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angiotensin receptor blocker treatment in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA-BAT): Rationale and design
Trial Designs
Randomized evaluation of beta blocker and ACE-inhibitor/angiotensin receptor blocker treatment in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA-BAT): Rationale and design Anna M Nordenskjöld, MD, PhD, a Stefan Agewall, MD, PhD, b Dan Atar, MD, PhD, b Tomasz Baron, MD, PhD, c John Beltrame, BMBS, PhD, d Olle Bergström, MD, e David Erlinge, MD, PhD, f Chris P Gale, PhD, FRCP, g Javier López-Pais, MD, h Tomas Jernberg, MD, PhD, i Pelle Johansson, j Annica Ravn-Fisher, MD, PhD, k Harmony R. Reynolds, MD, l Jithendra B. Somaratne, MBChB, FRACP, PhD, m Per Tornvall, MD, PhD, n and Bertil Lindahl, MD, PhD c Örebro, Uppsala, Lund, Stockholm, Sweden Adelaide, Australia Leeds, UK and NYU Grossman School of Medicine, New York
Background Myocardial infarction with non-obstructive coronary arteries (MINOCA) is common and occurs in 6–8% of all patients fulfilling the diagnostic criteria for acute myocardial infarction (AMI). This paper describes the rationale behind the trial ‘Randomized Evaluation of Beta Blocker and ACE-Inhibitor/Angiotensin Receptor Blocker Treatment (ACEI/ARB) of MINOCA patients’ (MINOCA-BAT) and the need to improve the secondary preventive treatment of MINOCA patients. Methods MINOCA-BAT is a registry-based, randomized, parallel, open-label, multicenter trial with 2:2 factorial design. The primary aim is to determine whether oral beta blockade compared with no oral beta blockade, and ACEI/ARB compared with no ACEI/ARB, reduce the composite endpoint of death of any cause, readmission because of AMI, ischemic stroke or heart failure in patients discharged after MINOCA without clinical signs of heart failure and with left ventricular ejection fraction ≥40%. A total of 3500 patients will be randomized into four groups; e.g. ACEI/ARB and beta blocker, beta blocker only, ACEI/ARB only and neither ACEI/ARB nor beta blocker, and followed for a mean of 4 years. Summary While patients with MINOCA have an increased risk of serious cardiovascular events and death, whether conventional secondary preventive therapies are beneficial has not been assessed in randomized trials. There is a limited basis for guideline recommendations in MINOCA. Furthermore, studies of routine clinical practice suggest that use of secondary prevention therapies in MINOCA varies considerably. Thus results from this trial may influence future treatment strategies and guidelines specific to MINOCA patients. (Am Heart J 2021;231:xxx.)
Background and rationale Myocardial infarction with non-obstructive coronary arteries (MINOCA) is common and affect 6% to 8% of all
patients with acute myocardial infarction (AMI). 1-3 The affliction has been recognized since the early 1980s, 4-6 but not until recently have diagnostic criteria been proposed
From the aDepartment of Cardiology, Faculty of Medicine and Health, Örebro University,
of Medicine, NYU Grossman School of Medicine, New York, mGreen Lane Cardiovascular
Örebro, Sweden, bDepartment of Cardiology, Oslo University Hospital, Norway, and Institute of Clinical Sciences, University of Oslo, Norway, cDepartment of Medical Sciences, Cardiology, and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden, dDiscipline of Medicine, University of Adelaide, Basil Hetzel Institute, Central Adelaide Local Health Network, Adelaide, Australia, eDepartment of Medicine/ Cardiology, County Hospital of Kronoberg, Sweden, fDepartment of Cardiology, Clinical Sciences, Lund University, Lund, Sweden, gLeeds Institute of Cardiovascular and Metabolic
Service, Auckland City Hospital, New Zealand, and nDepartment of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Stockholm, Sweden. Declarations of interest: none. Trial registrationEudraCT number: 2018-000889-11. ClinicalTrials.gov identifier: NCT03686696. Submitted May 19, 2020; accepted October 14, 2020. Reprint requests: Anna M Nordenskjöld, Department of Cardiology, Faculty of Medicine
Medicine, University of Leeds, Leeds, UK, hDepartment of Cardiology, University Hospital Complex of Santiago de Compostela, Spain, iDepartment of clinical sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden, jSenior research manager, The Swedish Heart and Lung Association, Sweden, kDepartment of Cardiology, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden, lSarah Ross Soter Center for Women's Cardiovascular Research, Leon H. Charney Division of Cardiology, Department
and Health, Örebro University, Södra Grev Rosengatan, 701 85 Örebro, Sweden. E-mail: [email protected] 0002-8703 © 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). https://doi.org/10.1016/j.ahj.2020.10.059
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and structured investigations recommended. 7 The notion of MINOCA as a working diagnosis is highlighted in several recent international guidelines and statements. 8-10 Besides the atherosclerotic status of the coronary arteries there are several fundamental differences between patients with MINOCA and patients with AMI and obstructive coronary artery disease (MI-CAD). MINOCA patients are more often female, younger on average and tend to have fewer comorbidities. 1 , 2 , 11 Regardless, for MINOCA patients, short- and long-term prognosis is only slightly more favorable as compared to MI-CAD patients and far worse as compared to the general population. 2 , 12-15 The six-month mortality after MINOCA was 2.4% among MINOCA patients in the Swedish Web based registry for Enhancement and Development of Evidence-based care in Heart disease (SWEDEHEART) 11 and the 1-year mortality was 3.5% in a systematic review of 28 publications. 2 In addition, almost 25% of the MINOCA patients registered in the SWEDEHEART registry suffered a major adverse cardiac event (MACE) within 4 years, defined as death, recurrent MI, heart failure hospitalization or stroke. 1 This high rate of long-term serious cardiovascular events is particular worrisome when considering the younger age and more favorable clinical profile of MINOCA patients compared to patients with MI-CAD. In a recent propensity score-matched analysis of 9138 patients with MINOCA enrolled in the SWEDEHEART registry we evaluated the relationship between treatment with statins, ACE-inhibitor/angiotensin receptor blocker (ACEI/ARB) treatment, beta-blockers, dual antiplatelet therapy and the composite of all-cause mortality or hospitalization for reinfarction, heart failure, or stroke. After a mean follow-up of 4.1 years, there was a significantly lower event rate associated with the use of statins (hazard ratio, 0.77 [95% CI, 0.68-0.87]), ACEI/ARBs (hazard ratio, 0.82 [95% CI, 0.73-0.93]) and a trend for a lower event rate with the use of beta-blockers (hazard ratio, 0.86 [95% CI, 0.74-1.01]). The use of dual antiplatelet agents was neither associated with a lower event rate nor with increased bleeding events at 1 year. 1 Structured follow-up and reaching target levels for secondary preventive goals have also been demonstrated to positively affect the prognosis of patients with MINOCA. 16 However, the treatment of MINOCA patients may differ greatly depending on the opinion of the individual professionals and the healthcare facilities. 1 , 11 For example, in the Chest Pain-Myocardial Infarction registry including nearly 6000 patients with MINOCA at over 150 high-volume hospitals, ACEI/ARB treatment was prescribed at discharge in 16–89% of patients and beta blockers to 28–98%. This marked variability in prescribing patterns indicates there is equipoise in the community about the need for these agents after a MINOCA event. 17 Here, we describe the rationale behind the trial Randomized Evaluation of Beta Blocker and ACEInhibitor/Angiotensin Receptor Blocker Treatment
(ACEI/ARB) in MINOCA patients (MINOCA-BAT) and the impending need to improve the secondary preventive treatment of MINOCA patients.
Methods MINOCA-BAT is a multicenter, prospective, randomized, controlled and open-label registry-based trial with 2:2 factorial design. All outcomes will be analyzed using the intention-to-treat principle. The study is supported by funds independently obtained by groups in each participating country. The Swedish Research Council, Sweden's largest governmental research funding body, have contributed with funding for the Swedish part of the study as well as for design and maintenance of the database and the international randomization module. Grant number: 2017–00478. The Australian part of the study have received funding from the Hospital Research Foundation, a non-for-profit organization, which provides research grants to South Australian public hospitals. The grant awarded was entitled ‘The Basil Hetzel Translational Grant 2017’. The primary aim is to determine whether beta blockade compared to no beta blockade, and whether ACEI/ARB compared to no ACEI/ARB, reduce the composite endpoint of death from any cause or readmission due to AMI, ischemic stroke or heart failure, in patients discharged following a clinical presentation with MINOCA but without clinical signs of heart failure and a left ventricular ejection fraction (LVEF) ≥40%. The secondary aims are to determine if any of the treatments reduce the individual components of the composite endpoint, cardiovascular mortality, readmission because of unstable angina pectoris or atrial fibrillation. A finding of a LVEF ≥40% is recognized as preserved systolic function. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents.
Definition of MINOCA MINOCA is in the study defined according to the ESC working group position paper on myocardial infarction with non-obstructive coronary arteries 7 with some modifications (Table I). The criteria for AMI are adjusted to follow the recommendations of the 4th Universal Definition of Myocardial Infarction, including the criteria for ECGchanges and significant rise and/or fall of troponin. 10 Furthermore, the position paper from the Working Group on MINOCA included the takotsubo syndrome in the definition of MINOCA, 7 whereas later scientific statements from the American Heart Association (AHA) considers the takotsubo syndrome as a separate entity, 9 consistent with the new 4th Universal Definition of Myocardial Infarction. 10 Transient regional wall motion abnormalities (hypokinesia, akinesia, or dyskinesia) in the
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Table I. Diagnostic criteria for MINOCA. All three criteria should be fulfilled. Adapted from reference. 7,
9, 10
Diagnostic criteria for MINOCA 1. AMI according to the universal definition (a) Positive cardiac troponin, defined as a rise and/or fall in serial levels, with at least one value above the 99th percentile upper reference limit. and (b) Corroborative clinical evidence of infarction evidenced by at least one of the following: (i) Symptoms of ischemia (ii) New ischemic ECG changes (iii) Development of pathological Q waves (iv) Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality 2. Non-obstructive coronary arteries on angiography Defined as the absence of obstructive CAD on angiography in any major epicardial artery. This include both patients with:
3
(i) normal coronary arteries (no stenosis >30%) (ii) mild coronary disease (stenosis >30% but <50%)*. No clinically overt specific cause for the acute presentation other than AMI At the time of angiography, the cause and thus a specific diagnosis for the clinical presentation is not apparent (e.g. clinically strong suspicion of myocarditis, takotsubo syndrome † or pulmonary embolism)
* In borderline cases where it is difficult to determine visually whether a stenosis is below the 50% cut-off, a fractional flow reserve (FFR) or instantaneous wave-fre ratio (iFR) may be performed. An FFR >0.80 or iFR >0.90 beyond the stenosis is considered to be hemodynamically insignificant and it is possible to include patients with these findings. † Patients showing (transient) regional wall motion abnormalities (hypokinesia, akinesia, or dyskinesia) in the left ventricle extending beyond a single epicardial vascular distribution at the initial left ventriculogram or echocardiographic examination are considered to have a strong suspicion of takotsubo syndrome and should not be included in the MINOCA-BAT trial. If these findings are not present the suspicion of takotsubo syndrome is not considered strong and the patient can be included in the trial.
left ventricle extending beyond a single epicardial vascular distribution in the initial left ventriculogram or echocardiograpy indicate takotsubo syndrome and such patients should not be included in the MINOCA-BAT trial. In the absence of such findings, takotsubo syndrome is an unlikely diagnosis and the patient can be included in the trial if the other clinical eligibility criteria are met. Myocarditis is also not included in the definition of MINOCA. Therefore, patients with cardiac magnetic resonance imaging (CMR) proven myocarditis or with a strong clinical suspicion of myocarditis as cause of the index event will not be included in the MINOCA-BAT trial. For example, patients with ongoing covid-19 infection should not be included in MINOCA-BAT since troponin elevation in these patients are usually unrelated to myocardial ischemia and are most often a sign of minor myocardial injury due to myocardial viral infection and/or myocarditis. If a later CMR finds a takotsubo or a myocarditis patient included in MINOCA-BAT, the patient will remain included in the trial.
Hypothesis and primary, secondary, and safety end points The study hypothesis is that long-term treatment with ACEI/ARBs and/or beta blockers will reduce the risk of allcause death and hospitalization for myocardial infarction, stroke and/or heart failure in patients diagnosed with MINOCA and with preserved ejection fraction. The primary end point is time to either death due to any cause, readmission for AMI, ischemic stroke or heart failure in patients with MINOCA randomized to one of the four different secondary preventive regimes.
Secondary end points are as follows: time to all-cause death, cardiovascular death, readmission for AMI, ischemic stroke, heart failure, unstable angina pectoris and atrial fibrillation. Safety end points include: time to readmission because for second or third degree AV-block, ventricular tachycardia, ventricular fibrillation, hypotension, acute kidney injury, syncope or need for pacemaker. In sub studies, the underlying mechanisms for MINOCA will be investigated with CMR, positron emission tomography, computed tomography and biochemical markers. In additional sub studies, healthrelated quality-of-life, anxiety, depression, psychiatric comorbidities and the prevalence of angina pectoris will be addressed.
Inclusion/exclusion criteria Inclusion and exclusion criteria are presented in Table II. Study protocol, randomization, participating countries, and ethics Eligible patients will be identified at the cardiology departments, including the coronary angiography labs and the wards. If a patient with MINOCA needs additional testing to confirm eligibility and is discharged, he/she may be screened at an outpatient follow-up visit within 30 days from admission. Performing CRM before randomization to exclude clinically undetected myocarditis is encouraged, but not mandatory. Patients fulfilling the inclusion criteria and without any exclusion criterion will, after signing the informed consent form, be randomized on day 1 to 30 after index MINOCA.
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Table II. Inclusion and exclusion criteria. Inclusion criteria Age ≥18 years A clinical diagnosis of MINOCA* within the last 30 days LVEF ≥40% measured with echocardiography, CMR† or left ventriculogram during hospitalization and prior to randomization Written informed consent obtained Exclusion criteria Any condition that may influence the patient's ability to comply with study protocol. Previous revascularization (CABG ǂ or PCI§) Clinical signs of heart failure CMR-proven myocarditis or a strong clinical suspicion of myocarditis as cause of the index event Contraindications for beta blocker or ACEI ǁ/ARB ¶ treatment Prior use of beta blocker, ACEI/ARB which must continue according to Investigator New indication for beta blocker or ACEI/ARB treatment other than as secondary prevention according to Investigator Ongoing pregnancy or woman of childbearing potential not using highly effective contraceptives Participation in a trial evaluating a drug known to interact with beta blockers or ACEI/ARB * Myocardial infarction with non-obstructive coronary arteries, † Cardiac magnetic resonance imaging, ǂ Coronary Artery Bypass Grafting, § Percutaneous coronary intervention, ǁ ACE Inhibitor, ¶ Angiotensin Receptor Blocker.
An overview of the study timeline, randomization and follow-up is shown in Figure 1 and Table III. The randomization will be performed in the module using permuted block randomization with 1:1:1:1 ratio, stratified by country. The patients will be randomized to either oral beta blockade alone, ACEI/ARB alone or a combination of oral beta blockade and ACE/ARB, or neither beta blockade nor ACEI/ARB. If randomized to beta blockade and/or ACEI/ARB, the investigator will in the randomization module note the agent(s) chosen, the starting dose(s)
and target dose(s) planned. Patients randomized to one or two drug classes will be encouraged to continue with the drug(s) until any possible contraindications appear. Control group patients randomized to neither beta blockade nor ACEI/ARB will be allowed to use these drugs only if strict medical indications develop outside secondary prevention after AMI. Drug doses will be decided by the physician in charge of the patient and reaching target doses will be strongly recommended. Other secondary preventive treatments, such as statins
Figure 1 Flowchart of the MINOCA-BAT trial. The follow-up times may differ slightly between Australia and other countries.
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Table III. Schedule of measurements.
Day Day Week 1 1–30 6–10 Onset of AMI Inclusion, informed consent, randomization* Sweden: Follow-up (visit/telephone): Drug titration, compliance and collection of endpoints † Australia/other countries ǂ: Follow-up (visit/telephone): Drug titration, compliance and collection of endpoints Sweden: Record linkage with SWEDEHEART register and collection of endpoints § Record linkage with other national registers ǁ
Month Month 3 6
Every 12 months until end of Month Month Every 3 months 9 12 until end of study study
4 years mean follow-up
X X
X
X
X
X
X
X
X
X
X
X
X
X
X X
* Inclusion/exclusion, informed consent and randomization will be performed at the baseline visit by the Investigator or delegated site staff. Routine registration in Sephia, part of the SWEDEHEART-register. Follow up every 3 months until end of study. † Follow-up visit in the study where the Investigator will collect information on endpoints and compliance to study medication. ǂ Visit/telephone at 6–10 weeks (optional), 6 and 12 months, then every year until end of study. Additional countries to be recruited may require customized follow-up schedules, which will be accommodated as long as the overall trial goals can be achieved. § Collection of endpoints (hospitalization for MI and death) from SWEDEHEART-register every 3 months until study closure. Additionally the patient can report endpoints the Investigator at any time point during the study. ǁ Data from SWEDEHEART-register merged with Cause of Death, National Patient and Prescribed Drug registers, supplemental with collection of endpoints (death of any cause, or readmission because of AMI, ischemic stroke or heart failure).
and single- or dual antiplatelet therapy, may be given according to the investigator. Swedish patients will be followed-up by outpatient visits or telephone at 6–10 weeks and 12 months after randomization. In addition, endpoints, e.g. hospitalization for MI or death, will be collected from the SWEDEHEART-registry every 3 months until study closure. After a mean of 4 years of follow-up a registry-based evaluation will be performed. Patients from Australia and other countries will be followed-up by a visit at 6–10 weeks after randomization and then by telephone at 6 months, 12 months, and then every year until end of study to collect information regarding drug compliance and outcome. The study commenced with patients enrolled in Australia in January 2019 and in Sweden June 2019. In the near future, hospitals in Norway and Spain are expected to join the study. Negotiations with representatives for hospitals in New Zealand, Italy, United States, United Kingdom and additional countries are ongoing. The SWEDEHEART register, covers approximately 90% of all AMIs in Sweden. 18 When comparing data from the Swedish Heart Intensive Care Admissions (RIKS-HIA) subregister with hospital records of randomly chosen patients at different hospitals an average agreement of 95% has been found and all variables are standardized. 18 The Secondary Prevention after Heart Intensive Care Admission (SEPHIA) sub-register collects data on patients <80 years old with a coverage of almost 80%. 19
The study was approved by Ethics Review Boards in each participating country, in Sweden dnr: 2019–02355. ClinicalTrials.gov Identifier: NCT03686696.
Preferred drugs and adherence to the randomized drugs The drugs prescribed will vary slightly between countries due to local regulations and practice. In Sweden, Ramipril and Enalapril are the preferred ACEIs, Candesartan and Losartan the preferred ARBs and Metoprolol and Bisoprolol the preferred beta blockers. In Australia, Perindopril Erbumine and Perindopril Arginine (ACEIs) are the preferred ACEIs, Candesartan preferred ARB and Atenolol the preferred beta blocker. Other participating countries may prefer the same or similar drugs. Investigators will be encouraged to aim for the target dose or highest tolerable dose for each drug. In Sweden the adherence to the randomized drug(s) will be assessed at the follow-up visits (visit/telephone) at 6–10 weeks and 12 months after randomization. These visits are registered in SWEDEHEART. In addition, initiation (whether the prescribed drug is dispensed), adherence (defined as proportion of prescribed tablets that are dispensed), and persistence (time on treatment) will be followed in the Swedish Prescribed Drug Register for the entire duration of the trial. In all other countries the adherence to the randomized drug(s) will be assessed at each visit/telephone follow-up during the duration of the trial.
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Outcome Randomized patients will be followed regarding allcause mortality; cardiovascular mortality; hospitalization for myocardial infarction, heart failure, ischemic stroke, unstable angina, atrial fibrillation, renal failure, second- or third-degrees AV-block, hypotension, syncope and pacemaker implantation. In Sweden the information about death will be obtained from the National Population Register. At the end of study, information on all other endpoints will be obtained from the National Patient Register and the Cause of Death Register of the National Board of Health and Welfare. In other countries the information about death and other endpoints will be obtained by telephone follow-up every 6 months and corresponding registries or administrative registries at the end of study. A local validation of all reported primary endpoints will be done at each center. At the end of the study the PI at each center will get a list of patients for whom a primary endpoint (MACE) is reported. The PI are requested to check that the reported diagnoses are correct according to a detailed charter. If the PI finds the diagnosis incorrect or doubtful, the event should be adjudicated centrally by an independent adjudication committee blinded to treatment. Safety In Sweden safety endpoints will be collected at visits or telephone interviews 6–10 weeks and 12 months, respectively, and thereafter by data obtained from the National Patient Register. In addition, a quarterly import from the SWEDEHEART register will be done throughout the trial, in order to check if there has been any deaths or hospitalizations due to myocardial infarction. If the SWEDEHEART register indicates an event not reported in the study, the study monitor will contact the Investigator. The Swedish patients are also encouraged, both orally and in writing, to notify their physician if they are admitted for any cardiac related condition during follow-up. For the other participating countries endpoints including safety endpoints will be collected at the regular follow-up visits/ telephone contacts. A Data and Safety Monitoring Board (DSMB) will ensure the safety of the intervention as well as the general execution of the trial on behalf of the trial participants. The DSMB will perform an outcome analysis after the first 1000 patients have been followed for 1 year. In addition, a statistician, not otherwise involved in the study, will after the inclusion of the first 500 patients every third months compile the data on death and MI extracted from the SWEDEHEART register and corresponding data from the regular follow-ups in the other countries, and send to the chairperson of the DSMB for review. Statistics The effect of beta blocker treatment will be evaluated by comparing the outcome between the two groups random-
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ized to beta blocker treatment and the two groups with no beta blocker treatment. The effect of ACE/ARB treatment will be evaluated by comparing the outcome between the two groups randomized to ACEI/ARB treatment and the two groups with no ACEI/ARB treatment. The same analyses will be provided for both treatment comparisons. Since the ACEI/ARB and beta blocker hypotheses are independent, no adjustment for multiple hypothesis testing is applicable. Primarily, analyses will be performed on the intention-totreat (ITT) set, defined as all intentionally randomized patients, by randomized treatment. Statistical testing will be performed on the 5% significance level using two-sided tests. The same analyses will be provided for the primary outcome and all secondary time-to-event outcomes. All time-to-event endpoints will be presented as Kaplan– Meier plots and frequency tables, by randomized treatment, and analyzed using Cox proportional hazards regression with factors randomized ACEI/ARB treatment (yes/no) and beta blocker treatment (yes/no), and adjustment for age at enrolment as a linear covariate on the log-hazard scale, and country, diagnosis of diabetes, antihypertensive treatment, previous myocardial infarction, previous stroke, LVEF <50%, and ST-elevation on admission ECG as factors, and presented as a hazard ratio for ACEI/ARB versus no ACEI/ARB, and a hazard ratio for beta blocker treatment vs no beta blocker, with 95% confidence intervals and associated p-values. The primary ITT analysis attempts to estimate the risk factor adjusted hazard ratio for an intentionally randomized patient, between the initially assigned treatment regimens, regardless of compliance or loss to follow-up. Hence, the analyses will be based on events during the entire follow-up time of each patient at end of follow-up, and patients without an event will be considered censored at last day of follow-up, regardless of compliance or loss to follow-up. Secondary on-treatment analyses will attempt to estimate the risk factor adjusted hazard ratio between the treatments in the hypothetical scenario that the patient would stay compliant regardless of treatment. The method will be to rerun the primary analysis with censoring at 1 year for patients that were no longer compliant (defined as recorded use of beta blockers and or ACE/ARBI at 12-month follow-up in agreement with randomization). Sensitivity analyses are intended to assess the robustness of the estimates to analytic assumptions. As sensitivity analyses for the ITT analyses, unadjusted analyses, analyses excluding patients with missing baseline data, analyses excluding patients lost to followup and analyses excluding any patients found to be ineligible after randomization will be performed, to assess the impact of missing data and choice of adjustment variables. Potential difference in concomitant nonrandomized treatment of the patients between different countries will be evaluated in additional sensitivity analyses.
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Discussion
challenge and even ambitious differential diagnostic efforts including intravascular ultrasound (IVUS), 21 , 23 optical coherence tomography (OCT), 9 invasive provocative testing for vasospasm, 24 testing for hypercoagulable disorders 2 and CMR 25 , 26 may fail to explain the mechanism behind a MINOCA. There is a strong evidence base for cardioprotective drugs (e.g. dual antiplatelet agents, statins, ACEI/ARB and beta blockers) recommended as secondary prevention therapies for patients with MI-CAD. 8 , 10 However, for MINOCA patients with less severe or no atherosclerotic lesions, guidelines are lacking. The ESC 7 and AHA 9 both emphasize individualized secondary preventive treatment based on the underlying mechanism for the MINOCA. However, in the absence of a certain underlying mechanism and evidence from randomized clinical trials, the treatment recommendations remain uncertain. 7,9 Aspirin, statins and, in cases of vasospasm, calcium channel blockers have been proposed as routine treatments by ESC 7 while AHA states that statins and antiplatelet therapy should be reserved for MINOCA patients with plaque disruption and not used and possibly even contraindicated in type 2 AMI. 9 The threshold of LVEF ≥40% is based on European and American guidelines which both recommend treatment with ACEI/ARB and beta blockers in patients with systolic LV dysfunction defined as LVEF <40%. 27 , 28 However, there are still no firm evidence for the routine use of ACEI/ARB and/or beta blockers in patients with LVEF ≥40%. Hence, the cut-off of 40% for the LVEF has often been used in other clinical trials. 29 The recent retrospective SWEDEHEART register study has, as the first in its kind, addressed the issue of secondary preventive treatment of MINOCA patients. 1 The use of statins and ACEI/ARB was associated with a significantly lower rate of adverse events. The use of beta blockers also tended to reduce the event rate. 1 Use of these drug classes is highly variable in current clinical practice reflecting the absence of data in this patient population and, therefore, of guidelines specific to MINOCA patients. 1 , 11 , 17 Considering the uncertainty regarding underlying pathophysiological mechanisms and large number of MINOCA patients with adverse long-term prognosis we need randomized trials investigating secondary preventive treatment.
MINOCA has been recognized for the past four decades, 5 , 6 however it is only in recent years that diagnostic criteria and differential diagnostic investigations have been proposed. 7-10 MINOCA patients form a heterogeneous group in which several underlying pathophysiological mechanisms such as plaque rupture or ulceration, coronary spasm, coronary dissection, MI due to supply–demand mismatch and clinically unrecognized myocarditis or takotsubo syndrome may be present. 7 , 20-22 The patients often constitute a diagnostic
Strength and limitations The major strength of MINOCA-BAT is the large number of patients to be recruited from several continents. MINOCA-BAT is designed as a pragmatic study that doesn't require various additional investigations such as CMR with late gadolinium enhancement to localize of the area of myocardial damage or intracoronary imaging with OCT and IVUS before inclusion. The extent of the clinical assessment will be adapted to the ability of the different
Secondary analyses regarding outcome are planned for pre-specified subgroups: age ≥75/<75 years, gender, patients with and without hypertension, diabetes, chronic kidney disease previous MI and ST-elevation on admission ECG. The findings on coronary angiography will be divided into stenosis <30%/30%-49% and LVEF into 40%-49%/≥50%. Data will also be analyzed for patients with a MRI performed before randomization compared to patients without MRI, respectively. All subgroup analyses will be performed using interaction models based on the primary analysis model, also including the subgroup in question and the treatmentsubgroup interaction as factors, and presented as treatment hazard ratios for each subgroup and the interaction p-value.
Determination of sample size A clinically relevant effect of ACEI/ARB and beta blocker was defined as a relative risk reduction of 20% for each of the treatments. Therefore, the sample was sized to detect a relative risk of 0.8 at 4 years. In the MINOCA study based on the SWEDEHEART registry the 4year risk of MACE was approximately 18% for patients with a LVEF ≥40% who were neither prescribed beta blockers nor ACEI/ARB treatment. 1 The event rate of the composite endpoint was assumed to be 18% in the control arm. A risk ratio of 0.8 at a proportion of 18% MACE in the control group corresponds to a HR of 0.7835, which can be detected with 80% power with at least 528 MACE events (at a two-sided significance level of 0.05). To obtain 528 events during a total study duration of 5.25 years with uniform patient accrual for 2.75 years, with negligible drop-out, 3374 patients would be needed. To compensate for any loss of patients with complete follow-up, 3500 patients will be included.
Results By October 1th 2020, 95 patients have been included, 54 in Sweden and 41 in Australia respectively. The majority were women (68.5% women and 31.5% men) and the mean age was 60 (SD 11) years. The women were slightly older than the men, 61 years compared to 57 years.
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sites and the included cohort will reflect a genuine, contemporary MINOCA population. The results will be applicable to the broad, real life, MINOCA population. Limitations include the open label design of the study that may inflict some drug associated bias. Additionally, due to the lack of systematic measures of drug adherence in the in entire cohort regional differences in both medication compliance and persistence may evade detection. Further limitations include the diverse pathophysiological mechanisms and their effect on intervention and outcome as well as the lack of central adjudication of all events. The pragmatic design means that some patients with non-ischemic mechanism may be included, but these should be few in number and balanced between arms. The pragmatic design of the study also prevents blinding of events. To ensure correct interpretation of events a local validation of all events reported as primary endpoints in registries or during follow-up will be performed. At the slightest uncertainty, the event will be adjudicated centrally by an independent adjudication committee blinded to treatment. Finally, the introduction of high sensitive troponin assays and the more widespread knowledge of the entity of MINOCA have probably made the MINOCA diagnosis more common and the MINOCA population slightly different from the population on which we estimated the event rate. Whether this will change the number of anticipated events is, however, unclear.
Conclusion MINOCA patients have an increased risk of death and serious adverse cardiac events after the acute event. However, there are no trials evaluating effects of secondary preventive treatments for MINOCA patients and thus no established guidelines for secondary preventive management after MINOCA. Accordingly, in clinical practice, the secondary prevention treatment of patients with MINOCA varies largely. There is clearly need for trials investigating preventive treatment for MINOCA patients, and we designed the MINOCA-BAT trial to meet this need. The results are expected to influence future treatment strategies and guidelines.
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in the ACTION Registry-GWTG (Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines). Circ Cardiovasc Qual Outcomes 2017;10(12), e003443. Brecker SJ, Stevenson RN, Roberts R, et al. Acute myocardial infarction in patients with normal coronary arteries. BMJ 1993;307 (6914):1255-6. DeWood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980;303(16):897-902. DeWood MA, Stifter WF, Simpson CS, et al. Coronary arteriographic findings soon after non-Q-wave myocardial infarction. N Engl J Med 1986;315(7):417-23. Agewall S, Beltrame JF, Reynolds HR, et al. ESC working group position paper on myocardial infarction with non-obstructive coronary arteries. Eur Heart J 2017;38(3):143-53. Ibanez B, James S, Agewall S, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Rev Esp Cardiol (Engl Ed) 2017;70(12): 1082. Tamis-Holland JE, Jneid H, Reynolds HR, et al. Contemporary diagnosis and management of patients with myocardial infarction in the absence of obstructive coronary artery disease: a scientific statement from the American Heart Association. Circulation 2019;139(18):e891-908. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of Myocardial Infarction (2018). Circulation 2018;138(20):e618-e51. Nordenskjold AM, Baron T, Eggers KM, et al. Predictors of adverse outcome in patients with myocardial infarction with non-obstructive coronary artery (MINOCA) disease. Int J Cardiol 2018;261:18-23. De Ferrari GM, Fox KA, White JA, et al. Outcomes among non–STsegment elevation acute coronary syndromes patients with no angiographically obstructive coronary artery disease: observations from 37,101 patients. Eur Heart J Acute Cardiovasc Care 2014;3(1): 37-45. Eggers KM, Hjort M, Baron T, et al. Morbidity and cause-specific mortality in first-time myocardial infarction with nonobstructive coronary arteries. J Intern Med 2019;285(4):419-28. Safdar B, Spatz ES, Dreyer RP, et al. Presentation, clinical profile, and prognosis of young patients with myocardial infarction with nonobstructive coronary arteries (MINOCA): Results From the VIRGO Study. J Am Heart Assoc 2018;7(13). Williams MJA, Barr PR, Lee M, et al. Outcome after myocardial infarction without obstructive coronary artery disease. Heart 2019;105(7):524-30. Eggers KM, Hadziosmanovic N, Baron T, et al. Myocardial Infarction with Nonobstructive Coronary Arteries: The Importance of Achieving Secondary Prevention Targets. Am J Med 2018;131(5): 524-31. e6. Reynolds HR, Smilowitz NR, Hellkramp A, et al. Variability of discharge medical therapy for secondary prevention along patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) in the united states. J AM Coll Cardiol 2020 Mar;2020. Jernberg T, Attebring MF, Hambraeus K, et al. The Swedish Websystem for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART). Heart 2010;96:1617-21. 27. SWEDEHEART. Annual report 2014. Stockholm: Karolinska University Hospital. 2015:1-138. Niccoli G, Scalone G, Crea F. Acute myocardial infarction with no obstructive coronary atherosclerosis: mechanisms and management. Eur Heart J 2015;36(8):475-81.
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21. Reynolds HR, Srichai MB, Iqbal SN, et al. Mechanisms of myocardial infarction in women without angiographically obstructive coronary artery disease. Circulation 2011;124(13): 1414-25. 22. Tornvall P, Gerbaud E, Behaghel A, et al. Myocarditis or "true" infarction by cardiac magnetic resonance in patients with a clinical diagnosis of myocardial infarction without obstructive coronary disease: A meta-analysis of individual patient data. Atherosclerosis 2015;241(1):87-91. 23. Ouldzein H, Elbaz M, Roncalli J, et al. Plaque rupture and morphological characteristics of the culprit lesion in acute coronary syndromes without significant angiographic lesion: analysis by intravascular ultrasound. Ann Cardiol Angeiol (Paris) 2012;61(1): 20-6. 24. Montone RA, Niccoli G, Fracassi F, et al. Patients with acute myocardial infarction and non-obstructive coronary arteries: safety and prognostic relevance of invasive coronary provocative tests. Eur Heart J 2018;39(2):91-8. 25. Collste O, Sorensson P, Frick M, et al. Myocardial infarction with normal coronary arteries is common and associated with normal findings on cardiovascular magnetic resonance imaging: results
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26. 27.
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from the Stockholm Myocardial Infarction with Normal Coronaries study. J Intern Med 2013;273(2):189-96. Sechtem U, Seitz A, Ong P. MINOCA: unravelling the enigma. Heart 2019;105(16):1219-20. Ponikowski P, Voors AA, Anker DS. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016 Jul 14;37(27): 2129-200, https://doi.org/10.1093/eurheartj/ehw128. Roffi M, Patrono C, Collet J, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes 391 in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016 Jan 14;37(3): 267-315. Kelly JP, Mentz RJ, Mebazaa A, et al. Patient selection in heart failure with preserved ejection fraction clinical trials. J Am Coll Cardiol 2015;65:1668-82.
Randomized evaluation of beta blocker and ACE-inhibitor/angiotensin receptor blocker treatment in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA-BAT): Rationale and design Anna M Nordenskjöld, MD, PhD, a Stefan Agewall, MD, PhD, b Dan Atar, MD, PhD, b Tomasz Baron, MD, PhD, c John Beltrame, BMBS, PhD, d Olle Bergström, MD, e David Erlinge, MD, PhD, f Chris P Gale, PhD, FRCP, g Javier López-Pais, MD, h Tomas Jernberg, MD, PhD, i Pelle Johansson, j Annica Ravn-Fisher, MD, PhD, k Harmony R. Reynolds, MD, l Jithendra B. Somaratne, MBChB, FRACP, PhD, m Per Tornvall, MD, PhD, n and Bertil Lindahl, MD, PhD c Örebro, Uppsala, Lund, Stockholm, Sweden Adelaide, Australia Leeds, UK and NYU Grossman School of Medicine, New York
Background Myocardial infarction with non-obstructive coronary arteries (MINOCA) is common and occurs in 6–8% of all patients fulfilling the diagnostic criteria for acute myocardial infarction (AMI). This paper describes the rationale behind the trial ‘Randomized Evaluation of Beta Blocker and ACE-Inhibitor/Angiotensin Receptor Blocker Treatment (ACEI/ARB) of MINOCA patients’ (MINOCA-BAT) and the need to improve the secondary preventive treatment of MINOCA patients. Methods MINOCA-BAT is a registry-based, randomized, parallel, open-label, multicenter trial with 2:2 factorial design. The primary aim is to determine whether oral beta blockade compared with no oral beta blockade, and ACEI/ARB compared with no ACEI/ARB, reduce the composite endpoint of death of any cause, readmission because of AMI, ischemic stroke or heart failure in patients discharged after MINOCA without clinical signs of heart failure and with left ventricular ejection fraction ≥40%. A total of 3500 patients will be randomized into four groups; e.g. ACEI/ARB and beta blocker, beta blocker only, ACEI/ARB only and neither ACEI/ARB nor beta blocker, and followed for a mean of 4 years. Summary While patients with MINOCA have an increased risk of serious cardiovascular events and death, whether conventional secondary preventive therapies are beneficial has not been assessed in randomized trials. There is a limited basis for guideline recommendations in MINOCA. Furthermore, studies of routine clinical practice suggest that use of secondary prevention therapies in MINOCA varies considerably. Thus results from this trial may influence future treatment strategies and guidelines specific to MINOCA patients. (Am Heart J 2021;231:xxx.)
Background and rationale Myocardial infarction with non-obstructive coronary arteries (MINOCA) is common and affect 6% to 8% of all
patients with acute myocardial infarction (AMI). 1-3 The affliction has been recognized since the early 1980s, 4-6 but not until recently have diagnostic criteria been proposed
From the aDepartment of Cardiology, Faculty of Medicine and Health, Örebro University,
of Medicine, NYU Grossman School of Medicine, New York, mGreen Lane Cardiovascular
Örebro, Sweden, bDepartment of Cardiology, Oslo University Hospital, Norway, and Institute of Clinical Sciences, University of Oslo, Norway, cDepartment of Medical Sciences, Cardiology, and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden, dDiscipline of Medicine, University of Adelaide, Basil Hetzel Institute, Central Adelaide Local Health Network, Adelaide, Australia, eDepartment of Medicine/ Cardiology, County Hospital of Kronoberg, Sweden, fDepartment of Cardiology, Clinical Sciences, Lund University, Lund, Sweden, gLeeds Institute of Cardiovascular and Metabolic
Service, Auckland City Hospital, New Zealand, and nDepartment of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Stockholm, Sweden. Declarations of interest: none. Trial registrationEudraCT number: 2018-000889-11. ClinicalTrials.gov identifier: NCT03686696. Submitted May 19, 2020; accepted October 14, 2020. Reprint requests: Anna M Nordenskjöld, Department of Cardiology, Faculty of Medicine
Medicine, University of Leeds, Leeds, UK, hDepartment of Cardiology, University Hospital Complex of Santiago de Compostela, Spain, iDepartment of clinical sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden, jSenior research manager, The Swedish Heart and Lung Association, Sweden, kDepartment of Cardiology, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden, lSarah Ross Soter Center for Women's Cardiovascular Research, Leon H. Charney Division of Cardiology, Department
and Health, Örebro University, Södra Grev Rosengatan, 701 85 Örebro, Sweden. E-mail: [email protected] 0002-8703 © 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). https://doi.org/10.1016/j.ahj.2020.10.059
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and structured investigations recommended. 7 The notion of MINOCA as a working diagnosis is highlighted in several recent international guidelines and statements. 8-10 Besides the atherosclerotic status of the coronary arteries there are several fundamental differences between patients with MINOCA and patients with AMI and obstructive coronary artery disease (MI-CAD). MINOCA patients are more often female, younger on average and tend to have fewer comorbidities. 1 , 2 , 11 Regardless, for MINOCA patients, short- and long-term prognosis is only slightly more favorable as compared to MI-CAD patients and far worse as compared to the general population. 2 , 12-15 The six-month mortality after MINOCA was 2.4% among MINOCA patients in the Swedish Web based registry for Enhancement and Development of Evidence-based care in Heart disease (SWEDEHEART) 11 and the 1-year mortality was 3.5% in a systematic review of 28 publications. 2 In addition, almost 25% of the MINOCA patients registered in the SWEDEHEART registry suffered a major adverse cardiac event (MACE) within 4 years, defined as death, recurrent MI, heart failure hospitalization or stroke. 1 This high rate of long-term serious cardiovascular events is particular worrisome when considering the younger age and more favorable clinical profile of MINOCA patients compared to patients with MI-CAD. In a recent propensity score-matched analysis of 9138 patients with MINOCA enrolled in the SWEDEHEART registry we evaluated the relationship between treatment with statins, ACE-inhibitor/angiotensin receptor blocker (ACEI/ARB) treatment, beta-blockers, dual antiplatelet therapy and the composite of all-cause mortality or hospitalization for reinfarction, heart failure, or stroke. After a mean follow-up of 4.1 years, there was a significantly lower event rate associated with the use of statins (hazard ratio, 0.77 [95% CI, 0.68-0.87]), ACEI/ARBs (hazard ratio, 0.82 [95% CI, 0.73-0.93]) and a trend for a lower event rate with the use of beta-blockers (hazard ratio, 0.86 [95% CI, 0.74-1.01]). The use of dual antiplatelet agents was neither associated with a lower event rate nor with increased bleeding events at 1 year. 1 Structured follow-up and reaching target levels for secondary preventive goals have also been demonstrated to positively affect the prognosis of patients with MINOCA. 16 However, the treatment of MINOCA patients may differ greatly depending on the opinion of the individual professionals and the healthcare facilities. 1 , 11 For example, in the Chest Pain-Myocardial Infarction registry including nearly 6000 patients with MINOCA at over 150 high-volume hospitals, ACEI/ARB treatment was prescribed at discharge in 16–89% of patients and beta blockers to 28–98%. This marked variability in prescribing patterns indicates there is equipoise in the community about the need for these agents after a MINOCA event. 17 Here, we describe the rationale behind the trial Randomized Evaluation of Beta Blocker and ACEInhibitor/Angiotensin Receptor Blocker Treatment
(ACEI/ARB) in MINOCA patients (MINOCA-BAT) and the impending need to improve the secondary preventive treatment of MINOCA patients.
Methods MINOCA-BAT is a multicenter, prospective, randomized, controlled and open-label registry-based trial with 2:2 factorial design. All outcomes will be analyzed using the intention-to-treat principle. The study is supported by funds independently obtained by groups in each participating country. The Swedish Research Council, Sweden's largest governmental research funding body, have contributed with funding for the Swedish part of the study as well as for design and maintenance of the database and the international randomization module. Grant number: 2017–00478. The Australian part of the study have received funding from the Hospital Research Foundation, a non-for-profit organization, which provides research grants to South Australian public hospitals. The grant awarded was entitled ‘The Basil Hetzel Translational Grant 2017’. The primary aim is to determine whether beta blockade compared to no beta blockade, and whether ACEI/ARB compared to no ACEI/ARB, reduce the composite endpoint of death from any cause or readmission due to AMI, ischemic stroke or heart failure, in patients discharged following a clinical presentation with MINOCA but without clinical signs of heart failure and a left ventricular ejection fraction (LVEF) ≥40%. The secondary aims are to determine if any of the treatments reduce the individual components of the composite endpoint, cardiovascular mortality, readmission because of unstable angina pectoris or atrial fibrillation. A finding of a LVEF ≥40% is recognized as preserved systolic function. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents.
Definition of MINOCA MINOCA is in the study defined according to the ESC working group position paper on myocardial infarction with non-obstructive coronary arteries 7 with some modifications (Table I). The criteria for AMI are adjusted to follow the recommendations of the 4th Universal Definition of Myocardial Infarction, including the criteria for ECGchanges and significant rise and/or fall of troponin. 10 Furthermore, the position paper from the Working Group on MINOCA included the takotsubo syndrome in the definition of MINOCA, 7 whereas later scientific statements from the American Heart Association (AHA) considers the takotsubo syndrome as a separate entity, 9 consistent with the new 4th Universal Definition of Myocardial Infarction. 10 Transient regional wall motion abnormalities (hypokinesia, akinesia, or dyskinesia) in the
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Table I. Diagnostic criteria for MINOCA. All three criteria should be fulfilled. Adapted from reference. 7,
9, 10
Diagnostic criteria for MINOCA 1. AMI according to the universal definition (a) Positive cardiac troponin, defined as a rise and/or fall in serial levels, with at least one value above the 99th percentile upper reference limit. and (b) Corroborative clinical evidence of infarction evidenced by at least one of the following: (i) Symptoms of ischemia (ii) New ischemic ECG changes (iii) Development of pathological Q waves (iv) Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality 2. Non-obstructive coronary arteries on angiography Defined as the absence of obstructive CAD on angiography in any major epicardial artery. This include both patients with:
3
(i) normal coronary arteries (no stenosis >30%) (ii) mild coronary disease (stenosis >30% but <50%)*. No clinically overt specific cause for the acute presentation other than AMI At the time of angiography, the cause and thus a specific diagnosis for the clinical presentation is not apparent (e.g. clinically strong suspicion of myocarditis, takotsubo syndrome † or pulmonary embolism)
* In borderline cases where it is difficult to determine visually whether a stenosis is below the 50% cut-off, a fractional flow reserve (FFR) or instantaneous wave-fre ratio (iFR) may be performed. An FFR >0.80 or iFR >0.90 beyond the stenosis is considered to be hemodynamically insignificant and it is possible to include patients with these findings. † Patients showing (transient) regional wall motion abnormalities (hypokinesia, akinesia, or dyskinesia) in the left ventricle extending beyond a single epicardial vascular distribution at the initial left ventriculogram or echocardiographic examination are considered to have a strong suspicion of takotsubo syndrome and should not be included in the MINOCA-BAT trial. If these findings are not present the suspicion of takotsubo syndrome is not considered strong and the patient can be included in the trial.
left ventricle extending beyond a single epicardial vascular distribution in the initial left ventriculogram or echocardiograpy indicate takotsubo syndrome and such patients should not be included in the MINOCA-BAT trial. In the absence of such findings, takotsubo syndrome is an unlikely diagnosis and the patient can be included in the trial if the other clinical eligibility criteria are met. Myocarditis is also not included in the definition of MINOCA. Therefore, patients with cardiac magnetic resonance imaging (CMR) proven myocarditis or with a strong clinical suspicion of myocarditis as cause of the index event will not be included in the MINOCA-BAT trial. For example, patients with ongoing covid-19 infection should not be included in MINOCA-BAT since troponin elevation in these patients are usually unrelated to myocardial ischemia and are most often a sign of minor myocardial injury due to myocardial viral infection and/or myocarditis. If a later CMR finds a takotsubo or a myocarditis patient included in MINOCA-BAT, the patient will remain included in the trial.
Hypothesis and primary, secondary, and safety end points The study hypothesis is that long-term treatment with ACEI/ARBs and/or beta blockers will reduce the risk of allcause death and hospitalization for myocardial infarction, stroke and/or heart failure in patients diagnosed with MINOCA and with preserved ejection fraction. The primary end point is time to either death due to any cause, readmission for AMI, ischemic stroke or heart failure in patients with MINOCA randomized to one of the four different secondary preventive regimes.
Secondary end points are as follows: time to all-cause death, cardiovascular death, readmission for AMI, ischemic stroke, heart failure, unstable angina pectoris and atrial fibrillation. Safety end points include: time to readmission because for second or third degree AV-block, ventricular tachycardia, ventricular fibrillation, hypotension, acute kidney injury, syncope or need for pacemaker. In sub studies, the underlying mechanisms for MINOCA will be investigated with CMR, positron emission tomography, computed tomography and biochemical markers. In additional sub studies, healthrelated quality-of-life, anxiety, depression, psychiatric comorbidities and the prevalence of angina pectoris will be addressed.
Inclusion/exclusion criteria Inclusion and exclusion criteria are presented in Table II. Study protocol, randomization, participating countries, and ethics Eligible patients will be identified at the cardiology departments, including the coronary angiography labs and the wards. If a patient with MINOCA needs additional testing to confirm eligibility and is discharged, he/she may be screened at an outpatient follow-up visit within 30 days from admission. Performing CRM before randomization to exclude clinically undetected myocarditis is encouraged, but not mandatory. Patients fulfilling the inclusion criteria and without any exclusion criterion will, after signing the informed consent form, be randomized on day 1 to 30 after index MINOCA.
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Table II. Inclusion and exclusion criteria. Inclusion criteria Age ≥18 years A clinical diagnosis of MINOCA* within the last 30 days LVEF ≥40% measured with echocardiography, CMR† or left ventriculogram during hospitalization and prior to randomization Written informed consent obtained Exclusion criteria Any condition that may influence the patient's ability to comply with study protocol. Previous revascularization (CABG ǂ or PCI§) Clinical signs of heart failure CMR-proven myocarditis or a strong clinical suspicion of myocarditis as cause of the index event Contraindications for beta blocker or ACEI ǁ/ARB ¶ treatment Prior use of beta blocker, ACEI/ARB which must continue according to Investigator New indication for beta blocker or ACEI/ARB treatment other than as secondary prevention according to Investigator Ongoing pregnancy or woman of childbearing potential not using highly effective contraceptives Participation in a trial evaluating a drug known to interact with beta blockers or ACEI/ARB * Myocardial infarction with non-obstructive coronary arteries, † Cardiac magnetic resonance imaging, ǂ Coronary Artery Bypass Grafting, § Percutaneous coronary intervention, ǁ ACE Inhibitor, ¶ Angiotensin Receptor Blocker.
An overview of the study timeline, randomization and follow-up is shown in Figure 1 and Table III. The randomization will be performed in the module using permuted block randomization with 1:1:1:1 ratio, stratified by country. The patients will be randomized to either oral beta blockade alone, ACEI/ARB alone or a combination of oral beta blockade and ACE/ARB, or neither beta blockade nor ACEI/ARB. If randomized to beta blockade and/or ACEI/ARB, the investigator will in the randomization module note the agent(s) chosen, the starting dose(s)
and target dose(s) planned. Patients randomized to one or two drug classes will be encouraged to continue with the drug(s) until any possible contraindications appear. Control group patients randomized to neither beta blockade nor ACEI/ARB will be allowed to use these drugs only if strict medical indications develop outside secondary prevention after AMI. Drug doses will be decided by the physician in charge of the patient and reaching target doses will be strongly recommended. Other secondary preventive treatments, such as statins
Figure 1 Flowchart of the MINOCA-BAT trial. The follow-up times may differ slightly between Australia and other countries.
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Table III. Schedule of measurements.
Day Day Week 1 1–30 6–10 Onset of AMI Inclusion, informed consent, randomization* Sweden: Follow-up (visit/telephone): Drug titration, compliance and collection of endpoints † Australia/other countries ǂ: Follow-up (visit/telephone): Drug titration, compliance and collection of endpoints Sweden: Record linkage with SWEDEHEART register and collection of endpoints § Record linkage with other national registers ǁ
Month Month 3 6
Every 12 months until end of Month Month Every 3 months 9 12 until end of study study
4 years mean follow-up
X X
X
X
X
X
X
X
X
X
X
X
X
X
X X
* Inclusion/exclusion, informed consent and randomization will be performed at the baseline visit by the Investigator or delegated site staff. Routine registration in Sephia, part of the SWEDEHEART-register. Follow up every 3 months until end of study. † Follow-up visit in the study where the Investigator will collect information on endpoints and compliance to study medication. ǂ Visit/telephone at 6–10 weeks (optional), 6 and 12 months, then every year until end of study. Additional countries to be recruited may require customized follow-up schedules, which will be accommodated as long as the overall trial goals can be achieved. § Collection of endpoints (hospitalization for MI and death) from SWEDEHEART-register every 3 months until study closure. Additionally the patient can report endpoints the Investigator at any time point during the study. ǁ Data from SWEDEHEART-register merged with Cause of Death, National Patient and Prescribed Drug registers, supplemental with collection of endpoints (death of any cause, or readmission because of AMI, ischemic stroke or heart failure).
and single- or dual antiplatelet therapy, may be given according to the investigator. Swedish patients will be followed-up by outpatient visits or telephone at 6–10 weeks and 12 months after randomization. In addition, endpoints, e.g. hospitalization for MI or death, will be collected from the SWEDEHEART-registry every 3 months until study closure. After a mean of 4 years of follow-up a registry-based evaluation will be performed. Patients from Australia and other countries will be followed-up by a visit at 6–10 weeks after randomization and then by telephone at 6 months, 12 months, and then every year until end of study to collect information regarding drug compliance and outcome. The study commenced with patients enrolled in Australia in January 2019 and in Sweden June 2019. In the near future, hospitals in Norway and Spain are expected to join the study. Negotiations with representatives for hospitals in New Zealand, Italy, United States, United Kingdom and additional countries are ongoing. The SWEDEHEART register, covers approximately 90% of all AMIs in Sweden. 18 When comparing data from the Swedish Heart Intensive Care Admissions (RIKS-HIA) subregister with hospital records of randomly chosen patients at different hospitals an average agreement of 95% has been found and all variables are standardized. 18 The Secondary Prevention after Heart Intensive Care Admission (SEPHIA) sub-register collects data on patients <80 years old with a coverage of almost 80%. 19
The study was approved by Ethics Review Boards in each participating country, in Sweden dnr: 2019–02355. ClinicalTrials.gov Identifier: NCT03686696.
Preferred drugs and adherence to the randomized drugs The drugs prescribed will vary slightly between countries due to local regulations and practice. In Sweden, Ramipril and Enalapril are the preferred ACEIs, Candesartan and Losartan the preferred ARBs and Metoprolol and Bisoprolol the preferred beta blockers. In Australia, Perindopril Erbumine and Perindopril Arginine (ACEIs) are the preferred ACEIs, Candesartan preferred ARB and Atenolol the preferred beta blocker. Other participating countries may prefer the same or similar drugs. Investigators will be encouraged to aim for the target dose or highest tolerable dose for each drug. In Sweden the adherence to the randomized drug(s) will be assessed at the follow-up visits (visit/telephone) at 6–10 weeks and 12 months after randomization. These visits are registered in SWEDEHEART. In addition, initiation (whether the prescribed drug is dispensed), adherence (defined as proportion of prescribed tablets that are dispensed), and persistence (time on treatment) will be followed in the Swedish Prescribed Drug Register for the entire duration of the trial. In all other countries the adherence to the randomized drug(s) will be assessed at each visit/telephone follow-up during the duration of the trial.
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Outcome Randomized patients will be followed regarding allcause mortality; cardiovascular mortality; hospitalization for myocardial infarction, heart failure, ischemic stroke, unstable angina, atrial fibrillation, renal failure, second- or third-degrees AV-block, hypotension, syncope and pacemaker implantation. In Sweden the information about death will be obtained from the National Population Register. At the end of study, information on all other endpoints will be obtained from the National Patient Register and the Cause of Death Register of the National Board of Health and Welfare. In other countries the information about death and other endpoints will be obtained by telephone follow-up every 6 months and corresponding registries or administrative registries at the end of study. A local validation of all reported primary endpoints will be done at each center. At the end of the study the PI at each center will get a list of patients for whom a primary endpoint (MACE) is reported. The PI are requested to check that the reported diagnoses are correct according to a detailed charter. If the PI finds the diagnosis incorrect or doubtful, the event should be adjudicated centrally by an independent adjudication committee blinded to treatment. Safety In Sweden safety endpoints will be collected at visits or telephone interviews 6–10 weeks and 12 months, respectively, and thereafter by data obtained from the National Patient Register. In addition, a quarterly import from the SWEDEHEART register will be done throughout the trial, in order to check if there has been any deaths or hospitalizations due to myocardial infarction. If the SWEDEHEART register indicates an event not reported in the study, the study monitor will contact the Investigator. The Swedish patients are also encouraged, both orally and in writing, to notify their physician if they are admitted for any cardiac related condition during follow-up. For the other participating countries endpoints including safety endpoints will be collected at the regular follow-up visits/ telephone contacts. A Data and Safety Monitoring Board (DSMB) will ensure the safety of the intervention as well as the general execution of the trial on behalf of the trial participants. The DSMB will perform an outcome analysis after the first 1000 patients have been followed for 1 year. In addition, a statistician, not otherwise involved in the study, will after the inclusion of the first 500 patients every third months compile the data on death and MI extracted from the SWEDEHEART register and corresponding data from the regular follow-ups in the other countries, and send to the chairperson of the DSMB for review. Statistics The effect of beta blocker treatment will be evaluated by comparing the outcome between the two groups random-
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ized to beta blocker treatment and the two groups with no beta blocker treatment. The effect of ACE/ARB treatment will be evaluated by comparing the outcome between the two groups randomized to ACEI/ARB treatment and the two groups with no ACEI/ARB treatment. The same analyses will be provided for both treatment comparisons. Since the ACEI/ARB and beta blocker hypotheses are independent, no adjustment for multiple hypothesis testing is applicable. Primarily, analyses will be performed on the intention-totreat (ITT) set, defined as all intentionally randomized patients, by randomized treatment. Statistical testing will be performed on the 5% significance level using two-sided tests. The same analyses will be provided for the primary outcome and all secondary time-to-event outcomes. All time-to-event endpoints will be presented as Kaplan– Meier plots and frequency tables, by randomized treatment, and analyzed using Cox proportional hazards regression with factors randomized ACEI/ARB treatment (yes/no) and beta blocker treatment (yes/no), and adjustment for age at enrolment as a linear covariate on the log-hazard scale, and country, diagnosis of diabetes, antihypertensive treatment, previous myocardial infarction, previous stroke, LVEF <50%, and ST-elevation on admission ECG as factors, and presented as a hazard ratio for ACEI/ARB versus no ACEI/ARB, and a hazard ratio for beta blocker treatment vs no beta blocker, with 95% confidence intervals and associated p-values. The primary ITT analysis attempts to estimate the risk factor adjusted hazard ratio for an intentionally randomized patient, between the initially assigned treatment regimens, regardless of compliance or loss to follow-up. Hence, the analyses will be based on events during the entire follow-up time of each patient at end of follow-up, and patients without an event will be considered censored at last day of follow-up, regardless of compliance or loss to follow-up. Secondary on-treatment analyses will attempt to estimate the risk factor adjusted hazard ratio between the treatments in the hypothetical scenario that the patient would stay compliant regardless of treatment. The method will be to rerun the primary analysis with censoring at 1 year for patients that were no longer compliant (defined as recorded use of beta blockers and or ACE/ARBI at 12-month follow-up in agreement with randomization). Sensitivity analyses are intended to assess the robustness of the estimates to analytic assumptions. As sensitivity analyses for the ITT analyses, unadjusted analyses, analyses excluding patients with missing baseline data, analyses excluding patients lost to followup and analyses excluding any patients found to be ineligible after randomization will be performed, to assess the impact of missing data and choice of adjustment variables. Potential difference in concomitant nonrandomized treatment of the patients between different countries will be evaluated in additional sensitivity analyses.
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Discussion
challenge and even ambitious differential diagnostic efforts including intravascular ultrasound (IVUS), 21 , 23 optical coherence tomography (OCT), 9 invasive provocative testing for vasospasm, 24 testing for hypercoagulable disorders 2 and CMR 25 , 26 may fail to explain the mechanism behind a MINOCA. There is a strong evidence base for cardioprotective drugs (e.g. dual antiplatelet agents, statins, ACEI/ARB and beta blockers) recommended as secondary prevention therapies for patients with MI-CAD. 8 , 10 However, for MINOCA patients with less severe or no atherosclerotic lesions, guidelines are lacking. The ESC 7 and AHA 9 both emphasize individualized secondary preventive treatment based on the underlying mechanism for the MINOCA. However, in the absence of a certain underlying mechanism and evidence from randomized clinical trials, the treatment recommendations remain uncertain. 7,9 Aspirin, statins and, in cases of vasospasm, calcium channel blockers have been proposed as routine treatments by ESC 7 while AHA states that statins and antiplatelet therapy should be reserved for MINOCA patients with plaque disruption and not used and possibly even contraindicated in type 2 AMI. 9 The threshold of LVEF ≥40% is based on European and American guidelines which both recommend treatment with ACEI/ARB and beta blockers in patients with systolic LV dysfunction defined as LVEF <40%. 27 , 28 However, there are still no firm evidence for the routine use of ACEI/ARB and/or beta blockers in patients with LVEF ≥40%. Hence, the cut-off of 40% for the LVEF has often been used in other clinical trials. 29 The recent retrospective SWEDEHEART register study has, as the first in its kind, addressed the issue of secondary preventive treatment of MINOCA patients. 1 The use of statins and ACEI/ARB was associated with a significantly lower rate of adverse events. The use of beta blockers also tended to reduce the event rate. 1 Use of these drug classes is highly variable in current clinical practice reflecting the absence of data in this patient population and, therefore, of guidelines specific to MINOCA patients. 1 , 11 , 17 Considering the uncertainty regarding underlying pathophysiological mechanisms and large number of MINOCA patients with adverse long-term prognosis we need randomized trials investigating secondary preventive treatment.
MINOCA has been recognized for the past four decades, 5 , 6 however it is only in recent years that diagnostic criteria and differential diagnostic investigations have been proposed. 7-10 MINOCA patients form a heterogeneous group in which several underlying pathophysiological mechanisms such as plaque rupture or ulceration, coronary spasm, coronary dissection, MI due to supply–demand mismatch and clinically unrecognized myocarditis or takotsubo syndrome may be present. 7 , 20-22 The patients often constitute a diagnostic
Strength and limitations The major strength of MINOCA-BAT is the large number of patients to be recruited from several continents. MINOCA-BAT is designed as a pragmatic study that doesn't require various additional investigations such as CMR with late gadolinium enhancement to localize of the area of myocardial damage or intracoronary imaging with OCT and IVUS before inclusion. The extent of the clinical assessment will be adapted to the ability of the different
Secondary analyses regarding outcome are planned for pre-specified subgroups: age ≥75/<75 years, gender, patients with and without hypertension, diabetes, chronic kidney disease previous MI and ST-elevation on admission ECG. The findings on coronary angiography will be divided into stenosis <30%/30%-49% and LVEF into 40%-49%/≥50%. Data will also be analyzed for patients with a MRI performed before randomization compared to patients without MRI, respectively. All subgroup analyses will be performed using interaction models based on the primary analysis model, also including the subgroup in question and the treatmentsubgroup interaction as factors, and presented as treatment hazard ratios for each subgroup and the interaction p-value.
Determination of sample size A clinically relevant effect of ACEI/ARB and beta blocker was defined as a relative risk reduction of 20% for each of the treatments. Therefore, the sample was sized to detect a relative risk of 0.8 at 4 years. In the MINOCA study based on the SWEDEHEART registry the 4year risk of MACE was approximately 18% for patients with a LVEF ≥40% who were neither prescribed beta blockers nor ACEI/ARB treatment. 1 The event rate of the composite endpoint was assumed to be 18% in the control arm. A risk ratio of 0.8 at a proportion of 18% MACE in the control group corresponds to a HR of 0.7835, which can be detected with 80% power with at least 528 MACE events (at a two-sided significance level of 0.05). To obtain 528 events during a total study duration of 5.25 years with uniform patient accrual for 2.75 years, with negligible drop-out, 3374 patients would be needed. To compensate for any loss of patients with complete follow-up, 3500 patients will be included.
Results By October 1th 2020, 95 patients have been included, 54 in Sweden and 41 in Australia respectively. The majority were women (68.5% women and 31.5% men) and the mean age was 60 (SD 11) years. The women were slightly older than the men, 61 years compared to 57 years.
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sites and the included cohort will reflect a genuine, contemporary MINOCA population. The results will be applicable to the broad, real life, MINOCA population. Limitations include the open label design of the study that may inflict some drug associated bias. Additionally, due to the lack of systematic measures of drug adherence in the in entire cohort regional differences in both medication compliance and persistence may evade detection. Further limitations include the diverse pathophysiological mechanisms and their effect on intervention and outcome as well as the lack of central adjudication of all events. The pragmatic design means that some patients with non-ischemic mechanism may be included, but these should be few in number and balanced between arms. The pragmatic design of the study also prevents blinding of events. To ensure correct interpretation of events a local validation of all events reported as primary endpoints in registries or during follow-up will be performed. At the slightest uncertainty, the event will be adjudicated centrally by an independent adjudication committee blinded to treatment. Finally, the introduction of high sensitive troponin assays and the more widespread knowledge of the entity of MINOCA have probably made the MINOCA diagnosis more common and the MINOCA population slightly different from the population on which we estimated the event rate. Whether this will change the number of anticipated events is, however, unclear.
Conclusion MINOCA patients have an increased risk of death and serious adverse cardiac events after the acute event. However, there are no trials evaluating effects of secondary preventive treatments for MINOCA patients and thus no established guidelines for secondary preventive management after MINOCA. Accordingly, in clinical practice, the secondary prevention treatment of patients with MINOCA varies largely. There is clearly need for trials investigating preventive treatment for MINOCA patients, and we designed the MINOCA-BAT trial to meet this need. The results are expected to influence future treatment strategies and guidelines.
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