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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 status1,2

  • The KCCQ-23 Clinical Summary Score (CS) represents the average of the symptom (frequency and burden) and physical limitation domains1,2

  • 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 enalapril1,2

*Clinically meaningful difference established as 5 points.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.

KCCQ LIMITATIONS

KCCQ limitations2,4

  • Recall period for KCCQ is 2 weeks, rather than daily

  • Patients who do not perform activities because of conditions other than their HF will have missing scores for the physical limitation domain

Additional limitations of KCCQ-23 analysis as utilized in PARADIGM-HF3

  • 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 HF hospitalizations

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 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. For the primary end point, composite of CV death or first HF hospitalization, ENTRESTO was superior to enalapril (P<0.0001).

ENTRESTO patients had improved HRQoL scores2,5

CHAMP-HF registry: Patients taking ENTRESTO experienced improvement in HRQoL overall summary score compared to those not taking ENTRESTO

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 KCCQ STUDY DESIGN

CHAMP-HF KCCQ analysis study design5,6

The CHAnge the Management of Patients with Heart Failure (CHAMP-HF) registry evaluated the care and outcomes of patients with chronic HFrEF by assessing real-world treatment patterns, as well as the reasons for and barriers to medication treatment changes. CHAMP-HF enrolled 5026 patients with HFrEF, and patients were followed for a maximum duration of 24 months, or until death or study withdrawal. CHAMP-HF utilized Kansas City Cardiomyopathy Questionnaire 12-item questionnaire (KCCQ-12) to assess patient-reported HF-related QOL.

CHAMP-HF was a multicenter, observational, prospective, nonrandomized study designed to capture the care and outcomes of patients with HFrEF across outpatient practices in the United States. Eligibility criteria included adults with a diagnosis of chronic HFrEF (left ventricular ejection fraction ≤40%) and use of at least 1 oral pharmacotherapy as part of routine outpatient management for heart failure.

Patients were classified as:

  1. New ARNI starts = patients who begin ARNI
    therapy at or after enrollment
  2. No-ARNI patients = patients who do not
    begin ARNI therapy

The KCCQ analysis cohort included 1524 patients, 508 who started an ARNI and 1016 who did not, matched in a 1:2 ratio.

  • Among the ARNI patients, 267 were on an ACEi/ARB in the 2 weeks prior to the ARNI (534 matched no ARNI) and 241 were not on an ACEi/ARB at the time of ARNI start (482 matched no-ARNI)

The primary outcome of the KCCQ analysis was the overall KCCQ score, from the first assessment that occurs at least 2 weeks after the ARNI initiation date, or that occurs on or after the match date for no ARNI patients.

CHAMP-HF KCCQ STUDY LIMITATIONS

KCCQ-12 limitations5

  • Limitations of the KCCQ-23 also apply

Additional limitations of KCCQ-12 analysis as utilized in CHAMP-HF

  • CHAMP-HF was an observational registry and is thereby susceptible to bias as a result of unmeasured confounding. The role of placebo effect due to open-label ARNI use cannot be excluded

  • Patients who start an ARNI may be different from patients who do not

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

  • Results only apply to outpatients with HFrEF

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. Data on file. LCZ696 Clinical Study Report (CLCZ696B2314). Novartis Pharmaceuticals Corp; 2014. 2. 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. 3. Lewis EF, Claggett BL, McMurray JJV, et al. Health-related quality of life outcomes in PARADIGM-HF. Circ Heart Fail. 2017;10(8):e003430. 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.

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