Statins have reached a prominent place in the control of cardiovascular risk. The original trials in the 1990s that showed the effectiveness of statins in reducing cardiovascular risk in coronary heart disease [1,2] have been followed up by long-term safety and efficacy trials [3-6]. These extended follow-up studies showed a legacy effect, with improved survival and a substantial reduction in cardiovascular outcomes over periods up to 20 years [3-6]. Furthermore, long-term statin treatment does not influence cancer or death from non-cardiovascular causes during long-term follow-up [5,6]. These studies support the wider adoption of statins in primary and secondary prevention strategies.
Further evidence for such a role of statins in primary prevention strategies has come from the recently published Heart Outcomes Prevention Evaluation (HOPE)-3 trial [7-10]. The primary results of this trial have been published in three articles in the New England Journal of Medicine [7-9] in conjunction with an editorial which puts the results into the perspective of primary prevention of cardiovascular risk . In brief, HOPE-3 was a double-blind randomised, placebo-controlled trial. It had a 2-by-2 factorial design, in which 12,705 intermediate risk men (≥55 years of age) and women (≥60 years of age) were randomly assigned to receive rosuvastatin at a dose of 10 mg per day or placebo. They were also randomly assigned to receive antihypertensive treatment with candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day or placebo for a median treatment period of 5.6 years. Treatment with rosuvastatin resulted in a 24% lower risk of cardiovascular events than with placebo. In the rosuvastatin group, there was no excess of diabetes or cancers, but there was an excess of muscle symptoms . The antihypertensive therapy did not result in a significantly lower risk of cardiovascular events. However, in one of the three pre-specified hypothesis-based subgroups, participants in the subgroup for the upper third of systolic blood pressure (˃143.5 mmHg) who were in the active treatment group had a significantly lower cardiovascular risk . Finally, the combination of rosuvastatin, candesartan and hypochlorothiazide was associated with a significantly lower rate of cardiovascular events than dual placebo among persons of intermediate risk who did not have cardiovascular disease .
The relative risk reduction (RRR) of rosuvastatin in this primary intervention trial was 24%. In absolute terms it was a reduction in the rate of cardiovascular events from 4.8% (over a period of 5.6 years) in the placebo-treated group to 3.7% in the rosuvastatin group. These data are in agreement with those of a meta-analysis of randomised trials of statin therapy which led to an RRR of 25% of cardiovascular events in a primary prevention population . Taken together, these data make a strong case for statin treatment in patients with an intermediate risk who do not yet have cardiovascular disease.
Additional considerations in statin use
Several aspects of these results need further attention. First of all, the potential gain in cardiovascular risk reduction should, in individual patients, be weighed against the discomfort, in particular due to muscle symptoms. In the HOPE-3 trial, more participants in the rosuvastatin group than in the placebo group had muscle pain or weakness (5.8% versus 4.7%), although there was no significant difference between the two groups in the number of participants in whom the assigned treatment was permanently discontinued because of muscle symptoms (1.3% versus 1.2%) . Another issue is the question as to whether the amount of LDL reduction is decisive for the degree of cardiovascular reduction. The HOPE-3 trial was not designed to answer this question. In contrast, the statin was given independently of the pre-treatment cholesterol or LDL level. Nevertheless, the statin treatment was associated with a 26.5% reduction in LDL cholesterol level.
Recent guidelines [12,13] recommend a risk-based approach to statin use rather than an approach that is based primarily on LDL cholesterol levels. The recently published IMPROVE-IT trial  aimed at studying the impact of further reducing the LDL cholesterol level in patients with acute coronary syndrome by adding ezetimibe to a standard treatment with 40 mg simvastatin. The combined ezetimibe/simvastatin treatment led to a 22% lower LDL cholesterol concentration than the placebo/simvastatin treatment. However, the RRR in cardiovascular events was only 6%. The results of these trials suggest that LDL reduction may not be the only mechanism whereby statins reduce cardiovascular risk. Pharmacological research in the past two decades has suggested pleiotropic effects of statins beyond LDL cholesterol reduction. Antioxidative, anti-inflammatory and antifibrotic effects are most prominent amongst these pleiotropic actions [15,16].
In conclusion, new insights from pharmacological studies as well as clinical trials suggest new paradigms for statin use in primary cardiovascular prevention. Even in patients with intermediate cardiovascular risk without overt cardiovascular disease, statin use may offer benefits, partly independent of LDL cholesterol reduction. Since hypertension contributes importantly to overall cardiovascular risk, the use of a statin should be considered in hypertensive patients. However, the individual decision to use a statin should be based upon individualised estimates of risk reduction and adverse effects [17,18].
- [No authors listed]. Randomized trial of cholesterol lowering in 4444 patients with coronary disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994 Nov 19;344(8934):1383-9.
- Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimar AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995 Nov 16; 333(20):1301-7.
- Pedersen TR, Wilhelmsen L, Faergeman O, Strandberg TE, Thorgeirsson G, Troedsson L, Kristianson J, Berg K, Cook TJ, Haghfelt T, Kjekshus J, Miettinen T, Olsson Ag, Pyörälä K, Wedel H. Follow-up study of patients randomized in the Scandinavian Simvastatin Survival Study (4S) of cholesterol lowering. Am J Cardiol. 2000 Aug 1;86(3):257-62.
- Ford I, Murray H, Packard CJ, Shepherd J, MacFarlane PW, Cobbe SM; West of Scotland Coronary Prevention Study Group. Long-term follow-up of the West Scotland Coronary Prevention Study Group. N Engl J Med. 2007 Oct 11;357(15):1477-86.
- Ford I, Murray H, McCowan C, Packard CJ. Long-Term Safety And Efficacy Of Lowering Low-Density Lipoprotein Cholesterol With Statin Therapy: 20-Year Follow-Up of West of Scotland Coronary Prevention Study. Circulation. 2016 Mar 15;133(11):1073-80.
- Hague WE, Simes J, Kirby A, Keech AC, White HD, Hunt D, Nestel PJ, Colquhoun DM, Pater H, Stewart RA, Sullivan DR, Thompson PL, West M, Glasziou PP, Tonkin AM; LIPID study investigators†. Long-term effectiveness and safety of pravastatin in patients with coronary heart disease: sixteen years of follow-up of the LIPID study. Circulation. 2016 May 10;133(19):1851-60.
- Yusuf S, Bosch J, Dagenais G, Zhu J, Xavier D, Liu L, Pais P, López-Jaramilli P, Leiter LA, Dans A, Avezum A, Piegas LS, Parkhomeko A, Keltai K, Keltai M, Sliwa K, Peters RJ, Held C, Chazova I, Yusoff K, Lewis BS, Jansky P, Khunti K, Toff WD, Reid CM, Varigos J, Sanchez-Vallejo G, McKelvie R, Pogue J, Jung H, Gao P, Diaz R, Lonn E; HOPE-3 Investigators. Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med. 2016 May 26;374(21):2021-31.
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- Cushman WC, Goff DC Jr. More HOPE for Prevention with Statins. N Engl J Med. 2016 May 26;374(21):2085-7.
- Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010 Nov 13;376(9753):1670-81.
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- Nayor M, Vasan RS. Recent Update to the US Cholesterol Treatment Guidelines. A Comparison With International Guidelines. Circulation. 2016 May 3;133(18):1795-806.
- Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, De Ferrari GM, Ruzyllo W, De Lucca P, Im K, Bohula EA, Reist C, Wiviott SD, Tershakovec AM, Musliner TA, Braunwald E, Califf RM; IMPROVE-IT Investigators. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015 Jun 18;372(25):2387-97.
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Notes to editor
Professor Harry Struijker-Boudier, Ph.D
Department of Pharmacology and Toxicology, Maastricht University, Maastricht, The Netherlands.
Address for correspondence:
Department of Pharmacology and Toxicology, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
Tel: +31-43-38 81420
The author has received research support and honoraria from Servier, Merck, Fukuda-Denshi and Durect.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.