Heart Failure Hospitalisation: An opportunity to reset chronic therapy with Entresto?

Transcription

1 Heart Failure Hospitalisation: An opportunity to reset chronic therapy with Entresto? Mark C Petrie Professor of Cardiology Honorary Consultant Cardiologist BHF Glasgow Cardiovascular Research Centre Glasgow Royal Infirmary and Golden Jubilee National Hospital Glasgow

2 Disclosures Speakers fees and consultancy fees Boehringer Ingelheim, Servier, Novartis, Maquet, Takeda, Astra, Daiichi Sankyo, Novo Nordisk, SC Pharmaceuticals, Corvia, Pfizer, Vifor, Pharmacosmos Member of Clinical Events Committees Boehringer Ingelheim, GSK, Astellas, Roche, Bayer, Cardiorentis, Reverslogix, Astra Zeneca, Stealth Pharmaceuticals, Novartis, Abbott, Abbvie

3 Disclaimer The following presentation may contain scientific / medical information on unapproved products/ dosages / indications currently under clinical investigation and/or regulatory review. Kindly note that the views and opinions of the speaker do not necessarily reflect those of Novartis. Novartis South Africa (Pty) Ltd recommends the use of their products in accordance with the locally approved Package Insert.

4 South African Indication for Entresto ENTRESTO is indicated as a second-line therapy, replacing ACE inhibitors or ARB for treatment of symptomatic heart failure (NYHA class II-IV) in patients with systolic dysfunction. ENTRESTO is administered in combination with other heart failure therapies as appropriate.

5 Admitted on: enalapril 7.5mg BD, carvedilol 25mg BD,spironolactone 50mg, furosemide 80mg A recent case Female AG Age 69 Known DCM for 8 years, CRTD 2014 Diabetes, COPD Hospitalised for the first time with DCM EF 36%, NT-BNP 800,

6 A recent case HR 94 BP 100/58 Oedema to knees Crackles bibasally JVP elevated to jaw

7 A recent case egfr 34; K 5.2 Hb 110 Ferritin 50; T sats 13% IV diuretics IV iron

8 A recent case Stablised HR 75, BP 110/62, euvolaemic Do you want to change her drug therapy? enalapril 7.5mg BD, carvedilol 25mg BD, spironolactone 50mg, furosemide 80mg

9 Thirty years of progress in HF-REF Positive drug trials

10 Thirty years of progress in HF-REF Positive drug, device and other trials PARADIGM

11 HF-REF: Where we were until recently Digoxin CABG Tx VAD CRT ICD Ivabradine H-ISDN Beta-blocker ACEi/ARB MRA ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; CABG, coronary artery bypass graft surgery; CRT, cardiac resynchronisation therapy; HF-REF, heart failure with reduced ejection fraction; H-ISDN, hydralazine/isosorbide dinitrate; ICD, implantable cardioverter defibrillator; MRA, mineralocorticoid (aldosterone) receptor antagonist; VAD, ventricular assist device McMurray et al. Eur Heart J 2012;33:

12 Sacubitril/valsartan: First in class dual-acting angiotensin receptor neprilysin inhibitor ARNi LCZ696 is a crystalline complex comprised of 6 valsartan moieties, 6 sacubitril (AHU377) moieties, sodium cations, and water held together by network of hydrogen bonds

13 What does sacubitril/valsartan do? Valsartan angiotensin receptor blocker Blocks angiotensin II effects - sodium and water retention - cardiac fibrosis/ hypertrophy - vasoconstriction

14 What does sacubitril/valsartan do? Valsartan angiotensin receptor blocker Blocks angiotensin II effects - sodium and water retention - cardiac fibrosis/ hypertrophy - vasoconstriction BOND Sacubitril neprilysin inhibitor

15 What does sacubitril/valsartan do? Valsartan angiotensin receptor blocker BOND Sacubitril neprilysin inhibitor Blocks angiotensin II effects - sodium and water retention - cardiac fibrosis/ hypertrophy - vasoconstriction Inhibits breakdown of good peptides(bnp, ANP, bradykinin ) - Vasodilatation - Inhibition of cardiac fibrosis/ LVH - Natriuresis/diuresis

16 Cumulative Proportion of Patients with Primary End Point (%) PARADIGM-HF: Primary outcome HR: 0.80 (0.73, 0.87) p = Enalapril 1117 (n=4212) sac/val (n=4187) Days after Randomization At risk enalapril: sac/val: McMurray, Packer et al. N Engl J Med 2014; 371(11):

17 Cumulative Proportion of Patients Who Died from Any Cause (%) PARADIGM-HF Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial Death from any cause 16% risk reduction 40 HR: 0.84 (0.76, 0.93) P = enalapril (n=4212) sac/val (n=4187) Days after Randomization

18 Reducing HF mortality Mortality with in 2017 HF treatment

19 PARADIGM-HF: Percentage of patients with at least 5 points deterioration in KCCQ scores at month 8 % Physical limitation Symptom stability Symptom frequency Symptom burden LCZ696 (N=3833) Total symptom score Enalapril (N=3873) P=0.004 P=0.029 P<0.001 P<0.005 P<0.001 P<0.001 P=0.001 P=0.001 P<0.001 P<0.001 Self efficacy Quality of life Social limitation Overall summary score Clinical summary score Clinical summary score based on the physical limitation and total symptom score domains. Death imputed as zero. The analysis included all patients with at least one KCCQ data point

20 Mortality All-cause mortality (%) after a HF hospitalisation (%) % 32.1% 30.8% 37.3% Okumura et al. Circulation : No event (993/6853) Intensifica on of therapy (116/361) Emergency department visit (24/78) Heart failure hospitaliza on (413/1107)

21 PARADIGM-HF Death from CV causes 20% risk reduction HF hospitalization 21% risk reduction P = P = McMurray, Packer et al. N Engl J Med 2014; 371(11):

22 Recurrent HF hospitalizations Mogensen et al. Circulation 2016; 134(Supl1): A19644

23 Recurrent HF hospitalizations Mogensen et al. Circulation 2016; 134(Supl1): A19644

24 The 2016 ESC guidelines ACEI/ARB + BB + MRA ARNI CRT=cardiac resyncronization therapy; H-ISDN=hydralazine and isosorbide dinitrate; HR=heart rate; ICD=implantable cardioverter defibrillator; LVAD=left ventricular assist device; MR=mineralocorticoid receptor; OMT=optimal medical therapy; VT/VF=ventricular tachycardia/ventricular fibrillation Ponikowski et al. Eur Heart J 2016;37:

25 Why might you not change to sacubitril/valsartan? Too old EF not low enough NYHA IV NT-BNP not high enough Diabetes Renal function Hyperkalaemia

26 Why might you not change to sacubitril/valsartan? Too old EF not low enough NYHA IV NT-BNP not high enough Diabetes Renal function Hyperkalaemia

27 EF <35% or <40%?

28 Sacubitril/valsartan was effective across the spectrum of ejection fraction * >2000 patients with EF between 35 and 40% Solomon et al. Circ Heart Fail Mar;9(3):e002744

29 Why might you not change to sacubitril/valsartan? Too old EF not low enough NYHA IV NT-BNP not high enough Diabetes Renal function Hyperkalaemia

30 NYHA Class IV in PARADIGM-HF Sacubitril/valsartan better NYHA IV 0.71 (0.30, 1.69) Enalapril better Overall trial 0.80 (0.73, 0.87) Sacubitril/valsartan n/n (%) Enalapril n/n (%) Risk Ratio Sacubitril/valsartan vs. Enalapril NYHA IV Overall Safety Hypotension 3/33 (9.1) 3/27 (11.1) 0.95 (0.19, 4.69) 1.39 (1.26, 1.52) Renal impairment 4/33 (12.1) 3/27 (11.1) 1.25 (0.28, 5.60) 0.90 (0.81, 1.00) Hyperkalemia 5/33 (15.2) 6/27 (22.2) 0.71 (0.22, 2.32) 0.81 (0.72, 0.91) McMurray et al. Circulation 2016; 134(Supl1): A20000

31 Why might you not change to sacubitril/valsartan? Too old EF not low enough NYHA IV NT-BNP not high enough Diabetes Renal function Hyperkalaemia

32 Raised NT-proBNP / BNP or not?

33 Zile et al J Am Coll Cardiol Dec 6;68(22): Effect of sacubitril/valsartan vs enalapril by NT-proBNP

34 Why might you not change to sacubitril/valsartan? Too old EF not low enough NYHA IV NT-BNP not high enough Diabetes Renal function Hyperkalaemia

35 Diabetes

36 Diabetes under-diagnosed in PARADIGM-HF Undiagnosed diabetes 13% 36% Diagnosed diabetes Pre-diabetes 25% 26% Normal Circ Heart Fail. 2016;9:e002560

37 Sac/val versus enalapril and HBA1c Seferovic et al Lancet Diabetes Endocrinol 2017;5:

38 Sac/val versus enalapril: CV outcomes in DM and no DM CV end point HF hosps or CV death No DM HR (95% CI) 0.68 ( ) Pre-DM HR (95% CI) 0.76 ( ) Undiagnosed DM HR (95% CI) 0.97 ( ) DM HR (95% CI) 0.87 ( ) Interaction p value 0.13 CV death 0.62 ( ) 0.76 ( ) 0.86 ( ) 0.92 ( ) 0.09 HF hosps 0.85 ( ) 0.73 ( ) 0.88 ( ) 0.79 ( ) 0.78 All-cause mortality 0.68 ( ) 0.77 ( ) 0.91 ( ) 0.97 ( ) 0.06 Circ Heart Fail. 2016;9:e002560

39 Why might you not change to sacubitril/valsartan? Too old EF not low enough NYHA IV NT-BNP not high enough Diabetes Renal function Hyperkalaemia

40 Efficacy or sac/val versus enalapril with and without renal dysfunction CV Endpoints CKD (n=2745) HR (95% CI) No CKD (n=5654) HR (95% CI) Interaction p value CV death or HF hosps 0.79 ( ) 0.81 ( ) 0.70 CV death 0.76 ( ) 0.84 ( ) 0.39 HF hosps 0.79 ( ) 0.81 ( ) 0.83 All-cause mortality 0.79 ( ) 0.89 ( ) 0.27 JACC Heart Fail 2018 Jun;6(6):

41 Sac/val versus enalapril: Mean change in egfr from baseline JACC HF 2008;6:489-98

42 Renal progression: Protocol-defined endpoint 50% decline in egfr >30 ml/min/1.73m 2 decline in egfr to <60 ml/min/1.73m 2 Reaching ESRD

43 Renal progression: Protocol-defined endpoint Endpoint Composite Hazard Ratio (95% CI) P- value 0.86 (0.65, 1.13) (i) 50% decline in egfr 0.75 (0.47, 1.19) (ii) >30 ml/min/1.73m 2 decline in egfr to <60 ml/min/1.73m (0.80, 1.53) (iii) Reaching ESRD 0.50 (0.21, 1.16) JACC HF 2008;6:489-98

44 Renal progression: Conventional renal endpoint (post-hoc analysis) Endpoint Hazard Ratio (95% CI) P Value 2-sided Composite 0.63 (0.42, 0.95) (i) 50% decline in egfr 0.75 (0.47, 1.19) (iii) Reaching ESRD 0.50 (0.21, 1.16) JACC HF 2008;6:489-98

45 PARADIGM-HF: Adverse events leading to permanent study drug discontinuation (%) Any adverse event p = 0.03 Enalapril 29 Hypotension p = 0.38 Sacubitril/valsartan Renal reasons p = Hyperkalaemia p = 0.56 McMurray et al. N Engl J Med 2014;371:

46 PARADIGM-HF: Renal safety (%) Enalapril Sacubitril/valsartan P= P=0.007 P=0.007 P= Cr 2.5 mg/dl Cr 3.0 mg/dl K+ > 5.5 mmol/l K+ > 6.0 mmol/l (221 µmol/l) (265 µmol/l) McMurray et al. N Engl J Med 2014;371:

47 Sac/val v enalapril renal summary Reduction in CV outcomes for sac/val versus enalapril is consistent for those with and without CKD Sac/ val slows decline in egfr>enalapril Less decline in composite of egfr>50% and ESRD with sac/val v enalapril Fewer discontinuations for renal reasons with sac/val than enalapril

48 Why might you not change to sacubitril/valsartan? Too old EF not low enough NYHA IV NT-BNP not high enough Diabetes Renal function Hyperkalaemia

49 Frailty and the elderly

50 rate per 100 patient years rate per 100 patient years rate per 100 patient years rate per 100 patient years Do the elderly benefit from sac/val versus enalapril? CV death or HF hospitalization < Age (years) CV death < Age (years) HF hospitalization All-cause death < Age (years) 0 < Age (years) Eur Heart J. 2015;36:

51 Sac/val versus enalapril: renal safety by age P for interaction >0.05 for all events <55 years years years 75 years Jhund et al. Eur Heart J. 2015;36:

52 Blood pressure

53 PARADIGM-HF: Systolic BP JACC Heart Fail Jun;6(6):

54 CV outcomes according to baseline systolic BP Primary endpoint Cardiovascular death Bohm et al Eur Heart J Feb 1. doi: /eurheartj/ehw570.

55 PARADIGM-HF: Adverse events leading to permanent study drug discontinuation (%) Any adverse event p = 0.03 Enalapril 29 Hypotension p = 0.38 Sacubitril/valsartan Renal reasons p = Hyperkalaemia p = 0.56 McMurray et al. N Engl J Med 2014;371:

56 Remember sudden death is common

57 The natural history of HF Diagnosis Progressive pump failure Adapted from Goodlin SJ. J Am Coll Cardiol. 2009;54(5):386-96

58 The natural history of HF SCD SCD SCD SCD Diagnosis Progressive pump failure Adapted from Goodlin SJ. J Am Coll Cardiol. 2009;54(5):386-96

59 The two major modes of death in HF Sudden death Death due to worsening HF Desai et al. Eur Heart J 2015;36:1990-7

60 Effect of sacubitril/valsartan on the two major modes of death in HF Sudden death Death due to worsening HF Enalapril HR=0.80 (0.68, 0.94) P=0.008 Sacubitril /valsartan HR=0.79 (0.64, 0.98) P=0.034 Enalapril Sacubitril /valsartan Sacubitril/ valsartan Sacubitril/ valsartan Desai et al. Eur Heart J 2015;36:1990-7

61 The clock is ticking 763 of 2309 (33%) of first primary endpoints were CV deaths 467 of these 763 deaths (61%) were sudden McMurray et al. N Eng J Med 2014;371: ; Desai As et al Eur Heart J. 2015;36:

62 Cumulative Proportion of Patients with Primary End Point (%) PARADIGM-HF: Primary outcome Cardiovascular death or heart failure hospitalization HR: 0.80 (0.73, 0.87) p = Enalapril 1117 (n=4212) 914 By 2030 days 0.65 ( 0.45, 0.93) P= Sacubitril/valsartan (n=4187) Days after Randomization At risk Enalapril: Sacubitril/valsartan: McMurray, Packer et al. N Engl J Med 2014; 371(11):

63 Benefit on top of other therapies

64 Incremental benefits of sacubitril/valsartan: CV death Diuretics Digoxin MRA ICD/CRT-D Prior coronary revascularization Number HR 95% CI No Yes No Yes No Yes No Yes No Yes Interaction P value Okumura et al Circ Heart Fail Sep;9(9). pii: e

65 Incremental benefits of sacubitril/valsartan according to background β-blocker use Cardiovascular death or HF hospitalization Number Interaction P value HR 95% CI Beta-blocker Beta-blocker % target dose No Yes <50% % Okumura et al Circ Heart Fail Sep;9(9). pii: e

66 De-mystify initiation

67 How to sacubitril/valsartan Population with HF-REF No patient characteristics requiring caution or dose reduction Currently only able to tolerate a low or submaximal target dose of ACEI or ARB* No ACEI or ARB in the past egfr <30 ml/min/m 2 ** Moderate hepatic impairment (Child Pugh Class B) Elderly Starting dose of sacubitril/valsartan 49/51 mg BID 24/26 mg BID 24/26 mg BID 24/26 mg BID 24/26 mg BID 24/26 mg BID Up titration and target dose Up titration by doubling of dose every 2 4 weeks until a target dose of 97/103 mg BID is reached *Target doses of ACE inhibitors and ARBs are: ACE inhibitors captopril 50 mg TID, enalapril 10 mg BID, lisinopril 20 mg OD, ramipril 5 mg BID, trandolopril 4 mg OD; ARBs candesartan 32 mg OD, losartan 150 mg OD, valsartan 160 mg OD **The European Medicines Agency also suggests that a dose of 24mg/26mg can be considered if egfr ml/min/m 2 Jhund and McMurray. Heart 2016;102:

68 How to ACEI /ARB Check renal function and electrolytes. Double the dose at not less than 2-week intervals in the community (can be done more rapidly in patients in hospital or who are otherwise closely monitored, tolerability permitting). Re-check blood chemistry 1-2 weeks after initiation and 1-2 weeks after dose titration Monitor blood chemistry 4 monthly thereafter Ponikowski P et al. Eur Heart J. 2016;37:

69 How to sac/val Check renal function and electrolytes. Double the dose at not less than 2-week intervals in the community (can be done more rapidly in patients in hospital or who are otherwise closely monitored, tolerability permitting). Re-check blood chemistry 1-2 weeks after initiation and 1-2 weeks after dose titration Monitor blood chemistry 4 monthly thereafter Ponikowski P et al. Eur Heart J. 2016;37:

70 What should I do if the patient experiences a side effect?

71 How to ACEI /ARB Asymptomatic low blood pressure: Does not usually require any change in therapy. Symptomatic hypotension: Dizziness/light headedness is common and often improves with time patients should be reassured. Reconsider need for nitrates, calcium-channel blockers and other vasodilators and reduce dose/stop, if possible. If no signs or symptoms of congestion, consider reducing diuretic dose. Ponikowski P et al. Eur Heart J. 2016;37:

72 Admitted on: enalapril 7.5mg BD, carvedilol 25mg BD,spironolactone 50mg, furosemide 80mg A recent case Female AG Age 69 Known DCM for 8 years, CRTD 2014 Diabetes, COPD Hospitalised for the first time with DCM EF 36%, NT-BNP 800,

73 Back to the case Sacubitril/ valsartan 24/26mg BD

74 Progress HF clinic Seen by heart failure nurses Generally keeping well No PND, no orthopnea, trace of oedema around ankles, JVP 4 cmh 2 O, BP 108/64 Bloods Sodium 136 mmol/l Potassium 5.1 mmol/l Urea 11 mmol/l Creatinine 105 µmol/l egfr 60 NAU2018AU134868

75 Progress HF clinic Uptitrated to sacubitril/valsartan 49/51mg BD NAU2018AU134868

76 Progress HF clinic Uptitrated to sacubitril/valsartan 49/51mg BD Bloods after uptitration Sodium 129 mmol/l Potassium 5.5 mmol/l Urea 16 mmol/l Creatinine 155 µmol/l egfr 38 BP 82/60 Feels dizzy especially on standing NAU2018AU134868

77 Progress HF clinic Eplerenone 25 mg OD Warfarin Carvedilol 25 mg BD Furosemide 80 mg BD Sacubitril/valsartan 49/51 mg BD NAU2018AU134868

78 Progress HF clinic Eplerenone 25 mg OD Warfarin Carvedilol 25 mg BD Furosemide 80 mg BD Furosemide 80 mg OD Sacubitril/valsartan 49/51 mg BD NAU2018AU134868

79 Current status NYHA II Trace of odema Renal function egfr 58 BP 97/64 no symptoms sacubitril/valsartan 97/103mg BD eplerenone 50mg OD carvediolol 25mg BD furosemide 40mg OD and warfarin NAU2018AU134868

80 Is initiation as an inpatient feasible? TRANSITION trial N =1002 pts hospitalised with HF Randomised to inpatient v outpatient initiation of sac/val. Pry end point proportion on 200mg BD sac/val at 10 weeks. Outcome 45% pre-discharge v 50% post-discharge on 200mg BD (HR % CI ) No difference in AEs or SAEs (ie well-tolerated) eg hypotension and hyperkalaemia <1.0%

81 Don t forget the outpatient who looks stable

82 Background JM 68 year old man Myocardial infarction 2006 Heart failure 2014 Reduced ejection fraction (32%) Not felt suitable for CABG Medical therapy optimised Implantable cardioverter defibrillator 2015 NAU2018AU134868

83 Background Feb 2016 NYHA class II SOB on stairs and hills Treated with: Enalapril 5mg BD Carvedilol 25mg BD Eplerenone 25mg OD Furosemide 80mg BD Warfarin NAU2018AU134868

84 Do we need anything more?

85 My patient seems to be stable My patient is low risk

86 EMPHASIS-HF Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure 2737 patients, 55 years, NYHA class II, with CV hospitalization within 6 months (or elevated BNP/NT pro BNP) and LVEF 0.30 (or 0.35 if QRS duration >130msec). Followed for a median of 21 months >25% of patients with MILD symptoms experience CV death or HF hospitalization within 3 years Zannad, McMurray et al. NEJM 2011;364:11-21

87 Cumulative Proportion of Patients with Primary End Point (%) PARADIGM-HF: Primary outcome Cardiovascular death or heart failure hospitalization HR: 0.80 (0.73, 0.87) p = Enalapril 1117 (n=4212) Sacubitril/valsartan (n=4187) Days after Randomization At risk Enalapril: Sacubitril/valsartan: McMurray, Packer et al. N Engl J Med 2014; 371(11):

88 Mild symptoms mild heart failure

89 PARADIGM-HF: Baseline Characteristics Sacubitril/valsartan (n=4187) Enalapril (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% CRT 7.0% 6.7% ICD 15% 15% McMurray et al. N Eng J Med 2014;371:

90 MAGGIC risk score 1. Age 2. Sex 3. Diabetes 4. COPD 5. BMI 6. Smoker 7. NYHA class 8. Diagnosis 18 months 9. Creatinine 10. SBP 11. LVEF 12. ACEi/ARB 13. Beta-blocker

91 MAGGIC Risk Score in PARADIGM-HF 40% chance of death at 3 years 50% chance of death at 3 years Simpson et al. J Am Coll Cardiol 2015;66:

92 Benefit of sacubitril/valsartan across MAGGIC risk score quintiles Enalapril Sacubitril/valsartan Simpson et al. J Am Coll Cardiol 2015;66:

93 RATE PER 100 PATIENT YEARS Benefit of sacubitril/valsartan across MAGGIC risk score quintiles 18 All-cause mortality Enalapril LCZ696 Sacubitril/valsartan QUINTILE OF RISK SCORE Simpson et al. J Am Coll Cardiol 2015;66:

94 HF-REF: The building blocks of therapy Digoxin CABG Tx VAD CRT ICD Ivabradine H-ISDN Beta-blocker ACEI/ARB MRA

95 HF-REF: The building blocks of therapy Digoxin CABG Tx VAD CRT ICD Ivabradine H-ISDN Beta-blocker ARNI MRA

96 Questions?

97

98 Back ups

99 Dementia and Neprilysin inhibition

100 Dementia and Neprilysin inhibition Cannon et al. Eur J Heart Fail (in press)

101 NYHA Class IV in PARADIGM-HF Sacubitril/valsartan better NYHA IV 0.71 (0.30, 1.69) Enalapril better Overall trial 0.80 (0.73, 0.87) Sacubitril/valsartan n/n (%) Enalapril n/n (%) Risk Ratio Sacubitril/valsartan vs. Enalapril NYHA IV Overall Safety Hypotension 3/33 (9.1) 3/27 (11.1) 0.95 (0.19, 4.69) 1.39 (1.26, 1.52) Renal impairment 4/33 (12.1) 3/27 (11.1) 1.25 (0.28, 5.60) 0.90 (0.81, 1.00) Hyperkalemia 5/33 (15.2) 6/27 (22.2) 0.71 (0.22, 2.32) 0.81 (0.72, 0.91) McMurray et al. Circulation 2016; 134(Supl1): A20000

102 Dose of enalapril in PARDIGM-HF Mean enalapril dose of enalapril in landmark studies of ACE inhibitors in HFREF CONSENSUS (1987): 18.4 mg 20 mg BID target dose SOLVD (1991): 16.6 mg 10 mg BID target dose V-HeFT II (1991): 15 mg 10 mg BID target dose Mean dose of enalapril in PARADIGM-HF = 18.9 mg daily Why not 20mg BID? More renal adverse events in CONSENSUS FDA mandated dose

103 Hypotension occurring during PARADIGM-HF Vardeny et al Circ Heart Fail. 2018;11:e004745