Day Two highlights from HM15, the Society of Hospital Medicine’s (SHM) annual meeting in National Harbor, Md., just outside Washington, D.C.

Day Two highlights from HM15, the Society of Hospital Medicine’s (SHM) annual meeting in National Harbor, Md., just outside Washington, D.C.

Day Two highlights from HM15, the Society of Hospital Medicine’s (SHM) annual meeting in National Harbor, Md., just outside Washington, D.C.

A month ago the American Board of Internal Medicine sent a letter to diplomates saying they “got it wrong,” referring to the process of maintenance of certification or MOC, that the board required. They acknowledged that “parts of the new program are not meeting the needs of physicians like yourself.” Some of the things they proposed include changing the content of the Internal Medicine recertification exam to be “more reflective of what physicians in practice are doing,” with a promise that subspecialty recertification exams will follow suit. They also talk about “new and more flexible ways ... to demonstrate ... medical knowledge,” likely making room for the continuing medical education or CME credits that state licensures require.

While the letter was evidence that physician grievances were being heard, it was widely criticized for not having gone far enough. Questions remained about the financial and time cost of certification, the relevance of the exam, and the motivation of the board.

Well, the ABIM has written us again. Except it’s still not saying much. They simply say that they have been listening to feedback, and they list some points about what they’ve been hearing and are presumably going to take into consideration. In summary, they are recognizing that the while we all agree that we need a way for physicians to keep up on their medical knowledge, there is “a shared sense that defining ‘keeping up’ is the work of the whole community, including physicians, specialty societies, patient groups, and health care institutions.”

They proceed to outline what they’ve heard and will presumably consider, including the suggestion that the recertification exam be eliminated completely, and that CME units count toward recertification. Like I said, they didn’t say much. But this is promising. Particularly telling is the part where they acknowledge that the job of defining ‘keeping up’ does not fall solely on, as a friend put it, people that sit in their ivory towers and are removed from the daily grind of patient care.

Apropos of all this, I recently got my first 10 points toward MOC by taking a 30-question exam posted by the American College of Rheumatology. Each question comes with a list of references that you can review should you need or want to. To my great surprise, one of the references was in German. So what does that tell you about the people writing the questions and the process they use? What does that tell you about the validity of the questions as a measure of my competence and ability to treat people?

Exams like the boards are a measure of test-taking skills and retention, neither one of which is a true measure of what a capable, competent physician should be. The ABIM is imposing on us an onerous and ill-conceived tool, one that most physicians agree is irrelevant. I am glad this conversation is happening, because frankly the process was enough to make me want to quit being a doctor.

Dr. Chan practices rheumatology in Pawtucket, R.I.

A month ago the American Board of Internal Medicine sent a letter to diplomates saying they “got it wrong,” referring to the process of maintenance of certification or MOC, that the board required. They acknowledged that “parts of the new program are not meeting the needs of physicians like yourself.” Some of the things they proposed include changing the content of the Internal Medicine recertification exam to be “more reflective of what physicians in practice are doing,” with a promise that subspecialty recertification exams will follow suit. They also talk about “new and more flexible ways ... to demonstrate ... medical knowledge,” likely making room for the continuing medical education or CME credits that state licensures require.

While the letter was evidence that physician grievances were being heard, it was widely criticized for not having gone far enough. Questions remained about the financial and time cost of certification, the relevance of the exam, and the motivation of the board.

Well, the ABIM has written us again. Except it’s still not saying much. They simply say that they have been listening to feedback, and they list some points about what they’ve been hearing and are presumably going to take into consideration. In summary, they are recognizing that the while we all agree that we need a way for physicians to keep up on their medical knowledge, there is “a shared sense that defining ‘keeping up’ is the work of the whole community, including physicians, specialty societies, patient groups, and health care institutions.”

They proceed to outline what they’ve heard and will presumably consider, including the suggestion that the recertification exam be eliminated completely, and that CME units count toward recertification. Like I said, they didn’t say much. But this is promising. Particularly telling is the part where they acknowledge that the job of defining ‘keeping up’ does not fall solely on, as a friend put it, people that sit in their ivory towers and are removed from the daily grind of patient care.

Apropos of all this, I recently got my first 10 points toward MOC by taking a 30-question exam posted by the American College of Rheumatology. Each question comes with a list of references that you can review should you need or want to. To my great surprise, one of the references was in German. So what does that tell you about the people writing the questions and the process they use? What does that tell you about the validity of the questions as a measure of my competence and ability to treat people?

Exams like the boards are a measure of test-taking skills and retention, neither one of which is a true measure of what a capable, competent physician should be. The ABIM is imposing on us an onerous and ill-conceived tool, one that most physicians agree is irrelevant. I am glad this conversation is happening, because frankly the process was enough to make me want to quit being a doctor.

Dr. Chan practices rheumatology in Pawtucket, R.I.

A month ago the American Board of Internal Medicine sent a letter to diplomates saying they “got it wrong,” referring to the process of maintenance of certification or MOC, that the board required. They acknowledged that “parts of the new program are not meeting the needs of physicians like yourself.” Some of the things they proposed include changing the content of the Internal Medicine recertification exam to be “more reflective of what physicians in practice are doing,” with a promise that subspecialty recertification exams will follow suit. They also talk about “new and more flexible ways ... to demonstrate ... medical knowledge,” likely making room for the continuing medical education or CME credits that state licensures require.

While the letter was evidence that physician grievances were being heard, it was widely criticized for not having gone far enough. Questions remained about the financial and time cost of certification, the relevance of the exam, and the motivation of the board.

Well, the ABIM has written us again. Except it’s still not saying much. They simply say that they have been listening to feedback, and they list some points about what they’ve been hearing and are presumably going to take into consideration. In summary, they are recognizing that the while we all agree that we need a way for physicians to keep up on their medical knowledge, there is “a shared sense that defining ‘keeping up’ is the work of the whole community, including physicians, specialty societies, patient groups, and health care institutions.”

They proceed to outline what they’ve heard and will presumably consider, including the suggestion that the recertification exam be eliminated completely, and that CME units count toward recertification. Like I said, they didn’t say much. But this is promising. Particularly telling is the part where they acknowledge that the job of defining ‘keeping up’ does not fall solely on, as a friend put it, people that sit in their ivory towers and are removed from the daily grind of patient care.

Apropos of all this, I recently got my first 10 points toward MOC by taking a 30-question exam posted by the American College of Rheumatology. Each question comes with a list of references that you can review should you need or want to. To my great surprise, one of the references was in German. So what does that tell you about the people writing the questions and the process they use? What does that tell you about the validity of the questions as a measure of my competence and ability to treat people?

Exams like the boards are a measure of test-taking skills and retention, neither one of which is a true measure of what a capable, competent physician should be. The ABIM is imposing on us an onerous and ill-conceived tool, one that most physicians agree is irrelevant. I am glad this conversation is happening, because frankly the process was enough to make me want to quit being a doctor.

Dr. Chan practices rheumatology in Pawtucket, R.I.

SAN DIEGO – Maintenance of long-term weight loss in obese or overweight individuals with atrial fibrillation was associated with nearly a sixfold greater likelihood of freedom from recurrent AF during nearly 5 years of active follow-up in the LEGACY study.

“The effect was dose dependent. The most important finding is that 46% of patients with at least a 10% weight loss were free from AF without the use of drugs or ablation procedures through nearly 5 years, versus 22% of those with 3%-9% weight loss, and just 13% with less than a 3% weight loss,” Dr. Rajeev K. Pathak said at the annual meeting of the American College of Cardiology.

Nick Piegari/Frontline Medical News

LEGACY (Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study) included 355 overweight or obese participants with paroxsymal or persistent AF who were offered the chance to participate in a dedicated weight-loss clinic. Regular participation in this clinic proved to be a key factor in losing weight, keeping it off, and reducing AF burden; the more frequently patients attended the quarterly sessions the better the outcomes, noted Dr. Pathak, a cardiologist and electrophysiology fellow at the University of Adelaide (Australia).

Of the 355 participants, 135 lost at least 10% of their body weight, 103 had a 3%-9% drop in body weight, and 117 had less than a 3% loss or a weight gain.

Year-by-year weight trends had a significant impact on outcome. The 141 patients with linear weight loss had a 76% AF-free rate with or without the use of drugs or ablation, compared with a 59% in the 179 patients with weight fluctuations and the 38% rate in those with no loss or a weight gain. Atrial fibrillation status was assessed by 7-day Holter monitoring at least annually.

Weight fluctuation – defined as a 1% or greater change in weight between two consecutive annual follow-ups – dampened the benefits conferred by weight loss. Patients who experienced more than a 5% weight fluctuation were 2.2-fold more likely to experience AF recurrence than were those without weight fluctuation.

Patients with a sustained 10% weight loss were 5.6-fold more likely to achieve long-term freedom from AF than were patients with lesser or no weight loss. The goal was 10% weight loss rather than a body mass index of 25 kg/m² or less because once AF patients get down to a BMI below 27 kg/m² the incremental benefit of each additional 1 BMI point in terms of freedom from AF becomes much smaller, said Dr. Pathak.

Weight loss also showed a dose-dependent effect on various cardiovascular risk factors. For example, mean systolic blood pressure fell by 18 mm Hg in subjects with at least a 10% weight loss, by 10 mm Hg with a 3%-9% loss, and by 7 mm Hg with a lesser weight loss. Triglycerides, LDL cholesterol, and glycemic control improved in similar fashion. In addition, weight loss showed beneficial effects on cardiac structure, with dose-dependent reductions in left atrial volume indexed for body surface area as well as interventricular septal thickness, Dr. Pathak continued.

He described the weight loss clinic as a “very simple” structured motivational and goal-directed program with face-to-face counseling.

“We have one patient, one physician, no props. We sit with the patient, discuss areas we can improve, then we devise a low-carb, low-fat, high-protein diet in consultation with the patient. Patients maintain a lifestyle journal where they log their meals and exercise. We prescribe at least 200 minutes of moderate-intensity activity per week. Eating is a behavioral pattern, and we have found this approach to be a very effective behavioral tool. Because the plan is developed in consultation with the patient, we’ve found patients tend to adhere to what they have planned,” he explained.

Discussant Dr. Bernard J. Gersh praised LEGACY as “a really wonderful study – very important.

“There are years of epidemiologic evidence suggesting that obesity contributes in a major way to the epidemic of atrial fibrillation, and you’ve taken it a step further,” added Dr. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.

Playing devil’s advocate, he asked whether the observed reduction in AF might have nothing to do with weight loss, but could be explained simply by LEGACY perhaps having enrolled a highly compliant group of patients who agreed to attend a clinic and were more willing to take their medications.

Dr. Pathak rejected the compliance factor as an explanation for the results. He noted that while cardiovascular risk factors improved with greater weight loss, the need for antihypertensive, lipid-lowering, and antiarrhythmic medications decreased.

“The effect can’t possibly be due to increased compliance with medications, but rather it’s a true effect of the weight loss itself. So I think this is a true clinical effect and not an epiphenomenon,” he replied.

Dr. Pathak added that he and his coinvestigators are organizing a randomized controlled confirmatory study.

Dr. Prediman K. Shah, who chaired a press conference where the LEGACY study was highlighted, said the study provided him with one of the major take-home lessons from ACC 15.

“We can argue about the mechanism of atrial fibrillation till kingdom come, but the fact is that the association is very strong that weight loss is associated with a reduced burden of atrial fibrillation, and with a very robust magnitude of benefit. That’s one of the messages that I’ll take home with me from this meeting: The next time I see my fat patient with atrial fibrillation, I’m putting him on a weight-reducing diet as the first approach,” declared Dr. Shah, professor of medicine at UCLA and director of the Oppenheimer Atherosclerosis Research Center at Cedars-Sinai Medical Center in Los Angeles.

Dr. Pathak reported having no financial conflicts regarding this study, which was supported by university funds.

Simultaneously with Dr. Pathak’s presentation at ACC 15, the LEGACY study was published online (J. Am. Coll. Cardiol. 2015 [doi: 10.1016/j.jacc.2015.03.002])

[email protected]

SAN DIEGO – Maintenance of long-term weight loss in obese or overweight individuals with atrial fibrillation was associated with nearly a sixfold greater likelihood of freedom from recurrent AF during nearly 5 years of active follow-up in the LEGACY study.

“The effect was dose dependent. The most important finding is that 46% of patients with at least a 10% weight loss were free from AF without the use of drugs or ablation procedures through nearly 5 years, versus 22% of those with 3%-9% weight loss, and just 13% with less than a 3% weight loss,” Dr. Rajeev K. Pathak said at the annual meeting of the American College of Cardiology.

Nick Piegari/Frontline Medical News

LEGACY (Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study) included 355 overweight or obese participants with paroxsymal or persistent AF who were offered the chance to participate in a dedicated weight-loss clinic. Regular participation in this clinic proved to be a key factor in losing weight, keeping it off, and reducing AF burden; the more frequently patients attended the quarterly sessions the better the outcomes, noted Dr. Pathak, a cardiologist and electrophysiology fellow at the University of Adelaide (Australia).

Of the 355 participants, 135 lost at least 10% of their body weight, 103 had a 3%-9% drop in body weight, and 117 had less than a 3% loss or a weight gain.

Year-by-year weight trends had a significant impact on outcome. The 141 patients with linear weight loss had a 76% AF-free rate with or without the use of drugs or ablation, compared with a 59% in the 179 patients with weight fluctuations and the 38% rate in those with no loss or a weight gain. Atrial fibrillation status was assessed by 7-day Holter monitoring at least annually.

Weight fluctuation – defined as a 1% or greater change in weight between two consecutive annual follow-ups – dampened the benefits conferred by weight loss. Patients who experienced more than a 5% weight fluctuation were 2.2-fold more likely to experience AF recurrence than were those without weight fluctuation.

Patients with a sustained 10% weight loss were 5.6-fold more likely to achieve long-term freedom from AF than were patients with lesser or no weight loss. The goal was 10% weight loss rather than a body mass index of 25 kg/m² or less because once AF patients get down to a BMI below 27 kg/m² the incremental benefit of each additional 1 BMI point in terms of freedom from AF becomes much smaller, said Dr. Pathak.

Weight loss also showed a dose-dependent effect on various cardiovascular risk factors. For example, mean systolic blood pressure fell by 18 mm Hg in subjects with at least a 10% weight loss, by 10 mm Hg with a 3%-9% loss, and by 7 mm Hg with a lesser weight loss. Triglycerides, LDL cholesterol, and glycemic control improved in similar fashion. In addition, weight loss showed beneficial effects on cardiac structure, with dose-dependent reductions in left atrial volume indexed for body surface area as well as interventricular septal thickness, Dr. Pathak continued.

He described the weight loss clinic as a “very simple” structured motivational and goal-directed program with face-to-face counseling.

“We have one patient, one physician, no props. We sit with the patient, discuss areas we can improve, then we devise a low-carb, low-fat, high-protein diet in consultation with the patient. Patients maintain a lifestyle journal where they log their meals and exercise. We prescribe at least 200 minutes of moderate-intensity activity per week. Eating is a behavioral pattern, and we have found this approach to be a very effective behavioral tool. Because the plan is developed in consultation with the patient, we’ve found patients tend to adhere to what they have planned,” he explained.

Discussant Dr. Bernard J. Gersh praised LEGACY as “a really wonderful study – very important.

“There are years of epidemiologic evidence suggesting that obesity contributes in a major way to the epidemic of atrial fibrillation, and you’ve taken it a step further,” added Dr. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.

Playing devil’s advocate, he asked whether the observed reduction in AF might have nothing to do with weight loss, but could be explained simply by LEGACY perhaps having enrolled a highly compliant group of patients who agreed to attend a clinic and were more willing to take their medications.

Dr. Pathak rejected the compliance factor as an explanation for the results. He noted that while cardiovascular risk factors improved with greater weight loss, the need for antihypertensive, lipid-lowering, and antiarrhythmic medications decreased.

“The effect can’t possibly be due to increased compliance with medications, but rather it’s a true effect of the weight loss itself. So I think this is a true clinical effect and not an epiphenomenon,” he replied.

Dr. Pathak added that he and his coinvestigators are organizing a randomized controlled confirmatory study.

Dr. Prediman K. Shah, who chaired a press conference where the LEGACY study was highlighted, said the study provided him with one of the major take-home lessons from ACC 15.

“We can argue about the mechanism of atrial fibrillation till kingdom come, but the fact is that the association is very strong that weight loss is associated with a reduced burden of atrial fibrillation, and with a very robust magnitude of benefit. That’s one of the messages that I’ll take home with me from this meeting: The next time I see my fat patient with atrial fibrillation, I’m putting him on a weight-reducing diet as the first approach,” declared Dr. Shah, professor of medicine at UCLA and director of the Oppenheimer Atherosclerosis Research Center at Cedars-Sinai Medical Center in Los Angeles.

Dr. Pathak reported having no financial conflicts regarding this study, which was supported by university funds.

Simultaneously with Dr. Pathak’s presentation at ACC 15, the LEGACY study was published online (J. Am. Coll. Cardiol. 2015 [doi: 10.1016/j.jacc.2015.03.002])

[email protected]

SAN DIEGO – Maintenance of long-term weight loss in obese or overweight individuals with atrial fibrillation was associated with nearly a sixfold greater likelihood of freedom from recurrent AF during nearly 5 years of active follow-up in the LEGACY study.

“The effect was dose dependent. The most important finding is that 46% of patients with at least a 10% weight loss were free from AF without the use of drugs or ablation procedures through nearly 5 years, versus 22% of those with 3%-9% weight loss, and just 13% with less than a 3% weight loss,” Dr. Rajeev K. Pathak said at the annual meeting of the American College of Cardiology.

Nick Piegari/Frontline Medical News

LEGACY (Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study) included 355 overweight or obese participants with paroxsymal or persistent AF who were offered the chance to participate in a dedicated weight-loss clinic. Regular participation in this clinic proved to be a key factor in losing weight, keeping it off, and reducing AF burden; the more frequently patients attended the quarterly sessions the better the outcomes, noted Dr. Pathak, a cardiologist and electrophysiology fellow at the University of Adelaide (Australia).

Of the 355 participants, 135 lost at least 10% of their body weight, 103 had a 3%-9% drop in body weight, and 117 had less than a 3% loss or a weight gain.

Year-by-year weight trends had a significant impact on outcome. The 141 patients with linear weight loss had a 76% AF-free rate with or without the use of drugs or ablation, compared with a 59% in the 179 patients with weight fluctuations and the 38% rate in those with no loss or a weight gain. Atrial fibrillation status was assessed by 7-day Holter monitoring at least annually.

Weight fluctuation – defined as a 1% or greater change in weight between two consecutive annual follow-ups – dampened the benefits conferred by weight loss. Patients who experienced more than a 5% weight fluctuation were 2.2-fold more likely to experience AF recurrence than were those without weight fluctuation.

Patients with a sustained 10% weight loss were 5.6-fold more likely to achieve long-term freedom from AF than were patients with lesser or no weight loss. The goal was 10% weight loss rather than a body mass index of 25 kg/m² or less because once AF patients get down to a BMI below 27 kg/m² the incremental benefit of each additional 1 BMI point in terms of freedom from AF becomes much smaller, said Dr. Pathak.

Weight loss also showed a dose-dependent effect on various cardiovascular risk factors. For example, mean systolic blood pressure fell by 18 mm Hg in subjects with at least a 10% weight loss, by 10 mm Hg with a 3%-9% loss, and by 7 mm Hg with a lesser weight loss. Triglycerides, LDL cholesterol, and glycemic control improved in similar fashion. In addition, weight loss showed beneficial effects on cardiac structure, with dose-dependent reductions in left atrial volume indexed for body surface area as well as interventricular septal thickness, Dr. Pathak continued.

He described the weight loss clinic as a “very simple” structured motivational and goal-directed program with face-to-face counseling.

“We have one patient, one physician, no props. We sit with the patient, discuss areas we can improve, then we devise a low-carb, low-fat, high-protein diet in consultation with the patient. Patients maintain a lifestyle journal where they log their meals and exercise. We prescribe at least 200 minutes of moderate-intensity activity per week. Eating is a behavioral pattern, and we have found this approach to be a very effective behavioral tool. Because the plan is developed in consultation with the patient, we’ve found patients tend to adhere to what they have planned,” he explained.

Discussant Dr. Bernard J. Gersh praised LEGACY as “a really wonderful study – very important.

“There are years of epidemiologic evidence suggesting that obesity contributes in a major way to the epidemic of atrial fibrillation, and you’ve taken it a step further,” added Dr. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.

Playing devil’s advocate, he asked whether the observed reduction in AF might have nothing to do with weight loss, but could be explained simply by LEGACY perhaps having enrolled a highly compliant group of patients who agreed to attend a clinic and were more willing to take their medications.

Dr. Pathak rejected the compliance factor as an explanation for the results. He noted that while cardiovascular risk factors improved with greater weight loss, the need for antihypertensive, lipid-lowering, and antiarrhythmic medications decreased.

“The effect can’t possibly be due to increased compliance with medications, but rather it’s a true effect of the weight loss itself. So I think this is a true clinical effect and not an epiphenomenon,” he replied.

Dr. Pathak added that he and his coinvestigators are organizing a randomized controlled confirmatory study.

Dr. Prediman K. Shah, who chaired a press conference where the LEGACY study was highlighted, said the study provided him with one of the major take-home lessons from ACC 15.

“We can argue about the mechanism of atrial fibrillation till kingdom come, but the fact is that the association is very strong that weight loss is associated with a reduced burden of atrial fibrillation, and with a very robust magnitude of benefit. That’s one of the messages that I’ll take home with me from this meeting: The next time I see my fat patient with atrial fibrillation, I’m putting him on a weight-reducing diet as the first approach,” declared Dr. Shah, professor of medicine at UCLA and director of the Oppenheimer Atherosclerosis Research Center at Cedars-Sinai Medical Center in Los Angeles.

Dr. Pathak reported having no financial conflicts regarding this study, which was supported by university funds.

Simultaneously with Dr. Pathak’s presentation at ACC 15, the LEGACY study was published online (J. Am. Coll. Cardiol. 2015 [doi: 10.1016/j.jacc.2015.03.002])

[email protected]

Lab mice

Photo by Aaron Logan

Increasing B-cell antigen receptor (BCR) signaling beyond “a point of no return” can lead to the selective elimination of leukemic cells, according to a group of researchers.

The team knew that proximal pre-BCR signaling is toxic to Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) cells, and their experiments revealed that SYK tyrosine kinase activity mimicked constitutively active pre-BCR signaling.

So it was no surprise that pharmacologic hyperactivation of SYK prompted the removal of self-reactive B cells and selective killing of Ph+ ALL cells in vivo.

Markus Müschen, MD, PhD, of the University of California, San Francisco, and his colleagues described these findings in Nature.

When the researchers tested proximal pre-BCR signaling in mouse BCR-ABL1 cells, they found that an incremental increase of SYK activity could induce cell death.

Additional experiments showed that patient-derived Ph+ ALL cells have high levels of the inhibitory receptors PECAM1, CD300A, and LAIR1. And these receptors are needed to calibrate oncogenic signaling strength via recruitment of the inhibitory phosphatases PTPN6 and INPP5D.

So the researchers wondered if a small-molecule inhibitor of INPP5D, known as 3-a-aminocholestane (3AC), could induce SYK hyperactivation and target Ph+ ALL cells in mice.

They found that 3AC eliminated imatinib-resistant Ph+ ALL cells via rapid and massive cell death, and this significantly prolonged survival in the mice.

Dr Müschen and his colleagues noted that only Ph+ ALL cells were marked for destruction, which suggests a BCR-targeted drug could overcome imatinib resistance without affecting normal B cells.

The team also pointed out that a short exposure to 3AC was sufficient to commit the leukemia cells to death and to clear most of the disease burden from mice.

Dr Müschen said 3AC’s fast action was encouraging, because it remains unknown whether prolonged BCR hyperactivation is safe. That is why he and his colleagues are now focusing on formulating hyperactivating drugs that could be administered for only a few hours.

“These experiments show that we can engage signaling checkpoints in a very short period of time and that, once these checkpoints are engaged, the cell is irreversibly slated for death; it’s a point of no return,” Dr Müschen said.

“The next step is to work with medicinal chemists to make better ALL drugs that will overstimulate the B-cell receptor pathway and . . . could be used on a treatment schedule to elicit a very strong, but time-limited, spike in signaling to engage negative B-cell selection.”

Lab mice

Photo by Aaron Logan

Increasing B-cell antigen receptor (BCR) signaling beyond “a point of no return” can lead to the selective elimination of leukemic cells, according to a group of researchers.

The team knew that proximal pre-BCR signaling is toxic to Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) cells, and their experiments revealed that SYK tyrosine kinase activity mimicked constitutively active pre-BCR signaling.

So it was no surprise that pharmacologic hyperactivation of SYK prompted the removal of self-reactive B cells and selective killing of Ph+ ALL cells in vivo.

Markus Müschen, MD, PhD, of the University of California, San Francisco, and his colleagues described these findings in Nature.

When the researchers tested proximal pre-BCR signaling in mouse BCR-ABL1 cells, they found that an incremental increase of SYK activity could induce cell death.

Additional experiments showed that patient-derived Ph+ ALL cells have high levels of the inhibitory receptors PECAM1, CD300A, and LAIR1. And these receptors are needed to calibrate oncogenic signaling strength via recruitment of the inhibitory phosphatases PTPN6 and INPP5D.

So the researchers wondered if a small-molecule inhibitor of INPP5D, known as 3-a-aminocholestane (3AC), could induce SYK hyperactivation and target Ph+ ALL cells in mice.

They found that 3AC eliminated imatinib-resistant Ph+ ALL cells via rapid and massive cell death, and this significantly prolonged survival in the mice.

Dr Müschen and his colleagues noted that only Ph+ ALL cells were marked for destruction, which suggests a BCR-targeted drug could overcome imatinib resistance without affecting normal B cells.

The team also pointed out that a short exposure to 3AC was sufficient to commit the leukemia cells to death and to clear most of the disease burden from mice.

Dr Müschen said 3AC’s fast action was encouraging, because it remains unknown whether prolonged BCR hyperactivation is safe. That is why he and his colleagues are now focusing on formulating hyperactivating drugs that could be administered for only a few hours.

“These experiments show that we can engage signaling checkpoints in a very short period of time and that, once these checkpoints are engaged, the cell is irreversibly slated for death; it’s a point of no return,” Dr Müschen said.

“The next step is to work with medicinal chemists to make better ALL drugs that will overstimulate the B-cell receptor pathway and . . . could be used on a treatment schedule to elicit a very strong, but time-limited, spike in signaling to engage negative B-cell selection.”

Lab mice

Photo by Aaron Logan

Increasing B-cell antigen receptor (BCR) signaling beyond “a point of no return” can lead to the selective elimination of leukemic cells, according to a group of researchers.

The team knew that proximal pre-BCR signaling is toxic to Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) cells, and their experiments revealed that SYK tyrosine kinase activity mimicked constitutively active pre-BCR signaling.

So it was no surprise that pharmacologic hyperactivation of SYK prompted the removal of self-reactive B cells and selective killing of Ph+ ALL cells in vivo.

Markus Müschen, MD, PhD, of the University of California, San Francisco, and his colleagues described these findings in Nature.

When the researchers tested proximal pre-BCR signaling in mouse BCR-ABL1 cells, they found that an incremental increase of SYK activity could induce cell death.

Additional experiments showed that patient-derived Ph+ ALL cells have high levels of the inhibitory receptors PECAM1, CD300A, and LAIR1. And these receptors are needed to calibrate oncogenic signaling strength via recruitment of the inhibitory phosphatases PTPN6 and INPP5D.

So the researchers wondered if a small-molecule inhibitor of INPP5D, known as 3-a-aminocholestane (3AC), could induce SYK hyperactivation and target Ph+ ALL cells in mice.

They found that 3AC eliminated imatinib-resistant Ph+ ALL cells via rapid and massive cell death, and this significantly prolonged survival in the mice.

Dr Müschen and his colleagues noted that only Ph+ ALL cells were marked for destruction, which suggests a BCR-targeted drug could overcome imatinib resistance without affecting normal B cells.

The team also pointed out that a short exposure to 3AC was sufficient to commit the leukemia cells to death and to clear most of the disease burden from mice.

Dr Müschen said 3AC’s fast action was encouraging, because it remains unknown whether prolonged BCR hyperactivation is safe. That is why he and his colleagues are now focusing on formulating hyperactivating drugs that could be administered for only a few hours.

“These experiments show that we can engage signaling checkpoints in a very short period of time and that, once these checkpoints are engaged, the cell is irreversibly slated for death; it’s a point of no return,” Dr Müschen said.

“The next step is to work with medicinal chemists to make better ALL drugs that will overstimulate the B-cell receptor pathway and . . . could be used on a treatment schedule to elicit a very strong, but time-limited, spike in signaling to engage negative B-cell selection.”

Citing a lack of evidence for its effectiveness, the American Academy of Pediatrics opposes school-based drug testing as a means of preventing substance abuse, although the AAP recognizes the need for school-based services for adolescents with substance use disorders, the organization announced in a statement.

Although a recently published study found that students subjected to school-based drug testing reported significantly lower rates of marijuana and other illicit drug use over a 30-day period, compared with students from schools without school-based drug testing, the AAP noted that students with substance abuse problems could be more likely to skip school to avoid testing, or simply use another drug, such as alcohol. Instead, the AAP recommends that schools should focus on enrolling adolescents with substance use disorders in substance abuse prevention programs and other intervention programs and referral systems (Pediatrics 2015 [doi:10.1542/peds.2015-0054]). “Using limited resources to provide advice, counseling, and even on-site treatment of adolescents could both serve a preventive role and increase the number of adolescents who have their substance use disorders addressed and ultimately have a larger effect on reducing student drug use than drug testing alone. The two strategies have never been compared in a scientific study,” according to the AAP statement.

Citing a lack of evidence for its effectiveness, the American Academy of Pediatrics opposes school-based drug testing as a means of preventing substance abuse, although the AAP recognizes the need for school-based services for adolescents with substance use disorders, the organization announced in a statement.

Although a recently published study found that students subjected to school-based drug testing reported significantly lower rates of marijuana and other illicit drug use over a 30-day period, compared with students from schools without school-based drug testing, the AAP noted that students with substance abuse problems could be more likely to skip school to avoid testing, or simply use another drug, such as alcohol. Instead, the AAP recommends that schools should focus on enrolling adolescents with substance use disorders in substance abuse prevention programs and other intervention programs and referral systems (Pediatrics 2015 [doi:10.1542/peds.2015-0054]). “Using limited resources to provide advice, counseling, and even on-site treatment of adolescents could both serve a preventive role and increase the number of adolescents who have their substance use disorders addressed and ultimately have a larger effect on reducing student drug use than drug testing alone. The two strategies have never been compared in a scientific study,” according to the AAP statement.

Citing a lack of evidence for its effectiveness, the American Academy of Pediatrics opposes school-based drug testing as a means of preventing substance abuse, although the AAP recognizes the need for school-based services for adolescents with substance use disorders, the organization announced in a statement.

Although a recently published study found that students subjected to school-based drug testing reported significantly lower rates of marijuana and other illicit drug use over a 30-day period, compared with students from schools without school-based drug testing, the AAP noted that students with substance abuse problems could be more likely to skip school to avoid testing, or simply use another drug, such as alcohol. Instead, the AAP recommends that schools should focus on enrolling adolescents with substance use disorders in substance abuse prevention programs and other intervention programs and referral systems (Pediatrics 2015 [doi:10.1542/peds.2015-0054]). “Using limited resources to provide advice, counseling, and even on-site treatment of adolescents could both serve a preventive role and increase the number of adolescents who have their substance use disorders addressed and ultimately have a larger effect on reducing student drug use than drug testing alone. The two strategies have never been compared in a scientific study,” according to the AAP statement.

Day One highlights from HM15, the Society of Hospital Medicine's (SHM) annual meeting in National Harbor, Md., just outside Washington, D.C.

Day One highlights from HM15, the Society of Hospital Medicine's (SHM) annual meeting in National Harbor, Md., just outside Washington, D.C.

Day One highlights from HM15, the Society of Hospital Medicine's (SHM) annual meeting in National Harbor, Md., just outside Washington, D.C.

SAN DIEGO – Preventive cardiovascular medicine will get “a big boost” from ongoing major randomized controlled trials due to report results during the next several years, Dr. Eric D. Peterson predicted at the annual meeting of the American College of Cardiology.

He presented an overview of eagerly anticipated clinical trials approaching completion in three of the hottest areas of research in general cardiology: new cardiovascular prevention agents and strategies; innovative health policy initiatives; and optimal antithrombotic regimens across the range of chronic coronary artery disease, peripheral vascular disease, patients with atrial fibrillation who’ve undergone percutaneous coronary intervention, and cerebrovascular disease.

Dr. Peterson is executive director of the Duke Clinical Research Institute (DCRI), a major player in some of these studies. To gain additional perspective regarding what’s in store, he consulted a who’s who list of eminent American cardiology clinical trialists as to what’s going to be big in 2016-2017 and shortly beyond.

One thing’s clear looking out at the research horizon: Megatrials enrolling tens of thousands of patients to answer key clinical questions are not a thing of the past.

Far from it.

Cardiovascular prevention

Exciting pivotal phase III cardiovascular prevention trials are well underway in the areas of lipid modification, diabetes, and hypertension. In addition, the possible preventive effect of vitamin D and omega-3 free fatty acid supplementation seen in hypothesis-generating epidemiologic studies is finally being put to a definitive test in a 26,000-subject randomized trial known as VITAL (the Vitamin D and omega-3 trial).

Lipids: All eyes are on ongoing pivotal phase III randomized clinical outcome trials of three monoclonal antibodies that inhibit proprotein convertase subtilisin kexin type 9 (PCSK9): the 22,500-patient FOURIER trial of evolocumab, which includes 9,000 patients older than 65 years; the 18,000-patient ODYSSEY Outcomes trial of alirocumab; and the SPIRE-1 and SPIRE-2 trials of bococizumab totaling 18,300 patients.

In phase II studies, these agents have generated enormous excitement, because they safely achieve unprecedented LDL lowering, with early hints of improved clinical outcomes beyond what’s achievable with today’s drugs, noted Dr. Peterson, professor of medicine at Duke University in Durham, N.C.

CETP inhibitors: The cholesteryl ester transfer protein inhibitors torcetrapib and dalcetrapib flamed out in clinical trials because of safety concerns and lack of clinical benefit. But pivotal phase III trials of two other CETP inhibitors are well underway: anacetrapib, which is the focus of the 30,000-patient REVEAL trial; and evacetrapib, featured in the 11,000-patient ACCELERATE trial. The CETP inhibitors simultaneously boost HDL while reducing LDL.

Diabetes: The search continues for new drugs that not only enhance diabetes control but also improve cardiovascular outcomes, or at the very least are safe in diabetes patients with coronary disease.

Next up is the nearly 15,000-patient Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), coordinated by the DCRI and University of Oxford. It’s due to be presented in June at the annual meeting of the American Diabetes Association in Boston. Trials of other dipeptidyl peptidase-4 inhibitors have shown evidence of an increased risk of heart failure, specifically with saxagliptin in the SAVOR-TIMI 53 trial and alogliptin in EXAMINE, so a lot is riding on TECOS.

The glucagon-like peptide-1 (GLP-1) agonists are under study in cardiovascular event-driven randomized clinical trials collectively totaling more than 33,000 patients with type 2 diabetes. The Exenatide Study of Cardiovascular Event Lowering (EXSCEL), also coordinated by the DCRI and University of Oxford, includes 14,000 randomized patients. Other major trials of GLP-1 agonists are ELIXA (lixisenatide), LEADER (liraglutide), and REWIND (dulaglutide).

In addition, ongoing phase III trials of sodium glucose cotransporter 2 (SGLT-2) inhibitors with cardiovascular endpoints include the Canagliflozin Cardiovascular Assessment Study (CANVAS) and a 7,000-patient study of empagliflozin known as EMPA-REG OUTCOME.

Hypertension: The Systolic Blood Pressure Intervention Trial (SPRINT) is an NIH-funded, randomized trial designed to finally answer a question bothering physicians for years: What’s the right amount of blood pressure lowering?

Nearly 9,400 high-risk patients with clinical or subclinical cardiovascular disease have been randomized to a target systolic blood pressure of less than 120 mm Hg, compared with less than 140 mm Hg. The primary composite endpoint is cardiovascular death, nonfatal MI or stroke, or hospitalization for acute coronary syndrome. Secondary endpoints focus on cognitive impairment, dementia, and rates of progression of chronic kidney disease. Results are expected in 2018.

Vitamin D: The VITAL trial, also sponsored by the NIH, has randomized 25,875 initially healthy men and women to 2,000 IU of vitamin D₃ per day or placebo, and further randomized them to 1 g/day of omega-3 fatty acids or placebo. Key endpoints are total cancers, MI, stroke, and cardiovascular death. Results are coming in 2017.

Optimal antithrombotic therapy

Chronic coronary artery disease: It’s remarkable that physicians still don’t know the right dose of aspirin to use, even though the drug has been around since 1897. The answer is finally on the way. It will come from the ADAPTABLE eTrial, the first comparative effectiveness research project funded by the Patient-Centered Outcomes Research Institute (PCORI).

Twenty thousand U.S. patients with known atherosclerotic cardiovascular disease and at least one extra risk factor will be randomized to daily aspirin at 81 mg or 325 mg and followed for a maximum of 30 months. The primary efficacy endpoint is all-cause mortality, nonfatal MI, or nonfatal stroke. The primary safety endpoint is major bleeding.

This is a groundbreaking innovative study: It’s a 20,000-patient trial budgeted at a mere $10 million – peanuts in the world of megatrials. By comparison, the NIH-funded SPRINT hypertension trial includes less than half as many patients, yet the price tag is $114 million.

The bargain-basement cost of the aspirin trial is possible because follow-up will be via electronic medical records and claims data provided every 3 months by 29 health data networks participating in PCORI’s National Patient-Centered Clinical Research Network (PCORnet). The aspirin study is sort of a shakedown cruise for an exciting new cost-effective approach to conducting comparative effectiveness research.

“This study could be a game changer,” Dr. Peterson declared. “Whether you think the research question is important or not, the ability to utilize electronic health records in long-term patient follow-up in randomized trials will be revolutionary in terms of answering key clinical questions cost effectively.”

Peripheral vascular disease: In search of the antithrombotic regimen that optimizes limb salvage while minimizing vascular event rate, the EUCLID trial has randomized 13,500 patients with symptomatic peripheral artery disease to ticagrelor at 90 mg BID or clopidogrel at 75 mg/day. Follow-up will be for 18 months, with the primary endpoint a composite of cardiovascular death, nonfatal MI, or ischemic stroke.

Atrial fibrillation patients who undergo coronary stent placement: The 2,100-patient PIONEER AF-PCI study, now recruiting, is evaluating different combinations of rivaroxaban in various dosing regimens coupled with clopidogrel, warfarin, and/or aspirin.

Stroke: The SOCRATES trial is recruiting 9,600 patients with acute ischemic stroke or high-risk transient ischemic attack to be randomized within 24 hours to ticagrelor at 90 mg BID or aspirin at 100 mg/day. As with PIONEER, results from SOCRATES are anticipated next year.

Health policy and implementation

The ARTEMIS study poses the question of whether providing a guideline-directed medication gratis will improve patient adherence and/or clinical outcomes.

Some 9,000 high-cardiovascular-risk patients at 300 sites are being randomized to free ticagrelor or clopidogrel – no copay – for 1 year or to usual care. Outcomes include choice of medication, adherence, and major adverse cardiovascular events.

“If this works, there’s the possibility that insurers can be persuaded to pay for medications and basically give them away as a means of ultimately resulting in better outcomes for patients and lower costs,” Dr. Peterson said.

IMPACT AF is an international quality improvement project aimed at improving the use of oral anticoagulation therapy in high-risk patients with atrial fibrillation in Argentina, Brazil, China, India, and Romania. Participating centers will be randomized to receive a provider education and feedback program or not. The primary outcome is a change from baseline through year 1 in the proportion of patients with atrial fibrillation taking an oral anticoagulant.

In summing up the state of research in general cardiology, Dr. Peterson observed, “The way we do trials is changing. The size of the studies is changing. But ultimately, we will find better ways to treat patients, and perhaps we can find better ways to encourage patients to take their medications long term.”

Dr. Peterson reported serving as a consultant to AstraZeneca Boehringer Ingelheim, Genentech, Janssen, and Sanofi, and receiving research funding from Eli Lilly and Janssen.

[email protected]


SAN DIEGO – Preventive cardiovascular medicine will get “a big boost” from ongoing major randomized controlled trials due to report results during the next several years, Dr. Eric D. Peterson predicted at the annual meeting of the American College of Cardiology.

He presented an overview of eagerly anticipated clinical trials approaching completion in three of the hottest areas of research in general cardiology: new cardiovascular prevention agents and strategies; innovative health policy initiatives; and optimal antithrombotic regimens across the range of chronic coronary artery disease, peripheral vascular disease, patients with atrial fibrillation who’ve undergone percutaneous coronary intervention, and cerebrovascular disease.

Dr. Peterson is executive director of the Duke Clinical Research Institute (DCRI), a major player in some of these studies. To gain additional perspective regarding what’s in store, he consulted a who’s who list of eminent American cardiology clinical trialists as to what’s going to be big in 2016-2017 and shortly beyond.

One thing’s clear looking out at the research horizon: Megatrials enrolling tens of thousands of patients to answer key clinical questions are not a thing of the past.

Far from it.

Cardiovascular prevention

Exciting pivotal phase III cardiovascular prevention trials are well underway in the areas of lipid modification, diabetes, and hypertension. In addition, the possible preventive effect of vitamin D and omega-3 free fatty acid supplementation seen in hypothesis-generating epidemiologic studies is finally being put to a definitive test in a 26,000-subject randomized trial known as VITAL (the Vitamin D and omega-3 trial).

Lipids: All eyes are on ongoing pivotal phase III randomized clinical outcome trials of three monoclonal antibodies that inhibit proprotein convertase subtilisin kexin type 9 (PCSK9): the 22,500-patient FOURIER trial of evolocumab, which includes 9,000 patients older than 65 years; the 18,000-patient ODYSSEY Outcomes trial of alirocumab; and the SPIRE-1 and SPIRE-2 trials of bococizumab totaling 18,300 patients.

In phase II studies, these agents have generated enormous excitement, because they safely achieve unprecedented LDL lowering, with early hints of improved clinical outcomes beyond what’s achievable with today’s drugs, noted Dr. Peterson, professor of medicine at Duke University in Durham, N.C.

CETP inhibitors: The cholesteryl ester transfer protein inhibitors torcetrapib and dalcetrapib flamed out in clinical trials because of safety concerns and lack of clinical benefit. But pivotal phase III trials of two other CETP inhibitors are well underway: anacetrapib, which is the focus of the 30,000-patient REVEAL trial; and evacetrapib, featured in the 11,000-patient ACCELERATE trial. The CETP inhibitors simultaneously boost HDL while reducing LDL.

Diabetes: The search continues for new drugs that not only enhance diabetes control but also improve cardiovascular outcomes, or at the very least are safe in diabetes patients with coronary disease.

Next up is the nearly 15,000-patient Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), coordinated by the DCRI and University of Oxford. It’s due to be presented in June at the annual meeting of the American Diabetes Association in Boston. Trials of other dipeptidyl peptidase-4 inhibitors have shown evidence of an increased risk of heart failure, specifically with saxagliptin in the SAVOR-TIMI 53 trial and alogliptin in EXAMINE, so a lot is riding on TECOS.

The glucagon-like peptide-1 (GLP-1) agonists are under study in cardiovascular event-driven randomized clinical trials collectively totaling more than 33,000 patients with type 2 diabetes. The Exenatide Study of Cardiovascular Event Lowering (EXSCEL), also coordinated by the DCRI and University of Oxford, includes 14,000 randomized patients. Other major trials of GLP-1 agonists are ELIXA (lixisenatide), LEADER (liraglutide), and REWIND (dulaglutide).

In addition, ongoing phase III trials of sodium glucose cotransporter 2 (SGLT-2) inhibitors with cardiovascular endpoints include the Canagliflozin Cardiovascular Assessment Study (CANVAS) and a 7,000-patient study of empagliflozin known as EMPA-REG OUTCOME.

Hypertension: The Systolic Blood Pressure Intervention Trial (SPRINT) is an NIH-funded, randomized trial designed to finally answer a question bothering physicians for years: What’s the right amount of blood pressure lowering?

Nearly 9,400 high-risk patients with clinical or subclinical cardiovascular disease have been randomized to a target systolic blood pressure of less than 120 mm Hg, compared with less than 140 mm Hg. The primary composite endpoint is cardiovascular death, nonfatal MI or stroke, or hospitalization for acute coronary syndrome. Secondary endpoints focus on cognitive impairment, dementia, and rates of progression of chronic kidney disease. Results are expected in 2018.

Vitamin D: The VITAL trial, also sponsored by the NIH, has randomized 25,875 initially healthy men and women to 2,000 IU of vitamin D₃ per day or placebo, and further randomized them to 1 g/day of omega-3 fatty acids or placebo. Key endpoints are total cancers, MI, stroke, and cardiovascular death. Results are coming in 2017.

Optimal antithrombotic therapy

Chronic coronary artery disease: It’s remarkable that physicians still don’t know the right dose of aspirin to use, even though the drug has been around since 1897. The answer is finally on the way. It will come from the ADAPTABLE eTrial, the first comparative effectiveness research project funded by the Patient-Centered Outcomes Research Institute (PCORI).

Twenty thousand U.S. patients with known atherosclerotic cardiovascular disease and at least one extra risk factor will be randomized to daily aspirin at 81 mg or 325 mg and followed for a maximum of 30 months. The primary efficacy endpoint is all-cause mortality, nonfatal MI, or nonfatal stroke. The primary safety endpoint is major bleeding.

This is a groundbreaking innovative study: It’s a 20,000-patient trial budgeted at a mere $10 million – peanuts in the world of megatrials. By comparison, the NIH-funded SPRINT hypertension trial includes less than half as many patients, yet the price tag is $114 million.

The bargain-basement cost of the aspirin trial is possible because follow-up will be via electronic medical records and claims data provided every 3 months by 29 health data networks participating in PCORI’s National Patient-Centered Clinical Research Network (PCORnet). The aspirin study is sort of a shakedown cruise for an exciting new cost-effective approach to conducting comparative effectiveness research.

“This study could be a game changer,” Dr. Peterson declared. “Whether you think the research question is important or not, the ability to utilize electronic health records in long-term patient follow-up in randomized trials will be revolutionary in terms of answering key clinical questions cost effectively.”

Peripheral vascular disease: In search of the antithrombotic regimen that optimizes limb salvage while minimizing vascular event rate, the EUCLID trial has randomized 13,500 patients with symptomatic peripheral artery disease to ticagrelor at 90 mg BID or clopidogrel at 75 mg/day. Follow-up will be for 18 months, with the primary endpoint a composite of cardiovascular death, nonfatal MI, or ischemic stroke.

Atrial fibrillation patients who undergo coronary stent placement: The 2,100-patient PIONEER AF-PCI study, now recruiting, is evaluating different combinations of rivaroxaban in various dosing regimens coupled with clopidogrel, warfarin, and/or aspirin.

Stroke: The SOCRATES trial is recruiting 9,600 patients with acute ischemic stroke or high-risk transient ischemic attack to be randomized within 24 hours to ticagrelor at 90 mg BID or aspirin at 100 mg/day. As with PIONEER, results from SOCRATES are anticipated next year.

Health policy and implementation

The ARTEMIS study poses the question of whether providing a guideline-directed medication gratis will improve patient adherence and/or clinical outcomes.

Some 9,000 high-cardiovascular-risk patients at 300 sites are being randomized to free ticagrelor or clopidogrel – no copay – for 1 year or to usual care. Outcomes include choice of medication, adherence, and major adverse cardiovascular events.

“If this works, there’s the possibility that insurers can be persuaded to pay for medications and basically give them away as a means of ultimately resulting in better outcomes for patients and lower costs,” Dr. Peterson said.

IMPACT AF is an international quality improvement project aimed at improving the use of oral anticoagulation therapy in high-risk patients with atrial fibrillation in Argentina, Brazil, China, India, and Romania. Participating centers will be randomized to receive a provider education and feedback program or not. The primary outcome is a change from baseline through year 1 in the proportion of patients with atrial fibrillation taking an oral anticoagulant.

In summing up the state of research in general cardiology, Dr. Peterson observed, “The way we do trials is changing. The size of the studies is changing. But ultimately, we will find better ways to treat patients, and perhaps we can find better ways to encourage patients to take their medications long term.”

Dr. Peterson reported serving as a consultant to AstraZeneca Boehringer Ingelheim, Genentech, Janssen, and Sanofi, and receiving research funding from Eli Lilly and Janssen.

[email protected]


SAN DIEGO – Preventive cardiovascular medicine will get “a big boost” from ongoing major randomized controlled trials due to report results during the next several years, Dr. Eric D. Peterson predicted at the annual meeting of the American College of Cardiology.

He presented an overview of eagerly anticipated clinical trials approaching completion in three of the hottest areas of research in general cardiology: new cardiovascular prevention agents and strategies; innovative health policy initiatives; and optimal antithrombotic regimens across the range of chronic coronary artery disease, peripheral vascular disease, patients with atrial fibrillation who’ve undergone percutaneous coronary intervention, and cerebrovascular disease.

Dr. Peterson is executive director of the Duke Clinical Research Institute (DCRI), a major player in some of these studies. To gain additional perspective regarding what’s in store, he consulted a who’s who list of eminent American cardiology clinical trialists as to what’s going to be big in 2016-2017 and shortly beyond.

One thing’s clear looking out at the research horizon: Megatrials enrolling tens of thousands of patients to answer key clinical questions are not a thing of the past.

Far from it.

Cardiovascular prevention

Exciting pivotal phase III cardiovascular prevention trials are well underway in the areas of lipid modification, diabetes, and hypertension. In addition, the possible preventive effect of vitamin D and omega-3 free fatty acid supplementation seen in hypothesis-generating epidemiologic studies is finally being put to a definitive test in a 26,000-subject randomized trial known as VITAL (the Vitamin D and omega-3 trial).

Lipids: All eyes are on ongoing pivotal phase III randomized clinical outcome trials of three monoclonal antibodies that inhibit proprotein convertase subtilisin kexin type 9 (PCSK9): the 22,500-patient FOURIER trial of evolocumab, which includes 9,000 patients older than 65 years; the 18,000-patient ODYSSEY Outcomes trial of alirocumab; and the SPIRE-1 and SPIRE-2 trials of bococizumab totaling 18,300 patients.

In phase II studies, these agents have generated enormous excitement, because they safely achieve unprecedented LDL lowering, with early hints of improved clinical outcomes beyond what’s achievable with today’s drugs, noted Dr. Peterson, professor of medicine at Duke University in Durham, N.C.

CETP inhibitors: The cholesteryl ester transfer protein inhibitors torcetrapib and dalcetrapib flamed out in clinical trials because of safety concerns and lack of clinical benefit. But pivotal phase III trials of two other CETP inhibitors are well underway: anacetrapib, which is the focus of the 30,000-patient REVEAL trial; and evacetrapib, featured in the 11,000-patient ACCELERATE trial. The CETP inhibitors simultaneously boost HDL while reducing LDL.

Diabetes: The search continues for new drugs that not only enhance diabetes control but also improve cardiovascular outcomes, or at the very least are safe in diabetes patients with coronary disease.

Next up is the nearly 15,000-patient Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), coordinated by the DCRI and University of Oxford. It’s due to be presented in June at the annual meeting of the American Diabetes Association in Boston. Trials of other dipeptidyl peptidase-4 inhibitors have shown evidence of an increased risk of heart failure, specifically with saxagliptin in the SAVOR-TIMI 53 trial and alogliptin in EXAMINE, so a lot is riding on TECOS.

The glucagon-like peptide-1 (GLP-1) agonists are under study in cardiovascular event-driven randomized clinical trials collectively totaling more than 33,000 patients with type 2 diabetes. The Exenatide Study of Cardiovascular Event Lowering (EXSCEL), also coordinated by the DCRI and University of Oxford, includes 14,000 randomized patients. Other major trials of GLP-1 agonists are ELIXA (lixisenatide), LEADER (liraglutide), and REWIND (dulaglutide).

In addition, ongoing phase III trials of sodium glucose cotransporter 2 (SGLT-2) inhibitors with cardiovascular endpoints include the Canagliflozin Cardiovascular Assessment Study (CANVAS) and a 7,000-patient study of empagliflozin known as EMPA-REG OUTCOME.

Hypertension: The Systolic Blood Pressure Intervention Trial (SPRINT) is an NIH-funded, randomized trial designed to finally answer a question bothering physicians for years: What’s the right amount of blood pressure lowering?

Nearly 9,400 high-risk patients with clinical or subclinical cardiovascular disease have been randomized to a target systolic blood pressure of less than 120 mm Hg, compared with less than 140 mm Hg. The primary composite endpoint is cardiovascular death, nonfatal MI or stroke, or hospitalization for acute coronary syndrome. Secondary endpoints focus on cognitive impairment, dementia, and rates of progression of chronic kidney disease. Results are expected in 2018.

Vitamin D: The VITAL trial, also sponsored by the NIH, has randomized 25,875 initially healthy men and women to 2,000 IU of vitamin D₃ per day or placebo, and further randomized them to 1 g/day of omega-3 fatty acids or placebo. Key endpoints are total cancers, MI, stroke, and cardiovascular death. Results are coming in 2017.

Optimal antithrombotic therapy

Chronic coronary artery disease: It’s remarkable that physicians still don’t know the right dose of aspirin to use, even though the drug has been around since 1897. The answer is finally on the way. It will come from the ADAPTABLE eTrial, the first comparative effectiveness research project funded by the Patient-Centered Outcomes Research Institute (PCORI).

Twenty thousand U.S. patients with known atherosclerotic cardiovascular disease and at least one extra risk factor will be randomized to daily aspirin at 81 mg or 325 mg and followed for a maximum of 30 months. The primary efficacy endpoint is all-cause mortality, nonfatal MI, or nonfatal stroke. The primary safety endpoint is major bleeding.

This is a groundbreaking innovative study: It’s a 20,000-patient trial budgeted at a mere $10 million – peanuts in the world of megatrials. By comparison, the NIH-funded SPRINT hypertension trial includes less than half as many patients, yet the price tag is $114 million.

The bargain-basement cost of the aspirin trial is possible because follow-up will be via electronic medical records and claims data provided every 3 months by 29 health data networks participating in PCORI’s National Patient-Centered Clinical Research Network (PCORnet). The aspirin study is sort of a shakedown cruise for an exciting new cost-effective approach to conducting comparative effectiveness research.

“This study could be a game changer,” Dr. Peterson declared. “Whether you think the research question is important or not, the ability to utilize electronic health records in long-term patient follow-up in randomized trials will be revolutionary in terms of answering key clinical questions cost effectively.”

Peripheral vascular disease: In search of the antithrombotic regimen that optimizes limb salvage while minimizing vascular event rate, the EUCLID trial has randomized 13,500 patients with symptomatic peripheral artery disease to ticagrelor at 90 mg BID or clopidogrel at 75 mg/day. Follow-up will be for 18 months, with the primary endpoint a composite of cardiovascular death, nonfatal MI, or ischemic stroke.

Atrial fibrillation patients who undergo coronary stent placement: The 2,100-patient PIONEER AF-PCI study, now recruiting, is evaluating different combinations of rivaroxaban in various dosing regimens coupled with clopidogrel, warfarin, and/or aspirin.

Stroke: The SOCRATES trial is recruiting 9,600 patients with acute ischemic stroke or high-risk transient ischemic attack to be randomized within 24 hours to ticagrelor at 90 mg BID or aspirin at 100 mg/day. As with PIONEER, results from SOCRATES are anticipated next year.

Health policy and implementation

The ARTEMIS study poses the question of whether providing a guideline-directed medication gratis will improve patient adherence and/or clinical outcomes.

Some 9,000 high-cardiovascular-risk patients at 300 sites are being randomized to free ticagrelor or clopidogrel – no copay – for 1 year or to usual care. Outcomes include choice of medication, adherence, and major adverse cardiovascular events.

“If this works, there’s the possibility that insurers can be persuaded to pay for medications and basically give them away as a means of ultimately resulting in better outcomes for patients and lower costs,” Dr. Peterson said.

IMPACT AF is an international quality improvement project aimed at improving the use of oral anticoagulation therapy in high-risk patients with atrial fibrillation in Argentina, Brazil, China, India, and Romania. Participating centers will be randomized to receive a provider education and feedback program or not. The primary outcome is a change from baseline through year 1 in the proportion of patients with atrial fibrillation taking an oral anticoagulant.

In summing up the state of research in general cardiology, Dr. Peterson observed, “The way we do trials is changing. The size of the studies is changing. But ultimately, we will find better ways to treat patients, and perhaps we can find better ways to encourage patients to take their medications long term.”

Dr. Peterson reported serving as a consultant to AstraZeneca Boehringer Ingelheim, Genentech, Janssen, and Sanofi, and receiving research funding from Eli Lilly and Janssen.

[email protected]


Thrombus

Image by Andre E.X. Brown

A new approach for treating thrombotic thrombocytopenic purpura (TTP) has proven effective in mice, according to a paper published in Blood.

Researchers showed they could “hide” functional recombinant human ADAMTS13 (rADAMTS13) inside mouse platelets to prevent antibodies from impairing ADAMTS13 activity.

These rADAMTS13-expressing platelets were able to inhibit thrombosis and prevent the development of hereditary and acquired TTP in mice.

If a similar technique were to prove effective in humans, it could reduce the amount of plasma transfusions TTP patients require, the researchers said.

They also believe such a method could be used in emergency situations to treat strokes, heart attacks, malignant malaria, and pre-eclampsia, as all of these conditions are associated with relative deficiency of plasma ADAMTS13 activity.

This research began when X. Long Zheng, MD, PhD, of the University of Alabama at Birmingham, had the idea that he could treat TTP by hiding ADAMTS13 inside platelets where autoantibodies can’t see it.

He reasoned that, if he could fill platelets with ADAMTS13, the platelets would then carry the enzyme right to the place it was most needed to dissolve thrombi.

So he and his colleagues developed transgenic mice that expressed rADAMTS13 in their platelets.

The platelets had normal agglutination and aggregation. And they released rADAMTS13 upon stimulation with thrombin and collagen, although they released less when stimulated with 2MesADP.

Mice with rADAMTS13-expressing platelets were significantly protected in a vascular injury model of thrombus formation.

In mice that lacked plasma ADAMTS13 activity due to ADAMTS13 gene deletion and those that had antibody-mediated inhibition of plasma ADAMTS13 activity, rADAMTS13-expressing platelets protected the animals against TTP induced by bacterial toxin or recombinant von Willebrand factor.

These results, the researchers said, “suggest that platelets may be ideal carriers for antithrombic ADAMTS13, allowing its release at high concentrations at the site of thrombus formation without being inactivated by the potential circulating anti-ADAMTS13 inhibitors.”

To employ this treatment method in humans, Dr Zheng said researchers could investigate how to load ADAMTS13 inside donated platelets. They could then test these platelets to learn how many ADAMTS13-loaded platelets need to be transfused to produce antithrombotic and anti-TTP effects in patients with TTP.

Thrombus

Image by Andre E.X. Brown

A new approach for treating thrombotic thrombocytopenic purpura (TTP) has proven effective in mice, according to a paper published in Blood.

Researchers showed they could “hide” functional recombinant human ADAMTS13 (rADAMTS13) inside mouse platelets to prevent antibodies from impairing ADAMTS13 activity.

These rADAMTS13-expressing platelets were able to inhibit thrombosis and prevent the development of hereditary and acquired TTP in mice.

If a similar technique were to prove effective in humans, it could reduce the amount of plasma transfusions TTP patients require, the researchers said.

They also believe such a method could be used in emergency situations to treat strokes, heart attacks, malignant malaria, and pre-eclampsia, as all of these conditions are associated with relative deficiency of plasma ADAMTS13 activity.

This research began when X. Long Zheng, MD, PhD, of the University of Alabama at Birmingham, had the idea that he could treat TTP by hiding ADAMTS13 inside platelets where autoantibodies can’t see it.

He reasoned that, if he could fill platelets with ADAMTS13, the platelets would then carry the enzyme right to the place it was most needed to dissolve thrombi.

So he and his colleagues developed transgenic mice that expressed rADAMTS13 in their platelets.

The platelets had normal agglutination and aggregation. And they released rADAMTS13 upon stimulation with thrombin and collagen, although they released less when stimulated with 2MesADP.

Mice with rADAMTS13-expressing platelets were significantly protected in a vascular injury model of thrombus formation.

In mice that lacked plasma ADAMTS13 activity due to ADAMTS13 gene deletion and those that had antibody-mediated inhibition of plasma ADAMTS13 activity, rADAMTS13-expressing platelets protected the animals against TTP induced by bacterial toxin or recombinant von Willebrand factor.

These results, the researchers said, “suggest that platelets may be ideal carriers for antithrombic ADAMTS13, allowing its release at high concentrations at the site of thrombus formation without being inactivated by the potential circulating anti-ADAMTS13 inhibitors.”

To employ this treatment method in humans, Dr Zheng said researchers could investigate how to load ADAMTS13 inside donated platelets. They could then test these platelets to learn how many ADAMTS13-loaded platelets need to be transfused to produce antithrombotic and anti-TTP effects in patients with TTP.

Thrombus

Image by Andre E.X. Brown

A new approach for treating thrombotic thrombocytopenic purpura (TTP) has proven effective in mice, according to a paper published in Blood.

Researchers showed they could “hide” functional recombinant human ADAMTS13 (rADAMTS13) inside mouse platelets to prevent antibodies from impairing ADAMTS13 activity.

These rADAMTS13-expressing platelets were able to inhibit thrombosis and prevent the development of hereditary and acquired TTP in mice.

If a similar technique were to prove effective in humans, it could reduce the amount of plasma transfusions TTP patients require, the researchers said.

They also believe such a method could be used in emergency situations to treat strokes, heart attacks, malignant malaria, and pre-eclampsia, as all of these conditions are associated with relative deficiency of plasma ADAMTS13 activity.

This research began when X. Long Zheng, MD, PhD, of the University of Alabama at Birmingham, had the idea that he could treat TTP by hiding ADAMTS13 inside platelets where autoantibodies can’t see it.

He reasoned that, if he could fill platelets with ADAMTS13, the platelets would then carry the enzyme right to the place it was most needed to dissolve thrombi.

So he and his colleagues developed transgenic mice that expressed rADAMTS13 in their platelets.

The platelets had normal agglutination and aggregation. And they released rADAMTS13 upon stimulation with thrombin and collagen, although they released less when stimulated with 2MesADP.

Mice with rADAMTS13-expressing platelets were significantly protected in a vascular injury model of thrombus formation.

In mice that lacked plasma ADAMTS13 activity due to ADAMTS13 gene deletion and those that had antibody-mediated inhibition of plasma ADAMTS13 activity, rADAMTS13-expressing platelets protected the animals against TTP induced by bacterial toxin or recombinant von Willebrand factor.

These results, the researchers said, “suggest that platelets may be ideal carriers for antithrombic ADAMTS13, allowing its release at high concentrations at the site of thrombus formation without being inactivated by the potential circulating anti-ADAMTS13 inhibitors.”

To employ this treatment method in humans, Dr Zheng said researchers could investigate how to load ADAMTS13 inside donated platelets. They could then test these platelets to learn how many ADAMTS13-loaded platelets need to be transfused to produce antithrombotic and anti-TTP effects in patients with TTP.

SAN DIEGO – Patients aged 80 years and older benefit from more invasive early treatment after non-ST-elevation myocardial infarction or unstable angina, the After Eighty Trial showed.

After a median follow-up of 1.5 years, an invasive strategy that included coronary angiography significantly reduced the primary endpoint of myocardial infarction (MI), need for urgent revascularization, stroke, and death from 61% with optimal medical treatment to 41% (risk ratio, 0.48; P value < .00001).

That drop was driven primarily by significantly fewer MIs (17% vs. 30%; RR, 0.50; P = .0003) and urgent revascularizations (2% vs. 11%; RR, 0.19; P = .0001), lead author Dr. Nicolai Tegn reported at the American College of Cardiology/Cardiovascular Research Foundation Innovation in Intervention Summit.

There were no significant differences between the invasive and conservative strategy groups in rates of stroke (3% vs. 6%; RR, 0.61; P = .26) or all-cause death (25% vs. 27%; RR, 0.87; P = .53).

The composite of death and MI, however, significantly favored the invasive group (35% vs. 48%; RR, 0.54; P < .0001), he said during a latebreaking clinical trial session.

After Eighty randomly assigned 457 patients, aged 80 years or older, to either optimal medical therapy with no invasive treatments or coronary angiography at a percutaneous coronary intervention (PCI) center the day after inclusion, plus optimal medical therapy after about 4-5 hours if PCI was not performed or about 6-18 hours if it was. Of the 225 patients receiving angiography, 48% went on to balloon angioplasty and/or coronary stenting, and 3% had bypass surgery.

Patients 80 years or older account for roughly one-third of all patients with non-STEMI and unstable angina, but they are underrepresented in clinical trials. As a result, the role of an early invasive strategy, and even an invasive strategy at all, in those elderly patients is still a subject of debate, observed Dr. Tegn, a cardiologist from Rikshospitalet, Oslo University Hospital, Oslo.

The study demonstrated that an invasive strategy is superior to a conservative strategy in patients at least 80 years with NSTEMI or unstable angina, he concluded.

After Eighty is a welcome study because of the under-representation of the elderly in clinical trials, Dr. David Kandzari, director of interventional cardiology at the Piedmont Heart Center in Atlanta, said during a press briefing at the meeting. But it raises the challenge of identifying patients in clinical practice with the same qualifying characteristics, he added, given that the study population represents only 10% of the entire screened population,

There was also a fairly high prevalence of patients who angiographically did not have significant coronary artery disease, yet MI and stroke rates were quite considerable.

That said, “the study in other ways reminds us that the coronary anatomy does not know the age of the patient, meaning that the findings of a benefit of an early invasive strategy seem consistent with previous studies we know across the management of patients with acute coronary syndromes,” Dr. Kandzari said.

After Eighty investigators screened 4,187 elderly patients presenting at 17 community hospitals in Norway with non-STEMI or unstable angina, with or without ST-segment depression in ECG, and normal or elevated troponin T or I levels. Patients had to have no chest pain or other ischemic symptoms after medical treatment and mobilization.

In all, 3,730 patients were excluded for life expectancy less than 12 months because of a serious comorbidity; ongoing or recent bleeding; inability to comply with protocol; clinically unstable including ongoing ischemia; refusal to participate; logistic reasons; or other reasons.

The average age was 84.7 years in the invasive group (range 80-93 years) and 84.9 years in the conservative group (range 80-94 years).

Medical treatment during the index admission included 75 mg aspirin in 97% of both the invasive and conservative groups, clopidogrel (85% vs. 82%), ticagrelor (both 5%), angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blockers (ARB) (43% vs. 50%), beta blocker (83% vs. 85%), statins (90% vs. 85%), loop or thiazide diuretics (41% vs. 33%), calcium channel blocker (20% vs. 21%), nitrates (45% vs. 55%), warfarin (17% vs. 9%), low molecular-weight heparin (both 76% ), and dabigatran in one patient in each group.

Medical therapy at discharge in the invasive and conservative groups was aspirin (both 93%), clopidogrel (both 72%), ticagrelor (both 4%), ACE inhibitor/ARB (52% vs. 54%), beta blockers (both 84%), statins (90% vs. 86%), diuretics (45% vs. 38%), calcium channel blocker (24% vs. 23%), nitrates (34% vs. 48%), warfarin (21% vs. 14%), rivaroxaban (three patients in both groups), and dabigatran (one patient vs. six patients).

There were no differences in bleeding rates between the two groups, Dr. Tegn said. Four major bleeding events were reported in both groups, while 23 patients in the invasive group and 16 patients in the conservative group had minor bleeds.

The Norwegian Health Association sponsored the study. Dr. Tegn reported nothing to disclose. Dr. Kandazari reported research and grant support from Abbott Vascular, Biotronic, Boston Scientific, and Medtronic, and minor consulting honoraria from Boston Scientific and Medtronic.

[email protected]

SAN DIEGO – Patients aged 80 years and older benefit from more invasive early treatment after non-ST-elevation myocardial infarction or unstable angina, the After Eighty Trial showed.

After a median follow-up of 1.5 years, an invasive strategy that included coronary angiography significantly reduced the primary endpoint of myocardial infarction (MI), need for urgent revascularization, stroke, and death from 61% with optimal medical treatment to 41% (risk ratio, 0.48; P value < .00001).

That drop was driven primarily by significantly fewer MIs (17% vs. 30%; RR, 0.50; P = .0003) and urgent revascularizations (2% vs. 11%; RR, 0.19; P = .0001), lead author Dr. Nicolai Tegn reported at the American College of Cardiology/Cardiovascular Research Foundation Innovation in Intervention Summit.

There were no significant differences between the invasive and conservative strategy groups in rates of stroke (3% vs. 6%; RR, 0.61; P = .26) or all-cause death (25% vs. 27%; RR, 0.87; P = .53).

The composite of death and MI, however, significantly favored the invasive group (35% vs. 48%; RR, 0.54; P < .0001), he said during a latebreaking clinical trial session.

After Eighty randomly assigned 457 patients, aged 80 years or older, to either optimal medical therapy with no invasive treatments or coronary angiography at a percutaneous coronary intervention (PCI) center the day after inclusion, plus optimal medical therapy after about 4-5 hours if PCI was not performed or about 6-18 hours if it was. Of the 225 patients receiving angiography, 48% went on to balloon angioplasty and/or coronary stenting, and 3% had bypass surgery.

Patients 80 years or older account for roughly one-third of all patients with non-STEMI and unstable angina, but they are underrepresented in clinical trials. As a result, the role of an early invasive strategy, and even an invasive strategy at all, in those elderly patients is still a subject of debate, observed Dr. Tegn, a cardiologist from Rikshospitalet, Oslo University Hospital, Oslo.

The study demonstrated that an invasive strategy is superior to a conservative strategy in patients at least 80 years with NSTEMI or unstable angina, he concluded.

After Eighty is a welcome study because of the under-representation of the elderly in clinical trials, Dr. David Kandzari, director of interventional cardiology at the Piedmont Heart Center in Atlanta, said during a press briefing at the meeting. But it raises the challenge of identifying patients in clinical practice with the same qualifying characteristics, he added, given that the study population represents only 10% of the entire screened population,

There was also a fairly high prevalence of patients who angiographically did not have significant coronary artery disease, yet MI and stroke rates were quite considerable.

That said, “the study in other ways reminds us that the coronary anatomy does not know the age of the patient, meaning that the findings of a benefit of an early invasive strategy seem consistent with previous studies we know across the management of patients with acute coronary syndromes,” Dr. Kandzari said.

After Eighty investigators screened 4,187 elderly patients presenting at 17 community hospitals in Norway with non-STEMI or unstable angina, with or without ST-segment depression in ECG, and normal or elevated troponin T or I levels. Patients had to have no chest pain or other ischemic symptoms after medical treatment and mobilization.

In all, 3,730 patients were excluded for life expectancy less than 12 months because of a serious comorbidity; ongoing or recent bleeding; inability to comply with protocol; clinically unstable including ongoing ischemia; refusal to participate; logistic reasons; or other reasons.

The average age was 84.7 years in the invasive group (range 80-93 years) and 84.9 years in the conservative group (range 80-94 years).

Medical treatment during the index admission included 75 mg aspirin in 97% of both the invasive and conservative groups, clopidogrel (85% vs. 82%), ticagrelor (both 5%), angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blockers (ARB) (43% vs. 50%), beta blocker (83% vs. 85%), statins (90% vs. 85%), loop or thiazide diuretics (41% vs. 33%), calcium channel blocker (20% vs. 21%), nitrates (45% vs. 55%), warfarin (17% vs. 9%), low molecular-weight heparin (both 76% ), and dabigatran in one patient in each group.

Medical therapy at discharge in the invasive and conservative groups was aspirin (both 93%), clopidogrel (both 72%), ticagrelor (both 4%), ACE inhibitor/ARB (52% vs. 54%), beta blockers (both 84%), statins (90% vs. 86%), diuretics (45% vs. 38%), calcium channel blocker (24% vs. 23%), nitrates (34% vs. 48%), warfarin (21% vs. 14%), rivaroxaban (three patients in both groups), and dabigatran (one patient vs. six patients).

There were no differences in bleeding rates between the two groups, Dr. Tegn said. Four major bleeding events were reported in both groups, while 23 patients in the invasive group and 16 patients in the conservative group had minor bleeds.

The Norwegian Health Association sponsored the study. Dr. Tegn reported nothing to disclose. Dr. Kandazari reported research and grant support from Abbott Vascular, Biotronic, Boston Scientific, and Medtronic, and minor consulting honoraria from Boston Scientific and Medtronic.

[email protected]

SAN DIEGO – Patients aged 80 years and older benefit from more invasive early treatment after non-ST-elevation myocardial infarction or unstable angina, the After Eighty Trial showed.

After a median follow-up of 1.5 years, an invasive strategy that included coronary angiography significantly reduced the primary endpoint of myocardial infarction (MI), need for urgent revascularization, stroke, and death from 61% with optimal medical treatment to 41% (risk ratio, 0.48; P value < .00001).

That drop was driven primarily by significantly fewer MIs (17% vs. 30%; RR, 0.50; P = .0003) and urgent revascularizations (2% vs. 11%; RR, 0.19; P = .0001), lead author Dr. Nicolai Tegn reported at the American College of Cardiology/Cardiovascular Research Foundation Innovation in Intervention Summit.

There were no significant differences between the invasive and conservative strategy groups in rates of stroke (3% vs. 6%; RR, 0.61; P = .26) or all-cause death (25% vs. 27%; RR, 0.87; P = .53).

The composite of death and MI, however, significantly favored the invasive group (35% vs. 48%; RR, 0.54; P < .0001), he said during a latebreaking clinical trial session.

After Eighty randomly assigned 457 patients, aged 80 years or older, to either optimal medical therapy with no invasive treatments or coronary angiography at a percutaneous coronary intervention (PCI) center the day after inclusion, plus optimal medical therapy after about 4-5 hours if PCI was not performed or about 6-18 hours if it was. Of the 225 patients receiving angiography, 48% went on to balloon angioplasty and/or coronary stenting, and 3% had bypass surgery.

Patients 80 years or older account for roughly one-third of all patients with non-STEMI and unstable angina, but they are underrepresented in clinical trials. As a result, the role of an early invasive strategy, and even an invasive strategy at all, in those elderly patients is still a subject of debate, observed Dr. Tegn, a cardiologist from Rikshospitalet, Oslo University Hospital, Oslo.

The study demonstrated that an invasive strategy is superior to a conservative strategy in patients at least 80 years with NSTEMI or unstable angina, he concluded.

After Eighty is a welcome study because of the under-representation of the elderly in clinical trials, Dr. David Kandzari, director of interventional cardiology at the Piedmont Heart Center in Atlanta, said during a press briefing at the meeting. But it raises the challenge of identifying patients in clinical practice with the same qualifying characteristics, he added, given that the study population represents only 10% of the entire screened population,

There was also a fairly high prevalence of patients who angiographically did not have significant coronary artery disease, yet MI and stroke rates were quite considerable.

That said, “the study in other ways reminds us that the coronary anatomy does not know the age of the patient, meaning that the findings of a benefit of an early invasive strategy seem consistent with previous studies we know across the management of patients with acute coronary syndromes,” Dr. Kandzari said.

After Eighty investigators screened 4,187 elderly patients presenting at 17 community hospitals in Norway with non-STEMI or unstable angina, with or without ST-segment depression in ECG, and normal or elevated troponin T or I levels. Patients had to have no chest pain or other ischemic symptoms after medical treatment and mobilization.

In all, 3,730 patients were excluded for life expectancy less than 12 months because of a serious comorbidity; ongoing or recent bleeding; inability to comply with protocol; clinically unstable including ongoing ischemia; refusal to participate; logistic reasons; or other reasons.

The average age was 84.7 years in the invasive group (range 80-93 years) and 84.9 years in the conservative group (range 80-94 years).

Medical treatment during the index admission included 75 mg aspirin in 97% of both the invasive and conservative groups, clopidogrel (85% vs. 82%), ticagrelor (both 5%), angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blockers (ARB) (43% vs. 50%), beta blocker (83% vs. 85%), statins (90% vs. 85%), loop or thiazide diuretics (41% vs. 33%), calcium channel blocker (20% vs. 21%), nitrates (45% vs. 55%), warfarin (17% vs. 9%), low molecular-weight heparin (both 76% ), and dabigatran in one patient in each group.

Medical therapy at discharge in the invasive and conservative groups was aspirin (both 93%), clopidogrel (both 72%), ticagrelor (both 4%), ACE inhibitor/ARB (52% vs. 54%), beta blockers (both 84%), statins (90% vs. 86%), diuretics (45% vs. 38%), calcium channel blocker (24% vs. 23%), nitrates (34% vs. 48%), warfarin (21% vs. 14%), rivaroxaban (three patients in both groups), and dabigatran (one patient vs. six patients).

There were no differences in bleeding rates between the two groups, Dr. Tegn said. Four major bleeding events were reported in both groups, while 23 patients in the invasive group and 16 patients in the conservative group had minor bleeds.

The Norwegian Health Association sponsored the study. Dr. Tegn reported nothing to disclose. Dr. Kandazari reported research and grant support from Abbott Vascular, Biotronic, Boston Scientific, and Medtronic, and minor consulting honoraria from Boston Scientific and Medtronic.

[email protected]

Earlier this week, an airplane headed from Barcelona to Dusseldorf crashed into the French Alps, leaving 150 people dead. The black box recorder indicated that the copilot was left alone in the cockpit, the pilot was locked out and attempted to gain re-entry, and the flight was reprogrammed to cruise at an altitude of 100 feet, causing the plane to crash after an 8-minute descent. The evidence indicates a deliberate action on the part of the 27-year-old co-pilot, Andreas Lubitz.

With nothing to point to terrorism at this point, the investigation will include the question of whether or not the copilot suffered from a mental illness as a way of explaining his unexplainable actions. In short, was this a combination mass murder/suicide? Was there any way to predict that such an atrocity might happen? Are there measures that can be taken to ensure that it doesn’t happen again?

In the United States, treatment with any psychotropic medication has been a reason to ground a pilot permanently. In April 2010, the Federal Aviation Administration’s rules changed such that a pilot could fly if he’d been treated for mild to moderate depression with a selective serotonin reuptake inhibitor after 12 months. At that time, the FAA announced a 6-month amnesty period where a pilot could come forward about a diagnosis of depression that he had not previously felt comfortable disclosing. Presumably, other countries also have rules that ground pilots for mental illness.

So far, some reports in the media indicate that the copilot was not obviously suffering from a psychiatric disorder; all those who have been interviewed for these reports have expressed shock that Lubitz might have deliberately crashed the plane.

There also has been speculation in the media that a break in the copilot’s training 6 years ago was due to depression, and the mother of a school mate reportedly said that Lubitz had been treated for depression. Finally, investigators found a doctor’s note excusing Lubitz from work. At this point, the Wall Street Journal is reporting that he was being treated for depression. Apparently, he had shredded the note and flew on Tuesday, despite the written work excuse.

Still, all discussion of the copilot’s mental state is purely speculation. The media is noted for sensationalist reporting – and in efforts to get information out quickly, the details are often confused or simply wrong, sometimes to a remarkable extent. We don’t know if the work excuse was written by a psychiatrist or another type of physician; we don’t know if it was for a psychiatric condition, cancer, or simply strep throat.

What we’ve been told is that a copilot who was cleared to fly did so despite a work excuse from a physician, he did not disclose this condition to his employer, and he crashed a plane killing 150 people.

We might assume that the pilot suffered from some type of psychic distress – whether he met criteria for a mental disorder or not, it’s not normal to kill 150 people. If the pilot did have a history of depression and was being treated at the time of this week’s flight, then we may be left with a very unsatisfactory answer.

The anti-psychiatry activists will say that psychotropic medications caused Lubitz to crash the plane. Psychiatrists will be left with no great answer with such a scenario and will be left to say that whatever treatment he was receiving, it wasn’t enough. Certainly, the physician who told Lubitz to take off from work was right: He didn’t belong in a cockpit that day. Presumably, that physician would have done more had he been aware that the patient was about to commit a mass murder.

If the copilot does have a history of depression, but his current work excuse was for an unrelated condition, we might wonder if an untreated recurrence of depression played some role in his actions. One might speculate that the copilot could have been afraid to seek care at this time, perhaps because of a fear that he would lose his vocation.

Still, major depression can hardly explain such an act, and it is unfortunate that the press has already begun to run headlines linking this man’s alleged psychiatric diagnosis to a catastrophic mass murder. Somehow, “mental illness” gets used as an endpoint explanation for why such things happen; and short of a severe psychotic delusional system, it’s a very unsatisfying answer for an unprecedented act of violence.

The facts will unfold and perhaps we’ll learn a little more. We’ll find out what condition the copilot was being treated for and whether there were other stresses going on in his personal life. But people get depressed, take antidepressants, and deal with stress all the time.

It’s possible, if not likely, that we’ll never understand why this copilot decided to end the lives of so many people along with his own.

Dr. Miller is a coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work (Baltimore: The Johns Hopkins University, 2011).

Earlier this week, an airplane headed from Barcelona to Dusseldorf crashed into the French Alps, leaving 150 people dead. The black box recorder indicated that the copilot was left alone in the cockpit, the pilot was locked out and attempted to gain re-entry, and the flight was reprogrammed to cruise at an altitude of 100 feet, causing the plane to crash after an 8-minute descent. The evidence indicates a deliberate action on the part of the 27-year-old co-pilot, Andreas Lubitz.

With nothing to point to terrorism at this point, the investigation will include the question of whether or not the copilot suffered from a mental illness as a way of explaining his unexplainable actions. In short, was this a combination mass murder/suicide? Was there any way to predict that such an atrocity might happen? Are there measures that can be taken to ensure that it doesn’t happen again?

In the United States, treatment with any psychotropic medication has been a reason to ground a pilot permanently. In April 2010, the Federal Aviation Administration’s rules changed such that a pilot could fly if he’d been treated for mild to moderate depression with a selective serotonin reuptake inhibitor after 12 months. At that time, the FAA announced a 6-month amnesty period where a pilot could come forward about a diagnosis of depression that he had not previously felt comfortable disclosing. Presumably, other countries also have rules that ground pilots for mental illness.

So far, some reports in the media indicate that the copilot was not obviously suffering from a psychiatric disorder; all those who have been interviewed for these reports have expressed shock that Lubitz might have deliberately crashed the plane.

There also has been speculation in the media that a break in the copilot’s training 6 years ago was due to depression, and the mother of a school mate reportedly said that Lubitz had been treated for depression. Finally, investigators found a doctor’s note excusing Lubitz from work. At this point, the Wall Street Journal is reporting that he was being treated for depression. Apparently, he had shredded the note and flew on Tuesday, despite the written work excuse.

Still, all discussion of the copilot’s mental state is purely speculation. The media is noted for sensationalist reporting – and in efforts to get information out quickly, the details are often confused or simply wrong, sometimes to a remarkable extent. We don’t know if the work excuse was written by a psychiatrist or another type of physician; we don’t know if it was for a psychiatric condition, cancer, or simply strep throat.

What we’ve been told is that a copilot who was cleared to fly did so despite a work excuse from a physician, he did not disclose this condition to his employer, and he crashed a plane killing 150 people.

We might assume that the pilot suffered from some type of psychic distress – whether he met criteria for a mental disorder or not, it’s not normal to kill 150 people. If the pilot did have a history of depression and was being treated at the time of this week’s flight, then we may be left with a very unsatisfactory answer.

The anti-psychiatry activists will say that psychotropic medications caused Lubitz to crash the plane. Psychiatrists will be left with no great answer with such a scenario and will be left to say that whatever treatment he was receiving, it wasn’t enough. Certainly, the physician who told Lubitz to take off from work was right: He didn’t belong in a cockpit that day. Presumably, that physician would have done more had he been aware that the patient was about to commit a mass murder.

If the copilot does have a history of depression, but his current work excuse was for an unrelated condition, we might wonder if an untreated recurrence of depression played some role in his actions. One might speculate that the copilot could have been afraid to seek care at this time, perhaps because of a fear that he would lose his vocation.

Still, major depression can hardly explain such an act, and it is unfortunate that the press has already begun to run headlines linking this man’s alleged psychiatric diagnosis to a catastrophic mass murder. Somehow, “mental illness” gets used as an endpoint explanation for why such things happen; and short of a severe psychotic delusional system, it’s a very unsatisfying answer for an unprecedented act of violence.

The facts will unfold and perhaps we’ll learn a little more. We’ll find out what condition the copilot was being treated for and whether there were other stresses going on in his personal life. But people get depressed, take antidepressants, and deal with stress all the time.

It’s possible, if not likely, that we’ll never understand why this copilot decided to end the lives of so many people along with his own.

Dr. Miller is a coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work (Baltimore: The Johns Hopkins University, 2011).

Earlier this week, an airplane headed from Barcelona to Dusseldorf crashed into the French Alps, leaving 150 people dead. The black box recorder indicated that the copilot was left alone in the cockpit, the pilot was locked out and attempted to gain re-entry, and the flight was reprogrammed to cruise at an altitude of 100 feet, causing the plane to crash after an 8-minute descent. The evidence indicates a deliberate action on the part of the 27-year-old co-pilot, Andreas Lubitz.

With nothing to point to terrorism at this point, the investigation will include the question of whether or not the copilot suffered from a mental illness as a way of explaining his unexplainable actions. In short, was this a combination mass murder/suicide? Was there any way to predict that such an atrocity might happen? Are there measures that can be taken to ensure that it doesn’t happen again?

In the United States, treatment with any psychotropic medication has been a reason to ground a pilot permanently. In April 2010, the Federal Aviation Administration’s rules changed such that a pilot could fly if he’d been treated for mild to moderate depression with a selective serotonin reuptake inhibitor after 12 months. At that time, the FAA announced a 6-month amnesty period where a pilot could come forward about a diagnosis of depression that he had not previously felt comfortable disclosing. Presumably, other countries also have rules that ground pilots for mental illness.

So far, some reports in the media indicate that the copilot was not obviously suffering from a psychiatric disorder; all those who have been interviewed for these reports have expressed shock that Lubitz might have deliberately crashed the plane.

There also has been speculation in the media that a break in the copilot’s training 6 years ago was due to depression, and the mother of a school mate reportedly said that Lubitz had been treated for depression. Finally, investigators found a doctor’s note excusing Lubitz from work. At this point, the Wall Street Journal is reporting that he was being treated for depression. Apparently, he had shredded the note and flew on Tuesday, despite the written work excuse.

Still, all discussion of the copilot’s mental state is purely speculation. The media is noted for sensationalist reporting – and in efforts to get information out quickly, the details are often confused or simply wrong, sometimes to a remarkable extent. We don’t know if the work excuse was written by a psychiatrist or another type of physician; we don’t know if it was for a psychiatric condition, cancer, or simply strep throat.

What we’ve been told is that a copilot who was cleared to fly did so despite a work excuse from a physician, he did not disclose this condition to his employer, and he crashed a plane killing 150 people.

We might assume that the pilot suffered from some type of psychic distress – whether he met criteria for a mental disorder or not, it’s not normal to kill 150 people. If the pilot did have a history of depression and was being treated at the time of this week’s flight, then we may be left with a very unsatisfactory answer.

The anti-psychiatry activists will say that psychotropic medications caused Lubitz to crash the plane. Psychiatrists will be left with no great answer with such a scenario and will be left to say that whatever treatment he was receiving, it wasn’t enough. Certainly, the physician who told Lubitz to take off from work was right: He didn’t belong in a cockpit that day. Presumably, that physician would have done more had he been aware that the patient was about to commit a mass murder.

If the copilot does have a history of depression, but his current work excuse was for an unrelated condition, we might wonder if an untreated recurrence of depression played some role in his actions. One might speculate that the copilot could have been afraid to seek care at this time, perhaps because of a fear that he would lose his vocation.

Still, major depression can hardly explain such an act, and it is unfortunate that the press has already begun to run headlines linking this man’s alleged psychiatric diagnosis to a catastrophic mass murder. Somehow, “mental illness” gets used as an endpoint explanation for why such things happen; and short of a severe psychotic delusional system, it’s a very unsatisfying answer for an unprecedented act of violence.

The facts will unfold and perhaps we’ll learn a little more. We’ll find out what condition the copilot was being treated for and whether there were other stresses going on in his personal life. But people get depressed, take antidepressants, and deal with stress all the time.

It’s possible, if not likely, that we’ll never understand why this copilot decided to end the lives of so many people along with his own.

Dr. Miller is a coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work (Baltimore: The Johns Hopkins University, 2011).