Akash Ghai MD, FACC February 27, 2015 No Disclosures
Epidemiology Lifetime risk is > 20% for American s older than 40 years old. > 650,000 new cases diagnosed each year. Incidence increases with age: 2% for those 60-69 vs. 8% for those > 85 years of age.
Epidemiology Blacks are the high risk sub-group to develop acute decompensated heart failure (ADHF). Incidence is 4.5% in black men, 3.8% in black women compared to 2.7% in white men and 1.8% in white women respectively. Mortality rate is about 50% within 5 years of diagnosis.
Epidemiology Overall more than five million patients manifest symptoms of CHF per year. More than one million of these patients need hospitalization. The number one reason for hospitalization amongst seniors in the country.
Epidemiology Readmission rate is about 25% with one month. In 2013, physician office visits for CHF cost $1.8 billion. Total cost for CHF in the US in 2013 was $30 billion with half of those costs spent on hospitalizations.
Prevalence and Cost
Revised Staging System for HF
Indications for Hospitalization Hypotension Worsening renal failure Altered mentation Dyspnea at rest reflected by O2 sat < 90% Hemodynamic arrhythmias (AF) Major electrolyte disturbance Repeated ICD firings Previously undiagnosed heart failure Co-morbid conditions (PNA, PE, DKA, CVA)
Treatment Goals for Patients with ADHF Improve symptoms Optimize volume status Identify etiology if possible Identify precipitating factors Optimize chronic oral therapy Minimize side effects Identify patient that might benefit from revascularization or device therapy Identify risk of thromboembolism and need for chronic oral anticoagulant therapy Educate patients concerning medications and self management of heart failure
Non-Pharmacologic Treatment Low sodium diet (< 2 g per day) is recommended for most with severe HF Less than 1.5 g per day recommended for those with recurrent or refractory volume overload. Fluid restriction < 2L/day recommended for those with moderate hyponatremia (< 130 meq/l) Fluid restriction < 1.5 L/day is serum sodium (< 125 meq/l)
Non-pharmacologic Therapy Nitrogen balance, caloric intake and pre-albumin may be helpful Caloric supplementation recommended Anabolic steroids not recommended for cachectic pts Avoid products containing ephedra (ma huang) CPAP for OSA pts. Supplemental O2 not recommended in absence of indication
Non-pharmacologic Therapy Pts with hypoxemia should be evaluated for fluid overload or concomitant pulmonary disease Pts with HF and insomnia: consider SDB, urologic abnormalities or restless leg syndrome Depression: screen for reactive depression SSRI s preferred over tricyclics Avoid NSAIDS worsen salt retention Stress reduction Limit drinking to < 2 in men and < 1 per day in women Pneumococcal vaccine and annual influenza vaccination in all HF pts
Diuretics Current Medical Treatment Recommended for fluid overload Loop diuretics are preferred over thiazide to restore normal volume status Consider oral torsemide in patient with poor absorption, especially those with right heart failure Causes of diuretic resistance Non-adherence Renal insufficiency Hypotension Low cardiac output Renal artery stenosis
Loop Diuretics Agent Initial daily dose Max total daily dose Elimination renal-met Duration of action Furosemide 20-40 mg qd or bid 600 mg 65%R/35%M 4-6 hrs Bumetanide 0.5-1.0 mg qd or bid 10 mg 62%R/38%M 6-8 hrs Torsemide 10-20 mg qd 200 mg 20%R/80%M 12-16 hrs Ethacrynic acid 25-50 mg qd or bid 200 mg 67%R/33%M 6 hrs
Current Medical Treatment of Congestive Heart Failure Standard therapy in compensated congestive heart failure 35 30 25 20 15 10 5 0 Decrease in Mortality (%)
Digoxin May be considered to improve symptoms in pts with LVEF < 40% and class II-IV. Dose based on lean body mass, renal function and contaminant medications. Starting dose 0.125 mg Level < 1.0 (0.7-0.9) Considered for rate control for atrial fibrillation High doses for rate control (>0.25 mg are not recommended)
The Lingering Problem Even with maximal medical therapy with these drugs, symptoms persist and mortality remains high. It has been 10 years since the last drug for heart failure was FDA approved for congestive heart failure A-HEFT (BiDil) 2005 EMPHASIS-HF (Eplerenone) 2003
The Problem Even with maximal medical therapy with these drugs, symptoms persist and mortality remains high. A new approach to the treatment of systolic heart failure angiotensin-neprilysin inhibition was investigated in the recently completed PARADIGM- HF trial.
Rationale for the study A number of compensatory neurohumoral mechanisms are activated in congestive heart failure. Increase in renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system activity are believed to be harmful in the long term. Increase in natiuretic peptides are thought to be a beneficial compensatory response leading to vasodilatation, natiuresis ameliorating many of the pathophysiological abnormalities of congestive heart failure.
Rationale for the study Prior research suggested the benefits of neprilysin inhibition (NEP) can only be taken advantage of with contaminant inhibition of the RAAS. However both RAAS and NEP inhibition can lead to excessive bradykinin level. Combined use may lead to significant risk of angioedema.
Angiotensin receptor-neprilysin Inhibition New compound represents a 1:1 mixture of two molecular entities. AHU 377 (Sacubitril)
Angiotensin receptor-neprilysin Inhibition New compound represents a 1:1 mixture of two molecular entities. Valsartan
Angiotensin receptor-neprilysin Inhibition LCZ696 AHU 377 (Sacubitril) Valsartan
Natiuretic and other vasoactive peptides Nepriliysn AHU 377 Inactive Metabolites
Natiuretic and other vasoactive peptides Nepriliysn Lower blood pressure Promote sodium excretion AHU 377 Inactive Metabolites
Bradykinin Inactive Metabolites Angiotensin 1 Metallopeptidase Angiotensin 2 Angiotensin 2 Receptor Valsartan Vasocontruction Sodium/water retention
Study Rationale Therefore LCZ696 is expected to deliver the benefits of combined RAAS and NEP inhibition without an increased risk of angioedema relative to ACE inhibitors.
Inclusion Criteria Age > 18 years LVEF < 40% with NYHA class 2-4 BNP > 150 pg/ml (NT-proBNP > 600 pg/ml) or BNP > 100 pg/ml (NT-proBNP > 400 pg/ml) with a CHF hospitalization within the last 12 months. Patients must be on ACE/ARB of enalapril 10 mg po or an equivalent for 4 weeks prior to randomization. Patients must have been on a Beta-blocker unless contraindicated for 3 weeks prior to randomization
Exclusion Criteria ACE/ARB intolerance/hypersensitivity Angioedema history Acute decompensated CHF SBP < 100 mm Hg GFR < 30 cc/min Decline in renal function of 25% during the study K > 5.2 mmol/l MACE < 3 months CRTD < 3 months
Screening Criteria, Run-in Periods, and Randomization. McMurray JJV et al. N Engl J Med 2014;371:993-1004
PARADIGM-HF December 2009 to March 2014 8000 + patients Received LCZ696 or enalapril Target dose LCZ696 was 200/160 mg po twice daily Target dose of enalapril was 10 mg po twice daily
PARADIGM-HF Primary end-point: death from cardiovascular cause or hospitalization for heart failure Secondary end-point: overall mortality
Baseline Characteristics No significant differences between the two groups. Average age: 63.8±11.5 yrs. Female sex: 21% White: 66%, Black 5% Systolic blood pressure: 122±5 mm Hg Serum creatinine: 1.13±0.3 mg/dl Ischemic cardiomyopathy: 60% LVEF: 30% Median BNP: 255 pg/ml NYHA Class 2 71%, Class 3 24%, Class 4 - < 1%
Baseline Characteristics Medication use at randomization Diuretic: 80% Digoxin: 30% Beta-blocker: 93% Mineralcorticoid antagonists: 55% AICD: 15% CRT: 7%
20% relative reduction 3.7% drop
16% relative reduction 3.2% drop
Additional Secondary Outcomes
Quality of Life Kansas City Quality of Life Questionnaire was also administered to patients. Scale of 0 to 100 with higher scores indicating fewer symptoms and physical limitations associated with congestive heart failure. (measured at 0 and 8 months)
PARADIGM-HF Conclusions Angiotensin receptor-neprilysin inhibition compared to ACE inhibition Reduces cardiovascular death and hospitalization for heart failure Reduces overall mortality Reduces symptoms and improves physical function
Safety Data
Who are these patients? 140 120 100 80 60 40 20 0 Age LVEF NYHA Class 2 NYHA Class 3 Blood Pressure
Medication use across studies 100 90 80 70 60 50 40 30 20 10 0 ACEI or ARB Beta-blockers Mineralocorticoid Antagonists ICD+/-CRT
Number Needed to Treat to Reduce One Death from Any Cause 220 72 22 23 26 34 35
Study Limitations and Further Questions. Study cannot tell if lower doses of LCZ696 have mortality benefit. Black population of the study (5%) was low and drug did not benefit these patients. Percent of AICD/CRT patients in the study was low (14%/5%). 12% of patients could not tolerate the drug due to side effects.
Study Limitations and Further Questions Fewer NYHA class 3 and 4 patients than other studies. Morbidity and mortality gains were more robust in patients who had less severe symptoms, who may be at lower risk but whose outcome may be more amenable to improvement with this therapy. Patients with EF > 35% did not benefit.
Remaining Issues When will be able to prescribe this medication? How much will it cost? National programs may need to be initiated to change patients from ACE/ARBS to LCZ696.