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Myocardial Infarction with Nonobstructive Coronary Arteries: The Importance of Achieving Secondary Prevention Targets
Accepted Manuscript Title: Myocardial Infarction with Non-Obstructive Coronary Arteries – the Importance of Achieving Secondary Prevention Targets Author: K.M. Eggers, N. Hadziosmanovic, T. Baron, K. Hambraeus, T. Jernberg, A. Nordenskjöld, P. Tornvall, B. Lindahl PII: DOI: Reference:
S0002-9343(17)31288-3 https://doi.org/10.1016/j.amjmed.2017.12.008 AJM 14439
To appear in:
The American Journal of Medicine
Please cite this article as: K.M. Eggers, N. Hadziosmanovic, T. Baron, K. Hambraeus, T. Jernberg, A. Nordenskjöld, P. Tornvall, B. Lindahl, Myocardial Infarction with Non-Obstructive Coronary Arteries – the Importance of Achieving Secondary Prevention Targets, The American Journal of Medicine (2017), https://doi.org/10.1016/j.amjmed.2017.12.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
CLINICAL RESEARCH STUDY
Myocardial infarction with non-obstructive coronary arteries – The importance of achieving secondary prevention targets
Eggers KM, MD, PhD a), Hadziosmanovic N, MSc a), Baron T, MD, PhD a), Hambraeus K, MD, PhD b), Jernberg T, MD, PhD c), Nordenskjöld A, MD, PhD d), Tornvall P, MD, PhD e), Lindahl B, MD, PhD a) a)
Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, 751 85 Uppsala, Sweden
b) c)
Department of Cardiology, Falun Hospital, Lasarettsvägen 10, 791 82 Falun, Sweden
Department of Clinical Sciences, Cardiology, Danderyd Hospital, Karolinska Institute, Mörbygårdsvägen 88, 182 88 Danderyd, Sweden
d)
Faculty of Health, Department of Cardiology, Örebro University, Södra Grev Rosengatan 701 85 Örebro, Sweden e)
Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Sjukhusbacken 10, 118 83 Stockholm, Sweden
Running title: Secondary prevention after myocardial infarction
We verify that all authors had access to the data and a role in writing the manuscript
Address for correspondence: Kai M Eggers Department of Medical Sciences, Cardiology Uppsala University 751 85 Uppsala, Sweden Tel: +46-18-611 00 00 Fax: +46-18-50 66 38 e-mail: [email protected] 1 Page 1 of 40
Clinical significance
Totally 9.6% of myocardial infarction patients had non-obstructive coronary arteries.
Low lipid levels are associated with 24-32% risk reduction in these patients.
Exercise training is associated with 10-23% risk reduction in these patients.
Abstract
Background
Around 5-10% of all myocardial infarction patients have non-obstructive coronary arteries. Studies investigating the importance of follow-up and achievement of conventional secondary prevention targets in these patients are lacking.
Methods
In this analysis from the SWEDEHEART registry, we investigated 5830 myocardial infarction patients with non-obstructive coronary arteries (group 1) and 54,637 myocardial infarction patients with significant coronary artery disease (≥50% stenosis; group 2). Multivariable- and propensity score-adjusted statistics were used to assess the reduction in the one-year risk of major adverse events associated with prespecified secondary preventive measures: participation in follow-up at 6-10 weeks after the hospitalization; achievement of secondary prevention targets (blood pressure and low-density lipoprotein cholesterol levels in the target ranges, non-smoking, participation in exercise training).
Results 2 Page 2 of 40
Patients in group 1 were less often followed up compared to patients in group 2 and less often achieved any of the secondary prevention targets. Participation in the 6-10 week follow-up was associated with a 3-20% risk reduction in group 1, similar as for group 2 according to interaction analysis. The improvement in outcome in group 1 was mainly mediated by achieving target range low-density lipoprotein cholesterol levels (24-32% risk reduction) and, to a smaller extent, by participation in exercise training (10-23% risk reduction).
Conclusions
Selected secondary preventive measures are associated with prognostic benefit in myocardial infarction patients with non-obstructive coronary arteries, in particular achieving target range low-density lipoprotein cholesterol levels. Our results indicate that these patients should receive similar follow-up as myocardial infarction patients with significant coronary stenoses.
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Keywords: Myocardial infarction; Myocardial infarction with non-obstructive coronary arteries; Follow-up; Secondary prevention; Prognosis
Introduction
About 5-10% of all patients diagnosed with myocardial infarction do not have significant (>50%) coronary stenoses [1-3]. For these patients, the term myocardial infarction with nonobstructive coronary arteries is used. This condition may be the result of various etiologies including plaque disruption, spasm, thromboembolism, dissection, microvascular dysfunction, myocardial injury due to supply/demand mismatch, clinically nondetected myocarditis or takotsubo syndrome [1-4]. Myocardial infarction with non-obstructive coronary arteries is thus, a heterogeneous disease state. Its importance has been emphasized in the 2017 European guidelines on the management of ST-segment elevation myocardial infarction [5]. Data on optimal clinical management however, are lacking although position papers have been published [2, 3].
Recent findings from the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) registry suggest that treatment with cardioprotective medications, i.e. statins and renin-angiotensin-aldosterone system-inhibitors, may exert prognostic benefit in myocardial infarction with non-obstructive coronary arteries [6]. It is however, not clear whether and how these patients should be followed up after the acute event and if they should be targeted to secondary preventive measures similar as myocardial infarction patients having
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significant coronary artery disease. Observational studies or randomized clinical trials investigating this important issue do not exist.
According to clinical routines in Sweden, myocardial infarction patients aged below 75 years are scheduled for a follow-up contact at 6-10 weeks after hospital discharge. Clinical data from this follow-up are collected in the nationwide Secondary Prevention after Heart Intensive care Admission (SEPHIA) registry which is a subregistry to SWEDEHEART. The availability of these data provides a unique opportunity to investigate the possible prognostic benefit of secondary preventive measures in myocardial infarction patients with nonobstructive coronary arteries. The primary objective of the present study was to examine whether participation in the 6-10 week follow-up and achieving prespecified secondary prevention targets would modify outcome in these patients. A secondary objective was to compare the potential prognostic benefits achieved by secondary preventive measures between myocardial infarction patients with non-obstructive coronary arteries and those with significant coronary artery disease.
Materials and Methods
Study population
This study is a part of the TOTAL-AMI (Tailoring Of Treatment in All comers with Acute Myocardial Infarction) project. The primary aim of TOTAL-AMI is to investigate the mechanisms and implications of different myocardial infarction subtypes [7] and of comorbidities (e.g. chronic obstructive pulmonary disease, atrial fibrillation, renal
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dysfunction) in myocardial infarction. TOTAL-AMI uses data from SWEDEHEART which is a nationwide registry enrolling consecutive patients admitted to Swedish coronary care units or other specialized facilities because of suspected acute coronary syndrome. SWEDEHEART prospectively collects information on >100 variables. On admission, patients receive written information about the registry, and have the right to deny participation and get their data erased upon request.
The population for the present study included all patients <75 years with a clinical diagnosis of myocardial infarction, admitted between January 2005 and August 2013. Myocardial infarction patients in whom coronary angiography results had not been recorded in SWEDEHEART were not considered. To fulfil the study criteria for myocardial infarction with non-obstructive coronary arteries (group 1), patients were required to have normal or near-normal coronary arteries (<50% stenosis), not to have undergone percutaneous coronary intervention during the hospitalization and to be free from a history of myocardial infarction or coronary intervention. Myocardial infarction patients with ≥50% coronary stenoses were regarded having significant coronary artery disease (group 2). To allow for comparisons of both cohorts on similar premises, patients from group 2 were excluded in case of previous myocardial infarction or coronary intervention.
All data had been made anonymous before the statistical analyses. The study was conducted according to the principles of the Declaration of Helsinki and had been approved by the Regional Ethical Review Board in Stockholm (2012/60-31/2).
The SEPHIA registry
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Data on the management of myocardial infarction patients in the rehabilitation phase after hospital discharge are collected in SEPHIA. This registry started in 2005, and 65 out of 73 Swedish hospitals participated in 2013. Data is collected at two follow-up occasions scheduled at 6-10 weeks and 1 year after the infarction, consisting of an outpatient visit or a phone call by a nurse or a physician. Upon each follow-up, information on cardiac symptoms, physical status, blood tests, medication, smoking habits, levels of physical activity, participation in a cardiac rehabilitation programme and clinical events is obtained. In the case of a follow-up phone call, results from blood tests and blood pressure measurements can be obtained from the patient’s primary health care facility.
Investigated secondary preventive measures
We investigated outcome prediction in relation to the following secondary preventive measures: participation in the 6-10 week follow-up; achievement of any of the following secondary prevention targets as reported in SEPHIA: systolic blood pressure <140 mmHg, low-density lipoprotein cholesterol levels in the target range (<2.5 mmol/L until 2012, thereafter <1.8 mmol/L), self-reported non-smoking including the proportion of smokers who had stopped smoking and participation in exercise training within a cardiac rehabilitation programme.
Prognostic evaluation
Information on patient outcome was obtained by merging data from SWEDEHEART with data from the mandatory Swedish Patient Registry (hospitalization dates and discharge diagnoses based on International Classification of Diseases, 10th revision, Clinical
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Modification [ICD-10-CM] codes) and the Swedish Cause of Death Registry, both held by the Swedish Board of Health and Welfare. Patients were followed for events until occurrence of death or December 31st, 2013.
The main outcome for this analysis was major adverse events, defined as the composite of all-cause mortality, non-fatal myocardial infarction (ICD-10-CM code I21), hospitalization for heart failure (ICD-10-CM code I50) or ischemic stroke (ICD-10-CM code I63). Only events occurring after the follow-up visit at 6-10 weeks were counted. For patients not participating in the 6-10 week follow-up, a fictive follow-up date at 61 days from hospital admission was anticipated. This corresponds to the mean period from the index infarction (61±15 days) at which follow-up took place in those who participated.
Statistical analysis
All continuous variables were skewed and are reported as medians with 25th and 75th percentiles. Differences in continuous variables were assessed using the Mann-Whitney Utest. Categorical variables are expressed as frequencies and percentages with differences being analyzed with the 2 test.
Cox regression models were used to investigate the associations of secondary preventive measures with outcome. Covariates included admission year, age, sex, current smoking, hypertension, diabetes, previous heart failure, previous stroke, ST-segment changes, estimated glomerular filtration rate, chronic obstructive pulmonary disease, dementia, previous or present cancer, peripheral vascular disease and in-hospital coronary revascularization, if appropriate. In addition, adjustment was made for hospital as a random effect in a mixed
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model. All continuous variables were ln-transformed to achieve normality. For comparative analyses between group 1 and 2, interaction terms were added to the fully adjusted models.
As a sensitivity analysis, significant multivariable associations between secondary preventive measures and major adverse events were re-assessed using 1:1 propensity scorematching of myocardial infarction patients with non-obstructive coronary arteries who did or did not achieve the target of the respective measure. The propensity score for each patient was computed from the predicted probabilities derived from logistic regression equations. Relevant covariates included variables assumed to affect the likelihood of achieving of any secondary prevention target (Supplemental Table 1). Due to partly small sample sizes, multiple imputation sets were created to handle missing data when constructing the propensity scores. In addition, Kaplan Meier curves regarding the incidence of major adverse events were computed applying a landmark design.
In all tests, a two-sided p-value <0.05 was considered significant. The software packages SPSS 21.0 (SPSS Inc., Chicago, IL), SAS Software 9.4. (SAS Institute, Cary, NC) and R 3.2.2 (R Foundation for Statistical Computing, Vienna, Austria) were used for the statistical analyses.
Results
Clinical characteristics and achievement rates of secondary prevention targets
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The study cohort consisted of 60,467 patients following exclusions (Supplemental Figure 1). Group 1 (myocardial infarction patients with non-obstructive coronary arteries) consisted of 5830 (9.6%) patients and 2907 (49.9%) of these participated in the 6-10 week follow-up. This was a patient visit in 2111 (72.6%) patients and a phone call in all other patients. The proportion of patients in group 1 who were followed up at 6-10 weeks tended to increase until 2009 with a slight decrease during the following years (Figure 1). Patients from group 1 were less often followed up compared to patients from group 2 (myocardial infarction patients with significant coronary artery disease).
Patients from group 1 who participated in the 6-10 week follow-up had lower prevalence of diabetes, previous heart failure, chronic obstructive pulmonary disease and atrial fibrillation compared to those not participating, presented more often with ST-segment elevation, tended to have better left-ventricular ejection fraction and were more often discharged with cardiovascular medications apart from oral anticoagulants (Table 1). For all other clinical data, no significant differences existed between both groups. Compared to patients from group 2 who participated in the 6-10 week follow-up, patients from group 1 being followed up had overall lower prevalence of cardiovascular risk indicators including comorbidities, STsegment elevation and impaired left-ventricular ejection fraction (Supplemental Table 2).
Table 1 also presents data on the achievement rates of secondary prevention targets for patients from group 1. While >60% of these patients had a systolic blood pressure <140 mmHg upon 6-10 week follow-up and almost 70% had low-density lipoprotein cholesterol levels in the target range, only 54.2% of smokers had stopped smoking and only 32.0% had participated in exercise training. Overall, the achievement rates of secondary prevention targets tended to be lower compared to patients from group 2 (Supplemental Table 2).
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Prognostic evaluation
In total, 980 (16.8%) patients from group 1 suffered a major adverse event during the observation period starting after the 6-10 week follow-up (median 3.6 years). This was similar as for patients from group 2 (n=9034 [16.5%]; p=0.592 for comparison). Data on the individual outcomes in patients from both groups is presented in the Supplemental Table 3.
Patients from group 1 who participated in the 6-10 week follow-up had a significantly lower of major adverse event rate compared to those who did not participate (Table 2). In a multivariable-adjusted Cox model, participation in the 6-10 week follow-up was associated with a significant 20% risk reduction. The magnitude of risk reduction was similar as for patients from group 2, as indicated by the non-significant interaction term (Table 2; Supplemental Table 4).
Patients from group 1 who achieved any of the secondary prevention targets had numerically lower major adverse event rates compared to those in whom these targets were not reached (Table 2; Figure 2). In multivariable-adjusted Cox models, these differences were statistically significant for achieving low-density lipoprotein cholesterol levels in the target range (32% risk reduction) and participation in exercise training (23% risk reduction). The non-significant interaction terms indicated that the magnitudes of risk reduction were similar as for patients from group 2 (Table 2; Supplemental Table 4). The beneficial effect of low-
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density lipoprotein cholesterol levels in the target range in patients from group 1 was mediated by lower risks of cardiovascular mortality, non-fatal myocardial infarction and readmission for heart failure (Supplemental Table 5A). For exercise training, the reduction in risk in these patients was mediated by lower risks of all-cause mortality and cardiovascular mortality (Supplemental Table 5B).
Smoking cessation among was associated with a non-significant 6% risk reduction in patients from group 1following multivariable adjustment (Table 2). The magnitude of risk reduction tended to be smaller compared to patients from group 2 according to interaction analysis. Achieving the blood pressure target was not associated with a significant risk reduction in neither group (Table 2; Supplemental Table 4).
The results of the prespecified sensitivity analyses re-investigating significant multivariable associations between secondary preventive measures and major adverse events in group 1 are presented in the Supplemental Table 6 and Supplemental Figures 2A-C. Using 1:1 propensity score-matching attenuated the risk reduction associated with participation in the 6-10 week follow-up (3% risk reduction) and participation in exercise training (10% risk reduction). On the contrary, low-density lipoprotein cholesterol levels in the target range still were associated with a 24% risk reduction although this association became non-significant. Applying the subset of covariates used for the propensity score computation in a Cox model yielded similar risk estimates as in the main analyses (Supplemental Table 6).
Discussion
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Around 5-10% of all myocardial infarction patients have non-obstructive coronary arteries [1-3]. Data from observational studies and systematic reviews demonstrate that these patients are at increased risk for adverse outcome [4, 8, 9]. The importance of myocardial infarction with non-obstructive coronary arteries has been emphasized in the 2017 European guidelines on the management of ST-segment elevation myocardial infarction [5] but information on optimal management is still limited. This depends in part on the fact that this condition can be the result of various etiologies that may require different modes of management. This rather emphasizes the importance of well-defined routines for follow-up, an issue that up until now has not been investigated in a larger context.
We made several important observations in our registry-based cohort study investigating data from >5800 myocardial infarction patients with non-obstructive coronary arteries. Achieving low-density lipoprotein cholesterol levels in the target range was associated with a 24-32% reduction in the risk of major adverse events. This corresponds with recent findings from our group demonstrating that statin treatment in these patients is associated with improved outcome in [6]. Interestingly, the magnitude in risk reduction was similar in the present analysis as for myocardial infarction patients with significant coronary artery disease. We hypothesize that our findings at least in part may reflect statin-related stabilization of angiographically non-significant and thus, untreated coronary plaques. This is supported by retrospective analyses demonstrating type 1 infarction as the underlying cause in 20-25% of myocardial infarction patients with non-obstructive coronary arteries [3, 4, 10, 11]. In another study investigating a female cohort with myocardial infarction with non-obstructive coronary arteries using intravascular ultrasound, 38% of the participants were found to have unstable coronary lesions [12]. These data fit also with our finding of a lower risk of non-fatal myocardial infarction associated with target range low-density lipoprotein cholesterol levels.
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In addition, statin-related pleiotrophic effects on endothelial function and cardiac remodeling [13] may contribute to the positive effects of target range low-density lipoprotein cholesterol levels. Participation in exercise training within a cardiac rehabilitation programme was associated with a 10-23% risk reduction among myocardial infarction patients with non-obstructive coronary arteries, similar as for those having significant coronary artery disease. Physical exercise exerts positive effects on many cardiovascular risk factors, improves cardiac function, attenuates adverse myocardial remodeling and has been shown to reduce risk across a broad range of cardiovascular conditions [14-16]. Our results for the first time extend this notion to myocardial infarction patients with non-obstructive coronary arteries. The low participation rate in exercise training among these patients from our cohort however, is worrisome. Limitations in healthcare resources might represent a possible explanation as additional 215 patients participated after the 6-10 week follow-up. Given the design of our study, these patients were not considered for the analyses. Nonetheless, our data demonstrate that overcoming the barriers behind the underuse of cardiac rehabilitation likely will contribute to further improvement of outcome in myocardial infarction with non-obstructive coronary arteries.
Despite a substantial risk reduction, the effects of smoking cessation on outcome after myocardial infarction with non-obstructive coronary arteries did not reach levels of statistical significance. This might reflect limitations in statistical power given the rather small number of smokers among these patients.
Even achievement of a systolic blood pressure <140 mmHg was not associated with a significant risk reduction in myocardial infarction patients with non-obstructive coronary
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arteries. Accordingly, the previously reported benefit from a discharge medication with reninangiotensin-aldosterone system-inhibitors in these patients [6] seems primarily to be mediated by other effects than lowering of blood pressure, possibly mechanisms preventing adverse myocardial remodeling [17].
Our study has limitations that need to be considered. Although all hospitals participating in SWEDEHEART are annually monitored, the data cannot be of the same quality as in a prospective observational study. However, the agreement of the information entered in the registry with the medical records is around 96% [18]. The data available in SWEDEHEART do not permit separation of patients into those without angiographic signs of coronary lesions and those with signs of coronary lesions but no stenosis of ≥50%. Coronary angiographies were evaluated locally at each hospital and not at a core laboratory. We lack information on the results of examinations performed after the hospitalization period. Some myocardial infarction patients with non-obstructive coronary arteries may thus, have subsequently been diagnosed with myocarditis on the basis of cardiac magnetic resonance performed after hospital discharge. There might also be some cases of takotsubo syndrome in the cohort, especially during the first years of the study period where the awareness of this condition was limited. We cannot exclude survival bias as we lack information on whether patients suffering death early after hospital discharge had been scheduled for follow-up or not. Measurements of low-density lipoprotein cholesterol levels and blood pressure were not mandatory in SEPHIA until 2013. This resulted in missing data for these variables, about 23% for low-density lipoprotein cholesterol and 12% for systolic blood pressure. We did not investigate risk reduction in relation to the decrease in low-density lipoprotein cholesterol levels as management routines in the post-infarction setting primarily focus on target ranges. We cannot comment on risk reduction in relation to the type, intensity, frequency and length of
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exercise training as this information is not collected in SEPHIA. In any observational study such as ours, it is difficult to draw conclusions regarding causality. Moreover, we cannot exclude residual confounding due to unmeasured variables that might have influenced medical decisions in myocardial infarction patients with non-obstructive coronary arteries and generated selection bias. To minimize this risk, we conducted sensitivity analyses using 1:1 propensity score-matching. In these analyses, the associations of participation in the 6-10 week follow-up and physical exercise training with major adverse events weakened. This discrepancy might reflect differences in the statistical approach and/or limitations in power given the smaller number of observations. Nonetheless, the interaction analyses indicated that myocardial infarction patients with non-obstructive coronary arteries achieved similar prognostic benefit from these measures as patients with significant coronary artery disease. Moreover, the low participation rate in physical exercise training from discharge to 6-10 week follow-up rather underestimates the prognostic effect of this intervention. Finally, without a scheduled follow-up, it would be doubtful whether any of the above-mentioned secondary preventive measures would have been effectuated. Our results can thus, be viewed rather as an argument for than against a systematic and standardized follow-up of patients with myocardial infarction with non-obstructive coronary arteries.
Conclusions
Taken together, our findings emphasize the importance of structured follow-up routines in myocardial infarction patients with non-obstructive coronary arteries. Although this condition may be the result of different etiologies, our results demonstrate that much of the prognostic benefit of follow-up is associated with the modification of cardiovascular risk factors, in
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particular low-density lipoprotein cholesterol levels. We also want to stress the need of further investigation, preferably using cardiac magnetic resonance, for etiologic clarification [2, 3, 11]. This will help to identify patients with undetected myocarditis or true infarction who require specific treatments.
Conflicts of interest
None of the authors reported conflicts of interest relevant to this study.
Acknowledgements
The TOTAL-AMI project has received funding from the Swedish Foundation of Strategic Research. This organization had no role in the design of study, the collection and interpretation of the data, the preparation of the manuscript and the decision to submit it for publication.
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2. Pasupathy S, Tavella R, Beltrame JF. The What, When, Who, Why, How and Where of Myocardial Infarction With Non-Obstructive Coronary Arteries (MINOCA). Circ J 2016;80:11-6. doi: 10.1253/circj.CJ-15-1096.
3. 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;38:143-53. doi: 10.1093/eurheartj/ehw149.
4. Pasupathy S, Air T, Dreyer RP, et al. Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries. Circulation 2015; 131: 861-70. doi: 10.1161/CIRCULATIONAHA.114.011201. Erratum in: Circulation 2015;131:e475. doi: 10.1161/CIR.0000000000000212.
5. 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: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2017. doi: 10.1093/eurheartj/ehx393. [Epub ahead of print].
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7. Thygesen K, Alpert JS, Jaffe AS, et al. Third Universal Definition of Myocardial Infarction. Circulation 2012;126:2020-35. doi: 10.1161/CIR.0b013e31826e1058.
8. Aldous S, Elliott J, McClean D, et al. Outcomes in patients presenting with symptoms suggestive of acute coronary syndrome with elevated cardiac troponin but non-obstructive coronary disease on angiography. Heart Lung Circ 2015;24:869-78. doi: 10.1016/j.hlc.2015.02.019.
9. Baron T, Hambraeus K, Sundström J, et al. Impact on Long-Term Mortality of Presence of Obstructive Coronary Artery Disease and Classification of Myocardial Infarction. Am J Med 2016;129:398-406. doi: 10.1016/j.amjmed.2015.11.035.
10. 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;241:87-91. doi: 10.1016/j.atherosclerosis.2015.04.816.
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Figure legends.
Figure 1. Proportions of myocardial infarction patients with non-obstructive coronary arteries and significant coronary artery disease who participated in the 6-10 week follow-up.
White bars represent myocardial infarction patients with non-obstructive coronary arteries, grey bars represent myocardial infarction patients with significant coronary artery disease. The numbers of patients within each cohort are given at the bottom of the bars. P-values refer to comparisons between both groups.
Figure 2. Crude rates and adjusted risks of major adverse events in myocardial infarction patients with non-obstructive coronary arteries in relation to the number of achieved of secondary preventive targets.
The secondary prevention targets included systolic blood pressure <140 mmHg, low-density lipoprotein cholesterol levels in the target range, self-reported non-smoking and participation in exercise training within a cardiac rehabilitation programme.
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The numbers at the bottom of the bars indicate the total numbers of patients per category and those suffering a major adverse event.
The multivariable analyses were adjusted for hospital, admission year, age, sex, current smoking, hypertension, diabetes, congestive heart failure, previous stroke, ST-segment changes, estimated glomerular filtration rate, chronic obstructive pulmonary disease, dementia, previous or present cancer and peripheral vascular disease. Hazard ratios (HR) are given with 95% confidence intervals.
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Table 1. Clinical characteristics of myocardial infarction patients with non-obstructive coronary arteries who did or did not participate in the 6-10 week follow-up SEPHIA patients
Non-SEPHIA
p-value
Total
(n=2907)
patients (n=2993)
1167 (40.1%)
1165 (39.9%)
0.831
2332 (40.0%)
63 (55-69)
64 (56-70)
<0.001
63 (55-69)
Current smoking
620 (21.3%)
636 (21.9%)
0.610
1256 (21.6%)
Hypertension
1083 (37.3%)
1120 (38.4%)
0.358
2203 (37.8%)
Diabetes
272 (9.4%)
330 (11.3%)
0.016
602 (10.3%)
Hyperlipidemia
481 (16.5%)
495 (16.9%)
0.700
976 (16.7%)
Body mass index (kg/m2)
26.3 (23.7-29.4)
26.2 (23.5-29.7)
0.385
26.3 (23.6-29.6)
eGFR (mL/min)
82.3 (70.5-95.1)
82.3 (69.0-95.1)
0.879
82.3 (69.5-96.6)
Previous heart failure
55 (1.9%)
86 (3.0%)
0.008
141 (2.4%)
Previous stroke
119 (4.1%)
118 (4.4%)
0.690
237 (4.2%)
Peripheral vascular disease
37 (1.3%)
37 (1.3%)
1.000
74 (1.3%)
Previous or present cancer
37 (1.3%)
58 (2.0%)
0.038
95 (1.6%)
COPD
207 (7.1%)
261 (8.9%)
0.012
468 (8.0%)
3 (0.1%)
4 (0.1%)
1.000
7 (0.1%)
2696 (92.9%)
2597 (89.1%)
<0.001
5293 (91.0%)
Atrial fibrillation
158 (5.4%)
240 (8.2%)
<0.001
398 (6.8%)
ST-segment elevation
414 (14.3%)
389 (13.4%)
0.342
803 (13.8%)
Echocardiography
2437 (83.8%)
2358 (80.7%)
0.002
4795 (82.2%)
· ≥0.50
1879 (77.5%)
1669 (73.9%)
0.028
3548 (75.8%)
· 0.40-0.49
311 (12.8%)
320 (14.2%)
(n=5830)
Risk factors Males Age (years)
History
Dementia ECG findings Sinus rhythm
LVEF*
631 (13.5%)
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· 0.30-0.39
162 (6.7%)
178 (7.9%)
340 (7.3%)
· <0.30
73 (3.0%)
90 (4.0%)
163 (3.5%)
Aspirin
2692 (92.6%)
2562 (88.0%)
<0.001
5254 (90.3%)
P2Y12 blockers
2287 (78.7%)
1829 (62.6%)
<0.001
4116 (70.6%)
198 (6.8%)
256 (8.8%)
0.006
454 (7.8%)
Betablockers
2445 (84.1%)
2318 (79.3%)
<0.001
4763 (81.7%)
RAAS-inhibitors
1835 (63.1%)
1710 (58.5%)
<0.001
3545 (60.8%)
Statins
2641 (90.8%)
2325 (79.5%)
<0.001
4966 (85.2%)
Medication at discharge
Oral anticoagulants
Medication at 6-10 week follow-up Aspirin
2613 (89.9%)
-
-
-
P2Y12 blockers
1985 (68.3%)
-
-
-
235 (8.1%)
-
-
-
Betablockers
2386 (82.1%)
-
-
-
RAAS-inhibitors
1826 (62.8%)
-
-
-
Statins
2548 (87.7%)
-
-
-
Oral anticoagulants
Achievement of secondary prevention targets Not smoking
2598 (89.5%)
-
-
-
Smoking cessation†
336 (54.2%)
-
-
-
Systolic BP <140 mmHg
1597 (61.8%)
-
-
-
LDL-C in target range
1552 (69.3%)
-
-
-
Participation in exercise
859 (32.0%)
-
-
-
training
Data given as numbers (with percentages) or medians (with 25 th, 75th percentiles). Patients with missing data were excluded from the analyses.
*Available data: n=4682. †Assessed in patients who had been smokers at admission.
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eGFR: estimated glomerular filtration rate; COPD: chronic obstructive pulmonary disease; LVEF: leftventricular ejection fraction; RAAS: renin-angiotensin-aldosterone system; BP: blood pressure; LDL-C: lowdensity lipoprotein cholesterol.
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Table 2. Crude rates and adjusted risks of major adverse events in patients with myocardial infarction with non-obstructive coronary arteries in relation to the achievement of secondary preventive measures. Secondary preventive measure achieved Data
No
Yes
available Participation in the
5830 (100%)
6-10 week follow-up
589
391
(20.2%)
(13.5%)
p-
Adjusted HR
p-
p-
value
(95% CI)
value
value*
<0.001
0.80 (0.70-
0.001
0.059
0.92)
Achievement of secondary preventive targets in patients who participated in the 6-10 week follow-up Not smoking
2904
46 (15.0%)
(99.9%) Smoking cessation†
620 (100%)
344
0.376
(13.2%) 39 (13.7%)
44 (13.1%)
0.92 (0.61-
0.705
0.002
0.792
0.073
0.759
0.432
0.003
0.097
0.048
0.807
1.40) 0.814
0.94 (0.591.51)
Systolic BP <140
2586
151
190
(89.0%)
(15.3%)
(11.9%)
2239
110
173
(77.0%)
(16.0%)
(11.1%)
Participation in
2684
272
83 (9.7%)
exercise training
(92.3%)
(14.9%)
mmHg LDL-C in target range
0.017
1.04 (0.821.31)
0.002
0.68 (0.530.88)
<0.001
0.77 (0.601.00)
The multivariable analyses were adjusted for hospital, admission year, age, sex, current smoking, hypertension, diabetes, previous heart failure, previous stroke, ST-segment changes, estimated glomerular filtration rate, chronic obstructive pulmonary disease, dementia, previous or present cancer and peripheral vascular disease.
*p-value for the interaction of the myocardial infarction type on the association of the achievement of secondary preventive measures with major adverse events. Adjustment was made as outlined above and for in-hospital coronary revascularization.
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†Assessed in patients who had been smokers at admission.
HR: hazard ratio; CI: confidence interval; BP: blood pressure; LDL-C: low-density lipoprotein cholesterol.
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SUPPLEMENTAL MATERIAL Supplemental Table 1. List of covariates for the propensity score computations. Supplemental Table 2. Clinical characteristics of myocardial infarction patients with non-obstructive coronary arteries and with significant coronary artery disease who participated in the 6-10 week follow-up. Supplemental Table 3. Crude event rates in myocardial infarction patients with non-obstructive coronary arteries and with significant coronary artery disease. Supplemental Table 4. Crude rates and adjusted risks of major adverse events in myocardial infarction patients with significant coronary artery disease in relation to the achievement of secondary preventive measures. Supplemental Tables 5A-B. Crude event rates and adjusted risks in myocardial infarction patients with non-obstructive coronary arteries in relation to the achievement of selected secondary preventive targets. Supplemental Table 6. Sensitivity analysis with and without 1:1 propensity score-matching. Risks of major adverse events in myocardial infarction patients with non-obstructive coronary arteries in relation to the achievement of selected secondary preventive measures.
Supplemental Figure 1. Flowchart – Selection of patients. Supplemental Figures 2A-C. 1:1 propensity score-matched analyses. Event-free survival curves in relation to the achievement of selected secondary preventive measures. A) Participation in the 6-10 week follow-up; B) target range lowdensity lipoprotein cholesterol levelsin the target range; C) participation in exercise training.
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Supplemental Figure 1. Flowchart – Selection of patients.
MI: myocardial infarction; PCI: percutaneous coronary intervention; MINOCA: myocardial infarction with nonobstructive coronary arteries; MI-CAD: myocardial infarction with significant coronary artery disease.
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Supplemental Figures 2A-C. 1:1 propensity score-matched analyses. Event-free survival curves in relation to the achievement of selected secondary preventive measures. A) Participation in the 6-10 week follow-up; B) target range lowdensity lipoprotein cholesterol levels ; C) participation in exercise training. A)
B)
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C)
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Supplemental Table 1. List of covariates for the propensity score computations. -
County of residence Year of admission Age Sex Smoking Diabetes Hypertension Previous heart failure Previous stroke Atrial fibrillation Peripheral vascular disease Previous or present cancer Chronic obstructive pulmonary disease Dementia iv treatment with diuretics during admission
-
Discharge treatment with warfarin Occupation status Estimated glomerular filtration rate Left-ventricular ejection fraction Discharge treatment with acetylsalicylic acid Discharge treatment with other antiplatelets Discharge treatment with betablockers Discharge treatment with RAAS-inhibitors Discharge treatment with digitalis Discharge treatment with diuretics Discharge treatment with statins*
* not included in the computation of the propensity score regarding achievement of low-density lipoprotein cholesterol levels in the target range. RAAS: renin-angiotensin-aldosterone system.
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Supplemental Table 2. Clinical characteristics of myocardial infarction patients with non-onstructive coronary arteries and with significant coronary artery disease who participated in the 6-10 week follow-up. MINOCA (n=2907)
MI-CAD (n=30,403)
p-value
1167 (40.1%) 63 (55-69) 620 (21.3%) 1083 (37.3%) 272 (9.4%) 481 (16.5%) 26.3 (23.7-29.4) 82.3 (70.5-95.1)
23,216 (76.4%) 63 (56-68) 10,232 (33.7%) 11,746 (38.6%) 4122 (13.6%) 4611 (15.2%) 26.9 (24.7-29.8) 84.6 (72.4-98.1)
<0.001 0.710 <0.001 0.146 <0.001 0.048 <0.001 <0.001
55 (1.9%) 119 (4.1%) 37 (1.3%)
261 (0.9%) 1048 (3.5%) 546 (1.8%)
<0.001 0.070 0.042
37 (1.3%) 207 (7.1%) 3 (0.1%)
363 (1.2%) 1073 (3.5%) 13 (0.0%)
0.729 <0.001 0.159
ECG findings Sinus rhythm Atrial fibrillation ST-segment elevation
2696 (92.9%) 158 (5.4%) 414 (14.3%)
28,725 (94.6%) 1057 (3.5%) 13,322 (43.9%)
<0.001 <0.001 <0.001
Examination findings Coronary status · normal /near-normal · 1-2 vessel disease · LM/3 vessel disease
2907 (100%) -
319 (1.0%)* 24,139 (79.4%) 5945 (19.6%)
-
2437 (83.8%)
26,244 (86.3%)
<0.001
1879 (77.5%) 311 (12.8%) 162 (6.7%) 73 (3.0%)
16,884 (65.4%) 5443 (21.1%) 2801 (10.8%) 703 (2.7%)
<0.001
2692 (92.6%) 2287 (78.7%) 198 (6.8%) 2445 (84.1%) 1835 (63.1%) 2641 (90.8%)
29,699 (97.7%) 27,728 (91.2%) 1164 (3.8%) 28,226 (92.8%) 23,877 (78.5%) 29,574 (97.3%)
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001
Medication at 6-10 week follow-up Aspirin 2613 (89.9%) P2Y12 blockers 1985 (68.3%) Oral anticoagulants 235 (8.1%) Betablockers 2386 (82.1%) RAAS-inhibitors 1826 (62.8%) Statins 2548 (87.7%)
29,282 (96.3%) 26,656 (87.7%) 1452 (4.8%) 27,871 (91.7%) 24,074 (79.2%) 29,958 (95.9%)
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001
Achievement of secondary prevention targets Not smoking 2598 (89.5%) Smoking cessation‡ 336 (54.2%) Systolic BP <140 mmHg 1597 (61.8%) LDL-C in target range 1552 (69.3%) Participation in exercise 859 (32.0%) training
26,714 (88.0%) 6803 (66.6%) 17,375 (65.3%) 16,722 (71.0%) 9762 (34.4%)
0.022 <0.001 <0.001 0.088 0.013
Risk factors Males Age (years) Current smoking Hypertension Diabetes Hyperlipidemia 2 Body mass index (kg/m ) eGFR (mL/min) History Previous heart failure Previous stroke Peripheral vascular disease Previous or present cancer COPD Dementia
Echocardiography LVEF† · ≥0.50 · 0.40-0.49 · 0.30-0.39 · <0.30 Medication at discharge Aspirin P2Y12 blockers Oral anticoagulants Betablockers RAAS-inhibitors Statins
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th
th
Data given as numbers (with percentages) or medians (with 25 , 75 percentiles). Patients with missing data were excluded from the analyses. *Patients with normal/near-normal coronary findings who had undergone percutaneous coronary intervention during the hospitalization were counted as myocardial infarction with significant coronary artery disease. †Available data: n=28,256. ‡Assessed in patients who had been smokers at admission. MINOCA: myocardial infarction with non-obstructive coronary arteries; MI-CAD: myocardial infarction with significant coronary artery disease; eGFR: estimated glomerular filtration rate; COPD: chronic obstructive pulmonary disease; LM: left main; LVEF: left-ventricular ejection fraction; PCI: percutaneous coronary intervention; CABG: coronary artery bypass grafting; RAAS: renin-angiotensin-aldosterone system; BP: blood pressure; LDL-C: low-density lipoprotein cholesterol.
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Supplemental Table 3. Crude event rates in myocardial infarction patients with non-obstructive coronary arteries and with significant coronary artery disease. Outcome All-cause mortality Cardiovascular mortality Non-fatal MI Heart failure Stroke
MINOCA (n=5830)
MI-CAD (n=54,637)
p-value
481 (8.3%) 158 (2.7%) 291 (5.0%) 229 (3.9%) 171 (2.9%)
3930 (7.2%) 1706 (3.1%) 3688 (6.8%) 2051 (3.8%) 1373 (2.5%)
0.003 0.088 <0.001 0.517 0.053
MINOCA: myocardial infarction with non-obstructive coronary arteries; MI-CAD: myocardial infarction with significant coronary artery disease; MI: myocardial infarction.
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Supplemental Table 4. Crude rates and adjusted risks of major adverse events in myocardial infarction patients with significant coronary artery disease in relation to the achievement of secondary preventive measures. Secondary preventive measure achieved
Participation in the 6-10 week follow-up
Data available
No
Yes
pvalue
Adjusted HR (95% CI)
pvalue
54,150 (100%)
4945 (20.4%)
4089 (13.4%)
<0.001
0.87 (0.83-0.91)
<0.001
Achievement of secondary preventive targets in patients who participated in the 6-10 week follow-up Not smoking Smoking cessation* Systolic BP <140 mmHg LDL-C in target range Participation in exercise training
30,355 (99.8%) 10,219 (100%) 26,600 (87.5%)
677 (18.6%) 616 (18.0%) 1339 (14.5%)
3399 (12.7%) 833 (12.2%) 2090 (12.0%)
<0.001 <0.001 <0.001
0.63 (0.57-0.70) 0.65 (0.59-0.73) 1.03 (0.96-1.10)
<0.001 <0.001 0.483
23,540 (77.4%)
902 (13.2%)
2024 (12.1%)
0.018
0.89 (0.83-0.97)
0.006
28,376 (93.3%)
2693 (14.5%)
959 (9.8%)
<0.001
0.77 (0.71-0.83)
<0.001
The multivariable analyses were adjusted for hospital, admission year, age, sex, current smoking, hypertension, diabetes, previous heart failure, previous stroke, ST-segment changes, estimated glomerular filtration rate, chronic obstructive pulmonary disease, dementia, previous or present cancer, peripheral vascular disease and inhospital coronary revascularization. *Assessed in patients who had been smokers at admission. HR: hazard ratio; CI: confidence interval; BP: blood pressure; LDL-C: low-density lipoprotein cholesterol.
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Supplemental Tables 5A-B. Crude event rates and adjusted risks in myocardial infarction patients with non-obstructive coronary arteries in relation to the achievement of selected secondary preventive targets. Secondary preventive measure achieved
A) LDL-C in target range (n=2239) All-cause mortality Cardiovascular mortality Non-fatal MI Heart failure Ischemic stroke
No
Yes
pvalue
Adjusted HR (95% CI)
pvalue
42 (6.1%) 19 (2.8%) 40 (5.8%) 27 (3.9%) 25 (3.6%)
75 (4.8%) 17 (1.1%) 58 (3.7%) 40 (2.6%) 32 (2.1%)
0.217 0.006 0.033 0.106 0.040
0.77 (0.52-1.14) 0.33 (0.17-0.64) 0.61 (0.40-0.93) 0.55 (0.33-0.91) 0.68 (0.38-1.21)
0.196 0.001 0.020 0.021 0.186
Secondary preventive measure achieved
B) Participation in exercise training (n=2684)
No
Yes
pvalue
Adjusted HR (95% CI)
pvalue
All-cause mortality Cardiovascular mortality Non-fatal MI Heart failure Ischemic stroke
122 (6.7%) 39 (2.1%) 88 (4.8%) 67 (3.7%) 50 (2.7%)
22 (2.6%) 3 (0.3%) 34 (4.0%) 18 (2.1%) 16 (2.9%)
<0.001 <0.001 0.371 0.033 0.184
0.51 (0.32-0.82) 0.21 (0.06-0.69) 0.81 (0.53-1.23) 0.73 (0.42-1.26) 0.99 (0.56-1.78)
0.005 0.010 0.810 0.253 0.982
The multivariable analyses were adjusted for hospital, admission year, age, sex, current smoking, hypertension, diabetes, previous heart failure, previous stroke, ST-segment changes, estimated glomerular filtration rate, chronic obstructive pulmonary disease, dementia, previous or present cancer and peripheral vascular disease. *Assessed in patients who had been smokers at admission. HR: hazard ratio; CI: confidence interval; LDL-C: low-density lipoprotein cholesterol; MI: myocardial infarction.
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Supplemental Table 6. Sensitivity analysis with and without 1:1 propensity score-matching. Risks of major adverse events in myocardial infarction patients with non-obstructive coronary arteries in relation to the achievement of selected secondary preventive measures. 1:1 propensity score-matched Cox regression
Participation in the 6-10 week follow-up
Standard Cox regression
n
Adjusted HR (95% CI)
p-value
n
Adjusted HR (95% CI)
p-value
4340
0.97 (0.82-1.13)
0.660
4497
0.84 (0.72-0.98)
0.026
Achievement of secondary preventive targets in patients who participated in the 6-10 week follow-up LDL-C in the target range Participation in exercise training
1294 1660
0.76 (0.55-1.04) 0.90 (0.66-1.22)
0.083 0.486
1791 2171
0.69 (0.52-0.92) 0.82 (0.61-1.09)
0.011 0.166
Adjustment was made for the covariates listed in the Supplemental Table 1. HR: hazard ratio; CI: confidence interval; low-density lipoprotein cholesterol.
Data statement
We do not have permission to share the data used for the present analysis, neither in part nor in total (Regional Ethical Review Board in Stockholm [2012/60-31/2]).
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Figure 1_Pub_bestsetConverted.png
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Figure 2_Pub_bestsetConverted.png
40 Page 40 of 40
S0002-9343(17)31288-3 https://doi.org/10.1016/j.amjmed.2017.12.008 AJM 14439
To appear in:
The American Journal of Medicine
Please cite this article as: K.M. Eggers, N. Hadziosmanovic, T. Baron, K. Hambraeus, T. Jernberg, A. Nordenskjöld, P. Tornvall, B. Lindahl, Myocardial Infarction with Non-Obstructive Coronary Arteries – the Importance of Achieving Secondary Prevention Targets, The American Journal of Medicine (2017), https://doi.org/10.1016/j.amjmed.2017.12.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
CLINICAL RESEARCH STUDY
Myocardial infarction with non-obstructive coronary arteries – The importance of achieving secondary prevention targets
Eggers KM, MD, PhD a), Hadziosmanovic N, MSc a), Baron T, MD, PhD a), Hambraeus K, MD, PhD b), Jernberg T, MD, PhD c), Nordenskjöld A, MD, PhD d), Tornvall P, MD, PhD e), Lindahl B, MD, PhD a) a)
Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, 751 85 Uppsala, Sweden
b) c)
Department of Cardiology, Falun Hospital, Lasarettsvägen 10, 791 82 Falun, Sweden
Department of Clinical Sciences, Cardiology, Danderyd Hospital, Karolinska Institute, Mörbygårdsvägen 88, 182 88 Danderyd, Sweden
d)
Faculty of Health, Department of Cardiology, Örebro University, Södra Grev Rosengatan 701 85 Örebro, Sweden e)
Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Sjukhusbacken 10, 118 83 Stockholm, Sweden
Running title: Secondary prevention after myocardial infarction
We verify that all authors had access to the data and a role in writing the manuscript
Address for correspondence: Kai M Eggers Department of Medical Sciences, Cardiology Uppsala University 751 85 Uppsala, Sweden Tel: +46-18-611 00 00 Fax: +46-18-50 66 38 e-mail: [email protected] 1 Page 1 of 40
Clinical significance
Totally 9.6% of myocardial infarction patients had non-obstructive coronary arteries.
Low lipid levels are associated with 24-32% risk reduction in these patients.
Exercise training is associated with 10-23% risk reduction in these patients.
Abstract
Background
Around 5-10% of all myocardial infarction patients have non-obstructive coronary arteries. Studies investigating the importance of follow-up and achievement of conventional secondary prevention targets in these patients are lacking.
Methods
In this analysis from the SWEDEHEART registry, we investigated 5830 myocardial infarction patients with non-obstructive coronary arteries (group 1) and 54,637 myocardial infarction patients with significant coronary artery disease (≥50% stenosis; group 2). Multivariable- and propensity score-adjusted statistics were used to assess the reduction in the one-year risk of major adverse events associated with prespecified secondary preventive measures: participation in follow-up at 6-10 weeks after the hospitalization; achievement of secondary prevention targets (blood pressure and low-density lipoprotein cholesterol levels in the target ranges, non-smoking, participation in exercise training).
Results 2 Page 2 of 40
Patients in group 1 were less often followed up compared to patients in group 2 and less often achieved any of the secondary prevention targets. Participation in the 6-10 week follow-up was associated with a 3-20% risk reduction in group 1, similar as for group 2 according to interaction analysis. The improvement in outcome in group 1 was mainly mediated by achieving target range low-density lipoprotein cholesterol levels (24-32% risk reduction) and, to a smaller extent, by participation in exercise training (10-23% risk reduction).
Conclusions
Selected secondary preventive measures are associated with prognostic benefit in myocardial infarction patients with non-obstructive coronary arteries, in particular achieving target range low-density lipoprotein cholesterol levels. Our results indicate that these patients should receive similar follow-up as myocardial infarction patients with significant coronary stenoses.
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Keywords: Myocardial infarction; Myocardial infarction with non-obstructive coronary arteries; Follow-up; Secondary prevention; Prognosis
Introduction
About 5-10% of all patients diagnosed with myocardial infarction do not have significant (>50%) coronary stenoses [1-3]. For these patients, the term myocardial infarction with nonobstructive coronary arteries is used. This condition may be the result of various etiologies including plaque disruption, spasm, thromboembolism, dissection, microvascular dysfunction, myocardial injury due to supply/demand mismatch, clinically nondetected myocarditis or takotsubo syndrome [1-4]. Myocardial infarction with non-obstructive coronary arteries is thus, a heterogeneous disease state. Its importance has been emphasized in the 2017 European guidelines on the management of ST-segment elevation myocardial infarction [5]. Data on optimal clinical management however, are lacking although position papers have been published [2, 3].
Recent findings from the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) registry suggest that treatment with cardioprotective medications, i.e. statins and renin-angiotensin-aldosterone system-inhibitors, may exert prognostic benefit in myocardial infarction with non-obstructive coronary arteries [6]. It is however, not clear whether and how these patients should be followed up after the acute event and if they should be targeted to secondary preventive measures similar as myocardial infarction patients having
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significant coronary artery disease. Observational studies or randomized clinical trials investigating this important issue do not exist.
According to clinical routines in Sweden, myocardial infarction patients aged below 75 years are scheduled for a follow-up contact at 6-10 weeks after hospital discharge. Clinical data from this follow-up are collected in the nationwide Secondary Prevention after Heart Intensive care Admission (SEPHIA) registry which is a subregistry to SWEDEHEART. The availability of these data provides a unique opportunity to investigate the possible prognostic benefit of secondary preventive measures in myocardial infarction patients with nonobstructive coronary arteries. The primary objective of the present study was to examine whether participation in the 6-10 week follow-up and achieving prespecified secondary prevention targets would modify outcome in these patients. A secondary objective was to compare the potential prognostic benefits achieved by secondary preventive measures between myocardial infarction patients with non-obstructive coronary arteries and those with significant coronary artery disease.
Materials and Methods
Study population
This study is a part of the TOTAL-AMI (Tailoring Of Treatment in All comers with Acute Myocardial Infarction) project. The primary aim of TOTAL-AMI is to investigate the mechanisms and implications of different myocardial infarction subtypes [7] and of comorbidities (e.g. chronic obstructive pulmonary disease, atrial fibrillation, renal
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dysfunction) in myocardial infarction. TOTAL-AMI uses data from SWEDEHEART which is a nationwide registry enrolling consecutive patients admitted to Swedish coronary care units or other specialized facilities because of suspected acute coronary syndrome. SWEDEHEART prospectively collects information on >100 variables. On admission, patients receive written information about the registry, and have the right to deny participation and get their data erased upon request.
The population for the present study included all patients <75 years with a clinical diagnosis of myocardial infarction, admitted between January 2005 and August 2013. Myocardial infarction patients in whom coronary angiography results had not been recorded in SWEDEHEART were not considered. To fulfil the study criteria for myocardial infarction with non-obstructive coronary arteries (group 1), patients were required to have normal or near-normal coronary arteries (<50% stenosis), not to have undergone percutaneous coronary intervention during the hospitalization and to be free from a history of myocardial infarction or coronary intervention. Myocardial infarction patients with ≥50% coronary stenoses were regarded having significant coronary artery disease (group 2). To allow for comparisons of both cohorts on similar premises, patients from group 2 were excluded in case of previous myocardial infarction or coronary intervention.
All data had been made anonymous before the statistical analyses. The study was conducted according to the principles of the Declaration of Helsinki and had been approved by the Regional Ethical Review Board in Stockholm (2012/60-31/2).
The SEPHIA registry
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Data on the management of myocardial infarction patients in the rehabilitation phase after hospital discharge are collected in SEPHIA. This registry started in 2005, and 65 out of 73 Swedish hospitals participated in 2013. Data is collected at two follow-up occasions scheduled at 6-10 weeks and 1 year after the infarction, consisting of an outpatient visit or a phone call by a nurse or a physician. Upon each follow-up, information on cardiac symptoms, physical status, blood tests, medication, smoking habits, levels of physical activity, participation in a cardiac rehabilitation programme and clinical events is obtained. In the case of a follow-up phone call, results from blood tests and blood pressure measurements can be obtained from the patient’s primary health care facility.
Investigated secondary preventive measures
We investigated outcome prediction in relation to the following secondary preventive measures: participation in the 6-10 week follow-up; achievement of any of the following secondary prevention targets as reported in SEPHIA: systolic blood pressure <140 mmHg, low-density lipoprotein cholesterol levels in the target range (<2.5 mmol/L until 2012, thereafter <1.8 mmol/L), self-reported non-smoking including the proportion of smokers who had stopped smoking and participation in exercise training within a cardiac rehabilitation programme.
Prognostic evaluation
Information on patient outcome was obtained by merging data from SWEDEHEART with data from the mandatory Swedish Patient Registry (hospitalization dates and discharge diagnoses based on International Classification of Diseases, 10th revision, Clinical
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Modification [ICD-10-CM] codes) and the Swedish Cause of Death Registry, both held by the Swedish Board of Health and Welfare. Patients were followed for events until occurrence of death or December 31st, 2013.
The main outcome for this analysis was major adverse events, defined as the composite of all-cause mortality, non-fatal myocardial infarction (ICD-10-CM code I21), hospitalization for heart failure (ICD-10-CM code I50) or ischemic stroke (ICD-10-CM code I63). Only events occurring after the follow-up visit at 6-10 weeks were counted. For patients not participating in the 6-10 week follow-up, a fictive follow-up date at 61 days from hospital admission was anticipated. This corresponds to the mean period from the index infarction (61±15 days) at which follow-up took place in those who participated.
Statistical analysis
All continuous variables were skewed and are reported as medians with 25th and 75th percentiles. Differences in continuous variables were assessed using the Mann-Whitney Utest. Categorical variables are expressed as frequencies and percentages with differences being analyzed with the 2 test.
Cox regression models were used to investigate the associations of secondary preventive measures with outcome. Covariates included admission year, age, sex, current smoking, hypertension, diabetes, previous heart failure, previous stroke, ST-segment changes, estimated glomerular filtration rate, chronic obstructive pulmonary disease, dementia, previous or present cancer, peripheral vascular disease and in-hospital coronary revascularization, if appropriate. In addition, adjustment was made for hospital as a random effect in a mixed
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model. All continuous variables were ln-transformed to achieve normality. For comparative analyses between group 1 and 2, interaction terms were added to the fully adjusted models.
As a sensitivity analysis, significant multivariable associations between secondary preventive measures and major adverse events were re-assessed using 1:1 propensity scorematching of myocardial infarction patients with non-obstructive coronary arteries who did or did not achieve the target of the respective measure. The propensity score for each patient was computed from the predicted probabilities derived from logistic regression equations. Relevant covariates included variables assumed to affect the likelihood of achieving of any secondary prevention target (Supplemental Table 1). Due to partly small sample sizes, multiple imputation sets were created to handle missing data when constructing the propensity scores. In addition, Kaplan Meier curves regarding the incidence of major adverse events were computed applying a landmark design.
In all tests, a two-sided p-value <0.05 was considered significant. The software packages SPSS 21.0 (SPSS Inc., Chicago, IL), SAS Software 9.4. (SAS Institute, Cary, NC) and R 3.2.2 (R Foundation for Statistical Computing, Vienna, Austria) were used for the statistical analyses.
Results
Clinical characteristics and achievement rates of secondary prevention targets
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The study cohort consisted of 60,467 patients following exclusions (Supplemental Figure 1). Group 1 (myocardial infarction patients with non-obstructive coronary arteries) consisted of 5830 (9.6%) patients and 2907 (49.9%) of these participated in the 6-10 week follow-up. This was a patient visit in 2111 (72.6%) patients and a phone call in all other patients. The proportion of patients in group 1 who were followed up at 6-10 weeks tended to increase until 2009 with a slight decrease during the following years (Figure 1). Patients from group 1 were less often followed up compared to patients from group 2 (myocardial infarction patients with significant coronary artery disease).
Patients from group 1 who participated in the 6-10 week follow-up had lower prevalence of diabetes, previous heart failure, chronic obstructive pulmonary disease and atrial fibrillation compared to those not participating, presented more often with ST-segment elevation, tended to have better left-ventricular ejection fraction and were more often discharged with cardiovascular medications apart from oral anticoagulants (Table 1). For all other clinical data, no significant differences existed between both groups. Compared to patients from group 2 who participated in the 6-10 week follow-up, patients from group 1 being followed up had overall lower prevalence of cardiovascular risk indicators including comorbidities, STsegment elevation and impaired left-ventricular ejection fraction (Supplemental Table 2).
Table 1 also presents data on the achievement rates of secondary prevention targets for patients from group 1. While >60% of these patients had a systolic blood pressure <140 mmHg upon 6-10 week follow-up and almost 70% had low-density lipoprotein cholesterol levels in the target range, only 54.2% of smokers had stopped smoking and only 32.0% had participated in exercise training. Overall, the achievement rates of secondary prevention targets tended to be lower compared to patients from group 2 (Supplemental Table 2).
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Prognostic evaluation
In total, 980 (16.8%) patients from group 1 suffered a major adverse event during the observation period starting after the 6-10 week follow-up (median 3.6 years). This was similar as for patients from group 2 (n=9034 [16.5%]; p=0.592 for comparison). Data on the individual outcomes in patients from both groups is presented in the Supplemental Table 3.
Patients from group 1 who participated in the 6-10 week follow-up had a significantly lower of major adverse event rate compared to those who did not participate (Table 2). In a multivariable-adjusted Cox model, participation in the 6-10 week follow-up was associated with a significant 20% risk reduction. The magnitude of risk reduction was similar as for patients from group 2, as indicated by the non-significant interaction term (Table 2; Supplemental Table 4).
Patients from group 1 who achieved any of the secondary prevention targets had numerically lower major adverse event rates compared to those in whom these targets were not reached (Table 2; Figure 2). In multivariable-adjusted Cox models, these differences were statistically significant for achieving low-density lipoprotein cholesterol levels in the target range (32% risk reduction) and participation in exercise training (23% risk reduction). The non-significant interaction terms indicated that the magnitudes of risk reduction were similar as for patients from group 2 (Table 2; Supplemental Table 4). The beneficial effect of low-
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density lipoprotein cholesterol levels in the target range in patients from group 1 was mediated by lower risks of cardiovascular mortality, non-fatal myocardial infarction and readmission for heart failure (Supplemental Table 5A). For exercise training, the reduction in risk in these patients was mediated by lower risks of all-cause mortality and cardiovascular mortality (Supplemental Table 5B).
Smoking cessation among was associated with a non-significant 6% risk reduction in patients from group 1following multivariable adjustment (Table 2). The magnitude of risk reduction tended to be smaller compared to patients from group 2 according to interaction analysis. Achieving the blood pressure target was not associated with a significant risk reduction in neither group (Table 2; Supplemental Table 4).
The results of the prespecified sensitivity analyses re-investigating significant multivariable associations between secondary preventive measures and major adverse events in group 1 are presented in the Supplemental Table 6 and Supplemental Figures 2A-C. Using 1:1 propensity score-matching attenuated the risk reduction associated with participation in the 6-10 week follow-up (3% risk reduction) and participation in exercise training (10% risk reduction). On the contrary, low-density lipoprotein cholesterol levels in the target range still were associated with a 24% risk reduction although this association became non-significant. Applying the subset of covariates used for the propensity score computation in a Cox model yielded similar risk estimates as in the main analyses (Supplemental Table 6).
Discussion
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Around 5-10% of all myocardial infarction patients have non-obstructive coronary arteries [1-3]. Data from observational studies and systematic reviews demonstrate that these patients are at increased risk for adverse outcome [4, 8, 9]. The importance of myocardial infarction with non-obstructive coronary arteries has been emphasized in the 2017 European guidelines on the management of ST-segment elevation myocardial infarction [5] but information on optimal management is still limited. This depends in part on the fact that this condition can be the result of various etiologies that may require different modes of management. This rather emphasizes the importance of well-defined routines for follow-up, an issue that up until now has not been investigated in a larger context.
We made several important observations in our registry-based cohort study investigating data from >5800 myocardial infarction patients with non-obstructive coronary arteries. Achieving low-density lipoprotein cholesterol levels in the target range was associated with a 24-32% reduction in the risk of major adverse events. This corresponds with recent findings from our group demonstrating that statin treatment in these patients is associated with improved outcome in [6]. Interestingly, the magnitude in risk reduction was similar in the present analysis as for myocardial infarction patients with significant coronary artery disease. We hypothesize that our findings at least in part may reflect statin-related stabilization of angiographically non-significant and thus, untreated coronary plaques. This is supported by retrospective analyses demonstrating type 1 infarction as the underlying cause in 20-25% of myocardial infarction patients with non-obstructive coronary arteries [3, 4, 10, 11]. In another study investigating a female cohort with myocardial infarction with non-obstructive coronary arteries using intravascular ultrasound, 38% of the participants were found to have unstable coronary lesions [12]. These data fit also with our finding of a lower risk of non-fatal myocardial infarction associated with target range low-density lipoprotein cholesterol levels.
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In addition, statin-related pleiotrophic effects on endothelial function and cardiac remodeling [13] may contribute to the positive effects of target range low-density lipoprotein cholesterol levels. Participation in exercise training within a cardiac rehabilitation programme was associated with a 10-23% risk reduction among myocardial infarction patients with non-obstructive coronary arteries, similar as for those having significant coronary artery disease. Physical exercise exerts positive effects on many cardiovascular risk factors, improves cardiac function, attenuates adverse myocardial remodeling and has been shown to reduce risk across a broad range of cardiovascular conditions [14-16]. Our results for the first time extend this notion to myocardial infarction patients with non-obstructive coronary arteries. The low participation rate in exercise training among these patients from our cohort however, is worrisome. Limitations in healthcare resources might represent a possible explanation as additional 215 patients participated after the 6-10 week follow-up. Given the design of our study, these patients were not considered for the analyses. Nonetheless, our data demonstrate that overcoming the barriers behind the underuse of cardiac rehabilitation likely will contribute to further improvement of outcome in myocardial infarction with non-obstructive coronary arteries.
Despite a substantial risk reduction, the effects of smoking cessation on outcome after myocardial infarction with non-obstructive coronary arteries did not reach levels of statistical significance. This might reflect limitations in statistical power given the rather small number of smokers among these patients.
Even achievement of a systolic blood pressure <140 mmHg was not associated with a significant risk reduction in myocardial infarction patients with non-obstructive coronary
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arteries. Accordingly, the previously reported benefit from a discharge medication with reninangiotensin-aldosterone system-inhibitors in these patients [6] seems primarily to be mediated by other effects than lowering of blood pressure, possibly mechanisms preventing adverse myocardial remodeling [17].
Our study has limitations that need to be considered. Although all hospitals participating in SWEDEHEART are annually monitored, the data cannot be of the same quality as in a prospective observational study. However, the agreement of the information entered in the registry with the medical records is around 96% [18]. The data available in SWEDEHEART do not permit separation of patients into those without angiographic signs of coronary lesions and those with signs of coronary lesions but no stenosis of ≥50%. Coronary angiographies were evaluated locally at each hospital and not at a core laboratory. We lack information on the results of examinations performed after the hospitalization period. Some myocardial infarction patients with non-obstructive coronary arteries may thus, have subsequently been diagnosed with myocarditis on the basis of cardiac magnetic resonance performed after hospital discharge. There might also be some cases of takotsubo syndrome in the cohort, especially during the first years of the study period where the awareness of this condition was limited. We cannot exclude survival bias as we lack information on whether patients suffering death early after hospital discharge had been scheduled for follow-up or not. Measurements of low-density lipoprotein cholesterol levels and blood pressure were not mandatory in SEPHIA until 2013. This resulted in missing data for these variables, about 23% for low-density lipoprotein cholesterol and 12% for systolic blood pressure. We did not investigate risk reduction in relation to the decrease in low-density lipoprotein cholesterol levels as management routines in the post-infarction setting primarily focus on target ranges. We cannot comment on risk reduction in relation to the type, intensity, frequency and length of
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exercise training as this information is not collected in SEPHIA. In any observational study such as ours, it is difficult to draw conclusions regarding causality. Moreover, we cannot exclude residual confounding due to unmeasured variables that might have influenced medical decisions in myocardial infarction patients with non-obstructive coronary arteries and generated selection bias. To minimize this risk, we conducted sensitivity analyses using 1:1 propensity score-matching. In these analyses, the associations of participation in the 6-10 week follow-up and physical exercise training with major adverse events weakened. This discrepancy might reflect differences in the statistical approach and/or limitations in power given the smaller number of observations. Nonetheless, the interaction analyses indicated that myocardial infarction patients with non-obstructive coronary arteries achieved similar prognostic benefit from these measures as patients with significant coronary artery disease. Moreover, the low participation rate in physical exercise training from discharge to 6-10 week follow-up rather underestimates the prognostic effect of this intervention. Finally, without a scheduled follow-up, it would be doubtful whether any of the above-mentioned secondary preventive measures would have been effectuated. Our results can thus, be viewed rather as an argument for than against a systematic and standardized follow-up of patients with myocardial infarction with non-obstructive coronary arteries.
Conclusions
Taken together, our findings emphasize the importance of structured follow-up routines in myocardial infarction patients with non-obstructive coronary arteries. Although this condition may be the result of different etiologies, our results demonstrate that much of the prognostic benefit of follow-up is associated with the modification of cardiovascular risk factors, in
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particular low-density lipoprotein cholesterol levels. We also want to stress the need of further investigation, preferably using cardiac magnetic resonance, for etiologic clarification [2, 3, 11]. This will help to identify patients with undetected myocarditis or true infarction who require specific treatments.
Conflicts of interest
None of the authors reported conflicts of interest relevant to this study.
Acknowledgements
The TOTAL-AMI project has received funding from the Swedish Foundation of Strategic Research. This organization had no role in the design of study, the collection and interpretation of the data, the preparation of the manuscript and the decision to submit it for publication.
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References
1. Reynolds HR. Myocardial infarction without obstructive coronary artery disease. Curr Opin Cardiol 2012;27:655-60. doi: 10.1097/HCO.0b013e3283583247.
2. Pasupathy S, Tavella R, Beltrame JF. The What, When, Who, Why, How and Where of Myocardial Infarction With Non-Obstructive Coronary Arteries (MINOCA). Circ J 2016;80:11-6. doi: 10.1253/circj.CJ-15-1096.
3. 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;38:143-53. doi: 10.1093/eurheartj/ehw149.
4. Pasupathy S, Air T, Dreyer RP, et al. Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries. Circulation 2015; 131: 861-70. doi: 10.1161/CIRCULATIONAHA.114.011201. Erratum in: Circulation 2015;131:e475. doi: 10.1161/CIR.0000000000000212.
5. 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: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2017. doi: 10.1093/eurheartj/ehx393. [Epub ahead of print].
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6. Lindahl B, Baron T, Erlinge D, et al. Medical therapy for secondary prevention and longterm outcome in patients with myocardial infarction with nonobstructive coronary artery disease. Circulation 2017;135:1481-9. doi: 10.1161/CIRCULATIONAHA.116.026336.
7. Thygesen K, Alpert JS, Jaffe AS, et al. Third Universal Definition of Myocardial Infarction. Circulation 2012;126:2020-35. doi: 10.1161/CIR.0b013e31826e1058.
8. Aldous S, Elliott J, McClean D, et al. Outcomes in patients presenting with symptoms suggestive of acute coronary syndrome with elevated cardiac troponin but non-obstructive coronary disease on angiography. Heart Lung Circ 2015;24:869-78. doi: 10.1016/j.hlc.2015.02.019.
9. Baron T, Hambraeus K, Sundström J, et al. Impact on Long-Term Mortality of Presence of Obstructive Coronary Artery Disease and Classification of Myocardial Infarction. Am J Med 2016;129:398-406. doi: 10.1016/j.amjmed.2015.11.035.
10. 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;241:87-91. doi: 10.1016/j.atherosclerosis.2015.04.816.
11. Dastidar AG, Rodrigues JC, Johnson TW, et al. Myocardial Infarction With Nonobstructed Coronary Arteries: Impact of CMR Early After Presentation. JACC Cardiovasc Imaging 2017;10:1204-06. doi: 10.1016/j.jcmg.2016.11.010.
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12. Reynolds HR, Srichai MB, Iqbal SN, et al. Mechanisms of myocardial infarction in women without angiographically obstructive coronary artery disease. Circulation 2011;124:1414-25. doi: 10.1161/CIRCULATIONAHA.111.026542.
13. Oesterle A, Laufs U, Liao JK. Pleiotropic Effects of Statins on the Cardiovascular System. Circ Res 2017;120:229-43. doi: 10.1161/CIRCRESAHA.116.308537
14. Piepoli MF, Davos C, Francis DP, et al. Exercise training meta-analysis of trials in patients with chronic heart failure (ExTraMATCH). BMJ 2004;328:189.
15. Talbot LA, Morrell CH, Fleg JL, Metter EJ. Changes in leisure time physical activity and risk of all-cause mortality in men and women: the Baltimore Longitudinal Study of Aging. Prev Med 2007;45:169-76.
16. Anderson L, Thompson DR, Oldridge N, et al. Exercise-based cardiac rehabilitation for coronary heart disease. Cochrane Database Syst Rev 2016;1:CD001800. doi: 10.1002/14651858.CD001800.pub3.
17. Werner C, Baumhäkel M, Teo KK, et al. RAS blockade with ARB and ACE inhibitors: current perspective on rationale and patient selection. Clin Res Cardiol 2008;97:418-31. doi: 10.1007/s00392-008-0668-3.
18. Jernberg T, Attebring MF, Hambraeus K, et al. The Swedish Web-system for enhancement and development of evidence-based care in heart disease evaluated according to
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recommended therapies (SWEDEHEART). Heart 2010;96:1617-21. doi: 10.1136/hrt.2010.198804.
Figure legends.
Figure 1. Proportions of myocardial infarction patients with non-obstructive coronary arteries and significant coronary artery disease who participated in the 6-10 week follow-up.
White bars represent myocardial infarction patients with non-obstructive coronary arteries, grey bars represent myocardial infarction patients with significant coronary artery disease. The numbers of patients within each cohort are given at the bottom of the bars. P-values refer to comparisons between both groups.
Figure 2. Crude rates and adjusted risks of major adverse events in myocardial infarction patients with non-obstructive coronary arteries in relation to the number of achieved of secondary preventive targets.
The secondary prevention targets included systolic blood pressure <140 mmHg, low-density lipoprotein cholesterol levels in the target range, self-reported non-smoking and participation in exercise training within a cardiac rehabilitation programme.
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The numbers at the bottom of the bars indicate the total numbers of patients per category and those suffering a major adverse event.
The multivariable analyses were adjusted for hospital, admission year, age, sex, current smoking, hypertension, diabetes, congestive heart failure, previous stroke, ST-segment changes, estimated glomerular filtration rate, chronic obstructive pulmonary disease, dementia, previous or present cancer and peripheral vascular disease. Hazard ratios (HR) are given with 95% confidence intervals.
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Table 1. Clinical characteristics of myocardial infarction patients with non-obstructive coronary arteries who did or did not participate in the 6-10 week follow-up SEPHIA patients
Non-SEPHIA
p-value
Total
(n=2907)
patients (n=2993)
1167 (40.1%)
1165 (39.9%)
0.831
2332 (40.0%)
63 (55-69)
64 (56-70)
<0.001
63 (55-69)
Current smoking
620 (21.3%)
636 (21.9%)
0.610
1256 (21.6%)
Hypertension
1083 (37.3%)
1120 (38.4%)
0.358
2203 (37.8%)
Diabetes
272 (9.4%)
330 (11.3%)
0.016
602 (10.3%)
Hyperlipidemia
481 (16.5%)
495 (16.9%)
0.700
976 (16.7%)
Body mass index (kg/m2)
26.3 (23.7-29.4)
26.2 (23.5-29.7)
0.385
26.3 (23.6-29.6)
eGFR (mL/min)
82.3 (70.5-95.1)
82.3 (69.0-95.1)
0.879
82.3 (69.5-96.6)
Previous heart failure
55 (1.9%)
86 (3.0%)
0.008
141 (2.4%)
Previous stroke
119 (4.1%)
118 (4.4%)
0.690
237 (4.2%)
Peripheral vascular disease
37 (1.3%)
37 (1.3%)
1.000
74 (1.3%)
Previous or present cancer
37 (1.3%)
58 (2.0%)
0.038
95 (1.6%)
COPD
207 (7.1%)
261 (8.9%)
0.012
468 (8.0%)
3 (0.1%)
4 (0.1%)
1.000
7 (0.1%)
2696 (92.9%)
2597 (89.1%)
<0.001
5293 (91.0%)
Atrial fibrillation
158 (5.4%)
240 (8.2%)
<0.001
398 (6.8%)
ST-segment elevation
414 (14.3%)
389 (13.4%)
0.342
803 (13.8%)
Echocardiography
2437 (83.8%)
2358 (80.7%)
0.002
4795 (82.2%)
· ≥0.50
1879 (77.5%)
1669 (73.9%)
0.028
3548 (75.8%)
· 0.40-0.49
311 (12.8%)
320 (14.2%)
(n=5830)
Risk factors Males Age (years)
History
Dementia ECG findings Sinus rhythm
LVEF*
631 (13.5%)
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· 0.30-0.39
162 (6.7%)
178 (7.9%)
340 (7.3%)
· <0.30
73 (3.0%)
90 (4.0%)
163 (3.5%)
Aspirin
2692 (92.6%)
2562 (88.0%)
<0.001
5254 (90.3%)
P2Y12 blockers
2287 (78.7%)
1829 (62.6%)
<0.001
4116 (70.6%)
198 (6.8%)
256 (8.8%)
0.006
454 (7.8%)
Betablockers
2445 (84.1%)
2318 (79.3%)
<0.001
4763 (81.7%)
RAAS-inhibitors
1835 (63.1%)
1710 (58.5%)
<0.001
3545 (60.8%)
Statins
2641 (90.8%)
2325 (79.5%)
<0.001
4966 (85.2%)
Medication at discharge
Oral anticoagulants
Medication at 6-10 week follow-up Aspirin
2613 (89.9%)
-
-
-
P2Y12 blockers
1985 (68.3%)
-
-
-
235 (8.1%)
-
-
-
Betablockers
2386 (82.1%)
-
-
-
RAAS-inhibitors
1826 (62.8%)
-
-
-
Statins
2548 (87.7%)
-
-
-
Oral anticoagulants
Achievement of secondary prevention targets Not smoking
2598 (89.5%)
-
-
-
Smoking cessation†
336 (54.2%)
-
-
-
Systolic BP <140 mmHg
1597 (61.8%)
-
-
-
LDL-C in target range
1552 (69.3%)
-
-
-
Participation in exercise
859 (32.0%)
-
-
-
training
Data given as numbers (with percentages) or medians (with 25 th, 75th percentiles). Patients with missing data were excluded from the analyses.
*Available data: n=4682. †Assessed in patients who had been smokers at admission.
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eGFR: estimated glomerular filtration rate; COPD: chronic obstructive pulmonary disease; LVEF: leftventricular ejection fraction; RAAS: renin-angiotensin-aldosterone system; BP: blood pressure; LDL-C: lowdensity lipoprotein cholesterol.
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Table 2. Crude rates and adjusted risks of major adverse events in patients with myocardial infarction with non-obstructive coronary arteries in relation to the achievement of secondary preventive measures. Secondary preventive measure achieved Data
No
Yes
available Participation in the
5830 (100%)
6-10 week follow-up
589
391
(20.2%)
(13.5%)
p-
Adjusted HR
p-
p-
value
(95% CI)
value
value*
<0.001
0.80 (0.70-
0.001
0.059
0.92)
Achievement of secondary preventive targets in patients who participated in the 6-10 week follow-up Not smoking
2904
46 (15.0%)
(99.9%) Smoking cessation†
620 (100%)
344
0.376
(13.2%) 39 (13.7%)
44 (13.1%)
0.92 (0.61-
0.705
0.002
0.792
0.073
0.759
0.432
0.003
0.097
0.048
0.807
1.40) 0.814
0.94 (0.591.51)
Systolic BP <140
2586
151
190
(89.0%)
(15.3%)
(11.9%)
2239
110
173
(77.0%)
(16.0%)
(11.1%)
Participation in
2684
272
83 (9.7%)
exercise training
(92.3%)
(14.9%)
mmHg LDL-C in target range
0.017
1.04 (0.821.31)
0.002
0.68 (0.530.88)
<0.001
0.77 (0.601.00)
The multivariable analyses were adjusted for hospital, admission year, age, sex, current smoking, hypertension, diabetes, previous heart failure, previous stroke, ST-segment changes, estimated glomerular filtration rate, chronic obstructive pulmonary disease, dementia, previous or present cancer and peripheral vascular disease.
*p-value for the interaction of the myocardial infarction type on the association of the achievement of secondary preventive measures with major adverse events. Adjustment was made as outlined above and for in-hospital coronary revascularization.
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†Assessed in patients who had been smokers at admission.
HR: hazard ratio; CI: confidence interval; BP: blood pressure; LDL-C: low-density lipoprotein cholesterol.
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SUPPLEMENTAL MATERIAL Supplemental Table 1. List of covariates for the propensity score computations. Supplemental Table 2. Clinical characteristics of myocardial infarction patients with non-obstructive coronary arteries and with significant coronary artery disease who participated in the 6-10 week follow-up. Supplemental Table 3. Crude event rates in myocardial infarction patients with non-obstructive coronary arteries and with significant coronary artery disease. Supplemental Table 4. Crude rates and adjusted risks of major adverse events in myocardial infarction patients with significant coronary artery disease in relation to the achievement of secondary preventive measures. Supplemental Tables 5A-B. Crude event rates and adjusted risks in myocardial infarction patients with non-obstructive coronary arteries in relation to the achievement of selected secondary preventive targets. Supplemental Table 6. Sensitivity analysis with and without 1:1 propensity score-matching. Risks of major adverse events in myocardial infarction patients with non-obstructive coronary arteries in relation to the achievement of selected secondary preventive measures.
Supplemental Figure 1. Flowchart – Selection of patients. Supplemental Figures 2A-C. 1:1 propensity score-matched analyses. Event-free survival curves in relation to the achievement of selected secondary preventive measures. A) Participation in the 6-10 week follow-up; B) target range lowdensity lipoprotein cholesterol levelsin the target range; C) participation in exercise training.
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Supplemental Figure 1. Flowchart – Selection of patients.
MI: myocardial infarction; PCI: percutaneous coronary intervention; MINOCA: myocardial infarction with nonobstructive coronary arteries; MI-CAD: myocardial infarction with significant coronary artery disease.
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Supplemental Figures 2A-C. 1:1 propensity score-matched analyses. Event-free survival curves in relation to the achievement of selected secondary preventive measures. A) Participation in the 6-10 week follow-up; B) target range lowdensity lipoprotein cholesterol levels ; C) participation in exercise training. A)
B)
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C)
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Supplemental Table 1. List of covariates for the propensity score computations. -
County of residence Year of admission Age Sex Smoking Diabetes Hypertension Previous heart failure Previous stroke Atrial fibrillation Peripheral vascular disease Previous or present cancer Chronic obstructive pulmonary disease Dementia iv treatment with diuretics during admission
-
Discharge treatment with warfarin Occupation status Estimated glomerular filtration rate Left-ventricular ejection fraction Discharge treatment with acetylsalicylic acid Discharge treatment with other antiplatelets Discharge treatment with betablockers Discharge treatment with RAAS-inhibitors Discharge treatment with digitalis Discharge treatment with diuretics Discharge treatment with statins*
* not included in the computation of the propensity score regarding achievement of low-density lipoprotein cholesterol levels in the target range. RAAS: renin-angiotensin-aldosterone system.
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Supplemental Table 2. Clinical characteristics of myocardial infarction patients with non-onstructive coronary arteries and with significant coronary artery disease who participated in the 6-10 week follow-up. MINOCA (n=2907)
MI-CAD (n=30,403)
p-value
1167 (40.1%) 63 (55-69) 620 (21.3%) 1083 (37.3%) 272 (9.4%) 481 (16.5%) 26.3 (23.7-29.4) 82.3 (70.5-95.1)
23,216 (76.4%) 63 (56-68) 10,232 (33.7%) 11,746 (38.6%) 4122 (13.6%) 4611 (15.2%) 26.9 (24.7-29.8) 84.6 (72.4-98.1)
<0.001 0.710 <0.001 0.146 <0.001 0.048 <0.001 <0.001
55 (1.9%) 119 (4.1%) 37 (1.3%)
261 (0.9%) 1048 (3.5%) 546 (1.8%)
<0.001 0.070 0.042
37 (1.3%) 207 (7.1%) 3 (0.1%)
363 (1.2%) 1073 (3.5%) 13 (0.0%)
0.729 <0.001 0.159
ECG findings Sinus rhythm Atrial fibrillation ST-segment elevation
2696 (92.9%) 158 (5.4%) 414 (14.3%)
28,725 (94.6%) 1057 (3.5%) 13,322 (43.9%)
<0.001 <0.001 <0.001
Examination findings Coronary status · normal /near-normal · 1-2 vessel disease · LM/3 vessel disease
2907 (100%) -
319 (1.0%)* 24,139 (79.4%) 5945 (19.6%)
-
2437 (83.8%)
26,244 (86.3%)
<0.001
1879 (77.5%) 311 (12.8%) 162 (6.7%) 73 (3.0%)
16,884 (65.4%) 5443 (21.1%) 2801 (10.8%) 703 (2.7%)
<0.001
2692 (92.6%) 2287 (78.7%) 198 (6.8%) 2445 (84.1%) 1835 (63.1%) 2641 (90.8%)
29,699 (97.7%) 27,728 (91.2%) 1164 (3.8%) 28,226 (92.8%) 23,877 (78.5%) 29,574 (97.3%)
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001
Medication at 6-10 week follow-up Aspirin 2613 (89.9%) P2Y12 blockers 1985 (68.3%) Oral anticoagulants 235 (8.1%) Betablockers 2386 (82.1%) RAAS-inhibitors 1826 (62.8%) Statins 2548 (87.7%)
29,282 (96.3%) 26,656 (87.7%) 1452 (4.8%) 27,871 (91.7%) 24,074 (79.2%) 29,958 (95.9%)
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001
Achievement of secondary prevention targets Not smoking 2598 (89.5%) Smoking cessation‡ 336 (54.2%) Systolic BP <140 mmHg 1597 (61.8%) LDL-C in target range 1552 (69.3%) Participation in exercise 859 (32.0%) training
26,714 (88.0%) 6803 (66.6%) 17,375 (65.3%) 16,722 (71.0%) 9762 (34.4%)
0.022 <0.001 <0.001 0.088 0.013
Risk factors Males Age (years) Current smoking Hypertension Diabetes Hyperlipidemia 2 Body mass index (kg/m ) eGFR (mL/min) History Previous heart failure Previous stroke Peripheral vascular disease Previous or present cancer COPD Dementia
Echocardiography LVEF† · ≥0.50 · 0.40-0.49 · 0.30-0.39 · <0.30 Medication at discharge Aspirin P2Y12 blockers Oral anticoagulants Betablockers RAAS-inhibitors Statins
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th
th
Data given as numbers (with percentages) or medians (with 25 , 75 percentiles). Patients with missing data were excluded from the analyses. *Patients with normal/near-normal coronary findings who had undergone percutaneous coronary intervention during the hospitalization were counted as myocardial infarction with significant coronary artery disease. †Available data: n=28,256. ‡Assessed in patients who had been smokers at admission. MINOCA: myocardial infarction with non-obstructive coronary arteries; MI-CAD: myocardial infarction with significant coronary artery disease; eGFR: estimated glomerular filtration rate; COPD: chronic obstructive pulmonary disease; LM: left main; LVEF: left-ventricular ejection fraction; PCI: percutaneous coronary intervention; CABG: coronary artery bypass grafting; RAAS: renin-angiotensin-aldosterone system; BP: blood pressure; LDL-C: low-density lipoprotein cholesterol.
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Supplemental Table 3. Crude event rates in myocardial infarction patients with non-obstructive coronary arteries and with significant coronary artery disease. Outcome All-cause mortality Cardiovascular mortality Non-fatal MI Heart failure Stroke
MINOCA (n=5830)
MI-CAD (n=54,637)
p-value
481 (8.3%) 158 (2.7%) 291 (5.0%) 229 (3.9%) 171 (2.9%)
3930 (7.2%) 1706 (3.1%) 3688 (6.8%) 2051 (3.8%) 1373 (2.5%)
0.003 0.088 <0.001 0.517 0.053
MINOCA: myocardial infarction with non-obstructive coronary arteries; MI-CAD: myocardial infarction with significant coronary artery disease; MI: myocardial infarction.
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Supplemental Table 4. Crude rates and adjusted risks of major adverse events in myocardial infarction patients with significant coronary artery disease in relation to the achievement of secondary preventive measures. Secondary preventive measure achieved
Participation in the 6-10 week follow-up
Data available
No
Yes
pvalue
Adjusted HR (95% CI)
pvalue
54,150 (100%)
4945 (20.4%)
4089 (13.4%)
<0.001
0.87 (0.83-0.91)
<0.001
Achievement of secondary preventive targets in patients who participated in the 6-10 week follow-up Not smoking Smoking cessation* Systolic BP <140 mmHg LDL-C in target range Participation in exercise training
30,355 (99.8%) 10,219 (100%) 26,600 (87.5%)
677 (18.6%) 616 (18.0%) 1339 (14.5%)
3399 (12.7%) 833 (12.2%) 2090 (12.0%)
<0.001 <0.001 <0.001
0.63 (0.57-0.70) 0.65 (0.59-0.73) 1.03 (0.96-1.10)
<0.001 <0.001 0.483
23,540 (77.4%)
902 (13.2%)
2024 (12.1%)
0.018
0.89 (0.83-0.97)
0.006
28,376 (93.3%)
2693 (14.5%)
959 (9.8%)
<0.001
0.77 (0.71-0.83)
<0.001
The multivariable analyses were adjusted for hospital, admission year, age, sex, current smoking, hypertension, diabetes, previous heart failure, previous stroke, ST-segment changes, estimated glomerular filtration rate, chronic obstructive pulmonary disease, dementia, previous or present cancer, peripheral vascular disease and inhospital coronary revascularization. *Assessed in patients who had been smokers at admission. HR: hazard ratio; CI: confidence interval; BP: blood pressure; LDL-C: low-density lipoprotein cholesterol.
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Supplemental Tables 5A-B. Crude event rates and adjusted risks in myocardial infarction patients with non-obstructive coronary arteries in relation to the achievement of selected secondary preventive targets. Secondary preventive measure achieved
A) LDL-C in target range (n=2239) All-cause mortality Cardiovascular mortality Non-fatal MI Heart failure Ischemic stroke
No
Yes
pvalue
Adjusted HR (95% CI)
pvalue
42 (6.1%) 19 (2.8%) 40 (5.8%) 27 (3.9%) 25 (3.6%)
75 (4.8%) 17 (1.1%) 58 (3.7%) 40 (2.6%) 32 (2.1%)
0.217 0.006 0.033 0.106 0.040
0.77 (0.52-1.14) 0.33 (0.17-0.64) 0.61 (0.40-0.93) 0.55 (0.33-0.91) 0.68 (0.38-1.21)
0.196 0.001 0.020 0.021 0.186
Secondary preventive measure achieved
B) Participation in exercise training (n=2684)
No
Yes
pvalue
Adjusted HR (95% CI)
pvalue
All-cause mortality Cardiovascular mortality Non-fatal MI Heart failure Ischemic stroke
122 (6.7%) 39 (2.1%) 88 (4.8%) 67 (3.7%) 50 (2.7%)
22 (2.6%) 3 (0.3%) 34 (4.0%) 18 (2.1%) 16 (2.9%)
<0.001 <0.001 0.371 0.033 0.184
0.51 (0.32-0.82) 0.21 (0.06-0.69) 0.81 (0.53-1.23) 0.73 (0.42-1.26) 0.99 (0.56-1.78)
0.005 0.010 0.810 0.253 0.982
The multivariable analyses were adjusted for hospital, admission year, age, sex, current smoking, hypertension, diabetes, previous heart failure, previous stroke, ST-segment changes, estimated glomerular filtration rate, chronic obstructive pulmonary disease, dementia, previous or present cancer and peripheral vascular disease. *Assessed in patients who had been smokers at admission. HR: hazard ratio; CI: confidence interval; LDL-C: low-density lipoprotein cholesterol; MI: myocardial infarction.
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Supplemental Table 6. Sensitivity analysis with and without 1:1 propensity score-matching. Risks of major adverse events in myocardial infarction patients with non-obstructive coronary arteries in relation to the achievement of selected secondary preventive measures. 1:1 propensity score-matched Cox regression
Participation in the 6-10 week follow-up
Standard Cox regression
n
Adjusted HR (95% CI)
p-value
n
Adjusted HR (95% CI)
p-value
4340
0.97 (0.82-1.13)
0.660
4497
0.84 (0.72-0.98)
0.026
Achievement of secondary preventive targets in patients who participated in the 6-10 week follow-up LDL-C in the target range Participation in exercise training
1294 1660
0.76 (0.55-1.04) 0.90 (0.66-1.22)
0.083 0.486
1791 2171
0.69 (0.52-0.92) 0.82 (0.61-1.09)
0.011 0.166
Adjustment was made for the covariates listed in the Supplemental Table 1. HR: hazard ratio; CI: confidence interval; low-density lipoprotein cholesterol.
Data statement
We do not have permission to share the data used for the present analysis, neither in part nor in total (Regional Ethical Review Board in Stockholm [2012/60-31/2]).
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Figure 1_Pub_bestsetConverted.png
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Figure 2_Pub_bestsetConverted.png
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