2016 saw the publication of the latest large randomised trial investigating the role of cholesterol lowering drugs known as Statins in preventing adverse cardiovascular events. The HOPE trial(1) investigated the effect of a low dose statin and a blood-pressure-reducing medication (candesartan/hydrochlorothiazide) on the incidence of cardiovascular events compared with placebo, in men ≥55years and women ≥65years who had no history of cardiovascular disease but who did have risk factors (at least 1) such as obesity, smoking, or a strong family history of premature cardiovascular disease. Over a median follow-up time of 5.6 years the end point of death from cardiovascular disease, non-fatal heart attack or non-fatal stoke, was significantly less likely to have occurred in the people taking the statin (rosuvastatan) than in those taking placebo, and the authors conclude that 10mg of rosuvastatin daily resulted in a significantly lower risk of cardiovascular events.
Large randomised controlled clinical trails, dating from the early 1990s (2) have repeatedly shown a benefit from taking these drugs, for patients with established cardiovascular disease (for example people who have previously had a heart attack). Importantly, the benefits of these medications are not related soley to the ability to alter cholesterol levels, and so even patients with ‘normal’ cholesterol levels are often routinely prescribed these drugs. The suggestion that people who have never had vascular heath problems would benefit from taking statins on a daily basis for the rest of their lives requires careful consideration.
Several highly regarded professional groups have issued recommendations. The United States Preventative Services Task Forces commissioned and published a review(3) of evidence to date, analysing the risks and benefits of statin therapy for adults >40 without prior cardiovascular events, but with risk factors such as those mentioned above, and concluded that there was significantly reduced risk of death from any reason as well as for cardiovascular reasons, associated with this treatment, the benefit being greater for those with the greater number of risk factors. The European Society of Cardiology also published recommendations in 2016(4) and recommends the use of a risk calculator to determine the point at which someone should be commenced on a statin. For example, a 50 year old male non-smoker with a systolic Blood Pressure of 140mmHg and a total Cholesterol level of 6mmol/L, does not get a statin, if systolic blood pressure was 180mmHg he is estimated to be at significantly greater risk of a cardiovascular event and so would be recommended to take a statin. A Cochrane analysis(5) in 2013, was also clear in recommending statins for those at risk but without any prior cardiovascular event, failing to find any evidence of serious adverse effects and concluding that the therapy is likely to be cost effective in primary prevention.
The findings of these and many other studies can be taken as justification for starting many many people, with no history of cardiovascular disease, on life long statin therapy. Taken even further, one might be criticised for not starting statin therapy in the presence of clear risk factors for cardiovascular disease. Of course there are two sides to every story and the benefits of this treatment must be seen in a broader context. Any benefit must be based on the assumption that prevention is better than cure, and also that this benefit comes at a justifiable cost. Statins (also know as HMGCoA-Reductase inhibitors) are the most successful pharmaceutical drugs of all time. The market in the US alone is estimated at $20 Billion per year, and the potential for bias in studies, design and reporting, and in subsequent recommendations must be kept in mind. Though thought to be ‘cost effective’, analysis of cost effectiveness centres on cost to a health care system and not to the individual. The individual most often commit to taking a drug daily, indefinitely and often at their own expense. The Cochrane analysis estimates that of 1000 people taking a statin for 5 years, 18 would avoid a major cardiovascular disease event(for example a heart attack or stroke). The HOPE trial reported that statin therapy resulted in 26.5% lower risk of the main adverse outcome studied. In absolute terms, 305 (of 6344) of those on placebo had an adverse outcome compared with 235 (of 6361) participants on the statin therapy, out of a total of 12,705 participants. So with a statin the chance of the adverse outcome is 3.7%, increased to 4.5% on placebo. Whether or not this benefit is enough to warrant lifelong medication, is a decision which potential patients might wish to be included in, bearing in mind that the great majority of patients taking life-long statins will see no benefit allowing only very small proportion to benefit greatly.
The potential for harmful effects related to statin therapy also requires consideration. Potentially fatal adverse effects are very rare. A link with cancer has been proposed but not proven or even demonstrated in any of the large trials, some of which have shown improvement in all cause mortality. Most trials examined the potential for this effect for up to 5 years of therapy, the West of Scotland Conorary Prevention Study to 10 years(6). Follow-up analysis of the Jupiter study(7) published after 4 years reported, not for the first time, an increased risk of diabetes in the statin treated patients (a risk significantly offset by reduced risks of cardiovascular events and death and of developing clots(8)). There was an increase in the number of patients undergoing cataract surgery in the statin group (3.8% versus 3.1%) in the HOPE trial, also reported in other studies. Perhaps the most commonly reported adverse effect of statin therapy is muscle pain. In the HOPE study, more participants in the statin group than in the placebo group reported muscle symptoms, 5.8% versus 4.7% ( though similar numbers in both groups reported symptoms requiring discontinuation of treatment (1%).Muscle symptoms have been suggested to occur in up to 20% of patients treated. Recent animal studies have shown that statin associated myopathy reduces exercise capacity in mice(9), the inference being that those on statin might be less inclined to exercise, which is at least as important if not more important important for cardiovascular disease prevention . There is yet no clinical evidence to support this theory. A more general concern of those cautioning against statin therapy for otherwise healthy people is that emphasis is taken off lifestyle and dietary advice, replacing perhaps more important measures such as improving cardiovascular fitness(10) with a pill.
Conclusion: For those with no previous cardiovascular problems, but judged to be at increased risk of the disease, the HOPE-3 trial reports that daily rosuvastatin results in a significantly lower risk of death, heart attack or stroke. Before deciding to take this medication for the long term, patients should be informed of the benefit is absolute terms; to prevent a premature adverse outcome in 1 person, 125 people would need to be taking the medication, with possibly with no benefit, for 5 years. Medication should not be a substitute for other risk reducing strategies in particular smoking cessation, daily exercise and dietary discretion.
Brian J Manning
May 30th 2017.
- Yusuf S, Bosch J, Dagenais G, et al. Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med. May 26;374(21):2021-2031.
- Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. Nov 19 1994;344(8934):1383-1389.
- Chou R, Dana T, Blazina I, Daeges M, Jeanne TL. Statins for Prevention of Cardiovascular Disease in Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. Nov 15;316(19):2008-2024.
- Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. Aug 01;37(29):2315-2381.
- Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. Jan 31 (1):CD004816.
- Ford I, Murray H, Packard CJ, Shepherd J, Macfarlane PW, Cobbe SM. Long-term follow-up of the West of Scotland Coronary Prevention Study. N Engl J Med. Oct 11 2007;357(15):1477-1486.
- Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. Nov 20 2008;359(21):2195-2207.
- Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. Aug 11;380(9841):565-571.
- Chung HR, Vakil M, Munroe M, et al. The Impact of Exercise on Statin-Associated Skeletal Muscle Myopathy. PLoS One.11(12):e0168065.
- Sui X, LaMonte MJ, Blair SN. Cardiorespiratory fitness as a predictor of nonfatal cardiovascular events in asymptomatic women and men. Am J Epidemiol. Jun 15 2007;165(12):1413-1423.