Hospitalization and Initiation

Hospitalization and Initiation

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HOSPITALIZATION

  • HOSPITALIZATION

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HOSPITALIZATION

INITIATION

PARADIGM-HF: ENTRESTO reduced 15-day HF readmissions vs enalapril

ENTRESTO demonstrated fewer 15-day HF readmissions in a post hoc analysis1

15-day HF readmissions

15-day-HF-readmissions

PARADIGM-HF: Readmission was defined as the second hospitalization within 30 days of the first hospitalization after initiation of study drug.

PARADIGM-HF: ENTRESTO reduced 30-day HF readmissions vs enalapril

ENTRESTO demonstrated fewer 30-day HF readmissions in a post hoc analysis1,2*†

30-day HF readmissions

30-day-HF-readmissions

PARADIGM-HF: Readmission was defined as the second hospitalization within 30 days of the first hospitalization after initiation of study drug.1 *Vs enalapril. Among patients hospitalized at least once for HF, patient characteristics were similar at baseline between treatment groups.

PARADIGM-HF PRIMARY END POINT KM CURVE

PARADIGM-HF: Time to first occurrence of CV death or HF hospitalization4
PARADIGM-HF: Time to first occurrence of CV death or HF hospitalization

ARR=absolute risk reduction; CI=confidence interval; HR=hazard ratio; KM=Kaplan—Meier; NNT=number needed to treat; RRR=relative risk reduction.

The median follow-up duration was 27 months and patients were treated for up to 4.3 years.

There was a reduction in each component: CV death 20% RRR, 3.2% ARR; HF hospitalization 21% RRR, 2.8% ARR.

PARADIGM-HF STUDY READMISSION ANALYSES LIMITATIONS

PARADIGM-HF post hoc study limitations2
  • Post hoc study was not a prespecified analysis of the PARADIGM-HF study

  • Patients were not randomized to treatment with ENTRESTO or enalapril at the time of index hospitalization

  • The apparent differences in readmission rate noted in this analysis could be attributed to differences in the patients

  • Analysis focused on HF readmissions following investigator-reported HF hospitalizations, which were vulnerable to misclassification

  • The primary unit of subsequent analysis was hospitalizations rather than patients

  • 15-day readmissions for HF is not a routinely examined time point in quality and clinical assessments, and such early time points may not reflect causality

PIONEER-HF: ENTRESTO reduced 8-week HF readmissions vs enalapril

Inpatient initiation of ENTRESTO in stabilized patients resulted in fewer HF readmissions at 8 weeks3

8-week HF readmissions: Prespecified Exploratory End point

PIONEER-HF: ENTRESTO reduced 8-week HF readmissions vs enalapril

PIONEER-HF: Readmission was defined as the first hospitalization after inpatient initiation of study drug.3

PIONEER-HF PRIMARY END POINT

PIONEER-HF was a multicenter, randomized, double-blind, active controlled clinical trial of in-hospital initiation of ENTRESTO (n=440) compared with enalapril (n=441) among HF patients with reduced EF (LVEF≤40%) who had been stabilized following admission for ADHF. At the primary efficacy outcome, time-averaged proportional change in NT-proBNP concentration from baseline through weeks 4 and 8, ENTRESTO was superior to enalapril (P<.001).

PIONEER-HF STUDY READMISSION ANALYSIS LIMITATIONS

PIONEER-HF study limitations3
  • The study was powered for changes in NT-proBNP and secondary and exploratory end points should be interpreted with caution

  • The event rate of HF readmission was a prespecified exploratory end point from the PIONEER-HF trial

The median time for patients to meet the stabilization criteria was less than 3 days after initial presentation to the hospital3

PIONEER-HF STABILIZATION CRITERIA

In PIONEER-HF, hospitalized patients were determined to be stabilized when they met all the following criteria:

PIONEER-HF STABILIZATION CRITERIA

BP=blood pressure; IV=intravenous.

ENTRESTO was started in the hospital in a diverse set of stabilized patients3

Patients enrolled in PIONEER-HF reflect the patients you are likely to treat in your hospital

PIONEER-HF SELECTED DEMOGRAPHIC INFORMATION

PIONEER-HF SELECTED DEMOGRAPHIC INFORMATION

*Patients were determined to be ACEi/ARB-naive if they were not receiving either medication at the time of index hospitalization.

Whether in the outpatient or inpatient setting, you can start with ENTRESTO across a wide range of patient types3,5,7

PIONEER-HF: demonstrated safety profile in inpatient initiations

PIONEER-HF ADVERSE EVENTS

PIONEER-HF ADVERSE EVENTS

Cardiac failure congestive and acute kidney injury were per investigator discretion on the Case Report Form.

  • For key safety outcomes, the ENTRESTO group and the enalapril group were generally comparable with regard to rates of worsening renal function, hyperkalemia, symptomatic hypotension, or angioedema7

  • Adverse event profile was comparable to the PARADIGM-HF trial3,5

  • No new safety signals were observed3,5

  • Safety data were collected for only 8 weeks, therefore adverse events that take longer to transpire may not have appeared in this study. Safety information should be interpreted in the context of prior trials with longer duration3

The ACC Expert Consensus Decision Pathway now supports the initiation of ENTRESTO during hospitalization for systolic HF8

Hospitalization is a pivotal opportunity to improve clinical trajectory in systolic HF patients—start ENTRESTO as a first-choice therapy in stabilized patients to help reduce risk of CV death and hospitalization for heart failure

ACC EXPERT CONSENSUS DECISION PATHWAY

A plan to initiate ENTRESTO can be considered as soon as the patient is admitted and therapy can be started once the patient is stabilized
ACC EXPERT CONSENSUS DECISION PATHWAY

Reprinted from the Journal of the American College of Cardiology; volume 74/issue 15; Hollenberg SM, Warner Stevenson L, Ahmad T, et al; 2019 ACC Expert Consensus Decision Pathway on Risk Assessment, Management, and Clinical Trajectory of Patients Hospitalized with Heart Failure; pp. 1966-2011; 2019; with permission from Elsevier.

ACC=American College of Cardiology; CV=cardiovascular.

Criteria for stabilization: systolic blood pressure ≥100 mm Hg for previous 6 hours; no escalation of IV diuretics or vasodilators within previous 6 hours; no IV inotropic therapy within previous 24 hours.

§Adequate decongestion, hemodynamically stable, and no complication.

ENTRESTO is not indicated in acute heart failure.

ENTRESTO IS AN ESSENTIAL HF TREATMENT—A FIRST CHOICE

INSTEAD OF AN ACEi/ARB FOR YOUR PATIENTS WITH SYSTOLIC HF

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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. PARADIGM-HF and all-cause readmission analysis. Novartis Pharmaceuticals Corp; August 1, 2019. 2. Desai AS, Claggett BL, Packer M, et al; for the PARADIGM-HF Investigators. Influence of sacubitril/valsartan (LCZ696) on 30-day readmission after heart failure hospitalization. J Am Coll Cardiol. 2016;68(3):241-248. 3. Velazquez EJ, Morrow DA, DeVore AD, et al; for the PIONEER-HF Investigators. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med. 2019;380(6):539-548. 4. Zile MR, Claggett BL, Prescott MF, et al. Prognostic implications of changes in N-terminal pro-B-type natriuretic peptide in patients with heart failure. J Am Coll Cardiol. 2016;68(22):2425-2436. 5. ENTRESTO [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; October 2019. 6. Bettencourt P, Azevedo A, Pimenta J, et al. N-terminal—pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients. Circulation. 2004;110(15):2168-2174. 7. Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med. November 11, 2018. https://www.nejm.org/doi/suppl/10.1056/NEJMoa1812851/supplfile/nejmoa1812851appendix.pdfhttps://www.nejm.org/doi/suppl/10.1056/NEJMoa1812851/supplfile/nejmoa1812851appendix.pdf. Accessed November 19, 2018. 8. Hollenberg SM, Stevenson LW. 2019 ACC Expert Consensus Decision Pathway on Risk Assessment, Management, and Clinical Trajectory of Patients Hospitalized with Heart Failure. J AM Coll Cardiol. 2019. Doi.org/10.1016/jacc2019.08001.

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