Author + information
- Jérémie Abtan, MD†,
- Yedid Elbez, MSc†,
- Deepak L. Bhatt, MD, MPH‡ and
- Philippe Gabriel Steg, MD†,§∗ ()
- †Département Hospitalo-Universitaire Fibrosis-Inflammation-REmodelling: Hôpital Bichat (Assistance Publique–Hôpitaux de Paris), and INSERM U-1148, Université Paris-Diderot, Paris, France
- ‡Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
- §National Heart and Lung Institute, Institute of Cardiovascular Medicine and Science, Royal Brompton Hospital, Imperial College, London, United Kingdom
- ↵∗Hôpital Bichat, 46 rue Henri Huchard, 75018 Paris, France
For many years, some have suggested that beta-blockers modify the metabolic profile of patients treated for high blood pressure. A pre-specified analysis of ASCOTAnglo-SCandinavian Outcomes Trial) (1) assessing the synergistic effects of lipid-lowering and blood-pressure-lowering therapies suggested a negative interaction between beta-blockers and statins, as compared with calcium-channel blockers (CCBs) and statins, with an increased rate of ischemic events among patients receiving both therapies. However, this observation was not officially confirmed (2) and therefore uncertainty persists. Given that many patients receive both types of agents, particularly in secondary prevention after acute coronary syndromes, clarifying whether such an interaction exists or not is important. A recent analysis of beta-blocker use in stable atherothrombotic patients failed to show a benefit of beta-blockers in this population (3). Whether this lack of benefit is due to a worsened metabolic profile on beta-blockers remains unknown.
We sought to study whether a negative interaction exists between beta-blocker use and the benefit of statins in patients with atherothrombosis treated in primary or secondary prevention, using the REACH (Reduction in Atherothrombosis for Continued Health) registry. The design, methods, and main results of REACH, an international, prospective, observational study, have been published (4,5). Briefly, REACH enrolled consecutive patients, aged 45 years or older, with established coronary artery disease (CAD), cerebrovascular disease (CVD), or peripheral arterial disease (PAD), or with at least 3 atherothrombotic risk factors. All patients provided signed informed consent and the institutional review board in each country approved the protocol. The study participants enrolled in the REACH registry were from 7 geographical regions in 44 countries. Data were collected using standardized case report forms. Patients were followed up prospectively for 2 years and in selected countries up to 4 years for the occurrence of cardiovascular outcomes, hospitalization, or vascular interventions.
Patients were categorized on the basis of statin and beta-blocker use at baseline. Interaction between beta-blocker and statin use was then tested. Analyses were performed in the entire cohort and in the subsets with established CAD, CVD, or PAD. The primary endpoint was a composite of cardiovascular death, nonfatal MI, or nonfatal stroke. Hazard ratios (HRs) were estimated between groups (no statin versus statin use).
Because of differences in key baselines characteristics between comparison groups, we introduced propensity score adjustment in HRs estimations. Propensity score was calculated using a multivariable logistic regression model, with the dependent variable of “statin use”, and 23 covariates describing baselines characteristics (sex, age, region, BMI), medical history (smoking status, history of transient ischemic stroke, stroke, stable angina, carotid angioplasty or stenting, carotid surgery, aortic valve stenosis, diabetes) and baseline medication (use of aspirin, anticoagulant, anti-diabetics agent, lipid-lowering agent other than statin, CCBs, nitrates, or other anti-anginal agents, diuretics, angiotensin-converting enzyme inhibitors, angiotensin-II receptor antagonists, other antihypertensive drugs, or peripheral arterial claudication drug). The same propensity scores were used for adjustment in global cohort and in subgroups analyses. Statistical analyses were all performed using SAS version 9.3 (SAS Institute, Cary, North Carolina).
Based on the REACH registry (n = 65,531), we assessed statins and beta-blockers at baseline in 65,181 patients (99.5%). Within this cohort, 45,312 patients (69.5%) were treated by statins and 30,971 patients (47.5%) by beta-blockers. Regarding the medical history, 38,758 patients (59.5%) had CAD, 18,102 patients (27.8%) had CVD, and 7,947 patients (12.2%) had PAD at baseline. Overall, median follow-up was 37 months (interquartile range [IQR]: 21 to 45 months).
Statin use was consistently associated with lower adjusted primary endpoint event rate. This was observed among patients treated with beta-blockers (942 [Kaplan-Meier estimate: 18.0%] vs. 2,346 events [Kaplan-Meier estimate: 13.6%], HR: 0.79 [95% CI: 0.72 to 0.86]), and also among patients not on beta-blockers (1,623 [16.9%] vs. 1,877 events [12.5%], HR: 0.73 [95% CI: 0.68 to 0.79]), for patients receiving statins or not respectively. There was no interaction between beta-blocker use and the benefit of statins (p value for interaction: 0.94). Consistent results were observed across all patient subsets (Fig. 1), with no evidence of negative interaction. Furthermore, results were similar for each of the components of the primary outcome analyzed separately.
There are some limitations to this analysis. The type of beta-blocker was not collected, and it has been suggested that a negative interaction of beta-blockers may be more marked for nonselective beta-blockers or for those with sympathomimetic activity. Although propensity score matching adjusts for baseline differences, the possibility of residual confounding cannot be ruled out. Furthermore, unlike ASCOT, a randomized trial with comparable groups, our data are from a registry, probably ruling out a quantitative but not qualitative interaction.
In this large international contemporary cohort for those patients at risk for atherothrombosis or not, there was no evidence of a negative interaction between beta-blockers and the benefit of statins on cardiovascular outcomes.
Please note: Dr. Bhatt is a member of Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences advisory boards; serves on the boards of directors of Boston Veterans Affairs Research Institute and Society of Cardiovascular Patient Care; is Chair of American Heart Association Get With The Guidelines Steering Committee; has received honoraria from American College of Cardiology (Editor, Clinical Trials, Cardiosource), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), and WebMD (CME steering committees); serves as Senior Associate Editor, Journal of Invasive Cardiology, and Data Monitoring Committee member of Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and Population Health Research Institute; and has received research grants from Amarin, AstraZenecahttp://dx.doi.org/10.13039/100004325, Bristol-Myers Squibbhttp://dx.doi.org/10.13039/100002491, Eisaihttp://dx.doi.org/10.13039/501100003769, Ethicon, Medtronichttp://dx.doi.org/10.13039/100004374, Sanofi-Aventis, and The Medicines Company; and unfunded research from FlowCo, PLx Pharma, and Takeda. Dr. Steg has received research grants through Unité INSERM U-1148 from Sanofi-Aventis and Servier; has consulted with and served as speaker for Amarin, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers-Squibb, Daiichi-Sankyo, GlaxoSmithKline, Iroko Cardio, Lilly, Merck, Novartis, Otsuka, Pfizer, Sanofi, Servier, The Medicines Company, and Vivus; and is a stockholder in Aterovax. All other authors have reported they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
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