New drugs for heart failure plus review chart

The pharmacotherapy management of patients with heart failure with reduced ejection fraction is a populated landscape with multiple drugs affecting morbidity and mortality.  Two new medications that are the first in two new classes were approved recently - a neprilysin inhibitor and a hyperpolarization-activated cyclic nucleotide-gated channel blocker.

But first here's a quick table and a few notes about the current use of medications for treating heart failure with reduced ejection fraction.

	Outcome reduction
Drug class	Symptoms	Hospitalization	Mortality
Diuretics	X
ACE inhibitors		X	X
Beta blockers		X	X
Aldosterone antagonists		X	X
ARBs		X	X
Hydralazine/nitrate		X	X
Digoxin	X	X
Calcium channel blockers
Statins

Additional points:

• Diuretics probably decrease hospitalizations and mortality but data isn’t as robust as the other classes – you don’t use them if the patient doesn’t have symptoms

• Beta blockers includes only 3: metoprolol succinate, carvedilol, and bisoprolol (metoprolol tartrate does not have a randomized controlled trial demonstrating benefit or comparing it to metoprolol succinate)

• ARBs should generally not be added to ACEIs although there are some exceptions

• Hydralazine/nitrate combination is beneficial for black and non-black patients though the evidence is stronger for black patients.  Can be used in addition to ACEI, not just as replacement (ACEIs are more effective).

• Digoxin’s benefit is dependent on low serum concentrations as post-hoc analyses showed patients did worse (higher mortality) when the concentration was ≥1.2 ng/mL (the lab’s reference range will often include higher than 1.2 as within range)

• Calcium channel blockers and statins haven’t been shown to improve heart failure outcomes but can be used if patients have other indications (like CAD which is the cause in more than half of heart failure)

• The drugs that reduce mortality were generally titrated to target doses in the trials so the titration strategy should be to get as close to that target dose as tolerated by the patient

Ivabradine

Ivabradine (brand name Corlanor) was approved by the FDA in April 2015 for stable, symptomatic heart failure with an ejection fraction ≤35%.  Patients also need to be in normal sinus rhythm and have a resting heart rate ≥70 bpm while taking the maximum tolerated dose of beta-blocker (or who have a contraindication to beta-blocker therapy).  

The SHIFT trial studied ivabradine compared to placebo in patients with heart failure as described above.  Of these patients, 49% were NYHA class II, 50% were class III, mean EF was 29%, 89% were on beta-blockers, 91% were on ACEI/ARB, 83% were on diuretics, and 60% were on aldosterone antagonists.  The study went on for about 2 years and tested the combined endpoint of hospitalization for heart failure or cardiovascular death.  The result was that hospitalizations for heart failure were reduced (20.2% down to 15.6%) but there was no improvement on mortality (about 9% in both).  When analyzed by what dose of beta-blockers patients were taking, the benefit was predominantly in those on lower doses, whereas those on the guideline-targeted beta-blocker dose had little, if any, benefit.

There are two studies to consider against the benefits of ivabradine - BEAUTIFUL and SIGNIFY.  BEAUTIFUL was in patients with CAD and heart failure with reduced ejection fraction but SIGNIFY was in patients with CAD but without heart failure.  Neither showed a difference versus placebo in a composite endpoint.

Mechanism of action
Ivabradine is the hyperpolarization-activated cyclic nucleotide-gated channel inhibitor (also called an I_f inhibitor for the current it blocks) which inhibits spontaneous pacemaker activity primarily in the sinus node, reducing the heart rate.  There are no significant effects on ventricular repolarization or myocardial contractility.

Dosing
It is started at a dose of 5 mg orally twice daily and titrated up or down after two weeks to either 7.5 mg or 2.5 mg twice daily, respectively, to achieve a goal resting heart rate of 50-60 bpm.  It has no adjustments for liver or kidney insufficiency but was not studied in severe liver impairment or with a creatinine clearance <15 mL/min so can't be recommended for these patients.

Other considerations
Ivabradine is contraindicated in strong cytochrome P450 inhibitors (think azoles, macrolides, and protease inhibitors), use caution in calcium channel blockers, it causes more atrial fibrillation (5% up from 3.9% in SHIFT), it causes bradycardia, conduction blocks, and visual effects known as phosphenes (thought to be due to effects at a different channel other than I_f).

Sacubitril/valsartan

Sacubitril/valsartan (brand name Entresto) was approved by the FDA in July 2015 for chronic heart failure with reduced ejection fraction and it is only to be used in patients not taking an ACEI.

The PARADIGM-HF trial studied sacubitril/valsartan compared to enalapril in patients with NYHA class II, III, or IV and an ejection fraction ≤40%.  Of these patients, 70% were NYHA class II, 24% were class III, mean EF was 29%, 93% were on beta-blockers, ~100% were on ACEI/ARB (before starting), 80% were on diuretics, and 56% were on aldosterone antagonists.  The study was stopped early after 27 months when an overwhelming benefit was seen with sacubitril/valsartan.  Both parts of the composite endpoint were reduced with sacubitril/valsartan compared to enalapril - first hospitalization from heart failure (15.6% down to 12.8%) and cardiovascular death (16.5% down to 13.3%).

Mechanism of action
Valsartan is an ARB which blocks the angiotensin II type-1 receptor.  Sacubitril is a neprilysin inhibitor resulting in increased concentrations of endogenous vasoactive peptides such as natriuretic peptides and bradykinin that are usually degraded by the enzyme.  These combat the vasoconstriction, sodium retention, and remodeling that are characteristic of heart failure.

Dosing
The combination is started at either 24/26 mg orally twice daily or 49/51 mg twice daily depending on if there is renal impairment or if the patient is already taking an ACEI/ARB and titrated up every two to four weeks up to a maximum dose of 97/103 mg twice daily.

Other considerations
Sacubitril/valsartan is contraindicated with ACEI due to increased risks of angioedema and should be separated by at least 36 hours if switching between these agents.  Other adverse effects include hyperkalemia, hypotension, angioedema, and renal impairment (think general adverse effects of ACEI/ARB or their combination).

So if we are to add these two new agents to our table, it would look like this:

	Outcome reduction
Drug class	Symptoms	Hospitalization	Mortality
Ivabradine		X
Sacubitril/valsartan		X	X

Take home points:

• Ivabradine and sacubitril/valsartan are two additional options for our armamentarium in treating heart failure with reduced ejection fraction
• Ivabradine moderately reduces hospitalizations but not mortality and its benefit wanes as beta-blockers reach guideline-target doses (perhaps just supports the importance of heart rate control in heart failure)
• Sacubitril/valsartan reduces mortality but serious vigilance is required to not combine with traditional ACEI or ARB treatment

References:
Swedberg K, Komajda M, Bohm M, et al.  Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebo-controlled study.  Lancet  2010;376:875-85.
Corlanor (R) [package insert]. Thousand Oaks, CA: Amgen, Inc; 2015.
McMurray JJ, Packer M, Desai AS, et al.  Angiotensin-neprilysin inhibitor versus enalapril in heart failure.  New Engl J Med  2014;371:993-1004.
Entresto (R) [package insert]. East Hanover, NJ: Novartis; 2015

photo by Eva Blue