In U.S. claims analysis, fracture risk lower with DOACs
This article was first published on Monday, November 25, 2019 in MedPage Today.
By Nicole Lou, Staff Writer, MedPage Today.
Warfarin (Coumadin) may not be the best oral anticoagulant in atrial fibrillation (Afib) in terms of bone health, a retrospective study suggested.
On multivariable-adjusted, propensity score-matched analyses of insurance claims, new users of direct oral anticoagulants (DOACs) were at lower fracture risk over an average 16.9 months of follow-up compared with new warfarin users:
Fractures requiring hospitalization: HR 0.87 (95% CI 0.79-0.96)
All clinical fractures: HR 0.93 (95% CI 0.88-0.98)
Hip fractures: HR 0.91 (95% CI 0.78-1.07)
The strongest effect estimates were observed when comparing apixaban (Eliquis) and warfarin, whereas head-to-head comparisons among DOACs showed similar fracture risk, Pamela Lutsey, PhD, of University of Minnesota School of Public Health in Minneapolis, and colleagues reported inJAMA Internal Medicine.
"Collectively, our findings support the notion that warfarin may be harmful to bone health," they concluded. They argued that the lack of statistical significance for the outcome of hip fracture may have to do with lower precision for this outcome.
Warfarin had been associated with higher fracture risk than dabigatran (Pradaxa) in a 2017 study from Hong Kong.
"Vitamin K is important in posttranslational glutamination of osteocalcin, the major noncollagenous bone matrix protein. Warfarin interferes with this process and consequently inhibits the activation of bone matrix proteins," the investigators noted.
They recommended caution when prescribing warfarin to patients with Afib at high risk of fracture.
The study used MarketScan administrative claims databases for information on a commercially-insured population of people with non-valvular Afib who were prescribed oral anticoagulants in 2010-2015. These were new users without known prior exposure to oral anticoagulation.
Groups were categorized according to the first oral anticoagulant they were prescribed: dabigatran (18.9%), rivaroxaban (Xarelto, 21.1%), apixaban (10.6%), warfarin (49.4%).
In the end, 167,275 individuals were matched for comparison. Their average age was 68.9 years; 38.0% were women. Each DOAC user was matched to up to three warfarin recipients.
The subgroup of people diagnosed with osteoporosis especially benefited from DOACs over warfarin, according to Lutsey's team.
Potential confounding is an inherent limitation to such a retrospective analysis, the authors acknowledged. Even after matching, the warfarin and apixaban groups in this study were older and had higher CHA2DS2-VASC scores compared to the dabigatran and rivaroxaban groups.
Furthermore, the databases used for the analysis excluded people without insurance, and edoxaban (Savaysa) was excluded from the study because there were too few users of this DOAC in the dataset.
The study was supported by grants from the National Heart, Lung, and Blood Institute; the National Institute on Aging; and the American Heart Association.
WASHINGTON -- As the Centers for Medicare & Medicaid Services works to get its new primary care physician payment models off the ground, the agency now also has to deal with resignations at the organization the government charged with developing new Medicare payment models.
The Physician-Focused Payment Model Technical Advisory Committee (PTAC) was created by the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) with the mission to make comments and recommendations to the Secretary of Health and Human Services on proposals for physician-focused payment models. "The secretary is required by MACRA to review PTAC's comments and recommendations on submitted proposals and post a detailed response on the CMS website," according toHHS's description of PTAC.
On Tuesday, PTAC member Harold Miller, MS, resigned from the committee; committee member Len Nichols, PhD, resigned the next day. Miller said his decision to resign was not contingent on anyone else's, while Nichols said that seeing Miller resign helped him make his own decision to do so also.
Frustrations with the Process
In their resignation letters, both men outlined their frustrations with the PTAC process -- specifically, with the fact that none of the models PTAC recommended have been approved by CMS for pilot-testing or implementation.
"Over the last 3 years, we have reviewed 32 proposals submitted by thoughtful practitioners in various fields of health care delivery (with one more on the docket for this December), and we recommended either testing or implementation for 16 of them," wrote Nichols, who is director of the Center for Health Policy Research and Ethics at George Mason University, in Fairfax, Virginia.
"Every single one of those recommendations has been declined by the secretary of HHS. Of late, public language has been used praising PTAC's various efforts and contributions, but the outcome is the same: HHS/CMS/CMMI remains opposed to implementing ideas submitted from the field." (CMMI refers to the Center for Medicare and Medicaid Innovation at CMS.)
The rejections "[are] not because PTAC has done a bad job; indeed, both in the formal responses to our recommendations and in a variety of public events, the secretary of HHS, the CMS administrator, and the director of CMMI have repeatedly praised PTAC for its work," Miller, who is president and CEO of the Center for Healthcare Quality & Payment Reform, in Pittsburgh, noted in his letter. However, he continued, "it also seems clear that future recommendations will meet the same fate; the former director of CMMI told us there was 'no circumstance' in which CMMI would ever directly implement a payment model submitted through the PTAC process."
Wide Variety of Models
CMMI has only said that it would incorporate some of the "concepts" from PTAC-recommended models within the programs that CMMI develops, which "is completely inconsistent with the spirit of MACRA; Congress clearly envisioned that at least some of the good payment models developed by physicians would be implemented if they were recommended by PTAC," Miller said. The 16 models recommended by PTAC have spanned many areas of practice, including oncology, primary care, and home hospitalization.
"I do not want to be part of a process that misleads physicians and other stakeholders into thinking that if they develop a good physician-focused payment model, go through the rigorous review process PTAC has established, and receive a positive recommendation, they will have a chance of seeing their work implemented," he wrote. "The people who have submitted proposals to PTAC have spent many hours and significant amounts of money to develop their proposals, respond to our questions, and attend our meetings. All of this work has been wasted since it has been made clear that their work will not be implemented, and it does not appear that the outcome will be any different for future proposals, no matter how good they are."
In an email to MedPage Today, Nichols described the concerns committee members had and their attempts to do something about it. "A number of us long-time members have discussed steps we might take, including resignation, that might alert more to how ineffective PTAC currently is," he wrote. "We tried to organize a public discussion of the state of PTAC, but were told such a discussion with applicants was out of our legislative scope and forbidden."
In addition, "quite a number of us contemplated resigning and discussed it after the 'big no' letter from the Secretary arrived in June of 2018," Nichols said, referring to a letter from HHS secretary Alex Azar declining to implement 10 of the models the committee had recommended. "Adam Boehler had just come on board [as head of CMMI] and had little or nothing to do with those letters, and so we were persuaded to give the process more time." However, "this last set of rejections, and the way the RFA [request for applications] for PCF [the Primary Care First model] and the oncology model were 'spun,' pushed me and perhaps others back over the edge."
Hopes for the Future
Nichols told MedPage Today that he hopes his resignation "helps convince people inside HHS and the Congress, and throughout the stakeholder community, that something must change for the PTAC portions of MACRA to be effective. At a minimum, the secretary should direct CMMI to comment on proposals before the PTAC in public, so that applicants and PTAC members have a chance of rebuttal before the PTAC letters are written and before the Secretary's response is sealed."
Asked to comment on the resignations, HHS thanked Miller and Nichols for their contributions and added that "PTAC's in-depth deliberations and recommendations are invaluable to HHS and CMS in crafting physician models. HHS and CMS are committed to value-based care, working with stakeholders, and using the extensive work of PTAC to inform physician models implemented through the CMS Innovation Center."
Health economists had varying reactions to the controversy. "When you have a group of experts that aren't listened to, the country suffers," said Paul Hughes-Cromwick, MA, co-director of Sustainable Health Spending Strategies at Altarum, a healthcare consulting firm here.
Michael Chernew, PhD, professor of health care policy at Harvard Medical School, said he didn't follow the PTAC models much, "but I think in general, we don't need a lot more models anyway [though] that doesn't mean there aren't any that could be good. I think we have to think about simplifying the vision of how we do things, so I am skeptical that more models are the solution." Rather than have narrow, specialty-focused models, "I believe we should have broader models and allow underlying things to work out individually between organizations," Chernew said.
CMS administrator also trumpets new hospital, insurer transparency rules.
This article was first published on Tuesday, November 19, 2019 in MedPage Today.
By Shannon Firth, Washington Correspondent, MedPage Today.
WASHINGTON -- Centers for Medicare & Medicaid Services Administrator Seema Verma blasted nonprofit hospitals for suing patients, plugged new price transparency rules, and blamed the uptick in the nation's uninsured rate on the Affordable Care Act, during an interview and panel discussion at the U.S. News & World Report Healthcare of Tomorrow summit Tuesday.
"We're hearing more and more stories about hospitals that are going after patients that don't have health insurance and ... they're [nonprofit] hospitals. They're taking people to court over prices that they would never charge anybody else," Verma said during a Q&A with Brian Kelly, U.S. News editorial director and executive vice president.
Nonprofit hospitals should not be suing patients who can't pay and they especially shouldn't be doing so if they aren't posting their charges online for the public to see, she said.
To that end, Verma touted two new CMS rules released Friday that focus on price transparency. The first targets hospitals and is slated to take effect in 2021; the second is still in draft form and addresses price transparency among insurers.
The hospital-focused rule would require systems to provide prices upfront for at least 300 "shoppable" services, such as hip replacements, in a patient-friendly format.
The second rule would allow patients to know the precise status of their deductible, and what their out-of-pocket costs would be for a particular service.
But Verma said the rules' critics are only defending the "status quo" because it serves them, and that hiding their prices simply allows them to "take advantage" of the consumer.
Prices in New Hampshire fell after the state developed its own all-payer database and made prices visible online, she said.
"I think the evidence shows [that when prices are made public], people will shop around. Not everybody ... but it's enough to potentially make the market respond with lower prices and increasing competition," she stated.
Verma was asked how CMS will respond if the Trump administration succeeds in eliminating the entire ACA in Texas v. United States of America.
Verma defended the lawsuit, arguing that the ACA has driven up premiums by over 200% for some beneficiaries and created "a new class of uninsured" -- those living at 300% and 400% of the federal poverty level who don't receive subsidies and therefore can't afford coverage.
A recent report from the Georgetown University Health Policy Institute focused on rising uninsurance rates among children and blamed the increase on the loss of public coverage.
Verma also pledged that "whatever comes out of the courts," the administration would ensure that people with pre-existing conditions are protected and that there's "no disruptions in coverage."
She also theorized that some people are so frustrated with our current healthcare system, they're willing to blow it up by eliminating the insurance system entirely and instead "[giving] all control to the government."
Verma has been relentless in her criticism of "Medicare for All" -- "the greatest threat to the American healthcare system," she once said -- and public option proposals. She continued to express those same concerns, calling alternative proposals for healthcare "dangerous" and "destructive."
She said that these alternatives would increase costs, delay innovation, and threaten the sustainability of the current Medicare program.
Instead, Verma highlighted the Trump administration's priorities for healthcare reform:
Increase price transparency
Improve interoperability of the electronic health record (EHR) system, including ensuring patients' EHRs travel with them
Shift towards a value-based payment system that rewards clinicians for providing better care rather than simply more services
In a panel discussion on measuring value in healthcare after the Q&A, Verma said that one core goal of the administration is to provide patients with more data, including more quality data, which she argued will promote competition. The administration has specifically asked for feedback regarding how to integrate quality data into pricing information in its proposed transparency rule for health plans.
Panelist Vivian Lee, MD, PhD, MBA, president for health platforms at Verily Life Sciences, suggested the idea of holding a community accountable for improving the health of its population. Lee suggested having health systems work together on these issues. Determining which individual patients each system is responsible for could be a challenge, but "I think that could be a very powerful driving force and it could be very, very useful," she said.
Asked whether the idea was practical, Rachel Werner, MD, PhD, professor of medicine and healthcare management at the University of Pennsylvania in Philadelphia, said that such an approach would be "complicated" in very competitive markets.
But any model holding health systems responsible for improvements to community health should focus heavily on the social determinants of health, such as access to housing, employment, and food, added Werner, who is executive director for the Leonard Davis Institute of Health Economics at the university.
"It's not a turnkey solution but I think is one worth striving for," she said.
PHILADELPHIA -- After the ISCHEMIA trial delivered its clear determination that early revascularization isn't better than medication alone for moderate-to-severe, but stable, heart disease, cardiologists saw little "reperfusion injury" for their practice overall.
"Everyone sees what the they want to see," Gregg Stone, MD, of the Icahn School of Medicine at Mount Sinai in New York City, quipped on Twitter, while Robert Yeh, MD, MBA, of Beth Israel Deaconess Medical Center in Boston tweeted, "Everything I believed yesterday, I believe even more strongly today."
Still, there were many others here at theAmerican Heart Association (AHA)meeting who concluded from the seminal trial that important changes are needed in the upstream testing that leads patients to this juncture in their care and in how aggressively to proceed.
"We have real proof that revascularization does not appear to have a marked effect on the natural history of stable ischemic heart disease," said James de Lemos, MD, of UT Southwestern Medical Center in Dallas. "I think the downstream implications of this with regard to noninvasive testing are massive."
"I think that is more where we will see it in our practice. Many of us as, a result of [Orbita] and COURAGE, have become more conservative inherently, but this will have major effects on cardiac testing," he stated.
The Best Gatekeeper?
The trial included 5,179 stable patients who had moderate or severe ischemia on clinically-indicated nuclear, echo, cardiac MRI, or exercise tolerance testing confirmed by coronary CT angiogram (CTA), which also ruled out unprotected left main disease.
Of the 3,339 screen failures, more than half were due to insufficient ischemia and most of the rest were due to no obstructive coronary artery disease found on CTA.
Since randomization to routine early revascularization or continued optimal medical care alone didn't make a difference on outcome, "it does beg the question of whether the stress test as a gatekeeper is that useful," said Athena Poppas, MD, of Brown University in Providence, Rhode Island.
"Are we doing too many stress tests on these patients who have moderate or mild symptoms -- one episode of angina per month? That's a big question. Maybe it's more important to rule out left main with CTA," said Roxana Mehran, MD, also of Mount Sinai.
"This will change practice, because at the moment most of these patients are landing in the cath lab and we're expected to fix them," she added.
Stress tests are still needed to screen whether symptoms are coming from ischemia, but shouldn't be enough to send patients to the cath lab, even in high risk cases, concluded Poppas.
"We all worry about patients who have a very positive stress test dropping dead or having a heart attack in short order," noted Judith Hochman, MD, of NYU Langone Medical Center in New York City, in discussing the main findings she presented at the AHA meeting. "The point here is these patients were treated with medication. Between the stress test and enrollment, they were treated, which means that stabilizing the plaque is really, really important."
"Trying to get patients to actually comply with risk factor modification and medications is absolutely our goal, should be our goal, in terms of the medical community going forward," she stated.
With this strategy, only 28% of the patients in the conservative group got cardiac catheterization and only 23% got revascularization by 4 years in the trial.
"Watchful waiting is as good," Poppas concluded.
The trial did show a quality of life (QoL) advantage to early invasive management but only for those with angina, as the revascularization arm had greater freedom from angina.
"After you optimize the medicines, if it bothers them, or they don't even like taking the medicines...at least the patient understands the trade-off, they want to be relieved of the angina, that's great," said John Spertus, MD, MPH, of St. Luke's Mid America Heart Institute in Kansas City, who presented the QoL data at the AHA meeting. "You could never have done that with confidence without these data to support that really there's no difference in death out to 4 years plus."
"The practice pattern seems simple and we should not lose the forest for the trees here," he added. "Health status and quality of life is important to our patients."
Left Main Disease
The only conundrum is how to ensure that patients don't wait on revascularization if they have left main disease, which has been shown to clearly benefit from it, noted Alice Jacobs, MD, of Boston University.
Based on the number of people excluded from ISCHEMIA, taking all-comers would leave about 5% with prognostically significant left main disease, noted Darshan Doshi, MD, of Massachusetts General Hospital in Boston.
Changing practice patterns to incorporate CTA upfront "if that's available might be reasonable" to rule it out, Jacobs said.
Another possibility, Poppas suggested: "It may be in the future that, on the heels of FAME or PROMISE, that coronary CT with fractional flow reserve would answer a lot of questions."
U.K. groups advocate a CTA-first strategy, noted Ajay Kirtane, MD, of of New York-Presbyterian/Columbia University in New York City.
Cost and access are issues, commented E. Magnus Ohman, MBBS, of Duke Clinical Research Institute in Durham, North Carolina. "The other fear in this country is the radiation exposure. Even though that's been mitigated, it's a concern especially in women. Repeated CT test is a driver. There is some downside."
New U.S. guidelines are underway, said Glenn Levine, MD, of Baylor College of Medicine in Houston. The American College of Cardiology and American Heart Association chest pain writing group, and the revascularization guideline writing group, have documents in the works that will presumably incorporate ISCHEMIA, he suggested.
Another next step is to expedite a tool for shared decision-making to explain the findings to patients, noted Elliott Antman, MD, of Brigham and Women's Hospital in Boston.
Long-Term Perspective
High on the priority list, too, is ensuring funding to continue to follow ISCHEMIA patients, a number of cardiologists at the AHA meeting said.
For both the primary composite of cardiac events and the key secondary of MI and cardiovascular death, the curves crossed over at about 2 years, with an absolute 1.9% more events in the first 6 months and 2.2% fewer at 4 years compared with optimal medical therapy alone.
The early difference looked like it was primarily driven by periprocedural MI, whereas "it looked like they were continuing to diverge in favor of an invasive approach," commented Doshi. "If patients were actually followed out longer, perhaps at statistically significant difference in favor of an invasive approach might be reached."
A similar pattern has been seen before, noted Kirtane, pointing to STICH, STICHES, and EXCEL.
"Any randomized trial of bypass surgery versus medical therapy, they all show exactly the same curves: early risk, later benefit," Ohman agreed.
"The late change makes me believe wholeheartedly that we cannot walk away without understanding what's next," Mehran said. "'ISCHEMIA LATE' now becomes the most important trial we must absolutely get done."
Hochman "There's been a lot on social media about the $100 million spent. We calculate that if asymptomatic patients didn't get PCI, we would save over $500 million every year. ...I believe it was money well invested."
This article was first published on Thursday, November 14, 2019 in MedPage Today.
Kristina Fiore, Director of Enterprise & Investigative Reporting, MedPage Today
Autopsies have been an important part of medical education and practice, but over the last 50 years they've been performed far less frequently -- and doctors may be missing out on useful information, according to anew perspective in the New England Journal of Medicine.
Older physicians may recall regular visits from the pathologist to confirm or disprove their diagnoses, and these were "a form of audit for the whole medical team," according to Kevin De Cock, MD, the Kenya country director for the CDC, and colleagues. "The experience could be humbling or reassuring, but it was always a deterrent to medical hubris."
Now, autopsies in the U.S. are typically reserved for cases in which a death is suspicious or a crime is suspected, De Cock said.
"Much more can be learned from the dead," he told MedPage Today.
There are many reasons for the decline: attempts to reduce healthcare costs; concerns about litigation if errors are identified; greater cultural aversion to interfering with cadavers.
De Cock also pointed to "our own medical hubris," in an interview with NEJM. "Our ability to investigate living patients clinically is so much better than it was in previous decades, so the assumption is, we don't need to be doing this anymore," emphasizing a rise in "medical overconfidence because of increased diagnostic and therapeutic capacities."
But according to data from full autopsies, the rate of misdiagnoses and mistakes hasn't changed much over time, hovering around 30%, he said.
Judy Melinek, MD, a forensic pathologist based in San Francisco, highlighted a previous NEJM article estimating that if an average U.S. hospital performed autopsies after all deaths, it would detect class I errors -- those that "would have resulted in a change in therapy and might have prolonged survival if identified earlier," she said -- in about 4% of cases, and class II errors -- "missed diagnoses that didn't affect survival but were still clinically important" -- in an additional 4%.
"Pathologists and academic physicians are very concerned about the international drop in autopsy rates," Melinek said.
While full autopsy remains the gold standard, De Cock noted that less invasive methods of postmortem examination have been developed, and could be applied in specific situations.
In Nairobi where De Cock is based, for instance, tissue sampling of cadavers for HIV has enabled researchers to calculate excess deaths due to the condition. In West Africa, oral swabs and subsequent testing have helped identify additional clusters of Ebola outbreaks that weren't previously suspected, and liver biopsies can help countries better estimate rates of hepatitis B and C, he said.
"Virtual" autopsies that rely on CT or MRI could also be another means of gleaning certain types of information, as well as "verbal" autopsies involving interviews with family members, particularly in low- and middle-income countries, De Cock wrote.
But Melinek cautioned about the limits of less-invasive means of "gleaning information about disease and death."
"These may be sufficient in cases where families have religious objections to autopsy, but they only answer the questions people know to ask," Melinek said. "As a forensic pathologist, I have seen radiology misidentify natural anomalies as injury, or miss fatal injuries that were too small to see radiographically and were only picked up by gross and microscopic analysis."
"If 'virtual autopsies' become the standard of postmortem care," she said, "then we will never know what we may be missing."
De Cock said it's time for a "global research and public health agenda that focuses on learning from the dead."
"We hope our paper will stimulate broader debate and result in a change of attitudes and practice," he told MedPage Today. "There is much to learn from the world's decedents and currently this global body of information is underutilized."
Also, newer designs need more data, disposable scopes not yet approved
This article was first published on Tuesday, November 11, 2019 in MedPage Today.
By Shannon Firth, Washington Correspondent, MedPage Today
GAITHERSBURG, Md. – Bullied, low-wage workers with poor training and oversight are one of the key factors in the ongoing contaminated duodenoscope saga, an expert advisory panel to the FDA suggested.
Tasked with making recommendations to reduce the risk of infection following duodenoscopes reprocessing – which involves manual cleaning and disinfection or sterilization – some members of the FDA's General Hospital and Personal Use Panel of the Medical Devices Advisory Committee argued on Thursday that the same intricate design (narrow channels, tiny screws, doors, levers, etc.) that allows duodenoscopes to inject image contrasting agents and provide "side visualization" through a camera can also easily trap microbes and makes the devices nearly impossible to clean.
Panel chair Frank Lewis Jr., MD, executive director emeritus for the American Board of Surgery, called the lack of adequate worker training and oversight the "dominant factor" behind the problems in reprocessing the scopes. Many of these technicians are low-wage, low-literacy workers who are asked to follow manuals that may include hundreds of steps, and some are bullied into working more quickly.
Guest speaker Cori Ofstead, MSPH, an expert on human factors and quality assurance from St. Paul, Minnesota, said recent surveys of reprocessing professionals from the International Association of Healthcare Central Service Materiel Management, showed that only 36% of technicians did any visible inspection of endoscopes after reprocessing, 17% skipped steps, and 40% reported experiencing or observing bullying on a daily basis.
Panelist Gary Socola, CEO of Highpower Validation Testing & Lab Services in Rochester, New York, noted that only four states in the U.S. require certification for these technicians.
"There's very good training out there ... and people want to learn, we just have to make that possible," he said.
Because the FDA has no jurisdiction over training, Lewis recommended that the agency work with manufacturers, the Joint Commission, and other relevant agencies (including the Centers for Medicare & Medicaid Services) on strategies for improving training and worker conditions.
Another speaker, microbiologist Michelle Alfa, PhD, from the University of Manitoba in Winnipeg, Canada, explained that microbes can survive a duodenoscope cleaning if a lever mechanism isn't placed at a 45° angle during reprocessing and is instead left in the down position. She also stressed the importance of automated or forced air drying, stating that "wet storage" is the "beginning of biofilm."
And yet another expert said organizations currently choose their own quality-monitoring protocols and evidence-based guidelines to follow.
The Baby or the Bath Water?
Panelist Stephen Wilcox, PhD, of Design Science in Philadelphia, agreed with many of the public speakers that reprocessing technicians are put "in an almost impossible situation," but insisted the problem was technology-driven.
"The reprocessing is so complex that it's very difficult to do well," Wilcox said.
His first recommendation was to get rid of traditional duodenoscopes completely and move to disposable ones or secondarily, simplify the devices to make them easier to reprocess, he said. He also recommended verifying the level of effective reprocessing through borescopes (flexible tubes with cameras that can be inserted into a duodenoscope to assess damage and search for debris).
On whether incremental (transitioning to disposable tips) or more substantial changes were recommended, Lewis said the panel was limited by the current state of technology. Two or three manufacturers are "actively working" on the design of fully disposable scopes, but none have been approved yet.
And panelists agreed that it was too soon to tell whether non-traditional duodenoscopes, including those with replaceable tips, could reduce contamination rates, given limited data for comparison.
Cost could also be a factor in any transition away from traditional duodenoscopes, they suggested.
Ashley Faulx, MD, a gastroenterologist at Case Western Reserve University in Cleveland, said that switching to disposable duodenoscopes (if and when approved) or to those with replaceable tips may be attractive to a hospital that has experienced an outbreak.
"But to mandate that everybody does it, I think, would be a really bad idea," she said, noting that such a mandate could reduce access to endoscopic retrograde cholangio-pancreatography (ERCP) procedures.
How Clean Is Clean?
When asked about the use of high-level disinfection versus sterilization, most members felt that high-level disinfection provides an "adequate margin of safety."
Sterilization offers a higher margin of safety but carries its own challenges. (The advisory committee also provided recommendations to the FDA on Wednesday and Thursday on how to address issues around ethylene oxide sterilization of medical devices.)
Jason Dominitz, MD, a gastroenterologist at the Veterans Health Administration in Seattle, held that requiring sterilization would limit access.
But Isaac Benowitz, MD, a pediatrician and epidemiologist for the CDC, said all the data he's seen suggest high-level disinfection is "rarely done properly" and urged switching to sterilization.
"We've been making incremental changes and improvements in high level disinfection and devices for decades and we're still here talking about it," said Benowitz.
Panelists punted on a technical question related to how many cycles of simulated use and cleaning were required in durability testing (an FDA proposal calls for 250 cycles), and called for more data collection.
The Trouble With Duodenoscopes
In 2015, dozens of patients developed abdominal infections after ERCP procedures using the duodenoscopes.
Since 2015, the FDA has held several meetings, issued warning letters, safety communications, and ordered companies to overhaul their post-procedural cleaning processes, but problems persist.
More recently, the agency cleared two duodenoscopes with disposable parts for use and in August recommended that hospitals and clinics plan to transition away from traditional duodenoscopes with fixed end caps toward those with single-use parts until entirely disposable devices are available.
Duodenoscopes are inserted through the mouth and wind down the throat, through the stomach and into the small intestine or duodenum and can be used to remove gall stones or tumors, insert stents to break up a blockage, and restore flow through the intestine, explained Shani Haugen, PhD, of the FDA's Centers for Devices and Radiological Health.
They have hinged elevator mechanisms at their distal tips, which can be incredibly challenging to clean but, as experts testified, other air channels in the device can also trap microbes.
In September 2013, the CDC shared information with the FDA regarding a link between these devices and multi-drug resistant organism infections, such as carbapenem-resistant Enterobacteriaceae.
Since then, multiple healthcare facilities have reported infections related to duodenoscopes.
In February 2015, the FDA released a safety communication regarding the design of ERCP duodenoscopes and cleaning challenges and in October, 2015, the agency ordered all three duodenoscope makers (Olympus, Fujifilm, and Pentax) to perform postmarket surveillance studies.
In May 2015, members of an FDA advisory committee on gastroenterology devices agreed that the duodenoscopes available at that time were indeed unsafe, yet did not recommend discontinuing their use as the alternative options, in some cases, carry even greater risk. Alternatives to duodenoscopes are open or laparoscopic surgical drainage or percutaneous transhepatic drainage.
The FDA continues to emphasize that for the "appropriate population," the benefits of duodenoscopes still outweigh their risks.
While medical device reporting data of infection rates associated with contaminated duodenoscopes have fallen since 2015, reports of contaminated duodenoscopes have risen, according to Haugen's presentation. The increased contamination rates may be due to improved sampling and culturing by healthcare facilities, she noted.
An analysis of data from 2015 to 2019 in and outside of the U.S. found two death reports, a sharp reduction from the peak of 39 deaths in the fall of 2016, Haugen said. Of the 79 total death reports, 69 occurred in the U.S.
Haugen noted that causality can't be established with these reports and that adverse event rates are often under-reported.
Interim results of FDA's mandated postmarket studies reported in July 2019 found that "high concern organisms" were found in about 4-6% of devices.
FMT also tied to shorter length of hospital stay, better overall survival vs antibiotics.
This article was first published on Monday, November 4, 2019 in MedPage Today.
By Molly Walker, Associate Editor, MedPage Today.
Patients with Clostridioides difficile infection treated with fecal microbiota transplant (FMT) had lower risk of bloodstream infection, fewer days of hospitalization, and a higher increase in overall survival versus those treated with antibiotics, researchers in Italy found.
In a propensity score-matched cohort, 4% of patients with C. difficile treated with FMT had bloodstream infections compared with 26% of the antibiotic-treated cohort, reported Gianluca Ianiro, MD, of Università Cattolica del Sacro Cuore in Rome, and colleagues.
Moreover, propensity score-matched patients in the FMT group had significantly shorter mean length of hospital stay compared to the antibiotic group (13.4 vs 27.8 days), they wrote in the Annals of Internal Medicine.
Despite the current controversies associated with FMT, including a warning from the FDA after patients developed a multi-drug resistant infection following the procedure, the authors described FMT as a promising approach to treat C. difficile infections, particularly more severe ones, and outlined what role the procedure could play in the reduction of bloodstream infections in these patients.
"In theory, the restoration of healthy microbiota through FMT might also prevent [C. difficile]-associated [bloodstream infections] via several mechanisms, including curing the infection, avoiding the need for vancomycin, and decreasing the expression of antibiotic resistance genes in the gut resistome of the patient," they wrote. "This could decrease the incidence of [bloodstream infections] related to multidrug-resistant bacteria."
However, they noted that "neither preclinical nor clinical data support this hypothesis."
This prospective cohort study at a single academic medical center in Italy involved 290 patients with recurrent C. difficile infections; from this group, 57 patients treated with FMT and 57 with antibiotics were selected for the matched-cohort analysis. Overall of the 290 patients, 109 were treated with FMT and 181 received antibiotic therapy, the authors said. They noted that a higher proportion of patients had sustained cure of C. difficile infection in the FMT group compared to the antibiotic group (97% vs 38%, respectively).
Propensity score matching was used based on a number of patient characteristics, including age, sex, number of C. difficile infection recurrences, and severity of C. difficile infection. In the propensity score cohort, FMT patients tended to be younger and had a lower Charlson Comorbidity Index score, while a higher portion of them had mild C. difficile infection and a lower portion of them had only one C. difficile infection recurrence compared with the antibiotic group.
Overall, in the whole cohort, 45 patients developed bloodstream infection during the 90-day follow-up period -- five in the FMT group and 40 in the antibiotic group.
Examining overall survival, 27% of patients in the whole cohort died during the 90-day follow-up period. Among 79 in the antibiotic group who died, 21 succumbed to bloodstream infection, with the remaining 58 died from other causes including C. difficile-related deterioration of clinical condition, complications after surgery for C. difficile infection, or other comorbidities such as ischemic heart disease.
The authors found that in the propensity score-matched cohort, 90-day overall survival was higher in the FMT group versus the antibiotic group (89% vs 58%).
Study limitations included that patients treated with FMT tended to present with worse clinical conditions versus those treated with antibiotics, which the authors tried to account for in their propensity score matching. However, they still noted differences between those groups in terms of baseline characteristics. They also said that they did not collect stool samples from patients before and after treatments to "assess shifts in gut microbiota composition" or assess the cost effectiveness of using fecal microbiota transplant in recurrent C. difficile infection.
"Should our results be confirmed by larger, randomized studies, FMT could be considered an effective treatment option to both cure [recurrent C. difficile infection] and prevent some of its complications, including [bloodstream infection]," the authors concluded.
Ianiro disclosed no relevant relationships with industry. A co-author disclosed support from Recordati, Pfizer, and Menarini.
Nearly 20 times more frequently than other residents.
This story was first published on Thursday, October 31, 2019 in MedPage Today.
By Ed Susman, Contributing Writer, MedPage Today
DENVER -- The Los Angeles homeless population made up 0.8% of the city's residents in 2018, but they accounted for 10.2% of all 911-emergency medical services (911-EMS) incidents, and 13.3% of all 911-EMS transports, a researcher reported here.
The rate of calls to 911-EMS was 1,135 per 1,000 among people without homes versus 81 per 1,000 people with housing, reported Joel Lombardi, MD, of the Los Angeles County-University of Southern California Keck School of Medicine.
Additionally, the rate of homeless individuals transported to hospitals was 18.9 times higher than people with housing, at 909 per 1,000 individuals versus 48 per 1,000, respectively, he said in a presentation at the American College of Emergency Physicians (ACEP) annual meeting.
"Homeless individuals in Los Angeles constituted a disproportionately high number of both 911-EMS incidents and transports in 2018," Lombardi and colleagues wrote. He added the problem will most likely get worse before it gets better as "Urban areas [in general] have seen a recent increase in homelessness."
L.A. city is 480 square miles with a population of about 4 million, of which 31,825 were estimated to be homeless in 2018 by the L.A. Homeless Services Authority. More recent estimates put that figure at 60,000, Lombardi said.
"There is a large concentration of homeless individuals in the downtown [Skid Row] area, which is the location of several homeless shelters and missions," Lombardi's group noted.
"Rescue 9 is the primary fire department station that handles the Skid Row area," Lombardi said. "It is not unusual for Rescue 9 to make 20 runs a day in response to calls from the area."
The study was a 12-month retrospective review from January to December 2018 of electronic health records for 911-EMS incidents attended by the Los Angeles Fire Department (LAFD), which is the sole EMS provider for the city of Los Angeles, the authors explained.
Housing status is a mandatory field on EHR patient care reports completed by out-of-hospital responders on scene for all incidents, they added.
During the study period, LAFD recorded 355,421 911-EMS incidents, of which 10.2% were for homeless individuals and 89.8% were for housed individuals.
The battalion covering the Skid Row area produced 3% of all 911-EMS incidents citywide, with 31.4% of incidents in this battalion being for homeless patients, the authors reported. Of the 217,977 calls resulting in treatment and transport, 13.3% were for homeless individuals and 86.7% were for housed individuals.
Lombardi's group also found that treatment with no transport against medical advice rates were higher for housed individuals at 5.4% than for homeless patients at 2.3%.
The situation in Los Angeles is not unique, said ACEP session moderator Ayanna Walker, MD, of the University of Central Florida College of Medicine in Orlando.
"We see a similar problem in Central Florida too" she said, "One of the things I would like to know is, whether there are super users? Of those people who are activating 911, are they the same few homeless people? Are these calls being activated by the homeless people, or by bystanders who are concerned about the health of someone who may be sleeping on the sidewalk? I think our situation in central Florida might be even worse because we don't have shelters for these people in our county."
Lombardi said that anecdotally he is aware of some homeless people in his area who call 911-EMS >100 times in a year. Also, some patients are taken directly to sober homes or to psychiatric services, depending on the circumstances.
"The emergency departments [ED] are becoming overcrowded and overwhelmed, so if we can do things to divert certain populations away from the ED resources ... do these people really need ED care or do they need something else," Walker stated.
Lombardi and Walker had no relevant relationships with industry.
Two E. coli infections with one fatal, transmitted to trial patients by same donor.
This article was first published on Wednesday, October 30, 2019 in MedPage Today.
By Diana Swift, Contributing Writer
Two immunocompromised trial patients became infected with extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli the day after undergoing fecal microbiota transplant (FMT), researchers said, suggesting a need for stricter stool donor screening and more scrutiny of such transplants' risk-benefit balance.
"Enhanced donor screening to limit the transmission of microorganisms that could lead to adverse infectious events and continued vigilance to define the benefits and risks of FMT across different patient populations are warranted," wrote Zachariah DeFilipp, MD, and colleagues from the Massachusetts General Hospital in Boston, in the New England Journal of Medicine.
After previously receiving reports of the two cases, one of which was fatal, the FDA issued a national alert in June urging more risk awareness of and additional screening for FMT, which has proven effective for treating recurrent and refractory Clostridioides difficile infections, though still considered investigational.
The patients
Enrolled in two separate FMT clinical trials, the patients both received stool from the same donor, who was screened and the stool tested according to national and institutional protocols. However, existing inventory was not retested after a 2019 FDA review prompted expansion of screening to include tests for ESBL-producing organisms.
The first patient, age 69, had liver cirrhosis related to hepatitis C infection. Over 3 weeks in March and April of 2019, he received oral stool capsules in an open-label trial of FMT for refractory hepatic encephalopathy. Adverse effects emerged 17 days after the final dose, at which point he developed a fever and cough. After failing to improve on a pneumonia antibiotic, he tested positive on blood culture for ESBL-producing E. coli and continued to improve on therapy with the beta-lactam carbapenem Merrem, which led to eventual elimination of ESBL-producing organisms from his stool.
The second patient, age 73, had therapy-related myelodysplastic syndrome. He was enrolled in a phase II trial of preemptive oral FMT before and after allogeneic hematopoietic stem-cell transplantation. Eight days after the last FMT dose, and on day 5 after stem-cell infusion, he developed a fever, chills, and altered mental status, followed by hypoxia and labored breathing. Death from severe sepsis occurred 2 days later, with blood cultures showing ESBL-producing E. coli.
All three lots of capsules from the single donor were found to harbor ESBL-producing E.coli with a similar resistance pattern to that in blood isolates from the patients. Pre-FMT stool samples from both recipients were negative for the pathogen. The same strain was also found in post-FMT specimens from several of the more than 20 other recipients of the index donor's stool.
The authors surmised that substantial overlap in bacterial species between donors and recipients may lead to underestimation of FMT-related infection risks. On the other hand, while other cases of bacteremiahave been reported after FMT, the benefits of FMT should be weighed against risks. "The development of defined, cultured, therapeutic microbial mixtures is an obvious and important future goal," they wrote.
According to an accompanying editorial, recognizing sentinel cases such as these is key to identifying the risks of FMT. "New hazards provide an impetus to develop improved approaches as we explore the dimensions of dysbiosis," wrote Martin J. Blaser, MD, of Rutgers University in New Brunswick, New Jersey, who was not involved in the two trials.
Noting the presence of ostensibly the same strain in other recipients, Blaser said, "The two reported cases represent the tip of the iceberg of that FMT-transmitted infection."
One problem, he pointed out, is that the risks of FMT may be identifiable only after the fact, as the two cases show, and "we often do not recognize new pathogens until after they have been transplanted to new hosts."
As the use of FMT continues to broaden beyond C. difficile treatment and new resistance mechanisms emerge, Blaser added, "the screening of microbiota transplants will need to be reevaluated and updated accordingly."
But a letter published in the same NEJM edition noted that screening FMT donors can be laborious. Zain Kassam, MD, MPH, of Finch Therapeutics in Somerville, Massachusetts, and colleagues pointed out that in evaluating donors for the non-profit stool bankOpenBiome, only 386 out of 15,317 original candidates were deemed suitable.
This work was supported by a grant to co-author Bloom from the American College of Gastroenterology.
DeFilipp reported having no conflicts of interest to disclose. Several co-authors disclosed various financial ties to industry, as did Blaser.
Findings suggest need for heightened surveillance through adulthood.
This article was first published on Tuesday, October 29, 2019 in MedPage Today.
By Pam Harrison, Contributing Writer, MedPage Today
Childhood cancer survivors have a dramatically higher risk for breast cancer and other subsequent malignancies, especially when treated with both chemotherapy and radiation, according to two studies examining the same cohort.
Among girls, the likelihood of a breast cancer diagnosis as an adult increased for every 10 Gy of radiation received (odds ratio [OR] 3.9, 95% CI 2.5-6.5) and for every 100 mg/m2 of anthracycline administered (OR 1.23, 95% CI 1.09-1.39), reported Lene Veiga, PhD, of the National Cancer Institute in Bethesda, Maryland, and colleagues.
"To our knowledge, this is the largest study of treatment-related breast cancer after childhood cancer," the investigators wrote in JAMA Pediatrics. "We also provide the first evidence that the combination of anthracyclines and radiotherapy may markedly increase breast cancer risks and is greater than the sum of their individual effects, consistent with an additive interaction."
Veiga's group looked at 14,358 childhood cancer patients from the North American Childhood Cancer Survivor Study who were initially diagnosed from 1970 to 1986 in Canada and the U.S., and survived at least 5 years. In all, 271 female patients later developed breast cancer at a median age of 39 years.
Children who received a radiation dose of 10 Gy or more but no anthracycline treatment were nearly 10 times more likely to be diagnosed with breast cancer in adulthood (OR 9.6, 95% CI 4.4-20.7) compared to those who received little to no radiation (<1 Gy), which grew to nearly 20 times more likely with the addition of anthracycline therapy (OR 19.1, 95% CI 7.6-48.0).
Paradoxically, higher doses of radiation (≥15 Gy) delivered to the ovaries resulted in a lower risk of developing breast cancer as an adult and this protective effect was seen for both estrogen receptor (ER)-positive and ER-negative breast cancers. That said, most patients who received 15 Gy or more to the ovaries reported either never menstruating or going into menopause within 5 years of their first cancer diagnosis.
When looking at the effect of cumulative anthracycline doses by ER status, only ER-positive disease remained significant (OR 1.49 for every 100 mg/m2, 95% CI 1.21-1.83). Interestingly, there was evidence of a dose response for doxorubicin -- the most commonly used anthracycline drug -- but not for daunorubicin.
Veiga's group noted that the dose of radiotherapy used for many childhood cancers has been dropping in the past few decades, as has the volume of tissue being irradiated.
"It is surprising therefore that there has not been clear evidence that these decreases have translated into lower breast cancer risks," they commented. "One possibility that our results suggest is that this increased breast cancer risk could be associated with the concurrent increase in the use of anthracycline therapy."
In a separate but related study published in the Journal of Clinical Oncology, investigators evaluated the effect of receiving treatment with chemotherapy alone on subsequent malignant neoplasms (SMN) in the same Childhood Cancer Survivor Study cohort.
As reported by researchers led by Lucie Turcotte, MD, of the University of Minnesota Medical School in Minneapolis, the SMN rate among childhood cancer survivors treated with chemotherapy alone was nearly three times as high as the general population (standardized incidence ratio [SIR] 2.8, 95% CI 2.5-3.2).
For their study, they looked at treatment data for 22,154 childhood cancer survivors who were diagnosed with their initial cancer at a median age of 7 years, and who had a median age of 31.9 years at last follow-up.
Of the 1,490 SMNs identified among 1,344 childhood cancer survivors, 229 of them occurred among 206 patients treated with chemotherapy only.
The increased risk from chemotherapy alone was linked to multiple subsequent cancers:
Leukemia and lymphoma (SIR 1.9, 95% CI 1.3-2.7)
Breast cancer (SIR 4.6, 95% CI 3.5-6.0)
Soft-tissue sarcoma (SIR 3.4, 95% CI 1.9-5.7)
Thyroid cancer (SIR 3.8, 95% CI 2.7-5.1)
Melanoma (SIR 2.3, 95% CI 1.5-3.5)
Elevated risks were also associated with high cumulative exposure to alkylating agents (relative rate [RR] 1.2 per 5,000 mg/m2, 95% CI 1.1-1.3) and platinums (RR 2.7 for doses greater 750 mg/m2, 95% CI 1.1-6.5). A linear dose-response relationship was seen between anthracycline use and the risk of breast cancer as well (RR 1.3 per 100 mg/m2, 95% CI 1.2-1.6).
"Here, in a large, well-characterized cohort of childhood cancer survivors, we demonstrated that survivors treated with chemotherapy alone are at increased risk for developing an SMN compared with the general population, though risk and cumulative incidence were approximately half of what was observed in survivors exposed to radiation plus chemotherapy," the study authors noted.
The 30-year cumulative incidence rate for an SMN was 3.9% for those treated with chemotherapy alone, 9.0% for those who received chemotherapy plus radiation, and 10.8% with radiation alone, as compared with 3.4% for those who received neither for their childhood cancer.
"We also showed that survivors treated with higher cumulative doses of alkylating agents and/or platinum-based drugs experienced increased rates of SMNs and there is a linear dose-response relationship between alkylating agent cumulative dose and SMN relative rate," they added. "These findings inform risk-based counseling and support the need for surveillance for early detection of SMNs among individuals treated with chemotherapy, particularly higher cumulative doses of alkylating agents and platinum and no radiotherapy."
Veiga and colleagues had no financial conflicts of interest to declare.