Management and outcome across the spectrum of high‐risk patients with myocardial infarction according to the thrmobolysis in myocardial infarction (TIMI) risk‐score for secondary prevention

Abstract Background Patients with myocardial infarction (MI) are at increased risk for recurrent cardiovascular events, yet some patients, such as the elderly and those with prior comorbidities, are particularly at the highest risk. Whether these patients benefit from contemporary management is not fully elucidated. Methods Included were consecutive patients with MI who underwent percutaneous coronary intervention (PCI) in a large tertiary medical center. Patients were stratified according to the thrombolysis in myocardial infarction (TIMI) risk score for secondary prevention (TRS2°P) to high (TRS2°P = 3), very high (TRS2°P = 4), or extremely high‐risk (TRS2°P = 5–9). Excluded were low and intermediate‐risk patients (TRS2°P < 3). Outcomes included 30‐day/1‐year major adverse cardiac events (MACE) and 1‐year mortality. Temporal trends were examined in the early (2004–2010) and late (2011–2016) time‐periods. Results Among 2053 patients, 50% were high‐risk, 30% very high‐risk and 20% extremely high‐risk. Extremely high‐risk patients were older (age 74 ± 10 year) and had significant comorbidities (chronic kidney disease 68%, prior CABG 40%, heart failure 78%, peripheral artery disease 29%). Drug‐eluting stents and potent antiplatelets were more commonly used over time in all risk‐strata. Over time, 30‐day MACE rates have decreased, mainly attributed to the very high (11.3% to 5.1%, p = .006) and extremely high‐risk groups (15.9% to 8.0%, p = .016), but not the high‐risk group, with similar quantitative results for 1‐year MACE. The rates of 1‐year mortality remained unchanged in either group. Conclusion Within a particularly high‐risk cohort of MI patients who underwent PCI, the implementation of guideline‐recommended therapies has improved over time, with the highest‐risk groups demonstrating the greatest benefit in outcomes.

K E Y W O R D S clinical outcomes, high-risk populations, myocardial infarction, risk-stratification, temporal trends

| INTRODUCTION
Patients who experience a myocardial infarction (MI) are at increased risk for recurrent cardiovascular events. Nevertheless, this risk is not similar in all patients, and it is determined by the patient's age, burden of coronary artery disease, and concomitant comorbidities. We previously demonstrated that post-MI patients who were at a higher risk for recurrent cardiovascular events according to the thrombolysis in myocardial infarction (TIMI) risk score for secondary prevention (TRS2 P) derived the most benefit from the improved implementation of guideline-directed care throughout a decade long. 1,2 This trend was observed despite the fact that these high-risk patients were oftentimes undertreated compared with lower-risk patients.
This inverse relationship between the estimated cardiovascular risk of patients and the delivery of guideline-recommended therapies has long been recognized and referred to as the "risk-treatment paradox." [3][4][5][6] Other studies in recent years have indicated a similar trend of proportionally greater clinical benefit with guideline-based therapies among those with higher baseline risk, [7][8][9][10][11][12][13][14][15] which usually make the perceptually more complex-to-treat patients, including the elderly and patients with a tendency to bleeding.
Since prior studies have seldom included patients at the highestrisk after an MI, it is not clear whether this trend applies to the very and extremely high-risk patients-those who are not only the sickest and most comorbid but also with a far more pronounced risk for adverse events from treatment. In the FAST-MI registry appropriate secondary prevention treatment and cardiac rehabilitation prescription at discharge were associated with larger relative risk reduction in clinical outcomes, particularly among highest-risk patients (TRS2 P ≥ 5). 13,14 Similarly, the net clinical outcome with the antiplatelet vorapaxar was more pronounced in the high-risk (TRS2 P ≥ 3) group of patients. 8 We aimed to examine temporal trends over more than a decade in the treatment and outcome across the spectrum of high-risk patients according to the TRS2 P in post-MI patients. We hypothesized that this high-risk group would demonstrate a graded benefit in clinical outcomes across the years.

| METHODS
A single-center retrospective cohort study including all consecutive patients identified from the percutaneous coronary intervention (PCI) registry of the Rabin Medical Center (RMC, a tertiary medical center in Israel), who had undergone PCI due to MI and were discharged alive during the years 2004-2016. The RMC's registry database entails all consecutive patients' demographic, clinical, and angiographic data, details of which, including data collection and protocol, were previously elaborated. 1 Data collection was approved by the hospital ethics committee in compliance with the Declaration of Helsinki, with a waiver for the need of individual informed consent. The index date for inclusion in the study cohort was the date of the first PCI performed for the indication of acute MI during the study period. In the case of several interventions for a single patient during that time, only the first was included in the analysis. MI was defined according to the standard universal definitions available at the time of the index hospitalization.
The TRS2 P is a simple risk score incorporating nine clinical characteristics, each is assigned a single point in the total count. These characteristics include age ≥ 75, diabetes mellitus, hypertension, current smoking, peripheral artery disease, prior stroke, prior coronary artery bypass graft surgery (CABG), chronic heart failure, and chronic kidney disease (defined by modification of diet in renal disease [MDRD] as <60 ml/min). This score was devised relatively recently 8 in order to predict a gradient of risk for major adverse cardiovascular events (MACE) at 3-years post-MI. It was later validated for secondary prevention in a number of studies 7,9,13,14,16 demonstrating the ability to risk-stratify patients for recurrent events and to distinguish a pattern of increasing benefit with optimal treatment. This study included only patients with TRS2 P ≥ 3. Patients with TRS2 P < 3 were excluded, as well as patients who had missing data regarding one or more components of the TRS2 P.

| Statistical analysis
All descriptive data presented, including baseline characteristics of patients, features and management of the index MI, and clinical outcomes, were stratified by the three TIMI groups. Continuous parameters were presented by the average and standard deviation. Ordinal

| RESULTS
Of 4921 post-MI patients, 2053 patients (42%) with TRS2 P ≥ 3 were included in the current study. Of these, 50% (n = 1036) were classified as high-risk, 30% (n = 602) as very high-risk, and 20% (n = 415) as extremely high-risk patients ( Figure S1). Baseline characteristics of patients are presented in Table S2. Compared with the other groups, extremely high-risk patients were older (mean age 74 ± 10 years) and With respect to the index MI, extremely high-risk patients presented more often with non-ST elevation MI and three-vessel coronary disease on angiography compared with the other risk groups (Table 1).
They had lower post-procedural nadir hemoglobin/hematocrit levels, and required blood transfusions to a larger extent, although the absolute rates were still fairly low. At discharge from the hospital, they were less commonly prescribed potent P2Y12 inhibitors and received clopidogrel more often. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) were also prescribed less often in extremely high-risk patients. Statins were recommended equally and extensively across all risk groups while diuretics and oral anticoagulants (primarily vitamin K antagonists) far prevailed in the extremely high-risk group.
The 30-day MACE of extremely high-risk patients was higher compared with very high and high-risk patients (12.5%, 8.5%, and 4.1%, respectively, p < .001, Table 2). This was driven mostly by a higher proportion of cerebrovascular accidents and unstable angina (8.4%, 5.3%, and 2.2%, p < .001; 1.7%, 0.7%, and 0.4%, p = .029, respectively). As expected, outcomes in 1 year reflected the same graded risk; The rate of 1-year MACE and each of its individual components (1-year mortality included, Figure S2) was proportionally T A B L E 3 Temporal trends in guideline recommended therapies

| DISCUSSION
In the present study, we demonstrated several findings; first, we substantiated the TRS2 P as a risk stratification tool that distinguishes a gradient of risk for MACE, not only in patients with prior MI, as was previously shown, 16 but also when applied specifically to a high-risk cohort. Second, we demonstrated that guideline- In this high-risk cohort of patients who were the subject of the current study, the utilization of drug-eluting stents and potent antiplatelets has improved considerably, in keeping with findings from prior studies. 1,2,4,6 Furthermore, owing to the study design, all included patients had undergone PCI, and while this was an inclusion criteria and not a treatment aspect to be compared between time periods, it is still noteworthy as revascularization is often underutilized in elderly and comorbid populations 17,18 (although the benefit appears to be maintained at older age 3,19 ) and as it probably did have a profound impact on these patients' outcomes.
We chose to focus on patients who are at the highest risk for recurrent cardiovascular events-A population who, due to the complexity of their comorbidities, poses a therapeutic challenge; they are uncommonly enrolled in randomized clinical trials, 20 they are oftentimes managed conservatively rather than invasively with angiography, and are usually infrequently treated with guideline-directed medical therapy. They ultimately experience higher rates of morbidity and mortality, far exceeding the previously reported 10-year atherosclerotic cardiovascular disease (ASCVD) risk 21,22 and the 10-year risk of fatal cardiovascular outcomes 23 attributed to very high-risk and extremely high-risk patients. Still, we found no studies specifically addressing the optimal management of these particularly high-risk patients, and most of the data were driven from subgroup analysis of other populations. 8,24 The extremely high-risk patients in this study had significant co- were unavailable. Therefore, we cannot vouch for medication adherence post-discharge date, though many of these patients continued follow-up in the hospital clinics. Second, we had no available information regarding the number, location, and specific types of stents deployed, nor did we pertain data concerning periprocedural bleeding complications. Nevertheless, we did obtain data regarding blood transfusions received and hemoglobin levels at several time points during hospitalization and at 1-year follow-up. In addition, we lacked data with respect to rehabilitation referral, an important part of guideline-directed management. Finally, our study cannot infer a causal relationship between the improved treatment and outcome.

| CONCLUSION
Within a cohort of patients with MI at high, very high, and extremely high-risk for recurrent cardiovascular events, the implementation of guideline-recommended therapies has improved over a decade long, with the higher-risk groups demonstrating the greatest benefit in cardiovascular clinical outcomes.

CONFLICT OF INTEREST
The authors declare that there is no conflict of interest.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.