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Meta-Analysis of Usefulness of Treatment of Hypercholesterolemia With Statins for Primary Prevention in Patients Older Than 75 Years
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Meta-analysis of Usefulness of Treatment of Hypercholesterolemia with Statins For Primary Prevention in Patients Older Than 75 Years John B. Kostis MD, DPhil , Michail Giakoumis MD, PhD , Stavros Zinonos PhD , Javier Cabrera PhD , William J. Kostis PhD, MD PII: DOI: Reference:
S0002-9149(20)30061-8 https://doi.org/10.1016/j.amjcard.2020.01.020 AJC 24401
To appear in:
The American Journal of Cardiology
Received date: Revised date: Accepted date:
14 October 2019 15 January 2020 17 January 2020
Please cite this article as: John B. Kostis MD, DPhil , Michail Giakoumis MD, PhD , Stavros Zinonos PhD , Javier Cabrera PhD , William J. Kostis PhD, MD , Meta-analysis of Usefulness of Treatment of Hypercholesterolemia with Statins For Primary Prevention in Patients Older Than 75 Years, The American Journal of Cardiology (2020), doi: https://doi.org/10.1016/j.amjcard.2020.01.020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc.
Meta-analysis of Usefulness of Treatment of Hypercholesterolemia with Statins For Primary Prevention in Patients Older Than 75 Years John B. Kostis, MD, DPhila, Michail Giakoumis, MD, PhDa, Stavros Zinonos, PhDa, Javier Cabrera, PhDb, William J. Kostis, PhD, MDa a
Cardiovascular Institute, Rutgers Robert Wood Johnson Medical School, New Brunswick, New
Jersey; bDepartment of Statistics, Rutgers University, Piscataway, New Jersey
Corresponding Author: John B. Kostis, MD, DPhil Director, Cardiovascular Institute Rutgers Robert Wood Johnson Medical School 125 Paterson Street, CAB-4180A New Brunswick, NJ 08901 Phone: 732-235-7685 Fax: 732-235-7039 Email: [email protected] Funding : None. Running Head: Statins for Primary Prevention Older Patients
1
Clinical guidelines from the US and Europe do not recommend treatment with statins for primary prevention in persons with hypercholesterolemia who are older than 75 years. Data from 35 randomized controlled trials in this age group where statin therapy for primary prevention was compared to placebo or usual care were analyzed. Using all-cause death as the outcome we performed two types of analyses: frequentist and Bayesian. Frequentist analysis indicated no significant difference in mortality between cases (on statins) and controls (on placebo or usual care, p=0.16). However, in the Bayesian analysis, persons >75 years had lower mortality from treatment with statins (p=0.03). In conclusion, Bayesian analysis indicates a definite, statistically significant and clinically relevant benefit of statin treatment for primary prevention in persons >75 years of age. Keywords: primary prevention, older age, Bayesian analysis, statins
2
Statins have been successfully used to reduce the risk of cardiovascular disease (CV) for more than 30 years and they have become one of the most proven pharmacologic interventions for atherosclerotic cardiovascular disease. Current American College of Cardiology (ACC)/American Heart Association (AHA) guidelines do not recommend use of statins for primary prevention in persons >75 years of age. Also, the 2019 Task Force for the management of dyslipidemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) includes a level IIb recommendation that “initiation of statin treatment for primary prevention in people >75 years may be considered, if at high risk or above”.1 Also, there is uncertainty regarding drug safety, possible interactions, polypharmacy, and financial burden issues currently being studied by the Statin Therapy for Reducing Events in the Elderly (STAREE) trial.2 To address the lack of sufficient information on using statins for primary prevention in people >75 years, we analyzed 35 randomized clinical trials using a Bayesian approach. Methods We performed a systematic literature search of MEDLINE, EMBASE, and the Cochrane Library for the following MeSH terms: “hyperlipidemia”, “hypercholesterolemia”, “statins”, “simvastatin”, “rosuvastatin”, “pravastatin”, “lovastatin”, “fluvastatin”, “atorvastatin”, “pitavastatin”, “cerivastatin”, “clinical trials”, and “coronary heart disease” through August 2019. Additional studies were identified from the 2019 Cholesterol Treatment Trialists Collaboration Metanalysis and the 2016 US Preventive Services Task Force systematic review.3,4 Randomized clinical trials published in English with placebo or usual care control and with the outcome of all-cause death were included in the analysis. Data on patients older than 75 were reported in 21 trials while 14 trials did not include data on individuals older than 75. The
3
outcome of this study was all-cause death. A total of 35 randomized controlled trials were selected.5-39 Twenty one of the 35 studies included data on persons >75 years as well as <75 and 14 studies had only data on persons <75. The studies were analyzed using both the frequentist and Bayesian approaches. For all-cause death, the log of the risk ratio (treatment/placebo) was modeled by a normal distribution. The prior distribution was assumed to have a mean equal to a weighted average of the logarithm of risk ratio (RR) with weights equal to the inverse of the sum of the estimates of between study variability and within study variability plus a drift term. The prior variance was divided into two components, an estimate of between-study variability and an estimate of within-study variability. The posterior distribution was calculated using Bayes’ rule and the 95% confidence interval was determined using the highest posterior density region.40 In toto, 192,079 individuals and 18,260 deaths were included in this analysis and were subdivided into 2 groups: patients aged 75 or younger versus patients older than 75. Data were extracted by two reviewers (JBK, MG) independently and disagreements were adjudicated by face to face discussion. Results For all cause death, frequentist analysis did not indicate a significant effect of treating patients older than 75 with statins (p=0.16, Figure). In contrast, using Bayesian analysis, the 95% confidence interval is less than 0 which indicates that there is an effect. Using this approach there is a 95% probability that the older individuals will have a lower mortality rate from treatment with statins compared to those not treated with statins (p=0.03). The number of individuals >75 years was 14,483 with average age of 78.8 and standard deviation of 2.8. Of these patients, 3,189 died. In addition, the following non-fatal events occurred in the 4
participants: 840 myocardial infarctions (5.8%), 339 percutaneous coronary interventions/coronary artery bypass grafting (2.3%), and 510 strokes (3.5%). There is no issue in sampling since all published data were included. The Bayesian analysis is significant at the p value 0.03 while the frequentist analysis is not significant (p=0.16). Discussion The key finding of this report is that the Bayesian analysis of available evidence indicates that individuals older than 75 with hypercholesterolemia should use statins for primary prevention. Current guidelines for the management for hypercholesterolemia both in the U.S. and Europe do not recommend statins for older people for primary prevention.1 The primary reason for this lack of recommendation to treat was that there were no sufficient clinical trial data to recommend treatment in this population subset. This concern is supported by the frequentist analysis reported here. Discussion of the occurrence of adverse effects of statins such as drug interactions, musculoskeletal symptoms, polypharmacy, hepatotoxicity, diabetes, and hemorrhagic stroke are beyond the scope of this paper since they occur in both younger individuals and those >75 years of age. On the other hand, dementia has been reported in persons >75 years of age, but not in younger individuals using statins and some people have developed memory loss or confusion. This fear appears unfounded since there was no increased rate of dementia or decrement in cognition in randomized clinical trials and observational studies.41 In conclusion, frequentist analysis of randomized controlled trials in persons >75 years where statin therapy for primary prevention was compared to placebo or usual care indicates a
5
non-significant difference in mortality between cases (on statins) and controls (on placebo or usual care, p=0.16). Bayesian analysis indicates a definite, statistically significant (p=0.03) and clinically relevant benefit of statin treatment for primary prevention in persons >75 years of age. This should be considered in future guidelines. Disclosures The authors have no conflict of interest to disclose.
6
1. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2019. Doi/10.1093/eurheartj/ehz455. 2. O’Hare F, Sparks S, Flanagan Z, Heritier S, Curtis A, Zoungas S; STAREE investigator Group. Impact of informed consent content and length on recruitment of older adults into a community based primary prevention trial. Contemp Clin Trials Commun 2018;11:8994. 3. Cholesterol Treatment Trialists' Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet 2019;393:407-415. 4. 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 2016;316:2008-2024. 5. Kjekshus J, Apetrei E, Barrios V, Böhm M, Cleland JG, Cornel JH, Dunselman P, Fonseca C, Goudev A, Grande P, Gullestad L, Hjalmarson A, Hradec J, Jánosi A, Kamenský G, Komajda M, Korewicki J, Kuusi T, Mach F, Mareev V, McMurray JJ, Ranjith N, Schaufelberger M, Vanhaecke J, van Veldhuisen DJ, Waagstein F, Wedel H, Wikstrand J; CORONA Group. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357:2248-2261. 6. Yusuf S, Bosch J, Dagenais G, Zhu J, Xavier D, Liu L, Pais P, López-Jaramillo P, Leiter LA, Dans A, Avezum A, Piegas LS, Parkhomenko A, Keltai K, Keltai M, Sliwa K, Peters
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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;374:2021-2031. 7. Wanner C, Krane V, März W, Olschewski M, Mann JF, Ruf G, Ritz E. German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;353:238-248. 8. Fellström BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J, Chae DW, Chevaile A, Cobbe SM, Grönhagen-Riska C, De Lima JJ, Lins R, Mayer G, McMahon AW, Parving HH, Remuzzi G, Samuelsson O, Sonkodi S, Sci D, Süleymanlar G, Tsakiris D, Tesar V, Todorov V, Wiecek A, Wüthrich RP, Gottlow M, Johnsson E, Zannad F; AURORA Study Group. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009;360:1395-1407. 9. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-2207. 10. GISSI Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico). Results of the low-dose (20 mg) pravastatin GISSI Prevenzione trial in 4271 patients with recent myocardial infarction: do stopped trials contribute to overall knowledge? Ital Heart J 2000;1:810-820. 11. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.
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Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002;288:2998-3007. 12. Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J; ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361:1149-1158. 13. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer 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;333:1301-1307. 14. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279:1615-1622. 15. Serruys PW, de Feyter P, Macaya C, Kokott N, Puel J, Vrolix M, Branzi A, Bertolami MC, Jackson G, Strauss B, Meier B; Lescol Intervention Prevention Study (LIPS) Investigators. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;287:32153222.
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16. Holdaas H, Fellström B, Jardine AG, Holme I, Nyberg G, Fauchald P, Grönhagen-Riska C, Madsen S, Neumayer HH, Cole E, Maes B, Ambühl P, Olsson AG, Hartmann A, Solbu DO, Pedersen TR; Assessment of LEscol in Renal Transplantation (ALERT) Study Investigators. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 2003;361:2024-2031. 17. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH; CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebocontrolled trial. Lancet 2004;364:685-696. 18. Koren MJ, Hunninghake DB; ALLIANCE Investigators. Clinical outcomes in managedcare patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the alliance study. J Am Coll Cardiol 2004;44:1772-1779. 19. Knopp RH, d’Emden M, Smilde JG, Pocock SJ. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN). Diabetes Care 2006;29:1478-1485. 20. Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y, Toyota T, Nakaya N, Nishimoto S, Muranaka M, Yamamoto A, Mizuno K, Ohashi Y; MEGA Study Group. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet 2006;368:1155-1163. 21. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM; Pravastatin or Atorvastatin Evaluation and Infection
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Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-1504. 22. de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, White HD, Rouleau JL, Pedersen TR, Gardner LH, Mukherjee R, Ramsey KE, Palmisano J, Bilheimer DW, Pfeffer MA, Califf RM, Braunwald E; Investigators. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004;292:1307-1316. 23. Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med 1997;336:153162. 24. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-1435. 25. Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, Larsen ML, Bendiksen FS, Lindahl C, Szarek M, Tsai J; Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005;294:2437-2445. 26. Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, Armitage J, Bowman L, Wallendszus K, Bulbulia R,
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Rahimi K, Haynes R, Parish S, Peto R, Collins R. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet 2010;376:1658-1669. 27. Miettinen TA, Pyörälä K, Olsson AG, Musliner TA, Cook TJ, Faergeman O, Berg K, Pedersen T, Kjekshus J. Cholesterol-lowering therapy in women and elderly patients with myocardial infarction or angina pectoris: findings from the Scandinavian Simvastatin Survival Study (4S). Circulation 1997;96:4211-4218. 28. Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-1357. 29. Lewis SJ, Moye LA, Sacks FM, Johnstone DE, Timmis G, Mitchell J, Limacher M, Kell S, Glasser SP, Grant J, Davis BR, Pfeffer MA, Braunwald E. Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range. Results of the Cholesterol and Recurrent Events (CARE) trial. Ann Intern Med 1998;129:681-689. 30. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22. 31. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C, Westendorp RG; PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in
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elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623-1630. 32. Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, Lucci D, Nicolosi GL, Porcu M, Tognoni G; Gissi-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372:1231-1239. 33. Athyros VG, Papageorgiou AA, Mercouris BR, Athyrou VV, Symeonidis AN, Basayannis EO, Demitriadis DS, Kontopoulos AG. Treatment with atorvastatin to the National Cholesterol Educational Program goal versus 'usual' care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Curr Med Res Opin 2002;18:220-228. 34. Beishuizen ED, van de Ree MA, Jukema JW, Tamsma JT, van der Vijver JC, Meinders AE, Putter H, Huisman MV. Two-year statin therapy does not alter the progression of intima-media thickness in patients with type 2 diabetes without manifest cardiovascular disease. Diabetes Care 2004;27:2887-2892. 35. Bone HG, Kiel DP, Lindsay RS, Lewiecki EM, Bolognese MA, Leary ET, Lowe W, McClung MR. Effects of atorvastatin on bone in postmenopausal women with dyslipidemia: a double-blind, placebo-controlled, dose-ranging trial. J Clin Endocrinol Metab 2007;92:4671-4677. 36. Salonen R, Nyyssönen K, Porkkala E, Rummukainen J, Belder R, Park JS, Salonen JT. Kuopio Atherosclerosis Prevention Study (KAPS): a population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Circulation 1995;92:1758-1764.
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37. Crouse JR III, Raichlen JS, Riley WA, Evans GW, Palmer MK, O'Leary DH, Grobbee DE, Bots ML; METEOR Study Group. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. JAMA 2007;297:1344-1353. 38. Asselbergs FW, Diercks GFH, Hillege HL, van Boven AJ, Janssen WM, Voors AA, de Zeeuw D, de Jong PE, van Veldhuisen DJ, van Gilst WH; Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT) Investigators. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation 2004;110:2809-2816. 39. Anderssen SA, Hjelstuen AK, Hjermann I, Bjerkan K, Holme I. Fluvastatin and lifestyle modification for reduction of carotid intima-media thickness and left ventricular mass progression in drug-treated hypertensives. Atherosclerosis 2005;178:387-397. 40. Lehman EL, Casella G. (1998). Theory of point estimation. Second edition. New York, NY: Springer-Verlag. 41. Power MC, Weuve J, Sharrett AR, Blacker D, Gottesman RF. Statins, cognition, and dementia-a systematic review and methodological commentary. Nat Rev Neurol 2015;11:220-229.
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Figure Legend
For all-cause death frequentist analysis indicated a non-significant effect for treating patients older than 75 with statins. However, using Bayesian analysis, a significant benefit in terms of allcause death is observed.
Red line is the prior distribution
Black line shows data in studies on patients older than 75
Green line is posterior distribution after consideration of the prior distribution and the data available on patients older than 75 using Bayes’ rule
15
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Meta-analysis of Usefulness of Treatment of Hypercholesterolemia with Statins For Primary Prevention in Patients Older Than 75 Years John B. Kostis MD, DPhil , Michail Giakoumis MD, PhD , Stavros Zinonos PhD , Javier Cabrera PhD , William J. Kostis PhD, MD PII: DOI: Reference:
S0002-9149(20)30061-8 https://doi.org/10.1016/j.amjcard.2020.01.020 AJC 24401
To appear in:
The American Journal of Cardiology
Received date: Revised date: Accepted date:
14 October 2019 15 January 2020 17 January 2020
Please cite this article as: John B. Kostis MD, DPhil , Michail Giakoumis MD, PhD , Stavros Zinonos PhD , Javier Cabrera PhD , William J. Kostis PhD, MD , Meta-analysis of Usefulness of Treatment of Hypercholesterolemia with Statins For Primary Prevention in Patients Older Than 75 Years, The American Journal of Cardiology (2020), doi: https://doi.org/10.1016/j.amjcard.2020.01.020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc.
Meta-analysis of Usefulness of Treatment of Hypercholesterolemia with Statins For Primary Prevention in Patients Older Than 75 Years John B. Kostis, MD, DPhila, Michail Giakoumis, MD, PhDa, Stavros Zinonos, PhDa, Javier Cabrera, PhDb, William J. Kostis, PhD, MDa a
Cardiovascular Institute, Rutgers Robert Wood Johnson Medical School, New Brunswick, New
Jersey; bDepartment of Statistics, Rutgers University, Piscataway, New Jersey
Corresponding Author: John B. Kostis, MD, DPhil Director, Cardiovascular Institute Rutgers Robert Wood Johnson Medical School 125 Paterson Street, CAB-4180A New Brunswick, NJ 08901 Phone: 732-235-7685 Fax: 732-235-7039 Email: [email protected] Funding : None. Running Head: Statins for Primary Prevention Older Patients
1
Clinical guidelines from the US and Europe do not recommend treatment with statins for primary prevention in persons with hypercholesterolemia who are older than 75 years. Data from 35 randomized controlled trials in this age group where statin therapy for primary prevention was compared to placebo or usual care were analyzed. Using all-cause death as the outcome we performed two types of analyses: frequentist and Bayesian. Frequentist analysis indicated no significant difference in mortality between cases (on statins) and controls (on placebo or usual care, p=0.16). However, in the Bayesian analysis, persons >75 years had lower mortality from treatment with statins (p=0.03). In conclusion, Bayesian analysis indicates a definite, statistically significant and clinically relevant benefit of statin treatment for primary prevention in persons >75 years of age. Keywords: primary prevention, older age, Bayesian analysis, statins
2
Statins have been successfully used to reduce the risk of cardiovascular disease (CV) for more than 30 years and they have become one of the most proven pharmacologic interventions for atherosclerotic cardiovascular disease. Current American College of Cardiology (ACC)/American Heart Association (AHA) guidelines do not recommend use of statins for primary prevention in persons >75 years of age. Also, the 2019 Task Force for the management of dyslipidemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) includes a level IIb recommendation that “initiation of statin treatment for primary prevention in people >75 years may be considered, if at high risk or above”.1 Also, there is uncertainty regarding drug safety, possible interactions, polypharmacy, and financial burden issues currently being studied by the Statin Therapy for Reducing Events in the Elderly (STAREE) trial.2 To address the lack of sufficient information on using statins for primary prevention in people >75 years, we analyzed 35 randomized clinical trials using a Bayesian approach. Methods We performed a systematic literature search of MEDLINE, EMBASE, and the Cochrane Library for the following MeSH terms: “hyperlipidemia”, “hypercholesterolemia”, “statins”, “simvastatin”, “rosuvastatin”, “pravastatin”, “lovastatin”, “fluvastatin”, “atorvastatin”, “pitavastatin”, “cerivastatin”, “clinical trials”, and “coronary heart disease” through August 2019. Additional studies were identified from the 2019 Cholesterol Treatment Trialists Collaboration Metanalysis and the 2016 US Preventive Services Task Force systematic review.3,4 Randomized clinical trials published in English with placebo or usual care control and with the outcome of all-cause death were included in the analysis. Data on patients older than 75 were reported in 21 trials while 14 trials did not include data on individuals older than 75. The
3
outcome of this study was all-cause death. A total of 35 randomized controlled trials were selected.5-39 Twenty one of the 35 studies included data on persons >75 years as well as <75 and 14 studies had only data on persons <75. The studies were analyzed using both the frequentist and Bayesian approaches. For all-cause death, the log of the risk ratio (treatment/placebo) was modeled by a normal distribution. The prior distribution was assumed to have a mean equal to a weighted average of the logarithm of risk ratio (RR) with weights equal to the inverse of the sum of the estimates of between study variability and within study variability plus a drift term. The prior variance was divided into two components, an estimate of between-study variability and an estimate of within-study variability. The posterior distribution was calculated using Bayes’ rule and the 95% confidence interval was determined using the highest posterior density region.40 In toto, 192,079 individuals and 18,260 deaths were included in this analysis and were subdivided into 2 groups: patients aged 75 or younger versus patients older than 75. Data were extracted by two reviewers (JBK, MG) independently and disagreements were adjudicated by face to face discussion. Results For all cause death, frequentist analysis did not indicate a significant effect of treating patients older than 75 with statins (p=0.16, Figure). In contrast, using Bayesian analysis, the 95% confidence interval is less than 0 which indicates that there is an effect. Using this approach there is a 95% probability that the older individuals will have a lower mortality rate from treatment with statins compared to those not treated with statins (p=0.03). The number of individuals >75 years was 14,483 with average age of 78.8 and standard deviation of 2.8. Of these patients, 3,189 died. In addition, the following non-fatal events occurred in the 4
participants: 840 myocardial infarctions (5.8%), 339 percutaneous coronary interventions/coronary artery bypass grafting (2.3%), and 510 strokes (3.5%). There is no issue in sampling since all published data were included. The Bayesian analysis is significant at the p value 0.03 while the frequentist analysis is not significant (p=0.16). Discussion The key finding of this report is that the Bayesian analysis of available evidence indicates that individuals older than 75 with hypercholesterolemia should use statins for primary prevention. Current guidelines for the management for hypercholesterolemia both in the U.S. and Europe do not recommend statins for older people for primary prevention.1 The primary reason for this lack of recommendation to treat was that there were no sufficient clinical trial data to recommend treatment in this population subset. This concern is supported by the frequentist analysis reported here. Discussion of the occurrence of adverse effects of statins such as drug interactions, musculoskeletal symptoms, polypharmacy, hepatotoxicity, diabetes, and hemorrhagic stroke are beyond the scope of this paper since they occur in both younger individuals and those >75 years of age. On the other hand, dementia has been reported in persons >75 years of age, but not in younger individuals using statins and some people have developed memory loss or confusion. This fear appears unfounded since there was no increased rate of dementia or decrement in cognition in randomized clinical trials and observational studies.41 In conclusion, frequentist analysis of randomized controlled trials in persons >75 years where statin therapy for primary prevention was compared to placebo or usual care indicates a
5
non-significant difference in mortality between cases (on statins) and controls (on placebo or usual care, p=0.16). Bayesian analysis indicates a definite, statistically significant (p=0.03) and clinically relevant benefit of statin treatment for primary prevention in persons >75 years of age. This should be considered in future guidelines. Disclosures The authors have no conflict of interest to disclose.
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Figure Legend
For all-cause death frequentist analysis indicated a non-significant effect for treating patients older than 75 with statins. However, using Bayesian analysis, a significant benefit in terms of allcause death is observed.
Red line is the prior distribution
Black line shows data in studies on patients older than 75
Green line is posterior distribution after consideration of the prior distribution and the data available on patients older than 75 using Bayes’ rule
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