Message for At-Risk Adults: Flu Vaccination Will Reduce Your Risk of Cardiovascular Disease and Death

With influenza apparently returning with a vengeance this season, the Centers for Disease Control and Prevention is once again alerting the public that vaccination is the most effective way to prevent infection from and to minimize risk of severe symptoms and hospitalization for serious flu-related complications.² Yet only about half of all U.S. adults plan to get a flu vaccine during the 2022-2023 flu season, according to a survey conducted this fall by the National Foundation for Infectious Diseases.³

As one would expect, flu vaccination rates differ widely by age category. Over the 2021-2022 flu season, 74 percent of adults age 65 and older received a flu jab, far higher than the 52 percent and 37 percent vaccination rate for adults age 50 to 64 years and 18 to 49 years, respectively.

Nevertheless, at least one-quarter of all seniors will not receive a flu vaccine, leaving them unnecessarily exposed to increased risk of severe complications that can result in hospitalization and death. In older as well as nonelderly adults, preexisting cardiovascular disease, diabetes, renal disease, asthma, cancer history and HIV/AIDS are known major risk factors for flu-related hospitalization and death. An estimated 94 percent of U.S. adults hospitalized with flu-related complications last season had at least one underlying medical condition or other risk factor. Yet just 43 percent of adults age 18 to 49 years with one or more existing chronic health conditions (mainly heart disease, diabetes and/or lung disease) were vaccinated against flu during the 2021-2022 season.²

Depending on multiple factors, including the pathogenicity of the circulating viruses, the protective effect of the flu vaccine and the vaccination rate, U.S. hospitalizations can range from roughly 150,000 to 700,000 and influenza-related deaths from around 10,000 to more than 50,000 over a single flu season (Figure 1).⁴

Figure 1. Estimated Range of Annual Burden of Flu in the U.S. from 2010-2020

This grim toll could be reduced by simply increasing the vaccination rate, particularly for individuals in high-risk categories. But this hasn’t happened to date; plainly, the messaging from providers and public health agencies isn’t overcoming apathy or entrenched resistance. But some remarkably powerful findings of several newly published studies now present an opportunity to shift the argument for flu vaccination from “you can cut your risk of getting the flu and end up in the hospital” to “you can cut your risk of a heart attack or other acute cardiovascular event, and possibly death.”

Flu and Cardiovascular History Begets Risk of New Cardiovascular Events

Existing cardiovascular disease is well- known to predispose individuals who contract seasonal influenza to a much-increased risk of hospitalization for pneumonia and other serious flu-related illness. In turn, the risk of a major adverse cardiovascular event (MACE) skyrockets in cases of influenza severe enough to land the patient in the hospital. In a cross-sectional study evaluating a sample of more than 80,000 U.S. adults hospitalized with laboratory-confirmed influenza over a recent eight-year period, nearly 12 percent — about one in every eight — experienced an acute cardiovascular event, most commonly acute heart failure and acute ischemic heart disease.⁵ Nearly one-third of these stricken patients were admitted to the intensive care unit, and seven percent died in the hospital.

The temporal association between influenza infection and acute myocardial infarction (MI) is well-documented.⁶ The virus is believed to predispose individuals with atherosclerotic coronary artery disease to heart attacks through a multiplicity of mechanisms (Figure 2), including inflammatory release of cytokines that result in a pro-thrombotic state; physiological effects, including hypoxia and tachycardia; increased metabolic demand resulting in inadequate coronary artery flow; and possibly even direct effects of the virus on the heart muscle itself.⁷

Figure 2. Mechanisms by Which Influenza Virus Infection May Precipitate Acute Myocardial Infarction

Can administering a standard flu vaccine therefore reduce the risk of a major cardiovascular event in patients hospitalized with influenza, in particular in those at increased risk of such an event? A Canadian-led investigative team set out to answer this question in a landmark meta-analysis of five high-quality randomized, placebo-controlled trials.8 Across all enrolled subjects with and without a cardiovascular disease history, vaccination was associated with a 36 percent lower risk of composite cardiovascular events (2.9 percent vs. 4.7 percent; relative risk [RR], 0.64; 95 percent confidence interval [CI], 0.48-0.86). But a highly significant interaction was detected in the 36 percent of subjects with a history of acute coronary syndrome (ACS) over the previous year: Their relative risk of composite cardiovascular events dropped to 0.45, while subjects without recent ACS had a nonsignificant relative risk of 0.94. “The use of standard influenza vaccine was associated with a lower risk of major adverse cardiovascular events,” the study authors concluded, and “the greatest treatment effect was seen among the highest-risk patients with more active coronary disease.”

Over just the last two years, several new studies have both validated these findings and helped to more clearly quantify the extent to which a single 0.5 mL dose of seasonal influenza vaccine can reduce the risks of hospitalization, acute cardiovascular events and death in at-risk older individuals and those with preexisting cardiovascular disease.

Table. Key Primary and Secondary Outcomes from a Randomized, Placebo-Controlled Trial of Inactivated Influenza Vaccine After Myocardial Infarction⁵

MI: Myocardial Infarction
NS: Nonsignificant

Post-Myocardial Infarction Flu Vaccination Cuts Risk of Death

Influenza Vaccination After Myocardial Infarction (IAMI) study. With support from the Swedish Heart-Lung Foundation and an unrestricted grant from Sanofi Pasteur, the multinational IAMI study randomized participants to receive inactivated influenza vaccine or a saline placebo injection within 72 hours after an invasive coronary procedure or hospitalization precipitated by a myocardial infarction (MI) event.⁹ Because flu vaccination is already considered standard medical practice, placebo group patients were permitted to independently pursue vaccination outside the trial; 13 percent actually did so, which the investigators acknowledged would actually understate the vaccine’s reported protective effect.

The primary endpoint — a composite of all-cause death, MI or stent thrombosis at 12 months — occurred in 67 of 1,272 participants assigned to receive flu vaccine (5.3 percent) and 91 of 1,260 participants assigned to placebo (7.2 percent), yielding a 28 percent reduction in MACE (95 percent CI, 0.52-0.99; p=0.040). The 2.9 percent mortality rate for subjects who were vaccinated was 41 percent lower than the 4.9 percent death rate in those who received placebo injections (HR, 0.59; 95 percent CI, 0.39-0.89; p=0.010). (Table)

While rates of MI in the two treatment groups were not significantly different (2.0 and 2.4 percent, respectively), the rate of cardiovascular death in the flu vaccine group was significantly lower by a remarkable 41 percent — 2.7 percent compared to 4.5 percent in the placebo group (HR, 0.59; 95 percent CI, 039-0.89; p=0.014). There was no increase in serious adverse events associated with post-MI flu vaccine administration, confirming its safety in the immediate post-MI period.

The IAMI investigators concluded that their findings “support and even strengthen” an existing American Heart Association/American College of Cardiology Guideline in place since 2006, which recommends flu vaccination for all patients with established coronary artery disease.

The nonsignificant reduction seen in postvaccination MI events over the 12-month follow-up period is consistent with a recent meta-analysis of 16 mainly observational studies, comprising almost 240,000 patients, that found just a 13 percent relative risk reduction in MACE over a median follow-up of 20 months.10 But this modest benefit of flu vaccination in reduced heart attack risk is dwarfed by its very large benefit in reduced risk of all-cause and cardiovascular death.

In an accompanying editorial, the commenters pointed out that the IAMI study’s impressive reduction in the cardiovascular death rate occurred in post-MI patients who were also well-managed with the full spectrum of supportive cardiac, anti-thrombotic, lipid-lowering and other drug treatments following hospital discharge. “The benefit of influenza vaccine was incremental to [these treatments],” they noted.¹¹

Updated meta-analysis of IAMI plus five other randomized controlled trials (RCTs). Published in April 2022, this new meta-analysis pooled a total of 9,001 patients from the IAMI trial and five high-quality RCTs evaluating trivalent or quadrivalent flu vaccine against placebo or no treatment.¹² Four of the six trials enrolled hospital inpatients or outpatients with recent ACS or stable coronary artery disease with planned percutaneous coronary intervention, while the other two trials enrolled unselected outpatients.

Once again, subjects with a recent ACS history who received a standard flu vaccine experienced a 45 percent lower risk of MACE than nonvaccinated control subjects. No treatment interaction was detected for those without a recent ACS (RR, 1.00, 95 percent CI, 0.68-1.47). Administration of flu vaccine was associated with an even more impressive 56 percent reduction in risk of cardiovascular mortality relative to nonvaccinated subjects.

How does flu vaccination so substantially reduce the cardiovascular and all-cause death rate in even the highest-risk post-MI population? In simplest terms, it likely boils down to the extent of the vaccine’s ability to prevent infection, mitigate symptomatic influenza infections and lessen the severity of a constellation of cardiovascular disease complications in individuals who do become infected (Figure 3).

Figure 3. Cardiovascular Complications of Influenza Infection

DANFLU-1: High Dose, Lower Death Rate

The natural decline in immunity with age largely accounts for the fact that people age 65 and older account for the majority of hospitalizations and 80 to 90 percent of U.S. flu-related deaths. To address this problem, Sanofi Pasteur developed the Fluzone High-Dose vaccine, which delivers four-fold higher quantities of haemagglutinin antigens than the standard 15 ug per strain and elicits substantially higher hemagglutinin inhibition titers.

The postulate that this higher antigen dose could translate into a lower rate of laboratory-confirmed influenza-like illness (ILI) was validated by a landmark U.S.-Canadian trial of Sanofi Pasteur’s Fluzone High-Dose vaccine nearly a decade ago.¹³ A subsequent retrospective cohort analysis of insurance claims for more than 2.5 million Medicare beneficiaries found that the high-dose flu vaccine was associated with 22 percent lower rates of both ILI and influenza-related hospital admissions than standard-dose flu vaccine.¹⁴

Then in August of this year, results from DANFLU-1, a Danish open-label pragmatic feasibility trial conducted in collaboration with Sanofi Pasteur, were presented at the European Society of Cardiology Congress in Barcelona. In 1,000 vaccination sessions across Denmark organized by a private vaccination provider, a total of 12,477 participants aged 65 to 79 years were randomized to receive quadrivalent high-dose or standard-dose vaccine. Their baseline characteristics were comparable to the overall Danish population of the same age; in particular, 20.4 percent of trial participants had chronic cardiovascular disease compared to 22.9 percent of the national population.

High-dose flu vaccine recipients had a nearly 65 percent lower risk of being hospitalized for influenza or pneumonia, with 10 cases (0.016 percent) compared to 28 cases (0.045 percent) among standard-dose recipients. And despite the fact that just one of every five participants in both groups had known preexisting cardiovascular disease, high-dose flu vaccine recipients experienced half the risk of all-cause mortality relative to standard-dose vaccine, with 21 versus 41 deaths, respectively. There were no significant differences in serious adverse events between the two dosage groups.

Now that the feasibility of integrating administrative health registries with an influenza vaccine trial has been demonstrated, “the next step is to conduct a fully powered trial of high-dose versus standard-dose quadrivalent flu vaccine in older adults,” according to lead investigator Professor Tor Biering-Sørensen at the University of Copenhagen. This new trial, dubbed DANFLU-2, is expected to enroll roughly 200,000 participants.

To date, no head-to-head studies have reported cardiovascular event outcomes with CSL Seqirus’ standard-dose MF59-adjuvanted influenza vaccine (Fluad) compared with nonadjuvanted flu vaccine. But numerous studies have established that, in adults age 65 years and older, Fluad elicits a greater immune response, has superior vaccine effectiveness and is more effective in preventing hospitalization caused by influenza complications.¹⁵ There is every reason, then, to postulate that Fluad Quadrivalent can also confer better protection against major cardiovascular complications in older individuals with preexisting cardiovascular disease than standard nonadjuvanted flu vaccines.

To Patients: Get the Shot to Prevent MI, Death

“It is time to change the thinking around vaccination as just being a prevention strategy for the avoidance of viral illness, but as a prevention strategy for avoidance of cardiovascular morbidity and mortality,” says University of Toronto cardiologist and flu vaccine clinical trialist Jacob Udell, MD, MPH.11 Going a step further, Dr. Udell calls for new implementation strategies to boost vaccination rates in demographic groups at highest risk of a heart attack or other MACE. For post-MI patients in particular, he offers several suggestions:

• Add influenza vaccination to their drug checklist, along with their cardiac and lipid-lowering drugs and lifestyle recommendations;
• Offer vaccination in the hospital before discharge; and
• Double-check and confirm receipt of vaccination on enrollment in cardiac rehabilitation.

In the future, large-scale studies like DANFLU-2 will provide more definitive estimates of the benefits of flu vaccination in reduced cardiovascular morbidity and mortality in older adults and in those with preexisting cardiovascular disease, as well as those with other risk factors such as diabetes and chronic lung disease. But in truth, we now have more than ample evidence that the lives of many thousands of these individuals can be saved each year by convincing them to receive a single dose of low-cost flu vaccine.

Flu vaccination is important for everyone, but it is especially so for those at higher risk from potentially serious complications of flu. But now, thanks to IAMI, DANFLU-1 and the newest published meta-analyses, you as physicians, pharmacists and ancillary medical staff have all the justification you need to encourage your resistant patients to get the flu vaccine recommended for them, and to deliver your message with perhaps a bit more clout: We’re in the flu season, and complications if you get the flu can be as severe as a fatal heart attack. The flu vaccine we’re recommending is safe and it’s the only effective treatment we have to help prevent that from happening to you. Now it’s your choice.