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New York Times delivers a one-sided attack on skeptics of a clot-busting drug for stroke

Mary Chris Jaklevic is a reporter-editor at HealthNewsReview.org. She tweets as @mcjaklevic.

A recent New York Times story decrying limited uptake of a clot-busting drug for stroke pigeonholed skeptics of the treatment as ill-informed “naysayers” while deeming the drug’s boosters to be “experts.”

At the same time, the story didn’t acknowledge the heavy hand of industry funding that has influenced discourse about the drug, tissue plasminogen activator (tPA), which may open blocked vessels after a stroke.

Those biases are among an array of problems we found with the story, For Many Strokes, There’s an Effective Treatment. Why Aren’t Some Doctors Offering It?

It also neglected to provide readers with data about the magnitude of purported benefits and harms, explore the costs of administering tPA, or delve deeply enough into the quality of the evidence.

Most egregiously, according to experts we talked to, it portrayed this as an area of settled science rather than one of lingering uncertainty. Patients and their families, who must decide quickly whether to opt for tPA in the first few hours following a suspected stroke, aren’t served by this kind of imbalanced, incomplete coverage.

Dan Mayer, MD, a HealthNewsReview.org contributor and retired professor of emergency medicine at the Albany Medical College, wrote in an email:

Having had a stroke, I often wonder: if 99% of my symptoms hadn’t cleared before I got to the hospital (60 minutes or well within the time for t-PA), would I have opted for t-PA? This is an area for shared decision making rather than doctrinaire pronouncements on either side.

Where’s the data?

The story was framed around a vignette about an emergency room doctor who was a researcher in a 1990s trial that the story said “proved (tPA) could prevent brain injury after a stroke.”

That doctor, Christopher Lewandowski, MD,  expressed dismay that the drug he thought would “change medicine” hasn’t become universally accepted by his fellow emergency room physicians more than two decades after the findings were published.

It seems that premise would warrant a deep dive into the quality of the data, but that’s not what happened here.

Rather, the story makes sweeping proclamations about the effectiveness of tPA.

It quotes Gregg C. Fonarow, MD, a cardiologist at the University of California, Los Angeles, warning that without tPA patients can end up disabled and facing “devastating consequences.”

It asserts that around 700,000 people in the U.S. who have strokes caused by blood clots each year “could be helped by tPA. Yet up to 30 percent of the stroke victims who arrive at hospitals on time and are prefect candidates for the clost-buster do not receive it.

“The result: paralysis and muscle weakness; impaired cognition, speech or vision; emotional and behavioral dysfunction; and many other permanent neurological injuries.”

One physician researcher pointed out on Twitter just how alarming that sounds:

The story didn’t explain where that 30% figure came from, and it didn’t acknowledge that patients might opt not to be treated after a careful consideration of the evidence.

It went on to state that “in most stroke patients [tPA] prevents brain injury,” which is contradicted even by the study that reported the most favorable outcomes for treatment with tPA.

In fact, that trial showed a very modest benefit. While at best one in five stroke patients are candidates for the drug, only one in eight of those were helped by it, with improved neurological function.

And as the story did mention, a reanalysis of that trial data showed those positive results could be explained by the fact that those who received tPA in the study had less severe symptoms.

The story waved off 11 other studies that didn’t show a benefit, citing tPA proponents’ contention that the failed trials don’t mean tPA “cannot help patients like those in the original clinical trials.”

Also not mentioned: no study conducted on tPA has found it saves lives, and some showed it increased mortality.

Risk of death is given short shrift

The story stated that tPA can present “a real risk” of bleeding in the brain, but didn’t say it can cause serious injury or death, which is the consequence that many ER docs worry about. That risk can be exacerbated by misdiagnoses, since stroke symptoms can resemble those of other maladies such as migraine headaches, infections, and tumors.

The story also stated that “rates of cerebral hemorrhage have declined as doctors have gained experience over the years.” Again, there’s no data given on what those rates are and what evidence shows that brain bleeding is becoming less common.

Mayer believes patients should be informed that the number needed to harm is 18, meaning that for every 18 patients treated with tPA, one additional patient will have a brain hemorrhage that can lead to serious injury or death.

Conflicts of tPA proponents

The story never acknowledged that some physicians advocating tPA and their hospitals stand to profit from administering the drug.

One source in the story has received payments from two companies that market tPA. Edward Jauch, MD, an emergency doctor and professor of neurosciences at the Medical University of South Carolina, received just over $20,000 from Genentech and Boehringer Ingelheim Pharmaceuticals, from 2013-16, according to Open Payments.

All four tPA proponents quoted in the story are affiliated with Joint Commission-accredited stroke centers, which attract patients with a range of services that include offering tPA.

Moreover, as medical journalist Jeanne Lenzer reported, Genentech employees served as “study monitors” in the trial that served as the basis for using tPA in stroke, which means the company exerted control over how data was collected.

The American Heart Association’s industry ties

The story noted that guidelines of the American Heart Association and its offshoot, the American Stroke Association, “strongly endorse tPA for patients after they’ve been properly evaluated.”

But the AHA also has a significant conflict of interest on this issue.

Lenzer wrote in 2002 that six of the nine members on an AHA committee that strongly recommended tPA for stroke “despite continuing controversy about the safety and efficacy of the treatment” had ties to the manufacturer, Genentech. Further, the association itself had received more than $11 million from Genetech in the decade preceding the recommendation.

The AHA continues to receive funding from companies that make tPA, reporting some $654,000 in cash and pledges from Genentech and Boehringer Ingelheim in the most recent financial report posted on its website, for the fiscal year that ended in 2017.

And there was no mention of the cost of the drug, which varies by hospital. Some hospitals reportedly pay as much as $8,000 per dose, although the costs of administering the drug are higher because patients must first undergo a CT scan to rule out a brain hemorrhage that could be worsened with tPA.

Attacking an independent messenger

Jerome Hoffman, MD

The story cast doubt on the credibility of independent doctors who are concerned this drug is harming patients as a minority of “vocal disbelievers” who get their information from social media.

In the original version of the story, University of California Los Angeles professor and emergency medicine specialist Jerome Hoffman, MD — who has combed the available evidence about tPA and performed the reanalysis of data from the 1995 trial — is described as a “charismatic, riveting speaker” who has “sold information tapes expounding his theory.”

As this blog was about to be published, the Times ran a correction stating Hoffman did not sell tapes.

All that was exacerbated by the use of leading words such as “experts” to describe those who disagree with Hoffman’s analysis and “claims” (rather the standard “said”) in attributing Hoffman’s statement about the quality of evidence.

Lenzer said the portrayal of Hoffman — who is considered an expert in emergency stroke care as well as scientific methodology — and other doctors who question the integrity of the evidence as uninformed is “very disturbing.”

“These doctors have a genuine concern for public safety,” she said.

In fact, Hoffman told HealthNewsReview.org that he’s never accepted industry money and has donated any compensation he’s received for testifying in court cases involving tPA to charity. “I didn’t want anyone to have any way of insinuating that I was saying what I did in order to make $,” he wrote in an email. He said the fact he was painted as the conflicted party in this story is “pretty ironic. I could make a lot of money if I just switched sides.”

Hoffman has spent much of his career educating doctors and medical students about the pitfalls of medical literature. Some of his presentations are available on YouTube, and you can watch him talk about tPA here.

‘Poster child’ for how proprietary interests distort data

The distorted narrative ended with tPA proponent Lewandowski relating how his own father was refused the drug by another ER physician who said he “doesn’t believe in the drug.”

His father had a facial droop and slurred speech. His right arm and right leg flopped about uselessly. His stroke scale was 7, moderately disabling, but he survived for a few more years.

“It was very difficult for me personally,” Dr. Lewandowski recalled. “I had spent so much of my professional life working on this treatment. It actually worked.”

“I felt like I had let my dad down.”

That dramatic conclusion might have been less compelling had the story explained the evidence that tPA offers a benefit is far from robust.

Hoffman noted the story could have been flipped to say Lewandowski’s father “got lucky because he didn’t get tPa and didn’t get a brain hemorrhage and die.”

But he said it’s wrong to declare a winning side when the evidence isn’t definitive.

“This is sort of a poster child for the way in which information is distorted by proprietary interests. For me, that’s the important message.”

Addendum 4/2/18: After this blog post ran, journalist Jeanne Lenzer wrote a guest post calling on health care journalists to be vigilant in reporting conflicts of interest of their sources.

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Comments (16)

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Ronald Hirsch, MD

March 30, 2018 at 8:53 am

I disagree that hospitals make money from tPA. An admission for a stroke with tPA can pay as little as $10,000. With the drug costing $8,000, that leaves very little to pay for all the other care.

    Mary Chris Jaklevic

    April 2, 2018 at 3:29 pm

    Thanks for your comment. Not all hospitals pay $8,000 for a dose of tPA. From reports I have seen, it appears some hospitals pay substantially less. And regardless of whether a hospital makes money administering tPA, providing that intervention means a hospital can market itself as a stoke center and attract patients for a range of stroke-related services.

Susan Molchan, MD

March 30, 2018 at 1:26 pm

I was surprised to see this hype about tPA in the NYT, as I know something of the controversy about the drug. Would think their seasoned health journalist should know better about getting so much of her information from one side, and such financially conflicted sources as we see this time and time again in articles in health and medicine. The number needed to harm is an important one–only 18.

Mark McConnell, MD

March 30, 2018 at 1:54 pm

Having read this article and the NY Times article, this one seems much more helpful.
It is hard to have discussions with patients and families in areas, like this, where there is nuance and uncertainty. But we must do the hard thing. Thanks for writing this.

Charles Carter MD

March 31, 2018 at 10:58 pm

Health News Review hits another home run. The ‘code strokes’ run in my hospital are disruptive, though that’s no reason to withhold truly effective treatment. I wasn’t up to date on the data because decisions have been taken out of my hands. Thank you!

David Pecora

April 2, 2018 at 12:48 am

I can think of no other intervention or medication in emergency medicine that still has NOT proven its significant benefits, as well as it’s small harms as does TPA. If, after 20 + years of weak evidence of benefit at most, has not shown great success, why is TPA still being heavily pushed by the AHA, as well as incompetent attorneys?

Kit Byatt

April 2, 2018 at 3:28 am

1) no single study will give the full picture. Systematic reviews (comparing *all* studies on a given topic) are accepted as the gold standard. In this topic, systematic reviews show a slight increase in mortality after thrombolysis (e.g. TPA), but they can reduce the risk of long-term dependency on others for daily activities,[1]

2) For many patients, dying from a stroke is preferable to ending up dependant on others [2], so this isn’t necessarily a problem.

If you give people high quality objective information, they can make their own minds up, based on their values and priorities, rather than simply accept their doctor’s opinion, based on their doctor’s values and priorities.[3]

=============
References:
1. http://www.cochrane.org/CD000213/STROKE_clot-dissolving-drugs-treating-ischaemic-stroke-early-stages
2. http://www.evidentlycochrane.net/living-and-dying-well-after-stroke/
3. Patients’ Preferences Matter – Stop the Silent Misdiagnosis
Al Mulley. 29 May 2012
https://www.kingsfund.org.uk/publications/patients-preferences-matter

John Galbraith Simmons

April 2, 2018 at 7:24 am

I take the strongest possible exception to the critique Mary Chris Jaklevic proposes in this article. There is not a question of “settled science” vs. “lingering uncertainty”” concerning tPA for stroke. The drug works when used according to protocol, and the fact that it works has been demonstrated in trial after trial, in the US and in Europe for more than 20 years. Jerome Hoffman, a charismatic figure in emergency medicine, has been indeed a powerful critic and he has done a great deal of harm concerning treatment for a unique cerebrovascular event in which “time is brain”; his payment has been in hero worship and accolades, not money. Genentech, which developed the drug, paid little attention of tPA as a stroke treatment, a situation I documented in a book published in 2010 (“tPA for Stroke: The Story of a Controversial Drug [in collaboration with Justin A Zivin MD PhD], Oxford University Press). Health Review News should retract this article by Ms. Jaklevic. It is egregiously ill-informed.

    Kevin Lomangino

    April 2, 2018 at 8:06 am

    [Update 4/5/18: As noted by another commenter on this post, the book referenced above by John Galbraith Simmons about tPA was co-authored with a paid consultant to Genentech, which makes tPA. That relationship is disclosed in this Northwestern University magazine article.]

    This comment demonstrates the same lack of critical analysis we found in the NY Times piece. It is not a question of whether the drug “works” or not. Clearly, it “works,” sometimes all too well resulting in brain bleeds. The question is whether the balance of benefits and harms is an acceptable one. Patients and physicians may differ in their opinions on that point, and they are not helped by coverage that lopsidedly cheerleads for one perspective or another. The NY Times piece exaggerated the benefits, downplayed the harms, and failed to provide key context about industry involvement in the research and expert recommendations for tPA. The commenter does not point to anything in the article that is inaccurate, and does not acknowledge the inaccuracies in the Times piece that we corrected. There is absolutely no basis for retracting this post.

    Kevin Lomanngino
    Managing Editor

James McCormack

April 2, 2018 at 12:28 pm

Agree very much that the NYT story provides virtually nothing but anecdotal evidence which is sad given the status of the NYT. I also agree with people who commented that the Health News Review doesn’t offer any evidence other than rightly pointing out the problems with the NYT in this regard.
Here is my take on TPA when looking at the evidence (for what it is worth). I’m primarily using the following reviews to make these comments and ignoring authors conclusions and just looking at the data Forest Plots myself. I also do not use adjectives to describe the magnitude of the benefit or harm as that informs a bias.
1) https://www.ncbi.nlm.nih.gov/pubmed/27561375 – COMPLETELY INDEPENDENT REVIEW – GREAT STUFF AND THE SUPPLEMENTAL MATERIAL IS VERY USEFUL AS WELL
2) http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)60584-5/abstract – LOOKS AT THE TIMING ISSUE
3) https://www.ncbi.nlm.nih.gov/pubmed/25072528 THE COCHRANE REVIEW – some conflicts but the results are similar to the first review above.
The “issues” with the all the evidence are as outlined in 1) above
Small numbers – agree but that is why we do meta-analyses
Use of secondary outcomes – not sure what they really mean by this – a study should have only one primary outcome (not necessarily the most important one) and we still have to look at the secondary outcomes as they are often clinically relevant
Definitions of outcome – I think the reviews above did a pretty good job of teasing out consistent outcomes when it comes to disability – not perfect but not too bad
Baseline imbalance – I didn’t see any baseline imbalances that I thought would be responsible for the results seen
Other sources of potential bias – agree some trials are unblinded – but many good trials are unblinded
Confounders – definitely an issue but difficult to manage when you have a stroke team dealing with all the other aspects of care
External validity – agree
Influence of pharmaceutical sponsorship – always a concern BUT I have similar concerns with people or groups of people whose job it seems is to discredit every study and treatment – I believe they have an academic bias almost as powerful as the industry bias. Given the above I still think the “best available evidence” – with all its warts etc suggest that – and these numbers are taken from both the independent review and the Cochrane review
1) If you use TPA within 1-3 (maybe 4.5) hours you get a 5-10% absolute benefit in the number of people with a residual disability
2) intracranial hemorrhage goes up by about 5% BUT not sure how relevant this is given that the number of overall people with a residual disability is reduced
3) overall mortality is unchanged
Would love to hear from others on their thoughts on the evidence – NOT just opinion or anecdotal issues.

    Kevin Lomangino

    April 2, 2018 at 3:15 pm

    James,

    Thanks for commenting. I take issue with your inaccurate statement that “Health News Review doesn’t offer any evidence other than rightly pointing out the problems with the NYT in this regard.”

    In fact, we linked to the trial that forms the basis for positive recommendations about the use of tPA for stroke, and we noted how even these rosiest of results do not support the Times’ description of tPA’s benefits. We said: “While at best one in five stroke patients are candidates for the drug, only one in eight of those were helped by it, with improved neurological function.”

    Our story also discussed harms, quoting an expert source who stated that “the number needed to harm is 18, meaning that for every 18 patients treated with tPA, one additional patient will have a brain hemorrhage that can lead to serious injury or death.”

    So, roughly 12% benefit under a best case scenario (a statistic the Times described as “most” people), and roughly 5% are harmed with possible serious injury or death.

    Those numbers look pretty darn close to those you cite in your comment.

    Kevin Lomangino
    Managing Editor

Robert Kilgo, MD, FACEP

April 2, 2018 at 6:51 pm

Thank you for this reasoned, short expose on the problems with beliefs and conflicts in the science in medicine. Probably the most read article from PLOS is Dr Ioannaides artice on why approx 90% of the medical literature(scientific!?) is wrong with the promotion of positive trials and the removal of negative trials, due to the unfortunate marriage of the medical industrial complex and the house of medicine. Untold numbers of patients have been hurt by the promotion of harmful therapies, tPA is simply one of them, and it should be controversial at best. Our college, the American College of Emergency Medicine has cleaned up it’s guidelines due to conflicts of interest(COI). A funded group of 12 back in 2012 put out a guideline suggesting that tPA was, well, wonderful. (9/12 had ties to genentech, the makers of tPA). There was a literal outcry and the guidelines were redone by 2013 and there were no suggestions that tPA was an incredible medicine. None of the authors on this guideline had ties to industry. I leave you with the simple question, what makes an expert?? Remove the COI from the house of medicine and we could have not only reasonable, non-industry funded guidelines, but we could also remove some of the hyperbole connected to industry sponsored, profit centered care. Patients should not be wondering why the house of medicine has become somewhat divided. tPA is simply one drug, how many others may cause harm out there? or may help.

Bob Kilgo, MD, FACEP, RDMS
Durango, CO

Jeanne Lenzer

April 3, 2018 at 10:19 am

Kitt Byatt suggests that the evidence isn’t a slam dunk and patient preferences might might lead some to choose tPA despite the risk of harms; her comment opens the door to something I overlooked in my commentary http://bit.ly/2Je2LtB and that has been overlooked in this important discussion: Do skeptical doctors refuse to give tPA or are they arguing for informed and shared decision making: The NYT article states that an ER doctor refused to administer tPA saying he didn’t believe in it. In my experience, that is so rare as to almost beg credulity. Even the foremost skeptic of tPA for stroke, Hoffman, agrees that there is no slam dunk on this issue and that patients and their loved ones should be engaged in shared decision making. He does say that many patients when given of the basic facts both of benefits and harms, often do decline treatment while others say yes. I suspect that the ER doctor so prominently featured in the NYT article is either an outlier, but he served the purpose of biasing readers about the genuine concerns of many emergency doctors. I’ll never forget an EM doctor giving a CME lecture to a group of emergency physicians and she related the case of a young man who had a stroke, whom she treated with tPA. He died of a brain hemorrhage. She became tearful relating that story saying that in the future, she wouldn’t give it, but she would refer patients to neurology if they believe in it (and assuming a patient/loved one wants it). The concerns about tPA didn’t arise because emergency doctors are stupid, or because they don’t read peer-reviewed literature as suggested in the NYT article; they arise because these doctors are indeed concerned with their patients’ well being and their right to informed consent and shared decision making.

James McCormack

April 4, 2018 at 12:33 am

In response to Kevin’s comment, I must apologise – the HNR article, did mention those numbers. I would however quibble a bit with the statement “So, roughly 12% benefit under a best case scenario (a statistic the Times described as “most” people), and roughly 5% are harmed with possible serious injury or death.” There is no overall mortality changes with tPA from my reading and – although I would be happy to be corrected – the 5% serious injury refers to intracranial bleeding but that is overall not an issue because overall disability is decreased by ~10% and this should account for any harm associated with the ICB.

    Kevin Lomangino

    April 4, 2018 at 8:57 am

    James,

    Thanks for your reply and your apology. As we note in our Comments Policy, this is not a forum for definitive discussions about medicine or science. It’s primarily a place to discuss media messages about health care. I don’t have the expertise to debate you on a difference of a few percentage points on this or that outcome — I was merely trying to demonstrate that those numbers were included in our analysis.

    However, I would not agree with your statement that intracranial bleeding “overall not an issue because overall disability is decreased by ~10% and this should account for any harm associated with the ICB.” Based on my understanding, individual patients may certainly choose not to be treated based on their own personal values and preferences, even though the raw numbers may suggest a modest net benefit. If you are someone looking at a future of mild stroke-related disability, you might not be willing to take a 1 in 18 chance that you’ll suffer a devastating (possibly deadly) bleed in exchange for a 1 in 8 chance that you’ll benefit. In my view that’s the main takeaway — there’s a balance of benefits and harms here and the suggestion that this is a slam dunk decision (as the Times article implies) is misguided.

    Kevin Lomangino
    Managing Editor

Jeanne Lenzer

April 5, 2018 at 3:22 pm

NOTE: John Simmons is a “contract medical writer” whose clients have included pharmaceutical companies https://www.linkedin.com/in/john-galbraith-simmons-462a1b3/ . He co-authored a promotional book for tPA with first author Justin Zivin, who was a paid consultant to Genentech http://www.northwestern.edu/magazine/fall2011/feature/a-stroke-of-genius.html