From PARADIGM-HF to Clinical Practice. Waleed AlHabeeb, MD, MHA Associate Professor of Medicine President of the Saudi Heart Failure Group

Transcription

1 From PARADIGM-HF to Clinical Practice Waleed AlHabeeb, MD, MHA Associate Professor of Medicine President of the Saudi Heart Failure Group

2 PARADIGM-HF: Inclusion Criteria Chronic HF NYHA FC II IV with LVEF 40%* BNP (or NT-proBNP) levels as follows: 150 (or 600 pg/ml), or 100 (or 400 pg/ml) and a hospitalization for HFrEF within the last 12 months 4 weeks stable treatment with an ACEI or an ARB #, and a β-blocker Aldosterone antagonist should be considered for all patients (with treatment with a stable dose for 4 weeks, if given) *The ejection fraction entry criteria was lowered to 35% in a protocol amendment # Dosage equivalent to enalapril 10 mg/day McMurray et al. Eur J Heart Fail. 2013;15:

3 PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) Kaplan-Meier Estimate of Cumulative Rates (%) Enalapril (n=4212) LCZ696 (n=4187) Patients at Risk LCZ696 Enalapril Days After Randomization HR = 0.80 ( ) P = Number needed to treat =

4 Kaplan-Meier Estimate of Cumulative Rates (%) PARADIGM-HF: Cardiovascular Death HR = 0.80 ( ) P = Number need to treat = 32 Enalapril (n=4212) LCZ696 (n=4187) Patients at Risk Days After Randomization LCZ696 Enalapril

5 Effect of LCZ696 on mode of death In PARADIGM-HF trial, CV causes accounted for 81% of all deaths Unknown, 4% Other CV death, 2% Presumed CV death, 10% Non-CV death, 15% Sudden death, 36% 45% of CV deaths 26% of CV deaths Fatal stroke, 4% Fatal MI, 4% Worsening HF, 21% Presumed sudden death, 3% Desai et al. Eur Heart J 2015; epub ahead of print: DOI: /eurheartj/ehv186;

6 Cumulative probability of event Sudden cardiac death Enalapril LCZ Hazard ratio = 0.80 (95% CI: ) p= ,080 1,260 Days since randomization No. at risk LCZ696 4,187 3,891 2,478 1,005 Enalapril 4,212 3,860 2, Desai et al. Eur Heart J 2015; epub ahead of print: DOI: /eurheartj/ehv186;

7 The LCZ696 treatment effect for sudden cardiac death was not influenced by the presence of implantable defibrillator devices Sudden cardiac death n (%) Hazard ratio, LCZ696 vs enalapril (95% CI) p-value for interaction ICD 525 (93.6%) 0.82 ( ) +ICD 36 (6.4%) 0.49 ( ) 0.17 CI=confidence interval; ICD=implantable cardioverter defibrillator; vs=versus Desai et al. Eur Heart J 2015;36:1990 7

8 Cumulative probability of event Death due to worsening heart failure Enalapril LCZ696 Hazard ratio = 0.79 (95% CI: ) p= ,080 1,260 Days since randomization No. at risk LCZ696 4,187 3,891 2,478 1,005 Enalapril 4,212 3,860 2, Desai et al. Eur Heart J 2015; epub ahead of print: DOI: /eurheartj/ehv186;

9 Kumulative Anzahl der Hospitalisierungen wegen HV pro 100 Patienten Cumulative number of HF hospitalisations (per 100 patients) 60 HR: 0,77 (0,67-0,89) p <0, Enalapril (n=4.212) LCZ696 (n=4.187) Patienten at Risk Tage nach Randomisierung LCZ Enalapril Packer et al, Circulation (2014): [doi: /circulationaha ]

10 Total numbers of hospitalizations were lower for LCZ696 Reason for hospitalization LCZ696 n (%) Enalapril n (%) Rate ratio (95% CI) p-value Relative risk reduction Heart Failure* 851 1, ( ) < % Cardiovascular* 2,216 2, ( ) < % Any reason* 3,564 4, ( ) < % *All (including repeat) hospitalizations N=4,187; N=4,212 With LCZ696, compared with enalapril Packer et al. Circulation 2014; epub ahead of print: DOI: /CIRCULATIONAHA

11 Total numbers of emergency department visits were significantly fewer with Entresto compared with enalapril Event Emergency department visit for heart failure* LCZ696 numbers of visits Enalapril numbers of visits Rate ratio (95% CI) p-value Relative risk reduction ( ) % *All (including repeat) emergency department visits (defined as those without subsequent hospitalization) N=4,187; N=4,212 With LCZ696, compared with enalapril Packer et al. Circulation 2014; epub ahead of print: DOI: /CIRCULATIONAHA

12 Proportion of patients with worsening NYHA functional class ( 1 class) (%) Fewer HFrEF patients receiving Entresto had worsening of NYHA functional class 8 6 p= % 5.4% p= % 6.1% p= % LCZ696 (N=4,187) Enalapril (N=4,212) 4.7% n=186 n=218 n=205 n=266 n=225 n=271 In patients surviving at 4 months In patients surviving at 8 months In patients surviving at 12 months Packer et al. Circulation 2014; epub ahead of print: DOI: /CIRCULATIONAHA

13 Proportion of HFrEF patients with worsening heart failure leading to intensification of outpatient therapy* (%) Less likely to require intensification of outpatient heart failure therapy (defined as treatment failure) HR 0.84 (95% CI: ) p= % 14.3% n=520 n=604 LCZ696 (N=4,187) Enalapril (N=4,212) *Addition of a new drug for treatment of heart failure, intravenous therapy or increase in daily dose of diuretic for >1 month, prospectively defined as a treatment failure Packer et al. Circulation 2014; epub ahead of print: DOI: /CIRCULATIONAHA

14 Biomarkers I IIa IIb III In ambulatory patients with dyspnea, measurement of BNP or N-terminal pro-b-type natriuretic peptide (NT-proBNP) is useful to support clinical decision making regarding the diagnosis of HF, especially in the setting of clinical uncertainty. I IIa IIb III Measurement of BNP or NT-proBNP is useful for establishing prognosis or disease severity in chronic HF.

15 I IIa IIb III BNP- or NT-proBNP guided HF therapy can be useful to achieve optimal dosing of GDMT in select clinically euvolemic patients followed in a well-structured HF disease management program. I IIa IIb III I IIa IIb III The usefulness of serial measurement of BNP or NT-proBNP to reduce hospitalization or mortality in patients with HF is not well established. Measurement of other clinically available tests such as biomarkers of myocardial injury or fibrosis may be considered for additive risk stratification in patients with chronic HF.

16 ACC/AHA 2013

17 ARNI

18 Exclusions prior to initiation Symptomatic hypotension SBP < 95 mm Hg egfr < 30 ml/min or reduction in GFR > 25% during first month of therapy (using MDRD or CKD-EPI) Potassium > 5.4 meq/l History of angioedema with ACEI or ARB Heart Failure with Preserved Ejection Fraction (HFpEF): Inclusion criteria was originally EF <40%, but modified to <35% after ~1 year; 3 years of patient enrollment in trial) Non-significant reduction in primary outcome in EF = 35-40% Severe Hepatic Impairment (Child-Pugh C)

19 Things to remember: Stop ACEI for 36 hours before starting Entresto May transition directly from ARB to Entresto Titrate to goal dose of 97/103 mg BiD as tolerated Uncertain benefit if not able to achieve target dose of 97/103 mg BiD Monitor renal function and potassium days after initiation, and every 1-3 months thereafter as clinically indicated based on individual patient factors (monitor similar to ACEIs and ARBs) BNP is expected to rise with initiation of Entresto since sacubitril inhibits neprilysin which normally metabolizes BNP Establish new baseline BNP after 2 months Nt-proBNP not affected No current data on effects on ST2 as of yet

20 Case 1 55 y/o F Ischemic cardiomyopathy LVEF 35% DM, HTN NYHA class II BP 134/65 HR 66 JVP 15 cm Cr 98 K 4.2 NT-ProBNP 2200 Lisinopril 20 mg OD

21 FU BP 142/65 HR 65 JVP 9 cm Cr 116 K 4.8 NT-ProBNP 836

22 Case 2 48 y/o M Ischemic cardiomyopathy LVEF 20% DM, HTN NYHA class II BP 130/68 HR 61 JVP 8 cm Cr 109 K 4.4 NT-ProBNP 1652 Lisinopril 10 mg

23 FU BP 94/52 HR 68 JVP 6 cm Cr 114 K 3.8 NT-ProBNP 1141

24 45 y/o M DCM LVEF 25% NYHA class III BP 126/76 HR 86 JVP 14 cm Cr 103 K 4.36 NT-ProBNP 1543 Lisinopril 10 mg OD Case 3

25 FU BP 120/70 HR 88 Cr 92 K 4.35 NT-ProBNP 569

26 Case 4 57 y/o F Ischemic cardiomyopathy LVEF 20-25% DM, HTN NYHA class II BP 147/70 HR 83 JVP 10 cm Cr 63 K 4.5 NT-ProBNP 2085 Valsartan 160 BID

27 FU BP 108/68 HR 98 JVP 8 cm Cr 67 K 4.5

28 Case 5 75 y/o M Ischemic Cardiomyopathy LVEF 25% DM, HTN NYHA class II BP 154/79 HR 58 JVP 15 cm Cr 76 K 5.1 NT-ProBNP 1900 Valsartan 160 BID

29 FU BP 121/61 HR 61 JVP 10 cm Cr 72 K 3.8 NT-ProBNP 259

30 52 y/o M Ischemic cardiomyopathy LVEF 25% NYHA class II-III BP 98/76 HR 77 JVP 18cm Cr 118 K 4.8 NT-ProBNP 3162 Candesartan 4 mg OD

31 FU BP 94/62 HR 67 JVP 17 cm Cr 125 K 4.9 NT-ProBNP 3589

32 Case 6 55 y/o F DM, HTN, Hypothyroidism NYHA class III Recurrent admissions with HF LVEF 55% Cr 140 K 4.5 NT-ProBNP 2300

33 PARAGON-HF Phase 3 A Multicenter, Randomized, Double-blind, Parallel Group, Active-controlled Study to Evaluate the Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients (NYHA Class II-IV) With Preserved Ejection Fraction

34 Case 7 34 y/o M DCM LVEF 30% On lisinopril 10 mg Carvediolol 12.5 BID Admitted with decompensated HF When to start Entresto?

35 TRANSITION Phase 4 A Multicenter, Randomized, Open Label, Parallel Group Study Comparing Pre-discharge and post-discharge treatment Initiation With LCZ696 in heart Failure patients With Reduced ejection-fraction hospitalized for an Acute decompensation event (ADHF)

36 Case 8 15 y/o M DCM LVEF 20% NYHA class II Valsartan 40 mg BID, Bisoprolol 2.5 mg OD Cr 68 K 4.1 NT-ProBNP 5000??

37 Case 9 64 y/o M DM Previously asymptomatic Post Acute AWMI LVEF 30% BP 130/80 HR 76??

38 Benefit Uncertain/Use Caution Class 4 CHF (<1% of pts enrolled), unlikely to benefit this late stage HF, though possible Age > 75 (no significant benefit demonstrated) in comparison to <75 subgroup Benefit significant if age cutoff lowered to 72 ( 72 yrs) Black (significantly increased risk of angioedema; if tolerated, likely beneficial)

39 Algorithm

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41 ENTRESTO REPLACES AN ACEi OR AN ARB 1 CURRENT HF THERAPY NEW HF THERAPY Step 1 Step 2 Step 3 Angiotensinconverting enzyme inhibitor (ACEi) Angiotensin Il receptor blocker (ARB) Stop ACEi for a 36-hour washout 1.5 days From high-dose ARB: Consider starting dose of ENTRESTO 100 mg twice daily From low-dose ARB: Consider starting dose of ENTRESTO 50 mg twice daily From high-dose ACEi: Consider starting dose of ENTRESTO 100 mg twice daily From low-dose ACEi: Consider starting dose of ENTRESTO 50 mg twice daily The dose of ENTR ESTO should be doubled every 2 to 4 weeks to the target dose of 200 mg twice daily, as tolerated by the patient Not on ACEÍ or ARB (Not currently taking ACEis or ARBs) Consider starting dose of ENTRESTO 50 mg twice daily ENTRESTO is available in 50 mg, 100 mg, and 200 mg tablets Target dose is 200 mg twice daily

42 THANK YOU