Key clinical point: A multi-dimensional “combined index” model using artificial intelligence and SHG/TPEF microscopy was a stronger predictor of HCC recurrence than alpha fetoprotein levels in HCC patients who underwent curative hepatectomy.

Major finding:  The sensitivity and specificity of the combined index model was 81.8% and 90.5%, respectively, compared to 68.2% and 47.6%, respectively, for alpha fetoprotein level as a predictor of recurrent HCC.

Study details: The data come from a study of 81 adults with hepatocellular carcinoma who underwent curative intent hepatectomy. Researchers used fibrotic features of resected tissue to create a recurrence prediction model.

Disclosures: The study was supported by the Taiwan Ministry of Health. The researchers had no financial conflicts to disclose.

Source: Liu I-T et al. Cancers (Basel). 2021 Oct 23. doi: 10.3390/cancers13215323.

Key clinical point: A multi-dimensional “combined index” model using artificial intelligence and SHG/TPEF microscopy was a stronger predictor of HCC recurrence than alpha fetoprotein levels in HCC patients who underwent curative hepatectomy.

Major finding:  The sensitivity and specificity of the combined index model was 81.8% and 90.5%, respectively, compared to 68.2% and 47.6%, respectively, for alpha fetoprotein level as a predictor of recurrent HCC.

Study details: The data come from a study of 81 adults with hepatocellular carcinoma who underwent curative intent hepatectomy. Researchers used fibrotic features of resected tissue to create a recurrence prediction model.

Disclosures: The study was supported by the Taiwan Ministry of Health. The researchers had no financial conflicts to disclose.

Source: Liu I-T et al. Cancers (Basel). 2021 Oct 23. doi: 10.3390/cancers13215323.

Key clinical point: A multi-dimensional “combined index” model using artificial intelligence and SHG/TPEF microscopy was a stronger predictor of HCC recurrence than alpha fetoprotein levels in HCC patients who underwent curative hepatectomy.

Major finding:  The sensitivity and specificity of the combined index model was 81.8% and 90.5%, respectively, compared to 68.2% and 47.6%, respectively, for alpha fetoprotein level as a predictor of recurrent HCC.

Study details: The data come from a study of 81 adults with hepatocellular carcinoma who underwent curative intent hepatectomy. Researchers used fibrotic features of resected tissue to create a recurrence prediction model.

Disclosures: The study was supported by the Taiwan Ministry of Health. The researchers had no financial conflicts to disclose.

Source: Liu I-T et al. Cancers (Basel). 2021 Oct 23. doi: 10.3390/cancers13215323.

Key clinical point: Liver decompensation is a common late complication in HCC patients treated with SIRT, although overall survival rates surpass those in patients treated with sorafenib.

Major finding:  Liver decompensation, based on a Child-Pugh (CP) score of B7 or higher, occurred in significantly more HCC patients treated with SIRT compared to those treated with sorafenib (62% vs 27%) in a case-matched analysis. However, the median overall survival was significantly longer in SIRT-treated patients compared with sorafenib patients (16 months vs 9 months).

Study details: The data come from 69 adults with advanced HCC who underwent selective internal radiation therapy (SIRT) and had not developed radioembolization-induced liver disease (REILD).

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.

Source: van Doorn DJ et al. Cancers (Basel). 2021 Oct 29. doi: 10.3390/cancers13215427.

Key clinical point: Liver decompensation is a common late complication in HCC patients treated with SIRT, although overall survival rates surpass those in patients treated with sorafenib.

Major finding:  Liver decompensation, based on a Child-Pugh (CP) score of B7 or higher, occurred in significantly more HCC patients treated with SIRT compared to those treated with sorafenib (62% vs 27%) in a case-matched analysis. However, the median overall survival was significantly longer in SIRT-treated patients compared with sorafenib patients (16 months vs 9 months).

Study details: The data come from 69 adults with advanced HCC who underwent selective internal radiation therapy (SIRT) and had not developed radioembolization-induced liver disease (REILD).

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.

Source: van Doorn DJ et al. Cancers (Basel). 2021 Oct 29. doi: 10.3390/cancers13215427.

Key clinical point: Liver decompensation is a common late complication in HCC patients treated with SIRT, although overall survival rates surpass those in patients treated with sorafenib.

Major finding:  Liver decompensation, based on a Child-Pugh (CP) score of B7 or higher, occurred in significantly more HCC patients treated with SIRT compared to those treated with sorafenib (62% vs 27%) in a case-matched analysis. However, the median overall survival was significantly longer in SIRT-treated patients compared with sorafenib patients (16 months vs 9 months).

Study details: The data come from 69 adults with advanced HCC who underwent selective internal radiation therapy (SIRT) and had not developed radioembolization-induced liver disease (REILD).

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.

Source: van Doorn DJ et al. Cancers (Basel). 2021 Oct 29. doi: 10.3390/cancers13215427.

Key clinical point: Patients who underwent laparoscopic liver resection for HCC had fewer complications and similar long-term outcomes to those who had open resection procedures.

Major finding:  Patients in the laparoscopic group had significantly fewer complications of Clavien-Dindo grade III or higher compared to those in the open group (14% vs 29%, P = .01). Overall survival rates at 1, 3, and 5 years were similar between the laparoscopic group and the open group, 90.9%, 79.3%, 70.5% vs 91.3%, 88.5%, 83.1%, respectively, and cumulative recurrence rates were not significantly different between the groups.

Study details: The data come from a retrospective study of 149 adults who underwent either laparoscopic or open liver resection between January 2008 and December 2019. Primary outcomes of overall survival and cumulative incidence of recurrence were assessed after propensity score matching.

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.

Source: Ivanics T et al. Surgery. 2021 Nov 3. doi: 10.1016/j.surg.2021.10.017.

Key clinical point: Patients who underwent laparoscopic liver resection for HCC had fewer complications and similar long-term outcomes to those who had open resection procedures.

Major finding:  Patients in the laparoscopic group had significantly fewer complications of Clavien-Dindo grade III or higher compared to those in the open group (14% vs 29%, P = .01). Overall survival rates at 1, 3, and 5 years were similar between the laparoscopic group and the open group, 90.9%, 79.3%, 70.5% vs 91.3%, 88.5%, 83.1%, respectively, and cumulative recurrence rates were not significantly different between the groups.

Study details: The data come from a retrospective study of 149 adults who underwent either laparoscopic or open liver resection between January 2008 and December 2019. Primary outcomes of overall survival and cumulative incidence of recurrence were assessed after propensity score matching.

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.

Source: Ivanics T et al. Surgery. 2021 Nov 3. doi: 10.1016/j.surg.2021.10.017.

Key clinical point: Patients who underwent laparoscopic liver resection for HCC had fewer complications and similar long-term outcomes to those who had open resection procedures.

Major finding:  Patients in the laparoscopic group had significantly fewer complications of Clavien-Dindo grade III or higher compared to those in the open group (14% vs 29%, P = .01). Overall survival rates at 1, 3, and 5 years were similar between the laparoscopic group and the open group, 90.9%, 79.3%, 70.5% vs 91.3%, 88.5%, 83.1%, respectively, and cumulative recurrence rates were not significantly different between the groups.

Study details: The data come from a retrospective study of 149 adults who underwent either laparoscopic or open liver resection between January 2008 and December 2019. Primary outcomes of overall survival and cumulative incidence of recurrence were assessed after propensity score matching.

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.

Source: Ivanics T et al. Surgery. 2021 Nov 3. doi: 10.1016/j.surg.2021.10.017.

Rituximab didn’t perform any worse or better at inducing remission after a year in patients with eosinophilic granulomatosis with polyangiitis (EGPA) than did conventional treatment with cyclophosphamide in the phase 3 REOVAS trial conducted in France.

The B-cell–depleting agent also had a safety profile similar to cyclophosphamide during that window of time, Benjamin Terrier, MD, PhD, said in presenting results of the trial at the virtual annual meeting of the American College of Rheumatology. He is a professor of rheumatology at Cochin Hospital in Paris, the University of Paris, and vice president of the French Vasculitis Study Group.

“So some of the major adverse events that we can consider with this treatment, especially with cyclophosphamide and specifically the fertility issues and the cancer issues, the follow-up of this study does not allow us to evaluate the potential benefit of rituximab over cyclophosphamide,” Dr. Terrier said in an interview.

“But on the short-term study of 1 year, for which the major adverse events are infections, there is almost no difference between the two treatments,” he said. A total of 11 patients taking rituximab and 9 patients taking cyclophosphamide had infections in the study period.

The REOVAS trial randomly assigned 105 adult patients with EPGA, otherwise known as Churg-Strauss syndrome, to either rituximab (52 patients) or the conventional strategy using cyclophosphamide (53). The patients had either newly diagnosed or relapsing disease. There was no significant differences in average daily glucocorticoid use between the two arms.

Patient characteristics were similar in both arms, including the percentages of patients with severe disease. Overall, 60% in each group had a Five-Factor Score (FFS) of 0, while the remainder had an FFS greater than 1. The FFS is calculated by giving 1 point for the presence of each of the following: proteinuria greater than 1 g/day, serum creatinine greater than 140 micromol/L, GI involvement, cardiomyopathy, and CNS involvement. The presence of each FFS component was similar between the groups at baseline, although 25% of the rituximab group and 30.2% of the conventional arm had myeloperoxidase-positive antineutrophilic cytoplasmic antibodies, and the absolute eosinophil count was 180 per mm³ in the former and 300 per mm³ in the latter.

Treatment outcomes at 6 months and 1 year were similar in both groups. At 1 year, remission occurred in 59.6% with rituximab and 64.2% with cyclophosphamide, Birmingham Vasculitis Activity Score equaled 0 in 85.7% with rituximab and 86.5% with cyclophosphamide, and prednisone dose was less than 7.5 mg/day in 77.1% with rituximab and 71.2% with cyclophosphamide.

The cumulative total weeks of complete remission was about 16 weeks in each group. Relapse-free survival, prednisone dosage, quality of life, and disease sequelae patterns also were similar.

Tailor treatment choice to the patient

Despite the equivocal findings between the two treatments, Dr. Terrier said there may be individual patients for whom rituximab would be preferred to cyclophosphamide. “It’s not dependent on the disease by itself but more on the patients we want to treat,” he said. “And clearly if there is a young female patient who wants to get pregnant, knowing that rituximab is not superior but does not appear to be inferior to cyclophosphamide can be interesting.”

The researchers opted to test the superiority rather than noninferiority of rituximab versus cyclophosphamide because a noninferiority design would have required a larger patient population, “which is not possible for a disease like this one,” he said.

“Ostensibly, [the trial] failed to show superiority, but given its favorable side-effect profile, it may be sufficient to show it’s more or less the same,” Michael Putman, MD, MSc, an associate professor and director of the vasculitis program at the Medical College of Wisconsin, Milwaukee, said in an interview. However, he noted that the study didn’t include some phenotypes seen in patients with EGPA, “in particular patients with neurological involvement.”

Dr. Putman added that the French REOVAS findings support recommendations in the 2021 ACR/Vasculitis Foundation guideline for using rituximab as a possible first-line agent to induce remission in severe granulomatosis with polyangiitis and microscopic polyangiitis. “I was somewhat surprised by that,” he said of the ACR/VF recommendation. “These are the best data to date comparing rituximab to cyclophosphamide in EGPA. I would feel more comfortable using rituximab in cases where previously I would have reached for cyclophosphamide.”

He also concurred with Dr. Terrier’s comment that rituximab may be preferred in people of child-bearing age, even extending that to men. “Cyclophosphamide can be quite toxic in terms of ovarian toxicity and premature ovarian failure,” he said. “Young men or women of child-bearing age are a group in whom I would strongly consider using rituximab.”

The French REOVAS investigators’ future research into rituximab for EGPA will include long-term follow-up for relapse and the induction of remission, Dr. Terrier said.

Dr. Terrier disclosed relationships with Roche, Chugai, Vifor, LFB, Grifols, GlaxoSmithKline, AstraZeneca, Bristol-Myers Squibb, Octapharma, and Janssen. Dr. Putnam has no relevant relationships to disclose

Rituximab didn’t perform any worse or better at inducing remission after a year in patients with eosinophilic granulomatosis with polyangiitis (EGPA) than did conventional treatment with cyclophosphamide in the phase 3 REOVAS trial conducted in France.

The B-cell–depleting agent also had a safety profile similar to cyclophosphamide during that window of time, Benjamin Terrier, MD, PhD, said in presenting results of the trial at the virtual annual meeting of the American College of Rheumatology. He is a professor of rheumatology at Cochin Hospital in Paris, the University of Paris, and vice president of the French Vasculitis Study Group.

“So some of the major adverse events that we can consider with this treatment, especially with cyclophosphamide and specifically the fertility issues and the cancer issues, the follow-up of this study does not allow us to evaluate the potential benefit of rituximab over cyclophosphamide,” Dr. Terrier said in an interview.

“But on the short-term study of 1 year, for which the major adverse events are infections, there is almost no difference between the two treatments,” he said. A total of 11 patients taking rituximab and 9 patients taking cyclophosphamide had infections in the study period.

The REOVAS trial randomly assigned 105 adult patients with EPGA, otherwise known as Churg-Strauss syndrome, to either rituximab (52 patients) or the conventional strategy using cyclophosphamide (53). The patients had either newly diagnosed or relapsing disease. There was no significant differences in average daily glucocorticoid use between the two arms.

Patient characteristics were similar in both arms, including the percentages of patients with severe disease. Overall, 60% in each group had a Five-Factor Score (FFS) of 0, while the remainder had an FFS greater than 1. The FFS is calculated by giving 1 point for the presence of each of the following: proteinuria greater than 1 g/day, serum creatinine greater than 140 micromol/L, GI involvement, cardiomyopathy, and CNS involvement. The presence of each FFS component was similar between the groups at baseline, although 25% of the rituximab group and 30.2% of the conventional arm had myeloperoxidase-positive antineutrophilic cytoplasmic antibodies, and the absolute eosinophil count was 180 per mm³ in the former and 300 per mm³ in the latter.

Treatment outcomes at 6 months and 1 year were similar in both groups. At 1 year, remission occurred in 59.6% with rituximab and 64.2% with cyclophosphamide, Birmingham Vasculitis Activity Score equaled 0 in 85.7% with rituximab and 86.5% with cyclophosphamide, and prednisone dose was less than 7.5 mg/day in 77.1% with rituximab and 71.2% with cyclophosphamide.

The cumulative total weeks of complete remission was about 16 weeks in each group. Relapse-free survival, prednisone dosage, quality of life, and disease sequelae patterns also were similar.

Tailor treatment choice to the patient

Despite the equivocal findings between the two treatments, Dr. Terrier said there may be individual patients for whom rituximab would be preferred to cyclophosphamide. “It’s not dependent on the disease by itself but more on the patients we want to treat,” he said. “And clearly if there is a young female patient who wants to get pregnant, knowing that rituximab is not superior but does not appear to be inferior to cyclophosphamide can be interesting.”

The researchers opted to test the superiority rather than noninferiority of rituximab versus cyclophosphamide because a noninferiority design would have required a larger patient population, “which is not possible for a disease like this one,” he said.

“Ostensibly, [the trial] failed to show superiority, but given its favorable side-effect profile, it may be sufficient to show it’s more or less the same,” Michael Putman, MD, MSc, an associate professor and director of the vasculitis program at the Medical College of Wisconsin, Milwaukee, said in an interview. However, he noted that the study didn’t include some phenotypes seen in patients with EGPA, “in particular patients with neurological involvement.”

Dr. Putman added that the French REOVAS findings support recommendations in the 2021 ACR/Vasculitis Foundation guideline for using rituximab as a possible first-line agent to induce remission in severe granulomatosis with polyangiitis and microscopic polyangiitis. “I was somewhat surprised by that,” he said of the ACR/VF recommendation. “These are the best data to date comparing rituximab to cyclophosphamide in EGPA. I would feel more comfortable using rituximab in cases where previously I would have reached for cyclophosphamide.”

He also concurred with Dr. Terrier’s comment that rituximab may be preferred in people of child-bearing age, even extending that to men. “Cyclophosphamide can be quite toxic in terms of ovarian toxicity and premature ovarian failure,” he said. “Young men or women of child-bearing age are a group in whom I would strongly consider using rituximab.”

The French REOVAS investigators’ future research into rituximab for EGPA will include long-term follow-up for relapse and the induction of remission, Dr. Terrier said.

Dr. Terrier disclosed relationships with Roche, Chugai, Vifor, LFB, Grifols, GlaxoSmithKline, AstraZeneca, Bristol-Myers Squibb, Octapharma, and Janssen. Dr. Putnam has no relevant relationships to disclose

Rituximab didn’t perform any worse or better at inducing remission after a year in patients with eosinophilic granulomatosis with polyangiitis (EGPA) than did conventional treatment with cyclophosphamide in the phase 3 REOVAS trial conducted in France.

The B-cell–depleting agent also had a safety profile similar to cyclophosphamide during that window of time, Benjamin Terrier, MD, PhD, said in presenting results of the trial at the virtual annual meeting of the American College of Rheumatology. He is a professor of rheumatology at Cochin Hospital in Paris, the University of Paris, and vice president of the French Vasculitis Study Group.

“So some of the major adverse events that we can consider with this treatment, especially with cyclophosphamide and specifically the fertility issues and the cancer issues, the follow-up of this study does not allow us to evaluate the potential benefit of rituximab over cyclophosphamide,” Dr. Terrier said in an interview.

“But on the short-term study of 1 year, for which the major adverse events are infections, there is almost no difference between the two treatments,” he said. A total of 11 patients taking rituximab and 9 patients taking cyclophosphamide had infections in the study period.

The REOVAS trial randomly assigned 105 adult patients with EPGA, otherwise known as Churg-Strauss syndrome, to either rituximab (52 patients) or the conventional strategy using cyclophosphamide (53). The patients had either newly diagnosed or relapsing disease. There was no significant differences in average daily glucocorticoid use between the two arms.

Patient characteristics were similar in both arms, including the percentages of patients with severe disease. Overall, 60% in each group had a Five-Factor Score (FFS) of 0, while the remainder had an FFS greater than 1. The FFS is calculated by giving 1 point for the presence of each of the following: proteinuria greater than 1 g/day, serum creatinine greater than 140 micromol/L, GI involvement, cardiomyopathy, and CNS involvement. The presence of each FFS component was similar between the groups at baseline, although 25% of the rituximab group and 30.2% of the conventional arm had myeloperoxidase-positive antineutrophilic cytoplasmic antibodies, and the absolute eosinophil count was 180 per mm³ in the former and 300 per mm³ in the latter.

Treatment outcomes at 6 months and 1 year were similar in both groups. At 1 year, remission occurred in 59.6% with rituximab and 64.2% with cyclophosphamide, Birmingham Vasculitis Activity Score equaled 0 in 85.7% with rituximab and 86.5% with cyclophosphamide, and prednisone dose was less than 7.5 mg/day in 77.1% with rituximab and 71.2% with cyclophosphamide.

The cumulative total weeks of complete remission was about 16 weeks in each group. Relapse-free survival, prednisone dosage, quality of life, and disease sequelae patterns also were similar.

Tailor treatment choice to the patient

Despite the equivocal findings between the two treatments, Dr. Terrier said there may be individual patients for whom rituximab would be preferred to cyclophosphamide. “It’s not dependent on the disease by itself but more on the patients we want to treat,” he said. “And clearly if there is a young female patient who wants to get pregnant, knowing that rituximab is not superior but does not appear to be inferior to cyclophosphamide can be interesting.”

The researchers opted to test the superiority rather than noninferiority of rituximab versus cyclophosphamide because a noninferiority design would have required a larger patient population, “which is not possible for a disease like this one,” he said.

“Ostensibly, [the trial] failed to show superiority, but given its favorable side-effect profile, it may be sufficient to show it’s more or less the same,” Michael Putman, MD, MSc, an associate professor and director of the vasculitis program at the Medical College of Wisconsin, Milwaukee, said in an interview. However, he noted that the study didn’t include some phenotypes seen in patients with EGPA, “in particular patients with neurological involvement.”

Dr. Putman added that the French REOVAS findings support recommendations in the 2021 ACR/Vasculitis Foundation guideline for using rituximab as a possible first-line agent to induce remission in severe granulomatosis with polyangiitis and microscopic polyangiitis. “I was somewhat surprised by that,” he said of the ACR/VF recommendation. “These are the best data to date comparing rituximab to cyclophosphamide in EGPA. I would feel more comfortable using rituximab in cases where previously I would have reached for cyclophosphamide.”

He also concurred with Dr. Terrier’s comment that rituximab may be preferred in people of child-bearing age, even extending that to men. “Cyclophosphamide can be quite toxic in terms of ovarian toxicity and premature ovarian failure,” he said. “Young men or women of child-bearing age are a group in whom I would strongly consider using rituximab.”

The French REOVAS investigators’ future research into rituximab for EGPA will include long-term follow-up for relapse and the induction of remission, Dr. Terrier said.

Dr. Terrier disclosed relationships with Roche, Chugai, Vifor, LFB, Grifols, GlaxoSmithKline, AstraZeneca, Bristol-Myers Squibb, Octapharma, and Janssen. Dr. Putnam has no relevant relationships to disclose

LAS VEGAS – New results from a single center, retrospective analysis suggest that individuals with diabetes and pancreatic cysts have larger cyst sizes at diagnosis, and a faster subsequent cyst growth rate. Smoking was independently associated with faster growth rate.

iStock/ThinkStock

Most pancreatic cancer patients were previously diagnosed with hyperglycemia and diabetes, and pancreatic cancer can cause diabetes. “This sort of dual causality raises questions as to whether or not hyperglycemia, or the new diagnosis of diabetes itself, could be a harbinger of cancer or precancer. And should these patients be more closely monitored?” David Robbins, MD, said in an interview.

MDedge News

Dr. Robbins, associate professor of medicine and program director in gastroenterology in the Northwell Health System, New York, presented the study at the annual meeting of the American College of Gastroenterology.

Faster growth rates of pancreatic cysts in the presence of diabetes are important because they represent a potential mark for cyst aggressiveness. “So the question really is, in the setting of diabetes, are there factors perhaps circulating in the bloodstream, or other intrinsic factors, that make these cysts more dangerous and require a different surveillance approach than someone who doesn’t have diabetes? We have (surveillance) guidelines that address the average population, but they don’t really hone in on what do you do with (individuals with diabetes),” Dr. Robbins said during the presentation.

The study could have implications for screening, said session moderator Dayna Early, MD, professor of medicine at Washington University and director of endoscopy at Barnes Jewish Hospital, both in St. Louis. “I think this is important information to guide us to look more closely at patients with diabetes who do have pancreatic cysts,” she said in an interview.

The study included 177 adults with pancreatic cysts or abnormal imaging results between 2013 and 2020. Sixty-five percent were female, and the mean age was 65.4 years; 64% were White, 10% were Black, and 8.5% were Asian. Among the participants, 24.8% were smokers and 32.2% had type 2 diabetes.

Patients with diabetes had larger cyst sizes (2.23 cm versus 2.76 cm), as well as a higher annual cyst growth rate (1.90 cm versus 1.30 cm). Cyst size and growth rate were similar between patients with controlled and uncontrolled diabetes. Smoking was associated with a larger cyst size overall (2.2 cm versus 1.81 cm), and were larger still among patients with diabetes who smoked (2.35 cm).

Seventy-one patients went on to have pathologic confirmation by endoscopic ultrasound-guided fine needle aspiration. “In the diabetic group, two developed adenocarcinoma, six of the nondiabetics developed adenocarcinoma, and there was no difference in CEA or serum CA 19-9,” Dr. Robbins said during his presentation.

Of 28 patients diagnosed with pancreatic cancer, 13 had type 2 diabetes.
 

Defining danger

There remains uncertainty about what cyst growth rate is most dangerous. Some guidelines recommend that individuals with new-onset or worsening diabetes and intraductal papillary mucinous neoplasm or mucinous cystic neoplasm cysts, or cysts alone that are growing faster than 3 mm per year, may be at significantly increased risk of pancreatic cancer. These guidelines recommend that they be screened with short-interval magnetic resonance imaging or endoscopic ultrasound (EUS) fine needle aspiration. However, this recommendation is conditional and is backed by a very low level of evidence.

Other reports have shown varying risks at different growth rates. “It’s not really clear at this point. And that’s why I think, while our study is small and exploratory, this is a particular area that is relatively easy to evaluate. We have huge databases of pancreatic cyst evolution, and we know that 30 million Americans have diabetes. So, the next obvious study is to do a more systematic look at that, and work towards refining and making sense of these divergent guidelines, all of which are saying the same thing but using different threshold numbers,” said Dr. Robbins.

The next step is do larger, multicenter studies in the context of other risk factors such as family history and smoking, but the current finding represents an opportunity to catch at least some pancreatic cancers earlier, according to Dr. Robbins. He suggested that individuals with diabetes who are diagnosed with a pancreatic cyst should be referred to a gastroenterologist or another specialist to track cyst growth. “That is going to miss a lot of folks who didn’t get imaging for whatever reason (and so don’t have a cyst identified), but it is an early opportunity, and it’s better than what we’re doing now.”

During the talk, Dr. Robbins said, “Given the ease, availability and low cost of diabetes screening in the general clinic population, we encourage the inclusion of HbA1c and fasting glucose in algorithms for pancreatic cyst surveillance.”

Dr. Early found the suggestion intriguing, but wasn’t ready to lend full support. “I think looking at the suggestion of possibly monitoring hemoglobin A1c levels was novel. I don’t know that we’ll necessarily adopt that as standard practice, but that’s something I think that could be looked at in the future as a way to help risk stratify whether patients need to be surveyed more frequently,” she said.

Dr. Robbins and Dr. Early have no relevant financial disclosures.

LAS VEGAS – New results from a single center, retrospective analysis suggest that individuals with diabetes and pancreatic cysts have larger cyst sizes at diagnosis, and a faster subsequent cyst growth rate. Smoking was independently associated with faster growth rate.

iStock/ThinkStock

Most pancreatic cancer patients were previously diagnosed with hyperglycemia and diabetes, and pancreatic cancer can cause diabetes. “This sort of dual causality raises questions as to whether or not hyperglycemia, or the new diagnosis of diabetes itself, could be a harbinger of cancer or precancer. And should these patients be more closely monitored?” David Robbins, MD, said in an interview.

MDedge News

Dr. Robbins, associate professor of medicine and program director in gastroenterology in the Northwell Health System, New York, presented the study at the annual meeting of the American College of Gastroenterology.

Faster growth rates of pancreatic cysts in the presence of diabetes are important because they represent a potential mark for cyst aggressiveness. “So the question really is, in the setting of diabetes, are there factors perhaps circulating in the bloodstream, or other intrinsic factors, that make these cysts more dangerous and require a different surveillance approach than someone who doesn’t have diabetes? We have (surveillance) guidelines that address the average population, but they don’t really hone in on what do you do with (individuals with diabetes),” Dr. Robbins said during the presentation.

The study could have implications for screening, said session moderator Dayna Early, MD, professor of medicine at Washington University and director of endoscopy at Barnes Jewish Hospital, both in St. Louis. “I think this is important information to guide us to look more closely at patients with diabetes who do have pancreatic cysts,” she said in an interview.

The study included 177 adults with pancreatic cysts or abnormal imaging results between 2013 and 2020. Sixty-five percent were female, and the mean age was 65.4 years; 64% were White, 10% were Black, and 8.5% were Asian. Among the participants, 24.8% were smokers and 32.2% had type 2 diabetes.

Patients with diabetes had larger cyst sizes (2.23 cm versus 2.76 cm), as well as a higher annual cyst growth rate (1.90 cm versus 1.30 cm). Cyst size and growth rate were similar between patients with controlled and uncontrolled diabetes. Smoking was associated with a larger cyst size overall (2.2 cm versus 1.81 cm), and were larger still among patients with diabetes who smoked (2.35 cm).

Seventy-one patients went on to have pathologic confirmation by endoscopic ultrasound-guided fine needle aspiration. “In the diabetic group, two developed adenocarcinoma, six of the nondiabetics developed adenocarcinoma, and there was no difference in CEA or serum CA 19-9,” Dr. Robbins said during his presentation.

Of 28 patients diagnosed with pancreatic cancer, 13 had type 2 diabetes.
 

Defining danger

There remains uncertainty about what cyst growth rate is most dangerous. Some guidelines recommend that individuals with new-onset or worsening diabetes and intraductal papillary mucinous neoplasm or mucinous cystic neoplasm cysts, or cysts alone that are growing faster than 3 mm per year, may be at significantly increased risk of pancreatic cancer. These guidelines recommend that they be screened with short-interval magnetic resonance imaging or endoscopic ultrasound (EUS) fine needle aspiration. However, this recommendation is conditional and is backed by a very low level of evidence.

Other reports have shown varying risks at different growth rates. “It’s not really clear at this point. And that’s why I think, while our study is small and exploratory, this is a particular area that is relatively easy to evaluate. We have huge databases of pancreatic cyst evolution, and we know that 30 million Americans have diabetes. So, the next obvious study is to do a more systematic look at that, and work towards refining and making sense of these divergent guidelines, all of which are saying the same thing but using different threshold numbers,” said Dr. Robbins.

The next step is do larger, multicenter studies in the context of other risk factors such as family history and smoking, but the current finding represents an opportunity to catch at least some pancreatic cancers earlier, according to Dr. Robbins. He suggested that individuals with diabetes who are diagnosed with a pancreatic cyst should be referred to a gastroenterologist or another specialist to track cyst growth. “That is going to miss a lot of folks who didn’t get imaging for whatever reason (and so don’t have a cyst identified), but it is an early opportunity, and it’s better than what we’re doing now.”

During the talk, Dr. Robbins said, “Given the ease, availability and low cost of diabetes screening in the general clinic population, we encourage the inclusion of HbA1c and fasting glucose in algorithms for pancreatic cyst surveillance.”

Dr. Early found the suggestion intriguing, but wasn’t ready to lend full support. “I think looking at the suggestion of possibly monitoring hemoglobin A1c levels was novel. I don’t know that we’ll necessarily adopt that as standard practice, but that’s something I think that could be looked at in the future as a way to help risk stratify whether patients need to be surveyed more frequently,” she said.

Dr. Robbins and Dr. Early have no relevant financial disclosures.

LAS VEGAS – New results from a single center, retrospective analysis suggest that individuals with diabetes and pancreatic cysts have larger cyst sizes at diagnosis, and a faster subsequent cyst growth rate. Smoking was independently associated with faster growth rate.

iStock/ThinkStock

Most pancreatic cancer patients were previously diagnosed with hyperglycemia and diabetes, and pancreatic cancer can cause diabetes. “This sort of dual causality raises questions as to whether or not hyperglycemia, or the new diagnosis of diabetes itself, could be a harbinger of cancer or precancer. And should these patients be more closely monitored?” David Robbins, MD, said in an interview.

MDedge News

Dr. Robbins, associate professor of medicine and program director in gastroenterology in the Northwell Health System, New York, presented the study at the annual meeting of the American College of Gastroenterology.

Faster growth rates of pancreatic cysts in the presence of diabetes are important because they represent a potential mark for cyst aggressiveness. “So the question really is, in the setting of diabetes, are there factors perhaps circulating in the bloodstream, or other intrinsic factors, that make these cysts more dangerous and require a different surveillance approach than someone who doesn’t have diabetes? We have (surveillance) guidelines that address the average population, but they don’t really hone in on what do you do with (individuals with diabetes),” Dr. Robbins said during the presentation.

The study could have implications for screening, said session moderator Dayna Early, MD, professor of medicine at Washington University and director of endoscopy at Barnes Jewish Hospital, both in St. Louis. “I think this is important information to guide us to look more closely at patients with diabetes who do have pancreatic cysts,” she said in an interview.

The study included 177 adults with pancreatic cysts or abnormal imaging results between 2013 and 2020. Sixty-five percent were female, and the mean age was 65.4 years; 64% were White, 10% were Black, and 8.5% were Asian. Among the participants, 24.8% were smokers and 32.2% had type 2 diabetes.

Patients with diabetes had larger cyst sizes (2.23 cm versus 2.76 cm), as well as a higher annual cyst growth rate (1.90 cm versus 1.30 cm). Cyst size and growth rate were similar between patients with controlled and uncontrolled diabetes. Smoking was associated with a larger cyst size overall (2.2 cm versus 1.81 cm), and were larger still among patients with diabetes who smoked (2.35 cm).

Seventy-one patients went on to have pathologic confirmation by endoscopic ultrasound-guided fine needle aspiration. “In the diabetic group, two developed adenocarcinoma, six of the nondiabetics developed adenocarcinoma, and there was no difference in CEA or serum CA 19-9,” Dr. Robbins said during his presentation.

Of 28 patients diagnosed with pancreatic cancer, 13 had type 2 diabetes.
 

Defining danger

There remains uncertainty about what cyst growth rate is most dangerous. Some guidelines recommend that individuals with new-onset or worsening diabetes and intraductal papillary mucinous neoplasm or mucinous cystic neoplasm cysts, or cysts alone that are growing faster than 3 mm per year, may be at significantly increased risk of pancreatic cancer. These guidelines recommend that they be screened with short-interval magnetic resonance imaging or endoscopic ultrasound (EUS) fine needle aspiration. However, this recommendation is conditional and is backed by a very low level of evidence.

Other reports have shown varying risks at different growth rates. “It’s not really clear at this point. And that’s why I think, while our study is small and exploratory, this is a particular area that is relatively easy to evaluate. We have huge databases of pancreatic cyst evolution, and we know that 30 million Americans have diabetes. So, the next obvious study is to do a more systematic look at that, and work towards refining and making sense of these divergent guidelines, all of which are saying the same thing but using different threshold numbers,” said Dr. Robbins.

The next step is do larger, multicenter studies in the context of other risk factors such as family history and smoking, but the current finding represents an opportunity to catch at least some pancreatic cancers earlier, according to Dr. Robbins. He suggested that individuals with diabetes who are diagnosed with a pancreatic cyst should be referred to a gastroenterologist or another specialist to track cyst growth. “That is going to miss a lot of folks who didn’t get imaging for whatever reason (and so don’t have a cyst identified), but it is an early opportunity, and it’s better than what we’re doing now.”

During the talk, Dr. Robbins said, “Given the ease, availability and low cost of diabetes screening in the general clinic population, we encourage the inclusion of HbA1c and fasting glucose in algorithms for pancreatic cyst surveillance.”

Dr. Early found the suggestion intriguing, but wasn’t ready to lend full support. “I think looking at the suggestion of possibly monitoring hemoglobin A1c levels was novel. I don’t know that we’ll necessarily adopt that as standard practice, but that’s something I think that could be looked at in the future as a way to help risk stratify whether patients need to be surveyed more frequently,” she said.

Dr. Robbins and Dr. Early have no relevant financial disclosures.

In May 2016, Tarrah Oliver had been working as a bench tech in hematology at Tséhootsooí Medical Center (TMC) for 4 years when the hospital launched a 5-point screen for detecting hantavirus cardiopulmonary syndrome (HCPS), a potentially fatal disease that disproportionately affects Native Americans.

Developed at the University of New Mexico, the 5-point screen was particularly useful for facilities like TMC, a 56-bed hospital in Arizona serving Navajo Nation patients. Although the Navajo make up only 1.7% of the population, they account for 18% of all reported HCPS cases in the US.

But Oliver, who was the laboratory Safety and Training supervisor, her department supervisor, and his assistant were the only people who knew how to do the screen. “I was storing completed worksheets in a folder,” Oliver said, “and soon I had to transfer them to a 3-inch binder because we had so many being ordered. I started saving slides that scored high so that I could show my fellow lab mates what certain characteristics looked like under the microscope.” She also created case studies to train staff using analyzer printouts and slides from the patients. “It was my little side project to take care of while I was working and training new employees in the hematology department.”

The screen was to become much more than a side project very quickly.

In 2017, there was a hantavirus outbreak in one of the nearby communities. A team from the Centers for Disease Control and Prevention (CDC) came out to visit the local hospitals to educate the medical staff on what to look for in their patients with suspected hantavirus. Among those: the TMC staff. The visit would prove both serendipitous and synergistic.

Mary Choi, MD, MPH, medical officer with the CDC Viral Special Pathogens Branch, said, “Members of my branch were asked to come to Navajo Nation [Lukachukai chapter, Arizona] because of a cluster of hantaviruses cases that had been occurring in the area over the course of a few years. During a meeting with medical providers at TMC, our team met Tarrah and she told us that TMC had implemented the screen. We were really intrigued and impressed by the initiative of this small community hospital.”

“We were excited that the CDC even knew we existed!” Oliver recalled. “This little lab in the middle of the reservation.”

HCPS is rare but severe. It can quickly progress from nonspecific initial symptoms, such as fever, body aches, and shortness of breath, to severe respiratory distress. Without immediate intervention, patients usually die within 24 to 48 hours of the onset of cardiopulmonary symptoms. “What makes the disease even more challenging,” said Choi, “is that some of the critical lifesaving measures that physicians normally employ to save a critically-ill patient can actually make the situation worse.

“For example, when HCPS patients reach the cardiopulmonary phase of the illness, their blood pressure will drop. The normal response to this is to give IV fluids (IVF). But in hantavirus, giving IVF can actually make the signs and symptoms of the disease worse and only judicious use of IVF is recommended.”

She gave other examples of treatment challenges: “Physicians are taught to intubate critically ill patients. However, intubation of hanta patients during the cardiopulmonary phase can actually be detrimental. Also, in general, extracorporeal membrane oxygenation (ECMO) is an intervention of last resort for most critically-ill patients. As the procedure essentially involves hooking the patient up to a heart-lung machine, which has a lot of complications, doctors do not do this unless they have to. But in hantavirus disease, early initiation of ECMO has been shown to significantly improve survival.”

“Another tricky thing about ECMO is that not all hospitals have an ECMO machine… oftentimes patients have to be transferred from one hospital to another because they need ECMO and it is not available where they are.” The ECMO-equipped facility closest to TMC is 170 miles away, at the University of New Mexico Hospital in Albuquerque.

 For all those reasons, Dr. Choi said, it is critically important for physicians to know if the patient they are treating has hantavirus or not. The problem is, there is no rapid test for hantavirus disease. The tests have to be sent out to a laboratory and it can take days before physicians receive a test result. “This is where the 5-point screen is such a valuable tool. Although it is not a diagnostic test, it is a very accurate screening tool. Even better, it is readily and widely available, because to perform the screen, you only need a complete blood count (CBC) and a peripheral blood smear…which can be performed in the vast majority of laboratories and clinics. In addition, the CBC and peripheral blood smear are very commonly ordered tests.”

The screen could be particularly crucial for small community hospitals and clinics. “[TMC] took a screen developed by hematopathologists for hematopathologists,” Choi said, “and adapted it so that it could be performed by clinical laboratorians—because hematopathologists don’t exactly grow on trees! Once we heard about the work that TMC was doing, we knew that this was something we wanted to support and advocate for.”

“We started to throw around the idea of teaching this method to other laboratories on the reservation,” Oliver said. She and Mary Choi teamed up to “knock on everyone’s door to see who was utilizing the screening or if they had their own methods of detecting hantavirus in their patients.”

Two years later, they began holding training sessions at a nearby community college; they also trained an entire laboratory at their hospital in late 2019. Plans were to set up other training sessions towards the border towns before spring of 2020.

Then SARS-CoV-2 showed up.

Hantavirus or coronavirus?

COVID-19 hit the Navajo Nation like a sledgehammer. Native Americans in rural areas, as many Navajo are, may have multigenerational and extended families living in tight quarters, with limited access to running water, miles from the nearest healthcare facility. They were particularly vulnerable to a virus that thrives on close contact, at a time when the most common preventives were distancing, frequent handwashing, and testing. By May 2020, the Navajo Nation had surpassed the epicenters—New York and New Jersey—in cases of infection. Even as late as November 2021, the Navah Nation has reported > 37,000 positive cases, and nearly 1,500 confirmed deaths, despite reaching a 70% vaccination rate.

Making things ever more challenging: How do you know whether the patient has hantavirus or COVID-19? The distinction is critical because the disease courses of the 2 infections differ greatly. “The importance of [TMC’s] work was really brought home by the COVID pandemic,” Mary Choi said. “The signs and symptoms of early COVID and hantavirus are really indistinguishable. But the problem is that most people with COVID will live, while most people with hantavirus will die without critical care.”

The overall US case fatality rates are drastically different: 36% to 38% for hantavirus, 1.6% for COVID-19. In Arizona alone, of 81 patients who developed hantavirus (as of 2019), 27 died. In New Mexico, of 117 patients, 51 died.

“The scary part,” said Tarrah Oliver, “was that when patients were flooding our ER with symptoms exactly like those of hantavirus, I kept thinking that it was now up to us in the lab to scrutinize CBC results for any characteristics of hantavirus because our locum providers and permanent providers would likely not have hanta on their minds right now to suspect it.”

“Once COVID hit Navajo Nation, we really worried about how clinicians were going to distinguish between the two disease entities and worried about possible excess deaths of hanta because they were mistaken for COVID-19,” Choi says. “Unfortunately, in the spring of 2020, 2 fatal cases of hantavirus were reported. Their deaths were initially thought to be due to COVID, but later testing showed that they both died of hantavirus. We knew that we had to study whether the 5-point screen could distinguish between hantavirus disease and COVID.”

They conducted the comparison study at TMC and Emory, in Atlanta. TMC, as a small hospital, might not get many COVID cases while Emory, a large hospital system, had many COVID cases but rarely hantavirus cases (Box).

The researchers found that the screen did indeed work as they had hoped. No matter who performed the screen, the demographics of the population screened, or when in the COVID-19 disease course the sample was taken, individuals positive for COVID-19 received a low score on the screen. None of the participants who were positive for COVID-19 demonstrated all 5 hallmarks of hantavirus infection, and only 3 patients received a score of 4.

The screen was most accurate when the specimen was collected during the cardiopulmonary phase. Before the cardiopulmonary phase [BOX], there is a short febrile prodromal phase in which the platelets are starting to drop but aren’t low enough to be considered thrombocytopenic. Hematocrit and hemoglobin levels are still normal, and immunoblasts or plasma cells haven’t been released into the blood yet. “A patient’s score is likely to be pretty low or intermediate,” Tarrah Oliver said. “In the febrile prodromal phase, the patient will have chills, fever, headache and myalgia lasting 3 to 6 days, which might be written off as the flu or even COVID-19, especially if a provider is not familiar with the endemic regions of the Navajo Nation.”

“When we found that the screen could distinguish between the 2 diseases,” Choi said, “we worked frantically to write up the findings and publish so that healthcare providers would be aware of the value of this tool.”

“I couldn’t be more excited that the word is getting out in the medical community,” Oliver said. They plan to share the information as widely as possible, booking local radio spots, for instance. “We’re trying to disseminate our research across our partners on the reservation.”

The results of the research were recently published in the American Journal of Clinical Pathology. “Our next follow-up research will be an inter-rater reliability between TMC’s 2-year and 4-year-degree medical laboratorians and Emory’s pathologists performing the 5-point hantavirus screen on the same slides. We want to show that rural hospitals without the expertise of pathologists can perform this screen for their patients in a timely manner and still get the same outcomes.”

Lastly, and the most exciting, Oliver said, is putting that training manual she created to wider use. In addition to all the case studies she collected, analyzer printouts, and PowerPoint slides about the epidemiology, the manual includes a procedure, billing codes, and layout of what it looks like on certain medical record software that most Indian Health Service hospitals use. “With the manual, we may be able to expand our reach, so I won’t need to travel,” Oliver said. “We could use Zoom to reach further and I could explain it all while they have the manual right in front them.”

So far, nearly 200 screens have been performed at TMC. Four cases of hantavirus disease have been identified. The screen has proved successful, but for Oliver, there’s a personal reward. “I heard stories as a kid of relatives and friends succumbing to this mystery flu in the 1990s and how our parents protected us from it,” she said. “Now I feel like it’s my turn to take care of my family and friends from both hantavirus and COVID, our current ‘mystery flu.’ … I’ve realized that now I’m doing this for our people, the Diné (Navajo) people.”

This article offers some background and follow-up to Hantavirus Disease and COVID-19: Evaluation of the Hantavirus 5-Point Screen in 139 COVID-19 Patients

In May 2016, Tarrah Oliver had been working as a bench tech in hematology at Tséhootsooí Medical Center (TMC) for 4 years when the hospital launched a 5-point screen for detecting hantavirus cardiopulmonary syndrome (HCPS), a potentially fatal disease that disproportionately affects Native Americans.

Developed at the University of New Mexico, the 5-point screen was particularly useful for facilities like TMC, a 56-bed hospital in Arizona serving Navajo Nation patients. Although the Navajo make up only 1.7% of the population, they account for 18% of all reported HCPS cases in the US.

But Oliver, who was the laboratory Safety and Training supervisor, her department supervisor, and his assistant were the only people who knew how to do the screen. “I was storing completed worksheets in a folder,” Oliver said, “and soon I had to transfer them to a 3-inch binder because we had so many being ordered. I started saving slides that scored high so that I could show my fellow lab mates what certain characteristics looked like under the microscope.” She also created case studies to train staff using analyzer printouts and slides from the patients. “It was my little side project to take care of while I was working and training new employees in the hematology department.”

The screen was to become much more than a side project very quickly.

In 2017, there was a hantavirus outbreak in one of the nearby communities. A team from the Centers for Disease Control and Prevention (CDC) came out to visit the local hospitals to educate the medical staff on what to look for in their patients with suspected hantavirus. Among those: the TMC staff. The visit would prove both serendipitous and synergistic.

Mary Choi, MD, MPH, medical officer with the CDC Viral Special Pathogens Branch, said, “Members of my branch were asked to come to Navajo Nation [Lukachukai chapter, Arizona] because of a cluster of hantaviruses cases that had been occurring in the area over the course of a few years. During a meeting with medical providers at TMC, our team met Tarrah and she told us that TMC had implemented the screen. We were really intrigued and impressed by the initiative of this small community hospital.”

“We were excited that the CDC even knew we existed!” Oliver recalled. “This little lab in the middle of the reservation.”

HCPS is rare but severe. It can quickly progress from nonspecific initial symptoms, such as fever, body aches, and shortness of breath, to severe respiratory distress. Without immediate intervention, patients usually die within 24 to 48 hours of the onset of cardiopulmonary symptoms. “What makes the disease even more challenging,” said Choi, “is that some of the critical lifesaving measures that physicians normally employ to save a critically-ill patient can actually make the situation worse.

“For example, when HCPS patients reach the cardiopulmonary phase of the illness, their blood pressure will drop. The normal response to this is to give IV fluids (IVF). But in hantavirus, giving IVF can actually make the signs and symptoms of the disease worse and only judicious use of IVF is recommended.”

She gave other examples of treatment challenges: “Physicians are taught to intubate critically ill patients. However, intubation of hanta patients during the cardiopulmonary phase can actually be detrimental. Also, in general, extracorporeal membrane oxygenation (ECMO) is an intervention of last resort for most critically-ill patients. As the procedure essentially involves hooking the patient up to a heart-lung machine, which has a lot of complications, doctors do not do this unless they have to. But in hantavirus disease, early initiation of ECMO has been shown to significantly improve survival.”

“Another tricky thing about ECMO is that not all hospitals have an ECMO machine… oftentimes patients have to be transferred from one hospital to another because they need ECMO and it is not available where they are.” The ECMO-equipped facility closest to TMC is 170 miles away, at the University of New Mexico Hospital in Albuquerque.

 For all those reasons, Dr. Choi said, it is critically important for physicians to know if the patient they are treating has hantavirus or not. The problem is, there is no rapid test for hantavirus disease. The tests have to be sent out to a laboratory and it can take days before physicians receive a test result. “This is where the 5-point screen is such a valuable tool. Although it is not a diagnostic test, it is a very accurate screening tool. Even better, it is readily and widely available, because to perform the screen, you only need a complete blood count (CBC) and a peripheral blood smear…which can be performed in the vast majority of laboratories and clinics. In addition, the CBC and peripheral blood smear are very commonly ordered tests.”

The screen could be particularly crucial for small community hospitals and clinics. “[TMC] took a screen developed by hematopathologists for hematopathologists,” Choi said, “and adapted it so that it could be performed by clinical laboratorians—because hematopathologists don’t exactly grow on trees! Once we heard about the work that TMC was doing, we knew that this was something we wanted to support and advocate for.”

“We started to throw around the idea of teaching this method to other laboratories on the reservation,” Oliver said. She and Mary Choi teamed up to “knock on everyone’s door to see who was utilizing the screening or if they had their own methods of detecting hantavirus in their patients.”

Two years later, they began holding training sessions at a nearby community college; they also trained an entire laboratory at their hospital in late 2019. Plans were to set up other training sessions towards the border towns before spring of 2020.

Then SARS-CoV-2 showed up.

Hantavirus or coronavirus?

COVID-19 hit the Navajo Nation like a sledgehammer. Native Americans in rural areas, as many Navajo are, may have multigenerational and extended families living in tight quarters, with limited access to running water, miles from the nearest healthcare facility. They were particularly vulnerable to a virus that thrives on close contact, at a time when the most common preventives were distancing, frequent handwashing, and testing. By May 2020, the Navajo Nation had surpassed the epicenters—New York and New Jersey—in cases of infection. Even as late as November 2021, the Navah Nation has reported > 37,000 positive cases, and nearly 1,500 confirmed deaths, despite reaching a 70% vaccination rate.

Making things ever more challenging: How do you know whether the patient has hantavirus or COVID-19? The distinction is critical because the disease courses of the 2 infections differ greatly. “The importance of [TMC’s] work was really brought home by the COVID pandemic,” Mary Choi said. “The signs and symptoms of early COVID and hantavirus are really indistinguishable. But the problem is that most people with COVID will live, while most people with hantavirus will die without critical care.”

The overall US case fatality rates are drastically different: 36% to 38% for hantavirus, 1.6% for COVID-19. In Arizona alone, of 81 patients who developed hantavirus (as of 2019), 27 died. In New Mexico, of 117 patients, 51 died.

“The scary part,” said Tarrah Oliver, “was that when patients were flooding our ER with symptoms exactly like those of hantavirus, I kept thinking that it was now up to us in the lab to scrutinize CBC results for any characteristics of hantavirus because our locum providers and permanent providers would likely not have hanta on their minds right now to suspect it.”

“Once COVID hit Navajo Nation, we really worried about how clinicians were going to distinguish between the two disease entities and worried about possible excess deaths of hanta because they were mistaken for COVID-19,” Choi says. “Unfortunately, in the spring of 2020, 2 fatal cases of hantavirus were reported. Their deaths were initially thought to be due to COVID, but later testing showed that they both died of hantavirus. We knew that we had to study whether the 5-point screen could distinguish between hantavirus disease and COVID.”

They conducted the comparison study at TMC and Emory, in Atlanta. TMC, as a small hospital, might not get many COVID cases while Emory, a large hospital system, had many COVID cases but rarely hantavirus cases (Box).

The researchers found that the screen did indeed work as they had hoped. No matter who performed the screen, the demographics of the population screened, or when in the COVID-19 disease course the sample was taken, individuals positive for COVID-19 received a low score on the screen. None of the participants who were positive for COVID-19 demonstrated all 5 hallmarks of hantavirus infection, and only 3 patients received a score of 4.

The screen was most accurate when the specimen was collected during the cardiopulmonary phase. Before the cardiopulmonary phase [BOX], there is a short febrile prodromal phase in which the platelets are starting to drop but aren’t low enough to be considered thrombocytopenic. Hematocrit and hemoglobin levels are still normal, and immunoblasts or plasma cells haven’t been released into the blood yet. “A patient’s score is likely to be pretty low or intermediate,” Tarrah Oliver said. “In the febrile prodromal phase, the patient will have chills, fever, headache and myalgia lasting 3 to 6 days, which might be written off as the flu or even COVID-19, especially if a provider is not familiar with the endemic regions of the Navajo Nation.”

“When we found that the screen could distinguish between the 2 diseases,” Choi said, “we worked frantically to write up the findings and publish so that healthcare providers would be aware of the value of this tool.”

“I couldn’t be more excited that the word is getting out in the medical community,” Oliver said. They plan to share the information as widely as possible, booking local radio spots, for instance. “We’re trying to disseminate our research across our partners on the reservation.”

The results of the research were recently published in the American Journal of Clinical Pathology. “Our next follow-up research will be an inter-rater reliability between TMC’s 2-year and 4-year-degree medical laboratorians and Emory’s pathologists performing the 5-point hantavirus screen on the same slides. We want to show that rural hospitals without the expertise of pathologists can perform this screen for their patients in a timely manner and still get the same outcomes.”

Lastly, and the most exciting, Oliver said, is putting that training manual she created to wider use. In addition to all the case studies she collected, analyzer printouts, and PowerPoint slides about the epidemiology, the manual includes a procedure, billing codes, and layout of what it looks like on certain medical record software that most Indian Health Service hospitals use. “With the manual, we may be able to expand our reach, so I won’t need to travel,” Oliver said. “We could use Zoom to reach further and I could explain it all while they have the manual right in front them.”

So far, nearly 200 screens have been performed at TMC. Four cases of hantavirus disease have been identified. The screen has proved successful, but for Oliver, there’s a personal reward. “I heard stories as a kid of relatives and friends succumbing to this mystery flu in the 1990s and how our parents protected us from it,” she said. “Now I feel like it’s my turn to take care of my family and friends from both hantavirus and COVID, our current ‘mystery flu.’ … I’ve realized that now I’m doing this for our people, the Diné (Navajo) people.”

This article offers some background and follow-up to Hantavirus Disease and COVID-19: Evaluation of the Hantavirus 5-Point Screen in 139 COVID-19 Patients

In May 2016, Tarrah Oliver had been working as a bench tech in hematology at Tséhootsooí Medical Center (TMC) for 4 years when the hospital launched a 5-point screen for detecting hantavirus cardiopulmonary syndrome (HCPS), a potentially fatal disease that disproportionately affects Native Americans.

Developed at the University of New Mexico, the 5-point screen was particularly useful for facilities like TMC, a 56-bed hospital in Arizona serving Navajo Nation patients. Although the Navajo make up only 1.7% of the population, they account for 18% of all reported HCPS cases in the US.

But Oliver, who was the laboratory Safety and Training supervisor, her department supervisor, and his assistant were the only people who knew how to do the screen. “I was storing completed worksheets in a folder,” Oliver said, “and soon I had to transfer them to a 3-inch binder because we had so many being ordered. I started saving slides that scored high so that I could show my fellow lab mates what certain characteristics looked like under the microscope.” She also created case studies to train staff using analyzer printouts and slides from the patients. “It was my little side project to take care of while I was working and training new employees in the hematology department.”

The screen was to become much more than a side project very quickly.

In 2017, there was a hantavirus outbreak in one of the nearby communities. A team from the Centers for Disease Control and Prevention (CDC) came out to visit the local hospitals to educate the medical staff on what to look for in their patients with suspected hantavirus. Among those: the TMC staff. The visit would prove both serendipitous and synergistic.

Mary Choi, MD, MPH, medical officer with the CDC Viral Special Pathogens Branch, said, “Members of my branch were asked to come to Navajo Nation [Lukachukai chapter, Arizona] because of a cluster of hantaviruses cases that had been occurring in the area over the course of a few years. During a meeting with medical providers at TMC, our team met Tarrah and she told us that TMC had implemented the screen. We were really intrigued and impressed by the initiative of this small community hospital.”

“We were excited that the CDC even knew we existed!” Oliver recalled. “This little lab in the middle of the reservation.”

HCPS is rare but severe. It can quickly progress from nonspecific initial symptoms, such as fever, body aches, and shortness of breath, to severe respiratory distress. Without immediate intervention, patients usually die within 24 to 48 hours of the onset of cardiopulmonary symptoms. “What makes the disease even more challenging,” said Choi, “is that some of the critical lifesaving measures that physicians normally employ to save a critically-ill patient can actually make the situation worse.

“For example, when HCPS patients reach the cardiopulmonary phase of the illness, their blood pressure will drop. The normal response to this is to give IV fluids (IVF). But in hantavirus, giving IVF can actually make the signs and symptoms of the disease worse and only judicious use of IVF is recommended.”

She gave other examples of treatment challenges: “Physicians are taught to intubate critically ill patients. However, intubation of hanta patients during the cardiopulmonary phase can actually be detrimental. Also, in general, extracorporeal membrane oxygenation (ECMO) is an intervention of last resort for most critically-ill patients. As the procedure essentially involves hooking the patient up to a heart-lung machine, which has a lot of complications, doctors do not do this unless they have to. But in hantavirus disease, early initiation of ECMO has been shown to significantly improve survival.”

“Another tricky thing about ECMO is that not all hospitals have an ECMO machine… oftentimes patients have to be transferred from one hospital to another because they need ECMO and it is not available where they are.” The ECMO-equipped facility closest to TMC is 170 miles away, at the University of New Mexico Hospital in Albuquerque.

 For all those reasons, Dr. Choi said, it is critically important for physicians to know if the patient they are treating has hantavirus or not. The problem is, there is no rapid test for hantavirus disease. The tests have to be sent out to a laboratory and it can take days before physicians receive a test result. “This is where the 5-point screen is such a valuable tool. Although it is not a diagnostic test, it is a very accurate screening tool. Even better, it is readily and widely available, because to perform the screen, you only need a complete blood count (CBC) and a peripheral blood smear…which can be performed in the vast majority of laboratories and clinics. In addition, the CBC and peripheral blood smear are very commonly ordered tests.”

The screen could be particularly crucial for small community hospitals and clinics. “[TMC] took a screen developed by hematopathologists for hematopathologists,” Choi said, “and adapted it so that it could be performed by clinical laboratorians—because hematopathologists don’t exactly grow on trees! Once we heard about the work that TMC was doing, we knew that this was something we wanted to support and advocate for.”

“We started to throw around the idea of teaching this method to other laboratories on the reservation,” Oliver said. She and Mary Choi teamed up to “knock on everyone’s door to see who was utilizing the screening or if they had their own methods of detecting hantavirus in their patients.”

Two years later, they began holding training sessions at a nearby community college; they also trained an entire laboratory at their hospital in late 2019. Plans were to set up other training sessions towards the border towns before spring of 2020.

Then SARS-CoV-2 showed up.

Hantavirus or coronavirus?

COVID-19 hit the Navajo Nation like a sledgehammer. Native Americans in rural areas, as many Navajo are, may have multigenerational and extended families living in tight quarters, with limited access to running water, miles from the nearest healthcare facility. They were particularly vulnerable to a virus that thrives on close contact, at a time when the most common preventives were distancing, frequent handwashing, and testing. By May 2020, the Navajo Nation had surpassed the epicenters—New York and New Jersey—in cases of infection. Even as late as November 2021, the Navah Nation has reported > 37,000 positive cases, and nearly 1,500 confirmed deaths, despite reaching a 70% vaccination rate.

Making things ever more challenging: How do you know whether the patient has hantavirus or COVID-19? The distinction is critical because the disease courses of the 2 infections differ greatly. “The importance of [TMC’s] work was really brought home by the COVID pandemic,” Mary Choi said. “The signs and symptoms of early COVID and hantavirus are really indistinguishable. But the problem is that most people with COVID will live, while most people with hantavirus will die without critical care.”

The overall US case fatality rates are drastically different: 36% to 38% for hantavirus, 1.6% for COVID-19. In Arizona alone, of 81 patients who developed hantavirus (as of 2019), 27 died. In New Mexico, of 117 patients, 51 died.

“The scary part,” said Tarrah Oliver, “was that when patients were flooding our ER with symptoms exactly like those of hantavirus, I kept thinking that it was now up to us in the lab to scrutinize CBC results for any characteristics of hantavirus because our locum providers and permanent providers would likely not have hanta on their minds right now to suspect it.”

“Once COVID hit Navajo Nation, we really worried about how clinicians were going to distinguish between the two disease entities and worried about possible excess deaths of hanta because they were mistaken for COVID-19,” Choi says. “Unfortunately, in the spring of 2020, 2 fatal cases of hantavirus were reported. Their deaths were initially thought to be due to COVID, but later testing showed that they both died of hantavirus. We knew that we had to study whether the 5-point screen could distinguish between hantavirus disease and COVID.”

They conducted the comparison study at TMC and Emory, in Atlanta. TMC, as a small hospital, might not get many COVID cases while Emory, a large hospital system, had many COVID cases but rarely hantavirus cases (Box).

The researchers found that the screen did indeed work as they had hoped. No matter who performed the screen, the demographics of the population screened, or when in the COVID-19 disease course the sample was taken, individuals positive for COVID-19 received a low score on the screen. None of the participants who were positive for COVID-19 demonstrated all 5 hallmarks of hantavirus infection, and only 3 patients received a score of 4.

The screen was most accurate when the specimen was collected during the cardiopulmonary phase. Before the cardiopulmonary phase [BOX], there is a short febrile prodromal phase in which the platelets are starting to drop but aren’t low enough to be considered thrombocytopenic. Hematocrit and hemoglobin levels are still normal, and immunoblasts or plasma cells haven’t been released into the blood yet. “A patient’s score is likely to be pretty low or intermediate,” Tarrah Oliver said. “In the febrile prodromal phase, the patient will have chills, fever, headache and myalgia lasting 3 to 6 days, which might be written off as the flu or even COVID-19, especially if a provider is not familiar with the endemic regions of the Navajo Nation.”

“When we found that the screen could distinguish between the 2 diseases,” Choi said, “we worked frantically to write up the findings and publish so that healthcare providers would be aware of the value of this tool.”

“I couldn’t be more excited that the word is getting out in the medical community,” Oliver said. They plan to share the information as widely as possible, booking local radio spots, for instance. “We’re trying to disseminate our research across our partners on the reservation.”

The results of the research were recently published in the American Journal of Clinical Pathology. “Our next follow-up research will be an inter-rater reliability between TMC’s 2-year and 4-year-degree medical laboratorians and Emory’s pathologists performing the 5-point hantavirus screen on the same slides. We want to show that rural hospitals without the expertise of pathologists can perform this screen for their patients in a timely manner and still get the same outcomes.”

Lastly, and the most exciting, Oliver said, is putting that training manual she created to wider use. In addition to all the case studies she collected, analyzer printouts, and PowerPoint slides about the epidemiology, the manual includes a procedure, billing codes, and layout of what it looks like on certain medical record software that most Indian Health Service hospitals use. “With the manual, we may be able to expand our reach, so I won’t need to travel,” Oliver said. “We could use Zoom to reach further and I could explain it all while they have the manual right in front them.”

So far, nearly 200 screens have been performed at TMC. Four cases of hantavirus disease have been identified. The screen has proved successful, but for Oliver, there’s a personal reward. “I heard stories as a kid of relatives and friends succumbing to this mystery flu in the 1990s and how our parents protected us from it,” she said. “Now I feel like it’s my turn to take care of my family and friends from both hantavirus and COVID, our current ‘mystery flu.’ … I’ve realized that now I’m doing this for our people, the Diné (Navajo) people.”

This article offers some background and follow-up to Hantavirus Disease and COVID-19: Evaluation of the Hantavirus 5-Point Screen in 139 COVID-19 Patients

When provided at the bedside of patients hospitalized for heart failure, an electronic health record (EHR) alert with prognostic information did not improve outcomes or appear to have any impact on what treatments were offered.

There was no signal that the EHR prognostic alerts, which identified the 12-month risk of mortality, had any impact on any of a variety of clinical-decision-making metrics or on any of the primary or secondary outcomes, according to Tariq Ahmad, MD, who reported results of the randomized REVEAL-HF trial, presented at the American Heart Association scientific sessions.

“These results call into question the hypothesis that accurate prognostic information alone will lead to better clinical decision-making,” said Dr. Ahmad, medical director of the Heart Transplant and Mechanical Circulatory Support Program at Yale University, New Haven, Conn., and principal investigator of REVEAL-HF.

He acknowledged that the possibility that many clinicians pay little or no attention to EHR alert might have played a role in the negative results.

At four participating Yale-affiliated clinical centers, all patients hospitalized for acute heart failure were randomized as long as they were over the age of 18, had an N-terminal pro-brain natriuretic peptide (NT-proBNP) level above 500 pg/mL, and had been placed on IV diuretics within 24 hours of admission. In the experimental arm, the provider at the time of entering orders received an EHR alert with an estimate of the risk of all-cause mortality at 12 months. There was no such alert for patients managed in the control arm.
 

Twelve-month mortality estimates calculated

The all-cause mortality risk was calculated on a sizeable list of variables that included laboratory results, such as cell counts, and patient characteristics, such as weight and age. The risk estimate was displayed along with a five-category color-coded bar to provide context for the risk in the spectrum of very low, low, medium, high, and very high likelihood of death within 12 months.

The 1,590 patients randomized to the experimental arm and the 1,534 patients randomized to the usual care arm did not differ significantly in any baseline characteristics. The median age was about 77 years, the mean left ventricular ejection fraction (LVEF) was 55%. About 29% had an LVEF below 40%, about 40% had chronic kidney disease, and about 30% had chronic obstructive pulmonary disease (COPD).

The composite primary outcome of all-cause mortality or rehospitalization within 12 months was reached by 38.9% and 39.3% (P = 0.82) of the intervention and control arms, respectively. The components of the primary outcome were also nearly identical, as was inpatient mortality (8.4% vs. 8.8%; P = 0.72).

There were no significant differences in any of the secondary outcomes, which included rates of 30-day rehospitalizations, discharge on guideline-recommended heart failure therapies, implantation of a cardioverter defibrillator, use of a left ventricular assist device, or heart transplant.

The proportion of patients referred for palliative care was almost identical in the very low, low, and medium risk groups. In the high (23.4 vs. 15.6; P = 0.19) and very high (50% vs. 40%; P = 0.92) groups, there were numerically more referrals in the group randomized to usual care, but these rates did not reach significance.
 

No differences seen in discharge meds

There was essentially no difference between groups in the rates at which patients were discharged on beta-blockers, renin-angiotensin system inhibitors, sodium-glucose co-transporter type 2 (SGLT2) inhibitors, or mineralocorticoid antagonists.

When prespecified subgroups, such as those older than age 75 years relative to those younger, males relative to females, Black versus White participants, patients with reduced ejection fraction (HFrEF) relative to preserved ejection fraction (HFpEF), and intensive care unit versus non-ICU patients, were compared, there were no indications that the EHR alert improved outcomes.

Invited discussant Harriette G. C. Van Spall, MD, director of digital health and virtual care and associate professor of cardiology at McMaster University, Hamilton, Ont., did not dispute the conclusions, but she pointed out several potential explanations for the neutral result.

Not least, nearly 75% of those enrolled had low risk or very low risk for adverse outcomes within 1 year, so the opportunity to show a reduction in events, including all-cause mortality, was limited.

“This was largely a HFpEF population, for which there are no treatments for which a risk score would change therapy,” she said.
 

EHR alert efficacy questioned

There is considerable evidence that risk prediction tools “are common but underutilized in HF,” Dr. Van Spall added. She noted that many clinicians find alerts in the EHR more annoying than informative, and it remains unknown what proportion of clinicians pay attention to them, particularly in the absence of evidence that they lead to meaningful improvements in care over their own clinical judgment.

Dr. Ahmad agreed.

“I think that we need to study these alerts in a clinical trial format,” he said. Acknowledging that alerts have been poorly received by many clinicians, Dr. Ahmad said that trials to validate the impact of any specific alert are needed to improve their credibility. If a positive impact cannot be shown, he said the alert should be eliminated, leaving only the alerts with proven clinical value.

Dr. Ahmad reported financial relationships with Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Novartis, and Relypsa. Dr. Van Spall reports no potential conflicts of interest.

When provided at the bedside of patients hospitalized for heart failure, an electronic health record (EHR) alert with prognostic information did not improve outcomes or appear to have any impact on what treatments were offered.

There was no signal that the EHR prognostic alerts, which identified the 12-month risk of mortality, had any impact on any of a variety of clinical-decision-making metrics or on any of the primary or secondary outcomes, according to Tariq Ahmad, MD, who reported results of the randomized REVEAL-HF trial, presented at the American Heart Association scientific sessions.

“These results call into question the hypothesis that accurate prognostic information alone will lead to better clinical decision-making,” said Dr. Ahmad, medical director of the Heart Transplant and Mechanical Circulatory Support Program at Yale University, New Haven, Conn., and principal investigator of REVEAL-HF.

He acknowledged that the possibility that many clinicians pay little or no attention to EHR alert might have played a role in the negative results.

At four participating Yale-affiliated clinical centers, all patients hospitalized for acute heart failure were randomized as long as they were over the age of 18, had an N-terminal pro-brain natriuretic peptide (NT-proBNP) level above 500 pg/mL, and had been placed on IV diuretics within 24 hours of admission. In the experimental arm, the provider at the time of entering orders received an EHR alert with an estimate of the risk of all-cause mortality at 12 months. There was no such alert for patients managed in the control arm.
 

Twelve-month mortality estimates calculated

The all-cause mortality risk was calculated on a sizeable list of variables that included laboratory results, such as cell counts, and patient characteristics, such as weight and age. The risk estimate was displayed along with a five-category color-coded bar to provide context for the risk in the spectrum of very low, low, medium, high, and very high likelihood of death within 12 months.

The 1,590 patients randomized to the experimental arm and the 1,534 patients randomized to the usual care arm did not differ significantly in any baseline characteristics. The median age was about 77 years, the mean left ventricular ejection fraction (LVEF) was 55%. About 29% had an LVEF below 40%, about 40% had chronic kidney disease, and about 30% had chronic obstructive pulmonary disease (COPD).

The composite primary outcome of all-cause mortality or rehospitalization within 12 months was reached by 38.9% and 39.3% (P = 0.82) of the intervention and control arms, respectively. The components of the primary outcome were also nearly identical, as was inpatient mortality (8.4% vs. 8.8%; P = 0.72).

There were no significant differences in any of the secondary outcomes, which included rates of 30-day rehospitalizations, discharge on guideline-recommended heart failure therapies, implantation of a cardioverter defibrillator, use of a left ventricular assist device, or heart transplant.

The proportion of patients referred for palliative care was almost identical in the very low, low, and medium risk groups. In the high (23.4 vs. 15.6; P = 0.19) and very high (50% vs. 40%; P = 0.92) groups, there were numerically more referrals in the group randomized to usual care, but these rates did not reach significance.
 

No differences seen in discharge meds

There was essentially no difference between groups in the rates at which patients were discharged on beta-blockers, renin-angiotensin system inhibitors, sodium-glucose co-transporter type 2 (SGLT2) inhibitors, or mineralocorticoid antagonists.

When prespecified subgroups, such as those older than age 75 years relative to those younger, males relative to females, Black versus White participants, patients with reduced ejection fraction (HFrEF) relative to preserved ejection fraction (HFpEF), and intensive care unit versus non-ICU patients, were compared, there were no indications that the EHR alert improved outcomes.

Invited discussant Harriette G. C. Van Spall, MD, director of digital health and virtual care and associate professor of cardiology at McMaster University, Hamilton, Ont., did not dispute the conclusions, but she pointed out several potential explanations for the neutral result.

Not least, nearly 75% of those enrolled had low risk or very low risk for adverse outcomes within 1 year, so the opportunity to show a reduction in events, including all-cause mortality, was limited.

“This was largely a HFpEF population, for which there are no treatments for which a risk score would change therapy,” she said.
 

EHR alert efficacy questioned

There is considerable evidence that risk prediction tools “are common but underutilized in HF,” Dr. Van Spall added. She noted that many clinicians find alerts in the EHR more annoying than informative, and it remains unknown what proportion of clinicians pay attention to them, particularly in the absence of evidence that they lead to meaningful improvements in care over their own clinical judgment.

Dr. Ahmad agreed.

“I think that we need to study these alerts in a clinical trial format,” he said. Acknowledging that alerts have been poorly received by many clinicians, Dr. Ahmad said that trials to validate the impact of any specific alert are needed to improve their credibility. If a positive impact cannot be shown, he said the alert should be eliminated, leaving only the alerts with proven clinical value.

Dr. Ahmad reported financial relationships with Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Novartis, and Relypsa. Dr. Van Spall reports no potential conflicts of interest.

When provided at the bedside of patients hospitalized for heart failure, an electronic health record (EHR) alert with prognostic information did not improve outcomes or appear to have any impact on what treatments were offered.

There was no signal that the EHR prognostic alerts, which identified the 12-month risk of mortality, had any impact on any of a variety of clinical-decision-making metrics or on any of the primary or secondary outcomes, according to Tariq Ahmad, MD, who reported results of the randomized REVEAL-HF trial, presented at the American Heart Association scientific sessions.

“These results call into question the hypothesis that accurate prognostic information alone will lead to better clinical decision-making,” said Dr. Ahmad, medical director of the Heart Transplant and Mechanical Circulatory Support Program at Yale University, New Haven, Conn., and principal investigator of REVEAL-HF.

He acknowledged that the possibility that many clinicians pay little or no attention to EHR alert might have played a role in the negative results.

At four participating Yale-affiliated clinical centers, all patients hospitalized for acute heart failure were randomized as long as they were over the age of 18, had an N-terminal pro-brain natriuretic peptide (NT-proBNP) level above 500 pg/mL, and had been placed on IV diuretics within 24 hours of admission. In the experimental arm, the provider at the time of entering orders received an EHR alert with an estimate of the risk of all-cause mortality at 12 months. There was no such alert for patients managed in the control arm.
 

Twelve-month mortality estimates calculated

The all-cause mortality risk was calculated on a sizeable list of variables that included laboratory results, such as cell counts, and patient characteristics, such as weight and age. The risk estimate was displayed along with a five-category color-coded bar to provide context for the risk in the spectrum of very low, low, medium, high, and very high likelihood of death within 12 months.

The 1,590 patients randomized to the experimental arm and the 1,534 patients randomized to the usual care arm did not differ significantly in any baseline characteristics. The median age was about 77 years, the mean left ventricular ejection fraction (LVEF) was 55%. About 29% had an LVEF below 40%, about 40% had chronic kidney disease, and about 30% had chronic obstructive pulmonary disease (COPD).

The composite primary outcome of all-cause mortality or rehospitalization within 12 months was reached by 38.9% and 39.3% (P = 0.82) of the intervention and control arms, respectively. The components of the primary outcome were also nearly identical, as was inpatient mortality (8.4% vs. 8.8%; P = 0.72).

There were no significant differences in any of the secondary outcomes, which included rates of 30-day rehospitalizations, discharge on guideline-recommended heart failure therapies, implantation of a cardioverter defibrillator, use of a left ventricular assist device, or heart transplant.

The proportion of patients referred for palliative care was almost identical in the very low, low, and medium risk groups. In the high (23.4 vs. 15.6; P = 0.19) and very high (50% vs. 40%; P = 0.92) groups, there were numerically more referrals in the group randomized to usual care, but these rates did not reach significance.
 

No differences seen in discharge meds

There was essentially no difference between groups in the rates at which patients were discharged on beta-blockers, renin-angiotensin system inhibitors, sodium-glucose co-transporter type 2 (SGLT2) inhibitors, or mineralocorticoid antagonists.

When prespecified subgroups, such as those older than age 75 years relative to those younger, males relative to females, Black versus White participants, patients with reduced ejection fraction (HFrEF) relative to preserved ejection fraction (HFpEF), and intensive care unit versus non-ICU patients, were compared, there were no indications that the EHR alert improved outcomes.

Invited discussant Harriette G. C. Van Spall, MD, director of digital health and virtual care and associate professor of cardiology at McMaster University, Hamilton, Ont., did not dispute the conclusions, but she pointed out several potential explanations for the neutral result.

Not least, nearly 75% of those enrolled had low risk or very low risk for adverse outcomes within 1 year, so the opportunity to show a reduction in events, including all-cause mortality, was limited.

“This was largely a HFpEF population, for which there are no treatments for which a risk score would change therapy,” she said.
 

EHR alert efficacy questioned

There is considerable evidence that risk prediction tools “are common but underutilized in HF,” Dr. Van Spall added. She noted that many clinicians find alerts in the EHR more annoying than informative, and it remains unknown what proportion of clinicians pay attention to them, particularly in the absence of evidence that they lead to meaningful improvements in care over their own clinical judgment.

Dr. Ahmad agreed.

“I think that we need to study these alerts in a clinical trial format,” he said. Acknowledging that alerts have been poorly received by many clinicians, Dr. Ahmad said that trials to validate the impact of any specific alert are needed to improve their credibility. If a positive impact cannot be shown, he said the alert should be eliminated, leaving only the alerts with proven clinical value.

Dr. Ahmad reported financial relationships with Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Novartis, and Relypsa. Dr. Van Spall reports no potential conflicts of interest.

Induction therapy with Janus kinase inhibitor upadacitinib is superior to placebo for patients with moderately to severely active ulcerative colitis (UC), regardless of prior biologic treatments, based on results of the phase 3 U-ACHIEVE trial.

Clinical responses in the upadacitinib group occurred as soon as 2 weeks and were sustained through the 8-week study period, reported lead author Silvio Danese, MD, PhD, of Humanitas Clinical and Research Center IRCCS and Hunimed, Milan.

“Despite availability of multiple treatment options, many patients with ulcerative colitis do not achieve disease remission with current therapies and unmet therapeutic need remains, especially in patients with moderate to severe disease,” said coauthor Peter Higgins, MD, PhD, of the University of Michigan, Ann Arbor, who presented findings at the annual meeting of the American College of Gastroenterology.

The U-ACHIEVE trial involved 474 patients with moderate to severe UC randomized to receive either upadacitinib induction therapy (45 mg once daily; n = 319) or placebo (n = 155). The primary endpoint was clinical remission at week 8. Secondary endpoints included endoscopic improvement at week 8, endoscopic remission at week 8, clinical response at week 8, clinical response at week 2, histologic-endoscopic mucosal improvement at week 8, and adverse events.

The study population was “very sick” and “very experienced,” Dr. Higgins said, noting that approximately half of the patients had inadequate responses to prior biologics, and within this subgroup of inadequate responders, approximately two-thirds of the patients had received more than one prior biologic. According to Dr. Higgins, this helps explain why 12.3% of the patients in the placebo group discontinued therapy, compared with just 3.8% in the upadacitinib group – because most patients involved were “quite ill.”

At week 8, 26.1% of the patients in the upadacitinib group had achieved clinical remission, versus 4.8% of the patients given placebo (26.1% vs. 4.8%; P < .0001). Clinical response at week 2 followed a similar pattern (60.1% vs. 27.3%; P < .001), as did clinical response at week 8 (72.6% vs. 27.3%; P < .0001).

All other 8-week secondary endpoints also significantly favored upadacitinib, including endoscopic improvement (36.3% vs 7.4%), endoscopic remission (13.7% vs 1.3%), and histologic-endoscopic mucosal improvement (29.9% vs. 6.5%).

Serious and severe adverse events were more common in the placebo group, and patients in the placebo group more frequently discontinued therapy because of treatment-related adverse events. While rates of serious infection were similar between groups, patients taking upadacitinib had higher rates of neutropenia and lymphopenia.

Based on these findings, the investigators concluded that upadacitinib induction therapy is superior to placebo for clinical remission and clinical response regardless of previous treatment failure.

According to Jordan E. Axelrad, MD, of New York University Langone Health, the findings reflect a real-world setting and clinicians should take note of the rapid response observed with upadacitinib.

“This was a relatively sick group, so you know this reflects what we’re seeing in clinical practice,” Dr. Axelrad said in an interview. “Clinical response was detected as early week 2, and that’s extremely important to highlight, because a lot of our drugs that we have on the market – some of these biologics – may take a little time to work. Having a drug that can work fast and is effective is critical.”

Dr. Axelrad suggested that second-line JAK inhibitors like upadacitinib, which target JAK proteins more selectively than first-generation agents, may alleviate some lingering concerns about JAK inhibitor safety; still, optimal treatment sequencing remains unclear.

“With more selective inhibition, you’re getting less of that side-effect profile,” Dr. Axelrad said, noting that long-term data is needed to confirm this likelihood. “The real question moving forward is: Will upadacitinib replace first-generation JAK inhibitors as a category, or, because of the broader safety profile, will it come earlier in the positioning of where we put our drugs for colitis?”

Dr. Axelrad suggested that the answer may ultimately come from regulators, although patients could also guide decision-making.

“Oral drugs are a really important mode of administration that we’re missing for the moderate to severe group,” he said. “Should [further clinical trials] demonstrate superior safety to nonselective JAK inhibitors, upadacitinib could be a first-line option for patients who don’t want to be taking an infusion or injection, more especially so for those that are already biologically experienced, or need something fast.”

Siddharth Singh, MD, director of the IBD Center at the University of California, San Diego, called U-ACHIEVE a “pivotal trial” that demonstrated the “remarkable efficacy” of upadacitinib for moderate to severe ulcerative colitis; still, he noted that drug sequencing remains undetermined.

“It’s unclear whether or not it’ll be the best in class for JAK inhibitors right now,” Dr. Singh said in an interview. “A lot of that hinges on the safety of this drug. In terms of positioning, it depends on whether the [Food and Drug Administration] requires patients to have failed anti–[tumor necrosis factor] therapy before using this drug, like tofacitinib.”

That may depend on long-term data, he suggested.

“Right now, it is hard to comment on the relative safety of upadacitinib versus tofacitinib,” Dr. Singh said. “While the JAK1 selectivity may contribute to efficacy by allowing us to use a higher dose, it’s unclear whether the higher dose of this medication is any safer than tofacitinib. Longer term, 5- to 7-year registry studies of real-world data are warranted to examine risk of cardiovascular disease, thromboembolism, malignancy, and mortality with upadacitinib.

“How to sequence and position these therapies in real-world practice is a key question,” he concluded.

The study was supported by AbbVie. The investigators disclosed additional affiliations with Genentech, Ferring, AstraZeneca, and others. Dr. Axelrad has previously consulted for AbbVie. Dr. Singh has received research funding from AbbVie, Pfizer, and Janssen in the last 24 months, as well as personal fees from Pfizer for an ad hoc grant review.

Induction therapy with Janus kinase inhibitor upadacitinib is superior to placebo for patients with moderately to severely active ulcerative colitis (UC), regardless of prior biologic treatments, based on results of the phase 3 U-ACHIEVE trial.

Clinical responses in the upadacitinib group occurred as soon as 2 weeks and were sustained through the 8-week study period, reported lead author Silvio Danese, MD, PhD, of Humanitas Clinical and Research Center IRCCS and Hunimed, Milan.

“Despite availability of multiple treatment options, many patients with ulcerative colitis do not achieve disease remission with current therapies and unmet therapeutic need remains, especially in patients with moderate to severe disease,” said coauthor Peter Higgins, MD, PhD, of the University of Michigan, Ann Arbor, who presented findings at the annual meeting of the American College of Gastroenterology.

The U-ACHIEVE trial involved 474 patients with moderate to severe UC randomized to receive either upadacitinib induction therapy (45 mg once daily; n = 319) or placebo (n = 155). The primary endpoint was clinical remission at week 8. Secondary endpoints included endoscopic improvement at week 8, endoscopic remission at week 8, clinical response at week 8, clinical response at week 2, histologic-endoscopic mucosal improvement at week 8, and adverse events.

The study population was “very sick” and “very experienced,” Dr. Higgins said, noting that approximately half of the patients had inadequate responses to prior biologics, and within this subgroup of inadequate responders, approximately two-thirds of the patients had received more than one prior biologic. According to Dr. Higgins, this helps explain why 12.3% of the patients in the placebo group discontinued therapy, compared with just 3.8% in the upadacitinib group – because most patients involved were “quite ill.”

At week 8, 26.1% of the patients in the upadacitinib group had achieved clinical remission, versus 4.8% of the patients given placebo (26.1% vs. 4.8%; P < .0001). Clinical response at week 2 followed a similar pattern (60.1% vs. 27.3%; P < .001), as did clinical response at week 8 (72.6% vs. 27.3%; P < .0001).

All other 8-week secondary endpoints also significantly favored upadacitinib, including endoscopic improvement (36.3% vs 7.4%), endoscopic remission (13.7% vs 1.3%), and histologic-endoscopic mucosal improvement (29.9% vs. 6.5%).

Serious and severe adverse events were more common in the placebo group, and patients in the placebo group more frequently discontinued therapy because of treatment-related adverse events. While rates of serious infection were similar between groups, patients taking upadacitinib had higher rates of neutropenia and lymphopenia.

Based on these findings, the investigators concluded that upadacitinib induction therapy is superior to placebo for clinical remission and clinical response regardless of previous treatment failure.

According to Jordan E. Axelrad, MD, of New York University Langone Health, the findings reflect a real-world setting and clinicians should take note of the rapid response observed with upadacitinib.

“This was a relatively sick group, so you know this reflects what we’re seeing in clinical practice,” Dr. Axelrad said in an interview. “Clinical response was detected as early week 2, and that’s extremely important to highlight, because a lot of our drugs that we have on the market – some of these biologics – may take a little time to work. Having a drug that can work fast and is effective is critical.”

Dr. Axelrad suggested that second-line JAK inhibitors like upadacitinib, which target JAK proteins more selectively than first-generation agents, may alleviate some lingering concerns about JAK inhibitor safety; still, optimal treatment sequencing remains unclear.

“With more selective inhibition, you’re getting less of that side-effect profile,” Dr. Axelrad said, noting that long-term data is needed to confirm this likelihood. “The real question moving forward is: Will upadacitinib replace first-generation JAK inhibitors as a category, or, because of the broader safety profile, will it come earlier in the positioning of where we put our drugs for colitis?”

Dr. Axelrad suggested that the answer may ultimately come from regulators, although patients could also guide decision-making.

“Oral drugs are a really important mode of administration that we’re missing for the moderate to severe group,” he said. “Should [further clinical trials] demonstrate superior safety to nonselective JAK inhibitors, upadacitinib could be a first-line option for patients who don’t want to be taking an infusion or injection, more especially so for those that are already biologically experienced, or need something fast.”

Siddharth Singh, MD, director of the IBD Center at the University of California, San Diego, called U-ACHIEVE a “pivotal trial” that demonstrated the “remarkable efficacy” of upadacitinib for moderate to severe ulcerative colitis; still, he noted that drug sequencing remains undetermined.

“It’s unclear whether or not it’ll be the best in class for JAK inhibitors right now,” Dr. Singh said in an interview. “A lot of that hinges on the safety of this drug. In terms of positioning, it depends on whether the [Food and Drug Administration] requires patients to have failed anti–[tumor necrosis factor] therapy before using this drug, like tofacitinib.”

That may depend on long-term data, he suggested.

“Right now, it is hard to comment on the relative safety of upadacitinib versus tofacitinib,” Dr. Singh said. “While the JAK1 selectivity may contribute to efficacy by allowing us to use a higher dose, it’s unclear whether the higher dose of this medication is any safer than tofacitinib. Longer term, 5- to 7-year registry studies of real-world data are warranted to examine risk of cardiovascular disease, thromboembolism, malignancy, and mortality with upadacitinib.

“How to sequence and position these therapies in real-world practice is a key question,” he concluded.

The study was supported by AbbVie. The investigators disclosed additional affiliations with Genentech, Ferring, AstraZeneca, and others. Dr. Axelrad has previously consulted for AbbVie. Dr. Singh has received research funding from AbbVie, Pfizer, and Janssen in the last 24 months, as well as personal fees from Pfizer for an ad hoc grant review.

Induction therapy with Janus kinase inhibitor upadacitinib is superior to placebo for patients with moderately to severely active ulcerative colitis (UC), regardless of prior biologic treatments, based on results of the phase 3 U-ACHIEVE trial.

Clinical responses in the upadacitinib group occurred as soon as 2 weeks and were sustained through the 8-week study period, reported lead author Silvio Danese, MD, PhD, of Humanitas Clinical and Research Center IRCCS and Hunimed, Milan.

“Despite availability of multiple treatment options, many patients with ulcerative colitis do not achieve disease remission with current therapies and unmet therapeutic need remains, especially in patients with moderate to severe disease,” said coauthor Peter Higgins, MD, PhD, of the University of Michigan, Ann Arbor, who presented findings at the annual meeting of the American College of Gastroenterology.

The U-ACHIEVE trial involved 474 patients with moderate to severe UC randomized to receive either upadacitinib induction therapy (45 mg once daily; n = 319) or placebo (n = 155). The primary endpoint was clinical remission at week 8. Secondary endpoints included endoscopic improvement at week 8, endoscopic remission at week 8, clinical response at week 8, clinical response at week 2, histologic-endoscopic mucosal improvement at week 8, and adverse events.

The study population was “very sick” and “very experienced,” Dr. Higgins said, noting that approximately half of the patients had inadequate responses to prior biologics, and within this subgroup of inadequate responders, approximately two-thirds of the patients had received more than one prior biologic. According to Dr. Higgins, this helps explain why 12.3% of the patients in the placebo group discontinued therapy, compared with just 3.8% in the upadacitinib group – because most patients involved were “quite ill.”

At week 8, 26.1% of the patients in the upadacitinib group had achieved clinical remission, versus 4.8% of the patients given placebo (26.1% vs. 4.8%; P < .0001). Clinical response at week 2 followed a similar pattern (60.1% vs. 27.3%; P < .001), as did clinical response at week 8 (72.6% vs. 27.3%; P < .0001).

All other 8-week secondary endpoints also significantly favored upadacitinib, including endoscopic improvement (36.3% vs 7.4%), endoscopic remission (13.7% vs 1.3%), and histologic-endoscopic mucosal improvement (29.9% vs. 6.5%).

Serious and severe adverse events were more common in the placebo group, and patients in the placebo group more frequently discontinued therapy because of treatment-related adverse events. While rates of serious infection were similar between groups, patients taking upadacitinib had higher rates of neutropenia and lymphopenia.

Based on these findings, the investigators concluded that upadacitinib induction therapy is superior to placebo for clinical remission and clinical response regardless of previous treatment failure.

According to Jordan E. Axelrad, MD, of New York University Langone Health, the findings reflect a real-world setting and clinicians should take note of the rapid response observed with upadacitinib.

“This was a relatively sick group, so you know this reflects what we’re seeing in clinical practice,” Dr. Axelrad said in an interview. “Clinical response was detected as early week 2, and that’s extremely important to highlight, because a lot of our drugs that we have on the market – some of these biologics – may take a little time to work. Having a drug that can work fast and is effective is critical.”

Dr. Axelrad suggested that second-line JAK inhibitors like upadacitinib, which target JAK proteins more selectively than first-generation agents, may alleviate some lingering concerns about JAK inhibitor safety; still, optimal treatment sequencing remains unclear.

“With more selective inhibition, you’re getting less of that side-effect profile,” Dr. Axelrad said, noting that long-term data is needed to confirm this likelihood. “The real question moving forward is: Will upadacitinib replace first-generation JAK inhibitors as a category, or, because of the broader safety profile, will it come earlier in the positioning of where we put our drugs for colitis?”

Dr. Axelrad suggested that the answer may ultimately come from regulators, although patients could also guide decision-making.

“Oral drugs are a really important mode of administration that we’re missing for the moderate to severe group,” he said. “Should [further clinical trials] demonstrate superior safety to nonselective JAK inhibitors, upadacitinib could be a first-line option for patients who don’t want to be taking an infusion or injection, more especially so for those that are already biologically experienced, or need something fast.”

Siddharth Singh, MD, director of the IBD Center at the University of California, San Diego, called U-ACHIEVE a “pivotal trial” that demonstrated the “remarkable efficacy” of upadacitinib for moderate to severe ulcerative colitis; still, he noted that drug sequencing remains undetermined.

“It’s unclear whether or not it’ll be the best in class for JAK inhibitors right now,” Dr. Singh said in an interview. “A lot of that hinges on the safety of this drug. In terms of positioning, it depends on whether the [Food and Drug Administration] requires patients to have failed anti–[tumor necrosis factor] therapy before using this drug, like tofacitinib.”

That may depend on long-term data, he suggested.

“Right now, it is hard to comment on the relative safety of upadacitinib versus tofacitinib,” Dr. Singh said. “While the JAK1 selectivity may contribute to efficacy by allowing us to use a higher dose, it’s unclear whether the higher dose of this medication is any safer than tofacitinib. Longer term, 5- to 7-year registry studies of real-world data are warranted to examine risk of cardiovascular disease, thromboembolism, malignancy, and mortality with upadacitinib.

“How to sequence and position these therapies in real-world practice is a key question,” he concluded.

The study was supported by AbbVie. The investigators disclosed additional affiliations with Genentech, Ferring, AstraZeneca, and others. Dr. Axelrad has previously consulted for AbbVie. Dr. Singh has received research funding from AbbVie, Pfizer, and Janssen in the last 24 months, as well as personal fees from Pfizer for an ad hoc grant review.

For over a decade, the influential National Comprehensive Cancer Network (NCCN) has been recommending that men with low-risk prostate cancer be offered active surveillance as the lone “preferred” initial treatment option.

But the NCCN has now reversed this long-standing recommendation in the latest revision of its prostate cancer guideline.

The organization now recommends that low-risk disease be managed with either active surveillance or radiation therapy or surgery, with equal weight given to all three of these initial options.

The change is seen by some as a retreat to the past and was harshly criticized by many experts on Twitter. The complaints were voiced in unusually blunt and strong language for physicians.

“This is a terrible step back that impacts every urologist,” commented John Griffith, MD, of Hartford Healthcare, who practices in New Britain, Conn.

Dr. Griffith explained that he prints out the NCCN guidance with “every patient newly diagnosed” and that the preferred designation is a “huge help” in reassuring them about not treating low-risk disease initially.

In a Twitter thread, Benjamin Davies, MD, of the University of Pittsburgh, facetiously wondered if a time warp was at play: “To suggest for a millisecond that active surveillance isn’t the preferred method for low-risk men is bizarre thinking ... Is this 1980?”

“I’m baffled,” said Brian Chapin, MD, of MD Anderson Cancer Center, Houston, in another Twitter thread.

“This is ludicrous,” said Andrew Vickers, PhD, of Memorial Sloan Kettering Cancer Center in New York City in a tweet.

Alexander Kutikov, MD, of Fox Chase Cancer Center in Philadelphia, commented on Twitter that the change “seems off the rails…a bit stunned by this.”

Matthew Cooperberg, MD, of the University of California San Francisco, and Minhaj Siddiqui, MD, of the University of Maryland in Baltimore both called the move a “step backward.”

Many others also expressed disappointment in the NCCN, whose guidelines are hugely influential because of the role they play clinically as well as with payors and the legal system.

“A huge setback & frankly a disgrace for @NCCN and its processes,” commented Fox Chase’s Dr. Kutikov.

Stacy Loeb, MD, of NYU Langone Health in New York City, suggested the new guidance may stunt use of active surveillance in the United States. She tweeted: “The updated NCCN guideline certainly won’t help the lagging and heterogenous uptake of active surveillance in the U.S. We should be carefully expanding the pool for active surveillance, not narrowing it.”

The purpose of active surveillance is to avoid adverse events from treatment, which can be life-changing as they include incontinence and erectile dysfunction.

The rationale is that many men with low-risk prostate cancer may not need treatment for their disease, as the disease may be slow-growing and may never threaten their life. With active surveillance, men are instead monitored with blood tests, scans, and biopsies to watch for worsening disease, and treated only when there are signs of disease progression.

This active surveillance approach has grown in acceptance among American patients since 2010.

The concern now is that the change in guidance from the NCCN will lead to a reduction in active surveillance, and an increase in initial treatment with surgery and radiotherapy for low-risk disease, which is considered by many to be “overtreatment’ of this disease and may not be medically necessary.  

For example, UCSF’s Dr. Cooperberg said he feared that the changed guidance “will be used by urologists and radiation oncologists to justify overtreatment of low-risk disease.”

Dr. Kutikov agreed but described that possibility differently, citing the risk of lawsuits. He observed that without the NCCN’s “medico-legal buffer” of active surveillance as the preferred initial treatment, there are “further incentives” for overtreatment.

The new NCCN guidance also conflicts with the American Urological Association’s guidelines and dissolves what was once a mostly united front from the two major organizations on active surveillance and low-risk disease.

The AUA Guideline reads: “Clinicians should recommend active surveillance as the preferable care option for most low-risk localized prostate cancer patients (Moderate Recommendation; Evidence Level: Grade B)
 

Patients protest change in wording

Not surprisingly, the revised NCCN guidance was criticized by multiple patient advocacy groups, including Active Surveillance Patients International (ASPI), which wrote a letter to the NCCN protesting the change.

In that letter, the ASPI writes that active surveillance is now chosen as the initial approach for low-risk prostate cancer in about 90% of cases in some European nations, and in about 50% of cases in the United States. It also warns that eliminating the word “preferred” from the NCCN guidelines represents a retreat, and “will have repercussions far beyond what we may first conceive.” 

“Active surveillance should be the preferred choice to preserve quality of life for men with low-risk cancer,” the advocacy group states. “The PIVOT trials indicate for low-risk disease there is basically no advantage to intervention. Why would one risk the side effects if they knew that?”
 

Why now?

The NCCN’s move to alter its low-risk prostate cancer guidance is especially striking because, 11 years ago, the NCCN broke new ground in recommending active surveillance as the sole initial treatment option for low-risk men. (It was also the first guidelines group to recommend the same for very low-risk men.)

So why the change now? This news organization requested, but did not receive,  comment from the NCCN and its chair of the prostate cancer panel, Edward Schaeffer, MD, of Northwestern University in Chicago.  

However, on Twitter, Dr. Schaeffer hinted at what had turned the tables for the NCCN panel – the risk that, over time, some men with low-risk disease who are on active surveillance are reclassified on biopsy as having a higher risk.

He highlighted a 2020 study on that very subject from the University of California, San Francisco, published in the Journal of Urology. Those authors concluded that: “Given the heterogeneity of the disease, some tumors characterized as low risk may merit early treatment while others may be followed much less intensely over some time interval.”

Dr. Schaeffer tweeted: “I think this nicely sums up the low-risk space ...”

Experts reacting to Dr. Schaeffer’s tweet were not swayed.

Looking at additional measures such as genomic scores and PSA density, as advocated by Dr. Schaeffer via the posted 2020 study, is good for assessing individual risk, “but still, active surveillance is the preferred option for low risk,” said MD Anderson’s Dr. Chapin.

UCSF’s Dr. Cooperberg, who was a co-author on that 2020 Journal of Urology paper,  commented that the university’s urology department had “spent the past quarter century arguing active surveillance is ‘preferred’ for almost all low risk [disease]!”

“Many on active surveillance need treatment someday, but that does not justify immediate overtreatment,” he concluded.

A version of this article first appeared on Medscape.com.

For over a decade, the influential National Comprehensive Cancer Network (NCCN) has been recommending that men with low-risk prostate cancer be offered active surveillance as the lone “preferred” initial treatment option.

But the NCCN has now reversed this long-standing recommendation in the latest revision of its prostate cancer guideline.

The organization now recommends that low-risk disease be managed with either active surveillance or radiation therapy or surgery, with equal weight given to all three of these initial options.

The change is seen by some as a retreat to the past and was harshly criticized by many experts on Twitter. The complaints were voiced in unusually blunt and strong language for physicians.

“This is a terrible step back that impacts every urologist,” commented John Griffith, MD, of Hartford Healthcare, who practices in New Britain, Conn.

Dr. Griffith explained that he prints out the NCCN guidance with “every patient newly diagnosed” and that the preferred designation is a “huge help” in reassuring them about not treating low-risk disease initially.

In a Twitter thread, Benjamin Davies, MD, of the University of Pittsburgh, facetiously wondered if a time warp was at play: “To suggest for a millisecond that active surveillance isn’t the preferred method for low-risk men is bizarre thinking ... Is this 1980?”

“I’m baffled,” said Brian Chapin, MD, of MD Anderson Cancer Center, Houston, in another Twitter thread.

“This is ludicrous,” said Andrew Vickers, PhD, of Memorial Sloan Kettering Cancer Center in New York City in a tweet.

Alexander Kutikov, MD, of Fox Chase Cancer Center in Philadelphia, commented on Twitter that the change “seems off the rails…a bit stunned by this.”

Matthew Cooperberg, MD, of the University of California San Francisco, and Minhaj Siddiqui, MD, of the University of Maryland in Baltimore both called the move a “step backward.”

Many others also expressed disappointment in the NCCN, whose guidelines are hugely influential because of the role they play clinically as well as with payors and the legal system.

“A huge setback & frankly a disgrace for @NCCN and its processes,” commented Fox Chase’s Dr. Kutikov.

Stacy Loeb, MD, of NYU Langone Health in New York City, suggested the new guidance may stunt use of active surveillance in the United States. She tweeted: “The updated NCCN guideline certainly won’t help the lagging and heterogenous uptake of active surveillance in the U.S. We should be carefully expanding the pool for active surveillance, not narrowing it.”

The purpose of active surveillance is to avoid adverse events from treatment, which can be life-changing as they include incontinence and erectile dysfunction.

The rationale is that many men with low-risk prostate cancer may not need treatment for their disease, as the disease may be slow-growing and may never threaten their life. With active surveillance, men are instead monitored with blood tests, scans, and biopsies to watch for worsening disease, and treated only when there are signs of disease progression.

This active surveillance approach has grown in acceptance among American patients since 2010.

The concern now is that the change in guidance from the NCCN will lead to a reduction in active surveillance, and an increase in initial treatment with surgery and radiotherapy for low-risk disease, which is considered by many to be “overtreatment’ of this disease and may not be medically necessary.  

For example, UCSF’s Dr. Cooperberg said he feared that the changed guidance “will be used by urologists and radiation oncologists to justify overtreatment of low-risk disease.”

Dr. Kutikov agreed but described that possibility differently, citing the risk of lawsuits. He observed that without the NCCN’s “medico-legal buffer” of active surveillance as the preferred initial treatment, there are “further incentives” for overtreatment.

The new NCCN guidance also conflicts with the American Urological Association’s guidelines and dissolves what was once a mostly united front from the two major organizations on active surveillance and low-risk disease.

The AUA Guideline reads: “Clinicians should recommend active surveillance as the preferable care option for most low-risk localized prostate cancer patients (Moderate Recommendation; Evidence Level: Grade B)
 

Patients protest change in wording

Not surprisingly, the revised NCCN guidance was criticized by multiple patient advocacy groups, including Active Surveillance Patients International (ASPI), which wrote a letter to the NCCN protesting the change.

In that letter, the ASPI writes that active surveillance is now chosen as the initial approach for low-risk prostate cancer in about 90% of cases in some European nations, and in about 50% of cases in the United States. It also warns that eliminating the word “preferred” from the NCCN guidelines represents a retreat, and “will have repercussions far beyond what we may first conceive.” 

“Active surveillance should be the preferred choice to preserve quality of life for men with low-risk cancer,” the advocacy group states. “The PIVOT trials indicate for low-risk disease there is basically no advantage to intervention. Why would one risk the side effects if they knew that?”
 

Why now?

The NCCN’s move to alter its low-risk prostate cancer guidance is especially striking because, 11 years ago, the NCCN broke new ground in recommending active surveillance as the sole initial treatment option for low-risk men. (It was also the first guidelines group to recommend the same for very low-risk men.)

So why the change now? This news organization requested, but did not receive,  comment from the NCCN and its chair of the prostate cancer panel, Edward Schaeffer, MD, of Northwestern University in Chicago.  

However, on Twitter, Dr. Schaeffer hinted at what had turned the tables for the NCCN panel – the risk that, over time, some men with low-risk disease who are on active surveillance are reclassified on biopsy as having a higher risk.

He highlighted a 2020 study on that very subject from the University of California, San Francisco, published in the Journal of Urology. Those authors concluded that: “Given the heterogeneity of the disease, some tumors characterized as low risk may merit early treatment while others may be followed much less intensely over some time interval.”

Dr. Schaeffer tweeted: “I think this nicely sums up the low-risk space ...”

Experts reacting to Dr. Schaeffer’s tweet were not swayed.

Looking at additional measures such as genomic scores and PSA density, as advocated by Dr. Schaeffer via the posted 2020 study, is good for assessing individual risk, “but still, active surveillance is the preferred option for low risk,” said MD Anderson’s Dr. Chapin.

UCSF’s Dr. Cooperberg, who was a co-author on that 2020 Journal of Urology paper,  commented that the university’s urology department had “spent the past quarter century arguing active surveillance is ‘preferred’ for almost all low risk [disease]!”

“Many on active surveillance need treatment someday, but that does not justify immediate overtreatment,” he concluded.

A version of this article first appeared on Medscape.com.

For over a decade, the influential National Comprehensive Cancer Network (NCCN) has been recommending that men with low-risk prostate cancer be offered active surveillance as the lone “preferred” initial treatment option.

But the NCCN has now reversed this long-standing recommendation in the latest revision of its prostate cancer guideline.

The organization now recommends that low-risk disease be managed with either active surveillance or radiation therapy or surgery, with equal weight given to all three of these initial options.

The change is seen by some as a retreat to the past and was harshly criticized by many experts on Twitter. The complaints were voiced in unusually blunt and strong language for physicians.

“This is a terrible step back that impacts every urologist,” commented John Griffith, MD, of Hartford Healthcare, who practices in New Britain, Conn.

Dr. Griffith explained that he prints out the NCCN guidance with “every patient newly diagnosed” and that the preferred designation is a “huge help” in reassuring them about not treating low-risk disease initially.

In a Twitter thread, Benjamin Davies, MD, of the University of Pittsburgh, facetiously wondered if a time warp was at play: “To suggest for a millisecond that active surveillance isn’t the preferred method for low-risk men is bizarre thinking ... Is this 1980?”

“I’m baffled,” said Brian Chapin, MD, of MD Anderson Cancer Center, Houston, in another Twitter thread.

“This is ludicrous,” said Andrew Vickers, PhD, of Memorial Sloan Kettering Cancer Center in New York City in a tweet.

Alexander Kutikov, MD, of Fox Chase Cancer Center in Philadelphia, commented on Twitter that the change “seems off the rails…a bit stunned by this.”

Matthew Cooperberg, MD, of the University of California San Francisco, and Minhaj Siddiqui, MD, of the University of Maryland in Baltimore both called the move a “step backward.”

Many others also expressed disappointment in the NCCN, whose guidelines are hugely influential because of the role they play clinically as well as with payors and the legal system.

“A huge setback & frankly a disgrace for @NCCN and its processes,” commented Fox Chase’s Dr. Kutikov.

Stacy Loeb, MD, of NYU Langone Health in New York City, suggested the new guidance may stunt use of active surveillance in the United States. She tweeted: “The updated NCCN guideline certainly won’t help the lagging and heterogenous uptake of active surveillance in the U.S. We should be carefully expanding the pool for active surveillance, not narrowing it.”

The purpose of active surveillance is to avoid adverse events from treatment, which can be life-changing as they include incontinence and erectile dysfunction.

The rationale is that many men with low-risk prostate cancer may not need treatment for their disease, as the disease may be slow-growing and may never threaten their life. With active surveillance, men are instead monitored with blood tests, scans, and biopsies to watch for worsening disease, and treated only when there are signs of disease progression.

This active surveillance approach has grown in acceptance among American patients since 2010.

The concern now is that the change in guidance from the NCCN will lead to a reduction in active surveillance, and an increase in initial treatment with surgery and radiotherapy for low-risk disease, which is considered by many to be “overtreatment’ of this disease and may not be medically necessary.  

For example, UCSF’s Dr. Cooperberg said he feared that the changed guidance “will be used by urologists and radiation oncologists to justify overtreatment of low-risk disease.”

Dr. Kutikov agreed but described that possibility differently, citing the risk of lawsuits. He observed that without the NCCN’s “medico-legal buffer” of active surveillance as the preferred initial treatment, there are “further incentives” for overtreatment.

The new NCCN guidance also conflicts with the American Urological Association’s guidelines and dissolves what was once a mostly united front from the two major organizations on active surveillance and low-risk disease.

The AUA Guideline reads: “Clinicians should recommend active surveillance as the preferable care option for most low-risk localized prostate cancer patients (Moderate Recommendation; Evidence Level: Grade B)
 

Patients protest change in wording

Not surprisingly, the revised NCCN guidance was criticized by multiple patient advocacy groups, including Active Surveillance Patients International (ASPI), which wrote a letter to the NCCN protesting the change.

In that letter, the ASPI writes that active surveillance is now chosen as the initial approach for low-risk prostate cancer in about 90% of cases in some European nations, and in about 50% of cases in the United States. It also warns that eliminating the word “preferred” from the NCCN guidelines represents a retreat, and “will have repercussions far beyond what we may first conceive.” 

“Active surveillance should be the preferred choice to preserve quality of life for men with low-risk cancer,” the advocacy group states. “The PIVOT trials indicate for low-risk disease there is basically no advantage to intervention. Why would one risk the side effects if they knew that?”
 

Why now?

The NCCN’s move to alter its low-risk prostate cancer guidance is especially striking because, 11 years ago, the NCCN broke new ground in recommending active surveillance as the sole initial treatment option for low-risk men. (It was also the first guidelines group to recommend the same for very low-risk men.)

So why the change now? This news organization requested, but did not receive,  comment from the NCCN and its chair of the prostate cancer panel, Edward Schaeffer, MD, of Northwestern University in Chicago.  

However, on Twitter, Dr. Schaeffer hinted at what had turned the tables for the NCCN panel – the risk that, over time, some men with low-risk disease who are on active surveillance are reclassified on biopsy as having a higher risk.

He highlighted a 2020 study on that very subject from the University of California, San Francisco, published in the Journal of Urology. Those authors concluded that: “Given the heterogeneity of the disease, some tumors characterized as low risk may merit early treatment while others may be followed much less intensely over some time interval.”

Dr. Schaeffer tweeted: “I think this nicely sums up the low-risk space ...”

Experts reacting to Dr. Schaeffer’s tweet were not swayed.

Looking at additional measures such as genomic scores and PSA density, as advocated by Dr. Schaeffer via the posted 2020 study, is good for assessing individual risk, “but still, active surveillance is the preferred option for low risk,” said MD Anderson’s Dr. Chapin.

UCSF’s Dr. Cooperberg, who was a co-author on that 2020 Journal of Urology paper,  commented that the university’s urology department had “spent the past quarter century arguing active surveillance is ‘preferred’ for almost all low risk [disease]!”

“Many on active surveillance need treatment someday, but that does not justify immediate overtreatment,” he concluded.

A version of this article first appeared on Medscape.com.

Extended follow-up of the PRAGUE-17 trial suggests left atrial appendage closure (LAAC) remains noninferior to direct-acting oral anticoagulants (DOACs) with regard to major cardiovascular and neurologic events in high-risk patients with atrial fibrillation.

At a median follow-up of 3.5 years, the annualized rate of the primary outcome – a composite of stroke, transient ischemic attack (TIA), systemic embolism, cardiovascular death, clinically relevant bleeding, or significant procedure- or device-related complications – was 8.6% in patients who underwent LAAC and 11.9% in those managed with DOACs (P value for noninferiority = .006).

The study was not powered to assess the individual components, but most were similar between the LAAC and DOAC groups, including cardiovascular death (20 vs. 30 events) and all stroke/TIA (16 vs. 18 events).

Nonprocedural clinically relevant bleeding was lower with LAAC (23 vs. 40 events; annualized rate, 3.4% vs. 5.9%; P = .039), said Pavel Osmancik, MD, PhD, Charles University and University Hospital Kralovske Vinohrady, both in Prague.

The data were presented at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando and sponsored by the Cardiovascular Research Foundation, and was published simultaneously in the Journal of the American College of Cardiology.

The results are generally in line with those reported in 2020 with an average follow-up of 20 months, when the annualized primary event rate was 11% with LAAC and 13% with DOACs, also known as novel OACs (NOACs).

The trial randomly assigned 415 patients to LAAC with the Amulet (Abbott Vascular) or Watchman/Watchman FLX devices (Boston Scientific) or to rivaroxaban, dabigatran, or preferably apixaban (96%). The modified intention-to-treat analysis included 201 patients in each group, with follow-up extending to 4.3 years in the LAAC group and 4.2 years in the DOAC group.

Dr. Osmancik said the trial enrolled a very-high-risk atrial fibrillation cohort, citing a CHA2DS2-VASc score of 4.7 in both groups and a HAS-BLED score of 3.0-3.1. More than half of the LAAC group (54.2%) and 47.3% of the DOAC group had a history of bleeding or bleeding predisposition.

During a discussion of the results, the panel questioned whether the continuing divergence of the primary event curves at 4 years was potentially related to the effect of noncompliance to the NOACs over time.

Dr. Osmancik replied: “We didn’t do any medication look among the patients, but I don’t think that the number of patients who stopped the NOAC treatment was too high because the rate of strokes was very similar to that in the NOAC trials.”

He reported that 26 patients in the DOAC group permanently stopped their DOAC during follow-up; 15 (58%) because of clinically relevant bleeding, and 13 crossed over to LAAC. Of the 13 patients, 12 cases were successful with dual antiplatelet therapy for 3 months.

In the LAAC group, 17 patients started a DOAC during follow-up. Of these, three (18%) initiated DOAC treatment because of device-related thrombus (DRT) on transesophageal echocardiography, three (18%) because of a peridevice leak (PDL), and five (29%) because of a stroke/TIA.

“Given the observed trend of significantly increased nonprocedural clinically relevant bleeding in the NOAC arm, it is likely that late bleeding events will increasingly favor LAAC over time,” Faisal Merchant, MD, Emory University, Atlanta, wrote in an accompanying editorial.

NOACs, he noted, have important indications beyond prevention of left atrial appendage thrombi, including prevention of non-LAA sources of stroke/systemic embolism (SSE) and treatment of venous thromboembolism. “If significant numbers of patients treated with LAAC end up on anticoagulation in the long run, the benefits of LAAC are likely to be attenuated.”

Although PRAGUE-17 provides some insights into the longer-term indications for resuming anticoagulation in patients previously treated with LAAC, Dr. Merchant said the trial is a “real missed opportunity” in terms of understanding late device-associated risks. Unfortunately, two-thirds of the follow-up transesophageal echocardiograms were canceled because of the COVID-19 pandemic.

“Although the incidence of late DRT and PDL isn’t known, the longer-term PRAGUE-17 data are helpful in demonstrating that rates of SSE remain similar in the LAAC and NOAC groups over time, without any obvious signal of late ischemic events in the LAAC group,” he wrote.

The editorialist also called attention to the “often overlooked” issue of aspirin adherence in long-term medical therapy. Although patients treated with LAAC typically remain on aspirin indefinitely, the percentage who discontinue long-term aspirin is not well described and is not reported in PRAGUE-17. In the AVERROES trial, comparing aspirin with apixaban in patients with atrial fibrillation, however, 20.5% of patients permanently discontinued aspirin at 2 years, compared with only 17.9% on apixaban.

“It is plausible that discontinuation of aspirin may contribute to late ischemic events in patients treated with LAAC, potentially by increasing the risk of late DRT or through other mechanisms,” Dr. Merchant wrote. “Adherence to, and the impact of, long-term antiplatelet therapy should be a focus of future LAAC studies.”

The study was funded by a research grant from the Ministry of Health, Czech Republic. Dr. Osmancik reported occasional speaking honoraria from Bayer and Abbott. Dr. Merchant disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Extended follow-up of the PRAGUE-17 trial suggests left atrial appendage closure (LAAC) remains noninferior to direct-acting oral anticoagulants (DOACs) with regard to major cardiovascular and neurologic events in high-risk patients with atrial fibrillation.

At a median follow-up of 3.5 years, the annualized rate of the primary outcome – a composite of stroke, transient ischemic attack (TIA), systemic embolism, cardiovascular death, clinically relevant bleeding, or significant procedure- or device-related complications – was 8.6% in patients who underwent LAAC and 11.9% in those managed with DOACs (P value for noninferiority = .006).

The study was not powered to assess the individual components, but most were similar between the LAAC and DOAC groups, including cardiovascular death (20 vs. 30 events) and all stroke/TIA (16 vs. 18 events).

Nonprocedural clinically relevant bleeding was lower with LAAC (23 vs. 40 events; annualized rate, 3.4% vs. 5.9%; P = .039), said Pavel Osmancik, MD, PhD, Charles University and University Hospital Kralovske Vinohrady, both in Prague.

The data were presented at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando and sponsored by the Cardiovascular Research Foundation, and was published simultaneously in the Journal of the American College of Cardiology.

The results are generally in line with those reported in 2020 with an average follow-up of 20 months, when the annualized primary event rate was 11% with LAAC and 13% with DOACs, also known as novel OACs (NOACs).

The trial randomly assigned 415 patients to LAAC with the Amulet (Abbott Vascular) or Watchman/Watchman FLX devices (Boston Scientific) or to rivaroxaban, dabigatran, or preferably apixaban (96%). The modified intention-to-treat analysis included 201 patients in each group, with follow-up extending to 4.3 years in the LAAC group and 4.2 years in the DOAC group.

Dr. Osmancik said the trial enrolled a very-high-risk atrial fibrillation cohort, citing a CHA2DS2-VASc score of 4.7 in both groups and a HAS-BLED score of 3.0-3.1. More than half of the LAAC group (54.2%) and 47.3% of the DOAC group had a history of bleeding or bleeding predisposition.

During a discussion of the results, the panel questioned whether the continuing divergence of the primary event curves at 4 years was potentially related to the effect of noncompliance to the NOACs over time.

Dr. Osmancik replied: “We didn’t do any medication look among the patients, but I don’t think that the number of patients who stopped the NOAC treatment was too high because the rate of strokes was very similar to that in the NOAC trials.”

He reported that 26 patients in the DOAC group permanently stopped their DOAC during follow-up; 15 (58%) because of clinically relevant bleeding, and 13 crossed over to LAAC. Of the 13 patients, 12 cases were successful with dual antiplatelet therapy for 3 months.

In the LAAC group, 17 patients started a DOAC during follow-up. Of these, three (18%) initiated DOAC treatment because of device-related thrombus (DRT) on transesophageal echocardiography, three (18%) because of a peridevice leak (PDL), and five (29%) because of a stroke/TIA.

“Given the observed trend of significantly increased nonprocedural clinically relevant bleeding in the NOAC arm, it is likely that late bleeding events will increasingly favor LAAC over time,” Faisal Merchant, MD, Emory University, Atlanta, wrote in an accompanying editorial.

NOACs, he noted, have important indications beyond prevention of left atrial appendage thrombi, including prevention of non-LAA sources of stroke/systemic embolism (SSE) and treatment of venous thromboembolism. “If significant numbers of patients treated with LAAC end up on anticoagulation in the long run, the benefits of LAAC are likely to be attenuated.”

Although PRAGUE-17 provides some insights into the longer-term indications for resuming anticoagulation in patients previously treated with LAAC, Dr. Merchant said the trial is a “real missed opportunity” in terms of understanding late device-associated risks. Unfortunately, two-thirds of the follow-up transesophageal echocardiograms were canceled because of the COVID-19 pandemic.

“Although the incidence of late DRT and PDL isn’t known, the longer-term PRAGUE-17 data are helpful in demonstrating that rates of SSE remain similar in the LAAC and NOAC groups over time, without any obvious signal of late ischemic events in the LAAC group,” he wrote.

The editorialist also called attention to the “often overlooked” issue of aspirin adherence in long-term medical therapy. Although patients treated with LAAC typically remain on aspirin indefinitely, the percentage who discontinue long-term aspirin is not well described and is not reported in PRAGUE-17. In the AVERROES trial, comparing aspirin with apixaban in patients with atrial fibrillation, however, 20.5% of patients permanently discontinued aspirin at 2 years, compared with only 17.9% on apixaban.

“It is plausible that discontinuation of aspirin may contribute to late ischemic events in patients treated with LAAC, potentially by increasing the risk of late DRT or through other mechanisms,” Dr. Merchant wrote. “Adherence to, and the impact of, long-term antiplatelet therapy should be a focus of future LAAC studies.”

The study was funded by a research grant from the Ministry of Health, Czech Republic. Dr. Osmancik reported occasional speaking honoraria from Bayer and Abbott. Dr. Merchant disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Extended follow-up of the PRAGUE-17 trial suggests left atrial appendage closure (LAAC) remains noninferior to direct-acting oral anticoagulants (DOACs) with regard to major cardiovascular and neurologic events in high-risk patients with atrial fibrillation.

At a median follow-up of 3.5 years, the annualized rate of the primary outcome – a composite of stroke, transient ischemic attack (TIA), systemic embolism, cardiovascular death, clinically relevant bleeding, or significant procedure- or device-related complications – was 8.6% in patients who underwent LAAC and 11.9% in those managed with DOACs (P value for noninferiority = .006).

The study was not powered to assess the individual components, but most were similar between the LAAC and DOAC groups, including cardiovascular death (20 vs. 30 events) and all stroke/TIA (16 vs. 18 events).

Nonprocedural clinically relevant bleeding was lower with LAAC (23 vs. 40 events; annualized rate, 3.4% vs. 5.9%; P = .039), said Pavel Osmancik, MD, PhD, Charles University and University Hospital Kralovske Vinohrady, both in Prague.

The data were presented at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando and sponsored by the Cardiovascular Research Foundation, and was published simultaneously in the Journal of the American College of Cardiology.

The results are generally in line with those reported in 2020 with an average follow-up of 20 months, when the annualized primary event rate was 11% with LAAC and 13% with DOACs, also known as novel OACs (NOACs).

The trial randomly assigned 415 patients to LAAC with the Amulet (Abbott Vascular) or Watchman/Watchman FLX devices (Boston Scientific) or to rivaroxaban, dabigatran, or preferably apixaban (96%). The modified intention-to-treat analysis included 201 patients in each group, with follow-up extending to 4.3 years in the LAAC group and 4.2 years in the DOAC group.

Dr. Osmancik said the trial enrolled a very-high-risk atrial fibrillation cohort, citing a CHA2DS2-VASc score of 4.7 in both groups and a HAS-BLED score of 3.0-3.1. More than half of the LAAC group (54.2%) and 47.3% of the DOAC group had a history of bleeding or bleeding predisposition.

During a discussion of the results, the panel questioned whether the continuing divergence of the primary event curves at 4 years was potentially related to the effect of noncompliance to the NOACs over time.

Dr. Osmancik replied: “We didn’t do any medication look among the patients, but I don’t think that the number of patients who stopped the NOAC treatment was too high because the rate of strokes was very similar to that in the NOAC trials.”

He reported that 26 patients in the DOAC group permanently stopped their DOAC during follow-up; 15 (58%) because of clinically relevant bleeding, and 13 crossed over to LAAC. Of the 13 patients, 12 cases were successful with dual antiplatelet therapy for 3 months.

In the LAAC group, 17 patients started a DOAC during follow-up. Of these, three (18%) initiated DOAC treatment because of device-related thrombus (DRT) on transesophageal echocardiography, three (18%) because of a peridevice leak (PDL), and five (29%) because of a stroke/TIA.

“Given the observed trend of significantly increased nonprocedural clinically relevant bleeding in the NOAC arm, it is likely that late bleeding events will increasingly favor LAAC over time,” Faisal Merchant, MD, Emory University, Atlanta, wrote in an accompanying editorial.

NOACs, he noted, have important indications beyond prevention of left atrial appendage thrombi, including prevention of non-LAA sources of stroke/systemic embolism (SSE) and treatment of venous thromboembolism. “If significant numbers of patients treated with LAAC end up on anticoagulation in the long run, the benefits of LAAC are likely to be attenuated.”

Although PRAGUE-17 provides some insights into the longer-term indications for resuming anticoagulation in patients previously treated with LAAC, Dr. Merchant said the trial is a “real missed opportunity” in terms of understanding late device-associated risks. Unfortunately, two-thirds of the follow-up transesophageal echocardiograms were canceled because of the COVID-19 pandemic.

“Although the incidence of late DRT and PDL isn’t known, the longer-term PRAGUE-17 data are helpful in demonstrating that rates of SSE remain similar in the LAAC and NOAC groups over time, without any obvious signal of late ischemic events in the LAAC group,” he wrote.

The editorialist also called attention to the “often overlooked” issue of aspirin adherence in long-term medical therapy. Although patients treated with LAAC typically remain on aspirin indefinitely, the percentage who discontinue long-term aspirin is not well described and is not reported in PRAGUE-17. In the AVERROES trial, comparing aspirin with apixaban in patients with atrial fibrillation, however, 20.5% of patients permanently discontinued aspirin at 2 years, compared with only 17.9% on apixaban.

“It is plausible that discontinuation of aspirin may contribute to late ischemic events in patients treated with LAAC, potentially by increasing the risk of late DRT or through other mechanisms,” Dr. Merchant wrote. “Adherence to, and the impact of, long-term antiplatelet therapy should be a focus of future LAAC studies.”

The study was funded by a research grant from the Ministry of Health, Czech Republic. Dr. Osmancik reported occasional speaking honoraria from Bayer and Abbott. Dr. Merchant disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.