Cytoreductive treatment patterns among US veterans with polycythemia vera

Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) [1] that affects > 140,000 patients in the United States [2]. In the National Cancer Institute−sponsored Surveillance, Epidemiology, and End Results cancer registry, the incidence of PV per 100,000 persons increased with advancing age (0.1 for < 34 years, 0.7 for 35–49 years, 2.4 for 50–74 years, and 5.3 for > 75 years) and was higher for men (1.3 vs 0.8 for women) and whites (1.1 vs 0.7 for African Americans and 0.8 for other race groups) [3]. Analyses of PV patient populations have estimated that arterial and venous thrombotic events occur at rates of 7 to 21 and 5 to 20 per 1000 person-years, respectively [4‐7]. Thrombotic and cardiovascular events are among the leading causes of death in patients with PV [8], contributing to lower overall survival compared with age- and sex-matched members of the general population [9].

The treatment goals for patients with PV focus primarily on preventing or managing thrombotic and bleeding complications [10]. The European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) study demonstrated that treatment with low-dose aspirin was associated with reduced risk of thrombotic events and death from cardiovascular causes [11]. Results from the Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial supported treatment with phlebotomy to maintain hematocrit levels < 45% and reduce the risk of cardiovascular events and deaths resulting from thrombotic or cardiovascular events [12]. In addition, some patients benefit from cytoreductive treatment with hydroxyurea [13], interferon-α [14], or ruxolitinib [15, 16]. Ruxolitinib was approved by the US Food and Drug Administration (FDA) in 2014 for patients with PV who have had an inadequate response to or are intolerant of hydroxyurea, and it remains the only pharmaceutical agent approved by the FDA for the PV setting [17].

Real-world data on patient characteristics and clinical management of patients with PV help inform the understanding of the population and identification of unmet clinical needs. The Veterans Health Administration (VHA), the largest integrated health-care system in the United States, maintains patient records for US veterans receiving care in Veterans Integrated Service Networks. This is the first study to describe the demographics, clinical characteristics, management, and thrombotic and cardiovascular event rates of patients with PV in the VHA population.

In this analysis of 7718 patients diagnosed with PV in the VHA population, there was a substantial burden of thrombotic and cardiovascular events. During follow-up, nearly a quarter of patients had a thrombotic event, and almost one-third experienced a cardiovascular event. The thrombotic event rate (60.5 per 1000 patient-years) was higher than rates reported for cohorts of patients with PV in the general population (14.3 to 38 per 1000 patient-years) [5‐7], even among high-risk patients (diagnosis before 2005, 40.1 per 1000 patient-years; after 2005, 29.3 per 1000 patient-years) [20].

There are several plausible contributors to the elevated thrombotic event rate in the VHA population. First, the VHA population may inherently have more risk factors for thrombotic events. Patients had a notable comorbid disease burden at baseline, and the prevalence of traditional cardiovascular risk factors such as hypertension, dyslipidemia, diabetes, and smoking [21] was high. Although not measured in our analysis, the prevalence of psychological comorbidities (eg, adjustment disorder, anxiety, depression, posttraumatic stress disorder, substance use disorder) [22] and other psychosocial issues (eg, homelessness) [23] are also elevated in the VHA patient population, which may complicate management of thrombotic and cardiovascular events. Finally, the catchment area overseen by VHA providers may be larger than the area covered by some traditional hematology providers, which could confound travel logistics and scheduling for some patients, thereby impeding some standard practices (eg, frequent phlebotomy, coordination of care, obtaining outside laboratory tests) [24].

Although the care provided during the follow-up period may have been appropriate by the standards of the time, current standard practice based on more recent evidence may be associated with improved patient care. Of interest, 3 in 4 patients had no documentation of any pharmacologic cytoreductive treatment, and more than half had no documentation of pharmacologic cytoreductive treatment or phlebotomy. The low cytoreductive treatment rate in this population may explain why 9 in 10 patients had elevated hematocrit levels and 1 in 3 had elevated WBC counts. These findings are important; the CYTO-PV study indicated that elevated hematocrit and WBC counts were associated with increased risk of PV-related clinical complications [12, 25]. The cytoreductive treatment patterns observed in our study may be related to the available evidence at the time. For example, CYTO-PV study results demonstrating the clinical benefit of hematocrit maintenance < 45% [12] and WBC counts < 11 × 10⁹/L [25] were not published until after the study period of this analysis. However, some data concerning the clinical benefits of cytoreductive therapy, in particular hydroxyurea, predated the study period [13, 26]. It is interesting that few patients had documented treatment with aspirin or other antiplatelet therapy. This may be a consequence of anticoagulant use or an artifact of low-dose aspirin being available over the counter (ie, may not be reflected in the medication dispensing forms). Findings from the ECLAP study published in 2004 demonstrated that low-dose aspirin reduced the risk of cardiovascular events in patients with PV [11]. Recent data suggest that patients with PV and hypertension who are treated with angiotensin-converting enzyme (ACE) inhibitors may require less cytoreductive treatment to control hematocrit levels compared with those who are treated with other antihypertensive agents [27]. The current analysis found that the majority of patients with PV received an ACE inhibitor during follow-up, but usage rates were similar regardless of cytoreductive treatment (data not shown). It may be important in future analyses to continue to report the association between ACE inhibitor and cytoreductive medication use on patient outcomes.

Of note, even among a subset of patients receiving cytoreductive treatment, the thrombotic and cardiovascular risk remained high. Approximately 1 in 4 patients treated with cytoreductive therapy experienced thrombotic events during follow-up, and nearly 1 in 3 had cardiovascular events. These data indicate an unmet clinical need in patients treated with traditional options and may in part explain why such a large proportion of patients were not receiving cytoreductive treatment during follow-up.

Limitations of this analysis are primarily related to the retrospective study design and reliance on the accuracy of the database. The PV disease diagnosis, thrombotic events, and other clinical conditions were identified using ICD-9-CM codes, which are subject to potential miscoding (eg, cases of secondary polycythemia may have been logged as PV). Some PV-related treatments (eg, over-the-counter aspirin, phlebotomy at blood centers) may not have been recorded in the database and could have been underrepresented in our analysis. Gaps between patient visits could be long, during which time blood cell counts and other clinical measures were unavailable; this may have precluded an ability to observe long-term changes in a consistent group of patients. Only 1 WBC count ≥11 × 10⁹/L was required for patients to have an elevated status, and it could have been caused by an acute illness. However, previous data suggest that this cutoff is important. In an analysis of the CYTO-PV study, WBC count ≥11 × 10⁹/L was associated with a 3.9-fold increased risk of major thrombosis compared with WBC count < 7 × 10⁹/L (P = 0.02) [25]. Furthermore, blood count analyses were incomplete because data were not available for an informative analysis of platelet counts. This VHA patient population was almost entirely male, precluding an analysis of treatment and management effects on thrombotic and cardiovascular events in female patients. Finally, the exploratory nature of the analysis precluded formal statistical analyses.

This retrospective analysis of the VHA population identified a substantial burden of thrombotic and cardiovascular events among 7718 patients with PV managed between 2005 and 2012, before publication of the CYTO-PV results. Approximately 9 in 10 patients had elevated hematocrit levels and 1 in 3 had elevated WBC counts, which may increase the risk of PV-related clinical complications. The prevalence of additional cardiovascular risk factors was high, placing this population at a greater risk for thrombotic events. Surprisingly, many patients did not have documented treatment with cytoreductive therapy or phlebotomy. Collectively, these data suggest that some patients with PV in the VHA have unmet clinical needs that may be ameliorated with the use of both traditional and targeted cytoreductive treatment options. Recent clinical practice guidelines from the National Comprehensive Cancer Network provide specific treatment recommendations based on PV disease severity and response history [28].