Objective Approximately 10% of patients with myocardial infarction (MI) have no obstructive coronary artery disease. The prognosis and role of intensified antiplatelet therapy in those patients were evaluated.
Methods We analysed data from the Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events–Seventh Organisation to Assess Strategies in Ischaemic Symptoms trial randomising patients with ACS referred for early intervention to receive either double-dose (600 mg, day 1; 150 mg, days 2–7; then 75 mg/day) or standard-dose (300 mg, day 1; then 75 mg/day) clopidogrel. Outcomes in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) versus those with obstructive coronary artery disease (CAD) and their relation to standard-dose versus double-dose clopidogrel were evaluated. The primary outcome was cardiovascular (CV) death, MI or stroke at 30 days.
Results We included 23 783 patients with MI and 1599 (6.7%) with MINOCA. Patients with MINOCA were younger, presented more frequently with non-ST-segment elevation MI and had fewer comorbidities. All-cause mortality (0.6% vs 2.3%, p=0.005), CV mortality (0.6% vs 2.2%, p=0.006), repeat MI (0.5% vs 2.3%, p=0.001) and major bleeding (0.6% vs 2.4%, p<0.0001) were lower among patients with MINOCA than among those with obstructive CAD. Among patients with MINOCA, 2.1% of patients in the double-dose clopidogrel group and 0.6% in the standard-dose group experienced a primary outcome (HR 3.57, 95% CI 1.31 to 9.76), whereas in those with obstructive CAD, rates were 4.3% and 4.7%, respectively (HR 0.91, 95% CI 0.80 to 1.03; p value for interaction=0.011).
Conclusions Patients with MINOCA are at lower risk of recurrent CV events compared with patients with MI with obstructive CAD. Compared with a standard clopidogrel-based dual antiplatelet therapy (DAPT) regimen, an intensified dosing strategy appears to offer no additional benefit with a signal of possible harm. Further randomised trials evaluating the effects of potent DAPT in patients with MINOCA are warranted.
Trial registration number NCT00335452.
- acute coronary syndromes
- acute myocardial infarction
- coronary artery disease
Data availability statement
Data are available upon reasonable request.
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Globally, coronary artery disease (CAD) and its acute manifestation, myocardial infarction (MI), are the leading causes of morbidity and mortality.1 2 Within the last two decades, the routine use of troponin and the early use of coronary angiography have improved diagnosis and management of patients with MI.2–5
There is growing awareness that more than 10% of all patients fulfilling current criteria for acute MI indeed have no obstructive CAD on coronary angiography.3 5–12 Clinically, the term myocardial infarction with non-obstructive coronary arteries (MINOCA) has been established to describe this heterogeneous entity.9 10 These patients may have either absent or only mild coronary lesions on angiography.7 Due to the widespread use of point-of-care and high-sensitivity troponin assays and angiographic imaging modalities used for the rapid evaluation of chest pain to rule out MI, patients with MINOCA are becoming increasingly common.9
It has been acknowledged that the underlying pathophysiology of MINOCA is diverse.3 5 7–11 Coronary causes may include plaque erosion or rupture, thromboembolism with thrombolysis prior to angiography, spontaneous coronary dissection, coronary microvascular disorders, spasm and perfusion, and oxygen demand and supply mismatch resulting in myocardial necrosis.3 8 In fact, it might be sometimes challenging to differentiate these entities from non-coronary causes responsible for the elevated cardiac enzymes levels, for example, including myopericariditis, takotsubo and other cardiomyopathies, and pulmonary embolism.3 7–9
Despite increasing data on the characteristics and prognosis of patients presenting with MINOCA, studies assessing therapies and thus evidence-based guidelines for the treatment of MINOCA are still limited.5 8 10 11 13 It remains unclear as to whether patients with MINOCA derive similar benefit from dual antiplatelet therapy (DAPT) as compared with patients with MI with obstructive CAD.
In this context, we analysed the impact of a standard-dose versus double-dose clopidogrel regimen on clinical outcomes of those patients with MINOCA enrolled in the large randomised, multinational Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events–Seventh Organisation to Assess Strategies in Ischaemic Symptoms (CURRENT-OASIS 7) trial.14
Study design, patients and patient involvement
This study is a post hoc analysis of CURRENT-OASIS 7, a 2×2-factorial randomised trial of high dose versus standard dose of clopidogrel and high versus low-dose aspirin in patients with acute coronary syndrome (ACS). The methodology and main results have been previously published.14–16 In brief, this trial was conducted between June 2006 and July 2009 at 597 centres in 39 countries. Patients with ACS (with or without ST-segment elevation), confirmed by elevated cardiac enzymes and electrocardiographic evidence of ischaemia, were enrolled. Patients were eligible if they were scheduled for early coronary angiography with an intention for percutaneous coronary intervention (PCI), no later than 72 hours after randomisation. The main exclusion criteria included an increased risk of bleeding or active bleeding.15
Although no patients had been directly involved in the trial design, they were actively involved in the conduct of the study. During any stage, priority of the research question and methods of recruitment were informed by discussions with patients. Once the trial has been published, participants and the public were able to access the primary results of the trial (www.nejm.org).
For the present analysis, we included 23 783 patients with ACS who underwent coronary angiography and had complete information about their troponin T or I levels at the time of enrolment. This represents a subset of the 25 086 patients in the original trial, of whom 237 had incomplete clinical, angiographic or laboratory data; 1055 had no significant CAD and troponin values within normal limits; 3 patients had aortic dissection; and 8 patients withdrew from the trial.
We identified all subjects who matched the MINOCA definition, which has been suggested by Agewall and colleagues (Consort diagram flow of patients, see figure 1).3 This definition had also been adopted by the 2020 ESC Guidelines focusing on non-ST-segment elevation myocardial infarction (NSTEMI).5 The MINOCA definition is summarised in box 1.
Diagnostic criteria of MINOCA3 5*
The diagnosis of MINOCA is made in patients with MI fulfilling the following criteria:
1. Acute MI (modified from the ‘Fourth Universal Definition of Myocardial Infarction’ criteria):
Detection of a rise or fall in cardiac troponin with at least one value above the 99th percentile upper reference limit.
Corroborative clinical evidence of infarction as shown by at least one of the following:
Symptoms of myocardial ischaemia.
New ischaemic electrocardiographic changes.
Development of pathological Q waves.
Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischaemic cause.
Identification of a coronary thrombus by angiography or autopsy.
2. Non-obstructive coronary arteries on angiography:
Defined as the absence of obstructive disease on angiography (ie, no coronary artery stenosis≥50%) in any major epicardial vessel†
This includes patients with
Normal coronary arteries (no angiographic stenosis).
Mild luminal irregularities (angiographic stenosis<30% stenoses).
Moderate coronary atherosclerotic lesions (stenoses>30% but <50%).
3. No specific alternate diagnosis for the clinical presentation:
Alternate diagnoses include, but are not limited to, non-ischaemic causes, such as sepsis, pulmonary embolism and myopericarditis.
* This has been adopted from the European Society of Cardiology working group position paper on MI with non-obstructive coronary arteries by Agewall and colleagues (Eur Heart J 2016) and the Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation (Eur Heart J 2020).
† Additional review of the angiogram may be required to ensure the absence of obstructive disease.
MI, myocardial infarction; MINOCA, myocardial infarction with non-obstructive coronary arteries.
The patients were randomised to different clopidogrel and aspirin dosing regimens.14–16 For the clopidogrel dose allocation, patients, treating physicians and those analysing the events and data were masked to group assignment. The aspirin dose allocation was open label, with blinded adjudication of outcomes.
After randomisation, the patients, who were randomly allocated to double-dose clopidogrel, received a 600 mg loading dose on day 1 followed by 150 mg once per day on days 2–7. Those assigned to standard-dose clopidogrel received a 300 mg loading dose on day 1 followed by 75 mg once per day on days 2–7. On days 8–30, both groups received 75 mg once per day.14–16 Everyone received a loading dose of aspirin (≥300 mg) on day 1. Subsequently, on days 2–30, patients randomly allocated low-dose aspirin received 75–100 mg/day, whereas those allocated to high-dose aspirin received 300–325 mg/day. Administration of vitamin K antagonists concurrently with the study drugs during the first 7 days was discouraged. Other therapies, including anticoagulants, glycoprotein IIb/IIIa antagonists (GPIIb/IIIa), and the used stents if needed, were left to the discretion of the treating physician.
The evaluated endpoints for the present study included as primary outcome the combination of cardiovascular (CV) death, MI or stroke up to 30 days.14–16 Other outcomes included all-cause death, CV death, MI, recurrent ischaemia and stroke from randomisation to day 30.14–16 Safety outcomes included severe and major bleeding events.14–16 The trial’s endpoint definitions have been described earlier.15 A central committee, blinded to the treatment allocation, adjudicated all outcomes.
Clinical end points were assessed in relation to the MI status (MINOCA vs MI with obstructive CAD). The baseline demographics were compared according to MI status. Differences in continuous variables were analysed by t-tests, Mann-Whitney U test and differences in categorical variables by χ2 tests.
All analyses were based on the intention-to-treat principle. Outcome analyses were performed using adjusted Cox proportional hazards models. To select covariates for multivariate adjustment, we identified independent predictors for MINOCA using a logistic regression model with stepwise selection process requiring a p=0.15 to enter and a p=0.1 to stay in the model. The list of identified variables is displayed in the online supplemental table 1.
Kaplan-Meier methods were used to estimate event rates of the main outcomes and its components at follow-up and to plot time-to-event curves; comparisons were made using the log-rank test. For the clinical time-to-event outcomes, the interaction between the treatment and MINOCA was added in the Cox regression model. The statistical interaction was tested using the Wald test. A p value of <0.05 was considered statistically significant. The analyses were performed using SAS V.9.4.
Clinical characteristics and medication use of the 23 783 patients with MI included in this analysis are displayed in table 1. The mean age was 61.5±11.9 years; 73.7% of the patients were men; and 30.0% presented with a STEMI. We identified 1599 patients with MINOCA, which represents a prevalence of 6.7% in this MI cohort (figure 1).
Patients with MINOCA were younger (mean age 57.6 years vs 61.7 years), and a very high percentage (91.2%) had an NSTEMI presentation. They also had a lower prevalence of CV risk factors and comorbidities, and less often had established CV disease and presentation with heart failure. Compared with patients with MI with obstructive CAD, patients with MINOCA had a significantly lower GRACE score (mean 111 vs 123, p<0.0001) but higher left ventricular ejection fraction (mean 56% vs 53%, p<0.0001). Regarding antithrombotic treatment, patients with MI and obstructive CAD more frequently had aspirin and clopidogrel prior to randomisation, and they were also more often treated with unfractionated heparin and GPIIb/IIIa inhibitors. Patients with MINOCA were also less likely to be discharged on beta blockers, calcium-channel blockers, ACE inhibitors, lipid-lowering agents and antidiabetic drugs. Of note, 40 (2.5%) of all patients with MINOCA were treated with PCI and stent implantation (online supplemental table 2).
Predictors for MINOCA
By multivariable analysis, independent predictors of MINOCA included younger age, female sex, NSTEMI presentation, heart failure, absence of diabetes, non-smoking status and absence of established CV disease, including history of MI, prior PCI, peripheral arterial disease and stroke. Also, lower white blood cell count and blood pressure and administration of antithrombotics prior to randomisation (eg, aspirin, clopidogrel or glycoprotein IIb/IIIa inhibitors) were predictors of MINOCA. The independent predictors of MINOCA are listed in online supplemental table 1. Moreover, predictors for the primary outcome (including cardiovascular death, myocardial infarction, or stroke up to 30 days) in MINOCA patients are displayed in online supplemental table 3.
Outcomes according to MI status
During follow-up, rates of the primary endpoint (including CV death, MI or stroke), all-cause mortality, CV mortality and repeat MI were significantly higher among patients with MI with obstructive CAD (figures 2 and 3A–E). Only four (0.3%) and eight (0.5%) patients with MINOCA required a repeat admission for recurrent ischaemia or MI, respectively. Compared with patients with MINOCA, patients with MI with obstructive CAD had a more than threefold higher risk of severe or major bleeding (HR 3.48, 95% CI 1.70 to 7.10, p=0.0006, and HR 3.73, 95% CI 1.97 to 7.05, p=0.0001, respectively). Overall, there were no differences in the rates of recurrent ischaemia and strokes between the two groups.
Clopidogrel dose comparison
The demographics of patients with MINOCA versus MI with obstructive CAD grouped according to the assigned clopidogrel-dosing regimens are displayed in online supplemental table 4. In the trial, the primary outcome occurred in 4.2% of patients assigned to double-dose clopidogrel as compared with 4.4% assigned to standard-dose clopidogrel (HR 0.94, 95% CI 0.83 to 1.06; p=0.30). In patients undergoing PCI, compared with the standard-dose, double-dose clopidogrel reduced the rate of the primary outcome (330 events (3.9%) vs 392 events (4.5%); adjusted HR 0.86, 95% CI 0.74 to 0.99; p=0.039).
For the overall comparison, there was a significant interaction in the comparison of double-dose versus standard-dose clopidogrel in patients with MINOCA versus those with MI and obstructive CAD (p value for interaction=0.011). In patients with MINOCA, 2.1% in the double-dose group vs 0.8% in the standard-dose group experienced a primary outcome (HR 3.57, 95% CI 1.31% to 9.76%; p=0.013) (table 2 and figure 4A). In patients with MI with obstructive CAD, 4.3% in the double-dose group and 4.7% in the standard-dose group experienced a primary outcome (HR 0.91, 95% CI 0.80% to 1.03%; p=0.126) (table 2). Regarding the safety endpoint of major bleeding, there was no difference between the double-dose and standard-dose clopidogrel regimens among patients with MINOCA (0.6% vs 0.7%, HR 0.99, 95% CI 0.27% to 3.59%; p=0.987) (figure 4B). In patients with MI with obstructive CAD, there was a significantly increased bleeding risk (2.7% vs 2.1%, HR 1.26, 95% CI 1.06% to 1.49%; p=0.010) (table 2 and figure 4B). The same applied for minor bleedings (table 2).
We performed a post hoc analysis evaluating outcomes of different clopidogrel-dosing strategies among patients with MINOCA versus MI with obstructive CAD in a large and well-characterised, multinational ACS population stemming from the CURRENT-OASIS 7 trial. Compared with patients with obstructive CAD, patients with MINOCA had a much lower risk of recurrent CV events, including CV death, MI, stroke and bleeding 1 month after initial presentation. In the randomised comparison of double-dose versus standard-dose clopidogrel regimens in these patients, we found no evidence of benefit of the double-dose regimen on CV outcomes. Importantly, administration of a higher-dose of clopidogrel was associated with a possible excess in CV death, MI or stroke in patients with MINOCA. To the best of our knowledge, this study represents the first to assess the potential impact of a more intensified antiplatelet regimen on outcomes in subjects with MINOCA.
As highlighted by our and earlier analyses, MINOCA is prevalent in 6%–15% of all patients presenting with a suspected MI, and it is more commonly encountered in patients who are younger, those who are more likely to be female, and in those who present initially with NSTEMI.6 8 12 13 17 18
The prognosis of MINOCA is generally considered benign given the absence of flow-limiting obstructive CAD. However, recent data suggest that the prognosis may be more guarded, with some studies reporting an all-cause mortality rate of 1%–3% at 30 days and 3%–6% at 12 months.8 19–21 In our study, the rates for adverse events, including recurrent ischaemia, MI, CV or all-cause death were much lower (between 0.3%–0.6%) than have been previously reported. This might be attributable to the fact that patients enrolled in randomised controlled trials are generally at lower risk than in clinical practice. In line with this, our patients were also younger than those in many other MINOCA studies.
Despite MINOCA’s relatively high prevalence, there are still limited data and consensus about diagnostic strategies, algorithms for risk stratification and therapeutic interventions in these patients. This might also reflect the fact that patients with MINOCA are less likely to be treated with guideline‐recommended therapies than those with obstructive CAD, including beta blockers, statins, ACE inhibitors/angiotensin receptor blockers and DAPT.18 21 22 A recent observational study using a propensity analysis approach implicated that statins, ACE inhibitors/angiotensin receptor blockers and beta blockers may reduce the risk for major adverse cardiac events at 12 months in patients with MINOCA.13 However, the same study also found no benefit with DAPT.13
DAPT mitigates the risk of repeat CV events after acute MI and is recommended for up to a year in current guidelines.4 5 MINOCA comprises a broad range of pathological entities as highlighted in the introduction section, and the mechanisms leading to MINOCA often share similarities with MI and obstructive CAD (ie, atherothrombosis due to plaque rupture or erosion).12 Whether unselected patients with MINOCA thus derive any clinical benefit from a more intense antiplatelet regimen has not been adequately assessed. Patients with MINOCA might be expected to exhibit a lower bleeding risk due to their younger age and fewer comorbidities, but as our results suggest, a more intensive clopidogrel dosing regimen could be harmful and could result in higher risk of CV death, MI or stroke. In this context, we found a numerical increase in strokes and CV deaths among patients with MINOCA treated with higher-dose clopidogrel regimen.
The exact mechanism for increased rate in events with the more intensive antiplatelet therapy remains uncertain, especially since we excluded patients with overt myocarditis and takotsubo cardiomyopathy. Patients with MINOCA may have other, perhaps unrecognised non-cardiac reasons accounting for their presentation hospitalisation, including infection (sepsis, pneumonia etc.), pulmonary embolism, anaemia and both tachy- and brady-arrhythmias, and therefore may be subject to an increased risk by an intensified antiplatelet regimen. The signal of increased CV events with more intensive DAPT that we observed in this trial highlights the importance of further prospective studies evaluating antiplatelet therapy in this group. At present, our data suggest that more potent antiplatelet regimens should probably not be routinely used in patients with MINOCA.
Clinicians should rather personalise the antiplatelet management based on the underlying pathology. For example, patients with MINOCA with underlying plaque erosion or rupture might benefit from more aggressive antithrombotic management.23 Indeed, in our study, patients with MINOCA did receive more aggressive antiplatelet therapy than patients who did not have MINOCA. On the other hand, in some scenarios with an apparent non-coronary cause of myocardial injury, such as atrial fibrillation or other tachyarrhythmia, hypertensive crisis, sepsis, heart failure with preserved ejection fraction, myopericarditis and stress cardiomyopathies, aggressive DAPT regimens should be avoided, and the use of standard regimens should be prospectively evaluated.
There are several limitations of the present study. First, this was a post hoc analysis of a randomised ACS trial and the number of events was limited in the MINOCA cohort and, despite robust multivariable modelling, should be regarded as hypothesis-generating. Second, high-sensitivity troponin assays were not broadly used, and this may have underestimated the number of patients with MINOCA. Third, degree of CAD reported by centres was not confirmed in an angiographic core laboratory. Fourth, the exact aetiology of MINOCA was not available among all analysed patients, and a small number might have been mislabelled. Fourth, whether these results apply to other more potent P2Y12 inhibitors, such as ticagrelor or prasugrel, remains unclear. Finally, the follow-up period was 30 days, which is relatively short. However, the highest risk of recurrent CV events after MI occurs within the first 30 days.
Patients with MINOCA are at lower risk of recurrent CV events compared with patients with MI with obstructive CAD. Compared with a standard clopidogrel-based DAPT regimen, an intensified dosing strategy appears to offer no additional benefit and may even be harmful. There is a need for prospective studies evaluating optimal antiplatelet therapy regimens in patients with MINOCA. In the meantime, antiplatelet therapy in these patients should be individualised based on underlying aetiology.
What is already known on this subject?
Approximately 10% of all patients, presenting with acute myocardial infarction (MI), show no significant obstructive coronary artery disease on angiography, an entity referred to as myocardial infarction with non-obstructive coronary arteries (MINOCA). Its underlying pathophysiology may be diverse. Data about outcomes and management remain scarce.
What might this study add?
This study shows that MINOCA is more common in younger and female patients and has a high non-ST-segment elevation myocardial infarction prevalence, and it appears associated with a low risk for adverse events (eg, MI, stroke or death). In the evaluated cohort, there was a signal indicating possible harm by more intensive antiplatelet regimens with clopidogrel in patients with MINOCA. This signal of potential harm needs to be interpreted cautiously but certainly mandates further investigation.
How might this impact on clinical practice?
This study highlights that there is an urgent need for more dedicated clinical trials assessing the optimal antiplatelet regimen in MINOCA. Based on current data, clinicians should be cautious and rather personalise the antiplatelet management based on the underlying pathology in patients with MINOCA.
Data availability statement
Data are available upon reasonable request.
Patient consent for publication
The trial complied with the Declaration of Helsinki. It was approved by national regulatory authorities and the ethics committees at the participating centres. All patients provided written informed consent (ClinicalTrials.gov).
Presented at An abstract of this study was presented at the European Society of Cardiology Congress 2019 in Paris (https://academic.oup.com/eurheartj/article-abstract/40/Supplement_1/ehz748.0145/5596076?redirectedFrom=fulltext).
Contributors MB: conceptualisation, methodology, validation, formal analysis, writing (original draft), visualisation; PG: conceptualisation, methodology, software, validation, formal analysis, data curation, writing (review and editing); WB: investigation, data curation, writing (review and editing); GS: investigation, data curation, writing (review and editing); J-FT: investigation, writing (review and editing); CJ: investigation, writing (review and editing); CBG and DF: investigation, data curation, writing (review and editing); AK, AB, PP, GDP, VV, MF and TM: investigation, writing (review and editing); SY: investigation, methodology, resources, data curation, writing (review and editing), project administration, funding acquisition; SRM: conceptualisation, methodology, validation, investigation, resources, data curation, writing (original draft), supervision, project administration, funding acquisition. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
Funding The CURRENT-OASIS 7 trial was sponsored by Sanofi and Bristol-Myers Squibb.
Competing interests MB received research grants from the University of Basel, the Freie Akademische Gesellschaft Basel and Bangerter-Rhyner Stiftung, consulting and speaking fees from Astra-Zeneca, Bayer and Amgen. PG received research grants from Amarin, Bayer, Merck, Sanofi, and Servier and speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer-Ingelheim, Bristol-Myers-Squibb, Idorsia, Lilly, Merck, Novartis, Novo-Nordisk, Pfizer, Regeneron, Sanofi and Servier. CBG reports grants from Duke University, grants and personal fees from Sanofi Aventis, grants and personal fees from Bristol Myers Squibb during the conduct of the study. AB received investigator’s, consulting and speaking fees from Sanofi-Aventis, Bristol-Myers Squibb and AstraZeneca.
Provenance and peer review Not commissioned; externally peer reviewed.
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