CLASS I CLASS I LEVEL OF EVIDENCE B-R GUIDELINE RECOMMENDED 3 ACC/AHA/HFSA GUIDELINE RECOMMENDED 3 LEVEL OF EVIDENCE B-R ACC/AHA/HFSA ENTRESTO ® demonstrated reduced risk of HF hospitalization and death vs enalapril in the largest trial ever conducted in HF 4,5 * † : CV DEATH OR HF HOSPITALIZATION AS FIRST EVENT 4 (primary end point) ( P <0.0001; HR [95% CI]: 0.80 [0.73, 0.87]) 20 % ARR 4.7 % RRR ALL-CAUSE MORTALITY 4‡ ( P =0.0009; HR [95% CI]: 0.84 [0.76, 0.93]) 16 % ARR 2.8 % RRR • Reduced the relative risk of CV death by 20% vs enalapril (3.2% ARR) 4†§ll • Reduced the relative risk of ﬁ rst HF hospitalization by 21% vs enalapril (2.8% ARR) 4† When you see symptoms, there’s risk, so it’s time for ENTRESTO . Impaired Renal Function, cont’d: In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, concomitant use of non-steroidal anti-inﬂ ammatory 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%). IMPORTANT SAFETY INFORMATION, CONT’D For more information, visit EntrestoHCP.com ACC = American College of Cardiology; AHA = American Heart Association; HFSA = Heart Failure Society of America; B-R = Class of Recommendation B, randomized trial; CV = cardiovascular; RRR = relative risk reduction; ARR = absolute risk reduction; HR = hazard ratio; CI = conﬁ dence interval; NYHA = New York Heart Association; HF r EF = heart failure with reduced ejection fraction; ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker. * PARADIGM-HF was a multinational, randomized, double-blind trial comparing ENTRESTO to enalapril in symptomatic (NYHA Class II-IV) adult HF r EF patients (left ventricular ejection fraction ≤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 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. † Analyses of the components of the primary composite end point were not prospectively planned to be adjusted for multiplicity. ‡ ENTRESTO improved overall survival. This ﬁ nding was driven entirely by a lower incidence of CV mortality on ENTRESTO. § Overall, sudden death accounted for 45% of CV deaths, followed by pump failure, which accounted for 26%. ll Includes subjects who had HF hospitalization prior to death. References: 1. Ekman L, Cleland JGF, Swedberg K, Charlesworth A, Metra M, Poole-Wilson PA. Symptoms in patients with heart failure are prognostic predictors: insights from COMET. J Card Fail . 2005; 11(4):288-292. 2. Wong M, Staszewsky L, Carretta E, et al. Signs and symptoms in chronic heart failure: relevance of clinical trial results to point of care—data from Val-HeFT. Eur J Heart Fail . 2006;8(5):502-508. 3. Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America [published online ahead of print May 20, 2016]. Circulation . doi: 10.1161/CIR.0000000000000435. 4. ENTRESTO [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2015. 5. McMurray JJV, Packer M, Desai AS, et al. Baseline characteristics and treatment of patients in Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail . 2014;16(7):817-825. Please see Brief Summary of Prescribing Information, including Boxed WARNING, on following pages.