Influenza vaccine to reduce adverse vascular events in patients with heart failure: a multinational randomised, double-blind, placebo-controlled trial

Loeb, Mark; Roy, Ambuj; Dokainish, Hisham; Dans, Antonio L.; Palileo-Villanueva, Lia M; Karaye, Kamilu M; Zhu, Jun; Liang, Yan; Goma, Fastone; Damasceno, Albertino; Alhabib, Khalid F; Yonga, Gerald; Mondo, Charles; Almahameed, Wael; Mulla, Arif Al; Thanabalan, Vitheya; Rao‐Melacini, Purnima; Grinvalds, Alex; McCready, Tara; Bangdiwala, Shrikant I.; Yusuf, Salim

doi:10.1016/s2214-109x(22)00432-6

Cited by 37 publications

(28 citation statements)

References 24 publications

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“…Randomized clinical trials and observational data have shown influenza vaccination may improve outcomes in patients with CVD. [3][4][5][6] Consequently, influenza vaccination is uniformly recommended for patients with CVD by major public health authorities and in clinical practice guidelines. 1,[7][8][9] Despite this strong endorsement, influenza vaccination rates remain suboptimal in patients with high-risk CVD.…”

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confidence: 99%

Effect of Electronic Nudges on Influenza Vaccination Rate in Older Adults With Cardiovascular Disease: Prespecified Analysis of the NUDGE-FLU Trial

et al. 2023

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Background: Influenza vaccines have been demonstrated to effectively reduce the incidence of influenza infection and potentially associated risks of cardiovascular events in patients with cardiovascular disease (CVD). Despite strong guideline and public health endorsements, global influenza vaccination rates in patients with CVD are highly variable. This prespecified analysis of NUDGE-FLU (Nationwide Utilization of Danish Government Electronic Letter System for Increasing InFLUenza Vaccine Uptake) examined the effect of digital behavioral nudges on influenza vaccine uptake based on the presence of cardiovascular disease. Methods: NUDGE-FLU was a randomized, pragmatic, nationwide, register-based trial including Danish citizens aged 65 years or older during the 2022-2023 influenza season. Households were randomized in a 9:1:1:1:1:1:1:1:1:1 ratio to usual care or 9 electronic letters with designs based on behavioral concepts. Danish nationwide registers were used to collect baseline and outcome data. The primary endpoint was receipt of an influenza vaccine on or before January 1, 2023. The effects of the intervention letters were examined according to the presence of cardiovascular disease and across cardiovascular subgroups including heart failure, ischemic heart disease, and atrial fibrillation. Results: Of 964,870 NUDGE-FLU participants from 691,820 households, 264,392 (27.4%) had CVD. During follow-up, 83.1% of participants with CVD vs 79.2% of participants without CVD received influenza vaccination (p<0.001). Compared with usual care, a letter emphasizing the potential cardiovascular benefits of influenza vaccination increased vaccination rates; this effect was consistent in participants with CVD (absolute difference +0.60 percentage points, 99.55% CI -0.48 to 1.68) and without CVD (+0.98 percentage points, 99.55% CI 0.27 to 1.70; P for interaction=0.41). A repeated letter strategy with a reminder follow-up letter 14 days later was also effective in increasing influenza vaccination, irrespective of CVD (CVD: absolute difference +0.80 percentage points, 99.55% CI -0.27 to 1.86; no CVD: +0.67 percentage points, 99.55% CI -0.06 to 1.40; P for interaction=0.77). Effectiveness of both nudging strategies was consistent across all major CVD subgroups. None of the other seven nudging strategies were effective, regardless of CVD status. Conclusions: Electronic letter interventions emphasizing the potential cardiovascular benefits of influenza vaccination and using a reminder letter strategy were similarly beneficial in increasing influenza vaccination rates among older adults with and without CVD and across cardiovascular subgroups. Electronic nudges may improve influenza vaccine uptake in individuals with CVD.

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confidence: 99%

Effect of Electronic Nudges on Influenza Vaccination Rate in Older Adults With Cardiovascular Disease: Prespecified Analysis of the NUDGE-FLU Trial

et al. 2023

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“…One study fulfilled inclusion criteria and was included in our analyses (the IVVE study). 21 on HR effect estimates, baseline characteristics and trial methods were secured upon request to the study chair. The trial characteristics are displayed in Table 1.…”

Section: Search Results and Trial Characteristicsmentioning

confidence: 99%

Influenza vaccination and cardiovascular events in patients with ischaemic heart disease and heart failure: A meta‐analysis

Modin

Lassen

Claggett

et al. 2023

European J of Heart Fail

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AimRandomized controlled trials (RCTs) enrolling patients at high cardiovascular risk have found that influenza vaccination may reduce the incidence of cardiovascular events. We performed an updated meta‐analysis assessing the effect of influenza vaccination on the incidence of cardiovascular events in patients with ischaemic heart disease or heart failure.Methods and resultsWe searched PubMed, EMBASE and other sources to identify RCTs examining the effect of influenza vaccination on the incidence of cardiovascular events assessed as efficacy outcomes in patients with ischaemic heart disease or heart failure. Eligible studies followed patients for at least one influenza season, defined as a minimum duration of 6 months. The primary endpoint was a composite of cardiovascular death, acute coronary syndrome, stent thrombosis or coronary revascularization, stroke or heart failure hospitalization. The secondary endpoints were cardiovascular death and all‐cause death. Two investigators independently identified and extracted data from studies. Results were compared using hazard ratios (HRs) in both random effects and fixed effects models. We included five peer‐reviewed and one non peer‐reviewed RCTs for a total of 9340 patients. Five trials included patients with ischaemic heart disease (n = 4211) and one trial included patients with heart failure (n = 5129). Influenza vaccination was associated with a reduced incidence of the primary composite endpoint (random effects HR [rHR] 0.74, 95% confidence interval [CI] 0.63–0.88, p < 0.001, I2 = 52%), cardiovascular death (rHR 0.63, 95% CI 0.42–0.95, p = 0.028, I2 = 58%) and all‐cause death (rHR 0.72, 95% CI 0.54–0.95, p = 0.0227, I2 = 52%). Results were similar when non peer‐reviewed data were excluded.ConclusionIn this meta‐analysis of available RCTs in patients at high cardiovascular risk, influenza vaccination was associated with a reduced incidence of cardiovascular events, cardiovascular death and all‐cause death as compared to placebo or no treatment.

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“…Based on other data comparing vaccination with placebo, it is likely that influenza vaccination with either dose would have more substantial benefits over placebo in patients with high risk. 23 Moreover, as the influenza virus is not the only circulating virus during the winter months, it is possible that other respiratory viruses may contribute to the association between time and…”

Section: Discussionmentioning

confidence: 99%

Temporal Association Among Influenza-Like Illness, Cardiovascular Events, and Vaccine Dose in Patients With High-Risk Cardiovascular Disease

Hegde,

Claggett,

Udell

et al. 2023

JAMA Netw Open

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ImportanceInfluenza-like illness (ILI) activity has been associated with increased risk of cardiopulmonary (CP) events during the influenza season. High-dose trivalent influenza vaccine was not superior to standard-dose quadrivalent vaccine for reducing these events in patients with high-risk cardiovascular (CV) disease in the Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial.ObjectiveTo evaluate whether high-dose trivalent influenza vaccination is associated with benefit over standard-dose quadrivalent vaccination in reducing CP events during periods of high, local influenza activity.Design, Setting, and ParticipantsThis study was a prespecified secondary analysis of INVESTED, a multicenter, double-blind, active comparator randomized clinical trial conducted over 3 consecutive influenza seasons from September 2016 to July 2019. Follow-up was completed in July 2019, and data were analyzed from September 21, 2016, to July 31, 2019. Weekly Centers for Disease Control and Prevention (CDC)–reported, state-level ILI activity was ascertained to assess the weekly odds of the primary outcome. The study population included 3094 patients with high-risk CV disease from participating centers in the US.InterventionParticipants were randomized to high-dose trivalent or standard-dose quadrivalent influenza vaccine and revaccinated for up to 3 seasons.Main Outcomes and MeasuresThe primary outcome was the time to composite of all-cause death or CP hospitalization within each season. Additional measures included weekly CDC-reported ILI activity data by state.ResultsAmong 3094 participants (mean [SD] age, 65 [12] years; 2309 male [75%]), we analyzed 129 285 person-weeks of enrollment, including 1396 composite primary outcome events (1278 CP hospitalization, 118 deaths). A 1% ILI increase in the prior week was associated with an increased risk in the primary outcome (odds ratio [OR], 1.14; 95% CI, 1.07-1.21; P &lt; .001), CP hospitalization (OR, 1.13; 95% CI, 1.06-1.21; P &lt; .001), and CV hospitalization (OR, 1.12; 95% CI, 1.04-1.19; P = .001), after adjusting for state, demographic characteristics, enrollment strata, and CV risk factors. Increased ILI activity was not associated with all-cause death (OR, 1.00; 95% CI, 0.88-1.13; P &gt; .99). High-dose compared with standard-dose vaccine did not significantly reduce the primary outcome, even when the analysis was restricted to weeks of high ILI activity (OR, 0.88; 95% CI, 0.65-1.20; P = .43). Traditionally warmer months in the US were associated with lower CV risk independent of local ILI activity.Conclusions and RelevanceIn this secondary analysis of a randomized clinical trial, ILI activity was temporally associated with increased CP events in patients with high-risk CV disease, and a higher influenza vaccine dose did not significantly reduce temporal CV risk. Other seasonal factors may play a role in the coincident high rates of ILI and CV events.Trial RegistrationClinicalTrials.gov Identifier: NCT02787044

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Influenza vaccine to reduce adverse vascular events in patients with heart failure: a multinational randomised, double-blind, placebo-controlled trial

Cited by 37 publications

References 24 publications

Effect of Electronic Nudges on Influenza Vaccination Rate in Older Adults With Cardiovascular Disease: Prespecified Analysis of the NUDGE-FLU Trial

Effect of Electronic Nudges on Influenza Vaccination Rate in Older Adults With Cardiovascular Disease: Prespecified Analysis of the NUDGE-FLU Trial

Influenza vaccination and cardiovascular events in patients with ischaemic heart disease and heart failure: A meta‐analysis

Temporal Association Among Influenza-Like Illness, Cardiovascular Events, and Vaccine Dose in Patients With High-Risk Cardiovascular Disease

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