Table 1
Class of Recommendation and Level of Evidence, ACC/AHA criteria [19].
| Class of Recommendation (CoR) | ||
|---|---|---|
| I | Strong | Benefit >>> Risk |
| IIa | Moderate | Benefit >> Risk |
| IIb | Weak | Benefit > Risk |
| III | No benefit or harm | Benefit = Risk, or Risk > Benefit |
| Level of Evidence (LoE) | ||
| A | High quality evidence of >1 RCT or meta-analysis of them | |
| B-R | Randomized | Moderate evidence from 1 RCT |
| B-NR | Non-Randomized | Moderate evidence from well-designed nonrandomized trial |
| C-LD | Limited Data | Randomized or nonrandomized clinical studies of limited quality. Meta-analysis of those studies. Mechanistic studies. |
| C-EO | Expert Opinion | Consensus of experts opinion based on clinical experience |
Table 2
Association between respiratory infections and cardiovascular events.
| Conclusions | CoR | LoE | |
|---|---|---|---|
| A | Influenza-like respiratory infections are associated with CV events during follow-up (AMI, stroke, hospitalizations for HF, AF, and CV death). | I | B-NR |
| B | The association between influenza and thromboembolic disease is controversial. | IIb | C-LD |
| C | There is not strong enough evidence to determine the incidence or mortality from CV disease for different types and subtypes of influenza viruses. | IIb | C-LD |
| D | There are proven pathophysiological mechanisms that explain the association of influenza with cardiovascular events. | IIb | C-LD |
Table 3
Clinical efficacy and/or effectiveness of influenza vaccines in cardiovascular events reduction.
| Conclusions | CoR | LoE | |
|---|---|---|---|
| A | IV in patients with coronary artery disease is associated with a reduction in CV events. | I | B – R |
| B | In patients over 65 years of age at low risk (absence of comorbidities, without established CV disease or diabetes) IV is associated with a reduction in CV events. | I | B – NR |
| C | Annual IV in patients with HF is associated with a reduction in all-cause mortality and HF hospitalization. | IIa | B – NR |
| D | In patients with diabetes or hypertension, in the absence of established CV disease, the IV could be associated with a reduction in CV events. | IIb | C – LD |
| Recommendations | |||
| A | IV for patients with a recent acute coronary syndrome (≤1 year) | I | B – R |
| B | Annual IV for patients >65 years even in the absence of CV disease or risk factors. | I | B – NR |
| C | Annual IV for patients with chronic coronary artery disease with or without history of revascularization. | IIa | B – R |
| D | Annual IV for patients with HF. | IIa | B – NR |
| E | Annual IV for patients with diabetes or hypertension without established CV disease. | IIb | C – LD |
Table 4
Safety of the influenza vaccine in patients with cardiovascular disease.
| Conclusions/Recommendations | CoR | LoE | |
|---|---|---|---|
| A | The different flu vaccines are generally safe; the reduction in the incidence of epidemic influenza is significantly greater than the incidence of adverse effects. | I | A |
| B | Co-administration of injectable IV and warfarin is safe, requiring only longer pressure at the intramuscular injection site. There is insufficient information to support determining the INR before or at the time of administration of the vaccine. | II a III | B-R C-EO |
| C | Co-administration of influenza and pneumococcal vaccines is safe and immunogenic. Co-administration was associated with a higher rate of adverse events, albeit mild. | II a II b | B-R C-LD |
| D | In the context of COVID-19 pandemic, it may be beneficial the SARS-CoV-2 vaccination and then IV after an interval of at least 14 days. | IIb | C-EO |
| E | It is recommended not to administer the LAIV together with aspirin in children given the risk of Reye’s syndrome. The LAIV is generally not recommended for patients with CV disease. | III III | C-EO C-EO |
| F | Individuals with history of severe egg anaphylaxis may receive chicken embryo-based vaccine but should be monitored for at least 30 minutes after the administration. | IIa | B-R |
Table 5
Efficacy of different vaccination schedules.
| Conclusions/Recommendations | CoR | LoE | |
|---|---|---|---|
| A | The vaccine should be administered at least annually before the annual season in which the incidence of influenza increases, or at the beginning of the season. | I | A |
| B | The high-dose inactivated influenza vaccine (IIV3-HD) is recommended compared to the standard dose (IIV3-SD) because it is more immunogenic, effective, and because it reduces cardiorespiratory outcomes | IIa | B-R |
| C | The quadrivalent inactivated influenza vaccine is recommended compared to the trivalent because it offers a broader protection. | IIa | B-NR |
| D | Adjuvant vaccines are indicated in elderly patients, with suboptimal immune responses, or when rapid responses to smaller doses are required during a pandemic. | IIa | B-NR |
| E | Influenza vaccines developed integrally in cell culture are more immunogenic than those developed in chicken embryos, requiring lower doses, and maintaining a comparable biosafety profile. | IIa | B-NR |
| F | The benefit regarding CV outcomes between IIV3-HD and quadrivalent vaccine could not be established due to methodological limitations in the only randomized clinical trial. | IIb | B-R |
| G | In tropical countries where it is proven that there is no seasonal variation in influenza, biannual vaccination could be beneficial, although there are still no studies to support this recommendation. | IIb | C-EO |
Table 6
Cost-effectiveness of influenza vaccination.
| Conclusions | CoR | LoE | |
|---|---|---|---|
| A | Vaccination for influenza with a trivalent vaccine is a CE strategy: In adults in general, it is CE for the reduction of ambulatory ILI cases, hospitalizations for pneumonia, quality-adjusted life years and total mortality. | I | B-NR |
| B | Vaccination for influenza is CE when evaluating CV outcomes: From an economic point of view, vaccination is reasonable in those over 50 years of age, and regardless of age in subjects with diabetes, coronary artery disease, or other established CV diseases. In the United States, mass vaccination was CE compared to vaccination only to risk groups. | IIa | B-NR |
| C | Vaccination for influenza is as CE as other primary health prevention strategies (colon cancer screening, breast cancer screening, or control of arterial hypertension). Vaccination for influenza is CE in tropical countries. | IIa | C-LD |
| D | There is little to no information on CE of influenza vaccines with new technologies (with adjuvants, tetravalent, high doses) in low-resource countries, so there is not enough evidence yet to recommend one over the other, from the pharmacoeconomic point of view specifically. | IIb | C-EO |
Figure 1
Doctor’s, context, and patient’s role in effective vaccination.
Red squares: barriers, green squares: facilitators.
Table 7
Barriers to influenza vaccination implementation related to physicians, patients, and their context.
| Conclusions | CoR | LoE | |
|---|---|---|---|
| A | Medical conviction is the main determinant (50–90%) of effective vaccination. Prescription or advice from a physician or healthcare worker is positively associated with effective vaccination. | I | C-LD |
| B | There are factors beyond access to the vaccine, which psychologically influence the patient’s decision to get vaccinated, encompassed in the concept of hesitancy. Cultural, geographic, economic, religious, and ethnic differences were found as determinants of the vaccination rate. | I | B-NR |
| C | The growing impact of fake news on mass media and social media contributes to the determinants of non-vaccination. | IIa | C-LD |
Table 8
Strategies for increasing influenza vaccination rate.
| Recommendations | CoR | LoE | |
|---|---|---|---|
| Physicians | Develop continuing medical education programs aimed at general practitioners and specialists that address the benefits and opportunities of IV, as well as its incorporation into the clinical practice guidelines. Incorporate the concept of vaccination as a CV prevention strategy together with other preventive interventions. Generate multimodal interventions aimed at outpatient doctors, nurses and students of both careers that allow the dissemination of this concept. Vaccinate prior to or immediately after discharge in patients with acute coronary syndrome. Increase the availability of vaccines in outpatient clinics. | IIa | C-EO |
| Patients | Educate patients and have strategies to overcome vaccine related hesitancy with simple, truthful, and reliable information. Carry out effective vaccination campaigns adapted to local or regional needs. Use clear, simple, multimodal communication oriented at the target population. Refute fake news and promote dialogue with anti-vaccines groups. | IIa | C-EO |
| Context | Improve access to IV, guaranteeing its free provision to target populations. Incorporate IV into the list of essential medicines. Incorporate IV into the annual vaccination calendar. Develop epidemiological surveillance programs to measure results (annual vaccination rates in risk groups). | IIa | C-EO |