High-dose flu vaccine no better than standard-dose in reducing death, CV hospitalization

Patients with high cardiovascular (CV) risk who received a high-dose trivalent influenza vaccine over three influenza seasons did not have a lower risk of cardiopulmonary hospitalization or death compared with those who received a standard-dose quadrivalent vaccine, according to the INVESTED* trial presented at AHA 2020.

Participants in this multicentre, double-blind trial were 5,260 patients from Canada and the US (mean age 65.5 years, 28 percent female) who had been hospitalized for myocardial infarction (MI) in the past 12 months (37 percent) or for heart failure (HF) in the past 24 months (63 percent), and had ≥1 additional CV risk factor**. There were randomized 1:1 to receive a high-dose trivalent (60 μg haemagglutinin per strain) or standard-dose quadrivalent (15 μg haemagglutinin per strain) inactivated influenza vaccine annually for up to three influenza seasons and followed up to four times a year. A total of 3,577 vaccinations were administered in each group.

Time to first all-cause mortality or hospitalization due to cardiopulmonary causes was comparable between patients who received the high-dose and standard-dose influenza vaccine (44.5 vs 41.9 per 100 patient-years; hazard ratio, 1.06, 95 percent confidence interval, 0.97–1.17; p=0.21). [AHA 2020, session LBS.08; JAMA 2020;doi:10.1001/jama.2020.23649]

There was also no between-group difference for the secondary endpoints including CV death or hospitalization in each vaccination season, all-cause mortality, or first or total cardiopulmonary hospitalizations and all-cause mortality across all enrolling seasons.

Post hoc analysis showed that hospitalization due to influenza or pneumonia was generally low in both vaccine groups (influenza: n=10 vs 8 [high- vs standard-dose vaccine]; p=0.63; pneumonia: n=47 vs 41; p=0.56).

Adverse events (AEs) were more common in the high-dose vs standard-dose group, specifically pain (26.1 percent vs 19.1 percent; p<0.001), swelling (5.5 percent vs 3.3 percent; p<0.001), and myalgia (14.0 percent vs 11.8 percent; p=0.007). Incidence of vaccination-related severe adverse reaction was rare and did not differ between groups (1.6 percent vs 1.3 percent; p=0.27). Six serious AEs were reported, two and four in the high- and standard-dose groups, respectively.

The study was terminated early for futility after 1,770 primary outcome events.  

“This trial was predicated on the concept that reducing influenza in a high-risk population would lead to reduction in CV and pulmonary hospitalizations and deaths,” said study author Associate Professor Orly Vardeny from the University of Minnesota and Minneapolis VA Health Care System, Minneapolis, Minnesota, US, and co-authors.

Patients with cardiovascular disease (CVD) have a high risk of complications and adverse clinical outcomes due to influenza, with previous research showing a reduced risk of CV complications following influenza vaccination. [JAMA 2013;310:1711-1720]

“[I]n the current trial, the potential benefit for high-dose vaccine to prevent influenza infection did not translate to a reduction in all-cause mortality or hospitalizations with high-dose vaccine,” he said.

Benefits not to be discounted

“[Despite the overall findings,] the incidence of hospitalization due to influenza was low in both vaccinated groups, and the benefit of either vaccine may be far greater than the incremental benefit of high-dose over standard-dose vaccines for influenza outcomes,” said the authors.

“These results need to be put into context. We compared two active vaccine formulations, and both reduce influenza illness, thus receipt of any influenza vaccine in high-risk patients may be protective and limit the potential benefit of high-dose vaccine in reducing cardiopulmonary events,” Vardeny pointed out.

“[Additionally,] patients in INVESTED were high-risk, and the incremental benefit of one influenza formulation may have been diluted by high ambient event rates,” he said.

“Importantly, these results do not detract from prior trials showing benefit of high-dose vaccine on reducing influenza illness, nor do they minimize the importance of influenza vaccination in patients with high-risk CVD, for whom vaccination remains strongly recommended,” he noted.