To the Editor,
1.
Myeloproliferative neoplasms (MPNs), especially polycythemia vera (PV) and essential thrombocythemia (ET), are associated with an increased risk of cardiovascular (CV) diseases [1]. Thromboembolic events are a primary cause of morbidity/mortality, and bleeding is the second most common CV complication in MPNs [2, 3, 4].
Atrial fibrillation (AF) is the most common arrhythmia (1%–2% of the general population) and is associated with high arterial thrombotic risk [5]. The prevalence of AF in patients with MPNs is higher than in the general population [6, 7], which might be mediated by the hypercoagulable state, the altered hematologic counts, prothrombotic factors, and pro‐inflammatory microenvironment characteristic of MPNs [8, 9].
AF effects in patients with MPNs have not yet been fully elucidated. The co‐occurrence of these two conditions has been correlated with higher thrombosis and bleeding risks [7, 10, 11, 12]. This study aimed to evaluate the incidence of thrombotic and hemorrhagic events in patients with MPNs and FA and the effects of anticoagulant therapy in a large, representative real‐world cohort of patients with PV or ET from the Spanish Registry of MPNs, a nationwide, observational, ambispective study started in 2015 and led by the Spanish Group of Ph‐negative Myeloproliferative Neoplasms (GEMFIN). The AF diagnosis was based on cardiologic reports following local standard clinical care and required electrocardiographic documentation. The study was approved by the ethics committee of Ramon y Cajal University Hospital (ref: 2020/392) and followed the Declaration of Helsinki, Good Clinical Practices, and applicable local regulations. For details on methodology, please refer to Supporting Information.
In January 2025, 4169 patients were included, 2168 (52%) with PV and 2001 (48%) with ET (Figure S1). The AF rates were 8.2% and 6.7% for PV and ET, respectively. Patients with AF were older and had significantly higher rates of previous CV risk factors, such as hypertension (76% vs. 45.8% for AF and no AF, respectively; p < 0.001), diabetes (17.9% vs. 13.2%; p = 0.02), history of cerebrovascular accident (16.9% vs. 5.1%; p < 0.001), and previous acute myocardial infarction (12.8% vs. 5.7%; p < 0.001) (Table 1).
TABLE 1.
Patient characteristics and comorbidities.
| Baseline characteristics | Full analysis set | Propensity score matched set | ||||
|---|---|---|---|---|---|---|
| Without AF (N = 3856) | With AF (N = 313) | p | Without AF (N = 603) | With AF (N = 302) | SMD | |
| Median age (IQR), years | 64.3 (51.6–74) | 77.1 (71.2–82.3) | < 0.001 | 76.8 (70.5–82.9) | 77.0 (71.1–82.2) | 0.016 |
| Sex; n (%) | ||||||
| Male | 1728 (45.2) | 168 (53.7) | 0.004 | 326 (54.1) | 160 (53.0) | 0.018 |
| MPN type; n (%) | ||||||
| PV | 1990 (51.6) | 178 (56.9) | 0.073 | 352 (58.4) | 177 (58.6) | 0.004 |
| ET | 1866 (48.4) | 135 (43.1) | 251 (41.6) | 125 (41.4) | ||
| Driver mutation; n (%) | ||||||
| JAK2V617F | 3099 (80.4) | 264 (84.3) | 0.082 | 527 (87.4) | 262 (86.8) | 0.016 |
| CALR | 307 (8.0) | 21 (6.7) | 0.407 | |||
| MPL | 59 (1.5) | 4 (1.3) | 0.711 | |||
| Triple negative | 191 (5.2) | 11 (3.7) | 0.239 | |||
| Unknown | 200 (5.2) | 13 (4.2) | 0.820 | |||
| Previous CV disease; n (%) | ||||||
| Arterial hypertension | 1765 (45.8) | 238 (76.0) | < 0.001 | 451 (74.8) | 228 (75.5) | −0.013 |
| Diabetes mellitus | 507 (13.1) | 56 (17.9) | 0.020 | 119 (19.7) | 52 (17.2) | 0.053 |
| Myocardial infarction | 219 (5.7) | 40 (12.8) | < 0.001 | 74 (12.3) | 39 (12.9) | −0.016 |
| Stroke | 197 (5.1) | 53 (16.9) | < 0.001 | 88 (14.6) | 49 (16.2) | −0.037 |
| VTE/PE | 171 (4.4) | 15 (4.8) | 0.768 | 22 (3.6) | 13 (4.3) | −0.028 |
| Bleeding | 220 (5.7) | 37 (11.8) | < 0.001 | 76 (12.6) | 35 (11.6) | 0.025 |
| Need for cytoreductive treatment during follow‐up; n (%) | 3135 (81.3) | 288 (92.0) | < 0.001 | 566 (93.9) | 280 (92.7) | 0.038 |
Abbreviations: AF, atrial fibrillation; CI, confidence interval; CV, cardiovascular; ET, essential thrombocythemia; PV, polycythemia vera; SMD, standardized media difference; VTE, venous thromboembolism.
After a median follow‐up of 5.2 years (IQR: 2.3–9.3), 402 patients (9.6%) reported a first‐ever ischemic event. The annual incidence of thrombotic events in the full dataset is shown in Table S1. To allow for an unbiased analysis of AF effect on thromboembolic rates, a propensity score matching (PSM) analysis was performed. The matched population comprised 302 patients with AF and 603 without AF, achieving balanced baseline characteristics between groups (Table 1). AF was independently associated with a significant increase in thrombotic rates in the PSM cohort (4.18, 95% CI: 3.24–5.39 vs. 2.15, 95% CI: 1.67–2.79 cases per 100 patient‐years for patients with and without AF, respectively; hazard ratio [HR] = 1.93, 95% CI: 1.34–2.77; p < 0.001) (Figure S2 and Table S2). In the PSM cohort, cerebrovascular event rates were 1.49 (95% CI: 0.99–2.24) versus 0.75 (95% CI: 0.49–1.14) cases per 100 patient‐years in patients with and without AF, respectively (HR = 2.04, 95% CI: 1.13–3.68; p = 0.024).
Bleeding rates in the full dataset are shown in Table S3. In the PSM cohort, the bleeding rate was 3.45 (95% CI: 2.63–4.53) versus 1.48 (95% CI: 1.09–2.01) cases per 100 patient‐years for patients with and without AF, respectively (HR = 2.33; 95% CI: 1.55–3.52; p < 0.001) (Table S4). The major bleeding (MBs) rate was also higher in patients with AF than in those without AF (2.72, 95% CI: 2.01–3.68 vs. 0.56, 95% CI: 0.34–0.92 cases per 100 patient‐years; HR = 4.86, 95% CI: 2.73–8.64, p < 0.001) (Figure S3).
Thrombosis risk was higher than that of bleeding throughout the follow‐up period, with an approximate incidence three times higher in patients with AF than in those without AF (Figure 1a).
FIGURE 1.
Thrombotic and bleeding incidences. (A) Evolution of thrombotic and bleeding incidences throughout the follow‐up period. (B) Balance of thrombotic and bleeding incidences across patient subgroups.
Thrombosis‐bleeding incidence ratios were calculated for patient subgroups, and thrombosis risk was higher across all subgroups except for patients with a history of bleeding (8.73 vs. 9.27 per 100 patient‐years for thrombosis and bleeding, respectively; p = 0.999). The net balance for thrombotic and bleeding risks was the highest for younger patients (thrombosis and bleeding rates: 6.91 vs. 2.21 per 100 patient‐years, respectively; p = 0.156) and those with a history of stroke (thrombosis and bleeding rates: 9.25 vs. 4.66 per 100 patient‐years, respectively; p = 0.075) (Figure 1b).
At baseline, 300 patients with AF (95.8%) were receiving anticoagulant treatment. The most common treatments were acenocoumarol (80.1%), direct oral anticoagulants (DOACs) (13.7%), and low‐molecular‐weight heparin (LMWH) (0.9%). During follow‐up, DOACs were prescribed to 27.7% of patients.
No differences in thromboembolic risk were reported between patients treated with VKs and DOACs (HR: 1.95; 95% CI: 0.69–5.46; p = 0.206) when compared using a multivariate model. Stroke/TIA risk was also similar across treatments (HR: 0.99; 95% CI: 0.29–3.45; p = 0.992). Bleeding risk was higher in patients who used VKAs (HR: 3.46; 95% CI: 1.06–11.22; p = 0.039) (Figure 2). The difference in MBs approached statistical significance (HR: 2.97, 95% CI: 0.90–9.73; p = 0.073). All 11 episodes of intracranial hemorrhage occurred in the VKA group. Only 9.5% received combined therapy with anticoagulants and antiplatelet treatment, showing an OR for bleeding of 2.71 (95% CI: 1.2–6.2) compared with patients receiving only anticoagulants (Table S5).
FIGURE 2.
Multivariable‐adjusted (model‐based) cumulative incidence of thrombotic and bleeding events in patients with MPNs and AF according to anticoagulation treatment. (A) Cumulative incidence of thromboembolic events. (B) cumulative incidence of cardiovascular events (CVA) or transient ischemic attacks (TIA). (C) Cumulative incidence of bleeding. (D) cumulative incidence of major bleeding (MB).
During the study period, 584 deaths (14%) occurred (Figure S4). In the PSM cohort, AF was associated with greater death rates (8.24 [95% CI: 6.96–9.76] vs. 4.69 [95% CI: 3.97–5.56] cases per 100 patient‐years; HR = 1.73 [95% CI: 1.36–2.20]; p < 0.001). The HR of CV mortality in patients with AF was 3.12 (95% CI: 1.80–5.4; p < 0.001).
In our cohort, AF was independently associated with higher thromboembolic risk, especially cerebrovascular events and bleeding. Literature reports diverse impacts on thrombotic and hemorrhagic risks. de Freitas et al. found AF had no higher thrombosis risk than controls, adjusting for variables such as age, sex, previous thrombosis, and smoking, with no significant differences in MB risk [12]. Mahe and colleagues showed AF associated with increased thrombosis risk (OR = 2.47 [1.12; 5.45]), independent of traditional risk factors such as age, other CV risk factors, the use of cytoreductive therapies, or the MPN subtype but reported no differences in bleeding or mortality [6]. The most recent study from the French cohort, including 179 patients with AF, showed AF was associated with increased thrombotic, hemorrhagic, and mortality risks [7], aligned with our observations. Study differences may reflect varied patient populations. For instance, our population was more anticoagulated, older, and had higher PV rates than Mahe et al. Differences in study design, such as analyzing CV risk factors separately and oral anticoagulation as a time‐varying factor, may have also influenced conclusions.
Stroke was three times more frequent after AF diagnosis, as previously described [13]. Notably, a significantly high proportion of patients with AF (16.9%) had a history of stroke, suggesting asymptomatic AF could play a prominent role, and prevention through proactive AF screening and anticoagulation therapy could be useful.
Anticoagulation therapy is recommended for AF [14]. DOACs and VKAs show comparable effectiveness in preventing thromboembolism, with DOACs reducing intracranial hemorrhage risk [15, 16]. No trials have compared VKAs and DOACs in MPN. In our cohort, thromboembolic events in AF patients on DOACs were substantially but not significantly lower than with VKAs, while bleeding incidence was significantly lower with DOACs. Similarly, previous studies reported thromboembolic events ranging from 2.15% to 4.9% of patients per year for DOACs and 4.5% to 8.6% for VKA [7, 17, 18, 19]. Altogether, evidence suggests DOACs offer advantages over VKAs in MPNs, supporting current recommendations from cardio‐oncology guidelines [20, 21].
The majority of our patients were anticoagulated (95% vs. 35.4%–63% in previous studies, although most met the criteria for chronic anticoagulation), potentially explaining the lower incidence of thrombotic events. Previous studies began follow‐up before 2010 and the publication of the CHA2DS2‐VASc scale, which could explain the low rate of patients receiving anticoagulation.
Despite high anticoagulant rates, the bleeding rates were below the thrombotic rates throughout the study period. The thrombotic risk was significantly higher than the hemorrhagic risk in the overall population and across subgroups throughout the study period, excluding patients with prior bleeding. The net risk balance observed in our study, comprising a large cohort, is consistent with that of the largest previous study [7], suggesting the use of anticoagulants may be beneficial overall [21].
The study faced limitations such as less rigorous monitoring compared to clinical trials. Selection bias could not be ruled out as treatments followed standard practice. More frequent follow‐up for AF may have increased event detection rates. The study lacked detailed information on AF subtype, burden, anticoagulation duration, and concomitant antiplatelet therapy over time. However, the long follow‐up period and systematic data verification enhanced reliability. The PSM methodology and large contemporary patient sample strengthened the validity. The longitudinal treatment analysis, accounting for time‐dependent treatment changes, provided a more robust methodology than previous studies.
In conclusion, AF is associated with a higher frequency of CV comorbidities and mortality in MPNs, even with broad anticoagulation use. The thrombosis/bleeding risk ratio suggests the convenience of anticoagulant therapy for most patients, with precautions for those with prior bleeding or contraindications. DOACs appear to be associated with a lower bleeding risk, which requires validation in prospective studies.
Funding
This study was sponsored and funded by the Spanish Group of Ph‐negative Myeloproliferative Neoplasms (GEMFIN).
Ethics Statement
The study was approved by the independent ethics committees of the participating sites (primary approval by the ethics committee of Ramon y Cajal University Hospital was obtained on June 1st, 2020 [ref: 2020/392]) and was conducted in accordance with the Declaration of Helsinki, Good Clinical Practices (GCPs), and applicable local regulations.
Consent
Written informed consent was obtained from alive patients. The ICF exemption was approved for patients who were dead to avoid bias.
Conflicts of Interest
Valentín Garcia‐Gutierrez declares: CTA: Honoraria; GSK: Consultancy; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis, Incyte: Speakers Bureau; Novartis, Incyte, GSK, Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis, BMS, Pfizer, Incyte, GSK: Consultancy. MMPE: Honorarios: MSD, GSK, Novartis. FFM: Novartis: Speakers bureau; Sobi, Incyte: Research funding. Gonzalo Caballero‐Navarro declares Novartis, Sobi: Speakers bureau. The other authors declare no conflicts of interest.
Supporting information
Table S1: Incidence of post‐diagnostic thromboembolic events in the full dataset.
Table S2: Incidence of post‐diagnostic thromboembolic events in the PSM cohort.
Table S3: Incidence of post‐diagnostic bleeding events in the full dataset.
Table S4: Incidence of post‐diagnostic bleeding events in the PSM cohort.
Table S5: Incidence of thromboembolic events post‐diagnostic thrombotic and hemorrhagic events in patients with MPNs and AF according to their antithrombotic therapy.
Figure S1: CONSORT diagram showing the number of patients and incidence of atrial fibrillation among patients with PV and ET.
Figure S2: Cumulative incidence of thromboembolic events in the PSM cohort.
Figure S3: Cumulative incidence of bleeding in the PSM cohort.
Figure S4: Estimated incidence of mortality and cardiovascular mortality in patients with MPNs and AF in the PSM cohort.
Acknowledgments
This study was sponsored and funded by the Spanish Group of Ph‐negative Myeloproliferative Neoplasms (GEMFIN). The authors thank all patients and families, investigators, and study staff involved in this study; the MFAR Clinical Research team; and Pau Doñate, PhD, for manuscript and language editing support.
Contributor Information
Rodrigo Ortega Perez, Email: rodrigortegaperez@gmail.com.
Alberto Álvarez Larrán, Email: aalvar@clinic.cat.
Data Availability Statement
The data are available from the corresponding author upon reasonable request (equivalent to the purposes for which the patients grant their consent to use the data). Requests will be considered on a case‐by‐case basis and in a timely manner. Data will be provided without personally identifiable data.
References
- 1. Barbui T., Finazzi G., and Falanga A., “Myeloproliferative Neoplasms and Thrombosis,” Blood 122, no. 13 (2013): 2176–2184, 10.1182/blood-2013-03-460154. [DOI] [PubMed] [Google Scholar]
- 2. Reikvam H. and Tiu R. V., “Venous Thromboembolism in Patients With Essential Thrombocythemia and Polycythemia Vera,” Leukemia 26, no. 4 (2012): 563–571, 10.1038/leu.2011.314. [DOI] [PubMed] [Google Scholar]
- 3. Nicol C., Lacut K., Pan‐Petesch B., Lippert E., and Ianotto J. C., “Hemorrhage in Essential Thrombocythemia or Polycythemia Vera: Epidemiology, Location, Risk Factors, and Lessons Learned From the Literature,” Thrombosis and Haemostasis 121, no. 5 (2021): 553–564, 10.1055/s-0040-1720979. [DOI] [PubMed] [Google Scholar]
- 4. Tefferi A. and Barbui T., “Polycythemia Vera and Essential Thrombocythemia: 2021 Update on Diagnosis, Risk‐Stratification and Management,” American Journal of Hematology 95, no. 12 (2020): 1599–1613, 10.1002/ajh.26008. [DOI] [PubMed] [Google Scholar]
- 5. Linz D., Gawalko M., Betz K., et al., “Atrial Fibrillation: Epidemiology, Screening and Digital Health,” Lancet Regional Health 37 (2024): 100786, 10.1016/j.lanepe.2023.100786. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Mahé K., Delluc A., Chauveau A., et al., “Incidence and Impact of Atrial Arrhythmias on Thrombotic Events in MPNs,” Annals of Hematology 97, no. 1 (2018): 101–107, 10.1007/s00277-017-3164-x. [DOI] [PubMed] [Google Scholar]
- 7. Herbreteau L., Couturaud F., Hoffmann C., et al., “Atrial Fibrillation and Peripheral Arterial Disease Define MPN Patients With Very High Risk of Thrombosis,” Thrombosis Research 226 (2023): 93–99, 10.1016/j.thromres.2023.04.021. [DOI] [PubMed] [Google Scholar]
- 8. Gerds A. T., Mesa R., Burke J. M., et al., “Association Between Elevated White Blood Cell Counts and Thrombotic Events in Polycythemia Vera: Analysis From REVEAL,” Blood 143, no. 16 (2024): 1646–1655, 10.1182/blood.2023020232. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Hasselbalch H. C., Elvers M., and Schafer A. I., “The Pathobiology of Thrombosis, Microvascular Disease, and Hemorrhage in the Myeloproliferative Neoplasms,” Blood 137, no. 16 (2021): 2152–2160, 10.1182/blood.2020008109. [DOI] [PubMed] [Google Scholar]
- 10. Leiva O., Jenkins A., Rosovsky R. P., Leaf R. K., Goodarzi K., and Hobbs G., “Predictors of Increased Risk of Adverse Cardiovascular Outcomes Among Patients With Myeloproliferative Neoplasms and Atrial Fibrillation,” Journal of Cardiology 81, no. 3 (2023): 260–267, 10.1016/j.jjcc.2022.10.007. [DOI] [PubMed] [Google Scholar]
- 11. Lucijanic M., Krecak I., Soric E., et al., “PB2220: Atrial Fibrillation Is Frequent in Patients With Myelofibrosis and Might Be Sub‐Optimally Treated,” HemaSphere 7, no. S3 (2023): e80756cf, 10.1097/01.HS9.0000975624.80756.cf. [DOI] [Google Scholar]
- 12. de Freitas A. S. and Alvarez‐Larrán A., “Risk of Thrombosis and Hemorrhage in Patients With Polycythemia Vera and Atrial Fibrillation Treated With Prophylactic Oral Anticoagulants,” Annals of Hematology 95, no. 11 (2016): 1903–1904, 10.1007/s00277-016-2783-y. [DOI] [PubMed] [Google Scholar]
- 13. Escudero‐Martínez I., Morales‐Caba L., and Segura T., “Atrial Fibrillation and Stroke: A Review and New Insights,” Trends in Cardiovascular Medicine 33, no. 1 (2023): 23–29, 10.1016/j.tcm.2021.12.001. [DOI] [PubMed] [Google Scholar]
- 14. Van Gelder I. C., Rienstra M., Bunting K. V., et al., “2024 ESC Guidelines for the Management of Atrial Fibrillation Developed in Collaboration With the European Association for Cardio‐Thoracic Surgery (EACTS): Developed by the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC), With the Special Contribution of the European Heart Rhythm Association (EHRA) of the ESC. Endorsed by the European Stroke Organisation (ESO),” European Heart Journal 45 (2024): 3314–3414. [DOI] [PubMed] [Google Scholar]
- 15. Patel M. R., Mahaffey K. W., Garg J., et al., “Rivaroxaban Versus Warfarin in Nonvalvular Atrial Fibrillation,” New England Journal of Medicine 365, no. 10 (2011): 883–891, 10.1056/NEJMoa1009638. [DOI] [PubMed] [Google Scholar]
- 16. Granger C. B., Alexander J. H., McMurray J. J. V., et al., “Apixaban Versus Warfarin in Patients With Atrial Fibrillation,” New England Journal of Medicine 365, no. 11 (2011): 981–992, 10.1056/NEJMoa1107039. [DOI] [PubMed] [Google Scholar]
- 17. Hernández‐Boluda J. C., Arellano‐Rodrigo E., Cervantes F., et al., “Oral Anticoagulation to Prevent Thrombosis Recurrence in Polycythemia Vera and Essential Thrombocythemia,” Annals of Hematology 94, no. 6 (2015): 911–918, 10.1007/s00277-015-2330-2. [DOI] [PubMed] [Google Scholar]
- 18. De Stefano V., Ruggeri M., Cervantes F., et al., “High Rate of Recurrent Venous Thromboembolism in Patients With Myeloproliferative Neoplasms and Effect of Prophylaxis With Vitamin K Antagonists,” Leukemia 30, no. 10 (2016): 2032–2038, 10.1038/leu.2016.85. [DOI] [PubMed] [Google Scholar]
- 19. Barbui T., De Stefano V., Carobbio A., et al., “Direct Oral Anticoagulants for Myeloproliferative Neoplasms: Results From an International Study on 442 Patients,” Leukemia 35, no. 10 (2021): 2989–2993, 10.1038/s41375-021-01279-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Vannucchi A. M., Barbui T., Cervantes F., et al., “Philadelphia Chromosome‐Negative Chronic Myeloproliferative Neoplasms: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow‐Up,” Annals of Oncology 26 (2015): v85–v99. [DOI] [PubMed] [Google Scholar]
- 21. Lyon A. R., López‐Fernández T., Couch L. S., et al., “2022 ESC Guidelines on Cardio‐Oncology Developed in Collaboration With the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio‐Oncology Society (IC‐OS): Developed by the Task Force on Cardio‐Oncology of the European Society of Cardiology (ESC),” European Heart Journal 43, no. 41 (2022): 4229–4361, 10.1093/eurheartj/ehac244. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: Incidence of post‐diagnostic thromboembolic events in the full dataset.
Table S2: Incidence of post‐diagnostic thromboembolic events in the PSM cohort.
Table S3: Incidence of post‐diagnostic bleeding events in the full dataset.
Table S4: Incidence of post‐diagnostic bleeding events in the PSM cohort.
Table S5: Incidence of thromboembolic events post‐diagnostic thrombotic and hemorrhagic events in patients with MPNs and AF according to their antithrombotic therapy.
Figure S1: CONSORT diagram showing the number of patients and incidence of atrial fibrillation among patients with PV and ET.
Figure S2: Cumulative incidence of thromboembolic events in the PSM cohort.
Figure S3: Cumulative incidence of bleeding in the PSM cohort.
Figure S4: Estimated incidence of mortality and cardiovascular mortality in patients with MPNs and AF in the PSM cohort.
Data Availability Statement
The data are available from the corresponding author upon reasonable request (equivalent to the purposes for which the patients grant their consent to use the data). Requests will be considered on a case‐by‐case basis and in a timely manner. Data will be provided without personally identifiable data.