Prise en charge des patients - PowerPoint Presentation

1. Prise en charge des patients insuffisants cardiaques ET insuffisants rénaux :un double enjeu relevé par les gliflozines ?Alexandre HERTIGNéphrologie, Dialyse, et Transplantation RénaleHôpital FOCH, Suresnesa.hertig@hopital-foch.com

2. Déclaration d’intérêtCette présentation a été contractualisée avec Astra Zeneca France

3. Reprenons le cas clinique fictif de Jean-Claude DibPatient de 75ansATCD de cardiopathie dilatée, non ischémiqueTraitement habituel : Ramipril 2,5mg, Bisoprolol 2,5mg, Furosemide 40mgConsulte pour dyspnée d’effort, Pas de signe de surcharge hydro sodée, TA 128/82ECG: R Sinusal 68/min, QRS 115msec (BBDt), HVG électriqueBiologie : HB 10,5gr, DFG 45ml/min, NTproBNP = 550 pg/mlETT: VG dilaté, FEVG 38%, IM minime, PAPS 45mm de Hg

4. Préjugé: néphropathie vasculaire (« néphro-angio-sclérose ») car: homme, âgé, insuffisant cardiaqueRecueil des signes négatifs: deux reins de contours réguliers et sans obstacle sur les voies urinairesAbsence de gammapathie monoclonaleÉchantillon urinaire: protéinurie < 0,5 gr/j et sédiment urinaire inactifP/C= 90 mg/0,894 g= 100 mg/g = 100 mg/j

5. Néphroprotection avant 2020 (retarder l’insuffisance rénale terminale)Traitement de la cause de la néphropathiePression artérielle systolique < 120 mm Hg (étude SPRINT1, KDIGO 20212)Consultation avec un(e) diététicien(ne): index de masse corporelle < 25 kg/m²apports protidiques < 0,8 g/kg/j éviction de la viande rougeEviction du tabac, des néphrotoxiques (AINS)Prise d’un inhibiteur de l’enzyme de conversion (et objectif P/C < 500 mg/g)N Engl J Med 2021; 384; 1921-1930Kidney Int (Suppl) 2021; 99: S1-S87

6. aDefined as ≥28 days; bESRD consisted of sustained eGFR below 15 mL/min/1.73m2, sustained dialysis or kidney transplantation. DAPA = dapagliflozin; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; HR = hazard ratio; PBO = placebo.Solomon SD et al. Presented at: ASN Kidney Week; November 5-10, 2019; Washington, DC. 2371227722012118197515371132600215Placebo2373229522272142200915701153622223DAPA 10 mgNumber at RiskDAPA 10 mgPlacebo01234503691215182124Months From RandomizationCumulative Percentage (%)OutcomeDAPA 10 mg, n (%)PBO, n (%)Renal Composite28 (1.2)39 (1.6)50% sustaineda decline in eGFR14 (0.6)23 (1.0)ESRDb16 (0.7)16 (0.7)Renal death01 (<0.1)Renal composite of ≥50% sustaineda decline in eGFR, ESRDb, or renal death HR 0.71 (0.44, 1.16)p=0.176Etude DAPA-HF Réduction numérique du composite d’événements rénaux

7. N Engl J Med 2020; 383: 1436-1446

8. DAPA-CKD:Dapagliflozin in Patients With Chronic Kidney Disease1,2aESKD defined as the need for maintenance dialysis (peritoneal or hemodialysis) for more than 28 days, renal transplantation or sustained eGFR <15mL/min/1.73m2 for at least 28 days.ACEi = angiotensin-converting enzyme inhibitor; ANCA = anti-neutrophil cytoplasmic antibody; ARB = angiotensin-receptor blocker; CKD = chronic kidney disease; CV = cardiovascular; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; hHF = hospitalization for heart failure; T1D = type 1 diabetes; T2D = type 2 diabetes; UACR = urinary albumin-to-creatinine ratio.1. Heerspink HJL et al. Nephrol Dial Transplant. 2020;35:274–282; 2. Heerspink HJL et al. N Engl J Med. 2020; 383:1436-1446.Composite of sustained ≥50% eGFR decline, ESKD, or renal death Composite of CV death or hHFAll-cause mortalitySecondary OutcomesDapagliflozin 10 mg + standard of carePlacebo + standard of care1:1Double-blindEnd PointsComposite of sustained  ≥50% eGFR decline, ESKDa, renal or CV death Primary Outcome4304 RandomizedMedian follow-up 2.4 yearsTo assess whether treatment with dapagliflozin, compared with placebo, reduced the risk of renal and CV events in patients with CKD with or without T2D, and who were receiving standard of care including a maximum tolerated dose of an ACEi or ARBObjective Key Inclusion Criteria≥18 years of ageeGFR ≥25 to ≤75 mL/min/1.73m2 UACR ≥200 to ≤5000 mg/gStable max tolerated dose of ACEi/ARB for ≥4 weeksWith and without T2DKey Exclusion CriteriaT1DPolycystic kidney disease, lupus nephritis, ANCA-associated vasculitisImmunosuppressive therapy ≤6 months prior to enrollment

9. Demographics and Baseline CharacteristicsaRace was reported by the investigators; the designation ‘other’ includes Native Hawaiian or other Pacific Islander; American Indian or Alaska Native and Other.BL = baseline.Heerspink HJL et al. N Engl J Med. 2020; 383:1436-1446.Dapagliflozin 10 mg (n=2152)Placebo (n=2152)Age, years, mean61.861.9Gender, female, %32.933.3Racea, %WhiteBlack or African-AmericanAsianOther52.24.834.88.154.24.033.48.4Weight, kg81.582.0Body mass index, kg/m229.429.6Current smoker, %13.214.0Blood pressure, mmHg, meanSystolic blood pressure136.7137.4Diastolic blood pressure77.577.5Hemoglobin, g/L128.6127.9Serum potassium, mEq/L4.64.6

10. Renal CharacteristicsCKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; UACR = urinary albumin-to-creatinine ratio.Heerspink HJL et al. N Engl J Med. 2020; 383:1436-1446.Dapagliflozin 10 mg (n=2152)Placebo (n=2152)eGFR, mL/min/1.73m2, mean 43.243.0eGFR ≥60 mL/min/1.73m2, %10.910.2eGFR 45 to <60 mL/min/1.73m2, %30.031.7eGFR 30 to <45 mL/min/1.73m2, %45.542.7eGFR <30 mL/min/1.73m2, %13.615.4UACR, mg/g, median965934UACR >1000 mg/g, %48.747.9

11. Medical History and Baseline MedicationsACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; BL = baseline; CKD = chronic kidney disease; CV = cardiovascular.Heerspink HJL et al. N Engl J Med. 2020; 383:1436-1446.Dapagliflozin 10 mg (n=2152)Placebo (n=2152)Type 2 diabetes, %67.667.4CV disease, %37.837.0Heart failure, %10.910.8Prior medication, %ACEi31.331.6ARB67.166.3Diuretic 43.144.3Statin64.865.0

12. Diabetes Status and Investigator-reported Cause of Kidney Diseaseat Baseline Wheeler DC et al. Nephrol Dial Transplant. 2020;35:1700–1711.58.3%Diabetes StatusInvestigator-reported Cause of Kidney Disease58.3%9.6%

13. Primary Composite Outcome: Sustained ≥50% eGFR Decline, ESKD, Renal or CV Deatha,1aESKD defined as the need for maintenance dialysis (peritoneal or hemodialysis) for at least 28 days and renal transplantation or sustained eGFR <15mL/min/1.73m2 for at least 28 days. Renal death was defined as death due to ESKD when dialysis treatment was deliberately withheld for any reason.3; b95% CI, 15 to 27.ARR = absolute risk reduction; CV = cardiovascular; DAPA = dapagliflozin;  eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; HR = hazard ratio; ; NNT = number needed to treat; RRR = relative risk reduction. 1. Heerspink HJL et al. N Engl J Med. 2020; 383:1436-1446; 2. Heerspink HJL. Presented at: ESC Congress – The Digital Experience; August 29 – September 1, 2020;3. Heerspink HJL et al. Nephrol Dial Transplant. 2020;35:274–282.21522001195518981841170112888313092152199319361858179116641232774270DAPA 10 mgPlaceboDAPA 10 mg197 eventsPlacebo312 events04812162024048121620242832Months from RandomizationCumulative Incidence %N at RiskNNT=19b39%​RRRDAPA9.2%Placebo14.5%HR (95% CI)0.61 (0.51-0.72)p-value20.0000000285.3% ARR

14. Statistical Significance Achieved for the Primary and All Secondary Outcomes1CV = cardiovascular; DAPA = dapagliflozin; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; HF = heart failure. 1. Heerspink HJL et al. N Engl J Med. 2020; 383:1436-1446; 2. Heerspink HJL. Presented at: ESC Congress – The Digital Experience; August 29 - September 1, 2020.Number of Events (%)HR (95% CI)DAPA 10 mg (n=2152)Placebo (n=2152)Hazard Ratio95% CIp-value2Primary Composite OutcomeComposite of ≥50% eGFR Decline, ESKD, and Renal or CV Death197 (9.2)312 (14.5)0.61(0.51, 0.72)<0.0001Secondary OutcomesComposite of ≥50% eGFR Decline, ESKD, or Renal Death142 (6.6)243 (11.3)0.56(0.45, 0.68)<0.0001Composite of CV Death or Hospitalization for HF100 (4.6)138 (6.4)0.71(0.55, 0.92)0.0089All-cause mortality101 (4.7)146 (6.8)0.69(0.53, 0.88)0.0035DAPA 10 mg BetterPlacebo Better

15. Exploratory Composite Outcome: Chronic Dialysis, Kidney Transplantation, or Renal Death1,2ARR = absolute risk reduction; DAPA = dapagliflozin; HR = hazard ratio; RRR = relative risk reduction. 1. Heerspink HJL. Presented at: ESC Congress – The Digital Experience; August 29 – September 1, 2020; 2. Heerspink HJL et al. Nephrol Dial Transplant. 2020;35:274–282.21522035202120041977188714819853732152203120061971193618491444955356DAPA 10 mgPlaceboDAPA 10 mg71 eventsPlacebo103 events0246810048121620242832Months from RandomizationCumulative Incidence %N at Risk34%​RRRDAPA3.3%Placebo4.8%HR (95% CI)0.66 (0.49-0.90)p-value0.00721.5% ARR

16. Primary Composite Outcome of Sustained ≥50% eGFR Decline, ESKD, or Renal or Cardiovascular Death by Baseline History of HF16eGFR = estimated glomerular filtration rate; ESKD = end stage kidney disease; HF = heart failure.McMurray JJV et al. Published online ahead of print August 23, 2021. JACC Heart Fail. 2021. doi: 10.1016/j.jchf.2021.06.017. Subgroup – Baseline History of HFHazard Ratio, 0.62 (95% CI, 0.51-0.75)PlaceboDapagliflozin191717731732163815171143735278191917691720159414771090693239DapagliflozinPlaceboNo at Risk16831651Hazard Ratio, 0.58 (95% CI, 0.37-0.91)PlaceboDapagliflozin23522822320318414596312332242161971871428131DapagliflozinPlaceboNo at Risk215207No History of Heart FailureHistory of Heart FailureMonths Since RandomizationCumulative Incidence (%)04121620242832801553510203025Months Since RandomizationCumulative Incidence (%)04121620242832801553510203025p-interaction=0.59

17. Comment ça marche ?

18. Change from Baseline in eGFR1,218BL = baseline; DAPA= dapagliflozin; eGFR = estimated glomerular filtration rate; PBO = placebo. 1. Heerspink HJL et al. N Engl J Med. 2020; 383:1436-1446; 2. Toto R. Presented at: ASN – Kidney Week 2020; October 22 – October 25, 2020.04812162024283236-15-10-50Months Since RandomizationLeast-Squares Mean Change in eGFR (mL/1.73m2)No. of PatientsDapagliflozin21522031200118961832178517051482978496157Placebo21522029198118661795175316721443935447157Total eGFR slope difference: 0.93mL/min/1.73m2/year (95% CI, 0.61, 1.25)Chronic eGFR slope difference: 1.92 mL/min/1.73m2/year (95% CI, 1.61, 2.24)PBO Chronic: –3.59 ± 0.11 mL/min/1.73m2/yearDAPA Chronic: –1.67 ± 0.11 mL/min/1.73m2/yearPBO eGFR change from baseline to Week 2:–0.82 ± 0.15 mL/min/1.73m2DAPA eGFR change from baseline to Week 2:–3.97 ± 0.15 mL/min/1.73m2

19. Change in Albuminuria in the Overall Population CI = confidence interval; IQR = interquartile range; UACR = urinary albumin-to-creatinine ratioJongs N et al. Presented at: ERA-EDTA Congress; June 5-8, 2021; Virtual.Mean reduction in UACR dapagliflozin vs. placebo: 29.3% (95% CI 25.2, 33.1); p<0.001Dapagliflozin 2152208520472048194318841843177816311172692233Placebo 2152209020542033190918541818174815811135640229Median (IQR) baseline UACR, mg/g Dapagliflozin: 965 (472–1903) Placebo: 934 (482–1868)Dapagliflozin 10 mg42.9% reductionPlacebo19.2% reduction0-60-40-20048121620242832Time, monthsAdjusted Mean Change in UACR, % (95% CI)236Exploratory analysis – Albuminuria

20. DAPAGLIFLOZINEAspects réglementaires en néphrologie (patient MRC, DFG > 25 ml/min)Octobre 2020PublicationDAPA-CKD5 août 2021AMM européenneMRC31 août 202110 mg, une fois par jour

21. Néphroprotection en 2021 (retarder l’insuffisance rénale terminale)Traitement de la cause de la néphropathiePression artérielle systolique < 120 mm Hg (étude SPRINT1, KDIGO 20212)Consultation avec un(e) diététicien(ne): index de masse corporelle < 25 kg/m²apports protidiques < 0,8 g/kg/j éviction de la viande rougeEviction du tabac, des néphrotoxiques (AINS)Prise d’un inhibiteur de l’enzyme de conversion (et objectif P/C < 500 mg/g)Prise de dapagliflozine, 10 mg/j3N Engl J Med 2021; 384; 1921-1930Kidney Int (Suppl) 2021; 99: S1-S87N Engl J Med 2020; 383: 1436-1446