Low Glomerular Filtration Rate, Recurrent Stroke Risk, and Effect of Renin–Angiotensin System Modulation
Background and Purpose—To investigate the association of low estimated glomerular filtration rate (eGFR) <60 mL/min with recurrent stroke risk and to evaluate whether add-on renin–angiotensin system modulator therapy is associated with lower recurrent stroke risk in patients with low eGFR.
Methods—We analyzed the database of a multicenter trial involving 18 666 patients with recent ischemic stroke followed for 2.5 years. Primary outcome was time to first recurrent stroke. Independent associations of low eGFR with outcome in the entire cohort and add-on telmisartan treatment with outcome among those with low eGFR were evaluated.
Results—Low eGFR was observed in 3630 (20.1%) patients. Patients with low eGFR were older, more likely women, with a known history of hypertension. In unadjusted analyses, patients with low eGFR were more likely to experience a recurrent stroke (hazard ratio, 1.34; 95% confidence interval, 1.20–1.49). After adjusting for confounders, low eGFR was still associated with recurrent stroke but to a lesser extent (hazard ratio, 1.16; 95% confidence interval, 1.04–1.31). Telmisartan treatment among patients with low eGFR was not independently associated with recurrent stroke (hazard ratio, 1.08; 95% confidence interval, 0.89–1.31).
Conclusions—Low eGFR is independently associated with a higher risk of recurrent stroke, but short-term add-on telmisartan therapy does not seem to mitigate this risk.
- glomerular filtration rate
- myocardial infarction
- renal insufficiency, chronic
- renin–angiotensin system
The relationship of low estimated glomerular filtration rate (eGFR) with recurrent stroke risk after a recent ischemic stroke has rarely been investigated.1 Furthermore, renin–angiotensin system (RAS) modulators that limit chronic kidney disease (CKD) progression,2 and reduce vascular risk in patients with cardiac disease, independent of their blood pressure lowering,3 have not been assessed for potential benefit in recent patients with stroke with CKD. In this study, we evaluate the association of low eGFR with recurrent stroke risk and assess whether add-on RAS modulator therapy is related to lower recurrent stroke risk among patients with stroke with low eGFR.
We reviewed data from the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) Trial. The methods and main results of this trial have previously been reported.4 Briefly, from September 2003 to July 2006, PRoFESS enrolled 20 332 patients from 695 centers in 35 countries who recently had an ischemic stroke. Patients with cardioembolic strokes requiring anticoagulation, known severe renal insufficiency defined as renal artery stenosis or serum creatinine >265 μmol/L (>3.0 mg/dL), were excluded.4 Average patient follow-up was 2.5 years. The primary outcome was first recurrence of stroke of any type. The trial was approved by the ethics committee or institutional review board at each national or local site, and all participants provided written informed consent.4
Because no difference in efficacy was discerned between any of the treatment arms in PRoFESS, all patients were included in this analysis.4 eGFR per the Modification of Diet in Renal Disease Study Group equation was calculated for each eligible patient.5 CKD was defined as eGFR<60 mL/min per 1.73 m2. Patients with implausibly low serum creatinine levels (<18 μmol/L [<0.2 mg/dL]) were excluded (n=1629). CKD was categorized by stage using a slightly modified version of the National Kidney Foundation guidelines.6 Stepwise Cox proportional hazard models were used to estimate the risk of the primary outcome, which was time to first recurrent stroke. We forced these baseline covariates into the stepwise model: age, sex, history of prior stroke, known diabetes mellitus, previous myocardial infarction, average trial blood pressure, known hypertension, and selecting other covariates with a P value ≤0.10. Tests for 2-way interactions involving telmisartan treatment were performed for prespecified baseline features, including age, history of diabetes mellitus, and small vessel stroke subtype.
Of the 20 332 subjects enrolled in PRoFESS, eGFR was determined in 18 666 (91.8%) patients with serum creatinine within the range of 18 to 265 μmol/L (0.2–3.0 mg/dL). Overall, mean age was 66.0±8.5 years, 6612 (35.9%) were women and 3630 (20.1%) had CKD. Among those with baseline CKD, mean age was 69.2±8.6 years and 1944 (50.0%) were women. Baseline characteristics are shown in Table I in the online-only Data Supplement. Patients with CKD were more likely to be older, women, with a baseline history of hypertension, coronary artery disease, symptomatic cerebrovascular disease, antihypertensive drug use, and less likely to be smokers.
Absolute risks of recurrent vascular events by baseline eGFR were consistently worse among patients with PRoFESS with low eGFR (Table II in the online-only Data Supplement), and CKD severity by modified National Kidney Foundation staging showed an association of eGFR with vascular events in a dose-dependent manner (Table III in the online-only Data Supplement). In unadjusted analyses, patients with low eGFR were more likely to experience a recurrent stroke (hazard ratio, 1.34; 95% confidence interval, 1.20–1.49). After adjusting for confounders, low eGFR was still associated with recurrent stroke but to a lesser extent (hazard ratio, 1.16; 95% confidence interval, 1.04–1.31). Telmisartan treatment among patients with low eGFR was not independently associated with recurrent stroke (hazard ratio, 1.08; 95% confidence interval, 0.89–1.31).
For the outcome of recurrent stroke, there were no significant 2-way interactions involving telmisartan treatment between eGFR category versus prespecified variables of age, small vessel disease stroke type, and diabetes mellitus.
We observed that among patients with a recent ischemic stroke, recurrent stroke risk was significantly higher for those patients with eGFR<60 mL/min than for those patients with higher eGFR values, even after adjusting for potential major confounders. These results suggest that there may be clinical relevance in the use of eGFR in recurrent stroke risk prognostication among patients with recent ischemic stroke. However, unlike results of analyses of patients with cardiac disease,3 we did not find that add-on treatment with a renin–angiotensin modulator was independently related to better clinical outcomes.
The strength of the association between CKD and recurrent stroke risk seems to be less than that reported with primary stroke.7 This difference may be because of insufficient follow-up period in the current study, or implementation of vascular risk reduction therapies after a primary stroke likely mitigates some of the avenues through which CKD may promote deleterious vascular effects. Multiple explanations have been proposed for the link between CKD and vascular demise, including an enhancement of less conventional vascular risk factors and activation of the RAS by the initial renal endothelial damage with resultant upregulation of inflammatory mediators (cytokines, chemokines, and adhesion molecules) and superoxide scavenging of NO.8 Meanwhile, the null effect of add-on RAS modulation in the patients with ischemic stroke with CKD in this study might be because of the heterogeneous nature of ischemic stroke, the dose of the agent used, differences among individual RAS modulators. Only a dedicated randomized clinical trial using a RAS modulator in patients with stroke with CKD can clarify this issue properly.
Our study is limited because it is a post hoc analysis of a completed randomized trial, these results may not apply to patients whose index stroke is caused by a presumed cardioembolic mechanism, and the follow-up time may have been too brief to see any potentially protective benefits of the RAS modulator. The study was strengthened by the rigorous procedures of the PRoFESS trial design, inclusion of subjects enrolled from around the world and large sample size.8
Study concept and design: Drs Ovbiagele, Bath, Diener; acquisition of data: Drs Ovbiagele, Bath, and Diener; analysis and interpretation of data: Drs Ovbiagele, Bath, D. Cotton, Drs Sha, Diener; drafting of the article: Dr Ovbiagele; critical revision of the article for important intellectual content: Drs Ovbiagele, Bath, D. Cotton, Drs Sha, Diener; statistical analysis: D. Cotton, Dr Sha.
Sources of Funding
The sponsor (Boehringer Ingelheim) provided grant monies and materials to execute the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial.
Dr Ovbiagele was supported by U01 NS079179 from the National Institute of Neurological Disorders and Stroke/National Institutes of Health (NIH). Dr Bath is The Stroke Association Professor of Stroke Medicine. Dr Diener received honoraria for participation in clinical trials, contribution to advisory boards or oral presentations from: Abbott, AstraZeneca, Bayer Vital, BMS, Boehringer Ingelheim, CoAxia, D-Pharm, Fresenius, GlaxoSmithKline, Janssen Cilag, Knoll, MSD, Medtronic, MindFrame, Neurobiological Technologies, Novartis, Novo-Nordisk, Paion, Parke-Davis, Pfizer, Sanofi-Aventis, Sankyo, Schering-Plow, Servier, Solvay, Thrombogenics, Wyeth, Yamaguchi. Financial support for research projects was provided by Astra/Zeneca, GSK, Boehringer Ingelheim, Lundbeck, Novartis, Janssen Cilag, Sanofi-Aventis, Syngis, Talecris. The Department of Neurology at the University Duisburg-Essen received research grants from the German Research Council, German Ministry of Education and Research, European Union, NIH, Bertelsmann Foundation and Heinz-Nixdorf Foundation. Dr Diener has no ownership interest and does not own stocks of any pharmaceutical company. D. Cotton and Dr Sha are employees of Boehringer Ingelheim. Dr Bath received honoraria for participation in clinical trials or Data Monitoring Committees, contribution to advisory boards or oral presentations from: Boehringer Ingelheim, Lundbeck, Mitsubishi, M’s Science, Phagenesis and ReNeuron. Dr Bath has received research grants from the Alzheimer’s Society, British Heart Foundation, Medical Research Council, and The Stroke Association. Dr Bath has no ownership interest and does not own stocks of any pharmaceutical company. The other authors report no conflicts.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.113.002463/-/DC1.
- Received June 12, 2013.
- Accepted August 7, 2013.
- © 2013 American Heart Association, Inc.
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