Abstract
Optimal medical therapy, including Beta-blockers (BB), inhibitors of the renin-angiotensin system (RAS), and statins, is recommended for patients with acute myocardial infarction (AMI) in the absence of contraindications. However, the optimal duration of these medications has not been clearly established in clinical studies. This observational study aimed to investigate the period during which these medications are associated with improved clinical outcomes. Among patients enrolled in the Korea Acute Myocardial Infarction Registry-National Institute of Health (KAMIR-NIH), in-hospital survivors were selected. In a Cox-proportional hazard analysis of 12,200 patients, BB (hazard ratio [HR] = 0.73; 95% confidence interval [CI] = 0.57–0.95; P = .019), RAS inhibitors (HR 0.70; 95% CI = 0.55–0.89; P = .004), and statins at discharge (HR = 0.65; 95% CI = 0.48–0.87; P = .004) were all associated with lower 1-year cardiac mortality. At 1-year, 10,613 patients without all-cause death, myocardial infarction, revascularization, or re-hospitalization due to heart failure were selected for further analysis. RAS inhibitors (HR = 0.53; 95% CI = 0.37–0.76; P = .001) and statins (HR = 0.30; 95% CI = 0.14–0.61; P = .001) prescribed at 1-year were associated with lower 2-year cardiac mortality, whereas BB were not (HR = 0.79; 95% CI = 0.51–1.23; P = .23). However, none of these medications prescribed at 2-years were associated with reduced 3-year cardiac mortality among the 9232 patients who remained event-free until then. RAS inhibitors and statins were associated with reduced cardiac mortality for up to 2-years, and BB for up to 1-year after the initial attack. The effectiveness of these medications beyond these periods remains questionable.
Keywords: beta-blockers, mortality, myocardial infarction, renin-angiotensin system, statin
1. Introduction
Acute myocardial infarction (AMI) is the primary cause of cardiac mortality and morbidity worldwide.[1,2] It necessitates evidence-based, long-term medical treatment to reduce future cardiovascular events following optimal initial reperfusion therapy. Beta-blockers (BB), inhibitors of the renin-angiotensin system (RAS), and statins are the 3 mainstream medications recommended for patients with AMI.[3–7] However, the optimal duration of these medications has not been clearly demonstrated in the randomized clinical trials, leading to the inconsistent recommendations.
The American guideline recommended long-term beta-blocker therapy for patients with a previous myocardial infarction (MI) and left ventricular ejection fraction (LVEF) ≤ 40%. It also suggested at least 3-years of beta-blocker therapy even in patients with normal LV function.[8] Recently, this guideline has been revised to reconsider the need of long-term beta-blocker therapy beyond 1-year for patients with prior MI and LVEF ≥ 50%.[9] Conversely, the European guideline continues to advocate for long-term treatment with BB for more than 1-year in patients with previous MI, even if they do not have heart failure (HF) or left ventricular (LV) systolic dysfunction, despite some studies questioning the benefits of such prolonged therapy.[10]
According to the American guideline, patients with stable ischemic heart disease (IHD) who have hypertension, diabetes mellitus (DM), a left ventricular ejection fraction (LVEF) ≤ 40%, or chronic kidney disease (CKD) are advised to take angiotensin-converting enzyme (ACE) inhibitors, unless otherwise indicated. These inhibitors are also recommended for patients with stable IHD who suffer from other vascular diseases. For those intolerant to ACE inhibitors, the use of angiotensin receptor blockers (ARBs) is recommended.[8] Additionally, the recent guideline suggests RAS inhibitors for patients with HF with mildly reduced ejection fraction (HFmrEF), regardless of the underlying cause.[9] Conversely, the European guideline advises that patients with chronic coronary syndrome (CCS) who do not have HF or significant cardiovascular risk generally should not take RAS inhibitors, except for blood pressure control.[10]
High-intensity statins are recommended to be started immediately after an MI to help achieve low-density lipoprotein (LDL)-cholesterol targets. Alongside lifestyle management, statins are typically prescribed as lifelong medication unless adverse effects necessitate discontinuation.[9,10]
The optimal duration of medical therapy after AMI may evolve in the era of early coronary reperfusion and potent antiplatelet therapy, but a paucity of randomized controlled trials limits clinical guidance. Although observational cohort studies using registry data have inherent limitations in establishing causality, and their findings do not always align with those of randomized controlled trials,[11] they offer the advantage of reflecting real-world clinical situations and treatment effects, with a simpler study design and execution compared to randomized controlled trials. This observational study aimed to investigate the period during which BB, RAS inhibitors, and statins are associated with improved clinical outcomes following an AMI, utilizing data from patients enrolled in the Korea Acute Myocardial Infarction-National Institutes of Health (KAMIR-NIH) registry.
2. Methods
2.1. Study population and data collection
The KAMIR-NIH, a prospective, multicenter, web-based observational cohort study involving 20 university hospitals across South Korea, enrolled consecutive patients admitted primarily for AMI who completed informed consent forms from November 1, 2011, to October 31, 2015.[12] This investigation was conducted in accordance with the ethical criteria outlined by the Declaration of Helsinki. The study’s protocol was approved by the ethical committees of each participating center, including Chonnam National University Hospital, Republic of Korea (IRB No. CNUH-2011-172). All participants or their legal representatives provided written informed consent. Data were collected using a web-based case report form within the clinical data management system of the Korea National Institutes of Health, with both the attending physician and a certified clinical study coordinator responsible for gathering the information. The exclusion criteria were patients who died during index hospitalization; patients who did not undergo echocardiographic studies during index hospitalization; and patients with incomplete data.
AMI was identified when at least 1 of the following conditions was present alongside evidence of myocardial necrosis (a spike or reduction in a cardiac biomarker, preferably cardiac troponin): ischemic symptoms; new or suspected significant ST-segment-T wave changes or a new left bundle branch block; the appearance of pathologic Q waves on the ECG; imaging evidence of a new regional wall motion abnormality or loss of viable myocardium; and detection of an intracoronary thrombus by angiography.[13] Percutaneous coronary intervention (PCI), thrombolysis, coronary artery bypass graft (CABG), as well as conditions like myocardial infarction with non-obstructed coronary arteries (MINOCA) and myocardial bridge, were considered forms of coronary reperfusion.
2.2. Clinical endpoints and definition
The primary clinical endpoint was the occurrence of cardiac death (CD). Secondary endpoints included all-cause death, MI, revascularization, re-admission due to HF, and major adverse cardiac events (MACE), which was defined as a composite of CD, MI, revascularization, and re-admission due to HF. Additionally, stroke and major adverse cardiac and cerebrovascular events (MACCE), defined as MACE plus stroke, along with MACE with noncardiac death (NCD), were also evaluated.
In the absence of a conclusive noncardiac cause, deaths were presumed to be due to cardiac issues. Revascularization included either target or nontarget vessel PCI or CABG, excluding staged PCI. Clinical follow-ups were routinely conducted at 6, 12, 24, and 36 months through hospital visits, and additional follow-ups were performed whenever a clinical incident occurred. If patients did not attend these hospital visits, outcome data were gathered through telephone interviews. Clinical outcomes were not adjudicated centrally. Instead, each event was identified by the attending physician, and verified by the primary investigator at each hospital.
2.3. Statistical analysis
For continuous variables, data were presented as either the mean plus or minus the standard deviation or as the median with the interquartile range. Differences between the 2 groups were assessed using either the unpaired t-test or the Mann–Whitney U test. For discrete variables, differences were quantified as counts and percentages and were evaluated using the χ2 test to compare the 2 groups. The study utilized Cox-proportional hazard models to evaluate the adjusted hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) for each clinical outcome. To control for potential confounding factors, a multivariate analysis was conducted including variables potentially relevant to the results. These variables included age, gender, body mass index (BMI), smoking status, Killip class upon admission, LVEF, cardiovascular risk factors or comorbidities (such as hypertension, DM, hyperlipidemia, previous HF, previous stroke, previous MI, and previous angina), initial estimated glomerular filtration rate (eGFR), co-medications (such as aspirin, P2Y12 inhibitors, calcium channel blockers, BB, RAS inhibitors, and statins), and the type of myocardial infarction (ST-elevation MI [STEMI] or non-ST-elevation MI [NSTEMI]). Kaplan–Meier estimates were used to generate survival curves for clinical endpoints and to calculate cumulative event rates, including incidence rates per 100 patient-years over a period of up to 3-years. Additionally, a post hoc subgroup analysis was conducted based on LVEF categories: ≤40%, >40% to <50%, and ≥50%.
Data analysis was performed using SPSS version 23 (IBM Co, Armonk, NY, US) and R version 3.1.3 (R Foundation for Statistical Computing, Vienna, Austria). A significance level of P < .05 was adopted for all analyses to determine statistical significance.
3. Results
The KAMIR-NIH registry initially enrolled 13,624 consecutive patients. After excluding 1424 individuals-including 252 who died during their initial hospital stay, 1153 who lacked echocardiographic data, and 19 with incomplete records-a total of 12,200 patients were included in the final analysis (Fig. 1). BB, RAS inhibitors, and statins were prescribed at the discretion of the attending physicians.
Figure 1.
Selection of patients for analysis. BB, beta-blockers; Echo, echocardiography; KAMIR-NIH, Korean Acute Myocardial Infarction Registry-National Institute of Health; MACE, major adverse cardiac events; RASI, inhibitors of the renin-angiotensin system.
3.1. Baseline clinical characteristics
Of the total 12,200 patients, 1949 (16%) were not prescribed BB at discharge. Patients who did not receive BB at discharge were characterized by several factors: advanced age, lower BMI, fewer current smokers, a lower prevalence of hypertension, a higher prevalence of previous episodes of angina and HF, classification as Killip class ≥ II, eGFR < 60 mL/min/1.73m², and NSTEMI, and a lower rate of coronary reperfusion and concomitant medications (Table 1). PCI using drug-eluting stents was the primary method for coronary reperfusion and patients who did not receive BB exhibited a higher incidence of MINOCA (Table S1, Supplemental Digital Content, http://links.lww.com/MD/O36). A review of BB prescribed at discharge, and at the 1-year and 2-year follow-ups, revealed that bisoprolol and carvedilol were the most commonly prescribed. Additionally, the doses administered were lower than those recommended by the guidelines (Table S2, Supplemental Digital Content, http://links.lww.com/MD/O36).
Table 1.
Baseline characteristics of patients with or without beta-blockers.
| All patients (N = 12,200) | With beta-blocker (N = 10,251) | Without beta-blocker (N = 1949) | P value | |
|---|---|---|---|---|
| Age (yr) | 63.6 ± 12.6 | 63.2 ± 12.5 | 65.6 ± 12.9 | <.001 |
| Male | 9067 (74.3) | 7655 (74.7) | 1414 (72.4) | .041 |
| Body mass index (kg/m2) | 24.05 ± 3.31 | 24.15 ± 3.29 | 23.53 ± 3.38 | <.001 |
| Hypertension | 6156 (50.5) | 5230 (51.0) | 926 (47.5) | .005 |
| Diabetes mellitus | 3411 (28.0) | 2902 (28.3) | 509 (26.1) | .051 |
| Prior angina pectoris | 1159 (9.5) | 908 (8.9) | 251 (12.9) | <.001 |
| Prior myocardial infarction | 934 (7.7) | 768 (7.5) | 166 (8.5) | .124 |
| Prior heart failure | 180 (1.5) | 137 (1.3) | 43 (2.2) | .004 |
| Prior stroke | 795 (6.5) | 674 (6.6) | 121 (6.2) | .580 |
| Current smoker | 4849 (39.7) | 4123 (40.2) | 726 (37.2) | .014 |
| Killip class ≥ II | 2436 (20.0) | 1977 (19.3) | 459 (23.6) | <.001 |
| eGFR < 60 mL/min/1.73m2 | 2217 (18.2) | 1791 (17.5) | 426 (21.9) | <.001 |
| Left ventricular EF (%) | 52.2 ± 11.0 | 52.2 ± 10.8 | 52.5 ± 12.1 | .309 |
| STEMI | 5806 (47.6) | 5065 (49.4) | 741 (38.0) | <.001 |
| Coronary reperfusion* | 11,661 (95.6) | 9844 (96.0) | 1817 (93.2) | <.001 |
| Medications at discharge | ||||
| Aspirin | 12,160 (99.7) | 10,235 (99.8) | 1925 (98.8) | <.001 |
| P2Y12 inhibitor | 11,666 (95.6) | 9986 (97.4) | 1680 (86.2) | <.001 |
| RAS inhibitors | 9729 (79.7) | 8.663 (84.5) | 1066 (54.7) | <.001 |
| Statins | 11,415 (93.6) | 9725 (94.9) | 1690 (86.7) | <.001 |
Values are mean ± standard deviation or number (%).
Abbreviations: EF = ejection fraction, eGFR = estimated glomerular filtration rate, RAS = renin-angiotensin system, STEMI = ST-elevation myocardial infarction.
Included reperfusion by percutaneous coronary intervention, thrombolysis, or coronary artery bypass graft, myocardial infarction with non-obstructed coronary arteries and myocardial bridge.
RAS inhibitors were not prescribed at discharge for 2471 (20%) patients. The patients that were not taken RAS inhibitors exhibited advanced age, lower BMI, and a lower occurrence of hypertension and current smoker, a greater proportion classified as Killip class ≥ II, and eGFR < 60 mL/min/1.73m², a higher incidence of NSTEMI, and a lower rate of coronary reperfusion and concomitant medications (Table 2). In patients who did not receive RAS inhibitors, fewer PCI procedures were performed alongside a higher prevalence of MINOCA (Table S3, Supplemental Digital Content, http://links.lww.com/MD/O36). Perindopril, ramipril, and candesartan were the most commonly prescribed RAS inhibitors at discharge and throughout the first and second years. Additionally, the doses administered were lower than those recommended by the guidelines (Table S4, Supplemental Digital Content, http://links.lww.com/MD/O36).
Table 2.
Baseline characteristics patients of with or without RAS inhibitors.
| All patients (N = 12,200) | With RAS inhibitors (N = 9729) | Without RAS inhibitors (N = 2471) | P value | |
|---|---|---|---|---|
| Age (yr) | 63.6 ± 12.6 | 63.4 ± 12.5 | 64.3 ± 12.8 | .001 |
| Male | 9067 (74.3) | 7240 (74.4) | 1827 (73.9) | .625 |
| Body mass index (kg/m2) | 24.05 ± 3.31 | 24.14 ± 3.30 | 23.70 ± 3.33 | <.001 |
| Hypertension | 6156 (50.5) | 5012 (51.5) | 1144 (46.3) | <.001 |
| Diabetes mellitus | 3411 (28.0) | 2709 (27.8) | 702 (28.4) | .581 |
| Prior angina pectoris | 1159 (9.5) | 887 (9.1) | 272 (11.0) | .005 |
| Prior myocardial infarction | 934 (7.7) | 742 (7.6) | 192 (7.8) | .802 |
| Prior heart failure | 180 (1.5) | 139 (1.4) | 41 (1.7) | .403 |
| Prior stroke | 795 (6.5) | 622 (6.4) | 173 (7.0) | .273 |
| Current smoker | 4849 (39.7) | 3921 (40.3) | 928 (37.6) | .013 |
| Killip class ≥ II | 2436 (20.0) | 1889 (19.4) | 547 (22.1) | .003 |
| eGFR < 60 mL/min/1.73m2 | 2217 (18.2) | 1674 (17.2) | 543 (22.0) | <.001 |
| Left ventricular EF (%) | 52.2 ± 11.0 | 52.2 ± 10.9 | 52.1 ± 11.4 | .568 |
| STEMI | 5806 (47.6) | 4716 (48.5) | 1090 (44.1) | <.001 |
| Coronary reperfusion* | 11,661 (95.6) | 9365 (96.3) | 2296 (92.9) | <.001 |
| Medications at discharge | ||||
| Aspirin | 12,160 (99.7) | 9714 (99.8) | 2446 (99.0) | <.001 |
| P2Y12 inhibitor | 11,666 (95.6) | 9437 (97.0) | 2229 (90.2) | <.001 |
| Beta-blockers | 10,251 (84.0) | 8663 (89.0) | 1588 (64.3) | <.001 |
| Statins | 11,415 (93.6) | 9232 (94.9) | 2183 (88.3) | <.001 |
Values are mean ± standard deviation or number (%).
Abbreviations: EF = ejection fraction, eGFR = estimated glomerular filtration rate, RAS = renin-angiotensin system, STEMI = ST-elevation myocardial infarction.
Included reperfusion by percutaneous coronary intervention, thrombolysis, or coronary artery bypass graft, myocardial infarction with non-obstructed coronary arteries and myocardial bridge.
Statins were not prescribed at discharge for 785 (6.4%) patients. A comparison between patients with and without statin treatment revealed significant differences in all baseline characteristics (Table 3). In patients who did not take statins, the rate of coronary reperfusion and PCI procedures were lower, while the proportions of CABG and MINOCA were higher (Table S5, Supplemental Digital Content, http://links.lww.com/MD/O36). Atorvastatin and rosuvastatin were the most frequently administered statins at the time of discharge, and at 1 and 2-years later, although doses lower than those recommended by the guidelines were prescribed (Table S6, Supplemental Digital Content, http://links.lww.com/MD/O36).
Table 3.
Baseline characteristics of patients with or without statins.
| All patients (N = 12,200) | With statins (N = 11,415) | Without statins (N = 785) | P value | |
|---|---|---|---|---|
| Age (yr) | 63.6 ± 12.6 | 63.4 ± 12.5 | 66.6 ± 12.5 | <.001 |
| Male | 9067 (74.3) | 8533 (74.8) | 534 (68.0) | <.001 |
| Body mass index (kg/m2) | 24.05 ± 3.31 | 24.08 ± 3.31 | 23.54 ± 3.32 | <.001 |
| Hypertension | 6156 (50.5) | 5731 (50.2) | 425 (54.1) | .035 |
| Diabetes mellitus | 3411 (28.0) | 3108 (27.2) | 303 (38.6) | <.001 |
| Prior angina pectoris | 1159 (9.5) | 1060 (9.3) | 99 (12.6) | .003 |
| Prior myocardial infarction | 934 (7.7) | 848 (7.4) | 86 (11.0) | <.001 |
| Prior heart failure | 180 (1.5) | 147 (1.3) | 33 (4.2) | <.001 |
| Prior stroke | 795 (6.5) | 717 (6.3) | 78 (9.9) | <.001 |
| Current smoker | 4849 (39.7) | 4615 (40.4) | 234 (29.8) | <.001 |
| Killip class ≥ II | 2436 (20.0) | 2147 (18.8) | 289 (36.8) | <.001 |
| eGFR < 60 mL/min/1.73m2 | 2217 (18.2) | 1946 (17.0) | 271 (34.5) | <.001 |
| Left ventricular EF (%) | 52.2 ± 11.0 | 52.4 ± 10.8 | 49.3 ± 12.7 | <.001 |
| STEMI | 5806 (47.6) | 5498 (48.2) | 308 (39.2) | <.001 |
| Coronary reperfusion* | 11,661 (95.6) | 10.964 (96.0) | 697 (88.8) | <.001 |
| Medications at discharge | ||||
| Aspirin | 12,160 (99.7) | 11,389 (99.8) | 771 (98.2) | <.001 |
| P2Y12 inhibitor | 11,666 (95.6) | 11,014 (96.5) | 652 (83.1) | <.001 |
| Beta-blockers | 10,251 (84.0) | 9725 (85.2) | 526 (67.0) | <.001 |
| RAS inhibitors | 9729 (79.7) | 9232 (80.9) | 497 (63.3) | <.001 |
Values are mean ± standard deviation or number (%).
Abbreviations: EF = ejection fraction, eGFR = estimated glomerular filtration rate, RAS = renin-angiotensin system, STEMI = ST-elevation myocardial infarction.
Included reperfusion by percutaneous coronary intervention, thrombolysis, or coronary artery bypass graft, myocardial infarction with non-obstructed coronary arteries and myocardial bridge.
3.2. Clinical outcomes at 3-years
The follow-up rates were 97.8% at 1-year, 95.7% at 2-years, and 93.6% at 3-years. In a Cox-proportional hazard analysis, BB (HR = 0.78; 95% CI = 0.64–0.94; P = .010), RAS inhibitors (HR = 0.82; 95% CI = 0.68–0.99; P = .039), and statins (HR = 0.74; 95% CI = 0.59–0.93; P = .011) prescribed at discharge were all associated with reduced 3-year cardiac mortality as shown in Tables 4, 5, and 6 and illustrated in Figure 2. Additionally, 3-year all-cause mortality was also significantly lower in patients treated with BB (HR = 0.79; 95% CI = 0.68–0.93; P = .003), RAS inhibitors (HR = 0.85; 95% CI = 0.74–0.99; P = .034), and statins (HR = 0.74; 95% CI = 0.61–0.89; P = .001) (Fig. S1, Supplemental Digital Content, http://links.lww.com/MD/O35). Furthermore, all these medications were all associated with lower rates of MACE, MACCE, and MACE with NCD (Tables 4, 5, and 6). A significant interaction between LVEF and cardiac mortality (P for interaction [Pint] = .004), all-cause mortality (Pint =.009), and MACE (Pint = .003) was noted in patients treated with BB at discharge. However, such interactions were not observed in patients treated with RAS inhibitors and statins at discharge (Fig. 3, Figs. S2 and S3, Supplemental Digital Content, http://links.lww.com/MD/O35).
Table 4.
Multivariate cox-proportional hazard analysis of 3-yr events, based on beta-blocker prescription at discharge (N = 12,200).
| Events | With beta-blockers (N = 10,251) | Without beat-blockers (N = 1949) | Hazard ratio* (95% CI) | P value |
|---|---|---|---|---|
| No. of patients with events (rate per 100 patient-year†) | ||||
| Cardiac death | 483 (1.8) | 162 (3.3) | 0.78 (0.64–0.94) | .010 |
| All-cause death | 787 (2.9) | 249 (5.0) | 0.79 (0.68–0.93) | .003 |
| MI | 334 (1.2) | 63 (1.3) | 1.06 (0.79–1.41) | .712 |
| Revascularization | 891 (3.4) | 155 (3.3) | 0.99 (0.83–1.19) | .920 |
| Heart failure‡ | 358 (1.3) | 102 (2.1) | 0.82 (0.65–1.03) | .089 |
| MACE | 1620 (6.4) | 388 (8.6) | 0.87 (0.77–0.97) | .017 |
| Stroke | 213 (0.8) | 40 (0.8) | 1.05 (0.73–1.50) | .800 |
| MACCE | 1786 (7.1) | 418 (9.3) | 0.89 (0.79–0.99) | .035 |
| NCD | 305 (1.1) | 87 (1.8) | 0.83 (0.64–1.07) | .151 |
| MACE with NCD | 1883 (7.4) | 458 (10.1) | 0.87 (0.78–0.97) | .010 |
Abbreviations: CI = confidence interval, MACCE = major adverse cardiocerebral event, MACE = major adverse cardiac event, MI = myocardial infarction, NCD = noncardiac death.
Adjusted for age, sex, body mass index, hypertension, diabetes mellitus, prior angina, prior MI, prior heart failure, current smoker status, Killip class, estimated glomerular filtration rate, left ventricular ejection fraction, type of myocardial infarction, coronary reperfusion, and medications at discharge (aspirin, P2Y12 inhibitors, inhibitors of the renin-angiotensin system, and statins).
Unadjusted event rate.
Re-hospitalization due to heart failure.
Table 5.
Multivariate cox-proportional hazard analysis of 3-yr events, based on RAS inhibitor prescription at discharge (N = 12,200).
| Events | With RAS inhibitors (N = 9729) | Without RAS inhibitors (N = 2471) | Hazard ratio* (95% CI) | P value |
|---|---|---|---|---|
| No. of patients with events (rate per 100 patient-year†) | ||||
| Cardiac death | 465 (1.8) | 180 (2.9) | 0.82 (0.68–0.99) | .039 |
| All-cause death | 761 (2.9) | 275 (4.4) | 0.85 (0.74–0.99) | .034 |
| MI | 319 (1.2) | 78 (1.3) | 1.04 (0.80–1.35) | .785 |
| Revascularization | 832 (3.4) | 214 (3.6) | 0.90 (0.77–1.05) | .165 |
| Heart failure‡ | 344 (1.3) | 116 (1.9) | 0.87 (0.70–1.09) | .231 |
| MACE | 1540 (6.4) | 468 (8.1) | 0.88 (0.79–0.98) | .024 |
| Stroke | 204 (0.8) | 49 (0.8) | 1.07 (0.77–1.48) | .699 |
| MACCE | 1699 (7.1) | 505 (8.8) | 0.90 (0.81–0.996) | .042 |
| NCD | 291 (1.1) | 95 (1.5) | 0.91 (0.71–1.17) | .459 |
| MACE with NCD | 1794 (7.4) | 547 (9.5) | 0.89 (0.80–0.98) | .021 |
Abbreviations: CI = confidence interval, MACCE = major adverse cardiocerebral event, MACE = major adverse cardiac event, MI = myocardial infarction, NCD = noncardiac death.
Adjusted for age, sex, body mass index, hypertension, diabetes mellitus, prior angina, prior MI, prior heart failure, current smoker status, Killip class, estimated glomerular filtration rate, left ventricular ejection fraction, type of myocardial infarction, coronary reperfusion, and medications at discharge (aspirin, P2Y12 inhibitors, beta-blockers, and statins).
Unadjusted event rate.
Re-hospitalization due to heart failure.
Table 6.
Multivariate cox-proportional hazard analysis of 3-year events, based on statins prescription at discharge (N = 12,200).
| Events | With statins (N = 11,415) | Without statins (N = 785) | Hazard ratio* (95% CI) | P value |
|---|---|---|---|---|
| No. of patients with events (rate per 100 patient-year†) | ||||
| Cardiac death | 549 (1.8) | 96 (5.1) | 0.74 (0.59–0.93) | .011 |
| All-cause death | 889 (2.9) | 147 (7.7) | 0.74 (0.61–0.89) | .001 |
| MI | 365 (1.2) | 32 (1.7) | 0.97 (0.66–1.43) | .880 |
| Revascularization | 973 (3.4) | 73 (4.1) | 0.83 (0.65–1.06) | .128 |
| Heart failure‡ | 404 (1.3) | 56 (3.1) | 0.83 (0.61–1.12) | .216 |
| MACE | 1809 (6.4) | 199 (11.7) | 0.81 (0.70–0.95) | .008 |
| Stroke | 230 (0.8) | 23 (1.2) | 0.78 (0.50–1.23) | .287 |
| MACCE | 1985 (7.1) | 219 (13.1) | 0.79 (0.68–0.92) | .002 |
| NCD | 51 (2.7) | 147 (7.7) | 0.73 (0.53–1.002) | .052 |
| MACE with NCD | 2103 (7.4) | 238 (14.0) | 0.81 (0.70–0.93) | .003 |
Abbreviations: CI = confidence interval, MACCE = major adverse cardiocerebral event, MACE = major adverse cardiac event, MI = myocardial infarction, NCD = noncardiac death.
Adjusted for age, sex, body mass index, hypertension, diabetes mellitus, prior angina, prior MI, prior heart failure, current smoker status, Killip class, estimated glomerular filtration rate, left ventricular ejection fraction, type of myocardial infarction, coronary reperfusion, and medications at discharge (aspirin, P2Y12 inhibitors, beta-blockers, and inhibitors of the renin-angiotensin system)
Unadjusted event rate.
Re-hospitalization due to heart failure.
Figure 2.
Unadjusted Kaplan–Meier curves, adjusted hazard ratio (HR) and 95% confidence interval (CI) for 3-yr cardiac death. (A) Beta-blockers (BB). (B) Renin-angiotensin system inhibitors (RASI). (C) Statins.
Figure 3.
Adjusted hazard ratio and 95% confidence interval (CI) for 3-yr cardiac death according to initial left ventricular ejection fraction (EF). (A) Beta-blockers (BB). (B) Renin-angiotensin system inhibitors (RASI). (C) Statins.
3.3. Clinical outcomes at 1-year, from 1 to 2-years, and from 2 to 3-years
At 1-year, beta-blocker therapy prescribed at discharge was associated with lower rates of cardiac mortality (HR = 0.73; 95% CI = 0.57–0.95; P = .019) and all-cause mortality (HR = 0.80; 95% CI = 0.65–0.997; P = .047) (Fig. 4, Fig. S4, Supplemental Digital Content, http://links.lww.com/MD/O35, and Table S7, Supplemental Digital Content, http://links.lww.com/MD/O36). In a cohort of 10,613 patients without any MACE or death until 1-year, a 1-year landmark analysis was conducted (Fig. 1). Of these, beta-blockers were not prescribed to 1662 patients (16%), and their clinical characteristics remained similar to those observed at baseline (Table S8, Supplemental Digital Content, http://links.lww.com/MD/O36). However, in a 1-year landmark analysis, BB were not associated with lower rates of 2-year cardiac mortality (HR = 0.79; 95% CI = 0.51–1.23; P = .30) or all-cause mortality (HR = 0.76; 95% CI = 0.55–1.05; P = .11) (Fig. 4, Fig. S4, Supplemental Digital Content, http://links.lww.com/MD/O35, and Table S9, Supplemental Digital Content, http://links.lww.com/MD/O36). Similarly, a 2-year landmark analysis was conducted in 9232 patients who had no MACE or death until 2-years (Fig. 1). Of these, 2277 patients (25%) were not prescribed BB, and their clinical characteristics are detailed in Table S10, Supplemental Digital Content, http://links.lww.com/MD/O36. The analysis showed that BB prescribed after 2-years were not associated with improved 3-year cardiac mortality (HR = 1.15; 95% CI = 0.65–2.05; P = .64) or all-cause mortality (HR = 0.83; 95% CI = 0.57–1.22; P = .34) (Fig. 4, Fig. S4, Supplemental Digital Content, http://links.lww.com/MD/O35, and Table S11, Supplemental Digital Content, http://links.lww.com/MD/O36). At 1-year, a high cross-over rate was observed: 39% of patients who were not prescribed BB at discharge were taking BB by the end of the year. However, only a small cross-over was observed after the first year (Table S12, Supplemental Digital Content, http://links.lww.com/MD/O36).
Figure 4.
1- and 2-yr landmark analysis for cardiac death: unadjusted Kaplan–Meier curves, adjusted hazard ratio (HR) and 95% confidence interval (CI) for cardiac death. (A) Beta-blockers (BB). (B) Renin-angiotensin system inhibitors (RASI). (C) Statins.
RAS inhibitors prescribed at discharge were associated with lower rates of cardiac mortality (HR = 0.70; 95% CI = 0.55–0.89; P = .004) and all-cause mortality (HR = 0.77; 95% CI = 0.63–0.95; P = .014) at 1-year (Fig. 4, Fig. S4, Supplemental Digital Content, http://links.lww.com/MD/O35, and Table S13, Supplemental Digital Content, http://links.lww.com/MD/O36). In a 1-year landmark analysis of 10,613 patients, 2939 patients (28%) were not prescribed RAS inhibitors, and their clinical characteristics remained similar to those observed at baseline (Table S14, Supplemental Digital Content, http://links.lww.com/MD/O36). RAS inhibitors prescribed after 1-year were associated with improved 2-year cardiac mortality (HR = 0.53; 95% CI = 0.37–0.76; P = .001) and all-cause mortality (HR = 0.62; 95% CI = 0.47–0.82; P = .001) (Fig. 4, Fig. S4, Supplemental Digital Content, http://links.lww.com/MD/O35, and Table S15, Supplemental Digital Content, http://links.lww.com/MD/O36). However, a 2-year landmark analysis performed in 9232 patients (Table S16, Supplemental Digital Content, http://links.lww.com/MD/O36) revealed that RAS inhibitors were not associated with lower 3-year cardiac mortality (HR = 1.27; 95% CI = 0.73–2.21; P = .40) or all-cause mortality (HR = 0.96; 95% CI = 0.66–1.39; P = .82) (Fig 4, Fig S4, Supplemental Digital Content, http://links.lww.com/MD/O35, and Table S17, Supplemental Digital Content, http://links.lww.com/MD/O36). The cross-over rates for patients not initially prescribed RAS inhibitors were high at 1-year (32%), but relatively lower rates were observed in the subsequent years (Table S18, Supplemental Digital Content, http://links.lww.com/MD/O36).
Statins prescribed at discharge were associated with a reduction in 1-year cardiac mortality (HR = 0.65; 95% CI = 0.48–0.87; P = .004) and all-cause mortality (HR = 0.66; 95% CI = 0.52–0.85; P = .001) (Fig. 4, Fig. S4, Supplemental Digital Content, http://links.lww.com/MD/O35, and Table S19, Supplemental Digital Content, http://links.lww.com/MD/O36). After 1-year, only a small percentage (2%) of patients was not prescribed statins, with their clinical characteristics detailed in Table S20, Supplemental Digital Content, http://links.lww.com/MD/O36. In a 1-year landmark analysis, a significantly lower rate of 2-year cardiac mortality (HR = 0.30; 95% CI = 0.14–0.61; P = .001) and all-cause mortality (HR = 0.33; 95% CI = 0.19–0.58; P < .001) was observed (Fig. 4, Fig. S4, Supplemental Digital Content, http://links.lww.com/MD/O35, and Table S21, Supplemental Digital Content, http://links.lww.com/MD/O36). However, a 2-year landmark analysis of 9232 patients (Table S22, Supplemental Digital Content, http://links.lww.com/MD/O36) revealed that statins were not associated with lower 3-year cardiac mortality (HR = 1.25; 95% CI = 0.76–2.07; P = .38) or all-cause mortality (HR = 1.09; 95% CI = 0.47–2.51; P = .84) (Fig. 4, Fig. S4, Supplemental Digital Content, http://links.lww.com/MD/O35, and Table S23, Supplemental Digital Content, http://links.lww.com/MD/O36). High cross-over rates were observed throughout 3-years in patients initially not prescribed statins: 94% at 1-year, 49% at 2-years, and 20% at 3-years (Table S24, Supplemental Digital Content, http://links.lww.com/MD/O36).
4. Discussion
BB, RAS inhibitors, and statins prescribed at discharge were all associated with lower 1-year cardiac mortality and all-cause mortality. In a 1-year landmark analysis of patients without any MACE or death, BB were no longer associated with better outcomes, whereas RAS inhibitors and statins continued to be associated with lower rates of cardiac mortality and all-cause mortality. However, this beneficial association with RAS inhibitors and statins was lost after 2-years.
4.1. Optimal duration of beta-blocker therapy after AMI
The optimal duration of beta-blocker therapy after AMI is an unresolved issue. Immediately after an AMI attack, activation of the sympathetic nervous system, characterized by increases in heart rate, myocardial contractility, and myocardial oxygen demand, is a common finding. This exacerbates myocardial ischemia and provokes ventricular arrhythmia, both of which are ameliorated by beta-blocker therapy.[14] A meta-analysis of clinical studies from before the reperfusion era clearly demonstrated the mortality benefits of beta-blocker therapy. Consequently, oral BB have been recommended as lifelong therapy for patients with AMI and an LVEF ≤ 40% and for at least 3-years in all patients with preserved LV function.[8]
However, clinical trials conducted in the era of widespread use of reperfusion therapy have questioned the long-term clinical benefits of beta-blocker therapy.[15] While a 1-year landmark observational analysis after AMI demonstrated the mortality benefits of beta-blocker therapy in patients without HF for up to 3-years,[16] other recent studies have not supported the long-term use of beta-blocker therapy in AMI patients without HF beyond 1-year.[17,18]
In this study, oral beta-blocker therapy at discharge was associated with reduced 3-year cardiac and all-cause mortality. However, neither 1-year nor 2-year landmark analyses showed improved clinical outcomes from oral beta-blocker therapy for patients without subsequent cardiac events or deaths. Furthermore, a significant interaction was noted between 3-year mortality rates and LVEF, revealing that oral beta-blocker therapy at discharge does not benefit patients with preserved LVEF ≥ 50%. These findings suggest that the advantages of oral beta-blocker therapy after an AMI are confined to patients with LVEF < 50% for up to 1-year.
Supporting these findings, a recent clinical study in AMI patients who underwent early coronary angiography and had an LVEF ≥ 50% indicated that oral beta-blocker therapy at discharge did not reduce all-cause mortality or new MI during a median follow-up of 3.5 years.[19] Additionally, a recent guideline revision suggests reassessing the necessity of beta-blocker therapy beyond 1-year in MI patients with an LVEF > 50% to potentially reduce cardiac events.[9] While this study has questioned the benefits of prolonged beta-blocker therapy beyond 1-year, guidelines continue to recommend lifelong beta-blocker therapy for MI patients with an LVEF < 50%.[8–10] However, since LVEF measurements at 1 or 2-year follow-ups were not available for all study patients, the favorable effects of BB in the subgroup of patients with LV systolic dysfunction could not be analyzed in the 1 and 2-year landmark analyses. Consequently, the findings of this study should be interpreted with caution. Two ongoing clinical trials exploring the long-term benefits (over 6 months) of oral beta-blocker therapy may soon provide clearer guidance on the optimal duration of treatment after an AMI.[14]
4.2. Optimal duration of RAS inhibitor therapy after AMI
ACE inhibitors have been shown to prevent LV dilatation and dysfunction following AMI and to reduce all-cause mortality in patients with AMI and LV systolic dysfunction.[20,21] Subsequent studies have demonstrated that an ARB is non-inferior to ACE inhibitors in similar patient groups.[22] While 2 large clinical trials reported that ACE inhibitors significantly reduced cardiac events in patients with stable IHD who exhibited high-risk characteristics,[23,24] with 1 trial showing equivalent benefits for ARB,[25] another clinical trial failed to demonstrate similar benefits.[26] These mixed results have led to inconsistent recommendations regarding both the use and the optimal duration of RAS inhibitors in patients with AMI.
According to this study, RAS inhibitor therapy prescribed at discharge was associated with reduced 3-year cardiac and all-cause mortality, without significant interaction with LVEF. Additionally, a 1-year landmark analysis, excluding patients who experienced cardiac events or deaths, indicated a mortality benefit from RAS inhibitors. However, 2-year landmark analyses did not show improved clinical outcomes from RAS inhibitor therapy. Long-term RAS inhibitors are typically recommended for MI patients with LV systolic dysfunction or HF. However, after stabilization from an AMI, the clinical benefits of RAS inhibitors in patients without LV systolic dysfunction or HF have not been clearly demonstrated. This study suggests that the beneficial effects of RAS inhibitors may extend up to 2-years after an AMI, irrespective of initial LVEF. Although no mortality benefit was observed from 2 to 3-years in patients without cardiac events after an AMI, this finding needs to be interpreted with caution. Due to data unavailability, the potential benefits of RAS inhibitors in the subgroup of patients with LV systolic dysfunction could not be comprehensively analyzed in the 2-year landmark analysis.
4.3. Optimal duration of statin therapy after AMI
Since 2 clinical trials demonstrated a reduction in cardiac events with early high-intensity statin therapy in patients with acute coronary syndrome, starting from 4 to 6 months after enrollment, immediate, high-intensity statins have generally been recommended for patients with AMI.[27,28] Statin therapy is recommended as a lifelong medications in conjunction with lifestyle management for patients who have experienced AMI unless adverse effects occur.[9,10] Furthermore, recent guidelines suggest maintaining LDL-cholesterol at the lowest feasible level.[7,9] In this study, patients treated with statins exhibited significant benefits over 3-years, including notable reductions in cardiac and all-cause mortality. These superior outcomes were also evident at 1-year and in the corresponding 1-year landmark analysis. However, no significant differences in events were detected between the second and third years. This outcome necessitates cautious interpretation due to high cross-over rates; by the third year, only a small number of patients had not been prescribed statins, potentially leading to statistical errors. Adequate lipid management after AMI requires measuring and monitoring LDL-cholesterol levels to achieve target goals. Due to the unavailability of lipid data for all study participants, a comprehensive analysis according to LDL-cholesterol levels was not possible. This lack of data may contribute to the observed lack of a positive association between statin use and cardiac events after 2-years.
4.4. Limitations
The interpretation of this observational study, which utilizes data from an AMI registry, is subject to several limitations. First, BB, RAS inhibitors, and statins were prescribed at discharge and at 1 and 2-years, based solely on the discretion of attending physicians, with no available documentation explaining why some patients did not receive these medications. Additionally, medication adherence was not evaluated to determine whether patients took the medications as prescribed and maintained adherence throughout the study period. Second, although a Cox-proportional hazard analysis was conducted, fully addressing all potential confounders proved challenging. Despite efforts to mitigate these issues through multivariable analysis, it was not possible to fully account for selection bias and other unrecorded or residual confounders, such as socioeconomic status, lifestyle factors, or medication adherence. Third, BB and RAS inhibitors were prescribed at only a quarter to half of the maximum recommended dosage, and moderate- or low-intensity statins were used. Additionally, individual medication doses at the time of clinical events were not recorded. However, registry data showed that BB were prescribed at <25% of the maximum recommended dose at discharge for 60% of patients with AMI, and even the > 12.5% to 25% dose group had the lowest mortality.[18,29] Although RAS inhibitors prescribed at > 50% of the target dose were associated with lower mortality in patients with HF and EF ≥ 40% compared to those receiving ≤50% of the target dose, ≤50% of the target dose was prescribed for 70% of patients.[30] High-intensity statins, compared with low- or moderate-intensity statins, showed better cardiovascular outcomes after AMI; however, in that study, only a quarter of patients were prescribed high-intensity statins.[31] These prescribing patterns of lower than-maximal recommended doses may be common clinical practice in ‘real-world’ registries. A randomized clinical trial may be necessary to determine the optimal dose of BB or RAS inhibitors after AMI, particularly in patients with EF ≥ 40%. Fourth, blood LDL-cholesterol levels were not available for patients at the time of clinical events, which hindered a comprehensive assessment of the relationship between LDL-cholesterol levels and clinical outcomes. Fifth, clinical outcomes were not centrally adjudicated. However, all-cause mortality, which was minimally affected by the bias of the attending physicians, along with cardiac mortality, was evaluated as clinical endpoints. Despite these limitations, this study offers valuable insights into the optimal duration of therapy with BB, RAS inhibitors, and statins within the same AMI cohort–insights that would be difficult to ascertain through randomized clinical trials.
5. Conclusions
BB, RAS inhibitors, and statins prescribed at discharge, were all associated with decreased 1-year cardiac mortality and all-cause mortality. However, 1-year and 2-year landmark analyses in patients without any cardiac events or death revealed that BB were no longer associated with improved outcomes 1-year after the initial attack. In contrast, RAS inhibitors and statins continued to be linked to lower rates of cardiac and all-cause mortality for up to 2-years. Nevertheless, the beneficial association with RAS inhibitors and statins became uncertain after 2-years.
Acknowledgments
We appreciate the contribution of the KAMIR-NIH investigators: Tae Hoon Ahn, MD, Department of Cardiology, Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea. Ki-Bae Seung, MD, Cardiology Division, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Chong-Jin Kim, MD, Kyunghee University Hospital at Gangdong, Seoul, Republic of Korea. Shung Chull Chae, MD, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea. Jin-Yong Hwang, MD, Department of Internal Medicine, Gyeonsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea. Seung-Ho Hur, MD, Keimyung University Dongsan Medical Center, Cardiovascular Medicine, Deagu, Republic of Korea. Seung-Woon Rha, MD, Cardiovascular Center, Korea University Guro Hospital, Seoul, Republic of Korea. Kwang Soo Cha, MD, Pusan National University Hospital, Busan, Republic of Korea. Chang-Hwan Yoon, MD, Cardiovascular Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea. Hyo-Soo Kim, MD, Cardiovascular Center, Department of Internal Medicine, Seoul, Republic of Korea. Hyeon-Cheol Gwon, MD, Heart Vascular and Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Jung-Hee Lee, MD, Division of Cardiology, Yeungnam University Medical Center, Yeungnam University College of Medicine, Daegu, Republic of Korea. Seok Kyu Oh, MD, Division of Cardiology, Department of Internal Medicine, Wonkwang University School of Medicine, Iksan, Republic of Korea. Junghan Yoon, MD, Division of Cardiology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju Severance Christian Hospital, Wonju, Republic of Korea. Jei Keon Chae, MD, Division of Cardiology, Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea. Seung-Jae Joo, MD, Department of Internal Medicine, Jeju National University College of Medicine, Jeju, Republic of Korea. In-Whan Seong, MD, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University College of Medicine, Daejeon, Republic of Korea. Kyung-Kuk Hwang, MD, Department of Internal Medicine, Chungbuk National University College of Medicine, Chungbuk Regional Cardiovascular Center, Division of Cardiology, Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea. Doo-Il Kim, MD, Department of Internal Medicine, Inje University College of Medicine, Haeundae Paik hospital, Busan, Republic of Korea. Myung Ho Jeong, MD, Chonnam National University Hospital, Gwangju, Republic of Korea.
Author contributions
Conceptualization: Seung-Jae Joo, Song-Yi Kim, Myung Ho Jeong.
Data curation: Ki Yung Boo, Seung-Jae Joo, Jae-Geun Lee, Joon-Hyouk Choi, Song-Yi Kim, Geum Ko.
Formal analysis: Ki Yung Boo, Seung-Jae Joo.
Funding acquisition: Myung Ho Jeong.
Investigation: Ki Yung Boo, Seung-Jae Joo, Song-Yi Kim, Myung Ho Jeong.
Methodology: Ki Yung Boo, Seung-Jae Joo.
Project administration: Seung-Jae Joo, Myung Ho Jeong.
Resources: Seung-Jae Joo, Myung Ho Jeong.
Software: Ki Yung Boo, Seung-Jae Joo, Joon-Hyouk Choi.
Supervision: Seung-Jae Joo.
Validation: Joon-Hyouk Choi.
Visualization: Ki Yung Boo, Seung-Jae Joo.
Writing – original draft: Ki Yung Boo, Seung-Jae Joo.
Writing – review & editing: Ki Yung Boo, Seung-Jae Joo, Jae-Geun Lee, Joon-Hyouk Choi, Song-Yi Kim, Geum Ko, Hae Eun Yun, Myung Ho Jeong.
Supplementary Material
Abbreviations:
- ACEi
- angiotensin-converting enzyme inhibitors
- AMI
- acute myocardial infarction
- ARB
- angiotensin receptor blockers
- CABG
- coronary artery bypass graft
- CAD
- coronary artery disease
- CCS
- chronic coronary syndrome
- CD
- cardiac death
- CI
- confidence interval
- EF
- ejection fraction
- eGFR
- estimated glomerular filtration rate
- HFmrEF
- heart failure with mildly reduced ejection fraction
- HR
- hazard ratio
- IHD
- ischemic heart disease
- KAMIR-NIH
- Korea Acute Myocardial Infarction Registry-National Institute of Health
- LV
- left ventricular
- MACCE
- major adverse cardiac and cerebrovascular events
- MACE
- major adverse cardiac events
- MINOCA
- myocardial infarction with non-obstructed coronary arteries
- NCD
- mon-cardiac death
- PCI
- percutaneous coronary intervention
- RAS
- renin-angiotensin system
- RASI
- renin-angiotensin inhibitor
- STEMI
- ST-elevation myocardial infarction
This study was supported by a fund [2016-ER6304-02] by Korea Centers for Disease Control and Prevention.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Supplemental Digital Content is available for this article.
How to cite this article: Boo KY, Joo S-J, Lee J-G, Choi J-H, Kim S-Y, Ko G, Yun HE, Jeong MH. Optimal duration of medical therapy for patients with acute myocardial infarction. Medicine 2024;103:48(e40697).
Contributor Information
Ki Yung Boo, Email: pidori@daum.net.
Jae-Geun Lee, Email: tedljg@naver.com.
Joon-Hyouk Choi, Email: valgom@naver.com.
Song-Yi Kim, Email: ttoromom@jejunu.ac.kr.
Geum Ko, Email: ssg36@naver.com.
Hae Eun Yun, Email: biocap99@naver.com.
Myung Ho Jeong, Email: myungho@chollian.net.
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