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High-Dose versus Standard-Dose Influenza Vaccination among Veterans Health Administration Patients: An Instrumental Variable Analysis
In randomized trials of adults aged 65 years or older, a high-dose influenza vaccine (HD) was more efficacious in preventing pneumonia admissions compared with the standard-dose vaccine (SD). An observational study in the Veterans Health Administration (VHA) population, however, did not show any additional benefit of HD over SD for this outcome. We reassessed the relative vaccine effectiveness (rVE) of HD vs. SD in the VHA population using the instrumental variable (IV) method to better control for confounding by indication, especially unmeasured confounding. Positive rVE indicates greater efficacy of HD compared to SD.
Methods
The study included Veterans aged 65 or older who received an influenza vaccine in the 2011-12 influenza season at the VHA. Electronic medical records were used to capture the treatment, outcome (hospitalizations due to pneumonia or influenza and all-cause hospitalizations) and baseline patient characteristics. The IV was the proportion of HD recipients at each VHA facility in the prior season, defined as the number of HD recipients divided by the total number of both HD and SD recipients at each VHA facility. The instrument was defined using the HD proportion from the prior season (2010-11), because it is a strong predictor of receipt of HD in 2011-2012 but less likely to be related to the health or treatment of patients in the 2011-2012 season. Because the dependent variable was a count variable (number of hospitalizations), we performed IV Poisson regression analysis, adjusting for age, sex, race, socioeconomic status as well as baseline comorbidities. We performed tests of the Correlation and the Exclusion Restriction criteria for IV analysis. Finally, we conducted a falsification test, using hospitalization associated with urinary tract infection as the outcome; receipt of HD versus SD vaccine should not affect this outcome.
Results
Our study population included 678,386 VHA patients who were vaccinated at 1,027 VHA facilities (medical centers and community-based outpatient clinics) in the 2011-2012 season. Of these, 20,880 patients (3%) received HD, while 657,506 patients (97%) received SD. The IV adjusted rVE estimate of HD was 47% (95% CI, 27%–62%) against influenza- or pneumonia-associated hospitalization, and 13% (95% CI, 4%-21%) against all-cause hospitalization. We found that our instrument was strongly predictive of receipt of HD. An F statistic greater than 10 is generally considered sufficient. The F statistic for our sample was 916,371. Every increment of 10% in a facility’s prior HD proportion was associated with doubling the likelihood of a patient being provided with HD. In addition, the instrument was not correlated with other factors that would affect the medical outcomes of patients, such as facility quality, facility type, regions, rurality or the overall health status of patients treated by the facility. The falsification test was confirmative as the IV adjusted rVE estimate of HD was 4% (95% CI, -22%–25%) against hospitalization associated with urinary tract infection.
Conclusions
HD is more effective than SD in protecting against hospitalizations due to pneumonia or influenza and against any hospitalization in the VHA population during the 2011-12 influenza season.