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Randomized Controlled Trial
. 2021 Sep 16;2(11):1761-1769.
doi: 10.34067/KID.0004272021. eCollection 2021 Nov 25.

Stroke in Hemodialysis Patients Randomized to Different Intravenous Iron Strategies: A Prespecified Analysis from the PIVOTAL Trial

Patrick B Mark  1 , Pardeep S Jhund  1 , Matthew R Walters  1 , Mark C Petrie  1 , Albert Power  2 , Claire White  3 , Michele Robertson  4 , Eugene Connolly  1 , Stefan D Anker  5 , Sunil Bhandari  6 , Kenneth Farrington  7 , Philip A Kalra  8 , Charles R V Tomson  9 , David C Wheeler  10 , Christopher G Winearls  11 , John J V McMurray  1 , Iain C Macdougall  3 , Ian Ford  4 ; PIVOTAL Investigators
Collaborators, Affiliations
Randomized Controlled Trial

Stroke in Hemodialysis Patients Randomized to Different Intravenous Iron Strategies: A Prespecified Analysis from the PIVOTAL Trial

Patrick B Mark et al. Kidney360. .

Abstract

Background: People with kidney failure treated with hemodialysis (HD) are at increased risk of stroke compared with similarly aged people with normal kidney function. One concern is that treatment of renal anemia might increase stroke risk. We studied risk factors for stroke in a prespecified secondary analysis of a randomized, controlled trial of intravenous iron treatment strategies in HD.

Methods: We analyzed data from the Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL) trial, focusing on variables associated with risk of stroke. The trial randomized 2141 adults who had started HD <12 months earlier and who were receiving an erythropoiesis-stimulating agent (ESA) to high-dose IV iron administered proactively or low-dose IV iron administered reactively in a 1:1 ratio. Possible stroke events were independently adjudicated. We performed analyses to identify variables associated with stroke during follow-up and assessed survival following stroke.

Results: During a median 2.1 years of follow-up, 69 (3.2%) patients experienced a first postrandomization stroke. Fifty-seven (82.6%) were ischemic strokes, and 12 (17.4%) were hemorrhagic strokes. There were 34 postrandomization strokes in the proactive arm and 35 postrandomization strokes in the reactive arm (hazard ratio, 0.90; 95% confidence interval, 0.56 to 1.44; P=0.66). In multivariable models, women, diabetes, history of prior stroke at baseline, higher baseline systolic BP, lower serum albumin, and higher C-reactive protein were independently associated with stroke events during follow-up. Hemoglobin, total iron, and ESA dose were not associated with risk of stroke. Fifty-eight percent of patients with a stroke event died during follow-up compared with 23% without a stroke.

Conclusions: In patients on HD, stroke risk is broadly associated with risk factors previously described to increase cardiovascular risk in this population. Proactive intravenous iron does not increase stroke risk.Clinical Trial registry name and registration number: Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL), 2013-002267-25.

Keywords: administration; anemia; cardiovascular disease; dialysis; heart failure; hemodialysis; iron; randomized controlled trials; renal dialysis; stroke; survival.

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Conflict of interest statement

S.D. Anker reports grants and personal fees from Abbott Vascular, grants and personal fees from Vifor Int, personal fees from Bayer, personal fees from Boehringer Ingelheim, personal fees from Impulse Dynamics, personal fees from Novartis, personal fees from Servier, and personal fees from SJM outside the submitted work. P.S. Jhund reports advisory board fees and grants from Boehringer Ingelheim, speakers and advisory board fees from AstraZeneca, and speakers and advisory board fees from Novartis. P.A. Kalra reports grants from BergenBio, grants and personal fees from Astellas, grants and personal fees from Vifor, personal fees from AstraZeneca, personal fees from Bayer, personal fees from Boehringer Ingelheim, personal fees from MundiPharma, personal fees from Napp, personal fees from Novonordisk, and personal fees from Pharmacosmos outside the submitted work. P.B. Mark reports grants from Boehringer Ingelheim; personal fees from Astellas, AstraZeneca, Janssen, and Novartis; and personal fees and nonfinancial support from Napp, Pharmacosmos, and Vifor outside the submitted work. I.C. Macdougall reports personal fees from GlaxoSmithKline and Vifor Pharma. The employer of J.J.V. McMurray, the University of Glasgow, has been remunerated by Abbvie, Amgen, AstraZeneca, Bayer, Bristol Myers and Squibb, Cardiorentis, DalCor, GlaxoSmithKline, Kidney Research UK, Merck, Novartis, Oxford University/Bayer, Pfizer, Theracos, and Vifor-Fresenius. M.C. Petrie reported receiving lecture fees from AstraZeneca and Eli Lilly during the conduct of the study and personal fees from AstraZeneca, NAPP Pharmaceuticals, Novo Nordisk, and Takeda. A. Power reports personal fees from Bayer GmBH and personal fees from Vifor Fresenius Renal Pharma outside the submitted work. D.C. Wheeler has an ongoing consultancy contract with AstraZeneca and has received honoraria from Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Merck Sharp and Dohme, Mundipharma, Napp, Tricida, and Vifor Fresenius. C.G. Winearls is an employee of Pfizer. All remaining authors have nothing to disclose.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Cumulative incidence of stroke in the proactive (blue) and reactive (red) treatment groups accounting for the competing risk of nonstroke deaths. Between-group hazard ratio, 0.90; 95% confidence interval, 0.56 to 1.44; P=0.66.
See this image and copyright information in PMC

Comment in

References

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