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Corresponding author at: Division of Cardiovascular Medicine (Ohashi), Department of Internal Medicine, Faculty of Medicine, Toho University, 2-22-36 Ohashi, Meguro-ku, Tokyo 153-8515, Japan.
The study was a first, randomized, prospective trial of two statins therapy.
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Pitavastatin reduced more cardiovascular events compared with atorvastatin.
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There were no differences in cholesterol profiles between two statin groups.
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This may suggest the action of statin beyond cholesterol-lowering effects.
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We may reconsider how to use statins for high-risk patients.
Abstract
Background
There has been no report about outcome of pitavastatin versus atorvastatin therapy in high-risk patients with hypercholesterolemia.
Methods
Hypercholesterolemic patients with one or more risk factors for atherosclerotic diseases (n = 664, age = 65, male = 54%, diabetes = 76%, primary prevention = 74%) were randomized to receive pitavastatin 2 mg/day (n = 332) or atorvastatin 10 mg/day (n = 332). Follow-up period was 240 weeks. The primary end point was a composite of cardiovascular death, sudden death of unknown origin, nonfatal myocardial infarction, nonfatal stroke, transient ischemic attack, or heart failure requiring hospitalization. The secondary end point was a composite of the primary end point plus clinically indicated coronary revascularization for stable angina.
Results
The mean low-density lipoprotein cholesterol (LDL-C) level at baseline was 149 mg/dL. The mean LDL-C levels at 1 year were 95 mg/dL in the pitavastatin group and 94 mg/dL in the atorvastatin group. There were no differences in LDL-C levels between both groups, however, pitavastatin significantly reduced the risk of the primary end point, compared to atorvastatin (pitavastatin = 2.9% and atorvastatin = 8.1%, HR, 0.366; 95% CI 0.170–0.787; P = 0.01 by multivariate Cox regression) as well as the risk of the secondary end point (pitavastatin = 4.5% and atorvastatin = 12.9%, HR = 0.350; 95%CI = 0.189–0.645, P = 0.001). The results for the primary and secondary end points were consistent across several prespecified subgroups. There were no differences in incidence of adverse events between the statins.
Conclusion
Pitavastatin therapy compared with atorvastatin more may prevent cardiovascular events in hypercholesterolemic patients with one or more risk factors for atherosclerotic diseases despite similar effects on LDL-C levels.
Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial.
Early statin treatment in patients with acute coronary syndrome: demonstration of the beneficial effect on atherosclerotic lesions by serial volumetric intravascular ultrasound analysis during half a year after coronary event: the ESTABLISH study.
Effect of rosuvastatin on coronary atheroma in stable coronary artery disease: multicenter coronary atherosclerosis study measuring effects of rosuvastatin using intravascular ultrasound in Japanese subjects (COSMOS).
Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.
Comparisons of short- and intermediate-term effects of pitavastatin versus atorvastatin on lipid profiles, fibrinolytic parameter, and endothelial function.
Comparative long-term efficacy and tolerability of pitavastatin 4 mg and atorvastatin 20-40 mg in patients with type 2 diabetes mellitus and combined (mixed) dyslipidaemia.
A 52-week, randomized, open-label, parallel-group comparison of the tolerability and effects of pitavastatin and atorvastatin on high-density lipoprotein cholesterol levels and glucose metabolism in Japanese patients with elevated levels of low-density lipoprotein cholesterol and glucose intolerance.
Randomized head-to-head comparison of pitavastatin, atorvastatin, and rosuvastatin for safety and efficacy (quantity and quality of LDL): the PATROL trial.
Effect of intensive statin therapy on regression of coronary atherosclerosis in patients with acute coronary syndrome: a multicenter randomized trial evaluated by volumetric intravascular ultrasound using pitavastatin versus atorvastatin (JAPAN-ACS [Japan assessment of pitavastatin and atorvastatin in acute coronary syndrome] study).
Japan Lipid Intervention Trial. Large scale cohort study of the relationship between serum cholesterol concentration and coronary events with low-dose simvastatin therapy in Japanese patients with hypercholesterolemia and coronary heart disease: secondary prevention cohort study of the Japan Lipid Intervention Trial (J-LIT).
International clinical harmonization of glycated hemoglobin in Japan: from Japan Diabetes Society to National Glycohemoglobin Standardization Program values.
Differential effects of atorvastatin and pitavastatin on inflammation, insulin resistance, and the carotid intima-media thickness in patients with dyslipidemia.
Comparison of pitavastatin with atorvastatin in increasing HDL-cholesterol and adiponectin in patients with dyslipidemia and coronary artery disease: the COMPACT-CAD study.
Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.
]. These have shown superiority of a statin therapy (atorvastatin, pravastatin) to placebo or that of intensive therapy with a strong statin to a standard therapy with a standard statin or that of structured care with atorvastatin to physicians' standard care for preventing atherosclerotic diseases. Consequently, three strong statins (atorvastatin, pitavastatin and rosuvastatin) have been used in Japan for hypercholesterolemic patients at high-risk of cardiovascular disease. Although the safety of statin therapy is well-established, there is still an unanswered question, such as “Which strong statin should be used?
Pitavastatin has a different chemical structure and pharmacokinetic profiles compared to atorvastatin. Therefore, these drugs may have different efficacies. In fact, pitavastatin showed greater improvement in endothelial function [
Comparisons of short- and intermediate-term effects of pitavastatin versus atorvastatin on lipid profiles, fibrinolytic parameter, and endothelial function.
Comparative long-term efficacy and tolerability of pitavastatin 4 mg and atorvastatin 20-40 mg in patients with type 2 diabetes mellitus and combined (mixed) dyslipidaemia.
]. A study on the changes in lipid profiles showed that pitavastatin increased high-density lipoprotein cholesterol (HDL C) and apolipoprotein A-1 levels in patients with hypercholesterolemia more than patients on atorvastatin [
A 52-week, randomized, open-label, parallel-group comparison of the tolerability and effects of pitavastatin and atorvastatin on high-density lipoprotein cholesterol levels and glucose metabolism in Japanese patients with elevated levels of low-density lipoprotein cholesterol and glucose intolerance.
]. These reports of atherosclerosis progression surrogate markers suggest that pitavastatin might be more effective in preventing atherosclerotic cardiovascular events than atorvastatin. However, one study showed that the effects of pitavastatin were equal to atorvastatin in regard to changes in the levels and patterns of lipoproteins [
Randomized head-to-head comparison of pitavastatin, atorvastatin, and rosuvastatin for safety and efficacy (quantity and quality of LDL): the PATROL trial.
]. Another study of coronary plaque volume in patients with acute coronary syndrome revealed that the reduction in plaque volume by pitavastatin was equal to that by atorvastatin [
Effect of intensive statin therapy on regression of coronary atherosclerosis in patients with acute coronary syndrome: a multicenter randomized trial evaluated by volumetric intravascular ultrasound using pitavastatin versus atorvastatin (JAPAN-ACS [Japan assessment of pitavastatin and atorvastatin in acute coronary syndrome] study).
]. These studies suggest that pitavastatin therapy may be equivalent to atorvastatin in the prevention of cardiovascular events. To date, it is unknown whether pitavastatin can perform equally to atorvastatin to prevent cardiovascular events, as there is no randomized prospective study of pitavastatin in a 1-to-1 fashion to atorvastatin. The aim of this multicenter open-label trial of a randomized head-to-head comparison of pitavastatin versus atorvastatin therapy was to compare pitavastatin therapy with atorvastatin therapy regarding cardiovascular event prevention in patients with hypercholesterolemia at high risk for atherosclerotic cardiovascular disease.
2. Methods
2.1 Study design
We conducted a randomized, controlled, parallel and multi-center clinical trial to determine if pitavastatin (2 mg/day), compared with atorvastatin (10 mg/day), would reduce cardiovascular events in patients with hypercholesterolemia who had one or more cardiovascular risk factors. Pitavastatin was developed by Kowa Pharmaceutical Co Ltd. (Tokyo, Japan) in 2003, and has been used widely across the United States and Europe. Atorvastatin was approved for medical use in the United States in 1996 and is available worldwide as a generic medication. Pitavastatin 2 mg/day has a low-density lipoprotein cholesterol (LDL-C)-lowering effect comparable to that of atorvastatin 10 mg/day [
Effect of intensive statin therapy on regression of coronary atherosclerosis in patients with acute coronary syndrome: a multicenter randomized trial evaluated by volumetric intravascular ultrasound using pitavastatin versus atorvastatin (JAPAN-ACS [Japan assessment of pitavastatin and atorvastatin in acute coronary syndrome] study).
Detailed inclusion and exclusion criteria are provided in Fig. 1. Since a strong statin (rosuvastatin) therapy did not reduce major adverse cardiovascular events in patients with systolic heart failure [
], patients with heart failure (New York Heart Association class III or more) were excluded in the study. Each subject provided written informed consent after the protocol was explained. For a registered patient with a history of taking statin, the off period was 4 weeks. Patients who met the inclusion and the exclusion criteria were randomized to either pitavastatin 2 mg/day or atorvastatin 10 mg/day, with dynamic allocation by the Internet Data and Information Center for Medical Research (INDICE) in University hospital Medical Information Network (UMIN) stratified by age (<65 or ≥65 years), sex (men or post/premenopausal women), diabetes mellitus, prior coronary artery disease, prior coronary revascularization, prior cerebral infarction (atheromatous, embolic, or lacunar), and a period of previous use of statin (< 4 or ≥4 months). The duration of treatment with the statins was 240 weeks. This was an open-label trial. However, the independent event committee adjudicated all end point events while blinded to the assigned group.
Fig. 1Disposition of patients. TC, total cholesterol; LDL, low density lipoprotein; HbA1c, hemoglobin A1c; JDS, Japan Diabetes Society; GA, glycoalbumin; MI, myocardial infarction; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; and NYHA, New York Heart Association.
During the follow-up, the patients' visits as dictated by the protocol were at 3 months in the first year and every 6 months thereafter. Fasting blood lipid levels such as T-C, triglycerides, and HDL C, as well as other blood tests such as creatine kinase, alanine aminotransferase, aspartate aminotransferase, creatinine, and hemoglobin A1c (HbA1c), were measured at baseline, 6 and 12 months, and yearly thereafter. Blood pressure was recorded at baseline.
All participants provided written informed consent. The study was conducted in accordance with the Declaration of Helsinki.
2.2 End point
The primary end point was a composite of cardiovascular death, sudden death of unknown origin, nonfatal acute myocardial infarction, nonfatal ischemic stroke, transient ischemic attack, or heart failure that required emergency hospitalization. Cardiovascular death consisted of cardiac death and noncardiac vascular death such as ischemic stroke. Sudden death of unknown origin was defined as when a cause could not be determined within 24 h of occurrence. Acute myocardial infarction was defined as an increase and gradual decrease in levels of biochemical markers of myocardial necrosis (troponin T or I or creatine kinase-MB values) together with at least one of the following factors: ischemic symptoms, development of pathologic Q waves on electrocardiography, changes in the electrocardiogram indicative of ischemia (ST-segment elevation or depression), or coronary artery intervention. Stroke was defined as tissue evidence of cerebral infarction or intracranial bleeding as diagnosed by X-ray computed tomography (CT) or magnetic resonance imaging associated with symptoms lasting >24 h. Transient ischemic attacks were defined with evidence of cerebral ischemia (neurological signs) associated with temporal symptoms lasting <24 h. Heart failure was diagnosed based on the need for admission and aggressive medical therapy, as well as several of the following: personal history, typical symptoms (dyspnea or orthopnea), neck vein distension, peripheral edema, lung rales, S3 gallop, and tachycardia, together with chest radiograph findings such as cardiomegaly, bilateral lung congestion, and/or pleural effusion. A final diagnosis of congestive heart failure was confirmed after admission using electrocardiography, echocardiography, and/or chest CT to exclude noncardiac diseases with similar symptoms or signs. The primary composite end points included heart failure because of the potential association between statin therapy and reduced mortality in heart failure patients [
A secondary composite end point was defined as a composite of the primary end point event plus clinically indicated coronary revascularization for stable angina.
The study evaluated adverse events that developed after the start of the assigned treatment, and the reasons for the study drug discontinuation. Adverse events and the study drug discontinuation reasons were assessed and reported by the site investigators and subsequently judged by the steering committee.
2.3 Statistical analysis
From the past trials among statins, we hypothesized that the present study would show non-inferiority in the 5-year prognosis between pitavastatin and atorvastatin treatment. We assumed that the required sample size for the trial on an annual primary-event rate would be 1.5% in each group, based on a previously published annual event rate in patients [
Japan Lipid Intervention Trial. Large scale cohort study of the relationship between serum cholesterol concentration and coronary events with low-dose simvastatin therapy in Japanese patients with hypercholesterolemia and coronary heart disease: secondary prevention cohort study of the Japan Lipid Intervention Trial (J-LIT).
]. The number of patients per group was calculated to be 322 (total, 644) with log-rank test of the confirmed primary composite cardiovascular event-free curves providing a power of 80%, an alpha value of 0.05 (one-sided). The noninferiority of pitavastatin therapy for preventive efficacy for primary end point, as compared with atorvastatin therapy, was confirmed with evidence that the upper limit of 95% confidence intervals of hazard ratio was less than a noninferiority margin of 1.08. Assuming an estimated drop-out rate of 20%, we proceeded with 327 patients per group, a total of 654 patients in total.
Analysis was performed according to the intention-to-treat principal with the use of adjudicated events. The cumulative incidence of clinical events was estimated by the Kaplan-Meier method and compared by the log-rank test. Hazard ratios (HRs), 95% confidence intervals (CIs), and P values for time-to-event analyses are reported for the primary and secondary end points and were derived from the Cox proportional hazard model in the overall population. All analyses were stratified according to the baseline atherosclerotic cardiovascular disease category, by established atherosclerotic cardiovascular disease or multiple risk factors for atherosclerotic cardiovascular disease. The formal interaction test was performed between subgroup factors and for the effect of pitavastatin relative to atorvastatin.
Safety analyses of adverse events, laboratory abnormalities, and study drug discontinuation were conducted using data from all enrolled patients who were received or had received trial drugs of pitavastatin or atorvastatin for whom data were available. Patients lost to follow-up were censored at the time when their final clinical follow-up information was available. The number needed to treat during the 5-year follow-up was estimated from the event rate at 5 years.
Time-varying measurements such as T-C, LDL-C, triglyceride, HDL C, non-HDL-C, blood pressure, and HbA1c, were analyzed with the mixed-effects models with robust variance adjustment and compound symmetry structure used as the initial assumption. To describe the time profile, the average value (least-squares means) including the baseline was estimated for each of the groups with time-group interaction terms set as covariates in the mixed-effects model to accommodate missing values. Time variables were modeled as categorical (dummy) variables. Group difference (treatment effect) and time-group interaction after the intervention were estimated with time, group, time-interaction, and baseline value as covariates. The baseline value was included in the model to reduce bias and variability resulting from the regression to the mean.
All statistical analyses were performed with SPSS (version 25, Chicago, IL, USA) or JMP Pro (version 14.2, Cary, NC, USA), except for sample size determination, which was performed using the program PASS 15 (PASS 15, NCSS, Kaysville, UT, USA).
3. Results
3.1 Analyzed patients with a high rate of follow-up
From April 1, 2006 to May 31, 2011, a total of 664 patients met the inclusion criteria were enrolled from 3 Medical Centers of Toho University in Japan (Fig. 1). It took a few days to acquire the necessary information to register a patient (number 654) who was scheduled to be the last one. During the time ten patients had been registered at a stretch. Consequently 664 patients were registered. After completing the 4-week off period, 664 patients were randomized to either pitavastatin 2 mg/day (n = 332) or atorvastatin 10 mg/day (n = 332). The efficacy and safety analysis population consisted of 622 patients (pitavastatin, n = 312; atorvastatin, n = 310) after excluding patients who were registered in duplicate, did not give consent, or did not actually take the study drugs, took misdirected drugs, were applicable to exclusion criteria, or withdrew their consent before follow-up or if events occurred before observation. In total, the full analysis sample consisted of 622 patients (pitavastatin, n = 312; atorvastatin, n = 310). The mean follow-up period for survivors was not different between the pitavastatin and the atorvastatin groups (205.7 ± 61.7 and 197.2 ± 71.5 weeks, respectively, P = 0.113). The follow-up at 52 weeks was completed in 306 patients (98.1%) of the pitavastatin group and in 303 patients (97.7%) of the atorvastatin group, and follow-up data at 204 weeks were available for 289 patients (92.6%) and 286 patients (92.3%), respectively. Final follow-up data at 240 weeks were available for 277 patients (88.9%) and for 278 patients (89.7%), respectively.
3.2 Patients' characteristics
The study sample represented a typical patient population with hypercholesterolemia (Table 1), excluding familial hypercholesterolemia, with advanced age and a preponderance of primary prevention (74%). Diabetes mellitus was present in 76% of patients and hypertension in 75%. A total of 26% were secondary prevention, 24% had prior acute coronary syndrome, and 23% had prior coronary revascularization predominantly by percutaneous coronary intervention. For baseline medications, antihypertensive therapy with a renin angiotensin system inhibitor was used in 53% of patients, antihyperglycemic agents with sulfonylurea was used in 40%, and antiplatelet therapy was used in 48%. Baseline characteristics and medications were well balanced between the 2 groups.
Table 1Baseline characteristics of trial participants.
Pitavastatin (n = 312)
Atorvastatin (n = 310)
P-value
Male (%)
168 (53.8)
168 (54.2)
0.936
Age (years)
65.3 ± 10.1
65.4 ± 9.4
0.932
BMI (kg/m2)
24.8 ± 3.9
24.3 ± 3.2
0.144
Systolic blood pressure (mmHg)
131 ± 16
132 ± 16
0.364
Diastolic blood pressure (mmHg)
77 ± 11
77 ± 10
0.624
Blood test
HbA1c, JDS (%)
6.7 ± 1.2
6.8 ± 1.3
0.393
HbA1c, NGSP (%)
7.1 ± 1.2
7.2 ± 1.3
0.393
AST (IU/L)
24 ± 10
23 ± 8
0.266
ALT (IU/L)
25 ± 15
23 ± 12
0.066
γ-GTP (IU/L)
37 ± 51
35 ± 42
0.591
Uric acid (mg/dL)
5.4 ± 1.5
5.4 ± 1.5
0.890
Creatinine (mg/dL)
0.80 ± 0.22
0.80 ± 0.21
0.900
Total cholesterol (mg/dL)
236 ± 45
236 ± 41
0.926
Triglyceride (mg/dL)
172 ± 107
165 ± 95
0.434
HDL-cholesterol (mg/dL)
55 ± 14
55 ± 14
0.934
NonHDL-cholesterol (mg/dL)
182 ± 46
181 ± 40
0.949
LDL-cholesterol (mg/dL)
148 ± 41
150 ± 37
0.652
Medications
Anti-hypertensive agents
ACE-I and/or ARB
173 (55.4)
153 (49.4)
0.418
Calcium channel blocker
140 (44.9)
144 (46.5)
0.747
Diuretics
54 (17.3)
59 (19.0)
0.604
β receptor antagonist
61 (19.6)
51 (16.5)
0.348
Anti-hyperglycemic agents
Insulin
53 (17.0)
50 (16.1)
0.829
Sulfonylurea
125 (40.1)
122 (39.4)
0.870
Biguanide
70 (22.4)
67 (21.6)
0.847
αglucosidase inhibiter
64 (20.5)
57 (18.4)
0.544
Thiazolidinedione
39 (12.5)
44 (14.2)
0.557
Warfarin
33 (10.6)
29 (9.4)
0.688
Anti-platelet agents
146 (46.8)
155 (50.0)
0.470
Prevalence of diabetes, hypertension, and prior atherosclerotic vascular events
Diabetes
238 (76.3)
234 (75.5)
0.852
Hypertension
232 (74.4)
231 (74.5)
1.000
Prior ACS (Myocardial infarction/Unstable angina)
66 (21.2)
67 (21.6)
0.922
Coronary revascularization
70 (22.4)
70 (22.6)
1.000
Stroke
50 (16.0)
46 (14.8)
0.739
Peripheral artery disease
11 (3.5)
7 (2.3)
0.474
Primary prevention
235 (75.3)
225 (72.6)
0.465
Diabetic patients without any prior cardiovascular disease
206 (66.0)
192 (61.9)
0.316
Secondary prevention
77 (24.7)
85 (27.4)
0.465
BMI, body mass index; HbA1c, hemoglobin A1c; AST, aspartate aminotransferase; ALT, alanine aminotransferase; γ-GTP, γ-glutamyl transpeptidase; HDL, high-density lipoprotein; LDL, low density lipoprotein; ACE I, angiotensin converting enzyme inhibitors; ARB, angiotensin receptor antagonists; ACS, acute coronary syndrome. Data are presented as n (%) or mean ± SD. P values were obtained using Mann-Whitney's U tests or Fisher's exact test if the number was less than six. Hypertension was defined as a systolic blood pressure ≥ 140 mmHg and/or a diastolic blood pressure ≥ 90 mmHg or if subjects were treated with antihypertensive agents.
LDL-C was calculated using Friedewald's formula: LDL-C = (T-C) – (HDL C) – (triglyceride/5). This formula is not valid for patients with triglycerides ≥400 mg/dL [
]. Therefore, subjects with triglycerides ≥400 mg/dL (4.5% at baseline, 2.1% at 1 year, 1.4% at 2 year, 1.8% at 3 year, 1.8% at 4 year) were excluded from the analysis for LDL-C only. Japan Atherosclerosis Society had recommended LDL-C levels were calculated according to Friedewald's formula in 2006 because LDL-C levels measured by direct methods using various reagents varied in value. The baseline LDL-C level immediately before the start of study drug was 148.4 ± 40.5 and 149.8 ± 37.0 mg/dL in the pitavastatin and the atorvastatin groups, respectively. At 12 months, the LDL-C level was reduced by 36.1% in the pitavastatin group and by 37.6% in the atorvastatin group (Fig. 2A ). During the entire of follow-up course, LDL-C levels were reduced similarly between pitavastatin and atorvastatin, and HDL-C levels were increased similarly between both groups (Fig. 2B). T-C levels were also reduced similarly in both groups (Fig. 2C). Non-HDL-C levels which were calculated as (T-C) - (HDL-C) were reduced similarly between both groups (Fig. 2D). Triglyceride levels were reduced in both groups, and the reduction was greater in atorvastatin than pitavastatin group (Fig. 2E).
Fig. 2Changes in lipid parameters and hemoglobin A1c levels over time and Kaplan-Meier curves for the primary and secondary composite end points (primary end point plus coronary revascularization). A–F: Changes through the trial period in low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, total cholesterol, non-HDL cholesterol, triglycerides, and hemoglobin A1c levels. Values are derived from measurements made at 3 medical centers at Toho University. G and H: Kaplan-Meier curves for the primary end point (a composite of cardiovascular death, sudden, nonfatal myocardial infarction, nonfatal stroke, or heart failure requiring hospitalization) and for a secondary composite end point (a composite of primary end point or coronary revascularization). HR, hazard ratio; CI, confidence interval.
HbA1c was measured in according with the Japan Diabetes Society (JDS) and converted to HbA1c values according to the National Glycohemoglobin Standardization Program (NGSP). The conversion equation from HbA1c (JDS) to HbA1c (NGSP) units is officially certified as follows: NGSP (%) = 1.02 × JDS (%) + 0.25% [
International clinical harmonization of glycated hemoglobin in Japan: from Japan Diabetes Society to National Glycohemoglobin Standardization Program values.
]. HbA1c levels were not changed in both groups throughout the trial period. HbA1c levels were well controlled and did not differ between the two groups during follow-up (Fig. 2F).
3.4 Pitavastatin versus atorvastatin therapy on cardiovascular events
We first confirmed the noninferiority of pitavastatin therapy for preventive efficacy for primary end point, as compared with atorvastatin therapy, with evidence that the upper limit of 95% confidence intervals of hazard ratio was 0.787 (multivariate Cox regression) which was less than a noninferiority margin of 1.08. After the demonstration of noninferiority for efficacy for the primary end point, an assessment of superiority for the primary efficacy end point, which was not prespecified before the database lock, was performed.
Pitavastatin 2 mg/day compared with atorvastatin 10 mg/day significantly reduced the primary end point. The primary end point occurred less frequently in the pitavastatin group with 9 patients (2.9%) and 25 patients (8.1%) in the atorvastatin group (HR, 0.342; 95% CI, 0.160–0.734; P = 0.006 by univariate Cox regression in Table 2, supplemental material and HR, 0.366; 95% CI 0.170–0.787; P = 0.01 by multivariate Cox regression in Fig. 3). Furthermore, we have calculated the power of test for superiority of pitavastatin therapy for primary end point efficacy. The power was 0.9561. The cumulative 5-year incidence of the primary end point was significantly lower in the pitavastatin group than in the atorvastatin group (2.9% and 8.1%, respectively; P = 0.006; Fig. 2G). The number needed to treat (NNT) of pitavastatin for the prevention of 1 primary end point event compared to atorvastatin was calculated [
Pitavastatin 2 mg/day compared with atorvastatin 10 mg/day also significantly reduced the secondary composite end point, including coronary revascularization (Fig. 2H), occurring in 14 patients (4.5%) in the pitavastatin group and 40 patients (12.9%) in the atorvastatin group (HR, 0.344; 95% CI, 0.186–0.635; P < 0.001; Table 2, supplemental material).
The risk reduction for the primary end point and for the secondary composite end point, including coronary revascularization, by pitavastatin 2 mg/day was consistent across several prespecified subgroups. In baseline HDL-C (≥40 mg/dL) or body mass index (<25 kg/m2) subgroup, the difference of primary/secondary end points between the two groups were significant (Fig. 3).
Fig. 3Subgroup analyses of the efficacy of pitavastatin vs atorvastatin for the primary end point and for a secondary composite end point (primary end point plus coronary revascularization) in prespecified subgroups. Numbers of patients with events were summarized for each subgroup within each treatment. Hazard ratios (HRs) were calculated within each subgroup level for the treatment effect of pitavastatin 2 mg/d relative to atorvastatin 10 mg/d. The P value was derived from an interaction test between the subgroup factors and the treatment effect of pitavastatin relative to atorvastatin. Horizontal bars indicate 95% confidence intervals (CIs). Coronary revascularization, as a component of the secondary composite end point, excluded target-lesion revascularization for lesions treated at the time of prior percutaneous coronary intervention. HR for overall patients was adjusted for confounding factors including age>65 years, sex, diabetes, systolic blood pressure >140 mmHg, high-density lipoprotein cholesterol (HDL-C) <40 mg/dL, body mass index (BMI) >25 kg/m2 and a history of acute coronary syndrome (ACS) and/or coronary revascularization.
The rates of serious adverse events, including rhabdomyolysis, were low and did not differ between the two groups. Although muscle complaints were reported more often in the atorvastatin group, the rate of creatine kinase elevation ≥5 times the upper limit of normal was low and did not differ significantly between the two groups. There was no between-group difference in the new onset of diabetes mellitus (Table 3, supplemental material). The study drug discontinuation did not differ between the pitavastatin and the atorvastatin groups (Table 4, supplemental material).
4. Discussion
The main finding in the present study was that cardiovascular events were reduced significantly by pitavastatin (2 mg/day) compared with atorvastatin (10 mg/day) therapy in patients with hypercholesterolemia with one or more risk factors for atherosclerotic cardiovascular disease.
TOHO-LIP was the first, randomized, prospective trial of comparison of two strong statins in preventing cardiovascular events. At the beginning of the trial, we hypothesized that pitavastatin had non-inferiority to atorvastatin in the prevention of cardiovascular events. However, the results showed that pitavastatin 2 mg/day prevented more cardiovascular events than atorvastatin 10 mg/day. The present study included patients with diabetes of >75% and some reports have shown adverse effects of atorvastatin on glucose metabolism compared with pitavastatin [
Randomized head-to-head comparison of pitavastatin, atorvastatin, and rosuvastatin for safety and efficacy (quantity and quality of LDL): the PATROL trial.
]. On the other hand, pitavastatin has previously been reported to have the same or better effects on glucose metabolism, including insulin resistance [
Comparative long-term efficacy and tolerability of pitavastatin 4 mg and atorvastatin 20-40 mg in patients with type 2 diabetes mellitus and combined (mixed) dyslipidaemia.
Differential effects of atorvastatin and pitavastatin on inflammation, insulin resistance, and the carotid intima-media thickness in patients with dyslipidemia.
]. In the present study, we cannot conclude whether such differences in glucose metabolism between the two statins had affected the results or not. However, there were no differences in HbA1c levels and the rate of new onset of diabetes mellitus between the two groups. There was a previous report in which pitavastatin (2 mg/day) presented with greater HDL-C-elevation than atorvastatin (10 mg/day) [
A 52-week, randomized, open-label, parallel-group comparison of the tolerability and effects of pitavastatin and atorvastatin on high-density lipoprotein cholesterol levels and glucose metabolism in Japanese patients with elevated levels of low-density lipoprotein cholesterol and glucose intolerance.
Comparison of pitavastatin with atorvastatin in increasing HDL-cholesterol and adiponectin in patients with dyslipidemia and coronary artery disease: the COMPACT-CAD study.
]. However, the present study demonstrated that there were no significant differences in HDL-C levels between the two groups and triglyceride levels were reduced greater in the atorvastatin group rather than the pitavastatin group during the entire period of follow-up, suggesting that the superior effect of pitavastatin compared to atorvastatin in preventing cardiovascular events is associated with something other than lipid profiles, which is the so-called pleiotropic effects of statins including an anti-inflammatory effect. C-reactive protein levels were measured only in the limited population before and after statin therapy in each group. C-reactive protein levels reduced one year after pitavastatin therapy, but did not reduced after atorvastatin (Fig. 5, supplementary material). Anti-inflammation effect of pitavastatin may have affected the results. Additional research is required to confirm the mechanisms of the pleiotropic effects of statins for prevention of cardiovascular events and a large sample trial also is required to confirm the benefit of pitavastatin.
The recent guidelines to reduce cardiovascular events are based on the concept that lower LDL-C leads to the lower incidence of cardiovascular events. This concept leads to the recommendation of a combination of a high-dose strong statin with other cholesterol-lowering drugs, such as ezetimibe, eicosapentaenoic acid, or protein convertase subtilisin/kexin type 9 inhibitors. We do not deny this concept. However, before using the higher-dose statin or the combination of a statin with the other cholesterol-lowering drugs, we may first reconsider which statin is used. This may be associated with cost effectiveness to prevent the cardiovascular events, because of no big difference in the cost among statins. This could be a scientifically and socially important issue to reduce cardiovascular events.
Our study has several important limitations that warrant discussion. First, this study was conducted as an open-label trial, which brings inherent limitations. However, the independent event committee adjudicated all end point events while blinded to the assigned group. Moreover, to compensate slightly for the open-label trial design, the primary end point was defined as not including coronary revascularization procedures because the decision for coronary revascularization is made by physicians who are aware of the assigned treatment group. Second, a final follow-up was not completed in a substantial proportion of patients (11%), which is a potential limitation of physician-initiated studies that rely on voluntary efforts by the site investigators. However, follow-up rates were comparable between pitavastatin and atorvastatin groups, suggesting that the patients lost to follow-up in both groups would have affected the trial outcome in the same manner. Third, we excluded subjects with triglycerides >400 mg/dL because of use of Friedewald's formula for the analysis of LDL-C levels. The subject exclusion may limit the evaluation of LDL-C levels although the analysis was done with the mixed-effects models with robust variance adjustment. Finally, there were no data regarding adherence to the study drug. In Japan, pharmacists teach medication after doctors prescribe and check the adherence of administered drugs in general. For this reason no data were collected for evaluating the drug adherence. However, adherence may have affected some of the effect of pitavastatin relative to atorvastatin therapy, but this is speculative.
In conclusion, pitavastatin (2 mg/day) compared with atorvastatin (10 mg/day) therapy significantly reduced cardiovascular events despite similar effects on LDL-C levels in hypercholesterolemic patients who have one or more cardiovascular disease risk factors.
The following are the supplementary data related to this article.
Kaplan-Meier curves for the typical 3-point cardiovascular major advanced events (3-point MACE) with cardiovascular death, nonfatal myocardial infarction, and nonfatal ischemic stroke (A) and a composite of end points with sudden death of unknown origin, heart failure requiring hospitalization, and transient ischemic attack (B). There was no significant difference in 3-point MACE between pitavastatin and atorvastatin group. A composite end point with sudden death of unknown origin, heart failure requiring hospitalization, and transient ischemic attack was reduced significantly by pitavastatin therapy compared with atorvastatin therapy.
C-reactive protein levels before and after statin treatment. C-reactive protein levels were measured only in the limited population before and after statin treatment in each group. C-reactive protein levels reduced one year after pitavastatin therapy, but did not reduced after atorvastatin.
Toho University funded this study. The company manufacturing the study drug (Kowa Pharmaceutical Co. Ltd.) provided financial support for Toho University but was not involved in the study design, analysis, data interpretation, or preparation of manuscript.
CRediT authorship contribution statement
Masao Moroi: Conceptualization, Methodology, Software, Writing - original draft, Supervision. Daiji Nagayama: Data curation, Software. Fumihiko Hara: Investigation, Data curation, Validation. Atsuhito Saiki: Software, Data curation, Validation. Kazuhiro Shimizu: Software, Data curation, Validation. Mao Takahashi: Software, Data curation, Validation. Naoko Sato: Data curation, Software. Teruo Shiba: Data curation, Software, Supervision. Hideki Sugimoto: Software, Data curation. Toshiki Fujioka: Methodology, Data curation, Supervision. Tatsuo Chiba: Software, Data curation. Kosuke Nishizawa: Software, Data curation. Shuki Usui: Software, Data curation. Yasuo Iwasaki: Data curation. Ichiro Tatsuno: Software, Investigation. Kaoru Sugi: Data curation, Software. Junichi Yamasaki: Software, Investigation. Shigeo Yamamura: Formal analysis. Kohji Shirai: Conceptualization, Methodology, Supervision.
Declaration of competing interest
Any potential conflicts of interest, including related consultancies, shareholding and funding grants:
Dr. Moroi received a research grant from, Bayer Yakuhin, Ltd, Sanofi KK, MSD KK, Novartis Pharma, Ltd., Teijin Pharma Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Co., Ltd., and Nihon Mediphysics, Ltd. Dr. Shiba received grants and personal fees from Mitsubishi Tanabe Pharma, grants and personal fees from Daiichi Sankyo Company, Limited, grants and personal fees from Ono Pharmaceutical Co., Ltd., personal fees from Eli Lilly Japan K.K., personal fees from Boehringer Ingelheim, personal fees from Merck Sharp & Dohme (MSD), personal fees from Novartis Pharma, personal fees from Novo Nordisk Pharma Ltd., outside the submitted work. The remaining authors have nothing to disclose.
Acknowledgements
The authors thank all patients and investigators who participated in this study (see affiliations), and Fusako Watanabe for assistance as the administrative officer at the Toho University Sakura Medical Center.
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