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

INTRODUCTION

Fractional flow reserve (FFR) measurement is an invasive procedure performed during coronary angiography to determine the functional significance of coronary stenoses.

In recent years, the instantaneous wave-free ratio (iFR) resting index has been developed to assess the functional significance of coronary stenoses without the need for adenosine administration. The optimal iFR cutoff value—equivalent to 0.80 in FFR—was initially established at 0.89.1 In 2017, 2 clinical studies comparing FFR with iFR found no significant differences in clinical outcomes at follow-up.2-3 After the publication of these 2 studies, the European Society of Cardiology guidelines on myocardial revascularization4 assigned resting indices the same grade of recommendation as FFR for the functional assessment of coronary lesions.

Despite the validation of these 2 techniques in clinical trials and their inclusion in clinical practice guidelines, up to 20% discordance has been reported between iFR+/FFR− or iFR−/FFR+5 Several clinical factors, such as diabetes,6 and anatomical factors, such as lesion location in the left main or proximal left anterior descending coronary arteries, have been identified in association with this discordance.7

Previous studies comparing FFR with iFR using a piezoelectric pressure sensor wire (PPSW) calculated the mean distal-to-aortic pressure ratio beginning 25% into diastole and ending 5 ms before end diastole.1

Recently, a new resting index—the diastolic pressure ratio (dPR)—has been developed to calculate the mean distal-to-aortic pressure ratio over the entire diastolic phase (from the lowest point of the dicrotic notch up to 50 ms before the onset of the upstroke of the next beat)8 using a fiber-optic sensor wire (FOSW).

A study that compared the values of different resting indices (iFR, dPR, dPR25-75, dPRmid, iFRmatlab, iFR50ms, and iFR100ms) revealed that all were numerically identical,8 meaning that the results obtained with the iFR can be extrapolated to other resting indices.

To date, no study has compared the agreement between dPR and FFR measured using a FOSW. One advantage of the FOSW over the PPSW is the lower loss of mean pressure matching in the wire compared with the measurement obtained in the guide catheter (drift).9 Although various iFR studies state that drifts < ± 0.02 are considered acceptable, the drifts reported with the FOSW were even lower at < ± 0.01.10

The diagnostic reproducibility of PPSW decreases significantly when close to the threshold value of 0.80 and is approximately 80% when measurements are < 0.77 or > 0.83, and around 90% with values < 0.76 or > 0.84.11 Since the FOSW is less sensitive to changes in humidity and temperature, greater reproducibility of results can be expected when the measurement is repeated.

Considering that most discordant measurements have been associated with cutoff values, the better reproducibility of measurements and practically nonexistent drift of the FOSW can more accurately determine FFR and dPR measurements and reduce discrepancies.

METHODS

Study design

In this prospective, observational, and multicenter registry of consecutive coronary stenoses, we conducted a study with FOSW based on our routine clinical practice.

We included consecutive patients with clinical signs and coronary angiography findings suggesting the need for a functional study with a pressure wire. We excluded patients with cardiogenic shock, heart failure, severe anemia (hemoglobin < 10 mg/dL), heart rate < 50 or > 100 bpm, baseline systolic blood pressure < 90 mmHg or > 160 mmHg, severe coronary artery lesions in distal segments, and contraindications for the administration of adenosine.

Objective

The aim of this study was to evaluate the incidence and factors related to diagnostic discrepancies between these indices using the FOSW. Secondary aims consisted of assessing the diagnostic reproducibility of FOSW in 2 consecutive measurements of FFR and dPR and evaluating the drift rate.

Procedure

The study was approved by the Drugs Research Ethics Committee of the Basque Country (internal code PS 2019039). All patients received information on the study and were asked to sign a written informed consent form prior to their participation in the study.

We performed coronary angiography using standard methods, with visual estimation of severity after intracoronary nitroglycerin administration. We included lesions with up to 50% to 75% percent diameter stenosis and collected data on the reference luminal diameter, minimum luminal diameter, lesion length, calcification, and vessel tortuosity for each studied lesion.

We performed 2 consecutive measurements of dPR (threshold, 0.89) and FFR (threshold, 0.80) for each studied lesion and analyzed the clinical and angiographic factors to determine their correlation with discordance (FFR−/dPR+ and FFR+/dPR−). We took dPR1 and FFR1 as reference values for discrepancy analysis.

We conducted the FOSW functional study with 5-, 6-, or 7-Fr guide catheters without side holes, using an OptoWire (Opsens Medical, Canada). After advancing the wire toward the tip of the guide catheter, we removed the introducer sheath and flushed the system with saline solution to prevent damping of the pressure wire resulting in equal pressure of the wire and the guide catheter at the tip of the catheter. After advancing the pressure wire distally, we administered 200 μg of intracoronary nitroglycerin before taking any measurements. We took the 2 dPR measurements after waiting the necessary time to obtain confirmation of a stable baseline distal-to-aortic coronary pressure ratio (Pd/Pa).

Subsequently, we took 2 different FFR measurements. Hyperemia was induced according to standard practice in each center (through intracoronary or IV adenosine infusion). If intracoronary adenosine was infused, for the second measurement, we waited until the baseline heart rate, blood pressure, and Pd/Pa were regained and then infused the same dose of adenosine. If IV adenosine was infused, the infusion was stopped until baseline heart rate, blood pressure, and Pd/Pa were regained, and then we infused adenosine at the same rate.

We evaluated the presence of drift upon removal of the pressure wire from the guide catheter. Drift was defined as a difference in Pd/Pa of at least ± 0.02 upon removal of the pressure wire from the guide catheter. In the presence of significant drift, measurements were repeated.

Cutoff values

The cutoff value was ≤ 0.80 for FFR and ≤ 0.89 for dPR.10 We categorized all studied vessels based on dPR and FFR values into 4 groups: concordant positive group (FFR ≤ 0.80 and dPR ≤ 0.89), concordant negative group (FFR > 0.80 and dPR > 0.89), discordant FFR+/dPR− group (FFR ≤ 0.80 and dPR > 0.89), and discordant FFR−/dPR+ group (FFR > 0.80 and dPR ≤ 0.89).

Statistical analysis

Continuous variables are expressed as mean and standard deviation, while categorical variables are expressed as percentages. We measured the association between continuous variables using Pearson’s correlation coefficient. To determine differences in variables in the FFR/dPR concordance groups we used ANOVA (for continuous variables) and the chi-square test (for categorical variables). We used the chi-square test to assess how each variable impacted FFR−/dPR+ and FFR+/dPR− discrepancies, and a multiple logistic regression model with backward elimination to determine the factors impacting FFR−/dPR+ and FFR+/dPR− discrepancies. On univariate analysis, we included variables with P < .1 in the logistic regression analysis and excluded those with a total n < 10. The analysis was conducted using SPSS software (version 20.1) and R (version 4.0.4).

RESULTS

We included a total of 428 stenoses in 361 patients. Table 1 and table 2 show the patients’ baseline characteristics, clinical presentation, and procedural characteristics.

Table 1. Patients’ baseline characteristics

Table 2. Clinical presentation and procedural characteristics

Sixty-seven percent of the patients received intracoronary adenosine; the mean doses of intracoronary adenosine administered were 324 μg (standard deviation [SD] ± 152) via the right coronary artery and 442 μg (SD ± 234) via the left coronary artery.

The medians of dPR measurements were 0.90 and 0.90 (SD ± 0.08) for the first and second measurements, with positivity rates of 27.4% and 27.9%, respectively. For FFR, the medians were 0.83 and 0.83 (SD ± 0.08) for the first and second measurements, with positivity rates of 28.1% and 30%, respectively.

The most widely studied vessel was the left anterior descending coronary artery (63%), followed by the left circumflex (20%) and right coronary arteries (16%).

The left anterior descending coronary artery showed a higher positivity rate (dPR+, 35.3%; FFR, 34%) than the left circumflex (dPR, 11.9%; FFR, 20.5%) and right coronary arteries (dPR, 15.9%; FFR, 17.4%).

Diagnostic reproducibility was 95.8% for dPR, with a correlation coefficient between the 2 measurements (dPR1 and dPR2) of 0.974 (P < .0001) and a mean difference of 0.019 (max, 0.12; min, −0.17). For dPR values < 0.86 or > 0.92, diagnostic reproducibility was 99.6%, decreasing to 90.7% when values were ≥ 0.86 or ≤ 0.92. For FFR, diagnostic reproducibility was 94.9%, with a correlation coefficient (FFR1 and FFR2) of 0.942 (P < .0001) and a mean difference of 0.029 (max, 0.14; min, −0.18) (figure 1). Values < 0.77 or > 0.83 showed a diagnostic reproducibility of 98.6%, decreasing to 86.4% when these values were ≥ 0.77 or ≤ 0.83.

Figure 1. Correlation coefficient and histogram of the differences between the 2 dPR and FFR measurements. dPR, diastolic pressure ratio; FFR, fractional flow reserve; SD, standard deviation.

The diagnostic concordance (figure 2) between FFR and dPR was 82%, with a correlation coefficient of 0.721 (P < .0001), while diagnostic discordance was 18.2% (FFR+/dPR–, 8.2% and FFR–/dPR+, 10.0%). In the FFR+/dPR– discordant group, FFR was 0.76 ± 0.04 and dPR, 0.93 ± 0.03. In the FFR–/dPR+ discordant group, FFR was 0.84 ± 0.03 and dPR, 0.86 ± 0.03.

Figure 2. Distribution of lesions according to FFR and dPR, with the rate of concordant and discordant measurements. dPR, diastolic pressure ratio; FFR, fractional flow reserve.

Out of the 75 discordant results reported, the measurements at the cutoff value (7 stenoses with FFR 0.80 and 18 stenoses with dPR 0.89) showed a discordance rate of 72%, which decreased as it moved away from the cutoff value (figure 3).

Figure 3. Probability of diagnostic discordance between FFR and dPR. The probability of discordance is close to 50% around the FFR cutoff point of 0.80 and decreases as it moves away from this point. Empirical model (bar chart) and model proposed by Petraco et al.11 (in grey). dPR, diastolic pressure ratio; FFR, fractional flow reserve.

Table 1 of the supplementary data illustrates the association between clinical and anatomical characteristics and the extent of agreement between FFR and dPR.

Out of all the variables analyzed in the multivariate analysis, hypertension (odds ratio [OR], 3.48, 95% confidence interval [95%CI], 1.01-11.98; P = .043) and intracoronary adenosine (OR, 7.04; 95%CI, 1.63-30.3; P = .001) were significantly associated with FFR–/dPR+ discordance. Age younger than 75 years (OR, 4.52; 95%CI, 1.03-20; P = .016) and percent diameter stenosis > 60% (OR, 6.69; 95%CI, 2.79-16; P < .001) were significantly associated with FFR+/dPR– discordance (table 3).

Table 3. Univariate analysis and multivariate logistic regression of variables associated with discordance

The drift rate was 5.7%.

DISCUSSION

We present the results of the first study conducted with a FOSW capable of measuring the diagnostic variability of 2 consecutive determinations of nonhyperemic and hyperemic indices, as well as the diagnostic discordance between the 2 techniques.

Previous discordance studies between the 2 indices with PPSW revealed discordance rates ranging from 12% to 22%,12,13 largely depending on the proximity of the values to the cutoff point. In a study by Lee et al.,12 the mean iFR and FFR values were 0.95 ± 0.10 and 0.87 ± 0.11, respectively, with a discordance rate of 12%, while in a study by Warisawa et al.,13 the mean iFR and FFR values were 0.89 ± 0.05 and 0.80 ± 0.03, respectively, with a discordance rate of 22%. In our study, the discordance rate was 18.2%, with a mean dPR of 0.90 (SD ± 0.08) and a mean FFR of 0.83 (SD ± 0.08), which is a slightly lower discordance rate than that reported by previous studies on PPSW and mean iFR and FFR values close to the cutoff point, which may be indicative of the accuracy of measurements obtained with FOSW.

The main findings of this study were the excellent diagnostic reproducibility of the FOSW, the clinical and anatomical variables related to FFR/dPR discordance, and the low drift rate reported in the measurements.

Diagnostic reproducibility with the fiber-optic sensor wire

Diagnostic reproducibility with the FOSW was excellent, with a variation between 2 consecutive measurements < 0.02 for dPR and < 0.03 for FFR. This accuracy in measurement confers excellent diagnostic reproducibility. These data are better than those previously reported with PPSW.11

Clinical and anatomical variables associated with FFR/dPR discordance

For FFR+/dPR− discordance, in the multivariate analysis, only age younger than 75 years and percent diameter stenosis > 60% were significantly associated with FFR+/dPR− discordance. This discordance in participants younger than 75 years could be explained by a slower baseline flow and a greater coronary flow reserve in younger patients with preserved microvascular function.14,15 Although discordance due to a higher percent diameter stenosis has already been described in previous studies,15,16 such discordance requires a preserved coronary flow reserve.6 When arterial flow velocity significantly increases during hyperemia, the pressure gradient does so too, decreasing distal coronary pressure during hyperemia substantially compared with baseline values, resulting in a low FFR value.

For FFR−/dPR+ discordance, in the multivariate analysis, the associated variables were hypertension and the administration of intracoronary adenosine. Although hypertension has not been associated with FFR−/dPR+ discordance in previous studies, it is known that patients with hypertension and left ventricular hypertrophy have a reduced coronary flow reserve17 and a possible lack of vasodilatory response to adenosine due to an increased left ventricular end-diastolic pressure. These 2 factors could play a key role in the association between hypertension and FFR−/dPR+ discordance.

Although IV adenosine is the most widely studied route of administration to achieve maximum hyperemia, intracoronary adenosine at doses > 300 μg may be equally or more effective in achieving maximum hyperemia18 and with fewer adverse events.19 In our study, the FFR−/dPR+ discordance reported when intracoronary adenosine was used could be a result of a failure to achieve adequate hyperemia.

These variables related to discordance demonstrate that dPR and FFR measure different aspects of coronary circulation, which may be affected differently in distinct patients or myocardial territories, leading to discordant FFR values and nonhyperemic indices.20

Drift in the fiber-optic pressure wire

The incidence of drift in clinical studies of pressure wires is not well known, and the drift considered acceptable has varied over the years. Previously, FFR measurement was repeated when drift was > 5 mmHg,21 while in more recent studies, drift > 3 mmHg has been considered significant. When FFR is between 0.77 and 0.82, drift ≤ 3 mmHg can reclassify 18.7% of stenoses,22 and this reclassification may be higher when a nonhyperemic diastolic or whole-cycle index is used.23 In the CONTRAST trial analysis of the PPSW, the drift rate (Pd/Pa ± 0.03) was 17.5%,24 while a more recent study comparing drift between FOSW and PPSW revealed a significantly lower rate with the FOSW (4.8% vs 26.7%; P = .02).9 In our study, the drift rate was 5.7%, which is consistent with other studies on FOSW, and much lower than that reported with PPSW, facilitating the use of pressure wire in routine clinical practice.

Limitations

Our study has several limitations. Both the severity and length of coronary lesions were quantified by the operator’s visual estimation at the time of the procedure, and since this was a study without a core laboratory, we cannot rule out the possibility that some of the discrepancies found were due to technical problems in determining the indices. Since the study was based on our routine clinical practice, most patients received intracoronary adenosine, and the protocol did not specify the intracoronary infusion comprehensively, which may have resulted in the lower hyperemia reported in some patients.

Target lesion revascularization was based on dPR or FFR values according to the operators’ decision. Patient selection for pressure guidance evaluation was also left to the treating physician’s discretion, which may have resulted in biases. However, our intention was to study dPR and FFR indices under real-world conditions.

CONCLUSIONS

Although FFR and dPR measurements with FOSW have excellent reproducibility and a low incidence of drift, the discordance rate remains similar to that reported by previous studies with PPSW, and largely depends on the proximity of values to the cutoff point. Intracoronary adenosine and hypertension, which imply a lack of hyperemia or increased microvascular resistance, are associated with FFR−/dPR+ discordance. Age younger than 75 years and the severity of stenosis, which may be associated with a preserved coronary flow reserve, are related to FFR+/dPR− discordance.

FUNDING

This study received no funding.

ETHICAL CONSIDERATIONS

This study was approved by the Drugs Research Ethics Committee of the Basque Country (internal code PS 2019039) for its implementation. All patients received a patient information sheet about the study and signed an informed consent form before enrollment. The study took into consideration sex and gender variables before drafting this article.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence has been used.

AUTHORS’ CONTRIBUTIONS

M. Sádaba Sagredo drafted the protocol, included patients as the lead investigator of his center, and drafted the manuscript. A. Subinas Elorriaga and A. Quirós contributed to the statistical analysis and drafting of the manuscript. The remaining authors are lead investigators of the READI EPIC-14 trial in their respective centers and contributed to patient inclusion and article review.

CONFLICTS OF INTEREST

None declared.

SUPPLEMENTARY DATA

Supplementary data associated with this article can be found in the online version available at https://doi.org/10.24875/ RECIC.M24000448.

ACKNOWLEDGEMENTS

We wish to thank M.ª Ángeles Carmona for her support in data collection and patient inclusion.

REFERENCES

INTRODUCTION

Coronary artery disease is the leading single cause of mortality worldwide, accounting for more than 7 million deaths annually1 and its prevalence has been increasing in the last 20 years.2 Percutaneous coronary intervention (PCI) has been crucial in the treatment of coronary artery disease.3,4 The advent of drug-eluting stents (DES) has substantially reduced restenosis rates through the deposition of antiproliferative drugs in the vessel wall. DES have evolved over the years and have become the gold standard in PCI.5 Drug-coated balloons (DCB) represent an alternative in the setting of PCI. DCB consist of a balloon coated with antiproliferative agents encapsulated in a polymer matrix.6 Upon inflation, the balloon brings the antiproliferative drug into contact with the vessel wall. The main goal of DCB is to eliminate the risk of stent thrombosis and achieve lower restenosis rates by not leaving any type of metal structure in the treated segment.6

The safety and efficacy of DCB have been extensively studied in de novo coronary artery disease.6 In small vessel disease, DCB have demonstrated noninferiority to DES in several randomized clinical trials.7 A recent meta-analysis has shown that the use of DCB, compared with that of DES, is associated with a lower risk of vessel thrombosis and a trend toward a lower risk of acute myocardial infarction.8 In large vessel de novo lesions, current data do not support the widespread use of DCB over DES, although DCB appear to be safe and effective.9,10 Nevertheless, there is a need to elucidate the elution on the vessel wall, healing processes, plaque remodeling, plaque composition and the impact on the coronary microcirculation following PCI with DCB.

The present report describes the design and rationale for a study of plaque modification and impact on the microcirculation after PCI with DCB (the PLAMI study).

METHODS

The study will be an investigator-initiated, single-center, single-arm, open-label, pilot study in patients undergoing PCI with DCB for de novo lesions. The study has been approved by the hospital ethics committee on research involving medical products. The study has been registered in ClinicalTrials.gov (NCT06080919).

Procedure

Eligible patients will be informed about the study and will be required to provide signed informed consent prior to inclusion. Patients will undergo DCB-PCI under intravascular ultrasound (IVUS) guidance. Angiography-derived coronary physiology will be assessed after the procedure using Angio Plus software (Pulse Medical Imaging Technology, China). The angiography images will be used to obtain the angiography-derived index of microcirculatory resistance (IMRangio) values, before and after DCB-PCI. All procedures will be performed according to current European guidelines5: the target lesion will be predilated with semicompliant balloons or noncompliant balloons, with a diameter equal to the reference vessel diameter and with an appropriate length. Multiple predilations will be accepted. The DCB will be the paclitaxel-coated balloon Pantera Lux (BIOTRONIK AG, Switzerland).

The lesion will then be treated with a DCB with a reference vessel diameter/balloon diameter ratio of 1:1. DCB length will be equal to lesion length + 5 mm. DCB inflation time will be set at 45 to 60 seconds to guarantee correct and complete drug elution. The prespecified reasons for DES implantation after DCB-PCI will be residual stenosis > 30%, dissections > type B and TIMI flow < 3.6 Angiographic follow-up with IVUS and IMRangio evaluation will be performed 3 months after the index procedure. The study timeline is summarized in figure 1.

Figure 1. Timeline of the PLAMI study. DCB, drug-coated balloon; IMRangio, angiography-based index of microcirculatory resistance; IVUS, intravascular ultrasound; PCI, percutaneous coronary intervention.

IVUS images will be taken before the DCB-PCI, immediately after, and at 3 months of follow-up using the Opticross HD 60 MHz (Boston Scientific Corp, United States) system. All IVUS studies will be performed after intracoronary administration of 200 μg of nitroglycerin. The IVUS images will be acquired at 30 frames per second with an automatic transducer pull back (at 0.5 mm/second) to the proximal reference vessel lesion. As there will be no stents to take as a reference, the proximal and distal side branches adjacent to the treated lesion will serve as references, matching the coronary angiographic images (figure 2). All IVUS images will be analyzed by an independent core lab.

Figure 2. Schematic representation of IVUS acquisition. The IVUS images will be acquired before (A) and after (C) DCB-PCI (B) at 30 frames per second with an automatic transducer pull back (at 0.5 mm/second) to the proximal reference vessel lesion. The same anatomic slice will be analyzed before, after, and at 3 months of follow-up after the PCI by using reproducible landmarks (side branches). The first frame analyzed will be the distal point of the treated vessel before the exit of the DB (represented by the rightmost dotted line), and the last frame analyzed will be the proximal point of the vessel before the split of the proximal branch. DB, distal branch; DCB-PCI, drug-coated balloon percutaneous coronary intervention; IVUS, intravascular ultrasound; PB, proximal branch.

Angiography-derived assessment of coronary physiology will be performed with Angio Plus software (Pulse Medical Imaging Technology, China). For the evaluation of each lesion, at least 2 projections with a difference of > 25° will be selected. The operator will manually mark the points proximal and distal to the lesion, and the system automatically outlines the contours of the detected vessel. If the traced vessel trajectory deviates from the normal lumen, the necessary manual modifications will be performed. The artificial intelligence-assisted software combines the intravascular imaging information with the estimated vessel flow to obtain the IMRangio. All the angiography images will be analyzed by an independent core lab to obtain the IMRangio.

Study population and enrolment criteria

Patients will be screened to ensure they meet the inclusion criteria and none of the exclusion criteria prior to study enrolment. Inclusion criteria consist of an indication to undergo PCI for a de novo lesion according to current guidelines (with no restrictions regarding vessel size).5 Inclusion and exclusion criteria are summarized in table 1.

Table 1. Inclusion and exclusion criteria

Sample size

Because of the exploratory nature of this study, no formal sample size calculation is required. Based on previous pilot studies with similar designs,12 a sample of 30 lesions is planned to evaluate the impact of DCB on coronary healing and the microcirculatory territory.

Study endpoints

The primary endpoint is the change in percentage atheroma volume evaluated by IVUS from baseline to 3 months of follow-up. Secondary endpoints will include a) lumen change from baseline to 3 months of follow-up (minimum, maximum, average areas), b) the percentage of progressors and percentage of regressors, c) external elastic membrane (EEM) change from baseline to post DCB-PCI (average), d) EEM change post-DCB-PCI to the 3-month follow-up (average), e) the percentage of remodeling types (neutral, negative, and positive), f) IMRangio change from baseline to post- DCB-PCI, g) IMRangio change from post-DCB-PCI to the 3-month follow-up.

An independent clinical event committee, consisting of cardiologists not participating in the trial, will review and adjudicate all major adverse cardiac events according to the study protocol.

Considering the luminal area as the area delimited by the luminal border, the minimal luminal area is defined as the smallest lumen area within the length of the treated lesion.13,14 The atheroma or plaque burden is defined as the ratio of atheroma area to the vessel EEM and is calculated by dividing the sum of plaque and media cross-sectional area (CSA) by the EEM CSA.13,14 As the atheroma area can be calculated in each frame, the total atheroma volume is obtained by taking the sum of the differences between the EEM CSA area and the luminal CSA for all available images.15 The percent of the volume of the EEM occupied by atheroma is called the percentage atheroma volume.15,16

Serial arterial remodeling types will be classified as usual: neutral if there is no change in EEM, negative if there is a decrease in the EEM and positive if vice versa.

Statistical considerations

Continuous variables will be described as mean ± standard deviation or median [interquartile range]. Categorical variables will be described as percentages. The paired t-test will be used to compare continuous variables measured before and after treatment in the same patient, and differences in proportions will be tested with the chi-square or Fisher exact test. A P value less than .05 (typically ≤ .05) will be considered statistically significant. Statistical analyses will be performed using Stata software version 13.1 (StataCorp LP, United States).

DISCUSSION

Although the use of DES remains predominant in the performance of PCI, complications such as stent thrombosis and in-stent restenosis led to the development of DCB. DCB have the theoretical benefit of not leaving metallic material in the vascular lumen, thereby reducing the possibility of mechanical complications such as malapposition, stent fracture, and stent thrombosis. This could potentially reduce neointimal proliferation and shorten the duration of dual antiplatelet therapy.6 Current guidelines assign a level IA recommendation to the treatment of in-stent restenosis.5 While the use of DCB in de novo lesions seems promising, it is not yet widespread. In addition, PCI is not without risks, as it involves a certain degree of injury to the artery wall from balloon inflations and stent struts.17,19 The vascular response to endothelial cell and smooth muscle cell injury represents a complex network of biochemical responses that involve the immune system. All these factors regulate the processes of neointimal hyperplasia, vascular remodeling, and normal reendothelialization of the arterial wall.17

The pathophysiology of restenosis and lumen loss after angioplasty is a complex process involving various factors and is not limited to neointimal hyperplasia.19 Acutely, plain old balloon angioplasty (POBA) generates an increase in luminal area that is mainly due to an expansion of the EEM, mainly attributed to the elastic properties of the vessel rather than to plaque compression or removal.20 Subsequently, within the first few minutes after PCI, there is an “acute recoil” due to the elastic properties of the arterial wall. In the chronic phase, IVUS data indicate that luminal loss is mainly due to a progressive reduction in EEM rather than an increase in atherosclerotic plaque volume. Unlike the acute phase where loss of area is solely due to elastic properties, “chronic recoil” leading to the loss of area also involves a combination factors such as fibrosis, apoptosis, and changes in the extracellular matrix.19,21 Interestingly, not all patients show negative remodeling with a decrease in EEM; around 25% show a persistent increase in EEM, which is correlated with a reduced restenosis rate. Consequently, restenosis appears to be primarily due to the direction and magnitude of changes in arterial remodeling,19 although neointimal hyperplasia also plays a role .

Nevertheless, the existing evidence is based on analysis after the use of traditional balloons. With DCB-PCI, late lumen enlargement has been observed compared with POBA.20 Although this finding has been partly attributed to the inhibition of neointimal proliferation by antiproliferative drugs,22 the role of plaque modification or vessel healing phenomena in influencing this process cannot be excluded. A previous study showed that late lumen enlargement was higher in areas with the highest plaque burden; however, that study was a retrospective assessment and used a quantitative coronary angio­graphy protocol.23 It could be hypothesized that, by inducing controlled damage to the artery wall, together with the antiproliferative effect of DCB, positive vessel remodeling might be achieved, reducing restenosis rates without the need for DES. Therefore, with DCB-PCI, we are able to treat coronary stenosis not only from a mechanical point of view, but can also change the natural history of the disease and restenosis. In this regard, IVUS analysis will be essential to evaluate the reasons behind the gain or loss of luminal area. The dynamic changes produced after PCI are depicted in figure 3.

Figure 3. Central illustration. Schematic representation of timeline of DCB-PCI and lumen variation. A: pre-DCB-PCI de novo lesion. B: DCB-PCI (blue), generating injury to the vessel wall and an increase in lumen and EEM CSA. C: acute recoil. D, chronic recoil with decrease in EEM and neointimal hyperplasia. E. LLE due to maintenance of EEM area and no neointimal hyperplasia. The dotted lines represent the variations of the luminal area throughout the process. The image exemplifies how changes in luminal area, as well as plaque burden, are mainly due to variations in EEM rather than plaque compression. CSA, cross-sectional area; DCB-PCI, drug-coated balloon percutaneous coronary intervention; EEM, external elastic membrane; LLE, late lumen enlargement.

The DCB that will be used in our study, paclitaxel, has been extensively analyzed as a balloon-coating drug due to its lipophilic properties and its ability to elute into the vessel wall.24 Moreover, the available paclitaxel-DCB have shown good results in patients undergoing PCI for native vessel disease.25 In contrast, because of the hydrophobic characteristics of sirolimus, maintaining an adequate percentage in the wall over the mid-term poses technical challenges. However, advances in the formulation of the new generation of sirolimus DCB are anticipated to address this issue by facilitating adequate drug release into the vessel wall.24

As previously mentioned, the coronary microcirculation is closely related to proper coronary functioning and the pathophysiology of coronary artery disease. While it is believed that the performance of PCI, as well as the injury and healing of the coronary artery, may affect the coronary microcirculation, the evidence regarding DCB-PCI is scarce. Moreover, the plaque rupture, intimal dissections and thrombus formation that occur during balloon angioplasty are a potential source of embolism to the microvascular bed.

Since direct visualization of the microcirculation is not feasible in clinical practice,26 its assessment relies on parameters reflecting its functional status, usually coronary flow reserve and the IMR. Coronary flow reserve is defined as the ratio between hyperemic flow in response to nonendothelial vasodilation and resting blood flow. It is crucial to exclude epicardial stenosis before using coronary flow reserve, as it provides an integrated measurement of both epicardial and coronary microcirculation.26 IMR is calculated as the product of distal coronary pressure at maximal hyperemia multiplied by the hyperemic mean transit time.

In our study, we will perform a noninvasive, nonhyperemic assessment of the coronary microcirculation using IMRangio. This approach aims to characterize the baseline status of the microcirculation and assess the microvasculature changes induced by PCI and their variation over a 3-month period.

By monitoring IMRangio before and after treating the stenotic epicardial lesion, we will be able to assess the effects of acute fracture of the atherosclerotic plaque and injury to the arterial wall in the microvascular bed. We also aim to investigate whether these collateral harmful changes provoked during angioplasty remain consistent or vary significantly at 3 months of follow-up. In this same context, the analysis of IVUS during follow-up will allow us to correlate the changes in the arterial wall and atherosclerotic plaque after DCB-PCI with microcirculation physiology. To date, no insights into the anatomical and physiological process of healing of the injured arterial wall after DCB-PCI have been available in the published literature.

CONCLUSIONS

The PLAMI study is a first-in-man pilot study that aims to provide new information on the modification of atherosclerotic plaque assessed by intracoronary imaging in patients with de novo lesions undergoing PCI with DCB.

FUNDING

None reported.

ETHICAL CONSIDERATIONS

The study has been approved by the hospital ethics committee on research involving medical products. Eligible patients will be informed about the study and must provide written informed consent prior to inclusion in the study. Possible gender/sex biases have been considered.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence has been used in the preparation of this article.

AUTHORS’ CONTRIBUTIONS

J.A Sorolla Romero, A.Teira Calderón, J. Sanz Sánchez and H.M. Garcia-Garcia contributed to the conception, design, drafting and revision of the article. J.P. Vílchez Tschischke, P. Aguar Carrascosa, F.Ten Morro, L. Andrés Lalaguna, L. Martínez Dolz and J.L. Díez Gil contributed to the critical revision of the intellectual content.

CONFLICTS OF INTEREST

None declared.

REFERENCES

INTRODUCTION

Ischemic heart disease is the leading cause of death worldwide. In Europe, despite the decline in incidence and mortality between 1990 and 2009, these trends have slowed in recent years. Moreover, Mediterranean countries showed lower rate of decline during this period.1

ST-segment elevation myocardial infarction (STEMI) is a particularly important presentation, associated with high mortality in young individuals.2,3 Primary percutaneous coronary intervention (PCI) is recommended as the first-line therapy to lower mortality and morbidity in STEMI patients.4-6 The timing of treatment is crucial for positive outcomes, and minimization of the time from symptom onset to revascularization is essencial.7,8 While several factors affect treatment timing, emergency system delays play a crucial role as they can be more easily altered by organizational measures and are often used as a quality measurement in STEMI networks.4,9-13

To ensure timely treatment, primary PCI centers included in STEMI networks are recommended to have a 24/7 service.4 However, the impact of admission time (on- vs off-hours) on treatment delay and patient outcomes remains a matter of debate. Some studies and a large meta-analysis have shown that off-hours admission is associated with worse outcomes, partially explained by longer system delays, less guideline-directed management, and less revascularization.14-16 Conversely, studies in high-volume PCI centers integrated in STEMI networks, demonstrated no differences in outcomes according to admission time.17-20 Overall, these results are heterogeneous and include populations from different health care systems.

In Europe, efforts have been made to improve STEMI care through public awareness, emergency medical system operations, and the implementation of a full national coverage 24/7 PCI network.21

The aim of this study was to determine the association between timing of admission in a PCI center and STEMI patients’ outcomes, within a STEMI network in south-western Europe.

METHODS

Study design and population

This retrospective observational cohort study identified 1369 consecutive patients treated with primary PCI at the catheterization laboratory of the Hospital de Braga (Portugal) between June 2011 and May 2016, through the local database that systematically includes all patients undergoing invasive coronary procedures. After an initial analysis, 115 patients were found to have evolved STEMI (> 12 hours since symptom onset) and were therefore excluded. To avoid duplication of results, we excluded 12 records of a repeat episode of STEMI in a patient previously identified in the selected time frame. Lastly, clinical follow-up data were not available for 20 patients, resulting in a final sample of 1222 patients (figure 1). These patients were divided into 2 groups according to admission time (on-hours and off-hours admission), and the main outcome measures evaluated were time delays, in-hospital mortality, and 1-year mortality.

Figure 1. Study flow-chart. PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction.

Definitions

STEMI was defined as the presence of symptoms of myocardial ischemia, associated with electrocardiographic criteria for ST-segment elevation.4

Admission time was based on arrival at the catheterization laboratory. On-hours were defined as admission from Monday to Friday between 8:00 AM and 6:00 PM on non-national holidays.

The first medical contact was defined as the first contact with a health service (hospital or primary care clinic). In patients primarily attended by the emergency medical system, the moment when the emergency vehicle carrying a trained physician arrived at the location of the patient was recorded. The reperfusion time was considered as the moment when the angioplasty guidewire crossed the culprit lesion. Time delays from symptom onset to first medical contact (patient-dependent time), from first medical contact to reperfusion (system-dependent time) and from symptom onset to reperfusion (total ischemic time) were characterized.

Patient stratification according to the Killip classification was based on physical examination and the development of heart failure. A Killip class IV classification was assigned to patients in cardiogenic shock.22

STEMI network organization

Hospital de Braga has a 24/7 catheterization laboratory service for primary PCI, performed by senior interventional cardiologists (on-call during off-hours). The hospital is the only primary PCI-capable hospital in the Minho region in the north of Portugal and serves approximately 1.1 million people (figure 2). First medical contact can be made by the emergency medical system or in non-PCI-capable hospitals and clinics, which decide whether to transfer the patient to the PCI-center after consulting the on-call clinical cardiologist. First medical contact can also be made in Hospital de Braga, with rapid triage to primary PCI.

Figure 2. Referral network of the catheterization laboratory of Hospital de Braga.

Data collection and statistical analysis

The data for the present study were obtained from the local database of the patient undergoing PCI, the patient’s clinical record, and the electronic health registry of Portugal. Clinical and demographic variables were collected.

The IBM Statistical Package for the Social Sciences (IBM SPSS) version 28.0 was used for data treatment. The variables studied to characterize the patients were divided into continuous variables and categorical variables. For the analysis of continuous variables, the distribution was first evaluated. If the variables showed symmetrical normal distribution, the results are presented as mean ± standard deviation, while for variables without normal distribution, the results are reported as median [interquartile range]. To compare continuous variables between the 2 groups of patients, parametric tests were applied for variables with normal distribution and nonparametric tests for the remainder. The Student t test for independent samples was used as the parametric test, after evaluation of the homogeneity of variances using the Levene test. The Mann-Whitney U test was the nonparametric test applied. For the description of categorical variables, absolute (No.) and relative (%) frequencies were calculated. The comparison of proportions between the study groups was made using the chi-square test or Fisher exact test when the percentage of cells in the table with an expected frequency less than 5 was greater than 20%. The 1-year survival analysis was performed using the Kaplan-Meier method, comparing the groups using the log-rank test. A multivariate analysis with Cox regression was performed, and was adjusted for confounding variables that were statistically significant in the univariate analysis (age, sex, smoking, diabetes mellitus, hypertension, cardiogenic shock, and total ischemia time), to determine if the timing of patient admission was an independent predictor of 1-year mortality. The adjusted hazard ratio (HR) and 95% confidence interval (95%CI) were analyzed to determine the significance of the predictor. In all analyses, results with probability values of P < .05 were considered statistically significant.

Confidentiality and ethical considerations

Informed consent for the procedure was obtained in all patients. The confidentiality and anonymity of all collected data were ensured during all phases of the study. This study was approved by the local ethics committee and complies with the provisions of the Helsinki Declaration. Informed consent for the present analysis was waived by the ethics committee due to the retrospective nature of the study.

RESULTS

Baseline characteristics

Between June 2011 and May 2016, of 1222 consecutive patients with confirmed STEMI, a total of 439 (36%) were admitted on-hours and 783 (64%) were admitted off-hours. Baseline characteristics were well-balanced between groups, including the percentage of patients admitted in cardiogenic shock (on-hours 5% vs off-hours 4%; P = .62) (table 1).

Table 1. Baseline characteristics

Comparison of treatment delays

The statistical analysis revealed no significant differences between groups for system-related, patient-related, and total ischemia time (table 2). Similarly, when examining patients directly admitted to the PCI-center, no significant differences were observed in terms of system-related, patient-related, and total ischemia time (table 2).

Table 2. Treatment delays

Association between admission time and outcomes

A 1-year follow-up was completed for all patients included in the analysis. There was no association between on- and off-hours admission time and in-hospital (5% vs 5%; P = .90) or 1-year mortality (10% vs 10%; P = .97). Equally, in patients admitted on- and off-hours directly to the PCI center, in-hospital (4% vs 7%; P = .30) and 1-year mortality (9% vs 13%; P = .27) was similar.

Patients who experienced cardiogenic shock had significantly higher rates of both in-hospital (55% vs 3%; P < .01) and 1-year mortality (71% vs 7%; P < .01) compared with stable patients. However, the time of admission to the hospital did not show a significant impact on the in-hospital (on-hours 50% vs off-hours 58%; P = .57) or 1-year mortality (on-hours 65% vs off-hours 74%; P = .48) for those with cardiogenic shock.

Hospital admissions for heart failure did not differ in patients admitted on- and off-hours (3% vs 3%; P = .60).

Kaplan-Meier curves showed no differences between timings in survival terms (log-rank P = .95) (figure 3). The timing of admission was not a predictor of 1-year mortality after adjustment (HR, 1.1; 95%CI, 0.74-1.64; P = .64). Independent predictors of mortality at 1-year are depicted in table 3, with cardiogenic shock emerging as the only strong predictor of 1-year mortality.

Figure 3. Kaplan-Meier curves for 1-year survival. STEMI, ST-segment elevation myocardial infarction.

Table 3. Predictive factors of 1-year mortality

DISCUSSION

This study suggests that there is no association between the timing of admission in the PCI center and adverse outcomes, in a structured STEMI network that offers PCI as the standard of care 24/7. Patients admitted off-hours had the same characteristics and were offered the same quality of care as those admitted on-hours, reflected by the similarity in treatment delays. Previous studies, in networks that provided the same quality of care whatever the admission time, reported no differences in outcomes.17-20

On the other hand, studies that report worst outcomes in patients admitted off-hours, mainly reflect differences in care during this period, with increased delay before revascularization, lower delivery of primary PCI, different procedural characteristics, and fewer available staff during off-hours.16,23-25 Additionally, several studies found that patients tended to have worse clinical status on admission during off-hours, which adversely impacted outcomes.16,26 A finding that supports the outmost importance of presentation status is the fact that cardiogenic shock at admission was found to be an independent predictor of 1-year mortality in this study. However, we did not find significant differences in presentation status according to admission time.

This analysis emphasizes that good organization of STEMI networks, with fast-track 24/7 primary PCI, is key to improve patient outcomes and to obviate the adverse impact of off-hours. However, time delays can still be optimized. Public awareness is key to reduce patient-dependent delays, and efforts should be made to improve recognition of symptoms and activation of emergency medical systems. System delays are quality of care indexes, and in this study, they are in the upper margin for benefit of PCI over fibrinolysis (120 minutes).4,27 This group previously analyzed the impact of interhospital transfer in time from first medical contact to reperfusion, and suggested improvements in chest pain work-up in emergency rooms and prompt transfer protocols after STEMI detection.28

Mortality rates in STEMI differ widely among analyses according to the geographical area, time frame analyzed, patient inclusion criteria, and patient management protocols.29,30 Nonetheless, in this analysis, mortality rates (5% in-hospital and 10% 1-year mortality) were in line with those reported in contemporary registries.2,31

To the best of our knowledge, this is the first study in a STEMI network in south-western Europe ensuring the feasibility and safety of on-call off-hours primary PCI in a contemporary STEMI network. This provides substantial reassurance to the usual organization of cath labs with on-call professionals, essential for workload management and organization of the laboratory workforce.

Study limitations

First, this is a single-center study and may not reflect regional differences in STEMI network organization. Moreover, the results of this study reflect those of a high-volume PC center with a long-standing 24/7 primary PCI program, which may differ from others due to diverse organizational features and available resources. This could be tackled by a future study analyzing national registry data.

Second, the retrospective nature of this study has the limitations inherent to this type of design.

Third, the definition of off-hours admission time is heterogeneous across the literature. In this study, it was defined according to the organizational features of the cath lab, which may not reflect off-hours in other centers/networks.

Additionally, overall mortality in this study may be underestimated, as the group of patients diagnosed in hospitals other than the PCI center and who died before or during transfer were not included in this analysis.

Another limitation of this study is the focus on the management of the patient exclusively until the performance of the primary PCI. Other factors that affect outcomes in these patients, most importantly the delivery of guideline directed medical therapies immediately after revascularization, were not analyzed.

Our findings, based on procedures conducted between 2011 and 2016, may not fully reflect the most current health care trends, given the continuous development of clinical guidelines and treatment approaches. For instance, the reduced use of thrombus aspiration, in line with updated guidelines, highlights the imperative for ongoing research to capture the latest developments in the field.

CONCLUSIONS

In a contemporary emergency network, STEMI patients’ admission time in the PCI-center was not associated with reperfusion delays or increased in-hospital and 1-year mortality. Mortality in efficient STEMI networks is primarily affected by the severity of clinical presentation.

FUNDING

None.

ETHICAL CONSIDERATIONS

Informed consent for the procedure was obtained in all cases. The confidentiality and anonymity of all collected data were ensured during all phases of the study. This study was approved by the local ethics committee and complied with the provisions of the Helsinki Declaration. Informed consent for the present analysis was waived by the ethics committee due to the retrospective nature of the study.

Possible sex/gender biases were taken into account and avoided.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

The authors did not use artificial intelligence tools during the preparation of this study.

AUTHORS’ CONTRIBUTIONS

All the authors contributed to the study design, performed a critical review of the manuscript, gave their final approval, and are fully responsible for all aspects of the study guaranteeing both its integrity and accuracy.

CONFLICTS OF INTEREST

None.

REFERENCES

INTRODUCTION

Ischemic heart disease is the leading cause of disability and mortality worldwide and is commonly characterized by the presence of obstructive coronary artery disease (CAD) (defined as any coronary artery stenosis ≥ 50% in diameter).1 However, up to 60% to 70% of patients with angina and/or documented myocardial ischemia do not have angiographic evidence of CAD.2 This condition is defined as angina with no obstructed coronary arteries (ANOCA) or ischemia with no obstructed coronary arteries (INOCA) when associated with evidence of myocardial ischemia.3 Of note, despite the absence of CAD, these patients are at an increased risk of future cardiovascular events such as acute coronary syndrome, heart failure hospitalization, stroke, and repeat cardiovascular procedures compared with healthy individuals.4,5 Therefore, appropriate management in terms of diagnosis and treatment is of the utmost importance to improve patients’ prognosis and outcomes.6 The Coronary Microvascular Angina (CorMicA) trial demonstrated that a strategy of adjunctive invasive testing for disorders of coronary function together with stratified medical therapy can improve outcomes (ie, reduction in angina severity and enhanced quality of life).7,8 However, there are still concerns about the implementation in real-world practice of a systematic diagnostic and therapeutic approach in INOCA and ANOCA patients, potentially impacting outcomes and quality of life.

We report our single-center experience of the implementation in clinical practice of a specific diagnostic and therapeutic protocol (no obstructed coronary arteries [NOCA] program) in INOCA and ANOCA patients.

METHODS

Eligibility criteria for the NOCA program

All consecutive patients diagnosed either at our hospital or at our referral centers with angina or ischemia with nonobstructive CAD on coronary angiography were referred to a specific outpatient clinic (the NOCA clinic at Hospital Clínic, Barcelona, Spain) for a screening visit. Nonobstructive CAD was defined as angiographic evidence of normal coronary arteries or diffuse atherosclerosis with stenosis < 50% and/or fractional flow reserve (FFR) > 0.80 if there was stenosis between 50% and 70%. During the screening visit, a team of expert cardiologists confirmed patients’ eligibility for the NOCA program based on the following criteria: a) diagnosis of ANOCA, defined as stable, chronic typical angina symptoms (eg, chest pain precipitated by physical exertion or emotional stress and relieved by rest or nitroglycerine); b) diagnosis of INOCA, defined as the demonstration of myocardial ischemia identified by a noninvasive test with pharmacologic or exercise stress tests such as cardiac single photon emission computed tomography, cardiac magnetic resonance, stress electrocardiography, or echocardiography.3 The exclusion criteria were: a) atypical angina symptoms, and b) clearly identifiable noncoronary causes of chest pain (figure 1). The study protocol adhered to the Declaration of Helsinki and the study was approved by our institutional review committee. All patients provided written informed consent to be included in this program and study. The clinical ethics committee gave their approval for a retrospective analysis of the collected data.

Figure 1. Central illustration. Flowchart for the inclusion of patients in the NOCA program. Cath lab, catheterization laboratory; INOCA: ischemia with no obstructed coronary arteries; NOCA, no obstructed coronary arteries; NOCAD, nonobstructive coronary artery disease.

NOCA program: diagnostic approach

After patient inclusion in the NOCA program, specialized counseling was provided by expert cardiologists and nurses. All patients were thoroughly informed about their disease, the importance of reaching a specific diagnosis, and the importance implementing tailored therapy. During the counseling sessions, the predicted benefits and low associated risks of an invasive procedure to specifically study coronary microcirculation and vasospasm were explained in detail. All patients provided written informed consent to undergo coronary angiography and intracoronary provocation testing with acetylcholine (ACh).

Subsequently, all patients underwent a scheduled coronary angiogram with a comprehensive diagnostic work-up consisting of the following: a) coronary function testing to assess coronary flow reserve (CFR) and the index of microvascular resistance (IMR); b) intracoronary ACh provocation testing to assess the presence of coronary vasomotion disorders (eg, epicardial or microvascular spasm).

Coronary function testing was performed using a pressure-temperature sensor guidewire (PressureWire X Guidewire and Coroventis CoroFlow Cardiovascular System, Abbott Vascular, United States) placed in the left anterior descending artery (LAD) as the prespecified target vessel, reflecting its subtended myocardial mass and coronary dominance. Steady-state hyperemia was induced using intravenous adenosine (140 µg/kg/min). If there was severe tortuosity of the LAD or evidence of myocardial ischemia in a region other than the territory of the LAD, the wire was placed in the right coronary artery or the left circumflex, as per the operator’s decision. CFR was calculated using thermodilution, defined as resting mean transit time divided by hyperemic mean transit time (abnormal CFR was defined as ≤ 2.5). IMR was calculated as the product of distal coronary pressure at maximal hyperemia multiplied by the hyperemic mean transit time (normal value < 25).6,9

Intracoronary ACh provocation testing was performed with a standardized protocol involving serial ACh infusions for 20 seconds at increasing concentrations (2-20-100 µg in the left coronary artery with an interval of 2-3 minutes between each injection) with concomitant assessment of the patient’s symptoms, electrocardiogram documentation, and angiographic scans. Patients taking vasoactive drugs (eg, calcium channel blockers and nitrates) underwent a wash-out period of at least 48 hours before the provocative test.10,11,12 Epicardial coronary spasm was defined as the reproduction of chest pain and ischemic electrocardiogram changes in association with a reduction in coronary diameter ≥ 90% from baseline in any epicardial coronary artery segment.13 Microvascular spasm was diagnosed when typical ischemic ST-segment changes (deviation ≥ 1 mm) and angina developed in the absence of epicardial coronary constriction (< 90% diameter reduction).14

Subsequently, patients were stratified into 4 endotypes: a) microvascular angina (MVA) (evidence of coronary microvascular dysfunction [CMD] defined as any abnormal CFR [< 2.5], IMR [≥ 25], or microvascular spasm); b) vasospastic angina (VSA) (CFR ≥ 2.5, IMR < 25 and epicardial spasm); c) both MVA and VSA (evidence of CMD and epicardial spasm); and d) noncoronary chest pain (CFR ≥ 2.5 and IMR < 25, with neither microvascular nor epicardial spasm).6

Any complications occurring during the invasive diagnostic work-up were documented, including bradyarrhythmias, atrial fibrillation, ventricular tachycardia or fibrillation, coronary perforations, death from any cause, and any other complications.

NOCA program: pharmacological and psychological therapeutic approach

Once the endotype was identified, medical treatment for each patient was optimized accordingly (table 1). In patients with MVA, treatment with beta-blockers and calcium channel blockers (CCBs) was started or up-titrated. Ranolazine was added if angina symptoms were not fully controlled by beta-blockers and CCBs. In patients with VSA, treatment with nondihydropyridine CCBs and long-acting nitrates was started or up-titrated. In patients with both MVA and VSA, treatment with nondihydropyridine CCBs or beta-blockers was started or up-titrated. In patients with noncoronary chest pain, vasoactive drugs were discontinued unless clinically indicated for other reasons. Additionally, treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and statins was started or up-titrated in all patients. If a patient showed intolerance or had contraindications to a specific medication (eg, asthma for beta-blockers, perimalleolar edema for CCBs, severe bradycardia for both beta-blockers and CCBs), the treatment was tailored and modified accordingly.

Because stress is an important trigger factor for angina symptoms, all patients were also referred to a team of expert psychologists for psychological support.15

NOCA program: clinical outcome and quality of life evaluation

All patients were followed up at 1, 3, 6, and 12-months for treatment titration and assessment of clinical outcomes. At the time of coronary angiography (ie, baseline) and at the 3-month follow-up, all patients were administered the Seattle Angina Questionnaire (SAQ) and quality of life questionnaire (EuroQol-5D [EQ-5D]). The SAQ is a validated 19-item self-administered questionnaire that measures 5 dimensions of CAD: physical limitation, angina stability, angina frequency, treatment satisfaction, and disease perception.16 The EQ-5D is a standardized, nondisease-specific questionnaire used to describe and evaluate patients’ health status and was intended to complement other quality-of life measures.17 Figure 2 provides a visual representation of all the steps involved for patients included in the NOCA program.

Figure 2. Visual representation of the NOCA program. EQ-5D, EuroQol-5D; NOCA, no obstructed coronary arteries; SAQ, Seattle Angina Questionnaire. * See text for more details.

Statistical analysis

Data distribution was assessed according to the Kolgormonov-Smirnov test. Continuous variables were compared using the unpaired Student t-test or the Mann–Whitney U test, as appropriate. The data are expressed as mean ± standard deviation (SD) or as median and interquartile range [IQR]. Categorical data are expressed as numbers and percentages and were evaluated using the chi-square test or Fisher exact test, as appropriate. A 2-sided P value < .05 was considered significant. All analyses were performed using SPSS version 21 (SPSS, United States).

RESULTS

Baseline characteristics of the study population

From January 2021 to December 2021, a total of 77 patients were screened at the NOCA clinic for inclusion in the NOCA program. Following the screening visit, 23 (29.9%) patients were excluded from the NOCA program: 12 due to atypical angina symptoms and 11 due to a clearly identifiable noncoronary cause. Consequently, 54 patients were included in the NOCA program (mean age 64.4 ± 9.4 years, 39 [63.9%] women). A total of 29 (53.7%) patients had INOCA and 25 (46.3%) had ANOCA. All clinical and angiographic characteristics of the study population are shown in table 1.

Table 1. Medical therapy according to the specific endotype of ANOCA/INOCA

NOCA program: diagnosis of the specific endotype and complications

The results of the invasive functional assessment are presented in table 2. The mean IMR and CFR values were 21.2 ± 10.6 and 2.3 ± 1.4, respectively. MVA was diagnosed in 19 (35.2%) patients, VSA in 12 (22.2%), and both MVA and VSA in 18 (33.3%). Finally, 5 (9.3%) patients were diagnosed with noncoronary chest pain.

Table 2. Clinical and angiographic characteristics of patients included in the NOCA program

Among INOCA patients, MVA was diagnosed in 11 (37.9%) patients, VSA in 7 (24.1%), both MVA and VSA in 8 (27.6%), and noncoronary chest pain in 3 (10.3%). Among ANOCA patients, MVA was diagnosed in 8 (32.0%) patients, VSA in 5 (20.0%), both MVA and VSA in 10 (40.0%), and noncoronary chest pain in 2 (8.0%). There were no statistically significant differences in the prevalence of any endotype between INOCA and ANOCA patients (all P > .05, figure 3).

Figure 3. Prevalence of the different endotypes among INOCA and ANOCA patients. ANOCA, angina with no obstructed coronary arteries; INOCA, ischemia with no obstructed coronary arteries; MVA, microvascular angina; NCCP, noncoronary chest pain; VSA, vasospastic angina.

Complications occurred in 3 (5.5%) patients during intracoronary ACh provocation testing: 2 (3.7%) patients had transient bradyarrhythmias and 1 (1.8%) patient had paroxysmal atrial fibrillation that spontaneously reverted to sinus rhythm.

NOCA program: treatment optimization according to the specific endotype

Inclusion in the NOCA program led to statistically significant changes in medications after diagnosis of the specific endotype. There was a significant increase in the use of beta-blockers (33.3% before vs 57.4% after, P = .008), nondihydropyridine CCBs (9.3% before vs 37.0% after, P < .001), and long-acting nitrates (46.3% before vs 63.0% after, P = .012). There were no statistically significant differences in any other medications before and after the invasive assessment (all P > .05, figure 4). All changes in medications according to the specific endotype of ANOCA/INOCA are shown in figure 5.

Figure 4. Differences in medical treatment before and after patient inclusion in the NOCA program. ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; DP-CCBs, dihydropyridine calcium channel blockers; LA, long-acting; ND-CCBs, nondihydropyridine calcium channel blockers.

Figure 5. Changes in medications according to the specific endotype of ANOCA/INOCA. A: patients with MVA. B: patients with VSA. C: Patients with MVA and VSA. D: patients with noncoronary chest pain. DP-CCBs, dihydropyridine calcium channel blockers; LA, long-acting; MVA, microvascular angina; ND-CCBs, nondihydropyridine calcium channel blockers; VSA, vasospastic angina.

NOCA program: clinical outcome evaluation

At 3 months of follow-up, there was no statistically significant difference in the mean EQ-5D score compared with baseline (64.8 ± 18.1 at baseline vs 66.1 ± 17.1 at 3 months of follow-up, P = .302) (figure 6). However, there was a statistically significant improvement in the SAQ score in terms of physical limitations (59.7 ± 19.3 at baseline vs 66.2 ± 16.9 at 3 months of follow-up, P = .037), angina stability (57.1 ± 28.1 at baseline vs 75.8 ± 22.3 at 3 months of follow-up, P = .010), and disease perception (42.5 ± 13.9 at baseline vs 50.8 ± 16.3 at 3 months follow-up, P = .015). No statistically significant difference was found in angina frequency (74.3 ± 20.4 at baseline vs 80.7 ± 19.8 at 3 months of follow-up, P = .193) or treatment satisfaction (68.1 ± 12.6 at baseline vs 70.5 ± 12.5 at 3 months of follow-up, P = .950) (figure 7). No events were recorded at the 1-year follow-up.

Figure 6. Differences in EuroQol-5D (EQ-5D) score at baseline and at 3 months of follow-up.

Figure 7. Differences in SAQ score at baseline and at 3 months of follow-up. AF, angina frequency; AS, angina stability; DP, disease perception; EQ-5D, EuroQol-5D; PL, physical limitations; SAQ, Seattle Angina Questionnaire; TS, treatment satisfaction.

DISCUSSION

The main results of our experience can be summarized as follows: a) the implementation of a specific diagnostic and therapeutic protocol (NOCA program) in patients with diagnosed with nonobstructive CAD is feasible and allowed a parsimonious use of medical resources; b) a comprehensive diagnostic work-up in INOCA and ANOCA patients is safe, with a low rate of mild and transient complications (5.5%); c) the inclusion of patients in the NOCA program led to significant changes in medications and a significant improvement in their angina symptoms at the 3-month follow-up with no adverse events at 1 year.

Although accumulating evidence has demonstrated that an approach consisting of a comprehensive diagnostic assessment and stratified medical therapy in INOCA and ANOCA is crucial to improve patients’ prognosis, such an approach is far from routinely implemented in clinical practice.7,8 There are still concerns mainly related to the cost-benefit ratio, the associated prolonged procedural time, increased costs, and the risk of possible associated complications. Furthermore, in the most recent European Society of Cardiology guidelines, invasive coronary function testing is assigned a class IIa (“should be considered”) recommendation, while ACh provocation testing is supported by a class IIb recommendation (“may be considered”) to assess microvascular spasm and class IIa in patients under consideration for VSA.3 As a result, the management of these patients is commonly left to physicians’ discretion or relies on the experience of each center. Consequently, diagnosis of a specific NOCA endotype is frequently missed, and medical therapy is not optimized. This, in turn, has a significant negative impact on patients’ quality of life and clinical outcomes, as well as on health care costs, due to the need for repeat hospitalization or invasive procedures.18

In reporting our experience, we demonstrate that a specific diagnostic and therapeutic protocol (ie, the NOCA program) in patients with a previous diagnosis of nonobstructive CAD can be easily implemented in clinical practice. A key innovation of our study, compared with prior publications, is the creation and implementation of a specific protocol for the INOCA/ANOCA population. Additionally, our approach involves a screening visit with assessment by a team of expert cardiologists for patients with a suspected diagnosis of INOCA/ANOCA. This approach improves identification of such patients, and, in our experience, led to the exclusion of almost one third of patients (29.9%) due to atypical angina symptoms or no clearly identifiable coronary causes of chest pain. This is another novelty of our study that could be extremely relevant in the management of these patients. Indeed, the selection of patients to be included in the program may allow clinical resources to be directed to patients who are most likely to benefit, while avoiding repeat invasive procedures and related risks in patients with unclear indications. Additionally, the specialized counseling provided by cardiologists and nurses during the screening visit, together with psychological support, are likely to be vital components of the management of INOCA/ANOCA patients. Indeed, recent studies have demonstrated how psychological factors, such as chronic stress, anxiety, depression, and social stressors are involved in the pathogenesis of MVA and VSA.19-23 Mental stress has been demonstrated to determine CMD mainly through endothelium-dependent mechanisms and endothelial dysfunction.24 Similarly, by activating brain areas involved in regulation of neuroendocrine and autonomic nervous systems, mental stress can lead to hyperreactivity of vascular smooth muscle cells, autonomic nervous system dysfunction, oxidative stress, vascular inflammation, and endothelial dysfunction, resulting in an increased propensity to coronary vasospasm.25-27

Furthermore, in line with previous studies,28-30 our experience demonstrates that performing a comprehensive invasive diagnostic assessment for the diagnosis of the specific endotype in INOCA and ANOCA patients is safe and is associated with a low rate of mild and transient complications. For all these reasons, patients and clinicians should be reassured about the lack of serious complications and cardiologists should be strongly encouraged to implement a specific diagnostic and therapeutic program in these patients. Indeed, the availability of such a program for INOCA and ANOCA patients may have significant clinical and therapeutic implications, as, in our experience, it resulted in substantial changes in medications and a marked improvement at the 3-month follow-up of the SAQ questionnaire regarding physical limitations, angina frequency, and disease perception. The lower and nonsignificant improvement in the other parameters (eg, angina frequency and treatment satisfaction) could be attributed to the already high baseline values (74.5 ± 19.9 and 69.6 ± 11.9, respectively). Similarly, the absence of a significant improvement in the EQ-5D questionnaire at 3 months might be due to the short follow-up period or the fact that it is a nondisease-specific questionnaire designed to describe and assess patients’ health status and is intended to complement other quality-of-life measures.31

Study limitations

Some limitations of this study should be acknowledged. First, this is a single-center study with a relatively small sample size and short follow-up. Second, we did not perform a cost-analysis and therefore we cannot speculate on the impact of the NOCA program on health care-related costs. Further studies in larger ANOCA and INOCA populations are warranted. Finally, the absence of a control group precluded a thorough assessment of the improvement in the quality of life among these patients.

CONCLUSIONS

Our experience demonstrates that a specific diagnostic and therapeutic protocol (NOCA program) can be easily and safely implemented in routine clinical practice. Such a protocol could ensure the best care for INOCA and ANOCA patients, as well as improve their quality of life and avoid inappropriate treatments and incomplete investigations. Future evidence from randomized clinical trials or recommendations from international clinical guidelines supporting the implementation of a specific protocol in these patients are strongly warranted.

FUNDING

This study received no funding.

ETHICAL CONSIDERATIONS

The study protocol complied with the Declaration of Helsinki and the study was approved by our Institutional Review Committee. All patients gave written informed consent to be included in this program and study. The clinical ethics committee gave their approval for a retrospective analysis of the data collected. In this work, the possible variables of sex and gender have been taken into account.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence tools were used during the preparation of this work.

AUTHORS’ CONTRIBUTIONS

R. Rinaldi, F. Spione, F.M. Verardi: data extraction and analysis and manuscript drafting; R. Rinaldi, F. Spione, S. Brugaletta: design and manuscript revision; P. Vidal Calés, V. Arévalos, R. Gabani, D. Cánovas, M. Gutiérrez, M. Pardo, R. Domínguez, L. Pintor, X. Torres, X. Freixa, A. Regueiro, O. Abdul-Jawad Altisent, M. Sabaté: manuscript revision. All authors have read and agreed to the published version of the manuscript.

CONFLICTS OF INTEREST

The authors have nothing to disclose.

ACKNOWLEDGMENTS

F. Spione has been supported by a research grant provided by the Cardiopath PhD program.z

REFERENCES