Abstract
Aims
Despite the well-established clinical benefits and strong recommendations in clinical guidelines, adherence to guideline-directed medical therapy (GDMT) is known to be insufficient. We investigated the adherence to GDMT and its impact on the 3-year clinical outcomes in patients with acute myocardial infarction (AMI).
Methods and results
Source data were obtained from KAMIR-NIH, a Korean multi-centre observational registry. GDMT was defined according to the ACC/AHA Class I recommendations. Adherence to GDMT was assessed at discharge and every year thereafter. The differences in clinical characteristics between patients receiving and those not receiving GDMT were adjusted using propensity score matching (PSM) or inverse probability of treatment weighting (IPTW). The primary endpoint was major adverse cardiovascular events (MACE), which was a composite of all-cause death and non-fatal MACE, including myocardial infarction (MI), revascularization, or stroke. Of 12 815 patients, GDMT adherence was 70.2% at discharge, and decreased gradually into 54.6% at 3-year. GDMT at discharge was associated with lower MACE risk in the unadjusted analysis [hazard ratio (HR) = 0.51, 95% confidence intervals (CI) = 0.47–0.55, P < 0.001] and also in the PSM- or IPTW-adjusted analyses (HR = 0.77, 95% CI = 0.69–0.86; HR = 0.79, 95% CI = 0.72–0.86; P < 0.001, all). These findings were replicated in the 1-year or 2-year landmark analyses (HR = 0.58 to 0.82, P < 0.01, all).
Conclusion
Adherence to GDMT was sub-optimal among patients with AMI in Korea. As the adherence to GDMT was associated with a lower incidence of MACE during 3-year follow-up, the maintenance of long-term GDMT might be crucial for patients with AMI.
Keywords: Guideline-directed medical therapy (GDMT), Acute myocardial infarction, Percutaneous coronary intervention, Landmark survival analysis
Structured Graphical Abstract
Structured Graphical Abstract.
Introduction
Guideline-directed medical therapy (GDMT) for secondary prevention is critical for better clinical outcomes in patients with acute myocardial infarction (AMI) and is highly recommended by evidence-based clinical guidelines.1–4 However, a significant gap in the adherence to GDMT has been demonstrated in most clinical studies. The frequency of GDMT in patients with AMI at discharge was 63–69% in observational studies,5–9 and 59–74% even in tightly controlled randomised clinical trials.10–12 Additionally, adherence to GDMT tended to decrease over time.13
Quantitative data showing the impact of GDMT on the clinical outcome of patients over time are limited. This study investigated the 3-year adherence to GDMT in patients from Korean Acute Myocardial Infarction Registry-National Institutes of Health (KAMIR-NIH), a large nationwide real-world AMI registry, and the association between the adherence to GDMT and clinical outcomes.
Methods
Study population and data source
KAMIR-NIH registry is a nationwide, all-comer, multi-centre, prospective registry of patients with AMI. Details of the study design and preliminary results have been previously published.14 Briefly, 13 104 consecutive patients with AMI were enrolled at one of 20 tertiary hospitals eligible for primary percutaneous coronary intervention (PCI) in Korea between November 2011 and December 2015. There were no exclusion criteria for patient enrolment. Informed consent was obtained from all the patients upon enrolment. The study protocol of the KAMIR-NIH registry was in accordance with the principles of the Declaration of Helsinki and was approved by the Institutional Review Board of each participating hospital.
Study variables
Guideline-directed medical therapy was defined according to the following four classes of drugs based on the ACC/AHA guidelines Class I recommendations: dual antiplatelet therapy (DAPT) which is a combination of aspirin and a P2Y12 inhibitor, statin, beta-blocker, and an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ACEi/ARB) for patients with left ventricular (LV) ejection fraction < 40%, hypertension, diabetes mellitus, or chronic kidney disease.15–17 Single antiplatelet therapy using aspirin or a P2Y12 inhibitor was also regarded as GDMT after 1-year based on the contemporary studies that demonstrated comparable clinical outcomes with 6 months vs. 12 months use of DAPT after PCI using modern second-generation drug-eluting stents.18 Adherence to GDMT at discharge and during follow-up at 1-, 2-, and 3-year was defined from the medical records by trained research professionals.
Primary endpoint was major adverse cardiovascular events (MACE), which included all-cause death, myocardial infarction, revascularization, and stroke. Adherence to GDMT and the components of MACE served as secondary endpoints.
Statistical analysis
Categorical variables and continuous variables were described as frequency and proportion (%) or mean ± SD, and compared using chi-squared or t-test, respectively. The 3-year cumulative incidence of MACE was plotted using Kaplan–Meier methods. Cox proportional model was used to estimate hazard ratio (HR) and 95% confidence intervals (CI) for the risks of 3-year clinical outcomes in patients with GDMT compared with those without GDMT.
As the baseline clinical characteristics were significantly different between two groups, the comparative outcomes between groups should be tested after minimising indication bias. The following covariates were selected based on the clinical variables with statistical significance by least absolute shrinkage and selection operator for MACE; age, chronic kidney disease, diabetes, prior history of MI, atrial fibrillation, LV ejection fraction < 40%, multi-vessel disease, PCI for left main disease, complete revascularization, cardiogenic shock, and multi-organ failure. Sex, hypertension, initial diagnosis of non-ST-elevation MI (NSTEMI) or ST-elevation MI (STEMI), and radial access were additionally included in the covariates as those were considered as basic essential variables and not to affect the adherence to GDMT significantly.19
Propensity score matching (PSM)- and inverse probability of treatment-weighting (IPTW)-adjusted analyses using the above covariates were performed to assess the average treatment effect on the control (ATC) and average treatment effect (ATE) estimands, respectively.20 As patients with GDMT outnumbered those without GDMT, ATC instead of average treatment effect on the treated (ATT) was measured. The covariate balance was evaluated by the distribution of propensity score and standardised mean difference < 0.10 in the dataset for ATC or ATE estimands. Restricted mean survival analysis was additionally performed to complement the results of the Cox model. The ratio of restricted mean time lost (RMTL) represents relative benefit and is a robust alternative to the HR in the Cox model. The difference of restricted mean survival time (RMST) represents absolute benefit and measures effect sizes that are not available from the Cox model.21
Adherence to GDMT at discharge was frequently not maintained throughout the follow-up period and crossovers were not uncommon. Therefore, landmark analyses conditional on 1- or 2-year survival were investigated. PSM- and IPTW-adjusted cumulative incidence of clinical events were calculated using covariates described above and adherence to GDMT at 1- or 2-year.
R version 4.2 (R Foundation for Statistical Computing) was used for statistical analyses. Statistical significance was defined by a two-sided P-value < 0.05.
Results
Study flow and overview of Guideline-directed medical therapy adherence
In total, 13 104 patients were included in the KAMIR-NIH registry. After excluding 289 patients with incomplete clinical data or timestamps, 12 815 patients were included in the analyses (Figure 1).
Figure 1.
Study flow. The 3-year clinical outcomes of patients with guideline-directed medical therapy and those without guideline-directed medical therapy were compared. In addition to unadjusted analysis, propensity score matching- and inverse probability of treatment-weighting-adjusted analyses were performed to assess the average treatment effect on the control and average treatment effect estimands.
Guideline-directed medical therapy was prescribed to 8994 (70.2%) patients at discharge. Then the adherence to GDMT decreased gradually from 60.0% at 1-year to 54.6% at 3-year. There was crossover between GDMT and no GDMT in 25.7, 13.9, and 11.3% of patients at 1-, 2-, and 3-year, respectively. The follow-up loss rate at 3-year was 6.3% (Figure 2).
Figure 2.
Trends of change in the adherence to guideline-directed medical therapy during clinical follow-up. Sankey diagram showing decreasing trends of adherence to guideline-directed medical therapy, from 70.2% at discharge to 54.6% at 3-year. The rate of crossover between guideline-directed medical therapy and no guideline-directed medical therapy was 25.7, 13.9, and 11.3% at 1-year, 2-year, and 3-year, respectively.
Baseline clinical characteristics
Patients with GDMT at discharge were more likely to be younger and male sex, and to be presented with STEMI than NSTEMI. They had lower frequencies of unfavourable clinical characteristics including hypertension, diabetes, prior history of MI, and atrial fibrillation. They underwent PCI for left main disease less frequently and underwent radial access and complete revascularization more frequently. Regarding in-hospital characteristics, they showed lower frequencies of LV ejection fraction < 40%, cardiogenic shock, and multi-organ failure (Table 1). These statistical differences were balanced in the PSM- and IPTW-adjusted datasets (see Supplementary material online, Table SA1, Figure SA1).
Table 1.
Clinical characteristics of patients with guideline-directed medical therapy and those without guideline-directed medical therapy
| No GDMT (n = 3821) | GDMT (n = 8994) | P-value | SMD | |
|---|---|---|---|---|
| Age | 66.3 (12.5) | 62.7 (12.4) | <0.001 | 0.287 |
| Male sex | 2716 (71.1) | 6810 (75.7) | <0.001 | 0.105 |
| Hypertension | 2185 (57.2) | 4329 (48.1) | <0.001 | 0.182 |
| Diabetes | 1344 (35.2) | 2297 (25.5) | <0.001 | 0.211 |
| Smoking | 1292 (33.8) | 3764 (41.9) | <0.001 | 0.166 |
| Chronic kidney disease | 365 (9.6) | 307 (3.4) | <0.001 | 0.251 |
| Previous myocardial infarction | 350 (9.2) | 628 (7.0) | <0.001 | 0.080 |
| Atrial fibrillation | 286 (7.5) | 392 (4.4) | <0.001 | 0.133 |
| STEMI | 1687 (44.2) | 4509 (50.1) | <0.001 | 0.120 |
| Multi-vessel disease | 1639 (42.9) | 4078 (45.3) | 0.011 | 0.049 |
| Complete revascularization | 2101 (55.0) | 5937 (66.0) | <0.001 | 0.227 |
| Radial approach | 953 (24.9) | 3402 (37.8) | <0.001 | 0.280 |
| PCI for left main disease | 103 (2.7) | 161 (1.8) | 0.001 | 0.061 |
| LV ejection fraction ≥ 40% | 3164 (82.8) | 8133 (90.4) | <0.001 | 0.225 |
| Major bleeding | 80 (2.1) | 92 (1.0) | <0.001 | 0.087 |
| Cardiogenic shock | 624 (16.3) | 458 (5.1) | <0.001 | 0.370 |
| Multi-organ failure | 74 (1.9) | 6 (0.1) | <0.001 | 0.189 |
| DAPT | 3723 (97.4) | 8994 (100.0) | <0.001 | 0.229 |
| Aspirin | 3772 (98.7) | 8994 (100.0) | <0.001 | 0.161 |
| Clopidogrel | 3077 (80.5) | 6955 (77.3) | <0.001 | 0.079 |
| Prasugrel | 375 (9.8) | 1181 (13.1) | <0.001 | 0.104 |
| Ticagrelor | 805 (21.1) | 2094 (23.3) | 0.007 | 0.053 |
| Beta-blocker | 1482 (38.8) | 8994 (100.0) | <0.001 | 1.777 |
| ACEi/ARB | 1531 (40.1) | 8414 (93.6) | <0.001 | 1.380 |
| Statin | 2721 (71.2) | 8994 (100.0) | <0.001 | 0.899 |
Unadjusted comparison of patients with GDMT and those without GDMT are shown.
SMD, standardised mean difference.
PSM- or IPTW-adjusted comparison is shown in Supplementary material online, Figure S1.
Clinical outcomes of patients with Guideline-directed medical therapy or without guideline-directed medical therapy
During the 3 years of follow-up period, MACE developed in 2692 (21.0%) patients, including 1398 (10.9%) death and 1456 (11.4%) non-fatal MACE. Among non-fatal MACE, there were 412 (3.2%) myocardial infarction, 1098 (8.6%) revascularization, and 283 (2.2%) stroke (Table 2).
Table 2.
Clinical outcome of patients with guideline-directed medical therapy and those without guideline-directed medical therapy
| No GDMT | GDMT | |
|---|---|---|
| (n = 3821) | (n = 8994) | |
| MACE | 1140 (29.8) | 1552 (17.3) |
| Death | 772 (20.2) | 626 (7.0) |
| Non-fatal MACE | 431 (11.3) | 1025 (11.4) |
| Myocardial infarction | 126 (3.3) | 286 (3.2) |
| Revascularization | 319 (8.3) | 779 (8.7) |
| PCI | 299 (7.8) | 741 (8.2) |
| Bypass surgery | 27 (0.7) | 42 (0.5) |
| Stroke | 91 (2.4) | 192 (2.1) |
Table shows 3-year cumulative incidence of clinical events. Results adjusted by PSM or IPTW, and results of 1- or 2-year landmark analyses are shown in the Supplementary material online, Table S2.
In the unadjusted analysis, the risk of MACE was 0.5-fold lower in patients with GDMT compared with those without GDMT (HR = 0.505; 95% CI = 0.468–0.545; P < 0.001). The risks of death and non-fatal MACE were 0.3- and 0.9-fold lower in patients with GDMT, respectively (HR = 0.306; 95% CI = 0.275–0.340; HR = 0.870; 95% CI = 0.777–0.973; P < 0.05, all) (Figure 3A–C). Among non-fatal MACE, the risks of myocardial infarction, revascularization, and stroke were not different or marginally lower in patients with GDMT (Figure 3D–F).
Figure 3.
Patients with guideline-directed medical therapy vs. those without guideline-directed medical therapy: unadjusted cumulative incidence of events. In this unadjusted analysis, compared with patients without guideline-directed medical therapy, the risks of major adverse cardiovascular events, death, and non-fatal major adverse cardiovascular events were 0.5-, 0.3-, and 0.9-fold lower in patients with guideline-directed medical therapy (A–C). The risks of the components of non-fatal major adverse cardiovascular events, including myocardial infarction, revascularization, and stroke, were not different or marginally lower in patients with guideline-directed medical therapy (D–F).
In the PSM-adjusted analyses, the risk of MACE was 0.8-fold lower in patients with GDMT compared with those without GDMT (HR = 0.767; 95% CI = 0.693–0.863; P < 0.001). The risk of death was 0.6-fold lower in patients with GDMT (HR = 0.611; 95% CI = 0.516–0.723; P < 0.001), whereas the risks of non-fatal MACE and components of non-fatal MACE were not different (P = NS [nonsignificant], all) (Figure 4A–F). IPTW-adjusted analyses also showed consistent results (see Supplementary material online, Figure SA2, Table SA1).
Figure 4.
Patients with guideline-directed medical therapy vs. those without guideline-directed medical therapy: propensity score matching-adjusted cumulative incidence of events. In this propensity score matching-adjusted analysis, the risks of major adverse cardiovascular events and death were 0.8- and 0.6-fold lower in patients with guideline-directed medical therapy (A, B). The risks of non-fatal major adverse cardiovascular events and the components of non-fatal major adverse cardiovascular events, including myocardial infarction, revascularization, and stroke, were not different between two groups (C–F).
The 1- or 2-year landmark analyses replicated lower risks of MACE or death but comparable risk of non-fatal MACE in patients with GDMT compared with those without GDMT (see Supplementary material online, Figures SB1–SB4, SC1–SC4, Tables SB1, SC1). These results are summarised in forest plots of hazard ratios (Figure 5; Supplementary material online, Figure SD1) and RMTL ratios (see Supplementary material online, Figures SD2 and SD3, Table SD1).
Figure 5.
Forest plots of hazard ratio: unadjusted and propensity score matching-adjusted comparison of patients with guideline-directed medical therapy vs. those without guideline-directed medical therapy in 0-, 1-, and 2-year landmark analyses. In both unadjusted and propensity score matching-adjusted analyses, the risks of major adverse cardiovascular events and death were lower in patients with guideline-directed medical therapy (A, B). These findings were consistent in analysis in 1- or 2-year landmark analyses (C–F).
These lower risks of MACE and death resulted in a significant increase in the event-free survival time in patients with GDMT. Restricted mean survival time differences in MACE and death were ≥ 4 months in unadjusted analyses (133 days, 95% CI = 118–147 days; 135 days, 95% CI = 123–147 days; P < 0.001, all) (Figure 6A), and ≥ 1 month in PSM-adjusted analyses over the 3-year follow-up period (50 days, 95% CI = 33–68 days; 49 days, 95% CI = 36–63 days; P < 0.001, all) (Figure 6B). The RMST differences in MACE and death in landmark analyses were shorter but still statistically meaningful (4–19 days, P < 0.01, all) (Figure 6C–F). IPTW-adjusted analyses replicated these results (see Supplementary material online, Figure SD4).
Figure 6.
Forest plots of restricted mean survival time difference: unadjusted and propensity score matching-adjusted comparison of patients with guideline-directed medical therapy vs. those without guideline-directed medical therapy in 0-, 1-, and 2-year landmark analyses. In both unadjusted and propensity score matching-adjusted analyses, restricted mean survival time of patients with guideline-directed medical therapy regarding major adverse cardiovascular events and death were significantly longer than those without guideline-directed medical therapy (A, B). These findings were consistent in analysis in 1- or 2-year landmark analyses (C–F).
As there was crossover in the adherence to GDMT, the clinical outcomes of patients with GDMT at discharge and discontinued GDMT thereafter and vice versa were investigated. In 1- or 2-year landmark analyses of unadjusted, PSM-, and IPTW-adjusted cohorts, patients with GDMT at discharge and subsequent years showed significantly lower risk of MACE compared with patients who discontinued GDMT at 1- or 2-year. This lower risk of MACE was mostly driven by lower risk of death (see Supplementary material online, Figures SE1–SE6).
The key findings of study results are shown in the Structured Graphical Abstract.
Discussion
This study investigated the 3-year clinical outcomes of a large nationwide AMI registry and reported two major findings. First, the adherence to GDMT of patients with AMI in real-world clinical practice was moderate and decreased over time. Second, patients with GDMT had lower risk of MACE compared with those without GDMT.
Importance of long-term maintenance of guideline-directed medical therapy
In this study, not only GDMT at discharge but also GDMT at 1- and 2-year was associated with lower 3-year risk of MACE. This study supports the long-term maintenance of GDMT for AMI patients at least for 3 years, which is highly recommended in clinical guidelines, but without a specified period.1,22 Regardless of preceding adherence to GDMT, the clinical outcome of patients who started GDMT after 1- or 2-year was better than patients without GDMT in the same period. This study reconfirms that optimising adherence to GDMT is of utmost importance to improve outcomes, which is notoriously difficult to achieve not only in real-world clinical practice but also in clinical trials.5–10,13
Potential reasons for insufficient adherence to guideline-directed medical therapy
Medication adherence is affected by multiple inter-related factors and may broadly be discussed under patient-, provider-, and system-related domains.23,24 Regarding patient-related domain, patients without GDMT showed higher frequency of unfavourable clinical or procedural characteristics. Intolerance or contraindication to GDMT in high-risk patients such as ACEi/ARB for chronic kidney disease or beta-blocker for bradycardia might partially contributed to lower adherence to GDMT in these patients. Interestingly, adherence to antiplatelet agents including aspirin (>98%) or statin (91%) was very high, whereas adherence to ACEi/ARB (82%) or beta-blocker (78%) was moderate at discharge, which is in line with prior studies.5–10 It might reflect the well-recognised effectiveness of antiplatelet agents or statin in the early post-PCI period,25 and relatively less recognised or limited use of beta-blocker or ACEi/ARB.26,27 Taken together, patients with unfavourable characteristics might have clinical reasons for discontinuing GDMT such as low blood pressure, bradycardia, impaired renal function, drug intolerance, or non-cardiovascular major illness. In such cases, use of all GDMT medication might be limited. These unfavourable characteristics might not be completely balanced with PSM- or IPTW-adjustments and cause significant bias. It may also be a clue to why not the risk of non-fatal MACE including myocardial infarction but the risk of death was consistently higher in patients without GDMT compared with those with GDMT in our study as well as prior studies.6
Regarding provider- and system-related domains, adherence to GDMT may be expected to be high in patients with acute clinical event who undergo invasive procedure and receive medications reimbursed by insurance. In Korea, primary PCI is being performed for most STEMI cases, and a nationwide healthcare insurance system that reimburses medications is mandatory for almost all residents.28,29 However, the adherence to GDMT in our study was sub-optimal and comparable to those reported in the other observational studies or clinical trials.5–8,10 Health literacy or socio-economical status, which were not investigated in our study, are known to be associated with poor adherence to medication.30 Our results suggest that there are still a lot of healthcare or non-medical factors that have a significant impact on the adherence to GDMT, besides access to healthcare, clinical severity, or insurance status.
Increasing adherence to guideline-directed medical therapy
Irrespective of the underlying reasons, non-adherence is a vexing challenge for patients with AMI who undergo PCI and require multiple daily medication regimens. Our results may further support the need to implement guidelines adherence which opens to a very wide landscape of possibilities. For example, digital platforms-based alerting feedback or decision support system are being developed to reduce the major problem of low adherence to medication.31–34
Conclusions
Optimising adherence to GDMT is essential to improve outcomes in real-world clinical practice. Adherence to GDMT was sub-optimal in Korean patients with AMI. Guideline-directed medical therapy was associated with a lower incidence of MACE during the 3-year follow-up period, which supports the need for long-term GDMT maintenance in patients with AMI.
Limitations
Source data were derived from real-world clinical practice without specifying information about the use or discontinuation of GDMT. Adherence to GDMT was defined at four cross-sectional points of discharge, 1-, 2-, and 3-year based on prescription records with the assumption that patients took their medication as filled, which may overestimate the true adherence. Patients without adherence in our study corresponds to non-adherence type 3 defined in the Non-Adherence Academic Research Consortium but did not have the exact timing, duration, or trajectory of medication.13,35 Despite their potential importance, non-laboratory-based risk factors including health literacy or socio-economic status were not investigated. Statistical adjustment of clinical characteristics by PSM or IPTW does not ensure free from residual confounding biases. The results were derived from the clinical practice in Korea and may not fit in the other regions.9,36
Supplementary Material
Contributor Information
Seung-Hwa Lee, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06355, Republic of Korea.
Dahee Hyun, Sungkyunkwan University School of Medicine, Seoul 03063, Republic of Korea.
Jungmin Choi, Department of Medical Device Management and Research, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul 06355, Republic of Korea.
Chang-Hwan Yoon, Cardiovascular Center, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea.
Kwang Soo Cha, Department of Internal Medicine, Pusan National University Hospital, Busan 49241, Republic of Korea.
SeokKyu Oh, Department of Internal Medicine, Wonkwang University School of Medicine, Iksan 54538, Republic of Korea.
In-Whan Seong, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University, College of Medicine, Daejeon 35015, Republic of Korea.
Myung Ho Jeong, Department of Internal Medicine, Chonnam National University Hospital, Gwangju 58128, Republic of Korea.
Jin-Ho Choi, Department of Emergency Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 115 Irwon-ro, Gangnam-gu, Seoul 06355, Republic of Korea.
Lead author biography
Seung-Hwa Lee graduated from Hallym University and received a Doctor of Philosophy for biomedical engineering from Seoul National University. He worked as an assistant professor in Samsung Medical Center and moved to Wiltse Memorial Hospital in Suwon, Republic of Korea. His research interest is coronary artery disease, hypertension, perioperative cardiac care, and biomedical informatics.
Dahee Hyun is a college student at Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Her academic interest is research of survival analysis of big data.
Data availability
The data underlying this article were provided by KAMIR team by permission. Data will be shared on request to the corresponding author with permission of KAMIR team.
Supplementary material
Supplementary material is available at European Heart Journal Open online.
Funding
This research was supported by the National Institute of Health Research Project of Kora (2016-ER6304-02).
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Data Availability Statement
The data underlying this article were provided by KAMIR team by permission. Data will be shared on request to the corresponding author with permission of KAMIR team.