Discontinuing statins or not in the elderly? Study protocol for a randomized controlled trial

Fabrice Bonnet, Antoine Bénard, Pierre Poulizac, Mélanie Afonso, Aline Maillard, Francesco Salvo, Driss Berdaï, Nathalie Salles, Nicolas Rousselot, Sébastien Marchi, Nathalie Hayes, Jean-Philippe Joseph, Fabrice Bonnet, Antoine Bénard, Pierre Poulizac, Mélanie Afonso, Aline Maillard, Francesco Salvo, Driss Berdaï, Nathalie Salles, Nicolas Rousselot, Sébastien Marchi, Nathalie Hayes, Jean-Philippe Joseph

Abstract

Background: The risk/benefit ratio of using statins for primary prevention of cardiovascular (CV) events in elderly people has not been established. The main objectives of the present study are to assess the cost-effectiveness of statin cessation and to examine the non-inferiority of statin cessation in terms of mortality in patients aged 75 years and over, treated with statins for primary prevention of CV events.

Methods: The "Statins in the elderly" (SITE) study is an ongoing 3-year follow-up, open-label comparative multi-centre, randomized clinical trial that is being conducted in two parallel groups in outpatient primary care offices. Participants meeting the following criteria are included: people aged 75 years and older being treated with statins as primary prevention for CV events, who provide informed consent. After randomization, patients in the statin-cessation strategy are instructed to withdraw their treatment. In the comparison strategy, patients continue their statin treatment at the usual dosage. The cost-effectiveness of the statin-cessation strategy compared to continuing statins will be estimated through the incremental cost per quality-adjusted life years (QALYs) gained at 36 months, from the perspective of the French healthcare system. Overall mortality will be the primary clinical endpoint. We assumed that the mortality rate at 3 years will be 15%. The sample size was computed to achieve 90% power in showing the non-inferiority of statin cessation, assuming a non-inferiority margin of 5% of the between-group difference in overall mortality. In total, the SITE study will include 2430 individuals.

Discussion: There is some debate on the value of statins in people over 75 years old, especially for primary prevention of CV events, due to a lack of evidence of their efficacy in this population, potential compliance-related events, drug-drug interactions and side effects that could impair quality of life. Data from clinical trials guide the initiation of medication therapy for primary or secondary prevention of CV disease but do not define the timing, safety, or risks of discontinuing the agents. The SITE study is one of the first to examine whether treatment cessation is a cost-effective and a safe strategy in people of 75 years and over, formerly treated with statins.

Trial registration: ClinicalTrials.gov: NCT02547883. Registered on 11 September 2015.

Keywords: Cost-effectiveness analysis; Elderly patients; Mortality; Primary prevention; Randomized controlled trial; Statins.

Conflict of interest statement

The authors declare that they have no competing interests.

References

    1. Moran AE, Forouzanfar MH, Roth GA, Mensah GA, Ezzati M, Murray CJ, Naghavi M. Temporal trends in ischemic heart disease mortality in 21 world regions, 1980 to 2010: the Global Burden of Disease 2010 study. Circulation. 2014;129:1483–1492. doi: 10.1161/CIRCULATIONAHA.113.004042.
    1. The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice 2016 European Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2016;37:2315–2381. doi: 10.1093/eurheartj/ehw106.
    1. A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. 2019 ACC/AHA Guideline on the primary prevention of cardiovascular disease. J Am Coll Cardiol. 2019. 10.1016/j.jacc.2019.03.010 [Epub ahead of print].
    1. Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013. 10.1002/14651858.CD004816.
    1. Population par sexe et groupe d'âges en 2019. . Accessed 31 May 2019.
    1. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AM, Jr, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–2207. doi: 10.1056/NEJMoa0807646.
    1. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623–1630. doi: 10.1016/S0140-6736(02)11600-X.
    1. Glynn RJ, Koenig W, Nordestgaard BG, Shepherd J, Ridker PM. Rosuvastatin for primary prevention in older individuals with high C-reactive protein and low LDL levels: exploratory analysis of a randomized trial. Ann Intern Med. 2010;152:488–496. doi: 10.7326/0003-4819-152-8-201004200-00005.
    1. Collier DJ, Poulter NR, Dahlöf B, Sever PS, Wedel H, Buch J, Caulfield MJ. Impact of atorvastatin among older and younger patients in the Anglo-Scandinavian Cardiac Outcomes Trial Lipid-Lowering Arm. ASCOT Investigators. J Hypertens. 2011;29:592–599. doi: 10.1097/HJH.0b013e328342c8f7.
    1. Savarese G, Gotto AM, Jr, Paolillo S, D'Amore C, Losco T, Musella F, et al. Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis. J Am Coll Cardiol. 2013;62:2090–2099. doi: 10.1016/j.jacc.2013.07.069.
    1. Alpérovitch A, Kurth T, Bertrand M, Ancelin ML, Helmer C, Debette S, Tzourio C. Primary prevention with lipid lowering drugs and long term risk of vascular events in older people: population based cohort study. BMJ. 2015. 10.1136/bmj.h2335.
    1. Anum EA, Adera T. Hypercholesterolemia and coronary heart disease in the elderly: a meta-analysis. Ann Epidemiol. 2004;14:705–721. doi: 10.1016/j.annepidem.2003.10.009.
    1. Prospective Studies Collaboration Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55 000 vascular deaths. Lancet. 2007;370:1829–1839. doi: 10.1016/S0140-6736(07)61778-4.
    1. Petersen LK, Christensen J, Kragstrup J. Lipid-lowering treatment to the end? A review of observational studies and RCTs on cholesterol and mortality in 80+−year olds. Age Ageing. 2010;39:674–680. doi: 10.1093/ageing/afq129.
    1. Chokshi NP, Messerli FH, Sutin D, Supariwala A, Shah NR. Appropriateness of statins in patients aged >80 years and comparison to other age groups. Am J Cardiol. 2012;110:1477–1481. doi: 10.1016/j.amjcard.2012.06.058.
    1. Goldfine AB. Statins: is it really time to reassess benefits and risks? N Engl J Med. 2012;366:19. doi: 10.1056/NEJMp1203020.
    1. Kutner JS, Blatchford PJ, Taylor DH, Ritchie CS, Bull JH, Fairclough DL, et al. Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting Illness: a randomized clinical trial. JAMA Intern Med. 2015;175:691–700. doi: 10.1001/jamainternmed.2015.0289.
    1. Chevalier J, De Pouvourville G. Valuing EQ-5D using time trade-off in France. Eur J Health Econ. 2013;14:57–66. doi: 10.1007/s10198-011-0351-x.
    1. Tuppin P, Rudant J, Constantinou P, Gastaldi-Menager C, Rachas A, de Roquefeuil L, et al. Value of a national administrative database to guide public decisions: from the systeme national d'information interregimes de l'Assurance Maladie (SNIIRAM) to the systeme national des donnees de sante (SNDS) in France. Rev Epidemiol Sante Publique. 2017;65(Suppl 4):S149–SS67. doi: 10.1016/j.respe.2017.05.004.
    1. Claxton K. The irrelevance of inference: a decision-making approach to the stochastic evaluation of health care technologies. J Health Econ. 1999;18:341–364. doi: 10.1016/S0167-6296(98)00039-3.
    1. Golomb BA. Implications of statin adverse effects in the elderly. Expert Opin Drug Saf. 2005;4:389–397. doi: 10.1517/14740338.4.3.389.
    1. Majeed A. Statins for primary prevention of cardiovascular disease. BMJ. 2014. 10.1136/bmj.g3491.
    1. McClure DL, Valuck RJ, Glanz M, Hokanson JE. Systematic review and meta-analysis of clinically relevant adverse events from HMG CoA reductase inhibitor trials worldwide from 1982 to present. Pharmacoepidemiol Drug Saf. 2007;16:132–143. doi: 10.1002/pds.1341.
    1. Bruckert E, Hayem G, Dejager S, Yau C, Begaud B. Mild to moderate muscular symptoms with highdosage statin therapy in hyperlipidemic patients–the PRIMO study. Cardiovasc Drugs Ther. 2005;19:403–414. doi: 10.1007/s10557-005-5686-z.
    1. Buettner C, Rippberger MJ, Smith JK, Leveille SG, Davis RB, Mittleman MA. Statin use and musculoskeletal pain among adults with and without arthritis. Am J Med. 2012;125:176–182. doi: 10.1016/j.amjmed.2011.08.007.
    1. Desai CS, Martin SS, Blumentha RS. Non-cardiovascular effects associated with statins. BMJ. 2014. 10.1136/bmj.g3743.
    1. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375:735–742. doi: 10.1016/S0140-6736(09)61965-6.
    1. Lee DS, Markwardt S, Goeres L, Lee CG, Eckstrom E, Williams C, et al. Statins and physical activity in older men: the osteoporotic fractures in men study. JAMA Intern Med. 2014;174:1263–1270. doi: 10.1001/jamainternmed.2014.2266.
    1. Golomb BA, Evans MA, Dimsdale JE, White HL. Effects of statins on energy and fatigue with exertion: results from a randomized controlled trial. Arch Intern Med. 2012;172:1180–1182.
    1. Lin L, Teng M, Zhao YJ, Khoo AL, Seet RC, Yong QW, et al. Long-term cost-effectiveness of statin treatment for primary prevention of cardiovascular disease in the Elderly. Cardiovasc Drugs Ther. 2015;29:187–197. doi: 10.1007/s10557-015-6584-7.
    1. Odden MC, Pletcher MJ, Coxson PG, Thekkethala D, Guzman D, Heller D, et al. Cost-effectiveness and population impact of statins for primary prevention in adults aged 75 years and older in the United States. Ann Int Med. 2015;162:533–545. doi: 10.7326/M14-1430.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner