Abstract: We included seven studies (1684 participants) in the review. One study enrolled participants from a residential care facility, and the other six studies from primary care and outpatient clinics. All-cause hospital admission data was available in four studies (556 participants). Participants in the NLT group experienced a lower rate of all-cause hospital admissions (RR 0.80, 95% CI 0.72 to 0.88, high-quality evidence) and fewer hospital admissions related to heart failure (RR 0.51, 95% CI 0.36 to 0.72, moderate-quality evidence) compared to the usual-care group. Six studies (902 participants) examined all-cause mortality. All-cause mortality was also lower in the NLT group (RR 0.66, 95% CI 0.48 to 0.92, moderate-quality evidence) compared to usual care. Approximately 27 deaths could be avoided for every 1000 people receiving NLT of beta-adrenergic blocking agents, ACEIs, and ARBs. Only three studies (370 participants) reported outcomes on all-cause and heart failure-related event-free survival. Participants in the NLT group were more likely to remain event free compared to participants in the usual-care group (RR 0.60, 95% CI 0.46 to 0.77, moderate-quality evidence). Five studies (966 participants) reported on the number of participants reaching target dose of beta-adrenergic blocking agents. This was also higher in the NLT group compared to usual care (RR 1.99, 95% CI 1.61 to 2.47, low-quality evidence). However, there was a substantial degree of heterogeneity in this pooled analysis. We rated the risk of bias in these studies as high mainly due to a lack of clarity regarding incomplete outcome data, lack of reporting on adverse events associated with the intervention, and the inability to blind participants and personnel. Participants in the NLT group reached maximal dose of beta-adrenergic blocking agents in half the time compared with participants in usual care. Two studies reported on adverse events; one of these studies stated there were no adverse events, and the other study found one adverse event but did not specify the type or severity of the adverse event. Participants in the NLT group experienced fewer hospital admissions for any cause and an increase in survival and number of participants reaching target dose within a shorter time period. However, the quality of evidence regarding the proportion of participants reaching target dose was low and should be interpreted with caution. We found high-quality evidence supporting NLT as one strategy that may improve the optimisation of beta-adrenergic blocking agents resulting in a reduction in hospital admissions. Despite evidence of a dose-dependent relationship of beta-adrenergic blocking agents, ACEIs, and ARBs with improving outcomes in patients with HFrEF, the translation of this evidence into clinical practice is poor. NLT is one strategy that facilitates the implementation of this evidence into practice.

Plain-language summary: We conducted a review of seven randomised controlled trials (1684 participants) comparing nurse titration of beta-adrenergic blocking agents, ACEIs, and ARBs with titration of these medications by a primary care physician. The demographic characteristics of participants within each study were similar. There was an equal number of men and women in four of the studies. The mean age of participants ranged from 59 to 81 years of age. The evidence is current up to December 2014. The review found that participants undergoing titration of these medications were less likely to experience a hospital admission or to die, and more participants reached the maximum dose compared to those participants having these medications titrated by their primary care physician. Approximately 27 deaths could be avoided for every 1000 patients undergoing titration of these medications by nurses under medical supervision or nurse practitioners. There was very little reported data on the titration of ACEIs and ARBs. Two studies reported on adverse events; one of these studies stated there were no adverse events, and the other study found one adverse event but did not specify the type or severity of the adverse event. In conclusion, titration of these medications by nurses under medical supervision or nurse practitioners may improve their up-titration, which may result in an improvement in patient outcomes. We rated the quality of evidence regarding the proportion of participants that reached optimal dose of these medications as low. This indicates uncertainty as to whether the number of participants reaching optimal dose of beta-adrenergic blocking agents was different due to NLT or usual care. We found high-quality evidence that NLT reduced hospitalisations for any cause compared to usual care. This indicates that we are confident that the reduction in all-cause hospitalisations was due to NLT, and further research is unlikely to change this finding.