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FDA approves Doptelet for liver disease patients undergoing procedures
Doptelet (avatrombopag) is the first drug to be approved by the Food and Drug Administration for thrombocytopenia in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure, the FDA announced in a statement.
“Patients with chronic liver disease who have low platelet counts and require a procedure are at increased risk of bleeding,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Doptelet was demonstrated to safely increase the platelet count. This drug may decrease or eliminate the need for platelet transfusions, which are associated with risk of infection and other adverse reactions.”
The safety and efficacy of two different doses of Doptelet administered orally over 5 days, as compared with placebo, was studied in the ADAPT trials (ADAPT-1 and ADAPT-2) involving 435 patients with chronic liver disease and severe thrombocytopenia who were scheduled to undergo a procedure that would typically require platelet transfusion. At both dose levels of Doptelet, a higher proportion of patients had increased platelet counts and did not require platelet transfusion or any rescue therapy on the day of the procedure and up to 7 days following the procedure as compared with those treated with placebo.
The most common side effects reported by clinical trial participants who received Doptelet were fever, stomach (abdominal) pain, nausea, headache, fatigue and edema in the hands or feet. People with chronic liver disease and people with certain blood clotting conditions may have an increased risk of developing blood clots when taking Doptelet, the FDA said in a press release announcing the approval.
The FDA granted the Doptelet approval to AkaRx.
Doptelet (avatrombopag) is the first drug to be approved by the Food and Drug Administration for thrombocytopenia in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure, the FDA announced in a statement.
“Patients with chronic liver disease who have low platelet counts and require a procedure are at increased risk of bleeding,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Doptelet was demonstrated to safely increase the platelet count. This drug may decrease or eliminate the need for platelet transfusions, which are associated with risk of infection and other adverse reactions.”
The safety and efficacy of two different doses of Doptelet administered orally over 5 days, as compared with placebo, was studied in the ADAPT trials (ADAPT-1 and ADAPT-2) involving 435 patients with chronic liver disease and severe thrombocytopenia who were scheduled to undergo a procedure that would typically require platelet transfusion. At both dose levels of Doptelet, a higher proportion of patients had increased platelet counts and did not require platelet transfusion or any rescue therapy on the day of the procedure and up to 7 days following the procedure as compared with those treated with placebo.
The most common side effects reported by clinical trial participants who received Doptelet were fever, stomach (abdominal) pain, nausea, headache, fatigue and edema in the hands or feet. People with chronic liver disease and people with certain blood clotting conditions may have an increased risk of developing blood clots when taking Doptelet, the FDA said in a press release announcing the approval.
The FDA granted the Doptelet approval to AkaRx.
Doptelet (avatrombopag) is the first drug to be approved by the Food and Drug Administration for thrombocytopenia in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure, the FDA announced in a statement.
“Patients with chronic liver disease who have low platelet counts and require a procedure are at increased risk of bleeding,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Doptelet was demonstrated to safely increase the platelet count. This drug may decrease or eliminate the need for platelet transfusions, which are associated with risk of infection and other adverse reactions.”
The safety and efficacy of two different doses of Doptelet administered orally over 5 days, as compared with placebo, was studied in the ADAPT trials (ADAPT-1 and ADAPT-2) involving 435 patients with chronic liver disease and severe thrombocytopenia who were scheduled to undergo a procedure that would typically require platelet transfusion. At both dose levels of Doptelet, a higher proportion of patients had increased platelet counts and did not require platelet transfusion or any rescue therapy on the day of the procedure and up to 7 days following the procedure as compared with those treated with placebo.
The most common side effects reported by clinical trial participants who received Doptelet were fever, stomach (abdominal) pain, nausea, headache, fatigue and edema in the hands or feet. People with chronic liver disease and people with certain blood clotting conditions may have an increased risk of developing blood clots when taking Doptelet, the FDA said in a press release announcing the approval.
The FDA granted the Doptelet approval to AkaRx.
Adding vasopressin in distributive shock may cut AF risk
In patients with distributive shock, the risk of atrial fibrillation may be lower when vasopressin is administered along with catecholamine vasopressors, results of a recent systematic review and meta-analysis suggest.
The relative risk of atrial fibrillation was reduced for the combination of vasopressin and catecholamines versus the current standard of care, which is catecholamines alone, according to study results published in JAMA.
Beyond atrial fibrillation, however, findings of the meta-analysis were consistent with regard to other endpoints, including mortality, according to William F. McIntyre, MD, of McMaster University, Hamilton, Ont., and his coinvestigators.
Mortality was lower with the combination approach when all studies were analyzed together. Yet, when the analysis was limited to the studies with the lowest risk of bias, the difference in mortality versus catecholamines alone was not statistically significant, investigators said.
Nevertheless, the meta-analysis does suggest that vasopressin may offer a clinical advantage regarding prevention of atrial fibrillation in patients with distributive shock, a frequently fatal condition most often seen in patients with sepsis.
Vasopressin is an endogenous peptide hormone that decreases stimulation of certain myocardial receptors associated with cardiac arrhythmia, the authors noted.
“This, among other mechanisms, may translate into a reduction in adverse events, including atrial fibrillation, injury to other organs, and death,” they said in their report.
Dr. McIntyre and his colleagues included 23 trials that had enrolled a total of 3,088 patients with distributive shock, a condition in which widespread vasodilation lowers vascular resistances and mean arterial pressure. Sepsis is its most common cause. The current study is one of the first to directly compare the combination of vasopressin and catecholamine to catecholamines alone, which is the current standard of care, the investigators wrote.
They found that the administration of vasopressin was associated with a significant 23% reduction in risk of atrial fibrillation.
“The absolute effect is that 68 fewer people per 1,000 patients will experience atrial fibrillation when vasopressin is added to catecholaminergic vasopressors,” Dr. McIntyre and his coauthors said of the results.
The atrial fibrillation finding was judged to be high-quality evidence, they said, noting that two separate sensitivity analyses confirmed the benefit.
Mortality data were less consistent, they said.
Pooled data showed administration of vasopressin along with catecholamines was associated an 11% relative reduction in mortality. In absolute terms, 45 lives would be saved for every 1,000 patients receiving vasopressin, they noted.
However, the mortality findings were different when the analysis was limited to the two studies with low risk of bias. That analysis yielded a relative risk of 0.96 and was not statistically significant.
Studies show patients with distributive shock have a relative vasopressin deficiency, providing a theoretical basis for vasopressin administration as part of care, investigators said.
The current Surviving Sepsis guidelines suggest either adding vasopressin to norepinephrine to help raise mean arterial pressure to target or adding vasopressin to decrease the dosage of norepinephrine. Those are considered weak recommendations based on moderate quality of evidence, Dr. McIntyre and colleagues noted in their report.
Authors of the study reported disclosures related to Tenax Therapeutics, Orion Pharma, Ferring Pharmaceuticals, GlaxoSmithKline, and Bristol-Myers Squibb, among other entities.
SOURCE: McIntyre WF et al. JAMA. 2018;319(18):1889-900.
In patients with distributive shock, the risk of atrial fibrillation may be lower when vasopressin is administered along with catecholamine vasopressors, results of a recent systematic review and meta-analysis suggest.
The relative risk of atrial fibrillation was reduced for the combination of vasopressin and catecholamines versus the current standard of care, which is catecholamines alone, according to study results published in JAMA.
Beyond atrial fibrillation, however, findings of the meta-analysis were consistent with regard to other endpoints, including mortality, according to William F. McIntyre, MD, of McMaster University, Hamilton, Ont., and his coinvestigators.
Mortality was lower with the combination approach when all studies were analyzed together. Yet, when the analysis was limited to the studies with the lowest risk of bias, the difference in mortality versus catecholamines alone was not statistically significant, investigators said.
Nevertheless, the meta-analysis does suggest that vasopressin may offer a clinical advantage regarding prevention of atrial fibrillation in patients with distributive shock, a frequently fatal condition most often seen in patients with sepsis.
Vasopressin is an endogenous peptide hormone that decreases stimulation of certain myocardial receptors associated with cardiac arrhythmia, the authors noted.
“This, among other mechanisms, may translate into a reduction in adverse events, including atrial fibrillation, injury to other organs, and death,” they said in their report.
Dr. McIntyre and his colleagues included 23 trials that had enrolled a total of 3,088 patients with distributive shock, a condition in which widespread vasodilation lowers vascular resistances and mean arterial pressure. Sepsis is its most common cause. The current study is one of the first to directly compare the combination of vasopressin and catecholamine to catecholamines alone, which is the current standard of care, the investigators wrote.
They found that the administration of vasopressin was associated with a significant 23% reduction in risk of atrial fibrillation.
“The absolute effect is that 68 fewer people per 1,000 patients will experience atrial fibrillation when vasopressin is added to catecholaminergic vasopressors,” Dr. McIntyre and his coauthors said of the results.
The atrial fibrillation finding was judged to be high-quality evidence, they said, noting that two separate sensitivity analyses confirmed the benefit.
Mortality data were less consistent, they said.
Pooled data showed administration of vasopressin along with catecholamines was associated an 11% relative reduction in mortality. In absolute terms, 45 lives would be saved for every 1,000 patients receiving vasopressin, they noted.
However, the mortality findings were different when the analysis was limited to the two studies with low risk of bias. That analysis yielded a relative risk of 0.96 and was not statistically significant.
Studies show patients with distributive shock have a relative vasopressin deficiency, providing a theoretical basis for vasopressin administration as part of care, investigators said.
The current Surviving Sepsis guidelines suggest either adding vasopressin to norepinephrine to help raise mean arterial pressure to target or adding vasopressin to decrease the dosage of norepinephrine. Those are considered weak recommendations based on moderate quality of evidence, Dr. McIntyre and colleagues noted in their report.
Authors of the study reported disclosures related to Tenax Therapeutics, Orion Pharma, Ferring Pharmaceuticals, GlaxoSmithKline, and Bristol-Myers Squibb, among other entities.
SOURCE: McIntyre WF et al. JAMA. 2018;319(18):1889-900.
In patients with distributive shock, the risk of atrial fibrillation may be lower when vasopressin is administered along with catecholamine vasopressors, results of a recent systematic review and meta-analysis suggest.
The relative risk of atrial fibrillation was reduced for the combination of vasopressin and catecholamines versus the current standard of care, which is catecholamines alone, according to study results published in JAMA.
Beyond atrial fibrillation, however, findings of the meta-analysis were consistent with regard to other endpoints, including mortality, according to William F. McIntyre, MD, of McMaster University, Hamilton, Ont., and his coinvestigators.
Mortality was lower with the combination approach when all studies were analyzed together. Yet, when the analysis was limited to the studies with the lowest risk of bias, the difference in mortality versus catecholamines alone was not statistically significant, investigators said.
Nevertheless, the meta-analysis does suggest that vasopressin may offer a clinical advantage regarding prevention of atrial fibrillation in patients with distributive shock, a frequently fatal condition most often seen in patients with sepsis.
Vasopressin is an endogenous peptide hormone that decreases stimulation of certain myocardial receptors associated with cardiac arrhythmia, the authors noted.
“This, among other mechanisms, may translate into a reduction in adverse events, including atrial fibrillation, injury to other organs, and death,” they said in their report.
Dr. McIntyre and his colleagues included 23 trials that had enrolled a total of 3,088 patients with distributive shock, a condition in which widespread vasodilation lowers vascular resistances and mean arterial pressure. Sepsis is its most common cause. The current study is one of the first to directly compare the combination of vasopressin and catecholamine to catecholamines alone, which is the current standard of care, the investigators wrote.
They found that the administration of vasopressin was associated with a significant 23% reduction in risk of atrial fibrillation.
“The absolute effect is that 68 fewer people per 1,000 patients will experience atrial fibrillation when vasopressin is added to catecholaminergic vasopressors,” Dr. McIntyre and his coauthors said of the results.
The atrial fibrillation finding was judged to be high-quality evidence, they said, noting that two separate sensitivity analyses confirmed the benefit.
Mortality data were less consistent, they said.
Pooled data showed administration of vasopressin along with catecholamines was associated an 11% relative reduction in mortality. In absolute terms, 45 lives would be saved for every 1,000 patients receiving vasopressin, they noted.
However, the mortality findings were different when the analysis was limited to the two studies with low risk of bias. That analysis yielded a relative risk of 0.96 and was not statistically significant.
Studies show patients with distributive shock have a relative vasopressin deficiency, providing a theoretical basis for vasopressin administration as part of care, investigators said.
The current Surviving Sepsis guidelines suggest either adding vasopressin to norepinephrine to help raise mean arterial pressure to target or adding vasopressin to decrease the dosage of norepinephrine. Those are considered weak recommendations based on moderate quality of evidence, Dr. McIntyre and colleagues noted in their report.
Authors of the study reported disclosures related to Tenax Therapeutics, Orion Pharma, Ferring Pharmaceuticals, GlaxoSmithKline, and Bristol-Myers Squibb, among other entities.
SOURCE: McIntyre WF et al. JAMA. 2018;319(18):1889-900.
FROM JAMA
Key clinical point: For patients with distributive shock, the addition of vasopressin to catecholamine vasopressors may reduce atrial fibrillation risk, compared with catecholamines alone.
Major finding: Vasopressin was associated with a 23% lower risk of atrial fibrillation.
Study details: A systematic review and meta-analysis including 23 randomized clinical trials enrolling a total of 3,088 patients.
Disclosures: Authors reported disclosures related to Tenax Therapeutics, Orion Pharma, Ferring Pharmaceuticals, GlaxoSmithKline, and Bristol-Myers Squibb, among other entities.
Source: McIntyre WF et al. JAMA. 2018;319(18):1889-900.
New BP guidelines synergize with transformed primary care
In mid-November, the American College of Cardiology, the American Heart Association, and nine other collaborating societies released a new and long-anticipated guideline for diagnosing and managing hypertension. The top-line, seismic change that the new guidelines called for – treating many patients with hypertension to a blood pressure below 130/80 mm Hg – rubbed the primary care community the wrong way, as described in Part 1 of this feature.
But the novel steps the guideline calls for, from including more careful and methodical measurement of BP, both in and out of the office, to increased reliance on lifestyle interventions, running a formal calculation to identify patients who warrant drug treatment, to a team approach to management, seem to dovetail nicely with the broader goals of primary care.
Part 2 of this feature explores how the approach to diagnosis and management of hypertension spelled out in the ACC/AHA guidelines fits into the protocol-driven, data-monitored, team-delivered primary care model that has come to dominate U.S. primary care in the decade following passage of the Affordable Care Act.
The importance of performance metrics
Regardless of what individual primary care physicians (PCPs) and other physicians and clinicians decide about the appropriate BP treatment target for hypertensive patients, their decisions these days are often strongly influenced by the standards set for population levels of BP control by the Centers for Medicare & Medicaid Services and other payers. In a trend traced by experts to the Affordable Care Act of 2009, many payers now emphasize value-based reimbursements and incentives based on health care organizations meeting performance-metric goals. One of the most common goals measured today in primary care is the percentage of patients with hypertension treated to a particular BP target that today is most commonly set as less than 140/90 mm Hg.
The “vast majority” of PCPs now work in practices that are subject to performance targets including levels of BP control, said Romsai T. Boonyasai, MD, an internist at Johns Hopkins Medicine in Baltimore who specializes in quality improvement research in hypertension and other chronic diseases and also works as a PCP.
Adoption of BP control to less than 130/80 mm Hg by groups such as the National Quality Forum (NQF), National Committee for Quality Assurance (NCQA), and America’s Health Insurance Plans (AHIP) “would add more pressure to comply, especially in an environment where there already is division of opinion between the ACC/AHA and American Association of Family Physicians,” agreed John P.A. Ioannidis, MD, professor of medicine and a preventive medicine specialist at Stanford (Calif.) University.
“The AHA is looking for endorsement from the metric groups,” noted Brent M. Egan, MD, vice president for research at the Care Coordination Institute in Greenville, S.C., and a consultant to the AHA.
But a new performance metric that reflects the ACC/AHA BP target won’t appear immediately. Step one is crafting performance measures based on the ACC/AHA guideline to submit to the NQF and similar groups, a process that will soon start, said Donald E. Casey Jr., MD, a member of the guideline-writing panel and chief clinical affairs officer at Medecision in Wayne, Pa.. He will chair a committee that will review existing hypertension management performance measures and as needed also write new measures based on the guideline, a process he expects to have completed by the end of 2018. After that comes field testing the measures, and if they prove effective and workable, the next step is to submit them to the performance metric groups for review and potential adoption, steps that may take another year. In short, performance metrics for hypertension management that call for a large segment of U.S. patients to be treated to a BP below 130/80 mm Hg likely won’t be in place until the end of 2019 or sometime in 2020 at the earliest, and of course only if the metric-setting groups decide to adopt the new measures as part of their standards.
“It takes a while for guidelines to go from publication to practice. Once [the new guideline] is systematized into performance measures it will help” adoption of what the new guideline recommends, Dr. Casey said in an interview.
Target:BP
Performance metrics are not the only path that could take U.S. medicine toward lower BP targets. Another active player is the Target:BP program, a voluntary quality-improvement program for increased U.S. hypertension awareness and better management launched in late 2015 as a collaboration between the AHA and the American Medical Association.
Given that both the new guideline and Target:BP were developed through partnerships involving the AHA, “it’s logical to connect [the guideline] to Target:BP, said Dr. Egan, an AHA spokesman for Target:BP and professor of medicine at the Medical University of South Carolina in Charleston.
Target:BP’s participants are health care organizations, including health systems, medical groups, community health centers, and physician practices. The program has two primary threads.
First, it functions as a recognition program that cites participating organizations if they achieve a prespecified level of BP control.
In 2017, the program released its initial list of successful participants, organizations that maintained at least 70% of their patients diagnosed with hypertension at a BP of less than 140/90 mm Hg. According to data reported by Willie E. Lawrence Jr., MD, during the AHA scientific sessions in November in Anaheim, Calif., 191 participating programs reached this level and won a “gold” designation from the program for their level of BP control during 2016, out of 310 participating organizations that submitted 2016 data to the program.
Dr. Lawrence also reported that nearly 1,200 total health care organizations were participating in Target:BP as of his presentation, and that the 310 programs that reported 2016 data cared for roughly 12 million people, numbers that extrapolate to more than 45 million Americans cared for in all 1,200 organizations now participating in Target:BP. Among all 310 organizations reporting 2016 data, the average level of hypertension control (patients with BPs maintained at less than 140/90 mm Hg) was 66%, said Dr. Lawrence, chief of cardiology at Research Medical Center in Kansas City, Mo. The cited “gold” programs averaged 76% of their hypertensive patients treated to less than 140/90 mm Hg.
The second thread of Target:BP’s program is to supply participating organizations with training and practice tools aimed at improving hypertension diagnosis and management. The core element of the tools the program currently promotes is the MAP checklists, which stands for Measure accurately, Act rapidly, and Partner with patients, families, and communities (J Clin Hypertens. 2017 Jul;19[7]:684-94).
Target:BP’s focus on a recognition program for organizational success in BP management is very reminiscent of the Get With the Guidelines programs that the AHA previously launched for the management of various cardiovascular diseases such as ischemic stroke. Get With the Guidelines–Stroke, begun in the early 2000s, helped achieve recent success in improving the rates at which U.S. stroke patients receive timely intervention with tissue plasminogen activator, demonstrating the power a recognition program can have for improving patient care.
Target:BP moved quickly to embrace the new ACC/AHA guideline BP targets, posting a treatment target of less than 130/80 mm Hg on its website by December 2017, scant weeks after the guideline’s release in mid-November. But for the time being, Target:BP will continue to use the NQF BP quality metric as the basis for its recognition program, according to an AMA spokesperson for the program. “While the AHA and AMA will keep our joint recognition program in accordance with the NQF measure, we will simultaneously build resources, including an updated treatment algorithm, that align with the new blood pressure guideline,” according to an AMA statement.
Part of the thinking about the timing for revising the BP recognition goal in Target:BP is that it would be too confusing and challenging for participating organizations to attend to two different treatment goals at once, one for Target:BP recognition and a different one for NQF compliance, Dr. Egan explained.
Development of the MAP checklists and several other tools promoted by Target:BP came into existence through a research program sponsored by the AMA in collaboration with researchers at Johns Hopkins Medicine (led by Dr. Boonyasai), and with Dr. Egan and the Care Coordination Institute. Some of these tools also received endorsement in the ACC/AHA guideline, such as the call for more accurate BP measurement. This link means that the experiences physicians have had implementing the Target:BP program provides a degree of foreshadowing for what U.S. physicians might face if they attempt to follow what the ACC/AHA guideline calls for.
Dr. Amofah and his colleagues at Community Health of South Florida, which serves about 76,000 patients with some 90 practitioners, started implementing Target:BP in the Spring of 2016. “Step one was adopting our own, customized algorithm that our entire staff could accept. Many of our clinicians practiced differently, so developing an algorithm yielded a lot of results. We gave clinicians a flow sheet for a hypertension visit,” Dr. Amofah said in an interview.
“We also pushed a program to measure BP accurately. Target:BP provided the training. Patient self-measurement of blood pressure is another key part of Target:BP. We pushed patient self-measurement, accurate measurement, and nurse-run blood pressure clinics. All these made a big difference in our success. Having a structured approach to blood pressure measurement was a major change for us.” Other “major changes” were quickly responding to uncontrolled BP, and empowering patients, he said. All of these also appear as practice recommendations in the new guideline.
When Community Health began participating in Target:BP, it had a 59% hypertension control rate (less than 140/90 mm Hg). By September 2017, roughly 18 months after starting with Target:BP, this had risen to 65%: a significant improvement, but still short of the program’s goal of 70%. Community Health had hoped to reach 70% by the end of 2017 – though as of January 2018 it remained unclear whether this had been achieved – and 80% control by the end of 2018. Reaching these goals is not completely unrealistic, but it’s challenging, Dr. Amofah said, because many of the patients at Community Health of South Florida are underserved, have poor access to medicine, have other survival priorities in their life, and have comorbidities that require attention and complicate their lives.
Dr. Amofah also serves as medical director for Health Choice Network, which includes 44 health organizations in 21 states with about 1 million patients. Of these 44 organizations, 16 have decided to participate in Target:BP, he said. The nonparticipating organizations decided to not be part of a structured program such as Target:BP and many also lacked the infrastructure that implementing Target:BP requires. But he has still tried to sell his colleagues at the nonparticipating organizations on the Target:BP approach, even if they don’t formally participate.
“Not having the support that Target:BP provides can prevent an organization from achieving its best potential,” he said. With Target:BP you get support and reinforcement. “It makes a difference; it creates a focus” Dr. Amofah said.
“Target:BP provides a lot of important guidance and tools that can help providers implement necessary changes” to aid BP control, said Jordana B. Cohen, MD, a nephrologist and hypertension researcher at the University of Pennsylvania in Philadelphia. Her practice does not participate in Target:BP, but she said that she is planning to look into joining.
Systematizing blood pressure management
“Hypertension is a microcosm of the changes that are already happening in U.S. medicine. A lot of what is now going on [in U.S. medicine] is reflected in the guideline,” said Dr. Casey. “Population medicine is now a big deal.”
Several experts trace the start of systematized U.S. primary care medicine to the advent of patient-centered medical homes, which date to 2007 (JAMA. 2009 May 20;301[19]:2038-40) and rapidly expanded with the quality demands of the Affordable Care Act (Health Aff [Millwood]. 2014 Oct;33[10]:1823-31).
These days, the systematization of U.S. primary care transcends the patient-centered medical home model and appears in several forms. Some of the unifying themes are health care organizations that monitor care through quality metrics, apply quality improvement methods, and provide integrated care through multidisciplinary teams of PCPs, various physician specialists, and an array of nonphysician clinicians, The new ACC/AHA guideline, with its call for new methods of BP measurement, home measurement, lifestyle interventions, team-based care, and use of telemedicine when needed both fits into the patient-centered medical home model and provides an added impetus for primary care medicine to move further down this road.
“The patient-centered medical home has been focused on managing diabetes, so I believe that a patient-centered medical home could be easily designed to deliver better hypertension care,” Dr. Casey noted.
When Paul K. Whelton, MD, chair of the ACC/AHA guideline panel, introduced the guideline during the AHA scientific sessions in November, he cited Kaiser Permanente Northern California and the VA Health System as examples of health care organizations that have already achieved high levels of BP control (at the less than 140/90 mm Hg level) in hypertensive patients. Clinicians at Kaiser Permanente Northern California reported that by 2013 they had reached 90% control in their hypertensive patients (J Clin Hypertens. 2016 Apr;18[4]:260-1).
“Primary care systems like Kaiser Permanente and Geisinger have had the most success in controlling hypertension due to their underlying infrastructures and multidisciplinary, team-based approach to blood pressure measurement and management,” noted Dr. Cohen of the University of Pennsylvania. “I am not certain that these [ACC/AHA] guidelines are enough to drive PCPs into different health systems from where they are now established to achieve these measures. Such a shift in practice would potentially leave certain high-risk populations with a greater dearth of care providers that already exists. Ideally, there needs to be more support from Medicare and Medicaid and for those who care for uninsured patients to aid them in implementing these changes broadly into practice.”
But other experts envision the guidelines either promoting further tweaks to existing systems, or providing a further push on PCP practices into more organized systems that can marshal greater resources.
“At the most recent meeting of the clinical practice committee of the Johns Hopkins Community Physicians [which includes about 200 PCPs], I presented the new guideline, and I expected some pushback. I was shocked” by the uniform acceptance the guideline received, said Dr. Boonyasai. “The consensus of our physicians was that the only way to do this is to keep building out our team-based care models, because we can’t do it all ourselves.
“The physicians were brainstorming ways to do it. The guidelines are a discussion point around this general trend toward team-based care that has been going on for a while. We’re trying to figure out how to make it work, at Hopkins and at primary care practices everywhere. The principles of team care also work for diabetes, chronic kidney disease, etc. What we struggle to figure out is how to engage patients so that they take an active role. We can prescribe medications, but if patients don’t take them their blood pressure won’t change. They also need to eat a DASH diet and lose weight. But we need to do more than just tell patients to lose weight. We need to help them do it and we’re looking for ways to help them do this, and that means involving our medical systems with education, follow-up, and patient involvement,” Dr. Boonyasai explained.
“The question is, how does a small practice do team care with their staffing? Where do you get the staff and how do you train them? The guideline spurs us to think more creatively about how we can take better care of more patients,” he said.
“A transition is occurring in U.S. medicine,” noted Dr. Egan. “What we are generally seeing is integration of small practices into larger groups. Larger groups have quality improvement specialists who help redesign the practice to have more efficient delivery of integrated care. Recognition that our health care system was not optimal for a lot of people in terms of results led us to a different model in which the health care system pays attention to a lot of social determinant of health. Not every practice has all the people to deliver this care, but collectively a system does,” noted Dr. Egan.
“Health care systems are reimbursed for quality; that provides some of the money to ensure that extra resources exist” to improve the quality and breadth of care, he said. Introduction of new technologies means “it does not require face-to-face visits to assist in lifestyle changes. The transition in health care is making it easier to do this. Succeeding in managing patients with multiple chronic diseases requires better integration of support services. Part of the barrier to success in implementing evidence-based guidelines is they involve too much work for one person to do. Even practices in remote locations are combining into groups so that their ability to get these resources through scaling is improving.”
Dr. Egan described his own experience consulting with variously sized local practices. “I’ve worked with practices in South Carolina for 18 years, and I’ve seen the majority now become part of health care systems. When a small practice is in a rural area, it shares electronic health records with a larger group, and they get access to a network of specialists and a broader range of resources. That’s the advantage to larger networks. They get access to treatment for medical and behavioral problems in pretty close to real time. The technology is spreading rapidly and is being used. I’ve seen groups with 20 practices that have the resources to hire three PharmDs, who then rotate to meet with patients [from all the practices] to do drug reconciliation and education. An individual practice couldn’t afford something like this. This is happening to treat things like depression and opioid addiction.”
“Hypertension management is no longer a patient going to see a doctor for 15 minutes, getting their blood pressure checked, and then leaving with a prescription,” said Dr. Casey. “We are not doing a good enough job measuring, diagnosing, and treating high blood pressure. We have to come up with better ways to do it. We think that the guideline provides the pathway forward for this.”
Just after the ACC/AHA guidelines had their introduction in November, Target:BP in collaboration with TEDMED organized a panel discussion of the new guideline that included Thomas H. Lee, MD, chief medical officer of Press Ganey in Boston and a practicing internal medicine physician at Brigham and Women’s Hospital in Boston.
During the webcast discussion, Dr. Lee delivered this message to U.S. PCPs and other physicians and health care providers about the future of U.S. hypertension management:
“Physicians and other providers will need to adapt, even those in systems. If we don’t adapt, someone else will fill the space. Patients will find someone else who can help them.
“If providers really are about the health of their patients, then they have a responsibility to try to do better. We need to measure our outcomes and put it out there.” If a health care provider responds, ‘I can’t do it in my current practice model,’ then they should think about how their model must change.”
Dr. Egan has been a consultant to AstraZeneca, Medtronic, and Valencia, has received honoraria from Merck Serono and Emcore, received royalties from UpToDate, and received research support from Medtronic and Quintiles. Dr. Lawrence has an ownership interest in Heka Health. Dr. Casey, Dr. Cohen, Dr. Ioannidis, Dr. Boonyasai, and Dr. Amofah had no disclosures.
In mid-November, the American College of Cardiology, the American Heart Association, and nine other collaborating societies released a new and long-anticipated guideline for diagnosing and managing hypertension. The top-line, seismic change that the new guidelines called for – treating many patients with hypertension to a blood pressure below 130/80 mm Hg – rubbed the primary care community the wrong way, as described in Part 1 of this feature.
But the novel steps the guideline calls for, from including more careful and methodical measurement of BP, both in and out of the office, to increased reliance on lifestyle interventions, running a formal calculation to identify patients who warrant drug treatment, to a team approach to management, seem to dovetail nicely with the broader goals of primary care.
Part 2 of this feature explores how the approach to diagnosis and management of hypertension spelled out in the ACC/AHA guidelines fits into the protocol-driven, data-monitored, team-delivered primary care model that has come to dominate U.S. primary care in the decade following passage of the Affordable Care Act.
The importance of performance metrics
Regardless of what individual primary care physicians (PCPs) and other physicians and clinicians decide about the appropriate BP treatment target for hypertensive patients, their decisions these days are often strongly influenced by the standards set for population levels of BP control by the Centers for Medicare & Medicaid Services and other payers. In a trend traced by experts to the Affordable Care Act of 2009, many payers now emphasize value-based reimbursements and incentives based on health care organizations meeting performance-metric goals. One of the most common goals measured today in primary care is the percentage of patients with hypertension treated to a particular BP target that today is most commonly set as less than 140/90 mm Hg.
The “vast majority” of PCPs now work in practices that are subject to performance targets including levels of BP control, said Romsai T. Boonyasai, MD, an internist at Johns Hopkins Medicine in Baltimore who specializes in quality improvement research in hypertension and other chronic diseases and also works as a PCP.
Adoption of BP control to less than 130/80 mm Hg by groups such as the National Quality Forum (NQF), National Committee for Quality Assurance (NCQA), and America’s Health Insurance Plans (AHIP) “would add more pressure to comply, especially in an environment where there already is division of opinion between the ACC/AHA and American Association of Family Physicians,” agreed John P.A. Ioannidis, MD, professor of medicine and a preventive medicine specialist at Stanford (Calif.) University.
“The AHA is looking for endorsement from the metric groups,” noted Brent M. Egan, MD, vice president for research at the Care Coordination Institute in Greenville, S.C., and a consultant to the AHA.
But a new performance metric that reflects the ACC/AHA BP target won’t appear immediately. Step one is crafting performance measures based on the ACC/AHA guideline to submit to the NQF and similar groups, a process that will soon start, said Donald E. Casey Jr., MD, a member of the guideline-writing panel and chief clinical affairs officer at Medecision in Wayne, Pa.. He will chair a committee that will review existing hypertension management performance measures and as needed also write new measures based on the guideline, a process he expects to have completed by the end of 2018. After that comes field testing the measures, and if they prove effective and workable, the next step is to submit them to the performance metric groups for review and potential adoption, steps that may take another year. In short, performance metrics for hypertension management that call for a large segment of U.S. patients to be treated to a BP below 130/80 mm Hg likely won’t be in place until the end of 2019 or sometime in 2020 at the earliest, and of course only if the metric-setting groups decide to adopt the new measures as part of their standards.
“It takes a while for guidelines to go from publication to practice. Once [the new guideline] is systematized into performance measures it will help” adoption of what the new guideline recommends, Dr. Casey said in an interview.
Target:BP
Performance metrics are not the only path that could take U.S. medicine toward lower BP targets. Another active player is the Target:BP program, a voluntary quality-improvement program for increased U.S. hypertension awareness and better management launched in late 2015 as a collaboration between the AHA and the American Medical Association.
Given that both the new guideline and Target:BP were developed through partnerships involving the AHA, “it’s logical to connect [the guideline] to Target:BP, said Dr. Egan, an AHA spokesman for Target:BP and professor of medicine at the Medical University of South Carolina in Charleston.
Target:BP’s participants are health care organizations, including health systems, medical groups, community health centers, and physician practices. The program has two primary threads.
First, it functions as a recognition program that cites participating organizations if they achieve a prespecified level of BP control.
In 2017, the program released its initial list of successful participants, organizations that maintained at least 70% of their patients diagnosed with hypertension at a BP of less than 140/90 mm Hg. According to data reported by Willie E. Lawrence Jr., MD, during the AHA scientific sessions in November in Anaheim, Calif., 191 participating programs reached this level and won a “gold” designation from the program for their level of BP control during 2016, out of 310 participating organizations that submitted 2016 data to the program.
Dr. Lawrence also reported that nearly 1,200 total health care organizations were participating in Target:BP as of his presentation, and that the 310 programs that reported 2016 data cared for roughly 12 million people, numbers that extrapolate to more than 45 million Americans cared for in all 1,200 organizations now participating in Target:BP. Among all 310 organizations reporting 2016 data, the average level of hypertension control (patients with BPs maintained at less than 140/90 mm Hg) was 66%, said Dr. Lawrence, chief of cardiology at Research Medical Center in Kansas City, Mo. The cited “gold” programs averaged 76% of their hypertensive patients treated to less than 140/90 mm Hg.
The second thread of Target:BP’s program is to supply participating organizations with training and practice tools aimed at improving hypertension diagnosis and management. The core element of the tools the program currently promotes is the MAP checklists, which stands for Measure accurately, Act rapidly, and Partner with patients, families, and communities (J Clin Hypertens. 2017 Jul;19[7]:684-94).
Target:BP’s focus on a recognition program for organizational success in BP management is very reminiscent of the Get With the Guidelines programs that the AHA previously launched for the management of various cardiovascular diseases such as ischemic stroke. Get With the Guidelines–Stroke, begun in the early 2000s, helped achieve recent success in improving the rates at which U.S. stroke patients receive timely intervention with tissue plasminogen activator, demonstrating the power a recognition program can have for improving patient care.
Target:BP moved quickly to embrace the new ACC/AHA guideline BP targets, posting a treatment target of less than 130/80 mm Hg on its website by December 2017, scant weeks after the guideline’s release in mid-November. But for the time being, Target:BP will continue to use the NQF BP quality metric as the basis for its recognition program, according to an AMA spokesperson for the program. “While the AHA and AMA will keep our joint recognition program in accordance with the NQF measure, we will simultaneously build resources, including an updated treatment algorithm, that align with the new blood pressure guideline,” according to an AMA statement.
Part of the thinking about the timing for revising the BP recognition goal in Target:BP is that it would be too confusing and challenging for participating organizations to attend to two different treatment goals at once, one for Target:BP recognition and a different one for NQF compliance, Dr. Egan explained.
Development of the MAP checklists and several other tools promoted by Target:BP came into existence through a research program sponsored by the AMA in collaboration with researchers at Johns Hopkins Medicine (led by Dr. Boonyasai), and with Dr. Egan and the Care Coordination Institute. Some of these tools also received endorsement in the ACC/AHA guideline, such as the call for more accurate BP measurement. This link means that the experiences physicians have had implementing the Target:BP program provides a degree of foreshadowing for what U.S. physicians might face if they attempt to follow what the ACC/AHA guideline calls for.
Dr. Amofah and his colleagues at Community Health of South Florida, which serves about 76,000 patients with some 90 practitioners, started implementing Target:BP in the Spring of 2016. “Step one was adopting our own, customized algorithm that our entire staff could accept. Many of our clinicians practiced differently, so developing an algorithm yielded a lot of results. We gave clinicians a flow sheet for a hypertension visit,” Dr. Amofah said in an interview.
“We also pushed a program to measure BP accurately. Target:BP provided the training. Patient self-measurement of blood pressure is another key part of Target:BP. We pushed patient self-measurement, accurate measurement, and nurse-run blood pressure clinics. All these made a big difference in our success. Having a structured approach to blood pressure measurement was a major change for us.” Other “major changes” were quickly responding to uncontrolled BP, and empowering patients, he said. All of these also appear as practice recommendations in the new guideline.
When Community Health began participating in Target:BP, it had a 59% hypertension control rate (less than 140/90 mm Hg). By September 2017, roughly 18 months after starting with Target:BP, this had risen to 65%: a significant improvement, but still short of the program’s goal of 70%. Community Health had hoped to reach 70% by the end of 2017 – though as of January 2018 it remained unclear whether this had been achieved – and 80% control by the end of 2018. Reaching these goals is not completely unrealistic, but it’s challenging, Dr. Amofah said, because many of the patients at Community Health of South Florida are underserved, have poor access to medicine, have other survival priorities in their life, and have comorbidities that require attention and complicate their lives.
Dr. Amofah also serves as medical director for Health Choice Network, which includes 44 health organizations in 21 states with about 1 million patients. Of these 44 organizations, 16 have decided to participate in Target:BP, he said. The nonparticipating organizations decided to not be part of a structured program such as Target:BP and many also lacked the infrastructure that implementing Target:BP requires. But he has still tried to sell his colleagues at the nonparticipating organizations on the Target:BP approach, even if they don’t formally participate.
“Not having the support that Target:BP provides can prevent an organization from achieving its best potential,” he said. With Target:BP you get support and reinforcement. “It makes a difference; it creates a focus” Dr. Amofah said.
“Target:BP provides a lot of important guidance and tools that can help providers implement necessary changes” to aid BP control, said Jordana B. Cohen, MD, a nephrologist and hypertension researcher at the University of Pennsylvania in Philadelphia. Her practice does not participate in Target:BP, but she said that she is planning to look into joining.
Systematizing blood pressure management
“Hypertension is a microcosm of the changes that are already happening in U.S. medicine. A lot of what is now going on [in U.S. medicine] is reflected in the guideline,” said Dr. Casey. “Population medicine is now a big deal.”
Several experts trace the start of systematized U.S. primary care medicine to the advent of patient-centered medical homes, which date to 2007 (JAMA. 2009 May 20;301[19]:2038-40) and rapidly expanded with the quality demands of the Affordable Care Act (Health Aff [Millwood]. 2014 Oct;33[10]:1823-31).
These days, the systematization of U.S. primary care transcends the patient-centered medical home model and appears in several forms. Some of the unifying themes are health care organizations that monitor care through quality metrics, apply quality improvement methods, and provide integrated care through multidisciplinary teams of PCPs, various physician specialists, and an array of nonphysician clinicians, The new ACC/AHA guideline, with its call for new methods of BP measurement, home measurement, lifestyle interventions, team-based care, and use of telemedicine when needed both fits into the patient-centered medical home model and provides an added impetus for primary care medicine to move further down this road.
“The patient-centered medical home has been focused on managing diabetes, so I believe that a patient-centered medical home could be easily designed to deliver better hypertension care,” Dr. Casey noted.
When Paul K. Whelton, MD, chair of the ACC/AHA guideline panel, introduced the guideline during the AHA scientific sessions in November, he cited Kaiser Permanente Northern California and the VA Health System as examples of health care organizations that have already achieved high levels of BP control (at the less than 140/90 mm Hg level) in hypertensive patients. Clinicians at Kaiser Permanente Northern California reported that by 2013 they had reached 90% control in their hypertensive patients (J Clin Hypertens. 2016 Apr;18[4]:260-1).
“Primary care systems like Kaiser Permanente and Geisinger have had the most success in controlling hypertension due to their underlying infrastructures and multidisciplinary, team-based approach to blood pressure measurement and management,” noted Dr. Cohen of the University of Pennsylvania. “I am not certain that these [ACC/AHA] guidelines are enough to drive PCPs into different health systems from where they are now established to achieve these measures. Such a shift in practice would potentially leave certain high-risk populations with a greater dearth of care providers that already exists. Ideally, there needs to be more support from Medicare and Medicaid and for those who care for uninsured patients to aid them in implementing these changes broadly into practice.”
But other experts envision the guidelines either promoting further tweaks to existing systems, or providing a further push on PCP practices into more organized systems that can marshal greater resources.
“At the most recent meeting of the clinical practice committee of the Johns Hopkins Community Physicians [which includes about 200 PCPs], I presented the new guideline, and I expected some pushback. I was shocked” by the uniform acceptance the guideline received, said Dr. Boonyasai. “The consensus of our physicians was that the only way to do this is to keep building out our team-based care models, because we can’t do it all ourselves.
“The physicians were brainstorming ways to do it. The guidelines are a discussion point around this general trend toward team-based care that has been going on for a while. We’re trying to figure out how to make it work, at Hopkins and at primary care practices everywhere. The principles of team care also work for diabetes, chronic kidney disease, etc. What we struggle to figure out is how to engage patients so that they take an active role. We can prescribe medications, but if patients don’t take them their blood pressure won’t change. They also need to eat a DASH diet and lose weight. But we need to do more than just tell patients to lose weight. We need to help them do it and we’re looking for ways to help them do this, and that means involving our medical systems with education, follow-up, and patient involvement,” Dr. Boonyasai explained.
“The question is, how does a small practice do team care with their staffing? Where do you get the staff and how do you train them? The guideline spurs us to think more creatively about how we can take better care of more patients,” he said.
“A transition is occurring in U.S. medicine,” noted Dr. Egan. “What we are generally seeing is integration of small practices into larger groups. Larger groups have quality improvement specialists who help redesign the practice to have more efficient delivery of integrated care. Recognition that our health care system was not optimal for a lot of people in terms of results led us to a different model in which the health care system pays attention to a lot of social determinant of health. Not every practice has all the people to deliver this care, but collectively a system does,” noted Dr. Egan.
“Health care systems are reimbursed for quality; that provides some of the money to ensure that extra resources exist” to improve the quality and breadth of care, he said. Introduction of new technologies means “it does not require face-to-face visits to assist in lifestyle changes. The transition in health care is making it easier to do this. Succeeding in managing patients with multiple chronic diseases requires better integration of support services. Part of the barrier to success in implementing evidence-based guidelines is they involve too much work for one person to do. Even practices in remote locations are combining into groups so that their ability to get these resources through scaling is improving.”
Dr. Egan described his own experience consulting with variously sized local practices. “I’ve worked with practices in South Carolina for 18 years, and I’ve seen the majority now become part of health care systems. When a small practice is in a rural area, it shares electronic health records with a larger group, and they get access to a network of specialists and a broader range of resources. That’s the advantage to larger networks. They get access to treatment for medical and behavioral problems in pretty close to real time. The technology is spreading rapidly and is being used. I’ve seen groups with 20 practices that have the resources to hire three PharmDs, who then rotate to meet with patients [from all the practices] to do drug reconciliation and education. An individual practice couldn’t afford something like this. This is happening to treat things like depression and opioid addiction.”
“Hypertension management is no longer a patient going to see a doctor for 15 minutes, getting their blood pressure checked, and then leaving with a prescription,” said Dr. Casey. “We are not doing a good enough job measuring, diagnosing, and treating high blood pressure. We have to come up with better ways to do it. We think that the guideline provides the pathway forward for this.”
Just after the ACC/AHA guidelines had their introduction in November, Target:BP in collaboration with TEDMED organized a panel discussion of the new guideline that included Thomas H. Lee, MD, chief medical officer of Press Ganey in Boston and a practicing internal medicine physician at Brigham and Women’s Hospital in Boston.
During the webcast discussion, Dr. Lee delivered this message to U.S. PCPs and other physicians and health care providers about the future of U.S. hypertension management:
“Physicians and other providers will need to adapt, even those in systems. If we don’t adapt, someone else will fill the space. Patients will find someone else who can help them.
“If providers really are about the health of their patients, then they have a responsibility to try to do better. We need to measure our outcomes and put it out there.” If a health care provider responds, ‘I can’t do it in my current practice model,’ then they should think about how their model must change.”
Dr. Egan has been a consultant to AstraZeneca, Medtronic, and Valencia, has received honoraria from Merck Serono and Emcore, received royalties from UpToDate, and received research support from Medtronic and Quintiles. Dr. Lawrence has an ownership interest in Heka Health. Dr. Casey, Dr. Cohen, Dr. Ioannidis, Dr. Boonyasai, and Dr. Amofah had no disclosures.
In mid-November, the American College of Cardiology, the American Heart Association, and nine other collaborating societies released a new and long-anticipated guideline for diagnosing and managing hypertension. The top-line, seismic change that the new guidelines called for – treating many patients with hypertension to a blood pressure below 130/80 mm Hg – rubbed the primary care community the wrong way, as described in Part 1 of this feature.
But the novel steps the guideline calls for, from including more careful and methodical measurement of BP, both in and out of the office, to increased reliance on lifestyle interventions, running a formal calculation to identify patients who warrant drug treatment, to a team approach to management, seem to dovetail nicely with the broader goals of primary care.
Part 2 of this feature explores how the approach to diagnosis and management of hypertension spelled out in the ACC/AHA guidelines fits into the protocol-driven, data-monitored, team-delivered primary care model that has come to dominate U.S. primary care in the decade following passage of the Affordable Care Act.
The importance of performance metrics
Regardless of what individual primary care physicians (PCPs) and other physicians and clinicians decide about the appropriate BP treatment target for hypertensive patients, their decisions these days are often strongly influenced by the standards set for population levels of BP control by the Centers for Medicare & Medicaid Services and other payers. In a trend traced by experts to the Affordable Care Act of 2009, many payers now emphasize value-based reimbursements and incentives based on health care organizations meeting performance-metric goals. One of the most common goals measured today in primary care is the percentage of patients with hypertension treated to a particular BP target that today is most commonly set as less than 140/90 mm Hg.
The “vast majority” of PCPs now work in practices that are subject to performance targets including levels of BP control, said Romsai T. Boonyasai, MD, an internist at Johns Hopkins Medicine in Baltimore who specializes in quality improvement research in hypertension and other chronic diseases and also works as a PCP.
Adoption of BP control to less than 130/80 mm Hg by groups such as the National Quality Forum (NQF), National Committee for Quality Assurance (NCQA), and America’s Health Insurance Plans (AHIP) “would add more pressure to comply, especially in an environment where there already is division of opinion between the ACC/AHA and American Association of Family Physicians,” agreed John P.A. Ioannidis, MD, professor of medicine and a preventive medicine specialist at Stanford (Calif.) University.
“The AHA is looking for endorsement from the metric groups,” noted Brent M. Egan, MD, vice president for research at the Care Coordination Institute in Greenville, S.C., and a consultant to the AHA.
But a new performance metric that reflects the ACC/AHA BP target won’t appear immediately. Step one is crafting performance measures based on the ACC/AHA guideline to submit to the NQF and similar groups, a process that will soon start, said Donald E. Casey Jr., MD, a member of the guideline-writing panel and chief clinical affairs officer at Medecision in Wayne, Pa.. He will chair a committee that will review existing hypertension management performance measures and as needed also write new measures based on the guideline, a process he expects to have completed by the end of 2018. After that comes field testing the measures, and if they prove effective and workable, the next step is to submit them to the performance metric groups for review and potential adoption, steps that may take another year. In short, performance metrics for hypertension management that call for a large segment of U.S. patients to be treated to a BP below 130/80 mm Hg likely won’t be in place until the end of 2019 or sometime in 2020 at the earliest, and of course only if the metric-setting groups decide to adopt the new measures as part of their standards.
“It takes a while for guidelines to go from publication to practice. Once [the new guideline] is systematized into performance measures it will help” adoption of what the new guideline recommends, Dr. Casey said in an interview.
Target:BP
Performance metrics are not the only path that could take U.S. medicine toward lower BP targets. Another active player is the Target:BP program, a voluntary quality-improvement program for increased U.S. hypertension awareness and better management launched in late 2015 as a collaboration between the AHA and the American Medical Association.
Given that both the new guideline and Target:BP were developed through partnerships involving the AHA, “it’s logical to connect [the guideline] to Target:BP, said Dr. Egan, an AHA spokesman for Target:BP and professor of medicine at the Medical University of South Carolina in Charleston.
Target:BP’s participants are health care organizations, including health systems, medical groups, community health centers, and physician practices. The program has two primary threads.
First, it functions as a recognition program that cites participating organizations if they achieve a prespecified level of BP control.
In 2017, the program released its initial list of successful participants, organizations that maintained at least 70% of their patients diagnosed with hypertension at a BP of less than 140/90 mm Hg. According to data reported by Willie E. Lawrence Jr., MD, during the AHA scientific sessions in November in Anaheim, Calif., 191 participating programs reached this level and won a “gold” designation from the program for their level of BP control during 2016, out of 310 participating organizations that submitted 2016 data to the program.
Dr. Lawrence also reported that nearly 1,200 total health care organizations were participating in Target:BP as of his presentation, and that the 310 programs that reported 2016 data cared for roughly 12 million people, numbers that extrapolate to more than 45 million Americans cared for in all 1,200 organizations now participating in Target:BP. Among all 310 organizations reporting 2016 data, the average level of hypertension control (patients with BPs maintained at less than 140/90 mm Hg) was 66%, said Dr. Lawrence, chief of cardiology at Research Medical Center in Kansas City, Mo. The cited “gold” programs averaged 76% of their hypertensive patients treated to less than 140/90 mm Hg.
The second thread of Target:BP’s program is to supply participating organizations with training and practice tools aimed at improving hypertension diagnosis and management. The core element of the tools the program currently promotes is the MAP checklists, which stands for Measure accurately, Act rapidly, and Partner with patients, families, and communities (J Clin Hypertens. 2017 Jul;19[7]:684-94).
Target:BP’s focus on a recognition program for organizational success in BP management is very reminiscent of the Get With the Guidelines programs that the AHA previously launched for the management of various cardiovascular diseases such as ischemic stroke. Get With the Guidelines–Stroke, begun in the early 2000s, helped achieve recent success in improving the rates at which U.S. stroke patients receive timely intervention with tissue plasminogen activator, demonstrating the power a recognition program can have for improving patient care.
Target:BP moved quickly to embrace the new ACC/AHA guideline BP targets, posting a treatment target of less than 130/80 mm Hg on its website by December 2017, scant weeks after the guideline’s release in mid-November. But for the time being, Target:BP will continue to use the NQF BP quality metric as the basis for its recognition program, according to an AMA spokesperson for the program. “While the AHA and AMA will keep our joint recognition program in accordance with the NQF measure, we will simultaneously build resources, including an updated treatment algorithm, that align with the new blood pressure guideline,” according to an AMA statement.
Part of the thinking about the timing for revising the BP recognition goal in Target:BP is that it would be too confusing and challenging for participating organizations to attend to two different treatment goals at once, one for Target:BP recognition and a different one for NQF compliance, Dr. Egan explained.
Development of the MAP checklists and several other tools promoted by Target:BP came into existence through a research program sponsored by the AMA in collaboration with researchers at Johns Hopkins Medicine (led by Dr. Boonyasai), and with Dr. Egan and the Care Coordination Institute. Some of these tools also received endorsement in the ACC/AHA guideline, such as the call for more accurate BP measurement. This link means that the experiences physicians have had implementing the Target:BP program provides a degree of foreshadowing for what U.S. physicians might face if they attempt to follow what the ACC/AHA guideline calls for.
Dr. Amofah and his colleagues at Community Health of South Florida, which serves about 76,000 patients with some 90 practitioners, started implementing Target:BP in the Spring of 2016. “Step one was adopting our own, customized algorithm that our entire staff could accept. Many of our clinicians practiced differently, so developing an algorithm yielded a lot of results. We gave clinicians a flow sheet for a hypertension visit,” Dr. Amofah said in an interview.
“We also pushed a program to measure BP accurately. Target:BP provided the training. Patient self-measurement of blood pressure is another key part of Target:BP. We pushed patient self-measurement, accurate measurement, and nurse-run blood pressure clinics. All these made a big difference in our success. Having a structured approach to blood pressure measurement was a major change for us.” Other “major changes” were quickly responding to uncontrolled BP, and empowering patients, he said. All of these also appear as practice recommendations in the new guideline.
When Community Health began participating in Target:BP, it had a 59% hypertension control rate (less than 140/90 mm Hg). By September 2017, roughly 18 months after starting with Target:BP, this had risen to 65%: a significant improvement, but still short of the program’s goal of 70%. Community Health had hoped to reach 70% by the end of 2017 – though as of January 2018 it remained unclear whether this had been achieved – and 80% control by the end of 2018. Reaching these goals is not completely unrealistic, but it’s challenging, Dr. Amofah said, because many of the patients at Community Health of South Florida are underserved, have poor access to medicine, have other survival priorities in their life, and have comorbidities that require attention and complicate their lives.
Dr. Amofah also serves as medical director for Health Choice Network, which includes 44 health organizations in 21 states with about 1 million patients. Of these 44 organizations, 16 have decided to participate in Target:BP, he said. The nonparticipating organizations decided to not be part of a structured program such as Target:BP and many also lacked the infrastructure that implementing Target:BP requires. But he has still tried to sell his colleagues at the nonparticipating organizations on the Target:BP approach, even if they don’t formally participate.
“Not having the support that Target:BP provides can prevent an organization from achieving its best potential,” he said. With Target:BP you get support and reinforcement. “It makes a difference; it creates a focus” Dr. Amofah said.
“Target:BP provides a lot of important guidance and tools that can help providers implement necessary changes” to aid BP control, said Jordana B. Cohen, MD, a nephrologist and hypertension researcher at the University of Pennsylvania in Philadelphia. Her practice does not participate in Target:BP, but she said that she is planning to look into joining.
Systematizing blood pressure management
“Hypertension is a microcosm of the changes that are already happening in U.S. medicine. A lot of what is now going on [in U.S. medicine] is reflected in the guideline,” said Dr. Casey. “Population medicine is now a big deal.”
Several experts trace the start of systematized U.S. primary care medicine to the advent of patient-centered medical homes, which date to 2007 (JAMA. 2009 May 20;301[19]:2038-40) and rapidly expanded with the quality demands of the Affordable Care Act (Health Aff [Millwood]. 2014 Oct;33[10]:1823-31).
These days, the systematization of U.S. primary care transcends the patient-centered medical home model and appears in several forms. Some of the unifying themes are health care organizations that monitor care through quality metrics, apply quality improvement methods, and provide integrated care through multidisciplinary teams of PCPs, various physician specialists, and an array of nonphysician clinicians, The new ACC/AHA guideline, with its call for new methods of BP measurement, home measurement, lifestyle interventions, team-based care, and use of telemedicine when needed both fits into the patient-centered medical home model and provides an added impetus for primary care medicine to move further down this road.
“The patient-centered medical home has been focused on managing diabetes, so I believe that a patient-centered medical home could be easily designed to deliver better hypertension care,” Dr. Casey noted.
When Paul K. Whelton, MD, chair of the ACC/AHA guideline panel, introduced the guideline during the AHA scientific sessions in November, he cited Kaiser Permanente Northern California and the VA Health System as examples of health care organizations that have already achieved high levels of BP control (at the less than 140/90 mm Hg level) in hypertensive patients. Clinicians at Kaiser Permanente Northern California reported that by 2013 they had reached 90% control in their hypertensive patients (J Clin Hypertens. 2016 Apr;18[4]:260-1).
“Primary care systems like Kaiser Permanente and Geisinger have had the most success in controlling hypertension due to their underlying infrastructures and multidisciplinary, team-based approach to blood pressure measurement and management,” noted Dr. Cohen of the University of Pennsylvania. “I am not certain that these [ACC/AHA] guidelines are enough to drive PCPs into different health systems from where they are now established to achieve these measures. Such a shift in practice would potentially leave certain high-risk populations with a greater dearth of care providers that already exists. Ideally, there needs to be more support from Medicare and Medicaid and for those who care for uninsured patients to aid them in implementing these changes broadly into practice.”
But other experts envision the guidelines either promoting further tweaks to existing systems, or providing a further push on PCP practices into more organized systems that can marshal greater resources.
“At the most recent meeting of the clinical practice committee of the Johns Hopkins Community Physicians [which includes about 200 PCPs], I presented the new guideline, and I expected some pushback. I was shocked” by the uniform acceptance the guideline received, said Dr. Boonyasai. “The consensus of our physicians was that the only way to do this is to keep building out our team-based care models, because we can’t do it all ourselves.
“The physicians were brainstorming ways to do it. The guidelines are a discussion point around this general trend toward team-based care that has been going on for a while. We’re trying to figure out how to make it work, at Hopkins and at primary care practices everywhere. The principles of team care also work for diabetes, chronic kidney disease, etc. What we struggle to figure out is how to engage patients so that they take an active role. We can prescribe medications, but if patients don’t take them their blood pressure won’t change. They also need to eat a DASH diet and lose weight. But we need to do more than just tell patients to lose weight. We need to help them do it and we’re looking for ways to help them do this, and that means involving our medical systems with education, follow-up, and patient involvement,” Dr. Boonyasai explained.
“The question is, how does a small practice do team care with their staffing? Where do you get the staff and how do you train them? The guideline spurs us to think more creatively about how we can take better care of more patients,” he said.
“A transition is occurring in U.S. medicine,” noted Dr. Egan. “What we are generally seeing is integration of small practices into larger groups. Larger groups have quality improvement specialists who help redesign the practice to have more efficient delivery of integrated care. Recognition that our health care system was not optimal for a lot of people in terms of results led us to a different model in which the health care system pays attention to a lot of social determinant of health. Not every practice has all the people to deliver this care, but collectively a system does,” noted Dr. Egan.
“Health care systems are reimbursed for quality; that provides some of the money to ensure that extra resources exist” to improve the quality and breadth of care, he said. Introduction of new technologies means “it does not require face-to-face visits to assist in lifestyle changes. The transition in health care is making it easier to do this. Succeeding in managing patients with multiple chronic diseases requires better integration of support services. Part of the barrier to success in implementing evidence-based guidelines is they involve too much work for one person to do. Even practices in remote locations are combining into groups so that their ability to get these resources through scaling is improving.”
Dr. Egan described his own experience consulting with variously sized local practices. “I’ve worked with practices in South Carolina for 18 years, and I’ve seen the majority now become part of health care systems. When a small practice is in a rural area, it shares electronic health records with a larger group, and they get access to a network of specialists and a broader range of resources. That’s the advantage to larger networks. They get access to treatment for medical and behavioral problems in pretty close to real time. The technology is spreading rapidly and is being used. I’ve seen groups with 20 practices that have the resources to hire three PharmDs, who then rotate to meet with patients [from all the practices] to do drug reconciliation and education. An individual practice couldn’t afford something like this. This is happening to treat things like depression and opioid addiction.”
“Hypertension management is no longer a patient going to see a doctor for 15 minutes, getting their blood pressure checked, and then leaving with a prescription,” said Dr. Casey. “We are not doing a good enough job measuring, diagnosing, and treating high blood pressure. We have to come up with better ways to do it. We think that the guideline provides the pathway forward for this.”
Just after the ACC/AHA guidelines had their introduction in November, Target:BP in collaboration with TEDMED organized a panel discussion of the new guideline that included Thomas H. Lee, MD, chief medical officer of Press Ganey in Boston and a practicing internal medicine physician at Brigham and Women’s Hospital in Boston.
During the webcast discussion, Dr. Lee delivered this message to U.S. PCPs and other physicians and health care providers about the future of U.S. hypertension management:
“Physicians and other providers will need to adapt, even those in systems. If we don’t adapt, someone else will fill the space. Patients will find someone else who can help them.
“If providers really are about the health of their patients, then they have a responsibility to try to do better. We need to measure our outcomes and put it out there.” If a health care provider responds, ‘I can’t do it in my current practice model,’ then they should think about how their model must change.”
Dr. Egan has been a consultant to AstraZeneca, Medtronic, and Valencia, has received honoraria from Merck Serono and Emcore, received royalties from UpToDate, and received research support from Medtronic and Quintiles. Dr. Lawrence has an ownership interest in Heka Health. Dr. Casey, Dr. Cohen, Dr. Ioannidis, Dr. Boonyasai, and Dr. Amofah had no disclosures.
Heart disease in GPA exacts high toll in year 2 and beyond
LIVERPOOL, ENGLAND – Cardiovascular disease was the predominant cause of death of patients with granulomatosis with polyangiitis 1-5 years after a diagnosis in a study by U.K. researchers, suggesting that this could be a target for future intervention.
While active disease was the No. 1 cause of death within the first year of diagnosis in 40% of patients with granulomatosis with polyangiitis (GPA), it was overtaken by cardiovascular disease (CVD) as the main cause of death in 37.5% of patients in the next 4 years from diagnosis.
“The idea for this study came from patients with vasculitis who were polled by Vasculitis UK,” Fiona A. Pearce, MBBS, explained at the British Society for Rheumatology annual conference.
“Further research into mortality was one of their top priorities as patients want to know the honest truth about what is going to happen to them,” added Dr. Pearce, of the division of epidemiology and public health at the University of Nottingham (England).
GPA is a rare type of vasculitis that is estimated to occur in around 1,350 people every year in the United Kingdom. Mortality is known to be high, with around 11%-14% of patients dying in the first year of diagnosis, but there are few data on what happens over a longer term.
The aim of the study was therefore to examine patient survival in the long term – what were the mortality rates several years post diagnosis? Did the risk of death remain high throughout this time and did the causes of death change?
“Of course, the important clinical question was, “Can we then improve things?’ ” Dr. Pearce said.
Two U.K. databases – Clinical Practice Research Datalink and Hospital Episode Statistics – were used to identify patients with GPA diagnosed between 1998 and 2014 and match each case to 10 controls based on age, gender, and family practice. Data on the cause and date of any deaths were then obtained from the Office of National Statistics.
Overall, 465 cases of GPA were matched to 4,610 controls. The median age of participants was 61 years and 57% were male. There were 50 cases with more than 10 years of follow-up data available and data on 139 deaths could be analyzed.
A survival analysis showed that there was a significant reduction in cases versus controls, “but it’s not a constant,” Dr. Pearce noted.
“In the time immediately after diagnosis, the risk of death in people with GPA is very high, and over the first 6 months it tails off.” Then the mortalities are very similar, albeit much lower, to those of controls, but with another dip around 8 years.
The number at risk of death in the second year was 310 for GPA vs. 3,543 for controls and 230 vs. 2,622 at 4 years, 138 vs. 1,704 at 6 years, 93 vs. 1,136 at 8 years, and 49 vs. 658 at 10 years.
Looking at the data another way, the hazard ratios for death comparing GPA cases to controls was 24.5 in the first month, 14.6 in months 1-2, 7.5 by 2-3 months, 4.3 at 3-6 months, 1.6 at 6 months to 8 years, and 3.2 at 8-10 years.
Mortality seems to have improved with time. Splitting the cohort into two time periods based on their diagnosis, those diagnosed between 2008 and 2014 had a lower risk of death than did those diagnosed between 1998 and 2007, although it was still more than four times higher than the background population.
The leading cause of death in patients with GPA 5-10 years after diagnosis was cancer (30.3% of cases), but when this was compared against the general population, the risk was no greater (hazard ratio, 1.0).
GPA cases were also 2.9 times more likely than controls to die as a result of an infection, suggesting that this together with CVD could be a target for mortality reduction strategies.
“We can’t get away from the fact that although this is a large study, there are still small numbers of patients because this is rare disease,” Dr. Pearce observed. “We also don’t have detailed clinical information on each patient, so we can’t look for associations or clinical phenotypes at diagnosis, and there are no biomarkers.”
From a clinical perspective, she noted, it is important to remember that deaths in the first year are mainly from active disease and to continue to try to diagnose and treat the condition as early as possible.
Arthritis Research UK funded the trial. Dr. Pearce had nothing to disclose.
SOURCE: Pearce F et al. Rheumatology. 2018;57(Suppl. 3):key075.204.
LIVERPOOL, ENGLAND – Cardiovascular disease was the predominant cause of death of patients with granulomatosis with polyangiitis 1-5 years after a diagnosis in a study by U.K. researchers, suggesting that this could be a target for future intervention.
While active disease was the No. 1 cause of death within the first year of diagnosis in 40% of patients with granulomatosis with polyangiitis (GPA), it was overtaken by cardiovascular disease (CVD) as the main cause of death in 37.5% of patients in the next 4 years from diagnosis.
“The idea for this study came from patients with vasculitis who were polled by Vasculitis UK,” Fiona A. Pearce, MBBS, explained at the British Society for Rheumatology annual conference.
“Further research into mortality was one of their top priorities as patients want to know the honest truth about what is going to happen to them,” added Dr. Pearce, of the division of epidemiology and public health at the University of Nottingham (England).
GPA is a rare type of vasculitis that is estimated to occur in around 1,350 people every year in the United Kingdom. Mortality is known to be high, with around 11%-14% of patients dying in the first year of diagnosis, but there are few data on what happens over a longer term.
The aim of the study was therefore to examine patient survival in the long term – what were the mortality rates several years post diagnosis? Did the risk of death remain high throughout this time and did the causes of death change?
“Of course, the important clinical question was, “Can we then improve things?’ ” Dr. Pearce said.
Two U.K. databases – Clinical Practice Research Datalink and Hospital Episode Statistics – were used to identify patients with GPA diagnosed between 1998 and 2014 and match each case to 10 controls based on age, gender, and family practice. Data on the cause and date of any deaths were then obtained from the Office of National Statistics.
Overall, 465 cases of GPA were matched to 4,610 controls. The median age of participants was 61 years and 57% were male. There were 50 cases with more than 10 years of follow-up data available and data on 139 deaths could be analyzed.
A survival analysis showed that there was a significant reduction in cases versus controls, “but it’s not a constant,” Dr. Pearce noted.
“In the time immediately after diagnosis, the risk of death in people with GPA is very high, and over the first 6 months it tails off.” Then the mortalities are very similar, albeit much lower, to those of controls, but with another dip around 8 years.
The number at risk of death in the second year was 310 for GPA vs. 3,543 for controls and 230 vs. 2,622 at 4 years, 138 vs. 1,704 at 6 years, 93 vs. 1,136 at 8 years, and 49 vs. 658 at 10 years.
Looking at the data another way, the hazard ratios for death comparing GPA cases to controls was 24.5 in the first month, 14.6 in months 1-2, 7.5 by 2-3 months, 4.3 at 3-6 months, 1.6 at 6 months to 8 years, and 3.2 at 8-10 years.
Mortality seems to have improved with time. Splitting the cohort into two time periods based on their diagnosis, those diagnosed between 2008 and 2014 had a lower risk of death than did those diagnosed between 1998 and 2007, although it was still more than four times higher than the background population.
The leading cause of death in patients with GPA 5-10 years after diagnosis was cancer (30.3% of cases), but when this was compared against the general population, the risk was no greater (hazard ratio, 1.0).
GPA cases were also 2.9 times more likely than controls to die as a result of an infection, suggesting that this together with CVD could be a target for mortality reduction strategies.
“We can’t get away from the fact that although this is a large study, there are still small numbers of patients because this is rare disease,” Dr. Pearce observed. “We also don’t have detailed clinical information on each patient, so we can’t look for associations or clinical phenotypes at diagnosis, and there are no biomarkers.”
From a clinical perspective, she noted, it is important to remember that deaths in the first year are mainly from active disease and to continue to try to diagnose and treat the condition as early as possible.
Arthritis Research UK funded the trial. Dr. Pearce had nothing to disclose.
SOURCE: Pearce F et al. Rheumatology. 2018;57(Suppl. 3):key075.204.
LIVERPOOL, ENGLAND – Cardiovascular disease was the predominant cause of death of patients with granulomatosis with polyangiitis 1-5 years after a diagnosis in a study by U.K. researchers, suggesting that this could be a target for future intervention.
While active disease was the No. 1 cause of death within the first year of diagnosis in 40% of patients with granulomatosis with polyangiitis (GPA), it was overtaken by cardiovascular disease (CVD) as the main cause of death in 37.5% of patients in the next 4 years from diagnosis.
“The idea for this study came from patients with vasculitis who were polled by Vasculitis UK,” Fiona A. Pearce, MBBS, explained at the British Society for Rheumatology annual conference.
“Further research into mortality was one of their top priorities as patients want to know the honest truth about what is going to happen to them,” added Dr. Pearce, of the division of epidemiology and public health at the University of Nottingham (England).
GPA is a rare type of vasculitis that is estimated to occur in around 1,350 people every year in the United Kingdom. Mortality is known to be high, with around 11%-14% of patients dying in the first year of diagnosis, but there are few data on what happens over a longer term.
The aim of the study was therefore to examine patient survival in the long term – what were the mortality rates several years post diagnosis? Did the risk of death remain high throughout this time and did the causes of death change?
“Of course, the important clinical question was, “Can we then improve things?’ ” Dr. Pearce said.
Two U.K. databases – Clinical Practice Research Datalink and Hospital Episode Statistics – were used to identify patients with GPA diagnosed between 1998 and 2014 and match each case to 10 controls based on age, gender, and family practice. Data on the cause and date of any deaths were then obtained from the Office of National Statistics.
Overall, 465 cases of GPA were matched to 4,610 controls. The median age of participants was 61 years and 57% were male. There were 50 cases with more than 10 years of follow-up data available and data on 139 deaths could be analyzed.
A survival analysis showed that there was a significant reduction in cases versus controls, “but it’s not a constant,” Dr. Pearce noted.
“In the time immediately after diagnosis, the risk of death in people with GPA is very high, and over the first 6 months it tails off.” Then the mortalities are very similar, albeit much lower, to those of controls, but with another dip around 8 years.
The number at risk of death in the second year was 310 for GPA vs. 3,543 for controls and 230 vs. 2,622 at 4 years, 138 vs. 1,704 at 6 years, 93 vs. 1,136 at 8 years, and 49 vs. 658 at 10 years.
Looking at the data another way, the hazard ratios for death comparing GPA cases to controls was 24.5 in the first month, 14.6 in months 1-2, 7.5 by 2-3 months, 4.3 at 3-6 months, 1.6 at 6 months to 8 years, and 3.2 at 8-10 years.
Mortality seems to have improved with time. Splitting the cohort into two time periods based on their diagnosis, those diagnosed between 2008 and 2014 had a lower risk of death than did those diagnosed between 1998 and 2007, although it was still more than four times higher than the background population.
The leading cause of death in patients with GPA 5-10 years after diagnosis was cancer (30.3% of cases), but when this was compared against the general population, the risk was no greater (hazard ratio, 1.0).
GPA cases were also 2.9 times more likely than controls to die as a result of an infection, suggesting that this together with CVD could be a target for mortality reduction strategies.
“We can’t get away from the fact that although this is a large study, there are still small numbers of patients because this is rare disease,” Dr. Pearce observed. “We also don’t have detailed clinical information on each patient, so we can’t look for associations or clinical phenotypes at diagnosis, and there are no biomarkers.”
From a clinical perspective, she noted, it is important to remember that deaths in the first year are mainly from active disease and to continue to try to diagnose and treat the condition as early as possible.
Arthritis Research UK funded the trial. Dr. Pearce had nothing to disclose.
SOURCE: Pearce F et al. Rheumatology. 2018;57(Suppl. 3):key075.204.
REPORTING FROM RHEUMATOLOGY 2018
Key clinical point:
Major finding: The main cause of death changed from active disease (40% of all cases) within the first year to cardiovascular disease at years 1-5 (37.5%).
Study details: Retrospective cohort study of 465 individuals newly diagnosed with granulomatosis with polyangiitis matched to 4,610 controls from the general U.K. primary care population.
Disclosures: Arthritis Research UK funded the trial. Dr. Pearce had nothing to disclose.
Source: Pearce F et al. Rheumatology. 2018;57(Suppl. 3):key075.204.
Drug-coated balloons: The future of hemodialysis access?
CHICAGO – Drug-coated balloons show promise of being a long-sought major advance in the endovascular treatment of stenotic arteriovenous fistulae and grafts for hemodialysis access, Syed M. Hussain, MD, said at a symposium on vascular surgery sponsored by Northwestern University.
Something significantly better than today’s standard treatment options is needed, according to Dr. Hussain. Medicare pays out more than $50 billion annually for the treatment of patients with end-stage renal disease, and a hefty chunk of that money goes for oft-repeated procedures aimed at preserving the patency of the access sites.
“Primary patency rates leave much room for improvement,” observed Dr. Hussain, a vascular surgeon at the Christie Clinic in Champaign, Ill.
Indeed, the 50% primary patency rate at 6 months that was optimistically declared a “reasonable goal” in the 2006 Kidney Disease Outcomes Quality Initiative is actually far-fetched using the conventional tools.
“That 50% patency at 6 months would be a tall order to try to meet. Anybody in this room that does fistulography and angioplasty knows the numbers are actually a lot lower than 50%,” said Dr. Hussain.
Plain old balloon angioplasty, the standard first-line intervention for stenotic hemodialysis access sites, has a 6-month patency rate of about 30%. Bare metal stents push the rate up to about 39%. Covered stent grafts are the most effective of the conventional treatment modalities, with a 6-month patency of 51%-53%; however, they are widely considered too expensive for routine use.
Drug-coated balloons (DCBs) have been available for close to 3 years for treatment of lower extremity peripheral artery disease, where they have achieved considerable success. The Food and Drug Administration has approved three commercially available DCBs for this purpose: Bard’s Lutonix 035 AV, Medtronic’s IN.PACT Admiral, and most recently the Stellarex DCB.
In addition, the Lutonix DCB is approved for treatment of dysfunctional or stenotic arteriovenous (AV) fistulae on the strength of the positive results of the first prospective randomized multicenter trial of a DCB versus balloon angioplasty for AV access stenosis as reported at a conference in Leipzig, Germany, in 2017 and summarized by Dr. Hussain.
The pathophysiology of arterial atherosclerotic stenosis is very different from the stenosis that plagues AV access for dialysis. Arterial atherosclerotic stenosis is due to neointimal hyperplasia caused by inflammation and barotrauma secondary to angioplasty. In contrast, the neointimal hyperplasia in AV access stenosis is due to smooth muscle cell proliferation in response to nonphysiologic blood flow dynamics and shear forces between a high-pressure arterial system and the low-pressure venous system to which it has been connected, with resultant stenosis at the venous outflow anastomosis and often at the cephalic arch, Dr. Hussain explained.
Other contributors to the high rate of early stenosis in AV fistulae and grafts include traumatic balloon dilation, uremia, and repetitive traumatic needle insertion.
The breakthrough for DCBs as a potential game changer in dialysis access stenosis came with the discovery that venous smooth muscle cells are much more sensitive to paclitaxel and other antiproliferative drugs than are arterial smooth muscle cells. All three commercially available DCBs utilize paclitaxel as their active agent.
Multiple small single-center studies involving off-label use of the DCBs for dialysis access stenosis strongly suggested 6-month patency rates were higher than with balloon angioplasty. Then came the core lab-adjudicated Lutonix multicenter trial, in which 285 hemodialysis patients at 23 sites were randomized to the DCB or balloon angioplasty. Participants had to have a target lesion less than 10 cm long and had to undergo successful predilatation with high-pressure balloon angioplasty.
“The key thing to remember when we talk about dialysis grafts or fistulae is that we have to look at patency in periods of months. We can’t look at years because it’s pretty unusual to see a fistula stay open that long. So most of the time we’re trying to achieve extra months on these types of circuits,” noted Dr. Hussain.
That being said, the 8-month target lesion primary patency rate was 61.6% in the Lutonix DCB group, compared with 49.4% for percutaneous angioplasty, a statistically significant and clinically meaningful difference. Moreover, 66 interventions were required to maintain target lesion patency during that time frame in the DCB group, versus 94 in the angioplasty group; that translated to a 30% reduction in repeat interventions.
“This clearly has the potential to save a lot of money for the health care system,” he said.
The two forms of treatment were equally safe.
The expanded indication for the Lutonix DCB that resulted from this large randomized trial has triggered considerable research interest in DCBs for AV access stenosis around the world. Major ongoing randomized trials include the PAVE trial in the United Kingdom, the Spanish FISBOL trial, the APERTO trial in the Netherlands, and an Israeli randomized trial restricted to patients with cephalic arch stenosis.
Dr. Hussain is particularly excited about the ongoing 330-patient, prospective, multicenter, single-blinded clinical trial of the IN.PACT Admiral DCB versus plain balloon angioplasty. The Medtronic DCB employs a higher dosage of paclitaxel: 3.5 mcg/mm2, compared with 2.0 mcg/mm2 for the Lutonix DCB. Also, due to differences in the excipients used in the two DCBs, the paclitaxel from the IN.PACT device stays in the media of blood vessels for up to 180 days, compared with 60 days following drug delivery with the Lutonix balloon. Whether this longer period of close range antiproliferative activity will translate into a higher patency rate remains to be seen.
Dr. Hussain reported having no financial conflicts of interest regarding his presentation.
Costs associated with the management of patients with chronic kidney disease, particularly those with end-stage renal disease requiring hemodialysis, is a huge component of the Medicare budget. The maintenance of functional vascular access in these patients remains an ongoing challenge and reduction of costs related to access failure is critical to the continued funding of the program. Traditional methods of maintaining access patency such as balloon angioplasty and bare metal stents have poor long-term outcomes, and moderate improvement is seen with the use of covered stents.
Dr. Hussain reviews the current status of drug-coated balloons (DCB) in the endovascular treatment of dysfunctional hemodialysis fistulas and grafts. Safety and efficacy data from a prospective randomized multicenter trial comparing the Bard Lutonix DCB and plain old balloon angioplasty demonstrated a significant improvement in primary patency and a 30% reduction in repeat interventions with the DCB. This led to FDA approval for the Lutonix DCB in the treatment of dysfunctional or stenotic arteriovenous fistulas. Encouraged by these results, researchers conducting ongoing international randomized trials are attempting to clarify the potential expanded indications for DCB in access stenosis. Of particular interest is the ongoing 330-patient prospective, multicenter IN-PACT trial comparing Admiral DCB to balloon angioplasty in failing arteriovenous fistulas. Both the Admiral DCB and Lutonix DCB utilize paclitaxel as the antiproliferative agent. Dr. Hussain describes the increased sensitivity of venous smooth muscle cells to paclitaxel and other antiproliferative drugs when compared with arterial smooth muscle cells. This exciting finding may explain the improved outcomes in the treatment of dialysis access lesions where pathology frequently occurs at the venous anastomosis or in the venous conduit.
Although early results with the use of DCBs are promising, ongoing clinical trials and careful analysis of data and cost effectiveness are critical to optimize outcomes in treating dialysis access dysfunction. Dr. Hussain appropriately expresses cautious optimism regarding the future of hemodialysis access with this new tool available to interventionists treating these complex patients.
Larry A. Scher, MD, is a vascular surgeon at Montefiore Einstein Center for Heart and Vascular Care, New York, and an associate medical editor for Vascular Specialist.
Costs associated with the management of patients with chronic kidney disease, particularly those with end-stage renal disease requiring hemodialysis, is a huge component of the Medicare budget. The maintenance of functional vascular access in these patients remains an ongoing challenge and reduction of costs related to access failure is critical to the continued funding of the program. Traditional methods of maintaining access patency such as balloon angioplasty and bare metal stents have poor long-term outcomes, and moderate improvement is seen with the use of covered stents.
Dr. Hussain reviews the current status of drug-coated balloons (DCB) in the endovascular treatment of dysfunctional hemodialysis fistulas and grafts. Safety and efficacy data from a prospective randomized multicenter trial comparing the Bard Lutonix DCB and plain old balloon angioplasty demonstrated a significant improvement in primary patency and a 30% reduction in repeat interventions with the DCB. This led to FDA approval for the Lutonix DCB in the treatment of dysfunctional or stenotic arteriovenous fistulas. Encouraged by these results, researchers conducting ongoing international randomized trials are attempting to clarify the potential expanded indications for DCB in access stenosis. Of particular interest is the ongoing 330-patient prospective, multicenter IN-PACT trial comparing Admiral DCB to balloon angioplasty in failing arteriovenous fistulas. Both the Admiral DCB and Lutonix DCB utilize paclitaxel as the antiproliferative agent. Dr. Hussain describes the increased sensitivity of venous smooth muscle cells to paclitaxel and other antiproliferative drugs when compared with arterial smooth muscle cells. This exciting finding may explain the improved outcomes in the treatment of dialysis access lesions where pathology frequently occurs at the venous anastomosis or in the venous conduit.
Although early results with the use of DCBs are promising, ongoing clinical trials and careful analysis of data and cost effectiveness are critical to optimize outcomes in treating dialysis access dysfunction. Dr. Hussain appropriately expresses cautious optimism regarding the future of hemodialysis access with this new tool available to interventionists treating these complex patients.
Larry A. Scher, MD, is a vascular surgeon at Montefiore Einstein Center for Heart and Vascular Care, New York, and an associate medical editor for Vascular Specialist.
Costs associated with the management of patients with chronic kidney disease, particularly those with end-stage renal disease requiring hemodialysis, is a huge component of the Medicare budget. The maintenance of functional vascular access in these patients remains an ongoing challenge and reduction of costs related to access failure is critical to the continued funding of the program. Traditional methods of maintaining access patency such as balloon angioplasty and bare metal stents have poor long-term outcomes, and moderate improvement is seen with the use of covered stents.
Dr. Hussain reviews the current status of drug-coated balloons (DCB) in the endovascular treatment of dysfunctional hemodialysis fistulas and grafts. Safety and efficacy data from a prospective randomized multicenter trial comparing the Bard Lutonix DCB and plain old balloon angioplasty demonstrated a significant improvement in primary patency and a 30% reduction in repeat interventions with the DCB. This led to FDA approval for the Lutonix DCB in the treatment of dysfunctional or stenotic arteriovenous fistulas. Encouraged by these results, researchers conducting ongoing international randomized trials are attempting to clarify the potential expanded indications for DCB in access stenosis. Of particular interest is the ongoing 330-patient prospective, multicenter IN-PACT trial comparing Admiral DCB to balloon angioplasty in failing arteriovenous fistulas. Both the Admiral DCB and Lutonix DCB utilize paclitaxel as the antiproliferative agent. Dr. Hussain describes the increased sensitivity of venous smooth muscle cells to paclitaxel and other antiproliferative drugs when compared with arterial smooth muscle cells. This exciting finding may explain the improved outcomes in the treatment of dialysis access lesions where pathology frequently occurs at the venous anastomosis or in the venous conduit.
Although early results with the use of DCBs are promising, ongoing clinical trials and careful analysis of data and cost effectiveness are critical to optimize outcomes in treating dialysis access dysfunction. Dr. Hussain appropriately expresses cautious optimism regarding the future of hemodialysis access with this new tool available to interventionists treating these complex patients.
Larry A. Scher, MD, is a vascular surgeon at Montefiore Einstein Center for Heart and Vascular Care, New York, and an associate medical editor for Vascular Specialist.
CHICAGO – Drug-coated balloons show promise of being a long-sought major advance in the endovascular treatment of stenotic arteriovenous fistulae and grafts for hemodialysis access, Syed M. Hussain, MD, said at a symposium on vascular surgery sponsored by Northwestern University.
Something significantly better than today’s standard treatment options is needed, according to Dr. Hussain. Medicare pays out more than $50 billion annually for the treatment of patients with end-stage renal disease, and a hefty chunk of that money goes for oft-repeated procedures aimed at preserving the patency of the access sites.
“Primary patency rates leave much room for improvement,” observed Dr. Hussain, a vascular surgeon at the Christie Clinic in Champaign, Ill.
Indeed, the 50% primary patency rate at 6 months that was optimistically declared a “reasonable goal” in the 2006 Kidney Disease Outcomes Quality Initiative is actually far-fetched using the conventional tools.
“That 50% patency at 6 months would be a tall order to try to meet. Anybody in this room that does fistulography and angioplasty knows the numbers are actually a lot lower than 50%,” said Dr. Hussain.
Plain old balloon angioplasty, the standard first-line intervention for stenotic hemodialysis access sites, has a 6-month patency rate of about 30%. Bare metal stents push the rate up to about 39%. Covered stent grafts are the most effective of the conventional treatment modalities, with a 6-month patency of 51%-53%; however, they are widely considered too expensive for routine use.
Drug-coated balloons (DCBs) have been available for close to 3 years for treatment of lower extremity peripheral artery disease, where they have achieved considerable success. The Food and Drug Administration has approved three commercially available DCBs for this purpose: Bard’s Lutonix 035 AV, Medtronic’s IN.PACT Admiral, and most recently the Stellarex DCB.
In addition, the Lutonix DCB is approved for treatment of dysfunctional or stenotic arteriovenous (AV) fistulae on the strength of the positive results of the first prospective randomized multicenter trial of a DCB versus balloon angioplasty for AV access stenosis as reported at a conference in Leipzig, Germany, in 2017 and summarized by Dr. Hussain.
The pathophysiology of arterial atherosclerotic stenosis is very different from the stenosis that plagues AV access for dialysis. Arterial atherosclerotic stenosis is due to neointimal hyperplasia caused by inflammation and barotrauma secondary to angioplasty. In contrast, the neointimal hyperplasia in AV access stenosis is due to smooth muscle cell proliferation in response to nonphysiologic blood flow dynamics and shear forces between a high-pressure arterial system and the low-pressure venous system to which it has been connected, with resultant stenosis at the venous outflow anastomosis and often at the cephalic arch, Dr. Hussain explained.
Other contributors to the high rate of early stenosis in AV fistulae and grafts include traumatic balloon dilation, uremia, and repetitive traumatic needle insertion.
The breakthrough for DCBs as a potential game changer in dialysis access stenosis came with the discovery that venous smooth muscle cells are much more sensitive to paclitaxel and other antiproliferative drugs than are arterial smooth muscle cells. All three commercially available DCBs utilize paclitaxel as their active agent.
Multiple small single-center studies involving off-label use of the DCBs for dialysis access stenosis strongly suggested 6-month patency rates were higher than with balloon angioplasty. Then came the core lab-adjudicated Lutonix multicenter trial, in which 285 hemodialysis patients at 23 sites were randomized to the DCB or balloon angioplasty. Participants had to have a target lesion less than 10 cm long and had to undergo successful predilatation with high-pressure balloon angioplasty.
“The key thing to remember when we talk about dialysis grafts or fistulae is that we have to look at patency in periods of months. We can’t look at years because it’s pretty unusual to see a fistula stay open that long. So most of the time we’re trying to achieve extra months on these types of circuits,” noted Dr. Hussain.
That being said, the 8-month target lesion primary patency rate was 61.6% in the Lutonix DCB group, compared with 49.4% for percutaneous angioplasty, a statistically significant and clinically meaningful difference. Moreover, 66 interventions were required to maintain target lesion patency during that time frame in the DCB group, versus 94 in the angioplasty group; that translated to a 30% reduction in repeat interventions.
“This clearly has the potential to save a lot of money for the health care system,” he said.
The two forms of treatment were equally safe.
The expanded indication for the Lutonix DCB that resulted from this large randomized trial has triggered considerable research interest in DCBs for AV access stenosis around the world. Major ongoing randomized trials include the PAVE trial in the United Kingdom, the Spanish FISBOL trial, the APERTO trial in the Netherlands, and an Israeli randomized trial restricted to patients with cephalic arch stenosis.
Dr. Hussain is particularly excited about the ongoing 330-patient, prospective, multicenter, single-blinded clinical trial of the IN.PACT Admiral DCB versus plain balloon angioplasty. The Medtronic DCB employs a higher dosage of paclitaxel: 3.5 mcg/mm2, compared with 2.0 mcg/mm2 for the Lutonix DCB. Also, due to differences in the excipients used in the two DCBs, the paclitaxel from the IN.PACT device stays in the media of blood vessels for up to 180 days, compared with 60 days following drug delivery with the Lutonix balloon. Whether this longer period of close range antiproliferative activity will translate into a higher patency rate remains to be seen.
Dr. Hussain reported having no financial conflicts of interest regarding his presentation.
CHICAGO – Drug-coated balloons show promise of being a long-sought major advance in the endovascular treatment of stenotic arteriovenous fistulae and grafts for hemodialysis access, Syed M. Hussain, MD, said at a symposium on vascular surgery sponsored by Northwestern University.
Something significantly better than today’s standard treatment options is needed, according to Dr. Hussain. Medicare pays out more than $50 billion annually for the treatment of patients with end-stage renal disease, and a hefty chunk of that money goes for oft-repeated procedures aimed at preserving the patency of the access sites.
“Primary patency rates leave much room for improvement,” observed Dr. Hussain, a vascular surgeon at the Christie Clinic in Champaign, Ill.
Indeed, the 50% primary patency rate at 6 months that was optimistically declared a “reasonable goal” in the 2006 Kidney Disease Outcomes Quality Initiative is actually far-fetched using the conventional tools.
“That 50% patency at 6 months would be a tall order to try to meet. Anybody in this room that does fistulography and angioplasty knows the numbers are actually a lot lower than 50%,” said Dr. Hussain.
Plain old balloon angioplasty, the standard first-line intervention for stenotic hemodialysis access sites, has a 6-month patency rate of about 30%. Bare metal stents push the rate up to about 39%. Covered stent grafts are the most effective of the conventional treatment modalities, with a 6-month patency of 51%-53%; however, they are widely considered too expensive for routine use.
Drug-coated balloons (DCBs) have been available for close to 3 years for treatment of lower extremity peripheral artery disease, where they have achieved considerable success. The Food and Drug Administration has approved three commercially available DCBs for this purpose: Bard’s Lutonix 035 AV, Medtronic’s IN.PACT Admiral, and most recently the Stellarex DCB.
In addition, the Lutonix DCB is approved for treatment of dysfunctional or stenotic arteriovenous (AV) fistulae on the strength of the positive results of the first prospective randomized multicenter trial of a DCB versus balloon angioplasty for AV access stenosis as reported at a conference in Leipzig, Germany, in 2017 and summarized by Dr. Hussain.
The pathophysiology of arterial atherosclerotic stenosis is very different from the stenosis that plagues AV access for dialysis. Arterial atherosclerotic stenosis is due to neointimal hyperplasia caused by inflammation and barotrauma secondary to angioplasty. In contrast, the neointimal hyperplasia in AV access stenosis is due to smooth muscle cell proliferation in response to nonphysiologic blood flow dynamics and shear forces between a high-pressure arterial system and the low-pressure venous system to which it has been connected, with resultant stenosis at the venous outflow anastomosis and often at the cephalic arch, Dr. Hussain explained.
Other contributors to the high rate of early stenosis in AV fistulae and grafts include traumatic balloon dilation, uremia, and repetitive traumatic needle insertion.
The breakthrough for DCBs as a potential game changer in dialysis access stenosis came with the discovery that venous smooth muscle cells are much more sensitive to paclitaxel and other antiproliferative drugs than are arterial smooth muscle cells. All three commercially available DCBs utilize paclitaxel as their active agent.
Multiple small single-center studies involving off-label use of the DCBs for dialysis access stenosis strongly suggested 6-month patency rates were higher than with balloon angioplasty. Then came the core lab-adjudicated Lutonix multicenter trial, in which 285 hemodialysis patients at 23 sites were randomized to the DCB or balloon angioplasty. Participants had to have a target lesion less than 10 cm long and had to undergo successful predilatation with high-pressure balloon angioplasty.
“The key thing to remember when we talk about dialysis grafts or fistulae is that we have to look at patency in periods of months. We can’t look at years because it’s pretty unusual to see a fistula stay open that long. So most of the time we’re trying to achieve extra months on these types of circuits,” noted Dr. Hussain.
That being said, the 8-month target lesion primary patency rate was 61.6% in the Lutonix DCB group, compared with 49.4% for percutaneous angioplasty, a statistically significant and clinically meaningful difference. Moreover, 66 interventions were required to maintain target lesion patency during that time frame in the DCB group, versus 94 in the angioplasty group; that translated to a 30% reduction in repeat interventions.
“This clearly has the potential to save a lot of money for the health care system,” he said.
The two forms of treatment were equally safe.
The expanded indication for the Lutonix DCB that resulted from this large randomized trial has triggered considerable research interest in DCBs for AV access stenosis around the world. Major ongoing randomized trials include the PAVE trial in the United Kingdom, the Spanish FISBOL trial, the APERTO trial in the Netherlands, and an Israeli randomized trial restricted to patients with cephalic arch stenosis.
Dr. Hussain is particularly excited about the ongoing 330-patient, prospective, multicenter, single-blinded clinical trial of the IN.PACT Admiral DCB versus plain balloon angioplasty. The Medtronic DCB employs a higher dosage of paclitaxel: 3.5 mcg/mm2, compared with 2.0 mcg/mm2 for the Lutonix DCB. Also, due to differences in the excipients used in the two DCBs, the paclitaxel from the IN.PACT device stays in the media of blood vessels for up to 180 days, compared with 60 days following drug delivery with the Lutonix balloon. Whether this longer period of close range antiproliferative activity will translate into a higher patency rate remains to be seen.
Dr. Hussain reported having no financial conflicts of interest regarding his presentation.
EXPERT ANALYSIS FROM THE NORTHWESTERN VASCULAR SYMPOSIUM
Early endovenous ablation speeds venous ulcer healing
Intervening early with endovenous ablation in patients with venous leg ulcers could significantly improve ulcer healing times and delay their recurrence, new research has found.
A randomized study presented at the International Charing Cross Symposium and published simultaneously in the April 24 issue of the New England Journal of Medicine compared the effects of early endovenous ablation with those of deferred ablation in 450 patients with venous leg ulcers, all of whom also received compression therapy.
The study showed that patients who received endovenous ablation within 2 weeks of randomization had significantly shorter healing times, compared with patients whose ablation was deferred for 6 months or until after the ulcer healed.
In the early-treatment group, the median time to ulcer healing was 56 days, while in the deferred-treatment group, it was 82 days. By 12 months, 93.8% of the early-intervention group had healed ulcers, compared with 85.8% in the deferred-intervention group.
Even after adjustment for factors such as patient age, ulcer size, ulcer duration, and recruitment center, patients who received early endovenous ablation were 38% more likely to have healed by 12 months, compared with the deferred-intervention group.
Researchers also saw significantly higher healing rates at 12 weeks in the early-intervention group, compared with the deferred-intervention group (63.5% vs. 51.6%, respectively).
“Observational studies have suggested that endovenous treatment of varicose veins – a treatment that may be particularly appropriate for the elderly population with venous leg ulcers – may improve ulcer healing,” wrote Manjit S. Gohel, MD, from the Cambridge (United Kingdom) University Hospitals NHS Foundation Trust and from Imperial College London and his coauthors. “In the current trial, we found that faster ulcer healing can be attained if an endovenous intervention is performed promptly.”
Early endovenous ablation also was associated with a delay in the recurrence of ulcers. The rate of recurrence was 11.4% among patients in the early-intervention group whose ulcers had healed and 16.5% among those in the delayed-intervention group whose ulcers had healed.
Patients who received the early endovenous ablation had a median ulcer-free time of 306 days, compared with 278 days in the delayed-intervention group, a significant difference.
The authors noted that all patients in the study also received high-quality compression therapy, which may account for the good healing rates seen in both groups that might not otherwise be observed in a real-world clinical setting.
“Accordingly, the improvement in ulcer healing with early endovenous intervention is likely to be greater in clinical practice than was observed in this trial,” the authors wrote. “Because endovenous intervention is usually performed as a single procedure, the clinical benefits are likely to be less dependent on ongoing patient adherence than they would be with compression therapy.”
The most common method for endovenous ablation used in this multicenter study was ultrasound-guided foam sclerotherapy, a minimally-invasive procedure the authors said had versatility and acceptability.
However, they commented that some previous, large randomized trials have suggested that the rates of complete venous occlusion are lower with foam sclerotherapy than with thermal ablation.
The main complications seen with endovenous ablation were pain and deep vein thrombosis.
The authors pointed out that two limitations of their trial were that patients with a leg ulcer that had been present for more than 6 months were excluded from patient selection and that the 450 patients enrolled had been selected from a larger group of around 6,500.
The study was supported by a grant from the National Institute for Health Research Health Technology Assessment Program. One author declared grants from a pharmaceutical company outside the submitted work, and seven declared funding from the NIHR as part of the conduct of the study. No other conflicts of interest were declared.
SOURCE: Gohel MS et al. NEJM. 2018 April 24. doi: 10.1056/NEJMoa1801214
Finally! A randomized controlled trial (RCT) which proves what we all kind of expected but which until now was unsupported by available literature. That is that endovenous ablation (EVA) in the presence of a concomitant venous ulcer not only decreases ulcer recurrence rates and increases ulcer-free time, it also significantly hastens ulcer healing times. I don’t know about you, but it always made sense to me that treatment of an incompetent saphenous vein, a known cause of ulceration, could be a factor in the time to ulcer healing.
But that’s what a whole host of retrospective and or nonrandomized studies seemed to suggest: Garbage in, garbage out. Enter the RCT – Issue resolved? Yes, with some caveats, and maybe no.
First, as the authors readily admit, the compression therapy which was applied to patients in both arms of the study was of “high quality” and would not likely be reproduced in real world practice. The authors also suggest that, in a real-world, clinical practice, the benefits of early EVA may prove to be even more pronounced because of poor patient compliance with compression. Not sure about that. In fact, if – in a real-world setting – the rate of compliance with compression in both groups turned out to be less than optimal, particularly in the patients who had EVA, the benefits of early ablation with respect to ulcer healing times might disappear.
In other words, we do not know from this study whether there would be the same advantages to early saphenous vein intervention without the addition of compression as compared with compression alone. This might explain why shorter ulcer healing times of EVA have been difficult to prove in non-RCT, more real-world studies. Perhaps a randomized trial comparing ulcer healing times with early EVA without compression versus compression therapy only? Hmmm.
Also, would the outcomes of the current study be similar on this side of the pond? Only 31.7% of limbs were treated with endothermal ablation only, by far the most common form of ablation performed in the United States. Almost 65% of limbs in the study were ablated with either foamed sclerotherapy alone or in conjunction with endothermal or mechanical modalities – not a common form of treatment here in the colonies. Inexplicably, the authors do not indicate whether outcomes were in any way influenced by the type of ablation performed. I am going to assume for now that it did not.
In summary, this study does not answer all the questions related to the use of EVA for the treatment of venous ulcers, but it comes pretty close. My take away is that there is no downside (or none that I can think of) to the use of EVA early on in the treatment of venous ulcers but a whole lot of potential upside for the patient. Now I, and probably you, have proof that what we were already doing really does have some increased benefit. Finally!
Alan M Dietzek, MD, is the Linda and Stephen R. Cohen Chair in Vascular Surgery at Danbury (Conn.) Hospital and a clinical professor of surgery at the University of Vermont, Burlington. He is also an associate medical editor for Vascular Specialist.
Finally! A randomized controlled trial (RCT) which proves what we all kind of expected but which until now was unsupported by available literature. That is that endovenous ablation (EVA) in the presence of a concomitant venous ulcer not only decreases ulcer recurrence rates and increases ulcer-free time, it also significantly hastens ulcer healing times. I don’t know about you, but it always made sense to me that treatment of an incompetent saphenous vein, a known cause of ulceration, could be a factor in the time to ulcer healing.
But that’s what a whole host of retrospective and or nonrandomized studies seemed to suggest: Garbage in, garbage out. Enter the RCT – Issue resolved? Yes, with some caveats, and maybe no.
First, as the authors readily admit, the compression therapy which was applied to patients in both arms of the study was of “high quality” and would not likely be reproduced in real world practice. The authors also suggest that, in a real-world, clinical practice, the benefits of early EVA may prove to be even more pronounced because of poor patient compliance with compression. Not sure about that. In fact, if – in a real-world setting – the rate of compliance with compression in both groups turned out to be less than optimal, particularly in the patients who had EVA, the benefits of early ablation with respect to ulcer healing times might disappear.
In other words, we do not know from this study whether there would be the same advantages to early saphenous vein intervention without the addition of compression as compared with compression alone. This might explain why shorter ulcer healing times of EVA have been difficult to prove in non-RCT, more real-world studies. Perhaps a randomized trial comparing ulcer healing times with early EVA without compression versus compression therapy only? Hmmm.
Also, would the outcomes of the current study be similar on this side of the pond? Only 31.7% of limbs were treated with endothermal ablation only, by far the most common form of ablation performed in the United States. Almost 65% of limbs in the study were ablated with either foamed sclerotherapy alone or in conjunction with endothermal or mechanical modalities – not a common form of treatment here in the colonies. Inexplicably, the authors do not indicate whether outcomes were in any way influenced by the type of ablation performed. I am going to assume for now that it did not.
In summary, this study does not answer all the questions related to the use of EVA for the treatment of venous ulcers, but it comes pretty close. My take away is that there is no downside (or none that I can think of) to the use of EVA early on in the treatment of venous ulcers but a whole lot of potential upside for the patient. Now I, and probably you, have proof that what we were already doing really does have some increased benefit. Finally!
Alan M Dietzek, MD, is the Linda and Stephen R. Cohen Chair in Vascular Surgery at Danbury (Conn.) Hospital and a clinical professor of surgery at the University of Vermont, Burlington. He is also an associate medical editor for Vascular Specialist.
Finally! A randomized controlled trial (RCT) which proves what we all kind of expected but which until now was unsupported by available literature. That is that endovenous ablation (EVA) in the presence of a concomitant venous ulcer not only decreases ulcer recurrence rates and increases ulcer-free time, it also significantly hastens ulcer healing times. I don’t know about you, but it always made sense to me that treatment of an incompetent saphenous vein, a known cause of ulceration, could be a factor in the time to ulcer healing.
But that’s what a whole host of retrospective and or nonrandomized studies seemed to suggest: Garbage in, garbage out. Enter the RCT – Issue resolved? Yes, with some caveats, and maybe no.
First, as the authors readily admit, the compression therapy which was applied to patients in both arms of the study was of “high quality” and would not likely be reproduced in real world practice. The authors also suggest that, in a real-world, clinical practice, the benefits of early EVA may prove to be even more pronounced because of poor patient compliance with compression. Not sure about that. In fact, if – in a real-world setting – the rate of compliance with compression in both groups turned out to be less than optimal, particularly in the patients who had EVA, the benefits of early ablation with respect to ulcer healing times might disappear.
In other words, we do not know from this study whether there would be the same advantages to early saphenous vein intervention without the addition of compression as compared with compression alone. This might explain why shorter ulcer healing times of EVA have been difficult to prove in non-RCT, more real-world studies. Perhaps a randomized trial comparing ulcer healing times with early EVA without compression versus compression therapy only? Hmmm.
Also, would the outcomes of the current study be similar on this side of the pond? Only 31.7% of limbs were treated with endothermal ablation only, by far the most common form of ablation performed in the United States. Almost 65% of limbs in the study were ablated with either foamed sclerotherapy alone or in conjunction with endothermal or mechanical modalities – not a common form of treatment here in the colonies. Inexplicably, the authors do not indicate whether outcomes were in any way influenced by the type of ablation performed. I am going to assume for now that it did not.
In summary, this study does not answer all the questions related to the use of EVA for the treatment of venous ulcers, but it comes pretty close. My take away is that there is no downside (or none that I can think of) to the use of EVA early on in the treatment of venous ulcers but a whole lot of potential upside for the patient. Now I, and probably you, have proof that what we were already doing really does have some increased benefit. Finally!
Alan M Dietzek, MD, is the Linda and Stephen R. Cohen Chair in Vascular Surgery at Danbury (Conn.) Hospital and a clinical professor of surgery at the University of Vermont, Burlington. He is also an associate medical editor for Vascular Specialist.
Intervening early with endovenous ablation in patients with venous leg ulcers could significantly improve ulcer healing times and delay their recurrence, new research has found.
A randomized study presented at the International Charing Cross Symposium and published simultaneously in the April 24 issue of the New England Journal of Medicine compared the effects of early endovenous ablation with those of deferred ablation in 450 patients with venous leg ulcers, all of whom also received compression therapy.
The study showed that patients who received endovenous ablation within 2 weeks of randomization had significantly shorter healing times, compared with patients whose ablation was deferred for 6 months or until after the ulcer healed.
In the early-treatment group, the median time to ulcer healing was 56 days, while in the deferred-treatment group, it was 82 days. By 12 months, 93.8% of the early-intervention group had healed ulcers, compared with 85.8% in the deferred-intervention group.
Even after adjustment for factors such as patient age, ulcer size, ulcer duration, and recruitment center, patients who received early endovenous ablation were 38% more likely to have healed by 12 months, compared with the deferred-intervention group.
Researchers also saw significantly higher healing rates at 12 weeks in the early-intervention group, compared with the deferred-intervention group (63.5% vs. 51.6%, respectively).
“Observational studies have suggested that endovenous treatment of varicose veins – a treatment that may be particularly appropriate for the elderly population with venous leg ulcers – may improve ulcer healing,” wrote Manjit S. Gohel, MD, from the Cambridge (United Kingdom) University Hospitals NHS Foundation Trust and from Imperial College London and his coauthors. “In the current trial, we found that faster ulcer healing can be attained if an endovenous intervention is performed promptly.”
Early endovenous ablation also was associated with a delay in the recurrence of ulcers. The rate of recurrence was 11.4% among patients in the early-intervention group whose ulcers had healed and 16.5% among those in the delayed-intervention group whose ulcers had healed.
Patients who received the early endovenous ablation had a median ulcer-free time of 306 days, compared with 278 days in the delayed-intervention group, a significant difference.
The authors noted that all patients in the study also received high-quality compression therapy, which may account for the good healing rates seen in both groups that might not otherwise be observed in a real-world clinical setting.
“Accordingly, the improvement in ulcer healing with early endovenous intervention is likely to be greater in clinical practice than was observed in this trial,” the authors wrote. “Because endovenous intervention is usually performed as a single procedure, the clinical benefits are likely to be less dependent on ongoing patient adherence than they would be with compression therapy.”
The most common method for endovenous ablation used in this multicenter study was ultrasound-guided foam sclerotherapy, a minimally-invasive procedure the authors said had versatility and acceptability.
However, they commented that some previous, large randomized trials have suggested that the rates of complete venous occlusion are lower with foam sclerotherapy than with thermal ablation.
The main complications seen with endovenous ablation were pain and deep vein thrombosis.
The authors pointed out that two limitations of their trial were that patients with a leg ulcer that had been present for more than 6 months were excluded from patient selection and that the 450 patients enrolled had been selected from a larger group of around 6,500.
The study was supported by a grant from the National Institute for Health Research Health Technology Assessment Program. One author declared grants from a pharmaceutical company outside the submitted work, and seven declared funding from the NIHR as part of the conduct of the study. No other conflicts of interest were declared.
SOURCE: Gohel MS et al. NEJM. 2018 April 24. doi: 10.1056/NEJMoa1801214
Intervening early with endovenous ablation in patients with venous leg ulcers could significantly improve ulcer healing times and delay their recurrence, new research has found.
A randomized study presented at the International Charing Cross Symposium and published simultaneously in the April 24 issue of the New England Journal of Medicine compared the effects of early endovenous ablation with those of deferred ablation in 450 patients with venous leg ulcers, all of whom also received compression therapy.
The study showed that patients who received endovenous ablation within 2 weeks of randomization had significantly shorter healing times, compared with patients whose ablation was deferred for 6 months or until after the ulcer healed.
In the early-treatment group, the median time to ulcer healing was 56 days, while in the deferred-treatment group, it was 82 days. By 12 months, 93.8% of the early-intervention group had healed ulcers, compared with 85.8% in the deferred-intervention group.
Even after adjustment for factors such as patient age, ulcer size, ulcer duration, and recruitment center, patients who received early endovenous ablation were 38% more likely to have healed by 12 months, compared with the deferred-intervention group.
Researchers also saw significantly higher healing rates at 12 weeks in the early-intervention group, compared with the deferred-intervention group (63.5% vs. 51.6%, respectively).
“Observational studies have suggested that endovenous treatment of varicose veins – a treatment that may be particularly appropriate for the elderly population with venous leg ulcers – may improve ulcer healing,” wrote Manjit S. Gohel, MD, from the Cambridge (United Kingdom) University Hospitals NHS Foundation Trust and from Imperial College London and his coauthors. “In the current trial, we found that faster ulcer healing can be attained if an endovenous intervention is performed promptly.”
Early endovenous ablation also was associated with a delay in the recurrence of ulcers. The rate of recurrence was 11.4% among patients in the early-intervention group whose ulcers had healed and 16.5% among those in the delayed-intervention group whose ulcers had healed.
Patients who received the early endovenous ablation had a median ulcer-free time of 306 days, compared with 278 days in the delayed-intervention group, a significant difference.
The authors noted that all patients in the study also received high-quality compression therapy, which may account for the good healing rates seen in both groups that might not otherwise be observed in a real-world clinical setting.
“Accordingly, the improvement in ulcer healing with early endovenous intervention is likely to be greater in clinical practice than was observed in this trial,” the authors wrote. “Because endovenous intervention is usually performed as a single procedure, the clinical benefits are likely to be less dependent on ongoing patient adherence than they would be with compression therapy.”
The most common method for endovenous ablation used in this multicenter study was ultrasound-guided foam sclerotherapy, a minimally-invasive procedure the authors said had versatility and acceptability.
However, they commented that some previous, large randomized trials have suggested that the rates of complete venous occlusion are lower with foam sclerotherapy than with thermal ablation.
The main complications seen with endovenous ablation were pain and deep vein thrombosis.
The authors pointed out that two limitations of their trial were that patients with a leg ulcer that had been present for more than 6 months were excluded from patient selection and that the 450 patients enrolled had been selected from a larger group of around 6,500.
The study was supported by a grant from the National Institute for Health Research Health Technology Assessment Program. One author declared grants from a pharmaceutical company outside the submitted work, and seven declared funding from the NIHR as part of the conduct of the study. No other conflicts of interest were declared.
SOURCE: Gohel MS et al. NEJM. 2018 April 24. doi: 10.1056/NEJMoa1801214
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Early endovenous ablation can speed healing of venous ulcers.
Major finding: Median ulcer healing time was 56 days with early venous ablation, compared with 82 days with deferred ablation.
Study details: Randomized controlled trial in 450 patients with venous leg ulcers.
Disclosures: The study was supported by a grant from the National Institute for Health Research Health Technology Assessment Program. One author declared grants from a pharmaceutical company outside the submitted work, and seven declared funding from the NIHR as part of the conduct of the study. No other conflicts of interest were declared.
Source: Gohel M et al. NEJM. 2018 April 24. doi: 10.1056/NEJMoa1801214
Controversy surrounds calf vein thrombosis treatment
CHICAGO – The use of therapeutic-dose anticoagulation in hospitalized patients with calf vein thrombosis significantly reduces the risk of venous thromboembolic complications, compared with lower-dose prophylactic anticoagulation or surveillance alone, Heron E. Rodriguez, MD, said at a symposium on vascular surgery sponsored by Northwestern University.
Moreover, placement of an inferior vena cava filter in patients with calf vein thrombosis when anticoagulation is contraindicated accomplishes nothing beneficial and had a 10% complication rate in a large retrospective single-center study, added Dr. Rodriguez of Northwestern University, Chicago.
Deep vein thrombosis (DVT) remains a significant source of morbidity and mortality despite worldwide awareness of the problem.
“Specifically, calf vein thrombosis [CVT] is very common, and we know that in some series up to 30% of patients end up propagating proximally if they’re not treated, and a good number of them develop chronic venous insufficiency, with long-term consequences,” he noted.
“Unfortunately there is no consensus regarding treatment. The guidelines are very vague. For example, there is no mention [in current American College of Chest Physicians guidelines] of how to manage muscular vein thrombosis and much ambiguity on how to treat calf vein thrombosis,” he continued.
Dr. Rodriguez cited as an indication of the lack of consensus on management of CVT a single-institution survey by other investigators of the practices of physicians in various specialties. Forty-nine percent of respondents indicated they anticoagulate patients with CVT; 51% don’t. Of those who did, 62% prescribed low-molecular-weight heparin and 11% intravenous heparin. Fifty-eight percent of physicians who anticoagulated did so for 3 months, 30% for 6. And 46% of physicians used an inferior vena cava (IVC) filter when anticoagulation was contraindicated (Vascular. 2014 Apr;22[2]:93-7).
That rate of IVC placement “seemed really high” given the paucity of supporting evidence for safety and efficacy of filter placement in the setting of CVT, so Dr. Rodriguez and coinvestigators decided to conduct a retrospective review of practices at Northwestern Memorial Hospital. He explained the study hypothesis: “Our thinking was that these kinds of thrombi are associated with low risk of propagation and pulmonary embolism, and they can and should be managed conservatively.”
Of 647 patients with isolated thrombosis of the anterior and posterior tibial, soleal, peroneal, or gastrocnemius veins, 44% received an IVC filter, and the rest got medical treatment alone. Of the 362 patients managed medically, 49% received therapeutic anticoagulation, 12% got low-dose prophylactic anticoagulation, and 39% underwent surveillance without anticoagulation.
The primary outcome was the incidence of venous thromboembolic complications – that is, propagation of DVT or pulmonary embolism. The incidence was 35% in the surveillance-only group, 30% with prophylactic anticoagulation, and 10% in patients who got therapeutic anticoagulation.
Of note, the rate of the most feared complication, pulmonary embolism, was low and similar in the filter recipients and medically managed group: 2.5% in the IVC group, 3.3% with medical management.
“Distal vein thromboses have low rates of pulmonary embolism, regardless of whether or not they are so-called protected with a filter. On the other hand, a filter was associated with a 10% rate of complications. I have to make clear that these were radiographic abnormalities – tilting, migration, caval perforation – that didn’t have clinical consequences, but we were very aggressive in removing the IVC filters, and I’m guessing if they’d been left inside they would create problems in the long term,” Dr. Rodriguez said.
An important point about this study is that these were all sick patients, and most were hospitalized. The filter recipients and medical groups differed in key ways. For example, 49% of the filter patients had a malignancy, and 56% had a baseline history of venous thromboembolic events, compared with 26% and 16%, respectively, of the medical group. For that reason, the investigators performed propensity score matching and came up with 157 closely matched patient pairs. The outcomes remained unchanged.
Of course, this was a retrospective study, with its inherent limitations, but Dr. Rodriguez characterized the published randomized trials on management of CVT as “small and limited.” The most frequently quoted study is the double-blind multicenter CACTUS trial, which randomized 252 outpatients with symptomatic CVT to 6 weeks of low-molecular-weight heparin or placebo and found no difference in the rates of proximal extension of venous thromboembolic events (Lancet Haematol. 2016 Dec;3[12]:e556-62). But these were all low-risk patients. Prior DVT or malignancy were exclusion criteria, so this was a very different population than treated at Northwestern.
Based upon the results of the retrospective study at Northwestern, which have been published (J Vasc Surg Venous Lymphat Disord. 2017 Jan;5[1]:25-32), the vascular surgery service has developed a management algorithm for DVT management based upon the lesion site. If a patient is unable to undergo anticoagulation, venous duplex ultrasound is repeated at 1 week. If the imaging shows propagation into the popliteal vein and anticoagulation remains contraindicated, only then is placement of an IVC filter warranted.
Dr. Rodriguez reported serving as a paid speaker for Abbott, Endologix, and W.L. Gore.
CHICAGO – The use of therapeutic-dose anticoagulation in hospitalized patients with calf vein thrombosis significantly reduces the risk of venous thromboembolic complications, compared with lower-dose prophylactic anticoagulation or surveillance alone, Heron E. Rodriguez, MD, said at a symposium on vascular surgery sponsored by Northwestern University.
Moreover, placement of an inferior vena cava filter in patients with calf vein thrombosis when anticoagulation is contraindicated accomplishes nothing beneficial and had a 10% complication rate in a large retrospective single-center study, added Dr. Rodriguez of Northwestern University, Chicago.
Deep vein thrombosis (DVT) remains a significant source of morbidity and mortality despite worldwide awareness of the problem.
“Specifically, calf vein thrombosis [CVT] is very common, and we know that in some series up to 30% of patients end up propagating proximally if they’re not treated, and a good number of them develop chronic venous insufficiency, with long-term consequences,” he noted.
“Unfortunately there is no consensus regarding treatment. The guidelines are very vague. For example, there is no mention [in current American College of Chest Physicians guidelines] of how to manage muscular vein thrombosis and much ambiguity on how to treat calf vein thrombosis,” he continued.
Dr. Rodriguez cited as an indication of the lack of consensus on management of CVT a single-institution survey by other investigators of the practices of physicians in various specialties. Forty-nine percent of respondents indicated they anticoagulate patients with CVT; 51% don’t. Of those who did, 62% prescribed low-molecular-weight heparin and 11% intravenous heparin. Fifty-eight percent of physicians who anticoagulated did so for 3 months, 30% for 6. And 46% of physicians used an inferior vena cava (IVC) filter when anticoagulation was contraindicated (Vascular. 2014 Apr;22[2]:93-7).
That rate of IVC placement “seemed really high” given the paucity of supporting evidence for safety and efficacy of filter placement in the setting of CVT, so Dr. Rodriguez and coinvestigators decided to conduct a retrospective review of practices at Northwestern Memorial Hospital. He explained the study hypothesis: “Our thinking was that these kinds of thrombi are associated with low risk of propagation and pulmonary embolism, and they can and should be managed conservatively.”
Of 647 patients with isolated thrombosis of the anterior and posterior tibial, soleal, peroneal, or gastrocnemius veins, 44% received an IVC filter, and the rest got medical treatment alone. Of the 362 patients managed medically, 49% received therapeutic anticoagulation, 12% got low-dose prophylactic anticoagulation, and 39% underwent surveillance without anticoagulation.
The primary outcome was the incidence of venous thromboembolic complications – that is, propagation of DVT or pulmonary embolism. The incidence was 35% in the surveillance-only group, 30% with prophylactic anticoagulation, and 10% in patients who got therapeutic anticoagulation.
Of note, the rate of the most feared complication, pulmonary embolism, was low and similar in the filter recipients and medically managed group: 2.5% in the IVC group, 3.3% with medical management.
“Distal vein thromboses have low rates of pulmonary embolism, regardless of whether or not they are so-called protected with a filter. On the other hand, a filter was associated with a 10% rate of complications. I have to make clear that these were radiographic abnormalities – tilting, migration, caval perforation – that didn’t have clinical consequences, but we were very aggressive in removing the IVC filters, and I’m guessing if they’d been left inside they would create problems in the long term,” Dr. Rodriguez said.
An important point about this study is that these were all sick patients, and most were hospitalized. The filter recipients and medical groups differed in key ways. For example, 49% of the filter patients had a malignancy, and 56% had a baseline history of venous thromboembolic events, compared with 26% and 16%, respectively, of the medical group. For that reason, the investigators performed propensity score matching and came up with 157 closely matched patient pairs. The outcomes remained unchanged.
Of course, this was a retrospective study, with its inherent limitations, but Dr. Rodriguez characterized the published randomized trials on management of CVT as “small and limited.” The most frequently quoted study is the double-blind multicenter CACTUS trial, which randomized 252 outpatients with symptomatic CVT to 6 weeks of low-molecular-weight heparin or placebo and found no difference in the rates of proximal extension of venous thromboembolic events (Lancet Haematol. 2016 Dec;3[12]:e556-62). But these were all low-risk patients. Prior DVT or malignancy were exclusion criteria, so this was a very different population than treated at Northwestern.
Based upon the results of the retrospective study at Northwestern, which have been published (J Vasc Surg Venous Lymphat Disord. 2017 Jan;5[1]:25-32), the vascular surgery service has developed a management algorithm for DVT management based upon the lesion site. If a patient is unable to undergo anticoagulation, venous duplex ultrasound is repeated at 1 week. If the imaging shows propagation into the popliteal vein and anticoagulation remains contraindicated, only then is placement of an IVC filter warranted.
Dr. Rodriguez reported serving as a paid speaker for Abbott, Endologix, and W.L. Gore.
CHICAGO – The use of therapeutic-dose anticoagulation in hospitalized patients with calf vein thrombosis significantly reduces the risk of venous thromboembolic complications, compared with lower-dose prophylactic anticoagulation or surveillance alone, Heron E. Rodriguez, MD, said at a symposium on vascular surgery sponsored by Northwestern University.
Moreover, placement of an inferior vena cava filter in patients with calf vein thrombosis when anticoagulation is contraindicated accomplishes nothing beneficial and had a 10% complication rate in a large retrospective single-center study, added Dr. Rodriguez of Northwestern University, Chicago.
Deep vein thrombosis (DVT) remains a significant source of morbidity and mortality despite worldwide awareness of the problem.
“Specifically, calf vein thrombosis [CVT] is very common, and we know that in some series up to 30% of patients end up propagating proximally if they’re not treated, and a good number of them develop chronic venous insufficiency, with long-term consequences,” he noted.
“Unfortunately there is no consensus regarding treatment. The guidelines are very vague. For example, there is no mention [in current American College of Chest Physicians guidelines] of how to manage muscular vein thrombosis and much ambiguity on how to treat calf vein thrombosis,” he continued.
Dr. Rodriguez cited as an indication of the lack of consensus on management of CVT a single-institution survey by other investigators of the practices of physicians in various specialties. Forty-nine percent of respondents indicated they anticoagulate patients with CVT; 51% don’t. Of those who did, 62% prescribed low-molecular-weight heparin and 11% intravenous heparin. Fifty-eight percent of physicians who anticoagulated did so for 3 months, 30% for 6. And 46% of physicians used an inferior vena cava (IVC) filter when anticoagulation was contraindicated (Vascular. 2014 Apr;22[2]:93-7).
That rate of IVC placement “seemed really high” given the paucity of supporting evidence for safety and efficacy of filter placement in the setting of CVT, so Dr. Rodriguez and coinvestigators decided to conduct a retrospective review of practices at Northwestern Memorial Hospital. He explained the study hypothesis: “Our thinking was that these kinds of thrombi are associated with low risk of propagation and pulmonary embolism, and they can and should be managed conservatively.”
Of 647 patients with isolated thrombosis of the anterior and posterior tibial, soleal, peroneal, or gastrocnemius veins, 44% received an IVC filter, and the rest got medical treatment alone. Of the 362 patients managed medically, 49% received therapeutic anticoagulation, 12% got low-dose prophylactic anticoagulation, and 39% underwent surveillance without anticoagulation.
The primary outcome was the incidence of venous thromboembolic complications – that is, propagation of DVT or pulmonary embolism. The incidence was 35% in the surveillance-only group, 30% with prophylactic anticoagulation, and 10% in patients who got therapeutic anticoagulation.
Of note, the rate of the most feared complication, pulmonary embolism, was low and similar in the filter recipients and medically managed group: 2.5% in the IVC group, 3.3% with medical management.
“Distal vein thromboses have low rates of pulmonary embolism, regardless of whether or not they are so-called protected with a filter. On the other hand, a filter was associated with a 10% rate of complications. I have to make clear that these were radiographic abnormalities – tilting, migration, caval perforation – that didn’t have clinical consequences, but we were very aggressive in removing the IVC filters, and I’m guessing if they’d been left inside they would create problems in the long term,” Dr. Rodriguez said.
An important point about this study is that these were all sick patients, and most were hospitalized. The filter recipients and medical groups differed in key ways. For example, 49% of the filter patients had a malignancy, and 56% had a baseline history of venous thromboembolic events, compared with 26% and 16%, respectively, of the medical group. For that reason, the investigators performed propensity score matching and came up with 157 closely matched patient pairs. The outcomes remained unchanged.
Of course, this was a retrospective study, with its inherent limitations, but Dr. Rodriguez characterized the published randomized trials on management of CVT as “small and limited.” The most frequently quoted study is the double-blind multicenter CACTUS trial, which randomized 252 outpatients with symptomatic CVT to 6 weeks of low-molecular-weight heparin or placebo and found no difference in the rates of proximal extension of venous thromboembolic events (Lancet Haematol. 2016 Dec;3[12]:e556-62). But these were all low-risk patients. Prior DVT or malignancy were exclusion criteria, so this was a very different population than treated at Northwestern.
Based upon the results of the retrospective study at Northwestern, which have been published (J Vasc Surg Venous Lymphat Disord. 2017 Jan;5[1]:25-32), the vascular surgery service has developed a management algorithm for DVT management based upon the lesion site. If a patient is unable to undergo anticoagulation, venous duplex ultrasound is repeated at 1 week. If the imaging shows propagation into the popliteal vein and anticoagulation remains contraindicated, only then is placement of an IVC filter warranted.
Dr. Rodriguez reported serving as a paid speaker for Abbott, Endologix, and W.L. Gore.
EXPERT ANALYSIS FROM NORTHWESTERN VASCULAR SYMPOSIUM
Late thrombectomy for stroke has low number needed to treat for benefit
LOS ANGELES – The number of ischemic stroke patients with a clinical core mismatch showing salvageable tissue who need to be treated with thrombectomy to obtain a significant benefit on functional outcomes is just 2 when the time frame from last known well extends out to 24 hours, according a subanalysis of results from the DAWN trial.
The Jan. 4, 2018, publication of the DAWN trial revealed that patients with ischemic strokes can benefit from thrombectomy long after the time window generally thought to afford benefits had closed (N Engl J Med. 2018;378:11-21). The procedure yielded significant benefits in functional outcomes at 90 days in patients with a clinical core mismatch showing salvageable tissue.
The results are important because health care systems must now make decisions about allocating resources for the treatment of these patients, which will include installing imaging techniques and expertise at various centers. “It will be practical in some primary stroke centers and not in others. We’re going to see a lot of interesting research about what frontline hospitals should do. There are lots of options at that screening step, and we’re going to need experience to see what’s best. It won’t be the same answer for everyone,” Jeffrey Saver, MD, said during a press conference announcing the results at the meeting, which was sponsored by the American Heart Association. Dr. Saver is director of the stroke unit at the University of California, Los Angeles, and professor of clinical neurology at the university.
The DAWN trial randomized 206 patients to thrombectomy plus standard care or standard care alone. The study was halted at an enrollment of 206 patients because of overwhelming efficacy. To be eligible, the patients had to have a mismatch between the severity of clinical deficit and the infarct volume as measured via automated analysis (RAPID software, SchemaView) of diffusion-weighted MRI or perfusion CT. They had to have substantial clinical deficits, but limited infarct size, with specific criteria varying with age, National Institutes of Health Stroke Scale score, and infarct size.
The NNT for an mRS score of 0 (asymptomatic) was 19. For freedom from disability (mRS, 0-1), the NNT was 4. For functional independence (mRS, 0-2), it was 3. To achieve ambulatory status (mRS, 0-3), it was 3. To avoid a requirement for constant care (mRS, 0-4), the NNT was 9.
To achieve any reduction in disability at all, the NNT was 2. This value was identical when looking at patients in the 6- to 12-hour window and those in the 12- to 24-hour window. However, the nature of the benefit was different. “In the late window (12-24 hours), outcomes went from really bad to pretty good. In the early window, it was somewhat bad to very good. So it’s still better to be treated early,” Dr. Saver said.
In short, for every 100 patients treated, 50 would gain an improvement in disability-related quality of life, and 36 would gain functional independence. In the 6- to 12-hour group, 45 of every 100 patients would experience lower disability as a result of treatment, as would 56 of every 100 treated patients in the 12- to 24-hour group.
Stryker Neurovascular funded the study. Dr. Saver has consulted for Stryker and received travel reimbursement.
LOS ANGELES – The number of ischemic stroke patients with a clinical core mismatch showing salvageable tissue who need to be treated with thrombectomy to obtain a significant benefit on functional outcomes is just 2 when the time frame from last known well extends out to 24 hours, according a subanalysis of results from the DAWN trial.
The Jan. 4, 2018, publication of the DAWN trial revealed that patients with ischemic strokes can benefit from thrombectomy long after the time window generally thought to afford benefits had closed (N Engl J Med. 2018;378:11-21). The procedure yielded significant benefits in functional outcomes at 90 days in patients with a clinical core mismatch showing salvageable tissue.
The results are important because health care systems must now make decisions about allocating resources for the treatment of these patients, which will include installing imaging techniques and expertise at various centers. “It will be practical in some primary stroke centers and not in others. We’re going to see a lot of interesting research about what frontline hospitals should do. There are lots of options at that screening step, and we’re going to need experience to see what’s best. It won’t be the same answer for everyone,” Jeffrey Saver, MD, said during a press conference announcing the results at the meeting, which was sponsored by the American Heart Association. Dr. Saver is director of the stroke unit at the University of California, Los Angeles, and professor of clinical neurology at the university.
The DAWN trial randomized 206 patients to thrombectomy plus standard care or standard care alone. The study was halted at an enrollment of 206 patients because of overwhelming efficacy. To be eligible, the patients had to have a mismatch between the severity of clinical deficit and the infarct volume as measured via automated analysis (RAPID software, SchemaView) of diffusion-weighted MRI or perfusion CT. They had to have substantial clinical deficits, but limited infarct size, with specific criteria varying with age, National Institutes of Health Stroke Scale score, and infarct size.
The NNT for an mRS score of 0 (asymptomatic) was 19. For freedom from disability (mRS, 0-1), the NNT was 4. For functional independence (mRS, 0-2), it was 3. To achieve ambulatory status (mRS, 0-3), it was 3. To avoid a requirement for constant care (mRS, 0-4), the NNT was 9.
To achieve any reduction in disability at all, the NNT was 2. This value was identical when looking at patients in the 6- to 12-hour window and those in the 12- to 24-hour window. However, the nature of the benefit was different. “In the late window (12-24 hours), outcomes went from really bad to pretty good. In the early window, it was somewhat bad to very good. So it’s still better to be treated early,” Dr. Saver said.
In short, for every 100 patients treated, 50 would gain an improvement in disability-related quality of life, and 36 would gain functional independence. In the 6- to 12-hour group, 45 of every 100 patients would experience lower disability as a result of treatment, as would 56 of every 100 treated patients in the 12- to 24-hour group.
Stryker Neurovascular funded the study. Dr. Saver has consulted for Stryker and received travel reimbursement.
LOS ANGELES – The number of ischemic stroke patients with a clinical core mismatch showing salvageable tissue who need to be treated with thrombectomy to obtain a significant benefit on functional outcomes is just 2 when the time frame from last known well extends out to 24 hours, according a subanalysis of results from the DAWN trial.
The Jan. 4, 2018, publication of the DAWN trial revealed that patients with ischemic strokes can benefit from thrombectomy long after the time window generally thought to afford benefits had closed (N Engl J Med. 2018;378:11-21). The procedure yielded significant benefits in functional outcomes at 90 days in patients with a clinical core mismatch showing salvageable tissue.
The results are important because health care systems must now make decisions about allocating resources for the treatment of these patients, which will include installing imaging techniques and expertise at various centers. “It will be practical in some primary stroke centers and not in others. We’re going to see a lot of interesting research about what frontline hospitals should do. There are lots of options at that screening step, and we’re going to need experience to see what’s best. It won’t be the same answer for everyone,” Jeffrey Saver, MD, said during a press conference announcing the results at the meeting, which was sponsored by the American Heart Association. Dr. Saver is director of the stroke unit at the University of California, Los Angeles, and professor of clinical neurology at the university.
The DAWN trial randomized 206 patients to thrombectomy plus standard care or standard care alone. The study was halted at an enrollment of 206 patients because of overwhelming efficacy. To be eligible, the patients had to have a mismatch between the severity of clinical deficit and the infarct volume as measured via automated analysis (RAPID software, SchemaView) of diffusion-weighted MRI or perfusion CT. They had to have substantial clinical deficits, but limited infarct size, with specific criteria varying with age, National Institutes of Health Stroke Scale score, and infarct size.
The NNT for an mRS score of 0 (asymptomatic) was 19. For freedom from disability (mRS, 0-1), the NNT was 4. For functional independence (mRS, 0-2), it was 3. To achieve ambulatory status (mRS, 0-3), it was 3. To avoid a requirement for constant care (mRS, 0-4), the NNT was 9.
To achieve any reduction in disability at all, the NNT was 2. This value was identical when looking at patients in the 6- to 12-hour window and those in the 12- to 24-hour window. However, the nature of the benefit was different. “In the late window (12-24 hours), outcomes went from really bad to pretty good. In the early window, it was somewhat bad to very good. So it’s still better to be treated early,” Dr. Saver said.
In short, for every 100 patients treated, 50 would gain an improvement in disability-related quality of life, and 36 would gain functional independence. In the 6- to 12-hour group, 45 of every 100 patients would experience lower disability as a result of treatment, as would 56 of every 100 treated patients in the 12- to 24-hour group.
Stryker Neurovascular funded the study. Dr. Saver has consulted for Stryker and received travel reimbursement.
REPORTING FROM ISC 2018
Key clinical point:
Major finding: To achieve a functional improvement at 90 days, the number needed to treat was 2.
Data source: Subanalysis of the randomized, controlled DAWN trial (n = 206).
Disclosures: Stryker Neurovascular funded the study. Dr. Saver has consulted for Stryker and received travel reimbursement.
Source: Saver J et al. ISC 2018 abstract LB3
New hematologic, cardiovascular system link may have therapeutic implications
ATLANTA – An intriguing link between the sex steroid hormonal milieu and platelet mitochondria has potential implications for reducing thrombosis risk.
The link, which involves a mitochondrial protein known as optic atrophy 1 (OPA1), appears to play a role in the regulation of thrombosis, and provides a possible explanation for the marked differences in cardiovascular risks between men and women, according to E. Dale Abel, MD, chair of the department of internal medicine, and director of the Fraternal Order of Eagles Diabetes Research Center at the University of Iowa, Iowa City.
The findings could lead to risk-stratification strategies and the identification of therapeutic targets, Dr. Abel said in an interview.
OPA1 is an inner mitochondrial membrane protein involved in mitochondrial fusion, he explained.
“My laboratory, for a very long time, has been interested in the cardiovascular complications of diabetes, and a lot of our work has focused on the heart and on the relationship between changes in metabolism and mitochondrial biology in those complications. We got interested in platelets because of a collaboration that actually started with Dr. [Andrew] Weyrich when my lab was at the University of Utah. There was a request for proposals from the National Heart, Lung, and Blood Institute for projects that would seek to understand the increased risk of thrombosis that occurs in people with diabetes,” he said.
Specifically, Dr. Weyrich had some preliminary data showing a backup of intermediates of glucose metabolism occurring in the platelets of diabetics.
“This suggested either that there was increased import of glucose into those cells or a decreased ability of those cells to metabolize glucose,” Dr. Abel said, adding that a closer look at the expression of certain genes in platelets as they related to the risk of thrombosis showed that a number of mitochondrial genes were involved, including OPA1.
Since Dr. Abel’s lab was already involved with studying glucose metabolism and mitochondrial metabolism, and had created a number of tools for modifying alleles, which would enable the targeting of expression of some of these genes, he and his colleagues began to look closer at the role of OPA1.
“The relationship between OPA1 and platelet biology, at least based on epidemiological studies from Dr. [Jane] Freedman’s analysis of platelet RNA expression in the Framingham cohort, really seemed to suggest that this had more to do with events in females rather than males,” Dr. Abel said.
He and his colleagues then generated a mouse model in which OPA1 levels in platelets could be manipulated. The goal was to determine if such manipulation would affect platelet function or platelet biology, and also to see if the effects differed between males and females.
“Initially, we didn’t have an expectation that we would see a difference between males and females, but in retrospect, it actually fits very nicely with what the epidemiological data in humans would suggest,” he said, referring to the differences in thrombosis risk between men and women.
Mitochondria go through a process of fusion and fission; OPA1 is involved in the fusion of the inner mitochondrial membrane, which has many folds known as cristae.
“These cristae are very important in the ability of mitochondria to generate energy, and OPA1 plays a very important role in maintaining the structure of these cristae,” he explained.
He and his colleagues generated mice that lacked OPA1 specifically in platelets. They then characterized the mitochondria and platelet function in these knockout mice.
“We saw that there was a difference between males and females in terms of how they responded to OPA1 deletion. Specifically, the males appeared to get more overt mitochondrial damage in terms of their structure and function, whereas the mitochondria appeared remarkably normal in females,” he said.
A look at platelet function showed that platelets in males were somewhat hyperactive, while in females they were somewhat underactive.
When the researchers used a model of deep venous thrombosis (DVT), more than 90% of male knockout mice developed a DVT versus 50% of wild-type controls. In contrast, there was no increase in DVT in female knockout mice relative to wild-type controls.
“So they were really opposite phenotypes in terms of platelet activity, and whenever one sees a difference between sexes in any biological variable or phenotype, you wonder if this is because of sex hormones,” he said.
This question led to a number of additional experiments.
In one of those experiments, Dr. Abel and his colleagues used a mouse model in which platelets were depleted and replaced via transfusion with platelets from another animal.
“We took male mice that were wild type and we depleted their platelets, and then we took platelets from an OPA1 deficient female and transfused these back into male mice, and took OPA1 deficient platelets from males and transfused them back into platelet-depleted female hosts. The really interesting thing in those experiments was that the phenotype switched,” he said.
That is, platelets in male mice with OPA1 deficiency, which had increased platelet activation in the male mice, became hypoactive when they were transfused into female mice. Similarly, hypoactive platelets from female mice became hyperactive when transfused into platelet-depleted male mice.
“What this told us then, is that the hormonal milieu interacts with OPA1 deficiency to modulate the function of the platelets,” he said.
Additional hormonal manipulations, involving orchiectomy in male mice to lower testosterone levels and increase estrogen levels, and ovariectomy in female mice to lower estrogen levels, showed that this could also modify platelet response.
“So we have discovered that somehow the amount of OPA1 in platelets interacts with circulating estrogens to modify the activity of platelets. This is not a trivial issue, because, as in the epidemiological study, the relationship is something that seems to be particularly true in females, and it also turned out that the OPA1 tended to track with increased cardiovascular events,” he said.
Preliminary studies involving pregnant women, looking at both the first and third trimester (when estrogen levels spike), also showed a correlation between increased platelet activity in the third trimester and higher levels of OPA1 in their platelets.
“It seems there is a relationship between OPA1 and platelets in women and estrogen levels that may then increase the risk of thrombosis. Maybe our mouse model phenotype is explained by the fact that we did the opposite: We reduced OPA1 in the platelets of females, and we actually saw that this was protective,” he said.
The findings are generating excitement, according to Dr. Weyrich, professor of internal medicine and vice president for research at the University of Utah, Salt Lake City, who was involved in the earlier studies that led Dr. Abel and his team to delve into the OPA1 research.
During a presentation of Dr. Abel’s findings at the annual meeting of the American Society of Hematology, Dr. Weyrich called the work “really, really striking,” and said the gender-specific findings are of particular importance.
“It’s something we often overlook and don’t think about, but I think it’s something that’s probably going to be more and more important as we begin to understand all types of diseases both in benign and malignant hematology,” he said.
Dr. Abel and his team plan to do their part to further that understanding. They are awaiting word on a new National Institutes of Health grant that will allow for expansion of their mouse studies into humans. Specifically, those studies will look at correlations between levels of OPA1 expression in platelets in women and history of/risk for developing a thrombotic event.
“Thrombosis is a significant problem in women who are exposed to estrogens ... and with the exception of a small number of specific genetic disorders of platelets, very little is known about what the risk factors are for this estrogen dependent increase in thrombotic risk,” he said.
What needs to be uncovered, Dr. Abel said, is whether women with the highest levels of OPA1 carry the highest risk of thrombosis.
“If we understand that, we may be in a position to stratify these women based on thrombosis risk in the setting of estrogen exposure. I think the other thing that will come out of the work, as we begin to understand the mechanisms for this relationship, is the identification of targets that we could therapeutically modulate to reduce this risk,” he added.
Eventually, as more is learned about the mechanisms that underlie the relationship between OPA1 and platelet activation, the findings might also lead to new approaches for reducing the risk of thrombosis in men, he noted.
Dr. Abel and Dr. Weyrich reported having no relevant financial disclosures.
ATLANTA – An intriguing link between the sex steroid hormonal milieu and platelet mitochondria has potential implications for reducing thrombosis risk.
The link, which involves a mitochondrial protein known as optic atrophy 1 (OPA1), appears to play a role in the regulation of thrombosis, and provides a possible explanation for the marked differences in cardiovascular risks between men and women, according to E. Dale Abel, MD, chair of the department of internal medicine, and director of the Fraternal Order of Eagles Diabetes Research Center at the University of Iowa, Iowa City.
The findings could lead to risk-stratification strategies and the identification of therapeutic targets, Dr. Abel said in an interview.
OPA1 is an inner mitochondrial membrane protein involved in mitochondrial fusion, he explained.
“My laboratory, for a very long time, has been interested in the cardiovascular complications of diabetes, and a lot of our work has focused on the heart and on the relationship between changes in metabolism and mitochondrial biology in those complications. We got interested in platelets because of a collaboration that actually started with Dr. [Andrew] Weyrich when my lab was at the University of Utah. There was a request for proposals from the National Heart, Lung, and Blood Institute for projects that would seek to understand the increased risk of thrombosis that occurs in people with diabetes,” he said.
Specifically, Dr. Weyrich had some preliminary data showing a backup of intermediates of glucose metabolism occurring in the platelets of diabetics.
“This suggested either that there was increased import of glucose into those cells or a decreased ability of those cells to metabolize glucose,” Dr. Abel said, adding that a closer look at the expression of certain genes in platelets as they related to the risk of thrombosis showed that a number of mitochondrial genes were involved, including OPA1.
Since Dr. Abel’s lab was already involved with studying glucose metabolism and mitochondrial metabolism, and had created a number of tools for modifying alleles, which would enable the targeting of expression of some of these genes, he and his colleagues began to look closer at the role of OPA1.
“The relationship between OPA1 and platelet biology, at least based on epidemiological studies from Dr. [Jane] Freedman’s analysis of platelet RNA expression in the Framingham cohort, really seemed to suggest that this had more to do with events in females rather than males,” Dr. Abel said.
He and his colleagues then generated a mouse model in which OPA1 levels in platelets could be manipulated. The goal was to determine if such manipulation would affect platelet function or platelet biology, and also to see if the effects differed between males and females.
“Initially, we didn’t have an expectation that we would see a difference between males and females, but in retrospect, it actually fits very nicely with what the epidemiological data in humans would suggest,” he said, referring to the differences in thrombosis risk between men and women.
Mitochondria go through a process of fusion and fission; OPA1 is involved in the fusion of the inner mitochondrial membrane, which has many folds known as cristae.
“These cristae are very important in the ability of mitochondria to generate energy, and OPA1 plays a very important role in maintaining the structure of these cristae,” he explained.
He and his colleagues generated mice that lacked OPA1 specifically in platelets. They then characterized the mitochondria and platelet function in these knockout mice.
“We saw that there was a difference between males and females in terms of how they responded to OPA1 deletion. Specifically, the males appeared to get more overt mitochondrial damage in terms of their structure and function, whereas the mitochondria appeared remarkably normal in females,” he said.
A look at platelet function showed that platelets in males were somewhat hyperactive, while in females they were somewhat underactive.
When the researchers used a model of deep venous thrombosis (DVT), more than 90% of male knockout mice developed a DVT versus 50% of wild-type controls. In contrast, there was no increase in DVT in female knockout mice relative to wild-type controls.
“So they were really opposite phenotypes in terms of platelet activity, and whenever one sees a difference between sexes in any biological variable or phenotype, you wonder if this is because of sex hormones,” he said.
This question led to a number of additional experiments.
In one of those experiments, Dr. Abel and his colleagues used a mouse model in which platelets were depleted and replaced via transfusion with platelets from another animal.
“We took male mice that were wild type and we depleted their platelets, and then we took platelets from an OPA1 deficient female and transfused these back into male mice, and took OPA1 deficient platelets from males and transfused them back into platelet-depleted female hosts. The really interesting thing in those experiments was that the phenotype switched,” he said.
That is, platelets in male mice with OPA1 deficiency, which had increased platelet activation in the male mice, became hypoactive when they were transfused into female mice. Similarly, hypoactive platelets from female mice became hyperactive when transfused into platelet-depleted male mice.
“What this told us then, is that the hormonal milieu interacts with OPA1 deficiency to modulate the function of the platelets,” he said.
Additional hormonal manipulations, involving orchiectomy in male mice to lower testosterone levels and increase estrogen levels, and ovariectomy in female mice to lower estrogen levels, showed that this could also modify platelet response.
“So we have discovered that somehow the amount of OPA1 in platelets interacts with circulating estrogens to modify the activity of platelets. This is not a trivial issue, because, as in the epidemiological study, the relationship is something that seems to be particularly true in females, and it also turned out that the OPA1 tended to track with increased cardiovascular events,” he said.
Preliminary studies involving pregnant women, looking at both the first and third trimester (when estrogen levels spike), also showed a correlation between increased platelet activity in the third trimester and higher levels of OPA1 in their platelets.
“It seems there is a relationship between OPA1 and platelets in women and estrogen levels that may then increase the risk of thrombosis. Maybe our mouse model phenotype is explained by the fact that we did the opposite: We reduced OPA1 in the platelets of females, and we actually saw that this was protective,” he said.
The findings are generating excitement, according to Dr. Weyrich, professor of internal medicine and vice president for research at the University of Utah, Salt Lake City, who was involved in the earlier studies that led Dr. Abel and his team to delve into the OPA1 research.
During a presentation of Dr. Abel’s findings at the annual meeting of the American Society of Hematology, Dr. Weyrich called the work “really, really striking,” and said the gender-specific findings are of particular importance.
“It’s something we often overlook and don’t think about, but I think it’s something that’s probably going to be more and more important as we begin to understand all types of diseases both in benign and malignant hematology,” he said.
Dr. Abel and his team plan to do their part to further that understanding. They are awaiting word on a new National Institutes of Health grant that will allow for expansion of their mouse studies into humans. Specifically, those studies will look at correlations between levels of OPA1 expression in platelets in women and history of/risk for developing a thrombotic event.
“Thrombosis is a significant problem in women who are exposed to estrogens ... and with the exception of a small number of specific genetic disorders of platelets, very little is known about what the risk factors are for this estrogen dependent increase in thrombotic risk,” he said.
What needs to be uncovered, Dr. Abel said, is whether women with the highest levels of OPA1 carry the highest risk of thrombosis.
“If we understand that, we may be in a position to stratify these women based on thrombosis risk in the setting of estrogen exposure. I think the other thing that will come out of the work, as we begin to understand the mechanisms for this relationship, is the identification of targets that we could therapeutically modulate to reduce this risk,” he added.
Eventually, as more is learned about the mechanisms that underlie the relationship between OPA1 and platelet activation, the findings might also lead to new approaches for reducing the risk of thrombosis in men, he noted.
Dr. Abel and Dr. Weyrich reported having no relevant financial disclosures.
ATLANTA – An intriguing link between the sex steroid hormonal milieu and platelet mitochondria has potential implications for reducing thrombosis risk.
The link, which involves a mitochondrial protein known as optic atrophy 1 (OPA1), appears to play a role in the regulation of thrombosis, and provides a possible explanation for the marked differences in cardiovascular risks between men and women, according to E. Dale Abel, MD, chair of the department of internal medicine, and director of the Fraternal Order of Eagles Diabetes Research Center at the University of Iowa, Iowa City.
The findings could lead to risk-stratification strategies and the identification of therapeutic targets, Dr. Abel said in an interview.
OPA1 is an inner mitochondrial membrane protein involved in mitochondrial fusion, he explained.
“My laboratory, for a very long time, has been interested in the cardiovascular complications of diabetes, and a lot of our work has focused on the heart and on the relationship between changes in metabolism and mitochondrial biology in those complications. We got interested in platelets because of a collaboration that actually started with Dr. [Andrew] Weyrich when my lab was at the University of Utah. There was a request for proposals from the National Heart, Lung, and Blood Institute for projects that would seek to understand the increased risk of thrombosis that occurs in people with diabetes,” he said.
Specifically, Dr. Weyrich had some preliminary data showing a backup of intermediates of glucose metabolism occurring in the platelets of diabetics.
“This suggested either that there was increased import of glucose into those cells or a decreased ability of those cells to metabolize glucose,” Dr. Abel said, adding that a closer look at the expression of certain genes in platelets as they related to the risk of thrombosis showed that a number of mitochondrial genes were involved, including OPA1.
Since Dr. Abel’s lab was already involved with studying glucose metabolism and mitochondrial metabolism, and had created a number of tools for modifying alleles, which would enable the targeting of expression of some of these genes, he and his colleagues began to look closer at the role of OPA1.
“The relationship between OPA1 and platelet biology, at least based on epidemiological studies from Dr. [Jane] Freedman’s analysis of platelet RNA expression in the Framingham cohort, really seemed to suggest that this had more to do with events in females rather than males,” Dr. Abel said.
He and his colleagues then generated a mouse model in which OPA1 levels in platelets could be manipulated. The goal was to determine if such manipulation would affect platelet function or platelet biology, and also to see if the effects differed between males and females.
“Initially, we didn’t have an expectation that we would see a difference between males and females, but in retrospect, it actually fits very nicely with what the epidemiological data in humans would suggest,” he said, referring to the differences in thrombosis risk between men and women.
Mitochondria go through a process of fusion and fission; OPA1 is involved in the fusion of the inner mitochondrial membrane, which has many folds known as cristae.
“These cristae are very important in the ability of mitochondria to generate energy, and OPA1 plays a very important role in maintaining the structure of these cristae,” he explained.
He and his colleagues generated mice that lacked OPA1 specifically in platelets. They then characterized the mitochondria and platelet function in these knockout mice.
“We saw that there was a difference between males and females in terms of how they responded to OPA1 deletion. Specifically, the males appeared to get more overt mitochondrial damage in terms of their structure and function, whereas the mitochondria appeared remarkably normal in females,” he said.
A look at platelet function showed that platelets in males were somewhat hyperactive, while in females they were somewhat underactive.
When the researchers used a model of deep venous thrombosis (DVT), more than 90% of male knockout mice developed a DVT versus 50% of wild-type controls. In contrast, there was no increase in DVT in female knockout mice relative to wild-type controls.
“So they were really opposite phenotypes in terms of platelet activity, and whenever one sees a difference between sexes in any biological variable or phenotype, you wonder if this is because of sex hormones,” he said.
This question led to a number of additional experiments.
In one of those experiments, Dr. Abel and his colleagues used a mouse model in which platelets were depleted and replaced via transfusion with platelets from another animal.
“We took male mice that were wild type and we depleted their platelets, and then we took platelets from an OPA1 deficient female and transfused these back into male mice, and took OPA1 deficient platelets from males and transfused them back into platelet-depleted female hosts. The really interesting thing in those experiments was that the phenotype switched,” he said.
That is, platelets in male mice with OPA1 deficiency, which had increased platelet activation in the male mice, became hypoactive when they were transfused into female mice. Similarly, hypoactive platelets from female mice became hyperactive when transfused into platelet-depleted male mice.
“What this told us then, is that the hormonal milieu interacts with OPA1 deficiency to modulate the function of the platelets,” he said.
Additional hormonal manipulations, involving orchiectomy in male mice to lower testosterone levels and increase estrogen levels, and ovariectomy in female mice to lower estrogen levels, showed that this could also modify platelet response.
“So we have discovered that somehow the amount of OPA1 in platelets interacts with circulating estrogens to modify the activity of platelets. This is not a trivial issue, because, as in the epidemiological study, the relationship is something that seems to be particularly true in females, and it also turned out that the OPA1 tended to track with increased cardiovascular events,” he said.
Preliminary studies involving pregnant women, looking at both the first and third trimester (when estrogen levels spike), also showed a correlation between increased platelet activity in the third trimester and higher levels of OPA1 in their platelets.
“It seems there is a relationship between OPA1 and platelets in women and estrogen levels that may then increase the risk of thrombosis. Maybe our mouse model phenotype is explained by the fact that we did the opposite: We reduced OPA1 in the platelets of females, and we actually saw that this was protective,” he said.
The findings are generating excitement, according to Dr. Weyrich, professor of internal medicine and vice president for research at the University of Utah, Salt Lake City, who was involved in the earlier studies that led Dr. Abel and his team to delve into the OPA1 research.
During a presentation of Dr. Abel’s findings at the annual meeting of the American Society of Hematology, Dr. Weyrich called the work “really, really striking,” and said the gender-specific findings are of particular importance.
“It’s something we often overlook and don’t think about, but I think it’s something that’s probably going to be more and more important as we begin to understand all types of diseases both in benign and malignant hematology,” he said.
Dr. Abel and his team plan to do their part to further that understanding. They are awaiting word on a new National Institutes of Health grant that will allow for expansion of their mouse studies into humans. Specifically, those studies will look at correlations between levels of OPA1 expression in platelets in women and history of/risk for developing a thrombotic event.
“Thrombosis is a significant problem in women who are exposed to estrogens ... and with the exception of a small number of specific genetic disorders of platelets, very little is known about what the risk factors are for this estrogen dependent increase in thrombotic risk,” he said.
What needs to be uncovered, Dr. Abel said, is whether women with the highest levels of OPA1 carry the highest risk of thrombosis.
“If we understand that, we may be in a position to stratify these women based on thrombosis risk in the setting of estrogen exposure. I think the other thing that will come out of the work, as we begin to understand the mechanisms for this relationship, is the identification of targets that we could therapeutically modulate to reduce this risk,” he added.
Eventually, as more is learned about the mechanisms that underlie the relationship between OPA1 and platelet activation, the findings might also lead to new approaches for reducing the risk of thrombosis in men, he noted.
Dr. Abel and Dr. Weyrich reported having no relevant financial disclosures.
EXPERT ANALYSIS FROM ASH 2017
Use of non–vitamin K antagonist oral anticoagulants in the acute care, periprocedural settings
Non–vitamin K antagonist anticoagulants (NOACs, also called novel or direct oral anticoagulants) are commonly used to treat and prevent venous thromboembolism (VTE) and to prevent ischemic stroke in patients with nonvalvular atrial fibrillation. These agents, which include the factor Xa inhibitors rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa), and the competitive thrombin inhibitor dabigatran (Pradaxa), often are preferred over warfarin because of their more predictable pharmacokinetics, comparable efficacy, comparable or lower risk of major bleeding complications, fewer drug interactions, and lack of need for frequent monitoring. However, the acute care of patients taking NOACS can be challenging, because only dabigatran has an approved reversal agent, and none have readily available, reliable measurement assays. The American Heart Association (AHA) published a statement on the periprocedural and acute care management of patients taking NOACs. Here are the findings and recommendations of the AHA that are most relevant to primary care physicians.
Measurement
While all NOACs affect coagulation tests, their effect on prothrombin time and activated partial thromboplastin time is neither predictable nor an accurate reflection of the degree of anticoagulation. Instead, use the time of last drug ingestion and the patient’s creatinine clearance to estimate the anticoagulation effect. Dabigatran takes 1 hour to reach peak effect, or 2 hours if taken with food. Its half-life is 12-17 hours, on the higher end in the elderly and in those with moderate renal impairment. In those with severe renal impairment, half-life can be 28 hours. Rivaroxaban’s time to peak is 2-4 hours, and its half-life is 5-9 hours or up to 13 in the elderly. Apixaban’s time to peak is 3-4 hours and its half-life is about 12 hours. An antifactor Xa activity assay does provide a quantitative assessment of the factor Xa inhibitors.
Kidney injury
Acute kidney injury increases risk of bleeding while taking a NOAC. Monitor these patients closely and consider temporarily switching to a different anticoagulant in the setting of kidney injury.
Bleeding
Lack of reversibility is a common concern. Use 5 g of IV idarucizumab (Praxbind) to reverse dabigatran within minutes in a patient experiencing major bleeding. Hemodialysis, which removes about half of dabigatran in 4 hours, is a suitable option in acute kidney injury or in patients with a creatinine clearance under 30mL/min.
Options are more limited for the Xa inhibitors, because there are no available reversal agents and hemodialysis does not clear these highly protein-bound drugs. While data are limited, prothrombin complex concentrate may be given for patients on rivaroxaban, apixaban, or edoxaban who are experiencing an intracranial hemorrhage or other form of severe bleeding. Simply holding the NOAC is acceptable for minor bleeding.
Overdose
Activated charcoal to induce vomiting will work within 1-2 hours of drug ingestion.
Intracranial hemorrhage
Assume that a patient taking a NOAC who displays any acute neurologic change is experiencing an intracranial hemorrhage until proven otherwise. After CT confirmation, reverse dabigatran with idarucizumab, or give prothrombin complex concentrate to patients on other NOACs.
Ischemic stroke
Patients who suffer an ischemic stroke despite NOAC therapy are not candidates for tissue plasminogen activators.
The primary care physician is likely to be involved in the decision of whether, when, and for how long to resume anticoagulation therapy after a stroke. The statement says, “guidelines support withholding oral anticoagulation until 1-2 weeks after stroke among individuals with NVAF [nonvalvular atrial fibrillation], with shorter times for those with transient ischemic attack or small, nondisabling strokes and longer times for moderate to severe strokes.” In addition, it is worthwhile to consider medication nonadherence if no other etiology for the stroke is found; patients who miss doses may benefit more from warfarin because of its longer half-life.
Procedures and surgeries
Each year approximately 10% of patients on anticoagulation require surgery or other invasive procedures, and 20% require a minor procedure. To determine whether to interrupt NOAC therapy prior to a procedure, first determine the procedure’s bleeding risk. Patients undergoing procedures with low risk of bleeding, including minor dental, dermatologic, and ophthalmologic procedures, and endoscopies without biopsies, do not require interruption. For procedures with a moderate bleeding risk (including cardiac ablation, endoscopy with biopsies, radial artery catheterization) or high bleeding risk (including major surgery and cardiac catheterization via femoral artery), the patient’s thromboembolic risk should be evaluated using the medical history and the CHA2DS2 VASc score. NOACs should be stopped for 24-48 hours prior to the moderate to high-risk procedures. Dabigatran should be held for 72 hours for patients with creatinine clearance less than 50mL/min. Bridging therapy with heparin is not recommended for patients taking NOACS who are to have surgery. The decision about when to restart NOAC is based on the risk of thromboembolism and the bleeding risk of surgery.
Spinal or epidural anesthesia
Anesthesia guidelines recommend holding NOACs 3-5 days prior to the intervention, however, this increases risk of TE and studies have shown a very low incidence of hematoma in patients anticoagulated with a NOAC. For patients with a high risk of VTE, the NOAC can be resumed 12 hours post-procedure.
The bottom line
NOACS are commonly used for treatment and prophylaxis of VTE and atrial fibrillation and are often preferred over warfarin due to their more predictable pharmacokinetics, comparable efficacy, comparable or lower risk of major bleeding complications, fewer drug interactions, and lack of need for frequent monitoring. The AHA scientific statement gives guidance on managing NOACS in the face of acute bleeding as well as during and after procedures. NOACS should be stopped 24-48 hours prior to major surgeries and may be restarted based on weighing the risk of bleeding and risk of thromboembolism.
Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, and associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Oh is a third-year resident in the family medicine residency program at Abington Jefferson Health.
Reference
Raval AN et al. Management of patients on non–vitamin K antagonist oral anticoagulants in the acute care and periprocedural setting: A scientific statement from the American Heart Association. Circulation. 2017 Feb 6;135[10]:e604-e33. doi: 10.1161/CIR.0000000000000477
Non–vitamin K antagonist anticoagulants (NOACs, also called novel or direct oral anticoagulants) are commonly used to treat and prevent venous thromboembolism (VTE) and to prevent ischemic stroke in patients with nonvalvular atrial fibrillation. These agents, which include the factor Xa inhibitors rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa), and the competitive thrombin inhibitor dabigatran (Pradaxa), often are preferred over warfarin because of their more predictable pharmacokinetics, comparable efficacy, comparable or lower risk of major bleeding complications, fewer drug interactions, and lack of need for frequent monitoring. However, the acute care of patients taking NOACS can be challenging, because only dabigatran has an approved reversal agent, and none have readily available, reliable measurement assays. The American Heart Association (AHA) published a statement on the periprocedural and acute care management of patients taking NOACs. Here are the findings and recommendations of the AHA that are most relevant to primary care physicians.
Measurement
While all NOACs affect coagulation tests, their effect on prothrombin time and activated partial thromboplastin time is neither predictable nor an accurate reflection of the degree of anticoagulation. Instead, use the time of last drug ingestion and the patient’s creatinine clearance to estimate the anticoagulation effect. Dabigatran takes 1 hour to reach peak effect, or 2 hours if taken with food. Its half-life is 12-17 hours, on the higher end in the elderly and in those with moderate renal impairment. In those with severe renal impairment, half-life can be 28 hours. Rivaroxaban’s time to peak is 2-4 hours, and its half-life is 5-9 hours or up to 13 in the elderly. Apixaban’s time to peak is 3-4 hours and its half-life is about 12 hours. An antifactor Xa activity assay does provide a quantitative assessment of the factor Xa inhibitors.
Kidney injury
Acute kidney injury increases risk of bleeding while taking a NOAC. Monitor these patients closely and consider temporarily switching to a different anticoagulant in the setting of kidney injury.
Bleeding
Lack of reversibility is a common concern. Use 5 g of IV idarucizumab (Praxbind) to reverse dabigatran within minutes in a patient experiencing major bleeding. Hemodialysis, which removes about half of dabigatran in 4 hours, is a suitable option in acute kidney injury or in patients with a creatinine clearance under 30mL/min.
Options are more limited for the Xa inhibitors, because there are no available reversal agents and hemodialysis does not clear these highly protein-bound drugs. While data are limited, prothrombin complex concentrate may be given for patients on rivaroxaban, apixaban, or edoxaban who are experiencing an intracranial hemorrhage or other form of severe bleeding. Simply holding the NOAC is acceptable for minor bleeding.
Overdose
Activated charcoal to induce vomiting will work within 1-2 hours of drug ingestion.
Intracranial hemorrhage
Assume that a patient taking a NOAC who displays any acute neurologic change is experiencing an intracranial hemorrhage until proven otherwise. After CT confirmation, reverse dabigatran with idarucizumab, or give prothrombin complex concentrate to patients on other NOACs.
Ischemic stroke
Patients who suffer an ischemic stroke despite NOAC therapy are not candidates for tissue plasminogen activators.
The primary care physician is likely to be involved in the decision of whether, when, and for how long to resume anticoagulation therapy after a stroke. The statement says, “guidelines support withholding oral anticoagulation until 1-2 weeks after stroke among individuals with NVAF [nonvalvular atrial fibrillation], with shorter times for those with transient ischemic attack or small, nondisabling strokes and longer times for moderate to severe strokes.” In addition, it is worthwhile to consider medication nonadherence if no other etiology for the stroke is found; patients who miss doses may benefit more from warfarin because of its longer half-life.
Procedures and surgeries
Each year approximately 10% of patients on anticoagulation require surgery or other invasive procedures, and 20% require a minor procedure. To determine whether to interrupt NOAC therapy prior to a procedure, first determine the procedure’s bleeding risk. Patients undergoing procedures with low risk of bleeding, including minor dental, dermatologic, and ophthalmologic procedures, and endoscopies without biopsies, do not require interruption. For procedures with a moderate bleeding risk (including cardiac ablation, endoscopy with biopsies, radial artery catheterization) or high bleeding risk (including major surgery and cardiac catheterization via femoral artery), the patient’s thromboembolic risk should be evaluated using the medical history and the CHA2DS2 VASc score. NOACs should be stopped for 24-48 hours prior to the moderate to high-risk procedures. Dabigatran should be held for 72 hours for patients with creatinine clearance less than 50mL/min. Bridging therapy with heparin is not recommended for patients taking NOACS who are to have surgery. The decision about when to restart NOAC is based on the risk of thromboembolism and the bleeding risk of surgery.
Spinal or epidural anesthesia
Anesthesia guidelines recommend holding NOACs 3-5 days prior to the intervention, however, this increases risk of TE and studies have shown a very low incidence of hematoma in patients anticoagulated with a NOAC. For patients with a high risk of VTE, the NOAC can be resumed 12 hours post-procedure.
The bottom line
NOACS are commonly used for treatment and prophylaxis of VTE and atrial fibrillation and are often preferred over warfarin due to their more predictable pharmacokinetics, comparable efficacy, comparable or lower risk of major bleeding complications, fewer drug interactions, and lack of need for frequent monitoring. The AHA scientific statement gives guidance on managing NOACS in the face of acute bleeding as well as during and after procedures. NOACS should be stopped 24-48 hours prior to major surgeries and may be restarted based on weighing the risk of bleeding and risk of thromboembolism.
Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, and associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Oh is a third-year resident in the family medicine residency program at Abington Jefferson Health.
Reference
Raval AN et al. Management of patients on non–vitamin K antagonist oral anticoagulants in the acute care and periprocedural setting: A scientific statement from the American Heart Association. Circulation. 2017 Feb 6;135[10]:e604-e33. doi: 10.1161/CIR.0000000000000477
Non–vitamin K antagonist anticoagulants (NOACs, also called novel or direct oral anticoagulants) are commonly used to treat and prevent venous thromboembolism (VTE) and to prevent ischemic stroke in patients with nonvalvular atrial fibrillation. These agents, which include the factor Xa inhibitors rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa), and the competitive thrombin inhibitor dabigatran (Pradaxa), often are preferred over warfarin because of their more predictable pharmacokinetics, comparable efficacy, comparable or lower risk of major bleeding complications, fewer drug interactions, and lack of need for frequent monitoring. However, the acute care of patients taking NOACS can be challenging, because only dabigatran has an approved reversal agent, and none have readily available, reliable measurement assays. The American Heart Association (AHA) published a statement on the periprocedural and acute care management of patients taking NOACs. Here are the findings and recommendations of the AHA that are most relevant to primary care physicians.
Measurement
While all NOACs affect coagulation tests, their effect on prothrombin time and activated partial thromboplastin time is neither predictable nor an accurate reflection of the degree of anticoagulation. Instead, use the time of last drug ingestion and the patient’s creatinine clearance to estimate the anticoagulation effect. Dabigatran takes 1 hour to reach peak effect, or 2 hours if taken with food. Its half-life is 12-17 hours, on the higher end in the elderly and in those with moderate renal impairment. In those with severe renal impairment, half-life can be 28 hours. Rivaroxaban’s time to peak is 2-4 hours, and its half-life is 5-9 hours or up to 13 in the elderly. Apixaban’s time to peak is 3-4 hours and its half-life is about 12 hours. An antifactor Xa activity assay does provide a quantitative assessment of the factor Xa inhibitors.
Kidney injury
Acute kidney injury increases risk of bleeding while taking a NOAC. Monitor these patients closely and consider temporarily switching to a different anticoagulant in the setting of kidney injury.
Bleeding
Lack of reversibility is a common concern. Use 5 g of IV idarucizumab (Praxbind) to reverse dabigatran within minutes in a patient experiencing major bleeding. Hemodialysis, which removes about half of dabigatran in 4 hours, is a suitable option in acute kidney injury or in patients with a creatinine clearance under 30mL/min.
Options are more limited for the Xa inhibitors, because there are no available reversal agents and hemodialysis does not clear these highly protein-bound drugs. While data are limited, prothrombin complex concentrate may be given for patients on rivaroxaban, apixaban, or edoxaban who are experiencing an intracranial hemorrhage or other form of severe bleeding. Simply holding the NOAC is acceptable for minor bleeding.
Overdose
Activated charcoal to induce vomiting will work within 1-2 hours of drug ingestion.
Intracranial hemorrhage
Assume that a patient taking a NOAC who displays any acute neurologic change is experiencing an intracranial hemorrhage until proven otherwise. After CT confirmation, reverse dabigatran with idarucizumab, or give prothrombin complex concentrate to patients on other NOACs.
Ischemic stroke
Patients who suffer an ischemic stroke despite NOAC therapy are not candidates for tissue plasminogen activators.
The primary care physician is likely to be involved in the decision of whether, when, and for how long to resume anticoagulation therapy after a stroke. The statement says, “guidelines support withholding oral anticoagulation until 1-2 weeks after stroke among individuals with NVAF [nonvalvular atrial fibrillation], with shorter times for those with transient ischemic attack or small, nondisabling strokes and longer times for moderate to severe strokes.” In addition, it is worthwhile to consider medication nonadherence if no other etiology for the stroke is found; patients who miss doses may benefit more from warfarin because of its longer half-life.
Procedures and surgeries
Each year approximately 10% of patients on anticoagulation require surgery or other invasive procedures, and 20% require a minor procedure. To determine whether to interrupt NOAC therapy prior to a procedure, first determine the procedure’s bleeding risk. Patients undergoing procedures with low risk of bleeding, including minor dental, dermatologic, and ophthalmologic procedures, and endoscopies without biopsies, do not require interruption. For procedures with a moderate bleeding risk (including cardiac ablation, endoscopy with biopsies, radial artery catheterization) or high bleeding risk (including major surgery and cardiac catheterization via femoral artery), the patient’s thromboembolic risk should be evaluated using the medical history and the CHA2DS2 VASc score. NOACs should be stopped for 24-48 hours prior to the moderate to high-risk procedures. Dabigatran should be held for 72 hours for patients with creatinine clearance less than 50mL/min. Bridging therapy with heparin is not recommended for patients taking NOACS who are to have surgery. The decision about when to restart NOAC is based on the risk of thromboembolism and the bleeding risk of surgery.
Spinal or epidural anesthesia
Anesthesia guidelines recommend holding NOACs 3-5 days prior to the intervention, however, this increases risk of TE and studies have shown a very low incidence of hematoma in patients anticoagulated with a NOAC. For patients with a high risk of VTE, the NOAC can be resumed 12 hours post-procedure.
The bottom line
NOACS are commonly used for treatment and prophylaxis of VTE and atrial fibrillation and are often preferred over warfarin due to their more predictable pharmacokinetics, comparable efficacy, comparable or lower risk of major bleeding complications, fewer drug interactions, and lack of need for frequent monitoring. The AHA scientific statement gives guidance on managing NOACS in the face of acute bleeding as well as during and after procedures. NOACS should be stopped 24-48 hours prior to major surgeries and may be restarted based on weighing the risk of bleeding and risk of thromboembolism.
Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, and associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Oh is a third-year resident in the family medicine residency program at Abington Jefferson Health.
Reference
Raval AN et al. Management of patients on non–vitamin K antagonist oral anticoagulants in the acute care and periprocedural setting: A scientific statement from the American Heart Association. Circulation. 2017 Feb 6;135[10]:e604-e33. doi: 10.1161/CIR.0000000000000477
