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

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

We searched MEDLINE, Embase, and CENTRAL for randomized 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 vs no vaccination) and a network meta-analysis comparing all 4 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 hospitalization. Risk ratios (RR) were pooled under random-effects models.

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 (RR, 0.75; 95% CI, 0.64-0.89), cardiovascular death (RR, 0.63; 95% CI, 0.42-0.93), and myocardial infarction (RR, 0.76; 95% CI, 0.62-0.94) compared with no vaccination. No significant reductions were observed for stroke (RR, 1.06; 95% CI, 0.72-1.54) or heart failure hospitalization (RR, 0.96; 95% CI, 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 hospitalization and stroke, though no head-to-head dose comparison reached statistical significance.

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 hospitalization was observed in a single trial and requires confirmation.