Insuffisance cardiaque en 2019 · 2019-03-04 · Primary CV death, HHF or urgent HF endpoint • Time to first event of adjudicated CV death or adjudicated HHF Time to first occurrence

Insuffisance cardiaque en 2019

Pr Ahmed BENNIS

FESC , FACC [email protected]

Incremental benefit of drug therapies for chronic heart failure with reduced ejection fraction: a network meta‐analysis

European Journal of Heart Failure, Volume: 20, Issue: 9, Pages: 1315-1322, First published: 27 May 2018, DOI: (10.1002/ejhf.1234)

3

Single-blind Double-blind

Strategy to switch to and achieve target

doses of enalapril (n=4212)

Strategy to switch to and achieve target doses of

sacubitril- valsartan (n=4187)

Randomization

Demonstration of tolerance to target doses of enalapril

for 1-2 weeks

Demonstration of tolerance to target

doses of sacubitril/valsartan for

2-4 weeks

10,521 patients receiving long-term

treatment with ACE

inhibitors or angiotensin

receptor blockers at subtarget doses

PARADIGM-HF: Study Design

4

Enalapril (n=4212)

Sacubitril-valsartan (n=4187)

HR = 0.80 (0.71-0.89)

P = 0.00008

Median prolongation of life:

1.5-2.0 years

Kap

lan

-Meie

r E

sti

mate

of

C

um

ula

tive R

ate

s (

%)

LCZ696 4187 4056 3891 3282 2478 1716 1005 280

Enalapril 4212 4051 3860 3231 2410 1726 994 279

180 360 540 720 900 1080 1260

Days After Randomization

0 0

Patients at Risk

16

32

24

8

693

558

PARADIGM-HF: Cardiovascular Death

5

Change in e

GF

R F

rom

Baselin

e

Enalapril

Sacubitril-valsartan

48 36 12 0 24

Months

PARADIGM-HF: Less Renal Insufficiency With Sacubitril-Valsartan Than Enalapril

6

PARADIGM-HF: Superiority of Sacubitril-Valsartan Even in Patients Not Maintained on Target Doses

100% of Target

50-100% of Target

< 50% of Target

21% lower risk

21% lower risk

21% lower risk

Sacubitril/Valsartan Prevents Severe Hyperkalemia in Patients Taking MRAs

Reduced loop diuretic use in patients taking sacubitril/valsartan compared with enalapril: the PARADIGM‐HF trial

European Journal of Heart Failure, First published: 11 February 2019, DOI: (10.1002/ejhf.1402)

Original Article Angiotensin–Neprilysin Inhibition in Acute

Decompensated Heart Failure

Eric J. Velazquez, M.D., David A. Morrow, M.D., M.P.H., Adam D. DeVore, M.D., M.H.S., Carol I. Duffy, D.O., Andrew P. Ambrosy, M.D., Kevin McCague, M.A., Ricardo

Rocha, M.D., Eugene Braunwald, M.D., for the PIONEER-HF Investigators

N Engl J Med Volume 380(6):539-548

February 7, 2019

Screening, Randomization, and Follow-up.

Velazquez EJ et al. N Engl J Med 2019;380:539-548

Change in the NT-proBNP Concentration.


Subgroup Analyses of Change in the NT-proBNP Concentration.


Characteristics of the Patients at Baseline.


Secondary Efficacy and Safety Outcomes.


Angiotensin Receptor Neprilysin Inhibitor for Functional Mitral Regurgitation: The PRIME StudyBackground: The morbidity and mortality of patients with functional mitral regurgitation (MR) remain high, but no pharmacological therapy has been proven effective. The hypothesis of this study was that sacubitril/valsartan would be superior to valsartan alone in improving functional MR via dual inhibition of the renin-angiotensin system and neprilysin. Methods: In this double-blind trial, we randomly assigned 118 heart failure patients with chronic functional MR secondary to left ventricular (LV) dysfunction to receive either sacubitril/valsartan or valsartan, in addition to standard medical therapy for heart failure. The primary end point was the change in effective regurgitant orifice area (EROA) of functional MR from baseline to the 12-month follow-up. Secondary end points included changes in regurgitant volume, LV end-systolic volume, LV end-diastolic volume and incomplete mitral leaflet closure area. Results: The decrease in EROA was significantly greater in the sacubitril/valsartan group compared to the valsartan group (-0.058±0.095 versus -0.018±0.105 cm2; P=0.032) in an intention-to-treat analysis including 117 (99%) patients. Regurgitant volume was also significantly decreased in the sacubitril/valsartan group compared with the valsartan group (mean difference -7.3 ml, 95% CI -12.6 to -1.9; P=0.009). There were no significant between-group differences regarding the changes in incomplete mitral leaflet closure area and LV volumes except LV end-diastolic volume index (P=0.044). We noted no significant difference in the change of blood pressure between the treatment groups and 7 patients (12%) in the sacubitril/valsartan group and 9 (16%) in the valsartan group had one or more serious adverse events (P=0.54). Conclusions: Among patients with secondary functional MR, sacubitril/valsartan reduced MR to a greater extent than did valsartan. Our findings suggest that an angiotensin receptor neprilysin inhibitor might be considered for optimal medical therapy of patients with heart failure and functional MR.

Original Article Tafamidis Treatment for Patients with Transthyretin

Amyloid Cardiomyopathy

Mathew S. Maurer, M.D., Jeffrey H. Schwartz, Ph.D., Balarama Gundapaneni, M.S., Perry M. Elliott, M.D., Giampaolo Merlini, M.D., Ph.D., Marcia Waddington-Cruz, M.D.,

Arnt V. Kristen, M.D., Martha Grogan, M.D., Ronald Witteles, M.D., Thibaud

Damy, M.D., Ph.D., Brian M. Drachman, M.D., Sanjiv J. Shah, M.D., Mazen Hanna, M.D., Daniel P. Judge, M.D., Alexandra I. Barsdorf, Ph.D., Peter Huber, R.Ph.,

Terrell A. Patterson, Ph.D., Steven Riley, Pharm.D., Ph.D., Jennifer Schumacher, Ph.D., Michelle Stewart, Ph.D., Marla B. Sultan, M.D., M.B.A., Claudio

Rapezzi, M.D., for the ATTR-ACT Study Investigators


September 13, 2018

18

Study Overview

• In this randomized, controlled, phase 3 trial of tafamidis for transthyretin amyloid cardiomyopathy, tafamidis was associated with lower all-cause mortality and lower rates of cardiovascular-related hospitalizations and decline in functional capacity and quality of life.

Randomization, Evaluation, and Outcomes.

Maurer MS et al. N Engl J Med 2018;379:1007-1016

Primary Analysis and Components.


Overall and Subgroup Results as Calculated with the Use of the Finkelstein–Schoenfeld Method, All-Cause Mortality, and Cardiovascular-Related Hospitalizations.


Key Secondary End Points.


Demographic and Clinical Characteristics of the Patients at Baseline.


24

Conclusions

• In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo.

Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial

Brian P Halliday, PhD, Rebecca Wassall, MSc, Amrit S Lota, BMBCh, Zohya Khalique, MBBS, John Gregson, PhD, Simon Newsome, MSc, Robert Jackson, MSc, Tsveta Rahneva, BSc, Rick Wage, DCR, Gillian Smith, PhD, Lucia Venneri, MD, Upasana Tayal, PhD, Dominique Auger, MD, William

Midwinter, BSc, Nicola Whiffin, PhD, Ronak Rajani, MD, Jason N Dungu, PhD, Antonis Pantazis, MD, Prof Stuart A Cook, PhD, James S Ware, PhD, A John Baksi, PhD, Prof Dudley J Pennell, MD, Stuart D Rosen, MD, Prof Martin R Cowie, MD, Prof John G F Cleland, MD, Sanjay K Prasad, MD

The Lancet Volume 393, Issue 10166, Pages 61-73 (January 2019)

DOI: 10.1016/S0140-6736(18)32484-X

Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Terms and Conditions

http://www.elsevier.com/termsandconditions



Figure 1

The Lancet 2019 393, 61-73DOI: (10.1016/S0140-6736(18)32484-X) Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Terms and Conditions




Figure 2





Figure 3





Figure 4





Figure 5





Original Article Rivaroxaban in Patients with Heart Failure, Sinus

Rhythm, and Coronary Disease

Faiez Zannad, M.D., Ph.D., Stefan D. Anker, M.D., Ph.D., William M. Byra, M.D., John G.F. Cleland, M.D., Min Fu, Ph.D., Mihai Gheorghiade, M.D., Carolyn S.P. Lam, M.D.,

Ph.D., Mandeep R. Mehra, M.D., James D. Neaton, Ph.D., Christopher C.

Nessel, M.D., Theodore E. Spiro, M.D., Dirk J. van Veldhuisen, M.D., Ph.D., Barry Greenberg, M.D., for the COMMANDER HF Investigators


October 4, 2018

32

Study Overview

• Patients with heart failure, coronary artery disease, and no atrial fibrillation were randomly assigned to receive 2.5 mg of rivaroxaban twice daily or placebo.

• Rivaroxaban did not have a significant effect on the composite outcome of death, myocardial infarction, or stroke.

Randomization and Follow-up.

Zannad F et al. N Engl J Med 2018;379:1332-1342

Kaplan–Meier Analysis of the Primary Efficacy Outcome and of Death from Cardiovascular Causes or Rehospitalization for Worsening Heart Failure.


Subgroup Analyses of the Primary Efficacy Outcome.


Characteristics of the Patients at Baseline.


Efficacy and Safety Outcomes.


38

Conclusions

• Rivaroxaban at a dose of 2.5 mg twice daily was not associated with a significantly lower rate of death, myocardial infarction, or stroke than placebo among patients with worsening chronic heart failure, reduced left ventricular ejection fraction, coronary artery disease, and no atrial fibrillation.

New Approaches To Reducing Blood Glucose

IncretinS

(GIP)

GLP-1

Stimulate insulin

release

Inhibit glucagon

release

Reduce

blood glucose

DPP4

Breakdown

products DPP4 inhibitors

(“gliptins”)

GLP-1 agonists/analogues Inhibit gastro-

intestinal absorption

(α-glucosidase inhib.)

inhibit renal

Glc-reabsorption

(SGLT2

inhibitors)

40

Mode of action

13

Glucose SGLT-2 inhibitors reduce glucose

reabsorption in the proximal tubule, leading

to glucosuria with low risk of hypoglycemia

Glucosuria

Loss of calories

BP reduction

SGSGLLTT-2-2 inhibitor

Empagliflozin

SGLT-1

41

EMPEROR-Preserved1 EMPEROR-Reduced2 Dapa-HF3 SOLOIST-WHF4,5

Sample size 4126 2850* 4500 40004 (6667 ?) 5

Key inclusion criteria

• Chronic HF†

• Elevated NT-proBNP

• eGFR ≥20 ml/min/1.73 m2

• Symptomatic HFrEF†


• eGFR ≥30 ml/min/1.73 m2

• Type 2 diabetes

• Chronic HF


• Hospital admission for worsening HF and haemodynamically stable HFpEF (LVEF >40%) HFrEF (LVEF ≤40%) HFrEF (LVEF ≤40%)

Primary endpoint

• Time to first event of adjudicated CV death or adjudicated HHF

• Time to first occurrence of CV death, HHF or urgent HF visit

• Time to first event of CV death or HHF (both EF<50% and ll)

Key secondary endpoints

• Individual components of primary endpoint

• All-cause mortality

• All-cause hospitalisation

• Time to first occurrence of sustained reduction of eGFR

• Change from baseline in KCCQ

• Total number of CV death or HHF

• All-cause mortality

• Composite of ≥50% sustained eGFR decline, ESRD or renal death

• Change from baseline in KCCQ

• Total number of CV death, HHF or urgent HF visit

• Composite of ≥50% sustained eGFR decline, chronic dialysis, renal transplant or sustained eGFR <15 ml/min/1.73 m2

Start date

Expected completion date

March 2017

June 2020

March 2017

June 2020

February 2017

December 2019

June 2018

January 2021

Randomised controlled trials of SGLT2 inhibitors in HF

*NT-proBNP-based enrichment of the population with patients at higher severity of HF; †NYHA class II–IV ESRD, end-stage renal disease; HHF, hospitalisation for heart failure; KCCQ, Kansas City Cardiomyopathy Questionnaire; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro−B-type natriuretic peptide 1. ClinicalTrials.gov NCT03057951; 2. ClinicalTrials.gov NCT03057977; 3. ClinicalTrials.gov NCT03036124; 4. ClinicalTrials.gov NCT03521934; 5. EU Clinical Trials Register 2017-003510-16. Available at: https://www.clinicaltrialsregister.eu 22

http://www.clinicaltrialsregister.eu/



Boehringer Ingelheim and Lilly announce the CAROLINA® cardiovascular outcome trial of Tradjenta® met its primary endpoint of non-inferiority compared with glimepiride Tradjenta (linagliptin) demonstrated no increased cardiovascular risk compared with glimepiride in adults with type 2 diabetes and cardiovascular risk With a median follow-up of more than 6 years, CAROLINA adds evidence to the long-term safety profile of Tradjenta

Ridgefield, Conn. and Indianapolis, February 14, 2019 – Boehringer Ingelheim and Eli Lilly and Company (NYSE: LLY) announced CAROLINA® (CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 diabetes) met its primary endpoint, defined as non-inferiority for Tradjenta® (linagliptin) versus glimepiride in time to first occurrence of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke (3P-MACE). CAROLINA is the only active-comparator cardiovascular outcome trial for a dipeptidyl peptidase-4 (DPP-4) inhibitor. The trial evaluated the cardiovascular safety of Tradjenta (5 mg once daily) compared with the sulfonylurea glimepiride, on top of standard of care, in 6,033 adults with type 2 diabetes and increased cardiovascular risk or established cardiovascular disease. The study assessed Tradjenta safety over the longest period ever studied in a DPP-4 inhibitor cardiovascular outcome trial, with a median follow-up of more than 6 years. The overall safety profile of Tradjenta in CAROLINA was consistent with previous data, and no new safety signals were observed.

Original Article Two-Year Outcomes with a Magnetically Levitated

Cardiac Pump in Heart Failure

Mandeep R. Mehra, M.D., Daniel J. Goldstein, M.D., Nir Uriel, M.D., Joseph C. Cleveland, Jr., M.D., Melana Yuzefpolskaya, M.D., Christopher Salerno, M.D., Mary N. Walsh, M.D., Carmelo A. Milano, M.D., Chetan B. Patel, M.D., Gregory A. Ewald, M.D.,

Akinobu Itoh, M.D., David Dean, M.D., Arun Krishnamoorthy, M.D., William G. Cotts, M.D., Antone J. Tatooles, M.D., Ulrich P. Jorde, M.D., Brian A. Bruckner, M.D.,

Jerry D. Estep, M.D., Valluvan Jeevanandam, M.D., Gabriel Sayer, M.D., Douglas Horstmanshof, M.D., James W. Long, M.D., Sanjeev Gulati, M.D., Eric R.

Skipper, M.D., John B. O’Connell, M.D., Gerald Heatley, M.S., Poornima Sood, M.D.,

Yoshifumi Naka, M.D., for the MOMENTUM 3 Investigators


April 12, 2018

45

Study Overview

• In a randomized trial, 366 patients with advanced heart failure received a centrifugal- or axial-flow LVAD.

• At 2 years, the centrifugal-flow LVAD was superior with regard to survival free of disabling stroke or reoperation to replace or remove a malfunctioning device.

Kaplan–Meier Estimates of the Primary End Point in the Intention-to-Treat Population.

Mehra MR et al. N Engl J Med 2018;378:1386-1395

Interactive CardioVascular and Thoracic Surgery, Volume 27, Issue 6, 09 October 2018, Pages 921–930, https://doi.org/10.1093/icvts/ivy282

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Insuffisance cardiaque en 2019 · 2019-03-04 · Primary CV death, HHF or urgent HF endpoint • Time to first event of adjudicated CV death or adjudicated HHF Time to first occurrence