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MDedge conference coverage features onsite reporting of the latest study results and expert perspectives from leading researchers.
Tendyne device shows promise for mitral annular calcification
Transcatheter implantation of the Tendyne mitral valve replacement device for treatment of mitral regurgitation in patients at prohibitive surgical risk because of severe mitral annular calcification showed considerable promise in a small feasibility study, Paul Sorajja, MD, reported at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.
There is a huge unmet need for safe and effective therapies for severe mitral annular calcification (MAC).
“Severe MAC often precludes surgical treatment, and there’s a poor prognosis in patients with MAC and mitral regurgitation when untreated, with 2-year survival of about 60% in some studies,” noted Dr. Sorajja, a cardiologist at the Minneapolis Heart Institute Foundation.
Attempts at repurposing transcatheter aortic valves for use in the mitral location have been largely unsatisfactory, he added.
The 6-month outcomes in the 11 patients who received the Tendyne device in the multicenter U.S. feasibility study featured low rates of mortality and nonfatal adverse events, elimination of mitral regurgitation, marked improvement on quality of life measures, and a mean gradient of 4.1 mm Hg. The acute procedural outcomes were encouraging as well.
“We had technical success in 11 of 11 patients, no procedural mortality or left ventricular outflow tract obstruction, no valve embolization or malposition, and no conversion to open heart surgery,” he said.
There was one death caused by mesenteric ischemia 16 days post Tendyne implantation. One patient experienced a nondisabling stroke at day 4. Two patients developed new-onset atrial fibrillation, one of whom cardioverted to sinus rhythm. And one patient had a moderate paravalvular leak that resolved with placement of a plug at 3 months. There were no MIs.
At baseline, 9 of 11 patients were New York Heart Association functional class III and the others were class II. At 6 months, six patients were class I, four were class II, and one was class III. The average score on the Kansas City Cardiomyopathy Questionnaire improved from 45.9 at baseline to 65.5 at 1 month, 77.4 at 3 months, and 70.3 at 6 months.
This was a highly selected study population with a Society of Thoracic Surgery Predicted Risk of Mortality score of 9.03%. Part of the screening process for study participation involved preprocedural CT imaging with simulated device overlay in order to identify candidates who were likely to have an optimal device fit.
Discussant Francesco Maisano, MD, was impressed by how well this simulation resembled the actual results as depicted in side-by-side pre- and postprocedural CT images presented by Dr. Sorajja.
“What really surprised me was the correlation between preprocedural simulation data and the actual CT scan after the procedure. This trial shows that the simulation works, and also that Tendyne is a great alternative to aortic valve-in-MAC for these very-high-risk patients,” said Dr. Maisano, professor of cardiac surgery at the University of Zürich and a pioneer of catheter-based mitral and tricuspid interventions.
Earlier this year the Tendyne device was approved in Europe for patients with mitral regurgitation who aren’t candidates for surgical valve replacement or transcatheter mitral valve repair. The approval does not, however, extend to MAC. The Abbott device remains investigational in the United States, where the pivotal SUMMIT trial is underway. In one arm of the trial, patients with mitral regurgitation are being randomized to the investigational Tendyne device or to Abbott’s MitraClip, which is approved for that indication. In the other arm, patients with severe MAC at prohibitive surgical risk will get the Tendyne device. Results are expected in 2020.
Dr. Sorajja reported receiving research grants from and serving as a consultant to Abbott, the feasibility study sponsor, as well as to several other medical device companies, as did Dr. Maisano.
Transcatheter implantation of the Tendyne mitral valve replacement device for treatment of mitral regurgitation in patients at prohibitive surgical risk because of severe mitral annular calcification showed considerable promise in a small feasibility study, Paul Sorajja, MD, reported at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.
There is a huge unmet need for safe and effective therapies for severe mitral annular calcification (MAC).
“Severe MAC often precludes surgical treatment, and there’s a poor prognosis in patients with MAC and mitral regurgitation when untreated, with 2-year survival of about 60% in some studies,” noted Dr. Sorajja, a cardiologist at the Minneapolis Heart Institute Foundation.
Attempts at repurposing transcatheter aortic valves for use in the mitral location have been largely unsatisfactory, he added.
The 6-month outcomes in the 11 patients who received the Tendyne device in the multicenter U.S. feasibility study featured low rates of mortality and nonfatal adverse events, elimination of mitral regurgitation, marked improvement on quality of life measures, and a mean gradient of 4.1 mm Hg. The acute procedural outcomes were encouraging as well.
“We had technical success in 11 of 11 patients, no procedural mortality or left ventricular outflow tract obstruction, no valve embolization or malposition, and no conversion to open heart surgery,” he said.
There was one death caused by mesenteric ischemia 16 days post Tendyne implantation. One patient experienced a nondisabling stroke at day 4. Two patients developed new-onset atrial fibrillation, one of whom cardioverted to sinus rhythm. And one patient had a moderate paravalvular leak that resolved with placement of a plug at 3 months. There were no MIs.
At baseline, 9 of 11 patients were New York Heart Association functional class III and the others were class II. At 6 months, six patients were class I, four were class II, and one was class III. The average score on the Kansas City Cardiomyopathy Questionnaire improved from 45.9 at baseline to 65.5 at 1 month, 77.4 at 3 months, and 70.3 at 6 months.
This was a highly selected study population with a Society of Thoracic Surgery Predicted Risk of Mortality score of 9.03%. Part of the screening process for study participation involved preprocedural CT imaging with simulated device overlay in order to identify candidates who were likely to have an optimal device fit.
Discussant Francesco Maisano, MD, was impressed by how well this simulation resembled the actual results as depicted in side-by-side pre- and postprocedural CT images presented by Dr. Sorajja.
“What really surprised me was the correlation between preprocedural simulation data and the actual CT scan after the procedure. This trial shows that the simulation works, and also that Tendyne is a great alternative to aortic valve-in-MAC for these very-high-risk patients,” said Dr. Maisano, professor of cardiac surgery at the University of Zürich and a pioneer of catheter-based mitral and tricuspid interventions.
Earlier this year the Tendyne device was approved in Europe for patients with mitral regurgitation who aren’t candidates for surgical valve replacement or transcatheter mitral valve repair. The approval does not, however, extend to MAC. The Abbott device remains investigational in the United States, where the pivotal SUMMIT trial is underway. In one arm of the trial, patients with mitral regurgitation are being randomized to the investigational Tendyne device or to Abbott’s MitraClip, which is approved for that indication. In the other arm, patients with severe MAC at prohibitive surgical risk will get the Tendyne device. Results are expected in 2020.
Dr. Sorajja reported receiving research grants from and serving as a consultant to Abbott, the feasibility study sponsor, as well as to several other medical device companies, as did Dr. Maisano.
Transcatheter implantation of the Tendyne mitral valve replacement device for treatment of mitral regurgitation in patients at prohibitive surgical risk because of severe mitral annular calcification showed considerable promise in a small feasibility study, Paul Sorajja, MD, reported at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.
There is a huge unmet need for safe and effective therapies for severe mitral annular calcification (MAC).
“Severe MAC often precludes surgical treatment, and there’s a poor prognosis in patients with MAC and mitral regurgitation when untreated, with 2-year survival of about 60% in some studies,” noted Dr. Sorajja, a cardiologist at the Minneapolis Heart Institute Foundation.
Attempts at repurposing transcatheter aortic valves for use in the mitral location have been largely unsatisfactory, he added.
The 6-month outcomes in the 11 patients who received the Tendyne device in the multicenter U.S. feasibility study featured low rates of mortality and nonfatal adverse events, elimination of mitral regurgitation, marked improvement on quality of life measures, and a mean gradient of 4.1 mm Hg. The acute procedural outcomes were encouraging as well.
“We had technical success in 11 of 11 patients, no procedural mortality or left ventricular outflow tract obstruction, no valve embolization or malposition, and no conversion to open heart surgery,” he said.
There was one death caused by mesenteric ischemia 16 days post Tendyne implantation. One patient experienced a nondisabling stroke at day 4. Two patients developed new-onset atrial fibrillation, one of whom cardioverted to sinus rhythm. And one patient had a moderate paravalvular leak that resolved with placement of a plug at 3 months. There were no MIs.
At baseline, 9 of 11 patients were New York Heart Association functional class III and the others were class II. At 6 months, six patients were class I, four were class II, and one was class III. The average score on the Kansas City Cardiomyopathy Questionnaire improved from 45.9 at baseline to 65.5 at 1 month, 77.4 at 3 months, and 70.3 at 6 months.
This was a highly selected study population with a Society of Thoracic Surgery Predicted Risk of Mortality score of 9.03%. Part of the screening process for study participation involved preprocedural CT imaging with simulated device overlay in order to identify candidates who were likely to have an optimal device fit.
Discussant Francesco Maisano, MD, was impressed by how well this simulation resembled the actual results as depicted in side-by-side pre- and postprocedural CT images presented by Dr. Sorajja.
“What really surprised me was the correlation between preprocedural simulation data and the actual CT scan after the procedure. This trial shows that the simulation works, and also that Tendyne is a great alternative to aortic valve-in-MAC for these very-high-risk patients,” said Dr. Maisano, professor of cardiac surgery at the University of Zürich and a pioneer of catheter-based mitral and tricuspid interventions.
Earlier this year the Tendyne device was approved in Europe for patients with mitral regurgitation who aren’t candidates for surgical valve replacement or transcatheter mitral valve repair. The approval does not, however, extend to MAC. The Abbott device remains investigational in the United States, where the pivotal SUMMIT trial is underway. In one arm of the trial, patients with mitral regurgitation are being randomized to the investigational Tendyne device or to Abbott’s MitraClip, which is approved for that indication. In the other arm, patients with severe MAC at prohibitive surgical risk will get the Tendyne device. Results are expected in 2020.
Dr. Sorajja reported receiving research grants from and serving as a consultant to Abbott, the feasibility study sponsor, as well as to several other medical device companies, as did Dr. Maisano.
REPORTING FROM EUROPCR 2020
Bariatric embolotherapy helps shed pounds in obese patients
Transcatheter bariatric embolotherapy (TBE) provides sustained weight loss without serious adverse effects among obese patients, results of a pilot sham-controlled study suggest.
At 6-month follow-up, the patients receiving the intervention had lost 7.4 kg (16.3 lbs), compared with 3.0 kg (6.6 lbs) in those randomized to a sham procedure in an intention-to-treat analysis (P = .034).
Results were similar in a per-protocol analysis (9.4 kg/20.7 lbs vs. 1.9 kg/4.1 lbs; P = .0002).
Weight loss after embolotherapy was sustained over 12 months, falling 7.8 kg (17.1 lbs) from baseline in the intention-to-treat population (P = .0011) and 9.3 kg (20.5 lbs) in the per-protocol population (P = .0005).
Safety events after TBE were mild nausea or vomiting, reported Vivek Reddy, MD, Mount Sinai Hospital, New York City. Five participants had minor, asymptomatic ulcers that required no additional treatment.
“In this randomized pilot trial, we established the proof of principle that transcatheter bariatric embolotherapy of the left gastric artery is safe and it promotes clinically significant weight loss,” he concluded at PCR e-Course, the virtual meeting of the Congress of European Association of Percutaneous Cardiovascular Interventions 2020.
Although bariatric surgery is highly effective, he noted that the associated morbidity and mortality limit its use to the severely obese with a body mass index (BMI) typically over 40 kg/m2.
TBE is a minimally invasive approach that uses a custom occlusion balloon microcatheter and robotic manifold to inject 300- to 500-mcm beads to the left gastric artery. Preclinical and case studies suggest it promotes weight loss by reducing ghrelin, an appetite-stimulating hormone secreted from the gastric fundus, Dr. Reddy said.
The study enrolled 44 patients (aged 21-60 years) with a BMI of 35-55, excluding those with prior bariatric surgery and a history of ulcers, type 2 diabetes, chronic aspirin or nonsteroidal inflammatory use, and active Helicobacter pylori infection.
A total of 40 patients were randomly assigned to TBE or a sham procedure, in which lidocaine was applied to the femoral area and propofol infused for 1 hour. The two groups were well matched, with a mean age of 45 vs. 46 years, weight of 110 kg vs. 119 kg, and BMI of 39 vs. 40, Dr. Reddy noted.
Embolotherapy was performed at a single center in Prague, and, on average, took 82.3 minutes and used 127 mL of contrast, 163 Gy/cm2 radiation, and 4.2 mL of microspheres. A single vessel was injected in 80% of cases.
The intention-to-treat population comprised 19 TBE and 18 control subjects, and the per-protocol population comprised 15 TBE and 16 control subjects, after the exclusion of patients in whom embolotherapy was unsuccessful or incomplete or who withdrew consent.
All patients received endoscopy at baseline and 1 week, as well as an intensive 19-session lifestyle and dietary education intervention out to 6 months.
Patients who underwent TBE had significant improvement in hunger scores at 6 and 12 months, compared with baseline. Similarly, quality of life improved across all six domains, including significant gains in physical function, self-esteem, and overall quality of life at both time points, Dr. Reddy reported.
Dr. Reddy disclosed receiving research support from Endobar Solutions.
This article first appeared on Medscape.com.
Transcatheter bariatric embolotherapy (TBE) provides sustained weight loss without serious adverse effects among obese patients, results of a pilot sham-controlled study suggest.
At 6-month follow-up, the patients receiving the intervention had lost 7.4 kg (16.3 lbs), compared with 3.0 kg (6.6 lbs) in those randomized to a sham procedure in an intention-to-treat analysis (P = .034).
Results were similar in a per-protocol analysis (9.4 kg/20.7 lbs vs. 1.9 kg/4.1 lbs; P = .0002).
Weight loss after embolotherapy was sustained over 12 months, falling 7.8 kg (17.1 lbs) from baseline in the intention-to-treat population (P = .0011) and 9.3 kg (20.5 lbs) in the per-protocol population (P = .0005).
Safety events after TBE were mild nausea or vomiting, reported Vivek Reddy, MD, Mount Sinai Hospital, New York City. Five participants had minor, asymptomatic ulcers that required no additional treatment.
“In this randomized pilot trial, we established the proof of principle that transcatheter bariatric embolotherapy of the left gastric artery is safe and it promotes clinically significant weight loss,” he concluded at PCR e-Course, the virtual meeting of the Congress of European Association of Percutaneous Cardiovascular Interventions 2020.
Although bariatric surgery is highly effective, he noted that the associated morbidity and mortality limit its use to the severely obese with a body mass index (BMI) typically over 40 kg/m2.
TBE is a minimally invasive approach that uses a custom occlusion balloon microcatheter and robotic manifold to inject 300- to 500-mcm beads to the left gastric artery. Preclinical and case studies suggest it promotes weight loss by reducing ghrelin, an appetite-stimulating hormone secreted from the gastric fundus, Dr. Reddy said.
The study enrolled 44 patients (aged 21-60 years) with a BMI of 35-55, excluding those with prior bariatric surgery and a history of ulcers, type 2 diabetes, chronic aspirin or nonsteroidal inflammatory use, and active Helicobacter pylori infection.
A total of 40 patients were randomly assigned to TBE or a sham procedure, in which lidocaine was applied to the femoral area and propofol infused for 1 hour. The two groups were well matched, with a mean age of 45 vs. 46 years, weight of 110 kg vs. 119 kg, and BMI of 39 vs. 40, Dr. Reddy noted.
Embolotherapy was performed at a single center in Prague, and, on average, took 82.3 minutes and used 127 mL of contrast, 163 Gy/cm2 radiation, and 4.2 mL of microspheres. A single vessel was injected in 80% of cases.
The intention-to-treat population comprised 19 TBE and 18 control subjects, and the per-protocol population comprised 15 TBE and 16 control subjects, after the exclusion of patients in whom embolotherapy was unsuccessful or incomplete or who withdrew consent.
All patients received endoscopy at baseline and 1 week, as well as an intensive 19-session lifestyle and dietary education intervention out to 6 months.
Patients who underwent TBE had significant improvement in hunger scores at 6 and 12 months, compared with baseline. Similarly, quality of life improved across all six domains, including significant gains in physical function, self-esteem, and overall quality of life at both time points, Dr. Reddy reported.
Dr. Reddy disclosed receiving research support from Endobar Solutions.
This article first appeared on Medscape.com.
Transcatheter bariatric embolotherapy (TBE) provides sustained weight loss without serious adverse effects among obese patients, results of a pilot sham-controlled study suggest.
At 6-month follow-up, the patients receiving the intervention had lost 7.4 kg (16.3 lbs), compared with 3.0 kg (6.6 lbs) in those randomized to a sham procedure in an intention-to-treat analysis (P = .034).
Results were similar in a per-protocol analysis (9.4 kg/20.7 lbs vs. 1.9 kg/4.1 lbs; P = .0002).
Weight loss after embolotherapy was sustained over 12 months, falling 7.8 kg (17.1 lbs) from baseline in the intention-to-treat population (P = .0011) and 9.3 kg (20.5 lbs) in the per-protocol population (P = .0005).
Safety events after TBE were mild nausea or vomiting, reported Vivek Reddy, MD, Mount Sinai Hospital, New York City. Five participants had minor, asymptomatic ulcers that required no additional treatment.
“In this randomized pilot trial, we established the proof of principle that transcatheter bariatric embolotherapy of the left gastric artery is safe and it promotes clinically significant weight loss,” he concluded at PCR e-Course, the virtual meeting of the Congress of European Association of Percutaneous Cardiovascular Interventions 2020.
Although bariatric surgery is highly effective, he noted that the associated morbidity and mortality limit its use to the severely obese with a body mass index (BMI) typically over 40 kg/m2.
TBE is a minimally invasive approach that uses a custom occlusion balloon microcatheter and robotic manifold to inject 300- to 500-mcm beads to the left gastric artery. Preclinical and case studies suggest it promotes weight loss by reducing ghrelin, an appetite-stimulating hormone secreted from the gastric fundus, Dr. Reddy said.
The study enrolled 44 patients (aged 21-60 years) with a BMI of 35-55, excluding those with prior bariatric surgery and a history of ulcers, type 2 diabetes, chronic aspirin or nonsteroidal inflammatory use, and active Helicobacter pylori infection.
A total of 40 patients were randomly assigned to TBE or a sham procedure, in which lidocaine was applied to the femoral area and propofol infused for 1 hour. The two groups were well matched, with a mean age of 45 vs. 46 years, weight of 110 kg vs. 119 kg, and BMI of 39 vs. 40, Dr. Reddy noted.
Embolotherapy was performed at a single center in Prague, and, on average, took 82.3 minutes and used 127 mL of contrast, 163 Gy/cm2 radiation, and 4.2 mL of microspheres. A single vessel was injected in 80% of cases.
The intention-to-treat population comprised 19 TBE and 18 control subjects, and the per-protocol population comprised 15 TBE and 16 control subjects, after the exclusion of patients in whom embolotherapy was unsuccessful or incomplete or who withdrew consent.
All patients received endoscopy at baseline and 1 week, as well as an intensive 19-session lifestyle and dietary education intervention out to 6 months.
Patients who underwent TBE had significant improvement in hunger scores at 6 and 12 months, compared with baseline. Similarly, quality of life improved across all six domains, including significant gains in physical function, self-esteem, and overall quality of life at both time points, Dr. Reddy reported.
Dr. Reddy disclosed receiving research support from Endobar Solutions.
This article first appeared on Medscape.com.
How many hormones make an ideal ‘artificial pancreas?’
Some automated insulin delivery systems currently in development add glucagon and/or pramlintide to insulin, but whether the extra hormones are worth the additional cost and effort is a subject of debate.
Also called closed-loop or artificial pancreas systems, they are comprised of an insulin pump and a continuous glucose monitor (CGM) that communicate via a built-in algorithm to deliver insulin based on glucose levels. Currently available systems are called hybrid closed loops because they still require user input for meals, exercise, illness, and other special circumstances.
Two hybrid closed-loop systems available in the United States, the Medtronic Minimed 670G and the Tandem Control-IQ, as well as the Medtronic Minimed 780G that was just approved in Europe, use insulin only.
Of all ongoing active closed-loop clinical studies, 44 involve insulin-only systems, as of May 2020.
However, two such systems in development add a glucagon analogue to insulin in the same pump (in separate cartridges), with the aim of minimizing the risk of hypoglycemia. And four investigational systems combine insulin with pramlintide (Symlin, AstraZeneca), an amylin analogue that reduces postmeal glucose spikes. Three systems in development combine all three hormones.
In a debate during the virtual American Diabetes Association 80th Scientific Sessions, Roman Hovorka, PhD, of the University of Cambridge (England) argued in favor of insulin-only systems on the basis of efficacy, less burden and complexity, and lower cost.
But Steven J. Russell, MD, PhD, of Massachusetts General Hospital, Boston, countered that glucagon adds safety and value to the system by allowing for more aggressive insulin dosing with lower hypoglycemia risk, benefits which he said would overcome any downsides.
Insulin-only systems are good enough
Dr. Hovorka began by defining a “good” artificial pancreas as one that produces consensus time-in-range targets of at least 70% of glucose values between 3.9 to 10 mmol/L (70-180 mg/dL) and less than 3% below 3.9 mmol/L (70 mg/dL). At the same time, he said, the burden should be low, which he suggested means no more than 10-20 minutes a day spent managing the system, low “alarm burden,” and minimal technical issues.
“We need to balance glucose control and the burden. For some people, reducing the burden is sometimes even more important than the glucose control,” Dr. Hovorka commented.
He pointed out that, in addition to Medtronic’s and Tandem’s systems, two other insulin-only hybrid closed-loop systems are marketed outside the United States. These are the CamDiab system, available in the United Kingdom, which uses his group’s Cambridge control algorithm in a Dana pump with the Dexcom G6 sensor, and the Diabeloop algorithm, available in Europe, that combines a patch pump with the Dexcom G6.
“Lots of energy and resources are going to taking [insulin-only] systems into clinic use,” Dr. Hovorka observed.
He reviewed recently published data for both the Tandem Control-IQ and the Cambridge control algorithm showing similar results meeting the “good artificial pancreas” definition.
In his current clinic population of 160 patients aged 2-80 years using the Cambridge algorithm, 69% of users have achieved 70% or greater time in range and 28% have achieved 80% or greater time in range.
“So, the insulin-only system can achieve acceptable, and in some instances very good, glucose control,” Dr. Hovorka said.
He acknowledged that there are still challenges with insulin-only systems, including exercise-related dysglycemia and postprandial hyperglycemia related to slow insulin absorption, missed or incorrect boluses, or large meals.
But, Dr. Hovorka said, downsides of dual-hormone systems include the need for room-temperature stable glucagon and for dual-chamber pumps with two cannulas and two infusion sites (in addition to the sensor site), and the unknown long-term biological risks of chronic subcutaneous glucagon or pramlintide delivery.
Moreover, he said, costs are expected to be higher for a two-chamber versus single-chamber pump, as well as for the second hormone, reservoir, and infusion set.
Data thus far from short-term studies suggest that insulin-only systems are sufficient in eliminating nocturnal hypoglycemia, while the addition of glucagon potentially reduces daytime hypoglycemia, especially during exercise.
However, longer-term head-to-head studies will be needed, Dr. Hovorka said, noting, “Comparative benefits of the single- and dual-hormone system for improving hemoglobin A1c and preventing severe hypoglycemia remain unknown.”
He suggested that glucagon dual-hormone closed-loop systems might be suitable for patients who are particularly prone to hypoglycemia, whereas pramlintide dual-hormone systems have the potential to more fully close the loop when used with ultra rapid-acting insulin analogues.
Nonetheless, he said, “Many, if not most, users may achieve acceptable control with insulin-only systems.”
Dual-hormone systems: Extra benefit worth it?
Dr. Russell, who is an investigator in multicenter pivotal studies of both insulin-only and bihormonal configurations of the Beta Bionics iLet bionic pancreas, began his debate presentation by endorsing the effectiveness of insulin-only hybrid systems and stating that he encourages his patients with type 1 diabetes to use them.
But, he said, adding glucagon can allow for better automation of hypoglycemia prevention and treatment in situations such as exercise.
“A bihormonal system achieves lower glucose, higher time-in-range, and less hypoglycemia than a well-functioning insulin-only system.”
Moreover, Dr. Russell said, “Glucagon reduces the need for medicinal carbohydrates, promotes satiety, and increases energy expenditure. ... Combined, these three factors may oppose weight gain or encourage weight loss as opposed to a system that uses insulin only.”
He pointed to a 2017 meta-analysis that showed improved time-in-range and greater reductions in hypoglycemia with dual- versus single-hormone systems.
And, in unpublished data from a randomized random-order crossover study of 23 patients with type 1 diabetes who each spent a week with usual care (insulin pump with or without CGM), insulin-only iLet, and bihormonal iLet, mean glucose levels were 165, 148, and 139 mg/dL, respectively. Time-in-range was 60%, 72%, and 79%, and median time with glucose below 54 mg/dL was 0.6%, 0.6%, and 0.2%, respectively.
Dr. Russell also addressed each of the arguments made by Dr. Hovorka and others against glucagon use.
Regarding the need for a stable glucagon formulation, he said that the analogue being developed for the iLet, dasiglucagon (Zealand pharma), is stable for more than a month at 40º C, with higher bioavailability and slightly slower absorption than glucagon.
And while he acknowledged the need for two separate hormone cartridges, Dr. Russell said that the Gen4 version of the iLet is fairly simple and intuitive, and the device itself is about the same size as the Tandem t:slim.
Use of glucagon didn’t increase insulin use in iLet trials, nor was it associated with increased reported nausea or liver glycogen depletion.
And users universally reported preferring the bihormonal system.
Long-term safety of chronic glucagon exposure has yet to be addressed, but animal data are reassuring, Dr. Russell said.
Regarding increased cost, he pointed to 2018 data showing that the incremental improvement in glycemic control from no automation to single-hormone automation is the same as from single to dual (mean glucose reductions of 7.4 and 13.6 mg/dL, respectively, and decreases in time spent in hypoglycemia of 1.28% vs. 2.95%).
“I would argue that, if one can justify adding automation, one could justify some additional expense to add the cost of glucagon.” And, he said, the cost would likely be based on a negotiation around the extra value offered by the dual-hormone system.
“The addition of glucagon, I believe, will be justified by the improved outcomes and improved quality of life,” he concluded.
Dr. Hovorka has reported receiving research support from MiniMed Medtronic, Abbott Diabetes Care, and Dexcom; being a speaker for Novo Nordisk, Eli Lilly, and Dexcom; holding license fees from B. Braun and Medtronic; and being director of CamDiab. Dr. Russell has reported holding patents on aspects of the bionic pancreas; receiving honoraria, travel expenses, and/or research support from Dexcom, Eli Lilly, Tandem Diabetes, Sanofi, Novo Nordisk, Roche, Ascensia, Zealand Pharma, and Beta Bionics; being a consultant for Flexion Therapeutics, Senseonics, and Beta Bionics; and participating in scientific advisory boards for Companion Medical, Tandem Diabetes, and Unomedical.
A version of this article originally appeared on Medscape.com.
Some automated insulin delivery systems currently in development add glucagon and/or pramlintide to insulin, but whether the extra hormones are worth the additional cost and effort is a subject of debate.
Also called closed-loop or artificial pancreas systems, they are comprised of an insulin pump and a continuous glucose monitor (CGM) that communicate via a built-in algorithm to deliver insulin based on glucose levels. Currently available systems are called hybrid closed loops because they still require user input for meals, exercise, illness, and other special circumstances.
Two hybrid closed-loop systems available in the United States, the Medtronic Minimed 670G and the Tandem Control-IQ, as well as the Medtronic Minimed 780G that was just approved in Europe, use insulin only.
Of all ongoing active closed-loop clinical studies, 44 involve insulin-only systems, as of May 2020.
However, two such systems in development add a glucagon analogue to insulin in the same pump (in separate cartridges), with the aim of minimizing the risk of hypoglycemia. And four investigational systems combine insulin with pramlintide (Symlin, AstraZeneca), an amylin analogue that reduces postmeal glucose spikes. Three systems in development combine all three hormones.
In a debate during the virtual American Diabetes Association 80th Scientific Sessions, Roman Hovorka, PhD, of the University of Cambridge (England) argued in favor of insulin-only systems on the basis of efficacy, less burden and complexity, and lower cost.
But Steven J. Russell, MD, PhD, of Massachusetts General Hospital, Boston, countered that glucagon adds safety and value to the system by allowing for more aggressive insulin dosing with lower hypoglycemia risk, benefits which he said would overcome any downsides.
Insulin-only systems are good enough
Dr. Hovorka began by defining a “good” artificial pancreas as one that produces consensus time-in-range targets of at least 70% of glucose values between 3.9 to 10 mmol/L (70-180 mg/dL) and less than 3% below 3.9 mmol/L (70 mg/dL). At the same time, he said, the burden should be low, which he suggested means no more than 10-20 minutes a day spent managing the system, low “alarm burden,” and minimal technical issues.
“We need to balance glucose control and the burden. For some people, reducing the burden is sometimes even more important than the glucose control,” Dr. Hovorka commented.
He pointed out that, in addition to Medtronic’s and Tandem’s systems, two other insulin-only hybrid closed-loop systems are marketed outside the United States. These are the CamDiab system, available in the United Kingdom, which uses his group’s Cambridge control algorithm in a Dana pump with the Dexcom G6 sensor, and the Diabeloop algorithm, available in Europe, that combines a patch pump with the Dexcom G6.
“Lots of energy and resources are going to taking [insulin-only] systems into clinic use,” Dr. Hovorka observed.
He reviewed recently published data for both the Tandem Control-IQ and the Cambridge control algorithm showing similar results meeting the “good artificial pancreas” definition.
In his current clinic population of 160 patients aged 2-80 years using the Cambridge algorithm, 69% of users have achieved 70% or greater time in range and 28% have achieved 80% or greater time in range.
“So, the insulin-only system can achieve acceptable, and in some instances very good, glucose control,” Dr. Hovorka said.
He acknowledged that there are still challenges with insulin-only systems, including exercise-related dysglycemia and postprandial hyperglycemia related to slow insulin absorption, missed or incorrect boluses, or large meals.
But, Dr. Hovorka said, downsides of dual-hormone systems include the need for room-temperature stable glucagon and for dual-chamber pumps with two cannulas and two infusion sites (in addition to the sensor site), and the unknown long-term biological risks of chronic subcutaneous glucagon or pramlintide delivery.
Moreover, he said, costs are expected to be higher for a two-chamber versus single-chamber pump, as well as for the second hormone, reservoir, and infusion set.
Data thus far from short-term studies suggest that insulin-only systems are sufficient in eliminating nocturnal hypoglycemia, while the addition of glucagon potentially reduces daytime hypoglycemia, especially during exercise.
However, longer-term head-to-head studies will be needed, Dr. Hovorka said, noting, “Comparative benefits of the single- and dual-hormone system for improving hemoglobin A1c and preventing severe hypoglycemia remain unknown.”
He suggested that glucagon dual-hormone closed-loop systems might be suitable for patients who are particularly prone to hypoglycemia, whereas pramlintide dual-hormone systems have the potential to more fully close the loop when used with ultra rapid-acting insulin analogues.
Nonetheless, he said, “Many, if not most, users may achieve acceptable control with insulin-only systems.”
Dual-hormone systems: Extra benefit worth it?
Dr. Russell, who is an investigator in multicenter pivotal studies of both insulin-only and bihormonal configurations of the Beta Bionics iLet bionic pancreas, began his debate presentation by endorsing the effectiveness of insulin-only hybrid systems and stating that he encourages his patients with type 1 diabetes to use them.
But, he said, adding glucagon can allow for better automation of hypoglycemia prevention and treatment in situations such as exercise.
“A bihormonal system achieves lower glucose, higher time-in-range, and less hypoglycemia than a well-functioning insulin-only system.”
Moreover, Dr. Russell said, “Glucagon reduces the need for medicinal carbohydrates, promotes satiety, and increases energy expenditure. ... Combined, these three factors may oppose weight gain or encourage weight loss as opposed to a system that uses insulin only.”
He pointed to a 2017 meta-analysis that showed improved time-in-range and greater reductions in hypoglycemia with dual- versus single-hormone systems.
And, in unpublished data from a randomized random-order crossover study of 23 patients with type 1 diabetes who each spent a week with usual care (insulin pump with or without CGM), insulin-only iLet, and bihormonal iLet, mean glucose levels were 165, 148, and 139 mg/dL, respectively. Time-in-range was 60%, 72%, and 79%, and median time with glucose below 54 mg/dL was 0.6%, 0.6%, and 0.2%, respectively.
Dr. Russell also addressed each of the arguments made by Dr. Hovorka and others against glucagon use.
Regarding the need for a stable glucagon formulation, he said that the analogue being developed for the iLet, dasiglucagon (Zealand pharma), is stable for more than a month at 40º C, with higher bioavailability and slightly slower absorption than glucagon.
And while he acknowledged the need for two separate hormone cartridges, Dr. Russell said that the Gen4 version of the iLet is fairly simple and intuitive, and the device itself is about the same size as the Tandem t:slim.
Use of glucagon didn’t increase insulin use in iLet trials, nor was it associated with increased reported nausea or liver glycogen depletion.
And users universally reported preferring the bihormonal system.
Long-term safety of chronic glucagon exposure has yet to be addressed, but animal data are reassuring, Dr. Russell said.
Regarding increased cost, he pointed to 2018 data showing that the incremental improvement in glycemic control from no automation to single-hormone automation is the same as from single to dual (mean glucose reductions of 7.4 and 13.6 mg/dL, respectively, and decreases in time spent in hypoglycemia of 1.28% vs. 2.95%).
“I would argue that, if one can justify adding automation, one could justify some additional expense to add the cost of glucagon.” And, he said, the cost would likely be based on a negotiation around the extra value offered by the dual-hormone system.
“The addition of glucagon, I believe, will be justified by the improved outcomes and improved quality of life,” he concluded.
Dr. Hovorka has reported receiving research support from MiniMed Medtronic, Abbott Diabetes Care, and Dexcom; being a speaker for Novo Nordisk, Eli Lilly, and Dexcom; holding license fees from B. Braun and Medtronic; and being director of CamDiab. Dr. Russell has reported holding patents on aspects of the bionic pancreas; receiving honoraria, travel expenses, and/or research support from Dexcom, Eli Lilly, Tandem Diabetes, Sanofi, Novo Nordisk, Roche, Ascensia, Zealand Pharma, and Beta Bionics; being a consultant for Flexion Therapeutics, Senseonics, and Beta Bionics; and participating in scientific advisory boards for Companion Medical, Tandem Diabetes, and Unomedical.
A version of this article originally appeared on Medscape.com.
Some automated insulin delivery systems currently in development add glucagon and/or pramlintide to insulin, but whether the extra hormones are worth the additional cost and effort is a subject of debate.
Also called closed-loop or artificial pancreas systems, they are comprised of an insulin pump and a continuous glucose monitor (CGM) that communicate via a built-in algorithm to deliver insulin based on glucose levels. Currently available systems are called hybrid closed loops because they still require user input for meals, exercise, illness, and other special circumstances.
Two hybrid closed-loop systems available in the United States, the Medtronic Minimed 670G and the Tandem Control-IQ, as well as the Medtronic Minimed 780G that was just approved in Europe, use insulin only.
Of all ongoing active closed-loop clinical studies, 44 involve insulin-only systems, as of May 2020.
However, two such systems in development add a glucagon analogue to insulin in the same pump (in separate cartridges), with the aim of minimizing the risk of hypoglycemia. And four investigational systems combine insulin with pramlintide (Symlin, AstraZeneca), an amylin analogue that reduces postmeal glucose spikes. Three systems in development combine all three hormones.
In a debate during the virtual American Diabetes Association 80th Scientific Sessions, Roman Hovorka, PhD, of the University of Cambridge (England) argued in favor of insulin-only systems on the basis of efficacy, less burden and complexity, and lower cost.
But Steven J. Russell, MD, PhD, of Massachusetts General Hospital, Boston, countered that glucagon adds safety and value to the system by allowing for more aggressive insulin dosing with lower hypoglycemia risk, benefits which he said would overcome any downsides.
Insulin-only systems are good enough
Dr. Hovorka began by defining a “good” artificial pancreas as one that produces consensus time-in-range targets of at least 70% of glucose values between 3.9 to 10 mmol/L (70-180 mg/dL) and less than 3% below 3.9 mmol/L (70 mg/dL). At the same time, he said, the burden should be low, which he suggested means no more than 10-20 minutes a day spent managing the system, low “alarm burden,” and minimal technical issues.
“We need to balance glucose control and the burden. For some people, reducing the burden is sometimes even more important than the glucose control,” Dr. Hovorka commented.
He pointed out that, in addition to Medtronic’s and Tandem’s systems, two other insulin-only hybrid closed-loop systems are marketed outside the United States. These are the CamDiab system, available in the United Kingdom, which uses his group’s Cambridge control algorithm in a Dana pump with the Dexcom G6 sensor, and the Diabeloop algorithm, available in Europe, that combines a patch pump with the Dexcom G6.
“Lots of energy and resources are going to taking [insulin-only] systems into clinic use,” Dr. Hovorka observed.
He reviewed recently published data for both the Tandem Control-IQ and the Cambridge control algorithm showing similar results meeting the “good artificial pancreas” definition.
In his current clinic population of 160 patients aged 2-80 years using the Cambridge algorithm, 69% of users have achieved 70% or greater time in range and 28% have achieved 80% or greater time in range.
“So, the insulin-only system can achieve acceptable, and in some instances very good, glucose control,” Dr. Hovorka said.
He acknowledged that there are still challenges with insulin-only systems, including exercise-related dysglycemia and postprandial hyperglycemia related to slow insulin absorption, missed or incorrect boluses, or large meals.
But, Dr. Hovorka said, downsides of dual-hormone systems include the need for room-temperature stable glucagon and for dual-chamber pumps with two cannulas and two infusion sites (in addition to the sensor site), and the unknown long-term biological risks of chronic subcutaneous glucagon or pramlintide delivery.
Moreover, he said, costs are expected to be higher for a two-chamber versus single-chamber pump, as well as for the second hormone, reservoir, and infusion set.
Data thus far from short-term studies suggest that insulin-only systems are sufficient in eliminating nocturnal hypoglycemia, while the addition of glucagon potentially reduces daytime hypoglycemia, especially during exercise.
However, longer-term head-to-head studies will be needed, Dr. Hovorka said, noting, “Comparative benefits of the single- and dual-hormone system for improving hemoglobin A1c and preventing severe hypoglycemia remain unknown.”
He suggested that glucagon dual-hormone closed-loop systems might be suitable for patients who are particularly prone to hypoglycemia, whereas pramlintide dual-hormone systems have the potential to more fully close the loop when used with ultra rapid-acting insulin analogues.
Nonetheless, he said, “Many, if not most, users may achieve acceptable control with insulin-only systems.”
Dual-hormone systems: Extra benefit worth it?
Dr. Russell, who is an investigator in multicenter pivotal studies of both insulin-only and bihormonal configurations of the Beta Bionics iLet bionic pancreas, began his debate presentation by endorsing the effectiveness of insulin-only hybrid systems and stating that he encourages his patients with type 1 diabetes to use them.
But, he said, adding glucagon can allow for better automation of hypoglycemia prevention and treatment in situations such as exercise.
“A bihormonal system achieves lower glucose, higher time-in-range, and less hypoglycemia than a well-functioning insulin-only system.”
Moreover, Dr. Russell said, “Glucagon reduces the need for medicinal carbohydrates, promotes satiety, and increases energy expenditure. ... Combined, these three factors may oppose weight gain or encourage weight loss as opposed to a system that uses insulin only.”
He pointed to a 2017 meta-analysis that showed improved time-in-range and greater reductions in hypoglycemia with dual- versus single-hormone systems.
And, in unpublished data from a randomized random-order crossover study of 23 patients with type 1 diabetes who each spent a week with usual care (insulin pump with or without CGM), insulin-only iLet, and bihormonal iLet, mean glucose levels were 165, 148, and 139 mg/dL, respectively. Time-in-range was 60%, 72%, and 79%, and median time with glucose below 54 mg/dL was 0.6%, 0.6%, and 0.2%, respectively.
Dr. Russell also addressed each of the arguments made by Dr. Hovorka and others against glucagon use.
Regarding the need for a stable glucagon formulation, he said that the analogue being developed for the iLet, dasiglucagon (Zealand pharma), is stable for more than a month at 40º C, with higher bioavailability and slightly slower absorption than glucagon.
And while he acknowledged the need for two separate hormone cartridges, Dr. Russell said that the Gen4 version of the iLet is fairly simple and intuitive, and the device itself is about the same size as the Tandem t:slim.
Use of glucagon didn’t increase insulin use in iLet trials, nor was it associated with increased reported nausea or liver glycogen depletion.
And users universally reported preferring the bihormonal system.
Long-term safety of chronic glucagon exposure has yet to be addressed, but animal data are reassuring, Dr. Russell said.
Regarding increased cost, he pointed to 2018 data showing that the incremental improvement in glycemic control from no automation to single-hormone automation is the same as from single to dual (mean glucose reductions of 7.4 and 13.6 mg/dL, respectively, and decreases in time spent in hypoglycemia of 1.28% vs. 2.95%).
“I would argue that, if one can justify adding automation, one could justify some additional expense to add the cost of glucagon.” And, he said, the cost would likely be based on a negotiation around the extra value offered by the dual-hormone system.
“The addition of glucagon, I believe, will be justified by the improved outcomes and improved quality of life,” he concluded.
Dr. Hovorka has reported receiving research support from MiniMed Medtronic, Abbott Diabetes Care, and Dexcom; being a speaker for Novo Nordisk, Eli Lilly, and Dexcom; holding license fees from B. Braun and Medtronic; and being director of CamDiab. Dr. Russell has reported holding patents on aspects of the bionic pancreas; receiving honoraria, travel expenses, and/or research support from Dexcom, Eli Lilly, Tandem Diabetes, Sanofi, Novo Nordisk, Roche, Ascensia, Zealand Pharma, and Beta Bionics; being a consultant for Flexion Therapeutics, Senseonics, and Beta Bionics; and participating in scientific advisory boards for Companion Medical, Tandem Diabetes, and Unomedical.
A version of this article originally appeared on Medscape.com.
Chewed prasugrel for primary PCI? Forget it!
And cangrelor, in turn, is superior to oral prasugrel, according to the randomized FABOLUS FASTER trial, Marco Valgimigli, MD, PhD, reported at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.
Moreover, contrary to conventional wisdom, chewed prasugrel (Effient) proved no better than swallowing the tablets whole for platelet inhibition, said Dr. Valgimigli, an interventional cardiologist at the University of Bern (Switzerland).
He explained that standard administration of the newer oral P2Y12 inhibitors prasugrel and ticagrelor (Brilinta) in patients undergoing percutaneous coronary intervention (PCI) for ST-elevation MI (STEMI) does not provide optimal early inhibition of platelet aggregation. The parenteral antiplatelet drugs tirofiban and cangrelor have been shown to provide faster and more prolonged inhibition of platelet aggregation than the oral P2Y12 inhibitors.
But there has been no head-to-head comparative data for the glycoprotein IIb/IIIA inhibitor tirofiban (Aggrastat) and the P2Y12 inhibitor cangrelor (Kengreal) in the setting of primary PCI for STEMI. This was the impetus for FABOLUS FASTER, the first study to compare the pharmacodynamic effects of the two parenteral antiplatelet agents. The trial also looked at how these potent parenteral drugs, compared with chewed prasugrel, another previously unexamined yet highly practical issue.
The three-center, multinational, open-label FABOLUS FASTER trial randomized 122 patients undergoing primary PCI for STEMI to one of three arms: a standard intravenous bolus and 2-hour infusion of either the P2Y12 inhibitor cangrelor (Kengreal) or the glycoprotein IIb/IIIA inhibitor tirofiban (Aggrastat), followed in either case by 60 mg of oral prasugrel, or a third arm in which patients didn’t receive either drug but were instead randomized to a 60-mg loading dose of chewed or whole prasugrel tablets.
The primary study endpoint was inhibition of platelet aggregation at 30 minutes as measured by light transmittance aggregometry in response to 20 mcmol/L of adenosine diphosphate (ADP).
Tirofiban was the unequivocal winner with 95% inhibition, as compared with 34.1% with cangrelor, 10.5% with chewed prasugrel, and 6.3% with prasugrel swallowed whole, even though the concentration of prasugrel’s active metabolite was far greater at 62.3 ng/mL after prasugrel was chewed, compared with 17.1 ng/mL when swallowed in integral tablet form.
The rate of nonresponsiveness to tirofiban as defined by greater than 59% platelet aggregation was zero for tirofiban during its 2-hour infusion, then a scant 8% thereafter during repeated testing at 3 and 4-6 hours. In contrast, the cangrelor nonresponsiveness rate was 50%-58% during the 2-hour infusion, rising to 82% at 3 hours.
FABOLUS FASTER, while not powered for clinical endpoints, might nevertheless have important clinical implications, according to Dr. Valgimigli. First, the superiority of the intravenous drugs tirofiban and cangrelor over prasugrel for early, strong platelet inhibition underscores the importance of giving parenteral antiplatelet drugs over oral therapy during the acute phase of STEMI therapy. Moreover, tirofiban’s outstanding performance – and the high residual platelet reactivity associated with cangrelor – makes a strong case for large comparative, randomized trials of the two drugs, with hard clinical endpoints.
Discussant Christoph K. Naber, MD, PhD, opined that he personally doesn’t consider the FABOLUS FASTER results practice changing, for a couple of reasons.
“Platelet inhibition measured by ADP in vitro is not necessarily related to true effects in vivo. We know that platelets are activated by multiple mechanisms, and the ADP pathway is just one of them,” said Dr. Naber, an interventional cardiologist at the Wilhemshaven (Germany) Clinic.
Also, there’s a good reason why no glycoprotein IIb/IIIA inhibitors are approved for treatment of STEMI, and why tirofiban, despite its impressive antiplatelet effects, is currently largely reserved for bailout situations, such as complex lesions with large thrombus burden. It’s because tirofiban’s potent antiplatelet activity is accompanied by a high risk of bleeding, he added.
However, Dr. Valgimigli noted that this conviction about excessive bleeding risk is mainly based on older studies in which glycoprotein IIb/IIIA inhibitors were administered for prolonged duration through femoral access sites. He argued that it’s time for large clinical trials examining the risk/benefit ratio of short infusion of these agents in the contemporary practice of primary PCI for STEMI.
Simultaneously with Dr. Valgimigli’s presentation, the FABOLUS FASTER results were published online (Circulation. 2020 Jun 27; doi: 10.1161/CIRCULATIONAHA.120.046928).
Dr. Valgimigli reported that Medicure, the sponsor of the FABOLUS FASTER trial, provided an institutional research grant to conduct the study. He also disclosed receiving research grants and personal fees outside the scope of this study from a dozen pharmaceutical and medical device companies. Dr. Naber reported having no financial conflicts.
And cangrelor, in turn, is superior to oral prasugrel, according to the randomized FABOLUS FASTER trial, Marco Valgimigli, MD, PhD, reported at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.
Moreover, contrary to conventional wisdom, chewed prasugrel (Effient) proved no better than swallowing the tablets whole for platelet inhibition, said Dr. Valgimigli, an interventional cardiologist at the University of Bern (Switzerland).
He explained that standard administration of the newer oral P2Y12 inhibitors prasugrel and ticagrelor (Brilinta) in patients undergoing percutaneous coronary intervention (PCI) for ST-elevation MI (STEMI) does not provide optimal early inhibition of platelet aggregation. The parenteral antiplatelet drugs tirofiban and cangrelor have been shown to provide faster and more prolonged inhibition of platelet aggregation than the oral P2Y12 inhibitors.
But there has been no head-to-head comparative data for the glycoprotein IIb/IIIA inhibitor tirofiban (Aggrastat) and the P2Y12 inhibitor cangrelor (Kengreal) in the setting of primary PCI for STEMI. This was the impetus for FABOLUS FASTER, the first study to compare the pharmacodynamic effects of the two parenteral antiplatelet agents. The trial also looked at how these potent parenteral drugs, compared with chewed prasugrel, another previously unexamined yet highly practical issue.
The three-center, multinational, open-label FABOLUS FASTER trial randomized 122 patients undergoing primary PCI for STEMI to one of three arms: a standard intravenous bolus and 2-hour infusion of either the P2Y12 inhibitor cangrelor (Kengreal) or the glycoprotein IIb/IIIA inhibitor tirofiban (Aggrastat), followed in either case by 60 mg of oral prasugrel, or a third arm in which patients didn’t receive either drug but were instead randomized to a 60-mg loading dose of chewed or whole prasugrel tablets.
The primary study endpoint was inhibition of platelet aggregation at 30 minutes as measured by light transmittance aggregometry in response to 20 mcmol/L of adenosine diphosphate (ADP).
Tirofiban was the unequivocal winner with 95% inhibition, as compared with 34.1% with cangrelor, 10.5% with chewed prasugrel, and 6.3% with prasugrel swallowed whole, even though the concentration of prasugrel’s active metabolite was far greater at 62.3 ng/mL after prasugrel was chewed, compared with 17.1 ng/mL when swallowed in integral tablet form.
The rate of nonresponsiveness to tirofiban as defined by greater than 59% platelet aggregation was zero for tirofiban during its 2-hour infusion, then a scant 8% thereafter during repeated testing at 3 and 4-6 hours. In contrast, the cangrelor nonresponsiveness rate was 50%-58% during the 2-hour infusion, rising to 82% at 3 hours.
FABOLUS FASTER, while not powered for clinical endpoints, might nevertheless have important clinical implications, according to Dr. Valgimigli. First, the superiority of the intravenous drugs tirofiban and cangrelor over prasugrel for early, strong platelet inhibition underscores the importance of giving parenteral antiplatelet drugs over oral therapy during the acute phase of STEMI therapy. Moreover, tirofiban’s outstanding performance – and the high residual platelet reactivity associated with cangrelor – makes a strong case for large comparative, randomized trials of the two drugs, with hard clinical endpoints.
Discussant Christoph K. Naber, MD, PhD, opined that he personally doesn’t consider the FABOLUS FASTER results practice changing, for a couple of reasons.
“Platelet inhibition measured by ADP in vitro is not necessarily related to true effects in vivo. We know that platelets are activated by multiple mechanisms, and the ADP pathway is just one of them,” said Dr. Naber, an interventional cardiologist at the Wilhemshaven (Germany) Clinic.
Also, there’s a good reason why no glycoprotein IIb/IIIA inhibitors are approved for treatment of STEMI, and why tirofiban, despite its impressive antiplatelet effects, is currently largely reserved for bailout situations, such as complex lesions with large thrombus burden. It’s because tirofiban’s potent antiplatelet activity is accompanied by a high risk of bleeding, he added.
However, Dr. Valgimigli noted that this conviction about excessive bleeding risk is mainly based on older studies in which glycoprotein IIb/IIIA inhibitors were administered for prolonged duration through femoral access sites. He argued that it’s time for large clinical trials examining the risk/benefit ratio of short infusion of these agents in the contemporary practice of primary PCI for STEMI.
Simultaneously with Dr. Valgimigli’s presentation, the FABOLUS FASTER results were published online (Circulation. 2020 Jun 27; doi: 10.1161/CIRCULATIONAHA.120.046928).
Dr. Valgimigli reported that Medicure, the sponsor of the FABOLUS FASTER trial, provided an institutional research grant to conduct the study. He also disclosed receiving research grants and personal fees outside the scope of this study from a dozen pharmaceutical and medical device companies. Dr. Naber reported having no financial conflicts.
And cangrelor, in turn, is superior to oral prasugrel, according to the randomized FABOLUS FASTER trial, Marco Valgimigli, MD, PhD, reported at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.
Moreover, contrary to conventional wisdom, chewed prasugrel (Effient) proved no better than swallowing the tablets whole for platelet inhibition, said Dr. Valgimigli, an interventional cardiologist at the University of Bern (Switzerland).
He explained that standard administration of the newer oral P2Y12 inhibitors prasugrel and ticagrelor (Brilinta) in patients undergoing percutaneous coronary intervention (PCI) for ST-elevation MI (STEMI) does not provide optimal early inhibition of platelet aggregation. The parenteral antiplatelet drugs tirofiban and cangrelor have been shown to provide faster and more prolonged inhibition of platelet aggregation than the oral P2Y12 inhibitors.
But there has been no head-to-head comparative data for the glycoprotein IIb/IIIA inhibitor tirofiban (Aggrastat) and the P2Y12 inhibitor cangrelor (Kengreal) in the setting of primary PCI for STEMI. This was the impetus for FABOLUS FASTER, the first study to compare the pharmacodynamic effects of the two parenteral antiplatelet agents. The trial also looked at how these potent parenteral drugs, compared with chewed prasugrel, another previously unexamined yet highly practical issue.
The three-center, multinational, open-label FABOLUS FASTER trial randomized 122 patients undergoing primary PCI for STEMI to one of three arms: a standard intravenous bolus and 2-hour infusion of either the P2Y12 inhibitor cangrelor (Kengreal) or the glycoprotein IIb/IIIA inhibitor tirofiban (Aggrastat), followed in either case by 60 mg of oral prasugrel, or a third arm in which patients didn’t receive either drug but were instead randomized to a 60-mg loading dose of chewed or whole prasugrel tablets.
The primary study endpoint was inhibition of platelet aggregation at 30 minutes as measured by light transmittance aggregometry in response to 20 mcmol/L of adenosine diphosphate (ADP).
Tirofiban was the unequivocal winner with 95% inhibition, as compared with 34.1% with cangrelor, 10.5% with chewed prasugrel, and 6.3% with prasugrel swallowed whole, even though the concentration of prasugrel’s active metabolite was far greater at 62.3 ng/mL after prasugrel was chewed, compared with 17.1 ng/mL when swallowed in integral tablet form.
The rate of nonresponsiveness to tirofiban as defined by greater than 59% platelet aggregation was zero for tirofiban during its 2-hour infusion, then a scant 8% thereafter during repeated testing at 3 and 4-6 hours. In contrast, the cangrelor nonresponsiveness rate was 50%-58% during the 2-hour infusion, rising to 82% at 3 hours.
FABOLUS FASTER, while not powered for clinical endpoints, might nevertheless have important clinical implications, according to Dr. Valgimigli. First, the superiority of the intravenous drugs tirofiban and cangrelor over prasugrel for early, strong platelet inhibition underscores the importance of giving parenteral antiplatelet drugs over oral therapy during the acute phase of STEMI therapy. Moreover, tirofiban’s outstanding performance – and the high residual platelet reactivity associated with cangrelor – makes a strong case for large comparative, randomized trials of the two drugs, with hard clinical endpoints.
Discussant Christoph K. Naber, MD, PhD, opined that he personally doesn’t consider the FABOLUS FASTER results practice changing, for a couple of reasons.
“Platelet inhibition measured by ADP in vitro is not necessarily related to true effects in vivo. We know that platelets are activated by multiple mechanisms, and the ADP pathway is just one of them,” said Dr. Naber, an interventional cardiologist at the Wilhemshaven (Germany) Clinic.
Also, there’s a good reason why no glycoprotein IIb/IIIA inhibitors are approved for treatment of STEMI, and why tirofiban, despite its impressive antiplatelet effects, is currently largely reserved for bailout situations, such as complex lesions with large thrombus burden. It’s because tirofiban’s potent antiplatelet activity is accompanied by a high risk of bleeding, he added.
However, Dr. Valgimigli noted that this conviction about excessive bleeding risk is mainly based on older studies in which glycoprotein IIb/IIIA inhibitors were administered for prolonged duration through femoral access sites. He argued that it’s time for large clinical trials examining the risk/benefit ratio of short infusion of these agents in the contemporary practice of primary PCI for STEMI.
Simultaneously with Dr. Valgimigli’s presentation, the FABOLUS FASTER results were published online (Circulation. 2020 Jun 27; doi: 10.1161/CIRCULATIONAHA.120.046928).
Dr. Valgimigli reported that Medicure, the sponsor of the FABOLUS FASTER trial, provided an institutional research grant to conduct the study. He also disclosed receiving research grants and personal fees outside the scope of this study from a dozen pharmaceutical and medical device companies. Dr. Naber reported having no financial conflicts.
REPORTING FROM EUROPCR 2020
Sotatercept reversed vascular remodeling in patients with PAH
for patients with pulmonary arterial hypertension (PAH) in a phase 2 trial.
The mean decline change in pulmonary vascular resistance (PVR) after 24 weeks of treatment was significantly greater for patients treated with sotatercept at either of two doses, compared with placebo, David B. Badesch, MD, FCCP, of the University of Colorado, Aurora, reported on behalf of coinvestigators in the PULSAR trial.
“Sotatercept has a novel mechanism of action, rebalancing pro- and antiproliferative signaling through a pathway distinct from the previously approved pulmonary arterial hypertension therapies,” he said in the American Thoracic Society’s virtual clinical trial session.
The drug is a ligand trap with high selectivity for proteins within the tumor growth factor-beta superfamily signaling pathway. Investigators propose a mechanism of action whereby sotatercept promotes a rebalancing of bone morphogenetic protein receptor–II (BMPR-II) signaling to restore vascular homeostasis.
In a preclinical study, sotatercept reduced pulmonary artery pressure, pulmonary arteriolar muscularization and occlusion, right ventricular hypertrophy, and cell proliferation in the lungs of rodent models of pulmonary hypertension (Sci Transl Med. 2020 May 13. doi: 10.1126/scitranslmed.aaz5660).
Two dose levels
The PULSAR trial (NCT03496207) was a phase 2 randomized, double-blind study conducted in the United States, Brazil, Western Europe, and Australia comparing the efficacy and safety of sotatercept vs. placebo added to the standard of care in patients with PAH.
A total of 106 patients with World Health Organization (WHO) group 1 PAH or WHO functional class II or III disease were enrolled. All patients had baseline right-heart e4rcatheterization with PVR of 5 Wood units or more, had baseline 6-minute walk distance from 150 to 550 m, and were on stable treatment with standard-of-care mono, double, or triple therapies, including an endothelin-receptor antagonist, phosphodiesterase 5 inhibitor, soluble guanylate cyclase stimulator, and/or a prostacyclin, including intravenous formulations.
The median patient age was 46 years among 32 patients in the placebo group, and 48.5 years in each sotatercept dose group: 0.3 mg/kg (32 patients) and 0.7 mg/kg (42 patients).
The primary endpoint of PVR change from baseline to week 24, the end of the placebo-controlled treatment period, showed a mean decrease of 162 dynes/cm2 in the 0.3-mg/kg sotatercept group (–20.5%), and a mean decrease of 256 dynes/cm2 in the 0.7-mg/kg group (–33.9%), compared with a mean 16 dyne/cm2 decline in the placebo group (–2,1%). Both doses were associated with significantly larger decreases, compared with placebo (P = .0027 for the 0.3-mg/kg dose, and P < .0001 for the 0.7-mg/kg dose).
Six-minute walk distance, a key secondary endpoint, improved over baseline in each active-drug arm, with a least square (LS) mean improvement of 58 m in the 0.7-mg/kg group, and 50 m in the 0.7-mg/kg group. The prespecified analysis of pooled data from the two sotatercept cohorts showed an LS-mean change of 54 m over baseline, compared with 25 m for the placebo group (nominal P = .03).
Exploratory endpoints also favoring sotatercept over placebo included a 51% reduction in amino-terminal brain natriuretic propeptide (NT-proBNP), and a 20% reduction in mean pulmonary arterial pressure.
There was no significant difference between the study arms in change in cardiac output, however.
Improvements in WHO functional class were seen in 12.5% of patients on placebo, compared with 23% of patients on sotatercept, a difference that was not statistically significant.
Two patients (6%) in the 0.3-mg/kg arm and 10 (24%) in the 0.7-mg/kg arm had a serious treatment-emergent adverse event (TEAE), as did three patients (9%) in the placebo arm. Serious TEAEs included leukopenia, neutropenia, pericardial infusion, tachycardia, chorioretinopathy, peripheral edema, pyrexia, bronchitis, influenza, respiratory tract infection, femur fracture, hypotension, device breakage, syncope, and red blood cell increase.
One patient in the 0.7-mg/kg arm died from cardiac arrest deemed unrelated to study treatment.
TEAEs of special interest included thrombocytopenia in two patients in 0.3– and five patients in the 0.7–mg/kg groups, vs. no patients in the placebo groups. Most patients had existing thrombocytopenia at baseline and all were on concomitant prostacyclin infusions. No patients had grade 3 thrombocytopenia or associated bleeding events.
One patient in the 0.3-mg/kg group and six patients in the 0.7-mg/kg group had an increase in hemoglobin.
“This was not a surprise,” Dr. Badesch said. “We were prepared to manage increases in hemoglobin with dose interruption or dose reduction if necessary, and phlebotomy was also an option if needed.”
One patient in the placebo arm, two in the 0.3-mg/kg and three patients in the 0.7-mg/kg arms had TEAEs leading to discontinuation.
TEAEs occurring in 10% or more of all patients in any arm and of any grade were headache, diarrhea, peripheral edema, dizziness, fatigue, hypokalemia, and nausea.
Why no cardiac improvement?
In the question-and-answer session following the online presentation, facilitator Steven M. Kawut MD, MS, of the University of Pennsylvania and Pennsylvania Hospital in Philadelphia, remarked on the surprising lack of an apparent cardiac benefit in the study.
“You showed pretty robust decreases in NT-proBNP, decreases in pulmonary vascular resistance and right atrial pressure, and increases in 6-minute walk distance, so it’s a bit surprising that cardiac output didn’t change,” he said.
“Unlike other medications that have been tried in this field and have had a significant pulmonary vasodilatory effect, this drug is acting largely on the structure of pulmonary blood vessels,” Dr. Badesch replied. “We have thought that its primary effect is likely remodeling of the pulmonary arteries and arterioles, decreasing pulmonary vascular resistance. Unlike other drugs that have been tested in the field, it probably has no direct inotropic effect, and that may explain why cardiac output didn’t improve.”
He said that there is some echocardiographic evidence that suggests a change in right ventricular function over time. Those data are currently being analyzed, and “it’s possible that we’ll see an effect on cardiac output later.”
As of June 22, 2020, 94 of 97 patients who opted to participate in an 18-month extension period of the trial were still enrolled, and 64 patients have now been treated with sotatercept for at least 12 months.
A phase 3 trial is in the works.
The study was supported by Acceleron Pharma. Badesch disclosed research support from and consulting/advising for the company and others. Dr. Kawut has disclosed grants from several companies and travel support from ATS and the Pulmonary Hypertension Association.
for patients with pulmonary arterial hypertension (PAH) in a phase 2 trial.
The mean decline change in pulmonary vascular resistance (PVR) after 24 weeks of treatment was significantly greater for patients treated with sotatercept at either of two doses, compared with placebo, David B. Badesch, MD, FCCP, of the University of Colorado, Aurora, reported on behalf of coinvestigators in the PULSAR trial.
“Sotatercept has a novel mechanism of action, rebalancing pro- and antiproliferative signaling through a pathway distinct from the previously approved pulmonary arterial hypertension therapies,” he said in the American Thoracic Society’s virtual clinical trial session.
The drug is a ligand trap with high selectivity for proteins within the tumor growth factor-beta superfamily signaling pathway. Investigators propose a mechanism of action whereby sotatercept promotes a rebalancing of bone morphogenetic protein receptor–II (BMPR-II) signaling to restore vascular homeostasis.
In a preclinical study, sotatercept reduced pulmonary artery pressure, pulmonary arteriolar muscularization and occlusion, right ventricular hypertrophy, and cell proliferation in the lungs of rodent models of pulmonary hypertension (Sci Transl Med. 2020 May 13. doi: 10.1126/scitranslmed.aaz5660).
Two dose levels
The PULSAR trial (NCT03496207) was a phase 2 randomized, double-blind study conducted in the United States, Brazil, Western Europe, and Australia comparing the efficacy and safety of sotatercept vs. placebo added to the standard of care in patients with PAH.
A total of 106 patients with World Health Organization (WHO) group 1 PAH or WHO functional class II or III disease were enrolled. All patients had baseline right-heart e4rcatheterization with PVR of 5 Wood units or more, had baseline 6-minute walk distance from 150 to 550 m, and were on stable treatment with standard-of-care mono, double, or triple therapies, including an endothelin-receptor antagonist, phosphodiesterase 5 inhibitor, soluble guanylate cyclase stimulator, and/or a prostacyclin, including intravenous formulations.
The median patient age was 46 years among 32 patients in the placebo group, and 48.5 years in each sotatercept dose group: 0.3 mg/kg (32 patients) and 0.7 mg/kg (42 patients).
The primary endpoint of PVR change from baseline to week 24, the end of the placebo-controlled treatment period, showed a mean decrease of 162 dynes/cm2 in the 0.3-mg/kg sotatercept group (–20.5%), and a mean decrease of 256 dynes/cm2 in the 0.7-mg/kg group (–33.9%), compared with a mean 16 dyne/cm2 decline in the placebo group (–2,1%). Both doses were associated with significantly larger decreases, compared with placebo (P = .0027 for the 0.3-mg/kg dose, and P < .0001 for the 0.7-mg/kg dose).
Six-minute walk distance, a key secondary endpoint, improved over baseline in each active-drug arm, with a least square (LS) mean improvement of 58 m in the 0.7-mg/kg group, and 50 m in the 0.7-mg/kg group. The prespecified analysis of pooled data from the two sotatercept cohorts showed an LS-mean change of 54 m over baseline, compared with 25 m for the placebo group (nominal P = .03).
Exploratory endpoints also favoring sotatercept over placebo included a 51% reduction in amino-terminal brain natriuretic propeptide (NT-proBNP), and a 20% reduction in mean pulmonary arterial pressure.
There was no significant difference between the study arms in change in cardiac output, however.
Improvements in WHO functional class were seen in 12.5% of patients on placebo, compared with 23% of patients on sotatercept, a difference that was not statistically significant.
Two patients (6%) in the 0.3-mg/kg arm and 10 (24%) in the 0.7-mg/kg arm had a serious treatment-emergent adverse event (TEAE), as did three patients (9%) in the placebo arm. Serious TEAEs included leukopenia, neutropenia, pericardial infusion, tachycardia, chorioretinopathy, peripheral edema, pyrexia, bronchitis, influenza, respiratory tract infection, femur fracture, hypotension, device breakage, syncope, and red blood cell increase.
One patient in the 0.7-mg/kg arm died from cardiac arrest deemed unrelated to study treatment.
TEAEs of special interest included thrombocytopenia in two patients in 0.3– and five patients in the 0.7–mg/kg groups, vs. no patients in the placebo groups. Most patients had existing thrombocytopenia at baseline and all were on concomitant prostacyclin infusions. No patients had grade 3 thrombocytopenia or associated bleeding events.
One patient in the 0.3-mg/kg group and six patients in the 0.7-mg/kg group had an increase in hemoglobin.
“This was not a surprise,” Dr. Badesch said. “We were prepared to manage increases in hemoglobin with dose interruption or dose reduction if necessary, and phlebotomy was also an option if needed.”
One patient in the placebo arm, two in the 0.3-mg/kg and three patients in the 0.7-mg/kg arms had TEAEs leading to discontinuation.
TEAEs occurring in 10% or more of all patients in any arm and of any grade were headache, diarrhea, peripheral edema, dizziness, fatigue, hypokalemia, and nausea.
Why no cardiac improvement?
In the question-and-answer session following the online presentation, facilitator Steven M. Kawut MD, MS, of the University of Pennsylvania and Pennsylvania Hospital in Philadelphia, remarked on the surprising lack of an apparent cardiac benefit in the study.
“You showed pretty robust decreases in NT-proBNP, decreases in pulmonary vascular resistance and right atrial pressure, and increases in 6-minute walk distance, so it’s a bit surprising that cardiac output didn’t change,” he said.
“Unlike other medications that have been tried in this field and have had a significant pulmonary vasodilatory effect, this drug is acting largely on the structure of pulmonary blood vessels,” Dr. Badesch replied. “We have thought that its primary effect is likely remodeling of the pulmonary arteries and arterioles, decreasing pulmonary vascular resistance. Unlike other drugs that have been tested in the field, it probably has no direct inotropic effect, and that may explain why cardiac output didn’t improve.”
He said that there is some echocardiographic evidence that suggests a change in right ventricular function over time. Those data are currently being analyzed, and “it’s possible that we’ll see an effect on cardiac output later.”
As of June 22, 2020, 94 of 97 patients who opted to participate in an 18-month extension period of the trial were still enrolled, and 64 patients have now been treated with sotatercept for at least 12 months.
A phase 3 trial is in the works.
The study was supported by Acceleron Pharma. Badesch disclosed research support from and consulting/advising for the company and others. Dr. Kawut has disclosed grants from several companies and travel support from ATS and the Pulmonary Hypertension Association.
for patients with pulmonary arterial hypertension (PAH) in a phase 2 trial.
The mean decline change in pulmonary vascular resistance (PVR) after 24 weeks of treatment was significantly greater for patients treated with sotatercept at either of two doses, compared with placebo, David B. Badesch, MD, FCCP, of the University of Colorado, Aurora, reported on behalf of coinvestigators in the PULSAR trial.
“Sotatercept has a novel mechanism of action, rebalancing pro- and antiproliferative signaling through a pathway distinct from the previously approved pulmonary arterial hypertension therapies,” he said in the American Thoracic Society’s virtual clinical trial session.
The drug is a ligand trap with high selectivity for proteins within the tumor growth factor-beta superfamily signaling pathway. Investigators propose a mechanism of action whereby sotatercept promotes a rebalancing of bone morphogenetic protein receptor–II (BMPR-II) signaling to restore vascular homeostasis.
In a preclinical study, sotatercept reduced pulmonary artery pressure, pulmonary arteriolar muscularization and occlusion, right ventricular hypertrophy, and cell proliferation in the lungs of rodent models of pulmonary hypertension (Sci Transl Med. 2020 May 13. doi: 10.1126/scitranslmed.aaz5660).
Two dose levels
The PULSAR trial (NCT03496207) was a phase 2 randomized, double-blind study conducted in the United States, Brazil, Western Europe, and Australia comparing the efficacy and safety of sotatercept vs. placebo added to the standard of care in patients with PAH.
A total of 106 patients with World Health Organization (WHO) group 1 PAH or WHO functional class II or III disease were enrolled. All patients had baseline right-heart e4rcatheterization with PVR of 5 Wood units or more, had baseline 6-minute walk distance from 150 to 550 m, and were on stable treatment with standard-of-care mono, double, or triple therapies, including an endothelin-receptor antagonist, phosphodiesterase 5 inhibitor, soluble guanylate cyclase stimulator, and/or a prostacyclin, including intravenous formulations.
The median patient age was 46 years among 32 patients in the placebo group, and 48.5 years in each sotatercept dose group: 0.3 mg/kg (32 patients) and 0.7 mg/kg (42 patients).
The primary endpoint of PVR change from baseline to week 24, the end of the placebo-controlled treatment period, showed a mean decrease of 162 dynes/cm2 in the 0.3-mg/kg sotatercept group (–20.5%), and a mean decrease of 256 dynes/cm2 in the 0.7-mg/kg group (–33.9%), compared with a mean 16 dyne/cm2 decline in the placebo group (–2,1%). Both doses were associated with significantly larger decreases, compared with placebo (P = .0027 for the 0.3-mg/kg dose, and P < .0001 for the 0.7-mg/kg dose).
Six-minute walk distance, a key secondary endpoint, improved over baseline in each active-drug arm, with a least square (LS) mean improvement of 58 m in the 0.7-mg/kg group, and 50 m in the 0.7-mg/kg group. The prespecified analysis of pooled data from the two sotatercept cohorts showed an LS-mean change of 54 m over baseline, compared with 25 m for the placebo group (nominal P = .03).
Exploratory endpoints also favoring sotatercept over placebo included a 51% reduction in amino-terminal brain natriuretic propeptide (NT-proBNP), and a 20% reduction in mean pulmonary arterial pressure.
There was no significant difference between the study arms in change in cardiac output, however.
Improvements in WHO functional class were seen in 12.5% of patients on placebo, compared with 23% of patients on sotatercept, a difference that was not statistically significant.
Two patients (6%) in the 0.3-mg/kg arm and 10 (24%) in the 0.7-mg/kg arm had a serious treatment-emergent adverse event (TEAE), as did three patients (9%) in the placebo arm. Serious TEAEs included leukopenia, neutropenia, pericardial infusion, tachycardia, chorioretinopathy, peripheral edema, pyrexia, bronchitis, influenza, respiratory tract infection, femur fracture, hypotension, device breakage, syncope, and red blood cell increase.
One patient in the 0.7-mg/kg arm died from cardiac arrest deemed unrelated to study treatment.
TEAEs of special interest included thrombocytopenia in two patients in 0.3– and five patients in the 0.7–mg/kg groups, vs. no patients in the placebo groups. Most patients had existing thrombocytopenia at baseline and all were on concomitant prostacyclin infusions. No patients had grade 3 thrombocytopenia or associated bleeding events.
One patient in the 0.3-mg/kg group and six patients in the 0.7-mg/kg group had an increase in hemoglobin.
“This was not a surprise,” Dr. Badesch said. “We were prepared to manage increases in hemoglobin with dose interruption or dose reduction if necessary, and phlebotomy was also an option if needed.”
One patient in the placebo arm, two in the 0.3-mg/kg and three patients in the 0.7-mg/kg arms had TEAEs leading to discontinuation.
TEAEs occurring in 10% or more of all patients in any arm and of any grade were headache, diarrhea, peripheral edema, dizziness, fatigue, hypokalemia, and nausea.
Why no cardiac improvement?
In the question-and-answer session following the online presentation, facilitator Steven M. Kawut MD, MS, of the University of Pennsylvania and Pennsylvania Hospital in Philadelphia, remarked on the surprising lack of an apparent cardiac benefit in the study.
“You showed pretty robust decreases in NT-proBNP, decreases in pulmonary vascular resistance and right atrial pressure, and increases in 6-minute walk distance, so it’s a bit surprising that cardiac output didn’t change,” he said.
“Unlike other medications that have been tried in this field and have had a significant pulmonary vasodilatory effect, this drug is acting largely on the structure of pulmonary blood vessels,” Dr. Badesch replied. “We have thought that its primary effect is likely remodeling of the pulmonary arteries and arterioles, decreasing pulmonary vascular resistance. Unlike other drugs that have been tested in the field, it probably has no direct inotropic effect, and that may explain why cardiac output didn’t improve.”
He said that there is some echocardiographic evidence that suggests a change in right ventricular function over time. Those data are currently being analyzed, and “it’s possible that we’ll see an effect on cardiac output later.”
As of June 22, 2020, 94 of 97 patients who opted to participate in an 18-month extension period of the trial were still enrolled, and 64 patients have now been treated with sotatercept for at least 12 months.
A phase 3 trial is in the works.
The study was supported by Acceleron Pharma. Badesch disclosed research support from and consulting/advising for the company and others. Dr. Kawut has disclosed grants from several companies and travel support from ATS and the Pulmonary Hypertension Association.
FROM ATS 2020
New data back use of medical cannabis for epilepsy, pain, anxiety
Two new studies offer positive news about medical cannabis, suggesting that marijuana products improve physical and cognitive symptoms, boost quality of life, and rarely produce signs of problematic use.
In one study, patients with epilepsy who used medical cannabis were nearly half as likely to have needed an emergency department visit within the last 30 days as was a control group. In the other study, 3 of 54 subjects who used medical cannabis showed signs of possible cannabis use disorder (CUD) over 12 months.
The findings show that “there is improvement in a range of outcome variables, and the adverse effects seem to be minimal, compared to what we might have hypothesized based on the bulk of the literature on the negative effects of cannabis on health outcomes,” cannabis researcher Ziva Cooper, PhD, of the University of California at Los Angeles, said in an interview. Dr. Cooper moderated a session about the studies at the virtual annual meeting of the College on Problems of Drug Dependence.
In one study, cannabis researcher Ryan Vandrey, PhD, of Johns Hopkins University, Baltimore, and colleagues compared medical cannabis users (number, 808; mean age, 38; percentage female, 63%) to a control group of people who were interested in medical cannabis (n, 468; mean age, 35; percentage female, 62%).
In both groups, 79% were White. The groups had similar levels of primary medical conditions, such as neurologic (38% and 36%, respectively, for the medical cannabis group and control group) and chronic pain (25% and 23%, respectively.)
The wide majority of those in the medical cannabis group – 58% – were cannabidiol (CBD) users, relying on a component of cannabis (marijuana) that does not make people high. Fewer than 20% used tetrahydrocannabinol (THC), which does make people high, or a combination of both CBD and THC.
Most of those in the medical cannabis group used the drug as an adjunct (39%) to other treatments or last-resort (29%) treatment instead of first line (11%) or second line (18%).
In patients with epilepsy, about 45% of controls reported a past-month ED visit, compared with about 25% of medical cannabis users. The gap in past-month hospital admissions was even wider, at about 35% for the controls and about 15% for the medical cannabis.
After an initial survey, the researchers followed subjects prospectively; some either started or stopped using medical cannabis. From baseline to follow-up, those in the medical cannabis group improved more, compared with those in the control group on a variety of measures of quality of life, anxiety, and depression.
“Folks who were in the control condition at baseline and then initiated cannabis use started to look more like the baseline cannabis users,” Dr. Vandrey said. “The folks who were cannabis users at baseline and then stopped for whatever reason started to look like the controls. And the controls [who never started using medical cannabis] stayed the same.”
As for adverse effects, two-thirds of medical cannabis users reported no problems; the highest number, 14%, reported high cost.
As for limitations, Dr. Vandrey reported missing data, a reliance on self-reports, and poor follow-up with about a third of participants agreeing to complete follow-up assessments. “We are continuing to collect data on this,” he said, “and we’re hoping we’ll be able to drill down more as we get bigger.”
The study was funded by the Realm of Caring Foundation.
In the other study, led by cannabis researcher Staci Gruber, PhD, of McLean Hospital in Belmont, Mass., and Harvard Medical School in Boston, researchers tracked 54 subjects (mean age, 49; 20 male and 34 female; 48 white) for up to 2 years after they began medical cannabis use. Most had pain (36) or anxiety/PTSD (31), and all had to have abstained from recreational cannabis use for at least 1 year.
At follow-ups, the users reported improved mood and anxiety via various measures, and they saw some improvement in quality of life. “We did not see worsening cognitive performance,” Dr. Gruber said. “In fact,
Research has suggested that as many as 30% of recreational cannabis users develop cannabis use disorder (CUD), Dr. Gruber said. But only 3 of the 54 patients showed signs of possible CUD at 12 months, she said, even though frequency of use jumped substantially vs. baseline.
Information about study funding was not available.
Dr. Cooper disclosed relationships with FSD Pharma, Beckley Canopy Therapeutics, and Insys Therapeutics. Dr. Vandrey disclosed work with Zynerba Pharmaceuticals, Canopy Health Innovations, and FSD Pharma. Dr. Gruber reported no disclosures.
Two new studies offer positive news about medical cannabis, suggesting that marijuana products improve physical and cognitive symptoms, boost quality of life, and rarely produce signs of problematic use.
In one study, patients with epilepsy who used medical cannabis were nearly half as likely to have needed an emergency department visit within the last 30 days as was a control group. In the other study, 3 of 54 subjects who used medical cannabis showed signs of possible cannabis use disorder (CUD) over 12 months.
The findings show that “there is improvement in a range of outcome variables, and the adverse effects seem to be minimal, compared to what we might have hypothesized based on the bulk of the literature on the negative effects of cannabis on health outcomes,” cannabis researcher Ziva Cooper, PhD, of the University of California at Los Angeles, said in an interview. Dr. Cooper moderated a session about the studies at the virtual annual meeting of the College on Problems of Drug Dependence.
In one study, cannabis researcher Ryan Vandrey, PhD, of Johns Hopkins University, Baltimore, and colleagues compared medical cannabis users (number, 808; mean age, 38; percentage female, 63%) to a control group of people who were interested in medical cannabis (n, 468; mean age, 35; percentage female, 62%).
In both groups, 79% were White. The groups had similar levels of primary medical conditions, such as neurologic (38% and 36%, respectively, for the medical cannabis group and control group) and chronic pain (25% and 23%, respectively.)
The wide majority of those in the medical cannabis group – 58% – were cannabidiol (CBD) users, relying on a component of cannabis (marijuana) that does not make people high. Fewer than 20% used tetrahydrocannabinol (THC), which does make people high, or a combination of both CBD and THC.
Most of those in the medical cannabis group used the drug as an adjunct (39%) to other treatments or last-resort (29%) treatment instead of first line (11%) or second line (18%).
In patients with epilepsy, about 45% of controls reported a past-month ED visit, compared with about 25% of medical cannabis users. The gap in past-month hospital admissions was even wider, at about 35% for the controls and about 15% for the medical cannabis.
After an initial survey, the researchers followed subjects prospectively; some either started or stopped using medical cannabis. From baseline to follow-up, those in the medical cannabis group improved more, compared with those in the control group on a variety of measures of quality of life, anxiety, and depression.
“Folks who were in the control condition at baseline and then initiated cannabis use started to look more like the baseline cannabis users,” Dr. Vandrey said. “The folks who were cannabis users at baseline and then stopped for whatever reason started to look like the controls. And the controls [who never started using medical cannabis] stayed the same.”
As for adverse effects, two-thirds of medical cannabis users reported no problems; the highest number, 14%, reported high cost.
As for limitations, Dr. Vandrey reported missing data, a reliance on self-reports, and poor follow-up with about a third of participants agreeing to complete follow-up assessments. “We are continuing to collect data on this,” he said, “and we’re hoping we’ll be able to drill down more as we get bigger.”
The study was funded by the Realm of Caring Foundation.
In the other study, led by cannabis researcher Staci Gruber, PhD, of McLean Hospital in Belmont, Mass., and Harvard Medical School in Boston, researchers tracked 54 subjects (mean age, 49; 20 male and 34 female; 48 white) for up to 2 years after they began medical cannabis use. Most had pain (36) or anxiety/PTSD (31), and all had to have abstained from recreational cannabis use for at least 1 year.
At follow-ups, the users reported improved mood and anxiety via various measures, and they saw some improvement in quality of life. “We did not see worsening cognitive performance,” Dr. Gruber said. “In fact,
Research has suggested that as many as 30% of recreational cannabis users develop cannabis use disorder (CUD), Dr. Gruber said. But only 3 of the 54 patients showed signs of possible CUD at 12 months, she said, even though frequency of use jumped substantially vs. baseline.
Information about study funding was not available.
Dr. Cooper disclosed relationships with FSD Pharma, Beckley Canopy Therapeutics, and Insys Therapeutics. Dr. Vandrey disclosed work with Zynerba Pharmaceuticals, Canopy Health Innovations, and FSD Pharma. Dr. Gruber reported no disclosures.
Two new studies offer positive news about medical cannabis, suggesting that marijuana products improve physical and cognitive symptoms, boost quality of life, and rarely produce signs of problematic use.
In one study, patients with epilepsy who used medical cannabis were nearly half as likely to have needed an emergency department visit within the last 30 days as was a control group. In the other study, 3 of 54 subjects who used medical cannabis showed signs of possible cannabis use disorder (CUD) over 12 months.
The findings show that “there is improvement in a range of outcome variables, and the adverse effects seem to be minimal, compared to what we might have hypothesized based on the bulk of the literature on the negative effects of cannabis on health outcomes,” cannabis researcher Ziva Cooper, PhD, of the University of California at Los Angeles, said in an interview. Dr. Cooper moderated a session about the studies at the virtual annual meeting of the College on Problems of Drug Dependence.
In one study, cannabis researcher Ryan Vandrey, PhD, of Johns Hopkins University, Baltimore, and colleagues compared medical cannabis users (number, 808; mean age, 38; percentage female, 63%) to a control group of people who were interested in medical cannabis (n, 468; mean age, 35; percentage female, 62%).
In both groups, 79% were White. The groups had similar levels of primary medical conditions, such as neurologic (38% and 36%, respectively, for the medical cannabis group and control group) and chronic pain (25% and 23%, respectively.)
The wide majority of those in the medical cannabis group – 58% – were cannabidiol (CBD) users, relying on a component of cannabis (marijuana) that does not make people high. Fewer than 20% used tetrahydrocannabinol (THC), which does make people high, or a combination of both CBD and THC.
Most of those in the medical cannabis group used the drug as an adjunct (39%) to other treatments or last-resort (29%) treatment instead of first line (11%) or second line (18%).
In patients with epilepsy, about 45% of controls reported a past-month ED visit, compared with about 25% of medical cannabis users. The gap in past-month hospital admissions was even wider, at about 35% for the controls and about 15% for the medical cannabis.
After an initial survey, the researchers followed subjects prospectively; some either started or stopped using medical cannabis. From baseline to follow-up, those in the medical cannabis group improved more, compared with those in the control group on a variety of measures of quality of life, anxiety, and depression.
“Folks who were in the control condition at baseline and then initiated cannabis use started to look more like the baseline cannabis users,” Dr. Vandrey said. “The folks who were cannabis users at baseline and then stopped for whatever reason started to look like the controls. And the controls [who never started using medical cannabis] stayed the same.”
As for adverse effects, two-thirds of medical cannabis users reported no problems; the highest number, 14%, reported high cost.
As for limitations, Dr. Vandrey reported missing data, a reliance on self-reports, and poor follow-up with about a third of participants agreeing to complete follow-up assessments. “We are continuing to collect data on this,” he said, “and we’re hoping we’ll be able to drill down more as we get bigger.”
The study was funded by the Realm of Caring Foundation.
In the other study, led by cannabis researcher Staci Gruber, PhD, of McLean Hospital in Belmont, Mass., and Harvard Medical School in Boston, researchers tracked 54 subjects (mean age, 49; 20 male and 34 female; 48 white) for up to 2 years after they began medical cannabis use. Most had pain (36) or anxiety/PTSD (31), and all had to have abstained from recreational cannabis use for at least 1 year.
At follow-ups, the users reported improved mood and anxiety via various measures, and they saw some improvement in quality of life. “We did not see worsening cognitive performance,” Dr. Gruber said. “In fact,
Research has suggested that as many as 30% of recreational cannabis users develop cannabis use disorder (CUD), Dr. Gruber said. But only 3 of the 54 patients showed signs of possible CUD at 12 months, she said, even though frequency of use jumped substantially vs. baseline.
Information about study funding was not available.
Dr. Cooper disclosed relationships with FSD Pharma, Beckley Canopy Therapeutics, and Insys Therapeutics. Dr. Vandrey disclosed work with Zynerba Pharmaceuticals, Canopy Health Innovations, and FSD Pharma. Dr. Gruber reported no disclosures.
FROM CPDD 2020
App links overdosing people to nearby volunteers with naloxone
Naloxone can reverse opioid overdoses, but time is crucial and its effectiveness wanes if medics can’t arrive right away. Now, a new app links overdose victims or their companions to trained volunteers nearby who may be able to administer the drug much faster.
Over a 1-year period, about half of 112 participants in a Philadelphia trial said they’d responded to overdoses via the app, and about half used it to report overdoses, according to a study released at the virtual annual meeting of the College on Problems of Drug Dependence.
“Thanks to the app, there may have been a life saved about twice a month that otherwise wouldn’t have been,” said public health researcher and study coauthor Stephen Lankenau, PhD, of Drexel University, Philadelphia, in an interview.
Philadelphia has the largest opioid overdose rate of any large city, Dr. Lankenau said, and people who overdose are often reluctant to call 911. “Police are often alerted when it’s determined that it’s a drug-related call. They’re concerned that police could show up and someone will get arrested.”
However, the app, called UnityPhilly, doesn’t remove professional medics from the picture. It’s designed to be a supplement to the existing first-response system – “it’s not meant to replace 911” – and allow a faster response to overdoses when minutes matter, Dr. Lankenau said.
“If someone is adamantly opposed to calling 911,” he said, “this may not be the best intervention for them.”
Here’s how the app works: Participants who overdose themselves or witness an overdose can send out an alert to nearby app users. When an alert goes out, the app also attempts to dial 911, although the participant can bypass this.
Nearby responders can reply by pressing “En route” and then go to the address of the overdose with a provided supply of naloxone (Narcan). The amateur responders, many of whom are or were opioid users themselves, are trained in how to administer the drug.
The study authors recruited 112 participants from the Philadelphia neighborhood of Kensington and tracked them from 2019 to 2020. About half (n = 57) reported using opioids within the past 30 days, and those participants had an average age of 42 years, were 54% men, and were 74% non-Hispanic white. Only 19% were employed, and 42% had been recently homeless. Nearly 80% had overdosed before, and all had witnessed overdoses.
The other participants (n = 55), defined as “community members,” had less experience with opioids (44% had misused them before), although 91% had witnessed overdoses. Their average age was 42 years, 56% were women, 53% were employed, and 16% had been recently homeless.
The percentages who reported being en route to an overdose was 47% (opioid users) and 46% (community members).
“The idea of people being trained as community responders has been around for quite a while, and there are hundreds of programs across the country. People are willing to carry naloxone and respond if they see an overdose in front of them,” Dr. Lankenau said. “Here, you have people becoming civilian responders to events they wouldn’t otherwise know about. This creates a community of individuals who can help out immediately and augment the work that emergency responders do.”
Opioid users who download the app may be drawn to the idea of responders who are nonjudgmental and supportive, compared with professional medics. “The system has not done well by people with substance abuse disorders,” said addiction medicine specialist Sukhpreet Klaire, MD, of the British Columbia Center on Substance Use in Vancouver. “In terms of overdose reversal, you may prefer that someone else [other than a medic] give you Narcan and support you through this experience. When it’s over after you’re reversed, you have a sudden onset of withdrawal symptoms. You feel terrible, and you don’t want to be sitting in an ambulance. You want to be in a supportive environment.”
As for adverse effects, there was concern that opioid users might take more risks with an app safety net in place. However, no one reported more risky behavior in interviews, Dr. Lankenau said.
The 3-year program costs $215,000, he said, and the next step is to get funding for a Philadelphia citywide trial.
The study was funded by the National Institute of Drug Abuse. Dr. Lankenau reported no relevant disclosures. Dr. Klaire disclosed participating in a research fellowship and a research in addiction medical scholars program, both funded by NIDA.
Naloxone can reverse opioid overdoses, but time is crucial and its effectiveness wanes if medics can’t arrive right away. Now, a new app links overdose victims or their companions to trained volunteers nearby who may be able to administer the drug much faster.
Over a 1-year period, about half of 112 participants in a Philadelphia trial said they’d responded to overdoses via the app, and about half used it to report overdoses, according to a study released at the virtual annual meeting of the College on Problems of Drug Dependence.
“Thanks to the app, there may have been a life saved about twice a month that otherwise wouldn’t have been,” said public health researcher and study coauthor Stephen Lankenau, PhD, of Drexel University, Philadelphia, in an interview.
Philadelphia has the largest opioid overdose rate of any large city, Dr. Lankenau said, and people who overdose are often reluctant to call 911. “Police are often alerted when it’s determined that it’s a drug-related call. They’re concerned that police could show up and someone will get arrested.”
However, the app, called UnityPhilly, doesn’t remove professional medics from the picture. It’s designed to be a supplement to the existing first-response system – “it’s not meant to replace 911” – and allow a faster response to overdoses when minutes matter, Dr. Lankenau said.
“If someone is adamantly opposed to calling 911,” he said, “this may not be the best intervention for them.”
Here’s how the app works: Participants who overdose themselves or witness an overdose can send out an alert to nearby app users. When an alert goes out, the app also attempts to dial 911, although the participant can bypass this.
Nearby responders can reply by pressing “En route” and then go to the address of the overdose with a provided supply of naloxone (Narcan). The amateur responders, many of whom are or were opioid users themselves, are trained in how to administer the drug.
The study authors recruited 112 participants from the Philadelphia neighborhood of Kensington and tracked them from 2019 to 2020. About half (n = 57) reported using opioids within the past 30 days, and those participants had an average age of 42 years, were 54% men, and were 74% non-Hispanic white. Only 19% were employed, and 42% had been recently homeless. Nearly 80% had overdosed before, and all had witnessed overdoses.
The other participants (n = 55), defined as “community members,” had less experience with opioids (44% had misused them before), although 91% had witnessed overdoses. Their average age was 42 years, 56% were women, 53% were employed, and 16% had been recently homeless.
The percentages who reported being en route to an overdose was 47% (opioid users) and 46% (community members).
“The idea of people being trained as community responders has been around for quite a while, and there are hundreds of programs across the country. People are willing to carry naloxone and respond if they see an overdose in front of them,” Dr. Lankenau said. “Here, you have people becoming civilian responders to events they wouldn’t otherwise know about. This creates a community of individuals who can help out immediately and augment the work that emergency responders do.”
Opioid users who download the app may be drawn to the idea of responders who are nonjudgmental and supportive, compared with professional medics. “The system has not done well by people with substance abuse disorders,” said addiction medicine specialist Sukhpreet Klaire, MD, of the British Columbia Center on Substance Use in Vancouver. “In terms of overdose reversal, you may prefer that someone else [other than a medic] give you Narcan and support you through this experience. When it’s over after you’re reversed, you have a sudden onset of withdrawal symptoms. You feel terrible, and you don’t want to be sitting in an ambulance. You want to be in a supportive environment.”
As for adverse effects, there was concern that opioid users might take more risks with an app safety net in place. However, no one reported more risky behavior in interviews, Dr. Lankenau said.
The 3-year program costs $215,000, he said, and the next step is to get funding for a Philadelphia citywide trial.
The study was funded by the National Institute of Drug Abuse. Dr. Lankenau reported no relevant disclosures. Dr. Klaire disclosed participating in a research fellowship and a research in addiction medical scholars program, both funded by NIDA.
Naloxone can reverse opioid overdoses, but time is crucial and its effectiveness wanes if medics can’t arrive right away. Now, a new app links overdose victims or their companions to trained volunteers nearby who may be able to administer the drug much faster.
Over a 1-year period, about half of 112 participants in a Philadelphia trial said they’d responded to overdoses via the app, and about half used it to report overdoses, according to a study released at the virtual annual meeting of the College on Problems of Drug Dependence.
“Thanks to the app, there may have been a life saved about twice a month that otherwise wouldn’t have been,” said public health researcher and study coauthor Stephen Lankenau, PhD, of Drexel University, Philadelphia, in an interview.
Philadelphia has the largest opioid overdose rate of any large city, Dr. Lankenau said, and people who overdose are often reluctant to call 911. “Police are often alerted when it’s determined that it’s a drug-related call. They’re concerned that police could show up and someone will get arrested.”
However, the app, called UnityPhilly, doesn’t remove professional medics from the picture. It’s designed to be a supplement to the existing first-response system – “it’s not meant to replace 911” – and allow a faster response to overdoses when minutes matter, Dr. Lankenau said.
“If someone is adamantly opposed to calling 911,” he said, “this may not be the best intervention for them.”
Here’s how the app works: Participants who overdose themselves or witness an overdose can send out an alert to nearby app users. When an alert goes out, the app also attempts to dial 911, although the participant can bypass this.
Nearby responders can reply by pressing “En route” and then go to the address of the overdose with a provided supply of naloxone (Narcan). The amateur responders, many of whom are or were opioid users themselves, are trained in how to administer the drug.
The study authors recruited 112 participants from the Philadelphia neighborhood of Kensington and tracked them from 2019 to 2020. About half (n = 57) reported using opioids within the past 30 days, and those participants had an average age of 42 years, were 54% men, and were 74% non-Hispanic white. Only 19% were employed, and 42% had been recently homeless. Nearly 80% had overdosed before, and all had witnessed overdoses.
The other participants (n = 55), defined as “community members,” had less experience with opioids (44% had misused them before), although 91% had witnessed overdoses. Their average age was 42 years, 56% were women, 53% were employed, and 16% had been recently homeless.
The percentages who reported being en route to an overdose was 47% (opioid users) and 46% (community members).
“The idea of people being trained as community responders has been around for quite a while, and there are hundreds of programs across the country. People are willing to carry naloxone and respond if they see an overdose in front of them,” Dr. Lankenau said. “Here, you have people becoming civilian responders to events they wouldn’t otherwise know about. This creates a community of individuals who can help out immediately and augment the work that emergency responders do.”
Opioid users who download the app may be drawn to the idea of responders who are nonjudgmental and supportive, compared with professional medics. “The system has not done well by people with substance abuse disorders,” said addiction medicine specialist Sukhpreet Klaire, MD, of the British Columbia Center on Substance Use in Vancouver. “In terms of overdose reversal, you may prefer that someone else [other than a medic] give you Narcan and support you through this experience. When it’s over after you’re reversed, you have a sudden onset of withdrawal symptoms. You feel terrible, and you don’t want to be sitting in an ambulance. You want to be in a supportive environment.”
As for adverse effects, there was concern that opioid users might take more risks with an app safety net in place. However, no one reported more risky behavior in interviews, Dr. Lankenau said.
The 3-year program costs $215,000, he said, and the next step is to get funding for a Philadelphia citywide trial.
The study was funded by the National Institute of Drug Abuse. Dr. Lankenau reported no relevant disclosures. Dr. Klaire disclosed participating in a research fellowship and a research in addiction medical scholars program, both funded by NIDA.
FROM CPDD 2020
Take-home test strips allow drug users to detect fentanyl
Illicit drug users seem to overwhelmingly appreciate being able to use take-home test strips to detect the extremely common presence of dangerous fentanyl in opioids and other drugs, a new study finds. More than 95% said they’d use the inexpensive strips again.
said study lead author addiction medicine specialist Sukhpreet Klaire, MD, of the British Columbia Center on Substance Use in Vancouver, in an interview.
Dr. Klaire presented the study findings at the virtual annual meeting of the College on Problems of Drug Dependence.
Researchers in Vancouver distributed take-home fentanyl test strip kits at 10 sites that allow users to test their illicit drugs. The 218 participants performed 1,680 tests, mainly (73%) for opioids, over 3 months in 2019. Of the participants, 61% were male, and the average age was 36 (interquartile range, 29-47). About 30% described themselves as indigenous Canadians (First Nations).
About 90% of the opioid samples tested at home were positive for fentanyl, about the same level as samples tested at clinics. Fentanyl is very potent and linked to the huge rise in overdose deaths in the United States.
Fentanyl test strips aren’t new. According to the Harm Reduction Coalition, they originally were developed to detect fentanyl in urine samples but were jury-rigged in Vancouver to work on samples of illicit drugs. “We literally just repurposed it,” Dr. Klaire said. “It’s the same strip.”
Users test their drugs by dissolving a small sample in water. Then then dip the test strip, which provides readings similar to those in a pregnancy test. If a sample turns up positive for fentanyl, Dr. Klaire said, users may discard the drug or “be more careful with it.”
When asked what they would do if a sample turned up positive, 27% said they’d make a “positive change,” such as using less or using more slowly (n = 45) or making sure that someone else is present in case of an overdose (n = 26). But most, 71%, reported no change in behavior.
Previously, researchers in Rhode Island and North Carolina also found that some users adopted safer behaviors – such as throwing out their drugs or using less often – after testing their drugs with the strips.
The strips cost about 75 cents, Dr. Klaire said.
Harm-reduction strategies are controversial, and fentanyl test strips aren’t any exemption. “The entire approach is based on the premise that a drug user poised to use a drug is making rational choices, is weighing pros and cons, and is thinking completely logically about his or her drug use. Based on my clinical experience, I know this could not be further from the truth,” wrote Elinore F. McCance-Katz, MD, PhD, assistant secretary for Mental Health and Substance Use with the Department of Health & Human Services, in a 2018 blog post.
But Dr. Klaire said the patients in the new study are highly dependent on opioids. “The drug supply is heavily contaminated [with fentanyl],” he said, “but even when people know it’s contaminated, they still need to go ahead and use it.”
In an interview, epidemiologist Brandon Marshall, PhD, of Brown University, Providence, R.I., who has conducted fentanyl test strip research, called the study results “compelling.”
“The researchers found that the fentanyl test strips had a very high level of acceptability – over 95% said they would use the strips again – which is remarkably similar to what we found in our work here in Rhode Island,” he said. “Taken together, these studies show that take-home test strips are a feasible, acceptable, and effective strategy for people who use drugs to reduce their risk of fentanyl overdose.”
He added that “fentanyl test strips help people make more informed decisions about their drug use and reducing their risk of overdose.”
However, he said, “one of important limitations of the strips is that they do not detect all contaminants that put persons at risk of overdose. Just because a test result is negative does not mean that the drug is 100% safe.”
Kimberly Sue, MD, PhD, medical director of the National Harm Reduction Coalition, said in an interview that the research is “important,” but noted that many drug users already have been using fentanyl test strips on their own. “We should be focusing on investing in variety of other interventions that could keep more people safe against nonfatal and fatal opioid overdoses, including structural interventions such as safe supply, housing and community with appropriate supports, low barrier access to medication for opioid use disorder, and safe consumption spaces,” she said.
No study funding was reported. Dr. Klaire disclosed participating in a research fellowship and a research in addiction medical scholars program, both funded by the National Institute of Drug Abuse. Dr. Sue reported no relevant disclosures. Dr. Marshall reported that he has collaborated frequently with one of the coauthors of the Vancouver study.
Illicit drug users seem to overwhelmingly appreciate being able to use take-home test strips to detect the extremely common presence of dangerous fentanyl in opioids and other drugs, a new study finds. More than 95% said they’d use the inexpensive strips again.
said study lead author addiction medicine specialist Sukhpreet Klaire, MD, of the British Columbia Center on Substance Use in Vancouver, in an interview.
Dr. Klaire presented the study findings at the virtual annual meeting of the College on Problems of Drug Dependence.
Researchers in Vancouver distributed take-home fentanyl test strip kits at 10 sites that allow users to test their illicit drugs. The 218 participants performed 1,680 tests, mainly (73%) for opioids, over 3 months in 2019. Of the participants, 61% were male, and the average age was 36 (interquartile range, 29-47). About 30% described themselves as indigenous Canadians (First Nations).
About 90% of the opioid samples tested at home were positive for fentanyl, about the same level as samples tested at clinics. Fentanyl is very potent and linked to the huge rise in overdose deaths in the United States.
Fentanyl test strips aren’t new. According to the Harm Reduction Coalition, they originally were developed to detect fentanyl in urine samples but were jury-rigged in Vancouver to work on samples of illicit drugs. “We literally just repurposed it,” Dr. Klaire said. “It’s the same strip.”
Users test their drugs by dissolving a small sample in water. Then then dip the test strip, which provides readings similar to those in a pregnancy test. If a sample turns up positive for fentanyl, Dr. Klaire said, users may discard the drug or “be more careful with it.”
When asked what they would do if a sample turned up positive, 27% said they’d make a “positive change,” such as using less or using more slowly (n = 45) or making sure that someone else is present in case of an overdose (n = 26). But most, 71%, reported no change in behavior.
Previously, researchers in Rhode Island and North Carolina also found that some users adopted safer behaviors – such as throwing out their drugs or using less often – after testing their drugs with the strips.
The strips cost about 75 cents, Dr. Klaire said.
Harm-reduction strategies are controversial, and fentanyl test strips aren’t any exemption. “The entire approach is based on the premise that a drug user poised to use a drug is making rational choices, is weighing pros and cons, and is thinking completely logically about his or her drug use. Based on my clinical experience, I know this could not be further from the truth,” wrote Elinore F. McCance-Katz, MD, PhD, assistant secretary for Mental Health and Substance Use with the Department of Health & Human Services, in a 2018 blog post.
But Dr. Klaire said the patients in the new study are highly dependent on opioids. “The drug supply is heavily contaminated [with fentanyl],” he said, “but even when people know it’s contaminated, they still need to go ahead and use it.”
In an interview, epidemiologist Brandon Marshall, PhD, of Brown University, Providence, R.I., who has conducted fentanyl test strip research, called the study results “compelling.”
“The researchers found that the fentanyl test strips had a very high level of acceptability – over 95% said they would use the strips again – which is remarkably similar to what we found in our work here in Rhode Island,” he said. “Taken together, these studies show that take-home test strips are a feasible, acceptable, and effective strategy for people who use drugs to reduce their risk of fentanyl overdose.”
He added that “fentanyl test strips help people make more informed decisions about their drug use and reducing their risk of overdose.”
However, he said, “one of important limitations of the strips is that they do not detect all contaminants that put persons at risk of overdose. Just because a test result is negative does not mean that the drug is 100% safe.”
Kimberly Sue, MD, PhD, medical director of the National Harm Reduction Coalition, said in an interview that the research is “important,” but noted that many drug users already have been using fentanyl test strips on their own. “We should be focusing on investing in variety of other interventions that could keep more people safe against nonfatal and fatal opioid overdoses, including structural interventions such as safe supply, housing and community with appropriate supports, low barrier access to medication for opioid use disorder, and safe consumption spaces,” she said.
No study funding was reported. Dr. Klaire disclosed participating in a research fellowship and a research in addiction medical scholars program, both funded by the National Institute of Drug Abuse. Dr. Sue reported no relevant disclosures. Dr. Marshall reported that he has collaborated frequently with one of the coauthors of the Vancouver study.
Illicit drug users seem to overwhelmingly appreciate being able to use take-home test strips to detect the extremely common presence of dangerous fentanyl in opioids and other drugs, a new study finds. More than 95% said they’d use the inexpensive strips again.
said study lead author addiction medicine specialist Sukhpreet Klaire, MD, of the British Columbia Center on Substance Use in Vancouver, in an interview.
Dr. Klaire presented the study findings at the virtual annual meeting of the College on Problems of Drug Dependence.
Researchers in Vancouver distributed take-home fentanyl test strip kits at 10 sites that allow users to test their illicit drugs. The 218 participants performed 1,680 tests, mainly (73%) for opioids, over 3 months in 2019. Of the participants, 61% were male, and the average age was 36 (interquartile range, 29-47). About 30% described themselves as indigenous Canadians (First Nations).
About 90% of the opioid samples tested at home were positive for fentanyl, about the same level as samples tested at clinics. Fentanyl is very potent and linked to the huge rise in overdose deaths in the United States.
Fentanyl test strips aren’t new. According to the Harm Reduction Coalition, they originally were developed to detect fentanyl in urine samples but were jury-rigged in Vancouver to work on samples of illicit drugs. “We literally just repurposed it,” Dr. Klaire said. “It’s the same strip.”
Users test their drugs by dissolving a small sample in water. Then then dip the test strip, which provides readings similar to those in a pregnancy test. If a sample turns up positive for fentanyl, Dr. Klaire said, users may discard the drug or “be more careful with it.”
When asked what they would do if a sample turned up positive, 27% said they’d make a “positive change,” such as using less or using more slowly (n = 45) or making sure that someone else is present in case of an overdose (n = 26). But most, 71%, reported no change in behavior.
Previously, researchers in Rhode Island and North Carolina also found that some users adopted safer behaviors – such as throwing out their drugs or using less often – after testing their drugs with the strips.
The strips cost about 75 cents, Dr. Klaire said.
Harm-reduction strategies are controversial, and fentanyl test strips aren’t any exemption. “The entire approach is based on the premise that a drug user poised to use a drug is making rational choices, is weighing pros and cons, and is thinking completely logically about his or her drug use. Based on my clinical experience, I know this could not be further from the truth,” wrote Elinore F. McCance-Katz, MD, PhD, assistant secretary for Mental Health and Substance Use with the Department of Health & Human Services, in a 2018 blog post.
But Dr. Klaire said the patients in the new study are highly dependent on opioids. “The drug supply is heavily contaminated [with fentanyl],” he said, “but even when people know it’s contaminated, they still need to go ahead and use it.”
In an interview, epidemiologist Brandon Marshall, PhD, of Brown University, Providence, R.I., who has conducted fentanyl test strip research, called the study results “compelling.”
“The researchers found that the fentanyl test strips had a very high level of acceptability – over 95% said they would use the strips again – which is remarkably similar to what we found in our work here in Rhode Island,” he said. “Taken together, these studies show that take-home test strips are a feasible, acceptable, and effective strategy for people who use drugs to reduce their risk of fentanyl overdose.”
He added that “fentanyl test strips help people make more informed decisions about their drug use and reducing their risk of overdose.”
However, he said, “one of important limitations of the strips is that they do not detect all contaminants that put persons at risk of overdose. Just because a test result is negative does not mean that the drug is 100% safe.”
Kimberly Sue, MD, PhD, medical director of the National Harm Reduction Coalition, said in an interview that the research is “important,” but noted that many drug users already have been using fentanyl test strips on their own. “We should be focusing on investing in variety of other interventions that could keep more people safe against nonfatal and fatal opioid overdoses, including structural interventions such as safe supply, housing and community with appropriate supports, low barrier access to medication for opioid use disorder, and safe consumption spaces,” she said.
No study funding was reported. Dr. Klaire disclosed participating in a research fellowship and a research in addiction medical scholars program, both funded by the National Institute of Drug Abuse. Dr. Sue reported no relevant disclosures. Dr. Marshall reported that he has collaborated frequently with one of the coauthors of the Vancouver study.
FROM CPDD 2020
Community programs improve psychosis outcomes
Community-based services that tap into local environments not only reduce the duration of untreated psychosis (DUP) but also provide improved long-term outcomes for patients with first-episode psychosis (FEP), results of two new studies show.
In the first study, investigators led by Vinod Srihari, MD, director of specialized treatment early in psychosis at Yale University, New Haven, Conn., developed a program to reduce DUP to complement their first-episode service (FES).
Through a combination of mass media and social media campaigns, outreach events with local professionals, and rapid triage, the team was able to nearly halve the time from diagnosis to initiation of antipsychotic treatment.
In the second study, a team led by Delbert G. Robinson, MD, of Hofstra University, Hempstead, N.Y., conducted a 5-year follow-up of RAISE-ETP, the first U.S. randomized trial to compare a 2-year comprehensive early intervention service (EIS) with usual care.
These trial results showed that, among more than 400 FEP patients, the EIS significantly improved both symptoms and quality of life and reduced inpatient days in comparison with standard care.
The research was scheduled to be presented at the Congress of the Schizophrenia International Research Society (SIRS) 2020, but the meeting was canceled because of the coronavirus pandemic.
Norwegian model
Dr. Srihari and colleagues note that a specialized treatment early in psychosis (STEP), which delivers a specialty team–based FES, was established at their institution in 2006.
However, in a bid to reduce DUP, in 2015 they launched MindMap, a 4-year early-detection campaign based on the Scandinavian TIPS Early Detection in Psychosis Study.
Dr. Srihari said in an interview that they visited the team that developed the TIPS program in Norway “to try to understand what elements of their approach had resulted in a successful reduction of DUP.”
He pointed out that the health care system in Norway has “more reliable pathways to care, with an ability to route people in more predictable ways from primary care to secondary care, and so on.”
In the United States, “there’s no expectation that people will go through a primary care provider,” he said. He noted that patients “make their way to specialty care in many different ways.”
Dr. Srihari said, “The other change we realized we’d have to make was that, since TIPS had been completed many years back, the media environment had changed substantially.
“At the time that TIPS was done, there was no such thing as social media, whereas when we began to think about designing our campaign, we thought social media would be a very efficient and also cost-effective way to target young people.”
MindMap, which covered a 10-town catchment area that has a population of 400,000, targeted both demand- and supply-side aspects of DUP. The former focused on delays in identifying illness and help-seeking, and the latter concentrated on referral and treatment access delays.
The researchers used a combination of mass media and social media messaging, professional detailing, and the rapid triage of referrals.
The media campaign included Facebook, Twitter, and other social media platforms that allowed the team to “target individuals in a somewhat more fine-grained way than mass media allows,” Dr. Srihari said. They focused on individuals in a particular age range and geographic location.
The professional detailing encompassed mental health agencies, emergency departments, and inpatient units, as well as colleges, college counseling centers, high schools, and police departments. The team hosted meetings, “often at local restaurants, where we provided a meal and provided some general education about what our mission was,” said Dr. Srihari. The researchers followed up these meetings with more in-person visits.
“The third arm was finding ways to basically eliminate any kind of a waiting time at our front door, such as ensuring that transportation issues were circumvented, in addition to cutting through any ambivalence they might have about finally making the leap to come to the center.”
More rapid treatment
Over the course of the baseline year and the 4 years of the MindMap program, almost 1,500 individuals were assessed. Of these, approximately 200 were eligible, and almost all were enrolled.
The researchers measured DUP at two time points from the onset of psychosis – the initiation of antipsychotic treatment (DUP1) and the initiation of FES care. Across the study period, they found that DUP1 fell significantly between the pre- and postprogram assessments, from 329 days to 185 days (P = .03). By contrast, there was no change over the same period for the Prevention and Recovery in Early Psychosis FES program in Boston, which served as a comparator.
There was also a cumulative effect on DUP, with each year of the 4-year program associated with a 46-day reduction in DUP1. However, the significant reduction was restricted to the third quintile of DUP1 and was not found in the other quintiles of DUP1 or for DUP2, despite all measures showing a consistent trend for reduction over time.
Dr. Srihari acknowledges that the team was “disappointed” that DUP2 did not fall significantly in their study. He suggested, “It might take longer for agencies to change their workloads and refer patients to STEP, which is what ended up resulting in the DUP2 not dropping as quickly.”
To see whether there was indeed a time lag in changes to practice, the team conducted an analysis in which they cut out the first year from the results and analyzed only the last 3 years. Then “we do see a decline in DUP2,” he said.
The study’s full results are currently being prepared for publication, and the investigators are considering relaunching the initiative.
“The question we are having now is how to resource the campaign without the research funds and which parts of it we think we can launch sustainably so we can continue the reduction of DUP,” Dr. Srihari said.
Plans may include developing partnerships with local businesses to help fund the media costs and working with the state government to build a learning health care network, which would make it easier for mental health agencies to consult with the team on problematic cases.
“We’re trying to reduce DUP referrals on the supply side by providing this kind of learning health collaborative ... that we also think might be fiscally a more sustainable way to do this vs. what we did in MindMap,” which would be “very expensive” to implement on a statewide basis, Dr. Srihari added.
Long-term benefit
In the second study, Dr. Robinson and colleagues highlight that EISs have been implemented worldwide for FEP patients and have been associated with improved outcomes.
However, these services typically provide care for a limited period, and cross-sectional follow-up studies have identified few advantages in comparison with standard care.
To provide a more robust longitudinal assessment of the ongoing effects of an EIS, the team conducted a 5-year follow-up of the first U.S.-based, multicenter, randomized clinical trial comparing an EIS, NAVIGATE, with usual clinical care in FEP.
RAISE-ETP was conducted at 34 sites across the United States. Seventeen sites provided NAVIGATE to 223 individuals with FEP, and the remaining 17 sites provided usual care to 181 patients.
NAVIGATE, which continued for 2 years, consisted of treatments and services delivered by a coordinated team of providers. Those services included the following:
- Education on schizophrenia and its treatment for patients and their families.
- Symptom and relapse prevention medication, using a computerized decision support system.
- Strategies for illness management building personal resilience.
- A supported employment/education model.
Patients were assessed every 6 months for up to 60 months via a video link using the Heinrichs-Carpenter Quality of Life Scale (QLS) and the Positive and Negative Syndrome Scale (PANSS).
The average age of the participants was 23 years; 78% of those who received NAVIGATE and 66% of those who received usual care were male. The opportunity for each participant to engage in NAVIGATE treatment lasted an average of 33.8 months. The longest was 44.4 months.
Over 5 years, NAVIGATE was associated with a significant improvement over usual care in QLS scores by an average of 13.14 units (P < .001). PANSS scores improved by an average of 7.73 units (P < .002). QLS scores were not affected either by the length of opportunity to participate in NAVIGATE or by DUP, the team reports. Patients who received NAVIGATE also had an average of 2.5 fewer inpatient days, compared with those on usual care (P = .02).
The investigators note that the study “provides compelling evidence of a substantial long-term benefit for FEP treatment with the NAVIGATE EIS, compared with standard care.”
A ‘great message’
Commenting on the findings in an interview, Ragy R. Girgis, MD, associate professor of clinical psychiatry at Columbia University, New York, and the New York State Psychiatric Institute, said
Dr. Girgis, who was not involved in either study, said that the research is “a great message.” He noted that it is “really important for people to know and it’s really important that we’re still doing research in those areas.”
However, he noted that psychosocial interventions such as these “sometimes take a lot of work.” Dr. Girgis said that it is “so easy to just give people a medication” but that approach has its own disadvantages, including adverse effects and sometimes a lack of efficacy.
“Psychosocial interventions, on the other hand, are very well tolerated by people. They are very effective, but they may require a lot more manpower, and in some ways they can also be more expensive.
“So this is a dialectic that we oftentimes have to deal with when we figure out the right balance between psychosocial vs. medication types of treatments,” he said.
STEP has received research funding from the National Institutes of Health and the Patrick and Catherine Weldon Donaghue Medical Research Foundation. RAISE-ETP was funded by the National Institute of Mental Health as part of the Recovery After an Initial Schizophrenia Episode (RAISE) Project. Dr. Gopal is an employee of Janssen Research & Development, and owns stock/equity in Johnson & Johnson. Dr. Girgis has received research support from Genentech, BioAdvantex, Allegran/Forest, and Otsuka, and royalties from Wipf and Stock and Routledge/Taylor and Francis.
A version of this article originally appeared on Medscape.com.
Community-based services that tap into local environments not only reduce the duration of untreated psychosis (DUP) but also provide improved long-term outcomes for patients with first-episode psychosis (FEP), results of two new studies show.
In the first study, investigators led by Vinod Srihari, MD, director of specialized treatment early in psychosis at Yale University, New Haven, Conn., developed a program to reduce DUP to complement their first-episode service (FES).
Through a combination of mass media and social media campaigns, outreach events with local professionals, and rapid triage, the team was able to nearly halve the time from diagnosis to initiation of antipsychotic treatment.
In the second study, a team led by Delbert G. Robinson, MD, of Hofstra University, Hempstead, N.Y., conducted a 5-year follow-up of RAISE-ETP, the first U.S. randomized trial to compare a 2-year comprehensive early intervention service (EIS) with usual care.
These trial results showed that, among more than 400 FEP patients, the EIS significantly improved both symptoms and quality of life and reduced inpatient days in comparison with standard care.
The research was scheduled to be presented at the Congress of the Schizophrenia International Research Society (SIRS) 2020, but the meeting was canceled because of the coronavirus pandemic.
Norwegian model
Dr. Srihari and colleagues note that a specialized treatment early in psychosis (STEP), which delivers a specialty team–based FES, was established at their institution in 2006.
However, in a bid to reduce DUP, in 2015 they launched MindMap, a 4-year early-detection campaign based on the Scandinavian TIPS Early Detection in Psychosis Study.
Dr. Srihari said in an interview that they visited the team that developed the TIPS program in Norway “to try to understand what elements of their approach had resulted in a successful reduction of DUP.”
He pointed out that the health care system in Norway has “more reliable pathways to care, with an ability to route people in more predictable ways from primary care to secondary care, and so on.”
In the United States, “there’s no expectation that people will go through a primary care provider,” he said. He noted that patients “make their way to specialty care in many different ways.”
Dr. Srihari said, “The other change we realized we’d have to make was that, since TIPS had been completed many years back, the media environment had changed substantially.
“At the time that TIPS was done, there was no such thing as social media, whereas when we began to think about designing our campaign, we thought social media would be a very efficient and also cost-effective way to target young people.”
MindMap, which covered a 10-town catchment area that has a population of 400,000, targeted both demand- and supply-side aspects of DUP. The former focused on delays in identifying illness and help-seeking, and the latter concentrated on referral and treatment access delays.
The researchers used a combination of mass media and social media messaging, professional detailing, and the rapid triage of referrals.
The media campaign included Facebook, Twitter, and other social media platforms that allowed the team to “target individuals in a somewhat more fine-grained way than mass media allows,” Dr. Srihari said. They focused on individuals in a particular age range and geographic location.
The professional detailing encompassed mental health agencies, emergency departments, and inpatient units, as well as colleges, college counseling centers, high schools, and police departments. The team hosted meetings, “often at local restaurants, where we provided a meal and provided some general education about what our mission was,” said Dr. Srihari. The researchers followed up these meetings with more in-person visits.
“The third arm was finding ways to basically eliminate any kind of a waiting time at our front door, such as ensuring that transportation issues were circumvented, in addition to cutting through any ambivalence they might have about finally making the leap to come to the center.”
More rapid treatment
Over the course of the baseline year and the 4 years of the MindMap program, almost 1,500 individuals were assessed. Of these, approximately 200 were eligible, and almost all were enrolled.
The researchers measured DUP at two time points from the onset of psychosis – the initiation of antipsychotic treatment (DUP1) and the initiation of FES care. Across the study period, they found that DUP1 fell significantly between the pre- and postprogram assessments, from 329 days to 185 days (P = .03). By contrast, there was no change over the same period for the Prevention and Recovery in Early Psychosis FES program in Boston, which served as a comparator.
There was also a cumulative effect on DUP, with each year of the 4-year program associated with a 46-day reduction in DUP1. However, the significant reduction was restricted to the third quintile of DUP1 and was not found in the other quintiles of DUP1 or for DUP2, despite all measures showing a consistent trend for reduction over time.
Dr. Srihari acknowledges that the team was “disappointed” that DUP2 did not fall significantly in their study. He suggested, “It might take longer for agencies to change their workloads and refer patients to STEP, which is what ended up resulting in the DUP2 not dropping as quickly.”
To see whether there was indeed a time lag in changes to practice, the team conducted an analysis in which they cut out the first year from the results and analyzed only the last 3 years. Then “we do see a decline in DUP2,” he said.
The study’s full results are currently being prepared for publication, and the investigators are considering relaunching the initiative.
“The question we are having now is how to resource the campaign without the research funds and which parts of it we think we can launch sustainably so we can continue the reduction of DUP,” Dr. Srihari said.
Plans may include developing partnerships with local businesses to help fund the media costs and working with the state government to build a learning health care network, which would make it easier for mental health agencies to consult with the team on problematic cases.
“We’re trying to reduce DUP referrals on the supply side by providing this kind of learning health collaborative ... that we also think might be fiscally a more sustainable way to do this vs. what we did in MindMap,” which would be “very expensive” to implement on a statewide basis, Dr. Srihari added.
Long-term benefit
In the second study, Dr. Robinson and colleagues highlight that EISs have been implemented worldwide for FEP patients and have been associated with improved outcomes.
However, these services typically provide care for a limited period, and cross-sectional follow-up studies have identified few advantages in comparison with standard care.
To provide a more robust longitudinal assessment of the ongoing effects of an EIS, the team conducted a 5-year follow-up of the first U.S.-based, multicenter, randomized clinical trial comparing an EIS, NAVIGATE, with usual clinical care in FEP.
RAISE-ETP was conducted at 34 sites across the United States. Seventeen sites provided NAVIGATE to 223 individuals with FEP, and the remaining 17 sites provided usual care to 181 patients.
NAVIGATE, which continued for 2 years, consisted of treatments and services delivered by a coordinated team of providers. Those services included the following:
- Education on schizophrenia and its treatment for patients and their families.
- Symptom and relapse prevention medication, using a computerized decision support system.
- Strategies for illness management building personal resilience.
- A supported employment/education model.
Patients were assessed every 6 months for up to 60 months via a video link using the Heinrichs-Carpenter Quality of Life Scale (QLS) and the Positive and Negative Syndrome Scale (PANSS).
The average age of the participants was 23 years; 78% of those who received NAVIGATE and 66% of those who received usual care were male. The opportunity for each participant to engage in NAVIGATE treatment lasted an average of 33.8 months. The longest was 44.4 months.
Over 5 years, NAVIGATE was associated with a significant improvement over usual care in QLS scores by an average of 13.14 units (P < .001). PANSS scores improved by an average of 7.73 units (P < .002). QLS scores were not affected either by the length of opportunity to participate in NAVIGATE or by DUP, the team reports. Patients who received NAVIGATE also had an average of 2.5 fewer inpatient days, compared with those on usual care (P = .02).
The investigators note that the study “provides compelling evidence of a substantial long-term benefit for FEP treatment with the NAVIGATE EIS, compared with standard care.”
A ‘great message’
Commenting on the findings in an interview, Ragy R. Girgis, MD, associate professor of clinical psychiatry at Columbia University, New York, and the New York State Psychiatric Institute, said
Dr. Girgis, who was not involved in either study, said that the research is “a great message.” He noted that it is “really important for people to know and it’s really important that we’re still doing research in those areas.”
However, he noted that psychosocial interventions such as these “sometimes take a lot of work.” Dr. Girgis said that it is “so easy to just give people a medication” but that approach has its own disadvantages, including adverse effects and sometimes a lack of efficacy.
“Psychosocial interventions, on the other hand, are very well tolerated by people. They are very effective, but they may require a lot more manpower, and in some ways they can also be more expensive.
“So this is a dialectic that we oftentimes have to deal with when we figure out the right balance between psychosocial vs. medication types of treatments,” he said.
STEP has received research funding from the National Institutes of Health and the Patrick and Catherine Weldon Donaghue Medical Research Foundation. RAISE-ETP was funded by the National Institute of Mental Health as part of the Recovery After an Initial Schizophrenia Episode (RAISE) Project. Dr. Gopal is an employee of Janssen Research & Development, and owns stock/equity in Johnson & Johnson. Dr. Girgis has received research support from Genentech, BioAdvantex, Allegran/Forest, and Otsuka, and royalties from Wipf and Stock and Routledge/Taylor and Francis.
A version of this article originally appeared on Medscape.com.
Community-based services that tap into local environments not only reduce the duration of untreated psychosis (DUP) but also provide improved long-term outcomes for patients with first-episode psychosis (FEP), results of two new studies show.
In the first study, investigators led by Vinod Srihari, MD, director of specialized treatment early in psychosis at Yale University, New Haven, Conn., developed a program to reduce DUP to complement their first-episode service (FES).
Through a combination of mass media and social media campaigns, outreach events with local professionals, and rapid triage, the team was able to nearly halve the time from diagnosis to initiation of antipsychotic treatment.
In the second study, a team led by Delbert G. Robinson, MD, of Hofstra University, Hempstead, N.Y., conducted a 5-year follow-up of RAISE-ETP, the first U.S. randomized trial to compare a 2-year comprehensive early intervention service (EIS) with usual care.
These trial results showed that, among more than 400 FEP patients, the EIS significantly improved both symptoms and quality of life and reduced inpatient days in comparison with standard care.
The research was scheduled to be presented at the Congress of the Schizophrenia International Research Society (SIRS) 2020, but the meeting was canceled because of the coronavirus pandemic.
Norwegian model
Dr. Srihari and colleagues note that a specialized treatment early in psychosis (STEP), which delivers a specialty team–based FES, was established at their institution in 2006.
However, in a bid to reduce DUP, in 2015 they launched MindMap, a 4-year early-detection campaign based on the Scandinavian TIPS Early Detection in Psychosis Study.
Dr. Srihari said in an interview that they visited the team that developed the TIPS program in Norway “to try to understand what elements of their approach had resulted in a successful reduction of DUP.”
He pointed out that the health care system in Norway has “more reliable pathways to care, with an ability to route people in more predictable ways from primary care to secondary care, and so on.”
In the United States, “there’s no expectation that people will go through a primary care provider,” he said. He noted that patients “make their way to specialty care in many different ways.”
Dr. Srihari said, “The other change we realized we’d have to make was that, since TIPS had been completed many years back, the media environment had changed substantially.
“At the time that TIPS was done, there was no such thing as social media, whereas when we began to think about designing our campaign, we thought social media would be a very efficient and also cost-effective way to target young people.”
MindMap, which covered a 10-town catchment area that has a population of 400,000, targeted both demand- and supply-side aspects of DUP. The former focused on delays in identifying illness and help-seeking, and the latter concentrated on referral and treatment access delays.
The researchers used a combination of mass media and social media messaging, professional detailing, and the rapid triage of referrals.
The media campaign included Facebook, Twitter, and other social media platforms that allowed the team to “target individuals in a somewhat more fine-grained way than mass media allows,” Dr. Srihari said. They focused on individuals in a particular age range and geographic location.
The professional detailing encompassed mental health agencies, emergency departments, and inpatient units, as well as colleges, college counseling centers, high schools, and police departments. The team hosted meetings, “often at local restaurants, where we provided a meal and provided some general education about what our mission was,” said Dr. Srihari. The researchers followed up these meetings with more in-person visits.
“The third arm was finding ways to basically eliminate any kind of a waiting time at our front door, such as ensuring that transportation issues were circumvented, in addition to cutting through any ambivalence they might have about finally making the leap to come to the center.”
More rapid treatment
Over the course of the baseline year and the 4 years of the MindMap program, almost 1,500 individuals were assessed. Of these, approximately 200 were eligible, and almost all were enrolled.
The researchers measured DUP at two time points from the onset of psychosis – the initiation of antipsychotic treatment (DUP1) and the initiation of FES care. Across the study period, they found that DUP1 fell significantly between the pre- and postprogram assessments, from 329 days to 185 days (P = .03). By contrast, there was no change over the same period for the Prevention and Recovery in Early Psychosis FES program in Boston, which served as a comparator.
There was also a cumulative effect on DUP, with each year of the 4-year program associated with a 46-day reduction in DUP1. However, the significant reduction was restricted to the third quintile of DUP1 and was not found in the other quintiles of DUP1 or for DUP2, despite all measures showing a consistent trend for reduction over time.
Dr. Srihari acknowledges that the team was “disappointed” that DUP2 did not fall significantly in their study. He suggested, “It might take longer for agencies to change their workloads and refer patients to STEP, which is what ended up resulting in the DUP2 not dropping as quickly.”
To see whether there was indeed a time lag in changes to practice, the team conducted an analysis in which they cut out the first year from the results and analyzed only the last 3 years. Then “we do see a decline in DUP2,” he said.
The study’s full results are currently being prepared for publication, and the investigators are considering relaunching the initiative.
“The question we are having now is how to resource the campaign without the research funds and which parts of it we think we can launch sustainably so we can continue the reduction of DUP,” Dr. Srihari said.
Plans may include developing partnerships with local businesses to help fund the media costs and working with the state government to build a learning health care network, which would make it easier for mental health agencies to consult with the team on problematic cases.
“We’re trying to reduce DUP referrals on the supply side by providing this kind of learning health collaborative ... that we also think might be fiscally a more sustainable way to do this vs. what we did in MindMap,” which would be “very expensive” to implement on a statewide basis, Dr. Srihari added.
Long-term benefit
In the second study, Dr. Robinson and colleagues highlight that EISs have been implemented worldwide for FEP patients and have been associated with improved outcomes.
However, these services typically provide care for a limited period, and cross-sectional follow-up studies have identified few advantages in comparison with standard care.
To provide a more robust longitudinal assessment of the ongoing effects of an EIS, the team conducted a 5-year follow-up of the first U.S.-based, multicenter, randomized clinical trial comparing an EIS, NAVIGATE, with usual clinical care in FEP.
RAISE-ETP was conducted at 34 sites across the United States. Seventeen sites provided NAVIGATE to 223 individuals with FEP, and the remaining 17 sites provided usual care to 181 patients.
NAVIGATE, which continued for 2 years, consisted of treatments and services delivered by a coordinated team of providers. Those services included the following:
- Education on schizophrenia and its treatment for patients and their families.
- Symptom and relapse prevention medication, using a computerized decision support system.
- Strategies for illness management building personal resilience.
- A supported employment/education model.
Patients were assessed every 6 months for up to 60 months via a video link using the Heinrichs-Carpenter Quality of Life Scale (QLS) and the Positive and Negative Syndrome Scale (PANSS).
The average age of the participants was 23 years; 78% of those who received NAVIGATE and 66% of those who received usual care were male. The opportunity for each participant to engage in NAVIGATE treatment lasted an average of 33.8 months. The longest was 44.4 months.
Over 5 years, NAVIGATE was associated with a significant improvement over usual care in QLS scores by an average of 13.14 units (P < .001). PANSS scores improved by an average of 7.73 units (P < .002). QLS scores were not affected either by the length of opportunity to participate in NAVIGATE or by DUP, the team reports. Patients who received NAVIGATE also had an average of 2.5 fewer inpatient days, compared with those on usual care (P = .02).
The investigators note that the study “provides compelling evidence of a substantial long-term benefit for FEP treatment with the NAVIGATE EIS, compared with standard care.”
A ‘great message’
Commenting on the findings in an interview, Ragy R. Girgis, MD, associate professor of clinical psychiatry at Columbia University, New York, and the New York State Psychiatric Institute, said
Dr. Girgis, who was not involved in either study, said that the research is “a great message.” He noted that it is “really important for people to know and it’s really important that we’re still doing research in those areas.”
However, he noted that psychosocial interventions such as these “sometimes take a lot of work.” Dr. Girgis said that it is “so easy to just give people a medication” but that approach has its own disadvantages, including adverse effects and sometimes a lack of efficacy.
“Psychosocial interventions, on the other hand, are very well tolerated by people. They are very effective, but they may require a lot more manpower, and in some ways they can also be more expensive.
“So this is a dialectic that we oftentimes have to deal with when we figure out the right balance between psychosocial vs. medication types of treatments,” he said.
STEP has received research funding from the National Institutes of Health and the Patrick and Catherine Weldon Donaghue Medical Research Foundation. RAISE-ETP was funded by the National Institute of Mental Health as part of the Recovery After an Initial Schizophrenia Episode (RAISE) Project. Dr. Gopal is an employee of Janssen Research & Development, and owns stock/equity in Johnson & Johnson. Dr. Girgis has received research support from Genentech, BioAdvantex, Allegran/Forest, and Otsuka, and royalties from Wipf and Stock and Routledge/Taylor and Francis.
A version of this article originally appeared on Medscape.com.
Once again, no survival benefit with PCI, surgery in stable CAD
Coronary revascularization does not confer a survival advantage over initial medical therapy in patients with stable ischemic heart disease (SIHD) but reduces unstable angina, according to a new study-level meta-analysis.
Routine upfront revascularization is also associated with less spontaneous myocardial infarction but this is at the cost of increased procedural infarctions, reported lead investigator Sripal Bangalore, MD, of New York University.
“These relationships should be taken into consideration for shared decision-making for the management of patients with stable ischemic heart disease,” he said in a late-breaking trial session at PCR e-Course 2020, the virtual meeting of the Congress of European Association of Percutaneous Cardiovascular Interventions (EuroPCR).
The results, simultaneously published in Circulation, are consistent with last year’s ISCHEMIA trial and other contemporary trials, such as COURAGE, FAME 2, and BARI 2D, that have failed to show a reduction in mortality with revascularization alone in SIHD. Guidelines continue, however, to recommend revascularization to improve survival in SIHD based on trials performed in the 1980s when medical therapy was limited, Dr. Bangalore observed.
The updated meta-analysis included 14 randomized controlled trials, including the aforementioned, and 14,877 patients followed for a weighted mean of 4.5 years. Most trials enrolled patients who had preserved left ventricular function and low symptom burden (Canadian Cardiovascular Society Class I/II).
In the revascularization group, 87.5% of patients underwent any revascularization. Percutaneous coronary intervention (PCI) was the first procedure in 71.3% and bypass surgery the first choice in 16.2%. In eight trials, stents were used in at least 50% of PCI patients; drug-eluting stents were mainly used in FAME 2, ISCHEMIA, and ISCHEMIA-CKD.
In eight trials, statins were used in at least 50% of patients. Nearly 1 in 3 patients (31.9%) treated initially with medical therapy underwent revascularization during follow-up.
Results show no reduction in mortality risk with routine revascularization in the overall analysis (relative risk, 0.99; 95% confidence interval, 0.90-1.09) or when analyzed by whether studies did or did not use stents (P for interaction = .85).
Trial sequential analysis also showed that the cumulative z-curve crossed the futility boundary, “suggesting we have great data to show that there is lack of even a 10% reduction in death with revascularization,” Dr. Bangalore said.
Results were very similar for cardiovascular death (RR, 0.92; 95% CI, 0.80-1.06), including when analyzed by study stent status (P for interaction = .60).
There was no significant reduction in overall MI risk with revascularization, although a borderline significant 11% decrease in MIs was found in the contemporary stent era trials (RR, 0.89; 95% CI, 0.80-0.998).
Revascularization was associated with a 148% increase in the risk of procedural MI (RR, 2.48; 95% CI, 1.86-3.31) but reduced risk of spontaneous MI (RR, 0.76; 95% CI, 0.67-0.85).
Unstable angina was reduced in patients undergoing revascularization (RR, 0.64; 95% CI, 0.45-0.92), driven by a 55% reduction in the contemporary stent era trials. Freedom from angina was also greater with routine revascularization but the difference was modest, Dr. Bangalore said. There was no difference between the two strategies in heart failure or stroke.
“This meta-analysis is well done but really doesn’t change what we already know,” Rasha Al-Lamee, MBBS, of Imperial College, London, said in an interview. “The most important message is that intervention in stable CAD does not change survival. We don’t need to rush to intervene: We have time to plan the best strategy for each patient and to modify our plans based on their response.”
The analysis addresses some of the issues with previous meta-analyses that have included trials that were not strictly stable CAD trials such as SWISSI-2, COMPARE-ACUTE, and DANAMI-3-PRIMULTI, she noted. “However a study like this is only as good as the trials that are included. We must remember that unblinded trials really cannot be used to accurately assess endpoints that are prone to bias such as unstable angina and freedom from angina.”
Following the presentation, dedicated discussant Davide Capodanno, MD, PhD, of the University of Catania (Italy) said, “We have seen beyond any doubt that there is no difference in mortality. For cardiovascular death, it’s pretty much the same. It’s a little bit more mixed and nuanced, the story of myocardial infarction.”
“Additional science is needed to understand the prognostic implications,” he said. “Of course we know that spontaneous myocardial infarction is bad, but I’m not so sure about periprocedural MI. Is this something that is as important as spontaneous myocardial infarction?”
The meta-analysis is the largest ever performed, but there was clinical heterogeneity in the individual studies, especially in the definition of MI, Dr. Capodanno observed. Because of the use of trial-level data rather than patient-level data, the analysis also could not account for adherence to treatment or the effect of stent type or medication dosage.
The MI issue really depends on the trial definition of MI, Dr. Al-Lamee said. “We need long-term follow-up from ISCHEMIA to understand what it means for our patients. While revascularization clearly increases procedural MI rates, it also results in lower spontaneous MI rates with no impact on overall MI or death,” she said. “We will only know if these MIs are important if we see what impact they have in the long term.”
Although the meta-analysis combined data from several decades, it’s likely that the outdated revascularization techniques in the older trials are balanced out by the outdated medical therapy in the same trials, Dr. Al-Lamee observed.
The new findings can certainly be used in patient-physician discussions, with more follow-up from ISCHEMIA to provide additional insights, she said.
“We will of course hear more about the placebo-controlled efficacy of PCI in the blinded ORBITA-2 trial. And I would really like to see some of the older studies of patients and perceptions of the effect of PCI repeated,” Dr. Al-Lamee said. “Now we have more data, are we informing our patients and referrers correctly of the impact of our procedures, and do they truly choose revascularization with a true awareness of what it does and does not do?”
Dr. Bangalore reported grants from the National Heart, Lung, and Blood Institute and Abbott Vascular; and serving on the advisory boards of Abbott Vascular, Biotronik, Meril, SMT, Pfizer, Amgen, and Reata. Dr. Al-Lamee reported speaker’s honorarium from Philips Volcano and Menarini Pharmaceuticals. Dr. Capodanno has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Coronary revascularization does not confer a survival advantage over initial medical therapy in patients with stable ischemic heart disease (SIHD) but reduces unstable angina, according to a new study-level meta-analysis.
Routine upfront revascularization is also associated with less spontaneous myocardial infarction but this is at the cost of increased procedural infarctions, reported lead investigator Sripal Bangalore, MD, of New York University.
“These relationships should be taken into consideration for shared decision-making for the management of patients with stable ischemic heart disease,” he said in a late-breaking trial session at PCR e-Course 2020, the virtual meeting of the Congress of European Association of Percutaneous Cardiovascular Interventions (EuroPCR).
The results, simultaneously published in Circulation, are consistent with last year’s ISCHEMIA trial and other contemporary trials, such as COURAGE, FAME 2, and BARI 2D, that have failed to show a reduction in mortality with revascularization alone in SIHD. Guidelines continue, however, to recommend revascularization to improve survival in SIHD based on trials performed in the 1980s when medical therapy was limited, Dr. Bangalore observed.
The updated meta-analysis included 14 randomized controlled trials, including the aforementioned, and 14,877 patients followed for a weighted mean of 4.5 years. Most trials enrolled patients who had preserved left ventricular function and low symptom burden (Canadian Cardiovascular Society Class I/II).
In the revascularization group, 87.5% of patients underwent any revascularization. Percutaneous coronary intervention (PCI) was the first procedure in 71.3% and bypass surgery the first choice in 16.2%. In eight trials, stents were used in at least 50% of PCI patients; drug-eluting stents were mainly used in FAME 2, ISCHEMIA, and ISCHEMIA-CKD.
In eight trials, statins were used in at least 50% of patients. Nearly 1 in 3 patients (31.9%) treated initially with medical therapy underwent revascularization during follow-up.
Results show no reduction in mortality risk with routine revascularization in the overall analysis (relative risk, 0.99; 95% confidence interval, 0.90-1.09) or when analyzed by whether studies did or did not use stents (P for interaction = .85).
Trial sequential analysis also showed that the cumulative z-curve crossed the futility boundary, “suggesting we have great data to show that there is lack of even a 10% reduction in death with revascularization,” Dr. Bangalore said.
Results were very similar for cardiovascular death (RR, 0.92; 95% CI, 0.80-1.06), including when analyzed by study stent status (P for interaction = .60).
There was no significant reduction in overall MI risk with revascularization, although a borderline significant 11% decrease in MIs was found in the contemporary stent era trials (RR, 0.89; 95% CI, 0.80-0.998).
Revascularization was associated with a 148% increase in the risk of procedural MI (RR, 2.48; 95% CI, 1.86-3.31) but reduced risk of spontaneous MI (RR, 0.76; 95% CI, 0.67-0.85).
Unstable angina was reduced in patients undergoing revascularization (RR, 0.64; 95% CI, 0.45-0.92), driven by a 55% reduction in the contemporary stent era trials. Freedom from angina was also greater with routine revascularization but the difference was modest, Dr. Bangalore said. There was no difference between the two strategies in heart failure or stroke.
“This meta-analysis is well done but really doesn’t change what we already know,” Rasha Al-Lamee, MBBS, of Imperial College, London, said in an interview. “The most important message is that intervention in stable CAD does not change survival. We don’t need to rush to intervene: We have time to plan the best strategy for each patient and to modify our plans based on their response.”
The analysis addresses some of the issues with previous meta-analyses that have included trials that were not strictly stable CAD trials such as SWISSI-2, COMPARE-ACUTE, and DANAMI-3-PRIMULTI, she noted. “However a study like this is only as good as the trials that are included. We must remember that unblinded trials really cannot be used to accurately assess endpoints that are prone to bias such as unstable angina and freedom from angina.”
Following the presentation, dedicated discussant Davide Capodanno, MD, PhD, of the University of Catania (Italy) said, “We have seen beyond any doubt that there is no difference in mortality. For cardiovascular death, it’s pretty much the same. It’s a little bit more mixed and nuanced, the story of myocardial infarction.”
“Additional science is needed to understand the prognostic implications,” he said. “Of course we know that spontaneous myocardial infarction is bad, but I’m not so sure about periprocedural MI. Is this something that is as important as spontaneous myocardial infarction?”
The meta-analysis is the largest ever performed, but there was clinical heterogeneity in the individual studies, especially in the definition of MI, Dr. Capodanno observed. Because of the use of trial-level data rather than patient-level data, the analysis also could not account for adherence to treatment or the effect of stent type or medication dosage.
The MI issue really depends on the trial definition of MI, Dr. Al-Lamee said. “We need long-term follow-up from ISCHEMIA to understand what it means for our patients. While revascularization clearly increases procedural MI rates, it also results in lower spontaneous MI rates with no impact on overall MI or death,” she said. “We will only know if these MIs are important if we see what impact they have in the long term.”
Although the meta-analysis combined data from several decades, it’s likely that the outdated revascularization techniques in the older trials are balanced out by the outdated medical therapy in the same trials, Dr. Al-Lamee observed.
The new findings can certainly be used in patient-physician discussions, with more follow-up from ISCHEMIA to provide additional insights, she said.
“We will of course hear more about the placebo-controlled efficacy of PCI in the blinded ORBITA-2 trial. And I would really like to see some of the older studies of patients and perceptions of the effect of PCI repeated,” Dr. Al-Lamee said. “Now we have more data, are we informing our patients and referrers correctly of the impact of our procedures, and do they truly choose revascularization with a true awareness of what it does and does not do?”
Dr. Bangalore reported grants from the National Heart, Lung, and Blood Institute and Abbott Vascular; and serving on the advisory boards of Abbott Vascular, Biotronik, Meril, SMT, Pfizer, Amgen, and Reata. Dr. Al-Lamee reported speaker’s honorarium from Philips Volcano and Menarini Pharmaceuticals. Dr. Capodanno has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Coronary revascularization does not confer a survival advantage over initial medical therapy in patients with stable ischemic heart disease (SIHD) but reduces unstable angina, according to a new study-level meta-analysis.
Routine upfront revascularization is also associated with less spontaneous myocardial infarction but this is at the cost of increased procedural infarctions, reported lead investigator Sripal Bangalore, MD, of New York University.
“These relationships should be taken into consideration for shared decision-making for the management of patients with stable ischemic heart disease,” he said in a late-breaking trial session at PCR e-Course 2020, the virtual meeting of the Congress of European Association of Percutaneous Cardiovascular Interventions (EuroPCR).
The results, simultaneously published in Circulation, are consistent with last year’s ISCHEMIA trial and other contemporary trials, such as COURAGE, FAME 2, and BARI 2D, that have failed to show a reduction in mortality with revascularization alone in SIHD. Guidelines continue, however, to recommend revascularization to improve survival in SIHD based on trials performed in the 1980s when medical therapy was limited, Dr. Bangalore observed.
The updated meta-analysis included 14 randomized controlled trials, including the aforementioned, and 14,877 patients followed for a weighted mean of 4.5 years. Most trials enrolled patients who had preserved left ventricular function and low symptom burden (Canadian Cardiovascular Society Class I/II).
In the revascularization group, 87.5% of patients underwent any revascularization. Percutaneous coronary intervention (PCI) was the first procedure in 71.3% and bypass surgery the first choice in 16.2%. In eight trials, stents were used in at least 50% of PCI patients; drug-eluting stents were mainly used in FAME 2, ISCHEMIA, and ISCHEMIA-CKD.
In eight trials, statins were used in at least 50% of patients. Nearly 1 in 3 patients (31.9%) treated initially with medical therapy underwent revascularization during follow-up.
Results show no reduction in mortality risk with routine revascularization in the overall analysis (relative risk, 0.99; 95% confidence interval, 0.90-1.09) or when analyzed by whether studies did or did not use stents (P for interaction = .85).
Trial sequential analysis also showed that the cumulative z-curve crossed the futility boundary, “suggesting we have great data to show that there is lack of even a 10% reduction in death with revascularization,” Dr. Bangalore said.
Results were very similar for cardiovascular death (RR, 0.92; 95% CI, 0.80-1.06), including when analyzed by study stent status (P for interaction = .60).
There was no significant reduction in overall MI risk with revascularization, although a borderline significant 11% decrease in MIs was found in the contemporary stent era trials (RR, 0.89; 95% CI, 0.80-0.998).
Revascularization was associated with a 148% increase in the risk of procedural MI (RR, 2.48; 95% CI, 1.86-3.31) but reduced risk of spontaneous MI (RR, 0.76; 95% CI, 0.67-0.85).
Unstable angina was reduced in patients undergoing revascularization (RR, 0.64; 95% CI, 0.45-0.92), driven by a 55% reduction in the contemporary stent era trials. Freedom from angina was also greater with routine revascularization but the difference was modest, Dr. Bangalore said. There was no difference between the two strategies in heart failure or stroke.
“This meta-analysis is well done but really doesn’t change what we already know,” Rasha Al-Lamee, MBBS, of Imperial College, London, said in an interview. “The most important message is that intervention in stable CAD does not change survival. We don’t need to rush to intervene: We have time to plan the best strategy for each patient and to modify our plans based on their response.”
The analysis addresses some of the issues with previous meta-analyses that have included trials that were not strictly stable CAD trials such as SWISSI-2, COMPARE-ACUTE, and DANAMI-3-PRIMULTI, she noted. “However a study like this is only as good as the trials that are included. We must remember that unblinded trials really cannot be used to accurately assess endpoints that are prone to bias such as unstable angina and freedom from angina.”
Following the presentation, dedicated discussant Davide Capodanno, MD, PhD, of the University of Catania (Italy) said, “We have seen beyond any doubt that there is no difference in mortality. For cardiovascular death, it’s pretty much the same. It’s a little bit more mixed and nuanced, the story of myocardial infarction.”
“Additional science is needed to understand the prognostic implications,” he said. “Of course we know that spontaneous myocardial infarction is bad, but I’m not so sure about periprocedural MI. Is this something that is as important as spontaneous myocardial infarction?”
The meta-analysis is the largest ever performed, but there was clinical heterogeneity in the individual studies, especially in the definition of MI, Dr. Capodanno observed. Because of the use of trial-level data rather than patient-level data, the analysis also could not account for adherence to treatment or the effect of stent type or medication dosage.
The MI issue really depends on the trial definition of MI, Dr. Al-Lamee said. “We need long-term follow-up from ISCHEMIA to understand what it means for our patients. While revascularization clearly increases procedural MI rates, it also results in lower spontaneous MI rates with no impact on overall MI or death,” she said. “We will only know if these MIs are important if we see what impact they have in the long term.”
Although the meta-analysis combined data from several decades, it’s likely that the outdated revascularization techniques in the older trials are balanced out by the outdated medical therapy in the same trials, Dr. Al-Lamee observed.
The new findings can certainly be used in patient-physician discussions, with more follow-up from ISCHEMIA to provide additional insights, she said.
“We will of course hear more about the placebo-controlled efficacy of PCI in the blinded ORBITA-2 trial. And I would really like to see some of the older studies of patients and perceptions of the effect of PCI repeated,” Dr. Al-Lamee said. “Now we have more data, are we informing our patients and referrers correctly of the impact of our procedures, and do they truly choose revascularization with a true awareness of what it does and does not do?”
Dr. Bangalore reported grants from the National Heart, Lung, and Blood Institute and Abbott Vascular; and serving on the advisory boards of Abbott Vascular, Biotronik, Meril, SMT, Pfizer, Amgen, and Reata. Dr. Al-Lamee reported speaker’s honorarium from Philips Volcano and Menarini Pharmaceuticals. Dr. Capodanno has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.