Table 3.

Overview of the Influenza Vaccine Cardiovascular Outcome Trials

	INVESTED	IAMI	RCT-IVVE
Trial title	INfluenza Vaccine to Effectively Stop cardioThoracic Events and Decompensated heart failure	Influenza Vaccination After Myocardial Infarction	Influenza Vaccine to Prevent Adverse Vascular Events
NCT number	NCT02787044	NCT02831608	NCT02762851
Trial design	Pragmatic, randomized, quadruple-masked, parallel-assignment, active-controlled trial	Prospective registry-based, randomized, quadruple-masked, parallel-assignment, placebo-controlled trial	Randomized, quadruple-masked, parallel-assignment, placebo-controlled trial
Recruitment started	September 2016	October 2016	June 2016
Anticipated enrollment	9,300	4,400	5,000
Estimated study completion	February 2021	September 2021	May 2021
Intervention	High-dose trivalent inactivated influenza vaccine (IIV3-HD)	Standard-dose trivalent inactivated influenza vaccine (IIV3) Standard-dose quadrivalent inactivated influenza vaccine (IIV4)	Standard-dose trivalent inactivated influenza vaccine (IIV3)
Comparator	Standard-dose quadrivalent inactivated influenza vaccine (IIV4)	Placebo, intramuscular saline injection	Placebo, intramuscular saline injection
Key inclusion criteria	≥18 yrs of age Documented history of either: Hospitalization for spontaneous (type 1) or secondary (type 2) MI within 1 yr of baseline visit, or HF hospitalization within 2 yrs of the baseline visit. 1+ additional risk factor, e.g.:  Age ≥65 yrs  Diabetes mellitus  Obesity (BMI ≥30 kg/m2)  Smoker  CKD (eGFR ≤ 60)  Reduced LVEF (<40%)  Prior MI or HF hospitalization  Peripheral artery disease  Ischemic stroke	Meet study definition for either: STEMI, or NSTEMI Stable CAD ≥75 yrs of age undergoing angiography/PCI AND with 1+ additional risk factor AND ≥18 yrs of age A finalized coronary angiography/PCI (optional for sites in Bangladesh)	≥18 yrs of age New York Heart Association functional class II, III, and IV HF
Recruitment time	4 influenza seasons	4 influenza seasons	3 influenza seasons
Trial participants, n	5,266 enrolled as of October 9, 2019	2,573 enrolled as of March 2, 2020	4,871 enrolled as of January 14, 2019
Primary endpoints	Time to first occurrence of all-cause death or cardiopulmonary hospitalization up to 3 yrs	Composite endpoint of time to all-cause death, a new MI or stent thrombosis (first occurring, ICD-10 codes), at 1 yr	Composite of cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalizations for HF at 6 months
Regions	North America (United States and Canada)	Europe, Australia, Asia (8 countries)	Asia, Middle East, and Africa (10 countries)
No. of sites	190	30	10
Substudy (Y/N)	Yes, vaccine immunogenicity	Yes, vaccine immunogenicity	Yes, serological substudy to assess influenza infection

BMI = body mass index; CAD = coronary artery disease; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; HF = heart failure; IAMI = Study on the Effect of Influenza Vaccination After Heart Attack on Future Cardiovascular Prognosis; ICD-10 = International Statistical Classification of Diseases and Related Health Problems-10th Revision; INVESTED = INfluenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure; LVEF = left ventricular ejection fraction; MI = myocardial infarction; NSTEMI = non–ST-segment elevation myocardial infarction; PCI = percutaneous coronary intervention; RCT-IVVE = Influenza Vaccine To Prevent Adverse Vascular Events; STEMI = ST-segment elevation myocardial infarction.