Abstract
Background
The use of high-intensity statins is recommended to improve the prognosis of coronary artery disease. However, it remains unclear whether they offer a short-term benefit after percutaneous coronary intervention (PCI), regardless of the acute coronary syndrome (ACS) status.
Methods and Results
We performed a post hoc analysis of STOPDAPT-3, which compared 1-month aspirin-free prasugrel monotherapy followed by clopidogrel monotherapy with 1-month dual antiplatelet therapy (DAPT) followed by aspirin monotherapy in patients with ACS or a high bleeding risk undergoing PCI. High-intensity statins were defined as the maximum approved dose of strong statins in Japan (e.g., rosuvastatin 10 mg, atorvastatin 20 mg, or pitavastatin 4 mg). Two co-primary endpoints were the study-defined cardiovascular composite endpoint and bleeding endpoint, assessed between hospital discharge and 1 year after randomization. Among 5,823 patients discharged alive, 2,829 (48.6%) received high-intensity statins (ACS 54.4%; non-ACS 31.5%; P<0.001). The 1-year post-discharge cumulative incidence of cardiovascular events was similar between patients who received high-intensity statins and those who did not (3.90% vs. 4.27%, P=0.51; adjusted HR 1.03; 95% CI 0.74–1.44; P=0.84).
Conclusions
In STOPDAPT-3, high-intensity statin therapy at discharge was not associated with a reduced risk of cardiovascular events 1 year after PCI, under the limitations of having no laboratory test or prescription data available during the follow up.
Key Words: Acute coronary syndrome, High-intensity statins, Low-density lipoprotein cholesterol, Percutaneous coronary intervention
Central Figure.
Alongside percutaneous coronary intervention (PCI) or coronary artery bypass grafting, optimal medical therapy is essential for long-term outcomes, with lipid-lowering therapy a key component recommended in recent guidelines.1–4 Guidelines recommend the maximum tolerated dose of strong statins for coronary artery disease, regardless of acute coronary syndrome (ACS), with low-density lipoprotein cholesterol (LDL-C) targets of 55 mg/dL in the USA and 70 mg/dL in Japan, and stepwise addition of ezetimibe or proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors when needed.1–4 Previously, ‘more vs. less’ studies have consistently demonstrated a favorable effect of high-intensity statins on a decrease of cardiovascular events with a follow-up period of 2–4 years.5–11 However, it remains controversial whether high-intensity statins have a favorable effect in the early period of treatment, such as within the first year. Nevertheless, an observational subanalysis from STOPDAPT-2 ACS reported that the use of high-intensity statins at discharge was associated with a relative 46% lower risk for the cardiovascular endpoints 1 year after the onset of ACS, suggesting that the favorable effect of high-intensity statins might be seen much earlier in patients with ACS than in stable patients.12
This study aimed to evaluate the efficacy of high-intensity statins for the secondary prevention of cardiovascular events at 1 year in patients receiving contemporary PCI, irrespective of ACS status, using the STOPDAPT-3 trial data.
Methods
Study Overview
STOPDAPT-3 (NCT04609111) was a physician-initiated, prospective, multicenter, open-label, and adjudicator-blinded randomized clinical trial comparing 2 regimens of antiplatelet therapy after PCI: 1-month aspirin-free prasugrel monotherapy followed by clopidogrel monotherapy, and 1-month dual antiplatelet therapy (DAPT) followed by aspirin monotherapy. The primary results at 30 days and 1 year have been reported previously.13,14 The inclusion criteria were patients with ACS or high bleeding risk (HBR), as defined by the Academic Research Consortium (ARC), and those planned for PCI with cobalt-chromium everolimus-eluting stents (Xience series, ABBOTT Vascular).15 Patients were randomly assigned in a 1-to-1 fashion immediately after coronary angiography to the 2 regimens mentioned above. Other protocol details are described in previous reports.13,14 The study was conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan. The ethical committees in all the participating centers approved the study protocol, and informed consent was obtained from all patients. The present study population included patients alive at discharge from the index hospitalization in the full analysis set of the STOPDAPT-3 1-year analysis.
Definitions and Endpoints
In the present study, high-intensity statins were defined as the maximum approved dose of strong statins in Japan (e.g., rosuvastatin 10 mg, atorvastatin 20 mg, or pitavastatin 4 mg). The study protocol provided no recommendations regarding discharge medication other than antiplatelet therapy, and the decision to administer high-intensity statins was left to the attending physicians. Investigators were required to provide baseline laboratory data obtained immediately before the index procedure or within 1 month of the index PCI. For low-density lipoprotein cholesterol (LDL-C), priority was given to directly measured values; however, values obtained using the Friedewald formula were also accepted.16
The study defined 2 co-primary endpoints: (1) the cardiovascular endpoint, a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischemic stroke; and (2) the bleeding endpoint defined as Bleeding Academic Research Consortium (BARC) criteria 3 or 5.17 The major secondary endpoint was the composite of these 2 co-primary endpoints, representing net adverse clinical events. The definitions of myocardial infarction and stent thrombosis are based on the ARC definitions.18 Other definitions of clinical endpoints are presented in Supplementary Appendix 1.
In this study, to evaluate the effect of high-intensity statins at hospital discharge, we analyzed only post-discharge clinical events (post-discharge analysis). As a sensitivity analysis, we also assessed clinical events over the full 1-year period from randomization (post-randomization analysis).
An independent clinical event committee evaluated each event, and the events were adjudicated by consensus of at least 2 blinded committee members.
Statistical Analysis
Categorical variables are presented as numbers and percentages, whereas continuous variables are presented as either the mean±standard deviation, or median and interquartile range (IQR), depending on their distributions. The cumulative incidence of clinical events was estimated using the Kaplan–Meier method and compared using log-rank tests. Cox proportional hazard models were used to evaluate the effects of high-intensity statins, and the relative effects are presented as hazard ratios (HRs) and 95% confidence intervals (CIs) calculated from the Wald statistic. Patient factors and the practices of participating centers influenced the administration of high-intensity statins. Therefore, the HRs were adjusted by 22 clinically relevant covariates, including complete revascularization, and 1 stratification variable that categorized participating centers by the frequency of high-intensity statin use (Supplementary Appendix 2). Data on complete revascularization were not prospectively collected and were coded post hoc based on lesion location and target lesions, which is described in the Supplementary Appendix 2 in detail.
We conducted 2 stratified subanalyses to evaluate differences in the effects of high-intensity statins: (1) patients with ACS or non-ACS; and (2) patients with complete revascularization or not. We also performed pre-specified and some subgroup analyses. The cut-off value of 100 mg/dL for LDL-C was chosen based on clinical relevance and prior publications.12 The definition of complex PCI was applied from a prior publication by Giustino et al.19 All reported P values were 2 sided. P values <0.05 were considered statistically significant. We performed all analyses using JMP Pro version 18.0 (SAS Institute Inc., Cary, NC, USA), except for the adjusted analysis with a stratification variable, which was conducted using SPSS version 25 (IBM, Armonk, NY, USA).
Results
Study Patients
Between January 2021 and April 2023, 6,002 patients were randomized in STOPDAPT-3, and 5,962 were included in the 1-year analysis. Additionally, we excluded 139 patients who died during the index hospitalization, leaving the present study population of 5,823 patients, comprising 2,829 (48.6%) who received high-intensity statins at discharge and 2,994 (51.4%) who did not (Figure 1).
Figure 1.
Study flowchart. ACS, acute coronary syndrome; CCS, chronic coronary syndrome; PCI, percutaneous coronary intervention; STOPDAPT-3, ShorT and Optimal duration of Dual AntiPlatelet Therapy after everolimus-eluting cobalt-chromium stent-3.
Prescription Rates of High-Intensity Statins Across the Participating Centers
Among 72 participating PCI centers, the prescription rates of high-intensity statins were 100%–≥75% in 14 centers, <75%–≥50% in 16 centers, <50%–≥25% in 14 centers, and <25%–0% in 28 centers. In 13 centers, no patients received high-intensity statins at discharge. There was no apparent relationship between enrollment and the prescription rate of high-intensity statins (Figure 2).
Figure 2.
Prevalence of high-intensity statin use across the participating centers. The graph shows the distribution of the prevalence of high-intensity statin use at discharge across the participating centers. The centers were classified into 4 groups depending on the prevalence of high-intensity statin use, which was incorporated into the adjusted Cox’s model as a stratification variable.
Baseline Characteristics in Patients With vs. Without High-Intensity Statins at Discharge
Baseline patient characteristics are shown in Table 1 and Supplementary Table 1. Patients with high-intensity statins at discharge, compared with those without, were younger and more often presented as ACS, including ST-segment elevation myocardial infarction (STEMI) and non-ST-elevation ACS, and cardiogenic shock. Dyslipidemia and smoking were more prevalent, but other ischemic risk factors and comorbidities were less prevalent. The median baseline LDL-C level was higher (117 vs. 102 mg/dL; P<0.001). In the procedural characteristics, patients receiving high-intensity statins had more PCI procedures, target lesions, bifurcation lesions, and multivessel target lesions. Moreover, patients receiving high-intensity statins had more stents, longer total stent length, and more complex PCIs. Nevertheless, the rate of complete revascularization was not different between the 2 groups. The use of imaging devices was more prevalent in patients receiving high-intensity statins. Regarding discharge medications, anticoagulants were used less often, while renin–angiotensin system antagonists, β-blockers, and ezetimibe were more often used in patients with high-intensity statins. Fibrates, eicosapentaenoic acid, and PCSK9 inhibitors were rarely used in both groups (Table 1, Supplementary Table 1).
Table 1.
Baseline Characteristics
| High-intensity statins at dischargea | P value | ||
|---|---|---|---|
| Yes (n=2,829) | No (n=2,994) | ||
| Patient demographics | |||
| Age (years) | 72 (62–79) | 75 (66–81) | <0.001 |
| ≥75 years† | 1,105 (39.1) | 1,534 (51.2) | <0.001 |
| Sex, male† | 2,223 (78.6) | 2,243 (74.9) | 0.001 |
| Body-mass index (kg/m2) | 23.6 [21.7–26.1] (n=2,829) | 23.5 [21.4–25.9] (n=2,993) | 0.02 |
| <25 kg/m2 † | 1,830/2,829 (64.7) | 1,977/2,993 (66.0) | 0.28 |
| Clinical presentation | |||
| Acute coronary syndrome† | 2361 (83.5) | 1,980 (66.1) | <0.001 |
| STEMI | 1,482 (52.4) | 964 (32.2) | <0.001 |
| Non-STEMI | 585 (20.7) | 488 (16.3) | <0.001 |
| Unstable angina | 294 (10.4) | 528 (17.6) | <0.001 |
| Cardiac arrest or ventricular fibrillation | 40 (1.4) | 16 (0.5) | <0.001 |
| Cardiogenic shock | 139 (4.9) | 85 (2.8) | <0.001 |
| Current heart failure† | 512 (18.1) | 511 (17.1) | 0.30 |
| Past history and comorbidities | |||
| Prior percutaneous coronary intervention | 339 (12.0) | 573 (19.1) | <0.001 |
| Prior coronary artery bypass grafting | 46 (1.6) | 76 (2.5) | 0.02 |
| Prior MI† | 186 (6.6) | 264 (8.8) | 0.001 |
| Prior stroke† | 203 (7.2) | 334 (11.2) | <0.001 |
| Prior heart failure† | 594 (21.0) | 693 (23.2) | 0.048 |
| Atrial fibrillation† | 181 (6.4) | 357 (11.9) | <0.001 |
| Peripheral artery disease† | 119 (4.2) | 207 (6.9) | <0.001 |
| Hypertension† | 2,129 (75.3) | 2,348 (78.4) | 0.004 |
| Hyperlipidemia | 1,988 (70.3) | 1,942 (64.9) | <0.001 |
| Diabetes† | 1,216 (43.0) | 1,405 (46.9) | 0.003 |
| With insulin therapy | 123 (4.4) | 189 (6.3) | <0.001 |
| Current smoker† | 770 (27.2) | 614 (20.5) | <0.001 |
| Left ventricular ejection fraction (%) | 53.4±10.9 (n=2,633) | 56.0±12.4 (2,793) | <0.001 |
| <40% | 250/2,633 (9.5) | 267/2,793 (9.6) | 0.94 |
| Anemia†,b | 771 (27.3) | 1,096 (36.6) | <0.001 |
| Thrombocytopeniac | 17 (0.6) | 52 (1.7) | <0.001 |
| Chronic kidney diseased | 1,311 (46.3) | 1,696 (56.7) | <0.001 |
| Moderate | 1,107 (39.1) | 1,258 (42.0) | 0.03 |
| Severe†, not on dialysis | 108 (3.8) | 189 (6.3) | <0.001 |
| Hemodialysis† | 96 (3.4) | 249 (8.3) | <0.001 |
| Cancer history | 259 (9.2) | 337 (11.3) | 0.008 |
| Long-term use of oral NSAIDs or steroids† | 130 (4.6) | 154 (5.1) | 0.33 |
| ARC-HBR | 1,297 (45.9) | 1,849 (61.8) | <0.001 |
| Laboratory data | |||
| Total cholesterol (mg/dL) | 193 [160–224] (n=2,375) | 176 [149–206] (n=2,496) | <0.001 |
| HDL (mg/dL) | 48 [40–57] (n=2,741) | 49 [41–58] (n=2,871) | 0.08 |
| Triglycerides (mg/dL) | 113 [77–169] (n=2,748) | 113 [78–169] (n=2,875) | 0.44 |
| LDLe (mg/dL) | 117 [90–144] (n=2,763) | 102 [79–126] (n=2,886) | <0.001 |
| <70 | 288/2,763 (10.4) | 480/2,886 (16.6) | <0.001 |
| ≥70 and <100 | 638/2,763 (23.1) | 870/2,886 (30.2) | |
| ≥100–<120 | 508/2,763 (18.4) | 630/2,886 (21.8) | |
| ≥120–<140 | 521/2,763 (18.9) | 450/2,886 (15.6) | |
| ≥140 | 808/2,763 (29.2) | 456/2,886 (15.8) | |
| HbA1c (NGSP; %) | 6.0 [5.7–6.8] (n=2,668) | 6.1 [5.7–6.9] (n=2,749) | 0.02 |
| eGFR (mL/min/1.73 m2) | 61.7 [48.1–74.4] (n=2,816) | 56.8 [41.8–70.6] (n=2,986) | <0.001 |
| Procedural characteristics | |||
| Staged PCI† | 671 (23.7) | 534 (17.8) | <0.001 |
| Complex PCIf | 727 (25.7) | 689 (23.0) | 0.02 |
| Complete revascularization†,g | 2,238 (79.1) | 2,340 (78.2) | 0.38 |
| Medication at dischargeh | |||
| Days from randomization to discharge | 8 [4–12] | 5.5 [2–11] | <0.001 |
| Aspirin only | 52 (1.8) | 42 (1.4) | 0.19 |
| Prasugrel only | 1,334 (47.2) | 1,449 (48.4) | 0.34 |
| Dual antiplatelet therapy | 1,396 (49.4) | 1,453 (48.5) | 0.53 |
| Anticoagulants | 343 (12.1) | 448 (15.0) | 0.002 |
| ACE inhibitor or ARB† | 2,243 (79.3) | 2,101 (70.2) | <0.001 |
| MRA† | 525 (18.6) | 438 (14.6) | <0.001 |
| β-blockers† | 1,977 (69.9) | 1,776 (59.3) | <0.001 |
| Proton-pump inhibitors† | 2,555 (90.3) | 2,558 (85.4) | <0.001 |
| Statins | 2,829 (100) | 2,618 (87.4) | <0.001 |
| Atorvastatin | 741 (26.2) | 378 (12.6) | <0.001 |
| Pitavastatin | 1,023 (36.2) | 288 (9.6) | <0.001 |
| Rosuvastatin | 1,065 (37.7) | 1,894 (63.3) | <0.001 |
| Other statins | 0 (0) | 58 (1.9) | <0.001 |
| Fibrates | 32 (1.1) | 61 (2.0) | 0.006 |
| EPA | 82 (2.9) | 98 (3.3) | 0.41 |
| Ezetimibe | 743 (26.3) | 715 (23.9) | 0.04 |
| PCSK9 inhibitor | 3 (0.11) | 1 (0.03) | 0.29 |
Unless indicated otherwise, data are presented as n (%), mean±SD, or median [IQR]. For missing values, the number of patients analyzed are presented as ’n=’ for continuous variables and ’/n’ for categorical variables. †Risk-adjusting variables incorporated into the multivariate models. aHigh-intensity statins were defined as the maximum approved dose of strong statins in Japan (e.g., rosuvastatin 10 mg, atorvastatin 20 mg, or pitavastatin 4 mg). bAnemia was defined as a pre-procedural hemoglobin level of <11 g/dL in both men and women. cThrombocytopenia was defined as pre-procedural platelet counts <100×109/L. dChronic kidney disease was defined as a pre-procedural eGFR <60 mL/min/1.73 m2 (moderate: <60 and ≥30 mL/min/1.73 m2 and severe: <30 mL/min/1.73 m2 or under maintenance dialysis). eLDL values were directly measured or calculated using the Friedewald formula. If both values were available, the directly measured values were indicated. fComplex PCI was defined as PCI with one or more of the following features, considering all staged procedures: at least 3 stents implanted, at least 3 lesions treated, 3 vessels treated, bifurcation with 2 stents implanted, total stent length >60 mm, and treatment of chronic total occlusion. gData for complete revascularization was coded post hoc based on the data of lesion location and treated lesions. See Supplementary Appendix 2. hMedication at discharge was analyzed for the patients who were discharged alive, irrespective of within 30 days or beyond 30 days after randomization. ACE, angiotensin converting enzyme; ARB, angiotensin-II receptor blocker; eGFR, estimated glomerular filtration rate; EPA, eicosapentaenoic acid; HDL, high-density lipoprotein; IQR, interquartile range; LDL, low-density lipoprotein; MRA, mineralocorticoid receptor antagonist; MI, myocardial infarction; NGSP, National Glycohemoglobin Standardization Program; NSAID, non-steroidal anti-inflammatory drug; PCI, percutaneous coronary intervention; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitor; STEMI, ST-segment elevation myocardial infarction.
When stratified by clinical presentation (ACS vs. non-ACS), high-intensity statins were more frequently prescribed at discharge in ACS patients (54.4% vs. 31.5%; P<0.001). In both ACS and non-ACS patients, those receiving high-intensity statins were younger and had fewer atherosclerotic risk factors other than hyperlipidemia (Supplementary Tables 2,3). The baseline LDL-C level was higher in ACS patients than in non-ACS patients (117 [95–143] vs. 82 [65–105] mg/dL; P<0.001). In the ACS subgroup, the baseline LDL-C level was higher in patients with high-intensity statins than in those without (123 [98–148] vs. 112 [89–135] mg/dL; P<0.001; Supplementary Table 2), while in the non-ACS subgroup, it was not different between the 2 groups (79 [62–109] vs. 84 [66–104] mg/dL; P=0.43; Supplementary Table 3). The rate of complete revascularization was higher in ACS patients than in non-ACS patients (80.0% vs. 74.7%; P<0.001). In the ACS subgroup, the rate of complete revascularization was not significantly different between patients with and without high-intensity statins (80.8% vs. 79.0%; P=0.14; Supplementary Table 2). In contrast, in the non-ACS subgroup, the rate of complete revascularization was significantly lower in patients with high-intensity statins (70.7% vs. 76.5%; P=0.02; Supplementary Table 3).
In the stratified analysis with completeness of revascularization, patients without complete revascularization were older and had more comorbidities than patients with complete revascularization. Across these groups, high-intensity statins were prescribed more frequently among younger patients (Supplementary Table 4).
Clinical Outcomes
The 1-year follow-up rate was >99% in both groups (Figure 1). In the post-discharge analysis, the cumulative 1-year incidence of the co-primary cardiovascular endpoint did not differ between patients with and without high-intensity statins (3.90% vs. 4.27%; crude HR 0.92 [95% CI 0.71–1.19]; P=0.51; adjusted HR 1.03 [0.74–1.44]; P=0.84; Figure 3A, Table 2). The rate of all-cause death was lower in patients with high-intensity statins, although the adjusted HR was no longer significant (2.98% vs. 4.34%; crude HR 0.69 [0.52–0.91]; adjusted HR 0.71 [0.50–1.01]; Figure 3B, Table 2). The rate of myocardial infarction and ischemic stroke was similar, although the adjusted HR for ischemic stroke was significantly higher with high-intensity statins (adjusted HR 2.04 [1.03–4.03]; Figure 3C,D, Table 2). The adjusted HR for ischemic stroke was not substantially changed even when anticoagulation at discharge was incorporated into the analysis (adjusted HR 2.02 [95% CI 1.02–4.00]), and when the study cohort was stratified with or without the presence of prior stroke, atrial fibrillation, or anticoagulants at discharge, a significantly increased risk was observed in patients without these 3 factors (adjusted HR 2.87 [95% CI 1.17–7.09]) but not in patients with these 3 factors (adjusted HR 1.46 [95% CI 0.49–4.37]; P for interaction=0.27).
Figure 3.
Time-to-event curves for the post-discharge clinical events. (A) The co-primary cardiovascular endpoint, (B) all-cause death, (C) myocardial infarction, (D) ischemic stroke, and (E) the co-primary bleeding endpoint. The median days of follow up was 356 (interquartile range 349–361). See the Methods section for the definitions of outcomes. CI, confidence interval; HR, hazard ratios.
Table 2.
Clinical Outcomes at 1 Year After Discharge
| Outcomes | No. patients with event (cumulative 1-year incidence)a |
Crude HRb
(95% CI) |
P value | Adjusted HRb
(95% CI) |
P value | |
|---|---|---|---|---|---|---|
| High-intensity statins at discharge | ||||||
| Yes (n=2,829) | No (n=2,994) | |||||
| Co-primary cardiovascular endpoint | ||||||
| A composite of cardiovascular death, MI, definite stent thrombosis, or ischemic stroke |
109 (3.90%) | 125 (4.27%) | 0.92 (0.71–1.19) | 0.51 | 1.03 (0.74–1.44) | 0.84 |
| Co-primary bleeding endpoint | ||||||
| BARC 3 or 5 bleeding | 51 (1.87%) | 76 (2.60%) | 0.70 (0.49–1.00) | 0.052 | 1.00 (0.64–1.56) | 0.99 |
| Major secondary endpoint | ||||||
| A composite of cardiovascular death, MI, definite stent thrombosis, ischemic stroke, or BARC 3 or 5 bleeding |
146 (5.25%) | 186 (6.35%) | 0.82 (0.66–1.02) | 0.08 | 0.97 (0.74–1.28) | 0.84 |
| Secondary endpoint | ||||||
| Death | 83 (2.98%) | 127 (4.34%) | 0.69 (0.52–0.91) | 0.71 (0.50–1.01) | ||
| Death from cardiovascular causes | 45 (1.61%) | 68 (2.33%) | 0.70 (0.48–1.01) | 0.80 (0.50–1.28) | ||
| Death from non-cardiovascular causes | 38 (1.39%) | 59 (2.06%) | 0.68 (0.45–1.02) | 0.63 (0.38–1.06) | ||
| MIc | 40 (1.44%) | 43 (1.49%) | 0.98 (0.63–1.50) | 0.93 (0.53–1.62) | ||
| Definite or probable stent thrombosisc | 8 (0.28%) | 7 (0.24%) | 1.21 (0.44–3.32) | 0.97 (0.25–3.80) | ||
| Definite | 4 (0.14%) | 4 (0.14%) | 1.05 (0.26–4.21) | 1.24 (0.18–8.49) | ||
| Probable | 4 (0.14%) | 3 (0.10%) | 1.41 (0.32–6.30) | 0.79 (0.12–5.06) | ||
| Stroke | 35 (1.25%) | 28 (0.96%) | 1.32 (0.80–2.16) | 2.03 (1.06–3.88) | ||
| Ischemic stroke | 31 (1.11%) | 25 (0.85%) | 1.31 (0.77–2.21) | 2.04 (1.03–4.03) | ||
| Hemorrhagic stroke | 4 (0.14%) | 3 (0.10%) | 1.40 (0.31–6.25) | 2.07 (0.22–19.16) | ||
| Any coronary revascularization | 126 (4.61%) | 142 (5.14%) | 0.94 (0.74–1.19) | 0.88 (0.65–1.20) | ||
| Bleeding | ||||||
| BARC 5 | 5 (0.18%) | 8 (0.27%) | 0.66 (0.21–2.01) | 0.71 (0.18–2.84) | ||
| BARC 3 | 46 (1.69%) | 68 (2.33%) | 0.71 (0.49–1.03) | 1.05 (0.66–1.69) | ||
| TIMI major or minor | 44 (1.62%) | 67 (2.30%) | 0.69 (0.47–1.01) | 0.98 (0.61–1.59) | ||
| GUSTO moderate or severe | 45 (1.65%) | 63 (2.16%) | 0.75 (0.51–1.10) | 1.08 (0.67–1.75) | ||
| Intracranial bleedinge | 14 (0.50%) | 17 (0.58%) | 0.86 (0.43–1.75) | 1.58 (0.64–3.92) | ||
| Gastrointestinal bleeding (BARC 3 or 5) | 24 (0.86%) | 24 (0.82%) | 1.05 (0.60–1.85) | 2.00 (0.92–4.32) | ||
| Gastrointestinal bleeding (BARC 2, 3, or 5) | 42 (1.51%) | 46 (1.58%) | 0.96 (0.63–1.46) | 1.42 (0.81–2.48) | ||
aCumulative incidence rates were calculated using the Kaplan–Meier method, and this analysis handled the events that occurred after hospital discharge. bHazard ratios were calculated using Cox’s proportional regression models. Risk-adjusting covariates incorporated into the multivariate models were as stated in the main text. The participating centers were categorized into 4 groups based on the prevalence of high-intensity statin use at discharge and were incorporated as a stratification variable .cMyocardial infarction (MI) and stent thrombosis were defined by the Academic Research Consortium criteria. dAny coronary revascularization excluded the scheduled staged PCI. eIntracranial bleedings were all classified as BARC 3 or 5. BARC, Bleeding Academic Research Consortium; CI, confidence interval; CKMB, creatine kinase MB; GUSTO, Global Use of Strategies to Open Occluded Arteries; HR, hazard ratios; TIMI, Thrombolysis in Myocardial Infarction; ULN, upper limits of normal.
The cumulative 1-year incidence of the co-primary bleeding endpoint was numerically lower in the patients with high-intensity statins than in those without, although the effect was not statistically significant after adjustment (1.87% vs. 2.60%; crude HR 0.70 [0.49–1.003]; P=0.052; adjusted HR 1.00 [0.64–1.56]; P=0.99; Figure 3E, Table 2). The adjusted effects of high-intensity statins were not significant for the major secondary endpoint and other secondary endpoints (Table 2, Supplementary Table 5).
Even in the post-randomization analysis, the results were consistent with those of the post-discharge analysis, except for the excess risk of high-intensity statins for ischemic stroke (Supplementary Figure 1, Supplementary Table 6).
Stratified Analysis and Other Subgroup Analysis
The cumulative 1-year incidence of the cardiovascular endpoint did not differ between patients with and without high-intensity statins in both the ACS and non-ACS subgroups, and even after adjusting for confounders, the effect of high-intensity statins remained insignificant regardless of ACS (Supplementary Figures 2,3, Supplementary Tables 7,8). Also, in the stratified analysis by revascularization completeness, the significant risk reduction in the cardiovascular endpoint with high-intensity statins was not observed, regardless of complete revascularization (Supplementary Table 9). In other subgroup analyses, there were no significant interactions between the analyzed subgroups and the effect of high-intensity statins on the co-primary cardiovascular endpoint (Figure 4).
Figure 4.
Subgroup analysis for the effect of high-intensity statins on the post-discharge co-primary cardiovascular endpoint. The incidence of events and relative effects of high-intensity statins at discharge for the post-discharge co-primary cardiovascular endpoint by the subgroups. See the Statistical Analysis section for the adjusted covariates. *LDL values were missing for 174 patients, and these patients were excluded from the analysis. **Post hoc analysis and the coding of complete revascularization were based on the information of lesion sites and PCI procedure input by each participating center. See Supplementary Appendix 2 for details. ACS, acute coronary syndrome; ARC-HBR, Academic Research Consortium for High Bleeding Risk; CI, confidence interval; CKD, chronic kidney disease; DAPT, dual antiplatelet therapy; HR, hazard ratio; LDL, low-density lipoprotein; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction.
Discussion
The present study demonstrated that: (1) despite of the strong recommendations in the present guidelines, high-intensity statins were administered only in 48.6% of patients at discharge after PCI and only in 54.4% even in ACS patients with very wide variation in their prescription rate across the participating centers; and (2) a beneficial effect of high-intensity statins at discharge in reducing cardiovascular events was not observed at 1 year after PCI in the present study population regardless of ACS.
Lipid-lowering therapy is essential in treating coronary artery disease, and present guidelines recommend high-intensity statins at the maximum approved dose regardless of ACS.1–4 The concept of ‘the lower, the better for LDL-C’ has been widely accepted since the meta-analysis published by the Cholesterol Treatment Trialists (CTT) in 2010.9 Two randomized trials assessed high vs. standard intensity statins in the acute phase of ACS. In the PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) trial, 4,162 ACS patients received atorvastatin 80 mg/day or pravastatin 40 mg/day within 10 days of hospitalization. Atorvastatin achieved lower LDL-C (62 vs. 95 mg/dL) and reduced cardiovascular events by 16% over 24 months.5 This study reported that the event curves were separated early, and the difference in event rate between the 2 groups reached significance at 180 days. In the A-to-Z trial, 4,497 ACS patients received early intensive simvastatin (40 mg then 80 mg) or delayed, lower-dose therapy. At 4 months, LDL-C was lower with intensive therapy (62 vs. 124 mg/dL), but it achieved an insignificant 11% reduction in cardiovascular events over 2 years.6 Combined with the results of the TNT (Treating to New Targets), IDEAL (Initiating Dialysis Early and Late), and SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) trials, the higher intensity statin therapy had a further significant 15% risk reduction in any vascular endpoint.7–10 Although the comparator was a placebo, the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) study demonstrated a significant 16% risk reduction at 16 weeks with high-dose atorvastatin (80 mg/day) started early in ACS patients.20 Even though the benefit of early intensive therapy after a coronary event is associated with favorable outcomes, the actual administration rate of high-intensity statins has been reported to be low.21,22 A recent European consensus recommends ‘strike early and strike strong’, including an early, aggressive post-ACS strategy with upfront combination lipid-lowering therapy.23 Further research in the real world on the implementation of intensive lipid-lowering therapy and its effect is required in Japan.
In this post hoc analysis of STOPDAPT-3, which enrolled patients between 2021 and 2023, 48.6% of patients were discharged on high-intensity statins, and 54.4% of ACS patients were discharged on high-intensity statins. The administration rate was slightly higher than the 44.2% reported in the STOPDAPT-2 ACS, which enrolled patients between 2018 and 2020.12 The distribution of high-intensity statin implementation rates varied by facility, and no trend was observed with the number of participants. High-intensity statins were less often prescribed in older patients and those with severe CKD, consistent with prior reports.12 Therefore, the results should be interpreted carefully, for patients without high-intensity statins tend to have more ischemic risk factors. At 1 year, co-primary cardiovascular events were numerically lower with high-intensity statins, but the adjusted risk was not significant. Among the ACS patients, no clear benefit was seen. Across subgroups – including younger age, STEMI, residual stenosis, and higher baseline LDL-C – high-intensity statins were neither associated with lower cardiovascular outcomes, nor with lower risk of coronary revascularization. In contrast, although the proportion of patients with ACS was higher in the high-intensity statins group, and baseline LDL-C levels were also higher, the lack of a difference in the incidence of co-primary cardiovascular events compared with patients without high-intensity statins may be attributable to the effects of high-intensity statins.
Compared with the previous report from STOPDAPT-2 ACS, where we found a significant association between high-intensity statins and a significantly lower incidence of the 1-year cardiovascular endpoint, the present study enrolled approximately twice as many patients, and both the number of events and the event rate were higher. Therefore, the statistical power was higher in the present analysis compared with the STOPDAPT-2 ACS. Compared with other studies, only PROVE-IT, which enrolled ACS patients exclusively, met statistical significance for the primary endpoint within 1 year. In contrast, other studies demonstrated no obvious benefit within 1 year. The discrepancy from PROVE-IT may relate to differences in study design, event profiles, more complete revascularization, and lower high-intensity statin doses in this study. In the present analysis, no clear benefit of high-intensity statins was observed, irrespective of ACS presentation or complete revascularization. Further research is needed to clarify the early cardiovascular benefits of high-intensity statins in current practice.
In the past, a strategy known as ‘fire-and-forget’, in which statin dosages were determined based on risk factors without setting specific LDL-C targets, was proposed.24 However, some reports indicate that only approximately 40% of patients achieved the LDL-C <70 mg/dL target recommended in recent guidelines through statin therapy alone.25 While the ‘fire-and-forget’ approach emphasizes the intensity of the statin itself, we discuss that simply initiating high-intensity statins at discharge is not a complete strategy. Clinical follow up remains essential to ensure that patients actually achieve and maintain the required management targets and to monitor long-term adherence. Based on the firmly established evidence from multiple clinical trials, initiating high-intensity statins earlier is crucial to improving long-term clinical outcomes in the present era of PCI. Nevertheless, a 1-year follow up might be too short to have substantial benefit from the high-intensity statins therapy.
In the present study, high-intensity statin use was associated with a significantly higher adjusted risk for ischemic stroke. Further analysis revealed that high-dose statins were associated with an increased risk in patients without risk factors for ischemic stroke, such as a history of stroke, atrial fibrillation, or anticoagulant therapy. This increased risk was not evident in patients with these risk factors. However, there have been no reports indicating that that high-dose statins increased the risk of stroke, while there have been reports suggesting that high-dose statins themselves reduce the risk of stroke. In the SPARCL trial, high-intensity statins for patients with recent transient ischemic attack or stroke reduced the overall incidence of stroke, despite a slight increase in the incidence of hemorrhagic stroke.26,27 A meta-analysis showed favorable results in the intensive lipid-lowering therapy for recurrent stroke risk reduction.28 The reason for the increased risk of stroke with high-intensity statins is difficult to explain. In addition to the possibility of type I error with multiple endpoints, the present study lacked adequate power to detect a reliable difference in ischemic stroke risk, and the excess risk was not consistent in the post-randomization analysis. Unobserved confounding factors associated with high-intensity statins may affect these results.
Study Limitations
The present study had several limitations. First, the present study was not a randomized trial of high-intensity statins. Despite multivariable adjustment, selection bias and residual confounding would remain. Second, the present study was underpowered to evaluate the effect of high-intensity statins due to low event rates and a short follow-up duration. Third, we collected laboratory data only once before index PCI and medication data only at discharge. Therefore, no data was available on the attained LDL-C level or on medication adherence during follow up. If the attained LDL levels were similar between the 2 groups, it might be one of the reasons for the current neutral findings. Additionally, we were unable to capture the change in statin type or dose, as well as the addition of ezetimibe or PCSK9 inhibitors, during the follow-up period. A stepwise approach after discharge, rather than early administration of a maximum statin dose, might attenuate the risk difference between the 2 groups. Fourth, STOPDAPT-3 was conducted only in Japan, and the participants were almost all Japanese. Smaller physiques, more advanced age, and higher risk of stroke or bleeding, and lower risk of coronary events, and the different dose of medication (including the definition of high-intensity statins) should be carefully considered for extrapolation to other countries. In particular, the lower dosage of high-intensity statins compared with overseas use is thought to be one of the reasons no significant results were obtained. Moreover, in the REAL-CAD trial, which demonstrated the efficacy of high-intensity statins therapy in reducing cardiovascular events among Japanese patients with chronic CAD, the patients in the control group received pitavastatin 1 mg, while in the present study, an average dose of piatavastatin in the control group was 1.8 mg. Therefore, the present study results might at least be partially related to the relatively higher statins dose in the control group.
Conclusions
In the present post hoc analysis of STOPDAPT-3, high-intensity statin therapy at discharge was not associated with a statistically significant reduction in cardiovascular events at 1 year after PCI, regardless of ACS status, under the limitation of residual confoundings and lack of data on the changes in LDL levels and lipid-lowering therapy during the follow-up period.
Disclosures
H.W. reports personal fees from Abbott Medical Japan during the conduct of the study, and personal fees from Amgen, Astellas, Daiichi Sankyo, and Pfizer outside of the submitted work. M.N. reports honoraria from Abbott Medical Japan, Daiichi Sankyo, Medtronic, Terumo, Japan Lifeline, Asahi Intecc, Bristol-Myers Squibb, Otsuka, Amgen, Sanofi, Takeda, and Bayer. T.M. reports lecturer’s fees from Astra Zeneca, Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Pfizer, and Tsumura, manuscript fees from Bristol-Myers Squibb and Pfizer, and advisory board for Novartis and Teijin. Y.O. reports a lecturer’s fee from Abbott Medical Japan. K.A. reports personal fees from Japan Lifeline, Abbott Medical Japan, Medtronic Japan, BIOTRONIK Japan and Novartis Pharma outside of the submitted work. S.S. reports personal fees from Abbott Medical Japan and Daiichi Sankyo outside of the submitted work. K.O. is a member of Circulation Reports’ Editorial Team. Ta.K. reports grants from Abbott Medical Japan and Boston Scientific, and is an advisory board member of Abbott Medical Japan and Terumo Japan. The other authors report no conflicts of interest.
IRB Information
STOPDAPT-3 was approved by the Kyoto University Certified Review Board and Ethics Committee (CRB5180002).
Supplementary Files
Supplementary Appendix 1. Supplementary Appendix 2. Supplementary Table 1. Supplementary Table 2. Supplementary Table 3. Supplementary Table 4. Supplementary Table 5. Supplementary Table 6. Supplementary Table 7. Supplementary Table 8. Supplementary Table 9. Supplementary Figure 1. Supplementary Figure 2. Supplementary Figure 3.
Acknowledgments
The authors extend their appreciation to the members of the Research Institute for Production Development for coordinating the study as the administrative office.
Funding Statement
Sources of Funding: STOPDAPT-3 is funded by Abbott. The funder had no role in the report’s design, data analysis, interpretation, or writing.
Data Availability
The deidentified participant data will not be shared.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Appendix 1. Supplementary Appendix 2. Supplementary Table 1. Supplementary Table 2. Supplementary Table 3. Supplementary Table 4. Supplementary Table 5. Supplementary Table 6. Supplementary Table 7. Supplementary Table 8. Supplementary Table 9. Supplementary Figure 1. Supplementary Figure 2. Supplementary Figure 3.
Data Availability Statement
The deidentified participant data will not be shared.