Scott Kaatz

Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation An Analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial

Background— Dabigatran 150 and 110 mg twice a day and warfarin are effective for stroke prevention in atrial fibrillation. The purpose of this study was to compare their risks of bleeding in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial. Methods and Results— The RE-LY trial randomized 18 113 patients to receive dabigatran 110 or 150 mg twice a day or warfarin dose adjusted to an international normalized ratio of 2.0 to 3.0 for a median follow-up of 2.0 years. Compared with warfarin, dabigatran 110 mg twice a day was associated with a lower risk of major bleeding (2.87% versus 3.57%; P=0.002), whereas dabigatran 150 mg twice a day was associated with a similar risk of major bleeding (3.31% versus 3.57%; P=0.32). There was a significant treatment-by-age interaction, such that dabigatran 110 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in patients aged <75 years (1.89% versus 3.04%; P<0.001) and a similar risk in those aged ≥75 years (4.43% versus 4.37%; P=0.89; P for interaction <0.001), whereas dabigatran 150 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in those aged <75 years (2.12% versus 3.04%; P<0.001) and a trend toward higher risk of major bleeding in those aged ≥75 years (5.10% versus 4.37%; P=0.07; P for interaction <0.001). The interaction with age was evident for extracranial bleeding, but not for intracranial bleeding, with the risk of the latter being consistently reduced with dabigatran compared with warfarin irrespective of age. Conclusions— In patients with atrial fibrillation at risk for stroke, both doses of dabigatran compared with warfarin have lower risks of both intracranial and extracranial bleeding in patients aged <75 years. In those aged ≥75 years, intracranial bleeding risk is lower but extracranial bleeding risk is similar or higher with both doses of dabigatran compared with warfarin. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT00262600.

Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation

Background— Dabigatran 150 and 110 mg twice a day and warfarin are effective for stroke prevention in atrial fibrillation. The purpose of this study was to compare their risks of bleeding in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial. Methods and Results— The RE-LY trial randomized 18 113 patients to receive dabigatran 110 or 150 mg twice a day or warfarin dose adjusted to an international normalized ratio of 2.0 to 3.0 for a median follow-up of 2.0 years. Compared with warfarin, dabigatran 110 mg twice a day was associated with a lower risk of major bleeding (2.87% versus 3.57%; P=0.002), whereas dabigatran 150 mg twice a day was associated with a similar risk of major bleeding (3.31% versus 3.57%; P=0.32). There was a significant treatment-by-age interaction, such that dabigatran 110 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in patients aged <75 years (1.89% versus 3.04%; P<0.001) and a similar risk in those aged ≥75 years (4.43% versus 4.37%; P=0.89; P for interaction <0.001), whereas dabigatran 150 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in those aged <75 years (2.12% versus 3.04%; P<0.001) and a trend toward higher risk of major bleeding in those aged ≥75 years (5.10% versus 4.37%; P=0.07; P for interaction <0.001). The interaction with age was evident for extracranial bleeding, but not for intracranial bleeding, with the risk of the latter being consistently reduced with dabigatran compared with warfarin irrespective of age. Conclusions— In patients with atrial fibrillation at risk for stroke, both doses of dabigatran compared with warfarin have lower risks of both intracranial and extracranial bleeding in patients aged <75 years. In those aged ≥75 years, intracranial bleeding risk is lower but extracranial bleeding risk is similar or higher with both doses of dabigatran compared with warfarin. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT00262600.

CONFIRMATION OF A HEART FAILURE EPIDEMIC: FINDINGS FROM THE RESOURCE UTILIZATION AMONG CONGESTIVE HEART FAILURE (REACH) STUDY

OBJECTIVES The purpose of this study was to create an automated surveillance tool for reporting the incidence, prevalence and processes of care for patients with heart failure. BACKGROUND Previous epidemiologic studies suggest that the increasing prevalence of heart failure is a consequence of improved survival coupled with minimal changes in disease prevention. Developing new, efficient methods of assessing the incidence and prevalence of heart failure could allow continued surveillance of these rates during an era of rapidly changing treatments and health care delivery patterns. METHODS Using administrative data sets, we created a definition of heart failure using diagnosis codes. After adjustment for patients leaving our health system or death, we derived the incidence, prevalence and mortality of the population with heart failure from 1989 to 1999. RESULTS A total of 29,686 patients of all ages, 52.6% women and 47.4% men, met the definition of heart failure. Mean ages were 71.1 +/- 14.5 for women and 67.7 +/- 14.4 for men, p < 0.0001. Race proportions were 50.5% white, 44.6% African American and 4.9% other race. Incidence rates were higher in men and African Americans across all age groups. There was an annual increase in prevalence of 1/1,000 for women and 0.9/1,000 for men, p = 0.001 for both trends. CONCLUSIONS Through the feasible and valid use of automated data, we have confirmed a chronic disease epidemic of heart failure manifested primarily by an increase in prevalence over the past decade. Our surveillance system mirrors the results of epidemiologic studies and may be a valid method for monitoring the impact of prevention and treatment programs.

Perioperative Bridging Anticoagulation in Patients With Atrial Fibrillation

BACKGROUND It is uncertain whether bridging anticoagulation is necessary for patients with atrial fibrillation who need an interruption in warfarin treatment for an elective operation or other elective invasive procedure. We hypothesized that forgoing bridging anticoagulation would be noninferior to bridging with low-molecular-weight heparin for the prevention of perioperative arterial thromboembolism and would be superior to bridging with respect to major bleeding. METHODS We performed a randomized, double-blind, placebo-controlled trial in which, after perioperative interruption of warfarin therapy, patients were randomly assigned to receive bridging anticoagulation therapy with low-molecular-weight heparin (100 IU of dalteparin per kilogram of body weight) or matching placebo administered subcutaneously twice daily, from 3 days before the procedure until 24 hours before the procedure and then for 5 to 10 days after the procedure. Warfarin treatment was stopped 5 days before the procedure and was resumed within 24 hours after the procedure. Follow-up of patients continued for 30 days after the procedure. The primary outcomes were arterial thromboembolism (stroke, systemic embolism, or transient ischemic attack) and major bleeding. RESULTS In total, 1884 patients were enrolled, with 950 assigned to receive no bridging therapy and 934 assigned to receive bridging therapy. The incidence of arterial thromboembolism was 0.4% in the no-bridging group and 0.3% in the bridging group (risk difference, 0.1 percentage points; 95% confidence interval [CI], -0.6 to 0.8; P=0.01 for noninferiority). The incidence of major bleeding was 1.3% in the no-bridging group and 3.2% in the bridging group (relative risk, 0.41; 95% CI, 0.20 to 0.78; P=0.005 for superiority). CONCLUSIONS In patients with atrial fibrillation who had warfarin treatment interrupted for an elective operation or other elective invasive procedure, forgoing bridging anticoagulation was noninferior to perioperative bridging with low-molecular-weight heparin for the prevention of arterial thromboembolism and decreased the risk of major bleeding. (Funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health; BRIDGE ClinicalTrials.gov number, NCT00786474.).

Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors

The new oral anticoagulants dabigatran, rivaroxaban and apixaban have advantages over warfarin which include no need for laboratory monitoring, less drug–drug interactions and less food‐drug interactions. However, there is no established antidote for patients who are bleeding or require emergent surgery and there is a paucity of evidence to guide the clinical care during these situations. Members of thrombosis and anticoagulation groups participating in the Thrombosis and Hemostasis Summit of North America formulated expert opinion guidance for reversing the anticoagulant effect of the new oral anticoagulants and suggest: routine supportive care, activated charcoal if drug ingestion was within a couple of hours, and hemodialysis if feasible for dabigatran. Also, the pros and cons of the possible use of four factor prothrombin complex concentrate are discussed. Am. J. Hematol. 2012.

Short-Term Inhibition of Parathyroid Hormone Secretion by a Calcium-Receptor Agonist in Patients with Primary Hyperparathyroidism

BACKGROUND Surgery is the usual therapy for patients with primary hyperparathyroidism. We investigated the ability of a calcimimetic drug that inhibits parathyroid hormone secretion in vitro to decrease serum parathyroid hormone and calcium concentrations in patients with this disorder. METHODS We performed a randomized, placebo-controlled study of single oral doses of 4 to 160 mg of the calcium-receptor agonist drug R-568 in 20 postmenopausal women with mild primary hyperparathyroidism. At base line, the mean (+/-SE) serum calcium concentration was 10.7+/-0.2 mg per deciliter (2.67+/-0.05 mmol per liter). Serum parathyroid hormone and calcium were measured repeatedly after each dose, and safety was assessed. RESULTS Administration of R-568 resulted in a dose-dependent inhibition of parathyroid hormone secretion. The mean serum parathyroid hormone concentration, which was 77+/-11 pg per milliliter (18.8+/-2.7 pmol per liter; normal range, 16 to 65 pg per milliliter [3.9 to 15.9 pmol per liter) at base line, fell by 26+/-8 percent after 20 mg of R-568 (P=0.03), by 42+/-7 percent after 80 mg (P = 0.01), and by 51+/-5 percent after 160 mg (P=0.005). Serum ionized calcium concentrations fell only after the 160-mg dose, with the decrease closely following the decrease in the serum parathyroid hormone concentration. CONCLUSIONS The calcimimetic drug R-568 reduces serum parathyroid hormone and ionized calcium concentrations in postmenopausal women with primary hyperparathyroidism.

Periprocedural Heparin Bridging in Patients Receiving Vitamin K Antagonists: Systematic Review and Meta-Analysis of Bleeding and Thromboembolic Rates

Background— Periprocedural bridging with unfractionated heparin or low-molecular-weight heparin aims to reduce the risk of thromboembolic events in patients receiving long-term vitamin K antagonists. Optimal periprocedural anticoagulation has not been established. Methods and Results— MEDLINE, EMBASE, and Cochrane databases (2001–2010) were searched for English-language studies including patients receiving heparin bridging during interruption of vitamin K antagonists for elective procedures. Data were independently collected by 2 investigators (&kgr;=0.90). The final review included 34 studies with 1 randomized trial. Thromboembolic events occurred in 73 of 7118 bridged patients (pooled incidence, 0.9%; 95% confidence interval [CI], 0.0.0–3.4) and 32 of 5160 nonbridged patients (pooled incidence, 0.6%; 95% CI, 0.0–1.2). There was no difference in the risk of thromboembolic events in 8 studies comparing bridged and nonbridged groups (odds ratio, 0.80; 95% CI, 0.42–1.54). Bridging was associated with an increased risk of overall bleeding in 13 studies (odds ratio, 5.40; 95% CI, 3.00–9.74) and major bleeding in 5 studies (odds ratio, 3.60; 95% CI, 1.52–8.50) comparing bridged and nonbridged patients. There was no difference in thromboembolic events (odds ratio, 0.30; 95% CI, 0.04–2.09) but an increased risk of overall bleeding (odds ratio, 2.28; 95% CI, 1.27–4.08) with full versus prophylactic/intermediate-dose low-molecular-weight heparin bridging. Low-thromboembolic-risk and/or non–vitamin K antagonist patient groups were used for comparison. Study quality was poor with heterogeneity for some analyses. Conclusions— Vitamin K antagonist–treated patients receiving periprocedural heparin bridging appear to be at increased risk of overall and major bleeding and at similar risk of thromboembolic events compared to nonbridged patients. Randomized trials are needed to define the role of periprocedural heparin bridging.Background— Periprocedural bridging with unfractionated heparin or low-molecular-weight heparin aims to reduce the risk of thromboembolic events in patients receiving long-term vitamin K antagonists. Optimal periprocedural anticoagulation has not been established. Methods and Results— MEDLINE, EMBASE, and Cochrane databases (2001–2010) were searched for English-language studies including patients receiving heparin bridging during interruption of vitamin K antagonists for elective procedures. Data were independently collected by 2 investigators (κ=0.90). The final review included 34 studies with 1 randomized trial. Thromboembolic events occurred in 73 of 7118 bridged patients (pooled incidence, 0.9%; 95% confidence interval [CI], 0.0.0–3.4) and 32 of 5160 nonbridged patients (pooled incidence, 0.6%; 95% CI, 0.0–1.2). There was no difference in the risk of thromboembolic events in 8 studies comparing bridged and nonbridged groups (odds ratio, 0.80; 95% CI, 0.42–1.54). Bridging was associated with an increased risk of overall bleeding in 13 studies (odds ratio, 5.40; 95% CI, 3.00–9.74) and major bleeding in 5 studies (odds ratio, 3.60; 95% CI, 1.52–8.50) comparing bridged and nonbridged patients. There was no difference in thromboembolic events (odds ratio, 0.30; 95% CI, 0.04–2.09) but an increased risk of overall bleeding (odds ratio, 2.28; 95% CI, 1.27–4.08) with full versus prophylactic/intermediate-dose low-molecular-weight heparin bridging. Low-thromboembolic-risk and/or non–vitamin K antagonist patient groups were used for comparison. Study quality was poor with heterogeneity for some analyses. Conclusions— Vitamin K antagonist–treated patients receiving periprocedural heparin bridging appear to be at increased risk of overall and major bleeding and at similar risk of thromboembolic events compared to nonbridged patients. Randomized trials are needed to define the role of periprocedural heparin bridging. # Clinical Perspective {#article-title-50}

Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial.

BACKGROUND Post-thrombotic syndrome (PTS) is a common and burdensome complication of deep venous thrombosis (DVT). Previous trials suggesting benefit of elastic compression stockings (ECS) to prevent PTS were small, single-centre studies without placebo control. We aimed to assess the efficacy of ECS, compared with placebo stockings, for the prevention of PTS. METHODS We did a multicentre randomised placebo-controlled trial of active versus placebo ECS used for 2 years to prevent PTS after a first proximal DVT in centres in Canada and the USA. Patients were randomly assigned to study groups with a web-based randomisation system. Patients presenting with a first symptomatic, proximal DVT were potentially eligible to participate. They were excluded if the use of compression stockings was contraindicated, they had an expected lifespan of less than 6 months, geographical inaccessibility precluded return for follow-up visits, they were unable to apply stockings, or they received thrombolytic therapy for the initial treatment of acute DVT. The primary outcome was PTS diagnosed at 6 months or later using Ginsbergs criteria (leg pain and swelling of ≥1 month duration). We used a modified intention to treat Cox regression analysis, supplemented by a prespecified per-protocol analysis of patients who reported frequent use of their allocated treatment. This study is registered with ClinicalTrials.gov, number NCT00143598, and Current Controlled Trials, number ISRCTN71334751. FINDINGS From 2004 to 2010, 410 patients were randomly assigned to receive active ECS and 396 placebo ECS. The cumulative incidence of PTS was 14·2% in active ECS versus 12·7% in placebo ECS (hazard ratio adjusted for centre 1·13, 95% CI 0·73-1·76; p=0·58). Results were similar in a prespecified per-protocol analysis of patients who reported frequent use of stockings. INTERPRETATION ECS did not prevent PTS after a first proximal DVT, hence our findings do not support routine wearing of ECS after DVT. FUNDING Canadian Institutes of Health Research.

Self-monitoring of oral anticoagulation: systematic review and meta-analysis of individual patient data

BACKGROUND Uptake of self-testing and self-management of oral anticoagulation [corrected] has remained inconsistent, despite good evidence of their effectiveness. To clarify the value of self-monitoring of oral anticoagulation, we did a meta-analysis of individual patient data addressing several important gaps in the evidence, including an estimate of the effect on time to death, first major haemorrhage, and thromboembolism. METHODS We searched Ovid versions of Embase (1980-2009) and Medline (1966-2009), limiting searches to randomised trials with a maximally sensitive strategy. We approached all authors of included trials and requested individual patient data: primary outcomes were time to death, first major haemorrhage, and first thromboembolic event. We did prespecified subgroup analyses according to age, type of control-group care (anticoagulation-clinic care vs primary care), self-testing alone versus self-management, and sex. We analysed patients with mechanical heart valves or atrial fibrillation separately. We used a random-effect model method to calculate pooled hazard ratios and did tests for interaction and heterogeneity, and calculated a time-specific number needed to treat. FINDINGS Of 1357 abstracts, we included 11 trials with data for 6417 participants and 12,800 person-years of follow-up. We reported a significant reduction in thromboembolic events in the self-monitoring group (hazard ratio 0·51; 95% CI 0·31-0·85) but not for major haemorrhagic events (0·88, 0·74-1·06) or death (0·82, 0·62-1·09). Participants younger than 55 years showed a striking reduction in thrombotic events (hazard ratio 0·33, 95% CI 0·17-0·66), as did participants with mechanical heart valve (0·52, 0·35-0·77). Analysis of major outcomes in the very elderly (age ≥85 years, n=99) showed no significant adverse effects of the intervention for all outcomes. INTERPRETATION Our analysis showed that self-monitoring and self-management of oral coagulation is a safe option for suitable patients of all ages. Patients should also be offered the option to self-manage their disease with suitable health-care support as back-up. FUNDING UK National Institute for Health Research (NIHR) Technology Assessment Programme, UK NIHR National School for Primary Care Research.

Evidence-Based Risk Communication: A Systematic Review

Shared decision making is a collaborative process that allows patients and medical professionals to consider the best scientific evidence available, along with patients values and preferences, to make health care decisions (1). A recent Institute of Medicine report concluded that although people desire a patient experience that includes deep engagement in shared decision making, there are gaps between what patients want and what they get (2). For patients to get the experience they want, providers must effectively communicate evidence about benefits and harms. To improve the decision-making process, the Institute of Medicine recommended development and dissemination of high-quality communication tools (2). New tools, however, must match patients numerical abilities, which are often limited. For example, in one study, as many as 40% of high school graduates could not perform basic numerical operations, such as converting 1% of 1000 to 10 of 1000. This collective statistical illiteracy is a major barrier to the interpretation of health statistics (3). Physicians may also find statistical information difficult to interpret and explain (4). Existing literature about methods of communicating benefits and harms is broad. One review, based on 19 studies, concluded that the choice of a specific graphic is not as important as whether the graphic frames the frequency of an event with a visual representation of the total population in which it occurs (5). Another review, involving a limited literature search, found that comprehension improved when using frequencies (such as 1 in 5) instead of event rates (such as 20%) and using absolute risk reductions (ARRs) instead of relative risk reductions (RRRs) (6). The review did not assess affective outcomes, such as patient satisfaction, and behavioral outcomes, such as changes in decision making. Yet another review identified strong evidence that patients misinterpret RRRs and supported the effectiveness of graphs in communicating harms (7). However, they did not examine the comparative effectiveness of such approaches. More narrowly focused Cochrane reviews examined the communication of risk specific to screening tests (8, 9); numerical presentations, such as ARRs, RRRs, and numbers needed to treat (NNTs) (10); and effects of decision aids (11). An expert commentary about effective risk communication recommended using plain language, icon arrays, and absolute risks and providing time intervals with risk information (12). A group of experts identified 11 key components of risk communication, including presenting numerical estimates in context with evaluative labels, conveying uncertainty, and tailoring estimates (13). The aim of this systematic review is to comprehensively examine the comparative effectiveness of all methods of communicating probabilistic information about benefits and harms to patients to maximize their understanding, satisfaction, and decision-making ability. Methods We developed and followed a plan for the review that included several searches and dual abstraction of study data using standardized abstraction forms. Data Sources and Study Selection We searched PubMed (1966 to March 2014), CINAHL, EMBASE, and the Cochrane Central Register of Controlled Trials (1966 to December 2011) using keywords and structured terms related to the concepts of patients; communication; riskbenefit; and outcomes, such as understanding or comprehension, preferences or satisfaction, and decision making. Supplement 1 shows the detailed search strategy. Supplement 1. Search Strategies We included cross-sectional or prospective, longitudinal trials that were published in English and had an active control group that recruited patients or healthy volunteers and compared any method of communicating probabilistic information with another method. We focused on different methods of communicating the same specific probabilities to eliminate any independent effects that could result from different probabilities being studied (for example, different magnitudes or directions of effect). Studies of personalized risks, which may vary from person to person, were included when participants were randomly assigned. When studies of personalized risks were not randomized, the risks were considered to differ between the groups and were excluded. No limits were placed on study size, location, or duration or on the nature of the communication method. When needed, we reviewed sources specified in the articles, such as Web sites, to directly review the interventions and determine whether probabilistic information was addressed. Studies of medical students, health professionals, and public health or mass media campaigns were excluded. One independent reviewer screened each title and abstract and excluded citations that were not original studies or were unrelated to probabilistic information. Two independent reviewers screened the full text of the remaining citations to identify eligible articles. Disagreements between the 2 reviewers were resolved by consensus, with a third reviewer arbitrating any unresolved disagreements. Data Extraction and Quality Assessment Two reviewers independently abstracted detailed information about the study population, interventions, primary outcomes, and risk of bias from each included study using a standardized abstraction form, which was developed a priori (Supplement 2). A third reviewer resolved any disagreements. We categorized outcomes in 1 of 3 domains: cognitive (or understanding, such as accuracy in answering questions related to probabilistic information, or general comprehension of the probabilistic information), affective (such as preferences for or satisfaction with the method of communicating probabilistic information), and behavioral (such as real or theoretical decision making). Supplement 2. Abstraction Form Risk of bias in randomized, controlled trials was assessed on the basis of adequacy of randomization, allocation concealment, similarity of study groups at baseline, blinding, equal treatment of groups throughout the study, completeness of follow-up, and intention to treat (participants analyzed in the groups to which they were randomly assigned) (14). Risk of bias in observational studies was assessed with a modified set of criteria adapted from the NewcastleOttawa Scale (15). Data Synthesis and Analysis Data were tabulated, and the frequency of all head-to-head comparisons in studies was assessed to identify clusters of comparisons. In many instances, several interventions were bundled in a single study group (such as event rate plus icon array, or event rate plus natural frequencies plus ARRs). Bundles were not separated or combined with similar interventions because it could not be determined which component of the bundle drove the intervention. Descriptive statistics were used. We decided a priori not to do meta-analysis because of study heterogeneity. We emphasized findings from randomized studies as well as nonrandomized studies when findings were supported by more than 1 study. Role of the Funding Source No funding supported this study. The authors participated within their role on the Evidence-Based Medicine Task Force of the Society of General Internal Medicine. Results The initial search through December 2011 retrieved 22103 citations (16661 from PubMed, 1194 from CINAHL, 2861 from the Cochrane Central Register of Controlled Trials, and 1387 from EMBASE), and 20076 remained after removing duplicates. We updated the PubMed search through 30 March 2014, yielding 6529 additional citations; 5970 remained after removing duplicates, for a total of 26046 citations for review. A total of 630 articles were selected for full-text review and 84 were included, representing 91 unique studies (1699). Reasons for exclusion are noted in Figure 1, and study details are provided in Supplement 3. Figure 1. Summary of evidence search and selection. Supplement 3. Details of All Included Studies Seventy-four (81.3%) of the 91 included studies were randomized trials, most with cross-sectional designs. The median number of participants in randomized trials was 268 (range, 31 to 4685), and the median in all studies was 268 (range, 24 to 16133). Thirty-three studies (36.3%) included patients at specific risk for the target condition of interest. Forty-eight studies (52.7%) presented probabilistic data about benefits of a therapy or intervention (with 7 [14.6%] also presenting harms), 21 (23.1%) presented data only on harms, and 9 (10%) involved screening tests. Forty-nine studies (54.4%) delivered interventions on paper and 39 (42.9%) on a computer, typically over the Internet. The characteristics of study participants are presented in Tables 1 and 2. Table 1. Characteristics of Study Participants Table 2. Proportion of Studies Including Participants at Risk Versus Not at Risk for Target Condition Risk of bias for the included randomized trials was moderate (Figure 2). Randomization was adequate in 32 trials (42.7%), inadequate in 3 (4.0%), and unclear in 40 (53.3%). Allocation concealment was not stated in 55 trials (73.3%). Similarity of groups at baseline was adequate in 37 trials (49.3%) and unclear in 32 (42.7%). Blinding, equal treatment, and intention-to-treat items were similarly difficult to assess from reported information. Figure 2. Risk of bias for randomized, controlled trials (n = 74). Adapted from reference 100. Study Interventions and Comparators A frequency table (heat map) of all study intervention comparisons was created to identify clusters of comparisons (Supplement 4). The heat map represents study group comparisons, so one study may contribute several comparisons. The most commonly studied numerical presentations of data were natural frequencies, defined as the numbers of persons with events juxtaposed with a baseline denominator of persons (for example, 4 out of 100 persons had the outcome); event rates, defined as the proportions of persons wi