Correspondence
Hydroxyurea in Essential Thrombocytosis
N Engl J Med 1995; 333:802-803September 21, 1995
- Article
To the Editor:
Although the study of Cortelazzo and colleagues (April 27 issue)1 was not designed to assess the role of antiplatelet drugs in preventing vascular thrombotic complications of essential thrombocythemia, the authors note that the relative risk of thrombosis was not significantly reduced by treatment with these drugs. Because 70 percent of the hydroxyurea group and 69 percent of the control group received antiplatelet drugs (aspirin and ticlopidine), the lack of reduction in risk with these drugs merely reflects adequate randomization rather than the lack of a favorable effect of antiplatelet drugs on the incidence of thrombosis. In several studies2-4 we have shown that recurrences of thrombosis in the acral,2 coronary,3 and cerebral4 arterial microcirculations may be prevented by either treatment with low-dose aspirin or cytoreduction. In the case of cytoreduction, it seems desirable to reduce the increased platelet count to the normal range (i.e., to less than 350,000 cells per cubic millimeter), because microvascular thrombotic complications may arise with even slightly increased platelet counts (more than 400,000 per cubic millimeter).1-4
In a recent follow-up study of 68 patients in whom thrombocythemia was diagnosed between January 1974 and December 1993, we observed 42 thrombotic events in 419 person-years of follow-up (mean follow-up, 6.2 years) (unpublished data). The incidence of thrombotic complications was high in patients who received no treatment but was remarkably reduced in patients who received low-dose aspirin, cytoreductive treatment, or both (Table 1Table 1
Incidence of Thrombotic Complications in 68 Patients with Essential Thrombocythemia Who Had Long-Term Follow-up, According to Treatment Strategy.). These data suggest that in addition to cytoreductive treatment, treatment with low-dose aspirin alone is effective in preventing thrombosis in patients with essential thrombocythemia. Prospective studies comparing the antithrombotic efficacy of cytoreductive treatment with that of treatment intended to prevent platelet aggregation are indicated, particularly since evidence is accumulating5 that hydroxyurea may induce secondary leukemia.5 ReferencesPerry J.J. van Genderen, M.D.
Jan J. Michiels, M.D., Ph.D.
University Hospital Dijkzigt, 3015 GD Rotterdam, the Netherlands1
Cortelazzo S ,Finazzi G ,Ruggeri M , et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995;332:1132-1136
Full Text | Web of Science | Medline2
Michiels JJ ,Abels J ,Steketee J ,van Vliet HH ,Vuzevski VD . Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia. Ann Intern Med 1985;102:466-471
Web of Science | Medline3
Scheffer MG ,Michiels JJ ,Simoons ML ,Roelandt JR . Thrombocythemia and coronary artery disease. Am Heart J 1991;122:573-576
CrossRef | Web of Science | Medline4
Michiels JJ ,Koudstaal PJ ,Mulder AH ,van Vliet HH . Transient neurologic and ocular manifestations in primary thrombocythemia. Neurology 1993;43:1107-1110
Web of Science | Medline5
Weinfeld A ,Swolin B ,Westin J . Acute leukaemia after hydroxyurea therapy in polycythaemia vera and allied disorders: prospective study of efficacy and leukaemogenicity with therapeutic implications. Eur J Haematol 1994;52:134-139
CrossRef | Web of Science | Medline
To the Editor:
The conclusion that hydroxyurea is effective as prophylaxis against thrombosis in patients with essential thrombocythemia1 was reached by lumping together patients with superficial thrombophlebitis, deep venous thrombosis, peripheral arterial occlusion, transient ischemic attacks, stroke, and myocardial infarction into a single category. Most patients would probably prefer several events such as superficial thrombophlebitis to a single myocardial infarction or stroke. The statistical analysis should reflect this fact. If one uses scores of 0 to represent no manifestations, 1 for superficial thrombophlebitis, 2 for deep venous thrombosis, peripheral arterial occlusion, or transient ischemic attacks, and 5 for stroke or myocardial infarction, 0.0959 is the two-sided P value obtained by the permutation test2 using exact methods.3 Other scoring systems would yield other P values, but assigning equal scores to all manifestations (as is done by using the chi-square test) is no less arbitrary. During the trial, nine patients died of cardiac failure. They were not included in the analysis, so the authors must have had evidence that their deaths were not related to thrombosis or to the treatment. This evidence should be presented, or the patients should be included.
The patients studied were thought to be at high risk of a thrombotic recurrence because of previous thrombotic episodes. However, in the multivariate analysis presented in Table 3 of the article, previous thrombosis was not found to be a significant independent prognostic factor. This makes it more difficult to select patients for a treatment that the authors find potentially dangerous, even if there were no doubts about the treatment effect.
3 ReferencesTroels Ring, M.D.
Aalborg Hospital, 9100 Aalborg, Denmark1
Cortelazzo S ,Finazzi G ,Ruggeri M , et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995;332:1132-1136
Full Text | Web of Science | Medline2
Siegel S, Castellan NJ Jr. Nonparametric statistics for the behavioral sciences. 2nd ed. New York: McGraw-Hill, 1988:151-5.
3
StatXact. Cambridge, Mass.: Cytel Software Corporation, 1992.
To the Editor:
Cortelazzo et al. are to be commended for their prospective, randomized trial of hydroxyurea in patients with essential thrombocythemia and a high risk of thrombosis. I find it interesting, however, that the great majority of thrombotic episodes in the control group (71 percent) were digital microvascular ischemia and transient ischemic attacks. There was no increased risk of stroke or myocardial infarction in that group. Since transient ischemic attacks and digital ischemia did not appear to result in considerable morbidity, it seems reasonable to continue to observe asymptomatic patients until these more usual therapy-initiating symptoms develop. This would seem to result in an equivalent risk of serious thrombotic events, sparing the expense, the inconvenience, and the as yet unknown long-term consequences of hydroxyurea therapy.
Robert H. Feiner, M.D.
Kaiser Permanente Medical Group, Santa Clara, CA 95051Author/Editor Response
The authors reply:
To the Editor: We agree with Drs. van Genderen and Michiels that antiplatelet drugs may have a role in the prevention of thrombosis in patients with essential thrombocythemia. However, we demonstrated that hydroxyurea adds a further protective effect in patients at high risk for thrombosis. Thus, we do not feel confident about enrolling patients in a study comparing treatment with antiplatelet drugs alone and treatment with hydroxyurea. Such a study could be done in lower-risk patients, in whom cytoreductive therapy has not yet provided any evidence of a clinical benefit.
Dr. Ring and Dr. Feiner raise questions about the clinical end points we chose to evaluate, and they dispute our decision to put thrombotic complications of differing clinical severities into a single category. Transient ischemic attacks and digital microvascular ischemia were the most common thrombotic episodes in our study; it is well known that these events can easily progress toward complete stroke, frank gangrene, and necrosis of the digits. Also, deep-vein thrombosis and thrombophlebitis in such high-risk patients cannot be regarded as minor clinical complications when overall quality of life is considered, especially in the case of elderly patients.
As for the other points raised by Dr. Ring, congestive heart failure can develop in elderly patients for several reasons. The patients in our study who died of heart failure had a median age of 78 years, and none of them had clear evidence of thrombosis. It is not surprising that previous thrombosis was not an independent risk factor for subsequent vascular occlusion. In this study,1 unlike our previous retrospective analysis,2 previous thrombosis was one of the criteria for inclusion and was evenly distributed by randomization between the two groups of patients.
2 ReferencesSergio Cortelazzo, M.D.
Guido Finazzi, M.D.
Tiziano Barbui, M.D.
Ospedali Riuniti di Bergamo, 24100 Bergamo, Italy1
Cortelazzo S ,Finazzi G ,Ruggeri M , et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995;332:1132-1136
Full Text | Web of Science | Medline2
Cortelazzo S ,Viero P ,Finazzi G ,D'Emilio A ,Rodeghiero F ,Barbui T . Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia. J Clin Oncol 1990;8:556-562
Web of Science | Medline
- Citing Articles (6)
Citing Articles
1
Petro E Petrides. (2004) Anagrelide: a decade of clinical experience with its use for the treatment of primary thrombocythaemia. Expert Opinion on Pharmacotherapy 5:8, 1781-1798
CrossRef2
Ming Fang, Samina Agha, Leslie Lockridge, Ronald Lee, Joseph P. Cleary, Eric M. Mazur. (2001) Medical Management of a Large Aortic Thrombus in a Young Woman With Essential Thrombocythemia. Mayo Clinic Proceedings 76:4, 427-431
CrossRef3
M Fang, S Agha, L Lockridge, R Lee, J P Cleary, E M Mazur. (2001) Medical management of a large aortic thrombus in a young woman with essential thrombocythemia.. Mayo Clinic Proceedings 76:4, 427-431
CrossRef4
Yigal Dror, Alvin Zipursky, Victor S. Blanchette. (1999) Essential Thrombocythemia in Children. Journal of Pediatric Hematology/Oncology 21:5, 356-363
CrossRef5
Herwig Lackner, Christian Urban, Christine Beham-Schmid, Martin Benesch, Reinhold Kerbl, Wolfgang Schwinger. (1998) Treatment of Children With Anagrelide for Thrombocythemia. Journal of Pediatric Hematology/Oncology 20:5, 469-473
CrossRef6
S. J. B. Willoughby, T. C. Pearson, S. Fairhead, B. E. Woodcock. (1997) Postpartum thrombosis in primary thrombocythaemia. European Journal of Haematology 59:2, 121-123
CrossRef
