Study Design and Population
. This was a randomized, prospective, controlled pilot study that used parallel groups from multiple centers. The enrollment criteria, the study design, the treatment protocol, and the endpoint definitions have been published. 9
From 6 care units in Argentina, we enrolled 301 patients from 2 different cohorts: a myocardial infarction group of 200 patients with a diagnosis of recent (within the last 72 hours) ST- or non-ST-segment elevation myocardial infarction, and an interventional group of 101 patients who were to undergo angioplasty and stenting. Our Institutional Review Board approved the study, and informed consent was obtained from all patients.
At admission, the 200 patients who were experiencing ST-segment elevation myocardial infarction or non-ST-segment myocardial infarction were so classified in accordance with new diagnostic criteria arrived at by recent consensus. 10
They were divided into 2 groups. Group A (100 patients) received a single intramuscular vaccination containing 0.5 mL of A/Moscow/10/99-like virus, A/New Caledonia/20/99 (H1N1)-like virus, and AB/Sichuan/379/99-like virus. Follow-up telephone visits were scheduled at 6 and 12 months after treatment. Group B (100 patients) served as a control group and received a saline infusion as placebo.
The PCI (Percutaneous Intervention)-Stenting Group comprised 101 subjects who were to undergo stenting angioplasty at 2 sites in the city of Buenos Aires. Before the interventional procedure, 51 of these patients received vaccination, and the other 50, as members of a control group, received the placebo.
The study began in May 2001. Because the timing of influenza activity varies by region, the vaccine for the present trial was administered after May (June marks the onset of winter in the southern hemisphere). Vaccination is usually recommended during the winter, because that is influenza season. 11
This strategy was adopted on the hypothesis that a nonspecific stimulation of the immune system could reduce the incidence and severity of subsequent ischemic events, in addition to serving as prophylaxis against influenza infection.
Endpoints. One-year follow-up was obtained in a prospective manner, in which each clinical site was responsible for telephone contact with all randomized patients. If a patient was lost to follow-up by telephone, a study investigator conducted a home visit to evaluate the patient. For the 1-year follow-up, the same endpoint definitions were used, and the primary endpoint was cardiovascular death.
Cardiovascular deaths were defined as those due to myocardial infarction, sudden death, death in the hospital after possible myocardial infarction, or death due to heart failure or another coronary cause. Cardiovascular deaths were confirmed by the patients' own physicians or by a death registry. Deaths for other reasons were not considered as primary endpoints.
The FLUVACS Registry
. All the cases studied were those of patients who participated in the FLUVACS Study, 9
whether or not they had been vaccinated during the winter of 2001.
During the summer of 2003 (January–March), we recorded the deaths and myocardial infarctions of those patients who participated in the initial FLUVACS Study. 9
Information on demographic characteristics was collected with the use of a structured questionnaire.
The patients or their survivors were asked whether the patients had been vaccinated during the 2nd influenza vaccination campaign (April 2002 in Argentina), whether they had been re-hospitalized for a new cardiovascular infarction, and whether death (if it occurred) was cardiovascular or noncardiovascular. In accordance with international recommendations made in 2002, those patients who were vaccinated received the same intramuscular vaccination (0.5 mL of A/Moscow/10/99-like virus, A/New Caledonia/20/99 (H1N1)-like virus, and AB/Sichuan/379/99-like virus) that they had received during the winter of 2001.
Endpoint Definitions for the Registry. The aim was to assess the composite endpoints of cardiovascular or noncardiovascular death (total deaths) and myocardial infarction defined as any value of creatine kinase-MB (CK-MB) above normal (5% or more of total CK, or a total CK value at least twice the upper limit of the normal reference range). A Q wave myocardial infarction (MI) was defined as chest pain lasting 20 minutes or longer, followed by the appearance of new significant Q waves (≥0.03 seconds) in at least 2 leads in the electrocardiogram (ECG).
Statistical Analysis. The analyses for the 1-year follow-up were done according to the intention-to-treat principle.
Statistical comparisons between groups were made using the time-to-event with the Kaplan-Meier survival technique (2-sided log-rank test, alpha = 0.05).
A χ2 statistic was calculated to test differences between proportions. The Mantel-Cox test was applied to evaluate differences between functions. In measuring the time to an event in cases in which a patient had multiple endpoints, the worst event was considered the endpoint. All patients who experienced no events or were lost to follow-up were recorded at the time of study termination or last contact. When it was possible only to establish whether a patient was alive or dead, the confirmation date determined the length of follow-up for death. However, if full information was available on an earlier date, that date determined the length of follow-up in the analysis of all events.