New Paradigms in Rx of Symptomati Heart Failure:Role of Ivabradine & Angiotensin Neprilysin Inhibition

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1 New Paradigms in Rx of Symptomati Heart Failure:Role of Ivabradine & Angiotensin Neprilysin Inhibition Prakash Deedwania, MD, FACC, FACP, FCCP, FAHA Professor of Medicine, UCSF School of Medicine, Director, Advanced Heart Failure Program,UCSF,Fresno,CA Disclosures Consultant/Advisor for the following: Abbott, Amgen, Astra Zeneca, Novartis, Pfizer, Relypsa, ZS Pharma 1

2 Stages, Phenotypes and Treatment of HF At Risk for Heart Failure Heart Failure STAGE A At high risk for HF but without structural heart disease or symptoms of HF STAGE B Structural heart disease but without signs or symptoms of HF STAGE C Structural heart disease with prior or current symptoms of HF STAGE D Refractory HF e.g., Patients with: HTN Atherosclerotic disease DM Obesity Metabolic syndrome or Patients Using cardiotoxins With family history of cardiomyopathy Structural heart disease e.g., Patients with: Previous MI LV remodeling including LVH and low EF Asymptomatic valvular disease Development of symptoms of HF e.g., Patients with: Known structural heart disease and HF signs and symptoms Refractory symptoms of HF at rest, despite GDMT e.g., Patients with: Marked HF symptoms at rest Recurrent hospitalizations despite GDMT HFpEF HFrEF THERAPY Goals Heart healthy lifestyle Prevent vascular, coronary disease Prevent LV structural abnormalities Drugs ACEI or ARB in appropriate patients for vascular disease or DM Statins as appropriate THERAPY Goals Prevent HF symptoms Prevent further cardiac remodeling Drugs ACEI or ARB as appropriate Beta blockers as appropriate In selected patients ICD Revascularization or valvular surgery as appropriate THERAPY Goals Control symptoms Improve HRQOL Prevent hospitalization Prevent mortality Strategies Identification of comorbidities Treatment Diuresis to relieve symptoms of congestion Follow guideline driven indications for comorbidities, e.g., HTN, AF, CAD, DM Revascularization or valvular surgery as appropriate THERAPY Goals Control symptoms Patient education Prevent hospitalization Prevent mortality Drugs for routine use Diuretics for fluid retention ACEI or ARB Beta blockers Aldosterone antagonists Drugs for use in selected patients Hydralazine/isosorbide dinitrate ACEI and ARB Digoxin In selected patients CRT ICD Revascularization or valvular surgery as appropriate THERAPY Goals Control symptoms Improve HRQOL Reduce hospital readmissions Establish patient s endof-life goals Options Advanced care measures Heart transplant Chronic inotropes Temporary or permanent MCS Experimental surgery or drugs Palliative care and hospice ICD deactivation Pharmacological Treatment for Stage C HFrEF I IIa IIb III See recommendations for stages A, B, and C LOE for LOE I IIa IIb III Measures listed as Class I recommendations for patients in stages A and B are recommended where appropriate for patients in stage C. (Levels of Evidence: A, B, and C as appropriate) GDMT as depicted in Figure 1 should be the mainstay of pharmacological therapy for HFrEF. 2

3 Pharmacological Treatment for Stage C HFrEF (cont.) I IIa IIb III I IIa IIb III I IIa IIb III Diuretics are recommended in patients with HFrEF who have evidence of fluid retention, unless contraindicated, to improve symptoms. ACE inhibitors are recommended in patients with HFrEF and current or prior symptoms, unless contraindicated, to reduce morbidity and mortality. ARBs are recommended in patients with HFrEF with current or prior symptoms who are ACE inhibitorintolerant, unless contraindicated, to reduce morbidity and mortality. Pharmacologic Treatment for Stage C HFrEF HFrEF Stage C NYHA Class I IV Treatment: Class I, LOE A ACEI or ARB AND Beta Blocker For all volume overload, NYHA class II-IV patients For persistently symptomatic African Americans, NYHA class III-IV For NYHA class II-IV patients. Provided estimated creatinine >30 ml/min and K+ <5.0 meq/dl Add Add Add Class I, LOE C Loop Diuretics Class I, LOE A Hydral-Nitrates Class I, LOE A Aldosterone Antagonist 3

4 % 10/10/2015 Improving Survival in Heart Failure Oneyear Mortality Digoxin/diuretic ACEI Beta blocker Candesartan cilexetil SOLVD (1991) RRR 23% CIBISII (1999) MERITHF (1999) COPERNICUS (2001) RRR 34% CHARMAdded (2003) RRR 28% SOLVD Investigators. N Engl J Med. 1991;325(5): CIBISII Investigators and Committees. Lancet. 1999;353(9146):913. MERITHF Study Group. Lancet. 1999;353(9169): Packer M, et al. N Engl J Med. 2001;344(22): Ostergren J, McMurray JJ. J Renin Angiotensin Aldosterone Syst. 2003;4(3):

5 Cumulative mortality 10/10/2015 The patient journey All-Cause Mortality After Each Subsequent Hospitalization for HF HF 1 st admission (n = 14,374) 2 nd admission (n = 3,358) 3 rd admission (n = 1,123) 4 th admission (n = 417) P< st hospitalization: 30-day mortality = 12%; 1-year mortality = 34% Time since admission Setoguchi S, et al. Am Heart J. 2007;154:

6 Probability of Survival 10/10/2015 Elevated HR at discharge is an predictor of one-year mortality in HF patients (OFICA) N=1658 (170 hospitals); HR at discharge 71 bpm; 1 year mortality: 33% 41% Logeart D, et al. Eur Heart J 2012;33 - Abstract Supplement 485 The prognostic significance of post-discharge HR (1-week HR) in patients with heart failure 1.0 N=1947 patients with HF and LVSD in sinus rhythm from EVEREST study (Efficacy of Vasopressin Antagonism in Herat Failure: Outcome Study With Tolvaptan) Log rank P< Q1: bpm Q2: bpm Q3: bpm Q4: >88 bpm % increase in death (p<0.002) for every 5-beat increase in 1-week post-discharge HR Time (days) Greene SJ et al. JACC: Heart Failure ;1,6:

7 In patients with HF in sinus rhythm, higher resting HR 70 bpm in the early post-discharge is independently associated with increased mortality during subsequent follow-up 13% increase in death (p<0.002) for every 5-beat increase in 1-week HR 12% increase in death (p<0.001) for every 5-beat increase in 4-week HR Elevated postdischarge HR may be a key finding that identifies high-risk patients during early post-discharge follow-up Improved survival was seen in patients with lower postdischarge HR irrespective of betablocker use, suggesting that the lower HR itself may be more important than the particular pharmacological agent used HR 70 bpm is extremely simple and extremely important clinical sign that we have to assess early after discharge. Its detection should prompt appropriate therapy based on guidelines and current evidence Stephen J. Greene et al. JACC: Heart Failure. December ;Volume 1, Issue 6: Association of HR at hospital discharge and hospitalizations in patients with heart failure N=9097 patients with HF discharged from hospital Association of discharge heart rate with readmissions bpm bpm >90 bpm 30 days heart failure readmissions referent Adjusted Hazard ratios 0.87 ( ) 1.26 ( ) P value days cardiovascular disease readmissions Adjusted Hazard ratios 0.93 ( ) 1.29 ( ) referent P value Habal MV et al. Circ Heart Fail doi: /CIRCHEARTFAILURE 7

8 Newly Approved Heart Failure Drug Ivabradine SA node Acts by inhibiting the If channel, present in the cardiac SA node Reduces persistently elevated heart rate Approved by FDA in April 2015 for stable HF pts who have a resting HR of at least 70 bpm, and who are also taking the highest tolerable dose of a beta blocker DiFrancesco D. Curr Med Res Opin. 2005;21: Ivabradine: pure heart rate reduction closed open closed RR 0 mv Pure heart rate reduction -40 mv -70 mv Ivabradine I f inhibition reduces the diastolic depolarization slope, thereby lowering heart rate Thollon et al. Br J Pharmacol. 1994;112:

9 Systolic Heart failure treatment with the I f inhibitor ivabradine Trial Objective, design and baseline Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81 Swedberg K, et al. Lancet. 2010;376(9744): Primary objective To evaluate whether the I f inhibitor ivabradine improves cardiovascular outcomes in patients with 1. Moderate to severe chronic heart failure 2. Left ventricular ejection fraction 35% 3. Heart rate 70 bpm in sinus rhythm 4. Best recommended therapy Swedberg K, et al. Eur J Heart Fail. 2010;12:

10 Baseline characteristics Ivabradine 3241 Placebo 3264 Mean age, y Male, % Ischaemic aetiology, % NYHA II, % NYHA III/IV, % Previous MI, % Diabetes, % Hypertension, % Swedberg K, et al. Lancet. 2010;376(9744): Baseline characteristics Ivabradine 3241 Placebo 3264 Mean heart rate, bpm Mean LVEF, % Mean SBP, mm Hg Mean DBP, mm Hg egfr, ml/min/1.73 m Swedberg K, et al. Lancet. 2010;376(9744):

11 Chronic HF background treatment Patients (%) Ivabradine Placebo Beta-blockers ACEIs and/or ARBs Diuretics Aldosterone antagonists Digitalis 3 4 ICD/CRT Swedberg K, et al. Lancet. 2010;376(9744): Background beta-blocker treatment Patients (%) Ivabradine Placebo BB at randomization At least 50% target daily dose Target daily dose Swedberg K, et al. Lancet. 2010;376(9744):

12 Background beta-blocker treatment Main reasons for not prescribing beta-blocker, % Main reasons for not achieving beta-blocker target dose, % Ivabradine n=344 Placebo n=341 Ivabradine n=2099 Placebo n=2126 COPD Hypotension Asthma Cardiac decomp. 7 9 Fatigue 5 6 Hypotension Fatigue Dyspnea Dizziness Bradycardia 6 6 Swedberg K, et al. Lancet. 2010;376(9744): Mean heart rate reduction Heart rate (bpm) 90 Mean ivabradine dose: 6.4 mg bid at 1 month Ivabradine Placebo 6.5 mg bid at 1 year weeks Months Swedberg K, et al. Lancet

13 Primary composite endpoint (CV death or hospital admission for worsening HF) Cumulative frequency (%) HR (95% CI), 0.82 ( ), p< Placebo - 18% 20 Ivabradine Swedberg K, et al. Lancet Months Hospitalization for worsening HF Cumulative frequency (%) HR (95% CI), 0.74 ( ), p< Placebo - 26% Ivabradine Swedberg K, et al. Lancet Months 13

14 Effect of ivabradine on outcomes Endpoints Hazard ratio 95% CI p value Primary composite endpoint 0.82 [0.75;0.90] p< All-cause death 0.90 [0.80;1.02] p=0.092 Death from HF 0.74 [0.58;0.94] p=0.014 Hospitalisation for any cause 0.89 [0.82;0.96] p=0.003 Hospitalisation for CV reason 0.85 [0.78;0.92] p= CV death/hospitalisation for HF or non-fatal MI 0.82 [0.74;0.89] p< Swedberg K, et al. Lancet Effect of ivabradine in prespecified subgroups Age <65 years 65 years Sex Male Female Beta-blockers No Yes Aetiology of heart failure Non-ischaemic Ischaemic NYHA class NYHA class II NYHA class III or IV Diabetes No Yes Hypertension No Yes Baseline heart rate <77 bpm 77 bpm Test for interaction p=0.029 Swedberg K, et al. Lancet Hazard ratio Favours ivabradine Favours placebo 14

15 Treatment discontinuation Patients with an adverse event, leading to withdrawal Ivabradine N=3232, % (n) Placebo p value N=3260, % (n) All adverse events 14% (467) 13% (416) Heart failure 2% (70) 3% (82) Symptomatic bradycardia 1% (20) <1% (5) Asymptomatic bradycardia 1% (28) <1% (5) < Atrial fibrillation 4% (135) 3% (113) Phosphenes <1% (7) <1% (3) Blurred vision <1% (1) <1% (1) Swedberg K, et al. Lancet Primary composite endpoint according to heart rate achieved at D28* in the ivabradine group Böhm et al Lancet 2010 Patients with primary composite endpoint (%) bpm 70-<75 bpm 60-<65 bpm 65-<70 bpm <60 bpm Day Months After Adjustment of Ivabradine Effect for Change in Heart Rate at 28 days: HR 0.95 ( ), P =

16 % Decrease in Mortality 10/10/2015 Clinical implications When a resting heart rate 70 bpm is observed in patients with systolic heart failure in sinus rhythm, the background pharmacological treatment should be reviewed, in particular focusing on the beta-blocker therapy. If an increase of the dose of the beta-blocker can be achieved and results in lowering the heart rate <70 bpm, therapy with beta-blocker alone is appropriate. If this goal is not achievable clinically, the addition of ivabradine should be considered to reduce the risk of future cardiovascular events. Drugs That Reduce Mortality in Heart Failure With Reduced Ejection Fraction 0% Angiotensin receptor blocker ACE inhibitor Beta blocker Mineralocorticoid receptor antagonist 10% 20% 30% 40% Drugs that inhibit the renin-angiotensin system have modest effects on survival Based on results of SOLVD-Treatment, CHARM-Alternative, COPERNICUS, MERIT-HF, CIBIS II, RALES and EMPHASIS-HF 16

17 Contemporary Heart Failure Drugs What Is the Need? Residual risk: ~10% event rate at 1 yr, ~20% event rate at 2 yr All patients well-treated on concomitant ACEI/ARB, BB, MRA Zannad F et al. N Engl J Med. 2011;364: Mechanisms of Progression in Heart Failure Myocardial or vascular stress or injury Increased activity or response to maladaptive mechanisms Decreased activity or response to adaptive mechanisms Evolution and progression of heart failure 17

18 Mechanisms of Progression in Heart Failure Myocardial or vascular stress or injury Increased activity or response to maladaptive mechanisms Angiotensin receptor blocker Decreased activity or response to adaptive mechanisms Inhibition of neprilysin Evolution and progression of heart failure Valsartan/Sacubitril () Mechanism of Action Vardney O et al. JACC:Heart Failure. 2014;2:

19 Aim of the PARADIGM-HF Trial Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) 400 mg daily 20 mg daily SPECIFICALLY DESIGNED TO REPLACE CURRENT USE OF ACE INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS AS THE CORNERSTONE OF THE TREATMENT OF HEART FAILURE PARADIGM-HF: Entry Criteria NYHA class II-IV heart failure LV ejection fraction 40% 35% BNP 150 (or NT-proBNP 600), but one-third lower if hospitalized for heart failure within 12 months Any use of ACE inhibitor or ARB, but able to tolerate stable dose equivalent to at least enalapril 10 mg daily for at least 4 weeks Guideline-recommended use of beta-blockers and mineralocorticoid receptor antagonists Systolic BP 95 mm Hg, egfr 30 ml/min and serum K 5.4 meq/l at randomization 19

20 PARADIGM-HF: Study Design Randomization Single-blind run-in period Double-blind period 200 mg BID (1:1 randomization) 10 mg BID 100 mg BID 200 mg BID 10 mg BID 2 weeks 1-2 weeks 2-4 weeks PARADIGM-HF: Patient Disposition 10,521 patients screened at 1043 centers in 47 countries Did not fulfill criteria for randomization (n=2079) Randomized erroneously or at sites closed due to GCP violations (n=43) 8399 patients randomized for ITT analysis (n=4187) At last visit 375 mg daily 11 lost to follow-up median 27 months of follow-up (n=4212) At last visit 18.9 mg daily 9 lost to follow-up 20

21 Kaplan-Meier Estimate of Cumulative Rates (%) 10/10/2015 PARADIGM-HF: Baseline Characteristics (n=4187) (n=4212) Age (years) 63.8 ± ± 11.3 Women (%) 21.0% 22.6% Ischemic cardiomyopathy (%) 59.9% 60.1% LV ejection fraction (%) 29.6 ± ± 6.3 NYHA functional class II / III (%) 71.6% / 23.1% 69.4% / 24.9% Systolic blood pressure (mm Hg) 122 ± ± 15 Heart rate (beats/min) 72 ± ± 12 N-terminal pro-bnp (pg/ml) 1631 ( ) 1594 ( ) B-type natriuretic peptide (pg/ml) 255 ( ) 251 ( ) History of diabetes 35% 35% Digitalis 29.3% 31.2% Beta-adrenergic blockers 93.1% 92.9% Mineralocorticoid antagonists 54.2% 57.0% ICD and/or CRT 16.5% 16.3% PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) (n=4212) Patients at Risk Days After Randomization

22 Kaplan-Meier Estimate of Cumulative Rates (%) Kaplan-Meier Estimate of Cumulative Rates (%) 10/10/2015 PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) (n=4212) (n=4187) Patients at Risk Days After Randomization PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) (n=4212) (n=4187) Patients at Risk Days After Randomization HR = 0.80 ( ) P = Number needed to treat =

23 Kaplan-Meier Estimate of Cumulative Rates (%) Kaplan-Meier Estimate of Cumulative Rates (%) 10/10/2015 PARADIGM-HF: Cardiovascular Death (n=4212) Patients at Risk Days After Randomization PARADIGM-HF: Cardiovascular Death (n=4212) (n=4187) Patients at Risk Days After Randomization

24 Kaplan-Meier Estimate of Cumulative Rates (%) 10/10/2015 PARADIGM-HF: Cardiovascular Death HR = 0.80 ( ) P = Number need to treat = 32 (n=4212) (n=4187) Patients at Risk Days After Randomization PARADIGM-HF: Effect of vs on Primary Endpoint and Its Components (n=4187) (n=4212) Hazard Ratio (95% CI) P Value Primary endpoint 914 (21.8%) 1117 (26.5%) 0.80 ( ) Cardiovascular death 558 (13.3%) 693 (16.5%) 0.80 ( ) Hospitalization for heart failure 537 (12.8%) 658 (15.6%) 0.79 ( )

25 Kaplan-Meier Estimate of Cumulative Rates (%) 10/10/2015 PARADIGM-HF: All-Cause Mortality HR = 0.84 ( ) P< (n=4212) (n=4187) Patients at Risk Days After Randomization PARADIGM-HF: Effect of vs on Secondary Endpoints (n=4187) (n=4212) Treatment effect P Value KCCQ clinical summary score at 8 months 2.99 ± ± (0.63, 2.65) New onset atrial fibrillation 84/2670 (3.2%) 83/2638 (3.2%) Hazard ratio 0.97 (0.72,1.31) 0.84 Protocol-defined decline in renal function 94/4187 (2.3%) 108/4212 (2.6%) Hazard ratio 0.86 (0.65, 1.13)

26 PARADIGM-HF: Adverse Events (n=4187) (n=4212) P Value Prospectively identified adverse events Serum potassium > 6.0 mmol/l Serum creatinine 2.5 mg/dl Cough < Discontinuation for adverse event Discontinuation for hyperkalemia NS Discontinuation for renal impairment PARADIGM-HF: Adverse Events (n=4187) (n=4212) P Value Prospectively identified adverse events Symptomatic hypotension < Serum potassium > 6.0 mmol/l Serum creatinine 2.5 mg/dl Cough < Discontinuation for adverse event Discontinuation for hypotension NS Discontinuation for hyperkalemia NS Discontinuation for renal impairment Angioedema (adjudicated) Medications, no hospitalization 16 9 NS Hospitalized; no airway compromise 3 1 NS Airway compromise

27 % Decrease in Mortality 10/10/2015 PARADIGM-HF: Summary of Findings In heart failure with reduced ejection fraction, when compared with recommended doses of enalapril: was more effective than enalapril in... Reducing the risk of CV death and HF hospitalization Reducing the risk of CV death by incremental 20% Reducing the risk of HF hospitalization by incremental 21% Reducing all-cause mortality by incremental 16% Incrementally improving symptoms and physical limitations was better tolerated than enalapril... Less likely to cause cough, hyperkalemia or renal impairment Less likely to be discontinued due to an adverse event More hypotension, but no increase in discontinuations Not more likely to cause serious angioedema Angiotensin Neprilysin Inhibition With Doubles Effect on Cardiovascular Death of Current Inhibitors of the Renin-Angiotensin System 0% Angiotensin receptor blocker ACE inhibitor Angiotensin neprilysin inhibition 10% 15% 18% 20% 30% 20% 40% Effect of ARB vs placebo derived from CHARM-Alternative trial Effect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial Effect of vs ACE inhibitor derived from PARADIGM-HF trial 27

28 Clinical Conundrum : Which new drug for Which Patient?? After 10 yrs gap we are fortunate to have 2 new drugs with novel mechanisms of action for Rx of HF, however, this presents a challenge for the clinicians to decide which of these drug is ideal (best suited) for which patients with HF?? Should we replace ACEI/ARBs for LCZ 696 given the results of the PARADIGM study. How many of their pts are suitable & who is going to pay for significant cost??. Can we really ignore the improvement in all endpoints including all cause mortality? Who are most suitable pts for ivabradine? Should BB be always pushed more before considering it?? Are the costs of these new drugs Justified?? 28