2017 Summer MAOFP Update

Transcription

1 2017 Summer MAOFP Update. Cardiology Update 2017 Landmark Trials Change Practice Guidelines David J. Strobl, DO, FNLA

2 Heart Failure: Epidemiology More than 4 million patients affected 400,000 new cases annually Approximately 1 million hospitalizations $10 billion/year treatment costs

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4 HFrEF Pathophysiology SNS and RAAS

5 Normal CV Neurohormonal Balance 5

6 CV Neurohormonal Imbalance in Heart Failure Traditional Therapies have not enhanced ECPs 6

7 Neprilysin Inhibition with Sacubitril 7

8 Effects of Neprilysin Inhibition 8

9 Sacubitril/Valsartan 9

10 A Comparison of Angiotensin Receptor- Neprilysin Inhibition (ARNI) With ACE Inhibition in the Long-Term Treatment of Chronic Heart Failure With a Reduced Ejection Fraction Milton Packer, John J.V. McMurray, Akshay S. Desai, Jianjian Gong, Martin P. Lefkowitz, Adel R. Rizkala, Jean L. Rouleau, Victor C. Shi, Scott D. Solomon, Karl Swedberg and Michael R. Zile for the PARADIGM-HF Investigators and Committees

11 PARADIGM-HF Study Design Phase 3 Trial to Examine the Efficacy of Sacubitril/Valsartan vs Enalapril in Patients With HFrEF 1,2 N=8442 patients with chronic HF (NYHA class II IV with LVEF 40%) and elevated BNP Double-Blind Randomized Treatment Period Enalapril a 10 mg BID Single-blind run-in period Sac/val b 49/51 mg BID Sac/val b 97/103 mg BID Randomization Sac/val 97/103 mg BID Enalapril 10 mg BID Testing tolerability to target doses of enalapril and sac/val On top of standard HF therapy, excluding ACEIs and ARBs 3 2 weeks 1 2 weeks 2 4 weeks Median duration of follow-up: 27 months A 36 hour washout was required after single blind enalapril run-in and also at end of entresto single blind run-in prior to being randomized Primary outcome: To demonstrate superiority of sacubitril/valsartan over enalapril in reducing composite of death from CV causes or a first hospitalization for HF BID, twice daily; BNP, brain natriuretic peptide; NYHA, New York Heart Association. a Enalapril 5 mg BID for 1 2 weeks followed by enalapril 10 mg BID was an optional starting run-in dose for patients treated with ARBs or with a low dose of ACEI. b Dosing in clinical trials was based on the total amount of both components of sac/val; 24/26 mg, 49/51 mg, and 97/103 mg were referred to as 50 mg, 100 mg, and 200 mg, respectively. Sac/val was formerly known as LCZ696 in clinical trials. 1. Entresto (sacubitril/valsartan) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August McMurray JJ et al. Eur J Heart Fail. 2013;15(9): McMurray JJ et al. N Engl J Med. 2014;371(11):

12 PARADIGM-HF Baseline Characteristics Characteristic* Sac/Val (N=4187) Enalapril (N=4212) Age, years 63.8 ± ± 11.3 Female, n (%) 879 (21.0) 953 (22.6) Ischemic cardiomyopathy, n (%) 2506 (59.9) 2530 (60.1) LVEF (%) 29.6 ± ± 6.3 NYHA functional class, n (%) II III 2998 (71.6) 969 (23.1) 2921 (69.3) 1049 (24.9) SBP, mm Hg 122 ± ± 15 Heart rate, BPM 72 ± ± 12 NT-proBNP, median, pg/ml (IQR) 1631 ( ) 1594 ( ) BNP, median, pg/ml (IQR) 255 ( ) 251 ( ) History of DM, n (%) 1451 (34.7) 1456 (34.6) Treatments at randomization, n (%) Diuretics Digitalis Beta-blockers MRAs ICD CRT 3363 (80.3) 1223 (29.2) 3899 (93.1) 2271 (54.2) 623 (14.9) 292 (7.0) 3375 (80.1) 1316 (31.2) 3912 (92.9) 2400 (57.0) 620 (14.7) 282 (6.7) BPM, beats per minute; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator; IQR, interquartile range; SBP, systolic blood pressure. *Mean ± standard deviation, unless stated. McMurray JJ et al. N Engl J Med. 2014;371:

13 PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) Kaplan-Meier Estimate of Cumulative Rates (%) Patients at Risk LCZ696 Enalapril 8 0 Enalapril (n=4212) Days After Randomization LCZ696 (n=4187) HR = 0.80 ( ) P = % ARR Number needed to treat = 21 over a median duration of 27 months

14 PARADIGM-HF: Cardiovascular Death 32 Kaplan-Meier Estimate of Cumulative Rates (%) HR = 0.80 ( ) P = % Relative Risk Reduction 3.2% Absolute Risk Reduction Number need to treat = 32 over a median duration of 27 months Enalapril (n=4212) LCZ696 (n=4187) Patients at Risk Days After Randomization LCZ696 Enalapril

15 PARADIGM-HF: All-Cause Mortality Kaplan-Meier Estimate of Cumulative Rates (%) HR = 0.84 ( ) P< % Relative Risk Reduction 2.8% Absolute Risk Reduction Enalapril (n=4212) LCZ696 (n=4187) Patients at Risk Days After Randomization LCZ696 Enalapril

16 PARADIGM-HF: Effect of LCZ696 vs Enalapril on Primary Endpoint and Its Components LCZ696 (n=4187) Enalapril (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 ( )

17 PARADIGM-HF: Effect of LCZ696 vs Enalapril on Secondary Endpoints LCZ696 (n=4187) Enalapril (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) 0.28

18 Sacubitril/Valsartan Adverse Reactions Occurring at an Incidence of 5% in the Double-Blind Period Adverse Reactions Occurring 5% Sac/Val N=4203 n (%) Enalapril N=4229 n (%) Hypotension Hyperkalemia Cough 9 13 Dizziness 6 5 Renal failure/acute renal failure 5 5 In the PARADIGM-HF trial, the incidence of angioedema was 0.1% in both the enalapril and sacubitril/valsartan run-in periods. In the double-blind period, the incidence of angioedema was higher in patients treated with sacubitril/valsartan than enalapril (0.5% and 0.2%, respectively). The incidence of angioedema in Black patients was 2.4% with sacubitril/valsartan and 0.5% with enalapril Orthostasis was reported in 2.1% of patients treated with sacubitril/valsartan compared to 1.1% of patients treated with enalapril during the double-blind period of PARADIGM-HF. Falls were reported in 1.9% of patients treated with sacubitril/valsartan compared to 1.3% of patients treated with enalapril Entresto (sacubitril/valsartan) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August

19 Sacubitril/Valsartan Permanent Discontinuation Rates During Run-in and Double Blind Periods of PARADIGM-HF Discontinuations during Enalapril run-in: 1,102 patients (10.5%) were discontinued 5.6% due to adverse event 1.7% renal dysfunction 1.7% hyperkalemia 1.4% hypotension Discontinuations during sac/val run-in: 977 Patients (10.4%) were discontinued 5.9% due to adverse event 1.8% renal dysfunction 1.3% hyperkalemia 1.7% hypotension Discontinuations During Double Blind Period Discontinuation Cause Sac/val (n=4187) Enalapril (n=4212) P Value Overall, any cause*, n(%) 746 (17.8%) 833 (19.8%) 0.02 Overall, adverse events, n(%) 450 (10.7%) 516 (12.2%) 0.03 Hypotension, n(%) 36 (0.9%) 29 (0.7%) 0.38 Renal Impairment 29 (0.7%) 59 (1.4%) Hyperkalemia 11 (0.3%) 15 (0.4%) 0.56 *except discontinuations due to death; / Based on safety evaluation for 4203 patients in sac/val group and 4229 patients in enalapril group McMurray JJ et al. NEJM. 2014;371(11): Entresto (sacubitril/valsartan) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August

20 Angiotensin Neprilysin Inhibition With LCZ696 Doubles Effect on Cardiovascular Death of Current Inhibitors of the Renin-Angiotensin System 0% Angiotensin receptor blocker ACE inhibitor Angiotensin neprilysin inhibition % Decrease in Mortality 10% 20% 30% 15% 18% 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 LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial

21 2017 ACC/AHA/HFSA Focused Update COR LOE Recommendations I ACE: A ARB: A ARNI: B-R COR LOE Recommendations I ARNI: B-R Updated Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor or ARB or ARNI (angiotensin receptor neprilysin inhibitor) The clinical strategy of inhibition of the renin-angiotensin system with ACE inhibitors (Level of Evidence: A), OR ARBs (Level of Evidence: A), OR ARNI (Level of Evidence: B-R) in conjunction with evidence-based beta blockers, and aldosterone antagonists in selected patients, is recommended for patients with chronic HFrEF to reduce morbidity and mortality. In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality. COR LOE Recommendations III: Harm B -R III: Harm C -EO ARNI should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor. ARNI should not be administered to patients with a history of angioedema. ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; CV, cardiovascular; HFrEF, heart failure with reduced ejection fraction; NYHA, New York Heart Association Yancy CW, Jessup M, Bozkurt B, et al ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2017;Apr 28:[Epub ahead of print]. 21

22 2017 ACC/AHA/HFSA Heart Failure Focused Update Yancy, et. al.

23 Sacubitril/Valsartan Warnings and Precautions Click on any of the warnings and precautions for more information Fetal Toxicity Angioedema Hypotension Impaired Renal Function Hyperkalemia Sacubitril/valsartan can cause fetal harm when administered to a pregnant woman Sacubitril/valsartan may cause angioedema. In the double-blind period of PARADIGM-HF, 0.5% of patients on sacubitril/valsartan and 0.2% of patients on enalapril had angioedema Sacubitril/valsartan lowers blood pressure and may cause symptomatic hypotension As a consequence of inhibiting the renin-angiotensin-aldosterone system (RAAS), decreases in renal function may be anticipated in susceptible individuals treated with sacubitril/valsartan Through its actions on the RAAS, hyperkalemia may occur with sacubitril/valsartan Entresto (sacubitril/valsartan) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August

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25 Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) USA (1) 2014 Amgen Inc. All rights reserved. Not for Reproduction.

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27 Mechanism

28 Regulation of PCSK9 is Dynamic

29 PCSK9 Inhibitors Evolocumab (Repatha ) Alirocumab (Praluent )

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55 Recommendations for Statin Treatment in People with Diabetes Age <40 years years >75 years None Risk Factors ASCVD risk factor(s)** ASCVD None ASCVD risk factors ACS & LDL >50 who can t tolerate high dose statin None ASCVD risk factors ASCVD ACS & LDL >50 who can t tolerate high dose statin None Statin Intensity * Moderate or high High Moderate High Moderate + ezetimibe Moderate Moderate or high High Moderate + ezetimibe

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57 AACE 2017 Guidelines

58 What Would Strobl Do? 1. Counsel patients on diet, weight loss, and exercise. 2. Add the highest tolerated dose of a potent statin in your patients with CAD, DM, or significant cardiac risk. 3. Consider treating residual cardiac risk if LDL-C and/or non-hdl remains elevated with an appropriate non-statin. THIS APPROACH IS NOT INCONSISTENT WITH THE GUIDELINES