HFrEF > Quality of Life

PARADIGM-HF: Patients taking ENTRESTO® felt better than those taking enalapril1

Patients taking ENTRESTO experienced less decline than those taking enalapril

ENTRESTO is available in 3 dosage strengths
  • PARADIGM-HF utilized the Kansas City Cardiomyopathy Questionnaire-23 (KCCQ-23), a measurement of health-related quality of life (HRQoL) assessing these domains: physical limitation, symptom frequency, symptom burden, symptom stability, self-efficacy, social limitation, and quality of life. Each domain is scored on a scale of 0-100; higher scores indicate better health status1,3

  • The KCCQ-23 Clinical Summary score (CS) represents the average of the symptom (frequency and burden) and physical limitation domains1,3

  • The KCCQ-23 Overall Summary score (OS) represents the average of the CS as well as the quality of life and social limitation domains. PARADIGM-HF KCCQ-23 change from baseline to Month 8 in OS was -2.35 for ENTRESTO and -4.27 for enalapril1,3

Analysis included all patients with at least 1 KCCQ data up to Month 8. For patients who died, the worst score (0) was imputed for the CS at all subsequent scheduled visits.

PARADIGM-HF: KCCQ-23 ANALYSIS & KCCQ-23 TOOL LIMITATIONS

PARADIGM-HF: KCCQ-23 analysis limitations2

  • Baseline KCCQ-23 CS in the overall PARADIGM-HF population was assessed at randomization. This may have resulted in higher baseline scores due to treatment during the run-in phase. Limited data exist assessing clinical meaningfulness of change scores in patients with relatively good baseline perceptions of HRQoL

  • Statistical analysis suggests that the difference between ENTRESTO and enalapril treatment arms may have been driven in part by the treatment effect on heart failure hospitalizations

KCCQ-23 tool limitations3,4

  • Two week recall period

  • Missing scores in physical limitation domain due to conditions other than heart failure

PARADIGM-HF PRIMARY END POINT

PARADIGM-HF was a multinational, randomized, double-blind trial comparing ENTRESTO to enalapril in 8442 symptomatic (NYHA Class Il-IV) adult HFrEF patients (LVEF ≤40%). After discontinuing their existing ACEi or ARB therapy, patients entered sequential single-blind run-in periods during which they received enalapril, followed by ENTRESTO. Patients who successfully completed the run-in periods were then randomized to receive either ENTRESTO 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. For the primary end point, composite of CV death or first heart failure hospitalization, ENTRESTO was superior to enalapril (P<0.0001).

LVEF=left ventricular ejection fraction;
NYHA=New York Heart Association.

ENTRESTO patients had improved HRQoL scores3,5

CHAMP-HF: Patients taking ENTRESTO reported less physical and social limitation, and improved QoL

ENTRESTO is available in 3 dosage strengths

A change of 5 points was considered a minimal clinically important difference. §Changes between pre- and postmatch scores shown over a median of 57 days (32-104).

  • The CHAnge the Management of Patients with Heart Failure (CHAMP-HF) registry evaluated the real-world care and outcomes of 5026 patients with chronic HFrEF

  • CHAMP-HF utilized the KCCQ-12, a shortened version of the KCCQ-23, which assesses the following domains: physical limitation, symptom frequency, social limitation, and quality of life

  • The KCCQ-12 Overall Summary Score represents the average of all 4 domains. A Clinical Summary Score is not a component of the KCCQ-12

CHAMP-HF REGISTRY DESIGN & KCCQ-12 ANALYSIS

CHAMP-HF Registry Design & KCCQ-12 analysis5,6

CHAnge the Management of Patients with Heart Failure (CHAMP-HF) was a multicenter, observational, prospective registry study that evaluated care and outcomes of 5026 adult heart failure patients with reduced EF (LVEF ≤40%) on at least 1 oral heart failure pharmacotherapy across practices in the United States. Patients were followed up to 24 months or until death/study withdrawal. CHAMP-HF utilized KCCQ-12, a shortened version of the KCCQ-23, which assesses the following domains: physical limitation, symptom frequency, social limitation, and quality of life. The KCCQ-12 Overall Summary Score (OS) represents the average of all 4 domains. A Clinical Summary Score is not a component of the KCCQ-12

This analysis cohort included 1524 patients–508 who started ENTRESTO after enrollment and 1016 who did not. Patients were propensity matched in a 1:2 ratio based on a time-dependent propensity score, most recent KCCQ-12 OS, and ACEi/ARB status.

The primary outcome was change in KCCQ-12 OS from the last pre-match assessment to the first post-match assessment (≥2 weeks after initiation, for ENTRESTO patients).

ACEi=angiotensin-converting enzyme inhibitor;
ARB=angiotensin II receptor blocker.

CHAMP-HF: KCCQ-12 ANALYSIS LIMITATIONS

CHAMP-HF: KCCQ-12 analysis limitations5

  • Observational registry design susceptible to bias due to unmeasured confounding. Role of placebo effect due to open-label ENTRESTO use cannot be excluded

  • Patients who started ENTRESTO may be different from patients who did not

  • Findings may not be generalizable throughout the United States or to other countries

  • KCCQ-23 tool limitations also apply to the KCCQ-12

Read about the effect that ENTRESTO had on
hospitalization vs enalapril

HFrEF=heart failure with reduced ejection fraction.

*In PARAGON-HF, defined as LVEF ≥45% with structural heart disease (LAE or LVH); median LVEF was 57%. LVEF is a variable measure and the normal range can vary.7

EXPAND

INDICATION

ENTRESTO is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.

LVEF is a variable measure, so use clinical judgment in deciding whom to treat.

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 adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.

LVEF is a variable measure, so use clinical judgment in deciding whom to treat.

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 of patients with heart failure with reduced ejection fraction, 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%). No new adverse reactions were identified in a trial of the remaining indicated population.

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References:

1. Data on file. LCZ696 Clinical Study Report (CLCZ696B2314). Novartis Pharmaceuticals Corp; 2014. 2. Lewis EF, Claggett BL, McMurray JJV, et al. Health-related quality of life outcomes in PARADIGM-HF. Circ Heart Fail. 2017;10(8):e003430. 3. Spertus JA, Jones PG. Development and validation of a short version of the Kansas City cardiomyopathy questionnaire. Circ Cardiovasc Qual Outcomes. 2015;8(5):469-476. 4. Kansas City Cardiomyopathy Questionnaire (KCCQ). Medical Device Development Tool (MDDT) Qualification Decision Summary. https://www.fda.gov/media/108301/download. Qualified October 19, 2017. Accessed July 2, 2019. 5. Data on file CHAMP-HF Khariton ARNI-KCCQ Final Analysis Results. Novartis Pharmaceuticals Corp; June 2020. 6. DeVore AD, Thomas L, Albert NM, et al. Change the management of patients with heart failure: rationale and design of the CHAMP-HF registry. Am Heart J. 2017;189:177-183. 7. ENTRESTO [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp.

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