Primary Care Corner with Geoffrey Modest MD: 3 Heart Failure Articles of Note

By Dr. Geoffrey Modest

There were 3 useful articles in the JACC-Heart Failure journal which I think are useful in primary care

1. This article (see doi.org/10.1016/j.jchf.2015.09.002​) looked at the target for b-blocker (BB) use in patients with heart failure and reduced ejection fraction (EF, <35%) within the HF-ACTION study, the largest trial of BB use involving 2331 medically stable outpatients and showing benefit from a structured aerobic exercise program over 2.5 years (see JAMA 2009; 301(14): 1439). The issue addressed is titration of the BB dose: the HF-ACTION and other trials have found that just lowering the heart rate (HR) improves mortality but raise the question of whether that explains the full BB effect, or is the achieved dose of the BB more important.

Details:

• 2320 patients (mean age 60, 28% female, 32% black, BMI 30, 62% NYHA Class II, 50% ischemic cardiomyopathy, EF 25%, SBP 110 mmHg, resting HR 70, 80% in sinus rhythm).
• Divided into 2 groups: those on high dose carvedilol (>=25mg/d) vs low dose (<25 mg/d); and those with high heart rate (>=70 bpm) vs low (<70 bpm)

Results:

• All-cause death or all-cause rehospitalization (all with adjusted HR values)
  • High vs low dose BB, hazard ratio 0.87 (0.77-0.99), p=0.03, i.e. 13% decrease in deaths/hospitalizations
  • High vs low HR, hazard ratio 11 (0.98-1.24), p=0.09, nonsignificant
  • And looking at the combination, adding HR to the analysis added no significant value
• There was a significant 21% decrease in all-cause death as well as a 23% decrease in cardiovascular death or heart failure rehospitalization with high-dose BB. HR was not significant for any of the outcomes in either unadjusted or adjusted analyses. Part of the reason for the lack of significance is the relatively low number of events, under powering the study.
• The association between BB dose and the above clinical outcomes was independent of the baseline HR
• There was no significant difference in the biomarker NT-proBNP between these groups, though there was more of a decrease in the biomarker in the high BB dose group, though nonsignificant. Related to small numbers?

So, this study reinforces maximizing the BB dosage, even in those with HR<70bpm. I’m not sure what the BP was for this group (not reported), but the high numbers of patients in the community not on optimal BB doses (in the 80-90% range!!) reflect perhaps a less aggressive approach to therapy than seems warranted. I should add the caveat that this is a post-hoc analysis, and as such is potentially limited by confounding.

 

2. A meta-analysis of 11 studies looking at the progression of asymptomatic heart failure (HF) to symptomatic HF, over an average of 7.9 years (see org/10.1016/j.jchf.2015.09.015), assessing both those with ALVSD (asymptomatic left ventricular systolic dysfunction), and ALVDD (asymptomatic left ventricular diastolic dysfunction).

Details:

• 11 studies identified with 5,369 patients. 5 with ALVSD, 3 with ALVDD, and 4 with both
• ALVSD somewhat variably defined, but typically ejection fraction (EF)<30-50%

Results:

• ALVSD: absolute risk of progression to symptomatic HF was 8.4/100 person-years (4.0-12.8 per 100 person-years); adjusted relative risk was 4.6 (2.2-9.8)
• ​ALVDD: absolute risk of progression to symptomatic HF was 2.8/100 person-years (1.9-3.7 per 100 person-years); adjusted relative risk was 1.7 (1.3-2.2)
• In controls (no ventricular dysfunction): absolute risk of progression to symptomatic HF was 1.04/100 person-years (0.0-2.2 per 100 person-years)
• ​Per a 1-SD change in EF, there is an overall 38% increased risk of developing clinical HF [RR=1.38 (1.14-1.67]
• The main predictors of progression were: age, sex, blood pressure, diabetes, and BMI

So, it is pretty clear that asymptomatic LV dysfunction is associated with a significant risk of becoming symptomatic, more so in those with reduced systolic function, and with increasing risk as the EF decreases. Studies have shown that asymptomatic LV dysfunction is also associated with reduced survival, and interventions as with ACE inhibitors prevent or delay the development of symptomatic HF and decreases mortality.

 

3. Looking at the CIBIS-ELD trial (Cardiac Insufficiency Bisoprolol Study in Elderly), researchers assessed the tolerability and efficacy of bisoprolol vs. carvedilol in symptomatic (at least NYHA class 2) patients > 65 yo with either HFrEF (heart failure with reduced ejection fraction) or HFpEF (heart failure with preserved EF) — doi.org/10.1016/j.jchf.2015.10.008​.

Details:

• 626 patients with HFrEF (mean age 73, 26% women, 61% NYHA class 2/32% class 3, 15% with peripheral edema, mean HR 75, mean BP 134/80, BMI 27, EF 35%, NT-proBNP 968; CAD in 68%, dilated cardiomyopathy in 19%, hypertension in 80%, 9% smokers, 48% with MI) and 250 with HFpEF (mean age 73, 66% women, 76% NYHA class 2/23% class 3, 35% with peripheral edema, mean HR 71, mean BP 146/80, BMI 29, EF 59%, NT-proBNP 253; CAD in 33%, dilated cardiomyop in 2%, hypertension in 90%, 8% smokers, 18% with MI) were randomized to bisoprolol vs carvedilol, with a goal to up-titrate to the target or maximally tolerated dose
• Carvedilol started at 6.25mg bid with target of 25 mg bid (or 50mg bid in those with body weight >85kg); bisoprolol was 2.5mg daily with target of 10mg daily, with biweekly dose doubling
• Titration was to be over 6 weeks (8 weeks for those >85kg and on 50mg carvediol), then 4 week maintenance period

Results:

• Mean daily dose of bisoprolol after titration was 4.93 mg in the HFpEF and 5.01 in HFrEF groups; for carvedilol it was 25.3 and 29.1 respectively) — nonsignificant differences (19% of HFpEF vs 27% with HPrEF reached target dose, regardless of treatment group, which was significant)
• ​It took longer to uptitrate those with preserved EF (12%) vs reduced EF (5%)
• Similar HR reductions, at 7 bpm in both those with preserved and reduced EFs. BP decreased more with the preserved EF group (14/5 mmHg) vs reduced (8/4)
• NYHA functional class improvement:
  • Reduced EF group had 34% improvement vs preserved EF group (decrease of 31% vs 18%): 23% improvement (p<0.001  for comparison), and no diff if on carvedilol vs bisoprolol
• 6-minute walk distances and physical quality of life measures improved in the HFrEF group but no change in HFpEF groups (20 vs 4 meters).
• In 3 measures of quality of life (SF-36 PFS, SF-36 PCS and SF-36 MCS, reflecting physical functioning, physical component, and mental component): there was only a significant change in the HFrEF group only
• ​Echo for systolic function: mean EF improved in those with reduced EF from 35% to 39% by week 12, no change in the preserved group.
• ​Echo for diastolic function: mean E/e’ and left atrial volume index not change in either group, but E/A mitral flow did increase in those with preserved EF [i.e., BBs did not change any markers of diastolic function in either those with preserved or reduced EF), and no difference between the BBs]
• ​Adverse effects: more in HFpEF patients (79%) vs HFrEF (58%), with p<0.001 for difference, mostly bradycardia (20% vs 11%), dizziness (15% vs 4%), and fatigue (18% vs 4%)

So, one of the major conundrums in treating HF is that about 50% have HFpEF (preserved EF), with increasing prevalence over time. This group in general has the same overall prognosis as those with reduced EF. And we have minimally effective treatments as compared with those with reduced EF. On the surface, BBs would seem to be reasonable drugs (they decrease BP, decrease LVH, decrease HR, and decrease ventricular arrhythmias — a leading cause of death in this group). This study did not find any really significant differences between using bisoprolol vs carvedilol, either in tolerability or efficacy. But there were real differences between those with reduced EF (easier ability to titrate dose up, more improvement in NYHA functional class and measures of quality of life, walking distance, EF, fewer adverse events) and much less in those with preserved EF (more decrease in HR, BP, and no real clinical improvement). This was a short-term study, and without a placebo group,

—–

So, why do I bring up these 3 articles?

• HF is really common (5.7 million US adults, lifetime risk in a young adult being 20%), has a substantial morbidity/mortality, and there are lots of people with asymptomatic HF (3-4x the number with symptomatic).
• The first article found that for those with reduced EF, trying to push BB to the targeted dose (which, unfortunately, does not happen so often in community practice), seems to confer the most benefit
  • The treatment algorithm is pretty straightforward (diuretics as needed, then ACE/ARB, then BB, then aldosterone antagonists; though can use hydralazine/isosorbide dinitrate in African-Americans and those not tolerant of ACE/ARBs), but these meds all lower blood pressure, and in my experience the not-so-uncommon limiting factor is that the blood pressure can’t abide this many agents at full dose, leaving us some unanswered questions:
    • What are the priority agents (in general the studies have assumed this medication order, but if the blood pressure is low, which individual agent is the most effective?)
    • Is it better to have low doses of multiple agents vs maxing out the meds in a specific order (studies do suggest that low doses of meds are useful)?
  • And another issue is hyperkalemia. Though the diuretics help counter this, all the other meds make it worse. And this is especially an issue in diabetics (not-so-uncommon), where hyperkalemia is more often an issue.
    • Again, should we give a little of many agents or push individual agents in a particular order? (E.g. my experience is that BBs are less hyperkalemic than the ACE/ARB or aldo antagonists. I should add that the CIBIS III trial did find that starting BBs first seems to be equivalent in outcome to ACE/ARBs, but the advantage of ACE/ARB first is that they work faster, and BBs can cause worsening heart failure in the short-term, further supporting starting first with ACE/ARB to better optimized initial treatment)
  • The second article found that those with asymptomatic HF have a real risk of progression to symptoms, more-so in those with reduced EF (systolic dysfunction). And these asymptomatic people, a very common issue, are at much higher risk of morbidity and mortality, raising:
    • The potential possibility that we should be screening more routinely for asymptomatic LV dysfunction, then doing interventions to improve the function and potentially decrease both the likelihood of symptomatic HF and mortality. Seems like a useful study to do, since the prevalence, morbidity and mortality of HF is so profound. But at this point it is not clear that early identification and treatment changes any clinical outcomes.
    • And, it reinforces the likely benefit of preventing ventricular dysfunction in the first place: decreasing systolic dysfunction by decreasing cardiovascular risk factors, the development of nonischemic cardiomyopathies (e.g. decreasing stress, treating infections such as chagas, lyme early and aggressively, etc.); and decreasing diastolic dysfunction (also treating hypertension, stress, development of myocardial ischemia)
  • And the third article, though actually a short-term tolerability study, highlights the difficulty of treating those with preserved EF, though it should be pointed out that this was a short-term study and the mechanism of disease in those with preserved EF is different from those with reduced EF (i.e., it may take longer to reverse the cardiac remodeling in those with preserved EF)
    • ​But the bigger and more relevant/longer-termstudies do not find the same benefit with current treatment of those with preserved EF as in those with reduced EF, though there are some data that ARBs decrease hospitalizations (CHARM-Preserved trial) and that spironolactone decreases hospitalizations and (secondary analysis) deaths in those with high BNP levels (TOPCAT trial) though with a fair amount of hyperkalemia
    • In fact, treatment of those with preserved EF is pretty much several decades behind where we are with patients with reduced EF (where we were basically using loop diuretics and digoxin for symptom control, without improving mortality)
    • e., we really need better drugs (and reinforcing the above interventions to decrease the development of left ventricular dysfunction with preserved EF to the extent we can)
  • But my experience is that treating HF, esp. in those with reduced EF, is really easy to do in the primary care setting in the vast majority of patients and that there is really a very remarkable response to the meds with the above-noted algorithm (I have had several patients with shockingly low EFs in the 10-15% range who function totally normally for more than 10 years…). And we can also provide symptom control for the majority of those with preserved EF, using diuretics, ACE/ARB, ?spironolactone (which are more effective than BBs anyway in improving left ventricular size and shape), and BBs as needed to help control HR, anginal symptoms, and BP. Treating HF one of the more rewarding primary care interventions, since patients pretty regularly respond so well clinically to these interventions and feel much better so rapidly.