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Serum creatinine elevation after renin-angiotensin system blockade and long term cardiorenal risks: cohort study

BMJ 2017; 356 doi: https://doi.org/10.1136/bmj.j791 (Published 09 March 2017) Cite this as: BMJ 2017;356:j791

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Re: Serum creatinine elevation after renin-angiotensin system blockade and long term cardiorenal risks: cohort study

In an observational study using a primary care dataset, Schmidt and colleagues concluded that increases in creatinine after the start of an angiotensin converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) “were associated with adverse cardiorenal outcomes in a graduated relation, even below the guideline recommended threshold of a 30% increase for stopping treatment”.1 In the accompanying “What this study adds” box, the authors also state “Increases in creatinine after starting ACEI/ARB treatment identify a high-risk group needing close monitoring and in whom the risks and benefits of ACEI/ARB prescribing should be considered”.1 We are very concerned that these statements based on non-randomized, non-placebo controlled, data are misleading and by encouraging inappropriate discontinuation of renin-angiotensin blocking drugs could endanger patients’ lives.

There is a wealth of data from clinical trials, little of which is cited by the authors, showing that despite commonly causing a small increase in creatinine, ACEI/ARBs improve survival (and reduce hospital admission rates) in patients with heart failure with reduced ejection fraction (and allied conditions such as myocardial infarction).2-4 In these studies, a rise in creatinine occurring on a renin-angiotensin blocker did not carry the same adverse prognostic significance as a rise occurring on placebo, a distinction that was not (and could not have been) examined by Schmidt and colleagues in an observational dataset. 2-4 Moreover, there is a difference between patients in whom renin-angiotensin blockers are life-saving and those in whom they are not, for example, heart failure with preserved ejection fraction (Schmidt et all did not examine the indications for renin-angiotensin blocker treatment in their analysis). 2-4 We believe doctors should continue to follow international guidelines based upon solid evidence from randomized controlled trials. 5 In this way, patients will receive the best treatments shown to improve clinical outcomes.

1: Schmidt M, Mansfield KE, Bhaskaran K, Nitsch D, Sørensen HT, Smeeth L, Tomlinson LA. Serum creatinine elevation after renin-angiotensin system blockade and long term cardiorenal risks: cohort study. BMJ. 2017 Mar 9;356:j791.

2: Testani JM, Kimmel SE, Dries DL, Coca SG. Prognostic importance of early worsening renal function after initiation of angiotensin-converting enzyme inhibitor therapy in patients with cardiac dysfunction. Circ Heart Fail. 2011;4:685-91.

3: Vardeny O, Wu DH, Desai A, Rossignol P, Zannad F, Pitt B, Solomon SD; RALES Investigators.. Influence of baseline and worsening renal function on efficacy of spironolactone in patients With severe heart failure: insights from RALES (Randomized Aldactone Evaluation Study). J Am Coll Cardiol. 2012;60:2082-9.

4: Beldhuis IE, Streng KW, Ter Maaten JM, Voors AA, van der Meer P, Rossignol P, McMurray JJ, Damman K. Renin-Angiotensin System Inhibition, Worsening Renal Function, and Outcome in Heart Failure Patients With Reduced and Preserved Ejection Fraction: A Meta-Analysis of Published Study Data. Circ Heart Fail. 2017;10. pii: e003588.

5: Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P; Authors/Task Force Members.; Document Reviewers. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18:891-975.

Competing interests: John McMurray - none Paul Kalra - receipt of grants/research supports: Pharmacosmos, Alere, Servier; receipt of honoraria or consultation fees: Alere, Amgen, BMS, Jannsen, Novartis, Pfizer, Pharmacosmos, Servier, Vifor Iain Squire - honoraria from Novartis for participation in educational events and advisory boards; received support for the conduct of clinical trials from Novartis

28 June 2017
John JV McMurray
Professor in Medical Cardiology
Paul Kalra, Iain Squire,
University of Glasgow
126 University Place, Glasgow, G12 8TA