Benefit-risk profile of cytoreductive drugs along with antiplatelet and antithrombotic therapy after transient ischemic attack or ischemic stroke in myeloproliferative neoplasms

Stefano, Valerio De; Carobbio, Alessandra; Lazzaro, Vincenzo Di; Guglielmelli, Paola; Iurlo, Alessandra; Finazzi, Maria Chiara; Rumi, Elisa; Cervantes, Francisco; Elli, Elena Maria; Randi, Maria Luigia; Grießhammer, Martin; Palandri, Francesca; Bonifacio, Massimiliano; Hernández‐Boluda, Juan Carlos; Cacciola, Rossella; Palová, Miroslava; Carli, Giuseppe; Beggiato, Eloise; Ellis, Martin; Musolino, Caterina; Gaïdano, Gianluca; Rapezzi, Davide; Tieghi, Alessia; Lunghi, Francesca; Loscocco, Giuseppe Gaetano; Cattaneo, Daniele; Cortelezzi, Agostino; Betti, Silvia; Rossi, Elena; Finazzi, Guido; Censori, Bruno; Cazzola, Mario; Bellini, Marta; Arellano‐Rodrigo, Eduardo; Bertozzi, Irene; Sadjadian, Parvis; Vianelli, Nicola; Scaffidi, Luigi; Gómez, Montse; Cacciola, Emma; Vannucchi, Alessandro M.; Barbui, Tiziano

doi:10.1038/s41408-018-0048-9

Cited by 30 publications

(58 citation statements)

References 42 publications

(44 reference statements)

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“…In our patient collective, 94% of the patients harbored a JAK2 V617F mutation. These results are in line with published literature, supporting the view that the JAK2 mutation is strongly associated with thromboembolic events [8]. Importantly, 29% of the patients presented with recurrent ICVEs prior to MPN diagnosis, with a range of two to three ICVEs per patient over the studied period.…”

Section: Discussionsupporting

confidence: 91%

“…The comparison of MPN patients with singular versus recurrent ICVEs revealed no significant differences between the two groups regarding sex, age, cardiovascular risk factors, type of MPN or JAK2 V617F mutation status. With regard to the latter, it is suggested that the lack of statistically significant differences between patients with singular versus recurrent ICVEs corroborates the argument that JAK2 V617F mutation is overrepresented in MPN-related ICVEs (as only one patient had negative mutation status) [8]. Crucially, our findings demonstrate that the only significant prognostic factor for ICVE recurrence in patients with underlying MPNs is the prompt diagnosis and initiation of MPN treatment after the first ICVE.…”

Section: Discussionsupporting

confidence: 83%

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Recurrent ischaemic cerebrovascular events as presenting manifestations of myeloproliferative neoplasms

Stefanou

Richter

Härtig

et al. 2019

Euro J of Neurology

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Background and purpose Myeloproliferative neoplasms (MPNs) – polycythemia vera, essential thrombocythemia and primary myelofibrosis – are associated with increased risk for ischaemic cerebrovascular events (ICVEs). Due to their low prevalence, MPNs often remain undiagnosed as the cause of ICVEs. Methods Case records at the University of Tübingen between 2014 and 2017 were screened to identify patients with MPN‐related ICVEs. Clinical features, brain imaging, laboratory findings, applied treatments and neurological outcomes were assessed. Results In all, 3318 patients with ICVEs were identified, and amongst them 17 patients with MPN‐related ICVEs were included in a retrospective study. In 58% of these patients, ICVEs were the first manifestation of the underlying MPN; 24% presented with transient ischaemic attack and 76% with ischaemic stroke. Potentially concurrent ICVE etiologies were noted in 70% of the patients. The majority (94%) of patients were positive for the JAK2 V617F mutation, whilst in 29% recurrent ICVEs (range two to three) were noted prior to MPN diagnosis. Early MPN diagnosis and management was the only significant prognostic factor for ICVE recurrence (P < 0.001). Discussion Evidence is provided that, although rare, MPNs represent an underdiagnosed cause of recurrent ICVEs. High clinical awareness is warranted to identify an underlying MPN in patients presenting with sustained, abnormal blood count findings. Clinical algorithms for prompt MPN diagnosis and initiation of MPN treatment (e.g. cytoreductive therapy, phlebotomy) are required. As MPN management comprises a significant protective factor against ICVE recurrence, induction of MPN treatment should be regarded as an integral component of secondary stroke prevention in MPN‐associated ICVEs.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 83%

Recurrent ischaemic cerebrovascular events as presenting manifestations of myeloproliferative neoplasms

Stefanou

Richter

Härtig

et al. 2019

Euro J of Neurology

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“…The selection included three reports on two RCT 4,17,18 (one comparing HU and IFN therapy, and one comparing HU to ruxolitinib), one RCT in which HU was not a comparator, 19 and 12 observational retrospective cohort studies. 7,[20][21][22][23][24][25][26][27][28][29][30][31][32][33] The great majority of the studies were conducted in Europe and some involved multiple countries; only one study in our selection 32 was conducted in the US.…”

Section: Literature Search and Study Characteristicsmentioning

confidence: 99%

“…In eight studies, we were able to univocally distinguish arterial and thrombotic events in 2,048 patients. 7,19,23,[26][27][28]31,33 Overall, demographics were incomplete or not stratified by HU treatment (6 studies), cardiovascular risk factors were missing (10 studies), and history of thrombosis was not reported (6 studies), antithrombotic drug therapy was not mentioned in ten studies. However, in spite of missing data, in each of these studies we were able to retrieve the number of events for at least one outcome.…”

Section: Number Of Hu-treated Patients Ranged From 25 To 890mentioning

confidence: 99%

Clinical outcomes under hydroxyurea treatment in polycythemia vera: a systematic review and meta-analysis

et al. 2019

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H ydroxyurea is the standard treatment in high-risk patients with polycythemia vera. However, estimates of its effect in terms of clinical outcomes (thrombosis, bleeding, hematologic transformations and mortality) are lacking. We performed a meta-analysis to determine the absolute risk of events in recent cases of patients under hydroxyurea treatment. We searched for relevant articles or abstracts in the following databases: Medline, EMBASE, clinicaltrials.gov, WHO International Clinical Trials Registry, LILACS. Sixteen studies published from 2008 to 2018 reporting number of events using World Health Organization diagnosis for polycythemia vera were selected. Through a random effect logistic model, incidences, study heterogeneity and confounder effects were estimated for each outcome at different follow ups. Overall, 3,236 patients were analyzed. While incidences of thrombosis and acute myeloid leukemia were stable over time, mortality and myelofibrosis varied depending on followup duration. Thrombosis rates were 1.9%, 3.6% and 6.8% persons/year at median ages 60, 70 and 80 years, respectively. Higher incidence of arterial events was predicted by previous cardiovascular complication. Leukemic transformation incidence was 0.4% persons/year. Incidence of transformation to myelofibrosis and mortality were significantly dependent on age and follow-up duration. For myelofibrosis, rates were 5.0 at five years and 33.7% at ten years; overall mortality was 12.6% and 56.2% at five and ten years, respectively. In conclusion, we provide reliable risk estimates for the main outcomes in polycythemia vera patients under hydroxyurea treatment. These findings can help design comparative clinical trials with new cytoreductive drugs and prove the feasibility of using critical end points for efficacy, such as major thrombosis.

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“…Given the high mortality associated with thrombotic events in patients with PV, the first goal of therapy is to reduce the risk of thrombosis, mainly by controlling HCT to < 45% [ 15 ], a target associated with reduced rates of cardiovascular death and major thrombosis [ 13 ]. Therapy for the treatment of PV is dependent on the patient’s thrombotic risk, which is currently based on age and history of thrombosis [ 15 , 30 , 42 ]. Patients < 60 years old with no history of thrombosis are categorized as low risk, whereas those ≥ 60 years old and/or those with a history of thrombosis are considered high risk [ 15 ].…”

Section: Preventing Thromboembolic Events: Treatment Options In Pvmentioning

confidence: 99%

Thromboembolic events in polycythemia vera

Grießhammer

Kiladjian

Besses³

2019

Ann Hematol

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Thromboembolic events and cardiovascular disease are the most prevalent complications in patients with polycythemia vera (PV) compared with other myeloproliferative disorders and are the major cause of morbidity and mortality in this population. Moreover, a vascular complication such as arterial or venous thrombosis often leads to the diagnosis of PV. The highest rates of thrombosis typically occur shortly before or at diagnosis and decrease over time, probably due to the effects of treatment. Important risk factors include age (≥ 60 years old) and a history of thrombosis; elevated hematocrit and leukocytosis are also associated with an increased risk of thrombosis. The goal of therapy is to reduce the risk of thrombosis by controlling hematocrit to < 45%, a target associated with reduced rates of cardiovascular death and major thrombosis. Low-risk patients (< 60 years old with no history of thrombosis) are managed with phlebotomy and low-dose aspirin, whereas high-risk patients (≥ 60 years old and/or with a history of thrombosis) should be treated with cytoreductive agents. Interferon and ruxolitinib are considered second-line therapies for patients who are intolerant of or have an inadequate response to hydroxyurea, which is typically used as first-line therapy. In this review, we discuss factors associated with thrombosis and recent data on current treatments, including anticoagulation, highlighting the need for more controlled studies to determine the most effective cytoreductive therapies for reducing the risk of thrombosis in patients with PV.

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Benefit-risk profile of cytoreductive drugs along with antiplatelet and antithrombotic therapy after transient ischemic attack or ischemic stroke in myeloproliferative neoplasms

Cited by 30 publications

References 42 publications

Recurrent ischaemic cerebrovascular events as presenting manifestations of myeloproliferative neoplasms

Recurrent ischaemic cerebrovascular events as presenting manifestations of myeloproliferative neoplasms

Clinical outcomes under hydroxyurea treatment in polycythemia vera: a systematic review and meta-analysis

Thromboembolic events in polycythemia vera

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