CHICAGO – Plecanatide, a drug recently approved for chronic idiopathic constipation, bested placebo in two randomized studies evaluating its effect in irritable bowel syndrome with constipation.

Results of the identical, 12-week, phase III studies propelled plecanatide (Trulance; Synergy Pharmaceuticals) into a supplemental new drug application for adult irritable bowel syndrome–constipation predominant (IBS-C), Ronald Fogel, MD, said at the annual Digestive Disease Week^®.

During the question-and-answer period, though, clinicians didn’t quite echo the corporate enthusiasm for plecanatide. Several pointed out that overall responder rates were somewhat low for both the 3-mg and 6-mg dose (study -04, 30% both doses; study -05, 21% and 24%), with a drug-placebo differential of about 12% and 7%, respectively. When questioned, Dr. Fogel didn’t have data on the number needed to treat to improve one case. But, he asserted, such response numbers are typical for drug trials in patients with functional bowel disorders and meaningful to those who did respond.

“The differences were statistically significant, and, as someone who was there for both trials, I would say they are also clinically significant,” said Dr. Fogel, founder of the Digestive Health Center of Michigan, Chesterfield. “Patients who did respond were very happy.”

The drug was also quite well-tolerated, with diarrhea as the only important treatment-related adverse event and. This occurred in less than 2% of patients, and only about 1% of either cohort discontinued the medication because of severe diarrhea.

Plecanatide, structurally, is almost identical to uroguanylin, a peptide that regulates sodium and bicarbonate secretion into the intestine but with 8 times greater binding potential to the guanylate cyclase-C receptor. Both the natural and manmade molecules promote fluid secretion into the lumen and inhibit fluid absorption. Uroguanylin is most active in an acidic environment; therefore, plecanatide exerts most of its action in the proximal small intestine.

Synergy also asserts on its website that activation of the GC-C-receptor “may lead to decreased inflammation and pain sensation in the GI tract.” Abdominal pain was not a primary outcome in the pivotal trials for plecanatide’s idiopathic constipation studies, but it was a coprimary endpoint, with stool frequency, for the IBS-C trials.

The studies enrolled a total of 2,189 patients with a diagnosis of IBS-S. They were equally randomized to placebo or plecanatide 3 mg or 6 mg, once daily. Most (75%) were women. The mean age was about 43 years. At baseline, they reported less than one complete, spontaneous bowel movement per week. They also completed an 11-point scale on abdominal symptoms of pain (mean, 6), discomfort (mean, 6.2), and bloating (mean, 6.5).

The study included a 2-week pretreatment assessment period, 12 weeks of daily therapy during which patients filled out an electronic diary of stool frequency and abdominal pain/discomfort, and a 2-week follow-up. The primary endpoint was the number of overall responders, who had to experience both a decrease of at least 30% in their weekly abdominal pain score and an increase of at least one complete, spontaneous bowel movement per week.

Both studies posted statistically significant overall responder rates, relative to placebo, in both doses.

In study -04, the final overall placebo response rate was 17.8%, compared with 30% in the plecanatide 3-mg group and 29.5% in the plecanatide 6-mg group. In study -05, the placebo responder rate was 14%, compared with 21.5% in the 3-mg group and 24% in the 6-mg group.

Dr. Fogel showed stool frequency data but not abdominal pain data. About 41% of patients taking the study drug had increased bowel movements for at least 6 weeks of treatment, compared with 31.4% of those taking placebo. This 9% absolute difference was remarked on during the question-and-answer period as a surprisingly small separation. However, Dr. Fogel said that it was clinically significant as well as statistically so, with a P value of less than 0.001.

Plecanatide worked quickly. By the end of treatment week 1, the placebo and both active groups had already significantly separated, and that separation remained significant throughout the entire treatment period. During the 2-week follow-up period, the effect of both active doses tailed off and fell to the same as placebo by the end of 2 weeks.

One of the drug’s strongest points was its low rate of treatment-related diarrhea. Any diarrhea occurred in about 4% of both dosage groups, compared to 1% of the placebo group. Severe diarrhea occurred in 1% of the 3-mg and 0.4% of the 6-mg group, compared with 0.1% of the placebo group. This caused about 1% of patients to discontinue the study medication.

The adverse event profile was notably better than that of linaclotide (Linzess; Allergan), plecanatide’s close competitor. Also a guanylate cyclase–C agonist, linaclotide provoked diarrhea in almost 20% of patients in its pivotal phase III trials. Symptoms were severe in 2%. Lincalotide’s effectiveness in promoting bowel movements was slightly higher than that of plecanatide (about 48% in the pivotal trials), with a similar placebo response rate.

Plecanatide was approved earlier this year for chronic idiopathic constipation in adults.

Synergy Pharmaceuticals sponsored the study. Dr. Fogel has no financial interest in the company or in plecanatide.

[email protected]

On Twitter @alz_gal

CHICAGO – Plecanatide, a drug recently approved for chronic idiopathic constipation, bested placebo in two randomized studies evaluating its effect in irritable bowel syndrome with constipation.

Results of the identical, 12-week, phase III studies propelled plecanatide (Trulance; Synergy Pharmaceuticals) into a supplemental new drug application for adult irritable bowel syndrome–constipation predominant (IBS-C), Ronald Fogel, MD, said at the annual Digestive Disease Week^®.

During the question-and-answer period, though, clinicians didn’t quite echo the corporate enthusiasm for plecanatide. Several pointed out that overall responder rates were somewhat low for both the 3-mg and 6-mg dose (study -04, 30% both doses; study -05, 21% and 24%), with a drug-placebo differential of about 12% and 7%, respectively. When questioned, Dr. Fogel didn’t have data on the number needed to treat to improve one case. But, he asserted, such response numbers are typical for drug trials in patients with functional bowel disorders and meaningful to those who did respond.

“The differences were statistically significant, and, as someone who was there for both trials, I would say they are also clinically significant,” said Dr. Fogel, founder of the Digestive Health Center of Michigan, Chesterfield. “Patients who did respond were very happy.”

The drug was also quite well-tolerated, with diarrhea as the only important treatment-related adverse event and. This occurred in less than 2% of patients, and only about 1% of either cohort discontinued the medication because of severe diarrhea.

Plecanatide, structurally, is almost identical to uroguanylin, a peptide that regulates sodium and bicarbonate secretion into the intestine but with 8 times greater binding potential to the guanylate cyclase-C receptor. Both the natural and manmade molecules promote fluid secretion into the lumen and inhibit fluid absorption. Uroguanylin is most active in an acidic environment; therefore, plecanatide exerts most of its action in the proximal small intestine.

Synergy also asserts on its website that activation of the GC-C-receptor “may lead to decreased inflammation and pain sensation in the GI tract.” Abdominal pain was not a primary outcome in the pivotal trials for plecanatide’s idiopathic constipation studies, but it was a coprimary endpoint, with stool frequency, for the IBS-C trials.

The studies enrolled a total of 2,189 patients with a diagnosis of IBS-S. They were equally randomized to placebo or plecanatide 3 mg or 6 mg, once daily. Most (75%) were women. The mean age was about 43 years. At baseline, they reported less than one complete, spontaneous bowel movement per week. They also completed an 11-point scale on abdominal symptoms of pain (mean, 6), discomfort (mean, 6.2), and bloating (mean, 6.5).

The study included a 2-week pretreatment assessment period, 12 weeks of daily therapy during which patients filled out an electronic diary of stool frequency and abdominal pain/discomfort, and a 2-week follow-up. The primary endpoint was the number of overall responders, who had to experience both a decrease of at least 30% in their weekly abdominal pain score and an increase of at least one complete, spontaneous bowel movement per week.

Both studies posted statistically significant overall responder rates, relative to placebo, in both doses.

In study -04, the final overall placebo response rate was 17.8%, compared with 30% in the plecanatide 3-mg group and 29.5% in the plecanatide 6-mg group. In study -05, the placebo responder rate was 14%, compared with 21.5% in the 3-mg group and 24% in the 6-mg group.

Dr. Fogel showed stool frequency data but not abdominal pain data. About 41% of patients taking the study drug had increased bowel movements for at least 6 weeks of treatment, compared with 31.4% of those taking placebo. This 9% absolute difference was remarked on during the question-and-answer period as a surprisingly small separation. However, Dr. Fogel said that it was clinically significant as well as statistically so, with a P value of less than 0.001.

Plecanatide worked quickly. By the end of treatment week 1, the placebo and both active groups had already significantly separated, and that separation remained significant throughout the entire treatment period. During the 2-week follow-up period, the effect of both active doses tailed off and fell to the same as placebo by the end of 2 weeks.

One of the drug’s strongest points was its low rate of treatment-related diarrhea. Any diarrhea occurred in about 4% of both dosage groups, compared to 1% of the placebo group. Severe diarrhea occurred in 1% of the 3-mg and 0.4% of the 6-mg group, compared with 0.1% of the placebo group. This caused about 1% of patients to discontinue the study medication.

The adverse event profile was notably better than that of linaclotide (Linzess; Allergan), plecanatide’s close competitor. Also a guanylate cyclase–C agonist, linaclotide provoked diarrhea in almost 20% of patients in its pivotal phase III trials. Symptoms were severe in 2%. Lincalotide’s effectiveness in promoting bowel movements was slightly higher than that of plecanatide (about 48% in the pivotal trials), with a similar placebo response rate.

Plecanatide was approved earlier this year for chronic idiopathic constipation in adults.

Synergy Pharmaceuticals sponsored the study. Dr. Fogel has no financial interest in the company or in plecanatide.

[email protected]

On Twitter @alz_gal

CHICAGO – Plecanatide, a drug recently approved for chronic idiopathic constipation, bested placebo in two randomized studies evaluating its effect in irritable bowel syndrome with constipation.

Results of the identical, 12-week, phase III studies propelled plecanatide (Trulance; Synergy Pharmaceuticals) into a supplemental new drug application for adult irritable bowel syndrome–constipation predominant (IBS-C), Ronald Fogel, MD, said at the annual Digestive Disease Week^®.

During the question-and-answer period, though, clinicians didn’t quite echo the corporate enthusiasm for plecanatide. Several pointed out that overall responder rates were somewhat low for both the 3-mg and 6-mg dose (study -04, 30% both doses; study -05, 21% and 24%), with a drug-placebo differential of about 12% and 7%, respectively. When questioned, Dr. Fogel didn’t have data on the number needed to treat to improve one case. But, he asserted, such response numbers are typical for drug trials in patients with functional bowel disorders and meaningful to those who did respond.

“The differences were statistically significant, and, as someone who was there for both trials, I would say they are also clinically significant,” said Dr. Fogel, founder of the Digestive Health Center of Michigan, Chesterfield. “Patients who did respond were very happy.”

The drug was also quite well-tolerated, with diarrhea as the only important treatment-related adverse event and. This occurred in less than 2% of patients, and only about 1% of either cohort discontinued the medication because of severe diarrhea.

Plecanatide, structurally, is almost identical to uroguanylin, a peptide that regulates sodium and bicarbonate secretion into the intestine but with 8 times greater binding potential to the guanylate cyclase-C receptor. Both the natural and manmade molecules promote fluid secretion into the lumen and inhibit fluid absorption. Uroguanylin is most active in an acidic environment; therefore, plecanatide exerts most of its action in the proximal small intestine.

Synergy also asserts on its website that activation of the GC-C-receptor “may lead to decreased inflammation and pain sensation in the GI tract.” Abdominal pain was not a primary outcome in the pivotal trials for plecanatide’s idiopathic constipation studies, but it was a coprimary endpoint, with stool frequency, for the IBS-C trials.

The studies enrolled a total of 2,189 patients with a diagnosis of IBS-S. They were equally randomized to placebo or plecanatide 3 mg or 6 mg, once daily. Most (75%) were women. The mean age was about 43 years. At baseline, they reported less than one complete, spontaneous bowel movement per week. They also completed an 11-point scale on abdominal symptoms of pain (mean, 6), discomfort (mean, 6.2), and bloating (mean, 6.5).

The study included a 2-week pretreatment assessment period, 12 weeks of daily therapy during which patients filled out an electronic diary of stool frequency and abdominal pain/discomfort, and a 2-week follow-up. The primary endpoint was the number of overall responders, who had to experience both a decrease of at least 30% in their weekly abdominal pain score and an increase of at least one complete, spontaneous bowel movement per week.

Both studies posted statistically significant overall responder rates, relative to placebo, in both doses.

In study -04, the final overall placebo response rate was 17.8%, compared with 30% in the plecanatide 3-mg group and 29.5% in the plecanatide 6-mg group. In study -05, the placebo responder rate was 14%, compared with 21.5% in the 3-mg group and 24% in the 6-mg group.

Dr. Fogel showed stool frequency data but not abdominal pain data. About 41% of patients taking the study drug had increased bowel movements for at least 6 weeks of treatment, compared with 31.4% of those taking placebo. This 9% absolute difference was remarked on during the question-and-answer period as a surprisingly small separation. However, Dr. Fogel said that it was clinically significant as well as statistically so, with a P value of less than 0.001.

Plecanatide worked quickly. By the end of treatment week 1, the placebo and both active groups had already significantly separated, and that separation remained significant throughout the entire treatment period. During the 2-week follow-up period, the effect of both active doses tailed off and fell to the same as placebo by the end of 2 weeks.

One of the drug’s strongest points was its low rate of treatment-related diarrhea. Any diarrhea occurred in about 4% of both dosage groups, compared to 1% of the placebo group. Severe diarrhea occurred in 1% of the 3-mg and 0.4% of the 6-mg group, compared with 0.1% of the placebo group. This caused about 1% of patients to discontinue the study medication.

The adverse event profile was notably better than that of linaclotide (Linzess; Allergan), plecanatide’s close competitor. Also a guanylate cyclase–C agonist, linaclotide provoked diarrhea in almost 20% of patients in its pivotal phase III trials. Symptoms were severe in 2%. Lincalotide’s effectiveness in promoting bowel movements was slightly higher than that of plecanatide (about 48% in the pivotal trials), with a similar placebo response rate.

Plecanatide was approved earlier this year for chronic idiopathic constipation in adults.

Synergy Pharmaceuticals sponsored the study. Dr. Fogel has no financial interest in the company or in plecanatide.

[email protected]

On Twitter @alz_gal

The practice of gastroenterology is challenging for community physicians, those employed in multi-specialty clinics or large health care systems and those in academic health centers. Unique challenges confront independent GI practices, and there are mounting regulatory, financial, and operational barriers. Election results of 2016 have thrown us into an even more confusing future. In this month’s Road Ahead column, national GI leaders summarize the major challenges facing independent practices. Each leads (or has led) large GI practices and each has extensive experience with the policies, politics, payers, and pitfalls that impact our specialty. They have written a clear and helpful article for all physicians trying to maintain their independence and patient-focused practices. I have worked in many settings from the VA, to small and then large, independent practice, within a health system and in 2 academic medical centers. There is much to treasure in every type of practice and also many challenges. Physician leaders, both old and young, need to be informed and active in shaping medical policy.

John I. Allen, MD, MBA, AGAF, Editor in Chief

Physicians practicing in independent settings report greater satisfaction with their careers compared with those employed in hospital systems. In a recent survey,1 nearly two-thirds of independent practitioners strongly agreed with the statement, “I like being a physician,” compared with approximately half of those employed by hospital systems. The rapid pace of change in care delivery is forcing all caregivers to modify how they provide care. For physicians practicing in independent settings, understanding, reacting, and adapting to these changes is especially challenging.

It is particularly difficult for physicians and practices to remain abreast and cognizant of the ever-changing rules governing how we deliver care for our patients. The Digestive Health Physicians Association was formed 2 years ago to provide an active voice specifically for independent gastroenterology (GI) practices. The mission of the Digestive Health Physicians Association is to promote and protect the high-quality and cost-efficient care provided in the integrated GI practice model.

In the past decade, meeting the goal of the Triple Aim (improving population health, improving patient experience of care, and reducing the per-capita cost of health care) has become a central tenet of our national health policy strategy, especially since the enactment of the Affordable Care Act. Achieving the goals of the Triple Aim and complying with the changes and new requirements challenges all gastroenterologists, but particularly those working in the independent practice setting, and especially those in small group practices. The Centers for Medicare and Medicaid Services (CMS) recently estimated that under the Merit-Based Incentive Payment System, payment reductions resulting from the first year of reporting in 2017 will occur in 87% of solo practices, in 70% of groups with 2 to 9 physicians, and in 60% of groups with 10 to 24 physicians.²

Preparing yourself and your practice for the changes ahead will require an understanding of the rules, an assessment of your practice’s readiness, and the creation of a plan for compliance to ensure success.

The care model has undergone major changes in the past decade. The development of regional hospital systems has resulted in increasing numbers of employed physicians. Independent gastroenterology practices also have made changes in how they provide care. Vertical integration by independent practices has been a major, positive, and continuing development. As practices have grown more sophisticated with greater areas of specialization, they are increasingly capable of providing services directly to their patients rather than outsourcing them to external providers. Beginning first with endoscopic procedures and now extending to anesthesia, pathology, infusion, and other critical services, increased integration of services across the entire continuum of care has led to improved efficiency and care coordination, benefitting patients with improved outcomes as well as lower costs to our health care system.

The benefits and successes of practice integration, unfortunately, also have made vertically integrated practices a target for regulators and policy makers. Attacks on the integrated delivery model in gastroenterology have at times been supported, if not directly initiated, by our own colleagues in the house of medicine. In this article, we describe some of the threats and challenges confronting independent GI practice.
 

Anesthesia services

In April 2016, the Florida Society of Anesthesiologists (FSA) made headlines by drawing attention to its role as the relator in a qui tam (whistleblower) lawsuit that it had filed against more than 50 physicians, Ambulatory Surgery Centers, and anesthesia entities. This legal action — which the FSA filed in October 2013 but remained under seal until earlier this year — alleged that the defendants perpetrated Medicare and Medicaid fraud through violations of the federal Anti-Kickback Statute and the False Claims Act. In this lawsuit, the FSA specifically targeted the company model used to provide anesthesia services. Based on publicly available documents, the case currently is in its early stages, although the FSA has made it clear that it views the lawsuit as a blueprint for attacking integrated anesthesia services.

The FSA’s qui tam action in Florida is part of a broader agenda by those who seek to undermine the integrated care model that enables gastroenterologists and other physician specialists to integrate anesthesia services into lawful care models. A website describing the Florida qui tam action hailed the American Society of Anesthesiology for having “repeatedly petitioned the Office of the Inspector General, brought the issue up with Congressional leaders and executive branch regulators, and provided information and legal resources to its members.”³ These efforts to undermine integrated, coordinated care at the federal level also have extended to the state level, in which efforts have been made in front of licensing boards and state legislatures – albeit unsuccessfully – to restrict the integration of anesthesia services.
 

In-Office Ancillary Services Exception

The In-Office Ancillary Services Exception (IOASE) to the federal physician self-referral statute (the Stark Law), allows physician practices to provide certain services, including diagnostic imaging and anatomic pathology, in an integrated and coordinated fashion within their respective practices when strict criteria are met.

Not surprisingly, competing providers of these services have long fought for the elimination of the IOASE. In 2013, Representative Jackie Speier (D-CA) introduced the Promoting Integrity in Medicare Act. This bill sought to eliminate those legal protections for providing those integrated medical services under the IOASE. Vigorous support for the legislation was provided by a group called the Alliance for Integrity in Medicine, a coalition of organizations including the College of American Pathologists, the American Society for Clinical Pathology, the American Clinical Laboratory Association, and the American College of Radiology. Although that bill did not even receive a vote during the last Congress, Representative Speier has re-introduced it in this current session, and continues to lobby aggressively in support of this legislation. President Obama’s budget for 2016, as the President’s budget proposal had done for the past several years, also included elimination of the IOASE provision. Extensive advocacy efforts by a broad range of specialty organizations have been instrumental to date in defeating this proposal. A study commissioned by the Digestive Health Physicians Association,⁴ using Medicare data, showed that GI-related anatomic pathology services actually increased more slowly in professional settings (physician offices and laboratories), at an annual rate of 1.2% from 2009 to 2013, compared with the outpatient hospital setting of 3.5% during that same period. Efforts to restrict practice integration similarly are being made at the state level. In California, legislation to eliminate the IOASE under the State’s self-referral law was introduced in 2014. Coordinated efforts by California patient- and physician-interest groups were successful in educating legislators on the value of the integrated care mode and the bill was soundly defeated.
 

Medicare Part B Drug Benefit

In March 2016, a new threat to integrated care in GI surfaced when the CMS released a proposed rule that would test a new Medicare Part B payment model for infused drugs including infliximab and vedolizumab. Under the proposal, the CMS would reduce the current reimbursement of 6% above average sales price (ASP) to ASP plus 2.5%, plus a flat fee of $16.85 per infusion. CMS calculations in this proposal failed to include the mandatory 2% sequestration of Medicare payments under the Budget Control Act, which means that the actual reimbursement will be less than 1% over ASP. Because many practices are unable to negotiate discounts for these drugs, unintended consequences of this proposal may disrupt care coordination efforts, resulting in movement of infusions performed in the office setting into the more costly hospital setting. Perversely, although the stated intent of this proposal was to reduce incentives for prescribing more expensive drugs, infused biologic agents are actually treatments of last choice for many inflammatory bowel disease patients.

In the absence of less-expensive alternatives, this proposed change in reimbursement likely will reduce access to effective therapy for some of our sickest patients and will not reduce costs. It is hoped that the vigorous advocacy by a coalition of more than 300 medical societies and patient-interest groups along with a majority of members of Congress may result in modifications to this proposal when the final rule is released later this year.
 

Stark Law

The Stark Law, commonly known as the Physician Self-Referral Law, originally was passed by Congress in 1989 and was substantially amended last in 1993. The Stark Law was enacted to address concerns of potential overuse or inappropriate use of services in a fee-for-service payment system. Health care delivery has changed dramatically since the Stark law was passed 27 years ago, but this statute has not kept pace and is incompatible with new and innovative delivery models that now mandate a shift from fee-for-service payment models to value-based care and the development of risk-sharing arrangements and bundling of services. In 2011, the CMS created a set of waivers for Accountable Care Organizations in the Medicare Shared Savings Program, but these waivers do not apply to many of the alternative payment models under development by independent physicians.

In the past year, Congress repealed the Sustainable Growth Rate formula. Both the Affordable Care Act and the Medicare Access and Children’s Health Insurance Program Reauthorization Act of 2015 were designed to move our health care system away from fee for service (volume) and toward payment for value. The current Stark Law was created to control arrangements in a fee-for-service system, but the Stark Law now obstructs the ability of physicians in independent practices to coordinate care and work as teams across specialties and with their colleagues who care for patients in other sites of service such as hospitals and academic medical centers.

Congress and CMS recently have heard from dozens of physician organizations, including all of the GI societies, about the need to modernize the Stark Law (by way of updates to the Stark statute and its corresponding regulations) to keep pace with the changes in health care delivery and to ensure successful implementation of the Medicare Access and Children’s Health Insurance Program Reauthorization Act. The changes sought include modifications to the definition of the term group practice to permit coordinated care across specialties and sites of service as well as to promote value-based compensation for all physicians.
 

Conclusions

To maximally amplify our voices as well our ability to effect positive change, gastroenterologists and other specialists should be actively engaged with the GI societies to help influence those changes proposed. Joining together will facilitate the adaptation by practices to change as it is mandated. The American Gastroenterological Association has long advocated for independent practices promoting optimal patient care delivery. Working cooperatively and collectively with colleagues in all GI professional organizations will enhance our ability to advance the best interests of our patients and our practices.
 

References

1. Great American Physician Survey 2013. Available from: Physicianspractice.com. Accessed: May 8, 2016.

2. Lowes, R. New Medicare penalty hits small groups, solo physicians hardest. Medscape Medical News. April 28, 2016;

3. The Anesthesia Company Model - FAQs. Available from: http://www.fsahq.org/anesthesia-company-model-faqs. Accessed: May 8, 2016.

4. Milliman White Paper, Medicare anatomic pathology utilization 2009-2013. Available: http://www.dhpassociation.org/wordpress/wp-content/uploads/2015/07/milliman-03-2009-2013-medicare-utilization-analysis.pdf. Accessed: May 8, 2016.

Dr. Rosenberg is a board-certified gastroenterologist who is currently the president of Illinois Gastroenterology Group, Highland Park, Ill; Dr Kim is a gastroenterologist at South Denver Gastroenterology, P.C., Lone Tree, Colo.; and Dr. Ketover is a gastroenterologist and is president and CEO of Minnesota Gastroenterology, P.A.; St. Paul. The authors disclose no conflicts.

The practice of gastroenterology is challenging for community physicians, those employed in multi-specialty clinics or large health care systems and those in academic health centers. Unique challenges confront independent GI practices, and there are mounting regulatory, financial, and operational barriers. Election results of 2016 have thrown us into an even more confusing future. In this month’s Road Ahead column, national GI leaders summarize the major challenges facing independent practices. Each leads (or has led) large GI practices and each has extensive experience with the policies, politics, payers, and pitfalls that impact our specialty. They have written a clear and helpful article for all physicians trying to maintain their independence and patient-focused practices. I have worked in many settings from the VA, to small and then large, independent practice, within a health system and in 2 academic medical centers. There is much to treasure in every type of practice and also many challenges. Physician leaders, both old and young, need to be informed and active in shaping medical policy.

John I. Allen, MD, MBA, AGAF, Editor in Chief

Physicians practicing in independent settings report greater satisfaction with their careers compared with those employed in hospital systems. In a recent survey,1 nearly two-thirds of independent practitioners strongly agreed with the statement, “I like being a physician,” compared with approximately half of those employed by hospital systems. The rapid pace of change in care delivery is forcing all caregivers to modify how they provide care. For physicians practicing in independent settings, understanding, reacting, and adapting to these changes is especially challenging.

It is particularly difficult for physicians and practices to remain abreast and cognizant of the ever-changing rules governing how we deliver care for our patients. The Digestive Health Physicians Association was formed 2 years ago to provide an active voice specifically for independent gastroenterology (GI) practices. The mission of the Digestive Health Physicians Association is to promote and protect the high-quality and cost-efficient care provided in the integrated GI practice model.

In the past decade, meeting the goal of the Triple Aim (improving population health, improving patient experience of care, and reducing the per-capita cost of health care) has become a central tenet of our national health policy strategy, especially since the enactment of the Affordable Care Act. Achieving the goals of the Triple Aim and complying with the changes and new requirements challenges all gastroenterologists, but particularly those working in the independent practice setting, and especially those in small group practices. The Centers for Medicare and Medicaid Services (CMS) recently estimated that under the Merit-Based Incentive Payment System, payment reductions resulting from the first year of reporting in 2017 will occur in 87% of solo practices, in 70% of groups with 2 to 9 physicians, and in 60% of groups with 10 to 24 physicians.²

Preparing yourself and your practice for the changes ahead will require an understanding of the rules, an assessment of your practice’s readiness, and the creation of a plan for compliance to ensure success.

The care model has undergone major changes in the past decade. The development of regional hospital systems has resulted in increasing numbers of employed physicians. Independent gastroenterology practices also have made changes in how they provide care. Vertical integration by independent practices has been a major, positive, and continuing development. As practices have grown more sophisticated with greater areas of specialization, they are increasingly capable of providing services directly to their patients rather than outsourcing them to external providers. Beginning first with endoscopic procedures and now extending to anesthesia, pathology, infusion, and other critical services, increased integration of services across the entire continuum of care has led to improved efficiency and care coordination, benefitting patients with improved outcomes as well as lower costs to our health care system.

The benefits and successes of practice integration, unfortunately, also have made vertically integrated practices a target for regulators and policy makers. Attacks on the integrated delivery model in gastroenterology have at times been supported, if not directly initiated, by our own colleagues in the house of medicine. In this article, we describe some of the threats and challenges confronting independent GI practice.
 

Anesthesia services

In April 2016, the Florida Society of Anesthesiologists (FSA) made headlines by drawing attention to its role as the relator in a qui tam (whistleblower) lawsuit that it had filed against more than 50 physicians, Ambulatory Surgery Centers, and anesthesia entities. This legal action — which the FSA filed in October 2013 but remained under seal until earlier this year — alleged that the defendants perpetrated Medicare and Medicaid fraud through violations of the federal Anti-Kickback Statute and the False Claims Act. In this lawsuit, the FSA specifically targeted the company model used to provide anesthesia services. Based on publicly available documents, the case currently is in its early stages, although the FSA has made it clear that it views the lawsuit as a blueprint for attacking integrated anesthesia services.

The FSA’s qui tam action in Florida is part of a broader agenda by those who seek to undermine the integrated care model that enables gastroenterologists and other physician specialists to integrate anesthesia services into lawful care models. A website describing the Florida qui tam action hailed the American Society of Anesthesiology for having “repeatedly petitioned the Office of the Inspector General, brought the issue up with Congressional leaders and executive branch regulators, and provided information and legal resources to its members.”³ These efforts to undermine integrated, coordinated care at the federal level also have extended to the state level, in which efforts have been made in front of licensing boards and state legislatures – albeit unsuccessfully – to restrict the integration of anesthesia services.
 

In-Office Ancillary Services Exception

The In-Office Ancillary Services Exception (IOASE) to the federal physician self-referral statute (the Stark Law), allows physician practices to provide certain services, including diagnostic imaging and anatomic pathology, in an integrated and coordinated fashion within their respective practices when strict criteria are met.

Not surprisingly, competing providers of these services have long fought for the elimination of the IOASE. In 2013, Representative Jackie Speier (D-CA) introduced the Promoting Integrity in Medicare Act. This bill sought to eliminate those legal protections for providing those integrated medical services under the IOASE. Vigorous support for the legislation was provided by a group called the Alliance for Integrity in Medicine, a coalition of organizations including the College of American Pathologists, the American Society for Clinical Pathology, the American Clinical Laboratory Association, and the American College of Radiology. Although that bill did not even receive a vote during the last Congress, Representative Speier has re-introduced it in this current session, and continues to lobby aggressively in support of this legislation. President Obama’s budget for 2016, as the President’s budget proposal had done for the past several years, also included elimination of the IOASE provision. Extensive advocacy efforts by a broad range of specialty organizations have been instrumental to date in defeating this proposal. A study commissioned by the Digestive Health Physicians Association,⁴ using Medicare data, showed that GI-related anatomic pathology services actually increased more slowly in professional settings (physician offices and laboratories), at an annual rate of 1.2% from 2009 to 2013, compared with the outpatient hospital setting of 3.5% during that same period. Efforts to restrict practice integration similarly are being made at the state level. In California, legislation to eliminate the IOASE under the State’s self-referral law was introduced in 2014. Coordinated efforts by California patient- and physician-interest groups were successful in educating legislators on the value of the integrated care mode and the bill was soundly defeated.
 

Medicare Part B Drug Benefit

In March 2016, a new threat to integrated care in GI surfaced when the CMS released a proposed rule that would test a new Medicare Part B payment model for infused drugs including infliximab and vedolizumab. Under the proposal, the CMS would reduce the current reimbursement of 6% above average sales price (ASP) to ASP plus 2.5%, plus a flat fee of $16.85 per infusion. CMS calculations in this proposal failed to include the mandatory 2% sequestration of Medicare payments under the Budget Control Act, which means that the actual reimbursement will be less than 1% over ASP. Because many practices are unable to negotiate discounts for these drugs, unintended consequences of this proposal may disrupt care coordination efforts, resulting in movement of infusions performed in the office setting into the more costly hospital setting. Perversely, although the stated intent of this proposal was to reduce incentives for prescribing more expensive drugs, infused biologic agents are actually treatments of last choice for many inflammatory bowel disease patients.

In the absence of less-expensive alternatives, this proposed change in reimbursement likely will reduce access to effective therapy for some of our sickest patients and will not reduce costs. It is hoped that the vigorous advocacy by a coalition of more than 300 medical societies and patient-interest groups along with a majority of members of Congress may result in modifications to this proposal when the final rule is released later this year.
 

Stark Law

The Stark Law, commonly known as the Physician Self-Referral Law, originally was passed by Congress in 1989 and was substantially amended last in 1993. The Stark Law was enacted to address concerns of potential overuse or inappropriate use of services in a fee-for-service payment system. Health care delivery has changed dramatically since the Stark law was passed 27 years ago, but this statute has not kept pace and is incompatible with new and innovative delivery models that now mandate a shift from fee-for-service payment models to value-based care and the development of risk-sharing arrangements and bundling of services. In 2011, the CMS created a set of waivers for Accountable Care Organizations in the Medicare Shared Savings Program, but these waivers do not apply to many of the alternative payment models under development by independent physicians.

In the past year, Congress repealed the Sustainable Growth Rate formula. Both the Affordable Care Act and the Medicare Access and Children’s Health Insurance Program Reauthorization Act of 2015 were designed to move our health care system away from fee for service (volume) and toward payment for value. The current Stark Law was created to control arrangements in a fee-for-service system, but the Stark Law now obstructs the ability of physicians in independent practices to coordinate care and work as teams across specialties and with their colleagues who care for patients in other sites of service such as hospitals and academic medical centers.

Congress and CMS recently have heard from dozens of physician organizations, including all of the GI societies, about the need to modernize the Stark Law (by way of updates to the Stark statute and its corresponding regulations) to keep pace with the changes in health care delivery and to ensure successful implementation of the Medicare Access and Children’s Health Insurance Program Reauthorization Act. The changes sought include modifications to the definition of the term group practice to permit coordinated care across specialties and sites of service as well as to promote value-based compensation for all physicians.
 

Conclusions

To maximally amplify our voices as well our ability to effect positive change, gastroenterologists and other specialists should be actively engaged with the GI societies to help influence those changes proposed. Joining together will facilitate the adaptation by practices to change as it is mandated. The American Gastroenterological Association has long advocated for independent practices promoting optimal patient care delivery. Working cooperatively and collectively with colleagues in all GI professional organizations will enhance our ability to advance the best interests of our patients and our practices.
 

References

1. Great American Physician Survey 2013. Available from: Physicianspractice.com. Accessed: May 8, 2016.

2. Lowes, R. New Medicare penalty hits small groups, solo physicians hardest. Medscape Medical News. April 28, 2016;

3. The Anesthesia Company Model - FAQs. Available from: http://www.fsahq.org/anesthesia-company-model-faqs. Accessed: May 8, 2016.

4. Milliman White Paper, Medicare anatomic pathology utilization 2009-2013. Available: http://www.dhpassociation.org/wordpress/wp-content/uploads/2015/07/milliman-03-2009-2013-medicare-utilization-analysis.pdf. Accessed: May 8, 2016.

Dr. Rosenberg is a board-certified gastroenterologist who is currently the president of Illinois Gastroenterology Group, Highland Park, Ill; Dr Kim is a gastroenterologist at South Denver Gastroenterology, P.C., Lone Tree, Colo.; and Dr. Ketover is a gastroenterologist and is president and CEO of Minnesota Gastroenterology, P.A.; St. Paul. The authors disclose no conflicts.

The practice of gastroenterology is challenging for community physicians, those employed in multi-specialty clinics or large health care systems and those in academic health centers. Unique challenges confront independent GI practices, and there are mounting regulatory, financial, and operational barriers. Election results of 2016 have thrown us into an even more confusing future. In this month’s Road Ahead column, national GI leaders summarize the major challenges facing independent practices. Each leads (or has led) large GI practices and each has extensive experience with the policies, politics, payers, and pitfalls that impact our specialty. They have written a clear and helpful article for all physicians trying to maintain their independence and patient-focused practices. I have worked in many settings from the VA, to small and then large, independent practice, within a health system and in 2 academic medical centers. There is much to treasure in every type of practice and also many challenges. Physician leaders, both old and young, need to be informed and active in shaping medical policy.

John I. Allen, MD, MBA, AGAF, Editor in Chief

Physicians practicing in independent settings report greater satisfaction with their careers compared with those employed in hospital systems. In a recent survey,1 nearly two-thirds of independent practitioners strongly agreed with the statement, “I like being a physician,” compared with approximately half of those employed by hospital systems. The rapid pace of change in care delivery is forcing all caregivers to modify how they provide care. For physicians practicing in independent settings, understanding, reacting, and adapting to these changes is especially challenging.

It is particularly difficult for physicians and practices to remain abreast and cognizant of the ever-changing rules governing how we deliver care for our patients. The Digestive Health Physicians Association was formed 2 years ago to provide an active voice specifically for independent gastroenterology (GI) practices. The mission of the Digestive Health Physicians Association is to promote and protect the high-quality and cost-efficient care provided in the integrated GI practice model.

In the past decade, meeting the goal of the Triple Aim (improving population health, improving patient experience of care, and reducing the per-capita cost of health care) has become a central tenet of our national health policy strategy, especially since the enactment of the Affordable Care Act. Achieving the goals of the Triple Aim and complying with the changes and new requirements challenges all gastroenterologists, but particularly those working in the independent practice setting, and especially those in small group practices. The Centers for Medicare and Medicaid Services (CMS) recently estimated that under the Merit-Based Incentive Payment System, payment reductions resulting from the first year of reporting in 2017 will occur in 87% of solo practices, in 70% of groups with 2 to 9 physicians, and in 60% of groups with 10 to 24 physicians.²

Preparing yourself and your practice for the changes ahead will require an understanding of the rules, an assessment of your practice’s readiness, and the creation of a plan for compliance to ensure success.

The care model has undergone major changes in the past decade. The development of regional hospital systems has resulted in increasing numbers of employed physicians. Independent gastroenterology practices also have made changes in how they provide care. Vertical integration by independent practices has been a major, positive, and continuing development. As practices have grown more sophisticated with greater areas of specialization, they are increasingly capable of providing services directly to their patients rather than outsourcing them to external providers. Beginning first with endoscopic procedures and now extending to anesthesia, pathology, infusion, and other critical services, increased integration of services across the entire continuum of care has led to improved efficiency and care coordination, benefitting patients with improved outcomes as well as lower costs to our health care system.

The benefits and successes of practice integration, unfortunately, also have made vertically integrated practices a target for regulators and policy makers. Attacks on the integrated delivery model in gastroenterology have at times been supported, if not directly initiated, by our own colleagues in the house of medicine. In this article, we describe some of the threats and challenges confronting independent GI practice.
 

Anesthesia services

In April 2016, the Florida Society of Anesthesiologists (FSA) made headlines by drawing attention to its role as the relator in a qui tam (whistleblower) lawsuit that it had filed against more than 50 physicians, Ambulatory Surgery Centers, and anesthesia entities. This legal action — which the FSA filed in October 2013 but remained under seal until earlier this year — alleged that the defendants perpetrated Medicare and Medicaid fraud through violations of the federal Anti-Kickback Statute and the False Claims Act. In this lawsuit, the FSA specifically targeted the company model used to provide anesthesia services. Based on publicly available documents, the case currently is in its early stages, although the FSA has made it clear that it views the lawsuit as a blueprint for attacking integrated anesthesia services.

The FSA’s qui tam action in Florida is part of a broader agenda by those who seek to undermine the integrated care model that enables gastroenterologists and other physician specialists to integrate anesthesia services into lawful care models. A website describing the Florida qui tam action hailed the American Society of Anesthesiology for having “repeatedly petitioned the Office of the Inspector General, brought the issue up with Congressional leaders and executive branch regulators, and provided information and legal resources to its members.”³ These efforts to undermine integrated, coordinated care at the federal level also have extended to the state level, in which efforts have been made in front of licensing boards and state legislatures – albeit unsuccessfully – to restrict the integration of anesthesia services.
 

In-Office Ancillary Services Exception

The In-Office Ancillary Services Exception (IOASE) to the federal physician self-referral statute (the Stark Law), allows physician practices to provide certain services, including diagnostic imaging and anatomic pathology, in an integrated and coordinated fashion within their respective practices when strict criteria are met.

Not surprisingly, competing providers of these services have long fought for the elimination of the IOASE. In 2013, Representative Jackie Speier (D-CA) introduced the Promoting Integrity in Medicare Act. This bill sought to eliminate those legal protections for providing those integrated medical services under the IOASE. Vigorous support for the legislation was provided by a group called the Alliance for Integrity in Medicine, a coalition of organizations including the College of American Pathologists, the American Society for Clinical Pathology, the American Clinical Laboratory Association, and the American College of Radiology. Although that bill did not even receive a vote during the last Congress, Representative Speier has re-introduced it in this current session, and continues to lobby aggressively in support of this legislation. President Obama’s budget for 2016, as the President’s budget proposal had done for the past several years, also included elimination of the IOASE provision. Extensive advocacy efforts by a broad range of specialty organizations have been instrumental to date in defeating this proposal. A study commissioned by the Digestive Health Physicians Association,⁴ using Medicare data, showed that GI-related anatomic pathology services actually increased more slowly in professional settings (physician offices and laboratories), at an annual rate of 1.2% from 2009 to 2013, compared with the outpatient hospital setting of 3.5% during that same period. Efforts to restrict practice integration similarly are being made at the state level. In California, legislation to eliminate the IOASE under the State’s self-referral law was introduced in 2014. Coordinated efforts by California patient- and physician-interest groups were successful in educating legislators on the value of the integrated care mode and the bill was soundly defeated.
 

Medicare Part B Drug Benefit

In March 2016, a new threat to integrated care in GI surfaced when the CMS released a proposed rule that would test a new Medicare Part B payment model for infused drugs including infliximab and vedolizumab. Under the proposal, the CMS would reduce the current reimbursement of 6% above average sales price (ASP) to ASP plus 2.5%, plus a flat fee of $16.85 per infusion. CMS calculations in this proposal failed to include the mandatory 2% sequestration of Medicare payments under the Budget Control Act, which means that the actual reimbursement will be less than 1% over ASP. Because many practices are unable to negotiate discounts for these drugs, unintended consequences of this proposal may disrupt care coordination efforts, resulting in movement of infusions performed in the office setting into the more costly hospital setting. Perversely, although the stated intent of this proposal was to reduce incentives for prescribing more expensive drugs, infused biologic agents are actually treatments of last choice for many inflammatory bowel disease patients.

In the absence of less-expensive alternatives, this proposed change in reimbursement likely will reduce access to effective therapy for some of our sickest patients and will not reduce costs. It is hoped that the vigorous advocacy by a coalition of more than 300 medical societies and patient-interest groups along with a majority of members of Congress may result in modifications to this proposal when the final rule is released later this year.
 

Stark Law

The Stark Law, commonly known as the Physician Self-Referral Law, originally was passed by Congress in 1989 and was substantially amended last in 1993. The Stark Law was enacted to address concerns of potential overuse or inappropriate use of services in a fee-for-service payment system. Health care delivery has changed dramatically since the Stark law was passed 27 years ago, but this statute has not kept pace and is incompatible with new and innovative delivery models that now mandate a shift from fee-for-service payment models to value-based care and the development of risk-sharing arrangements and bundling of services. In 2011, the CMS created a set of waivers for Accountable Care Organizations in the Medicare Shared Savings Program, but these waivers do not apply to many of the alternative payment models under development by independent physicians.

In the past year, Congress repealed the Sustainable Growth Rate formula. Both the Affordable Care Act and the Medicare Access and Children’s Health Insurance Program Reauthorization Act of 2015 were designed to move our health care system away from fee for service (volume) and toward payment for value. The current Stark Law was created to control arrangements in a fee-for-service system, but the Stark Law now obstructs the ability of physicians in independent practices to coordinate care and work as teams across specialties and with their colleagues who care for patients in other sites of service such as hospitals and academic medical centers.

Congress and CMS recently have heard from dozens of physician organizations, including all of the GI societies, about the need to modernize the Stark Law (by way of updates to the Stark statute and its corresponding regulations) to keep pace with the changes in health care delivery and to ensure successful implementation of the Medicare Access and Children’s Health Insurance Program Reauthorization Act. The changes sought include modifications to the definition of the term group practice to permit coordinated care across specialties and sites of service as well as to promote value-based compensation for all physicians.
 

Conclusions

To maximally amplify our voices as well our ability to effect positive change, gastroenterologists and other specialists should be actively engaged with the GI societies to help influence those changes proposed. Joining together will facilitate the adaptation by practices to change as it is mandated. The American Gastroenterological Association has long advocated for independent practices promoting optimal patient care delivery. Working cooperatively and collectively with colleagues in all GI professional organizations will enhance our ability to advance the best interests of our patients and our practices.
 

References

1. Great American Physician Survey 2013. Available from: Physicianspractice.com. Accessed: May 8, 2016.

2. Lowes, R. New Medicare penalty hits small groups, solo physicians hardest. Medscape Medical News. April 28, 2016;

3. The Anesthesia Company Model - FAQs. Available from: http://www.fsahq.org/anesthesia-company-model-faqs. Accessed: May 8, 2016.

4. Milliman White Paper, Medicare anatomic pathology utilization 2009-2013. Available: http://www.dhpassociation.org/wordpress/wp-content/uploads/2015/07/milliman-03-2009-2013-medicare-utilization-analysis.pdf. Accessed: May 8, 2016.

Dr. Rosenberg is a board-certified gastroenterologist who is currently the president of Illinois Gastroenterology Group, Highland Park, Ill; Dr Kim is a gastroenterologist at South Denver Gastroenterology, P.C., Lone Tree, Colo.; and Dr. Ketover is a gastroenterologist and is president and CEO of Minnesota Gastroenterology, P.A.; St. Paul. The authors disclose no conflicts.

The Food and Drug Administration has granted regular approval to pembrolizumab (Keytruda) for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Accelerated approval was granted for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.

[email protected]

The Food and Drug Administration has granted regular approval to pembrolizumab (Keytruda) for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Accelerated approval was granted for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.

[email protected]

The Food and Drug Administration has granted regular approval to pembrolizumab (Keytruda) for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Accelerated approval was granted for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.

[email protected]

The latest update to U.S. guidelines for heart failure management, released at the end of April , puts unprecedented emphasis on heart failure prevention and also shines a brighter light on patients at risk for developing heart failure – people with hypertension, diabetes, or coronary artery disease.

“We have embraced the fact that heart failure can be prevented and that the progression of heart failure can be interrupted, and we articulated how we can use biomarkers to screen patients with asymptomatic left ventricular dysfunction,” said Clyde W. Yancy, MD, chair of the writing group that issued the 2017 focused update to the heart failure management guidelines on behalf of the American College of Cardiology, the American Heart Association, and the Heart Failure Society of America. (Circulation. 2017 Apr 28. doi: 10.1161/CIR.0000000000000509).

It starts with blood pressure

The guidelines contain an entirely new section devoted to blood pressure, and, while part of the section deals with a target blood pressure for symptomatic (stage C) heart failure patients (a goal systolic pressure of less than 130 mm Hg for patients with either a preserved or reduced ejection fraction), the first entry is a target blood pressure of less than 130/80 mm Hg for all stage A heart failure patients.

Courtesy Stony Brook University

New role for BNP screening

Stage A patients are more than just the target for more aggressive hypertension control. They are now also potential candidates for screening for an elevated blood level of brain natriuretic peptide (BNP) or N-terminal (NT)–proBNP. The guidelines panel makes this a level IIa recommendation, saying that a screening BNP test in patients at risk for developing heart failure can be useful if followed by team-based care and optimized guideline directed medical therapy.

This guideline follows the lead of two successful controlled trials that focused more aggressive preventive treatments on stage A patients with an elevated level of BNP or NT-proBNP – the STOP-HF (JAMA. 2013 July 3;310[1]:66-74) and PONTIAC (J Am Coll Cardiol. 2013 Oct;62[15]:1365-72) trials. The target population for some type of BNP screening are patients with cardiovascular disease, vascular disease, diabetes, obesity, or hypertension, Dr. Yancy said. “It was evident in STOP-HF that, if you screened and intervened, you could make a difference” in the development of heart failure.

The STOP-HF intervention included “optimal risk factor management” and “coaching by a specialist nurse who emphasized individual risk status and the importance of adherence to medication and healthy lifestyle behaviors.”

The guidelines aren’t clear on which patients at risk for developing heart failure, stage A patients, should get screened with BNP or NT-proBNP. Dr. Jessup said that it’s for patients in whom a positive result would trigger more aggressive management.

HFpEF treatment now possible

Another groundbreaking change in the guidelines is inclusion, for the first time, of a medical treatment specific for HFpEF. The aldosterone receptor antagonists (ARAs) spironolactone and eplerenone received a class IIb recommendation: An ARA might be considered to decrease hospitalizations in patients with HFpEF with an ejection fraction of at least 45%, an elevated BNP or recent hospitalization, and good renal function and potassium level.

The “might be considered” recommendation is guarded but understandable given that the evidence comes from the somewhat controversial, post-hoc analysis of data from the pivotal TOPCAT trial (N Engl J Med. 2014 Apr 10;370[15]:1383-92) that focused on just the roughly half of patients seen at centers in North or South America (Circulation. 2015 Jan 6;131[1]:34-42).

“It would be irresponsible to overlook the potential that [ARAs] may help patients who looks like the ones enrolled in TOPCAT in the Americas,” said Dr. Yancy. “We blended evidence and pragmatism and said that the field needs this” treatment. He said that an ARA was a reasonable option for HFpEF patients with symptoms of heart failure and a positive biomarker test result.

Dr. Butler largely agreed. ARA treatment is for HFpEF patients with symptomatic heart failure and either a history of hospitalization or a high BNP level, he said.

“I was surprised by how strongly the committee felt there was a reasonable signal of help from ARAs in HFpEF,” said Dr. Jessup. “I believe in them too,” she added.

Dr. Jessup suggested targeting an ARA to a HFpEF patient with some hypertension, some volume problem, some peripheral edema, and a lot of breathlessness but with no underlying ischemia. “I use an ARA on these patients pretty quickly,” Dr. Jessup said. It’s best to start with a low dosage and see how the patient responds. “The best responders have a really stiff heart” and are usually not the more elderly HFpEF patients. ARA treatment also provides more steady volume control, superior to furosemide, she said.

Yet more additions

The revised guidelines contain even more changes. “We say that checking for anemia is important and how iron is an intervention that might make a difference,” said Dr. Jessup. Also, primary care physicians and cardiologists “should look for obstructive sleep apnea” in heart failure patients for whom “intervention with weight loss might help,” she said.

Another feature is the focus on tailored treatment, with many treatment elements that need customizing to each different type of heart failure patient. “Not every drug needs to be given to every patient,” Dr. Yancy warned.

The specifics of how to orchestrate all the guidelines into a coherent management plan may become clearer later this year, when the ACC/AHA group will release a follow-up “Heart Failure Pathways” document, aimed at bridging the gap between guidelines and actual clinical practice, Dr. Yancy said. “We want more value from writing the guidelines. The biggest obstacle is how to implement them,” and that’s what the pathways follow-up will address.

“The biggest challenge the societies have is how to motivate physicians and nurses to more aggressively treat heart failure,” said Dr. Butler.

Dr. Yancy and Dr. Jessup had no disclosures. Dr. Butler has been a consultant to 11 companies. Dr. Januzzi has been a consultant to Critical Diagnostics, Novartis, Phillips, Roche Diagnostics, and Sphingotec, and he has received research support from Amgen, Boehringer Ingelheim, Janssen, and Prevencio.

[email protected]

On Twitter @mitchelzoler

The latest update to U.S. guidelines for heart failure management, released at the end of April , puts unprecedented emphasis on heart failure prevention and also shines a brighter light on patients at risk for developing heart failure – people with hypertension, diabetes, or coronary artery disease.

“We have embraced the fact that heart failure can be prevented and that the progression of heart failure can be interrupted, and we articulated how we can use biomarkers to screen patients with asymptomatic left ventricular dysfunction,” said Clyde W. Yancy, MD, chair of the writing group that issued the 2017 focused update to the heart failure management guidelines on behalf of the American College of Cardiology, the American Heart Association, and the Heart Failure Society of America. (Circulation. 2017 Apr 28. doi: 10.1161/CIR.0000000000000509).

It starts with blood pressure

The guidelines contain an entirely new section devoted to blood pressure, and, while part of the section deals with a target blood pressure for symptomatic (stage C) heart failure patients (a goal systolic pressure of less than 130 mm Hg for patients with either a preserved or reduced ejection fraction), the first entry is a target blood pressure of less than 130/80 mm Hg for all stage A heart failure patients.

Courtesy Stony Brook University

New role for BNP screening

Stage A patients are more than just the target for more aggressive hypertension control. They are now also potential candidates for screening for an elevated blood level of brain natriuretic peptide (BNP) or N-terminal (NT)–proBNP. The guidelines panel makes this a level IIa recommendation, saying that a screening BNP test in patients at risk for developing heart failure can be useful if followed by team-based care and optimized guideline directed medical therapy.

This guideline follows the lead of two successful controlled trials that focused more aggressive preventive treatments on stage A patients with an elevated level of BNP or NT-proBNP – the STOP-HF (JAMA. 2013 July 3;310[1]:66-74) and PONTIAC (J Am Coll Cardiol. 2013 Oct;62[15]:1365-72) trials. The target population for some type of BNP screening are patients with cardiovascular disease, vascular disease, diabetes, obesity, or hypertension, Dr. Yancy said. “It was evident in STOP-HF that, if you screened and intervened, you could make a difference” in the development of heart failure.

The STOP-HF intervention included “optimal risk factor management” and “coaching by a specialist nurse who emphasized individual risk status and the importance of adherence to medication and healthy lifestyle behaviors.”

The guidelines aren’t clear on which patients at risk for developing heart failure, stage A patients, should get screened with BNP or NT-proBNP. Dr. Jessup said that it’s for patients in whom a positive result would trigger more aggressive management.

HFpEF treatment now possible

Another groundbreaking change in the guidelines is inclusion, for the first time, of a medical treatment specific for HFpEF. The aldosterone receptor antagonists (ARAs) spironolactone and eplerenone received a class IIb recommendation: An ARA might be considered to decrease hospitalizations in patients with HFpEF with an ejection fraction of at least 45%, an elevated BNP or recent hospitalization, and good renal function and potassium level.

The “might be considered” recommendation is guarded but understandable given that the evidence comes from the somewhat controversial, post-hoc analysis of data from the pivotal TOPCAT trial (N Engl J Med. 2014 Apr 10;370[15]:1383-92) that focused on just the roughly half of patients seen at centers in North or South America (Circulation. 2015 Jan 6;131[1]:34-42).

“It would be irresponsible to overlook the potential that [ARAs] may help patients who looks like the ones enrolled in TOPCAT in the Americas,” said Dr. Yancy. “We blended evidence and pragmatism and said that the field needs this” treatment. He said that an ARA was a reasonable option for HFpEF patients with symptoms of heart failure and a positive biomarker test result.

Dr. Butler largely agreed. ARA treatment is for HFpEF patients with symptomatic heart failure and either a history of hospitalization or a high BNP level, he said.

“I was surprised by how strongly the committee felt there was a reasonable signal of help from ARAs in HFpEF,” said Dr. Jessup. “I believe in them too,” she added.

Dr. Jessup suggested targeting an ARA to a HFpEF patient with some hypertension, some volume problem, some peripheral edema, and a lot of breathlessness but with no underlying ischemia. “I use an ARA on these patients pretty quickly,” Dr. Jessup said. It’s best to start with a low dosage and see how the patient responds. “The best responders have a really stiff heart” and are usually not the more elderly HFpEF patients. ARA treatment also provides more steady volume control, superior to furosemide, she said.

Yet more additions

The revised guidelines contain even more changes. “We say that checking for anemia is important and how iron is an intervention that might make a difference,” said Dr. Jessup. Also, primary care physicians and cardiologists “should look for obstructive sleep apnea” in heart failure patients for whom “intervention with weight loss might help,” she said.

Another feature is the focus on tailored treatment, with many treatment elements that need customizing to each different type of heart failure patient. “Not every drug needs to be given to every patient,” Dr. Yancy warned.

The specifics of how to orchestrate all the guidelines into a coherent management plan may become clearer later this year, when the ACC/AHA group will release a follow-up “Heart Failure Pathways” document, aimed at bridging the gap between guidelines and actual clinical practice, Dr. Yancy said. “We want more value from writing the guidelines. The biggest obstacle is how to implement them,” and that’s what the pathways follow-up will address.

“The biggest challenge the societies have is how to motivate physicians and nurses to more aggressively treat heart failure,” said Dr. Butler.

Dr. Yancy and Dr. Jessup had no disclosures. Dr. Butler has been a consultant to 11 companies. Dr. Januzzi has been a consultant to Critical Diagnostics, Novartis, Phillips, Roche Diagnostics, and Sphingotec, and he has received research support from Amgen, Boehringer Ingelheim, Janssen, and Prevencio.

[email protected]

On Twitter @mitchelzoler

The latest update to U.S. guidelines for heart failure management, released at the end of April , puts unprecedented emphasis on heart failure prevention and also shines a brighter light on patients at risk for developing heart failure – people with hypertension, diabetes, or coronary artery disease.

“We have embraced the fact that heart failure can be prevented and that the progression of heart failure can be interrupted, and we articulated how we can use biomarkers to screen patients with asymptomatic left ventricular dysfunction,” said Clyde W. Yancy, MD, chair of the writing group that issued the 2017 focused update to the heart failure management guidelines on behalf of the American College of Cardiology, the American Heart Association, and the Heart Failure Society of America. (Circulation. 2017 Apr 28. doi: 10.1161/CIR.0000000000000509).

It starts with blood pressure

The guidelines contain an entirely new section devoted to blood pressure, and, while part of the section deals with a target blood pressure for symptomatic (stage C) heart failure patients (a goal systolic pressure of less than 130 mm Hg for patients with either a preserved or reduced ejection fraction), the first entry is a target blood pressure of less than 130/80 mm Hg for all stage A heart failure patients.

Courtesy Stony Brook University

New role for BNP screening

Stage A patients are more than just the target for more aggressive hypertension control. They are now also potential candidates for screening for an elevated blood level of brain natriuretic peptide (BNP) or N-terminal (NT)–proBNP. The guidelines panel makes this a level IIa recommendation, saying that a screening BNP test in patients at risk for developing heart failure can be useful if followed by team-based care and optimized guideline directed medical therapy.

This guideline follows the lead of two successful controlled trials that focused more aggressive preventive treatments on stage A patients with an elevated level of BNP or NT-proBNP – the STOP-HF (JAMA. 2013 July 3;310[1]:66-74) and PONTIAC (J Am Coll Cardiol. 2013 Oct;62[15]:1365-72) trials. The target population for some type of BNP screening are patients with cardiovascular disease, vascular disease, diabetes, obesity, or hypertension, Dr. Yancy said. “It was evident in STOP-HF that, if you screened and intervened, you could make a difference” in the development of heart failure.

The STOP-HF intervention included “optimal risk factor management” and “coaching by a specialist nurse who emphasized individual risk status and the importance of adherence to medication and healthy lifestyle behaviors.”

The guidelines aren’t clear on which patients at risk for developing heart failure, stage A patients, should get screened with BNP or NT-proBNP. Dr. Jessup said that it’s for patients in whom a positive result would trigger more aggressive management.

HFpEF treatment now possible

Another groundbreaking change in the guidelines is inclusion, for the first time, of a medical treatment specific for HFpEF. The aldosterone receptor antagonists (ARAs) spironolactone and eplerenone received a class IIb recommendation: An ARA might be considered to decrease hospitalizations in patients with HFpEF with an ejection fraction of at least 45%, an elevated BNP or recent hospitalization, and good renal function and potassium level.

The “might be considered” recommendation is guarded but understandable given that the evidence comes from the somewhat controversial, post-hoc analysis of data from the pivotal TOPCAT trial (N Engl J Med. 2014 Apr 10;370[15]:1383-92) that focused on just the roughly half of patients seen at centers in North or South America (Circulation. 2015 Jan 6;131[1]:34-42).

“It would be irresponsible to overlook the potential that [ARAs] may help patients who looks like the ones enrolled in TOPCAT in the Americas,” said Dr. Yancy. “We blended evidence and pragmatism and said that the field needs this” treatment. He said that an ARA was a reasonable option for HFpEF patients with symptoms of heart failure and a positive biomarker test result.

Dr. Butler largely agreed. ARA treatment is for HFpEF patients with symptomatic heart failure and either a history of hospitalization or a high BNP level, he said.

“I was surprised by how strongly the committee felt there was a reasonable signal of help from ARAs in HFpEF,” said Dr. Jessup. “I believe in them too,” she added.

Dr. Jessup suggested targeting an ARA to a HFpEF patient with some hypertension, some volume problem, some peripheral edema, and a lot of breathlessness but with no underlying ischemia. “I use an ARA on these patients pretty quickly,” Dr. Jessup said. It’s best to start with a low dosage and see how the patient responds. “The best responders have a really stiff heart” and are usually not the more elderly HFpEF patients. ARA treatment also provides more steady volume control, superior to furosemide, she said.

Yet more additions

The revised guidelines contain even more changes. “We say that checking for anemia is important and how iron is an intervention that might make a difference,” said Dr. Jessup. Also, primary care physicians and cardiologists “should look for obstructive sleep apnea” in heart failure patients for whom “intervention with weight loss might help,” she said.

Another feature is the focus on tailored treatment, with many treatment elements that need customizing to each different type of heart failure patient. “Not every drug needs to be given to every patient,” Dr. Yancy warned.

The specifics of how to orchestrate all the guidelines into a coherent management plan may become clearer later this year, when the ACC/AHA group will release a follow-up “Heart Failure Pathways” document, aimed at bridging the gap between guidelines and actual clinical practice, Dr. Yancy said. “We want more value from writing the guidelines. The biggest obstacle is how to implement them,” and that’s what the pathways follow-up will address.

“The biggest challenge the societies have is how to motivate physicians and nurses to more aggressively treat heart failure,” said Dr. Butler.

Dr. Yancy and Dr. Jessup had no disclosures. Dr. Butler has been a consultant to 11 companies. Dr. Januzzi has been a consultant to Critical Diagnostics, Novartis, Phillips, Roche Diagnostics, and Sphingotec, and he has received research support from Amgen, Boehringer Ingelheim, Janssen, and Prevencio.

[email protected]

On Twitter @mitchelzoler

PORTLAND, ORE. – Patients prescribed photosensitizing antihypertensive drugs had a 16% increase in risk of cutaneous squamous cell carcinoma (cSCC) in a large retrospective cohort study.

These drugs include alpha-2 receptor agonists and loop diuretics, potassium-sparing diuretics, thiazide diuretics, and combination diuretics, Katherine Levandoski said in an oral presentation at the annual meeting of the Society for Investigative Dermatology.

Furthermore, taking antihypertensive drugs of unknown photosensitizing potential conferred a 10% increase in risk of cSCC in the study, she added. Such medications include angiotensin–converting enzyme inhibitors, calcium channel blockers, and vasodilators, she said.

More than 50 million Americans take antihypertensive drugs, many of which are photosensitizing, noted Ms. Levandoski, a research assistant in the Patient Oriented Research on the Epidemiology of Skin Diseases Unit in the department of dermatology, Massachusetts General Hospital, and the department of population medicine, Harvard University, Boston. However, few studies have explored the oncogenic effects of exposure to these drugs, and those that have done so were subject to confounding, small sample sizes, missing data, lack of pathologic verification, and reliance on self-reported medication history, she added.

To help fill this knowledge gap, she and her associates studied 28,357 non-Hispanic whites diagnosed with hypertension and treated at Kaiser Permanente Northern California between 1997 and 2012. They limited the cohort to non-Hispanic whites because they represent the group with most cases of cSCC.

During follow-up, 3,010 patients were diagnosed with new-onset, pathologically verified cSCC, Ms. Levandoski said. Compared with nonusers of antihypertensives, users of photosensitizing antihypertensives had about a 16% increase in the rate of cSCC (hazard ratio, 1.16; 95% confidence interval, 1.06-1.27), even after accounting for age, sex, smoking, comorbidities, health care utilization, skin cancer history, length of health plan membership, and prior exposure to photosensitizing medications.

Strikingly, patients who used antihypertensives of unknown photosensitizing effect had a 10% increase in risk of incident cSCC (RR, 1.10; 95% CI, 1.02-1.19). Some antihypertensive drugs that are classified as unknown photosensitizers “may actually have photosensitizing properties,” Ms. Levandoski commented. Patients taking antihypertensives of known or unknown photosensitizing potential “should be educated on safe sun practices and may benefit from closer screening for cutaneous squamous cell carcinoma,” she added.

The risk of cSCC was not increased among users of nonphotosensitizing antihypertensives (HR, 0.99; 95% CI, 0.91-1.07), including alpha-blockers, beta-blockers, central agonists, and angiotensin receptor blockers, Ms. Levandoski reported.

Patients in the study cohort averaged aged 60 years (standard deviation, 10.6 years), and 56% were female. In all, 1,530 had never been prescribed antihypertensives, while about 17,000-19,000 had been prescribed unknown, known, or nonphotosensitizing antihypertensives.

The work was funded by the National Institutes of Health, a travel award from the Society for Investigative Dermatology, and a Massachusetts General Hospital Medical Student Award. Ms. Levandoski had no conflicts of interest.

PORTLAND, ORE. – Patients prescribed photosensitizing antihypertensive drugs had a 16% increase in risk of cutaneous squamous cell carcinoma (cSCC) in a large retrospective cohort study.

These drugs include alpha-2 receptor agonists and loop diuretics, potassium-sparing diuretics, thiazide diuretics, and combination diuretics, Katherine Levandoski said in an oral presentation at the annual meeting of the Society for Investigative Dermatology.

Furthermore, taking antihypertensive drugs of unknown photosensitizing potential conferred a 10% increase in risk of cSCC in the study, she added. Such medications include angiotensin–converting enzyme inhibitors, calcium channel blockers, and vasodilators, she said.

More than 50 million Americans take antihypertensive drugs, many of which are photosensitizing, noted Ms. Levandoski, a research assistant in the Patient Oriented Research on the Epidemiology of Skin Diseases Unit in the department of dermatology, Massachusetts General Hospital, and the department of population medicine, Harvard University, Boston. However, few studies have explored the oncogenic effects of exposure to these drugs, and those that have done so were subject to confounding, small sample sizes, missing data, lack of pathologic verification, and reliance on self-reported medication history, she added.

To help fill this knowledge gap, she and her associates studied 28,357 non-Hispanic whites diagnosed with hypertension and treated at Kaiser Permanente Northern California between 1997 and 2012. They limited the cohort to non-Hispanic whites because they represent the group with most cases of cSCC.

During follow-up, 3,010 patients were diagnosed with new-onset, pathologically verified cSCC, Ms. Levandoski said. Compared with nonusers of antihypertensives, users of photosensitizing antihypertensives had about a 16% increase in the rate of cSCC (hazard ratio, 1.16; 95% confidence interval, 1.06-1.27), even after accounting for age, sex, smoking, comorbidities, health care utilization, skin cancer history, length of health plan membership, and prior exposure to photosensitizing medications.

Strikingly, patients who used antihypertensives of unknown photosensitizing effect had a 10% increase in risk of incident cSCC (RR, 1.10; 95% CI, 1.02-1.19). Some antihypertensive drugs that are classified as unknown photosensitizers “may actually have photosensitizing properties,” Ms. Levandoski commented. Patients taking antihypertensives of known or unknown photosensitizing potential “should be educated on safe sun practices and may benefit from closer screening for cutaneous squamous cell carcinoma,” she added.

The risk of cSCC was not increased among users of nonphotosensitizing antihypertensives (HR, 0.99; 95% CI, 0.91-1.07), including alpha-blockers, beta-blockers, central agonists, and angiotensin receptor blockers, Ms. Levandoski reported.

Patients in the study cohort averaged aged 60 years (standard deviation, 10.6 years), and 56% were female. In all, 1,530 had never been prescribed antihypertensives, while about 17,000-19,000 had been prescribed unknown, known, or nonphotosensitizing antihypertensives.

The work was funded by the National Institutes of Health, a travel award from the Society for Investigative Dermatology, and a Massachusetts General Hospital Medical Student Award. Ms. Levandoski had no conflicts of interest.

PORTLAND, ORE. – Patients prescribed photosensitizing antihypertensive drugs had a 16% increase in risk of cutaneous squamous cell carcinoma (cSCC) in a large retrospective cohort study.

These drugs include alpha-2 receptor agonists and loop diuretics, potassium-sparing diuretics, thiazide diuretics, and combination diuretics, Katherine Levandoski said in an oral presentation at the annual meeting of the Society for Investigative Dermatology.

Furthermore, taking antihypertensive drugs of unknown photosensitizing potential conferred a 10% increase in risk of cSCC in the study, she added. Such medications include angiotensin–converting enzyme inhibitors, calcium channel blockers, and vasodilators, she said.

More than 50 million Americans take antihypertensive drugs, many of which are photosensitizing, noted Ms. Levandoski, a research assistant in the Patient Oriented Research on the Epidemiology of Skin Diseases Unit in the department of dermatology, Massachusetts General Hospital, and the department of population medicine, Harvard University, Boston. However, few studies have explored the oncogenic effects of exposure to these drugs, and those that have done so were subject to confounding, small sample sizes, missing data, lack of pathologic verification, and reliance on self-reported medication history, she added.

To help fill this knowledge gap, she and her associates studied 28,357 non-Hispanic whites diagnosed with hypertension and treated at Kaiser Permanente Northern California between 1997 and 2012. They limited the cohort to non-Hispanic whites because they represent the group with most cases of cSCC.

During follow-up, 3,010 patients were diagnosed with new-onset, pathologically verified cSCC, Ms. Levandoski said. Compared with nonusers of antihypertensives, users of photosensitizing antihypertensives had about a 16% increase in the rate of cSCC (hazard ratio, 1.16; 95% confidence interval, 1.06-1.27), even after accounting for age, sex, smoking, comorbidities, health care utilization, skin cancer history, length of health plan membership, and prior exposure to photosensitizing medications.

Strikingly, patients who used antihypertensives of unknown photosensitizing effect had a 10% increase in risk of incident cSCC (RR, 1.10; 95% CI, 1.02-1.19). Some antihypertensive drugs that are classified as unknown photosensitizers “may actually have photosensitizing properties,” Ms. Levandoski commented. Patients taking antihypertensives of known or unknown photosensitizing potential “should be educated on safe sun practices and may benefit from closer screening for cutaneous squamous cell carcinoma,” she added.

The risk of cSCC was not increased among users of nonphotosensitizing antihypertensives (HR, 0.99; 95% CI, 0.91-1.07), including alpha-blockers, beta-blockers, central agonists, and angiotensin receptor blockers, Ms. Levandoski reported.

Patients in the study cohort averaged aged 60 years (standard deviation, 10.6 years), and 56% were female. In all, 1,530 had never been prescribed antihypertensives, while about 17,000-19,000 had been prescribed unknown, known, or nonphotosensitizing antihypertensives.

The work was funded by the National Institutes of Health, a travel award from the Society for Investigative Dermatology, and a Massachusetts General Hospital Medical Student Award. Ms. Levandoski had no conflicts of interest.

In some women with heavily pretreated locally advanced or metastatic endometrial cancers, treatment with the immune checkpoint inhibitor pembrolizumab (Keytruda) produced partial, durable responses, investigators reported.

The women were participants in the KEYNOTE-028 trial, a multicohort, open-label phase Ib basket trial of patients with advanced solid tumors positive for programmed death ligand 1 (PD-L1). Of 24 women with PD-L1-positive endometrial tumors, 3 (13%) had confirmed partial responses, and 2 of these patients remained on therapy with a continued response at the time of data cutoff, reported Patrick A. Ott, MD, PhD, of Dana-Farber Cancer Institute, Boston, and his colleagues.

“[T]he results from the KEYNOTE-028 trial presented herein indicate that pembrolizumab shows promise as a treatment for advanced endometrial cancer, a disease for which current treatment options are limited,” they wrote (J Clin Oncol. 2017 May 10; doi: 10.1200/JCO.2017.72.5952).

Patients with advanced endometrial cancer have a poor prognosis, with 5-year survival rates below 50% for patients with lymph node metastases, and less than 20% for those with distant metastases or disease that has spread to the peritoneum, the investigators noted.

“Treatment options for patients presenting with advanced disease are limited, with no consensus on a standard regimen. Similarly, no optimal therapy for patients who experience progression during first-line therapy has been identified, with second-line chemotherapeutic options producing only modest activity,” they wrote.

PD-L1 was shown to be expressed on 83% of primary endometrial tumors and 100% of metastatic endometrial cancers in one study (Cancer Immunol Immunother. 2014;63[6]:545-57), suggesting that could be a viable target in this difficult-to-treat disease, noted Dr. Ott and his colleagues.

In their study, 24 women with locally advanced or metastatic PD-L1–positive endometrial cancer who had experienced progression after standard therapy were treated with pembrolizumab 10 mg/kg every 2 weeks for up to 24 months or until disease progression or unacceptable toxicity. As noted, 3 of the 24 patients met the primary efficacy endpoint of objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) with a partial response, with the median duration of response (a secondary endpoint) not reached at the time of data cutoff on Feb. 17, 2016.

Three other patients (13%) had stable disease, with a median duration of 24.6 weeks.

Safety, also a secondary endpoint, was comparable to that seen in other studies with pembrolizumab. Four patients had grade 3 treatment-related adverse events (AEs). There were no grade 4 AEs of any kind, no immune-mediated AEs of any grade, and no treatment-related deaths.

One of the patients who had a partial response was found through genomic profiling to have a polymerase E, or POLE mutation, and this patient had a rapid improvement after starting on pembrolizumab, with the response lasting longer than 14 months.

“These exceptional results support the theory that the presence of POLE mutations may aid in identifying patients for whom pembrolizumab may be particularly effective, a concept that should be investigated further,” wrote Dr. Ott and his colleagues.

Merck Sharp & Dohme sponsored the study. Dr. Ott and multiple coauthors disclosed institution research funding, honoraria, consulting, or advising with the company, and three are Merck employees..

[email protected]

In some women with heavily pretreated locally advanced or metastatic endometrial cancers, treatment with the immune checkpoint inhibitor pembrolizumab (Keytruda) produced partial, durable responses, investigators reported.

The women were participants in the KEYNOTE-028 trial, a multicohort, open-label phase Ib basket trial of patients with advanced solid tumors positive for programmed death ligand 1 (PD-L1). Of 24 women with PD-L1-positive endometrial tumors, 3 (13%) had confirmed partial responses, and 2 of these patients remained on therapy with a continued response at the time of data cutoff, reported Patrick A. Ott, MD, PhD, of Dana-Farber Cancer Institute, Boston, and his colleagues.

“[T]he results from the KEYNOTE-028 trial presented herein indicate that pembrolizumab shows promise as a treatment for advanced endometrial cancer, a disease for which current treatment options are limited,” they wrote (J Clin Oncol. 2017 May 10; doi: 10.1200/JCO.2017.72.5952).

Patients with advanced endometrial cancer have a poor prognosis, with 5-year survival rates below 50% for patients with lymph node metastases, and less than 20% for those with distant metastases or disease that has spread to the peritoneum, the investigators noted.

“Treatment options for patients presenting with advanced disease are limited, with no consensus on a standard regimen. Similarly, no optimal therapy for patients who experience progression during first-line therapy has been identified, with second-line chemotherapeutic options producing only modest activity,” they wrote.

PD-L1 was shown to be expressed on 83% of primary endometrial tumors and 100% of metastatic endometrial cancers in one study (Cancer Immunol Immunother. 2014;63[6]:545-57), suggesting that could be a viable target in this difficult-to-treat disease, noted Dr. Ott and his colleagues.

In their study, 24 women with locally advanced or metastatic PD-L1–positive endometrial cancer who had experienced progression after standard therapy were treated with pembrolizumab 10 mg/kg every 2 weeks for up to 24 months or until disease progression or unacceptable toxicity. As noted, 3 of the 24 patients met the primary efficacy endpoint of objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) with a partial response, with the median duration of response (a secondary endpoint) not reached at the time of data cutoff on Feb. 17, 2016.

Three other patients (13%) had stable disease, with a median duration of 24.6 weeks.

Safety, also a secondary endpoint, was comparable to that seen in other studies with pembrolizumab. Four patients had grade 3 treatment-related adverse events (AEs). There were no grade 4 AEs of any kind, no immune-mediated AEs of any grade, and no treatment-related deaths.

One of the patients who had a partial response was found through genomic profiling to have a polymerase E, or POLE mutation, and this patient had a rapid improvement after starting on pembrolizumab, with the response lasting longer than 14 months.

“These exceptional results support the theory that the presence of POLE mutations may aid in identifying patients for whom pembrolizumab may be particularly effective, a concept that should be investigated further,” wrote Dr. Ott and his colleagues.

Merck Sharp & Dohme sponsored the study. Dr. Ott and multiple coauthors disclosed institution research funding, honoraria, consulting, or advising with the company, and three are Merck employees..

[email protected]

In some women with heavily pretreated locally advanced or metastatic endometrial cancers, treatment with the immune checkpoint inhibitor pembrolizumab (Keytruda) produced partial, durable responses, investigators reported.

The women were participants in the KEYNOTE-028 trial, a multicohort, open-label phase Ib basket trial of patients with advanced solid tumors positive for programmed death ligand 1 (PD-L1). Of 24 women with PD-L1-positive endometrial tumors, 3 (13%) had confirmed partial responses, and 2 of these patients remained on therapy with a continued response at the time of data cutoff, reported Patrick A. Ott, MD, PhD, of Dana-Farber Cancer Institute, Boston, and his colleagues.

“[T]he results from the KEYNOTE-028 trial presented herein indicate that pembrolizumab shows promise as a treatment for advanced endometrial cancer, a disease for which current treatment options are limited,” they wrote (J Clin Oncol. 2017 May 10; doi: 10.1200/JCO.2017.72.5952).

Patients with advanced endometrial cancer have a poor prognosis, with 5-year survival rates below 50% for patients with lymph node metastases, and less than 20% for those with distant metastases or disease that has spread to the peritoneum, the investigators noted.

“Treatment options for patients presenting with advanced disease are limited, with no consensus on a standard regimen. Similarly, no optimal therapy for patients who experience progression during first-line therapy has been identified, with second-line chemotherapeutic options producing only modest activity,” they wrote.

PD-L1 was shown to be expressed on 83% of primary endometrial tumors and 100% of metastatic endometrial cancers in one study (Cancer Immunol Immunother. 2014;63[6]:545-57), suggesting that could be a viable target in this difficult-to-treat disease, noted Dr. Ott and his colleagues.

In their study, 24 women with locally advanced or metastatic PD-L1–positive endometrial cancer who had experienced progression after standard therapy were treated with pembrolizumab 10 mg/kg every 2 weeks for up to 24 months or until disease progression or unacceptable toxicity. As noted, 3 of the 24 patients met the primary efficacy endpoint of objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) with a partial response, with the median duration of response (a secondary endpoint) not reached at the time of data cutoff on Feb. 17, 2016.

Three other patients (13%) had stable disease, with a median duration of 24.6 weeks.

Safety, also a secondary endpoint, was comparable to that seen in other studies with pembrolizumab. Four patients had grade 3 treatment-related adverse events (AEs). There were no grade 4 AEs of any kind, no immune-mediated AEs of any grade, and no treatment-related deaths.

One of the patients who had a partial response was found through genomic profiling to have a polymerase E, or POLE mutation, and this patient had a rapid improvement after starting on pembrolizumab, with the response lasting longer than 14 months.

“These exceptional results support the theory that the presence of POLE mutations may aid in identifying patients for whom pembrolizumab may be particularly effective, a concept that should be investigated further,” wrote Dr. Ott and his colleagues.

Merck Sharp & Dohme sponsored the study. Dr. Ott and multiple coauthors disclosed institution research funding, honoraria, consulting, or advising with the company, and three are Merck employees..

[email protected]

MACRA (Medicare Access and CHIP Reauthorization Act of 2015) replaces the flawed sustainable growth rate (SGR) formula and significantly changes the way Medicare pays physicians.

Many things about the Affordable Care Act (ACA; Obamacare) are likely to change under the new administration, but MACRA and the commitment to cost-effective, value-based care is here to stay. MACRA is separate from the ACA. Congress overwhelmingly passed MACRA legislation with bipartisan support. MACRA will eventually transition physicians toward more value-based payments.

It is important to understand MACRA to ensure you are doing everything required under the current rules in 2017. Ignore MACRA in 2017 and you will face an automatic reduction of 4% to your payments under Medicare in 2019.

AGA offers educational webinars and videos to help you prepare. Visit gastro.org/MACRA to learn more.
 

[email protected]

MACRA (Medicare Access and CHIP Reauthorization Act of 2015) replaces the flawed sustainable growth rate (SGR) formula and significantly changes the way Medicare pays physicians.

Many things about the Affordable Care Act (ACA; Obamacare) are likely to change under the new administration, but MACRA and the commitment to cost-effective, value-based care is here to stay. MACRA is separate from the ACA. Congress overwhelmingly passed MACRA legislation with bipartisan support. MACRA will eventually transition physicians toward more value-based payments.

It is important to understand MACRA to ensure you are doing everything required under the current rules in 2017. Ignore MACRA in 2017 and you will face an automatic reduction of 4% to your payments under Medicare in 2019.

AGA offers educational webinars and videos to help you prepare. Visit gastro.org/MACRA to learn more.
 

[email protected]

MACRA (Medicare Access and CHIP Reauthorization Act of 2015) replaces the flawed sustainable growth rate (SGR) formula and significantly changes the way Medicare pays physicians.

Many things about the Affordable Care Act (ACA; Obamacare) are likely to change under the new administration, but MACRA and the commitment to cost-effective, value-based care is here to stay. MACRA is separate from the ACA. Congress overwhelmingly passed MACRA legislation with bipartisan support. MACRA will eventually transition physicians toward more value-based payments.

It is important to understand MACRA to ensure you are doing everything required under the current rules in 2017. Ignore MACRA in 2017 and you will face an automatic reduction of 4% to your payments under Medicare in 2019.

AGA offers educational webinars and videos to help you prepare. Visit gastro.org/MACRA to learn more.
 

[email protected]

Patients who have undergone complete resection of biliary tract cancers live longer if they receive the oral chemotherapy agent capecitabine instead of simple observation, according to findings of the phase III randomized controlled BILCAP trial.

“The only curative treatment [for these cancers] is surgical resection, but even in that circumstance, most patients will ultimately succumb to the disease,” lead study author John N. Primrose, MD, professor of surgery at the University of Southampton (England), said in a presscast leading up to the annual meeting of the American Society of Clinical Oncology.

Study details

Patients enrolled in BILCAP had macroscopically completely resected cholangiocarcinoma or gallbladder cancer (including liver and pancreatic resection, as appropriate). They were randomized evenly to eight cycles of capecitabine (Xeloda) at a conventional dose or observation (Capecitabine is approved by the Food and Drug Administration for treatment of breast and colorectal cancers).

With more than 80% of patients having at least 3 years of follow-up, median overall survival in the intention-to-treat population – the trial’s primary endpoint – was 51 months with capecitabine and 36 months with observation (hazard ratio [HR], 0.81; P = .097), Dr. Primrose reported. The benefit became significant in a sensitivity analysis that adjusted for prognostic factors (HR, 0.70; P = .007).

In addition, median overall survival in the per-protocol population was significantly longer with capecitabine, at 53 months, than with observation, at 36 months (HR, 0.75; P = .028).

Median recurrence-free survival in the intention-to-treat population was 25 months for the capecitabine group and 18 months for the observation group.

“The toxicity associated with chemotherapy was relatively modest and in fact very similar to what has been observed in other studies,” Dr. Primrose said. The predominant grade 3 or 4 toxicity seen with capecitabine was plantar-palmar erythema, which occurred in 20.7% of patients who received the drug. There were no capecitabine-related deaths.

“Our quality of life analysis showed that there was very little difference in quality of life related to chemotherapy over those who did not have chemotherapy,” he added.

Dr. Primrose reported that he had no disclosures. Dr. Bridgewater disclosed ties with Merck Serono, Servier, Roche, Celgene, and MSD Oncology.

Patients who have undergone complete resection of biliary tract cancers live longer if they receive the oral chemotherapy agent capecitabine instead of simple observation, according to findings of the phase III randomized controlled BILCAP trial.

“The only curative treatment [for these cancers] is surgical resection, but even in that circumstance, most patients will ultimately succumb to the disease,” lead study author John N. Primrose, MD, professor of surgery at the University of Southampton (England), said in a presscast leading up to the annual meeting of the American Society of Clinical Oncology.

Study details

Patients enrolled in BILCAP had macroscopically completely resected cholangiocarcinoma or gallbladder cancer (including liver and pancreatic resection, as appropriate). They were randomized evenly to eight cycles of capecitabine (Xeloda) at a conventional dose or observation (Capecitabine is approved by the Food and Drug Administration for treatment of breast and colorectal cancers).

With more than 80% of patients having at least 3 years of follow-up, median overall survival in the intention-to-treat population – the trial’s primary endpoint – was 51 months with capecitabine and 36 months with observation (hazard ratio [HR], 0.81; P = .097), Dr. Primrose reported. The benefit became significant in a sensitivity analysis that adjusted for prognostic factors (HR, 0.70; P = .007).

In addition, median overall survival in the per-protocol population was significantly longer with capecitabine, at 53 months, than with observation, at 36 months (HR, 0.75; P = .028).

Median recurrence-free survival in the intention-to-treat population was 25 months for the capecitabine group and 18 months for the observation group.

“The toxicity associated with chemotherapy was relatively modest and in fact very similar to what has been observed in other studies,” Dr. Primrose said. The predominant grade 3 or 4 toxicity seen with capecitabine was plantar-palmar erythema, which occurred in 20.7% of patients who received the drug. There were no capecitabine-related deaths.

“Our quality of life analysis showed that there was very little difference in quality of life related to chemotherapy over those who did not have chemotherapy,” he added.

Dr. Primrose reported that he had no disclosures. Dr. Bridgewater disclosed ties with Merck Serono, Servier, Roche, Celgene, and MSD Oncology.

Patients who have undergone complete resection of biliary tract cancers live longer if they receive the oral chemotherapy agent capecitabine instead of simple observation, according to findings of the phase III randomized controlled BILCAP trial.

“The only curative treatment [for these cancers] is surgical resection, but even in that circumstance, most patients will ultimately succumb to the disease,” lead study author John N. Primrose, MD, professor of surgery at the University of Southampton (England), said in a presscast leading up to the annual meeting of the American Society of Clinical Oncology.

Study details

Patients enrolled in BILCAP had macroscopically completely resected cholangiocarcinoma or gallbladder cancer (including liver and pancreatic resection, as appropriate). They were randomized evenly to eight cycles of capecitabine (Xeloda) at a conventional dose or observation (Capecitabine is approved by the Food and Drug Administration for treatment of breast and colorectal cancers).

With more than 80% of patients having at least 3 years of follow-up, median overall survival in the intention-to-treat population – the trial’s primary endpoint – was 51 months with capecitabine and 36 months with observation (hazard ratio [HR], 0.81; P = .097), Dr. Primrose reported. The benefit became significant in a sensitivity analysis that adjusted for prognostic factors (HR, 0.70; P = .007).

In addition, median overall survival in the per-protocol population was significantly longer with capecitabine, at 53 months, than with observation, at 36 months (HR, 0.75; P = .028).

Median recurrence-free survival in the intention-to-treat population was 25 months for the capecitabine group and 18 months for the observation group.

“The toxicity associated with chemotherapy was relatively modest and in fact very similar to what has been observed in other studies,” Dr. Primrose said. The predominant grade 3 or 4 toxicity seen with capecitabine was plantar-palmar erythema, which occurred in 20.7% of patients who received the drug. There were no capecitabine-related deaths.

“Our quality of life analysis showed that there was very little difference in quality of life related to chemotherapy over those who did not have chemotherapy,” he added.

Dr. Primrose reported that he had no disclosures. Dr. Bridgewater disclosed ties with Merck Serono, Servier, Roche, Celgene, and MSD Oncology.

Answer: E

Critique: Children with early-onset inflammatory bowel disease tend to present with colonic disease. Many of them eventually develop signs and symptoms consistent with Crohn’s disease as they get older. They are often diagnosed as “indeterminant” colitis or even ulcerative colitis but the diagnosis often changes. The colitis does not usually improve with age and these early-onset patients often follow a complicated course. This boy may eventually require enteral tube feedings or even a colectomy — however that cannot be predicted at this time. Provided his disease is well managed, he should reach his expected mid-parental height. 

References

1. Oliva-Hemker M., Hutfless S., Al Kazzi E., et al. Clinical presentation and five-year therapeutic management of very early-onset inflammatory bowel disease in a large North American cohort. J Pediatr. 2015;167:527-32.

2. Aloi M., Lionetti P., Barabino A., et al. Phenotype and disease course of early-onset pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2014;20:597-605.

3. Mamula P., Markowitz J.E., Baldassano R.N. Inflammatory bowel disease in early childhood and adolescence: special considerations. Gastroenterol Clin North Am. 2003;32(3):967–95, viii.

Answer: E

Critique: Children with early-onset inflammatory bowel disease tend to present with colonic disease. Many of them eventually develop signs and symptoms consistent with Crohn’s disease as they get older. They are often diagnosed as “indeterminant” colitis or even ulcerative colitis but the diagnosis often changes. The colitis does not usually improve with age and these early-onset patients often follow a complicated course. This boy may eventually require enteral tube feedings or even a colectomy — however that cannot be predicted at this time. Provided his disease is well managed, he should reach his expected mid-parental height. 

References

1. Oliva-Hemker M., Hutfless S., Al Kazzi E., et al. Clinical presentation and five-year therapeutic management of very early-onset inflammatory bowel disease in a large North American cohort. J Pediatr. 2015;167:527-32.

2. Aloi M., Lionetti P., Barabino A., et al. Phenotype and disease course of early-onset pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2014;20:597-605.

3. Mamula P., Markowitz J.E., Baldassano R.N. Inflammatory bowel disease in early childhood and adolescence: special considerations. Gastroenterol Clin North Am. 2003;32(3):967–95, viii.

Answer: E

Critique: Children with early-onset inflammatory bowel disease tend to present with colonic disease. Many of them eventually develop signs and symptoms consistent with Crohn’s disease as they get older. They are often diagnosed as “indeterminant” colitis or even ulcerative colitis but the diagnosis often changes. The colitis does not usually improve with age and these early-onset patients often follow a complicated course. This boy may eventually require enteral tube feedings or even a colectomy — however that cannot be predicted at this time. Provided his disease is well managed, he should reach his expected mid-parental height. 

References

1. Oliva-Hemker M., Hutfless S., Al Kazzi E., et al. Clinical presentation and five-year therapeutic management of very early-onset inflammatory bowel disease in a large North American cohort. J Pediatr. 2015;167:527-32.

2. Aloi M., Lionetti P., Barabino A., et al. Phenotype and disease course of early-onset pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2014;20:597-605.

3. Mamula P., Markowitz J.E., Baldassano R.N. Inflammatory bowel disease in early childhood and adolescence: special considerations. Gastroenterol Clin North Am. 2003;32(3):967–95, viii.

Answer: D

Objective: Recognize that spontaneous bacterial peritonitis may present in an asymptomatic manner.

Discussion: It is important to recognize that patients with spontaneous bacterial peritonitis may present in various ways and may not exhibit classic abdominal pain or fevers. Patients may have atypical or no overt symptoms at all. With direct inoculation of ascitic fluid into culture bottles at bedside, cultures may identify bacteria in up to 40%-50% of cases.

Patients who survive an episode of SBP have a very high risk of recurrence (70%) within the first year of the index episode. It is therefore essential that patients recovering from SBP be started on prophylactic therapy prior to hospital discharge. Nonabsorbable (or poorly absorbable) antibiotics are most effective for such prophylaxis by selectively eliminating gram-negative organisms in the gut.

These agents reduce the rate of SBP recurrence to around 15–20%. Nosocomial infections respond poorly (~40% of cases) to 3rd generation cephalosporins. Those who have been in the hospital and received antibiotics within the past 90 days should receive extended-spectrum antibiotics.

References

1. Rimola A., Garcia-Tsao G., Navasa M., et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peri- tonitis: a consensus document. J Hepatol. 2000;32:142-53.

2. Tandon P., Garcia-Tsao G. Bacterial infections, sepsis, and multiorgan failure in cirrhosis. Semin Liver Dis. 2008;28(1):26-42.

Answer: D

Objective: Recognize that spontaneous bacterial peritonitis may present in an asymptomatic manner.

Discussion: It is important to recognize that patients with spontaneous bacterial peritonitis may present in various ways and may not exhibit classic abdominal pain or fevers. Patients may have atypical or no overt symptoms at all. With direct inoculation of ascitic fluid into culture bottles at bedside, cultures may identify bacteria in up to 40%-50% of cases.

Patients who survive an episode of SBP have a very high risk of recurrence (70%) within the first year of the index episode. It is therefore essential that patients recovering from SBP be started on prophylactic therapy prior to hospital discharge. Nonabsorbable (or poorly absorbable) antibiotics are most effective for such prophylaxis by selectively eliminating gram-negative organisms in the gut.

These agents reduce the rate of SBP recurrence to around 15–20%. Nosocomial infections respond poorly (~40% of cases) to 3rd generation cephalosporins. Those who have been in the hospital and received antibiotics within the past 90 days should receive extended-spectrum antibiotics.

References

1. Rimola A., Garcia-Tsao G., Navasa M., et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peri- tonitis: a consensus document. J Hepatol. 2000;32:142-53.

2. Tandon P., Garcia-Tsao G. Bacterial infections, sepsis, and multiorgan failure in cirrhosis. Semin Liver Dis. 2008;28(1):26-42.

Answer: D

Objective: Recognize that spontaneous bacterial peritonitis may present in an asymptomatic manner.

Discussion: It is important to recognize that patients with spontaneous bacterial peritonitis may present in various ways and may not exhibit classic abdominal pain or fevers. Patients may have atypical or no overt symptoms at all. With direct inoculation of ascitic fluid into culture bottles at bedside, cultures may identify bacteria in up to 40%-50% of cases.

Patients who survive an episode of SBP have a very high risk of recurrence (70%) within the first year of the index episode. It is therefore essential that patients recovering from SBP be started on prophylactic therapy prior to hospital discharge. Nonabsorbable (or poorly absorbable) antibiotics are most effective for such prophylaxis by selectively eliminating gram-negative organisms in the gut.

These agents reduce the rate of SBP recurrence to around 15–20%. Nosocomial infections respond poorly (~40% of cases) to 3rd generation cephalosporins. Those who have been in the hospital and received antibiotics within the past 90 days should receive extended-spectrum antibiotics.

References

1. Rimola A., Garcia-Tsao G., Navasa M., et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peri- tonitis: a consensus document. J Hepatol. 2000;32:142-53.

2. Tandon P., Garcia-Tsao G. Bacterial infections, sepsis, and multiorgan failure in cirrhosis. Semin Liver Dis. 2008;28(1):26-42.