1.0      THE NEED FOR A TRIAL

1.1      What is the problem to be addressed? Cardiovascular disease is a leading cause of death globally estimated to be responsible for ~ 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. Mechanisms that have been postulated to explain this increased risk include the precipitation  of plaque  rupture,  endothelial dysfunction,  reactivation  of  other latent infections leading to plaque rupture, fever-associated tachycardia, and metabolic derangements related to infection, including elevation of triglycerides and serum glucose levels. It follows that vaccinating such a high risk group as patients with CHF against influenza may prevent adverse vascular events. Studies examining influenza vaccination and vascular events however have shown conflicting results. As we describe below, we recently conducted an observational study using databases from two large clinical trials, indicating that influenza vaccination may be associated with a reduction of major adverse vascular  events;  however,  because  of  the  strong  possibility  of  bias,  these  results  need  to be rigorously confirmed in a prospective, randomized trial. Therefore, while national guidelines endorse influenza vaccination for patients with chronic cardiac disease, actual vaccination rates remain low, and importantly, these guidelines are largely based on observational  data and expert opinion, with data lacking from adequately powered, prospective, randomized trials. Clinical equipoise exists as to whether influenza vaccine in fact prevents cardiovascular events in patients with CHF. Consequently, a randomized controlled trial is needed to address the question. Adverse vascular events are a global threat to health and have an enormous impact in low to middle income countries.

1.2      Why is a trial needed now?

1.2.1   Preliminary data. Using a large clinical database consisting of prospectively collected data from the ONTARGET and TRANSCEND randomized controlled trials (these include most INTER-

CHF sites),  we  performed  an  analysis  to determine the association between influenza vaccination

and major adverse vascular events. Annual immunization status with trivalent influenza vaccine was determined using a self-reported questionnaire at the study enrolment visit, 2-year follow-up visit and end of study visit. There was an associated reduced risk of the primary outcome in the influenza vaccinated group when the influenza virus matched the vaccine antigen well (2004-2005 (OR 0.62,

95% CI 0.50 – 0.77), 2005-2006 (OR 0.69, 95% CI 0.53 – 0.91) and 2006-2007 (OR 0.52 95% CI

0.42 – 0.65)), but there was no association in 2003- 2004 when there was an incomplete vaccine antigen match with the circulating influenza virus (odds ratio 0.96 95% CI 0.73-1.27). The summary OR for the 4 adjusted OR from the influenza seasons was 0.65 (95% CI 0.58 – 0.74, p<0.001), and there was statistically significant heterogeneity (p=0.003). Although our findings suggest an association, residual confounding cannot be excluded and it remains uncertain as to whether influenza vaccination can reduce major adverse vascular events.

1.2.2   Systematic  reviews:  There  have  been  3  systematic  reviews  of  the  effect  of  influenza

vaccination on major adverse vascular events. A Cochrane review summarized the results of 2 small randomized controlled trials. One of these trials, the FLUVAC study, although reported as one study, consisted of two randomized controlled trials, one of which randomized 200 patients with acute MI to influenza vaccine or placebo (FLUVAC MI) and the second randomized 102 patients planned to have PCI (FLUVAC PCI). The FLUCAD study was a randomized double blinded placebo controlled single centre trial where 658 patients with coronary disease were randomized to influenza vaccine or placebo. The pooled RR for cardiovascular death in these studies was 0.39 (95%CI 0.20 to 0.77) and meta- analysis led to a pooled RR of 0.85 (95% CI 0.44 to 1.62) for MI. A recent trial randomized patients with a history of ACS to either influenza vaccination or no treatment. Twenty-one of 221 patients in the vaccine group compared to 42 of 218 in the comparison group had major adverse vascular events (unadjusted HR 0.70; 95% CI, 0.57 to 0.86). Although these findings suggest an effect, the fact that the trial was open label may have introduced bias, and an accompanying editorial to this study stressed the need for a large simple randomized controlled trial of influenza vaccination. Two trials of participants that were not enrolled on the basis of cardiovascular illness and reported a risk ratio of 0.64 (0.48 to

0.86) for adverse cardiovascular events and a risk ratio of 0.81 (95% CI 0.36 to 1.83) for cardiovascular death. The conclusion of the authors in the latest systematic review was that “A large, adequately powered, multicenter trial is warranted to address these findings and assess individual cardiovascular

end points”.

1.2.3   Pilot work. We have piloted logistics of conducting this trial using internal funding. We have

conducted a survey of participants in INTER-CHF sites (all low to middle income countries) for influenza vaccination and observed that vaccine update was 11% on average and < 25% in all sites.. We have established recruitment through INTER-CHF where 5,813 participants have been successfully enrolled. We have previously demonstrated our ability to randomize and measure outcomes in landmark cardiovascular trials (ONTARGET, ORIGIN) conducted in these same sites using the same data collection methods that we propose in this study. We obtained ethics approval from McMaster University in October 2013. Ethics submissions have been submitted and approved for three Southern Hemisphere sites in Philippines, Uganda and Mozambique. We have demonstrated feasibility of shipping vaccine, as we have successfully sent mock vaccine shipments to Nigeria, Uganda, Mozambique and Philippines and trial vaccine to Mozambique and Philippines. We have completed enrolment at two Southern Hemisphere sites in Spring 2015. We are in the process of submitting for ethics approval and finalizing contracts with all Northern Hemisphere sites.

1.3      How will the results of the trial be used? 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 is 11% on average and < 25% in all sites. 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.

1.4      Describe any risks to the safety of participants involved in the trial.

The major risk of influenza vaccine, although rare (1 per 200,000 doses), is an anaphylactic reaction, characterized by hives, swelling of mouth and throat, difficulty breathing, and low blood pressure. Such a rare event occurs immediately after injection. Less than one third of individuals receiving study vaccine may experience some soreness or redness at the site for 1-2 days. Fever, malaise, nausea, loss of appetite, muscle aches occur infrequently and may last 1-2 days. It is unclear whether Guillain- Barré syndrome is associated with influenza vaccination, however it has been estimated that if there was such an association, it would be at a rate of 1 or 2 incremental episodes of Guillain-Barré syndrome per million doses of influenza vaccine given. There is no evidence that receiving two influenza vaccines (i.e. for participants who are randomized to influenza vaccine and also receive a vaccine outside of the trial) within a given season leads to any additional adverse events other than those described above. In fact, children under the age of 9 years are routinely immunized with two doses of influenza vaccine four weeks apart to increase protection against influenza. By contrast the risks of death and other major cardiovascular disease events exceeds 30%.

1.5      Ethical considerations. There is uncertainty in the medical community about the benefit

of influenza vaccination to prevent adverse vascular events as outlined below in sections 3.2 and 3.3. Observational studies cannot definitely address the question because of confounding.  There is also uncertainty about the non-cardiovascular benefits of the vaccine. A recent Cochrane review of influenza vaccine in persons > 65 years, pooled 3 RCTs (2217 participants, including those from a nursing home and a psychiatric hospital) found a RR of 0. 42 (0.27, 0.66) for preventing influenza but complications were not assessed. However, in observational studies, vaccines were ineffective in the prevention of influenza, RR 0.19 (0.02, 2.01), influenza-like illness, RR 0.75 (0.42, 1.33), pneumonia, RR 0.88 (0.64, 1.20), or hospital admissions or deaths from any respiratory disease, RR0.88 (0.54,1.43).  Selection bias because of differential vaccine uptake has been extensively cited as the most likely explanation for these counter-intuitive results (i.e. lack of effect on influenza, influenza-like illness,  pneumonia,  respiratory hospital  admissions  but  prevention  of influenza  and  pneumonia hospitalizations  and  death). In  fact,  the  reduction  in  death  from  all causes far exceeds the estimated impact of influenza vaccine on winter season mortality of 5% in an average season.  A report of reduced influenza/pneumonia hospitalization (RR 0.72; 0.59, 0.89) and reduced all  cause death  (RR  0.39;    0.33,  0.47)  when  seniors  were  vaccinated  and  outcomes  assessed prior to influenza season offers evidence of selection bias due to preferential vaccination of healthy seniors. Seniors with greater frailty (i.e. at increased risk for hospitalization and death) were shown to be less likely to receive influenza vaccination.  The authors of the Cochrane review conclude that “to resolve the uncertainty of the role of vaccines, an adequately powered, publicly-funded, high quality placebo- controlled trial run over several seasons should be undertaken”. Given broad consensus among experts in the field that clinical equipoise exists on the effect of influenza vaccine in CHF patients, a large, prospective randomized trial is delivery.