HHS Public Access Author manuscript Author Manuscript
JAMA Cardiol. Author manuscript; available in PMC 2016 October 06. Published in final edited form as: JAMA Cardiol. 2016 June 1; 1(3): 341–349. doi:10.1001/jamacardio.2016.0218.
DRUGS FOR PRIMARY PREVENTION OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE: AN OVERVIEW OF SYSTEMATIC REVIEWS Kunal N. Karmali1, Donald M. Lloyd-Jones1, Mark Berendsen2, David C. Goff3, Darshak M. Sanghavi4, Nina Brown4, Liliya Korenovska5, and Mark D. Huffman1
Author Manuscript
1Departments
of Preventive Medicine and Medicine-Cardiology, Northwestern University Feinberg School of Medicine, Chicago, USA 2Galter Health Sciences Library, Northwestern University Feinberg School of Medicine, Chicago, USA 3Colorado School of Public Health, University of Colorado Anschutz Medical Center, Colorado, USA 4Center for Medicare and Medicaid Services, Baltimore, Maryland
Abstract Importance—The Million Hearts initiative emphasizes the “ABCS” - aspirin, blood pressure control, cholesterol management, and smoking cessation. Evidence for the effects of drugs used to achieve the ABCS has not been comprehensively synthesized in primary atherosclerotic cardiovascular disease (ASCVD) prevention.
Author Manuscript
Objective—To compare the efficacy and safety of aspirin, blood pressure-lowering therapy, statin, and tobacco cessation drugs on fatal and non-fatal ASCVD outcomes in primary ASCVD prevention.
Author Manuscript
Evidence Review—Structured search of the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database (HTA), MEDLINE, EMBASE, and PROSPERO International Prospective Systematic Review Trial Register to identify systematic reviews published from January 1, 2005, to June 17, 2015, that reported the effect of aspirin, BP-lowering therapy, statin, or tobacco cessation drugs on ASCVD events in individuals without prevalent ASCVD. Additional studies were identified by searching the reference lists of included systematic reviews, meta-analyses, and health technology assessment reports. Reviews were selected according to predefined criteria and appraised formethodologic quality using the Assessment of Multiple Systematic Reviews (AMSTAR) tool (range, 0–11). Studies were independently reviewed for key participant and intervention characteristics. Outcomes that were meta-analyzed in each included review were extracted. Qualitative synthesis was performed, and data were analyzed from July 2 to August 13, 2015.
Corresponding address: Mark D. Huffman, Northwestern University Feinberg School of Medicine, Department of Preventive Medicine, 680 N. Lake Shore Drive, Suite 1400, Chicago, IL 60660, [email protected], T: 312-503-5513. 5Senior Healthcare Analyst at MITRE Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Additional Contributions: Janet S. Wright, MD, Executive Director, Million Hearts initiative, Centers for Disease Control provided input in preparing this manuscript.
Karmali et al.
Page 2
Author Manuscript
Findings—From a total of 1967 reports, 35 systematic reviews of randomized clinical trials were identified, including 15 reviews of aspirin, 4 reviews of BP-lowering therapy, 12 reviews of statins, and 4 reviews of tobacco cessation drugs. Methodologic quality varied, but 30 reviews had AMSTAR ratings of 5 or higher. Compared with placebo, aspirin (relative risk [RR], 0.90; 95%CI, 0.85–0.96) and statins (RR, 0.75; 95%CI, 0.70–0.81) reduced the risk for ASCVD. Compared with placebo, BP-lowering therapy reduced the risk for coronary heart disease (RR, 0.84; 95%CI, 0.79– 0.90) and stroke (RR, 0.64; 95%CI, 0.56–0.73). Tobacco cessation drugs increased the odds of continued abstinence at 6 months (odds ratio range, 1.82 [95%CI, 1.60–2.06] to 2.88 [95%CI, 2.40–3.47]), but the direct effects on ASCVD were poorly reported. Aspirin increased the risk for major bleeding (RR, 1.54; 95%CI, 1.30–1.82), and statins did not increase overall risk for adverse effects (RR, 1.00; 95%CI, 0.97–1.03). Adverse effects of BP-lowering therapy and tobacco cessation drugs were poorly reported.
Author Manuscript
Conclusions and Relevance—This overview demonstrates high quality evidence to support aspirin, blood pressure-lowering therapy, and statins for primary ASCVD prevention and tobacco cessation drugs for smoking cessation. Treatment effects of each drug can be used to enrich clinician-patient discussions in primary ASCVD prevention.
INTRODUCTION
Author Manuscript
In 2011, the United States Department of Health and Human Services launched the Million Hearts initiative to prevent 1 million heart attacks and strokes over 5 years.1 Million Hearts includes a clinical emphasis on the ABCS, that is, aspirin for high-risk patients, bloodpressure control, cholesterol management, and smoking cessation. Projections estimate that optimizing ABCS management could reduce the burden of atherosclerotic cardiovascular disease (ASCVD) substantially.2 To support the Million Hearts goal and identify new models of care delivery and payment, the Center for Medicare and Medicaid Innovation launched the Million Hearts Cardiovascular Risk Reduction Model in 2016, a cluster randomized payment model test to evaluate the effect of value-based payment to incentivize ASCVD risk assessment and reduction. This effort requires rigorous and transparent quantification of treatment effects for aspirin, blood pressure-lowering therapy, statins, and tobacco cessation drugs in primary ASCVD prevention.3 Despite the wealth of evidence synthesis activities within individual drug classes, we are not aware of any reports that have summarized the efficacy and safety of all 4 drug classes highlighted in the Million Hearts initiative for primary ASCVD prevention.
Author Manuscript
An overview of systematic reviews is a novel approach to appraise and synthesize results from multiple systematic reviews into a single, useful document that can be used to guide health care providers and policy makers.4–7 To address this evidence gap, we performed an overview of systematic reviews to compare the efficacy and safety of aspirin, blood pressure-lowering therapy, statin, and tobacco cessation drugs on fatal and non-fatal outcomes for primary ASCVD prevention.
METHODS This overview followed guidelines outlined by the Cochrane Collaboration to synthesize effects of multiple interventions for an overarching clinical question using data from JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 3
Author Manuscript
published systematic reviews.4 We established a protocol and published it in PROSPERO.8 The clinical question guiding this overview is presented in PICOTSS (patient, intervention, comparators, outcomes, timing, setting, and study design) format (Box). We also performed a supplemental systematic review to evaluate for potential interactions when combination drug therapy is used but found none (detailed search methods and results outlined in eAppendix 1 and 2 in the Supplement). Review Eligibility Criteria
Author Manuscript
We included systematic reviews of randomized and quasi-randomized clinical trials comparing the pooled treatment effects of aspirin, blood pressure-lowering therapy, statin, or tobacco cessation drugs against placebo or usual care in adults (≥ 18 years of age) without ASCVD. For systematic reviews that included a combination of individuals with and without prevalent ASCVD, we included reviews that reported effect estimates for participants defined as “primary prevention.” When reports included both primary and secondary prevention populations, we included only those reports with 90% without prevalent vascular disease). A summary of systematic review characteristics is provided in eAppendix 3 in the Supplement.
Author Manuscript
Trial quality assessment and review quality—The authors reported that trials generally had low risk of bias, but many were funded by pharmaceutical companies.45 AMSTAR ratings ranged from a score of 5/11 to 11/11. The most comprehensive and highest rated systematic review was by Taylor et al.45
Author Manuscript
Efficacy and cardiovascular benefits—Treatment effects of statins on all-cause mortality, total cardiovascular disease events, myocardial infarction, and stroke were broadly comparable across all systematic reviews. The systematic review by Taylor et al.45 reported a 14% reduction in all-cause mortality (OR 0.86, 95% CI 0.79–0.94), 25% reduction in major cardiovascular events (RR 0.75, 95% CI 0.70–0.81), and reductions in fatal and nonfatal coronary heart disease and stroke events.45 Mean baseline (SD) low-density lipoprotein cholesterol (LDL) in CTT trials was 143.1 (27.1) mg/dL and mean (SD) difference in LDL between statin regimen and control was 41.8 mg/dL. Treatment effects standardized per 40.6 mg/dl (1 mmol/L) reduction in LDL cholesterol were also reported by the CTT for all-cause mortality (RR 0.91, 95% CI 0.85–0.97) and major vascular events (RR 0.75, 95% CI 0.70–0.80).38 Effects of statin treatment in participants with diabetes mellitus were reported in 3 systematic reviews and demonstrated similar proportional benefits compared with the general primary prevention group.36,39,41 Sex-specific treatment effects were also reported in 3 systematic reviews,34,37,43 of which one was an individual participant data metaanalysis.37 After adjusting for baseline differences in prognostic characteristics and 5-year vascular risk, no sex-specific heterogeneity was seen.37 Additional statin treatment effects are provided in eAppendix 3 in the Supplement.
Author Manuscript
Safety, Adverse effects, and other Secondary Outcomes—Data on adverse effects of statin treatment were included in 7 systematic reviews and included risks of cancer, creatine kinase elevation, rhabdomyolysis, liver enzyme elevation, hemorrhagic stroke, type 2 diabetes, and serious adverse effects.34,35,37,38,42,45,46 Taylor et al.45 reported no evidence of increased risk of overall adverse effects (defined as cancers, myalgia and rhabdomyolysis, type 2 diabetes, hemorrhagic stroke, and other adverse effects leading to treatment discontinuation) among individuals treated with statin compared to control/placebo (RR 1.00, 95% CI 0.97–1.03). However, there was an 18% increased risk for the individual outcome of type 2 diabetes for those treated with statin (RR 1.18, 95% CI 1.01–1.39).
JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 9
Author Manuscript
Data on health-related quality of life were not reported. Data on cost-effectiveness were reported in Taylor et al45 from 3 statin trials, all demonstrating cost-effectiveness of statin therapy in primary prevention. In the West of Scotland Coronary Prevention Study (WOSCOPS), statin treatment led to 2,460 years of life at £8,121 (or $12,788) per life-year gained. In the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, statin therapy had a cost-effectiveness of £25,796 (or $40,315) per quality adjusted life year. Last, in an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS), Taylor et al.45 reported an incremental cost effectiveness ratio of £2,320 (or $3,626) per quality adjusted life year at 10 years.
Author Manuscript
GRADE assessment—We rated the quality of evidence for the effect of statins on reducing the risk of all-cause mortality, major cardiovascular events, coronary heart disease events, and stroke as high. We rated the quality of evidence for the safety of statins as moderate, downgrading because of indirectness of evidence. Tobacco cessation drugs Characteristics of included reviews—We included 4 systematic reviews of tobacco cessation drugs.47–50 None of the reviews differentiated between trials that included participants with and without prevalent vascular disease. Moreover, reviews reported limited information about the effects of tobacco cessation drugs on cardiovascular outcomes or risk factors. The primary efficacy outcome for most reviews was continuous smoking cessation at 6 months. Diabetes-specific or sex-specific treatment effects were not reported. The latest search ran through 2012.48 Mean age among participants in the most comprehensive systematic review was 57 years.48
Author Manuscript
The most comprehensive systematic review was an overview of several Cochrane systematic reviews by Cahill et al. addressing drug therapy for smoking cessation.48 This overview synthesized information from 267 trials of 101,804 participants. Among the trials, there were 150 trials of nicotine replacement therapy, 72 trials of antidepressants (primarily buproprion hydrochloride), and 24 trials of nicotine receptor partial agonists (primarily varenicline tartarate). A summary of systematic review characteristics is provided in eAppedix 3 in the Supplement.
Author Manuscript
Trial quality assessment and review quality—Authors reported that trials of nicotine replacement therapy and bupropion did not clearly describe methods of randomization or allocation concealment and were therefore at “high risk of bias.” Trials of varenicline were more contemporary and generally lower risk of bias, although they were industry funded.48 AMSTAR ratings ranged from 7/11 to 11/11, and the highest rated systematic review was Cahill et al48 (eAppendix 3 in the Supplement). Efficacay and smoking cessation—The overview by Cahill et al.48 reported treatment effects of tobacco cessation drugs on 6 months of continuous smoking abstinence, which was primarily biochemically verified. The overview reported that nicotine replacement therapy, buproprion, and varenicline all increased the odds of smoking cessation at 6 months compared to placebo (nicotine replacement therapy OR 1.84, 95% CI 1.71–1.99; bupropion
JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 10
Author Manuscript
OR 1.82, 95% CI 1.60–2.06; and varenicline 2.88, 95% CI 2.40–3.47). Cahill et al.48 also reported the effects of a limited number of tobacco cessation drugs on cardiovascular disease events. However, individual studies were underpowered for this endpoint, events were poorly reported, and many trials included participants with prevalent CVD. Treatment estimates for buproprion and varenicline for smoking cessation outcomes are listed in eAppendix 3 in the Supplement. Safety, Adverse effects, and Other Secondary Outcomes—Cahill et al.48 also reported the effects of tobacco cessation drugs on serious adverse events for a limited number of therapies. For nicotine replacement therapy, limited information on serious adverse effects was reported in trials.48 Data for buproprion and varenicline were reported (RR 1.29, 95% CI 0.99–1.69 and RR 1.06, 95% CI 0.72–1.55, respectively).48 Data on health-related quality of life and direct costs were not reported.
Author Manuscript
GRADE Assessment—We rated the quality of evidence for the effect of varenicline on smoking cessation as high and the quality of evidence for the effect of buproprion and nicotine replacement therapy on smoking cessation as moderate, downgrading because of study limitations. We rated the quality of evidence for the safety of tobacco cessation drugs as moderate, downgrading because of indirectness of evidence. We rated the quality of evidence for the effect of tobacco cessation drugs on all-cause mortality and cardiovascular outcomes as low, downgrading because of study limitations, inconsistency, and imprecision.
DISCUSSION Principal findings
Author Manuscript
We performed an overview of systematic reviews that synthesized evidence of the efficacy and safety of drugs that can be used in primary ASCVD prevention to achieve targets set by the Million Hearts initiative and that will be used in the Million Hearts Cardiovascular Risk Reduction model. There is high quality evidence that aspirin, BP-lowering therapy, and statins reduce the risk of ASCVD events from 10% to 25% among individuals without prevalent ASCVD. There is also high quality evidence that BP-lowering therapy and statins reduce the risk of all-cause mortality by 11% and 14%, respectively. There was no heterogeneity in treatment effect among subgroups of individuals with diabetes mellitus or by sex. There is moderate to high quality evidence that tobacco cessation drugs increase the odds of continued abstinence by 88% to 188%, but the direct effects on cardiovascular events are uncertain. A summary of findings table is presented in the Table.
Author Manuscript
Adverse effects of drug therapy were either not reported or poorly reported in many systematic reviews, and many review authors noted “under-reporting” of adverse events in the individual trials. Our search demonstrated high quality evidence that aspirin increases the risk of major bleeding by 54% and moderate quality evidence that statins do not increase the overall risk of adverse events, but risk for type 2 diabetes mellitus was increased among individuals taking statins. Adverse effects of BP-lowering therapy and tobacco cessation drugs were poorly reported.
JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 11
Strengths
Author Manuscript
Our overview has several strengths. First, we focused this evidence synthesis on systematic reviews and meta-analyses of randomized clinical trials, because randomized clinical trials represent the highest-quality evidence to determine the effects of health care interventions. Second, we used a comprehensive, transparent search strategy to identify studies and followed a prespecified protocol to guide our evidence synthesis, noting any deviations from protocol. Third, we performed all title screening, data extraction, and quality assessments in duplicate to minimize potential bias in generation of this overview. Fourth, we used a validated instrument (the AMSTAR tool) to assess the methodologic quality of included systematic reviews and factored this quality assessment to guide our conclusions regarding the effects of pharmacologic interventions. This systematic process, with study quality assessment using standardized tools, could be used as a potential model for more rapid development of trustworthy guidelines.
Author Manuscript
Limitations
Author Manuscript
Our overview also has important limitations to acknowledge. First, we did not retrieve data from primary trials and therefore were limited to the information and judgments of the authors who wrote the systematic reviews. Selection criteria, search strategies, and definitions of primary prevention often varied between reviews, and authors of the included reviews often used different criteria to define primary prevention, which led to different numbers of trials for systematic reviews of the same drug. Second, our conclusions were limited by the available data. Although data were generally well reported for drug efficacy, limited information was reported on safety, particularly for BP-lowering therapy and tobacco cessation drugs. Third, we had limited ability to comment on the potential of differential treatment effects by race/ethnicity. Nevertheless, several reviews noted consistent proportional treatment effects regardless of baseline characteristics, suggesting that treatment effect does not demonstrate heterogeneity. Fourth, our treatment effect estimates were limited by the short-term horizon of the clinical trials. Thus, we may have underestimated the potential added benefits and risks of sustained treatment. Fifth, our overview does not include evidence from recent trials like the Japanese Primary Prevention Project (JPPP)51 or cost-effectiveness analyses of long-term statin use from WOSCOPS.52 However, inclusion of these studies would not have changed our overall conclusions. For example, the point estimate for treatment effect from low-dose aspirin in the JPPP trial was similar to our reported effect, though with wider confidence intervals (HR 0.94, 95% CI 0.77–1.15) and primary prevention statin therapy was also shown to be cost-effective at 15 years of follow-up. Finally, our overview does not provide information on the added effects of lifestyle interventions such as diet, exercise, and weight loss in combination with drug therapy. However, essentially all included clinical trials of ASCVD prevention included background recommendations of therapeutic lifestyle change in combination with study drugs.
Author Manuscript
Conclusions This overview of systematic reviews demonstrates high quality evidence to support aspirin, BP-lowering therapy, and statins for primary ASCVD prevention and tobacco cessation
JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 12
Author Manuscript
drugs for smoking cessation. It provides reliable, evidence-based pooled estimates for these interventions on the lowered risk of primary ASCVD events and best-available evidence for the effect of tobacco cessation drugs on continuous abstinence at 6 months. These treatment effects can be used to enrich discussions between health care professionals and patients.
Supplementary Material Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
Author Manuscript
Dr. Huffman reports grants from Center for Medicare and Medicaid Innovation via subcontract from the MITRE Corporation, during the conduct of the study; grants from World Heart Federation, outside the submitted work; and serves as an associate editor for JAMA Cardiology and the coordinating editor of the Cochrane Heart Group US Satellite. Dr. Lloyd-Jones reports grants from Center for Medicare and Medicaid Innovation via subcontract from the MITRE Corporation, during the conduct of the study. Funding/Support: This study was funded by the Center for Medicare and Medicaid Innovation and MITRE Corporation. Role of Funder/Sponsor: Design and conduct of the study: The work was performed to provide a synthesis of available evidence to support development of a longitudinal cardiovascular risk calculator that will be used in the Million Hearts Cardiovascular Risk Reduction Model. The Center for Medicare and Medicaid Innovation (CMMI) provided an initial description of key questions. However, the final protocol was developed independently by the authors. Collection, management, analysis, and interpretation of the data: The authors were solely responsible for data collection, management, analysis, and interpretation. Members of CMMI and MITRE Corporation reviewed a draft version of a full, more detailed report, and the final version used by the group explicitly addressed comments/ suggestions provided. Final data interpretation, including judgments of evidence quality, were solely the responsibility of the authors. Preparation, review, or approval of the manuscript: This manuscript was prepared solely by the authors, with no review or approval by the sponsor. Decision to submit the manuscript for publication: The sponsor was involved in the decision to submit the manuscript for publication in JAMA to provide transparency regarding the evidence base for the new cardiovascular risk calculator.
Author Manuscript
References
Author Manuscript
1. Frieden TR, Berwick DM. The "Million Hearts" initiative--preventing heart attacks and strokes. N. Engl. J. Med. 2011; 365(13):e27. [PubMed: 21913835] 2. Farley TA, Dalal MA, Mostashari F, Frieden TR. Deaths preventable in the U.S. by improvements in use of clinical preventive services. Am. J. Prev. Med. 2010; 38(6):600–609. [PubMed: 20494236] 3. Sanghavi DM, Conway PH. Paying for prevention: A novel test of medicare value-based payment for cardiovascular risk reduction. JAMA. 2015; 314(2):123–124. [PubMed: 26021568] 4. Higgins, JPT.; Green, Se. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration; 2011. Available from http:// www.cochrane-handbook.org [Accessed 2 February 2016] 5. Lavis JN. How can we support the use of systematic reviews in policymaking? PLoS Med. 2009; 6(11):e1000141. [PubMed: 19936223] 6. Thomson D, Russell K, Becker L, Klassen T, Hartling L. The evolution of a new publication type: Steps and challenges of producing overviews of reviews. Research synthesis methods. 2010; 1(3–4): 198–211. [PubMed: 26061466] 7. Baker PR, Costello JT, Dobbins M, Waters EB. The benefits and challenges of conducting an overview of systematic reviews in public health: a focus on physical activity. J Public Health (Oxf). 2014; 36(3):517–521. [PubMed: 25085438] 8. PROSPERO International prospective register of systematic reviews. [Accessed 2 February 2016] Available at: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015023444.
JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 13
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
9. Ebrahim S, Taylor F, Ward K, Beswick A, Burke M, Davey Smith G. Multiple risk factor interventions for primary prevention of coronary heart disease. Cochrane Database Syst Rev. 2011; (1):CD001561. [PubMed: 21249647] 10. Shea BJ, Grimshaw JM, Wells GA, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol. 2007; 7:10. [PubMed: 17302989] 11. Cheung A, Weir M, Mayhew A, Kozloff N, Brown K, Grimshaw J. Overview of systematic reviews of the effectiveness of reminders in improving healthcare professional behavior. Systematic reviews. 2012; 1:36. [PubMed: 22898173] 12. Smith V, Devane D, Begley CM, Clarke M. Methodology in conducting a systematic review of systematic reviews of healthcare interventions. BMC Med Res Methodol. 2011; 11(1):15. [PubMed: 21291558] 13. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008; 336(7650):924–926. [PubMed: 18436948] 14. Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009; 373(9678):1849–1860. [PubMed: 19482214] 15. Berger JS, Lala A, Krantz MJ, Baker GS, Hiatt WR. Aspirin for the prevention of cardiovascular events in patients without clinical cardiovascular disease: a meta-analysis of randomized trials. Am. Heart J. 2011; 162(1):115–124.e112. [PubMed: 21742097] 16. Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA. 2006; 295(3):306–313. [PubMed: 16418466] 17. Brotons C, Benamouzig R, Filipiak KJ, Limmroth V, Borghi C. A systematic review of aspirin in primary prevention: is it time for a new approach? Am J Cardiovasc Drugs. 2015; 15(2):113–133. [PubMed: 25502483] 18. Butalia S, Leung AA, Ghali WA, Rabi DM. Aspirin effect on the incidence of major adverse cardiovascular events in patients with diabetes mellitus: a systematic review and meta-analysis. Cardiovasc Diabetol. 2011; 10:25. [PubMed: 21453547] 19. Calvin AD, Aggarwal NR, Murad MH, et al. Aspirin for the primary prevention of cardiovascular events: a systematic review and meta-analysis comparing patients with and without diabetes. Diabetes Care. 2009; 32(12):2300–2306. [PubMed: 19741185] 20. De Berardis G, Sacco M, Strippoli GF, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials. BMJ. 2009; 339:b4531. [PubMed: 19897665] 21. Raju N, Sobieraj-Teague M, Hirsh J, O'Donnell M, Eikelboom J. Effect of aspirin on mortality in the primary prevention of cardiovascular disease. Am. J. Med. 2011; 124(7):621–629. [PubMed: 21592450] 22. Raju NC, Eikelboom JW. The aspirin controversy in primary prevention. Curr. Opin. Cardiol. 2012; 27(5):499–507. [PubMed: 22874127] 23. Seshasai SR, Wijesuriya S, Sivakumaran R, et al. Effect of aspirin on vascular and nonvascular outcomes: meta-analysis of randomized controlled trials. Arch. Intern. Med. 2012; 172(3):209– 216. [PubMed: 22231610] 24. Stavrakis S, Stoner JA, Azar M, Wayangankar S, Thadani U. Low-dose aspirin for primary prevention of cardiovascular events in patients with diabetes: a meta-analysis. Am. J. Med. Sci. 2011; 341(1):1–9. [PubMed: 21191260] 25. Sutcliffe P, Connock M, Gurung T, et al. Aspirin for prophylactic use in the primary prevention of cardiovascular disease and cancer: a systematic review and overview of reviews. Health Technol. Assess. 2013; 17(43):1–253. 26. Sutcliffe P, Connock M, Gurung T, et al. Aspirin in primary prevention of cardiovascular disease and cancer: a systematic review of the balance of evidence from reviews of randomized trials. PLoS One. 2013; 8(12):e81970. [PubMed: 24339983]
JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 14
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
27. Wolff T, Miller T, Ko S. Aspirin for the primary prevention of cardiovascular events: an update of the evidence for the U.S. Preventive Services Task Force. Ann. Intern. Med. 2009; 150(6):405– 410. [PubMed: 19293073] 28. Younis N, Williams S, Ammori B, Soran H. Role of aspirin in the primary prevention of cardiovascular disease in diabetes mellitus: a meta-analysis. Expert Opin Pharmacother. 2010; 11(9):1459–1466. [PubMed: 20429671] 29. Zhang C, Sun A, Zhang P, et al. Aspirin for primary prevention of cardiovascular events in patients with diabetes: A meta-analysis. Diabetes Res. Clin. Pract. 2010; 87(2):211–218. [PubMed: 19853947] 30. Diao D, Wright JM, Cundiff DK, Gueyffier F. Pharmacotherapy for mild hypertension. Cochrane Database of Systematic Reviews. 2012; 8:CD006742. [PubMed: 22895954] 31. Fretheim A, Odgaard-Jensen J, Brors O, et al. Comparative effectiveness of antihypertensive medication for primary prevention of cardiovascular disease: systematic review and multiple treatments meta-analysis. BMC Medicine. 2012; 10 32. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009; 338:b1665. [PubMed: 19454737] 33. Sundstrom J, Arima H, Jackson R, et al. Effects of blood pressure reduction in mild hypertension: a systematic review and meta-analysis. Ann. Intern. Med. 2015; 162(3):184–191. [PubMed: 25531552] 34. Brugts JJ, Yetgin T, Hoeks SE, et al. The benefits of statin therapy in patients without cardiovascular disease: Meta-analysis of randomized controlled trials. Eur. Heart J. 2009; 30:510– 511. 35. Bukkapatnam RN, Gabler NB, Lewis WR. Statins for primary prevention of cardiovascular mortality in women: a systematic review and meta-analysis. Prev Cardiol. 2010; 13(2):84–90. [PubMed: 20377811] 36. Chen YH, Feng B, Chen ZW. Statins for primary prevention of cardiovascular and cerebrovascular events in diabetic patients without established cardiovascular diseases: a meta-analysis. Experimental and clinical endocrinology & diabetes. 2012; 120(2):116–120. [PubMed: 22187291] 37. Fulcher J, O'Connell R, et al. Cholesterol Treatment Trialists C. Efficacy and safety of LDLlowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet. 2015; 385(9976):1397–1405. [PubMed: 25579834] 38. Mihaylova B, Emberson J, et al. Cholesterol Treatment Trialists C. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012; 380(9841):581–590. [PubMed: 22607822] 39. Costa J, Borges M, David C, Vaz Carneiro A. Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. BMJ. 2006; 332(7550): 1115–1124. [PubMed: 16585050] 40. Costanzo P, Perrone-Filardi P, Petretta M, et al. Impact of gender in primary prevention of coronary heart disease with statin therapy: A meta-analysis. J. Am. Coll. Cardiol. 2009; 53(10):A210. [abstract]. 41. de Vries FM, Denig P, Pouwels KB, Postma MJ, Hak E. Primary prevention of major cardiovascular and cerebrovascular events with statins in diabetic patients a meta-analysis. Drugs. 2012; 72(18):2365–2373. [PubMed: 23186103] 42. Mills EJ, Rachlis B, Wu P, Devereaux PJ, Arora P, Perri D. Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patients. J. Am. Coll. Cardiol. 2008; 52(22):1769–1781. [PubMed: 19022156] 43. Petretta M, Costanzo P, Perrone-Filardi P, Chiariello M. Impact of gender in primary prevention of coronary heart disease with statin therapy: a meta-analysis. Int. J. Cardiol. 2010; 138(1):25–31. [PubMed: 18793814] 44. Ray KK, Seshasai SR, Erqou S, et al. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. Arch. Intern. Med. 2010; 170(12):1024–1031. [PubMed: 20585067]
JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 15
Author Manuscript Author Manuscript
45. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013; 1:CD004816. [PubMed: 23440795] 46. Thavendiranathan P, Bagai A, Brookhart MA, Choudhry NK. Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials. Arch. Intern. Med. 2006; 166(21):2307–2313. [PubMed: 17130382] 47. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database of Systematic Reviews. 2012; (4):CD006103. [PubMed: 22513936] 48. Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database of Systematic Reviews. 2013; 5:CD009329. [PubMed: 23728690] 49. Ebbert J, Montori VM, Erwin PJ, Stead LF. Interventions for smokeless tobacco use cessation. Cochrane Database of Systematic Reviews. 2011; (2):CD004306. [PubMed: 21328266] 50. Secretariat MA. Population-based smoking cessation strategies: A summary of a select group of evidence-based reviews. Ontario Health Technology Assessment Series. 2010; 10(1) 51. Ikeda Y, Shimada K, Teramoto T, et al. Low-dose aspirin for primary prevention of cardiovascular events in Japanese patients 60 years or older with atherosclerotic risk factors: a randomized clinical trial. JAMA. 2014; 312(23):2510–2520. [PubMed: 25401325] 52. McConnachie A, Walker A, Robertson M, et al. Long-term impact on healthcare resource utilization of statin treatment, and its cost effectiveness in the primary prevention of cardiovascular disease: a record linkage study. Eur. Heart J. 2014; 35(5):290–298. [PubMed: 23839541]
Author Manuscript Author Manuscript JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 16
Author Manuscript
Box 1. Patients, Interventions, Comparators, Outcomes, Timing, Setting, and Study design (PICOTSS) Patients •
Adults ≥ 18 years of age
•
People without prevalent atherosclerotic cardiovascular disease (ASCVD)
•
Systematic reviews or trials that included people with Alzheimer’s disease, end-stage renal disease, macular degeneration, and aortic stenosis were excluded
Interventions
Author Manuscript
•
Aspirin
•
BP-lowering therapy
•
Statin
•
Tobacco cessation drug (i.e. nicotine replacement therapy, varenicline, buproprion)
Comparators •
Placebo
•
Usual care
Outcomes
Author Manuscript
Primary outcomes •
All-cause mortality
•
Fatal and nonfatal cardiovascular events, including myocardial infarction and stroke (ASCVD)
•
Adverse events as reported by study authors
Secondary outcomes
Author Manuscript
•
Fatal and non-fatal ischemic heart disease events, including myocardial infarction, angina, and coronary revascularization)
•
Fatal and non-fatal cerebrovascular events, including stroke and transient ischemic attack
•
Total and non-fatal ASCVD events
•
Total and low-density lipoprotein (LDL) cholesterol
•
Systolic and diastolic BP
•
Health-related quality of life
•
Direct Costs
JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 17
Timing
Author Manuscript
•
Studies of any duration
Setting •
Any setting
Study design •
Systematic reviews of randomized and quasi-randomized clinical trials
Author Manuscript Author Manuscript Author Manuscript JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 18
Author Manuscript Author Manuscript Author Manuscript Figure 1.
PRISMA flowchart for overview of systematic reviews of primary prevention drugs
Author Manuscript JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 19
Table 1
Author Manuscript
Summary of key findings for the effect of drugs for primary prevention of atherosclerotic cardiovascular diseases. Outcomes
Relative risk (95% CI)
Quality of evidence (GRADE)
Comment
All-cause mortality
RR 0.94 (95% CI 0.88–1.00)
Moderate
Downgraded due to imprecision
Major cardiovascular events
RR 0.90 (95% CI 0.85–0.96)
High
NA
Adverse effects (Major bleeding)
RR 1.54 (95% CI 1.30–1.82)
High
NA
All-cause mortality
RR 0.89 (95% CI 0.84–0.95)
High
NA
Coronary heart disease (CHD) events
RR 0.84 (95% CI 0.79–0.90)
High
NA
CHD events, standardized to a BP reduction of 10 mmHg/5mmHg
RR 0.79 (95% CI 0.72–0.86)
High
NA
Stroke events
RR 0.64 (95% CI 0.56–0.73)
High
NA
Stroke events, standardized to a BP reduction of 10 mmHg/5mmHg
RR 0.54 (95% CI 0.45–0.65)
High
NA
Adverse effects (Treatment withdrawal)
RR 4.80 (95%CI 4.14–5.57)
Low
Downgraded due to study limitations, inconsistency
All-cause mortality
OR 0.86 (95% CI 0.79–0.94)
High
NA
Major cardiovascular events
RR 0.75 (95% CI 0.70–0.81)
High
NA
Major vascular events per 1 mmol/L of LDL reduction
RR 0.75 (95% CI 0.70–0.80)
High
NA
CHD events
RR 0.73 (95% CI 0.67–0.80)
High
NA
Stroke events
RR 0.78 (95% CI 0.68–0.89)
High
NA
Adverse effects (all)
RR 1.00 (95% CI 0.97–1.03)
Moderate
Downgraded due to indirectness of evidence
Adverse effects diabetes)
RR 1.18 (95% CI 1.01–1.39)
Moderate
Downgraded due to indirectness of evidence
Nicotine replacement therapy, continuous smoking abstinence at ≥6 months
OR 1.84 (95% CI 1.71–1.99)
Moderate
Downgraded due to study limitations
Buproprion hydrochloride, continuous smoking abstinence at ≥6 months
OR 1.82 (95% CI 1.60–2.06)
Moderate
Downgraded due to study limitations
Varenicline tartarate, continuous smoking abstinence at ≥6 months
OR 2.88 (95% CI 2.40–3.47)
High
Aspirin
BP-lowering therapies
Author Manuscript
Statins
Author Manuscript
Tobacco cessation drugs
NA
Author Manuscript
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
JAMA Cardiol. Author manuscript; available in PMC 2016 October 06. Published in final edited form as: JAMA Cardiol. 2016 June 1; 1(3): 341–349. doi:10.1001/jamacardio.2016.0218.
DRUGS FOR PRIMARY PREVENTION OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE: AN OVERVIEW OF SYSTEMATIC REVIEWS Kunal N. Karmali1, Donald M. Lloyd-Jones1, Mark Berendsen2, David C. Goff3, Darshak M. Sanghavi4, Nina Brown4, Liliya Korenovska5, and Mark D. Huffman1
Author Manuscript
1Departments
of Preventive Medicine and Medicine-Cardiology, Northwestern University Feinberg School of Medicine, Chicago, USA 2Galter Health Sciences Library, Northwestern University Feinberg School of Medicine, Chicago, USA 3Colorado School of Public Health, University of Colorado Anschutz Medical Center, Colorado, USA 4Center for Medicare and Medicaid Services, Baltimore, Maryland
Abstract Importance—The Million Hearts initiative emphasizes the “ABCS” - aspirin, blood pressure control, cholesterol management, and smoking cessation. Evidence for the effects of drugs used to achieve the ABCS has not been comprehensively synthesized in primary atherosclerotic cardiovascular disease (ASCVD) prevention.
Author Manuscript
Objective—To compare the efficacy and safety of aspirin, blood pressure-lowering therapy, statin, and tobacco cessation drugs on fatal and non-fatal ASCVD outcomes in primary ASCVD prevention.
Author Manuscript
Evidence Review—Structured search of the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database (HTA), MEDLINE, EMBASE, and PROSPERO International Prospective Systematic Review Trial Register to identify systematic reviews published from January 1, 2005, to June 17, 2015, that reported the effect of aspirin, BP-lowering therapy, statin, or tobacco cessation drugs on ASCVD events in individuals without prevalent ASCVD. Additional studies were identified by searching the reference lists of included systematic reviews, meta-analyses, and health technology assessment reports. Reviews were selected according to predefined criteria and appraised formethodologic quality using the Assessment of Multiple Systematic Reviews (AMSTAR) tool (range, 0–11). Studies were independently reviewed for key participant and intervention characteristics. Outcomes that were meta-analyzed in each included review were extracted. Qualitative synthesis was performed, and data were analyzed from July 2 to August 13, 2015.
Corresponding address: Mark D. Huffman, Northwestern University Feinberg School of Medicine, Department of Preventive Medicine, 680 N. Lake Shore Drive, Suite 1400, Chicago, IL 60660, [email protected], T: 312-503-5513. 5Senior Healthcare Analyst at MITRE Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Additional Contributions: Janet S. Wright, MD, Executive Director, Million Hearts initiative, Centers for Disease Control provided input in preparing this manuscript.
Karmali et al.
Page 2
Author Manuscript
Findings—From a total of 1967 reports, 35 systematic reviews of randomized clinical trials were identified, including 15 reviews of aspirin, 4 reviews of BP-lowering therapy, 12 reviews of statins, and 4 reviews of tobacco cessation drugs. Methodologic quality varied, but 30 reviews had AMSTAR ratings of 5 or higher. Compared with placebo, aspirin (relative risk [RR], 0.90; 95%CI, 0.85–0.96) and statins (RR, 0.75; 95%CI, 0.70–0.81) reduced the risk for ASCVD. Compared with placebo, BP-lowering therapy reduced the risk for coronary heart disease (RR, 0.84; 95%CI, 0.79– 0.90) and stroke (RR, 0.64; 95%CI, 0.56–0.73). Tobacco cessation drugs increased the odds of continued abstinence at 6 months (odds ratio range, 1.82 [95%CI, 1.60–2.06] to 2.88 [95%CI, 2.40–3.47]), but the direct effects on ASCVD were poorly reported. Aspirin increased the risk for major bleeding (RR, 1.54; 95%CI, 1.30–1.82), and statins did not increase overall risk for adverse effects (RR, 1.00; 95%CI, 0.97–1.03). Adverse effects of BP-lowering therapy and tobacco cessation drugs were poorly reported.
Author Manuscript
Conclusions and Relevance—This overview demonstrates high quality evidence to support aspirin, blood pressure-lowering therapy, and statins for primary ASCVD prevention and tobacco cessation drugs for smoking cessation. Treatment effects of each drug can be used to enrich clinician-patient discussions in primary ASCVD prevention.
INTRODUCTION
Author Manuscript
In 2011, the United States Department of Health and Human Services launched the Million Hearts initiative to prevent 1 million heart attacks and strokes over 5 years.1 Million Hearts includes a clinical emphasis on the ABCS, that is, aspirin for high-risk patients, bloodpressure control, cholesterol management, and smoking cessation. Projections estimate that optimizing ABCS management could reduce the burden of atherosclerotic cardiovascular disease (ASCVD) substantially.2 To support the Million Hearts goal and identify new models of care delivery and payment, the Center for Medicare and Medicaid Innovation launched the Million Hearts Cardiovascular Risk Reduction Model in 2016, a cluster randomized payment model test to evaluate the effect of value-based payment to incentivize ASCVD risk assessment and reduction. This effort requires rigorous and transparent quantification of treatment effects for aspirin, blood pressure-lowering therapy, statins, and tobacco cessation drugs in primary ASCVD prevention.3 Despite the wealth of evidence synthesis activities within individual drug classes, we are not aware of any reports that have summarized the efficacy and safety of all 4 drug classes highlighted in the Million Hearts initiative for primary ASCVD prevention.
Author Manuscript
An overview of systematic reviews is a novel approach to appraise and synthesize results from multiple systematic reviews into a single, useful document that can be used to guide health care providers and policy makers.4–7 To address this evidence gap, we performed an overview of systematic reviews to compare the efficacy and safety of aspirin, blood pressure-lowering therapy, statin, and tobacco cessation drugs on fatal and non-fatal outcomes for primary ASCVD prevention.
METHODS This overview followed guidelines outlined by the Cochrane Collaboration to synthesize effects of multiple interventions for an overarching clinical question using data from JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 3
Author Manuscript
published systematic reviews.4 We established a protocol and published it in PROSPERO.8 The clinical question guiding this overview is presented in PICOTSS (patient, intervention, comparators, outcomes, timing, setting, and study design) format (Box). We also performed a supplemental systematic review to evaluate for potential interactions when combination drug therapy is used but found none (detailed search methods and results outlined in eAppendix 1 and 2 in the Supplement). Review Eligibility Criteria
Author Manuscript
We included systematic reviews of randomized and quasi-randomized clinical trials comparing the pooled treatment effects of aspirin, blood pressure-lowering therapy, statin, or tobacco cessation drugs against placebo or usual care in adults (≥ 18 years of age) without ASCVD. For systematic reviews that included a combination of individuals with and without prevalent ASCVD, we included reviews that reported effect estimates for participants defined as “primary prevention.” When reports included both primary and secondary prevention populations, we included only those reports with 90% without prevalent vascular disease). A summary of systematic review characteristics is provided in eAppendix 3 in the Supplement.
Author Manuscript
Trial quality assessment and review quality—The authors reported that trials generally had low risk of bias, but many were funded by pharmaceutical companies.45 AMSTAR ratings ranged from a score of 5/11 to 11/11. The most comprehensive and highest rated systematic review was by Taylor et al.45
Author Manuscript
Efficacy and cardiovascular benefits—Treatment effects of statins on all-cause mortality, total cardiovascular disease events, myocardial infarction, and stroke were broadly comparable across all systematic reviews. The systematic review by Taylor et al.45 reported a 14% reduction in all-cause mortality (OR 0.86, 95% CI 0.79–0.94), 25% reduction in major cardiovascular events (RR 0.75, 95% CI 0.70–0.81), and reductions in fatal and nonfatal coronary heart disease and stroke events.45 Mean baseline (SD) low-density lipoprotein cholesterol (LDL) in CTT trials was 143.1 (27.1) mg/dL and mean (SD) difference in LDL between statin regimen and control was 41.8 mg/dL. Treatment effects standardized per 40.6 mg/dl (1 mmol/L) reduction in LDL cholesterol were also reported by the CTT for all-cause mortality (RR 0.91, 95% CI 0.85–0.97) and major vascular events (RR 0.75, 95% CI 0.70–0.80).38 Effects of statin treatment in participants with diabetes mellitus were reported in 3 systematic reviews and demonstrated similar proportional benefits compared with the general primary prevention group.36,39,41 Sex-specific treatment effects were also reported in 3 systematic reviews,34,37,43 of which one was an individual participant data metaanalysis.37 After adjusting for baseline differences in prognostic characteristics and 5-year vascular risk, no sex-specific heterogeneity was seen.37 Additional statin treatment effects are provided in eAppendix 3 in the Supplement.
Author Manuscript
Safety, Adverse effects, and other Secondary Outcomes—Data on adverse effects of statin treatment were included in 7 systematic reviews and included risks of cancer, creatine kinase elevation, rhabdomyolysis, liver enzyme elevation, hemorrhagic stroke, type 2 diabetes, and serious adverse effects.34,35,37,38,42,45,46 Taylor et al.45 reported no evidence of increased risk of overall adverse effects (defined as cancers, myalgia and rhabdomyolysis, type 2 diabetes, hemorrhagic stroke, and other adverse effects leading to treatment discontinuation) among individuals treated with statin compared to control/placebo (RR 1.00, 95% CI 0.97–1.03). However, there was an 18% increased risk for the individual outcome of type 2 diabetes for those treated with statin (RR 1.18, 95% CI 1.01–1.39).
JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 9
Author Manuscript
Data on health-related quality of life were not reported. Data on cost-effectiveness were reported in Taylor et al45 from 3 statin trials, all demonstrating cost-effectiveness of statin therapy in primary prevention. In the West of Scotland Coronary Prevention Study (WOSCOPS), statin treatment led to 2,460 years of life at £8,121 (or $12,788) per life-year gained. In the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, statin therapy had a cost-effectiveness of £25,796 (or $40,315) per quality adjusted life year. Last, in an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS), Taylor et al.45 reported an incremental cost effectiveness ratio of £2,320 (or $3,626) per quality adjusted life year at 10 years.
Author Manuscript
GRADE assessment—We rated the quality of evidence for the effect of statins on reducing the risk of all-cause mortality, major cardiovascular events, coronary heart disease events, and stroke as high. We rated the quality of evidence for the safety of statins as moderate, downgrading because of indirectness of evidence. Tobacco cessation drugs Characteristics of included reviews—We included 4 systematic reviews of tobacco cessation drugs.47–50 None of the reviews differentiated between trials that included participants with and without prevalent vascular disease. Moreover, reviews reported limited information about the effects of tobacco cessation drugs on cardiovascular outcomes or risk factors. The primary efficacy outcome for most reviews was continuous smoking cessation at 6 months. Diabetes-specific or sex-specific treatment effects were not reported. The latest search ran through 2012.48 Mean age among participants in the most comprehensive systematic review was 57 years.48
Author Manuscript
The most comprehensive systematic review was an overview of several Cochrane systematic reviews by Cahill et al. addressing drug therapy for smoking cessation.48 This overview synthesized information from 267 trials of 101,804 participants. Among the trials, there were 150 trials of nicotine replacement therapy, 72 trials of antidepressants (primarily buproprion hydrochloride), and 24 trials of nicotine receptor partial agonists (primarily varenicline tartarate). A summary of systematic review characteristics is provided in eAppedix 3 in the Supplement.
Author Manuscript
Trial quality assessment and review quality—Authors reported that trials of nicotine replacement therapy and bupropion did not clearly describe methods of randomization or allocation concealment and were therefore at “high risk of bias.” Trials of varenicline were more contemporary and generally lower risk of bias, although they were industry funded.48 AMSTAR ratings ranged from 7/11 to 11/11, and the highest rated systematic review was Cahill et al48 (eAppendix 3 in the Supplement). Efficacay and smoking cessation—The overview by Cahill et al.48 reported treatment effects of tobacco cessation drugs on 6 months of continuous smoking abstinence, which was primarily biochemically verified. The overview reported that nicotine replacement therapy, buproprion, and varenicline all increased the odds of smoking cessation at 6 months compared to placebo (nicotine replacement therapy OR 1.84, 95% CI 1.71–1.99; bupropion
JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 10
Author Manuscript
OR 1.82, 95% CI 1.60–2.06; and varenicline 2.88, 95% CI 2.40–3.47). Cahill et al.48 also reported the effects of a limited number of tobacco cessation drugs on cardiovascular disease events. However, individual studies were underpowered for this endpoint, events were poorly reported, and many trials included participants with prevalent CVD. Treatment estimates for buproprion and varenicline for smoking cessation outcomes are listed in eAppendix 3 in the Supplement. Safety, Adverse effects, and Other Secondary Outcomes—Cahill et al.48 also reported the effects of tobacco cessation drugs on serious adverse events for a limited number of therapies. For nicotine replacement therapy, limited information on serious adverse effects was reported in trials.48 Data for buproprion and varenicline were reported (RR 1.29, 95% CI 0.99–1.69 and RR 1.06, 95% CI 0.72–1.55, respectively).48 Data on health-related quality of life and direct costs were not reported.
Author Manuscript
GRADE Assessment—We rated the quality of evidence for the effect of varenicline on smoking cessation as high and the quality of evidence for the effect of buproprion and nicotine replacement therapy on smoking cessation as moderate, downgrading because of study limitations. We rated the quality of evidence for the safety of tobacco cessation drugs as moderate, downgrading because of indirectness of evidence. We rated the quality of evidence for the effect of tobacco cessation drugs on all-cause mortality and cardiovascular outcomes as low, downgrading because of study limitations, inconsistency, and imprecision.
DISCUSSION Principal findings
Author Manuscript
We performed an overview of systematic reviews that synthesized evidence of the efficacy and safety of drugs that can be used in primary ASCVD prevention to achieve targets set by the Million Hearts initiative and that will be used in the Million Hearts Cardiovascular Risk Reduction model. There is high quality evidence that aspirin, BP-lowering therapy, and statins reduce the risk of ASCVD events from 10% to 25% among individuals without prevalent ASCVD. There is also high quality evidence that BP-lowering therapy and statins reduce the risk of all-cause mortality by 11% and 14%, respectively. There was no heterogeneity in treatment effect among subgroups of individuals with diabetes mellitus or by sex. There is moderate to high quality evidence that tobacco cessation drugs increase the odds of continued abstinence by 88% to 188%, but the direct effects on cardiovascular events are uncertain. A summary of findings table is presented in the Table.
Author Manuscript
Adverse effects of drug therapy were either not reported or poorly reported in many systematic reviews, and many review authors noted “under-reporting” of adverse events in the individual trials. Our search demonstrated high quality evidence that aspirin increases the risk of major bleeding by 54% and moderate quality evidence that statins do not increase the overall risk of adverse events, but risk for type 2 diabetes mellitus was increased among individuals taking statins. Adverse effects of BP-lowering therapy and tobacco cessation drugs were poorly reported.
JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 11
Strengths
Author Manuscript
Our overview has several strengths. First, we focused this evidence synthesis on systematic reviews and meta-analyses of randomized clinical trials, because randomized clinical trials represent the highest-quality evidence to determine the effects of health care interventions. Second, we used a comprehensive, transparent search strategy to identify studies and followed a prespecified protocol to guide our evidence synthesis, noting any deviations from protocol. Third, we performed all title screening, data extraction, and quality assessments in duplicate to minimize potential bias in generation of this overview. Fourth, we used a validated instrument (the AMSTAR tool) to assess the methodologic quality of included systematic reviews and factored this quality assessment to guide our conclusions regarding the effects of pharmacologic interventions. This systematic process, with study quality assessment using standardized tools, could be used as a potential model for more rapid development of trustworthy guidelines.
Author Manuscript
Limitations
Author Manuscript
Our overview also has important limitations to acknowledge. First, we did not retrieve data from primary trials and therefore were limited to the information and judgments of the authors who wrote the systematic reviews. Selection criteria, search strategies, and definitions of primary prevention often varied between reviews, and authors of the included reviews often used different criteria to define primary prevention, which led to different numbers of trials for systematic reviews of the same drug. Second, our conclusions were limited by the available data. Although data were generally well reported for drug efficacy, limited information was reported on safety, particularly for BP-lowering therapy and tobacco cessation drugs. Third, we had limited ability to comment on the potential of differential treatment effects by race/ethnicity. Nevertheless, several reviews noted consistent proportional treatment effects regardless of baseline characteristics, suggesting that treatment effect does not demonstrate heterogeneity. Fourth, our treatment effect estimates were limited by the short-term horizon of the clinical trials. Thus, we may have underestimated the potential added benefits and risks of sustained treatment. Fifth, our overview does not include evidence from recent trials like the Japanese Primary Prevention Project (JPPP)51 or cost-effectiveness analyses of long-term statin use from WOSCOPS.52 However, inclusion of these studies would not have changed our overall conclusions. For example, the point estimate for treatment effect from low-dose aspirin in the JPPP trial was similar to our reported effect, though with wider confidence intervals (HR 0.94, 95% CI 0.77–1.15) and primary prevention statin therapy was also shown to be cost-effective at 15 years of follow-up. Finally, our overview does not provide information on the added effects of lifestyle interventions such as diet, exercise, and weight loss in combination with drug therapy. However, essentially all included clinical trials of ASCVD prevention included background recommendations of therapeutic lifestyle change in combination with study drugs.
Author Manuscript
Conclusions This overview of systematic reviews demonstrates high quality evidence to support aspirin, BP-lowering therapy, and statins for primary ASCVD prevention and tobacco cessation
JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 12
Author Manuscript
drugs for smoking cessation. It provides reliable, evidence-based pooled estimates for these interventions on the lowered risk of primary ASCVD events and best-available evidence for the effect of tobacco cessation drugs on continuous abstinence at 6 months. These treatment effects can be used to enrich discussions between health care professionals and patients.
Supplementary Material Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
Author Manuscript
Dr. Huffman reports grants from Center for Medicare and Medicaid Innovation via subcontract from the MITRE Corporation, during the conduct of the study; grants from World Heart Federation, outside the submitted work; and serves as an associate editor for JAMA Cardiology and the coordinating editor of the Cochrane Heart Group US Satellite. Dr. Lloyd-Jones reports grants from Center for Medicare and Medicaid Innovation via subcontract from the MITRE Corporation, during the conduct of the study. Funding/Support: This study was funded by the Center for Medicare and Medicaid Innovation and MITRE Corporation. Role of Funder/Sponsor: Design and conduct of the study: The work was performed to provide a synthesis of available evidence to support development of a longitudinal cardiovascular risk calculator that will be used in the Million Hearts Cardiovascular Risk Reduction Model. The Center for Medicare and Medicaid Innovation (CMMI) provided an initial description of key questions. However, the final protocol was developed independently by the authors. Collection, management, analysis, and interpretation of the data: The authors were solely responsible for data collection, management, analysis, and interpretation. Members of CMMI and MITRE Corporation reviewed a draft version of a full, more detailed report, and the final version used by the group explicitly addressed comments/ suggestions provided. Final data interpretation, including judgments of evidence quality, were solely the responsibility of the authors. Preparation, review, or approval of the manuscript: This manuscript was prepared solely by the authors, with no review or approval by the sponsor. Decision to submit the manuscript for publication: The sponsor was involved in the decision to submit the manuscript for publication in JAMA to provide transparency regarding the evidence base for the new cardiovascular risk calculator.
Author Manuscript
References
Author Manuscript
1. Frieden TR, Berwick DM. The "Million Hearts" initiative--preventing heart attacks and strokes. N. Engl. J. Med. 2011; 365(13):e27. [PubMed: 21913835] 2. Farley TA, Dalal MA, Mostashari F, Frieden TR. Deaths preventable in the U.S. by improvements in use of clinical preventive services. Am. J. Prev. Med. 2010; 38(6):600–609. [PubMed: 20494236] 3. Sanghavi DM, Conway PH. Paying for prevention: A novel test of medicare value-based payment for cardiovascular risk reduction. JAMA. 2015; 314(2):123–124. [PubMed: 26021568] 4. Higgins, JPT.; Green, Se. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration; 2011. Available from http:// www.cochrane-handbook.org [Accessed 2 February 2016] 5. Lavis JN. How can we support the use of systematic reviews in policymaking? PLoS Med. 2009; 6(11):e1000141. [PubMed: 19936223] 6. Thomson D, Russell K, Becker L, Klassen T, Hartling L. The evolution of a new publication type: Steps and challenges of producing overviews of reviews. Research synthesis methods. 2010; 1(3–4): 198–211. [PubMed: 26061466] 7. Baker PR, Costello JT, Dobbins M, Waters EB. The benefits and challenges of conducting an overview of systematic reviews in public health: a focus on physical activity. J Public Health (Oxf). 2014; 36(3):517–521. [PubMed: 25085438] 8. PROSPERO International prospective register of systematic reviews. [Accessed 2 February 2016] Available at: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015023444.
JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 13
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
9. Ebrahim S, Taylor F, Ward K, Beswick A, Burke M, Davey Smith G. Multiple risk factor interventions for primary prevention of coronary heart disease. Cochrane Database Syst Rev. 2011; (1):CD001561. [PubMed: 21249647] 10. Shea BJ, Grimshaw JM, Wells GA, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol. 2007; 7:10. [PubMed: 17302989] 11. Cheung A, Weir M, Mayhew A, Kozloff N, Brown K, Grimshaw J. Overview of systematic reviews of the effectiveness of reminders in improving healthcare professional behavior. Systematic reviews. 2012; 1:36. [PubMed: 22898173] 12. Smith V, Devane D, Begley CM, Clarke M. Methodology in conducting a systematic review of systematic reviews of healthcare interventions. BMC Med Res Methodol. 2011; 11(1):15. [PubMed: 21291558] 13. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008; 336(7650):924–926. [PubMed: 18436948] 14. Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009; 373(9678):1849–1860. [PubMed: 19482214] 15. Berger JS, Lala A, Krantz MJ, Baker GS, Hiatt WR. Aspirin for the prevention of cardiovascular events in patients without clinical cardiovascular disease: a meta-analysis of randomized trials. Am. Heart J. 2011; 162(1):115–124.e112. [PubMed: 21742097] 16. Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA. 2006; 295(3):306–313. [PubMed: 16418466] 17. Brotons C, Benamouzig R, Filipiak KJ, Limmroth V, Borghi C. A systematic review of aspirin in primary prevention: is it time for a new approach? Am J Cardiovasc Drugs. 2015; 15(2):113–133. [PubMed: 25502483] 18. Butalia S, Leung AA, Ghali WA, Rabi DM. Aspirin effect on the incidence of major adverse cardiovascular events in patients with diabetes mellitus: a systematic review and meta-analysis. Cardiovasc Diabetol. 2011; 10:25. [PubMed: 21453547] 19. Calvin AD, Aggarwal NR, Murad MH, et al. Aspirin for the primary prevention of cardiovascular events: a systematic review and meta-analysis comparing patients with and without diabetes. Diabetes Care. 2009; 32(12):2300–2306. [PubMed: 19741185] 20. De Berardis G, Sacco M, Strippoli GF, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials. BMJ. 2009; 339:b4531. [PubMed: 19897665] 21. Raju N, Sobieraj-Teague M, Hirsh J, O'Donnell M, Eikelboom J. Effect of aspirin on mortality in the primary prevention of cardiovascular disease. Am. J. Med. 2011; 124(7):621–629. [PubMed: 21592450] 22. Raju NC, Eikelboom JW. The aspirin controversy in primary prevention. Curr. Opin. Cardiol. 2012; 27(5):499–507. [PubMed: 22874127] 23. Seshasai SR, Wijesuriya S, Sivakumaran R, et al. Effect of aspirin on vascular and nonvascular outcomes: meta-analysis of randomized controlled trials. Arch. Intern. Med. 2012; 172(3):209– 216. [PubMed: 22231610] 24. Stavrakis S, Stoner JA, Azar M, Wayangankar S, Thadani U. Low-dose aspirin for primary prevention of cardiovascular events in patients with diabetes: a meta-analysis. Am. J. Med. Sci. 2011; 341(1):1–9. [PubMed: 21191260] 25. Sutcliffe P, Connock M, Gurung T, et al. Aspirin for prophylactic use in the primary prevention of cardiovascular disease and cancer: a systematic review and overview of reviews. Health Technol. Assess. 2013; 17(43):1–253. 26. Sutcliffe P, Connock M, Gurung T, et al. Aspirin in primary prevention of cardiovascular disease and cancer: a systematic review of the balance of evidence from reviews of randomized trials. PLoS One. 2013; 8(12):e81970. [PubMed: 24339983]
JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 14
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
27. Wolff T, Miller T, Ko S. Aspirin for the primary prevention of cardiovascular events: an update of the evidence for the U.S. Preventive Services Task Force. Ann. Intern. Med. 2009; 150(6):405– 410. [PubMed: 19293073] 28. Younis N, Williams S, Ammori B, Soran H. Role of aspirin in the primary prevention of cardiovascular disease in diabetes mellitus: a meta-analysis. Expert Opin Pharmacother. 2010; 11(9):1459–1466. [PubMed: 20429671] 29. Zhang C, Sun A, Zhang P, et al. Aspirin for primary prevention of cardiovascular events in patients with diabetes: A meta-analysis. Diabetes Res. Clin. Pract. 2010; 87(2):211–218. [PubMed: 19853947] 30. Diao D, Wright JM, Cundiff DK, Gueyffier F. Pharmacotherapy for mild hypertension. Cochrane Database of Systematic Reviews. 2012; 8:CD006742. [PubMed: 22895954] 31. Fretheim A, Odgaard-Jensen J, Brors O, et al. Comparative effectiveness of antihypertensive medication for primary prevention of cardiovascular disease: systematic review and multiple treatments meta-analysis. BMC Medicine. 2012; 10 32. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009; 338:b1665. [PubMed: 19454737] 33. Sundstrom J, Arima H, Jackson R, et al. Effects of blood pressure reduction in mild hypertension: a systematic review and meta-analysis. Ann. Intern. Med. 2015; 162(3):184–191. [PubMed: 25531552] 34. Brugts JJ, Yetgin T, Hoeks SE, et al. The benefits of statin therapy in patients without cardiovascular disease: Meta-analysis of randomized controlled trials. Eur. Heart J. 2009; 30:510– 511. 35. Bukkapatnam RN, Gabler NB, Lewis WR. Statins for primary prevention of cardiovascular mortality in women: a systematic review and meta-analysis. Prev Cardiol. 2010; 13(2):84–90. [PubMed: 20377811] 36. Chen YH, Feng B, Chen ZW. Statins for primary prevention of cardiovascular and cerebrovascular events in diabetic patients without established cardiovascular diseases: a meta-analysis. Experimental and clinical endocrinology & diabetes. 2012; 120(2):116–120. [PubMed: 22187291] 37. Fulcher J, O'Connell R, et al. Cholesterol Treatment Trialists C. Efficacy and safety of LDLlowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet. 2015; 385(9976):1397–1405. [PubMed: 25579834] 38. Mihaylova B, Emberson J, et al. Cholesterol Treatment Trialists C. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012; 380(9841):581–590. [PubMed: 22607822] 39. Costa J, Borges M, David C, Vaz Carneiro A. Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. BMJ. 2006; 332(7550): 1115–1124. [PubMed: 16585050] 40. Costanzo P, Perrone-Filardi P, Petretta M, et al. Impact of gender in primary prevention of coronary heart disease with statin therapy: A meta-analysis. J. Am. Coll. Cardiol. 2009; 53(10):A210. [abstract]. 41. de Vries FM, Denig P, Pouwels KB, Postma MJ, Hak E. Primary prevention of major cardiovascular and cerebrovascular events with statins in diabetic patients a meta-analysis. Drugs. 2012; 72(18):2365–2373. [PubMed: 23186103] 42. Mills EJ, Rachlis B, Wu P, Devereaux PJ, Arora P, Perri D. Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patients. J. Am. Coll. Cardiol. 2008; 52(22):1769–1781. [PubMed: 19022156] 43. Petretta M, Costanzo P, Perrone-Filardi P, Chiariello M. Impact of gender in primary prevention of coronary heart disease with statin therapy: a meta-analysis. Int. J. Cardiol. 2010; 138(1):25–31. [PubMed: 18793814] 44. Ray KK, Seshasai SR, Erqou S, et al. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. Arch. Intern. Med. 2010; 170(12):1024–1031. [PubMed: 20585067]
JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 15
Author Manuscript Author Manuscript
45. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013; 1:CD004816. [PubMed: 23440795] 46. Thavendiranathan P, Bagai A, Brookhart MA, Choudhry NK. Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials. Arch. Intern. Med. 2006; 166(21):2307–2313. [PubMed: 17130382] 47. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database of Systematic Reviews. 2012; (4):CD006103. [PubMed: 22513936] 48. Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database of Systematic Reviews. 2013; 5:CD009329. [PubMed: 23728690] 49. Ebbert J, Montori VM, Erwin PJ, Stead LF. Interventions for smokeless tobacco use cessation. Cochrane Database of Systematic Reviews. 2011; (2):CD004306. [PubMed: 21328266] 50. Secretariat MA. Population-based smoking cessation strategies: A summary of a select group of evidence-based reviews. Ontario Health Technology Assessment Series. 2010; 10(1) 51. Ikeda Y, Shimada K, Teramoto T, et al. Low-dose aspirin for primary prevention of cardiovascular events in Japanese patients 60 years or older with atherosclerotic risk factors: a randomized clinical trial. JAMA. 2014; 312(23):2510–2520. [PubMed: 25401325] 52. McConnachie A, Walker A, Robertson M, et al. Long-term impact on healthcare resource utilization of statin treatment, and its cost effectiveness in the primary prevention of cardiovascular disease: a record linkage study. Eur. Heart J. 2014; 35(5):290–298. [PubMed: 23839541]
Author Manuscript Author Manuscript JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 16
Author Manuscript
Box 1. Patients, Interventions, Comparators, Outcomes, Timing, Setting, and Study design (PICOTSS) Patients •
Adults ≥ 18 years of age
•
People without prevalent atherosclerotic cardiovascular disease (ASCVD)
•
Systematic reviews or trials that included people with Alzheimer’s disease, end-stage renal disease, macular degeneration, and aortic stenosis were excluded
Interventions
Author Manuscript
•
Aspirin
•
BP-lowering therapy
•
Statin
•
Tobacco cessation drug (i.e. nicotine replacement therapy, varenicline, buproprion)
Comparators •
Placebo
•
Usual care
Outcomes
Author Manuscript
Primary outcomes •
All-cause mortality
•
Fatal and nonfatal cardiovascular events, including myocardial infarction and stroke (ASCVD)
•
Adverse events as reported by study authors
Secondary outcomes
Author Manuscript
•
Fatal and non-fatal ischemic heart disease events, including myocardial infarction, angina, and coronary revascularization)
•
Fatal and non-fatal cerebrovascular events, including stroke and transient ischemic attack
•
Total and non-fatal ASCVD events
•
Total and low-density lipoprotein (LDL) cholesterol
•
Systolic and diastolic BP
•
Health-related quality of life
•
Direct Costs
JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 17
Timing
Author Manuscript
•
Studies of any duration
Setting •
Any setting
Study design •
Systematic reviews of randomized and quasi-randomized clinical trials
Author Manuscript Author Manuscript Author Manuscript JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 18
Author Manuscript Author Manuscript Author Manuscript Figure 1.
PRISMA flowchart for overview of systematic reviews of primary prevention drugs
Author Manuscript JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
Karmali et al.
Page 19
Table 1
Author Manuscript
Summary of key findings for the effect of drugs for primary prevention of atherosclerotic cardiovascular diseases. Outcomes
Relative risk (95% CI)
Quality of evidence (GRADE)
Comment
All-cause mortality
RR 0.94 (95% CI 0.88–1.00)
Moderate
Downgraded due to imprecision
Major cardiovascular events
RR 0.90 (95% CI 0.85–0.96)
High
NA
Adverse effects (Major bleeding)
RR 1.54 (95% CI 1.30–1.82)
High
NA
All-cause mortality
RR 0.89 (95% CI 0.84–0.95)
High
NA
Coronary heart disease (CHD) events
RR 0.84 (95% CI 0.79–0.90)
High
NA
CHD events, standardized to a BP reduction of 10 mmHg/5mmHg
RR 0.79 (95% CI 0.72–0.86)
High
NA
Stroke events
RR 0.64 (95% CI 0.56–0.73)
High
NA
Stroke events, standardized to a BP reduction of 10 mmHg/5mmHg
RR 0.54 (95% CI 0.45–0.65)
High
NA
Adverse effects (Treatment withdrawal)
RR 4.80 (95%CI 4.14–5.57)
Low
Downgraded due to study limitations, inconsistency
All-cause mortality
OR 0.86 (95% CI 0.79–0.94)
High
NA
Major cardiovascular events
RR 0.75 (95% CI 0.70–0.81)
High
NA
Major vascular events per 1 mmol/L of LDL reduction
RR 0.75 (95% CI 0.70–0.80)
High
NA
CHD events
RR 0.73 (95% CI 0.67–0.80)
High
NA
Stroke events
RR 0.78 (95% CI 0.68–0.89)
High
NA
Adverse effects (all)
RR 1.00 (95% CI 0.97–1.03)
Moderate
Downgraded due to indirectness of evidence
Adverse effects diabetes)
RR 1.18 (95% CI 1.01–1.39)
Moderate
Downgraded due to indirectness of evidence
Nicotine replacement therapy, continuous smoking abstinence at ≥6 months
OR 1.84 (95% CI 1.71–1.99)
Moderate
Downgraded due to study limitations
Buproprion hydrochloride, continuous smoking abstinence at ≥6 months
OR 1.82 (95% CI 1.60–2.06)
Moderate
Downgraded due to study limitations
Varenicline tartarate, continuous smoking abstinence at ≥6 months
OR 2.88 (95% CI 2.40–3.47)
High
Aspirin
BP-lowering therapies
Author Manuscript
Statins
Author Manuscript
Tobacco cessation drugs
NA
Author Manuscript
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
JAMA Cardiol. Author manuscript; available in PMC 2016 October 06.
