Comparative effectiveness of influenza vaccination dosing strategies for cardiovascular protection: a systematic review and network meta-analysis of randomised controlled trials

BACKGROUND: Influenza vaccination is recommended for cardiovascular secondary prevention, but the comparative effectiveness of different dose strategies remains incompletely characterised.

METHODS: We searched MEDLINE, Embase, and CENTRAL for randomised trials comparing high-dose (HD-IIV), double standard-dose, standard-dose (SD-IIV), and no vaccination in adults with established cardiovascular disease. A pairwise meta-analysis (SD-IIV versus no vaccination) and a network meta-analysis comparing all four dosing strategies were performed. The primary endpoint was the trial-reported composite cardiovascular endpoint. Secondary endpoints were all-cause death, cardiovascular death, myocardial infarction, stroke, and heart failure hospitalisation. Risk ratios (RR) were pooled under random-effects models.

RESULTS: Ten trials enrolling 131,908 participants were included. In the pairwise analysis, SD-IIV was associated with a significantly lower risk of the composite cardiovascular endpoint (RR, 0.74; 95% confidence interval [CI], 0.61-0.90), all-cause death (0.75; 0.64-0.89), cardiovascular death (0.63; 0.42-0.93), and myocardial infarction (0.76; 0.62-0.94) compared with no vaccination. No significant reductions were observed for stroke (1.06; 0.72-1.54) or heart failure hospitalisation (0.96; 0.60-1.54). In the network meta-analysis, SD-IIV ranked highest across mortality and composite endpoints while HD-IIV ranked highest for heart failure hospitalisation and stroke, though no head-to-head dose comparison reached statistical significance.

CONCLUSIONS: Influenza vaccination was associated with lower risks of cardiovascular events, all-cause death, cardiovascular death, and myocardial infarction in patients with cardiovascular disease, with mortality benefits concentrated in trials enrolling patients during acute cardiovascular admission. Higher-dose formulations did not demonstrate incremental cardiovascular benefit over standard-dose vaccination, although a directional advantage for HD-IIV against heart failure hospitalisation was observed in a single trial and requires confirmation.