This is a pragmatic study where medications, during hospitalization and at follow-up, will be re prescribed by the treating physician.1,2

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  Beta-blocker therapy will be started on the day of randomization. The type and dose of beta-blocker, including titration of therapy to ensure an adequate effect, will be at the discretion of the treating physician (the comparator arm will receive no beta-blocker therapy).

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  Short (1-month) vs prolonged (12-month) antiplatelet therapy will be initiated on the day of randomization. Aspirin monotherapy for 1 month is the recommended regimen in the short antiplatelet arm. However, investigators will be given the option to consider the use of dual antiplatelet therapy (DAPT) for a period no longer than 1 month. This approach has been implemented given that DAPT remains an integral part of conservatively managed ACS patients.3,4 Alternatively, for patients randomized to prolonged DAPT, the use of both aspirin and clopidogrel for 1 year is recommended. Although the potent P2Y12 inhibitors (ie, ticagrelor and prasugrel) are preferred over clopidogrel in ACS patients according to practice guidelines,3,4 there are no data for their use in SCAD.1,2 Nevertheless, the pragmatic nature of this trial will allow the choice of P2Y12 inhibitor to be at the discretion of the treating physician and at a dosing regimen recommended by guidelines and in line with the product label. Patients allocated to the prolonged antiplatelet regimen arm will be recommended to maintain a single antiplatelet agent (preferably aspirin) after the first year.

Other cardiovascular medications will be prescribed at the discretion of the treating physician according to guideline recommendations.3,4 Anticoagulation will be discontinued once SCAD has been confirmed on angiography. Since patients with reduced left ventricular ejection fraction (LVEF) <40% have a class IA recommendation for receiving beta-blockers and additional medications (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) according to guidelines,3 these patients will not be randomized in the stratum of beta-blockers but only in the antiplatelet part of the study. Similarly, patients requiring coronary revascularization will be treated with prolonged DAPT and, therefore, will not be included in the antiplatelet part of the trial. Patients with an indication for oral anticoagulants (eg, atrial fibrillation, mechanical valves), will not be randomized to the antiplatelet stratum of the trial (table 1). Coronary risk factors will be aggressively treated and followed up as recommended by clinical practice guidelines.3,4 Antihypertensive agents different from beta-blockers should be prescribed as required in patients not allocated to beta-blockers, according to the guidelines. Women of child-bearing age will be advised to use a highly effective contraceptive method considering the pregnancy-associated risk of recurrent SCAD. Cardiac rehabilitation will be recommended.1,2

Importantly, chronic obstructive pulmonary artery disease (COPD) will not be considered a contraindication to the use of beta-blockers. A recent large meta-analysis17 demonstrated that the use of beta-blockers in cardiac patients with COPD is not only safe but reduces their mortality. Cardioselective beta-blockers did not affect the action of bronchodilators and actually reduced COPD exacerbations.17 The use of cardioselective beta-blockers will be recommended in patients with COPD allocated to this therapeutic strategy.

The primary endpoint of the study is the composite of death, MI, stroke, coronary revascularization, and recurrent SCAD or hospital admission for ACS-with dynamic electrocardiographic changes-or heart failure, at 1-year follow-up. For a suspected ACS episode to qualify as an event, dynamic electrocardiographic changes, or abnormal cardiac markers (ie, MI) are required. This was predefined to avoid the inclusion of episodes of nonischemic chest pain that are frequently seen in these patients. The 2 x 2 factorial design of the BA-SCAD trial enables 2 study hypotheses to be addressed. The first study hypothesis is that treatment with beta-blockers will reduce the primary endpoint compared with no treatment with beta-blockers. The second study hypothesis is that short (1-month) single antiplatelet therapy will be noninferior to 1-year DAPT on the primary endpoint. However, prolonged DAPT will cause an increased risk of bleeding (secondary endpoint) as assessed using the Bleeding Academic Research Consortium (BARC) criteria. Specifically, both BARC ≥ 2 and ≥ 3 will be considered for the safety endpoint. However, BARC ≥ 2 bleeding is a particularly clinically relevant problem for these relatively young patients.

A secondary combined clinical endpoint (composite of death, MI, stroke, coronary revascularization, recurrent dissection, hospital admission for ACS or heart failure admission, and bleeding) will be used to assess the “net clinical benefit” of the antiplatelet strategy. Individual components of the primary endpoint will be assessed as secondary endpoints. Moreover, major secondary combined endpoints will be the composite outcome measure of “hard” clinical events (including death, MI, stroke, recurrent dissection, and coronary revascularization) and also combined death and MI alone. The primary endpoint, all the combined secondary endpoints and the individual events will be also assessed at an extended 2-year clinical follow-up.

The current study design is underpowered for a final combined “hard” endpoint (death, MI), but following the recommendations of the International Scientific Committee, this important outcome measure should be prespecified to allow the possibility of prospective integration of the current study with co-organized international initiatives that may be devised to complement the current trial. Members of the International Scientific Committee are committed to use the study protocol to develop research initiatives to obtain additional grant support in their respective countries (UK-ESC, Canada, USA).

The main objective of the trial is to evaluate the clinical efficacy of the 2 most widely used pharmacological therapeutic strategies in patients with SCAD in clinical practice. Namely, to assess the role of beta-blockers and different antiplatelet regimens (short [1 month] duration of single antiplatelet therapy vs DAPT for 1 year) in these patients. The consistency of the treatment effect will be examined among 10 predefined relevant clinical subgroups (table 2).

A number of secondary objectives will be also addressed using predefined ancillary studies.18–25 These prospective systematic substudies include: a) angiographic and quantitative coronary angiography analyses; b) coronary revascularization (selection of ideal candidates and optimization of the results of different coronary interventions; c) intracoronary imaging (optical coherence tomography and intravascular ultrasound); d) cardiac computed tomography and magnetic resonance imaging; e) assessment of extracoronary vascular abnormalities including fibromuscular dysplasia; f) inflammatory, immunologic, and micro-RNA analyses, and g) genetics and pharmacogenetics.

Randomization will be performed as soon as possible after initial clinical stabilization (within 48hours of diagnosis) so that in-hospital events occurring after randomization, but before discharge, will be captured in the primary endpoint. The literature on in-hospital events is heterogeneous, including 1% mortality, 2% recurrent MI, and 5% to 10% of unplanned revascularization (nonexclusive events).1,2,5–8,13–16 It is estimated that half of the in-hospital events (∼5%) will be counted in the primary endpoint of the study.1,2,5–8 The available data on event rates after discharge and within 1 to 2 years is also highly heterogeneous partly because of inconsistent definitions and the inclusion of different individual endpoints. A study performed at the Mayo Clinic suggested an adverse event rate of 28% at 21 months.6 Overall, the expected event rate during this time period may be summarized as follows: recurrent SCAD 15%, recurrent MI 15%, stroke 1%, revascularization 10%, readmission for ACS 15%, readmission for heart failure 5%.1,2,5–8,13–16 However, we should acknowledge that readmission rates for ACS or heart failure remain unreported in most previous studies. Therefore, a total rate of 10% to 25% (estimated mean 12.5%) of major adverse cardiovascular events are expected at 1 year.

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  Assuming an event rate (combined primary endpoint at 1 year) of 8% in the treatment arm (beta-blocker stratum) and of 15% in the no-treatment arm (relative risk reduction of 47%), 278 patients per arm (278 x 2=556 patients in total) will provide a power of 80% with 95% confidence intervals.

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  This sample size will also allow adequate comparison of the arms of the antiplatelet stratum (assuming a 12% event rate for the primary endpoint in the prolonged DAPT arm with a 3% noninferiority margin in the 1-month single antiplatelet therapy).

According to these assumptions, 600 patients will be required (figure 2 and figure 3). Nevertheless, more accurate final decisions in this regard will be made following an adaptive flexible design according to real event results. The Steering Committee will decide on potential changes in the sample size if there is a lower than anticipated event rate. In this regard, the information accrued in this interim analysis will be used to inform Bayesian statistics and mathematical models and, eventually, to adjust the sample size as required. An independent and blinded Clinical Events Committee will adjudicate all adverse events after reviewing the corresponding anonymized source documents and images.

Figure 2.

Beta-blocker (ß-blockers) stratum randomization. LVEF, left ventricular ejection fraction.

(0.29MB).

Figure 3.

Antiplatelet agent randomization. APT, antiplatelet therapy. DAPT, dual antiplatelet therapy; PCI, percutaneous coronary intervention.

(0.28MB).

Routine care after ACS includes early electrocadiographic and hemodynamic monitoring and serial electrocardiograms and biomarkers to assess the extent of myocardial injury. Left ventricular function will be assessed before discharge. Hospitalization for 3 to 5 days will be recommended as a reasonable strategy to allow observation for adverse ischemic events.1,2 Clinical follow-up evaluations will be scheduled at 1 month, 3 months, 6 months, 1 year, and yearly thereafter.

Systematic screening for extracoronary vascular abnormalities including fibromuscular dysplasia is currently recommended in these patients.1,2 Individual sites should select the preferred screening strategy according to local resources, logistics, and experience. Notwithstanding the importance of these studies, they will not be mandated, given the pragmatic study design.

The study will allow the possibility of enhancing the information obtained on this disease by additional predefined multidisciplinary “ancillary” substudies. Accordingly, as part of a comprehensive and systematic approach to SCAD, the different centers will be invited to participate in several ancillary studies (clinical, revascularization, invasive and noninvasive imaging, biomarkers, novel inflammatory molecules and mRNAs, genetics, quality of life questionnaire), which will be carefully organized to provide a comprehensive and multidisciplinary view of this disease.18–25 However, these studies are not required by the main protocol and will only be performed as selected by the local investigators.

Factorial designs allow efficient evaluation of multiple treatments within a single trial without increasing the sample size and ensuring that the treatments under evaluation work independently.26 In our study, there is an absence of biological plausibility for an interaction between the 2 strata (beta-blockers and antiplatelet agents). However, potential treatment interaction affecting the results of the trial will be evaluated using significance tests and by presenting the size of interaction term as a measure of uncertainty (95% confidence intervals). The study will also present results from a “multi-arm” analysis to allow further comparison between the 2 strata (and margins) independently. The study will be reported following the “modified” CONSORT guidelines for pragmatic trials, from the CONSORT and PRACTIHC (Pragmatic Trials in Healthcare Systems) groups, to better assess the applicability of the results.27 The extended 8 CONSORT checklist items for the reporting of pragmatic trials (background, participants, interventions, outcomes, sample size, blinding, participant flow, and generalizability of the findings) will be followed.27

As no interaction between the treatment strategies is expected, the factorial designed should not be statistically penalized regarding the statistical power.26 The main analysis is based on the time from randomization to the first occurrence of any component of the primary composite endpoint. The main analysis will be performed according to the intention-to-treat principle and will include all adjudicated endpoint events occurring from randomization to the end of the trial. Exploratory sensitivity analyses of the primary endpoint and the co-primary endpoint in the on-treatment and per protocol data set will be also performed.

Predefined hierarchical testing of ranked secondary endpoints will be performed. Cox-proportional hazard models and regression analyses will be used to identify independent predictors of adverse clinical outcomes. Hazard ratios (HR, 95% confidence intervals) will be calculated. Event-free survival will be analyzed using Kaplan-Meier curves and will be compared by the log-rank test. The number needed to treat will be established for the treatment modalities. A 2-tailed P value <.05 will be considered statistically significant.

The unmet clinical need and research priorities in SCAD have been identified by recent expert consensus documents from both sides of the Atlantic.1,2 The recently reported Scientific Statement on SCAD of the American Heart Association highlights the importance of addressing major persistent knowledge gaps on this clinical entity.1 The document states that, as most currently available information comes from retrospective observational studies, there is high risk of gender bias, referral bias, and survivor bias. This suggests that the incidence and recurrence risk of SCAD are likely underestimated. Therefore, major efforts should be made to provide robust evidence-based knowledge on this “orphan” disease. The American Heart Association statement calls for large-scale prospective studies to gain insight on treatment options and prevention of recurrences. Regarding medical therapy, due to the lack of controlled trials to support an evidence-based approach, recommendations “are based largely on expert opinions derived from clinical experience of members of the writing group”. The writing committee specifically identified that a major remaining question is optimal medical therapy, specifically, the value of beta-blockers and antiplatelet therapy. Currently, there are no data from prospective controlled studies supporting the value of beta-blockers or antiplatelet agents in SCAD patients. A strong “call for action” was issued to initiate collaborative research efforts in this regard.1

The European Society of Cardiology recently issued a position paper on SCAD.2 The first sentence on medical management in this document clearly underscores the unmet needs in this challenging condition: “There are to date no randomized clinical trials comparing different pharmacological treatment strategies for SCAD”. Regarding antiplatelet therapy, this document further states “The use of antiplatelet therapies and the duration of treatment remains an area of controversy and divergent practice”. With respect to the use of beta-blockers, the document states the following: “more controversial is the management of SCAD-survivors in patients without significant impairment of left ventricular systolic function”. This European Society of Cardiology position paper identifies major research priorities in SCAD, highlighting that “there is no specific disease-modifying therapy”. In addition, it also declares: “prospective studies (including ultimately randomized studies) assessing the best medical therapies (eg, role and duration of antiplatelet therapy, use of beta-blockers) … are urgently needed”.2

SCAD is typified as “rare disease” according to EURORDIS (ORPHA:458718). Promoting the study of rare diseases, as a public health priority, is of paramount importance considering that—by definition—medical expertise is rare, knowledge scarce, care offerings inadequate, and research very limited. Despite their large overall number, patients with rare diseases are the orphans of health systems, often denied diagnosis, treatment, and the benefits of research. Nationwide prospective initiatives, such as the current project, will help to advance our knowledge on SCAD. The controlled design of the BA-SCAD trial will shed important light on this unique condition and will provide evidence-based knowledge to inform everyday clinical decisions.

In addition, major scientific and academic groups highlight the importance of research initiatives in women, considering the existence of a major gender bias in most areas of medicine. Women are systematically underrepresented in clinical trials. This is more than evident in studies on coronary artery disease, ACS, and MI. Notably, recent information suggests that up to 25% of MI in premenopausal women is caused by SCAD.1,2 Unfortunately, the diagnosis remains frequently overlooked. The current study will further expand our understanding of the pathophysiology of SCAD (a disease disproportionately affecting female patients) and ACS in women.

The rationale of this trial is clear. In brief, beta-blockers have been approved by clinical practice guidelines for the treatment of patients with MI.3,4 These drugs reduce total and cardiovascular mortality after MI.3,4,28,29 Beta-blockers are also frequently used in SCAD patients to reduce coronary shear stress, blood pressure, and myocardial contractility and aim to mitigate coronary injury and further vessel wall disruption.1,2 However, these drugs may predispose patients to coronary spasm and might even be detrimental in patients with SCAD as the result of their effects on the injured vessel wall and the reduced residual coronary lumen. Beta-blockers with alpha-blocker activity are particularly attractive to avoid enhancing the risk of coronary spasm and, therefore, should be considered in these patients. Alternatively, the use of DAPT for 1 year is the guideline-recommended therapy for patients with ACS as a result of atherosclerotic coronary artery disease.3,4 Accordingly, antiplatelet drugs are also frequently prescribed, albeit with a variable duration, in patients with SCAD.1,2 However, in SCAD, intramural bleeding appears to be the initiating pathophysiological event and, therefore, this therapy might be of no value or even deleterious. Whether SCAD patients benefit from the general recommendations for ACS patients (namely prolonged DAPT) or, due to a unique underlying pathophysiology, they are better off with a very limited antiplatelet strategy is currently unknown. Nowadays, both the prescription and nonprescription of beta-blockers and the use of single antiplatelet therapy or DAPT (with variable duration), are valid options in the management of patients with SCAD.1,2 This is an area of intense controversy not only in the scientific community but also in routine clinical practice.1,2

Many practical issues might affect the external validity of the trial results to the general population. The requirement to clinically stabilize the patients before randomization may induce a selection bias by excluding sicker patients with SCAD. Accordingly, a registry will be kept of SCAD patients not randomized in this trial. Some members of the research team are leading experts in the field of beta-blocker therapy in the acute and chronic MI setting and have gained experience in actions to reduce the risk associated with lack of compliance and crossovers in pragmatic open-label trials using beta-blockers. Based on previous experience, we are confident that the type and dose of beta-blocker prescribed in patients randomized to active treatment will not significantly impact the study results.29 During follow-up, we will keep track of the agent and dose being taken by the patient at each follow-up visit. An Achilles heel of open-label randomized clinical trial is the possibility of having a high rate of crossovers. This is especially true when the medications being tested are highly prescribed. Major care will be used to ensure treatment adherence and address the implications of crossovers. Patients will be contacted by telephone immediately after discharge and at 1 month to remind them that if any physician asks for a change in the allocated treatment, it is desirable that they contact the research team for discussion. The low-intervention and pragmatic trial design coupled with a carefully organized clinical follow-up (for adherence and compliance) will be of major value to ensure follow-up completeness.

According to the inclusion and exclusion criteria and data from the Spanish population using the International Classification of Diseases, Ninth Revision (ICD-9) the incidence SCAD in Spain was estimated. Data from the Spanish Ministry of Health (available from the Spanish Society of Cardiology and IMAS Foundation) suggests a stepwise increase in the number of patients diagnosed with SCAD each year in Spain (187 patients in 2005, 288 patients in 2010, 650 patients in 2015). The reasons explaining this increment may include increased awareness of the disease and unrestricted use of early coronary angiography for ACS patients. Considering this trend, it is estimated that ∼900 SCAD cases will be diagnosed yearly during the study period (2021-2023). Accordingly, and considering the pragmatic, all-comers study design, it is assumed that 300 patients will be enrolled trial in the first year (2021-2022) and 300 patients in the second (2022-2023) in the present trial (figure 1). Data from the Spanish SCAD registry5,30 (currently 30 active sites) suggests that 60 centers (each enrolling a mean of 5 SCAD patients/year) will be required to achieve the estimated sample size. All centers participating in the SCAD registry have agreed to participate in the trial (supplementary data). However, the number of centers will be increased and modified as required according to the actual enrollment data.