The protection against vascular morbidity and mortality that resulted from lowering LDL cholesterol with simvastatin over a period of about 5 years in the Heart Protection Study persisted for nearly 6 additional years after study treatment ended, according to findings from an extended follow-up of the large randomized controlled trial.
Furthermore, no evidence of emerging safety concerns was apparent during the follow-up, the Heart Protection Study Collaborative Group reported online on Nov. 23 in the Lancet.
Participants in the Medical Research Council and British Heart Foundation Heart Protection Study (HPS) was composed of 20,536 adults aged 40-80 years who were at increased risk of vascular events and who were enrolled between July 1994 and May 1997. Those allocated to receive simvastatin experienced a mean reduction in LDL cholesterol of 1.0 mmol/L and a proportional reduction of 23% in major cardiovascular events during the 5-year study period.
The findings, along with those from other major trials of statins, provided "compelling evidence" of the value of lowering LDL cholesterol – and led to the widespread use of long-term statin treatment – but evidence from observational studies has raised concerns about possible increases in the risk of certain types of cancer and other nonvascular morbidity and mortality in patients with lower blood cholesterol concentrations, according to the study group.
The findings of the HPS extended follow-up appear to lay those concerns to rest.
At a mean of 5.3 years (for a total HPS follow-up of 11 years), the rate of first vascular events in previously event-free participants was similar in both the initial simvastatin group and the initial placebo (21.7% and 22.5%, respectively; risk ratio 0.95), the investigators said (Lancet 2011 Nov. 23 [doi:10.1016/S0140-6736(11)61125-2]).
Although a further 14% decrease in vascular events occurred in the first year in the simvastatin group, little difference was seen between the treatment and placebo groups thereafter. Similar patterns were seen for major coronary events, strokes, and revascularization procedures.
Vascular mortality was also similar in the two groups during the post-trial follow-up (11.5% and 11.6% in the simvastatin and placebo groups). During the in-trial period, an 18% proportional reduction in vascular mortality was seen in the treatment group, so the follow-up findings indicate that the in-trial survival gains persisted, they investigators said.
Nonvascular mortality rates were also similar in the two groups during the post-trial follow-up (10.6% and 10.9%). There were no differences in deaths from cancer, respiratory disease, or nonmedical causes.
"When the 11 years of in-trial and post-trial follow-up are considered together, allocation to about 5 years of statin treatment was not associated with any increase in nonvascular mortality, either overall [14.8% vs. 15.1%] or for any prespecified category of death," they said.
As for first diagnoses of any type of cancer, rates were also similar in the in-trial and post-trial periods, for a combined incidence of 17% in each group.
"Indeed, even during the later years of this prolonged follow-up, no suggestion was noted of any emerging difference in the overall incidence of cancer," the investigators said, noting that the large numbers of incident cancer that occurred during the entire in-trial and post-trial period allowed for reliable assessment of the effects of the substantial 5-year reduction in cholesterol on 11-year risks of common cancer types. No significant differences were seen in the incidences of genitourinary, gastrointestinal, respiratory, hematologic, or any other malignant disease, even in those aged 70 years or older at baseline, and in those with below-average pretreatment cholesterol concentrations.
Statin use was encouraged in all HPS participants following the initial study treatment period and was similar in both treatment groups during the post-trial follow-up at about 59% in the first year and increasing to about 84% in the fifth year. LDL cholesterol concentrations were also similar at 2.6 mmol/L in both groups at 3.2 years, the investigators noted.
Although 11 years might not be long enough to fully discern all cancer and other risks in this study population, it is notable that no adverse trend was noted, even during the later years of follow-up, the researchers wrote.
The findings are consistent with those from four other large randomized trials of statin treatment, and, taken together, the data support the prompt initiation and long-term continuation of statin treatment in individuals at increased risk of vascular events, they concluded.
This study was supported by the UK Medical Research Council, the British Heart Foundation, Merck & Co., and Roche Vitamins. The HPS Collaborative Study Group is bound by a policy of not accepting honoraria or other payments from the pharmaceutical industry other than reimbursement of costs to participate in scientific meetings. As a result, the only disclosures of the group relate to such reimbursement.