high-dose vs standard dose influenza vaccine in elderly

 a recent large RCT found that patients at particularly high risk of cardiovascular disease did not seem to benefit clinically from high dose vs standard dose influenza vaccine, in the INVESTED trial, though their conclusion is highly suspect... (see influenza high dose not dec mortality jama2020 in dropbox or doi:10.1001/jama.2020.23649) 

 

Details: 

-- 5260 participants were randomized to receive high-dose trivalent influenza vaccine vs regular quadrivalent inactivated influenza vaccine, and could be revaccinated for up to 3 seasons. In a pragmatic, multicenter trial in 157 sites in the US and Canada between September 2016 and February 2019 

-- study patients all had had an acute MI in the past 12 months or heart failure hospitalization in the past 24 months, and at least one additional risk factor (see below)

-- mean age 66, 72% men, 63% with heart failure, 78% white/15% Black/3% Asian/10% Latinx, LVEF 42%, BMI 31 

-- risk factors: age>65 57%, BMI>30 49%, LVEF<40% 42%, diabetes 37%, eGFR<60 30%, current smoker 17%, prior heart failure hospitalization 70%, prior MI 14% (1 risk factor in 21%, 2 risk factors in 27%, 3 risk factors in 24%, at least 4 risk factors in 28%).  NYHA functional class 1: 70%/2: 48%/3: 28% 

-- other comorbidities: hypertension 77%, dyslipidemia 69%, PCI 41%,  atrial fibrillation 33%, CABG 20%, COPD 19%, ICD implanted 18%, asthma 11%  

-- 7154 total vaccinations were administered and 99% of patients completed the trial 

-- primary outcome: time to the composite of all-cause death or cardiopulmonary hospitalization during each enrolling season; analysis was only on those receiving vaccinations in any given year with events accrued from 14 days after vaccination until July 31 of each enrolling season 

 

Results: 

-- high-dose vaccination group: 975 primary outcomes (883 hospitalizations for cardiovascular or pulmonary causes, 92 deaths from any cause) among 884 participants during 3577 participant seasons, event rate 45 per 100 patient-yrs 

-- standard dose quadrivalent vaccine group: 924 primary outcome events (846 hospitalizations for cardiovascular or pulmonary causes and 78 deaths from any cause) among 837 participants during 3577 participant seasons, event rate 42 per100 patient-yrs 

     -- nonsignificant difference, hazard ratio 1.06 (0.97-1.17), p=0.21 

-- results were similar for each component of the primary outcome and within each enrolling season 

    -- cardiovascular deaths or hospitalization for heart failure: high-dose 36 per 100 person-yrs vs standard dose 33 per 100 person-yrs, HR 1.08 (0.97-1.20) 

    -- all-cause death: high-dose 7.8 per 100 person-yrs vs low dose 7.7 per 100 person-yrs, HR 1.01 (0.84-1.21) 

--post hoc analysis of the primary endpoints:  

    -- attributable to influenza: 10 in high-dose and 8 in standard dose groups [pretty shockingly low numbers of patients were actually found to have influenza]

    -- attributable to pneumonia: 47 and high-dose group and 41 in the standard dose group 

-- vaccine-related adverse reactions: high-dose 1449 (40.5%) vs standard dose 1229 (34.4%) of participants, primarily related to injection site pain (27%), myalgia (80%), and swelling (6%) 

    -- severe adverse reactions occurred in 55 (2.1%) vs 44 (1.7%) 

 

Commentary: 

-- the study yielded the perhaps surprising result that patients at very high risk for cardiovascular and all-cause mortality (recent MI or heart failure hospitalization) did not find clinical benefit in terms of cardiopulmonary hospitalizations or for all-cause mortality with the high-dose influenza vaccine 

-- prior randomized clinical trials have documented lower risk of major adverse cardiovascular events through influenza vaccination 

-- the high-dose vaccine does elicit a higher antibody response, which with standard dose vaccine tends to be lower in older people as well as in those with known cardiovascular disease

-- high-dose influenza vaccine has 4 times the amount of hemagglutinin and large randomized clinical trials have found reduced laboratory-confirmed symptomatic influenza in the elderly (eg see https://www.nejm.org/doi/full/10.1056/NEJMoa1315727?query=featured_home , or https://www.thelancet.com/journals/lanres/article/PIIS2213-2600%2817%2930235-7/fulltext )

-- the study did include a quadrivalent standard vaccine, and some of the prior studies finding superiority of the high-dose vaccine compared it to trivalent influenza vaccines, raising the possibility that it is that 4th influenza type in the regular vaccine that improves its effectiveness to that of the high-dose one

   -- BUT, in the last year of comparison, which still had the same outcome equipoise between the 2 vaccines, only 1% of influenza illnesses were caused by that 4^thvaccine type

-- also, of note in those years studied in INVESTED,  the vaccine effectiveness overall was particularly low (29 to 40% overall, and even lower in those >65yo at 12 to 20%), which would attenuate any of the potential difference between these different vaccine formulations 

-- Though almost all of primary endpoints in the above INVESTED trial were related to non-influenza/non-pneumonia causes, the study did suggest a few things: 

-- these very high-risk patients for influenza are at really high risk for severe cardiopulmonary events

    -- though, importantly, this study does not include data on influenza illnesses that were less severe 

    --and, this study confirmed that very few people had a primary outcome with actual documented influenza (did influenza play any role in the bad outcomes??)

        -- it was notable that in those with an MI as index event: 94% were on statins, 91% on aspirin, and 86% were on beta blockers 

        -- and, for those with a heart failure index event, 85% on beta blockers, 79% on diuretics, 67% on an ACE inhibitor/ARB/ARNI, 34% on a mineralocorticoid receptor antagonist, and 10% were on digoxin

            --these meds suggest that these patients may have been undertreated for their cardiac disease (though, unfortunately, there was not enough granular data to know for sure about the heart failure treatment, since we do not know if they had heart failure with reduced vs preserved ejection fractions)

            --and, we also have no information about the nonpharmacologic therapies: weight control, diet, exercise, stress relief, income/other inequalities, depression.....

        --so, all of this reinforces the primacy of aggressive treatment for the underlying cardiac condition. 

    -- therefore, these points do not undercut the potential benefit of high-dose influenza vaccine in preventing influenzal disease or significant morbidity, just that those with very serious cardiac conditions are much more likely to be hospitalized or die from these underlying conditions than from influenza-related problem 

Limitations: 

-- influenza infection was not specifically assessed in all of these patients; so, we do not have accurate information as to whether influenza infection was reduced in this pragmatic trial

    --and, given the remarkably low numbers of people getting documented influenza, it is very hard to generalize their conclusion that high-dose vaccines are not beneficial 

-- this trial did not include in unvaccinated control group (would be a tad unethical), so we don’t have clear information suggesting that either vaccine was better than placebo for these years

-- and, there was no information about the potential benefit of high-dose vaccine in decreasing less severe influenza-related events than those assessed in this study

-- the current recommendations for the high-dose vaccine is for those >65yo. only 57% in this study were in that age bracket. so, this study does not reflect the current recommendations and there was no subgroup breakdown to see if those >65yo fared differently from the younger cohort (where the difference between the two vaccination doses has not been widely validated)

 

So, not a great study, and with limited generalizability/utility. But it brings up a few issues: 

-- in studies such as this, it is hard to really interpret the data without a placebo control. These were years where vaccine efficacy was low, so there is less ability to attribute a decrease in morbidity/mortality to the use of any vaccine. And, it seemed that very few in this study actually got influenza anyway  

-- these individuals were at high risk for a recurring cardiovascular event, perhaps made higher by what may have been suboptimal cardiovascular therapy

-- i am concerned that this study, which i do not think merits much attention, might lead clinicians or patients to have less enthusiasm for the flu vaccine, and undercut what seems to be the pretty clear superiority of the high-dose vaccine 

     --of note, the CDC makes a strong argument that the high-dose vaccine is better, but they do not recommend it exclusively:  it is more important to get a vaccine than not. so if the high-dose one is not available, okay to give the standard dose one (see https://www.cdc.gov/flu/prevent/qa_fluzone.htm )      --so, one of the reasons i reviewed this study is to bring up these concerns with the study, which really do NOT support their conclusions

--and, the review in Physician's First Watch, for example, is uncritical, with headline on 12/6/20: "High-Dose Flu Shot No Better Than Standard Shot in High-Risk CVD Patients" and NO critical analysis

    --we clinicians are bombarded with so many studies that could/should affect our clinical practice, cannot come close to reading them all, and often have to incorporate brief summaries or conclusions from study abstracts or brief reviews by Physician's First Watch, etc (which usually are quite reasonable) into our clinical algorithms. So, strong uncritical statements may well hold sway (and, in the course of these many blogs, it happens not-so-rarely that the abstract and content of the article are at odds with each other)

    --and, i think there seems be more influence of the newest study on the block, as almost a negation of former studies. Older studies may well be better, more generalizable/applicable, and should sometimes have much more clinical influence over the newer ones....

so, the main reason i reviewed this really not-so-useful study was to share my concerns about this specific study, we well as these larger issues of interpreting the literature. and to help with the message that flu shots, including these high-dose ones in the elderly, are important

geoff

 

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