Good Echo Response to CRT Meant Better Diuretic, ACE-I Dosing in MADIT-CRT: Analysis

April 01, 2015

ROCHESTER, NY — The more patients responded hemodynamically to cardiac resynchronization therapy (CRT) in the MADIT-CRT trial, the likelier they were to go off loop diuretics and to stay on ACE inhibitors and angiotensin-receptor blockers (ARB), both of which independently improved prognosis, suggests a post hoc analysis[1].

That CRT responders were more likely to stay on HF meds known to boost survival and to be off those shown to worsen mortality "suggests a complementary effect of CRT and medications in HF patients," write the authors, led by Dr Justin Penn (University of Colorado School of Medicine, Aurora). Their analysis was published March 20, 2015 in the Journal of Cardiac Failure.

It wasn't possible to show the relative effects of CRT vs medical therapy on clinical improvements seen in the trial, which had randomized 1820 patients in NYHA class 1–2, wide-QRS heart failure to receive implantable defibrillators with vs without biventricular pacing. Nor could it be proven whether gains in echo measures were a cause or effect of changes in medical therapy, observed senior author Dr Jeffrey Alexis (University of Rochester School of Medicine and Dentistry, NY) for heartwire from Medscape.

However, "I think we can hypothesize that there may be a direct effect from CRT of increasing the likelihood of patients being on an ACE inhibitor or coming off a diuretic," he said when interviewed.

Positive Feedback

Clinicians look to fine-tune HF medications, especially diuretics, based on the patient's clinical picture, Alexis observed. But further, he described a kind of positive-feedback loop involving both echo findings and the effects of medical therapy.

In that scenario, Alexis proposed, improved hemodynamic function at echo follow-up encourages upward adjustments of ACE inhibitors or ARBs and lessening of diuretics. Going off loop diuretics, usually furosemide in MADIT-CRT, helps preserve renal function and prolong survival in heart failure, while uptitrating ACE-I/ARBs likely improves symptoms, cardiac structure, and survival.

"We think there is an interplay between CRT and medication," Alexis said. "We think that CRT may allow patients to better tolerate the uptitration." And that, in turn, shows up as improved hemodynamics at the next echo follow-up.

Medication Effects on Primary Results

In MADIT-CRT, those randomized to CRT showed a 34% drop in the adjusted hazard ratio (HR) for the primary end point of death from any cause or nonfatal heart-failure events (P <0.001). In the current analysis, use of diuretics at any point in the trial was associated with an HR of 1.87 (95% CI 1.45–2.41, P<0.001) for the same end point. The corresponding HR fell to 0.49 (95% CI 0.37-0.65, P<0.001) for patients who were not on diuretics at either baseline or follow-up.

Treatment with an ACE inhibitor or ARB at any point presented an HR of 0.58 (95% CI 0.42-0.80, P=0.001) for the death/HF-event end point. But that benefit turned around for patients who went off those agents during the trial. The HR was 2.10 (95% CI 1.40-3.16, P<0.001) for those starting the trial on ACE inhibitors or ARBs but who weren't on them at follow-up.

CRT efficacy was measured by changes in echocardiographic LV end-systolic volume (LVESV) from baseline to one year, at which time 57.4% were judged superresponders (LVESV decrease ≥30%), 32.6% responders (LVESV decrease 15% to 29%), and 10% nonresponders (LVESV decrease <15%).

Being off diuretics at follow-up was inversely correlated with CRT response, ranging from 33.8% not on diuretics among superresponders to 21.9% for nonresponders (P=0.02). Being on ACE-I/ARBs at follow-up was positively related to CRT response; they were used by 95.5% of CRT superresponders, which went down to 87.7% in nonresponders (P=0.009). A similar pattern was seen for change in LVEF.

The practical message, said Alexis, is that both CRT and medical therapy are important in treating such patients and that "the guidelines are correct," in that, at any given point, more of ACE-I/ARBs and less of diuretics should be given as tolerated.

The primary MADIT-CRT trial was supported by a research grant from Boston Scientific; the company did not fund the current study. Alexis and Penn report that they have no relevant financial relationships. Disclosures for the coauthors are listed in the report.

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