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Paradigm HF

LCZ696, which inhibits the angiotensin receptor and neprilysin, reduced the risk of cardiovascular death or heart failure hospitalization by 20% compared to enalapril in the PARADIGM-HF trial. LCZ696 also reduced the risks of cardiovascular death alone by 20% and all-cause mortality by 16% compared to enalapril. The results suggest that LCZ696 should replace current use of ACE inhibitors as the standard treatment for chronic heart failure with reduced ejection fraction.

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Thomas Smith
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76 views16 pages

Paradigm HF

LCZ696, which inhibits the angiotensin receptor and neprilysin, reduced the risk of cardiovascular death or heart failure hospitalization by 20% compared to enalapril in the PARADIGM-HF trial. LCZ696 also reduced the risks of cardiovascular death alone by 20% and all-cause mortality by 16% compared to enalapril. The results suggest that LCZ696 should replace current use of ACE inhibitors as the standard treatment for chronic heart failure with reduced ejection fraction.

Uploaded by

Thomas Smith
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© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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A Comparison of Angiotensin ReceptorNeprilysin Inhibition 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

Disclosures for Presenter


Within past 3 years (related to any aspect of heart
failure):
Consultant to: AMAG, Amgen, BioControl,
CardioKinetix, CardioMEMS, Cardiorentis, Daiichi,
Janssen, Novartis, Sanofi

Drugs That Reduce Mortality in Heart


Failure With Reduced Ejection Fraction
Angiotensin
receptor
blocker

ACE
inhibitor

Beta
blocker

Mineralocorticoid
receptor
antagonist

% Decrease in Mortality

0%

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

Neprilysin Inhibition Potentiates Actions of


Endogenous Vasoactive Peptides That Counter
Maladaptive Mechanisms in Heart Failure
Endogenous
vasoactive peptides
(natriuretic peptides, adrenomedullin,
bradykinin, substance P,
calcitonin gene-related peptide)

Neprilysin
Inactive metabolites

Neurohormonal
activation
Vascular tone
Cardiac fibrosis,
hypertrophy
Sodium retention
Neprilysin
inhibition

LCZ696: Angiotensin Receptor Neprilysin Inhibition

LCZ696

Angiotensin
receptor blocker

Inhibitor of
neprilysin

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)
LCZ696
400 mg daily

Enalapril
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 35-40%

At least mild increases in BNP or N-terminal proBNP

Any use of ACE inhibitor or ARB, but able to tolerate


stable dose equivalent to at least enalapril 10 mg
daily for 4 weeks

Guideline-recommended use of beta-blockers and


mineralocorticoid receptor antagonists

Systolic BP 95 mm Hg, eGFR 30 ml/min/1.73 m2


and serum K 5.4 mEq/L at randomization

PARADIGM-HF: Primary Objective


Primary endpoint was cardiovascular death or
hospitalization for heart failure, but PARADIGMHF was designed as a cardiovascular mortality
trial
The trial size was determined by effect on cardiovascular
mortality. The Data Monitoring Committee was allowed to stop
the trial only for a compelling effect on cardiovascular
mortality.
Difference of 15% in cardiovascular mortality between
LCZ696 and enalapril was prospectively identified as being
clinically important, since it would allow us to detect LCZ696related doubling of the survival benefits of current inhibitors of

PARADIGM-HF: Baseline Characteristics of


8399 Randomized Patients in ITT Analysis
Age (years)
Women (%)
Ischemic cardiomyopathy (%)
LV ejection fraction (%)
NYHA functional class II / III (%)
Systolic blood pressure (mm Hg)
Heart rate (beats/min)
N-terminal pro-BNP (pg/ml)
B-type natriuretic peptide (pg/ml)
History of diabetes
Digitalis
Beta-adrenergic blockers
Mineralocorticoid antagonists

LCZ696
(n=4187)

Enalapril
(n=4212)

63.8 11.5
21.0%
59.9%
29.6 6.1
71.6% / 23.1%
122 15
72 12
1631 (885-3154)
255 (155-474)
35%
29.3%
93.1%
54.2%

63.8 11.3
22.6%
60.1%
29.4 6.3
69.4% / 24.9%
121 15
73 12
1594 (886-3305)
251 (153-465)
35%
31.2%
92.9%
57.0%

PARADIGM-HF: Cardiovascular Death or Heart


Failure Hospitalization (Primary Endpoint)

Kaplan-Meier Estimate of
Cumulative Rates (%)

40

32

(n=4212)

914

24

LCZ696
(n=4187)

16

HR = 0.80 (0.73-0.87)
P = 0.0000002
Number needed to treat = 21

8
0

180

360

540

720

900

1080

1260

896
853

249
236

Days After Randomization

Patients at Risk
LCZ696
Enalapril

1117

Enalapril

4187
4212

3922
3883

3663
3579

3018
2922

2257
2123

1544
1488

PARADIGM-HF: Cardiovascular Death

Kaplan-Meier Estimate of
Cumulative Rates (%)

32

Enalapril
24

HR = 0.80 (0.71-0.89)
P = 0.00004
Number need to treat = 32

(n=4212)

693
558

16

LCZ696

8
0

(n=4187)

180

360

540

720

900

1080

1260

1005
994

280
279

Days After Randomization


Patients at Risk
LCZ696
Enalapril

4187
4212

4056
4051

3891
3860

3282
3231

2478
2410

1716
1726

PARADIGM-HF: All-Cause Mortality

Kaplan-Meier Estimate of
Cumulative Rates (%)

32
HR = 0.84 (0.76-0.93)
P<0.0001

24

835

(n=4212)

711

16

LCZ696
(n=4187)

180

360

540

720

900

1080

1260

1005
994

280
279

Days After Randomization

Patients at Risk
LCZ696
Enalapril

Enalapril

4187
4212

4056
4051

3891
3860

3282
3231

2478
2410

1716
1726

PARADIGM-HF: Additional Findings


LCZ696 was also more effective than enalapril in . . .

Reducing the risk of a heart failure hospitalization by


incremental 21%

Incrementally improving symptoms and physical


limitations of heart failure

LCZ696 was better tolerated than enalapril . . .

Less likely to cause cough, hyperkalemia or renal


impairment or be discontinued for an adverse event

More hypotension, but no increase in


discontinuations

No increase in risk of serious angioedema

The primary results of the PARADIGM-HF trial are


being published online today at nejm.org

Angiotensin Neprilysin Inhibition With LCZ696


Doubles Effect on Cardiovascular Death of Current
Inhibitors of the Renin-Angiotensin System

% Decrease in Mortality

0%

10%

Angiotensin
receptor
blocker

Angiotensin
neprilysin
inhibition

ACE
inhibitor

15%

18%

20%

20%
30%

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

Clinical Importance of the Findings


of the PARADIGM-HF Trial
For the last 25 years, the magnitude of the effect of
ACE inhibitors on cardiovascular mortality (18%)
has created an ethical mandate for their use in all
patients with chronic heart failure who could
tolerate treatment with these drugs.

The finding that LCZ696 has an 20% greater effect


on cardiovascular mortality than ACE inhibitors
strongly supports the conclusion that LCZ696
should replace current use of ACE inhibitors and
angiotensin receptor blockers in the management
of chronic heart failure.

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