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Adam SS, McDuffie JR, Lachiewicz PF, et al. Comparative Effectiveness of Newer Oral Anticoagulants and Standard Anticoagulant Regimens for Thromboprophylaxis in Patients Undergoing Total Hip or Knee Replacement [Internet]. Washington (DC): Department of Veterans Affairs; 2012 Dec.

Cover of Comparative Effectiveness of Newer Oral Anticoagulants and Standard Anticoagulant Regimens for Thromboprophylaxis in Patients Undergoing Total Hip or Knee Replacement

Comparative Effectiveness of Newer Oral Anticoagulants and Standard Anticoagulant Regimens for Thromboprophylaxis in Patients Undergoing Total Hip or Knee Replacement [Internet].

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EXECUTIVE SUMMARY

BACKGROUND

Venous thromboembolic (VTE) events are important causes of morbidity in elective total hip replacement (THR) and total knee replacement (TKR) procedures. Current guidelines recommend thromboprophylaxis in patients undergoing THR or TKR, although the American Academy of Orthopaedic Surgeons (AAOS) guidelines suggest individual assessment of patients when choosing the specific thromboprophylaxis strategy. Low molecular weight heparin (LMWH) and adjusted-dose warfarin are the most commonly used anticoagulants for thromboprophylaxis in the United States, but a number of other treatment options are available, including unfractionated heparin, aspirin, mechanical devices, and newer oral anticoagulants.

Prior to 1980, rates of symptomatic VTE were 15 to 30 percent. However, improved surgical care and techniques have decreased the rate of symptomatic VTE. A recent analysis that incorporated data from trials and observational studies estimated the contemporary 35-day rate of symptomatic VTE without thromboprophylaxis at 4.3 percent.

Pharmacological thromboprophylaxis for THR or TKR surgery decreases VTE by approximately 50 percent but with the tradeoff of increased bleeding. The risk of bleeding is a concern because bleeding can lead to infections, reoperation, delayed wound healing, and extended hospital stay. The choice of which antithrombotic thus becomes pivotal for balancing the prevention of thromboembolism with the risk of bleeding. Newer oral anticoagulants have been developed with the goal of overcoming the limitations of warfarin and the available parenteral agents. These newer anticoagulants belong to two drug classes, based on their target coagulation protein: factor Xa (FXa) inhibitors and direct thrombin inhibitors (DTIs). These drugs are given as fixed oral doses and have the advantage of a more predictable anticoagulant effect, eliminating the need for monitoring when used for short-term thromboprophylaxis. Disadvantages of newer oral anticoagulants include the lack of specific antidotes to reverse their anticoagulant effect in a timely fashion in case of bleeding, and drug costs.

Given the emerging data on new oral anticoagulants, this report was commissioned by the VA to examine the following key questions (KQs):

KQ 1.

For patients undergoing total hip or total knee replacement, what is the comparative effectiveness of newer oral anticoagulants and standard drug classes (low molecular weight heparin, injectable factor Xa inhibitors, unfractionated heparin, warfarin, aspirin) on the incidence of symptomatic, objectively confirmed venous thromboembolism (VTE), other VTE events, total mortality, and bleeding outcomes?

KQ 2.

For patients undergoing total hip or total knee replacement, what are the effects of combined pharmacological and mechanical modalities versus pharmacological treatment alone on the incidence of symptomatic, objectively confirmed VTE, other VTE events, total mortality, and bleeding outcomes?

KQ 3.

For patients undergoing total hip or total knee replacement, what is the comparative efficacy of individual newer oral anticoagulants on the incidence of symptomatic, objectively confirmed VTE, other VTE events, total mortality, and bleeding outcomes?

METHODS

During the topic development phase of this study, we identified a number of published high-quality systematic reviews that addressed our KQs. We conducted a synthesis of these reviews as they pertained to the KQs and the Veteran population and followed a standard protocol for all steps of this review. We searched MEDLINE® (via PubMed®), Embase®, and the Cochrane Database of Systematic Reviews for systematic review publications comparing the newer oral anticoagulants to other types of anticoagulation (aspirin, warfarin, LMWH, unfractionated heparin, etc.) from January 2009 through September 2012. Our search strategy used the National Library of Medicine’s medical subject headings (MeSH) keyword nomenclature and text words for newer oral anticoagulants, the conditions of interest, and validated search terms for systematic reviews.

Using prespecified inclusion and exclusion criteria, two reviewers assessed titles and abstracts for relevance to the KQs. Full-text systematic reviews identified by either reviewer as potentially relevant were retrieved for further review. Select data from published reports were then abstracted into the final abstraction form by a trained reviewer. All data abstractions were confirmed by a second reviewer. We also abstracted data necessary for assessing the quality of systematic reviews, adapted from the AMSTAR criteria. Based on these criteria, systematic reviews were categorized as good, fair, or poor quality. Poor-quality reviews were excluded.

DATA SYNTHESIS

We categorized each systematic review by the key research questions they addressed and critically analyzed them to compare their characteristics, methods, and findings. We summarized the key findings and conclusions from each included review and produced summary tables for comparison across reviews. We prioritized the evidence from these reviews by the quality of methodological designs, more complete drug comparisons, and detailed information about population, specific drug intervention, and definitions of outcomes. In addition to summary measures of relative effects (e.g., risk ratios), we report absolute risk differences in the summary strength of evidence tables. For these estimates, baseline risk for patients treated with LMWH— the common comparator for newer anticoagulants—was estimated for each major outcome as symptomatic deep vein thrombosis (DVT), 9 per 1000 patients; nonfatal pulmonary embolism (PE), 3 per 1000 patients; mortality, 3 per 1000 patients; and major bleeding, 7 per 1000 patients.

Our synthesis focused on identifying patterns in efficacy and safety of the different drugs. To determine the consistency of results and conclusions, we then compared each additional review that addressed the same key question. If findings or conclusions differed importantly across reviews, we analyzed potential reasons for discrepancies such as the primary literature included, inclusion/exclusion criteria, differences in outcome definition, analytic approach, and conflict of interest. Because total hip and knee replacement have distinct primary endpoints, we examined the groups of studies as they pertained to these diagnoses separately.

RATING THE BODY OF EVIDENCE

In addition to rating the quality of individual studies, we evaluated the overall quality of the evidence for each KQ. In brief, this approach requires assessment of four domains: risk of bias, consistency, directness, and precision. For risk of bias, we considered study design using the quality assessments of the primary literature reported in the systematic reviews. We used results from meta-analyses when evaluating consistency, precision, strength of association, and whether publication bias was detected. Optimal information size and consideration of whether the confidence interval crossed the clinical decision threshold for a therapy were also used when evaluating precision.

PEER REVIEW

A draft version of the report was reviewed by technical experts and clinical leadership. A transcript of their comments can be found in the appendix, which elucidates how each comment was considered in the final report.

RESULTS

Our search for systematic reviews (SRs) identified 182 unique citations from a combined search of MEDLINE via PubMed, Embase, the Cochrane Database of Systematic Reviews, and bibliographies of key articles. After applying inclusion and exclusion criteria at both the title-and-abstract and full-text review levels, the final set of articles used in this evidence report consisted of six recently published, high-quality systematic reviews.

All of the SRs compared newer oral anticoagulants with other drug classes used for thromboprophylaxis in THR or TKR (KQ 1), but specific strategies varied. Two SRs used random-effects meta-analyses to compare drug classes as a whole (e.g., FXa inhibitors versus LMWH) while the other four SRs compared individual drugs, some analyzing THR and TKR studies separately. Two of the six SRs compared one newer oral anticoagulant with another (KQ 3) though all results were based on indirect comparisons; i.e., through common comparison with enoxaparin. Only one SR compared a pharmacological agent plus mechanical modality versus pharmacologic prophylaxis alone (KQ 2).

All reviews assessed the quality of included trials, and overall quality was judged to be good. Publication bias was assessed and did not indicate bias that would favor newer oral anticoagulants. Three of the SRs were unfunded and reported no conflicts of interest. One SR was unfunded but did report a conflict of interest for one author. Two SRs were funded by government agencies.

Key Question 1. For patients undergoing total hip or total knee replacement, what is the comparative effectiveness of newer oral anticoagulants and standard drug classes (low molecular weight heparin, injectable factor Xa inhibitors, unfractionated heparin, warfarin, aspirin) on the incidence of symptomatic, objectively confirmed venous thromboembolism (VTE), other VTE events, total mortality, and bleeding outcomes?

Key Points

  • For all-cause mortality and nonfatal PE, there were no important differences between oral FXa inhibitors and LMWH (high strength of evidence). Using a base rate of 9 events per 1000 patients with LMWH, FXa inhibitors were associated with lower symptomatic DVT (4 fewer events per 1000 patients; 95% CI, 3 to 6). Overall, FXa inhibitors were associated with an increased risk of major bleeding, but major bleeding did not differ importantly at low to moderate doses (moderate strength of evidence). Based on subgroup analyses, there was not a consistent pattern of differences in treatment effects for THR and TKR.
  • There were fewer studies evaluating oral DTIs than oral FXa inhibitors; all trials compared dabigatran with enoxaparin. Although estimates of effect were often imprecise, there were no significant differences between oral DTIs and enoxaparin for any major outcome.
  • Neither oral FXa inhibitors nor DTIs have been compared directly with adjusted-dose warfarin, oral antiplatelet drugs, or unfractionated heparin in existing SRs.

FXa inhibitors. Rivaroxaban and apixaban are the most commonly studied FXa inhibitors, and rivaroxaban is the only FXa inhibitor marketed in the United States. The risk of symptomatic DVT was reduced with FXa inhibitors compared with LMWH, while the risks of nonfatal PE and mortality were not significantly different (all high strength of evidence). The estimated absolute risk difference was 4 fewer symptomatic DVT events for each 1000 patients receiving thromboprophylaxis with FXa inhibitors over 5 weeks compared with LMWH. However, these benefits were offset by an increase in major bleeding (moderate strength of evidence). The absolute risk difference was 2 more major bleeding events per 1000 patients receiving thromboprophylaxis with FXa inhibitors over 5 weeks. Higher doses of FXa inhibitors, but not intermediate or low doses, were associated with increased major bleeding. Subgroup analysis by specific drug and type of surgery showed a reduced risk of bleeding with apixaban compared with LMWH in TKR but not in THR; risk of major bleeding with rivaroxaban did not differ significantly for either surgery. No reviews identified trials comparing oral FXa inhibitors with warfarin, unfractionated heparin, or oral antiplatelet agents.

Direct thrombin inhibitors. Dabigatran is the only FDA-approved oral DTI and the only DTI evaluated in existing SRs. Compared with LMWH, dabigatran was not associated with significant differences for any outcome examined. The strength of evidence was low for most outcomes due to few events and imprecise estimates of effect; also, effects on mortality varied substantially across studies. In addition to the major outcomes, a subgroup analysis in one SR found no significant difference between both treatment groups on bleeding requiring rehospitalization. No reviews identified trials comparing oral DTIs with warfarin, unfractionated heparin, or oral antiplatelet agents. Table 1 summarizes the findings and strength of evidence for the effects of newer oral anticoagulant drug classes compared with enoxaparin in patients undergoing THR or TKR surgery.

Table 1. Summary of the strength of evidence for KQ 1.

Table 1

Summary of the strength of evidence for KQ 1.

Key Question 2. For patients undergoing total hip or total knee replacement, what are the effects of combined pharmacological and mechanical modalities versus pharmacological treatment alone on the incidence of symptomatic, objectively confirmed VTE, other VTE events, total mortality, and bleeding outcomes?

Key Points

  • In the included SRs, no studies were identified that compared the combination of newer oral anticoagulants and mechanical thromboprophylaxis with pharmacological treatment alone.
  • Few studies compared older antithrombotics (LMWH, oral antiplatelet agents, or unfractionated heparin) combined with mechanical prophylaxis to pharmacological or mechanical prophylaxis alone.
  • The strength of evidence is insufficient to determine the comparative effectiveness for combined pharmacological and mechanical prophylaxis compared with pharmacological prophylaxis alone for all major outcomes prioritized for this report.

No reviews identified trials comparing newer oral anticoagulants combined with mechanical prophylaxis to pharmacological prophylaxis alone. Even when considering standard treatments, very little data are available comparing combined-modality thromboprophylaxis and pharmacologic prophylaxis only. One SR found moderate strength of evidence that combined-modality thromboprophylaxis was associated with a decreased risk of overall DVT (including asymptomatic events) compared with pharmacologic prophylaxis alone. The evidence was insufficient for all other outcomes.

Key Question 3. For patients undergoing total hip or total knee replacement, what is the comparative efficacy of individual newer oral anticoagulants on the incidence of symptomatic, objectively confirmed VTE, other VTE events, total mortality, and bleeding outcomes?

Key Points

  • No clinical trials directly compared newer oral anticoagulants with each other for thromboprophylaxis of THR or TKR.
  • The included SRs did not estimate the comparative efficacy of newer oral anticoagulants for symptomatic DVT, nonfatal PE, all-cause mortality, or surgical site bleeding.
  • Based on indirect comparisons, there were few differences between newer oral anticoagulants for the outcomes examined. Rivaroxaban was associated with more major bleeding than apixaban (RR 1.59; 95% CI, 0.84 to 3.02). In contrast, the risk of symptomatic VTE was lower for rivaroxaban than apixaban or dabigatran, but confidence intervals included the possibility of a chance association.

Only indirect comparisons of rivaroxaban, apixaban, and dabigatran were performed through common comparison with LMWH. These comparisons were made for only two of our major outcomes—symptomatic VTE (DVT or PE) and major bleeding. There were no significant differences in treatment effect for symptomatic VTE or major bleeding. Because these indirect comparisons are subject to confounding and the treatment effects were imprecise, we considered the strength of evidence low. Other outcomes reported included clinically relevant bleeding and net clinical endpoints. Rivaroxaban was found to be associated with an increased risk of clinically relevant bleeding, but there was no significant difference in net clinical endpoints (symptomatic VTE, major bleeding, and death). Table 2 summarizes the findings and strength of evidence for between-drug comparisons of newer oral anticoagulants in patients undergoing THR or TKR.

Table 2. Summary of the strength of evidence for KQ 3.

Table 2

Summary of the strength of evidence for KQ 3.

RECOMMENDATIONS FOR FUTURE RESEARCH

We used a structured framework to identify gaps in evidence and classify why these gaps exist (Table 3).

Table 3. Evidence gaps and future research.

Table 3

Evidence gaps and future research.

CONCLUSION

For THR or TKR, the 35-day rate of symptomatic VTE without thromboprophylaxis is estimated to be 4.3 percent. Pharmacological thromboprophylaxis decreases VTE by approximately 50 percent but with the tradeoff of increased bleeding. Newer oral anticoagulants have a more convenient route of administration compared with LMWH, and unlike adjusted dose warfarin, they do not require regular laboratory monitoring. Compared with LMWH, FXa inhibitors are associated with a reduced risk of symptomatic DVT, but mortality and nonfatal PE are not significantly different, and the risk of major bleeding episodes is increased.

There are no available studies on head-to-head comparisons of these novel anticoagulants. Longer clinical experience and direct drug-drug comparisons are needed to better assess the risk-to-benefit ratio of newer oral anticoagulants for surgical thromboprophylaxis. Based on current evidence, newer anticoagulants—particularly FXa inhibitors—are a reasonable option for thromboprophylaxis in patients undergoing total hip replacement or total knee replacement.

ABBREVIATIONS TABLE

CI

confidence interval

DTI

direct thrombin inhibitor

DVT

deep vein thrombosis

FDA

U.S. Food and Drug Administration

FXa

factor Xa inhibitor

INR

international normalized ratio

KQ

key question

LMWH

low molecular weight heparin

MeSH

medical subject heading

NA

not applicable

NR

not reported

OR

odds ratio

PE

pulmonary embolism

RCT

randomized controlled trial

RD

risk difference

RR

risk ratio

SOE

strength of evidence

THR

total hip replacement

TKR

total knee replacement

VA

Department of Veterans Affairs

VHA

Veterans Health Administration

VKA

vitamin K antagonist

VTE

venous thromboembolism

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