Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 50th Annual Meeting and Exhibition of the American Society of Hematology

San Francisco, California / December 6-9, 2008

The RECORD (Regulation of Coagulation in Major Orthopaedic Surgery Reducing the Risk of DVT and PE) clinical trials programme comprised four multicentre randomized, double-blind studies of similar design involving a total of 12,729 patients. RECORD 1 and 2 compared the Factor Xa inhibitor rivaroxaban with the low molecular-weight heparin (LMWH) enoxaparin at the dose of 40 mg o.d., administered for different durations after hip replacement. RECORD 3 and 4 compared the novel agent against different doses of enoxaparin after knee replacement (40 mg o.d. and 30 mg b.i.d). The trials had the same efficacy and safety outcomes, and the same independent blinded committee adjudicated all outcomes in all four trials.

“The number of [certain] events was expected to be low in the individual studies,” indicated Dr. Alexander Turpie, McMaster University, Hamilton, Ontario. “Pooling of the data increases the statistical precision and allows for a better assessment of [further] clinically relevant end points.”

The primary outcome of the pooled analysis was the composite of symptomatic venous thromboembolism (VTE) (deep vein thrombosis [DVT] plus nonfatal pulmonary embolism [PE]) and all-cause mortality. Secondary outcomes were all-cause mortality, the composite of PE and all-cause mortality, and of all major clinical outcomes (death, myocardial infarction, stroke, symptomatic VTE, major bleeding) (abstract 36).

The primary safety outcome was treatment-emergent major bleeding. Also, major bleeding including surgical-site bleeding, major and clinically relevant non-major bleeding, and any bleeding were assessed. Other secondary safety end points consisted of other adverse events, including cardiovascular (CV) events.

Across the four clinical trials, the primary outcome occurred in 1.3% of LMWH-treated patients compared with 0.6% of rivaroxaban patients, representing a 58% reduction in the hazard ratio (HR) (P<0.001). Analysis of the individual components of the composite end point demonstrated consistent advantages favouring the Factor Xa inhibitor: DVT, 19 vs. 49, HR 0.39,P<0.001; PE, 10 vs. 19, HR 0.52, P=0.098; and all-cause mortality, 8 vs. 16, HR 0.50, P=0.108.

Analysis of safety outcomes showed incidence of bleeding was similar between the two groups. The only significant difference was in the composite of major and clinically relevant non-major bleeding, which occurred more often with rivaroxaban (P=0.039). In a separate analysis of bleeding up to postsurgical day 12 (when bleeding risk is greatest), none of the bleeding outcomes differed significantly between patients treated with either agent.

CV events occurred in 39 patients treated with enoxaparin and 30 treated with rivaroxaban, a nonsignificant difference. Regarding liver safety, a similar proportion of patients treated with either anticoagulant had elevated liver enzymes on day 0 and on day 1.

“The RECORD programme demonstrated that in patients undergoing major orthopedic surgery, rivaroxaban 10 mg o.d. significantly improved the composite outcome of symptomatic VTE, CV events, all-cause mortality, and major bleeding compared with enoxaparin regimens,” noted Dr. Turpie.

Anticoagulant Options

The RECORD programme demonstrated the efficacy and safety of rivaroxaban compared with enoxaparin. However, the new agent’s performance relative to other available anticoagulants has not been examined in clinical comparisons.

According to Alex Diamantopoulos, IMS Health, London, UK, indirect comparisons offer a means to evaluate therapies in the absence of clinical trial data and he used such a strategy to compare rivaroxaban with warfarin, fondaparinux and dabigatran (abstract 1292).

By means of a literature review, Diamantopoulos and colleagues identified randomized clinical studies comparing enoxaparin with warfarin, fondaparinux, or dabigatran for VTE prophylaxis in patients undergoing total knee replacement. Data from the two RECORD trials pertaining to knee replacement reflected the performance of rivaroxaban vs. enoxaparin.

Investigators then compared each anticoagulant’s relative efficacy vs. enoxaparin. An analysis involving enoxaparin 30 mg b.i.d. showed that rivaroxaban reduced the risk of total VTE by 56% vs. warfarin (P<0.001) and by 29% vs. dabigatran (P<0.05). When the enoxaparin comparator dose was 40 mg o.d., rivaroxaban reduced total VTE by 67% vs. warfarin (P<0.001) and by 47% vs. dabigatran (P<0.001). Similar differences were observed for total DVT. Rivaroxaban and fondaparinux demonstrated similar efficacy vs. enoxaparin. The comparisons revealed no increased risk of bleeding with rivaroxaban vs. the other anticoagulants.

Cost-Effectiveness

Dr. Phil Wells, University of Ottawa, Ontario, examined the cost-effectiveness of rivaroxaban vs. enoxaparin from the RECORD 1 and 2 trials involving patients undergoing total hip replacement (abstract 1291).

RECORD 1 compared rivaroxaban 10 mg o.d. vs. subcutaneous enoxaparin 40 mg o.d. for 35 days post-operatively. RECORD 2 compared the same dose of enoxaparin administered for 10 to 14 days, followed by placebo to day 35 with rivaroxaban given for 35 days. Dr. Wells and colleagues developed an economic model to assess the cost-effectiveness of rivaroxaban in Canada vs. both durations of enoxaparin prophylaxis. When both anticoagulants were given for 35 days, rivaroxaban was associated with improved clinical outcomes, an incremental gain of 0.0006 quality-adjusted life-years (QALYs), and an estimated savings of $264.93 per patient. The savings were driven by improved efficacy, reduced long-term complications, and lower outpatient administration costs. Sensitivity analysis showed that rivaroxaban remained more effective and less expensive than enoxaparin in 98% of the simulations.

In the analysis of the shorter duration of enoxaparin therapy, rivaroxaban prophylaxis resulted in an incremental cost of $90.34 and a QALY gain of 0.0027 per patient. The increased cost of 35 days of rivaroxaban was partially offset by reduced costs associated with VTE events and long-term complications. The resulting incremental cost per QALY gained was $33,323. Sensitivity analysis showed that rivaroxaban is cost-effective at a threshold of $50,000/QALY in more than 70% of the simulations vs. enoxaparin.

“Our analysis showed that rivaroxaban is superior to the LMWH and because of that, even with the slight increase in cost and increased duration of use—35 days vs. 14 days—it’s still cost-effective, saves lives, and the QALYs are within accepted parameters for cost,” remarked Dr. Wells. “The analysis is totally robust. We did all sensitivity analyses, and everything came out pretty much the same way. When you compare the Factor Xa inhibitor and [the] LMWH [enoxaparin], both given for 35 days, then rivaroxaban is wholly cost-effective.”

Adherence to VTE Prophylaxis Guidelines

Dr. Wells also presented results from an examination of the clinical impact of adherence to VTE prophylaxis guidelines in patients undergoing total hip or knee replacement (abstract 170). The study focused on adherence to the American College of Chest Physicians (ACCP) guidelines, which recommended pharmacologic prophylaxis with LMWH, fondaparinux, or vitamin K antagonists, for at least 10 days and for up to 35 days (Chest 2008;133(6 suppl):381S-453S).

Investigators compared expected outcomes from adherence to the ACCP guidelines with nonadherence, including no prophylaxis and prophylaxis started later than recommended or continued for <10 days (in the absence of a major bleed, VTE event, or death).

Dr. Wells and colleagues used medical histories of 3497 patients from a hospital database. The two primary outcomes were percentage of patients who received prophylaxis in alignment with ACCP recommendations, and frequency of DVT, PE, major and minor bleeding episodes.

The analysis showed that 40% of patients received VTE prophylaxis in accordance with the ACCP guidelines. Adherence was similar for patients undergoing hip or knee replacement. Lack of alignment with the guidelines almost doubled the risk of DVT (3.76% vs. 2.01%, P=0.003) and increased the risk of PE eightfold (1.19% vs. 0.14%, P=0.001) in comparison to patients treated in accordance with the guidelines. The risk of major or minor bleeding did not differ significantly between patients treated in accordance with the guidelines vs. those who were not.

According to logistic regression analysis, adherence to the ACCP guidelines was the only significant predictor of VTE as it reduced the risk of DVT by almost half (OR 0.54, P=0.006) and the risk of PE by almost 90% (OR 0.12, P=0.004).

Dr. Wells told the audience, “Underutilization of VTE prophylactic medications is associated with worse clinical outcomes. Complete alignment with the ACCP recommendations would significantly reduce the rates of DVT and PE. The reasons for underutilization are unknown and require further study.”