Evaluating the efficacy of antiplatelet therapy in spontaneous coronary artery dissection: a scoping review

Introduction

Spontaneous coronary artery dissection (SCAD) is typically a manifestation in patients with non-inflammatory and non-atherosclerotic disease and can be a marker for an underlying collagen vascular disorder (1,2). Women are more prone to SCAD compared to men, potentially due to the differences in platelet activation between men and women both in healthy states and during myocardial infarction (MI) (3). A tear, also known as dissection, in the inner layer of coronary arteries can result in the creation of a false lumen in the wall of the artery, which may lead to a reduction or diversion of blood flow, and under-perfused myocardium that can precipitate MI (4,5). While dual antiplatelet therapy (DAPT) is considered the standard of care following MI in patients with atherosclerotic disease and acute plaque rupture, the appropriate antiplatelet therapy—if even required—following SCAD is not clear. While DAPT is the standard of care for acute coronary syndrome (ACS) as a consequence of a transmural MI or atheroembolism, the role of DAPT following SCAD is unclear and has never been fully investigated. Single antiplatelet therapy (SAPT) is recommended by consensus guidelines, yet marked practice variation persists in the medical community with some clinicians prescribed DAPT, even for a shorter period of time and also if a stent was not placed, without evidence for doing so.

There is inherent risk to patients taking an antithrombotic agent following a diagnosis of SCAD. For example: platelet inhibition in the context of arterial dissection can lead to intramural hemorrhage, a known and potentially severe consequence of SCAD (3,6). While robust platelet inhibition reduces thrombotic risks associated with sub-intimal exposure and release of mediators that promote thrombosis, as well as shear- stress-mediated platelet activation, this also increases the risk of aggravating the already vulnerable vessel wall and increasing risk to the patient with unclear benefit (1,2,5,7).

Current ACS by the American Heart Association (AHA) guidelines recommend administering a potent P2Y₁₂ inhibitor for 12 months as part of a DAPT (7,8). Some studies found that clopidogrel, a P2Y₁₂ receptor antagonist, reduces the risk of bleeding in SCAD compared with other antiplatelet drugs (5-7).

There is a significant gap in the literature regarding antiplatelet therapy in SCAD, despite various treatment approaches being adopted in clinical practice (5-7,9). There are currently no evidence-based guidelines tailored to SCAD patients due to this lack of targeted research.

This scoping review of the literature is an attempt to identify evidence regarding which antiplatelet regimen is appropriate for patients following SCAD. The major objective of this study was to compare DAPT with SAPT for medical management of SCAD following ACS. Comparing an aggressive DAPT regimen with a more conservative SAPT approach following SCAD is an important consideration and high quality data to guide decision-making in this regard is not available. We present this article in accordance with the PRISMA-ScR reporting checklist (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-108/rc).

Methods

This scoping review evaluated the impact of antiplatelet therapy on SCAD patients in a comprehensive and structured manner. Two reviewers independently screened studies and extracted data, with disagreements resolved by a third reviewer. Data accuracy was cross-verified. This review aimed to identify, assess, and synthesize relevant studies that compare the outcomes of DAPT and SAPT in patients with SCAD following the PRSIMA reporting algorithm.

Search strategy and selection criteria

A comprehensive literature search was conducted in the PubMed, SCOPUS, and Ovid, targeting a period of time between 2000 and 2023. The search was limited to studies published between 2000 and 2023 to ensure more relevant and up-to-date data, as SCAD-related research before 2000 is very limited. The initial search criteria utilized specific keywords and phrases in the title and abstract, such as (spontaneous coronary artery dissection [Title/Abstract]) AND (Antiplatelet therapy [Title/Abstract]), (spontaneous coronary artery dissection [Title/Abstract]) AND (DAPT [Title/Abstract]). This initial search resulted in the identification of 17 potential studies (Table 1). Incorporate SAPT and synonyms (e.g., antithrombotic therapy) and employ MeSH terms for better comprehensiveness.

Inclusion criteria

This search focused on English language articles, as this is a scoping review, the focus is on primary research and excluded secondary studies like meta-analyses unless their findings directly support the narrative. Additionally, studies were screened based on outcomes reported, including mortality due to any cause, recurrent SCAD, angina, and major adverse cardiovascular events (MACEs). A SCAD diagnosis required visualizing of the coronary arteries by diagnostic angiography in each case. Only some cases utilized advanced intravascular imaging including intravascular ultrasound (IVUS) or optical coherence tomography (OCT). The MACE process encompassed MI, ischemic stroke, death, hospitalization, and bleeding complications. A total of 17 relevant studies were identified through this process (Figure 1). Extended patient demographics for each study is displayed in Table S1.

Figure 1 PRISMA flow diagram showing search strategy. Flow diagram showing the reasons for exclusion of articles from the study. DAPT, dual antiplatelet therapy; SAPT, single antiplatelet therapy; SCAD, spontaneous coronary artery dissection.

Study group categorization

Study participants were categorized based on which antiplatelet regimen they were prescribed following diagnosis of SCAD. Two primary groups were identified: SAPT, initiated at the time of SCAD diagnosis, primarily comprising aspirin, and DAPT, which included aspirin in combination with a P2Y₁₂ inhibitor (most commonly clopidogrel, ticagrelor, or prasugrel). Direct comparisons between the two therapeutic approaches were facilitated by this categorization. Additionally, we collected data on patient characteristics (such as age, gender, and ethnicity), SCAD subtype, and treatment methods [including conservative management, percutaneous coronary intervention (PCI), or coronary artery bypass grafting (CABG)].

Exclusion of studies with incomplete data

Excluding studies without comprehensive data on cardiovascular medication use was a crucial part of the study selection process. In particular, studies that did not report the concurrent use of beta-blockers and statins, which are pivotal in the management of cardiovascular conditions, were excluded. As a result of these exclusion criteria, we ensured the review only considered studies offering a comprehensive view of patient management. To avoid duplication, patient cohorts across studies were cross-referenced, and studies using overlapping data were excluded. Also, patients undergoing PCI were excluded, as the focus was on medically managed SCAD cases. The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

Statistical analysis

The patients receiving SAPT and DAPT were analyzed using descriptive statistical methods. The mean recurrence rate (%) for each group was calculated as the sum of all observed mortality, MACE, presence of angina and recurrence of SCAD percentages divided by the total number of observations. Variability within each group was assessed using the standard deviation (SD), while the range was determined as the difference between the maximum and minimum values. The standard error of the mean (SE) was calculated to estimate the precision of the mean, and 95% confidence intervals (CIs) for the medians were determined using a non-parametric bootstrap method to account for sample variability. Results were expressed as mean ± SD, range, and 95% CIs. Statistical analyses were conducted using PRISM providing a comprehensive summary of mortality, MACE, presence of angina and recurrence of SCAD rates in both treatment groups.

Results

Of the 72 studies identified to study SCAD, several were eliminated due to the absence of required data or elements required for study evaluation, leaving 17 studies available for evaluation. The total number of patients considered across all the studies included in the review is 3,142. Heterogeneity analysis of reported outcomes revealed significant findings. A P value less than 0.05 suggests that the observed effect or association is statistically significant. There was an increase in mortality among DAPT-treated patients compared with SAPT-treated patients, with an average of 4.96% in the DAPT group versus 1.55% in the SAPT group. There was also an increase in MACE in the DAPT group. In patients receiving DAPT showed more frequent compared to SAPT, with 12.13% in the DAPT group versus 6.91% in the SAPT group, on average. MACE included MI, stroke, and the need for urgent cardiovascular interventions. In patients receiving DAPT following a diagnosis of SCAD, hospitalizations for angina were more frequent compared to SAPT, with an average of 23.75% in the DAPT group versus 2.60% in the SAPT group. Lastly, there was a an increase in the rate of recurrence in the SCAD group following DAPT compared to the SAPT group with an average of 5.54% in the DAPT group versus 2.33% in the SAPT group. Overall, DAPT was associated with more adverse events in patients with SCAD, primarily due to MI and unplanned PCIs.

Discussion

In this scoping review, we analyzed diverse studies to elucidate clinical outcomes associated with SCAD, focusing on mortality, MACE, recurrence of SCAD (Re-SCAD), and present of angina. Specifically, mortality data were extracted from twelve studies (10-13,16-19,23-26) providing invaluable insights into the fatal outcomes of SCAD. Furthermore, an in-depth evaluation of MACE was conducted through seventeen studies (10-26), offering a comprehensive understanding of the major adverse cardiac events following SCAD. Recurrence of SCAD, a critical aspect of patient prognosis and management, was analyzed through twelve studies (10,11,13,15-19,23-26). Additionally, eight studies (10,11,15,18,23-26) were included to specifically address the presence of angina, rounding out our examination of the vascular challenges presented by SCAD.

Patients with SCAD appear to benefit less from DAPT compared to SAPT, experiencing more frequent angina, recurrent SCAD, and increased mortality overall on DAPT. In hospitals unaccustomed to treating SCAD, DAPT may be administered for at least 12 months, a duration typically reserved for MI from atheroembolic disease or plaque rupture, despite the lack of high-quality outcomes data. Based on these findings, treatment protocols for SCAD require reevaluation taking into account the unique pathophysiological aspects of the disease and individual patient characteristics. In specific SCAD patient populations, a more conservative SAPT regimen may offer benefits, through further research is necessary to develop definitive guidelines.

Patients undergoing DAPT experienced higher rates of mortality, MACE, angina, and recurrent SCAD, as opposed to those on SAPT. The higher mortality rate observed in the DAPT group raises concerns regarding the safety and efficacy of this treatment approach for patients with SCAD. In addition, the recent meta-analysis revealed that in a meta regression analysis incorporating observational studies, the use of aspirin was associated with lower long-term rates of hospital admissions for angina. Additionally, a borderline association was observed between the use of DAPT and the recurrence rates of SCAD (27). Comparative analysis indicated that patients on DAPT had a worse prognosis than SAPT patients. The outcome measures were statistically significant, indicating that the differences observed can probably be generalizable to SCAD patients. In the DAPT group, nonfatal MIs and unplanned coronary interventions accounted for the majority of adverse outcomes. These findings challenge the current treatment protocols for SCAD, particularly the generalized inclination towards DAPT use. A personalized treatment plan is needed for patients who experience SCAD, perhaps due to their variable response to antiplatelet therapy which should be formally investigated.

While SCAD does present less frequently in men—typically those with collagen vascular disorders—SCAD has a predilection for women, and requires a nuanced understanding of patient-specific factors, including hormonal influences, underlying vascular conditions, and unique characteristics of arterial dissection compared to atherosclerotic coronary artery disease (1,28,29). To determine the appropriate antiplatelet regimen, it is important to recognize and respond to these differences.

Several factors might contribute to recurrent SCAD, in addition to comparing SAPT and DAPT. Beta-blockers are common medications prescribed for the treatment of cardiovascular conditions, including SCAD. Although in this review most patients treated with SAPT or DAPT are also prescribed beta-blockers, recurrent SCAD seems to be more prevalent among those on DAPT. Beta-blockers are known to reduce blood pressure, heart rate, and myocardial oxygen demand, and arterial shear stress. The finding that patients taking DAPT have a higher incidence of angina than those taking SAPT is interesting. While monotherapy consisting of a P2Y₁₂ receptor antagonist would not be expected to impact arterial tone, aspirin is known to decrease endothelial-derived dilating prostaglandins which may precipitate vasospasm (13,30,31) and arterial spasm may be underrecognized in patients following SCAD (27,31,32). There is some evidence suggesting that beta-blockers may also have potential adverse effects, in SCAD by causing hypotension and bradycardia (29). The exact mechanism of beta-blockers causing recurrent SCAD is unknown, but this may be from an alteration in arterial tone, predisposing to vascular fragility and the risk of recurrence.

The association between beta-blocker use and recurrent SCAD is predominantly observed in patients receiving DAPT rather than SAPT. A potential interaction between beta-blockers and DAPT warrants further investigation. Future studies should investigate specific mechanisms underlying this association and assess the overall risk-benefit profile of beta-blocker therapy in SCAD patients receiving different antiplatelet regimens.

As part of our study, we also tracked variables such as hypertension, diabetes, smoking status, dyslipidemia, stress-related SCAD, and pregnancy or hormone-related SCAD (Table S1). There were no significant differences between patients treated with SAPT and those treated with DAPT in terms of these factors. Furthermore, we monitored the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), statins, PCI, and beta blockers for their potential influence on outcomes (Table S1). While the majority of studies reported similar CV risk profiles between groups, a few studies indicated slight imbalances in factors such as age or hypertension; however, these differences were insufficient to account for the higher incidence of MACE observed in the DAPT group.

In spite of controlling for these variables, we consistently found that patients receiving DAPT had significantly higher rates of mortality, MACE, angina, and recurrent SCAD compared to those receiving SAPT. Further research is necessary to elucidate the mechanisms driving the adverse outcomes associated with DAPT in SCAD patients and to refine treatment strategies accordingly. Only a limited number of studies have specifically examined recurrent SCAD cases (10,11,13,15-19,23-26). The limited number of studies examining recurrent SCAD emphasizes the complexity and rarity of the condition, as well as the difficulties associated with its diagnosis and treatment (27,28). Investing in research focusing on recurrent SCAD cases will contribute to a better understanding of the underlying mechanisms and risk factors associated with recurrence, as well as to the development of evidence-based treatment strategies for these patients.

To provide a deeper understanding of the optimal management of SCAD, randomized controlled trials of DAPT compared with SAPT, and SAPT consisting of aspirin alone of a P2Y₁₂ receptor antagonist alone will be needed. A study of this type would be aimed at establishing definitive guidelines for the use of antiplatelet therapy in SCAD, potentially distinguishing it from the general protocol for patients following ACS.

Limitation

Several limitations were identified within the current body of research on SCAD, which is crucial for understanding the scope of our findings and guiding future research. Studies included in this review were limited in size. This constraint potentially affects generalizability, highlighting the need for larger, more inclusive studies. Heterogeneity was noted in data available from each study. Ideally, we would have liked to compare SAPT to DAPT as well as to no antiplatelet therapy. However, 12 months of DAPT is guideline-based for treating patients who present with ACS, and we unfortunately could not perform this comparison. To address this gap, we advocate the development of prospective, multicenter registries for patients with SCAD. SCAD registries would facilitate the detection of SCAD with greater accuracy and the collection of comprehensive patient data, improving the depth and breadth of information available for analysis. Across the studies reviewed, we observed considerable variation in the length and rationale of long-term follow-up. Most studies conducted follow-ups at 1, 6, and 12 months and annually after that for 3 to 10 years, but the average follow-up period was about five years. Despite concerted efforts to collect comprehensive follow-up data, it is possible that unrecognized cardiac or extracardiac vascular events or bleeding may occur. Thus, standardized follow-up protocols are essential to capture all relevant outcomes, thereby enhancing the reliability of long-term safety and efficacy data for patients with SCAD. We also examine the comparative outcomes of SAPT versus DAPT in patients with SCAD. As a result of the need for more high-quality data regarding the optimal duration and effectiveness of DAPT, it is necessary to reevaluate current treatment protocols. SCAD patients have a variety of characteristics and treatment responses, making it challenging to devise tailored treatment plans tailored to their individual needs. This underscores the importance of further research for developing tailor-made guidelines that consider the unique characteristics and treatment responses of patients with SCAD. Another limitation is the possibility of biases in selecting patients for fibromuscular dysplasia (FMD) screening. The study by Saw et al. (28) showed no difference in 3-year MACE between those screened for FMD and those not screened, although selection bias cannot be completely excluded. Further emphasizing the need for comprehensive, unbiased research methodologies, this observation calls for a more nuanced understanding of FMD screening in the context of SCAD. These limitations are indicative of the complexity of SCAD, as well as the varied challenges faced by researchers in this area. A concerted effort is required to address these limitations by conducting large, methodologically sound studies with standardized protocols for diagnosis, follow-up, and treatment. SCAD can be better understood and improved for patients by overcoming these challenges.

Conclusions

Exposing patients to DAPT following a diagnosis from MI as a consequence of SCAD appears to increase the risk of adverse cardiovascular events and mortality compared with SAPT. Mechanistic, and high-quality randomized clinical trials will be required to determine optimum antiplatelet for patients following a diagnosis of SCAD.

Acknowledgments

We thank Mr. Matthew Weaver for technical expertise in assessing the prior literature on SCAD.

Footnote

Reporting Checklist: The authors have completed the PRISMA-ScR reporting checklist. Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-108/rc

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-108/prf

Funding: We would like to express our sincere gratitude to the following agencies for funding support, notably Pinkert Family Foundation for their generous donation to Cleveland Clinic for SCAD research, and the National Institute of Health HL158801-01 (to S.J.C.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-108/coif). S.J.C. declares grants from NHLBI Grant R01HL158801-01; small honorarium for lecture at VIVA Interventions 2023 (antiplatelet therapy); and professional service with Sanofi Inc. as an adjudicator within the last 24 months (the relationship ended in December 2022). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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