Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20,536 high-risk individuals: a randomised controlled trial

Abstract

Background: Findings of large randomised trials have shown that lowering LDL cholesterol with statins reduces vascular morbidity and mortality rapidly, but limited evidence exists about the long-term efficacy and safety of statin treatment. The aim of the extended follow-up of the Heart Protection Study (HPS) is to assess long-term efficacy and safety of lowering LDL cholesterol with statins, and here we report cause-specific mortality and major morbidity in the in-trial and post-trial periods.

Methods: 20,536 patients at high risk of vascular and non-vascular outcomes were allocated either 40 mg simvastatin daily or placebo, using minimised randomisation. Mean in-trial follow-up was 5·3 years (SD 1·2), and post-trial follow-up of surviving patients yielded a mean total duration of 11·0 years (SD 0·6). The primary outcome of the long-term follow-up of HPS was first post-randomisation major vascular event, and analysis was by intention to treat. This trial is registered with ISRCTN, number 48489393.

Findings: During the in-trial period, allocation to simvastatin yielded an average reduction in LDL cholesterol of 1·0 mmol/L and a proportional decrease in major vascular events of 23% (95% CI 19-28; p<0·0001), with significant divergence each year after the first. During the post-trial period (when statin use and lipid concentrations were similar in both groups), no further significant reductions were noted in either major vascular events (risk ratio [RR] 0·95 [0·89-1·02]) or vascular mortality (0·98 [0·90-1·07]). During the combined in-trial and post-trial periods, no significant differences were recorded in cancer incidence at all sites (0·98 [0·92-1·05]) or any particular site, or in mortality attributed to cancer (1·01 [0·92-1·11]) or to non-vascular causes (0·96 [0·89-1·03]).

Interpretation: More prolonged LDL-lowering statin treatment produces larger absolute reductions in vascular events. Moreover, even after study treatment stopped in HPS, benefits persisted for at least 5 years without any evidence of emerging hazards. These findings provide further support for the prompt initiation and long-term continuation of statin treatment.

Funding: UK Medical Research Council, British Heart Foundation, Merck & Co, Roche Vitamins.

Figure 1

First major vascular event during in-trial and post-trial follow-up Analyses are of numbers of participants having a first post-randomisation event of each type during follow-up, so there is some non-additivity between different types of event. Denominators during the post-trial period are the numbers of randomised patients who had not had the particular outcome or died during the in-trial period. Risk ratios (RRs) are plotted (black squares with area proportional to amount of statistical information in each subdivision) comparing outcome among the participants allocated 40 mg simvastatin daily to that among those allocated placebo, along with their 95% CIs (horizontal lines; ending with arrow head when CI extends beyond scale). For particular subtotals and totals, the result and its 95% CI are represented by a diamond, with the relative risk reduction (and 95% CI) and statistical significance given alongside. A broken vertical line indicates the overall RR.

Figure 2

First major vascular event by year during in-trial and post-trial follow-up Conventions as in figure 1. Denominators are the numbers of patients at risk of a first post-randomisation major vascular event at the start of each year.

Figure 3

First major vascular event during total follow-up period Life-table plot of the effects of simvastatin allocation on percentage of major vascular events during the in-trial and post-trial periods.

Figure 4

Vascular and non-vascular mortality during in-trial and post-trial follow-up Conventions as in figure 1.

Figure 5

First incident cancer by year during total follow-up period Conventions as in figure 1.

Figure 6

Incidence of site-specific cancer during total follow-up period Conventions as in figure 1. Not including non-melanoma skin cancer, which was prospectively to be considered separately (561 [5·5%] vs 512 [5·0%]; risk ratio 1·08 [0·96–1·21]; p=0·22).