Novel treatments and update in Heart Failure in CKD

Transcription

1 Cardiovascular Disease Mortality General Population vs ESRD Dialysis Patients Novel treatments and update in Heart Failure in CKD Annual CVD Mortality (%) 100 David Goldsmith, London, UK 10 GP Male 1 GP Female GP Black GP White 0.1 Dialysis Male Dialysis Female 0.01 Dialysis Black Dialysis White >85 Age (years) RENAL UPDATE MEETING UTRECHT, NETHERLANDS, GP: General Population. Foley RN, et al. Am J Kidney Dis. 1998;32:S112-S119. USRDS 2004 Cause-specific mortality GUSTAV KLIMT (c.1915) LEOPOLD MUSEUM Tod und Leben Causes of death (%) for all dialysis patients by age years Rate: 95 deaths/103 patient years WIEN, AUSTRIA years Rate: 173 deaths/103 patient years Cardiac arrest Acute MI Heart failure and other cardiac Cerebrovascular Non-cardiac years Rate: 341 deaths/103 patient years USRDS. AJKD,

2 CV, cardiovascular; NCDs, non-communicable diseases World Health Organization Noncommunicable Diseases Country Profiles 2014 (accessed on on ) a Dec lining trends in the number of crude and age-adjusted rates for heart failure deaths from 2000 through 2009 were statistically significant (P<0.05) and their increases from 2009 to 2014 were also significant (P<0.05); b Declining trend in the age-adjusted rate for heart failure-related deaths from 2000 through 2012 was statistically significant (P<0.05); c Increase in the age-adjusted rate from 2012 through 2014 was significant (P<0.05) CV, cardiovascular NCHS Data Brief (No. 231, Dec 2015), Recent Trends in Heart Failure-related Mortality: United States, Accessed on gov/nchs/data/ databriefs/ db231.pdf on SCD in CKD Latest (2017) statistics show HF rising incidence The number of adults living with heart failure increased from about 5.7 million ( ) to about 6.5 million ( ), according to the American Heart Association s 2017 Heart Disease and Stroke Statistics Update. The number of people diagnosed is projected to rise by 46% by 2030, resulting in >8 million adults in the USA with heart failure. Cardiovascular diseases were the most common cause of death in the world as of 2013, claiming about 17.3 million lives. In the United States, 92.1 million adults have cardiovascular diseases, accounting for 807,775 deaths in About 790,000 people in the US have heart attacks each year Circulation. 2017;CIR Originally published January 25, 2017 United States of America Total population: 318,000,000 Income group: high Age-standardized death rates Age-standardized death rate per 100, Males Females 27 30% lowering of CV death rates! Percentage of population living in urban areas: 82.4% Population proportion between ages 30 and 70 years: 50.3% Proportion mortality (% of total deaths, all ages, both sexes) Cardiovascular diseases Chronic respiratory diseases Cancers Diabetes Total deaths: 2,656,000 NCDs are estimated to account for 88% of total deaths 8 CV Deaths in the USA Declined between 2000 and 2009, but Increased from Death rate (per 100,000 population) Number of crude and age-adjusted rates for heart failure-related deaths: USA, Heart failure-associated death rates Crude rate in the USA have begun a to rise! Age-adjusted rate b,c Deaths a Number of deaths (thousands)

3 LVH CKD and LVF BUT IN CKD. HISTORY OFTEN ATYPICAL OR ABSENT - DIABETES FLUID EXCESS, OR, LV DISEASE? Pro-NT BNP very sensitive to GFR LVH ubiquitous both concentric and dilated Pre dialysis to Post dialysis changes can be major: Dialysis LV stunning Patrient status Health impact Up to 50 % re-hospitalisation risk Up to 35% risk of death 1- year post discharge Impaired quality of life The Issue Major costs / hospitalisation Overall cost/ patient / y:

4 Causes of heart failure in CKD Hypertension (chronic), leading to dilated CM and decompensation Very like African American hypertension -> terminal heart disease Chronic fluid overload likely to be the same (major overlap) Gross elevation in arterial stiffness / afterload Maybe possibly a role for myocardial metabolism, and stunning Ischaemic burden Anaemia Valves Pericardium AVF likely role for CKD-MBD factors phosphate, FGF23 ANAEMIA (and IV iron) Diagnosis of heart failure in CKD Clinical (not specific, and sometimes, not sensitive) Biomarkers: serial measurements, baselines, can help but confounded Echocardiography, including lung comets (interstitial pulmonary fluid) Multi-frequency Bio-impedance (hydration, and fluid in compartments) Heart Failure reduced FSI or LVEF ( systolic ) Severe anaemia is an important, independent risk factor for the development of HF. Prior to the availability of ESAs, one study of 432 dialysis patients (mean baseline Hb level of 8.8 g/dl) found that each 1 g/dl lower Hb was associated with an higher odds of left ventricular dilatation (odds ratio [OR] 1.46), de novo HF (OR 1.28), and recurrent HF (OR 1.20) [6]. Foley RN, Parfrey PS, Harnett JD, et al. The impact of anemia on cardiomyopathy, morbidity, and and mortality in endstage renal disease. Am J Kidney Dis 1996; 28:53 Treatments and Interventions for heart failure in CKD Many available, but none overwhelming in impact Low sodium / good diuretics / dialysis to control hydration and BP Correct / reverse severe anaemia (Hb < 80 g/l) ACEi, ARB, MRA, BB (NOVEL Rx FEW DATA YET) ALL OF THE ABOVE MIGHT TEND TO ACT TO REVERSE LVH. SGLT2 inhibitors, in T2DM (and maybe others CKD)?? Cinacalcet?? Machines and Devices - cardiac?? Machines and Devices renal?? Heart Failure treatment with ESA EFFECT OF TREATMENT OF ANAEMIA Uncontrolled studies, none very recent, have described improvement in the clinical manifestations of HF after prolonged treatment of anaemia in CKD patients. As an example, in one study of 126 CKD patients with HF, an increase in the mean Hb level from 10.3 to 13.1 g/dl (with intravenous iron and ESAs) over a mean period of 12 months was associated with a rise in the mean left ventricular ejection fraction (33 to 40 percent), falls in the mean New York Heart Association (NYHA) class (3.8 to 2.7), and number of hospitalizations (3.7/patient to 0.2/patient) [7]. An index of fatigue and shortness of breath also fell significantly. Similar results were noted in another uncontrolled study that included 179 CKD patients with severe HF studied over a mean of nearly 12 months [8]. [7] Silverberg DS, Wexler D, Blum M, et al. Aggressive therapy of congestive heart failure and associated chronic renal failure with medications and correction of anemia stops or slows the progression of both diseases. Perit Dial Int 2001; 21 Suppl 3:S236. [8] Silverberg DS, Wexler D, Blum M, et al. The effect of correction of anaemia in diabetics and nondiabetics with severe resistant congestive heart failure and chronic renal failure by subcutaneous erythropoietin and intravenous iron. Nephrol Dial Transplant 2003; 18:141. 4

5 Heart Failure treatment with ESA / IV iron A systematic review of nine randomized trials of ESAs in HF, not all specifically in patients with CKD, concluded that anaemia treatment improved exercise duration and capacity, ejection fraction, NYHA class, quality-of-life indicators, and HF-related hospitalizations [9]. Another, more recent meta-analysis of randomized, controlled trials found that ESA treatment improved dyspnoea and NYHA class; there was no significant improvement in mortality or hospitalization, but there was increased risk of thromboembolic events [10]. Increased morbidity and/or mortality has been associated with attaining normal or near-normal Hb levels with ESAs. IV iron can improve 6 minute walking tests and QoL in HF patients, but NOT through any measured change in Hct [9] Kotecha D, Ngo K, Walters JA, et al. Erythropoietin as a treatment of anemia in heart failure: systematic review of randomized trials. Am Heart J 2011; 161:822. [10] Kang J, Park J, Lee JM, et al. The effects of erythropoiesis stimulating therapy for anemia in chronic heart failure: A meta-analysis of randomized clinical trials. Int J Cardiol 2016; 218:12 Empagliflozin wonder drug? Published in 2015, the multicentre Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial (EMPA-REG OUTCOME) randomized 7,020 patients to daily empagliflozin 10 or 25 mg or placebo. At 3.1 years of follow up, empagliflozin was associated with a reduction in CV mortality, nonfatal MI, or nonfatal stroke (10.5% vs. 12.1%; P=0.04; NNT 62), as well as a reduction in all-cause mortality (5.7% vs. 8.3%; P<0.001; NNT 38) and CV mortality (3.7% vs. 5.9%; P<0.001; NNT 45). The medication was generally well tolerated. There were no differences in UTI or sepsis of urinary origin between the groups though there was a greater incidence of genital infections with the medication (6.4% vs. 1.8%; P<0.001; NNH 22). Empagliflozin was associated with reduction in weight and SBP. Follow-up data published in 2016 showed that patients on empagliflozin had lower rates of new or worsening renal dysfunction compared to placebo (12.7% vs. 18.8%; P<0.001) NOVEL DRUGS FOR TYPE II DIABETES T2DM most deaths are CV Excess mortality in T2DM is largely related to an increased incidence of CV disease. In the 1998 UKPDS 34 study, metformin was associated with reduced all-cause mortality. The 2005 PROactive study not only failed to demonstrate a reduction in all-cause mortality with pioglitazone; the drug was associated with excess HF hospitalizations. Subsequent studies of newer agents, including the DPP-4 inhibitor sitagliptin (TECOS, 2015) and the GLP-1 inhibitor lixisenatide (ELIXA, 2015), have also been unable to demonstrate a significant improvement in cardiovascular outcomes among selected patients with T2DM. Interestingly, the level of HbA1c reduction with empagliflozin was modest at best (~ 0.5%). Given that multiple previous clinical trials: (ACCORD 2008, ADVANCE 2008, VADT 2009) did not demonstrate a reduction in major adverse cardiovascular events with intensive glucoselowering therapy, it remains unclear what mechanisms drive the benefits seen with empagliflozin. The additional benefits of weight loss, blood pressure reduction, and diuresis may be contributing factors. This theory is supported by the fact the reduction in cardiovascular deaths was partially driven by a reduction in deaths from heart failure, while rates of myocardial infarction remained similar. 5

6 CALCIMIMETICS TREATED WITH CINACALCET TREATED WITH PLACEBO 6

7 TREATED WITH CINACALCET ONLY HYPOTHESIS GENERATING A TRIAL IN HF PATIENTS ON DIALYSIS WOULD BE WORTH DOING ACEi, ARB, MRA (RAASi); BB; others. Side-effects / dose-limiting issues HYPOTENSION (10-20%) HYPERKALAEMIA (10-30%) WORSENING RENAL FUNCTION (20%) Not same populations: WRF BP K+ 7

8 RAAS, renin-angiotensin-aldosterone system Epstein M. Kidney Int Suppl 2016;6:20 28 Baseline variables were included as covariate Effect of Eplerenone on egfr in all patients Treatment with Renin-Angiotensin-Aldosterone System (RAAS) Inhibitors Reduce Water and Sodium, But Increase Potassium A 67,5 66,5 65,5 64,5 63,5 62,5 egfr (ml/min/1.73m²) * * * * * All patients - Eplerenone All patients - Placebo Renin Inhibitors Angiotensin I ACE Inhibitors Angiotensinogen K Retention Hyperkalaemia is an inherent risk in the treatment of HF with RAAS Inhibitors 61,5 60,5 Overall p< (mixed ANOVA) J0 M1 M3 M6 M12 M18 M24 VISIT Angiotensin II ARBs Na/Water Uptake Mineralcorticoid Receptor The mean annual subsequent changes in egfr were similar in the 2 treatment groups (eplerenone vs. placebo: vs ml/min/1.73 m2/year, p= 0.34), regardless of the presence or absence of CKD. Rossignol et al, Circulation, 2012 AT1 Receptor Aldosterone Production MRAs epv change (%) Eplerenone exerts an early (1-month) diuretic-like effect 0,0-0,5-1,0-1,5-2,0-2,5-3,0-3,5 M0 M1 M3 n =2826 n = 2796 Eplerenone Placebo n = 2580 n = 2557 Change at M1: p = Change x group: p < Rossignol P., Ménard J., Fay R., Gustafsson F., Pitt B., Zannad F JACC 2011 Hyperkalaemia Frequently Leads to Dose Reduction or Discontinuation of RAAS Inhibitor hyperkalaemia events (%) Observational study of 205,108 patients with 1 outpatient prescription for RAAS inhibitor Maximum-dose RAAS inhibitor Mild hyperkalaemia (K meq/l) 23,556 events Moderate-to-severe hyperkalaemia (K meq/l) 11,608 events Submaximum-dose RAAS inhibitor Maintained dose Down-titrated dose Discontinued Maintained dose Down-titrated dose Discontinued hyperkalaemia events (%) Mild hyperkalaemia (K meq/l) 85,567 events Moderate-to-severe hyperkalaemia (K meq/l) 43,170 events 47 New agents for hyperkalaemia Patiromer in Patients with Kidney Disease and Hyperkalemia Receiving RAAS Inhibitors Matthew R. Weir, M.D., George L. Bakris, M.D., and Bertram Pitt, M.D., for the OPAL-HK Investigators* N Engl J Med 2015; 372: January 15, 2015DOI: /NEJMoa Patiromer (Relypsa) CKD and Diabetic Nephropathy 52 weeks 8

9 ZS-9 Is a First-in-Class Selective Potassium Trap Ivrabadine ZS-9 Crystal Structure K + Average Width of Micropore Opening 3Å Z-9 PROPERTIES Unique microporous zirconium silicate compound Designed to be selective for K + trapping Insoluble and highly stable Non-systemically absorbed Builds on long history of Zr use in dialysis and other biomedical applications Long-term ZS-9 Data from Phase 3 Efficacy maintained at up to 52 weeks 0.7 to 1.0 mmol/l reduction across GFR range Safety 7% oedema rate, BP stable, GI disturbance < 10% In this case, the exchange is sodium for potassium, so, some positive sodium balance is expected using ZS-9 (not ideal). Ivrabadine (Corlanor TM) Titrate to achieve pulse rate of bpm some risk of AF (1 in 200 per year Rx) No change in PK / activity with GFR down to 15 mls/min No data for dialysis patients (but might be safe as not renally cleared) From the 6505 patients who were randomized in SHIFT, baseline creatinine and at least one follow-up measurement were available in 6160 patients. Median follow-up was 22.9 months. Worsening renal function (WRF) was defined as a creatinine increase of 0.3 mg/dl and 25% from the baseline value. WRF developed in 1029 (17%) patients and was directly related to baseline heart rate, with an incremental risk of 5% for every 5 b.p.m. heart rate increment (P=0.003). WRF was associated with an increased risk of the primary composite endpoint of hospitalization for worsening heart failure or cardiovascular death [hazard ratio (HR) 1.38, P<0.001] and of all-cause mortality (HR 1.42, P<0.001). Ivabradine use was associated with a reduction of the primary composite endpoint in patients both with (HR 0.82, P=0.023) and without renal dysfunction (HR 0.81, P<0.001) at baseline (P for interaction=0.89), and tolerability of ivabradine was comparable in the two groups. Amgen s Corlanor and Novartis Entresto are both twice-a-day pills that cost roughly $4,500 a year Amgen s Corlanor and Novartis Entresto are both twice-a-day pills that cost roughly $4,500 a year 9

10 Simplified schematic of the natriuretic peptide system (NPS). von Lueder T G et al. Circ Heart Fail. 2013;6: Copyright American Heart Association, Inc. All rights reserved. NEJM 9/11/2014 LCZ 696 Simplified schematic of the renin angiotensin aldosterone system. AROUND 20% BETTER von Lueder T G et al. Circ Heart Fail. 2013;6: Copyright American Heart Association, Inc. All rights reserved. 10

11 1.0 What about haemodialysis? FOSIDIAL Fosinopril Placebo p = NS days The Fosinopril in Dialysis Study failed to demonstrate the efficacy of 2-year angiotensin-converting enzyme inhibition with fosinopril versus placebo in 397 hemodialysis patients with left ventricular hypertrophy but provided an opportunity to assess the influence of BP variability on cardiovascular events. The primary end point was the occurrence of a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina, stroke, revascularization, hospitalization for heart failure, and resuscitated cardiac arrest Zannad F et al Kidney Int 2006 SIGNIFICANTLY FEWER EPISODES OF WRF USING LCZ696 vs ENALAPRIL in PARADIGM-HF STUDY French Ministry of Health grant, 2011 P. Rossignol (PI) and L. Frimat (co-pi) Z. Massy, G. London, F. Zannad et al Haemodialysis LVH, or LVEF <40% or diabetes, or history of CV events Placebo (n=375) Spironolactone 25 mg/d (n=375) MI, HF hospitalisation, stroke, or CV mortality DEVICES 11

12 LVADs - pumps Benefits of Beta-blockers in HD 114 patients on HD RCT followed for 24 months Cice JACC Dialysis for terminal / refractory heart failure 12

13 CARESS-HF, UNLOAD, RAPID-CHF SUMMARY AND CONCLUSIONS HF remains a serious public health challenge, especially in the context of chronic hypertension, and CKD Treatment remains unsatisfactory, with appreciable morbidity and mortality Especially so in CKD Diagnosis, investigation and treatment schedules and guidelines exist Though everything is much harder in CKD RAASi blockade and BB are pivotal interventions When these fail, Ivrabadine and Sacubitril-Valsartan are next medical Rx, and there are resynchronisers, and artificial LV assist pumps as a bridge to cardiac transplant What we can do about this in CKD depends on whether we can apply non-ckd evidence-based Rx at appropriate dosing (WKF, hyperkalaemia, low BP), perhaps mitigating some of these concerns new potassium-removing agents We lack proper RCTs of these interventions in CKD and in dialysis patients Better BP management, and volume management, might help in prevention Novel agents, possibly, might help: Calcimimetics, SGLT2 inhibitors (but not Vit D) Not (yet) mainstream Rx Standard x 3/wk HD rarely enhances QoL Dialysis access, infection, thrombus (and AVF effect on LV) PD is more patient friendly But using what criteria reminds me of the early days of all dialysis. Some short-term studies do show improvements in QoL but no proper comparator (as not RCT) Need a good cardio-renal collaboration, a willing and able patient, and some good luck (at last) Stepwise Rx, and stepwise impact: NON CKD 13

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