Cardio-Renal Syndrome in Acute Heart Failure:

Transcription

1 Cardio-Renal Syndrome in Acute Heart Failure: Target for Therapy Marvin A. Konstam, M.D. Research support and/or consulting relevant to this lecture: Merck, Otsuka, Johnson & Johnson; Amgen; Cardiokine

2 Heart Failure: A Cardio-Renal-Vascular Syndrome Compliance and Contractilty HEART Pulmonary Congestion Systemic Congestion Functional Incapacity

3 % survival GFR and Survival: SOLVD GFR >75 GFR GFR < Follow-up (days) Al-Ahmad A et al. JACC. 2001;38:

4 Association Between egfr (CKD-EPI) and All-Cause Mortality in Patients with HF, Grouped by LVEF McAlister F A et al. Circ Heart Fail 2012;5:

5 Predictors of Renal Impairment During ARB Treatment: HEAAL Kiernan M et al. Eur J HF, 2012

6 Impact of Incident Adverse Events on Outcomes: HEAAL Kidney Impairment Hyperkalemia Hypotension HR (95% CI) p-value HR (95% CI) p- value HR (95% CI) p-value Death 2.36 (2.07, 2.70) < (1.47, 2.13) < (1.69, 2.38) <0.001 First Hospitalization 1.61 (1.40, 1.84) < (1.47, 2.14) < (1.14, 1365) <0.001 Death or First Hospitalization 1.63 (1.44, 1.85) < (1.44, 2.05) < (1.11, 1.56) *Model includes variables corresponding to age, gender, aldosterone blocker use, associated baseline laboratory value, and ACEi indicators. Kiernan M et al. Eur J HF, 2012

7 ADHERE CART: Predictors of In-Hospital Mortality Less than BUN 43 N = 33,324 Greater than 2.68% n = 25, % n = 7202 SYS BP 115 n = 24,933 SYS BP 115 n = % n = % n = 20, % n = % n = 5102 Highest to Lowest Risk Cohort OR 12.9 (95% CI ) Cr % n = % n = 620 Fonarow GC et al. JAMA 2005; 293:

8 Baseline Kidney Function as Predictor of CV Mortality/HF Hospitalization Creatinine BUN 3-months Overall 2 nd vs 1 st quartile 1.32 ( ) 1.10 ( ) 3 rd vs 1 st quartile 1.55 ( ) 1.37 ( ) 4 th vs 1 st quartile 1.68 ( ) 1.50 ( ) 3 months Overall 2 nd vs 1 st quartile 1.15 ( ) 1.08 ( ) 3 rd vs 1 st quartile 1.25 ( ) 1.20 ( ) Adjusted for: Age, Race, Region, HF hospitalization, Previous MI, Diabetes, Dyspnea, NYHA Class, ACE/ARB, Beta Blockers, Systolic BP, EF, Serum Sodium, BNP, Pro-BNP, QRS Duration, and Atrial Fibrillation on admission Gheorghiade M, et al: ESC, th vs 1 st quartile 1.50 ( ) 1.60 ( ) 10

9 Post-discharge Kidney Function Change and Outcomes BUN BUN < 25% increase N = 2776 (79.3%) BUN 25% increase N = 725 (20.7%) Adjusted HR (95% CI) Death 542 (19.5%) 195 (26.9%) 1.25 ( ) CV Death/HF Hospitalization 1045 (37.6%) 325 (44.8%) 1.17 ( ) Cr BUN/Cr egfr Cr < 25% increase N = 3159 (90.2%) Cr 25% increase N = 345 (9.8%) Adjusted HR (95% CI) Death 636 (20.1%) 103 (29.9%) 1.37 ( ) CV Death/HF Hospitalization 1203 (38.1%) 168 (48.7%) 1.29 ( ) BUN/ Cr < 25% increase N = 2852 (81.5%) BUN/Cr 25% increase N = 648 (18.5%) Adjusted HR (95% CI) Death 563 (19.7%) 174 (26.9%) 1.30 ( ) CV Death/HF Hospitalization 1097 (38.5%) 272 (42.0%) 1.05 ( ) egfr < 25% decrease N = 3229 (92.2%) egfr 25% decrease N = 273 (7.8%) Adjusted HR (95% CI) Death 649 (20.1%) 89 (32.6%) 1.49 ( ) CV Death/HF Hospitalization 1233 (38.2% 137 (50.2%) 1.31 ( ) 11 Gheorghiade M, et al: ESC, 2008

10 Possible Mechanisms Linking Renal Function and Survival in Heart Failure A B Survival Survival HF Kidney Injury GFR HF Kidney Injury GFR Treatment RAS Inhibition Konstam MA. Circ Heart Fail (6):677-9.

11 Cardio-Renal Mechanisms in Acute Heart Failure Right Heart Dysfunction Ventricular Shift + Pericardial Constraint Left Heart Dysfunction LVEDP Vasodilation and Natriureisis Down Regulation NP Receptors CVP SV CO Kinnin NP NO Prostacy clin Renal Vein Pressure Vasopres sin RAAS SNS Vasoconstriction & Sodium + Water Retention ET-1 Inflamm ation Adenosine RAAS and SNS response overwhelms NP and NO response Interstial Edema Decreased Renal Perfusion / Ischemia Acute Kidney Injury Intrinsic Renal Disease NSAIDs RAS ACE-I ARB Contrast Kiernan MS, Udelson JE, Sarnak M, Konstam MA: Cardiorenal syndrome UpToDate, 2011

12 Figure 1. Admission-to-discharge percentage change in GFR grouped by presence or absence of hemoconcentration. Testani J M et al. Circulation 2010;122: Copyright American Heart Association

13 drops/min mg/dl mmhg Renal Vein Pressure and Function in Canine Kidney Renal vein pressure BUN Urine output Time (min) Adapted from Wencker D, Curr HF Reports 2007;4:134-8; Winton FR. J Physiol 1931;72:49-61 & 73:151-12

14 Renal Function Tends to Improve in Patients with RV Dysfunction Testani JM et al. Am J Cardiol 2010;105:

15 Diuretic Resistance in Heart Failure and Kidney Failure Ellison DH. Cardiology 2001; 96:

16 All Rights Reserved, Duke Medicine 2007 HF Network 1.0 HF Network 2.0

17 DOSE Trial Patients' Global Assessment of Symptoms during the 72-Hour Study-Treatment Period. Felker GM et al. N Engl J Med 2011;364:

18 Furosemide Dosing and Renal Function: DOSE Trial Felker GM et al. N Engl J Med 2011;364:

19 Safety End Points: Change in Serum Creatinine

20 CARRESS-HF Randomized trial to evaluate the effects of ultrafiltration vs. stepped pharmacologic care in ADHF with cardiorenal syndrome Primary endpoint: Change in serum creatinine and weight assessed at 96 hrs considered together as a bivariate outcome All Rights Reserved, Duke Medicine 2007

21 Role of Low-Dose Dopamine Patients with AHF(n=60); post 40 mg furosemide bolus HDF = Furosemide 20mg/hr LDFD = Furosemide 5mg/hr + Dopamine 5μg kg-1 min-1 Giamouzis G, et al, J Cardiac Fail 2010;16:

22 ROSE - AHF Population: Acute heart failure with renal dysfunction Intervention: Three-arm trial comparing low-dose dopamine vs. placebo and low-dose nesiritide vs. placebo Study Design: Randomized, double-blind, placebo-controlled trial to evaluate 1) low-dose dopamine and 2) low-dose nesiritide for enhancing renal function in patients with acute heart failure and renal dysfunction Primary endpoints: Safety: change in Cystatin C from randomization to 72 hours Efficacy: cumulative urinary volume at 72 hours All Rights Reserved, Duke Medicine 2007

23 3 Renal Sites of Action of A 1 Adenosine Antagonists Effects of Blockade of Renal A 1 Adenosine Receptors 1 Afferent Arteriole 2 Proximal tubule 3 Distal Tubule Improves renal function Promotes K+ neutral natriuresis

24 Renal Function A 1 Adenosine Antagonists in CHF INVESTIGATIONAL BG9719 prevents reduction of renal function caused by diuretic therapy via interruption of TGFand augments natriuresis via effect on tubules (% change in CrCl) (1-8 hours) Renal Output Urine Volume ( ml) (0-8 hours - chg -base) N = 31 BG9719 dose 0.75 ugm/ml All patients on ACEi Placebo BG9719 Alone Furosemide BG Furosemide (Gottlieb et al, Circulation 2002)

25 PROTECT INVESTIGATIONAL Trial design: Patients with AHF were randomized in a double-blind manner to rolofylline 30 mg/day (n = 1,356) or placebo (n = 677). Treatment was administered as a 4-hour daily infusion and repeated for 3 days. % ,2 (p = NS) 44,5 (p = NS) Results Moderate or marked dyspnea improvement at 24 and 48 hours: 51.2% with rolofylline vs. 44.5% with placebo Death by 7 days: 1.7% vs. 2.1% HF readmission by 7 days: 0.4% vs. 0.6% Persistent renal impairment: 12.7% vs. 11.1% 15 12,7 11,1 Conclusions 0 Dyspnea improvement at 24 & 48 hours Persistent renal impairment Among patients with acute heart failure, composite outcomes were similar with rolofylline vs. placebo Due to lack of efficacy, research on rolofylline has been discontinued by the study sponsor Rolofylline Placebo Presented by Dr. Marco Metra at ESC 2009

26 Arginine Vasopressin 4 Median Plasma AVP (pg/ml) in SOLVD Trial V 1a V 2 Blood vessels Myocardium Renal tubules 0 Control Prevention Treatment ( ) ( ) ( ) Tolvaptan Francis et al. Circulation 1990;82:

27 % Change vs Placebo Effects of Tolvaptan and Furosemide on GFR, ERPF, and RBF 10 * * TLV FURO GFR (ml/min) ERPF (ml/min) RBF (ml/min) * ** Burnett et al, 2003 * P < 0.05 vs. Placebo; **P < vs. Placebo

28 Secondary Endpoints: Day 1 Δ in BW (kg) 1.7 ± 1.8 Trial A 1.0 ± ± 2.0 Trial B Tolvaptan Placebo Tolvaptan Placebo Difference 0.7 kg 0.9 kg 0.9 ± 1.9 Both trials P<0.001 Improved Δ in Dyspnea (% of pts with baseline dyspnea) worsened Tolvaptan Placebo Tolvaptan Placebo (n=894) (n=915) (n=941) (n=914) Both trials P<0.001 Markedly better Moderately better Minimally better Worse INVESTIGATIONAL

29 Proportion Alive Proportion Without Event All-Cause Mortality Primary End Points CV Mortality or HF Hospitalization HR 0.98; 95%CI ( ) Meets criteria for non-inferiority HR 1.04; 95%CI ( ) Median follow-up: 9.9 mos Peto-Peto Wilcoxon Test: P= TLV 30 mg PLACEBO TLV Peto-Peto Wilcoxon Test: P= TLV 30 mg PLACEBO TLV PLC PLC Months In Study Months In Study

30 Changes in Renal Function 8 6 Inpatient Outpatient INVESTIGATIONAL BUN (mg/dl) Day Day 7 or Discharge TLV PLC Tolvaptan Placebo Serum Cr (mg/dl) Day Day 7 or Discharge TLV PLC Inpatient After Discharge (wk)

31 SECRET of CHF TRIAL The Study to Evaluate Challenging REsponders to Therapies for decongestion in Heart Failure Trial Multi-center, randomized, double-blind, placebo-controlled trial to assess the effects of vasopressin receptor antagonism (30 mg q.d. of tolvaptan) on dyspnea in patients hospitalized for worsening HF, who have any of: Hyponatremia Renal insufficiency Inadequate initial diuretic response

32 The Cardio-Renal Syndrome in Acute Heart Failure: Conclusions Abnormal and worsening renal function are adverse prognostic markers. Nevertheless, WRF should not unduly deter use of evidence-based Rx. Complex mechanisms contribute to renal impairment in HF Reduced cardiac output and renal hypoperfusion Elevated CVP and renal venous congestion Neurohormonal activation CRS contributes to diuretic resistance. Conversely, volume correction impacts renal function in complex ways Pharmacologic approaches to renal impairment have promise, but have not yet yielded clear benefit. Renal injury and dysfunction remain important treatment targets.