Antiplatelet therapy in conservatively managed spontaneous coronary artery dissection: is less better?

This commentary deals with the recent paper by Cerrato and colleagues titled ‘Antiplatelet therapy in patients with conservatively managed spontaneous coronary artery dissection from the multicentre DISCO registry’, recently published in the European Heart Journal.

SUMMARY OF THE ARTICLE

Spontaneous coronary artery dissection (SCAD) is a rare but increasingly recognised cause of acute coronary syndromes (ACS), including type 2 myocardial infarction (MI).¹ In contrast to most other ACS events, it occurs proportionally more in women, particularly those who are pre-menopausal. There are few data on which to base treatment recommendations and practice varies considerably, both when choosing conservative or invasive management and the strength and duration of antiplatelet therapy (APT).² Cerrato and colleagues have recently reported data from the multicentre DIssezioni Spontanee COronariche (DISCO) registry relating to use of antiplatelet therapy (APT) and outcomes.³ Including 199 patients with SCAD who were conservatively managed with either single (SAPT: either aspirin or a P2Y₁₂ inhibitor) or dual APT (DAPT: aspirin plus a P2Y₁₂ inhibitor), they performed an analysis with a primary endpoint of major adverse cardiovascular event rate (MACE, defined as all-cause death, non-fatal MI or unplanned percutaneous coronary intervention [PCI]) at 12 months, stratified by intensity of APT treatment. 132 patients received DAPT whilst 67 received SAPT, almost all with aspirin alone. There did not appear to be significant differences in clinical or angiographic characteristics between the groups, other than greater use of statin in the DAPT group. At 12 months, the incidence of MACE was significantly greater in those that had received DAPT compared to SAPT (18.9% vs. 6.0%, adjusted hazard ratio 2.62, 95% confidence interval 1.22 to 5.61, p=0.013), driven by higher numbers of non-fatal MI (15.2% vs. 3.0%, p=0.009) and unplanned PCI (12.1% vs. 1.5%, p=0.0010). Bleeding events were small in number but their frequency did not appear different between the groups. Multivariate Cox regression analysis identified type 2a SCAD and APT intensity as significant independent predictors of 12-month MACE.

JUNIOR MEMBER DISCUSSION

Dr William Parker MA MB PhD MRCP, University of Sheffield, UK; Vice Co-ordinator, Young Thrombosis Researchers’ Group, ESC WG on Thrombosis

Spontaneous coronary artery dissection presents a real challenge for clinicians trying to manage it. Common enough to be encountered on a reasonably regular basis in a typical cardiology centre, yet rare enough to make adequately powered trials difficult to perform, coming up with robust treatment recommendations is challenging. DAPT has been the cornerstone of ACS management for around 20 years,⁴ yet in the subset of patients with SCAD who do not have another indication such as PCI, it has remained uncertain as to whether it offers benefits over SAPT and practice has largely been based on physician preference.²

Now, intriguing data from the DISCO registry, the largest European case series of SCAD patients to date, has suggested that use of DAPT may be associated with a significantly greater incidence of cardiovascular events at 12 months when compared to SAPT.³ Importantly for an observational analysis, the relationship appeared to survive adjustment for multiple variables.

Clearly, as the authors accept, there are limitations of a retrospective analysis and the numbers of patients and events were, in statistical terms, small, with unbalanced numbers in the groups, so the findings can only be regarded as hypothesis-generating. Nevertheless, the data are provocative, and in the absence of higher quality evidence raise questions around the approach to APT in SCAD patients who do not undergo PCI.

Why might DAPT cause more ischaemic events than SAPT in SCAD? The signal appeared driven by non-fatal MI and unplanned PCI. Furthermore, most events in the DAPT group occurred in hospital compared to none in the SAPT group. This potentially suggests a harmful effect of DAPT in the very early phase of conservatively managed SCAD. In contrast to plaque-related ACS events, intramural haemorrhage with resulting haematoma, which may be flow-limiting, can be a prominent feature.¹ It is therefore plausible that greater inhibition of intramural haemostasis by DAPT compared to SAPT is an important factor in determining outcome in SCAD, particularly during its early stages. This needs to be balanced against the fact that SCAD may result i exposure of blood constituents to prothrombotic submatrix and abnormal shear stress forces, which has been the rationale for use of APT.

These data certainly suggest that in conservatively managed SCAD, the choice of APT intensity may influence outcomes in ways not previously recognised. Above all, the need for prospective study of APT intensity in conservatively managed SCAD is clearer than ever.

SENIOR MEMBER DISCUSSION

Prof Dr. Tobias Geisler, MD, MHBA, University Hospital Tübingen, Germany, Secretary ESC WG on Thrombosis

SCAD is a rare but threatening event. The etiology and the consequences are heterogenous, thus representing a challenging scenario for the interventionalist. Should I use a stent at all to seal the dissection or should I treat SCAD conservatively? How should I estimate thrombotic risk in future?

Given the lack of systematic trials which are difficult to plan in this rare scenario, the authors should be commended for providing information from a retrospective analysis in 199 patients enrolled in the multicenter DISCO registry³. The variable strategy is also reflected by the screened population: of 314 patients with SCAD, 63% were treated conservatively (without PCI) and the present paper is focusing on this subgroup of patients.

First of all, the analysis gives important information about the characteristics of the SCAD population. SCAD patients, who are treated conservatively, are mainly younger patients (mean age 52 years) and in a vast majority female (in almost 90%) with only few if any comorbidities. The primary analysis stratifies according to the intensity of antiplatelet therapy (single (SAPT) versus dual antiplatelet therapy (DAPT)). Although the authors show that apparently both groups are balanced with regard to their baseline risk factors and angiographic and lesion characteristics, there is a still a potential bias by treatment decision. For instance, patients in the DAPT group were significantly more often treated with statins than in the SAPT group (82% versus 51%, p<0.001), indicating that the former group might have shown a more extensive vascular disease or risk factor profile (e.g. more elevated cholesterol levels). This might partly explain the higher MACE rate in the DAPT group, which was mainly driven by an increased rate of non-fatal MI. The argument that more intensified APT could promote intramural bleeding causing propagation of the dissection and subsequent events is speculative without evidence from intravascular imaging studies and needs to be counterbalanced by beneficial antithrombotic effects in case of intra-luminal thrombi in SCAD. Of note, there were no adverse safety signals, as bleeding events, in particular major bleeding, were not significantly different between DAPT versus SAPT-treated patients. This finding is plausible but also assuring given the relatively low bleeding risk profile of this population.

The diagnosis of SCAD is often challenging and requires measures to increase the pre-test probability to exclude “SCAD mimickers”⁵. In this context, information on biomarkers of myocardial injury would have been informative, as in SCAD, especially serial monitoring of high-sensitivity troponin⁶, is almost invariably elevated, except in cases in which presentation is very early or has been delayed⁵. Most patients (~55%) in the DISCO analysis were NSTE-ACS patients, which even could have been (biomarker negative) unstable angina patients. In addition, only 10% received any type of intravascular imaging and 3.5% CCTA to confirm SCAD in the present study, making the inclusion of ambiguous cases (e.g. Takotsubo disease, microvascular disease) with different prevalence between the APT groups possible.

Ninety-three percentage of patients in the SAPT arm received aspirin and 99% either aspirin + clopidogrel (63%) or aspirin + ticagrelor (36%). Thus, mainly an aspirin monotherapy was compared to a clopidogrel/ticagrelor based DAPT. The present analysis cannot give answers about the risk/benefit ratio of a P2Y12 inhibitors therapy versus DAPT after SCAD, which might be a considerable option.

The retrospective design of the study raises concerns about the causality of DAPT on the primary efficacy endpoint of this analysis. In another series of 134 SCAD patients treated with both DAPT and single antiplatelet agents long term outcomes did not differ significantly between groups making the estimation of the clear association event more difficult⁷. Thus, to my point of view, the findings are interesting but a definite conclusion to guide antithrombotic therapy after SCAD cannot be drawn. A randomized trial would be needed to exclude confounding bias and prove these hypothesis-generating results. Until then, the antithrombotic strategy after SCAD remains an individual decision based on the clinical situation, angiographic and imaging findings and the risk factor profile of the patient.