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MEDI-NEWS - Based on the following article: Long-term benefit of high-density lipoprotein cholesterol-raising therapy with bezafibrate: 16-year mortality follow-up of the Bezafibrate Infarction Prevention Trial. Arch Intern Med 2009;169(5):508-14.

May 2010

A substantial proportion of patients with coronary artery disease (CAD) have low levels of HDL-C despite statin therapy. To that end, the BIP (Bezafibrate Infarction Prevention) trial was launched to evaluate whether raising HDL-C levels and reducing elevated triglycerides with bezafibrate would alter cardiac risk in patients with known CAD whose total serum cholesterol levels were relatively normal or only slightly elevated. In the original trial (Circulation 2000;102:21-7), treatment with bezafibrate at a dose of 400 mg/day was associated with a reduction in nonfatal myocardial infarction (MI) compared with placebo, but mortality rates between the two treatment groups were not significantly different at two years.

An extended follow-up of the same trial, again reported by Goldenberg et al. (J Am Coll Cardiol 2008;51:459-65), showed that the combined end point of cardiac death or nonfatal MI occurred in 17.8% of the active treatment group and 20.3% of placebo patients (P=0.09), during a mean follow-up of 8.2 years. After a total follow-up of nine years, the cumulative probability of the combined end point was 23.8% in the placebo group and 19.7% in the bezafibrate group, representing a 17.6% reduction in the rate of cardiac death or nonfatal MI (P=0.03).

Importantly, non-study lipid-lowering drugs were given to an increasing number of placebo patients during the double-blind phase of the study. Adjusting for this confounding factor in several different ways, the investigators determined that bezafibrate therapy was still associated with a significant 15% to 18% reduction in the risk of the combined end point compared with placebo, depending on the model used.

The investigators also determined that the benefit of bezafibrate therapy was most prominent among patients with baseline triglycerides equal to or over 200 mg/dL (2.26 mmol/L), in whom treatment led to a 37% reduction in the primary end point, as well as in patients who had a baseline body mass index (BMI) in excess of 27 kg/m2, among whom bezafibrate was associated with a 27% reduction in the primary end point. In contrast, treatment response to active therapy was “significantly attenuated” among patients with advanced heart failure or those with ischemic symptoms.

Further Evidence

Further evidence that CAD patients with dyslipidemia enjoy significant long-term protection against major CV events long after treatment is discontinued was provided by findings from a 16-year follow-up of the original BIP cohort. “We assessed the relationship between on-treatment changes in HDL-C levels during the double-blind phase of the study and the risk of all-cause mortality at 16 years of follow-up,” the study authors noted (Arch Intern Med 2009;169:508-14). Response to treatment was divided into tertiles defined by increase in HDL-C during treatment. In the upper tertile, on-treatment increase varied from >0.21 to 30.0 mmol/L and from -0.31 to 0.21 mmol/L in the two lower tertiles combined.

Similar analyses were used to evaluate the effect of triglyceride reductions on long-term mortality, where upper-tertile triglyceride responses were defined as a decrease of >43 mg/dL (>0.49 mmol/L) and a lower tertile response was defined as a <10 mg/dL (<0.11 mmol/L) reduction. During a median follow-up of 15.7 years, 37.3% of patients allocated to the original placebo group had died vs. 34.8% of those originally allocated to bezafibrate.

“The respective cumulative probabilities of death at 16 years were 37.9% and 35.3% (respectively), representing a 7% reduction in the rate of death at 16 years among patients allocated to the original bezafibrate group (P=0.12),” the study authors added. Mortality differences between the two groups appeared after seven years of follow-up and persisted thereafter.

The long-term benefits of the study drug were again more prominent among patients with elevated baseline triglyceride levels (27% reduction in mortality risk); those with an elevated BMI (21% reduction); and women (27% reduction). Event rates were also assessed according to HDL-C response to bezafibrate therapy. Among patients with an upper-tertile HDL-C response to treatment, cumulative mortality rates at 32.1% were significantly lower compared with the placebo group at 37.9% (P=0.02).

In contrast, cumulative mortality rates were similar between patients who had a lower HDL-C response and placebo. “Notably,” the study authors observed, “the lower mortality rate in patients with an upper-tertile HDL-C response appeared after 2 years of follow-up and persisted thereafter.” Multivariate adjustment for baseline clinical and lipid factors revealed that the 11% reduction in the risk of long-term mortality among patients allocated to the original bezafibrate group was related to a significant 22% reduction in the risk of death in patients who had an upper-tertile HDL-C response to treatment.

Similar trends were seen for the cardioprotective benefits associated with on-treatment reductions in triglycerides, where patients who had an upper-tertile response to treatment had an 18% lower risk of long-term mortality vs. placebo patients (P=0.03). Again, patients with a lower triglyceride response had a mortality risk similar to that of placebo patients.

“These findings suggest that HDL-C-raising therapy with bezafibrate has important long-term clinical implications that may extend for many years after termination of active treatment with the drug,” the study authors concluded.

Special Populations

In assessing the potential for bezafibrate to reduce MI risk in special populations, Tenenbaum et al. (Arch Intern Med 2005;165:1154-60) noted that because of their favourable effect on glucose and lipid metabolism, PPAR-alpha agonists such as the fibrates are good candidates to reduce the risk of MI in patients with the metabolic syndrome (MS). Having randomized 740 patients to the fibrate arm and 730 to placebo, the investigators documented a new MI in 11.1% of patients treated with active therapy vs. 15.2% of placebo patients (P=0.02) at a mean follow-up of 6.2 years for events.

Patients with four out of five risk factors for MS had a far more striking reduction in new MI rates at 11.4% compared with 17.1% for placebo patients, while there was a 56% reduction in cardiac mortality in the same subgroup on active therapy (HR, 0.44). “Bezafibrate, compared with other fibrates, has a unique characteristic profile of action since it activates all three PPAR subtypes...at comparable doses,” the authors noted, “[so it] operates as a pan-agonist for all three PPAR isoforms.”

This unique mechanism of action may possibly explain the lack of benefit that ACCORD (Action to Control Cardiovascular Risk in Diabetes) study investigators found following treatment of 5518 patients with type 2 diabetes on background simvastatin therapy to which either fenofibrate or placebo was added. At a mean follow-up of 4.7 years, the combination did not reduce the rate of fatal CV events, nonfatal MI or nonfatal stroke vs. simvastatin alone (N Engl J Med 2010;362(17):1563-74).

The investigators suggested that these results might be explained by their use of broader inclusion criteria for plasma lipid levels than might have been used if the lipid trial had been an independent study. (The study was designed to simultaneously test the effects of intensive glycemic control and combination lipid therapy on CV outcomes.)

Alternatively, it is possible that fenofibrate may not be as effective as, for example, gemfibrozil, which did show benefit in the Helsinki Heart Study and in VA-HIT, neither of which included background statin therapy. As the authors pointed out, ACCORD patients who had both a baseline triglyceride level in the highest tertile and an HDL-C in the lowest tertile did appear to benefit from fenofibrate, although all other patients receiving the fibrate did not.

The study authors noted that findings in this ACCORD subgroup are thus consistent with those seen in other major fibrate trials including the Helsinki Heart Study and the BIP trial.