Comparison of cost-effectiveness of anticoagulation with dabigatran, rivaroxaban and apixaban in patients with non-valvular atrial fibrillation across countries.

We did a cost-utility analysis for the new oral anticoagulants (NOACs) in the German population based on the quality-adjusted life years (QALY), total costs, and incremental cost-effectiveness ratios (ICER). The aim of our investigation was to examine cost-utility for current German drug market costs and compared to other countries. Outcome data were taken from dabigatran's RE-LY, rivaroxaban's ROCKET AF, and apixaban's ARISTOTLE trials. A Markov decision model, the Monte Carlo simulation (MCS), and further sensitivity analyses were used to simulate comparisons between NOACs over a follow up period of 20 years. The main perspective used for the analyses is from a German public health care insurance perspective. The base-case analyses of a 65 years old person with a CHADS2 score >1 resulted in 7.56-7.64 QALYs gained for warfarin. NOACs added 0.04-0.19 QALYs. Total costs for warfarin ranged from 7622 to 9069 and for NOACs from 19537 to 20048. The sensitivity analysis indicated that current German market costs for the NOACs exceed a willingness-to-pay threshold of (hypothetical) 50000/QALY in all treatment regimen. The MCS showed willingness-to-pay thresholds from 60500/QALY for apixaban to 278000/QALY for dabigatran 110 mg bid, with values for dabigatran 150 mg bid and rivaroxaban in between. In conclusion, from a German public health care insurance perspective current market costs are high in relation to the quality of life gained. These results from clinical studies (efficacy) remain to be confirmed under real life conditions (effectiveness).

Laparoscopic Heller myotomy versus endoscopic balloon dilatation for the treatment of achalasia: a network meta-analysis.

OBJECTIVE: Comparison of short- and long-term effects after laparoscopic Heller myotomy (LHM) and endoscopic balloon dilation (EBD) considering the need for retreatment. BACKGROUND: Previously published studies have indicated that LHM is the most effective treatment for Achalasia. In contrast to that a recent randomized trial found EBD equivalent to LHM 2 years after initial treatment. METHODS: A search in Medline, PubMed, and Cochrane Central Register of Controlled Trials was conducted for prospective studies on interventional achalasia therapy with predefined exclusion criteria. Data on success rates after the initial and repeated treatment were extracted. An adjusted network meta-analysis and meta-regression analysis was used, combined with a head-to-head comparison, for follow-up at 12, 24, and 60 months. RESULTS: Sixteen studies including results of 590 LHM and EBD patients were identified. Odds ratio (OR) was 2.20 at 12 months (95% confidence interval: 1.18-4.09; P = 0.01); 5.06 at 24 months (2.61-9.80; P < 0.00001) and 29.83 at 60 months (3.96-224.68; P = 0.001). LHM was also significantly superior for all time points when therapy included re-treatments [OR = 4.83 (1.87-12.50), 19.61 (5.34-71.95), and 17.90 (2.17-147.98); P ≤ 0.01 for all comparisons) Complication rates were not significantly different. Meta-regression analysis showed that amount of dilations had a significant impact on treatment effects (P = 0.009). Every dilation (up to 3) improved treatment effect by 11.9% (2.8%-21.8%). CONCLUSIONS: In this network meta-analysis, LHM demonstrated superior short- and long-term efficacy and should be considered first-line treatment of esophageal achalasia.

Interpretation of endpoints in a network meta-analysis of new oral anticoagulants following total hip or total knee replacement surgery.

New oral anticoagulant (NOAC) regimens [dabigatran 150 mg (D150) and 220 mg (D220), rivaroxaban 10 mg (R20), and apixaban 2.5 mg bid (A5)] were effective and safe compared to enoxaparin for the prevention of venous thromboembolism (VTE) following elective total knee (TKR) or hip replacement (THR) surgery. First a cluster analysis was used to identify homogeneous studies for the trial programs of each NOAC. Second, only studies reporting VTE and VTE-related death, major bleeding, and mortality were included. The odds ratio (OR) and 95% confidence interval (CI) were calculated for each NOAC regimen versus the comparator. Third, these data were used for the indirect comparison between NOACs. Cluster analysis identified duration of treatment (10 ± 5 and 34 ± 5 days) as the only homogeneous parameter across all NOAC programs (p>0.05) except for A5 and VTE over 10 ± 5 days (analysis not performed). The results of the calculated OR and 95% CI of the four NOAC regimens over 10 ± 5 and 34 ± 5 days showed inferiority of D150 and D220 compared to R10 for VTE (p<0.01, p<0.001). Comparisons of major bleeding and mortality were not different for all indirect comparisons. Despite the lack of standard definitions for VTE and bleeding outcomes, cluster analysis seems to be an appropriate tool to identify homogeneity across trial programs and to perform an indirect comparison for NOACs for prevention of VTE following TKR and THR surgery.

Determination of rivaroxaban in human plasma samples.

Rivaroxaban is one of the novel oral direct factor Xa inhibitors, which is effective in preventing thromboembolic complications at fixed doses (i.e., once daily), without the need for dose adjustment according to laboratory monitoring. Nearly 60% of rivaroxaban is cleared from circulation by glomerular filtration, 30% of which is excreted as active drug. Therefore, as renal elimination plays a pivotal role in the metabolism of this drug, impairment of renal function may be important during anticoagulation with rivaroxaban over long periods of time. The assessment of the anticoagulant effect/concentration of rivaroxaban may thus be useful in special patient populations such as in the elderly and eldest, during acute diseases with concurrent dehydration, before surgery, during bleeding or thrombotic episodes, or to verify adherence to therapy. Rivaroxaban prolongs prothrombin time in a dose-dependent, linear fashion. Activated partial thromboplastin time (APTT) is also prolonged, but in an exponential manner. Substantial differences in test results might be generated by different thromboplastin and APTT reagents. One-step prothrombin-induced clotting time assay is sensitive to low concentrations of rivaroxaban. Chromogenic substrate assays specific for factor Xa are also sensitive to rivaroxaban. Several initiatives are currently ongoing to standardize the various methods to determine rivaroxaban in human plasma samples, some of which will be summarized in this article along with the dose-dependent effects of rivaroxaban on relevant coagulation parameters. Therefore, although rivaroxaban prolongs all coagulation assays used to assess the anticoagulant effects of most anticoagulants, the most specific assay cannot be identified at present. Moreover, clinical trials are needed to determine the relationship of assay results with bleeding or thrombotic complications.

Determination of dabigatran in human plasma samples.

The oral direct thrombin inhibitor dabigatran effectively prevents arterial and venous thromboembolism using fixed doses without the need for adjustment according to laboratory results. Dabigatran is eliminated from the circulation by ∼80% through the kidneys. However, the in vitro anticoagulant effect of dabigatran may be necessary to determine in special patient populations such as in the elderly, for renal impairment, before operations, bleeding or thrombotic episodes, and to monitor self-compliance. Several clotting and thrombin-specific chromogenic substrate assays are available to analyze the biological activity of dabigatran. All of them are prolonged in the presence of dabigatran. This article reports the effects of dabigatran on clinical routine assays and the potential usefulness for determination in special risk groups of patients when overdose or lack of compliance are suspected.

Determination of the anticoagulant effects of new oral anticoagulants: an unmet need.

Thromboembolic diseases require anticoagulation for their prevention and treatment. New oral anticoagulants, specifically direct factor Xa and thrombin inhibitors, were developed to overcome the limitations of conventional anticoagulants. Their benefit has been demonstrated using fixed doses without laboratory-guided dose adjustment for patients following elective knee and hip replacement, treatment of venous thromboembolism and prevention of embolic events in atrial fibrillation. These anticoagulants are excreted by glomerular filtration at a rate of between 25 and 80%. Thus, lower doses are required for patients with impaired renal function. Therefore, determination of the anticoagulant effects may be needed in other specific patient populations. Prothrombin time, activated partial thromboplastin time, prothrombin-induced clotting time, ecarin clotting time, hemoclot assay, other specific coagulation assays and chromogenic substrate are available to determine the effect of the anticoagulants. Standardization of methods, development of point-of-care tests and identification of patient groups is ongoing.

New anticoagulants - promising and failed developments.

New direct and indirect acting factor Xa (FXa) and thrombin inhibitors are being developed to overcome the downsides of the conventional anticoagulants - unfractionated and low molecular weight heparins and vitamin K antagonists. Ximelagatran and idraparinux failed to demonstrate an acceptable safety profile. Rivaroxaban and dabigatran are approved for the post-operative prevention of thromboembolic complications after elective hip or knee replacement surgery; dabigatran is approved for the prevention of embolism in patients with atrial fibrillation in an increasing number of countries. Several novel indirect antithrombin-dependent anticoagulants as well as antithrombin-independent oral direct FXa and thrombin inhibitors are investigated in multiple indications for the prophylaxis and treatment of venous thromboembolism and the prophylaxis of arterial thrombotic disorders. Quality-adjusted life years costs and incremental cost-effectiveness ratios are relatively high at present, but may decrease after approval of more new anticoagulants for additional indications.

Determination of an international sensitivity index of thromboplastin reagents using a WHO thromboplastin as calibrator for plasma spiked with rivaroxaban.

Rivaroxaban and other direct factor Xa inhibitors are used at fixed doses without drug monitoring and dose adjustment. Patients may require determination of the anticoagulant effect during treatment. The aim of this study was to develop a method to reduce the differences between thromboplastin reagents and coagulation analysers for determination of the anticoagulant effect of rivaroxaban in human plasma. Purity of rivaroxaban extracted from commercially available drug was confirmed by mass spectrometry, elemental analysis and 1H-NMR spectroscopy. Coagulation times of pooled human plasma spiked with 50-900  ng/ml rivaroxaban were analysed. Thromboplastin reagents, WHO RBT/90, Innovin, RecombiPlasTin 2G, STA Neoplastin Plus, Technoclot PT Plus and Thromborel S, the manual Kolle-Hook method and the KC10 analyser were used. An international sensitivity index (ISI) was determined for each reagent and coagulation method using the RBT/90 thromboplastin reagent as reference. The orthogonal, used for the determination of the ISI of coumarin plasmas, and ordinary regression analyses were compared. The results showed than increasing concentrations of rivaroxaban prolonged coagulation values of all thromboplastin assays linearly (r (2)= 0.96 and r(2) = 0.99, respectively). The coefficient of variation between the slopes of the dilution curves and the ratios of the thromboplastin reagents were reduced using the international normalized ratio (INR) and ISI calculated for rivaroxaban. The ISIs of the thromboplastin reagents ranged from 0.73 to 1.67 as compared with the WHO reagent using the manual technique. The coefficient of variations between the thromboplastin reagents comparing the orthogonal and the ordinary regression analysis were 6.8 versus 3.7% (Kolle-Hook method, P = 0.0011) and 8.5 versus 4.8% (KC10 method, P < 0.0001). Using ISI for vitamin-K antagonist and rivaroxaban, the INRs for the rivaroxaban-containing samples were significantly different for one of five commercial thromboplastin reagents. In conclusion, the determination of an ISI for rivaroxaban using a WHO thromboplastin reagent is required for commercial thromboplastin reagents. The manual Kolle-Hook method and an ordinary linear regression analysis should be adopted.

Determination of rivaroxaban by different factor Xa specific chromogenic substrate assays: reduction of interassay variability.

Rivaroxaban and other oral direct factor Xa inhibitors (ODiXa) are currently developed for prophylaxis and treatment of thromboembolic diseases using fixed doses. Although routine monitoring is not required, assessing the intensity of anticoagulation may be useful under certain clinical conditions. ODiXa prolong coagulation times of several clotting assays and, thus, their concentration may be determined in factor Xa specific chromogenic substrate assays. So far, no standardized and validated assay is commercially available. Here, five methods (A through E) are studied and optimized to reduce interassay variability. Human pooled plasma was spiked by a serial dilution of rivaroxaban (25-900 ng/ml). The release of para-nitroaniline from the chromogenic substrates was measured by the optical density (OD) at 405 nm. Method B was identified to yield the lowest sum of deviations from the mean value of the OD concentration curve calculated from all assays. Spline functions were developed for OD versus concentration curves for all methods. The calculated OD versus concentration curves overlapped for all methods. The coefficient of variation for all assays and concentrations of rivaroxaban decreased from 25.3 ± 11.4% using the original data to 3.8 ± 2.2% using the calculated data (P < 0.0001). The robustness of the chromogenic assay (method B) remains to be corroborated in interlaboratory comparisons.