Lower enalapril dose effective in heart failure

One of the more common problems with managing patients with heart failure who have reduced ejection fraction (HFrEF) is that, though there are great medications available to reduce morbidity and mortality, they all reduce blood pressure, and many patients cannot tolerate the addition of all of these medications at their target doses.  In this light, a post-hoc analysis of the SOLVD trial was helpful, finding that below-target enalapril had similar clinical efficacy as the full target dose (see doi:10.1002/ejhf.937).

 

Details:

--2458 patients with HFrEF (EF<35%) were randomized to enalapril 5-10mg/d vs placebo; then 1 month later, were blindly up-titrated to target enalapril or placebo dose of 20mg/d. Followed average of 2.7 yrs, with 4.6 yrs for all-cause mortality (primary endpoint in SOLVD)

--mean age 60, 20% women, NYHA class II in 54%/NYHA class III in 30%, 20% current smoker, 72% ischemic heart failure, 65% hx acute MI, 42% hypertension, 26% diabetic, 38% angina, 7% atrial fib, BP 126/76, wt 77 kg, creat 1.3 mEq/L, LVEF 25%.

--meds: 67% digoxin, 85% diuretics, 9% potassium-sparing diuretics (not stated which ones were used), 32% calcium channel blockers, 43% nitrates, 35% anti-platelet agents, 18% anticoagulants, 8% b-blockers.

--1444 patients achieved the target dose up-titration: 61% of those on placebo and 57% of those on enalapril

--of those not achieving target dose, mean dose was 8.8 mg/d, with 76% on 10mg/d, and pretty much the rest were on 5mg/d.

 

Results:

--patients who achieved the target enalapril 20mg/d (n=696), vs 20 mg placebo (n=748): 9% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality, a 30% decrease, HR 0.70 (0.60-0.81), p<0.001.

    --all-cause mortality (multivariate analysis): 10% decrease, HR 0.90 (0.82-0.98), p=0.017

--patients who were below-target, receiving a mean enalapril dose of 8.8 mg/d (n=528) vs placebo (which happened also to be 8.8 mg) (n=486): 12% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality, a 32% decrease, HR 0.68 (0.57-0.81), p<0.001.

    --all-cause mortality (multivariate analysis): 10% decrease, HR 0.90 (0.81-1.00), p=0.057 (borderline significant)

--no difference in outcome comparing the patients who achieved target-dose 20mg enalapril vs those averaging 8.8 mg/d, for the primary or all of the secondary outcomes. And no difference in outcomes in the 2 placebo groups (those achieving target dose and those unable to titrate to target)

 

Commentary:

--a couple of comments about the original SOLVD trial:

    --it was done in 1991, and as noted in the baseline characteristics above, treatment was very different then than currently:  they used lots of digoxin, moderate amounts of calcium-channel blockers and only 35% on anti-platelet drugs, minimal use of b-blockers (8%) and potassium-sparing diuretics (and not sure which ones were used), and no statins

    --it was pretty striking here that the placebo group had almost the same rate of adverse events as the enalapril group in the original SOLVD trial (see N Engl J Med 1991; 325: 293): 87% of enalapril vs 82% of placebo reported apparent adverse effects, more (somewhat) with enalapril in terms of dizziness/fainting (57% vs 50%), cough (37% vs 31%). no difference in angioedema (4% in each). not sure what to make of this, other than these were pretty sick patients, perhaps more aware of minor changes in their conditions.... though still a bit shocking that there was no real difference in dizziness, coughing, or angioedema.

--review of other studies comparing different ACE-I/ARB doses all post-hoc analyses):

    --ATLAS trial: lisinopril 2.5-5mg vs 32.5-35mg: no difference in all-cause mortality, but pretty large difference in HF hospitalizations (1576 vs 1199, p =0.002) favoring the high dose

    --HEALL trial: losartan 50mg vs 150 mg: no significant difference in all-cause mortality; HF hospitalizations 503 vs 450 (p=0.025), 26% vs 23%, and combo of HF hospitalizations or all-cause mortality 12% vs 11% (p=0.027), favoring high dose (ie, significant, but the latter difference was only 1%)

    --in the PARADIGM-HF trial, about 40% of the patients had a dose reduction in both the sacubitril/valsartan and the enalapril arms, to below the target doses of 10mg bid for enalapril and 200mg bid for sacubitril/valsartan. They found similar efficacy for sacubitril/valsartan in the below-target group, compared to enalapril (HR 0.80, p<0.001) vs essentially the same benefit of sacubitril/valsartan​ at-target as compared to enalapril (HR 0.79, p<0.001), though almost 40% of the patients were able to return to the target dose (see chf sacubitril paradigmHF lower dose EurJHF2016 in dropbox, or doi:10.1002/ejhf.580). those having dose reductions were older, had worse renal function, and had more severe HF. A few other findings in this post-hoc analysis: there was no difference in outcome between the groups if they transiently vs permanently decreased the dose of the meds, and those on sacubitril/valsartan did better than those on enalapril at each level of target dose reduction (though those on <50% of target dose had a similar 20% risk reduction vs enalapril, but that did not reach statistical significance)

    --so, though there was a difference in these studies between low and high dose meds, the difference was largely driven by changes in HF hospitalizations (for the sacubitril/valsartan trial, they only reported the primary outcome, which was cardiovascular mortality and heart failure hospitalizations). And, there was a significant potential confounder in these trials: none of these trials, other than SOLVD, compared the below-target groups with their equivalent placebo groups (though PARADIGM-HF had no placebo one, just sacubitril/valsartan vs enalapril). so, it is quite possible that those patients in the other trials not reaching their target ACE dosage were actually significantly sicker than those who could (ie, their blood pressure was lower or their creatinine was higher, etc); see further comment below. In the SOLVD trial, they did compare the two placebo groups (those achieving full-dose vs those unable to do so) and found no difference in outcomes, suggesting that there were not major differences in baseline characteristics of the 2 groups.

--one concern, as per usual in these post-hoc analyses of meds used at different doses, is that there may be underlying important but uncontrolled differences between the patients who can vs cannot achieve the target dose, despite the comment above about comparing the placebo groups. there really dose need to be an RCT which randomly assigns patients to the different doses of meds and assesses predefined outcomes. that way we could see pretty clearly what the low-dose threshold for ACE-I is, the optimal one where there is minimal difference with the presupposition of the higher appropriate target-dose

 

--a potentially important side issue is the relationship between the achieved blood pressure on meds and mortality.  another recent article (see Lee SE. JACC:Heart Failure. 2017; 5(11). 810) looked retrospectively at the Korean Acute Heart Failure registry of 5,625 consecutive patients hospitalized for HF in 10 university hospitals between 2011-2014, finding that overall there was a one year mortality of 18.2% But there was a reverse J-curve relationship with all-cause mortality, related to the follow-up outpatient blood pressures, with a maximal clinical benefit at BP of 132.4/74.2. Notably, this maximal benefit inflection point was independent of whether the patient had HFrEF (136.0/76.6) or HFpEF (127.9/72.7), and was overall in patients on apparently pretty good meds (70% on ACE/ARB, 55% of b-blocker, 50% aldosterone antagonist, 75% on loop diuretics). unfortunately, there was no breakdown of mortality by the exact meds taken, though they did comment that there was no interaction on the results by the meds used.

 

so, HFrEF has become very treatable over the past couple of decades, with pretty dramatic reductions in many important clinical outcomes. But a pretty frequent conundrum is what to do when patients cannot tolerate them, typically because of hypotension or renal dysfunction. which agents need to be maximized to get benefit? which can be used at lower doses without major degradation in effect? this article, based on the seminal SOLVD trial, helps answer this question with the above noted limitations, suggesting that ACE inhibitors (and, likely, ARBs and the ARNI sacubitril/valsartan) seem to do well at lower doses, thereby allowing for the addition of b-blockers, aldosterone antagonists, and even increases in diuretics, all of which might help with further decreasing morbidity and mortality. The Korean reverse J-curve study furthers the question: what is the balance between optimizing adding on these different beneficial meds vs maintaining a blood pressure in the optimal range? should we be adding on many meds at reduced levels? are some at the meds’ current target doses more important to use than adding on another beneficial med (eg, should we prescribe b-blockers at lower levels in order to be able to add on sprironolactone; are b-blockers more important than spironolactone)?  Unfortunately, these above articles lead to the general refrain from editorialists: more studies need to be done (studies beget studies....).  my best guess is that if hypotension or increasing renal dysfunction happen in patients with HFrEF on meds, it probably makes sense to dial back on the ACE/ARB as an initial strategy.​