Stop the Hemorrhaging and Stand up for TXA

Figure 1: Drugs and money. Shutterstock. Accessed February 2, 2025. https://www.shutterstock.com/image-photo/medical-business-prices-concept-making-money-1538103698NovoSeven®, otherwise known as recombinant Factor VIIa (rFVIIa), costs about $14,000 per adult dose.1 About 20 years ago, physicians started injecting this pricey concoction into non-hemophiliacs, and Wall Street swooned. “[NovoSeven] is fast becoming a blockbuster, with physicians around the world using it to stanch severe bleeding from car accidents, gunshot wounds and postsurgery hemorrhaging,” reported the Wall Street Journal back in 2004.2 “Some doctors are hailing NovoSeven as a lifesaver, with word spreading about near-miraculous cures of dying patients.” The Journal recounted how “a dying Israeli soldier, suffering from a gunshot wound, got two doses of NovoSeven and soon recovered. The results were published in the medical journal Lancet.” A Baltimore woman shot nine times was “bleeding so profusely that bedpans were put on the floor under her hospital bed to catch the blood ... As her situation deteriorated rapidly, surgeons decided to inject a dose of NovoSeven. The bleeding stopped, and she recovered completely.” The director of Baltimore's Shock Trauma Center told the newspaper that NovoSeven was a “wonder drug” they had used “80 times in three years, saving about 35 lives.” Amazing! Inspiring! Why, with 2.1 million US trauma admissions per year,3 NovoSeven might be worth billions! The excitement was based on anecdotes (that, and dollar signs). The Journal reported that “Novo Nordisk officials acknowledge the problem,” that problem being that they had neither FDA approval nor scientific support for their desired activity but had come up with workarounds.2 “The company's sales force can't sell the drug for non-hemophilia treatments and must rely on passive ‘medical education’ and responses to calls from doctors [with questions]. The drug maker, though, has a staff of 25 in the US to handle the flood of inquiries.” The drug maker expected a staff of 25 to manage physicians frantic to hear about NovoSeven? Really? No. From whistleblower allegations, we later learned that Novo Nordisk trained its staff “to prompt physicians to ask such questions” by reaching out with offers of unrestricted grant money.4 As to that passive “medical education,” physicians did get paid to uptalk NovoSeven for trauma. “Specifically,” according to a Justice Department-endorsed whistleblower complaint, which the company would later pay millions to settle, “Novo Nordisk targeted influential Army doctors who Novo Nordisk supported monetarily and, in turn, expected support for Factor VIIa use in the military theater. Novo Nordisk then pointed to the Army's use of the product [abroad] in promoting it widely among civilian physicians.”4 Multiple, small, randomized trials were organized in the hopes of confirming those near-miraculous cures. (Novo Nordisk salespeople—styled as the company's “medical science liaisons”—were graded at performance review on how many academic publications they helped to generate. Recruiting doctors to study NovoSeven for trauma, and shepherding that work into abstracts and papers, was a marketing and sales job.) The early results were not promising. The FDA began to officially mutter that little was known about using Factor VIIa in non-hemophiliacs.5 Meanwhile, US military doctors may have accepted honoraria for the occasional case report or lecture, but they were mostly interested in saving critically wounded soldiers. In a chaotic and rapidly changing warzone environment, trauma doctors were using NovoSeven. But as demonstrated in the MATTERs6 and MATTERs II7 observational studies, they saw better results with cryoprecipitate and tranexamic acid (TXA). Unlike NovoSeven, TXA was dirt cheap. No one was putting doctors up in the Ritz Carlton or flying them to Florida to talk about it. Novo Nordisk started to take heat for experimenting on soldiers. “American military doctors in Iraq have injected more than 1,000 of the war's wounded troops with a potent and largely experimental blood-coagulating drug despite mounting medical evidence linking it to deadly blood clots that lodge in the lungs, heart and brain,” reported The Baltimore Sun in 2006.8 The Sun reports the following consequences: “The U.S. Army medical command considers Factor VII to be a medical breakthrough in the war, giving frontline physicians a powerful new means of controlling bleeding. They have posted guidelines at military field hospitals encouraging its liberal use... During one 24-hour period in May, while journalists for The Sun were at the 10th Combat Support Hospital in Baghdad, three U.S. Army soldiers arrived in the emergency room with traumatic injuries, and all of them were injected with Factor VII. Two subsequently died, not from their battlefield injuries but from complications related to blood clots.”8 These were lurid and emotive anecdotes to be sure. But these at least were consistent with the science. By 2011, a Cochrane review of 29 randomized trials of NovoSeven for trauma found that no lives were being saved.9 Instead, even in these smallish studies (all 29 of them together included only 4,290 patients), there was a rise in arterial thromboembolic events, both heart attacks and strokes. The United States Department of Justice eventually declared much of the NovoSeven boosterism to have been illegal, and in 2011 Novo Nordisk opted to settle for $25 million.10 That equaled about 3% of that single year's NovoSeven sales revenues of $804 million11—hardly a behavior-influencing penalty. The two whistleblowers received a $3.5 million cut. Meanwhile, a year earlier, The Lancet published CRASH-2.12 At a cost of $5.70 per intravenous dose, TXA conferred a 1.5% survival advantage in trauma, with a number needed to treat (NNT) to save one life out of 67. If it was given in the first hour, the NNT was 48. It was a massive trial—nearly five times larger than all 29 NovoSeven trials to date combined. There were no heart attacks, strokes or PEs. It just saved lives. But the world of trauma care yawned in boredom and looked away. A handful of nitpicky critiques, written by authors with funding from viscoelastic test makers, came out suggesting that doctors should get a thromboelastography (TEG) test before giving TXA. They had no hard evidence for that idea.13,14 Medicine Is Hemorrhaging Self-Respect When it came to bleeding, NovoSeven wasn't the only pricey (and dicey) medication on the market. Aprotinin, for example, was used for years to help control bleeding during cardiac surgeries. Sold by Bayer as Trasylol®, it would cost $1,400 for use during a 4-hour cardiac surgery.15 From the moment it hit the market, there were murmurs that aprotinin had to be reserved for high-risk cases because it might cause kidney problems. Other anti-fibrinolytics were available and far cheaper. Aminocaproic acid would have cost $4 for that same surgery.15 And TXA, a generic that has been available since after the end of World War II, had proven safety and efficacy. One review of TXA's use to prevent intraoperative bleeding, published in the British Medical Journal in 2012, found 129 randomized trials—11 involving children!—with a total of 10,488 patients.16 TXA was so consistently shown to safely reduce the need for blood transfusions that the BMJ authors tartly suggested we stop studying that. Why pay $1,400 for a possibly dangerous, new medication when you could pay $4 for a safe, old one? According to a US Department of Justice-endorsed complaint, “Bayer routinely paid kickbacks and illegal remuneration to physicians and hospitals in order to induce the use and/or prescribing of Trasylol.”17 Only about two years ago did Bayer pay $40 million to settle this and related allegations. The whistleblower herself, a former Bayer employee, got $11 million of that. Sadly, Trasylol was not just pricey, but also harmful. Long-brewing concerns came to a head in 2006 when two observational studies were published in the same month. One study, published in Transfusion, looked at cardiac surgeries at Toronto General Hospital and compared 449 that used aprotinin to 449 that used TXA. There was a 7% higher rate of renal failure with aprotinin.18 A second study, published in The New England Journal of Medicine, of more than 4,300 cardiac surgeries, showed that intraoperative use of aprotinin—but not TXA or aminocaproic acid—had strong associations with heart attacks, strokes, and death.19 Aprotinin was associated in particular with a dose-dependent doubling or even tripling of the risk for subsequent dialysis. The FDA notified doctors about these studies and announced it would convene an advisory committee.20 Bayer quietly ordered its own study, a review of more than 78,000 patients—33,517 who had received aprotonin and 44,682 who'd received aminocaproic acid.21 Bayer's study also found aprotonin associated with increased death. When the FDA committee met, Bayer stayed silent about its own study. The committee weighed the available evidence—all of it observational data—and voted to keep Trasylol on the market. A week later, a researcher tipped off the FDA about Bayer's secret study. The media declared it a scandal, even as a study underway in Canada was about to confirm the worst. The BART trial of 2,331 high-risk cardiac surgery cases randomized patients to one of three antifibrinolytics.15 It was stopped early over more deaths at 30 days with aprotonin: 6%, compared to 3.9% with TXA and 4% with aminocaproic acid. Bayer, under FDA pressure, pulled the drug from the market.22 From the release of the Transfusion18 and NEJM19 articles to Trasylol's end had taken 22 months. When the CBS News show, “60 Minutes,” summarized it all, they cited one researcher's assertion that 1,000 people died from aprotinin for every month of that 22-month delay.23 When we can save thousands of lives, why don't we? We physicians must navigate a world where information—“the science”—has been created, shaped, delivered, distorted or obscured in response to financial pressures most of us never even learn about. We've often been fooled—from NovoSeven to Paxlovid, from OxyContin to Trasylol. Many of us have learned to be suspicious when people with financial and emotional attachments hype a new medicine. But we're less attuned to the idea that lifesaving medications without boosters get ignored, disrespected, or even actively dismissed. TXA has been proven to control bleeding and to save lives—a truth reiterated a little over a year ago in the latest meta-analysis. But that's embarrassing and inconvenient to anyone who was all-in on NovoSeven or Trasylol. (It's also an annoyance to anyone planning a future wonder drug for trauma, which now has to prove itself superior not to placebo, but to TXA.) The trials for TXA in trauma tell a scientifically pleasing and consistent story. Everywhere, mortality falls. The only questions are whether a particular study achieves statistical significance when it shows this. In CRASH-2, the survival benefit among 20,000 patients was statistically significant.12 In STAAMP, which trialed prehospital TXA in 903 US trauma patients, the same signal shows up.24 But the STAAMP trial was more than 20 times smaller and its results did not achieve statistical significance. Ergo, “STAAMP is a negative trial,” so “prehospital TXA doesn't work in America,” mainly because TXA doesn't have a marketing department paying doctors to make a case for it. (I have no disclosures). STAAMP, of course, did show that those treated within one hour of injury saw a 3% reduction in death (p < 0.002), for an NNT of 33. In short, quickly treat 33 hypotensive or tachycardic trauma patients, save one life. And it showed a 17% (!) survival benefit for those with traumatic shock (systolic BP < 70 mm Hg)—treat six such patients, save one. That's the same effect observed in the military's MATTERs trials. But those are “subgroup analyses of a negative study,” cries the chorus, adding, “why don't you get a TEG test before giving TXA?” A better question would be: if TXA might save 4,000 lives a year across America, why are trauma and EMS physicians not doing everything possible to get it to every trauma patient in the field as rapidly as possible? Is it really because no one's offering a $1,000 honoraria for presenting that particular PowerPoint®?DR BIVENS works at emergency departments in Massachusetts, including St. Luke's in New Bedford and Beth Israel Deaconess Medical Center in Boston. He is double-boarded in emergency medicine and addiction medicine. Follow him on X @matt_bivens. Read his past columns at http://tinyurl.com/EMN-Bivens.Share this article on X and Facebook. Access the links in EMN by reading this on our website: www.EM-News.com. Comments? Write to us at [email protected].

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