INVESTED: INfluenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure
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 |
---|---|---|
|
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
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
- 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
- Total Cardiopulmonary Hospitalizations or Death [Up to 3 years]
Total (first and recurrent) cardiopulmonary hospitalizations or death
- 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
- Death or Cardiopulmonary Hospitalization Across Enrolling Seasons [Up to three years]
First cardiopulmonary Hospitalization or all-cause death across enrolling seasons
- All-Cause Mortality [Up to 3 years]
Number of patients with first occurrence of all-cause mortality
Eligibility Criteria
Criteria
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
- Albrecht CM, Sweitzer NK, Johnson MR, Vardeny O. Lack of persistence of influenza vaccine antibody titers in patients with heart failure. J Card Fail. 2014 Feb;20(2):105-9. doi: 10.1016/j.cardfail.2013.12.008. Epub 2013 Dec 19.
- Udell JA, Farkouh ME, Solomon SD, Vardeny O. Does influenza vaccination influence cardiovascular complications? Expert Rev Cardiovasc Ther. 2015 Jun;13(6):593-6. doi: 10.1586/14779072.2015.1044439. Epub 2015 May 14.
- Udell JA, Zawi R, Bhatt DL, Keshtkar-Jahromi M, Gaughran F, Phrommintikul A, Ciszewski A, Vakili H, Hoffman EB, Farkouh ME, Cannon CP. Association between influenza vaccination and cardiovascular outcomes in high-risk patients: a meta-analysis. JAMA. 2013 Oct 23;310(16):1711-20. doi: 10.1001/jama.2013.279206.
- Van Ermen A, Hermanson MP, Moran JM, Sweitzer NK, Johnson MR, Vardeny O. Double dose vs. standard dose influenza vaccination in patients with heart failure: a pilot study. Eur J Heart Fail. 2013 May;15(5):560-4. doi: 10.1093/eurjhf/hfs207. Epub 2013 Jan 4.
- Vardeny O, Claggett B, Udell JA, Packer M, Zile M, Rouleau J, Swedberg K, Desai AS, Lefkowitz M, Shi V, McMurray JJV, Solomon SD; PARADIGM-HF Investigators. Influenza Vaccination in Patients With Chronic Heart Failure: The PARADIGM-HF Trial. JACC Heart Fail. 2016 Feb;4(2):152-158. doi: 10.1016/j.jchf.2015.10.012. Epub 2015 Dec 30.
- Vardeny O, Moran JJ, Sweitzer NK, Johnson MR, Hayney MS. Decreased T-cell responses to influenza vaccination in patients with heart failure. Pharmacotherapy. 2010 Jan;30(1):10-6. doi: 10.1592/phco.30.1.10.
- Vardeny O, Sweitzer NK, Detry MA, Moran JM, Johnson MR, Hayney MS. Decreased immune responses to influenza vaccination in patients with heart failure. J Card Fail. 2009 May;15(4):368-73. doi: 10.1016/j.cardfail.2008.11.009. Epub 2008 Dec 18.
- Vardeny O, Udell JA, Joseph J, Farkouh ME, Hernandez AF, McGeer AJ, Talbot HK, Bhatt DL, Cannon CP, Goodman SG, Anand I, DeMets DL, Temte J, Wittes J, Nichol K, Yancy CW, Gaziano JM, Cooper LS, Kim K, Solomon SD. High-dose influenza vaccine to reduce clinical outcomes in high-risk cardiovascular patients: Rationale and design of the INVESTED trial. Am Heart J. 2018 Aug;202:97-103. doi: 10.1016/j.ahj.2018.05.007. Epub 2018 May 23.
- 2015P001823
- U01HL130163
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
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 |
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 |
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 |
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 |
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
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 |
ssolomon@bwh.harvard.edu |
- 2015P001823
- U01HL130163