INVESTED: INfluenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure

Sponsor
Brigham and Women's Hospital (Other)
Overall Status
Completed
CT.gov ID
NCT02787044
Collaborator
National Heart, Lung, and Blood Institute (NHLBI) (NIH), University of Wisconsin, Madison (Other), University of Toronto (Other), Boston VA Research Institute, Inc. (Other), Patient-Centered Outcomes Research Institute (Other), University of Minnesota (Other)
5,388
190
2
46
28.4
0.6

Study Details

Study Description

Brief Summary

INVESTED will test the hypothesis that high dose trivalent influenza vaccine will reduce cardiopulmonary events to a greater extent than standard dose quadrivalent influenza vaccine in high-risk cardiovascular patients with a recent history of myocardial infarction or heart failure. The trial will enroll 9300 participants over one Vanguard (pilot) season and three additional influenza seasons. The primary endpoint will be a composite of all-cause mortality or cardiopulmonary hospitalization.

Condition or Disease Intervention/Treatment Phase
  • Biological: High Dose Trivalent Influenza Vaccine
  • Biological: Standard Dose Quadrivalent Influenza Vaccine
Phase 4

Detailed Description

Influenza leads to significant morbidity and mortality, particularly in patients with cardiovascular disease. Influenza-related death is more common in patients with cardiovascular disease than any other chronic health condition. Influenza infection has been temporally associated with acute cardiovascular events, such as acute coronary syndrome and acute heart failure. Due to the increased risk for influenza-related complications, annual influenza immunization is recommended by the Centers for Disease Control and Prevention, (CDC) the American Heart Association, and the American College of Cardiology, and widespread influenza vaccination has been associated with reduced cardiac-related hospital admissions, acute exacerbations of heart failure, and winter mortality. Moreover, a meta-analysis has shown that annual vaccination reduces the risk for major adverse cardiovascular events (MACE) by 36%, with a more prominent effect in those with recent acute myocardial infarction (AMI).

Several lines of evidence suggest that a strategy of utilizing high-dose influenza vaccine in at risk cardiovascular patients would reduce morbidity and mortality. Immune responses to influenza vaccine, normally subject to variability by age and concomitant medical conditions, are substantially reduced in patients with heart failure evidenced by lower vaccine-induced antibody titers compared to healthy controls. In a randomized trial, antibody responses in patients with heart failure were augmented by using a higher dose of influenza vaccine. In a meta-analysis, higher dose influenza vaccination was associated with a 27% reduced risk for MACE compared to standard dose vaccine. A randomized study of high dose versus standard dose influenza vaccine in medically-stable patients over age 65 showed that participants receiving high dose vaccine had a 24% reduced risk of laboratory-confirmed influenza associated with protocol-defined influenza-like-illness, and had a low risk for adverse events. High dose influenza vaccine is FDA approved for use in medically stable adults over the age of 65, but has not been studied for patients under the age of 65 or in those with unstable, high risk medical conditions. The CDC does not preferentially recommend one influenza vaccine over another, and the optimal vaccine formulation that offers the most clinical protection in these high risk patients is unknown.

The high morbidity and health care costs among patients with high risk cardiovascular disease along with the reduced immune responses to standard dose influenza vaccines in patients with heart failure provides a compelling rationale to investigate alternative influenza vaccination strategies in this group. INVESTED is an outcomes study in patients with recent acute myocardial infarction (AMI) or heart failure (HF) to test whether a four-fold higher dose of trivalent influenza vaccine will reduce morbidity and mortality compared to standard dose quadrivalent vaccine. INVESTED will test the hypothesize that high dose vaccine will reduce the composite of all cause death or cardiopulmonary hospitalizations in this population, with the following specific aims:

Specific Aim 1. To test the hypothesis that high dose trivalent influenza vaccine will reduce the composite of death or cardiopulmonary events compared with standard dose quadrivalent influenza vaccine in high-risk cardiovascular patients. Patients with recent AMI or HF hospitalization will be randomized to high dose versus standard dose vaccine for up to three influenza seasons. The primary endpoint will be time to first occurrence of death or cardiopulmonary hospitalization within each influenza season. Hospitalizations will be ascertained utilizing multiple approaches (phone, patient report, and electronic health records). Key secondary outcome measures will include total (first and recurrent) cardiopulmonary hospitalizations or death, time to first occurrence of cardiovascular death or cardiopulmonary hospitalization, time to occurrence of all-cause death or cardiopulmonary hospitalization across all enrolled influenza seasons, time to occurrence of all-cause death, and time to first occurrence of cardiopulmonary hospitalizations.

Specific Aim 2. To test the hypothesis that antibody titers to influenza vaccine antigens are associated with cardiopulmonary outcomes. In a subset of participants, antibody titers by hemagglutination inhibition assays to influenza vaccine antigens at baseline and at 4 weeks following randomization will be determined, corresponding to achievement of maximal antibody titer levels after vaccination. The association between geometric mean titers post-vaccination and the occurrence of death or cardiopulmonary hospitalization (primary outcome measure of Specific Aim 1) will be assessed.

Other key correlative study (immune) outcome measures will include:

Change in antibody titers at 4 weeks post-vaccination from baseline to influenza vaccine antigens Seroconversion (demonstration of 4-fold rise in antibody concentrations from baseline) and seroprotection (demonstration of antibody titer level of 1:40) to A/H1N1, A/H3N2, and B-type vaccine antigens

The results of this trial have the potential to inform health care policy regarding optimal influenza vaccination for individuals with high risk cardiovascular disease, which may in turn reduce morbidity from this annual threat to health stability in patients with cardiovascular conditions.

Study Design

Study Type:
Interventional
Actual Enrollment :
5388 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Prevention
Official Title:
INfluenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure
Actual Study Start Date :
Aug 1, 2016
Actual Primary Completion Date :
May 31, 2020
Actual Study Completion Date :
May 31, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: High Dose Influenza Vaccine

High Dose Influenza Vaccine

Biological: High Dose Trivalent Influenza Vaccine
High Dose Trivalent Influenza Vaccine

Active Comparator: Standard Dose Influenza Vaccine

Standard Dose Influenza Vaccine

Biological: Standard Dose Quadrivalent Influenza Vaccine
Standard Dose Quadrivalent Influenza Vaccine

Outcome Measures

Primary Outcome Measures

  1. All-Cause Death or Cardiopulmonary Hospitalization Within Each Vaccination Season [Up to 1 year from vaccination (repeats seasonally)]

    Number of patients with first occurrence of death or cardiopulmonary hospitalization within each vaccination season

Secondary Outcome Measures

  1. Total Cardiopulmonary Hospitalizations or Death [Up to 3 years]

    Total (first and recurrent) cardiopulmonary hospitalizations or death

  2. Cardiovascular Death or Hospitalization Within Each Vaccination Season [Up to one year from vaccination]

    Number of patients with first cardiovascular death or cardiovascular hospitalization within each influenza season

  3. Death or Cardiopulmonary Hospitalization Across Enrolling Seasons [Up to three years]

    First cardiopulmonary Hospitalization or all-cause death across enrolling seasons

  4. All-Cause Mortality [Up to 3 years]

    Number of patients with first occurrence of all-cause mortality

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • = 18 years of age

  • history of hospitalization for myocardial infarction within 1 year of enrollment OR a history of hospitalization for heart failure within 2 years of enrollment

  • At least one of the following additional risk factors:

  • Prior MI (if HF the index event above; or a second MI)

  • Prior HF hospitalization (if MI the index event above; or a second HF event)

  • Age ≥ 65

  • Left ventricular ejection fraction (LVEF) < 40%

  • Diabetes mellitus

  • Obesity (BMI ≥ 30)

  • Renal impairment (eGFR ≤ 60)

  • History of ischemic stroke

  • History of peripheral artery disease

  • Current smoking

Exclusion Criteria:
  • Known allergy, hypersensitivity (anaphylaxis), or Guillain-Barré Syndrome within 6 weeks after influenza vaccine

  • Any non-cardiac condition that in the opinion of the investigator would lead to life expectancy less than 9 months.

  • Receipt of influenza vaccine during current influenza season

  • Any illness requiring treatment with antibiotics or anti-inflammatory medication within the past 14 days.

  • Any fever over 100 degrees Fahrenheit or 38 degrees Celsius within the past 7 days.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Birmingham VAMC Birmingham Alabama United States 35233
2 University of Alabama Hypertension Program Birmingham Alabama United States 35294
3 Heart Center Research, LLC Huntsville Alabama United States 35801
4 Alaska Heart & Vascular Institute Anchorage Alaska United States 99508
5 Banner University Medicine North Tucson Arizona United States 85719
6 University of Arizona- Sarver Heart Center Tucson Arizona United States 85724
7 CAVHS Little Rock Arkansas United States 72205
8 VA Loma Linda Healthcare System Loma Linda California United States 92357
9 Long Beach VAMC Long Beach California United States 90822
10 University of California Davis Medical Center Sacramento California United States 95817
11 VA San Diego Healthcare System San Diego California United States 92161
12 UCSF Medical Center San Francisco California United States 94143
13 VA West Haven West Haven Connecticut United States 06516
14 Washington DC VAMC Washington District of Columbia United States 20422
15 Clearwater Cardiovascular Consultants Clearwater Florida United States 33756
16 N FL/S GA Veterans Health System Gainesville Florida United States 32608
17 OneFlorida CDRN Gainesville Florida United States 32611
18 Clearwater Cardiovascular Consultants-Largo Largo Florida United States 33777
19 Inpatient Research Corporation Miami Florida United States 33014
20 ITB Research Miami Florida United States 33173
21 Charlotte Heart Group Research Center Port Charlotte Florida United States 33952
22 Clearwater Cardiovascular Consultants-SH Safety Harbor Florida United States 34695
23 Bond Community Health Center, Inc. Tallahassee Florida United States 32301
24 Piedmont Heart Institute Atlanta Georgia United States 30309
25 Morehouse School of Medicine Atlanta Georgia United States 30310
26 Atlanta VA Health Care System Decatur Georgia United States 30033
27 Peidmont Fayette Fayetteville Georgia United States 30214
28 University of Hawaii Honolulu Hawaii United States 96813
29 Northwestern University Chicago Illinois United States 60611
30 Jesse Brown VA Medical Center Chicago Illinois United States 60612
31 University of Chicago Medicine Chicago Illinois United States 60637
32 Chicago Medical Research Hazel Crest Illinois United States 60429
33 Northwester Medicine Lake Forest Lake Forest Illinois United States 60045
34 Loyola University Medical Center Maywood Illinois United States 60153
35 Captain James A. Lovell Federal Health Care Center North Chicago Illinois United States 60064
36 UnityPoint Health Methodist Peoria Illinois United States 61606
37 Central DuPage Hospital Winfield Illinois United States 60190
38 Krannert Institute of Cardiology Indianapolis Indiana United States 46202
39 St. Vincent Medical Group Indianapolis Indiana United States 46260
40 University of Iowa Iowa City Iowa United States 52242
41 The University of Kansas Medical Center Kansas City Kansas United States 66160
42 VA Eastern Kansas Health Care System Leavenworth Kansas United States 66048
43 Robley Rex VA Louisville Kentucky United States 40206
44 The Heart Clinic of Hamond Hammond Louisiana United States 70403
45 Southeast Louisiana Veterans Healthcare System New Orleans Louisiana United States 70112
46 Ochsner Health System- Baton Rouge New Orleans Louisiana United States 70121
47 ENRM VA Hospital Bedford Massachusetts United States 01730
48 Brigham and Women's Hospital Boston Massachusetts United States 02115
49 Brigham and Women's Faulkner Hospital Boston Massachusetts United States 02130
50 Beth Israel Deaconess Medical Center Boston Massachusetts United States 02215
51 Pentucket Medical Associates Haverhill Massachusetts United States 01830
52 Charles River Medical Associates Natick Massachusetts United States 01760
53 Boston/West Roxbury VA Hospital West Roxbury Massachusetts United States 02132
54 VA Boston Healthcase System West Roxbury Massachusetts United States 02132
55 VA Ann Harbor Healthcare System Ann Arbor Michigan United States 48105
56 Abbott Northwestern Hospital Minneapolis Minnesota United States 55407
57 HealthPartners - Riverside Research Minneapolis Minnesota United States 55454
58 University of Minnesota Minneapolis Minnesota United States 55455
59 Mayo Clinic Rochester Minnesota United States 55905
60 HealthEast Medical Research Institute Saint Paul Minnesota United States 55102
61 University of Mississippi Medical Center Jackson Mississippi United States 39216
62 Kansas City VA Medical Center Kansas City Missouri United States 64128
63 VA St. Louis Health Care System Saint Louis Missouri United States 63106
64 St. Louis University Saint Louis Missouri United States 63110
65 Washington University School of Medicine Saint Louis Missouri United States 63110
66 Nebraska Heart Institute- Grand Island Grand Island Nebraska United States 68803
67 Darthmouth-Hitchcock Medical Center Lebanon New Hampshire United States 03756
68 Cardio Assoc. of the Del. Valley- Elmer Elmer New Jersey United States 08318
69 Cardio. Assoc. of the Del. Valley- Haddon Heights Haddon Heights New Jersey United States 08035
70 Cardio. Assoc. of the Del. Valley- Sewell Sewell New Jersey United States 08080
71 Lourdes Cardiology Services Voorhees New Jersey United States 08043
72 New Mexico VA Health Care System Albuquerque New Mexico United States 87108
73 Albany Medical College Albany New York United States 12208
74 New York Presbyterian Brooklyn Methodist Hospital Brooklyn New York United States 11215
75 New York Presbyterian Queens Bayside/Whitestone Flushing New York United States 11355
76 New York Presbyterian/Queens Flushing New York United States 11355
77 NYPQ - Cardiology Outpatient Clinic Flushing New York United States 11355
78 Winthrop University Hospital Mineola New York United States 11501
79 New York VA New York New York United States 10010
80 NYU Langone Medical Center New York New York United States 10016
81 New York Presbyterian New York New York United States 10021
82 Columbia University Medical Center New York New York United States 10032
83 University of Rochester Medical Center Rochester New York United States 14642
84 Stony Brook University Hospital Stony Brook New York United States 11794
85 Charles George VA Asheville North Carolina United States 28805
86 University of North Carolina at Chapel Hill Chapel Hill North Carolina United States 27599
87 Duke Durham North Carolina United States 27710
88 Louis Stokes Cleveland VA Medical Center Cleveland Ohio United States 44106
89 Cleveland Clinic Cleveland Ohio United States 44195
90 Ohio State University Columbus Ohio United States 43210
91 Heart House Research Foundation Springfield Ohio United States 45504
92 Oregon Health & Science Portland Oregon United States 97239
93 VA Portland Health Care Systems (VAPHCS) Portland Oregon United States 97239
94 Temple University Philadelphia Pennsylvania United States 19140
95 University of Pittsburgh Pittsburgh Pennsylvania United States 15213
96 Providence VA Medical Center Providence Rhode Island United States 02908
97 Medical University of South Carolina Charleston South Carolina United States 29425
98 WJB Dorn VAMC Columbia South Carolina United States 29209
99 Palmetto Research Center, LLC Spartanburg South Carolina United States 29302
100 VAMC Memphis Memphis Tennessee United States 38104
101 Meharry Medical College Nashville Tennessee United States 37208
102 Tennessee Valley Healthcare Systems-Nashville Nashville Tennessee United States 37212
103 Vanderbilt University Nashville Tennessee United States 37232
104 Austin Heart- Heart Hospital Austin Texas United States 78756
105 Baylor Scott and White Heart and Vascular Hospital Dallas Texas United States 75226
106 Michael E. DeBakey VAMC, Houston Houston Texas United States 77030
107 Houston Heart & Vascular Associates Kingwood Texas United States 77339
108 Houston Methodist Research Institute-CCAT Pearland Pearland Texas United States 77584
109 St. David's Heath & Vascular PLLC Round Rock Texas United States 78681
110 South Texas Veterans Healthcare System San Antonio Texas United States 78229
111 STAR Clinical Trials San Antonio Texas United States 78229
112 Austin Heart San Marcos San Marcos Texas United States 78666
113 Baylor Scott and White Research Institute Temple Texas United States 76508
114 University of Utah Salt Lake City Utah United States 84108
115 George E. Wahlen Dept of VA Affairs Medical Center Salt Lake City Utah United States 84148
116 VA Medical Center White River Junction White River Junction Vermont United States 05009
117 Inova Heart and Vascular Institute Alexandria Virginia United States 22306
118 Carient Heart & Vascular Manassas Virginia United States 20109
119 Louis A Johnson VAMC Clarksburg West Virginia United States 26301
120 Gundersen Clinic La Crosse Wisconsin United States 54601
121 University of Wisconsin Madison Wisconsin United States 53705
122 Willam S. Middleton Memorial Veterans Hospital Madison Wisconsin United States 53705
123 University of Wisconsin Madison Madison Wisconsin United States 57305
124 Marshfield Clinic Marshfield Wisconsin United States 54449
125 Medical College of Wisconsin Milwaukee Wisconsin United States 53226
126 Aurora Research Institute, LLC Milwaukee Wisconsin United States 53233
127 Celement J. Zablocki VA Medical Center Milwaukee Wisconsin United States 53295
128 TotalCardiology Calgary Alberta Canada T2E 7C5
129 University of Calgary Calgary Alberta Canada T2N4Z6
130 CK Hui Heart Centre, Royal Alexandra Hospital Edmonton Alberta Canada T5H3V9
131 Dr. MPJ Senaratne Professional Corporation Edmonton Alberta Canada T6K4C1
132 Northwest Echocardiolography Grande Prairie Alberta Canada T8V 2E7
133 The CARe Clinic (Central Alberta Research) Red Deer Alberta Canada T4N6V7
134 University of Alberta Hospital- Mazankoski Heart Institute Edmonton British Columbia Canada T6G2B7
135 Kelowna General Hospital Kelowna British Columbia Canada V1Y1T2
136 SMH Cardiology Clinical Surrey British Columbia Canada V3V 0C6
137 Manna Research Inc. (Vancouver) Vancouver British Columbia Canada V5X0C4
138 Vancouver General Hospital - Gordon Leslie Diamond Centre Vancouver British Columbia Canada V5Z1M9
139 St. Paul's Hospital Vancouver British Columbia Canada V6Z1Y6
140 Victoria Heart Institute Foundation Victoria British Columbia Canada V8R4R2
141 St. Boniface Hospital/University of Manitoba Winnipeg Manitoba Canada R2H2A6
142 University of Sherbrooke Dieppe New Brunswick Canada
143 G.A Research Associates Ltd. Moncton New Brunswick Canada E1G 1A7
144 QEII Health Sciences Halifax Nova Scotia Canada B3H2Y9
145 Brampton Research Assocaites Brampton Ontario Canada L6Z 4N5
146 Manna Research Inc. (Burlington North) Burlington Ontario Canada L7M 4Y1
147 Manna Research Inc. (Burlington South) Burlington Ontario Canada L7R 1A4
148 Cambridge Cardiac Care Center Cambridge Ontario Canada N1R 6V6
149 Vizel Cardiac Research Cambridge Ontario Canada N1R 7R1
150 Dr. Alan David Bell Downsview Ontario Canada M3M 3E5
151 Hamilton Health Sciences General Hospital/ McMaste Hamilton Ontario Canada L8L 2X2
152 Queen's University CardioPulmonary Unit Kingston Ontario Canada K7L 3N6
153 St. Joseph's Health Care London Ontario Canada N6A 4V2
154 Dixie Medical Group Mississauga Ontario Canada L4W 0C2
155 Apple Hills Medical Associates Mississauga Ontario Canada L4Y 2N8
156 PACE Newmarket Ontario Canada L3Y 2P6
157 North York General Hospital North York Ontario Canada M2K 1E1
158 Sewa Ram Singal Med Prof Corporation North York Ontario Canada M3N 1N1
159 Heart Care Research Oshawa Ontario Canada L1J 2J9
160 Dr. James Cha Oshawa Ontario Canada L1J 2K1
161 Montfort Hospital and Ottawa Cardiovascular Centre Ottawa Ontario Canada K1K 0T2
162 University of Ottawa Heart Institute Ottawa Ontario Canada K1Y 4W7
163 Heart Function Clinic Queensway Carleton Ottawa Ontario Canada K2H 8P4
164 Kawartha Cardiology Peterborough Ontario Canada K9J0B2
165 Scarborough General Hospital Scarborough Ontario Canada M1P 2T7
166 St. Catherines Hospital St. Catherines Ontario Canada L2M 5V4
167 Manna Research (Stoney Creek) Stoney Creek Ontario Canada L8J 3W2
168 Health Sciences North Research Institute Sudbury Ontario Canada P3E 5J1
169 Dr. D. Shukla Professional Medicine Corporation Sudbury Ontario Canada P3E 5M4
170 Dr. R. Labonte Professional Medicine Corporation Sudbury Ontario Canada P3E 5M4
171 Thunder Bay Regional Health Sciences Center Thunder Bay Ontario Canada P7B 6V4
172 Sunnybrook Health Sciences Centre Toronto Ontario Canada M4N 3M5
173 St. Michael's Hospital Toronto Ontario Canada M5B 1W8
174 Mount Sinai Hospital Toronto Ontario Canada M5G 1X5
175 Toronto General Hospital Toronto Ontario Canada M5G 2N2
176 Women's College Hospital Toronto Ontario Canada M5S 1B2
177 University of Toronto Toronto Ontario Canada
178 iHealthCentre Vaughan Ontario Canada L4H 0P6
179 CISSS de Laval, Hopital Cite de la Sante Laval Quebec Canada H7M 3L9
180 Montreal Heart Institute Montréal Quebec Canada H1T 1C8
181 McGill University Health Centre Montréal Quebec Canada H3G 1A4
182 Jewish General Hospital Montréal Quebec Canada H3T 1E2
183 CIUSSS NÎM Hopital du Sacre-Coeur de Montreal Montréal Quebec Canada H4J 1C5
184 Manna Research Inc. (Montreal) Montréal Quebec Canada H9R 4S3
185 IUCPQ Quebec City Quebec Canada G1V 4G5
186 Centre hospitalier régional de Lanaudière St-Charles Borromee Quebec Canada J6E 6J2
187 CISSSI- Hopital Pierre-Le Gardeur Terrebonne Quebec Canada J6V 2H2
188 Centre Hospitalier de Regional Trois-Rivieres Trois-Rivières Quebec Canada G8Z 3R9
189 Prairie Vascular Research Inc. Regina Saskatchewan Canada 54P 0W5
190 VA Caribbean Healthcare System San Juan Puerto Rico 00921

Sponsors and Collaborators

  • Brigham and Women's Hospital
  • National Heart, Lung, and Blood Institute (NHLBI)
  • University of Wisconsin, Madison
  • University of Toronto
  • Boston VA Research Institute, Inc.
  • Patient-Centered Outcomes Research Institute
  • University of Minnesota

Investigators

  • Principal Investigator: Orly Vardeny, PharmD, MS, University of Minnesota
  • Principal Investigator: Scott D Solomon, MD, Brigham and Women's Hospital
  • Principal Investigator: KyungMann Kim, PhD, University of Wisconsin, Madison

Study Documents (Full-Text)

More Information

Additional Information:

Publications

Responsible Party:
Scott David Solomon, Professor of Medicine, Brigham and Women's Hospital
ClinicalTrials.gov Identifier:
NCT02787044
Other Study ID Numbers:
  • 2015P001823
  • U01HL130163
First Posted:
Jun 1, 2016
Last Update Posted:
Jan 21, 2022
Last Verified:
Dec 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Keywords provided by Scott David Solomon, Professor of Medicine, Brigham and Women's Hospital
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail A total of 5388 patients were consented for the study. Of these, 15 patients were not randomized (decided not to participate prior to randomization). 5373 patients were randomized and a total of 113 patients were excluded from all efficacy analyses prior to database lock because they had been enrolled at a site that was closed for major violations of good clinical practice, leaving 5260 participants in the efficacy and safety analysis.
Arm/Group Title High Dose Influenza Vaccine Standard Dose Influenza Vaccine
Arm/Group Description High Dose Influenza Vaccine High Dose Trivalent Influenza Vaccine: High Dose Trivalent Influenza Vaccine Standard Dose Influenza Vaccine Standard Dose Quadrivalent Influenza Vaccine: Standard Dose Quadrivalent Influenza Vaccine
Period Title: Overall Study
STARTED 2630 2630
COMPLETED 2615 2611
NOT COMPLETED 15 19

Baseline Characteristics

Arm/Group Title High Dose Influenza Vaccine Standard Dose Influenza Vaccine Total
Arm/Group Description High Dose Influenza Vaccine High Dose Trivalent Influenza Vaccine: High Dose Trivalent Influenza Vaccine Standard Dose Influenza Vaccine Standard Dose Quadrivalent Influenza Vaccine: Standard Dose Quadrivalent Influenza Vaccine Total of all reporting groups
Overall Participants 2630 2630 5260
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
65.5
(12.6)
65.5
(12.5)
65.5
(12.5)
Sex: Female, Male (Count of Participants)
Female
717
27.3%
756
28.7%
1473
28%
Male
1904
72.4%
1869
71.1%
3773
71.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
250
9.5%
267
10.2%
517
9.8%
Not Hispanic or Latino
2349
89.3%
2334
88.7%
4683
89%
Unknown or Not Reported
31
1.2%
29
1.1%
60
1.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
17
0.6%
32
1.2%
49
0.9%
Asian
81
3.1%
74
2.8%
155
2.9%
Native Hawaiian or Other Pacific Islander
13
0.5%
12
0.5%
25
0.5%
Black or African American
407
15.5%
377
14.3%
784
14.9%
White
2042
77.6%
2061
78.4%
4103
78%
More than one race
12
0.5%
14
0.5%
26
0.5%
Unknown or Not Reported
58
2.2%
60
2.3%
118
2.2%
Region of Enrollment (participants) [Number]
Canada
838
31.9%
838
31.9%
1676
31.9%
United States
1792
68.1%
1792
68.1%
3584
68.1%
Ejection Fraction (Percentage) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage]
42.5
(16.1)
41.9
(16.2)
42.2
(16.2)
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]
30.7
(7.2)
31.0
(7.7)
30.9
(7.4)
Qualifying Event (Count of Participants)
Heart Failure
1641
62.4%
1648
62.7%
3289
62.5%
Myocardial Infarction
982
37.3%
978
37.2%
1960
37.3%
Hypertension (Count of Participants)
Count of Participants [Participants]
1986
75.5%
2060
78.3%
4046
76.9%
Dyslipidemia (Count of Participants)
Count of Participants [Participants]
1793
68.2%
1823
69.3%
3616
68.7%
History of Percutaneous Coronary Intervention (Count of Participants)
Count of Participants [Participants]
1103
41.9%
1059
40.3%
2162
41.1%
Atrial Fibrillation (Count of Participants)
Count of Participants [Participants]
854
32.5%
871
33.1%
1725
32.8%
History of Coronary Artery Bypass Graft (Count of Participants)
Count of Participants [Participants]
503
19.1%
537
20.4%
1040
19.8%
History of Chronic Obstructive Pulmonary Disease (Count of Participants)
Count of Participants [Participants]
486
18.5%
520
19.8%
1006
19.1%
History of Implantable Cardioverter Defibrillator (Count of Participants)
Count of Participants [Participants]
463
17.6%
493
18.7%
956
18.2%
Asthma (Count of Participants)
Count of Participants [Participants]
308
11.7%
294
11.2%
602
11.4%
Statins (MI group) (Count of Participants)
Count of Participants [Participants]
920
35%
915
34.8%
1835
34.9%
Aspirin (MI Group) (Count of Participants)
Count of Participants [Participants]
907
34.5%
878
33.4%
1785
33.9%
Beta Blocker (MI Group) (Count of Participants)
Count of Participants [Participants]
839
31.9%
840
31.9%
1679
31.9%
Diuretic (HF group) (Count of Participants)
Count of Participants [Participants]
1294
49.2%
1313
49.9%
2607
49.6%
ACE Inhibitor/ Angiotensin Receptor Blocker / Angiotensin Receptor Neprilysin Inhibitor (Count of Participants)
Count of Participants [Participants]
1086
41.3%
1111
42.2%
2197
41.8%
Mineralocorticoid Receptor Antagonist (MRA) (HF group) (Count of Participants)
Count of Participants [Participants]
572
21.7%
546
20.8%
1118
21.3%
Digoxin (HF Group) (Count of Participants)
Count of Participants [Participants]
155
5.9%
159
6%
314
6%
Beta Blocker (HF Group) (Count of Participants)
Count of Participants [Participants]
1381
52.5%
1398
53.2%
2779
52.8%

Outcome Measures

1. Primary Outcome
Title All-Cause Death or Cardiopulmonary Hospitalization Within Each Vaccination Season
Description Number of patients with first occurrence of death or cardiopulmonary hospitalization within each vaccination season
Time Frame Up to 1 year from vaccination (repeats seasonally)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title High Dose Influenza Vaccine Standard Dose Influenza Vaccine
Arm/Group Description High Dose Influenza Vaccine High Dose Trivalent Influenza Vaccine: High Dose Trivalent Influenza Vaccine; Note primary analysis is of participant-seasons (n = 3577) Standard Dose Influenza Vaccine Standard Dose Quadrivalent Influenza Vaccine: Standard Dose Quadrivalent Influenza Vaccine; Note primary analysis is of participant-seasons (n = 3577)
Measure Participants 2630 2630
Measure Participant-Seasons 3577 3577
Count of Units [Participant-Seasons]
975
924
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection High Dose Influenza Vaccine, Standard Dose Influenza Vaccine
Comments Note, each participant can be included in the primary analysis up to 3 times (participating seasons).
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.21
Comments
Method Regression, Cox
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.06
Confidence Interval (2-Sided) 95%
0.97 to 1.17
Parameter Dispersion Type:
Value:
Estimation Comments
2. Secondary Outcome
Title Total Cardiopulmonary Hospitalizations or Death
Description Total (first and recurrent) cardiopulmonary hospitalizations or death
Time Frame Up to 3 years

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title High Dose Influenza Vaccine Standard Dose Influenza Vaccine
Arm/Group Description High Dose Influenza Vaccine High Dose Trivalent Influenza Vaccine: High Dose Trivalent Influenza Vaccine Standard Dose Influenza Vaccine Standard Dose Quadrivalent Influenza Vaccine: Standard Dose Quadrivalent Influenza Vaccine
Measure Participants 2630 2630
Number [All CP hospitalizations/death]
1857
1784
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection High Dose Influenza Vaccine, Standard Dose Influenza Vaccine
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.44
Comments
Method Regression, Cox
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.04
Confidence Interval (2-Sided) 95%
0.94 to 1.15
Parameter Dispersion Type:
Value:
Estimation Comments
3. Secondary Outcome
Title Cardiovascular Death or Hospitalization Within Each Vaccination Season
Description Number of patients with first cardiovascular death or cardiovascular hospitalization within each influenza season
Time Frame Up to one year from vaccination

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title High Dose Influenza Vaccine Standard Dose Influenza Vaccine
Arm/Group Description High Dose Influenza Vaccine High Dose Trivalent Influenza Vaccine: High Dose Trivalent Influenza Vaccine; Note: primary analysis is of participant-seasons (n = 3577) Standard Dose Influenza Vaccine Standard Dose Quadrivalent Influenza Vaccine: Standard Dose Quadrivalent Influenza Vaccine; Note: primary analysis is of participant-seasons (n = 3577)
Measure Participants 2630 2630
Measure Participant-Seasons 3577 3577
Count of Units [Participant-Seasons]
805
752
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection High Dose Influenza Vaccine, Standard Dose Influenza Vaccine
Comments Each participant can be analyzed up to three times (seasons)
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.16
Comments
Method Regression, Cox
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.08
Confidence Interval (2-Sided) 95%
.97 to 1.2
Parameter Dispersion Type:
Value:
Estimation Comments
4. Secondary Outcome
Title Death or Cardiopulmonary Hospitalization Across Enrolling Seasons
Description First cardiopulmonary Hospitalization or all-cause death across enrolling seasons
Time Frame Up to three years

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title High Dose Influenza Vaccine Standard Dose Influenza Vaccine
Arm/Group Description High Dose Influenza Vaccine High Dose Trivalent Influenza Vaccine: High Dose Trivalent Influenza Vaccine Standard Dose Influenza Vaccine Standard Dose Quadrivalent Influenza Vaccine: Standard Dose Quadrivalent Influenza Vaccine
Measure Participants 2630 2630
Number [first CP hospitalization/death]
955
918
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection High Dose Influenza Vaccine, Standard Dose Influenza Vaccine
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.26
Comments
Method Regression, Cox
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.05
Confidence Interval (2-Sided) 95%
.96 to 1.15
Parameter Dispersion Type:
Value:
Estimation Comments
5. Secondary Outcome
Title All-Cause Mortality
Description Number of patients with first occurrence of all-cause mortality
Time Frame Up to 3 years

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title High Dose Influenza Vaccine Standard Dose Influenza Vaccine
Arm/Group Description High Dose Influenza Vaccine High Dose Trivalent Influenza Vaccine: High Dose Trivalent Influenza Vaccine Standard Dose Influenza Vaccine Standard Dose Quadrivalent Influenza Vaccine: Standard Dose Quadrivalent Influenza Vaccine
Measure Participants 2630 2630
Number [All cause deaths]
223
222
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection High Dose Influenza Vaccine, Standard Dose Influenza Vaccine
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.96
Comments
Method Regression, Cox
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.01
Confidence Interval (2-Sided) 95%
0.84 to 1.21
Parameter Dispersion Type:
Value:
Estimation Comments

Adverse Events

Time Frame 1 week for post-vaccination adverse events; 1-3 years, depending on length of participation for serious adverse events
Adverse Event Reporting Description Post-vaccination AEs were collected via participant self report up to 1 week post vaccination. Potential SAEs during study participation were reviewed by study monitors. For all-cause mortality, the number of patients at risk are the total number of patients randomized who were included in the efficacy analyses: 2630 per group. For all other adverse events, the safety analysis set consists of patients who received study vaccination (2606 in high-dose group and 2604 in standard-dose group).
Arm/Group Title High Dose Influenza Vaccine Standard Dose Influenza Vaccine
Arm/Group Description High Dose Influenza Vaccine High Dose Trivalent Influenza Vaccine: High Dose Trivalent Influenza Vaccine Standard Dose Influenza Vaccine Standard Dose Quadrivalent Influenza Vaccine: Standard Dose Quadrivalent Influenza Vaccine
All Cause Mortality
High Dose Influenza Vaccine Standard Dose Influenza Vaccine
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 223/2630 (8.5%) 222/2630 (8.4%)
Serious Adverse Events
High Dose Influenza Vaccine Standard Dose Influenza Vaccine
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 2/2606 (0.1%) 4/2604 (0.2%)
Cardiac disorders
Cardiac Arrest 1/2606 (0%) 1 0/2604 (0%) 0
Gastrointestinal disorders
Dysgusia 0/2606 (0%) 0 1/2604 (0%) 1
General disorders
Fever 1/2606 (0%) 1 0/2604 (0%) 0
Nervous system disorders
Bell's Palsy 0/2606 (0%) 0 1/2604 (0%) 1
Neuritis 0/2606 (0%) 0 1/2604 (0%) 1
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure 0/2606 (0%) 0 1/2604 (0%) 1
Other (Not Including Serious) Adverse Events
High Dose Influenza Vaccine Standard Dose Influenza Vaccine
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 1241/2606 (47.6%) 1096/2604 (42.1%)
General disorders
Myalgia 447/2606 (17.2%) 500 391/2604 (15%) 423
Overall Discomfort 290/2606 (11.1%) 310 266/2604 (10.2%) 280
Headache 265/2606 (10.2%) 279 253/2604 (9.7%) 272
Injury, poisoning and procedural complications
Pain at injection site 788/2606 (30.2%) 932 594/2604 (22.8%) 683
Swelling 179/2606 (6.9%) 198 115/2604 (4.4%) 119
Erythema 144/2606 (5.5%) 157 150/2604 (5.8%) 157

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title Dr. Scott Solomon
Organization Brigham and Women's Hospital
Phone 857-307-1960
Email ssolomon@bwh.harvard.edu
Responsible Party:
Scott David Solomon, Professor of Medicine, Brigham and Women's Hospital
ClinicalTrials.gov Identifier:
NCT02787044
Other Study ID Numbers:
  • 2015P001823
  • U01HL130163
First Posted:
Jun 1, 2016
Last Update Posted:
Jan 21, 2022
Last Verified:
Dec 1, 2021