Thrombotic Events in Polycythemia
Vera: Clinical Significance and
Therapeutic Interventions

By Zoe L. Larned, M.D., and
Thomas L. Ortel, M.D., Ph.D.

Much regarding the molecular mechanisms, etiology, and pathogenesis of polycythemia vera (PV) remains largely unknown. This makes the approach to therapy a difficult one. However, because of the serious complications related to this disease including thrombotic events, hemorrhage, and transformation into myelofibrosis or acute leukemias, it remains an area of continued study. The results of data from the European Collaboration on Low-dose Aspirin in Polycythemia vera (ECLAP) and other studies presented at ASH this year help to provide greater understandings of both the natural history of and treatments for PV.

In Sunday’s Plenary Session, Dr. Raffaele Landolfi and colleagues reviewed the efficacy and safety data of low dose aspirin (100 mg po qd) in PV They identified 518 low-risk PV patients from the patients enrolled in ECLAP who did not require antithrombotic therapy or have contraindications to aspirin and randomized them to receive aspirin versus placebo. The following primary endpoints were evaluated: fatal and non-fatal major arterial events (vascular death, non-fatal myocardial infarction, non-fatal stroke), and fatal and non-fatal arterial (all of the above plus pulmonary embolus) and venous thrombotic events. At a follow-up of three years, the aspirin arm was found to have a significantly lower risk of: cardiovascular disease, non-fatal myocardial infarction, non-fatal stroke, and all major venous and arterial thrombotic events. Bleeding complications, with the exception of epistaxis, were not significantly increased. They were able to conclude that for the low-risk subset of PV patients, where aspirin was not contraindicated, the benefits of aspirin use exceeded the risks when evaluating for safety and prevention of certain well-established thrombotic complications of PV.

The question as to the actual risk of arterial and venous thrombotic events (as well as other complications) in the PV population was addressed in other trials utilizing the ECLAP data and also reported at ASH. Dr. Roberto Marchioli and colleagues (Sunday, December 7) reported on the clinical course for the entire cohort of patients (1638) identified for the ECLAP study. Their trial evaluated for the following clinical endpoints: overall survival, cumulative rate of cardiovascular death and thrombosis (arterial and venous), and the cumulative rate of leukemia, myelodysplasia, and myelofibrosis. They found that while PV patients have a high mortality rate, the highest component of this rate actually results from death from non-cardiovascular causes (primarily malignant transformation). Patient age (>65) and, interestingly, history of thrombosis were found to be the two most important prognostic factors for both non-cardiac and cardiac causes of death.

This data was further supported by a case-controlled study by Dr. Vanessa Caruso and colleagues where patients from the ECLAP study were matched with patients from the GISSI-Prevenzione Study, a study that evaluated patients with recent myocardial infarction. The groups were compared for mortality, causes of death, and incidence of non-fatal myocardial infarction and stroke. The PV patients were reported to have similar overall mortality rates but increased rates of hematologic transformation and cancer, higher risk of cerebrovascular events, but lower risk of cardiac events.

Data on other agents for the treatment of PV have been reported at ASH. This includes two studies with anagrelide reported by Dr. Steven M. Fruchtman and colleagues (Simultaneous Session, Sunday, 4:15 p.m. and Poster Session, today, 5:30 p.m.) Their data revealed that treatment with anagrelide resulted in an effective reduction of platelet counts in a variety of myeloproliferative disorders, including PV. (abstract 3413). Another trial (abstract 102) correlated the decrease in platelet count to a statistically significant reduction in a number of hemorrhagic and thrombotic symptoms associated with thrombocythemia for patients on anagrelide.

An overview of the clinical evidence regarding treatment strategies for PV were reviewed by Dr. Tiziano Barbui in the Chronic Myeloproliferative Disorders Education Program (Saturday, December 6). During this session, the data from the ECLAP study was extensively reviewed by Dr. Gianni Tognoni.