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Use ENTRESTO ™ in place of ACEis and ARBs for HFrEF patients 1

ENTRESTO was studied in the largest HF trial ever conducted 2

• Trial stopped early due to finding of significantly reduced risk of CV death and the primary end point being met 3

ENTRESTO has been proven superior to enalapril , a current standard-of-care 4 medication 1

• Superiority vs enalapril , a standard-of-care ACEi therapy , across a range of NYHA class II – IV patients with chronic HF and reduced ejection fraction

REDUCED RISK OF CV DEATH OR FIRST HF HOSPITALIZATION

VS ENALAPRIL 1

ABSOLUTE RISK

REDUCTION 1

P < 0.0001 HR ( 95 % CI ): 0.80 ( 0.73 , 0.87 )

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 . 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 reninangiotensin-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 m 2 ).

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 .

REDEFINE EXPECTATIONS IN HEART FAILURE

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

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 %).

Please see Brief Summary of Prescribing Information , including Boxed WARNING , on following pages .

STUDY DESIGN : PARADIGM-HF was a multinational , randomized , double-blind trial comparing ENTRESTO to enalapril in 8442 symptomatic ( NYHA class II – IV ) adult HFrEF 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 . The primary end point was the first event in the composite of CV death or first HF hospitalization . 1

ACEi = angiotensin-converting enzyme inhibitor ; ARB = angiotensin II receptor blocker ; HFrEF = heart failure with reduced ejection fraction ; CV = cardiovascular ; NYHA = New York Heart Association ; HF = heart failure .

For more information , visit EntrestoHCP . com

References : 1 . ENTRESTO [ prescribing information ]. East Hanover , NJ : Novartis Pharmaceuticals Corp ; August 2015 . 2 . 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 . 3 . McMurray JJV , Packer M , Desai AS , et al . Angiotensin – neprilysin inhibition versus enalapril in heart failure . N Engl J Med . 2014 ; 371 ( 11 ): 993-1004 . 4 . Yancy CW , Jessup M , Bozkurt B , et al . 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 Practice Guidelines . Circulation . 2013 ; 128 ( 16 ): e240-e327 .

ENTRESTO is a trademark of Novartis AG .