The Sense and Nonsense of Anaemia Analysis in Relation to Mortality in General Practice
Authors: Stouten Karlijn , Riedl Jurgen A , van Houten Ron , van Rosmalen Joost , Sonneveld Pieter , Levin Mark-David 
Published: October 2019

Abstract
Introduction: Anaemia is a common finding in general practice, with a prevalence rising from about 5% in the age group 50-64 years to over 20% in the age group 85+ years. Anaemia has been associated with increased all-cause mortality in a general practice population. However, only the influence of the four main causes of anaemia (anaemia of chronic disease, nutrient deficiency, renal anaemia and unknown anaemia) on mortality has been analysed.
We prospectively studied the influence of a wide range of causes of anaemia on mortality, including less prevalent causes such as folic acid deficiency and haemolysis. In addition, we calculated the standardized mortality ratio for men and women per five-year age group to determine up to which age anaemia continues to exert a negative influence on mortality.
Methods: Between the 1st of February 2007 and the 1st of February 2014, patients aged 50 years or older and presenting to their general practitioner with a newly diagnosed anaemia (i.e. no anaemia the preceding two years) were included in the study. Anaemia was defined as a haemoglobin level below 13.7 g/dL (8.5 mmol/L, men) and below 12.1 g/dL (7.5 mmol/L, women). A wide range of laboratory parameters was established for each patient. Based on the laboratory results, two independent experts determined the cause or causes of anaemia.
Patients were followed until either their deaths or until the 1st of September 2014, at which moment they were censored at the last date they were documented as alive in the hospital or laboratory information system. Mortality risk of the overall Dutch population in the year 2010 was extracted from Statistics Netherlands, which collects all population statistics in the Netherlands, and compared to the mortality risk of the anaemic cohort.
Results: A total of 2929 patients were included in the study, 1428 men (median age 72 years, range 50-101) and 1501 women (median age 77 years, range 50-103). Among the patients presenting with a single cause of anaemia, anaemia of chronic disease was found 848 times (29.0%), haemoglobinopathy 18 times (0.6%), haemolysis 10 times (0.3%), possible bone marrow disease 42 times (1.4%), other causes 64 times (2.2%) and renal anaemia 290 times (9.9%). Iron deficiency was found 499 times (17.0%), vitamin B12 deficiency 61 times (2.1%) and folic acid deficiency 11 times (0.4%). A total of 260 patients (8.9%) presented with multiple causes while the cause remained unknown in 826 patients (28.2%).
A Cox proportional hazards model was used to assess the influence of the different causes of anaemia on mortality, correcting for age, gender and severity of anaemia. Patients presenting with an unknown cause were used as the reference group. We found significant hazard ratios for the following causes: anaemia of chronic disease (HR = 2.1 95% CI 1.64-2.70, P < 0.001), possible bone marrow disease (HR = 3.08 95% CI 1.72-5.52, P < 0.001), folic acid deficiency (HR = 6.89 95% CI 2.79-17.04, P < 0.001), renal anaemia (HR = 2.15 95% CI 1.61-2.87, P < 0.001) and multiple causes (HR = 2.31 95% CI 1.69-3.16, P < 0.001).
The mortality risk of the anaemic general practice population was compared to the mortality risk of the overall Dutch population. Statistically significant standardized mortality ratios were observed for both men (M) and women (W) in the age groups 50-54 years (M:5.01, and W:5.30), 60-64 years (M:4.32, and W:3.57), 70-74 years (M:1.96, and W:2.04), 75-79 years (M:1.69, and W:2.09) and 80-84 years (M:1.34, and W:1.50). In addition, significant ratios were observed for men in the age groups 55-59 years (4.40) and 65-69 years (2.91). From age group 85-89 years and up, no significant effect of all-cause anaemia on mortality was found.
Conclusion: Anaemia of chronic disease, possible bone marrow disease, folic acid deficiency, renal anaemia and presenting with multiple causes of anaemia are associated with a higher mortality. An increased standardized mortality ratio was demonstrated until the age of 85 years. The ratio showed a linear decrease with age. Above 85 years no increased mortality risk for patients with all-cause anaemia was found.

Disclosures
Sonneveld: Janssen-Cilag, Celgene, Onyx, Karyopharm: Honoraria, Research Funding; novartis: Honoraria.