Abstract: We included two randomised controlled trials (three reports) with 1674 participants, with mean age between 64.1 and 67.8 years. Follow-up ranged from 2 years to mean 4.3 years. For primary outcome measures, effect estimates from a single study showed uncertainty for the effect of NP-guided treatment on cardiovascular mortality in patients with cardiovascular risk factors and without heart failure (RR 0.33, 95% CI 0.04 to 3.17; 1 study; 300 participants; low-quality evidence). Pooled analysis demonstrated that in comparison to standard care, NP-guided treatment probably reduces the risk of cardiovascular hospitalisation (RR 0.52, 95% CI 0.40 to 0.68; 2 studies; 1674 participants; moderate-quality evidence). This corresponds to a risk of 163 per 1000 in the control group and 85 (95% CI 65 to 111) per 1000 in the NP-guided treatment group. When secondary outcome measures were evaluated, evidence from a pooled analysis showed uncertainty for the effect of NP-guided treatment on all-cause mortality (RR 0.90, 95% CI 0.60 to 1.35; 2 studies; 1354 participants; low-quality evidence). Pooled analysis indicates that NP-guided treatment probably reduces the risk of all-cause hospitalisation (RR 0.83, 95% CI 0.75 to 0.92; 2 studies; 1354 participants; moderate-quality evidence). This corresponds to a risk of 601 per 1000 in the control group and 499 (95% CI 457 to 553) per 1000 in the NP-guided treatment group. The effect estimate from a single study indicates that NP-guided treatment reduced the risk of ventricular dysfunction (RR 0.61, 95% CI 0.41 to 0.91; 1374 participants; high-quality evidence). The risk in this study's control group was 87 per 1000, compared with 53 (95% CI 36 to 79) per 1000 with NP-guided treatment. Results from the same study show that NP-guided treatment does not affect change in NP level at the end of follow-up, relative to standard care (MD -4.06 pg/mL, 95% CI -15.07 to 6.95; 1 study; 1374 participants; moderate-quality evidence). This review shows that NP-guided treatment is likely to reduce ventricular dysfunction and cardiovascular and all-cause hospitalisation for patients who have cardiovascular risk factors and who do not have heart failure. Effects on mortality and natriuretic peptide levels are less certain. Neither of the included studies were powered to evaluate mortality. Available evidence shows uncertainty regarding the effects of NP-guided treatment on both cardiovascular mortality and all-cause mortality; very low event numbers resulted in a high degree of imprecision in these effect estimates. Evidence also shows that NP-guided treatment may not affect NP level at the end of follow-up. As both trials included in our review were pragmatic studies, non-blinding of patients and practices may have biased results towards a finding of equivalence. Further studies with more adequately powered sample sizes and longer duration of follow-up are required to evaluate the effect of NP-guided treatment on mortality. As two trials are ongoing, one of which is a large multi-centre trial, it is hoped that future iterations of this review will benefit from larger sample sizes across a wider geographical area.

Plain-language summary: Evidence in this review is current to July 2019. We included two randomised controlled trials (where participants have an equal chance of being assigned to either treatment) including 1674 adult participants who had one or more risk factors for developing CVD, which compared NP-guided treatment with standard care. We excluded patients with symptoms of heart failure. The mean age of participants varied between 64.1 and 67.8 years. Patients were followed-up for between 2 years and a mean of 4.2 years. Effects of NP-guided treatment on death due to CVD or for any other reason remain uncertain as our results were imprecise. Moderate-quality evidence suggests that NP-guided treatment probably reduces the number of hospitalisations due to cardiovascular events and due to all causes in patients with cardiovascular risk factors. We would expect that of 1000 patients who received standard care, 163 would be admitted to hospital as the result of a cardiovascular event, compared to between 65 and 111 patients who received NP-guided treatment. Out of 1000 patients with cardiovascular risk factors who received standard care, 601 would be admitted to hospital for any reason, compared to between 457 and 553 patients who received NP-guided treatment. High-quality evidence indicates that NP-guided treatment reduces the risk of ventricular dysfunction (a condition that often leads to heart failure) compared to standard care. Our results suggest that of 1000 patients with cardiovascular risk factors who received standard care, 87 would develop ventricular dysfunction, compared to between 36 and 79 patients who received NP-guided treatment. No evidence suggests that NP-guided treatment affected NP level at completion of the studies. The quality of evidence ranged from low to high across outcomes. Key reasons for concern about the quality of the evidence included risk of bias, as patients and medical staff caring for patients knew whether they were in the control or intervention group and this may have affected the care they received; some results obtained were imprecise, and it is unclear if the intervention was beneficial or harmful. As we identified only two studies that were suitable for inclusion in this review, the generalisability of the review is limited.