***TASK*** the task is to summarize an input biomedical literature in six sentences 
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    Input: Background To demonstrate the use of risk-benefit analysis for comparing multiple competing interventions in the absence of r and omized trials , we applied this approach to the evaluation of five anticoagulants to prevent thrombosis in patients undergoing orthopedic surgery . Methods Using a cost-effectiveness approach from a clinical perspective ( i.e. risk benefit analysis ) we compared thromboprophylaxis with warfarin , low molecular weight heparin , unfractionated heparin , fondaparinux or ximelagatran in patients undergoing major orthopedic surgery , with sub-analyses according to surgery type . Proportions and variances of events defining risk ( major bleeding ) and benefit ( thrombosis averted ) were obtained through a meta- analysis and used to define beta distributions . Monte Carlo simulations were conducted and used to calculate incremental risks , benefits , and risk-benefit ratios . Finally , net clinical benefit was calculated for all replications across a range of risk-benefit acceptability thresholds , with a reference range obtained by estimating the case fatality rate - ratio of thrombosis to bleeding . Results The analysis showed that compared to placebo ximelagatran was superior to other options but final results were influenced by type of surgery , since ximelagatran was superior in total knee replacement but not in total hip replacement . Conclusions Using simulation and economic techniques we demonstrate a method that allows comparing multiple competing interventions in the absence of r and omized trials with multiple arms by determining the option with the best risk-benefit profile . It can be helpful in clinical decision making since it incorporates risk , benefit , and personal risk acceptance PURPOSE Within the last two decades , a new underst and ing of the biology of myelodysplastic syndrome ( MDS ) has developed . With this underst and ing , new classification systems , such as the WHO diagnostic criteria , and the International Prognostic Scoring System and response criteria guidelines reported by the International Working Group ( IWG ) have been developed . We report the combined results of three previously reported clinical trials ( n = 309 ) with azacitidine using the WHO classification system for MDS and acute myeloid leukemia ( AML ) and IWG criteria for response . PATIENTS AND METHODS Data from three sequential Cancer and Leukemia Group B trials with azacitidine  were recollected and reanalyzed as part of the New Drug Application process . The trials were conducted with either intravenous or subcutaneous azacitidine ( 75 mg/m2/d for 7 days every 28 days ) . RESULTS Complete remissions were seen in 10 % to 17 % of azacitidine-treated patients ; partial remissions were rare ; 23 % to 36 % of patients had hematologic improvement ( HI ) . The median number of cycles to first response was three , and 90 % of responses were seen by cycle 6 . Using current WHO criteria , 103 patients had AML at baseline ; 35 % to 48 % had HI or better responses . The median survival time for the 27 AML patients r and omly assigned to azacitidine was 19.3 months compared with 12.9 months for the 25 patients assigned to observation . Furthermore , azacitidine did not increase the rate of infection or bleeding above the rate caused by underlying disease . CONCLUSION Azacitidine provides important clinical benefits for patients with high-risk MDS Acute myeloid leukemia ( AML ) patients aged ≥60 years tolerate st and ard induction chemotherapy poorly . Therapy with azacitidine at a dose of 75 mg/m2/day for 7 days appears to be better tolerated , and is approved by the Food and Drug Administration ( FDA ) for the treatment of elderly AML patients with bone marrow ( BM ) blast counts of 20–30 % . Here , we report the results of a prospect i ve , phase 2 , open‐label study that evaluated the tolerability and efficacy of a 5‐day regimen of single‐agent subcutaneous azacitidine 100 mg/m2/day administered every 28 days in 15 elderly patients with newly diagnosed AML , 14 of whom had BM blast counts > 30 % . The overall response rate was 47 % . Complete remission , partial remission , and hematologic improvement were achieved by 20 , 13 , and 13 % of patients , respectively . Median overall survival was 355 days for the entire cohort , and 532 days for responders . Median time to best response was 95 days , and median treatment duration was 198 days ( range = 13–724 days ) . Grade 3–4 hematologic toxicities comprised predominantly febrile neutropenia ( 40 % ) and thrombocytopenia ( 20 % ) . Febrile neutropenia was the most common cause of hospitalization . Nonhematologic toxicities , consisting of injection‐site skin reactions and fatigue ( Grade s 1–2 ) , occurred in 73 % ( n = 11 ) of patients . No treatment‐related deaths occurred during the study . The dose and schedule of therapy remained constant in all but four patients . The findings of this study suggest that administration of subcutaneous azacitidine 100 mg/m2/day for 5 days every 28 days is a feasible , well‐tolerated , and effective alternative to st and ard induction chemotherapy in elderly patients with AML Abstract This phase II trial treated elderly or frail patients with acute myeloid leukemia ( AML ) with single-agent subcutaneous azacytidine at 100 mg/m2 , on 5 of 28 days for up to six cycles . Treatment was stopped for lack of response , or continued to progression in responders . The primary endpoint was response within 6 months . A response rate ≥ 34 % was considered a positive trial outcome . From September 2008 to April 2010 , 45 patients from 10 centers ( median age 74 [ 55–86 ] years ) were accrued . Patients received four ( 1–21 ) cycles . Best response was complete response/complete response with incomplete recovery of neutrophils and /or platelets ( CR/CRi ) in eight ( 18 % ; 95 % confidence interval [ CI ] : 8–32 % . ) , 0 ( 0 % ) partial response ( PR ) , seven ( 16 % ) hematologic improvement , 17 ( 38 % ) stable disease . Three non-responding patients stopped treatment after six cycles , 31 patients stopped early and 11 patients continued treatment for 8–21 cycles . Adverse events ( grade ≥ III ) were infections ( n = 13 ) , febrile neutropenia ( n = 8) , thrombocytopenia ( n = 7 ) , dyspnea ( p = 6 ) , bleeding ( n = 5 ) and anemia ( n = 4 ) . Median overall survival was 6 months . Peripheral blood blast counts , grouped at 30 % , had a borderline significant association with response ( p = 0.07 ) . This modified azacytidine schedule is feasible for elderly or frail patients with AML in an outpatient setting with moderate , mainly hematologic , toxicity and response in a proportion of patients , although the primary objective was not reached The myelodysplastic syndromes ( MDSs ) are heterogeneous with respect to clinical characteristics , pathologic features , and cytogenetic abnormalities . This heterogeneity is a challenge for evaluating response to treatment . Therapeutic trials in MDS have used various criteria to assess results , making cross- study comparisons problematic . In 2000 , an International Working Group ( IWG ) proposed st and ardized response criteria for evaluating clinical ly significant responses in MDS . These criteria included measures of alteration in the natural history of disease , hematologic improvement , cytogenetic response , and improvement in health-related quality of life . The relevance of the response criteria has now been vali date d prospect ively in MDS clinical trials , and they have gained acceptance in research studies and in clinical practice . Because limitations of the IWG criteria have surfaced , based on practical and reported experience , some modifications were warranted . In this report , we present recommendations for revisions of some of the initial criteria Azacitidine 's  efficacy in therapy-related myeloid neoplasms ( t-MN ) has not been well-studied . In our retrospective review of 84 t-MN patients treated with azacitidine  , median overall survival ( OS ) was 14.5 months and overall response rate was 43 % , including 11 % complete remission , 4 % marrow complete remission , and 11 % partial remission . In patients who underwent allogeneic transplant ( 25 % ) , median OS was 19.2 versus 12.8 months ( P=0.023 ) for those who did not . Response rates were comparable to those reported for de novo myelodysplastic syndrome . When we analyzed outcomes according to five scoring systems , only the Global MD And erson Risk Model predicted survival with statistical significance The phase III AZA-001 study established that azacitidine significantly improves overall survival compared with conventional care regimens ( hazard ratio 0.58 [ 95 % confidence interval 0.43–0.77 ] , P<0.001 ) . This analysis was conducted to investigate the relationship between treatment response and overall survival .  AZA-001 data were analyzed in a multivariate Cox regression analysis with response as a time-varying covariate . Response categories were “ Overall Response ” ( defined as complete remission , partial remission , or any hematologic improvement ) and “ Stable Disease ” ( no complete or partial remission , hematologic improvement , or progression ) or “ Other ” ( e.g. disease progression ) . Achieving an Overall Response with azacitidine reduced risk of death by 95 % compared with achieving an Overall Response with the conventional care regimens ( hazard ratio 0.05 [ 95%CI : 0.01–0.43 ] , P=0.006 ) . Sensitivity analyses indicated that significantly improved overall survival remained manifest for patients with a hematologic improvement who had never achieved complete or partial remission ( hazard ratio 0.19 [ 95%CI : 0.08–0.46 ] , P<0.001 ) . Stable Disease in both azacitidine-treated and conventional care-treated patients was also associated with a significantly reduced risk of death ( hazard ratio 0.09 , [ 95%CI : 0.06–0.15 ] ; P<0.001 ) . These results demonstrate azacitidine benefit on overall survival compared with conventional care regimens in patients with higher-risk myelodysplastic syndromes who achieve hematologic response but never attain complete or partial remission , in addition to the survival advantage conferred by achievement of complete or partial remission . This study was registered with clinical trials.gov ( NCT00071799 ) This prospect i ve phase II study evaluated the efficacy of azacitidine (Aza)+erythropoietin ( Epo ) in transfusion-dependent patients with lower-risk myelodysplastic syndrome ( MDS ) . Patients ineligible for or refractory to full-dose Epo+granulocyte colony stimulation factors for > 8 weeks and a transfusion need of ⩾4 units over 8 weeks were included .  Aza 75 mg m−2 d−1 , 5/28 days , was given for six cycles ; non-responding patients received another three cycles combined with Epo 60 000 units per week . Primary end point was transfusion independence ( TI ) . All patients underwent targeted mutational screen for 42 c and i date genes . Thirty enrolled patients received ⩾one cycle of Aza . Ten patients discontinued the study early , 7 due to adverse events including 2 deaths . Thirty-eight serious adverse events were reported , the most common being infection . Five patients achieved TI after six cycles and one after Aza+Epo , giving a total response rate of 20 % . Mutational screening revealed a high frequency of recurrent mutations . Although no single mutation predicted for response , SF3A1 ( n=3 ) and DNMT3A ( n=4 ) were only observed in non-responders . We conclude that Aza can induce TI in severely anemic MDS patients , but efficacy is limited , toxicity substantial and most responses of short duration . This treatment can not be generally recommended in lower-risk MDS . Mutational screening revealed a high frequency of mutations Hypomethylating agents , such as 5-azacitidine ( 5-AZA ) and 5-aza-2’-deoxycytidine ( decitabine ) , have recently been approved for the treatment of myelodysplastic syndromes ( MDS ) . Several r and omized trials have shown favorable results concerning response rate , survival , transformation to acute leukemia , and quality of life . In these trials , treatment was administered continuously until progression . In the retrospective study presented here , we evaluated the outcome of patients with higher risk MDS or secondary acute myeloid leukemia ( sAML ) treated with a limited number of 5-AZA cycles . A total of 32 patients received 5-AZA alone ( n = 30 ) or in combination with valproic acid and all-trans retinoic acid ( n = 2 ) . 5-AZA was administered subcutaneously at a fixed dose of 75 mg/m2 daily for 7 days and repeated every 28 days . 5-AZA was given for a median of four courses . Treatment was continued for two more cycles as consolidation in patients who had achieved complete remission ( CR ) , marrow CR , or stable disease with hematologic improvement . The overall response rate was 50 % according to the modified International Working Group criteria . Complete remissions were achieved in 15.6 % and stable disease in  
    Output:
    
Conclusions Indirect comparison of alternative azacitidine dosing regimens in MDS and AML shows a benefit for the 7-day regimen in attaining ORR .