Serum erythropoietin and outcome after ischaemic stroke: a prospective study

Abstract

Objectives: Erythropoietin (EPO), which is inversely associated with blood haemoglobin (Hb), exerts neuroprotective effects in experimental ischaemic stroke (IS). However, clinical treatment trials have so far been negative. Here, in patients with IS, we analysed whether serum EPO is associated with (1) initial stroke severity, (2) recovery and (3) functional outcome.

Design: Prospective. Controls available at baseline.

Setting: A Swedish hospital-initiated study with outpatient follow-up after 3 months.

Participants: Patients (n=600; 64% males, mean age 56 years, controls n=600) were included from the Sahlgrenska Academy Study on IS (SAHLSIS).

Primary and secondary outcome measures: In addition to EPO and Hb, initial stroke severity was assessed by the Scandinavian Stroke Scale (SSS) and compared with SSS after 3 months (follow-up) as a measure of recovery. Functional outcome was evaluated using the modified Rankin Scale (mRS) at follow-up. Serum EPO and SSS were divided into quintiles in the multivariate regression analyses.

Results: Serum EPO was 21% and 31% higher than in controls at the acute phase of IS and follow-up, respectively. In patients, acute serum EPO was 19.5% higher in severe versus mild IS. The highest acute EPO quintile adjusted for sex, age and Hb was associated with worse stroke severity quintile (OR 1.70, 95% CI 1.00 to 2.87), better stroke recovery quintile (OR 1.93, CI 1.09 to 3.41) and unfavourable mRS 3-6 (OR 2.59, CI 1.15 to 5.80). However, the fourth quintile of EPO increase (from acute to follow-up) was associated with favourable mRS 0-2 (OR 3.42, CI 1.46 to 8.03). Only the last association withstood full adjustment.

Conclusions: The crude associations between EPO and worse stroke severity and outcome lost significance after multivariate modelling. However, in patients in whom EPO increased, the association with favourable outcome remained after adjustment for multiple covariates.

Keywords: EPIDEMIOLOGY; erythropoietin.

Figure 1

Stroke severity and recovery according to quintiles (q1–q5) of serum EPO during the acute phase. (A) Initial stroke severity according to the SSS units. (B) Stroke recovery (ΔSSS) after 3 months (q1 indicating deterioration and q5 improvement). (C) ORs and 95% CIs for the associations (ordinal logistic regression) between acute EPO quintiles and initial stroke severity, as measured by SSS quintiles. (D) As in panel C, but for stroke recovery (ΔSSS quintiles). For (A–D), numbers of included patients are shown above each quintile (q1–q5). Statistically significant differences between groups (as evaluated by ANOVA followed by Tukey's post hoc test) are shown with brackets. In A and B, the boxes show the overall correlation coefficients according to Pearson including p values. In C and D, the boxes show the overall association using acute EPO quintiles as a continuous variable (p trends). Different models of adjustment in which sex (S), age (A), cardiovascular factors (C) and CRP are included as indicated. ANOVA, analysis of variance; CRP, C reactive protein; EPO, erythropoietin; Hb, haemoglobin; SSS, Scandinavian Stroke Scale.

Figure 2

Functional outcome after stroke as indexed by the modified Rankin Scale (mRS) and regressions of favourable mRS according to quintiles (q1–q5) of acute serum erythropoietin (EPO), 3-month serum EPO and changes in EPO (ΔEPO). (A) Functional outcome (mRS units) according to acute EPO quintiles. (B) Functional outcome (mRS units) according to 3-month EPO quintiles. (C) Functional outcome (mRS units) according to ΔEPO quintiles. (D) ORs and 95% CIs for the associations (binary logistic regression) of mRS (values 3–6) over favourable (mRS 0–2) functional recovery according to quintiles of acute EPO. (E) Same as in D but mRS 0–2 over mRS 3–6 according to ΔEPO quintiles. Numbers of included patients are shown above each quintile (q1–q5). No statistically significant differences were found between groups as evaluated by analysis of variance. In A–C, the boxes show the overall correlation coefficients according to Pearson and the corresponding p values. In D and E, the boxes show the overall association using acute EPO quintiles as a continuous variable (p trends). Different models of adjustment with abbreviations as in ‘C’.