Essential Evidence Topics NDAFP 59th Annual Meeting and Scientific Assembly

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1 Essential Evidence Topics 2014 NDAFP 59th Annual Meeting and Scientific Assembly Learning Objective Discuss recent research important to family physicians for updating their diagnostic and treatment approaches to selected issues in cardiovascular disease, diabetes, mens health and sports medicine. Objectives for each presentation are listed at the beginning of each talk. Faculty John Hickner, MD, MSc. is Professor and Head of Family Medicine at the University of Illinois at Chicago and Editor in Chief of the Journal of Family Practice. His research centers on patient safety, especially testing safety and medication safety in primary care practice. After receiving his medical degree from Indiana University School of Medicine, Dr. Hickner completed his residency in family medicine at the Medical University of South Carolina and received a master s degree in Biostatistics and Research Design from the University of Michigan School of Public Health. Gary Ferenchick, MD, MS. is Division Chief, General Internal Medicine, and Professor of Medicine at Michigan State University College of Human Medicine. He earned his master s degree in human nutrition and medical degree from Michigan State University. He completed his residency training in internal medicine at Michigan State University College of Human Medicine. Dr. Ferenchick is a Past- President of the Clerkship Directors in Internal Medicine. His research interest is the interface between medical education and information technology. Speaker and Faculty Disclosures John Hickner, MD, MSc disclosed no relevant financial relationship or interest with a proprietary entity producing health care goods or services. Gary Ferenchick, MD disclosed no relevant financial relationship or interest with a proprietary entity producing health care goods or services. Essential Evidence and all content in this handout is copyright by John Wiley and Sons, Inc, This syllabus may not be reproduced without permission from the publisher. 1

2 Information Mastery Key Points Objectives 1. Learn the importance of patient oriented evidence for interpretation of research studies. 2. Learn an efficient way to use PubMed to search for information Usefulness of medical information = (relevance x validity) / work Relevance is a continuum: Rat studies Surrogates Disease-specific All-cause mortality/qol Validity is a continuum: Case study Case-control Cohort RCT Systematic review Patient oriented evidence: anything that helps patients live a longer or better life. Disease oriented evidence: everything else; surrogate or physiologic markers POEMs (Patient Oriented Evidence that Matters): a study that addresses a common or important condition, demonstrates improved patient oriented outcomes, and matters because it would change what we do. Evidence-based sources to explore: Essential Evidence: Clinical Evidence: Cochrane Library: DynaMed: TRIP Database: Bandolier: National Guidelines Clearinghouse: Search hints Use Clinical Queries at the PubMed site Select Narrow filter Use quotes to narrow search to only those words appearing next to each other, i.e. acute bronchitis eliminates acute exacerbation of chronic bronchitis Combination of drug and disease is useful: acute bronchitis azithromycin; infectious mononucleosis corticosteroid; influenza osletamivir Optionally, See all and then add additional limits (English, abstract, human) Use Not terms to exclude groups of articles Then, select Related articles once you have a good hit. 2

3 ANTICOAGULATION UPDATE: 2014 NEW AGENTS Gary Ferenchick MD Objective 1. Understand the evidence behind the FDA approved uses of newer oral anticoagulants (i.e. NOAs) including dabigatran and apixaban and rivaroxaban What is the role of newer anticoagulants in the prevention of thromboembolic disease? Some of the difference between the newer anticoagulants and the older anticoagulants, such as warfarin and heparin, is that the new agents target a single enzyme within the coagulation pathway (e.g. thrombin [aka activated factor IIa] or factor Xa); whereas warfarin inhibits the synthesis of factors II, VII, IX, and X, and heparin increases the activity of antithrombin (AT) which exerts an inhibitory effect on factor Xa, thrombin and other factors. Additionally the newer agents have a more rapid onset of action than warfarin, lack the need for bridging anticoagulation and have fewer dietary and drug restrictions and possess a predictable anticoagulant effect limiting the need for routine monitoring protocols. The development of thrombus is a fast process, taking < 5 minutes from the activation of the clotting cascade to the development of clot. Factor Xa is located at the convergence point of both the intrinsic and extrinsic pathways and has proven to be an effective target for anticoagulation. Note that one molecule of factor Xa catalyzes the formation of ~ 1000 molecules of thrombin. The oral direct Xa inhibitors, rivaroxaban, apixaban and edoxaban, inhibit both free and bound factor Xa, whereas the indirect factor Xa inhibitor is fondaparinux, which is given subcutaneously and acts by enhancing the activity of AT, only inhibits free factor Xa. Am J Emerg Med 2012;30:2046 The direct thrombin inhibitor dabigatran inhibits thrombin (thus preventing fibrin formation) and thrombin-mediated activation of several clotting factors (V, VIII and XI) along with inhibiting thrombin mediated platelet activation. Dabigatran was the first new oral anticoagulant to become available in 50 years and directly inhibits thrombin (see figure). In 2011 the American College of Cardiology and the American Heart Association published an update on the management of patients with atrial fibrillation with a focus on dabigatran. They issued a new recommendation that endorsed dabigatran (with a Class I recommendation, meaning the treatment should be administered) as a useful alternative "... to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal to permanent AF and risk factors for stroke or systemic embolization who do not have a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure (creatinine clearance <15 ml/min), or advanced liver disease (impaired baseline clotting function)." The recommendation also states that patients already taking warfarin with excellent INR control may have little to gain by switching to dabigatran. (Circulation 2011;123: ) Additionally, as of January of 2014 edoxaban, this directly inhibits factor Xa, is awaiting FDA approval for stroke prophylaxis in patients with atrial fibrillation among other indications. As a general rule for patients with non-valvular atrial fibrillation, aspirin in doses mg decreases the combination of CVA, MI and vascular death by about 29% compared to placebo in primary prevention trials; and oral anticoagulants 3

4 (warfarin) decreases the risk of stroke and other major vascular events by another 33% compared to aspirin, and by about 64% in those with atrial fibrillation and a history of a TIA. Drug (Trade Name) Mechanism FDA Approved Indication(s) General Dosing DDIs Apixaban (Eliquis) Factor Xa inhibitor Nonvalvular atrial fib mg bid itraconazole, clarithromycin among others Rivaroxaban (Xarelto) Factor Xa inhibitor Nonvalvular atrial fib Treatment of DVT and/or PE Prevent of recurrent DVT and PE following initial 6 months treatment for DVT and/or PE Dosing more complex: AF: mg with evening meal for AF (depending on creatinine clearance) (DDI major = amiodarone diltiazem, verapamil, felodipine, azithromycin among others) Prevention of DVT/PE in pts undergoing knee or hip replacement surgery Rx DVT/PE: 15 bid with food for 21 days, then 20 mg daily with food Prevent DVT/PE recurrence: 20 daily with food DVT prophylaxis with hip and knee surgery: 10 mg once daily for 12 (knee) or 35 (hip) days Edoxaban (Savaysa) Factor Xa inhibitor Seeking approval for Non-valvular atrial fibrillation (NVAF) The treatment of DVT/PE Dabigatran (Pradaxa) Direct thrombin inhibitor The prevention of recurrence of symptomatic venous thromboembolism Nonvalvular atrial fib mg bid depending on Cr Clearance 4

5 Drug Major studies supporting FDA approval FDA approved indications Rivaroxaban (Xarelto) ROCKET AF Treatment non valvular AF EINSTEIN DVT EINSTEIN PE RECORD1-4 Treatment of DVT, PE AND Reduction of the risk of recurrence of DVT and PE Prevention of DVT in patients undergoing knee or hip replacement surgery Apixiban (Eloquiis) ARISTOTLE, AVERROES Treatment of non-valvular atrial fib Dabigitran (Pradaxa) RE-LY Treatment of non valvular as Oct 2010 According to the FDA Specific antidotes or reversal agents for all of the above are not available Note also many other studies from the manufacturers are on-going in an attempt to expand indications for their drugs Note most of these newer anticoagulants have renal cautions; both in initiating the drugs and a caution to Periodically assess renal function Atrial Fibrillation #1: Dabigatran reduces risk of stroke and embolism in patients with AF (RE-LY) Clinical question: Is dabigatran more safe and effective than warfarin for the prevention of complications of atrial fibrillation? Study design: Randomized controlled trial (single-blinded) Setting: Outpatient (any) Synopsis: Dabigatran etexilate is an oral alternative to warfarin that directly inhibits thrombin. In this study, patients were randomized to receive dabigatran 110 mg twice daily, dabigatran 150 mg twice daily, or warfarin targeted to an INR between 2.0 and 3.0. Although patients and physicians were masked to the dose of dabigatran, they were not masked to the choice of dabigatran or warfarin. However, outcome assessors were masked to both, which is more important. The researchers enrolled 18,113 patients, with a mean age of 71 years. Groups were balanced at the start of the study, analysis was by intention to treat, and patients were followed up for a median of 2 years. Only 20 patients were lost to follow-up. In general, clinical outcomes were similar between the 110 mg dose of dabigatran and the warfarin. When compared with warfarin, the 150 mg dose of dabigatran was associated with a lower risk of stroke and death from vascular causes, but a slightly higher risk of myocardial infarction. Major bleeding was less common with the 110 mg dose than with warfarin (but not with the 150 mg dose). On balance, the net benefit was similar between the 2 doses of dabigatran; the lower risk of ischemia with the higher dose was balanced by a lower risk of bleeding with the higher dose. All-cause mortality was 3.75% in the 110 mg dose group, 3.64% in the 150 mg dose group, and 4.13% in the warfarin group. The comparison between dabigatran 150 mg and warfarin was of borderline statistical significance (P =.051, NNT = 200 for 2 years). Using the CHADS score as a measure of risk of stroke, only patients with a score of 3 or higher benefited from the lower dose, while all patients benefited from the higher dose. Bottom line: Dabigatran was slightly more effective than warfarin at preventing stroke and embolism, especially the dosage of 150 mg given twice daily, and may reduce all-cause mortality (number needed to treat [NNT] = 200 over 2 years). It will be important to balance efficacy with the higher cost but greater convenience of dabigatran when comparing it with standard warfarin therapy. Reference: Connolly SJ, Ezekowitz MD, Yusuf S, et al, for the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361(12): #2: Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. (ROCKET AF) BACKGROUND: The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin. METHODS: In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. The per-protocol, as-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism. RESULTS: In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority). In the intention-to-treat analysis, the primary end point occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; 5

6 P<0.001 for noninferiority; P=0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P=0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group. CONCLUSIONS: In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. (Funded by Johnson & Johnson and Bayer; ROCKET AF ClinicalTrials.gov.number, NCT ). Reference: Patel MR, Mahaffey KW, Garg J, Pan G, et al. ROCKET AF Investigators. N Engl J Med Sep 8;365(10): doi: /NEJMoa #3: Apixaban slightly more effective and safe than warfarin, but more expensive (ARISTOTLE) Clinical question: Is apixaban safer and more effective than warfarin for patients with atrial fibrillation? Study design: Randomized controlled trial (double-blinded). Funding source: Industry. Allocation: Concealed. Setting: Outpatient (any) Synopsis: This study of apixaban, an oral factor Xa inhibitor, included patients with atrial fibrillation or flutter and at least one risk factor for stroke (aged 75 years or older, previous stroke, transient ischemic attack, systemic embolism, heart failure, diabetes mellitus, or hypertension). Patients with recent stroke, mitral stenosis, prosthetic heart valve, need for aspirin, or renal insufficiency (serum creatinine > 2.5 mg/dl or 221 umol/l) were excluded. Patients (N = 18,201) were randomized with concealed allocation to receive apixaban 5 mg twice daily or matching placebo; patients older than 80 years, those who weighed less than 60 kg, and those with serum creatinine levels of less than 1.5 mg/dl (133 umol/l) received a dose of 2.5 mg twice daily. Patients also received warfarin adjusted to an INR of 2.0 to 3.0, or matching placebo with sham adjustments. Thus, half of patients got apixaban twice daily plus sham warfarin, while half got placebo twice daily plus real warfarin. The mean age of participants was 70 years, 35% were women, and 85% had persistent or permanent atrial fibrillation (as opposed to paroxysmal). Patients were followed up for a median of 1.8 years, which is somewhat short for a study of a chronic disease. The primary efficacy outcome was the rate of stroke (ischemic, hemorrhagic, or uncertain) or systemic embolism, which occurred in 1.3% of patients receiving apixaban and 1.6% receiving warfarin (absolute risk reduction = 0.3%; number needed to treat [NNT] = 333/year; P =.01). When you look at the individual end points, the only one that improved was hemorrhagic stroke (0.24% vs 0.47%; P <.001; NNT = 434/year). Death from any cause was marginally less likely with apixaban (3.52% vs 3.94%; P =.047; NNT = 238/year), and major bleeding was also slightly less likely with apixaban (2.13% vs 3.09%/year; P <.001; NNT = 105). There was no difference between groups regarding liver function or hepatic outcomes, and there was no difference regarding the likelihood of myocardial infarction, pulmonary embolism, or deep vein thrombosis. Bottom line: In low-risk patients with atrial fibrillation, apixaban (Eliquis) was associated with a slightly lower risk of stroke or venous thromboembolism, as well as a slighly lower risk of major bleeding. It is more convenient than warfarin (as an oral drug that does not require regular INR testing) but is more expensive. Although pricing has not been established, it is likely to be similar to that for Pradaxa: approximately $200 per month. Of course, this higher drug cost has to be balanced against the costs of monitoring for warfarin and the slightly higher risk of stroke and bleeding with warfarin; an objective cost-effectiveness analysis is needed to help sort this out. Reference: Granger CB, Alexander JH, McMurray JJ, et al, for the ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365(11): #4: Edoxaban noninferior to warfarin for atrial fibrillation BACKGROUND: Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known. METHODS: We conducted a randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years). The primary efficacy end point was stroke or systemic embolism. Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period. The principal safety end point was major bleeding. RESULTS: The annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (hazard ratio, 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; P<0.001 for noninferiority) and 1.61% with low-dose edoxaban (hazard ratio, 1.07; 97.5% CI, 0.87 to 1.31; P=0.005 for noninferiority). In the intention-to-treat analysis, there was a trend favoring high-dose edoxaban versus warfarin (hazard ratio, 0.87; 97.5% CI, 0.73 to 1.04; P=0.08) and an unfavorable trend with low-dose edoxaban versus warfarin (hazard ratio, 1.13; 97.5% CI, 0.96 to 1.34; P=0.10). The annualized rate of major bleeding was 3.43% with warfarin versus 2.75% with high-dose edoxaban (hazard ratio, 0.80; 95% CI, 0.71 to 0.91; P<0.001) and 1.61% with low-dose edoxaban (hazard ratio, 0.47; 95% CI, 0.41 to 0.55; P<0.001). The corresponding annualized rates of death from cardiovascular causes were 3.17% versus 2.74% (hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), and 2.71% (hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P=0.008), and the corresponding rates of the key secondary end point (a composite of stroke, systemic embolism, or death from cardiovascular causes) were 4.43% versus 3.85% (hazard ratio, 0.87; 95% CI, 0.78 to 0.96; P=0.005), and 4.23% (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.32). CONCLUSIONS: Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes. (Funded by Daiichi Sankyo Pharma Development; ENGAGE AF-TIMI 48 ClinicalTrials.gov number, NCT ). REFERENCE: Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med Nov 28;369(22): #5: Apixaban versus warfarin in nonvalvular atrial fibrillation: warfarin naïve vs warfarin experienced patients 6

7 BACKGROUND: Patients with atrial fibrillation who are vitamin K antagonist (VKA)-naive may have a higher risk of thrombosis and/or bleeding than VKA-experienced patients. METHODS AND RESULTS: Using data from ARISTOTLE, we assessed baseline characteristics and the treatment effect of apixaban versus warfarin in the VKA-naive and VKA-experienced cohorts. We compared rates of study drug discontinuation and time-intherapeutic range. Overall, 7,800 (43%) were VKA naive, and 10,401 were VKA experienced. At baseline, both groups were similar with respect to age and congestive heart failure, hypertension, age, diabetes, stroke score (CHADS2). Fewer VKA-naive patients had a history of prior stroke (18% vs 21%) or prior bleeding (10% vs 22%) and were more often female (39% vs 33%). The effect of apixaban on the primary efficacy and safety outcomes was similar in VKA-naive (stroke/systemic embolism: hazard ratio [HR] 0.86, 95% CI and major bleeding: HR 0.73, 95% CI ) and VKA-experienced populations (stroke/systemic embolism: HR 0.73, 95% CI , P value for interaction = 0.39 and major bleeding: HR 0.66, 95% CI , P value for interaction = 0.50). Permanent study drug discontinuation was numerically less likely in patients receiving apixaban whether they were VKA naive (HR for discontinuation: 0.87, 95% CI ) or VKA experienced (HR for discontinuation: 0.93, 95% CI ). Among patients receiving warfarin, the mean/median times in therapeutic range were lower in the VKA-naive group (VKA-naive: 57.5/61.4, VKAexperienced: 66.0/69.1, P <.001). CONCLUSION: The treatment effects of apixaban (vs warfarin) were not modified by VKA naivety. The rates of stroke/systemic embolism and major bleeding were numerically lower among the patients assigned to apixaban, irrespective of prior VKA use. REFERENCE: Garcia DA, Wallentin L, Lopes RD, et al. Apixaban versus warfarin in patients with atrial fibrillation according to prior warfarin use: results from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial. Am Heart J Sep;166(3): #6: Rivaroxaban versus warfarin in nonvalvular atrial fibrillation: warfarin naïve vs warfarin experienced patients BACKGROUND: In ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), a large randomized, clinical trial, rivaroxaban was noninferior to warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation. OBJECTIVE: To determine the efficacy and safety of rivaroxaban compared with warfarin among vitamin K antagonist (VKA)-naive and VKA-experienced patients. DESIGN: Prespecified subgroup analysis. (ClinicalTrials.gov: NCT ). SETTING: Global. PATIENTS: 14,264 persons with atrial fibrillation. MEASUREMENTS: Interaction of the relative treatment effect of rivaroxaban and warfarin on stroke or systemic embolism among VKAnaive and VKA-experienced patients. RESULTS: Overall, 7897 (55.4%) patients were VKA-experienced and 6367 (44.6%) were VKA-naive. The effect of rivaroxaban versus warfarin on stroke or systemic embolism was consistent: Rates per 100 patient-years of follow-up were 2.32 versus 2.87 for VKA-naive patients (hazard ratio [HR], 0.81 [95% CI, 0.64 to 1.03]) and 1.98 versus 2.09 for VKA-experienced patients (HR, 0.94 [CI, 0.75 to 1.18]; interaction P = 0.36). During the first 7 days, rivaroxaban was associated with more bleeding than warfarin (HR in VKA-naive patients, 5.83 [CI, 3.25 to 10.44], and in VKA-experienced patients, 6.66 [CI, 3.83 to 11.58]; interaction P = 0.53). After 30 days, rivaroxaban was associated with less bleeding than warfarin in VKA-naive patients (HR, 0.84 [CI, 0.74 to 0.95]) and similar bleeding in VKAexperienced patients (HR, 1.06 [CI, 0.96 to 1.17]; interaction P = 0.003). LIMITATION: The trial was not designed to detect differences in these subgroups. CONCLUSION: The efficacy of rivaroxaban in VKA-experienced and VKA-naive patients was similar to that of the overall trial. There were more bleeding events within 7 days of study drug initiation with rivaroxaban, but after 30 days, rivaroxaban was associated with less bleeding in VKA-naive patients and similar bleeding in VKA-experienced patients. This information may be useful to clinicians considering a transition to rivaroxaban for patients receiving VKA therapy. PRIMARY FUNDING SOURCE: Johnson & Johnson and Bayer HealthCare. REFERENCE: Mahaffey KW, Wojdyla D, Hankey GJ, ET AL. Clinical outcomes with rivaroxaban in patients transitioned from vitamin K antagonist therapy: a subgroup analysis of a randomized trial. Ann Intern Med Jun 18;158(12): VTE Treatment/Prophylaxis #7: Rivaroxaban effective for acute DVT (EINSTEIN DVT) Clinical question: Is rivaroxaban safe and effective for the treatment of acute deep vein thrombosis? Study design: Randomized controlled trial (single-blinded). Funding source: Industry. Allocation: Concealed. Setting: Outpatient (any). Synopsis: Rivaroxaban is a direct inhibitor of coagulation factor Xa, and is given orally either once or twice a day. In this industry-sponsored study, patients with acute proximal DVT and no evidence of pulmonary embolism were randomized (allocation concealed) to receive either rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily) or standard therapy (enoxaparin 1 mg/kg twice a day, followed by warfarin titrated to an international normalized ratio of between 2.0 and 3.0). The duration of therapy was based on a risk factor assessment and was determined by the treating physician. Analysis was by intention to treat, groups were balanced at the start of the study, and outcomes were adjudicated by a central committee masked to treatment assignment. The mean age of the 3449 participants was 56 years, and the intended duration of therapy was 6 months for 63%, 12 months for 25%, and 3 months for 12%. Outcomes favored rivaroxaban: recurrent venous thromboembolism occurred less often (2.1% vs 3.0%; P <.001; number needed to treat [NNT] = 111), largely due to fewer episodes of DVT (14 vs 28). There was no difference in episodes of major bleeding between groups (14 for rivaroxaban vs 20 for standard therapy) and no difference in all-cause mortality (38 vs 49). In a second phase of the trial, the researchers enrolled

8 patients who were felt to be at equipoise for continued anticoagulation after 6 months to 12 months (ie, their physician believed it was a toss-up whether they needed continued anticoagulation). In this phase, the patients were randomized in double-blind fashion to receive continued rivaroxaban or placebo and were followed up for up to 1 year. During that time, the combined outcome of major bleeding or recurrent VTE occurred in 2.0% in the rivaroxaban group and 7.1% in the placebo group (P <.001; NNT = 20). There was no evidence of hepatic toxicity, which was seen with an earlier factor Xa inhibitor. Bottom line: Rivaroxaban provides an oral alternative to warfarin for patients with acute deep vein thrombosis (DVT). The risk of major bleeding during a 1-year follow-up was approximately 0.7%, which is similar to that seen in other studies of long-term anticoagulant use. Although rivaroxaban is more convenient than warfarin, the cost is certain to be much higher. Reference: The EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363(26): #8: Oral rivaroxaban as effective as standard therapy for treatment of acute PE. (EINSTEIN PE) Clinical question: Is rivaroxaban as effective as enoxaparin plus an adjusted-dose vitamin K antagonist for the treatment of symptomatic pulmonary embolism? Study design: Randomized controlled trial (nonblinded). Funding source: Industry. Allocation: Concealed. Setting: Inpatient (any location) with outpatient follow-up Synopsis: In this open-label study, rivaroxaban was compared with enoxaparin plus a vitamin K antagonist for the treatment of PE. Adult patients with acute symptomatic PE were enrolled. Those with clinically significant kidney disease or liver disease were excluded. In the rivaroxaban group (n = 2419), patients received oral rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg once daily. In the standard therapy group (n = 2413), patients received enoxaparin at a dose of 1 mg per kg twice daily along with either warfarin or acenocoumarol. Enoxaparin was discontinued after at least 5 days or after a therapeutic international normalized ratio (INR) was achieved. Duration of anticoagulation of 3, 6, or 12 months was determined by the treating physician prior to randomization. Almost 90% of the included patients were hospitalized and the majority was diagnosed with an unprovoked PE. It is noted that the use of nonsteroidal anti-inflammatory drugs and antiplatelet agents was discouraged, and if used, doses were limited to 100 mg of aspirin and 75 mg of clopidogrel. However, no data regarding these characteristics amongst the study population was reported. The primary efficacy analysis was by intention to treat, while the safety analysis included patients who received at least one dose of the study drug. For the primary outcome of symptomatic recurrent venous thromboembolism, there was no difference between rivaroxaban and standard therapy (50 events vs 44 events). For the primary safety outcome, there was no significant difference in the rates of overall clinically relevant bleeding between the 2 groups (10.3% in the rivaroxaban group vs 11.4% in the standard therapy group). However, the rivaroxaban group did have a lower rate of major bleeding events (1.1% vs 2.2%; hazard ratio = 0.49; 95% CI, ; number needed to treat = 90). Bottom line: For patients with acute symptomatic pulmonary embolism (PE), oral rivaroxaban was shown to be noninferior to standard therapy (enoxaparin and a vitamin K antagonist) in preventing recurrent venous thromboembolism. Although there is no significant difference in overall clinically relevant bleeding rates between the 2 groups, the rivaroxaban group had fewer major bleeding events. We would have to treat 90 people with rivaroxaban instead of standard therapy to prevent 1 major bleed. Reference: EINSTEIN-PE Investigators, Büller HR, Prins MH, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366(14): #9: Apixaban for VTE Clinical question: Is apixaban safer and more effective than conventional anticoagulation for venous thromboembolism? Bottom line: Apixaban (Eliquis) is no more effective than conventional anticoagulation for the treatment of venous thromboembolism. There is a small benefit in terms of reducing major bleeds in critical sites (approximately 1 fewer for every 270 patients given apixaban), but it is not clear whether this benefit is cost-effective. If apixaban costs $100 more per month than conventional therapy, then the cost per prevented critical site bleed is well over $150,000 for 6 months. A full cost-effectiveness analysis could better clarify the balance of benefits, harms, and costs. It is likely that this drug is a good choice for selected patients (those who may have difficulty complying with warfarin and international normalized ratio (INR) monitoring, or those who have higher bleeding risk), but is unlikely to be cost-effective for many others. (LOE = 1b) Study design: Randomized controlled trial (double-blinded) Funding source: Industry Allocation: Concealed Setting: Outpatient (any) Synopsis: Apixaban is an oral factor Xa inhibitor given twice daily. In this trial, 5395 adults with venous thromboembolism (n = 3532), pulmonary embolism (n = 1359), or both (n = 477) were randomized to receive apixaban or usual therapy with enoxaparin 1 mg per kg every 12 hours for at least 5 days, and then warfarin for 6 months at a target range INR of 2.0 to 3.0. Apixaban was given in a dosage of 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months. The groups were balanced at the beginning of the study: mean age 57 years, 58% male, and a median of 5 days from onset of symptoms to randomization. Patients were followed up for 6 months by telephone or in the clinic, and outcomes were assessed by committee members masked to treatment assignment. The authors excluded patients with active bleeding, anemia, impaired renal function, or cancer, and those who were taking aspirin. They also excluded patients who had a clear cause for the clot that could be removed (for example, a postoperative or travel-related clot, which is often treated with only 3 months of anticoagulation). Major bleeding occurred more often in the conventional therapy group (1.8% vs 0.6%; P <.001; number needed to treat = 83). Critical site bleeds -- a subset of major bleeds that included intracranial, retroperitoneal, intrathoracic, intraocular, and intraarticular bleeds -- were also somewhat less common (4 vs 14), but a test of statistical significance is not provided. If we assume that it is significant, that is approximately 1 fewer critical site bleed for every 270 patients 8

9 given apixaban instead of conventional therapy. There was no difference in the likelihood of death or recurrent venous thromboembolism. Approximately half of the recurrences and major bleeds occurred during the first month of therapy for both groups. Reference: Agnelli G, Buller HR, Cohen A, et al, for the AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369(9): #10: Dabigatran for prevention of VTE recurrence BACKGROUND: Dabigatran, which is administered in a fixed dose and does not require laboratory monitoring, may be suitable for extended treatment of venous thromboembolism. METHODS: In two double-blind, randomized trials, we compared dabigatran at a dose of 150 mg twice daily with warfarin (activecontrol study) or with placebo (placebo-control study) in patients with venous thromboembolism who had completed at least 3 initial months of therapy. RESULTS: In the active-control study, recurrent venous thromboembolism occurred in 26 of 1430 patients in the dabigatran group (1.8%) and 18 of 1426 patients in the warfarin group (1.3%) (hazard ratio with dabigatran, 1.44; 95% confidence interval [CI], 0.78 to 2.64; P=0.01 for noninferiority). Major bleeding occurred in 13 patients in the dabigatran group (0.9%) and 25 patients in the warfarin group (1.8%) (hazard ratio, 0.52; 95% CI, 0.27 to 1.02). Major or clinically relevant bleeding was less frequent with dabigatran (hazard ratio, 0.54; 95% CI, 0.41 to 0.71). Acute coronary syndromes occurred in 13 patients in the dabigatran group (0.9%) and 3 patients in the warfarin group (0.2%) (P=0.02). In the placebo-control study, recurrent venous thromboembolism occurred in 3 of 681 patients in the dabigatran group (0.4%) and 37 of 662 patients in the placebo group (5.6%) (hazard ratio, 0.08; 95% CI, 0.02 to 0.25; P<0.001). Major bleeding occurred in 2 patients in the dabigatran group (0.3%) and 0 patients in the placebo group. Major or clinically relevant bleeding occurred in 36 patients in the dabigatran group (5.3%) and 12 patients in the placebo group (1.8%) (hazard ratio, 2.92; 95% CI, 1.52 to 5.60). Acute coronary syndromes occurred in 1 patient each in the dabigatran and placebo groups. CONCLUSIONS: Dabigatran was effective in the extended treatment of venous thromboembolism and carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo. (Funded by Boehringer Ingelheim; RE-MEDY and RE-SONATE ClinicalTrials.gov numbers, NCT and NCT , respectively.). REFERENCE: Schulman S(1), Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med Feb 21;368(8): #11: Edoxaban for prevention of VTE recurrence BACKGROUND: Whether the oral factor Xa inhibitor edoxaban can be an alternative to warfarin in patients with venous thromboembolism is unclear. METHODS: In a randomized, double-blind, noninferiority study, we randomly assigned patients with acute venous thromboembolism, who had initially received heparin, to receive edoxaban at a dose of 60 mg once daily, or 30 mg once daily (e.g., in the case of patients with creatinine clearance of 30 to 50 ml per minute or a body weight below 60 kg), or to receive warfarin. Patients received the study drug for 3 to 12 months. The primary efficacy outcome was recurrent symptomatic venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding. RESULTS: A total of 4921 patients presented with deep-vein thrombosis, and 3319 with a pulmonary embolism. Among patients receiving warfarin, the time in the therapeutic range was 63.5%. Edoxaban was noninferior to warfarin with respect to the primary efficacy outcome, which occurred in 130 patients in the edoxaban group (3.2%) and 146 patients in the warfarin group (3.5%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.70 to 1.13; P<0.001 for noninferiority). The safety outcome occurred in 349 patients (8.5%) in the edoxaban group and 423 patients (10.3%) in the warfarin group (hazard ratio, 0.81; 95% CI, 0.71 to 0.94; P=0.004 for superiority). The rates of other adverse events were similar in the two groups. A total of 938 patients with pulmonary embolism had right ventricular dysfunction, as assessed by measurement of N-terminal pro-brain natriuretic peptide levels; the rate of recurrent venous Thromboembolism in this subgroup was 3.3% in the edoxaban group and 6.2% in the warfarin group (hazard ratio, 0.52;95% CI, 0.28 to 0.98). CONCLUSIONS: Edoxaban administered once daily after initial treatment with heparin was noninferior to high-quality standard therapy and caused significantly less bleeding in a broad spectrum of patients with venous thromboembolism, including those with severe pulmonary embolism. (Funded by Daiichi-Sankyo; Hokusai-VTE ClinicalTrials.gov number, NCT ). REFERENCE: Hokusai-VTE Investigators, Büller HR, Décousus H, ET AL. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med Oct 10;369(15): #12: Meta-analysis: Warfarin more effective but has higher bleeding risk vs newer agents in secondary VTE prevention OBJECTIVE: To summarise and compare the efficacy and safety of various oral anticoagulants (dabigatran, rivaroxaban, apixaban, and vitamin K antagonists) and antiplatelet agents (acetylsalicylic acid) for the secondary prevention of venous thromboembolism. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Literature search using Medline (1950 to present), Embase (1980 to present), and the Cochrane Register of Controlled Trials using the OVID interface. Publications from potentially relevant journals were also searched by hand. REVIEW METHODS: Randomised controlled trials of patients receiving anticoagulants, antiplatelet drugs, or placebo or observation for secondary prevention of venous thromboembolism. Selected outcomes were rates of recurrent venous thromboembolism and major bleeding. Two reviewers independently extracted data onto standardised forms. 9

10 RESULTS: 12 articles met our inclusion criteria, with 11,999 patients evaluated for efficacy and 12,167 for safety. All treatments reduced the risk of recurrent venous thromboembolism. Compared with placebo or observation, vitamin K antagonists at a standard adjusted dose (target international normalised ratio ) showed the highest risk difference (odds ratio 0.07; 95% credible interval 0.03 to 0.15) and acetylsalicylic acid showed the lowest risk difference (0.65; 0.39 to 1.03). Risk of major bleeding was higher with a standard adjusted dose of vitamin K antagonists (5.24; 1.78 to 18.25) than with placebo or observation. Fatal recurrent venous thromboembolism and fatal bleeding were rare. Detailed subgroup and individual patient level data were not available. CONCLUSIONS: All oral anticoagulants and antiplatelet agents investigated in this analysis were associated with a reduced recurrence of venous thromboembolism compared with placebo or observation, although acetylsalicylic acid was associated with the lowest risk reduction. Vitamin K antagonists given at a standard adjusted dose was associated with the greatest risk reduction in recurrent venous thromboembolism, but also the greatest risk of major bleeding. REFERENCE: Castellucci LA, Cameron C, Le Gal G, et al. Efficacy and safety outcomes of oral anticoagulants and antiplatelet drugs in the secondary prevention of venous thromboembolism: systematic review and network meta-analysis. BMJ Aug 30;347 The following is one of the four RECORD trials on the use of rivaroxaban in THROMBOPROPHYLAXIS in THR and TKR patients. #13: Oral rivaroxaban for thromboprophylaxis in THR patients. (RECORD 1) BACKGROUND: This phase 3 trial compared the efficacy and safety of rivaroxaban, an oral direct inhibitor of factor Xa, with those of enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty. METHODS: In this randomized, double-blind study, we assigned 4541 patients to receive either 10 mg of oral rivaroxaban once daily, beginning after surgery, or 40 mg of enoxaparin subcutaneously once daily, beginning the evening before surgery, plus a placebo tablet or injection. The primary efficacy outcome was the composite of deep-vein thrombosis (either symptomatic or detected by bilateral venography if the patient was asymptomatic), nonfatal pulmonary embolism, or death from any cause at 36 days (range, 30 to 42). The main secondary efficacy outcome was major venous thromboembolism (proximal deep-vein thrombosis, nonfatal pulmonary embolism, or death from venous thromboembolism). The primary safety outcome was major bleeding. RESULTS: A total of 3153 patients were included in the superiority analysis (after 1388 exclusions), and 4433 were included in the safety analysis (after 108 exclusions). The primary efficacy outcome occurred in 18 of 1595 patients (1.1%) in the rivaroxaban group and in 58 of 1558 patients (3.7%) in the enoxaparin group (absolute risk reduction, 2.6%; 95% confidence interval [CI], 1.5 to 3.7; P<0.001). Major venous thromboembolism occurred in 4 of 1686 patients (0.2%) in the rivaroxaban group and in 33 of 1678 patients (2.0%) in the enoxaparin group (absolute risk reduction, 1.7%; 95% CI, 1.0 to 2.5; P<0.001). Major bleeding occurred in 6 of 2209 patients (0.3%) in the rivaroxaban group and in 2 of 2224 patients (0.1%) in the enoxaparin group (P=0.18). CONCLUSIONS: A once-daily, 10-mg oral dose of rivaroxaban was significantly more effective for extended thromboprophylaxis than a once-daily, 40-mg subcutaneous dose of enoxaparin in patients undergoing elective total hip arthroplasty. The two drugs had similar safety profiles. REFERENCE: Eriksson BI, Borris LC, Friedman RJ, et al. RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med Jun 26;358(26): #14: Clinical benefits of newer agents for thromboprophylaxis are marginal BACKGROUND: Pharmacologic thromboprophylaxis reduces the risk for venous thromboembolism after total hip replacement (THR) or total knee replacement (TKR). New oral anticoagulants (NOACs), including direct thrombin inhibitors and factor Xa inhibitors, are emerging options for thromboprophylaxis after these procedures. PURPOSE: To compare the benefits and risks of NOACs versus standard thromboprophylaxis for adults having THR or TKR. DATA SOURCES: MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews from January 2009 through March STUDY SELECTION: English-language systematic reviews. DATA EXTRACTION: Two independent reviewers abstracted data and rated study quality and strength of evidence. DATA SYNTHESIS: Six good-quality systematic reviews compared NOACs with low-molecular-weight heparin (LMWH) for thromboprophylaxis after THR or TKR. Risk for symptomatic deep venous thrombosis, but not risk for death or nonfatal pulmonary embolism, was reduced with factor Xa inhibitors compared with LMWH (4 fewer events per 1000 patients). Conversely, the risk for major bleeding increased (2 more events per 1000 patients). Outcomes of dabigatran did not significantly differ from those of LMWH. Indirect evaluation of NOACs by common comparison with LMWH showed nonsignificantly reduced risks for venous thromboembolism with rivaroxaban compared with dabigatran (risk ratio [RR], 0.68 [95% CI, 0.21 to 2.23]) and apixaban (RR, 0.59 [CI, 0.26 to 1.33]) but increased major bleeding. New oral anticoagulants have not been compared with warfarin,aspirin, or unfractionated heparin. LIMITATIONS: Head-to-head comparisons among NOACs were not available. Efficacy is uncertain in routine clinical practice. CONCLUSION: New oral anticoagulants are effective for thromboprophylaxis after THR and TKR. Their clinical benefits over LMWH are marginal and offset by increased risk for major bleeding. REFERENCE: Adam SS, McDuffie JR, Lachiewicz PF, et al. Comparative effectiveness of new oral anticoagulants and standard thromboprophylaxis in patients having total hip or knee replacement: a systematic review. Ann Intern Med Aug 20;159(4): PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs. Safety issues 10

11 The following 3 abstracts remind us that if an anticoagulant is safe and effective for one indication, it does not follow that is safe to stretch the indications nor that the new drug is effective for non-approved indications. Therefore pay attention to FDA approved indications #15: Dabigatran is neither safe nor effective for anticoagulation with mechanical heart valves Clinical question: Is dabigatran a safe and effective anticoagulant for patients with mechanical heart valves? Bottom line: Warfarin is a safer and more effective alternative than dabigatran for anticoagulation of patients with a mechanical heart valve. (LOE = 1b) Study design: Randomized controlled trial (single-blinded) Funding source: Industry Allocation: Concealed Setting: Outpatient (specialty) Synopsis: The authors identified adults undergoing implantation of a mechanical valve for the aortic or mitral valve (or both), as well as patients who had received a mechanical valve at least 3 months previously. Patients were randomized with concealed allocation to receive either dabigatran or warfarin. Dabigatran was initially dosed in a range from 150 mg twice daily to 300 mg twice daily (depending on renal function), and the dose was adjusted to maintain a level of at least 50 ng/ml. Warfarin was dosed to maintain an international normalized ratio (INR) between 2.5 and 3.5 for those with a mechanical aortic valve and additional risk factors for thromboembolism and for those with a mitral valve; patients with an aortic valve and no risk factors were maintained at an INR range of 2.0 to 3.0. A total of 252 patients, with a mean age of 56 years, were randomized; 68% had a mechanical aortic valve, 28% a mitral valve, and 4% both. This was an open-label trial, but with masked outcome assessment and appropriate concealment of allocation. Patients were followed up for 12 weeks, and at that time could choose whether or not to continue to take the assigned study drug as part of an extension trial. A total of 168 patients participated in the extension trial (99 in the dabigatran group, 59 in the warfarin group), with a median duration of treatment between 136 days and 152 days, depending on the study drug and population. The study was terminated prematurely because of an excess of strokes (5% in the dabigatran group vs 0% in the warfarin group), major bleeding (4% vs 2%) and any bleeding (27% vs 12%). Although only the difference in any bleeds was statistically significant, the weight of the evidence led the researchers to discontinue the trial. The major bleeds were all pericardial. Reference: Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013;369: #16: Dabigatran associated with increased risk of coronary events Clinical question: Does the use of dabigatran increase the risk of acute coronary events? Bottom line: The increased risk of myocardial infarction (MI) or acute coronary syndrome (ACS) associated with dabigatran is small, but statistically significant. You would have to treat 250 patients with dabigatran to cause one additional acute coronary event. Study design: Meta-analysis (randomized controlled trials) Funding source: Unknown/not stated Setting: Various (meta-analysis)synopsis The original RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) study, comparing dabigatran with warfarin for stroke prophylaxis in atrial fibrillation, revealed a slightly higher risk of MI with dabigatran (Connolly et al; Daily POEM, 11/9/09). To investigate the association of dabigatran and acute coronary events, these authors searched PubMed, Scopus, and the Web of Science and selected 7 randomized controlled trials (N = 30,514) that evaluated the efficacy of dabigatran for different indications, including stroke prophylaxis for atrial fibrillation, treatment of acute venous thrombembolism, and deep venous thrombosis prophylaxis in joint replacement patients. All of the included trials also reported on secondary outcomes of MI or ACS. One author independently extracted data, which was then reviewed by the second author. Study quality was assessed using the Jadad scale. Of note, the 7 included studies were all industry funded. Pooled together, the data showed that dabigatran is associated with a higher risk of MI or ACS than warfarin, enoxaparin, and placebo (1.19% vs 0.79%; odds ratio = 1.33; 95% CI, ; P =.03). The RE-LY study, which comprised 59% of the cohort for this meta-analysis, had the largest effect on the result. This risk remained high when using the revised data from RE-LY that added previously unreported events, including 4 clinical MIs and 28 silent MIs. Data from the 6 trials that reported on mortality showed that dabigatran was associated with a lower risk of death than the control group (4.83% vs 5.02%; P =.04). However, this was not the primary outcome studied in this meta-analysis. Furthermore, given the different disease processes represented, there was significant heterogeneity across studies in the measure of absolute risk reduction for mortality. Reference: Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events. Arch Intern Med 2012;172: #17 Apixaban increases bleeding with no benefit in high-risk patients with ACS Clinical question: Does the use of apixaban along with standard antiplatelet therapy decrease recurrent ischemic events following acute coronary syndrome? Bottom line: Apixaban added to standard antiplatelet therapy in high-risk patients with recent acute coronary syndrome (ACS) increases bleeding without significantly reducing recurrent ischemic events, such as stroke, myocardial infarction, or death. Study design: Randomized controlled trial (double-blinded). Funding source: Industry. Allocation: Concealed. Setting: Inpatient (any location) with outpatient follow-up. Synopsis: Apixaban, an oral direct factor Xa inhibitor, can be used to prevent venous thromboembolism in patients undergoing orthopedic surgery and thromboembolic events in patients with atrial fibrillation. This study examined the effect of apixaban in preventing ishcemic events in high-risk patients with ACS. Using concealed 11

12 allocation, investigators randomized 7392 patients with ACS within the previous 7 days to receive apixaban 5 mg twice daily or placebo. Patients were also receiving standard treatment with aspirin alone or aspirin and clopidogrel. In addition, eligible patients had 2 or more high-risk factors, such as older age, diabetes, peripheral vascular disease, heart failure, history of stroke, renal dysfunction, or lack of revascularization after the index event. At baseline, patients in both groups were well matched with similar comorbidities. The authors performed both intention-to-treat and on-treatment analyses. Because of an excess of clinically significant bleeding events, the trial was stopped early. For the composite outcome of cardiovascular death, myocardial infarction, or ischemic stroke, there was no difference detected between the apixaban and the placebo groups. This was true in patients receiving aspirin alone and in patients receiving both aspirin and clopidogrel. Bleeding, however, was more prominent in the apixaban group; major bleeding, including fatal and intracranial bleeding, was found in 1.3% of patients taking apixaban compared with 0.5% of patients taking placebo (hazard ratio = 2.59; 95% CI, ; P =.001).Reference: Alexander JH, Lopes RD, James S, et al, for the the APPRAISE-2 Investigators. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011; Jul 24. #18: ICH risk with newer anticoagulants 0.6% vs 1.2% with warfarin/asa Clinical question: Are the newer anticoagulants less likely to cause intracranial hemorrhage than warfarin or aspirin? Bottom line: This meta-analysis of randomized trials comparing newer anticoagulants against warfarin or aspirin for patients with atrial fibrillation (AF) showed that patients in the treatment groups had fewer intracranial hemorrhages (ICHs) than those in the control groups. It remains to be seen if this result will hold up with longer duration of use in patients less selected than those enrolled in clinical trials. (LOE = 1a) Study design: Meta-analysis (randomized controlled trials) Funding source: Unknown/not stated Setting: Various (meta-analysis) Synopsis: The newer anticoagulants dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis) are marketed heavily as not needing frequent laboratory monitoring, and the manufacturers claim greater effectiveness than warfarin. Although anticoagulants can prevent ischemic stroke in patients with AF, they also cause ICH, a catastrophic event. These authors searched multiple databases, conference abstracts, references of included papers, and a clinical trials registry to identify randomized trials of newer anticoagulants against any comparison intervention in preventing stroke in patients with nonvalvular AF. Two authors independently determined study inclusion and assessed study quality. For these elements, they don't say how disagreements were handled. Additionally, 2 authors independently extracted the data and resolved any discrepancies through consensus. In addition to the usual statistical methods used in meta-analyses, these authors did a whole bunch of additional nerdy stuff (Bayesian analyses, Monte Carlo simulation, Gibbs sampling) to obfuscate their real intent. Ultimately, they included 6 studies with more than 57,000 patients. Five studies compared the new agent against warfarin (target INR = ) and one compared them against aspirin ( mg/day). Five studies went beyond 1 year and one was only 12 weeks duration. Needless to say, all the included studies were industry sponsored. The authors, however, reported no conflicts of interest. If you ignore all the nerdy stuff and just look at the raw data, the rate of ICH in each of the included studies was lower in the patients receiving the newer agents, although the confidence intervals were enormous in most studies and not statistically significant in 3 studies. When you pool the data, the rate of ICH in patients treated with newer agents was 0.6% compared with 1.2% in the comparison groups (number needed to treat to prevent 1 ICH = 154; 95% CI, ). So, this is a good example of how reducing by half the rate of a bad event can sound good until you realize the event rate is rare. Keep in mind that industry-sponsored studies, while having decent internal validity, are designed to weed out those patients who are unlikely to respond and who are among the healthiest. When we try to use these products in the real world, where we stretch the eligibility and give them to our frailest patients, we often find that our patients don't have the same experiences as did those in the studies. Perhaps the only important outcome from all the other analyses was that, indirectly, no newer agent appeared any safer than the rest. Reference: Chatterjee S, Sardar P, Biondi-Zoccai G, Kumbhani DJ. New oral anticoagulants and the risk of intracranial hemorrhage: traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation. JAMA Neurol 2013;70:

13 Bottom Lines 1. The three newer oral anticoagulants (dabigatran and apixaban and rivaroxaban) have all been approved for the treatment of non-valvular atrial fibrillation. Whether these drugs should be used in place of warfarin for this indication is still undetermined. The NNTs for differences in clinical outcomes between these drugs and warfarin are between 100 and Rivaroxaban has also been FDA approved for the treatment of VTE and prophylaxis of VTE in patients undergoing THR and TKR. 3. Note which drugs have which indications, as extrapolating from one indication to another indication may be unsafe. 4. Newer drugs and studies on broader indications are in the pipeline so stay tuned! 13

14 Appendix: Data tables from the 3 major studies on the newer oral anticoagulants vs warfarin Table 1 Data from the RE-LY Study on dabigatran vs warfarin for atrial fibrillation. N Engl J Med 2009;361(12): Warfarin Dabigatran 150 bid * NNT All CVA or systemic emboli per year (%) Major bleeding per year (%) Intracerebral hemorrhages per year (%) % (p=.001) % (p=.31) % (p=.001) 357 Dyspepsia (% of patients) % (p=.001) 18 MI (% of patients) % (p=.048) 476 Mortality (%) all cause % (p=.051) 204 Mean follow up duration was 2 years No difference in mortality between groups Shaded = favoring dabigitran Not shaded = favoring warfarin Dabigatran 150 bid was superior to warfarin in primary outcome Note there is no specific antidote to dabigatran, its half-life is hours (major hemorrhage treatment is supportive, and transfusions and surgery if needed The FDA approved dabigatran in October of 2010 at a dose of 150 mg bid if the GFR is > 30, and 75 bid if the GFR is < 30 but > 15; there are no dosing recommendations for patients with a GFR < 15 or on dialysis The 110 mg dose was not approved Table 2 Data from the Rocket AF. Rivaroxaban vs Warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365): Warfarin Rivaroxaban * NNT All CVA or systemic emboli per year (%) Major bleeding per year (%) Intracerebral hemorrhages per year (%) % (p=.001) % (p=.58) % (p=.02) 500 MI (% of patients) % (p=.12) 500 Mortality (%) all cause % (p=.15) 250 Mean follow up duration was ~ 2 years No difference in mortality between groups Shaded = favoring rivaroxaban Not shaded = favoring warfarin Rivaroxaban was non inferior to warfarin in primary outcome Note there is no specific antidote to rivaroxaban (major hemorrhage treatment is supportive, and transfusions and surgery if needed Table 3 14

15 Data from Aristotle. Apixiban vs Warfarin in patients with atrial fibrillation. N Engl J Med 2011;365): Warfarin Apixaban * All CVA or systemic emboli per year (%) Major bleeding per year (%) Intracerebral hemorrhages per year (%) % (p=.01) % (p=.001) % (p=.001) 212 MI (% of patients) % (p=.37) 1111 Mortality (%) all cause % (p=.047) 238 Mean follow up duration was 1.8 years Shaded = favoring Apixaban Not shaded = favoring warfarin Apixaban was non inferior and superior to warfarin in primary outcome Note there is no specific antidote to apixiban (major hemorrhage treatment is supportive, and transfusions and surgery if needed 15

16 Table 4 Comparisons between warfarin and 4 NOAs for atrial fibrillation Table 5 Comparisons between warfarin and 4 NOAs for VTE 16

17 Table 6 17

18 Men s Health: Low T, Andropause, ED, BPH Steve Brown, MD and John Hickner, MD, MSc Objectives 1. Review BPH diagnostic criteria and effective treatments. 2. Discuss the effectiveness of PDE-5 inhibitors for erectile dysfunction and the limited role of testosterone in treatment. 3. Review the limited role of testosterone therapy despite the strong marketing emphasis on Low-T. Diagnosing benign prostatic hyperplasia Source: auanet.org Guidelines, Management of BPH The AUA recommends treatment at score of >7, but patient preferences should be considered. One study showed patients were only discouraged from performing normal daily activity when the symptom score exceeded 20. (J Urol 2001;166(2)563). What medications are effective for BPH? Alpha-1 blockers Alfuzosin (Uroxatral) Doxazosin* (Cardura) Prazosin* (Minipress) Silodosin# (Rapaflo) Tamsulosin*# (Flomax) Terazosin* (Hytrin) Medications for BPH 5-alpha reductase inhibitors Dutasteride (Avodart) Finasteride* (Proscar) *generic available #selective alpha 1a blockers #1: Cochrane: Terazosin for benign prostatic hyperplasia Background: Lower urinary tract symptoms associated with benign prostatic obstruction (BPO) occur in up to 70% of men over the age of 60 years. To relieve these bothersome symptoms, treatment options include alpha-antagonists, also know as alpha-blockers. 18

19 Objectives: We conducted a systematic review to evaluate the effectiveness and adverse effects of the alpha-blocker, terazosin, for treatment of urinary symptoms associated with BPO. Main results: Seventeen studies involving 5151 subjects met inclusion criteria (placebo-controlled (n = 10); alpha-blockers (n = 7); finasteride alone or in combination with terazosin as well as placebo (1); microwave therapy (TUMT) (1). Study duration ranged from 4 to 52 weeks. Mean age was 65 years and 82% of men were white. Baseline urologic symptom scale scores and flow rates demonstrated that men had moderate BPO. Efficacy outcomes were rarely reported in a fashion that allowed for data pooling but indicated that terazosin improved symptom scores and flow rates more than placebo or finasteride and similarly to other alpha antagonists. The pooled mean percentage improvements for the Boyarsky symptom score was 37% for terazosin versus 15% for placebo (n = 4 studies). The mean percentage improvement for the American Urological Association symptom score (AUA) was 38% compared to 17% and 20% for placebo and finasteride, respectively (n = 2 studies). The pooled mean improvement in the International Prostate Symptom Score (IPSS) (40%) was similar to tamsulosin (43%). Peak urine flow rates improved greater with terazosin (22%), than placebo (11%) and finasteride (15%) but did not differ significantly from the other alpha-blockers. The percentage of men discontinuing terazosin was comparable to men receiving placebo and finasteride but was greater then with other alpha-antagonists. Adverse effects were greater than placebo and included dizziness, asthenia, headache, and postural hypotension. Authors' conclusions: The available evidence suggests that terazosin improves urinary symptoms and flow measures associated with BPO. Effectiveness is superior to placebo or finasteride, similar to other alpha-blockers but less than TUMT. Adverse effects were generally mild but more frequent than other alpha-blockers and associated with between a two-to-four fold increase in treatment discontinuation. Wilt, Timothy; Howe, R William; Rutks, Indy; MacDonald, Roderick; Wilt, Timothy. Terazosin for benign prostatic hyperplasia (Cochrane Review). In: The Cochrane Library 2008 Issue 4. Chichester, UK: John Wiley and Sons, Ltd. #2: Cochrane: Tamsulosin for benign prostatic hyperplasia Background: Benign prostatic hyperplasia (BPH) is a nonmalignant enlargement of the prostate which can result in bothersome lower urinary tract symptoms. The treatment goal for men with BPH is to relieve these bothersome symptoms. Objectives: This systematic review assessed the effects of tamsulosin in the treatment of lower urinary tract symptoms (LUTS) compatible with BPH. Main results: Fourteen studies involving 4122 subjects met inclusion criteria. Study duration ranged from 4 to 26 weeks, and no placebo-controlled study lasted longer than 13 weeks. The mean age of subjects was 64 years. Baseline symptom scores and urine flow rates demonstrated that men had moderate LUTS. Tamsulosin improved symptoms and peak urine flow relative to placebo. The weighted mean differences (WMD) for mean change from baseline for the Boyarsky symptom score for 0.4 mg and 0.8 mg doses of tamsulosin relative to placebo were -1.1 points (95% CI = to -0.72; 12% improvement) and -1.6 points (95% CI = -2.3 to -1.0; 16% improvement), respectively. The WMD for mean change from baseline in peak urine flow were 1.1 ml/sec (95% CI = 0.59 to 1.51) and 1.1 ml/sec (95% CI= 0.65 to 1.48) for 0.4 mg and 0.8 mg, respectively. Tamsulosin (0.2 mg to 0.4 mg) was as effective as other alpha antagonists and the phytotherapeutic agent Permixon in improving symptoms and flow rates though the doses of all alpha-antagonists studied may not have been optimal. Discontinuations from treatment for any reason and discontinuations "due to adverse events" were similar in the low dose tamsulosin (0.2 mg) and placebo groups but increased to 16% in trials utilizing a 0.8 mg dose of tamsulosin. Low dose tamsulosin was generally well tolerated although not all the trials reported specific adverse events. The most frequently reported adverse events that were significantly greater than placebo included dizziness, rhinitis and abnormal ejaculation. Adverse effects increased markedly as tamsulosin dosing increased, and were reported in 75% of men receiving the 0.8 mg dose. Men receiving a 0.2 mg dose tamsulosin were less likely to discontinue treatment compared to men receiving terazosin. Authors' conclusions: Tamsulosin provided a small to moderate improvement in urinary symptoms and flow compared to men receiving placebo in men with BPH. Effectiveness was similar to other alpha antagonists and increased only slightly with higher doses. Long term effectiveness and ability to reduce complications due to BPH progression could not be determined. Adverse effects were generally mild but their frequency, including withdrawals, increased substantially with the higher doses that are generally available for treatment. Wilt, Timothy; MacDonald, Roderick; Rutks, Indy; Wilt, Timothy. Tamsulosin for benign prostatic hyperplasia (Cochrane Review). In: The Cochrane Library 2008 Issue 4. Chichester, UK: John Wiley and Sons, Ltd. #3: Cochrane: Finasteride modestly effective for benign prostatic hyperplasia Background: Benign prostatic hyperplasia (BPH), a non-malignant enlargement of the prostate in aging men, can cause bothersome urinary symptoms (intermittency, weak stream, straining, urgency, frequency, incomplete emptying). Finasteride, a five-alpha reductase inhibitor (5ARI), blocks the conversion of testosterone to dihydrotestosterone, reduces prostate size, and is commonly used to treat symptoms associated with BPH. Objectives: To compare the clinical effectiveness and harms of finasteride versus placebo and active controls in the treatment of lower urinary tract symptoms (LUTS). Main results: Finasteride consistently improved urinary symptom scores more than placebo in trials of > 1 year duration, and significantly lowered the risk of BPH progression (acute urinary retention, risk of surgical intervention, = 4 point increase in the AUASI/IPSS). In comparison to alpha-blocker monotherapy, finasteride was less effective than either doxazosin or terazosin, but equally effective compared to tamsulosin. Both doxazosin and terazosin were significantly more likely than finasteride to improve peak urine flow and nocturia, versus finasteride. Versus tamsulosin, peak urine flow and QoL improved equally well versus finasteride. However, finasteride was associated with a lower risk of surgical intervention compared to doxazosin, but not to terazosin, while finasteride and doxazosin were no different for risk of acute urinary retention. Two small trials reported no difference in urinary symptom scores between finasteride and tamsulosin. Finasteride + doxazosin and doxazosin monotherapy improved urinary symptoms equally well (= 4 point improvement). For finasteride, there was an increased risk of ejaculation disorder, impotence, and lowered libido, versus 19

20 placebo. Versus doxazosin, finasteride had a lower risk of asthenia, dizziness, and postural hypotension, and versus terazosin, finasteride had a significant, lower risk of asthenia, dizziness, and postural hypotension. Authors' conclusions: Finasteride improves long-term urinary symptoms versus placebo, but is less effective than doxazosin. Longterm combination therapy with alpha blockers (doxazosin, terazosin) improves symptoms significantly better than finasteride monotherapy. Finasteride + doxazosin improves symptoms equally - and clinically - to doxazosin alone. In comparison to doxazosin, finasteride + doxazosin appears to improve urinary symptoms only in men with medium (25 to < 40 ml) or large prostates (= 40 ml), but not in men with small prostates (25 ml).comparing short to long-term therapy, finasteride does not improve symptoms significantly better than placebo at the short term, but in the long term it does, although the magnitude of differences was very small (from < 1.0 point to 2.2 points). Doxazosin improves symptoms better than finasteride both short and long term, with the magnitude of differences ~2.0 points and 1.0 point, respectively. Finasteride + doxazosin improves scores versus finasteride alone at both short and long term, with mean differences ~2.0 points for both time points. Finasteride + doxazosin versus doxazosin improves scores equally for short and long term.drug-related adverse effects for finasteride are rare; nevertheless, men taking finasteride are at increased risk for impotence, erectile dysfunction, decreased libido, and ejaculation disorder, versus placebo. Versus doxazosin, which has higher rates of dizziness, postural hypotension, and asthenia, men taking finasteride are at increased risk for impotence, erectile dysfunction, decreased libido, and ejaculation disorder. Finasteride significantly reduces asthenia, postural hypotension, and dizziness versus terazosin. Finasteride significantly lowers the risk of asthenia, dizziness, ejaculation disorder, and postural hypotension, versus finasteride + terazosin. Tacklind, James; Fink, Howard A; MacDonald, Roderick; Rutks, Indy; Wilt, Timothy J; Tacklind, James. Finasteride for benign prostatic hyperplasia (Cochrane Review). In: The Cochrane Library 2010 Issue 10. Chichester, UK: John Wiley and Sons, Ltd. #4: Finasteride + doxazosin effective for selected BPH patients Clinical question: Is the combination of finasteride and doxazosin more effective than either drug alone? Study design: Randomized controlled trial (double-blinded) Setting: Outpatient (any) Synopsis: Doxazosin is an alpha-blocker that reduces smooth muscle tone in the prostate and bladder neck; finasteride is a 5-alphareductase inhibitor that reduces prostate volume. Although it makes sense that there may be greater benefit to the combination of both than each alone, short-term studies have not demonstated this. In this study, men with BPH were randomized (allocation concealed) to either doxazosin (4 mg to 8 mg, as tolerated), finasteride (5 mg orally each day), both, or neither. A total of 3047 men were recruited at 17 centers, all with an American Urological Association (AUA) score of at least 8, where 0 = no symptoms and 35 = severe symptoms. Groups were balanced at the start of the study, and analysis was by intention to treat. Men with hypotension, a PSA higer than 10 ng/ml, or previous prostate surgery were excluded. The primary outcome was the worsening in the AUA score of at least 4 points, acute urinary retention, renal insufficiency, recurrent urinary tract infection, and urinary incontinence. At the end of the 4-year study, the primary outcome was significantly less likely in the combination therapy group (5%) than in the groups getting either drug alone (10% each) or no drug at all (17%). You would have to treat 20 patients with combined therapy instead of doxazosin or finasteride alone for 4 years to prevent 1 from having a progression of their BPH. Most adverse events were more common in the combination therapy group, although this difference was only significant for abnormal ejaculation, peripheral edema, and dyspnea. The benefit of combination therapy was greatest in patients with a prostate volume greater than 40 ml and a PSA higher than 4 ng/ml. Bottom line: Combination therapy with finasteride (Proscar) and doxazosin (Cardura) for at least 4 years reduces the risk of clinical progression of benign prostatic hyperplasia (BPH). However, long-term finasteride use is also associated with an increase in the risk of high-grade prostate cancer (N Eng J Med 2003; 349:215-24). (LOE = 1b) McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003; 349: #5: PubMed: Alpha-adrenergic blockers and vascular-related events Objectives: To evaluate the safety profile and efficacy of alpha1-adrenergic receptor blockers (A1Bs) currently prescribed for benign prostatic hyperplasia (BPH). Data sources: A systematic literature search of MEDLINE, the Cochrane Database and the Food and Drug Administration Web site through December 2006 identified double-blinded, prospective, placebo-controlled trials, evaluating agents commercially available by prescription for the symptomatic treatment of BPH. Results: Of 2389 potential citations, 25 were usable for evaluation of safety data, 26 for efficacy. A1B use was associated with a statistically significant increase in the odds of developing a vascular-related event [odds ratio (OR) 2.54; 95% confidence interval (CI): ; p < ]. The odds of developing a vascular-related adverse event were: alfuzosin, OR 1.66, 95% CI: ; terazosin, OR 3.71, 95% CI: ; doxazosin, OR 3.32, 95% CI: and tamsulosin, OR 1.42, 95% CI: A1Bs increased Q(max) by 1.32 ml/min (95% CI: ) compared with placebo. Difference from placebo in American Urological Association symptom index/international Prostate Symptom Score was points (95% CI: to -1.14). Conclusions: Alfuzosin, terazosin and doxazosin showed a statistically significant increased risk of developing vascular-related events compared with placebo. Tamsulosin showed a numerical increase that was not statistically significant. All agents significantly improved Q(max) and symptom signs compared with placebo. Nickel JC, Sander S, Moon TD. A meta-analysis of the vascular-related safety profile and efficacy of alpha-adrenergic blockers for symptoms related to benign prostatic hyperplasia. Int J Clin Pract Oct;62(10): #6: High-dose saw palmetto no better than placebo for BPH symptoms Clinical question: Is high-dose saw palmetto effective in reducing lower urinary tract symptoms associated with benign prostatic hyperplasia? 20

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