Renin Angiotensin Inhibitors Reduce Thrombotic Adverse Effects in Chronic Myeloproliferative Neoplasms

Patients with essential thrombocythemia and polycythemia vera (PV) who also had arterial hypertension experienced a higher cumulative incidence of thrombotic adverse effects (AEs) compared with those without hypertension and fewer thrombotic complications following treatment with renin‑angiotensin system (RAS) inhibitors, according to findings from a retrospective study published in Annals of Hematology.

In the overall cohort of patients with myeloproliferative neoplasms (MPNs; n = 404), treatment with RAS inhibitors conferred a protective effect from thrombotic AEs (HR, 0.46; 95% CI, 0.21-0.98; P = .04), including those with a thrombotic high-risk score (n = 272; HR, 0.49; 95% CI, 0.24-1.01; P = .04). Moreover, patients with essential thrombocythemia and a thrombotic high-risk score experienced an especially defined benefit following treatment with RAS inhibitors (HR, 0.27; 95% CI, 0.07-1.01; P = .03).

“The main goal of managing MPNs is to prevent thrombotic incidents,” study authors wrote. “The results indicated that patients [with MPNs] had a significantly higher risk [4.9-fold] of arterial thrombosis than the healthy controls. We found a protective association between the use of RAS inhibitors and the reduction in thrombotic AEs in our cohort of patients [with MPNs].”

To conduct their study, investigators collected data from patients diagnosed with PV or essential thrombocythemia by WHO 2016 classification who were treated at the Hematology Unit of the Businco Hospital in Cagliari, Italy, from November 2000 through August 2021. Patients with PV were stratified by low risk of developing thrombosis (age < 60 years and no history of thrombosis) and high risk of developing thrombosis (age ≥ 60 years or a history of thrombosis). Patients with essential thrombocythemia were stratified by International Prognostic Score for Essential Thrombocythemia score, cardiovascular risk factors, age over 60 years, thrombosis history, and the presence of a JAK2 V617F mutation. Study authors also collected clinical data at the time of diagnosis, including constitutional symptom, performance status, hemoglobin, white blood cell counts, and the presence of somatic driver gene mutations among other data.

Patients had PV (n = 133) or essential thrombocythemia (n = 271). The median age at diagnosis was 63 years (range, 17-98) and the median follow-up was 5.5 years (range, 0-24) in the overall population. Most patients had comorbidities at diagnosis (70%) and a high thrombotic risk score (67.3%). Cardiovascular AEs experienced before (66.3%) MPN diagnosis included ischemic heart disease (7.7%), peripheral arterial disease (3.5%), cerebrovascular event (6.9%), atrial fibrillation (6.2%), deep vein thrombosis (4.7%), and other (4.2%); after diagnosis, thrombotic AEs (15.0%) that occurred were ischemic heart disease (3.5%), peripheral arterial disease (2.9%), cerebrovascular event (3.7%), and deep vein thrombosis (4.4%). 

Most patients also had a positive mutational status (89.3%), including mutations in JAK2 V617F (78.5%), calreticulin (8.9%), and MPL (1.5%); 48.2% of patients also had essential thrombocythemia JAK2 V617F positivity. The therapies received for MPNs were low-dose aspirin (72.3%), phlebotomy (30.0%), cytoreduction therapy (62.9%), and IFN-2a (0.2%).

Median values were 10.5 × 103 /μL (range, 1.0-96.1) for leukocytes, 15.0 g/dL (range, 7.0–15.0) for hemoglobin, and 696 × 103/μL (range, 87–2320) for platelets. Median hematocrit was 48% (range, 29.0%-77.0%).

Investigators noted that “there was a significant difference in the JAK2 V617F mutation status within the group of patients [with essential thrombocythemia] with hypertension (27% vs 21.2%, P = .01).”

Most patients in the study had hypertension (53.7%) and in this subgroup, patients had PV (n = 78/217) and essential thrombocythemia (n = 139/217). Those with positive mutational status (n = 197/217) had JAK2 V617F (n = 182/217), calreticulin (n = 12/217), MPL (n = 3/217), and essential thrombocythemia– positive JAK2 V617F (n = 109/217) mutations. Median values were 10.9 × 103/μL (range, 1.09-19.2) for leukocytes, 15.2 g/dL (range, 10.4-21.0) for hemoglobin, and 720 × 103/μL (139–1170) for platelets. Median hematocrit was 47.6% (range, 33.1%-69.0%).

The majority of patients with hypertension had cardiovascular AEs before being diagnosed with an MPN (n = 216/217) including ischemic heart disease (n = 20/217), peripheral arterial disease (n = 7/217), cerebrovascular event (n = 19/217), atrial fibrillation (n = 15/217), deep vein thrombosis (n = 11/217), and other (n = 9/217); after diagnosis, 39 patients experienced thrombotic AEs; these included ischemic heart disease (n = 10/217), peripheral arterial disease (n = 6/217), cerebrovascular event (n = 12/217), and deep vein thrombosis (n = 11/217).

Additionally, patients with hypertension underwent prior hypertension therapy with a RAS inhibitor (n = 147/217) including angiotensin receptors blockers (n = 87/217), angiotensin-converting enzyme inhibitors (n = 59/217), and inhibitors without association (n = 116/217). Calcium antagonists were given to 52 patients and other agents including thiazide diuretics, beta-blockers, and doxazosin were given to 101 patients. Patients with hypertension also received treatment with low-dose aspirin (148/217), phlebotomy (70/217), cytoreduction therapy (159/217) and IFN-2a (1/217) as therapy for their MPN.

Additional findings showed that the cumulative incidence of thrombotic AEs over 15 years was significantly higher among patients with hypertension (66.8% ± 10.3%) compared with those without (38.5% ± 8.4%; HR, 1.83; 95% CI, 1.08-3.1). Findings from a multivariate analysis also revealed that hypertension (HR, 1.8; 95% CI, 0.983-3.550; P = .05) and PV diagnosis (HR, 3.5; 95% CI, 1.928-6.451; P < .001) were both associated with an increased risk of developing thrombotic AEs. Considering only patients with MPNs and hypertension, diagnosis of PV displayed a predictive role in developing thrombotic AEs (HR, 4.4; 95% CI, 1.92-10.09; P < .01).

“In conclusion, to improve the treatment of patients with MPNs, it is crucial to pay close attention to their cardiovascular risk factors, as these factors play a significant role in the complications of the disease. A more targeted approach could provide more effective and personalized care for patients with MPNs. Although the study's retrospective nature poses limitations, the robust connections between the RAS system and hematological disorders make it crucial to conduct a more comprehensive analysis of the effects of RAS inhibitors on MPNs,” investigators wrote in summary.

Reference

Mulas O, Mola B, Costa A, et al. Renin-angiotensin inhibitors reduce thrombotic complications in essential thrombocythemia and polycythemia vera patients with arterial hypertension. Ann Hematol. Published online August 21, 2023. doi:10.1007/s00277-023-05417-w