Risk factors for thromboembolic events in patients with paroxysmal nocturnal hemoglobinuria (PNH): a nested case-control study in the International PNH Registry

Abstract

The objective of this analysis was to identify risk factors for thromboembolic events (TE) in patients with paroxysmal nocturnal hemoglobinuria (PNH) who were not treated with C5 inhibitors. Patients with PNH and a history of ≥ 1 TE at enrollment in the International PNH Registry (NCT01374360; registration date, January 2011) were each matched with up to 5 patients without TE. Multivariable analysis was performed with the following variables: percentage glycosylphosphatidylinositol (GPI)-negative cells, high disease activity (HDA), non-TE major adverse vascular event history, and recent anticoagulation. Of 2541 eligible patients, 57 with TE and 189 matched controls were analyzed. Multivariable analysis (odds ratio [95% CI]) identified the following factors as being associated with increased thrombotic risk: patients with no history of TE (with recent anticoagulation, 9.30 [1.20-72.27]), patients with history of TE (with recent anticoagulation, 8.91 [0.86-92.62]; without recent anticoagulation, 5.33 [0.26-109.57]), patients with ≥ 30% GPI-negative granulocytes (≥ 30% to < 50%, 4.94 [0.54-45.32]; ≥ 50%, 1.97 [0.45-8.55]), or patients with lactate dehydrogenase (LDH) ratio ≥ 1.5 × upper limit of normal (ULN) plus ≥ 2 HDA criteria (2-3 criteria, 3.18 [0.44-23.20]; ≥ 4 criteria, 3.60 [0.38-33.95]). History of TE, ≥ 30% GPI-negative granulocytes, and LDH ratio ≥ 1.5 × ULN with ≥ 2 HDA criteria are TE risk factors for patients with PNH. These findings will aid physicians by providing important clinical and laboratory risk factors that can be used to identify and manage patients with PNH who are at risk of developing TE.

Keywords: Cohort study; Multivariable analysis; Paroxysmal nocturnal hemoglobinuria; Risk factors; Thromboembolism.

Fig. 1

TE case and control selection from the International PNH Registry. PNH, paroxysmal nocturnal hemoglobinuria; TE, thromboembolic event

Fig. 2

Physician-reported symptoms within 6 months before the index date. (a) TE cases. (b) Controls. ^†TE cases (n = 31), controls (n = 103). ED, erectile dysfunction; TE, thromboembolic event

Fig. 3

Univariable analysis of TE risk by laboratory and clinical parameters. Data are based on assessments within 6 months before the TE index date. Patient numbers are reported as [TE cases, controls] per parameter. Exact OR and estimated CIs are from univariable conditional logistic regression model of risk of TE event. The increased risk of TE observed in patients receiving anticoagulation with no history of TE likely reflects prescribing decisions based on physician assessment of TE risk (ie, primary prophylaxis) rather than contributing to risk itself and should be interpreted accordingly. ^‡HDA defined as LDH ratio ≥ 1.5 × ULN, hemoglobin < 10 g/dL, and one of the following symptoms 6 months before and including the index date: abdominal pain, dyspnea, dysphagia, fatigue, hemoglobinuria, or erectile dysfunction. ^§Assessments based on the entire patient history from PNH diagnosis to index date. GPI, glycosylphosphatidylinositol; HDA, high disease activity; LDH, lactate dehydrogenase; MAVEs, major adverse vascular events; OR, odds ratio; TE, thromboembolic event; ULN, upper limit of normal

Fig. 4

Univariable analysis of TE risk by physician-documented symptom. Data are based on assessments within 6 months before the TE index date. Patient numbers are reported as [TE cases, controls] per parameter. Exact OR and estimated CIs are from univariable conditional logistic regression model of risk of TE event. OR, odds ratio; TE, thromboembolic event

Fig. 5

Multivariable analysis of TE risk by laboratory and clinical parameters. Data are based on assessments within 6 months before the TE index date. Patient numbers are reported as [TE cases, controls] per parameter. OR and 95% CIs are Wald’s estimates from multivariable conditional logistic regression model of risk of TE event. The increased risk of TE observed in patients receiving anticoagulation with no history of TE likely reflects prescribing decisions based on physician assessment of TE risk (ie, primary prophylaxis) rather than contributing to risk itself and should be interpreted accordingly. ^‡HDA defined as LDH ratio ≥ 1.5 × ULN, hemoglobin < 10 g/dL, and one of the following symptoms 6 months before and including the index date: abdominal pain, dyspnea, dysphagia, fatigue, hemoglobinuria, or erectile dysfunction. ^§Assessments based on the entire patient history from PNH diagnosis to index date. ^¶Recent is defined as within 6 months before the index date. GPI, glycosylphosphatidylinositol; HDA, high disease activity; LDH, lactate dehydrogenase; MAVE, major adverse vascular event; OR, odds ratio; TE, thromboembolic event; ULN, upper limit of normal