Although multiple VTE prophylaxis regimens are supported by the American College of Chest Physicians (ACCP) and the American Academy of Orthopedic Surgeons (AAOS), our systematic review suggests that not all of them may be cost-effective relative to other regimens. There was no consensus about the cost-effectiveness of LMWH compared with warfarin. By contrast, fondaparinux dominated LMWH in nearly every comparison we found. Extended duration prophylaxis with LMWH after THR appeared to be cost-effective with multiple studies indicating extended duration prophylaxis dominates short duration LMWH or cost no more than an additional $10,000 /VTE avoided. Small numbers, predominance of studies analyzing only a short horizon, lack of established cost-effectiveness thresholds for VTE based effectiveness units, and reliance by study authors on venographic endpoints prohibit robust conclusions about the comparisons analyzed.
Comparisons of our work with previous reviews of the economic literature are limited by differences in type of surgery included and publication dates of the included articles. Sullivan et al.
summarized the prophylaxis literature between 1984 and 2000 and found that most studies presented consistent findings including that LMWH is cost-effective compared with warfarin. Our results do not support this conclusion. Sullivan et al. based their conclusions on many studies that we excluded because they were published prior to 1997 or which included outcomes from patients undergoing hip fracture surgery. We believe temporal trends[55, 56]
in the care of total hip and knee replacement necessitated excluding earlier studies. We also felt that hip fracture surgery identified a distinctive patient population with respect to cost, risk, and benefit issues.
Similar to our findings, Sullivan et al. also found that extended duration LMWH was generally cost-effective compared with short duration therapy.
Ivanovic et al.
summarized the literature about fondaparinux. These authors concluded that fondaparinux was more
cost-effective than LMWH (enoxaparin) 40 mg daily initiated preoperatively
cost-effective than LMWH 30 mg twice daily initiated postoperatively
. Our review did not specifically compare the cost-effectiveness of regimens with LMWH initiated at different times but we found that fondaparinux dominated LMWH in all but one when considering the longer horizon. LMWH dosages in the included studies were evenly distributed between 40 mg daily and 30 mg twice daily. Ivanovic et al. also report not being able to calculate ICERs for two studies whereas we were able to calculate them based on data presented in tables included by the study authors.
Wolowacz et al.
also published a review discussing the evolution of model building over a twenty year time span (1987-2006). In terms of quality, the findings of that review were generally consistent with the abstractions we performed, particularly with respect to the paucity of studies measuring QALYs over a sufficiently long period. Unlike their review, we abstracted cost and effect information and independently calculated incremental cost effectiveness ratios for each comparison discussed. We converted costs to 2009 USD and measured effects in common units (total VTE events avoided for short horizon studies and QALYs for long horizon studies). This facilitated comparisons between the multiple regimens supported by major professional societies.
The most salient finding of our review is that fondaparinux dominates LMWH. These results should, however, be interpreted cautiously. There have been only four randomized controlled trials comparing fondaparinux with enoxaparin[59-62]
and only one
involved patients with TKR surgery. A summary estimate of risk calculated by Turpie et al
suggested that fondaparinux offers a 55% reduction in the odds of venographic VTE but no difference in the incidence of symptomatic VTE at postoperative day 11 when screening venography was performed. The studies of cost-effectiveness evaluating fondaparinux generally extrapolated these short horizon venographic rates to estimate the number of symptomatic VTE events. Recent evidence
suggests that the ratio of asymptomatic venographic DVT rate to symptomatic DVT rate is between 3 and 7 for THR and between 15 and 24 for TKR. These ratios, however, came from trials using enoxaparin only. Although they do not address this point specifically for fondaparinux, the 2008 ACCP guidelines
state that initial efficacy studies using venographic endpoints should be followed with trials that use symptomatic (and objectively confirmed) VTE as endpoints.
There is less conclusive evidence about the duration of prophylaxis although extended prophylaxis with LMWH appears cost-effective compared with short duration therapy in the case of THR surgery. Authors of cost-effectiveness studies included in this review generally summarized efficacy of extended duration prophylaxis with LMWH using one or more of the seven randomized controlled trials[65-71]
which reported on the efficacy of extended duration prophylaxis. At least two of these trials[65, 66]
did not require venography at the time of discharge from the hospital, permitting assessment of symptomatic VTE rates from four to seven weeks after operation. We cannot draw firm conclusions on the question of extended duration versus short duration of therapy with other agents which have not been studied extensively. Our review also suggests that there is insufficient cost-effectiveness evidence to support extended prophylaxis for TKR. The most recent update of the ACCP guidelines “recommends” extended prophylaxis for THR and “suggests” extended prophylaxis for TKR.
Limitations to our work include differences in economic perspective and setting. As our results overwhelmingly suggest that fondaparinux dominates LMWH, we believe our conclusions are sound for this comparison keeping in mind the absence of trial data measuring symptomatic endpoints. The economic perspective did not appear to explain the variations in results found but we did not have sufficient numbers of studies within each major comparison to make firm statements about the influence of individual differences in analytic methods. Although we converted from foreign currencies to USD using purchasing power parity, cost structures between countries may not be comparable as highlighted by Drumond and Tang
We also acknowledge the potential bias exerted by pharmaceutical company sponsorship of multiple studies. This bias could have played a role in the comparisons between LMWH and warfarin and extended duration with short duration therapy. They do not appear to have played a role in the comparisons including fondaparinux. Multiple studies sponsored by the manufacturer of LMWH found fondaparinux to be dominant to LMWH. In general, however, we did not have sufficient numbers within each comparison type to determine if variation in study results was related to pharmaceutical company sponsorship
Another major limitation is that there is no established threshold for declaring a prophylaxis regimen cost-effective when disease based units are used to express effectiveness. The QALY permits comparing the value of interventions across diseases given that the utilities which are used to calculate them are standardized to estimates between 0 and 1 where 1 represents perfect health and 0 represents death.
Another limitation includes absence of cost-effectiveness analyses about certain comparisons such as fondaparinux versus warfarin, fondaparinux versus aspirin, and low intensity warfarin (INR < 2) vs. any of the other regimens. We also acknowledge the possibility of English language and publication bias as with any systematic review.
The demand for cost-effectiveness research is growing at a fervent pace. In early 2009, the U.S. government dedicated $1.1 billion to comparative effectiveness research including cost-effectiveness research.
The U.S. Centers for Disease Control adopted the results of cost-effectiveness research when it prepared guidelines
about screening for HIV infection. Similarly, the United States Preventive Services Task Forces incorporated model results when it updated its most recent colorectal cancer screening recommendations
. As the demand for cost-effectiveness work grows, the need to be able to summarize and standardize the information will grow as well. Our work was a comprehensive, systematic review of the cost-effectiveness literature regarding VTE prophylaxis for patients undergoing total joint replacement. In addition, we improved upon previous reviews by standardizing cost-effectiveness information to a common currency and effectiveness unit.
In summary, we found that fondaparinux dominated LMWH in virtually all studies we analyzed but firm conclusions cannot be made until trial data are available which measure symptomatic VTE rates. Extended duration LMWH prophylaxis also appears cost-effective compared with short duration prophylaxis in the case of THR. There is limited evidence to determine the cost-effectiveness of other regimens including extended duration fondaparinux, extended duration LMWH after TKR, prophylaxis with new oral anticoagulants, low-intensity warfarin therapy, or aspirin. These knowledge gaps represent important areas for future research.