Long-term followup of patients enrolled in the Heart Protection Study (HPS) demonstrates continued benefits in the group originally randomized to receive simvastatin instead of placebo. The main results of the HPS, published in 2002, showed a significant 23% reduction at 5.3 years in major vascular events associated with simvastatin treatment among the 20,536 patients with coronary disease enrolled in the trial.
Now the HPS investigators report the followup results after a mean of 11 years in a paper published online in the Lancet. After the trial ended statin use and, consequently, LDL levels were similar between the two groups. In the first post-trial year patients who had been randomized to simvastatin during the trial had an additional 14% reduction in events compared to patients who had been randomized to placebo (p=0.05). After the first post-trial year there were no further additional differences between the former groups, but the relative difference between the two groups remained unchanged.
Overall during the post-trial period, there were no significant differences between the two original randomized groups: 21.7% and 22.5% of the patients originally allocated simvastatin and placebo had a first event (RR 0.95, CI 0.89-1.02, p=0.17). The incidence of cancer was the same in both groups: 17%. No other safety signals emerged during the 11 years.
In an accompanying comment, Payal Kohli and Christopher Cannon write that the long-term results of HPS "suggest that the early benefit of statins is likely to be followed by a prolonged legacy period, with benefit maintained over time" and "that extended use of statins is safe with respect to possible risk of cancer and non-vascular mortality."
Here is the press release from the Lancet:
Long-term follow-up of statin trial shows continued benefit and confirms safety of statin therapy, with no increase in cancer deaths or other non-vascular morbidity or mortality during 11 years of follow-up
Long-term follow-up of the randomised Heart Protection Study (HPS), published Online First in The Lancet, shows that the benefits of statin therapy (ie, reductions in heart attacks, strokes, and other vascular disease) increased as statin treatment continued and persisted for several years after treatment had stopped. Furthermore, it provides reassurance that statins are safe, with no emergence of hazards, such as increases in cancer incidence or other non-vascular morbidity or mortality, during an 11 year follow-up period. Thus, patients who are at increased risk of cardiovascular events should consider starting statin treatment promptly and continuing it long-term. The Article is by the Heart Protection Study Collaborative Group, Clinical Trial Service Unit, Oxford, UK.
In HPS, over 20 000 patients at increased risk of vascular disease were randomly allocated either 40 mg simvastatin daily, or placebo, for around 5 years, and analysis of this in-trial period provided clear evidence that lowering LDL (or “bad”) cholesterol by around 1 mmol/L reduces the risk of heart attacks, strokes, and other vascular disease by around one quarter. Moreover, the absolute benefits increased as treatment continued during the 5 year period. However, the long-term efficacy and safety of statins continue to be debated.
Therefore, since the end of the randomised trial, all surviving HPS participants were followed-up for a further 6 years, during which time statin use (which was encouraged) and blood cholesterol concentrations were similar in both groups.
There are 2 important findings: firstly, the substantial reductions in fatal and non-fatal heart attacks, strokes, and other vascular disease seen among those participants allocated simvastatin during the 5-year trial period persisted largely unchanged during the post-trial period, despite similar use of statins among the surviving study population. Secondly, during a total 11 year follow-up period, there was no evidence that allocation to simvastatin was associated with any emergence of hazard, with no increase in cancer incidence or non-vascular mortality observed.
The authors conclude: “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 5 years. These findings provide further support for the prompt initiation and long-term continuation of statin treatment in people at increased risk of vascular events.”
Richard Bulbulia, one of the study authors, adds*: “The persistence of benefit we observed among participants originally allocated simvastatin during the subsequent 6 year post-trial period is remarkable. In addition, the reliable evidence of safety, with no excess risk of cancer or other major illnesses during over 11 years follow-up, is very reassuring for doctors who prescribe statins and the increasingly large numbers of patients who take them long-term to reduce their risk of vascular disease.”
In a linked Comment, Dr Payal Kohli and Dr Christopher P Cannon, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA, say: “We now have strong evidence from HPS and several other randomised controlled trials that prolonged treatment with statins is indeed efficacious, safe, and has long-lasting beneficial effects, even after discontinuation of therapy. For this reason, concerns 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.”