Cardiac Remodeling

Cardiac
Remodeling

In the PROVE-HF trial, reduction in NT-proBNP with ENTRESTO significantly correlated with improvement across measures of cardiac structure and function1

PROVE-HF PRIMARY END POINT

  • The primary end point was correlation
    (Pearson r) between change in echocardiographic
    remodeling parameters and NT-proBNP at 12 months*
PROVE-HF-PRIMARY-END-POINT

PROVE-HF PRIMARY END POINT

  • The primary end point was correlation
    (Pearson r) between change in echocardiographic
    remodeling parameters and NT-proBNP at 12 months*

*P<0.001.

E/e'=filling pressure (early diastolic filling velocity/early diastolic mitral annular velocity); LAVI=left atrial volume index; LVEDVI=left ventricular end-diastolic volume index; LVEF=left ventricular ejection fraction; LVESVI=left ventricular end-systolic volume index.

A Pearson correlation coefficient (Pearson r) measures how strong the association is between 2 variables. It ranges from 1 (exactly correlated) to -1 (exactly inversely correlated).

*P<0.001.

Patients in the PROVE-HF trial showed reverse cardiac remodeling and biomarker improvement1

ENTRESTO improved key echocardiographic measures of cardiac remodeling, including increased LVEF, and reduced NT-proBNP

ls-lean-change

Reduction in NT-proBNP was demonstrated at 6 months (35%) and 12 months (37%)

The primary end point was the correlation between change in NT-proBNP and cardiac remodeling parameters at 12 months.

A secondary end point was the correlation between change in NT-proBNP and change in cardiac remodeling parameters at 6 months.§

Lower, yet significant correlations were seen from baseline to 6 months.§

LVEF (%) are median values. Changes in LVEF are LS (least-square) mean change values from baseline.

LS geometric mean concentration changes from baseline NT-proBNP to follow-up.

§P<0.001.

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PROVE-HF STUDY DESIGN

PROVE-HF study design1

52-week, single-arm, prospective, open-label phase IV evaluation of 794 HFrEF patients in the United States. The primary end point was correlation of change in NT-proBNP to change in cardiac remodeling parameters. At each study visit, a blood sample was sent to a central laboratory for measurement of plasma NT-proBNP. Following completion, echocardiograms were transmitted in a secure fashion to a core laboratory, where they were interpreted following completion of all study protocols in a temporally and clinically blinded fashion.

Key inclusion criteria:

  • Aged ≥18 years

  • Patients with HFrEF who were candidates for on-label sacubitril/valsartan treatment per the standard of care

  • NYHA Functional Class II, III, or IV

  • LVEF ≤40% within the preceding 6 months according to any local measurement and no subsequent documentation of EF >40%

  • Stable dose of loop diuretic for the 2 weeks preceding study start

Key exclusion criteria:

  • History of hypersensitivity/allergy or suspected contraindication to any study drug component or to drugs of similar chemical classes, including ACEis, angiotensin receptor blockers, or neprilysin inhibitors

  • Any angioedema history (drug-related or otherwise)

  • Concomitant use of ACEi therapy, nesiritide, aliskiren, or drugs that may affect absorption of the study medication

  • Current or previous treatment with sacubitril/valsartan

  • Inadequate washout of other investigational drugs before study initiation

  • Enrollment in another clinical trial within 30 days of screening

  • Potassium >5.2 mEq/L at screening

  • History of malignancy within 1 year

  • Pregnancy, lactation, or use of any method of contraception that is not highly effective

  • Implantation of CRT-D within 6 months of screening visit

  • Prior heart transplant or left ventricular assist device or intent to implant either

ACEi=angiotensin converting enzyme inhibitor; CRT-D=cardiac resynchronization therapy defibrillator; EF=ejection fraction; NYHA=New York Heart Association.

PROVE-HF: STUDY LIMITATIONS

PROVE-HF study limitations1

  • Observational, single-group, open-label design

  • A broad range of factors may affect NT-proBNP concentrations besides cardiac remodeling

  • Multiple comparisons may have increased risk of type 1 error

  • Not all echocardiographic measurements were available at each time point

  • Race was investigator-determined, with potential risk for inaccuracy

Reduction in NT-proBNP has been associated with reverse cardiac remodeling1-3

Cardiac remodeling leads to disease progression and increased risk of CV death and HF hospitalization in patients with systolic HF4-6

CARDIAC REMODELING OVERVIEW

Cardiac Remodeling

PARADIGM-HF OVERVIEW AND NT-proBNP ANALYSIS

PARADIGM-HF was a multinational, randomized, double-blind trial comparing ENTRESTO to enalapril in 8442 symptomatic (NYHA Class Il-IV) adult systolic HF patients (LVEF ≤40%). After discontinuing their existing ACEi or ARB therapy, patients entered sequential single-blind run-in periods during which they received enalapril 10 mg twice daily, followed by ENTRESTO 100 mg (49/51 mg) twice daily, increasing to 200 mg (97/103 mg) twice daily. Patients who successfully completed the run-in periods were then randomized to receive either ENTRESTO 200 mg (97/103 mg) (n=4209) twice daily or enalapril 10 mg (n=4233) twice daily. The median follow-up duration was 27 months, and patients were treated for up to 4.3 years.3 For the primary end point, composite of CV death or first HF hospitalization, ENTRESTO was superior to enalapril (P<0.0001). In an exploratory analysis, ENTRESTO lowered NT-proBNP.

PARADIGM-HF post-hoc NT-proBNP analysis limitations:

  • Biomarker measurements, including NT-proBNP, were drawn and analyzed in a subgroup of the total PARADIGM-HF patient population and therefore might not represent the entire cohort of systolic HF patients studied

  • Biological variability may influence the accuracy of a predictive value of a change in biomarkers. The change from baseline data should be interpreted in light of this influence

ENTRESTO CV effects are due to increased peptides and decreased angiotensin II effects, which resulted in decreased NT-proBNP.

EXPAND

INDICATION

ENTRESTO® is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

ENTRESTO is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB.

IMPORTANT SAFETY INFORMATION

WARNING: FETAL TOXICITY

  • When pregnancy is detected, discontinue ENTRESTO as soon as possible

  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus

COLLAPSE

INDICATION

ENTRESTO® is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

ENTRESTO is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB.

IMPORTANT SAFETY INFORMATION

WARNING: FETAL TOXICITY

  • When pregnancy is detected, discontinue ENTRESTO as soon as possible

  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus

ENTRESTO is contraindicated in patients with hypersensitivity to any component. ENTRESTO is contraindicated in patients with a history of angioedema related to previous angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy.

ENTRESTO is contraindicated with concomitant use of ACE inhibitors. Do not administer within 36 hours of switching from or to an ACE inhibitor. ENTRESTO is contraindicated with concomitant use of aliskiren in patients with diabetes.

Angioedema: ENTRESTO may cause angioedema. Angioedema associated with laryngeal edema may be fatal. ENTRESTO has been associated with a higher rate of angioedema in Black patients and in patients with a prior history of angioedema. ENTRESTO should not be used in patients with hereditary angioedema. If angioedema occurs, discontinue ENTRESTO immediately, provide appropriate therapy, and monitor for airway compromise. ENTRESTO must not be re-administered.

Hypotension: ENTRESTO lowers blood pressure and may cause symptomatic hypotension. Patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), are at greater risk. Correct volume or salt depletion prior to administration of ENTRESTO or start at a lower dose. If hypotension persists despite dose adjustment of diuretics, concomitant antihypertensive drugs, and treatment of other causes of hypotension (e.g., hypovolemia) reduce the dosage or temporarily discontinue ENTRESTO. Permanent discontinuation of therapy is usually not required.

Impaired Renal Function: Decreases in renal function may be anticipated in susceptible individuals treated with ENTRESTO. In patients whose renal function depends upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria, progressive azotemia and, rarely, acute renal failure and death. Closely monitor serum creatinine, and down-titrate or interrupt ENTRESTO in patients who develop a clinically significant decrease in renal function.

ENTRESTO may increase blood urea and serum creatinine levels in patients with bilateral or unilateral renal artery stenosis. In patients with renal artery stenosis, monitor renal function. Avoid use with aliskiren in patients with renal impairment (eGFR <60 mL/min/1.73 m2).

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors, with ENTRESTO may result in worsening of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically.

Hyperkalemia: Hyperkalemia may occur with ENTRESTO. Monitor serum potassium periodically and treat appropriately, especially in patients with risk factors for hyperkalemia such as severe renal impairment, diabetes, hypoaldosteronism, or a high potassium diet. Dosage reduction or interruption of ENTRESTO may be required.

Concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.

ARBs: Avoid use of ENTRESTO with an ARB, because ENTRESTO contains the angiotensin II receptor blocker valsartan.

Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use with ENTRESTO.

Common Adverse Events: In a clinical trial, the most commonly observed adverse events with ENTRESTO vs enalapril, occurring at a frequency of at least 5% in either group, were hypotension (18%, 12%), hyperkalemia (12%, 14%), cough (9%, 13%) dizziness (6%, 5%) and renal failure/acute renal failure (5%, 5%).

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References:

1. Januzzi JL Jr, Prescott MF, Butler J, et al; for the PROVE-HF Investigators. Association of change in N-terminal pro—b-type natriuretic peptide following initiation of sacubitril-valsartan treatment with cardiac structure and function in patients with heart failure with reduced ejection fraction [published online ahead of print September 2, 2019]. JAMA. doi:10.1001/jama.2019.12821. Accessed October 30, 2019. 2. Daubert MA, Adams K, Yow E, et al. NT-proBNP goal achievement is associated with significant reverse remodeling and improved clinical outcomes in HFrEF. JACC Heart Fail. 2019;7(2):158-168. doi:10.1016/j.jchf.2018.10.014. 3. Weiner RB, Baggish AL, Chen-Tournoux A, et al. Improvement in structural and functional echocardiographic parameters during chronic heart failure therapy guided by natriuretic peptides: mechanistic insights from the ProBNP Outpatient Tailored Chronic Heart Failure (PROTECT) study. Eur J Heart Fail. 2013;15(3):342-351. doi:10.1093/eurjhf/hfs180. 4. Konstam MA, Kramer DG, Patel AR, Maron MS, Udelson JE. Left ventricular remodeling in heart failure: current concepts in clinical significance and assessment. JACC Cardiovasc Imaging. 2011;4(1):98-108. 5. Cohn JN, Ferrari R, Sharpe N; on behalf of an International Forum on Cardiac Remodeling. Cardiac remodeling—concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. J Am Coll Cardiol. 2000;35(3):569-582. 6. Udelson JE, Konstam MA. Ventricular remodeling: fundamental to the progression (and regression) of heart failure. J Am Coll Cardiol. 2011;57(13):1477-1479.

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