By Dr. Geoffrey Modest
The Am Heart Assn/Am College of Cardiol just published their updated 2016 guidelines on the pharmacological therapy of heart failure (HF), focusing on the newer therapies (see doi:10.1161/CIR.0000000000000435/-/DC1)
- Meds for Stage C (symptomatic) HF with reduced ejection fraction (HFrEF). Clinical strategy is to use one of these meds in combo with evidence-based b-blocker and aldosterone antagonist in appropriate patients.
- ACE-I (Level A evidence): reduces morbidity and mortality in patients with any stage of symptomatic HF (also in asymptomatic, as an aside), with or without coronary artery disease (CAD). Associated with hypotension; renal insufficiency; elevated K; angioedema in <1%, though higher in women and black patients.
- ARBs (Level A evidence): thought to help also with decreasing angiotensin II production (which continues despite ACE-I through alternative enzymatic pathways). ARBs reduce mortality, esp in ACE-I intolerant patients (they have the same adverse effects, though less cough, presumably because of the ACE-I associated bradykinin increases). [They do point out that an ARB should be used in those intolerant of ACE-I for cough or angioedema, but commenting that they be used in caution in those who develop angioedema with ACE-I; and I have personally sent a patient to the ICU twice with severe angioedema, first from an ACE-I, then from an ARB. So I am really cautious to the point of avoiding ARBs if at all possible in ACE-I associated angioedema]. ACE-I may have some advantage over ARBs in their beneficial vasodilatory effects through the kininase inhibition.
- ARNI(Level B evidence — moderate quality from 1 or more RCTs): a combo of an ARB and neprilysin, an enzyme that degrades natriuetic peptides, bradykinin, adrenomedullin, and other vasoactive peptides. Valsartan/sacubitril vs enalapril was associated with 20% decrease in composite of cardiovascular death or HF hospitalization (see McMurray JJ. N Engl J Med. 2014;371:993). ARNIs are also associated with renal insufficiency, hypotension. And they should not be given within 36 hours of last dose of ACE-I, since they can lead to angioedema (because both ACE and neprilysin affect bradykinin). Also, should not use ARNI in setting of patient with any history of angioedema. No head-to-head comparison of ARB and ARNI
- Ivabradine (Level B evidence — moderate quality from 1 or more RCTs): lowers heart rate by a direct effect on the sinoatrial node, with heart rate lowering being the posited mechanism of action for improving HF. one RCT (the SHIFT trial, Swedberg K. Lancet 2010; 376: 875)showed reduction in HF hospitalizations. The target of treatment was lowering the heart rate, BUT only 23% of the patients were on the optimal dose of b-blockers
- One confusing thing in this guideline is that, though they promote ACE-I and ARB with strong ratings (both Level A evidence), they pretty clearly highlight the one positive study of valsartan/sacubitril and do seem to push the ARNI, albeit with caveats about the angioedema (e.g., stating: “In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality”). One general concern of mine is that ARNIs do have a pretty wide effect on major enzyme systems (i.e., shotgun vs targeted bullet), which does raise the concern about other adverse effects, those not detected in the short-term 27-month N Engl J Med study above. This study did find twice as many patients developed angioedema (19 vs 10 patients, in a study of 8442 patients, though statistically nonsignficant). Would that number increase with more prolonged use? What about the long-term effects of all the other vasoactive/other enzymes which are inhibited by neprilysin? [i.e., those general enzyme systems are likely there for a reason….]
- Ivabradine has a somewhat lower recommendation: it “can be beneficial to reduce HF hospitalizations for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF<35%)… on a beta blocker at maximum tolerated dose” and who are in sinus rhythm with a resting heart rate of >=70.
- The committee chairs had no conflicts of interest reported, though 6 of the 15 committee members did.
So, how should this change practice?
- It is important to remember and acknowledge the baseline: the use of ACE-I, ARB, b-blockers and aldosterone antagonists has so dramatically improved the prognosis and function of patients with HFrEF over the past couple of decades, such that many of my patients, even with symptomatic HF and severely reduced EF are living long and active lives.
- The data on valsartan/sacubitril is indeed impressive (including the 20% decrease in mortality on subgroup analysis), though given how well patients are doing with optimized older medical therapy, and given the somewhat shotgun effects that this new drug combo has on several important enzyme systems, I personally am not ready to use it until more and longer-term data is available (though I would really consider it in patients with suboptimal functional improvement with ACE-I/ARBs).
- In terms of ivabradine, I am less enthusiastic because of the study limitations. This was also short term trial (23 months), and a significant majority were not on full-dose b-blockers. Given the strong data supporting the use of b-blockers, I would primarily promote them. I would consider ivabradine in those not tolerant of b-blockers, though keeping in mind that in the SHIFT trial there was a 15% higher rate of atrial fibrillation, and more symptomatic bradycardia and visual side-effects