Last month signified a victory for high-value care with the approval of a new patient safety metric, Excessive Radiation Dose or Inadequate Image Quality for Diagnostic Computed Tomography in Adults. Starting in 2025, the measure will be integrated into the Centers for Medicare and Medicaid Services (CMS)’s Merit-based Incentive Payment System (MIPS) and Hospital Inpatient and Outpatient Quality Reporting Programs, with the goal of regulating patients’ exposure to radiation during computed tomography (CT) scans. 

This new measure of radiation quality sheds light on an important potential harm of imaging overuse. Here’s what it means for the future of provider accountability and patient safety.

Radiation exposure during CT scans

Each year, it is estimated that more than 80 million CT scans are performed in the United States. The computerized x-ray imaging procedure has the power to inform diagnostic decisions for everything from tumors and lesions to heart disease and pneumonia. 

While CT scans are an essential diagnostic tool in doctors’ medical toolkits, it’s important they be used carefully. Each time a CT scan is performed, the patient is exposed to ionizing radiation, which is required to produce an internal image for the physician to review and make diagnostic and treatment-related decisions. However, in large doses, exposure to such radiation can damage genetic and cellular material, increasing the risk for mutations and consequently, cancer. 

“Many patients still routinely receive radiation doses two or three times what they should. That will lead to cancer in a small percentage of patients, approximately thirty-six thousand cancers every year. This means that CT causes two percent of annual cancers, and we can reduce that risk substantially without reducing the value of the scans.”

Dr. Rebecca Smith-Bindman, UCSF

Given how common CT scans are and the potential risks of radiation exposure, it seems obvious that there would be standard measures for how much radiation doctors can use. But in fact, the amount of radiation that a patient gets in a CT scan varies widely, largely due to differences in the ways in which physicians use CT machines across institutions. The results of studies exploring the implications of this are alarming, with one citing a 13-fold mean variation between the lowest and highest dosages used across different CT scans. 

Measuring what matters in imaging

To tackle the widespread variation and lack of regulation surrounding CT radiation dosage, UCSF Professor in Residence Dr. Rebecca Smith-Bindman and her team developed a new measure, Excessive Radiation Dose or Inadequate Image Quality for Diagnostic Computed Tomography in Adults. The measure sets lower and upper thresholds for radiation dose based on patient characteristics and type of CT scan. The radiation dose floor ensures that enough radiation is used to create an image of acceptable quality, while the ceiling prevents over-radiation that could increase cancer risk. 

Here’s an example from researchers at UCSF:

The measure is implemented through software that links to providers’ electronic health records, so clinicians can get real-time feedback on their performance. CMS will evaluate providers based on “the percentage of CT exams that are out-of-range based on having either excessive radiation dose or inadequate image quality.”

The future of overuse metrics

The new radiation quality metric is a great example of how overuse measures can help improve quality and reduce patient harm. CMS estimates this measure could prevent nearly 14,000 cancers among Medicare beneficiaries and save as much as $5 billion to Medicare each year.

This overuse metric is one of many that deserve broader use among providers. Through our research on the Lown Hospitals Index, we’ve seen how common unnecessary imaging and procedures can be in U.S. hospitals. For example, a Lown Institute report from October 2023 found that US hospitals delivered nearly 230,000 unnecessary coronary stents from 2019-2021– that’s a rate of one every seven minutes. The Lown Hospitals Index for Social Responsibility evaluates hospitals on 11 other low-value services, including unnecessary imaging like CT scans for fainting and procedures like spinal fusion for lower back pain. We look forward to incorporating the new metric of CT radiation quality into the Index as data becomes available. 

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How often are these procedures happening, and where? How much are we wasting on these low-value services? And what can we do to prevent unnecessary care?

Join us Tuesday, October 31 as we discuss the impact of unnecessary stents with leading health experts and policymakers.

Meet the panelists

David L. Brown, MD

David L. Brown, MD is a general cardiologist and Clinical Professor of Medicine in the Division of Cardiovascular Medicine at Keck Medicine of USC. Dr. Brown received his undergraduate degree from the University of Texas and his medical degree at Baylor College of Medicine where he also trained in internal medicine and served as a chief medical resident. He trained in cardiology and hematology at University of California, San Francisco and interventional cardiology at the Cleveland Clinic. During his career he has practiced and taught interventional cardiology, critical care cardiology, consultative cardiology, and outpatient cardiology. He has published more than 300 abstracts, manuscripts and book chapters. His work has been cited more than 8500 times resulting in an h-index of 37. His primary research focus has been on outcomes research in cardiovascular disease with most of his research projects attempting to fill gaps in the knowledge base that come to light during direct patient care. He currently serves on the editorial board of JAMA Internal Medicine. 

Thomas Power, MD, MBA, FACC, MRCPI

Thomas Power is the Senior Medical Director of Cardiology and Sleep Programs at Carelon Medical Benefits Management and is responsible for the clinical components of those programs. Before coming to Carelon MBM, Dr. Power had three years of experience in cardiac imaging utilization management. He attended medical school at the University of Dublin (Trinity College) and completed residency and fellowship in cardiovascular diseases at Allegheny General Hospital in Pittsburgh, Pennsylvania. 

Dr. Power is board certified in cardiovascular diseases and is a Fellow of the American College of Cardiology (FACC). In addition, he holds a certificate from the Certification Council for Nuclear Cardiology, and he is a Professional of the Academy of Healthcare Management. He has been the recipient of several awards for excellence in clinical teaching and a research grant from the American Heart Association (AHA).

Betty Rambur, PhD, RN, FAAN

Betty Rambur, PhD, RN, FAAN is the Routhier Endowed Chair for Practice, Professor of Nursing, and Interim Dean of the College of Nursing at the University of Rhode Island.  She serves on the state’s Cost Trends Steering Committee, the Technical Advisory Panel for Reimagining Nursing Initiative “Reducing Barriers to Value-based Care Payments in NP-led Primary Care,” and as a member of the Medicare Payment Advisory Commission (MEDPAC).

Vikas Saini, MD

Vikas Saini, MD, president of the Lown Institute, is a clinical cardiologist trained by Dr. Bernard Lown at Harvard. He also serves as co-chair of the Right Care Alliance, a grassroots network of clinicians, patient activists, and community leaders organizing to put patients, not profits, at the heart of health care. Dr. Saini is an expert on the optimal medical management of cardiologic conditions, medical overuse, hospital performance and evaluation, and health equity. He has spoken and presented research at professional meetings around the world, and has been quoted in numerous print media, radio, and television.

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As these surgeries have become more prevalent, researchers are taking a closer look at the evidence behind them. Although orthopedic surgeries have the potential to reduce pain and improve mobility, they are among the most costly and come with risks of complications.

In a recent analysis in The BMJ, professor Ashley Blom at the National Institute for Health Research in the UK and colleagues looked extensively at the evidence behind ten of the most common orthopedic procedures. In particular, they wanted to find out what results randomized controlled trials (RCTs) show for these procedures, as RCTs are the gold standard for evaluating the clinical effectiveness of an intervention. Randomizing treatment groups is key to neutralizing the placebo effect of medical procedures. As we have seen from RCTs of stents, vertebroplasty, shoulder arthroscopy, and others, even common procedures thought to be effective may not stand up to the rigorous test of randomization.

Blom and colleagues found that when focusing on RCT data, only two of the ten orthopedic procedures (carpal tunnel decompression and knee replacement) were superior to medications or physical therapy (non-surgical treatment). For two procedures (hip replacement and arthroscopic meniscal repair), there were no RCTs comparing these surgeries to a placebo or non-surgical treatment. For all the other procedures studied, RCT data showed no difference on measures of disability or function compared to non-surgical care.

“Although they may be effective overall or in certain subgroups, no strong, high quality evidence base shows that many commonly performed elective orthopedic procedures are more effective than non-operative alternatives,” the authors write. Yet, some of these procedures are recommended in national guidelines.

This study opens up a necessary conversation about what kind of evidence we accept as enough to adopt a new standard of care. Should we encode procedures within guidelines if they haven’t shown to be better than non-surgical treatment? Given how often we see medical reversals after RCTs are conducted, the gap in evidence for certain orthopedic procedures means that we don’t really know if they work — and there may be a reckoning later when we finally do the trials.

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“If doctors don’t understand how likely — or unlikely — it is that a treatment will help, they can’t give patients the best advice for their care.”

Dr. Daniel Morgan

What is the difference between these two questions? The example of remdesivir can lend some insight. The antiviral drug recently approved to treat Covid-19 has had mixed evidence, but in one study was found to reduce the risk of death in hospitalized Covid-19 patients from 15.2% to 11.4% after 30 days. According to that study, the likelihood that it works for any one patient is small. This means that clinicians and patients or family members have to discuss the potential benefits in context of side effects and cost.

As Morgan writes, most medical treatments fall into this gray area of having a known but unlikely benefit for patients. This is especially true when it comes to preventive treatments for patients without symptoms.

For example, for patients without existing heart disease, taking a statin reduces the risk of having a heart attack or stroke, but only by 0.4%. On a population level, that adds up to a lot of heart attacks prevented over the years. But on an individual level — when patients want to know if this medication is “right for me”– the small benefit may not be seen as worth it, especially for people who are already taking many medications, or those who have experienced disruptive side effects from statins.

“Our job isn’t only to cure people; it’s also to help them make it through when there is no easy cure.”

Dr. Daniel Morgan

It might make sense that patients who aren’t trained in medicine may overestimate the benefits of medications. But surprisingly, doctors are also overly optimistic when it comes to the potential benefits of treatments — why? Morgan cites several potential reasons: There is very little training for doctors (if any) in statistics and probability, which are skills needed to evaluate benefits and harms of medications; promotion from drug and device companies may influence clinician thinking; clinicians may fear getting sued for not doing enough; and performance metrics often use “one size fits all” guidelines, even when a certain treatment doesn’t benefit all patients.

For better patient-centered care and less overuse, we have to reverse some of these trends. Providing better clinician training in basic probability, removing performance metrics that incentivize overuse, and prioritizing spending time with patients and having shared decision making conversations would go a long way, Morgan writes.

He also calls on doctors to embrace the gray area rather than avoiding tough conversations. Acknowledging the limits of medical treatments can be difficult for clinicians that view themselves as needing to be “invincible.” But doing this will help “foster a more holistic and meaningful sense of the doctor’s role,” Morgan writes. “Our job isn’t only to cure people; it’s also to help them make it through when there is no easy cure.”

Read Dr. Morgan’s full piece in the Washington Post!

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“They gave me Regeneron and it was like unbelievable, I felt good immediately….I call that a cure.”

Throughout the Covid-19 pandemic, President Donald Trump has touted unproven remedies, both before and after he was diagnosed with the disease. His rhetoric sends the message to Americans that we don’t need to wait for clinical evidence before declaring that something works and waiting for evidence would unjustly deprive people of access to cures. In this framework, a single positive response to a new treatment is the same as a “cure,” and making unproven treatments available to everyone is the same as “equality.”

Even though President-elect Joseph Biden is planning a different approach to the Covid-19 pandemic, the injection of partisan politics into discussions of clinical effectiveness could have a lasting impact, making efforts to reduce low-value care more difficult (low-value care refers to health care services that offer little or no clinical benefit). Decisions involving clinical evidence with multiple stakeholders have always been political, but they generally involve specific health care groups representing their interests. As debates on evidence and effectiveness have moved more into the public view, discussions around these decisions have taken on a political tinge, to the point where they fall along party lines.

In this framework, a single positive response to a new treatment is the same as a “cure,” and making unproven treatments available to everyone is the same as “equality.”

As researchers and advocates for safe and effective care, we see the need for the “Less is More” movement to anticipate this potential division and reframe our message to improve public and bipartisan political support. We want the public, the media, and policymakers to understand that high-value care is as much about freedom from harm as it is about cost and efficiency.

More than a decade’s worth of research on low-value care has given the medical field a solid understanding of the widespread prevalence of overuse and its cost to the health system. Less well understood is the rate of preventable harm it causes to patients, but there is widespread agreement that the harm is not negligible. Despite the cost and harm, large and lasting reductions in overuse have been elusive.

If clinical evidence becomes a political — or worse — partisan issue, creating such a coalition and achieving needed reforms will be increasingly difficult.

To create a health system that avoids low-value care, we need significant changes in health care policy, as well as a cultural shift away from the “more is better” default. That will require a broad coalition of clinicians, patients, and policymakers. If clinical evidence becomes a political — or worse — partisan issue, creating such a coalition and achieving needed reforms will be increasingly difficult.

President Trump’s statements have already fueled public demand for unproven Covid-19 treatments. In the days after Trump claimed that he was “cured” by the Regeneron antibody cocktail, leaders of the clinical trials reported receiving more requests from patients to participate. Researchers found similar effects after Trump touted the curative effects of hydroxychloroquine, a drug that was later found to be harmful, and convalescent plasma.

Increased public enthusiasm for experimental treatments could create hurdles for helpful policies. One effective way to reduce low-value care is to stop reimbursing clinicians for these services. But if the standard for patients and clinicians becomes “one good outcome,” no service will ever be off the table. And if industry, hospitals, and other institutions reap financial and political gains from selling unproven therapies, they will fight against policies to reduce low-value care.

This has concerning implications for future administrations’ efforts to increase health insurance coverage, because expanding access to care will be nearly impossible if the public demands that all services be covered. Additionally, those who oppose the efforts to expand health insurance will likely use demand for unproven treatments as a weapon to attack single payer, by saying that a public health plan would restrict patients’ “freedom of choice.” The more political and health care industry interests converge around this message, the more difficult it will be to move toward affordable universal health care.

We want Americans to think about high-value care as a movement for saving lives, rather than saving money.

If we want systemic change, we need to review how clinicians, policymakers, and the public view value in health care. Avoiding overuse may be seen as just a cost-saving measure, when it is as much about preventing harm to patients. Our goal is for Americans to think about high-value care as a movement for saving lives, rather than saving money for the government and insurance companies. To that end, we should focus on framing high-value care as “freedom to receive the best care without fear of harm.”

This will require engaging the media, policymakers, and the public on the potential for low-value care to hurt patients. For every celebrity’s story in the popular media about an unproven medication or cancer screening that “saved my life,” we need another celebrity sharing a story of overtreatment. When politicians say they will protect our “right to try” unproven treatments, we need them to also say how they protect our freedom from unnecessary harm.

Rather than just telling the public to “listen to the experts,” we should empower people to think critically about claims they hear about new medical treatments (as well as the people making these claims), and give them the tools they need to do so. At the same time, clinicians should be empowered to objectively evaluate the treatments they use, and to see their job not just as serving patients, but also protecting them from unnecessary interventions.  

The pandemic gives us an opportunity to change the conversation, to make high-value care an essential element of what we consider health care quality, safety, and even freedom.

The Biden administration will need to address the political divide around low-value care, and do so quickly and clearly, in ways that acknowledge the sense shared by too many Americans that they are being shut out from care that could help them. They should avoid the temptation to create hype around untested treatments, be it new Covid-19 treatments or a cure for cancer.

Many of us in the health care field are alarmed by the increasingly political rhetoric that has developed around clinical evidence in the Covid-19 era. Yet the pandemic also gives us an opportunity to change the conversation, to make high-value care an essential element of what we consider health care quality, safety, and even freedom.

Judith Garber and Shannon Brownlee also contributed to this piece.

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How could the FDA Commissioner get this so wrong? And why was convalescent plasma approved for emergency use just four days after the approval was put on hold due to data concerns? We’re taking a look at the roller coaster of events behind this emergency approval, and what it means for the FDA and approvals going forward.

What is convalescent plasma?

On August 19, The New York Times reported that the FDA’s Emergency Use Authorization (EUA) approval for convalescent plasma was on hold, due to concerns from leading federal health officials about the lack of data showing efficacy. But then four days later, the FDA changed course, giving its approval for emergency use for the treatment. What happened?

Convalescent plasma, or CP, refers to the infusion of blood plasma from people who have recovered from Covid-19. The plasma is assessed for safety, purified, and given to another patient suffering from Covid-19, so the antibodies in the plasma can help them fight the virus.

Many Covid-19 patients have already received CP through the FDA’s “compassionate use” program. CP for Covid-19 appears to be safe, with less than 1% of 20,000 patients having a serious reaction one week after transfusion, according to a Mayo Clinic trial.

However, the treatment has not yet shown to be effective for Covid-19. The most recent data on CP is from a Mayo Clinic trial of 35,000 patients with Covid-19 comparing the death rates of those who were treated with plasma within three days of diagnosis with those treated later. The researchers found that the death rate after seven days was 8.7% in patients treated with CP early and 11.9% in those treated later. Death rates after one month were also lower in patients who received plasma rich in antibodies compared to patients who received plasma with fewer antibodies. But the trial had no control group and was not randomized, which means that the lower death rate in the patients who got CP early or high-antibody plasma could be due to other factors having nothing to do with the treatment.

It was these concerns about the lack of sufficient data that compelled National Institutes of Health (NIH) leaders Francis Collins, Anthony Fauci, and H. Clifford Lane to try to put the brakes on the Emergency Use Operation until better evidence emerges.

FDA under pressure

In the days following the NIH intervention, President Trump put Hahn’s feet to the fire by lashing out at the FDA on Twitter and in the media, and accusing the agency of collaborating with “the deep state” to delay the approval. By August 23, the FDA had changed course and approved CP for emergency use.

But Hahn did more than just approve CP, he praised its effectiveness. At the news conference about the EUA, both Trump and Hahn said that convalescent plasma reduced deaths by 35%. Where did this number come from? Apparently, this was the relative reduction in deaths among a small subset of patients in the Mayo Clinic study who were under 80 years old, not on ventilators, and received plasma with high levels of antibodies early in their diagnosis. Investigators of the Mayo Clinic trial were confused, as this subset analysis was not part of the study they conducted, nor was this statistic in the FDA’s authorization letter.

Even worse, Hahn seemed to forget the difference between relative and absolute risk when he spoke at the news conference when he claimed that “35 out of 100 Covid-19 patients would have been saved because of the administration of plasma.” Scientists quickly denounced the statement as “blatantly wrong” and called for a public correction (so far, Hahn has made a correction on Twitter but not an official statement).

Other experts have pointed out that the problem is not just Hahn mistaking relative vs absolute risk, but also his failure to explain that there was no randomization or control group in the trial to begin with. Because of these features of the trial, we don’t know if there is any real survival benefit to CP yet.

that was just PART of the error; the entire comparison is flawed.
It is not a suitable control.
The data don't show anything useful
And that is precisely a regulatory failure https://t.co/5v3bU5knOi

— Vinay Prasad (@VPrasadMDMPH) August 25, 2020

What this means for future treatments

This isn’t the first time the FDA has gone against scientific consensus in what appears to be an effort to appease demands from the White House. The FDA’s emergency approval of CP mirrors their original approval of hydroxychloroquine, which later had to be walked back because it was found to harm patients more than help them. Although CP appears safer than hydroxychloroquine, there is still no high-quality evidence to support its use for Covid-19. 

“The rush to offer unproven treatments outside of well-designed clinical studies undermines high-quality science and condemns us to repeat age-old errors.”

Shannon Brownlee and Jeanne Lenzer, in Issues in Science and Technology

The irony is that we could have conducted randomized controlled trials for CP months ago but did not, what StatNews reporter Matthew Herper calls a “big failure on the part of the government response.” Unfortunately, the emergency approval threatens future randomized trials, because once a treatment is deemed successful in some way, people will be unlikely to agree to be randomly assigned to standard treatment. The New York Times reported that in the case of CP, “scientists have struggled to recruit patients for randomized trials, as many patients and their doctors — knowing they could get the treatment under the Mayo program — have been unwilling to risk receiving a placebo.”

The circumstances of the approval has also raises concerns about whether the FDA is adequately maintaining its independence from the White House. The more that politics affects or appears to affect FDA decisions, the less the public can trust that the treatments approved by the FDA are scientifically proven to work.

This does not bode well for the rollout of a Covid-19 vaccine–a case in which establishing treatment safety and efficacy is paramount and securing public trust is vital. With already dangerous levels of vaccine hesitancy in the US, the possibility that politics rather than evidence is driving vaccine approval decisions could delay the eradication of Covid-19.

If an EUA for #COVID19 vaccine is managed like today’s convalescent plasma announcement, we are in trouble. We need to know the process for evaluating safety/efficacy is based on science not politics. Today’s announcement did not provide that assurance. We must do better. 1/x

— Vivek Murthy (@vivek_murthy) August 23, 2020

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It was the neurologist Dr. John Hughlings Jackson who said “It takes 50 years to get a wrong idea out of medicine, and 100 years a right one into medicine.” Ironically, a common neurological treatment is one of those ideas that many emergency physicians consider to be wrong while most neurologists consider it to be right, no matter how much research is done.

We all want patients with a stroke to get the right care, at the right time with the right treatment, guided by the best available evidence. Whether or not using thrombolysis, treatment that tries to dissolve blood clots, improves outcomes for patients with acute ischemic stroke has been arguably the most controversial debate in emergency medicine and neurology over the last few decades. Theoretically, drugs like tissue plasma activator, or tPA, can dissolve the blood clots that cause some strokes. However, these drugs can also cause bleeding in the brain, a serious and sometimes fatal side effect.

The question is, do the potential benefits of tPA outweigh the potential harm of brain hemorrhage? We examine this issue in light of new evidence.

What do the randomized trials find?

There have been twelve randomized controlled trials (RCTs) of thrombolysis for acute ischemic stroke between 1995 and 2012. (See the table below for a summary of the results from these studies). These led to different treatment recommendations by American College of Emergency Physicians  (ACEP) and American Heart Association/American Stroke Association (AHA/ASA) for thrombolysis using tPA, up to 4.5 hours after stroke onset.

This list does not include two newer trials (one from 2019 and another from 2016) looking at extending the therapeutic window to 4.5 to 9 hours. These newer trials were done with advanced brain imaging (CT perfusion or perfusion-diffusion MRI) selecting patients with a perfusion mismatch. Both trials were stopped early which can introduce bias towards efficacy. In addition, the majority of patients included in the two RCTs extending the time window would now qualify for endovascular therapy (EVT) clot retrieval. EVT has more evidence for efficacy than systemic thrombolysis. A recent trial has even shown that EVT alone is non-inferior to EVT plus tPA .

Of the twelve thrombolysis RCTs, only two claimed benefit (NINDS-2 and ECASS-3), and four were stopped early for harm (bleeding) or futility. The other eight RCTs failed to demonstrate efficacy of these drugs. Let’s look a little closer at some of the key trials for tPA, which is currently the only FDA-approved thrombolytic for acute ischemic stroke.

Trials that failed to show benefit of tPA:

ECASS-I randomized patients to receive 1.1mg/kg of tPA or placebo up to six hours. The results favored tPA at 90 days. However, there were more bleeds in the tPA group, no statistical difference in mortality at 30 days, but more deaths at 90 days in the tPA group. The conclusions were the potential benefit of treatment did not outweigh the harms.

NINDS -1 randomized patients to receive 0.9mg/kg of tPA up to three hours after onset of symptoms. There was no statistical difference in their primary outcome of improvement of four points over base-line values in NIHSS (National Institutes of Health Stroke Severity score) or resolution of the neurologic deficit within 24 hours of the stroke onset.

ECASS-2 randomized stroke patients to receive 0.9 mg/kg tPA up to six hours. There was not a statistical difference in the modified Rankin Scale (mRS) score at three months. There was increase in bleeding but no difference in mortality at 30 or 90 days between groups. Notably, the subgroup analysis of patients in the less than 3-hour treatment window did not confirm the benefit of tPA reported in NINDS-2.

IST-3 was the largest RCT, randomizing 3,035 patients to 0.9mg/kg of tPA or placebo up to six hours. They found no statistical difference in alive/independent of activities of daily living at six months. There was a 4% absolute increase in death within seven days with tPA and a 6% increase in fatal or non-fatal intracranial hemorrhage with tPA. This means that for every 25 patients treated with tPA there would be one additional death in the first week. There were many problems with IST-3 that have been described in post-publication review, including the lack of blinding and selection bias.

It is important to note that IST-3 had a 3 and 4.5 hour subgroup of 1,177 patients. This represents almost a 50% greater number of patients than were included in ECASS-3 (n=821) claiming benefit with tPA. In this pre-specified subgroup analysis, there was a 6% absolute worse outcome with tPA.  Good neurologic outcome was 38% in the placebo group and only 32% in patients randomized to tPA. This 6% difference is statistically significant using the 95% confidence intervals.

Trials that claim to show benefit of tPA

NINDS -2 is one of the two RCTs claiming to demonstrate superiority of tPA over placebo in stroke patients. It randomized 333 patients to receive 0.9mg/kg of tPA up to three hours after stroke symptoms. There was a 12% absolute benefit at 90 days, 6% absolute harm (intracerebral hemorrhage) and no statistical difference in mortality at 90 days.

If tPA really works, the trial would show that there was a bigger improvement in outcomes with tPA, compared to the starting point.

The problems/limitations with NINDS have been pointed out in post-publication review. A reanalysis of the NINDS data by Dr. Hoffman and Dr. Schriger was published in Annals of Emergency Medicine in 2009. The bottom line from this reanalysis was that the baseline imbalance in stroke severity led to the difference in outcomes. After adjusting for the baseline imbalance, tPA failed to show superiority. A neurologist, Dr. Saver, and colleagues have questioned this reanalysis of NINDS.

Why is it important to adjust for patients’ severity of the stroke? People who start out with a more severe stroke will typically have a worse outcome than people who started with a mild stroke. So, if tPA really works, the trial would show that there was a bigger improvement in outcomes with tPA, compared to the starting point (baseline stroke severity). However, in the NINDS-2 trial, there were more people with severe strokes in the placebo group and more mild strokes in the tPA group. That is why the results made it look like tPA was more effective than placebo, but the reanalysis shows that the two groups of patients simply had a different starting point. When you take the starting point into account, there was no difference between tPA and placebo, but a lot more instances of harm with tPA.

What does the new research tell us?

ECASS-3 is the only other of the two RCTs claiming to demonstrate superiority of tPA. This trial randomized patients to receive 0.9mg/kg of tPA between 3 and 4.5 hours after onset of symptoms or placebo. ECASS-3 reported a 7% absolute benefit of improved mRS score at 90 days compared to placebo, 9% increase in intracranial hemorrhage, 2% increase in symptomatic intracranial hemorrhage and no significant difference in mortality.

A recently published reanalysis of ECASS-3 by Dr. Brian Scott Alper and other researchers at EBSCO Health and McMaster University calls into question the efficacy of tPA between 3 and 4.5 hours after onset of stroke symptoms.

In their reanalysis, the authors adjusted for baseline imbalances in stroke severity. Using multiple approaches, the authors were unable to demonstrate any significant benefit to tPA while reconfirming the harm. They concluded by calling upon clinicians, patients and policymakers to re-consider using tPA in patients with acute ischemic strokes.

This study is similar to the reanalysis of NINDS-2: when you take into account the starting point of how severe the stroke was when they received the tPA or placebo, there was no difference in outcome. In addition, in ECASS-3 there were significantly more people in the placebo group who had had a previous stroke, than in the tPA group. Typically, when someone has had a previous stroke and then has a recurrence, they will not do as well as someone with a first-time stroke. The whole trial result can be explained by these differences between the groups. When Alper et al. took these baseline differences into account in their reanalysis, they found no evidence for using tPA.

Examining conflicts of interest

It is known that financial conflicts of interest (fCOI) can influence studies and introduce bias into research. This can be also be seen when studies are analyzed in a Systematic Review/Meta Analysis  (SRMA), which is when researchers analyze a body of already-published research on a subject. Publications with fCOI tend to have more positive conclusions and are of lower methodological quality compared to those without fCOI, according to a Cochrane Review. In addition, journalist Jeanne Lenzer has published in the BMJ why we can’t trust the clinical guidelines on this issue of tPA for acute ischemic stroke.

Looking at two SRMAs of the research, one can see how fCOI may impact the results. One review by Emberson et al. found that tPA “significantly improves the overall odds of a good stroke outcome when delivered within 4.5 h of stroke onset,” but the authors only included nine of the available RCTs. When you look at the disclosures reported in the study by Emberson et al., there are multiple conflicts reported including: research grants, advisory board membership, honoraria, speaker fees, travel support from Boehringer Ingelheim who markets and sells tPA. In contrast, a review from Donaldson et al., which looked at 26 RCTs of thrombolytics and found no benefit, the authors report no competing interests.

To summarize, there are no RCTs in patients not qualifying for EVT that show benefit of tPA for acute ischemic stroke now that NINDS-2 and ECASS-3 have been reanalyzed. We agree with Alper et al., Donaldson et al., Hoffman and Cooper, and others that have questioned this treatment modality and called upon it to be re-evaluated. Hopefully this won’t take 50 years to 100 years to get the right answer.

W. Ken Milne MSc, MD, CCFP-EM is Chief of Staff at the South Huron Hospital Association and Adjunct Professor at the Schulich School of Medicine and Dentistry.

Daniel M. Fatovich, MBBS, FACEM, PhD is an Emergency Physician and Director of Research at Royal Perth Hospital; Head of the Centre for Clinical Research in Emergency Medicine at the Harry Perkins Institute of Medical Research; and Professor of Emergency Medicine at the University of Western Australia.

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Then, a week later, leaked results from another remdesivir trial in China found that the drug was not effective in improving patients’ condition or preventing death from Covid-19, compared to a control group. However, this trial was ended prematurely due to not having enough patients.

But good news for Gilead came again with the results of the National Institutes of Health study of remdesivir, a randomized controlled trial with 1000+ patients. The NIH study found that patients with advanced Covid-19 who received the drug had a shorter time to recovery by 4 days compared to patients who received a placebo drug, which is a statistically significant result. White House health advisor Dr. Anthony Fauci declared that the trial “has proven is a drug can block this virus” and that remdesivir “will be the standard of care” for Covid-19 treatment.

Case closed, right? Not exactly. Since the release of these initial NIH study results, clinicians and researchers have posed many questions about remdesivir, which have so far gone unanswered. Here are a few of them:

Where is the full data set?

When the NIH released their clinical trial results, issued a press release with the top-level findings, but not the full comprehensive data set. Two weeks later, the report with full data is still not available.

“Rather than release information in dribs and drabs, study sponsors — whether a government, company, or university — should release all the results lickety-split,” writes pharmaceutical industry journalist Ed Silverman in a Stat News editorial.

Good news is sparse in the pandemic, and people understandably want to share the positive result of the remdesivir trial. But releasing the NIH study without the full data instantly turned remdesivir into the new standard of care, even though we don’t know about potential side effects, how the drug should best be allocated, or even whether the drug saves lives.

Does remdesivir improve survival?

If remdesivir helps patients recover from Covid-19 faster, that is a positive result. However, it is not the same as knowing whether remdesivir saves lives. The NIH results found that patients who took remdesivir were less likely to die than patients who recieved a placebo (8% vs 11.5%) but the difference was not statistically significant.

Unfortunately, this is all of the information clinicians and researchers have to go on, because the decided to stop the trial prematurely and start giving all trial participants remdesivir, before researchers could collect the information necessary to know whether or not the drug improves survival. Although some argue that the mortality results were “trending” toward significance, they could have just as easily been proved not significant with more data–we just don’t know.

Stopping the trial was undoubtably a tough ethical decision. But some experts are disappointed that the trial was stopped early. “Mortality is the right endpoint,” said Dr. Peter Bach, director of the Center for Health Policy and Outcomes at Memorial Sloan Kettering Cancer Center, in Stat News. “The reason we have shut our whole society down is not to prevent Covid-19 patients from spending a few more days in the hospital. It is to prevent patients from dying.”

How should this drug be used?

After the NIH study results were released, the US Food and Drug Administration acted fast to approve emergency use of remdesivir for Covid-19 patients, and the drug began to be distributed throughout the country. However, due to the absence of data, clinicians still have questions about which patients will receive the most benefit from the drug, and how the drug should be allocated.

The available clinical studies do not give clinicians enough information about which patients benefited most from the drug based on age or clinical severity. There is not enough remdesivir to give to all patients, but doctors do not know which patients to prioritize.

“In deciding who should receive this medication, how does one choose between, say, the 34-year-old health-care worker requiring oxygen support and the 65-year-old liver transplant recipient who has spent the past two weeks on a ventilator?” write doctors at Massachusetts General Hospital Mark Siedner, Alyssa Letourneau and Rochelle Walensky in an op-ed in The Washington Post.

The hype surrounding remdesivir and desperate situation of the pandemic, clinicians are under pressure to use the drug, but with basically no information to help them do this.

“In the wake of this media bombshell and data tease, we are left with a treatment that the FDA has permitted us to use, and that patients and families will justifiably expect, but with an extremely limited drug supply and no evidence-driven guidance on how to use it,” write Siedner et al.

Their conclusion: We need more data! Clinicians, researchers, and policymakers are relying on the full results of the NIH trial as well as new studies to guide their application of remdesivir–let’s hope this information arrives swiftly.

The post Key questions about remdesivir still unanswered appeared first on Lown Institute.

The issue of poor science in medicine is not new, write Lown Senior Vice President Shannon Brownlee and medical investigative journalist Jeanne Lenzer, in a recent article in Issues in Science and Technology. In fact, medicine has a long history of doing things that don’t work, but in this pandemic, these deficiencies have been exposed.

The pandemic has revealed several major fault lines in medical research, write Brownlee and Lenzer:

1. A lack of rigorous studies that provide meaningful results with as little bias as possible
2. Our rush to do more in medicine, regardless of whether we know it works
3. The media’s role in hyping unproven treatments, and
4. The lack of regulation of new medical treatments, and the invasion of politics into these decisions.

Lenzer and Brownlee explain the history of medical research, from the 1918 pandemic (in which anti-malarial drugs were also touted as a cure), to the start of the era of evidence-based medicine. Although we have come a long way, the coronavirus shows how we are still repeating the errors of centuries past.

These mistakes will not only have an impact on patient health now, but they will make it more difficult to fight the next pandemic. They write:

"The first rule of a good clinical trial is to establish an appropriate control group. It was the only thing that persuaded doctors to abandon bloodletting. If we don’t follow that rule now, SARS-CoV-2 or another novel virus will roll around again, and we will still have no effective medicines to treat it."

Read the full article in Issues in Science and Technology!

The post Why pandemic science has gone out of control appeared first on Lown Institute.

The very next day, President Trump tweeted about a “miracle cure” for coronavirus: Hydroxychloroquine, an antimalarial drug that has not been approved by the U.S. FDA to treat coronavirus.

Insufficient evidence

Why make the claim that hydroxychloroquine is a “game changer” for coronavirus treatment? Hydroxychloroquine and chloroquine are known to provide in-vitro protection against coronaviruses, but so far there is no peer-reviewed clinical evidence showing that it is effective against COVID-19. The hype is based on reports of success with the drug in China and a small French study that examined the effects of taking hydroxycholoroquine along with azythromysin (an antibiotic) on the viral loads of COVID-19 patients.

The study included just 42 hospitalized COVID-19 patients, with 26 given hydroxychloroquine and 16 given no treatment. After six days, the percentage of patients with no viral load detected in testing fell to about 30% in the treatment group, compared to 85% in the control group. Those treated with azythromysin as well as hydroxychloroquine appeared to do even better, with 100% showing no viral load on tests after 6 days.

Looking at this study quickly, one might agree that hydroxychloroquine is indeed a miracle cure. But on closer examination, there are serious methodological issues with the study that should make readers think twice about the results.

First, a significant portion of patients originally in the treatment group (6/26 patients) were excluded from the final analysis. Why? Three were transferred to the ICU, one died, one left the hospital, and one withdrew due to nausea. The fact that these cases were “excluded” rather than counted as failures of the treatment is suspicious.

Second, as Dr. Jason Pogue pointed out on Twitter, the patients in the control arm of the study appeared to have higher viral loads to begin with, compared with patients in the treatment arm. Therefore, it would be more difficult for them to have a zero viral load on a test, compared to patients in the treatment arm.

Why do I bring this up. Because it means there was a chunk of pts in the monotherapy arm who would need a greater antiviral effect to reach “negative” or undetectable virus. In this analysis negative was defined as Ct>35. It’s also notable that negative is often defined at Ct>40.

— Jason Pogue (@jpogue1) March 20, 2020

What’s the harm in hype?

We do not have strong evidence that hydroxychloroquine helps COVID-19 patients, but that does not mean that it cannot help them. If this drug has the potential to help in this pandemic, what’s wrong with bringing attention to it?

It is just as likely that giving COVID-19 patients hydroxychloroquine could harm them as help them. Hydroxychloroquine has several side effects, including–in rare cases–fatal cardiac failure. Exposing patients to these side effects without evidence that they will benefit from the treatment is risky.

Misleading claims about COVID-19 cures can also lead to people hoarding drugs or harming themselves by taking drugs without medical supervision. Unfortunately, many such events have already happened as a result of Trump’s actions. Overdoses of chloroquine have been reported across the world. An American couple ingested chloroquine phosphate, a chemical typically used to clean fish tanks; the woman became seriously ill and the man died.

Those who need hydroxychloroquine for indicated conditions like lupus or rheumatoid arthritis are having trouble accessing their medications. For these patients, “stopping the medication could cause them to flare, which means that they then need to go on other immunosuppressants … or even get admitted and potentially get exposed [to the coronavirus] in the clinical setting,” said Brigham and Women’s rheumatologist Dr. Jeff Sparks, in a WBUR interview.

Ironically, hype about this drug may make it more difficult to find out whether the drug really works. As hospitals start clinical trials to test the effects of hydroxychloroquine for COVID-19, it may be harder to recruit patients to be randomized, if they already believe that the drug is effective.

Not having a vaccine or a cure is scary, but now is not the time to throw evidence out the window. As Dr. Ezekiel Emanuel and Dr. Vinay Prasad wrote in a recent op-ed in The Washington Post, “When it comes to fearsome, fatal conditions, it is human nature to try something because it should help, because it might help, because it must help, or because it couldn’t hurt. But often it does harm people and our quest for a real cure.”

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