Thrombosis

Giving crushed prasugrel (Effient) to patients with ST-segment elevation myocardial infarction (STEMI) en route to a planned primary percutaneous coronary intervention (PCI) does not improve reperfusion rates, results of the COMPARE CRUSH trial show.

Patients assigned to prasugrel as crushed or integral tablets had similar rates of the study’s co-primary endpoints of thrombolysis in myocardial infarction (TIMI) 3 flow in the infarct-related artery at first angiography (31% vs. 32.7%; P = .64) and complete ST-segment resolution 1 hour post PCI (59.9% vs. 57.3%; P = .55).

“These findings hold in spite of the fact that crushed tablets of prasugrel led to more potent platelet inhibition compared with integral tablets,” said study author Georgios Vlachojannis, MD, PhD, University Medical Center Utrecht, the Netherlands.

“Whether faster and more potent antiplatelet therapy can improve coronary reperfusion in contemporary STEMI treatment regimen warrants further investigation.”

The results were reported in a late-breaking clinical science session at the Transcatheter Cardiovascular Therapeutics virtual annual meeting and published simultaneously in the journal Circulation. The meeting was sponsored by the Cardiovascular Research Foundation.

Fibrinolytics and glycoprotein IIb/IIIa inhibitors have demonstrated improved coronary reperfusion and outcomes when given pre hospital. Prior studies have also shown that early administration of a crushed P2Y12 inhibitor increases bioavailability and speeds platelet inhibition in STEMI patients, Dr. Vlachojannis noted.

However, the large randomized ATLANTIC trial, which compared prehospital to cath lab administration of crushed or integral ticagrelor (Brilinta), also found no difference in either TIMI flow in the infarct-related artery or ST-segment resolution.

Between November 2017 and March 2020, the investigator-initiated COMPARE CRUSH trial randomly allocated 727 STEMI patients (mean age, 62 years; 23% female) undergoing primary PCI to receive in the ambulance a 60-mg loading dose of prasugrel as either crushed or integral tablets.

The median time from onset of symptoms to first medical contact was 59 minutes, from first medical contact to study treatment 22 minutes, and from study treatment to primary PCI 57 minutes. These times did not differ between groups.

Platelet reactivity at the beginning of coronary angiography was significantly lower in the crushed group than in the integral group (P2Y12 reactivity units 192 vs. 227; P < .01). This resulted in significantly fewer patients in the crushed group with high platelet reactivity, defined as P2Y12 reactivity units >208, prior to the start of PCI (43.3% vs. 62.6%; P < .01).

There was no difference between the crushed and integral groups in the primary safety endpoint of TIMI major and BARC type 3 or higher bleeding within 48 hours after study treatment (0.4% vs 0.7%).

Death, MI, stroke, and urgent revascularization rates were also similar between groups during index hospitalization and at 30 days. Definite stent thrombosis occurred in one patient in the crushed group and two patients in the integral group.

In an exploratory analysis, the co-primary endpoint results were consistent across multiple subgroups, although there was a trend toward greater benefit on TIMI 3 flow in the crushed tablet group in patients older than age 75 years (P for interaction = .04), presenting with anterior infarction (P for interaction = .03), or with a history of prior PCI (P for interaction < .01).

“However, these results should be regarded as hypothesis-generating,” the authors wrote. “Opioids use in the ambulance was remarkably low in our study compared with the ATLANTIC trial, which might explain that we did not observe any significant interaction.”

Notably, morphine was used in half the ATLANTIC patients and was thought to have possibly delayed the absorption of ticagrelor.

During discussion following the presentation, Sunil V. Rao, MD, Duke University Medical Center, Durham, N.C., asked: “Based on what you found, which is really no clinical advantage but no safety issue either, are you having your patients with ST-segment MI administering crushed prasugrel now?”

Dr. Vlachojannis said they didn’t see any clinical impact but reiterated that high platelet reactivity was reduced by one-third. “If this now translates into a safer primary PCI procedure, we can’t say. The study wasn’t powered for this kind of endpoint. Is this enough to give you a recommendation, Sunil, I’m not sure.”

“What we know with COMPARE CRUSH, and this is important, is that we tried to give the medication as soon as possible and tried to give this medication in a formulation which has the most favorable pharmacodynamics profile, and we still see it’s not doing the job,” he added.

Fellow panelist Philippe Gabriel Steg, MD, Imperial College London, questioned whether treatment time may play a role in teasing out the relatively modest differences that platelet reactivity may have on clinical outcomes.

Dr. Vlachojannis said the time from symptom onset to first medical contact was very fast and similar to that in the ATLANTIC trial. “The short time intervals have certainly influenced the outcomes.”

Panelist Marco Valgimigli, MD, PhD, University Hospital Bern, Switzerland, followed up on the morphine issue, asking whether the investigators tested for an interaction between morphine or opioid use and platelet reactivity at the time of PCI.

“We haven’t looked into this but you probably have the ON-TIME 3 data in your mind when you’re asking this, where crushed ticagrelor given in the ambulance didn’t influence platelet reactivity at the time point of PCI,” Dr. Vlachojannis said. “We are going to look further into the data and certainly the platelet reactivity analysis is going to be very interesting in this data set.”

The study was an investigator-initiated trial sponsored by Maasstad Cardiovascular Research B.V. with unrestricted grants from Shanghai MicroPort Medical and Daiichi Sankyo. Dr. Vlachojannis declared receiving consulting fees from AstraZeneca, and research grants from Daiichi Sankyo and Shanghai MicroPort.

A version of this article originally appeared on Medscape.com.

Giving crushed prasugrel (Effient) to patients with ST-segment elevation myocardial infarction (STEMI) en route to a planned primary percutaneous coronary intervention (PCI) does not improve reperfusion rates, results of the COMPARE CRUSH trial show.

Patients assigned to prasugrel as crushed or integral tablets had similar rates of the study’s co-primary endpoints of thrombolysis in myocardial infarction (TIMI) 3 flow in the infarct-related artery at first angiography (31% vs. 32.7%; P = .64) and complete ST-segment resolution 1 hour post PCI (59.9% vs. 57.3%; P = .55).

“These findings hold in spite of the fact that crushed tablets of prasugrel led to more potent platelet inhibition compared with integral tablets,” said study author Georgios Vlachojannis, MD, PhD, University Medical Center Utrecht, the Netherlands.

“Whether faster and more potent antiplatelet therapy can improve coronary reperfusion in contemporary STEMI treatment regimen warrants further investigation.”

The results were reported in a late-breaking clinical science session at the Transcatheter Cardiovascular Therapeutics virtual annual meeting and published simultaneously in the journal Circulation. The meeting was sponsored by the Cardiovascular Research Foundation.

Fibrinolytics and glycoprotein IIb/IIIa inhibitors have demonstrated improved coronary reperfusion and outcomes when given pre hospital. Prior studies have also shown that early administration of a crushed P2Y12 inhibitor increases bioavailability and speeds platelet inhibition in STEMI patients, Dr. Vlachojannis noted.

However, the large randomized ATLANTIC trial, which compared prehospital to cath lab administration of crushed or integral ticagrelor (Brilinta), also found no difference in either TIMI flow in the infarct-related artery or ST-segment resolution.

Between November 2017 and March 2020, the investigator-initiated COMPARE CRUSH trial randomly allocated 727 STEMI patients (mean age, 62 years; 23% female) undergoing primary PCI to receive in the ambulance a 60-mg loading dose of prasugrel as either crushed or integral tablets.

The median time from onset of symptoms to first medical contact was 59 minutes, from first medical contact to study treatment 22 minutes, and from study treatment to primary PCI 57 minutes. These times did not differ between groups.

Platelet reactivity at the beginning of coronary angiography was significantly lower in the crushed group than in the integral group (P2Y12 reactivity units 192 vs. 227; P < .01). This resulted in significantly fewer patients in the crushed group with high platelet reactivity, defined as P2Y12 reactivity units >208, prior to the start of PCI (43.3% vs. 62.6%; P < .01).

There was no difference between the crushed and integral groups in the primary safety endpoint of TIMI major and BARC type 3 or higher bleeding within 48 hours after study treatment (0.4% vs 0.7%).

Death, MI, stroke, and urgent revascularization rates were also similar between groups during index hospitalization and at 30 days. Definite stent thrombosis occurred in one patient in the crushed group and two patients in the integral group.

In an exploratory analysis, the co-primary endpoint results were consistent across multiple subgroups, although there was a trend toward greater benefit on TIMI 3 flow in the crushed tablet group in patients older than age 75 years (P for interaction = .04), presenting with anterior infarction (P for interaction = .03), or with a history of prior PCI (P for interaction < .01).

“However, these results should be regarded as hypothesis-generating,” the authors wrote. “Opioids use in the ambulance was remarkably low in our study compared with the ATLANTIC trial, which might explain that we did not observe any significant interaction.”

Notably, morphine was used in half the ATLANTIC patients and was thought to have possibly delayed the absorption of ticagrelor.

During discussion following the presentation, Sunil V. Rao, MD, Duke University Medical Center, Durham, N.C., asked: “Based on what you found, which is really no clinical advantage but no safety issue either, are you having your patients with ST-segment MI administering crushed prasugrel now?”

Dr. Vlachojannis said they didn’t see any clinical impact but reiterated that high platelet reactivity was reduced by one-third. “If this now translates into a safer primary PCI procedure, we can’t say. The study wasn’t powered for this kind of endpoint. Is this enough to give you a recommendation, Sunil, I’m not sure.”

“What we know with COMPARE CRUSH, and this is important, is that we tried to give the medication as soon as possible and tried to give this medication in a formulation which has the most favorable pharmacodynamics profile, and we still see it’s not doing the job,” he added.

Fellow panelist Philippe Gabriel Steg, MD, Imperial College London, questioned whether treatment time may play a role in teasing out the relatively modest differences that platelet reactivity may have on clinical outcomes.

Dr. Vlachojannis said the time from symptom onset to first medical contact was very fast and similar to that in the ATLANTIC trial. “The short time intervals have certainly influenced the outcomes.”

Panelist Marco Valgimigli, MD, PhD, University Hospital Bern, Switzerland, followed up on the morphine issue, asking whether the investigators tested for an interaction between morphine or opioid use and platelet reactivity at the time of PCI.

“We haven’t looked into this but you probably have the ON-TIME 3 data in your mind when you’re asking this, where crushed ticagrelor given in the ambulance didn’t influence platelet reactivity at the time point of PCI,” Dr. Vlachojannis said. “We are going to look further into the data and certainly the platelet reactivity analysis is going to be very interesting in this data set.”

The study was an investigator-initiated trial sponsored by Maasstad Cardiovascular Research B.V. with unrestricted grants from Shanghai MicroPort Medical and Daiichi Sankyo. Dr. Vlachojannis declared receiving consulting fees from AstraZeneca, and research grants from Daiichi Sankyo and Shanghai MicroPort.

A version of this article originally appeared on Medscape.com.

Giving crushed prasugrel (Effient) to patients with ST-segment elevation myocardial infarction (STEMI) en route to a planned primary percutaneous coronary intervention (PCI) does not improve reperfusion rates, results of the COMPARE CRUSH trial show.

Patients assigned to prasugrel as crushed or integral tablets had similar rates of the study’s co-primary endpoints of thrombolysis in myocardial infarction (TIMI) 3 flow in the infarct-related artery at first angiography (31% vs. 32.7%; P = .64) and complete ST-segment resolution 1 hour post PCI (59.9% vs. 57.3%; P = .55).

“These findings hold in spite of the fact that crushed tablets of prasugrel led to more potent platelet inhibition compared with integral tablets,” said study author Georgios Vlachojannis, MD, PhD, University Medical Center Utrecht, the Netherlands.

“Whether faster and more potent antiplatelet therapy can improve coronary reperfusion in contemporary STEMI treatment regimen warrants further investigation.”

The results were reported in a late-breaking clinical science session at the Transcatheter Cardiovascular Therapeutics virtual annual meeting and published simultaneously in the journal Circulation. The meeting was sponsored by the Cardiovascular Research Foundation.

Fibrinolytics and glycoprotein IIb/IIIa inhibitors have demonstrated improved coronary reperfusion and outcomes when given pre hospital. Prior studies have also shown that early administration of a crushed P2Y12 inhibitor increases bioavailability and speeds platelet inhibition in STEMI patients, Dr. Vlachojannis noted.

However, the large randomized ATLANTIC trial, which compared prehospital to cath lab administration of crushed or integral ticagrelor (Brilinta), also found no difference in either TIMI flow in the infarct-related artery or ST-segment resolution.

Between November 2017 and March 2020, the investigator-initiated COMPARE CRUSH trial randomly allocated 727 STEMI patients (mean age, 62 years; 23% female) undergoing primary PCI to receive in the ambulance a 60-mg loading dose of prasugrel as either crushed or integral tablets.

The median time from onset of symptoms to first medical contact was 59 minutes, from first medical contact to study treatment 22 minutes, and from study treatment to primary PCI 57 minutes. These times did not differ between groups.

Platelet reactivity at the beginning of coronary angiography was significantly lower in the crushed group than in the integral group (P2Y12 reactivity units 192 vs. 227; P < .01). This resulted in significantly fewer patients in the crushed group with high platelet reactivity, defined as P2Y12 reactivity units >208, prior to the start of PCI (43.3% vs. 62.6%; P < .01).

There was no difference between the crushed and integral groups in the primary safety endpoint of TIMI major and BARC type 3 or higher bleeding within 48 hours after study treatment (0.4% vs 0.7%).

Death, MI, stroke, and urgent revascularization rates were also similar between groups during index hospitalization and at 30 days. Definite stent thrombosis occurred in one patient in the crushed group and two patients in the integral group.

In an exploratory analysis, the co-primary endpoint results were consistent across multiple subgroups, although there was a trend toward greater benefit on TIMI 3 flow in the crushed tablet group in patients older than age 75 years (P for interaction = .04), presenting with anterior infarction (P for interaction = .03), or with a history of prior PCI (P for interaction < .01).

“However, these results should be regarded as hypothesis-generating,” the authors wrote. “Opioids use in the ambulance was remarkably low in our study compared with the ATLANTIC trial, which might explain that we did not observe any significant interaction.”

Notably, morphine was used in half the ATLANTIC patients and was thought to have possibly delayed the absorption of ticagrelor.

During discussion following the presentation, Sunil V. Rao, MD, Duke University Medical Center, Durham, N.C., asked: “Based on what you found, which is really no clinical advantage but no safety issue either, are you having your patients with ST-segment MI administering crushed prasugrel now?”

Dr. Vlachojannis said they didn’t see any clinical impact but reiterated that high platelet reactivity was reduced by one-third. “If this now translates into a safer primary PCI procedure, we can’t say. The study wasn’t powered for this kind of endpoint. Is this enough to give you a recommendation, Sunil, I’m not sure.”

“What we know with COMPARE CRUSH, and this is important, is that we tried to give the medication as soon as possible and tried to give this medication in a formulation which has the most favorable pharmacodynamics profile, and we still see it’s not doing the job,” he added.

Fellow panelist Philippe Gabriel Steg, MD, Imperial College London, questioned whether treatment time may play a role in teasing out the relatively modest differences that platelet reactivity may have on clinical outcomes.

Dr. Vlachojannis said the time from symptom onset to first medical contact was very fast and similar to that in the ATLANTIC trial. “The short time intervals have certainly influenced the outcomes.”

Panelist Marco Valgimigli, MD, PhD, University Hospital Bern, Switzerland, followed up on the morphine issue, asking whether the investigators tested for an interaction between morphine or opioid use and platelet reactivity at the time of PCI.

“We haven’t looked into this but you probably have the ON-TIME 3 data in your mind when you’re asking this, where crushed ticagrelor given in the ambulance didn’t influence platelet reactivity at the time point of PCI,” Dr. Vlachojannis said. “We are going to look further into the data and certainly the platelet reactivity analysis is going to be very interesting in this data set.”

The study was an investigator-initiated trial sponsored by Maasstad Cardiovascular Research B.V. with unrestricted grants from Shanghai MicroPort Medical and Daiichi Sankyo. Dr. Vlachojannis declared receiving consulting fees from AstraZeneca, and research grants from Daiichi Sankyo and Shanghai MicroPort.

A version of this article originally appeared on Medscape.com.

Major thromboembolic complications and adverse cardiovascular events occurred with high frequency in patients with COVID-19, especially in the intensive care setting, despite a high use of thromboprophylaxis, in a new large observational U.S. study.

“Despite very high rate of antithrombotic prophylaxis there were a high rate of thromboembolic events suggesting that we are probably not providing enough thromboprophylaxis,” lead author Gregory Piazza, MD, Brigham and Women’s Hospital, Boston, said in an interview. 

“Standard prophylaxis as recommended in the guidelines is a low dose of low-molecular-weight heparin once daily, but these results suggest [patients] probably need higher doses,” he added.

However, Dr. Piazza cautioned that this is an observational study and randomized trials are needed to make changes in treatment strategies. Several such trials are currently underway.

The current study was published online ahead of print in the Nov. 3 issue of the Journal of the American College of Cardiology.
 

Rates similar to other very sick patients

The study showed that while thromboembolic complications were high, they were not as high as seen in some of the earlier studies from Asia and Europe, Dr. Piazza noted.

“The numbers we were seeing in early reports were so high we couldn’t figure out how that was possible,” he said. “Our study suggests that, in a U.S. population receiving thromboprophylaxis, the rate of thromboembolic complications [are] more in line with what we would expect to see in other very sick patients who end up in ICU.”

He suggested that the very high rates of thromboembolic complications in the early studies from Asia may have been because of the lack of thromboprophylaxis, which is not routine in hospitalized patients there. “Some of the earlier studies also used routine ultrasound and so picked up asymptomatic thrombotic events, which was not the case in our study. So our results are more representative of the U.S. population.”

Dr. Piazza attributed the high rate of thromboembolic complications being reported with COVID-19 to the sheer number of very sick patients being admitted to the hospital.

“We are accustomed to seeing a rare case of thrombosis despite prophylaxis in hospitalized patients, but we are seeing more in COVID patients. This is probably just because we have more critically ill patients,” he said.

“We are seeing an incredible influx of patients to the ICU that we have never experienced before, so the increase in thromboembolic complications is more obvious. In prior years we probably haven’t had enough critically ill patients at any one time to raise the flag about thromboprophylaxis,” he commented.

The study also found a high rate of cardiovascular complications. They are seeing an increase in the risk of MI, which is to be expected in such sick patients, but they also see quite a bit of new atrial fibrillation, myocarditis, and heart failure in patients who don’t always have underlying cardiovascular disease, he said.

“So this virus does appear to have a predilection to causing cardiovascular complications, but this is probably because it is making patients so sick,” Dr. Piazza said. “If flu was this virulent and resulted in such high rates of acute respiratory distress syndrome (ARDS), we would probably see similar cardiovascular complication rates.”

For the current report, the researchers analyzed a retrospective cohort of 1,114 patients with COVID-19 diagnosed through the Mass General Brigham integrated health network. Of these, 170 had been admitted to the ICU, 229 had been hospitalized but not treated in ICU, and 715 were outpatients. In terms of ethnicity, 22% were Hispanic/Latino and 44% were non-White. 

Cardiovascular risk factors were common, with 36% of patients having hypertension, 29% hyperlipidemia, and 18% diabetes. Prophylactic anticoagulation was prescribed in 89% of patients with COVID-19 in the intensive care cohort and 85% of those in the hospitalized non–intensive care setting.

Results showed that major arterial or venous thromboembolism (VTE) occurred in 35% of the intensive care cohort, 2.6% of those hospitalized but not treated in ICU, and 0% of outpatients.

Major adverse cardiovascular events occurred in 46% of the intensive care cohort, 6.1% of those hospitalized but non-ICU, and 0% of outpatients.

Symptomatic VTE occurred in 27% of those admitted to ICU, 2.2% of those hospitalized but non-ICU, and 0% of outpatients.

“We found that outpatients had a very low rate of thromboembolic complications, with the vast majority of the risk being in hospitalized patients, especially those in ICU,” Dr. Piazza said.

“These results suggest that we don’t need routine thromboprophylaxis for all outpatients with COVID-19, but there will probably be some patients who need it – those with risk factors for thromboembolism.”

Catheter- and device-associated deep vein thrombosis accounted for 76.9% of the DVTs observed in the study.

“Our finding of high frequency of catheter-associated DVT supports the judicious use of central venous catheters that have been widely implemented, especially in the ICU, to minimize recurrent health care team exposure and facilitate monitoring,” the researchers wrote.
 

ARDS biggest risk factor

Of all the markers of disease severity, the presence of ARDS had the strongest association with adverse outcomes, including major arterial or VTE, major adverse cardiovascular events, symptomatic VTE, and death.

“The severe inflammatory state associated with ARDS and other complications of COVID-19 and its resultant hypercoagulability may explain, at least in part, the high frequency of thromboembolic events. Improved risk stratification, utilizing biochemical markers of inflammation and activated coagulation as well as clinical indicators, such as ARDS, may play an important role in the early identification of patients with an increased likelihood of developing symptomatic VTE or arterial thrombosis,” the researchers wrote. “They may benefit from full- or intermediate-intensity antithrombotic therapy rather than prophylactic anticoagulation.”

They point out that this study provides a cross-sectional view of the cardiovascular complications of COVID-19 in a large health care network, consisting of two academic medical centers serving the greater Boston area, several community hospitals, and numerous outpatient care sites.

“The study incorporates a wide scope of clinically meaningful cardiovascular endpoints and utilizes a rigorous process of event adjudication. Although data on patients with COVID-19 in the ICU have been the subject of most reports, our study provides insights into the broad spectrum of all hospitalized and outpatient populations,” the authors noted.

“The high frequency of arterial or venous thromboembolism in hospitalized patients despite routine thromboprophylaxis suggests the need for improved risk stratification and enhanced preventive efforts,” they concluded.

The study is continuing, and the researchers expect to have data on 10,000 patients by the end of winter.
 

Wait for randomized trials

In an accompanying editorial, Robert McBane, MD, Mayo Clinic, Rochester, Minn., said that these data provide important real-world arterial and venous thrombotic event rates across a large, integrated health care network and an experienced roster of clinician-scientists devoted to thrombosis research.

Noting that whether to interpret these results as alarming or reassuring requires a comparison of expected thromboembolic event rates separate from the pandemic, he pointed out that, while the overall VTE rate among ICU patients was high, the vast majority of these events were attributable to central venous lines, and apart from these, the event rates do not appear inflated relative to prior published incidence rates from the pre–COVID-19 era.

“It is therefore important to resist the urge to overprevent or overtreat patients and expose them to the serious risks of major bleeding,” Dr. McBane wrote, adding that “the systematized approach to delivery of guideline-driven VTE prophylaxis across this large, integrated health network likely contributed to the relatively low rates of serious thrombotic outcomes reported.”

He further noted that, as the majority of VTE events were related to central venous lines in ICU patients, “this underscores the importance of a bundled care approach to central venous line management with daily assessment of the continued necessity of central access.

“A number of important clinical trials aimed at optimizing thromboprophylaxis during hospitalization, following hospital dismissal, and in ambulatory settings are underway. Until available, the lessons of thoughtful anticoagulant prophylaxis and treatment guidelines harvested from years of clinical research appear to apply,” he concluded.

This study was funded, in part, by a research grant from Janssen Pharmaceuticals. Dr. Piazza has received research grant support from EKOS Corporation, Bayer, Bristol-Myers Squibb/Pfizer, Portola Pharmaceuticals, and Janssen Pharmaceuticals; and has received consulting fees from Amgen, Pfizer, Boston Scientific, Agile, and Thrombolex. Dr. McBane reported no relevant disclosures.

A version of this article originally appeared on Medscape.com.

Major thromboembolic complications and adverse cardiovascular events occurred with high frequency in patients with COVID-19, especially in the intensive care setting, despite a high use of thromboprophylaxis, in a new large observational U.S. study.

“Despite very high rate of antithrombotic prophylaxis there were a high rate of thromboembolic events suggesting that we are probably not providing enough thromboprophylaxis,” lead author Gregory Piazza, MD, Brigham and Women’s Hospital, Boston, said in an interview. 

“Standard prophylaxis as recommended in the guidelines is a low dose of low-molecular-weight heparin once daily, but these results suggest [patients] probably need higher doses,” he added.

However, Dr. Piazza cautioned that this is an observational study and randomized trials are needed to make changes in treatment strategies. Several such trials are currently underway.

The current study was published online ahead of print in the Nov. 3 issue of the Journal of the American College of Cardiology.
 

Rates similar to other very sick patients

The study showed that while thromboembolic complications were high, they were not as high as seen in some of the earlier studies from Asia and Europe, Dr. Piazza noted.

“The numbers we were seeing in early reports were so high we couldn’t figure out how that was possible,” he said. “Our study suggests that, in a U.S. population receiving thromboprophylaxis, the rate of thromboembolic complications [are] more in line with what we would expect to see in other very sick patients who end up in ICU.”

He suggested that the very high rates of thromboembolic complications in the early studies from Asia may have been because of the lack of thromboprophylaxis, which is not routine in hospitalized patients there. “Some of the earlier studies also used routine ultrasound and so picked up asymptomatic thrombotic events, which was not the case in our study. So our results are more representative of the U.S. population.”

Dr. Piazza attributed the high rate of thromboembolic complications being reported with COVID-19 to the sheer number of very sick patients being admitted to the hospital.

“We are accustomed to seeing a rare case of thrombosis despite prophylaxis in hospitalized patients, but we are seeing more in COVID patients. This is probably just because we have more critically ill patients,” he said.

“We are seeing an incredible influx of patients to the ICU that we have never experienced before, so the increase in thromboembolic complications is more obvious. In prior years we probably haven’t had enough critically ill patients at any one time to raise the flag about thromboprophylaxis,” he commented.

The study also found a high rate of cardiovascular complications. They are seeing an increase in the risk of MI, which is to be expected in such sick patients, but they also see quite a bit of new atrial fibrillation, myocarditis, and heart failure in patients who don’t always have underlying cardiovascular disease, he said.

“So this virus does appear to have a predilection to causing cardiovascular complications, but this is probably because it is making patients so sick,” Dr. Piazza said. “If flu was this virulent and resulted in such high rates of acute respiratory distress syndrome (ARDS), we would probably see similar cardiovascular complication rates.”

For the current report, the researchers analyzed a retrospective cohort of 1,114 patients with COVID-19 diagnosed through the Mass General Brigham integrated health network. Of these, 170 had been admitted to the ICU, 229 had been hospitalized but not treated in ICU, and 715 were outpatients. In terms of ethnicity, 22% were Hispanic/Latino and 44% were non-White. 

Cardiovascular risk factors were common, with 36% of patients having hypertension, 29% hyperlipidemia, and 18% diabetes. Prophylactic anticoagulation was prescribed in 89% of patients with COVID-19 in the intensive care cohort and 85% of those in the hospitalized non–intensive care setting.

Results showed that major arterial or venous thromboembolism (VTE) occurred in 35% of the intensive care cohort, 2.6% of those hospitalized but not treated in ICU, and 0% of outpatients.

Major adverse cardiovascular events occurred in 46% of the intensive care cohort, 6.1% of those hospitalized but non-ICU, and 0% of outpatients.

Symptomatic VTE occurred in 27% of those admitted to ICU, 2.2% of those hospitalized but non-ICU, and 0% of outpatients.

“We found that outpatients had a very low rate of thromboembolic complications, with the vast majority of the risk being in hospitalized patients, especially those in ICU,” Dr. Piazza said.

“These results suggest that we don’t need routine thromboprophylaxis for all outpatients with COVID-19, but there will probably be some patients who need it – those with risk factors for thromboembolism.”

Catheter- and device-associated deep vein thrombosis accounted for 76.9% of the DVTs observed in the study.

“Our finding of high frequency of catheter-associated DVT supports the judicious use of central venous catheters that have been widely implemented, especially in the ICU, to minimize recurrent health care team exposure and facilitate monitoring,” the researchers wrote.
 

ARDS biggest risk factor

Of all the markers of disease severity, the presence of ARDS had the strongest association with adverse outcomes, including major arterial or VTE, major adverse cardiovascular events, symptomatic VTE, and death.

“The severe inflammatory state associated with ARDS and other complications of COVID-19 and its resultant hypercoagulability may explain, at least in part, the high frequency of thromboembolic events. Improved risk stratification, utilizing biochemical markers of inflammation and activated coagulation as well as clinical indicators, such as ARDS, may play an important role in the early identification of patients with an increased likelihood of developing symptomatic VTE or arterial thrombosis,” the researchers wrote. “They may benefit from full- or intermediate-intensity antithrombotic therapy rather than prophylactic anticoagulation.”

They point out that this study provides a cross-sectional view of the cardiovascular complications of COVID-19 in a large health care network, consisting of two academic medical centers serving the greater Boston area, several community hospitals, and numerous outpatient care sites.

“The study incorporates a wide scope of clinically meaningful cardiovascular endpoints and utilizes a rigorous process of event adjudication. Although data on patients with COVID-19 in the ICU have been the subject of most reports, our study provides insights into the broad spectrum of all hospitalized and outpatient populations,” the authors noted.

“The high frequency of arterial or venous thromboembolism in hospitalized patients despite routine thromboprophylaxis suggests the need for improved risk stratification and enhanced preventive efforts,” they concluded.

The study is continuing, and the researchers expect to have data on 10,000 patients by the end of winter.
 

Wait for randomized trials

In an accompanying editorial, Robert McBane, MD, Mayo Clinic, Rochester, Minn., said that these data provide important real-world arterial and venous thrombotic event rates across a large, integrated health care network and an experienced roster of clinician-scientists devoted to thrombosis research.

Noting that whether to interpret these results as alarming or reassuring requires a comparison of expected thromboembolic event rates separate from the pandemic, he pointed out that, while the overall VTE rate among ICU patients was high, the vast majority of these events were attributable to central venous lines, and apart from these, the event rates do not appear inflated relative to prior published incidence rates from the pre–COVID-19 era.

“It is therefore important to resist the urge to overprevent or overtreat patients and expose them to the serious risks of major bleeding,” Dr. McBane wrote, adding that “the systematized approach to delivery of guideline-driven VTE prophylaxis across this large, integrated health network likely contributed to the relatively low rates of serious thrombotic outcomes reported.”

He further noted that, as the majority of VTE events were related to central venous lines in ICU patients, “this underscores the importance of a bundled care approach to central venous line management with daily assessment of the continued necessity of central access.

“A number of important clinical trials aimed at optimizing thromboprophylaxis during hospitalization, following hospital dismissal, and in ambulatory settings are underway. Until available, the lessons of thoughtful anticoagulant prophylaxis and treatment guidelines harvested from years of clinical research appear to apply,” he concluded.

This study was funded, in part, by a research grant from Janssen Pharmaceuticals. Dr. Piazza has received research grant support from EKOS Corporation, Bayer, Bristol-Myers Squibb/Pfizer, Portola Pharmaceuticals, and Janssen Pharmaceuticals; and has received consulting fees from Amgen, Pfizer, Boston Scientific, Agile, and Thrombolex. Dr. McBane reported no relevant disclosures.

A version of this article originally appeared on Medscape.com.

Major thromboembolic complications and adverse cardiovascular events occurred with high frequency in patients with COVID-19, especially in the intensive care setting, despite a high use of thromboprophylaxis, in a new large observational U.S. study.

“Despite very high rate of antithrombotic prophylaxis there were a high rate of thromboembolic events suggesting that we are probably not providing enough thromboprophylaxis,” lead author Gregory Piazza, MD, Brigham and Women’s Hospital, Boston, said in an interview. 

“Standard prophylaxis as recommended in the guidelines is a low dose of low-molecular-weight heparin once daily, but these results suggest [patients] probably need higher doses,” he added.

However, Dr. Piazza cautioned that this is an observational study and randomized trials are needed to make changes in treatment strategies. Several such trials are currently underway.

The current study was published online ahead of print in the Nov. 3 issue of the Journal of the American College of Cardiology.
 

Rates similar to other very sick patients

The study showed that while thromboembolic complications were high, they were not as high as seen in some of the earlier studies from Asia and Europe, Dr. Piazza noted.

“The numbers we were seeing in early reports were so high we couldn’t figure out how that was possible,” he said. “Our study suggests that, in a U.S. population receiving thromboprophylaxis, the rate of thromboembolic complications [are] more in line with what we would expect to see in other very sick patients who end up in ICU.”

He suggested that the very high rates of thromboembolic complications in the early studies from Asia may have been because of the lack of thromboprophylaxis, which is not routine in hospitalized patients there. “Some of the earlier studies also used routine ultrasound and so picked up asymptomatic thrombotic events, which was not the case in our study. So our results are more representative of the U.S. population.”

Dr. Piazza attributed the high rate of thromboembolic complications being reported with COVID-19 to the sheer number of very sick patients being admitted to the hospital.

“We are accustomed to seeing a rare case of thrombosis despite prophylaxis in hospitalized patients, but we are seeing more in COVID patients. This is probably just because we have more critically ill patients,” he said.

“We are seeing an incredible influx of patients to the ICU that we have never experienced before, so the increase in thromboembolic complications is more obvious. In prior years we probably haven’t had enough critically ill patients at any one time to raise the flag about thromboprophylaxis,” he commented.

The study also found a high rate of cardiovascular complications. They are seeing an increase in the risk of MI, which is to be expected in such sick patients, but they also see quite a bit of new atrial fibrillation, myocarditis, and heart failure in patients who don’t always have underlying cardiovascular disease, he said.

“So this virus does appear to have a predilection to causing cardiovascular complications, but this is probably because it is making patients so sick,” Dr. Piazza said. “If flu was this virulent and resulted in such high rates of acute respiratory distress syndrome (ARDS), we would probably see similar cardiovascular complication rates.”

For the current report, the researchers analyzed a retrospective cohort of 1,114 patients with COVID-19 diagnosed through the Mass General Brigham integrated health network. Of these, 170 had been admitted to the ICU, 229 had been hospitalized but not treated in ICU, and 715 were outpatients. In terms of ethnicity, 22% were Hispanic/Latino and 44% were non-White. 

Cardiovascular risk factors were common, with 36% of patients having hypertension, 29% hyperlipidemia, and 18% diabetes. Prophylactic anticoagulation was prescribed in 89% of patients with COVID-19 in the intensive care cohort and 85% of those in the hospitalized non–intensive care setting.

Results showed that major arterial or venous thromboembolism (VTE) occurred in 35% of the intensive care cohort, 2.6% of those hospitalized but not treated in ICU, and 0% of outpatients.

Major adverse cardiovascular events occurred in 46% of the intensive care cohort, 6.1% of those hospitalized but non-ICU, and 0% of outpatients.

Symptomatic VTE occurred in 27% of those admitted to ICU, 2.2% of those hospitalized but non-ICU, and 0% of outpatients.

“We found that outpatients had a very low rate of thromboembolic complications, with the vast majority of the risk being in hospitalized patients, especially those in ICU,” Dr. Piazza said.

“These results suggest that we don’t need routine thromboprophylaxis for all outpatients with COVID-19, but there will probably be some patients who need it – those with risk factors for thromboembolism.”

Catheter- and device-associated deep vein thrombosis accounted for 76.9% of the DVTs observed in the study.

“Our finding of high frequency of catheter-associated DVT supports the judicious use of central venous catheters that have been widely implemented, especially in the ICU, to minimize recurrent health care team exposure and facilitate monitoring,” the researchers wrote.
 

ARDS biggest risk factor

Of all the markers of disease severity, the presence of ARDS had the strongest association with adverse outcomes, including major arterial or VTE, major adverse cardiovascular events, symptomatic VTE, and death.

“The severe inflammatory state associated with ARDS and other complications of COVID-19 and its resultant hypercoagulability may explain, at least in part, the high frequency of thromboembolic events. Improved risk stratification, utilizing biochemical markers of inflammation and activated coagulation as well as clinical indicators, such as ARDS, may play an important role in the early identification of patients with an increased likelihood of developing symptomatic VTE or arterial thrombosis,” the researchers wrote. “They may benefit from full- or intermediate-intensity antithrombotic therapy rather than prophylactic anticoagulation.”

They point out that this study provides a cross-sectional view of the cardiovascular complications of COVID-19 in a large health care network, consisting of two academic medical centers serving the greater Boston area, several community hospitals, and numerous outpatient care sites.

“The study incorporates a wide scope of clinically meaningful cardiovascular endpoints and utilizes a rigorous process of event adjudication. Although data on patients with COVID-19 in the ICU have been the subject of most reports, our study provides insights into the broad spectrum of all hospitalized and outpatient populations,” the authors noted.

“The high frequency of arterial or venous thromboembolism in hospitalized patients despite routine thromboprophylaxis suggests the need for improved risk stratification and enhanced preventive efforts,” they concluded.

The study is continuing, and the researchers expect to have data on 10,000 patients by the end of winter.
 

Wait for randomized trials

In an accompanying editorial, Robert McBane, MD, Mayo Clinic, Rochester, Minn., said that these data provide important real-world arterial and venous thrombotic event rates across a large, integrated health care network and an experienced roster of clinician-scientists devoted to thrombosis research.

Noting that whether to interpret these results as alarming or reassuring requires a comparison of expected thromboembolic event rates separate from the pandemic, he pointed out that, while the overall VTE rate among ICU patients was high, the vast majority of these events were attributable to central venous lines, and apart from these, the event rates do not appear inflated relative to prior published incidence rates from the pre–COVID-19 era.

“It is therefore important to resist the urge to overprevent or overtreat patients and expose them to the serious risks of major bleeding,” Dr. McBane wrote, adding that “the systematized approach to delivery of guideline-driven VTE prophylaxis across this large, integrated health network likely contributed to the relatively low rates of serious thrombotic outcomes reported.”

He further noted that, as the majority of VTE events were related to central venous lines in ICU patients, “this underscores the importance of a bundled care approach to central venous line management with daily assessment of the continued necessity of central access.

“A number of important clinical trials aimed at optimizing thromboprophylaxis during hospitalization, following hospital dismissal, and in ambulatory settings are underway. Until available, the lessons of thoughtful anticoagulant prophylaxis and treatment guidelines harvested from years of clinical research appear to apply,” he concluded.

This study was funded, in part, by a research grant from Janssen Pharmaceuticals. Dr. Piazza has received research grant support from EKOS Corporation, Bayer, Bristol-Myers Squibb/Pfizer, Portola Pharmaceuticals, and Janssen Pharmaceuticals; and has received consulting fees from Amgen, Pfizer, Boston Scientific, Agile, and Thrombolex. Dr. McBane reported no relevant disclosures.

A version of this article originally appeared on Medscape.com.

No hint of increased mortality risk in association with the use of paclitaxel-coated devices for treatment of peripheral artery disease was detected in VOYAGER PAD, a multithousand-patient randomized trial with long-term follow-up and ascertainment of vital status in 99.6% of participants.

Observers opined that the VOYAGER PAD findings effectively put to rest a nearly 2-year-old controversy over whether paclitaxel-coated devices for treatment of peripheral artery disease (PAD) carry an increased mortality risk. The imbroglio, which was ignited by a meta-analysis of clinical trials with substantial amounts of missing follow-up data, triggered an Food and Drug Administration warning letter to health care providers which threw the field of vascular medicine into disarray.

“Although as a community we’ve continued to struggle with this issue of paclitaxel and mortality, VOYAGER PAD does fill many of the gaps and addresses many of the limitations of currently available data,” Connie N. Hess, MD, said in reporting results of a prespecified analysis of the trial at the Transcatheter Cardiovascular Research Therapeutics virtual annual meeting. “I think these are the most definitive data to date supporting the safety of drug-coated device use.”

VOYAGER PAD was a double-blind, placebo-controlled clinical trial in which 6,564 patients undergoing lower-extremity revascularization for symptomatic PAD were randomized to rivaroxaban at 2.5 mg twice daily or placebo on top of background low-dose aspirin. In the previously reported primary outcome, the group on rivaroxaban plus aspirin had a significant 15% reduction in the risk of the composite endpoint of cardiovascular death, acute limb ischemia, MI, ischemic stroke, or major amputation for vascular causes.

Of the 4,316 patients included in the prespecified analysis by Dr. Hess, a cardiologist at the University of Colorado at Denver, Aurora, 31% received a paclitaxel-coated device. At 3.5 years of follow-up, they had a 10.2% all-cause mortality rate, significantly less than the 13.5% rate in patients who didn’t get a drug-coated device. But since study participants weren’t randomized for drug-coated device use, the investigators utilized a rigorous form of propensity adjustment called inverse probability treatment weighting to neutralize all between-group differences in potentially confounding baseline characteristics, including statin use, prevalence of claudication, and target lesion length.

In the weighted analysis, the all-cause mortality rate at 3.5 years was 12.1% in paclitaxel-coated device recipients and 12.6% in those who didn’t get such devices. The difference was not statistically significant, and the hazard ratio of 0.95 had tight confidence intervals.

“We don’t see a mortality benefit, but I think more importantly, we don’t see any risk for mortality,” the cardiologist observed at the meeting sponsored by the Cardiovascular Research Foundation.

There was no between-group difference in causes of mortality. Nor did all-cause mortality differ by device type, be it paclitaxel-coated balloon versus plain balloon angioplasty, or drug-eluting stent versus bare-metal stent.

Also, the benefit of rivaroxaban plus aspirin over aspirin alone in terms of cardiovascular and ischemic limb outcomes was consistent regardless of whether patients got a drug-coated device or not.

Discussant Robert Lookstein, MD, praised Dr. Hess for “a really enlightening presentation.”

“The entire vascular community has been waiting for a prospective, independently adjudicated trial to try to make determinations of whether we can put this issue behind us, and I think this trial is it,” said Dr. Lookstein, professor of interventional radiology and surgery at the Icahn School of Medicine at Mount Sinai, New York.

“Personally, I think this is probably the most impactful data seen regarding the paclitaxel issue in almost 2 years because it is randomized data, it’s prospectively collected data, and – most importantly from my perspective – they were able to collect vital statistics on more than 99.5% of the patients,” he added. “I think this is incredibly impactful to my practice.”

Frank Veith, MD, professor of surgery at New York University, concurred, declaring, “I think this study is a game changer. And I think the paclitaxel game is over.”

The VOYAGER PAD study was funded by institutional research grants from Bayer and Janssen.

[email protected]

No hint of increased mortality risk in association with the use of paclitaxel-coated devices for treatment of peripheral artery disease was detected in VOYAGER PAD, a multithousand-patient randomized trial with long-term follow-up and ascertainment of vital status in 99.6% of participants.

Observers opined that the VOYAGER PAD findings effectively put to rest a nearly 2-year-old controversy over whether paclitaxel-coated devices for treatment of peripheral artery disease (PAD) carry an increased mortality risk. The imbroglio, which was ignited by a meta-analysis of clinical trials with substantial amounts of missing follow-up data, triggered an Food and Drug Administration warning letter to health care providers which threw the field of vascular medicine into disarray.

“Although as a community we’ve continued to struggle with this issue of paclitaxel and mortality, VOYAGER PAD does fill many of the gaps and addresses many of the limitations of currently available data,” Connie N. Hess, MD, said in reporting results of a prespecified analysis of the trial at the Transcatheter Cardiovascular Research Therapeutics virtual annual meeting. “I think these are the most definitive data to date supporting the safety of drug-coated device use.”

VOYAGER PAD was a double-blind, placebo-controlled clinical trial in which 6,564 patients undergoing lower-extremity revascularization for symptomatic PAD were randomized to rivaroxaban at 2.5 mg twice daily or placebo on top of background low-dose aspirin. In the previously reported primary outcome, the group on rivaroxaban plus aspirin had a significant 15% reduction in the risk of the composite endpoint of cardiovascular death, acute limb ischemia, MI, ischemic stroke, or major amputation for vascular causes.

Of the 4,316 patients included in the prespecified analysis by Dr. Hess, a cardiologist at the University of Colorado at Denver, Aurora, 31% received a paclitaxel-coated device. At 3.5 years of follow-up, they had a 10.2% all-cause mortality rate, significantly less than the 13.5% rate in patients who didn’t get a drug-coated device. But since study participants weren’t randomized for drug-coated device use, the investigators utilized a rigorous form of propensity adjustment called inverse probability treatment weighting to neutralize all between-group differences in potentially confounding baseline characteristics, including statin use, prevalence of claudication, and target lesion length.

In the weighted analysis, the all-cause mortality rate at 3.5 years was 12.1% in paclitaxel-coated device recipients and 12.6% in those who didn’t get such devices. The difference was not statistically significant, and the hazard ratio of 0.95 had tight confidence intervals.

“We don’t see a mortality benefit, but I think more importantly, we don’t see any risk for mortality,” the cardiologist observed at the meeting sponsored by the Cardiovascular Research Foundation.

There was no between-group difference in causes of mortality. Nor did all-cause mortality differ by device type, be it paclitaxel-coated balloon versus plain balloon angioplasty, or drug-eluting stent versus bare-metal stent.

Also, the benefit of rivaroxaban plus aspirin over aspirin alone in terms of cardiovascular and ischemic limb outcomes was consistent regardless of whether patients got a drug-coated device or not.

Discussant Robert Lookstein, MD, praised Dr. Hess for “a really enlightening presentation.”

“The entire vascular community has been waiting for a prospective, independently adjudicated trial to try to make determinations of whether we can put this issue behind us, and I think this trial is it,” said Dr. Lookstein, professor of interventional radiology and surgery at the Icahn School of Medicine at Mount Sinai, New York.

“Personally, I think this is probably the most impactful data seen regarding the paclitaxel issue in almost 2 years because it is randomized data, it’s prospectively collected data, and – most importantly from my perspective – they were able to collect vital statistics on more than 99.5% of the patients,” he added. “I think this is incredibly impactful to my practice.”

Frank Veith, MD, professor of surgery at New York University, concurred, declaring, “I think this study is a game changer. And I think the paclitaxel game is over.”

The VOYAGER PAD study was funded by institutional research grants from Bayer and Janssen.

[email protected]

No hint of increased mortality risk in association with the use of paclitaxel-coated devices for treatment of peripheral artery disease was detected in VOYAGER PAD, a multithousand-patient randomized trial with long-term follow-up and ascertainment of vital status in 99.6% of participants.

Observers opined that the VOYAGER PAD findings effectively put to rest a nearly 2-year-old controversy over whether paclitaxel-coated devices for treatment of peripheral artery disease (PAD) carry an increased mortality risk. The imbroglio, which was ignited by a meta-analysis of clinical trials with substantial amounts of missing follow-up data, triggered an Food and Drug Administration warning letter to health care providers which threw the field of vascular medicine into disarray.

“Although as a community we’ve continued to struggle with this issue of paclitaxel and mortality, VOYAGER PAD does fill many of the gaps and addresses many of the limitations of currently available data,” Connie N. Hess, MD, said in reporting results of a prespecified analysis of the trial at the Transcatheter Cardiovascular Research Therapeutics virtual annual meeting. “I think these are the most definitive data to date supporting the safety of drug-coated device use.”

VOYAGER PAD was a double-blind, placebo-controlled clinical trial in which 6,564 patients undergoing lower-extremity revascularization for symptomatic PAD were randomized to rivaroxaban at 2.5 mg twice daily or placebo on top of background low-dose aspirin. In the previously reported primary outcome, the group on rivaroxaban plus aspirin had a significant 15% reduction in the risk of the composite endpoint of cardiovascular death, acute limb ischemia, MI, ischemic stroke, or major amputation for vascular causes.

Of the 4,316 patients included in the prespecified analysis by Dr. Hess, a cardiologist at the University of Colorado at Denver, Aurora, 31% received a paclitaxel-coated device. At 3.5 years of follow-up, they had a 10.2% all-cause mortality rate, significantly less than the 13.5% rate in patients who didn’t get a drug-coated device. But since study participants weren’t randomized for drug-coated device use, the investigators utilized a rigorous form of propensity adjustment called inverse probability treatment weighting to neutralize all between-group differences in potentially confounding baseline characteristics, including statin use, prevalence of claudication, and target lesion length.

In the weighted analysis, the all-cause mortality rate at 3.5 years was 12.1% in paclitaxel-coated device recipients and 12.6% in those who didn’t get such devices. The difference was not statistically significant, and the hazard ratio of 0.95 had tight confidence intervals.

“We don’t see a mortality benefit, but I think more importantly, we don’t see any risk for mortality,” the cardiologist observed at the meeting sponsored by the Cardiovascular Research Foundation.

There was no between-group difference in causes of mortality. Nor did all-cause mortality differ by device type, be it paclitaxel-coated balloon versus plain balloon angioplasty, or drug-eluting stent versus bare-metal stent.

Also, the benefit of rivaroxaban plus aspirin over aspirin alone in terms of cardiovascular and ischemic limb outcomes was consistent regardless of whether patients got a drug-coated device or not.

Discussant Robert Lookstein, MD, praised Dr. Hess for “a really enlightening presentation.”

“The entire vascular community has been waiting for a prospective, independently adjudicated trial to try to make determinations of whether we can put this issue behind us, and I think this trial is it,” said Dr. Lookstein, professor of interventional radiology and surgery at the Icahn School of Medicine at Mount Sinai, New York.

“Personally, I think this is probably the most impactful data seen regarding the paclitaxel issue in almost 2 years because it is randomized data, it’s prospectively collected data, and – most importantly from my perspective – they were able to collect vital statistics on more than 99.5% of the patients,” he added. “I think this is incredibly impactful to my practice.”

Frank Veith, MD, professor of surgery at New York University, concurred, declaring, “I think this study is a game changer. And I think the paclitaxel game is over.”

The VOYAGER PAD study was funded by institutional research grants from Bayer and Janssen.

[email protected]

The risk for death goes up for patients with atrial fibrillation (AFib) who are put on direct oral anticoagulants (DOAC) at dosages other than those approved for stroke prevention, whether higher or lower than doses specified in the labeling, suggests a large registry study.

A quarter of more than 10,000 patients in the registry took the drugs at such nonrecommended higher or lower dosages. Overwhelmingly it was the latter, perhaps reflecting caution on the part of some practitioners looking to minimize the risk of bleeding complications.

The risk of major bleeding indeed dropped sharply for those taking DOACs at lower-than-recommended levels, but at the cost of a 25% jump in all-cause mortality over 2 years, report investigators from their analysis of patients in the GARFIELD-AF registry published Sept. 14 in the Journal of the American College of Cardiology.

Risks of major bleeding and of stroke or systemic embolism didn’t climb significantly for patients either under- or overdosed.

In general, “physicians are worried about giving too much anticoagulant, and they tend to favor erring on the low-dose side,” lead author A. John Camm, MD, St. George’s University of London, said in an interview. That’s how it was when an oral anticoagulation meant a vitamin K antagonist (VKA) and underdosing was frequent; and it remains an issue in the DOAC era. “It’s not just a little problem. It’s a very big problem.”

Today, clinicians may prescribe DOACs similar to how they prescribed VKAs, by cautiously choosing a lower dosage for selected patients based on their risk profile, Dr. Camm observed. But in contrast to the VKAs, the DOACs “were studied with different dose-reduction strategies, and their labeling requires them to be prescribed according to different parameters.”

They variously base dosage reductions on age, body weight, renal function, or drug-drug interactions, for example, but some clinicians “tend to think that all of those factors should be applied in every instance, with every drug,” he said.

“So I think there’s some confusion and a lot of caution that physicians use with anticoagulants, and they often forget that the purpose of the anticoagulant is to prevent strokes and adverse outcomes such as mortality,” Dr. Camm said. “But by reducing the dose, they expose their patients to these other major cardiovascular events.”

Numerically, the excess mortality among underdosed patients appeared to be driven by death from heart failure or myocardial infarction. There was little or no contribution from sudden death, fatal strokes, or noncardiovascular death.

The findings “remind clinicians to dose DOACs properly and that there are consequences of dosing errors,” observes Gerald V. Naccarelli, MD, of Penn State University and the Milton S. Hershey Medical Center, Hershey, in an accompanying editorial.

Based on the major clinical trials that established the drugs as mainstream stroke-preventive therapy in AFib, as well as extensive regulatory review, each DOAC’s label-recommended dosing “is a guidance of the truth to achieve the highest efficacy and most safety in our patients,” Dr. Naccarelli wrote. “As clinicians are risk adverse, underdosing might result in lower major bleeding rates, and physicians are blamed for bleeding but not necessarily for allowing embolic strokes to occur. These data raise the issue that underdosing is associated with worse patient outcomes.”

The GARFIELD-AF analysis covered 10,426 adults with nonvalvular AFib in 35 countries who initiated a DOAC from 2013 to 2016. The drugs were prescribed at dosages consistent with recommendations in each respective country’s labeling for stroke prevention in AFib in 72.9% of the cohort. Most full and adjusted dose levels approved by the European Medicines Agency, Food and Drug Administration, and regulators in Japan were the same or similar.

But there were a few exceptions. All dosing criteria across the three regulatory domains were the same for apixaban (Eliquis). But variations included lower dosage options for rivaroxaban (Xarelto) and edoxaban (Savaysa, Lixiana) in Japan, and a uniquely low dabigatran (Pradaxa) dosage option in the United States.

The DOAC used least often was the one most frequently underdosed. More than half of patients prescribed edoxaban were given it at a lower-than-recommended dosage.

The adjusted hazard ratio for all-cause mortality at 2 years for DOAC under- or overdosing, compared with dosing at recommended levels, was 1.24 (95% confidence interval, 1.04-1.48). The difference was driven by underdosing, for which the HR was 1.25 (95% CI, 1.04-1.50). The HR for over-dosing was only 1.19 (95% CI, 0.83-1.71).

Multivariate adjustment accounted for age, sex, and ethnicity; type of AFib; diabetes; hypertension; history of bleeding; prior stroke, transient ischemic attack, or systemic embolism; heart failure; vascular disease; smoking; and heavy alcohol consumption.

The risk of stroke or systemic embolism didn’t go up or down significantly for either overdosed or underdosed patients. Neither group showed an increased risk for major bleeding; however, the HR for major bleeding in underdosed patients fell to 0.50 (95% CI, 0.28-0.88).

Underdosing was more common in some world regions than others. The rate exceeded 30% in all Latin American countries except Argentina, the report stated, and in all Asian countries except Singapore.

Japanese patients have long received oral anticoagulation at lower dosages than are used in the West, Dr. Camm observed. When VKAs were the only choice, for example, international normalized ratio targets were consistently a bit lower in Japan than in, for example, North America or Europe.

“And when [novel] OACs were developed, again, the Japanese took the view that their patients are more vulnerable to bleeding, and therefore a lower dose would be appropriate. In some instances, lower-dose regimens have been specifically studied in the Japanese,” Dr. Camm said. “Having said that, this concept of bleeding being more problematic in Asian patients has expanded well beyond Japan, and therefore in many Asian communities, lower doses of [novel] OACs are chosen.”

Many other factors may contribute to DOAC underdosing, including differences in dosing strategies between primary care practitioners and specialists, or between hospital-based and office-based clinicians, for example.

“It might also be argued that a physician who fails to treat a patient adequately in one arena may also be failing to treat the patient well in other aspects of their care,” Dr. Camm proposed. “Therefore you could have increased mortality due to other cardiovascular causes, or even noncardiovascular events, through absence of good quality care. Our study did not address that specifically. But it might be the case, speculatively.”

The study was supported by a grant from Bayer to the Thrombosis Research Institute, “which sponsors the GARFIELD-AF registry.” Dr. Camm discloses receiving grants and personal fees from Bayer, Boehringer Ingelheim, Pfizer/Bristol-Myers Squibb, and Daiichi Sankyo. Disclosures for the other authors are in the report. Dr. Naccarelli disclosed consulting and participating in research for Janssen and serving as a consultant for Milestone, Sanofi, Omeicos, and Acesion Pharma.

A version of this article originally appeared on Medscape.com.

The risk for death goes up for patients with atrial fibrillation (AFib) who are put on direct oral anticoagulants (DOAC) at dosages other than those approved for stroke prevention, whether higher or lower than doses specified in the labeling, suggests a large registry study.

A quarter of more than 10,000 patients in the registry took the drugs at such nonrecommended higher or lower dosages. Overwhelmingly it was the latter, perhaps reflecting caution on the part of some practitioners looking to minimize the risk of bleeding complications.

The risk of major bleeding indeed dropped sharply for those taking DOACs at lower-than-recommended levels, but at the cost of a 25% jump in all-cause mortality over 2 years, report investigators from their analysis of patients in the GARFIELD-AF registry published Sept. 14 in the Journal of the American College of Cardiology.

Risks of major bleeding and of stroke or systemic embolism didn’t climb significantly for patients either under- or overdosed.

In general, “physicians are worried about giving too much anticoagulant, and they tend to favor erring on the low-dose side,” lead author A. John Camm, MD, St. George’s University of London, said in an interview. That’s how it was when an oral anticoagulation meant a vitamin K antagonist (VKA) and underdosing was frequent; and it remains an issue in the DOAC era. “It’s not just a little problem. It’s a very big problem.”

Today, clinicians may prescribe DOACs similar to how they prescribed VKAs, by cautiously choosing a lower dosage for selected patients based on their risk profile, Dr. Camm observed. But in contrast to the VKAs, the DOACs “were studied with different dose-reduction strategies, and their labeling requires them to be prescribed according to different parameters.”

They variously base dosage reductions on age, body weight, renal function, or drug-drug interactions, for example, but some clinicians “tend to think that all of those factors should be applied in every instance, with every drug,” he said.

“So I think there’s some confusion and a lot of caution that physicians use with anticoagulants, and they often forget that the purpose of the anticoagulant is to prevent strokes and adverse outcomes such as mortality,” Dr. Camm said. “But by reducing the dose, they expose their patients to these other major cardiovascular events.”

Numerically, the excess mortality among underdosed patients appeared to be driven by death from heart failure or myocardial infarction. There was little or no contribution from sudden death, fatal strokes, or noncardiovascular death.

The findings “remind clinicians to dose DOACs properly and that there are consequences of dosing errors,” observes Gerald V. Naccarelli, MD, of Penn State University and the Milton S. Hershey Medical Center, Hershey, in an accompanying editorial.

Based on the major clinical trials that established the drugs as mainstream stroke-preventive therapy in AFib, as well as extensive regulatory review, each DOAC’s label-recommended dosing “is a guidance of the truth to achieve the highest efficacy and most safety in our patients,” Dr. Naccarelli wrote. “As clinicians are risk adverse, underdosing might result in lower major bleeding rates, and physicians are blamed for bleeding but not necessarily for allowing embolic strokes to occur. These data raise the issue that underdosing is associated with worse patient outcomes.”

The GARFIELD-AF analysis covered 10,426 adults with nonvalvular AFib in 35 countries who initiated a DOAC from 2013 to 2016. The drugs were prescribed at dosages consistent with recommendations in each respective country’s labeling for stroke prevention in AFib in 72.9% of the cohort. Most full and adjusted dose levels approved by the European Medicines Agency, Food and Drug Administration, and regulators in Japan were the same or similar.

But there were a few exceptions. All dosing criteria across the three regulatory domains were the same for apixaban (Eliquis). But variations included lower dosage options for rivaroxaban (Xarelto) and edoxaban (Savaysa, Lixiana) in Japan, and a uniquely low dabigatran (Pradaxa) dosage option in the United States.

The DOAC used least often was the one most frequently underdosed. More than half of patients prescribed edoxaban were given it at a lower-than-recommended dosage.

The adjusted hazard ratio for all-cause mortality at 2 years for DOAC under- or overdosing, compared with dosing at recommended levels, was 1.24 (95% confidence interval, 1.04-1.48). The difference was driven by underdosing, for which the HR was 1.25 (95% CI, 1.04-1.50). The HR for over-dosing was only 1.19 (95% CI, 0.83-1.71).

Multivariate adjustment accounted for age, sex, and ethnicity; type of AFib; diabetes; hypertension; history of bleeding; prior stroke, transient ischemic attack, or systemic embolism; heart failure; vascular disease; smoking; and heavy alcohol consumption.

The risk of stroke or systemic embolism didn’t go up or down significantly for either overdosed or underdosed patients. Neither group showed an increased risk for major bleeding; however, the HR for major bleeding in underdosed patients fell to 0.50 (95% CI, 0.28-0.88).

Underdosing was more common in some world regions than others. The rate exceeded 30% in all Latin American countries except Argentina, the report stated, and in all Asian countries except Singapore.

Japanese patients have long received oral anticoagulation at lower dosages than are used in the West, Dr. Camm observed. When VKAs were the only choice, for example, international normalized ratio targets were consistently a bit lower in Japan than in, for example, North America or Europe.

“And when [novel] OACs were developed, again, the Japanese took the view that their patients are more vulnerable to bleeding, and therefore a lower dose would be appropriate. In some instances, lower-dose regimens have been specifically studied in the Japanese,” Dr. Camm said. “Having said that, this concept of bleeding being more problematic in Asian patients has expanded well beyond Japan, and therefore in many Asian communities, lower doses of [novel] OACs are chosen.”

Many other factors may contribute to DOAC underdosing, including differences in dosing strategies between primary care practitioners and specialists, or between hospital-based and office-based clinicians, for example.

“It might also be argued that a physician who fails to treat a patient adequately in one arena may also be failing to treat the patient well in other aspects of their care,” Dr. Camm proposed. “Therefore you could have increased mortality due to other cardiovascular causes, or even noncardiovascular events, through absence of good quality care. Our study did not address that specifically. But it might be the case, speculatively.”

The study was supported by a grant from Bayer to the Thrombosis Research Institute, “which sponsors the GARFIELD-AF registry.” Dr. Camm discloses receiving grants and personal fees from Bayer, Boehringer Ingelheim, Pfizer/Bristol-Myers Squibb, and Daiichi Sankyo. Disclosures for the other authors are in the report. Dr. Naccarelli disclosed consulting and participating in research for Janssen and serving as a consultant for Milestone, Sanofi, Omeicos, and Acesion Pharma.

A version of this article originally appeared on Medscape.com.

The risk for death goes up for patients with atrial fibrillation (AFib) who are put on direct oral anticoagulants (DOAC) at dosages other than those approved for stroke prevention, whether higher or lower than doses specified in the labeling, suggests a large registry study.

A quarter of more than 10,000 patients in the registry took the drugs at such nonrecommended higher or lower dosages. Overwhelmingly it was the latter, perhaps reflecting caution on the part of some practitioners looking to minimize the risk of bleeding complications.

The risk of major bleeding indeed dropped sharply for those taking DOACs at lower-than-recommended levels, but at the cost of a 25% jump in all-cause mortality over 2 years, report investigators from their analysis of patients in the GARFIELD-AF registry published Sept. 14 in the Journal of the American College of Cardiology.

Risks of major bleeding and of stroke or systemic embolism didn’t climb significantly for patients either under- or overdosed.

In general, “physicians are worried about giving too much anticoagulant, and they tend to favor erring on the low-dose side,” lead author A. John Camm, MD, St. George’s University of London, said in an interview. That’s how it was when an oral anticoagulation meant a vitamin K antagonist (VKA) and underdosing was frequent; and it remains an issue in the DOAC era. “It’s not just a little problem. It’s a very big problem.”

Today, clinicians may prescribe DOACs similar to how they prescribed VKAs, by cautiously choosing a lower dosage for selected patients based on their risk profile, Dr. Camm observed. But in contrast to the VKAs, the DOACs “were studied with different dose-reduction strategies, and their labeling requires them to be prescribed according to different parameters.”

They variously base dosage reductions on age, body weight, renal function, or drug-drug interactions, for example, but some clinicians “tend to think that all of those factors should be applied in every instance, with every drug,” he said.

“So I think there’s some confusion and a lot of caution that physicians use with anticoagulants, and they often forget that the purpose of the anticoagulant is to prevent strokes and adverse outcomes such as mortality,” Dr. Camm said. “But by reducing the dose, they expose their patients to these other major cardiovascular events.”

Numerically, the excess mortality among underdosed patients appeared to be driven by death from heart failure or myocardial infarction. There was little or no contribution from sudden death, fatal strokes, or noncardiovascular death.

The findings “remind clinicians to dose DOACs properly and that there are consequences of dosing errors,” observes Gerald V. Naccarelli, MD, of Penn State University and the Milton S. Hershey Medical Center, Hershey, in an accompanying editorial.

Based on the major clinical trials that established the drugs as mainstream stroke-preventive therapy in AFib, as well as extensive regulatory review, each DOAC’s label-recommended dosing “is a guidance of the truth to achieve the highest efficacy and most safety in our patients,” Dr. Naccarelli wrote. “As clinicians are risk adverse, underdosing might result in lower major bleeding rates, and physicians are blamed for bleeding but not necessarily for allowing embolic strokes to occur. These data raise the issue that underdosing is associated with worse patient outcomes.”

The GARFIELD-AF analysis covered 10,426 adults with nonvalvular AFib in 35 countries who initiated a DOAC from 2013 to 2016. The drugs were prescribed at dosages consistent with recommendations in each respective country’s labeling for stroke prevention in AFib in 72.9% of the cohort. Most full and adjusted dose levels approved by the European Medicines Agency, Food and Drug Administration, and regulators in Japan were the same or similar.

But there were a few exceptions. All dosing criteria across the three regulatory domains were the same for apixaban (Eliquis). But variations included lower dosage options for rivaroxaban (Xarelto) and edoxaban (Savaysa, Lixiana) in Japan, and a uniquely low dabigatran (Pradaxa) dosage option in the United States.

The DOAC used least often was the one most frequently underdosed. More than half of patients prescribed edoxaban were given it at a lower-than-recommended dosage.

The adjusted hazard ratio for all-cause mortality at 2 years for DOAC under- or overdosing, compared with dosing at recommended levels, was 1.24 (95% confidence interval, 1.04-1.48). The difference was driven by underdosing, for which the HR was 1.25 (95% CI, 1.04-1.50). The HR for over-dosing was only 1.19 (95% CI, 0.83-1.71).

Multivariate adjustment accounted for age, sex, and ethnicity; type of AFib; diabetes; hypertension; history of bleeding; prior stroke, transient ischemic attack, or systemic embolism; heart failure; vascular disease; smoking; and heavy alcohol consumption.

The risk of stroke or systemic embolism didn’t go up or down significantly for either overdosed or underdosed patients. Neither group showed an increased risk for major bleeding; however, the HR for major bleeding in underdosed patients fell to 0.50 (95% CI, 0.28-0.88).

Underdosing was more common in some world regions than others. The rate exceeded 30% in all Latin American countries except Argentina, the report stated, and in all Asian countries except Singapore.

Japanese patients have long received oral anticoagulation at lower dosages than are used in the West, Dr. Camm observed. When VKAs were the only choice, for example, international normalized ratio targets were consistently a bit lower in Japan than in, for example, North America or Europe.

“And when [novel] OACs were developed, again, the Japanese took the view that their patients are more vulnerable to bleeding, and therefore a lower dose would be appropriate. In some instances, lower-dose regimens have been specifically studied in the Japanese,” Dr. Camm said. “Having said that, this concept of bleeding being more problematic in Asian patients has expanded well beyond Japan, and therefore in many Asian communities, lower doses of [novel] OACs are chosen.”

Many other factors may contribute to DOAC underdosing, including differences in dosing strategies between primary care practitioners and specialists, or between hospital-based and office-based clinicians, for example.

“It might also be argued that a physician who fails to treat a patient adequately in one arena may also be failing to treat the patient well in other aspects of their care,” Dr. Camm proposed. “Therefore you could have increased mortality due to other cardiovascular causes, or even noncardiovascular events, through absence of good quality care. Our study did not address that specifically. But it might be the case, speculatively.”

The study was supported by a grant from Bayer to the Thrombosis Research Institute, “which sponsors the GARFIELD-AF registry.” Dr. Camm discloses receiving grants and personal fees from Bayer, Boehringer Ingelheim, Pfizer/Bristol-Myers Squibb, and Daiichi Sankyo. Disclosures for the other authors are in the report. Dr. Naccarelli disclosed consulting and participating in research for Janssen and serving as a consultant for Milestone, Sanofi, Omeicos, and Acesion Pharma.

A version of this article originally appeared on Medscape.com.

Abnormal coagulation is a hallmark of COVID-19. Now, as we’re learning more about the high risk of thrombosis, physicians need to prescribe prophylaxis routinely in the hospital, stay alert, and act immediately when signs of trouble appear. “We must have a low suspicion for diagnosis and treatment of thrombosis,” said hematologist-oncologist Thomas DeLoughery, MD, professor of medicine at Oregon Health & Science University in Portland in a presentation at the virtual 2020 annual meeting of the Association of VA Hematology/Oncology (AVAHO).

Still, research is sparse, and there are disagreements about the best strategies to protect patients, said DeLoughery. Physicians recognized coagulation problems early on during the course of the COVID-19 pandemic, he said, and they’re very common. According to DeLoughery, most patients have abnormal coagulation, very high D-dimer test results, and very high fibrinogen levels—even to the extraordinary level of 1,500 mg/dL, he said. And unlike in typical patients with septic shock, patients with thrombosis have a higher risk than bleeding.

A high D-dimer level is a major prognostic indicator of thrombosis and bad outcomes. “It’s representative of widespread coagulation activation, and it can be a sign of pulmonary thrombosis and local thrombosis happening at the site of the COVID infection,” he said.

DeLoughery highlighted an April 2020 study that found that “patients with D‐dimer levels ≥ 2.0 µg/mL had a higher incidence of mortality when compared with those who with D‐dimer levels < 2.0 µg/mL (12/67 vs 1/267; P < .001; hazard ratio, 51.5; 95% CI, 12.9‐206.7).”

Research also suggests that “there's something about getting COVID and going to the intensive care unit (ICU) that dramatically raises the risk of thrombosis,” he said, and the risk goes up over time in the ICU. Venous thrombosis isn’t the only risk. Relatively young patients with COVID have suffered from arterial thrombosis, even though they have minimal to no respiratory symptoms and no cardiovascular risk factors.

As for treatments, DeLoughery noted that thrombosis can occur despite standard prophylaxis, and patients may show resistance to heparin and, therefore, need massive doses. Still, there’s consensus that every patient with COVID-19 in the hospital should get thromboprophylaxis with low-molecular-weight heparin (LMWH), he said, and unfractionated heparin is appropriate for those with renal failure.

“The problem is everything else is controversial,” he said. For example, hematologists are split evenly on whether heparin dosing should be increased beyond standard protocol for patients in the ICU with 1.5 to 3 times normal D-dimers levels. He agreed with this approach but notes that some centers set their D-dimer triggers higher—at 3 to 6 times the normal level.

“The problem is that there’s limited data,” he said. “We have lots of observational studies suggesting benefits from higher doses, but we have no randomized trial data, and the observational studies are not uniform in their recommendations.”

What about outpatient prophylaxis? It appears that risk of thrombosis is < 1% percent when patients are out of the hospital, he said. “This is very reassuring that once the patient gets better, their prothrombotic drive goes away.”

Dr. DeLoughery highlighted the protocol at Oregon Health & Science University:

• Prophylaxis. Everyone with COVID-19 admitted to the hospital receives enoxaparin 40 mg daily. If the patient’s body mass index > 40, it should be increased to twice daily. For patients with renal failure, use unfractionated heparin 5000 u twice daily or enoxaparin 30 mg daily.
• In the ICU. Screen for deep vein thrombosis at admission and every 4 to 5 days thereafter. Increase enoxaparin to 40 mg twice daily, and to 1 mg/kg twice daily if signs of thrombosis develop, such as sudden deterioration, respiratory failure, the patient is too unstable to get a computed tomography, or with D-dimer > 3.0 µg/mL. “People’s thresholds for initiating empiric therapy differ, but this is an option,” he said.

For outpatient patients who are likely to be immobile for a month, 40 mg enoxaparin or 10 mg rivaroxaban are appropriate. “We’re not as aggressive as we used to be about outpatient prophylaxis,” he said.

Moving forward, he said, “this is an area where we really need clinical trials. There's just so much uncertainty.”

DeLoughery reported no disclosures.

Abnormal coagulation is a hallmark of COVID-19. Now, as we’re learning more about the high risk of thrombosis, physicians need to prescribe prophylaxis routinely in the hospital, stay alert, and act immediately when signs of trouble appear. “We must have a low suspicion for diagnosis and treatment of thrombosis,” said hematologist-oncologist Thomas DeLoughery, MD, professor of medicine at Oregon Health & Science University in Portland in a presentation at the virtual 2020 annual meeting of the Association of VA Hematology/Oncology (AVAHO).

Still, research is sparse, and there are disagreements about the best strategies to protect patients, said DeLoughery. Physicians recognized coagulation problems early on during the course of the COVID-19 pandemic, he said, and they’re very common. According to DeLoughery, most patients have abnormal coagulation, very high D-dimer test results, and very high fibrinogen levels—even to the extraordinary level of 1,500 mg/dL, he said. And unlike in typical patients with septic shock, patients with thrombosis have a higher risk than bleeding.

A high D-dimer level is a major prognostic indicator of thrombosis and bad outcomes. “It’s representative of widespread coagulation activation, and it can be a sign of pulmonary thrombosis and local thrombosis happening at the site of the COVID infection,” he said.

DeLoughery highlighted an April 2020 study that found that “patients with D‐dimer levels ≥ 2.0 µg/mL had a higher incidence of mortality when compared with those who with D‐dimer levels < 2.0 µg/mL (12/67 vs 1/267; P < .001; hazard ratio, 51.5; 95% CI, 12.9‐206.7).”

Research also suggests that “there's something about getting COVID and going to the intensive care unit (ICU) that dramatically raises the risk of thrombosis,” he said, and the risk goes up over time in the ICU. Venous thrombosis isn’t the only risk. Relatively young patients with COVID have suffered from arterial thrombosis, even though they have minimal to no respiratory symptoms and no cardiovascular risk factors.

As for treatments, DeLoughery noted that thrombosis can occur despite standard prophylaxis, and patients may show resistance to heparin and, therefore, need massive doses. Still, there’s consensus that every patient with COVID-19 in the hospital should get thromboprophylaxis with low-molecular-weight heparin (LMWH), he said, and unfractionated heparin is appropriate for those with renal failure.

“The problem is everything else is controversial,” he said. For example, hematologists are split evenly on whether heparin dosing should be increased beyond standard protocol for patients in the ICU with 1.5 to 3 times normal D-dimers levels. He agreed with this approach but notes that some centers set their D-dimer triggers higher—at 3 to 6 times the normal level.

“The problem is that there’s limited data,” he said. “We have lots of observational studies suggesting benefits from higher doses, but we have no randomized trial data, and the observational studies are not uniform in their recommendations.”

What about outpatient prophylaxis? It appears that risk of thrombosis is < 1% percent when patients are out of the hospital, he said. “This is very reassuring that once the patient gets better, their prothrombotic drive goes away.”

Dr. DeLoughery highlighted the protocol at Oregon Health & Science University:

• Prophylaxis. Everyone with COVID-19 admitted to the hospital receives enoxaparin 40 mg daily. If the patient’s body mass index > 40, it should be increased to twice daily. For patients with renal failure, use unfractionated heparin 5000 u twice daily or enoxaparin 30 mg daily.
• In the ICU. Screen for deep vein thrombosis at admission and every 4 to 5 days thereafter. Increase enoxaparin to 40 mg twice daily, and to 1 mg/kg twice daily if signs of thrombosis develop, such as sudden deterioration, respiratory failure, the patient is too unstable to get a computed tomography, or with D-dimer > 3.0 µg/mL. “People’s thresholds for initiating empiric therapy differ, but this is an option,” he said.

For outpatient patients who are likely to be immobile for a month, 40 mg enoxaparin or 10 mg rivaroxaban are appropriate. “We’re not as aggressive as we used to be about outpatient prophylaxis,” he said.

Moving forward, he said, “this is an area where we really need clinical trials. There's just so much uncertainty.”

DeLoughery reported no disclosures.

Abnormal coagulation is a hallmark of COVID-19. Now, as we’re learning more about the high risk of thrombosis, physicians need to prescribe prophylaxis routinely in the hospital, stay alert, and act immediately when signs of trouble appear. “We must have a low suspicion for diagnosis and treatment of thrombosis,” said hematologist-oncologist Thomas DeLoughery, MD, professor of medicine at Oregon Health & Science University in Portland in a presentation at the virtual 2020 annual meeting of the Association of VA Hematology/Oncology (AVAHO).

Still, research is sparse, and there are disagreements about the best strategies to protect patients, said DeLoughery. Physicians recognized coagulation problems early on during the course of the COVID-19 pandemic, he said, and they’re very common. According to DeLoughery, most patients have abnormal coagulation, very high D-dimer test results, and very high fibrinogen levels—even to the extraordinary level of 1,500 mg/dL, he said. And unlike in typical patients with septic shock, patients with thrombosis have a higher risk than bleeding.

A high D-dimer level is a major prognostic indicator of thrombosis and bad outcomes. “It’s representative of widespread coagulation activation, and it can be a sign of pulmonary thrombosis and local thrombosis happening at the site of the COVID infection,” he said.

DeLoughery highlighted an April 2020 study that found that “patients with D‐dimer levels ≥ 2.0 µg/mL had a higher incidence of mortality when compared with those who with D‐dimer levels < 2.0 µg/mL (12/67 vs 1/267; P < .001; hazard ratio, 51.5; 95% CI, 12.9‐206.7).”

Research also suggests that “there's something about getting COVID and going to the intensive care unit (ICU) that dramatically raises the risk of thrombosis,” he said, and the risk goes up over time in the ICU. Venous thrombosis isn’t the only risk. Relatively young patients with COVID have suffered from arterial thrombosis, even though they have minimal to no respiratory symptoms and no cardiovascular risk factors.

As for treatments, DeLoughery noted that thrombosis can occur despite standard prophylaxis, and patients may show resistance to heparin and, therefore, need massive doses. Still, there’s consensus that every patient with COVID-19 in the hospital should get thromboprophylaxis with low-molecular-weight heparin (LMWH), he said, and unfractionated heparin is appropriate for those with renal failure.

“The problem is everything else is controversial,” he said. For example, hematologists are split evenly on whether heparin dosing should be increased beyond standard protocol for patients in the ICU with 1.5 to 3 times normal D-dimers levels. He agreed with this approach but notes that some centers set their D-dimer triggers higher—at 3 to 6 times the normal level.

“The problem is that there’s limited data,” he said. “We have lots of observational studies suggesting benefits from higher doses, but we have no randomized trial data, and the observational studies are not uniform in their recommendations.”

What about outpatient prophylaxis? It appears that risk of thrombosis is < 1% percent when patients are out of the hospital, he said. “This is very reassuring that once the patient gets better, their prothrombotic drive goes away.”

Dr. DeLoughery highlighted the protocol at Oregon Health & Science University:

• Prophylaxis. Everyone with COVID-19 admitted to the hospital receives enoxaparin 40 mg daily. If the patient’s body mass index > 40, it should be increased to twice daily. For patients with renal failure, use unfractionated heparin 5000 u twice daily or enoxaparin 30 mg daily.
• In the ICU. Screen for deep vein thrombosis at admission and every 4 to 5 days thereafter. Increase enoxaparin to 40 mg twice daily, and to 1 mg/kg twice daily if signs of thrombosis develop, such as sudden deterioration, respiratory failure, the patient is too unstable to get a computed tomography, or with D-dimer > 3.0 µg/mL. “People’s thresholds for initiating empiric therapy differ, but this is an option,” he said.

For outpatient patients who are likely to be immobile for a month, 40 mg enoxaparin or 10 mg rivaroxaban are appropriate. “We’re not as aggressive as we used to be about outpatient prophylaxis,” he said.

Moving forward, he said, “this is an area where we really need clinical trials. There's just so much uncertainty.”

DeLoughery reported no disclosures.

For patients with severe thrombocytopenia and chronic liver diseases, including hepatocellular carcinoma, treatment with lusutrombopag prior to invasive procedures significantly decreased the need for platelet transfusions without increasing the need for rescue treatment for bleeding or the rate of thromboembolic events.

In a post hoc analysis of data from 270 patients in two manufacturer-sponsored, multicenter, randomized, double-blind, placebo-controlled, phase 3 trials, significantly more lusutrombopag recipients met the primary efficacy endpoint, including patients with hepatocellular carcinoma (68.0% vs. 8.9% in the placebo group; P < .0001) and those without it (77.0% vs. 21.6%; P < .0001). Rates of treatment-emergent adverse events were similar between the lusutrombopag and placebo groups, and patients with hepatocellular carcinoma were not at increased risk for thrombosis, Naim Alkhouri, MD, of Texas Liver Institute in San Antonio, and associates wrote in Clinical Gastroenterology and Hepatology.

Platelet transfusion is the treatment mainstay for patients with thrombocytopenia related to cirrhosis who are undergoing invasive procedures, but its effects are short-lived, and at least one in five transfusions fails. Thrombopoietin agonists such as lusutrombopag are efficacious and approved in this setting, but they can be prothrombotic, particularly in patients with hepatocellular carcinoma, who already are at heightened risk for portal vein thrombosis.

Dr. Alkhouri and associates performed an integrated analysis of the PLUS 1 trial (Japan, October 2013–May 2014) and the L-PLUS 2 (global, June 2015–April 2017). Participants were adults with Child-Pugh Class A or B chronic liver disease and baseline platelet counts under 50 x 10⁹ per L who were scheduled for invasive procedures. Of the 270 patients, 95 had hepatocellular carcinoma. Patients were randomly assigned on a one-to-one basis to receive either lusutrombopag (3 mg) or placebo daily for up to 7 days before procedures. The primary endpoint was the percentage of patients in the per-protocol population who did not need a platelet transfusion before the invasive procedure or rescue therapy within 7 days afterward.

The treatment and placebo arms were similar except that patients with hepatocellular carcinoma were about 10 years older on average. In patients with hepatocellular carcinoma, 60.5% more lusutrombopag recipients than placebo recipients met the primary endpoint, and rates of bleeding-related adverse events were 9.1% and 15.7%, respectively. In patients with other chronic liver diseases, 52.6% more lusutrombopag recipients met the primary endpoint. Rates of bleeding-related adverse events were 5% and 10.6%.

“Approximately 88% of patients with hepatocellular carcinoma underwent a liver-related procedure, compared with approximately 10% of patients without hepatocellular carcinoma,” the investigators wrote. “This is significant because ablations or transcatheter arterial chemoembolizations can be associated with serious bleeding complications. It is clinically important that, given the greater number of liver-related procedures, the incidence of bleeding-related adverse events was lower in patients treated with lusutrombopag than placebo.”

Imaging after the procedures confirmed low rates of thromboses in both groups and subgroups. Four patients developed portal vein thromboses, including two lusutrombopag recipients (one of whom had hepatocellular carcinoma) and two placebo recipients without hepatocellular carcinoma.

These trials excluded patients undergoing major surgical procedures and those with decompensated cirrhosis; portal vein thrombosis; hematopoietic tumors; aplastic anemia; myelodysplastic syndrome; myelofibrosis; liver transplantation; splenectomy; and thrombocytopenia that was congenital, autoimmune, or drug induced. “A limitation of this study was the high rate of protocol violations related to platelet transfusions,” the researchers noted. “A number of patients [42 in all] were excluded from the per-protocol population owing to receipt of unnecessary platelet transfusions, or because they did not receive a needed platelet transfusion.”Shionogi makes lusutrombopag and sponsored the study. Dr. Alkhouri reported an advisory relationship with Shionogi and Dova Pharma. Two coinvestigators reported being employed by Shionogi. Three coinvestigators also disclosed ties to Shionogi and to several other pharmaceutical companies.

SOURCE: Alkhouri N et al. Clin Gastroenterol Hepatol. 2020 Mar 20. doi: 10.1016/j.cgh.2020.03.032.

For patients with severe thrombocytopenia and chronic liver diseases, including hepatocellular carcinoma, treatment with lusutrombopag prior to invasive procedures significantly decreased the need for platelet transfusions without increasing the need for rescue treatment for bleeding or the rate of thromboembolic events.

In a post hoc analysis of data from 270 patients in two manufacturer-sponsored, multicenter, randomized, double-blind, placebo-controlled, phase 3 trials, significantly more lusutrombopag recipients met the primary efficacy endpoint, including patients with hepatocellular carcinoma (68.0% vs. 8.9% in the placebo group; P < .0001) and those without it (77.0% vs. 21.6%; P < .0001). Rates of treatment-emergent adverse events were similar between the lusutrombopag and placebo groups, and patients with hepatocellular carcinoma were not at increased risk for thrombosis, Naim Alkhouri, MD, of Texas Liver Institute in San Antonio, and associates wrote in Clinical Gastroenterology and Hepatology.

Platelet transfusion is the treatment mainstay for patients with thrombocytopenia related to cirrhosis who are undergoing invasive procedures, but its effects are short-lived, and at least one in five transfusions fails. Thrombopoietin agonists such as lusutrombopag are efficacious and approved in this setting, but they can be prothrombotic, particularly in patients with hepatocellular carcinoma, who already are at heightened risk for portal vein thrombosis.

Dr. Alkhouri and associates performed an integrated analysis of the PLUS 1 trial (Japan, October 2013–May 2014) and the L-PLUS 2 (global, June 2015–April 2017). Participants were adults with Child-Pugh Class A or B chronic liver disease and baseline platelet counts under 50 x 10⁹ per L who were scheduled for invasive procedures. Of the 270 patients, 95 had hepatocellular carcinoma. Patients were randomly assigned on a one-to-one basis to receive either lusutrombopag (3 mg) or placebo daily for up to 7 days before procedures. The primary endpoint was the percentage of patients in the per-protocol population who did not need a platelet transfusion before the invasive procedure or rescue therapy within 7 days afterward.

The treatment and placebo arms were similar except that patients with hepatocellular carcinoma were about 10 years older on average. In patients with hepatocellular carcinoma, 60.5% more lusutrombopag recipients than placebo recipients met the primary endpoint, and rates of bleeding-related adverse events were 9.1% and 15.7%, respectively. In patients with other chronic liver diseases, 52.6% more lusutrombopag recipients met the primary endpoint. Rates of bleeding-related adverse events were 5% and 10.6%.

“Approximately 88% of patients with hepatocellular carcinoma underwent a liver-related procedure, compared with approximately 10% of patients without hepatocellular carcinoma,” the investigators wrote. “This is significant because ablations or transcatheter arterial chemoembolizations can be associated with serious bleeding complications. It is clinically important that, given the greater number of liver-related procedures, the incidence of bleeding-related adverse events was lower in patients treated with lusutrombopag than placebo.”

Imaging after the procedures confirmed low rates of thromboses in both groups and subgroups. Four patients developed portal vein thromboses, including two lusutrombopag recipients (one of whom had hepatocellular carcinoma) and two placebo recipients without hepatocellular carcinoma.

These trials excluded patients undergoing major surgical procedures and those with decompensated cirrhosis; portal vein thrombosis; hematopoietic tumors; aplastic anemia; myelodysplastic syndrome; myelofibrosis; liver transplantation; splenectomy; and thrombocytopenia that was congenital, autoimmune, or drug induced. “A limitation of this study was the high rate of protocol violations related to platelet transfusions,” the researchers noted. “A number of patients [42 in all] were excluded from the per-protocol population owing to receipt of unnecessary platelet transfusions, or because they did not receive a needed platelet transfusion.”Shionogi makes lusutrombopag and sponsored the study. Dr. Alkhouri reported an advisory relationship with Shionogi and Dova Pharma. Two coinvestigators reported being employed by Shionogi. Three coinvestigators also disclosed ties to Shionogi and to several other pharmaceutical companies.

SOURCE: Alkhouri N et al. Clin Gastroenterol Hepatol. 2020 Mar 20. doi: 10.1016/j.cgh.2020.03.032.

For patients with severe thrombocytopenia and chronic liver diseases, including hepatocellular carcinoma, treatment with lusutrombopag prior to invasive procedures significantly decreased the need for platelet transfusions without increasing the need for rescue treatment for bleeding or the rate of thromboembolic events.

In a post hoc analysis of data from 270 patients in two manufacturer-sponsored, multicenter, randomized, double-blind, placebo-controlled, phase 3 trials, significantly more lusutrombopag recipients met the primary efficacy endpoint, including patients with hepatocellular carcinoma (68.0% vs. 8.9% in the placebo group; P < .0001) and those without it (77.0% vs. 21.6%; P < .0001). Rates of treatment-emergent adverse events were similar between the lusutrombopag and placebo groups, and patients with hepatocellular carcinoma were not at increased risk for thrombosis, Naim Alkhouri, MD, of Texas Liver Institute in San Antonio, and associates wrote in Clinical Gastroenterology and Hepatology.

Platelet transfusion is the treatment mainstay for patients with thrombocytopenia related to cirrhosis who are undergoing invasive procedures, but its effects are short-lived, and at least one in five transfusions fails. Thrombopoietin agonists such as lusutrombopag are efficacious and approved in this setting, but they can be prothrombotic, particularly in patients with hepatocellular carcinoma, who already are at heightened risk for portal vein thrombosis.

Dr. Alkhouri and associates performed an integrated analysis of the PLUS 1 trial (Japan, October 2013–May 2014) and the L-PLUS 2 (global, June 2015–April 2017). Participants were adults with Child-Pugh Class A or B chronic liver disease and baseline platelet counts under 50 x 10⁹ per L who were scheduled for invasive procedures. Of the 270 patients, 95 had hepatocellular carcinoma. Patients were randomly assigned on a one-to-one basis to receive either lusutrombopag (3 mg) or placebo daily for up to 7 days before procedures. The primary endpoint was the percentage of patients in the per-protocol population who did not need a platelet transfusion before the invasive procedure or rescue therapy within 7 days afterward.

The treatment and placebo arms were similar except that patients with hepatocellular carcinoma were about 10 years older on average. In patients with hepatocellular carcinoma, 60.5% more lusutrombopag recipients than placebo recipients met the primary endpoint, and rates of bleeding-related adverse events were 9.1% and 15.7%, respectively. In patients with other chronic liver diseases, 52.6% more lusutrombopag recipients met the primary endpoint. Rates of bleeding-related adverse events were 5% and 10.6%.

“Approximately 88% of patients with hepatocellular carcinoma underwent a liver-related procedure, compared with approximately 10% of patients without hepatocellular carcinoma,” the investigators wrote. “This is significant because ablations or transcatheter arterial chemoembolizations can be associated with serious bleeding complications. It is clinically important that, given the greater number of liver-related procedures, the incidence of bleeding-related adverse events was lower in patients treated with lusutrombopag than placebo.”

Imaging after the procedures confirmed low rates of thromboses in both groups and subgroups. Four patients developed portal vein thromboses, including two lusutrombopag recipients (one of whom had hepatocellular carcinoma) and two placebo recipients without hepatocellular carcinoma.

These trials excluded patients undergoing major surgical procedures and those with decompensated cirrhosis; portal vein thrombosis; hematopoietic tumors; aplastic anemia; myelodysplastic syndrome; myelofibrosis; liver transplantation; splenectomy; and thrombocytopenia that was congenital, autoimmune, or drug induced. “A limitation of this study was the high rate of protocol violations related to platelet transfusions,” the researchers noted. “A number of patients [42 in all] were excluded from the per-protocol population owing to receipt of unnecessary platelet transfusions, or because they did not receive a needed platelet transfusion.”Shionogi makes lusutrombopag and sponsored the study. Dr. Alkhouri reported an advisory relationship with Shionogi and Dova Pharma. Two coinvestigators reported being employed by Shionogi. Three coinvestigators also disclosed ties to Shionogi and to several other pharmaceutical companies.

SOURCE: Alkhouri N et al. Clin Gastroenterol Hepatol. 2020 Mar 20. doi: 10.1016/j.cgh.2020.03.032.

A single educational mailing sent by several U.S. health plans to their patients with atrial fibrillation who were candidates for oral anticoagulation, but had not yet started a regimen, failed to boost them over their prescription hurdle and facilitate starting an antithrombotic regimen.

By 1 year following the intervention, a mere 10% of patients in both the intervention and a control arm of the randomized trial had begun treatment, with no signal of incremental uptake because of the mailing, Sean D. Pokorney, MD, said at the virtual annual congress of the European Society of Cardiology. Included in the mailing was an educational letter citing the patient’s atrial fibrillation (AFib) diagnosis, a statement regarding their suitability for oral anticoagulation, some information about the treatment, and a suggestion that recipients discuss this with their personal physician.

Dr. Pokorney acknowledged that the single mailing to patients may not have been adequate to capture patients’ attention and trigger an action, and that repeated messaging via multiple platforms and in coordination with interventions aimed at their health care providers may be what’s needed.

“It will take repeated interventions and engagements. We will need different methods to move the needle,” said Dr. Pokorney, a cardiac electrophysiologist at Duke University in Durham, N.C. The goal is to “empower patients to talk with their health care providers, and to become agents of change” in their care, he explained, but the single, mailed prod wasn’t enough.

An earlier study run by Dr. Pokorney and several of his colleagues used a broader panel of interventions aimed at both patients and clinicians to encourage increased prescribing of oral anticoagulants in five middle income countries, and documented successfully increasing the uptake rate by threefold compared with control patients (Lancet. 2017 Oct 14;390[10104]:1737-46). The current study tested the efficacy of a “much lower-impact intervention,” he admitted.

“The data are “sobering and eye-opening,” said Kalyanam Shivkumar, MD, a cardiac electrophysiologist and professor of medicine at the University of California, Los Angeles. “We’re stuck with this big challenge,” the gap between “what medicine can do and what it actually does” when evidence-based interventions fail to gain traction in everyday practice, he said in an interview.

The numbers collected during the new study highlighted the treatment gap. The IMPACT-AFib study randomized 23,546 patients with AFib and a CHA2DS2-VASc score of at least 2, denoting a stroke risk that warrants oral anticoagulation, to the intervention group, and 23,787 patients to the control arm. The patient selection process began with nearly 200,000 patients who met these criteria, but the researchers excluded 67% because they were already on an oral anticoagulant regimen, an uptake level that roughly matched the 50%-60% level usually seen among U.S. patients, Dr. Pokorney noted. That number coupled with the incremental uptake rate of only 10% of the enrolled patients during the trial, despite their uniform suitability for treatment, underscored how low uptake rates tend to remain stuck over time.

Enrolled patients averaged 78 years of age, with nearly two-thirds at least 75 years old, and with an average CHA2DS2-VASc score of 4.5.

The trial featured a novel design as the first clinical trial to take advantage of the Sentinel program for phase 4 data collection and study devised by the Food and Drug Administration, said Dr. Pokorney. The Sentinel program relies on data partners to provide information; for the IMPACT-AFib study, data came from five large U.S. health systems: Aetna, HealthCore, Humana, Harvard Pilgrim Healthcare, and Optum. Each of these systems sent the mailing to their targeted member patients.

In addition to sending just a single, mailed intervention, the study may have also been limited by the mailing’s content. The educational text, presented by Dr. Pokorney during his talk, focused largely on the potential risks of oral anticoagulation, the limited availability of antidote agents, potential drug and food interactions, and a brief entry about the risk for stroke associated with AFib along with a chart that a patient could use to hand calculate their CHA₂DS₂-VASc score. What the mailing lacked was discussion of the benefits of oral anticoagulation, noted study discussant Christophe LeClercq, MD, a cardiac electrophysiologist and professor of cardiology at the University of Rennes, France.

IMPACT-AFib received no commercial funding, and Dr. Pokorney and Dr. Shivkumar had no disclosures. Dr. Leclercq has received honoraria from Abbott, Biotronik, Boston Scientific, Livanova, and Medtronic.

[email protected]

A single educational mailing sent by several U.S. health plans to their patients with atrial fibrillation who were candidates for oral anticoagulation, but had not yet started a regimen, failed to boost them over their prescription hurdle and facilitate starting an antithrombotic regimen.

By 1 year following the intervention, a mere 10% of patients in both the intervention and a control arm of the randomized trial had begun treatment, with no signal of incremental uptake because of the mailing, Sean D. Pokorney, MD, said at the virtual annual congress of the European Society of Cardiology. Included in the mailing was an educational letter citing the patient’s atrial fibrillation (AFib) diagnosis, a statement regarding their suitability for oral anticoagulation, some information about the treatment, and a suggestion that recipients discuss this with their personal physician.

Dr. Pokorney acknowledged that the single mailing to patients may not have been adequate to capture patients’ attention and trigger an action, and that repeated messaging via multiple platforms and in coordination with interventions aimed at their health care providers may be what’s needed.

“It will take repeated interventions and engagements. We will need different methods to move the needle,” said Dr. Pokorney, a cardiac electrophysiologist at Duke University in Durham, N.C. The goal is to “empower patients to talk with their health care providers, and to become agents of change” in their care, he explained, but the single, mailed prod wasn’t enough.

An earlier study run by Dr. Pokorney and several of his colleagues used a broader panel of interventions aimed at both patients and clinicians to encourage increased prescribing of oral anticoagulants in five middle income countries, and documented successfully increasing the uptake rate by threefold compared with control patients (Lancet. 2017 Oct 14;390[10104]:1737-46). The current study tested the efficacy of a “much lower-impact intervention,” he admitted.

“The data are “sobering and eye-opening,” said Kalyanam Shivkumar, MD, a cardiac electrophysiologist and professor of medicine at the University of California, Los Angeles. “We’re stuck with this big challenge,” the gap between “what medicine can do and what it actually does” when evidence-based interventions fail to gain traction in everyday practice, he said in an interview.

The numbers collected during the new study highlighted the treatment gap. The IMPACT-AFib study randomized 23,546 patients with AFib and a CHA2DS2-VASc score of at least 2, denoting a stroke risk that warrants oral anticoagulation, to the intervention group, and 23,787 patients to the control arm. The patient selection process began with nearly 200,000 patients who met these criteria, but the researchers excluded 67% because they were already on an oral anticoagulant regimen, an uptake level that roughly matched the 50%-60% level usually seen among U.S. patients, Dr. Pokorney noted. That number coupled with the incremental uptake rate of only 10% of the enrolled patients during the trial, despite their uniform suitability for treatment, underscored how low uptake rates tend to remain stuck over time.

Enrolled patients averaged 78 years of age, with nearly two-thirds at least 75 years old, and with an average CHA2DS2-VASc score of 4.5.

The trial featured a novel design as the first clinical trial to take advantage of the Sentinel program for phase 4 data collection and study devised by the Food and Drug Administration, said Dr. Pokorney. The Sentinel program relies on data partners to provide information; for the IMPACT-AFib study, data came from five large U.S. health systems: Aetna, HealthCore, Humana, Harvard Pilgrim Healthcare, and Optum. Each of these systems sent the mailing to their targeted member patients.

In addition to sending just a single, mailed intervention, the study may have also been limited by the mailing’s content. The educational text, presented by Dr. Pokorney during his talk, focused largely on the potential risks of oral anticoagulation, the limited availability of antidote agents, potential drug and food interactions, and a brief entry about the risk for stroke associated with AFib along with a chart that a patient could use to hand calculate their CHA₂DS₂-VASc score. What the mailing lacked was discussion of the benefits of oral anticoagulation, noted study discussant Christophe LeClercq, MD, a cardiac electrophysiologist and professor of cardiology at the University of Rennes, France.

IMPACT-AFib received no commercial funding, and Dr. Pokorney and Dr. Shivkumar had no disclosures. Dr. Leclercq has received honoraria from Abbott, Biotronik, Boston Scientific, Livanova, and Medtronic.

[email protected]

A single educational mailing sent by several U.S. health plans to their patients with atrial fibrillation who were candidates for oral anticoagulation, but had not yet started a regimen, failed to boost them over their prescription hurdle and facilitate starting an antithrombotic regimen.

By 1 year following the intervention, a mere 10% of patients in both the intervention and a control arm of the randomized trial had begun treatment, with no signal of incremental uptake because of the mailing, Sean D. Pokorney, MD, said at the virtual annual congress of the European Society of Cardiology. Included in the mailing was an educational letter citing the patient’s atrial fibrillation (AFib) diagnosis, a statement regarding their suitability for oral anticoagulation, some information about the treatment, and a suggestion that recipients discuss this with their personal physician.

Dr. Pokorney acknowledged that the single mailing to patients may not have been adequate to capture patients’ attention and trigger an action, and that repeated messaging via multiple platforms and in coordination with interventions aimed at their health care providers may be what’s needed.

“It will take repeated interventions and engagements. We will need different methods to move the needle,” said Dr. Pokorney, a cardiac electrophysiologist at Duke University in Durham, N.C. The goal is to “empower patients to talk with their health care providers, and to become agents of change” in their care, he explained, but the single, mailed prod wasn’t enough.

An earlier study run by Dr. Pokorney and several of his colleagues used a broader panel of interventions aimed at both patients and clinicians to encourage increased prescribing of oral anticoagulants in five middle income countries, and documented successfully increasing the uptake rate by threefold compared with control patients (Lancet. 2017 Oct 14;390[10104]:1737-46). The current study tested the efficacy of a “much lower-impact intervention,” he admitted.

“The data are “sobering and eye-opening,” said Kalyanam Shivkumar, MD, a cardiac electrophysiologist and professor of medicine at the University of California, Los Angeles. “We’re stuck with this big challenge,” the gap between “what medicine can do and what it actually does” when evidence-based interventions fail to gain traction in everyday practice, he said in an interview.

The numbers collected during the new study highlighted the treatment gap. The IMPACT-AFib study randomized 23,546 patients with AFib and a CHA2DS2-VASc score of at least 2, denoting a stroke risk that warrants oral anticoagulation, to the intervention group, and 23,787 patients to the control arm. The patient selection process began with nearly 200,000 patients who met these criteria, but the researchers excluded 67% because they were already on an oral anticoagulant regimen, an uptake level that roughly matched the 50%-60% level usually seen among U.S. patients, Dr. Pokorney noted. That number coupled with the incremental uptake rate of only 10% of the enrolled patients during the trial, despite their uniform suitability for treatment, underscored how low uptake rates tend to remain stuck over time.

Enrolled patients averaged 78 years of age, with nearly two-thirds at least 75 years old, and with an average CHA2DS2-VASc score of 4.5.

The trial featured a novel design as the first clinical trial to take advantage of the Sentinel program for phase 4 data collection and study devised by the Food and Drug Administration, said Dr. Pokorney. The Sentinel program relies on data partners to provide information; for the IMPACT-AFib study, data came from five large U.S. health systems: Aetna, HealthCore, Humana, Harvard Pilgrim Healthcare, and Optum. Each of these systems sent the mailing to their targeted member patients.

In addition to sending just a single, mailed intervention, the study may have also been limited by the mailing’s content. The educational text, presented by Dr. Pokorney during his talk, focused largely on the potential risks of oral anticoagulation, the limited availability of antidote agents, potential drug and food interactions, and a brief entry about the risk for stroke associated with AFib along with a chart that a patient could use to hand calculate their CHA₂DS₂-VASc score. What the mailing lacked was discussion of the benefits of oral anticoagulation, noted study discussant Christophe LeClercq, MD, a cardiac electrophysiologist and professor of cardiology at the University of Rennes, France.

IMPACT-AFib received no commercial funding, and Dr. Pokorney and Dr. Shivkumar had no disclosures. Dr. Leclercq has received honoraria from Abbott, Biotronik, Boston Scientific, Livanova, and Medtronic.

[email protected]

The pragmatic Hestia criteria proved as safe as the more structured, points-based simplified Pulmonary Embolism Severity Index (sPESI) score for selection of patients with acute pulmonary embolism for outpatient care in the large, randomized HOME-PE trial presented at the virtual annual congress of the European Society of Cardiology.

Courtesy Wikimedia Commons/Walter Serra, Giuseppe De Iaco, Claudio Reverberi, and Tiziano Gherli/Creative Commons License

“These results support outpatient management of acute pulmonary embolism patients using either the Hestia method or the sPESI score with the option for the physician-in-charge to override the decision. In hospitals organized for outpatient management, both triaging strategies enable more than a third of pulmonary embolism patients to be managed at home with a low rate of complications,” Pierre-Marie Roy, MD, said in presenting the HOME-PE findings.

The study clarifies a transatlantic controversy regarding how best to triage patients with acute pulmonary embolism (PE) for outpatient care. The answer? It’s basically a tie between the points-based sPESI score recommended in the current ESC guidelines (Eur Respir J. 2019 Oct 9;54[3]:1901647) and the Hestia method endorsed in the American College of Chest Physician guidelines (Chest. 2016 Feb;149[2]:315-52).

The sPESI is a validated tool that grants 1 point each for age over 80 years, background cardiopulmonary disease, a systolic blood pressure below 100 mm Hg, cancer, a heart rate of 110 bpm or more, and an oxygen saturation level below 90%. A patient needs a score of zero to be eligible for outpatient management. In contrast, the Hestia method relies upon 11 simple bedside criteria rather than a points system, explained Dr. Roy of University Hospital of Angers, France (J Thromb Haemost. 2011 Aug;9[8]:1500-7).

HOME-PE was a randomized, open-label, noninferiority trial conducted at 26 hospitals in France, Belgium, Switzerland, and the Netherlands. The study included 1,974 patients presenting to the emergency department with non–high-risk acute PE as defined by hemodynamic stability. About 39% of patients in the Hestia group were eligible for outpatient care on the basis of ‘no’ answers regarding all 11 criteria, while 48% of patients had an sPESI score of 0 and were thus initially considered appropriate for outpatient management.

However, the investigators recognized that no scoring system for acute PE is perfect, and that the judgment of a physician with extensive experience in managing this life-threatening condition counts for a lot. So they stipulated that a patient’s physician-in-charge could overrule a decision for early discharge. This happened 29% of the time in patients with a sPESI score of 0, as compared with a 3% overrule rate with the Hestia rule. The physician-in-charge also moved small numbers of patients who were Hestia or sPESI positive into the outpatient care group. As a result, a similar proportion of patients in both groups were discharged home within 24 hours for outpatient treatment: 38% of the total Hestia group and 37% in the sPESI arm.

Major adverse event rates were reassuringly low in both groups managed on an outpatient basis. The composite of recurrent venous thromboembolism, bleeding, or death within 30 days occurred in 1.3% of Hestia outpatients and 1.1% of sPESI outpatients. Among patients managed in the hospital, these rates were 5.6% in the Hestia group and 4.7% in the sPESI group.

Discussant Stavros V. Konstantinides, MD, who chaired the ESC guideline committee, asked rhetorically, “who’s happy with the HOME-PE trial? I think everybody.”

“The Hestia criteria integrate the feasibility of family support of the individual patient. This is a good thing. And eligibility based on the Hestia criteria, unlike sPESI, does not require age younger than 80 years or no cancer, and it appears from the HOME-PE study that this is okay,” observed Dr. Konstantinides of the Center for Thrombosis and Hemostasis at the University of Mainz (Germany).

In an interview, Hadley Wilson, MD, called the HOME-PE trial “transformative” and predicted it will change clinical practice. He was particularly impressed with the high quality of the trial, noting that 87% of participants managed as outpatients received a direct oral anticoagulant.

The Hestia rule is simpler and more user-friendly. And greater use of this triaging strategy might have advantages in terms of economics and health care utilization by potentially encouraging movement of decision-making regarding outpatient management of acute PE out of the hospital wards and into emergency departments, said Dr. Wilson, executive vice chair of the Sanger Heart and Vascular Institute and a cardiologist at the University of North Carolina at Chapel Hill.

Dr. Roy reported receiving research grants to conduct HOME-PE from the French Ministry of Health, the study sponsor. In addition, he is on scientific advisory boards and/or speakers’ panels for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Aspen, Daiichi Sankyo, and Sanofi Aventis.
 

[email protected]

The pragmatic Hestia criteria proved as safe as the more structured, points-based simplified Pulmonary Embolism Severity Index (sPESI) score for selection of patients with acute pulmonary embolism for outpatient care in the large, randomized HOME-PE trial presented at the virtual annual congress of the European Society of Cardiology.

Courtesy Wikimedia Commons/Walter Serra, Giuseppe De Iaco, Claudio Reverberi, and Tiziano Gherli/Creative Commons License

“These results support outpatient management of acute pulmonary embolism patients using either the Hestia method or the sPESI score with the option for the physician-in-charge to override the decision. In hospitals organized for outpatient management, both triaging strategies enable more than a third of pulmonary embolism patients to be managed at home with a low rate of complications,” Pierre-Marie Roy, MD, said in presenting the HOME-PE findings.

The study clarifies a transatlantic controversy regarding how best to triage patients with acute pulmonary embolism (PE) for outpatient care. The answer? It’s basically a tie between the points-based sPESI score recommended in the current ESC guidelines (Eur Respir J. 2019 Oct 9;54[3]:1901647) and the Hestia method endorsed in the American College of Chest Physician guidelines (Chest. 2016 Feb;149[2]:315-52).

The sPESI is a validated tool that grants 1 point each for age over 80 years, background cardiopulmonary disease, a systolic blood pressure below 100 mm Hg, cancer, a heart rate of 110 bpm or more, and an oxygen saturation level below 90%. A patient needs a score of zero to be eligible for outpatient management. In contrast, the Hestia method relies upon 11 simple bedside criteria rather than a points system, explained Dr. Roy of University Hospital of Angers, France (J Thromb Haemost. 2011 Aug;9[8]:1500-7).

HOME-PE was a randomized, open-label, noninferiority trial conducted at 26 hospitals in France, Belgium, Switzerland, and the Netherlands. The study included 1,974 patients presenting to the emergency department with non–high-risk acute PE as defined by hemodynamic stability. About 39% of patients in the Hestia group were eligible for outpatient care on the basis of ‘no’ answers regarding all 11 criteria, while 48% of patients had an sPESI score of 0 and were thus initially considered appropriate for outpatient management.

However, the investigators recognized that no scoring system for acute PE is perfect, and that the judgment of a physician with extensive experience in managing this life-threatening condition counts for a lot. So they stipulated that a patient’s physician-in-charge could overrule a decision for early discharge. This happened 29% of the time in patients with a sPESI score of 0, as compared with a 3% overrule rate with the Hestia rule. The physician-in-charge also moved small numbers of patients who were Hestia or sPESI positive into the outpatient care group. As a result, a similar proportion of patients in both groups were discharged home within 24 hours for outpatient treatment: 38% of the total Hestia group and 37% in the sPESI arm.

Major adverse event rates were reassuringly low in both groups managed on an outpatient basis. The composite of recurrent venous thromboembolism, bleeding, or death within 30 days occurred in 1.3% of Hestia outpatients and 1.1% of sPESI outpatients. Among patients managed in the hospital, these rates were 5.6% in the Hestia group and 4.7% in the sPESI group.

Discussant Stavros V. Konstantinides, MD, who chaired the ESC guideline committee, asked rhetorically, “who’s happy with the HOME-PE trial? I think everybody.”

“The Hestia criteria integrate the feasibility of family support of the individual patient. This is a good thing. And eligibility based on the Hestia criteria, unlike sPESI, does not require age younger than 80 years or no cancer, and it appears from the HOME-PE study that this is okay,” observed Dr. Konstantinides of the Center for Thrombosis and Hemostasis at the University of Mainz (Germany).

In an interview, Hadley Wilson, MD, called the HOME-PE trial “transformative” and predicted it will change clinical practice. He was particularly impressed with the high quality of the trial, noting that 87% of participants managed as outpatients received a direct oral anticoagulant.

The Hestia rule is simpler and more user-friendly. And greater use of this triaging strategy might have advantages in terms of economics and health care utilization by potentially encouraging movement of decision-making regarding outpatient management of acute PE out of the hospital wards and into emergency departments, said Dr. Wilson, executive vice chair of the Sanger Heart and Vascular Institute and a cardiologist at the University of North Carolina at Chapel Hill.

Dr. Roy reported receiving research grants to conduct HOME-PE from the French Ministry of Health, the study sponsor. In addition, he is on scientific advisory boards and/or speakers’ panels for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Aspen, Daiichi Sankyo, and Sanofi Aventis.
 

[email protected]

The pragmatic Hestia criteria proved as safe as the more structured, points-based simplified Pulmonary Embolism Severity Index (sPESI) score for selection of patients with acute pulmonary embolism for outpatient care in the large, randomized HOME-PE trial presented at the virtual annual congress of the European Society of Cardiology.

Courtesy Wikimedia Commons/Walter Serra, Giuseppe De Iaco, Claudio Reverberi, and Tiziano Gherli/Creative Commons License

“These results support outpatient management of acute pulmonary embolism patients using either the Hestia method or the sPESI score with the option for the physician-in-charge to override the decision. In hospitals organized for outpatient management, both triaging strategies enable more than a third of pulmonary embolism patients to be managed at home with a low rate of complications,” Pierre-Marie Roy, MD, said in presenting the HOME-PE findings.

The study clarifies a transatlantic controversy regarding how best to triage patients with acute pulmonary embolism (PE) for outpatient care. The answer? It’s basically a tie between the points-based sPESI score recommended in the current ESC guidelines (Eur Respir J. 2019 Oct 9;54[3]:1901647) and the Hestia method endorsed in the American College of Chest Physician guidelines (Chest. 2016 Feb;149[2]:315-52).

The sPESI is a validated tool that grants 1 point each for age over 80 years, background cardiopulmonary disease, a systolic blood pressure below 100 mm Hg, cancer, a heart rate of 110 bpm or more, and an oxygen saturation level below 90%. A patient needs a score of zero to be eligible for outpatient management. In contrast, the Hestia method relies upon 11 simple bedside criteria rather than a points system, explained Dr. Roy of University Hospital of Angers, France (J Thromb Haemost. 2011 Aug;9[8]:1500-7).

HOME-PE was a randomized, open-label, noninferiority trial conducted at 26 hospitals in France, Belgium, Switzerland, and the Netherlands. The study included 1,974 patients presenting to the emergency department with non–high-risk acute PE as defined by hemodynamic stability. About 39% of patients in the Hestia group were eligible for outpatient care on the basis of ‘no’ answers regarding all 11 criteria, while 48% of patients had an sPESI score of 0 and were thus initially considered appropriate for outpatient management.

However, the investigators recognized that no scoring system for acute PE is perfect, and that the judgment of a physician with extensive experience in managing this life-threatening condition counts for a lot. So they stipulated that a patient’s physician-in-charge could overrule a decision for early discharge. This happened 29% of the time in patients with a sPESI score of 0, as compared with a 3% overrule rate with the Hestia rule. The physician-in-charge also moved small numbers of patients who were Hestia or sPESI positive into the outpatient care group. As a result, a similar proportion of patients in both groups were discharged home within 24 hours for outpatient treatment: 38% of the total Hestia group and 37% in the sPESI arm.

Major adverse event rates were reassuringly low in both groups managed on an outpatient basis. The composite of recurrent venous thromboembolism, bleeding, or death within 30 days occurred in 1.3% of Hestia outpatients and 1.1% of sPESI outpatients. Among patients managed in the hospital, these rates were 5.6% in the Hestia group and 4.7% in the sPESI group.

Discussant Stavros V. Konstantinides, MD, who chaired the ESC guideline committee, asked rhetorically, “who’s happy with the HOME-PE trial? I think everybody.”

“The Hestia criteria integrate the feasibility of family support of the individual patient. This is a good thing. And eligibility based on the Hestia criteria, unlike sPESI, does not require age younger than 80 years or no cancer, and it appears from the HOME-PE study that this is okay,” observed Dr. Konstantinides of the Center for Thrombosis and Hemostasis at the University of Mainz (Germany).

In an interview, Hadley Wilson, MD, called the HOME-PE trial “transformative” and predicted it will change clinical practice. He was particularly impressed with the high quality of the trial, noting that 87% of participants managed as outpatients received a direct oral anticoagulant.

The Hestia rule is simpler and more user-friendly. And greater use of this triaging strategy might have advantages in terms of economics and health care utilization by potentially encouraging movement of decision-making regarding outpatient management of acute PE out of the hospital wards and into emergency departments, said Dr. Wilson, executive vice chair of the Sanger Heart and Vascular Institute and a cardiologist at the University of North Carolina at Chapel Hill.

Dr. Roy reported receiving research grants to conduct HOME-PE from the French Ministry of Health, the study sponsor. In addition, he is on scientific advisory boards and/or speakers’ panels for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Aspen, Daiichi Sankyo, and Sanofi Aventis.
 

[email protected]

The first revision since 2015 to the European Society of Cardiology’s guidelines for diagnosing and managing non ST-elevation acute coronary syndrome placed increased reliance on high-sensitivity cardiac troponin testing for diagnosis, and embraced coronary CT to rule out lower-risk patients.

It also highlighted the need for personalized antiplatelet regimens, systems of care, and quality improvement.

The society released the new guidelines on August 29 (Eur Heart J. 2020 Aug 29;doi: 10.1093/eurheartj/ehaa575), and then devoted a session to them the next day at the virtual annual congress of the European Society of Cardiology to highlight some of the key updates, starting with the further emphasis placed on high-sensitivity cardiac troponin (hs-cTn), a reliance that contrasts with what remains inconsistent use of this metric in U.S. practice.

An hs-cTn test is the “preferred” diagnostic test and a “key” testing element, said Marco Roffi, MD, professor and director of interventional cardiology at University Hospital, Geneva, and a member of the guideline committee. He also stressed an update to the time frame of initial hs-cTn testing, which now involves a baseline reading and then a second measure after 2 hours to discern how the marker level is evolving with time. The guidelines advise against measuring any other biomarker of myocardial injury.
 

U.S. lags in measuring high-sensitivity cardiac troponin

U.S. medical systems and centers “are not uniform in adopting hs-cTn,” noted Richard J. Kovacs, MD, professor of cardiology at the Indiana University School of Medicine in Indianapolis. “The new European guidelines should spur U.S. institutions to at least take a close look at the advantages of hs-cTn. There is a strong case that it leads to more efficient emergency care and allows for quicker decisions and triage,” added Dr. Kovacs in an interview.

The new guideline’s emphasis on hs-cTn should hasten broader uptake in U.S. practice, agreed Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston and a member of the guideline-writing panel

Another plus of the guidelines is its endorsement of an “organized approach to risk assessment” early on in these patients, said Dr. Kovacs, who is also the immediate past-president of the American College of Cardiology (ACC). An ACC committee is developing a new set of recommendations for managing patients with cardiac chest pain and is on track for release in 2021. It would represent the first update to U.S. guidelines for non ST-elevation ACS patients since 2014.

The new ESC guidelines give coronary CT angiography a class Ia rating as an alternative to invasive coronary angiography for assessing patients with a low or intermediate risk of having coronary disease, a “tremendous upgrade,” commented Ashish Pershad, MD, an interventional cardiologist at Banner-University Medical Heart Institute in Phoenix. While he welcomes this support for using coronary CT angiography in this setting, he acknowledged that the method remains limited in availability as it requires highly trained technicians to obtain good images and experienced clinicians to interpret the results.

Personalizing antiplatelet and antithrombotic treatments

Notable revisions to medical treatments to minimize ischemia included an admonition not to use routine pretreatment with a P2Y₁₂ receptor inhibitor (such as clopidogrel) before testing determines coronary anatomy.

Not using one of these antiplatelet drugs upfront on all patients “is a tremendous change,” Dr. Pershad said in an interview. Many patients currently get these drugs while awaiting an angiogram, but a more selected and deferred antiplatelet approach would be better when angiography shows that some patients need coronary bypass surgery, he noted. Recent study results have shown no added benefit from pretreatment, and its use can be especially problematic for patients who are slated for a planned invasive strategy, said Dr. Bhatt.

Dr. Pershad, Dr. Bhatt, and Dr. Kovacs all praised the overall emphasis on a personalized approach to treating patients with antiplatelet and antithrombotic drugs, with endorsement of a flexible approach to treatment intensity and duration. The guideline acknowledges the need to take into account a patient’s bleeding risk and comorbidities, and specifically endorsed the Academic Research Consortium’s formula for identifying and stratifying high bleeding risk (Eur Heart J. 2019 Aug 14;40[31]:2632-53).

The new guidelines also provide guidance on how to apply recent study results that addressed balancing efficacy and safety when pairing an antiplatelet drug with a direct-acting oral anticoagulant (DOAC) for patients who potentially need both drug classes, such as patients with atrial fibrillation and a recent ACS event. “It’s tremendous to get clarity on this issue; there’s been a lot of uncertainty,” said Dr. Pershad. The guidelines call for a week of triple therapy with a DOAC, aspirin, and a second antiplatelet drug, followed by 12 months on a DOAC plus a single antiplatelet drug, and then the DOAC alone as the “default” strategy for most patients, but also presents alternative options for patients with high risk for either bleeding or ischemia.

The new guidelines also give much-needed direction on how to apply an invasive strategy, with an emphasis on immediate intervention for within 2 hours for very-high-risk patients, and early intervention within 24 hours for high-risk patients. Adhering to this timetable can mean increasing catheter laboratory availability on an urgent basis over weekends, Dr. Bhatt noted.
 

Improving quality of care

A novel section in the new guidelines was devoted to nine quality measures that can help health systems and medical centers monitor their adherence to the guideline recommendations, track their performance relative to peer institutions, and follow changes in performance that result from quality improvement steps. It’s something of a “futuristic” step for a guideline to take, with a goal of persuading administrators to implement tracking of these measures and improve patient outcomes, noted Dr. Bhatt.

“It’s very important to see that this is not just a set of guidelines but also a tool to improve quality of care,” commented Dr. Kovacs. The key to success in this effort will be to follow registered patients, set benchmarks that systems can aspire to achieve, and use this to improve the quality of care.

Until now, optimizing care for patients with NSTE-ACS has been “challenging,” he said. “The focus must be on moving toward systems of care” that can provide consistent patient evaluation and care, and do it quickly, said Dr. Kovacs.

Dr. Roffi has received research funding from Biotronik, Boston Scientific, GE Healthcare, and Medtronic. Dr. Kovacs was formerly an employee of Eli Lilly. Dr. Bhatt has been a consultant to and has received research funding from several companies. Dr. Pershad had no disclosures.
 

[email protected]

The first revision since 2015 to the European Society of Cardiology’s guidelines for diagnosing and managing non ST-elevation acute coronary syndrome placed increased reliance on high-sensitivity cardiac troponin testing for diagnosis, and embraced coronary CT to rule out lower-risk patients.

It also highlighted the need for personalized antiplatelet regimens, systems of care, and quality improvement.

The society released the new guidelines on August 29 (Eur Heart J. 2020 Aug 29;doi: 10.1093/eurheartj/ehaa575), and then devoted a session to them the next day at the virtual annual congress of the European Society of Cardiology to highlight some of the key updates, starting with the further emphasis placed on high-sensitivity cardiac troponin (hs-cTn), a reliance that contrasts with what remains inconsistent use of this metric in U.S. practice.

An hs-cTn test is the “preferred” diagnostic test and a “key” testing element, said Marco Roffi, MD, professor and director of interventional cardiology at University Hospital, Geneva, and a member of the guideline committee. He also stressed an update to the time frame of initial hs-cTn testing, which now involves a baseline reading and then a second measure after 2 hours to discern how the marker level is evolving with time. The guidelines advise against measuring any other biomarker of myocardial injury.
 

U.S. lags in measuring high-sensitivity cardiac troponin

U.S. medical systems and centers “are not uniform in adopting hs-cTn,” noted Richard J. Kovacs, MD, professor of cardiology at the Indiana University School of Medicine in Indianapolis. “The new European guidelines should spur U.S. institutions to at least take a close look at the advantages of hs-cTn. There is a strong case that it leads to more efficient emergency care and allows for quicker decisions and triage,” added Dr. Kovacs in an interview.

The new guideline’s emphasis on hs-cTn should hasten broader uptake in U.S. practice, agreed Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston and a member of the guideline-writing panel

Another plus of the guidelines is its endorsement of an “organized approach to risk assessment” early on in these patients, said Dr. Kovacs, who is also the immediate past-president of the American College of Cardiology (ACC). An ACC committee is developing a new set of recommendations for managing patients with cardiac chest pain and is on track for release in 2021. It would represent the first update to U.S. guidelines for non ST-elevation ACS patients since 2014.

The new ESC guidelines give coronary CT angiography a class Ia rating as an alternative to invasive coronary angiography for assessing patients with a low or intermediate risk of having coronary disease, a “tremendous upgrade,” commented Ashish Pershad, MD, an interventional cardiologist at Banner-University Medical Heart Institute in Phoenix. While he welcomes this support for using coronary CT angiography in this setting, he acknowledged that the method remains limited in availability as it requires highly trained technicians to obtain good images and experienced clinicians to interpret the results.

Personalizing antiplatelet and antithrombotic treatments

Notable revisions to medical treatments to minimize ischemia included an admonition not to use routine pretreatment with a P2Y₁₂ receptor inhibitor (such as clopidogrel) before testing determines coronary anatomy.

Not using one of these antiplatelet drugs upfront on all patients “is a tremendous change,” Dr. Pershad said in an interview. Many patients currently get these drugs while awaiting an angiogram, but a more selected and deferred antiplatelet approach would be better when angiography shows that some patients need coronary bypass surgery, he noted. Recent study results have shown no added benefit from pretreatment, and its use can be especially problematic for patients who are slated for a planned invasive strategy, said Dr. Bhatt.

Dr. Pershad, Dr. Bhatt, and Dr. Kovacs all praised the overall emphasis on a personalized approach to treating patients with antiplatelet and antithrombotic drugs, with endorsement of a flexible approach to treatment intensity and duration. The guideline acknowledges the need to take into account a patient’s bleeding risk and comorbidities, and specifically endorsed the Academic Research Consortium’s formula for identifying and stratifying high bleeding risk (Eur Heart J. 2019 Aug 14;40[31]:2632-53).

The new guidelines also provide guidance on how to apply recent study results that addressed balancing efficacy and safety when pairing an antiplatelet drug with a direct-acting oral anticoagulant (DOAC) for patients who potentially need both drug classes, such as patients with atrial fibrillation and a recent ACS event. “It’s tremendous to get clarity on this issue; there’s been a lot of uncertainty,” said Dr. Pershad. The guidelines call for a week of triple therapy with a DOAC, aspirin, and a second antiplatelet drug, followed by 12 months on a DOAC plus a single antiplatelet drug, and then the DOAC alone as the “default” strategy for most patients, but also presents alternative options for patients with high risk for either bleeding or ischemia.

The new guidelines also give much-needed direction on how to apply an invasive strategy, with an emphasis on immediate intervention for within 2 hours for very-high-risk patients, and early intervention within 24 hours for high-risk patients. Adhering to this timetable can mean increasing catheter laboratory availability on an urgent basis over weekends, Dr. Bhatt noted.
 

Improving quality of care

A novel section in the new guidelines was devoted to nine quality measures that can help health systems and medical centers monitor their adherence to the guideline recommendations, track their performance relative to peer institutions, and follow changes in performance that result from quality improvement steps. It’s something of a “futuristic” step for a guideline to take, with a goal of persuading administrators to implement tracking of these measures and improve patient outcomes, noted Dr. Bhatt.

“It’s very important to see that this is not just a set of guidelines but also a tool to improve quality of care,” commented Dr. Kovacs. The key to success in this effort will be to follow registered patients, set benchmarks that systems can aspire to achieve, and use this to improve the quality of care.

Until now, optimizing care for patients with NSTE-ACS has been “challenging,” he said. “The focus must be on moving toward systems of care” that can provide consistent patient evaluation and care, and do it quickly, said Dr. Kovacs.

Dr. Roffi has received research funding from Biotronik, Boston Scientific, GE Healthcare, and Medtronic. Dr. Kovacs was formerly an employee of Eli Lilly. Dr. Bhatt has been a consultant to and has received research funding from several companies. Dr. Pershad had no disclosures.
 

[email protected]

The first revision since 2015 to the European Society of Cardiology’s guidelines for diagnosing and managing non ST-elevation acute coronary syndrome placed increased reliance on high-sensitivity cardiac troponin testing for diagnosis, and embraced coronary CT to rule out lower-risk patients.

It also highlighted the need for personalized antiplatelet regimens, systems of care, and quality improvement.

The society released the new guidelines on August 29 (Eur Heart J. 2020 Aug 29;doi: 10.1093/eurheartj/ehaa575), and then devoted a session to them the next day at the virtual annual congress of the European Society of Cardiology to highlight some of the key updates, starting with the further emphasis placed on high-sensitivity cardiac troponin (hs-cTn), a reliance that contrasts with what remains inconsistent use of this metric in U.S. practice.

An hs-cTn test is the “preferred” diagnostic test and a “key” testing element, said Marco Roffi, MD, professor and director of interventional cardiology at University Hospital, Geneva, and a member of the guideline committee. He also stressed an update to the time frame of initial hs-cTn testing, which now involves a baseline reading and then a second measure after 2 hours to discern how the marker level is evolving with time. The guidelines advise against measuring any other biomarker of myocardial injury.
 

U.S. lags in measuring high-sensitivity cardiac troponin

U.S. medical systems and centers “are not uniform in adopting hs-cTn,” noted Richard J. Kovacs, MD, professor of cardiology at the Indiana University School of Medicine in Indianapolis. “The new European guidelines should spur U.S. institutions to at least take a close look at the advantages of hs-cTn. There is a strong case that it leads to more efficient emergency care and allows for quicker decisions and triage,” added Dr. Kovacs in an interview.

The new guideline’s emphasis on hs-cTn should hasten broader uptake in U.S. practice, agreed Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston and a member of the guideline-writing panel

Another plus of the guidelines is its endorsement of an “organized approach to risk assessment” early on in these patients, said Dr. Kovacs, who is also the immediate past-president of the American College of Cardiology (ACC). An ACC committee is developing a new set of recommendations for managing patients with cardiac chest pain and is on track for release in 2021. It would represent the first update to U.S. guidelines for non ST-elevation ACS patients since 2014.

The new ESC guidelines give coronary CT angiography a class Ia rating as an alternative to invasive coronary angiography for assessing patients with a low or intermediate risk of having coronary disease, a “tremendous upgrade,” commented Ashish Pershad, MD, an interventional cardiologist at Banner-University Medical Heart Institute in Phoenix. While he welcomes this support for using coronary CT angiography in this setting, he acknowledged that the method remains limited in availability as it requires highly trained technicians to obtain good images and experienced clinicians to interpret the results.

Personalizing antiplatelet and antithrombotic treatments

Notable revisions to medical treatments to minimize ischemia included an admonition not to use routine pretreatment with a P2Y₁₂ receptor inhibitor (such as clopidogrel) before testing determines coronary anatomy.

Not using one of these antiplatelet drugs upfront on all patients “is a tremendous change,” Dr. Pershad said in an interview. Many patients currently get these drugs while awaiting an angiogram, but a more selected and deferred antiplatelet approach would be better when angiography shows that some patients need coronary bypass surgery, he noted. Recent study results have shown no added benefit from pretreatment, and its use can be especially problematic for patients who are slated for a planned invasive strategy, said Dr. Bhatt.

Dr. Pershad, Dr. Bhatt, and Dr. Kovacs all praised the overall emphasis on a personalized approach to treating patients with antiplatelet and antithrombotic drugs, with endorsement of a flexible approach to treatment intensity and duration. The guideline acknowledges the need to take into account a patient’s bleeding risk and comorbidities, and specifically endorsed the Academic Research Consortium’s formula for identifying and stratifying high bleeding risk (Eur Heart J. 2019 Aug 14;40[31]:2632-53).

The new guidelines also provide guidance on how to apply recent study results that addressed balancing efficacy and safety when pairing an antiplatelet drug with a direct-acting oral anticoagulant (DOAC) for patients who potentially need both drug classes, such as patients with atrial fibrillation and a recent ACS event. “It’s tremendous to get clarity on this issue; there’s been a lot of uncertainty,” said Dr. Pershad. The guidelines call for a week of triple therapy with a DOAC, aspirin, and a second antiplatelet drug, followed by 12 months on a DOAC plus a single antiplatelet drug, and then the DOAC alone as the “default” strategy for most patients, but also presents alternative options for patients with high risk for either bleeding or ischemia.

The new guidelines also give much-needed direction on how to apply an invasive strategy, with an emphasis on immediate intervention for within 2 hours for very-high-risk patients, and early intervention within 24 hours for high-risk patients. Adhering to this timetable can mean increasing catheter laboratory availability on an urgent basis over weekends, Dr. Bhatt noted.
 

Improving quality of care

A novel section in the new guidelines was devoted to nine quality measures that can help health systems and medical centers monitor their adherence to the guideline recommendations, track their performance relative to peer institutions, and follow changes in performance that result from quality improvement steps. It’s something of a “futuristic” step for a guideline to take, with a goal of persuading administrators to implement tracking of these measures and improve patient outcomes, noted Dr. Bhatt.

“It’s very important to see that this is not just a set of guidelines but also a tool to improve quality of care,” commented Dr. Kovacs. The key to success in this effort will be to follow registered patients, set benchmarks that systems can aspire to achieve, and use this to improve the quality of care.

Until now, optimizing care for patients with NSTE-ACS has been “challenging,” he said. “The focus must be on moving toward systems of care” that can provide consistent patient evaluation and care, and do it quickly, said Dr. Kovacs.

Dr. Roffi has received research funding from Biotronik, Boston Scientific, GE Healthcare, and Medtronic. Dr. Kovacs was formerly an employee of Eli Lilly. Dr. Bhatt has been a consultant to and has received research funding from several companies. Dr. Pershad had no disclosures.
 

[email protected]

Aspirin alone after transcatheter aortic valve implantation (TAVI) significantly reduced bleeding, compared with aspirin plus clopidogrel, without increasing thromboembolic events, in the latest results from the POPular TAVI study.

“Physicians can easily and safely reduce rate of bleeding by omitting clopidogrel after TAVI,” lead author, Jorn Brouwer, MD, St Antonius Hospital, Nieuwegein, the Netherlands, said.

“Aspirin alone should be used in patients undergoing TAVI who are not on oral anticoagulants and have not recently undergone coronary stenting,” he concluded.

Senior author, Jurriën ten Berg, MD, PhD, also from St Antonius Hospital, said in an interview: “I think we can say for TAVI patients, when it comes to antithrombotic therapy, less is definitely more.”

“This is a major change to clinical practice, with current guidelines recommending 3-6 months of dual antiplatelet therapy after a TAVI procedure,” he added. “We expected that these guidelines will change after our results.”

These latest results from POPular TAVI were presented at the virtual European Society of Cardiology Congress 2020 and simultaneously published online in The New England Journal of Medicine.

The trial was conducted in two cohorts of patients undergoing TAVI. The results from cohort B – in patients who were already taking an anticoagulant for another indication – were reported earlier this year and showed no benefit of adding clopidogrel and an increase in bleeding. Now the current results in cohort A – patients undergoing TAVI who do not have an established indication for long-term anticoagulation – show similar results, with aspirin alone preferred over aspirin plus clopidogrel.

Dr. ten Berg explained that the recommendation for dual antiplatelet therapy (DAPT) was adopted mainly because this has been shown to be beneficial in patients undergoing percutaneous coronary intervention (PCI) with stenting; it was thought the same benefits would be seen in TAVI, which also uses a stent-based delivery system.

“However, TAVI patients are a different population – they are generally much older than PCI patients, with an average age of 80 plus, and they have many more comorbidities, so they are much higher bleeding risk,” Dr. ten Berg explained. “In addition, the catheters used for TAVI are larger than those used for PCI, forcing the femoral route to be employed, and both of these factors increases bleeding risk.”

“We saw that, in the trial, patients on dual antiplatelet therapy had a much greater rate of major bleeding and the addition of clopidogrel did not reduce the risk of major thrombotic events,” such as stroke, myocardial infarction (MI), or cardiovascular (CV) death.

Given that the TAVI procedure is associated with an increase in stroke in the immediate few days after the procedure, it would seem logical that increased antiplatelet therapy would be beneficial in reducing this, Dr. ten Berg noted.

“But this is not what we are seeing,” he said. “The stroke incidence was similar in the two groups in POPular TAVI. This suggests that the strokes may not be platelet mediated. They might be caused by another mechanism, such as dislodgement of calcium from the valve or tissue from the aorta.”

For the current part of the study, 690 patients who were undergoing TAVI and did not have an indication for long-term anticoagulation were randomly assigned to receive aspirin alone or aspirin plus clopidogrel for 3 months.

The two primary outcomes were all bleeding (including minor, major, and life-threatening or disabling bleeding) and non–procedure-related bleeding over a period of 12 months. Most bleeding at the TAVI puncture site was counted as not procedure related.

Results showed that a bleeding event occurred in 15.1% of patients receiving aspirin alone and 26.6% of those receiving aspirin plus clopidogrel (risk ratio, 0.57; P = .001). Non–procedure-related bleeding occurred 15.1% of patients receiving aspirin alone vs 24.9% of those receiving aspirin plus clopidogrel (risk ratio, 0.61; P = .005). Major, life-threatening, or disabling bleeding occurred in 5.1% of the aspirin-alone group versus 10.8% of those in the aspirin plus clopidogrel group.

Two secondary outcomes included thromboembolic events. The secondary composite one endpoint of death from cardiovascular causes, non–procedure-related bleeding, stroke, or MI at 1 year occurred in 23.0% of those receiving aspirin alone and in 31.1% of those receiving aspirin plus clopidogrel (difference, −8.2 percentage points; P for noninferiority < .001; risk ratio, 0.74; P for superiority = .04).

The secondary composite two endpoint of death from cardiovascular causes, ischemic stroke, or MI at 1 year occurred in 9.7% of the aspirin-alone group versus 9.9% of the dual-antiplatelet group (difference, −0.2 percentage points; P for noninferiority = .004; risk ratio, 0.98; P for superiority = .93).

Dr. ten Berg pointed out that the trial was not strictly powered to look at thrombotic events, but he added: “There was no hint of an increase in the aspirin-alone group and there was quite a high event rate, so we should have seen something if it was there.”

The group has also performed a meta-analysis of these results, with some previous smaller studies also comparing aspirin and DAPT in TAVI which again showed no reduction in thrombotic events with dual-antiplatelet therapy.

Dr. ten Berg noted that the trial included all-comer TAVI patients. “The overall risk was quite a low [STS score, 2.5]. This is a reflection of the typical TAVI patient we are seeing but I would say our results apply to patients of all risk.”
 

Simplifies and clarifies

Discussant of the trial at the ESC Hotline session, Anna Sonia Petronio, MD, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy, said, “This was an excellent and essential study that simplifies and clarifies aspects of TAVI treatment and needs to change the guidelines.”

“These results will have a large impact on clinical practice in this elderly population,” she said. But she added that more data are needed for younger patients and more complicated cases, such as valve-in-valve and bicuspid valves.

Commenting on the results, Robert Bonow, MD, Northwestern University, Chicago, said, “The optimal antithrombotic management of patients undergoing TAVI who do not otherwise have an indication for anticoagulation [such as atrial fibrillation] has been uncertain and debatable. Aspirin plus clopidogrel for 3-6 months has been the standard, based on the experience with coronary stents.”

“Thus, the current results of cohort A of the POPular TAVI trial showing significant reduction in bleeding events with aspirin alone compared to DAPT for 3 months, with no difference in ischemic events, are important observations,” he said. “It is noteworthy that most of the bleeding events occurred in the first 30 days.

“This is a relatively small randomized trial, so whether these results will be practice changing will depend on confirmation by additional studies, but it is reassuring to know that patients at higher risk for bleeding would appear to do well with low-dose aspirin alone after TAVI,” Dr. Bonow added.

“These results complete the circle in terms of antithrombotic therapy after TAVI,” commented Michael Reardon, MD, Houston Methodist DeBakey Heart & Vascular Institute, Texas.

“I would add two caveats: First is that most of the difference in the primary endpoint occurs in the first month and levels out between the groups after that,” Dr. Reardon said. “Second is that this does not address the issue of leaflet thickening and immobility.”

Ashish Pershad, MD, Banner – University Medicine Heart Institute, Phoenix, added: “This trial answers a very important question and shows dual-antiplatelet therapy is hazardous in TAVI patients. Clopidogrel is not needed.”

Dr. Pershad says he still wonders about patients who receive very small valves who may have a higher risk for valve-induced thrombosis. “While there were some of these patients in the trial, the numbers were small, so we need more data on this group,” he commented.

“But for bread-and-butter TAVI, aspirin alone is the best choice, and the previous results showed, for patients already taking oral anticoagulation, no additional antithrombotic therapy is required,” Dr. Pershad concluded. “This is a big deal and will change the way we treat patients.”

 The POPular trial was supported by the Netherlands Organization for Health Research and Development. Brouwer reports no disclosures.
 

A version of this article originally appeared on Medscape.com.

Aspirin alone after transcatheter aortic valve implantation (TAVI) significantly reduced bleeding, compared with aspirin plus clopidogrel, without increasing thromboembolic events, in the latest results from the POPular TAVI study.

“Physicians can easily and safely reduce rate of bleeding by omitting clopidogrel after TAVI,” lead author, Jorn Brouwer, MD, St Antonius Hospital, Nieuwegein, the Netherlands, said.

“Aspirin alone should be used in patients undergoing TAVI who are not on oral anticoagulants and have not recently undergone coronary stenting,” he concluded.

Senior author, Jurriën ten Berg, MD, PhD, also from St Antonius Hospital, said in an interview: “I think we can say for TAVI patients, when it comes to antithrombotic therapy, less is definitely more.”

“This is a major change to clinical practice, with current guidelines recommending 3-6 months of dual antiplatelet therapy after a TAVI procedure,” he added. “We expected that these guidelines will change after our results.”

These latest results from POPular TAVI were presented at the virtual European Society of Cardiology Congress 2020 and simultaneously published online in The New England Journal of Medicine.

The trial was conducted in two cohorts of patients undergoing TAVI. The results from cohort B – in patients who were already taking an anticoagulant for another indication – were reported earlier this year and showed no benefit of adding clopidogrel and an increase in bleeding. Now the current results in cohort A – patients undergoing TAVI who do not have an established indication for long-term anticoagulation – show similar results, with aspirin alone preferred over aspirin plus clopidogrel.

Dr. ten Berg explained that the recommendation for dual antiplatelet therapy (DAPT) was adopted mainly because this has been shown to be beneficial in patients undergoing percutaneous coronary intervention (PCI) with stenting; it was thought the same benefits would be seen in TAVI, which also uses a stent-based delivery system.

“However, TAVI patients are a different population – they are generally much older than PCI patients, with an average age of 80 plus, and they have many more comorbidities, so they are much higher bleeding risk,” Dr. ten Berg explained. “In addition, the catheters used for TAVI are larger than those used for PCI, forcing the femoral route to be employed, and both of these factors increases bleeding risk.”

“We saw that, in the trial, patients on dual antiplatelet therapy had a much greater rate of major bleeding and the addition of clopidogrel did not reduce the risk of major thrombotic events,” such as stroke, myocardial infarction (MI), or cardiovascular (CV) death.

Given that the TAVI procedure is associated with an increase in stroke in the immediate few days after the procedure, it would seem logical that increased antiplatelet therapy would be beneficial in reducing this, Dr. ten Berg noted.

“But this is not what we are seeing,” he said. “The stroke incidence was similar in the two groups in POPular TAVI. This suggests that the strokes may not be platelet mediated. They might be caused by another mechanism, such as dislodgement of calcium from the valve or tissue from the aorta.”

For the current part of the study, 690 patients who were undergoing TAVI and did not have an indication for long-term anticoagulation were randomly assigned to receive aspirin alone or aspirin plus clopidogrel for 3 months.

The two primary outcomes were all bleeding (including minor, major, and life-threatening or disabling bleeding) and non–procedure-related bleeding over a period of 12 months. Most bleeding at the TAVI puncture site was counted as not procedure related.

Results showed that a bleeding event occurred in 15.1% of patients receiving aspirin alone and 26.6% of those receiving aspirin plus clopidogrel (risk ratio, 0.57; P = .001). Non–procedure-related bleeding occurred 15.1% of patients receiving aspirin alone vs 24.9% of those receiving aspirin plus clopidogrel (risk ratio, 0.61; P = .005). Major, life-threatening, or disabling bleeding occurred in 5.1% of the aspirin-alone group versus 10.8% of those in the aspirin plus clopidogrel group.

Two secondary outcomes included thromboembolic events. The secondary composite one endpoint of death from cardiovascular causes, non–procedure-related bleeding, stroke, or MI at 1 year occurred in 23.0% of those receiving aspirin alone and in 31.1% of those receiving aspirin plus clopidogrel (difference, −8.2 percentage points; P for noninferiority < .001; risk ratio, 0.74; P for superiority = .04).

The secondary composite two endpoint of death from cardiovascular causes, ischemic stroke, or MI at 1 year occurred in 9.7% of the aspirin-alone group versus 9.9% of the dual-antiplatelet group (difference, −0.2 percentage points; P for noninferiority = .004; risk ratio, 0.98; P for superiority = .93).

Dr. ten Berg pointed out that the trial was not strictly powered to look at thrombotic events, but he added: “There was no hint of an increase in the aspirin-alone group and there was quite a high event rate, so we should have seen something if it was there.”

The group has also performed a meta-analysis of these results, with some previous smaller studies also comparing aspirin and DAPT in TAVI which again showed no reduction in thrombotic events with dual-antiplatelet therapy.

Dr. ten Berg noted that the trial included all-comer TAVI patients. “The overall risk was quite a low [STS score, 2.5]. This is a reflection of the typical TAVI patient we are seeing but I would say our results apply to patients of all risk.”
 

Simplifies and clarifies

Discussant of the trial at the ESC Hotline session, Anna Sonia Petronio, MD, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy, said, “This was an excellent and essential study that simplifies and clarifies aspects of TAVI treatment and needs to change the guidelines.”

“These results will have a large impact on clinical practice in this elderly population,” she said. But she added that more data are needed for younger patients and more complicated cases, such as valve-in-valve and bicuspid valves.

Commenting on the results, Robert Bonow, MD, Northwestern University, Chicago, said, “The optimal antithrombotic management of patients undergoing TAVI who do not otherwise have an indication for anticoagulation [such as atrial fibrillation] has been uncertain and debatable. Aspirin plus clopidogrel for 3-6 months has been the standard, based on the experience with coronary stents.”

“Thus, the current results of cohort A of the POPular TAVI trial showing significant reduction in bleeding events with aspirin alone compared to DAPT for 3 months, with no difference in ischemic events, are important observations,” he said. “It is noteworthy that most of the bleeding events occurred in the first 30 days.

“This is a relatively small randomized trial, so whether these results will be practice changing will depend on confirmation by additional studies, but it is reassuring to know that patients at higher risk for bleeding would appear to do well with low-dose aspirin alone after TAVI,” Dr. Bonow added.

“These results complete the circle in terms of antithrombotic therapy after TAVI,” commented Michael Reardon, MD, Houston Methodist DeBakey Heart & Vascular Institute, Texas.

“I would add two caveats: First is that most of the difference in the primary endpoint occurs in the first month and levels out between the groups after that,” Dr. Reardon said. “Second is that this does not address the issue of leaflet thickening and immobility.”

Ashish Pershad, MD, Banner – University Medicine Heart Institute, Phoenix, added: “This trial answers a very important question and shows dual-antiplatelet therapy is hazardous in TAVI patients. Clopidogrel is not needed.”

Dr. Pershad says he still wonders about patients who receive very small valves who may have a higher risk for valve-induced thrombosis. “While there were some of these patients in the trial, the numbers were small, so we need more data on this group,” he commented.

“But for bread-and-butter TAVI, aspirin alone is the best choice, and the previous results showed, for patients already taking oral anticoagulation, no additional antithrombotic therapy is required,” Dr. Pershad concluded. “This is a big deal and will change the way we treat patients.”

 The POPular trial was supported by the Netherlands Organization for Health Research and Development. Brouwer reports no disclosures.
 

A version of this article originally appeared on Medscape.com.

Aspirin alone after transcatheter aortic valve implantation (TAVI) significantly reduced bleeding, compared with aspirin plus clopidogrel, without increasing thromboembolic events, in the latest results from the POPular TAVI study.

“Physicians can easily and safely reduce rate of bleeding by omitting clopidogrel after TAVI,” lead author, Jorn Brouwer, MD, St Antonius Hospital, Nieuwegein, the Netherlands, said.

“Aspirin alone should be used in patients undergoing TAVI who are not on oral anticoagulants and have not recently undergone coronary stenting,” he concluded.

Senior author, Jurriën ten Berg, MD, PhD, also from St Antonius Hospital, said in an interview: “I think we can say for TAVI patients, when it comes to antithrombotic therapy, less is definitely more.”

“This is a major change to clinical practice, with current guidelines recommending 3-6 months of dual antiplatelet therapy after a TAVI procedure,” he added. “We expected that these guidelines will change after our results.”

These latest results from POPular TAVI were presented at the virtual European Society of Cardiology Congress 2020 and simultaneously published online in The New England Journal of Medicine.

The trial was conducted in two cohorts of patients undergoing TAVI. The results from cohort B – in patients who were already taking an anticoagulant for another indication – were reported earlier this year and showed no benefit of adding clopidogrel and an increase in bleeding. Now the current results in cohort A – patients undergoing TAVI who do not have an established indication for long-term anticoagulation – show similar results, with aspirin alone preferred over aspirin plus clopidogrel.

Dr. ten Berg explained that the recommendation for dual antiplatelet therapy (DAPT) was adopted mainly because this has been shown to be beneficial in patients undergoing percutaneous coronary intervention (PCI) with stenting; it was thought the same benefits would be seen in TAVI, which also uses a stent-based delivery system.

“However, TAVI patients are a different population – they are generally much older than PCI patients, with an average age of 80 plus, and they have many more comorbidities, so they are much higher bleeding risk,” Dr. ten Berg explained. “In addition, the catheters used for TAVI are larger than those used for PCI, forcing the femoral route to be employed, and both of these factors increases bleeding risk.”

“We saw that, in the trial, patients on dual antiplatelet therapy had a much greater rate of major bleeding and the addition of clopidogrel did not reduce the risk of major thrombotic events,” such as stroke, myocardial infarction (MI), or cardiovascular (CV) death.

Given that the TAVI procedure is associated with an increase in stroke in the immediate few days after the procedure, it would seem logical that increased antiplatelet therapy would be beneficial in reducing this, Dr. ten Berg noted.

“But this is not what we are seeing,” he said. “The stroke incidence was similar in the two groups in POPular TAVI. This suggests that the strokes may not be platelet mediated. They might be caused by another mechanism, such as dislodgement of calcium from the valve or tissue from the aorta.”

For the current part of the study, 690 patients who were undergoing TAVI and did not have an indication for long-term anticoagulation were randomly assigned to receive aspirin alone or aspirin plus clopidogrel for 3 months.

The two primary outcomes were all bleeding (including minor, major, and life-threatening or disabling bleeding) and non–procedure-related bleeding over a period of 12 months. Most bleeding at the TAVI puncture site was counted as not procedure related.

Results showed that a bleeding event occurred in 15.1% of patients receiving aspirin alone and 26.6% of those receiving aspirin plus clopidogrel (risk ratio, 0.57; P = .001). Non–procedure-related bleeding occurred 15.1% of patients receiving aspirin alone vs 24.9% of those receiving aspirin plus clopidogrel (risk ratio, 0.61; P = .005). Major, life-threatening, or disabling bleeding occurred in 5.1% of the aspirin-alone group versus 10.8% of those in the aspirin plus clopidogrel group.

Two secondary outcomes included thromboembolic events. The secondary composite one endpoint of death from cardiovascular causes, non–procedure-related bleeding, stroke, or MI at 1 year occurred in 23.0% of those receiving aspirin alone and in 31.1% of those receiving aspirin plus clopidogrel (difference, −8.2 percentage points; P for noninferiority < .001; risk ratio, 0.74; P for superiority = .04).

The secondary composite two endpoint of death from cardiovascular causes, ischemic stroke, or MI at 1 year occurred in 9.7% of the aspirin-alone group versus 9.9% of the dual-antiplatelet group (difference, −0.2 percentage points; P for noninferiority = .004; risk ratio, 0.98; P for superiority = .93).

Dr. ten Berg pointed out that the trial was not strictly powered to look at thrombotic events, but he added: “There was no hint of an increase in the aspirin-alone group and there was quite a high event rate, so we should have seen something if it was there.”

The group has also performed a meta-analysis of these results, with some previous smaller studies also comparing aspirin and DAPT in TAVI which again showed no reduction in thrombotic events with dual-antiplatelet therapy.

Dr. ten Berg noted that the trial included all-comer TAVI patients. “The overall risk was quite a low [STS score, 2.5]. This is a reflection of the typical TAVI patient we are seeing but I would say our results apply to patients of all risk.”
 

Simplifies and clarifies

Discussant of the trial at the ESC Hotline session, Anna Sonia Petronio, MD, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy, said, “This was an excellent and essential study that simplifies and clarifies aspects of TAVI treatment and needs to change the guidelines.”

“These results will have a large impact on clinical practice in this elderly population,” she said. But she added that more data are needed for younger patients and more complicated cases, such as valve-in-valve and bicuspid valves.

Commenting on the results, Robert Bonow, MD, Northwestern University, Chicago, said, “The optimal antithrombotic management of patients undergoing TAVI who do not otherwise have an indication for anticoagulation [such as atrial fibrillation] has been uncertain and debatable. Aspirin plus clopidogrel for 3-6 months has been the standard, based on the experience with coronary stents.”

“Thus, the current results of cohort A of the POPular TAVI trial showing significant reduction in bleeding events with aspirin alone compared to DAPT for 3 months, with no difference in ischemic events, are important observations,” he said. “It is noteworthy that most of the bleeding events occurred in the first 30 days.

“This is a relatively small randomized trial, so whether these results will be practice changing will depend on confirmation by additional studies, but it is reassuring to know that patients at higher risk for bleeding would appear to do well with low-dose aspirin alone after TAVI,” Dr. Bonow added.

“These results complete the circle in terms of antithrombotic therapy after TAVI,” commented Michael Reardon, MD, Houston Methodist DeBakey Heart & Vascular Institute, Texas.

“I would add two caveats: First is that most of the difference in the primary endpoint occurs in the first month and levels out between the groups after that,” Dr. Reardon said. “Second is that this does not address the issue of leaflet thickening and immobility.”

Ashish Pershad, MD, Banner – University Medicine Heart Institute, Phoenix, added: “This trial answers a very important question and shows dual-antiplatelet therapy is hazardous in TAVI patients. Clopidogrel is not needed.”

Dr. Pershad says he still wonders about patients who receive very small valves who may have a higher risk for valve-induced thrombosis. “While there were some of these patients in the trial, the numbers were small, so we need more data on this group,” he commented.

“But for bread-and-butter TAVI, aspirin alone is the best choice, and the previous results showed, for patients already taking oral anticoagulation, no additional antithrombotic therapy is required,” Dr. Pershad concluded. “This is a big deal and will change the way we treat patients.”

 The POPular trial was supported by the Netherlands Organization for Health Research and Development. Brouwer reports no disclosures.
 

A version of this article originally appeared on Medscape.com.