Atrial Fibrillation after RSV Vaccination Among Older Adults

Introduction

In May 2023, the U.S. Food and Drug Administration (FDA) approved the first two vaccines (RSVpreF3 and RSVpreF), for prevention of RSV infection in adults aged 60 years and older. In clinical trials for both RSV vaccines, atrial fibrillation events were more frequent in the treatment groups compared to control groups¹, necessitating post-market surveillance in a real-world cohort to help assess potential risk. In this study, we investigated the number of atrial fibrillation events occurring up to 42 days after RSV vaccine compared to persons receiving influenza or tetanus, diphtheria, and pertussis (Tdap) vaccination.

Methods

We used the cloud-based TriNetX Analytics Platform, US Collaborative Network, to obtain web-based real-time secure access to fully deidentified electronic health records of 108 million patients from 66 health care organizations, representing 27% of the US population from all 50 states. Both inpatient and outpatient settings as well as persons from diverse geographic, age, race and ethnicity, income, and insurance groups are represented. TriNetX Analytics built-in functions allow for patient-level analyses. Because this study used only deidentified patient records, it was exempted from review by the MetroHealth System institutional review board.

The study population comprised of persons ≥60 years of age who received RSV or influenza vaccine between May 3,2023 (date of FDA approval for RSV Vaccine) and May 3,2024 to ensure at least 42 days of follow-up at time of data collection on October 9, 2024. RSV vaccine was compared with influenza vaccine to match for health-seeking behavior and electronic medical record completeness, with analyses stratified by atrial fibrillation history (Figure). Cohorts were propensity score matched for age, sex, race, ethnicity, and preexisting medical conditions (Supplemental Table 1). To minimize confounding, persons receiving both RSV vaccine and influenza on same or separate days at any time during the study period were excluded from analysis, as their inclusion could obscure the independent effects of each vaccine on atrial fibrillation risk (15–25% excluded).

Figure 1:

Risks of new-onset and recurrent atrial fibrillation among persons with RSV vaccination compared against a) Influenza or b) Tdap vaccination; Abbreviations, AF, atrial fibrillation, RSV; Respiratory Syncytial Virus, Tdap; Tetanus, diphtheria, pertussis, RR; relative risk, CI; confidence interval

^ACohorts were propensity score matched for sex (male, female), ethnicity (Hispanic/Latino, not Hispanic/Latino, unknown), race (Black, Asian, American Indian or Alaska Native, Native Hawaiian or Other Pacific islander, Other, White, and Unknown), adverse socioeconomic determinants of health, Preexisting medical conditions (obesity & overweight hypertension, hyperlipidemia, tobacco use, alcohol use disorder, type 2 diabetes mellitus, ischemic heart disease, obstructive sleep apnea, HIV, organ transplant), and prior immunizations (mRNA COVID-19)

Using the matched cohorts, we calculated the relative risk (RR) of new-onset and recurrent atrial fibrillation within 42 days after index events (vaccine receipt). The theoretical risk time window was chosen based on biological plausibility and prior vaccine safety studies^2,3. RSV preventive therapeutics have historically been administered during the fall and winter (i.e. nirsevimab), coinciding with the typical timing of influenza vaccination. However, the RSV vaccine is currently not recommended on an annual basis due to its potentially long-lasting protection. Consequently, RSV vaccine administration may occur more frequently in the spring or summer compared to the influenza vaccine, potentially introducing confounding in the atrial fibrillation risk assessment, as atrial fibrillation risk peaks during the winter season⁴. Moreover, the influenza vaccine may confer a protective effect against atrial fibrillation⁵, potentially resulting in a relatively higher apparent risk associated with the RSV vaccine. To address these factors, we performed an additional analysis comparing persons receiving RSV vaccines against persons receiving tetanus, diphtheria, and pertussis (Tdap) vaccination (administered year-round), stratified by atrial fibrillation history using the same criteria as the original analysis. All statistical analysis were performed with the TriNetX Advanced Analytics Platform using built-in functions (R, version 3.2–3 [R Program for Statistical Computing]), with statistical significance defined as a 95% CI excluding 1. Standard mean difference greater than 0.1 was determined to indicate a group imbalance.

Results

When evaluating new-onset atrial fibrillation, prior to propensity matching, the RSV vaccine cohort (n=99,822) was significantly older than the influenza vaccine cohort (n=257,992), but differences in comorbidities were non-significant after matching (Supplemental Table 2). After matching, persons receiving the RSV vaccine (n=94,104) cohort had 295 events (0.3%) compared to 279 events (0.3%) in the influenza vaccine cohort (n=94,104). RSV vaccine was not associated with a statistically significant increased risk for new-onset atrial fibrillation compared with influenza vaccine (RR 1.06, 95% CI 0.90–1.25) (Figure).

Among those with history of atrial fibrillation, RSV vaccine recipients (n=16,033) differed in racial and ethnic composition and comorbidity burden to the influenza vaccine cohort (n=41,333); however, no differences were significant after matching (Supplemental Table 2). Among matched cohorts (n=15,680/cohort), the RSV vaccine cohort had 5,172 events (33.0%) compared to 5,488 events (35.0%) in the influenza vaccine cohort. The RSV vaccine was associated with decreased risk for recurrent atrial fibrillation compared to influenza vaccine (RR 0.94, 95% CI 0.91–0.97) (Figure).

In an additional analysis among those without atrial fibrillation history, performed to mitigate confounding from seasonal variations in vaccine administration, Tdap vaccine recipients (n=103,187) differed in age, sex, and comorbidity distribution when compared to RSV vaccine recipients (n=53,320); however, differences were non-significant after matching (Supplemental Table 2). In the matched cohort (53,520/cohort), the RSV vaccine had 150 events (0.3%) compared to 182 events (0.3%) in the Tdap vaccine cohort. The RSV vaccine was not associated with increased atrial fibrillation risk (RR 0.82, 95% CI 0.66–1.02) (Figure).

Among those with history of atrial fibrillation, baseline characteristics again differed between RSV vaccine(n=18,470) and Tdap vaccine recipients(n=13,470); but, again were non-significant after matching (Supplemental Table 2). In the matched cohort (n=8,148/cohort), the RSV vaccine cohort had 2,589 events (31.8%) compared to 2,904 events (35.6%) in the Tdap vaccine cohort. The RSV vaccine was associated with reduced risk of recurrent atrial fibrillation (RR 0.89, 95% CI 0.85–0.93) (Figure).

Discussion

To our knowledge, this is the first real-world, observational study assessing rates of atrial fibrillation events after RSV vaccine. This study found that RSV vaccination compared to influenza or Tdap vaccination was not associated with a statistically significant increased risk for new-onset atrial fibrillation, and possibly a decreased risk for recurrent atrial fibrillation when compared to these vaccines.

Randomized, double-blind, placebo-controlled clinical trials for both RSVpreF3 and RSVpreF raised concerns for increased incidence of atrial fibrillation¹. In an ongoing phase 3 trial and a phase 1/2 trial of RSVpreF3, atrial fibrillation events were reported more frequently in the intervention group compared to the control group (10 events, 0.1%, vs 4 events, <0.1%). Of these 10 events, 8 were classified as severe adverse events, disproportionately affecting the intervention group (7 events vs 1 in control group). Notably, 3 of the serious adverse events involved new-onset atrial fibrillation (2 in intervention vs 1 in the control group). Similarly, clinical trials evaluating RSVpreF, also reported a numerically higher number of atrial fibrillation events in the treatment groups compared to control groups (10 <0.1% in intervention vs 4 (0.1%) in control).

In the cohort study, although not statistically significant, we observed a potential mild increase in new-onset atrial fibrillation when comparing RSV vaccination to influenza vaccination (RR 1.06, 95% CI 0.90–1.25), but not when assessed against Tdap vaccination (RR 0.82, 95% CI 0.66–1.02). Notably, influenza vaccination has been suggested to be protective against atrial fibrillation⁵, which may confound results and contribute to the observation of a relatively higher rate of atrial fibrillation among those vaccinated against RSV. The additional comparison against Tdap vaccination helps support the lack of increased risk. Nonetheless, given the small effect size and wide confidence intervals, the possibility of a mild increased risk for new-onset atrial fibrillation cannot be excluded. Reassuringly, our data suggests RSV vaccination is associated with decreased risk of recurrent atrial fibrillation, potentially due its ability to prevent RSV-related cardiovascular complications in high-risk populations.

Limitations

Our study has limitations that bear consideration when interpreting the results. There is potential missed data from retail pharmacy vaccinations. Further, seasonal variation may not be fully accounted for in our study and contribute to residual confounding. Moreover, the time-period evaluated does not provide insight into risk outside the 42-day window and alternatively may not fully capture the long-term health benefits of RSV prevention.

It is also important to note that clinical trials for RSV vaccines have reported higher rates of atrial fibrillation events compared to placebo, whereas our study used other vaccines as comparators. While the use of a vaccine comparator group is necessary when using retrospective clinical data to ensure a population with similar health-seeking behaviors, it may obscure any atrial fibrillation risk associated generally with vaccine immunogenicity.

Conclusion

The RSV vaccine is currently recommended among older adults with chronic medical conditions, a group at elevated risk for atrial fibrillation. Therefore, while RSV vaccines can be a life-saving intervention, its potential may have been limited due to concerns regarding adverse cardiovascular effects. Our study suggests there is no significant increased risk for atrial fibrillation after RSV vaccine in the first 42 days after administration, potentially encouraging its broader use in high-risk populations.

Data sharing:

This study used population-level aggregate and deidentified data generated by the TriNetX Platform. Due to data privacy, patient-level data was not used and cannot be shared