Kimberly A. Gudzune, MD, MPH; Anne K. Monroe, MD, MSPH; Ritu Sharma, BSc; Padmini D. Ranasinghe, MD, MPH; Yohalakshmi Chelladurai, MBBS, MPH; Karen A. Robinson, PhD
Disclaimer: The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
Grant Support: This project was funded under contract HHSA290201200007I from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services.
Potential Conflicts of Interest: Dr. Gudzune: Grant: Agency for Healthcare Research and Quality; Salary support: Johns Hopkins Adjusted Clinical Groups Software. Dr. Monroe: Grant: Agency for Healthcare Research and Quality; Personal fees: Pri-Med CME. Ms. Sharma: Grant: Agency for Healthcare Research and Quality. Dr. Robinson: Grant: Agency for Healthcare Research and Quality. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-2526.
Requests for Single Reprints: Kimberly A. Gudzune, MD, MPH, Division of General Internal Medicine, The Johns Hopkins University School of Medicine, 2024 East Monument Street, Room 2-611, Baltimore, MD 21287; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Gudzune: Division of General Internal Medicine, The Johns Hopkins University School of Medicine, 2024 East Monument Street, Room 2-611, Baltimore, MD 21287.
Drs. Monroe and Robinson: The Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 8060, Baltimore, MD 21287.
Ms. Sharma and Dr. Chelladurai: The Johns Hopkins University Bloomberg School of Public Health, 624 North Broadway, Room 680, Baltimore, MD 21205.
Dr. Ranasinghe: The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Park 215, Baltimore, MD 21287.
Author Contributions: Conception and design: K.A. Gudzune, A.K. Monroe, R. Sharma, P.D. Ranasinghe, K.A. Robinson.
Analysis and interpretation of the data: K.A. Gudzune, A.K. Monroe, R. Sharma, P.D. Ranasinghe, Y. Chelladurai, K.A. Robinson.
Drafting of the article: K.A. Gudzune, A.K. Monroe, R. Sharma, P.D. Ranasinghe, Y. Chelladurai, K.A. Robinson.
Critical revision of the article for important intellectual content: K.A. Gudzune, A.K. Monroe, R. Sharma, Y. Chelladurai, K.A. Robinson.
Final approval of the article: K.A. Gudzune, A.K. Monroe, P.D. Ranasinghe, Y. Chelladurai, K.A. Robinson.
Statistical expertise: K.A. Robinson.
Obtaining of funding: K.A. Robinson.
Administrative, technical, or logistic support: R. Sharma, Y. Chelladurai, K.A. Robinson.
Collection and assembly of data: K.A. Gudzune, A.K. Monroe, R. Sharma, P.D. Ranasinghe, Y. Chelladurai, K.A. Robinson.
Gudzune KA, Monroe AK, Sharma R, Ranasinghe PD, Chelladurai Y, Robinson KA. Effectiveness of Combination Therapy With Statin and Another Lipid-Modifying Agent Compared With Intensified Statin Monotherapy: A Systematic Review. Ann Intern Med. 2014;160:468-476. doi: 10.7326/M13-2526
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Published: Ann Intern Med. 2014;160(7):468-476.
Some patients do not tolerate or respond to high-intensity statin monotherapy. Lower-intensity statin combined with nonstatin medication may be an alternative, but the benefits and risks compared with those of higher-intensity statin monotherapy are unclear.
To compare the clinical benefits, adherence, and harms of lower-intensity statin combination therapy with those of higher-intensity statin monotherapy among adults at high risk for atherosclerotic cardiovascular disease (ASCVD).
MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from inception to July 2013, with an updated MEDLINE search through November 2013.
Randomized, controlled trials published in English.
Two reviewers extracted information on study design, population characteristics, interventions, and outcomes (deaths, ASCVD events, low-density lipoprotein [LDL] cholesterol level, adherence, and adverse events). Two independent reviewers assessed risk of bias.
A total of 36 trials were included. Low-intensity statin plus bile acid sequestrant decreased LDL cholesterol level 0% to 14% more than mid-intensity monotherapy among high-risk hyperlipidemic patients. Mid-intensity statin plus ezetimibe decreased LDL cholesterol level 5% to 15% and 3% to 21% more than high-intensity monotherapy among patients with ASCVD and diabetes mellitus, respectively. Evidence was insufficient to evaluate LDL cholesterol for fibrates, niacin, and ω-3 fatty acids. Evidence was insufficient for long-term clinical outcomes, adherence, and harms for all regimens.
Many trials had short durations and high attrition rates, lacked blinding, and did not assess long-term clinical benefits or harms.
Clinicians could consider using lower-intensity statin combined with bile acid sequestrant or ezetimibe among high-risk patients intolerant of or unresponsive to statins; however, this strategy should be used with caution given the lack of evidence on long-term clinical benefits and harms.
Agency for Healthcare Research and Quality.
Summary of evidence search and selection.
ASCVD = atherosclerotic cardiovascular disease; CENTRAL = Cochrane Central Register of Controlled Trials; FDA = U.S. Food and Drug Administration; RCT = randomized, controlled trial; SIP = scientific information packet.
* Citations could be excluded for >1 reason; therefore, the sum of excluded studies listed from each category may exceed the actual number of citations excluded.
Table. Population Characteristics and Study Quality of Included Trials, by Combination Therapy Agent and Potency Comparison
Evidence map for studies reporting long-term clinical outcomes, by combination agent and outcome.
The figure includes the clinical outcomes of death (green), ACS (black), and CVA (white). No studies reported on revascularization procedures. The different combination therapy agents are represented by the different symbols (diamond = ezetimibe [27, 34, 38, 43, 51]; circle = fibrates ; square = niacin ). No trials with bile acid sequestrants or ω-3 fatty acids reported on any clinical outcomes. Each marker represents a different trial, where the sample size is represented by the size of the marker and the y-axis reflects the study duration. Differences in populations, potency comparisons, or event rates are not represented. Most event rates were very low or no events occurred, which limited our ability to make any inferences. ACS = acute coronary syndrome; CVA = cerebrovascular event.
Difference in mean percentage of change in LDL cholesterol level among high-risk groups, by nonstatin agent, between higher-intensity statin monotherapy and lower-intensity statin combination therapy.
To convert LDL cholesterol values to mmol/L, multiply by 0.026. ASCVD = subgroup with preexisting atherosclerotic cardiovascular disease; DM = subgroup with diabetes mellitus; HLD = subgroup with LDL cholesterol level ≥4.91 mmol/L (≥190 mg/dL); LDL = low-density lipoprotein; NR = not reported; PMSG = Pravastatin Multicenter Study Group.
* Two eligible combination therapy groups were available at this time point. We report the comparison between monotherapy and combination therapy with the lower-dose nonstatin agent on the first line and the higher-dose nonstatin agent on the second.
† These study results were reported in multiple articles, which are listed in Table 3 of the Supplement.
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Tetsuro Tsujimoto, Ritsuko Yamamoto-Honda
Department of Diabetes, Endocrinology, and Metabolism, National Center for Global Health and Medicine, Tokyo, Japan
February 24, 2014
Effectiveness of Combination Therapy With Statin and Another Lipid-Modifying Agent Compared With Intensified Statin Monotherapy: A Systematic Review
Kimberly et al. have reported a study on the effect of the combination therapy with statin and other lipid-modifying agents such as bile acid sequestrants and ezetimibe (1). Although this study had several important findings regarding the combination therapy, it had several substantial problems, and the results should be carefully interpreted from various perspectives. This study indeed revealed that, compared with the mid to high intensity statin monotherapy, the combination therapy significantly decreased the levels of low-density lipoprotein (LDL) cholesterol (1). However, this does not mean that the combination therapy is better than the statin monotherapy. The combination therapy may not be superior to the high-dose statin monotherapy with regard to improving the outcomes of mortality and cardiovascular events (2). It is also unclear whether the combination therapy could achieve better target values for LDL cholesterol than the statin monotherapy. Moreover, low-dose statin in the combination therapy may have lower pleiotropic effects than the high-dose statin (3). In addition, the cost-effectiveness and long term cancer risk associated with the combination therapy with statin and ezetimibe should be assessed (4, 5). Therefore, it may be too early to predict the beneficial effects of the combination therapy as a therapeutic option for patients at a high risk for atherosclerotic cardiovascular disease. Further studies are required to elucidate the strategies for better management of such patients.
1. Gudzune KA, Monroe AK, Sharma R, Ranasinghe PD, Chelladurai Y, Robinson KA. Effectiveness of Combination Therapy With Statin and Another Lipid-Modifying Agent Compared With Intensified Statin Monotherapy: A Systematic Review. Ann Intern Med. 2014;
2. Sharma M, Ansari MT, Abou-Setta AM, et al. Systematic review: comparative effectiveness and harms of combination therapy and monotherapy for dyslipidemia. Ann Intern Med. 2009;151:622-30.
3. Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation. 2004;109:III39-43.
4. Pletcher MJ, Lazar L, Bibbins-Domingo K, et al. Comparing impact and cost-effectiveness of primary prevention strategies for lipid-lowering. Ann Intern Med. 2009;150:243-54.
5. Peto R, Emberson J, Landray M, et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med. 2008;359:1357-66.
Cardiology, Coronary Risk Factors, Dyslipidemia.
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