How do the factor Xa inhibitors stack up against warfarin and heparin for thromboprophylaxis?
Now that baby boomers have reached the age of Medicare eligibility, joint replacements are on the rise. Because patients who undergo hip or knee arthroplasty require anticoagulation, primary care physicians have a key role in the care of these persons— before as well as after surgery.
Thromboprophylaxis has proved to be effective (lifesaving in some instances) in patients who undergo knee and hip arthroplasties. In fact, anticoagulation in this specific setting is one of the highest-rated patient safety interventions.1 Consensus guidelines recommend prophylaxis to prevent thrombosis and embolization for a period of between 10 and 35 days after surgery.2 In addition, there is evidence that anticoagulation of longer duration is superior to shorter treatment schedules.3
Why then are only 60% of patients who undergo lower extremity joint replacements offered anticoagulation? 4 It seems that the variable cost, potential complications of treatment (bleeding), control over the intensity of anticoagulation, and the route of administration make health care providers justifiably suspicious and even skeptical. Some recent “Top Papers” may clarify some aspects of therapy but will muddy others.1,4-7
NEW OPTIONS FOR ANTICOAGULATION
Currently, approved therapy for anticoagulation in the setting of arthroplasty consists of a choice between warfarin and heparin, usually low molecular weight, which lends itself to ambulatory use. A new category of anticoagulants, oral factor Xa inhibitors, is undergoing clinical trials in the same setting. In fact, the authors of one editorial boldly suggested that clinicians may be one step closer to a replacement for warfarin.5
Factor Xa inhibitors target then inhibit activated Stuart factor (factor Xa) and have a number of impressive attributes. They are given orally once a day and they have a high bioavailability when taken by mouth, a rapid onset of action, and a short half-life. Another advantage is that because of predictable pharmacological effects, this class of agents does not require monitoring (eg, with the international normalized ratio [INR] or activated partial thromboplastin time).
In the studies and editorials referenced here, rivaroxaban (a factor Xa inhibitor) was superior to enoxaparin for anticoagulation after hip or knee arthroplasty. Outcome measures included prevention of deep venous thrombosis, nonfatal pulmonary embolism, and all-cause mortality. There was no difference in bleeding frequency between the 2 treatment arms.
So what will the balance sheet look like if this class of medications is approved? In the realm of efficacy, factor Xa inhibitors may become number one. Based on safety, heparin and factor Xa inhibitors probably best warfarin, especially in elderly patients. For ease of administration, warfarin and factor Xa inhibitors are taken orally, but heparin is injected. Monitoring and predictability of dose response are better with heparin and factor Xa agents because warfarin is associated with variable responses and requires careful monitoring. Moreover, a prolonged INR from warfarin is difficult to reverse.
THE COST FACTOR
None of the “Top Papers” discussed the comparative costs of the 3 drug classes. Warfarin is inexpensive. Enoxaparin (for all its clinical uses, not just anticoagulation for arthroplasty), however, carries a $2-billion-a-year price tag. As for the factor Xa inhibitors, this new class of drugs is expected to generate $7.8 billion in sales by 2016!8
Although factor Xa inhibitors are safe, effective, and easier to administer and monitor than currently available anticoagulants, they will be prohibitively expensive. The question is whether arthroplasty patients and Medicare can afford to pay the price.
1. Kakkar AK, Brenner B, Dahl OE, et al; RECORD2 Investigators. Extended
duration rivaroxaban versus short-term enoxaparin for the prevention of venous
thromboembolism after total hip arthroplasty: a double-blind, randomised controlled
trial. Lancet. 2008;372:31-39.
2. National Institute for Health and Clinical Excellence. Venous thromboembolism:
reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary
embolism) in inpatients undergoing surgery. NICE clinical guidelines.
April 2007. www.nice.org.uk/nicemedia/pdf/VTEfullguide.pdf. Accessed
September 16, 2008.
3. Hull RD, Pineo GF, Stein PD, et al. Extended out-of-hospital low-molecularweight
heparin prophylaxis against deep venous thrombosis in patients after
elective hip arthroplasty: a systematic review. Ann Intern Med. 2001;135:858-869.
4. Lohrmann J, Becker RC. New anticoagulants—the path from discovery to
clinical practice. N Engl J Med. 2008;358:2827-2829.
5. Eikelboom JW, Weitz JI. Selective factor Xa inhibition for thromboprophylaxis.
6. Eriksson BI, Borris LC, Friedman RJ, et al; RECORD1 Study Group. Rivaroxaban
versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J
7. Lassen MR, Ageno W, Borris LC, et al; RECORD3 Investigators. Rivaroxaban
versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J
8. Factor Xa inhibitors. TradingMarkets.com. http://www.tradingmarkets.com/.site/news/stock%20news/1069371. Accessed July 11, 2008.