0.3; P < .001 with respect to a high-volume of TAVI and SAVR performed).

DISCUSSION

This study findings that included real-world data in our country, show a consistent correlation between the hospital structural characteristics and the results obtained in aortic valve replacement procedures, both surgical and transcatheter (figure 1). High-volume hospitals with cardiac surgery and intensive care units (CICU) have lower risk-adjusted mortality rates in both procedures.

In relation to the association between volume and results, our study also shows TAVI results that are consistent to those described by the medical literature,10-14 with mortality rates that are similar to those seen in other countries in the study period (2014-2015) and higher to those published for 2015-2017.14 In Spain, the mortality rate differences seen after adjusting for high and low-volume centers are lower to the ones reported, which may be explained because, actually in those years in Spain, low-volume centers were being compared to very low-volume centers. Therefore, 52 out of the 53 center that performed TAVIs in Spain from 2014 through 2015 were within the range of the 2 lower quartiles (5-54 procedures per year), per volume of procedures performed, in the study conducted by Vemulapalli et al.14. Only 7 of those centers were above the range of the lower tercile in the study conducted by Kaier et al.15.

These data should be interpreted in the context of the learning curve of this technique in our country.29

The correlation between a higher volume and a lower RA-SMR was also found for SAVR. Again in this case, low-volume centers were being compared since only 12 and 10 out of the 42 centers, in 2014 and 2015 respectively, performed > 200 SAVRs, and over 70% of the centers were within the 2 lower quartiles of SAVR volume according to the study conducted by Hirji et al.30.

In this study, TAVI and SAVR high-volume centers had a lower TAVI-adjusted mortality rate compared to low-volume centers for both procedures, which is consistent with the findings reported by Mao et al.31. However, the only hospital identified as a high-volume center for TAVI and a low-volume center for SAVR had excellent TAVI results; since it was a single center with limited number of cases (4% of all TAVIs performed), this finding, suggestive that specific experience is more relevant than global experience in aortic valve replacement procedures, should be studied in the future. However, this is reasonable because it shows that here experience accumulates per processes or specific dedicated teams rather than centers in general.

Since no references were found in the medical literature, the newest finding of this study was the association between the presence of a CICU and the lower mortality rate reported for both techniques. This correlation is even more solid and clinically significant for TAVI rather than SAVR, which seems somehow intuitive, since patients treated with SAVR are often referred to general intensive care units.

The association between CICU availability and optimal results in the management of cardiogenic shock in the AMI setting20 had been described by the Spanish National Healthcare System. However, this association had not been reported in surgical procedures. Medical literature describes a virtuous relation between the volume of SAVRs performed and TAVI results, which is probably associated with the greater experience of the heart team.29,31 The presence of a CICU can be a variable that includes both the cardiologists’ greater experience and higher participation in the management of patients in critical cardiac condition and the experience of the hospital, cardiology unit, and cardiac surgery unit. In both cases, the CICU contributes to a better management of patients treated with interventional procedures (TAVI and SAVR) across the entire healthcare process.

Therefore, the results described may me important to plan healthcare and allocate resources such as teaching and training in the 2 aforementioned procedures.

Limitations

This study is a retrospective analysis of administrative data. However, even with its inherent limitations, the validity of its design has been compared to clinical registries.26,32 Such reliability allows us to compare the results of multiple hospitals33 and has been used specifically to analyze TAVI results.11-13,29,30 However, we should mention that data from the MBD should be interpreted with caution because they were not audited. Finally, this study shows the early experience with TAVI, probably still within the learning curve of this technique in the centers studied, which is why findings should be compared to more recent and larger series.

CONCLUSIONS

There is a correlation between the structural characteristics of the treating centers and the results obtained in aortic valve replacement, both surgical and endovascular, with great heterogeneity among the various centers. Large volume hospitals with cardiac surgery units and CICU capabilities have a lower risk-adjusted mortality rate in both procedures.

FUNDING

This study has been funded by an unconditional grant from the Interhospital Foundation for Cardiovascular Research.

CONFLICTS OF INTEREST

None reported.

ACKNOWLEDGEMENTS

We wish to thank the Health Information Institute of the Spanish National Healthcare System at the Spanish Ministry of Health, Consumer Affairs and Social Welfare for partially disclosing the MBD database.

WHAT IS KNOWN ABOUT THE TOPIC?

  • Symptomatic severe aortic stenosis is a common cause of morbidity and mortality in our country. The treatment recommended here is aortic valve replacement.
  • In numerous medical and surgical procedures, the volume of procedures performed by the treating hospital has proven to play a significant role in the results obtained.
  • This correlation between volume and results has been specifically reported for TAVI. In Spain, it has been reported for AMI, cardiogenic shock, and coronary revascularization surgery, among others.

WHAT DOES THIS STUDY ADD?

  • This article analyses real-world data in our country from over 17000 patients who received a prosthetic aortic valve through SAVR or TAVI.
  • The findings show an important heterogeneity and a consistent correlation between the structural character-istics of the treating centers and the results obtained in aortic valve replacement both through SAVR and TAVI.
  • Large-volume centers with cardiac surgery units and CICU capabilities run by cardiologists have lower risk-adjusted mortality rates in both procedures.

SUPPLEMENTARY DATA

Supplementary data associated with this article can be found in the online version available at https://doi.org/ 10.24875/RECICE.M20000154.

REFERENCES

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2. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2017;38:2739-2791.

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4. Thiemann DR, Coresh J, Oetgen WJ, Powe NR. The association between hospital volume and survival after acute myocardial infarction in elderly patients. N Engl J Med. 1999;340:1640-1648.

5. Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital volume and surgical mortality in the United States. N Engl J Med. 2002;346:1128-1137.

6. Gandjour A, Bannenberg A, Lauterbach KW. Threshold volumes associated with higher survival in health care:a systematic review. Med Care. 2003;41:1129-1141.

7. Ross JS, Normand ST, Wang Y, et al. Hospital Volume and 30-Day Mortality for Three Common Medical Conditions. N Engl J Med. 2010;362:1110-1118.

8. Luft HS, Bunker JP, Enthoven AC. Should operations be regionalized?The empirical relation between surgical volume and mortality. N Engl J Med. 1979;301:1364-1369.

9. Canto JG, Every NR, Magid DJ, et al. The volume of primary angioplasty procedures and survival after acute myocardial infarction. N Engl J Med. 2000;342:1573-1580.

10. Vakili BA, Kaplan R, Brown DL. Volume-Outcome Relation for Physicians and Hospitals Performing Angioplasty for Acute Myocardial Infarction in New York State. Circulation. 2001;104:2171-2176.

11. Srinivas VS, Hailpern SM, Koss E, Monrad ES, Alderman MH. Effect of Physician Volume on the Relationship Between Hospital Volume and Mortality During Primary Angioplasty. J Am Coll Cardiol. 2009;53:574-579.

12. Kim LK, Minutello RM, Feldman DN, et al. Association between transcath eter aortic valve implantation volume and outcomes in the United States. Am J Cardiol. 2015;116:1910-1915.

13. Badheka AO, Patel NJ, Panaich SS, et al. Effect of hospital volume on outcomes of transcatheter aortic valve implantation. Am J Cardiol. 2015;116:587-594.

14. Vemulapalli S, Carroll JD, Mack MJ, et al. Procedural Volume and Outcomes for Transcatheter Aortic-Valve Replacement. N Engl J Med. 2019;380:2541-2550.

15. Kaier K, Oettinger V, Reinecke H, et al. Volume–outcome relationship in transcatheter aortic valve implantations in Germany 2008–2014:a secondary data analysis of electronic health records. BMJ Open. 2018;8:e020204.

16. Goicolea Ruigómez FJ, Elola J, Durante-López A, Fernández-Pérez C, Bernal JL, Macaya C. Cirugía de revascularización aortocoronaria en España. Influencia del volumen de procedimientos en los resultados. Rev Esp Cardiol. 2020;73:488-494.

17. Bertomeu V, Cequier A, Bernal JL, et al. Mortalidad intrahospitalaria por infarto agudo de miocardio. Relevancia del tipo de hospital y la atención dispensada. Estudio RECALCAR. Rev Esp Cardiol. 2013;66:935-942.

18. Worner F, San Román A, Sánchez PL, Viana A, González-Juanatey JR. Atención a los pacientes con enfermedades cardiacas agudas y críticas. Posición de la Sociedad Española de Cardiología. Rev Esp Cardiol. 2015;69:239-242.

19. Rodriguez-Padial L, Elola FJ, Fernández-Pérez C, et al. Patterns of inpatient care for acute myocardial infarction and 30-day, 3-month and 1-year cardiac readmission rates in Spain. Int J Cardiol. 2017;230:14-20.

20. Sánchez-Salado JC, Burgos V, Ariza-SoléA, et al. Trends in cardiogenic shock management and prognostic impact of type of treating center. Rev Esp Cardiol. 2019. https://doi.org/10.1016/j.rec.2019.10.004.

21. Íñiguez Romo A, Bertomeu Martínez V, Rodríguez Padial L, et al. The RECALCAR project. Healthcare in the cardiology units of the Spanish National Health System, 2011 to 2014. Rev Esp Cardiol. 2017;70:567-575.

22. Worner F, San Román A, Sánchez PL, Viana Tejedor A, González-Juanatey JR. The healthcare of patients with acute and critical heart disease. Position of the Spanish Society of Cardiology. Rev Esp Cardiol. 2016;69:239-242.

23. Procedure-Specific Measure Updates and Specifications Report Hospital-Level 30-Day Risk-Standardized Mortality Measure Isolated Coronary Artery Bypass Graft (CABG) Surgery –Version 4.0. Yale New Haven Health Services Corporation/Center for Outcomes Research & Evaluation (YNHHSC/CORE). Centers for Medicare & Medicaid Services (CMS). 2017.

24. Society of Thoracic Surgeons'. Online STS Adult Cardiac Surgery Risk Calculator. Available online:http://riskcalc.sts.org/stswebriskcalc/#/. Consultado 20 Dic 2019.

25. Pope GC, Ellis RP, Ash AS, et al. Principal inpatient diagnostic cost group model for Medicare risk adjustment. Health Care Financ Rev. 2000;21:93-118.

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28. Shahian DM, Normand SL, Torchiana DF, et al. Cardiac surgery report cards:comprehensive review and statistical critique. Ann Thorac Surg. 2001;72:2155-2168.

29. Lunardi M, Pesarini G, Zivelonghi C, et al. Clinical outcomes of transcatheter aortic valve implantation:from learning curve to proficiency. Open Heart. 2016;3:e000420.

30. Hirji SA, McCarthy E, Kim D, et al. Relationship Between Hospital Surgical Aortic Valve Replacement Volume and Transcatheter Aortic Valve Replacement Outcomes. JACC Cardiovasc Interv. 2020;13:335-343.

31. Mao J, Redberg RF, Carroll JD, et al. Association Between Hospital Surgical Aortic Valve Replacement Volume and Transcatheter Aortic Valve Replacement Outcomes. JAMA Cardiol. 2018;3:1070-1078.

32. Bernal JL, Barrabés JA, Íñiguez A, et al. Clinical and administrative data on the research of acute coronary syndrome in Spain:minimum basic data set validity. Rev Esp Cardiol. 2018;72:56-62.

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Corresponding author: Unidad de Cardiología Intervencionista, Hospital Clínico San Carlos, IdISSC, Prof. Martín Lagos s/n, 28040 Madrid, Spain.
E-mail address: (I.J. Núñez-Gil).

ABSTRACT

Introduction and objectives: The presence of comorbidities in elderly patients with non-ST-segment elevation acute coronary syndrome worsens its prognosis. The objective of the study was to analyze the impact of the burden of comorbidities in the decision of using invasive management in these patients.

Methods: A total of 7211 patients > 70 years old from 11 Spanish registries were included. Individual data were analyzed in a common database. We assessed the presence of 6 comorbidities and their association with coronary angiography during admission.

Results: The mean age was 79 ± 6 years and the mean CRACE score was 150 ± 21 points. A total of 1179 patients (16%) were treated conservatively. The presence of each comorbidity was associated with less invasive management (adjusted for predictive clinical variables): cerebrovascular disease (OR, 0.78; 95%CI, 0.64-0.95; P = .01), anemia (OR, 0.64; 95%CI, 0.54-0.76; P < .0001), chronic kidney disease (OR, 0.65; 95%CI, 0.56-0.75; P < .0001), peripheral arterial disease (OR, 0.79; 95%CI, 0.65-0.96; P = .02), chronic lung disease (OR, 0.85; IC95%, 0.71-0.99; P = .05), and diabetes mellitus (OR, 0.85; 95%CI, 0.74-0.98; P < .03). The increase in the number of comorbidities (comorbidity burden) was associated with a reduction in coronary angiographies after adjusting for the GRACE score: 1 comorbidity (OR, 0.66; 95%CI, 0.54-0.81), 2 comorbidities (OR, 0.55; 95%CI, 0.45-0.69), 3 comorbidities (OR, 0.37; 95%CI, 0.29-0.47), 4 comorbidities (OR, 0.33; 95%CI, 0.24-0.45), ≥ 5 comorbidities (OR, 0.21; 95%CI, 0.12-0.36); all P values < .0001 compared to 0.

Conclusions: The number of coronary angiographies performed drops as the number of comorbidities increases in elderly patients with non-ST-segment elevation acute coronary syndrome. More studies are still needed to know what the best management of these patients should be.

Keywords: Comorbidities. Elderly. Acute coronary syndrome. Coronary angiography.

Resumen

Introducción y objetivos: La comorbilidad en ancianos con síndrome coronario agudo sin elevación del segmento ST empeora el pronóstico. El objetivo fue analizar la influencia de la carga de comorbilidad en la decisión del tratamiento invasivo en ancianos con SCASEST.

Métodos: Se incluyeron 7.211 pacientes mayores de 70 años procedentes de 11 registros españoles. Los datos se analizaron en una base de datos conjunta. Se evaluó la presencia de 6 enfermedades simultáneas y su asociación con la realización de coronariografía durante el ingreso.

Resultados: La edad media fue de 79 ± 6 años y la puntuación GRACE media fue de 150 ± 21 puntos. Fueron tratados de manera conservadora 1.179 pacientes (16%). La presencia de cada enfermedad se asoció con un menor abordaje invasivo (ajustado por variables clínicas predictivas): enfermedad cerebrovascular (odds ratio [OR] = 0,78; intervalo de confianza del 95% [IC95%], 0,64-0,95; p = 0,01), anemia (OR = 0,64; IC95%, 0,54-0,76; p < 0,0001), insuficiencia renal (OR = 0,65; IC95%, 0,56-0,75; p < 0,0001), arteriopatía periférica (OR = 0,79; IC95%, 0,65-0,96; p = 0,02), enfermedad pulmonar crónica (OR = 0,85; IC95%, 0,71-0,99; p = 0,05) y diabetes mellitus (OR = 0,85; IC95%, 0,74-0,98; p = 0,03). Asimismo, el aumento del número de enfermedades (carga de comorbilidad) se asoció con menor realización de coronariografías, ajustado por la escala GRACE: 1 enfermedad (OR = 0,66; IC95%, 0,54-0,81); 2 (OR = 0,55; IC95%, 0,45-0,69); 3 (OR = 0,37; IC95%, 0,29-0,47); 4 (OR = 0,33; IC95%, 0,24-0,45); ≥ 5 (OR = 0,21; IC95%, 0,12-0,36); todos p < 0,0001, en comparación con ninguna enfermedad.

Conclusiones: Conforme aumenta la comorbilidad disminuye la realización de coronariografías en ancianos con síndrome coronario agudo sin elevación del segmento ST. Se necesitan estudios que investiguen la mejor estrategia diagnóstico-terapéutica en estos pacientes.

Palabras clave: Comorbilidad. Ancianos. Síndrome coronario agudo. Coronariografía.

Abbreviations: ACS: acute coronary syndrome. DM: diabetes mellitus. NSTEACS: non-ST-segment elevation acute coronary syndrome.

INTRODUCTION

Population ageing leads to an increase in the number of elderly patients who suffer non-ST-segment elevation acute coronary syndrome (NSTEACS). This population group, that has been misrepresented in large studies, has a great comorbidity burden that increases with age1 and an important impact on prognosis.2-4 The ideal therapeutic strategy for the management of these patients is still unknown. The benefit of an invasive strategy in elderly patients with NSTEACS and comorbidities is still unclear.5-9 In general, elderly patients with comorbidities undergo fewer coronary angiographies despite their worse prognosis.10 This clinical practice —apparently in contrast with the recommendations published in the clinical practice guidelines11— seems to be based on the perception of a scarce benefit due to the worse intrinsic prognosis associated with comorbidities.

In this study the data of 11 Spanish NSTEACS registries were collected to set up a common database with over 7000 elderly patients with NSTEACS. In this preliminary analysis, the objective was to study the impact of comorbidities on the decision to go with invasive approach.

METHODS

Study design

The study was conducted from 11 cohorts of Spanish registries of patients with NSTEACS (annex).2,12-20 All cases were included in a single database of patients with chest pain and a diagnosis of NSTEACS, > 70 years of age and with, at least, a 1-year follow-up.

ANNEX. Registries included in the study.

Hospital Clínico Universitario, Valencia2
Hospital Universitario Joan XXIII, Tarragona12
Hospital Universitario de Bellvitge, Barcelona13
Hospital Ramón y Cajal, Madrid14
Hospital Universitario de San Juan, Alicante15
LONGEVO multicenter registry16
ACHILLES multicenter registry17
Hospital Álvaro Cunqueiro, Vigo18
Hospital Clínico Universitario, Santiago de Compostela19
Hospital Universitario Vall d’Hebron, Barcelona20
Hospital Universitario de La Princesa, Madrid*

* Unpublished data.

The anthropometric and social-demographic data, main cardiovascular risk factors, and analytical and hemodynamic data at admission or during hospitalization were registered.

Patients were treated according to each center routine clinical practice and the decision to treat the NSTEACS invasively, with or without a coronary angiography, was left to the discretion of the treating physician. The 6-month mortality GRACE risk score was determined in all the patients.21

A total of 6 conditions that proved to have a higher prognostic impact on elderly patients hospitalized due to acute coronary syndrome (ACS) in a previous study were included:22 renal failure (glomerular filtration rate < 60mL/min/1.73m2), anemia (hemoglobin levels < 11 g/dL), diabetes mellitus (DM), cerebrovascular disease, peripheral arterial disease, and chronic pulmonary disease.

Endpoints

The study primary endpoint was to assess how the presence of comorbidities impacted the decision to perform a coronary angiography during admission.

Statistical analysis

Categorical variables were expressed as absolute values (percentages) and compared using the unpaired Student t test or the ANOVA. The continuous ones were expressed as mean ± standard deviation and compared using the chi-square test.

Initially, the correlation between each disease and the performance of a coronary angiography through univariable analysis were assessed. Then, a first binary logistics regression model was conducted including the 6 conditions and the clinical variables associated with the performance of the coronary angiography in the univariable analysis. The odds ratio (OR) and the 95% confidence intervals (95%CI) were estimated. Afterwards, patients were classified according to their comorbidity burden, defined by the number of concomitant conditions (from 0 to 6). A second logistics regression model was conducted where comorbidity burden was adjusted for the predictive clinical variables in the previous analysis. Finally, a third logistics regression model was conducted where the comorbidity burden was adjusted based on the GRACE risk score. Differences were considered statistically significant with P values < .05

RESULTS

A total of 7211 patients with a mean age of 79 ± 6 years were included; 62% were males. Table 1 shows the population baseline characteristics. The prevalence of comorbidities was DM in 2874 patients (40%), chronic kidney disease in 3070 patients (42.6%), anemia in 1025 (14.2%), peripheral arterial disease in 1006 (14%), chronic pulmonary disease in 1161 (16%), and previous stroke in 831 (11.5%).

Table 1. Differences in the baseline characteristics based on the therapeutic approach

All n = 7211 Conservative approach n = 1 179 (16) Invasive approach n = 6 032 (84) P
Age (years) 79 ± 6 82 ± 6 78 ± 5 .001
Males 4 441 (61.6) 597 (50.6) 3 844 (63.7) .0001
Smoking 621 (8.6) 72 (6.1) 549 (9.1) .0001
Hypertension 5 723 (79.4) 943 (80) 4 780 (79.2) .58
Dyslipidemia 4 262 (59) 609 (51.7) 3 653 (60.6) .0001
Previous myocardial infarction 1 682 (23.3) 371 (31.7) 1 308 (21.7) .0001
Pervious percutaneous coronary intervention 1 334 (19) 175 (14.8) 1 159 (19.2) .0001
Previous coronary surgery 573 (7.9) 104 (8.8) 469 (7.8) .24
Previous heart failure 641 (8.9) 198 (16.8) 443 (7.3) .0001
Killip ≥ 2 1 889 (26.2) 463 (39.3) 1 426 (23.6) .0001
ST-segment depression 2 638 (36.6) 396 (33.6) 2 242 (37.2) .02
High troponin levels 5 319 (73.7) 920 (78) 4 399 (73) .001
Left ventricular ejection fraction (%) 54 ± 11 54 ± 12 55 ± 11 .03
GRACE 150 ± 21 159 ± 21 147 ± 19 .0001
Comorbidities
Anemia 1 025 (14.2) 273 (23.2) 752 (12.5) .0001
Peripheral arterial disease 1 006 (14) 196 (16.6) 810 (13.4) .04
Chronic pulmonary disease 1 161 (16.1) 210 (17.8) 951 (15.8) .08
Diabetes mellitus 2 874 (39.9) 522 (44.3) 2 352 (39) .0001
Cerebrovascular disease 831 (11.5) 186 (15.8) 645 (10.7) .0001
Chronic kidney disease 3 070 (42.6) 716 (60.7) 2 354 (39) .0001

Data are expressed as no. (%) or mean ± standard deviation.

During admission 6032 patients (84%) underwent a coronary angiography. A total of 4339 patients (60%) were revascularized: 3848 (53%) of them through percutaneous coronary intervention and 491 (7%) through surgery. Patients on conservative management (1179, 16%) were predominantly women with higher scores in the GRACE score, and a past medical history of infarction or heart failure. Conversely, smoking and high levels of troponins or ST-segment depressions on the electrocardiogram performed at admission and a previous percutaneous coronary intervention were associated with a higher invasive approach (table 1). The GRACE risk score was lower in patients who underwent catheterization (147 ± 19 vs 159 ± 21; P = .0001).

The presence of each of the 6 conditions studied was associated with fewer coronary angiographies performed: chronic kidney disease, 60.7% vs 39% (P = .0001); anemia, 23.2% vs 12.5% (P = .0001); DM, 44.3% vs 39% (P = .0001); cerebrovascular disease, 15.8% vs 10.7% (P = .0001); peripheral arterial disease, 16.6% vs 13.4% (p = .04); and chronic pulmonary disease, 17.8% vs 15.8% (P = .08) (table 1).

In the multivariable analysis adjusted for the main cardiovascular risk factors and clinical variables that were statistically significant in the univariable analysis, the 6 conditions associated with a lower probability of an indication for coronary angiography were: cerebrovascular disease, OR, 0.78 (IC95%, 0.64-0.95; P = .01); anemia, OR, 0.64 (IC95%, 0.54-0.76; P < .0001); chronic kidney disease, OR, 0.65 (IC95%, 0.56-0.75; P < .0001); peripheral arterial disease, OR, 0.79 (IC95%, 0.65-0.96; P = .02); chronic pulmonary disease, OR, 0.85 (IC95%, 0.71-0.99; P = .05); and DM, OR, 0.85 (IC95%, 0.74-0.98; P = .03). Table 2 shows the clinical variables associated with the indication for coronary angiography.

Table 2. Results: multivariable analysis for the indication of a coronary angiography

Variable OR 95%CI P
Age (years) 0.89 0.88-0.91 .0001
Males 1.48 1.28-1.71 .0001
Dyslipidemia 1.44 1.26-1.66 .0001
Previous myocardial infarction 0.46 0.39-0.54 .0001
Previous heart failure 0.68 0.56-0.84 .0001
Previous percutaneous coronary intervention 1.91 1.55-2.34 .0001
Killip ≥ 2 0.68 0.56-0.80 .0001
ST-segment depression 1.44 1.25-1.66 .0001
Left ventricular ejection fraction (by 5%) 0.98 0.98-0.99 .001
Anemia 0.64 0.54-0.76 .0001
Peripheral artery disease 0.79 0.65-0.96 .02
Chronic pulmonary disease 0.85 0.71-0.99 .05
Diabetes mellitus 0.85 0.74-0.98 .03
Cerebrovascular disease 0.78 0.64-0.95 .01
Chronic kidney disease 0.65 0.56-0.75 .0001

95%CI: 95% confidence interval; OR: odds ratio.

Comorbidity burden was defined as the number of present conditions (from 0 to 6). This was their distribution: 0 conditions, n = 1891 (26%); 1 condition, n = 2413 (33.5%); 2 conditions, n = 1638 (22.7%); 3 conditions, n = 879 (12.2%); 4 conditions, n = 314 (4.4%); and 5 or 6 conditions, n = 76 (1.1%). The analysis of the comorbidity burden adjusted for the clinical variables associated with the indication for coronary angiography showed a negative correlation between the number of conditions and the probability to perform a coronary angiography: 1 condition, OR, 0.66 (95%CI, 0.54-0.81); 2 conditions, OR, 0.55 (95%CI, 0.45-0.69); 3 conditions, OR, 0.37 (95%CI, 0.29-0.46); 4 conditions, OR, 0.32 (95%CI, 0.23-0.45); and 5 or 6 conditions, OR, 0.21 (95%CI, 0.12-0.37); All P values < .0001 compared to no condition.

With more conditions, higher GRACE risk scores (table 3). The negative correlation between the comorbidity burden and the performance of the coronary angiography was kept after adjusting for the GRACE risk score. Figure 1 shows that with more conditions, the probability to perform a coronary angiography increased too (figure 1A) despite the higher risk posed by higher GRACE risk scores (figure 1B, table 3).

Table 3. Distribution of comorbidity burden and the score obtained in the GRACE risk score (P < .0001 for the tendency)

Conditions N = 7 211 GRACE risk score
0 1891 (26) 141 ± 18
1 2413 (33.5) 148 ± 19
2 1638 (22.7) 153 ± 20
3 879 (12.2) 160 ± 19
4 314 (4.4) 162 ± 19
≥ 5 76 (1.1) 166 ± 17

Data are expressed as no. (%) or mean ± standard deviation.

Figure 1. A: chances of undergoing a coronary angiography based on the number of concomitant conditions. The odds ratio (OR) with a 95% confidence interval (95%IC) can be seen. Analysis adjusted for the GRACE risk score. B: Representation of the correlation between comorbidity burden and the GRACE risk score. The mean ± standard deviation (SD) of the GRACE risk score can be seen.

DISCUSSION

The main findings of our study were: a) the 6 conditions studied (cerebrovascular disease, anemia, chronic kidney disease, peripheral arterial disease, chronic pulmonary disease, and DM) were independently associated with a lower probability to use the invasive approach; b) with higher comorbidity burdens, considered as the number of concomitant conditions, lower chances of performing coronary angiographies.

There is a high prevalence of comorbidities in elderly patients with NSTEACS that greatly impacts prognosis in the short and mid-term.2,4 The Charlson index is the most commonly used tool to assess comorbidities.23,24 However, the analysis of the 6 conditions studied (chronic kidney disease, anemia, DM, cerebrovascular disease, peripheral arterial disease, and chronic pulmonary disease) has proven to be a useful risk stratification tool and have great predictive discriminatory capabilities that are similar to the Charlson index.22

Comorbidity burden is very important for the in-hospital management of NSTEACS.2,3,6,9,10 Although the optimal therapeutic strategy for the management of elderly patients with NSTEACS is still unknown, several studies show certain benefits with revascularization.5,7,8,25-30

Our study shows that with higher comorbidity burdens, lower chances of undergoing coronary angiographies. This may be due to the fact that comorbidities are seen as contraindications for the invasive approach.10 However, the risk of suffering an acute myocardial infarction according to the GRACE risk score increases parallel to the number of concomitant conditions. Actually, these may be the patients who would benefit the most from an invasive approach.31,32

The presence of each one of these 6 conditions was independently associated with fewer invasive approaches. On the one hand, cerebrovascular disease and peripheral arterial disease are responsible for a greater spread of atherosclerotic disease.33 Anemia has proven to be a powerful predictor of mortality in the ACS setting;34-36 we used the 11 g/dL threshold as the cut-off value that had the greatest impact on mortality in former studies.34 Its specific weight in the decision to administer conservative treatment may be justified by its clear association with the occurrence of hemorrhagic events in the ACS setting.37 Chronic kidney disease is an expression of a greater spread of cardiovascular disease and is independently associated with more mortality after an ACS. There is a linear correlation between the risk of death due to cardiovascular causes and lower glomerular filtration rates.17,38 DM is a powerful predictor of mortality, and not only due to cardiovascular causes. There is a clear correlation between DM and major adverse cardiovascular events, and these are patients at very high risk.39 Chronic pulmonary disease is associated with a worse short-term prognosis after an acute myocardial infarction. Also, in the management of NSTEACS it is associated with diagnostic delays, fewer invasive approaches, and a lower use of drugs for secondary prevention purposes.40

In the multivariable analysis, age, previous acute myocardial infarctions, previous heart failure, Killip class ≥ 2 at admission, and a reduced ejection fraction were associated with fewer invasive approaches. Elderly patients receive fewer evidence-based therapies. The older the age, the lower the rate of performing coronary angiographies.41 On top of age, a past medical history of infarction, heart failure, a reduced ejection fraction, and scores ≥ 2 in the Killip classification are important aspects in the prognosis of ACS that, in general, translate into a worse ventricular function. Paradoxically, our findings suggest that the higher the risk, the lower the chances of performing a coronary angiography. Actually, these findings are consistent with former studies published.10,42 It is possible that the perception of fewer benefits from revascularization or higher risk in the revascularization procedures may explain these results.2 On the other hand, male sex, dyslipidemia, previous percutaneous coronary interventions, and ST-segment depressions at admission were associated with more invasive approaches. Several studies suggest that women undergo fewer invasive approaches compared to men despite the mortality benefits seen.43 Previous angioplasties, ST-segment depressions, and dyslipidemia are probably interpreted as ischemic risk factors, which may explain their association with a higher frequency of invasive approaches.20,28,44

Limitations

The main limitation of our study is that it is an observational registry with its corresponding selection bias and differences in the management of patients depending on the different centers involved. On the other hand, although the multivariable model was adjusted for percutaneous coronary intervention or previous coronary surgeries, it was not adjusted for previous coronary angiographies. It is possible that the previous knowledge of the coronary anatomy impacted the decision to perform fewer coronary angiographies in patients at higher risk.

CONCLUSIONS

The presence of comorbidities greatly impacts the therapeutic decision in elderly patients with ACS. With more conditions, higher GRACE risk scores, and lower chances of indicating a coronary angiography

This paradox of higher-risk and more conservative treatment justifies conducting new studies to determine the benefits of the invasive strategy in elderly patients with NSTEACS and comorbidities to establish the best therapeutic decision.

CONFLICTS OF INTEREST

J. Sanchis is an associate editor of REC: Interventional Cardiology; the journal’s editorial procedure to ensure impartial handling of the manuscript has been followed. J. Núñez has received funding from Novartis, Vitor Pharma, and Boehringer Ingelheim, and a grant from Astra Zeneca and Vitor Pharma. J.A. Barrabés has received funding for the educational activities conducted for AstraZeneca, and for his job as consultor for Bayer. The remaining authors did not declare any conflicts of interest whatsoever.

WHAT IS KNOWN ABOUT THE TOPIC?

  • Elderly patients with NSTEACS have a higher comorbidity burden. Concomitant conditions are associated with worse prognosis. Elderly patients with comorbidities undergo fewer coronary angiographies despite their worse prognosis, which is in sharp contrast with the recommendations published in the clinical practice guidelines.

WHAT DOES THIS STUDY ADD?

  • This analysis of a multicenter registry shows the correlation between comorbidity burden and invasive therapeutic approach in elderly patients with NSTEACS. With more concomitant conditions, higher GRACE risk scores, but lower chances of indicating a coronary angiography.

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13. Ariza-SoléA, Sánchez-Salado JC, Lorente V, et al. Is it possible to separate ischemic and bleeding risk in patients with non-ST segment elevation acute coronary syndromes?Int J Cardiol. 2014;171:448-450.

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15. Cordero A, López-Palop R, Carrillo P, et al. Prevalence and Postdischarge Incidence of Malignancies in Patients With Acute Coronary Syndrome. Rev Esp Cardiol. 2018;71:267-273.

16. Alegre O, Formiga F, López-Palop R, et al. An Easy Assessment of Frailty at Baseline Independently Predicts Prognosis in Very Elderly Patients With Acute Coronary Syndromes. J Am Med Dir Assoc. 2018;19:296-303.

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26. Sillano D, Resmini C, Meliga E, et al. Retrospective multicenter observational study of the interventional management of coronary disease in the very elderly:the NINETY. Catheter Cardiovasc Interv. 2013;82:414-421.

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28. Núñez J, Ruiz V, Bonanad C, et al. Percutaneous coronary intervention and recurrent hospitalizations in elderly patients with non ST-segment acute coronary syndrome:The role of frailty. Int J Cardiol. 2017;228:456-458.

29. LlaóI, Ariza-SoléA, Sanchis J, et al. Invasive strategy and frailty in very elderly patients with acute coronary syndromes. EuroIntervention. 2018;14:e336-342.

30. Sanchis J, Ariza-SoléA, Abu-Assi E, et al. Invasive Versus Conservative Strategy in Frail Patients With NSTEMI:The MOSCA-FRAIL Clinical Trial Study Design. Rev Esp Cardiol. 2019;72:154-159.

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35. Ford I, Bezlyak V, Stott DJ, et al. Reduced glomerular filtration rate and its association with clinical outcome in older patients at risk of vascular events:secondary analysis. PLoS Med. 2009;6:e16.

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Corresponding author: Servicio de Cardiología, Hospital Clínico Universitario de Valencia, Blasco Ibáñez 17, 46010 Valencia, Spain.
E-mail address: (J. Sanchis).

ABSTRACT

Introduction and objectives: The STENTYS Xposition S stent (STENTYS S.A, Paris, France) is the only self-apposing sirolimus- eluting stent available in the market. The stent features make it useful to treat challenging lesions with proximal-distal different vessel diameter, ectasia, high thrombus burden, bifurcation lesions including the left main coronary artery or vein grafts. We describe our own experience with the use of this stent and evaluate its efficacy and safety profile.

Methods: We included all consecutive patients treated with the STENTYS Xposition S from January 2018 to October 2019. All coronary lesions were quantified using QCA (quantitative coronary angiography).

Results: A total of 62 lesions in 50 patients were treated with the STENTYS Xposition S. The median age of the patients was 66 years (49-92). The most common clinical presentation was ST-segment elevation acute coronary syndrome in 23 patients (46%). Ectasia and significant vessel diameter variance were the most common scenario in 72.6% of cases and bifurcation in the remaining 27.4% (2 of them in the left main coronary artery). Pre-dilatation was performed in 32 lesions (51.6%) and post-dilatation in 37 (59.7%). Angiographic success was achieved in all patients except for 1. At the median 373-day follow-up (256-439), 1 patient had an acute myocardial infarction 3 months after the percutaneous intervention and 1 patient died due to cardiac failure during admission. There were no cases of definitive stent thrombosis or target lesion revascularization.

Conclusions: The STENTYS Xposition S self-apposing stent showed good angiographic and clinical outcomes in our real-world experience.

Keywords: Self-apposing stent. Coronary lesion. Major adverse cardiovascular events.

RESUMEN

Introducción y objetivos: El stent STENTYS Xposition S (STENTYS S.A., París, Francia) es el único stent autoexpandible liberador de sirolimus disponible en el mercado. Sus características hacen que resulte útil en lesiones que presentan gran diferencia del diámetro del vaso proximal-distal, ectasia, alta carga de trombo o que se encuentren en bifurcaciones e injertos venosos. Describimos nuestra experiencia con el uso de este tipo de stent, evaluando su seguridad y eficacia.

Métodos: Se incluyeron todos los pacientes consecutivos tratados con STENTYS desde enero de 2018 hasta octubre de 2019. Todas las lesiones coronarias fueron cuantificadas por angiografía coronaria cuantitativa.

Resultados: Se trataron con STENTYS Xposition S 62 lesiones en 50 pacientes. La mediana de edad de los pacientes fue de 66 años (49-92). La clínica de presentación más frecuente fue el síndrome coronario agudo con elevación del segmento ST en 23 pacientes (46%). La ectasia coronaria y la gran diferencia en los diámetros proximal y distal a la lesión fue la indicación más frecuente para el uso de este tipo de stent, en el 72,6% de los casos, seguida del intervencionismo sobre bifurcación en el 27,4% de los pacientes (2 de ellos en el tronco coronario izquierdo). Se realizó predilatación en 32 lesiones (51,6%) y posdilatación en 37 (59,7%). Se logró el éxito angiográfico en todos los pacientes excepto en 1. Tras una mediana de seguimiento de 373 días (256-439), 1 paciente presentó infarto agudo de miocardio a los 3 meses y 1 paciente falleció durante el ingreso por insuficiencia cardiaca. No hubo ningún caso de trombosis definitiva del stent ni de revascularización de la lesión tratada.

Conclusiones: En nuestra experiencia de la vida real, el stent STENTYS Xposition S demostró un buen resultado angiográfico y clínico.

Palabras clave: Stent autoexpandible. Lesión coronaria. Eventos cardiovasculares adversos mayores.

Abbreviations LMCA: left main coronary artery. MACE: major adverse cardiovascular events.

INTRODUCTION

The STENTYS Xposition S (STENTYS S.A., Paris, France) is a sirolimus-eluting self-expanding nitinol stent designed to adapt its size to the vessel diameter and facilitate its complete apposition when exerting chronic strength towards the outside. It has long been confirmed that one of the most important factors of stent thrombosis is the incorrect apposition of the stent.1 The characteristics of this stent make it especially useful to revascularize acute coronary syndromes (ACS), especially ST-segment elevation acute coronary syndromes with lesions with high thrombotic load. Also, a potential benefit in ectatic coronary vessels and lesions with great proximal and the distal diameter mismatch has been confirmed, bifurcations (left main coronary artery [LMCA] included), and venous grafts.

The objective of this study was to assess the benefit of this stent in the routine clinical practice by analyzing the type of lesions this stent is used with and the immediate angiographic results and at the clinical follow-up.

METHODS

A cohort of consecutive patients treated with the STENTYS Xposition S stent was analyzed from January 2018 through October 2019 in a tertiary hospital where over 1000 percutaneous coronary interventions are performed each year. All coronary lesions were quantified using a quantitative coronary angiography. Lesions in vessels with changes in size (ectasia or proximal-distal diameter mismatch of the lesion), in a bifurcation, in the presence of a high thrombotic load or in a venous graft were analyzed. The interventional strategy to be followed, imaging modalities included, was left to the operator’s criterion. The clinical and follow-up data were obtained from the electronical clinical records of the healthcare system of our autonomous community. All events were defined in a standard way according to the Academic Research Consortium-2 (ARC-2) consensus document.2

The data analysis was conducted using the IBM SPSS 20.0 statistical software package. Continuous variables were expressed as mean ± standard deviation or median with interquartile range depending on whether they followed a normal distribution or not, respectively. Qualitative variables were expressed as relative percentage. The cumulative incidence of events at the follow-up was estimated.

RESULTS

From January 2018 through September 2019, 1692 percutaneous coronary interventions with stent implantation were performed. The STENTYS Xposition S stent was used in 50 patients (62 lesions). The patients’ median age was 66 years [49-92]. Eighty-eight per cent of the patients were males. Table 1 shows the clinical characteristic of patients and coronary lesions. The most common clinical presentation was ST-segment elevation acute coronary syndrome in 23 patients (46%) followed by non-ST-segment elevation acute coronary syndrome in 22 patients (44%), and stable angina in 5 patients (10%). According to the classification established by the American College of Cardiology/American Heart Association the most common type of lesion was B1 lesion (38.7%). The right coronary artery was the most frequently treated vessel in 33 patients (53.2%).

Table 1 Clinical characteristics of patients and angiographic characteristics of the lesions

Patients (n) 50
Age (years) 66.6 (49-92)
Males 44 (88%)
Arterial hypertension 33 (66%)
Body mass index (kg/m2) 27.9 ± 4.9
Dyslipidemia 32 (64%)
Diabetes mellitus 12 (24%)
Smoking 27 (54%)
Family history of ischemic heart disease 3 (6%)
Peripheral vasculopathy 3 (6%)
Atrial fibrillation 6 (12%)
Chronic pulmonary disease 6 (12%)
Kidney disease 6 (12%)
Stable angina pectoris 5 (10%)
NSTEACS 22 (44%)
STEACS 23 (46%)
Lesions (n) 62
Lesion length (mm) 14.56 ± 3.64
Reference diameter (mm) 4.1 ± 0.8
Percent stenosis. QCA (%) 70.08 ± 17
Location of the lesion
 Left main coronary artery 3 (4.8)
 Left anterior descending coronary artery 11 (17.7)
 Left circumflex artery 15 (24.2)
 Right coronary artery 33 (53.2)
Classification of the lesion
 A 0
 B1 24 (38.8)
 B2 19 (30.6)
 C 19 (30.6)
Indication for STENTYS
 Ectasia. Proximal-distal diameter mismatch 45 (72.6)
 Bifurcation 17 (27.4)
 Provisional stenting technique 15 (88.2)
 Double stent technique 2 (11.8)

NSTEACS, non-ST-segment elevation acute coronary syndrome; QCA, quantitative coronary angiography; STEACS, ST-segment elevation acute coronary syndrome.

Kidney damage: glomerular filtration rate < 60 mL/min/1.73 m2.

Data are expressed as n (%) o mean ± standard deviation.

Ectasia and great proximal-distal diameter mistmatch at the lesion were the main indication for the use of this stent, in 72.6% of the lesions, with a mean vessel reference diameter of 4.1 mm ± 0.8 mm. A certain size was required to use this type of stent. The percutaneous coronary interventional on a bifurcation was the second most common indication, in 27.4% of the patients (2 of them on the LMCA). The most common type of bifurcation according to the Medina classification was 1-1-0, in 9 cases (52.9%). The secondary branch was damaged in 17% of the patients. The provisional stenting technique was the most widely used in 15 cases (88.2% of bifurcations) re-crossing to the secondary branch in 9 of them (60%). The dilatation of the secondary branch only occurred in 7 patients and only in the other 2 stents were implanted: one in a 0-1-1 bifurcation according to the Medina classification (minicrash technique) and the other in a 1-1-1 bifurcation according to this classification (TAP technique [T-and protrusion technique]). In both cases the STENTYS Xposition S stent was implanted in the main vessel and a non-self-apposing stent in the secondary branch (figure 1).

Figure 1. A: lesion with significant thrombotic load in the mid right coronary artery, which remains after thrombus aspiration. B: 3.5-4.5 mm × 27 mm Xposition S direct stent implantation. C: final angiographic result. D: significant stenosis in distal left main coronary artery. E: 3-3.5 mm × 27 mm Xposition S stent implantation from the proximal left main coronary artery to the left anterior descending coronary artery. F: angiographic result after postdilatation.

A high thrombotic load (Thrombolysis in Myocardial Infarction flow grade 4-5) was seen in 8 lesions. All of them in ectatic coronary vessels or with proximal-distal caliber mismatch. No case of venous graft treated with STENTYS was reported.

Predilatation occurred in 32 lesions (51.6%) and postdilatation in 37 (59.7%). The criterion used for postdilatation was angiography guided visual underexpansion. Intravascular ultrasound was performed in 15 patients (30%) before the implant. It was also used in 2 patients to optimize the percutaneous coronary intervention given the persistent stent underexpansion seen on the angiography. In both cases the minimum lumen area was > 5.5 mm2 with stent expansion > 80% and lack of incomplete apposition (defined as a strut separation of > 0.4 mm axial and 1 mm longitudinal) (figure 2). The optical coherence tomography was performed in a patient with ST-segment elevation acute coronary syndrome before and after the implant. It revealed a high thrombotic load with lack of immediate stent malapposition.

Figure 2. A: acute thrombotic occlusion in left circumflex artery with Thrombolysis in Myocardial Infarction flow grade 0. B: the intravascular ultrasound shows a great deal of thrombus in the lesions despite thrombus aspiration. C: implantation of 2 3.5-4.5 mm × 27 mm Xposition S overlapping stents. D: the intravascular ultrasound performed after stent implantation confirms the good angiographic results and lack of stent malapposition.

Angiographic success was achieved (with the stent properly implanted, a residual lesion ≤ 10%, and Thrombolysis in Myocardial Infarction flow grade 3) in all patients but 1, in whom stent implantation failed in a severely calcified LMCA lesion. In this case, predilatation was first attempted using a conventional balloon and then a cutting balloon on the LMCA severe distal lesion. A 3.3-4.5 mm × 22 mm STENTYS Xposition S stent was implanted with stent loss during retrieval, which remained braced to the guide catheter. Afterwards, a balloon-expandable drug-eluting stent was successfully implanted. The un-crimped stent was retrieved by crossing a guidewire from the femoral access through the stent distal struts. It was finally captured with a snare.

The median score obtained in the PRECISE-DAPT risk calculator (Predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy) was 16.5 (7-25), and the median score obtained in the DAPT index (Dual antiplatelet therapy) was 1.15 (−2-4). Ticagrelor was the most commonly used P2Y12 inhibitor (58.1%). A 12-month course of dual antiplatelet therapy was prescribed in 48 patients (96%).

After a median follow-up of 373 days (256-439), 1 patient had an acute myocardial infarction 3 months after the intervention. However, the coronary angiography did not reveal coronary artery disease progression but confirmed the good results of the previous intervention. An 84-year-old woman died at admission due to heart failure. Three patients died of non-cardiac causes: 1 due to septic shock at admission, the other patient died 6 months after the percutaneous coronary intervention due to high-grade lymphoma, and the third one 4 months after the percutaneous coronary intervention due to lung cancer. No cases of definitive stent thrombosis or revascularization of the treated lesion were reported. No bleeding was seen either at the follow-up.

DISCUSSION

This type of stent is not widely used in our setting and we believe 2 are the reasons why. The first one is the need for a learning curve to know how to handle this implant. In former iterations of the device, the delivery system had some technical limitations like the jumping phenomenon that could occur right when the sheath was being released due to the elastic properties of nitinol. Unlike its predecessor (STENTYS sirolimus DES), the stent of the new STENTYS Xposition S system, is mounted over a semicompliant balloon and covered by a 0.0032 in-thick sheath. The reason for balloon inflation is not to dilate the stent, but to rupture the external sheath from the distal to the proximal border to allow a proper vessel-wall stent apposition. This has reduced the complexity of the release mechanism.3 However, we should remember that after the implant, the retrieval of both the balloon and the device sheath should be conducted with care by separating the guide catheter from the ostium to avoid deep intubation. The other reason that may explain why this stent is still not widely used can the augmented profile of the device and its rigidity, which both reduce its navigational and crossing capabilities compared to balloon-expandable stents.

Due to the characteristics of the stent and the experienced gained using it, the clinical settings where it can be useful are: ectatic vessel, since the stent reaches 6.5 mm of diameter with the device L size; proximal and distal diameter mismatch due to its adaptative capabilities to the vessel caliber; lesions with high thrombotic load, since this stent self-expanding capabilities facilitate its expansion until it reaches the vessel wall if thrombus reabsorption occurs, which avoids late stent malapposition; and bifurcations with ostial damage and 30º to 70° angles. The stent z-shaped mesh and the presence of small interconnectors facilitate re-crossing the lateral branch and disconnecting the struts without having to use the final kissing balloon technique. Thanks to its self-expanding capabilities, the unconnected struts cover the lateral branch ostium making the double stent technique unnecessary on many occasions.

In the studies published on former iterations of the device, the self-expanding stent proved superior to the balloon-expandable stent regarding better apposition. The randomized APOSSITION II clinical trial,4 conducted among patients with acute myocardial infarction, showed a lower rate of stent malapposition (defined as > 5% of struts per patient as seen on the optical coherence tomography) 3 days after the primary percutaneous coronary intervention. The APOSSITION IV clinical trial,5 also conducted among patients with acute myocardial infarction, showed a significantly lower percentage of stent malapposition at the 4-month follow-up in patients treated with self-expanding stents compared to patients treated with balloon-expandable stents (0.07% vs 1.16%; P = .002). However, no inter-group differences were found at the 9-month follow-up (0.43% vs 0.28%; P = .55) or in the rate of major adverse cardiovascular events (MACE). The clinical repercussions of this improvement in the early apposition of the stent has not been studied thoroughly. The APOSSITTION III trial6 showed that the use of STENTYS BMS in the percutaneous coronary intervention setting was associated with acceptable cardiovascular results at the 2-year follow-up, an overall rate of MACE of 11.2%, and a rate of stent thrombosis of 3.3%. We should mention that this study revealed a significant reduction of adverse events after the systematic implementation of a standard protocol (predilatation, implantation, postdilatation). The data available support the hypothesis of the need for mild postdilatation to avoid early complications probably because the stent does not have enough radial strength to achieve a proper expansion in rigid often calcified lesions, especially when predilatation is not fully effective. Therefore, postdilatation would avoid the incomplete expansion of the stent, which may increase the risk of stent thrombosis.7

Our study with the STENTYS Xposition S stent reached angiographic success in 98.4% of the cases, although we should remember that, from the anatomical point of view, they were not complex lesions (only 30% were type C lesion). Stent implantation failed in 1 severely calcified LMCA lesion; it is precisely in this type of lesions where its use is ill-advised, especially if predilatation is not effective.8

Regarding its use in bifurcations the studies published to this day have also discussed a former iteration of this device with good results. In the observational, multicenter, and prospective OPEN II trial,9 the rate of MACE at the 12-month follow-up was 13% (10.1% at 6 months). This rate of events was basically due to the need for revascularization of the treated lesion, while the rate of stent thrombosis at the 12-month follow-up was 1%. We should also mention that the kissing balloon technique was only used in 21.7% of the patients. Also, there were no significant differences in the rate of MACE between patients in whom the kissing balloon technique was used and those in whom it was not used.9

To this day, the only study published on the new STENTYS Xposition S model is the TRUNC, a prospective and multicenter study that assessed the efficacy and safety profile of this type of stent in the LMCA. Angiographic success was achieved in 96.6% of the patients and the overall rate of MACE was 8.3% at the 12-month follow-up, basically due to revascularization of the lesion treated in 5.4%.10 Here we should mention the preliminary results reported by the SIZING (Worldwide every-day practice registry assessing the Xposition S self-apposing stent in challenging lesions with vessel diameter variance) and WIN (World-wide registry to assess the STENTYS Xposition S for revascularization of coronary arteries in routine clinical practice) registries. Both registries confirm the safety and efficacy profile of the current iteration of the stent in the routine clinical practice.

Limitations

Our study has several limitations. Because of its retrospective, single-center nature and the limited number of cases involved, we cannot draw definitive conclusions on the device safety and efficacy profile. No intracoronary imaging modality was performed systematically to guide the implant, which may have been useful, especially the optical coherence tomography. However, we believe that this study is relevant due to the scarce evidence available on the last iteration of this stent.

CONCLUSIONS

In our series of lesions located in ectatic vessels or with proximal-distal diameter mismatch and in bifurcations, the STENTYS Xposition S stent is a good therapeutic alternative that achieves good immediate angiographic results and good mid-term clinical results.

CONFLICTS OF INTEREST

None declared.

WHAT IS KNOWN ABOUT THE TOPIC?

  • Balloon expandable stents can have limitation in certain scenarios like in the revascularization of lesions with significant proximal-distal diameter mismatch, high thrombotic loads, and situations of bifurcations or in venous grafts. In these situations, the STENTYS Xposition S self-expanding stent can be especially useful.

WHAT DOES THIS STUDY ADD?

  • This type of stent is not widely used in our specialty. We described the experience of our own center with the STENTYS Xposition S stent. Despite the greater difficulty when trying to advance it and the complexity involved in its delivery, the rate of successful implantation was high. We should not forget that this type of stent is recommended in non-complex or non-calcified anatomical lesions. In general, predilatation is recommended to prepare the lesion and postdilatation to secure the proper expansion of the stent since the stent lacks the necessary radial strength. In our series of patients, the STENTYS Xposition S stent was safe and with a low rate of adverse cardiovascular adverse events at the 1-year follow-up.

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8. Verheye S, Ramcharitar S, Grube E, et al. Six-month clinical and angiographic results of the STENTYS R self-apposing stent in bifurcation lesions. EuroIntervention. 2011;7:580-587.

9. Naber CK, Pyxaras SA, Nef H, et al. Final results of a self-apposing paclitaxel-eluting stent for the percutaneous treatment of de novo lesions in native bifurcated coronary arteries study. EuroIntervention. 2016;12:356-358.

10. Tamburino C, Briguori C, Jessurun GA, et al. TCT-329 prospective evaluation of drug eluting selfapposing stent for the treatment of unprotected left main coronary artery disease:1-year results of the TRUNC study. J Am Coll Cardiol. 2018;72:134-135.

Corresponding author: Servicio de Cardiología, Hospital Universitario Miguel Servet, Paseo Isabel la Católica 1-3, 50009 Zaragoza, Spain.
E-mail address: (A. Pérez Guerrero).

ABSTRACT

Introduction and objectives: patients with long, sequential and diffuse coronary lesions who undergo a percutaneous coronary intervention remain at a high risk of suffering cardiovascular events despite the improved safety and efficacy of the new drug-eluting stents. The objective of this study was to analyze the utility of SyncVision/iFR-guided revascularization (SyncVision version 4.1.0.5, Philips Volcano, Belgium) in this type of lesions.

Methods: Randomized, multicenter, controlled, and open-label trial designed to compare SyncVision/iFR-guided and angiography-guided revascularizations in patients with long, sequential or diffuse significant angiographic coronary stenosis (ClinicalTrials.gov identifier: NCT04283734). A total of 100 patients will be randomized (1:1, no stratification). The primary endpoint is the average length of the stent implanted. The secondary endpoint is a composite of cardiac death, myocardial infarction, definitive or probable stent thrombosis, new target lesion revascularization or new target lesion failure; and the presence of residual ischemia as seen on single-photon emission computed tomography at the 6-month follow-up. Patients will be followed for 12 months after the procedure.

Results: The trial is currently in the recruitment phase, and it has already recruited the first 7 patients. We expect to complete the recruitment phase by February 2021 and the follow-up by February 2022.

Conclusions: The iLARDI study is the first randomized trial to assess the potential utility of SyncVision-guided revascularization in long, sequential and diffuse coronary lesions.

Keywords: Diffuse coronary artery disease. Long coronary artery disease. Instantaneous wave-free ratio. SyncVision software.

RESUMEN

Introducción y objetivos: Los pacientes con lesiones coronarias largas, secuenciales o difusas tratadas percutáneamente continúan presentando un riesgo alto de eventos cardiovasculares a pesar de la mejoría de la seguridad y de la eficacia de los nuevos stents liberadores de fármacos. El objetivo de este estudio es analizar la utilidad del software Syncvision/iFR (Syncvision versión 4.1.0.5, Philips Volcano, Belgium) para guiar la revascularización en este tipo de lesiones.

Métodos: Estudio aleatorizado, multicéntrico, controlado y abierto para comparar la revascularización guiada por Syncvision/iFR respecto a la revascularización guiada por angiografía en pacientes con lesiones coronarias largas, secuenciales o difusas (identificador de ClinicalTrials.gov: NCT04283734). Serán incluidos 100 pacientes (aleatorización 1:1 no estratificada). El objetivo primario es la longitud total del stent implantado. Como objetivo secundario se ha establecido un combinado de muerte cardiaca, infarto de miocardio, trombosis definitiva o probable del stent, nueva revascularización de la lesión tratada en el procedimiento basal o nueva revascularización de la lesión analizada en el procedimiento basal, y la presencia de isquemia residual evaluada por tomografía computarizada por emisión de fotón simple a los 6 meses de seguimiento. El tiempo de seguimiento será de 12 meses tras el procedimiento índice.

Resultados: El estudio se encuentra actualmente en fase de reclutamiento, con los primeros 7 pacientes ya incluidos. Esperamos completar el reclutamiento en febrero de 2021 y el seguimiento en febrero de 2022.

Conclusiones: El estudio iLARDI es el primer estudio aleatorizado para la evaluación de la potencial utilidad de la revascularización guiada por Syncvision en lesiones coronarias largas, secuenciales y difusas.

Palabras clave: Lesiones coronarias difusas. Lesiones coronarias largas. Relación en el periodo instantáneo libre de ondas. Software Syncvision.

Abbreviations: PCI: percutaneous coronary intervention. iFR: instantaneous wave-free ratio. MACE: major adverse cardiovascular events.

INTRODUCTION

The physiological assessment of coronary lesions is a routine practice in contemporary cath labs and is strongly recommended by the European guidelines to guide the percutaneous coronary intervention (PCI) decision-making process.1 Unlike fractional flow reserve, the new instantaneous wave-free ratio (iFR) index allows us to analyze the physiological significance of each lesion and each coronary segment.2-5 This has led to the creation of the new and specific SyncVision software package (SyncVision version 4.1.0.5, Philips Volcano, Belgium), that shows the functional compromise of each lesion and predicts the expected iFR improvement after percutaneous treatment.3,4

Few observational studies published have analyzed the reduction in the length of the stent implanted compared to angiography-guided revascularization in long and diffuse coronary lesions.4,5 However, this reduction could be detrimental to the complete coverage of the plaque in this type of lesions, which has proven to be a predictor of major adverse cardiovascular events at the follow-up.6

The objective of our study is to analyze the utility of the iFR and SyncVision software to guide the PCI decision-making process in long, sequential, and diffuse coronary lesions.

METHODS

We have designed a multicenter, randomized, controlled, and open-label trial to compare SyncVision/iFR-guided revascularization to angiography-guided revascularization in patients with long, sequential or diffuse significant angiographic coronary lesions (ClinicalTrials.gov identifier: NCT04283734). All the variables that will be analyzed during the study are shown on table 1.

Table 1. Variables that will be analyzed during the study

Variable Expressed as
Personal medical history
1 Sex (men/women) no. (%)
2 Age (years) no. ± SD
3 Hypertension no. (%)
4 Diabetes mellitus no. (%)
5 Dyslipidemia no. (%)
6 Former smoker no. (%)
7 Previous ischemic cardiomyopathy no. (%)
8 Previous revascularization no. (%)
9 Atrial fibrillation no. (%)
10 Heart failure no. (%)
11 Previous stroke no. (%)
12 Peripheral artery disease no. (%)
13 Previous significant bleeding no. (%)
14 Basal hemoglobin levels (mg/dL) no. ± SD
15 Basal creatinine levels (mg/dL) no. ± SD
16 Left ventricular ejection fraction (%) no. ± SD
17 Clinical presentation (stable angina/NSTEMI/STEMI) no. (%)
18 Baseline ultra-sensitive troponin levels (ng/L) no. ± SD
Procedural data
19 Arterial access (radial/femoral/other) no. (%)
20 P2Y12 inhibitor preload no. (%)
21 IIb/IIIa inhibitor use during the procedure no. (%)
22 Multivessel disease no. (%)
23 Syntax score no. ± SD
24 Randomized vessel (LAD/LCx/RCA/other) no. (%)
25 Vessel lesion length (mm) no. ± SD
26 Vessel reference diameter (mm) no. ± SD
27 Vessel stenosis (%) no. ± SD
28 Total stent length as seen on the angiography (mm) no. ± SD
29 Total length of the stent implanted (mm) no. ± SD
30 Differences between stent length estimated and implanted (mm) no. ± SD
31 Stent diameter (mm) no. ± SD
32 Optimal angiographic result (final TIMI III flow, absence of dissections and residual stenosis < 20%) no. (%)
33 Contrast (milliliters) no. ± SD
34 Use of intracoronary imaging no. (%)
35 Use of rotablation no. (%)
36 Procedural complications (no reflow/ dissection/acute vessel closure/perforation/other) no. (%)
37 Baseline iFR in the intervention group no. ± SD
38 Diffuse improvement of iFR by SyncVision no. (%)
39 Estimated stent length to achieve an iFR > 0.89 (mm) no. ± SD
40 Final iFR in the intervention group no. ± SD
41 Need to implant an additional stent no. (%)
Hospitalization data
42 Bleeding complications no. (%)
43 Ultra-sensitive troponin peak levels (ng/L) no. ± SD
44 Periprocedural myocardial infarction no. (%)
45 In-hospital death no. (%)
46 In-hospital stroke no. (%)
47 In-hospital stent thrombosis no. (%)
Pharmacological treatment at discharge
48 Aspirin no. (%)
49 P2Y12 Inhibitor (no/clopidogrel/ticagrelor/prasugrel) no. (%)
50 Anticoagulation (no/acenocumarol/rivaroxaban/ dabigatran/apixaban/edoxaban) no. (%)
51 Beta-blockers no. (%)
52 ACEI/ARB/ARNI no. (%)
53 Calcium antagonists no. (%)
54 Other anti-ischemic drugs no. (%)
Follow-up visits (after 3, 6, and 12 months)
55 Bleeding complications no. (%)
56 Dual antiplatelet therapy no. (%)
57 Anticoagulation (no/acenocumarol/rivaroxaban/ dabigatran/apixaban/edoxaban) no. (%)
58 Probable or definitive stent thrombosis no. (%)
59 Spontaneous myocardial infarction no. (%)
60 New target lesion revascularization no. (%)
61 New target vessel revascularization no. (%)
62 Revascularization of other vessel no. (%)
63 Death no. (%)
64 Cause of death (cardiac/non cardiac) no. (%)
65 Stroke no. (%)
66 Beta-blockers no. (%)
67 ACEI/ARB/ARNI no. (%)
68 Calcium antagonists no. (%)
69 Other anti-ischemic drugs no. (%)
70 Residual angina (I/II/III/IV) no. (%)
71 Withdrawal from the study no. (%)
72 Lost to follow-up no. (%)

ACEI, angiotensin-converting-enzyme inhibitors; ARB, angiotensin receptor blockers; ARNI, angiotensin receptor blocker and neprilysin inhibitor; LAD, left anterior descending coronary artery; LCx, left circunflex artery; RCA, right coronary artery; SD, standard deviation; TIMI, Thrombolysis in Myocardial Infarction. NSTEMI, non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction.

Inclusion and exclusion criteria

Patients with the following criteria are being included: a) patients > 18 years old who require percutaneous coronary treatment due to ischemia (silent, stable angina or acute coronary syndrome); b) presence of a vessel with sequential lesions separated by < 10 mm from each other with a total lesion length > 25 mm and a percent diameter stenosis > 60% (as seen on the quantitative coronary angiography assessment) in, at least, 1 segment; or a coronary segment > 30 mm with diffuse disease, and a percent diameter stenosis > 60% (as seen on the quantitative coronary angiography assessment) in, at least, 1 region; c) baseline iFR ≤ 0.89 distal to a potentially randomizable lesion.

We have stablished the following exclusion criteria: a) patients with acute coronary syndrome with non-optimal results in the culprit vessel (final Thrombolysis in Myocardial Infarction (TIMI) flow grade < III, non-reflow phenomenon during treatment, residual coronary dissection, lost or compromise of a major side branch); b) patients with acute coronary syndrome and left ventricular ejection fraction < 45%; c) life expectancy < 12 months; d) patients with severe aortic stenosis; e) contraindication for dual antiplatelet therapy for at least 12 months; f) presence of significant thrombocytopenia (< 10 x 109/L); g) patients with an indication for bypass surgery according to the heart team; h) pregnancy; i) inability to understand the informed consent.

Endpoints

The study primary endpoint is the reduction of the average length of the stent implanted in the SyncVision-guided group measured in millimeters (mm) compared to the angiography-guided group. The study secondary endpoint is a composite of cardiac death, myocardial infarction, definitive or probable stent thrombosis, new target lesion revascularization or new target lesion failure (major adverse cardiovascular events [MACE]); and the assessment of residual ischemia through single-photon emission computed tomography at the 6-month follow-up.

Procedure

After the diagnostic phase, the use of intracoronary vasodilators is mandatory to exclude possible coronary spasms. Lesions will be assessed by 2 expert operators (prior to randomization) to determine the coronary segment to treat when the revascularization is angiography-guided based on current routine clinical practice. Afterwards, the iFR will be determined at baseline. If the obtained iFR is ≤ 0.89, patients will be randomized to the angiography-guided revascularization group (the control group) or to the iFR pullback-guided revascularization group using the SyncVision software (figure 1). Intracoronary imaging can be used in both groups based on the operator’s criteria to optimize the angiographic result.

Figure 1. Summary of randomization, treatment targets, and follow-up of the iLARDI study. iFR, instantaneous wave-free ratio; MACE, major adverse cardiovascular events; PCI, percutaneous coronary intervention.

In the intervention group, a pressure wire (Verrata pressure guidewire, Philips Volcano, Belgium) will be inserted trough a guide catheter towards the vessel ostium to normalize the pressure between the aortic and the vessel ostium. Secondly, the pressure wire will be advanced distally to the lesion. Under stable hemodynamic conditions (without the administration of vasodilators), we will determine the baseline iFR. Afterwards, the wire will be removed under continuous fluoroscopy, and in the same projection. If the iFR at the vessel ostium is 1 ± 0.02, the absence of drift will be confirmed and an angiogram in the same angiographic position will be performed. The SyncVision software can recognize the vessel analyzed and identify the physiological contribution of every lesion and every segment, predicting the improvement of the iFR after treatment. The iFR improvement is depicted as yellow dots. Each yellow dot represents an iFR improvement of 0.01 if that zone was percutaneously treated. The accumulation of many yellow dots suggests that the contribution of that lesion to physiological compromise is high. After performing the physiological assessment of each lesion, the operator would have to treat the minimum segment needed to achieve an iFR of 0.90. Cases without an accumulation of dots have been considered as physiological diffuse disease (defined as the presence of < 20% of the total number of dots) in the coronary segment physiologically assessed. Those cases will be medically treated due to the theoretical absence of benefit of the percutaneous treatment (figure 2 and figure 3).

Figure 2. Flowchart of technical treatment details of patients randomized to the intervention group.

* We consider as optimization the postdilatation of the previous stented area if an in-stent accumulation of yellow dots is seen; or the percutaneous treatment of a new segment with physiological compromise not seen in the baseline iFR-pullback study. iFR, instantaneous wave-free ratio.

Figure 3. Image of iFR co-registration using the SyncVision software in a patient included in the study and randomized to the intervention group with a diffuse lesion in the left anterior descending coronary artery, and the physiological contribution of every segment. The estimated length of the stent to achieve an iFR > 0.89 is 50.6 mm.

Follow-up

Patients will be followed either through phone calls or physical examination at the 3, 6 and 12-month follow-up. At the 6-month follow-up a stress single-photon emission computed tomography (physiological or pharmacological) will be performed in all patients. The composite of cardiovascular death, definitive or probably stent thrombosis, new target lesion failure or new target lesion revascularization will be considered as MACE.

Quantitative coronary measurements

Quantitative coronary measurements will be performed using a validated system (CAAS system, Pie Medica Imaging, Netherlands). The measurements analyzed will be the vessel reference diameter, the vessel minimal lumen diameter, and the percentage of stenosis. All measurements will be taken at baseline and after the PCI.

Statistical analysis

Regarding the statistical analysis, quantitative variables will be expressed as mean ± standard deviation and qualitative variables as absolute numbers and percentages. To determine the relationship among quantitative variables, we will be using the paired Student t test for paired data. To determine the relationship among the qualitative ones, we will use the chi-squared test. In all cases, differences will be considered significant with P values < .05. We will be using the IBM SPSS Statistics software package (version 24.0 for Macintosh, SPSS Corp., United States). To calculate the sample size, we have performed a retrospective analysis of the last 20 patients who were treated at our centre and showed a sequential or diffuse lesion in the coronary vessel analyzed from the iFR-pullback study. The mean length of the stent implanted was 43 ± 9 mm and the reduction of stent length was 12 ± 8 mm on the angiographic analysis. With these data, we have stablished an expected length reduction of 15 mm. The calculated sample size to achieve the primary endpoint with an 80% confidence level and a 5% margin of error was 100 patients.

RESULTS

The recruitment of patients started back in February 2020. After 1 month, we have included the first 7 patients. We expect to complete the recruitment by February 2021 and the follow-up by February 2022.

DISCUSSION

To our knowledge, this randomized study is, the first one to assess the potential benefits of using the SyncVision software in long, sequential or diffuse coronary lesions. Currently, the study is in the recruitment phase and the first patients have already been recruited.

The iFR has proven to be useful in the PCI guide decision-making process.7,8 However, the evidence supporting the use of SyncVision is scarce and controversial in long, sequential or diffuse lesions. On the one hand, the software allows us to know the coronary segments with the highest physiological compromise. This allows us to revascularize only those segments that immediately improve the physiological result with a potential reduction of the length of the stent implanted, which happens to be a predictor of MACE at the follow-up.9 On the other hand, it’s possible that even if we obtain a good immediate physiological result and a reduction of the stent length implanted we won’t be fully covering the plaque in some lesions or coronary segments, which has also proven to be a predictor of MACE.6

A limitation of the study is the sample size, enough to achieve the primary endpoint, but probably inadequate to see differences in MACE. However, we think that it can provide an early insight on the utility of iFR pullback study to guide the PCI decision-making process in this type of lesion. Also, it can be a hypothesis-generator study for future larger-scale studies to show benefits in terms of clinical events reduction.

For these reasons, we believe that the iLARDI is an interesting study that will shows us the potential benefit of SyncVision to guide the PCI decision-making process in long, sequential or diffuse coronary lesions. We intend to complete the results by February 2022.

CONCLUSIONS

The iLARDI study is the first randomized trial to assess the potential utility of SyncVision-guided revascularization in long, sequential and diffuse coronary lesions.

FUNDING

Funds from the Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI) have been used to pay for the liability insurance associated with clinical research.

CONFLICTS OF INTEREST

F. Hidalgo, S. Ojeda, and J. Segura received personal fees from Philips Volcano. M. Pan received minor fees from Abbott, Philips Volcano, and Terumo. The remaining authors declared no conflicts of interest whatsoever.

WHAT IS KNOWN ABOUT THE TOPIC?

  • The physiological assessment of coronary lesions is a routine practice in the cath lab. The iFR and the SyncVision software allow us to know what is the individual contribution of every coronary lesion and contribute in the PCI decision-making process. However, to our knowledge, no randomized studies have been published on the utility of their use in long, sequential and diffuse coronary lesions.

WHAT DOES THIS STUDY ADD?

  • The iLARDI study will show the potential utility of SyncVision/iFR-guided revascularizations in this type of lesions (long, sequential and diffuse coronary lesions) regarding the reduction of the stent length and the potential reduction of major adverse cardiovascular events at the follow-up.

REFERENCES

1. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J. 2019;40:87-165.

2. Kim H-L, Koo B-K, Nam C-W, et al. Clinical and physiological outcomes of fractional flow reserve guided percutaneous coronary intervention in patients with serial stenosis within one coronary artery. JACC Cardiovasc Interv. 2012;5:1013?1018.

3. Nijjer SS, Sen S, Petraco R et al. The Instantaneous Wave-Free Ratio (iFR) pullback:a novel innovation using baseline physiology to optimise coronary angioplasty in tandem lesions. Cardiovasc Revasc Med. 2015;16:167-171.

4. Nijjer SS, Sen S, Petraco R et al. Pre-Angioplasty Instantaneous Wave-Free Ratio Pullback Provides Virtual Intervention and Predicts Hemodynamic Outcome for Serial Lesions and Diffuse Coronary Artery Disease. JACC Cardiovasc Interv. 2014;7:1386-1396.

5. Kikuta Y, Cook CM, Sharp ASP et al. Pre-Angioplasty Instantaneous Wave-Free Ratio Pullback Predicts Hemodynamic Outcome In Humans With Coronary Artery Disease. Primary Results of the International Mul-ticenter iFR GRADIENT Registry. JACC Cardiovasc Interv. 2018;11:757-767.

6. Costa MA, Angiolillo DJ, Tannenbaum M et al. Impact of Stent Deployment Procedural Factors on Long-Term Effectiveness and Safety of Sirolimus-Eluting Stents (Final Results of the Multicenter Prospective STLLR Trial). Am J Cardiol. 2008;101:1704-1711.

7. Davies JE, Sen S, Dehbi HM, Al-Lamee R, Petraco R, Nijjer SS et al. Use of instantaneous wave-free ratio or fractional flow reserve in PCI. N Engl J Med. 2017;376:1824-1834.

8. Gotberg M, Crhistiansen EH, Gudmundsdottir IJ, et al. Instantaneous wave-free ratio versus fractional flow reserve to guide PCI. N Engl J Med. 2017;376:1813?1823.

9. Coner A, Cicek D, Akinci S, et al. Mid-term clinical outcomes of new generation drug-eluting stents for treatment of diffuse coronary artery ||aadisease. Turk Kardiyol Dern Ars. 2018;46:659-666.

Corresponding author: Servicio de Cardiología, Hospital Universitario Reina Sofía, Avenida Menéndez Pidal 1, 14004 Cordoba, Spain.
E-mail address: (F. Hidalgo Lesmes).

ABSTRACT

Introduction and objectives: There is great interest in the development of devices for the percutaneous management of mitral regurgitation (MR). For this reason, having an experimental model that reproduces the conditions of the disease is of great importance. Our objective was to validate an experimental model of MR in a porcine model.

Methods: For the model creation phase 3, 2-month-old 25 ± 3 kg large white pigs were used. An acute myocardial infarction was caused in the circumflex artery territory that hampered the perfusion of the posteromedial papillary muscle. Then, volume overload was induced in the animal by creating an arteriovenous shunt and connecting the aorta and the pulmonary artery using a Dacron tube. Echocardiography and magnetic resonance imaging were performed before the intervention and on week 8. Afterwards, the animal was euthanized to conduct the pathological study.

Results: One out of the 3 pigs died during the intervention due to ventricular fibrillation. The remaining 2 pigs survived the procedure and were euthanized as scheduled on week 8. In both cases a transmural infarction occurred, 1 at lateral level and the other one at posteroinferior level with moderate secondary mitral regurgitation. Ventricular dimensions and volumes increased and the overall contractility was maintained despite segmental alterations.

Conclusions: The experimental model of chronic MR based on the ischemic damage of the posteromedial papillary muscle associated with volume overload is feasible, safe and reproducible. Also, it can be very useful to test the safety and efficacy of future devices for the management of this condition.

Keywords: Mitral regurgitation. Experimental model. Porcine model.

RESUMEN

Introducción y objetivos: Existe un creciente interés en el desarrollo de dispositivos para el tratamiento de la insuficiencia mitral (IM) de forma mínimamente invasiva. Para este propósito, disponer de un modelo experimental que reproduzca las condiciones de la enfermedad sería de gran utilidad. Nuestro objetivo fue validar un modelo experimental de IM en cerdos.

Métodos: Para esta fase de creación del modelo se han utilizado 3 cerdos de raza large white, de 2 meses de edad y un peso de 25 ± 3 kg. Se provocó un infarto en el territorio de la arteria circunfleja que afectó la perfusión del músculo papilar posteromedial, y posteriormente se sometió al animal a una sobrecarga de volumen mediante creación de un shunt arteriovenoso, con la conexión de la aorta y la pulmonar mediante un tubo de dacrón. Se realizó análisis mediante ecocardiografía y resonancia magnética antes de la intervención y a las 8 semanas, y posteriormente el animal fue eutanasiado para realizar el estudio anatomopatológico.

Resultados: De los 3 cerdos, 1 falleció durante la intervención por fibrilación ventricular y los otros 2 sobrevivieron al procedimiento y fueron eutanasiados como estaba previsto a las 8 semanas. En ambos se produjo un infarto transmural, uno lateral y otro posteroinferior, con IM moderada secundaria. Las dimensiones y los volúmenes ventriculares aumentaron, y la contractilidad global se mantuvo a pesar de las alteraciones segmentarias.

Conclusiones: El modelo experimental de IM crónica basado en el daño isquémico del músculo papilar posteromedial asociado a una sobrecarga de volumen es factible, seguro y reproducible, y puede ser de gran utilidad para comprobar la seguridad y la eficacia de los futuros dispositivos para el tratamiento de esta afección.

Palabras clave: Insuficiencia mitral. Modelo experimental. Modelo porcino.

Abbreviations: MR: mitral regurgitation.

INTRODUCTION

Mitral valve repair surgery is the treatment of choice for the management of patients with severe mitral regurgitation (MR) who meet the criteria and indications proposed in the clinical practice guidelines.1 However, almost 50% of the patients referred to surgery are not operated on,2,3 mainly due to the presence of comorbidities, left ventricular dysfunction or age related issues.4 In these cases, the use of transcatheter techniques has become a valid alternative.

Given the complexity of the mitral valve, there are several devices in the pipeline to reduce the degree of regurgitation using transcatheter approaches.5,6 Of all the devices available, very few have been eventually used for the management of patients. Among these, only MitraClip—inspired in the Alfieri technique—has proven great clinical utility.7-9

That is why it is important to have an animal model of MR available to test the safety, efficacy, and tissue response of these new devices in a scenario that reproduces the future clinical situations we may encounter faithfully. Our objective was to assess the feasibility of creating an experimental model of MR capable of reproducing the actual conditions with an acceptable safety and efficacy profile.

METHODS

Animal model

Different experimental models have been described by the medical literature to induce MR by causing ischemic damage through the selective occlusion of the circumflex artery and rupture of a mitral chorda tendinae,10 the production of ischemia in both the circumflex and right coronary arteries11 or the production of selective ischemia in the marginal arteries that supply the papillary muscle.12 A Spanish group studied the role of atrial infarction in ischemic MR and atrial and ventricular remodeling through the occlusion of the circumflex artery before or after the origin of the atrial branch.13 The models based on the production of ischemic damage only caused moderate MR. Only the model designed by Cui et al.,10 that combined mitral chordae tendinae ruptures with the corresponding volume overload, induced severe regurgitation. Our group designed a new model to induce MR by combining ischemic damage and the creation of an aortopulmonary shunt as the mechanism of volume overload.

To create this experimental model, 3 Large White domestic pigs were used. They were 2 months old and weighted 25 ± 3 kg. All procedures were performed in full compliance with the national legislation in force (Royal Decree 53/2013 of February 1st on the basic standards for the protection of animals used for scientific purposes) and European Directive 2010/63/EU.

The echocardiographic studies were conducted using a Vivid I GE ultrasound system with 3S cardiac sector probe (1.5-4 MHz). Parasternal short-axis and long-axis slice planes and apical 4-chamber planes were acquired.

The magnetic resonance imaging study was conducted using a Signa HDx 3.0 T GE MR system through FIESTA balanced steady-state free precision multifarious sequences of specific cardiac planes (of 2, 3, and 4 chambers, and in the short axis) to assess both the anatomy and the cardiac function. All images were processed using the ReportCard 4.0 software package.

Conceiving the experimental model

Anesthetic procedure to perform the procedure destined to induce MR and magnetic resonance imaging study

On the day of the surgery, anesthetic premedication was administered based on a combination of midazolam (0.35 mg/kg, Midazolam Normon, Normon), ketamine (5 mg/kg, Imalgene 1000, Merial), and methadone (0.1 mg/kg, Semfortan, Dechra) via intramuscular access. After confirming the correct sedation of the animals, preoxygenation with oxygen mask at 100% concentration was administered. Then, venoclysis was performed in the marginal atrial vein using a 20-gauge endovenous catheter followed by maintenance fluid therapy with lactated Ringer’s solution at an infusion rate of 10 mL/kg per hour. Propofol (2-4 mg/kg, Propovet, Esteve) was used for the induction of anesthesia followed by conventional tracheal intubation. The maintenance anesthetic agent used was sevoflurane (Sevorane, Abbot) at a dose of 1-1.5 MAC. Fentanyl (Fentanest, Janssen) was the intraoperative analgesic used. It was administered through a slow IV bolus of 5 µg/kg and followed by the continuous infusion of a 6 µg/kg/hour dose during the entire procedure. Bail-out doses were administered if necessary.

Prior to the thoracotomy the neuromuscular blocking agent atracurium (Tracrium, Glaxo SmithKline) was administered intravenously at a dose of 0.25 mg/kg. This dose was repeated after 30 minutes if necessary.

As an additional analgesic measure and prior to performing the thoracotomy, intercostal nerve block was achieved using bupivacaine at 0.5% (Bupivacaine, Braun) at a dose of 2 mg/kg in 5 sites: the intercostal space of the surgical site, 2 cranial spaces, and 2 spaces immediately caudal to this one.

The anticoagulant therapy used was sodium heparin at a dose of 200 IU/kg via IV access. The antiarrhythmic therapy used was an infusion of amiodarone (Trangorex, Sanofi-Aventis) at a dose of 5 mg/kg every hour.

Volume controlled ventilation was used during the entire procedure. The ventilator parameters used were: inspired oxygen fraction (0.4), tidal volume (10 mL/kg) by controlling maximal inspiratory pressure and adjusting respiratory rate based on the volume per minute and partial pressure of carbon dioxide, inspiratory/expiratory ratio (1:2-1:3) (based on arterial oxygenation and arterial pressures), inspiratory pause time (10%), and positive end-expiratory pressure of 4 that gradually went up to 8 after the thoracotomy. Alveolar recruitment maneuvers were performed every 20 minutes to avoid alveolar collapse and atelectases.

Vital signs were monitored every 10 minutes and arterial blood-gas tests were performed by measuring the ventilator parameters during the procedure.

During the immediate postoperative 1.6 mg/kg of furosemide (Seguril, Aventis) and 4 mg/kg of carprofen (Rimadyl, Pfizer) were administered via IV access. The postoperative analgesic agent used was transdermal fentanyl (Durogesic, Janssen) at a dose of 50 µg/h within the first 72 hours followed by buprenorphine (Buprex, Life) at a dose of 0.01 mg/kg via subcutaneous access every 8 hours for 3 days. Also, oral carprofen (Rimadyl) was administered at a dose of 4 mg/kg every 24 hours as anti-inflammatory therapy for 5 days followed by a 9-day course of oral amoxicillin-clavulanic acid (Synulox, Pfizer) at a dose of 20 mg/kg every 12 hours as antibiotic therapy.

The protocol to perform the magnetic resonance imaging included the administration, on the day of the procedure, of anesthetic premedication: a combination of midazolam (0.35 mg/kg, Midazolam Normon) and ketamine (5 mg/kg, Imalgene 1000) via intramuscular access. Once the correct sedation of the animals was confirmed, they were transferred to the preparation area and preoxygenation with oxygen mask at 100% concentration was started. Then, venoclysis was performed in the marginal atrial vein using a 20-gauge endovenous catheter. Propofol (2-4 mg/kg, Propovet) was used for the induction of anesthesia followed by conventional tracheal intubation. Sevoflurane (Sevorane) at 1-1.5 CAM was used as maintenance anesthesia.

Mechanical ventilation followed the same parameters as during the entire procedure with periodic monitoring of the vital signs and arterial blood-gas tests.

Inducing the infarction in the circumflex artery territory

After anesthetizing the animal, its thorax was opened, and the pericardium dissected to access the circumflex coronary artery and induce the infarction in this artery through surgical ligation. Prior to this an injection of contrast and echocardiographic study were used to see what branches of this artery were supplying the posteromedial papillary muscle. Once identified, ligation was attempted to occlude the 2 and 3 obtuse marginal arteries to avoid inducing a massive MR.

Creation of an arteriovenous shunt

After the infarction volume overload was attempted through the creation of an arteriovenous shunt by connecting a branch of the pulmonary artery to the aorta using a Dacron tube graft. This procedure was performed with clamping and without extracorporeal circulation.

After performing both procedures the thorax was closed, and the pig was transferred to its storage facility the for control and maintenance.

Follow-up

The presence of MR and the effect of cardiac remodeling were assessed through echocardiographic and magnetic resonance imaging 8 weeks after the procedure and through ventriculography during euthanasia.

The degree of MR was assessed with an ultrasound scan using semi-quantitative methods (estimation of color area, vena contracta). In these ultrasound and MRI studies the volumes of the cardiac chambers (right and left ventricular diameters and volumes, left atrial diameters and volumes) and their function were measured.

Anatomopathological study

At the 8-week follow-up, the animals were euthanized following the directives established by Royal Decree 53/2013 on animal protection.

A complete, organized, and systematic necropsy of each animal corpse was conducted to identify and diagnose any possible conditions associated with the procedure. The samples obtained were fixed in formaldehyde at 10% for histopathological study. In the macroscopic study of the heart, its weight was recorded and its cavities, walls, papillary muscles, mitral chordae tendinae, annulus, and valve leaflets analyzed. All the possible anomalies seen in these structures were documented photographically. Afterwards, the leaflets were extracted from their insertion location and up to their free borders including their chordae tendinae and they were fixed in formaldehyde at 10% and included in paraffin for histopathological study. Three µm thick serial sections were stained with the usual hematoxylin and eosin technique; the Van Gieson elastin stain protocol was used to study elastic and collagen fibers; the Masson trichrome stain protocol was used to differentiate muscular from collagen fibers; finally, the alcian-blue PAS staining protocol was used for the detection of mucopolysaccharides. The histopathological changes identified were semi-quantitatively assessed by establishing the different degrees of damage.

After collecting the leaflets to characterize the infarction, another 4 cross-sectional cuts were performed from the vertex of the heart towards its base. They were weighted and stained with triphenyltetrazolium chloride histochemical staining to enhance the viable area (red color) of the necrotic region (white color). For that purposes, the levels established were submerged in a solution of triphenyltetrazolium chloride (Sigma-Aldrich) at 1% in a phosphate buffered saline solution (pH 7.4) for 5 to 10 minutes at 37 °C, and then they were submerged in formaldehyde at 10%. The sections were photographed, and the areas measured using the Image J system. Samples of the infarction region, limit, and non-infarcted region were collected from every level, submerged in paraffin, and stained using the hematoxylin and eosin technique and the Masson trichrome stain protocol to characterize ischemic damage.

RESULTS

The first animal died during the procedure due to an unresponsive ventricular fibrillation; the remaining 2 completed the 8-week follow-up without complications.

Echocardiographic study

Animal #1

Echocardiographic data at baseline and at the 8-week follow-up from the parasternal short-axis and apical 4-chamber planes are shown on table 1. In the baseline study, ventricular thickness at anteroseptal level was 10.6 mm and at posteroinferior level, 9 mm. The mitral valve was morphologically normal with thin normally moving leaflets and no regurgitation on the color Doppler ultrasound. At the 8-week follow-up there were segmental alterations of contractility that were seriously hypokinetic in the 3 segments of the lateral side with hypercontractility of the remaining segments. Also, a mitral valve with a thickened posterior leaflet and low motility, and moderate mitral regurgitation in the form of posteriorly directed eccentric regurgitation jet was seen too.

Table 1. Echocardiographic data at baseline and at the 8-week follow-up (animal #1)

LVEDD (mm) LVESD (mm) FS (%) EF (%) Color area (cm2) Vena contracta (mm)
Baseline 46 30 34 62 0 0
8-week follow-up 49 32 34 60 4 4

EF, ejection fraction; FS, fractional shortening; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter.

Animal #2

Echocardiographic data at baseline and at the 8-week follow-up are shown on table 2. In the baseline study, ventricular thickness at anteroseptal level was 9 mm and at posteroinferior level, 6 mm. The mitral valve was morphologically normal with thin normally moving leaflets and no sign of regurgitation on the color Doppler ultrasound. At the 8-week follow-up, segmental alterations of contractility were seen in the medium and basal segments of the posterior side, a mitral valve with thickening of both leaflets, and moderate mitral regurgitation in the form of a mitral regurgitation central jet.

Table 2. Echocardiographic data at baseline and at the 8-week follow- (animal #2)

LVEDD (mm) LVESD (mm) FS (%) EF (%) Color area (cm2) Vena contracta (mm)
Baseline 44 28 36 65 0 0
8-week follow-up 47 30 36 63 6 5

EF, ejection fraction; FS, fractional shortening; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter.

Magnetic resonance imaging

The baseline study showed ventricles of normal dimensions, thickness, and also normal overall and segmental contractility for our cath lab in similar populations.

The 8-week follow-up revealed segmental alterations of contractility, lateral wall thinning, and fat transformation at posterior level in pig #1 and at posteroinferior level in pig #2 (figure 1). Ventricular volumes grew 10% and 7%, respectively.

Figure 1. Magnetic resonance imaging of animal #2. Short axis of the left ventricle. Presence of fat transformation at posterior level.

The values found in this study are shown on table 3 and table 4.

Table 3. MRI study at baseline and at the 8-week follow-up (animal #1)

LVEDD (mm) LVESD (mm) LVEDV (ml) LVESV (ml) EF (%) Left atrium (cm2)
Baseline 46 31 68 29 57 12
8-week follow-up 49 32 75 30 60 14

EF, ejection fraction; LVEDD, left ventricular end-diastolic diameter; LVEDV, left ventricular end-diastolic volume; LVESD, left ventricular end-systolic diameter; LVESV, left ventricular end-systolic volume.

Table 4. MRI study at baseline and at the 8-week follow-up (animal #2)

LVEDD (mm) LVESD (mm) LVEDV (ml) LVESV (ml) EF (%) Left atrium (cm2)
Baseline 42 29 58 29 50 10
8-week follow-up 44 31 62 30 52 11

EF, ejection fraction; LVEDD, left ventricular end-diastolic diameter; LVEDV, left ventricular end-diastolic volume; LVESD, left ventricular end-systolic diameter; LVESV, left ventricular end-systolic volume.

Anatomopathological study

Animal #1

The macroscopic examination revealed an infarction region in the lateral side from apical to basal level. The use of triphenyltetrazolium chloride stain confirmed the occurrence of a transparietal infarction (figure 2) whose size is shown on table 1 of the supplementary data together with the weight of each level.

Figure 2. Animal #1. Presence of transparietal infarction areas from basal (A) to apical level (D). Triphenyltetrazolium chloride stain.

The mitral valve showed a thickened posterior leaflet without damage to the anterior one. Microscopically, the posterior leaflet showed focal thickening with increased deposition of mucopolysaccharides and vascularization of the proximal part with distal reduction in the number of vessels. The infarction regions were histologically characterized by the presence of mature connective tissue including islets of cardiac muscle fibers and inflammatory cells.

Animal #2

The macroscopic evaluation revealed the presence of a transparietal infarction region in the posterior side damaging the medium and basal segments (figure 3) and papillary muscle (figure 4). The spread of this lesion into the different levels is shown on table 2 of the supplementary data.

Figure 3. Animal #2. Presence of transparietal infarction areas from medium (B) to basal level (D). Triphenyltetrazolium chloride stain.

Figure 4. Papillary muscle lesion. Lower part of level C. Triphenyltetrazolium chloride stain.

In the macroscopic examination, the mitral valve showed thickened leaflets with hemorrhages in their atrial surface (figure 1A of the supplementary data). Histologically and added to the already mentioned hemorrhages, both leaflets appeared thickened due to the deposition of mucopolysaccharides, especially in the middle layer (figure 1B,C of the supplementary data). Small caliber vessels were seen together with a mild inflammatory response figure 2 of the supplementary data. The infarction regions were characterized by the presence of mature connective tissue including islets of cardiac muscle fibers with similar characteristics compared to animal #1.

DISCUSSION

Our group developed a safe and feasible experimental porcine model to induce ischemic MR after causing an infarction associated with volume overload by creating an aortopulmonary shunt.

Currently, several studies on experimental models (sheep and pigs, basically) have been conducted to induce and maintain MR. All of them have pros and cons and imitate different etiologies of MR such as dilated cardiomyopathy, ischemic MR, and even rupture of a mitral chorda tendinae.

In the model of ischemic MR, Llaneras et al.14 were able to induce MR in sheep through obtuse marginal artery ligation. The authors said that for this event to appear 2 prerequisites are required: a) the papillary muscle needs to be infarcted; b) the ventricle needs to be dilated. With just 1 of the 2 requirements no MR would be induced. In their results, the ligation of marginal arteries 2 and 3 induced a gradually developing MR. On the other hand, the ligation of marginal arteries 2, 3 plus the posterolateral artery led to the development of a massive MR with high lethality.

This model has been modified later on by inducing MR through the rupture of a mitral chordae tendinae and the association of an ischemic event in the territory of the circumflex artery by implanting an aneroid.10 This would induce an ischemic lesion with a dysfunctional papillary muscle and volume overload. However, the uncontrolled rupture of a mitral chorda tendinae may lead to a high mortality rate in animals when inducing massive MR, which is often poorly tolerated. The adverse events of the animals or if some of them died during the procedure was not reported in this study.

Considering the pros and cons of the models described, our objective was to create a sustainable model of ischemic MR that, according to the medical literature, seems to be reproducible. To that end, taking into consideration what has already been described in former studies, the model of ischemic damage to the posteromedial papillary muscle associated with volume overload seems to be the safest and most effective one. Since volume overload following the rupture of a chorda or the production of a major myocardial infarction can induce massive MR and severe deterioration of the animal, our objective was to create an arteriovenous shunt as a safe way to induce volume overload since former studies have proven that the creation of a systemic-to-pulmonary shunt induces biventricular remodeling.15

In our study we induced a small size acute myocardial infarction probably due to the isolated occlusion of the obtuse marginal arteries. Other authors occluded the marginal and posterolateral arteries too, which induced bigger acute myocardial infarctions, but at a price of a significantly higher mortality rate, which is why in our study we decided to occlude obtuse marginal arteries only.

Maybe the small size of the acute myocardial infarction was the cause for the moderate MR and discrete ventricular remodeling induced (10% and 7% increase in pigs #1 and #2) yet despite the segmental alterations of contractility seen. However, the possibility that an arteriovenous shunt of inadequate magnitude contributed to this cannot be discarded.

Finally, the possibility that in this model there is a mixed etiology for mitral regurgitation cannot be discarded either: the anatomopathological analyses revealed morphological anomalies in mitral leaflets, meaning that regurgitation would not be strictly functional only. This brings about new hypotheses on the repercussions of hemodynamic overload on mitral leaflets that may go beyond annular dilatation or the ischemic restriction of its movement.

Limitations

The limitations of our study are associated with its small sample size, which is a problem when trying to draw definitive conclusions. However, we think it is very useful to disclose this new experimental model to induce ischemic MR through coronary ligation and volume overload by the creation of an aortopulmonary shunt. However, the results should be confirmed in future studies.

Whether ventricular remodeling impacts the creation of the aortopulmonary shunt is still unknow. In light of this study results, future phases of this model should analyze whether the magnitude of the shunt truly impacts ventricular remodeling.

Infarcts created through surgical ligation of the circumflex artery were small. Maybe the implantation of a coil or other occlusion devices into the proximal circumflex artery would have induced bigger infarctions. In any case, the study design anticipated the surgical approach since a thoracotomy would be needed to create the arteriovenous shunt.

Another possible limitation may be the short period of time animals were followed (8 weeks). This may explain why the remodeling process after the acute myocardial infarction was not completed, which is the reason why ventricular volumes did not reach greater dimensions.

CONCLUSIONS

In our own early experience, the experimental model of chronic MR based on ischemic damage to the posteromedial papillary muscle and associated with volume overload is feasible, safe, and reproducible. It may be useful to assess the safety and efficacy profile of future devices for the management of this heart disease.

FUNDING

This study was partially funded through a grant from the Regional Healthcare Management of Castille and León, Spain (GRS1396_A_16).

CONFLICTS OF INTEREST

R. Estévez-Loureiro is a proctor for MitraClip and received a research grant from Abbott Vascular. A. Pérez de Prado participated and received funding for his consultancy job done for Boston Scientific and iVascular SL, and lectures given for Abbott, Braun Surgical, Terumo Medical Corporation, and Philips Volcano. The remaining authors declared no conflicts of interest whatsoever.

SUPPLEMENTARY DATA

WHAT IS KNOWN ABOUT THE TOPIC?

  • MR is the second most common valve disease. Mitral valve repair surgery is the standard treatment, but over 50% of the patients are not operated on due to their comorbidities.
  • There are several devices available today to reduce the degree of regurgitation through transcatheter approaches. Also, there are several studies on experimental models to induce and maintain MR in order to test these devices. All of them have pros and cons and imitate different etiologies of MR such as dilated cardiomyopathy, ischemic MR, and even rupture of a mitral chorda tendinae.
  • After studying the models already published, 2 are the prerequisites to induce a sustainable model of MR: ischemic lesion with damage to the papillary muscle, and ventricular dilatation.

WHAT DOES THIS STUDY ADD?

  • A new experimental model to induce ischemic MR by combining the production of ischemic damage through the coronary occlusion of the branches supplying the papillary muscle and left ventricular volume overload with aortopulmonary sunt following the implantation of a Dacron tube graft between the aorta and a pulmonary branch.
  • We should mention that none of the animals survived surgery and died at the follow-up, which is indicative of a feasible and safe model of ischemic MR.

REFERENCES

1. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2017;38:2739-2791.

2. Mirabel M, Iung B, Baron G, et al. What are the characteristics of patients with severe, symptomatic, mitral regurgitation who are denied surgery?Eur Heart J. 2007;28:1358-1365.

3. Borger MA, Alam A, Murphy PM, Doenst T, David TE. Chronic ischemic mitral regurgitation:repair, replace or rethink?Ann Thorac Surg. 2006;81:1153-1161.

4. Jamieson WR, Edwards FH, Schwartz M, Bero JW, Clark RE, Grover FL. Risk stratification for cardiac valve replacement. National Cardiac Surgery. Ann Thorac Surg. 1999;67:943-951.

5. Herrmann HC, Maisano F. Transcatheter therapy of mitral regurgitation. Circulation. 2014;130:1712-1722.

6. Maisano F, Alfieri O, Banai S, et al. The future of transcatheter mitral valve interventions:competitive or complementary role of repair vs. replacement?Eur Heart J. 2015;36:1651-1659.

7. Mauri L, Foster E, Glower DD, et al. 4-year results of a randomized controlled trial of percutaneous repair versus surgery for mitral regurgitation. J Am Coll Cardiol. 2013;62:317-328.

8. Nickenig G, Estevez-Loureiro R, Franzen O, et al. Percutaneous Mitral Valve Edge-to-Edge Repair:In-Hospital Results and 1-Year Follow-Up of 628 Patients of the 2011-2012 Pilot European Sentinel Registry. J Am Coll Cardiol. 2014;64:875-84.

9. Maisano F, Franzen O, Baldus S, et al. Percutaneous mitral valve interventions in the real world:early and 1-year results from the ACCESS-EU, a prospective, multicenter, nonrandomized post-approval study of the MitraClip therapy in Europe. J Am Coll Cardiol. 2013;62:1052-1061.

10. Cui YC, Li K, Tian Y, et al. A pig model of ischemic mitral regurgitation induced by mitral chordae tendinae rupture and implantation of an ameroid constrictor. PloS One. 2014;9:e111689.

11. Minakawa M, Robb JD, Morital M, et al. A model of ischemic mitral regurgitation in pigs with three-dimensional echocardiographic assessment. J Heart Valve Dis. 2014;23:713-720.

12. Hamza O, Kiss A, Kramer AM, Tillmann KE, Podesser BK. Characterization of a novel percutaneous closed chest swine model of ischemic mitral regurgitation guided by contrast echocardiography. Eurointervention. 2019. pii:EIJ-D-19-00095.

13. Aguero J, Galan-Arriola C, Fernandez-Jimenez R, et al. Atrial Infarction and Ischemic Mitral Regurgitation Contribute to post-MI Remodeling of the Left Atrium. J Am Coll Cardiol. 2017;70:2878-2889.

14. Llaneras MR, Nance ML, Streicher JT, et al. Large animal model of ischemic mitral regurgitation. Ann Thorac Surg. 1994;57:432-439.

15. Pereda D, García-Lunar I, Sierra F, et al. Magnetic Resonance Characterization of Cardiac Adaptation and Myocardial Fibrosis in Pulmonary Hypertension Secondary to Systemic-To-Pulmonary Shunt. Circ Cardiovasc Imaging. 2016;9:e004566.

Corresponding author: Unidad de Cardiología Intervencionista, Hospital Álvaro Cunqueiro, Estrada de Clara Campoamor 341, 36213 Vigo, Pontevedra, Spain.
E-mail address: (R. Estévez-Loureiro).

ABSTRACT

Introduction and objectives: Between 10% and 25% of patients hospitalized due to an acute coronary syndrome develop acute kidney injury, a condition associated with higher morbidity and mortality rates. Scores have been developed to predict the occurrence of post-coronary angiography contrast-induced nephropathy (CIN) in patients with acute coronary syndrome. The objective of this study was to assess the association between microalbuminuria and post-coronary angiography CIN in patients with acute coronary syndrome.

Methods: Patients admitted with acute coronary syndrome in whom a coronary angiography was performed during their hospitalization and with urinary albumin-to-creatinine ratio (ACR) assessment within the first 24 hours were analyzed. The best ACR cutoff value for coronary angiography-induced CIN was determined using the C-statistic measure. The receiver operating characteristic (ROC) curves were built to compare between the predictive ability of the Mehran score alone and also in combination with the ACR.

Results: A total of 148 patients were analyzed. Median age was 64 years (56-73), 35% were women, mean creatinine clearance rate at admission was 86 mL/min (66-107) and the ACR was 5 mg/g (0-14). The analysis showed that 9.6% of the patients developed post-coronary angiography CIN with ACR levels ≥ 20 mg/g compared to 1.6% when these levels were < 20 mg/g. The area under the ROC curve of the Mehran score to predict the development of post-coronary angiography CIN was 0.75 (95%CI, 0.68-0.81) and when the ACR was added it went up to 0.82 (95%CI, 0.76-0.87).

Conclusions: The ACR levels at admission were associated with the development of post-coronary angiography CIN and bring added value to an already validated predictive score. Therefore, the ACR should be used as a simple and accessible tool to detect and prevent this severe complication in patients with acute coronary syndrome.

Keywords: Contrast media. Coronary angiography. Microalbuminuria. Contrast-induced nephropathy. Urine albumin-to-creatinine ratio.

RESUMEN

Introducción y objetivos: Entre el 10 y el 25% de los pacientes hospitalizados por síndrome coronario agudo desarrollan insuficiencia renal aguda, lo que aumenta la morbimortalidad. Existen escalas para predecir la aparición de nefropatía inducida por contraste (NIC) tras la realización de una angiografía coronaria en pacientes con síndrome coronario agudo. El objetivo de este estudio fue evaluar la asociación entre el índice albúmina-creatinina (IAC) urinario y el desarrollo de NIC tras una angiografía coronaria en pacientes con síndrome coronario agudo.

Métodos: Se analizaron pacientes internados por síndrome coronario agudo a quienes se realizó angiografía coronaria durante el ingreso, con el cálculo del IAC en las primeras 24 horas. Se determinó el mejor valor de corte por curva ROC (Receiver Operating Characteristic)del IAC asociado a NIC. Se compararon las curvas ROC de la escala de Mehran sola y con el agregado de la variable de IAC.

Resultados: Se analizaron 148 pacientes. La mediana de la edad fue de 64 años (56-73), el 35% eran mujeres, el aclaramiento de creatinina fue de 86 ml/min (66-107) y el IAC de 5 mg/g (0-14). El 9,6% de los pacientes desarrollaron NIC tras la angiografía coronaria cuando su IAC fue ≥ 20 mg/g y el 1,6% cuando fue < 20 mg/g. El área bajo la curva ROC de la escala de Mehran para predecir el desarrollo de NIC tras la angiografía coronaria fue de 0,75 (intervalo de confianza del 95% [IC 95%], 0,68-0,81); cuando se agregó la variable de IAC fue de 0,82 (IC 95%, 0,76-0,87).

Conclusiones: El IAC basal se asoció con el desarrollo de NIC tras la angiografía coronaria. Al añadirlo a la escala de Mehran aumentó la capacidad discriminativa. El IAC podría ser una herramienta de simple uso, bajo costo y amplia disponibilidad para detectar pacientes en riesgo de desarrollar NIC y adoptar medidas preventivas apropiadas.

Palabras clave: Contraste intravenoso. Angiografía coronaria. Microalbuminuria. Nefropatía inducida por contraste. Índice albúmina-creatinina urinario.

Abbreviations: ACR: Albumin-to-creatinine ratio. ACS: Acute coronary syndrome. AKI: Acute kidney injury. CIN: Contrast-induced nephropathy.

INTRODUCTION

Renal function impairment is associated with poor prognosis in patients with stable or acute coronary syndrome (ACS). One of the most common causes of acute kidney injury (AKI) in hospitalized patients is the nephropathy induced by the IV administration of contrast agents.1Its incidence varies between 1% and 6%, and increases considerably in high-risk conditions like in the ACS setting. The reported frequency of post-coronary angiography contrast-induced nephropathy (CIN) goes from 12% to 46% in patients with ACS.2,3

There are several potential causes that trigger CIN in patients without a past medical history of kidney failure such as hemodynamic instability, the IV administration of contrast agents, thromboembolic events, and adverse drug reactions, among others. Also, it is important to consider the type of contrast used, its osmolarity, the volume administered, and the lack of preventive measures.4-6

Because CIN is associated with poor prognosis in hospitalized patients, predictive scores have been designed to identify the most vulnerable patients who can develop this complication. The Mehran score is one of the most popular indices to estimate the chances of post-coronary angiography CIN.7

It is well-established that microalbuminuria is a predictor of kidney dysfunction mainly in diabetic and hypertensive patients.8-14Also, there is a correlation between high levels of microalbuminuria and the poor outcomes seen in patients with ACS.15-16 Currently, microalbuminuria is estimated through the dosage of the albumin-to-creatinine ratio (ACR) through a simple urine sample.17

The objective of this study is to calculate microalbuminuria using the ACR as a predictive variable of post-coronary angiography CIN in patients with ACS.

METHODS

Population

Patients with ACS consecutively admitted to the coronary care unit of a community hospital were analyzed. Those undergoing an in-hospital coronary angiography with non-ionic, hyperosmolar IV contrast agents such as iopamidol, optiray or xenetix, were included in the study. The volume of IV contrast for each angiographic study was calculated retrospectively. It was estimated that each injection of contrast material into the left coronary artery required an average 10 cc to 8 cc for the right coronary artery.

Patients with a past medical history of renal failure, macroalbuminuria, treatment with diuretics and patients with secondary angina were excluded from the study.

The urinary ACR was assessed in all patients included in the study using an immunoturbidimetric assay in simple urine samples within the first 24 hours after hospitalization.

Definitions

IV contrast-induced nephropathy(CIN) was defined as an increase in serum creatinine levels ≥ 25% 48 hours after performing the coronary angiography or an absolute increase of ≥ 0.5 mg/dL compared to levels at admission.

Microalbuminuria was defined as an abnormal urinary albumin excretion rate between 30 to 200 mg/min or 30 to 229 mg/day.

The study protocol was approved by the center review board and conducted in compliance with the Declaration of Helsinki, good clinical practice guidelines, and local regulatory requirements. Informed consents were obtained from all patients.

Biochemical considerations

A urine sample collected within the first 24 hours after admission (preferably during morning hours) was centrifuged at 3000 rpm and stored at -20° Celsius until biochemical analysis was conducted. The principle of the ACR test is immunoturbidimetry. This method is based on the reaction of human albumin antibodies to the antigen. Complexes are then measured after agglutination. The COBAS 6000 analyzer (ROCHE, Switzerland) was used to process the sample. The analytical detection limits of the assay were between 3 mg/g and 400 mg/g. The test variation coefficient was 3.8%.

Statistical analysis

The Kolmogorov-Smirnov test was used to analyze the distribution of continuous variables and their kurtosis-skewness measures. Data were expressed as mean and standard deviation or as median with interquartile range (25%-75%) and compared using Student’s t test or Mann-Whitney-Wilcoxon test for independent groups according to their parametric or non-parametric distribution, respectively.

Discrete variables were expressed as percentages and compared using the chi-square test. The cross-product ratio was expressed as odds ratio (OR) with its 95% confidence interval (95%CI). The C-statistic measure was used to detect the best ACR cutoff value associated with the primary endpoint and compare the discrimination capacity of the Mehran score alone and with the ACR combined.

A multivariable regression analysis will be built to predict CIN including ACR and adjusted using the Mehran score.

Both the IBM SPSS Statistics version 19 software and the MedCalc version 11.6.1 software (Mariakerke, Belgium) were used for statistical analysis and to calculate and compare the C-statistic measure. To test the additional predictive value of ACR, the C-statistic measurewas compared using the Mehran score alone and after adding the ACR information obtained.

RESULTS

Out of a total of 397 patients diagnosed with ACS, 148 (59.4%) underwent a coronary angiography during hospitalization and this was the study population. The mean age was 64 ± 12 years; 35% were women, 20% had diabetes, 54% dyslipidemia, 65% hypertension, and 42% were active smokers. The mean blood sugar levels on admission were 110 mg/dL (98-133 mg/dL), the median creatinine clearance rate (estimated using the MDRD) was 86 mL/min (66-107), and the ACR was 5 mg/g (0-14) (table 1). The patient comparison between these groups with or without CIN showed a higher rate of overweight and obesity, left bundle branch block, atrial fibrillation, and AMI Killip and Kimball class III-IV (table 2).

Table 1. Baseline characteristics of the patients

Total number of patients N = 148
Age (years), median [25-75] 64 [56-73]
Women 35
Hypertension 65
Diabetes mellitus 20
Dyslipidemia 54
Smoking 42
Previous AMI 24.5
STEAMI 20.9
NSTEACS 79.1
Fasting blood glucose levels, mg/dL 110 [98-133]
Serum creatinine levels, mg/dL 0.9 [0.8-1.0]
Creatinine clearance rate, mL/min 86 [66-107]
Urinary albumin-to-creatinine ratio, mg/gr 5 [0-14]
CPK, IU/L 121 [73-264]
CK-MB, IU/L 16 [12-34]
Troponin T levels, ng/mL 0.01 [0.01-0.27]
Moderate to severe LVSF impairment (EF < 40%) 5.79

Unless specified otherwise, data are expressed as % or mean and standard deviation. AMI, acute myocardial infarction; CK-MB, creatine kinase myocardial band; CPK, creatine phosphokinase; EF, ejection fraction; IQR, interquartile range; IU, international units; LVSF, left ventricular shortening fraction; NSTEACS, non-ST-segment elevation acute coronary syndrome; STEMI, ST-segment elevation myocardial infarction.

Table 2. Comparison of patients with and without contrast-induced nephropathy

CIN - (136) CIN + (12) P
Age (years) 63.7 [55-74] 68 [61-76] NS
Women 25.3 16.7 NS
Hypertensive 67.7 58.3 NS
Diabetic 20 33.3 NS
Body mass index 26 [24-29] 29 [25-31] .05
Creatinineclearence rate mg/dL 85 [65-108] 74 [50-98] NS
Blood glucose levels at admission, mg/dL 112 [100-142] 143 [108-209] NS
Previous AMI 26 16 NS
Previous PCI 17 8.3 NS
Previous stroke or TIA 3.6 8.3 NS
NSTEACS 17.7 25 NS
STEMI 30.8 33.3 NS
Left bundle branch block 3.6 16.7 .02
Atrial fibrillation 0.9 8.3 .02
Killip and Kimball III-IV 4.1 22 .001

Unless specified otherwise, data are expressed as % or mean and standard deviation 25%-75%. ACEI, angiotensin-converting enzyme inhibitors; AMI, acute myocardial infarction; ARA II, angiotensin II receptor antagonists; ASA, acetylsalicylic acid; CK-MB, creatine kinase myocardial band; CPK, creatine phosphokinase; EF, ejection fraction; HR, heart rate; IQR, interquartile range; IU, international units; LVSF, left ventricular shortening fraction; NS, not significant; NSTEACS, non-ST-segment elevation acute coronary syndrome; PCI, percutaneous coronary intervention; SBP, systolic blood pressure; STEMI, ST-segment elevation myocardial infarction; TIA, transient ischemic attack.

The C-statistic measure showed that the best CIN related ACR cutoff value was 20 mg/g. Twelve patients developed CIN (8.1%) and the ACR of 22% of the patients was >20 mg/g. The rate of ACR > 20 mg/g among patients without CIN was 2.9% and 11.3% (P = .01) among patients with CIN. Contrast-induced nephropathy was significantly higher when the ACR was ≥ 20 mg/g compared to when it was < 20 mg/g (≥ 9.6% vs 1.6%, res­- pectively, P < .001). When the ACR was added to the Mehran score, its predictive power went up to 0.82 (95%CI, 0.76-0.87).(Figure 1).

Figure 1. Effect of albumin-to-creatinine ratio when added to the Mehran score. When the albumin-to-creatinine ratio was added to the Mehran score, its predictive power went up from 0.75 to 0.82 (95%CI, 0.76-0.87).

Using a multivariable regression analysis model the ACR > 20 mg/g turned out to be an independent predictor for CIN: OR, 3.2 (0.7-6.2); P = .01, adjusted by the Mehran score variables (age, women, body mass index, atrial fibrillation, Killip Class III-IV, and creatinine clearance rate).

DISCUSSION

Our study proved the association between the ACR and the development of CIN in patients admitted with ACS.

Acute kidney injury in the ACS setting predisposes to more complications such as in-hospital and long-term mortality; therefore, predicting it is of critical clinical importance. A recent study reported that the rate of AKI was close to 17% in the ACS setting with significant peaks of cardiovascular complications. In this study, the ACR was not used as an early marker of AKI. The development of CIN was not specifically analyzed either as a post-coronary angiography compli­cation.18-22

Microalbuminuria calculated through the ACR obtained from a simple urine sample is also an established marker of endothelial dysfunction that has been validated to predict cardiovascular events and mortality in different clinical settings. A previous analysis of our group revealed that higher ACR levels are associated with significantly worse outcomes in patients with non-ST-segment elevation ACS, and with a higher rate of hard endpoints like mortality and/or non-fatal acute myocardial infarction at the long-term follow-up (12% vs 2.2%, P =/< .0001).23 Also, other authors proved its utility to assess the risk of developing AKI, mainly in the ACS setting or while being exposed to cardiac surgery.24Tziakas et al confirmed the significant correlation between AMI related higher ACR levels and the development of AKI after this event (area under the ROC curve 0.72; 95%CI, 0.67-0.77). However, the authors did not report on the clinical impact of this complication on the patient’s clinical course or its association with the use of contrast during coronary angiography.25

Special attention should be paid to patients with post-angiographic AKI in the ACS setting. Several studies have shown that CIN negatively impacts the prognosis of hospitalized and long-term patients. In our population, mortality in patients with CIN was significantly higher compared to those without this disease (33% vs 1.8%).

The use of urinary ACR has been less studied in this context. Meng et al. reported that high microalbuminuria levels (ACR in between 30 mg/g and 300 mg/g) were associated significantly with the development of post-contrast acute kidney injury in patients undergoing coronary catheterization (12.1% vs. 5.0%; P = .005). A key point here that distinguishes this study from ours is that they included patients with scheduled coronary angiographies only and out of the ACS setting.26Another relevant point is that the ACR cutoff value to develop CIN was determined from the analysis of the area under the ROC curve, and its value of 20 mg/g was even lower compared to the conventional standard threshold of 30 mg/g, a finding that was consistent with what other clinical studies reported.27

The rate of CIN and its impact on the clinical outcome of coronary patients triggered the development of predictive scores for this disease. One of the best known indices is the Mehran score that includes variables like age > 75 years, hypertension, functional class III/IV heart failure, diabetes mellitus, anemia, use of intra-aortic balloon pump, volume of contrast administered, and past medical history of renal dysfunction and is capable of identifying who the most vulnerable patients are to develop post-coronary angiography CIN (the area under the ROC curve was 0.75). Adding the ACR to this score showed an even greater discriminatory power to predict post-coronary angiography CIN in patients with ACS. This would prove the practical utility of adding this index as a variable to the Mehran score.

CIN, one of the most common causes for acute nephrotoxicity, is a multi-factor event. Among its causes we should mention the direct nephrotoxic effect of the contrast substances used during endovascular procedures on the renal endothelium and the development of acute tubular necrosis. It is estimated that the nephrotoxicity of hyperosmolar contrast enhanced by the hemodynamic alterations produced by the ongoing ACS could alter vascular resistance with changes in the regulation of the release and balance of vasoactive substances like adenosine, endothelin, and nitric oxide. The damage perpetuates the slowing down of renal perfusion, spinal hypoxemia, ischemic injury, and ultimately cell death. In addition to reducing the clearance of oxidative stress products, the lower glomerular filtration rate levels increase the concentration of inflammatory mediators triggering structural alterations at renal tubular epithelium level like edema, vacuolization, and death.28,29

We believe that these findings could help identify patients at high-risk of developing post-coronary angiography CIN in the ACS setting to promote preventive measures, behaviors, and strategies to avoid this complication.

Limitations

First, one of the main limitations of our work is its single center nature. However, we should mention that the population included was representative and covered the entire spectrum of patients with ACS admitted to our coronary care unit, which secures the internal validity and representativeness of our study. Secondly, the underpowered sample may have conditioned the appearance of false negative results due to its alpha error or lower power and stopped us from performing a proper multivariable analysis. Finally, certain data such as the volume of contrast used in each study was calculated retrospectively with the usual biases of this type of analysis.

CONCLUSIONS

The albumin-to-creatinine ratio, a recognized predictor of renal and endothelial dysfunction, was also a marker of CIN in patients with ACS with an added value when it was included in a widely validated clinical score. These results may be the beginning of a hypothesis-generating study to be confirmed prospectively at a multi-center level.

CONFLICTS OF INTEREST

None declared.

ACKNOWLEDGEMENTS

We wish to thank the entire staff of the Hospital Alemán Coronary Care Unit, particularly the nursing staff who helped collect the urine samples that were crucial to conduct this study.

WHAT’S KNOWN ABOUT THE TOPIC?

  • CIN is one of the most common causes for AKI in hospitalized patients. Microalbuminuria is an established marker of endothelial dysfunction and has been validated to predict cardiovascular events and mortality in different clinical settings. The ACR is useful to assess the risk of developing CIN basically in the ACS setting or while exposed to cardiac surgery.

WHAT DOES THIS STUDY ADD?

  • Our study proved the association that exists between the ACR and the development of post-coronary angiography CIN in patients admitted with ACS. The C-statistic measure showed that the best CIN related ACR cutoff value was 20 mg/g. The ACR brings an added value when included in the Mehran score to assess the risk of developing post-coronary angiography CIN in the ACS setting.

REFERENCES

1. Hsiao PG, Hsieh CA, Yeh CF, et al. Early prediction of acute kidney injury in patients with acute myocardial injury. J Crit Care. 2012;27:525.e1-e7.

2. McCullough PA. Contrast-induced acute kidney injury. J Am Coll Cardiol. 2008;51:1419-1428.

3. Mehran R, Nikolski E. Contrast-induced nephropathy:Definition, epidemiology, and patients at risk. Kidney International. 2006;69:S11-S15.

4. Parikh CR, Coca SG, Wang Y et al. Long-term prognosis of acute kidney injury after acute myocardial infarction. Arch Intern Med. 2008;168:987-995

5. Persson PB, Hansell P, Liss P. Pathophysiology of contrast medium-induced nephropathy, Kidney Int. 2005;68:14-22.

6. Tsai TT, Patel UD, Chag TI, et al. Contemporary incidence, predictors and outcomes of acute kidney injury in patients undergoing percutaneous coronary interventions:insights from the NCDR Cath-PCI Registry. JACC Cardiovasc Interv. 2014;7:1-9.

7. Mehran R, Aymong ED, Nikolsky E, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention. J Am Coll Cardiol. 2004;44:1393-1399.

8. Mogensen CE, Christensen CK. Predicting diabetic nephropathy in insulin-dependent patients. N Engl J Med. 1984;31:89-93.

9. Valmadrid CT, Klein R, Moss SE, Klein BE. The risk of cardiovascular disease morbidity associated with microalbuminuria and gross proteinuria in persons with older-onset diabetes mellitus. Arch Intern Med. 2000;160:1093-1100.

10. Dogra G, Rich L, Stanton K, Watts Parving H. Microalbuminuria in essential hypertension and diabetes. J Hypertens. 1996;14:S89-S94.

11. Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A. Albuminuria reflects under-spread vascular damage:the steno hypothesis. Diabetologia. 1989;32:219-226.

12. Estacio RO, Dale RA, Schrier R, Krantz MJ. Relation of reduction in urinary albumin excretion to ten-year cardiovascular mortality in patients with type 2 diabetes and systemic hypertension. Am J Cardiol. 2012;109:1743-1748.

13. Stehouwer CD, Smulders YM. Microalbuminuria and risk for cardiovascular disease:Analysis of potential mechanisms. J Am Soc Nephrol. 2006;17:2106-2111.

14. Bennett PH, Haffner S, Kasiske BL, et al. Screening and management of microalbuminuria in patients with diabetes mellitus:recommendations to the Scientific Advisory Board of the National Kidney Foundations from an ad hoc committee of the Council on Diabetes Mellitus of the National Kidney Foundation. Am J Kidney Dis. 1995;25:107-12.

15. Berton G, Cordiano R, Palmieri F, Cucchini R, De Toni R, Palatini P. Microalbuminuria during acute myocardial infarction. A strong predictor for 1-year morbidity. Eur Heart J. 2001;22:1466-1475.

16. Nazer B, Ray KK, Murphy SA, Gibson M, Cannon CP. Urinary albumin concentration and long-term cardiovascular risk in acute coronary syndrome patients:A PROVE IT-TIMI 22 sub-study. J Thromb Thrombolysis. 2013;36:233-239.

17. Jensen JS, Clausen P, Borch-Johnsen K, Jensen G, Feldt-Rasmussen B. Detecting microalbuminuria by urinary albumin/keratinize concentration ratio. Nephrol Dial Transplant. 1997;12S2:6-9.

18. Marenzi G, Assanelli E, Campodonico J, et al. Contrast volume during primary percutaneous coronary intervention and subsequent contrast-induced nephropathy and mortality. Ann Intern Med. 2009;150:170-177.

19. Rihal CS, Textor SC, Grill DE, et al. Incidence and prognostic importance of Acute Renal Failure after percutaneous coronary intervention. Circulation. 2002;105:2259-2264.

20. Garcia S, Ko B, Adabag S. Contrast-induced nephropathy and risk of acute kidney injury and mortality after cardiac operations. Ann Thorac Surg. 2012;94:772-777.

21. Bouzas-Mosquera A, Vázquez-Rodríguez JM, Calviño-Santos R, et al. Contrast-Induced Nephropathy and Acute Renal Failure Following Emergent Cardiac Catheterization:Incidence, Risk Factors and Prognosis. Rev Esp Cardiol. 2007;60:1026-1034.

22. Ueda J, Nygren A, Hansell P, Ulfendahl HR. Effect of intravenous contrast media on proximal and distal tubular hydrostatic pressure in the rat kidney. Acta Radiologica. 1993;34:83-87.

23. Higa CC, Novo FA, Nogues I, Ciambrone MG, Donato MS, Gambarte MJ, Rizzo N, Catalano MP, Korolov E, Comignani PD. Single spot albumin to creatinine ratio:A simple marker of long-term prognosis in non-ST segment elevation acute coronary syndromes. Cardiology J. 2016;23:236-241

24. Coca SG, Jammalamadaka D, Sint K, et al. Preoperative proteinuria predicts acute kidney injury in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg. 2012;143:495-502.

25. Tziakas D, Chalikias G, Kareli D, et al. Spot urine albumin to creatinine ratio outperforms novel acute kidney injury biomarkers in patients with acute myocardial infarction. Int J Cardiol. 2015;197:48-55.

26. Meng H, Wu P, Zhao Y, et al. Microalbuminuria in patients with preserved renal function as a risk factor for contrast-Induced acute kidney injury following invasive coronary angiography. Eur J Radiol. 2016;85:1063-1067.

27. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus:Results of the HOPE study and MICRO HOPE sub-study. Lancet. 2000;355:253-259.

28. Maioli M, Toso A, Gallopin M, et al. Preprocedural score for risk of contrast-induced nephropathy in elective coronary angiography and intervention. J Cardiovasc Med (Hagerstown). 2010;11:444-449.

29. Goldenberg I, Matetzky S. Nephropathy induced by contrast media:pathogenesis, risk factors and preventive strategies. CMAJ. 2005;172:1461-1471.

Corresponding author: Servicio de Cardiología, Hospital Alemán, Avenida Pueyrredón 1640, Ciudad Autónoma de Buenos Aires C1118, Argentine Republic.
E-mail address: (Y. Korolov).

ABSTRACT

Introductionand objectives: We assessed whether the routine use of subcutaneous nitroglycerin prior to a cannulation attempt improves transradial access significantly (the NiSAR study [subcutaneous nitroglycerin in radial access]).

Methods: Patients undergoing a coronary angiography were enrolled in a prospective, double-blind, multicenter, randomized trial in 2 groups (nitroglycerin group vs control group). The primary endpoints were the overall number of puncture attempts, access and procedural time, switch to transfemoral access, and local perceived discomfort score. The secondary endpoints were the pre- and post-anesthetic pulse score. A subgroup of patients underwent ultrasound scans performed through the radial artery.

Results: 736 patients were enrolled in the trial: 379 in the nitroglycerin group and 357 in control group. The average number of puncture attempts was similar (1.70 vs 1.76; P = .42). Access and procedural time did not change significantly (61.1 s and 33.3 s vs 63 s and 33.4 s; P = .66 and P = .64, respectively). No significant differences were found either between the 2 groups in the number of switches to transfemoral access (7.1% vs 8.4%; P = .52). However, the average local perceived discomfort score and post-anesthetic pulse score were significantly better in the nitroglycerin group (2.34 vs 2.76; P< .001 and 2.47 vs 2.22; P< .001). The ultrasound scan performed through the radial artery showed post-anesthetic radial artery lumen diameters that were significantly higher in the nitroglycerin group in both the longitudinal (3.11 mm vs 2.43 mm; P = .002) and cross-sectional planes (2.83 mm vs 2.41 mm; P = .002). A trend towards fewer local hematomas in the nitroglycerin group was seen (6.1% vs 9.8%; P = .059). Headaches were more common in the nitroglycerin group (3.2% vs 0.6%; P = .021).

Conclusions: The routine use of subcutaneous nitroglycerin prior to radial puncture was not associated with fewer punctures or shorter access times. However, the lower local perceived discomfort and enlargement of the radial artery size would justify its daily use in the routine clinical practice to enhance the transradial experience for both patients and operators.

Keywords: Transradial access. Subcutaneous nitroglycerin. Radial spasm.

RESUMEN

Introducción y objetivos: Se evaluó si la utilización sistemática de nitroglicerina subcutánea previa a cualquier intento de canulación podía mejorar de forma significativa el acceso transradial (nitroglicerina subcutánea acceso radial [NiSAR]).

Métodos: Se incluyeron todos los pacientes sometidos a angiografía coronaria en un estudio prospectivo, multicéntrico, doble ciego y aleatorizado, y se dividió la población en 2 grupos: grupo de nitroglicerina y grupo control. Los objetivos primarios del estudio fueron el número total de punciones radiales, el tiempo total de acceso y de procedimiento, la necesidad de cambio a acceso femoral y la puntuación de disconfort local. El objetivo secundario fue la evaluación del pulso antes y tras la anestesia. Además, un subgrupo de pacientes fue evaluado con ecografía de la arteria radial.

Resultados: Se incluyeron736 pacientes: 379 en el grupo de nitroglicerina y 357 en el grupo C. El número promedio de intentos de punción radial fue similar en ambos (1,70 frente a 1,76; p = 0,42). No hubo diferencias significativas en los 2 grupos con respecto al tiempo total del acceso y del procedimiento (61,1 y 33,3 s frente a 63 y 33,4 s; p = 0,66 y p = 0,64, respectivamente). Tampoco se encontraron diferencias significativas entre los 2 grupos en la tasa de conversión a acceso femoral (7,1 en el grupo de nitroglicerina frente a 8,4% en el grupo C; p = 0,52). Sin embargo, el índice de malestar local y el de pulso tras la anestesia fueron significativamente mejores en el grupo de nitroglicerina (2,34 frente a 2,76, p < 0,001; 2,47 frente a 2,22, p < 0,001). La ecografía mostró un diámetro radial significativamente mayor en el grupo de nitroglicerina tanto en la vista longitudinal (3,11 frente a 2,43 mm; p = 0,002) como en la transversal (2,83 frente a 2,41 mm; p = 0,002). Hubo una menor incidencia de hematoma en el antebrazo en el grupo de nitroglicerina (6,1 frente a 9,8%; p = 0,059). La cefalea fue más frecuente en los pacientes del grupo de nitroglicerina (3,2 frente a 0,6%; p = 0,021).

Conclusiones: El uso sistemático de nitroglicerina subcutánea previo a la punción radial no estuvo asociado a una reducción en el número de punciones ni en el tiempo de acceso, pero el menor malestar local y el aumento del calibre de la arteria radial podrían justificar su uso en la práctica clínica para mejorar la experiencia del acceso transradial tanto en el paciente como en el operador.

Palabras clave: Espasmo radial. Nitroglicerina subcutánea. Acceso radial.

INTRODUCTION

Transradial access to perform coronary and peripheral procedures is becoming more successful compared to transfemoral access thanks to several advantages including more comfort as reported by the patients, early ambulation and discharge, less bleeding, and overall better outcomes.1-5However, the radial artery is more susceptible to spasm, which can stop the advance of the catheter, extend the duration of the procedure, and increase its difficulty.6Also, radial artery spasm has been identified as an independent predictor of radial access failure.7

When radial artery spasm occurs after an introducer sheath has been inserted, the intra-arterial administration of vasodilator drugs has proved to improve the conduit effectively.8Still, the subcutaneous administration of nitroglycerin relieves the spasm causing the reduction significantly and the eventual loss of pulse volume after several ineffective attempts to cannulate the radial artery.9Also, it enhances radial pulse palpation, and eventually makes the puncture of radial artery easier.10,11

Because the first puncture failure is a powerful predictor of radial artery spasm,12we conducted a double-blind, randomized, controlled trial in 4 Argentinian centers to see whether the routine subcutaneous administration of nitroglycerin prior to a cannulation attempt improved transradial access significantly (the NISAR study [subcutaneous nitroglycerin in radial access]).

Specifically, the primary endpoints of the study were to assess the number of radial artery puncture attempts, the time required to place the sheath introducer, the number of times that switching to transfemoral access was required, and the patients’ tolerance to the procedure. The secondary endpoints included the assessment of the radial artery pulse and diameter and local and systemic complications.

METHODS

Patients and procedures

Patients undergoing a coronary angiography with evidence of myocardial ischemia were enrolled in a prospective, multicenter, and randomized clinical trial conducted in 4 Argentinian centers into 2 different groups based on the periradial subcutaneous administration of nitroglycerin. In the nitroglycerin group, 2% xylocaine (1 mL) was used followed by 200 mcg of nitroglycerin (2 mL). In control group, 2% xylocaine (1 mL) was followed by the infusion of a normal saline solution (2 mL) used as placebo. Trained nurses from each center prepared the syringes following a 1:1 randomization scheme and making sure that their content was unknown to both the operators and the patients.

The coronary angiographies and revascularization procedures were performed using 5-Fr or 6-Fr diagnostic and guiding catheters as selected by the operators. In all cases a properly sized sheath introducer was inserted using the Seldinger or modified Seldinger technique. Five thousand units of heparin were consistently administered through a bolus injection with further additions to keep the activated clotting time between 250 and 300 seconds if a percutaneous coronary intervention was performed.

All procedures were performed after patients gave their informed consent by 8 skilled and experienced operators who had performed over 1500 transradial procedures. All operators used the right radial artery as the access of choice; the left radial artery was spared for cases with right radial artery occlusion and patients with left internal mammary artery graft.

Outcome measures

The primary outcome measures were the overall number of puncture attempts, access, and procedural time, switch to transfemoral access, and local perceived discomfort score.

Access time was defined as the time elapsed between the administration of local anesthesia and the insertion of the radial sheath introducer. When the initial radial access could not be completed, the contralateral radial access was never tried and access site changed to the femoral access. The local perceived discomfort score was assessed by the patient after undergoing the procedure and graded according to a radial-related pain score between 0 = no pain and 10 = unbearable pain.

The secondary outcome measures were the pre- and post-anesthetic pulse score assessed by the operator by palpating the radial pulse before and 1 minute after the administration of local anesthesia and graded as: 1 = weak pulse; 2 = easily palpable pulse; 3 = strong pulse. Also, local and systemic complications including forearm hematomas, radial artery spasm, headaches, and symptomatic hypotension were recorded. Also, a subgroup of patients underwent a radial artery ultrasound scan both at the baseline and after the administration of anesthesia. Patients were examined in the supine position using a commercially available ultrasound system. The radial artery lumen diameter was measured on M-mode imaging in both the longitudinal and cross-sectional planes and 1 cm proximal to the radius styloid process. Three measures were taken in each plane and their values averaged.

Statistics

Continuous variables were compared using the Student t test. Categorical variables were compared using Pearson chi-square test. Data were expressed as mean ± standard deviation or frequency (percentage). Two-tailed P values < .05 were considered statistically significant.

RESULTS

Characteristics of patients and procedural details

Overall, 736 patients (450 men, age 65 ± 10 years) were enrolled in the trial: 379 (51.5%) in the nitroglycerin group and 357 (48.5%) in control group. Table 1 shows their general characteristics. Active smoking and diabetes mellitus were reported by 292 (39.7%) and 168 (22.8%) of the patients, respectively and 240 (46.1%) showed an unstable presentation. The radial access was the first access attempted in 597 patients (81.1%).

Table 1. General characteristics of the patients

Overall (n = 736) Nitroglycerin group (n = 379) Control group (n = 357) P
Age (years) 64.9 ± 10.1 64.9 ± 10.1 65.1 ± 10.1 .80
Male gender 450 (61.1%) 230 (60.7%) 220 (61.6%) .79
Body mass index 28.5 ± 4.2 28.5 ± 4.2 28.4 ± 4.2 .82
Active smoking 292 (39.7%) 153 (40.3%) 139 (38.9%) .69
Hypertension 520 (70.6%) 277 (73.1%) 243 (68.1%) .14
High cholesterol 365 (49.6%) 189 (49.8%) 176 (49.3%) .88
Diabetes mellitus 168 (22.8%) 97 (25.6%) 71 (19.9%) .07
Clinical presentation
 ST-segment elevation myocardial infarction 55 (7.5%) 28 (7.4%) 27 (7.6%) .68
 Non-ST-elevation acute myocardial infarction 285 (38.7%) 139 (36.7%) 146 (40.9%)
 Chronic stable angina 90 (12.2%) 51 (13.4%) 39 (10.9%)
 Silent ischemia 123 (16.7%) 67 (17.7%) 56 (15.7%)
 Preoperative assessment 64 (8.7%) 33 (8.7%) 31 (8.7%)
First transradial access attempt 597 (81.1%) 307 (81%) 290 (81.2%) .94
Procedure
 Coronary angiography 507 (68.9%) 259 (68.3%) 248 (69.5%) .55
 Percutaneous coronary intervention 24 (3.3%) 15 (3.9%) 9 (2.5%)
 Coronary angiography and ad hoc revascularization procedure 205 (27.9%) 105 (27.7%) 100 (28%)

Procedural details are shown on table 2. In most cases, the radial artery was punctured with a 20G IV catheter using the modified Seldinger technique and a plastic-jacked mini-guidewire advanced through the artery lumen. Small and short sheath introducers were used in less than half of the patients.

Table 2. Procedural details

Overall (n = 736) Nitroglycerin group (n = 379) Control group (n = 357) P
Allen test result
 Normal 659 (89.5%) 338 (89.2%) 321 (89.9%) .94
 Intermediate 66 (9%) 35 (9.2%) 31 (8.7%)
 Abnormal 11 (1.5%) 6 (1.6%) 5 (1.4%)
Radial puncture and introducer placement
 20G IV catheter 719 (97.7%) 371 (97.9%) 348 (97.5%) .71
 0.021 in mini-guidewire 701 (95.2%) 364 (96%) 337 (94.4%) .29
 Plastic-jacketed mini-guidewire 684 (92.9%) 358 (94.4%) 326 (91.3%) .10
 Introducer length < 10 cm 292 (39.7%) 162 (42.7%) 130 (36.4%) .08
 Introducer size < 6-Fr 318 (43.2%) 166 (43.8%) 152 (42.5%) .74
Radial artery angiography 271 (36.8%) 144 (38%) 127 (35.6%) .50

Outcomes

The average number of puncture attempts was similar in the nitroglycerin group compared to control group (1.70 vs 1.76; P = .42). Access and procedural times did not change significantly in either one of the 2 groups (61.1 s and 33.3 s vs 63 s and 33.4 s; P = .66 and P = .64, respectively). No significant inter-group differences were found either in the rate of switch to transfemoral access (7.1% in the nitroglycerin group vs 8.4% in control group, P = .52).

The main results of the patients and their local perceived discomfort score are shown on figure 1. The average local perceived discomfort score was significantly better in the nitroglycerin group (2.34 vs 2.76; P< .001) with a significantly higher rate of grade 0/1 (34.3% vs 25.2%; P = .088) and a lower rate of grade > 3 (33.5% vs 50.4%; P< .001).

Figure 1. Patients tolerance to the transradial procedure. The average local perceived discomfort score was significantly better in patients in whom nitroglycerin was administered subcutaneously compared to those in whom placebo was used (2.34 vs 2.76; P < .001).

figure 2 shows the results of pre- and post-anesthetic pulse score assessment. No significant differences were seen in the pre-anesthetic pulse score. However, the post-anesthetic pulse score was significantly higher in the nitroglycerin group (2.47 vs 2.22, P< .001). The rate of post-anesthetic pulse score < 3 was significantly lower in the nitroglycerin group compared to group C (41.7% vs 57.1%, P< .001).

Figure 2. Operator assessment of radial pulse. The left panel shows that no significant differences were found in the pre-anesthetic pulse score between patients in whom nitroglycerin was administered subcutaneously (nitroglycerin group) and those in whom placebo was used control group. The right panel shows that the post-anesthetic pulse score was significantly higher in the nitroglycerin group compared to control group (2.47 vs 2.22; P < .001).

Radial artery ultrasound scans were performed in 70 patients; the results are shown on figure 3. No significant inter-group differences were seen at the baseline between the longitudinal (2.37 mm vs 2.34 mm; P = .84) and cross-sectional planes (2.31 mm vs 2.34 mm; P = .97). However, the post-anesthetic radial artery lumen diameter was significantly higher in the nitroglycerin group in both the longitudinal (3.11 mm vs 2.43 mm; P = .002) and cross-sectional planes (2.83 mm vs 2.41 mm; P = .002).

Figure 3. Radial artery ultrasound scan. No significant inter-group differences were seen at the baseline between the longitudinal (2.37 mm vs 2.34 mm; P= .84) and the cross-sectional planes (2.31 mm vs 2.34 mm; P = .97). However, the post-anesthetic radial artery lumen diameter was significantly higher in the nitroglycerin group compared to control group in both the longitudinal (3.11 mm vs 2.43 mm; P = .002) and cross-sectional planes (2.83 mm vs 2.41 mm; P = .002).

As shown on table 3, no significant differences in local complications were seen, although a trend towards a lower rate of local hematomas was seen in the nitroglycerin group (6.1% vs 9.8% P = .059). Headaches were more common among patients from nitroglycerin groups (3.2% vs 0.6%, P = .021).

Table 3. Main local and systemic complications

Overall (n = 736) Nitroglycerin group (n = 379) Control group (n = 357) P
Local complications
 Forearm hematoma 58 (7.9%) 23 (6.1%) 35 (9.8%) .059
 Radial artery spasm 109 (14.8%) 49 (12.9%) 60 (16.8%) .14
Systemic complications
 Headache 14 (1.9%) 12 (3.2%) 2 (0.6%) .021
 Symptomatic hypotension 16 (2.2%) 11 (2.9%) 5 (1.4%) .25

DISCUSSION

The main findings of our study are that the subcutaneous administration of nitroglycerin plus the administration of a local anesthetic agent prior to radial artery puncture did not show any statistically significant differences in the number of punctures attempted, access and procedural time or switch to transfemoral access. However, it significantly improved: a) the patients’ perceived comfort during the procedure; b) the radial artery pulse; and c) the radial artery size. Also, our data suggest a possible reduction in the occurrence of local hematomas. Also consistent with former studies, the subcutaneous use of nitroglycerin significantly increased the diameter of the radial artery in patients in whom an ultrasound scan was performed.10,13

The radial artery spasm is the most common complication of transradial access in both coronary angiographies and procedures. It often holds up the regular course of the procedure impacting the patients’ compliance and interfering with the cath lab proceedings.6,9Also, the occurrence of radial artery spasm before radial artery cannulation is even more frustrating to treat and may anticipate that the cannulation of the vessel will be impossible.

Multiple puncture attempts are the leading cause for radial artery spasm and may be a specific issue in the teaching environment.14,15Also, the administration of local anesthetics such as lidocaine has vasoconstrictive properties16 and the radial artery has a relatively small diameter and a relatively thicker tunica media of smooth muscle cells, which leads to a high receptor-mediated vasomotion compared to other muscular arteries.17,18Conversely, the radial artery is particularly sensitive to nitroglycerin.19

Former studies have shown that nitroglycerin delivered through IV,20topical,21or intra-arterial16,22-24routes of administration determines the radial artery dilatation; current evidence with subcutaneous nitroglycerin to facilitate radial access suggests that it can be beneficial to increase the radial pulse and reduce the number of attempts. However, the evidence on this regard is scarce and based on small studies.10,11A review that assessed this issue also failed to find significant differences between both strategies.25Our study rigorously used a double-blind, randomized protocol to assess the role of the subcutaneous administration of nitroglycerin prior to radial artery puncture. It concluded that its systematic use can improve the patient’s perceived discomfort and make puncture easier for the operator but without reducing the number of punctures attempted or access time. Our findings are especially relevant in light of the improved safety associated with transradial access.26

The subcutaneous administration of nitroglycerin is a straightforward and inexpensive technique that allows a high concentration and long persistence of the vasoactive agent at the spasm site level without entering the bloodstream significantly.9As a matter of fact, in our study no significant differences were seen in the hemodynamic effect of patients who received subcutaneous nitroglycerin or placebo.

Also, the Doppler ultrasound scans performed on the radial artery pre- and post-nitroglycerin in a subgroup of patients triggered the new NISAR study (Eco nitroglicerina subcutánea acceso radial)—currently in its design phase—with echocardiographic evaluation of all the patients included.

Limitations

All the patients of this study were taking standard anti-ischemic drugs including nitrates. We did not study the confounding effect of the vasodilation caused by these drugs. The inter-observer and inter-operator variabilities were not studied either. The Doppler ultrasound scan was used in a small subgroup of patients.

CONCLUSIONS

The routine use of subcutaneous nitroglycerin prior to radial puncture was not associated with a lower number of punctures or shorter access times. However, the lower local perceived discomfort and improved radial artery size would justify its daily use in the routine clinical practice to enhance the transradial experience of both patients and operators.

CONFLICTS OF INTEREST

None declared.

WHAT IS KNOWN ABOUT THE TOPIC?

  • Radial artery spasm is still an issue; intra-arterial nitroglycerin and calcium blockers are systematically used after achieving radial access to prevent it. However, the use of subcutaneous nitroglycerin plus the administration of a local anesthetic agent prior to radial puncture is still controversial. This is so because the studies conducted so far on this issue are mostly scarce, small, and not randomized. This was confirmed in a review published back in 2018.

WHAT DOES THIS STUDY ADD?

  • The strength of our study is that it is the first prospective, randomized, multicenter, double-blind trial to assess this issue.
  • Regarding the results from the trial and although some hard endpoints did not reach statistically significant differences, we believe that the fact that patients tolerated the procedure better, the increase seen in the pulse score and the radial artery diameter after the administration of subcutaneous nitroglycerin added to the simplicity, security and great availability of the procedure is indicative that this technique should be widely used.

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Corresponding author: Av. Roca (S) 342, 4º Piso, 4200 Santiago del Estero, Argentine.
E-mail address: (S. Coroleu).

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