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The most common causes of death in patients with paroxysmal nocturnal hemoglobinuria were cardiovascular disease and associated hematologic disease.
Multiple factors contribute to early death due to paroxysmal nocturnal hemoglobinuria (PNH), researchers in Denmark report.
“Our study indicates that age, previous solid cancer, cardiovascular comorbidity, and comorbidity at the time of diagnosis are associated with early mortality after PNH diagnosis. In addition, mortality due to hematological disease and infections prevail as frequent causes of death among patients with early mortality,” lead author Anne Lykke Sørensen, MD, and her colleagues at the Odense University Hospital write in Cureus.
“The increased mortality in older patients could suggest that older patients remain undiagnosed for longer periods and therefore succumb to PNH-related complications shortly after diagnosis and that undertreatment is a potential risk in these high-risk patients,” they add.
PNH, a rare, acquired clonal hematopoietic stem cell disease, causes non-immune hemolysis that can lead to a wide range of outcomes, including anemia, fatigue, abdominal pain, smooth muscle dystonia, thromboembolism, and death. Newer medications have increased overall survival.
In their investigation of PNH-linked mortality, the researchers identified 115 patients with PNH from the 1977-2016 Danish National Patient Register (DNPR). For each patient with PNH, they selected 50 age- and sex-matched general-population comparators. At diagnosis, around 50% of people with PNH and comparators were female, and in both groups, the median age was 48.2 years.
The study team used the Kaplan-Meier estimator and Cox regression to compare the overall survival of patients with comparators. They used cumulative incidences to analyze the effects of comorbidities and causes of death.
Dr. Sørensen and colleagues found that the one-year survival among patients was 92.2% compared with 99.4% among comparators. The ten-year survival among patients was 68.4% versus 85.8% among comparators. The median age at death was 67.3 years for patients with PNH and 77.7 years for comparators.
The adjusted HR for death in patients with PNH was 10.5 times (95% confidence interval, 6.3-17.3) the risk among comparators. Mortality in patients was high the first two years after diagnosis but gradually approached that of the general population thereafter.
The authors found no difference in survival for patients with PNH diagnosed before versus after 2006, when new pharmaceutical treatments became available. However, too few patients in the DNPR were registered with exposure to the drug to analyze its effect on survival.
The most common causes of death among patients with PNH were cardiovascular disease at 22.3% and associated hematologic disease at 20.7%. During the first year after diagnosis, 3.5% of deaths among patients with PNH, and 0% among comparators, were attributed to hematologic disease. After 10 years, hematologic causes of death increased to 12.3% among patients and 0.2% among comparators (Table).
Although thromboembolism is considered a common cause of death with PNH, the authors found no deaths among the registry patients with PNH. They speculate that this discrepancy may be explained by the registry data collection algorithm that records the most probable main (but not a contributory) cause of death, by data entry errors, and by the decline in autopsies performed in Denmark.
Study Provides a Foundation to Build Upon
“This study is important because it demonstrates the natural history and mortality risks of PNH over almost four decades. Its description of a large (relatively speaking for this rare disease) cohort of patients over a long time in a single registry provides the baseline foundation for future interventions to improve upon,” says Ryotaro Nakamura, MD, who was not involved in the study.
“The study emphasizes the importance of multi-disciplinary approaches to patient care in this rare hematologic disease in which the dominant clinical feature is hemolysis and anemia, but with systemic impact on health status,” he notes. “Hematologists need to recognize that PNH can cause multiple health issues besides its classic hemolytic anemia and that it requires their comprehensive attention as well as collaboration with primary care physicians and other specialists.”
The authors agree. “The rarity of the disease calls for international collaboration to investigate rare events and complications associated with PNH, particularly when subgroups such as elderly patients are considered,” they conclude.
