Review: In HF with reduced EF, nurse-led titration of HF drugs reduces hospitalizations and mortality

Question In patients with heart failure (HF) and reduced ejection fraction, does nurse-led titration (NLT) of angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), and -adrenergic blockers reduce hospitalizations and mortality compared with usual care? Review scope Included studies compared titration of ACE inhibitors, ARBs, and -adrenergic blockers by HF nurse specialists or nurse practitioners in outpatient clinics or patients' homes with titration by primary care physicians (usual care) in patients 18 years of age. These patients had symptomatic HF and reduced ejection fraction and were prescribed 1 of the 3 drug classes. Outcomes were all-cause and HF hospitalization, all-cause mortality, all-cause event-free survival (based on all-cause hospitalization or mortality events), and adverse events. Review methods MEDLINE, EMBASE/Excerpta Medica, and Cochrane Central Register of Controlled Trials (Dec 2014); World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov (Jul 2015); reference lists; and gray literature were searched for randomized controlled trials (RCTs). 7 RCTs (n =1684, mean age 59 to 81 y, about 50% women in 4 RCTs and 79% in 1 RCT) met the inclusion criteria. 1 additional study published in abstract form met the inclusion criteria but was excluded because insufficient data were available. 2 RCTs titrated all 3 drug classes; 2 titrated ACE inhibitors and -adrenergic blockers, and 3 titrated only -adrenergic blockers. 1 RCT had adequate allocation concealment, 2 had adequate outcome data, and 4 blinded outcome assessors; no RCTs blinded patients or health care professionals. Follow-up ranged from 6 to 18 months (median 12 mo). Main results NLT reduced all-cause and HF hospitalizations, all-cause mortality, and a composite of hospitalization or all-cause mortality compared with usual care (Table). 2 RCTs provided adverse event data: 1 reported 1 adverse event in the NLT group, and 1 reported no adverse events in either group. Conclusion In patients with heart failure and reduced ejection fraction, nurse-led titration of angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and -adrenergic blockers reduces hospitalizations and all-cause mortality compared with usual care. Nurse-led titration of angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and -adrenergic blockers vs usual care in patients with HF and reduced ejection fraction* Outcomes Number of trials (n) Weighted event rates At a median 12 mo Nurse-led titration Usual care RRR (95% CI) NNT (CI) All-cause hospitalization 4 (560) 61% 76% 20% (12 to 28) 7 (5 to 12) HF-related hospitalization 4 (642) 13% 25% 49% (28 to 64) 9 (6 to 17) All-cause mortality 6 (902) 11% 17% 34% (8 to 52) 18 (10 to 80) Hospitalization or all-cause mortality 3 (370) 29% 49% 40% (23 to 54) 6 (4 to 10) *HF = heart failure; other abbreviations defined in Glossary. Weighted event rates, RRR, NNT, and CI calculated from relative risk, risk difference, and usual care event rates obtained using the review RevMan file and a fixed-effect model. Commentary RCTs show that ACE inhibitors and ARBs result in 17% and 31% relative risk reductions in mortality and HF admissions, respectively, and -blocker therapy results in reductions of 34% and 41%, respectively (1). However, in practice, patients are often treated with drug doses below those shown to be effective in trials. Driscoll and colleagues conducted the first systematic review to compare outcomes in HF patients randomized to NLT of ACE inhibitors, ARBs, or -blockers vs usual care by primary care physicians. Although the effect of NLT seems impressive, several issues should be considered before recommending widespread implementation of this strategy. Trials included in the review were heterogeneous. The largest trial (n =706) did not report mortality or hospitalization, and sample sizes of the other trials ranged from 28 to 406, with varied clinical outcomes. The 20% relative reduction in all-cause hospitalizations with NLT was based on an analysis of 4 trials but mainly influenced by 1 large study (weight 85%). The magnitude of benefit for mortality and hospitalization may be exaggerated, because it is comparable to that seen in large clinical trials of blockers or ACE inhibitors/ARBs compared with placebo (1). Although pooled analyses suggested that patients in the NLT group were more likely to reach target doses of -blockers, heterogeneity among the studies was high; only 1 small study reported these data for patients receiving an ACE inhibitor. Further, in most trials, the intervention was not confined to NLT of medications but included other elements of disease management strategies that could be responsible for, or contribute to, the benefits. Multicenter RCTs with large sample sizes would be valuable to confirm and explain the benefits attributable to NLT. Cost-effectiveness and feasibility studies, which were not explored in any of the included trials, are needed before large-scale implementation of NLT strategies is considered.