Pitfalls in Using Estimated Glomerular Filtration Rate Slope as a Surrogate for the Effect of Drugs on the Risk of Serious Adverse Renal Outcomes in Clinical Trials of Patients With Heart Failure

HomeCirculation: Heart FailureVol. 14, No. 6Pitfalls in Using Estimated Glomerular Filtration Rate Slope as a Surrogate for the Effect of Drugs on the Risk of Serious Adverse Renal Outcomes in Clinical Trials of Patients With Heart Failure Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessArticle CommentaryPDF/EPUBPitfalls in Using Estimated Glomerular Filtration Rate Slope as a Surrogate for the Effect of Drugs on the Risk of Serious Adverse Renal Outcomes in Clinical Trials of Patients With Heart Failure Milton Packer, MD Milton PackerMilton Packer Correspondence to: Milton Packer, MD, Baylor Heart and Vascular Institute, 621 N. Hall St, Dallas, TX 75226. Email E-mail Address: [email protected] https://orcid.org/0000-0003-1828-2387 Baylor University Medical Center, Dallas, TX. Imperial College, London, United Kingdom. Search for more papers by this author Originally published15 Jun 2021https://doi.org/10.1161/CIRCHEARTFAILURE.121.008537Circulation: Heart Failure. 2021;14:e008537Both type 2 diabetes and chronic heart failure increase the risk of serious adverse renal outcomes, and the onset of kidney failure is generally preceded by a progressive decline in estimated glomerular filtration rate (eGFR). Long-term treatment with inhibitors of the renin-angiotensin system, neprilysin, and the SGLT2 (sodium-glucose cotransporter 2) slows the rate of decline in eGFR, and these drugs decrease the risk of end-stage renal disease in certain populations. This apparent parallelism has led some investigators to propose that drug-induced changes in rate of decline in eGFR might represent a surrogate for the effect of a drug to reduce the risk of end-stage renal disease.1The rate of decline in eGFR is commonly assessed by the measurement of eGFR slope, but this calculation is fraught with methodological difficulties. Estimation of slope relies on statistical models that make assumptions about linearity and are typically skewed by values measured late in the course of follow-up. However, the patients who provide data at late time points are those who were first recruited into the trial, and they represent a small fraction of those with baseline values (Figure). Furthermore, slope can be reliably calculated only over meaningful periods of time (about 3–5 years).1 However, many trials in heart failure have a median duration of follow-up of <18 months.Download figureDownload PowerPointFigure. Treatment effects on glomerular filtration rate and serious adverse renal outcomes in the EMPEROR-Reduced trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced] trial). Shown are the changes in eGFR (estimated glomerular filtration rate; left) and the occurrence of serious adverse renal outcomes (right) in the placebo and empagliflozin groups in the EMPEROR-Reduced trial. Serious adverse renal outcomes included chronic dialysis, renal transplantation, and sustained profound decreases in renal function. CI indicates confidence interval; HR, hazard ratio.Influence of Direct Intrarenal Effects of DrugsThe meaningfulness of eGFR slope is confounded by the fact that certain decreases in eGFR do not represent an irreversible loss of functioning renal mass. For example, SGLT2 inhibitors produce an immediate decrease in eGFR, which has been attributed to an intrarenal hemodynamic action to lower intraglomerular filtration pressures, an effect that is maintained for the duration of treatment. This lowering of intraglomerular filtration pressures is not a form of kidney injury and does not presage renal failure; withdrawal of the SGLT2 inhibitor reverses the effect, even after many years of treatment.2,3 However, every measurement of eGFR during treatment with a SGLT2 inhibitor is the net result of (1) the reversible intrarenal hemodynamic effect and (2) the effect of treatment on the progression of kidney disease. Therefore, during SGLT2 inhibition, the intrarenal hemodynamic effect biases every measurement of eGFR.The importance of this bias is well-illustrated by a side-by-side comparison of changes in eGFR and serious adverse renal outcomes in the same trial. In the EMPEROR-Reduced trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced] trial), the influence of the intrarenal hemodynamic effect of empagliflozin on eGFR (estimated by the decline in eGFR during the first 4 weeks of treatment) was sufficiently large that eGFR in the empagliflozin group was lower than in the placebo group for the first 18 months of double-blind therapy.3 Yet, empagliflozin reduced the risk of serious adverse renal outcomes by 50% (95% CI, 33%–68%), and the event curves separated meaningfully after 7 months. Therefore, empagliflozin prevented the onset of kidney failure for a period of almost 1 year during which eGFR was lower in the empaglifozin group than in the placebo group (Figure).Exclusion of Early Changes in eGFR From the Calculation of SlopeInvestigators have attempted to correct for the bias created by the initial reversible effects of drugs by excluding the early values in their calculation of slope. The baseline used for the calculation of eGFR slope is not assessed at randomization, but instead, relies on a postrandomization value performed after 1 to 4 months of treatment.3,4However, such an approach has its own biases. First, the use of a postrandomization value for baseline results in a loss of the protection provided by the randomization process. Second, by eliminating the initial decline from the calculation of eGFR slope, the slope is artifactually flattened, which serves to exaggerate the magnitude of the treatment effect and disrupts the ability to use a drug’s effect on eGFR slope to predict the drug’s effect to prevent serious renal outcomes. For example, neprilysin inhibition in the PARAGON-HF trial (Efficacy of LCZ696 Compared to Valsartan on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF] trial) produced an effect to reduce the risk of serious adverse renal outcomes that was similar in magnitude to that seen with SGLT2 inhibition in the EMPEROR-Reduced trial (ie, ≈50% reduction in risk).2,5 Yet, when changes in eGFR slope were reported, the effect of empagliflozin to slow the decline in renal function was ≈2.5× larger than that of sacubitril/valsartan (1.7 versus 0.7 mL/min per 1.73 m2/y, respectively). This striking discrepancy demonstrates that the magnitude of the drug effect on eGFR slope cannot be used to predict the size of the drug’s effect to reduce the risk of clinically important kidney end points.To complicate matters further, the significance of early changes in eGFR may vary according the underlying disease. Inhibitors of the renin-angiotensin system produce a rapid early decline in eGFR in both type 2 diabetes and in chronic heart failure. In diabetic patients, the decline alleviates glomerular hyperfiltration and (when sustained) contributes to the prevention of diabetic nephropathy.6 However, in heart failure, the decline in eGFR with angiotensin-converting enzyme inhibitors may be sufficient to precipitate acute renal failure,7,8 and there is no evidence that long-term treatment with these drugs reduces the risk of end-stage kidney disease in patients with heart failure.9 Any calculation of eGFR slope that ignores early changes in eGFR produced by an inhibitor of the renin-angiotensin system would flatten the eGFR slope, yielding the false impression that these drugs are nephroprotective in heart failure. Similarly, mineralocorticoid receptor antagonists reduce serious renal outcomes in patients with diabetes but can worsen renal function in chronic heart failure.4,10ConclusionsDespite its appeal, the estimation of eGFR slope as a surrogate for the progression of kidney disease is problematic, especially if the calculation ignores the early effects of treatment. These difficulties may be particularly important in patients with heart failure, who may be adversely affected by early changes in eGFR produced by some classes of drugs and in whom complexities of the eGFR calculation related to a relatively short follow-up period are compounded by the fact that the steepness of slope is strongly influenced by values measured in a small and biased fraction of the initial cohort.Disclosures Within the past 3 years, Dr Packer has received consulting fees from Abbvie, Akcea, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, Lilly, Novartis, Moderna, ParatusRx, Pfizer, Relypsa, Sanofi, Synthetic Biologics and Theravance.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Disclosures, see page 736.Correspondence to: Milton Packer, MD, Baylor Heart and Vascular Institute, 621 N. Hall St, Dallas, TX 75226. Email milton.[email protected]eduReferences1. Inker LA, Heerspink HJL, Tighiouart H, Levey AS, Coresh J, Gansevoort RT, Simon AL, Ying J, Beck GJ, Wanner C, et al.. GFR slope as a surrogate end point for kidney disease progression in clinical trials: a meta-analysis of treatment effects of randomized controlled trials.J Am Soc Nephrol. 2019; 30:1735–1745. doi: 10.1681/ASN.2019010007CrossrefMedlineGoogle Scholar2. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B; EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes.N Engl J Med. 2016; 375:323–334. doi: 10.1056/NEJMoa1515920CrossrefMedlineGoogle Scholar3. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, et al.; EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure.N Engl J Med. 2020; 383:1413–1424. doi: 10.1056/NEJMoa2022190CrossrefMedlineGoogle Scholar4. Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, Kolkhof P, Nowack C, Schloemer P, Joseph A, et al.; FIDELIO-DKD Investigators. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.N Engl J Med. 2020; 383:2219–2229. doi: 10.1056/NEJMoa2025845CrossrefMedlineGoogle Scholar5. Mc Causland FR, Lefkowitz MP, Claggett B, Anavekar NS, Senni M, Gori M, Jhund PS, McGrath MM, Packer M, Shi V, et al.. Angiotensin-neprilysin inhibition and renal outcomes in heart failure with preserved ejection fraction.Circulation. 2020; 142:1236–1245. doi: 10.1161/CIRCULATIONAHA.120.047643LinkGoogle Scholar6. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345:851–860. doi: 10.1056/NEJMoa011303CrossrefMedlineGoogle Scholar7. McMurray J, Matthews DM. Reversible renal failure after combined treatment with enalapril and frusemide in a patient with congestive heart failure.Br Heart J. 1986; 56:490. doi: 10.1136/hrt.56.5.490-aCrossrefMedlineGoogle Scholar8. Stewart JT, Lovett D, Joy M. Reversible renal failure after combined treatment with enalapril and frusemide in a patient with congestive heart failure.Br Heart J. 1986; 56:489–490.CrossrefMedlineGoogle Scholar9. McCallum W, Tighiouart H, Ku E, Salem D, Sarnak MJ. Trends in kidney function outcomes following RAAS inhibition in patients with heart failure with reduced ejection fraction.Am J Kidney Dis. 2020; 75:21–29. doi: 10.1053/j.ajkd.2019.05.010CrossrefMedlineGoogle Scholar10. 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; 60:2082–2089. doi: 10.1016/j.jacc.2012.07.048CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByInker L, Heerspink H, Vonesh E and Greene T (2022) Letter by Inker et al Regarding Article, “Pitfalls in Using Estimated Glomerular Filtration Rate Slope as a Surrogate for the Effect of Drugs on the Risk of Serious Adverse Renal Outcomes in Clinical Trials of Patients With Heart Failure”, Circulation: Heart Failure, 15:3, Online publication date: 1-Mar-2022. June 2021Vol 14, Issue 6Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.121.008537PMID: 34129360 Originally publishedJune 15, 2021 Keywordsglomerular filtration raterenin-angiotensin systemneprilysinkidneyheart failurePDF download Advertisement SubjectsHeart FailureQuality and Outcomes