Original Research Article

Medical Therapy for Secondary Prevention and Long-Term Outcome in Patients With Myocardial Infarction With Nonobstructive Coronary Artery DiseaseClinical Perspective

Bertil Lindahl, Tomasz Baron, David Erlinge, Nermin Hadziosmanovic, Anna Nordenskjöld, Anton Gard, Tomas Jernberg
https://doi.org/10.1161/CIRCULATIONAHA.116.026336
Circulation. 2017;135:1481-1489
Originally published February 8, 2017

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Abstract

Background: Myocardial infarction with nonobstructive coronary arteries (MINOCA) occurs in 5% to 10% of all patients with myocardial infarction. Clinical trials of secondary prevention treatment in MINOCA patients are lacking. Therefore, the aim of this study was to examine the associations between treatment with statins, renin-angiotensin system blockers, β-blockers, dual antiplatelet therapy, and long-term cardiovascular events.

Methods: This is an observational study of MINOCA patients recorded in the SWEDEHEART registry (the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapy) between July 2003 and June 2013 and followed until December 2013 for outcome events in the Swedish Cause of Death Register and National Patient Register. Of 199 162 myocardial infarction admissions, 9466 consecutive unique patients with MINOCA were identified. Among those, the 9136 patients surviving the first 30 days after discharge constituted the study population. Mean age was 65.3 years, and 61% were women. No patient was lost to follow-up. A stratified propensity score analysis was performed to match treated and untreated groups. The association between treatment and outcome was estimated by comparing between treated and untreated groups by using Cox proportional hazards models. The exposures were treatment at discharge with statins, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blockers, and dual antiplatelet therapy. The primary end point was major adverse cardiac events defined as all-cause mortality, hospitalization for myocardial infarction, ischemic stroke, and heart failure.

Results: At discharge, 84.5%, 64.1%, 83.4%, and 66.4% of the patients were on statins, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blockers, and dual antiplatelet therapy, respectively. During the follow-up of a mean of 4.1 years, 2183 (23.9%) patients experienced a major adverse cardiac event. The hazard ratios (95% confidence intervals) for major adverse cardiac events were 0.77 (0.68–0.87), 0.82 (0.73–0.93), and 0.86 (0.74–1.01) in patients on statins, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and β-blockers, respectively. For patients on dual antiplatelet therapy followed for 1 year, the hazard ratio was 0.90 (0.74–1.08).

Conclusions: The results indicate long-term beneficial effects of treatment with statins and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers on outcome in patients with MINOCA, a trend toward a positive effect of β-blocker treatment, and a neutral effect of dual antiplatelet therapy. Properly powered randomized clinical trials to confirm these results are warranted.

Introduction

Editorial, see p 1490

It is increasingly recognized that a group of patients diagnosed with myocardial infarction (MI) have no angiographically obstructive (≥50% diameter stenosis) coronary artery disease (CAD) and the term myocardial infarction with nonobstructive coronary arteries (MINOCA) has been coined for this entity.1,2 MINOCA occurs in 5% to 10% of all patients with acute MI and these patients are younger and more often women in comparison with patients with MI and obstructive CAD.3,4 The underlying pathophysiological mechanisms are poorly understood, although several different mechanisms have been proposed, including plaque disruption, spasm, thromboembolism, dissection, microvascular dysfunction, ischemic myocardial injury attributable to supply/demand mismatch, and clinically nondetected myocarditis or Takotsubo cardiomyopathy.2,5 The effects of secondary preventive treatments proven beneficial in patients with classical type 1 MI are unknown in MINOCA patients; randomized clinical trials, and large observational studies, as well, evaluating different treatments in MINOCA patients do not exist. Hence, evidence-based guidelines for treatment of MINOCA are lacking. Elucidating the associations between different treatments and outcome may also increase the understanding of underlying mechanisms of MINOCA.

All patients in Sweden with MI, in whom coronary angiography is performed, are registered in the SWEDEHEART registry (Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapy).6,7 By merging data from the SWEDEHEART registry with data from the mandatory National Board of Health and Welfare’s Cause of Death Register and National Patient Register, we have the unique possibility of long-term follow-up regarding mortality and morbidity in a large number of patients with MINOCA.

Therefore, we aimed to examine the associations between treatment with dual antiplatelet therapy (DAPT), statins, renin-angiotensin system blockers (angiotensin-converting enzyme inhibitors [ACEIs]/angiotensin receptor blockers [ARBs]), β-blockers, and long-term cardiovascular events.

Methods

Patients

We identified 9466 unique patients with MINOCA among the 199 162 acute MI admissions recorded in the SWEDEHEART registry between July 1, 2003, and June 30, 2013. Patients were identified as having MINOCA if the discharge diagnosis was acute MI (International Classification of Diseases, 10th Revision code: I21-I22) and a coronary angiography performed during the index hospitalization did not show a stenosis of ≥50%. Because very early deaths are less likely to be preventable by secondary preventive treatments and, conversely, a terminal condition may be the reason to abstain initiation of secondary preventive treatment, we excluded the 330 patients who died within 30 days after discharge. Hence, the study cohort in the present study contained of 9136 patients with MINOCA who had survived the first 30 days after discharge (Figure 1).

Figure 1.
Figure 1.

Study population. AMI indicates acute myocardial infarction; CAD, coronary artery disease; and MINOCA, myocardial infarction with nonobstructive coronary arteries.

Primary and Secondary End Points

The primary end point was major adverse cardiac events (MACE) defined as all-cause mortality, hospitalization for MI, ischemic stroke, and heart failure. Secondary end points were the individual components of the primary end point and, in addition, cardiovascular mortality and hospitalization for a bleeding event. For definition of the end points, see online-only Data Supplement Table I for list of International Classification of Diseases, 10th Revision codes.

Follow-Up

Follow-up data were available by merging data from the mandatory Swedish Cause of Death Register and the National Patient Register (containing data including International Classification of Diseases, 10th Revision codes on all hospital admissions in Sweden) with SWEDEHEART. The merging was performed at the National Board of Health and Welfare in Sweden based on the personal identification number that all Swedish citizens and all permanent residents of Sweden have. Patients were followed for events occurring from 30 days after discharge date to occurrence of death or until December 31, 2013, with a mean follow-up of 4.1 years. For statins, β-blockers, and ACEI/ARBs, the analysis of the association between the respective treatment and outcome was based on the entire follow-up period. However, for DAPT, the analysis was based on 1-year follow-up because the guideline recommendation during the study period for the duration of DAPT after MI was up to 1 year,8 and few patients continue on DAPT thereafter.

The SWEDEHEART registry contains data on baseline characteristics, ECG changes, biochemical markers, coronary angiography results, medical and invasive treatment and outcome (see the SWEDEHEART registry7 for details).

To ensure the quality of the data entered into the database, a monitor visit is performed at each hospital every second year. Over the years, there has been a >95% agreement between data in the registry and in the patients’ records.6

According to Swedish law, all patients must be informed about their participation in the registry and the right to get their data erased from the registry on request. The study was approved by the Regional Ethical Review Board in Stockholm (2012/60-31/2).

Statistics

The statistical methods are described in detail in the online-only Data Supplement Statistical Methods. In summary, categorical variables are presented as frequency values and compared by χ2 tests. Continuous variables are presented as mean±standard deviation. Multiple imputation of missing values of smoking, plasma creatinine, and treatment at admission with ACEI or ARB was performed. A stratified propensity score (PS) analysis was performed to match treated and untreated groups for each separate treatment. Relevant covariates (n=26) were entered into a multivariable logistic regression model for each evaluated treatment (see online-only Data Supplement Table II). The predicted probability derived from the logistic regression equation was used as the PS for each individual. Subjects were then ranked according to their estimated PS. Areas at the extremes of the PS histograms with visually no or very little overlap in PSs between treated and nontreated was removed9 (see online-only Data Supplement Figure I) and then 4 equal-size strata were formed, using the quartiles of the estimated PSs. Within each stratum, the association between treatment and outcome was estimated by comparing treated and untreated subjects using Cox proportional hazards models with adjustment for discharge medications. The stratum-specific estimates of hazard ratios (HRs) were pooled across strata to estimate an overall association by using a fixed-effects model. Results are presented as HRs and 95% confidence intervals (CIs) by strata and overall. Pooled HRs were calculated in the total study population and in subgroups based on age and sex. In a post hoc analysis regarding the association between ACEI/ARB and MACE in patients with available echocardiographic data, we included left ventricular ejection fraction in the Cox proportional hazards model. In addition, we estimated the associations between the different treatments and outcome using 1:1 PS matching. We also used the 1:1 matched populations for producing survival curves regarding MACE for treated and nontreated patients by using the Kaplan-Meier method.

All analyses were performed using SAS Software Version 9.4 (SAS Institute) and R (version 3.2.2).

Results

The clinical characteristics and medication at admission of the 9136 patients with MINOCA are shown in Table 1; the mean age was 65.6 (standard deviation 11.5) years, and 61% were women. At discharge, 83.4%, 64.1%, 84.5%, and 66.4% of the patients were on β-blockers, ACEI/ARB, statins, and DAPT, respectively. During the follow-up of a mean of 4.1 years, 2183 (23.9%) patients experienced a MACE, 1222 (13.4%) patients died, 648 (7.1%) had a MI, 389 (4.3%) had an ischemic stroke, and 587 (6.4%) were hospitalized with congestive heart failure. Of the deaths, only 526 (43.0%) were classified as cardiovascular deaths. In addition, 326 (3.6%) patients were hospitalized with a bleeding event.

View this table:
Table 1.

Baseline Characteristics, Medications at Admission, and Medication at Discharge

Associations Between Treatments and Outcomes in the Stratified PS-Matched Population

Clinical characteristics between those with and without treatment were well balanced in the 4 PS strata (online-only Data Supplement Tables III through VI). The association of the different treatments and MACE and the individual components of MACE, respectively, are shown in Table 2 and online-only Data Supplement Figure II. The risk of experiencing a MACE was 18% lower (HR, 0.82; 95% CI, 0.73–0.93) in patients with ACEI/ARB in comparison with no ACEI/ARB; and 23% lower (HR, 0.77; 95% CI, 0.68–0.87) in patients with statins in comparison with no statins. In patients on β-blockers in comparison with patients not using β-blockers, there was a 14% reduction in MACE (HR, 0.86; 95% CI, 0.74–1.01). For patients on DAPT in comparison with without DAPT, there was a nonsignificant 10% lower risk of MACE (HR, 0.90; 95% CI, 0.74–1.08) during the first year after discharge and a nonsignificant 33% higher risk of hospitalization for a bleeding event (HR, 1.33; 95% CI, 0.73–2.42).

View this table:
Table 2.

Outcomes

The associations between the different treatments and MACE were consistent across subgroups based on sex and age, with the exception of a significant interaction (P=0.002) between ACI/ARB treatment and age (Table 3).

View this table:
Table 3.

Subgroups

Kaplan-Meier curves of survival free of MACE in the 1:1 PS-matched populations are shown for the 4 treatments in Figure 2.

Figure 2.
Figure 2.

Survival curves for treated and untreated in the 1:1 propensity score–matched populations. A, Statins. B, angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). C, β-blockers. D, Dual antiplatelet treatment.

Sensitivity Analysis

We performed a number of sensitivity analyses. First, analyses of the association between treatment and MACE in PS-matched 1:1 pairs gave similar point estimates for the HRs as in the main analyses (online-only Data Supplement Table VII). Second, we did a separate analysis of the association between ACEI/ARB and MACE in the patients with available data on left ventricular ejection fraction (n=4684). The inclusion of left ventricular ejection fraction in the Cox proportional hazards model lowered the HR somewhat in comparison with the model without the left ventricular ejection fraction (HR, 0.75; 95% CI, 0.64–0.88 versus HR, 0.82; 95% CI, 0.73–0.93). Third, as expected, there was no significant association between treatment and bleeding complications with HRs close to 1 in those treatments not expected to influence bleeding: statins (HR, 0.99; 95% CI, 0.70–1.39), ACEI/ARB (HR, 1.04; 95% CI, 0.75–1.43), and β-blockers (HR, 0.92; 95% CI, 0.63–1.35) (Table 2).

Discussion

The present study is the first study to evaluate the association between commonly used secondary prevention treatments and long-term outcome in a large cohort of unselected patients with MINOCA. Among 9136 consecutive MINOCA patients admitted to a cardiac unit in Sweden between 2003 and 2013 and followed for a mean of 4.1 years we can report a significantly 23% and 18% lower adjusted risk of MACE in patients treated with statins and ACEI/ARB, respectively. For treatment with β-blockers, there was a 14% reduction in MACE, not reaching statistical significance. In contrast, DAPT treatment was not associated with a significantly lower risk of MACE during 1-year follow-up.

MI With Nonobstructive Coronary Arteries

With the widespread use of coronary angiography in the management of acute MI there has been an increasing awareness that a proportion of MI patients have no evidence of significant obstructions of the coronary arteries. A systematic review of the literature4 estimated the prevalence of MINOCA to be 6% among patients diagnosed with MI, which is close to the prevalence of 8.0% in the present SWEDEHEART registry cohort.

Although patients with MINOCA seem to have a better short- and long-term prognosis than patients with MI with significant CAD,4 the rate of long-term serious cardiovascular events is not trivial, especially considering that MINOCA patients are younger and have fewer comorbidities.3,4,10 The 4-year mortality of ≈13% in the present study is in line with the 3.5% 1-year mortality found in the systematic review by Pasupathy et al4 and the 3.3% 1-year mortality in a French registry study.11 The lower use of long-term secondary prevention treatments in the MINOCA patients in the present SWEDEHEART cohort is also consistent with what previously has been described.10 Given this consistency with data from the literature and the large unselected population from a whole nation, the present study cohort seems representative for the general MINOCA population.

Association Between Treatments and Outcome

The association between treatment with statins and outcome in the present study is in line with the consistent results of statin treatment in secondary and in primary prevention randomized controlled trials (RCTs), as well.12 The effect size on MACE in the present study are also comparable to the effect size seen in these RCTs.12 Probable mechanisms explaining the effect of statins are slowing of the progress of atherosclerotic lesions and stabilizing of plaques, especially in those MINOCA patients with minor, nonsignificant CAD, because plaque ruptures causing MI may also occur from nonsignificant plaques.13 In addition, the protective effects on endothelial function14 may be a possible mechanism of the positive effects in MINOCA patients. There is strong evidence for the use of renin-angiotensin system blockers (ACEI/ARB) in patients with MI and heart failure and depressed left ventricular function.15–17 Also, in patients with CAD and absence of heart failure or depressed left ventricular function, ACEI treatment has shown beneficial effects on mortality, and morbidity, as well, in a meta-analysis of RCTs.18 Suggested mechanisms for the positive effects in the latter group are blood pressure–lowering effect, sympathoinhibitory effects, effects on the endothelial function, and antifibrotic effects on the myocardium,17,19 all of which may also be of relevance in MINOCA patients and may explain the association between ACEI/ARB treatment in the present study.

There is experimental evidence that increased sympathetic activation is of importance for the occurrence of cardiovascular events, and therefore β-blocker treatment after MI would be beneficial.19 However, there is a lack of contemporary RCTs evaluating β-blocker treatment in MI patients, and in MINOCA patients, as well. International guidelines differ in their recommendations about the use of β-blockers after acute MI; American guidelines recommend routine treatment with β-blockers,20 whereas European guidelines restrict the recommendation to patients with heart failure or left ventricular systolic dysfunction.21 In MINOCA patients, some authorities recommend treatment with β-blockers, mostly based on theoretical considerations.22 Observational studies in post-MI patients and in patients with Takotsubo cardiomyopathy have failed to show long-term beneficial effects of β-blocker treatment on cardiovascular events.23–25 Also, in the present study of MINOCA patients, we were not able to show a significantly reduced occurrence of MACE in patients on β-blockers. However, β-blocker treatment, unlike the 3 other studied treatments, was associated with a significantly decreased adjusted risk for MI (Table 2).

DAPT decreases the risk of cardiac events after acute MI26,27 and is recommended for up to a year in current guidelines.21 During the time of the present study, DAPT in Sweden consisted almost exclusively of a combination of aspirin 75 mg once daily and clopidogrel 75 mg once daily, and the recommended length of treatment after acute MI varied greatly from 3 months up to a maximum of 1 year at different hospitals. It is rather unlikely that DAPT would have lasting effects after the patient has stopped taking the treatment. Hence, we chose a 1-year follow-up period for the evaluation of DAPT treatment. We could not show a significant association between DAPT and MACE, and in the 1:1 propensity-matched population the survival curves in the Kaplan-Meier analysis were superimposed during the 1-year follow-up. There was no significant association with new MIs, which should be the primary effect of DAPT.26 However, there was not a significantly higher risk of bleeding events during follow-up. Taken together, our findings question the hypothesis that transient thrombus formation overlying a plaque rupture or erosion is a common cause of MINOCA. However, our findings must be interpreted cautiously, because the CI was rather wide and the exact duration of DAPT in the individual patient is not known.

Limitations

A number of inherent limitations in observational studies also apply to this study. First, residual confounding can never be fully excluded. However, we have used PS matching to minimize the risk of residual confounding and have performed several sensitivity analyzes indicating that the PS matching was successful in making the groups with and without respective treatment comparable. Nevertheless, our findings should be verified in randomized clinical trials. Second, in a quality registry like SWEDEHEART there will always be some missing data and the quality of data are not as high as in a properly monitored RCT. However, the rates of missing data on key variables in the present study were low and the accuracy of the data in SWEDEHEART has been found to be high.6 Because of the unique Swedish personal identification number and the mandatory health registries managed by the National Board of Health and Welfare we had complete follow-up in all patients. In Sweden, the diagnoses of MI, stroke, and heart failure have all been shown to have high validity.28–30 Third, the data available in SWEDEHEART do not permit separation of the patients into those without any signs of atherosclerotic lesions and those with signs of atherosclerotic lesions but no stenosis of ≥50% on the coronary angiogram. Studies have indicated that these subgroups constitute ≈50% each of the MINOCA population.3 Furthermore, because all coronary angiographies were performed in clinical routine and the evaluations of the angiograms were done locally at each hospital, there might be a proportion of the patients in the present study that would have been deemed to have significant stenosis and thus not MINOCA or vice versa, if all angiograms had been evaluated at a core laboratory. Fourth, we only counted events occurring ≥30 days after discharge, and there were 2 reasons for that: During the first 30 days it is not possible to separate a new MI from a second hospitalization for the index MI in the National Patient Register; and it is also unlikely that the evaluated treatments have large immediate protective effects (except for DAPT) and that events occurring the first few weeks more closely reflect the seriousness of the index infarct. Fifth, we lack information on the long-term adherence to the discharge medications in the present study. However, data from the secondary prevention part of the SWEDEHEART registry indicate that the adherence to secondary prevention treatment the first year after MI in Sweden is high.31 Sixth, MINOCA patients constitute a heterogeneous group. We have no information in the registry on whether further examinations were performed after the hospitalization, eg, MRI looking for evidence of myocarditis that was not recognized clinically. In studies of MINOCA patients evaluated with late-enhancement MRI, approximately one-third had signs of myocarditis.4 Ideally, it would have been preferable to be able to exclude patients with MRI-proven myocarditis. There might also be some cases of Takotsubo cardiomyopathy in the cohort, especially during the first years of the study period where the awareness of the diagnosis of Takotsubo was limited. Nevertheless, from a pragmatic point of view, we think the study population is appropriate, because these are the patients the clinicians meet in clinical routine and for whom they have to make decisions regarding secondary prevention treatments.

Conclusions

The results of this large observational study in patients with MINOCA indicate long-term beneficial effects on outcome of treatment with statins and ACEI/ARBs and possibly of β-blockers, but no benefit of DAPT. Despite the careful statistical methodology, some residual confounding cannot be excluded. Therefore, properly designed and powered randomized clinical trials to confirm these results are warranted.

Acknowledgments

Dr Lindahl had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Editorial support was provided by Emma Sandberg, Uppsala Clinical Research Center, Uppsala, Sweden.

Sources of Funding

This study was supported by grant from the Swedish Foundation for Strategic Research. The SWEDEHEART registry is supported by the Swedish Society of Cardiology, the Swedish Society of Thoracic Radiology, the Swedish Society of Thoracic Surgery, and the Swedish Heart Association. The registry is financed by the government and the Swedish Association of Local Authorities and Regions (SALAR). The Swedish Foundation for Strategic Research had no role in the design of the study; collection, management, analysis, and interpretation of the data; preparation, review, or decision to submit the manuscript for publication.

Disclosures

Drs Lindahl, Baron, Erlinge, Hadziosmanovic, Nordenskjöld, and Gard have no conflict of interests in relation to the present study. Dr Jernberg received modest lecture and consultancy/advisory board fees from AstraZeneca, Aspen, Amgen, and MSD.

Footnotes

  • Received November 8, 2016.
  • Accepted January 31, 2017.

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Clinical Perspective

What Is New?

  • This is the first study evaluating secondary prevention treatments in a large group of patients with myocardial infarction with nonobstructive coronary arteries.

  • Patients treated with statins and renin-angiotensin system blockers had a significantly 23% and 18% lower risk of a major adverse cardiac event during follow-up.

  • In contrast, there were no significant reductions in risk of major adverse cardiac events after treatment with β-blockers and dual antiplatelet therapy.

What Are the Clinical Implications?

  • The results indicate that long-term treatment with statins and renin-angiotensin system blockers may be beneficial in patients with myocardial infarction with nonobstructive coronary arteries.

  • Treatment with β-blockers and dual antiplatelet therapy seem less likely to reduce the risk of new cardiovascular events in patients with myocardial infarction with nonobstructive coronary arteries.

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  • Medical Therapy for Secondary Prevention and Long-Term Outcome in Patients With Myocardial Infarction With Nonobstructive Coronary Artery DiseaseClinical Perspective
    Bertil Lindahl, Tomasz Baron, David Erlinge, Nermin Hadziosmanovic, Anna Nordenskjöld, Anton Gard and Tomas Jernberg
    Circulation. 2017;135:1481-1489, originally published February 8, 2017
    https://doi.org/10.1161/CIRCULATIONAHA.116.026336
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