User login
MD-IQ only
ASH guidelines for venous thromboembolism: What family physicians need to know
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. .
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. .
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. .
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.
VTE prophylaxis is feasible, effective in some high-risk cancer patients
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.
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.
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.
FROM THE THSNA BIENNIAL SUMMIT
Factor XI inhibitor–based anticoagulation strategies gain ground
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-FXIRx, an antisense oligonucleotide against FXI, is furthest along. In a study published in Blood, ISIS-FXIRx 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-FXIRx 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-FXIRx 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-FXIRx 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.
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-FXIRx, an antisense oligonucleotide against FXI, is furthest along. In a study published in Blood, ISIS-FXIRx 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-FXIRx 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-FXIRx 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-FXIRx 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.
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-FXIRx, an antisense oligonucleotide against FXI, is furthest along. In a study published in Blood, ISIS-FXIRx 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-FXIRx 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-FXIRx 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-FXIRx 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.
FROM THE THSNA BIENNIAL SUMMIT
VTEs tied to immune checkpoint inhibitor cancer treatment
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.
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.
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.
FROM AHA 2020
Switching to riociguat effective for some patients with PAH not at treatment goal
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.
FROM CHEST 2020
Selexipag has no effect on daily activity in PAH patients
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.
HOME-PE trial clarifies which pulmonary embolism patients to treat at home
The pragmatic Hestia criteria proved as safe as the more structured, points-based simplified Pulmonary Embolism Severity Index (sPESI) score for selection of patients with acute pulmonary embolism for outpatient care in the large, randomized HOME-PE trial presented at the virtual annual congress of the European Society of Cardiology.
“These results support outpatient management of acute pulmonary embolism patients using either the Hestia method or the sPESI score with the option for the physician-in-charge to override the decision. In hospitals organized for outpatient management, both triaging strategies enable more than a third of pulmonary embolism patients to be managed at home with a low rate of complications,” Pierre-Marie Roy, MD, said in presenting the HOME-PE findings.
The study clarifies a transatlantic controversy regarding how best to triage patients with acute pulmonary embolism (PE) for outpatient care. The answer? It’s basically a tie between the points-based sPESI score recommended in the current ESC guidelines (Eur Respir J. 2019 Oct 9;54[3]:1901647) and the Hestia method endorsed in the American College of Chest Physician guidelines (Chest. 2016 Feb;149[2]:315-52).
The sPESI is a validated tool that grants 1 point each for age over 80 years, background cardiopulmonary disease, a systolic blood pressure below 100 mm Hg, cancer, a heart rate of 110 bpm or more, and an oxygen saturation level below 90%. A patient needs a score of zero to be eligible for outpatient management. In contrast, the Hestia method relies upon 11 simple bedside criteria rather than a points system, explained Dr. Roy of University Hospital of Angers, France (J Thromb Haemost. 2011 Aug;9[8]:1500-7).
HOME-PE was a randomized, open-label, noninferiority trial conducted at 26 hospitals in France, Belgium, Switzerland, and the Netherlands. The study included 1,974 patients presenting to the emergency department with non–high-risk acute PE as defined by hemodynamic stability. About 39% of patients in the Hestia group were eligible for outpatient care on the basis of ‘no’ answers regarding all 11 criteria, while 48% of patients had an sPESI score of 0 and were thus initially considered appropriate for outpatient management.
However, the investigators recognized that no scoring system for acute PE is perfect, and that the judgment of a physician with extensive experience in managing this life-threatening condition counts for a lot. So they stipulated that a patient’s physician-in-charge could overrule a decision for early discharge. This happened 29% of the time in patients with a sPESI score of 0, as compared with a 3% overrule rate with the Hestia rule. The physician-in-charge also moved small numbers of patients who were Hestia or sPESI positive into the outpatient care group. As a result, a similar proportion of patients in both groups were discharged home within 24 hours for outpatient treatment: 38% of the total Hestia group and 37% in the sPESI arm.
Major adverse event rates were reassuringly low in both groups managed on an outpatient basis. The composite of recurrent venous thromboembolism, bleeding, or death within 30 days occurred in 1.3% of Hestia outpatients and 1.1% of sPESI outpatients. Among patients managed in the hospital, these rates were 5.6% in the Hestia group and 4.7% in the sPESI group.
Discussant Stavros V. Konstantinides, MD, who chaired the ESC guideline committee, asked rhetorically, “who’s happy with the HOME-PE trial? I think everybody.”
“The Hestia criteria integrate the feasibility of family support of the individual patient. This is a good thing. And eligibility based on the Hestia criteria, unlike sPESI, does not require age younger than 80 years or no cancer, and it appears from the HOME-PE study that this is okay,” observed Dr. Konstantinides of the Center for Thrombosis and Hemostasis at the University of Mainz (Germany).
In an interview, Hadley Wilson, MD, called the HOME-PE trial “transformative” and predicted it will change clinical practice. He was particularly impressed with the high quality of the trial, noting that 87% of participants managed as outpatients received a direct oral anticoagulant.
The Hestia rule is simpler and more user-friendly. And greater use of this triaging strategy might have advantages in terms of economics and health care utilization by potentially encouraging movement of decision-making regarding outpatient management of acute PE out of the hospital wards and into emergency departments, said Dr. Wilson, executive vice chair of the Sanger Heart and Vascular Institute and a cardiologist at the University of North Carolina at Chapel Hill.
Dr. Roy reported receiving research grants to conduct HOME-PE from the French Ministry of Health, the study sponsor. In addition, he is on scientific advisory boards and/or speakers’ panels for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Aspen, Daiichi Sankyo, and Sanofi Aventis.
The pragmatic Hestia criteria proved as safe as the more structured, points-based simplified Pulmonary Embolism Severity Index (sPESI) score for selection of patients with acute pulmonary embolism for outpatient care in the large, randomized HOME-PE trial presented at the virtual annual congress of the European Society of Cardiology.
“These results support outpatient management of acute pulmonary embolism patients using either the Hestia method or the sPESI score with the option for the physician-in-charge to override the decision. In hospitals organized for outpatient management, both triaging strategies enable more than a third of pulmonary embolism patients to be managed at home with a low rate of complications,” Pierre-Marie Roy, MD, said in presenting the HOME-PE findings.
The study clarifies a transatlantic controversy regarding how best to triage patients with acute pulmonary embolism (PE) for outpatient care. The answer? It’s basically a tie between the points-based sPESI score recommended in the current ESC guidelines (Eur Respir J. 2019 Oct 9;54[3]:1901647) and the Hestia method endorsed in the American College of Chest Physician guidelines (Chest. 2016 Feb;149[2]:315-52).
The sPESI is a validated tool that grants 1 point each for age over 80 years, background cardiopulmonary disease, a systolic blood pressure below 100 mm Hg, cancer, a heart rate of 110 bpm or more, and an oxygen saturation level below 90%. A patient needs a score of zero to be eligible for outpatient management. In contrast, the Hestia method relies upon 11 simple bedside criteria rather than a points system, explained Dr. Roy of University Hospital of Angers, France (J Thromb Haemost. 2011 Aug;9[8]:1500-7).
HOME-PE was a randomized, open-label, noninferiority trial conducted at 26 hospitals in France, Belgium, Switzerland, and the Netherlands. The study included 1,974 patients presenting to the emergency department with non–high-risk acute PE as defined by hemodynamic stability. About 39% of patients in the Hestia group were eligible for outpatient care on the basis of ‘no’ answers regarding all 11 criteria, while 48% of patients had an sPESI score of 0 and were thus initially considered appropriate for outpatient management.
However, the investigators recognized that no scoring system for acute PE is perfect, and that the judgment of a physician with extensive experience in managing this life-threatening condition counts for a lot. So they stipulated that a patient’s physician-in-charge could overrule a decision for early discharge. This happened 29% of the time in patients with a sPESI score of 0, as compared with a 3% overrule rate with the Hestia rule. The physician-in-charge also moved small numbers of patients who were Hestia or sPESI positive into the outpatient care group. As a result, a similar proportion of patients in both groups were discharged home within 24 hours for outpatient treatment: 38% of the total Hestia group and 37% in the sPESI arm.
Major adverse event rates were reassuringly low in both groups managed on an outpatient basis. The composite of recurrent venous thromboembolism, bleeding, or death within 30 days occurred in 1.3% of Hestia outpatients and 1.1% of sPESI outpatients. Among patients managed in the hospital, these rates were 5.6% in the Hestia group and 4.7% in the sPESI group.
Discussant Stavros V. Konstantinides, MD, who chaired the ESC guideline committee, asked rhetorically, “who’s happy with the HOME-PE trial? I think everybody.”
“The Hestia criteria integrate the feasibility of family support of the individual patient. This is a good thing. And eligibility based on the Hestia criteria, unlike sPESI, does not require age younger than 80 years or no cancer, and it appears from the HOME-PE study that this is okay,” observed Dr. Konstantinides of the Center for Thrombosis and Hemostasis at the University of Mainz (Germany).
In an interview, Hadley Wilson, MD, called the HOME-PE trial “transformative” and predicted it will change clinical practice. He was particularly impressed with the high quality of the trial, noting that 87% of participants managed as outpatients received a direct oral anticoagulant.
The Hestia rule is simpler and more user-friendly. And greater use of this triaging strategy might have advantages in terms of economics and health care utilization by potentially encouraging movement of decision-making regarding outpatient management of acute PE out of the hospital wards and into emergency departments, said Dr. Wilson, executive vice chair of the Sanger Heart and Vascular Institute and a cardiologist at the University of North Carolina at Chapel Hill.
Dr. Roy reported receiving research grants to conduct HOME-PE from the French Ministry of Health, the study sponsor. In addition, he is on scientific advisory boards and/or speakers’ panels for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Aspen, Daiichi Sankyo, and Sanofi Aventis.
The pragmatic Hestia criteria proved as safe as the more structured, points-based simplified Pulmonary Embolism Severity Index (sPESI) score for selection of patients with acute pulmonary embolism for outpatient care in the large, randomized HOME-PE trial presented at the virtual annual congress of the European Society of Cardiology.
“These results support outpatient management of acute pulmonary embolism patients using either the Hestia method or the sPESI score with the option for the physician-in-charge to override the decision. In hospitals organized for outpatient management, both triaging strategies enable more than a third of pulmonary embolism patients to be managed at home with a low rate of complications,” Pierre-Marie Roy, MD, said in presenting the HOME-PE findings.
The study clarifies a transatlantic controversy regarding how best to triage patients with acute pulmonary embolism (PE) for outpatient care. The answer? It’s basically a tie between the points-based sPESI score recommended in the current ESC guidelines (Eur Respir J. 2019 Oct 9;54[3]:1901647) and the Hestia method endorsed in the American College of Chest Physician guidelines (Chest. 2016 Feb;149[2]:315-52).
The sPESI is a validated tool that grants 1 point each for age over 80 years, background cardiopulmonary disease, a systolic blood pressure below 100 mm Hg, cancer, a heart rate of 110 bpm or more, and an oxygen saturation level below 90%. A patient needs a score of zero to be eligible for outpatient management. In contrast, the Hestia method relies upon 11 simple bedside criteria rather than a points system, explained Dr. Roy of University Hospital of Angers, France (J Thromb Haemost. 2011 Aug;9[8]:1500-7).
HOME-PE was a randomized, open-label, noninferiority trial conducted at 26 hospitals in France, Belgium, Switzerland, and the Netherlands. The study included 1,974 patients presenting to the emergency department with non–high-risk acute PE as defined by hemodynamic stability. About 39% of patients in the Hestia group were eligible for outpatient care on the basis of ‘no’ answers regarding all 11 criteria, while 48% of patients had an sPESI score of 0 and were thus initially considered appropriate for outpatient management.
However, the investigators recognized that no scoring system for acute PE is perfect, and that the judgment of a physician with extensive experience in managing this life-threatening condition counts for a lot. So they stipulated that a patient’s physician-in-charge could overrule a decision for early discharge. This happened 29% of the time in patients with a sPESI score of 0, as compared with a 3% overrule rate with the Hestia rule. The physician-in-charge also moved small numbers of patients who were Hestia or sPESI positive into the outpatient care group. As a result, a similar proportion of patients in both groups were discharged home within 24 hours for outpatient treatment: 38% of the total Hestia group and 37% in the sPESI arm.
Major adverse event rates were reassuringly low in both groups managed on an outpatient basis. The composite of recurrent venous thromboembolism, bleeding, or death within 30 days occurred in 1.3% of Hestia outpatients and 1.1% of sPESI outpatients. Among patients managed in the hospital, these rates were 5.6% in the Hestia group and 4.7% in the sPESI group.
Discussant Stavros V. Konstantinides, MD, who chaired the ESC guideline committee, asked rhetorically, “who’s happy with the HOME-PE trial? I think everybody.”
“The Hestia criteria integrate the feasibility of family support of the individual patient. This is a good thing. And eligibility based on the Hestia criteria, unlike sPESI, does not require age younger than 80 years or no cancer, and it appears from the HOME-PE study that this is okay,” observed Dr. Konstantinides of the Center for Thrombosis and Hemostasis at the University of Mainz (Germany).
In an interview, Hadley Wilson, MD, called the HOME-PE trial “transformative” and predicted it will change clinical practice. He was particularly impressed with the high quality of the trial, noting that 87% of participants managed as outpatients received a direct oral anticoagulant.
The Hestia rule is simpler and more user-friendly. And greater use of this triaging strategy might have advantages in terms of economics and health care utilization by potentially encouraging movement of decision-making regarding outpatient management of acute PE out of the hospital wards and into emergency departments, said Dr. Wilson, executive vice chair of the Sanger Heart and Vascular Institute and a cardiologist at the University of North Carolina at Chapel Hill.
Dr. Roy reported receiving research grants to conduct HOME-PE from the French Ministry of Health, the study sponsor. In addition, he is on scientific advisory boards and/or speakers’ panels for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Aspen, Daiichi Sankyo, and Sanofi Aventis.
REPORTING FROM ESC CONGRESS 2020
TNF inhibitors cut odds of VTE in RA patients
The risk for venous thromboembolism is almost 50% lower in patients with RA taking TNF inhibitors than in those taking conventional synthetic disease-modifying antirheumatic drugs (DMARDs), according to data from the German RABBIT registry.
“Some rheumatologists have thought TNF inhibitors could increase the risk for venous thromboembolism events, but we don’t think this is true, based on our findings,” said investigator Anja Strangfeld, MD, PhD, from the German Rheumatism Research Center in Berlin.
The risk is more than one-third lower in RA patients treated with other newer biologics, such as abatacept, rituximab, sarilumab, and tocilizumab.
However, risk for a serious venous thromboembolism is twice as high in patients with C-reactive protein (CRP) levels above 5 mg/L and is nearly three times as high in patients 65 years and older.
For the study, Dr. Strangfeld and her colleagues followed about 11,000 patients for more than 10 years. The findings were presented at the European League Against Rheumatism (EULAR) 2020 Congress.
“Patients with RA have a greater risk for venous thromboembolism compared with the general population, but we didn’t know the risk conveyed by different DMARD treatments,” Dr. Strangfeld told Medscape Medical News. “It is also evident that higher age and lower capacity for physical function increase the risk, which was not so surprising.”
Chronic inflammation in RA patients elevates the risk for deep vein and pulmonary thrombosis by two to three times, said John Isaacs, MBBS, PhD, from Newcastle University in Newcastle Upon Tyne, United Kingdom, who is chair of the EULAR scientific program committee.
Among the supporting studies Dr. Isaacs discussed during an online press conference was a Swedish trial of more than 46,000 RA patients, which had been presented earlier by Viktor Molander, a PhD candidate from the Karolinska Institute in Stockholm (abstract OP0034).
Mr. Molander’s team showed that one in 100 patients with high disease activity will develop venous thromboembolism within a year, which is twice the number of events seen among patients in remission.
Combined with the RABBIT data, both studies “show if you can control their disease in the right way, you’re not only helping rheumatoid arthritis patients feel better, but you could be prolonging their lives,” Dr. Isaacs said.
The prospective RABBIT study followed RA patients who began receiving a new DMARD after treatment failed with at least one conventional synthetic DMARD, such as methotrexate or leflunomide. At baseline, those taking TNF inhibitors or other biologics had higher CRP levels on average, as well as a higher rate of existing cardiovascular disease. They also received glucocorticoids, such as prednisone, more often.
The observational nature of the RABBIT study is a weakness, Dr. Strangfeld said, and it could not prove cause and effect. But the methodology had several strengths, including input on patient factors from participating rheumatologists at least every 6 months.
“We enrolled patients at the start of treatment and observed them, regardless of any treatment changes, for up to 10 years,” she added. “That’s a really long observation period.”
The RABBIT data can help shape treatment decisions, said Loreto Carmona, MD, PhD, from the Musculoskeletal Health Institute in Madrid, who is chair of the EULAR abstract selection committee.
For a woman with RA who smokes and takes oral contraceptives, for example, “if she has high levels of inflammation, I think it’s okay to use TNF inhibitors, where maybe in the past we wouldn’t have thought that,” she said.
“The TNF inhibitors are actually reducing the inflammation and, therefore, reducing the risk,” Dr. Carmona told Medscape Medical News. “It could be an effect of using the drugs on people with higher levels of inflammation. It’s an indirect protective effect.”
The study was funded by a joint unconditional grant from AbbVie, Amgen, BMS, Fresenius-Kabi, Hexal, Lilly, MSD, Mylan, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, and UCB. Dr. Strangfeld is on the speakers bureau of AbbVie, BMS, Pfizer, Roche and Sanofi-Aventis. Dr. Isaacs is a consultant or has received honoraria or grants from Pfizer, AbbVie, Amgen, Merck, Roche, and UCB. Dr. Carmona has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
The risk for venous thromboembolism is almost 50% lower in patients with RA taking TNF inhibitors than in those taking conventional synthetic disease-modifying antirheumatic drugs (DMARDs), according to data from the German RABBIT registry.
“Some rheumatologists have thought TNF inhibitors could increase the risk for venous thromboembolism events, but we don’t think this is true, based on our findings,” said investigator Anja Strangfeld, MD, PhD, from the German Rheumatism Research Center in Berlin.
The risk is more than one-third lower in RA patients treated with other newer biologics, such as abatacept, rituximab, sarilumab, and tocilizumab.
However, risk for a serious venous thromboembolism is twice as high in patients with C-reactive protein (CRP) levels above 5 mg/L and is nearly three times as high in patients 65 years and older.
For the study, Dr. Strangfeld and her colleagues followed about 11,000 patients for more than 10 years. The findings were presented at the European League Against Rheumatism (EULAR) 2020 Congress.
“Patients with RA have a greater risk for venous thromboembolism compared with the general population, but we didn’t know the risk conveyed by different DMARD treatments,” Dr. Strangfeld told Medscape Medical News. “It is also evident that higher age and lower capacity for physical function increase the risk, which was not so surprising.”
Chronic inflammation in RA patients elevates the risk for deep vein and pulmonary thrombosis by two to three times, said John Isaacs, MBBS, PhD, from Newcastle University in Newcastle Upon Tyne, United Kingdom, who is chair of the EULAR scientific program committee.
Among the supporting studies Dr. Isaacs discussed during an online press conference was a Swedish trial of more than 46,000 RA patients, which had been presented earlier by Viktor Molander, a PhD candidate from the Karolinska Institute in Stockholm (abstract OP0034).
Mr. Molander’s team showed that one in 100 patients with high disease activity will develop venous thromboembolism within a year, which is twice the number of events seen among patients in remission.
Combined with the RABBIT data, both studies “show if you can control their disease in the right way, you’re not only helping rheumatoid arthritis patients feel better, but you could be prolonging their lives,” Dr. Isaacs said.
The prospective RABBIT study followed RA patients who began receiving a new DMARD after treatment failed with at least one conventional synthetic DMARD, such as methotrexate or leflunomide. At baseline, those taking TNF inhibitors or other biologics had higher CRP levels on average, as well as a higher rate of existing cardiovascular disease. They also received glucocorticoids, such as prednisone, more often.
The observational nature of the RABBIT study is a weakness, Dr. Strangfeld said, and it could not prove cause and effect. But the methodology had several strengths, including input on patient factors from participating rheumatologists at least every 6 months.
“We enrolled patients at the start of treatment and observed them, regardless of any treatment changes, for up to 10 years,” she added. “That’s a really long observation period.”
The RABBIT data can help shape treatment decisions, said Loreto Carmona, MD, PhD, from the Musculoskeletal Health Institute in Madrid, who is chair of the EULAR abstract selection committee.
For a woman with RA who smokes and takes oral contraceptives, for example, “if she has high levels of inflammation, I think it’s okay to use TNF inhibitors, where maybe in the past we wouldn’t have thought that,” she said.
“The TNF inhibitors are actually reducing the inflammation and, therefore, reducing the risk,” Dr. Carmona told Medscape Medical News. “It could be an effect of using the drugs on people with higher levels of inflammation. It’s an indirect protective effect.”
The study was funded by a joint unconditional grant from AbbVie, Amgen, BMS, Fresenius-Kabi, Hexal, Lilly, MSD, Mylan, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, and UCB. Dr. Strangfeld is on the speakers bureau of AbbVie, BMS, Pfizer, Roche and Sanofi-Aventis. Dr. Isaacs is a consultant or has received honoraria or grants from Pfizer, AbbVie, Amgen, Merck, Roche, and UCB. Dr. Carmona has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
The risk for venous thromboembolism is almost 50% lower in patients with RA taking TNF inhibitors than in those taking conventional synthetic disease-modifying antirheumatic drugs (DMARDs), according to data from the German RABBIT registry.
“Some rheumatologists have thought TNF inhibitors could increase the risk for venous thromboembolism events, but we don’t think this is true, based on our findings,” said investigator Anja Strangfeld, MD, PhD, from the German Rheumatism Research Center in Berlin.
The risk is more than one-third lower in RA patients treated with other newer biologics, such as abatacept, rituximab, sarilumab, and tocilizumab.
However, risk for a serious venous thromboembolism is twice as high in patients with C-reactive protein (CRP) levels above 5 mg/L and is nearly three times as high in patients 65 years and older.
For the study, Dr. Strangfeld and her colleagues followed about 11,000 patients for more than 10 years. The findings were presented at the European League Against Rheumatism (EULAR) 2020 Congress.
“Patients with RA have a greater risk for venous thromboembolism compared with the general population, but we didn’t know the risk conveyed by different DMARD treatments,” Dr. Strangfeld told Medscape Medical News. “It is also evident that higher age and lower capacity for physical function increase the risk, which was not so surprising.”
Chronic inflammation in RA patients elevates the risk for deep vein and pulmonary thrombosis by two to three times, said John Isaacs, MBBS, PhD, from Newcastle University in Newcastle Upon Tyne, United Kingdom, who is chair of the EULAR scientific program committee.
Among the supporting studies Dr. Isaacs discussed during an online press conference was a Swedish trial of more than 46,000 RA patients, which had been presented earlier by Viktor Molander, a PhD candidate from the Karolinska Institute in Stockholm (abstract OP0034).
Mr. Molander’s team showed that one in 100 patients with high disease activity will develop venous thromboembolism within a year, which is twice the number of events seen among patients in remission.
Combined with the RABBIT data, both studies “show if you can control their disease in the right way, you’re not only helping rheumatoid arthritis patients feel better, but you could be prolonging their lives,” Dr. Isaacs said.
The prospective RABBIT study followed RA patients who began receiving a new DMARD after treatment failed with at least one conventional synthetic DMARD, such as methotrexate or leflunomide. At baseline, those taking TNF inhibitors or other biologics had higher CRP levels on average, as well as a higher rate of existing cardiovascular disease. They also received glucocorticoids, such as prednisone, more often.
The observational nature of the RABBIT study is a weakness, Dr. Strangfeld said, and it could not prove cause and effect. But the methodology had several strengths, including input on patient factors from participating rheumatologists at least every 6 months.
“We enrolled patients at the start of treatment and observed them, regardless of any treatment changes, for up to 10 years,” she added. “That’s a really long observation period.”
The RABBIT data can help shape treatment decisions, said Loreto Carmona, MD, PhD, from the Musculoskeletal Health Institute in Madrid, who is chair of the EULAR abstract selection committee.
For a woman with RA who smokes and takes oral contraceptives, for example, “if she has high levels of inflammation, I think it’s okay to use TNF inhibitors, where maybe in the past we wouldn’t have thought that,” she said.
“The TNF inhibitors are actually reducing the inflammation and, therefore, reducing the risk,” Dr. Carmona told Medscape Medical News. “It could be an effect of using the drugs on people with higher levels of inflammation. It’s an indirect protective effect.”
The study was funded by a joint unconditional grant from AbbVie, Amgen, BMS, Fresenius-Kabi, Hexal, Lilly, MSD, Mylan, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, and UCB. Dr. Strangfeld is on the speakers bureau of AbbVie, BMS, Pfizer, Roche and Sanofi-Aventis. Dr. Isaacs is a consultant or has received honoraria or grants from Pfizer, AbbVie, Amgen, Merck, Roche, and UCB. Dr. Carmona has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Renal function data improve risk stratification in patients with PAH
The REVEAL-based risk-management strategy was significantly more effective than the current European Society of Cardiology guidelines at discriminating risk in adults with pulmonary arterial hypertension, and renal function significantly improved risk stratification, findings from a retrospective registry study suggest.
“Although the importance of identification of low or high risk is intuitive, the clinical utility of stratification into the intermediate-risk category is less certain” in patients with pulmonary arterial hypertension (PAH), wrote Jason G.E. Zelt, MSc, of the University of Ottawa and colleagues. “Despite the importance of renal function in the PAH population, it has not been formally incorporated into many of the contemporary PAH risk tools, including current guidelines,” they noted.
In a study published in the Journal of Heart and Lung Transplantation, the researchers compared several current research tools for risk assessment in PAH, including the registry to evaluate early and long-term pulmonary arterial hypertension disease management (REVEAL) risk calculator, the French Pulmonary Hypertension Registry (FPHR), and guidelines from the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). They also reviewed REVEAL 2.0, an update that included the estimated glomerular filtration rate (eGFR) as a measure of renal function.
The study population included 211 adults with PAH seen at a single pulmonary hypertension clinic; the average age was 63 years and 65% were women. In addition, 42% had at least stage 3 chronic kidney disease. The primary endpoint was transplant-free survival, which was a median of 7 years. Creatinine was assessed at baseline in all patients. In addition, patients were grouped based on the percent change in renal function between diagnosis and 6 months.
Although the ESC and REVEAL algorithms significantly stratified transplant-free survival risk, the researchers found little agreement among the algorithms in stratifying transplant-free survival for patients in the intermediate-risk category.
However, using REVEAL 2.0, both renal function at diagnosis and renal function at 6 months were significant predictors (P < .0001 for both) from intermediate-risk to higher- or lower-risk groups, the researchers said.
“A decrease in renal function may be a harbinger of both [right ventricle] dysfunction and further PAH disease progression. However, further research is needed to confirm whether declining eGFR is a sentinel biomarker in prospective cohorts,” the researchers said.
The study findings were limited by several factors including the retrospective design and the use of mainly baseline data without information on long-term risk assessment, the researchers noted. However, “a key finding of our study was the ability of baseline eGFR to robustly restratify ESC/ERS-based risk strategies,” they said. “Our work highlights key limitations of the ESC/ERS-based risk assessment, and suggests that incorporating measures of kidney function are important strategies moving forward,” they concluded.
Mr. Zelt is an MD/PhD student and had no financial conflicts to disclose. Some coauthors disclosed relationships with Actelion Pharmaceuticals, Bayer Pharmaceuticals, and Northern Therapeutics.
SOURCE: Zelt JGE et al. J Heart Lung Transplant. 2020 Apr 5. doi: 10.1016/j.healun.2020.03.026.
The REVEAL-based risk-management strategy was significantly more effective than the current European Society of Cardiology guidelines at discriminating risk in adults with pulmonary arterial hypertension, and renal function significantly improved risk stratification, findings from a retrospective registry study suggest.
“Although the importance of identification of low or high risk is intuitive, the clinical utility of stratification into the intermediate-risk category is less certain” in patients with pulmonary arterial hypertension (PAH), wrote Jason G.E. Zelt, MSc, of the University of Ottawa and colleagues. “Despite the importance of renal function in the PAH population, it has not been formally incorporated into many of the contemporary PAH risk tools, including current guidelines,” they noted.
In a study published in the Journal of Heart and Lung Transplantation, the researchers compared several current research tools for risk assessment in PAH, including the registry to evaluate early and long-term pulmonary arterial hypertension disease management (REVEAL) risk calculator, the French Pulmonary Hypertension Registry (FPHR), and guidelines from the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). They also reviewed REVEAL 2.0, an update that included the estimated glomerular filtration rate (eGFR) as a measure of renal function.
The study population included 211 adults with PAH seen at a single pulmonary hypertension clinic; the average age was 63 years and 65% were women. In addition, 42% had at least stage 3 chronic kidney disease. The primary endpoint was transplant-free survival, which was a median of 7 years. Creatinine was assessed at baseline in all patients. In addition, patients were grouped based on the percent change in renal function between diagnosis and 6 months.
Although the ESC and REVEAL algorithms significantly stratified transplant-free survival risk, the researchers found little agreement among the algorithms in stratifying transplant-free survival for patients in the intermediate-risk category.
However, using REVEAL 2.0, both renal function at diagnosis and renal function at 6 months were significant predictors (P < .0001 for both) from intermediate-risk to higher- or lower-risk groups, the researchers said.
“A decrease in renal function may be a harbinger of both [right ventricle] dysfunction and further PAH disease progression. However, further research is needed to confirm whether declining eGFR is a sentinel biomarker in prospective cohorts,” the researchers said.
The study findings were limited by several factors including the retrospective design and the use of mainly baseline data without information on long-term risk assessment, the researchers noted. However, “a key finding of our study was the ability of baseline eGFR to robustly restratify ESC/ERS-based risk strategies,” they said. “Our work highlights key limitations of the ESC/ERS-based risk assessment, and suggests that incorporating measures of kidney function are important strategies moving forward,” they concluded.
Mr. Zelt is an MD/PhD student and had no financial conflicts to disclose. Some coauthors disclosed relationships with Actelion Pharmaceuticals, Bayer Pharmaceuticals, and Northern Therapeutics.
SOURCE: Zelt JGE et al. J Heart Lung Transplant. 2020 Apr 5. doi: 10.1016/j.healun.2020.03.026.
The REVEAL-based risk-management strategy was significantly more effective than the current European Society of Cardiology guidelines at discriminating risk in adults with pulmonary arterial hypertension, and renal function significantly improved risk stratification, findings from a retrospective registry study suggest.
“Although the importance of identification of low or high risk is intuitive, the clinical utility of stratification into the intermediate-risk category is less certain” in patients with pulmonary arterial hypertension (PAH), wrote Jason G.E. Zelt, MSc, of the University of Ottawa and colleagues. “Despite the importance of renal function in the PAH population, it has not been formally incorporated into many of the contemporary PAH risk tools, including current guidelines,” they noted.
In a study published in the Journal of Heart and Lung Transplantation, the researchers compared several current research tools for risk assessment in PAH, including the registry to evaluate early and long-term pulmonary arterial hypertension disease management (REVEAL) risk calculator, the French Pulmonary Hypertension Registry (FPHR), and guidelines from the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). They also reviewed REVEAL 2.0, an update that included the estimated glomerular filtration rate (eGFR) as a measure of renal function.
The study population included 211 adults with PAH seen at a single pulmonary hypertension clinic; the average age was 63 years and 65% were women. In addition, 42% had at least stage 3 chronic kidney disease. The primary endpoint was transplant-free survival, which was a median of 7 years. Creatinine was assessed at baseline in all patients. In addition, patients were grouped based on the percent change in renal function between diagnosis and 6 months.
Although the ESC and REVEAL algorithms significantly stratified transplant-free survival risk, the researchers found little agreement among the algorithms in stratifying transplant-free survival for patients in the intermediate-risk category.
However, using REVEAL 2.0, both renal function at diagnosis and renal function at 6 months were significant predictors (P < .0001 for both) from intermediate-risk to higher- or lower-risk groups, the researchers said.
“A decrease in renal function may be a harbinger of both [right ventricle] dysfunction and further PAH disease progression. However, further research is needed to confirm whether declining eGFR is a sentinel biomarker in prospective cohorts,” the researchers said.
The study findings were limited by several factors including the retrospective design and the use of mainly baseline data without information on long-term risk assessment, the researchers noted. However, “a key finding of our study was the ability of baseline eGFR to robustly restratify ESC/ERS-based risk strategies,” they said. “Our work highlights key limitations of the ESC/ERS-based risk assessment, and suggests that incorporating measures of kidney function are important strategies moving forward,” they concluded.
Mr. Zelt is an MD/PhD student and had no financial conflicts to disclose. Some coauthors disclosed relationships with Actelion Pharmaceuticals, Bayer Pharmaceuticals, and Northern Therapeutics.
SOURCE: Zelt JGE et al. J Heart Lung Transplant. 2020 Apr 5. doi: 10.1016/j.healun.2020.03.026.
FROM THE JOURNAL OF HEART AND LUNG TRANSPLANTATION
PCSK9 inhibitors unexpectedly link with lower VTE, aortic stenosis
Post hoc analyses of recent large, clinical outcomes studies of PCSK9 inhibitors have revealed two tantalizing and unexpected potential benefits from these drugs: an ability to substantially reduce the incidence or severity of venous thromboembolism and aortic stenosis.
The evidence also suggests that these effects are linked to the ability of these drugs to reduce blood levels of Lp(a) lipoprotein by roughly a quarter, currently the biggest known effect on Lp(a) levels of any approved medication.
One study ran post hoc analyses of venous thromboembolism (VTE) events in the FOURIER pivotal trial of evolocumab (Repatha), with more than 27,500 randomized patients (N Engl J Med. 2017 May 4; 376[18]:1713-22), and in the ODYSSEY OUTCOMES pivotal trial of alirocumab (Praluent), with nearly 19,000 randomized patients (N Engl J Med. 2018 Nov 29;379[22]:2097-2107). The analyses showed that, with evolocumab treatment, the incidence of VTE events fell by a statistically significant 29%, compared with patients on placebo, while in ODYSSEY OUTCOMES patients treated with alirocumab had a 33% cut in VTE events, compared with placebo-treated patients, a difference that just missed statistical significance (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046524) in analyses that were not prespecified before these trials started, Nicholas A. Marston, MD, said in a presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
A combined analysis of 46,488 patients from both studies showed a 31% cut in VTE events with PCSK9 inhibitor treatment, a highly significant finding using VTE endpoints that were not specifically tallied nor adjudicated but collected as part of the serious adverse event reporting in the two pivotal trials, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. This is the first report of a statistically significant link between treatment with PCSK9-inhibiting agents and a reduction in VTE, he added. Researchers from the ODYSSEY OUTCOMES trial had reported a VTE analysis in 2019, and while data from that trial on its own showed a nominal 33% lower VTE rate with alirocumab treatment, it just missed statistical significance.
The VTE effect took about a year on treatment to start to manifest. During the first 12 months of FOURIER, the rate of VTE events among patients in the two treatment arms was virtually identical. But starting during months 13-18 on treatment, the event curves in the two arms began to increasingly diverge, and overall during the period from month 13 to the end of the study treatment with evolocumab was linked with a statistically significant 46% reduction in VTE events, compared with patients who received placebo. The results Dr. Marston reported were also published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046397).
The suggestion that this association may be linked to the impact of PCSK9 inhibitors on Lp(a) came from an additional analysis that Dr. Marston presented, which looked at the link between evolocumab use and a change in VTE event rates, compared with placebo, depending on baseline lipoprotein levels. Evolocumab treatment was associated with a roughly similar, modest, and not statistically significant reduction in VTE events, compared with placebo regardless of whether patients had baseline levels of LDL cholesterol below the median or at or above the median. In contrast, when a similar analysis divided patients based on whether their Lp(a) level at baseline was below, or at or above, the median the results showed no discernible effect of evolocumab treatment, compared with on VTE events in patients with lower baseline Lp(a), but in those with higher levels treatment with evolocumab linked with a 48% cut in VTE events, compared with placebo, a statistically significant difference.
In FOURIER, treatment with evolocumab lowered baseline Lp(a) levels by a median of 27%, compared with placebo, among the 25,096 enrolled patients who had their baseline levels measured. As previously reported, prespecified analysis of FOURIER data also showed that the impact of evolocumab, compared with placebo, on the combined rate of coronary heart disease death, MI, or need for urgent coronary revascularization was enhanced among patients with elevated baseline Lp(a) and moderated in those who entered with lower levels. Among patients who entered FOURIER with Lp(a) levels at or below the median treatment with evolocumab cut the primary endpoint by 7%, compared with placebo, a difference that was not statistically significant. Among patients who began the study with Lp(a) levels above the median, evolocumab treatment cut the primary endpoint by 23%, compared with placebo, a statistically significant effect (Circulation. 2019 Mar 19;139[12]:1483-92).
The aortic stenosis connection
A second study reported in the online scientific sessions (Abstract 914-08) used only FOURIER data, and showed that patients treated with evolocumab had a roughly similar response pattern in their incidence of aortic stenosis (AS) events as they did for VTE events.
During the first year of the study, the incidence of AS events was virtually identical among patients treated with evolocumab and those who received placebo. But after the first 12 months and through the study’s end, patients on evolocumab showed a statistically significant 52% relative reduction in AS events, compared with control patients, said Brian A. Bergmark, MD. For the entire study duration, treatment with evolocumab linked with a 34% relative reduction in AS events, compared with placebo, a difference that did not reach statistical significance, added Dr. Bergmark, an interventional cardiologist also at Brigham and Women’s Hospital. The observed halving in total AS events that linked with evolocumab treatment after the first year of the study included a similar-magnitude reduction specifically in the incidence of aortic valve replacement procedures in the evolocumab-treated patients.
Further analysis of both total AS events and aortic valve replacements in FOURIER patients showed that they occurred at a significantly elevated rate in patients who entered the study with higher baseline Lp(a) levels in a multivariate analysis, but a similar analysis showed no significant association between the incidence of these AS-related events and baseline levels of LDL cholesterol, he said.
The AS analysis carried the same important limitations as the VTE analysis: It ran on a post hoc basis and focused on events that were relatively uncommon and not adjudicated, Dr. Bergmark cautioned. Nonetheless, other investigators saw important potential implications from both the VTE and AS observations, with the huge caveat that they need replication in prospective studies designed to specifically address the validity of these findings.
What it could mean
These observed associations between PCSK9 inhibitor treatment and apparent reductions in the rate of both VTE and AS events “represent a tremendous clinical breakthrough,” commented Michelle L. O’Donoghue, MD, a cardiologist at Brigham and Women’s Hospital who is a FOURIER coinvestigator and has led some of the Lp(a) analyses run from that study.
“To date, we have not identified any therapies that slow progression of AS. Other classes of lipid-lowering therapies, such as statins, have been tested and not demonstrated a significant effect,” Dr. O’Donoghue said in an interview.
“For AS, the results are very intriguing. If confirmed, it could be groundbreaking. AS is the most common valve disease in the developed world, and no medical therapy exists. The potential is immense,” commented George Thanassoulis, MD, director of preventive and genomic cardiology at McGill University, Montreal. “Having a medical treatment that could slow AS progression would completely change the disease. It’s conceivable to slow the disease enough that patients may never require valve replacement.” But an interview he cautioned that, “although the results are exciting, the analysis has many limitations. What we need is a dedicated, randomized trial for AS. I hope this stimulates that.”
“For VTE, it’s an interesting finding, but I don’t think it will have clinical utility because we have good treatment for VTE,” added Dr. Thanassoulis, but others saw more opportunity from what could be a new way to reduce VTE risk.
“Given that many patients have difficulty with the bleeding risk from anticoagulants, this option [a PCSK9 inhibitor] may be quite welcome for preventing VTE,” commented Gregory Piazza, MD, a cardiologist and VTE specialist at Brigham and Women’s Hospital who was not involved in any of the PCSK9 inhibitor studies.
“At this time we would not suggest that PCSK9 inhibitors replace an anticoagulant for patients with an established clot or at high risk for a recurrent clot, but if patients have an indication for a PCSK9 inhibitor, the further reduction in venous clot can be viewed as an additional benefit of this therapy,” said Dr. O’Donoghue.
How it might work
A possible mechanism underlying a VTE effect is unclear. Results from the JUPITER trial more than a decade ago had shown a significant association between treatment with 20 mg/day of rosuvastatin and a cut in VTE episodes, compared with placebo, in a prespecified, secondary analysis of the trial with nearly 18,000 patients selected for having a relatively high level of high-sensitivity C-reactive protein (N Engl J Med. 2009 Apr 30;360[18]:1851-61). But a meta-analysis of 29 controlled statin trials that used a variety of statin types and dosages (and included the JUPITER results) failed to confirm a statistically significant change in VTE rates from statins, though they produced a small, nominal reduction (PLoS Med. 2012 Sep 18. doi: 10.1371/journal.pmed.1001310).
Lp(a) “has long been linked to thrombosis, in particular arterial thrombosis,” so the link observed in the PCSK9 inhibitor trials “is not surprising,” said Dr. Piazza. Dr. O’Donoghue agreed that prior evidence had “suggested a prothrombotic role for Lp(a).”
Dr. Thanassoulis was more skeptical of a Lp(a) connection to VTE. “There has always been controversy regarding the prothrombotic effects of Lp(a) and whether it’s clinically relevant,” he said. “The genetic data, from Mendelian randomization studies, is not consistent” with a Lp(a) and VTE link.
The association of AS and Lp(a) may be stronger. “Our team showed that people with genetic variants that predispose to high Lp(a) have a much higher incidence of AS,” Dr. Thanassoulis noted. “We and others have also demonstrated that both Lp(a) and LDL are likely causal mediators of aortic valve calcification and stenosis.”
Dr. O’Donoghue also cited observational genetic data that linked elevated Lp(a) with AS. “Mendelian randomization studies have demonstrated that Lp(a) is a causal contributer to AS, and evolocumab reduced Lp(a) by 25%-30%, raising the possibility that Lp(a) lowering with these drugs may be the mechanism,” she said.
The future of Lp(a) lowering
This last point from Dr. O’Donoghue, that PCSK9 inhibitors cut Lp(a) levels by about 25%-30%, means that they are the most potent Lp(a)-lowering agents currently available, but it also leaves lots of room for other agents to do even better in cutting Lp(a).
“There are now drugs in development that block production of the Lp(a) protein and dramatically reduce its concentration, by about 80%,” Dr. O’Donoghue noted. “It will be of interest to study whether these novel therapies, now in phase 2 and phase 3 studies, have any effect on the risk for VTE and AS.”
“Several drugs in development, including antisense RNA and RNA-interfering molecules, are much more potent and lower Lp(a) by 80%-90%. Because of this potency they can completely normalize Lp(a) in most patients. For Lp(a) lowering, the future is in these new molecules. Randomized trials have started, and we will hopefully have some results in about 5 years,” said Dr. Thanassoulis.
Until then, the prospect of possibly soon documenting benefits from PCSK9 inhibitors beyond their impact on cutting LDL cholesterol raises some hope to get more bang for the considerable buck these drugs cost. But Dr. Thanassoulis was skeptical it would move the cost-benefit ratio much. “VTE and AS are relatively rare, compared with atherosclerotic cardiovascular events, and therefore the added value at the population level would be small,” he predicted. But if treatment with a drug could help patients avoid surgical or percutaneous valve interventions “that could be really interesting from a cost-benefit perspective.”
FOURIER was funded by Amgen, the company that markets evolocumab (Repatha). ODYSSEY OUTCOMES was funded by Sanofi and Regeneron, the companies that developed and market alirocumab (Praluent). Dr. Marston had no disclosures. Dr. Bergmark has been a consultant to Daiichi Sankyo, Janssen, Quark, and Servier and has received research funding from Abbott Vascular, AstraZeneca, and MedImmune. Dr. O’Donoghue has been a consultant to and has received research funding from Amgen; has been a consultant to Janssen and Novartis; and has received research funding from AstraZeneca, Eisai, GlaxoSmithKline, Janssen, Medimmune, Merck, and The Medicines Company. Dr. Thanassoulis has been an adviser to and speaker for Amgen; an adviser to Ionis and Sanofi/Regeneron; a speaker on behalf of Boehringer Ingelheim, Sanofi, and Servier; and has received research funding from Ionis and Servier. Dr. Piazza has been a consultant to Optum, Pfizer, and Thrombolex and he has received research funding from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Ekos, Janssen, and Portola.
Post hoc analyses of recent large, clinical outcomes studies of PCSK9 inhibitors have revealed two tantalizing and unexpected potential benefits from these drugs: an ability to substantially reduce the incidence or severity of venous thromboembolism and aortic stenosis.
The evidence also suggests that these effects are linked to the ability of these drugs to reduce blood levels of Lp(a) lipoprotein by roughly a quarter, currently the biggest known effect on Lp(a) levels of any approved medication.
One study ran post hoc analyses of venous thromboembolism (VTE) events in the FOURIER pivotal trial of evolocumab (Repatha), with more than 27,500 randomized patients (N Engl J Med. 2017 May 4; 376[18]:1713-22), and in the ODYSSEY OUTCOMES pivotal trial of alirocumab (Praluent), with nearly 19,000 randomized patients (N Engl J Med. 2018 Nov 29;379[22]:2097-2107). The analyses showed that, with evolocumab treatment, the incidence of VTE events fell by a statistically significant 29%, compared with patients on placebo, while in ODYSSEY OUTCOMES patients treated with alirocumab had a 33% cut in VTE events, compared with placebo-treated patients, a difference that just missed statistical significance (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046524) in analyses that were not prespecified before these trials started, Nicholas A. Marston, MD, said in a presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
A combined analysis of 46,488 patients from both studies showed a 31% cut in VTE events with PCSK9 inhibitor treatment, a highly significant finding using VTE endpoints that were not specifically tallied nor adjudicated but collected as part of the serious adverse event reporting in the two pivotal trials, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. This is the first report of a statistically significant link between treatment with PCSK9-inhibiting agents and a reduction in VTE, he added. Researchers from the ODYSSEY OUTCOMES trial had reported a VTE analysis in 2019, and while data from that trial on its own showed a nominal 33% lower VTE rate with alirocumab treatment, it just missed statistical significance.
The VTE effect took about a year on treatment to start to manifest. During the first 12 months of FOURIER, the rate of VTE events among patients in the two treatment arms was virtually identical. But starting during months 13-18 on treatment, the event curves in the two arms began to increasingly diverge, and overall during the period from month 13 to the end of the study treatment with evolocumab was linked with a statistically significant 46% reduction in VTE events, compared with patients who received placebo. The results Dr. Marston reported were also published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046397).
The suggestion that this association may be linked to the impact of PCSK9 inhibitors on Lp(a) came from an additional analysis that Dr. Marston presented, which looked at the link between evolocumab use and a change in VTE event rates, compared with placebo, depending on baseline lipoprotein levels. Evolocumab treatment was associated with a roughly similar, modest, and not statistically significant reduction in VTE events, compared with placebo regardless of whether patients had baseline levels of LDL cholesterol below the median or at or above the median. In contrast, when a similar analysis divided patients based on whether their Lp(a) level at baseline was below, or at or above, the median the results showed no discernible effect of evolocumab treatment, compared with on VTE events in patients with lower baseline Lp(a), but in those with higher levels treatment with evolocumab linked with a 48% cut in VTE events, compared with placebo, a statistically significant difference.
In FOURIER, treatment with evolocumab lowered baseline Lp(a) levels by a median of 27%, compared with placebo, among the 25,096 enrolled patients who had their baseline levels measured. As previously reported, prespecified analysis of FOURIER data also showed that the impact of evolocumab, compared with placebo, on the combined rate of coronary heart disease death, MI, or need for urgent coronary revascularization was enhanced among patients with elevated baseline Lp(a) and moderated in those who entered with lower levels. Among patients who entered FOURIER with Lp(a) levels at or below the median treatment with evolocumab cut the primary endpoint by 7%, compared with placebo, a difference that was not statistically significant. Among patients who began the study with Lp(a) levels above the median, evolocumab treatment cut the primary endpoint by 23%, compared with placebo, a statistically significant effect (Circulation. 2019 Mar 19;139[12]:1483-92).
The aortic stenosis connection
A second study reported in the online scientific sessions (Abstract 914-08) used only FOURIER data, and showed that patients treated with evolocumab had a roughly similar response pattern in their incidence of aortic stenosis (AS) events as they did for VTE events.
During the first year of the study, the incidence of AS events was virtually identical among patients treated with evolocumab and those who received placebo. But after the first 12 months and through the study’s end, patients on evolocumab showed a statistically significant 52% relative reduction in AS events, compared with control patients, said Brian A. Bergmark, MD. For the entire study duration, treatment with evolocumab linked with a 34% relative reduction in AS events, compared with placebo, a difference that did not reach statistical significance, added Dr. Bergmark, an interventional cardiologist also at Brigham and Women’s Hospital. The observed halving in total AS events that linked with evolocumab treatment after the first year of the study included a similar-magnitude reduction specifically in the incidence of aortic valve replacement procedures in the evolocumab-treated patients.
Further analysis of both total AS events and aortic valve replacements in FOURIER patients showed that they occurred at a significantly elevated rate in patients who entered the study with higher baseline Lp(a) levels in a multivariate analysis, but a similar analysis showed no significant association between the incidence of these AS-related events and baseline levels of LDL cholesterol, he said.
The AS analysis carried the same important limitations as the VTE analysis: It ran on a post hoc basis and focused on events that were relatively uncommon and not adjudicated, Dr. Bergmark cautioned. Nonetheless, other investigators saw important potential implications from both the VTE and AS observations, with the huge caveat that they need replication in prospective studies designed to specifically address the validity of these findings.
What it could mean
These observed associations between PCSK9 inhibitor treatment and apparent reductions in the rate of both VTE and AS events “represent a tremendous clinical breakthrough,” commented Michelle L. O’Donoghue, MD, a cardiologist at Brigham and Women’s Hospital who is a FOURIER coinvestigator and has led some of the Lp(a) analyses run from that study.
“To date, we have not identified any therapies that slow progression of AS. Other classes of lipid-lowering therapies, such as statins, have been tested and not demonstrated a significant effect,” Dr. O’Donoghue said in an interview.
“For AS, the results are very intriguing. If confirmed, it could be groundbreaking. AS is the most common valve disease in the developed world, and no medical therapy exists. The potential is immense,” commented George Thanassoulis, MD, director of preventive and genomic cardiology at McGill University, Montreal. “Having a medical treatment that could slow AS progression would completely change the disease. It’s conceivable to slow the disease enough that patients may never require valve replacement.” But an interview he cautioned that, “although the results are exciting, the analysis has many limitations. What we need is a dedicated, randomized trial for AS. I hope this stimulates that.”
“For VTE, it’s an interesting finding, but I don’t think it will have clinical utility because we have good treatment for VTE,” added Dr. Thanassoulis, but others saw more opportunity from what could be a new way to reduce VTE risk.
“Given that many patients have difficulty with the bleeding risk from anticoagulants, this option [a PCSK9 inhibitor] may be quite welcome for preventing VTE,” commented Gregory Piazza, MD, a cardiologist and VTE specialist at Brigham and Women’s Hospital who was not involved in any of the PCSK9 inhibitor studies.
“At this time we would not suggest that PCSK9 inhibitors replace an anticoagulant for patients with an established clot or at high risk for a recurrent clot, but if patients have an indication for a PCSK9 inhibitor, the further reduction in venous clot can be viewed as an additional benefit of this therapy,” said Dr. O’Donoghue.
How it might work
A possible mechanism underlying a VTE effect is unclear. Results from the JUPITER trial more than a decade ago had shown a significant association between treatment with 20 mg/day of rosuvastatin and a cut in VTE episodes, compared with placebo, in a prespecified, secondary analysis of the trial with nearly 18,000 patients selected for having a relatively high level of high-sensitivity C-reactive protein (N Engl J Med. 2009 Apr 30;360[18]:1851-61). But a meta-analysis of 29 controlled statin trials that used a variety of statin types and dosages (and included the JUPITER results) failed to confirm a statistically significant change in VTE rates from statins, though they produced a small, nominal reduction (PLoS Med. 2012 Sep 18. doi: 10.1371/journal.pmed.1001310).
Lp(a) “has long been linked to thrombosis, in particular arterial thrombosis,” so the link observed in the PCSK9 inhibitor trials “is not surprising,” said Dr. Piazza. Dr. O’Donoghue agreed that prior evidence had “suggested a prothrombotic role for Lp(a).”
Dr. Thanassoulis was more skeptical of a Lp(a) connection to VTE. “There has always been controversy regarding the prothrombotic effects of Lp(a) and whether it’s clinically relevant,” he said. “The genetic data, from Mendelian randomization studies, is not consistent” with a Lp(a) and VTE link.
The association of AS and Lp(a) may be stronger. “Our team showed that people with genetic variants that predispose to high Lp(a) have a much higher incidence of AS,” Dr. Thanassoulis noted. “We and others have also demonstrated that both Lp(a) and LDL are likely causal mediators of aortic valve calcification and stenosis.”
Dr. O’Donoghue also cited observational genetic data that linked elevated Lp(a) with AS. “Mendelian randomization studies have demonstrated that Lp(a) is a causal contributer to AS, and evolocumab reduced Lp(a) by 25%-30%, raising the possibility that Lp(a) lowering with these drugs may be the mechanism,” she said.
The future of Lp(a) lowering
This last point from Dr. O’Donoghue, that PCSK9 inhibitors cut Lp(a) levels by about 25%-30%, means that they are the most potent Lp(a)-lowering agents currently available, but it also leaves lots of room for other agents to do even better in cutting Lp(a).
“There are now drugs in development that block production of the Lp(a) protein and dramatically reduce its concentration, by about 80%,” Dr. O’Donoghue noted. “It will be of interest to study whether these novel therapies, now in phase 2 and phase 3 studies, have any effect on the risk for VTE and AS.”
“Several drugs in development, including antisense RNA and RNA-interfering molecules, are much more potent and lower Lp(a) by 80%-90%. Because of this potency they can completely normalize Lp(a) in most patients. For Lp(a) lowering, the future is in these new molecules. Randomized trials have started, and we will hopefully have some results in about 5 years,” said Dr. Thanassoulis.
Until then, the prospect of possibly soon documenting benefits from PCSK9 inhibitors beyond their impact on cutting LDL cholesterol raises some hope to get more bang for the considerable buck these drugs cost. But Dr. Thanassoulis was skeptical it would move the cost-benefit ratio much. “VTE and AS are relatively rare, compared with atherosclerotic cardiovascular events, and therefore the added value at the population level would be small,” he predicted. But if treatment with a drug could help patients avoid surgical or percutaneous valve interventions “that could be really interesting from a cost-benefit perspective.”
FOURIER was funded by Amgen, the company that markets evolocumab (Repatha). ODYSSEY OUTCOMES was funded by Sanofi and Regeneron, the companies that developed and market alirocumab (Praluent). Dr. Marston had no disclosures. Dr. Bergmark has been a consultant to Daiichi Sankyo, Janssen, Quark, and Servier and has received research funding from Abbott Vascular, AstraZeneca, and MedImmune. Dr. O’Donoghue has been a consultant to and has received research funding from Amgen; has been a consultant to Janssen and Novartis; and has received research funding from AstraZeneca, Eisai, GlaxoSmithKline, Janssen, Medimmune, Merck, and The Medicines Company. Dr. Thanassoulis has been an adviser to and speaker for Amgen; an adviser to Ionis and Sanofi/Regeneron; a speaker on behalf of Boehringer Ingelheim, Sanofi, and Servier; and has received research funding from Ionis and Servier. Dr. Piazza has been a consultant to Optum, Pfizer, and Thrombolex and he has received research funding from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Ekos, Janssen, and Portola.
Post hoc analyses of recent large, clinical outcomes studies of PCSK9 inhibitors have revealed two tantalizing and unexpected potential benefits from these drugs: an ability to substantially reduce the incidence or severity of venous thromboembolism and aortic stenosis.
The evidence also suggests that these effects are linked to the ability of these drugs to reduce blood levels of Lp(a) lipoprotein by roughly a quarter, currently the biggest known effect on Lp(a) levels of any approved medication.
One study ran post hoc analyses of venous thromboembolism (VTE) events in the FOURIER pivotal trial of evolocumab (Repatha), with more than 27,500 randomized patients (N Engl J Med. 2017 May 4; 376[18]:1713-22), and in the ODYSSEY OUTCOMES pivotal trial of alirocumab (Praluent), with nearly 19,000 randomized patients (N Engl J Med. 2018 Nov 29;379[22]:2097-2107). The analyses showed that, with evolocumab treatment, the incidence of VTE events fell by a statistically significant 29%, compared with patients on placebo, while in ODYSSEY OUTCOMES patients treated with alirocumab had a 33% cut in VTE events, compared with placebo-treated patients, a difference that just missed statistical significance (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046524) in analyses that were not prespecified before these trials started, Nicholas A. Marston, MD, said in a presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
A combined analysis of 46,488 patients from both studies showed a 31% cut in VTE events with PCSK9 inhibitor treatment, a highly significant finding using VTE endpoints that were not specifically tallied nor adjudicated but collected as part of the serious adverse event reporting in the two pivotal trials, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. This is the first report of a statistically significant link between treatment with PCSK9-inhibiting agents and a reduction in VTE, he added. Researchers from the ODYSSEY OUTCOMES trial had reported a VTE analysis in 2019, and while data from that trial on its own showed a nominal 33% lower VTE rate with alirocumab treatment, it just missed statistical significance.
The VTE effect took about a year on treatment to start to manifest. During the first 12 months of FOURIER, the rate of VTE events among patients in the two treatment arms was virtually identical. But starting during months 13-18 on treatment, the event curves in the two arms began to increasingly diverge, and overall during the period from month 13 to the end of the study treatment with evolocumab was linked with a statistically significant 46% reduction in VTE events, compared with patients who received placebo. The results Dr. Marston reported were also published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046397).
The suggestion that this association may be linked to the impact of PCSK9 inhibitors on Lp(a) came from an additional analysis that Dr. Marston presented, which looked at the link between evolocumab use and a change in VTE event rates, compared with placebo, depending on baseline lipoprotein levels. Evolocumab treatment was associated with a roughly similar, modest, and not statistically significant reduction in VTE events, compared with placebo regardless of whether patients had baseline levels of LDL cholesterol below the median or at or above the median. In contrast, when a similar analysis divided patients based on whether their Lp(a) level at baseline was below, or at or above, the median the results showed no discernible effect of evolocumab treatment, compared with on VTE events in patients with lower baseline Lp(a), but in those with higher levels treatment with evolocumab linked with a 48% cut in VTE events, compared with placebo, a statistically significant difference.
In FOURIER, treatment with evolocumab lowered baseline Lp(a) levels by a median of 27%, compared with placebo, among the 25,096 enrolled patients who had their baseline levels measured. As previously reported, prespecified analysis of FOURIER data also showed that the impact of evolocumab, compared with placebo, on the combined rate of coronary heart disease death, MI, or need for urgent coronary revascularization was enhanced among patients with elevated baseline Lp(a) and moderated in those who entered with lower levels. Among patients who entered FOURIER with Lp(a) levels at or below the median treatment with evolocumab cut the primary endpoint by 7%, compared with placebo, a difference that was not statistically significant. Among patients who began the study with Lp(a) levels above the median, evolocumab treatment cut the primary endpoint by 23%, compared with placebo, a statistically significant effect (Circulation. 2019 Mar 19;139[12]:1483-92).
The aortic stenosis connection
A second study reported in the online scientific sessions (Abstract 914-08) used only FOURIER data, and showed that patients treated with evolocumab had a roughly similar response pattern in their incidence of aortic stenosis (AS) events as they did for VTE events.
During the first year of the study, the incidence of AS events was virtually identical among patients treated with evolocumab and those who received placebo. But after the first 12 months and through the study’s end, patients on evolocumab showed a statistically significant 52% relative reduction in AS events, compared with control patients, said Brian A. Bergmark, MD. For the entire study duration, treatment with evolocumab linked with a 34% relative reduction in AS events, compared with placebo, a difference that did not reach statistical significance, added Dr. Bergmark, an interventional cardiologist also at Brigham and Women’s Hospital. The observed halving in total AS events that linked with evolocumab treatment after the first year of the study included a similar-magnitude reduction specifically in the incidence of aortic valve replacement procedures in the evolocumab-treated patients.
Further analysis of both total AS events and aortic valve replacements in FOURIER patients showed that they occurred at a significantly elevated rate in patients who entered the study with higher baseline Lp(a) levels in a multivariate analysis, but a similar analysis showed no significant association between the incidence of these AS-related events and baseline levels of LDL cholesterol, he said.
The AS analysis carried the same important limitations as the VTE analysis: It ran on a post hoc basis and focused on events that were relatively uncommon and not adjudicated, Dr. Bergmark cautioned. Nonetheless, other investigators saw important potential implications from both the VTE and AS observations, with the huge caveat that they need replication in prospective studies designed to specifically address the validity of these findings.
What it could mean
These observed associations between PCSK9 inhibitor treatment and apparent reductions in the rate of both VTE and AS events “represent a tremendous clinical breakthrough,” commented Michelle L. O’Donoghue, MD, a cardiologist at Brigham and Women’s Hospital who is a FOURIER coinvestigator and has led some of the Lp(a) analyses run from that study.
“To date, we have not identified any therapies that slow progression of AS. Other classes of lipid-lowering therapies, such as statins, have been tested and not demonstrated a significant effect,” Dr. O’Donoghue said in an interview.
“For AS, the results are very intriguing. If confirmed, it could be groundbreaking. AS is the most common valve disease in the developed world, and no medical therapy exists. The potential is immense,” commented George Thanassoulis, MD, director of preventive and genomic cardiology at McGill University, Montreal. “Having a medical treatment that could slow AS progression would completely change the disease. It’s conceivable to slow the disease enough that patients may never require valve replacement.” But an interview he cautioned that, “although the results are exciting, the analysis has many limitations. What we need is a dedicated, randomized trial for AS. I hope this stimulates that.”
“For VTE, it’s an interesting finding, but I don’t think it will have clinical utility because we have good treatment for VTE,” added Dr. Thanassoulis, but others saw more opportunity from what could be a new way to reduce VTE risk.
“Given that many patients have difficulty with the bleeding risk from anticoagulants, this option [a PCSK9 inhibitor] may be quite welcome for preventing VTE,” commented Gregory Piazza, MD, a cardiologist and VTE specialist at Brigham and Women’s Hospital who was not involved in any of the PCSK9 inhibitor studies.
“At this time we would not suggest that PCSK9 inhibitors replace an anticoagulant for patients with an established clot or at high risk for a recurrent clot, but if patients have an indication for a PCSK9 inhibitor, the further reduction in venous clot can be viewed as an additional benefit of this therapy,” said Dr. O’Donoghue.
How it might work
A possible mechanism underlying a VTE effect is unclear. Results from the JUPITER trial more than a decade ago had shown a significant association between treatment with 20 mg/day of rosuvastatin and a cut in VTE episodes, compared with placebo, in a prespecified, secondary analysis of the trial with nearly 18,000 patients selected for having a relatively high level of high-sensitivity C-reactive protein (N Engl J Med. 2009 Apr 30;360[18]:1851-61). But a meta-analysis of 29 controlled statin trials that used a variety of statin types and dosages (and included the JUPITER results) failed to confirm a statistically significant change in VTE rates from statins, though they produced a small, nominal reduction (PLoS Med. 2012 Sep 18. doi: 10.1371/journal.pmed.1001310).
Lp(a) “has long been linked to thrombosis, in particular arterial thrombosis,” so the link observed in the PCSK9 inhibitor trials “is not surprising,” said Dr. Piazza. Dr. O’Donoghue agreed that prior evidence had “suggested a prothrombotic role for Lp(a).”
Dr. Thanassoulis was more skeptical of a Lp(a) connection to VTE. “There has always been controversy regarding the prothrombotic effects of Lp(a) and whether it’s clinically relevant,” he said. “The genetic data, from Mendelian randomization studies, is not consistent” with a Lp(a) and VTE link.
The association of AS and Lp(a) may be stronger. “Our team showed that people with genetic variants that predispose to high Lp(a) have a much higher incidence of AS,” Dr. Thanassoulis noted. “We and others have also demonstrated that both Lp(a) and LDL are likely causal mediators of aortic valve calcification and stenosis.”
Dr. O’Donoghue also cited observational genetic data that linked elevated Lp(a) with AS. “Mendelian randomization studies have demonstrated that Lp(a) is a causal contributer to AS, and evolocumab reduced Lp(a) by 25%-30%, raising the possibility that Lp(a) lowering with these drugs may be the mechanism,” she said.
The future of Lp(a) lowering
This last point from Dr. O’Donoghue, that PCSK9 inhibitors cut Lp(a) levels by about 25%-30%, means that they are the most potent Lp(a)-lowering agents currently available, but it also leaves lots of room for other agents to do even better in cutting Lp(a).
“There are now drugs in development that block production of the Lp(a) protein and dramatically reduce its concentration, by about 80%,” Dr. O’Donoghue noted. “It will be of interest to study whether these novel therapies, now in phase 2 and phase 3 studies, have any effect on the risk for VTE and AS.”
“Several drugs in development, including antisense RNA and RNA-interfering molecules, are much more potent and lower Lp(a) by 80%-90%. Because of this potency they can completely normalize Lp(a) in most patients. For Lp(a) lowering, the future is in these new molecules. Randomized trials have started, and we will hopefully have some results in about 5 years,” said Dr. Thanassoulis.
Until then, the prospect of possibly soon documenting benefits from PCSK9 inhibitors beyond their impact on cutting LDL cholesterol raises some hope to get more bang for the considerable buck these drugs cost. But Dr. Thanassoulis was skeptical it would move the cost-benefit ratio much. “VTE and AS are relatively rare, compared with atherosclerotic cardiovascular events, and therefore the added value at the population level would be small,” he predicted. But if treatment with a drug could help patients avoid surgical or percutaneous valve interventions “that could be really interesting from a cost-benefit perspective.”
FOURIER was funded by Amgen, the company that markets evolocumab (Repatha). ODYSSEY OUTCOMES was funded by Sanofi and Regeneron, the companies that developed and market alirocumab (Praluent). Dr. Marston had no disclosures. Dr. Bergmark has been a consultant to Daiichi Sankyo, Janssen, Quark, and Servier and has received research funding from Abbott Vascular, AstraZeneca, and MedImmune. Dr. O’Donoghue has been a consultant to and has received research funding from Amgen; has been a consultant to Janssen and Novartis; and has received research funding from AstraZeneca, Eisai, GlaxoSmithKline, Janssen, Medimmune, Merck, and The Medicines Company. Dr. Thanassoulis has been an adviser to and speaker for Amgen; an adviser to Ionis and Sanofi/Regeneron; a speaker on behalf of Boehringer Ingelheim, Sanofi, and Servier; and has received research funding from Ionis and Servier. Dr. Piazza has been a consultant to Optum, Pfizer, and Thrombolex and he has received research funding from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Ekos, Janssen, and Portola.
REPORTING FROM ACC 20