Short and Long-Term Risk of Major Cardiovascular Events after Ischemic Stroke or Transient Ischemic Attack in Myeloproliferative Neoplasms

BACKGROUND. Very few previous studies have estimated the risk of recurrence after cerebral transient ischemic attack (TIA) or ischemic stroke (IS) in patients with myeloproliferative neoplasms (MPN). PRISM (Preventing Ischemic Stroke in Myeloproliferative Neoplasms) is an international investigator-driven study with three purposes: (1) to describe the clinical profile at presentation of ischemic TIA/IS in contemporary patients with polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF); (2) to evaluate the short and long-term outcomes beyond the acute phase and to explore their comparability with non MPN population; (3) to refine the risk assessment for recurrences and cardiovascular mortality.

METHODS. From January 2005 through December 2015, 597 patients with objectively proven TIA (n= 270) or IS (n=327) at 22 sites of 5 countries were enrolled. We estimated the 1- and 5-year risk of composite cardiovascular (CV) outcome, including recurrent TIA, IS, myocardial infarction (AMI) and CV deaths, and analyzed the incidence of each single outcome by competing risk method.

RESULTS. The distribution of single MPN and baseline blood counts were similar in IS and TIA groups; atrial fibrillation was observed in a minority of cases (4% TIA and 7% IS) as compared with the general population (11-18% and 20%-30%, respectively); other comorbidities were approximately half of those of non-MPN patients [ Weimar C et al, Arch Neurol 2002;59:1584; Buchwald F et al, Stroke 2016;47:2456; Amarenco P et al, N Engl J Med 2016;374:1533 ]; a substantial proportion of TIA cases had a higher history of microvascular disturbances while arterial hypertension was more frequent in IS than TIA. Secondary prophylaxis included aspirin, oral anticoagulants and cytoreductive therapy.

After one year since the TIA index event, the incidence of cumulative outcome was 4.21%. However, no IS happened in the first 2 years after TIA and this event after 5 years happened in only 1.24% of cases. The corresponding incidence in the general population was 4.4% to 5.1% after one year and 12-16% after 5 years [ Weimar C et al, Arch Neurol 2002;59:1584; Buchwald F et al, Stroke 2016;47:2456; Amarenco P et al, N Engl J Med 2016;374:1533 ]. In contrast, new TIA episodes progressively increased year by year reaching 12% incidence after 5 years.

After the IS index event, new strokes occurred with cumulative incidence lower than in the general population: after 1 and 5 years, the incidence was 2.03% and 6.52% vs 11.1%-12% and 26.4% of non-MPN patients [ Mohan KM et al, Stroke 2011;42:1489; Bergstrom L et al, Stroke 2017 Jul 13, AOP ]. The rate of deep venous thrombosis (DVT) in the first year, was higher after index IS than TIA, but was the same by 5 years (3.68% and 4.60%, respectively; p=0.47).

Predictors of recurrent TIA and IS were the same index events (HR=2.41 and 4.41), and for recurrent TIA the remote history of cerebrovascular TIA episodes (HR=3.40) and microvascular disturbances (HR=2.30). Other prognostic factors of recurrent IS were arterial hypertension (HR=4.24) and occurrence of IS during the course of MPN (HR=4.27). On the contrary, cytoreductive therapy emerged as a strong protective factor able to reduce the probability of new strokes in 76% of patients (HR=0.24). The history of peripheral thrombosis, both venous and arterial events, independently predicted the occurrence of AMI (HR=6.30), while age over 60 years (HR=3.98), index IS (HR=3.61), occurrence after MPN diagnosis (HR=2.62), were all prognostically significant for CV mortality. During median follow-up of 4.2 years, major bleeding occurred with a frequency similar to that observed in the general population receiving long-term antiplatelet secondary prophylaxis (0.90 % pts/year) [ Li L et al, Lancet 2017 Jun 13, AOP ].

CONCLUSION. Current antithrombotic therapy and cytoreductive drugs after index TIA and IS led to a reduction of cardio-vascular recurrences and mortality in a proportion of MPN patients greater than in general population. This would indicate that ischemic cerebral vascular events recognize a specific pathogenesis of thrombosis linked to the clonal disorder. Although the benefit-risk profile of secondary prophylaxis appears favorable, some high risk categories need new intervention strategies to be defined in prospective studies.