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

INTRODUCTION

Optimal stenting is crucial in the long-term clinical outcomes while proper stent expansion and apposition reduce the risk of thrombosis and restenosis.1 Coronary stent postdilatation increases luminal area while reducing stent strut malapposition.2,3

Unlike semicompliant balloons, noncompliant (NC) balloon postdilatation allows uniform dilatation at higher pressures, which reduces the risk of damage to the vessel wall (edge dissection or coronary perforation),4 and is associated with greater stent expansion and a lower rate of target lesion revascularization.5 Therefore, postdilatation using NC balloons is a common strategy to increase the luminal area of underexpanded stents or increase the stent proximal caliber in long lesions or in bifurcation techniques like the proximal optimization technique (POT) or the conventional kissing-balloon technique in a safe and predictable way.6,7

The navigability of NC balloons is more limited, a significant setback in cases of coronary tortuosity, calcified lesions or proximal stent edge malapposition. Regular noncompliant balloons (RegNC) include a cone-shaped tip that can collide with the struts or with the proximal stent edge, thus conditioning a force vector opposed to the push force that can potentially interfere with its advancement (figure 1A), and eventually lead to mechanical stent failure in cases of inadequate coaxiality. In these cases, the use of complex techniques (buddy-wire, buddy-balloon, anchoring...) or specific devices (guide catheter extension systems) are often needed to advance the balloon, which increases the cost of the procedure.

Figure 1. A: the cone-shaped tip of a regular noncompliant balloon can collide with the stent struts thus conditioning a force (F) vector opposed to the push force that can potentially interfere with its advancement. B: the spherical tip contributes to decomposing and reducing the resistance force vector opposed to the push vector, thus facilitating the balloon advancement towards the inside of the stent. Courtesy of APT Medical, China.

The cone-shaped tip has been replaced by a spherical tip in a new NC balloon (NC Conqueror Spherical tip, APT Medical, China) (SphNC). Despite its greater crossing profile (0.039 in), the spherical tip contributes to decomposing and reducing the resistance force vector opposed to the push vector (figure 1B), facilitating the advancement of the balloon until reaching the inside of the stent and the post-dilatable segment.

Figure 2. Actual appearance of the spherical tip noncompliant balloon used in the study. Courtesy of APT Medical, China.

Our objective is to assess the effectiveness of this new SphNC in coronary postdilatation during percutaneous coronary intervention (PCI) in the routine clinical practice.

METHODS

The RECONQUISTHA trial is a prospective and multicenter technical registry conducted in 16 high volume PCI-capable centers (> 500 PCIs/year)8 designed to assess the effectiveness of SphNC in coronary postdilatation during PCI in the routine clinical practice. Since it is a technical registry that used no personal or clinical data on a device approved with CE marking no ethics committee approval or informed consent forms were required.

Inclusion and exclusion criteria

The only inclusion criterion was the indication for coronary postdilatation with the SphNC according to the operator (long, calcified, ostial lesion, bifurcation and angiographic or stent balloon underexpansion). The exclusion criteria were the use of a ≤ 5-Fr guide catheter, vessel size < 2mm or > 5mm, jailed branch postdilatation without previous opening of the stent struts of the main vessel towards such branch or finding 1 of the following scenarios before postdilatation: mechanical stent failure, stent edge dissection ≥ C, coronary perforation or TIMI grade ≤ 2 flow in the main vessel or lateral branch.

Procedure

All lesions were treated with stenting according to the operator’s criterion and according to the routine clinical practice (arterial access, guide catheter caliber, predilatation or plaque modification, and intracoronary imaging). Also, they should be treated with standard antithrombotic treatment (dual antiplatelet therapy with acetylsalicylic acid, and P2Y₁₂ receptor inhibitors prior to the PCI plus weight-adjusted unfractionated heparin at doses of 100 IU/kg with further boluses to achieve activated coagulation times between 250 s and 300 s).

The use of the SphNC was considered in 2 different clinical settings that categorized the lesions into 2 study groups: use of SphNC as first-line treatment, and use of SphNC as a second choice after failed RegNC advancement. Complex techniques like the buddy-wire, buddy-balloon, anchoring or guide catheter extension system were allowed to advance both the RegNC and the SphNC. In cases where the second choice after failed RegNCn advancement was used despite the use of a complex technique, the same complex technique with the SphNC was advised too.

The spherical tip noncompliant balloon

The NC Conqueror Spherical tip balloon (APT Medical, China) is a rapid exchange balloon catheter for percutaneous coronary interventions that is compatible with a 0.014 in intracoronary guidewire. This device has a distinctive tungsten radiopaque spherical tip (0.039 in crossing profile) designed to minimize resistance while advancing the balloon towards the inside of the stent (figure 2). It is available in calibers ranging from 2 mm to 5 mm in intervals of 0.25 mm to 0.5 mm, and lengths of 6 mm, 8 mm, 12 mm, 15 mm, 20 mm, and 30 mm. Nominal pressure stands at 12 atm, and rated pressure burst at around 20 atm (18 atm in 4.5 mm to 5 mm calibers). The device has the CE marking.

Definition of endpoints

The study primary endpoint was technical success defined as the successful advancement of the SphNC until reaching the stent post-dilatable segment. Secondary endpoints were angiographic success—defined as technical success with residual stenosis < 30% with final TIMI grade-3 flow—and procedural success defined as angiographic success without mechanical stent failure or perioperative major adverse cardiovascular events like myocardial infarction—based on the criteria established by the Academic Research Consortium [ARC]-29—stroke, coronary perforation, need for emergency heart surgery or death.

The hypothesis was to consider the study positive if technical success was achieved in > 80% of the lesions regarding the use of the SphNC as the go-to option (according to data published on technical success rates with postdilatation balloons10), and in > 30% regarding the use of the SphNC after failed RegNC advancement (random criterion based on the success of the new balloon in 1 out of 3 cases of failed RegNC advancement).

Data curation

The characteristics of the lesion and the PCI, the indication for postdilatation, any information on the devices used, and quantitative and procedural angiographic results were collected prospectively. Data was introduced in an anonymized electronic database specifically designed for the purpose of the study. Lesions were categorized based on the classification established by the American College of Cardiology and the American Heart Association (ACC/AHA).11 Coronary calcification was defined as moderate whenever coronary radiopacities would be found prior to the injection of contrast or severe whenever these radiopacities would damage both sides of the arterial lumen.12 Coronary tortuosity was defined as moderate if ≥ 3 consecutive curvatures between 45° and 90° were found during diastole or severe if any previous curvatures between 90° and 180° would be found or that encompassed the lesion.13 Angulation inside the lesion was measured as the angle between the start and the end of stenosis. The presence of ostial stenosis > 50% in the branch lateral to the lesion or the need to place the protection guidewire in the lateral branch was considered bifurcation. The stent suboptimal expansion was defined as residual stenosis ≥ 10% on the coronary quantitative angiography after the PCI. Residual stenosis ≥ 30% was considered stent underexpansion (the use of intracoronary imaging was not mandatory). Mechanical stent failure was defined as longitudinal stent deformation or fracture. The patients’ personal or clinical data were not collected.

Statistical analysis

In each of the study groups the overall and individual data were analyzed (SphNC as the go-to option, and as the second choice after failed RegNC advancement). Data was expressed as percentages regarding the categorical variables or as mean and standard deviation regarding the continuous ones. Categorical variables were compared using the chi-square test (or Fisher’s exact test when appropriate). Continuous variables were compared using the Student t test. P values < .05 were considered statistically significant.

RESULTS

From February through June 2021, the SphNC was used in 263 lesions (in 177 lesions as the go-to option, and in 86 lesions after failed RegNC advancement) in a total of 250 procedures. All the lesions were treated with state-of-the-art drug-eluting stents. The characteristics of the lesions and the PCIs, and the immediate angiographic results—both overall and with the use of the SphNC as the first choice or after failed RegNC advancement—are shown on table 1 and table 2. A total of 9.9% of the lesions required complex techniques to move the SphNC forward. Lesions in the failed RegNC group were more unfavorable with a lower rate of direct stenting, greater tortuosity and angulation inside the lesion, more need for cutting balloon during predilatation, shorter SphNC length, and a higher rate of angiographic data of suboptimal stent expansion.

Table 1. Characteristics of the lesions

Table 2. Characteristics of percutaneous coronary intervention and angiographic outcomes

The overall rates of technical, angiographic, and procedural success were very high and similar between both groups (table 3).

Table 3. Rates of primary and secondary endpoints

The rate of technical success in the same lesion where the RegNC had failed was very high (98.8%): only 1 SphNC failed too (figure 3). The SphNC and the RegNC had a similar mean caliber (3.39 ± 0.6 mm vs 3.34 ± 0.6 mm; P = .06) while the SphNC had a shorter mean length (11 ± 2 mm vs 12 ± 3 mm; P = .005). The length of the SphNC was shorter, similar or longer in 36%, 46.5%, and 17.5% of the lesions, respectively. The same complex techniques were used to advance the RegNC and the SphNC in 7 lesions (the guide catheter extension system and the buddy-wire technique were used in 6 and 1 cases, respectively). The buddy-wire technique was used in 2 lesions to advance the SphNC, but not previously with the RegNC. In 1 lesion where the RegNC could not be advanced despite anchoring, the SphNC was moved forward without the need for a complex technique. Both the RegNC and the SphNC had been previously used on 3 and 9 occasions, respectively for predilatation purposes.

The description of failed primary and secondary endpoints with the SphNC is shown on table 4. In 2 of the 3 cases without technical success regarding the SphNC, a shorter RegNC was eventually advanced. No instances of mechanical stent failure were reported. One proximal fracture of the catheter hypotube was reported due to excessive resistance during push in 1 SphNC. Nonetheless, the device could be retrieved uneventfully. Only 1 major adverse cardiovascular event was reported: 1 distal branch perforation due to an angioplasty guidewire unrelated with the use of the SphNC that occurred while unsuccessfully trying to advance the RegNC. However, according to the definitions of the study protocol, it was adjudicated as lack of procedural success.

Table 4. Description of cases of failed spherical tip noncompliant balloon

Figure 3. Overall technical success and failure of the spherical tip noncompliant balloon (SphNC), as well as in cases of failed regular noncompliant balloon (RegNC); section chart on the right.

DISCUSSION

As far as we know, it is the first time that a clinical trial—the REPIC02-RECONQUISTHA—reports on the most extensive experience using SphNC for coronary stent postdilatation. The registry included 16 high volume PCI-capable centers and collected data from 263 lesions where SphNCs were used at the operator’s discretion both as the go-to and second choice after failed RegNC advancement in the same lesion. Based on the initial hypothesis, the study can be considered positive; findings can be summarized as follows: a) very high rates of technical, angiographic and procedural success defined, respectively, as the capacity to move forward towards the inside of the stent and reach an adequate expansion without mechanical stent failure or periprocedural complications; b) very high rates of technical, angiographic and procedural success in the same lesions where the RegNC failed; and c) lower need for complex techniques to achieve technical success.

Over the last few years, the arrival of new techniques and modern devices has facilitated the performance of successful PCIs on more complex lesions in the routine clinical practice. Although the operators were not specifically encouraged to include complex lesions in the study, our data show this reality where over 70% of the lesions were type B2/C, and nearly 50% showed significant calcification, tortuosity or angulation inside the lesion. These characteristics reduce the success of the PCI14,15 and can eventually lead to stent malapposition16 and underexpansion17 or difficulties advancing the devices until reaching such stents, which means that the availability of effective and safe postdilatation balloons is essential to perform successful PCIs.

There is no data in the medical literature to compare or discuss our findings. Our study can be considered positive as it exceeded 80% of the success anticipated in the initial hypothesis. Despite the complexity of the lesions reported, the overall and subgroup outcomes of use of the SphNCs as the go-to option are nothing new since they can be expected in the assessment of any NC balloons (rate of success and proper stent expansion > 90%)10 since it is rare to find difficulties or impossibilities if complex techniques are used to advance these devices. However, these maneuvers can lead to severe complications like mechanical stent deformation.18,19 The lack of mechanical stent failure in our series places the SphNC as an effective and safe device for coronary postdilatation.

After the first 200 procedures, the percentage of cases where the SphNC was used in lesions where the RegNC would have failed was low. Since focus was on assessing the SphNC performance in this context, only inclusions in this subgroup were allowed later on. As already mentioned, the rate of RegNC failure is rare, and the rhythm of inclusion of the next 50 procedures was a slower. We designed this study group considering that the sequential use of a SphNC in the same lesion where a RegNC had failed would show the potential benefit of this new device. The SphNC achieved technical success in 98.8% of the lesions in this subgroup and validated its superiority in the exact same lesions where the RegNC had failed, which can be considered the most valuable piece of information from our study. The mean SphNC length was shorter compared to the RegNC (a 1 mm difference, which is statistically significant due to similar and narrow standard deviations, yet of uncertain practical significance). However, the operators used SphNCs and RegNCs of similar length in most of the lesions. In this study subgroup, lesions were more unfavorable, which may explain the rate of failure with RegNCs, the discretely low rate of angiographic and procedural success reported, and the presence of the complications described (fracture of the SphNC hypotube or coronary perforation).

It has been reported that the tortuosity and angulation seen until the lesion are predictors of failed PCI or perioperative complications.14,15,20 In our series, their prevalence was high—around 40%—and up to 50% in lesions where the RegNC failed. Several complex techniques for the management of these anatomies have been described,21 but they increase procedural time and cost. Eddin et al.22 determined that tortuosity and angulation were the main predictors for the use of a guide catheter extension system. Also, angulations > 45° proximal to the lesion predict its use with a 73% sensitivity and a 74% specificity. In different series, tortuosity and angulation justify the use of a guide catheter extension system in 22% to 43% of the cases.18 Despite the significant tortuosity and angulation of our series, the need for a guide catheter extension system or any other kind of complex technique to advance the SphNC was low (< 8% and 10% respectively), which is why this device emerges as a useful tool in the coronary tortuosity setting with potential to reduce procedural costs.

The study design was moderately ambitious since we hypothesized that if the SphNC were successful in 1 out of 3 lesions where the RegNC had failed this outcome would have been good enough for the new device. The fact that it exceeded the success rate of 30% proposed in the hypothesis makes us think of the results as positive. To better understand these outcomes, 5 videos have been provided as supplementary data including examples of failed RegNCs and succesful SphNCs in the same lesion.

Limitations

Despite its prospective design, the study has several limitations. The indication of postdilatation with SphNC based only on the operator’s criterion may have conditioned selection biases, thus preventing the inclusion of very unfavorable lesions. The study design does not allow us to assess the superiority of the SphNC over the RegNC regarding the lower need for complex techniques, mechanical stent failure or better angiographic and procedural outcomes. The use of intracoronary imaging was low, and a more comprehensive assessment of stent expansion with imaging techniques could have changed the data of the PCI final outcomes and, consequently, the secondary endpoints. The SphNC recrossing after first inflation was anecdotal and is, therefore, ill-advised. We should mention that our results cannot be extrapolated to coronary predilatation because the device has not been tested prior to stenting. Finally, the lack of follow-up to monitor the patients’ clinical course does not allow us to assess the clinical impact derived from the use of SphNC.

CONCLUSIONS

Coronary postdilatation with the SphNC during PCI in the routine clinical practice has a very high rate of technical success both as first choice (98.9%), and in cases of failed RegNC advancement (98.8%) with a lower need for complex techniques, and a good safety profile.

FUNDING

RECONQUISTHA is an investigator-initiated trial promoted and developed by Fundación EPIC, Spain as the clinical research organization sponsored by IZASA Medical, Spain. All the authors received research grants for their participation in the study.

AUTHORS’ CONTRIBUTIONS

J. A. Linares Vicente: design, data curation, analysis, and interpretation, and manuscript drafting. A. Pérez de Prado, and J. R. Rumoroso Cuevas: design, data curation, manuscript drafting, and critical review of its content. K. García San Román, F. Lozano Ruiz-Póveda, G. Veiga Fernández, A. Gómez Menchero, G. Moreno Terribas, G. Miñana Escrivà, J. Sánchez Gila, C. Arellano Serrano, G. Martín Cáceres, P. Bazal Chacón, P. Martín Lorenzo, F. Rebollal Leal, and J. Moreu Burgos: data curation, critical review of the content of the manuscript, and final approval.

CONFLICTS OF INTEREST

A. Pérez de Prado is an associate editor of REC: Interventional Cardiology; the journal’s editorial procedure to ensure impartial handling of the manuscript has been followed. J. A. Linares has received lecture fees from IZASA Medical, Spain.

REFERENCES

INTRODUCTION

Systemic coronary artery embolism is one of the mechanisms of acute myocardial infarction (AMI) of non-atherosclerotic origin and represents 3% to 14% of all acute coronary syndromes (ACS) reported, according to angiographic and autopsy studies. However, the real prevalence of this entity remains unknown due to the uncertainty of its diagnosis in the acute setting.1,2

Atrial fibrillation (AF), cardiomyopathies, valvular heart disease, malignancies, and infective endocarditis have previously been associated with ACS due to systemic embolism (ACS-E).1,3 Nevertheless, the epidemiological, clinical, and angiographic profile of this entity has not been properly established yet.

Our objective was to describe the clinical characteristics, angiographic features, therapeutic management, and prognosis of ACS-E, compare it to ACS due to coronary atherosclerosis (ACS-A), and identify predictive clinical factors of ACS-E.

METHODS

Study population

All consecutive patients with ACS­—admitted to a tertiary hospital from January 2003 through December 2018—were evaluated, classified as ACS-E or ACS-A, and prospectively recruited on a multipurpose database. The protocol was approved by the local ethics committee (internal code 22/137-E), and patients’ informed consent was waived because it involved only the analysis of data obtained during standard clinical practice.

AMI was defined as elevated cardiac troponin levels (myocardial injury) with clinical evidence of acute myocardial ischemia including symptoms, new ischemic electrocardiographic changes, development of pathological Q waves on the electrocardiogram, new regional wall motion abnormalities in a pattern consistent with ischemic aetiology, and/or angiographic identification of a coronary thrombus.4 All patients underwent a thorough diagnostic work-up including detailed clinical histories and physical examinations, serial electrocardiograms, blood tests, transthoracic echocardiographies, and invasive coronary angiographies. Intracoronary imaging techniques like optical coherence tomography or intravascular ultrasound were left to the operator’s discretion.

Diagnosis of ACS-E was achieved according to the angiographic evidence of coronary artery thrombosis without atherosclerotic components, concomitant multi-site coronary artery embolism or concomitant systemic embolization excluding left ventricular thrombus due to AMI.1 Only emboli of principal coronary arteries were considered. Patients with the following angiographic findings were systematically excluded: a) presence of atherosclerosis at culprit lesion level, b) evidence of > 25% coronary artery stenosis outside the culprit lesion, c) plaque rupture or coronary erosion at culprit lesion level found on the intravascular imaging, d) coronary artery ectasia, and e) other causes of non-atherosclerotic AMI (vasospasm, spontaneous coronary artery dissection).

Angiographic evaluation of the culprit site was performed by 2 expert operators with an intention to rule out a) the presence of thrombus (defined as noncalcified filling defect outlined by contrast media), b) presence of angiographic stenosis, and c) signs of atherosclerosis (eg, vessel wall calcification). The rest of the angiogram was assessed looking for angiographic stenosis or atherosclerosis.

Clinical events

Epidemiological data, clinical features, angiographic characteristics, management, and outcomes were prospectively collected as patients were recruited and retrospectively analysed. The long-term follow-up of ACS-E was performed by monitoring any recurrences of systemic emboli (including cardiogenic stroke), and the occurrence of major adverse cardiovascular and cerebrovascular events including cardiac death, myocardial infarction, new percutaneous coronary intervention (PCI), hospitalization due to heart failure or stroke more than 30 days after admission due to ACS-E.

In the present study, we first performed a detailed description of the episodes of ACS-E followed by a comparison to ACS-A to identify clinical peculiarities, and predictors.

Statistical analysis

Quantitative variables were expressed as median and interquartile range [IQR] or mean and standard deviation. The assessment of normality and equality of variances for continuous data was performed using the Shapiro-Wilk test and the Levene test, respectively. Thereafter, continuous variables were compared using the Student t test, the Fisher-Pittman permutation test or the median test when appropriate. Categorical variables were expressed as frequencies and percentages.

Variables in which statistically significant differences were seen in the univariate model and those clinically relevant were introduced in a multivariate analysis using stepwise logistic regression to identify clinical predictors of ACS-E.

All tests were 2-sided, and differences were considered statistically significant with P values < .05. Statistical analyses were performed using Stata/IC12.1 statistical software package (StataCorp, College Station, Texas, United States).

RESULTS

During the study period, a total of 5029 patients with ACS were included. After applying the previously described diagnostic criteria, 40 patients (0.8%) were classified as ACS-E and 4989 (99.2%) as ACS-A.

Acute coronary syndrome due to systemic embolism population

Regarding patients with ACS-E, 17 were women (42.5%), and the population’s mean age was 60.3 years old. A total of 2 patients (5.0%) had a past medical history of exertional angina, 4 (10.0%) carried a prosthetic valve, and 2 (5.0%) and 1 (2.5%) had non-corrected severe mitral regurgitation, and severe aortic stenosis, respectively. The mean left ventricular ejection fraction was 55.0% ± 12.3%, and 16 patients (40.0%) had any form of AF. Also, 1 patient (2.5%) was diagnosed with infective endocarditis in the aortic valve right after being admitted due to ACS. Regarding other medical conditions, 7 patients (17.5%) had active neoplasms, and 3 (7.5%) chronic kidney disease. Information associated with other baseline characteristics is shown on table 1 of the supplementary data.

Table 1. Baseline epidemiological and clinical characteristics

A total of 32 patients (80.0%) had ST-segment elevation myocardial infarction (STEMI) 3 of whom received fibrinolytic therapy, undergoing bailout PCI in 2 of the cases. A total of 28 patients (70.0%) underwent a primary PCI and the remaining 12 (30.0%) were catheterized in another scenario. The most frequent culprit vessel was the left anterior descending coronary artery (LAD) that accounted for 13 (32.5%) of the cases followed by the right coronary artery (n = 10; 25.0%), and the left circumflex artery (n = 9; 22.5%). Besides, the proximal (n = 12; 30.0%) and medium (n = 12; 30.0%) segments of the vessels were the ones most often compromised (table 2 of the supplementary data).

Table 2. Lesions distribution

On the coronary angiography, 25 patients (62.5%) showed TIMI grade-0 flow (Thrombolysis in Myocardial Infarction) before crossing the wire. Twenty-nine cases (72.5%) received thrombus aspiration therapy and 7 underwent balloon angioplasty. None of the patients were treated with stenting, but TIMI grade-3 flow was observed in 32 cases (77.5%) after the PCI (table 3 of the supplementary data). Regarding intracoronary imaging during the PCI, pre- and postoperative optical coherence tomography and intravascular ultrasound were performed in 3 (7.5%) and 1 (2.5%) patients, respectively. Antithrombotic treatment at presentation and after PCI is shown on table 4 of the supplementary data.

Table 3. Complications during PCI, hospitalization, and follow-up in patients with ACS-E

Table 4. Multivariate analysis to identify clinical predictors of acute coronary syndrome due to systemic embolism

Comparison between acute coronary syndrome due to systemic embolism and acute coronary syndrome due to atherosclerosis

Baseline characteristics

Compared to ACS-A, there was a significantly higher proportion of patients under 45 and over 80 years old in the ACS-E group. Besides, a higher proportion of women was observed (42.5% vs 22.5%; P = .003). Among these patients, cardiovascular risk factors were less prevalent compared to those with ACS-A, although statistically significant differences were only seen regarding dyslipidemia. A significantly higher proportion of patients with ACS-E had active neoplasms, AF, previous strokes, and had undergone heart valve surgery. Also, 27.5% of the patients from the ACS-E group were on warfarin (P < .001) at presentation whereas the patients with ACS-A often had a past medical history of angina (34.0% vs 5.0%; P < .001). The inter-group differences regarding other medical conditions are also shown on table 1.

Clinical and angiographic characteristics and outcomes

Regarding the episode of ACS, no differences were seen regarding the presentation as STEMI between both groups (ACS-E, 80.0% vs ACS-A, 67.0%; P = .082). However, patients with ACS-A showed significantly longer times between the diagnosis of ACS and the performance of a coronary angiography (1.16 ± 0.8 hours vs 0.81 ± 0.5 hours; P = .003). No differences were seen regarding the rate of cardiogenic shock.

The presence of other moderate or severe stenoses, apart from the culprit one, was significantly more frequent among patients with ACS-A (table 2). PCI was attempted in all the patients with ACS-A and in 75.0% of those with ACS-E (P < .001) being successful in 99.1% and 80.0%, respectively. Conversely, adjuvant treatment with GP IIb/IIIa inhibitors was used in 55.0% of the patients with ACS-E and 36.0% of the patients from the ACS-A group (P = .020).

Complications during PCI and hospitalization in the ACS-E group are shown on table 3 including death that occurred in 5 patients (12.5%) due to heart failure/cardiogenic shock and anoxic encephalopathy after cardiac arrest in another case. A control coronary angiography was performed in 14 cases (40.0%) with persistence of culprit vessel compromise in 2 (14.3%). The median follow-up after the episode was 5.8 ± 4.8 years. Three days after emergency thrombus aspiration due to acute LAD occlusion, a 51-year-old woman with acute myeloid leukemia presented a recurrent ACS-E with new compromise of both the LAD and a marginal branch. No recurrent emboli in other systemic territories were identified in any of the cases. However, major adverse cardiovascular and cerebrovascular events at the follow-up occurred in 13 patients with ACS-E (38.2%) while death occurred in 12 patients (35.3%) being attributed to cardiac causes in 6 cases (50.0%) (table 3). The overall major adverse cardiovascular and cerebrovascular events-free survival during hospitalization and at the follow-up was estimated using Kaplan-Meier curves (figure 1).

Figure 1. MACCE-free survival during admission and at the 4-year follow-up in patients with ACS-E. ACS-E, acute coronary syndrome due to systemic embolism, FU, follow-up; IQR, interquartile range; MACCE, major adverse cardiovascular and cerebrovascular events.

The in-hospital all-cause mortality rate was 15.0% in the ACS-E group and 4.0% in the control group (P < .001).

Predictors of acute coronary syndrome due to systemic embolism

To determine the clinical predictors of ACS-E, a multivariate analysis was performed including those variables with statistically significant differences in the univariate model and those considered clinically relevant. Therefore, younger age, female sex, an active neoplasm, previous heart valve surgery, and a past medical history of AF were identified as independent predictive factors for ACS-E (table 4, figure 2).

Figure 2. Independent clinical predictors of ACS-E. ACS-E, acute coronary syndrome due to systemic embolism.

DISCUSSION

The main findings of our study include a) the prevalence of ACS-E in patients admitted due to AMI was low (0.8%); b) the in-hospital mortality rate was higher among patients with ACS-E as compared to ACS of atherosclerotic origin; and c) being younger, female sex, an active neoplasm, previous heart valve surgery, and AF were identified as ACS-E predictors.

Systemic coronary artery embolism is one of the underlying mechanisms of AMI of non-atherosclerotic cause.4 First autopsy studies reported a prevalence of coronary emboli in patients with AMI of 13%5 although subsequent studies conducted at the clinical setting described a frequency of around 3%.1 The low prevalence seen in our series (0.8%) may be associated with strict diagnostic criteria excluding patients with coronary artery stenosis > 25% outside the culprit lesion, and emboli due to secondary coronary arteries. However, the real occurrence of ACS-E remains unknown since the early presentation can be indistinguishable from an ACS-A.6

Also, the limited rate of coronary artery emboli reported compared to other vascular territories may also be associated with intrinsic anatomical and physiological characteristics like aortic caliber differences, the acute angle at which the coronary arteries originate at the sinus of Valsalva,7 and the position of the coronary ostia behind the valve cusps during systole.3,8

Although some series comparing ACS-A and ACS-E have not described gender differences when focusing on STEMI,2 in our study, the proportion of women was significantly higher among ACS-E (43% vs 22%; P = .003). Similarly, Shibata et al. reported rates of 40% vs 29% (P = .087).1 Besides, according to the aforementioned authors, a lower prevalence of traditional cardiovascular risk factors was seen within the embolic group of our cohort, although statistically significant differences were only noticed regarding dyslipidemia (27.5% vs 43.9%; P = .037).

Regarding the compromise of coronary arteries, the LAD was the most commonly affected vessel in both the ACS-E and the ACS-A (table 3). Similarly, a previous autopsy study had shown that coronary emboli are up to 4 times more common in the LAD compared to the right coronary artery, and in the LAD compared to the the left circumflex artery.5 Also, in a recent systematic review including 129 case reports and case series of coronary emboli, Lacey et al. described that the LAD was the most frequently affected vessel (45.3%).6 However, such differences in the distribution of culprit coronary vessels may be explained by bias associated with the fact that arteries with larger territories are more likely to be involved in autopsies1 and case reports.

On the interventional treatment used, in our study, 30 patients (75.0%) from the ACS-E group underwent thrombus aspiration followed by balloon angioplasty in 8 cases. None of the patients from this group were treated with stenting. Similarly, Shibata et al. performed initial thrombus aspiration in 96.6% of embolic patients undergoing PCI followed by balloon angioplasty in 14.3% of the cases and stenting in 17.9%.1 Thrombus aspiration has proven to be a feasible option to treat AMI with angiographic evidence of thrombus including cases associated with coronary emboli.9 However, these devices may be less useful to aspirate large thrombi due to the smaller diameter of the lumen of the inner catheter.10 Besides, in specific situations like small arteries or distal coronary occlusions, simple wire manipulation added to antithrombotic drugs (including glycoprotein IIb/IIIa inhibitors, which were more frequently used in the ACS-E group) may be the preferred option to achieve reperfusion.2

At the follow-up after an episode of ACS-E (5.8 ± 4.8 years) in our series, the major adverse cardiovascular and cerebrovascular events occurred in 37.1% of the patients. However, no recurrences of systemic emboli were documented in accordance with other previous series.2 The in-hospital all-cause mortality rate was significantly higher among patients with ACS-E (15% vs 4%; P < .001) mainly due to cardiovascular causes. Shibata et al. reported no differences in the 30-day mortality rate, but significantly higher cardiovascular and all-cause mortality rates in ACS-E compared to ACS-A.1 Similarly, Popovic et al. observed that 64% of all deaths reported at the follow-up after an episode of STEMI due to coronary embolism were due to cardiac causes.2

Finally, after multivariate analysis, AF, previous heart valve surgery, active neoplasm, female sex, and younger age were identified as clinical predictors of ACS-E. AF has been described as the most frequent condition predisposing to coronary artery embolism being present in 40.0% of ACS-E in our study and in up to 73% in other current series.1,3 However, early studies reported that valvular heart disease, especially rheumatic, and infective endocarditis represented the most common causes of coronary artery embolism.5,11 This disparity may be associated with the advances made in antibiotic therapy implementation over the last few decades, and the remarkable increase of AF prevalence parallel to the gradual aging of the population.1,2,12,13 Furthermore, it has been reported that the risk of AMI associated with AF is significantly higher in women14,15 and patients without coronary artery disease.15-18

On the other hand, it is fully recognized that patients with active neoplasms are at a significantly higher risk of developing thrombotic events, both venous and arterial.19 The pathogenesis of cancer-associated coagulopathy is complex including a multifactorial interaction among the patient’s comorbidities, the specific malignancy, and treatment with several chemotherapeutic agents or immunomodulatory drugs that often lead to hypercoagulability, platelet activation, and endothelial injury.20 Besides, it has also been described that malignancy is associated with a higher risk of developing AF following interactions at the pathophysiological level.21,22 In our series, 17.5% of the patients presented active neoplasms in accordance with Popovic et al.2 who reported a prevalence of 15.1% notably higher than the one reported by Shibata et al.1 and Lacey et al.6 of 10% and 1.4%, respectively.

Limitations

The present study presents several limitations. First, being a retrospective study may have resulted in a certain degree of bias. Secondly, applying strict diagnostic criteria which excluded patients with ≥ 25% coronary artery stenosis outside the culprit lesion may have omitted cases of ACS-E in patients with concomitant coronary artery disease. Thirdly, in contrast with all previous reports on this matter, only emboli of major coronary arteries were considered, which possibly resulted in a lower number of ACS-E being diagnosed. Finally, including patients over a long period of time may explain some differences in treatment modalities, and the low use of intracoronary imaging seen in our series.

CONCLUSIONS

ACS-E and ACS-A have different clinical and angiographic characteristics. Female sex, younger age, past medical history of active neoplasms, previous valvular surgery, and AF were all independent predictors of ACS-E. Patients with ACS-E had a higher in-hospital mortality rate mainly due to cardiovascular causes.

FUNDING

None whatsoever.

AUTHORS’ CONTRIBUTIONS

All authors contributed to the study conception and design. Material preparation and data collection were prepared by A. Jerónimo, A. Travieso, A. McInerney, B. Hennessey, and L. Marroquín. Statistical analysis was conducted by A. Jerónimo, M.J. Pérez- Vyzcaino, and N. Gonzalo. The manuscript first draft was written by A. Jerónimo, and N. Gonzalo, and all authors commented on previous versions of the manuscript. All authors read and approved the manuscript final version.

CONFLICTS OF INTEREST

None reported.

SUPPLEMENTARY DATA

REFERENCES

INTRODUCTION

By the end of December 2019, The People’s Republic of China reported the World Health Organization on the first cases detected of an unknown pneumonia caused by a new type of coronavirus in the City of Wuhan, China.1,2 Since then, the disease caused by this virus has spread rapidly bringing the healthcare systems of several countries to the point of collapse ultimately triggering dramatic preventive measures by the health authorities.

The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a tremendous social, economic, and health impact across the world. Again and again, the healthcare setting has sustained several organizational and care changes that have triggered significant variations in the management therapeutic approach of the remaining diseases.3-5 Some studies have reported a lower number of admissions due to cardiovascular diseases, which has had a significant impact on morbidity and mortality alike.6-8

Pressure to the healthcare system due to COVID-19, the lockdown, and the lower demand for assistance are some of the reasons that may account for these changes. The objective of this study is to assess the rate of acute coronary syndrome (ACS) across the different stages of the pandemic in Spain, as well as the impact it has had on morbidity, mortality, and therapeutic management.

METHODS

Retrospective, observational, and multicenter study including data from patients admitted to 4 tertiary care centers of our country from 3 autonomous communities due to ACS from February 14, 2020 through June 24, 2020. Patients with ST-segment elevation acute coronary syndrome (STEACS), and non-ST-segment elevation acute coronary syndrome and were included. Patients with acute myocardial infarction and without significant lesions in coronary arteries were excluded. Patients were categorized into 3 groups based on the length of hospital stay: group A, from February 14 through March 14, 2020 (1 month before the lockdown); group B, from March 15 through May 24, 2020 (during the lockdown), and group C, from May 25 through June 24, 2020 (1 month after the stay-at-home lockdown). The patients’ baseline characteristics, acute complications, and cardiovascular events reported at the follow-up like all-cause mortality, cardiac death, stroke, reinfarction, stent thrombosis, and need for rehospitalization were recorded. In patients with STEACS the times elapsed between symptom onset and the first medical contact (FMC), and between electrocardiographic diagnosis until reperfusion were recorded. Clinical follow-up was completed back in July 25, 2020. Data curation was approved by the local ethics committee of each participant center.

The study primary endpoint was to assess the differences reported in all-cause mortality after 30 days since the onset of the acute coronary event among the 3 study groups. The study secondary endpoint was to analyze the differences reported in a composite of cardiac death, stroke, admission due to new ACS, stent thrombosis, and need for new revascularization. Complications reported after infarction at the follow-up, a high left ventricular ejection fraction, and revascularization times (from symptom onset until the first medical contact, and from diagnosis until reperfusion) were also studied in a secondary analysis and compared among the 3 groups.

Statistical analysis

Categorical variables were expressed as number and percentage using brackets and compared using the chi-square test or Fisher’s exact test, when appropriate. Continuous variables were expressed as mean and standard deviation or median and interquartile range in cases without a normal distribution. The Shapiro-Wilk test was used to assess the normal distribution of continuous variables that were compared using the analysis of variance (ANOVA) for independent samples or Kruskall-Wallis H test based on their normal distribution looking for differences among the 3 groups. Survival was studied using the Kaplan-Meier curves, and differences were assessed using the log-rank test. Cox proportional hazards regression analysis was used to assess the impact of group B (lockdown period) in the overall mortality of the patients. All estimates were performed using the statistical software package STATA version 15.1. P values < .05 were considered statistically significant.

RESULTS

A total of 634 patients were included from February 14, 2020 through June 24, 2020. Of these, 205 were patients from group A, 303 from group B, and 126 from group C with a median follow-up of 98 days (63-137 days). The number of admissions due to ACS was 120, 138, and 151 within the first, second, and third months since the state of alarm declared. This lowered the rate of admissions due to ACS by 41%, 33%, and 26%, respectively compared to the rates reported 1 month before the lockdown for the same 30-day period (figure 1).

Figure 1. Absolute number of patients admitted due to acute coronary syndrome, expressed in weeks and categorized into group A, B, and C.

A total of 356 (56.2%) from the overall number of patients were admitted due to STEACS, and 278 (43.8%) due to non-ST-segment elevation acute coronary syndrome. The cohort baseline characteristics are shown on table 1. Patients admitted during the lockdown (group B) were younger (P = .012) and had lower levels of hypertension and dyslipidemia. On the other hand, these patients’ past medical history showed less ischemic heart disease, and coronary revascularization (P < .001).

Table 1. Baseline characteristics, diagnosis at admission, and treatment

A diagnostic coronary angiography was performed on 97.1% of the cohort without any differences being reported regarding percutaneous coronary intervention throughout the different periods studied (P = .652); however, a significant reduction in the number of surgical coronary revascularizations performed during the lockdown was reported (group A, 5.4%; group B, 2.7%; group C, 8.1%; P = .045) including the subgroup of patients with left main coronary artery disease or 3-vessel disease (P = .003) (table 1).

A total of 36 deaths were reported, 22 of which were due to cardiovascular causes. No statistically significant differences were reported in the all-cause mortality rate after 30 days among the 3 groups (P = .327). According to a Cox regression analysis, being in the lockdown group (group B) was not associated with a higher all-cause mortality rate (P = .60). No survival differences were reported either among the 3 groups (figure 2).

Figure 2. Kaplan-Meier survival curves for all-cause mortality in groups A (February 14-March 14), B (March 15-May 24), and C (May 25-June 24).

No significant differences were reported at the follow-up in a composite of cardiac death, stroke, readmission due to new ACS, stent thrombosis, and new revascularization (P = .120). The remaining clinical events at the follow-up are shown on table 2 and the in-hospital events on table 3.

Table 2. Clinical events at the follow-up

Table 3. In-hospital events

Regarding delay times, significant differences were reported among the different groups with longer times elapsed between symptom onset and the first medical contact during (group B) and after lockdown (group C) compared to the previous period (group A): group A, 66 min (45-180), group B, 120 min (60-240), group C, 120 min (60-240); P = .007). The time elapsed between symptom onset until the first medical contact was similar in groups B and C (P = .7102). Finally, the time elapsed between diagnosis and reperfusion was shorter in patients from group C (P = .025) compared to the remaining cohort (table 4).

Table 4. Times between symptom onset and the first medical contact, and between electrocardiographic diagnosis and reperfusion (guidewire passage), in minutes, in the cohort of patients with ST-segment elevation acute coronary syndrome

DISCUSSION

The main findings from this study were a lower number of admissions due to ACS within the first few months of lockdown, and longer periods of time elapsed between symptom onset and the first medical contact in patients with STEACS that did not translate into higher morbidity and mortality rates.

Lower rate of acute coronary syndrome

Former studies have reported less activity at the cath lab due to fewer admissions due to ACS during the pandemic, especially in the STEACS setting.7,9-11 Our findings confirm this trend with a significant 41% drop within the first 30 days compared to the previous month. This reduction was kept in the remaining time during and after lockdown; however, as the isolation measures were being lifted and the rate of cases of COVID-19 dropped, a gradual increase in the number of admissions due to ACS was confirmed. One of the contributing factors may have been the intense pressure put to the healthcare system within the first few months of lockdown with the corresponding underdiagnosis of ACS and fewer admissions reported.12 Another hypothesis that may justified the lower rate of ACS during this time is the higher number of out-of-hospital sudden deaths reported. Although reported by other authors in the past, this was not cause for analysis in our study.13-16

Times elapsed among symptom onset, the first medical contact, and revascularization in patients with ST-segment elevation myocardial infarction, and association with adverse events

During the lockdown (group B) patients with STEACS were admitted more often (P = .003). The time elapsed between symptom onset and the first medical contact was significantly longer during this time compared to other times, which is consistent with the peak number of cases reported (similar findings to those reported by former studies);17 however, this delay did not increase the rates of mechanical complications or mortality. This can be explained because patients admitted during the lockdown (group B) were younger and had fewer comorbidities.18,19 Data suggests that elderly patients with more serious past medical histories and associated comorbidities may have delayed or even postponed indefinitely their access to the healthcare system over fears of getting infected.20,21

Rodríguez-Leor et al.22 reported time delays between symptom onset and the first medical contact, and similar times between diagnosis and reperfusion. This delay was associated with a higher mortality rate during the pandemic (7.5% vs 5.1%), which contradicts our findings. The lack of a direct association between time delays until diagnosis and the appearance of adverse events is not easy to explain. However, a plausible hypothesis can be the higher number of out-of-hospital sudden deaths reported due to mechanical complications or malignant arrhythmias followed by the corresponding selection bias since this study included hospitalized patients only.

Therapeutic strategies: percutaneous coronary intervention and surgical revascularization

No differences were found regarding the percutaneous invasive management of patients with ACS before, during or after lockdown. This data is consistent with most studies published on the management of ACS during the pandemic.12,22

However, we should mention the significant decrease of myocardial revascularization procedures despite the non-negligible number of patients with left main coronary artery disease or 3-vessel disease. A total of 17.7% of these patients were treated with myocardial revascularization 1 month before the lockdown, only 5.5% during the lockdown, and 34.5% the following month. Although some registries confirm the lower number of coronary artery bypass grafts performed,23 this tendency has not been confirmed in other studies.18,23

The fact that fewer myocardial revascularization procedures were performed during the lockdown can be explained by the overall tendency to delay any surgical acts as much as possible during these months, something already hypothesized in other studies.24

Limitations

This study has some limitations associated with the analysis of multicenter and observational data. Also, the study short follow-up period may have prevented the finding of potential consequences or differential events among the study groups. The lack of information on cases of ACS treated during the pandemic that never really made it to tertiary care centers also casts a shadow over the conclusions that can be drawn.

CONCLUSIONS

Significantly fewer admissions due to ACS were reported during the lockdown. Also, although time between symptom onset and the first medical contact was longer during this period in patients with STEACS, the mortality rate was similar among the 3 study groups.

FUNDING

None reported.

AUTHORS’ CONTRIBUTIONS

J. Echarte-Morales: clinical data mining, manuscript drafting, project design, and management of the study. C. Minguito-Carazo: data analysis, manuscript drafting and revision process. PL Cepas-Guillén, V. Vallejo García, ID. Poveda Pinedo, A. Salazar Rodríguez, E. Arbas Redondo, J. Guzmán Bofarull, and D. Tebar Márquez: data mining and manuscript revision process. E. Sánchez Muñoz: data mining. E. Martínez Gómez: data mining, manuscript drafting and revision process. T. Benito-González: statistical counselling, and manuscript revision process. M. López Benito, A. Viana Tejedor, I. Cruz-González, PL Sánchez Fernández, M. Sabaté, and F. Fernández-Vázquez: project organization. Authors submitting this manuscript accept full responsibility for its content as defined by the International Committee of Medical Journal Editors (ICMJE).

CONFLICTS OF INTEREST

None whatsoever.

REFERENCES

INTRODUCTION

Coronary artery disease and mental health disorders frequently coexist and have a bidirectional relationship.1,2 Patients with mental health disorders have an increased risk of coronary artery disease and, inversely, it is not rare for patients to experience symptoms of depression or anxiety after a cardiac event.3 Moreover, depression in patients with CHD is associated with a poor adherence to treatment, unhealthy lifestyle habits, and a poor prognosis.4-8

Selective serotonin reuptake inhibitors (SSRIs) are often prescribed as first-line agents to treat depression and anxiety,9,10 but have a potential for increased bleeding risk due to the concomitant inhibitory effect on the platelet serotonin reuptake transporter (5-HTT).11 Platelet 5-HTT inhibition has been associated with a reduced platelet activation and aggregation, and with a prolonged bleeding time.12,13 On the other hand, some studies have linked SSRI-related bleeding risk to older age, comorbidities or polypharmacy.14,15

Bleeding risk due to antithrombotic therapy is a major concern following percutaneous coronary intervention (PCI) as hemorrhagic events are prognostically unfavorable as recurrent ischemic events.16,17 While bleeding risk depends on multiple clinical and laboratory features,18,19 the identification of potential modifiable factors is key to optimize the balance between ischemic and bleeding risk.20 Prior studies have evaluated the bleeding risk of patients with a concomitant treatment of SSRIs and dual antiplatelet therapy (DAPT) plus aspirin and clopidogrel with contradictory results.21-23 However, the impact of SSRIs plus therapy with more potent P2Y₁₂ inhibitors (eg, ticagrelor or prasugrel) or triple antithrombotic therapy with DAPT plus an oral anticoagulant (OAC) has never been explored. In this study we tried to compare the 1-year risk of bleeding after PCI and concomitant guideline-recommended antithrombotic therapy (including clopidogrel, ticagrelor or prasugrel-based DAPT and triple antithrombotic therapy) in patients with or without prescribed SSRIs.

METHODS

Study design and setting

Retrospective study including all consecutive patients discharged after PCI performed at a single center during 2018. Those treated with SSRIs were propensity score-matched (PSM) to a control group to compare bleeding outcomes at the 1-year follow-up. Antithrombotic treatment was decided by the clinical cardiologist in accordance with the current clinical practice guidelines.24 This study was conducted according to the Declaration of Helsinki and was approved by the local clinical research ethics committee. Written informed consent was obtained from all patients before the PCI.

Population

All patients discharged after the PCI performed during the study period were eligible. Those treated at discharge with single antiplatelet therapy, DAPT were excluded—not including acetylsalicylic acid—as well as those anticoagulated with low-molecular-weight heparin for other reasons. Patients with missing information at the follow-up were also excluded. Clinical and procedural data, treatment at discharge, and outcomes during the first year were reviewed through electronic health records. Patients were treated with SSRIs if their list of prescriptions at discharge included one of the following: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine or sertraline.

Endpoints

The primary safety endpoint was major bleeding at the 1-year follow-up. Secondary endpoints were a composite of major or non-major clinically relevant bleeding, and a composite of major adverse cardiovascular events (MACE). Major bleeding was defined as a bleeding event type 3 or 5 according to the Bleeding Academic Research Consortium (BARC). Major/non-major clinically relevant bleeding was defined as BARC type 2, 3 or 5 bleeding event.25 MACE was defined as a composite outcome of cardiovascular death, non-fatal myocardial infarction or unplanned revascularization. Events were independently adjudicated by 2 cardiologists who were unaware of the SSRIs group.

Statistical analysis

Categorical variables were expressed as counts (percentages), and the continuous ones as mean ± standard deviation or median [interquartile range] according to their distribution assessed using the Shapiro-Wilk test. P values were obtained using the chi-square test or the Mann-Whitney U test, as appropriate. PSM was conducted to account for the confounding biases.26 Logistic regression was used to determine the probability of being treated with SSRIs and included the following confounding variables potentially associated with SSRIs treatment and the primary endpoint:27 age, sex, prior relevant bleeding, hypertension, cancer, past medical history of hematologic disease or anemia, liver disease, creatinine clearance, treatment with potent P2Y₁₂ inhibitors or concomitant OAC. The nearest neighbor matching method with no replacement, and a caliper width of 0.1 were used in the PSM on a 1:1 ratio. Propensity score histograms and standardized mean differences before and after the PSM were used to evaluate the balance of the groups regarding the covariates.28 Time-to-event analyses were conducted using the Kaplan-Meier and Cox proportional hazards methods. To determine major bleeding predictors in the unmatched cohort, a multivariate Cox regression model was conducted that used a purposeful selection model and prioritized parsimony. Clinical meaningful variables and those showing P values < 0.2 in the univariate analysis were included. Statistical analyses were performed using SPSS software (version 24; IBM Corp., United States) and R software (version 4.0.3; R Foundation for Statistical Computing, Austria). Matching was performed using the MatchIt R package (Ho, Imai, King, & Stuart, 2011) while covariate balance was assessed using the Cobalt R package (Greifer, 2021).

RESULTS

Baseline clinical characteristics

A total of 1063 patients were treated with PCI during the study period, 1002 of whom met the selection criteria and were included in the analysis. A total of 139 patients (13.9%) were treated with SSRIs at discharge (figure 1). Median age was 66 years (58-75), and 745 patients (74.4%) were male with a median PRECISE-DAPT score of 13 [9-22]. Regarding antithrombotic therapy, 684 patients (68.3%) were treated with potent P2Y₁₂ inhibitors and 102 (10.2%) were concomitantly treated with OAC. The baseline clinical characteristics of the overall population and the unmatched groups are shown on table 1. Patients from the SSRIs group were more likely to be women. They also had a more extensive past medical history of hypertension, diabetes mellitus, cancer, significant bleeding, and hematologic disease or anemia. Both the HAS-BLED and the PRECISE-DAPT bleeding risk scores were higher in the SSRIs group.

Figure 1. Patient flowchart. PCI, percutaneous coronary intervention; SSRIs, selective serotonin reuptake inhibitors.

Table 1. Baseline clinical characteristics of the overall population, and SSRIs/non-SSRIs users before matching

Unmatched analysis

In the overall population there were a total of 19 major bleeding events at the 1-year follow-up: 4 (2.9%) in the SSRIs group, and 15 (1.7%) in the unmatched non-SSRIs group (P = .350). Of these, 4 (21.1%) were fatal, 10 (52.6%) GI bleedings, 4 (21.1%) intracranial bleedings while the remaining ones occurred in other locations.

The multivariable Cox model identified the following independent predictors for the primary endpoint of major bleeding: PRECISE-DAPT score ≥ 25, and concomitant anticoagulation. Table 2 shows the univariable and multivariable Cox predictors for the primary endpoint.

Table 2. Univariable and multivariable Cox predictors for major bleeding

The major/non-major clinically relevant bleeding endpoint occurred in 4 patients (2.9%) from the SSRIs group, and in 43 patients (4.9%) from the unmatched no-SSRIs group (P = .290). The rate of MACE was similar in both groups: 11 events (7.9%) in the SSRIs group and 50 events (5.8%) in the non-SSRIs group.

The Kaplan-Meier curves and the associated risk tables for each endpoint of the unmatched cohorts are shown on figure 2.

Figure 2. Kaplan-Meier curves for the primary bleeding outcome (A), the secondary composite bleeding (B), and the ischemic outcomes (C). Unmatched cohort. SSRIs, selective serotonin reuptake inhibitors.

Propensity score matching analysis

The variables used in the PSM, the standardized mean differences, and the Propensity score distributions of the unmatched and matched samples are shown on figure 3. PSM resulted in an excellent balance of covariates with standardized mean differences ≤ 10% in all variables included in the Propensity score. There was also a very good balance across the other baseline characteristics and bleeding risk scores except for diabetes mellitus and hyperlipemia that were more prevalent in the SSRIs group (table 3).

Figure 3. Variables used in the propensity score matching analysis and their standardized differences (A), and the propensity score distributions (B) of the unmatched and matched samples. OAC, oral anticoagulant.

Table 3. Baseline clinical characteristics of SSRIs/non-SSRIs users after matching

The rate of major bleeding at the 1-year follow-up was 2.9% for both patients on SSRIs and the matched SSRIs non-users (HR, 1.01; 95%CI, 0.25-4.03; P = .991). There were no non-major clinically relevant bleedings in the SSRIs group and 6 (4.3%) among SSRIs non-users (HR, 0.39; 95%CI, 0.16-1.27; P = .120). No differences in MACE were reported between the SSRI and the non-SSRIs groups (HR, 1.01; 95%CI, 0.44-2.33; P = .979) (figure 4).

Figure 4. Kaplan-Meier curves for the primary bleeding outcome (A), the secondary composite bleeding (B), and the ischemic outcomes (C). Matched cohorts. SSRIs, selective serotonin reuptake inhibitors.

DISCUSSION

The main findings of this study can be summarized as follows: a) the use of SSRIs was frequent among patients undergoing PCI; b) patients prescribed with SSRIs had a higher baseline bleeding risk; c) despite the imbalance reported in the baseline characteristics, after adjustment SSRIs users were not associated with a significant excess of major or clinically relevant bleeding at the 1-year follow-up.

There is a strict correlation between coronary artery disease and mental health disorders. In our study up to 13.9% of patients treated with PCI were prescribed SSRIs. This group has more comorbidities and bleeding risk factors with the potential to complicate the clinical decision-making process regarding antithrombotic therapy selection. Importantly, whether SSRIs trigger a higher bleeding risk through a biological effect on platelet 5-HTT receptors or are a marker of a higher bleeding risk through concomitant comorbidities has been the matter of discussion in prior studies.

Labos et al.21 reported an increased risk of bleeding in patients taking both SSRIs and acetylsalicylic acid or clopidogrel-based DAPT after myocardial infarction. On the contrary, Lasella et al.22 assessed the impact of SSRI therapy on patients on DAPT after PCI finding no excessive bleedings in patients on SSRIs. Interestingly, they reported a lower risk of MACE in patients on SSRIs compared to those on mirtazapine, but a higher risk compared to patients on either one of the 2 antidepressants. This may be explained by a protective effect of SSRIs on MACE29 that could be exceeded by the unfavorable effect of mental health disorders on cardiovascular events.30 Another interpretation could be associated with the pharmacokinetics of clopidogrel since it is a prodrug that requires enzymatic conversion into its active metabolite by cytochrome P450 (CYP).31 Bykov et al.23 reported an increased risk of ischemic events in patients on clopidogrel and a CYP2C19-inhibiting SSRI compared to those on noninhibiting SSRIs. No differences were found regarding major bleeding. The study did not include a group of patients without SSRI treatment.

We should mention that none of the aforementioned studies included patients treated with potent P2Y₁₂ inhibitors, which is currently the standard of care of patients with ACS. To our knowledge, this is the first study to assess the impact of SSRIs on a cohort of patients treated with potent P2Y₁₂ inhibitors prasugrel or ticagrelor. In our population, two thirds of the patients were treated with potent P2Y₁₂ inhibitors, which is more consistent with the antiplatelet strategies recommended by the current clinical practice guidelines.32,33 In this clinical setting, despite the imbalances reported in the baseline bleeding risk in an unadjusted analysis, we found no differences regarding major or clinically relevant bleeding events among patients on SSRIs and the matched group without a SSRI prescription. Hence, while the prescription of SSRIs can be a marker of a higher risk population with more comorbidities and risk factors, this may not translate into an independent predictor of bleeding events after accounting for the potential confounders. This is consistent with prior evidence in the medical literature. In the study conducted by Labos et al.21 patients on SSRI had a more significant past medical history of hypertension, renal failure, anemia or other hematologic disease, and non-GI bleeding. Lasella et al.22 reported that SSRIs users were more likely to have diabetes, hypertension, dyslipidemia, COPD, and chronic kidney disease.

Our findings are clinically relevant for different reasons. Although SSRIs have been associated with a potential for an increased bleeding risk, a direct translation into an excess of adverse events has not been confirmed yet. Our data provide reassurance on the relative safety profile of potent antithrombotic therapies in association with SSRIs, which did not substantially increase the risk of bleeding during the first year after PCI when the treatment decision-making process is based on a thorough evaluation of the features of bleeding and ischemic risk.

Our study also included a proportion of patients treated with concomitant antiplatelet and OAC therapy (~10%), which is consistent with the current standard practice.34 The impact of SSRIs on bleeding outcomes in patients with AF treated with OAC has also been examined in the past. Various authors have reported a higher risk of major bleeding in patients concurrently treated with SSRIs and warfarin.35,36 On the contrary, Quinn et al.37 did not find a significantly increased risk of bleeding among patients from the ROCKET AF trial assigned to warfarin or rivaroxaban who were also on SSRIs. However, there was a modest but non-statistically significant higher risk of major bleeding in the warfarin group. Since SSRIs are CYP2C9 inhibitors, an increase of warfarin plasma concentrations could explain these findings.38 This reaffirms the importance of non-vitamin k antagonists to reduce the risk of bleeding also in this population given the need for multiple antithrombotic agents after the PCI and the higher baseline bleeding risk reported.39

Limitations

The current study has several limitations. First, its retrospective observational design, and the relatively small size of the sample limits our ability to provide definitive conclusions due to the residual possibility of type-2 errors. Secondly, despite the PSM resulted in a good balance between the selected potential confounders and the other baseline characteristics, the presence of residual confounding factors cannot be completely ruled out. For example, some variables associated with bleeding like the presence of diabetes mellitus or peripheral arterial disease were not included in the propensity score model. Yet similar findings were observed in the adjusted and unadjusted analyses. Thirdly, the classification of SSRI users was based on treatment at discharge without accounting for treatment adherence or discontinuation.

CONCLUSIONS

In this real-world study, a combination of SSRIs and potent antithrombotic therapies was frequently prescribed after PCI. Although the prescription of SSRIs was associated with a higher baseline bleeding risk in the unadjusted analysis this was not the case with an excess of major or clinically relevant bleeding reported at the follow-up.

FUNDING

None reported.

AUTHORS’ CONTRIBUTIONS

R. González-Manzanares, and S. Ojeda conceived and designed the study. R. González-Manzanares, M. Ruiz-Moreno, C. Fernández-Avilés, L. Carmona-Artime, G. Flores-Vergara, and F. Costa collected analyzed data and interpreted the results. R. González-Manzanares, M. Ruiz-Moreno, S. Ojeda, and F. Hidalgo drafted the manuscript and completed the critical revisions. S. Ojeda, F. Hidalgo, G. Flores-Vergara, F. Costa, J. Suárez de Lezo, and M. Pan reviewed and revised the manuscript, and approved its final version before submission. All authors gave their final approval to the version that would eventually be published.

CONFLICTS OF INTEREST

S. Ojeda is an associate editor of REC: Interventional Cardiology. The journal’s editorial procedure to ensure impartial handling of the manuscript has been followed. S. Ojeda, and M. Pan declared having received honoraria for lectures given for Abbott, Boston, World Medical, and Terumo. J Suárez de Lezo declared having received honoraria for lectures given for Abbott. The remaining authors declared no conflicts of interest whatsoever.

REFERENCES