Showing posts with label Cochrane. Show all posts
Showing posts with label Cochrane. Show all posts

Wednesday, April 30, 2014

Sandman & Lanard On The Cochrane Tamiflu Report

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# 8550

 

Somehow, with all of the MERS news coming out of the Middle East, I managed to miss a terrific piece of analysis by our favorite Risk Communications experts, Dr. Peter Sandman and Dr. Jody Lanard,  published last week on the The Peter M. Sandman Risk Communication Website.

 

Their website is a repository of invaluable risk management advice, that quite frankly should be second home for anyone involved in public relations or risk communications.

Peter Sandman Website logo

 

I’ve highlighted their work often in the past,including Sandman & Lanard: WHO, Pandemic Phases & Public Preparedness, Sandman: A Tale Of Two CDCs, Lanard: China’s Risk Communication On H7N9, and Referral: Sandman On The H5N1 Moratorium.

 

Their latest analysis centers on the  recent release of (and media hype surrounding) a recent Cochrane group analysis that found insufficient evidence to show whether Oseltamivir (Tamiflu ®)  and other NAI antivirals reduces influenza complications and transmission. 

 

I wrote about  this report earlier this month in  Revisiting Tamiflu Efficacy (Again) & The CDC Responds To The Cochrane Tamiflu Study, where I posited the preponderance of evidence supports the use of NAI antivirals for severe influenza.

 

Early last week Declan Butler, writing for the Journal Nature, wrote a piece called Tamiflu report comes under fire, for which Sandman & Lanard have supplied some quotes. Building on their emailed comments to Butler, they penned and posted a longer analysis on their website the following day.

 

Since it would do an injustice to the authors to try to excerpt highlights, I would simply suggest you follow the link below to read it in its entirety. 

 

Overstated Attack Hiding Behind Scientific Assessment: An April 2014 Cochrane Review Trashes the Usefulness of Influenza Antiviral Drugs

by Peter M. Sandman and Jody Lanard

(an April 15, 2014 email responding to Declan Butler of Nature)

Declan Butler’s April 22, 2014 article drew from this email.

Introductory Note

In early April 2014, the Cochrane Collective published two journal articles and a news release that went out of their way to understate the value of Tamiflu and Relenza, the two antiviral drugs used against influenza. When Nature reporter Declan Butler asked for our comment, we quickly sent back the short email posted below.

 

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The Sandman site is a treasure trove of risk communications information, and you could literally spend days just hitting the highlights. 

 

Highly recommended.

Thursday, April 10, 2014

The CDC Responds To The Cochrane Tamiflu Study

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Photo Credit CDC

 


# 8457

 

Earlier today, in Revisiting Tamiflu Efficacy (Again), I wrote at some length on the BMJ –  Cochrane Library review Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children – that examined a subset of the scientific literature and cast doubt on its effectiveness in treating influenza.

While I too lamented the lack of solid, well mounted Randomized controlled trials (RCTs) proving the effectiveness of Oseltamivir (particularly in high risk patients, or with novel flu strains), I listed a number observational studies that strongly support the effectiveness of Oseltamivir.


But you don’t have to take my word for it.  This afternoon the CDC, has issued their own response. I’ve posted the link and some excerpts below.  Follow the link to read their rationale in its entirety.

 

CDC Recommendations for Influenza Antiviral Medications Remain Unchanged

April 10, 2014 -- CDC continues to recommend the use of the neuraminidase inhibitor antiviral drugs (oral oseltamivir and inhaled zanamivir) as an important adjunct to influenza vaccination in the treatment of influenza. CDC’s current influenza antiviral recommendations are available on the CDC website and are based on all available data, including the most recent Cochrane report, about the benefits of antiviral drugs in treating influenza.

 

CDC considers all of the published evidence available from Randomized Control Trials (RCT) conducted among outpatients and observational studies conducted among hospitalized patients, including benefits and risks from safety data, when issuing recommendations on antiviral treatment of influenza. These CDC recommendations emphasize early antiviral treatment as soon as possible for patients who are severely ill and for those who are at greatest risk for complications from influenza. This includes hospitalized patients with suspected or confirmed influenza, those with severe or progressive illness, and outpatients who are at high risk for influenza complications (for example, young children, people aged 65 years and older, pregnant women, and persons with certain underlying chronic medical conditions). In addition, because other reviews of RCTs and observational studies have found consistent clinical benefit of early oseltamivir treatment in reducing the risk of lower respiratory tract complications such as those requiring antibiotics, persons with uncomplicated influenza who are not in a high risk group and who present within 48 hours of illness onset can be treated with antiviral medications based upon clinical judgment.

 

One large study that was published recently, “Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A(H1N1pdm09) virus infection: a meta-analysis of individual participant data”, adds to the growing body of evidence which supports that neuraminidase inhibitor treatment can reduce the risk of death in hospitalized patients with influenza.  In this meta-analysis of published studies, researchers compiled individual-level data from 78 observational studies across 38 countries on more than 29,000 patients who were hospitalized with 2009 H1N1 influenza virus infection during the 2009-10 pandemic. In this study among patients aged >16 years, treatment with a neuraminidase inhibitor antiviral drug was associated with a 25% reduction in the likelihood of death compared to no antiviral treatment. Early treatment with neuraminidase inhibitor antiviral drugs (i.e., within 48 hours of development of influenza illness) halved the risk of death compared to no antiviral treatment. This confirms findings from previous observational studies in hospitalized influenza patients that the clinical benefit of neuraminidase inhibitor antiviral treatment is greatest when started within two days of influenza illness onset.

 

A review of RCT data for the influenza neuraminidase inhibitor antiviral medications published by the Cochrane Collaboration updates a previous Cochrane review published in 2012, and raises questions about the value of antiviral medications for the prevention and treatment of influenza. The updated Cochrane review assessed full internal clinical study reports from manufacturers containing published and unpublished data from 46 randomized controlled trials (RCTs) of oral oseltamivir or inhaled zanamivir versus placebo for preventing and treating outpatients with mild illness who were otherwise healthy adults and children. The review concluded that in adults and children with influenza-like illness, early oral oseltamivir treatment shortens the duration of symptoms by approximately 17 hours and 29 hours, respectively, compared to placebo. This finding is similar to results in previously published RCTs which reported a reduction of approximately one day of laboratory-confirmed uncomplicated influenza illness in outpatients by early oral oseltamivir treatment verus placebo. One RCT in outpatients who were aged 1 to 3 years with uncomplicated influenza found a reduction of 3.5 days when oral oseltamivir treatment was started within 24 hours after illness onset. The Cochrane review concluded that inhaled zanamivir reduced symptoms in adults by approximately half a day compared to placebo, but had no significant effect in children. The Cochrane review reported no significant effect of oral oseltamivir treatment of outpatients on hospitalizations for adults or children, and the authors conclude that the treatment trials do not settle the question of whether the complications of influenza are reduced by treatment in outpatients because of a lack of diagnostic definitions.

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Revisiting Tamiflu Efficacy (Again)

 

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# 8455

 

Just over two years ago in The Tamiflu Controversy Continues, we looked at the ongoing debate over the effectiveness of oseltamivir (Tamiflu ®) in the wake of the release of a Cochrane group analysis that found insufficient evidence to show whether the drug reduces influenza complications and transmission.

 

Three weeks later the CDC responded with a statement on their Have You Heard? website, which published their rationale for continuing to recommend the use of Oseltamivir for severe influenza.

 

CDC Recommendations for Influenza Antiviral Medications Remain Unchanged

February 7, 2012 -- A recent review of randomized clinical trial data for the influenza neuraminidase inhibitor antiviral medications published by the Cochrane Collaboration, and two related commentaries [“Rethinking credible evidence synthesis” and “Questions Remain over safety and effectiveness of oseltamivir”] published in the British Medical Journal, raised questions about the value of antiviral medications for the prevention and treatment of influenza. After careful consideration of all available evidence, CDC guidance on the use of antiviral medications remains unchanged. The Centers for Disease Control and Prevention (CDC) continues to recommend the use of the neuraminidase inhibitor antiviral drugs (oral oseltamivir and inhaled zanamivir) as an important adjunct in the prevention and treatment of influenza.

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Since then the CDC and the World Health Organization have continued to promote Oseltamivir and other NAI antivirals as important drugs in our limited arsenal against the influenza virus (see November 2013 CDC Research On Benefits Of Antivirals For Uncomplicated Influenza).

 

Yesterday the BMJ and the Cochrane Group published a new assessment of the antiviral drug Tamiflu, and as they have in the past, cast doubts on its efficacy and on the wisdom of governments around the world stockpiling the drug.

The entire study is available online. You’ll find the link and a small excerpt below:

 

Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments

BMJ 2014; 348 doi: http://dx.doi.org/10.1136/bmj.g2545 (Published 10 April 2014)

Cite this as: BMJ 2014;348:g2545

Tom Jefferson, reviewer, Mark Jones, senior research fellow (biostatistics), Peter Doshi, assistant professor, Elizabeth A Spencer, nutritional epidemiologist, Igho Onakpoya, research fellow in evidence-based practice and pharmacovigilance, Carl J Heneghan, professor

Conclusions In prophylactic studies oseltamivir reduces the proportion of symptomatic influenza. In treatment studies it also modestly reduces the time to first alleviation of symptoms, but it causes nausea and vomiting and increases the risk of headaches and renal and psychiatric syndromes. The evidence of clinically significant effects on complications and viral transmission is limited because of rarity of such events and problems with study design. The trade-off between benefits and harms should be borne in mind when making decisions to use oseltamivir for treatment, prophylaxis, or stockpiling.

The Cochrane Summary is available at:

 

Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children

Editorial Group: Cochrane Acute Respiratory Infections Group

Published Online: 10 APR 2014

 

While research purists may applaud their methods, the problem that I (and many others) have with this analysis is that the Cochrane group set the bar very high as to what studies they would consider, excluding many observational studies.

 

Randomized controlled trials (RCTs) are considered the `gold standard’  for drug research, but these types of studies are expensive and notoriously difficult to conduct ethically when trying to evaluate a potentially life saving drug.

 

Overnight some elements of the British press have morphed their findings into incendiary headlines, such as this one from the Daily Mail: Ministers blew £650MILLION on useless anti-flu drugs.

 

Much of this ire has been well-earned through Roche’s long-standing resistance to releasing all of the testing data on their antiviral drug, and that has led to critical editorials in the BMJ, and frequent excoriation in the British press.

 

For a different perspective, we turn to NBC’s Senior health writer Maggie Fox, who spoke to doctors whose job it is to treat patients with influenza.

 

Flu Experts Line Up to Defend Tamiflu Against New Study

By Maggie Fox

A team of researchers who have been studying the flu drugs Tamiflu and Relenza released a new report that they say raises new doubts about the benefits of the drugs. But flu experts lined up to defend the medications, which they say can help reduce the most severe and deadly effects of the virus.

The report, published jointly by the influential Cochrane Review and the British Medical Journal, seeks to cast doubt on the widespread use of the two drugs, which doctors give to treat influenza and to prevent it in people who have a high risk of complications.

(Continue . . . )

 

Despite its critics, there are studies that show that Tamiflu can significantly reduce morbidity and mortality associated with influenza – particularly with severe, or novel infections. Some we’ve looked at in the past include:

 

Their main finding was antiviral therapy - principally oseltamivir - initiated within 48 hours of onset, reduced the likelihood of severe outcomes, namely admission to a critical care unit or death, by 49 to 65%.

 

And finally, for those who question the value of Tamiflu in novel flu pandemic, in Study: Antiviral Therapy For H5N1, we saw the largest study to date on outcomes of H5N1 patients who either received, or did not receive, antiviral treatment. The research appears in the IDSA’s Journal of Infectious Diseases. The bottom line is essentially out of 308 cases studied, the overall survival rate was a dismal 43.5%.

 

But . . . of those who received at least one dose of Tamiflu . . .  60% survived . . .  as opposed to only 24% who received no antivirals.

 

While we would all prefer to have rock-solid, indisputable evidence based on well-mounted RCTs proving the effectiveness of Oseltamivir, the preponderance of evidence we have today still indicates that NAIs can have a substantial positive therapeutic effect on influenza, particularly in high risk patients or with novel flu strains.


Besides, unless and until better therapeutic options become available, they pretty much the only game in town.

Tuesday, October 01, 2013

The Emergency Oxygen Debate: Revisited

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Photo Credit – Wikipedia Commons

 

# 7825

 

Supplemental oxygen has been a mainstay treatment by emergency rooms, ICUs, paramedics, and EMTs for decades, and is most often employed for shortness of breath and/or chest pain.  But, as my old paramedic instructor warned more than 40 years ago, `Oxygen is a drug.  And if administered improperly, can do more harm than good.”

 

The primary concern (four decades ago) was that patients with COPD receiving too much oxygen would suffer respiratory failure.   The rule of thumb was no more than 2 to 3 liters of O2 for an emphysema (COPD) patient.

 

Sometime in the mid-1980s, the thinking changed, and it became standard  protocol for a lot of EMS services not to deprive COPD patients in serious respiratory distress of high flow rates of oxygen. Running contrary to that opinion, in 2008 the British Thoracic Society came up with guidelines that restricted in-the-field oxygen delivery for COPD patients – and those were adopted by British Ambulance services in 2009.

 

That guideline recommended that oxygen be administered to patients whose oxygen saturation falls below the target saturation ranges (94-98% for most acutely ill patients and 88-92% for those at risk of type 2 respiratory failure with raised carbon dioxide level in the blood), and that those who administer oxygen therapy should monitor the patient and keep within those specified target saturation ranges.

But elsewhere in the world, delivery of high flow rates of oxygen for COPD patients (both pre-hospital and in-hospital) remained common.

 

In 2010,  a study (Effect of high flow oxygen on mortality in chronic obstructive pulmonary disease patients in prehospital setting: randomised controlled trial)  was published in the BMJ that looked at the outcomes of patients with COPD who received high flow oxygen (compared to those who did not), and found their 30 day survival rate was worse.

 

I described the study in BMJ: Oxygen Delivery and COPD, and while the study was small, and subject to other limitations, they found:

  • Titrated oxygen treatment reduces mortality, acidosis, and hypercarbia in patients with acute exacerbation of chronic obstructive pulmonary disease treated before arrival at hospital
  • The risk of death was reduced by 78% by use of titrated oxygen rather than high flow oxygen, with a number needed to harm of 14
  • These findings provide strong evidence that titrated oxygen treatment should be used for hypoxic or breathless patients with chronic obstructive pulmonary disease in prehospital settings

 

Fast forward a little over a year (January 2012), and in a blog called Oxygen Delivery & The Emergency Patient: Revisited, we looked at a retrospective study that appeared in the Archives of Internal Medicine that lent weight to the argument that when it comes to oxygen for emergency patients, less may be more.

Supplemental Oxygen Therapy in Medical Emergencies: More Harm Than Benefit?

Alexander D. Cornet, MD; Albertus J. Kooter, MD; Mike J. L. Peters, MD, PhD; Yvo M. Smulders, MD, PhD

Arch Intern Med. Published online January 9, 2012. doi:10.1001/archinternmed.2011.624

 

Smulders' team reviewed 18 previously conducted studies that looked at patient outcomes following oxygen treatment for common medical emergencies that included heart attacks, strokes, cardiac arrest, and COPD.

What they claim to have found is little or no evidence that high-dose oxygen improves survival, and weak evidence that it may even be detrimental. 

And not just for COPD patients.

 

The authors suggest that hyperoxia (excessive oxygen levels in the lungs, blood, or tissues) may cause hemodynamic changes that may actually increase myocardial ischemia (depriving heart muscle of oxygen) during a heart attack. They also propose that a relationship exists between hyperoxia and greater mortality and complications in non-cardiac emergencies as well.

 

All of which brings us to a new  Cochrane Review,  conducted by researchers at The University of Surrey and The City University London, that questions whether emergency oxygen is therapeutic for heart attack victims, and suggests it may even be detrimental.

 

First stop, the Cochrane review summary, then excerpts from the University of Surrey press release, after which I’ll return with a bit more.

 

Routine use of oxygen in people who have had a heart attack Updated

Cabello JB, Burls A, Emparanza JI, Bayliss S, Quinn T

Published Online:

August 21, 2013

(EXCERPT)

We found four randomised controlled trials that compared one group given oxygen to another group given air. These trials involved a total of 430 participants of whom 17 died. In that group, more than twice as many people known to have been given oxygen died compared to those known to have been given air. However, because the trials had few participants and few deaths, this result does not necessarily mean that giving oxygen increases the risk of death. The difference in numbers may have occurred simply by chance. Nonetheless, since the evidence suggests that oxygen may in fact be harmful, we think it is important to evaluate this widely-used treatment in a large trial as soon as possible, to make sure that current practice is not causing harm to people who have had a heart attack.

 

The Cochrane review process involves examining existing studies, eliminating those that do not meet certain strict standards, and then analyzing the results of those studies that they believe are well-mounted. While the intent is only to rely on `the best scientific evidence’, this process can winnow down the field of research to the point where there is insufficient data on which to make a determination.

 

And basically, that’s where this issue stands.  In their abstract, the author’s write::

 

There is no conclusive evidence from randomised controlled trials to support the routine use of inhaled oxygen in people with AMI. A definitive randomised controlled trial is urgently required, given the mismatch between trial evidence suggestive of possible harm from routine oxygen use and recommendations for its use in clinical practice guidelines.

In other words, we haven’t enough high quality studies to conclude – one way or the other – whether oxygen is helpful or detrimental to the heart attack victim.  Although I’d have put it in the lede, that assessment appears about 3/4ths of the way down the University of Surrey’s press release, in the following caveat:

 

Currently the number of participants involved is too low to enable conclusions about the effectiveness or harms of oxygen to be drawn.

 

Here are some excerpts from the press release. Follow the link to read it in its entirety.

 

No evidence to support giving oxygen to people having a heart attack, research shows

Monday 30 September 2013

Research shows that oxygen therapy following a heart attack may do more harm than good. 

For 100 years inhaled oxygen has been a standard treatment for those with a suspected or confirmed heart attack. The latest research, was led by academics from City University London and the University of Surrey, suggests that oxygen therapy may be doing more harm than good. 

More than seven million people – worldwide - die each year from coronary heart disease (CHD) and it is now the leading cause of death in the UK and US. A heart attack, or acute myocardial infarction, is often the first manifestation of CHD and a timely and appropriate intervention can make a significant difference to mortality rates. 

However, more than three years on from their first call for further research on the use of oxygen therapy, there are still wide variations in practice and the possibility that patients are either being harmed or deprived of benefit. 

Professor Tom Quinn, from the University of Surrey, comments: “While the changes to international guidelines for heart attack following our 2010 review are welcome, this new review suggests that we still do not have an evidence-based answer, based on an adequately powered and well conducted randomised trial, to confirm to clinicians and patients the role of oxygen therapy in heart attack treatment.  It is likely that a global collaboration will be required to deliver such a trial.” 

Professor Amanda Burls, from City University, said: “Our first review in 2010 on this topic called for more research to find out whether oxygen was useful or harmful. 

“While the review had a huge impact on practice, with many national and international guidelines changing from recommending routine use of oxygen to recommending it not to be used routinely, funding to run a trial to settle this important uncertainty has not yet been forthcoming.” 

(Continue . . . )

 

Amazingly, after a century of routine use, we don’t really know whether oxygen therapy is a help or a hindrance during a heart attack. The lack of well-mounted studies showing its efficacy isn’t enough to condemn it use, of course. 

 

But when coupled with other studies that suggest some degree of harm from oxygen is possible, and with the fate of millions of people each year in the balance, the need for better scientific evidence becomes glaringly obvious.

 

Stay tuned.

Friday, January 20, 2012

The Tamiflu Controversy Continues

 

 

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Photo Credit – Wikipedia  

# 6085

 

 

The debate over the effectiveness of oseltamivir (Tamiflu ®) is back in the news once more with the release of a new Cochrane group analysis that finds insufficient evidence to prove that the drug reduces flu complications and transmission.

 

If it seems we’ve been here before, you are right (see Effect Measure’s The Tamiflu doesn't work non-story from 2009).

 

Many researchers point out anecdotal and observational data showing that early administration of oseltamivir does reduce complications from influenza, and can be lifesaving.

 

As an example, In 2010 we saw an observational study that appeared in JAMA  (see Study: Antivirals Saved Lives Of Pregnant Women) that strongly suggested that Tamiflu was life saving for some patients with pandemic flu.

 

And again in 2010, in BMJ: Efficacy of Oseltamivir In Mild H1N1, we saw a study which suggested that the administration of oseltamivir may have significantly reduced the incidence of pneumonia among otherwise healthy pandemic H1N1 patients.

 

And lastly, in Study: Antiviral Therapy For H5N1, we saw the largest study to date on the outcomes of H5N1 patients who either received, or did not receive, antiviral treatment.

 

The research appears in the IDSA’s  Journal of Infectious Diseases. The bottom line is essentially out of 308 cases studied, the overall survival rate was a dismal 43.5%.

 

But . . . of those who received at least one dose of Tamiflu . . .  60% survived . . .  as opposed to only 24% who received no antivirals.

 

 

Alas, these are observational studies, which are not considered the `best evidence’ by most scientists.

 

Ideally what researchers want are a series of well mounted Randomized controlled trials (RCTs) – long considered the `gold standard’ for drug research. But these are expensive, and difficult to conduct ethically when trying to evaluate a potentially life saving drug.

 

So we are left with is a choice that reminds one of the one offered by Chico Marx in the 1933 classic Duck Soup (“Who you gonna believe, me or your own eyes?”).

 

Choosing between observational data that suggests a clinical benefit verses a lack of well mounted studies that actually prove a benefit.

 

Complicating matters, there are ongoing charges that Roche Laboratories has not been forthcoming with all of the data that has been requested by the Cochrane group.

 

Admittedly, there are other concerns when it comes to use of oseltamivir, including the possibility of incurring side effects and the (potential, at least) of generating resistant strains of the influenza virus.

 

Robert Roos of CIDRAP News takes us on a detailed journey down this rabbit hole, with as good a summary of the issues as you are apt to find anywhere.

 

Review renews questions about oseltamivir benefits

Robert Roos * News Editor

Jan 19, 2012 (CIDRAP News) – A lengthy new analysis of unpublished clinical trial data is renewing questions about the effectiveness of the influenza drug oseltamivir (Tamiflu), saying that although the drug shortens flu symptoms by about a day, there is no evidence that it reduces hospital admissions.

(Continue . . .)

 

Despite a lot of unanswered questions, for now at least, oseltamivir remains one of the few pharmacological options likely to be available during a pandemic.