What can we learn from observational studies of oseltamivir to treat influenza in healthy adults?
BMJ 2009; 339 doi: https://doi.org/10.1136/bmj.b5248 (Published 08 December 2009) Cite this as: BMJ 2009;339:b5248
All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
The BMJ articles and the new Cochrane report do not really tell us any more about the response to oseltamivir than we knew before. In essence, it might not have a major impact on complication rate in healthy adults, but then again, the available data indicate it just might. No-one can be sure yet, and Cochrane says so. And because these studies include very few patients who are in risk groups for complications of flu they are unable to comment of the use in this situation. These studies also include lots of patients who don't even have flu in the first place, and admittedly it will always be hard to demonstrate drug efficacy in treating flu when the studies are diluted by the inclusion of more people without the flu than actually have it in the first place.
Freemantle and Calvert's review indicates that other studies indicate there is a likely benefit. Again, this is for healthy adults.
National Policy and medical advice is for healthy adults to suffer their flu in silence, without taking oseltamivir. Yet for those at greatest risk of complications, observational evidence supports use of oseltamivir and it should continue to be used in this situation.
So what have the public and the media made of this (not so) news? If the internet is anything to go by, it would seem that oseltamivir is regarded as next to useless. The quality press is hardly any better, with The Times claiming: "There is no clear evidence that Tamiflu prevents complications in people with flu, an analysis suggests."
That should really read: "There is no clear evidence that Tamiflu prevents complications in healthy adults with flu, but equally there is no clear evidence that it doesn't, and there is evidence it prevents complications in patients at greatest risk."
Thanks to scurrilous scaremongering in the media about the supposed complications of the vaccine, we have had a hard time explaining its benefits to those at most risk from pandemic flu. Now I suspect that those who get flu as a result will refuse to contemplate treatment. Is it any wonder some of us have such a low opinion of the reporting of science in the media, and the way in which it is communicated to the public?
(1) http://www.timesonline.co.uk/tol/news/uk/health/Swine_flu/article6949293...
Competing interests:
None declared
Competing interests: No competing interests
It is appropriate that Freemantle and Calvert carefully discuss the
observational studies of oseltamivir [1] and yet I am afraid it is
inappropriate to conclude that oseltamivir may reduce the risk of
pneumonia in otherwise healthy people who contract flu, because potential
major two risk factors that might deteriorate the outcome of influenza are
not discussed at all (on NSAIDs) or little discussed (on oseltamivir). I
would like to discuss the former issue in this rapid response and the
latter in the next.
As for aspirin in the 1918 influenza pandemic [2,3], non-steroidal
anti-inflammatory drugs (NSAIDs) are suspected as one of the most
important deteriorating causes in not only seasonal influenza but also in
09AH1N1 influenza [4-6].
One of the major features of died patients during acute phase of
influenza not only in 09AH1N1 influenza but also in 1918 pandemic is
progression to acute lung injury or acute respiratory distress syndrome
(ARDS) with multiorgan system failure (MOF) which is induced by
hypercytokinemia without major bacterial infection [3,7].
NSAIDs promote induction of hypercytokinemia and increase mortality
of infected animals: pooled Peto odds ratio (OR) using the results of 16
animal experiments including ibuprofen and aspirin is 7.68 (95 %CI:
4.70,12.56, p=0.00000) [4, 5].
Many case-control studies revealed that aspirin is the major risk
factor of Reye's syndrome (odds ratio 10 to 40) and that NSAIDs use is
that of fatal influenza-associated encephalopathy (odds ratio 47) [4].
In a randomized controlled trials (RCTs) of oseltamivir for treatment
influenza done in Japan, pharmaceutical companies recommended not to use
NSAIDs concomitantly with oseltamivir (paracetamol was allowed to use)
[8]. However, among 251 participants 27 used NSAIDs. The average time to
resolution of symptoms of 27 NSAIDs users were estimated 5.8 days compared
with 4.4 days in 224 non-users. Among 121 who were given Tamiflu, 5.5 days
in 11 NSAIDs users compared with 3.9 days in 110 NSAIDs non-users. Among
130 who were given Tamiflu, 6.0 days in 16 NSAIDs users compared with 4.9
days in 114 NSAIDs non-users [9].
These differences in average time to resolution of symptoms may not
be significant, but well coincides with the evidence indicated above
(aspirin in Rey�fs syndrome, NSAIDs in fatal encephalopathy and NSAIDs in
infected animals).
So the pharmaceutical companies have well known the adverse effects
of NSAIDs use in influenza, even if oseltamivir were used.
One study [10] referred by Freemantle and Calvert [1] compared the
use of analgesics and antipyretic, but only of baseline use and not the
use of antipyretics for the symptomatic treatment of influenza. Thus, none
of the referred papers compared the use of NSAIDs between the groups in
case control studies or between oseltamivir users and non users in cohort
studies before deterioration of influenza.
I do not know the reason why no case-control study nor cohort study
compared the use of NSAIDs in order to show the beneficial effects of
Tamiflu, while the use of NSAIDs in the RCT of Tamiflu were restricted.
However, we should carefully consider that any observational studies
may be useless in order to assess the efficacy and safety of antiviral
agents unless data for NSAIDs use as antipyretics for influenza are
obtained and examined.
References
1) Freemantle N and Calvert M. What can we learn from observational
studies of oseltamivir to treat influenza in healthy adults? BMJ 2009 339:
b5248.
2) Shimazu T. A/H1N1 flu. Aspirin in the 1918 pandemic. BMJ. 2009 Jun
15;338:b2398. doi: 10.1136/bmj.b2398.
3) Starko KM. Salicylates and pandemic influenza mortality, 1918-1919
pharmacology, pathology, and historic evidence. Clin Infect Dis. 2009 Nov
1;49(9):1405-10.
4) Hama R. Fatal neuropsychiatric adverse reactions to oseltamivir?F
case series and overview of causal relationships. Internat J Risk Safety
Med 2008;20:5-36. : available at : http://npojip.org/english/no11.html
5) Hama R. A/H1N1 flu. NSAIDs and flu. BMJ. 2009 Jun 15;338:b2345.
doi: 10.1136/bmj.b2345.
6) Herxheimer A, Clarke M, Edwards R, Jefferson T, Loke Y. A/H1N1
flu. Time for case-control studies of NSAIDs and oseltamivir. BMJ. 2009
Jul 28;339:b3048. doi: 10.1136/bmj.b3048.
7) Perez-Padilla R and the INER Working Group on Influenza. Pneumonia
and Respiratory Failure from Swine-Origin Influenza A (H1N1) in Mexico. N
Engl J Med. 2009 Jun 29. (Epub ahead of print)
8) Chugai Pharm Co (2000) New drug approval package (NAP) of
oseltmivir (in Japanese); Tamiflu capsule for treatment (in Japanese):
available at
http://211.132.8.246/shinyaku/g0012/07/53039900_21200AMY00238.html
9) Hama R. Influenza, NSAIDs antipyretics and oseltamivir. The
Informed Prescriber 2003: 18 (11): 129-133 (in Japanese).
10) Orzeck EA, Shi N, Blumentals WA. Oseltamivir and the Risk of
Influenza-Related Complications and Hospitalizations in Patients with
Diabetes. Clin Ther 2007;29:2246-55
Competing interests:
None declared
Competing interests: No competing interests
Oseltamivir is not only ineffective but also harmful: that's the matter
As I wrote in several rapid responses [1-6] and in a paper on a case
series and overview of adverse reactions to oseltamivir [7], it is not
merely the matter that it is ineffective (at least no proof of efficacy
and effectiveness) to prevent complication for otherwise healthy people
and no proof to prevent complication for people with underling diseases,
More serious problem is the harmful effects of oseltamivir. For
example there is substantial evidence that major psychotic and/or
psychiatric reactions, renal and diabetic complications were significantly
more observed in oseltamivir group when used in the randomized controlled
trials (RCTs) for prevention of influenza targeted otherwise healthy
people [1].
Moreover, early use [2, 3] and late use [4, 5] are both related to
serious harmful effects on survival if users have hypercytokinemia. It
does not depend on the patients' risk situations. However, if they have
severe hypercytokinemia induced in various complications of influenza such
as acute respiratory failure, encephalopathy, sepsis with multi-organ
failures, oseltamivir may affect more seriously: please see the attached
figure of reference [4].
It is risky not only in those people who have complications of
influenza but also in people who have underlying diseases before infection
with influenza. For example, central nervous system may be easily
depressed by the unchanged oseltamivir in patients who have nervous system
disorders resulting in sudden respiratory arrest. Sleep apnea may be
enhanced in extremely obese people resulting sudden death during sleep.
Respiratory failure may be enhanced in patients who are suffering
pulmonary complication and/or cardiac diseases if respiration is depressed
causing hypoxemia. Plasma and brain concentration of unchanged oseltamivir
may increase in patients with liver failure such as liver cirrhosis
because of decreased metabolism of oseltamivir to oseltamivir carboxylate
(OC). Plasma concentration of OC increases six times higher than that in
those who has normal renal function by a single dose in patients who are
under hemodialysis it may cause various complications [7].
Moreover, note that more unweaned animals [7], pregnant
animals and newborn animals that were exposed
to oseltamivir during pregnancy [8, 9] die significantly and dose-
dependently. It is consistent with the results of pregnant women's deaths
[4] reported from the United States [10].
I would like to conclude that it should be remembered that the real
matter is the harm of oseltamivir.
references
1.Hama R. Oseltamivir: psychotic and neurological adverse reactions
in the randomized controlled trials
http://www.bmj.com/cgi/eletters/339/dec07_2/b5106#227187
2.Hama R. Early use of oseltamivir: a case of respiratory depression
after each of two doses, with sudden death. Rapid response:
http://www.bmj.com/cgi/eletters/339/nov13_2/b4831#227027
3.Hama R. Early use of oseltamivir and deaths in 09A-flu
http://www.bmj.com/cgi/eletters/339/dec07_2/b5106#227726
4.Hama R. Oseltamivir: early use and late use are both related to
harmful effects especially in hypercytokinemia in patients with or without
risk.
http://www.bmj.com/cgi/eletters/339/dec07_2/b5106#227363
5.Hama R. Another evidence on association of oseltamivir and death in
09A flu http://www.bmj.com/cgi/eletters/339/dec07_2/b5106#227747
6.Hama R. What can we learn from observational studies of oseltamivir
without examining NSAIDs use?
http://www.bmj.com/cgi/eletters/339/dec07_2/b5248#227268
7.Hama R. Fatal neuropsychiatric adverse reactions to oseltamivir?F
case series and overview of causal relationships. Internat J Risk Safety
Med 2008;20:5-36. : available at : http://npojip.org/english/no11.html
8. Hama R. Oseltamivir (Tamiflu) is harmful for pregnant women (1).
The Informed Prescriber: 2009: 24 (6): 66-70.(in Japanese)
9. Hama R. Oseltamivir (Tamiflu) is harmful for pregnant women (2).
The Informed Prescriber: 2009: 24 (7): 77-82.(in Japanese)
10. Novel Influenza A (H1N1) Pregnancy Working Group. Jamieson DJ,
Honein MA, Rasmussen SA, H1N1 2009 influenza virus infection during
pregnancy in the USA. Lancet. 2009 Aug 8;374(9688):451-8. Epub 2009 Jul
28.
Competing interests:
None declared
Competing interests: No competing interests