Venous Thromboembolism

A new study may help doctors assess the long-term risk for major bleeding if anticoagulation for unprovoked venous thromboembolisms (VTE) is continued beyond 3-6 months.

The meta-analysis of data from 27 studies with 17,202 patients was published in the Annals of Internal Medicine. According to two of the paper’s coauthors, Faizan Khan, MSc, and Marc A. Rodger, MD, it “provides best available estimates of long-term bleeding risk with different anticoagulants in patients with unprovoked VTE,” including subgroups at increased risk.

Patients at increased risk for major bleeding include those who are older; those using antiplatelet therapy; and patients with kidney disease, a history of bleeding, or anemia, noted the coauthors, who work for the Ottawa Hospital Research Institute.

The researchers focused on randomized controlled trials (RCTs) and prospective cohort studies that reported major bleeding among patients with a first unprovoked or weakly provoked VTE who received oral anticoagulation for at least 6 months beyond an initial anticoagulant treatment course of at least 3 months.

The investigators analyzed data from 14 RCTs and 13 cohort studies. In all, 9,982 patients received a vitamin K antagonist (VKA), and 7,220 received a direct oral anticoagulant (DOAC).

The incidence of major bleeding per 100 person-years was 1.7 events with VKAs, compared with 1.1 events with DOACs. The researchers estimated that the 5-year cumulative incidence of major bleeding with VKAs was 6.3%. The available data for DOACs were insufficient to estimate the incidence of major bleeding beyond 1 year.

“This information can help clinicians counsel patients and inform shared decision-making about extended therapy,” the researchers said.

Risks of serious bleeding ‘not trivial’

Margaret Fang, MD, with the University of California, San Francisco, agreed that the study can help clinicians and patients weigh the risks of extended anticoagulation for common types of VTE.

The study also “highlights that the risks of serious bleeding are not trivial” and points out gaps in the literature regarding the long-term use of DOACs for extended VTE therapy, Dr. Fang said.

Better ways to predict which patients will develop bleeding on anticoagulants are needed, Dr. Fang added. “It will also be important to establish which of the various therapies for preventing recurrent VTE – full dose versus lowered dose, or even aspirin – has the best balance of safety and efficacy,” she said.

‘Standardized approach’ for identifying high-risk patients lacking

Clinical practice guidelines recommend indefinite anticoagulation for an unprovoked VTE, except when patients are at high risk of bleeding, the authors noted. But clinicians lack a “standardized approach to identify patients at high risk of bleeding,” Mr. Khan and Dr. Rodger said. “Evidence from randomized trials on net long-term benefit of extended therapy is limited, and current guideline recommendations are largely based on expert consensus opinion. Major bleeding events are two to three times more likely to be fatal than recurrent VTE events, so extended therapy is not always associated with a net mortality benefit, particularly in patients at low risk of recurrent VTE or high risk of bleeding.”

The analysis indicates that there is “a clinically meaningful difference in long-term risk for anticoagulant-related major bleeding among patients with a first unprovoked VTE stratified according to presence or absence of the following risk factors: age older than 65 years, creatinine clearance less than 50 mL/min, history of bleeding, concomitant use of antiplatelet therapy, and hemoglobin level less than 100 g/L,” the authors said.

For example, the researchers found that the incidence of major bleeding was higher among those older than 65 years, compared with younger patients (incidence rate ratio, 1.84 with VKAs and 2.92 with DOACs), and among those with creatinine clearance less than 50 mL/min (IRR, 2.83 with VKAs and 3.71 with DOACs).

The case-fatality rate of major bleeding was 8.3% with VKAs and 9.7% with DOACs.

The study received funding from the Canadian Institutes of Health Research. Some of the coauthors are employees of or have financial ties to pharmaceutical companies. Mr. Khan, Dr. Rodger, and Dr. Fang had no relevant disclosures.

jremaly@mdedge.com

A new study may help doctors assess the long-term risk for major bleeding if anticoagulation for unprovoked venous thromboembolisms (VTE) is continued beyond 3-6 months.

The meta-analysis of data from 27 studies with 17,202 patients was published in the Annals of Internal Medicine. According to two of the paper’s coauthors, Faizan Khan, MSc, and Marc A. Rodger, MD, it “provides best available estimates of long-term bleeding risk with different anticoagulants in patients with unprovoked VTE,” including subgroups at increased risk.

Patients at increased risk for major bleeding include those who are older; those using antiplatelet therapy; and patients with kidney disease, a history of bleeding, or anemia, noted the coauthors, who work for the Ottawa Hospital Research Institute.

The researchers focused on randomized controlled trials (RCTs) and prospective cohort studies that reported major bleeding among patients with a first unprovoked or weakly provoked VTE who received oral anticoagulation for at least 6 months beyond an initial anticoagulant treatment course of at least 3 months.

The investigators analyzed data from 14 RCTs and 13 cohort studies. In all, 9,982 patients received a vitamin K antagonist (VKA), and 7,220 received a direct oral anticoagulant (DOAC).

The incidence of major bleeding per 100 person-years was 1.7 events with VKAs, compared with 1.1 events with DOACs. The researchers estimated that the 5-year cumulative incidence of major bleeding with VKAs was 6.3%. The available data for DOACs were insufficient to estimate the incidence of major bleeding beyond 1 year.

“This information can help clinicians counsel patients and inform shared decision-making about extended therapy,” the researchers said.

Risks of serious bleeding ‘not trivial’

Margaret Fang, MD, with the University of California, San Francisco, agreed that the study can help clinicians and patients weigh the risks of extended anticoagulation for common types of VTE.

The study also “highlights that the risks of serious bleeding are not trivial” and points out gaps in the literature regarding the long-term use of DOACs for extended VTE therapy, Dr. Fang said.

Better ways to predict which patients will develop bleeding on anticoagulants are needed, Dr. Fang added. “It will also be important to establish which of the various therapies for preventing recurrent VTE – full dose versus lowered dose, or even aspirin – has the best balance of safety and efficacy,” she said.

‘Standardized approach’ for identifying high-risk patients lacking

Clinical practice guidelines recommend indefinite anticoagulation for an unprovoked VTE, except when patients are at high risk of bleeding, the authors noted. But clinicians lack a “standardized approach to identify patients at high risk of bleeding,” Mr. Khan and Dr. Rodger said. “Evidence from randomized trials on net long-term benefit of extended therapy is limited, and current guideline recommendations are largely based on expert consensus opinion. Major bleeding events are two to three times more likely to be fatal than recurrent VTE events, so extended therapy is not always associated with a net mortality benefit, particularly in patients at low risk of recurrent VTE or high risk of bleeding.”

The analysis indicates that there is “a clinically meaningful difference in long-term risk for anticoagulant-related major bleeding among patients with a first unprovoked VTE stratified according to presence or absence of the following risk factors: age older than 65 years, creatinine clearance less than 50 mL/min, history of bleeding, concomitant use of antiplatelet therapy, and hemoglobin level less than 100 g/L,” the authors said.

For example, the researchers found that the incidence of major bleeding was higher among those older than 65 years, compared with younger patients (incidence rate ratio, 1.84 with VKAs and 2.92 with DOACs), and among those with creatinine clearance less than 50 mL/min (IRR, 2.83 with VKAs and 3.71 with DOACs).

The case-fatality rate of major bleeding was 8.3% with VKAs and 9.7% with DOACs.

The study received funding from the Canadian Institutes of Health Research. Some of the coauthors are employees of or have financial ties to pharmaceutical companies. Mr. Khan, Dr. Rodger, and Dr. Fang had no relevant disclosures.

jremaly@mdedge.com

A new study may help doctors assess the long-term risk for major bleeding if anticoagulation for unprovoked venous thromboembolisms (VTE) is continued beyond 3-6 months.

The meta-analysis of data from 27 studies with 17,202 patients was published in the Annals of Internal Medicine. According to two of the paper’s coauthors, Faizan Khan, MSc, and Marc A. Rodger, MD, it “provides best available estimates of long-term bleeding risk with different anticoagulants in patients with unprovoked VTE,” including subgroups at increased risk.

Patients at increased risk for major bleeding include those who are older; those using antiplatelet therapy; and patients with kidney disease, a history of bleeding, or anemia, noted the coauthors, who work for the Ottawa Hospital Research Institute.

The researchers focused on randomized controlled trials (RCTs) and prospective cohort studies that reported major bleeding among patients with a first unprovoked or weakly provoked VTE who received oral anticoagulation for at least 6 months beyond an initial anticoagulant treatment course of at least 3 months.

The investigators analyzed data from 14 RCTs and 13 cohort studies. In all, 9,982 patients received a vitamin K antagonist (VKA), and 7,220 received a direct oral anticoagulant (DOAC).

The incidence of major bleeding per 100 person-years was 1.7 events with VKAs, compared with 1.1 events with DOACs. The researchers estimated that the 5-year cumulative incidence of major bleeding with VKAs was 6.3%. The available data for DOACs were insufficient to estimate the incidence of major bleeding beyond 1 year.

“This information can help clinicians counsel patients and inform shared decision-making about extended therapy,” the researchers said.

Risks of serious bleeding ‘not trivial’

Margaret Fang, MD, with the University of California, San Francisco, agreed that the study can help clinicians and patients weigh the risks of extended anticoagulation for common types of VTE.

The study also “highlights that the risks of serious bleeding are not trivial” and points out gaps in the literature regarding the long-term use of DOACs for extended VTE therapy, Dr. Fang said.

Better ways to predict which patients will develop bleeding on anticoagulants are needed, Dr. Fang added. “It will also be important to establish which of the various therapies for preventing recurrent VTE – full dose versus lowered dose, or even aspirin – has the best balance of safety and efficacy,” she said.

‘Standardized approach’ for identifying high-risk patients lacking

Clinical practice guidelines recommend indefinite anticoagulation for an unprovoked VTE, except when patients are at high risk of bleeding, the authors noted. But clinicians lack a “standardized approach to identify patients at high risk of bleeding,” Mr. Khan and Dr. Rodger said. “Evidence from randomized trials on net long-term benefit of extended therapy is limited, and current guideline recommendations are largely based on expert consensus opinion. Major bleeding events are two to three times more likely to be fatal than recurrent VTE events, so extended therapy is not always associated with a net mortality benefit, particularly in patients at low risk of recurrent VTE or high risk of bleeding.”

The analysis indicates that there is “a clinically meaningful difference in long-term risk for anticoagulant-related major bleeding among patients with a first unprovoked VTE stratified according to presence or absence of the following risk factors: age older than 65 years, creatinine clearance less than 50 mL/min, history of bleeding, concomitant use of antiplatelet therapy, and hemoglobin level less than 100 g/L,” the authors said.

For example, the researchers found that the incidence of major bleeding was higher among those older than 65 years, compared with younger patients (incidence rate ratio, 1.84 with VKAs and 2.92 with DOACs), and among those with creatinine clearance less than 50 mL/min (IRR, 2.83 with VKAs and 3.71 with DOACs).

The case-fatality rate of major bleeding was 8.3% with VKAs and 9.7% with DOACs.

The study received funding from the Canadian Institutes of Health Research. Some of the coauthors are employees of or have financial ties to pharmaceutical companies. Mr. Khan, Dr. Rodger, and Dr. Fang had no relevant disclosures.

jremaly@mdedge.com

Prophylactic anticoagulation to prevent venous thromboembolism (VTE) was associated with reduced 60-day mortality in patients with COVID-19 who were ill enough to require hospitalization, a new report shows.

In a cohort study of more than 1,300 hospitalized patients with COVID-19 infection across 30 hospitals in Michigan, both prophylactic- and therapeutic-dose anticoagulation were associated with reduced in-hospital mortality; however, at 60 days, only prophylactic-dose anticoagulation remained associated with lower mortality.

And adherence was key; nonadherence, or missing 2 days or more of anticoagulation, was linked to more deaths at 60 days.

The findings, which were published online June 11 in JAMA Network Open, are final proof that a prophylactic anticoagulation strategy for the hospitalized COVID population is, indeed, the right one, Valerie M. Vaughn, MD, director of hospital medicine research at the University of Utah, Salt Lake City, said in an interview.

“We’ve probably always known that patients with COVID need prophylaxis for VTE, but we found that early on, unfortunately, that wasn’t being done,” Dr. Vaughn said.

“Now, we see that prophylactic rates have increased. We always knew to use anticoagulation prophylactically in patients who were hospitalized with infection because of their risk for VTE, so this study just drives home that proper adherence to an anticoagulation protocol improves mortality,” she said.

Dr. Vaughn was on the front lines when COVID-19 came to Michigan, where the research was conducted.

“We probably should have been anticoagulating from the get-go, but you have to remember that in the early days of COVID, the hospitals in Michigan were being overwhelmed. They didn’t have PPE. They were taking care of patients outside of their typical hospital beds or setting up field hospitals,” she said. “It was not quite as bad as New York, but at the University of Michigan, we set up four or five ICUs outside of our normal care.”

They also converted the top floor of their pediatric hospital into an ICU to take care of patients with COVID during the first surge, she added. “We didn’t know much about this disease, but faced with this influx of patients, many of whom were dying with blood clots, we had to do something.”  

Some hospitals began prophylactically anticoagulating their patients, but others hesitated before adopting the strategy. “But now we feel confident that prophylactic anticoagulation, done according to the right protocol, with no interruptions in the treatment, is beneficial,” Dr. Vaughn said.

The best medication choice is enoxaparin (Lovenox), which can be given once a day, as opposed to heparin, which needs to be given via injection three times a day, she said.

“Prophylactic dose anticoagulation is typically given by an injection under the skin, but a lot of times, I’ve had patients tell me they feel like a human pin cushion and have all these bruises from being stuck with needles every day, which I can totally relate to,” she said.

“It is important for us as clinicians to explain that we’re having to poke our patients because it is good for them and will help them fight COVID,” she added. “Also having the once-a-day option is going to be a lot better for adherence, and adherence to the protocol, not missing any days, is key to the better outcome.”

Dr. Vaughn and her team reviewed the charts of 1,351 patients (48% women, 49% Black, median age 64 [range 52-75]) who were hospitalized throughout Michigan during the first several months of the COVID-19 pandemic, from March to June 2020.

Only 18 patients (1.3%) had a confirmed VTE and 219 patients (16.2%) received treatment-dose anticoagulation.

The researchers noted that use of treatment-dose anticoagulation without imaging ranged from 0% to 29% across hospitals and increased significantly over time.

Of the 1,127 patients who received anticoagulation, 392 (34.8%) missed 2 days or more of prophylaxis.

In addition, there were varying rates of missed prophylaxis among the hospitals, from 11% to 61%, but these rates decreased markedly over time.

Missed doses were associated with a higher 60-day mortality (adjusted hazard ratio, 1.31; 95% confidence interval, 1.03-1.67), but not in-hospital mortality (aHR, 0.97; 95% CI, 0.91-1.03).

Compared with no anticoagulation, receiving any dose of anticoagulation was associated with lower in-hospital mortality.

However, only prophylactic-dose anticoagulation remained associated with lower mortality at 60 days. The adjusted hazard ratio for prophylactic-dose anticoagulation was 0.71 (95% CI, 0.51-0.90), compared with 0.92 (95% CI, 0.63-1.35) for treatment-dose anticoagulation.
 

Study boosts confidence

Despite its limitations, the study should make clinicians more confident that the use of prophylactic anticoagulation is warranted for hospitalized patients with COVID-19, write Andrew B. Dicks, MD, and Ido Weinberg, MD, from Massachusetts General Hospital, Boston, in an invited commentary.

“Practically, we still lack the granular data we need to help guide us in patient-by-patient decision-making – such as anticoagulation agent choice, dosage, and duration of therapy – especially as dictated by acuity of patient illness,” Dr. Dicks and Dr. Weinberg note.

“While we still await the data from randomized controlled trials to guide the optimal anticoagulation dose and duration, this study adds significant merit to the previously published recommendations from several different medical organizations regarding the use of prophylactic anticoagulation in hospitalized patients with COVID-19,” Dr. Dicks told this news organization.

The study was supported by Blue Cross and Blue Shield of Michigan and Blue Care Network as part of their Value Partnerships program. Dr. Vaughn has reported receiving speaking fees from Thermo Fisher Scientific. Dr. Dicks and Dr. Weinberg have reported no relevant financial relationships.

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

Prophylactic anticoagulation to prevent venous thromboembolism (VTE) was associated with reduced 60-day mortality in patients with COVID-19 who were ill enough to require hospitalization, a new report shows.

In a cohort study of more than 1,300 hospitalized patients with COVID-19 infection across 30 hospitals in Michigan, both prophylactic- and therapeutic-dose anticoagulation were associated with reduced in-hospital mortality; however, at 60 days, only prophylactic-dose anticoagulation remained associated with lower mortality.

And adherence was key; nonadherence, or missing 2 days or more of anticoagulation, was linked to more deaths at 60 days.

The findings, which were published online June 11 in JAMA Network Open, are final proof that a prophylactic anticoagulation strategy for the hospitalized COVID population is, indeed, the right one, Valerie M. Vaughn, MD, director of hospital medicine research at the University of Utah, Salt Lake City, said in an interview.

“We’ve probably always known that patients with COVID need prophylaxis for VTE, but we found that early on, unfortunately, that wasn’t being done,” Dr. Vaughn said.

“Now, we see that prophylactic rates have increased. We always knew to use anticoagulation prophylactically in patients who were hospitalized with infection because of their risk for VTE, so this study just drives home that proper adherence to an anticoagulation protocol improves mortality,” she said.

Dr. Vaughn was on the front lines when COVID-19 came to Michigan, where the research was conducted.

“We probably should have been anticoagulating from the get-go, but you have to remember that in the early days of COVID, the hospitals in Michigan were being overwhelmed. They didn’t have PPE. They were taking care of patients outside of their typical hospital beds or setting up field hospitals,” she said. “It was not quite as bad as New York, but at the University of Michigan, we set up four or five ICUs outside of our normal care.”

They also converted the top floor of their pediatric hospital into an ICU to take care of patients with COVID during the first surge, she added. “We didn’t know much about this disease, but faced with this influx of patients, many of whom were dying with blood clots, we had to do something.”  

Some hospitals began prophylactically anticoagulating their patients, but others hesitated before adopting the strategy. “But now we feel confident that prophylactic anticoagulation, done according to the right protocol, with no interruptions in the treatment, is beneficial,” Dr. Vaughn said.

The best medication choice is enoxaparin (Lovenox), which can be given once a day, as opposed to heparin, which needs to be given via injection three times a day, she said.

“Prophylactic dose anticoagulation is typically given by an injection under the skin, but a lot of times, I’ve had patients tell me they feel like a human pin cushion and have all these bruises from being stuck with needles every day, which I can totally relate to,” she said.

“It is important for us as clinicians to explain that we’re having to poke our patients because it is good for them and will help them fight COVID,” she added. “Also having the once-a-day option is going to be a lot better for adherence, and adherence to the protocol, not missing any days, is key to the better outcome.”

Dr. Vaughn and her team reviewed the charts of 1,351 patients (48% women, 49% Black, median age 64 [range 52-75]) who were hospitalized throughout Michigan during the first several months of the COVID-19 pandemic, from March to June 2020.

Only 18 patients (1.3%) had a confirmed VTE and 219 patients (16.2%) received treatment-dose anticoagulation.

The researchers noted that use of treatment-dose anticoagulation without imaging ranged from 0% to 29% across hospitals and increased significantly over time.

Of the 1,127 patients who received anticoagulation, 392 (34.8%) missed 2 days or more of prophylaxis.

In addition, there were varying rates of missed prophylaxis among the hospitals, from 11% to 61%, but these rates decreased markedly over time.

Missed doses were associated with a higher 60-day mortality (adjusted hazard ratio, 1.31; 95% confidence interval, 1.03-1.67), but not in-hospital mortality (aHR, 0.97; 95% CI, 0.91-1.03).

Compared with no anticoagulation, receiving any dose of anticoagulation was associated with lower in-hospital mortality.

However, only prophylactic-dose anticoagulation remained associated with lower mortality at 60 days. The adjusted hazard ratio for prophylactic-dose anticoagulation was 0.71 (95% CI, 0.51-0.90), compared with 0.92 (95% CI, 0.63-1.35) for treatment-dose anticoagulation.
 

Study boosts confidence

Despite its limitations, the study should make clinicians more confident that the use of prophylactic anticoagulation is warranted for hospitalized patients with COVID-19, write Andrew B. Dicks, MD, and Ido Weinberg, MD, from Massachusetts General Hospital, Boston, in an invited commentary.

“Practically, we still lack the granular data we need to help guide us in patient-by-patient decision-making – such as anticoagulation agent choice, dosage, and duration of therapy – especially as dictated by acuity of patient illness,” Dr. Dicks and Dr. Weinberg note.

“While we still await the data from randomized controlled trials to guide the optimal anticoagulation dose and duration, this study adds significant merit to the previously published recommendations from several different medical organizations regarding the use of prophylactic anticoagulation in hospitalized patients with COVID-19,” Dr. Dicks told this news organization.

The study was supported by Blue Cross and Blue Shield of Michigan and Blue Care Network as part of their Value Partnerships program. Dr. Vaughn has reported receiving speaking fees from Thermo Fisher Scientific. Dr. Dicks and Dr. Weinberg have reported no relevant financial relationships.

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

Prophylactic anticoagulation to prevent venous thromboembolism (VTE) was associated with reduced 60-day mortality in patients with COVID-19 who were ill enough to require hospitalization, a new report shows.

In a cohort study of more than 1,300 hospitalized patients with COVID-19 infection across 30 hospitals in Michigan, both prophylactic- and therapeutic-dose anticoagulation were associated with reduced in-hospital mortality; however, at 60 days, only prophylactic-dose anticoagulation remained associated with lower mortality.

And adherence was key; nonadherence, or missing 2 days or more of anticoagulation, was linked to more deaths at 60 days.

The findings, which were published online June 11 in JAMA Network Open, are final proof that a prophylactic anticoagulation strategy for the hospitalized COVID population is, indeed, the right one, Valerie M. Vaughn, MD, director of hospital medicine research at the University of Utah, Salt Lake City, said in an interview.

“We’ve probably always known that patients with COVID need prophylaxis for VTE, but we found that early on, unfortunately, that wasn’t being done,” Dr. Vaughn said.

“Now, we see that prophylactic rates have increased. We always knew to use anticoagulation prophylactically in patients who were hospitalized with infection because of their risk for VTE, so this study just drives home that proper adherence to an anticoagulation protocol improves mortality,” she said.

Dr. Vaughn was on the front lines when COVID-19 came to Michigan, where the research was conducted.

“We probably should have been anticoagulating from the get-go, but you have to remember that in the early days of COVID, the hospitals in Michigan were being overwhelmed. They didn’t have PPE. They were taking care of patients outside of their typical hospital beds or setting up field hospitals,” she said. “It was not quite as bad as New York, but at the University of Michigan, we set up four or five ICUs outside of our normal care.”

They also converted the top floor of their pediatric hospital into an ICU to take care of patients with COVID during the first surge, she added. “We didn’t know much about this disease, but faced with this influx of patients, many of whom were dying with blood clots, we had to do something.”  

Some hospitals began prophylactically anticoagulating their patients, but others hesitated before adopting the strategy. “But now we feel confident that prophylactic anticoagulation, done according to the right protocol, with no interruptions in the treatment, is beneficial,” Dr. Vaughn said.

The best medication choice is enoxaparin (Lovenox), which can be given once a day, as opposed to heparin, which needs to be given via injection three times a day, she said.

“Prophylactic dose anticoagulation is typically given by an injection under the skin, but a lot of times, I’ve had patients tell me they feel like a human pin cushion and have all these bruises from being stuck with needles every day, which I can totally relate to,” she said.

“It is important for us as clinicians to explain that we’re having to poke our patients because it is good for them and will help them fight COVID,” she added. “Also having the once-a-day option is going to be a lot better for adherence, and adherence to the protocol, not missing any days, is key to the better outcome.”

Dr. Vaughn and her team reviewed the charts of 1,351 patients (48% women, 49% Black, median age 64 [range 52-75]) who were hospitalized throughout Michigan during the first several months of the COVID-19 pandemic, from March to June 2020.

Only 18 patients (1.3%) had a confirmed VTE and 219 patients (16.2%) received treatment-dose anticoagulation.

The researchers noted that use of treatment-dose anticoagulation without imaging ranged from 0% to 29% across hospitals and increased significantly over time.

Of the 1,127 patients who received anticoagulation, 392 (34.8%) missed 2 days or more of prophylaxis.

In addition, there were varying rates of missed prophylaxis among the hospitals, from 11% to 61%, but these rates decreased markedly over time.

Missed doses were associated with a higher 60-day mortality (adjusted hazard ratio, 1.31; 95% confidence interval, 1.03-1.67), but not in-hospital mortality (aHR, 0.97; 95% CI, 0.91-1.03).

Compared with no anticoagulation, receiving any dose of anticoagulation was associated with lower in-hospital mortality.

However, only prophylactic-dose anticoagulation remained associated with lower mortality at 60 days. The adjusted hazard ratio for prophylactic-dose anticoagulation was 0.71 (95% CI, 0.51-0.90), compared with 0.92 (95% CI, 0.63-1.35) for treatment-dose anticoagulation.
 

Study boosts confidence

Despite its limitations, the study should make clinicians more confident that the use of prophylactic anticoagulation is warranted for hospitalized patients with COVID-19, write Andrew B. Dicks, MD, and Ido Weinberg, MD, from Massachusetts General Hospital, Boston, in an invited commentary.

“Practically, we still lack the granular data we need to help guide us in patient-by-patient decision-making – such as anticoagulation agent choice, dosage, and duration of therapy – especially as dictated by acuity of patient illness,” Dr. Dicks and Dr. Weinberg note.

“While we still await the data from randomized controlled trials to guide the optimal anticoagulation dose and duration, this study adds significant merit to the previously published recommendations from several different medical organizations regarding the use of prophylactic anticoagulation in hospitalized patients with COVID-19,” Dr. Dicks told this news organization.

The study was supported by Blue Cross and Blue Shield of Michigan and Blue Care Network as part of their Value Partnerships program. Dr. Vaughn has reported receiving speaking fees from Thermo Fisher Scientific. Dr. Dicks and Dr. Weinberg have reported no relevant financial relationships.

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

The incidence of venous thromboembolism (VTE) in nonhospitalized patients with COVID-19 was not significantly different from patients without the infectious disease, according to a new study published in JAMA Internal Medicine.

Design Cells/Getty Images

National Institutes of Health guidelines recommend blood thinners to prevent blood clots in patients hospitalized with COVID-19. However, the new study provides more insight on the best treatment approach for COVID-19 outpatients.

“[COVID-19’s] rapid global progression and impact has caused us to make and modify treatment decisions at a pace that we never have in modern medicine,” study author Nareg Roubinian, MD, an investigator at Kaiser Permanente, Oakland, Calif., said in an interview.

“As with other potential therapies for COVID-19, blood thinners need to be prospectively studied in a clinical trial to determine if they improve patient outcomes,” Dr. Roubinian added.

The increased risk of blood clots in patients hospitalized with COVID-19 has been a major issue throughout the pandemic. In fact, one study published in November 2020 found that more than half of patients hospitalized with the illness have prothrombotic antiphospholipid (aPL) autoantibodies in their blood, which could contribute to venous and arterial thromboembolism.

Although it was clear many hospitalized patients diagnosed with COVID-19 were developing more clots, researchers of the current study were not sure if this trend would also be seen in outpatients.

“Most people with COVID-19 do not need to be hospitalized, and we needed to know how often patients outside the hospital were having blood clots,” said Dr. Roubinian.

For the study, Dr. Roubinian and colleagues examined data on 220,588 patients who were members of Kaiser Permanente Northern California health plan and were tested for COVID-19 between Feb. 25 and Aug. 31, 2020. They then reported on the 30-day incidence of outpatient and hospital-associated blood clots following the COVID-19 diagnosis. Patients who were asymptomatic at the time of testing or had received anticoagulants within the last year were excluded.

“We knew from other studies that patients with COVID-19 often get sicker in the first few weeks after infection. What we didn’t know was whether COVID-19 patients were developing blood clots but not pneumonia or were developing blood clots at the same time as they developed pneumonia,” said Dr. Roubinian, an intensive care doctor with the Permanente Medical Group in Oakland, Calif. “Following the patients for 30 days allowed us to focus on the time period from infection to when blood clots were most likely to develop.”

Researchers found that of the cohort who took the COVID-19 test, 11.8% had a positive result. Within 30 days of the COVID-19 test, 0.8% of patients with a positive result were diagnosed with VTE compared to 0.5% of those who received a negative test result. They also found that viral testing took place in an outpatient setting for 59.1% of the patients with a positive viral test who later developed VTE. Of those patients, 76.1% had to be hospitalized.

Dr. Roubinian said he was surprised to see that the blood clotting in outpatients with COVID-19 was similar in frequency to what he saw in patients without the infection.

“Our findings suggest that blood clots do occur in COVID-19 patients but not on a scale where we need to put all or many COVID outpatients on blood thinners,” he said. “As with other potential therapies for COVID-19, blood thinners need to be prospectively studied in a clinical trial to determine if they improve patient outcomes.”

In December 2020, three trials investigating the risk and benefits of increased levels of anticoagulation in hospitalized COVID-19 patients were paused because of safety issues. The trials would have enrolled critically ill COVID-19 patients for whom therapeutic doses of anticoagulation drugs showed no benefit.

Anticoagulants are associated with bleeding risks, including prolonged nosebleeds and vomiting or coughing up blood.

Instead of prescribing the routine use of thromboprophylactic drugs to COVID-19 outpatients, Dr. Roubinian believes it would be helpful to learn how to determine whether a patient at risk of becoming sick or being hospitalized would benefit from being treated with such drugs.

Dr. Roubinian reported receiving grants from the National Institutes of Health and the National Heart, Lung, and Blood Institute during the conduct of the study.
 

The incidence of venous thromboembolism (VTE) in nonhospitalized patients with COVID-19 was not significantly different from patients without the infectious disease, according to a new study published in JAMA Internal Medicine.

Design Cells/Getty Images

National Institutes of Health guidelines recommend blood thinners to prevent blood clots in patients hospitalized with COVID-19. However, the new study provides more insight on the best treatment approach for COVID-19 outpatients.

“[COVID-19’s] rapid global progression and impact has caused us to make and modify treatment decisions at a pace that we never have in modern medicine,” study author Nareg Roubinian, MD, an investigator at Kaiser Permanente, Oakland, Calif., said in an interview.

“As with other potential therapies for COVID-19, blood thinners need to be prospectively studied in a clinical trial to determine if they improve patient outcomes,” Dr. Roubinian added.

The increased risk of blood clots in patients hospitalized with COVID-19 has been a major issue throughout the pandemic. In fact, one study published in November 2020 found that more than half of patients hospitalized with the illness have prothrombotic antiphospholipid (aPL) autoantibodies in their blood, which could contribute to venous and arterial thromboembolism.

Although it was clear many hospitalized patients diagnosed with COVID-19 were developing more clots, researchers of the current study were not sure if this trend would also be seen in outpatients.

“Most people with COVID-19 do not need to be hospitalized, and we needed to know how often patients outside the hospital were having blood clots,” said Dr. Roubinian.

For the study, Dr. Roubinian and colleagues examined data on 220,588 patients who were members of Kaiser Permanente Northern California health plan and were tested for COVID-19 between Feb. 25 and Aug. 31, 2020. They then reported on the 30-day incidence of outpatient and hospital-associated blood clots following the COVID-19 diagnosis. Patients who were asymptomatic at the time of testing or had received anticoagulants within the last year were excluded.

“We knew from other studies that patients with COVID-19 often get sicker in the first few weeks after infection. What we didn’t know was whether COVID-19 patients were developing blood clots but not pneumonia or were developing blood clots at the same time as they developed pneumonia,” said Dr. Roubinian, an intensive care doctor with the Permanente Medical Group in Oakland, Calif. “Following the patients for 30 days allowed us to focus on the time period from infection to when blood clots were most likely to develop.”

Researchers found that of the cohort who took the COVID-19 test, 11.8% had a positive result. Within 30 days of the COVID-19 test, 0.8% of patients with a positive result were diagnosed with VTE compared to 0.5% of those who received a negative test result. They also found that viral testing took place in an outpatient setting for 59.1% of the patients with a positive viral test who later developed VTE. Of those patients, 76.1% had to be hospitalized.

Dr. Roubinian said he was surprised to see that the blood clotting in outpatients with COVID-19 was similar in frequency to what he saw in patients without the infection.

“Our findings suggest that blood clots do occur in COVID-19 patients but not on a scale where we need to put all or many COVID outpatients on blood thinners,” he said. “As with other potential therapies for COVID-19, blood thinners need to be prospectively studied in a clinical trial to determine if they improve patient outcomes.”

In December 2020, three trials investigating the risk and benefits of increased levels of anticoagulation in hospitalized COVID-19 patients were paused because of safety issues. The trials would have enrolled critically ill COVID-19 patients for whom therapeutic doses of anticoagulation drugs showed no benefit.

Anticoagulants are associated with bleeding risks, including prolonged nosebleeds and vomiting or coughing up blood.

Instead of prescribing the routine use of thromboprophylactic drugs to COVID-19 outpatients, Dr. Roubinian believes it would be helpful to learn how to determine whether a patient at risk of becoming sick or being hospitalized would benefit from being treated with such drugs.

Dr. Roubinian reported receiving grants from the National Institutes of Health and the National Heart, Lung, and Blood Institute during the conduct of the study.
 

The incidence of venous thromboembolism (VTE) in nonhospitalized patients with COVID-19 was not significantly different from patients without the infectious disease, according to a new study published in JAMA Internal Medicine.

Design Cells/Getty Images

National Institutes of Health guidelines recommend blood thinners to prevent blood clots in patients hospitalized with COVID-19. However, the new study provides more insight on the best treatment approach for COVID-19 outpatients.

“[COVID-19’s] rapid global progression and impact has caused us to make and modify treatment decisions at a pace that we never have in modern medicine,” study author Nareg Roubinian, MD, an investigator at Kaiser Permanente, Oakland, Calif., said in an interview.

“As with other potential therapies for COVID-19, blood thinners need to be prospectively studied in a clinical trial to determine if they improve patient outcomes,” Dr. Roubinian added.

The increased risk of blood clots in patients hospitalized with COVID-19 has been a major issue throughout the pandemic. In fact, one study published in November 2020 found that more than half of patients hospitalized with the illness have prothrombotic antiphospholipid (aPL) autoantibodies in their blood, which could contribute to venous and arterial thromboembolism.

Although it was clear many hospitalized patients diagnosed with COVID-19 were developing more clots, researchers of the current study were not sure if this trend would also be seen in outpatients.

“Most people with COVID-19 do not need to be hospitalized, and we needed to know how often patients outside the hospital were having blood clots,” said Dr. Roubinian.

For the study, Dr. Roubinian and colleagues examined data on 220,588 patients who were members of Kaiser Permanente Northern California health plan and were tested for COVID-19 between Feb. 25 and Aug. 31, 2020. They then reported on the 30-day incidence of outpatient and hospital-associated blood clots following the COVID-19 diagnosis. Patients who were asymptomatic at the time of testing or had received anticoagulants within the last year were excluded.

“We knew from other studies that patients with COVID-19 often get sicker in the first few weeks after infection. What we didn’t know was whether COVID-19 patients were developing blood clots but not pneumonia or were developing blood clots at the same time as they developed pneumonia,” said Dr. Roubinian, an intensive care doctor with the Permanente Medical Group in Oakland, Calif. “Following the patients for 30 days allowed us to focus on the time period from infection to when blood clots were most likely to develop.”

Researchers found that of the cohort who took the COVID-19 test, 11.8% had a positive result. Within 30 days of the COVID-19 test, 0.8% of patients with a positive result were diagnosed with VTE compared to 0.5% of those who received a negative test result. They also found that viral testing took place in an outpatient setting for 59.1% of the patients with a positive viral test who later developed VTE. Of those patients, 76.1% had to be hospitalized.

Dr. Roubinian said he was surprised to see that the blood clotting in outpatients with COVID-19 was similar in frequency to what he saw in patients without the infection.

“Our findings suggest that blood clots do occur in COVID-19 patients but not on a scale where we need to put all or many COVID outpatients on blood thinners,” he said. “As with other potential therapies for COVID-19, blood thinners need to be prospectively studied in a clinical trial to determine if they improve patient outcomes.”

In December 2020, three trials investigating the risk and benefits of increased levels of anticoagulation in hospitalized COVID-19 patients were paused because of safety issues. The trials would have enrolled critically ill COVID-19 patients for whom therapeutic doses of anticoagulation drugs showed no benefit.

Anticoagulants are associated with bleeding risks, including prolonged nosebleeds and vomiting or coughing up blood.

Instead of prescribing the routine use of thromboprophylactic drugs to COVID-19 outpatients, Dr. Roubinian believes it would be helpful to learn how to determine whether a patient at risk of becoming sick or being hospitalized would benefit from being treated with such drugs.

Dr. Roubinian reported receiving grants from the National Institutes of Health and the National Heart, Lung, and Blood Institute during the conduct of the study.
 

New guidelines from the American Society of Hematology “strongly recommend” using no thromboprophylaxis over using parenteral thromboprophylaxis in ambulatory patients receiving cancer chemotherapy who have low venous thromboembolism (VTE) risk, and using no thromboprophylaxis over oral thromboprophylaxis with vitamin K antagonists in those at any VTE risk level.

The evidence-based guidelines for the prevention and treatment of VTE in patient with cancer, published online in Blood Advances, also include a “conditional recommendation” for using either thromboprophylaxis with the direct oral anticoagulants (DOACs) apixaban or rivaroxaban or using no thromboprophylaxis in ambulatory patients with intermediate risk and using the DOACs over no thromboprophylaxis in those with high VTE risk.

The purpose of the guidelines, which also address VTE prophylaxis in hospitalized patients with cancer and the use of anticoagulation for VTE treatment in patients with cancer, is to provide clinical decision support for shared decision-making by patients and clinicians, Gary H. Lyman, MD, of Fred Hutchinson Cancer Research Center, Seattle and Marc Carrier, MD, of the University of Ottawa, and their colleagues from the multidisciplinary guidelines panel explained.

“The recommendations take into consideration the strength of the evidence, risks of mortality, VTE, and bleeding, as well as quality of life, acceptability, and cost considerations,” they wrote, noting that VTE is a common complication in patients with cancer, who are at markedly increased risk for morbidity and mortality from VTE.
 

Levels of evidence

The panel members relied on updated and original systematic evidence reviews. Conditional recommendations, as opposed to strong recommendations, are defined by the panel as “suggestions,” and all 33 recommendations that make up the guidelines include a statement on the strength of the relevant evidence.

For example, the thromboprophylaxis recommendations for low, intermediate, and high VTE risk are made based on “moderate certainty in the evidence of effects,” and the recommendation for no thromboprophylaxis over oral thromboprophylaxis with vitamin K antagonists is a strong recommendation based on “very low certainty in the evidence of benefits, but high certainty about the harms.”

The guidelines panel also strongly recommends, based on moderate certainty in the evidence of effects, using low-molecular-weight heparin over unfractionated heparin for the initial treatment of VTE in patients with cancer, and suggests, based on “very low certainty in the evidence of effects,” using LMWH over fondaparinux in this setting.

In addition to primary prophylaxis in ambulatory and hospitalized patients and initial VTE treatment, they also address primary prophylaxis for patients with cancer who have a central venous catheter, VTE treatment in surgical patients with cancer, short-term VTE treatment, and long-term VTE treatment.

For example, the guidelines panel conditionally recommends:

• Not using parenteral or oral thromboprophylaxis in patients with cancer and a central venous catheter
• Using LMWH or fondaparinux for surgical patients with cancer
• Using DOACS for the short-term treatment of VTE, and LMWH or DOACs for the long-term treatment of VTE in patients with cancer.

The perils of VTE

VTE in patients with cancer can interfere with treatment, increase mortality risk, and increase costs, the authors noted, adding that VTE can also adversely affect cancer patients’ quality of life.

“Some have even reported the experience of VTE to be more upsetting than that of the cancer,” they wrote. “More than 50% of thrombotic events occur within 3 months of the cancer diagnosis, a time when most cancer treatments will be underway. Patients, who are still coming to terms with a recent cancer diagnosis, often view the occurrence of VTE as a further threat to life, confirmation of the severity of their condition, and a poor prognostic sign.”

Therefore, the new guidelines aim to reduce VTE frequency, risk of bleeding complications, morbidity, and costs, thereby improving quality of life and the patient experience, the authors said, noting that three other recent guidelines on VTEs in patients with cancer have been published: the 2019 American Society of Clinical Oncology guidelines, the 2019 International Initiative on Thrombosis and Cancer guidelines, and the 2020 National Comprehensive Cancer Network guidelines.

The ASH guidelines are similar in many ways to the other guidelines, but differ in some ways, as well. An example is the timing of initiation of pharmacological thromboprophylaxis in patients undergoing cancer-related major abdominal surgery. The ASCO and ITAC guidelines advise starting thromboprophylaxis preoperatively, whereas the ASH guidelines recommend initiating thromboprophylaxis postoperatively, citing “the limited advantages to initiating thromboprophylaxis preoperatively, in addition to the potential bleeding and logistical considerations associated with neuraxial anesthesia.”

These differences highlight a lack of data in that setting and the need for additional studies, the authors said.
 

ASH vs. ASCO

James Douketis, MD, a practicing clinician and professor of medicine at McMaster University, Hamilton, Ont., highlighted another difference between the ASH and ASCO guidelines.

“For the treatment of [cancer-associated thrombosis], ASCO gives a strong recommendation to use LMWH or DOACs (with some caveats), which is easy to follow. ASH, on the other hand, suggests LMWH or a DOAC for the first 7-10 days, DOACs for the first 3-6 months, and back to LMWH or DOACs after 6 months,” he said in an interview.

The recommendation is “very evidence based but ambiguous and not helpful for the practicing clinician,” added Dr. Douketis, who helped develop the ITAC guidelines, but was not part of the ASH or ASCO guideline panels.

ASCO also provides a clear recommendation for giving VTE prophylaxis for 4 weeks after cancer surgery in patients with high VTE risk, whereas ASH gives “a somewhat vague recommendation” for thromboprophylaxis after hospital discharge.

The guidelines are “pretty well aligned” with respect to recommendations on VTE prophylaxis in medical cancer patients receiving chemotherapy, and although the “extremely academic” ASH guidelines were developed by “a superb team using the same evidence and excellent methodology,” they are interpreted in slightly different ways and fall short when it comes to being clinician friendly, Dr. Douketis said.

“At the end of day, for practicing clinicians, the ASH guidelines don’t provide a message that’s easy to digest,” he added.

ASH has, however, provided a resource page that includes tools and information for implementing the guidelines in clinical practice, and will maintain the guidelines “through surveillance for new evidence, ongoing review by experts, and regular revisions,” the authors said.

sworcester@mdedge.com

New guidelines from the American Society of Hematology “strongly recommend” using no thromboprophylaxis over using parenteral thromboprophylaxis in ambulatory patients receiving cancer chemotherapy who have low venous thromboembolism (VTE) risk, and using no thromboprophylaxis over oral thromboprophylaxis with vitamin K antagonists in those at any VTE risk level.

The evidence-based guidelines for the prevention and treatment of VTE in patient with cancer, published online in Blood Advances, also include a “conditional recommendation” for using either thromboprophylaxis with the direct oral anticoagulants (DOACs) apixaban or rivaroxaban or using no thromboprophylaxis in ambulatory patients with intermediate risk and using the DOACs over no thromboprophylaxis in those with high VTE risk.

The purpose of the guidelines, which also address VTE prophylaxis in hospitalized patients with cancer and the use of anticoagulation for VTE treatment in patients with cancer, is to provide clinical decision support for shared decision-making by patients and clinicians, Gary H. Lyman, MD, of Fred Hutchinson Cancer Research Center, Seattle and Marc Carrier, MD, of the University of Ottawa, and their colleagues from the multidisciplinary guidelines panel explained.

“The recommendations take into consideration the strength of the evidence, risks of mortality, VTE, and bleeding, as well as quality of life, acceptability, and cost considerations,” they wrote, noting that VTE is a common complication in patients with cancer, who are at markedly increased risk for morbidity and mortality from VTE.
 

Levels of evidence

The panel members relied on updated and original systematic evidence reviews. Conditional recommendations, as opposed to strong recommendations, are defined by the panel as “suggestions,” and all 33 recommendations that make up the guidelines include a statement on the strength of the relevant evidence.

For example, the thromboprophylaxis recommendations for low, intermediate, and high VTE risk are made based on “moderate certainty in the evidence of effects,” and the recommendation for no thromboprophylaxis over oral thromboprophylaxis with vitamin K antagonists is a strong recommendation based on “very low certainty in the evidence of benefits, but high certainty about the harms.”

The guidelines panel also strongly recommends, based on moderate certainty in the evidence of effects, using low-molecular-weight heparin over unfractionated heparin for the initial treatment of VTE in patients with cancer, and suggests, based on “very low certainty in the evidence of effects,” using LMWH over fondaparinux in this setting.

In addition to primary prophylaxis in ambulatory and hospitalized patients and initial VTE treatment, they also address primary prophylaxis for patients with cancer who have a central venous catheter, VTE treatment in surgical patients with cancer, short-term VTE treatment, and long-term VTE treatment.

For example, the guidelines panel conditionally recommends:

• Not using parenteral or oral thromboprophylaxis in patients with cancer and a central venous catheter
• Using LMWH or fondaparinux for surgical patients with cancer
• Using DOACS for the short-term treatment of VTE, and LMWH or DOACs for the long-term treatment of VTE in patients with cancer.

The perils of VTE

VTE in patients with cancer can interfere with treatment, increase mortality risk, and increase costs, the authors noted, adding that VTE can also adversely affect cancer patients’ quality of life.

“Some have even reported the experience of VTE to be more upsetting than that of the cancer,” they wrote. “More than 50% of thrombotic events occur within 3 months of the cancer diagnosis, a time when most cancer treatments will be underway. Patients, who are still coming to terms with a recent cancer diagnosis, often view the occurrence of VTE as a further threat to life, confirmation of the severity of their condition, and a poor prognostic sign.”

Therefore, the new guidelines aim to reduce VTE frequency, risk of bleeding complications, morbidity, and costs, thereby improving quality of life and the patient experience, the authors said, noting that three other recent guidelines on VTEs in patients with cancer have been published: the 2019 American Society of Clinical Oncology guidelines, the 2019 International Initiative on Thrombosis and Cancer guidelines, and the 2020 National Comprehensive Cancer Network guidelines.

The ASH guidelines are similar in many ways to the other guidelines, but differ in some ways, as well. An example is the timing of initiation of pharmacological thromboprophylaxis in patients undergoing cancer-related major abdominal surgery. The ASCO and ITAC guidelines advise starting thromboprophylaxis preoperatively, whereas the ASH guidelines recommend initiating thromboprophylaxis postoperatively, citing “the limited advantages to initiating thromboprophylaxis preoperatively, in addition to the potential bleeding and logistical considerations associated with neuraxial anesthesia.”

These differences highlight a lack of data in that setting and the need for additional studies, the authors said.
 

ASH vs. ASCO

James Douketis, MD, a practicing clinician and professor of medicine at McMaster University, Hamilton, Ont., highlighted another difference between the ASH and ASCO guidelines.

“For the treatment of [cancer-associated thrombosis], ASCO gives a strong recommendation to use LMWH or DOACs (with some caveats), which is easy to follow. ASH, on the other hand, suggests LMWH or a DOAC for the first 7-10 days, DOACs for the first 3-6 months, and back to LMWH or DOACs after 6 months,” he said in an interview.

The recommendation is “very evidence based but ambiguous and not helpful for the practicing clinician,” added Dr. Douketis, who helped develop the ITAC guidelines, but was not part of the ASH or ASCO guideline panels.

ASCO also provides a clear recommendation for giving VTE prophylaxis for 4 weeks after cancer surgery in patients with high VTE risk, whereas ASH gives “a somewhat vague recommendation” for thromboprophylaxis after hospital discharge.

The guidelines are “pretty well aligned” with respect to recommendations on VTE prophylaxis in medical cancer patients receiving chemotherapy, and although the “extremely academic” ASH guidelines were developed by “a superb team using the same evidence and excellent methodology,” they are interpreted in slightly different ways and fall short when it comes to being clinician friendly, Dr. Douketis said.

“At the end of day, for practicing clinicians, the ASH guidelines don’t provide a message that’s easy to digest,” he added.

ASH has, however, provided a resource page that includes tools and information for implementing the guidelines in clinical practice, and will maintain the guidelines “through surveillance for new evidence, ongoing review by experts, and regular revisions,” the authors said.

sworcester@mdedge.com

New guidelines from the American Society of Hematology “strongly recommend” using no thromboprophylaxis over using parenteral thromboprophylaxis in ambulatory patients receiving cancer chemotherapy who have low venous thromboembolism (VTE) risk, and using no thromboprophylaxis over oral thromboprophylaxis with vitamin K antagonists in those at any VTE risk level.

The evidence-based guidelines for the prevention and treatment of VTE in patient with cancer, published online in Blood Advances, also include a “conditional recommendation” for using either thromboprophylaxis with the direct oral anticoagulants (DOACs) apixaban or rivaroxaban or using no thromboprophylaxis in ambulatory patients with intermediate risk and using the DOACs over no thromboprophylaxis in those with high VTE risk.

The purpose of the guidelines, which also address VTE prophylaxis in hospitalized patients with cancer and the use of anticoagulation for VTE treatment in patients with cancer, is to provide clinical decision support for shared decision-making by patients and clinicians, Gary H. Lyman, MD, of Fred Hutchinson Cancer Research Center, Seattle and Marc Carrier, MD, of the University of Ottawa, and their colleagues from the multidisciplinary guidelines panel explained.

“The recommendations take into consideration the strength of the evidence, risks of mortality, VTE, and bleeding, as well as quality of life, acceptability, and cost considerations,” they wrote, noting that VTE is a common complication in patients with cancer, who are at markedly increased risk for morbidity and mortality from VTE.
 

Levels of evidence

The panel members relied on updated and original systematic evidence reviews. Conditional recommendations, as opposed to strong recommendations, are defined by the panel as “suggestions,” and all 33 recommendations that make up the guidelines include a statement on the strength of the relevant evidence.

For example, the thromboprophylaxis recommendations for low, intermediate, and high VTE risk are made based on “moderate certainty in the evidence of effects,” and the recommendation for no thromboprophylaxis over oral thromboprophylaxis with vitamin K antagonists is a strong recommendation based on “very low certainty in the evidence of benefits, but high certainty about the harms.”

The guidelines panel also strongly recommends, based on moderate certainty in the evidence of effects, using low-molecular-weight heparin over unfractionated heparin for the initial treatment of VTE in patients with cancer, and suggests, based on “very low certainty in the evidence of effects,” using LMWH over fondaparinux in this setting.

In addition to primary prophylaxis in ambulatory and hospitalized patients and initial VTE treatment, they also address primary prophylaxis for patients with cancer who have a central venous catheter, VTE treatment in surgical patients with cancer, short-term VTE treatment, and long-term VTE treatment.

For example, the guidelines panel conditionally recommends:

• Not using parenteral or oral thromboprophylaxis in patients with cancer and a central venous catheter
• Using LMWH or fondaparinux for surgical patients with cancer
• Using DOACS for the short-term treatment of VTE, and LMWH or DOACs for the long-term treatment of VTE in patients with cancer.

The perils of VTE

VTE in patients with cancer can interfere with treatment, increase mortality risk, and increase costs, the authors noted, adding that VTE can also adversely affect cancer patients’ quality of life.

“Some have even reported the experience of VTE to be more upsetting than that of the cancer,” they wrote. “More than 50% of thrombotic events occur within 3 months of the cancer diagnosis, a time when most cancer treatments will be underway. Patients, who are still coming to terms with a recent cancer diagnosis, often view the occurrence of VTE as a further threat to life, confirmation of the severity of their condition, and a poor prognostic sign.”

Therefore, the new guidelines aim to reduce VTE frequency, risk of bleeding complications, morbidity, and costs, thereby improving quality of life and the patient experience, the authors said, noting that three other recent guidelines on VTEs in patients with cancer have been published: the 2019 American Society of Clinical Oncology guidelines, the 2019 International Initiative on Thrombosis and Cancer guidelines, and the 2020 National Comprehensive Cancer Network guidelines.

The ASH guidelines are similar in many ways to the other guidelines, but differ in some ways, as well. An example is the timing of initiation of pharmacological thromboprophylaxis in patients undergoing cancer-related major abdominal surgery. The ASCO and ITAC guidelines advise starting thromboprophylaxis preoperatively, whereas the ASH guidelines recommend initiating thromboprophylaxis postoperatively, citing “the limited advantages to initiating thromboprophylaxis preoperatively, in addition to the potential bleeding and logistical considerations associated with neuraxial anesthesia.”

These differences highlight a lack of data in that setting and the need for additional studies, the authors said.
 

ASH vs. ASCO

James Douketis, MD, a practicing clinician and professor of medicine at McMaster University, Hamilton, Ont., highlighted another difference between the ASH and ASCO guidelines.

“For the treatment of [cancer-associated thrombosis], ASCO gives a strong recommendation to use LMWH or DOACs (with some caveats), which is easy to follow. ASH, on the other hand, suggests LMWH or a DOAC for the first 7-10 days, DOACs for the first 3-6 months, and back to LMWH or DOACs after 6 months,” he said in an interview.

The recommendation is “very evidence based but ambiguous and not helpful for the practicing clinician,” added Dr. Douketis, who helped develop the ITAC guidelines, but was not part of the ASH or ASCO guideline panels.

ASCO also provides a clear recommendation for giving VTE prophylaxis for 4 weeks after cancer surgery in patients with high VTE risk, whereas ASH gives “a somewhat vague recommendation” for thromboprophylaxis after hospital discharge.

The guidelines are “pretty well aligned” with respect to recommendations on VTE prophylaxis in medical cancer patients receiving chemotherapy, and although the “extremely academic” ASH guidelines were developed by “a superb team using the same evidence and excellent methodology,” they are interpreted in slightly different ways and fall short when it comes to being clinician friendly, Dr. Douketis said.

“At the end of day, for practicing clinicians, the ASH guidelines don’t provide a message that’s easy to digest,” he added.

ASH has, however, provided a resource page that includes tools and information for implementing the guidelines in clinical practice, and will maintain the guidelines “through surveillance for new evidence, ongoing review by experts, and regular revisions,” the authors said.

sworcester@mdedge.com

Each year in the United States, approximately one to two out of every thousand people suffer from venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. The American Society of Hematology (ASH) issued new guidelines for the management of VTE, including primary treatment, secondary prevention, and treatment of recurrent events, earlier this year.

These guidelines, which were recently published in Blood Advances (Ortel T L et al. Blood Adv 2020 doi: 10.1182/bloodadvances.2020001830), include 28 recommendations.

How to treat uncomplicated patients

For uncomplicated deep vein thrombosis (DVT) and/or pulmonary embolism (PE), the guidelines suggest treating patients at home rather than in the hospital. This is especially important for family physicians to note as many of these patients will now be the responsibility of the primary care doctor to treat and follow. Patients treated at home can avoid the risk of nosocomial infections, especially in the days of COVID-19. Evidence also suggests that being treated at home was shown to reduce the risk of PE versus being treated in the hospital. It is, therefore, crucial that family physicians know which patients are low versus high risk.

Further, the guidelines suggest that these patients with low risk of complications are better treated with direct oral anticoagulants (DOACs) instead of vitamin K antagonists, such as Coumadin.

Medication-related suggestions

The guidelines also suggest that no DOAC is preferred over another. Since DOACs are relatively newer agents, family doctors need to become comfortable with their use. For proximal DVTs, anticoagulation alone can be used without thrombolytics.

Family physicians are often tasked with the decision on when to stop anticoagulation. The authors recommend against using diagnostic tests such as D-Dimer or ultrasound to decide when to stop these medications in low-risk patients. In patients at risk of recurrent VTE due to chronic medical conditions, it is suggested to continue anti-coagulants indefinitely. While anticoagulant therapy effectively reduces risk of VTE, it does increase the risk of bleeding events.

The guidelines are quite extensive and specific in their recommendations and family physicians need to understand them. We are often the first ones in the medical system to diagnose VTE, and it is quite possible to keep these patients home, thereby eliminating risks they may encounter by being hospitalized. In addition, the recommendation regarding the use of DOACs may ease some of the burden of monitoring patients on long-term Coumadin. These medications do not come without risks, and we must be comfortable evaluating for any complications. In our current health care system, different insurance companies have different formularies making it necessary for us to know all these medications.

In the past, the diagnosis of PE and even a DVT would mean a hospital stay. We now know, and these guidelines reaffirm, that this is not necessary in uncomplicated cases.

In addition to diagnosing VTE, family physicians are also tasked with following up with patients who were hospitalized or started on treatment by other physicians. We need to know the plan on when to stop the medication or when to reevaluate its use. Patients often bring this question to us, and these guidelines will help us answer that question.

Many patients who have more complicated medical conditions often see multiple specialists. The ASH recommendations help standardize the care of these patients across specialties.

What the recommendations are missing

As family doctors, we often treat patients with multiple comorbidities. These guidelines do not make recommendations for patients with cancer, who are at high risk of VTE events. Some patients also have conditions that increase their risk of bleeding or have contraindications to the use of anticoagulants. It would be helpful to have more recommendations for both of these types of patients in addition to the use of inferior vena cava filter in patients with proximal DVT. The document is also missing recommendations for pregnant patients, which would be useful.

Overall, these guidelines include much of what we already do in our practices while doing a great job of incorporating the newer DOACs. These guidelines are easy for family physicians to put into practice.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at fpnews@mdedge.com.

Each year in the United States, approximately one to two out of every thousand people suffer from venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. The American Society of Hematology (ASH) issued new guidelines for the management of VTE, including primary treatment, secondary prevention, and treatment of recurrent events, earlier this year.

These guidelines, which were recently published in Blood Advances (Ortel T L et al. Blood Adv 2020 doi: 10.1182/bloodadvances.2020001830), include 28 recommendations.

How to treat uncomplicated patients

For uncomplicated deep vein thrombosis (DVT) and/or pulmonary embolism (PE), the guidelines suggest treating patients at home rather than in the hospital. This is especially important for family physicians to note as many of these patients will now be the responsibility of the primary care doctor to treat and follow. Patients treated at home can avoid the risk of nosocomial infections, especially in the days of COVID-19. Evidence also suggests that being treated at home was shown to reduce the risk of PE versus being treated in the hospital. It is, therefore, crucial that family physicians know which patients are low versus high risk.

Further, the guidelines suggest that these patients with low risk of complications are better treated with direct oral anticoagulants (DOACs) instead of vitamin K antagonists, such as Coumadin.

Medication-related suggestions

The guidelines also suggest that no DOAC is preferred over another. Since DOACs are relatively newer agents, family doctors need to become comfortable with their use. For proximal DVTs, anticoagulation alone can be used without thrombolytics.

Family physicians are often tasked with the decision on when to stop anticoagulation. The authors recommend against using diagnostic tests such as D-Dimer or ultrasound to decide when to stop these medications in low-risk patients. In patients at risk of recurrent VTE due to chronic medical conditions, it is suggested to continue anti-coagulants indefinitely. While anticoagulant therapy effectively reduces risk of VTE, it does increase the risk of bleeding events.

The guidelines are quite extensive and specific in their recommendations and family physicians need to understand them. We are often the first ones in the medical system to diagnose VTE, and it is quite possible to keep these patients home, thereby eliminating risks they may encounter by being hospitalized. In addition, the recommendation regarding the use of DOACs may ease some of the burden of monitoring patients on long-term Coumadin. These medications do not come without risks, and we must be comfortable evaluating for any complications. In our current health care system, different insurance companies have different formularies making it necessary for us to know all these medications.

In the past, the diagnosis of PE and even a DVT would mean a hospital stay. We now know, and these guidelines reaffirm, that this is not necessary in uncomplicated cases.

In addition to diagnosing VTE, family physicians are also tasked with following up with patients who were hospitalized or started on treatment by other physicians. We need to know the plan on when to stop the medication or when to reevaluate its use. Patients often bring this question to us, and these guidelines will help us answer that question.

Many patients who have more complicated medical conditions often see multiple specialists. The ASH recommendations help standardize the care of these patients across specialties.

What the recommendations are missing

As family doctors, we often treat patients with multiple comorbidities. These guidelines do not make recommendations for patients with cancer, who are at high risk of VTE events. Some patients also have conditions that increase their risk of bleeding or have contraindications to the use of anticoagulants. It would be helpful to have more recommendations for both of these types of patients in addition to the use of inferior vena cava filter in patients with proximal DVT. The document is also missing recommendations for pregnant patients, which would be useful.

Overall, these guidelines include much of what we already do in our practices while doing a great job of incorporating the newer DOACs. These guidelines are easy for family physicians to put into practice.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at fpnews@mdedge.com.

Each year in the United States, approximately one to two out of every thousand people suffer from venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. The American Society of Hematology (ASH) issued new guidelines for the management of VTE, including primary treatment, secondary prevention, and treatment of recurrent events, earlier this year.

These guidelines, which were recently published in Blood Advances (Ortel T L et al. Blood Adv 2020 doi: 10.1182/bloodadvances.2020001830), include 28 recommendations.

How to treat uncomplicated patients

For uncomplicated deep vein thrombosis (DVT) and/or pulmonary embolism (PE), the guidelines suggest treating patients at home rather than in the hospital. This is especially important for family physicians to note as many of these patients will now be the responsibility of the primary care doctor to treat and follow. Patients treated at home can avoid the risk of nosocomial infections, especially in the days of COVID-19. Evidence also suggests that being treated at home was shown to reduce the risk of PE versus being treated in the hospital. It is, therefore, crucial that family physicians know which patients are low versus high risk.

Further, the guidelines suggest that these patients with low risk of complications are better treated with direct oral anticoagulants (DOACs) instead of vitamin K antagonists, such as Coumadin.

Medication-related suggestions

The guidelines also suggest that no DOAC is preferred over another. Since DOACs are relatively newer agents, family doctors need to become comfortable with their use. For proximal DVTs, anticoagulation alone can be used without thrombolytics.

Family physicians are often tasked with the decision on when to stop anticoagulation. The authors recommend against using diagnostic tests such as D-Dimer or ultrasound to decide when to stop these medications in low-risk patients. In patients at risk of recurrent VTE due to chronic medical conditions, it is suggested to continue anti-coagulants indefinitely. While anticoagulant therapy effectively reduces risk of VTE, it does increase the risk of bleeding events.

The guidelines are quite extensive and specific in their recommendations and family physicians need to understand them. We are often the first ones in the medical system to diagnose VTE, and it is quite possible to keep these patients home, thereby eliminating risks they may encounter by being hospitalized. In addition, the recommendation regarding the use of DOACs may ease some of the burden of monitoring patients on long-term Coumadin. These medications do not come without risks, and we must be comfortable evaluating for any complications. In our current health care system, different insurance companies have different formularies making it necessary for us to know all these medications.

In the past, the diagnosis of PE and even a DVT would mean a hospital stay. We now know, and these guidelines reaffirm, that this is not necessary in uncomplicated cases.

In addition to diagnosing VTE, family physicians are also tasked with following up with patients who were hospitalized or started on treatment by other physicians. We need to know the plan on when to stop the medication or when to reevaluate its use. Patients often bring this question to us, and these guidelines will help us answer that question.

Many patients who have more complicated medical conditions often see multiple specialists. The ASH recommendations help standardize the care of these patients across specialties.

What the recommendations are missing

As family doctors, we often treat patients with multiple comorbidities. These guidelines do not make recommendations for patients with cancer, who are at high risk of VTE events. Some patients also have conditions that increase their risk of bleeding or have contraindications to the use of anticoagulants. It would be helpful to have more recommendations for both of these types of patients in addition to the use of inferior vena cava filter in patients with proximal DVT. The document is also missing recommendations for pregnant patients, which would be useful.

Overall, these guidelines include much of what we already do in our practices while doing a great job of incorporating the newer DOACs. These guidelines are easy for family physicians to put into practice.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at fpnews@mdedge.com.

Primary thromboprophylaxis is feasible and worth considering for high-risk ambulatory patients with cancer who are initiating systemic chemotherapy, according to Marc Carrier, MD.

Risk scores can identify patients at high risk for venous thromboembolism (VTE), and treatments that are effective and associated with low bleeding risk are available, Dr. Carrier explained at the biennial summit of the Thrombosis & Hemostasis Societies of North America.

However, caution is advised in patients with certain types of cancer, including some gastrointestinal and genitourinary cancers, because of the possibility of increased major and clinically relevant nonmajor bleeding risk, he said.
 

VTE and cancer

VTE is relatively rare in the general population, occurring in about 1 or 2 per 1,000 people annually. The risk increases 4.1-fold in patients with cancer, and 6.5-fold in patients with cancer receiving chemotherapy.

“So just putting these numbers together, we’re no longer talking about 1 in 1,000, but 1 in 200, so [this is] something that is very common among cancer patients,” said Dr. Carrier, a professor at the University of Ottawa and chief of the division of hematology at The Ottawa Hospital.

The mortality rate associated with cancer-associated thrombosis is about 9%, comparable to that associated with infection in the cancer outpatient setting, which underscores the importance of educating patients about the signs and symptoms of VTE so they can seek medical treatment quickly if necessary, he added.

It may also be useful to discuss prophylaxis or other ways to prevent venous thromboembolic complications with certain patients, he said, noting that in an observational cohort study of nearly 600 patients at the University of Ottawa, 25% of those initiating chemotherapy were identified as intermediate or high risk using the validated Khorana risk score, and thus would likely benefit from thromboprophylaxis.
 

Risk assessment

The Khorana risk score assesses VTE risk based on cancer site, blood counts, and body mass index. It is simple to use and has been validated in more than 20,000 people in multiple countries, Dr. Carrier said.

In a well-known validation study, Ay et al. showed a VTE complication rate of 10% in patients with a Khorana risk score of 2 or higher who were followed up to 6 months.

“This is huge,” Dr. Carrier stressed. “This is much higher than what we tolerate for all sorts of different populations for which we would recommend anticoagulation or thromboprophylaxis.”

The question is whether the risk score can be helpful in a real-world clinic setting, he said, adding: “I’d like to think the answer to that is yes.”

In the University of Ottawa cohort study, 11% of high-risk patients experienced a VTE complication, compared with 4% of those with lower risk, suggesting that the validation data for the Khorana risk score is not only accurate, it is “actually applicable in real-world practice, and you can use it in your own center,” he said.

Further, recent studies have demonstrated that treatment based on Khorana risk score assessment reduces VTE complications.
 

Prophylaxis options

Low-molecular-weight heparin (LMWH) has been shown in several studies to be associated with a significant relative VTE risk reduction in patients with cancer initiating chemotherapy – with only a slight, nonsignificant increase in the risk of major bleeding.

However, the absolute benefit was small, and LMWH is “parenteral, relatively costly, and, based on that, although we showed relatively good risk-benefit ratio, it never really got translated to clinical practice,” Dr. Carrier said.

In fact, a 2015 American Society of Clinical Oncology guidelines update recommended against routine thromboprophylaxis in this setting, but stated that it could be considered in select high-risk patients identified using a validated risk-assessment tool.

The guidelines noted that “individual risk factors such as biomarkers and cancer site don’t reliably identify high-risk patients.”

More recent data provide additional support for risk assessment and treatment based on Khorana risk score of 2 or higher.

The AVERT trial, for which Dr. Carrier was the first author, showed that the direct-acting oral anticoagulant (DOAC) apixaban reduced VTE incidence, compared with placebo, in patients with Khorana score of 2 or higher (4.2% vs. 10.2%; hazard ratio, 0.41 overall, and 1.0 vs. 7.3; HR, 0.14 on treatment), and the CASSINI trial showed that another DOAC, rivaroxaban, reduced VTE incidence, compared with placebo, in those with Khorana score of 2 or higher (5.9 vs. 6.7; HR, 0.6 overall, and 2.6 vs. 6.4; HR, 0.40 on treatment). The differences in the on-treatment populations were statistically significant.

The two trials, which included a variety of tumor types, showed similar rates of major bleeding, with an absolute difference of about 1% between treatment and placebo, which was not statistically significant in the on-treatment analyses (HR, 1.89 in AVERT and HR, 1.96 in CASSINI).

A systematic review of these trials showed an overall significant decrease in VTE complication risk with treatment in high-risk patients, and a nonstatistically significant major bleeding risk increase.

Based on these findings, ASCO guidelines were updated in 2020 to state that “routine thromboprophylaxis should not be offered to all patients with cancer. ... However, high-risk outpatients with cancer may be offered thromboprophylaxis with apixaban, rivaroxaban or LMWH, providing there are no significant risk factors for bleeding or drug-drug interactions, and after having a full discussion with patients ... to make sure they understand the risk-benefit ratio and the rationale for that particular recommendation,” he said.
 

Real-world implementation

Implementing this approach in the clinic setting requires a practical model, such as the Venous Thromboembolism Prevention in the Ambulatory Cancer Clinic (VTEPACC) program, a prospective quality improvement research initiative developed in collaboration with the Jeffords Institute for Quality at the University of Vermont Medical Center and described in a recent report, Dr. Carrier said.

The “Vermont model” is “really a comprehensive model that includes identifying patients with the electronic medical records, gathering the formal education and insight from other health care providers like pharmacists and nurses in order to really come up with personalized care for your patients,” he explained.

In 918 outpatients with cancer who were included in the program, VTE awareness increased from less than 5% before VTEPACC to nearly 82% during the implementation phase and 94.7% after 2 years, with nearly 94% of high-risk patients receiving VTE prophylaxis at that time.

“So we can certainly do that in our own center.” he said. “It’s a matter of coming up with the model and making sure that the patients are seen at the right time.”

Given the high frequency of VTE in patients with cancer initiating chemotherapy, the usefulness of risk scores such as the Khorana risk score for identifying those at high risk, and the availability of safe and effective interventions for reducing risk, “we should probably use the data and incorporate them into clinical practice by implementation of programs for primary prevention,” he said.
 

A word of caution

Caution is warranted, however, when it comes to using DOACs in patients with higher-risk or potentially higher-risk tumor types, he added.

“It’s an important question we are facing as clinicians on a daily basis,” he said, responding to an attendee’s query, as shared by session moderator James Douketis, MD, professor of medicine at McMaster University, Hamilton, Ont., regarding possible bleeding risks in certain genitourinary cancers.

A recent meta-analysis published in Nature, for example, noted that, in the SELECT-D trial, rivaroxaban was associated with significantly higher incidence of clinically relevant nonmajor bleeding, most often in bladder and colorectal cancers, and most often at genitourinary and gastrointestinal sites.

Both Dr. Carrier and fellow panelist Michael Streiff, MD, professor of medicine at Johns Hopkins University and medical director at the Johns Hopkins Hospital Special Coagulation Laboratory, Baltimore, said they approach DOAC use cautiously, but don’t rule it out entirely, in patients with unresected genitourinary tumors that could pose a risk of bleeding.

“It’s worth mentioning and being cautious. In my own personal practice, I’m very careful with unresected urothelial-type tumors or, for example, bladder cancer, for the same reason as [with] unresected luminal GI tumors,” Dr. Carrier said, adding that he’s also mindful that patients with nephropathy were excluded from U.S. DOAC trials because of bleeding risk.

He said he sometimes tries a LMWH challenge first in higher-risk patients, and then might try a DOAC if no bleeding occurs.

“But it certainly is controversial,” he noted.

Dr. Streiff added that he also worries less with genitourinary cancers than with upper GI lesions because “the signals weren’t as big as in GI” cancers, but he noted that “the drugs are going out through the kidneys ... so I’m cautious in those populations.”

“So caution, but not complete exclusion, is the operative management,” Dr. Douketis said, summarizing the panelists’ consensus.

Dr. Carrier reported clinical trial or advisory board participation for Bayer, Pfizer, Servier, Leo Pharma, and/or BMS.

sworcester@mdedge.com

Primary thromboprophylaxis is feasible and worth considering for high-risk ambulatory patients with cancer who are initiating systemic chemotherapy, according to Marc Carrier, MD.

Risk scores can identify patients at high risk for venous thromboembolism (VTE), and treatments that are effective and associated with low bleeding risk are available, Dr. Carrier explained at the biennial summit of the Thrombosis & Hemostasis Societies of North America.

However, caution is advised in patients with certain types of cancer, including some gastrointestinal and genitourinary cancers, because of the possibility of increased major and clinically relevant nonmajor bleeding risk, he said.
 

VTE and cancer

VTE is relatively rare in the general population, occurring in about 1 or 2 per 1,000 people annually. The risk increases 4.1-fold in patients with cancer, and 6.5-fold in patients with cancer receiving chemotherapy.

“So just putting these numbers together, we’re no longer talking about 1 in 1,000, but 1 in 200, so [this is] something that is very common among cancer patients,” said Dr. Carrier, a professor at the University of Ottawa and chief of the division of hematology at The Ottawa Hospital.

The mortality rate associated with cancer-associated thrombosis is about 9%, comparable to that associated with infection in the cancer outpatient setting, which underscores the importance of educating patients about the signs and symptoms of VTE so they can seek medical treatment quickly if necessary, he added.

It may also be useful to discuss prophylaxis or other ways to prevent venous thromboembolic complications with certain patients, he said, noting that in an observational cohort study of nearly 600 patients at the University of Ottawa, 25% of those initiating chemotherapy were identified as intermediate or high risk using the validated Khorana risk score, and thus would likely benefit from thromboprophylaxis.
 

Risk assessment

The Khorana risk score assesses VTE risk based on cancer site, blood counts, and body mass index. It is simple to use and has been validated in more than 20,000 people in multiple countries, Dr. Carrier said.

In a well-known validation study, Ay et al. showed a VTE complication rate of 10% in patients with a Khorana risk score of 2 or higher who were followed up to 6 months.

“This is huge,” Dr. Carrier stressed. “This is much higher than what we tolerate for all sorts of different populations for which we would recommend anticoagulation or thromboprophylaxis.”

The question is whether the risk score can be helpful in a real-world clinic setting, he said, adding: “I’d like to think the answer to that is yes.”

In the University of Ottawa cohort study, 11% of high-risk patients experienced a VTE complication, compared with 4% of those with lower risk, suggesting that the validation data for the Khorana risk score is not only accurate, it is “actually applicable in real-world practice, and you can use it in your own center,” he said.

Further, recent studies have demonstrated that treatment based on Khorana risk score assessment reduces VTE complications.
 

Prophylaxis options

Low-molecular-weight heparin (LMWH) has been shown in several studies to be associated with a significant relative VTE risk reduction in patients with cancer initiating chemotherapy – with only a slight, nonsignificant increase in the risk of major bleeding.

However, the absolute benefit was small, and LMWH is “parenteral, relatively costly, and, based on that, although we showed relatively good risk-benefit ratio, it never really got translated to clinical practice,” Dr. Carrier said.

In fact, a 2015 American Society of Clinical Oncology guidelines update recommended against routine thromboprophylaxis in this setting, but stated that it could be considered in select high-risk patients identified using a validated risk-assessment tool.

The guidelines noted that “individual risk factors such as biomarkers and cancer site don’t reliably identify high-risk patients.”

More recent data provide additional support for risk assessment and treatment based on Khorana risk score of 2 or higher.

The AVERT trial, for which Dr. Carrier was the first author, showed that the direct-acting oral anticoagulant (DOAC) apixaban reduced VTE incidence, compared with placebo, in patients with Khorana score of 2 or higher (4.2% vs. 10.2%; hazard ratio, 0.41 overall, and 1.0 vs. 7.3; HR, 0.14 on treatment), and the CASSINI trial showed that another DOAC, rivaroxaban, reduced VTE incidence, compared with placebo, in those with Khorana score of 2 or higher (5.9 vs. 6.7; HR, 0.6 overall, and 2.6 vs. 6.4; HR, 0.40 on treatment). The differences in the on-treatment populations were statistically significant.

The two trials, which included a variety of tumor types, showed similar rates of major bleeding, with an absolute difference of about 1% between treatment and placebo, which was not statistically significant in the on-treatment analyses (HR, 1.89 in AVERT and HR, 1.96 in CASSINI).

A systematic review of these trials showed an overall significant decrease in VTE complication risk with treatment in high-risk patients, and a nonstatistically significant major bleeding risk increase.

Based on these findings, ASCO guidelines were updated in 2020 to state that “routine thromboprophylaxis should not be offered to all patients with cancer. ... However, high-risk outpatients with cancer may be offered thromboprophylaxis with apixaban, rivaroxaban or LMWH, providing there are no significant risk factors for bleeding or drug-drug interactions, and after having a full discussion with patients ... to make sure they understand the risk-benefit ratio and the rationale for that particular recommendation,” he said.
 

Real-world implementation

Implementing this approach in the clinic setting requires a practical model, such as the Venous Thromboembolism Prevention in the Ambulatory Cancer Clinic (VTEPACC) program, a prospective quality improvement research initiative developed in collaboration with the Jeffords Institute for Quality at the University of Vermont Medical Center and described in a recent report, Dr. Carrier said.

The “Vermont model” is “really a comprehensive model that includes identifying patients with the electronic medical records, gathering the formal education and insight from other health care providers like pharmacists and nurses in order to really come up with personalized care for your patients,” he explained.

In 918 outpatients with cancer who were included in the program, VTE awareness increased from less than 5% before VTEPACC to nearly 82% during the implementation phase and 94.7% after 2 years, with nearly 94% of high-risk patients receiving VTE prophylaxis at that time.

“So we can certainly do that in our own center.” he said. “It’s a matter of coming up with the model and making sure that the patients are seen at the right time.”

Given the high frequency of VTE in patients with cancer initiating chemotherapy, the usefulness of risk scores such as the Khorana risk score for identifying those at high risk, and the availability of safe and effective interventions for reducing risk, “we should probably use the data and incorporate them into clinical practice by implementation of programs for primary prevention,” he said.
 

A word of caution

Caution is warranted, however, when it comes to using DOACs in patients with higher-risk or potentially higher-risk tumor types, he added.

“It’s an important question we are facing as clinicians on a daily basis,” he said, responding to an attendee’s query, as shared by session moderator James Douketis, MD, professor of medicine at McMaster University, Hamilton, Ont., regarding possible bleeding risks in certain genitourinary cancers.

A recent meta-analysis published in Nature, for example, noted that, in the SELECT-D trial, rivaroxaban was associated with significantly higher incidence of clinically relevant nonmajor bleeding, most often in bladder and colorectal cancers, and most often at genitourinary and gastrointestinal sites.

Both Dr. Carrier and fellow panelist Michael Streiff, MD, professor of medicine at Johns Hopkins University and medical director at the Johns Hopkins Hospital Special Coagulation Laboratory, Baltimore, said they approach DOAC use cautiously, but don’t rule it out entirely, in patients with unresected genitourinary tumors that could pose a risk of bleeding.

“It’s worth mentioning and being cautious. In my own personal practice, I’m very careful with unresected urothelial-type tumors or, for example, bladder cancer, for the same reason as [with] unresected luminal GI tumors,” Dr. Carrier said, adding that he’s also mindful that patients with nephropathy were excluded from U.S. DOAC trials because of bleeding risk.

He said he sometimes tries a LMWH challenge first in higher-risk patients, and then might try a DOAC if no bleeding occurs.

“But it certainly is controversial,” he noted.

Dr. Streiff added that he also worries less with genitourinary cancers than with upper GI lesions because “the signals weren’t as big as in GI” cancers, but he noted that “the drugs are going out through the kidneys ... so I’m cautious in those populations.”

“So caution, but not complete exclusion, is the operative management,” Dr. Douketis said, summarizing the panelists’ consensus.

Dr. Carrier reported clinical trial or advisory board participation for Bayer, Pfizer, Servier, Leo Pharma, and/or BMS.

sworcester@mdedge.com

Primary thromboprophylaxis is feasible and worth considering for high-risk ambulatory patients with cancer who are initiating systemic chemotherapy, according to Marc Carrier, MD.

Risk scores can identify patients at high risk for venous thromboembolism (VTE), and treatments that are effective and associated with low bleeding risk are available, Dr. Carrier explained at the biennial summit of the Thrombosis & Hemostasis Societies of North America.

However, caution is advised in patients with certain types of cancer, including some gastrointestinal and genitourinary cancers, because of the possibility of increased major and clinically relevant nonmajor bleeding risk, he said.
 

VTE and cancer

VTE is relatively rare in the general population, occurring in about 1 or 2 per 1,000 people annually. The risk increases 4.1-fold in patients with cancer, and 6.5-fold in patients with cancer receiving chemotherapy.

“So just putting these numbers together, we’re no longer talking about 1 in 1,000, but 1 in 200, so [this is] something that is very common among cancer patients,” said Dr. Carrier, a professor at the University of Ottawa and chief of the division of hematology at The Ottawa Hospital.

The mortality rate associated with cancer-associated thrombosis is about 9%, comparable to that associated with infection in the cancer outpatient setting, which underscores the importance of educating patients about the signs and symptoms of VTE so they can seek medical treatment quickly if necessary, he added.

It may also be useful to discuss prophylaxis or other ways to prevent venous thromboembolic complications with certain patients, he said, noting that in an observational cohort study of nearly 600 patients at the University of Ottawa, 25% of those initiating chemotherapy were identified as intermediate or high risk using the validated Khorana risk score, and thus would likely benefit from thromboprophylaxis.
 

Risk assessment

The Khorana risk score assesses VTE risk based on cancer site, blood counts, and body mass index. It is simple to use and has been validated in more than 20,000 people in multiple countries, Dr. Carrier said.

In a well-known validation study, Ay et al. showed a VTE complication rate of 10% in patients with a Khorana risk score of 2 or higher who were followed up to 6 months.

“This is huge,” Dr. Carrier stressed. “This is much higher than what we tolerate for all sorts of different populations for which we would recommend anticoagulation or thromboprophylaxis.”

The question is whether the risk score can be helpful in a real-world clinic setting, he said, adding: “I’d like to think the answer to that is yes.”

In the University of Ottawa cohort study, 11% of high-risk patients experienced a VTE complication, compared with 4% of those with lower risk, suggesting that the validation data for the Khorana risk score is not only accurate, it is “actually applicable in real-world practice, and you can use it in your own center,” he said.

Further, recent studies have demonstrated that treatment based on Khorana risk score assessment reduces VTE complications.
 

Prophylaxis options

Low-molecular-weight heparin (LMWH) has been shown in several studies to be associated with a significant relative VTE risk reduction in patients with cancer initiating chemotherapy – with only a slight, nonsignificant increase in the risk of major bleeding.

However, the absolute benefit was small, and LMWH is “parenteral, relatively costly, and, based on that, although we showed relatively good risk-benefit ratio, it never really got translated to clinical practice,” Dr. Carrier said.

In fact, a 2015 American Society of Clinical Oncology guidelines update recommended against routine thromboprophylaxis in this setting, but stated that it could be considered in select high-risk patients identified using a validated risk-assessment tool.

The guidelines noted that “individual risk factors such as biomarkers and cancer site don’t reliably identify high-risk patients.”

More recent data provide additional support for risk assessment and treatment based on Khorana risk score of 2 or higher.

The AVERT trial, for which Dr. Carrier was the first author, showed that the direct-acting oral anticoagulant (DOAC) apixaban reduced VTE incidence, compared with placebo, in patients with Khorana score of 2 or higher (4.2% vs. 10.2%; hazard ratio, 0.41 overall, and 1.0 vs. 7.3; HR, 0.14 on treatment), and the CASSINI trial showed that another DOAC, rivaroxaban, reduced VTE incidence, compared with placebo, in those with Khorana score of 2 or higher (5.9 vs. 6.7; HR, 0.6 overall, and 2.6 vs. 6.4; HR, 0.40 on treatment). The differences in the on-treatment populations were statistically significant.

The two trials, which included a variety of tumor types, showed similar rates of major bleeding, with an absolute difference of about 1% between treatment and placebo, which was not statistically significant in the on-treatment analyses (HR, 1.89 in AVERT and HR, 1.96 in CASSINI).

A systematic review of these trials showed an overall significant decrease in VTE complication risk with treatment in high-risk patients, and a nonstatistically significant major bleeding risk increase.

Based on these findings, ASCO guidelines were updated in 2020 to state that “routine thromboprophylaxis should not be offered to all patients with cancer. ... However, high-risk outpatients with cancer may be offered thromboprophylaxis with apixaban, rivaroxaban or LMWH, providing there are no significant risk factors for bleeding or drug-drug interactions, and after having a full discussion with patients ... to make sure they understand the risk-benefit ratio and the rationale for that particular recommendation,” he said.
 

Real-world implementation

Implementing this approach in the clinic setting requires a practical model, such as the Venous Thromboembolism Prevention in the Ambulatory Cancer Clinic (VTEPACC) program, a prospective quality improvement research initiative developed in collaboration with the Jeffords Institute for Quality at the University of Vermont Medical Center and described in a recent report, Dr. Carrier said.

The “Vermont model” is “really a comprehensive model that includes identifying patients with the electronic medical records, gathering the formal education and insight from other health care providers like pharmacists and nurses in order to really come up with personalized care for your patients,” he explained.

In 918 outpatients with cancer who were included in the program, VTE awareness increased from less than 5% before VTEPACC to nearly 82% during the implementation phase and 94.7% after 2 years, with nearly 94% of high-risk patients receiving VTE prophylaxis at that time.

“So we can certainly do that in our own center.” he said. “It’s a matter of coming up with the model and making sure that the patients are seen at the right time.”

Given the high frequency of VTE in patients with cancer initiating chemotherapy, the usefulness of risk scores such as the Khorana risk score for identifying those at high risk, and the availability of safe and effective interventions for reducing risk, “we should probably use the data and incorporate them into clinical practice by implementation of programs for primary prevention,” he said.
 

A word of caution

Caution is warranted, however, when it comes to using DOACs in patients with higher-risk or potentially higher-risk tumor types, he added.

“It’s an important question we are facing as clinicians on a daily basis,” he said, responding to an attendee’s query, as shared by session moderator James Douketis, MD, professor of medicine at McMaster University, Hamilton, Ont., regarding possible bleeding risks in certain genitourinary cancers.

A recent meta-analysis published in Nature, for example, noted that, in the SELECT-D trial, rivaroxaban was associated with significantly higher incidence of clinically relevant nonmajor bleeding, most often in bladder and colorectal cancers, and most often at genitourinary and gastrointestinal sites.

Both Dr. Carrier and fellow panelist Michael Streiff, MD, professor of medicine at Johns Hopkins University and medical director at the Johns Hopkins Hospital Special Coagulation Laboratory, Baltimore, said they approach DOAC use cautiously, but don’t rule it out entirely, in patients with unresected genitourinary tumors that could pose a risk of bleeding.

“It’s worth mentioning and being cautious. In my own personal practice, I’m very careful with unresected urothelial-type tumors or, for example, bladder cancer, for the same reason as [with] unresected luminal GI tumors,” Dr. Carrier said, adding that he’s also mindful that patients with nephropathy were excluded from U.S. DOAC trials because of bleeding risk.

He said he sometimes tries a LMWH challenge first in higher-risk patients, and then might try a DOAC if no bleeding occurs.

“But it certainly is controversial,” he noted.

Dr. Streiff added that he also worries less with genitourinary cancers than with upper GI lesions because “the signals weren’t as big as in GI” cancers, but he noted that “the drugs are going out through the kidneys ... so I’m cautious in those populations.”

“So caution, but not complete exclusion, is the operative management,” Dr. Douketis said, summarizing the panelists’ consensus.

Dr. Carrier reported clinical trial or advisory board participation for Bayer, Pfizer, Servier, Leo Pharma, and/or BMS.

sworcester@mdedge.com

Factor XI has emerged as a promising target for new anticoagulants, and several strategies for inhibiting the enzyme to reduce stroke, thromboembolism, and bleeding risk are under investigation, according to Jeffrey I. Weitz, MD.

These strategies could pick up where direct-acting oral anticoagulants leave off, he suggested during a presentation at the biennial summit of the Thrombosis & Hemostasis Societies of North America.

“We all know that the direct oral anticoagulants – the DOACs – are an advance over vitamin K antagonists,” said Dr. Weitz, professor of medicine and biochemistry at McMaster University, Hamilton, Ontario.

Not only are DOACs at least as effective as vitamin K antagonists such as warfarin for stroke prevention in atrial fibrillation or for treatment of venous thromboembolism (VTE), but they also reduce intracranial bleeding and major bleeding risk in those settings, respectively, and they are more convenient to administer because they can be delivered using fixed doses without the need for coagulation monitoring, he added.

Still, new targets are needed, he said, explaining that, although DOACs moved closer to the goal of attenuating thrombosis without increasing the risk of bleeding, annual rates of major bleeding remain at 2%-3% in the atrial fibrillation population, and rates of major and clinically relevant nonmajor bleeding are about 10%.

“The fear of bleeding leads to underuse of anticoagulants for eligible patients with atrial fibrillation and inappropriate use of low-dose [non–vitamin K antagonist oral anticoagulant] regimens, which can leave patients unprotected from thrombotic complications,” he said.
 

Factor XI

That’s where Factor XI (FXI) may come in, Dr. Weitz said.

Current anticoagulants target enzymes, including FXa or thrombin, in the common pathway of coagulation, but the intrinsic pathway at the level of FXI and FXII has attracted attention in recent years.

The intrinsic pathway is activated when blood comes into contact with medical devices like stents, mechanical heart valves, or central venous catheters, but evidence also suggests that it plays a role in clot stabilization and growth, he explained, noting additional evidence of attenuation of thrombosis in mice deficient in FXI or FXII and in animals with FXI or FXII inhibitors.

“There is no bleeding with congenital FXII deficiency, and patients with FXI deficiency rarely have spontaneous bleeding, although they can bleed with surgery or trauma,” he noted. “Therefore, the promise of contact pathway inhibition is that we can attenuate thrombosis with little or no disruption of hemostasis.”

The initiators of the intrinsic pathway are naturally occurring polyphosphates that can activate FXI and FXII, promote platelet activation, and lead to thrombosis. A number of agents are being investigated to target these enzymes – particularly FXI, for which the strongest epidemiological and other evidence of its link with thrombosis exists. He noted that FXI deficiency appears protective against deep-vein thrombosis (DVT) and ischemic stroke, whereas high levels are linked with an increased risk of venous and arterial thrombosis.

Investigative strategies include the use of antisense oligonucleotides to reduce hepatic synthesis of FXI, aptamers to bind FXI and block its activity, antibodies to bind FXI and block its activation or activity, and small molecules to bind reversibly to the active site of FXI and block its activity “much like the DOACs block the activity of FXa or thrombin.”

“We have to remember that the DOACs have taken over from vitamin K antagonists, like warfarin, for many indications, and as they go generic their uptake will increase even further,” Dr. Weitz said. “When we compare the FXI inhibitors with existing anticoagulants, we don’t necessarily want to go up against the DOACs – we’re looking for indications where [DOACs] have yet to be tested or may be unsafe.”

Potential indications include the following:

Prevention of major adverse cardiovascular events in patients with end-stage renal disease with or without atrial fibrillation.

Provision of a safer platform for antiplatelet therapy in patients with acute coronary syndrome.

Secondary stroke prevention.

Prevention or treatment of cancer-associated VTE.

Prevention of thrombosis associated with central venous catheters, left ventricular assist devices, or mechanical heart valves.

Agents in development

Of the FXI inhibitors in development, ISIS-FXI_Rx, an antisense oligonucleotide against FXI, is furthest along. In a study published in Blood, ISIS-FXI_Rx produced a dose-dependent and sustained reduction in FXI levels in healthy volunteers, and in a later randomized study published in The New England Journal of Medicine, it significantly reduced the incidence of DVT in patients undergoing voluntary total knee arthroplasty (30.4% with enoxaparin vs. 4.2% with ISIS-FXI_Rx at a dose of 300 mg). Bleeding rates were 8.3% and 2.6%, respectively.

The findings showed the potential for reducing thrombosis without increasing bleeding by targeting FXI, Dr. Weitz said, adding that ISIS-FXIR_x was also evaluated in a small study of patients with end-stage renal disease undergoing hemodialysis and was shown to produce a dose-dependent reduction in FXI levels and to reduce the incidence of category 3 and 4 clotting in the air trap and dialyzer, compared with placebo, when given in addition to heparin.

This suggests that FXI knockdown can attenuate device-associated clotting to a greater extent than heparin alone, Dr. Weitz said.

The FXIa-directed inhibitory antibody osocimab has also been evaluated in both healthy volunteers and in patients undergoing total knee arthroplasty. In a 2019 study of healthy volunteers, a single IV injection showed a dose-dependent pharmacokinetic profile and produced FXI inhibition for about 1 month, and in the FOXTROT trial published in January in JAMA by Dr. Weitz and colleagues, osocimab was shown to reduce the incidence of symptomatic VTE, asymptomatic DVT, and VTE-related death up to day 10-13 after total knee arthroplasty.

Osocimab at doses ranging from 0.3-1.8 mg/kg given postoperatively or preoperatively were noninferior to enoxaparin (rates of 15.7%-23.7% vs. 26.3%), and osocimab at a preoperative dose of 1.8 mg/kg was superior to both enoxaparin and apixaban (11.5% vs. 26.3% and 14.5%, respectively), he said.

Bleeding rates ranged from 0%-5% with osocimab, compared with 6% with enoxaparin and 2% with apixaban
 

Ongoing studies

Currently ongoing studies of FXI-directed anticoagulation strategies include a study comparing ISIS-FXI_Rx with placebo in 200 patients with end-stage renal disease, a study comparing osocimab with placebo in 600 patients with end-stage renal disease, and a study comparing abelacimab – an antibody that binds to FXI and prevents its activation by either FXIIa or thrombin, with enoxaparin in 700 patients undergoing total knee arthroplasty, Dr. Weitz said.

Additionally, there is “considerable activity” with small molecule inhibitors of FXIa, including a phase 2, placebo-controlled, dose-ranging study looking at the novel JNG-7003/BMS-986177 agent for secondary stroke/transient ischemic attack prevention in 2,500 patients and a phase 2 study comparing it with enoxaparin for postoperative thromboprophylaxis in 1,200 patients undergoing total knee arthroplasty.

Parallel phase 2 studies are also underway to compare the novel BAY-2433334 small molecule inhibitor with placebo for stroke/transient ischemic attack prevention, with apixaban for atrial fibrillation, and for prevention of major adverse cardiovascular events in patients with acute MI.

These ongoing trials will help determine the risk-benefit profile of FXI inhibitors he said.

Session comoderator Anne Rose, PharmD, pharmacy coordinator at the University of Wisconsin, Madison, noted that these types of agents have been discussed “for quite some time” and asked whether they will be available for use in clinical practice in the near future.

Dr. Weitz predicted it will be at least a few years. The studies are just now moving to phase 2b and will still need to be evaluated in phase 3 trials and for appropriate new indications, he said.

Dr. Weitz reported research support from Canadian Institutes of Health research, Heart and Stroke Foundation, and Canadian Fund for Innovation, and he is a consultant and/or scientific advisory board member for Anthos, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen, Merck, Novartis, Pfizer, Portola, Servier , and Thetherex.

sworcester@mdedge.com

Factor XI has emerged as a promising target for new anticoagulants, and several strategies for inhibiting the enzyme to reduce stroke, thromboembolism, and bleeding risk are under investigation, according to Jeffrey I. Weitz, MD.

These strategies could pick up where direct-acting oral anticoagulants leave off, he suggested during a presentation at the biennial summit of the Thrombosis & Hemostasis Societies of North America.

“We all know that the direct oral anticoagulants – the DOACs – are an advance over vitamin K antagonists,” said Dr. Weitz, professor of medicine and biochemistry at McMaster University, Hamilton, Ontario.

Not only are DOACs at least as effective as vitamin K antagonists such as warfarin for stroke prevention in atrial fibrillation or for treatment of venous thromboembolism (VTE), but they also reduce intracranial bleeding and major bleeding risk in those settings, respectively, and they are more convenient to administer because they can be delivered using fixed doses without the need for coagulation monitoring, he added.

Still, new targets are needed, he said, explaining that, although DOACs moved closer to the goal of attenuating thrombosis without increasing the risk of bleeding, annual rates of major bleeding remain at 2%-3% in the atrial fibrillation population, and rates of major and clinically relevant nonmajor bleeding are about 10%.

“The fear of bleeding leads to underuse of anticoagulants for eligible patients with atrial fibrillation and inappropriate use of low-dose [non–vitamin K antagonist oral anticoagulant] regimens, which can leave patients unprotected from thrombotic complications,” he said.
 

Factor XI

That’s where Factor XI (FXI) may come in, Dr. Weitz said.

Current anticoagulants target enzymes, including FXa or thrombin, in the common pathway of coagulation, but the intrinsic pathway at the level of FXI and FXII has attracted attention in recent years.

The intrinsic pathway is activated when blood comes into contact with medical devices like stents, mechanical heart valves, or central venous catheters, but evidence also suggests that it plays a role in clot stabilization and growth, he explained, noting additional evidence of attenuation of thrombosis in mice deficient in FXI or FXII and in animals with FXI or FXII inhibitors.

“There is no bleeding with congenital FXII deficiency, and patients with FXI deficiency rarely have spontaneous bleeding, although they can bleed with surgery or trauma,” he noted. “Therefore, the promise of contact pathway inhibition is that we can attenuate thrombosis with little or no disruption of hemostasis.”

The initiators of the intrinsic pathway are naturally occurring polyphosphates that can activate FXI and FXII, promote platelet activation, and lead to thrombosis. A number of agents are being investigated to target these enzymes – particularly FXI, for which the strongest epidemiological and other evidence of its link with thrombosis exists. He noted that FXI deficiency appears protective against deep-vein thrombosis (DVT) and ischemic stroke, whereas high levels are linked with an increased risk of venous and arterial thrombosis.

Investigative strategies include the use of antisense oligonucleotides to reduce hepatic synthesis of FXI, aptamers to bind FXI and block its activity, antibodies to bind FXI and block its activation or activity, and small molecules to bind reversibly to the active site of FXI and block its activity “much like the DOACs block the activity of FXa or thrombin.”

“We have to remember that the DOACs have taken over from vitamin K antagonists, like warfarin, for many indications, and as they go generic their uptake will increase even further,” Dr. Weitz said. “When we compare the FXI inhibitors with existing anticoagulants, we don’t necessarily want to go up against the DOACs – we’re looking for indications where [DOACs] have yet to be tested or may be unsafe.”

Potential indications include the following:

Prevention of major adverse cardiovascular events in patients with end-stage renal disease with or without atrial fibrillation.

Provision of a safer platform for antiplatelet therapy in patients with acute coronary syndrome.

Secondary stroke prevention.

Prevention or treatment of cancer-associated VTE.

Prevention of thrombosis associated with central venous catheters, left ventricular assist devices, or mechanical heart valves.

Agents in development

Of the FXI inhibitors in development, ISIS-FXI_Rx, an antisense oligonucleotide against FXI, is furthest along. In a study published in Blood, ISIS-FXI_Rx produced a dose-dependent and sustained reduction in FXI levels in healthy volunteers, and in a later randomized study published in The New England Journal of Medicine, it significantly reduced the incidence of DVT in patients undergoing voluntary total knee arthroplasty (30.4% with enoxaparin vs. 4.2% with ISIS-FXI_Rx at a dose of 300 mg). Bleeding rates were 8.3% and 2.6%, respectively.

The findings showed the potential for reducing thrombosis without increasing bleeding by targeting FXI, Dr. Weitz said, adding that ISIS-FXIR_x was also evaluated in a small study of patients with end-stage renal disease undergoing hemodialysis and was shown to produce a dose-dependent reduction in FXI levels and to reduce the incidence of category 3 and 4 clotting in the air trap and dialyzer, compared with placebo, when given in addition to heparin.

This suggests that FXI knockdown can attenuate device-associated clotting to a greater extent than heparin alone, Dr. Weitz said.

The FXIa-directed inhibitory antibody osocimab has also been evaluated in both healthy volunteers and in patients undergoing total knee arthroplasty. In a 2019 study of healthy volunteers, a single IV injection showed a dose-dependent pharmacokinetic profile and produced FXI inhibition for about 1 month, and in the FOXTROT trial published in January in JAMA by Dr. Weitz and colleagues, osocimab was shown to reduce the incidence of symptomatic VTE, asymptomatic DVT, and VTE-related death up to day 10-13 after total knee arthroplasty.

Osocimab at doses ranging from 0.3-1.8 mg/kg given postoperatively or preoperatively were noninferior to enoxaparin (rates of 15.7%-23.7% vs. 26.3%), and osocimab at a preoperative dose of 1.8 mg/kg was superior to both enoxaparin and apixaban (11.5% vs. 26.3% and 14.5%, respectively), he said.

Bleeding rates ranged from 0%-5% with osocimab, compared with 6% with enoxaparin and 2% with apixaban
 

Ongoing studies

Currently ongoing studies of FXI-directed anticoagulation strategies include a study comparing ISIS-FXI_Rx with placebo in 200 patients with end-stage renal disease, a study comparing osocimab with placebo in 600 patients with end-stage renal disease, and a study comparing abelacimab – an antibody that binds to FXI and prevents its activation by either FXIIa or thrombin, with enoxaparin in 700 patients undergoing total knee arthroplasty, Dr. Weitz said.

Additionally, there is “considerable activity” with small molecule inhibitors of FXIa, including a phase 2, placebo-controlled, dose-ranging study looking at the novel JNG-7003/BMS-986177 agent for secondary stroke/transient ischemic attack prevention in 2,500 patients and a phase 2 study comparing it with enoxaparin for postoperative thromboprophylaxis in 1,200 patients undergoing total knee arthroplasty.

Parallel phase 2 studies are also underway to compare the novel BAY-2433334 small molecule inhibitor with placebo for stroke/transient ischemic attack prevention, with apixaban for atrial fibrillation, and for prevention of major adverse cardiovascular events in patients with acute MI.

These ongoing trials will help determine the risk-benefit profile of FXI inhibitors he said.

Session comoderator Anne Rose, PharmD, pharmacy coordinator at the University of Wisconsin, Madison, noted that these types of agents have been discussed “for quite some time” and asked whether they will be available for use in clinical practice in the near future.

Dr. Weitz predicted it will be at least a few years. The studies are just now moving to phase 2b and will still need to be evaluated in phase 3 trials and for appropriate new indications, he said.

Dr. Weitz reported research support from Canadian Institutes of Health research, Heart and Stroke Foundation, and Canadian Fund for Innovation, and he is a consultant and/or scientific advisory board member for Anthos, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen, Merck, Novartis, Pfizer, Portola, Servier , and Thetherex.

sworcester@mdedge.com

Factor XI has emerged as a promising target for new anticoagulants, and several strategies for inhibiting the enzyme to reduce stroke, thromboembolism, and bleeding risk are under investigation, according to Jeffrey I. Weitz, MD.

These strategies could pick up where direct-acting oral anticoagulants leave off, he suggested during a presentation at the biennial summit of the Thrombosis & Hemostasis Societies of North America.

“We all know that the direct oral anticoagulants – the DOACs – are an advance over vitamin K antagonists,” said Dr. Weitz, professor of medicine and biochemistry at McMaster University, Hamilton, Ontario.

Not only are DOACs at least as effective as vitamin K antagonists such as warfarin for stroke prevention in atrial fibrillation or for treatment of venous thromboembolism (VTE), but they also reduce intracranial bleeding and major bleeding risk in those settings, respectively, and they are more convenient to administer because they can be delivered using fixed doses without the need for coagulation monitoring, he added.

Still, new targets are needed, he said, explaining that, although DOACs moved closer to the goal of attenuating thrombosis without increasing the risk of bleeding, annual rates of major bleeding remain at 2%-3% in the atrial fibrillation population, and rates of major and clinically relevant nonmajor bleeding are about 10%.

“The fear of bleeding leads to underuse of anticoagulants for eligible patients with atrial fibrillation and inappropriate use of low-dose [non–vitamin K antagonist oral anticoagulant] regimens, which can leave patients unprotected from thrombotic complications,” he said.
 

Factor XI

That’s where Factor XI (FXI) may come in, Dr. Weitz said.

Current anticoagulants target enzymes, including FXa or thrombin, in the common pathway of coagulation, but the intrinsic pathway at the level of FXI and FXII has attracted attention in recent years.

The intrinsic pathway is activated when blood comes into contact with medical devices like stents, mechanical heart valves, or central venous catheters, but evidence also suggests that it plays a role in clot stabilization and growth, he explained, noting additional evidence of attenuation of thrombosis in mice deficient in FXI or FXII and in animals with FXI or FXII inhibitors.

“There is no bleeding with congenital FXII deficiency, and patients with FXI deficiency rarely have spontaneous bleeding, although they can bleed with surgery or trauma,” he noted. “Therefore, the promise of contact pathway inhibition is that we can attenuate thrombosis with little or no disruption of hemostasis.”

The initiators of the intrinsic pathway are naturally occurring polyphosphates that can activate FXI and FXII, promote platelet activation, and lead to thrombosis. A number of agents are being investigated to target these enzymes – particularly FXI, for which the strongest epidemiological and other evidence of its link with thrombosis exists. He noted that FXI deficiency appears protective against deep-vein thrombosis (DVT) and ischemic stroke, whereas high levels are linked with an increased risk of venous and arterial thrombosis.

Investigative strategies include the use of antisense oligonucleotides to reduce hepatic synthesis of FXI, aptamers to bind FXI and block its activity, antibodies to bind FXI and block its activation or activity, and small molecules to bind reversibly to the active site of FXI and block its activity “much like the DOACs block the activity of FXa or thrombin.”

“We have to remember that the DOACs have taken over from vitamin K antagonists, like warfarin, for many indications, and as they go generic their uptake will increase even further,” Dr. Weitz said. “When we compare the FXI inhibitors with existing anticoagulants, we don’t necessarily want to go up against the DOACs – we’re looking for indications where [DOACs] have yet to be tested or may be unsafe.”

Potential indications include the following:

Prevention of major adverse cardiovascular events in patients with end-stage renal disease with or without atrial fibrillation.

Provision of a safer platform for antiplatelet therapy in patients with acute coronary syndrome.

Secondary stroke prevention.

Prevention or treatment of cancer-associated VTE.

Prevention of thrombosis associated with central venous catheters, left ventricular assist devices, or mechanical heart valves.

Agents in development

Of the FXI inhibitors in development, ISIS-FXI_Rx, an antisense oligonucleotide against FXI, is furthest along. In a study published in Blood, ISIS-FXI_Rx produced a dose-dependent and sustained reduction in FXI levels in healthy volunteers, and in a later randomized study published in The New England Journal of Medicine, it significantly reduced the incidence of DVT in patients undergoing voluntary total knee arthroplasty (30.4% with enoxaparin vs. 4.2% with ISIS-FXI_Rx at a dose of 300 mg). Bleeding rates were 8.3% and 2.6%, respectively.

The findings showed the potential for reducing thrombosis without increasing bleeding by targeting FXI, Dr. Weitz said, adding that ISIS-FXIR_x was also evaluated in a small study of patients with end-stage renal disease undergoing hemodialysis and was shown to produce a dose-dependent reduction in FXI levels and to reduce the incidence of category 3 and 4 clotting in the air trap and dialyzer, compared with placebo, when given in addition to heparin.

This suggests that FXI knockdown can attenuate device-associated clotting to a greater extent than heparin alone, Dr. Weitz said.

The FXIa-directed inhibitory antibody osocimab has also been evaluated in both healthy volunteers and in patients undergoing total knee arthroplasty. In a 2019 study of healthy volunteers, a single IV injection showed a dose-dependent pharmacokinetic profile and produced FXI inhibition for about 1 month, and in the FOXTROT trial published in January in JAMA by Dr. Weitz and colleagues, osocimab was shown to reduce the incidence of symptomatic VTE, asymptomatic DVT, and VTE-related death up to day 10-13 after total knee arthroplasty.

Osocimab at doses ranging from 0.3-1.8 mg/kg given postoperatively or preoperatively were noninferior to enoxaparin (rates of 15.7%-23.7% vs. 26.3%), and osocimab at a preoperative dose of 1.8 mg/kg was superior to both enoxaparin and apixaban (11.5% vs. 26.3% and 14.5%, respectively), he said.

Bleeding rates ranged from 0%-5% with osocimab, compared with 6% with enoxaparin and 2% with apixaban
 

Ongoing studies

Currently ongoing studies of FXI-directed anticoagulation strategies include a study comparing ISIS-FXI_Rx with placebo in 200 patients with end-stage renal disease, a study comparing osocimab with placebo in 600 patients with end-stage renal disease, and a study comparing abelacimab – an antibody that binds to FXI and prevents its activation by either FXIIa or thrombin, with enoxaparin in 700 patients undergoing total knee arthroplasty, Dr. Weitz said.

Additionally, there is “considerable activity” with small molecule inhibitors of FXIa, including a phase 2, placebo-controlled, dose-ranging study looking at the novel JNG-7003/BMS-986177 agent for secondary stroke/transient ischemic attack prevention in 2,500 patients and a phase 2 study comparing it with enoxaparin for postoperative thromboprophylaxis in 1,200 patients undergoing total knee arthroplasty.

Parallel phase 2 studies are also underway to compare the novel BAY-2433334 small molecule inhibitor with placebo for stroke/transient ischemic attack prevention, with apixaban for atrial fibrillation, and for prevention of major adverse cardiovascular events in patients with acute MI.

These ongoing trials will help determine the risk-benefit profile of FXI inhibitors he said.

Session comoderator Anne Rose, PharmD, pharmacy coordinator at the University of Wisconsin, Madison, noted that these types of agents have been discussed “for quite some time” and asked whether they will be available for use in clinical practice in the near future.

Dr. Weitz predicted it will be at least a few years. The studies are just now moving to phase 2b and will still need to be evaluated in phase 3 trials and for appropriate new indications, he said.

Dr. Weitz reported research support from Canadian Institutes of Health research, Heart and Stroke Foundation, and Canadian Fund for Innovation, and he is a consultant and/or scientific advisory board member for Anthos, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen, Merck, Novartis, Pfizer, Portola, Servier , and Thetherex.

sworcester@mdedge.com

Cancer patients who receive an immune checkpoint inhibitor have more than a doubled rate of venous thromboembolism during the subsequent 2 years, compared with their rate during the 2 years before treatment, according to a retrospective analysis of more than 2,800 patients treated at a single U.S. center.

The study focused on cancer patients treated with an immune checkpoint inhibitor (ICI) at Massachusetts General Hospital in Boston. It showed that during the 2 years prior to treatment with any type of ICI, the incidence of venous thromboembolic events (VTE) was 4.85/100 patient-years that then jumped to 11.75/100 patient-years during the 2 years following treatment. This translated into an incidence rate ratio of 2.43 during posttreatment follow-up, compared with pretreatment, Jingyi Gong, MD, said at the virtual American Heart Association scientific sessions.

The increased VTE rate resulted from rises in both the rate of deep vein thrombosis, which had an IRR of 3.23 during the posttreatment period, and for pulmonary embolism, which showed an IRR of 2.24, said Dr. Gong, a physician at Brigham and Women’s Hospital in Boston. She hypothesized that this effect may result from a procoagulant effect of the immune activation and inflammation triggered by ICIs.


Hypothesis-generating results

Cardiologists cautioned that these findings should only be considered hypothesis generating, but raise an important alert for clinicians to have heightened awareness of the potential for VTE following ICI treatment.

“A clear message is to be aware that there is this signal, and be vigilant for patients who might present with VTE following ICI treatment,” commented Richard J. Kovacs, MD, a cardiologist and professor at Indiana University, Indianapolis. The data that Dr. Gong reported are “moderately convincing,” he added in an interview.

“Awareness that patients who receive ICI may be at increased VTE risk is very important,” agreed Umberto Campia, MD, a cardiologist, vascular specialist, and member of the cardio-oncology group at Brigham and Women’s Hospital, who was not involved in the new study.

The potential impact of ICI treatment on VTE risk is slowly emerging, added Dr. Campia. Until recently, the literature primarily was case reports, but recently another retrospective, single-center study came out that reported a 13% incidence of VTE in cancer patients following ICI treatment. On the other hand, a recently published meta-analysis of more than 20,000 patients from 68 ICI studies failed to find a suggestion of increased VTE incidence following ICI interventions.

Attempting to assess the impact of treatment on VTE risk in cancer patients is challenging because cancer itself boosts the risk. Recommendations on the use of VTE prophylaxis in cancer patients most recently came out in 2014 from the American Society of Clinical Oncology, which said that VTE prophylaxis for ambulatory cancer patients “may be considered for highly select high-risk patients.” The impact of cancer therapy on VTE risk and the need for prophylaxis is usually assessed by applying the Khorana score, Dr. Campia said in an interview.
 

VTE spikes acutely after ICI treatment

Dr. Gong analyzed VTE incidence rates by time during the total 4-year period studied, and found that the rate gradually and steadily rose with time throughout the 2 years preceding treatment, spiked immediately following ICI treatment, and then gradually and steadily fell back to roughly the rate seen just before treatment, reaching that level about a year after treatment. She ran a sensitivity analysis that excluded patients who died during the first year following their ICI treatment, and in this calculation an acute spike in VTE following ICI treatment still occurred but with reduced magnitude.

She also reported the results of several subgroup analyses. The IRRs remained consistent among women and men, among patients who were aged over or under 65 years, and regardless of cancer type or treatment with corticosteroids. But the subgroup analyses identified two parameters that seemed to clearly split VTE rates.

Among patients on treatment with an anticoagulant agent at the time of their ICI treatment, roughly 10% of the patients, the IRR was 0.56, compared with a ratio of 3.86 among the other patients, suggesting possible protection. A second factor that seemed linked with VTE incidence was the number of ICI treatment cycles a patient received. Those who received more than five cycles had a risk ratio of 3.95, while those who received five or fewer cycles had a RR of 1.66.

Her analysis included 2,842 cancer patients who received treatment with an ICI at Massachusetts General Hospital. Patients averaged 64 years of age, slightly more than half were men, and 13% had a prior history of VTE. Patients received an average of 5 ICI treatment cycles, but a quarter of the patients received more than 10 cycles.

During the 2-year follow-up, 244 patients (9%) developed VTE. The patients who developed VTE were significantly younger than those who did not, with an average age of 63 years, compared with 65. And the patients who eventually developed VTE had a significantly higher prevalence of prior VTE at 18%, compared with 12% among the patients who stayed VTE free.

The cancer types patients had were non–small cell lung, 29%; melanoma, 28%; head and neck, 12%; renal genitourinary, 6%; and other, 25%. ICIs have been available for routine U.S. practice since 2011. The class includes agents such as pembrolizumab (Keytruda) and durvalumab (Imfinzi).

Researchers would need to perform a prospective, randomized study to determine whether anticoagulant prophylaxis is clearly beneficial for patients receiving ICI treatment, Dr. Gong said. But both Dr. Kovacs and Dr. Campia said that more data on this topic are first needed.

“We need to confirm that treatment with ICI is associated with VTEs. Retrospective data are not definitive,” said Dr. Campia. “We would need to prospectively assess the impact of ICI,” which will not be easy, as it’s quickly become a cornerstone for treating many cancers. “We need to become more familiar with the adverse effects of these drugs. We are still learning about their toxicities.”

The study had no commercial funding. Dr. Gong, Dr. Kovacs, and Dr. Campia had no disclosures.

mzoler@mdedge.com

Cancer patients who receive an immune checkpoint inhibitor have more than a doubled rate of venous thromboembolism during the subsequent 2 years, compared with their rate during the 2 years before treatment, according to a retrospective analysis of more than 2,800 patients treated at a single U.S. center.

The study focused on cancer patients treated with an immune checkpoint inhibitor (ICI) at Massachusetts General Hospital in Boston. It showed that during the 2 years prior to treatment with any type of ICI, the incidence of venous thromboembolic events (VTE) was 4.85/100 patient-years that then jumped to 11.75/100 patient-years during the 2 years following treatment. This translated into an incidence rate ratio of 2.43 during posttreatment follow-up, compared with pretreatment, Jingyi Gong, MD, said at the virtual American Heart Association scientific sessions.

The increased VTE rate resulted from rises in both the rate of deep vein thrombosis, which had an IRR of 3.23 during the posttreatment period, and for pulmonary embolism, which showed an IRR of 2.24, said Dr. Gong, a physician at Brigham and Women’s Hospital in Boston. She hypothesized that this effect may result from a procoagulant effect of the immune activation and inflammation triggered by ICIs.


Hypothesis-generating results

Cardiologists cautioned that these findings should only be considered hypothesis generating, but raise an important alert for clinicians to have heightened awareness of the potential for VTE following ICI treatment.

“A clear message is to be aware that there is this signal, and be vigilant for patients who might present with VTE following ICI treatment,” commented Richard J. Kovacs, MD, a cardiologist and professor at Indiana University, Indianapolis. The data that Dr. Gong reported are “moderately convincing,” he added in an interview.

“Awareness that patients who receive ICI may be at increased VTE risk is very important,” agreed Umberto Campia, MD, a cardiologist, vascular specialist, and member of the cardio-oncology group at Brigham and Women’s Hospital, who was not involved in the new study.

The potential impact of ICI treatment on VTE risk is slowly emerging, added Dr. Campia. Until recently, the literature primarily was case reports, but recently another retrospective, single-center study came out that reported a 13% incidence of VTE in cancer patients following ICI treatment. On the other hand, a recently published meta-analysis of more than 20,000 patients from 68 ICI studies failed to find a suggestion of increased VTE incidence following ICI interventions.

Attempting to assess the impact of treatment on VTE risk in cancer patients is challenging because cancer itself boosts the risk. Recommendations on the use of VTE prophylaxis in cancer patients most recently came out in 2014 from the American Society of Clinical Oncology, which said that VTE prophylaxis for ambulatory cancer patients “may be considered for highly select high-risk patients.” The impact of cancer therapy on VTE risk and the need for prophylaxis is usually assessed by applying the Khorana score, Dr. Campia said in an interview.
 

VTE spikes acutely after ICI treatment

Dr. Gong analyzed VTE incidence rates by time during the total 4-year period studied, and found that the rate gradually and steadily rose with time throughout the 2 years preceding treatment, spiked immediately following ICI treatment, and then gradually and steadily fell back to roughly the rate seen just before treatment, reaching that level about a year after treatment. She ran a sensitivity analysis that excluded patients who died during the first year following their ICI treatment, and in this calculation an acute spike in VTE following ICI treatment still occurred but with reduced magnitude.

She also reported the results of several subgroup analyses. The IRRs remained consistent among women and men, among patients who were aged over or under 65 years, and regardless of cancer type or treatment with corticosteroids. But the subgroup analyses identified two parameters that seemed to clearly split VTE rates.

Among patients on treatment with an anticoagulant agent at the time of their ICI treatment, roughly 10% of the patients, the IRR was 0.56, compared with a ratio of 3.86 among the other patients, suggesting possible protection. A second factor that seemed linked with VTE incidence was the number of ICI treatment cycles a patient received. Those who received more than five cycles had a risk ratio of 3.95, while those who received five or fewer cycles had a RR of 1.66.

Her analysis included 2,842 cancer patients who received treatment with an ICI at Massachusetts General Hospital. Patients averaged 64 years of age, slightly more than half were men, and 13% had a prior history of VTE. Patients received an average of 5 ICI treatment cycles, but a quarter of the patients received more than 10 cycles.

During the 2-year follow-up, 244 patients (9%) developed VTE. The patients who developed VTE were significantly younger than those who did not, with an average age of 63 years, compared with 65. And the patients who eventually developed VTE had a significantly higher prevalence of prior VTE at 18%, compared with 12% among the patients who stayed VTE free.

The cancer types patients had were non–small cell lung, 29%; melanoma, 28%; head and neck, 12%; renal genitourinary, 6%; and other, 25%. ICIs have been available for routine U.S. practice since 2011. The class includes agents such as pembrolizumab (Keytruda) and durvalumab (Imfinzi).

Researchers would need to perform a prospective, randomized study to determine whether anticoagulant prophylaxis is clearly beneficial for patients receiving ICI treatment, Dr. Gong said. But both Dr. Kovacs and Dr. Campia said that more data on this topic are first needed.

“We need to confirm that treatment with ICI is associated with VTEs. Retrospective data are not definitive,” said Dr. Campia. “We would need to prospectively assess the impact of ICI,” which will not be easy, as it’s quickly become a cornerstone for treating many cancers. “We need to become more familiar with the adverse effects of these drugs. We are still learning about their toxicities.”

The study had no commercial funding. Dr. Gong, Dr. Kovacs, and Dr. Campia had no disclosures.

mzoler@mdedge.com

Cancer patients who receive an immune checkpoint inhibitor have more than a doubled rate of venous thromboembolism during the subsequent 2 years, compared with their rate during the 2 years before treatment, according to a retrospective analysis of more than 2,800 patients treated at a single U.S. center.

The study focused on cancer patients treated with an immune checkpoint inhibitor (ICI) at Massachusetts General Hospital in Boston. It showed that during the 2 years prior to treatment with any type of ICI, the incidence of venous thromboembolic events (VTE) was 4.85/100 patient-years that then jumped to 11.75/100 patient-years during the 2 years following treatment. This translated into an incidence rate ratio of 2.43 during posttreatment follow-up, compared with pretreatment, Jingyi Gong, MD, said at the virtual American Heart Association scientific sessions.

The increased VTE rate resulted from rises in both the rate of deep vein thrombosis, which had an IRR of 3.23 during the posttreatment period, and for pulmonary embolism, which showed an IRR of 2.24, said Dr. Gong, a physician at Brigham and Women’s Hospital in Boston. She hypothesized that this effect may result from a procoagulant effect of the immune activation and inflammation triggered by ICIs.


Hypothesis-generating results

Cardiologists cautioned that these findings should only be considered hypothesis generating, but raise an important alert for clinicians to have heightened awareness of the potential for VTE following ICI treatment.

“A clear message is to be aware that there is this signal, and be vigilant for patients who might present with VTE following ICI treatment,” commented Richard J. Kovacs, MD, a cardiologist and professor at Indiana University, Indianapolis. The data that Dr. Gong reported are “moderately convincing,” he added in an interview.

“Awareness that patients who receive ICI may be at increased VTE risk is very important,” agreed Umberto Campia, MD, a cardiologist, vascular specialist, and member of the cardio-oncology group at Brigham and Women’s Hospital, who was not involved in the new study.

The potential impact of ICI treatment on VTE risk is slowly emerging, added Dr. Campia. Until recently, the literature primarily was case reports, but recently another retrospective, single-center study came out that reported a 13% incidence of VTE in cancer patients following ICI treatment. On the other hand, a recently published meta-analysis of more than 20,000 patients from 68 ICI studies failed to find a suggestion of increased VTE incidence following ICI interventions.

Attempting to assess the impact of treatment on VTE risk in cancer patients is challenging because cancer itself boosts the risk. Recommendations on the use of VTE prophylaxis in cancer patients most recently came out in 2014 from the American Society of Clinical Oncology, which said that VTE prophylaxis for ambulatory cancer patients “may be considered for highly select high-risk patients.” The impact of cancer therapy on VTE risk and the need for prophylaxis is usually assessed by applying the Khorana score, Dr. Campia said in an interview.
 

VTE spikes acutely after ICI treatment

Dr. Gong analyzed VTE incidence rates by time during the total 4-year period studied, and found that the rate gradually and steadily rose with time throughout the 2 years preceding treatment, spiked immediately following ICI treatment, and then gradually and steadily fell back to roughly the rate seen just before treatment, reaching that level about a year after treatment. She ran a sensitivity analysis that excluded patients who died during the first year following their ICI treatment, and in this calculation an acute spike in VTE following ICI treatment still occurred but with reduced magnitude.

She also reported the results of several subgroup analyses. The IRRs remained consistent among women and men, among patients who were aged over or under 65 years, and regardless of cancer type or treatment with corticosteroids. But the subgroup analyses identified two parameters that seemed to clearly split VTE rates.

Among patients on treatment with an anticoagulant agent at the time of their ICI treatment, roughly 10% of the patients, the IRR was 0.56, compared with a ratio of 3.86 among the other patients, suggesting possible protection. A second factor that seemed linked with VTE incidence was the number of ICI treatment cycles a patient received. Those who received more than five cycles had a risk ratio of 3.95, while those who received five or fewer cycles had a RR of 1.66.

Her analysis included 2,842 cancer patients who received treatment with an ICI at Massachusetts General Hospital. Patients averaged 64 years of age, slightly more than half were men, and 13% had a prior history of VTE. Patients received an average of 5 ICI treatment cycles, but a quarter of the patients received more than 10 cycles.

During the 2-year follow-up, 244 patients (9%) developed VTE. The patients who developed VTE were significantly younger than those who did not, with an average age of 63 years, compared with 65. And the patients who eventually developed VTE had a significantly higher prevalence of prior VTE at 18%, compared with 12% among the patients who stayed VTE free.

The cancer types patients had were non–small cell lung, 29%; melanoma, 28%; head and neck, 12%; renal genitourinary, 6%; and other, 25%. ICIs have been available for routine U.S. practice since 2011. The class includes agents such as pembrolizumab (Keytruda) and durvalumab (Imfinzi).

Researchers would need to perform a prospective, randomized study to determine whether anticoagulant prophylaxis is clearly beneficial for patients receiving ICI treatment, Dr. Gong said. But both Dr. Kovacs and Dr. Campia said that more data on this topic are first needed.

“We need to confirm that treatment with ICI is associated with VTEs. Retrospective data are not definitive,” said Dr. Campia. “We would need to prospectively assess the impact of ICI,” which will not be easy, as it’s quickly become a cornerstone for treating many cancers. “We need to become more familiar with the adverse effects of these drugs. We are still learning about their toxicities.”

The study had no commercial funding. Dr. Gong, Dr. Kovacs, and Dr. Campia had no disclosures.

mzoler@mdedge.com

In patients with intermediate-risk pulmonary arterial hypertension (PAH) who are not at treatment goal on standard therapy, switching to riociguat is a promising strategy across a broad range of patient subgroups, an investigator said at the annual meeting of the American College of Chest Physicians, held virtually this year.

Patients switching to riociguat in the REPLACE study more frequently met the primary efficacy endpoint, compared with patients who remained on a phosphodiesterase-5 (PDE5) inhibitor, said Marius M. Hoeper, MD, of the Clinic for Respiratory Medicine at Hannover (Germany) Medical School.

That clinical benefit of switching to riociguat, a soluble guanylate cyclase (sGC) stimulator, was relatively consistent across patient subgroups including age, sex, PAH subtype, according to Dr. Hoeper.

“At the end of the day, we believe that switching from a PDE5 inhibitor to riociguat can benefit patients with PAH at intermediate risk and may serve as a new strategic option for treatment escalation,” he said in a live virtual presentation of the study results.

About 40% of patients switching to riociguat met the primary endpoint of clinical improvement in absence of clinical worsening versus just 20% of patients who stayed on a PDE5 inhibitor, according to top-line results of the phase 4 REPLACE study, which were reported Sept. 7 at the annual meeting of the European Respiratory Society.

Results of REPLACE presented at the CHEST meeting show a benefit across most patient subgroups, including PAH subtype and whether patients came from monotherapy or combination treatment to riociguat. Some groups did not appear to respond quite as well to switching, including elderly patients, patients with a 6-minute walk distance (6MWD) of less than 320 meters at baseline, and patients switching from tadalafil as opposed to sildenafil. However, these findings were not statistically significant and may have been chance findings, according to Dr. Hoeper.

These results of REPLACE suggest the efficacy of riociguat “across the board” for intermediate-risk PAH patients with inadequate response to standard therapy, said Vijay Balasubramanian, MD, FCCP, clinical professor of medicine at the University of California San Francisco, Fresno.

Based on REPLACE results, switching from a PDE5 inhibitor to riociguat is now a “strong potential option” beyond adding a third drug such as selexipag or an inhaled prostacyclin to usual treatment with a PDE5 inhibitor plus an endothelin receptor antagonist, Dr. Balasubramanian said in an interview.

“We now have an evidence-based option where you can stay on a two-drug regimen and see whether the switch would work just as well,” said Dr. Balasubramanian, vice chair of the Pulmonary Vascular Disease Steering Committee for the American College of Chest Physicians.

REPLACE is a randomized phase 4 study including 226 patients with PAH considered to be at intermediate risk according to World Health Organization functional class III or 6MWD of 165-440 meters. The composite primary endpoint was defined as no clinical worsening (death, disease progression, or hospitalization for worsening PAH) plus clinical improvement on at least two measures including an improvement in 6MWD, achieving WHO functional class I/II, or a decrease in N-terminal pro-brain natriuretic peptide (NT-proBNP).

The primary endpoint of REPLACE was met, showing that 45 patients (41%) who switched to riociguat had clinical improvement without clinical worsening versus 22 patient (20%) who stayed on the PDE5 inhibitor (odds ratio, 2.78; 95% confidence interval, 1.53-5.06; P = .0007), Dr. Hoeper reported.

The benefit appeared consistent across PAH subgroups, according to Dr. Hoeper. In patients with idiopathic, heritable, or drug- and toxin-induced PAH, the primary endpoint favored riociguat over PDE5 inhibitor, at 45% and 23%, respectively. Similarly, a higher proportion of patients with PAH associated with congenital heart disease or portal hypertension achieved the primary endpoint (46% vs. 8%), as did patients with PAH associated with connective tissue disease (25% vs. 16%).

Adverse events were seen in 71% of riociguat-treated patients and 66% of PDE5 inhibitor–treated patients, according to Dr. Hoeper, who said severe adverse events were more frequent with PDE5-inhibitor treatment, at 17% versus 7% for riociguat. There were three clinical worsening events in the PDE5 inhibitor group leading to death, while a fourth patient died in safety follow-up, according to the reported results, whereas there were no deaths reported with riociguat.

The REPLACE study was cofunded by Bayer AG and Merck Sharpe & Dohme, a subsidiary of Merck & Co. Dr. Hoeper reported receiving fees for consultations or lectures from Acceleron, Actelion, Bayer AG, Janssen, MSD, and Pfizer.

SOURCE: Hoeper MM. CHEST 2020, Abstract A2156-A2159.

In patients with intermediate-risk pulmonary arterial hypertension (PAH) who are not at treatment goal on standard therapy, switching to riociguat is a promising strategy across a broad range of patient subgroups, an investigator said at the annual meeting of the American College of Chest Physicians, held virtually this year.

Patients switching to riociguat in the REPLACE study more frequently met the primary efficacy endpoint, compared with patients who remained on a phosphodiesterase-5 (PDE5) inhibitor, said Marius M. Hoeper, MD, of the Clinic for Respiratory Medicine at Hannover (Germany) Medical School.

That clinical benefit of switching to riociguat, a soluble guanylate cyclase (sGC) stimulator, was relatively consistent across patient subgroups including age, sex, PAH subtype, according to Dr. Hoeper.

“At the end of the day, we believe that switching from a PDE5 inhibitor to riociguat can benefit patients with PAH at intermediate risk and may serve as a new strategic option for treatment escalation,” he said in a live virtual presentation of the study results.

About 40% of patients switching to riociguat met the primary endpoint of clinical improvement in absence of clinical worsening versus just 20% of patients who stayed on a PDE5 inhibitor, according to top-line results of the phase 4 REPLACE study, which were reported Sept. 7 at the annual meeting of the European Respiratory Society.

Results of REPLACE presented at the CHEST meeting show a benefit across most patient subgroups, including PAH subtype and whether patients came from monotherapy or combination treatment to riociguat. Some groups did not appear to respond quite as well to switching, including elderly patients, patients with a 6-minute walk distance (6MWD) of less than 320 meters at baseline, and patients switching from tadalafil as opposed to sildenafil. However, these findings were not statistically significant and may have been chance findings, according to Dr. Hoeper.

These results of REPLACE suggest the efficacy of riociguat “across the board” for intermediate-risk PAH patients with inadequate response to standard therapy, said Vijay Balasubramanian, MD, FCCP, clinical professor of medicine at the University of California San Francisco, Fresno.

Based on REPLACE results, switching from a PDE5 inhibitor to riociguat is now a “strong potential option” beyond adding a third drug such as selexipag or an inhaled prostacyclin to usual treatment with a PDE5 inhibitor plus an endothelin receptor antagonist, Dr. Balasubramanian said in an interview.

“We now have an evidence-based option where you can stay on a two-drug regimen and see whether the switch would work just as well,” said Dr. Balasubramanian, vice chair of the Pulmonary Vascular Disease Steering Committee for the American College of Chest Physicians.

REPLACE is a randomized phase 4 study including 226 patients with PAH considered to be at intermediate risk according to World Health Organization functional class III or 6MWD of 165-440 meters. The composite primary endpoint was defined as no clinical worsening (death, disease progression, or hospitalization for worsening PAH) plus clinical improvement on at least two measures including an improvement in 6MWD, achieving WHO functional class I/II, or a decrease in N-terminal pro-brain natriuretic peptide (NT-proBNP).

The primary endpoint of REPLACE was met, showing that 45 patients (41%) who switched to riociguat had clinical improvement without clinical worsening versus 22 patient (20%) who stayed on the PDE5 inhibitor (odds ratio, 2.78; 95% confidence interval, 1.53-5.06; P = .0007), Dr. Hoeper reported.

The benefit appeared consistent across PAH subgroups, according to Dr. Hoeper. In patients with idiopathic, heritable, or drug- and toxin-induced PAH, the primary endpoint favored riociguat over PDE5 inhibitor, at 45% and 23%, respectively. Similarly, a higher proportion of patients with PAH associated with congenital heart disease or portal hypertension achieved the primary endpoint (46% vs. 8%), as did patients with PAH associated with connective tissue disease (25% vs. 16%).

Adverse events were seen in 71% of riociguat-treated patients and 66% of PDE5 inhibitor–treated patients, according to Dr. Hoeper, who said severe adverse events were more frequent with PDE5-inhibitor treatment, at 17% versus 7% for riociguat. There were three clinical worsening events in the PDE5 inhibitor group leading to death, while a fourth patient died in safety follow-up, according to the reported results, whereas there were no deaths reported with riociguat.

The REPLACE study was cofunded by Bayer AG and Merck Sharpe & Dohme, a subsidiary of Merck & Co. Dr. Hoeper reported receiving fees for consultations or lectures from Acceleron, Actelion, Bayer AG, Janssen, MSD, and Pfizer.

SOURCE: Hoeper MM. CHEST 2020, Abstract A2156-A2159.

In patients with intermediate-risk pulmonary arterial hypertension (PAH) who are not at treatment goal on standard therapy, switching to riociguat is a promising strategy across a broad range of patient subgroups, an investigator said at the annual meeting of the American College of Chest Physicians, held virtually this year.

Patients switching to riociguat in the REPLACE study more frequently met the primary efficacy endpoint, compared with patients who remained on a phosphodiesterase-5 (PDE5) inhibitor, said Marius M. Hoeper, MD, of the Clinic for Respiratory Medicine at Hannover (Germany) Medical School.

That clinical benefit of switching to riociguat, a soluble guanylate cyclase (sGC) stimulator, was relatively consistent across patient subgroups including age, sex, PAH subtype, according to Dr. Hoeper.

“At the end of the day, we believe that switching from a PDE5 inhibitor to riociguat can benefit patients with PAH at intermediate risk and may serve as a new strategic option for treatment escalation,” he said in a live virtual presentation of the study results.

About 40% of patients switching to riociguat met the primary endpoint of clinical improvement in absence of clinical worsening versus just 20% of patients who stayed on a PDE5 inhibitor, according to top-line results of the phase 4 REPLACE study, which were reported Sept. 7 at the annual meeting of the European Respiratory Society.

Results of REPLACE presented at the CHEST meeting show a benefit across most patient subgroups, including PAH subtype and whether patients came from monotherapy or combination treatment to riociguat. Some groups did not appear to respond quite as well to switching, including elderly patients, patients with a 6-minute walk distance (6MWD) of less than 320 meters at baseline, and patients switching from tadalafil as opposed to sildenafil. However, these findings were not statistically significant and may have been chance findings, according to Dr. Hoeper.

These results of REPLACE suggest the efficacy of riociguat “across the board” for intermediate-risk PAH patients with inadequate response to standard therapy, said Vijay Balasubramanian, MD, FCCP, clinical professor of medicine at the University of California San Francisco, Fresno.

Based on REPLACE results, switching from a PDE5 inhibitor to riociguat is now a “strong potential option” beyond adding a third drug such as selexipag or an inhaled prostacyclin to usual treatment with a PDE5 inhibitor plus an endothelin receptor antagonist, Dr. Balasubramanian said in an interview.

“We now have an evidence-based option where you can stay on a two-drug regimen and see whether the switch would work just as well,” said Dr. Balasubramanian, vice chair of the Pulmonary Vascular Disease Steering Committee for the American College of Chest Physicians.

REPLACE is a randomized phase 4 study including 226 patients with PAH considered to be at intermediate risk according to World Health Organization functional class III or 6MWD of 165-440 meters. The composite primary endpoint was defined as no clinical worsening (death, disease progression, or hospitalization for worsening PAH) plus clinical improvement on at least two measures including an improvement in 6MWD, achieving WHO functional class I/II, or a decrease in N-terminal pro-brain natriuretic peptide (NT-proBNP).

The primary endpoint of REPLACE was met, showing that 45 patients (41%) who switched to riociguat had clinical improvement without clinical worsening versus 22 patient (20%) who stayed on the PDE5 inhibitor (odds ratio, 2.78; 95% confidence interval, 1.53-5.06; P = .0007), Dr. Hoeper reported.

The benefit appeared consistent across PAH subgroups, according to Dr. Hoeper. In patients with idiopathic, heritable, or drug- and toxin-induced PAH, the primary endpoint favored riociguat over PDE5 inhibitor, at 45% and 23%, respectively. Similarly, a higher proportion of patients with PAH associated with congenital heart disease or portal hypertension achieved the primary endpoint (46% vs. 8%), as did patients with PAH associated with connective tissue disease (25% vs. 16%).

Adverse events were seen in 71% of riociguat-treated patients and 66% of PDE5 inhibitor–treated patients, according to Dr. Hoeper, who said severe adverse events were more frequent with PDE5-inhibitor treatment, at 17% versus 7% for riociguat. There were three clinical worsening events in the PDE5 inhibitor group leading to death, while a fourth patient died in safety follow-up, according to the reported results, whereas there were no deaths reported with riociguat.

The REPLACE study was cofunded by Bayer AG and Merck Sharpe & Dohme, a subsidiary of Merck & Co. Dr. Hoeper reported receiving fees for consultations or lectures from Acceleron, Actelion, Bayer AG, Janssen, MSD, and Pfizer.

SOURCE: Hoeper MM. CHEST 2020, Abstract A2156-A2159.

Selexipag (Uptravi) does not change the level of daily activity of patients with pulmonary arterial hypertension (PAH), results from the phase 4 TRACE trial suggest.

“We had no preconceived idea if this drug would improve exercise capacity,” said Luke Howard, MD, of Imperial College Healthcare NHS Trust in London. It was clear, however, that 6-minute walk tests conducted a few times a year “don’t paint a picture of what daily life is like for patients on selexipag.”

The oral prostacyclin IP receptor agonist is prescribed to slow the progression of PAH and reduce hospital admissions, but there are no studies that show whether it improves quality of life.

Dr. Howard and his team turned to wearable technology to “capture a snapshot of everyday life,” he explained during his presentation at the annual meeting of the American College of Chest Physicians (CHEST 2020), held virtually this year.

The primary concern of the investigators was to get TRACE participants – all with PAH – to wear a wrist device; they did not encourage patients to become more active. “We wanted a true picture of the impact of the drug itself,” he noted.

After 24 months of daily tracking, “there was no benefit to increased daily activity for patients taking this drug,” Dr. Howard said in an interview. “That was a bit deflating.”

The daily activity of TRACE participants was “slightly more elevated” in the selexipag group than in the placebo group. “We saw some numerical drops in activity in the placebo group, and a trend that might make a difference over a longer, bigger study, but not in a statically significant way,” he reported.

In the randomized, blinded trial – the first to track the activity of PAH patients – 53 participants received selexipag and 55 received placebo. All 108 wore a wrist accelerometer (GT9X Link) that counted the number of steps taken each day, providing an indication of daily activity.

Device compliance – the mean number of days in which the device was worn for at least 7 hours during a 14-day predrug period – was similar in the selexipag and placebo groups (13.2 vs 13.0 days).

“We wanted to make sure we had people who were stable and weren’t enrolled in a rehabilitation program; we didn’t want any competing influences,” Dr. Howard explained. All in all, the participants were in pretty good shape. “There was a low risk of a bad outcome.”

The primary endpoint was change in activity from baseline to week 24. The secondary endpoints were PAH-SYMPACT health quality-of-life tests and 6-minute walk distance.
 

Similar activity levels in both groups

As expected in a population in which the majority of patients meet the criteria for WHO functional class II PAH, all participants had low PAH-SYMPACT domain scores throughout the trial.

All adverse events were “consistent with the known profile” of selexipag, and there were no deaths, Dr. Howard reported.

“We did not show any significant benefit to taking the drug,” he said, but the drug is marketed for the prevention of disease progression, and this finding “doesn’t change that.”
 

Pulmonary rehabilitation

“Pulmonary rehabilitation is one of the most vital management issues with chronic lung disease,” Riddhi Upadhyay, MD, of Carle Foundation Hospital in Urbana, Ill., said during her CHEST 2020 presentation on improving PAH rehabilitation referral rates.

“We know it improves exercise capacity, lung function, and decreases total hospital stays and recurrent hospital admission,” she explained. And studies have shown that PAH rehabilitation “also reduces frailty and improves quality of life.”

In their study, Dr. Upadhyay and colleagues showed that when pulmonary rehabilitation is added to the discharge order set, referrals increase by 60%.

They attribute their success to “recognizing the benefits of pulmonary rehab and understanding where interventions are required.”

An encouraging takeaway from the TRACE data is that it established that daily activity can be tracked in this patient population. “We think we might need to encourage these patients to get active, maybe combine the drug with a formal rehabilitation program; that might increase motivation,” Dr. Howard said.

“People don’t necessarily do more just because they can,” he noted.

Dr. Howard has received consulting fees from Actelion.
 

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

Selexipag (Uptravi) does not change the level of daily activity of patients with pulmonary arterial hypertension (PAH), results from the phase 4 TRACE trial suggest.

“We had no preconceived idea if this drug would improve exercise capacity,” said Luke Howard, MD, of Imperial College Healthcare NHS Trust in London. It was clear, however, that 6-minute walk tests conducted a few times a year “don’t paint a picture of what daily life is like for patients on selexipag.”

The oral prostacyclin IP receptor agonist is prescribed to slow the progression of PAH and reduce hospital admissions, but there are no studies that show whether it improves quality of life.

Dr. Howard and his team turned to wearable technology to “capture a snapshot of everyday life,” he explained during his presentation at the annual meeting of the American College of Chest Physicians (CHEST 2020), held virtually this year.

The primary concern of the investigators was to get TRACE participants – all with PAH – to wear a wrist device; they did not encourage patients to become more active. “We wanted a true picture of the impact of the drug itself,” he noted.

After 24 months of daily tracking, “there was no benefit to increased daily activity for patients taking this drug,” Dr. Howard said in an interview. “That was a bit deflating.”

The daily activity of TRACE participants was “slightly more elevated” in the selexipag group than in the placebo group. “We saw some numerical drops in activity in the placebo group, and a trend that might make a difference over a longer, bigger study, but not in a statically significant way,” he reported.

In the randomized, blinded trial – the first to track the activity of PAH patients – 53 participants received selexipag and 55 received placebo. All 108 wore a wrist accelerometer (GT9X Link) that counted the number of steps taken each day, providing an indication of daily activity.

Device compliance – the mean number of days in which the device was worn for at least 7 hours during a 14-day predrug period – was similar in the selexipag and placebo groups (13.2 vs 13.0 days).

“We wanted to make sure we had people who were stable and weren’t enrolled in a rehabilitation program; we didn’t want any competing influences,” Dr. Howard explained. All in all, the participants were in pretty good shape. “There was a low risk of a bad outcome.”

The primary endpoint was change in activity from baseline to week 24. The secondary endpoints were PAH-SYMPACT health quality-of-life tests and 6-minute walk distance.
 

Similar activity levels in both groups

As expected in a population in which the majority of patients meet the criteria for WHO functional class II PAH, all participants had low PAH-SYMPACT domain scores throughout the trial.

All adverse events were “consistent with the known profile” of selexipag, and there were no deaths, Dr. Howard reported.

“We did not show any significant benefit to taking the drug,” he said, but the drug is marketed for the prevention of disease progression, and this finding “doesn’t change that.”
 

Pulmonary rehabilitation

“Pulmonary rehabilitation is one of the most vital management issues with chronic lung disease,” Riddhi Upadhyay, MD, of Carle Foundation Hospital in Urbana, Ill., said during her CHEST 2020 presentation on improving PAH rehabilitation referral rates.

“We know it improves exercise capacity, lung function, and decreases total hospital stays and recurrent hospital admission,” she explained. And studies have shown that PAH rehabilitation “also reduces frailty and improves quality of life.”

In their study, Dr. Upadhyay and colleagues showed that when pulmonary rehabilitation is added to the discharge order set, referrals increase by 60%.

They attribute their success to “recognizing the benefits of pulmonary rehab and understanding where interventions are required.”

An encouraging takeaway from the TRACE data is that it established that daily activity can be tracked in this patient population. “We think we might need to encourage these patients to get active, maybe combine the drug with a formal rehabilitation program; that might increase motivation,” Dr. Howard said.

“People don’t necessarily do more just because they can,” he noted.

Dr. Howard has received consulting fees from Actelion.
 

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

Selexipag (Uptravi) does not change the level of daily activity of patients with pulmonary arterial hypertension (PAH), results from the phase 4 TRACE trial suggest.

“We had no preconceived idea if this drug would improve exercise capacity,” said Luke Howard, MD, of Imperial College Healthcare NHS Trust in London. It was clear, however, that 6-minute walk tests conducted a few times a year “don’t paint a picture of what daily life is like for patients on selexipag.”

The oral prostacyclin IP receptor agonist is prescribed to slow the progression of PAH and reduce hospital admissions, but there are no studies that show whether it improves quality of life.

Dr. Howard and his team turned to wearable technology to “capture a snapshot of everyday life,” he explained during his presentation at the annual meeting of the American College of Chest Physicians (CHEST 2020), held virtually this year.

The primary concern of the investigators was to get TRACE participants – all with PAH – to wear a wrist device; they did not encourage patients to become more active. “We wanted a true picture of the impact of the drug itself,” he noted.

After 24 months of daily tracking, “there was no benefit to increased daily activity for patients taking this drug,” Dr. Howard said in an interview. “That was a bit deflating.”

The daily activity of TRACE participants was “slightly more elevated” in the selexipag group than in the placebo group. “We saw some numerical drops in activity in the placebo group, and a trend that might make a difference over a longer, bigger study, but not in a statically significant way,” he reported.

In the randomized, blinded trial – the first to track the activity of PAH patients – 53 participants received selexipag and 55 received placebo. All 108 wore a wrist accelerometer (GT9X Link) that counted the number of steps taken each day, providing an indication of daily activity.

Device compliance – the mean number of days in which the device was worn for at least 7 hours during a 14-day predrug period – was similar in the selexipag and placebo groups (13.2 vs 13.0 days).

“We wanted to make sure we had people who were stable and weren’t enrolled in a rehabilitation program; we didn’t want any competing influences,” Dr. Howard explained. All in all, the participants were in pretty good shape. “There was a low risk of a bad outcome.”

The primary endpoint was change in activity from baseline to week 24. The secondary endpoints were PAH-SYMPACT health quality-of-life tests and 6-minute walk distance.
 

Similar activity levels in both groups

As expected in a population in which the majority of patients meet the criteria for WHO functional class II PAH, all participants had low PAH-SYMPACT domain scores throughout the trial.

All adverse events were “consistent with the known profile” of selexipag, and there were no deaths, Dr. Howard reported.

“We did not show any significant benefit to taking the drug,” he said, but the drug is marketed for the prevention of disease progression, and this finding “doesn’t change that.”
 

Pulmonary rehabilitation

“Pulmonary rehabilitation is one of the most vital management issues with chronic lung disease,” Riddhi Upadhyay, MD, of Carle Foundation Hospital in Urbana, Ill., said during her CHEST 2020 presentation on improving PAH rehabilitation referral rates.

“We know it improves exercise capacity, lung function, and decreases total hospital stays and recurrent hospital admission,” she explained. And studies have shown that PAH rehabilitation “also reduces frailty and improves quality of life.”

In their study, Dr. Upadhyay and colleagues showed that when pulmonary rehabilitation is added to the discharge order set, referrals increase by 60%.

They attribute their success to “recognizing the benefits of pulmonary rehab and understanding where interventions are required.”

An encouraging takeaway from the TRACE data is that it established that daily activity can be tracked in this patient population. “We think we might need to encourage these patients to get active, maybe combine the drug with a formal rehabilitation program; that might increase motivation,” Dr. Howard said.

“People don’t necessarily do more just because they can,” he noted.

Dr. Howard has received consulting fees from Actelion.
 

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