A randomized controlled trial of influenza vaccine to prevent adverse vascular events.

Cardiovascular disease is a leading cause of death globally estimated to be responsible for approximately 17 million deaths annually. Heart disease and stroke account for nearly one third of all deaths and are a major cause of hospitalization. Patients with congestive heart failure (CHF) are at particularly high risk. Clinical trials demonstrate that nearly one third of patients with CHF will experience a myocardial infarction (MI), stroke, or hospitalization for CHF. Observational studies have established an association between influenza infection and major adverse vascular events . It follows that vaccinating such a high risk group as patients with CHF against influenza may prevent adverse vascular events. However, these studies are subject to bias and a well designed clinical trial is needed to test the effect of influenza vaccination on preventing adverse vascular events. The goal of this study is to assess whether inactivated influenza vaccine can reduce adverse vascular events in high risk participants. We will address the question by randomizing patients at high risk for adverse vascular events to either annual inactivated influenza vaccine or to placebo over three influenza seasons. The primary outcome is a composite of cardiovascular (CV) death, non-fatal myocardial infarction (MI), non- fatal stroke, and hospitalization for CHF. We will enroll 3,500 participants from centres in seven countries: Philippines (the lead centre), Mozambique, Sudan, Uganda, Saudi Arabia, Malaysia, China. This proposed randomized trial has important implications for the management of patients at high risk for major adverse vascular events. Although the influenza vaccine is recommended annually for groups with diabetes and cardiovascular disease in many counties, uptake of these recommendations is relatively low. Cardiologists in most jurisdictions do not routinely recommend annual influenza vaccine for their patients as a strategy to reduce future adverse vascular events such as acute coronary syndrome or stroke. Uptake of influenza vaccine in patients with heart disease varies by country but in INTER-CHF sites (where are trial will be conducted) is 11% on average. Rigorous demonstration of influenza vaccine leading to a reduction in major adverse vascular events would represent a landmark study. We anticipate that such a trial would influence management decisions by physicians for patients at high risk for major vascular events. The effect size we propose testing is comparable to secondary prevention strategies available and given the fact that a vaccine is given once annually it is simple and inexpensive. Given the large burden of disease, the possibility to reduce cardiovascular and stroke related death is a compelling argument for this trial. If influenza vaccine is shown to reduce adverse vascular events, it will represent an important change in how prevention of adverse vascular events is thought about. The fact that our primary outcome is a composite, including various forms of vascular disease will increase generalizability. The study would be a milestone in contributing to evidence-based clinical as well public health policy.

The goal of this study is to assess whether inactivated influenza vaccine can reduce adverse vascular events in high risk participants. We will address the question by randomizing patients at high risk for adverse vascular events to either annual inactivated influenza vaccine or to placebo over three influenza seasons. Participants will aged 18 years and over and have New York Heart Association functional class II, III and IV heart failure. Patients will be randomized to either influenza vaccine or placebo. We will enroll 3,500 participants from centres in seven countries: Philippines (the lead centre), Mozambique, Sudan, Uganda, Saudi Arabia, Malaysia, China. The primary outcome is a composite of cardiovascular (CV) death, non-fatal myocardial infarction (MI), non- fatal stroke, and hospitalization for CHF. We hypothesize that the intervention will lead to a 25% risk reduction in the primary outcome. This proposed randomized trial has important implications for the management of patients at high risk for major adverse vascular events. Although the influenza vaccine is recommended annually for groups with diabetes and cardiovascular disease in many counties, uptake of these recommendations is relatively low. Cardiologists in most jurisdictions do not routinely recommend annual influenza vaccine for their patients as a strategy to reduce future adverse vascular events such as acute coronary syndrome or stroke. Uptake of influenza vaccine in patients with heart disease varies by country but in study sites is 11% on average. Rigorous demonstration of influenza vaccine leading to a reduction in major adverse vascular events would represent a landmark study.

There are a wide variety of stakeholders that will benefit from this research. Firstly, patients at risk of cardiovascular disease will benefit by a potential reduction in adverse vascular events including unstable angina, myocardial infarction, stroke, and hospitalization for congestive heart failure. This alone represents a huge societal benefit. There are important quality of life implications if it can be proven that an annual vaccine prevents catastrophic cardiovascular events both for patients and their families. The uptake of influenza vaccination in this group is low in middle to low income countries, averaging about 10% or less. As the results will be broadly disseminated to vaccinators (i.e. physicians and public health officials), there will be a resultant greater uptake of influenza vaccination in at risk groups. Specific patient groups that will benefit include those at risk for heart failure, angina, myocardial infarction, and stroke. The burden of disease in the countries that we are targeting is huge. Globally, cardiovascular disease is responsible for 30% of the 17 million deaths that occur annually, with 80% of these deaths occurring in lower income countries. If our clinical trial shows a clinically important reduction in adverse vascular events, there will be a shift in cardiovascular prevention strategy where influenza vaccination will feature prominently. This will have an impact on primary care physicians, cardiologists, and infectious disease physicians, all of whom are stakeholders in that they are involved in vaccinating high risk patients. The findings of a reduction in adverse vascular events in a large well done randomized controlled trial due to influenza vaccination would lead to not only a pragmatic benefit, but also to a philosophical shift in thinking about cardiovascular disease. We do not believe that it is an exaggeration to say that the impact of this trial, should it show a reduction in adverse vascular events, will go well beyond that of the vast majority of funded studies that are done worldwide. The impact will be a key advance in knowledge about cardiovascular events and importantly about prevention. The economic impact for the prevention of even hospitalization for congestive heart failure alone would be enormous. Healthcare systems globally would benefit because the intervention, administration of an influenza vaccine, is likely to save costs. Health policy makers will be keenly interested in the results, including policy makers at the local, regional, national, and global levels. Scientists ranging from basic investigators, clinical scientists, economists, health policy analysts will benefit from our results. If a reduction in adverse vascular events is demonstrated, new avenues of inquiry will be opened in each of these fields. The results will be important to hospital administrators who have a vested interest in reduction of hospital admissions. The results of the study will change practise guidelines to emphasize the importance of influenza vaccination in high risk cardiovascular populations. Staff working on the project will benefit from enhancement of data management and organizational skills. Vaccine manufactures will benefit as well since the results will create new markets for the influenza vaccine. Students working on the grant (e.g. undergraduate, graduate, post-doc fellows) will benefit by exposure to a global study. The timescales for benefit would be short because the study would be conclusive about whether influenza vaccination can prevent adverse vascular outcomes.