Cardiovascular Drugs and Therapy 18 67–75 2004 C 2004 Kluwer Academic Publishers. Manufactured in The United States


CLINICAL TRIALS

Fluvastatin Reduces Cardiac Mortality in Patients with Coronary Heart Disease Christie M. Ballantyne,1 Gunter Riegger,2 ¨ 3 Nicholas Moore, Francesco Saia,4 and Patrick W.J.C. Serruys4 1 Center

for Cardiovascular Disease Prevention, Methodist DeBakey Heart Center; and Department of Medicine, Baylor College of Medicine, Houston, Texas, USA; 2 Department of Internal Medicine II, University of Regensburg, Regensburg, Germany; 3 Department of Pharmacology, Victor Segalen Bordeaux 2 University, Bordeaux, France; 4 Department of Interventional Cardiology, Thoraxcenter, Academic Hospital Rotterdam-Dijkzigt, Rotterdam, The Netherlands

Summary. Purpose: To test the effectiveness of fluvastatin, 40–80 mg, in reducing the occurrence of cardiac and allcause mortality in patients with coronary heart disease (CHD). Methods: Meta-analysis of all clinical trials that assessed the effects of fluvastatin in CHD patients on major adverse cardiac events (MACE) as a prespecified endpoint was performed. A pooled analysis of four studies (n = 3525) was performed on an intent-to-treat basis. Clinical endpoints were the incidence, and time to first occurrence, of MACE (cardiac death, nonfatal MI, revascularization), noncardiac death, or all-cause death. Lipid parameters were also analyzed. Results: Fluvastatin treatment significantly prolonged the time to cardiac death ( p = 0.0174) and the time to cardiac death or nonfatal MI ( p = 0.0055) compared with placebo. Fluvastatin significantly reduced the risk of any MACE (Cox risk ratio [RR], 0.85; 95% confidence interval [CI], 0.73–0.98), cardiac death (RR, 0.53; 95% CI, 0.31– 0.90), cardiac death or MI (RR, 0.66; 95% CI, 0.49–0.89), all-cause death (RR, 0.65; 95% CI, 0.45–0.94) and all-cause death or MI (RR, 0.69; 95% CI, 0.53–0.90). Fluvastatin significantly lowered total cholesterol and low-density lipoprotein cholesterol levels and was well tolerated, with no cases of rhabdomyolysis in any of the studies assessed in the metaanalysis. Conclusions: This meta-analysis demonstrates clear beneficial effects of fluvastatin on cardiac and all-cause mortality in CHD patients, and supports the use of fluvastatin to reduce the incidence of MACE in a wide range of at-risk patients.

(statins) has been shown to be effective in reducing the incidence of cardiovascular events in patients with CHD, with large outcome studies demonstrating beneficial effects of treatment with simvastatin [1,2], pravastatin [3,4], lovastatin [5], atorvastatin [6], and fluvastatin [7]. Some studies have reported reduced outcome benefits of statin therapy in patients with normal or low baseline cholesterol levels [8,9]. The Lescol Intervention Prevention Study (LIPS) investigated the effects of early fluvastatin treatment on the incidence of major adverse cardiac events (MACE: cardiac death, nonfatal myocardial infarction [MI] or revascularization) in patients with average cholesterol levels after a first successful percutaneous coronary intervention (PCI) [10]. In LIPS, fluvastatin treatment significantly decreased the risk for MACE by 22% ( p = 0.01). Importantly, all components of the composite endpoint (MACE) contributed to this result. There were trends toward reductions in cardiac death and the combined endpoint of cardiac death/nonfatal MI, but these failed to reach statistical significance ( p = 0.07 for both) [7]. To provide additional information on the efficacy of fluvastatin in reducing cardiac death and nonfatal MI in patients with established CHD, a meta-analysis was performed that included all secondary prevention trials of fluvastatin in which MACE was a prespecified endpoint.

Key Words. atherosclerosis, cholesterol, coronary disease, meta-analysis, statin.

Introduction Coronary heart disease (CHD) is one of the leading causes of adult morbidity and mortality in developed countries. Lipid-lowering treatment with 3-hydroxy3-methylglutaryl coenzyme A reductase inhibitors

This analysis was supported by a nonrestricted educational grant from Novartis Pharma A.G. (Basel, Switzerland).

Address for correspondence: Christie M. Ballantyne, MD, Center for Cardiovascular Disease Prevention, Baylor College of Medicine, 6565 Fannin, M.S. A-601, Houston, TX 77030, USA. E-mail: [email protected] 67

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Methods

Definition of events and endpoint time

Studies included in the meta-analysis

Clinical endpoints evaluated were

All trials conducted by Novartis that assessed the effects of fluvastatin on the occurrence of MACE in patients with CHD were included in the meta-analysis. In addition to LIPS, the trials included in the metaanalysis were the Fluvastatin Angiographic Restenosis trial (FLARE) [11], the Lescol in Severe Atherosclerosis trial (LiSA) [12], and the Lipoprotein and Coronary Atherosclerosis Study (LCAS) [13]. MACE endpoints included in the analysis were cardiac death, nonfatal MI, and revascularization. For the individual trials, the primary endpoint was MACE-free survival time in LIPS, incidence of MACE in LiSA, and change in angiographic minimum lumen diameter in FLARE and LCAS; MACE-free survival (LCAS) and MACE incidence (LCAS and FLARE) were also prespecified endpoints in the angiographic studies. All these trials were double-blind, randomized, placebo-controlled studies. MACE were reviewed centrally and adjudicated after a blind review by an independent event committee according to similar criteria in each study. The demographic profiles and lipid parameters for patients enrolled in the four studies were similar. It was therefore considered appropriate to conduct an individual-patient-based meta-analysis to confirm the effects of fluvastatin on the occurrence of MACE. In addition, because the frequency of revascularization procedures may be influenced by restenosis after PCI and the clinical judgment of the physician, we examined the endpoints of nonfatal MI, cardiac death, and total mortality. In addition, changes in the following lipid parameters were also examined: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol, and triglycerides. Safety parameters monitored included all reported adverse events, creatine kinase (CK) elevation >10 times the upper limit of normal (ULN), and alanine transaminase (ALT) and/or aspartate transaminase (AST) elevations ≥3 times the ULN on 2 consecutive occasions.

(1) Time from randomization (study day 0) to the first occurrence of MACE. In patients with multiple endpoints, the time to the first MACE was used for the primary analysis. For patients who had no MACE endpoints, data were right-censored at the date of the last study visit. (2) Incidence of, and time to, cardiac death (any death unless an unequivocal noncardiac cause could be established) (3) Incidence of, and time to, nonfatal MI (appearance of pathological Q waves that were absent at baseline or a total CK level >2 times the ULN with the presence of CK isoenzyme MB higher than the ULN) (4) Incidence of, and time to, cardiac death or nonfatal MI (5) Incidence of, and time to, revascularization (coronary artery bypass grafting, repeat PCI, or PCI for a new lesion) (6) Incidence of, and time to, noncardiac death (7) Incidence of, and time to, all death (8) Incidence of, and time to, all death or nonfatal MI

Analysis population The primary population for the pooled analysis was the intent-to-treat population, which included all patients randomized into the four studies. The number and percentage of patients who were followed up for the planned duration of the study were also calculated. Patients were considered to have been followed up for the planned duration of each study if the last follow-up visit with the patient was within a week of the planned study duration, as defined in the study protocols. The accepted minimal planned duration was 1095 days in LIPS, 357 days in LiSA, 272 days in FLARE, and 905 days in LCAS.

Treatment groups Treatment groups for the meta-analysis were placebo and fluvastatin. The fluvastatin group included patients who were randomized to receive fluvastatin at doses of 20 mg b.i.d. (n = 214), 40 mg q.d. (n = 102), or 40 mg b.i.d. (n = 1455) (Table 1). LCAS patients who also received cholestyramine in addition to the randomized study drug (fluvastatin or placebo) after 12 weeks were included in the group to which they were randomized.

Statistical analysis All statistical tests were two-sided, with a significance level of α = 0.05. Time to first MACE was analyzed using a log-rank test corrected for study/country, to test the hypothesis that there was no difference in the distributions of the variable “time to MACE” between the fluvastatin and placebo groups. A Cox proportional hazards regression analysis was performed on the time-toMACE data, including all patients in the intent-to-treat population and incorporating study/country as stratum variable and treatment groups as covariate. The hazard ratio for treatment groups was estimated together with the 95% confidence interval for the hazard ratio and the p-value from the Wald chi-squared test. The time from randomization to each component of MACE (cardiac death, nonfatal MI, revascularization) and the time to all-cause death were also analyzed using the same Cox proportional hazards regression model. For patients who had a nonfatal MI prior to a revascularization procedure, the variable “time to revascularization”

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Table 1. Studies included in the meta-analysis Study (no. patients)

Design

Population

MACE included in analysis

LIPS [7] (n = 1677: n = 844 fluvastatin, 40 mg b.i.d.; n = 833 placebo)

Multicenter, double-blind, randomized, placebo-controlled study for 3–4 years; primary endpoint: MACE-free survival time

Cardiac death Nonfatal MI Revascularization (CABG, repeat PCI, or PCI of a new lesion)

LiSA [12] (n = 365: n = 187 fluvastatin, 40 mg/day, n = 85 increased to 40 mg b.i.d. [LDL-C decreased by ≤30% at 6 weeks]; n = 178 placebo) FLARE [11] (n = 1054: n = 526 fluvastatin, 40 mg b.i.d.; n = 528 placebo)

Multicenter, double-blind, randomized, placebo-controlled study for 1 year; primary endpoint: incidence of cardiac events

Patients (aged 18–80 years) with stable or unstable angina or silent ischemia after successful first PCI Total cholesterol 135–270 mg/dL, and TG <400 mg/dL Patients (aged 40–70 years) with stable symptomatic CHD LDL-C >160 mg/dL (on diet) and TG ≤300 mg/dL

Multicenter, double-blind, randomized, placebo-controlled study for 40 weeks; primary endpoint: change in MLD

Patients with successful PTCA LDL-C <232 mg/dL (intent-to-treat population)

Single-center, double-blind, randomized, placebo-controlled study for 130 weeks; primary endpoint: change in MLD

Patients with angiographic CHD LDL-C 115–190 mg/dL (on diet) and TG ≤300 mg/dL (≤250 mg/dL if LDL-C ≥160 mg/dL)

Cardiac or noncardiac death Nonfatal MI Revascularization (CABG, repeat PTCA, or alternative percutaneous revascularization) Cardiac death Nonfatal MI CABG, PTCA, other cardiac special procedure

LCAS [13] (n = 429: n = 214 fluvastatin, 20 mg b.i.d.; n = 215 placebo; cholestyramine, up to 12 g/d, added at week 12 if prerandomization LDL-C ≥160 mg/dL [in n = 55 fluvastatin; n = 51 placebo])

Cardiac death Nonfatal MI PTCA or CABG

Abbreviations: CABG = coronary artery bypass grafting; CHD = coronary heart disease; FLARE = Fluvastatin Angiographic Restenosis trial [11]; LCAS = Lipoprotein and Coronary Atherosclerosis Study [13]; LDL-C = low-density lipoprotein cholesterol; LIPS = Lescol Intervention Prevention Study [7]; LiSA = Lescol in Severe Atherosclerosis trial [12]; MACE = major adverse coronary events; MI = myocardial infarction; MLD = minimum lumen diameter; PCI = percutaneous coronary intervention; PTCA = percutaneous transluminal coronary angioplasty; TG = triglycerides.

was censored on the date of the MI. MACE survival distribution functions were estimated for each treatment group using the Kaplan–Meier method. Incidence of MACE was compared between treatment groups using the Mantel–Haenszel test with study/country as the stratum variable. The incidence of each component of MACE (cardiac death, nonfatal MI, revascularization) and the incidence of all-cause death were also analyzed in the same manner. Changes in lipid parameters were also assessed.

Results Patient population In the four studies, 1771 patients were randomized to receive treatment with fluvastatin, and 1754 patients were randomized to placebo. Of these, 91.2% of the fluvastatin group and 90.4% of the placebo group were followed up for the planned duration of the studies; in addition to the 46 fluvastatin patients (2.6%) and 69 placebo patients (3.9%) who died, 110 (6.2%) fluvastatin and 99 (5.6%) placebo patients were not followed up for the planned duration of the studies (2.3% of the patients in LIPS, 22.7% in LiSA, 6.3% in FLARE, and 5.8% in LCAS).

Baseline demographic and lipid data are shown in Table 2. There were no significant differences between the treatment groups. Age distribution was similar in both groups, with 65.3% and 65.6% of patients under the Table 2. Baseline demographic characteristics of pooled patient groups Treatment Parameter, mean (SD) or %

Fluvastatin

Placebo

Number of patients Age, years Male gender, % Men above age 65, % of men Women above age 65, % of women Diabetes mellitus Previous MI Previous PTCA or CABG Total cholesterol, mg/dl LDL-C, mg/dl HDL-C, mg/dl Triglycerides, mg/dl

1771 59.8 (9.4) 80.7 31.8 46.8 9.1 39.5 7.1 213.3 (36.2) 141.4 (31.2) 41.4 (12.9) 156.0 (69.9)

1753 60.3 (9.1) 80.8 32.4 42.3 7.5 40.9 7.5 212.9 (36.8) 140.8 (31.9) 41.7 (13.6) 154.3 (69.6)

Abbreviations: CABG = coronary artery bypass grafting; HDL-C = highdensity lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; PTCA = Percutaneous transluminal coronary angioplasty.

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age of 65 years in the fluvastatin and placebo groups, respectively, although there was a greater proportion of women above the age of 65 years in the fluvastatin group.

Endpoints The number of patients with endpoints is shown in Table 3. Fluvastatin treatment significantly reduced the incidence of all MACE ( p = 0.019), cardiac death ( p = 0.016), cardiac death or nonfatal MI ( p = 0.0043), all-cause death ( p = 0.023) and all-cause death or MI ( p = 0.0046) compared with placebo. There was also a trend towards a reduced incidence of nonfatal MI in the fluvastatin group ( p = 0.084). Fluvastatin treatment had no significant effect compared with placebo on the incidence of revascularization or noncardiac death. Some patients had multiple endpoints; 336 fluvastatin patients had 441 endpoints, and 387 placebo patients had 517 endpoints. The Kaplan–Meier curves for time to cardiac death, time to cardiac death or nonfatal MI, time to first MACE, and time to any death are shown in Figure 1. Survival analysis revealed that fluvastatin significantly prolonged the time to first MACE ( p = 0.0258). There were also significant differences between treatment groups for time to cardiac death (log-rank test; p = 0.0174), time to cardiac death or nonfatal MI ( p = 0.0055), time to any death ( p = 0.0227), and time to any death or MI ( p = 0.0059). In the Cox proportional hazards analysis, all the risk ratios were <1, indicating a consistent effect across all clinical events in favor of fluvastatin treatment (Fig. 2). There was a 47% reduction in the risk of cardiac death for fluvastatin-treated patients compared with patients receiving placebo (hazard ratio 0.53, 95% confidence interval [CI] 0.31–0.90, p = 0.019), and the risk of cardiac death or nonfatal MI was significantly reduced by 34% (hazard ratio 0.66, 95% CI 0.49–0.89, p = 0.006). Table 3. Number of patients with endpoint events in treatment groups Treatment

Endpoint event Major cardiac event Cardiac death Nonfatal MI Revascularization Cardiac death or nonfatal MI Noncardiac death Any death Any death or MI

Fluvastatin (n = 1771)

Placebo (n = 1753)

p-value∗

336 (19.0%) 21 (1.2%) 52 (2.9%) 301 (17.0%)

387 (22.1%) 39 (2.2%) 70 (4.0%) 326 (18.6%)

0.019 0.016 0.084 0.19

71 (4.0%) 25 (1.4%) 46 (2.6%) 96 (5.4%)

107 (6.1%) 30 (1.7%) 69 (3.9%) 136 (7.8%)

0.0043 0.44 0.023 0.0046

Abbreviation: MI = myocardial infarction. ∗ p-values were obtained from a Mantel-Haenszel test with country/study as stratum variable.

Consistent with the reduction in cardiac death, fluvastatin treatment also significantly reduced the risk of all-cause death (risk reduction 35%; hazard ratio 0.65, 95% CI 0.45–0.94, p = 0.024), and all-cause death or MI (risk reduction 31%; hazard ratio 0.69, 95% CI 0.53– 0.90, p = 0.006) relative to placebo. There was a trend towards a reduction in the risk of nonfatal MI in the fluvastatin group, with a 26% relative risk reduction that did not reach statistical significance (hazard ratio 0.74, 95% CI 0.52–1.06, p = 0.100). No significant differences in the risk of revascularization or noncardiac death were observed between the fluvastatin and placebo groups.

Lipid levels Changes in lipid parameters from baseline to week 6 of treatment, pooled across the four studies, are shown in Table 4. Fluvastatin treatment significantly reduced levels of LDL-C, total cholesterol, and triglycerides compared with placebo, but no significant differences in HDL-C levels were observed between the two treatment groups.

Safety and tolerability As previously reported for the four individual studies, fluvastatin treatment was well tolerated, with a similar incidence of adverse events observed in the fluvastatin and placebo groups. The incidence of ALT or AST elevations (defined as ≥3 times the ULN on 2 consecutive occasions), or CK elevation (defined as >10 times the ULN) for each study in the meta-analysis is shown in Table 5. CK elevations observed during fluvastatin treatment did not lead to rhabdomyolysis in any of the studies investigated in the meta-analysis.

Discussion The results of the present study demonstrate that fluvastatin significantly reduced the incidence of “hard” endpoints in CHD patients. Fluvastatin-treated patients had a significant 47% reduction in the risk of cardiac death compared with placebo ( p = 0.019). This reduction was apparent after only 6 months of treatment, and was substantial enough to reduce overall mortality by 35% ( p = 0.024). Fluvastatin also significantly reduced the combined endpoint of cardiac death or nonfatal MI by 34% ( p = 0.006). The risk ratios for all clinical endpoints were <1, which indicates a consistent effect across all clinical events in favor of fluvastatin treatment. This meta-analysis therefore supports the use of fluvastatin in the prevention of cardiac death and nonfatal MI in patients with CHD. Individual outcome studies often do not have sufficient power to detect changes in individual components of a composite endpoint, or in individual subgroups of a patient population. Consequently, meta-analyses are

Cardiac Mortality Benefits with Fluvastatin

often used in order to characterize the effect of a drug optimally, and a similar pooled analysis of outcome studies using pravastatin has recently been carried out [8]. The present study fulfills all the quality criteria for meta-analyses. Thus it includes all placebo-controlled trials conducted by Novartis that have investigated the effects of fluvastatin in CHD patients with the incidence of MACE as a primary or secondary endpoint. All the studies included in the analysis were of a similar design, and the fluvastatin and placebo groups were well matched. All patients included in these studies had established CHD, and the study population of this meta-

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analysis includes all categories of cardiac risk, including smokers, hypertensive or diabetic patients, patients with prior MI or angina (stable or unstable), and patients with a broad range of cholesterol levels. It is important to note, however, that results obtained from pooled analyses of groups of patients cannot necessarily be extrapolated to all individual patient subgroups. The reductions in cardiac mortality observed with fluvastatin treatment in this meta-analysis are in line with findings from meta-analyses conducted on data from other statin outcome trials [14,15]. In an analysis of 5 primary and secondary prevention statin trials

(a)

(b) Fig. 1. Kaplan–Meier curves showing survival time free of major adverse cardiac events (MACE) in patients randomized to receive treatment with fluvastatin or placebo. A log-rank test corrected for study/country was used to test the effect of fluvastatin on time to (a) cardiac death; (b) cardiac death or nonfatal myocardial infarction (MI); (c) first MACE; (d) all-cause death. (Continued on next page.)

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(c)

(d) Fig. 1. (Continued.)

with clinical disease or death as the primary endpoint, including a total of 30,817 patients, coronary mortality was reduced by 29% and all-cause mortality was reduced by 21% [14]. Moreover, as with other statins, fluvastatin treatment did not increase mortality from noncardiac causes, consistent with results from a previous meta-analysis of cholesterol-lowering interventions [16]. It is notable that the reductions in risk seen with fluvastatin treatment were achieved in a patient population with relatively low LDL-C levels, with mean baseline LDL-C levels for patients in LIPS and LCAS of 132 mg/dl and 145 mg/dl, respectively [7,13]. Post hoc analyses of trials using pravastatin called into question

whether patients with levels of LDL-C below 125 mg/dl benefit from lipid-lowering therapy [3,8]. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) lipid arm, which also used pravastatin and enrolled a large number of patients with low LDL-C levels, also did not show benefit in reducing CHD events [17], but the high drop-in rate of the placebo group and relatively low compliance with pravastatin may have influenced the results [18]. The results of LIPS with fluvastatin, 80 mg (mean baseline LDL-C 132 mg/dl) [7], the Heart Protection Study with simvastatin, 40 mg (mean baseline LDL-C 131 mg/dl) [2], and the lipid arm of the Anglo-Scandinavian Cardiac Outcomes Trial (mean baseline LDL-C 133 mg/dl)

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Fig. 2. Cox proportional hazards analysis of the effect of fluvastatin on MACE. Hazard ratios and confidence intervals were determined by a Cox proportional hazards analysis with factors for treatment and study/country. p-values were obtained from the Wald test, as described in the Methods. MI = myocardial infarction.

[6] all support the benefits of statin therapy in high-risk patients with low levels of LDL-C. Indeed, subgroup analyses of the results of LIPS and HPS showed that patients with LDL-C levels below average obtained similar outcome benefits to those with higher LDL-C levels [2,7]. The lack of effect of fluvastatin treatment on the incidence of revascularizations observed in this analysis is consistent with several studies that have shown that restenosis post-PCI is not influenced by statin therapy [19–21]. Indeed, the LIPS study design took this factor into account by incorporating a prespecified secondary endpoint excluding interventions within the first 6 months to treat a restenotic lesion; whereas risk for any MACE was reduced by 22% with fluvastatin treatment (relative risk 0.78, 95% CI 0.64–0.95, p = 0.01), risk for MACE other than revascularization of target lesions during the first 6 months post-PCI was reduced by 33% (relative risk 0.67, 95% CI 0.54– 0.84, p < 0.001) [7]. The frequency of revascularizations is a “soft” endpoint as it is driven by both the occurrence of symptoms and the medical choice and training of the cardiologist. Indeed, recent studies advocating early revascularization in angina patients [22] have contributed to a dramatic growth in the number of PCI

procedures performed in recent years. Hence the 26% lower risk of nonfatal MI observed in the fluvastatin group, which failed to reach significance ( p = 0.099), may be an underestimation of the real effect of fluvastatin due to the confounding effect of early revascularizations. Death from CHD and nonfatal MI are the most “firm” endpoints, as they are driven primarily by plaque instability and thrombotic events. Notably, experimental data suggest that statin therapy may stabilize vulnerable plaques by converting lipid-rich plaques (which are at high risk of rupture) into more stable fibrotic plaques [23,24]. The survival curves for time to cardiac death and time to cardiac death or MI show marked benefits of fluvastatin after 6 months of treatment. The exact mechanism by which fluvastatin and other statins improve outcome is not clear, but it is important to note that, as well as slowing the progression of atherosclerotic CHD [13], fluvastatin treatment has been shown to enhance myocardial perfusion [25], improve microcirculation [26] and endothelial function [27], and exert important antioxidant effects [28] in patients with hyperlipidemia. The anti-inflammatory actions of fluvastatin, which include inhibition of leukocyte adhesion and migration to sites of inflammation, may also

Table 4. Change in lipid parameters from baseline to week 6 Lipid parameter, mg/dl

Treatment

n

Baseline

Week 6

Change from baseline (%)

p-value∗

LDL-C

Fluvastatin Placebo Fluvastatin Placebo Fluvastatin Placebo Fluvastatin Placebo

1450 1429 1457 1439 1515 1503 1515 1502

141.4 (31.2) 140.8 (31.9) 41.4 (12.9) 41.7 (13.6) 213.3 (36.2) 212.9 (36.8) 156.0 (69.9) 154.3 (69.6)

105.6 (31.8) 150.0 (34.2) 43.9 (13.0) 44.0 (12.7) 176.6 (40.1) 225.4 (39.7) 139.3 (78.7) 160.3 (84.2)

−23.6 (23.5) +9.8 (32.9) +9.4 (27.9) +9.4 (29.1) −16.4 (17.4) +7.3 (17.9) −4.9 (47.2) +10.9 (50.2)

0.0001

HDL-C Total cholesterol Triglycerides

Values are presented as mean (SD). ∗ p-values were obtained from an analysis of covariance model.

0.6949 0.0001 0.0001

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Table 5. Safety parameters in studies included in the meta-analysis Safety parameter

Study

Fluvastatin Placebo

ALT or AST elevation (≥3 × ULN on 2 consecutive occasions), number of patients (%)

LCAS LiSA FLARE LIPS Total LCAS LiSA FLARE LIPS Total

5 (2.3%) 0 0 10 (1.2%) 15 (0.9%) 1 (0.5%) 0 0 0 1 (0.06%)

Creatine kinase elevation (>10 × ULN), number of patients (%)

1 (0.5%) 0 0 3 (0.4%) 4 (0.2%) 2 (0.9%) 1 (0.6%) 0 3 (0.4%) 6 (0.35%)

Abbreviations: ALT = alanine transaminase; AST = aspartate transaminase; FLARE = Fluvastatin Angiographic Restenosis trial [11]; LCAS = Lipoprotein and Coronary Atherosclerosis Study [13]; LIPS = Lescol Intervention Prevention Study [7]; LiSA = Lescol in Severe Atherosclerosis trial [12]; ULN = upper limit of normal.

were reported with a similar frequency in the fluvastatin and placebo groups. In conclusion, the results of this meta-analysis clearly demonstrate significant and early beneficial effects of fluvastatin on cardiac and all-cause mortality with an excellent safety profile in high-risk patients, who on average had relatively low baseline levels of LDL-C.

Acknowledgments The authors acknowledge the statistical analysis of John Owen Logan (Novartis Pharma AG, Basel, Switzerland) and Jeffrey D. Vest, Ph.D. (Medpace LLC, Cincinnati, Ohio, USA), and the editorial assistance of Richard White and Kerrie Jara. This analysis was performed by Medpace and supported by a nonrestricted educational grant from Novartis Pharma AG.

References be clinically important [29]. These so-called pleiotropic benefits of fluvastatin, which may or may not be a consequence of the lipid-lowering actions of the drug, may have contributed to the outcome benefits observed in the present study [30]. The outcome benefits of fluvastatin treatment revealed by the present meta-analysis were achieved with the immediate-release formulation of fluvastatin, 20 mg or 40 mg, administered once or twice daily. Fluvastatin is now also available in an extended-release formulation as a once-daily, 80 mg dose (which was not available when the trials investigated in this metaanalysis were initiated) that may provide improved compliance compared with a twice-daily dosing regimen. Recent studies have demonstrated that this formulation gives significantly enhanced cholesterollowering effects compared with immediate-release fluvastatin, with maintained excellent tolerability. The starting dose of 80 mg of the extended release formulation of fluvastatin currently recommended for highrisk patients provided improvements in the lipid profile at least as great as 40 mg immediate-release twice daily, and superior to 40 mg immediate-release once daily [31,32]. The safety and tolerability of lipid-lowering treatments are of great importance because of the need for long-term treatment with these drugs. There were no cases of rhabdomyolysis and no increase in the percentage of patients with CK elevation >10 times the ULN (1 case with fluvastatin, 6 with placebo in the pooled analysis) during treatment with fluvastatin, 40 or 80 mg, across all 4 of the studies included in the present meta-analysis. Although the incidence of hepatic enzyme elevations was slightly higher in the fluvastatin group compared with the placebo group, the absolute incidence of 0.9% across the 4 studies is very low and compares favorably with the 1–3% reported for the statin class as a whole [33,34]. Other adverse events

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