It’s about time...

ENTRESTO® is now the first and only treatment approved for most HF patients.1-4

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

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.Please see additional Important Safety Information throughout and click here for full Prescribing Information.

HF=heart failure.

Hospitalization mattersAfter each hospitalization, patients are at increased risk of death, rehospitalization, and other poor outcomes5-7

IMPORTANT SAFETY INFORMATION (cont) 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.

HF hospitalizations for patients with HFpEF with LVEF below normal* in the US annually2,3,8≈300,000

UNTIL NOW, NO TREATMENT HAS BEEN SHOWN TO IMPACT HOSPITALIZATIONS IN THESE HFpEF PATIENTS

Please see additional Important Safety Information throughout and click here for full Prescribing Information.

HF=heart failure; HFpEF=heart failure with preserved ejection fraction; LVEF=left ventricular ejection fraction.

HFpEF with LVEF below normal defined as LVEF 41% to 60%.2*

In HFpEF

of hospitalized patients will be readmitted within a year

9,1020%>

IMPORTANT SAFETY INFORMATION (cont) 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.

Please see additional Important Safety Information throughout and click here for full Prescribing Information.

†The median LVEF was 57%. LVEF is a variable measure that can change over time, and the normal range differs according to patient characteristics and method of assessment.1‡Event rate per 100 patient years.ARR=absolute rate reduction; CI=confidence interval; CV=cardiovascular; HF=heart failure; HFpEF=heart failure with preserved ejection fraction; HR=hazard ratio; LAE=left atrial enlargement; LVEF=left ventricular ejection fraction; LVH=left ventricular hypertrophy; RR=rate ratio; RRR=relative rate reduction.

The patient population of PARAGON-HF met the protocol definition of HFpEF with an LVEF ≥45%, structural heart disease (either LAE or LVH), and no prior echocardiographic LVEF <40%.11

*

Time since randomization (days)

0

60

50

40

30

10

20

180 360 540 720 900 1080 1260 1440

ENTRESTONo. of patients1239 1219 1196 1156 1128 928 577 277 93

Valsartan 1256 1226 1199 1168 1141 938 566 100

Mea

n HF

hos

pita

lizat

ions

per

100

pat

ient

s

292

0

ENTRESTO® in HFpEF*

Helping keep patients out of the hospital

CV death: HR 0.99 (95% CI: 0.77, 1.26); ARR 0.1‡

In PARAGON-HF, no new safety signals were observed compared with previous ENTRESTO trials.1

ENTRESTO reduced total HF hospitalizations vs valsartan12,13

PARAGON-HF: Total HF hospitalizations in patients with LVEF at or below the median†

At the primary end point, a composite of total (first and recurrent) HF hospitalizations and CV death, ENTRESTO did not achieve statistical significance vs valsartan (13% RRR; 95% CI: 0.75, 1.01; P=0.06). See detailed study information on page 5.

IN TOTAL HF HOSPITALIZATIONS

RR 0.75 (95% CI: 0.60, 0.95); ARR 3.6‡

25%RRR

IN COMPOSITE END POINT VS VALSARTAN

RR 0.78 (95% CI: 0.64, 0.95); ARR 3.6‡

22%RRR

In a prespecified subgroup analysis of PARAGON-HF patients with LVEF at

or below the median†

ENTRESTO reduced total HF hospitalizations and CV death1,12

Proven safety profile

ACC=American College of Cardiology; ACEi=angiotensin converting enzyme inhibitor; ARB=angiotensin receptor blocker; ARR=absolute rate reduction; CI=confidence interval; CV=cardiovascular; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; HR=hazard ratio; KCCQ=Kansas City Cardiomyopathy Questionnaire; NT-proBNP=N-terminal pro–B-type natriuretic peptide; QOL=quality of life; RRR=relative risk reduction.

See detailed study information and limitations of analyses on page 5.

ENTRESTO® in HFrEF

Change the heart. Change heart failure.

IMPORTANT SAFETY INFORMATION (cont) 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.

Proven superior to enalapril (ACEi) in both outpatient and inpatient settingsIn PARADIGM-HF, ENTRESTO was proven superior to enalapril at reducing the risk of HF hospitalization or CV death for outpatients: 20% RRR (ARR 4.7%; HR 0.80; 95% CI: 0.73, 0.87; P<0.0001)1,14

• In an exploratory analysis, ENTRESTO decreased NT-proBNP1,14

In PIONEER-HF, ENTRESTO was superior to enalapril in reducing NT-proBNP in participants who initiated inpatient15

Improved cardiac structure and function, correlated with reduction in NT-proBNP In PROVE-HF, ENTRESTO patients showed correlation between improvement in parameters of cardiac remodeling and biomarker improvement16

• Patients in PROVE-HF showed reverse cardiac remodeling correlated with reduction in NT-proBNP16

Improved QOLPatients taking ENTRESTO felt better than those taking enalapril based on the KCCQ-23 Clinical Summary Score14,17

AN UPDATE TO THE ACC EXPERT CONSENSUS DECISION PATHWAY RECOMMENDS ENTRESTO AHEAD OF AN ACEi/ARB FOR THE TREATMENT OF HFrEF

18

Please see additional Important Safety Information throughout and click here for full Prescribing Information.

STUDY INFORMATION AND LIMITATIONS OF ANALYSESPARAGON-HF was a randomized, double-blind, active-controlled trial comparing ENTRESTO® to valsartan in 4796 adult patients with symptomatic (NYHA Class II–IV) HFpEF (LVEF ≥45%), elevated levels of natriuretic peptides, and structural heart disease. After completing the run-in period with valsartan followed by ENTRESTO, patients entered the double-blind period and were randomly assigned (1:1) to ENTRESTO 97/103 mg BID (n=2407) or valsartan 160 mg BID (n=2389). The median follow-up duration was 35 months, and patients were treated for up to 4.7 years. For the primary end point, reduction in the composite of total (first and recurrent) HF hospitalizations and CV death, ENTRESTO did not achieve statistical significance vs valsartan (13% RRR; 95% CI: 0.75, 1.01; P=0.06).1

PARADIGM-HF was a multinational, randomized, double-blind trial comparing ENTRESTO to enalapril in 8442 symptomatic (NYHA Class II–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 either ENTRESTO 97/103 mg BID (n=4209) or enalapril 10 mg BID (n=4233). 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). In an exploratory analysis, ENTRESTO also lowered NT-proBNP. The CV effects of ENTRESTO are attributed to increased levels of peptides and decreased angiotensin II effects, which resulted in decreased NT-proBNP.1

PARADIGM-HF NT-proBNP analysis limitation: This was a prespecified exploratory end point. NT-proBNP was drawn and analyzed in a subgroup of the total PARADIGM-HF patient population and therefore might not represent the entire cohort of patients studied.

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 HFrEF patients (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<0.001).15

PROVE-HF was a 52-week, single-arm, prospective, open-label phase IV study of 794 adult HFrEF (LVEF ≤40%) outpatients initiated on ENTRESTO. For the primary end point, change in NT-proBNP was correlated with changes in echocardiographic parameters of cardiac structure and function (P<0.001).16

PROVE-HF study limitations: 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.16

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 status. The KCCQ-23 CS represents the average of symptom (frequency and burden) and physical limitation domains.14,17,20

KCCQ-23 tool limitations: Two-week recall period. Missing scores in physical limitation domain may be missing because activities were not performed due to conditions other than HF.20,21

PARADIGM-HF KCCQ-23 analysis limitations: 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.19

IMPORTANT SAFETY INFORMATION (cont) Impaired Renal Function (cont): 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.

Please see additional Important Safety Information throughout and click here for full Prescribing Information, including Boxed WARNING.

ENTRESTO® offers easy access for both you and your patients Over 80% of all patients have access to ENTRESTO with no prior authorization at the lowest branded co-pay.19

Time is essential. Start ENTRESTO now as a first choice instead of an ACEi/ARB.

ACEi=angiotensin converting enzyme inhibitor; ARB=angiotensin receptor blocker; eGFR=estimated glomerular filtration rate.

References: 1. ENTRESTO [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; February 2021. 2. Fonarow GC, Stough WG, Abraham WT, et al. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol. 2007;50(8):768-777. 3. Ibrahim NE, Song Y, Cannon CP, et al. Heart failure with mid-range ejection fraction: characterization of patients from the PINNACLE Registry®. ESC Heart Fail. 2019;6(4):784-792. 4. Virani SS, Alonso A, Aparicio HJ, et al; on behalf of the American Heart AssociationCouncil on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2021 update: a report from the American Heart Association. Circulation. 2021;143:e1-e490. 5. Carson PE, Anand IS, Win S, et al. The hospitalization burden and post-hospitalization mortality risk in heart failure with preserved ejection fraction: results from the I-PRESERVE trial (Irbesartan in heart failure and preserved ejection fraction). JACC Heart Fail. 2015;3(6):429-441. 6. Solomon SD, Dobson J, Pocock S, et al. Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure. Circulation. 2007;116(13):1482-1487. 7. Bello NA, Claggett B, Desai AS, et al. Influence of previous heart failure hospitalizations on cardiovascular events in patients with reduced and preserved ejection fraction. Circ Heart Fail. 2014;7(4):590-595. 8. HCUP Fast Stats. Healthcare Cost and Utilization Project (HCUP). May 2020. Agency for Healthcare Research and Quality, Rockville, MD. www.hcup-us.ahrq.gov/faststats/national/inpatientcommondiagnoses.jsp. Accessed19 February 2021. 9. Cheng RK, Cox M, NeelyML, et al. Outcomes in patients with heart failure with preserved, borderline, and reduced ejection fraction in the Medicare population. Am Heart J. 2014;168(5):721-730. 10. Shah KS, Xu H, Matsouaka RA, et al. Heart failure with preserved, borderline, and reduced ejection fraction. J Am Coll Cardio. 2017;70(20):2476-2483. 11. Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019;381(suppl):1609-1620. Supplementary material accessed at https://www.nejm.org/doi/suppl/10.1056/NEJMoa1908655/suppl_file/nejmoa1908655_appendix.pdf. Accessed 19 February 2021. 12. U.S. Food and Drug Administration. Novartis Cardiovascular and Renal Drugs Advisory Committee Briefing Document, December 15, 2020. ENTRESTO® (sacubitril/valsartan) for chronic heart failure and preserved ejection fraction. https://www.fda.gov/media/144379/download. Accessed February 18, 2021. 13. Data on file. Novartis Pharmaceuticals Corp; February, 2021. 14. McMurray JJV, Packer M, Desai AS, et al; for the PARADIGM-HF investigators and committees. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. 15. 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. 16. 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. JAMA. 2019;322(11):1085-1095. 17. Lewis EF, Claggett BL, McMurray JJV, et al. Health-related quality of life outcomes in PARADIGM-HF. Circ Heart Fail. 2017;10(8):e003430. 18. Maddox TM, Januzzi JL, Allen LA, et al. 2021 update to the 2017 ACC Expert Consensus Decision Pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction. J Am Coll Cardiol. Published online January 11, 2021. doi: 10.1016/j.jacc.2020.11.022. 19. Data on file. ENTRESTO Access. Data from January 2021. Novartis Pharmaceuticals Corp; January 2021. 20. 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. 21. 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.

Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936-1080 © 2021 Novartis 3/21 T-ETR-1402513

ENTRESTO and the ENTRESTO logo are registered trademarks of Novartis AG.

Please see additional Important Safety Information throughout and click here for full Prescribing Information, including Boxed WARNING.

IMPORTANT SAFETY INFORMATION (cont)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.