Lancet: Patients benefit from LDL-C lowering strategies long-term
Longer-term LDL-cholesterol lowering statin therapies can greatly reduce vascular events, according to the results of the Heart Protection Study (HPS) published Nov. 23 in The Lancet. Additionally, researchers found that even after the study treatments were stopped, the benefits lasted for at least five years without any emerging dangers.

“Collectively, findings of HPS and other major trials of statins provide compelling evidence that lowering LDL cholesterol by about 1 mmol/L reduces vascular mortality and morbidity by about a quarter in a wide range of patients (including elderly people and those with low cholesterol concentrations), without increasing the risk of non-vascular mortality or morbidity (apart from a small myopathy excess) during about five years of treatment,” according to background information from the study.

Previous studies have alluded to the fact that lower blood cholesterol concentrations have been linked to an increased risk of cancer and non-vascular morbidity and mortality. “It has been suggested, therefore, that lowering LDL cholesterol (particularly to low levels) might produce increases in the rates of cancers and other types of adverse events that take longer than five years to emerge,” the authors wrote.

During the HPS study, conducted by the HPS Collaborative Group, 20,536 patients who were at a high risk of vascular and nonvascular outcomes were enrolled and randomized to receive either 40 mg of simvastatin or placebo. Mean in-trial follow-up was 5.3 years and post-trial follow-up yielded a mean total duration of 11 years.

Between July 1994 and May 1997, of the 17,519 patients who were alive at the start of the post-trial follow-up period, 8,863 received simvastatin (Zocor, Merck) and 8,656 patients were randomized to receive placebo.

The study used first post-randomization major vascular event as the primary endpoint.

The researchers found that self-reported statin use was similar in both groups, rising from about 59 percent at the end of the first year to 84 percent by the end of the fifth year.

Additionally, the researchers reported that 2,153 major vascular events were reported in the 10,269 patients administered simvastatin vs. 2,712 events in 10,267 who were administered placebo. This related to a 23 percent reduction.

While no significant differences were noted in the first year, the authors did report reductions of about a quarter during the subsequent in-trial year. Among those who were event-free at the start of the post-trial period, 1,636 first events arose in patients previously administered simvastatin vs. 1,566 patients who were previously administered placebo.

The researchers reported a 14 percent additional decrease that was recorded in the first post-trial year in patients who were originally administered simvastatin. However, thereafter, little difference was seen between the two groups. Meanwhile, a 27 percent reduction for major coronary events was noted during the in-trial period. A 24 percent reduction in stroke risk was also found during the in-trial period.

Lastly, vascular mortality was linked to 826 deaths in those administered simvastatin and 998 in those administered placebo, an 18 percent proportional reduction. Vascular mortality rates were similar in both treatment groups during the post-trial period, 1,019 vs. 1,007, respectively.

Non-vascular mortality during the in-trial period was responsible for 580 deaths in those administered simvastatin compared with 613 administered placebo. However, death from cancer or other non-vascular reasons did not statistically differ. During the post-trial period, the rates of non-vascular mortality were similar.

“Similarly, the large numbers of other types of outcome recorded during prolonged follow-up provide compelling evidence that five years of statin therapy is not associated with excesses of any particular type of non-vascular death, site specific cancer, or other major non-vascular morbidity,” the authors noted. “Moreover, although 11 years might still not be long enough for deleterious effects on cancer to emerge fully, no adverse trend was noted, even during the later years of post-trial follow-up.

“As well as providing reliable evidence about the long-term benefits of statin therapy, the large numbers of other major health outcomes recorded during prolonged follow-up in HPS provide considerable reassurance—both to prescribers and to patients—about the long-term safety of lowering LDL cholesterol substantially for about five years,” the authors concluded.

“Statins have revolutionized modern cardiovascular treatment by producing a striking reduction in coronary risk,” Payal Kohli, MD, and Christopher P. Cannon, MD, both of the TIMI Study Group and Brigham and Women’s Hospital in Boston, wrote in an accompanying editorial.

The authors noted that the results of the current study show the long-term benefits of statin use, despite the previous concerns of adverse event risk. Cannon and Kohli concluded that "[C]oncerns should be put to rest and doctors should feel reassured about the long-term safety of this life-saving treatment for patients at increased cardiovascular risk.”