Relation of renal function to mid-term prognosis of stable angina patients with high- or low-dose pitavastatin treatment: REAL-CAD substudy
Mitsuru Abe, MD,PhD a, Yukio Ozaki, MD,PhD b, Hiroshi Takahashi, BSc c, Mitsuru Ishii, MD,PhD a, Nobutoyo Masunaga, MD a, Tevfik F. Ismail, PhD,FRCP d, Satoshi Iimuro, MD,PhD e, Retsu Fujita, MS e, Hiroshi Iwata, MD,PhD f, Ichiro Sakuma, MD,PhD g, Yoshihisa Nakagawa, MD,PhD h, Kiyoshi Hibi, MD,PhD i, Takafumi Hiro, MD,PhD j, Yoshihiro Fukumoto, MD,PhD k, Seiji Hokimoto, MD,PhD l, Katsumi Miyauchi, MD,PhD f, Hisao Ogawa, MD,PhD m, Hiroyuki Daida, MD,PhD f, Hiroaki Shimokawa, MD,PhD n, Yasushi Saito, MD,PhD o, Masunori Matsuzaki, MD,PhD p, Masaharu Akao, MD,PhD a, Takeshi Kimura, MD,PhD q, and Ryozo Nagai, MD,PhD r Kyoto, Toyoake, Sapporo, Otsu, Yokohama, Kurume, Kumamoto, Sendai, Chiba, Ube, Shimotsuke, Japan; London, United Kingdom
Abstract
Background It has not yet been established whether higher-dose statins have beneficial effects on cardiovascular events in patients with stable coronary artery disease (CAD) and renal dysfunction.
Methods The REAL-CAD study is a prospective, multicenter, open-label trial. As a substudy, we categorized patients by an estimated glomerular filtration rate (eGFR) as follows: eGFR ≥60 (n = 7,768); eGFR ≥45 and <60 (n = 3,176); and eGFR <45 mL/Min/1.73 m2 (n = 1,164), who were randomized to pitavastatin 4mg or 1mg therapy. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina, and was assessed by the log-rank test and Cox proportional hazards model.
Results The baseline characteristics and medications were largely well-balanced between two groups. The magnitude of low-density lipoprotein cholesterol (LDL-C) reduction at 6 months in high- and low-dose pitavastatin groups was comparable among all eGFR categories. During a median follow-up of 3.9 years, high- compared with low-dose pitavastatin significantly reduced cardiovascular events in patients with eGFR ≥60 (hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.58-0.91; P = .006), and reduced but not significant for patients with eGFR ≥45 and <60 (HR 0.85; 95% CI, 0.63-1.14; P = .27) or eGFR <45 mL/Min/1.73 m2 (HR 0.90; 95% CI 0.62-1.33; P = .61). An interaction test of treatment by eGFR category was not significant (P value for interaction = .30).
Conclusion Higher-dose pitavastatin therapy reduced LDL levels and cardiovascular events in stable CAD patients irrespective of eGFR level, although the effect on events appeared to be numerically lower in patients with lower eGFR. (Am Heart J 2021;240:89–100.)
Keywords: Statins; Renal function; Cardiovascular events
Introduction
Statin-mediated low-density lipoprotein cholesterol (LDL-C) lowering therapy has been shown to be effec- tive for primary and secondary prevention of cardiovas- cular events in several randomized control trials.1-9 We also recently demonstrated that high- (4 mg/D) com- pared with low- (1 mg/D) dose pitavastatin therapy sig- nificantly reduced cardiovascular events in Japanese pa- tients with stable coronary artery disease (CAD) in the Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study.10 However, data are conflict- ing concerning the favorable effect of high-dose statins on cardiovascular events in patients with CAD and renal dysfunction.11-15 While higher-dose atorvastatin in the sub-analysis of the Treating to New Targets (TNT) study as well as the combination of simvastatin with ezetim- ibe treatments reduced the risk of major atherosclerotic events in patients with advanced renal dysfunction,12,15 the Incremental Decrease in Endpoints through Aggres- sive Lipid-lowering (IDEAL) substudy failed to show a significant benefit of high- over low-dose statins regard- ing cardiovascular outcomes.14 To clarify whether high- compared with low- dose pitavastatin has any effects on cardiovascular events in CAD patients stratified by an es- timated glomerular filtration rate (eGFR), we conducted this REAL-CAD substudy.
Methods
Study design
The REAL-CAD study was a prospective, multicen- ter, randomized, open-label, blinded endpoint, physician- initiated superiority trial to determine whether high- as compared with low-dose pitavastatin therapy could re- duce cardiovascular events in Japanese patients with stable CAD (Clinical Trial Registration: http://www. clinicaltrials.gov. Unique identifier: NCT01042730).10 We included patients who were 20 to 80 years of age with stable CAD and excluded those patients with LDL- C <100 mg/dL without statin therapy before enroll- ment. Eligible patients who provided informed consent were enrolled and received pitavastatin 1 mg once daily orally for a run-in period of at least one month. Patients achieved LDL-C <120 mg/dL during a run-in period were randomized in a 1-to-1 fashion to oral pitavastatin, ei- ther 4 mg/D (high-dose group) or 1 mg/D (low-dose group), using an electronic data capture system and dynamic allocation stratified by facility, age (<65 or ≥65 years), sex, diabetes mellitus, and statins use before enrolment.10 The detailed study design, patient enrolment, definition of the measurements, and subjects’ baseline clinical characteristics of the REAL-CAD study were previously described.10 The authors are solely responsible for the design and conduct of this study, all study anal- yses, the drafting and editing of the paper, and its final contents. The Comprehensive Support Project for Clin- ical Research of Lifestyle-Related Disease of the Public Health Research Foundation (PHRF) funded this study. The company manufacturing the study drug (Kowa Phar- maceutical Co. Ltd.) provided financial support, but was not involved in design, analysis, data interpretation, or manuscript preparation.
Ethical approval was granted by the PHRF ethics re- view committee and by ethical committees at all partic- ipating sites. All participants provided written informed consent. The study was conducted in accordance with the Declaration of Helsinki.
Renal function was assessed by eGFR, which was cal- culated using an equation specific to Japanese patients.16
This equation was eGFR (mL/Min/1.73 m2) = 194 x Serum creatinine−1.094 x Age−0.287 x 0.739 (if female). In this sub-analysis, patients were categorized as follows: (1) eGFR ≥60 mL/Min/1.73 m2, (2) eGFR ≥45 and <60 mL/Min/1.73 m2, and (3) eGFR <45 mL/Min/1.73 m2. Patients on hemodialysis were excluded from this study. During follow-up, patient visits dictated by the protocol were at 6 and 12 months in the first year and every 12 months thereafter. Serum lipid levels such as LDL-C, total cholesterol, triglycerides (TG), and high-density lipopro- tein cholesterol (HDL-C), as well as other blood tests such as creatine kinase, alanine aminotransferase, aspar- tate aminotransferase, creatinine, and hemoglobin A1c, were measured at the baseline after the run-in period, at 6 and 12 months, and yearly thereafter, while high- sensitivity C-reactive protein (hsCRP) was measured at baseline after the run-in period and at 6 months. The site investigators reported follow-up information through the web-based electronic data capturing system. Data were monitored by the data center, and any inconsistencies were resolved by queries. Final clinical follow-up data were collected through January to March 2016 as pre- viously described elsewhere.10
Study endpoints
The primary endpoint was the same as in the main study: a composite of cardiovascular death, non-fatal my- ocardial infarction (MI), non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization. A secondary composite endpoint was defined as a compos- ite of the primary endpoint event and clinically indicated coronary revascularization excluding target-lesion revas- cularization for lesions treated at prior percutaneous coronary intervention. Other secondary endpoints and details of the definitions of endpoints are described else- where.10
The adverse events that developed after the start of the assigned treatment and for which a causal relationship to study drug administration could not be ruled out were assessed and reported by the site investigators.10 The com- mon definition of rhabdomyolysis was used as the devel- opment of symptoms including myalgia, weakness and myoglobinuria associated with a serum creatine kinase elevation greater than 5 times or more of the upper limit of the normal range.
Statistical analysis
Categorical variables are expressed as numbers and/or percentages and compared using the chi-square test. Continuous variables for each group are presented as the mean ± standard deviation or median (interquartile range) and compared using paired Student’s t-test or the Wilcoxon signed-rank test based on their distribu- tions. The cumulative incidence of clinical events was estimated by the Kaplan-Meier method and compared by the log-rank test. The effect of the high- relative to low-dose pitavastatin was assessed by the Cox propor- tional hazards model and is expressed as a hazard ratio (HR) and associated 95% confidence interval (CI). Pro- portional hazard assumptions were assessed on the plots of log (time) versus log [-log (survival)], and the assump- tions were verified in the total cohort.10 Patients lost to follow-up were censored at the time when their final clin- ical follow-up information was available. Two-tailed val- ues of P<.05 were considered significant. We used JMP 10 (SAS Institute Inc., Cary, NC, USA) for all analyses.
Results
Study patients
The REAL CAD study consisted of 12,413 patients (high-dose: n = 6,199, low-dose: n = 6,214) as the full analysis population recruited from a total of 733 aca- demic and general hospitals and clinics which participated from the beginning of enrolment of the patients (January 2010) to the end of follow-up period (March 2016). Following the exclusion of 295 patients who did not have eGFR data, the remaining 12,118 patients who were categorized by eGFR were finally analyzed in this substudy. The numbers of patients categorized into eGFR ≥60, eGFR ≥45 and <60, and eGFR <45 mL/Min/1.73 m2 were 7,778 (64%), 3,176 (26%), and 1,164 (10%), respectively. The median follow-up period was 3.9 years.
The baseline characteristics and medications were well-balanced except for smoking status in the eGFR <45 mL/Min/1.73 m2 (P =.029) between high- and low-dose groups for all variables (Table I).
Serum lipid parameters and high-sensitivity C-reactive protein
The values of serum lipid parameters and hsCRP at the baseline after the run-in period and at 6 months are pre- sented in Table II. The mean LDL-C levels at the baseline after the run-in period were similar, and the magnitude of LDL-C reduction at 6 months was significantly greater in the high- than low-dose groups across all categories based on eGFR. The magnitude of mean LDL-C reduction at 6 months in high- (88 to 74 mg/dL, 87 to 72 mg/dL, and 87 to 72 mg/dL in patients with eGFR ≥60, eGFR ≥45 and <60, and eGFR <45 mL/Min/1.73 m2, respectively) or low-dose pitavastatin groups (mean: 89 to 90mg/dL, 87 to 88 mg/dL, and 86 to 85 mg/dL in patients with eGFR ≥60, eGFR ≥45 and <60, and eGFR <45 mL/Min/1.73 m2, respectively) was comparable across all categories based on eGFR. At 6 months, the magnitude of TG reduction at 6 months was greater in the high- than low-dose groups among all groups. The HDL-C level at 6 months in the high-dose group was significantly higher than that at the baseline after the run-in period only in patients with eGFR ≥60 mL/Min/1.73 m2.
Although serum levels of hsCRP at 6 months in the high-dose pitavastatin group were significantly lower than those at the baseline after the run-in period in pa- tients with eGFR ≥60 (median, 0.47 to 0.41 mg/L; P < .0001) and eGFR; ≥45 and <60 (median, 0.55 to 0.46mg/L; P < .0001), this effect was not observed in patients with eGFR <45 mL/Min/1.73 m2 (median, 0.66 to 0.67 mg/L; P =.058). No significant difference in the change of hsCRP between high- and low-dose groups was observed in patients with eGFR ≥60 (P for interac- tion = .52), eGFR ≥45 and <60 (P for interaction = .64), or eGFR <45 mL/Min/1.73 m2 (P for interaction = .57).
Clinical outcomes
High- compared with low-dose pitavastatin signifi- cantly reduced the primary endpoint in patients with eGFR ≥60 (HR 0.73; 95% CI 0.58-0.91; P = .006), and reduced but the effect was not significant in patients with eGFR ≥45 and <60 (HR 0.85; 95% CI 0.63-1.14; P = .27) or eGFR <45 mL/Min/1.73 m2 (HR 0.90; 95% CI 0.62-1.33; P = .61). An interaction test of treatment by eGFR category was not significant (P value for interac- tion =.30) (Table III). The cumulative 4-year incidence of the primary endpoint was significantly lower in the high- than low-dose group only in patients with eGFR ≥60 (3.4% and 4.6%, respectively; log-rank P = .006), but not with eGFR ≥45 and <60 (5.6 and 6.9%, respectively; log-rank P = .27) or eGFR <45 mL/Min/1.73 m2 (9.1% and 9.8%, respectively; log-rank P = .61) (Figure 1).
High- compared with low-dose pitavastatin signifi- cantly reduced the secondary composite endpoint in patients with eGFR ≥60 (HR 0.80; 95% CI 0.69-0.94; P = .0067), and reduced but the effect was not significant in patients with eGFR ≥45 and <60 (HR 0.80; 95% CI 0.63-1.01; P = .056) or eGFR <45 mL/Min/1.73 m2 (HR 0.87; 95% CI 0.64-1.19; P = .39). A test for interaction of treatment by eGFR category was not significant (P value for interaction = .71) (Table III). The cumula- tive 4-year incidence of the secondary composite end- point was significantly lower in the high- than low-dose group only in patients with eGFR ≥60 (7.4% and 9.4%, respectively; log-rank P = .0069), but not in patients with eGFR; ≥45 and <60 (9.1% and 11.3%, respectively; log- rank P = .056) or eGFR <45 mL/Min/1.73 m2 (13.8% and 15.7%, respectively; log-rank P = .39) (Figure 2).
High-dose pitavastatin significantly reduced the risks of MI and any coronary revascularization in patients with eGFR ≥60; however, the effects were reduced in patients with eGFR ≥45 and <60, or eGFR <45 mL/Min/1.73 m2.
There was no significant difference between high- and low-dose pitavastatin treatment in the risks of all-cause mortality, cardiovascular death, ischemic stroke, or un- stable angina requiring emergency hospitalization among all categories (Table III).
The rate of serious adverse events, such as rhabdomy- olysis, was very low and not significantly different among the three categories based on eGFR. Muscle complaints were more often observed in the high- than low-dose group among all categories. However, a higher rate of creatine kinase elevation ≥5 times the upper limit of normal on administering high- compared with low-dose pitavastatin was only seen in patients with eGFR <45 mL/Min/1.73 m2 (Table IV).
Discussion
The main findings of the present study in Japanese pa- tients with stable CAD are the following: (1) high- com- pared with low-dose pitavastatin reduced cardiovascu- lar events in patients with stable CAD irrespective of eGFR level, although the effect appeared to be numeri- cally lower in patients with lower eGFR; (2) the magni- tude of LDL-C reduction at 6 months in high- and low- dose pitavastatin groups was comparable among all cat- egories based on eGFR; and (3) serum level of hsCRP at Kaplan-Meier Curves for the Secondary Composite Endpoint (Primary Endpoint plus Coronary Revascularization), (A) eGFR ≥60, (B) eGFR ≥45 and <60, and (C) eGFR <45 mL/min/1.73 m2 . The cumulative incidence was estimated by the Kaplan-Meier method. The secondary composite endpoint was a composite of the primary endpoint plus coronary revascularization based on the clinical indication. Coronary revascularization as a component of the secondary composite endpoint excluded target-lesion revascularization for lesions treated at the time of prior percutaneous coronary intervention.
6 months in the high-dose pitavastatin group was signifi- cantly lower than that at the baseline after the run-in period in patients with eGFR ≥60 and GFR ≥45 and <60, but not in patients with eGFR <45 mL/Min/1.73 m2, while no significant difference in the change of hsCRP between high- and low-dose groups was observed.
Rosuvastatin was reported to be effective in reducing cardiovascular events and all-cause mortality in patients with renal dysfunction as primary prevention.17 In addi- tion, the combination of simvastatin with ezetimibe re- duced the risk of major atherosclerotic events in patients with advanced renal dysfunction.15 However, two statin trials involving hemodialysis patients failed to show a significant benefit regarding cardiovascular events,11,13 while these studies did not have high intensity regimens such as atorvastatin of 20 mg11 or rosuvastatin of 10mg.13
In the sub-analysis of the TNT study, high- as compared with low-dose atorvastatin was more effective in reduc- ing cardiovascular events in patients with renal dysfunc- tion (ie, eGFR <60 mL/Min/1.73 m2) and CAD,12 while in the IDEAL substudy, high-dose atorvastatin compared to usual-dose simvastatin did not show a significant ben- efit on major coronary events in patients with renal dys- function (ie, eGFR <60 mL/Min/1.73 m2) and previous MI.14 Whilst conflicting evidence has been provided in previous studies with different dose, duration and kinds of statin, and some of rather small population, it has not yet been firmly established whether high- compared with low-dose statins have beneficial effects on cardio-vascular events in patients with renal dysfunction and CAD.
Our study is the largest to date to randomize patients to high- compared with low-dose statin therapy for sec- ondary prevention of cardiovascular disease (12,413 pa- tients in the REAL-CAD study).6,7,10 High- compared with low-dose pitavastatin reduced cardiovascular events in patients with stable CAD irrespective of eGFR level, al- though the effect appeared to be numerically lower in patients with lower eGFR. High- compared with low- dose pitavastatin also significantly reduced MI and any coronary revascularization only in patients with eGFR ≥60 mL/Min/1.73 m2. The sub-analysis of the IDEAL study also reported that the reduction of MI by high- dose atorvastatin was observed only in patients with nor- mal renal function, but not in patients with renal dys- function.14 Since a beneficial effect of statins on car- diovascular outcomes in patients on hemodialysis was not detected,11,13 some of the favorable effects of statins might be limited in the end stages of advanced coronary atherosclerotic lesions especially with calcium deposits due to inflammation, oxidative stress, derangement of bone and mineral metabolism, and accelerated ageing in patients with renal dysfunction. In fact, the relationship between coronary plaque morphology and renal func- tion has been well established from IVUS trials and the histological studies.18-21 In addition, some studies have reported that subjects with insulin resistance and dia- betes have coronary plaques with abundant lipid or high necrotic core, and patients with renal dysfunction fre- quently have these comorbidities.22,23 Increased coro- nary artery lipid content, dense calcium, and necrotic core volume were observed in patients with lower eGFR levels, therefore, these factors could partially explain the results of the study. There was no significant difference between high- and low-dose pitavastatin treatment in the risk of all-cause mortality, which is consistent with previ- ous studies including the TNT substudy and IDEAL sub- study.12,14
The magnitude of LDL-C reduction at 6 months in high- or low-dose pitavastatin groups was comparable among the three categories based on eGFR, therefore, effective- ness of LDL lowering is not affected by the range of GFRs included in the trial. No significant difference in the change of hsCRP between high- and low-dose groups was observed, although serum levels of hsCRP at 6 months in the high-dose pitavastatin group were significantly lower than those at baseline after the run-in period in patients with eGFR ≥60 and eGFR ≥45 and <60, but not in pa- tients with eGFR <45 mL/Min/1.73 m2. Given that a re- duction in hsCRP was reported to be an indicator of suc- cessful treatment with rosuvastatin with regard to the in- flammatory hypothesis of atherothrombosis,24 the mag- nitude of hsCRP reduction at 6 months by high-dose pitavastatin might partially explain the significant reduc- tion of cardiovascular events in eGFR ≥60 patients and weaker reduction of cardiovascular events in patients with eGFR ≥45 and <60 mL/Min/1.73 m2 observed in this study.
Our study has several limitations. First, the present sub- study might be underpowered in patients with eGFR ≥45 and <60, or eGFR <45 mL/Min/1.73 m2. However, the REAL-CAD study had the greatest number of patients ran- domized to high- compared with low-dose statin therapy to date. Second, the present study was conducted as an open-label trial with its inherent limitations. Third, we excluded patients on hemodialysis because of safety con- cerns related to potential toxic effects of higher-intensity statins in patients with reduced renal clearance, particularly as the benefits of statins in patients on hemodialysis are unclear.11,13 Fourth, the presence of proteinuria is known to be associated with adverse clinical outcomes in even patients without reduced eGFR,25-27 however, urine measurements were not systematically performed in the present study. Finally, this study included those pa- tients prescribed only pitavastatin and we did not exam- ine the effects of other statins. However, we previously compared pitavastatin and atorvastatin, and obtained a similar degree of plaque regression in patients with acute coronary syndromes.28
Conclusion
High- compared with low-dose pitavastatin therapy re- duced LDL levels and cardiovascular events in stable CAD patients irrespective of eGFR level, although the effect on events appeared to be numerically lower in patients with lower eGFR.
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