Mitchel is a reporter for MDedge based in the Philadelphia area. He started with the company in 1992, when it was International Medical News Group (IMNG), and has since covered a range of medical specialties. Mitchel trained as a virologist at Roswell Park Memorial Institute in Buffalo, and then worked briefly as a researcher at Boston Children's Hospital before pivoting to journalism as a AAAS Mass Media Fellow in 1980. His first reporting job was with Science Digest magazine, and from the mid-1980s to early-1990s he was a reporter with Medical World News. @mitchelzoler

CABANA: Ablation surpassed drugs for raising AF quality of life

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– Ablation of atrial fibrillation led to significantly better quality of life improvements, compared with antiarrhythmic drug therapy, in a prespecified, secondary analysis of data from the CABANA multicenter, randomized trial with 2,204 patients.

Mitchel L. Zoler/MDedge News
Dr. Douglas L. Packer

The improvements in quality of life measures in atrial fibrillation (AF) patients following ablation were “clinically meaningful” relative to drug therapy and were sustained for 5 years of follow-up, said Douglas L. Packer, MD, at the annual International AF Symposium.

The apparent incremental benefit in quality of life after ablation, compared with patients treated with drug therapy, added to the benefits previously reported from CABANA (Catheter Ablation vs. Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial) using ablation that included a highly significant reduction in recurrent AF and a significant reduction in the combined endpoint of mortality or cardiovascular hospitalization. However, the trial’s results were neutral for the study’s prespecified primary endpoint, a combination of the rate of total mortality, disabling stroke, serious bleeding, or cardiac arrest in an intention-to-treat analysis, a result first reported by Dr. Packer at the annual scientific sessions of the Heart Rhythm Society in May 2018.

When Dr. Packer spoke at the AF Symposium in late January 2019, the CABANA results had still not been published. He said that he expected an article with the main findings to appear online sometime in February 2019.



The quality of life analysis, focused on two measures, the Mayo AF-Specific Symptoms Inventory (MAFSI) (Circulation. 2008 Oct 28;118[suppl 18]:S589) and the Atrial Fibrillation Affect on Quality of Life (AFEQT) (Circ Arrhythm Electrophysiol. 2011 Feb;4[1]:15-25). The patients enrolled in the two treatment arms of CABANA had essentially identical baseline MAFSI frequency scores, but starting 3 months after entry patients randomized to the ablation arm had an average, statistically significant 1.6-point improvement in their adjusted MAFSI frequency score, compared with patients in the drug-therapy arm; this reduction persisted at about the same statistically significant level through 5 years, said Dr. Packer, an electrophysiologist and professor of medicine at the Mayo Clinic in Rochester, Minn., and lead investigator of CABANA. Patients who remained in follow-up throughout the study’s entire 60 months underwent a total of seven MAFSI assessments after their initial treatment; the average, adjusted difference in MAFSI frequency scores throughout CABANA was a statistically significant 1.4 points lower among ablated patients, compared with those randomized to drug therapy, said Dr. Packer, who presented data first reported by the CABANA researchers in 2018.

The pattern of change in the AFEQT scores was very similar. The average, adjusted AFEQT summary scores were virtually identical at baseline for the two treatment arms, but at 3 months after the study began patients in the ablation arm had an average, adjusted, statistically significant 3-point improvement in their AFEQT summary scores, compared with drug-treated patients; this incremental increase in AFEQT scores remained consistent and statistically significant through 5 years of follow-up. Throughout the study, the average, adjusted, incremental improvement in AFEQT after ablation was a statistically significant 3.4 points, said Dr. Packer.

Mitchel L. Zoler/MDedge News
Dr. Peter R. Kowey

But these quality of life measures in patients who received unblinded assignment to an ablation procedure or drug treatment in CABANA are likely unreliable, commented Peter R. Kowey, MD, an electrophysiologist at the Lankenau Heart Institute in Wynnewood, Penn., and professor of medicine at Jefferson Medical College, Philadelphia.

“Assessing quality of life in an unblinded trial seems to me to be pretty shallow,” said Dr. Kowey, a member of the CABANA steering committee and a participant in a panel at the Symposium that discussed the results. Patients who have just gone through a 6-hour procedure will often say they now feel a whole lot better, he suggested. “They’re concerned what will get done to them if they don’t say they feel better.” The same confounding also applies to other “soft” secondary endpoints used in CABANA, such as hospitalization rates.

The reliability of these more subjective outcome measures is reduced in an unblinded trial, Dr. Kowey maintained. The CABANA results “don’t change the fundamental principal of using hard endpoints,” such as those that made up the primary endpoint of the study, he said in an interview. “We put secondary endpoints into the study because they are legitimate things to look at, but they have questionable reliability,” as measures of ablation’s efficacy.

Dr. Kowey also cautioned against focusing on the per-protocol and treatment-received analyses of the CABANA results, prespecified analyses that Dr. Packer highlighted because of the high number of crossovers in the trial: 9% of patients assigned to ablation never received it and 28% of patients assigned to drug therapy actually received ablation.

The CABANA steering committee anticipated a high crossover rate, but still set the intention-to-treat analysis as primary because “per protocol introduces many biases and can’t be relied on for a study of this magnitude,” Dr. Kowey said. He also cited the statistical pitfalls of looking at multiple secondary endpoints in the CABANA results and the danger of reading too much into subgroup analyses, all from a trial with a neutral primary endpoint.

Another concern he raised centered on the generalizability of CABANA’s safety findings, which showed roughly similar adverse event rates between the two treatment arms – about 9% with ablation, 4% with drugs – although the distribution of complications types differed between the two arms. The “ ‘remarkably safe’ performance of ablation in CABANA can be attributed to ‘cherry-picked’ investigators” who performed the ablation procedures at high-volume centers, said Dr. Kowey. “The safety of ablation was predictable” in CABANA because of the selection of participating centers. “Seventy percent of U.S. ablations are being done at centers that do fewer than 25 ablations annually,” Dr. Kowey said. “We don’t know what goes on” at lower-volume centers; “ablation can’t be considered as safe as we presume” when done at centers outside the 118 sites that participated in CABANA, he maintained.

CABANA received partial funding from Biosense Webster, Boston Scientific, Medtronic, and St. Jude. Dr. Packer has been a consultant to these four companies as well as to CyberHeart, nContact, Sanofi-Aventis, and Toray. He has received research funding from AG, Biosense Webster, Boston Scientific, CryoCath, EP Limited, and Medtronic, and has a financial interest in AF mapping technology. Dr. Kowey has been a consultant to several companies that market antiarrhythmic drugs or market arrhythmia devices and has an equity interest in BioTelemetry.

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– Ablation of atrial fibrillation led to significantly better quality of life improvements, compared with antiarrhythmic drug therapy, in a prespecified, secondary analysis of data from the CABANA multicenter, randomized trial with 2,204 patients.

Mitchel L. Zoler/MDedge News
Dr. Douglas L. Packer

The improvements in quality of life measures in atrial fibrillation (AF) patients following ablation were “clinically meaningful” relative to drug therapy and were sustained for 5 years of follow-up, said Douglas L. Packer, MD, at the annual International AF Symposium.

The apparent incremental benefit in quality of life after ablation, compared with patients treated with drug therapy, added to the benefits previously reported from CABANA (Catheter Ablation vs. Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial) using ablation that included a highly significant reduction in recurrent AF and a significant reduction in the combined endpoint of mortality or cardiovascular hospitalization. However, the trial’s results were neutral for the study’s prespecified primary endpoint, a combination of the rate of total mortality, disabling stroke, serious bleeding, or cardiac arrest in an intention-to-treat analysis, a result first reported by Dr. Packer at the annual scientific sessions of the Heart Rhythm Society in May 2018.

When Dr. Packer spoke at the AF Symposium in late January 2019, the CABANA results had still not been published. He said that he expected an article with the main findings to appear online sometime in February 2019.



The quality of life analysis, focused on two measures, the Mayo AF-Specific Symptoms Inventory (MAFSI) (Circulation. 2008 Oct 28;118[suppl 18]:S589) and the Atrial Fibrillation Affect on Quality of Life (AFEQT) (Circ Arrhythm Electrophysiol. 2011 Feb;4[1]:15-25). The patients enrolled in the two treatment arms of CABANA had essentially identical baseline MAFSI frequency scores, but starting 3 months after entry patients randomized to the ablation arm had an average, statistically significant 1.6-point improvement in their adjusted MAFSI frequency score, compared with patients in the drug-therapy arm; this reduction persisted at about the same statistically significant level through 5 years, said Dr. Packer, an electrophysiologist and professor of medicine at the Mayo Clinic in Rochester, Minn., and lead investigator of CABANA. Patients who remained in follow-up throughout the study’s entire 60 months underwent a total of seven MAFSI assessments after their initial treatment; the average, adjusted difference in MAFSI frequency scores throughout CABANA was a statistically significant 1.4 points lower among ablated patients, compared with those randomized to drug therapy, said Dr. Packer, who presented data first reported by the CABANA researchers in 2018.

The pattern of change in the AFEQT scores was very similar. The average, adjusted AFEQT summary scores were virtually identical at baseline for the two treatment arms, but at 3 months after the study began patients in the ablation arm had an average, adjusted, statistically significant 3-point improvement in their AFEQT summary scores, compared with drug-treated patients; this incremental increase in AFEQT scores remained consistent and statistically significant through 5 years of follow-up. Throughout the study, the average, adjusted, incremental improvement in AFEQT after ablation was a statistically significant 3.4 points, said Dr. Packer.

Mitchel L. Zoler/MDedge News
Dr. Peter R. Kowey

But these quality of life measures in patients who received unblinded assignment to an ablation procedure or drug treatment in CABANA are likely unreliable, commented Peter R. Kowey, MD, an electrophysiologist at the Lankenau Heart Institute in Wynnewood, Penn., and professor of medicine at Jefferson Medical College, Philadelphia.

“Assessing quality of life in an unblinded trial seems to me to be pretty shallow,” said Dr. Kowey, a member of the CABANA steering committee and a participant in a panel at the Symposium that discussed the results. Patients who have just gone through a 6-hour procedure will often say they now feel a whole lot better, he suggested. “They’re concerned what will get done to them if they don’t say they feel better.” The same confounding also applies to other “soft” secondary endpoints used in CABANA, such as hospitalization rates.

The reliability of these more subjective outcome measures is reduced in an unblinded trial, Dr. Kowey maintained. The CABANA results “don’t change the fundamental principal of using hard endpoints,” such as those that made up the primary endpoint of the study, he said in an interview. “We put secondary endpoints into the study because they are legitimate things to look at, but they have questionable reliability,” as measures of ablation’s efficacy.

Dr. Kowey also cautioned against focusing on the per-protocol and treatment-received analyses of the CABANA results, prespecified analyses that Dr. Packer highlighted because of the high number of crossovers in the trial: 9% of patients assigned to ablation never received it and 28% of patients assigned to drug therapy actually received ablation.

The CABANA steering committee anticipated a high crossover rate, but still set the intention-to-treat analysis as primary because “per protocol introduces many biases and can’t be relied on for a study of this magnitude,” Dr. Kowey said. He also cited the statistical pitfalls of looking at multiple secondary endpoints in the CABANA results and the danger of reading too much into subgroup analyses, all from a trial with a neutral primary endpoint.

Another concern he raised centered on the generalizability of CABANA’s safety findings, which showed roughly similar adverse event rates between the two treatment arms – about 9% with ablation, 4% with drugs – although the distribution of complications types differed between the two arms. The “ ‘remarkably safe’ performance of ablation in CABANA can be attributed to ‘cherry-picked’ investigators” who performed the ablation procedures at high-volume centers, said Dr. Kowey. “The safety of ablation was predictable” in CABANA because of the selection of participating centers. “Seventy percent of U.S. ablations are being done at centers that do fewer than 25 ablations annually,” Dr. Kowey said. “We don’t know what goes on” at lower-volume centers; “ablation can’t be considered as safe as we presume” when done at centers outside the 118 sites that participated in CABANA, he maintained.

CABANA received partial funding from Biosense Webster, Boston Scientific, Medtronic, and St. Jude. Dr. Packer has been a consultant to these four companies as well as to CyberHeart, nContact, Sanofi-Aventis, and Toray. He has received research funding from AG, Biosense Webster, Boston Scientific, CryoCath, EP Limited, and Medtronic, and has a financial interest in AF mapping technology. Dr. Kowey has been a consultant to several companies that market antiarrhythmic drugs or market arrhythmia devices and has an equity interest in BioTelemetry.

 

– Ablation of atrial fibrillation led to significantly better quality of life improvements, compared with antiarrhythmic drug therapy, in a prespecified, secondary analysis of data from the CABANA multicenter, randomized trial with 2,204 patients.

Mitchel L. Zoler/MDedge News
Dr. Douglas L. Packer

The improvements in quality of life measures in atrial fibrillation (AF) patients following ablation were “clinically meaningful” relative to drug therapy and were sustained for 5 years of follow-up, said Douglas L. Packer, MD, at the annual International AF Symposium.

The apparent incremental benefit in quality of life after ablation, compared with patients treated with drug therapy, added to the benefits previously reported from CABANA (Catheter Ablation vs. Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial) using ablation that included a highly significant reduction in recurrent AF and a significant reduction in the combined endpoint of mortality or cardiovascular hospitalization. However, the trial’s results were neutral for the study’s prespecified primary endpoint, a combination of the rate of total mortality, disabling stroke, serious bleeding, or cardiac arrest in an intention-to-treat analysis, a result first reported by Dr. Packer at the annual scientific sessions of the Heart Rhythm Society in May 2018.

When Dr. Packer spoke at the AF Symposium in late January 2019, the CABANA results had still not been published. He said that he expected an article with the main findings to appear online sometime in February 2019.



The quality of life analysis, focused on two measures, the Mayo AF-Specific Symptoms Inventory (MAFSI) (Circulation. 2008 Oct 28;118[suppl 18]:S589) and the Atrial Fibrillation Affect on Quality of Life (AFEQT) (Circ Arrhythm Electrophysiol. 2011 Feb;4[1]:15-25). The patients enrolled in the two treatment arms of CABANA had essentially identical baseline MAFSI frequency scores, but starting 3 months after entry patients randomized to the ablation arm had an average, statistically significant 1.6-point improvement in their adjusted MAFSI frequency score, compared with patients in the drug-therapy arm; this reduction persisted at about the same statistically significant level through 5 years, said Dr. Packer, an electrophysiologist and professor of medicine at the Mayo Clinic in Rochester, Minn., and lead investigator of CABANA. Patients who remained in follow-up throughout the study’s entire 60 months underwent a total of seven MAFSI assessments after their initial treatment; the average, adjusted difference in MAFSI frequency scores throughout CABANA was a statistically significant 1.4 points lower among ablated patients, compared with those randomized to drug therapy, said Dr. Packer, who presented data first reported by the CABANA researchers in 2018.

The pattern of change in the AFEQT scores was very similar. The average, adjusted AFEQT summary scores were virtually identical at baseline for the two treatment arms, but at 3 months after the study began patients in the ablation arm had an average, adjusted, statistically significant 3-point improvement in their AFEQT summary scores, compared with drug-treated patients; this incremental increase in AFEQT scores remained consistent and statistically significant through 5 years of follow-up. Throughout the study, the average, adjusted, incremental improvement in AFEQT after ablation was a statistically significant 3.4 points, said Dr. Packer.

Mitchel L. Zoler/MDedge News
Dr. Peter R. Kowey

But these quality of life measures in patients who received unblinded assignment to an ablation procedure or drug treatment in CABANA are likely unreliable, commented Peter R. Kowey, MD, an electrophysiologist at the Lankenau Heart Institute in Wynnewood, Penn., and professor of medicine at Jefferson Medical College, Philadelphia.

“Assessing quality of life in an unblinded trial seems to me to be pretty shallow,” said Dr. Kowey, a member of the CABANA steering committee and a participant in a panel at the Symposium that discussed the results. Patients who have just gone through a 6-hour procedure will often say they now feel a whole lot better, he suggested. “They’re concerned what will get done to them if they don’t say they feel better.” The same confounding also applies to other “soft” secondary endpoints used in CABANA, such as hospitalization rates.

The reliability of these more subjective outcome measures is reduced in an unblinded trial, Dr. Kowey maintained. The CABANA results “don’t change the fundamental principal of using hard endpoints,” such as those that made up the primary endpoint of the study, he said in an interview. “We put secondary endpoints into the study because they are legitimate things to look at, but they have questionable reliability,” as measures of ablation’s efficacy.

Dr. Kowey also cautioned against focusing on the per-protocol and treatment-received analyses of the CABANA results, prespecified analyses that Dr. Packer highlighted because of the high number of crossovers in the trial: 9% of patients assigned to ablation never received it and 28% of patients assigned to drug therapy actually received ablation.

The CABANA steering committee anticipated a high crossover rate, but still set the intention-to-treat analysis as primary because “per protocol introduces many biases and can’t be relied on for a study of this magnitude,” Dr. Kowey said. He also cited the statistical pitfalls of looking at multiple secondary endpoints in the CABANA results and the danger of reading too much into subgroup analyses, all from a trial with a neutral primary endpoint.

Another concern he raised centered on the generalizability of CABANA’s safety findings, which showed roughly similar adverse event rates between the two treatment arms – about 9% with ablation, 4% with drugs – although the distribution of complications types differed between the two arms. The “ ‘remarkably safe’ performance of ablation in CABANA can be attributed to ‘cherry-picked’ investigators” who performed the ablation procedures at high-volume centers, said Dr. Kowey. “The safety of ablation was predictable” in CABANA because of the selection of participating centers. “Seventy percent of U.S. ablations are being done at centers that do fewer than 25 ablations annually,” Dr. Kowey said. “We don’t know what goes on” at lower-volume centers; “ablation can’t be considered as safe as we presume” when done at centers outside the 118 sites that participated in CABANA, he maintained.

CABANA received partial funding from Biosense Webster, Boston Scientific, Medtronic, and St. Jude. Dr. Packer has been a consultant to these four companies as well as to CyberHeart, nContact, Sanofi-Aventis, and Toray. He has received research funding from AG, Biosense Webster, Boston Scientific, CryoCath, EP Limited, and Medtronic, and has a financial interest in AF mapping technology. Dr. Kowey has been a consultant to several companies that market antiarrhythmic drugs or market arrhythmia devices and has an equity interest in BioTelemetry.

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REPORTING FROM THE AF SYMPOSIUM 2019

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Key clinical point: In CABANA, atrial fibrillation ablation led to a clinically meaningful improvement of quality of life measures, compared with drug therapy.

Major finding: After ablation, the MAFSI score averaged a 1.4-point improvement; the AFEQT score averaged a 3.4-point improvement over drug therapy.

Study details: CABANA, a multicenter, randomized trial with 2,204 atrial fibrillation patients.

Disclosures: CABANA received partial funding from Biosense Webster, Boston Scientific, Medtronic, and St. Jude. Dr. Packer has been a consultant to these four companies as well as to CyberHeart, nContact, Sanofi-Aventis, and Toray. He has received research funding from AG, Biosense Webster, Boston Scientific, CryoCath, EP Limited, and Medtronic, and has a financial interest in atrial fibrillation mapping technology. Dr. Kowey has been a consultant to several companies that market antiarrhythmic drugs or market arrhythmia devices and has an equity interest in BioTelemetry.

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Oncology research does crowdsourcing

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Crowdsourcing is now happening at multiple steps in cancer research, from linking patients with studies to data collection, to an end game that offers the data to anyone interested in taking a crack at analyzing it, drawing conclusions, or generating hypotheses for further study. Generally defined today as electronic-based communication that links otherwise disparate individuals or groups, crowdsourcing has quietly over the past decade or so begun to transform a significant segment of all types of biomedical research, with effects on oncology that seemingly are among the strongest.

Dr. Daniel Gallahan

Crowdsourcing data analysis “is an opportunity to take on complex problems in cancer research and attract researchers who would not usually work on it. With the complexity of cancer we need to tap into every resource; this is a way to do it with low overhead,” explained Daniel Gallahan, PhD, deputy director of the Division of Cancer Biology of the National Cancer Institute. “It’s been a workable model that we’ve had success with, and there is not a lot of upfront cost,” Dr. Gallahan said in an interview.

“A lot of data is produced in oncology, and the ability of an individual to analyze the data is fairly limited, but if we can focus a community of people around a specific question, we can answer it much more quickly,” explained James C. Costello, PhD, a bioinformatics researcher at the University of Colorado in Aurora.

Traced to first usage in 2006, the term crowdsourcing as it applies to data analysis means combining “the bottom-up creative intelligence of a community that volunteers solutions with the top-down management of an organization that poses the problem,” according to a 2016 review (Nat Rev Genet. 2016 July 15;17[8]:470-86). The bioinformatics experts who wrote this review, as well as most anyone else who saw the way crowdsourcing has taken hold over the last decade, link this increased role to the huge amounts of data generated by and needing analysis in biomedical research in general – and in oncology in particular. Companies like Sage Bionetworks have came on the scene built to expedite crowdsourced data analysis.

Dr. Gallahan cited as examples of crowdsourced cancer studies a pair of DREAM (Dialogue for Reverse Engineering Assessments and Methods) challenges, one for developing an improved algorithm for predicting drug sensitivity in breast cancer cells (Nat Biotechnol. 2014 Dec;32[12]:1202-12) and a second that developed a better prognostic model for patients with metastatic, castration-resistant prostate cancer (Lancet Oncol. 2017 Jan;18[1]:132-42). The National Cancer Institute “has been actively involved in DREAM challenges,” he noted.

In addition to competing research teams working individually to find the best solution to these problems, the prostate cancer challenge, for example, then “asked the best performing teams to work together to further improve the methodology,” said Dr. Costello, who helped organize and run both the breast cancer and prostate cancer challenges cited by Dr. Gallahan. “The challenge phase was separate, but then [the teams] worked together to come up with even better solutions. We put together the best of seven models, and none of the teams had ever worked together before,” explained Dr. Costello, (JCO Clin Cancer Inform. 2017 Aug 4. doi: 10.1200/CCI.17.00018). He called this opportunity another attraction of a crowdsourced challenge for problem solving.



Crowdsourced data analysis is also vulnerable to several possible problems. It potentially can “lose specificity and the hypothesis-driven aspect,” cautioned Dr. Costello. “There are also issues of who owns the data and who receives credit” for a solution based on the data, and there are inherent limitations in finding associations that are independent of a study’s original primary endpoint. “It’s a different approach that does not replace the traditional, standard research approach of hypothesis-driven studies,” he said.

Other caveats on the output of DREAM challenges and other crowdsourced data analysis are the need for validation of the solution and a way to follow up on a solution to take it from an academic exercise to a useful application, said Dr. Gallahan.

Despite their limitations crowdsourced analyses began appearing a little more than a decade ago and have steadily grown in number “as more and more data get generated,” more than can be easily analyzed by the people collecting the data, Dr. Gallahan noted.

In fact, some studies now accumulate data with the express intent of posting the findings online and making them available for crowdsourced analyses. The Count Me In study is a collaboration of researchers at Dana-Farber Cancer Institute in Boston and three other organizations to engage and collect data from patients with a wide range of cancer types. The study began enrolling patients with metastatic breast cancer, with about 5,100 of these patients included by early 2019 in the Metastatic Breast Cancer Project. Count Me In has expanded to also include patients with prostate cancer, angiosarcoma, and gastroesophageal cancer. The program’s overall goal is to enroll more than 100,000 patients diagnosed with any type of cancer.

Dr. Eliezer van Allen

“The concept is using online recruitment to involve patients who wouldn’t otherwise engage” with this sort of study, said Eliezer van Allen, MD, a Dana-Farber oncologist who runs the prostate cancer arm of Count Me In. “Patients are the ones who spread the word” about Count Me In to other patients, largely through social media, an approach representing another way that crowdsourcing has seeped into cancer research.

“There was an inflection point in about 2013-2015” when a critical mass of patients with cancers interacted with other cancer patients in various social media and other online groups sufficient to make Count Me In viable, Dr. van Allen said in an interview.

Once data come in – from donated specimens that underwent genetic analysis, blood work, and clinical records – the researchers formated the information and then put it out with open access at the cBioPortal. Among the research questions that Dr. van Allen looks forward to getting addressed with these data are what factors define exceptional treatment responders, what are the genetic profiles of metastatic tumors, and what are characteristics of patients not treated at academic medical centers.

 

 


But the coolest thing about crowdsourcing these data is that some people “will use it to answer questions that I haven’t thought of,” Dr. van Allen said.

He conceded that the clinical-record data are limited by their uncertain reliability and that the model for patient recruitment introduces bias, although the organizers of Count Me In are developing paper-based tools for patient enrollment to complement electronic enrollment. “Our goal is to cast a wide net for patients,” with eventual expansion to all cancer types. The prostate cancer arm of Count Me In tallied 623 participating patients as of the start of 2019 and after the first year of patient recruitment into the prostate cancer section. Dr. van Allen planned to release the first batch of data from the prostate cancer study by the end of January 2019.

The first publication of findings from the breast cancer project of Count Me In appeared in late 2018, an analysis of acquired HER2 mutations found in tumor biopsies from eight patients with estrogen-receptor-positive metastatic breast cancer and the linkage of these mutations to drug resistance (Nature Gen. 2018 Dec 10. doi: 10.1038/s41588-018-0287-5).

Crowdsourcing to get cancer patients into studies is also an initiative of patients themselves, like the patient-trial matching service provided by the Myeloma Crowd, which works in partnership with the SparkCures website. Myeloma Crowd began in 2013 as a series of interviews with researchers running cancer trials who explained their studies and the types of patients they were seeking. By 2015, this effort added a partnership with SparkCures that runs an online tool that matches myeloma patients with an individualized short list of available trials.

Jenny Ahlstrom

In late 2018, Myeloma Crowd launched a new website, HealthTree, that combines at one site disease information, trial matching (still using SparkCures), and several platforms for patient interaction. Myeloma Crowd also seeks HealthTree to be a vehicle for patient-data collection, such as a recent survey on vaccination experiences following myeloma treatment, said Jenny Ahlstrom, a myeloma patient and founder of Myeloma Crowd. “We use tech to build a patient constituency, and now we’re using it to collect data and do research,” she said in an interview. Patients “invite each other to contribute data,” an approach that makes Myeloma Crowd unique, she maintained. One goal is to “speed up the clinical trial process,” as well as link patients with the more conventional trials they qualify for, Ms. Ahlstrom said.

Any effective effort to link patients with appropriate trials is a big plus, commented Dr. Gallahan. It both “empowers patients,” while also offering a novel path for informing patients about trials. “Any time you can get more patients into trials, it’s a success,” although of course patients must still meet enrollment criteria for a trial, he said. Privacy-protected online patient networks also provide an easier way for patients to submit their data into a trial.

But often, these issues aren’t so easily resolved. “It’s difficult to guarantee whether participants meet eligibility criteria” when they enter through a crowdsourced portal because “there is no way to validate,” said Young Ji Lee, PhD, a biomedical informatics researcher at the University of Pittsburgh. An analysis based on patient data collected by crowdsourcing is also subject to a selection bias, and confidentiality is not easily ensured. A crowdsourced study still needs institutional review board oversight, she said in an interview,

Dr. Young Ji Lee

Dr. Lee cited a 2018 review that identified 202 studies published through March 2016 that involved health-related crowdsourcing, with 36% involving research. Oncology-related studies made up 7% of the total, fourth highest after public health, psychiatry, and surgery (J Med Internet Res. 2018 May;20[5]:e187). Dr. Lee ran her own study of published reports of crowdsourcing research in cancer through June 2016 and identified 12 studies (Cancer Med. 2017 Nov;6[11]:2595-605). “Crowdsourcing will continue to expand in biomedical research, including oncology, with the growing trends of patient-centered, participatory medicine,” she concluded.

Dr. Gallahan, Dr. Costello, and Dr. Lee had no disclosures. Dr. van Allen has been a consultant or advisor to Dynamo, Foresite Capital, Genome Medical, Illumina, Invitae, and Tango Therapeutics, he has received research funding from Bristol-Myers Squibb and Novartis, and he has an equity interest in Genome Medical, Microsoft, Synapse, and Tango Therapeutics. Ms. Ahlstrom said that Myeloma Crowd has received funding from Bristol-Myers Squibb, Celgene, Janssen, Sanofi, and Takeda.

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Crowdsourcing is now happening at multiple steps in cancer research, from linking patients with studies to data collection, to an end game that offers the data to anyone interested in taking a crack at analyzing it, drawing conclusions, or generating hypotheses for further study. Generally defined today as electronic-based communication that links otherwise disparate individuals or groups, crowdsourcing has quietly over the past decade or so begun to transform a significant segment of all types of biomedical research, with effects on oncology that seemingly are among the strongest.

Dr. Daniel Gallahan

Crowdsourcing data analysis “is an opportunity to take on complex problems in cancer research and attract researchers who would not usually work on it. With the complexity of cancer we need to tap into every resource; this is a way to do it with low overhead,” explained Daniel Gallahan, PhD, deputy director of the Division of Cancer Biology of the National Cancer Institute. “It’s been a workable model that we’ve had success with, and there is not a lot of upfront cost,” Dr. Gallahan said in an interview.

“A lot of data is produced in oncology, and the ability of an individual to analyze the data is fairly limited, but if we can focus a community of people around a specific question, we can answer it much more quickly,” explained James C. Costello, PhD, a bioinformatics researcher at the University of Colorado in Aurora.

Traced to first usage in 2006, the term crowdsourcing as it applies to data analysis means combining “the bottom-up creative intelligence of a community that volunteers solutions with the top-down management of an organization that poses the problem,” according to a 2016 review (Nat Rev Genet. 2016 July 15;17[8]:470-86). The bioinformatics experts who wrote this review, as well as most anyone else who saw the way crowdsourcing has taken hold over the last decade, link this increased role to the huge amounts of data generated by and needing analysis in biomedical research in general – and in oncology in particular. Companies like Sage Bionetworks have came on the scene built to expedite crowdsourced data analysis.

Dr. Gallahan cited as examples of crowdsourced cancer studies a pair of DREAM (Dialogue for Reverse Engineering Assessments and Methods) challenges, one for developing an improved algorithm for predicting drug sensitivity in breast cancer cells (Nat Biotechnol. 2014 Dec;32[12]:1202-12) and a second that developed a better prognostic model for patients with metastatic, castration-resistant prostate cancer (Lancet Oncol. 2017 Jan;18[1]:132-42). The National Cancer Institute “has been actively involved in DREAM challenges,” he noted.

In addition to competing research teams working individually to find the best solution to these problems, the prostate cancer challenge, for example, then “asked the best performing teams to work together to further improve the methodology,” said Dr. Costello, who helped organize and run both the breast cancer and prostate cancer challenges cited by Dr. Gallahan. “The challenge phase was separate, but then [the teams] worked together to come up with even better solutions. We put together the best of seven models, and none of the teams had ever worked together before,” explained Dr. Costello, (JCO Clin Cancer Inform. 2017 Aug 4. doi: 10.1200/CCI.17.00018). He called this opportunity another attraction of a crowdsourced challenge for problem solving.



Crowdsourced data analysis is also vulnerable to several possible problems. It potentially can “lose specificity and the hypothesis-driven aspect,” cautioned Dr. Costello. “There are also issues of who owns the data and who receives credit” for a solution based on the data, and there are inherent limitations in finding associations that are independent of a study’s original primary endpoint. “It’s a different approach that does not replace the traditional, standard research approach of hypothesis-driven studies,” he said.

Other caveats on the output of DREAM challenges and other crowdsourced data analysis are the need for validation of the solution and a way to follow up on a solution to take it from an academic exercise to a useful application, said Dr. Gallahan.

Despite their limitations crowdsourced analyses began appearing a little more than a decade ago and have steadily grown in number “as more and more data get generated,” more than can be easily analyzed by the people collecting the data, Dr. Gallahan noted.

In fact, some studies now accumulate data with the express intent of posting the findings online and making them available for crowdsourced analyses. The Count Me In study is a collaboration of researchers at Dana-Farber Cancer Institute in Boston and three other organizations to engage and collect data from patients with a wide range of cancer types. The study began enrolling patients with metastatic breast cancer, with about 5,100 of these patients included by early 2019 in the Metastatic Breast Cancer Project. Count Me In has expanded to also include patients with prostate cancer, angiosarcoma, and gastroesophageal cancer. The program’s overall goal is to enroll more than 100,000 patients diagnosed with any type of cancer.

Dr. Eliezer van Allen

“The concept is using online recruitment to involve patients who wouldn’t otherwise engage” with this sort of study, said Eliezer van Allen, MD, a Dana-Farber oncologist who runs the prostate cancer arm of Count Me In. “Patients are the ones who spread the word” about Count Me In to other patients, largely through social media, an approach representing another way that crowdsourcing has seeped into cancer research.

“There was an inflection point in about 2013-2015” when a critical mass of patients with cancers interacted with other cancer patients in various social media and other online groups sufficient to make Count Me In viable, Dr. van Allen said in an interview.

Once data come in – from donated specimens that underwent genetic analysis, blood work, and clinical records – the researchers formated the information and then put it out with open access at the cBioPortal. Among the research questions that Dr. van Allen looks forward to getting addressed with these data are what factors define exceptional treatment responders, what are the genetic profiles of metastatic tumors, and what are characteristics of patients not treated at academic medical centers.

 

 


But the coolest thing about crowdsourcing these data is that some people “will use it to answer questions that I haven’t thought of,” Dr. van Allen said.

He conceded that the clinical-record data are limited by their uncertain reliability and that the model for patient recruitment introduces bias, although the organizers of Count Me In are developing paper-based tools for patient enrollment to complement electronic enrollment. “Our goal is to cast a wide net for patients,” with eventual expansion to all cancer types. The prostate cancer arm of Count Me In tallied 623 participating patients as of the start of 2019 and after the first year of patient recruitment into the prostate cancer section. Dr. van Allen planned to release the first batch of data from the prostate cancer study by the end of January 2019.

The first publication of findings from the breast cancer project of Count Me In appeared in late 2018, an analysis of acquired HER2 mutations found in tumor biopsies from eight patients with estrogen-receptor-positive metastatic breast cancer and the linkage of these mutations to drug resistance (Nature Gen. 2018 Dec 10. doi: 10.1038/s41588-018-0287-5).

Crowdsourcing to get cancer patients into studies is also an initiative of patients themselves, like the patient-trial matching service provided by the Myeloma Crowd, which works in partnership with the SparkCures website. Myeloma Crowd began in 2013 as a series of interviews with researchers running cancer trials who explained their studies and the types of patients they were seeking. By 2015, this effort added a partnership with SparkCures that runs an online tool that matches myeloma patients with an individualized short list of available trials.

Jenny Ahlstrom

In late 2018, Myeloma Crowd launched a new website, HealthTree, that combines at one site disease information, trial matching (still using SparkCures), and several platforms for patient interaction. Myeloma Crowd also seeks HealthTree to be a vehicle for patient-data collection, such as a recent survey on vaccination experiences following myeloma treatment, said Jenny Ahlstrom, a myeloma patient and founder of Myeloma Crowd. “We use tech to build a patient constituency, and now we’re using it to collect data and do research,” she said in an interview. Patients “invite each other to contribute data,” an approach that makes Myeloma Crowd unique, she maintained. One goal is to “speed up the clinical trial process,” as well as link patients with the more conventional trials they qualify for, Ms. Ahlstrom said.

Any effective effort to link patients with appropriate trials is a big plus, commented Dr. Gallahan. It both “empowers patients,” while also offering a novel path for informing patients about trials. “Any time you can get more patients into trials, it’s a success,” although of course patients must still meet enrollment criteria for a trial, he said. Privacy-protected online patient networks also provide an easier way for patients to submit their data into a trial.

But often, these issues aren’t so easily resolved. “It’s difficult to guarantee whether participants meet eligibility criteria” when they enter through a crowdsourced portal because “there is no way to validate,” said Young Ji Lee, PhD, a biomedical informatics researcher at the University of Pittsburgh. An analysis based on patient data collected by crowdsourcing is also subject to a selection bias, and confidentiality is not easily ensured. A crowdsourced study still needs institutional review board oversight, she said in an interview,

Dr. Young Ji Lee

Dr. Lee cited a 2018 review that identified 202 studies published through March 2016 that involved health-related crowdsourcing, with 36% involving research. Oncology-related studies made up 7% of the total, fourth highest after public health, psychiatry, and surgery (J Med Internet Res. 2018 May;20[5]:e187). Dr. Lee ran her own study of published reports of crowdsourcing research in cancer through June 2016 and identified 12 studies (Cancer Med. 2017 Nov;6[11]:2595-605). “Crowdsourcing will continue to expand in biomedical research, including oncology, with the growing trends of patient-centered, participatory medicine,” she concluded.

Dr. Gallahan, Dr. Costello, and Dr. Lee had no disclosures. Dr. van Allen has been a consultant or advisor to Dynamo, Foresite Capital, Genome Medical, Illumina, Invitae, and Tango Therapeutics, he has received research funding from Bristol-Myers Squibb and Novartis, and he has an equity interest in Genome Medical, Microsoft, Synapse, and Tango Therapeutics. Ms. Ahlstrom said that Myeloma Crowd has received funding from Bristol-Myers Squibb, Celgene, Janssen, Sanofi, and Takeda.

 

Crowdsourcing is now happening at multiple steps in cancer research, from linking patients with studies to data collection, to an end game that offers the data to anyone interested in taking a crack at analyzing it, drawing conclusions, or generating hypotheses for further study. Generally defined today as electronic-based communication that links otherwise disparate individuals or groups, crowdsourcing has quietly over the past decade or so begun to transform a significant segment of all types of biomedical research, with effects on oncology that seemingly are among the strongest.

Dr. Daniel Gallahan

Crowdsourcing data analysis “is an opportunity to take on complex problems in cancer research and attract researchers who would not usually work on it. With the complexity of cancer we need to tap into every resource; this is a way to do it with low overhead,” explained Daniel Gallahan, PhD, deputy director of the Division of Cancer Biology of the National Cancer Institute. “It’s been a workable model that we’ve had success with, and there is not a lot of upfront cost,” Dr. Gallahan said in an interview.

“A lot of data is produced in oncology, and the ability of an individual to analyze the data is fairly limited, but if we can focus a community of people around a specific question, we can answer it much more quickly,” explained James C. Costello, PhD, a bioinformatics researcher at the University of Colorado in Aurora.

Traced to first usage in 2006, the term crowdsourcing as it applies to data analysis means combining “the bottom-up creative intelligence of a community that volunteers solutions with the top-down management of an organization that poses the problem,” according to a 2016 review (Nat Rev Genet. 2016 July 15;17[8]:470-86). The bioinformatics experts who wrote this review, as well as most anyone else who saw the way crowdsourcing has taken hold over the last decade, link this increased role to the huge amounts of data generated by and needing analysis in biomedical research in general – and in oncology in particular. Companies like Sage Bionetworks have came on the scene built to expedite crowdsourced data analysis.

Dr. Gallahan cited as examples of crowdsourced cancer studies a pair of DREAM (Dialogue for Reverse Engineering Assessments and Methods) challenges, one for developing an improved algorithm for predicting drug sensitivity in breast cancer cells (Nat Biotechnol. 2014 Dec;32[12]:1202-12) and a second that developed a better prognostic model for patients with metastatic, castration-resistant prostate cancer (Lancet Oncol. 2017 Jan;18[1]:132-42). The National Cancer Institute “has been actively involved in DREAM challenges,” he noted.

In addition to competing research teams working individually to find the best solution to these problems, the prostate cancer challenge, for example, then “asked the best performing teams to work together to further improve the methodology,” said Dr. Costello, who helped organize and run both the breast cancer and prostate cancer challenges cited by Dr. Gallahan. “The challenge phase was separate, but then [the teams] worked together to come up with even better solutions. We put together the best of seven models, and none of the teams had ever worked together before,” explained Dr. Costello, (JCO Clin Cancer Inform. 2017 Aug 4. doi: 10.1200/CCI.17.00018). He called this opportunity another attraction of a crowdsourced challenge for problem solving.



Crowdsourced data analysis is also vulnerable to several possible problems. It potentially can “lose specificity and the hypothesis-driven aspect,” cautioned Dr. Costello. “There are also issues of who owns the data and who receives credit” for a solution based on the data, and there are inherent limitations in finding associations that are independent of a study’s original primary endpoint. “It’s a different approach that does not replace the traditional, standard research approach of hypothesis-driven studies,” he said.

Other caveats on the output of DREAM challenges and other crowdsourced data analysis are the need for validation of the solution and a way to follow up on a solution to take it from an academic exercise to a useful application, said Dr. Gallahan.

Despite their limitations crowdsourced analyses began appearing a little more than a decade ago and have steadily grown in number “as more and more data get generated,” more than can be easily analyzed by the people collecting the data, Dr. Gallahan noted.

In fact, some studies now accumulate data with the express intent of posting the findings online and making them available for crowdsourced analyses. The Count Me In study is a collaboration of researchers at Dana-Farber Cancer Institute in Boston and three other organizations to engage and collect data from patients with a wide range of cancer types. The study began enrolling patients with metastatic breast cancer, with about 5,100 of these patients included by early 2019 in the Metastatic Breast Cancer Project. Count Me In has expanded to also include patients with prostate cancer, angiosarcoma, and gastroesophageal cancer. The program’s overall goal is to enroll more than 100,000 patients diagnosed with any type of cancer.

Dr. Eliezer van Allen

“The concept is using online recruitment to involve patients who wouldn’t otherwise engage” with this sort of study, said Eliezer van Allen, MD, a Dana-Farber oncologist who runs the prostate cancer arm of Count Me In. “Patients are the ones who spread the word” about Count Me In to other patients, largely through social media, an approach representing another way that crowdsourcing has seeped into cancer research.

“There was an inflection point in about 2013-2015” when a critical mass of patients with cancers interacted with other cancer patients in various social media and other online groups sufficient to make Count Me In viable, Dr. van Allen said in an interview.

Once data come in – from donated specimens that underwent genetic analysis, blood work, and clinical records – the researchers formated the information and then put it out with open access at the cBioPortal. Among the research questions that Dr. van Allen looks forward to getting addressed with these data are what factors define exceptional treatment responders, what are the genetic profiles of metastatic tumors, and what are characteristics of patients not treated at academic medical centers.

 

 


But the coolest thing about crowdsourcing these data is that some people “will use it to answer questions that I haven’t thought of,” Dr. van Allen said.

He conceded that the clinical-record data are limited by their uncertain reliability and that the model for patient recruitment introduces bias, although the organizers of Count Me In are developing paper-based tools for patient enrollment to complement electronic enrollment. “Our goal is to cast a wide net for patients,” with eventual expansion to all cancer types. The prostate cancer arm of Count Me In tallied 623 participating patients as of the start of 2019 and after the first year of patient recruitment into the prostate cancer section. Dr. van Allen planned to release the first batch of data from the prostate cancer study by the end of January 2019.

The first publication of findings from the breast cancer project of Count Me In appeared in late 2018, an analysis of acquired HER2 mutations found in tumor biopsies from eight patients with estrogen-receptor-positive metastatic breast cancer and the linkage of these mutations to drug resistance (Nature Gen. 2018 Dec 10. doi: 10.1038/s41588-018-0287-5).

Crowdsourcing to get cancer patients into studies is also an initiative of patients themselves, like the patient-trial matching service provided by the Myeloma Crowd, which works in partnership with the SparkCures website. Myeloma Crowd began in 2013 as a series of interviews with researchers running cancer trials who explained their studies and the types of patients they were seeking. By 2015, this effort added a partnership with SparkCures that runs an online tool that matches myeloma patients with an individualized short list of available trials.

Jenny Ahlstrom

In late 2018, Myeloma Crowd launched a new website, HealthTree, that combines at one site disease information, trial matching (still using SparkCures), and several platforms for patient interaction. Myeloma Crowd also seeks HealthTree to be a vehicle for patient-data collection, such as a recent survey on vaccination experiences following myeloma treatment, said Jenny Ahlstrom, a myeloma patient and founder of Myeloma Crowd. “We use tech to build a patient constituency, and now we’re using it to collect data and do research,” she said in an interview. Patients “invite each other to contribute data,” an approach that makes Myeloma Crowd unique, she maintained. One goal is to “speed up the clinical trial process,” as well as link patients with the more conventional trials they qualify for, Ms. Ahlstrom said.

Any effective effort to link patients with appropriate trials is a big plus, commented Dr. Gallahan. It both “empowers patients,” while also offering a novel path for informing patients about trials. “Any time you can get more patients into trials, it’s a success,” although of course patients must still meet enrollment criteria for a trial, he said. Privacy-protected online patient networks also provide an easier way for patients to submit their data into a trial.

But often, these issues aren’t so easily resolved. “It’s difficult to guarantee whether participants meet eligibility criteria” when they enter through a crowdsourced portal because “there is no way to validate,” said Young Ji Lee, PhD, a biomedical informatics researcher at the University of Pittsburgh. An analysis based on patient data collected by crowdsourcing is also subject to a selection bias, and confidentiality is not easily ensured. A crowdsourced study still needs institutional review board oversight, she said in an interview,

Dr. Young Ji Lee

Dr. Lee cited a 2018 review that identified 202 studies published through March 2016 that involved health-related crowdsourcing, with 36% involving research. Oncology-related studies made up 7% of the total, fourth highest after public health, psychiatry, and surgery (J Med Internet Res. 2018 May;20[5]:e187). Dr. Lee ran her own study of published reports of crowdsourcing research in cancer through June 2016 and identified 12 studies (Cancer Med. 2017 Nov;6[11]:2595-605). “Crowdsourcing will continue to expand in biomedical research, including oncology, with the growing trends of patient-centered, participatory medicine,” she concluded.

Dr. Gallahan, Dr. Costello, and Dr. Lee had no disclosures. Dr. van Allen has been a consultant or advisor to Dynamo, Foresite Capital, Genome Medical, Illumina, Invitae, and Tango Therapeutics, he has received research funding from Bristol-Myers Squibb and Novartis, and he has an equity interest in Genome Medical, Microsoft, Synapse, and Tango Therapeutics. Ms. Ahlstrom said that Myeloma Crowd has received funding from Bristol-Myers Squibb, Celgene, Janssen, Sanofi, and Takeda.

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RE-SPECT ESUS: Dabigatran matched aspirin for second stroke prevention

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– For the second time in the past year, an anticoagulant failed to show superiority when it was compared with aspirin for preventing a second stroke in patients who had had an index embolic stroke of undetermined source (ESUS). But the most recent results gave a tantalizing suggestion that the anticoagulant approach might be effective for older patients, those at least 75 years old, possibly because these patients have the highest incidence of atrial fibrillation.

Mitchel L. Zoler/MDedge News
Dr. Hans-Christoph Diener

“The fact that we saw a treatment benefit in patients 75 and older [in a post hoc, subgroup analysis] means that development of atrial fibrillation (AF) is probably the most important factor,” Hans-Christoph Diener, MD, said at the World Stroke Congress. Another clue that incident AF drove a treatment benefit hidden in the new trial’s overall neutral result was that a post hoc, landmark analysis showed that, while the rate of second strokes was identical during the first year of follow-up in patients on either aspirin or the anticoagulant dabigatran (Pradaxa) after an index ESUS, patients on dabigatran had significantly fewer second strokes during subsequent follow-up.

More follow-up time was needed to see a benefit from anticoagulation because “it takes time for AF to develop, and then once a patient has AF, it takes time for a stroke to occur,” explained Dr. Diener, professor of neurology at the University of Duisburg-Essen in Essen, Germany.

The RE-SPECT ESUS (Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source) trial randomized 5,390 patients at more than 500 sites in 41 countries, including the United States, within 6 months of an index ESUS who had no history of AF and no severe renal impairment. All enrollees had to have less than 6 minutes of AF episodes during at least 20 hours of cardiac monitoring, and they had to be free of flow-limiting stenoses (50% or more) in arteries supplying their stroke region. Patients received either 150 mg or 110 mg of dabigatran twice daily depending on their age and renal function or 100 mg of aspirin daily. About a quarter of patients randomized to dabigatran received the lower dosage. The enrolled patients averaged 66 years old, almost two-thirds were men, and they started treatment a median of 44 days after their index stroke.

During a median 19 months’ follow-up, the incidence of a second stroke of any type was 4.1%/year among the patients on dabigatran and 4.8%/year among those on aspirin, a difference that was not statistically significant. However, the post hoc landmark analysis showed a significant reduction in second strokes with dabigatran treatment after the first year. In addition, a post hoc subgroup analysis showed that, among patients aged at least 75 years old, treatment with dabigatran linked with a statistically significant 37% reduction in second strokes, compared with treatment with aspirin, Dr. Diener reported.

The primary safety endpoint was major bleeds, as defined by the International Society on Thrombosis and Haemostasis, which occurred in 1.7%/year of patients on dabigatran and 1.4%/year of those on aspirin, a difference that was not statistically significant. Patients on dabigatran had a significant excess of major bleeds combined with clinically significant nonmajor bleeds: 3.3%/year versus 2.3%/year among those on aspirin.

A little over 4 months before Dr. Diener’s report, a separate research group published primary results from the NAVIGATE ESUS (Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source) trial, which compared the anticoagulant rivaroxaban (Xarelto) with aspirin for prevention of a second stroke in 7,213 ESUS patients. The results showed no significant efficacy difference between rivaroxaban and aspirin (N Engl J Med. 2018 June 7;378[23]:2191-2201).

RE-SPECT ESUS was funded by Boehringer Ingelheim, the company that markets dabigatran (Pradaxa). Dr. Diener has been a consultant to and has received research funding from Boehringer Ingelheim, as well as several other companies.

SOURCE: Diener H-C et al. Int J Stroke. 2018;13(2_suppl):27. Abstract 100.

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– For the second time in the past year, an anticoagulant failed to show superiority when it was compared with aspirin for preventing a second stroke in patients who had had an index embolic stroke of undetermined source (ESUS). But the most recent results gave a tantalizing suggestion that the anticoagulant approach might be effective for older patients, those at least 75 years old, possibly because these patients have the highest incidence of atrial fibrillation.

Mitchel L. Zoler/MDedge News
Dr. Hans-Christoph Diener

“The fact that we saw a treatment benefit in patients 75 and older [in a post hoc, subgroup analysis] means that development of atrial fibrillation (AF) is probably the most important factor,” Hans-Christoph Diener, MD, said at the World Stroke Congress. Another clue that incident AF drove a treatment benefit hidden in the new trial’s overall neutral result was that a post hoc, landmark analysis showed that, while the rate of second strokes was identical during the first year of follow-up in patients on either aspirin or the anticoagulant dabigatran (Pradaxa) after an index ESUS, patients on dabigatran had significantly fewer second strokes during subsequent follow-up.

More follow-up time was needed to see a benefit from anticoagulation because “it takes time for AF to develop, and then once a patient has AF, it takes time for a stroke to occur,” explained Dr. Diener, professor of neurology at the University of Duisburg-Essen in Essen, Germany.

The RE-SPECT ESUS (Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source) trial randomized 5,390 patients at more than 500 sites in 41 countries, including the United States, within 6 months of an index ESUS who had no history of AF and no severe renal impairment. All enrollees had to have less than 6 minutes of AF episodes during at least 20 hours of cardiac monitoring, and they had to be free of flow-limiting stenoses (50% or more) in arteries supplying their stroke region. Patients received either 150 mg or 110 mg of dabigatran twice daily depending on their age and renal function or 100 mg of aspirin daily. About a quarter of patients randomized to dabigatran received the lower dosage. The enrolled patients averaged 66 years old, almost two-thirds were men, and they started treatment a median of 44 days after their index stroke.

During a median 19 months’ follow-up, the incidence of a second stroke of any type was 4.1%/year among the patients on dabigatran and 4.8%/year among those on aspirin, a difference that was not statistically significant. However, the post hoc landmark analysis showed a significant reduction in second strokes with dabigatran treatment after the first year. In addition, a post hoc subgroup analysis showed that, among patients aged at least 75 years old, treatment with dabigatran linked with a statistically significant 37% reduction in second strokes, compared with treatment with aspirin, Dr. Diener reported.

The primary safety endpoint was major bleeds, as defined by the International Society on Thrombosis and Haemostasis, which occurred in 1.7%/year of patients on dabigatran and 1.4%/year of those on aspirin, a difference that was not statistically significant. Patients on dabigatran had a significant excess of major bleeds combined with clinically significant nonmajor bleeds: 3.3%/year versus 2.3%/year among those on aspirin.

A little over 4 months before Dr. Diener’s report, a separate research group published primary results from the NAVIGATE ESUS (Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source) trial, which compared the anticoagulant rivaroxaban (Xarelto) with aspirin for prevention of a second stroke in 7,213 ESUS patients. The results showed no significant efficacy difference between rivaroxaban and aspirin (N Engl J Med. 2018 June 7;378[23]:2191-2201).

RE-SPECT ESUS was funded by Boehringer Ingelheim, the company that markets dabigatran (Pradaxa). Dr. Diener has been a consultant to and has received research funding from Boehringer Ingelheim, as well as several other companies.

SOURCE: Diener H-C et al. Int J Stroke. 2018;13(2_suppl):27. Abstract 100.

– For the second time in the past year, an anticoagulant failed to show superiority when it was compared with aspirin for preventing a second stroke in patients who had had an index embolic stroke of undetermined source (ESUS). But the most recent results gave a tantalizing suggestion that the anticoagulant approach might be effective for older patients, those at least 75 years old, possibly because these patients have the highest incidence of atrial fibrillation.

Mitchel L. Zoler/MDedge News
Dr. Hans-Christoph Diener

“The fact that we saw a treatment benefit in patients 75 and older [in a post hoc, subgroup analysis] means that development of atrial fibrillation (AF) is probably the most important factor,” Hans-Christoph Diener, MD, said at the World Stroke Congress. Another clue that incident AF drove a treatment benefit hidden in the new trial’s overall neutral result was that a post hoc, landmark analysis showed that, while the rate of second strokes was identical during the first year of follow-up in patients on either aspirin or the anticoagulant dabigatran (Pradaxa) after an index ESUS, patients on dabigatran had significantly fewer second strokes during subsequent follow-up.

More follow-up time was needed to see a benefit from anticoagulation because “it takes time for AF to develop, and then once a patient has AF, it takes time for a stroke to occur,” explained Dr. Diener, professor of neurology at the University of Duisburg-Essen in Essen, Germany.

The RE-SPECT ESUS (Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source) trial randomized 5,390 patients at more than 500 sites in 41 countries, including the United States, within 6 months of an index ESUS who had no history of AF and no severe renal impairment. All enrollees had to have less than 6 minutes of AF episodes during at least 20 hours of cardiac monitoring, and they had to be free of flow-limiting stenoses (50% or more) in arteries supplying their stroke region. Patients received either 150 mg or 110 mg of dabigatran twice daily depending on their age and renal function or 100 mg of aspirin daily. About a quarter of patients randomized to dabigatran received the lower dosage. The enrolled patients averaged 66 years old, almost two-thirds were men, and they started treatment a median of 44 days after their index stroke.

During a median 19 months’ follow-up, the incidence of a second stroke of any type was 4.1%/year among the patients on dabigatran and 4.8%/year among those on aspirin, a difference that was not statistically significant. However, the post hoc landmark analysis showed a significant reduction in second strokes with dabigatran treatment after the first year. In addition, a post hoc subgroup analysis showed that, among patients aged at least 75 years old, treatment with dabigatran linked with a statistically significant 37% reduction in second strokes, compared with treatment with aspirin, Dr. Diener reported.

The primary safety endpoint was major bleeds, as defined by the International Society on Thrombosis and Haemostasis, which occurred in 1.7%/year of patients on dabigatran and 1.4%/year of those on aspirin, a difference that was not statistically significant. Patients on dabigatran had a significant excess of major bleeds combined with clinically significant nonmajor bleeds: 3.3%/year versus 2.3%/year among those on aspirin.

A little over 4 months before Dr. Diener’s report, a separate research group published primary results from the NAVIGATE ESUS (Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source) trial, which compared the anticoagulant rivaroxaban (Xarelto) with aspirin for prevention of a second stroke in 7,213 ESUS patients. The results showed no significant efficacy difference between rivaroxaban and aspirin (N Engl J Med. 2018 June 7;378[23]:2191-2201).

RE-SPECT ESUS was funded by Boehringer Ingelheim, the company that markets dabigatran (Pradaxa). Dr. Diener has been a consultant to and has received research funding from Boehringer Ingelheim, as well as several other companies.

SOURCE: Diener H-C et al. Int J Stroke. 2018;13(2_suppl):27. Abstract 100.

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REPORTING FROM THE WORLD STROKE CONGRESS

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Key clinical point: Dabigatran was no better than aspirin for preventing a second stroke after an embolic stroke of undetermined source (ESUS).

Major finding: A second stroke occurred at 4.1%/year with dabigatran and 4.8%/year with aspirin, not a statistically significant difference.

Study details: RE-SPECT ESUS, an international randomized trial with 5,390 ESUS patients.

Disclosures: RE-SPECT ESUS was funded by Boehringer Ingelheim, the company that markets dabigatran (Pradaxa). Dr. Diener has been a consultant to and has received research funding from Boehringer Ingelheim, as well as several other companies.

Source: Diener H-C et al. Int J Stroke. 2018;13(2_suppl):27. Abstract 100.

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Biodegradable polymer shows no long-term benefit in heart stents

Results question value of biodegradable polymers
Article Type
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Tue, 07/21/2020 - 14:18

– The idea behind putting a biodegradable polymer on a drug-eluting coronary stent is that, once the antirestenosis drug elutes and the polymer that held it degrades, the bare-metal stent left behind would trigger fewer long-term episodes of in-stent thrombosis than would stents that retain their polymer coating. But 10-year follow-up from a large trial that matched two second-generation drug-eluting stents, one with a biodegradable polymer and the other with a durable polymer, showed no statistically significant difference between the two for any clinical outcome, including the incidence of in-stent thrombosis, Sebastian Kufner, MD, said at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News
Dr. Sebastian Kufner

The potential advantage of a biodegradable polymer “is expected to occur over time,” and hence following patients for 10 or more years should start to show a clear advantage, at least for the endpoint of stent thrombosis, but that didn’t happen. After a median follow-up of 10.6 years, the cumulative rate of definite or probable stent thrombosis was 1.8% among 1,299 patients who received a sirolimus-eluting stent with a biodegradable polymer (Yukon Choice) and 2.5% among 652 patients who received a second-generation everolimus-eluting stent with a durable polymer (Xience), a difference that was not statistically significant, reported Dr. Kufner, a cardiologist at the The German Heart Centre in Munich.

These two stents also produced comparable 10-year outcomes that showed no statistically significant differences for the outcomes of all-cause death, MI, need for target-lesion revascularization, or the combined incidence of all three of these outcomes. In contrast, both of these second-generation stents showed statistically significant improvements in the combined cardiac endpoint, as well as in all-cause death, and definite stent thrombosis compared with the 652 patients who received the first-generation sirolimus-eluting stent Cypher. Concurrently with Dr. Kufner’s report, the results appeared in an article online (Circulation. 2018 Nov 11. doi: 10.1161/CIRCULATIONAHA.118.038065).


Another notable finding from the 10-year follow-up was the poor prognosis these patients faced after their interventions, including the patients who received second-generation drug-eluting stents. The 10-year rate of all cause death was 30% among patients who received Xience stents, 32% among those treated with Yukon Choice stents, and 37% among patients treated with Cypher stents.

“I’m daunted by this 10-year mortality rate even with the best current drug-eluting stents,” said Roxana Mehran, MD, professor of medicine at Icahn School of Medicine at Mount Sinai in New York and a cochair of the session. “I’m depressed about this as an interventionalist. We need to do better, although it might not just be about the revascularization.” The high mortality in these patients after 10 years may also reflect a lack of optimal medical treatment in some, she suggested.

Dr. Roxana Mehran


The ISAR-TEST-4 (Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents) trial randomized 2,603 patients during the period of September 2007–August 2008 at either of two centers in Munich. The study’s primary endpoint was the combined rate of cardiac death, MI, and target-lesion revascularization by 12 months after treatment. The 12-month results showed a similar 14% rate of this combined endpoint in the subgroup of patients treated with the biodegradable-polymer stent and in those treated with stents that used durable polymers, which proved the noninferiority of the stent with a biodegradable polymer (Eur Heart J. 2009 Oct 1;30[20]:2441-9). This initial analysis combined the patients who received Cypher and Xience stents into one comparator group: patients who received stents with durable polymers.

The new, long-term follow-up analysis included 2,153 patients (83%) followed for at least 10 years after their intervention.

ISAR-TEST-4 received no commercial funding. Dr. Kufner had no disclosures. Dr. Mehran has an ownership interest in Claret Medical and Elixir Medical, has been a consultant or adviser to Abbott Laboratories, Boston Scientific, Bristol-Myers Squibb, Janssen, Roivant Sciences, and Siemens Medical Solutions, and has received research funding from several companies.

SOURCE: Kufner S et al. AHA scientific sessions, Abstract 18630.

Body

The absence of incremental benefit from a stent with a biodegradable polymer compared with the second generation everolimus-eluting stent with a durable polymer in this 10-year follow-up is consistent with prior reports from medium-term follow-up. At best, drug-eluting coronary stents with a biodegradable polymer are noninferior to the current generation of those with a durable polymer. Late clinical benefit from a biodegradable polymer over a second-generation drug-eluting stent with a durable polymer remains elusive. The findings begs the public health question of whether paying a higher price for a biodegradable coronary stent with a durable-polymer is a good investment.

Mitchel L. Zoler/MDedge News
Dr. Sripal Bangalore

These 10-year results also highlight that, despite using drug-eluting stent technology that remains more or less standard of care today, the treated patients showed a staggering rate of major adverse cardiac events that exceeded 3% each year. This finding suggests an urgent need to address this residual risk through further improvements in medical therapy and stent technology.

Right now, accumulated evidence supports the notion that thinner struts are less thrombogenic than thicker struts, and that not all durable polymers are equal, with some associated with less inflammation and thrombogenicity. The next frontier for stent design seems to be ultrathin struts that are less than 70 mcm in diameter. We need to now see results from a study that compares an ultrathin-strut stent with a durable polymer against one with a biodegradable polymer.

Sripal Bangalore, MD , is an interventional cardiologist and professor of medicine at New York University. He has been a consultant or adviser to Abbott Vascular, Amgen, Biotronik, and Pfizer, and he has received research funding from Abbott Vascular. He made these comments as designated discussant for ISAR-TEST-4, and in an editorial published online concurrently with his talk (Circulation. 2018 Nov 11. doi: 10.1161/CIRCULATIONAHA.118.038378 ).

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The absence of incremental benefit from a stent with a biodegradable polymer compared with the second generation everolimus-eluting stent with a durable polymer in this 10-year follow-up is consistent with prior reports from medium-term follow-up. At best, drug-eluting coronary stents with a biodegradable polymer are noninferior to the current generation of those with a durable polymer. Late clinical benefit from a biodegradable polymer over a second-generation drug-eluting stent with a durable polymer remains elusive. The findings begs the public health question of whether paying a higher price for a biodegradable coronary stent with a durable-polymer is a good investment.

Mitchel L. Zoler/MDedge News
Dr. Sripal Bangalore

These 10-year results also highlight that, despite using drug-eluting stent technology that remains more or less standard of care today, the treated patients showed a staggering rate of major adverse cardiac events that exceeded 3% each year. This finding suggests an urgent need to address this residual risk through further improvements in medical therapy and stent technology.

Right now, accumulated evidence supports the notion that thinner struts are less thrombogenic than thicker struts, and that not all durable polymers are equal, with some associated with less inflammation and thrombogenicity. The next frontier for stent design seems to be ultrathin struts that are less than 70 mcm in diameter. We need to now see results from a study that compares an ultrathin-strut stent with a durable polymer against one with a biodegradable polymer.

Sripal Bangalore, MD , is an interventional cardiologist and professor of medicine at New York University. He has been a consultant or adviser to Abbott Vascular, Amgen, Biotronik, and Pfizer, and he has received research funding from Abbott Vascular. He made these comments as designated discussant for ISAR-TEST-4, and in an editorial published online concurrently with his talk (Circulation. 2018 Nov 11. doi: 10.1161/CIRCULATIONAHA.118.038378 ).

Body

The absence of incremental benefit from a stent with a biodegradable polymer compared with the second generation everolimus-eluting stent with a durable polymer in this 10-year follow-up is consistent with prior reports from medium-term follow-up. At best, drug-eluting coronary stents with a biodegradable polymer are noninferior to the current generation of those with a durable polymer. Late clinical benefit from a biodegradable polymer over a second-generation drug-eluting stent with a durable polymer remains elusive. The findings begs the public health question of whether paying a higher price for a biodegradable coronary stent with a durable-polymer is a good investment.

Mitchel L. Zoler/MDedge News
Dr. Sripal Bangalore

These 10-year results also highlight that, despite using drug-eluting stent technology that remains more or less standard of care today, the treated patients showed a staggering rate of major adverse cardiac events that exceeded 3% each year. This finding suggests an urgent need to address this residual risk through further improvements in medical therapy and stent technology.

Right now, accumulated evidence supports the notion that thinner struts are less thrombogenic than thicker struts, and that not all durable polymers are equal, with some associated with less inflammation and thrombogenicity. The next frontier for stent design seems to be ultrathin struts that are less than 70 mcm in diameter. We need to now see results from a study that compares an ultrathin-strut stent with a durable polymer against one with a biodegradable polymer.

Sripal Bangalore, MD , is an interventional cardiologist and professor of medicine at New York University. He has been a consultant or adviser to Abbott Vascular, Amgen, Biotronik, and Pfizer, and he has received research funding from Abbott Vascular. He made these comments as designated discussant for ISAR-TEST-4, and in an editorial published online concurrently with his talk (Circulation. 2018 Nov 11. doi: 10.1161/CIRCULATIONAHA.118.038378 ).

Title
Results question value of biodegradable polymers
Results question value of biodegradable polymers

– The idea behind putting a biodegradable polymer on a drug-eluting coronary stent is that, once the antirestenosis drug elutes and the polymer that held it degrades, the bare-metal stent left behind would trigger fewer long-term episodes of in-stent thrombosis than would stents that retain their polymer coating. But 10-year follow-up from a large trial that matched two second-generation drug-eluting stents, one with a biodegradable polymer and the other with a durable polymer, showed no statistically significant difference between the two for any clinical outcome, including the incidence of in-stent thrombosis, Sebastian Kufner, MD, said at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News
Dr. Sebastian Kufner

The potential advantage of a biodegradable polymer “is expected to occur over time,” and hence following patients for 10 or more years should start to show a clear advantage, at least for the endpoint of stent thrombosis, but that didn’t happen. After a median follow-up of 10.6 years, the cumulative rate of definite or probable stent thrombosis was 1.8% among 1,299 patients who received a sirolimus-eluting stent with a biodegradable polymer (Yukon Choice) and 2.5% among 652 patients who received a second-generation everolimus-eluting stent with a durable polymer (Xience), a difference that was not statistically significant, reported Dr. Kufner, a cardiologist at the The German Heart Centre in Munich.

These two stents also produced comparable 10-year outcomes that showed no statistically significant differences for the outcomes of all-cause death, MI, need for target-lesion revascularization, or the combined incidence of all three of these outcomes. In contrast, both of these second-generation stents showed statistically significant improvements in the combined cardiac endpoint, as well as in all-cause death, and definite stent thrombosis compared with the 652 patients who received the first-generation sirolimus-eluting stent Cypher. Concurrently with Dr. Kufner’s report, the results appeared in an article online (Circulation. 2018 Nov 11. doi: 10.1161/CIRCULATIONAHA.118.038065).


Another notable finding from the 10-year follow-up was the poor prognosis these patients faced after their interventions, including the patients who received second-generation drug-eluting stents. The 10-year rate of all cause death was 30% among patients who received Xience stents, 32% among those treated with Yukon Choice stents, and 37% among patients treated with Cypher stents.

“I’m daunted by this 10-year mortality rate even with the best current drug-eluting stents,” said Roxana Mehran, MD, professor of medicine at Icahn School of Medicine at Mount Sinai in New York and a cochair of the session. “I’m depressed about this as an interventionalist. We need to do better, although it might not just be about the revascularization.” The high mortality in these patients after 10 years may also reflect a lack of optimal medical treatment in some, she suggested.

Dr. Roxana Mehran


The ISAR-TEST-4 (Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents) trial randomized 2,603 patients during the period of September 2007–August 2008 at either of two centers in Munich. The study’s primary endpoint was the combined rate of cardiac death, MI, and target-lesion revascularization by 12 months after treatment. The 12-month results showed a similar 14% rate of this combined endpoint in the subgroup of patients treated with the biodegradable-polymer stent and in those treated with stents that used durable polymers, which proved the noninferiority of the stent with a biodegradable polymer (Eur Heart J. 2009 Oct 1;30[20]:2441-9). This initial analysis combined the patients who received Cypher and Xience stents into one comparator group: patients who received stents with durable polymers.

The new, long-term follow-up analysis included 2,153 patients (83%) followed for at least 10 years after their intervention.

ISAR-TEST-4 received no commercial funding. Dr. Kufner had no disclosures. Dr. Mehran has an ownership interest in Claret Medical and Elixir Medical, has been a consultant or adviser to Abbott Laboratories, Boston Scientific, Bristol-Myers Squibb, Janssen, Roivant Sciences, and Siemens Medical Solutions, and has received research funding from several companies.

SOURCE: Kufner S et al. AHA scientific sessions, Abstract 18630.

– The idea behind putting a biodegradable polymer on a drug-eluting coronary stent is that, once the antirestenosis drug elutes and the polymer that held it degrades, the bare-metal stent left behind would trigger fewer long-term episodes of in-stent thrombosis than would stents that retain their polymer coating. But 10-year follow-up from a large trial that matched two second-generation drug-eluting stents, one with a biodegradable polymer and the other with a durable polymer, showed no statistically significant difference between the two for any clinical outcome, including the incidence of in-stent thrombosis, Sebastian Kufner, MD, said at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News
Dr. Sebastian Kufner

The potential advantage of a biodegradable polymer “is expected to occur over time,” and hence following patients for 10 or more years should start to show a clear advantage, at least for the endpoint of stent thrombosis, but that didn’t happen. After a median follow-up of 10.6 years, the cumulative rate of definite or probable stent thrombosis was 1.8% among 1,299 patients who received a sirolimus-eluting stent with a biodegradable polymer (Yukon Choice) and 2.5% among 652 patients who received a second-generation everolimus-eluting stent with a durable polymer (Xience), a difference that was not statistically significant, reported Dr. Kufner, a cardiologist at the The German Heart Centre in Munich.

These two stents also produced comparable 10-year outcomes that showed no statistically significant differences for the outcomes of all-cause death, MI, need for target-lesion revascularization, or the combined incidence of all three of these outcomes. In contrast, both of these second-generation stents showed statistically significant improvements in the combined cardiac endpoint, as well as in all-cause death, and definite stent thrombosis compared with the 652 patients who received the first-generation sirolimus-eluting stent Cypher. Concurrently with Dr. Kufner’s report, the results appeared in an article online (Circulation. 2018 Nov 11. doi: 10.1161/CIRCULATIONAHA.118.038065).


Another notable finding from the 10-year follow-up was the poor prognosis these patients faced after their interventions, including the patients who received second-generation drug-eluting stents. The 10-year rate of all cause death was 30% among patients who received Xience stents, 32% among those treated with Yukon Choice stents, and 37% among patients treated with Cypher stents.

“I’m daunted by this 10-year mortality rate even with the best current drug-eluting stents,” said Roxana Mehran, MD, professor of medicine at Icahn School of Medicine at Mount Sinai in New York and a cochair of the session. “I’m depressed about this as an interventionalist. We need to do better, although it might not just be about the revascularization.” The high mortality in these patients after 10 years may also reflect a lack of optimal medical treatment in some, she suggested.

Dr. Roxana Mehran


The ISAR-TEST-4 (Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents) trial randomized 2,603 patients during the period of September 2007–August 2008 at either of two centers in Munich. The study’s primary endpoint was the combined rate of cardiac death, MI, and target-lesion revascularization by 12 months after treatment. The 12-month results showed a similar 14% rate of this combined endpoint in the subgroup of patients treated with the biodegradable-polymer stent and in those treated with stents that used durable polymers, which proved the noninferiority of the stent with a biodegradable polymer (Eur Heart J. 2009 Oct 1;30[20]:2441-9). This initial analysis combined the patients who received Cypher and Xience stents into one comparator group: patients who received stents with durable polymers.

The new, long-term follow-up analysis included 2,153 patients (83%) followed for at least 10 years after their intervention.

ISAR-TEST-4 received no commercial funding. Dr. Kufner had no disclosures. Dr. Mehran has an ownership interest in Claret Medical and Elixir Medical, has been a consultant or adviser to Abbott Laboratories, Boston Scientific, Bristol-Myers Squibb, Janssen, Roivant Sciences, and Siemens Medical Solutions, and has received research funding from several companies.

SOURCE: Kufner S et al. AHA scientific sessions, Abstract 18630.

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Key clinical point: Second-generation coronary stents had similar long-term performance regardless of whether their polymer was durable or biodegradable.

Major finding: The rate of adverse cardiac events was 48% with a biodegradable-polymer stent and 46% with a durable polymer.

Study details: Long-term follow-up of 2,153 patients in the ISAR-TEST-4 trial.

Disclosures: ISAR-TEST-4 received no commercial funding. Dr. Kufner had no disclosures. Dr. Mehran has an ownership interest in Claret Medical and Elixir Medical, has been a consultant or adviser to Abbott Laboratories, Boston Scientific, Bristol-Myers Squibb, Janssen, Roivant Sciences, and Siemens Medical Solutions, and has received research funding from several companies.

Source: Kufner S et al. AHA 2018, Abstract 18630.

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New diabetes drugs solidify their cardiovascular and renal benefits

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– When the first results from a large trial that showed profound and unexpected benefits for preventing heart failure hospitalizations associated with use of the antihyperglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin came out – a little over 3 years ago – the general reaction from clinicians was some variant of “Could this be real?”

Dr. Eugene Braunwald

Since then, as results from some five other large, international trials have come out showing both similar benefits from two other drugs in the same SGLT2 inhibitor class, canagliflozin and dapagliflozin, as well as results showing clear cardiovascular disease benefits from three drugs in a second class of antihyperglycemics, the glucagonlike peptide–1 receptor agonists (GLP-1 RAs), the general consensus among cardiologists became: “The cardiovascular and renal benefits are real. How can we now best use these drugs to help patients?”

This change increasingly forces cardiologists, as well as the primary care physicians who often manage patients with type 2 diabetes mellitus, to become more comfortable prescribing these two classes of antihyperglycemic drugs. During a talk at the American Heart Association scientific sessions, Eugene Braunwald, MD, arguably the top thought leader in cardiology, coined a new name for the medical subspecialty that he foresees navigating this overlap between diabetes care and cardiovascular disease prevention: diabetocardiology (although a more euphonic alternative might be cardiodiabetology, while the more comprehensive name could be cardionephrodiabetology).

“I was certainly surprised” by the first report in 2015 from the EMPA-REG OUTCOME trial (N Engl J Med. 2015 Nov 26;373[22]:2117-28), said Dr. Braunwald, who is professor of medicine at Harvard Medical School in Boston. A lot of his colleagues were surprised and said, “It’s just one trial.”

“Now we have three trials,” with the addition of the CANVAS trial for canagliflozin (N Engl J Med. 2017 Aug 17;377[7]:644-57) and the DECLARE-TIMI 58 trial (N Engl J Med. 2018 Nov 10. doi:10.1056/NEJMoa1812389) for dapagliflozin reported at the AHA meeting in November.

“We are in the midst of two pandemics: heart failure and type 2 diabetes. As cardiologists, we have to learn how to deal with this,” said Dr. Braunwald, and the evidence now clearly shows that these drugs can help with that.

Mitchel L. Zoler/MDedge News
Dr. Javed Butler

As another speaker at the meeting, Javed Butler, MD, a heart failure specialist, observed in a separate talk at the meeting, “Heart failure is one of the most common, if not the most common complication, of patients with diabetes.” This tight link between heart failure and diabetes helps make cardiovascular mortality “the number one cause of death” in patients with diabetes, said Dr. Butler, professor and chairman of medicine at the University of Mississippi in Jackson.

“Thanks to the cardiovascular outcome trials, we now have a much broader and deeper appreciation of heart failure and renal disease as integral components of the cardiovascular-renal spectrum in people with diabetes,” said Subodh Verma, MD, a professor at the University of Toronto and cardiac surgeon at St. Michael’s Hospital in Toronto. Dr. Braunwald spelled out in his talk some of the interrelationships of diabetes, heart failure, and renal dysfunction that together produce a downward-spiraling vicious circle for patients, a pathophysiological process that clinicians can now short-circuit by treatment with a SGLT2 inhibitor.
 

 

 

Cardiovascular outcome trials show the way

Mitchel L. Zoler/MDedge News
Dr. Subodh Verma

In the context of antihyperglycemic drugs, the “cardiovascular outcome trials” refers to a series of large trials mandated by the Food and Drug Administration in 2008 to assess the cardiovascular disease effects of new agents coming onto the U.S. market to treat type 2 diabetes mellitus (T2DM). By the time Dr. Verma spoke at the AHA meeting, he could cite reported results from 12 of these trials: 5 different drugs in the GLP-1 RA class, 4 drugs in the dipeptidyl peptidase-4 (DPP-4) inhibitor class, and 3 drugs from the SGLT2 inhibitor class. Dr. Verma summed what the findings have shown.

The four tested DDP-4 inhibitors (alogliptin, linagliptin, saxagliptin, and sitagliptin) consistently showed neutrality for the primary outcome of major adverse cardiovascular disease events (MACE), constituted by cardiovascular disease death, MI, or stroke.

The five tested GLP-1 RAs (albiglutide, exenatide, liraglutide, lixisenatide, and semaglutide) showed a mixed pattern of MACE results that seemed to be linked with the subclass the drug fell into. The two exedin-4–based drugs, exenatide and lixisenatide, each showed a statistically neutral effect for MACE, as well as collectively in a combined analysis. In contrast, three human GLP-1–based drugs, albiglutide, liraglutide, and semaglutide, each showed a consistent, statistically-significant MACE reduction in their respective outcome trials, and collectively they showed a highly significant 18% reduction in MACE, compared with placebo, Dr. Verma said. Further, recent analysis by Dr. Verma that used data from liraglutide treatment in the LEADER trial showed the MACE benefit occurred only among enrolled patients treated with liraglutide who had established atherosclerotic cardiovascular disease (ASCVD). Patients enrolled in the trial with only multiple risk factors (in addition to having T2DM) but without established ASCVD showed no significant benefit from liraglutide treatment for the MACE endpoint, compared with control patients.

Recently a press-release announcement of results from a sixth GLP-1 RA, dulaglutide, in the REWIND trial of MACE outcomes suggested that a drug in this class could have broader effect. The majority, 69%, of the 9,901 patients with T2DM enrolled in REWIND had risk factors but not established ASCVD at enrollment. A Nov. 5, 2018, statement from the company developing this drug, Lilly, reported that the study overall produced a statistically significant reduction in MACE, although it provided no additional details. As the released noted, this made REWIND the first trial to show a MACE benefit from a drug in the GLP-1 RA class in patients without established ASCVD.



The MACE outcome results from the three SGLT2 inhibitor trials showed a similar pattern as liraglutide: In patients with established ASCVD, the drugs individually each produced a MACE reduction, although dapagliflozin just missed having a statistically significant reduction. Collectively, the three drugs showed a statistically significant, 14% relative risk reduction for MACE, compared with control patients. But among patients with multiple risk factors only, but without established ASCVD, included in two of the three trials (CANVAS and DECLARE-TIMI 58), the results showed both individually and collectively a neutral MACE effect.

But unlike the other antihyperglycemic drugs tested in the cardiovascular outcome trials, the SGLT2 inhibitors have shown two additional, highly important secondary outcomes: a consistent reduction in hospitalization for heart failure and a consistent reduction in renal-disease progression.

A meta-analysis of the three SGLT2 inhibitor trials published coincident with the release of the DECLARE-TIMI 58 results showed that, for the outcome of either cardiovascular death or hospitalization for heart failure, the SGLT2 inhibitors collectively showed a significant 29% relative decrease in this incidence among patients with a history of heart failure, and a significant 21% relative decrease among patients without history of heart failure (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32590-X). Among the subset of patients with established ASCVD, treatment with a SGLT2 inhibitor across all three trials showed a significant 16% relative risk reduction, and in the subset with multiple risk factors but no established ASCVD, the two SGLT2 inhibitors collectively produced a 16% relative cut in cardiovascular death or heart failure hospitalization with a P value of .06. Finally, the Lancet meta-analysis showed that, for a combined endpoint that reflected renal worsening, the SGLT2 inhibitors showed a significant relative reduction of about 45% in both the subgroup of patients with established ASCVD and in the subgroup of those with just risk factors.

“This is a big step forward for patients with multiple risk factors and diabetes but without ASCVD, that both renal disease and hospitalization for heart failure are sensitive” to the SGLT2 inhibitors, Dr. Verma noted. “We see renal protection and reduction of heart failure hospitalization across both primary and secondary prevention patients, with no need to distinguish them based on ASCVD.” In contrast, he noted, the MACE benefit from the SGLT2 inhibitors seems limited to patients with ASCVD. The day before making this point in a talk during the meeting, Dr. Verma had published the same message in a commentary (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32824-1).

Although the “nomenclature of primary versus secondary prevention is appropriate for atherosclerotic outcomes, it is likely to be inappropriate for a person with type 2 diabetes who is at risk of hospitalization for heart failure and renal disease,” Dr. Verma wrote with his associates in the commentary.

 

 

What it means for clinicians

The upshot of all of these cardiovascular outcome trial results that came out over the past 3 years has been a new appreciation of how antihyperglycemic drugs can have cardiovascular and renal benefits that transcend their effects on glycemia. The evidence has put the SGLT2 inhibitors and GLP-1 RAs on track to challenge, and potentially displace, metformin as the top drug to prescribe for patients with T2DM.

Clinicians should realize that they should prescribe SGLT2 inhibitors and selected GLP-1 RAs “as early as metformin in patients with established ASCVD,” said Dr. Verma. “For patients with recalcitrant atherosclerotic disease and a history of MI and ischemia, I’d primarily treat with a GLP-1 RA. In a patient with left ventricular dysfunction or evidence of heart failure, I’d use an SGLT2 inhibitor. But it’s not a fight between these two. You could treat a patients with type 2 diabetes with both classes,” although the practicality of this approach is limited by the high cost of these drugs.

The SGLT2 inhibitors “should now be considered as first-line therapy after metformin in most people with type 2 diabetes, irrespective of whether or not they have established atherosclerotic vascular disease, chronic kidney disease, or heart failure,” he and his associates wrote in their recent commentary.

“What I struggle with the most is how we prioritize and individualize secondary-prevention therapies based on risk for ischemia and heart failure. Some therapies [the SGLT2 inhibitors] are predominantly for heart failure prevention, and some [the GLP-1 RAs] are primarily for ischemia. How do we choose when a patient cannot afford to take both? Does a combination of a SGLT2 inhibitor and a GLP-1 RA offer the greatest CVD benefit? We need to test this in a trial. And will metformin be displaced as first-line treatment?” Dr. Verma asked.

Mitchel L. Zoler/MDedge News
Dr. John McMurray

“The day will probably come when, for maximal protection, you treat with both classes. But right now we’re forced to choose because of the cost,” said John McMurray, MD, professor of cardiology at the University of Glasgow, in a talk during the meeting.

As to specifically which SGLT2 inhibitor to prescribe, “they all look pretty much the same” in the newly published meta-analysis, Dr. McMurray said, although he noted that safety differences among agents in the class remain possible.

“For patients similar to those studied in the three SGLT2 inhibitor trials, clinicians should use one of these drugs to reduce the risk for incident heart failure, irrespective of their effect on MACE,” said Dr. Butler. Reducing the risk for incident heart failure and of progressive renal dysfunction are two new goals for antihyperglycemic therapy that now overlay the long-standing goals of controlling glycemia and reducing cardiovascular disease risk and the more recent goals of cutting cardiovascular disease mortality and cutting the risk for a MACE event.

A current limitation for practice is that the none of the three drug companies that market the tested SGLT2 inhibitor drugs has sought regulatory approval for an indication of reducing the risk for heart failure hospitalization. Despite that, “these drugs should be used for renal protection and reducing heart failure hospitalizations,” Dr. Butler said. “We need to start thinking about this and not get lost thinking about only their MACE effect because, when you focus on MACE, there is a competition between the SGLT2 inhibitors and the GLP-1 RA. If we think of GLP-1 RAs as drugs to prevent MACE, and SGLT2 inhibitors as drugs that primarily prevent heart failure and renal dysfunction, then there is no competition. Perhaps combined treatment is where we need to go,” he said in an interview.

But the enthusiasm that experts like Dr. Butler, Dr. McMurray, and Dr. Verma have for wider use of both classes of drugs in appropriate patients is not necessarily matched right now among many community physicians. Cardiologist David J. Becker, MD, is an example of the clinicians who appreciate the growing evidence that supports wider use of these antihyperglycemic drugs but remain uneasy about applying this evidence in their practice.

Dr. David J.Becker

Dr. Becker, associate director of the Preventive and Integrative Heart Health Program of the Temple Heart and Vascular Institute in Philadelphia, writes a column for the Philadelphia Inquirer on medical care. In a December 2018 piece, he said “like most cardiologists, I ‘don’t do diabetes’ – because it’s not my expertise. The new drugs, however, mean I need to learn more” about treating these patients. “The problem: There are so many of these medications that they present a bewildering choice for patients and doctors.”

Dr. Becker cited several barriers he sees for himself and his nonendocrinologist colleagues to prescribe these drugs – and for patients to take them:

 

 

  • High cost, with prices that run close to $20/day for each medication.
  • A thicket of names and choices that “lead to confusion and paralysis,” which has been exacerbated by “advertising wars” among competing drug companies.
  • Cardiologists and primary care physicians usually defer to endocrinologists to prescribe these drugs, but most patients with T2DM aren’t seen by endocrinologists. The result: “Few doctors prescribe them.”

The cardiovascular disease benefits of these drugs have not been adequately promoted. Until that changes, “cardiologists like me will not realize their importance,” Dr. Becker concluded.

While christening the new diabetocardiology subspecialty, Dr. Braunwald placed the onus for managing this emerging facet of diabetes largely outside the scope of endocrinology.

“We can’t call in a consultant every time we have a patient with diabetes; it would bankrupt the system,” he said. Training of cardiologists now needs to include several months of treating patients with diabetes, Dr. Braunwald advised, just like 30 or so years ago when cardiologists like himself had to become more familiar with blood clotting to better manage thrombotic disease.

Dr. Braunwald has been a consultant to Cardurion, Myokardia, and Sanofi; an advisor to Endcardia; and has received research funding from AstraZeneca, Daiishi Sankyo, and Novartis. Dr. Butler has been a consultant or advisor to AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi. Dr. Verma has received honoraria and research funding from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, NovoNordisk, Sanofi, and Valeant. Dr. McMurray has received research funding from 12 companies. Dr. Becker had no disclosures.

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– When the first results from a large trial that showed profound and unexpected benefits for preventing heart failure hospitalizations associated with use of the antihyperglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin came out – a little over 3 years ago – the general reaction from clinicians was some variant of “Could this be real?”

Dr. Eugene Braunwald

Since then, as results from some five other large, international trials have come out showing both similar benefits from two other drugs in the same SGLT2 inhibitor class, canagliflozin and dapagliflozin, as well as results showing clear cardiovascular disease benefits from three drugs in a second class of antihyperglycemics, the glucagonlike peptide–1 receptor agonists (GLP-1 RAs), the general consensus among cardiologists became: “The cardiovascular and renal benefits are real. How can we now best use these drugs to help patients?”

This change increasingly forces cardiologists, as well as the primary care physicians who often manage patients with type 2 diabetes mellitus, to become more comfortable prescribing these two classes of antihyperglycemic drugs. During a talk at the American Heart Association scientific sessions, Eugene Braunwald, MD, arguably the top thought leader in cardiology, coined a new name for the medical subspecialty that he foresees navigating this overlap between diabetes care and cardiovascular disease prevention: diabetocardiology (although a more euphonic alternative might be cardiodiabetology, while the more comprehensive name could be cardionephrodiabetology).

“I was certainly surprised” by the first report in 2015 from the EMPA-REG OUTCOME trial (N Engl J Med. 2015 Nov 26;373[22]:2117-28), said Dr. Braunwald, who is professor of medicine at Harvard Medical School in Boston. A lot of his colleagues were surprised and said, “It’s just one trial.”

“Now we have three trials,” with the addition of the CANVAS trial for canagliflozin (N Engl J Med. 2017 Aug 17;377[7]:644-57) and the DECLARE-TIMI 58 trial (N Engl J Med. 2018 Nov 10. doi:10.1056/NEJMoa1812389) for dapagliflozin reported at the AHA meeting in November.

“We are in the midst of two pandemics: heart failure and type 2 diabetes. As cardiologists, we have to learn how to deal with this,” said Dr. Braunwald, and the evidence now clearly shows that these drugs can help with that.

Mitchel L. Zoler/MDedge News
Dr. Javed Butler

As another speaker at the meeting, Javed Butler, MD, a heart failure specialist, observed in a separate talk at the meeting, “Heart failure is one of the most common, if not the most common complication, of patients with diabetes.” This tight link between heart failure and diabetes helps make cardiovascular mortality “the number one cause of death” in patients with diabetes, said Dr. Butler, professor and chairman of medicine at the University of Mississippi in Jackson.

“Thanks to the cardiovascular outcome trials, we now have a much broader and deeper appreciation of heart failure and renal disease as integral components of the cardiovascular-renal spectrum in people with diabetes,” said Subodh Verma, MD, a professor at the University of Toronto and cardiac surgeon at St. Michael’s Hospital in Toronto. Dr. Braunwald spelled out in his talk some of the interrelationships of diabetes, heart failure, and renal dysfunction that together produce a downward-spiraling vicious circle for patients, a pathophysiological process that clinicians can now short-circuit by treatment with a SGLT2 inhibitor.
 

 

 

Cardiovascular outcome trials show the way

Mitchel L. Zoler/MDedge News
Dr. Subodh Verma

In the context of antihyperglycemic drugs, the “cardiovascular outcome trials” refers to a series of large trials mandated by the Food and Drug Administration in 2008 to assess the cardiovascular disease effects of new agents coming onto the U.S. market to treat type 2 diabetes mellitus (T2DM). By the time Dr. Verma spoke at the AHA meeting, he could cite reported results from 12 of these trials: 5 different drugs in the GLP-1 RA class, 4 drugs in the dipeptidyl peptidase-4 (DPP-4) inhibitor class, and 3 drugs from the SGLT2 inhibitor class. Dr. Verma summed what the findings have shown.

The four tested DDP-4 inhibitors (alogliptin, linagliptin, saxagliptin, and sitagliptin) consistently showed neutrality for the primary outcome of major adverse cardiovascular disease events (MACE), constituted by cardiovascular disease death, MI, or stroke.

The five tested GLP-1 RAs (albiglutide, exenatide, liraglutide, lixisenatide, and semaglutide) showed a mixed pattern of MACE results that seemed to be linked with the subclass the drug fell into. The two exedin-4–based drugs, exenatide and lixisenatide, each showed a statistically neutral effect for MACE, as well as collectively in a combined analysis. In contrast, three human GLP-1–based drugs, albiglutide, liraglutide, and semaglutide, each showed a consistent, statistically-significant MACE reduction in their respective outcome trials, and collectively they showed a highly significant 18% reduction in MACE, compared with placebo, Dr. Verma said. Further, recent analysis by Dr. Verma that used data from liraglutide treatment in the LEADER trial showed the MACE benefit occurred only among enrolled patients treated with liraglutide who had established atherosclerotic cardiovascular disease (ASCVD). Patients enrolled in the trial with only multiple risk factors (in addition to having T2DM) but without established ASCVD showed no significant benefit from liraglutide treatment for the MACE endpoint, compared with control patients.

Recently a press-release announcement of results from a sixth GLP-1 RA, dulaglutide, in the REWIND trial of MACE outcomes suggested that a drug in this class could have broader effect. The majority, 69%, of the 9,901 patients with T2DM enrolled in REWIND had risk factors but not established ASCVD at enrollment. A Nov. 5, 2018, statement from the company developing this drug, Lilly, reported that the study overall produced a statistically significant reduction in MACE, although it provided no additional details. As the released noted, this made REWIND the first trial to show a MACE benefit from a drug in the GLP-1 RA class in patients without established ASCVD.



The MACE outcome results from the three SGLT2 inhibitor trials showed a similar pattern as liraglutide: In patients with established ASCVD, the drugs individually each produced a MACE reduction, although dapagliflozin just missed having a statistically significant reduction. Collectively, the three drugs showed a statistically significant, 14% relative risk reduction for MACE, compared with control patients. But among patients with multiple risk factors only, but without established ASCVD, included in two of the three trials (CANVAS and DECLARE-TIMI 58), the results showed both individually and collectively a neutral MACE effect.

But unlike the other antihyperglycemic drugs tested in the cardiovascular outcome trials, the SGLT2 inhibitors have shown two additional, highly important secondary outcomes: a consistent reduction in hospitalization for heart failure and a consistent reduction in renal-disease progression.

A meta-analysis of the three SGLT2 inhibitor trials published coincident with the release of the DECLARE-TIMI 58 results showed that, for the outcome of either cardiovascular death or hospitalization for heart failure, the SGLT2 inhibitors collectively showed a significant 29% relative decrease in this incidence among patients with a history of heart failure, and a significant 21% relative decrease among patients without history of heart failure (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32590-X). Among the subset of patients with established ASCVD, treatment with a SGLT2 inhibitor across all three trials showed a significant 16% relative risk reduction, and in the subset with multiple risk factors but no established ASCVD, the two SGLT2 inhibitors collectively produced a 16% relative cut in cardiovascular death or heart failure hospitalization with a P value of .06. Finally, the Lancet meta-analysis showed that, for a combined endpoint that reflected renal worsening, the SGLT2 inhibitors showed a significant relative reduction of about 45% in both the subgroup of patients with established ASCVD and in the subgroup of those with just risk factors.

“This is a big step forward for patients with multiple risk factors and diabetes but without ASCVD, that both renal disease and hospitalization for heart failure are sensitive” to the SGLT2 inhibitors, Dr. Verma noted. “We see renal protection and reduction of heart failure hospitalization across both primary and secondary prevention patients, with no need to distinguish them based on ASCVD.” In contrast, he noted, the MACE benefit from the SGLT2 inhibitors seems limited to patients with ASCVD. The day before making this point in a talk during the meeting, Dr. Verma had published the same message in a commentary (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32824-1).

Although the “nomenclature of primary versus secondary prevention is appropriate for atherosclerotic outcomes, it is likely to be inappropriate for a person with type 2 diabetes who is at risk of hospitalization for heart failure and renal disease,” Dr. Verma wrote with his associates in the commentary.

 

 

What it means for clinicians

The upshot of all of these cardiovascular outcome trial results that came out over the past 3 years has been a new appreciation of how antihyperglycemic drugs can have cardiovascular and renal benefits that transcend their effects on glycemia. The evidence has put the SGLT2 inhibitors and GLP-1 RAs on track to challenge, and potentially displace, metformin as the top drug to prescribe for patients with T2DM.

Clinicians should realize that they should prescribe SGLT2 inhibitors and selected GLP-1 RAs “as early as metformin in patients with established ASCVD,” said Dr. Verma. “For patients with recalcitrant atherosclerotic disease and a history of MI and ischemia, I’d primarily treat with a GLP-1 RA. In a patient with left ventricular dysfunction or evidence of heart failure, I’d use an SGLT2 inhibitor. But it’s not a fight between these two. You could treat a patients with type 2 diabetes with both classes,” although the practicality of this approach is limited by the high cost of these drugs.

The SGLT2 inhibitors “should now be considered as first-line therapy after metformin in most people with type 2 diabetes, irrespective of whether or not they have established atherosclerotic vascular disease, chronic kidney disease, or heart failure,” he and his associates wrote in their recent commentary.

“What I struggle with the most is how we prioritize and individualize secondary-prevention therapies based on risk for ischemia and heart failure. Some therapies [the SGLT2 inhibitors] are predominantly for heart failure prevention, and some [the GLP-1 RAs] are primarily for ischemia. How do we choose when a patient cannot afford to take both? Does a combination of a SGLT2 inhibitor and a GLP-1 RA offer the greatest CVD benefit? We need to test this in a trial. And will metformin be displaced as first-line treatment?” Dr. Verma asked.

Mitchel L. Zoler/MDedge News
Dr. John McMurray

“The day will probably come when, for maximal protection, you treat with both classes. But right now we’re forced to choose because of the cost,” said John McMurray, MD, professor of cardiology at the University of Glasgow, in a talk during the meeting.

As to specifically which SGLT2 inhibitor to prescribe, “they all look pretty much the same” in the newly published meta-analysis, Dr. McMurray said, although he noted that safety differences among agents in the class remain possible.

“For patients similar to those studied in the three SGLT2 inhibitor trials, clinicians should use one of these drugs to reduce the risk for incident heart failure, irrespective of their effect on MACE,” said Dr. Butler. Reducing the risk for incident heart failure and of progressive renal dysfunction are two new goals for antihyperglycemic therapy that now overlay the long-standing goals of controlling glycemia and reducing cardiovascular disease risk and the more recent goals of cutting cardiovascular disease mortality and cutting the risk for a MACE event.

A current limitation for practice is that the none of the three drug companies that market the tested SGLT2 inhibitor drugs has sought regulatory approval for an indication of reducing the risk for heart failure hospitalization. Despite that, “these drugs should be used for renal protection and reducing heart failure hospitalizations,” Dr. Butler said. “We need to start thinking about this and not get lost thinking about only their MACE effect because, when you focus on MACE, there is a competition between the SGLT2 inhibitors and the GLP-1 RA. If we think of GLP-1 RAs as drugs to prevent MACE, and SGLT2 inhibitors as drugs that primarily prevent heart failure and renal dysfunction, then there is no competition. Perhaps combined treatment is where we need to go,” he said in an interview.

But the enthusiasm that experts like Dr. Butler, Dr. McMurray, and Dr. Verma have for wider use of both classes of drugs in appropriate patients is not necessarily matched right now among many community physicians. Cardiologist David J. Becker, MD, is an example of the clinicians who appreciate the growing evidence that supports wider use of these antihyperglycemic drugs but remain uneasy about applying this evidence in their practice.

Dr. David J.Becker

Dr. Becker, associate director of the Preventive and Integrative Heart Health Program of the Temple Heart and Vascular Institute in Philadelphia, writes a column for the Philadelphia Inquirer on medical care. In a December 2018 piece, he said “like most cardiologists, I ‘don’t do diabetes’ – because it’s not my expertise. The new drugs, however, mean I need to learn more” about treating these patients. “The problem: There are so many of these medications that they present a bewildering choice for patients and doctors.”

Dr. Becker cited several barriers he sees for himself and his nonendocrinologist colleagues to prescribe these drugs – and for patients to take them:

 

 

  • High cost, with prices that run close to $20/day for each medication.
  • A thicket of names and choices that “lead to confusion and paralysis,” which has been exacerbated by “advertising wars” among competing drug companies.
  • Cardiologists and primary care physicians usually defer to endocrinologists to prescribe these drugs, but most patients with T2DM aren’t seen by endocrinologists. The result: “Few doctors prescribe them.”

The cardiovascular disease benefits of these drugs have not been adequately promoted. Until that changes, “cardiologists like me will not realize their importance,” Dr. Becker concluded.

While christening the new diabetocardiology subspecialty, Dr. Braunwald placed the onus for managing this emerging facet of diabetes largely outside the scope of endocrinology.

“We can’t call in a consultant every time we have a patient with diabetes; it would bankrupt the system,” he said. Training of cardiologists now needs to include several months of treating patients with diabetes, Dr. Braunwald advised, just like 30 or so years ago when cardiologists like himself had to become more familiar with blood clotting to better manage thrombotic disease.

Dr. Braunwald has been a consultant to Cardurion, Myokardia, and Sanofi; an advisor to Endcardia; and has received research funding from AstraZeneca, Daiishi Sankyo, and Novartis. Dr. Butler has been a consultant or advisor to AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi. Dr. Verma has received honoraria and research funding from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, NovoNordisk, Sanofi, and Valeant. Dr. McMurray has received research funding from 12 companies. Dr. Becker had no disclosures.

 

– When the first results from a large trial that showed profound and unexpected benefits for preventing heart failure hospitalizations associated with use of the antihyperglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin came out – a little over 3 years ago – the general reaction from clinicians was some variant of “Could this be real?”

Dr. Eugene Braunwald

Since then, as results from some five other large, international trials have come out showing both similar benefits from two other drugs in the same SGLT2 inhibitor class, canagliflozin and dapagliflozin, as well as results showing clear cardiovascular disease benefits from three drugs in a second class of antihyperglycemics, the glucagonlike peptide–1 receptor agonists (GLP-1 RAs), the general consensus among cardiologists became: “The cardiovascular and renal benefits are real. How can we now best use these drugs to help patients?”

This change increasingly forces cardiologists, as well as the primary care physicians who often manage patients with type 2 diabetes mellitus, to become more comfortable prescribing these two classes of antihyperglycemic drugs. During a talk at the American Heart Association scientific sessions, Eugene Braunwald, MD, arguably the top thought leader in cardiology, coined a new name for the medical subspecialty that he foresees navigating this overlap between diabetes care and cardiovascular disease prevention: diabetocardiology (although a more euphonic alternative might be cardiodiabetology, while the more comprehensive name could be cardionephrodiabetology).

“I was certainly surprised” by the first report in 2015 from the EMPA-REG OUTCOME trial (N Engl J Med. 2015 Nov 26;373[22]:2117-28), said Dr. Braunwald, who is professor of medicine at Harvard Medical School in Boston. A lot of his colleagues were surprised and said, “It’s just one trial.”

“Now we have three trials,” with the addition of the CANVAS trial for canagliflozin (N Engl J Med. 2017 Aug 17;377[7]:644-57) and the DECLARE-TIMI 58 trial (N Engl J Med. 2018 Nov 10. doi:10.1056/NEJMoa1812389) for dapagliflozin reported at the AHA meeting in November.

“We are in the midst of two pandemics: heart failure and type 2 diabetes. As cardiologists, we have to learn how to deal with this,” said Dr. Braunwald, and the evidence now clearly shows that these drugs can help with that.

Mitchel L. Zoler/MDedge News
Dr. Javed Butler

As another speaker at the meeting, Javed Butler, MD, a heart failure specialist, observed in a separate talk at the meeting, “Heart failure is one of the most common, if not the most common complication, of patients with diabetes.” This tight link between heart failure and diabetes helps make cardiovascular mortality “the number one cause of death” in patients with diabetes, said Dr. Butler, professor and chairman of medicine at the University of Mississippi in Jackson.

“Thanks to the cardiovascular outcome trials, we now have a much broader and deeper appreciation of heart failure and renal disease as integral components of the cardiovascular-renal spectrum in people with diabetes,” said Subodh Verma, MD, a professor at the University of Toronto and cardiac surgeon at St. Michael’s Hospital in Toronto. Dr. Braunwald spelled out in his talk some of the interrelationships of diabetes, heart failure, and renal dysfunction that together produce a downward-spiraling vicious circle for patients, a pathophysiological process that clinicians can now short-circuit by treatment with a SGLT2 inhibitor.
 

 

 

Cardiovascular outcome trials show the way

Mitchel L. Zoler/MDedge News
Dr. Subodh Verma

In the context of antihyperglycemic drugs, the “cardiovascular outcome trials” refers to a series of large trials mandated by the Food and Drug Administration in 2008 to assess the cardiovascular disease effects of new agents coming onto the U.S. market to treat type 2 diabetes mellitus (T2DM). By the time Dr. Verma spoke at the AHA meeting, he could cite reported results from 12 of these trials: 5 different drugs in the GLP-1 RA class, 4 drugs in the dipeptidyl peptidase-4 (DPP-4) inhibitor class, and 3 drugs from the SGLT2 inhibitor class. Dr. Verma summed what the findings have shown.

The four tested DDP-4 inhibitors (alogliptin, linagliptin, saxagliptin, and sitagliptin) consistently showed neutrality for the primary outcome of major adverse cardiovascular disease events (MACE), constituted by cardiovascular disease death, MI, or stroke.

The five tested GLP-1 RAs (albiglutide, exenatide, liraglutide, lixisenatide, and semaglutide) showed a mixed pattern of MACE results that seemed to be linked with the subclass the drug fell into. The two exedin-4–based drugs, exenatide and lixisenatide, each showed a statistically neutral effect for MACE, as well as collectively in a combined analysis. In contrast, three human GLP-1–based drugs, albiglutide, liraglutide, and semaglutide, each showed a consistent, statistically-significant MACE reduction in their respective outcome trials, and collectively they showed a highly significant 18% reduction in MACE, compared with placebo, Dr. Verma said. Further, recent analysis by Dr. Verma that used data from liraglutide treatment in the LEADER trial showed the MACE benefit occurred only among enrolled patients treated with liraglutide who had established atherosclerotic cardiovascular disease (ASCVD). Patients enrolled in the trial with only multiple risk factors (in addition to having T2DM) but without established ASCVD showed no significant benefit from liraglutide treatment for the MACE endpoint, compared with control patients.

Recently a press-release announcement of results from a sixth GLP-1 RA, dulaglutide, in the REWIND trial of MACE outcomes suggested that a drug in this class could have broader effect. The majority, 69%, of the 9,901 patients with T2DM enrolled in REWIND had risk factors but not established ASCVD at enrollment. A Nov. 5, 2018, statement from the company developing this drug, Lilly, reported that the study overall produced a statistically significant reduction in MACE, although it provided no additional details. As the released noted, this made REWIND the first trial to show a MACE benefit from a drug in the GLP-1 RA class in patients without established ASCVD.



The MACE outcome results from the three SGLT2 inhibitor trials showed a similar pattern as liraglutide: In patients with established ASCVD, the drugs individually each produced a MACE reduction, although dapagliflozin just missed having a statistically significant reduction. Collectively, the three drugs showed a statistically significant, 14% relative risk reduction for MACE, compared with control patients. But among patients with multiple risk factors only, but without established ASCVD, included in two of the three trials (CANVAS and DECLARE-TIMI 58), the results showed both individually and collectively a neutral MACE effect.

But unlike the other antihyperglycemic drugs tested in the cardiovascular outcome trials, the SGLT2 inhibitors have shown two additional, highly important secondary outcomes: a consistent reduction in hospitalization for heart failure and a consistent reduction in renal-disease progression.

A meta-analysis of the three SGLT2 inhibitor trials published coincident with the release of the DECLARE-TIMI 58 results showed that, for the outcome of either cardiovascular death or hospitalization for heart failure, the SGLT2 inhibitors collectively showed a significant 29% relative decrease in this incidence among patients with a history of heart failure, and a significant 21% relative decrease among patients without history of heart failure (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32590-X). Among the subset of patients with established ASCVD, treatment with a SGLT2 inhibitor across all three trials showed a significant 16% relative risk reduction, and in the subset with multiple risk factors but no established ASCVD, the two SGLT2 inhibitors collectively produced a 16% relative cut in cardiovascular death or heart failure hospitalization with a P value of .06. Finally, the Lancet meta-analysis showed that, for a combined endpoint that reflected renal worsening, the SGLT2 inhibitors showed a significant relative reduction of about 45% in both the subgroup of patients with established ASCVD and in the subgroup of those with just risk factors.

“This is a big step forward for patients with multiple risk factors and diabetes but without ASCVD, that both renal disease and hospitalization for heart failure are sensitive” to the SGLT2 inhibitors, Dr. Verma noted. “We see renal protection and reduction of heart failure hospitalization across both primary and secondary prevention patients, with no need to distinguish them based on ASCVD.” In contrast, he noted, the MACE benefit from the SGLT2 inhibitors seems limited to patients with ASCVD. The day before making this point in a talk during the meeting, Dr. Verma had published the same message in a commentary (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32824-1).

Although the “nomenclature of primary versus secondary prevention is appropriate for atherosclerotic outcomes, it is likely to be inappropriate for a person with type 2 diabetes who is at risk of hospitalization for heart failure and renal disease,” Dr. Verma wrote with his associates in the commentary.

 

 

What it means for clinicians

The upshot of all of these cardiovascular outcome trial results that came out over the past 3 years has been a new appreciation of how antihyperglycemic drugs can have cardiovascular and renal benefits that transcend their effects on glycemia. The evidence has put the SGLT2 inhibitors and GLP-1 RAs on track to challenge, and potentially displace, metformin as the top drug to prescribe for patients with T2DM.

Clinicians should realize that they should prescribe SGLT2 inhibitors and selected GLP-1 RAs “as early as metformin in patients with established ASCVD,” said Dr. Verma. “For patients with recalcitrant atherosclerotic disease and a history of MI and ischemia, I’d primarily treat with a GLP-1 RA. In a patient with left ventricular dysfunction or evidence of heart failure, I’d use an SGLT2 inhibitor. But it’s not a fight between these two. You could treat a patients with type 2 diabetes with both classes,” although the practicality of this approach is limited by the high cost of these drugs.

The SGLT2 inhibitors “should now be considered as first-line therapy after metformin in most people with type 2 diabetes, irrespective of whether or not they have established atherosclerotic vascular disease, chronic kidney disease, or heart failure,” he and his associates wrote in their recent commentary.

“What I struggle with the most is how we prioritize and individualize secondary-prevention therapies based on risk for ischemia and heart failure. Some therapies [the SGLT2 inhibitors] are predominantly for heart failure prevention, and some [the GLP-1 RAs] are primarily for ischemia. How do we choose when a patient cannot afford to take both? Does a combination of a SGLT2 inhibitor and a GLP-1 RA offer the greatest CVD benefit? We need to test this in a trial. And will metformin be displaced as first-line treatment?” Dr. Verma asked.

Mitchel L. Zoler/MDedge News
Dr. John McMurray

“The day will probably come when, for maximal protection, you treat with both classes. But right now we’re forced to choose because of the cost,” said John McMurray, MD, professor of cardiology at the University of Glasgow, in a talk during the meeting.

As to specifically which SGLT2 inhibitor to prescribe, “they all look pretty much the same” in the newly published meta-analysis, Dr. McMurray said, although he noted that safety differences among agents in the class remain possible.

“For patients similar to those studied in the three SGLT2 inhibitor trials, clinicians should use one of these drugs to reduce the risk for incident heart failure, irrespective of their effect on MACE,” said Dr. Butler. Reducing the risk for incident heart failure and of progressive renal dysfunction are two new goals for antihyperglycemic therapy that now overlay the long-standing goals of controlling glycemia and reducing cardiovascular disease risk and the more recent goals of cutting cardiovascular disease mortality and cutting the risk for a MACE event.

A current limitation for practice is that the none of the three drug companies that market the tested SGLT2 inhibitor drugs has sought regulatory approval for an indication of reducing the risk for heart failure hospitalization. Despite that, “these drugs should be used for renal protection and reducing heart failure hospitalizations,” Dr. Butler said. “We need to start thinking about this and not get lost thinking about only their MACE effect because, when you focus on MACE, there is a competition between the SGLT2 inhibitors and the GLP-1 RA. If we think of GLP-1 RAs as drugs to prevent MACE, and SGLT2 inhibitors as drugs that primarily prevent heart failure and renal dysfunction, then there is no competition. Perhaps combined treatment is where we need to go,” he said in an interview.

But the enthusiasm that experts like Dr. Butler, Dr. McMurray, and Dr. Verma have for wider use of both classes of drugs in appropriate patients is not necessarily matched right now among many community physicians. Cardiologist David J. Becker, MD, is an example of the clinicians who appreciate the growing evidence that supports wider use of these antihyperglycemic drugs but remain uneasy about applying this evidence in their practice.

Dr. David J.Becker

Dr. Becker, associate director of the Preventive and Integrative Heart Health Program of the Temple Heart and Vascular Institute in Philadelphia, writes a column for the Philadelphia Inquirer on medical care. In a December 2018 piece, he said “like most cardiologists, I ‘don’t do diabetes’ – because it’s not my expertise. The new drugs, however, mean I need to learn more” about treating these patients. “The problem: There are so many of these medications that they present a bewildering choice for patients and doctors.”

Dr. Becker cited several barriers he sees for himself and his nonendocrinologist colleagues to prescribe these drugs – and for patients to take them:

 

 

  • High cost, with prices that run close to $20/day for each medication.
  • A thicket of names and choices that “lead to confusion and paralysis,” which has been exacerbated by “advertising wars” among competing drug companies.
  • Cardiologists and primary care physicians usually defer to endocrinologists to prescribe these drugs, but most patients with T2DM aren’t seen by endocrinologists. The result: “Few doctors prescribe them.”

The cardiovascular disease benefits of these drugs have not been adequately promoted. Until that changes, “cardiologists like me will not realize their importance,” Dr. Becker concluded.

While christening the new diabetocardiology subspecialty, Dr. Braunwald placed the onus for managing this emerging facet of diabetes largely outside the scope of endocrinology.

“We can’t call in a consultant every time we have a patient with diabetes; it would bankrupt the system,” he said. Training of cardiologists now needs to include several months of treating patients with diabetes, Dr. Braunwald advised, just like 30 or so years ago when cardiologists like himself had to become more familiar with blood clotting to better manage thrombotic disease.

Dr. Braunwald has been a consultant to Cardurion, Myokardia, and Sanofi; an advisor to Endcardia; and has received research funding from AstraZeneca, Daiishi Sankyo, and Novartis. Dr. Butler has been a consultant or advisor to AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi. Dr. Verma has received honoraria and research funding from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, NovoNordisk, Sanofi, and Valeant. Dr. McMurray has received research funding from 12 companies. Dr. Becker had no disclosures.

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Ticagrelor holds no edge over aspirin in CABG patients

TiCAB convincing for similarity of ticagrelor, aspirin
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Tue, 07/21/2020 - 14:18

– Ticagrelor performed about as well as aspirin did as monotherapy for preventing coronary bypass graft failure during the year following surgery in a randomized, multicenter trial with almost 1,900 patients.

Mitchel L. Zoler/MDedge News
Dr. Heribert Schunkert

Ticagrelor monotherapy also produced about the same number of major bleeding events as did aspirin monotherapy, Heribert Schunkert, MD, said at the American Heart Association scientific sessions. There were two limitations of the trial: The incidence of cardiovascular disease events that served as the efficacy endpoint for the study was less than what Dr. Schunkert and his associates expected, and they enrolled about half the projected number of patients because the study lost industry support and then, a couple of years later, showed a relentlessly neutral result leading to early termination of recruitment, said Dr. Schunkert, professor of cardiology and medical director of the German Heart Center in Munich.



The TiCAB (Study Comparing Ticagrelor With Aspirin for Prevention of Vascular Events in Patients Undergoing CABG) trial randomized 1,893 patients during 2013-2017 who underwent CABG at any of 26 centers in Austria, Germany, or Switzerland. Eligible patients underwent surgery for three-vessel disease, left main disease, or had two-vessel disease plus a left ventricular ejection fraction of less than 50%. About 31% of patients had unstable angina or non-ST elevation MI, with the remaining 69% having stable angina. The study included 931 patients who received 90 mg oral ticagrelor (Brilinta) b.i.d. plus aspirin placebo, and 928 who received 100 mg aspirin once daily plus ticagrelor placebo. The study medications began prior to surgery.


The study’s primary efficacy endpoint was the combined rate of cardiovascular death, MI, stroke, or need for revascularization by 1 year after surgery. This occurred in 9.7% of the ticagrelor patients and in 8.2% of those who received aspirin, a difference that was not statistically significant. Several secondary efficacy endpoints examined also showed a neutral result. The primary safety measure was the incidence of major bleeds by the Bleeding Academic Research Consortium criteria, which occurred in 3.7% of the ticagrelor patients and 3.2% of those on aspirin, not a statistically significant difference. After the year of follow-up about 85% of patients in both treatment arms remained on their assigned regimen, Dr. Schunkert said.

TiCAB received funding from AstraZeneca, which markets ticagrelor (Brilinta). Dr. Schunkert has received honoraria and research support from, and has been a speaker on behalf of, AstraZeneca. He has also received honoraria from Amgen, Bayer Vital, Boehringer Ingelheim, Daiichi Sankyo, Merck Sharp & Dohme, Novartis, Pfizer, Sanofi, and Servier.

SOURCE: Schunkert H et al. AHA 2018, Abstract 19561.

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Because the TiCAB study was about half the size of the planned study, its power was low and yielded a result with wide confidence intervals. Despite that, I do not believe that a further, larger study is warranted. The TiCAB results are sufficient to show that monotherapy with ticagrelor is not superior to monotherapy with aspirin in patients undergoing coronary artery bypass grafting and during the year following surgery. The TiCAB results add to a larger body of evidence indicating ticagrelor’s noninferiority to and lack of superiority to aspirin as monotherapy for patients with coronary artery disease or a history of ischemic stroke or transient ischemic attack.

Mitchel L. Zoler/MDedge News
Dr. Robert F. Storey

How can these two drugs produce similar efficacy outcomes? Aspirin is an effective antiplatelet drug, and evidence also suggests that treatment with opiates such as morphine (Circ Cardiovasc Interv. 2016 Sept;9[9]:e004229) and fentanyl (Circulation. 2018 Jan 16;137[3]:307-9) during and after surgery can interfere with the intestinal absorption of ticagrelor and other oral P2Y12 receptor antagonists, such as clopidogrel and prasugrel.

Another interesting finding in TiCAB was that aspirin and ticagrelor monotherapy produced similar rates of major bleeds. Results from prior studies had raised concerns about ticagrelor’s safety in patients undergoing coronary artery bypass surgery, but the new results show that this may be a problem when patients receive dual antiplatelet therapy but not when they receive ticagrelor monotherapy. Current evidence favors dual antiplatelet therapy to achieve a greater decrease in cardiovascular disease events, but this occurs at the expense of increased bleeding. Larger trials of dual therapy after coronary artery bypass grafting are warranted; further study of monotherapy is not.

Robert F. Storey, MD , is a professor of cardiology at the University of Sheffield (England). He has been a consultant to, and received honoraria and research support from, AstraZeneca, and he has been a consultant to Actelion, Avacta, Bayer, Bristol-Myers Squibb/Pfizer, Haemonetics, Novartis, PlaqueTec, and Thromboserin. He made these comments as designated discussant for the TiCAB report.

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Because the TiCAB study was about half the size of the planned study, its power was low and yielded a result with wide confidence intervals. Despite that, I do not believe that a further, larger study is warranted. The TiCAB results are sufficient to show that monotherapy with ticagrelor is not superior to monotherapy with aspirin in patients undergoing coronary artery bypass grafting and during the year following surgery. The TiCAB results add to a larger body of evidence indicating ticagrelor’s noninferiority to and lack of superiority to aspirin as monotherapy for patients with coronary artery disease or a history of ischemic stroke or transient ischemic attack.

Mitchel L. Zoler/MDedge News
Dr. Robert F. Storey

How can these two drugs produce similar efficacy outcomes? Aspirin is an effective antiplatelet drug, and evidence also suggests that treatment with opiates such as morphine (Circ Cardiovasc Interv. 2016 Sept;9[9]:e004229) and fentanyl (Circulation. 2018 Jan 16;137[3]:307-9) during and after surgery can interfere with the intestinal absorption of ticagrelor and other oral P2Y12 receptor antagonists, such as clopidogrel and prasugrel.

Another interesting finding in TiCAB was that aspirin and ticagrelor monotherapy produced similar rates of major bleeds. Results from prior studies had raised concerns about ticagrelor’s safety in patients undergoing coronary artery bypass surgery, but the new results show that this may be a problem when patients receive dual antiplatelet therapy but not when they receive ticagrelor monotherapy. Current evidence favors dual antiplatelet therapy to achieve a greater decrease in cardiovascular disease events, but this occurs at the expense of increased bleeding. Larger trials of dual therapy after coronary artery bypass grafting are warranted; further study of monotherapy is not.

Robert F. Storey, MD , is a professor of cardiology at the University of Sheffield (England). He has been a consultant to, and received honoraria and research support from, AstraZeneca, and he has been a consultant to Actelion, Avacta, Bayer, Bristol-Myers Squibb/Pfizer, Haemonetics, Novartis, PlaqueTec, and Thromboserin. He made these comments as designated discussant for the TiCAB report.

Body

Because the TiCAB study was about half the size of the planned study, its power was low and yielded a result with wide confidence intervals. Despite that, I do not believe that a further, larger study is warranted. The TiCAB results are sufficient to show that monotherapy with ticagrelor is not superior to monotherapy with aspirin in patients undergoing coronary artery bypass grafting and during the year following surgery. The TiCAB results add to a larger body of evidence indicating ticagrelor’s noninferiority to and lack of superiority to aspirin as monotherapy for patients with coronary artery disease or a history of ischemic stroke or transient ischemic attack.

Mitchel L. Zoler/MDedge News
Dr. Robert F. Storey

How can these two drugs produce similar efficacy outcomes? Aspirin is an effective antiplatelet drug, and evidence also suggests that treatment with opiates such as morphine (Circ Cardiovasc Interv. 2016 Sept;9[9]:e004229) and fentanyl (Circulation. 2018 Jan 16;137[3]:307-9) during and after surgery can interfere with the intestinal absorption of ticagrelor and other oral P2Y12 receptor antagonists, such as clopidogrel and prasugrel.

Another interesting finding in TiCAB was that aspirin and ticagrelor monotherapy produced similar rates of major bleeds. Results from prior studies had raised concerns about ticagrelor’s safety in patients undergoing coronary artery bypass surgery, but the new results show that this may be a problem when patients receive dual antiplatelet therapy but not when they receive ticagrelor monotherapy. Current evidence favors dual antiplatelet therapy to achieve a greater decrease in cardiovascular disease events, but this occurs at the expense of increased bleeding. Larger trials of dual therapy after coronary artery bypass grafting are warranted; further study of monotherapy is not.

Robert F. Storey, MD , is a professor of cardiology at the University of Sheffield (England). He has been a consultant to, and received honoraria and research support from, AstraZeneca, and he has been a consultant to Actelion, Avacta, Bayer, Bristol-Myers Squibb/Pfizer, Haemonetics, Novartis, PlaqueTec, and Thromboserin. He made these comments as designated discussant for the TiCAB report.

Title
TiCAB convincing for similarity of ticagrelor, aspirin
TiCAB convincing for similarity of ticagrelor, aspirin

– Ticagrelor performed about as well as aspirin did as monotherapy for preventing coronary bypass graft failure during the year following surgery in a randomized, multicenter trial with almost 1,900 patients.

Mitchel L. Zoler/MDedge News
Dr. Heribert Schunkert

Ticagrelor monotherapy also produced about the same number of major bleeding events as did aspirin monotherapy, Heribert Schunkert, MD, said at the American Heart Association scientific sessions. There were two limitations of the trial: The incidence of cardiovascular disease events that served as the efficacy endpoint for the study was less than what Dr. Schunkert and his associates expected, and they enrolled about half the projected number of patients because the study lost industry support and then, a couple of years later, showed a relentlessly neutral result leading to early termination of recruitment, said Dr. Schunkert, professor of cardiology and medical director of the German Heart Center in Munich.



The TiCAB (Study Comparing Ticagrelor With Aspirin for Prevention of Vascular Events in Patients Undergoing CABG) trial randomized 1,893 patients during 2013-2017 who underwent CABG at any of 26 centers in Austria, Germany, or Switzerland. Eligible patients underwent surgery for three-vessel disease, left main disease, or had two-vessel disease plus a left ventricular ejection fraction of less than 50%. About 31% of patients had unstable angina or non-ST elevation MI, with the remaining 69% having stable angina. The study included 931 patients who received 90 mg oral ticagrelor (Brilinta) b.i.d. plus aspirin placebo, and 928 who received 100 mg aspirin once daily plus ticagrelor placebo. The study medications began prior to surgery.


The study’s primary efficacy endpoint was the combined rate of cardiovascular death, MI, stroke, or need for revascularization by 1 year after surgery. This occurred in 9.7% of the ticagrelor patients and in 8.2% of those who received aspirin, a difference that was not statistically significant. Several secondary efficacy endpoints examined also showed a neutral result. The primary safety measure was the incidence of major bleeds by the Bleeding Academic Research Consortium criteria, which occurred in 3.7% of the ticagrelor patients and 3.2% of those on aspirin, not a statistically significant difference. After the year of follow-up about 85% of patients in both treatment arms remained on their assigned regimen, Dr. Schunkert said.

TiCAB received funding from AstraZeneca, which markets ticagrelor (Brilinta). Dr. Schunkert has received honoraria and research support from, and has been a speaker on behalf of, AstraZeneca. He has also received honoraria from Amgen, Bayer Vital, Boehringer Ingelheim, Daiichi Sankyo, Merck Sharp & Dohme, Novartis, Pfizer, Sanofi, and Servier.

SOURCE: Schunkert H et al. AHA 2018, Abstract 19561.

– Ticagrelor performed about as well as aspirin did as monotherapy for preventing coronary bypass graft failure during the year following surgery in a randomized, multicenter trial with almost 1,900 patients.

Mitchel L. Zoler/MDedge News
Dr. Heribert Schunkert

Ticagrelor monotherapy also produced about the same number of major bleeding events as did aspirin monotherapy, Heribert Schunkert, MD, said at the American Heart Association scientific sessions. There were two limitations of the trial: The incidence of cardiovascular disease events that served as the efficacy endpoint for the study was less than what Dr. Schunkert and his associates expected, and they enrolled about half the projected number of patients because the study lost industry support and then, a couple of years later, showed a relentlessly neutral result leading to early termination of recruitment, said Dr. Schunkert, professor of cardiology and medical director of the German Heart Center in Munich.



The TiCAB (Study Comparing Ticagrelor With Aspirin for Prevention of Vascular Events in Patients Undergoing CABG) trial randomized 1,893 patients during 2013-2017 who underwent CABG at any of 26 centers in Austria, Germany, or Switzerland. Eligible patients underwent surgery for three-vessel disease, left main disease, or had two-vessel disease plus a left ventricular ejection fraction of less than 50%. About 31% of patients had unstable angina or non-ST elevation MI, with the remaining 69% having stable angina. The study included 931 patients who received 90 mg oral ticagrelor (Brilinta) b.i.d. plus aspirin placebo, and 928 who received 100 mg aspirin once daily plus ticagrelor placebo. The study medications began prior to surgery.


The study’s primary efficacy endpoint was the combined rate of cardiovascular death, MI, stroke, or need for revascularization by 1 year after surgery. This occurred in 9.7% of the ticagrelor patients and in 8.2% of those who received aspirin, a difference that was not statistically significant. Several secondary efficacy endpoints examined also showed a neutral result. The primary safety measure was the incidence of major bleeds by the Bleeding Academic Research Consortium criteria, which occurred in 3.7% of the ticagrelor patients and 3.2% of those on aspirin, not a statistically significant difference. After the year of follow-up about 85% of patients in both treatment arms remained on their assigned regimen, Dr. Schunkert said.

TiCAB received funding from AstraZeneca, which markets ticagrelor (Brilinta). Dr. Schunkert has received honoraria and research support from, and has been a speaker on behalf of, AstraZeneca. He has also received honoraria from Amgen, Bayer Vital, Boehringer Ingelheim, Daiichi Sankyo, Merck Sharp & Dohme, Novartis, Pfizer, Sanofi, and Servier.

SOURCE: Schunkert H et al. AHA 2018, Abstract 19561.

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Key clinical point: Ticagrelor was similar to aspirin for preventing graft failure in CABG patients.

Major finding: After 1 year, the combined cardiovascular disease endpoint occurred in 9.7% of ticagrelor patients and in 8.2% on aspirin.

Study details: TiCAB, a multicenter, randomized trial with 1,893 patients.

Disclosures: TiCAB received funding from AstraZeneca, which markets ticagrelor (Brilinta). Dr. Schunkert has received honoraria and research support from, and has been a speaker on behalf of, AstraZeneca. He has received honoraria from Amgen, Bayer Vital, Boehringer Ingelheim, Daiichi Sankyo, Merck Sharp & Dohme, Novartis, Pfizer, Sanofi, and Servier.

Source: Schunkert H et al. AHA 2018, Abstract 19561.

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Extended Holter screening finds A-fib faster after ischemic strokes

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– Enhanced and prolonged rhythm monitoring for atrial fibrillation in patients with a recent acute ischemic stroke did not find more arrhythmias, it just found them faster, in a randomized study with 398 German patients.

Mitchel L. Zoler/MDedge News
Dr. Rolf Wachter

“Prolonged and enhanced monitoring identified atrial fibrillation cases that otherwise were detected years later,” Rolf Wachter, MD, said at the World Stroke Congress. Enhanced and prolonged monitoring (EPM) “should be considered for all stroke patients, regardless of the suspected stroke etiology, if detection of atrial fibrillation is of clinical relevance,” said Dr. Wachter, a cardiologist and professor at the University Clinic in Leipzig, Germany.

Based on 3-year follow-up of patients enrolled in the FIND-AF study, which randomized patients within 7 days of an acute ischemic stroke to either EPM for atrial fibrillation (AF) or standard work-up and follow-up, Dr. Wachter calculated that every six such patients who underwent EMP for AF yielded one added patient who could receive anticoagulant prophylaxis for 1 year, an effect that should result in fewer incident strokes and deaths. The data he reported showed after 3 years a “favorable trend” toward fewer strokes and deaths among patients who underwent EPM.



FIND-AF RANDOMISED (A Prospective, Randomised, Controlled Study to Determine the Detection of Atrial Fibrillation by Prolonged and Enhanced Holter Monitoring as Compared to Usual Care in Stroke Patients) ran at four German centers during May 2013–August 2014. It enrolled 398 patients aged 60 years or older within 7 days of an acute ischemic stroke who were in sinus rhythm and had no AF history. Enrolled patients could have any type of suspected stroke etiology, but the study excluded patients with severe stenosis in their ipsilateral carotid or intracranial arteries. The study randomized patients to received EPM or a standard work-up. The “enhanced” part of EPM meant review of Holter monitor recordings by a single, dedicated core laboratory. The “prolonged” part meant routinely screening patients for an atrial arrhythmia using a Holter monitor worn for 10 consecutive days on three occasions: at entry into the study, 3 months later, and 6 months later.

The study’s primary endpoint was the number of patients diagnosed with AF after 6 months, which was 27 of 200 patients (13.5%) in the EPM arm and 9 of 198 patients (4.5%) in the control arm, a statistically significant difference, Dr. Wachter and his associates reported in Lancet Neurology (2017 Apr 1;16[4]:282-90).

The additional 30 months of follow-up included in the new report by Dr. Wachter resulted in identification of 3 more patients with AF in the EPM group and 13 more patients in the control arm, which brought the total number of patients with AF identified over 3 years to 30 in the EPM group (15%), and 22 in the control group (11%), a difference that was not statistically significant. In other words, both approaches found roughly the same percentage of patients with AF, but the EPM method found them quicker.



During the extended 36-month follow-up, 12 patients in the EPM group had an ischemic stroke and 9 patients died, with a combined stroke and death rate of about 8%. In the control group, 19 patients had a second ischemic stroke and 13 died, with a combined rate of about 15%. A statistical test of the difference between the combined stroke and death rates in these two groups produced a P value of .08.

FIND-AF was funded by Boehringer Ingelheim. Dr. Wachter has been a speaker on behalf of and has received research funding from Boehringer Ingelheim, and he has also been a speaker on behalf of Bayer, BMS/Pfizer, and Daiichi Sankyo.

SOURCE: Wachter R et al. World Stroke Congress, Abstract.

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– Enhanced and prolonged rhythm monitoring for atrial fibrillation in patients with a recent acute ischemic stroke did not find more arrhythmias, it just found them faster, in a randomized study with 398 German patients.

Mitchel L. Zoler/MDedge News
Dr. Rolf Wachter

“Prolonged and enhanced monitoring identified atrial fibrillation cases that otherwise were detected years later,” Rolf Wachter, MD, said at the World Stroke Congress. Enhanced and prolonged monitoring (EPM) “should be considered for all stroke patients, regardless of the suspected stroke etiology, if detection of atrial fibrillation is of clinical relevance,” said Dr. Wachter, a cardiologist and professor at the University Clinic in Leipzig, Germany.

Based on 3-year follow-up of patients enrolled in the FIND-AF study, which randomized patients within 7 days of an acute ischemic stroke to either EPM for atrial fibrillation (AF) or standard work-up and follow-up, Dr. Wachter calculated that every six such patients who underwent EMP for AF yielded one added patient who could receive anticoagulant prophylaxis for 1 year, an effect that should result in fewer incident strokes and deaths. The data he reported showed after 3 years a “favorable trend” toward fewer strokes and deaths among patients who underwent EPM.



FIND-AF RANDOMISED (A Prospective, Randomised, Controlled Study to Determine the Detection of Atrial Fibrillation by Prolonged and Enhanced Holter Monitoring as Compared to Usual Care in Stroke Patients) ran at four German centers during May 2013–August 2014. It enrolled 398 patients aged 60 years or older within 7 days of an acute ischemic stroke who were in sinus rhythm and had no AF history. Enrolled patients could have any type of suspected stroke etiology, but the study excluded patients with severe stenosis in their ipsilateral carotid or intracranial arteries. The study randomized patients to received EPM or a standard work-up. The “enhanced” part of EPM meant review of Holter monitor recordings by a single, dedicated core laboratory. The “prolonged” part meant routinely screening patients for an atrial arrhythmia using a Holter monitor worn for 10 consecutive days on three occasions: at entry into the study, 3 months later, and 6 months later.

The study’s primary endpoint was the number of patients diagnosed with AF after 6 months, which was 27 of 200 patients (13.5%) in the EPM arm and 9 of 198 patients (4.5%) in the control arm, a statistically significant difference, Dr. Wachter and his associates reported in Lancet Neurology (2017 Apr 1;16[4]:282-90).

The additional 30 months of follow-up included in the new report by Dr. Wachter resulted in identification of 3 more patients with AF in the EPM group and 13 more patients in the control arm, which brought the total number of patients with AF identified over 3 years to 30 in the EPM group (15%), and 22 in the control group (11%), a difference that was not statistically significant. In other words, both approaches found roughly the same percentage of patients with AF, but the EPM method found them quicker.



During the extended 36-month follow-up, 12 patients in the EPM group had an ischemic stroke and 9 patients died, with a combined stroke and death rate of about 8%. In the control group, 19 patients had a second ischemic stroke and 13 died, with a combined rate of about 15%. A statistical test of the difference between the combined stroke and death rates in these two groups produced a P value of .08.

FIND-AF was funded by Boehringer Ingelheim. Dr. Wachter has been a speaker on behalf of and has received research funding from Boehringer Ingelheim, and he has also been a speaker on behalf of Bayer, BMS/Pfizer, and Daiichi Sankyo.

SOURCE: Wachter R et al. World Stroke Congress, Abstract.

 

– Enhanced and prolonged rhythm monitoring for atrial fibrillation in patients with a recent acute ischemic stroke did not find more arrhythmias, it just found them faster, in a randomized study with 398 German patients.

Mitchel L. Zoler/MDedge News
Dr. Rolf Wachter

“Prolonged and enhanced monitoring identified atrial fibrillation cases that otherwise were detected years later,” Rolf Wachter, MD, said at the World Stroke Congress. Enhanced and prolonged monitoring (EPM) “should be considered for all stroke patients, regardless of the suspected stroke etiology, if detection of atrial fibrillation is of clinical relevance,” said Dr. Wachter, a cardiologist and professor at the University Clinic in Leipzig, Germany.

Based on 3-year follow-up of patients enrolled in the FIND-AF study, which randomized patients within 7 days of an acute ischemic stroke to either EPM for atrial fibrillation (AF) or standard work-up and follow-up, Dr. Wachter calculated that every six such patients who underwent EMP for AF yielded one added patient who could receive anticoagulant prophylaxis for 1 year, an effect that should result in fewer incident strokes and deaths. The data he reported showed after 3 years a “favorable trend” toward fewer strokes and deaths among patients who underwent EPM.



FIND-AF RANDOMISED (A Prospective, Randomised, Controlled Study to Determine the Detection of Atrial Fibrillation by Prolonged and Enhanced Holter Monitoring as Compared to Usual Care in Stroke Patients) ran at four German centers during May 2013–August 2014. It enrolled 398 patients aged 60 years or older within 7 days of an acute ischemic stroke who were in sinus rhythm and had no AF history. Enrolled patients could have any type of suspected stroke etiology, but the study excluded patients with severe stenosis in their ipsilateral carotid or intracranial arteries. The study randomized patients to received EPM or a standard work-up. The “enhanced” part of EPM meant review of Holter monitor recordings by a single, dedicated core laboratory. The “prolonged” part meant routinely screening patients for an atrial arrhythmia using a Holter monitor worn for 10 consecutive days on three occasions: at entry into the study, 3 months later, and 6 months later.

The study’s primary endpoint was the number of patients diagnosed with AF after 6 months, which was 27 of 200 patients (13.5%) in the EPM arm and 9 of 198 patients (4.5%) in the control arm, a statistically significant difference, Dr. Wachter and his associates reported in Lancet Neurology (2017 Apr 1;16[4]:282-90).

The additional 30 months of follow-up included in the new report by Dr. Wachter resulted in identification of 3 more patients with AF in the EPM group and 13 more patients in the control arm, which brought the total number of patients with AF identified over 3 years to 30 in the EPM group (15%), and 22 in the control group (11%), a difference that was not statistically significant. In other words, both approaches found roughly the same percentage of patients with AF, but the EPM method found them quicker.



During the extended 36-month follow-up, 12 patients in the EPM group had an ischemic stroke and 9 patients died, with a combined stroke and death rate of about 8%. In the control group, 19 patients had a second ischemic stroke and 13 died, with a combined rate of about 15%. A statistical test of the difference between the combined stroke and death rates in these two groups produced a P value of .08.

FIND-AF was funded by Boehringer Ingelheim. Dr. Wachter has been a speaker on behalf of and has received research funding from Boehringer Ingelheim, and he has also been a speaker on behalf of Bayer, BMS/Pfizer, and Daiichi Sankyo.

SOURCE: Wachter R et al. World Stroke Congress, Abstract.

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Key clinical point: Enhanced and prolonged monitoring for atrial fibrillation did not find more arrhythmias, but it did find them faster.

Major finding: Every six patients who underwent extended arrhythmia screening produced one additional patient eligible for a year of anticoagulant prophylaxis.

Study details: Three-year follow-up of FIND-AF, a multicenter, German study with 398 patients.

Disclosures: FIND-AF was funded by Boehringer Ingelheim. Dr. Wachter has been a speaker on behalf of and has received research funding from Boehringer Ingelheim, and he has also been a speaker on behalf of Bayer, BMS/Pfizer, and Daiichi Sankyo.

Source: Wachter R et al. World Stroke Congress.

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CABG surpasses PCI for diabetics out to 7.5 years

Further evidence shows CABG usually better for diabetics
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– Patients with diabetes who underwent coronary artery bypass grafting had significantly better survival than patients with diabetes who underwent percutaneous coronary intervention after a median 7.5 years of follow-up.

MItchel L. Zoler/MDedge News
Dr. Valentin Fuster

Those patients comprised about half the patients enrolled in the FREEDOM randomized trial.

Long-term follow-up was only possible for just under half the 1,900 patients with diabetes and multivessel coronary disease originally enrolled in FREEDOM, but when researchers combined the long-term results with the data collected in the original study that had a median 3.8-year follow-up, they found all-cause mortality occurred in 18.3% of the patients who underwent coronary artery bypass grafting (CABG) and in 24.3% of patients treated with percutaneous coronary intervention (PCI), a 6% absolute between-group difference that was statistically significant, Valentin Fuster, MD, said at the American Heart Association scientific sessions. This fully jibed with the primary FREEDOM results, which found after 5 years a statistically significant reduction in all-cause death with CABG, compared with PCI, and also a significant reduction in the study’s primary endpoint (a combination of all-cause death, MI, and stroke), which occurred in 18.7% of patients randomized to CABG and in 26.6% of those randomized to PCI (N Engl J Med. 2012 Dec 20;367[25]:2375-84).

The extended follow-up finding lent additional support to existing society recommendations that CABG is the preferred revascularization strategy for patients with diabetes and multivessel coronary disease, most recently from the European Society of Cardiology (Eur Heart J. 2018 Aug 25. doi: 10.1093/eurheartj/ehy394), said Dr. Fuster, professor of medicine at the Icahn School of Medicine at Mount Sinai and director of Mount Sinai Heart in New York. A subgroup analysis of the extended follow-up also suggested that the survival benefit from CABG, compared with PCI, was especially strong among patients at or below the study’s median age of 63 years. In the younger subgroup survival among patients treated with CABG was twice as good as it was among patients treated with PCI.



Dr. Fuster noted that few data have been previously reported for survival rates beyond 5 years after revascularization. “This was a difficult study. Following patients for more than 5 years is hard,” he said. Concurrently with his report at the meeting the results also appeared online (J Am Coll Cardiol. 2018 Nov 11. doi: 10.1016/j.jacc.2018.11.001).

The FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial enrolled patients at 140 participating centers during 2005-2010. A total of 25 sites agreed to participate in the extended follow-up and could track 943 patients, 50% of the starting cohort of 1,900 and 89% of the patients originally enrolled at these 25 centers. Dr. Fuster stressed that the 957 patients not included in the follow-up had not been lost, but rather had been managed at sites that declined to participate in this additional study.

Dr. Fuster acknowledged that methods and hardware for PCI have changed since the study ran a decade ago, as have options for medical management. He also highlighted that the long-term follow-up results had no data on rates of MIs and strokes.

FREEDOM had no commercial funding. Dr. Fuster reported no relevant disclosures.

SOURCE: Fuster V et al. AHA 2018, Abstract 18609.

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These extended results from the FREEDOM trial that followed many patients for 10 years or longer add to the consistent evidence base that supports coronary artery bypass grafting (CABG) as the preferred revascularization strategy for patients with diabetes and multivessel coronary disease. The new findings support existing society guidelines that recommend CABG over percutaneous coronary intervention in these patients, most recently in the revascularization guidelines from the European Society of Cardiology (Eur Heart J. 2018 Aug 25. doi: 10.1093/eurheartj/ehy394). An update to the U.S. guidelines should appear in 2019.

MItchel L. Zoler/MDedge News
Dr. Alice K. Jacobs
An important limitation of the extended follow-up analysis reported by Dr. Fuster was that it included half of the patients originally enrolled in FREEDOM. This introduced a potential bias and also underpowered the study, but the 89% follow-up of patients at centers that opted to participate in the longer-term phase helps mitigate the potential for bias.

Continued improvement of revascularization techniques, hardware, and medical management of patients with diabetes and multivessel coronary artery disease makes it challenging to apply the results of studies run in earlier eras to today’s practice. It is possible that continued evolution of coronary stent technology may reduce the differences in outcomes between bypass surgery and percutaneous coronary interventions, although this is less likely if much of CABG’s success relates to the protection it gives against new disease. Future comparisons of different approaches with revascularization will need to take into account the potential contribution of other procedures, other adverse outcomes aside from mortality during long-term follow-up, the consequences of incomplete revascularization, and the impact of new medications for treating diabetes that have been recently shown to also have cardiovascular disease effects. All these factors in concert will define the optimal approach to managing these patients.

Alice K. Jacobs, MD , is director of the cardiac catheterization laboratory at Boston Medical Center and a professor of medicine at Boston University. She has received research support from Abbott Vascular. She made these comments as designated discussant for the study.

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These extended results from the FREEDOM trial that followed many patients for 10 years or longer add to the consistent evidence base that supports coronary artery bypass grafting (CABG) as the preferred revascularization strategy for patients with diabetes and multivessel coronary disease. The new findings support existing society guidelines that recommend CABG over percutaneous coronary intervention in these patients, most recently in the revascularization guidelines from the European Society of Cardiology (Eur Heart J. 2018 Aug 25. doi: 10.1093/eurheartj/ehy394). An update to the U.S. guidelines should appear in 2019.

MItchel L. Zoler/MDedge News
Dr. Alice K. Jacobs
An important limitation of the extended follow-up analysis reported by Dr. Fuster was that it included half of the patients originally enrolled in FREEDOM. This introduced a potential bias and also underpowered the study, but the 89% follow-up of patients at centers that opted to participate in the longer-term phase helps mitigate the potential for bias.

Continued improvement of revascularization techniques, hardware, and medical management of patients with diabetes and multivessel coronary artery disease makes it challenging to apply the results of studies run in earlier eras to today’s practice. It is possible that continued evolution of coronary stent technology may reduce the differences in outcomes between bypass surgery and percutaneous coronary interventions, although this is less likely if much of CABG’s success relates to the protection it gives against new disease. Future comparisons of different approaches with revascularization will need to take into account the potential contribution of other procedures, other adverse outcomes aside from mortality during long-term follow-up, the consequences of incomplete revascularization, and the impact of new medications for treating diabetes that have been recently shown to also have cardiovascular disease effects. All these factors in concert will define the optimal approach to managing these patients.

Alice K. Jacobs, MD , is director of the cardiac catheterization laboratory at Boston Medical Center and a professor of medicine at Boston University. She has received research support from Abbott Vascular. She made these comments as designated discussant for the study.

Body

 

These extended results from the FREEDOM trial that followed many patients for 10 years or longer add to the consistent evidence base that supports coronary artery bypass grafting (CABG) as the preferred revascularization strategy for patients with diabetes and multivessel coronary disease. The new findings support existing society guidelines that recommend CABG over percutaneous coronary intervention in these patients, most recently in the revascularization guidelines from the European Society of Cardiology (Eur Heart J. 2018 Aug 25. doi: 10.1093/eurheartj/ehy394). An update to the U.S. guidelines should appear in 2019.

MItchel L. Zoler/MDedge News
Dr. Alice K. Jacobs
An important limitation of the extended follow-up analysis reported by Dr. Fuster was that it included half of the patients originally enrolled in FREEDOM. This introduced a potential bias and also underpowered the study, but the 89% follow-up of patients at centers that opted to participate in the longer-term phase helps mitigate the potential for bias.

Continued improvement of revascularization techniques, hardware, and medical management of patients with diabetes and multivessel coronary artery disease makes it challenging to apply the results of studies run in earlier eras to today’s practice. It is possible that continued evolution of coronary stent technology may reduce the differences in outcomes between bypass surgery and percutaneous coronary interventions, although this is less likely if much of CABG’s success relates to the protection it gives against new disease. Future comparisons of different approaches with revascularization will need to take into account the potential contribution of other procedures, other adverse outcomes aside from mortality during long-term follow-up, the consequences of incomplete revascularization, and the impact of new medications for treating diabetes that have been recently shown to also have cardiovascular disease effects. All these factors in concert will define the optimal approach to managing these patients.

Alice K. Jacobs, MD , is director of the cardiac catheterization laboratory at Boston Medical Center and a professor of medicine at Boston University. She has received research support from Abbott Vascular. She made these comments as designated discussant for the study.

Title
Further evidence shows CABG usually better for diabetics
Further evidence shows CABG usually better for diabetics

 

– Patients with diabetes who underwent coronary artery bypass grafting had significantly better survival than patients with diabetes who underwent percutaneous coronary intervention after a median 7.5 years of follow-up.

MItchel L. Zoler/MDedge News
Dr. Valentin Fuster

Those patients comprised about half the patients enrolled in the FREEDOM randomized trial.

Long-term follow-up was only possible for just under half the 1,900 patients with diabetes and multivessel coronary disease originally enrolled in FREEDOM, but when researchers combined the long-term results with the data collected in the original study that had a median 3.8-year follow-up, they found all-cause mortality occurred in 18.3% of the patients who underwent coronary artery bypass grafting (CABG) and in 24.3% of patients treated with percutaneous coronary intervention (PCI), a 6% absolute between-group difference that was statistically significant, Valentin Fuster, MD, said at the American Heart Association scientific sessions. This fully jibed with the primary FREEDOM results, which found after 5 years a statistically significant reduction in all-cause death with CABG, compared with PCI, and also a significant reduction in the study’s primary endpoint (a combination of all-cause death, MI, and stroke), which occurred in 18.7% of patients randomized to CABG and in 26.6% of those randomized to PCI (N Engl J Med. 2012 Dec 20;367[25]:2375-84).

The extended follow-up finding lent additional support to existing society recommendations that CABG is the preferred revascularization strategy for patients with diabetes and multivessel coronary disease, most recently from the European Society of Cardiology (Eur Heart J. 2018 Aug 25. doi: 10.1093/eurheartj/ehy394), said Dr. Fuster, professor of medicine at the Icahn School of Medicine at Mount Sinai and director of Mount Sinai Heart in New York. A subgroup analysis of the extended follow-up also suggested that the survival benefit from CABG, compared with PCI, was especially strong among patients at or below the study’s median age of 63 years. In the younger subgroup survival among patients treated with CABG was twice as good as it was among patients treated with PCI.



Dr. Fuster noted that few data have been previously reported for survival rates beyond 5 years after revascularization. “This was a difficult study. Following patients for more than 5 years is hard,” he said. Concurrently with his report at the meeting the results also appeared online (J Am Coll Cardiol. 2018 Nov 11. doi: 10.1016/j.jacc.2018.11.001).

The FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial enrolled patients at 140 participating centers during 2005-2010. A total of 25 sites agreed to participate in the extended follow-up and could track 943 patients, 50% of the starting cohort of 1,900 and 89% of the patients originally enrolled at these 25 centers. Dr. Fuster stressed that the 957 patients not included in the follow-up had not been lost, but rather had been managed at sites that declined to participate in this additional study.

Dr. Fuster acknowledged that methods and hardware for PCI have changed since the study ran a decade ago, as have options for medical management. He also highlighted that the long-term follow-up results had no data on rates of MIs and strokes.

FREEDOM had no commercial funding. Dr. Fuster reported no relevant disclosures.

SOURCE: Fuster V et al. AHA 2018, Abstract 18609.

 

– Patients with diabetes who underwent coronary artery bypass grafting had significantly better survival than patients with diabetes who underwent percutaneous coronary intervention after a median 7.5 years of follow-up.

MItchel L. Zoler/MDedge News
Dr. Valentin Fuster

Those patients comprised about half the patients enrolled in the FREEDOM randomized trial.

Long-term follow-up was only possible for just under half the 1,900 patients with diabetes and multivessel coronary disease originally enrolled in FREEDOM, but when researchers combined the long-term results with the data collected in the original study that had a median 3.8-year follow-up, they found all-cause mortality occurred in 18.3% of the patients who underwent coronary artery bypass grafting (CABG) and in 24.3% of patients treated with percutaneous coronary intervention (PCI), a 6% absolute between-group difference that was statistically significant, Valentin Fuster, MD, said at the American Heart Association scientific sessions. This fully jibed with the primary FREEDOM results, which found after 5 years a statistically significant reduction in all-cause death with CABG, compared with PCI, and also a significant reduction in the study’s primary endpoint (a combination of all-cause death, MI, and stroke), which occurred in 18.7% of patients randomized to CABG and in 26.6% of those randomized to PCI (N Engl J Med. 2012 Dec 20;367[25]:2375-84).

The extended follow-up finding lent additional support to existing society recommendations that CABG is the preferred revascularization strategy for patients with diabetes and multivessel coronary disease, most recently from the European Society of Cardiology (Eur Heart J. 2018 Aug 25. doi: 10.1093/eurheartj/ehy394), said Dr. Fuster, professor of medicine at the Icahn School of Medicine at Mount Sinai and director of Mount Sinai Heart in New York. A subgroup analysis of the extended follow-up also suggested that the survival benefit from CABG, compared with PCI, was especially strong among patients at or below the study’s median age of 63 years. In the younger subgroup survival among patients treated with CABG was twice as good as it was among patients treated with PCI.



Dr. Fuster noted that few data have been previously reported for survival rates beyond 5 years after revascularization. “This was a difficult study. Following patients for more than 5 years is hard,” he said. Concurrently with his report at the meeting the results also appeared online (J Am Coll Cardiol. 2018 Nov 11. doi: 10.1016/j.jacc.2018.11.001).

The FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial enrolled patients at 140 participating centers during 2005-2010. A total of 25 sites agreed to participate in the extended follow-up and could track 943 patients, 50% of the starting cohort of 1,900 and 89% of the patients originally enrolled at these 25 centers. Dr. Fuster stressed that the 957 patients not included in the follow-up had not been lost, but rather had been managed at sites that declined to participate in this additional study.

Dr. Fuster acknowledged that methods and hardware for PCI have changed since the study ran a decade ago, as have options for medical management. He also highlighted that the long-term follow-up results had no data on rates of MIs and strokes.

FREEDOM had no commercial funding. Dr. Fuster reported no relevant disclosures.

SOURCE: Fuster V et al. AHA 2018, Abstract 18609.

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Key clinical point: The survival advantage of coronary artery bypass grafting over percutaneous coronary intervention in patients with diabetes continued out to a median of 7.5 years post procedure.

Major finding: After 7.5 years, mortality in the full FREEDOM cohort was 18% after coronary artery bypass grafting and 24% after percutaneous coronary intervention.

Study details: An extended follow-up of 943 of patients enrolled in FREEDOM, a randomized, multicenter trial.

Disclosures: FREEDOM had no commercial funding. Dr. Fuster reported no relevant disclosures.

Source: Fuster V et al. AHA 2018, Abstract 18609.

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Thrombectomy shows efficacy for basilar artery strokes

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– A randomized trial designed to definitively test the efficacy of mechanical thrombectomy for treating acute ischemic strokes caused by basilar artery occlusion fell victim to slow recruitment and crossovers that muddied the intention-to-treat results, but the per-protocol and as-treated analyses both showed that thrombectomy was superior to best medical therapy in a multicenter, randomized study with 131 Chinese patients.

Mitchel L. Zoler/MDedge News
Dr. Raul G. Nogueira

“Our findings should be considered in the context of the best evidence currently available, and progressive loss of equipoise for endovascular therapy for severe, large-vessel occlusion strokes,” Raul G. Nogueira, MD, said at the World Stroke Congress. “This was not a perfect trial, but it’s the best data we have, by far, at least for now” on the value of mechanical thrombectomy for treating acute ischemic stroke caused by a basilar artery occlusion, added Dr. Nogueira, professor of neurology and director of the neuroendovascular service at Emory University, Atlanta.

In the study’s per-protocol analysis, which considered patients who received their randomized treatment, the study’s primary endpoint of a modified Rankin Scale (mRS) score of 0-3 at 90 days after treatment was 44% in 63 patients who underwent thrombectomy and 26% in 51 patients randomized to best medical therapy who remained on that regimen, a statistically significant difference, Dr. Nogueira reported. In the as-treated analysis, which considered all enrolled patients based on the treatment they actually received regardless of randomization group, 77 patients treated with thrombectomy had a 47% rate of achieving the primary outcome, compared with 24% of 54 controls, also a statistically significant difference.

In contrast, the prespecified primary analysis for the study, the intention-to-treat analysis that considered patients based on their randomization assignment regardless of the treatment they actually received, showed that after 90 days the rate of patients with a mRS score of 0-3 was 42% in 66 thrombectomy patients and 32% among 65 controls, a difference that was not significant; this is a finding that, from a purist’s standpoint, makes the trial’s result neutral. The per-protocol and as-treated analyses were also prespecified steps in the study’s design, but not primary endpoints.

Despite the shortcoming for the primary analysis, Dr. Nogueira said that he found the per-protocol and as-treated findings very persuasive. “I personally could not randomize these patients” in the future to not receive mechanical thrombectomy, he confessed from the podium.



The BEST trial randomized 131 patients at any of 28 Chinese sites between April 2015 and September 2017. Patients had to enter within 8 hours of stroke onset. The original trial design called for enrolling 344 patients, but the steering committee decided in 2017 to prematurely stop the study because of a progressive drop in enrollment of patients, and “excessive” crossovers from the control arm to thrombectomy, a total of 14 patients. During the final month of the trial, 6 of 10 patients assigned by randomization to receive best medical care instead underwent thrombectomy. “At that point, we pretty much had to stop,” Dr. Nogueira said. Enrolled patients averaged about 65 years old, about 90% had a basilar artery occlusion and about 10% a vertebral artery occlusion, about 30% received intravenous alteplase, and the median National Institutes of Health Stroke Scale score at entry was about 30.

The major adverse effect from thrombectomy seen in the study was symptomatic intracranial hemorrhage, which occurred in 5 of the 77 patients (6%) actually treated with thrombectomy, compared with none of the 54 patients not treated with thrombectomy. This modest rate of intracranial hemorrhages was “not unexpected,” Dr. Nogueira noted.

Acute ischemic strokes caused by a basilar artery occlusion are relatively uncommon, accounting for about 1% of all acute ischemic strokes and 5%-10% of acute ischemic strokes caused by occlusion of a proximal intracranial artery. But when these strokes occur, they are a “neurological catastrophe,” Dr. Nogueira said, causing severe disability or mortality in about 70% of patients.

BEST had no commercial funding. Dr. Nogueira reported no disclosures.

SOURCE: Nogueira RG et al. Int J Stroke. 2018;13(2_suppl):227, Abstract 978.


 

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– A randomized trial designed to definitively test the efficacy of mechanical thrombectomy for treating acute ischemic strokes caused by basilar artery occlusion fell victim to slow recruitment and crossovers that muddied the intention-to-treat results, but the per-protocol and as-treated analyses both showed that thrombectomy was superior to best medical therapy in a multicenter, randomized study with 131 Chinese patients.

Mitchel L. Zoler/MDedge News
Dr. Raul G. Nogueira

“Our findings should be considered in the context of the best evidence currently available, and progressive loss of equipoise for endovascular therapy for severe, large-vessel occlusion strokes,” Raul G. Nogueira, MD, said at the World Stroke Congress. “This was not a perfect trial, but it’s the best data we have, by far, at least for now” on the value of mechanical thrombectomy for treating acute ischemic stroke caused by a basilar artery occlusion, added Dr. Nogueira, professor of neurology and director of the neuroendovascular service at Emory University, Atlanta.

In the study’s per-protocol analysis, which considered patients who received their randomized treatment, the study’s primary endpoint of a modified Rankin Scale (mRS) score of 0-3 at 90 days after treatment was 44% in 63 patients who underwent thrombectomy and 26% in 51 patients randomized to best medical therapy who remained on that regimen, a statistically significant difference, Dr. Nogueira reported. In the as-treated analysis, which considered all enrolled patients based on the treatment they actually received regardless of randomization group, 77 patients treated with thrombectomy had a 47% rate of achieving the primary outcome, compared with 24% of 54 controls, also a statistically significant difference.

In contrast, the prespecified primary analysis for the study, the intention-to-treat analysis that considered patients based on their randomization assignment regardless of the treatment they actually received, showed that after 90 days the rate of patients with a mRS score of 0-3 was 42% in 66 thrombectomy patients and 32% among 65 controls, a difference that was not significant; this is a finding that, from a purist’s standpoint, makes the trial’s result neutral. The per-protocol and as-treated analyses were also prespecified steps in the study’s design, but not primary endpoints.

Despite the shortcoming for the primary analysis, Dr. Nogueira said that he found the per-protocol and as-treated findings very persuasive. “I personally could not randomize these patients” in the future to not receive mechanical thrombectomy, he confessed from the podium.



The BEST trial randomized 131 patients at any of 28 Chinese sites between April 2015 and September 2017. Patients had to enter within 8 hours of stroke onset. The original trial design called for enrolling 344 patients, but the steering committee decided in 2017 to prematurely stop the study because of a progressive drop in enrollment of patients, and “excessive” crossovers from the control arm to thrombectomy, a total of 14 patients. During the final month of the trial, 6 of 10 patients assigned by randomization to receive best medical care instead underwent thrombectomy. “At that point, we pretty much had to stop,” Dr. Nogueira said. Enrolled patients averaged about 65 years old, about 90% had a basilar artery occlusion and about 10% a vertebral artery occlusion, about 30% received intravenous alteplase, and the median National Institutes of Health Stroke Scale score at entry was about 30.

The major adverse effect from thrombectomy seen in the study was symptomatic intracranial hemorrhage, which occurred in 5 of the 77 patients (6%) actually treated with thrombectomy, compared with none of the 54 patients not treated with thrombectomy. This modest rate of intracranial hemorrhages was “not unexpected,” Dr. Nogueira noted.

Acute ischemic strokes caused by a basilar artery occlusion are relatively uncommon, accounting for about 1% of all acute ischemic strokes and 5%-10% of acute ischemic strokes caused by occlusion of a proximal intracranial artery. But when these strokes occur, they are a “neurological catastrophe,” Dr. Nogueira said, causing severe disability or mortality in about 70% of patients.

BEST had no commercial funding. Dr. Nogueira reported no disclosures.

SOURCE: Nogueira RG et al. Int J Stroke. 2018;13(2_suppl):227, Abstract 978.


 

 

– A randomized trial designed to definitively test the efficacy of mechanical thrombectomy for treating acute ischemic strokes caused by basilar artery occlusion fell victim to slow recruitment and crossovers that muddied the intention-to-treat results, but the per-protocol and as-treated analyses both showed that thrombectomy was superior to best medical therapy in a multicenter, randomized study with 131 Chinese patients.

Mitchel L. Zoler/MDedge News
Dr. Raul G. Nogueira

“Our findings should be considered in the context of the best evidence currently available, and progressive loss of equipoise for endovascular therapy for severe, large-vessel occlusion strokes,” Raul G. Nogueira, MD, said at the World Stroke Congress. “This was not a perfect trial, but it’s the best data we have, by far, at least for now” on the value of mechanical thrombectomy for treating acute ischemic stroke caused by a basilar artery occlusion, added Dr. Nogueira, professor of neurology and director of the neuroendovascular service at Emory University, Atlanta.

In the study’s per-protocol analysis, which considered patients who received their randomized treatment, the study’s primary endpoint of a modified Rankin Scale (mRS) score of 0-3 at 90 days after treatment was 44% in 63 patients who underwent thrombectomy and 26% in 51 patients randomized to best medical therapy who remained on that regimen, a statistically significant difference, Dr. Nogueira reported. In the as-treated analysis, which considered all enrolled patients based on the treatment they actually received regardless of randomization group, 77 patients treated with thrombectomy had a 47% rate of achieving the primary outcome, compared with 24% of 54 controls, also a statistically significant difference.

In contrast, the prespecified primary analysis for the study, the intention-to-treat analysis that considered patients based on their randomization assignment regardless of the treatment they actually received, showed that after 90 days the rate of patients with a mRS score of 0-3 was 42% in 66 thrombectomy patients and 32% among 65 controls, a difference that was not significant; this is a finding that, from a purist’s standpoint, makes the trial’s result neutral. The per-protocol and as-treated analyses were also prespecified steps in the study’s design, but not primary endpoints.

Despite the shortcoming for the primary analysis, Dr. Nogueira said that he found the per-protocol and as-treated findings very persuasive. “I personally could not randomize these patients” in the future to not receive mechanical thrombectomy, he confessed from the podium.



The BEST trial randomized 131 patients at any of 28 Chinese sites between April 2015 and September 2017. Patients had to enter within 8 hours of stroke onset. The original trial design called for enrolling 344 patients, but the steering committee decided in 2017 to prematurely stop the study because of a progressive drop in enrollment of patients, and “excessive” crossovers from the control arm to thrombectomy, a total of 14 patients. During the final month of the trial, 6 of 10 patients assigned by randomization to receive best medical care instead underwent thrombectomy. “At that point, we pretty much had to stop,” Dr. Nogueira said. Enrolled patients averaged about 65 years old, about 90% had a basilar artery occlusion and about 10% a vertebral artery occlusion, about 30% received intravenous alteplase, and the median National Institutes of Health Stroke Scale score at entry was about 30.

The major adverse effect from thrombectomy seen in the study was symptomatic intracranial hemorrhage, which occurred in 5 of the 77 patients (6%) actually treated with thrombectomy, compared with none of the 54 patients not treated with thrombectomy. This modest rate of intracranial hemorrhages was “not unexpected,” Dr. Nogueira noted.

Acute ischemic strokes caused by a basilar artery occlusion are relatively uncommon, accounting for about 1% of all acute ischemic strokes and 5%-10% of acute ischemic strokes caused by occlusion of a proximal intracranial artery. But when these strokes occur, they are a “neurological catastrophe,” Dr. Nogueira said, causing severe disability or mortality in about 70% of patients.

BEST had no commercial funding. Dr. Nogueira reported no disclosures.

SOURCE: Nogueira RG et al. Int J Stroke. 2018;13(2_suppl):227, Abstract 978.


 

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Key clinical point: Thrombectomy produced improved outcomes in patients with basilar-artery occlusion strokes.

Major finding: In the as-treated analysis, thrombectomy produced a 47% rate of modified Rankin Scale scores of 0-3 after 90 days, compared with 24% in controls.

Study details: BEST, a multicenter, randomized trial with 131 Chinese patients.

Disclosures: BEST had no commercial funding. Dr. Nogueira reported no disclosures.

Source: Nogueira RG et al. Int J Stroke. 2018;13(2_suppl):227, Abstract 978.

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Acute stroke thrombolysis worked safely despite GI bleed or malignancy

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– A recent history of GI bleeding or malignancy may not be a valid contraindication to thrombolytic therapy in patients with an acute ischemic stroke, based on a review of outcomes from more than 40,000 U.S. stroke patients.

Dr. Taku Inohara

The analysis showed that, among 40,396 U.S. patients who had an acute ischemic stroke during 2009-2015 and received timely treatment with alteplase, “we did not find statistically significant increased rates of in-hospital mortality or bleeding” in the small number of patients who received alteplase (Activase) despite a recent GI bleed or diagnosed GI malignancy, Taku Inohara, MD, said at the American Heart Association scientific sessions. The 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke deemed thrombolytic therapy with alteplase in these types of patients contraindicated, based on consensus expert opinion (Stroke. 2018 March;49[3]:e66-e110).

“Further study is needed to evaluate the safety of recombinant tissue–type plasminogen activator [alteplase] in this specific population,” suggested Dr. Inohara, a cardiologist and research fellow at Duke University, Durham, N.C.

His analysis used data collected by the Get With the Guidelines–Stroke program, a voluntary quality promotion and improvement program that during 2009-2015 included records for more than 633,000 U.S. stroke patients that could be linked with records kept by the Centers for Medicare & Medicaid Services. From this database, 40,396 patients (6%) treated with alteplase within 4.5 hours of stroke onset were identified. The alteplase-treated patients included 93 with a diagnosis code during the prior year for a GI malignancy and 43 with a diagnostic code within the prior 21 days for a GI bleed.


Dr. Inohara and his associates determined patients’ mortality during their stroke hospitalization, as well as several measures of functional recovery at hospital discharge and thrombolysis-related complications. For each of these endpoints, the rate among patients with a GI malignancy, a GI bleed, or the rate among a combined group of both patients showed no statistically significant differences, compared with the more than 40,000 other patients without a GI complication after adjustment for several demographic and clinical between-group differences. However, Dr. Inohara cautioned that residual or unmeasured confounding may exist that distorts these findings. The rate of in-hospital mortality, the prespecified primary endpoint for the analysis, was 10% among patients with either type of GI complication and 9% in those without. The rate of serious thrombolysis-related complications was 7% in the patients with GI disease and 9% in those without.

In a separate analysis of the complete database of more than 633,000 patients, Dr. Inohara and his associates found 148 patients who had either a GI bleed or malignancy and otherwise qualified for thrombolytic therapy but did not receive this treatment. This meant that overall, in this large U.S. experience, 136 of 284 (48%) acute ischemic stroke patients who qualified for thrombolysis but had a GI complication nonetheless received thrombolysis. Further analysis showed that the patients not treated with thrombolysis had at admission an average National Institutes of Health Stroke Scale score of 11, compared with an average score of 14 among patients who received thrombolysis.

This apparent selection for thrombolytic treatment of patients with more severe strokes “may have overestimated risk in the patients with GI disease,” Dr. Inohara said.

Dr. Inohara reported receiving research funding from Boston Scientific.

SOURCE: Inohara T et al. Circulation. 2018 Nov 6;138[suppl 1], Abstract 12291.

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– A recent history of GI bleeding or malignancy may not be a valid contraindication to thrombolytic therapy in patients with an acute ischemic stroke, based on a review of outcomes from more than 40,000 U.S. stroke patients.

Dr. Taku Inohara

The analysis showed that, among 40,396 U.S. patients who had an acute ischemic stroke during 2009-2015 and received timely treatment with alteplase, “we did not find statistically significant increased rates of in-hospital mortality or bleeding” in the small number of patients who received alteplase (Activase) despite a recent GI bleed or diagnosed GI malignancy, Taku Inohara, MD, said at the American Heart Association scientific sessions. The 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke deemed thrombolytic therapy with alteplase in these types of patients contraindicated, based on consensus expert opinion (Stroke. 2018 March;49[3]:e66-e110).

“Further study is needed to evaluate the safety of recombinant tissue–type plasminogen activator [alteplase] in this specific population,” suggested Dr. Inohara, a cardiologist and research fellow at Duke University, Durham, N.C.

His analysis used data collected by the Get With the Guidelines–Stroke program, a voluntary quality promotion and improvement program that during 2009-2015 included records for more than 633,000 U.S. stroke patients that could be linked with records kept by the Centers for Medicare & Medicaid Services. From this database, 40,396 patients (6%) treated with alteplase within 4.5 hours of stroke onset were identified. The alteplase-treated patients included 93 with a diagnosis code during the prior year for a GI malignancy and 43 with a diagnostic code within the prior 21 days for a GI bleed.


Dr. Inohara and his associates determined patients’ mortality during their stroke hospitalization, as well as several measures of functional recovery at hospital discharge and thrombolysis-related complications. For each of these endpoints, the rate among patients with a GI malignancy, a GI bleed, or the rate among a combined group of both patients showed no statistically significant differences, compared with the more than 40,000 other patients without a GI complication after adjustment for several demographic and clinical between-group differences. However, Dr. Inohara cautioned that residual or unmeasured confounding may exist that distorts these findings. The rate of in-hospital mortality, the prespecified primary endpoint for the analysis, was 10% among patients with either type of GI complication and 9% in those without. The rate of serious thrombolysis-related complications was 7% in the patients with GI disease and 9% in those without.

In a separate analysis of the complete database of more than 633,000 patients, Dr. Inohara and his associates found 148 patients who had either a GI bleed or malignancy and otherwise qualified for thrombolytic therapy but did not receive this treatment. This meant that overall, in this large U.S. experience, 136 of 284 (48%) acute ischemic stroke patients who qualified for thrombolysis but had a GI complication nonetheless received thrombolysis. Further analysis showed that the patients not treated with thrombolysis had at admission an average National Institutes of Health Stroke Scale score of 11, compared with an average score of 14 among patients who received thrombolysis.

This apparent selection for thrombolytic treatment of patients with more severe strokes “may have overestimated risk in the patients with GI disease,” Dr. Inohara said.

Dr. Inohara reported receiving research funding from Boston Scientific.

SOURCE: Inohara T et al. Circulation. 2018 Nov 6;138[suppl 1], Abstract 12291.

– A recent history of GI bleeding or malignancy may not be a valid contraindication to thrombolytic therapy in patients with an acute ischemic stroke, based on a review of outcomes from more than 40,000 U.S. stroke patients.

Dr. Taku Inohara

The analysis showed that, among 40,396 U.S. patients who had an acute ischemic stroke during 2009-2015 and received timely treatment with alteplase, “we did not find statistically significant increased rates of in-hospital mortality or bleeding” in the small number of patients who received alteplase (Activase) despite a recent GI bleed or diagnosed GI malignancy, Taku Inohara, MD, said at the American Heart Association scientific sessions. The 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke deemed thrombolytic therapy with alteplase in these types of patients contraindicated, based on consensus expert opinion (Stroke. 2018 March;49[3]:e66-e110).

“Further study is needed to evaluate the safety of recombinant tissue–type plasminogen activator [alteplase] in this specific population,” suggested Dr. Inohara, a cardiologist and research fellow at Duke University, Durham, N.C.

His analysis used data collected by the Get With the Guidelines–Stroke program, a voluntary quality promotion and improvement program that during 2009-2015 included records for more than 633,000 U.S. stroke patients that could be linked with records kept by the Centers for Medicare & Medicaid Services. From this database, 40,396 patients (6%) treated with alteplase within 4.5 hours of stroke onset were identified. The alteplase-treated patients included 93 with a diagnosis code during the prior year for a GI malignancy and 43 with a diagnostic code within the prior 21 days for a GI bleed.


Dr. Inohara and his associates determined patients’ mortality during their stroke hospitalization, as well as several measures of functional recovery at hospital discharge and thrombolysis-related complications. For each of these endpoints, the rate among patients with a GI malignancy, a GI bleed, or the rate among a combined group of both patients showed no statistically significant differences, compared with the more than 40,000 other patients without a GI complication after adjustment for several demographic and clinical between-group differences. However, Dr. Inohara cautioned that residual or unmeasured confounding may exist that distorts these findings. The rate of in-hospital mortality, the prespecified primary endpoint for the analysis, was 10% among patients with either type of GI complication and 9% in those without. The rate of serious thrombolysis-related complications was 7% in the patients with GI disease and 9% in those without.

In a separate analysis of the complete database of more than 633,000 patients, Dr. Inohara and his associates found 148 patients who had either a GI bleed or malignancy and otherwise qualified for thrombolytic therapy but did not receive this treatment. This meant that overall, in this large U.S. experience, 136 of 284 (48%) acute ischemic stroke patients who qualified for thrombolysis but had a GI complication nonetheless received thrombolysis. Further analysis showed that the patients not treated with thrombolysis had at admission an average National Institutes of Health Stroke Scale score of 11, compared with an average score of 14 among patients who received thrombolysis.

This apparent selection for thrombolytic treatment of patients with more severe strokes “may have overestimated risk in the patients with GI disease,” Dr. Inohara said.

Dr. Inohara reported receiving research funding from Boston Scientific.

SOURCE: Inohara T et al. Circulation. 2018 Nov 6;138[suppl 1], Abstract 12291.

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Key clinical point: Thrombolysis for acute ischemic stroke appeared safe in patients with a recent GI bleed or malignancy.

Major finding: In-hospital mortality after thrombolysis was 10% in those with a GI bleed or malignancy and 9% in those without.

Study details: A review of Medicare records for 40,396 acute ischemic stroke patients treated with thrombolysis during 2009-2015.

Disclosures: Dr. Inohara reported receiving research funding from Boston Scientific.

Source: Inohara T et al. Circulation. 2018 Nov 6;138[suppl 1], Abstract A12291.

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