Residual risk for coronary heart disease events and mortality despite intensive medical management after myocardial infarction

Journal Pre-proof Residual Risk for Coronary Heart Disease Events and Mortality Despite Intensive Medical Management Following Myocardial Infarction Todd M. Brown, MD, MSPH, Vera Bittner, MD, Lisandro D. Colantonio, MD, PhD, Luqin Deng, PhD, Michael E. Farkouh, MD, MSc, Nita Limdi, PharmD, PhD, MSPH, Keri L. Monda, PhD, Robert S. Rosenson, MD, Maria-Corina Serban, MSc, PhD, MD, Ransi M. Somaratne, MD, Hong Zhao, MS, Mark Woodward, PhD, Paul Muntner, PhD PII:

S1933-2874(20)30004-0

DOI:

https://doi.org/10.1016/j.jacl.2020.01.004

Reference:

JACL 1539

To appear in:

Journal of Clinical Lipidology

Received Date: 22 June 2019 Revised Date:

17 November 2019

Accepted Date: 12 January 2020

Please cite this article as: Brown TM, Bittner V, Colantonio LD, Deng L, Farkouh ME, Limdi N, Monda KL, Rosenson RS, Serban M-C, Somaratne RM, Zhao H, Woodward M, Muntner P, Residual Risk for Coronary Heart Disease Events and Mortality Despite Intensive Medical Management Following Myocardial Infarction, Journal of Clinical Lipidology (2020), doi: https://doi.org/10.1016/ j.jacl.2020.01.004. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2020 Published by Elsevier Inc. on behalf of National Lipid Association.

Residual Risk for Coronary Heart Disease Events and Mortality Despite Intensive Medical Management Following Myocardial Infarction

Todd M. Brown, MD, MSPH,1 Vera Bittner, MD,1 Lisandro D. Colantonio, MD, PhD,2 Luqin Deng, PhD,2 Michael E. Farkouh, MD, MSc,3 Nita Limdi, PharmD, PhD, MSPH,4 Keri L. Monda, PhD,5 Robert S. Rosenson, MD,6 Maria-Corina Serban, MSc, PhD, MD,7 Ransi M. Somaratne, MD,8 Hong Zhao, MS,2 Mark Woodward, PhD,9-11 Paul Muntner, PhD 2

1. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 2. Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 3. Peter Munk Cardiac Centre and Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto, Canada 4. Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 5. Center for Observational Research, Amgen Inc., Thousand Oaks, CA 6. Icahn School of Medicine at Mount Sinai, New York, NY 7. Department of Functional Sciences, University of Medicine and Pharmacy “Victor Babes” Timisoara, Romania 8. Global Development, Amgen Inc., Thousand Oaks, CA 9. The George Institute for Global Health, University of Oxford, United Kingdom 10. The George Institute for Global Health, University of New South Wales, Sydney, Australia 11. Department of Epidemiology, Johns Hopkins University, Baltimore, MD

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Running Title: Residual Risk Post Myocardial Infarction

Word Count: Abstract: 233 Manuscript text: 3,273 Tables: 6 Figures: 1 Supplemental Tables: 3 Supplemental Figures: 1

Corresponding Author: Todd M. Brown, MD, MSPH UAB Division of Cardiovascular Disease LHRB 313, 1720 Second Avenue South, Birmingham, AL, 35294 [email protected], phone: 205-934-9630, fax: 205-975-6237

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ABSTRACT Background: High-intensity statins, beta-blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and antiplatelet agents (i.e. intensive medical management) reduce coronary heart disease (CHD) risk following myocardial infarction (MI).

Objective: Determine the risk of CHD events or death despite receiving intensive medical management following MI.

Methods: We studied 16,853 US adults with health insurance in the MarketScan and Medicare databases who underwent percutaneous coronary intervention while hospitalized for MI between January 1, 2014 and June 30, 2015 and received intensive medical management within 30 days following hospital discharge. MI, CHD, and allcause mortality rates from 30 days after hospital discharge through December 31, 2015 were compared to 67,412 individuals in each of three groups: (1) the general MarketScan and Medicare populations, (2) with diabetes, and (3) with a CHD history.

Results: Among beneficiaries intensively medically managed after their MI, recurrent MI, CHD events, and all-cause mortality rates were 47.1, 72.0, and 57.5 per 1,000 person-years, respectively. The multivariable-adjusted hazard ratio (95% CI) comparing intensively medically managed beneficiaries following MI to the general population, those with diabetes, and those with a history of CHD were 8.54 (7.52-9.70), 7.40 (6.618.28) and 5.45 (4.92-6.05), respectively, for recurrent MI; 7.82 (7.07-8.64), 6.27 (5.74-

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6.86), and 4.45 (4.10-4.82), respectively, for CHD events; and 1.15 (1.05-1.25), 1.05 (0.97-1.14), and 1.06 (0.97-1.15), respectively, for all-cause mortality.

Conclusion: Substantial residual risk for MI and CHD events remains despite intensive medical management following MI.

KEYWORDS: coronary heart disease, myocardial infarction, recurrent events, residual risk, secondary prevention

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INTRODUCTION Over 500,000 United States (US) adults are discharged annually following a myocardial infarction (MI).1 To prevent recurrent events, current guidelines recommend a strategy of comprehensive secondary prevention, including high-intensity statins, beta-blockers, renin-angiotensin-aldosterone system inhibitors, and dual antiplatelet therapy.2-9 Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have the strongest indications for use in those with high risk features but can be considered in all other patients following MI.2, 3, 7, 8 The remaining agents are indicated in all individuals post-MI in the absence of contraindications.2, 3, 7-9 Although not all patients have indications for each of these medications, people who receive medications from each of these classes represent a subgroup that is being as intensively medically managed as is feasible with traditional strategies.

In addition to the traditional medications discussed above, there are new agents which could further reduce the risk for cardiovascular events including ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, glucagon like peptide 1 (GLP-1) receptor agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and icosapent ethyl.9-14 In order to provide guidance to clinicians, the National Lipid Association (NLA) has recently published a statement on the use of PCSK9 inhibitors in patients with cardiovascular disease.15 This statement, and others, emphasize that in order to direct these additional therapies to individuals with MI who are most likely to benefit, it is first necessary to quantify the residual risk for CHD events following a MI in

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those who are as intensively medically managed as is feasible with traditional strategies and identify sub-groups who are at particularly increased risk.9, 15, 16

Prior analyses which have examined residual risk following MI, including those in the NLA statement,15 have frequently included patients only from clinical trial populations or those not taking evidence-based medications, or have been restricted to high-risk subgroups of individuals, such as those with diabetes.14-26 Therefore, we examine the risk for, and risk factors associated with, recurrent MI and CHD events and the mortality rate among a broader group of US adults who were intensively medically managed following hospital discharge for MI. Better quantification of the magnitude of the residual risk in this population will help inform clinicians as they determine which subgroups of patients might benefit most from additional risk reduction measures following MI.

METHODS We conducted a retrospective cohort study among US adults in the MarketScan and Medicare databases who had an MI between January 1, 2014 and June 30, 2015 and among three comparison groups. The MarketScan database contains data for individuals in the US with commercial and Medicare supplemental health insurance and was obtained from Truven Health Analytics. Medicare is a US federal program that provides health insurance for adults aged ≥65 years and adults <65 years with endstage renal disease or who are disabled. Data from all Medicare beneficiaries with an MI hospitalization and a 5% random sample of all beneficiaries were obtained from the

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Centers for Medicare and Medicaid Services (CMS) Chronic Conditions Warehouse.

The primary cohort included beneficiaries in the MarketScan and Medicare databases who were hospitalized for MI with an admission date on or after January 1, 2014 and a discharge date on or before June 30, 2015 (eFigure 1). Hospitalizations for MI were identified by a claim with an International Classification of Diseases, ninth version (ICD-9) diagnosis code of 410.XX, except for 410.X2, which indicates a subsequent episode of care, in the primary discharge diagnosis position. We restricted the analysis to beneficiaries who received a percutaneous coronary intervention (PCI), identified by an ICD-9 procedure code of 00.66, 36.0, 36.01-36.09, or a current procedural terminology code of 92980-92982, 92984, 92995, 92996, during their MI hospitalization. We did not include beneficiaries who underwent coronary artery bypass graft surgery as these individuals would differ significantly from the post-PCI population and have excess early mortality and risk for CVD events unrelated to the index MI. For this cohort, we refer to the date of hospital discharge following MI as the index date. To be included, beneficiaries were required to be at least 19, and less than 65 years of age if in the MartketScan database or at least 65.5, and less than 110 years of age if in the Medicare database on the date of their hospital admission for MI; have a hospitalization duration less than or equal to 30 days; live in the US; and have continuous fee-for-service health insurance coverage, including pharmacy benefits, and no hospice care for the 182 days before hospital admission through 30 days after discharge. We excluded beneficiaries who died in-hospital or within 30 days of hospital discharge. Beneficiaries having a recurrent MI or CHD event (defined below) within 30 days of discharge were also excluded. We used

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pharmacy claims to identify beneficiaries who were intensively medically managed following their MI hospitalization. Intensive medical management was defined as filling a prescription from all four of the following medication classes within 30 days of hospital discharge for MI: (1) high-intensity statin, (2) beta-blocker, (3) ACE inhibitor or ARB, and (4) prescription antiplatelet agent. High-intensity statins included atorvastatin 40 mg or 80 mg or rosuvastatin 20 mg or 40 mg. Antiplatelet agents included clopidogrel, prasugrel, or ticagrelor. Beneficiaries filling prescriptions for prasugrel were only included if they were <75 years with no history of stroke or transient ischemic attack consistent with Food and Drug Administration labelling. We did not include aspirin or the use of dual antiplatelet therapy as non-prescription medications are not captured in MarketScan or Medicare claims. In a secondary analysis, we restricted the study population to beneficiaries intensively medically managed in the primary analysis who also maintained high adherence with each of these four medication classes for the 182 days following hospital discharge for MI. For each medication class, adherence was estimated using the interval-based proportion of days covered (PDC) approach, with high adherence defined as a PDC ≥80%.27, 28

Although the main goal of this analysis was to determine the recurrent event rates for beneficiaries intensively medically managed post-MI, to provide context and aid in the interpretation of the magnitude of these event rates, three comparison populations were analyzed: (1) a random sample of beneficiaries in the MarketScan and Medicare databases, and beneficiaries in the MarketScan and Medicare databases with (2) diabetes or (3) a history of CHD. Diabetes and a history of CHD were defined using previously validated

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claims-based algorithms.29, 30 Each comparison population was identified using the MarketScan database and a 5% random sample of Medicare beneficiaries. We assigned every patient in the MarketScan and 5% Medicare sample a random date (i.e., an index date) between January 1, 2014 and June 30, 2015 for which they had insurance coverage. We restricted the analysis to MarketScan and Medicare beneficiaries who had continuous insurance coverage including pharmacy benefits and no hospice care for the 182 days before their index date. We matched a random sample of beneficiaries and those with diabetes and CHD to the intensively medically managed cohort based on five-year age groupings, sex, and calendar year of the index date using frequency matching. Specifically, for each beneficiary in the intensively medically managed cohort, four beneficiaries from the overall comparison population, four beneficiaries with diabetes, and four beneficiaries with CHD were selected from all possible age group, sex, and calendar year matches using a random number generator in SAS version 9.4 (SAS Institute, Cary N.C.).

Other potential confounders Among Medicare beneficiaries, race/ethnicity was defined using data in the beneficiary summary file. Data on race/ethnicity are not available in the MarketScan database. We used all available claims prior to each beneficiary’s index date to determine the presence of comorbid conditions including prior CHD, diabetes, chronic kidney disease, prior stroke, and heart failure (eTable 1).

Outcomes

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We identified the occurrence of MI and CHD events from 30 days after each beneficiary’s hospital discharge for their index MI, or the index date for the comparison populations, through December 31, 2015. All-cause mortality was analyzed for Medicare beneficiaries but is not available for beneficiaries in the MarketScan database. Beneficiaries not experiencing an event were censored upon loss of fee-for-service insurance coverage or December 31, 2015. As an outcome, MI was defined by an inpatient claim with an ICD-9 diagnosis code of 410.XX, except 410.X2, or an ICD-10 diagnosis code of I21.XX in any position. In a separate analysis, we defined the outcome of MI as claims with an ICD-9 diagnosis code of 410.XX, except 410.X2 or an ICD-10 diagnosis code of I21.XX, in the primary discharge diagnosis position. The transition from ICD-9 to ICD-10 diagnosis codes in the US occurred in October 2015. A CHD event was defined by an inpatient claim for MI in any discharge diagnosis position or inpatient or outpatient revascularization procedure, including PCI or coronary artery bypass grafting. Data on all-cause mortality were obtained for Medicare beneficiaries using Social Security Administration validated death dates in the Medicare beneficiary summary file.

Statistical Analysis Data from MarketScan and Medicare were pooled into a single data set for all analyses. We calculated characteristics of beneficiaries who were intensively medically managed following MI and for the three matched cohorts: the overall general population, those with diabetes, and those with a history of CHD. We calculated the cumulative incidence and incidence rates for MI and CHD events for each cohort. Also, for

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Medicare beneficiaries, we calculated cumulative mortality rates. We used proportional hazard regression models to calculate the hazard ratios for MI, CHD events, and, in Medicare only, all-cause mortality for beneficiaries receiving intensive medical management versus each matched population, separately. In addition to an unadjusted model, we constructed a model that included adjustment for age, sex, calendar year, race/ethnicity (available for Medicare beneficiaries only), history of CHD, diabetes, chronic kidney disease, stroke, and heart failure. Among the population that was intensively medically managed following their MI, we calculated the multivariableadjusted hazard ratios for recurrent MI, CHD events, and all-cause mortality associated with beneficiary characteristics and co-morbid conditions. We repeated the above analyses after restricting the intensively medically managed population to the subset of beneficiaries who filled all four medications within 30 days of hospital discharge and had high adherence for each medication class during the 182 days following hospital discharge for MI. For these analyses, follow-up for outcomes was initiated 182 days following hospital discharge for MI or the index date for the comparison groups. All analyses were conducted using SAS 9.4 (SAS Institute, Cary, NC) treating an alpha of < 0.05 as indicating statistical significance. Institutional review boards at the University of Alabama at Birmingham approved these analyses.

RESULTS A total of 16,853 of 72,116 (23%) beneficiaries meeting the eligibility criteria were intensively medically managed following MI (eFigure 1). Their characteristics and those of the three comparison populations are shown in Table 1. Beneficiaries who were

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intensively medically managed following MI were more likely to have diabetes and heart failure and less likely to have a history of stroke when compared to their counterparts in the overall population. They were more likely to be white and have a history of heart failure and less likely to have a history of CHD, chronic kidney disease, and stroke when compared to their counterparts with diabetes and less likely to have a history of diabetes, chronic kidney disease, and stroke when compared to their counterparts with a history of CHD.

MI, CHD Events, and Mortality Following MI Over a median follow-up of one year, there were 790 recurrent MIs, 1,184 CHD events, and 717 deaths among beneficiaries who were intensively medically managed following MI. Intensively managed beneficiaries had a higher incidence of MI and CHD events compared to their counterparts from the general population and those with diabetes or a history of CHD (Table 2 and Figure 1). All-cause mortality rates were also higher for Medicare beneficiaries who were intensively medically managed following MI compared to the general Medicare population, but rates were lower than for those with diabetes or a history of CHD. After multivariable adjustment, the hazard ratios for MI in any position and in the primary position, and CHD events were increased when comparing beneficiaries who were intensively medically managed following MI to those in the general population and those with diabetes or a history of CHD (Table 3). After multivariable adjustment, Medicare beneficiaries who were intensively medically managed following MI had an increased risk for all-cause mortality compared to matched beneficiaries in the general population. Mortality risk was not statistically

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significantly different between Medicare beneficiaries intensively medically managed and their counterparts with diabetes or a history of CHD after multivariable adjustment. An increased risk for MI and CHD events among beneficiaries who were intensively medically managed following their MI versus their counterparts in the three comparison populations was present when MarketScan and Medicare data were analyzed separately eTables 2 and 3).

Factors Associated with Increased Risk Following MI Among beneficiaries who were intensively medically managed following their MI, African Americans, relative to whites, and those with a history of CHD, diabetes, chronic kidney disease, stroke, and heart failure had increased risk for recurrent MI and CHD events and all-cause mortality (Table 4). A history of stroke was associated with recurrent MI in any position, CHD events, and all-cause mortality but not recurrent MI in the primary position. Older age (≥70 versus 65.5 to 69 years of age) was associated with a higher risk for all-cause mortality but not recurrent MI or CHD events. Male sex was associated with a lower risk for recurrent MI in any position and was not associated with risk for recurrent MI in the primary position or CHD events or all-cause mortality.

Secondary Analyses Overall, 14,777 of the 16,853 beneficiaries who were intensively medically managed had at least 182 days of follow-up after their MI hospital discharge date to assess medication adherence. Of these beneficiaries, 7,570 (51%) had high adherence to each of the four medication classes (eFigure 1). These beneficiaries had higher

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incidence rates and adjusted hazard ratios for MI and CHD events than their counterparts from the general population and those with diabetes or a history of CHD (Tables 5 and 6). The rates and adjusted hazard ratios for all-cause mortality were lower among beneficiaries who were intensively medically managed as compared with those in the general population and those with diabetes or a history of CHD.

DISCUSSION Beneficiaries in the current study who were intensively medically managed following MI had high rates for recurrent MI and CHD events (33 - 72 events per 1,000 person years). These event rates were much higher than those observed in a group of matched beneficiaries in the general MartketScan and Medicare population and those with diabetes or a history of CHD. The increased risk persisted even when the analysis was restricted to beneficiaries with high adherence to all four classes of medications for the initial 182 days following hospital discharge. Medicare beneficiaries intensively medically managed following MI had increased risk for all-cause mortality when compared to the general Medicare population, but a similar risk for all-cause mortality when compared to those with diabetes or a history of CHD. The risk for all-cause mortality was lower among Medicare beneficiaries intensively medically managed versus those in the general Medicare population or those with diabetes or a history of CHD when the analysis was restricted to MI patients with high adherence.

Results from the current study suggest that substantial residual cardiovascular risk remains present following MI despite intensive medical management in

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contemporary practice. Clinical trials, by design, describe the risk reduction associated with the use of one agent compared to placebo or lower intensity therapy but do not evaluate the residual risk associated with the use of a broad spectrum of risk reducing agents. Based on pooled data from large US cohort studies, 12%-45% of adults ≥65 years of age have a recurrent MI or fatal CHD event and over 25% die within 5 years of a first MI.1 However, these estimates do not account for the substantial percentage of patients with low adherence to secondary prevention medications. To emphasize this point, an analysis from the 1999-2012 US National Health and Nutrition Examination Surveys identified low utilization of secondary prevention medications following MI as a missed opportunity to modify risk.15 In addition, patients and families frequently ask about their risk for future events while taking multiple secondary prevention therapies and providers are faced with making decisions about which populations have sufficient residual risk to justify additional therapies.31 Quantifying this residual risk despite the use of a traditional secondary prevention regimen will help to inform these conversations. In the current analysis, the recurrent CHD event rate over approximately 2 years of follow-up after a MI was 10% despite intensive medical management.

Similar to other studies, African Americans and those with several comorbidities including a prior history of CHD, diabetes, chronic kidney disease, and heart failure had a particularly increased risk for recurrent CHD events and all-cause mortality.14, 17 These groups, many of which are risk enhancing factors that define individuals at very high risk in current guidelines,9 would likely benefit most from additional therapies following an MI. Given we observed that 10% of individuals experienced a recurrent

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event in the first 2 years following MI, identifying sub-groups at particularly increased risk and implementing additional risk reducing strategies immediately following MI is warranted.

Individuals with diabetes are traditionally considered to be at particularly high risk for recurrent events and death following MI. Cziraky et al. have reported a very high risk for recurrent CHD events in commercially insured individuals with diabetes receiving antiplatelet and antihypertensive medications.18 In the current study, those with diabetes had over an 83% increased risk for recurrent MI, 58% increased risk for recurrent CHD events, and a 30% increased risk for all-cause mortality as compared to those without diabetes despite intensive medical management. These data support directing interventions to reduce residual risk post-MI towards people with diabetes.

The current study has multiple strengths. Medicare and MarketScan data represent real world clinical care of large populations of adults from across the US. Over 70% of adults ≥65 years in the US have fee-for-service health insurance coverage through Medicare. Additionally, Marketscan provides representation of younger adults with commercial health insurance. Therefore, the results of this analysis are highly generalizable to patients receiving intensive medical management following an MI. Additionally, Medicare and Marketscan provide longitudinal data facilitating the examination of patients following hospital discharge for MI. However, the current study has a number of limitations. We excluded individuals who died within 30 days of hospital discharge. As a result, the event rates that we observed would not apply to this

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subset of MI patients. We relied on pharmacy claims data to identify filled prescriptions, so we may have failed to identify all beneficiaries who were receiving intensive medical therapy. Because we defined intensive medical management based on the first 30 days following MI, it is possible that some patients filling medications after 30 days were not included. However, in a previous analysis, over 80% of patients who filled secondary prevention medications did so within 10 days of hospital discharge for MI.32 We were unable to identify the use of aspirin since pharmacy claims data do not capture overthe-counter medication use. Finally, we did not require the use of cardiac rehabilitation services following MI as an inclusion criterion because low utilization rates would have substantially limited the study sample size.

CONCLUSIONS Despite intensive medical management with a high-intensity statin, beta-blocker, an ACE inhibitor or ARB, and prescription antiplatelet agent, MI patients have a high risk for recurrent MI and CHD events and a higher risk for all-cause mortality as compared with the general population. Interventions to reduce this residual risk are warranted.

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ACKNOWLEDGEMENTS The design and conduct of the study, analysis, and interpretation of the data, and preparation of the manuscript, was supported through a research grant from Amgen, Inc. (Thousand Oaks, CA). Drs. Monda and Somaratne are employees of Amgen, Inc. The academic authors conducted all analyses and maintain the rights to publish this article. Dr. Rosenson receives research support from Akcea, Amgen, The Medicines Company, and Regeneron, serves on Advisory Boards for Akcea, Amgen, Inc., the Medicines Company, and Regeneron, receives honoraria from Akcea, Kowa and Pfizer, and has stock holdings in MediMergent. Dr. Bittner has participated in advisory panels for Sanofi and has research funding through contracts between the University of Alabama at Birmingham and Amgen, Astra Zeneca, Dalcor, Bayer, Esperion, Sanofi, and The Medicines Company. Dr. Limdi has served as an advisor/ consultant for Admera Health. Dr. Brown has research funding through contracts between the University of Alabama at Birmingham and Astra Zeneca. Dr. Woodward has received personal support from Amgen. Dr. Muntner receives research grant support from Amgen, Inc. The remaining authors report no disclosures. All authors contributed to the design of the analyses and the interpretation of the data. Drs. Deng and Zhao conducted all statistical analyses. Dr. Brown wrote the first draft of the manuscript, and all authors reviewed and edited the manuscript. The final manuscript was approved for submission by all authors.

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26. Arnold SV, Spertus JA, Jones PG, et al. Predicting adverse outcomes after myocardial infarction among patients with diabetes mellitus. Circ Cardiovasc Qual Outcomes 2016;9:00-00. DOI: 10.1161/CIRCOUTCOMES.115.002365. 27. Raebel MA, Schmittdiel J, Karter AJ, Konieczny JL, Steiner JF. Standardizing terminology and definitions of medication adherence and persistence in research employing electronic data bases. Medical Care 2013;51(8 Suppl 3):S11-21. 28. Rasmussen JN, Chong A, Alter DA. Relationship between adherence to evidencebased pharmacotherapy and long-term mortality after acute myocardial infarction. JAMA 2007;297(2):177-186. 29. Schneider KM, O'Donnell BE, Dean D. Prevalence of multiple chronic conditions in the United States' Medicare population. Health Qual Life Outcomes 2009;7:82. 30. Kent ST, Safford MM, Zhao H, et al. Optimal use of available claims to identify a Medicare population free of coronary heart disease. Am J Epidemiol 2015;182(9):808-819. 31. Patel KV, Pandey A, deLemos JA. A conceptual framework for addressing residual atherosclerotic cardiovascular disease risk in the era of precision medicine. Circulation 2018. 10.1161/CIRCULATIONAHA.118.035289. 32. Yun H, Safford MM, Brown TM, et al. Statin use following hospitalization among Medicare beneficiaries with a secondary discharge diagnosis of acute myocardial infarction. J Am Heart Assoc 2015;4(10):e001208.

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Table 1. Characteristics of beneficiaries receiving intensive medical management following a myocardial infarction hospitalization with a percutaneous coronary intervention and matched comparison populations of beneficiaries.

Intensive medically managed post-MIa (n=16,853)

Overall (n=67,412)

Matched beneficiaries With diabetes With prior (n=67,412) history of CHD (n=67,412)

Calendar year 2014 11,293 (67.0) 45,172 (67.0) 45,172 (67.0) 45,172 (67.0) 2015 5,560 (33.0) 22,240 (33.0) 22,240 (33.0) 22,240 (33.0) Age, years <40 199 (1.2) 796 (1.2) 796 (1.2) 796 (1.2) 40-54 2,100 (12.5) 8,400 (12.5) 8,400 (12.5) 8,400 (12.5) 55-64 2,909 (17.3) 11,636 (17.3) 11,636 (17.3) 11,636 (17.3) 65.5-69 3,440 (20.4) 13,760 (20.4) 13,760 (20.4) 13,760 (20.4) 70-74 3,159 (18.7) 12,636 (18.7) 12,636 (18.7) 12,636 (18.7) 75-79 2,342 (13.9) 9,368 (13.9) 9,368 (13.9) 9,368 (13.9) 80-84 1,588 (9.4) 6,352 (9.4) 6,352 (9.4) 6,352 (9.4) ≥85 1,116 (6.6) 4,464 (6.6) 4,464 (6.6) 4,464 (6.6) Race/ethnicityb White 10,077 (86.5) 39,829 (85.5) 36,879 (79.2) 39,243 (84.2) African American 818 (7.0) 3,602 (7.7) 5,555 (11.9) 4,258 (9.1) Hispanic American 208 (1.8) 886 (1.9) 1,350 (2.9) 959 (2.1) Asian American 226 (1.9) 965 (2.1) 1,303 (2.8) 1,002 (2.2) Other 316 (2.7) 1,298 (2.8) 1,493 (3.2) 1,118 (2.4) Male sex 10,739 (63.7) 42,956 (63.7) 42,956 (63.7) 42,956 (63.7) Comorbidityc Prior CHD 5,634 (33.4) 21,077 (31.3) 29,231 (43.4) 67,412 (100.0) Diabetes 6,031 (35.8) 19,155 (28.4) 67,412 (100.0) 28,401 (42.1) CKD 4,367 (25.9) 16,985 (25.2) 25,753 (38.2) 24,966 (37.0) Stroke 759 (4.5) 5,277 (7.8) 7,563 (11.2) 8,458 (12.5) Heart failure 4,150 (24.6) 7,832 (11.6) 13,247 (19.7) 16,526 (24.5) Numbers in table are sample size (column percentage). CHD – coronary heart disease; MI – myocardial infarction, CKD - chronic kidney disease a

Beneficiaries who filled a high-intensity statin, beta blocker, angiotensin converting enzyme inhibitor or angiotensin receptor blocker, and prescription antiplatelet agent within 30 days of hospital discharge for myocardial infarction with a percutaneous coronary intervention were considered intensively medical managed.

b

Restricted to beneficiaries in Medicare.

c

Comorbidities defined in claims data prior to index date.

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Table 2. Myocardial infarction, coronary heart disease, and all-cause mortality event rates among beneficiaries receiving intensive medical management following a myocardial infarction hospitalization with a percutaneous coronary intervention and matched comparison populations of beneficiaries. Intensive Matched beneficiaries medically Overall With diabetes With history of managed post(n=67,412) (n=67,412) CHD (n=67,412) MIa (n=16,853) Recurrent myocardial infarction Any positionb N, events 790 359 549 722 Person-years 16,772 73,158 72,020 72,000 Rate (95% CI)c 47.1 (43.9, 50.5) 4.9 (4.4, 5.4) 7.6 (7.0, 8.3) 10.0 (9.3, 10.8) Primary positionb N, events 557 223 325 459 Person-years 16,901 73,219 72,119 72,125 Rate (95% CI)c 33.0 (30.3, 35.8) 3.0 (2.7, 3.5) 4.5 (4.0, 5.0) 6.4 (5.8, 7.0) CHD events N, events 1,184 601 925 1,281 Person-years 16,450 72,993 71,775 71,626 Rate (95% CI)c 72.0 (68.0, 76.2) 8.2 (7.6, 8.9) 12.9 (12.1, 13.7) 17.9 (16.9, 18.9) All-cause mortalityd N, events 717 2,378 3,192 3,182 Person-years 12,465 50,251 49,364 49,640 Rate (95% CI)c 57.5 (53.5, 61.9) 47.3 (45.5, 49.3) 64.7 (62.5, 66.9) 64.1 (61.9, 66.4) MI – myocardial infarction, CHD – coronary heart disease, CI – confidence interval. a

Beneficiaries who filled a high-intensity statin, beta blocker, angiotensin converting enzyme inhibitor or angiotensin receptor blocker, and prescription antiplatelet agent within 30 days of hospital discharge for myocardial infarction with a percutaneous coronary intervention were considered intensively medical managed.

b

Primary position refers to hospitalizations with a discharge diagnosis code for MI in the primary discharge diagnosis position, which represents the main reason for hospitalization. Any position refers to hospitalizations with a discharge diagnosis code for MI in the primary discharge diagnosis position or in any secondary discharge diagnosis position.

c

Rates are expressed per 1,000 person-years.

d

Restricted to beneficiaries in Medicare.

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Table 3. Hazard ratios for myocardial infarction, coronary heart disease, and all-cause mortality events comparing beneficiaries receiving intensive medical management following a myocardial infarction hospitalization with a percutaneous coronary intervention versus matched comparison populations of beneficiaries. Intensively medically managed post-MIa vs. general vs. diabetes vs. history of CHD population Unadjusted HR (95% CI) Myocardial infarction Any positionb Primary positionb CHD events All-cause mortalityc

9.48 (8.37-10.74) 10.72 (9.18-12.53) 8.57 (7.77-9.46) 1.22 (1.12-1.32)

6.13 (5.50-6.83) 7.26 (6.33-8.33) 5.51 (5.05-6.00) 0.89 (0.82-0.96) Adjusted HR (95% CI)

4.67 (4.22-5.16) 5.16 (4.56-5.83) 3.98 (3.68-4.31) 0.90 (0.83-0.97)

Myocardial infarction Any positionb 8.54 (7.52-9.70) 7.40 (6.61-8.28) 5.45 (4.92-6.05) b Primary position 9.56 (8.16-11.20) 8.60 (7.46-9.90) 5.91 (5.21-6.71) CHD events 7.82 (7.07-8.64) 6.27 (5.74-6.86) 4.45 (4.10-4.82) All-cause mortalityc 1.15 (1.05-1.25) 1.05 (0.97-1.14) 1.06 (0.97-1.15) MI – myocardial infarction, CHD – coronary heart disease, HR (95% CI) – hazard ratio (95% confidence interval) The adjusted analysis has adjustment for age, sex, calendar year, race/ethnicity, history of coronary heart disease (except for the comparison with beneficiaries with a history of coronary heart disease), diabetes (except for the comparison with beneficiaries with diabetes), chronic kidney disease, stroke, and heart failure. a

Beneficiaries who filled a high-intensity statin, beta blocker, angiotensin converting enzyme inhibitor or angiotensin receptor blocker, and prescription antiplatelet agent within 30 days of hospital discharge for myocardial infarction with a percutaneous coronary intervention were considered intensively medical managed.

b

Primary position refers to hospitalizations with a discharge diagnosis code for MI in the primary discharge diagnosis position, which represents the main reason for hospitalization. Any position refers to hospitalizations with a discharge diagnosis code for MI in the primary discharge diagnosis position or in any secondary discharge diagnosis position.

c

Restricted to beneficiaries in Medicare.

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Table 4. Hazard ratios for recurrent myocardial infarction, coronary heart disease, and all-cause mortality events among beneficiaries receiving intensive medical management following a myocardial infarction with a percutaneous coronary intervention. Myocardial infarction Any position Primary position

Coronary heart disease event

All-cause mortality

Calendar year 2014 1 (ref) 1 (ref) 1 (ref) 1 (ref) 2015 0.95 (0.80-1.13) 0.89 (0.72-1.10) 0.87 (0.75-1.00) 1.14 (0.95-1.37) Age, years <40 0.92 (0.34-2.48) b 0.44 (0.16-1.19) NA 40-54 0.82 (0.59-1.14) 0.75 (0.51-1.12) 0.69 (0.54-0.89) NA 55-64 0.80 (0.60-1.05) 0.57 (0.40-0.83) 0.75 (0.61-0.92) NA 65.5-69 1 (ref) 1 (ref) 1 (ref) 1 (ref) 70-74 0.78 (0.63-0.97) 0.83 (0.65-1.07) 0.79 (0.67-0.94) 1.43 (1.13-1.80) 75-79 1.04 (0.84-1.29) 1.04 (0.81-1.34) 1.00 (0.84-1.19) 1.50 (1.18-1.91) 80-84 0.84 (0.65-1.09) 0.88 (0.65-1.19) 0.73 (0.58-0.91) 1.97 (1.53-2.52) ≥85 1.15 (0.89-1.50) 1.23 (0.91-1.67) 0.82 (0.65-1.04) 2.77 (2.16-3.56) Race/ethnicitya White 1 (ref) 1 (ref) 1 (ref) 1 (ref) African American 1.57 (1.25-1.98) 1.54 (1.17-2.01) 1.40 (1.14-1.71) 1.31 (1.03-1.66) Hispanic American 1.38 (0.90-2.13) 1.46 (0.90-2.39) 1.22 (0.82-1.81) 0.87 (0.51-1.49) Asian American 1.17 (0.72-1.90) 0.91 (0.48-1.70) 1.11 (0.72-1.70) 0.77 (0.45-1.31) Other 1.01 (0.62-1.65) 0.94 (0.53-1.68) 1.07 (0.74-1.57) 0.62 (0.34-1.13) Male sex 0.85 (0.74-0.99) 0.93 (0.78-1.11) 1.01 (0.89-1.14) 1.01 (0.87-1.17) Comorbidity CHD 1.98 (1.70-2.30) 1.99 (1.66-2.39) 1.61 (1.43-1.82) 1.56 (1.33-1.83) Diabetes 1.83 (1.57-2.13) 2.00 (1.67-2.40) 1.58 (1.40-1.78) 1.30 (1.11-1.52) CKD 1.61 (1.38-1.89) 1.69 (1.40-2.03) 1.45 (1.27-1.64) 1.64 (1.40-1.93) Stroke 1.32 (1.04-1.67) 0.99 (0.73-1.35) 1.25 (1.02-1.54) 1.42 (1.13-1.79) Heart failure 1.82 (1.56-2.12) 1.78 (1.48-2.13) 1.65 (1.46-1.87) 2.67 (2.28-3.14) CHD – coronary heart disease, CKD – chronic kidney disease. NA – not applicable as mortality data were not available for beneficiaries less than 65 years of age. a

Restricted to beneficiaries in Medicare.

b

There were no myocardial infarctions in the primary position among beneficiaries <40 years of age. All analyses include adjustment for age, sex, calendar year, race/ethnicity, history of coronary heart disease, diabetes, chronic kidney disease, stroke, and heart failure.

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Table 5. Myocardial infarction, coronary heart disease, and all-cause mortality rates among beneficiaries maintaining high adherence for at least 182 days to intensive medical management following a myocardial infarction hospitalization with a percutaneous coronary intervention and matched comparison populations of beneficiaries. Intensive medically managed post-MIa (n=7,570) Recurrent myocardial infarction Any positionb N, events 152 Person-years 5,057 Rate (95% CI) 30.1 (25.6, 35.2) Primary positionb N, events 107 Person-years 5,076 Rate (95% CI) 21.1 (17.4, 25.5) CHD events N, events 207 Person-years 5,022 Rate (95% CI) 41.2 (36.0, 47.2) All-cause mortalityc N, events 107 Person-years 3,559 Incidence rate (95% CI) 30.1 (24.9, 36.3)

Overall (n=30,280)

Matched beneficiaries With diabetes With history of (n=30,280) CHD (n=30,280)

79 21,402 3.7 (3.0, 4.6)

159 21,238 7.5 (6.4, 8.7)

193 21,127 9.1 (7.9, 10.5)

43 21,412 2.0 (1.5, 2.7)

99 21,258 4.7 (3.8, 5.7)

126 21,153 6.0 (5.0, 7.1)

140 21,373 6.6 (5.6, 7.7)

254 21,194 12 (10.6, 13.6)

328 21,062 15.6 (14.0, 17.4)

630 14,377 43.8 (40.5, 47.4)

811 14,209 57.1 (53.3, 61.1)

895 14,211 63.0 (59.0, 67.2)

MI – myocardial infarction, CHD – coronary heart disease, CI – confidence interval. a

Beneficiaries who filled a high intensity statin, beta blocker, angiotensin converting enzyme inhibitor or angiotensin receptor blocker, and prescription antiplatelet agent within 30 days of hospital discharge for myocardial infarction with a percutaneous coronary intervention and who had high adherence to all four medications (proportion of days covered ≥ 80%) for 182 days following hospital discharge were considered intensively medical managed. b

Primary position refers to hospitalizations with a discharge diagnosis code for MI in the primary discharge diagnosis position, which represents the main reason for hospitalization. Any position refers to hospitalizations with a discharge diagnosis code for MI in the primary discharge diagnosis position or in any secondary discharge diagnosis position.

c

Restricted to beneficiaries in Medicare.

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Table 6. Hazard ratios for myocardial infarction, coronary heart disease events, and all-cause mortality comparing beneficiaries maintaining high adherence for at least 182 days to intensive medical management following a myocardial infarction hospitalization with a percutaneous coronary intervention and matched comparison populations of beneficiaries. Intensively medically managed post-MIa vs. general vs. diabetes vs. history of CHD population Unadjusted HR (95% CI) Myocardial infarction Any positionb 8.12 (6.19-10.65) 4.02 (3.22-5.02) 3.29 (2.66-4.07) Primary positionb 10.49 (7.36-14.95) 4.54 (3.45-5.97) 3.55 (2.74-4.59) CHD events 6.25 (5.04-7.74) 3.43 (2.86-4.12) 2.64 (2.22-3.14) All-cause mortalityc 0.69 (0.56-0.84) 0.53 (0.43-0.65) 0.48 (0.39-0.58) Adjusted HR (95% CI) Myocardial infarction Any positionb 8.15 (6.17-10.77) 5.09 (4.02-6.43) 3.85 (3.09-4.79) Primary positionb 10.43 (7.27-14.97) 5.56 (4.17-7.42) 3.98 (3.05-5.19) CHD events 6.20 (4.98-7.72) 4.10 (3.38-4.97) 2.94 (2.46-3.51) c All-cause mortality 0.70 (0.57-0.86) 0.62 (0.50-0.76) 0.57 (0.47-0.70) MI – myocardial infarction, CHD – coronary heart disease, HR (95% CI) – hazard ratio (95% confidence interval) The adjusted analysis includes adjustment for age, sex, calendar year, race/ethnicity, history of coronary heart disease (except for the comparison with beneficiaries with a history of coronary heart disease), diabetes (except for the comparison with beneficiaries with diabetes), chronic kidney disease, stroke, and heart failure. a

Beneficiaries who filled a high-intensity statin, beta blocker, angiotensin converting enzyme inhibitor or angiotensin receptor blocker, and prescription antiplatelet agent within 30 days of hospital discharge for myocardial infarction with a percutaneous coronary intervention and who had high adherence to all four medications (proportion of days covered ≥ 80%) for 182 days following hospital discharge were considered intensively medical managed. b

Primary position refers to hospitalizations with a discharge diagnosis code for MI in the primary discharge diagnosis position, which represents the main reason for hospitalization. Any position refers to hospitalizations with a discharge diagnosis code for MI in the primary discharge diagnosis position or in any secondary discharge diagnosis position.

c

Restricted to beneficiaries in Medicare.

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Figure Title and Legend Figure 1. Cumulative risk for myocardial infarction, coronary heart disease event, and all-cause mortality among beneficiaries receiving intensive medical management† following a myocardial infarction hospitalization with a percutaneous coronary intervention versus matched comparison populations of beneficiaries. †

Beneficiaries who filled a high-intensity statin, beta blocker, angiotensin converting enzyme inhibitor or angiotensin receptor blocker, and prescription antiplatelet agent within 30 days of hospital discharge for myocardial infarction with a percutaneous coronary intervention were considered intensively medical managed. The comparison populations were derived from a 5% sample of Medicare beneficiaries and the MarketScan database and were matched 4:1 to those receiving intensive medical management following hospital discharge for myocardial infarction with a percutaneous coronary intervention. We matched a random sample of beneficiaries and those with diabetes and a history of CHD to the intensively medically managed cohort based on five-year age groupings, sex, and calendar year of the index date. Upper left panel (myocardial infarction) – Hospitalizations with myocardial infarction in any discharge diagnosis position. Upper right panel (primary myocardial infarction) – Hospitalizations with myocardial infarction in the primary discharge diagnosis position. Bottom left panel (coronary heart disease) – Hospitalizations with myocardial infarction in any discharge diagnosis position or an inpatient or outpatient coronary revascularization procedure. Bottom right panel (all-cause mortality) – Deaths were identified through Social Security Administration validated death dates.

30

Highlights

Risk post myocardial infarction is high despite intensive secondary prevention.

AHA/ACC guideline risk enhancing factors predict risk after myocardial infarction.

New therapies targeting residual risk following myocardial infarction are warranted.