Top POEMs of 2014: Cardiovascular Disease

Top 20 POEMs of 2014

Greatest Benefits from HTN Treatment in Patients at High Risk for CVD

Clinical question
Is baseline cardiovascular risk associated with the outcomes of hypertension treatment?

Bottom line
This study reinforces a concept long known from other studies: Treating patients at the highest risk of bad outcomes is associated with the greatest treatment benefit. (LOE = 1a-)

Reference
Blood Pressure Lowering Treatment Trialists' Collaboration, Sundström J, Arima H, et al. Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data. Lancet 2014;384(9943):591-598.

Study design: Meta-analysis (other)

Funding source: Self-funded or unfunded

Setting: Outpatient (any)

Synopsis
These authors pooled individual patient data from 11 randomized trials in which patients were randomly allocated to blood pressure–lowering medication or placebo, or to different levels of treatment intensity. The trials pooled available data from nearly 52,000 patients with a median follow up of 4 years. The authors plugged a ton of data into a model based on the actual trial outcomes and then shuffled the deck to find the relationship between the baseline risk, treatment intensity, and 5-year outcomes. This is quite different from randomizing patients to different treatments based on baseline risk assessed a priori. This was an incredible data mining effort that is probably best for generating hypotheses. After gathering their data, the researchers identified 4 different risk strata based on the 5-year likelihood of experiencing a cardiovascular event: less than 11%, 11% to 15%, 15% to 21%, and more than 21%. Compared with the lowest risk stratum, the researchers found no significant relative difference across the other strata (13% - 18%). However, the absolute rate of reduced events for each treatment stratum was approximately 1.5%, 2%, 2.5%, and 4%, respectively. The authors report that if one treated 1000 patients from each stratum for 5 years, there would be 14, 20, 24, and 38 fewer events.

Henry C. Barry, MD, MS
Professor
Michigan State University
East Lansing, MI

New Anticoagulants vs Warfarin in A Fib: No Clear Winner

Clinical question
Are the newer anticoagulants safer or more effective than warfarin in patients with atrial fibrillation?

Bottom line
In this meta-analysis, newer anticoagulants appear to be slightly more effective than warfarin in the short term (2 years) in preventing strokes of all kinds in patients with atrial fibrillation. However, they are no more effective than warfarin in preventing ischemic strokes, and they cause more gastrointestinal hemorrhage. The short-term nature of the included studies and a significant concern about publication bias suggests that the newer agents are by no means a slam dunk over warfarin. Since the patients taking warfarin only spent two thirds of their time in therapeutic range, perhaps efforts to improve performance may be a wiser use of resources. (LOE = 1a-)

Reference
Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383(9921):955-962.

Study design: Meta-analysis (randomized controlled trials)

Funding source: Self-funded or unfunded

Setting: Various (meta-analysis)

Synopsis
The authors of this study and the editors of Lancet did a fairly abysmal job in communicating how this study was conducted. The abstract claims the authors searched a single database to identify phase randomized trials comparing newer anticoagulants with warfarin in patients with atrial fibrillation. However, the methods section reports the authors conducted a prespecified analysis of 4 studies and doesn’t describe a thing about the search strategy. Additionally, the authors don't include data on ximelagatran, which was pulled because of safety concerns. The authors pooled the data for nearly 72,000 patients with atrial fibrillation who received one of the newer anticoagulants (dabigatran, rivaroxaban, apixaban, or edoxaban; n = 42,411) or warfarin (n = 29,272). The authors evaluated the outcomes by intention to treat "when possible," but made no adjustments for performing multiple analyses. Two of the four trials included nearly one third of the patients with CHADS2 scores of 0 to 1, which is a group that may not need anticoagulation. Overall, approximately one fourth of the patients had paroxysmal atrial fibrillation. The median duration of follow-up was 2.2 years and the warfarin-treated patients were in therapeutic range only two thirds of the time. Patients receiving the newer agents had a lower risk of stroke or systemic embolic events than patients taking warfarin (3.1% vs 3.8%; relative risk = 0.81; number needed to treat (NNT) =148; 95% CI, 103 - 261). There was no statistically significant differences in the rate of ischemic stroke or myocardial infarction. Patients taking the newer agents had fewer hemorrhagic strokes (0.4% vs 0.9%; NNT = 220; 170 - 308) and intracranial hemorrhages (0.7% vs 1.4%; NNT = 132; 108 - 169). Furthermore, all-cause mortality was slightly lower in patients receiving the newer agents (6.9% vs 7.7%; NNT = 129; 84 - 279). However, patients taking newer agents had more gastrointestinal bleeding (2.6% vs 2%; number needed to treat to harm = 185; 128 - 335). Although the study was unfunded, the authors had heavy ties to industry, which may explain their sloppiness in describing their methods. For example, they don't even try to evaluate the potential for publication bias, an issue especially important since industry-sponsored studies have a long track record of not finding their way to publication.

Henry C. Barry, MD, MS
Professor
Michigan State University
East Lansing, MI

Patients with AF Taking Aspirin with Anticoagulant at Increased Bleeding Risk Without Clear Benefit (ORBIT-AF)

Clinical question
In patients with atrial fibrillation, does use of aspirin in addition to an anticoagulant improve or worsen clinical outcomes?

Bottom line
Many patients with atrial fibrillation (AF) are receiving aspirin (A) in addition to an oral anticoagulant (OAC), despite the fact that 40% of the patients in this study had no indication for aspirin (eg, no known atherosclerotic disease). Concomitant use of aspirin increased the risk of bleeding over OAC alone (adjusted hazard ratio [aHR] = 1.5) without any clear benefit regarding cardiovascular events. This practice persists despite lack of support from randomized trials (the lone potential exception is the group of patients with a mechanical heart valve). This is a case in which less may be more, and randomized trials comparing OAC with A+OAC are needed in this population. (LOE = 2b)

Reference
Steinberg BA, Kim S, Piccini JP, et al, for the ORBIT-AF Investigators and Patients. Use and associated risks of concomitant aspirin therapy with oral anticoagulation in patients with atrial fibrillation: insights from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry. Circulation 2013;128(7):721-728.

Study design: Cohort (retrospective)

Funding source: Industry + Government

Setting: Population-based

Synopsis
Most patients with AF are treated with an anticoagulant. Those who also have an indication for an antithrombotic, such as known coronary artery or cerebrovascular disease, may also be given aspirin. The benefit of this incremental therapy (aspirin plus oral anticoagulant [A+OAC]) is uncertain.The authors used a registry of 10,126 adult outpatients being treated for AF; those with reversible cause or short life expectancy were excluded. After also excluding those who were not taking an anticoagulant and those taking other antithrombotics, they were left with 4804 patients who were taking OAC and 2543 who were taking A+OAC. Those using combination therapy were more likely to be male (53% OAC, 66% A+OAC) and more likely to smoke, have hyperlipidemia, diabetes mellitus, or heart failure. A multivariate analysis found that those being given A+OAC had a higher likelihood of known coronary artery disease (adjusted odds ratio [aOR] = 2.2), previous ablation (aOR = 1.6), previous stent placement (aOR 1.5), or previous stroke or transient ischemic attack (aOR = 1.5). Older patients, those with long-standing or persistent AF, those living in the southern or western states, patients with liver or renal disease, and those being cared for by a primary care physician were less likely to be using combination therapy. Using an adjusted propensity score analysis, the authors also looked at the likelihood of adverse outcomes at 6 months between groups. Major bleeding (aHR = 1.5; 95% CI 1.2 - 2.0) and bleeding resulting in hospitalization [aHR = 1.5; 1.2 - 2.0) were both significantly more likely in patients receiving concomitant aspirin therapy. When limiting the analysis to only those patients with previous myocardial infarction (n = 947) or stroke (n = 1042), although the overall number of cardiovascular or bleeding events was small, there was no apparent difference in the likelihood of these events between groups.

Mark H. Ebell, MD, MS
Associate Professor
University of Georgia
Athens, GA

Anticoagulant Plus NSAID or Aspirin Use Associated with Increased Bleeding Risk

Clinical question
For patients with acute venous thromboembolism, is the use of anticoagulants plus nonsteroidal anti-inflammatory drugs or aspirin associated with an increased risk of bleeding?

Bottom line
For patients treated with anticoagulants for acute venous thromboembolism (VTE), the use of concomitant nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin is associated with an increased risk of bleeding. This can occur in patients treated with rivaroxaban, as well as in those treated with enoxaparin plus a vitamin K antagonist (VKA). (LOE = 2b)

Reference
Davidson BL, Verheijen S, Lensing AW, et al. Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin. JAMA Intern Med 2014;174(6):947-953.

Study design: Cohort (prospective)

Funding source: Industry

Allocation: Uncertain

Setting: Outpatient (any)

Synopsis
The worldwide EINSTEIN DVT and EINSTEIN PE clinical trials compared rivaroxaban with enoxaparin plus a VKA for the treatment of acute VTE. These investigators used data from this cohort to examine the association between rivaroxaban or enoxaparin-VKA plus concomitant NSAID or aspirin use and the risk of clinically relevant and major bleeding. Clinically relevant bleeding was defined as nonmajor bleeding that resulted in either medical intervention, temporary cessation of study treatment, or patient discomfort. Major bleeding was that which resulted in death, occurred at a critical site, required tranfusion of at least 2 units of red blood cells, or was associated with a 2 g/dL drop in hemoglobin. The cohort comprised 8246 patients, with half receiving rivaroxaban and half receiving enoxaparin-VKA. The NSAID analysis was adjusted for sex, as there were more women in the NSAID group. The aspirin analysis was adjusted for age and creatinine clearance, as patients in the aspirin group tended to be older with worse kidney function than the nonaspirin group. The NSAID or aspirin exposure period included 7 days after stopping the medication to reflect an ongoing risk. Clinically relevant bleeding was more likely to occur in the NSAID group as compared with the non-NSAID group (37.5 bleeding events per 100 patient-years vs 16.6 per 100 patient-years; hazard ratio [HR] = 1.77; 95% CI, 1.46-2.14). Findings were similar for both the NSAID-rivaroxaban-treated patients and NSAID-enoxaparin-VKA-treated patients. In the aspirin group, clinically relevant bleeding was also increased as compared with the nonaspirin group (36.6 bleeding events per 100 patient-years vs 16.9 per 100 patient-years; HR = 1.70; 1.38-2.11). For both the NSAID and the aspirin groups, the bleeding events were spread evenly over the duration of the use, suggesting that longer duration of use does not increase the risk of bleeding. Major bleeding increased 2.4-fold in the NSAID group and 1.5-fold in the aspirin group.

Nita Shrikant Kulkarni, MD
Assistant Professor in Hospital Medicine
Northwestern University
Chicago, IL

Increasing HDL Level Ineffective at Decreasing Cardiovascular Events

Clinical question
Does treatment aimed at increasing high-density lipoprotein levels, in addition to treatment with statins, decrease cardiovascular events and deaths due to any cause?

Bottom line
I guess being the "good" cholesterol is not the same as being the "useful" cholesterol. Drug therapy aimed at increasing high-density lipoprotein (HDL) cholesterol levels, when added to statin treatment, does not decrease patients' likelihood of experiencing a cardiovascular event or dying earlier. (LOE = 1a)

Reference
Keene D, Price C, Shun-Shin MJ, Francis DP. Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117 411 patients. BMJ 2014;349:g4379 doi: 10.1136/bmj.g4379.

Study design: Meta-analysis (randomized controlled trials)

Funding source: Self-funded or unfunded

Setting: Various (meta-analysis)

Synopsis
The researchers searched 3 databases, including the Cochrane Library, reference lists of previous meta-analyses and reviews, and conference proceedings to find large (> 1000 patients) randomized trials that compared drugs aimed at increasing HDL cholesterol levels with various interventions that do not increase HDL. Two authors independently completed the searches and 3 authors extracted the data. They found 11 studies of niacin, 20 of fibrates, and 8 studies of cholesteryl ester transfer protein (CETP) inhibitors such as anacetrapib and dalcetrapib (this class of drugs is not available in the United States, Canada, or the United Kingdom). All told, the studies enrolled more than 100,000 patients and found that attempting to increase the HDL level conferred no benefit on all-cause mortality, coronary heart disease mortality, or stroke likelihood. The problem, if you want to call it that, is the effect of statins -- studies conducted in the current "statin era" do not show an added benefit of trying to bump HDL levels even though early studies of niacin by itself showed a pronounced effect in reducing nonfatal myocardial infarction.

Allen F. Shaughnessy, PharmD, MMedEd
Professor of Family Medicine
Tufts University
Boston, MA

POEMs are provided by Essential Evidence Plus, a point-of-care clinical decision support system published by Wiley-Blackwell. For more information, please see http://www.essentialevidenceplus.com(www.essentialevidenceplus.com).

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