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1 May 2009
The PRIME study: both statins and fibrates reduce 10-year mortality in dyslipidemic subjects

All-cause mortality reduced by 2.0- and 1.5-fold in dyslipidemic patients treated with statins and fibrates, respectively, compared with untreated dyslipidemic patients.

Gardette V, Bongard V, Dallongeville J, et al.
Summary
Comments & References
STUDY SUMMARY
Methods

The Prospective Epidemiological Study of Myocardial Infarction (PRIME) study compared 10-year all-cause mortality according to initial dyslipidemia status and lipid-lowering drug exposure in 7,722 French men aged 50 to 59 years at baseline.
Four groups were compared: normolipidemic (69.1% of the cohort), untreated dyslipidemic (19.0%), and dyslipidemic subjects on fibrate (7.9%) or statin (4.0%) therapy.

Data were analyzed using multivariate Cox models
Main results

Only 4.8% of the subjects were lost to follow-up after 10 years. A total of 416 deaths were recorded (due to cardiovascular disease in 17.1% of cases, cancer in 53.1%, and other causes in 29.8%).
Multi-adjusted analyses showed a significant reduction in all-cause mortality in patients on statins or fibrates compared with untreated dyslipidemic patients. In addition, fibrate therapy significantly reduced cancer mortality. Statin therapy showed a non-significant trend for reduced cancer mortality

Hazard Ratios :

Group

All cause
death

CVD
death

Cancer
death

Death from
other cause

Statins

0.49
(0.26-0.94)
p=0.031

0.55
(0.16-1.92)
p=0.348

0.41
(0.16-1.06)
p=0.067

0.68
(0.19-2.40)
p=0.546

Fibrates

0.65
(0.42-0.99)
p=0.046

0.76
(0.34-1.70)
p=0.499

0.52
(0.28-0.97)
p=0.041

0.87
(0.37-2.02)
p=0.746

Normolipidemic

0.76
(0.56-1.03)
p=0.080

0.44
(0.22-0.88)
p=0.020

0.72
(0.47-1.10)
p=0.124

1.19
(0.64-2.24)
p=0.580


COMMENT

The PRIME study was designed to assess the contribution of various genetic and environmental exposures to the development of coronary heart disease (CHD) in two countries at contrasting risk of CHD (France and Northern Ireland). The analysis published by V. Gardette and colleagues was conducted in a population-based sample from Southern, Eastern and Northern France. It was designed to clarify some uncertainties about the effect of lipid-modifying therapies on overall mortality and about conflicting data about the effect of such therapies on cancer-associated death.

A total of 7,855 men were initially recruited, from whom 133 were excluded because they were on combination statin-fibrate treatment, other lipid-lowering treatments or because they had no lipid assessment.

Simvastatin accounted for about 60% of statin use and pravastatin for 40%. Fenofibrate accounted for 60% of fibrate use.

As numerous patient’s characteristics differed between groups at baseline, mortality rates were adjusted for center, age, educational level, cardiovascular risk factors, lipids, alcohol intake, and history of cardiovascular and severe chronic diseases.

This large study cohort showed that the probability of dying during the 10-year follow-up was 2.0- and 1.5-fold lower among subjects treated with statins and fibrates, respectively compared with untreated dyslipidemic subjects. These reductions in CVD death observed in the 2 treatment groups did not reach statistical significance. The study proved however to be underpowered to analyze CV mortality, as the latter represented only 17.1% of all-cause mortality.

There was no increased risk of cancer death observed in both the fibrates and statins group, with a significant reduction of cancer mortality in patients treated with fibrates.

The study has some other limitations. No record of smoking exposure was done at the end of the study. Drug exposure was not recorded throughout the study and baseline exposure was considered as constant. However, for the Toulouse city area, available information showed that 2/3 of subjects did not change treatment after more than 3 years. For the other third, the proportion of men in the fibrate group exposed more than once to a statin during follow-up was close to the proportion of men exposed more than once to a fibrate in the statin group (47% and 52%, respectively).

In addition, some untreated subjects at baseline may have started lipid-lowering treatment during follow-up. This drop-in factor implies that the death rates in the group of untreated dyslipidemic patients may have been underestimated and that the magnitude of the differences may actually have been larger than those reported.

Statin/fibrate combination therapy to further reduce mortality in dyslipidemic patients

Statins act primarily by decreasing LDL-C cholesterol while their action on HDL-C and triglycerides levels is only modest. Conversely, fibrates increase HDL-C and decrease triglycerides levels but moderately decrease LDL-C. That both classes of lipid-lowering agents significantly reduce all-cause mortality in dyslipidemic patients suggests that combination statin-fibrate therapy might potentially act complementary or synergistically to reduce cardiovascular events. In this respect, results of the SAFARI trial1, showing greater improvement of all lipid parameters tested in patients treated with a simvastatatin/fenofibrate combination compared with those treated with simvastatin alone, add to the rationale to prospectively explore this path in populations with high prevalence of atherogenic dyslipidemia, such as type 2 diaetes. The ongoing ACCORD trial, in which the same lipid-lowering treatments will be tested (simvastatatin/fenofibrate vs. simvastatin), will provide key information as to whether such combination results in improved clinical outcomes in type 2 diabetes patients

References
  1. Grundy SM, Vega GL, Yuan Z, et al. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial). Am J Cardiol. 2005;95:462-8