Low-Dose Aspirin in Polycythemia Vera
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《新英格兰医药杂志》
To the Editor: The European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) trial, as reported by Landolfi et al. (Jan. 8 issue),1 does not entirely clarify the role of aspirin in the treatment of polycythemia vera. There were more smokers in the placebo group than in the aspirin group. The treatment of polycythemia vera has clearly been suboptimal in most patients. In the study by Landolfi et al., the hematocrit was higher than 48 percent in 25 percent of the patients, and 25 percent had platelet counts that were higher than 460,000 per cubic millimeter.
Carol Alliot, M.D.
General Hospital of Annemasse
74100 Annemasse, France
References
Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004;350:114-124.
To the Editor: Landolfi and colleagues show that low-dose aspirin can safely prevent thrombotic complications in patients with polycythemia vera. As in polycythemia vera, thrombotic and bleeding events are frequent in essential thrombocythemia, and aspirin use is controversial.1 The Registry of Hematological Malignancies of C?te d'Or (France)2 recorded 142 cases of essential thrombocythemia between 1980 and 1997, and 134 cases were studied retrospectively. During a mean (±SD) follow-up period of 64.5±49.0 months, thrombotic events occurred in 39 of the 134 patients in spite of cytoreductive treatment (in 118 of 134). Antithrombotic therapy (aspirin in 81 percent of patients) with cytoreductive therapy during follow-up significantly decreased the rate of thrombotic events, as compared with cytoreductive therapy alone (from 58.3 percent to 11 percent, P<0.001). Bleeding complications occurred in only 30 of the 134 patients (major bleeding in 12). Moreover 72.5 percent of the patients with bleeding had presented with risk factors for bleeding. Surprisingly, no relationship was found between bleeding and antithrombotic treatment (mainly aspirin) or a platelet count greater than 1 million per cubic millimeter. Our results in a well-defined population of patients with essential thrombocythemia are in accordance with those of Landolfi and colleagues in a population of patients with polycythemia vera and support the use of aspirin for the treatment of these myeloproliferative diseases.
Fabienne Dutrillaux, M.D.
Marc Maynadié, M.D., Ph.D.
Paule-Marie Carli, M.D.
Registre des Hémopathies Malignes de C?te d'Or
21079 Dijon, France
pmcarli@u-bourgogne.fr
References
Barbui T. What is the standard treatment in essential thrombocythemia. Int J Hematol 2002;76:Suppl 2:311-317.
Carli PM, Milan C, Lange A, Devilliers E, Guy H, Faivre J. Haematopoietic malignancies in C?te d'Or (France): a population based study. Br J Cancer 1986;53:811-815.
To the Editor: In his Perspective article on the report by Landolfi et al., Spivak1 provides an excellent review of the mechanism (or mechanisms) of thrombosis in polycythemia vera. His conclusion misses the point, however.
Landolfi et al. report a reduction in both arterial thrombosis and overall thrombosis in patients receiving low-dose aspirin. The benefits of aspirin were most striking in patients with a shorter duration of illness (5 years), those with lower platelet counts (<334,000 per cubic millimeter), those with higher hematocrit values (48 percent), and those who had not received cytoreductive therapy. These features are generally characteristic of patients with recently diagnosed polycythemia vera.
The reduction in cardiovascular events with the use of low-dose aspirin (relative risk, 0.41) reported by Landolfi et al. is actually greater than the benefit of aspirin in the Physicians' Health Study2 (relative risk, 0.56). The results of this trial are important and should lead to the early incorporation of low-dose aspirin in the management of polycythemia vera.
Alex E. Denes, M.D.
Washington University
St. Louis, MO 63110
adenes@im.wustl.edu
References
Spivak J. Daily aspirin -- only half the answer. N Engl J Med 2004;350:99-101.
Steering Committee of the Physicians' Health Study Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med 1989;321:129-135.
The authors reply: Dr. Alliot expresses concern about the increased prevalence of smoking in the placebo group in the ECLAP study. Though randomization provides comparability of populations, some imbalance in base-line characteristics is likely in trials of the size of ECLAP. Because of the slightly different prevalence of several factors in the two study groups, we performed a multivariate analysis adjusted for major risk factors. This analysis showed, in comparison with unadjusted data, a higher rather than lower antithrombotic efficacy of aspirin.1
Dr. Alliot also suggests that the criteria used for selecting and treating the study subjects may argue against a wide applicability of the ECLAP results. The issue of the efficacy of aspirin in "well treated" subjects with polycythemia was raised in Dr. Spivak's Perspective article, which, however, proposed an opposite view regarding the amount of chemotherapy used in our patients.
Both Alliot and Spivak argue that control of the hematocrit during the ECLAP study was inadequate. Without addressing the controversial issue of the optimal treatment of patients with polycythemia, we would like to emphasize that patients with a confirmed diagnosis of polycythemia vera were recruited by an international network of highly qualified centers, which used their best standard of treatment. The median hematocrit value of 46 percent maintained during follow-up reflects real-life care of patients with polycythemia vera. As for the possible interaction of the hematocrit, platelet count, or chemotherapeutic treatment, or some combination of these factors, with the antithrombotic effect of aspirin, these speculations are not supported by the results of the subgroup analysis shown in Figure 3 of our article.1 More generally, because of the safety of low-dose aspirin in patients with polycythemia vera, it is difficult to predict the subgroups in which the benefits of aspirin would be offset by harm.
Further studies of aspirin in patients with polycythemia vera are hard to imagine and may be more appropriately performed in those with essential thrombocythemia. Dutrillaux et al. rightly draw attention to the possibility that aspirin may also be effective and safe in patients with thrombocythemia, especially because patients with thrombocythemia and those with polycythemia have largely similar thrombotic manifestations, and both groups of patients have increased thromboxane biosynthesis that is suppressible by aspirin.2,3 The safety of aspirin use in patients with thrombocythemia is still uncertain, however, and needs to be appropriately tested.
Raffaele Landolfi, M.D.
Università Cattolica
00195 Rome, Italy
rlandolfi@rm.unicatt.it
Roberto Marchioli, M.D.
Consorzio Mario Negri Sud
66030 Santa Maria Imbaro, Italy
Tiziano Barbui, M.D.
Ospedali Riuniti di Bergamo
24100 Bergamo, Italy
References
Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004;350:114-124.
Landolfi R, Ciabattoni G, Patrignani P, et al. Increased thromboxane biosynthesis in patients with polycythemia vera: evidence for aspirin-suppressible platelet activation in vivo. Blood 1992;80:1965-1971.
Rocca B, Ciabattoni G, Tartaglione R, et al. Increased thromboxane biosynthesis in essential thrombocythemia. Thromb Haemost 1995;74:1225-1230.
Dr. Spivak replies: Denes is correct: I am confused. Although physiology is no longer a staple of medical education, it does not follow that the laws governing blood rheology have been repealed. Therefore, I do not understand why Denes and many other physicians fail to appreciate that elevation of the red-cell mass, not the platelet number, is responsible for major vessel thrombosis in polycythemia vera.1 Certainly, in the study by Landolfi et al., normalization of the platelet count did not prevent thrombosis, nor did inhibition of platelet function, if the red-cell mass was not reduced.2
Contrary to Denes's contention, Landolfi et al. proved only that low-dose aspirin was safe in patients with polycythemia vera who were heavily pretreated with chemotherapy in order to normalize both platelet and leukocyte counts, and that it reduced the risk of thrombosis most when the red-cell mass was elevated. It has not been proved that aspirin is effective or even necessary in patients with polycythemia vera when the red-cell mass has been normalized by phlebotomy, or that it is safe in patients with polycythemia vera who have elevated platelet counts. The Physicians' Health Study is not germane here.
Jerry L. Spivak, M.D.
Johns Hopkins University School of Medicine
Baltimore, MD 21205
jlspivak@jhmi.edu
References
Pearson TC, Weatherly-Mein G. Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia. Lancet 1978;2:1219-1222.
Tartaglia AP, Goldberg JD, Berk PD, Wasserman LR. Adverse effects of antiaggregating platelet therapy in the treatment of polycythemia vera. Semin Hematol 1986;23:172-176.
Carol Alliot, M.D.
General Hospital of Annemasse
74100 Annemasse, France
References
Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004;350:114-124.
To the Editor: Landolfi and colleagues show that low-dose aspirin can safely prevent thrombotic complications in patients with polycythemia vera. As in polycythemia vera, thrombotic and bleeding events are frequent in essential thrombocythemia, and aspirin use is controversial.1 The Registry of Hematological Malignancies of C?te d'Or (France)2 recorded 142 cases of essential thrombocythemia between 1980 and 1997, and 134 cases were studied retrospectively. During a mean (±SD) follow-up period of 64.5±49.0 months, thrombotic events occurred in 39 of the 134 patients in spite of cytoreductive treatment (in 118 of 134). Antithrombotic therapy (aspirin in 81 percent of patients) with cytoreductive therapy during follow-up significantly decreased the rate of thrombotic events, as compared with cytoreductive therapy alone (from 58.3 percent to 11 percent, P<0.001). Bleeding complications occurred in only 30 of the 134 patients (major bleeding in 12). Moreover 72.5 percent of the patients with bleeding had presented with risk factors for bleeding. Surprisingly, no relationship was found between bleeding and antithrombotic treatment (mainly aspirin) or a platelet count greater than 1 million per cubic millimeter. Our results in a well-defined population of patients with essential thrombocythemia are in accordance with those of Landolfi and colleagues in a population of patients with polycythemia vera and support the use of aspirin for the treatment of these myeloproliferative diseases.
Fabienne Dutrillaux, M.D.
Marc Maynadié, M.D., Ph.D.
Paule-Marie Carli, M.D.
Registre des Hémopathies Malignes de C?te d'Or
21079 Dijon, France
pmcarli@u-bourgogne.fr
References
Barbui T. What is the standard treatment in essential thrombocythemia. Int J Hematol 2002;76:Suppl 2:311-317.
Carli PM, Milan C, Lange A, Devilliers E, Guy H, Faivre J. Haematopoietic malignancies in C?te d'Or (France): a population based study. Br J Cancer 1986;53:811-815.
To the Editor: In his Perspective article on the report by Landolfi et al., Spivak1 provides an excellent review of the mechanism (or mechanisms) of thrombosis in polycythemia vera. His conclusion misses the point, however.
Landolfi et al. report a reduction in both arterial thrombosis and overall thrombosis in patients receiving low-dose aspirin. The benefits of aspirin were most striking in patients with a shorter duration of illness (5 years), those with lower platelet counts (<334,000 per cubic millimeter), those with higher hematocrit values (48 percent), and those who had not received cytoreductive therapy. These features are generally characteristic of patients with recently diagnosed polycythemia vera.
The reduction in cardiovascular events with the use of low-dose aspirin (relative risk, 0.41) reported by Landolfi et al. is actually greater than the benefit of aspirin in the Physicians' Health Study2 (relative risk, 0.56). The results of this trial are important and should lead to the early incorporation of low-dose aspirin in the management of polycythemia vera.
Alex E. Denes, M.D.
Washington University
St. Louis, MO 63110
adenes@im.wustl.edu
References
Spivak J. Daily aspirin -- only half the answer. N Engl J Med 2004;350:99-101.
Steering Committee of the Physicians' Health Study Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med 1989;321:129-135.
The authors reply: Dr. Alliot expresses concern about the increased prevalence of smoking in the placebo group in the ECLAP study. Though randomization provides comparability of populations, some imbalance in base-line characteristics is likely in trials of the size of ECLAP. Because of the slightly different prevalence of several factors in the two study groups, we performed a multivariate analysis adjusted for major risk factors. This analysis showed, in comparison with unadjusted data, a higher rather than lower antithrombotic efficacy of aspirin.1
Dr. Alliot also suggests that the criteria used for selecting and treating the study subjects may argue against a wide applicability of the ECLAP results. The issue of the efficacy of aspirin in "well treated" subjects with polycythemia was raised in Dr. Spivak's Perspective article, which, however, proposed an opposite view regarding the amount of chemotherapy used in our patients.
Both Alliot and Spivak argue that control of the hematocrit during the ECLAP study was inadequate. Without addressing the controversial issue of the optimal treatment of patients with polycythemia, we would like to emphasize that patients with a confirmed diagnosis of polycythemia vera were recruited by an international network of highly qualified centers, which used their best standard of treatment. The median hematocrit value of 46 percent maintained during follow-up reflects real-life care of patients with polycythemia vera. As for the possible interaction of the hematocrit, platelet count, or chemotherapeutic treatment, or some combination of these factors, with the antithrombotic effect of aspirin, these speculations are not supported by the results of the subgroup analysis shown in Figure 3 of our article.1 More generally, because of the safety of low-dose aspirin in patients with polycythemia vera, it is difficult to predict the subgroups in which the benefits of aspirin would be offset by harm.
Further studies of aspirin in patients with polycythemia vera are hard to imagine and may be more appropriately performed in those with essential thrombocythemia. Dutrillaux et al. rightly draw attention to the possibility that aspirin may also be effective and safe in patients with thrombocythemia, especially because patients with thrombocythemia and those with polycythemia have largely similar thrombotic manifestations, and both groups of patients have increased thromboxane biosynthesis that is suppressible by aspirin.2,3 The safety of aspirin use in patients with thrombocythemia is still uncertain, however, and needs to be appropriately tested.
Raffaele Landolfi, M.D.
Università Cattolica
00195 Rome, Italy
rlandolfi@rm.unicatt.it
Roberto Marchioli, M.D.
Consorzio Mario Negri Sud
66030 Santa Maria Imbaro, Italy
Tiziano Barbui, M.D.
Ospedali Riuniti di Bergamo
24100 Bergamo, Italy
References
Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004;350:114-124.
Landolfi R, Ciabattoni G, Patrignani P, et al. Increased thromboxane biosynthesis in patients with polycythemia vera: evidence for aspirin-suppressible platelet activation in vivo. Blood 1992;80:1965-1971.
Rocca B, Ciabattoni G, Tartaglione R, et al. Increased thromboxane biosynthesis in essential thrombocythemia. Thromb Haemost 1995;74:1225-1230.
Dr. Spivak replies: Denes is correct: I am confused. Although physiology is no longer a staple of medical education, it does not follow that the laws governing blood rheology have been repealed. Therefore, I do not understand why Denes and many other physicians fail to appreciate that elevation of the red-cell mass, not the platelet number, is responsible for major vessel thrombosis in polycythemia vera.1 Certainly, in the study by Landolfi et al., normalization of the platelet count did not prevent thrombosis, nor did inhibition of platelet function, if the red-cell mass was not reduced.2
Contrary to Denes's contention, Landolfi et al. proved only that low-dose aspirin was safe in patients with polycythemia vera who were heavily pretreated with chemotherapy in order to normalize both platelet and leukocyte counts, and that it reduced the risk of thrombosis most when the red-cell mass was elevated. It has not been proved that aspirin is effective or even necessary in patients with polycythemia vera when the red-cell mass has been normalized by phlebotomy, or that it is safe in patients with polycythemia vera who have elevated platelet counts. The Physicians' Health Study is not germane here.
Jerry L. Spivak, M.D.
Johns Hopkins University School of Medicine
Baltimore, MD 21205
jlspivak@jhmi.edu
References
Pearson TC, Weatherly-Mein G. Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia. Lancet 1978;2:1219-1222.
Tartaglia AP, Goldberg JD, Berk PD, Wasserman LR. Adverse effects of antiaggregating platelet therapy in the treatment of polycythemia vera. Semin Hematol 1986;23:172-176.