Arrhythmias & EP

Early results from the massive National Cardiovascular Data Registry Left Atrial Appendage Occlusion Registry indicate that the rollout of the Watchman device into routine clinical practice is going smoothly, with a higher implant success rate and a substantially lower in-hospital complication rate than that seen in the pivotal randomized clinical trials, James V. Freeman, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

American College of Cardiology

These real-world results are particularly impressive because the 38,158 registry participants were on average significantly older and sicker than were patients in the clinical trials. They were at higher risk of both stroke and bleeding, yet they fared better in terms of procedural safety, observed Dr. Freeman, an electrophysiologist and director of the Yale University Atrial Fibrillation Center in New Haven, Conn.

“You always worry that once you get outside of the clinical trials setting and you roll out to a large number of centers, including some that are relatively low volume, that you’re going to start to see higher rates of complications. And overall, broadly speaking, the rates of adverse events were quite reassuring,” he said.

The registry, maintained by the ACC, serves as the postmarketing surveillance tool mandated by the Food and Drug Administration and Centers for Medicare & Medicaid Services. The 38,158 participants make this registry the world’s largest patient experience with the Watchman device by many orders of magnitude. Dr. Freeman’s report included patients enrolled during 2016-2018 who were treated at 495 hospitals by 1,318 physician interventionalists. CMS reimbursement requires participation in the registry, which captures more than 95% of all Watchman procedures done in the United States. Although Dr. Freeman presented only the acute in-hospital outcomes, active follow-up for adverse events and medical therapy will be conducted at 45 days, 6 months, and 1 and 2 years.

Participants in the Left Atrial Appendage Occlusion (LAAO) Registry averaged 76.1 years of age, which is 2-4 years older than patients in the pivotal PROTECT-AF and PREVAIL trials or the 1,025-patient EWOLUTION registry. The LAAO Registry participants had a mean CHA2DS2-VASc score of 4.6, compared with 3.4 in PROTECT-AF and 3.8 in PREVAIL. Their mean HAS BLED score was 3.0. Thirty percent had a prior ischemic stroke or transient ischemic attack, 12% had a prior intracranial hemorrhage, and 69% had a history of clinically relevant bleeding. Thirty percent had heart failure, 92% were hypertensive, and 30% had diabetes.

“The take home here is that these patients were at moderate to high risk of stroke and they also carried a high risk of bleeding and therefore had some relative contraindication to anticoagulation,” according to the cardiologist. “The patient population overall is really in accordance with the CMS guidance. We’re not seeing a lot of patients who are getting this device for a lifestyle indication. Most of these patients are really stuck between a rock and a hard place.”

Most hospitals offering the Watchman did 10-40 cases per year. The median annual physician volume was 12 cases. However, there was substantial variation in both hospital and physician volumes.

The device was deployed in 93% of procedures attempted; roughly half of cancellations were cause by LAAO thrombus detected on the day of the procedure. The acute procedural success rate when the device was deployed was 98.3%, compared with 90.9% in PROTECT-AF and 95.1% in PREVAIL. The rate of device margin residual leak of 5 mm or more among registry participants with an acutely successful procedure was 0.2%.

The rate of any major in-hospital complication in the LAAO Registry was 2.16%, the most common of which was pericardial effusion requiring intervention, which occurred in 1.39% of cases. The major bleeding rate was 1.25%. The stroke/transient ischemic attack rate was 0.17%. Systemic arterial embolism was a rare event, occurring in less than 0.01% of patients, as was acute MI, with an incidence of 0.04%. Device embolization occurred in 0.07% of patients.

By comparison, the 7-day rate of pericardial effusion requiring intervention was 4.0% in PROTECT-AF and 1.9% in PREVAIL, with procedure-related stroke rates of 1.1% and 0.7%, respectively, and device embolization rates of 0.4% and 0.7%. The major bleeding rate in PROTECT-AF was 3.5%, nearly triple that in the real-world registry.

Discussant Mark A. Estes, MD, characterized the acute outcomes in the LAAO Registry as “an improvement – a considerable improvement – over some of the early data in PREVAIL and PROTECT-AF.” He credited this to the “very robust validation procedure” the Watchman closure device has undergone, which included the clinical trials, regulatory requirements for training and patient selection, and mandatory reporting of outcomes in the registry.

He noted that a lot is happening now with the Watchman device. There are a couple of dozen prospective clinical trials, including one on the Watchman versus direct oral anticoagulant (DOAC) therapy and another on left atrial ablation plus left atrial appendage closure versus a DOAC. A new-generation Watchman device, the Watchman FLX, is approved in Europe and undergoing an ongoing FDA-mandated approval trial in the United States.

“It has a lot of technical advantages,” according to Dr. Estes, an electrophysiologist and professor of medicine at the University of Pittsburgh.

Current guidelines give LAAO a class IIb rating, meaning it “could be considered” in patients with atrial fibrillation at increased risk of stroke who have a contraindication to long-term anticoagulation. Dr. Estes asked: Does the LAAO Registry data warrant a rating upgrade to a stronger recommendation?

Dr. Freeman replied that the new data should allay the guideline writers’ and government regulators’ concerns regarding acute procedural safety. But that’s only part of the picture. He and his coinvestigators are busy gathering data on intermediate-term outcomes, analyzing the impact of various strategies for periprocedural and long-term management of antiplatelet and anticoagulant medications with an eye toward identifying best practices, and investigating the relationship between procedural volume and outcomes, information, which could have an impact on the next iteration of the guidelines.

Simultaneous with his presentation at ACC 2020, the study was published online (J Am Coll Cardiol. 2020 Mar 13;75[13]1503-18).

In an accompanying editorial, Dhanunjaya Lakkireddy, MD, commented that an important contribution of the LAAO Registry is its inclusion of an enormous number of patients with contraindications to oral anticoagulation, a population excluded from the PROTECT-AF and PREVAIL randomized trials.

The short-term results of the registry suggest a relaxation of the current strict requirement for surgical backup during Watchman procedures is in order, added Dr. Lakkireddy, professor of medicine at the University of Missouri, Columbia, and medical director of the Kansas City Heart Rhythm Institute (J Am Coll Cardiol. 2020 Mar 13;75[13]:1519-22).

Dr. Freeman reported serving as a consultant to Boston Scientific, which markets the Watchman, as well as to Medtronic, Janssen, and Biosense Webster.

[email protected]

SOURCE: Freeman JF. ACC 2020, Abstract 409-10.

Early results from the massive National Cardiovascular Data Registry Left Atrial Appendage Occlusion Registry indicate that the rollout of the Watchman device into routine clinical practice is going smoothly, with a higher implant success rate and a substantially lower in-hospital complication rate than that seen in the pivotal randomized clinical trials, James V. Freeman, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

American College of Cardiology

These real-world results are particularly impressive because the 38,158 registry participants were on average significantly older and sicker than were patients in the clinical trials. They were at higher risk of both stroke and bleeding, yet they fared better in terms of procedural safety, observed Dr. Freeman, an electrophysiologist and director of the Yale University Atrial Fibrillation Center in New Haven, Conn.

“You always worry that once you get outside of the clinical trials setting and you roll out to a large number of centers, including some that are relatively low volume, that you’re going to start to see higher rates of complications. And overall, broadly speaking, the rates of adverse events were quite reassuring,” he said.

The registry, maintained by the ACC, serves as the postmarketing surveillance tool mandated by the Food and Drug Administration and Centers for Medicare & Medicaid Services. The 38,158 participants make this registry the world’s largest patient experience with the Watchman device by many orders of magnitude. Dr. Freeman’s report included patients enrolled during 2016-2018 who were treated at 495 hospitals by 1,318 physician interventionalists. CMS reimbursement requires participation in the registry, which captures more than 95% of all Watchman procedures done in the United States. Although Dr. Freeman presented only the acute in-hospital outcomes, active follow-up for adverse events and medical therapy will be conducted at 45 days, 6 months, and 1 and 2 years.

Participants in the Left Atrial Appendage Occlusion (LAAO) Registry averaged 76.1 years of age, which is 2-4 years older than patients in the pivotal PROTECT-AF and PREVAIL trials or the 1,025-patient EWOLUTION registry. The LAAO Registry participants had a mean CHA2DS2-VASc score of 4.6, compared with 3.4 in PROTECT-AF and 3.8 in PREVAIL. Their mean HAS BLED score was 3.0. Thirty percent had a prior ischemic stroke or transient ischemic attack, 12% had a prior intracranial hemorrhage, and 69% had a history of clinically relevant bleeding. Thirty percent had heart failure, 92% were hypertensive, and 30% had diabetes.

“The take home here is that these patients were at moderate to high risk of stroke and they also carried a high risk of bleeding and therefore had some relative contraindication to anticoagulation,” according to the cardiologist. “The patient population overall is really in accordance with the CMS guidance. We’re not seeing a lot of patients who are getting this device for a lifestyle indication. Most of these patients are really stuck between a rock and a hard place.”

Most hospitals offering the Watchman did 10-40 cases per year. The median annual physician volume was 12 cases. However, there was substantial variation in both hospital and physician volumes.

The device was deployed in 93% of procedures attempted; roughly half of cancellations were cause by LAAO thrombus detected on the day of the procedure. The acute procedural success rate when the device was deployed was 98.3%, compared with 90.9% in PROTECT-AF and 95.1% in PREVAIL. The rate of device margin residual leak of 5 mm or more among registry participants with an acutely successful procedure was 0.2%.

The rate of any major in-hospital complication in the LAAO Registry was 2.16%, the most common of which was pericardial effusion requiring intervention, which occurred in 1.39% of cases. The major bleeding rate was 1.25%. The stroke/transient ischemic attack rate was 0.17%. Systemic arterial embolism was a rare event, occurring in less than 0.01% of patients, as was acute MI, with an incidence of 0.04%. Device embolization occurred in 0.07% of patients.

By comparison, the 7-day rate of pericardial effusion requiring intervention was 4.0% in PROTECT-AF and 1.9% in PREVAIL, with procedure-related stroke rates of 1.1% and 0.7%, respectively, and device embolization rates of 0.4% and 0.7%. The major bleeding rate in PROTECT-AF was 3.5%, nearly triple that in the real-world registry.

Discussant Mark A. Estes, MD, characterized the acute outcomes in the LAAO Registry as “an improvement – a considerable improvement – over some of the early data in PREVAIL and PROTECT-AF.” He credited this to the “very robust validation procedure” the Watchman closure device has undergone, which included the clinical trials, regulatory requirements for training and patient selection, and mandatory reporting of outcomes in the registry.

He noted that a lot is happening now with the Watchman device. There are a couple of dozen prospective clinical trials, including one on the Watchman versus direct oral anticoagulant (DOAC) therapy and another on left atrial ablation plus left atrial appendage closure versus a DOAC. A new-generation Watchman device, the Watchman FLX, is approved in Europe and undergoing an ongoing FDA-mandated approval trial in the United States.

“It has a lot of technical advantages,” according to Dr. Estes, an electrophysiologist and professor of medicine at the University of Pittsburgh.

Current guidelines give LAAO a class IIb rating, meaning it “could be considered” in patients with atrial fibrillation at increased risk of stroke who have a contraindication to long-term anticoagulation. Dr. Estes asked: Does the LAAO Registry data warrant a rating upgrade to a stronger recommendation?

Dr. Freeman replied that the new data should allay the guideline writers’ and government regulators’ concerns regarding acute procedural safety. But that’s only part of the picture. He and his coinvestigators are busy gathering data on intermediate-term outcomes, analyzing the impact of various strategies for periprocedural and long-term management of antiplatelet and anticoagulant medications with an eye toward identifying best practices, and investigating the relationship between procedural volume and outcomes, information, which could have an impact on the next iteration of the guidelines.

Simultaneous with his presentation at ACC 2020, the study was published online (J Am Coll Cardiol. 2020 Mar 13;75[13]1503-18).

In an accompanying editorial, Dhanunjaya Lakkireddy, MD, commented that an important contribution of the LAAO Registry is its inclusion of an enormous number of patients with contraindications to oral anticoagulation, a population excluded from the PROTECT-AF and PREVAIL randomized trials.

The short-term results of the registry suggest a relaxation of the current strict requirement for surgical backup during Watchman procedures is in order, added Dr. Lakkireddy, professor of medicine at the University of Missouri, Columbia, and medical director of the Kansas City Heart Rhythm Institute (J Am Coll Cardiol. 2020 Mar 13;75[13]:1519-22).

Dr. Freeman reported serving as a consultant to Boston Scientific, which markets the Watchman, as well as to Medtronic, Janssen, and Biosense Webster.

[email protected]

SOURCE: Freeman JF. ACC 2020, Abstract 409-10.

Early results from the massive National Cardiovascular Data Registry Left Atrial Appendage Occlusion Registry indicate that the rollout of the Watchman device into routine clinical practice is going smoothly, with a higher implant success rate and a substantially lower in-hospital complication rate than that seen in the pivotal randomized clinical trials, James V. Freeman, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

American College of Cardiology

These real-world results are particularly impressive because the 38,158 registry participants were on average significantly older and sicker than were patients in the clinical trials. They were at higher risk of both stroke and bleeding, yet they fared better in terms of procedural safety, observed Dr. Freeman, an electrophysiologist and director of the Yale University Atrial Fibrillation Center in New Haven, Conn.

“You always worry that once you get outside of the clinical trials setting and you roll out to a large number of centers, including some that are relatively low volume, that you’re going to start to see higher rates of complications. And overall, broadly speaking, the rates of adverse events were quite reassuring,” he said.

The registry, maintained by the ACC, serves as the postmarketing surveillance tool mandated by the Food and Drug Administration and Centers for Medicare & Medicaid Services. The 38,158 participants make this registry the world’s largest patient experience with the Watchman device by many orders of magnitude. Dr. Freeman’s report included patients enrolled during 2016-2018 who were treated at 495 hospitals by 1,318 physician interventionalists. CMS reimbursement requires participation in the registry, which captures more than 95% of all Watchman procedures done in the United States. Although Dr. Freeman presented only the acute in-hospital outcomes, active follow-up for adverse events and medical therapy will be conducted at 45 days, 6 months, and 1 and 2 years.

Participants in the Left Atrial Appendage Occlusion (LAAO) Registry averaged 76.1 years of age, which is 2-4 years older than patients in the pivotal PROTECT-AF and PREVAIL trials or the 1,025-patient EWOLUTION registry. The LAAO Registry participants had a mean CHA2DS2-VASc score of 4.6, compared with 3.4 in PROTECT-AF and 3.8 in PREVAIL. Their mean HAS BLED score was 3.0. Thirty percent had a prior ischemic stroke or transient ischemic attack, 12% had a prior intracranial hemorrhage, and 69% had a history of clinically relevant bleeding. Thirty percent had heart failure, 92% were hypertensive, and 30% had diabetes.

“The take home here is that these patients were at moderate to high risk of stroke and they also carried a high risk of bleeding and therefore had some relative contraindication to anticoagulation,” according to the cardiologist. “The patient population overall is really in accordance with the CMS guidance. We’re not seeing a lot of patients who are getting this device for a lifestyle indication. Most of these patients are really stuck between a rock and a hard place.”

Most hospitals offering the Watchman did 10-40 cases per year. The median annual physician volume was 12 cases. However, there was substantial variation in both hospital and physician volumes.

The device was deployed in 93% of procedures attempted; roughly half of cancellations were cause by LAAO thrombus detected on the day of the procedure. The acute procedural success rate when the device was deployed was 98.3%, compared with 90.9% in PROTECT-AF and 95.1% in PREVAIL. The rate of device margin residual leak of 5 mm or more among registry participants with an acutely successful procedure was 0.2%.

The rate of any major in-hospital complication in the LAAO Registry was 2.16%, the most common of which was pericardial effusion requiring intervention, which occurred in 1.39% of cases. The major bleeding rate was 1.25%. The stroke/transient ischemic attack rate was 0.17%. Systemic arterial embolism was a rare event, occurring in less than 0.01% of patients, as was acute MI, with an incidence of 0.04%. Device embolization occurred in 0.07% of patients.

By comparison, the 7-day rate of pericardial effusion requiring intervention was 4.0% in PROTECT-AF and 1.9% in PREVAIL, with procedure-related stroke rates of 1.1% and 0.7%, respectively, and device embolization rates of 0.4% and 0.7%. The major bleeding rate in PROTECT-AF was 3.5%, nearly triple that in the real-world registry.

Discussant Mark A. Estes, MD, characterized the acute outcomes in the LAAO Registry as “an improvement – a considerable improvement – over some of the early data in PREVAIL and PROTECT-AF.” He credited this to the “very robust validation procedure” the Watchman closure device has undergone, which included the clinical trials, regulatory requirements for training and patient selection, and mandatory reporting of outcomes in the registry.

He noted that a lot is happening now with the Watchman device. There are a couple of dozen prospective clinical trials, including one on the Watchman versus direct oral anticoagulant (DOAC) therapy and another on left atrial ablation plus left atrial appendage closure versus a DOAC. A new-generation Watchman device, the Watchman FLX, is approved in Europe and undergoing an ongoing FDA-mandated approval trial in the United States.

“It has a lot of technical advantages,” according to Dr. Estes, an electrophysiologist and professor of medicine at the University of Pittsburgh.

Current guidelines give LAAO a class IIb rating, meaning it “could be considered” in patients with atrial fibrillation at increased risk of stroke who have a contraindication to long-term anticoagulation. Dr. Estes asked: Does the LAAO Registry data warrant a rating upgrade to a stronger recommendation?

Dr. Freeman replied that the new data should allay the guideline writers’ and government regulators’ concerns regarding acute procedural safety. But that’s only part of the picture. He and his coinvestigators are busy gathering data on intermediate-term outcomes, analyzing the impact of various strategies for periprocedural and long-term management of antiplatelet and anticoagulant medications with an eye toward identifying best practices, and investigating the relationship between procedural volume and outcomes, information, which could have an impact on the next iteration of the guidelines.

Simultaneous with his presentation at ACC 2020, the study was published online (J Am Coll Cardiol. 2020 Mar 13;75[13]1503-18).

In an accompanying editorial, Dhanunjaya Lakkireddy, MD, commented that an important contribution of the LAAO Registry is its inclusion of an enormous number of patients with contraindications to oral anticoagulation, a population excluded from the PROTECT-AF and PREVAIL randomized trials.

The short-term results of the registry suggest a relaxation of the current strict requirement for surgical backup during Watchman procedures is in order, added Dr. Lakkireddy, professor of medicine at the University of Missouri, Columbia, and medical director of the Kansas City Heart Rhythm Institute (J Am Coll Cardiol. 2020 Mar 13;75[13]:1519-22).

Dr. Freeman reported serving as a consultant to Boston Scientific, which markets the Watchman, as well as to Medtronic, Janssen, and Biosense Webster.

[email protected]

SOURCE: Freeman JF. ACC 2020, Abstract 409-10.

The guidelines allow for the addition of short-term clopidogrel to an oral anticoagulant (OAC) in patients with an established OAC indication, such as atrial fibrillation (AF), who undergo transcatheter aortic valve replacement (TAVR). But does the extra antithrombotic protection come with safety issues?

It apparently did in the POPULAR-TAVI trial, which saw an excess of major and minor bleeding in such patients already on an OAC when they underwent TAVR and who then took the antiplatelet agent for the next 3 months.

The patients who instead continued on their OAC as the only post-TAVR antithrombotic, compared with those on double therapy, showed a 37% lower 1-year risk of any bleeding, including major and disabling bleeding.

Importantly, they didn’t seem to pay a price in excess ischemic events, such as stroke or myocardial infarction (MI).

The trial argues against adding clopidogrel on top of OAC in TAVR patients with an OAC indication in order to reduce their risk of bleeding, Jurriën ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, the Netherlands, told theheart.org | Medscape Cardiology.

Whether the ischemic event risk was comparable with and without clopidogrel is less clear. “As the study is not powered for the ischemic end points, the answer is less definite. But we did not see a hint of a higher ischemic event rate, especially stroke, in the OAC-alone group,” ten Berg said.

“So we are pretty confident in saying that OAC alone is the optimal treatment.”

The results of POPULAR-TAVI were presented by Vincent Nijenhuis, MD, also from St. Antonius Hospital, on March 29 during the virtual presentation of the American College of Cardiology 2020 Scientific Session/World Congress of Cardiology. Nijenhuis is also first author on the trial’s simultaneous publication in the New England Journal of Medicine.

The only reason to add an antiplatelet in TAVR patients who need to be on an OAC for another indication is to prevent ischemic events like MI, stroke, or death, agreed George D. Dangas, MD, PhD, Mount Sinai Hospital, New York City, for theheart.org | Medscape Cardiology.

But that protection apparently wasn’t needed; for patients on OAC only, “the overall risk–benefit ratio was favorable for them both ways. Although the study is small, I think the findings would be clinically meaningful,” said Dangas, who was not involved in POPULAR-TAVI but was lead author on the GALILEO trial publication.

GALILEO tested a direct oral anticoagulant (DOAC) against dual antiplatelet therapy in patients undergoing TAVR but without a conventional OAC indication. The trial was halted because the DOAC group started to show an excess of bleeding, thromboembolic events, and mortality.

Most POPULAR-TAVI patients were on vitamin K antagonists, but about a quarter were taking DOACs. Clopidogrel was given on an open-label basis.

The trial suggests that, for TAVR patients with an indication for lifelong OAC, “it does appear to be safe to give only an anticoagulant, whether it’s warfarin or a DOAC, and not add clopidogrel,” Robert O. Bonow, MD, Northwestern University, Chicago, told theheart.org | Medscape Cardiology.

“The bottom line appears to be that it’s no worse, and is probably better in terms of bleeding events,” said Bonow, who wasn’t involved in POPULAR-TAVI.

But there are difficulties in interpreting the trial that stem from its design and other issues, he said. For example, it can’t really be concluded that adding an antiplatelet agent to OAC in such patients who undergo TAVR, according to commonly practiced techniques, will increase the risk of bleeding compared with OAC alone.

To begin with, Bonow said, substituting aspirin for clopidogrel might have produced better double-therapy results. But the bigger issues, Bonow said, center on the discretion its operators had in whether to maintain or suspend the patients’ OAC during the TAVR procedure, as well as the unusual bleeding definitions used in the trial.

The first POPULAR-TAVI primary end point was any bleeding that met Valve Academic Research Consortium (VARC) criteria; the second was nonprocedural bleeding that met the Bleeding Academic Research Consortium (BARC) definition.

“Because the VARC-2 classification does not distinguish between procedure-related and nonprocedure-related bleeding events, procedure-related events were defined as BARC type 4 severe bleeding,” the trial’s journal report states. Therefore, “most bleeding at the puncture site was counted as nonprocedure-related.”

It may be Bonow’s biggest issue with the trial, he said. “They’re terming these events that occurred periprocedurally, in the first day or first hours of the procedure, as being ‘nonprocedural’ because they didn’t represent severe BARC bleeding, where you have a subarachnoid hemorrhage or require transfusions.”

An editorial accompanying the trial report also knocks this aspect of the trial design. Although the trial “confirmed” a higher incidence of any bleeding in the double-therapy group, “there are concerns regarding the classification of bleeding and the reliability of secondary outcome analysis,” writes Frederick Feit, MD, NYU Grossman School of Medicine, New York City.

“Bleeding occurring during TAVI or the index hospitalization was unadvisedly defined as non-procedure related, even if it occurred at the access site,” the editorial notes.

Ten Berg noted that procedural bleeding is frequent in TAVI, but the VARC-2 definition doesn’t accommodate them. So “we also used the BARC definition for procedural bleeding, BARC-4,” he told theheart.org | Medscape Cardiology.

“However, BARC-4 describes bleeding during surgery, and it turned out that in POPULAR- TAVI only one patient had BARC-4 bleeding. So we do not at all agree with the editorial.”

Still, the trial’s reported event-rate curves show that “most of the step-up in bleeding, in either arm of the trial, occurred immediately,” Bonow observed. A more consistent, flat trend followed thereafter out to 3 months.

“So half of the bleeding in both arms of the trial occurred at the site of the arterial puncture. Though it wasn’t considered severe, it was indeed periprocedural,” Bonow said, interpreting the results.

The POPULAR-TAVI journal report says the procedures were performed according to local site protocols, and site physicians were allowed to decide whether to continue or suspend OAC. But “the trial protocol advised physicians to continue oral anticoagulation during admission for the TAVI procedure.”

Many of the patients, regardless of randomization group, “went through the procedure under full anticoagulation,” Dangas agreed. POPULAR-TAVI, it seems, “is the first anticoagulation study ever to start anticoagulation before the procedure.”

Bleeding event rates in the trial “are somewhat high because of this unusual procedural feature of the study,” Dangas said.

“It’s therefore not surprising that so much of the bleeding occurred in the first hours of the procedure itself,” observed Bonow.

The trial enrolled 313 patients in four European countries who were on OAC for an approved indication, predominantly AF, and underwent TAVR. Their mean age was about 81 years, and 45.4% were women. They were randomly assigned to receive or not receive clopidogrel in a loading dose, followed by 75 mg/d on top of their OAC for 3 months, and were followed out to a year.

All bleeding that met VARC-2 criteria, the first primary end point, occurred in 21.7% of the 157 patients on OAC alone and 34.6% of the 156 who received double therapy (risk ratio [RR], 0.63; 95% CI, 0.43 - 0.90; P = .011).

The second primary end point, “nonprocedural” bleeding that met BARC-4 criteria, occurred in 21.7% and 34.0%, respectively, of patients (RR, 0.64; 95% CI, 0.44 - 0.92; P = .015).

There were also two secondary composite outcomes. The first consisted of nonprocedural bleeding, cardiovascular (CV) death, any stroke, and MI, and was seen in 31.2% of patients on OAC alone and 45.5% of those on OAC plus clopidogrel (RR, 0.69; 95% CI, 0.51 - 0.92), an absolute difference that was within the prospectively defined noninferiority margins.

The other secondary end point — CV death, ischemic stroke, and MI — occurred in 13.4% of those receiving only OAC and 17.3% on added clopidogrel (RR, 0.77; 95% CI, 0.46 - 1.31), which was nonsignificant for superiority.

“Could they have done better by holding the anticoagulation, whether warfarin or a DOAC, during that time? That’s what I think many centers might do if they’re performing a TAVR,” Bonow said.

“It seems to me that could have been done in this trial as well: they could have stopped the anticoagulation, done the procedure, and started the anticoagulation after, the way you would normally in a patient getting a TAVR.”

Such a practice might have reduced the risk of procedural bleeding as it is usually defined in TAVR in both groups, thereby potentially blunting any difference in bleeding rate between the two groups.

“That’s my take on it.” Still, he said, the trial’s message remains: OAC without clopidogrel is safe in POPULAR-TAVI-like patients.

Nijenhuis had no disclosures. Ten Berg disclosed no industry ties. Disclosures for the other authors are in the report. Bonow has previously reported no disclosures. Dangas has previously disclosed receiving grants and fees from Bayer, fees from Janssen; grants and personal fees from Daiichi-Sankyo; and other compensation from Medtronic. Feit discloses personal fees from Abbott Vascular and other relationships with Medtronic, Boston Scientific, and Sapheon.

This article first appeared on Medscape.com.

The guidelines allow for the addition of short-term clopidogrel to an oral anticoagulant (OAC) in patients with an established OAC indication, such as atrial fibrillation (AF), who undergo transcatheter aortic valve replacement (TAVR). But does the extra antithrombotic protection come with safety issues?

It apparently did in the POPULAR-TAVI trial, which saw an excess of major and minor bleeding in such patients already on an OAC when they underwent TAVR and who then took the antiplatelet agent for the next 3 months.

The patients who instead continued on their OAC as the only post-TAVR antithrombotic, compared with those on double therapy, showed a 37% lower 1-year risk of any bleeding, including major and disabling bleeding.

Importantly, they didn’t seem to pay a price in excess ischemic events, such as stroke or myocardial infarction (MI).

The trial argues against adding clopidogrel on top of OAC in TAVR patients with an OAC indication in order to reduce their risk of bleeding, Jurriën ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, the Netherlands, told theheart.org | Medscape Cardiology.

Whether the ischemic event risk was comparable with and without clopidogrel is less clear. “As the study is not powered for the ischemic end points, the answer is less definite. But we did not see a hint of a higher ischemic event rate, especially stroke, in the OAC-alone group,” ten Berg said.

“So we are pretty confident in saying that OAC alone is the optimal treatment.”

The results of POPULAR-TAVI were presented by Vincent Nijenhuis, MD, also from St. Antonius Hospital, on March 29 during the virtual presentation of the American College of Cardiology 2020 Scientific Session/World Congress of Cardiology. Nijenhuis is also first author on the trial’s simultaneous publication in the New England Journal of Medicine.

The only reason to add an antiplatelet in TAVR patients who need to be on an OAC for another indication is to prevent ischemic events like MI, stroke, or death, agreed George D. Dangas, MD, PhD, Mount Sinai Hospital, New York City, for theheart.org | Medscape Cardiology.

But that protection apparently wasn’t needed; for patients on OAC only, “the overall risk–benefit ratio was favorable for them both ways. Although the study is small, I think the findings would be clinically meaningful,” said Dangas, who was not involved in POPULAR-TAVI but was lead author on the GALILEO trial publication.

GALILEO tested a direct oral anticoagulant (DOAC) against dual antiplatelet therapy in patients undergoing TAVR but without a conventional OAC indication. The trial was halted because the DOAC group started to show an excess of bleeding, thromboembolic events, and mortality.

Most POPULAR-TAVI patients were on vitamin K antagonists, but about a quarter were taking DOACs. Clopidogrel was given on an open-label basis.

The trial suggests that, for TAVR patients with an indication for lifelong OAC, “it does appear to be safe to give only an anticoagulant, whether it’s warfarin or a DOAC, and not add clopidogrel,” Robert O. Bonow, MD, Northwestern University, Chicago, told theheart.org | Medscape Cardiology.

“The bottom line appears to be that it’s no worse, and is probably better in terms of bleeding events,” said Bonow, who wasn’t involved in POPULAR-TAVI.

But there are difficulties in interpreting the trial that stem from its design and other issues, he said. For example, it can’t really be concluded that adding an antiplatelet agent to OAC in such patients who undergo TAVR, according to commonly practiced techniques, will increase the risk of bleeding compared with OAC alone.

To begin with, Bonow said, substituting aspirin for clopidogrel might have produced better double-therapy results. But the bigger issues, Bonow said, center on the discretion its operators had in whether to maintain or suspend the patients’ OAC during the TAVR procedure, as well as the unusual bleeding definitions used in the trial.

The first POPULAR-TAVI primary end point was any bleeding that met Valve Academic Research Consortium (VARC) criteria; the second was nonprocedural bleeding that met the Bleeding Academic Research Consortium (BARC) definition.

“Because the VARC-2 classification does not distinguish between procedure-related and nonprocedure-related bleeding events, procedure-related events were defined as BARC type 4 severe bleeding,” the trial’s journal report states. Therefore, “most bleeding at the puncture site was counted as nonprocedure-related.”

It may be Bonow’s biggest issue with the trial, he said. “They’re terming these events that occurred periprocedurally, in the first day or first hours of the procedure, as being ‘nonprocedural’ because they didn’t represent severe BARC bleeding, where you have a subarachnoid hemorrhage or require transfusions.”

An editorial accompanying the trial report also knocks this aspect of the trial design. Although the trial “confirmed” a higher incidence of any bleeding in the double-therapy group, “there are concerns regarding the classification of bleeding and the reliability of secondary outcome analysis,” writes Frederick Feit, MD, NYU Grossman School of Medicine, New York City.

“Bleeding occurring during TAVI or the index hospitalization was unadvisedly defined as non-procedure related, even if it occurred at the access site,” the editorial notes.

Ten Berg noted that procedural bleeding is frequent in TAVI, but the VARC-2 definition doesn’t accommodate them. So “we also used the BARC definition for procedural bleeding, BARC-4,” he told theheart.org | Medscape Cardiology.

“However, BARC-4 describes bleeding during surgery, and it turned out that in POPULAR- TAVI only one patient had BARC-4 bleeding. So we do not at all agree with the editorial.”

Still, the trial’s reported event-rate curves show that “most of the step-up in bleeding, in either arm of the trial, occurred immediately,” Bonow observed. A more consistent, flat trend followed thereafter out to 3 months.

“So half of the bleeding in both arms of the trial occurred at the site of the arterial puncture. Though it wasn’t considered severe, it was indeed periprocedural,” Bonow said, interpreting the results.

The POPULAR-TAVI journal report says the procedures were performed according to local site protocols, and site physicians were allowed to decide whether to continue or suspend OAC. But “the trial protocol advised physicians to continue oral anticoagulation during admission for the TAVI procedure.”

Many of the patients, regardless of randomization group, “went through the procedure under full anticoagulation,” Dangas agreed. POPULAR-TAVI, it seems, “is the first anticoagulation study ever to start anticoagulation before the procedure.”

Bleeding event rates in the trial “are somewhat high because of this unusual procedural feature of the study,” Dangas said.

“It’s therefore not surprising that so much of the bleeding occurred in the first hours of the procedure itself,” observed Bonow.

The trial enrolled 313 patients in four European countries who were on OAC for an approved indication, predominantly AF, and underwent TAVR. Their mean age was about 81 years, and 45.4% were women. They were randomly assigned to receive or not receive clopidogrel in a loading dose, followed by 75 mg/d on top of their OAC for 3 months, and were followed out to a year.

All bleeding that met VARC-2 criteria, the first primary end point, occurred in 21.7% of the 157 patients on OAC alone and 34.6% of the 156 who received double therapy (risk ratio [RR], 0.63; 95% CI, 0.43 - 0.90; P = .011).

The second primary end point, “nonprocedural” bleeding that met BARC-4 criteria, occurred in 21.7% and 34.0%, respectively, of patients (RR, 0.64; 95% CI, 0.44 - 0.92; P = .015).

There were also two secondary composite outcomes. The first consisted of nonprocedural bleeding, cardiovascular (CV) death, any stroke, and MI, and was seen in 31.2% of patients on OAC alone and 45.5% of those on OAC plus clopidogrel (RR, 0.69; 95% CI, 0.51 - 0.92), an absolute difference that was within the prospectively defined noninferiority margins.

The other secondary end point — CV death, ischemic stroke, and MI — occurred in 13.4% of those receiving only OAC and 17.3% on added clopidogrel (RR, 0.77; 95% CI, 0.46 - 1.31), which was nonsignificant for superiority.

“Could they have done better by holding the anticoagulation, whether warfarin or a DOAC, during that time? That’s what I think many centers might do if they’re performing a TAVR,” Bonow said.

“It seems to me that could have been done in this trial as well: they could have stopped the anticoagulation, done the procedure, and started the anticoagulation after, the way you would normally in a patient getting a TAVR.”

Such a practice might have reduced the risk of procedural bleeding as it is usually defined in TAVR in both groups, thereby potentially blunting any difference in bleeding rate between the two groups.

“That’s my take on it.” Still, he said, the trial’s message remains: OAC without clopidogrel is safe in POPULAR-TAVI-like patients.

Nijenhuis had no disclosures. Ten Berg disclosed no industry ties. Disclosures for the other authors are in the report. Bonow has previously reported no disclosures. Dangas has previously disclosed receiving grants and fees from Bayer, fees from Janssen; grants and personal fees from Daiichi-Sankyo; and other compensation from Medtronic. Feit discloses personal fees from Abbott Vascular and other relationships with Medtronic, Boston Scientific, and Sapheon.

This article first appeared on Medscape.com.

The guidelines allow for the addition of short-term clopidogrel to an oral anticoagulant (OAC) in patients with an established OAC indication, such as atrial fibrillation (AF), who undergo transcatheter aortic valve replacement (TAVR). But does the extra antithrombotic protection come with safety issues?

It apparently did in the POPULAR-TAVI trial, which saw an excess of major and minor bleeding in such patients already on an OAC when they underwent TAVR and who then took the antiplatelet agent for the next 3 months.

The patients who instead continued on their OAC as the only post-TAVR antithrombotic, compared with those on double therapy, showed a 37% lower 1-year risk of any bleeding, including major and disabling bleeding.

Importantly, they didn’t seem to pay a price in excess ischemic events, such as stroke or myocardial infarction (MI).

The trial argues against adding clopidogrel on top of OAC in TAVR patients with an OAC indication in order to reduce their risk of bleeding, Jurriën ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, the Netherlands, told theheart.org | Medscape Cardiology.

Whether the ischemic event risk was comparable with and without clopidogrel is less clear. “As the study is not powered for the ischemic end points, the answer is less definite. But we did not see a hint of a higher ischemic event rate, especially stroke, in the OAC-alone group,” ten Berg said.

“So we are pretty confident in saying that OAC alone is the optimal treatment.”

The results of POPULAR-TAVI were presented by Vincent Nijenhuis, MD, also from St. Antonius Hospital, on March 29 during the virtual presentation of the American College of Cardiology 2020 Scientific Session/World Congress of Cardiology. Nijenhuis is also first author on the trial’s simultaneous publication in the New England Journal of Medicine.

The only reason to add an antiplatelet in TAVR patients who need to be on an OAC for another indication is to prevent ischemic events like MI, stroke, or death, agreed George D. Dangas, MD, PhD, Mount Sinai Hospital, New York City, for theheart.org | Medscape Cardiology.

But that protection apparently wasn’t needed; for patients on OAC only, “the overall risk–benefit ratio was favorable for them both ways. Although the study is small, I think the findings would be clinically meaningful,” said Dangas, who was not involved in POPULAR-TAVI but was lead author on the GALILEO trial publication.

GALILEO tested a direct oral anticoagulant (DOAC) against dual antiplatelet therapy in patients undergoing TAVR but without a conventional OAC indication. The trial was halted because the DOAC group started to show an excess of bleeding, thromboembolic events, and mortality.

Most POPULAR-TAVI patients were on vitamin K antagonists, but about a quarter were taking DOACs. Clopidogrel was given on an open-label basis.

The trial suggests that, for TAVR patients with an indication for lifelong OAC, “it does appear to be safe to give only an anticoagulant, whether it’s warfarin or a DOAC, and not add clopidogrel,” Robert O. Bonow, MD, Northwestern University, Chicago, told theheart.org | Medscape Cardiology.

“The bottom line appears to be that it’s no worse, and is probably better in terms of bleeding events,” said Bonow, who wasn’t involved in POPULAR-TAVI.

But there are difficulties in interpreting the trial that stem from its design and other issues, he said. For example, it can’t really be concluded that adding an antiplatelet agent to OAC in such patients who undergo TAVR, according to commonly practiced techniques, will increase the risk of bleeding compared with OAC alone.

To begin with, Bonow said, substituting aspirin for clopidogrel might have produced better double-therapy results. But the bigger issues, Bonow said, center on the discretion its operators had in whether to maintain or suspend the patients’ OAC during the TAVR procedure, as well as the unusual bleeding definitions used in the trial.

The first POPULAR-TAVI primary end point was any bleeding that met Valve Academic Research Consortium (VARC) criteria; the second was nonprocedural bleeding that met the Bleeding Academic Research Consortium (BARC) definition.

“Because the VARC-2 classification does not distinguish between procedure-related and nonprocedure-related bleeding events, procedure-related events were defined as BARC type 4 severe bleeding,” the trial’s journal report states. Therefore, “most bleeding at the puncture site was counted as nonprocedure-related.”

It may be Bonow’s biggest issue with the trial, he said. “They’re terming these events that occurred periprocedurally, in the first day or first hours of the procedure, as being ‘nonprocedural’ because they didn’t represent severe BARC bleeding, where you have a subarachnoid hemorrhage or require transfusions.”

An editorial accompanying the trial report also knocks this aspect of the trial design. Although the trial “confirmed” a higher incidence of any bleeding in the double-therapy group, “there are concerns regarding the classification of bleeding and the reliability of secondary outcome analysis,” writes Frederick Feit, MD, NYU Grossman School of Medicine, New York City.

“Bleeding occurring during TAVI or the index hospitalization was unadvisedly defined as non-procedure related, even if it occurred at the access site,” the editorial notes.

Ten Berg noted that procedural bleeding is frequent in TAVI, but the VARC-2 definition doesn’t accommodate them. So “we also used the BARC definition for procedural bleeding, BARC-4,” he told theheart.org | Medscape Cardiology.

“However, BARC-4 describes bleeding during surgery, and it turned out that in POPULAR- TAVI only one patient had BARC-4 bleeding. So we do not at all agree with the editorial.”

Still, the trial’s reported event-rate curves show that “most of the step-up in bleeding, in either arm of the trial, occurred immediately,” Bonow observed. A more consistent, flat trend followed thereafter out to 3 months.

“So half of the bleeding in both arms of the trial occurred at the site of the arterial puncture. Though it wasn’t considered severe, it was indeed periprocedural,” Bonow said, interpreting the results.

The POPULAR-TAVI journal report says the procedures were performed according to local site protocols, and site physicians were allowed to decide whether to continue or suspend OAC. But “the trial protocol advised physicians to continue oral anticoagulation during admission for the TAVI procedure.”

Many of the patients, regardless of randomization group, “went through the procedure under full anticoagulation,” Dangas agreed. POPULAR-TAVI, it seems, “is the first anticoagulation study ever to start anticoagulation before the procedure.”

Bleeding event rates in the trial “are somewhat high because of this unusual procedural feature of the study,” Dangas said.

“It’s therefore not surprising that so much of the bleeding occurred in the first hours of the procedure itself,” observed Bonow.

The trial enrolled 313 patients in four European countries who were on OAC for an approved indication, predominantly AF, and underwent TAVR. Their mean age was about 81 years, and 45.4% were women. They were randomly assigned to receive or not receive clopidogrel in a loading dose, followed by 75 mg/d on top of their OAC for 3 months, and were followed out to a year.

All bleeding that met VARC-2 criteria, the first primary end point, occurred in 21.7% of the 157 patients on OAC alone and 34.6% of the 156 who received double therapy (risk ratio [RR], 0.63; 95% CI, 0.43 - 0.90; P = .011).

The second primary end point, “nonprocedural” bleeding that met BARC-4 criteria, occurred in 21.7% and 34.0%, respectively, of patients (RR, 0.64; 95% CI, 0.44 - 0.92; P = .015).

There were also two secondary composite outcomes. The first consisted of nonprocedural bleeding, cardiovascular (CV) death, any stroke, and MI, and was seen in 31.2% of patients on OAC alone and 45.5% of those on OAC plus clopidogrel (RR, 0.69; 95% CI, 0.51 - 0.92), an absolute difference that was within the prospectively defined noninferiority margins.

The other secondary end point — CV death, ischemic stroke, and MI — occurred in 13.4% of those receiving only OAC and 17.3% on added clopidogrel (RR, 0.77; 95% CI, 0.46 - 1.31), which was nonsignificant for superiority.

“Could they have done better by holding the anticoagulation, whether warfarin or a DOAC, during that time? That’s what I think many centers might do if they’re performing a TAVR,” Bonow said.

“It seems to me that could have been done in this trial as well: they could have stopped the anticoagulation, done the procedure, and started the anticoagulation after, the way you would normally in a patient getting a TAVR.”

Such a practice might have reduced the risk of procedural bleeding as it is usually defined in TAVR in both groups, thereby potentially blunting any difference in bleeding rate between the two groups.

“That’s my take on it.” Still, he said, the trial’s message remains: OAC without clopidogrel is safe in POPULAR-TAVI-like patients.

Nijenhuis had no disclosures. Ten Berg disclosed no industry ties. Disclosures for the other authors are in the report. Bonow has previously reported no disclosures. Dangas has previously disclosed receiving grants and fees from Bayer, fees from Janssen; grants and personal fees from Daiichi-Sankyo; and other compensation from Medtronic. Feit discloses personal fees from Abbott Vascular and other relationships with Medtronic, Boston Scientific, and Sapheon.

This article first appeared on Medscape.com.

PHOENIX, ARIZ. – Cardiovascular deaths and death rates related to atrial fibrillation have risen since 1999, with significant acceleration following 2009, results from a cross-sectional analysis of national data show.

Doug Brunk/MDedge News

“AFib is the most common arrhythmia disorder in the United States and it is estimated that it will effect more than 12 million Americans by 2030,” Yoshihiro Tanaka, MD, PhD, said at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting. “The predicted lifetime risk ranges from 25% to 35%, and AFib is associated with an increased risk for heart failure, stroke, and death.”

A recent review reported that declines in total heart disease mortality rates in the United States have plateaued since 2011 (JAMA 2019;322[8]:780-2). However, it is not well understood what factors such as AFib contribute to this rate of plateau. In an effort to quantify U.S. trends in AFib-related CVD death rates, Dr. Tanaka and colleagues conducted a serial cross-sectional analysis of death certificate data from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research (WONDER) database during 1999-2017.

Outcomes included age-adjusted mortality per 100,000 based on the 2000 U.S. standard population. The researchers also used joinpoint regression to calculate the average annual percentage change over time and conducted subgroup analyses by race and sex and across two age groups: 35-64 years and 65-84 years.

In all, 522,104 AFib-related CVD deaths were identified during 1999-2017. Dr. Tanaka reported that age-adjusted mortality increased from 16.0 per 100,000 persons in 1999 to 22.2 per 100,000 person in 2017, with an acceleration following an inflection point in 2009. Specifically, the average annual percentage change in AFib-related CVD deaths rose from 0.4% in 2009 to 3.5% in 2017 (P < .001). “These increases were consistent across all race-sex subgroups,” said Dr. Tanaka, of the department of preventive medicine at Northwestern University, Chicago. “Relative increases were also greater in younger compared with older adults, although the absolute number of deaths in younger adults was less.”

The researchers observed that age-adjusted mortality increased across blacks and whites in both age groups, with a more pronounced increase among black and white men. Black men had the highest age-adjusted mortality among persons aged 35-64 (6.5 per 100,000 persons, compared with 4.2 among white men, 2.8 in black women, and 1.6 in white women 1.6 per 100,000). At the same time, white men had the highest age-adjusted mortality rate among those aged 65-84 years (112.5 per 100,000 persons, compared with 87.7 in black men, 77.4 in white women, and 61.3 in black women).

In an interview, one of the session’s moderators, Alvaro Alonso, MD, PhD, said that the study’s reliance on mortality data is a limitation. “You have to be careful with that, because it’s not the whole picture,” said Dr. Alonso, professor of epidemiology at the Rollins School of Public Health at Emory University, Atlanta. “It could be an underestimation of what is going on. The increase in recent years is probably due to a higher awareness of AFib as a risk factor for stroke; it’s more on the radar. Also, around 2009-2010, we started having new anticoagulants for AFib. It’s getting diagnosed more. When you look at coronary heart disease and stroke, there has been a decrease over time. In mortality and incidence of AFib, we don’t have that. That’s probably because we don’t know very much about what the risk factors for AFib are and how to prevent it.”

Dr. Tanaka said that the cause of increase in AFib-related CVD mortality can be classified into two major categories: a balance between case fatality of AFib and the prevalence of AFib. “The case fatality rate should have decreased over the last years,” he said at the meeting, which was sponsored by the American Heart Association. “In contrast, in the context of the aging of the population, the prevalence of AFib increased over the past years. Contributing factors include increasing awareness of AFib, a change in coding between ICD-9 and ICD-10, and a change in coding practices by physicians.”

Strengths of the study, he said, include its large sample size and the fact that the researchers were able to capture data from all death certificates filed in the United States. Limitations include the fact that the data “do not identify if changes in age-adjusted mortality rates are due to changing incidence or to case fatality rates,” he said. “CDC WONDER does not allow us to explore causes of these descriptive findings, but this would be an important next step.”

Dr. Tanaka reported having no financial disclosures.

[email protected]

SOURCE: Tanaka Y. EPI/Lifestyle 2020, Session 5, Abstract 15.

PHOENIX, ARIZ. – Cardiovascular deaths and death rates related to atrial fibrillation have risen since 1999, with significant acceleration following 2009, results from a cross-sectional analysis of national data show.

Doug Brunk/MDedge News

“AFib is the most common arrhythmia disorder in the United States and it is estimated that it will effect more than 12 million Americans by 2030,” Yoshihiro Tanaka, MD, PhD, said at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting. “The predicted lifetime risk ranges from 25% to 35%, and AFib is associated with an increased risk for heart failure, stroke, and death.”

A recent review reported that declines in total heart disease mortality rates in the United States have plateaued since 2011 (JAMA 2019;322[8]:780-2). However, it is not well understood what factors such as AFib contribute to this rate of plateau. In an effort to quantify U.S. trends in AFib-related CVD death rates, Dr. Tanaka and colleagues conducted a serial cross-sectional analysis of death certificate data from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research (WONDER) database during 1999-2017.

Outcomes included age-adjusted mortality per 100,000 based on the 2000 U.S. standard population. The researchers also used joinpoint regression to calculate the average annual percentage change over time and conducted subgroup analyses by race and sex and across two age groups: 35-64 years and 65-84 years.

In all, 522,104 AFib-related CVD deaths were identified during 1999-2017. Dr. Tanaka reported that age-adjusted mortality increased from 16.0 per 100,000 persons in 1999 to 22.2 per 100,000 person in 2017, with an acceleration following an inflection point in 2009. Specifically, the average annual percentage change in AFib-related CVD deaths rose from 0.4% in 2009 to 3.5% in 2017 (P < .001). “These increases were consistent across all race-sex subgroups,” said Dr. Tanaka, of the department of preventive medicine at Northwestern University, Chicago. “Relative increases were also greater in younger compared with older adults, although the absolute number of deaths in younger adults was less.”

The researchers observed that age-adjusted mortality increased across blacks and whites in both age groups, with a more pronounced increase among black and white men. Black men had the highest age-adjusted mortality among persons aged 35-64 (6.5 per 100,000 persons, compared with 4.2 among white men, 2.8 in black women, and 1.6 in white women 1.6 per 100,000). At the same time, white men had the highest age-adjusted mortality rate among those aged 65-84 years (112.5 per 100,000 persons, compared with 87.7 in black men, 77.4 in white women, and 61.3 in black women).

In an interview, one of the session’s moderators, Alvaro Alonso, MD, PhD, said that the study’s reliance on mortality data is a limitation. “You have to be careful with that, because it’s not the whole picture,” said Dr. Alonso, professor of epidemiology at the Rollins School of Public Health at Emory University, Atlanta. “It could be an underestimation of what is going on. The increase in recent years is probably due to a higher awareness of AFib as a risk factor for stroke; it’s more on the radar. Also, around 2009-2010, we started having new anticoagulants for AFib. It’s getting diagnosed more. When you look at coronary heart disease and stroke, there has been a decrease over time. In mortality and incidence of AFib, we don’t have that. That’s probably because we don’t know very much about what the risk factors for AFib are and how to prevent it.”

Dr. Tanaka said that the cause of increase in AFib-related CVD mortality can be classified into two major categories: a balance between case fatality of AFib and the prevalence of AFib. “The case fatality rate should have decreased over the last years,” he said at the meeting, which was sponsored by the American Heart Association. “In contrast, in the context of the aging of the population, the prevalence of AFib increased over the past years. Contributing factors include increasing awareness of AFib, a change in coding between ICD-9 and ICD-10, and a change in coding practices by physicians.”

Strengths of the study, he said, include its large sample size and the fact that the researchers were able to capture data from all death certificates filed in the United States. Limitations include the fact that the data “do not identify if changes in age-adjusted mortality rates are due to changing incidence or to case fatality rates,” he said. “CDC WONDER does not allow us to explore causes of these descriptive findings, but this would be an important next step.”

Dr. Tanaka reported having no financial disclosures.

[email protected]

SOURCE: Tanaka Y. EPI/Lifestyle 2020, Session 5, Abstract 15.

PHOENIX, ARIZ. – Cardiovascular deaths and death rates related to atrial fibrillation have risen since 1999, with significant acceleration following 2009, results from a cross-sectional analysis of national data show.

Doug Brunk/MDedge News

“AFib is the most common arrhythmia disorder in the United States and it is estimated that it will effect more than 12 million Americans by 2030,” Yoshihiro Tanaka, MD, PhD, said at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting. “The predicted lifetime risk ranges from 25% to 35%, and AFib is associated with an increased risk for heart failure, stroke, and death.”

A recent review reported that declines in total heart disease mortality rates in the United States have plateaued since 2011 (JAMA 2019;322[8]:780-2). However, it is not well understood what factors such as AFib contribute to this rate of plateau. In an effort to quantify U.S. trends in AFib-related CVD death rates, Dr. Tanaka and colleagues conducted a serial cross-sectional analysis of death certificate data from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research (WONDER) database during 1999-2017.

Outcomes included age-adjusted mortality per 100,000 based on the 2000 U.S. standard population. The researchers also used joinpoint regression to calculate the average annual percentage change over time and conducted subgroup analyses by race and sex and across two age groups: 35-64 years and 65-84 years.

In all, 522,104 AFib-related CVD deaths were identified during 1999-2017. Dr. Tanaka reported that age-adjusted mortality increased from 16.0 per 100,000 persons in 1999 to 22.2 per 100,000 person in 2017, with an acceleration following an inflection point in 2009. Specifically, the average annual percentage change in AFib-related CVD deaths rose from 0.4% in 2009 to 3.5% in 2017 (P < .001). “These increases were consistent across all race-sex subgroups,” said Dr. Tanaka, of the department of preventive medicine at Northwestern University, Chicago. “Relative increases were also greater in younger compared with older adults, although the absolute number of deaths in younger adults was less.”

The researchers observed that age-adjusted mortality increased across blacks and whites in both age groups, with a more pronounced increase among black and white men. Black men had the highest age-adjusted mortality among persons aged 35-64 (6.5 per 100,000 persons, compared with 4.2 among white men, 2.8 in black women, and 1.6 in white women 1.6 per 100,000). At the same time, white men had the highest age-adjusted mortality rate among those aged 65-84 years (112.5 per 100,000 persons, compared with 87.7 in black men, 77.4 in white women, and 61.3 in black women).

In an interview, one of the session’s moderators, Alvaro Alonso, MD, PhD, said that the study’s reliance on mortality data is a limitation. “You have to be careful with that, because it’s not the whole picture,” said Dr. Alonso, professor of epidemiology at the Rollins School of Public Health at Emory University, Atlanta. “It could be an underestimation of what is going on. The increase in recent years is probably due to a higher awareness of AFib as a risk factor for stroke; it’s more on the radar. Also, around 2009-2010, we started having new anticoagulants for AFib. It’s getting diagnosed more. When you look at coronary heart disease and stroke, there has been a decrease over time. In mortality and incidence of AFib, we don’t have that. That’s probably because we don’t know very much about what the risk factors for AFib are and how to prevent it.”

Dr. Tanaka said that the cause of increase in AFib-related CVD mortality can be classified into two major categories: a balance between case fatality of AFib and the prevalence of AFib. “The case fatality rate should have decreased over the last years,” he said at the meeting, which was sponsored by the American Heart Association. “In contrast, in the context of the aging of the population, the prevalence of AFib increased over the past years. Contributing factors include increasing awareness of AFib, a change in coding between ICD-9 and ICD-10, and a change in coding practices by physicians.”

Strengths of the study, he said, include its large sample size and the fact that the researchers were able to capture data from all death certificates filed in the United States. Limitations include the fact that the data “do not identify if changes in age-adjusted mortality rates are due to changing incidence or to case fatality rates,” he said. “CDC WONDER does not allow us to explore causes of these descriptive findings, but this would be an important next step.”

Dr. Tanaka reported having no financial disclosures.

[email protected]

SOURCE: Tanaka Y. EPI/Lifestyle 2020, Session 5, Abstract 15.

LOS ANGELES – The edge that the direct-acting oral anticoagulant apixaban (Eliquis) has over warfarin for safely preventing ischemic events in patients with atrial fibrillation and either a recent acute coronary syndrome event or a recent percutaneous coronary intervention held up even in patients with a history of stroke, transient ischemic attack, or thromboembolic event, according to a prespecified secondary analysis of data collected in the AUGUSTUS trial.

Mitchel L. Zoler/MDedge News

The treatment advantages of apixaban, compared with warfarin, seen in the overall AUGUSTUS results, first reported in March 2019, “were consistent” with the benefits seen in the subgroup of enrolled patients with a prior stroke, transient ischemic attack (TIA), or thromboembolic (TE) event, M. Cecilia Bahit, MD, said at the International Stroke Conference sponsored by the American Heart Association.

All patients in AUGUSTUS received a P2Y12 inhibitor antiplatelet drug, which was clopidogrel for more than 90% of patients. The two-by-two factorial design of AUGUSTUS also assessed the safety and efficacy of either adding or withholding aspirin from the two-drug regimen that all patients in the study received with a P2Y12 inhibitor plus an anticoagulant (apixaban or warfarin). The most notable finding of the aspirin versus placebo analysis was that patients without a prior stroke, TIA, or TE event had a “more profound” increase in their rate of major or clinically relevant minor bleeds when also treated with aspirin, compared with patients who received aspirin and had a history of stroke, TIA, or TE event, reported Dr. Bahit, a chief of cardiology and director of clinical research at the INECO Foundation in Rosario, Argentina.

In general, the findings of the secondary analysis that took into account stroke, TIA, or TE history “confirmed” the main AUGUSTUS findings, Dr. Bahit said; an antithrombotic regimen of apixaban plus clopidogrel (or other P2Y12 inhibitor) without aspirin was superior for both efficacy and safety, compared with the alternative regimens that either substituted warfarin for apixaban or that added aspirin.

AUGUSTUS enrolled 4,614 atrial fibrillation (AFib) patients who either had a recent acute coronary syndrome (ACS) event or had recently undergone percutaneous coronary intervention (PCI) at any of 492 sites in 33 countries during 2015-2018. The study’s primary endpoint was the incidence of major or clinically relevant minor bleeds after 6 months, which was significantly lower in the subgroups that received apixaban instead of warfarin and in patients who received placebo instead of aspirin. The secondary endpoint of death or hospitalization after 6 months was also significantly lower in the apixaban-treated patients, compared with those on warfarin, while the aspirin and placebo subgroups showed no difference in the incidence of these events (N Engl J Med. 2019 Apr 18;380[16]:1509-24).

The results reported by Dr. Bahit also highlighted both the high risk faced by patients with AFib who also have had an ACS event or PCI, as well as a prior stroke, TIA, or TE event, noted Larry B. Goldstein, MD, professor and chairman of neurology at the University of Kentucky, Lexington. “It’s difficult, because these patients had an ACS event or PCI, and you don’t want a coronary too close up, but do these patients really need a P2Y12 inhibitor plus an anticoagulant? Could these patients do as well on apixaban only? I would have liked to see that treatment arm in the study,” Dr. Goldstein commented in an interview.

“These are challenging patients because they often require anticoagulation for the AFib as well as antiplatelet agents” for the recent PCI or ACS event, commented Mitchell S.V. Elkind, MD, professor of neurology at Columbia University, New York. “The question has always been: How many blood thinners should these patients be on? Potentially they could be on three different agents [an anticoagulant and two antiplatelet drugs], and we know that all of those drugs together pretty dramatically increase the risk of bleeding. About 15% of the patients in the overall AUGUSTUS trial had either cerebrovascular disease or systemic thromboembolism, so this was a small subgroup of the overall trial, but the overall trial was large so it’s a significant number of patients who met this criteria. The results confirmed that even in a group of patients who may be considered at high risk because they have a prior history of cerebrovascular disease use of apixaban instead of warfarin seemed safer, and that those patients did not need to be on aspirin as well as their other antiplatelet agent. Patients with a history of stroke, in fact, had a lower risk of bleeding than the other patients in this trial, so one could argue that they should be on an agent like apixaban as well as an antiplatelet agent like clopidogrel without addition of aspirin,” he said in a recorded statement.

In addition to implications for using prescription drugs like apixaban and clopidogrel, the findings also send a message about the need for very aggressive implementation of lifestyle measures that can reduce cardiovascular disease risk in these patients, added Dr. Goldstein. The AUGUSTUS outcome analyses that subdivided the study population into those with a prior stroke, TIA, or TE event – 633 patients or about 14% of the 4,581 patients eligible for this analysis – and those who did not have this history showed the extremely high, incrementally elevated risk faced by patients with these prior events.

A history of stroke, TIA, or TE event linked with a jump in the 90-day rate of major or clinically relevant minor bleeds from 13% without this history to 17%, which is a 31% relative increase; it boosted the 90-day rate of death or hospitalization from 25% to 31%, a 24% relative increase; and it jacked up the rate of death or ischemic events from 6% to 9%, a 50% relative increase, Dr. Bahit reported.

These substantial increases “suggest we need to be very aggressive” in managing these high-risk patients who combine a background of AFib, a prior stroke, TIA, or TE events, and a recent ACS event or PCI, Dr. Goldstein observed. In these patients, he suggested that clinicians make sure to address smoking cessation, obesity, exercise, diet, and statin use, and get each of these to an optimal level to further cut risk. If all five of these basic interventions were successfully administered to a patient they could collectively cut the patient’s event risk by about 80%, he added.

AUGUSTUS was funded by Bristol-Myers Squibb and Pfizer, the companies that jointly market apixaban. Dr. Bahit has received honoraria from Pfizer, and from CSL Behring and Merck. Dr. Elkind and Dr. Goldstein had no relevant disclosures.

[email protected]

SOURCE: Bahit MC et al. ISC 2020, Abstract LB22.

LOS ANGELES – The edge that the direct-acting oral anticoagulant apixaban (Eliquis) has over warfarin for safely preventing ischemic events in patients with atrial fibrillation and either a recent acute coronary syndrome event or a recent percutaneous coronary intervention held up even in patients with a history of stroke, transient ischemic attack, or thromboembolic event, according to a prespecified secondary analysis of data collected in the AUGUSTUS trial.

Mitchel L. Zoler/MDedge News

The treatment advantages of apixaban, compared with warfarin, seen in the overall AUGUSTUS results, first reported in March 2019, “were consistent” with the benefits seen in the subgroup of enrolled patients with a prior stroke, transient ischemic attack (TIA), or thromboembolic (TE) event, M. Cecilia Bahit, MD, said at the International Stroke Conference sponsored by the American Heart Association.

All patients in AUGUSTUS received a P2Y12 inhibitor antiplatelet drug, which was clopidogrel for more than 90% of patients. The two-by-two factorial design of AUGUSTUS also assessed the safety and efficacy of either adding or withholding aspirin from the two-drug regimen that all patients in the study received with a P2Y12 inhibitor plus an anticoagulant (apixaban or warfarin). The most notable finding of the aspirin versus placebo analysis was that patients without a prior stroke, TIA, or TE event had a “more profound” increase in their rate of major or clinically relevant minor bleeds when also treated with aspirin, compared with patients who received aspirin and had a history of stroke, TIA, or TE event, reported Dr. Bahit, a chief of cardiology and director of clinical research at the INECO Foundation in Rosario, Argentina.

In general, the findings of the secondary analysis that took into account stroke, TIA, or TE history “confirmed” the main AUGUSTUS findings, Dr. Bahit said; an antithrombotic regimen of apixaban plus clopidogrel (or other P2Y12 inhibitor) without aspirin was superior for both efficacy and safety, compared with the alternative regimens that either substituted warfarin for apixaban or that added aspirin.

AUGUSTUS enrolled 4,614 atrial fibrillation (AFib) patients who either had a recent acute coronary syndrome (ACS) event or had recently undergone percutaneous coronary intervention (PCI) at any of 492 sites in 33 countries during 2015-2018. The study’s primary endpoint was the incidence of major or clinically relevant minor bleeds after 6 months, which was significantly lower in the subgroups that received apixaban instead of warfarin and in patients who received placebo instead of aspirin. The secondary endpoint of death or hospitalization after 6 months was also significantly lower in the apixaban-treated patients, compared with those on warfarin, while the aspirin and placebo subgroups showed no difference in the incidence of these events (N Engl J Med. 2019 Apr 18;380[16]:1509-24).

The results reported by Dr. Bahit also highlighted both the high risk faced by patients with AFib who also have had an ACS event or PCI, as well as a prior stroke, TIA, or TE event, noted Larry B. Goldstein, MD, professor and chairman of neurology at the University of Kentucky, Lexington. “It’s difficult, because these patients had an ACS event or PCI, and you don’t want a coronary too close up, but do these patients really need a P2Y12 inhibitor plus an anticoagulant? Could these patients do as well on apixaban only? I would have liked to see that treatment arm in the study,” Dr. Goldstein commented in an interview.

“These are challenging patients because they often require anticoagulation for the AFib as well as antiplatelet agents” for the recent PCI or ACS event, commented Mitchell S.V. Elkind, MD, professor of neurology at Columbia University, New York. “The question has always been: How many blood thinners should these patients be on? Potentially they could be on three different agents [an anticoagulant and two antiplatelet drugs], and we know that all of those drugs together pretty dramatically increase the risk of bleeding. About 15% of the patients in the overall AUGUSTUS trial had either cerebrovascular disease or systemic thromboembolism, so this was a small subgroup of the overall trial, but the overall trial was large so it’s a significant number of patients who met this criteria. The results confirmed that even in a group of patients who may be considered at high risk because they have a prior history of cerebrovascular disease use of apixaban instead of warfarin seemed safer, and that those patients did not need to be on aspirin as well as their other antiplatelet agent. Patients with a history of stroke, in fact, had a lower risk of bleeding than the other patients in this trial, so one could argue that they should be on an agent like apixaban as well as an antiplatelet agent like clopidogrel without addition of aspirin,” he said in a recorded statement.

In addition to implications for using prescription drugs like apixaban and clopidogrel, the findings also send a message about the need for very aggressive implementation of lifestyle measures that can reduce cardiovascular disease risk in these patients, added Dr. Goldstein. The AUGUSTUS outcome analyses that subdivided the study population into those with a prior stroke, TIA, or TE event – 633 patients or about 14% of the 4,581 patients eligible for this analysis – and those who did not have this history showed the extremely high, incrementally elevated risk faced by patients with these prior events.

A history of stroke, TIA, or TE event linked with a jump in the 90-day rate of major or clinically relevant minor bleeds from 13% without this history to 17%, which is a 31% relative increase; it boosted the 90-day rate of death or hospitalization from 25% to 31%, a 24% relative increase; and it jacked up the rate of death or ischemic events from 6% to 9%, a 50% relative increase, Dr. Bahit reported.

These substantial increases “suggest we need to be very aggressive” in managing these high-risk patients who combine a background of AFib, a prior stroke, TIA, or TE events, and a recent ACS event or PCI, Dr. Goldstein observed. In these patients, he suggested that clinicians make sure to address smoking cessation, obesity, exercise, diet, and statin use, and get each of these to an optimal level to further cut risk. If all five of these basic interventions were successfully administered to a patient they could collectively cut the patient’s event risk by about 80%, he added.

AUGUSTUS was funded by Bristol-Myers Squibb and Pfizer, the companies that jointly market apixaban. Dr. Bahit has received honoraria from Pfizer, and from CSL Behring and Merck. Dr. Elkind and Dr. Goldstein had no relevant disclosures.

[email protected]

SOURCE: Bahit MC et al. ISC 2020, Abstract LB22.

LOS ANGELES – The edge that the direct-acting oral anticoagulant apixaban (Eliquis) has over warfarin for safely preventing ischemic events in patients with atrial fibrillation and either a recent acute coronary syndrome event or a recent percutaneous coronary intervention held up even in patients with a history of stroke, transient ischemic attack, or thromboembolic event, according to a prespecified secondary analysis of data collected in the AUGUSTUS trial.

Mitchel L. Zoler/MDedge News

The treatment advantages of apixaban, compared with warfarin, seen in the overall AUGUSTUS results, first reported in March 2019, “were consistent” with the benefits seen in the subgroup of enrolled patients with a prior stroke, transient ischemic attack (TIA), or thromboembolic (TE) event, M. Cecilia Bahit, MD, said at the International Stroke Conference sponsored by the American Heart Association.

All patients in AUGUSTUS received a P2Y12 inhibitor antiplatelet drug, which was clopidogrel for more than 90% of patients. The two-by-two factorial design of AUGUSTUS also assessed the safety and efficacy of either adding or withholding aspirin from the two-drug regimen that all patients in the study received with a P2Y12 inhibitor plus an anticoagulant (apixaban or warfarin). The most notable finding of the aspirin versus placebo analysis was that patients without a prior stroke, TIA, or TE event had a “more profound” increase in their rate of major or clinically relevant minor bleeds when also treated with aspirin, compared with patients who received aspirin and had a history of stroke, TIA, or TE event, reported Dr. Bahit, a chief of cardiology and director of clinical research at the INECO Foundation in Rosario, Argentina.

In general, the findings of the secondary analysis that took into account stroke, TIA, or TE history “confirmed” the main AUGUSTUS findings, Dr. Bahit said; an antithrombotic regimen of apixaban plus clopidogrel (or other P2Y12 inhibitor) without aspirin was superior for both efficacy and safety, compared with the alternative regimens that either substituted warfarin for apixaban or that added aspirin.

AUGUSTUS enrolled 4,614 atrial fibrillation (AFib) patients who either had a recent acute coronary syndrome (ACS) event or had recently undergone percutaneous coronary intervention (PCI) at any of 492 sites in 33 countries during 2015-2018. The study’s primary endpoint was the incidence of major or clinically relevant minor bleeds after 6 months, which was significantly lower in the subgroups that received apixaban instead of warfarin and in patients who received placebo instead of aspirin. The secondary endpoint of death or hospitalization after 6 months was also significantly lower in the apixaban-treated patients, compared with those on warfarin, while the aspirin and placebo subgroups showed no difference in the incidence of these events (N Engl J Med. 2019 Apr 18;380[16]:1509-24).

The results reported by Dr. Bahit also highlighted both the high risk faced by patients with AFib who also have had an ACS event or PCI, as well as a prior stroke, TIA, or TE event, noted Larry B. Goldstein, MD, professor and chairman of neurology at the University of Kentucky, Lexington. “It’s difficult, because these patients had an ACS event or PCI, and you don’t want a coronary too close up, but do these patients really need a P2Y12 inhibitor plus an anticoagulant? Could these patients do as well on apixaban only? I would have liked to see that treatment arm in the study,” Dr. Goldstein commented in an interview.

“These are challenging patients because they often require anticoagulation for the AFib as well as antiplatelet agents” for the recent PCI or ACS event, commented Mitchell S.V. Elkind, MD, professor of neurology at Columbia University, New York. “The question has always been: How many blood thinners should these patients be on? Potentially they could be on three different agents [an anticoagulant and two antiplatelet drugs], and we know that all of those drugs together pretty dramatically increase the risk of bleeding. About 15% of the patients in the overall AUGUSTUS trial had either cerebrovascular disease or systemic thromboembolism, so this was a small subgroup of the overall trial, but the overall trial was large so it’s a significant number of patients who met this criteria. The results confirmed that even in a group of patients who may be considered at high risk because they have a prior history of cerebrovascular disease use of apixaban instead of warfarin seemed safer, and that those patients did not need to be on aspirin as well as their other antiplatelet agent. Patients with a history of stroke, in fact, had a lower risk of bleeding than the other patients in this trial, so one could argue that they should be on an agent like apixaban as well as an antiplatelet agent like clopidogrel without addition of aspirin,” he said in a recorded statement.

In addition to implications for using prescription drugs like apixaban and clopidogrel, the findings also send a message about the need for very aggressive implementation of lifestyle measures that can reduce cardiovascular disease risk in these patients, added Dr. Goldstein. The AUGUSTUS outcome analyses that subdivided the study population into those with a prior stroke, TIA, or TE event – 633 patients or about 14% of the 4,581 patients eligible for this analysis – and those who did not have this history showed the extremely high, incrementally elevated risk faced by patients with these prior events.

A history of stroke, TIA, or TE event linked with a jump in the 90-day rate of major or clinically relevant minor bleeds from 13% without this history to 17%, which is a 31% relative increase; it boosted the 90-day rate of death or hospitalization from 25% to 31%, a 24% relative increase; and it jacked up the rate of death or ischemic events from 6% to 9%, a 50% relative increase, Dr. Bahit reported.

These substantial increases “suggest we need to be very aggressive” in managing these high-risk patients who combine a background of AFib, a prior stroke, TIA, or TE events, and a recent ACS event or PCI, Dr. Goldstein observed. In these patients, he suggested that clinicians make sure to address smoking cessation, obesity, exercise, diet, and statin use, and get each of these to an optimal level to further cut risk. If all five of these basic interventions were successfully administered to a patient they could collectively cut the patient’s event risk by about 80%, he added.

AUGUSTUS was funded by Bristol-Myers Squibb and Pfizer, the companies that jointly market apixaban. Dr. Bahit has received honoraria from Pfizer, and from CSL Behring and Merck. Dr. Elkind and Dr. Goldstein had no relevant disclosures.

[email protected]

SOURCE: Bahit MC et al. ISC 2020, Abstract LB22.

LOS ANGELES – When a patient with atrial fibrillation (AFib) has a cardioembolic stroke, the best blood thinner to start may be a direct-acting oral anticoagulant (DOAC), possibly beginning 7-10 days after the index stroke, according to an analysis of 90-day, observational outcomes data from nearly 1,300 patients.

Mitchel L. Zoler/MDedge News

The analysis also suggested that the use of “bridging” anticoagulant treatment by injection before a patient with atrial fibrillation (AFib) starts a daily oral anticoagulant regimen following a cardioembolic stroke is not a good idea. Patients who received bridging anticoagulation had a nearly threefold higher rate of symptomatic intracranial hemorrhage than did patients who did not, and their bridging treatment failed to protect them from recurrent ischemic events, Shadi Yaghi, MD, said at the International Stroke Conference, sponsored by the American Heart Association. The bridging regimens delivered either heparin or low-molecular-weight heparin.

Based on the findings, “it seems reasonable to avoid bridging unless absolutely necessary, to initiate a DOAC unless it’s contraindicated, and to start the DOAC on day 7-10 following the stroke in most patients,” said Dr. Yaghi, a vascular neurologist and director of stroke research at NYU Langone Health in New York.

“It’s been hard to develop a broad guideline on when to start oral anticoagulation” after a cardioembolic stroke in AFib patients. The best time “depends on a lot of variables and how the patient responded to acute treatment,” commented Alexis Simpkins, MD, a vascular and stroke neurologist at the University of Florida in Gainesville. “You want to start treatment before the patient has another stroke, but not so soon that the treatment causes symptomatic hemorrhagic transformation.”

Dr. Yaghi’s suggestion, based on his findings, to start treatment for most patients with a DOAC 7-10 days after their index stroke “shows consistency” with the prevailing guideline recommendation from the AHA/American Stroke Association to start oral anticoagulation in this patient population 4-14 days after the index stroke (Stroke. 2018 March;49[3]:e46-e99), she noted.

A recent article reviewed the uncertainty about the best time to start oral anticoagulation in AFib patients after a cardioembolic stroke and the subtle differences that distinguish various international medical groups that, like the ASA, have made recommendations (Lancet Neurol. 2019 Jan 1;18[1]:117-26). According to this review, a major limitation of these various recommendations has been the lack of actual evidence collected from AFib patients who began receiving a DOAC shortly after a cardioembolic stroke, although the article added that several studies in progress are collecting these data.

The study reported by Dr. Yaghi pooled data collected from 2,084 recent AFib patients with a cardioembolic stroke treated at any of eight comprehensive U.S. stroke centers. They excluded patients who died from causes unrelated to the primary endpoint, those who did not receive an anticoagulant or had incomplete data, and patients lost to follow-up, leaving 1,289 evaluable patients. During their 90-day follow-up, 10% of the patients had an ischemic event, a symptomatic intracranial hemorrhage, or an extracranial hemorrhage.

The study’s primary analysis showed no statistically significant difference in the incidence of recurrent ischemic events, symptomatic intracranial hemorrhage, or both based on when oral anticoagulant treatment began: 0-3 days, 4-14 days, or more than 14 days after the index stroke.

The investigators then subdivided patients into the subgroup that started treatment with a DOAC and the subgroup that started treatment with warfarin and also further subdivided the 4-14 day time window for starting treatment. Results of this analysis showed that patients who received a DOAC and began this treatment 7-10 days after their stroke had a 50% cut in their 90-day events compared with other patients, a difference that fell just short of statistical significance at P = .07. All the other combinations of oral anticoagulant and time of treatment initiation analyzed showed neutral effects that never came near statistical significance.

Secondary data analyses also showed that both patients with a history of a stroke prior to their index stroke and patients with ipsilateral atherosclerosis came close to having a statistically significant increased rate of a subsequent ischemic event during 90-day follow-up. Furthermore, women, patients with a history of hyperlipidemia, and patients who developed hemorrhagic transformation of their index stroke all had significantly increased rates of developing a symptomatic intracranial hemorrhage during 90-day follow-up. When the endpoint was limited to recurrent ischemic events only, patients who received a DOAC were 50% less likely to have an event than were patients treated with warfarin, a statistically significant difference.

Although starting a DOAC 7-10 days after the index stroke seems reasonable based on this analysis, the question needs a prospective, randomized study to create an appropriate evidence base, Dr. Yaghi said.

Dr. Yaghi disclosed a financial relationship with Medtronic. Dr. Simpkins had no disclosures.

[email protected]

SOURCE: Yaghi S et al. Stroke. 2020 Feb;51(suppl 1):A119.

LOS ANGELES – When a patient with atrial fibrillation (AFib) has a cardioembolic stroke, the best blood thinner to start may be a direct-acting oral anticoagulant (DOAC), possibly beginning 7-10 days after the index stroke, according to an analysis of 90-day, observational outcomes data from nearly 1,300 patients.

Mitchel L. Zoler/MDedge News

The analysis also suggested that the use of “bridging” anticoagulant treatment by injection before a patient with atrial fibrillation (AFib) starts a daily oral anticoagulant regimen following a cardioembolic stroke is not a good idea. Patients who received bridging anticoagulation had a nearly threefold higher rate of symptomatic intracranial hemorrhage than did patients who did not, and their bridging treatment failed to protect them from recurrent ischemic events, Shadi Yaghi, MD, said at the International Stroke Conference, sponsored by the American Heart Association. The bridging regimens delivered either heparin or low-molecular-weight heparin.

Based on the findings, “it seems reasonable to avoid bridging unless absolutely necessary, to initiate a DOAC unless it’s contraindicated, and to start the DOAC on day 7-10 following the stroke in most patients,” said Dr. Yaghi, a vascular neurologist and director of stroke research at NYU Langone Health in New York.

“It’s been hard to develop a broad guideline on when to start oral anticoagulation” after a cardioembolic stroke in AFib patients. The best time “depends on a lot of variables and how the patient responded to acute treatment,” commented Alexis Simpkins, MD, a vascular and stroke neurologist at the University of Florida in Gainesville. “You want to start treatment before the patient has another stroke, but not so soon that the treatment causes symptomatic hemorrhagic transformation.”

Dr. Yaghi’s suggestion, based on his findings, to start treatment for most patients with a DOAC 7-10 days after their index stroke “shows consistency” with the prevailing guideline recommendation from the AHA/American Stroke Association to start oral anticoagulation in this patient population 4-14 days after the index stroke (Stroke. 2018 March;49[3]:e46-e99), she noted.

A recent article reviewed the uncertainty about the best time to start oral anticoagulation in AFib patients after a cardioembolic stroke and the subtle differences that distinguish various international medical groups that, like the ASA, have made recommendations (Lancet Neurol. 2019 Jan 1;18[1]:117-26). According to this review, a major limitation of these various recommendations has been the lack of actual evidence collected from AFib patients who began receiving a DOAC shortly after a cardioembolic stroke, although the article added that several studies in progress are collecting these data.

The study reported by Dr. Yaghi pooled data collected from 2,084 recent AFib patients with a cardioembolic stroke treated at any of eight comprehensive U.S. stroke centers. They excluded patients who died from causes unrelated to the primary endpoint, those who did not receive an anticoagulant or had incomplete data, and patients lost to follow-up, leaving 1,289 evaluable patients. During their 90-day follow-up, 10% of the patients had an ischemic event, a symptomatic intracranial hemorrhage, or an extracranial hemorrhage.

The study’s primary analysis showed no statistically significant difference in the incidence of recurrent ischemic events, symptomatic intracranial hemorrhage, or both based on when oral anticoagulant treatment began: 0-3 days, 4-14 days, or more than 14 days after the index stroke.

The investigators then subdivided patients into the subgroup that started treatment with a DOAC and the subgroup that started treatment with warfarin and also further subdivided the 4-14 day time window for starting treatment. Results of this analysis showed that patients who received a DOAC and began this treatment 7-10 days after their stroke had a 50% cut in their 90-day events compared with other patients, a difference that fell just short of statistical significance at P = .07. All the other combinations of oral anticoagulant and time of treatment initiation analyzed showed neutral effects that never came near statistical significance.

Secondary data analyses also showed that both patients with a history of a stroke prior to their index stroke and patients with ipsilateral atherosclerosis came close to having a statistically significant increased rate of a subsequent ischemic event during 90-day follow-up. Furthermore, women, patients with a history of hyperlipidemia, and patients who developed hemorrhagic transformation of their index stroke all had significantly increased rates of developing a symptomatic intracranial hemorrhage during 90-day follow-up. When the endpoint was limited to recurrent ischemic events only, patients who received a DOAC were 50% less likely to have an event than were patients treated with warfarin, a statistically significant difference.

Although starting a DOAC 7-10 days after the index stroke seems reasonable based on this analysis, the question needs a prospective, randomized study to create an appropriate evidence base, Dr. Yaghi said.

Dr. Yaghi disclosed a financial relationship with Medtronic. Dr. Simpkins had no disclosures.

[email protected]

SOURCE: Yaghi S et al. Stroke. 2020 Feb;51(suppl 1):A119.

LOS ANGELES – When a patient with atrial fibrillation (AFib) has a cardioembolic stroke, the best blood thinner to start may be a direct-acting oral anticoagulant (DOAC), possibly beginning 7-10 days after the index stroke, according to an analysis of 90-day, observational outcomes data from nearly 1,300 patients.

Mitchel L. Zoler/MDedge News

The analysis also suggested that the use of “bridging” anticoagulant treatment by injection before a patient with atrial fibrillation (AFib) starts a daily oral anticoagulant regimen following a cardioembolic stroke is not a good idea. Patients who received bridging anticoagulation had a nearly threefold higher rate of symptomatic intracranial hemorrhage than did patients who did not, and their bridging treatment failed to protect them from recurrent ischemic events, Shadi Yaghi, MD, said at the International Stroke Conference, sponsored by the American Heart Association. The bridging regimens delivered either heparin or low-molecular-weight heparin.

Based on the findings, “it seems reasonable to avoid bridging unless absolutely necessary, to initiate a DOAC unless it’s contraindicated, and to start the DOAC on day 7-10 following the stroke in most patients,” said Dr. Yaghi, a vascular neurologist and director of stroke research at NYU Langone Health in New York.

“It’s been hard to develop a broad guideline on when to start oral anticoagulation” after a cardioembolic stroke in AFib patients. The best time “depends on a lot of variables and how the patient responded to acute treatment,” commented Alexis Simpkins, MD, a vascular and stroke neurologist at the University of Florida in Gainesville. “You want to start treatment before the patient has another stroke, but not so soon that the treatment causes symptomatic hemorrhagic transformation.”

Dr. Yaghi’s suggestion, based on his findings, to start treatment for most patients with a DOAC 7-10 days after their index stroke “shows consistency” with the prevailing guideline recommendation from the AHA/American Stroke Association to start oral anticoagulation in this patient population 4-14 days after the index stroke (Stroke. 2018 March;49[3]:e46-e99), she noted.

A recent article reviewed the uncertainty about the best time to start oral anticoagulation in AFib patients after a cardioembolic stroke and the subtle differences that distinguish various international medical groups that, like the ASA, have made recommendations (Lancet Neurol. 2019 Jan 1;18[1]:117-26). According to this review, a major limitation of these various recommendations has been the lack of actual evidence collected from AFib patients who began receiving a DOAC shortly after a cardioembolic stroke, although the article added that several studies in progress are collecting these data.

The study reported by Dr. Yaghi pooled data collected from 2,084 recent AFib patients with a cardioembolic stroke treated at any of eight comprehensive U.S. stroke centers. They excluded patients who died from causes unrelated to the primary endpoint, those who did not receive an anticoagulant or had incomplete data, and patients lost to follow-up, leaving 1,289 evaluable patients. During their 90-day follow-up, 10% of the patients had an ischemic event, a symptomatic intracranial hemorrhage, or an extracranial hemorrhage.

The study’s primary analysis showed no statistically significant difference in the incidence of recurrent ischemic events, symptomatic intracranial hemorrhage, or both based on when oral anticoagulant treatment began: 0-3 days, 4-14 days, or more than 14 days after the index stroke.

The investigators then subdivided patients into the subgroup that started treatment with a DOAC and the subgroup that started treatment with warfarin and also further subdivided the 4-14 day time window for starting treatment. Results of this analysis showed that patients who received a DOAC and began this treatment 7-10 days after their stroke had a 50% cut in their 90-day events compared with other patients, a difference that fell just short of statistical significance at P = .07. All the other combinations of oral anticoagulant and time of treatment initiation analyzed showed neutral effects that never came near statistical significance.

Secondary data analyses also showed that both patients with a history of a stroke prior to their index stroke and patients with ipsilateral atherosclerosis came close to having a statistically significant increased rate of a subsequent ischemic event during 90-day follow-up. Furthermore, women, patients with a history of hyperlipidemia, and patients who developed hemorrhagic transformation of their index stroke all had significantly increased rates of developing a symptomatic intracranial hemorrhage during 90-day follow-up. When the endpoint was limited to recurrent ischemic events only, patients who received a DOAC were 50% less likely to have an event than were patients treated with warfarin, a statistically significant difference.

Although starting a DOAC 7-10 days after the index stroke seems reasonable based on this analysis, the question needs a prospective, randomized study to create an appropriate evidence base, Dr. Yaghi said.

Dr. Yaghi disclosed a financial relationship with Medtronic. Dr. Simpkins had no disclosures.

[email protected]

SOURCE: Yaghi S et al. Stroke. 2020 Feb;51(suppl 1):A119.

NATIONAL HARBOR, MD. – Thermal injury of a patient’s esophagus during radiofrequency catheter ablation of atrial fibrillation is notorious as a relatively common and problematic complication of the procedure, but two new approaches showed promise for substantially cutting the risk of esophageal thermal injury and the potential for the most severe damage: perforation.

Mitchel L. Zoler/MDedge News

One of these innovations is intensive esophageal cooling with a commercially marketed, fluid-chilled catheter placed in a patient’s esophagus during radiofrequency catheter ablation that keeps the inner surface of the esophagus at 4°C. This approach cut the incidence of periprocedural episodes of endoscopically detected esophageal thermal injury from 20% among controls to 3% in patients who had esophageal cooling in a randomized study with 120 patients, Mark M. Gallagher, MD, said at the annual International AF Symposium. The same device can also maintain a temperature on the inner surface of the esophagus of 42 ° C in patients undergoing cryoablation of atrial fibrillation, noted Dr. Gallagher, a cardiac electrophysiologist at St. George’s University Hospitals in London.

A second approach to cutting esophageal damage focuses on modifying the energy delivery with a radiofrequency ablation method known as high-power short-duration (HPSD). As the name says, this strategy uses a relatively high level of radiofrequency energy, 50 watts in the reported experience, for the brief interval of about 7 seconds, ideally delivering an overall Ablation Index of at least 350 but below 360, said Thomas Deneke, MD, an electrophysiologist, professor, and cochief of cardiology at the Heart Center in Bad Neustadt, Germany.

Dr. Deneke and his associates in Bad Neustadt began using this HPSD approach in mid-2019, and by early 2020 they had data from 179 patients who underwent first-time catheter ablation of atrial fibrillation (AFib), all of whom had undergone routine esophageal endoscopy 1-3 days after their treatment. Eight patients (4%) showed evidence of endoscopically detected esophageal lesions (EDEL), including three patients (2%) with an actual esophageal ulcer, and one (0.6%) who developed a perforation that healed after 52 days, Dr. Deneke reported. An additional 55 patients underwent a redo catheter ablation procedure using the HPSD method during this period, and in that group follow-up endoscopy in all patients showed EDEL in two patients (4%). In contrast, during Jan. 2012–May 2019, the same German center treated 2,102 patients who had a first radiofrequency catheter ablation using convention energy levels and treatment times, which resulted in 291 patients having an EDEL (14%), including 94 (4%) with an ulcer, and six patients (0.3%) with an esophageal perforation, he said.

Mitchel L. Zoler/MDedge News

His center’s recent safety experience with HPSD radiofrequncy ablation, compared with the historical controls, suggests that this technique can produce a substantial reduction in esophageal thermal injury, but HPSD has not completely eliminated the risk and hence there is need for continued alertness for this potential complication Dr. Deneke concluded. The HPSD method is also limited by having “a very narrow window” between efficacy at an Ablation Index of 350 and safety when the index remains below 360, he added.

The randomized study that Dr. Gallagher ran at St. George’s followed an analysis he and his associates recently published that suggested efficacy using esophageal cooling in prior reports when the data combined in a meta-analysis (J Interv Card Electrophysiol. 2019 Nov 22. doi: 10.1007/s10840-019-00661-5). They also concluded that the clinical setting required a temperature control device with an enhanced capacity for rapid cooling, which prior studies had lacked. So they turned to a Food and Drug Administration–approved catheter designed for placement in the esophagus for the purpose of either whole-body cooling or warming.

The study randomized a total of 187 patients, but collected follow-up endoscopy at 5-7 days after the ablation procedure on 120 patients, of whom 60 received esophageal cooling and 60 did not. The types of ablations performed on patients in the two study arms were similar, and use of esophageal cooling had no impact on treatment duration or efficacy, either acute and longer term, Dr. Gallagher reported.

Cooling had a marked and statistically significant impact on endoscopically detected thermal injury. Although two patients in the group that underwent cooling had injuries, in one of these cases the injury involved a protocol violation: Radiofrequency ablation mistakenly occurred after the cooling device shut off, and it was during this period when the injury happened. In the second case of thermal injury, blinded scoring judged the injury as grade 2 in severity – an erosion of less than 5 mm – on a nine-item scale that ranged from zero to grade 6, the most severe level denoting a fistula. By contrast, among the 12 patients with thermal injury in the nonprotected subgroup, one patient had a grade 5a lesion denoting a deep ulcer, one had a 4b denoting a superficial ulcer with a clot, and four had a 4a lesion defined as a clean superficial ulcer.

“This is really effective. It’s the first study to show reduced damage without affecting ablation efficacy,” Dr. Gallagher said. He plans to now use this method of esophageal protection routinely for his AFib ablation patients who pay privately, and for patients insured under the national U.K. system once this coverage is approved. Dr. Deneke expressed his interest in also using this approach to esophageal protection, but noted that currently he did not have access to the cooling catheter that Dr. Gallagher used because of regulatory constraints.

The esophageal cooling study was sponsored by Attune Medical, which markets the cooling device. Dr. Gallagher has received research funding from Attune Medical, and has received honoraria as a speaker on behalf of Biosense Webster and Medtronic. Dr. Deneke has been a speaker on behalf of Abbott, Biosense Webster, Biotronik, and Boston Scientific, and his institution has received research funding from Biosense Webster and Securus/Boston Scientific.

[email protected]

NATIONAL HARBOR, MD. – Thermal injury of a patient’s esophagus during radiofrequency catheter ablation of atrial fibrillation is notorious as a relatively common and problematic complication of the procedure, but two new approaches showed promise for substantially cutting the risk of esophageal thermal injury and the potential for the most severe damage: perforation.

Mitchel L. Zoler/MDedge News

One of these innovations is intensive esophageal cooling with a commercially marketed, fluid-chilled catheter placed in a patient’s esophagus during radiofrequency catheter ablation that keeps the inner surface of the esophagus at 4°C. This approach cut the incidence of periprocedural episodes of endoscopically detected esophageal thermal injury from 20% among controls to 3% in patients who had esophageal cooling in a randomized study with 120 patients, Mark M. Gallagher, MD, said at the annual International AF Symposium. The same device can also maintain a temperature on the inner surface of the esophagus of 42 ° C in patients undergoing cryoablation of atrial fibrillation, noted Dr. Gallagher, a cardiac electrophysiologist at St. George’s University Hospitals in London.

A second approach to cutting esophageal damage focuses on modifying the energy delivery with a radiofrequency ablation method known as high-power short-duration (HPSD). As the name says, this strategy uses a relatively high level of radiofrequency energy, 50 watts in the reported experience, for the brief interval of about 7 seconds, ideally delivering an overall Ablation Index of at least 350 but below 360, said Thomas Deneke, MD, an electrophysiologist, professor, and cochief of cardiology at the Heart Center in Bad Neustadt, Germany.

Dr. Deneke and his associates in Bad Neustadt began using this HPSD approach in mid-2019, and by early 2020 they had data from 179 patients who underwent first-time catheter ablation of atrial fibrillation (AFib), all of whom had undergone routine esophageal endoscopy 1-3 days after their treatment. Eight patients (4%) showed evidence of endoscopically detected esophageal lesions (EDEL), including three patients (2%) with an actual esophageal ulcer, and one (0.6%) who developed a perforation that healed after 52 days, Dr. Deneke reported. An additional 55 patients underwent a redo catheter ablation procedure using the HPSD method during this period, and in that group follow-up endoscopy in all patients showed EDEL in two patients (4%). In contrast, during Jan. 2012–May 2019, the same German center treated 2,102 patients who had a first radiofrequency catheter ablation using convention energy levels and treatment times, which resulted in 291 patients having an EDEL (14%), including 94 (4%) with an ulcer, and six patients (0.3%) with an esophageal perforation, he said.

Mitchel L. Zoler/MDedge News

His center’s recent safety experience with HPSD radiofrequncy ablation, compared with the historical controls, suggests that this technique can produce a substantial reduction in esophageal thermal injury, but HPSD has not completely eliminated the risk and hence there is need for continued alertness for this potential complication Dr. Deneke concluded. The HPSD method is also limited by having “a very narrow window” between efficacy at an Ablation Index of 350 and safety when the index remains below 360, he added.

The randomized study that Dr. Gallagher ran at St. George’s followed an analysis he and his associates recently published that suggested efficacy using esophageal cooling in prior reports when the data combined in a meta-analysis (J Interv Card Electrophysiol. 2019 Nov 22. doi: 10.1007/s10840-019-00661-5). They also concluded that the clinical setting required a temperature control device with an enhanced capacity for rapid cooling, which prior studies had lacked. So they turned to a Food and Drug Administration–approved catheter designed for placement in the esophagus for the purpose of either whole-body cooling or warming.

The study randomized a total of 187 patients, but collected follow-up endoscopy at 5-7 days after the ablation procedure on 120 patients, of whom 60 received esophageal cooling and 60 did not. The types of ablations performed on patients in the two study arms were similar, and use of esophageal cooling had no impact on treatment duration or efficacy, either acute and longer term, Dr. Gallagher reported.

Cooling had a marked and statistically significant impact on endoscopically detected thermal injury. Although two patients in the group that underwent cooling had injuries, in one of these cases the injury involved a protocol violation: Radiofrequency ablation mistakenly occurred after the cooling device shut off, and it was during this period when the injury happened. In the second case of thermal injury, blinded scoring judged the injury as grade 2 in severity – an erosion of less than 5 mm – on a nine-item scale that ranged from zero to grade 6, the most severe level denoting a fistula. By contrast, among the 12 patients with thermal injury in the nonprotected subgroup, one patient had a grade 5a lesion denoting a deep ulcer, one had a 4b denoting a superficial ulcer with a clot, and four had a 4a lesion defined as a clean superficial ulcer.

“This is really effective. It’s the first study to show reduced damage without affecting ablation efficacy,” Dr. Gallagher said. He plans to now use this method of esophageal protection routinely for his AFib ablation patients who pay privately, and for patients insured under the national U.K. system once this coverage is approved. Dr. Deneke expressed his interest in also using this approach to esophageal protection, but noted that currently he did not have access to the cooling catheter that Dr. Gallagher used because of regulatory constraints.

The esophageal cooling study was sponsored by Attune Medical, which markets the cooling device. Dr. Gallagher has received research funding from Attune Medical, and has received honoraria as a speaker on behalf of Biosense Webster and Medtronic. Dr. Deneke has been a speaker on behalf of Abbott, Biosense Webster, Biotronik, and Boston Scientific, and his institution has received research funding from Biosense Webster and Securus/Boston Scientific.

[email protected]

NATIONAL HARBOR, MD. – Thermal injury of a patient’s esophagus during radiofrequency catheter ablation of atrial fibrillation is notorious as a relatively common and problematic complication of the procedure, but two new approaches showed promise for substantially cutting the risk of esophageal thermal injury and the potential for the most severe damage: perforation.

Mitchel L. Zoler/MDedge News

One of these innovations is intensive esophageal cooling with a commercially marketed, fluid-chilled catheter placed in a patient’s esophagus during radiofrequency catheter ablation that keeps the inner surface of the esophagus at 4°C. This approach cut the incidence of periprocedural episodes of endoscopically detected esophageal thermal injury from 20% among controls to 3% in patients who had esophageal cooling in a randomized study with 120 patients, Mark M. Gallagher, MD, said at the annual International AF Symposium. The same device can also maintain a temperature on the inner surface of the esophagus of 42 ° C in patients undergoing cryoablation of atrial fibrillation, noted Dr. Gallagher, a cardiac electrophysiologist at St. George’s University Hospitals in London.

A second approach to cutting esophageal damage focuses on modifying the energy delivery with a radiofrequency ablation method known as high-power short-duration (HPSD). As the name says, this strategy uses a relatively high level of radiofrequency energy, 50 watts in the reported experience, for the brief interval of about 7 seconds, ideally delivering an overall Ablation Index of at least 350 but below 360, said Thomas Deneke, MD, an electrophysiologist, professor, and cochief of cardiology at the Heart Center in Bad Neustadt, Germany.

Dr. Deneke and his associates in Bad Neustadt began using this HPSD approach in mid-2019, and by early 2020 they had data from 179 patients who underwent first-time catheter ablation of atrial fibrillation (AFib), all of whom had undergone routine esophageal endoscopy 1-3 days after their treatment. Eight patients (4%) showed evidence of endoscopically detected esophageal lesions (EDEL), including three patients (2%) with an actual esophageal ulcer, and one (0.6%) who developed a perforation that healed after 52 days, Dr. Deneke reported. An additional 55 patients underwent a redo catheter ablation procedure using the HPSD method during this period, and in that group follow-up endoscopy in all patients showed EDEL in two patients (4%). In contrast, during Jan. 2012–May 2019, the same German center treated 2,102 patients who had a first radiofrequency catheter ablation using convention energy levels and treatment times, which resulted in 291 patients having an EDEL (14%), including 94 (4%) with an ulcer, and six patients (0.3%) with an esophageal perforation, he said.

Mitchel L. Zoler/MDedge News

His center’s recent safety experience with HPSD radiofrequncy ablation, compared with the historical controls, suggests that this technique can produce a substantial reduction in esophageal thermal injury, but HPSD has not completely eliminated the risk and hence there is need for continued alertness for this potential complication Dr. Deneke concluded. The HPSD method is also limited by having “a very narrow window” between efficacy at an Ablation Index of 350 and safety when the index remains below 360, he added.

The randomized study that Dr. Gallagher ran at St. George’s followed an analysis he and his associates recently published that suggested efficacy using esophageal cooling in prior reports when the data combined in a meta-analysis (J Interv Card Electrophysiol. 2019 Nov 22. doi: 10.1007/s10840-019-00661-5). They also concluded that the clinical setting required a temperature control device with an enhanced capacity for rapid cooling, which prior studies had lacked. So they turned to a Food and Drug Administration–approved catheter designed for placement in the esophagus for the purpose of either whole-body cooling or warming.

The study randomized a total of 187 patients, but collected follow-up endoscopy at 5-7 days after the ablation procedure on 120 patients, of whom 60 received esophageal cooling and 60 did not. The types of ablations performed on patients in the two study arms were similar, and use of esophageal cooling had no impact on treatment duration or efficacy, either acute and longer term, Dr. Gallagher reported.

Cooling had a marked and statistically significant impact on endoscopically detected thermal injury. Although two patients in the group that underwent cooling had injuries, in one of these cases the injury involved a protocol violation: Radiofrequency ablation mistakenly occurred after the cooling device shut off, and it was during this period when the injury happened. In the second case of thermal injury, blinded scoring judged the injury as grade 2 in severity – an erosion of less than 5 mm – on a nine-item scale that ranged from zero to grade 6, the most severe level denoting a fistula. By contrast, among the 12 patients with thermal injury in the nonprotected subgroup, one patient had a grade 5a lesion denoting a deep ulcer, one had a 4b denoting a superficial ulcer with a clot, and four had a 4a lesion defined as a clean superficial ulcer.

“This is really effective. It’s the first study to show reduced damage without affecting ablation efficacy,” Dr. Gallagher said. He plans to now use this method of esophageal protection routinely for his AFib ablation patients who pay privately, and for patients insured under the national U.K. system once this coverage is approved. Dr. Deneke expressed his interest in also using this approach to esophageal protection, but noted that currently he did not have access to the cooling catheter that Dr. Gallagher used because of regulatory constraints.

The esophageal cooling study was sponsored by Attune Medical, which markets the cooling device. Dr. Gallagher has received research funding from Attune Medical, and has received honoraria as a speaker on behalf of Biosense Webster and Medtronic. Dr. Deneke has been a speaker on behalf of Abbott, Biosense Webster, Biotronik, and Boston Scientific, and his institution has received research funding from Biosense Webster and Securus/Boston Scientific.

[email protected]

NATIONAL HARBOR, MD. – Researchers have created an artificial intelligence algorithm that can evaluate a 10-second ECG recording of a person in normal sinus rhythm and tell with a sensitivity and specificity of almost 80% whether or not that person ever had atrial fibrillation episodes some time in the past or will have a first arrhythmia episode in the near future.

Mitchel L. Zoler/MDedge News

Although this algorithm – derived from and then validated with a dataset of nearly 650,000 ECG recordings from more than 180,000 patients – still needs prospective validation, it offers the prospect for a potential revolution in screening for atrial fibrillation (AFib), Paul A. Friedman, MD, cautioned at the annual International AF Symposium. If initial clinical findings are confirmed, it would show that a 10-second, 12-lead ECG recording can provide the same screening scope as what otherwise takes weeks of ambulatory ECG recording with a Holter monitor or an implanted device, explained Dr. Friedman, professor of medicine and chair of the department of cardiovascular medicine at the Mayo Clinic in Rochester, Minn.

This finding “could have important implications for atrial fibrillation screening and for the management of patients with unexplained stroke,” Dr. Friedman and his associates noted in the published report of their study (Lancet. 2019 Sep 7;394[10201]:861-7). “We’re still working to define the window of ECG” recording time that provides the optimal assessment for a history of asymptomatic AFib, but the “possibilities this opens are huge,” Dr. Friedman said in his talk at the symposium. This work sprang from the premise that “subtle signatures” in a brief, apparently normal sinus rhythm ECG tracing can harbor reliable clues about AFib history or an imminent episode.

The 2019 report by Dr. Friedman and associates documented that in the validation phase of their study, the trained artificial intelligence (AI) program identified patients with a history of AFib or an impending arrhythmia event from a single, 10-second ECG that to the naked eye seemed to show normal sinus rhythm with a sensitivity of 79.0%, a specificity of 79.5%, and an accuracy of 79.4%. It also showed an area under a receiver operating characteristic curve of 0.87, meaning that screening for AFib by this method compared favorably with the area-under-the-curve (AUC) results tallied by several widely accepted screening tools, including Pap smears for cervical cancer (AUC of 0.70), mammograms for breast cancer (AUC of 0.85), and CHA2DS2-VASc scoring for estimating stroke risk in AFib patients (AUC of 0.57-0.72), Dr. Friedman said.

The researchers developed the AI algorithm with more than 450,000 10-second ECG tracings collected from roughly 126,000 patients who underwent at least one ECG recording as part of their routine care at the Mayo Clinic during 1993-2017. The goal was for the program to find and validate recurring characteristics in the ECG that consistently linked with a history of or an impending AFib episode and that did not appear in ECG recordings from people without any AFib history. The program this effort produced then underwent further adjustment with the use of more than 64,340 ECGs from an additional 18,116 patients, and then the final product underwent validation testing with a further 130,802 ECGs collected from an additional 36,280 people, the study phase that resulted in the reported sensitivity and specificity estimates.

It’s currently unclear to Dr. Friedman and associates what specific features the program uses to classify patients. It’s an important question, but if the results are reproducible and reliable, this uncertainty shouldn’t slow clinical adoption, he said in an interview.

While “this particular algorithm needs prospective vetting,” a similar algorithm developed by Dr. Friedman and the same research team that uses a 10-second ECG to identify patients with a left ventricular ejection fraction of 35% or less is further advanced in development, and a device that uses this algorithm will soon receive Food and Drug Administration review under a fast track designation that the agency approved in late 2019.

The researchers developed this algorithm for estimating left ventricular function using a strategy similar to their development of a tool for diagnosing AFib (Nat Med. 2019 Jan 7;25[1]:70-4), and results from 100 patients prospectively studied with this approach to ECG analysis and reported at the American Heart Association scientific sessions in November 2019 showed that the algorithm identified substantial left ventricular dysfunction with an AUC of 0.906 (Circulation. 2019 Nov 19;140[suppl 1]:A13447). The same team of investigators has developed an AI algorithm that can calculate a person’s physiologic age based on the ECG recording (Circ Arrhythm Electrophysiol. 2019 Sep;12[9]: 10.1161/CIRCEP.119.007284).

The study received no commercial funding, and Dr. Friedman and coauthors had no relevant disclosures. The Mayo Clinic has licensed a related artificial intelligence algorithm to EKO, and Dr. Friedman may benefit financially from this arrangement.

[email protected]

NATIONAL HARBOR, MD. – Researchers have created an artificial intelligence algorithm that can evaluate a 10-second ECG recording of a person in normal sinus rhythm and tell with a sensitivity and specificity of almost 80% whether or not that person ever had atrial fibrillation episodes some time in the past or will have a first arrhythmia episode in the near future.

Mitchel L. Zoler/MDedge News

Although this algorithm – derived from and then validated with a dataset of nearly 650,000 ECG recordings from more than 180,000 patients – still needs prospective validation, it offers the prospect for a potential revolution in screening for atrial fibrillation (AFib), Paul A. Friedman, MD, cautioned at the annual International AF Symposium. If initial clinical findings are confirmed, it would show that a 10-second, 12-lead ECG recording can provide the same screening scope as what otherwise takes weeks of ambulatory ECG recording with a Holter monitor or an implanted device, explained Dr. Friedman, professor of medicine and chair of the department of cardiovascular medicine at the Mayo Clinic in Rochester, Minn.

This finding “could have important implications for atrial fibrillation screening and for the management of patients with unexplained stroke,” Dr. Friedman and his associates noted in the published report of their study (Lancet. 2019 Sep 7;394[10201]:861-7). “We’re still working to define the window of ECG” recording time that provides the optimal assessment for a history of asymptomatic AFib, but the “possibilities this opens are huge,” Dr. Friedman said in his talk at the symposium. This work sprang from the premise that “subtle signatures” in a brief, apparently normal sinus rhythm ECG tracing can harbor reliable clues about AFib history or an imminent episode.

The 2019 report by Dr. Friedman and associates documented that in the validation phase of their study, the trained artificial intelligence (AI) program identified patients with a history of AFib or an impending arrhythmia event from a single, 10-second ECG that to the naked eye seemed to show normal sinus rhythm with a sensitivity of 79.0%, a specificity of 79.5%, and an accuracy of 79.4%. It also showed an area under a receiver operating characteristic curve of 0.87, meaning that screening for AFib by this method compared favorably with the area-under-the-curve (AUC) results tallied by several widely accepted screening tools, including Pap smears for cervical cancer (AUC of 0.70), mammograms for breast cancer (AUC of 0.85), and CHA2DS2-VASc scoring for estimating stroke risk in AFib patients (AUC of 0.57-0.72), Dr. Friedman said.

The researchers developed the AI algorithm with more than 450,000 10-second ECG tracings collected from roughly 126,000 patients who underwent at least one ECG recording as part of their routine care at the Mayo Clinic during 1993-2017. The goal was for the program to find and validate recurring characteristics in the ECG that consistently linked with a history of or an impending AFib episode and that did not appear in ECG recordings from people without any AFib history. The program this effort produced then underwent further adjustment with the use of more than 64,340 ECGs from an additional 18,116 patients, and then the final product underwent validation testing with a further 130,802 ECGs collected from an additional 36,280 people, the study phase that resulted in the reported sensitivity and specificity estimates.

It’s currently unclear to Dr. Friedman and associates what specific features the program uses to classify patients. It’s an important question, but if the results are reproducible and reliable, this uncertainty shouldn’t slow clinical adoption, he said in an interview.

While “this particular algorithm needs prospective vetting,” a similar algorithm developed by Dr. Friedman and the same research team that uses a 10-second ECG to identify patients with a left ventricular ejection fraction of 35% or less is further advanced in development, and a device that uses this algorithm will soon receive Food and Drug Administration review under a fast track designation that the agency approved in late 2019.

The researchers developed this algorithm for estimating left ventricular function using a strategy similar to their development of a tool for diagnosing AFib (Nat Med. 2019 Jan 7;25[1]:70-4), and results from 100 patients prospectively studied with this approach to ECG analysis and reported at the American Heart Association scientific sessions in November 2019 showed that the algorithm identified substantial left ventricular dysfunction with an AUC of 0.906 (Circulation. 2019 Nov 19;140[suppl 1]:A13447). The same team of investigators has developed an AI algorithm that can calculate a person’s physiologic age based on the ECG recording (Circ Arrhythm Electrophysiol. 2019 Sep;12[9]: 10.1161/CIRCEP.119.007284).

The study received no commercial funding, and Dr. Friedman and coauthors had no relevant disclosures. The Mayo Clinic has licensed a related artificial intelligence algorithm to EKO, and Dr. Friedman may benefit financially from this arrangement.

[email protected]

NATIONAL HARBOR, MD. – Researchers have created an artificial intelligence algorithm that can evaluate a 10-second ECG recording of a person in normal sinus rhythm and tell with a sensitivity and specificity of almost 80% whether or not that person ever had atrial fibrillation episodes some time in the past or will have a first arrhythmia episode in the near future.

Mitchel L. Zoler/MDedge News

Although this algorithm – derived from and then validated with a dataset of nearly 650,000 ECG recordings from more than 180,000 patients – still needs prospective validation, it offers the prospect for a potential revolution in screening for atrial fibrillation (AFib), Paul A. Friedman, MD, cautioned at the annual International AF Symposium. If initial clinical findings are confirmed, it would show that a 10-second, 12-lead ECG recording can provide the same screening scope as what otherwise takes weeks of ambulatory ECG recording with a Holter monitor or an implanted device, explained Dr. Friedman, professor of medicine and chair of the department of cardiovascular medicine at the Mayo Clinic in Rochester, Minn.

This finding “could have important implications for atrial fibrillation screening and for the management of patients with unexplained stroke,” Dr. Friedman and his associates noted in the published report of their study (Lancet. 2019 Sep 7;394[10201]:861-7). “We’re still working to define the window of ECG” recording time that provides the optimal assessment for a history of asymptomatic AFib, but the “possibilities this opens are huge,” Dr. Friedman said in his talk at the symposium. This work sprang from the premise that “subtle signatures” in a brief, apparently normal sinus rhythm ECG tracing can harbor reliable clues about AFib history or an imminent episode.

The 2019 report by Dr. Friedman and associates documented that in the validation phase of their study, the trained artificial intelligence (AI) program identified patients with a history of AFib or an impending arrhythmia event from a single, 10-second ECG that to the naked eye seemed to show normal sinus rhythm with a sensitivity of 79.0%, a specificity of 79.5%, and an accuracy of 79.4%. It also showed an area under a receiver operating characteristic curve of 0.87, meaning that screening for AFib by this method compared favorably with the area-under-the-curve (AUC) results tallied by several widely accepted screening tools, including Pap smears for cervical cancer (AUC of 0.70), mammograms for breast cancer (AUC of 0.85), and CHA2DS2-VASc scoring for estimating stroke risk in AFib patients (AUC of 0.57-0.72), Dr. Friedman said.

The researchers developed the AI algorithm with more than 450,000 10-second ECG tracings collected from roughly 126,000 patients who underwent at least one ECG recording as part of their routine care at the Mayo Clinic during 1993-2017. The goal was for the program to find and validate recurring characteristics in the ECG that consistently linked with a history of or an impending AFib episode and that did not appear in ECG recordings from people without any AFib history. The program this effort produced then underwent further adjustment with the use of more than 64,340 ECGs from an additional 18,116 patients, and then the final product underwent validation testing with a further 130,802 ECGs collected from an additional 36,280 people, the study phase that resulted in the reported sensitivity and specificity estimates.

It’s currently unclear to Dr. Friedman and associates what specific features the program uses to classify patients. It’s an important question, but if the results are reproducible and reliable, this uncertainty shouldn’t slow clinical adoption, he said in an interview.

While “this particular algorithm needs prospective vetting,” a similar algorithm developed by Dr. Friedman and the same research team that uses a 10-second ECG to identify patients with a left ventricular ejection fraction of 35% or less is further advanced in development, and a device that uses this algorithm will soon receive Food and Drug Administration review under a fast track designation that the agency approved in late 2019.

The researchers developed this algorithm for estimating left ventricular function using a strategy similar to their development of a tool for diagnosing AFib (Nat Med. 2019 Jan 7;25[1]:70-4), and results from 100 patients prospectively studied with this approach to ECG analysis and reported at the American Heart Association scientific sessions in November 2019 showed that the algorithm identified substantial left ventricular dysfunction with an AUC of 0.906 (Circulation. 2019 Nov 19;140[suppl 1]:A13447). The same team of investigators has developed an AI algorithm that can calculate a person’s physiologic age based on the ECG recording (Circ Arrhythm Electrophysiol. 2019 Sep;12[9]: 10.1161/CIRCEP.119.007284).

The study received no commercial funding, and Dr. Friedman and coauthors had no relevant disclosures. The Mayo Clinic has licensed a related artificial intelligence algorithm to EKO, and Dr. Friedman may benefit financially from this arrangement.

[email protected]

NATIONAL HARBOR, MD. – Cardiac electrophysiologists have reported using pulsed field ablation, a new power source for catheter ablation of atrial fibrillation, on fewer than 150 patients worldwide in initial clinical studies, but its performance so far and the promise it carries for substantially improving the safety and efficacy of catheter ablation has convinced many experts that it represents the future for this intervention.

“I’m very excited about PFA [pulsed field ablation]. It may make everything else obsolete,” Andrea Natale, MD, said at the annual International AF Symposium. “We need to see more efficacy data, but just for safety alone there is no reason to use anything else,” commented Dr. Natale, executive medical director of the Texas Cardiac Arrhythmia Institute at St. David’s Medical Center in Austin,Tex.

“The main issue is safety, and if PFA lives up to its promise, then [using it preferentially] is not a difficult decision,” commented Francis E. Marchlinski, MD, professor of medicine and director of electrophysiology at the University of Pennsylvania.

The pulsed field ablation studies have been sponsored by Farapulse, the company developing this device, which in May 2019 received breakthrough designation for priority review from the Food and Drug Administration.

Dr. Reddy and Dr. Jaïs are both consultants to and shareholders in Farapulse. Dr. Natale has received honoraria from or has been a consultant to Biotronik, Janssen, Medtronic, and St. Jude. Dr. Marchlinski has been a consultant to or has received honoraria from Abbott EP/St. Jude, Biotronik, and Medtronic. Dr. Mansour has been a consultant for Abbott and Medtronic, has an equity interest or stock options in NewPace and EPD Solutions, and has received research grants from Abbott, Boehringer Ingelheim, Pfizer, and Sentre Heart. In addition, all sources have received consulting fees, honoraria, and/or research grants from Biosense Webster and Boston Scientific.

[email protected]

NATIONAL HARBOR, MD. – Cardiac electrophysiologists have reported using pulsed field ablation, a new power source for catheter ablation of atrial fibrillation, on fewer than 150 patients worldwide in initial clinical studies, but its performance so far and the promise it carries for substantially improving the safety and efficacy of catheter ablation has convinced many experts that it represents the future for this intervention.

“I’m very excited about PFA [pulsed field ablation]. It may make everything else obsolete,” Andrea Natale, MD, said at the annual International AF Symposium. “We need to see more efficacy data, but just for safety alone there is no reason to use anything else,” commented Dr. Natale, executive medical director of the Texas Cardiac Arrhythmia Institute at St. David’s Medical Center in Austin,Tex.

“The main issue is safety, and if PFA lives up to its promise, then [using it preferentially] is not a difficult decision,” commented Francis E. Marchlinski, MD, professor of medicine and director of electrophysiology at the University of Pennsylvania.

The pulsed field ablation studies have been sponsored by Farapulse, the company developing this device, which in May 2019 received breakthrough designation for priority review from the Food and Drug Administration.

Dr. Reddy and Dr. Jaïs are both consultants to and shareholders in Farapulse. Dr. Natale has received honoraria from or has been a consultant to Biotronik, Janssen, Medtronic, and St. Jude. Dr. Marchlinski has been a consultant to or has received honoraria from Abbott EP/St. Jude, Biotronik, and Medtronic. Dr. Mansour has been a consultant for Abbott and Medtronic, has an equity interest or stock options in NewPace and EPD Solutions, and has received research grants from Abbott, Boehringer Ingelheim, Pfizer, and Sentre Heart. In addition, all sources have received consulting fees, honoraria, and/or research grants from Biosense Webster and Boston Scientific.

[email protected]

NATIONAL HARBOR, MD. – Cardiac electrophysiologists have reported using pulsed field ablation, a new power source for catheter ablation of atrial fibrillation, on fewer than 150 patients worldwide in initial clinical studies, but its performance so far and the promise it carries for substantially improving the safety and efficacy of catheter ablation has convinced many experts that it represents the future for this intervention.

“I’m very excited about PFA [pulsed field ablation]. It may make everything else obsolete,” Andrea Natale, MD, said at the annual International AF Symposium. “We need to see more efficacy data, but just for safety alone there is no reason to use anything else,” commented Dr. Natale, executive medical director of the Texas Cardiac Arrhythmia Institute at St. David’s Medical Center in Austin,Tex.

“The main issue is safety, and if PFA lives up to its promise, then [using it preferentially] is not a difficult decision,” commented Francis E. Marchlinski, MD, professor of medicine and director of electrophysiology at the University of Pennsylvania.

The pulsed field ablation studies have been sponsored by Farapulse, the company developing this device, which in May 2019 received breakthrough designation for priority review from the Food and Drug Administration.

Dr. Reddy and Dr. Jaïs are both consultants to and shareholders in Farapulse. Dr. Natale has received honoraria from or has been a consultant to Biotronik, Janssen, Medtronic, and St. Jude. Dr. Marchlinski has been a consultant to or has received honoraria from Abbott EP/St. Jude, Biotronik, and Medtronic. Dr. Mansour has been a consultant for Abbott and Medtronic, has an equity interest or stock options in NewPace and EPD Solutions, and has received research grants from Abbott, Boehringer Ingelheim, Pfizer, and Sentre Heart. In addition, all sources have received consulting fees, honoraria, and/or research grants from Biosense Webster and Boston Scientific.

[email protected]

SNOWMASS, COLO. – Catheter ablation of atrial fibrillation was associated with a significant reduction in the composite endpoint of all-cause mortality, stroke, major bleeding, or cardiac arrest, compared with rhythm and/or rate control drugs in a propensity score–weighted, retrospective, observational study.

Bruce Jancin/MDedge News

Findings of the investigation, which included more than 183,000 real-world patients in routine clinical practice, were reported by Peter S. Noseworthy, MD, during the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

The results breathe new life into the controversy created by the previously reported CABANA trial (Catheter Ablation vs. Antiarrhythmic Drug Therapy for Atrial Fibrillation), a 10-country study in which 2,204 patients with atrial fibrillation (AFib) were randomized to catheter ablation or antiarrhythmic and/or rhythm control medications and followed for a mean of about 4 years. CABANA yielded a negative result (JAMA. 2019 Apr 2;321[13]:1261-74), with the prespecified intent-to-treat analysis indicating no significant between-group difference in the primary composite endpoint – the very same one that was positive in the large observational study.

However, CABANA was marred by major problems arising from protocol deviations: Nearly 28% of patients assigned to medical therapy crossed over to catheter ablation, typically because their antiarrhythmic drugs failed, and 10% of patients randomized to catheter ablation never got it. This muddies the waters when trying to identify a true stroke/mortality benefit for catheter ablation, if indeed any such benefit was actually present.

Here’s where the controversy arose: While CABANA must be called a negative trial based upon the disappointing results of the intent-to-treat analysis, a prespecified post hoc analysis of patients as actually treated showed a statistically significant 27% relative risk reduction for the primary composite endpoint in the catheter ablation group. That’s strikingly similar to the 30% relative risk reduction for catheter ablation seen in the huge observational study, where the CABANA-type primary outcome occurred in 22.5% of the medically managed patients and 16.8% of those who underwent catheter ablation, noted Dr. Noseworthy, professor of medicine and director of heart rhythm and physiology at the Mayo Clinic in Rochester, Minn.

He ought to know: He was both an investigator in CABANA and first author of the published observational study (Eur Heart J. 2019 Apr 21;40[16]:1257-64).

In the observational study, Dr. Noseworthy and coinvestigators utilized a huge U.S. administrative health claims database in order to identify a nationally representative group of 183,760 AFib patients, 12,032 of whom were treated with catheter ablation and the rest with antiarrhythmic and/or rhythm control drugs during the same years the CABANA trial was enrolling patients. The two groups were balanced using propensity score weighting to adjust for baseline differences in 90 variables.

The investigators sought to learn if the CABANA study population was representative of real-world AFib patients, and whether the observational experience could help resolve the CABANA controversy. It turned out that most AFib patients seen in daily clinical practice were CABANA like; that is, 74% of them would have been eligible for the clinical trial because they were symptomatic, over age 65, or younger than 65 with at least one CHADS2 stroke risk factor. About 22% of the large real-world sample would have been excluded from CABANA because they’d failed on amiodarone and other antiarrhythmic agents or had previously undergone ablation. About 4% of patients failed to meet the CABANA inclusion criteria.

The risk reduction for the composite endpoint associated with catheter ablation in the large retrospective study was greatest in the CABANA-like patients, at 30%. It was less robust but still statistically significant at 15% in patients who met at least one of the exclusion criteria for the trial.

The sheer size of this study provides greater statistical power than in CABANA. Of course, a nonrandomized, propensity score–based comparison such as this is always susceptible to confounding, even after adjustment for 90 variables. But the observational study does offer “a glimmer of hope” that catheter ablation, done in the right patients, might confer a stroke risk reduction and mortality benefit, he said.

The 33% relative risk reduction in the small group of real-world patients who failed to meet the CABANA inclusion criteria, while numerically impressive, wasn’t close to statistical significance, probably because event rates in that population were so low.

“Even if you could reduce stroke risk with ablation in that low-risk group, it would be a very inefficient way to reduce the population burden of stroke,” Dr. Noseworthy observed.

Putting together the results of CABANA and the large observational study to sum up his view of where catheter ablation for AF[ib] stands today, Dr. Noseworthy commented, “Ablation is reasonable for symptom control in many patients, basically anyone who is either breaking through on drugs or doesn’t want to take the drugs and is highly symptomatic. And there may be a small stroke and/or mortality benefit for people who are in the sweet spot – and those are people who look a lot like the patients enrolled in CABANA.”

Patients who met the exclusion criteria for CABANA are too advanced in their AFib to be likely to derive a stroke or mortality benefit from catheter ablation. “It’s very hard to move the needle in these patients with either a drug or catheter ablation approach. I wouldn’t try to reduce the risk of stroke here with an expensive and invasive procedure,” the electrophysiologist concluded.

He reported having no financial conflicts regarding his presentation.

[email protected]

SNOWMASS, COLO. – Catheter ablation of atrial fibrillation was associated with a significant reduction in the composite endpoint of all-cause mortality, stroke, major bleeding, or cardiac arrest, compared with rhythm and/or rate control drugs in a propensity score–weighted, retrospective, observational study.

Bruce Jancin/MDedge News

Findings of the investigation, which included more than 183,000 real-world patients in routine clinical practice, were reported by Peter S. Noseworthy, MD, during the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

The results breathe new life into the controversy created by the previously reported CABANA trial (Catheter Ablation vs. Antiarrhythmic Drug Therapy for Atrial Fibrillation), a 10-country study in which 2,204 patients with atrial fibrillation (AFib) were randomized to catheter ablation or antiarrhythmic and/or rhythm control medications and followed for a mean of about 4 years. CABANA yielded a negative result (JAMA. 2019 Apr 2;321[13]:1261-74), with the prespecified intent-to-treat analysis indicating no significant between-group difference in the primary composite endpoint – the very same one that was positive in the large observational study.

However, CABANA was marred by major problems arising from protocol deviations: Nearly 28% of patients assigned to medical therapy crossed over to catheter ablation, typically because their antiarrhythmic drugs failed, and 10% of patients randomized to catheter ablation never got it. This muddies the waters when trying to identify a true stroke/mortality benefit for catheter ablation, if indeed any such benefit was actually present.

Here’s where the controversy arose: While CABANA must be called a negative trial based upon the disappointing results of the intent-to-treat analysis, a prespecified post hoc analysis of patients as actually treated showed a statistically significant 27% relative risk reduction for the primary composite endpoint in the catheter ablation group. That’s strikingly similar to the 30% relative risk reduction for catheter ablation seen in the huge observational study, where the CABANA-type primary outcome occurred in 22.5% of the medically managed patients and 16.8% of those who underwent catheter ablation, noted Dr. Noseworthy, professor of medicine and director of heart rhythm and physiology at the Mayo Clinic in Rochester, Minn.

He ought to know: He was both an investigator in CABANA and first author of the published observational study (Eur Heart J. 2019 Apr 21;40[16]:1257-64).

In the observational study, Dr. Noseworthy and coinvestigators utilized a huge U.S. administrative health claims database in order to identify a nationally representative group of 183,760 AFib patients, 12,032 of whom were treated with catheter ablation and the rest with antiarrhythmic and/or rhythm control drugs during the same years the CABANA trial was enrolling patients. The two groups were balanced using propensity score weighting to adjust for baseline differences in 90 variables.

The investigators sought to learn if the CABANA study population was representative of real-world AFib patients, and whether the observational experience could help resolve the CABANA controversy. It turned out that most AFib patients seen in daily clinical practice were CABANA like; that is, 74% of them would have been eligible for the clinical trial because they were symptomatic, over age 65, or younger than 65 with at least one CHADS2 stroke risk factor. About 22% of the large real-world sample would have been excluded from CABANA because they’d failed on amiodarone and other antiarrhythmic agents or had previously undergone ablation. About 4% of patients failed to meet the CABANA inclusion criteria.

The risk reduction for the composite endpoint associated with catheter ablation in the large retrospective study was greatest in the CABANA-like patients, at 30%. It was less robust but still statistically significant at 15% in patients who met at least one of the exclusion criteria for the trial.

The sheer size of this study provides greater statistical power than in CABANA. Of course, a nonrandomized, propensity score–based comparison such as this is always susceptible to confounding, even after adjustment for 90 variables. But the observational study does offer “a glimmer of hope” that catheter ablation, done in the right patients, might confer a stroke risk reduction and mortality benefit, he said.

The 33% relative risk reduction in the small group of real-world patients who failed to meet the CABANA inclusion criteria, while numerically impressive, wasn’t close to statistical significance, probably because event rates in that population were so low.

“Even if you could reduce stroke risk with ablation in that low-risk group, it would be a very inefficient way to reduce the population burden of stroke,” Dr. Noseworthy observed.

Putting together the results of CABANA and the large observational study to sum up his view of where catheter ablation for AF[ib] stands today, Dr. Noseworthy commented, “Ablation is reasonable for symptom control in many patients, basically anyone who is either breaking through on drugs or doesn’t want to take the drugs and is highly symptomatic. And there may be a small stroke and/or mortality benefit for people who are in the sweet spot – and those are people who look a lot like the patients enrolled in CABANA.”

Patients who met the exclusion criteria for CABANA are too advanced in their AFib to be likely to derive a stroke or mortality benefit from catheter ablation. “It’s very hard to move the needle in these patients with either a drug or catheter ablation approach. I wouldn’t try to reduce the risk of stroke here with an expensive and invasive procedure,” the electrophysiologist concluded.

He reported having no financial conflicts regarding his presentation.

[email protected]

SNOWMASS, COLO. – Catheter ablation of atrial fibrillation was associated with a significant reduction in the composite endpoint of all-cause mortality, stroke, major bleeding, or cardiac arrest, compared with rhythm and/or rate control drugs in a propensity score–weighted, retrospective, observational study.

Bruce Jancin/MDedge News

Findings of the investigation, which included more than 183,000 real-world patients in routine clinical practice, were reported by Peter S. Noseworthy, MD, during the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

The results breathe new life into the controversy created by the previously reported CABANA trial (Catheter Ablation vs. Antiarrhythmic Drug Therapy for Atrial Fibrillation), a 10-country study in which 2,204 patients with atrial fibrillation (AFib) were randomized to catheter ablation or antiarrhythmic and/or rhythm control medications and followed for a mean of about 4 years. CABANA yielded a negative result (JAMA. 2019 Apr 2;321[13]:1261-74), with the prespecified intent-to-treat analysis indicating no significant between-group difference in the primary composite endpoint – the very same one that was positive in the large observational study.

However, CABANA was marred by major problems arising from protocol deviations: Nearly 28% of patients assigned to medical therapy crossed over to catheter ablation, typically because their antiarrhythmic drugs failed, and 10% of patients randomized to catheter ablation never got it. This muddies the waters when trying to identify a true stroke/mortality benefit for catheter ablation, if indeed any such benefit was actually present.

Here’s where the controversy arose: While CABANA must be called a negative trial based upon the disappointing results of the intent-to-treat analysis, a prespecified post hoc analysis of patients as actually treated showed a statistically significant 27% relative risk reduction for the primary composite endpoint in the catheter ablation group. That’s strikingly similar to the 30% relative risk reduction for catheter ablation seen in the huge observational study, where the CABANA-type primary outcome occurred in 22.5% of the medically managed patients and 16.8% of those who underwent catheter ablation, noted Dr. Noseworthy, professor of medicine and director of heart rhythm and physiology at the Mayo Clinic in Rochester, Minn.

He ought to know: He was both an investigator in CABANA and first author of the published observational study (Eur Heart J. 2019 Apr 21;40[16]:1257-64).

In the observational study, Dr. Noseworthy and coinvestigators utilized a huge U.S. administrative health claims database in order to identify a nationally representative group of 183,760 AFib patients, 12,032 of whom were treated with catheter ablation and the rest with antiarrhythmic and/or rhythm control drugs during the same years the CABANA trial was enrolling patients. The two groups were balanced using propensity score weighting to adjust for baseline differences in 90 variables.

The investigators sought to learn if the CABANA study population was representative of real-world AFib patients, and whether the observational experience could help resolve the CABANA controversy. It turned out that most AFib patients seen in daily clinical practice were CABANA like; that is, 74% of them would have been eligible for the clinical trial because they were symptomatic, over age 65, or younger than 65 with at least one CHADS2 stroke risk factor. About 22% of the large real-world sample would have been excluded from CABANA because they’d failed on amiodarone and other antiarrhythmic agents or had previously undergone ablation. About 4% of patients failed to meet the CABANA inclusion criteria.

The risk reduction for the composite endpoint associated with catheter ablation in the large retrospective study was greatest in the CABANA-like patients, at 30%. It was less robust but still statistically significant at 15% in patients who met at least one of the exclusion criteria for the trial.

The sheer size of this study provides greater statistical power than in CABANA. Of course, a nonrandomized, propensity score–based comparison such as this is always susceptible to confounding, even after adjustment for 90 variables. But the observational study does offer “a glimmer of hope” that catheter ablation, done in the right patients, might confer a stroke risk reduction and mortality benefit, he said.

The 33% relative risk reduction in the small group of real-world patients who failed to meet the CABANA inclusion criteria, while numerically impressive, wasn’t close to statistical significance, probably because event rates in that population were so low.

“Even if you could reduce stroke risk with ablation in that low-risk group, it would be a very inefficient way to reduce the population burden of stroke,” Dr. Noseworthy observed.

Putting together the results of CABANA and the large observational study to sum up his view of where catheter ablation for AF[ib] stands today, Dr. Noseworthy commented, “Ablation is reasonable for symptom control in many patients, basically anyone who is either breaking through on drugs or doesn’t want to take the drugs and is highly symptomatic. And there may be a small stroke and/or mortality benefit for people who are in the sweet spot – and those are people who look a lot like the patients enrolled in CABANA.”

Patients who met the exclusion criteria for CABANA are too advanced in their AFib to be likely to derive a stroke or mortality benefit from catheter ablation. “It’s very hard to move the needle in these patients with either a drug or catheter ablation approach. I wouldn’t try to reduce the risk of stroke here with an expensive and invasive procedure,” the electrophysiologist concluded.

He reported having no financial conflicts regarding his presentation.

[email protected]

Clinical trials supporting Food and Drug Adminstration approval of contemporary cancer therapies frequently failed to capture major adverse cardiovascular events (MACE) and, when they did, reported rates 2.6-fold lower than noncancer trials, new research shows.

Overall, 51.3% of trials did not report MACE, with that number reaching 57.6% in trials enrolling patients with baseline cardiovascular disease (CVD).

Nearly 40% of trials did not report any CVD events in follow-up, the authors reported online Feb. 10, 2020, in the Journal of the American College of Cardiology (2020;75:620-8).

“Even in drug classes where there were established or emerging associations with cardiotoxic events, often there were no reported heart events or cardiovascular events across years of follow-up in trials that examined hundreds or even thousands of patients. That was actually pretty surprising,” senior author Daniel Addison, MD, codirector of the cardio-oncology program at the Ohio State University Medical Center, Columbus, said in an interview.

The study was prompted by a series of events that crescendoed when his team was called to the ICU to determine whether a novel targeted agent played a role in the heart decline of a patient with acute myeloid leukemia. “I had a resident ask me a very important question: ‘How do we really know for sure that the trial actually reflects the true risk of heart events?’ to which I told him, ‘it’s difficult to know,’ ” he said.

“I think many of us rely heavily on what we see in the trials, particularly when they make it to the top journals, and quite frankly, we generally take it at face value,” Dr. Addison observed.
 

Lower Rate of Reported Events

The investigators reviewed CV events reported in 97,365 patients (median age, 61 years; 46% female) enrolled in 189 phase 2 and 3 trials supporting FDA approval of 123 anticancer drugs from 1998 to 2018. Biologic, targeted, or immune-based therapies accounted for 72.5% of drug approvals.

Over 148,138 person-years of follow-up (median trial duration, 30 months), there were 1,148 incidents of MACE (375 heart failure, 253 MIs, 180 strokes, 65 atrial fibrillation, 29 coronary revascularizations, and 246 CVD deaths). MACE rates were higher in the intervention group than in the control group (792 vs. 356; P less than .01). Among the 64 trials that excluded patients with baseline CVD, there were 269 incidents of MACE.

To put this finding in context, the researchers examined the reported incidence of MACE among some 6,000 similarly aged participants in the Multi-Ethnic Study of Atherosclerosis (MESA). The overall weighted-average incidence rate was 1,408 per 100,000 person-years among MESA participants, compared with 542 events per 100,000 person-years among oncology trial participants (716 per 100,000 in the intervention arm). This represents a reported-to-expected ratio of 0.38 – a 2.6-fold lower rate of reported events (P less than .001) – and a risk difference of 866.

Further, MACE reporting was lower by a factor of 1.7 among all cancer trial participants irrespective of baseline CVD status (reported-to-expected ratio, 0.56; risk difference, 613; P less than .001).

There was no significant difference in MACE reporting between independent or industry-sponsored trials, the authors report.
 

No malicious intent

“There are likely some that might lean toward not wanting to attribute blame to a new drug when the drug is in a study, but I really think that the leading factor is lack of awareness,” Dr. Addison said. “I’ve talked with several cancer collaborators around the country who run large clinical trials, and I think often, when an event may be brought to someone’s attention, there is a tendency to just write it off as kind of a generic expected event due to age, or just something that’s not really pertinent to the study. So they don’t really focus on it as much.”

“Closer collaboration between cardiologists and cancer physicians is needed to better determine true cardiac risks among patients treated with these drugs.”

Breast cancer oncologist Marc E. Lippman, MD, of Georgetown University Medical Center and Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C., isn’t convinced a lack of awareness is the culprit.

“I don’t agree with that at all,” he said in an interview. “I think there are very, very clear rules and guidelines these days for adverse-event reporting. I think that’s not a very likely explanation – that it’s not on the radar.”

Part of the problem may be that some of the toxicities, particularly cardiovascular, may not emerge for years, he said. Participant screening for the trials also likely removed patients with high cardiovascular risk. “It’s very understandable to me – I’m not saying it’s good particularly – but I think it’s very understandable that, if you’re trying to develop a drug, the last thing you’d want to have is a lot of toxicity that you might have avoided by just being restrictive in who you let into the study,” Dr. Lippman said.

The underreported CVD events may also reflect the rapidly changing profile of cardiovascular toxicities associated with novel anticancer therapies.

“Providers, both cancer and noncancer, generally put cardiotoxicity in the box of anthracyclines and radiation, but particularly over the last decade, we’ve begun to understand it’s well beyond any one class of drugs,” Dr. Addison said.

“I agree completely,” Dr. Lippman said. For example, “the checkpoint inhibitors are so unbelievably different in terms of their toxicities that many people simply didn’t even know what they were getting into at first.”
 

One size does not fit all

Javid Moslehi, MD, director of the cardio-oncology program at Vanderbilt University, Nashville, Tenn., said echocardiography – recommended to detect changes in left ventricular function in patients exposed to anthracyclines or targeted agents like trastuzumab (Herceptin) – isn’t enough to address today’s cancer therapy–related CVD events.

Courtesy Joe Howell

“Initial drugs like anthracyclines or Herceptin in cardio-oncology were associated with systolic cardiac dysfunction, whereas the majority of issues we see in the cardio-oncology clinics today are vascular, metabolic, arrhythmogenic, and inflammatory,” he said in an interview. “Echocardiography misses the big and increasingly complex picture.”

His group, for example, has been studying myocarditis associated with immunotherapies, but none of the clinical trials require screening or surveillance for myocarditis with a cardiac biomarker like troponin.

The group also recently identified 303 deaths in patients exposed to ibrutinib, a drug that revolutionized the treatment of several B-cell malignancies but is associated with higher rates of atrial fibrillation, which is also associated with increased bleeding risk. “So there’s a little bit of a double whammy there, given that we often treat atrial fibrillation with anticoagulation and where we can cause complications in patients,” Dr. Moslehi noted.

Although there needs to be closer collaboration between cardiologists and oncologists on individual trials, cardiologists also have to realize that oncology care has become very personalized, he suggested.

“What’s probably relevant for the breast cancer patient may not be relevant for the prostate cancer patient and their respective treatments,” Dr. Moslehi said. “So if we were to say, ‘every person should get an echo,’ that may be less relevant to the prostate cancer patient where treatments can cause vascular and metabolic perturbations or to the patient treated with immunotherapy who may have myocarditis, where many of the echos can be normal. There’s no one-size-fits-all for these things.”

Wearable technologies like smartwatches could play a role in improving the reporting of CVD events with novel therapies but a lot more research needs to be done to validate these tools, Dr. Addison said. “But as we continue on into the 21st century, this is going to expand and may potentially help us,” he added.

In the interim, better standardization is needed of the cardiovascular events reported in oncology trials, particularly the Common Terminology Criteria for Adverse Events (CTCAE), said Dr. Moslehi, who also serves as chair of the American Heart Association’s subcommittee on cardio-oncology.

“Cardiovascular definitions are not exactly uniform and are not consistent with what we in cardiology consider to be important or relevant,” he said. “So I think there needs to be better standardization of these definitions, specifically within the CTCAE, which is what the oncologists use to identify adverse events.”

In a linked editorial (J Am Coll Cardiol. 2020;75:629-31), Dr. Lippman and cardiologist Nanette Bishopric, MD, of the Medstar Heart and Vascular Institute in Washington, D.C., suggested it may also be time to organize a consortium that can carry out “rigorous multicenter clinical investigations to evaluate the cardiotoxicity of emerging cancer treatments,” similar to the Thrombosis in Myocardial Infarction Study Group.

“The success of this consortium in pioneering and targeting multiple generations of drugs for the treatment of MI, involving tens of thousands of patients and thousands of collaborations across multiple national borders, is a model for how to move forward in providing the new hope of cancer cure without the trade-off of years lost to heart disease,” the editorialists concluded.

The study was supported in part by National Institutes of Health grants, including a K12-CA133250 grant to Dr. Addison. Dr. Bishopric reported being on the scientific board of C&C Biopharma. Dr. Lippman reports being on the board of directors of and holding stock in Seattle Genetics. Dr. Moslehi reported having served on advisory boards for Pfizer, Novartis, Bristol-Myers Squibb, Deciphera, Audentes Pharmaceuticals, Nektar, Takeda, Ipsen, Myokardia, AstraZeneca, GlaxoSmithKline, Intrexon, and Regeneron.

This article first appeared on Medscape.com.

Clinical trials supporting Food and Drug Adminstration approval of contemporary cancer therapies frequently failed to capture major adverse cardiovascular events (MACE) and, when they did, reported rates 2.6-fold lower than noncancer trials, new research shows.

Overall, 51.3% of trials did not report MACE, with that number reaching 57.6% in trials enrolling patients with baseline cardiovascular disease (CVD).

Nearly 40% of trials did not report any CVD events in follow-up, the authors reported online Feb. 10, 2020, in the Journal of the American College of Cardiology (2020;75:620-8).

“Even in drug classes where there were established or emerging associations with cardiotoxic events, often there were no reported heart events or cardiovascular events across years of follow-up in trials that examined hundreds or even thousands of patients. That was actually pretty surprising,” senior author Daniel Addison, MD, codirector of the cardio-oncology program at the Ohio State University Medical Center, Columbus, said in an interview.

The study was prompted by a series of events that crescendoed when his team was called to the ICU to determine whether a novel targeted agent played a role in the heart decline of a patient with acute myeloid leukemia. “I had a resident ask me a very important question: ‘How do we really know for sure that the trial actually reflects the true risk of heart events?’ to which I told him, ‘it’s difficult to know,’ ” he said.

“I think many of us rely heavily on what we see in the trials, particularly when they make it to the top journals, and quite frankly, we generally take it at face value,” Dr. Addison observed.
 

Lower Rate of Reported Events

The investigators reviewed CV events reported in 97,365 patients (median age, 61 years; 46% female) enrolled in 189 phase 2 and 3 trials supporting FDA approval of 123 anticancer drugs from 1998 to 2018. Biologic, targeted, or immune-based therapies accounted for 72.5% of drug approvals.

Over 148,138 person-years of follow-up (median trial duration, 30 months), there were 1,148 incidents of MACE (375 heart failure, 253 MIs, 180 strokes, 65 atrial fibrillation, 29 coronary revascularizations, and 246 CVD deaths). MACE rates were higher in the intervention group than in the control group (792 vs. 356; P less than .01). Among the 64 trials that excluded patients with baseline CVD, there were 269 incidents of MACE.

To put this finding in context, the researchers examined the reported incidence of MACE among some 6,000 similarly aged participants in the Multi-Ethnic Study of Atherosclerosis (MESA). The overall weighted-average incidence rate was 1,408 per 100,000 person-years among MESA participants, compared with 542 events per 100,000 person-years among oncology trial participants (716 per 100,000 in the intervention arm). This represents a reported-to-expected ratio of 0.38 – a 2.6-fold lower rate of reported events (P less than .001) – and a risk difference of 866.

Further, MACE reporting was lower by a factor of 1.7 among all cancer trial participants irrespective of baseline CVD status (reported-to-expected ratio, 0.56; risk difference, 613; P less than .001).

There was no significant difference in MACE reporting between independent or industry-sponsored trials, the authors report.
 

No malicious intent

“There are likely some that might lean toward not wanting to attribute blame to a new drug when the drug is in a study, but I really think that the leading factor is lack of awareness,” Dr. Addison said. “I’ve talked with several cancer collaborators around the country who run large clinical trials, and I think often, when an event may be brought to someone’s attention, there is a tendency to just write it off as kind of a generic expected event due to age, or just something that’s not really pertinent to the study. So they don’t really focus on it as much.”

“Closer collaboration between cardiologists and cancer physicians is needed to better determine true cardiac risks among patients treated with these drugs.”

Breast cancer oncologist Marc E. Lippman, MD, of Georgetown University Medical Center and Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C., isn’t convinced a lack of awareness is the culprit.

“I don’t agree with that at all,” he said in an interview. “I think there are very, very clear rules and guidelines these days for adverse-event reporting. I think that’s not a very likely explanation – that it’s not on the radar.”

Part of the problem may be that some of the toxicities, particularly cardiovascular, may not emerge for years, he said. Participant screening for the trials also likely removed patients with high cardiovascular risk. “It’s very understandable to me – I’m not saying it’s good particularly – but I think it’s very understandable that, if you’re trying to develop a drug, the last thing you’d want to have is a lot of toxicity that you might have avoided by just being restrictive in who you let into the study,” Dr. Lippman said.

The underreported CVD events may also reflect the rapidly changing profile of cardiovascular toxicities associated with novel anticancer therapies.

“Providers, both cancer and noncancer, generally put cardiotoxicity in the box of anthracyclines and radiation, but particularly over the last decade, we’ve begun to understand it’s well beyond any one class of drugs,” Dr. Addison said.

“I agree completely,” Dr. Lippman said. For example, “the checkpoint inhibitors are so unbelievably different in terms of their toxicities that many people simply didn’t even know what they were getting into at first.”
 

One size does not fit all

Javid Moslehi, MD, director of the cardio-oncology program at Vanderbilt University, Nashville, Tenn., said echocardiography – recommended to detect changes in left ventricular function in patients exposed to anthracyclines or targeted agents like trastuzumab (Herceptin) – isn’t enough to address today’s cancer therapy–related CVD events.

Courtesy Joe Howell

“Initial drugs like anthracyclines or Herceptin in cardio-oncology were associated with systolic cardiac dysfunction, whereas the majority of issues we see in the cardio-oncology clinics today are vascular, metabolic, arrhythmogenic, and inflammatory,” he said in an interview. “Echocardiography misses the big and increasingly complex picture.”

His group, for example, has been studying myocarditis associated with immunotherapies, but none of the clinical trials require screening or surveillance for myocarditis with a cardiac biomarker like troponin.

The group also recently identified 303 deaths in patients exposed to ibrutinib, a drug that revolutionized the treatment of several B-cell malignancies but is associated with higher rates of atrial fibrillation, which is also associated with increased bleeding risk. “So there’s a little bit of a double whammy there, given that we often treat atrial fibrillation with anticoagulation and where we can cause complications in patients,” Dr. Moslehi noted.

Although there needs to be closer collaboration between cardiologists and oncologists on individual trials, cardiologists also have to realize that oncology care has become very personalized, he suggested.

“What’s probably relevant for the breast cancer patient may not be relevant for the prostate cancer patient and their respective treatments,” Dr. Moslehi said. “So if we were to say, ‘every person should get an echo,’ that may be less relevant to the prostate cancer patient where treatments can cause vascular and metabolic perturbations or to the patient treated with immunotherapy who may have myocarditis, where many of the echos can be normal. There’s no one-size-fits-all for these things.”

Wearable technologies like smartwatches could play a role in improving the reporting of CVD events with novel therapies but a lot more research needs to be done to validate these tools, Dr. Addison said. “But as we continue on into the 21st century, this is going to expand and may potentially help us,” he added.

In the interim, better standardization is needed of the cardiovascular events reported in oncology trials, particularly the Common Terminology Criteria for Adverse Events (CTCAE), said Dr. Moslehi, who also serves as chair of the American Heart Association’s subcommittee on cardio-oncology.

“Cardiovascular definitions are not exactly uniform and are not consistent with what we in cardiology consider to be important or relevant,” he said. “So I think there needs to be better standardization of these definitions, specifically within the CTCAE, which is what the oncologists use to identify adverse events.”

In a linked editorial (J Am Coll Cardiol. 2020;75:629-31), Dr. Lippman and cardiologist Nanette Bishopric, MD, of the Medstar Heart and Vascular Institute in Washington, D.C., suggested it may also be time to organize a consortium that can carry out “rigorous multicenter clinical investigations to evaluate the cardiotoxicity of emerging cancer treatments,” similar to the Thrombosis in Myocardial Infarction Study Group.

“The success of this consortium in pioneering and targeting multiple generations of drugs for the treatment of MI, involving tens of thousands of patients and thousands of collaborations across multiple national borders, is a model for how to move forward in providing the new hope of cancer cure without the trade-off of years lost to heart disease,” the editorialists concluded.

The study was supported in part by National Institutes of Health grants, including a K12-CA133250 grant to Dr. Addison. Dr. Bishopric reported being on the scientific board of C&C Biopharma. Dr. Lippman reports being on the board of directors of and holding stock in Seattle Genetics. Dr. Moslehi reported having served on advisory boards for Pfizer, Novartis, Bristol-Myers Squibb, Deciphera, Audentes Pharmaceuticals, Nektar, Takeda, Ipsen, Myokardia, AstraZeneca, GlaxoSmithKline, Intrexon, and Regeneron.

This article first appeared on Medscape.com.

Clinical trials supporting Food and Drug Adminstration approval of contemporary cancer therapies frequently failed to capture major adverse cardiovascular events (MACE) and, when they did, reported rates 2.6-fold lower than noncancer trials, new research shows.

Overall, 51.3% of trials did not report MACE, with that number reaching 57.6% in trials enrolling patients with baseline cardiovascular disease (CVD).

Nearly 40% of trials did not report any CVD events in follow-up, the authors reported online Feb. 10, 2020, in the Journal of the American College of Cardiology (2020;75:620-8).

“Even in drug classes where there were established or emerging associations with cardiotoxic events, often there were no reported heart events or cardiovascular events across years of follow-up in trials that examined hundreds or even thousands of patients. That was actually pretty surprising,” senior author Daniel Addison, MD, codirector of the cardio-oncology program at the Ohio State University Medical Center, Columbus, said in an interview.

The study was prompted by a series of events that crescendoed when his team was called to the ICU to determine whether a novel targeted agent played a role in the heart decline of a patient with acute myeloid leukemia. “I had a resident ask me a very important question: ‘How do we really know for sure that the trial actually reflects the true risk of heart events?’ to which I told him, ‘it’s difficult to know,’ ” he said.

“I think many of us rely heavily on what we see in the trials, particularly when they make it to the top journals, and quite frankly, we generally take it at face value,” Dr. Addison observed.
 

Lower Rate of Reported Events

The investigators reviewed CV events reported in 97,365 patients (median age, 61 years; 46% female) enrolled in 189 phase 2 and 3 trials supporting FDA approval of 123 anticancer drugs from 1998 to 2018. Biologic, targeted, or immune-based therapies accounted for 72.5% of drug approvals.

Over 148,138 person-years of follow-up (median trial duration, 30 months), there were 1,148 incidents of MACE (375 heart failure, 253 MIs, 180 strokes, 65 atrial fibrillation, 29 coronary revascularizations, and 246 CVD deaths). MACE rates were higher in the intervention group than in the control group (792 vs. 356; P less than .01). Among the 64 trials that excluded patients with baseline CVD, there were 269 incidents of MACE.

To put this finding in context, the researchers examined the reported incidence of MACE among some 6,000 similarly aged participants in the Multi-Ethnic Study of Atherosclerosis (MESA). The overall weighted-average incidence rate was 1,408 per 100,000 person-years among MESA participants, compared with 542 events per 100,000 person-years among oncology trial participants (716 per 100,000 in the intervention arm). This represents a reported-to-expected ratio of 0.38 – a 2.6-fold lower rate of reported events (P less than .001) – and a risk difference of 866.

Further, MACE reporting was lower by a factor of 1.7 among all cancer trial participants irrespective of baseline CVD status (reported-to-expected ratio, 0.56; risk difference, 613; P less than .001).

There was no significant difference in MACE reporting between independent or industry-sponsored trials, the authors report.
 

No malicious intent

“There are likely some that might lean toward not wanting to attribute blame to a new drug when the drug is in a study, but I really think that the leading factor is lack of awareness,” Dr. Addison said. “I’ve talked with several cancer collaborators around the country who run large clinical trials, and I think often, when an event may be brought to someone’s attention, there is a tendency to just write it off as kind of a generic expected event due to age, or just something that’s not really pertinent to the study. So they don’t really focus on it as much.”

“Closer collaboration between cardiologists and cancer physicians is needed to better determine true cardiac risks among patients treated with these drugs.”

Breast cancer oncologist Marc E. Lippman, MD, of Georgetown University Medical Center and Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C., isn’t convinced a lack of awareness is the culprit.

“I don’t agree with that at all,” he said in an interview. “I think there are very, very clear rules and guidelines these days for adverse-event reporting. I think that’s not a very likely explanation – that it’s not on the radar.”

Part of the problem may be that some of the toxicities, particularly cardiovascular, may not emerge for years, he said. Participant screening for the trials also likely removed patients with high cardiovascular risk. “It’s very understandable to me – I’m not saying it’s good particularly – but I think it’s very understandable that, if you’re trying to develop a drug, the last thing you’d want to have is a lot of toxicity that you might have avoided by just being restrictive in who you let into the study,” Dr. Lippman said.

The underreported CVD events may also reflect the rapidly changing profile of cardiovascular toxicities associated with novel anticancer therapies.

“Providers, both cancer and noncancer, generally put cardiotoxicity in the box of anthracyclines and radiation, but particularly over the last decade, we’ve begun to understand it’s well beyond any one class of drugs,” Dr. Addison said.

“I agree completely,” Dr. Lippman said. For example, “the checkpoint inhibitors are so unbelievably different in terms of their toxicities that many people simply didn’t even know what they were getting into at first.”
 

One size does not fit all

Javid Moslehi, MD, director of the cardio-oncology program at Vanderbilt University, Nashville, Tenn., said echocardiography – recommended to detect changes in left ventricular function in patients exposed to anthracyclines or targeted agents like trastuzumab (Herceptin) – isn’t enough to address today’s cancer therapy–related CVD events.

Courtesy Joe Howell

“Initial drugs like anthracyclines or Herceptin in cardio-oncology were associated with systolic cardiac dysfunction, whereas the majority of issues we see in the cardio-oncology clinics today are vascular, metabolic, arrhythmogenic, and inflammatory,” he said in an interview. “Echocardiography misses the big and increasingly complex picture.”

His group, for example, has been studying myocarditis associated with immunotherapies, but none of the clinical trials require screening or surveillance for myocarditis with a cardiac biomarker like troponin.

The group also recently identified 303 deaths in patients exposed to ibrutinib, a drug that revolutionized the treatment of several B-cell malignancies but is associated with higher rates of atrial fibrillation, which is also associated with increased bleeding risk. “So there’s a little bit of a double whammy there, given that we often treat atrial fibrillation with anticoagulation and where we can cause complications in patients,” Dr. Moslehi noted.

Although there needs to be closer collaboration between cardiologists and oncologists on individual trials, cardiologists also have to realize that oncology care has become very personalized, he suggested.

“What’s probably relevant for the breast cancer patient may not be relevant for the prostate cancer patient and their respective treatments,” Dr. Moslehi said. “So if we were to say, ‘every person should get an echo,’ that may be less relevant to the prostate cancer patient where treatments can cause vascular and metabolic perturbations or to the patient treated with immunotherapy who may have myocarditis, where many of the echos can be normal. There’s no one-size-fits-all for these things.”

Wearable technologies like smartwatches could play a role in improving the reporting of CVD events with novel therapies but a lot more research needs to be done to validate these tools, Dr. Addison said. “But as we continue on into the 21st century, this is going to expand and may potentially help us,” he added.

In the interim, better standardization is needed of the cardiovascular events reported in oncology trials, particularly the Common Terminology Criteria for Adverse Events (CTCAE), said Dr. Moslehi, who also serves as chair of the American Heart Association’s subcommittee on cardio-oncology.

“Cardiovascular definitions are not exactly uniform and are not consistent with what we in cardiology consider to be important or relevant,” he said. “So I think there needs to be better standardization of these definitions, specifically within the CTCAE, which is what the oncologists use to identify adverse events.”

In a linked editorial (J Am Coll Cardiol. 2020;75:629-31), Dr. Lippman and cardiologist Nanette Bishopric, MD, of the Medstar Heart and Vascular Institute in Washington, D.C., suggested it may also be time to organize a consortium that can carry out “rigorous multicenter clinical investigations to evaluate the cardiotoxicity of emerging cancer treatments,” similar to the Thrombosis in Myocardial Infarction Study Group.

“The success of this consortium in pioneering and targeting multiple generations of drugs for the treatment of MI, involving tens of thousands of patients and thousands of collaborations across multiple national borders, is a model for how to move forward in providing the new hope of cancer cure without the trade-off of years lost to heart disease,” the editorialists concluded.

The study was supported in part by National Institutes of Health grants, including a K12-CA133250 grant to Dr. Addison. Dr. Bishopric reported being on the scientific board of C&C Biopharma. Dr. Lippman reports being on the board of directors of and holding stock in Seattle Genetics. Dr. Moslehi reported having served on advisory boards for Pfizer, Novartis, Bristol-Myers Squibb, Deciphera, Audentes Pharmaceuticals, Nektar, Takeda, Ipsen, Myokardia, AstraZeneca, GlaxoSmithKline, Intrexon, and Regeneron.

This article first appeared on Medscape.com.