The Australian–New Zealand SCAD observational cohort study: major adverse cardiovascular events are associated with ticagrelor combined with aspirin, FMD, and history of stroke

This editorial refers to ‘The Australian-New Zealand spontaneous coronary artery dissection cohort study: predictors of major adverse cardiovascular events and recurrence’, by Q.M. Dang et al., https://doi.org/10.1093/eurheartj/ehaf097.

In the last decade, the medical and scientific communities have increasingly recognized non-atherosclerotic spontaneous coronary artery dissection (SCAD) as an important aetiology of myocardial infarction and sudden cardiac arrest. Unlike patients with atherosclerotic acute coronary syndromes (ACS), most patients diagnosed with SCAD are women in the age range of 40–55 years old.^1,2 Moreover, the mechanism of SCAD ACS is different from that of atherosclerotic ACS. Rather than an acute coronary stenosis due to acute plaque rupture and thrombosis as is seen in patients with atherosclerosis, SCAD is hypothesized to occur due to: (i) a disruption of the coronary intima-media with development of a false lumen; (ii) medial haematoma ± an intimal decompressive dissection; or (iii) a combination of both (Graphical Abstract).^3,4 Intracoronary clot is not usually present and is probably not the primary mechanism for stenosis among patients with acute SCAD.⁵

Graphical Abstract.

Acute spontaneous coronary artery dissection.

ACEI, angiotensin-converting enzyme inhibitor; ACS, acute coronary syndrome; ARB, angiotensin receptor blocker; CABG, coronary artery bypass grafting; CTA, computed tomography angiography; CTD, connective tissue disease; DAPT, dual antiplatelet therapy; FMD, fibromuscular dysplasia; GDMT, guideline-directed medical therapy; HF, heart failure; HTN, hypertension; LM, left main; LV, left ventricular; LVEF, left ventricular ejection fraction; MRA, magnetic resonance imaging; PCI, percutaneous coronary intervention; SCAD, spontaneous coronary artery dissection; tx, therapy.

There is dire need to evaluate treatments for acute SCAD that align with the underlying mechanism rather than relying on strategies only shown to be efficacious for atherosclerotic ACS. Although randomized controlled trials are the gold standard for best treatment strategies, the required time and resources for such studies, combined with SCAD being a less common condition and thus there being inherent challenges with subject enrolment, have led to a limitation of current available knowledge. As such, observational studies give valuable insight on best approaches to SCAD management, and there are now numerous active observational SCAD studies and registries around the globe. The current multicentre study by Dang, Zaman, and colleagues, published in this issue of the European Heart Journal, is an observational cohort study reporting predictors of major adverse cardiovascular events (MACE) among 448 women and 57 men across 23 hospitals in Australia and New Zealand with angiographically confirmed SCAD occurring at a mean patient age of 52.2 ± 10.6 years with a median follow-up time of 1.75 years.⁶ The cohort included two groups of patients: those who were identified retrospectively upon chart review and those who were prospectively consented. The authors are to be congratulated on their efforts with this study, which is notable for several reasons, not the least of which is the inclusion of Indigenous participants from both Australia and New Zealand.

MACE were defined in this cohort as the following: death from any cause, myocardial infarction including recurrent SCAD, stroke, heart failure, or coronary revascularization. Recurrent SCAD referred to a de novo SCAD not involving extension of the index SCAD in a patient with new symptoms and cardiac biomarker elevation. At the time of median follow-up (1.75 years), MACE and recurrent SCAD occurred in 8.6% and 3.6% of patients, respectively. MACE were mostly due to non-fatal myocardial infarction. However, a total of nine patients died: five during the index SCAD hospitalization and four in follow-up.

As perhaps the most important finding to arise from this study which has the potential to change clinical practice, the investigators observed that patient discharge on potent blood thinning regimens was statistically associated with adverse outcomes. Patients who were on oral anticoagulation at the time of discharge had a 3.8 times higher likelihood of MACE. Patients who were discharged on dual antiplatelet therapy (DAPT) with the more potent P2Y₁₂ inhibitor ticagrelor with aspirin (but not clopidogrel and aspirin) were 1.8 times more likely to have MACE and 2.6 times more likely to have recurrent SCAD. When the analyses were performed on the subgroup of 451 patients who were managed conservatively without percutaneous coronary intervention, anticoagulation at discharge and DAPT including ticagrelor were associated with adjusted hazard ratios (HRs) for MACE of 3.3 and 2.2, respectively. While these associations could reflect unmeasured confounders such as more extensive or severe dissection (that drove the use of these more potent agents), and only account for discharge medications without consideration for whether patients were still on the therapy at the time of the adverse event, these findings align with the observations that SCAD most commonly arises due to bleeding within the coronary artery wall rather than intraluminal clotting. Prospective randomized studies are needed to support the notion that the standard of care for acute SCAD ACS should be different from that for atherosclerotic ACS. However, until such prospective data are available, it would appear prudent for clinicians to avoid the use of these more potent antiplatelet and anticoagulation regimens after acute SCAD, unless otherwise indicated.

Fibromuscular dysplasia (FMD) and history of stroke were also independently associated with 2.2 and 3.8 times higher risk of MACE, respectively, and 3.9 and 6.2 times higher risk of recurrent SCAD, respectively. The association of FMD and stroke history with adverse outcomes show SCAD and FMD as heterogenous diseases. While this is an evolving field of research, SCAD and FMD are thought in most cases to be polygenic conditions associated with common variants in the genome, and implicated genes for both conditions predominantly include those which affect collagen, the extracellular matrix, coagulation, and blood pressure.^7–9 Identification of rare and common variants within the genome that are associated with more adverse events, or the development of improved polygenic risk scores based upon common variants, will not only help to predict the patients with greatest risk but will also highlight the foremost priorities for future study and intervention.

As a limitation, it is important to note that in this specific study only 36% of patients (n = 182) were screened for FMD, the majority of whom were in the prospective patient group. It is possible that those who were screened may have had other adverse clinical factors that predispose to risk and which prompted the evaluation, such as a positive family history of arterial dissection or aneurysm, prior stroke, headache, hypertension, or tinnitus. The patients who were not assessed, and who therefore may have been at lower risk, were assumed not to have FMD for the statistical analyses. It is quite likely that among the significant number of SCAD patients in this study that were not assessed for FMD (∼64%, n = 323), some have undiagnosed or ‘missed’ FMD. These ‘missed FMD’ patients (who were classified as not having FMD), or other unmeasured confounders, may have skewed the statistical analysis and final findings. Interestingly, coronary tortuosity is independently associated with FMD even within a cohort of SCAD patients.¹⁰ However, the authors did not find coronary tortuosity to be an independent predictor of future risk.

Other factors of interest were not found to be significantly associated with subsequent adverse events. Specifically, beta-blocker therapy has been associated with a diminished risk of recurrent SCAD (HR 0.36) in a Canadian cohort study of 327 patients published in 2017,¹¹ but this finding has not been reproduced by the current cohort or other studies.¹² This may be due to limitations with statistical power, including a high number of patients on beta-blockers and low event rates. However, other unmeasured factors may have affected the prior observations, such as type and dose of beta-blocker, and duration of treatment. Beta-blockade is a mainstay of therapy of early ACS regardless of aetiology due to the reduction of myocardial oxygen consumption and workload. However, whether long-term beta-blockers should be routinely recommended to patients after SCAD including patients with normal left ventricular systolic function, symptomatic hypotension, or medication intolerance is unclear and requires future study. Similarly, slightly over half of the patients were discharged on statin therapy which seemed neither to prevent nor to increase future events. These data suggest that while statins are a critical treatment for patients with atherothrombotic ACS, their role in SCAD is seemingly less important. Certainly, there remains a role for statins in patients with co-existing dyslipidaemia or atherosclerosis, and perhaps the pleiotropic effects of statins are beneficial in SCAD patients, especially if there is concurrent vasospasm or intimal tear. However, current data and lack of diminished risk imply that statins are not as essential for treatment of SCAD ACS as compared with atherosclerotic ACS.

Best practice for acute care of SCAD patients is a work in progress and will evolve as future studies are performed. Key take-aways from the study of Dang et al. suggest that if DAPT is to be used, the preference perhaps should be for less potent P2Y₁₂ inhibition with clopidogrel, and limiting the use of anticoagulation to situations when it is clearly indicated. FMD and history of stroke were also associated with increased risk, giving insight into predicting outcomes. Fortunately, research on SCAD has expanded drastically over the past decade but has generated even more questions. A broader grasp of genetic predisposition, mechanisms, predictors, and treatment strategies among SCAD patients will inform strategies towards reducing and ultimately preventing adverse outcomes, thereby creating a safer and more certain future for SCAD patients and their families.

Declarations

Disclosure of Interest

All authors declare no disclosure of interest for this contribution.

Funding

M.S.T. is supported by the National Institutes of Health NHLBIK23HL155506 award and acknowledges SCAD Research, Inc. support to the Mayo Clinic SCAD Research program. J.C.K. acknowledges research support from the US National Institutes of Health (R01HL148167), New South Wales health grant RG194194, the Bourne Foundation, Snow Medical, SCAD Research Inc. and Agilent.