Systematic Review: Comparative Effectiveness and Harms of Combination Therapy and Monotherapy for Dyslipidemia

doi:10.1059/0003-4819-151-9-200911030-00144

Systematic Review: Comparative Effectiveness and Harms of Combination Therapy and Monotherapy for Dyslipidemia

Mukul Sharma, MD, MSc;
Mohammed T. Ansari, MBBS, MMedSc, MPhil;
Ahmed M. Abou-Setta, MD, PhD;
Karla Soares-Weiser, MD, PhD;
Teik Chye Ooi, MBBS;
Margaret Sears, PhD;
Fatemeh Yazdi, MSc;
Alexander Tsertsvadze, MD, MSc; and
David Moher, PhD

From the University of Ottawa, Clinical Epidemiology Program, Ottawa Hospital Research Institute, and Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada; Alberta Research Centre for Health Evidence, University of Alberta, Edmonton, Alberta, Canada; and Enhance Reviews, Kfar-Saba, Israel.

Abstract

Background: Statin therapy effectively prevents vascular disease, but treatment targets are often not achieved.

Purpose: To compare the benefits and harms of high-dose statin monotherapy with those of combination therapy in adults at high risk for coronary disease.

Data Sources: English-language records from MEDLINE (1966 to 2009), EMBASE (1980 to 2009), and the Cochrane Library (third quarter of 2008).

Study Selection: A reviewer screened records, and a second reviewer verified selection of randomized, controlled trials in adult patients that compared combinations of statins and bile-acid sequestrants, fibrates, ezetimibe, niacin, or ω-3 fatty acids with statin monotherapy, as well as nonrandomized comparative studies that were longer than 24 weeks and reported clinical and harms outcomes.

Data Extraction: Data were abstracted for studies by using standardized forms, and study quality was rated with a standardized scale and strength of evidence by using the Grading of Recommendations Assessment, Development, and Evaluation approach.

Data Synthesis: 102 studies met eligibility criteria. The main analysis compared combination therapy with high-dose statin monotherapy in high-risk patients. Very-low-strength evidence showed that statin–ezetimibe (2 trials; n = 439) and statin–fibrate (1 trial; n = 166) combinations did not reduce mortality more than high-dose statin monotherapy. No trials compared the effect of combination therapy versus high-dose statin monotherapy on the incidence of myocardial infarction, stroke, or revascularization procedures. Two statin–ezetimibe trials (n = 295) demonstrated higher low-density lipoprotein cholesterol goal attainment with combination therapy (odds ratio, 7.21 [95% CI, 4.30 to 12.08]). Trials in lower-risk patients did not show a difference in mortality.

Limitations: Studies were generally short, focused on surrogate outcomes, and were heterogeneous in the sample's risk for coronary disease. Few studies examined treatment combinations other than statin–ezetimibe.

Conclusion: Limited evidence suggests that combinations of lipid-lowering agents do not improve clinical outcomes more than high-dose statin monotherapy. Very-low-quality evidence favors statin–ezetimibe treatment for attainment of low-density lipoprotein cholesterol goals.

Primary Funding Source: Agency for Healthcare Research and Quality.

Article and Author Information

Acknowledgment: The authors thank Margaret Sampson, Chantelle Garritty, Heather Clark, Robert Côté, Nick Barrowman, Raymond Daniel, and Sophia Tsouros for their collective efforts.
Grant Support: By AHRQ, U.S. Department of Health and Human Services (contract 290-02-0021).
Potential Conflicts of Interest: Honoraria: M. Sharma (Merck & Co., Schering-Plough), T.C. Ooi (Oryx Pharmaceuticals, Fournier Pharma, AstraZeneca, Merck Frosst, Solvay Pharma, Schering-Plough).
Requests for Single Reprints: Mukul Sharma, MD, MSc, Canadian Stroke Network, Regional Stroke Program, The Ottawa Hospital, Civic Campus, C2, Room 2182, 1053 Carling Avenue, Ottawa, Ontario K1Y 4E9, Canada.
Current Author Addresses: Dr. Sharma: Canadian Stroke Network, Regional Stroke Program, The Ottawa Hospital, Civic Campus, C2, Room 2182, 1053 Carling Avenue, Ottawa, Ontario K1Y 4E9, Canada.
Drs. Ansari and Tsertsvadze and Ms. Yazdi: University of Ottawa Evidence-based Practice Center, CHEO-RI, 401 Smyth Road, Ottawa, Ontario K1H 8LI, Canada.
Dr. Abou-Setta: University of Alberta Evidence-based Practice Center, Alberta Research Centre for Health Evidence, Aberhart Centre One, Room 8412, 11402 University Avenue, Edmonton, Alberta T6G 2J3, Canada.
Dr. Soares-Weiser: Enhance Reviews, PO Box 137, Kfar-Saba, 44101, Israel.
Dr. Ooi: Division of Endocrinology and Metabolism, University of Ottawa, The Ottawa Hospital, Riverside Campus, 1967 Riverside Drive, Ottawa, Ontario K1H 7W9, Canada.
Dr. Sears: RR 1, Box 9012, Dunrobin, Ontario K0A 1T0, Canada.
Dr. Moher: University of Ottawa Evidence-based Practice Center, University of Ottawa, and Ottawa Methods Centre, Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Road, 6th Floor, Critical Care Wing, Room W6112, Ottawa, Ontario K1H 8L6, Canada.
Author Contributions: Conception and design: M. Sharma, M.T. Ansari, A.M. Abou-Setta, T.C. Ooi, A. Tsertsvadze, D. Moher.
Analysis and interpretation of the data: M. Sharma, M.T. Ansari, A.M. Abou-Setta, K. Soares-Weiser, T.C. Ooi, M. Sears, A. Tsertsvadze, D. Moher.
Drafting of the article: M. Sharma, M.T. Ansari, A.M. Abou-Setta, M. Sears, A. Tsertsvadze, D. Moher.
Critical revision of the article for important intellectual content: M. Sharma, M.T. Ansari, A.M. Abou-Setta, T.C. Ooi, M. Sears, A. Tsertsvadze, D. Moher.
Final approval of the article: M. Sharma, M.T. Ansari, A.M. Abou-Setta, K. Soares-Weiser, T.C. Ooi, M. Sears, D. Moher.
Provision of study materials or patients: F. Yazdi.
Statistical expertise: M.T. Ansari, A.M. Abou-Setta, D. Moher.
Obtaining of funding: D. Moher.
Administrative, technical, or logistic support: M.T. Ansari, A.M. Abou-Setta, M. Sears, F. Yazdi, D. Moher.
Collection and assembly of data: M. Sharma, M.T. Ansari, A.M. Abou-Setta, K. Soares-Weiser, T.C. Ooi, M. Sears, F. Yazdi, A. Tsertsvadze.