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Mortality as Primary End Point in Studies of Heparin Thromboprophylaxis

      To the Editor:
      I read with interest Lederle and colleagues’
      • Lederle F.A.
      • Sacks J.M.
      • Fiore L.
      • et al.
      The Prophylaxis of Medical Patients for Thromboembolism Pilot Study.
      article on prophylaxis of thromboembolism. The authors raise some interesting points regarding the lack of hard evidence supporting pharmacoprophylaxis of venous thromboembolism (VTE) with heparin in medical patients. However, I disagree with the authors’ suggestion that total mortality remains the best measure for evaluating the effectiveness of heparin prophylaxis.
      Although death from fatal pulmonary embolism remains the most dramatic manifestation of VTE, I suggest that the morbidity from nonfatal pulmonary embolism and deep vein thrombosis (which includes the serious and chronic medical conditions of pulmonary hypertension and postphlebitic syndrome) is of much greater import when evaluating the effectiveness of pharmacoprophylaxis.
      In an article published in 2000, Goldhaber et al
      • Goldhaber S.Z.
      • Dunn K.
      • MacDougall R.C.
      New onset of venous thromboembolism among hospitalized patients at Brigham and Women’s Hospital is caused more often by prophylaxis failure than by withholding treatment.
      looked at consecutive cases of VTE at their institution and found 14 deaths attributed to VTE. Twelve of 14 of those patients who died of VTE were critically ill, had cancer, or had spinal cord injuries. If we accept Goldhaber and colleagues’ data (which is consistent with my own experience) as an accurate reflection of those patients who die of VTE in the hospital, by advocating total mortality as the best measure for evaluating the effectiveness of heparin prophylaxis, Lederle et al
      • Lederle F.A.
      • Sacks J.M.
      • Fiore L.
      • et al.
      The Prophylaxis of Medical Patients for Thromboembolism Pilot Study.
      are selecting a unique patient population (ie, the very sick) to evaluate. Mortality as a primary end point makes studying a less sick population difficult (as the authors discovered). It also results in placing a high value on preventing a fatal pulmonary embolism in a patient with a terminal illness or serious comorbidities and discounts the prevention of a nonfatal VTE event (with its potential lifelong and serious complications of pulmonary hypertension and postphlebitic syndrome) in a person with an extended and high-quality life expectancy.
      Although Lederle et al
      • Lederle F.A.
      • Sacks J.M.
      • Fiore L.
      • et al.
      The Prophylaxis of Medical Patients for Thromboembolism Pilot Study.
      correctly point out that none of the properly randomized trials that they reference in their article demonstrated a mortality benefit with heparin prophylaxis, it is important to point out that only 1 was designed or powered to do so. Further, in this 1 study with more than 11,000 patients, Gardlund
      • Gardlund B.
      The Heparin Prophylaxis Study Group
      Randomized, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases.
      noted a 40% reduction in nonfatal thromboembolic events (P=.0012). Although Gardlund notes methodologic concerns and regards these secondary end point data as “inconclusive,” I do not think Lederle et al should fully discount them. As a pragmatic matter, given the robust relative risk reduction and “P value” combined with the relative safety and low expense of low-dose unfractionated heparin, it is hard to ignore this potential benefit.
      In contrast with the authors, I believe that current guidelines
      • Geerts W.H.
      • Pineo G.F.
      • Heit J.A.
      • et al.
      Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.
      recommending heparin prophylaxis in selected medical patients are an appropriate reflection of the available scientific data, cost, safety, and efficacy.

      References

        • Lederle F.A.
        • Sacks J.M.
        • Fiore L.
        • et al.
        The Prophylaxis of Medical Patients for Thromboembolism Pilot Study.
        Am J Med. 2006; 119: 54-59
        • Goldhaber S.Z.
        • Dunn K.
        • MacDougall R.C.
        New onset of venous thromboembolism among hospitalized patients at Brigham and Women’s Hospital is caused more often by prophylaxis failure than by withholding treatment.
        Chest. 2000; 118: 1680-1684
        • Gardlund B.
        • The Heparin Prophylaxis Study Group
        Randomized, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases.
        Lancet. 1996; 347: 1357-1361
        • Geerts W.H.
        • Pineo G.F.
        • Heit J.A.
        • et al.
        Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.
        Chest. 2004; 126: 338S-400S

      Linked Article

      • The Reply
        The American Journal of MedicineVol. 120Issue 5
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          We agree with Locke that morbidity resulting from non-fatal venous thromboembolism, such as pulmonary hypertension and post-thrombotic syndrome, is an important clinical outcome. However, less than 4% of survivors of pulmonary embolism develop pulmonary hypertension within 2 years,1 and the clinical manifestations that define post-thrombotic syndrome occur only half again as often in patients who have had asymptomatic deep venous thrombosis as in controls.2 As a result, detecting a difference in these outcomes in a clinical trial of prophylaxis has not been attempted and would require a much larger study than even the 25,000 patient mortality trial we were piloting.
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