Target Population of Non-deferrable Surgery and Uncontrolled Severe Bleeding Related to Dabigatran.

PURPOSE: This observational study was aimed to identify patients who experienced non-deferrable surgery and/or uncontrolled severe bleeding following dabigatran administration and then are potentially eligible to the use of the specific antidote idarucizumab in a real-world setting. METHODS: From the big Italian real-world database ARCO, a cohort of adult patients treated with dabigatran and hospitalized due to diagnoses attributable to urgent interventions and/or major bleeding was selected in 2014. Baseline characteristics and all-cause hospitalizations, specialist/diagnostic outpatient services, and healthcare costs over the 1-year follow-up were described. RESULTS: Out of 16,756,843 Italian citizens, 271,540 (1.9%) were prescribed with oral anticoagulants, and specifically, 17,450 with dabigatran. Patients identified to be hospitalized for non-deferrable surgery (n = 106) and/or uncontrolled severe bleeding (n = 190) following dabigatran use were 289 (1.7%) [mean age (± SD) 79 ± 7, 50% of female sex]. On average, patients stayed in hospital 13.7 and 17.0 days, respectively. The per patient and per year cost to the Italian National Health System was on average 19,708€ (specifically 1487€ for drugs, of which 311€ for dabigatran, 17,353€ for all-cause hospitalizations, and 869€ for outpatient care), about four times more than the mean healthcare integrated cost of a single patient treated with dabigatran (4775€). CONCLUSIONS: This analysis of the ARCO database reliably describes the population potentially eligible to the dabigatran reversal agent, idarucizumab. These data may be useful for Healthcare Decision Makers to organize, define, and improve present and future emergency healthcare, mainly as starting point for cost-effectiveness analyses of new reversal agents.

[Use of a Delphi survey to assess the hospital economic impact of innovative products: The example of idarucizumab a dabigatran-specific reversal agent]. / Utilisation du questionnaire Delphi pour anticiper l'impact économique des innovations thérapeutiques à l'hôpital : application à l'idarucizumab, le nouvel agent de réversion spécifique au dabigatran.

OBJECTIVES: The economic impact of therapeutic innovations on the hospital patient management cannot be easily estimated. The objective of this study is to illustrate the use of a Delphi survey as a support tool to identify the changes following the use of idarucizumab in dabigatran-treated patients with uncontrolled/life-threatening bleeding or who required emergency surgery/urgent procedures. METHODS: The Delphi questionnaires have been administrated to 8 emergency physicians or anesthetists from 6 different hospital centers. Following the answers, an economic valorization has been carried out on every parameter on which a consensus was reached (at least 4 answers showing an identical trend). A mean management cost for each etiology with and without the use of idarucizumab has thus been identified. RESULTS: For gastro-intestinal and other life-threatening bleedings (excepted intracranial bleedings), the total management cost of the hospital stay was respectively 6058 € (-35%) and 6219 € (-34%) following the use of the reversal agent. The hospital management cost for intracranial bleeding is slightly increasing to 9790 € (+3%). The cost of a stay for emergency surgery decreases to 6962€ (-2%). CONCLUSIONS: This study shows a positive economic impact following the use of the dabigatran-specific reversal agent for patients with uncontrolled/life-threatening bleeding excepted in the case of intracranial bleeding. Moreover, it points out that a Delphi survey is an easy way to predict the hospital economic impact of a therapeutic innovation when no other evaluation is possible.

Safety and feasibility of lower antithrombin replacement targets in adult patients with hematological malignancies receiving asparaginase therapy.

The optimal antithrombin(AT) activity parameters for replacement as thromboprophylaxis following asparaginase remains unclear. This single-center, retrospective study evaluated two sets of AT replacement thresholds and targets in adults receiving asparaginase-containing chemotherapy. AT supplementation adhered to institutional standards, which lowered the AT activity target from 100% to 80% in 6/2014. Ninety-two patients were evaluated. Cumulative thrombosis incidence was 16% at 6 months (95%CI:6.8-24.0, maximum follow-up 315 days) with similar incidence between the 80% and 100% target groups, 14% (2 of the 14) and 13% (10 of the 78), respectively, with a small non-Line-Related DVT incidence (3%). Most thrombotic events occurred during induction chemotherapy and demonstrated no associations with replacement target, cumulative days or cumulative area under AT activity target, number of asparaginase doses, or cumulative asparaginase dose. Median estimated AT replacement expenditure was $34,963USD (IQR $16,260USD to $79,319USD) per patient. Cost-effectiveness and optimization of AT replacement for thromboprophylaxis following asparaginase requires prospective evaluation.

New anticoagulants as thromboprophylaxis after total hip or knee replacement.

OBJECTIVES: Due to a high risk of thromboembolism in patients undergoing major orthopedic surgery, it has become standard practice to give thromboprophylactic treatment. We assessed the relative efficacy and cost-effectiveness of two new oral anticoagulants, rivaroxaban and dabigatran, relative to subcutaneous enoxaparin for the prevention of thromboembolism after total hip replacement (THR) and total knee replacement surgery (TKR). METHODS: We conducted a systematic review of the literature to assess efficacy and safety, and evaluated quality of documentation using GRADE. Cost-effectiveness was assessed by developing a decision model. The model combined two modules; a decision tree for the short-term prophylaxis and a Markov model for the long-term complications and survival gain. RESULTS: For rivaroxaban compared with enoxaparin, we found statistically significant decreases in deep vein thrombosis, but also a trend toward increased risk of major bleeding. For mortality and pulmonary embolism there were no statistically significant differences between the treatments. We did not find statistically significant differences between dabigatran and enoxaparin for our efficacy and safety outcomes. Assuming a willingness to pay of EUR62,500 per QALY, rivaroxaban following THR had a probability of 38 percent, and enoxaparin following TKR had a probability of 34 percent of being cost-effective. Clinical efficacy had the greatest impact on decision uncertainty. CONCLUSIONS: Dabigatran and rivaroxaban are comparable with enoxaparin following THR and TKR regarding the efficacy and safety outcomes. However, there is great uncertainty regarding which strategy is the most cost-effective. More research on clinical efficacy of rivaroxaban and dabigatran is likely to change our results.

Bivalirudin: a pharmacoeconomic profile of its use in patients with acute coronary syndromes.

Bivalirudin (Angiox®; Angiomax®), a direct thrombin inhibitor, is an intravenous anticoagulant. The efficacy of bivalirudin in the management of patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) or ST-segment elevation myocardial infarction (STEMI) planned for invasive interventions has been shown in large, pivotal, open-label trials. Bivalirudin provided similar ischaemic protection to heparin plus a glycoprotein (GP) IIb/IIIa inhibitor, but with a significant reduction in bleeding events, in patients with NSTE-ACS planned for urgent or early intervention and those with STEMI planned for primary percutaneous coronary intervention (PCI). Mortality rates were also significantly lower in patients with STEMI receiving bivalirudin than in those receiving heparin plus a GP IIb/IIIa inhibitor in the key trial of patients with STEMI. Based on this clinical data, modelled cost-utility analyses from the perspective of various UK NHS providers have predicted that bivalirudin would be highly likely to be cost effective with regard to the cost per QALY gained relative to a heparin plus GP IIb/IIIa inhibitor-based strategy over a lifetime horizon in these patient populations. In patients with NSTE-ACS planned for urgent or early invasive intervention, a bivalirudin-based strategy was considered to be cost effective in the UK, Scotland and Wales. In patients with STEMI planned for primary PCI, a bivalirudin-based strategy was dominant in the UK and Scotland. Parallel and sensitivity analyses demonstrated that base-case conclusions were robust over a range of plausible changes in parameter estimates and assumptions, including changes made to more closely reflect current local clinical practice. In addition, budgetary impact analyses in several countries suggested that the implementation of a bivalirudin-based strategy, instead of a heparin plus GP IIb/IIIa inhibitor-based strategy, would be cost saving from a hospital perspective in patients with NSTE-ACS undergoing urgent or early PCI, as well as in patients with STEMI undergoing primary PCI. Likewise, prospective and retrospective treatment cost studies in the US indicated that treatment with bivalirudin was less costly than treatment with heparin plus a GP IIb/IIIa inhibitor in these indications. In conclusion, available pharmacoeconomic data from several countries, despite some inherent limitations, support the use of strategies based on bivalirudin over those based on heparin plus a GP IIb/IIIa inhibitor in patients with NSTE-ACS planned for urgent or early invasive intervention or STEMI planned for primary PCI. These pharmacoeconomic advantages primarily reflect that, relative to heparin plus a GP IIb/IIIa inhibitor, bivalirudin is associated with lower rates of bleeding over the short term, and is associated with lower rates of early mortality that are subsequently maintained over the longer term in patients with STEMI.

Economic impact of switching to bivalirudin for a primary percutaneous coronary intervention in a US hospital.

BACKGROUND: The addition of glycoprotein IIb/IIIa inhibitors (GPIs) to heparin in percutaneous coronary intervention (PCI) procedures has been demonstrated to reduce ischemic complications; however, GPI use is known to increase the risk of bleeding events, which are linked to increased mortality, longer hospital length of stay, greater medical resource utilization, and increased costs. New antithrombotic therapies have the potential to improve clinical outcomes and decrease costs. The Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) study of bivalirudin demonstrated significantly reduced clinical event rates (mortality and bleeding) compared with an unfractionated heparin (UFH)+GPI regimen. OBJECTIVE: The potential clinical and economic value of implementing a bivalirudin-based strategy for ST-segment elevation myocardial infarction (STEMI) patients receiving primary PCI (PPCI) is compared with current UFH+GPI-based practice from a US hospital perspective. METHODS: A budget impact model was developed to compare treatment of STEMI patients undergoing PPCI with a bivalirudin- or UFH+GPI-based strategy. Clinical data for the model were derived from the HORIZONS-AMI trial, and included 30-day event rates for major complications (eg, protocol bleeding, Q-wave MI, repeat PCI, and coronary artery bypass graft procedures). United States cost data and clinical practice data were derived from a Premier Perspective™ database analysis and published sources. RESULTS: Overall, average procedure costs per UFH+GPI-treated patient were $18,561. Treating patients with bivalirudin (incorporating 7.2% provisional GPI use per HORIZONS-AMI) may save $1690 per patient (average procedural cost, $16,872). In extrapolating these benefits to the American College of Cardiology/American Heart Association recommended institutional minimum of 36 PPCIs annually, 1 major bleeding event (3.7%) and 3 minor bleeding events (6.8%) could be averted with use of bivalirudin. In addition, introducing a bivalirudin-based strategy to treat a minimum cohort of 36 STEMI patients would save the hospital budget $60,807 (9%) per year. CONCLUSION: Using a bivalirudin-based strategy in STEMI patients undergoing PPCI is associated with favorable clinical and economic outcomes when compared with an UFH+GPI-based strategy in a US hospital setting.

[Clinical and economical evaluation of bivalirudin during percutaneous coronary interventions]. / Evaluations clinique et économique de la bivalirudine au cours des procédures d'angioplasties coronaires.

Bivalirudin, with provisional GP IIb/IIIa inhibitor use allows the same protection against ischemic complications while reducing the hemorrhagic complications compared with the systematic association of a GP IIb/IIIa inhibitor plus heparin (The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events-2 [Replace-2]). In clinical practice, the use of heparin is not systematically associated with a GP IIb/IIIa inhibitor. That's why we studied the clinical and economic interest of bivalirudin only versus heparin (UFH) only. Opened pragmatic monocentric study carried out in 2007. We made a chronological matching: for each patient treated with bivalirudin, we included the next patient with the same clinical presentation treated with unfractionated heparin. Ninety-two patients were included (46 in each group). The need for a GP IIb/IIIa inhibitor during the PCI was not significantly different between the two groups (p=0.11). No major hemorrhagic complications were observed in the two groups. Prevalence of ecchymosis was not significantly different: 22 % in the UFH group versus 13 % in the bivalirudin group (p=0.27). The average troponin level the next day was significantly higher in the bivalirudin group (p=0,049), although the change in troponin levels before and after the procedure was similar in the two groups. The average cost by patient of anticoagulation by bivalirudin and HNF is very different, respectively 473+/-150 and 51+/-146 euro (p=0.0001). Bivalirudin can be an interesting alternative for patients with a high risk of having complications. But considering its cost this therapy must be used only for selected patients.

Outcomes of patients with acute coronary syndromes who are treated with bivalirudin during percutaneous coronary intervention: an analysis from the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) trial.

BACKGROUND: The REPLACE-2 trial demonstrated that bivalirudin with provisional glycoprotein IIb/IIIa (GPIIb/IIIa) inhibition is not inferior to heparin plus GPIIb/IIIa inhibition in patients undergoing percutaneous coronary intervention. The extent to which this applies to patients with acute coronary syndromes (ACS) is unclear. Therefore, we sought to determine if bivalirudin has similar efficacy in ACS patients as compared with "stable" patients in the REPLACE-2 trial. METHODS: We analyzed the outcomes of ACS patients compared with stable patients and the outcomes of ACS patients according to whether or not they had received bivalirudin, including the economic costs. The trial enrolled 1351 ACS patients (myocardial infarction within 7 days or unstable angina within 48 hours, but not on ongoing GPIIb/IIIa or heparin therapy) and 4554 stable patients. RESULTS: Patients with ACS had a similar rate of death or myocardial infarction at 30 days compared to stable patients (7.2% vs 6.7%, P = .51) and death at 1 year (1.6% vs 2.2%, P = .169), but a higher rate of urgent coronary artery bypass graft at 30 days (1.0% vs 0.3%, P = .002). Patients with ACS treated with bivalirudin had a similar rate of 30-day death, myocardial infarction, or urgent revascularization compared with ACS patients treated with heparin and GPIIb/IIIa inhibitors (8.7% vs 8.0%, P = .616) and death at 1 year (1.5% vs 1.8%, P = .701), but a higher rate of revascularization at 6 months (12% vs 8.4%, P = .04). Patients with ACS treated with bivalirudin had less major bleeding than ACS patients treated with heparin and GPIIb/IIIa inhibitors, although this was not statistically significant (2.7% vs 4.5%, P = .07). Mean 30-day costs for patients with ACS were dollar 12415 for those treated with bivalirudin and dollar 12806 for those treated with heparin plus GPIIb/IIIa inhibitors (P = .022). CONCLUSION: Bivalirudin with provisional GPIIb/IIIa inhibitor use in low-risk ACS patients (not receiving preprocedural GPIIb/IIIa blockade) appears to provide similar protection against death and myocardial infarction as the combination of heparin and GPIIb/IIIa inhibitors, although we observed a higher rate of revascularization at 6 months.

Cost-effectiveness analysis of antithrombotic therapy in nonurgent percutaneous coronary intervention.

STUDY OBJECTIVE: To perform a cost-effectiveness analysis comparing three treatment approaches during nonurgent percutaneous coronary intervention (PCI): bivalirudin with provisional glycoprotein (GP) IIb-IIIa inhibitor therapy, unfractionated heparin (UFH) with eptifibatide, and UFH with abciximab. DESIGN: Literature-based decision model from an institutional perspective. DATA SOURCE: Patient data from the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 study and three other randomized controlled trials that included UFH and routine GP IIb-IIIa inhibitor (eptifibatide or abciximab) therapy. All included studies were comparable based on patient population, procedural techniques, and general treatment approaches. MEASUREMENTS AND MAIN RESULTS: We included patient populations undergoing contemporary nonurgent PCI to identify probabilities of success or complications (myocardial infarction, urgent revascularization, thrombocytopenia, and major or minor bleeding at 30 days). Costs were assigned to each outcome by incorporating diagnosis-related group-- and/or Current Procedural Terminology--associated costs, institutional drug acquisition costs, and unit replacement costs of platelets and red blood cells. In the base-case analysis, the use of bivalirudin with provisional GP IIb-IIIa inhibitor therapy dominated the UFH and planned GP IIb-IIIa inhibitor approach: UFH with eptifibatide was 74 US dollars more expensive and 1.2% less effective, and UFH with abciximab was 777 US dollars more expensive and 2.3% less effective. Sensitivity analyses indicated that the model results were robust, but also revealed that bivalirudin lost its cost-effectiveness, resulting in UFH with eptifibatide becoming more cost-effective, when two or more vials of bivalirudin were necessary in greater than 27% of cases or when the use of provisional GP IIb-IIIa inhibitor therapy exceeded 20%. CONCLUSION: This analysis indicates that bivalirudin with provisional GP IIb-IIIa inhibitor therapy is the most cost-effective antithrombotic treatment strategy in nonurgent PCI when its use and dosing are consistent with the REPLACE-2 trial.

Economic implications of bivalirudin in the cardiac catheterization laboratory.

More than 1.2 million percutaneous coronary intervention (PCI) procedures are performed each year in the United States, with average hospital costs of more than $10,000 per procedure. Despite ongoing improvements in device technology and adjunct pharmacology, both ischemic complications (eg, periprocedural myocardial infarction) and bleeding complications remain relatively common and are associated with both increased costs (in the short term) and mortality (in the longer term). Recently, the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 clinical trial demonstrated that the use of the direct thrombin inhibitor, bivalirudin, with provisional glycoprotein (GP) IIb/IIIa inhibitor for selected patients in place of a conventional anticoagulation strategy of heparin and routine use of a GP IIb/IIIa inhibitor, resulted in comparable rates of ischemic complications and a significant reduction in the frequency of both major and minor bleeding complications. A prospectively designed economic analysis was performed using data from 4651 US patients who participated in REPLACE-2. In this analysis, patients who were assigned to the bivalirudin and provisional GP IIb/IIIa inhibitor strategy had anticoagulation costs during PCI that were approximately $400 per patient lower than those with heparin plus routine GP IIb/IIIa inhibition. Bivalirudin also produced corresponding decreases in total in-hospital costs and aggregate 30-day medical care costs. These cost savings derived both from the lower acquisition cost of the antithrombotic therapy and the reduced rate of bleeding complications, which accounted for approximately 20% of the cost offsets. These results suggest that for patients similar to those studied in REPLACE-2 (ie, low to moderate risk PCI procedures), use of bivalirudin and provisional GP IIb/IIIa inhibition compared with heparin and routine GP IIb/IIIa inhibition can result in similar rates of ischemic complications, reduced bleeding, and substantial cost savings to both hospitals and the healthcare system. Whether these benefits can be extended to higher risk patient subsets including patients with non-ST elevation or ST elevation myocardial infarction is currently under investigation.