The results of extended follow-up of the Heart Protection Study (HPS) have been published early online in the Lancet.

The authors note that the HPS was established to evaluate the long-term safety and efficacy of lowering LDL cholesterol with statin treatment.  This is one of the major statin trials that collectively provide evidence that lowering LDL cholesterol by around 1mmol/L reduces vascular morbidity and mortality by about a quarter in a wide range of patients; many are now prescribed this treatment long-term to reduce their vascular risk.  Despite this, there is limited evidence about the long-term efficacy and safety of statin treatment available from statin trials.  Observational data have suggested that lower blood cholesterol concentrations may be associated with an increased risk of certain types of cancer, and of other non-vascular conditions; it has therefore been suggested that lowering LDL cholesterol may be associated with adverse events that take longer than five years to emerge. 

In the current article, the authors report their findings from extended follow-up of the HPS, reporting cause-specific mortality and major morbidity in the in-trial and post-trial periods.  Briefly, the study randomised 20,536 patients aged 40-80 years at an increased risk of vascular events to treatment with simvastatin (40mg daily) or placebo.  After the final follow-up (2001), patients and their doctors made a decision as to whether non-trial statins should be prescribed; study assignment was not unblinded unless there was a particular request (to aid the unbiased assessment of subsequent long-term effects; unblinded in 15% of cases).  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. 

Patients were followed up for a mean of 11 years (including 5.3 years in the main trial).  A total of 17,519 participants were still alive at the start of the post-trial follow-up 8,863 who were allocated simvastatin and 8,656 placebo (overall follow-up of 96,784 and 95,084 person-years of follow-up available, respectively).  The main findings reported are as follows:

• In the trial, randomisation to simvastatin was associated with an average reduction in LDL cholesterol of around 1mmol/L and a 23% (95% CI 19-28; p<0.0001) relative reduction in the risk of major vascular events, with significant divergence each year after the first.

• During the post-trial follow-up period (when statin use and lipid concentrations were similar in both groups – mean of 2.6mmol/L for each), 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 entire study and follow-up period, no significant differences were recorded in cancer incidence at all sites (0.98 [0.92-1.05]) or at any particular site (the authors note that the large number of incident cancers reported permitted a reliable assessment of these endpoints)

• No difference in mortality attributed to cancer (1.01 [0.92-1.11]) or to non-vascular causes (0.96 [0.89-1.03]) was seen.  The incidence of genitourinary, gastrointestinal, respiratory, haematological, or any other malignant disease did not differ significantly.

The authors conclude from their results that the benefits seen with simvastatin in the main part of the HPS persisted largely unchanged during the follow-up period, and that no adverse effects on particular causes of non-vascular mortality or major morbidity (including cancers) were seen to emerge during prolonged follow-up.  They say that their findings support prompt initiation and long-term continuation of statin treatment in people at increased risk of vascular events.