Influenza Vaccination After Myocardial Infarction Trial
During influenza epidemics, cardiovascular events increase, prompting the need for influenza vaccination after myocardial infarction. This randomized, double-blind, multicenter trial aims to assess the impact of influenza vaccination on clinical outcomes in patients with recent myocardial infarction or high-risk coronary disease. With a focus on cardiovascular causes of death and the potential protective effect of vaccination, the study involves 30 hospitals across 8 countries over 4 influenza seasons. Enrollment targets 4400 patients to provide valuable insights into the benefit of influenza vaccination in this patient population.
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Influenza Vaccination after Myocardial Infarction - a randomized, double-blind, placebo-controlled, multicenter trial Ole Fr bert, MD, PhD, FESC - on behalf of the IAMI investigators rebro University Hospital, Sweden 1 ClinicalTrials.gov Identifier: NCT02831608
Background During influenza epidemics more people die from cardiovascular causes Numerous observational studies suggest a protective effect from influenza vaccination on cardiovascular events Three, smaller single-center randomized trials support registry findings Influenza vaccination carries a class I, level of Evidence B recommendation in both AHA/ACC and ESC secondary prevention guidelines but uptake is low and vaccination timing undecided 2
Influenza and cardiovascular disease Fever Tachycardia Metabolic demand Oxygen saturation BT Vasoconstriction Influenza virus infection Cytokines Plaque destabilization Plaque rupture Prothrombotic state Atherosclerosis AMI 3 Adaptadfrom Barnes M, Heart. 2016;102:1953
Outline Objective. To determine whether influenza vaccination (Vaxigrip, Vaxigrip Tetra, FluQuadri, Sanofi Pasteur) improves clinical outcomes in patients with recent myocardial infarction or high-risk coronary disease Design. Investigator-initiated, international, multicenter, double blind, randomized controlled trial Enrollment. Thirty hospitals across 8 countries, over 4 influenza seasons between 1 Oct 2016 and 1 Mar 2020. Target: 4400 patients 4
Inclusion and exclusion criteria Inclusion criteria STEMI Or NSTEMI Or high risk stable patients >75 y Coronary angiography/PCI (not Bangladesh) Male or female subjects 18 y Written informed consent Exclusion criteria Influenza vaccine during the current flu season Intention to be vaccinated during the current flu season Indication for influenza vaccination (as per investigator discretion) Severe allergy to eggs or previous allergic reaction to influenza vaccine Febrile illness or acute, ongoing infection Endogenic or iatrogenic immunosuppression Inability to provide informed consent Age below 18 y Previous randomization in the iami trial 5
Endpoints Primary endpoint Composite of all-cause death, MI, or stent thrombosis at 12 months Key secondary endpoints 1. All-cause death 2. Cardiovascular death 3. MI 4. Stent thrombosis A hierarchical testing approach was pre-specified for the key secondary endpoints (in the order shown) if the primary endpoint was statistically significant 6
8 countries and 30 centers Denmark Aarhus University Hospital Odense University Hospital Aalborg University Hospital Rigshospitalet Bispebjerg Hospital Norway LHL-sykehuset Gardermoen Oslo Latvia Pauls Stradins University Hospital Riga Sweden Sahlgrenska University Hospital rebro University Hospital University Hospital Link ping Centrallasarettet V ster s J nk ping Hospital Sk ne University Hospital Ume University Hospital Karolinska University Hospital Danderyd University Hospital Uppsala University Hospital Karlstad Central Hospital Stockholm South General Hospital Bangladesh National Institute of CV Diseases National Heart Foundation Australia Blacktown Hospital Sydney Scotland Golden Jubilee National Hospital Royal Infirmary of Edinburgh Victoria Hospital, Kirkcaldy Aberdeen Royal Infirmary University Hospital Hairmyres Ninewells Hospital, Dundee Czech Republic University Hospital Kralovske Vinohrady St. Anne University Hospital 7
Challenges during the course of the study Slow recruitment Additional centers and countries Broader inclusion criteria Enrichment group: stable high-risk coronary disease (>75y + at least one additional risk factor) Trial halted prematurely on April 7, 2020 by the DSMB due to the COVID-19 pandemic after enrollment of 2571 patients (58% of target) 8
Enrollment and randomization 6696 patients were screened 4125 patients were not enrolled 1439 already vaccinated or intending vaccination 1202 patients declined 580 patients not eligible 430 other medical reasons 326 logistical reasons 148 other 2571 were randomized 1290 assigned to vaccine 1281 assigned to placebo 21 did not receive study treatment 3 transferred 10 withdrew consent 5 incorrectly randomized 3 other 18 did not receive study treatment 4 transferred 11 withdrew consent 3 incorrectly randomized Follow-up 12 months. Final vital status known in 99.5% 1260 (98.4%) received placebo 1272 (98.6%) received vaccine 9
Baseline data Vaccine (N=1272) 60.1 ( 11.0) 1036 (81.4) 665/1239 (53.7) 568/1239 (45.8) 6/1239 (0.5) 27.5 ( 5.0) 281/1253 (22.4) Placebo (N=1260) 59.6 ( 11.4) 1034 (82.1) 683/1236 (55.3) 551/1236 (44.6) 2/1236 (0.2) 27.4 ( 5.1) 247/1254 (19.7) Age, yr Male sex no. (%) ST-segment elevation MI no. (%) Non-ST-segment elevation MI no. (%) Stable coronary artery disease no. (%) Body-mass index, kg/m2 Diabetes no. (%) Smoking status no. (%) Never smoked Former smoker Current smoker Hyperlipidemia no. (%) Hypertension no. (%) Previous MI no. (%) Previous PCI no. (%) Previous CABG no. (%) Killip class 2 no. (%) 463/1232 (37.6) 332/1232 (26.9) 437/1232 (35.5) 427/1257 (34.0) 650/1251 (52.0) 191/1253 (15.2) 138/1257 (11.0) 28/1258 (2.2) 50/1157 (4.3) 461/1222 (37.7) 328/1222 (26.8) 433/1222 (35.4) 409/1249 (32.7) 595/1251 (47.6) 172/1249 (13.8) 129/1257 (10.3) 37/1257 (2.9) 45/1155 (3.9) 10
Primary composite endpoint HR 0.72; 95% CI 0.52-0.99; P=0.040 Placebo 91 vs vaccine 67 11
Key secondary endpoints All-cause death CV death MI HR 0.59; 95% CI 0.39-0.89; P=0.010 Placebo 61 vs vaccine 37 HR 0.59; 95% CI 0.39-0.90; P=0.014 Placebo 56 vs vaccine 34 HR 0.86; 95% CI 0.50-1.46; P=0.57 Placebo 29 vs vaccine 25 12
All endpoints Vaccine (N=1272) Placebo (N=1260) Hazard Ratio (95% CI) P-value Primary Endpoint, no.(%) All-cause death, myocardial infarction, stent thrombosis 67 (5.3) 91 (7.2) 0.72 (0.52-0.99) 0.040 Key Secondary Endpoints, no.(%) All-cause death CV death Myocardial infarction Stent thrombosis 37 (2.9) 34 (2.7) 25 (2.0) 6 (0.5) 61 (4.9) 56 (4.5) 29 (2.4) 3 (0.2) 0.59 (0.39-0.89) 0.59 (0.39-0.90) 0.86 (0.50-1.46) 1.94 (0.48-7.76) 0.010 0.014 0.57 0.34 Other Secondary Endpoints, no.(%) CV death, myocardial infarction, stent thrombosis Stroke, including TIA Hospitalisation for heart failure Non-CV death Unplanned revascularisation Hospitalisation for arrhythmia 64 (5.1) 6 (0.5) 29 (2.3) 3 (0.2) 87/1205 (7.3) 3/1263 (0.2) 86 (6.9) 8 (0.7) 16 (1.3) 5 (0.4) 76/1190 (6.5) 7/1253 (0.6) 0.73 (0.53-1.01) 0.72 (0.25-2.08) 1.77 (0.96-3.27) 0.57 (0.14-2.40) 1.13 (0.83-1.54) 0.43 (0.11-1.64) 0.064 0.74 0.062 0.27 0.42 0.20 13
Pre-specified subgroups 14
Vaccine (N=1272) 1066 (83.8) Placebo (N=1260) 1046 (83.0) Reaction P-value Patients returning 7-day questionnaire - no.(%) Safety, self-reported 7-day questionnaire Systemic reaction - no. (%) Shivering Fever Headache Muscle ache Disturbed sleep Feeling of general discomfort Other 63 (5.9) 101 (9.5) 80 (7.5) 75 (7.0) 55 (5.2) 65 (6.1) 101 (9.5) 56 (5.4) 93 (8.9) 87 (8.3) 60 (5.7) 66 (6.3) 57 (5.4) 99 (9.5) 0.579 0.642 0.484 0.222 0.255 0.523 0.994 Injection site reaction - no. (%) Pain of any intensity Severe or extreme pain Redness Severe or extreme redness Swelling Severe or extreme swelling Itching Severe or extreme itching Hardening Severe or extreme hardening Bruising Severe or extreme bruising 129 (12.1) 3 (0.3) 72 (6.8) 7 (0.7) 67 (6.3) 6 (0.6) 38 (3.6) 7 (0.7) 77 (7.2) 12 (1.1) 48 (4.5) 9 (0.8) 68 (6.5) 6 (0.6) 23 (2.2) 4 (0.4) 16 (1.5) 0 (0.0) 24 (2.3) 7 (0.7) 19 (1.8) 0 (0.0) 44 (4.2) 10 (1.0) <0.0001 0.338 <0.0001 0.548 <0.0001 0.031 0.084 1.000 <0.0001 0.0005 0.739 0.822 15
Safety, site-reported (no differences) Vaccine (N=1272) 4 (0.3) 1 (0.1) 0 5 (0.4) 0 4 (0.3) 0 5 (0.4) 0 4 (0.3) 11 (0.9) Placebo (N=1260) 3 (0.2) 5 (0.4) 3 (0.2) 3 (0.2) 1 (0.1) 3 (0.2) 1 (0.1) 2 (0.2) 1 (0.1) 2 (0.2) 5 (0.4) System Organ Class, no. (%) P-value Cardiac disorders Gastrointestinal General disorders Infections and infestations Investigations Musculoskeletal Neoplasms Nervous system Renal and urinary disorders Respiratory Skin and administration site Numbers in table are frequency (percentage) of patients with an adverse event within 12 months of randomization; p-value from Fisher's exact test 1.00 0.12 0.12 0.73 0.50 1.00 0.50 0.45 0.50 0.60 0.21 16
CV death exploratory meta-analysis Phrommintikul A et al. Eur Heart J 2011;32:1730 Gurfinkel EP et al. Eur Heart J 2004;25:25 17 Ciszewski A et al. Eur Heart J 2008;29:1350
Summary In patients with MI or high-risk coronary disease influenza vaccination Reduced the risk of: The primary composite endpoint: All-cause death, MI and stent thrombosis Key secondary endpoints: All-cause death and CV death Was well-tolerated and safe Serious adverse events were rare and of similar type and incidence in both groups Influenza vaccination should be considered as part of in-hospital treatment after MI 18
