Access to side branches with a sharply angulated origin: usefulness of a specific wire for chronic occlusions

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.

FUNDING

No funding or grants were received for this work.

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.

 

REFERENCES

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. The Ethics Committe reviewed and approved this study. Patients' informed consent to publish was obtained.

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.

FUNDING

No funding was received for this work.

CONFLICTS OF INTEREST

None declared.

 

 

REFERENCES

INTRODUCTION

The management of ST-segment elevation acute coronary syndrome (STEACS) is based on the quick opening of the culprit artery through the use of fibrinolytic drugs or a percutaneous coronary intervention (PCI) that limits the size of the infarction and improves prognosis.1 Fibrinolytic drugs have proven capable of increasing survival,2 but they are more effective when administered within the first 3 hours after symptom onset. The primary percutaneous coronary intervention (pPCI) improves survival and reduces recurrent infarctions and strokes, which is why it is seen as the optimal therapy as long as it can be performed in a timely manner.3^,4

The pPCI main limitation is the impossibility to use it in the entire population due to its limited geographic availability and the delays involved in the transfer of patients from non-pPCI centers to reference hospitals. Clinical practice guidelines recommend performing pPCI < 120 min. after the diagnosis of STEACS.1 Regional networks have been created to speed up these times and increase access to pPCI for patients with STEACS in non-pPCI hospitals. Yet despite this effort, many patients with STEACS are transferred late to pPCI centers which increases mortality and morbidity rates.

In order to improve results and administer reperfusion therapy as early as possible the so-called pharmacoinvasive strategy was implemented. It consists of the administration of fibrinolytic drugs in the pre-hospital or non-pPCI setting followed by the immediate transfer of the patient to a pPCI center capable of performing a bailout angioplasty if drug therapy fails or an early systematic angiography if it is successful.5^,6

The experience gained over the years performing pPCIs at the Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA) has been used for the optimal management of patients with STEACS. The recommendations established by the clinical guidelines have been followed and adapted to the geographic characteristics of the region, structure, and healthcare resources available. A protocol for the management of reperfusion in the acute phase that distinguished 2 groups has been established: the first group with patients treated in pPCI centers; the second one, with patients from regional hospitals who live in remote areas far from reference hospitals where the treatment recommended is fibrinolysis in the absence of contraindications.

METHODS

Retrospective study of a cohort of 679 patients diagnosed with STEACS from 2006 through 2010 in 2 groups of healthcare regions: region I, with pPCI capabilities at the HCUVA (El Palmar, Murcia), and non-pPCI regions assigned to the HCUVA intensive care unit. This second group includes region IV with the Hospital Comarcal del Noroeste (Caravaca de la Cruz) and region V with the Hospital Virgen del Castillo (Yecla).

Patients diagnosed with STEACS based on traditional criteria1 and symptoms of less than 24-hour duration were included. Selection was done by reviewing the HCUVA catheterization laboratory database on all ICU admissions, hospital urgent care provided, and 061 ambulance emergency transfer reports during the study period. The most adequate reperfusion therapy was administered following recommendations and the regional protocol.

Follow-up was conducted by reviewing the patients’ medical records by phone or through physical consultations.

The variables analyzed were past medical history, time elapsed since symptom onset until reperfusion therapy, electrocardiogram, echocardiographic and angiographic characteristics of angioplasty, patient progression, and treatment after hospital discharge. Major hemorrhages were defined as lethal or symptomatic in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, pericardial or intramuscular) causing compartmental syndrome or bleeding with reduced hemoglobin levels > 20 g/L (1.24 mmol/L) or need for 2 concentrate transfusions.

The short and long-term cardiovascular events were recorded at the 30-day and 1-year follow-up, respectively including the rates of overall mortality and cardiac mortality, acute myo- cardial reinfarction (re-AMI), stroke, and need for a new re­vascu­larization.

The study primary endpoint was to compare mortality and major cardiovascular events in patients treated of STEACS from the Region of Murcia based on the healthcare region they received care at. The study secondary endpoints were the analysis and comparison of the clinical characteristics of these populations and the identification of angiographic or PCI differences.

Statistical analysis

The results of continuous variables were expressed as mean ± standard deviation, and those of categorical variables as frequency or percentage. Categorical variables were compared using the chi-square test with Yates correction when necessary. Quantitative variables were compared using the Student t test based on the variables normal distribution. Event-free survival rates (overall and cardiac mortality, stroke, re-AMI, and restenosis) were calculated using the Kaplan-Meier method and their results were represented through survival curves. The log rank test was used to compare the event-free survival rate. The level of statistical significance used for hypothesis testing was P < .05. The Mac OS version of the SPSS statistical software (version 20) was used.

The study was conducted in full compliance with the Declaration of Helsinki and the good clinical practice guidelines approved by HCUVA Research Ethics Committee.

RESULTS

From January 2006 through December 2010, 679 patients from regions I, IV, and V of the Region of Murcia Healthcare System were treated of STEACS of less than 24-hour duration and received reperfusion therapy (figure 1). Ninety-seven-point-six per cent of the 494 patients from region I (HCUVA) underwent pPCI (482) while 2.4% received thrombolysis (12). Seventy-three percent (135) and 27% (50) of patients from regions IV and V (127 and 58, respectively) underwent thrombolysis and pPCI, respectively. Thirty-four percent (46) of those who received thrombolysis required a bailout angioplasty and 58.5% (79) a scheduled coronary angiography (pharmacoinvasive strategy) during their hospital stay. Only 10 patients (7.4%) did not undergo a coronary angiography.

Figure 1. Summary of the study patients and the reperfusion strategies used based on the patients’ healthcare regions. HCUVA, Hospital Clínico Universitario Virgen de la Arrixaca; PCI, percutaneous coronary intervention or angioplasty; STEACS, ST-segment elevation acute coronary syndrome.

Baseline characteristics of the populations

Baseline characteristics are shown on table 1. The HCUVA population was older and had more diabetic patients compared to the population from regional hospitals. On the contrary, the rate of atrial fibrillation was higher in the latter. No significant differences were seen based on sex or the remaining risk factors.

Table 1. Baseline characteristics of the population

	HCUVA (n = 494)	Regional hospitals (n = 185)	P
Age (years)	65.3 ± 13.7	62.9 ± 13	.044
Sex (women)	111 (22.5)	41 (22.2)	.93
High blood pressure	290 (58.7)	111 (60)	.76
Diabetes	180 (36.4)	52 (28.1)	.042
Dyslipidemia	200 (40.5)	64 (34.6)	.16
Smoking	304 (61.5)	112 (60.5)	.81
Previous ischemic heart disease	53 (10.7)	21 (11.4)	.810
Previous revascularization	53 (10.7)	18 (9.7)	.88
Peripheral arterial disease	25 (5.1)	4 (2.2)	.096
Previous stroke	43 (8.7)	12 (6.5)	.35
Atrial fibrillation	21 (4.3)	16 (8.6)	.025
Heart failure	12 (2.4)	2 (1.1)	.271
Kidney disease	39 (7.9)	19 (10.3)	.324
COPD	43 (8.7)	18 (9.7)	.677
Valve disease	9 (1.8)	1 (0.5)	.217
Previous angina	122 (24.7)	39 (21.1)	.324
COPD, chronic obstructive pulmonary disease; HCUVA, Hospital Clínico Universitario Virgen de la Arrixaca. Data are expressed as no. (%) or mean ± standard deviation.

No differences were seen in the time to reperfusion between both groups with a mean of 180 min. (interquartile range: [120-240]) in HCUVA vs 150 min. in regional hospitals (interquartile range: [90-240]; P = .4). Ischemia times < 3 hours were achieved in 59.6% of the HCUVA patients compared to 68.9% of patients from regional hospitals (table 2). Forty-nine patients (9.9%) from the first group had cardiogenic shock vs 17 patients (9.2%) from the second one (not statistically significant differences).

Table 2. Progression time (from symptom onset to reperfusion) and angiographic and electrocardiographic characteristics

	HCUVA (n = 494)	Regional hospitals (n = 185)	P
Progression time(median,min.)	180	150	.4
< 3 h	295 (59.7)	128 (69.1)
3-6 h	141 (28.5)	33 (17.7)
6-9 h	32 (6.4)	10 (5.6)
9h -12 h	15 (3.1)	7 (4)
> 12 h	11 (2.2)	7 (4)
STEACS location			.298
Anterior	205 (41.6)	89 (48.1)
Inferior	236 (47.7)	75 (40.5)
Lateral	49 (9.9)	18 (9.7)
Indeterminate	4 (0.8)	3 (1.6)
Culprit vessel			.022
Left anterior descending coronary artery	205 (41.5)	83 (44.9)	.429
Circumflex artery	62 (12.6)	25 (13.5)	.738
Right coronary artery	204 (41.3)	64 (34.6)	.111
Left main coronary artery/graft	9 (1.8)	0	.065
Unidentified	14 (2.8)	13 (7)	.013
Previous stent thrombosis	24 (4.8)	3 (1.6)	.075
Number of injured vessels			.001
0	5 (1)	15 (8)	.001
1	274 (55.4)	109 (58.9)	.416
2	133 (27)	38 (20.6)	.093
3	82 (16.6)	23 (12.6)	.227
Initial TIMI flow			.001
0	351 (71.1)	65 (34.9)	.001
1	21 (4.2)	4 (2.4)	.281
2	13 (2.7)	9 (4.7)	.206
3	109 (22)	107 (58)	.001
Final TIMI flow grade 3	464 (93.9)	171 (92.3)	.845
Second revascularization	95 (19.2)	30 (16.2)	.322
Complete revascularization	347 (70.2)	138 (74.6)
HCUVA, Hospital Clínico Universitario Virgen de la Arrixaca; STEACS, ST-segment elevation acute coronary syndrome; TIMI, Thrombolysis in Myocardial Infarction. Data are expressed as no. (%)

Regarding the coronary angiography, the percentage of radial access was similar: 45% and 48%, respectively. No significant differences were found either in the location of the STEACS (table 2). However, significant differences were seen in the culprit artery since it was a common thing to not be able to identify the vessel in patients from regional hospitals because the coronary arteries were patent. Differences were seen too in the initial TIMI flow (Thrombolysis in Myocardial Infarction) between both groups (P = .001) at the expense of a worse initial flow in HCUVA patients. After reperfusion therapy, TIMI flow grade-3 was achieved in the culprit artery in 93.9% of HCUVA patients and 92.3% of patients from regional hospitals. Revascularization was complete in 70.2% of the patients from region I and 74.6% of the patients from regions IV and V.

Analytic and echocardiographic characteristics and clinical progression

No differences were seen in the highest levels of cardiac necrosis markers between the different regions (table 3). On average the left ventricular ejection fraction was 52.15% in HCUVA patients and 52.29% in patients from regional hospitals without any significant differences in the systolic or diastolic function (table 3).

Table 3. Analytic, echocardiographic and disease progression characteristics at the hospital floor

	HCUVA (n = 494)	Regional hospitals (n = 185)	P
Peak creatine kinase levels (µg/dL)	1864.4 ± 1917.3	1938.3 ± 1834.4	.671
Peak creatine kinase-MB levels	175.39 ± 132.34	182.26 ± 159.86	.668
Peak troponin T levels	5.79 ± 9.4	9.38 ± 27.5	.118
Ejection fraction (%)	52.15 ± 10.93	52.29 ± 11.46	.886
Normal	255 (50.6)	95 (51.5)
Mild dysfunction	152 (30.7)	52 (28.1)
Moderate dysfunction	63 (12.8)	32 (17.3)
Severe dysfunction	29 (5.9)	6 (3.5)
Diastolic pattern			.056
Restrictive pattern	19 (3.9)	10 (5.3)
Pseudo-normal pattern	125 (25.3)	33 (18)
Prolonged relaxation	307 (62.2)	113 (61.3)
Normal	37 (7.6)	23 (12.4)
Atrial fibrillation	5 (1.1)	6 (3.3)
Hospital stay (days)	9.04 ± 5.72	9.81 ± 7.94	.259
Major hemorrhage	11 (2.2)	7 (3.8)	.261
STEACS related complications	6 (1.2)	3 (1.6)	.71
Killip Class I	357 (72.3)	154 (83.3)	.012
HCUVA, Hospital Clínico Universitario Virgen de la Arrixaca; STEACS, ST-segment elevation acute coronary syndrome; Data are expressed as no. (%) or median ± standard deviation.

No differences were seen in the rates of major bleeding and complications (cardiac ruptures: 2 and 2; intraventricular communication: 1 in regional hospitals, 2 in the HCUVA; papillary muscle rupture: 1 and 1). Patients from region I had more heart failure during their hospital stay (28.7% in the HCUVA vs 16.7% in regional hospitals).

30-day and 1-year follow-up results

Mean follow-up was 962 days in HCUVA patients and 1062 days in patients from regional hospitals. No differences were seen in the overall mortality or cardiac mortality rates at the 30-day or 1-year follow-up. No differences were seen either in the rates of AMI, stroke, and revascularization at the follow-up (table 4). Kaplan-Meier survival curves (figure 2) did not show any significant differences regarding mortality, cardiac death, AMI, and stroke.

Figure 2. Survival curves. Mortality, cardiac death, stroke, and AMI at the follow-up. AMI, acute myocardial infarction; HCUVA, Hospital Clínico Universitario Virgen de la Arrixaca.

Table 4. Mortality and major cardiovascular events

Results (%)	HCUVA (n = 494)	Regional hospitals (n = 185)	P
Mortality
30 days	41 (8.3)	11 (6)	.312
1 year	56 (11.3)	15 (8,2)	.229
Cardiac death
30 days	35 (7.1)	8 (4.3)	.19
1 year	43 (8.7)	9 (4.9)	.095
Reinfarction
30 days	7 (1.4)	2 (1.1)	.735
1 year	20 (4)	5 (2.7)	.409
Stroke
30 days	8 (1.6)	3 (1.6)	.996
1 year	15 (3)	3 (1.6)	.309
Revascularization
30 days	7 (1.4)	4 (2.2)	.494
1 year	35 (7.1)	9 (4.9)	.294
HCUVA: Hospital Clínico Universitario Virgen de la Arrixaca. Data are expressed as no. (%).

DISCUSSION

This study assessed the results of the management of STEACS from a population perspective and analyzed the consequences of the different care provided in each patient’s healthcare region. This was an observational and retrospective study conducted in 3 population areas from the Region of Murcia that share the same interventional cardiology unit and the same intensive care unit. A 5-year period was analyzed with an mean annual rate of 140 patients with STEACS who were admitted to the ER with symptoms of < 24-hour duration. To make the analysis more consistent and thorough, the past medical histories of patients admitted to their respective hospitals and the out-of-hospital ER system and 061 emergency service reports were reviewed to detect prehospital deaths.

The regional plan for the management of STEACS7 is part of the recommendation of designing regional networks beyond the idea of isolated hospital healthcare towards more comprehensive community healthcare systems including scientific recommendations, geographical peculiarities, resources and infrastructures available, and the characteristics of healthcare organization. This plan suggests initiating reperfusion therapy as early as possible whether mechanical with pPCI o pharmacological with fibrinolysis.

The pPCI is considered the treatment of choice for patients admitted to the ER within 60 min. since symptom onset.1^,8^,9 This is how patients diagnosed with STEACS in the metropolitan area of Murcia and nearby municipalities are treated.7 For remote areas such as healthcare regions IV and V, fibrinolytic therapy is recommended in the absence of contraindications followed by transfer to the HCUVA ICU plus urgent coronary angiography in the absence of reperfusion signs (bailout PCI) or elective coronary angiography within the first 24 hours to 48 hours (pharmacoinvasive strategy).7 The hospitals from such areas are 75 km and 110 km away (figure 3) respectively from the pPCI reference hospital.

Figure 3. Healthcare regions within the Region of Murcia, Spain.

Populations from pPCI-capable regions (494 patients) and those from remote regions (185 patients) are rather similar: 78% males, many diabetic patients (> 28%), and over 60% smokers. The only differences between both groups are that patients from region I are older and have a higher prevalence of diabetes (36.4% vs 28.1%). The percentage of diabetics in this series is higher compared to that of international studies like the STREAM trial (12.1% to 13.1%) and other national studies like those conducted by Rodríguez-Leor et al.10 (24.8%), and Hernández-Pérez et al.11 (19.1%), and similar to the EUROASPIRE-IV registry (27%).12

The studies conducted until 2006 in patients with STEACS admitted to the ER in a timely manner showed that up to 25% to 30% did not receive reperfusion therapy.13^,14 This has improved with the implementation of STEACS care networks. Proof of this are the results from several networks in Europe and the United States with percentages from 100% (the Mayo Clinic network)15 to 84% (the Alberta network, Canada).16 Our data are indicative of a high percentage of reperfusion therapy in the studied regions.

In region I the pPCI was performed in almost all of the cases (97.6%) while in the remaining 2 regions 27% of the 185 patients were referred to other centers for mechanical reperfusion. The existence of contraindications for thrombolysis, the long progression time or the possibility of agile hospital transfers to the interventional cardiology unit facilitated the performance of pPCI in 1 out of every 4 patients with STEACS from these regions; the rest (73%) received fibrinolysis. These data are indicative of a greater use of fibrinolytic therapy compared to the one reported by other studies. Thus, a Belgium registry17 reported that fibrinolytic therapy was prescribed to 28.7% of the population from regional hospitals over the first few years (2007-2008). However, this percentage dropped to 12.6% over the last few years (2009-2010). The higher percentage of thrombolytic therapy seen in our study is associated with a longer distance between regional hospitals and the reference pPCI hospital. Even so, over the last few years, a higher percentage of patients with STEACS referred to pPCI centers has been reported in our region. At the program early stages,18 in healthcare regions IV and V, the percentage of pPCIs performed was between 1% and 2% of all reperfusion therapies. In our study, this percentage grew to 27% after reducing patient transfer times between hospitals.

Coronary angiography was performed in 95% of the patients who received fibrinolytic therapy, a similar percentage compared to that reported by other registries (96% in the FAST-MI,19 and 97% in the Mayo Clinic Care Network registry15) and higher to the one reported by the Belgium registry (69%).17

Reperfusion mean times are also similar to those reported by the registries mentioned above. Time delay until reperfusion therapy was < 3 hours in 59.6% of the patients from region I and 68.9% of the patients from regions IV and V. These are similar rates to those from the Belgium trial17 in which the time elapsed since symptom onset until reperfusion therapy was < 4 hours in 67% of the patients from pPCI hospitals and 63% of the patients from regional hospitals and to those from the Mayo Clinic Care Network AMI protocol.15 This protocol establishes a pharmacoinvasive strategy where total ischemia times were 103 min. in patients who received thrombolysis and 278 min. in those referred to undergo pPCI (with a mean time until reperfusion in regional hospitals of 181 min.).

No differences were seen in the location of the infarction between both groups. Patients referred from regional hospitals had more coronary arteries without lesions and a higher preprocedural rate of TIMI flow grade-3 compared to a higher rate of occluded infarct related culprit arteries in those referred for pPCI. Upon arrival to the catheterization laboratory, the initial TIMI flow grade was 0-1 in 75.6% of the patients referred for pPCI and 37.3% in those who received thrombolysis. Different studies show that when the coronary angiography is performed there is a higher percentage of patients with TIMI flow grade-3 among patients who received thrombolysis.20

Clinical progression was similar with no differences regarding major bleeding complications (2.2% vs 3.8%), stroke (1.6% vs 1.6% at 30 days), re-AMI (1.4% vs 1.1% at 30 days), and need for revascularization (1.4% vs 2.2% at 30 days, 7.1% vs 4.9% at 1 year). However, the rate of heart failure during the hospital stay was higher in HCUVA patients (27.3% vs 16.7%). This result may be explained by a tendency towards a greater grade of advanced diastolic dysfunction in these patients (25.3% vs 18%). However, despite the longer ischemia time there were no significant differences in the AMI size due to systolic dysfunction or peak creatinine kinase-MB levels with peak values of 175 vs 182 µg/dL.

The mortality of patients looked after in regions assigned to non-pPCI regional hospitals is similar to that of patients looked after in the reference pPCI hospital. At 1-month, the overall mortality rate was 8.3% in region I with pPCI capabilities and 6% in the most remote areas assigned to regional hospitals; cardiovascular mortality rate was 7.1% and 4.3%, respectively. These rates are similar to those reported by other studies conducted in our setting like the 7.5% from the RESCATE II,21 7.26% from the RECALCAR trial,22 11% from the PRIAMHO-II trial,23 and 7.6% from the MASCARA trial.24 They are also similar to those from the Belgium infarction care network17 where the mortality rates of regional and pPCI hospitals were 7% and 6.7%, respectively or the Mayo Clinic AMI Care Network where the mortality rates of patients from regional hospitals and pPCI hospitals were 5.2% and 7.2%, respectively.15

Based on these findings a reflection is to be made on some of the things that worry healthcare providers, Administration, and patients such as accessibility and equity in the healthcare system. In the STEACS setting there is an ongoing debate on how to make pPCI available for the entire population. Data from this and other studies,19^,25 show that even if pPCI is the preferred reperfusion strategy, it is not the only one. In patients looked after in remote areas far from hospitals with experienced heart teams a pharmacoinvasive strategy with fibrinolytic treatment in the absence of complications is a good alternative.

Limitations

The scarce population from regions IV and V brings down the annual number of patients with STEACS, which is why the timeframe studied had to be a large one in order to study a representative sample. This was a retrospective analysis with the limitations of this type of studies. Basically, this shows how difficult it was to obtain certain data like those regarding different timeframes. The findings from this study where patients were always transferred to the reference hospital intensive care unit may vary from those of other regions where delays could occur if fibrinolysis was not successful. Another possible limitation would be that only patients treated with reperfusion therapy were studied. As already discussed, patients who may have died during the transfer or at the ER were searched for to discard differences in the results obtained from patients assigned to a reperfusion strategy and those finally treated. However, patients with STEACS who did not receive reperfusion therapy were not studied (cases with long symptom duration, etc.). The study compared the results based on the patients’ healthcare region, which may be decisive when assessing the management of STEACS in different healthcare regions, and the different ways of administering various types of reperfusion therapy. This does not seem to be a problem at the moment since reperfusion therapy is administered to over 80% of the cases without significant regional differences.

CONCLUSIONS

Patients diagnosed with STEACS from the most remote healthcare regions of the Region of Murcia (regions IV and V) show similar clinical characteristics compared to patients from region I. However, they are younger patients with not so much diabetes. Yet despite the lower accessibility to immediate pPCI for populations from these healthcare regions, the regional network gives results that are similar to those of populations from pPCI-capable healthcare regions. Pharmacoinvasive strategy is a valid reperfusion therapy for populations from non-pPCI healthcare regions within the times recommended, with similar survival rates to those of pPCI regions, without a higher rate of complications, and with similar short and long-term results.

CONFLICTS OF INTEREST

The authors declared no conflicts of interest whatsoever.

 

 

REFERENCES

INTRODUCTION

Drug-eluting bioresorbable vascular scaffolds (BVS) were initially presented as a technological breakthrough to overcome the limitations and adverse events associated with permanent bare-metal stents, especially the development of neoatherosclerosis that is associated with a risk of thrombosis (0.2% per year) and secondary revascularization (2% to 3% per year).1^-3

At the time, the implantation of a BVS was an innovative approach to treat coronary atherosclerosis by releasing the artery from a permanent metal jail and restoring the flow architecture. Also, it preserved parietal motility and its response to stimuli generated by coronary flow (shear stress). The Absorb (Abbott Vascular, United States)—a polymer everolimus-eluting scaffold with 157 µm-thick struts—was one of the first ones to be available in Spain and several clinical trials were conducted.4^-8 The excellent initial results led to the widespread use of this device for several clinical indications.9^-10 The Absorb BVS was approved by the U.S. Food and Drug Administration and obtained the CE marking certification in January 2011.11

However, the mid- and long-term data of the AIDA research group12^,13 on the Absorb were disappointing. They showed a higher rate of late scaffold thrombosis compared to the XIENCE (Abbott Vascular, United States) (3.5% vs 0.9%; hazard ratio [HR], 3.87; 95% confidence interval [95%CI], 1.78-8.42; P < .001), an everolimus-eluting stent (EES).14^,15 Therefore, the manufacturer stopped making the Absorb BVS and removed it from the market according to the European regulatory agency; however, some of these devices remain approved and are still available in Europe.16

Since the Absorb BVS was widely used in different clinical settings during market launch more than 7 years ago, the long-term follow-up results are available today. The objective of this study is to describe the incidence of long-term adverse events in a series of patients implanted with the Absorb BVS in different clinical settings of our multicenter registry.17

METHODS

Population, design, and definitions

The cases treated with percutaneous transluminal coronary angioplasty with at least 1 Absorb BVS in 3 hospitals between May 2012 and December 2016 were studied.17 Implantation was performed to the discretion of the operator in charge.

The study primary composite endpoint was the target vessel failure rate, a composite event of target vessel revascularization, target vessel related acute myocardial infarction (AMI), and cardiac death. The study secondary endpoint was the rate of the overall clinical endpoint including these adverse events: all-cause mortality, myocardial infarction, and all the new coronary revascularizations (including those of the non-target vessel).

The registry of the interventional cardiology unit of our hospital network was periodically reviewed every 6 to 12 months at the follow-up consultation at the interventional cardiology unit by a cardiologist. Also, it was completed through follow-up phone calls.

Statistical analysis

Data regarding quantitative variables are expressed as mean ± standard deviation and qualitative variables are expressed as percentages. Patients were grouped according to whether they had target vessel failure or not; inter-group averages were compared using the Student t test. Percentages were compared using the chi-square test. Kaplan-Meier analysis was conducted to estimate the likelihood of target vessel failure-free survival and BVS thrombosis and restenosis. Finally, the multivariate Cox regression analysis was conducted to study the survival function adjusted by different predefined variables: sex, age, cardiovascular risk factors, past medical history, clinical signs, size and length of the BVS implanted, overlapping of, at least, 2 BVSs, and use of intracoronary imaging modalities (optical coherence tomography [OCT] or intravascular ultrasound [IVUS]). Two-tailed P ≤ values .05 were considered statistically significant in all tests. Data were analyzed using the statistical software package Stata IC 14 (StataCorp, United States).

RESULTS

Study population

Two hundred and thirteen consecutive patients implanted with, at least, 1 Absorb BVS between May 2012 and December 2016 were included. Table 1 shows the baseline clinical characteristics of these patients. Most of the participants were males (75.12%) with a mean age of 61.40 ± 12.74 years, and a high prevalence of dyslipidemia (62.44%) and smoking (65.26%). Diabetes mellitus was present in 23.94% and 21.60% had been previously treated with a percutaneous coronary intervention. The most common clinical presentation during recruitment was non-ST-segment elevation acute coronary syndrome (53.52%).

Table 1. Baseline clinical characteristics of patients and differences based on the primary endpoint

Characteristics	Patients who received BVS (n = 213)	Patients with BVS and target vessel failure (n = 17)	Patients with BVS without target vessel failure (n = 196)	P
Age (years)	61.40 ± 12.74	66.71 ± 9.62	61.14 ± 12.98	.07
Sex (male)	160 (75.12)	12 (70.59)	148 (75.51)	.65
Risk factors
Diabetes mellitus	51 (23.94)	7 (41.18)	44 (22.45)	.06
Hypertension	118 (55.40)	11 (64.71)	107 (54.59)	.42
Dyslipidemia	133 (62.44)	13 (76.47)	120 (61.22)	.21
Active smoking	139 (65.26)	10 (58.82)	129 (65.82)	.56
Past medical history
Chronic kidney disease	8 (3.76)	1 (5.88)	7 (3.57)	.63
LVEF < 30%	5 (4.5)	1 (5.88)	4 (2.04)	.55
Previous stroke or TIA	9 (4.2)	3 (17.65)	6 (3.06)	.01
Chronic oral anticoagulation	10 (4.69)	3 (17.65)	7 (3.57)	.01
Peripheral vascular disease	13 (6.10)	1 (5.88)	12 (6.12)	.96
Previous myocardial infarction	31 (14.55)	1 (5.88)	30 (15.31)	.29
Previous PCI	46 (21.60)	4 (23.53)	42 (21.43)	.84
Previous coronary artery bypass surgery	7 (3.29)	2 (11.76)	5 (2.55)	.04
Clinical presentation
STEACS	31 (14.55)	4 (23.53)	27 (13.78)	.25
Non-Q-wave AMI type of NSTEACS	77 (36.15)	6 (35.29)	71 (36.22)	.66
Unstable angina type of SCASEST	37 (17.37)	3 (17.65)	34 (17.35)	.88
Stable angina or documented ischemia	68 (31.4)	4 (23.53)	64 (32.65)	.52
AMI, acute myocardial infarction; BVS, bioresorbable vascular scaffold; LVEF, left ventricular ejection fraction; NSTEACS, non-ST-segment elevation acute coronary syndrome; PCI, percutaneous coronary intervention; STEACS, ST-segment elevation acute coronary syndrome; TIA, transient ischemic attack. Data are expressed as no. (%) or mean ± standard deviation.

Index procedure of the bioresorbable vascular scaffold implantation

Table 2 shows the characteristics of the patients’ index procedure. Two hundred and thirty-three coronary lesions were treated with an average 1.3 ± 0.3 lesions per patient. Implantation was successful in 99.5% of the cases but failed in 1 patient due to the difficulty advancing the device across the lesions. The patient required the implantation of a DES, which is why he was excluded from the analysis. Predilatation occurred in 89.3% of the cases and postdilatation in 33.5% of the cases. Intracoronary imaging modalities (OCT or IVUS) were used to optimize the BVS implantation in 86 patients (40.38%).

Table 2. Characteristics of the index procedure and treatment

Characteristics	Patients who received BVS (n = 213)
Lesions treated per patient	1.3 ± 0.3
Number of devices per patient	1.2 ± 0.4
Total length of the device per patient (mm)	21.5 ± 13.5
Minimum device diameter per patient (mm)	2.75 ± 0.25
Device implantation
At least 1 BVS	212 (99.5)
BVS only	204 (95.8)
Overlapping with at least 2 AVBs	20 (9.39)
Any DES	8 (3.8)
After BVS implantation failure	1 (0.5)
Procedural time (min.)	44 ± 23
Iodinated contrast used per procedure (mL)	161 ± 72
Predilatation of the first lesion treated	189 (88.7)
Procedural success	212 (99.5)
Lesions treated
Total number	233
Predilatation	208 (89.3)
Postdilatation	78 (33.5)
0.5 mm postdilatation balloon plus BVS	21 (9.86)
Overall number of devices implanted	261
Overall number of devices per lesion	1.12 ± 0.4
Intracoronary imaging modality during implantation
OCT or IVUS	86 (40.38)
BVS, bioresorbable vascular scaffold; DES, drug-eluting stent; IVUS, intravascular ultrasound; OCT, optical coherence tomography. Data are expressed as no. (%) or mean ± standard deviation.

Clinical follow-up

The median follow-up was 44 months [28 months] with minimum times < 1 month. The primary composite endpoint of target vessel failure rate was 6.57% at the 24-month follow-up (table 3) and 7.98% at the end of the follow-up. Figure 1 shows the target vessel failure-free survival curve; at the 48-month follow-up it was 0.92 (95%CI, 0.87-0.95; P = .02). Regarding the secondary endpoint, the overall rate was 11.74% at the 24-month follow-up (table 3) and 17.84% at the end of the follow-up.

Table 3. Adverse events at the 2-year follow-up

Adverse event	Patients who received BVS 2-year follow-up (n = 213)
Clinical events
All-cause mortality	5 (2.34)
Cardiac	3 (1.41)
Non-cardiac	2 (0.94)
All myocardial infarctions	6 (2.82)
During index procedure	2 (0.94)
Not during index procedure	4 (1.88)
Target vessel	3 (1.41)
Non-target vessel	1 (0.47)
Death or myocardial infarction	11 (5.16)
Any revascularization	18 (8.46)
Target vessel	11 (5.16)
Target lesion	11 (5.16)
Device thrombosis	3 (1.41)
Device restenosis	8 (3.76)
Any other vessel	7 (3.29)
Composite endpoint
Target vessel failure	14 (6.57)
Overall clinical endpoint	25 (11.74)
Device thrombosis
Definite	3 (1.41)
Probable	2 (0.94)
Possible	1 (0.47)
BVS, bioresorbable vascular scaffold. Data are expressed as no. (%).

Figure 1. Kaplan-Meier survival curve for target vessel failure.

Figure 2 shows the rate of all adverse events depending on the time of clinical presentation. Regarding the primary endpoint, there were 3 (1.41%) cases of cardiac death, 4 (1.87%) cases of target vessel related AMI, and 14 (6.57%) cases of target vessel revascularization. Regarding the secondary endpoint, there were 7 (3.29%) cases of all-cause mortality, 7 (3,29%) cases of AMI, and 31 (14.56%) cases of any coronary revascularizations. Finally, regarding the device, there were 6 (2.81%) cases of thrombosis (definite, probable, and possible) all reported within the first 12 months. Dual antiplatelet therapy was kept, at least, for 12 months in 157 (73.7%) patients and 1 patient with late definite thrombosis received dual antithrombotic therapy (acenocoumarol and clopidogrel). Similarly, there were 10 (4.69%) cases of BVS restenosis within the first 48 months of follow-up (figure 3).

Figure 2. Chart of adverse events based on the time of presentation after the index procedure. AMI, acute myocardial infarction; BVS, bioresorbable vascular scaffold.

Figure 3. Kaplan-Meier survival curves for bioresorbable vascular scaffold restenosis and thrombosis.

Patients with target vessel failure had a higher prevalence of cerebrovascular disease (17.65% vs 3.06%; P = 0.01), chronic oral anticoagulation (17.65% vs 3.57%; P = .01), and previous coronary artery bypass graft surgery (11.76% vs 2.55%; P = .04). Similarly, there was a tendency towards a higher prevalence of diabetes mellitus in this group (41.18 vs 22.45%; P = .06) (table 1).

In the multivariate Cox regression analysis, a prior history of diabetes mellitus (HR, 1.72; 95%CI, 1.01-2.95; P = .05) and chronic oral anticoagulation (HR, 5.71; 95%CI, 1.12-28.94; P = .04) were identified as risk factors to develop target vessel failure at the follow-up. On the other hand, the use of intracoronary imaging modalities (OCT or IVUS) during BVS implantation showed a clear tendency towards significance as a protective factor (HR, 0.33; 95%CI, 0.10-1.07; P = .06) (table 4).

Table 4. Factors associated with target vessel failure: Cox regression analysis

	Univariate analysis	Multivariate analysis
HR	95%CI	P	HR	95%CI	P
Past medical history
Diabetes mellitus	1.72	1.04-2.86	.04	1.72	1.01-2.95	.05
Previous stroke or TIA	6.28	1.76-22.31	.01	1.94	0.40-9.23	.40
Chronic oral anticoagulation	5.34	1.51-18.97	.01	5.71	1.12-28.95	.04
Use of intracoronary imaging modalities during implantation
OCT or IVUS	0.32	0.11-1.03	.06	0.33	0.10-1.06	.06
95%CI, 95% confidence interval; HR, hazard ratio; IVUS, intravascular ultrasound; OCT, optical coherence tomography; TIA, transient ischemic attack.

DISCUSSION

This study analyzed a consecutive series of patients who were implanted with, at least, 1 BVS in a high-volume setting and in real-life conditions. The primary composite endpoint of target vessel failure and the overall secondary composite clinical endpoint were similar to what had been reported by other previous randomized clinical trials on percutaneous coronary interventions.18^-22

The AIDA clinical trial20 confirmed the lower rate of target vessel failure related AMI from our series. In our study, the patients’ baseline clinical characteristics and clinical presentation were similar to those of the population of the AIDA clinical trial. However, regarding the index procedure, the use of postdilatation was lower in our series. It has been reported that postdilatation does not bring any additional benefits to the implantation of a BVS in the ST-segment elevation acute coronary syndrome clinical setting. If elevation is excessive it could even have deleterious effects when destructuring or tearing the nonmetallic structure of the scaffold.23 The GHOST-EU registry24 proved that the PSP strategy (predilatation, scaffold sizing, and postdilatation) was a predictor of cardiovascular events.

The right selection of the lesion plays a crucial role in the clinical performance of BVS. Most of the patients of this series showed acute coronary syndrome. It is feasible that patients with AMI may benefit the most from BVS treatments.18 First, patients with acute coronary syndrome (with or without ST-segment elevation) often show a visible thrombus in the proximal segments and a less complex morphology with thin-cap fibroatheroma plaques and fewer calcified lesions. Secondly, aggressive antithrombotic therapy after an acute coronary syndrome may mitigate the rate of thrombotic complications.

Bioresorbable vascular scaffold thrombosis

A few studies have reported on a higher rate of BVS thrombosis associated with next-generation DESs,25^,26 especially all in off-label uses.27 In our series, the definite or probable device thrombosis occurred in a similar percentage of the patients to that previously reported.12 Several mechanisms that may explain BVS thrombosis have been suggested including edge dissection, strut fracture, malapposition, and inadequate BVS sizing.28 In our series there were 2 cases of subacute definite thrombosis. In the coronary angiography, the OCT performed confirmed the presence of some structural mechanism (underexpansion or malapposition) that favored it. Early presentation at the follow-up is consistent with what has already been reported.29

Similarly, we identified that the use of intracoronary imaging modalities (OCT or IVUS) during BVS implantation showed a clear tendency towards significance as a protective factor of target vessel failure as Caixeta et al.30 had already confirmed in an international registry of 1933 patients. The recommendation here is to use intracoronary imaging modalities to optimize implantation and secure the correct apposition of the BVS, lack of underexpansion, and proper cover of the lesion.31

The main setback of the Absorb BVS is probably strut thickness and width (157 x 190.5 µm in 2.5 mm and 3.0 mm BVSs, and 157 µm x 216 µm in 3.5 mm BVSs), which can make the device more thrombogenic, especially when apposition is not the right one or expansion is incomplete. Today, ultra-thin drug-eluting stents (strut thickness < 70 µm) have lowered the risk of target lesion failure to just 1 year compared to modern second-generation DESs thanks to fewer AMIs and stent thrombosis.32 On this issue, the sirolimus-eluting MeRes100 BVS (Meril Life Sciences Pvt. Ltd., India) with thinner strut thickness (100 µm) confirmed the sustained efficacy and safety profile at the 2- and 3-year follow-up.33

Resistance to antiplatelet therapy can also be an important cause for BVS thrombosis.34 Both acetylsalicylic acid and clopidogrel are effective antiplatelet drugs for the secondary prevention of cardiovascular events. Still their clinical efficacy varies from one individual to the next.35 In our series, most of the patients remained on dual antiplatelet therapy for, at least, 12 months and there was 1 case of late thrombosis with dual antithrombotic therapy (acenocoumarol and clopidogrel). Due to his high bleeding risk, this last patient received dual antiplatelet therapy for the first 3 months; we do not know the international normalized ratio when the complication occurred, which is why the possibility of antiplatelet drug resistance cannot be discarded. However, the potential association between the BVS thrombosis and oral antiplatelet therapy had already been described.36 We know that the selection of duration of antiplatelet therapy following the implantation of the Absorb BVS was difficult,37 especially in anticoagulated patients because they are a population with comorbidities and high cardiovascular risk. Our data show that the implantation of the Absorb BVS in patients at high bleeding risk (including anticoagulated patients) shouldn’t probably be recommended according to the consensus document reached by the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery. This document does not recommend the use of the Absorb BVS in patients intolerant to prolonged dual antiplatelet therapy or who require oral anticoagulation.16

Bioresorbable vascular scaffold restenosis

The most common cause for target lesion revascularization was stent restenosis within the first 48 months of follow-up. The mechanisms involved in bioresorbable vascular scaffold restenosis that may occur in the same patient are varied.38^,39 The less intrinsic radial strength and its possible destructuring with an aggressive implantation may explain some of the early recurrences. In this study, aggressive implantation was less common since postdilatation with an up to 0.5 mm balloon combined with BVS implantation occurred in 9.86% of the cases. Also, postdilatation was not associated with restenosis at the follow-up. Also, it has been suggested that the slow resorption of the study device may have been associated with a significant spatial abnormality with loss of alignment of its structural elements, which favors restenosis.40^,41 The complete disappearance of the BVS from the vascular wall won’t happen for another 3 years6 and most cases of scaffold restenosis occurred within the first 2 years of follow-up.

Our study results show that there is a correlation between the history of diabetes mellitus and chronic oral anticoagulation and the development of target vessel failure. It is well-known that this past medical history elevates cardiovascular morbimortality and that the CHADS2 and CHA2DS2-VASc scores can be used to estimate the risk of adverse clinical events in patients with acute coronary syndrome.42 In this sense, patients with a past medical history of diabetes mellitus, chronic oral anticoagulation, and coronary artery disease start with CHA2DS2-VASc scores of 4, that is, high risk of adverse clinical events.

Limitations

Selection bias was inevitable because, according to the operator’s criterion, the clinical assessment that may have influenced the decision to implant a BVS maybe did not come from the database, which is a common problem with observational studies like this one. However, the study shows a pragmatic approach to the use of this device in the real world.

CONCLUSIONS

In this series of patients implanted with the Absorb BVS, the composite endpoint of target vessel failure and the overall clinical composite endpoint were similar to what had already been reported by randomized clinical trials. Adverse events were more common within the first 2 years of follow-up in case of greater cardiovascular comorbidity and without intracoronary imaging modalities (OCT or IVUS) during implantation. Although the BVS studied is not available anymore there other bioresorbable devices are in the pipeline.16

FUNDING

R. Mori-Junco received the 2018 training grant from the European Society of Cardiology (APP000019660). L. Furuya-Kanamori received funding from the Australian National Health and Medical Research Council Early Career Fellowships (APP1158469).

CONFLICTS OF INTEREST

The authors declared no conflicts of interest whatsoever.

 

 

REFERENCES