Abbreviated Class Update: Anticoagulants. Month/Year of Review: July 2014 End date of literature search: June PDF

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Copyright 2012 Oregon State University. All Rights Reserved Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35, Salem, Oregon Phone Fax
Copyright 2012 Oregon State University. All Rights Reserved Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35, Salem, Oregon Phone Fax Abbreviated Class Update: Anticoagulants Month/Year of Review: July 2014 End date of literature search: June 2014 Last Review: March 2013 Source: OSU College of Pharmacy Current Status of PDL Class: Preferred Agents: lovenox (branded product), dalteparin (Fragmin ), unfractionated heparin (UFH), warfarin Non Preferred Agents: enoxaparin, fondaparinux (Arixtra ), rivaroxaban (Xarelto ), dabigatran (Pradaxa ), apixaban (Eliquis ) Current PA: Oral direct thrombin inhibitors (dabigatran) and oral direct factor Xa inhibitors (apixaban and rivaroxaban) are subject to prior authorization criteria to promote safe and effective use among patients requiring anticoagulation (Appendix 2). Research Questions: Is there any new evidence of efficacy differences between approved anticoagulants in adults requiring treatment or prevention of deep vein thrombosis (DVT) or pulmonary embolism (PE), orthopedic prophylaxis of venous thromboembolism (VTE), or patients with atrial fibrillation (AF)? Is there evidence of differences in harms between the available anticoagulants products? Are there indications or subpopulations where one agent may be more effective or safe than other available agents? Conclusions: The new oral anticoagulants (dabigatran, apixaban and rivaroxaban) have been shown to be superior or non-inferior to warfarin for the prevention of stroke and systemic embolism in patient with non-valvular AF based on high strength of evidence (SOE) 1, however, clinical differences remain small. 2 Guidelines recommend warfarin in preference to the newer agents or offer that patient characteristics and discussion of the risks and benefits of all treatments be the determining factors in anticoagulant selection. 3,4 For the treatment of VTE, apixaban demonstrated non-inferiority to conventional therapy in one good quality study with reduced rates of major bleeding (moderate SOE). 5 For extended VTE treatment, dabigatran proved to be non-inferior to warfarin with less risk of major or clinically relevant bleeding and that dabigatran is superior to placebo (NNT 19) but with increased risk of bleeding (moderate SOE). 6,7 Low molecular weight heparins (LMWH) are preferred for long-term VTE prophylaxis in patients with cancer, based on high SOE. 8 Meta-analysis data in patients undergoing total hip or total knee surgery that require VTE prophylaxis, demonstrated that factor Xa inhibitors (apixaban and rivaroxaban) reduced the rate of symptomatic DVT to a greater extent than LMWH (4 fewer events per 1000 patients) based on high SOE, with a higher occurrence of major bleeding compared to LMWH (2 more events per 1000 patients treated), based on moderate evidence. 9 There was no significant difference in efficacy outcomes between LMWH and dabigatran 220mg daily (strength not available). 9 1 Based on low strength of evidence, rivaroxaban was shown to be as effective as enoxaparin at day 10 and superior to enoxaparin at day 35 when used for thrombus prevention in patients who were medically ill. Enoxaparin treatment was associated with less risk of bleeding compared to rivaroxaban based on low strength of evidence. There is insufficient evidence for the use of rivaroxaban long-term in this population. 10 Recommendations: - Atrial Fibrillation: Recommend warfarin as first-line therapy and offer dabigatran and apixaban as non-preferred agents subject to PA approval. No changes to the PDL are recommended. - VTE treatment: Recommend warfarin or enoxaparin first line with dabigatran, rivaroxaban and apixaban as non-preferred options if clinical criteria are met. Recommend adding apixaban to current PA criteria as a second line option. - Orthopedic Prophylaxis: Recommend LMWH as an appropriate first-line treatment option. Recommend rivaroxaban and apixaban as non-preferred options if clinical criteria are met. Recommend adding apixaban to current PA criteria as a second line option. - Medically Ill: If continued anticoagulation is warranted in medically ill patients recommend warfarin as first-line option. Fourteen day supply of rivaroxaban allows transition to preferred therapy in current PA criteria. No changes to the PDL are recommended. - Add difficulty obtaining INR monitoring to questions #5 and #9 in Oral Direct Factor Xa Inhibitors PA criteria, and questions #3 and #8 in Oral Direct Thrombin Inhibitors PA (Appendix 2). Reasons for the Review: As the range of treatment options for patients requiring anticoagulation expands, new evidence becomes available. Data on newer oral anticoagulants (NOA) continues to evolve with the additional FDA approved indications and additions to the literature. The recent Drug Effectiveness Review Project (DERP) scan will be reviewed with applicable literature added. New indications and safety alerts since the last drug class update in 2013 will summarized. Previous Conclusions and Recommendations: Atrial Fibrillation There is moderate level of evidence that the new oral anticoagulants are superior (dabigatran and apixaban) or non-inferior (rivaroxaban) to warfarin in patients with non-valvular AF as demonstrated by the reduced risk of stroke and systemic embolism The risk of major bleeding was less with the NOAs compared to warfarin based on moderate strength of evidence. There are no studies directly comparing the new oral agents. Treatment beyond two years has not been studied. Concerns over lack of antidote for the new oral anticoagulants, unexplained increases in coronary events with dabigatran and limited clinical experience in the general population remain. Clinical prior authorization criteria are required for the utilization of the new oral anticoagulants while warfarin is available without restrictions. Acute or Chronic DVT or PE Treatment Based on four, fair- good quality studies the NOAs have been shown to be non-inferior to warfarin (±previous enoxaparin therapy) for acute and chronic DVT and PE treatment based on moderate level of evidence Direct comparison among the new agents is lacking. Patients with severe renal disease and those at high risk of bleeding have not been studied. Guidelines favor the use of warfarin followed by LMWH for this indication and these treatments are available without restriction. 18 Dabigatran and rivaroxaban are available upon meeting clinical PA requirements. VTE Prophylaxis in Orthopedic Surgery (Total Knee Replacement [TKR] and Total Hip Replacement [THR) Data from five studies suggested NOAs are non-inferior or superior to enoxaparin when used for orthopedic prophylaxis in patients undergoing THR Studies of the NOAs in patients undergoing TKR have shown conflicting results with evidence suggesting non-inferiority or superiority of the NOAs over enoxaparin when the 40 mg daily dose for enoxaparin is used. 24,25 Studies utilizing the US enoxaparin recommended dose for TKR, 30 mg twice daily, has shown the NOAs to be inferior to enoxaparin with the exception of rivaroxaban which has demonstrated superiority based on moderate strength of evidence No direct comparisons are available, however, indirect data suggests apixaban, dabigatran, and rivaroxaban prevent symptomatic VTEs to a similar extent based on moderate SOE. 30 Guidelines favors LMWH over fondaparinux, apixaban, dabigatran, rivaroxaban, or UFH based on moderate evidence. 18 LMWH are considered an appropriate first-line treatment and are not subject to PA criteria. Rivaroxaban is considered the most appropriate second-line option. Background: Anticoagulants are used in the prevention and treatment of a variety of medical conditions. Thrombosis results from damage to the endothelial lining of blood vessels which trigger activation of the coagulation cascade leading to thrombus formation. 30 Injectable anticoagulants work by enhancing antithrombin (AT) which is responsible for inhibiting a variety of clotting factors. 30 Oral anticoagulants exhibit anticoagulant activity through blocking the formation of vitamin K clotting factors (warfarin), direct thrombin inhibition (dabigatran) or factor Xa inhibition (rivaroxaban and apixaban) Commonly used oral and injectable anticoagulants are presented in table 1. Table 1. Anticoagulants FDA Approved Indications Drug DVT/PE DVT/PE Atrial Cardiac Valve Post- MI Prophylaxis Treatment Fibrillation Replacement Warfarin (Coumadin ) Dabigatran (Pradaxa ) (nonvalvular only) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) + (Studied in THR and TKR) + (Studied in THR and TKR) + + (nonvalvular only) (nonvalvular only) Enoxaparin (Lovenox ) * MI- myocardial infarction, DVT deep vein thrombosis, THR- total hip replacement, TKR- total knee replacement The most important outcomes in assessing therapy for treatment and prevention of VTE include the occurrence or reoccurrence of VTE, major bleeding and allcause mortality. Additional relevant outcomes include: minor bleeding, cardiovascular events and withdrawals due to adverse events. Early research relied primarily on symptomatic VTE and fatal PE as measures of antithrombotic prophylaxis efficacy. When evaluating anticoagulation therapies for patients undergoing hip or knee replacement surgeries current literature has incorporated the use of the surrogate outcome, asymptomatic DVT, detected by mandatory venography. 36 The American College of Chest Physicians (ACCP) guidelines find this outcome fundamentally unsatisfactory due to the inability to weigh the risks and benefits of efficacy (knowledge of symptomatic events) compared to serious bleeding. 18 The guidelines provide suggestions to estimate reductions in symptomatic thrombosis, dependent upon available evidence. Many studies that evaluate the effectiveness of anticoagulants in surgery patients rely on asymptomatic DVT events to determine treatment differences and are not powered to detect a difference in the frequency of symptomatic events, due to low occurrence rates. 37 Rates of stroke, systemic embolisms and mortality are appropriate outcomes in evaluating treatment for AF. Secondary outcomes of interest are rates of ischemic and hemorrhagic strokes and incidence of myocardial infarctions (MI). Important safety outcomes include major bleeds, clinically relevant non-major bleeds and gastrointestinal bleeding. VTE Prophylaxis For patients undergoing THR or TKR, prophylactic anticoagulants are considered standard practice. ACCP guidelines recommend the use of LMWHs over other available anticoagulants (moderate evidence). 18 A minimum treatment duration of days is recommended (moderate evidence). 18 There is moderate evidence suggesting thromboprophylaxis be continued for up to 35 days from the day of the surgery. 17 The FDA approved doses for subcutaneous enoxaparin prophylaxis in patients undergoing hip replacement surgery is 30 mg every 12 hours or 40 mg once daily and for knee replacement surgery is 30 mg given every 12 hours. 36 This is in contrast to the common European dosing regimen of enoxaparin 40 mg given once daily for prophylaxis in patients undergoing knee replacement, which is used in some trial designs. Dabigatran has demonstrated similar efficacy to LMWH, while rivaroxaban has shown superiority to LMWH in a comparative effectiveness review evaluating patients undergoing orthopedic surgery. 37 For patients who are medically ill and at risk for VTE, prophylaxis is recommended with one of the following therapies; LMWH, unfractionated heparin (UFH) or fondaparinux. 18 Acute VTE Treatment ACCP guidelines recommend the use of LMWH, fondaparinux, intravenous (IV) UFH or subcutaneous UFH for the acute treatment of DVT and PE. The treatment duration is indication dependent, however, long-term anticoagulation is recommended, ranging from 3 months to extended therapy. 17 Treatment with vitamin K antagonists (VKA) are recommended over LMWH for extended anticoagulation in most patients (Grade I, low evidence), except those with cancer in which LMWHs are preferred, based on moderate evidence. 18 Atrial Fibrillation Patients with AF are at increased risk of stroke and systemic embolism. Risk estimates are based on the CHADS 2 and CHA 2 DS 2 -VASc Classification Scheme (Table 2). 2 The CHADS 2 risk stratification scheme has demonstrated a 2% increase in stroke rate for each one point increase in score. The CHADS 2 system designates intermediate risk to those with a score of 1, lacking a clear risk assessment for those at lowest risk. 2 Those with prior history of prior stroke may have their risk underestimated by CHADS 2 classification. The CHA 2 DS 2 -VASc scoring system has a wider scoring system which correlates to better predictability of risk in those with a lower initial stroke risk. CHEST guidelines on antithrombotic and thrombolytic therapy recommend anticoagulation for patients with AF and a CHAD 2 score 1 and the AHA/ACC/HRS guidelines recommend anticoagulation for those with prior stroke, TIA or CHA 2 DS 2 -VASc score 2. 2,18 Table2. CHADS 2 and CHA 2 DS 2 -VASc Classification Risk Stratification Scores for Subjects with Nonvalvular AF 2,18 Definition and Scores for CHADS 2 and CHA 2 DS 2 -VASc CHADS 2 acronym Score CHA 2 DS 2 -VASc acronym Score Congestive HF 1 Congestive HF 1 Hypertension 1 Hypertension 1 Age 75yr 1 Age 75yr 2 Diabetes mellitus 1 Diabetes mellitus 1 Stroke/TIA/TE 2 Stroke/TIA/TE 2 Maximum Score 6 Vascular disease (prior MI, PAD, or aortic plaque) 1 Age y 1 Sex category (i.e., female sex) 1 Maximum Score 9 Methods: A Medline literature search beginning January 2013 (since last anticoagulant drug class update) and ending May 2014 for new systematic reviews and randomized controlled trials (RCTs) of anticoagulant therapies was performed. The Agency for Healthcare Research and Quality (AHRQ), Cochrane Collection, National Institute for Health and Care Excellence (NICE), Department of Veterans Affairs, Clinical Evidence, Up To Date, Dynamed, and the Canadian Agency for Drugs and Technologies in Health (CADTH) resources were manually searched for high quality and relevant systematic reviews. The FDA website was searched for new drugs, indications, and safety alerts, and the AHRQ National Guideline Clearinghouse (NGC) was searched for updated and recent evidence-based guidelines. The primary focus of the evidence is on high quality systematic reviews and evidence based guidelines for this class update. Randomized controlled trials will be emphasized if evidence is lacking or insufficient from those preferred sources. Systematic Reviews: Veterans Affairs - Comparative Effectiveness of New Oral Anticoagulants and Standard Thromboprophylaxis in Patients Having Total Hip or Knee Replacement 9 A recent systematic review compared the efficacy and harms new oral anticoagulants to standard treatment (LMWH) in patients undergoing THR or TKR. Literature was analyzed and graded using the Assessment of Multiple Systematic Reviews and QUOROM (Quality of Reporting of Meta-analyses) criteria. Six, good-quality reviews were included in the analysis. The new oral anticoagulants studied included: apixaban, dabigatran, rivaroxaban, and edoxaban (not available in the United States [US]). All studies used a LMWH as a comparator. Factor Xa inhibitors were found to reduce the rate of symptomatic DVT to a greater extent than LMWH based on high SOE (4 fewer events per 1000 patients; OR 0.46; 95% CI ). The risk of non-fatal PE (OR 1.07; 95% CI 0.65 to 1.73) and death (OR 0.95; 95% CI 0.55 to 1.63) were similar. There was moderate SOE that factor Xa inhibitors were associated with a non-significant higher occurrence of major bleeding compared to LMWH (2 more events per 1000 patients treated; OR 1.27; 95% CI 0.98 to 1.65). The direct thrombin inhibitor, dabigatran, was not statistically different from LMWH, regardless of outcome studied (based on low and moderate SOE). Rivaroxaban was shown to reduce the risk of VTE to a greater extent than dabigatran and apixaban, based on indirect comparisons. COCHRANE Factor Xa Inhibitors Versus Vitamin K Antagonists for Preventing Cerebral or Systemic Embolism in Patients with Atrial Fibrillation 3 In a 2013 review, the Cochrane Collaboration evaluated the efficacy and safety of factor Xa inhibitors compared to VKAs in stroke and systemic embolism prevention. Ten, moderate to high quality trials involving 42,084 participants with AF were included. Apixaban and rivaroxaban studies accounted for approximately 80% of the factor Xa inhibitors studied, however, studies of therapies not approved in the US were also included (betrixaban, darexaban, edoxaban and idraparinux). The primary outcome of composite strokes and systemic embolism was reported in nine of the studies. Factor Xa inhibitors were found to be statistically superior to warfarin for the composite primary outcome of stroke and systemic embolic events (OR 0.81, 95% CI 0.72 to 0.91; 9 studies), as well as the individual components. These results translate into of number needed to treat (NNT) of 304 per year for apixaban and 369 for rivaroxaban, when including only larger studies with follow-up of at least a year. Major bleeding was also found to be significantly less with factor Xa inhibitors compared to warfarin (OR 0.81, 95% CI 0.81 to 0.98). Due to high heterogeneity, a second analysis was performed and showed that major bleeds were not significantly less with factor Xa inhibitors (OR 0.92, 95% CI 0.63 to 1.34). Clinically relevant non-major bleeding was not statistically different between the two groups. Intracranial hemorrhage rates and all-cause death were also found be significantly less with factor Xa inhibitors compared to warfarin. Quality of anticoagulation (time in therapeutic range) with warfarin did not effect the efficacy results when compared to rivaroxaban and apixaban. Authors note that while factor Xa inhibitors were shown to be more effective than warfarin the clinical difference between the agents remains very small. Ruff et al - Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials 39 Apixaban, dabigatran, edoxaban, and rivaroxaban were included in a recent meta-analysis evaluating the efficacy and safety of these agents in patients with AF. In dabigatran and edoxaban studies, two dosing schemes were used and therefore analyzed in separate analyses: low dose (dabigatran 110mg twice daily and edoxaban 30mg once daily) and high dose (dabigatran 150mg twice daily, edoxaban 60mg once daily, rivaroxaban 20mg once daily and apixaban 5mg twice daily). There were 42,411 patients who received new oral anticoagulants and 29,272 who received warfarin. The mean ages included in the trials ranged from with approximately one-third being women. The mean baseline CHADS 2 score was 2.1 in studies with dabigatran and apixaban, 2.8 with edoxaban and highest with rivaroxaban with a score of 3.5. Time in therapeutic range (TTR) was 58-68% across the trials. Follow-up ranged from 1.8 to 2.8 years. The meta-analysis comparative efficacy combined results for stroke and systemic embolism favored high-dose NOAs over warfarin (RR 0.81, 95% CI 0.73 to 0.91, p ). As in many of the individual trials, the results were driven by reductions in hemorrhagic stroke. All cause mortality rates were also significantly reduced in the patients allocated to the high-dose NOAs compared to those in the warfarin groups (RR 0.90, 95% CI 0.85 to 0.95, p = 0003). Safety findings illustrated a reduction in major bleeding (RR 86, 95% CI 0.73 to 1.00, p = 0.06) and intracranial hemorrhage (RR 0.48, 95% CI 0.39 to 0.59, p ). Gastrointestinal bleeding was significantly higher in high-dose NOAs compared to warfarin (RR 1.25, 95% CI 1.01 to 1.55, p = 0.043). The efficacy benefits seen with high dose NOAs compared to warfarin were consistent across subgrou
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