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Few acutely ill hospitalized patients receive VTE prophylaxis
SAN DIEGO – Among patients hospitalized for acute medical illnesses, the risk of venous thromboembolism (VTE) remained elevated 30-40 days after discharge, results from a large analysis of national data showed.
Moreover, only 7% of at-risk patients received VTE prophylaxis in both the inpatient and outpatient setting.
“The results of this real-world study imply that there is a significantly unmet medical need for effective VTE prophylaxis in both the inpatient and outpatient continuum of care among patients hospitalized for acute medical illnesses,” researchers led by Alpesh Amin, MD, wrote in a poster presented at the biennial summit of the Thrombosis & Hemostasis Societies of North America.
According to Dr. Amin, who chairs the department of medicine at the University of California, Irvine, hospitalized patients with acute medical illnesses face an increased risk for VTE during hospital discharge, mainly within 40 days following hospital admission. However, the treatment patterns of VTE prophylaxis in this patient population have not been well studied in the “real-world” setting. In an effort to improve this area of clinical practice, the researchers used the Marketscan database between Jan. 1, 2012, and June 30, 2015, to identify acutely ill hospitalized patients, such as those with heart failure, respiratory diseases, ischemic stroke, cancer, infectious diseases, and rheumatic diseases. The key outcomes of interest were the proportion of patients receiving inpatient and outpatient VTE prophylaxis and the proportion of patients with VTE events during and after the index hospitalization. They used Kaplan-Meier analysis to examine the risk for VTE events after the index inpatient admission.
The mean age of the 17,895 patients was 58 years, 55% were female, and most (77%) were from the Southern area of the United States. Their mean Charlson Comborbidity Index score prior to hospitalization was 2.2. Nearly all hospitals (87%) were urban based, nonteaching (95%), and large, with 68% having at least 300 beds. Nearly three-quarters of patients (72%) were hospitalized for infectious and respiratory diseases, and the mean length of stay was 5 days.
Dr. Amin and his associates found that 59% of hospitalized patients did not receive any VTE prophylaxis, while only 7% received prophylaxis in both the inpatient and outpatient continuum of care. At the same time, cumulative VTE rates within 40 days of index admission were highest among patients hospitalized for infectious diseases and cancer (3.4% each), followed by those with heart failure (3.1%), respiratory diseases (2%), ischemic stroke (1.5%), and rheumatic diseases (1.3%). The cumulative VTE event rate for the overall study population within 40 days from index hospitalization was nearly 3%, with 60% of VTE events having occurred within 40 days.
The study was funded by Portola Pharmaceuticals. Dr. Amin reported having no financial disclosures.
SOURCE: Amin A et al. THSNA 2018, Poster 51.
SAN DIEGO – Among patients hospitalized for acute medical illnesses, the risk of venous thromboembolism (VTE) remained elevated 30-40 days after discharge, results from a large analysis of national data showed.
Moreover, only 7% of at-risk patients received VTE prophylaxis in both the inpatient and outpatient setting.
“The results of this real-world study imply that there is a significantly unmet medical need for effective VTE prophylaxis in both the inpatient and outpatient continuum of care among patients hospitalized for acute medical illnesses,” researchers led by Alpesh Amin, MD, wrote in a poster presented at the biennial summit of the Thrombosis & Hemostasis Societies of North America.
According to Dr. Amin, who chairs the department of medicine at the University of California, Irvine, hospitalized patients with acute medical illnesses face an increased risk for VTE during hospital discharge, mainly within 40 days following hospital admission. However, the treatment patterns of VTE prophylaxis in this patient population have not been well studied in the “real-world” setting. In an effort to improve this area of clinical practice, the researchers used the Marketscan database between Jan. 1, 2012, and June 30, 2015, to identify acutely ill hospitalized patients, such as those with heart failure, respiratory diseases, ischemic stroke, cancer, infectious diseases, and rheumatic diseases. The key outcomes of interest were the proportion of patients receiving inpatient and outpatient VTE prophylaxis and the proportion of patients with VTE events during and after the index hospitalization. They used Kaplan-Meier analysis to examine the risk for VTE events after the index inpatient admission.
The mean age of the 17,895 patients was 58 years, 55% were female, and most (77%) were from the Southern area of the United States. Their mean Charlson Comborbidity Index score prior to hospitalization was 2.2. Nearly all hospitals (87%) were urban based, nonteaching (95%), and large, with 68% having at least 300 beds. Nearly three-quarters of patients (72%) were hospitalized for infectious and respiratory diseases, and the mean length of stay was 5 days.
Dr. Amin and his associates found that 59% of hospitalized patients did not receive any VTE prophylaxis, while only 7% received prophylaxis in both the inpatient and outpatient continuum of care. At the same time, cumulative VTE rates within 40 days of index admission were highest among patients hospitalized for infectious diseases and cancer (3.4% each), followed by those with heart failure (3.1%), respiratory diseases (2%), ischemic stroke (1.5%), and rheumatic diseases (1.3%). The cumulative VTE event rate for the overall study population within 40 days from index hospitalization was nearly 3%, with 60% of VTE events having occurred within 40 days.
The study was funded by Portola Pharmaceuticals. Dr. Amin reported having no financial disclosures.
SOURCE: Amin A et al. THSNA 2018, Poster 51.
SAN DIEGO – Among patients hospitalized for acute medical illnesses, the risk of venous thromboembolism (VTE) remained elevated 30-40 days after discharge, results from a large analysis of national data showed.
Moreover, only 7% of at-risk patients received VTE prophylaxis in both the inpatient and outpatient setting.
“The results of this real-world study imply that there is a significantly unmet medical need for effective VTE prophylaxis in both the inpatient and outpatient continuum of care among patients hospitalized for acute medical illnesses,” researchers led by Alpesh Amin, MD, wrote in a poster presented at the biennial summit of the Thrombosis & Hemostasis Societies of North America.
According to Dr. Amin, who chairs the department of medicine at the University of California, Irvine, hospitalized patients with acute medical illnesses face an increased risk for VTE during hospital discharge, mainly within 40 days following hospital admission. However, the treatment patterns of VTE prophylaxis in this patient population have not been well studied in the “real-world” setting. In an effort to improve this area of clinical practice, the researchers used the Marketscan database between Jan. 1, 2012, and June 30, 2015, to identify acutely ill hospitalized patients, such as those with heart failure, respiratory diseases, ischemic stroke, cancer, infectious diseases, and rheumatic diseases. The key outcomes of interest were the proportion of patients receiving inpatient and outpatient VTE prophylaxis and the proportion of patients with VTE events during and after the index hospitalization. They used Kaplan-Meier analysis to examine the risk for VTE events after the index inpatient admission.
The mean age of the 17,895 patients was 58 years, 55% were female, and most (77%) were from the Southern area of the United States. Their mean Charlson Comborbidity Index score prior to hospitalization was 2.2. Nearly all hospitals (87%) were urban based, nonteaching (95%), and large, with 68% having at least 300 beds. Nearly three-quarters of patients (72%) were hospitalized for infectious and respiratory diseases, and the mean length of stay was 5 days.
Dr. Amin and his associates found that 59% of hospitalized patients did not receive any VTE prophylaxis, while only 7% received prophylaxis in both the inpatient and outpatient continuum of care. At the same time, cumulative VTE rates within 40 days of index admission were highest among patients hospitalized for infectious diseases and cancer (3.4% each), followed by those with heart failure (3.1%), respiratory diseases (2%), ischemic stroke (1.5%), and rheumatic diseases (1.3%). The cumulative VTE event rate for the overall study population within 40 days from index hospitalization was nearly 3%, with 60% of VTE events having occurred within 40 days.
The study was funded by Portola Pharmaceuticals. Dr. Amin reported having no financial disclosures.
SOURCE: Amin A et al. THSNA 2018, Poster 51.
REPORTING FROM THSNA 2018
Key clinical point: There is a significant unmet medical need for VTE prophylaxis in the continuum of care of patients hospitalized for acute medical illnesses.
Major finding: Of the overall study population, only 7% received both inpatient and outpatient VTE prophylaxis.
Study details: An analysis of national data from 17,895 acutely ill hospitalized patients.
Disclosures: The study was funded by Portola Pharmaceuticals. The presenter reported having no financial conflicts.
Source: Amin A et al. THSNA 2018, Poster 51.
JAK inhibitors for RA: Is VTE risk overblown?
MAUI, HAWAII – Rheumatologists, regulatory agencies, and the pharmaceutical industry all have gone off the deep end in their fretting over what appears to be a low rate of venous thromboembolic events in the major randomized trials of the oral Janus kinase inhibitors for RA, Mark C. Genovese, MD, asserted at the 2018 Rheumatology Winter Clinical Symposium.
“The reality is all of our drugs pose potential risks. Unfortunately, I think that at least for the moment, the field has turned all attention in one direction: VTE [venous thromboembolic] events. I suspect there’s some truth [to the possible associated risk]. Certainly we are seeing these events. The question is, how overdone is this?” according to Dr. Genovese, professor of medicine and cochief of the division of immunology and rheumatology at Stanford (Calif.) University.
“I think the upadacitinib data has been entirely overshadowed by concerns about VTEs,” he said. “In the last year, we saw three significant phase 3 studies on upadacitinib arrive in the rheumatology community, and I think the only thing we talked about was VTEs.”
All parties interested in developing Janus kinase (JAK) inhibitors for the treatment of RA began to freak out about a possible increase in VTEs when in April 2017 the Food and Drug Administration turned down Eli Lilly and Incyte’s initial application for marketing approval of the JAK inhibitor baricitinib. Among the problems the agency cited was evidence of potential thrombotic risk.
The VTE rate in baricitinib clinical trials up to 48 weeks in duration was 0.53 events/100 patient-years, with no significant difference in risk between the2-mg and 4-mg doses. This appears to be a class effect for the oral JAK inhibitors, as low rates of VTE, albeit numerically higher than in placebo-treated controls, have also been recorded in the RA development programs for tofacitinib (Xeljanz) as well as the investigational agents filgotinib and upadacitinib, the rheumatologist noted.
This begs the question of whether these VTE rates are significantly higher than background rates in patients with RA or other rheumatologic diseases, which are known to be elevated relative to the general population. Indeed, a retrospective study of insurance claims data by investigators at Brigham and Women’s Hospital, Boston, concluded that the VTE rate in RA patients was 0.61 events/100 patient-years, 120% greater than in a matched patient population without RA. After fully adjusting for comorbid conditions and demographics, the relative risk increase associated with RA dropped to 40%, still significantly higher than in controls (Arthritis Care Res [Hoboken]. 2013 Oct;65[10]:1600-7).
Similarly, Canadian investigators conducted a meta-analysis of 25 studies with VTE data in patients with RA, systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, or inflammatory myositis. This meta-analysis included 10 studies of more than 5.2 million RA patients and nearly 900,000 controls. The conclusion: each of these rheumatic diseases was associated with a VTE rate more than three times higher than in the general population (Arthritis Res Ther. 2014 Sep 25;16[5]:435).
“Patients with RA are at higher risk for VTE than those without RA. It’s unfortunate, and it’s certainly something I don’t think many of us have thought much about before. It’s something we don’t often get to see and something we don’t like to think about,” the rheumatologist observed.
Dr. Genovese admitted to a degree of personal frustration with the current tunnel vision focus on VTEs in JAK inhibitor trials. At the 2017 annual meeting of the American College of Rheumatology he presented the results of the phase 3 SELECT-BEYOND study in which 499 RA patients who had previously failed to respond or were intolerant to biologic therapy were randomized to once daily upadacitinib at 15 or 30 mg or placebo on top of background methotrexate. At week 12, the ACR 20 response rate was 65% for upadacitinib at 15 mg, 56% at 30 mg, and 28% in placebo-treated controls.
“That’s almost a 40% placebo-adjusted response rate. In fact, it’s the highest response I’ve ever seen in a biologic inadequate-responder population. This really looked pretty good, but I don’t think anyone ever took notice. Why not? Because we were all worried about VTE,” he said.
There were in fact a handful of VTEs in upadacitinib-treated patients, Dr. Genovese was quick to note. But he was more impressed by the week 12 ACR 20 responses in patients who had previously failed on three or more biologics: 71% with upadacitinib at 15 mg and 50% at 30 mg, compared with 23% in controls. Moreover, among patients with a baseline history of failure to respond to anti–interleukin-6 therapy, the week 12 ACR 20 rate was 56% with upadacitinib at 15 mg and 58% at 30 mg, versus 20% in controls.
“This looks like a pretty effective drug for patients who’ve failed everything else in our practice,” he commented.
Dr. Genovese reminded his audience that the rheumatology community has a history of overreacting to safety signals in the early days after introduction of new therapies. Examples: tuberculosis with tumor necrosis factor inhibitors, lymphoma with abatacept (Orencia), lymphoma with anti–tumor necrosis factor agents, and cardiovascular events with anti–interleukin-6 inhibition.
“PML [progressive multifocal leukoencephalopathy] is a breathtaking side effect with rituximab [Rituxan], but we’ve gotten over that. We recognize that it’s a potential problem, but we still prescribe rituximab,” the rheumatologist noted. “We’re probably going to need to address the issue of which of our patients are potentially at higher risk for VTE, and maybe we avoid this class in those patients. Like we now do as we look at patients we think are at increased risk for infection, or multiple sclerosis, or TB, we may also need to think of VTE risk.”
But , he argued. There is a pressing unmet need for new therapies for RA with novel mechanisms of action. Only about one-half of patients on contemporary biologic therapies are still on that agent 5 years after initiating therapy.
“Virtually all our patients are partial responders. Everybody gets some benefit. But true remission is achieved by only a minority,” Dr. Genovese said. “The gap between where we are and where we want to be is actually much greater than we often perceive.”
He reported having financial relationships with AbbVie, which is developing upadacitinib, and more than a dozen other medical companies.
MAUI, HAWAII – Rheumatologists, regulatory agencies, and the pharmaceutical industry all have gone off the deep end in their fretting over what appears to be a low rate of venous thromboembolic events in the major randomized trials of the oral Janus kinase inhibitors for RA, Mark C. Genovese, MD, asserted at the 2018 Rheumatology Winter Clinical Symposium.
“The reality is all of our drugs pose potential risks. Unfortunately, I think that at least for the moment, the field has turned all attention in one direction: VTE [venous thromboembolic] events. I suspect there’s some truth [to the possible associated risk]. Certainly we are seeing these events. The question is, how overdone is this?” according to Dr. Genovese, professor of medicine and cochief of the division of immunology and rheumatology at Stanford (Calif.) University.
“I think the upadacitinib data has been entirely overshadowed by concerns about VTEs,” he said. “In the last year, we saw three significant phase 3 studies on upadacitinib arrive in the rheumatology community, and I think the only thing we talked about was VTEs.”
All parties interested in developing Janus kinase (JAK) inhibitors for the treatment of RA began to freak out about a possible increase in VTEs when in April 2017 the Food and Drug Administration turned down Eli Lilly and Incyte’s initial application for marketing approval of the JAK inhibitor baricitinib. Among the problems the agency cited was evidence of potential thrombotic risk.
The VTE rate in baricitinib clinical trials up to 48 weeks in duration was 0.53 events/100 patient-years, with no significant difference in risk between the2-mg and 4-mg doses. This appears to be a class effect for the oral JAK inhibitors, as low rates of VTE, albeit numerically higher than in placebo-treated controls, have also been recorded in the RA development programs for tofacitinib (Xeljanz) as well as the investigational agents filgotinib and upadacitinib, the rheumatologist noted.
This begs the question of whether these VTE rates are significantly higher than background rates in patients with RA or other rheumatologic diseases, which are known to be elevated relative to the general population. Indeed, a retrospective study of insurance claims data by investigators at Brigham and Women’s Hospital, Boston, concluded that the VTE rate in RA patients was 0.61 events/100 patient-years, 120% greater than in a matched patient population without RA. After fully adjusting for comorbid conditions and demographics, the relative risk increase associated with RA dropped to 40%, still significantly higher than in controls (Arthritis Care Res [Hoboken]. 2013 Oct;65[10]:1600-7).
Similarly, Canadian investigators conducted a meta-analysis of 25 studies with VTE data in patients with RA, systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, or inflammatory myositis. This meta-analysis included 10 studies of more than 5.2 million RA patients and nearly 900,000 controls. The conclusion: each of these rheumatic diseases was associated with a VTE rate more than three times higher than in the general population (Arthritis Res Ther. 2014 Sep 25;16[5]:435).
“Patients with RA are at higher risk for VTE than those without RA. It’s unfortunate, and it’s certainly something I don’t think many of us have thought much about before. It’s something we don’t often get to see and something we don’t like to think about,” the rheumatologist observed.
Dr. Genovese admitted to a degree of personal frustration with the current tunnel vision focus on VTEs in JAK inhibitor trials. At the 2017 annual meeting of the American College of Rheumatology he presented the results of the phase 3 SELECT-BEYOND study in which 499 RA patients who had previously failed to respond or were intolerant to biologic therapy were randomized to once daily upadacitinib at 15 or 30 mg or placebo on top of background methotrexate. At week 12, the ACR 20 response rate was 65% for upadacitinib at 15 mg, 56% at 30 mg, and 28% in placebo-treated controls.
“That’s almost a 40% placebo-adjusted response rate. In fact, it’s the highest response I’ve ever seen in a biologic inadequate-responder population. This really looked pretty good, but I don’t think anyone ever took notice. Why not? Because we were all worried about VTE,” he said.
There were in fact a handful of VTEs in upadacitinib-treated patients, Dr. Genovese was quick to note. But he was more impressed by the week 12 ACR 20 responses in patients who had previously failed on three or more biologics: 71% with upadacitinib at 15 mg and 50% at 30 mg, compared with 23% in controls. Moreover, among patients with a baseline history of failure to respond to anti–interleukin-6 therapy, the week 12 ACR 20 rate was 56% with upadacitinib at 15 mg and 58% at 30 mg, versus 20% in controls.
“This looks like a pretty effective drug for patients who’ve failed everything else in our practice,” he commented.
Dr. Genovese reminded his audience that the rheumatology community has a history of overreacting to safety signals in the early days after introduction of new therapies. Examples: tuberculosis with tumor necrosis factor inhibitors, lymphoma with abatacept (Orencia), lymphoma with anti–tumor necrosis factor agents, and cardiovascular events with anti–interleukin-6 inhibition.
“PML [progressive multifocal leukoencephalopathy] is a breathtaking side effect with rituximab [Rituxan], but we’ve gotten over that. We recognize that it’s a potential problem, but we still prescribe rituximab,” the rheumatologist noted. “We’re probably going to need to address the issue of which of our patients are potentially at higher risk for VTE, and maybe we avoid this class in those patients. Like we now do as we look at patients we think are at increased risk for infection, or multiple sclerosis, or TB, we may also need to think of VTE risk.”
But , he argued. There is a pressing unmet need for new therapies for RA with novel mechanisms of action. Only about one-half of patients on contemporary biologic therapies are still on that agent 5 years after initiating therapy.
“Virtually all our patients are partial responders. Everybody gets some benefit. But true remission is achieved by only a minority,” Dr. Genovese said. “The gap between where we are and where we want to be is actually much greater than we often perceive.”
He reported having financial relationships with AbbVie, which is developing upadacitinib, and more than a dozen other medical companies.
MAUI, HAWAII – Rheumatologists, regulatory agencies, and the pharmaceutical industry all have gone off the deep end in their fretting over what appears to be a low rate of venous thromboembolic events in the major randomized trials of the oral Janus kinase inhibitors for RA, Mark C. Genovese, MD, asserted at the 2018 Rheumatology Winter Clinical Symposium.
“The reality is all of our drugs pose potential risks. Unfortunately, I think that at least for the moment, the field has turned all attention in one direction: VTE [venous thromboembolic] events. I suspect there’s some truth [to the possible associated risk]. Certainly we are seeing these events. The question is, how overdone is this?” according to Dr. Genovese, professor of medicine and cochief of the division of immunology and rheumatology at Stanford (Calif.) University.
“I think the upadacitinib data has been entirely overshadowed by concerns about VTEs,” he said. “In the last year, we saw three significant phase 3 studies on upadacitinib arrive in the rheumatology community, and I think the only thing we talked about was VTEs.”
All parties interested in developing Janus kinase (JAK) inhibitors for the treatment of RA began to freak out about a possible increase in VTEs when in April 2017 the Food and Drug Administration turned down Eli Lilly and Incyte’s initial application for marketing approval of the JAK inhibitor baricitinib. Among the problems the agency cited was evidence of potential thrombotic risk.
The VTE rate in baricitinib clinical trials up to 48 weeks in duration was 0.53 events/100 patient-years, with no significant difference in risk between the2-mg and 4-mg doses. This appears to be a class effect for the oral JAK inhibitors, as low rates of VTE, albeit numerically higher than in placebo-treated controls, have also been recorded in the RA development programs for tofacitinib (Xeljanz) as well as the investigational agents filgotinib and upadacitinib, the rheumatologist noted.
This begs the question of whether these VTE rates are significantly higher than background rates in patients with RA or other rheumatologic diseases, which are known to be elevated relative to the general population. Indeed, a retrospective study of insurance claims data by investigators at Brigham and Women’s Hospital, Boston, concluded that the VTE rate in RA patients was 0.61 events/100 patient-years, 120% greater than in a matched patient population without RA. After fully adjusting for comorbid conditions and demographics, the relative risk increase associated with RA dropped to 40%, still significantly higher than in controls (Arthritis Care Res [Hoboken]. 2013 Oct;65[10]:1600-7).
Similarly, Canadian investigators conducted a meta-analysis of 25 studies with VTE data in patients with RA, systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, or inflammatory myositis. This meta-analysis included 10 studies of more than 5.2 million RA patients and nearly 900,000 controls. The conclusion: each of these rheumatic diseases was associated with a VTE rate more than three times higher than in the general population (Arthritis Res Ther. 2014 Sep 25;16[5]:435).
“Patients with RA are at higher risk for VTE than those without RA. It’s unfortunate, and it’s certainly something I don’t think many of us have thought much about before. It’s something we don’t often get to see and something we don’t like to think about,” the rheumatologist observed.
Dr. Genovese admitted to a degree of personal frustration with the current tunnel vision focus on VTEs in JAK inhibitor trials. At the 2017 annual meeting of the American College of Rheumatology he presented the results of the phase 3 SELECT-BEYOND study in which 499 RA patients who had previously failed to respond or were intolerant to biologic therapy were randomized to once daily upadacitinib at 15 or 30 mg or placebo on top of background methotrexate. At week 12, the ACR 20 response rate was 65% for upadacitinib at 15 mg, 56% at 30 mg, and 28% in placebo-treated controls.
“That’s almost a 40% placebo-adjusted response rate. In fact, it’s the highest response I’ve ever seen in a biologic inadequate-responder population. This really looked pretty good, but I don’t think anyone ever took notice. Why not? Because we were all worried about VTE,” he said.
There were in fact a handful of VTEs in upadacitinib-treated patients, Dr. Genovese was quick to note. But he was more impressed by the week 12 ACR 20 responses in patients who had previously failed on three or more biologics: 71% with upadacitinib at 15 mg and 50% at 30 mg, compared with 23% in controls. Moreover, among patients with a baseline history of failure to respond to anti–interleukin-6 therapy, the week 12 ACR 20 rate was 56% with upadacitinib at 15 mg and 58% at 30 mg, versus 20% in controls.
“This looks like a pretty effective drug for patients who’ve failed everything else in our practice,” he commented.
Dr. Genovese reminded his audience that the rheumatology community has a history of overreacting to safety signals in the early days after introduction of new therapies. Examples: tuberculosis with tumor necrosis factor inhibitors, lymphoma with abatacept (Orencia), lymphoma with anti–tumor necrosis factor agents, and cardiovascular events with anti–interleukin-6 inhibition.
“PML [progressive multifocal leukoencephalopathy] is a breathtaking side effect with rituximab [Rituxan], but we’ve gotten over that. We recognize that it’s a potential problem, but we still prescribe rituximab,” the rheumatologist noted. “We’re probably going to need to address the issue of which of our patients are potentially at higher risk for VTE, and maybe we avoid this class in those patients. Like we now do as we look at patients we think are at increased risk for infection, or multiple sclerosis, or TB, we may also need to think of VTE risk.”
But , he argued. There is a pressing unmet need for new therapies for RA with novel mechanisms of action. Only about one-half of patients on contemporary biologic therapies are still on that agent 5 years after initiating therapy.
“Virtually all our patients are partial responders. Everybody gets some benefit. But true remission is achieved by only a minority,” Dr. Genovese said. “The gap between where we are and where we want to be is actually much greater than we often perceive.”
He reported having financial relationships with AbbVie, which is developing upadacitinib, and more than a dozen other medical companies.
EXPERT ANALYSIS FROM RWCS 2018
Controversy surrounds calf vein thrombosis treatment
CHICAGO – The use of therapeutic-dose anticoagulation in hospitalized patients with calf vein thrombosis significantly reduces the risk of venous thromboembolic complications, compared with lower-dose prophylactic anticoagulation or surveillance alone, Heron E. Rodriguez, MD, said at a symposium on vascular surgery sponsored by Northwestern University.
Moreover, placement of an inferior vena cava filter in patients with calf vein thrombosis when anticoagulation is contraindicated accomplishes nothing beneficial and had a 10% complication rate in a large retrospective single-center study, added Dr. Rodriguez of Northwestern University, Chicago.
Deep vein thrombosis (DVT) remains a significant source of morbidity and mortality despite worldwide awareness of the problem.
“Specifically, calf vein thrombosis [CVT] is very common, and we know that in some series up to 30% of patients end up propagating proximally if they’re not treated, and a good number of them develop chronic venous insufficiency, with long-term consequences,” he noted.
“Unfortunately there is no consensus regarding treatment. The guidelines are very vague. For example, there is no mention [in current American College of Chest Physicians guidelines] of how to manage muscular vein thrombosis and much ambiguity on how to treat calf vein thrombosis,” he continued.
Dr. Rodriguez cited as an indication of the lack of consensus on management of CVT a single-institution survey by other investigators of the practices of physicians in various specialties. Forty-nine percent of respondents indicated they anticoagulate patients with CVT; 51% don’t. Of those who did, 62% prescribed low-molecular-weight heparin and 11% intravenous heparin. Fifty-eight percent of physicians who anticoagulated did so for 3 months, 30% for 6. And 46% of physicians used an inferior vena cava (IVC) filter when anticoagulation was contraindicated (Vascular. 2014 Apr;22[2]:93-7).
That rate of IVC placement “seemed really high” given the paucity of supporting evidence for safety and efficacy of filter placement in the setting of CVT, so Dr. Rodriguez and coinvestigators decided to conduct a retrospective review of practices at Northwestern Memorial Hospital. He explained the study hypothesis: “Our thinking was that these kinds of thrombi are associated with low risk of propagation and pulmonary embolism, and they can and should be managed conservatively.”
Of 647 patients with isolated thrombosis of the anterior and posterior tibial, soleal, peroneal, or gastrocnemius veins, 44% received an IVC filter, and the rest got medical treatment alone. Of the 362 patients managed medically, 49% received therapeutic anticoagulation, 12% got low-dose prophylactic anticoagulation, and 39% underwent surveillance without anticoagulation.
The primary outcome was the incidence of venous thromboembolic complications – that is, propagation of DVT or pulmonary embolism. The incidence was 35% in the surveillance-only group, 30% with prophylactic anticoagulation, and 10% in patients who got therapeutic anticoagulation.
Of note, the rate of the most feared complication, pulmonary embolism, was low and similar in the filter recipients and medically managed group: 2.5% in the IVC group, 3.3% with medical management.
“Distal vein thromboses have low rates of pulmonary embolism, regardless of whether or not they are so-called protected with a filter. On the other hand, a filter was associated with a 10% rate of complications. I have to make clear that these were radiographic abnormalities – tilting, migration, caval perforation – that didn’t have clinical consequences, but we were very aggressive in removing the IVC filters, and I’m guessing if they’d been left inside they would create problems in the long term,” Dr. Rodriguez said.
An important point about this study is that these were all sick patients, and most were hospitalized. The filter recipients and medical groups differed in key ways. For example, 49% of the filter patients had a malignancy, and 56% had a baseline history of venous thromboembolic events, compared with 26% and 16%, respectively, of the medical group. For that reason, the investigators performed propensity score matching and came up with 157 closely matched patient pairs. The outcomes remained unchanged.
Of course, this was a retrospective study, with its inherent limitations, but Dr. Rodriguez characterized the published randomized trials on management of CVT as “small and limited.” The most frequently quoted study is the double-blind multicenter CACTUS trial, which randomized 252 outpatients with symptomatic CVT to 6 weeks of low-molecular-weight heparin or placebo and found no difference in the rates of proximal extension of venous thromboembolic events (Lancet Haematol. 2016 Dec;3[12]:e556-62). But these were all low-risk patients. Prior DVT or malignancy were exclusion criteria, so this was a very different population than treated at Northwestern.
Based upon the results of the retrospective study at Northwestern, which have been published (J Vasc Surg Venous Lymphat Disord. 2017 Jan;5[1]:25-32), the vascular surgery service has developed a management algorithm for DVT management based upon the lesion site. If a patient is unable to undergo anticoagulation, venous duplex ultrasound is repeated at 1 week. If the imaging shows propagation into the popliteal vein and anticoagulation remains contraindicated, only then is placement of an IVC filter warranted.
Dr. Rodriguez reported serving as a paid speaker for Abbott, Endologix, and W.L. Gore.
CHICAGO – The use of therapeutic-dose anticoagulation in hospitalized patients with calf vein thrombosis significantly reduces the risk of venous thromboembolic complications, compared with lower-dose prophylactic anticoagulation or surveillance alone, Heron E. Rodriguez, MD, said at a symposium on vascular surgery sponsored by Northwestern University.
Moreover, placement of an inferior vena cava filter in patients with calf vein thrombosis when anticoagulation is contraindicated accomplishes nothing beneficial and had a 10% complication rate in a large retrospective single-center study, added Dr. Rodriguez of Northwestern University, Chicago.
Deep vein thrombosis (DVT) remains a significant source of morbidity and mortality despite worldwide awareness of the problem.
“Specifically, calf vein thrombosis [CVT] is very common, and we know that in some series up to 30% of patients end up propagating proximally if they’re not treated, and a good number of them develop chronic venous insufficiency, with long-term consequences,” he noted.
“Unfortunately there is no consensus regarding treatment. The guidelines are very vague. For example, there is no mention [in current American College of Chest Physicians guidelines] of how to manage muscular vein thrombosis and much ambiguity on how to treat calf vein thrombosis,” he continued.
Dr. Rodriguez cited as an indication of the lack of consensus on management of CVT a single-institution survey by other investigators of the practices of physicians in various specialties. Forty-nine percent of respondents indicated they anticoagulate patients with CVT; 51% don’t. Of those who did, 62% prescribed low-molecular-weight heparin and 11% intravenous heparin. Fifty-eight percent of physicians who anticoagulated did so for 3 months, 30% for 6. And 46% of physicians used an inferior vena cava (IVC) filter when anticoagulation was contraindicated (Vascular. 2014 Apr;22[2]:93-7).
That rate of IVC placement “seemed really high” given the paucity of supporting evidence for safety and efficacy of filter placement in the setting of CVT, so Dr. Rodriguez and coinvestigators decided to conduct a retrospective review of practices at Northwestern Memorial Hospital. He explained the study hypothesis: “Our thinking was that these kinds of thrombi are associated with low risk of propagation and pulmonary embolism, and they can and should be managed conservatively.”
Of 647 patients with isolated thrombosis of the anterior and posterior tibial, soleal, peroneal, or gastrocnemius veins, 44% received an IVC filter, and the rest got medical treatment alone. Of the 362 patients managed medically, 49% received therapeutic anticoagulation, 12% got low-dose prophylactic anticoagulation, and 39% underwent surveillance without anticoagulation.
The primary outcome was the incidence of venous thromboembolic complications – that is, propagation of DVT or pulmonary embolism. The incidence was 35% in the surveillance-only group, 30% with prophylactic anticoagulation, and 10% in patients who got therapeutic anticoagulation.
Of note, the rate of the most feared complication, pulmonary embolism, was low and similar in the filter recipients and medically managed group: 2.5% in the IVC group, 3.3% with medical management.
“Distal vein thromboses have low rates of pulmonary embolism, regardless of whether or not they are so-called protected with a filter. On the other hand, a filter was associated with a 10% rate of complications. I have to make clear that these were radiographic abnormalities – tilting, migration, caval perforation – that didn’t have clinical consequences, but we were very aggressive in removing the IVC filters, and I’m guessing if they’d been left inside they would create problems in the long term,” Dr. Rodriguez said.
An important point about this study is that these were all sick patients, and most were hospitalized. The filter recipients and medical groups differed in key ways. For example, 49% of the filter patients had a malignancy, and 56% had a baseline history of venous thromboembolic events, compared with 26% and 16%, respectively, of the medical group. For that reason, the investigators performed propensity score matching and came up with 157 closely matched patient pairs. The outcomes remained unchanged.
Of course, this was a retrospective study, with its inherent limitations, but Dr. Rodriguez characterized the published randomized trials on management of CVT as “small and limited.” The most frequently quoted study is the double-blind multicenter CACTUS trial, which randomized 252 outpatients with symptomatic CVT to 6 weeks of low-molecular-weight heparin or placebo and found no difference in the rates of proximal extension of venous thromboembolic events (Lancet Haematol. 2016 Dec;3[12]:e556-62). But these were all low-risk patients. Prior DVT or malignancy were exclusion criteria, so this was a very different population than treated at Northwestern.
Based upon the results of the retrospective study at Northwestern, which have been published (J Vasc Surg Venous Lymphat Disord. 2017 Jan;5[1]:25-32), the vascular surgery service has developed a management algorithm for DVT management based upon the lesion site. If a patient is unable to undergo anticoagulation, venous duplex ultrasound is repeated at 1 week. If the imaging shows propagation into the popliteal vein and anticoagulation remains contraindicated, only then is placement of an IVC filter warranted.
Dr. Rodriguez reported serving as a paid speaker for Abbott, Endologix, and W.L. Gore.
CHICAGO – The use of therapeutic-dose anticoagulation in hospitalized patients with calf vein thrombosis significantly reduces the risk of venous thromboembolic complications, compared with lower-dose prophylactic anticoagulation or surveillance alone, Heron E. Rodriguez, MD, said at a symposium on vascular surgery sponsored by Northwestern University.
Moreover, placement of an inferior vena cava filter in patients with calf vein thrombosis when anticoagulation is contraindicated accomplishes nothing beneficial and had a 10% complication rate in a large retrospective single-center study, added Dr. Rodriguez of Northwestern University, Chicago.
Deep vein thrombosis (DVT) remains a significant source of morbidity and mortality despite worldwide awareness of the problem.
“Specifically, calf vein thrombosis [CVT] is very common, and we know that in some series up to 30% of patients end up propagating proximally if they’re not treated, and a good number of them develop chronic venous insufficiency, with long-term consequences,” he noted.
“Unfortunately there is no consensus regarding treatment. The guidelines are very vague. For example, there is no mention [in current American College of Chest Physicians guidelines] of how to manage muscular vein thrombosis and much ambiguity on how to treat calf vein thrombosis,” he continued.
Dr. Rodriguez cited as an indication of the lack of consensus on management of CVT a single-institution survey by other investigators of the practices of physicians in various specialties. Forty-nine percent of respondents indicated they anticoagulate patients with CVT; 51% don’t. Of those who did, 62% prescribed low-molecular-weight heparin and 11% intravenous heparin. Fifty-eight percent of physicians who anticoagulated did so for 3 months, 30% for 6. And 46% of physicians used an inferior vena cava (IVC) filter when anticoagulation was contraindicated (Vascular. 2014 Apr;22[2]:93-7).
That rate of IVC placement “seemed really high” given the paucity of supporting evidence for safety and efficacy of filter placement in the setting of CVT, so Dr. Rodriguez and coinvestigators decided to conduct a retrospective review of practices at Northwestern Memorial Hospital. He explained the study hypothesis: “Our thinking was that these kinds of thrombi are associated with low risk of propagation and pulmonary embolism, and they can and should be managed conservatively.”
Of 647 patients with isolated thrombosis of the anterior and posterior tibial, soleal, peroneal, or gastrocnemius veins, 44% received an IVC filter, and the rest got medical treatment alone. Of the 362 patients managed medically, 49% received therapeutic anticoagulation, 12% got low-dose prophylactic anticoagulation, and 39% underwent surveillance without anticoagulation.
The primary outcome was the incidence of venous thromboembolic complications – that is, propagation of DVT or pulmonary embolism. The incidence was 35% in the surveillance-only group, 30% with prophylactic anticoagulation, and 10% in patients who got therapeutic anticoagulation.
Of note, the rate of the most feared complication, pulmonary embolism, was low and similar in the filter recipients and medically managed group: 2.5% in the IVC group, 3.3% with medical management.
“Distal vein thromboses have low rates of pulmonary embolism, regardless of whether or not they are so-called protected with a filter. On the other hand, a filter was associated with a 10% rate of complications. I have to make clear that these were radiographic abnormalities – tilting, migration, caval perforation – that didn’t have clinical consequences, but we were very aggressive in removing the IVC filters, and I’m guessing if they’d been left inside they would create problems in the long term,” Dr. Rodriguez said.
An important point about this study is that these were all sick patients, and most were hospitalized. The filter recipients and medical groups differed in key ways. For example, 49% of the filter patients had a malignancy, and 56% had a baseline history of venous thromboembolic events, compared with 26% and 16%, respectively, of the medical group. For that reason, the investigators performed propensity score matching and came up with 157 closely matched patient pairs. The outcomes remained unchanged.
Of course, this was a retrospective study, with its inherent limitations, but Dr. Rodriguez characterized the published randomized trials on management of CVT as “small and limited.” The most frequently quoted study is the double-blind multicenter CACTUS trial, which randomized 252 outpatients with symptomatic CVT to 6 weeks of low-molecular-weight heparin or placebo and found no difference in the rates of proximal extension of venous thromboembolic events (Lancet Haematol. 2016 Dec;3[12]:e556-62). But these were all low-risk patients. Prior DVT or malignancy were exclusion criteria, so this was a very different population than treated at Northwestern.
Based upon the results of the retrospective study at Northwestern, which have been published (J Vasc Surg Venous Lymphat Disord. 2017 Jan;5[1]:25-32), the vascular surgery service has developed a management algorithm for DVT management based upon the lesion site. If a patient is unable to undergo anticoagulation, venous duplex ultrasound is repeated at 1 week. If the imaging shows propagation into the popliteal vein and anticoagulation remains contraindicated, only then is placement of an IVC filter warranted.
Dr. Rodriguez reported serving as a paid speaker for Abbott, Endologix, and W.L. Gore.
EXPERT ANALYSIS FROM NORTHWESTERN VASCULAR SYMPOSIUM
Thrombosis risk is elevated with myeloproliferative neoplasms
Patients with myeloproliferative neoplasms (MPNs) have a higher rate of arterial and venous thrombosis than does the general population, with the greatest risk occurring around the time of diagnosis, according to results of a retrospective study.
Hazard ratios at 3 months after diagnosis were 3.0 (95% CI, 2.7-3.4) for arterial thrombosis and 9.7 (95% CI, 7.8-12.0) for venous thrombosis, compared with matched controls, Malin Hultcrantz, MD, PhD, of the Karolinska University Hospital, Stockholm, and her coauthors reported in the Annals of Internal Medicine.
Although previous studies have suggested patients with MPNs are at increased risk for thrombotic events, this large, population-based analysis is believed to be the first study to provide estimates of excess risk compared with matched control participants.
“These results are encouraging, and we believe that further refinement of risk scoring systems (such as by including time since MPN diagnosis and biomarkers); rethinking of recommendations for younger patients with MPNs; and emerging, more effective treatments will further improve outcomes for patients with MPNs,” the researchers wrote.
The retrospective, population-based cohort study included 9,429 Swedish patients diagnosed with MPNs between 1987 and 2009 and 35,820 matched control participants. Patient follow-up through 2010 was included in the analysis.
Thrombosis risk was highest near the time of diagnosis but decreased during the following year “likely because of effective thromboprophylactic and cytoreductive treatment of the MPN;”still, the risk remained elevated, the researchers wrote.
“This novel finding underlines the importance of initiating phlebotomy as well as thromboprophylactic and cytoreductive treatment, when indicated, as soon as the MPN is diagnosed,” they added.
Arterial thrombosis hazard ratios for MPN patients, compared with control participants, were 3.0 at 3 months after diagnosis, 2.0 at 1 year, and 1.5 at 5 years. Similarly, venous thrombosis hazard ratios were 9.7 at 3 months, 4.7 at 1 year, and 3.2 at 5 years.
Thrombosis risk was elevated in all age groups and all MPN subtypes, including primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Of note, the study confirmed prior thrombosis and older age (60 years or older) as risk factors. Among patients with both of those risk factors, risk of thrombosis was increased 7-fold, according to the researchers.
Hazard ratios for thrombosis decreased during more recent time periods, suggesting a “positive effect” of improved treatment strategies, including increased use of aspirin as primary prophylaxis, better cardiovascular risk management, and better adherence to recommendations for cytoreductive treatment and phlebotomy, the researchers noted. Additionally, treatment with interferon and Janus kinase 2 inhibitors, such as ruxolitinib, “may be effective in further reducing risk for thrombosis,” the researchers wrote.
The study was funded by the Cancer Research Foundations of Radiumhemmet, the Swedish Research Council, and Memorial Sloan Kettering Cancer Center, among other sources. The researchers reported having no financial disclosures relevant to the study.
SOURCE: Hultcrantz M et al. Ann Intern Med. 2018. doi: 10.7326/M17-0028.
The most notable contribution of the large cohort study by Hultcrantz and her colleagues is quantification of the magnitude of thrombotic risk that MPNs confer, according to Alison R. Moliterno, MD, and Elizabeth V. Ratchford, MD.
“Hultcrantz and colleagues have opened our eyes to the magnitude of thrombotic risk MPNs bring to affected patients,” Dr. Moliterno and Dr. Ratchford wrote in an editorial in Annals of Internal Medicine. “Their study shows us that the traditional approach to assessing thrombotic risk in patients with MPNs [who are age 60 years and older, have prior thrombotic event, and have traditional cardiovascular risk factors] lacks precision and personalization.”
Both arterial and venous thrombotic events were increased throughout patients’ lifetimes, though the highest risk was around the time of MPN diagnosis. According to study results, 10% of patients had a thrombotic event in the 30 days before or after diagnosis.
“Patients and clinicians should be keenly aware of this particularly risky period, during which risk for thrombosis is similar to that in the month after a transient ischemic attack,” Dr. Moliterno and Dr. Ratchford wrote.
Unfortunately, the study did not include data on genomics, they noted. The acquired JAK2 V617F mutation, which drives MPN phenotypes, is associated with elevated inflammatory cytokines, and inflammation is a recognized risk factor for thrombosis, according to the editorial authors.
Alison R. Moliterno, MD, and Elizabeth V. Ratchford, MD, are with Johns Hopkins University, Baltimore. These comments are adapted from an accompanying editorial (Ann Intern Med. 2018. doi: 10.7326/M17-3153). The authors reported having no relevant conflicts related to the study.
The most notable contribution of the large cohort study by Hultcrantz and her colleagues is quantification of the magnitude of thrombotic risk that MPNs confer, according to Alison R. Moliterno, MD, and Elizabeth V. Ratchford, MD.
“Hultcrantz and colleagues have opened our eyes to the magnitude of thrombotic risk MPNs bring to affected patients,” Dr. Moliterno and Dr. Ratchford wrote in an editorial in Annals of Internal Medicine. “Their study shows us that the traditional approach to assessing thrombotic risk in patients with MPNs [who are age 60 years and older, have prior thrombotic event, and have traditional cardiovascular risk factors] lacks precision and personalization.”
Both arterial and venous thrombotic events were increased throughout patients’ lifetimes, though the highest risk was around the time of MPN diagnosis. According to study results, 10% of patients had a thrombotic event in the 30 days before or after diagnosis.
“Patients and clinicians should be keenly aware of this particularly risky period, during which risk for thrombosis is similar to that in the month after a transient ischemic attack,” Dr. Moliterno and Dr. Ratchford wrote.
Unfortunately, the study did not include data on genomics, they noted. The acquired JAK2 V617F mutation, which drives MPN phenotypes, is associated with elevated inflammatory cytokines, and inflammation is a recognized risk factor for thrombosis, according to the editorial authors.
Alison R. Moliterno, MD, and Elizabeth V. Ratchford, MD, are with Johns Hopkins University, Baltimore. These comments are adapted from an accompanying editorial (Ann Intern Med. 2018. doi: 10.7326/M17-3153). The authors reported having no relevant conflicts related to the study.
The most notable contribution of the large cohort study by Hultcrantz and her colleagues is quantification of the magnitude of thrombotic risk that MPNs confer, according to Alison R. Moliterno, MD, and Elizabeth V. Ratchford, MD.
“Hultcrantz and colleagues have opened our eyes to the magnitude of thrombotic risk MPNs bring to affected patients,” Dr. Moliterno and Dr. Ratchford wrote in an editorial in Annals of Internal Medicine. “Their study shows us that the traditional approach to assessing thrombotic risk in patients with MPNs [who are age 60 years and older, have prior thrombotic event, and have traditional cardiovascular risk factors] lacks precision and personalization.”
Both arterial and venous thrombotic events were increased throughout patients’ lifetimes, though the highest risk was around the time of MPN diagnosis. According to study results, 10% of patients had a thrombotic event in the 30 days before or after diagnosis.
“Patients and clinicians should be keenly aware of this particularly risky period, during which risk for thrombosis is similar to that in the month after a transient ischemic attack,” Dr. Moliterno and Dr. Ratchford wrote.
Unfortunately, the study did not include data on genomics, they noted. The acquired JAK2 V617F mutation, which drives MPN phenotypes, is associated with elevated inflammatory cytokines, and inflammation is a recognized risk factor for thrombosis, according to the editorial authors.
Alison R. Moliterno, MD, and Elizabeth V. Ratchford, MD, are with Johns Hopkins University, Baltimore. These comments are adapted from an accompanying editorial (Ann Intern Med. 2018. doi: 10.7326/M17-3153). The authors reported having no relevant conflicts related to the study.
Patients with myeloproliferative neoplasms (MPNs) have a higher rate of arterial and venous thrombosis than does the general population, with the greatest risk occurring around the time of diagnosis, according to results of a retrospective study.
Hazard ratios at 3 months after diagnosis were 3.0 (95% CI, 2.7-3.4) for arterial thrombosis and 9.7 (95% CI, 7.8-12.0) for venous thrombosis, compared with matched controls, Malin Hultcrantz, MD, PhD, of the Karolinska University Hospital, Stockholm, and her coauthors reported in the Annals of Internal Medicine.
Although previous studies have suggested patients with MPNs are at increased risk for thrombotic events, this large, population-based analysis is believed to be the first study to provide estimates of excess risk compared with matched control participants.
“These results are encouraging, and we believe that further refinement of risk scoring systems (such as by including time since MPN diagnosis and biomarkers); rethinking of recommendations for younger patients with MPNs; and emerging, more effective treatments will further improve outcomes for patients with MPNs,” the researchers wrote.
The retrospective, population-based cohort study included 9,429 Swedish patients diagnosed with MPNs between 1987 and 2009 and 35,820 matched control participants. Patient follow-up through 2010 was included in the analysis.
Thrombosis risk was highest near the time of diagnosis but decreased during the following year “likely because of effective thromboprophylactic and cytoreductive treatment of the MPN;”still, the risk remained elevated, the researchers wrote.
“This novel finding underlines the importance of initiating phlebotomy as well as thromboprophylactic and cytoreductive treatment, when indicated, as soon as the MPN is diagnosed,” they added.
Arterial thrombosis hazard ratios for MPN patients, compared with control participants, were 3.0 at 3 months after diagnosis, 2.0 at 1 year, and 1.5 at 5 years. Similarly, venous thrombosis hazard ratios were 9.7 at 3 months, 4.7 at 1 year, and 3.2 at 5 years.
Thrombosis risk was elevated in all age groups and all MPN subtypes, including primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Of note, the study confirmed prior thrombosis and older age (60 years or older) as risk factors. Among patients with both of those risk factors, risk of thrombosis was increased 7-fold, according to the researchers.
Hazard ratios for thrombosis decreased during more recent time periods, suggesting a “positive effect” of improved treatment strategies, including increased use of aspirin as primary prophylaxis, better cardiovascular risk management, and better adherence to recommendations for cytoreductive treatment and phlebotomy, the researchers noted. Additionally, treatment with interferon and Janus kinase 2 inhibitors, such as ruxolitinib, “may be effective in further reducing risk for thrombosis,” the researchers wrote.
The study was funded by the Cancer Research Foundations of Radiumhemmet, the Swedish Research Council, and Memorial Sloan Kettering Cancer Center, among other sources. The researchers reported having no financial disclosures relevant to the study.
SOURCE: Hultcrantz M et al. Ann Intern Med. 2018. doi: 10.7326/M17-0028.
Patients with myeloproliferative neoplasms (MPNs) have a higher rate of arterial and venous thrombosis than does the general population, with the greatest risk occurring around the time of diagnosis, according to results of a retrospective study.
Hazard ratios at 3 months after diagnosis were 3.0 (95% CI, 2.7-3.4) for arterial thrombosis and 9.7 (95% CI, 7.8-12.0) for venous thrombosis, compared with matched controls, Malin Hultcrantz, MD, PhD, of the Karolinska University Hospital, Stockholm, and her coauthors reported in the Annals of Internal Medicine.
Although previous studies have suggested patients with MPNs are at increased risk for thrombotic events, this large, population-based analysis is believed to be the first study to provide estimates of excess risk compared with matched control participants.
“These results are encouraging, and we believe that further refinement of risk scoring systems (such as by including time since MPN diagnosis and biomarkers); rethinking of recommendations for younger patients with MPNs; and emerging, more effective treatments will further improve outcomes for patients with MPNs,” the researchers wrote.
The retrospective, population-based cohort study included 9,429 Swedish patients diagnosed with MPNs between 1987 and 2009 and 35,820 matched control participants. Patient follow-up through 2010 was included in the analysis.
Thrombosis risk was highest near the time of diagnosis but decreased during the following year “likely because of effective thromboprophylactic and cytoreductive treatment of the MPN;”still, the risk remained elevated, the researchers wrote.
“This novel finding underlines the importance of initiating phlebotomy as well as thromboprophylactic and cytoreductive treatment, when indicated, as soon as the MPN is diagnosed,” they added.
Arterial thrombosis hazard ratios for MPN patients, compared with control participants, were 3.0 at 3 months after diagnosis, 2.0 at 1 year, and 1.5 at 5 years. Similarly, venous thrombosis hazard ratios were 9.7 at 3 months, 4.7 at 1 year, and 3.2 at 5 years.
Thrombosis risk was elevated in all age groups and all MPN subtypes, including primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Of note, the study confirmed prior thrombosis and older age (60 years or older) as risk factors. Among patients with both of those risk factors, risk of thrombosis was increased 7-fold, according to the researchers.
Hazard ratios for thrombosis decreased during more recent time periods, suggesting a “positive effect” of improved treatment strategies, including increased use of aspirin as primary prophylaxis, better cardiovascular risk management, and better adherence to recommendations for cytoreductive treatment and phlebotomy, the researchers noted. Additionally, treatment with interferon and Janus kinase 2 inhibitors, such as ruxolitinib, “may be effective in further reducing risk for thrombosis,” the researchers wrote.
The study was funded by the Cancer Research Foundations of Radiumhemmet, the Swedish Research Council, and Memorial Sloan Kettering Cancer Center, among other sources. The researchers reported having no financial disclosures relevant to the study.
SOURCE: Hultcrantz M et al. Ann Intern Med. 2018. doi: 10.7326/M17-0028.
FROM ANNALS OF INTERNAL MEDICINE
Key clinical point:
Major finding: Hazard ratios (HRs) at 3 months were 3.0 (95% confidence interval, 2.7-3.4) for arterial thrombosis and 9.7 (95% CI, 7.8-12.0) for venous thrombosis, compared with matched controls.
Study details: A Swedish retrospective, population-based study including 9,429 patients with MPNs and 35,820 matched control participants.
Disclosures: The study was funded by the Cancer Research Foundations of Radiumhemmet, the Swedish Research Council, and Memorial Sloan Kettering Cancer Center, among other sources. The researchers reported having no relevant financial disclosures.
Source: Hultcrantz M et al. Ann Intern Med. 2018. doi: 10.7326/M17-0028.
Edoxaban noninferior to dalteparin for cancer-associated VTE
ATLANTA – Twelve months of daily treatment with the novel oral factor Xa inhibitor edoxaban was noninferior to standard subcutaneous therapy with dalteparin for treatment of venous thromboembolism in patients with cancer, according to late-breaking results from a randomized, open-label, blinded-outcomes trial.
Throughout follow-up, trial arms had nearly identical rates of survival free from recurrent VTE or major bleeding, Gary E. Raskob, PhD, reported during a late-breaking oral presentation at the annual meeting of the American Society of Hematology. “Edoxaban was associated with a lower rate of recurrent VTE, which was offset by a similar increase in risk of major bleeding,” he said. “Therefore, oral edoxaban was noninferior to subcutaneous dalteparin for the [combined] primary outcome.”
Venous thromboembolism affects about one in five patients with active cancer and is difficult to treat because patients face increased risks of recurrence and bleeding. The struggle to balance these risks fuels morbidity and mortality and can hamper cancer treatment, said Dr. Raskob of the University of Oklahoma, Oklahoma City.
Pharmacy and medical oncology societies recommend long-term low-molecular-weight heparin for cancer patients with VTE, but the daily burden of subcutaneous injections leads many to stop after about 2-4 months of treatment, Dr. Raskob said. “Direct oral anticoagulants may be an attractive alternative.”
For the trial, 1,446 adults with cancer and lower limb VTE from 114 clinics in North America, Europe, Australia, and New Zealand received either edoxaban (60 mg daily) or dalteparin (200 IU/kg for 30 days, followed by 150 IU/kg) for up to 12 months. Nearly all patients had active cancer. Tumor types reflected what’s most common in practice, such as malignancies of the lung, colon, and breast. About 50 patients had primary or metastatic brain cancers. Approximately two-thirds had pulmonary embolism with or without deep-vein thrombosis, while the rest had isolated deep-vein thrombosis.
After 12 months of follow-up, 12.8% of edoxaban patients had at least one recurrence of VTE or a major bleed, compared with 13.5% of dalteparin patients (hazard ratio, 0.97; 95% confidence interval, 0.70-1.36; P = .006 for noninferiority). Edoxaban also was noninferior to dalteparin after the first 6 months of treatment and in the per-protocol analysis (HRs, 1.0; P = .02 for noninferiority in each analysis). Thus, differences in efficacy did not only reflect better compliance to oral therapy, Dr. Raskob said.
He also reported on individual outcomes. In all, 10.3% of dalteparin recipients had a VTE recurrence, as did 6.5% of edoxaban recipients, for a risk difference of 3.8% (95% CI, 7.1%-0.4%). More than half of recurrences in each group were symptomatic, and none were fatal. Bleeding caused no deaths in either study arm, and each therapy conferred an identical chance of a grade 3-4 major bleed (2.3%).
Edoxaban was associated, however, with a greater frequency of major bleeds (33 events; 6.3%) than was dalteparin (17 events; 3.2%; risk difference, 3.1%; 95% CI, 0.5%-5.7%). In particular, patients who received edoxaban had a slightly higher rate of upper gastrointestinal bleeds. Most had gastric cancer.
Future studies should evaluate whether these patients should receive a lower dose of edoxaban, said Dr. Raskob. “We don’t yet fully know the minimum effective dose [of edoxaban] in cancer patients.”
He also addressed the idea that heparin has antineoplastic activity, calling it “one we should probably abandon. The concept originates from older trials in which researchers probably did not recognize that heparin was preventing fatal pulmonary embolism, he said.
The investigators soon will begin deeper analyses that should inform patient selection, he said. For now, he recommends discussing these findings with patients to help them make an informed choice between oral anticoagulation, with its ease of use but slightly higher rate of major bleeds, and subcutaneous heparin, with its lower bleeding rate and treatment burden.
Daiichi Sankyo provided funding. Dr. Raskob disclosed consulting relationships and honoraria from Daiichi Sankyo, Eli Lilly, Janssen, and several other pharmaceutical companies.
SOURCE: Raskob G et al. ASH Abstract LBA-6.
ATLANTA – Twelve months of daily treatment with the novel oral factor Xa inhibitor edoxaban was noninferior to standard subcutaneous therapy with dalteparin for treatment of venous thromboembolism in patients with cancer, according to late-breaking results from a randomized, open-label, blinded-outcomes trial.
Throughout follow-up, trial arms had nearly identical rates of survival free from recurrent VTE or major bleeding, Gary E. Raskob, PhD, reported during a late-breaking oral presentation at the annual meeting of the American Society of Hematology. “Edoxaban was associated with a lower rate of recurrent VTE, which was offset by a similar increase in risk of major bleeding,” he said. “Therefore, oral edoxaban was noninferior to subcutaneous dalteparin for the [combined] primary outcome.”
Venous thromboembolism affects about one in five patients with active cancer and is difficult to treat because patients face increased risks of recurrence and bleeding. The struggle to balance these risks fuels morbidity and mortality and can hamper cancer treatment, said Dr. Raskob of the University of Oklahoma, Oklahoma City.
Pharmacy and medical oncology societies recommend long-term low-molecular-weight heparin for cancer patients with VTE, but the daily burden of subcutaneous injections leads many to stop after about 2-4 months of treatment, Dr. Raskob said. “Direct oral anticoagulants may be an attractive alternative.”
For the trial, 1,446 adults with cancer and lower limb VTE from 114 clinics in North America, Europe, Australia, and New Zealand received either edoxaban (60 mg daily) or dalteparin (200 IU/kg for 30 days, followed by 150 IU/kg) for up to 12 months. Nearly all patients had active cancer. Tumor types reflected what’s most common in practice, such as malignancies of the lung, colon, and breast. About 50 patients had primary or metastatic brain cancers. Approximately two-thirds had pulmonary embolism with or without deep-vein thrombosis, while the rest had isolated deep-vein thrombosis.
After 12 months of follow-up, 12.8% of edoxaban patients had at least one recurrence of VTE or a major bleed, compared with 13.5% of dalteparin patients (hazard ratio, 0.97; 95% confidence interval, 0.70-1.36; P = .006 for noninferiority). Edoxaban also was noninferior to dalteparin after the first 6 months of treatment and in the per-protocol analysis (HRs, 1.0; P = .02 for noninferiority in each analysis). Thus, differences in efficacy did not only reflect better compliance to oral therapy, Dr. Raskob said.
He also reported on individual outcomes. In all, 10.3% of dalteparin recipients had a VTE recurrence, as did 6.5% of edoxaban recipients, for a risk difference of 3.8% (95% CI, 7.1%-0.4%). More than half of recurrences in each group were symptomatic, and none were fatal. Bleeding caused no deaths in either study arm, and each therapy conferred an identical chance of a grade 3-4 major bleed (2.3%).
Edoxaban was associated, however, with a greater frequency of major bleeds (33 events; 6.3%) than was dalteparin (17 events; 3.2%; risk difference, 3.1%; 95% CI, 0.5%-5.7%). In particular, patients who received edoxaban had a slightly higher rate of upper gastrointestinal bleeds. Most had gastric cancer.
Future studies should evaluate whether these patients should receive a lower dose of edoxaban, said Dr. Raskob. “We don’t yet fully know the minimum effective dose [of edoxaban] in cancer patients.”
He also addressed the idea that heparin has antineoplastic activity, calling it “one we should probably abandon. The concept originates from older trials in which researchers probably did not recognize that heparin was preventing fatal pulmonary embolism, he said.
The investigators soon will begin deeper analyses that should inform patient selection, he said. For now, he recommends discussing these findings with patients to help them make an informed choice between oral anticoagulation, with its ease of use but slightly higher rate of major bleeds, and subcutaneous heparin, with its lower bleeding rate and treatment burden.
Daiichi Sankyo provided funding. Dr. Raskob disclosed consulting relationships and honoraria from Daiichi Sankyo, Eli Lilly, Janssen, and several other pharmaceutical companies.
SOURCE: Raskob G et al. ASH Abstract LBA-6.
ATLANTA – Twelve months of daily treatment with the novel oral factor Xa inhibitor edoxaban was noninferior to standard subcutaneous therapy with dalteparin for treatment of venous thromboembolism in patients with cancer, according to late-breaking results from a randomized, open-label, blinded-outcomes trial.
Throughout follow-up, trial arms had nearly identical rates of survival free from recurrent VTE or major bleeding, Gary E. Raskob, PhD, reported during a late-breaking oral presentation at the annual meeting of the American Society of Hematology. “Edoxaban was associated with a lower rate of recurrent VTE, which was offset by a similar increase in risk of major bleeding,” he said. “Therefore, oral edoxaban was noninferior to subcutaneous dalteparin for the [combined] primary outcome.”
Venous thromboembolism affects about one in five patients with active cancer and is difficult to treat because patients face increased risks of recurrence and bleeding. The struggle to balance these risks fuels morbidity and mortality and can hamper cancer treatment, said Dr. Raskob of the University of Oklahoma, Oklahoma City.
Pharmacy and medical oncology societies recommend long-term low-molecular-weight heparin for cancer patients with VTE, but the daily burden of subcutaneous injections leads many to stop after about 2-4 months of treatment, Dr. Raskob said. “Direct oral anticoagulants may be an attractive alternative.”
For the trial, 1,446 adults with cancer and lower limb VTE from 114 clinics in North America, Europe, Australia, and New Zealand received either edoxaban (60 mg daily) or dalteparin (200 IU/kg for 30 days, followed by 150 IU/kg) for up to 12 months. Nearly all patients had active cancer. Tumor types reflected what’s most common in practice, such as malignancies of the lung, colon, and breast. About 50 patients had primary or metastatic brain cancers. Approximately two-thirds had pulmonary embolism with or without deep-vein thrombosis, while the rest had isolated deep-vein thrombosis.
After 12 months of follow-up, 12.8% of edoxaban patients had at least one recurrence of VTE or a major bleed, compared with 13.5% of dalteparin patients (hazard ratio, 0.97; 95% confidence interval, 0.70-1.36; P = .006 for noninferiority). Edoxaban also was noninferior to dalteparin after the first 6 months of treatment and in the per-protocol analysis (HRs, 1.0; P = .02 for noninferiority in each analysis). Thus, differences in efficacy did not only reflect better compliance to oral therapy, Dr. Raskob said.
He also reported on individual outcomes. In all, 10.3% of dalteparin recipients had a VTE recurrence, as did 6.5% of edoxaban recipients, for a risk difference of 3.8% (95% CI, 7.1%-0.4%). More than half of recurrences in each group were symptomatic, and none were fatal. Bleeding caused no deaths in either study arm, and each therapy conferred an identical chance of a grade 3-4 major bleed (2.3%).
Edoxaban was associated, however, with a greater frequency of major bleeds (33 events; 6.3%) than was dalteparin (17 events; 3.2%; risk difference, 3.1%; 95% CI, 0.5%-5.7%). In particular, patients who received edoxaban had a slightly higher rate of upper gastrointestinal bleeds. Most had gastric cancer.
Future studies should evaluate whether these patients should receive a lower dose of edoxaban, said Dr. Raskob. “We don’t yet fully know the minimum effective dose [of edoxaban] in cancer patients.”
He also addressed the idea that heparin has antineoplastic activity, calling it “one we should probably abandon. The concept originates from older trials in which researchers probably did not recognize that heparin was preventing fatal pulmonary embolism, he said.
The investigators soon will begin deeper analyses that should inform patient selection, he said. For now, he recommends discussing these findings with patients to help them make an informed choice between oral anticoagulation, with its ease of use but slightly higher rate of major bleeds, and subcutaneous heparin, with its lower bleeding rate and treatment burden.
Daiichi Sankyo provided funding. Dr. Raskob disclosed consulting relationships and honoraria from Daiichi Sankyo, Eli Lilly, Janssen, and several other pharmaceutical companies.
SOURCE: Raskob G et al. ASH Abstract LBA-6.
REPORTING FROM ASH 2017
Key clinical point: Oral anticoagulation with edoxaban is easier, but has a slightly higher rate of major bleeds than does subcutaneous heparin.
Major finding: .
Data source: A randomized, multicenter, open-label trial of 1,046 adults with cancer and VTE.
Disclosures: Daiichi Sankyo provided funding. Dr. Raskob disclosed consulting relationships and honoraria from Daiichi Sankyo, Eli Lilly, Janssen, and several other pharmaceutical companies.
Source: Raskob G et al. ASH Abstract LBA-6.
Acute kidney injury linked with doubled inpatient VTEs
TORONTO – Hospitalized patients with acute kidney injury had more than double the inpatient rate of venous thromboembolism as had patients without acute kidney injury in a prospective, observational study of more than 6,000 hospitalized U.S. soldiers.
He offered four possible mechanisms to explain a link between AKI and VTE:
- Patients with AKI are in a hypercoagulable state.
- AKI alters the pharmacodynamics or pharmacokinetics of VTE prophylactic treatments.
- AKI is a marker of an illness that causes VTE.
- VTE leads to an increased rate of AKI rather than the other way around.
Dr. McMahon’s analysis also revealed that two other clinical conditions that are generally believed to raise VTE risk – obesity and impaired overall renal function identified with stagnant measures – did not correspond with a significantly elevated VTE rate in this study.
The data came from 6,552 adults hospitalized for at least 2 days at Walter Reed between September 2009 and March 2011. The study excluded patients with VTE at the time of admission and also those who had been treated with an anticoagulant at the time of admission. The patients averaged 55 years of age and were hospitalized for a median of 4 days. About 22% of patients received VTE prophylaxis with unfractionated heparin, about 41% received prophylaxis with low-molecular-weight heparin, and about 39% received no VTE prophylaxis (percentages total 102% because of rounding).
About 16% of the patients had been diagnosed with AKI at the time of admission, and an additional 8% developed AKI while hospitalized, defined as an increase in serum creatinine during hospitalization of at least 50% above baseline levels or an increase of more than 0.3 mg/dL above the level at time of admission. During hospitalization, 160 patients (2%) developed a new onset VTE.
In an analysis that adjusted for baseline differences in type of surgery, body mass index, sex, age, and prior hospitalizations during the prior 90 days, the results showed that patients with preexisting or new onset AKI had a 2.2-fold higher rate of VTE, compared with patients without AKI, and this difference was statistically significant, Dr. McMahon reported.
The analysis also showed a significant 62% relatively higher rate of VTE among soldiers hospitalized for a deployment-related event, as well as a significant 63% relatively lower VTE rate among patients not receiving medical prophylaxis, compared with patients receiving an anticoagulant. Dr. McMahon suggested that this lower rate of VTEs among patients not on prophylaxis reflected success in identifying which patients had an increased risk for VTE and hence received prophylaxis.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
TORONTO – Hospitalized patients with acute kidney injury had more than double the inpatient rate of venous thromboembolism as had patients without acute kidney injury in a prospective, observational study of more than 6,000 hospitalized U.S. soldiers.
He offered four possible mechanisms to explain a link between AKI and VTE:
- Patients with AKI are in a hypercoagulable state.
- AKI alters the pharmacodynamics or pharmacokinetics of VTE prophylactic treatments.
- AKI is a marker of an illness that causes VTE.
- VTE leads to an increased rate of AKI rather than the other way around.
Dr. McMahon’s analysis also revealed that two other clinical conditions that are generally believed to raise VTE risk – obesity and impaired overall renal function identified with stagnant measures – did not correspond with a significantly elevated VTE rate in this study.
The data came from 6,552 adults hospitalized for at least 2 days at Walter Reed between September 2009 and March 2011. The study excluded patients with VTE at the time of admission and also those who had been treated with an anticoagulant at the time of admission. The patients averaged 55 years of age and were hospitalized for a median of 4 days. About 22% of patients received VTE prophylaxis with unfractionated heparin, about 41% received prophylaxis with low-molecular-weight heparin, and about 39% received no VTE prophylaxis (percentages total 102% because of rounding).
About 16% of the patients had been diagnosed with AKI at the time of admission, and an additional 8% developed AKI while hospitalized, defined as an increase in serum creatinine during hospitalization of at least 50% above baseline levels or an increase of more than 0.3 mg/dL above the level at time of admission. During hospitalization, 160 patients (2%) developed a new onset VTE.
In an analysis that adjusted for baseline differences in type of surgery, body mass index, sex, age, and prior hospitalizations during the prior 90 days, the results showed that patients with preexisting or new onset AKI had a 2.2-fold higher rate of VTE, compared with patients without AKI, and this difference was statistically significant, Dr. McMahon reported.
The analysis also showed a significant 62% relatively higher rate of VTE among soldiers hospitalized for a deployment-related event, as well as a significant 63% relatively lower VTE rate among patients not receiving medical prophylaxis, compared with patients receiving an anticoagulant. Dr. McMahon suggested that this lower rate of VTEs among patients not on prophylaxis reflected success in identifying which patients had an increased risk for VTE and hence received prophylaxis.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
TORONTO – Hospitalized patients with acute kidney injury had more than double the inpatient rate of venous thromboembolism as had patients without acute kidney injury in a prospective, observational study of more than 6,000 hospitalized U.S. soldiers.
He offered four possible mechanisms to explain a link between AKI and VTE:
- Patients with AKI are in a hypercoagulable state.
- AKI alters the pharmacodynamics or pharmacokinetics of VTE prophylactic treatments.
- AKI is a marker of an illness that causes VTE.
- VTE leads to an increased rate of AKI rather than the other way around.
Dr. McMahon’s analysis also revealed that two other clinical conditions that are generally believed to raise VTE risk – obesity and impaired overall renal function identified with stagnant measures – did not correspond with a significantly elevated VTE rate in this study.
The data came from 6,552 adults hospitalized for at least 2 days at Walter Reed between September 2009 and March 2011. The study excluded patients with VTE at the time of admission and also those who had been treated with an anticoagulant at the time of admission. The patients averaged 55 years of age and were hospitalized for a median of 4 days. About 22% of patients received VTE prophylaxis with unfractionated heparin, about 41% received prophylaxis with low-molecular-weight heparin, and about 39% received no VTE prophylaxis (percentages total 102% because of rounding).
About 16% of the patients had been diagnosed with AKI at the time of admission, and an additional 8% developed AKI while hospitalized, defined as an increase in serum creatinine during hospitalization of at least 50% above baseline levels or an increase of more than 0.3 mg/dL above the level at time of admission. During hospitalization, 160 patients (2%) developed a new onset VTE.
In an analysis that adjusted for baseline differences in type of surgery, body mass index, sex, age, and prior hospitalizations during the prior 90 days, the results showed that patients with preexisting or new onset AKI had a 2.2-fold higher rate of VTE, compared with patients without AKI, and this difference was statistically significant, Dr. McMahon reported.
The analysis also showed a significant 62% relatively higher rate of VTE among soldiers hospitalized for a deployment-related event, as well as a significant 63% relatively lower VTE rate among patients not receiving medical prophylaxis, compared with patients receiving an anticoagulant. Dr. McMahon suggested that this lower rate of VTEs among patients not on prophylaxis reflected success in identifying which patients had an increased risk for VTE and hence received prophylaxis.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
AT CHEST 2017
Key clinical point:
Major finding: Inpatients with AKI had an adjusted 2.2-fold higher rate of VTE, compared with other inpatients.
Data source: Prospective, observational data from 6,552 inpatients at a single U.S. military hospital.
Disclosures: Dr. McMahon had no disclosures.
Pharmacomechanical thrombolysis does not reduce post-thrombotic syndrome risk
In patients with acute proximal deep vein thrombosis who were undergoing anticoagulation, adding pharmacomechanical catheter-directed thrombolysis did not reduce risk of the post-thrombotic syndrome, according to results of a phase 3, randomized, controlled trial.
Moreover, addition of pharmacomechanical thrombolysis increased risk of major bleeding risk, investigators wrote in a report published online Dec. 6 in the New England Journal of Medicine.
“Our trial, for uncertain reasons, did not confirm these findings,” wrote Suresh Vedantham, MD of Washington University, St. Louis, and his coauthors.
Post-thrombotic syndrome is associated with chronic limb swelling and pain, and can lead to leg ulcers, impaired quality of life, and major disability. About half of patients with proximal deep vein thrombosis (DVT) will develop the post-thrombotic syndrome within 2 years, despite use of anticoagulation therapy, Dr. Vedantham and his colleagues noted.
Pharmacomechanical thrombosis is the catheter-directed delivery of a fibrinolytic agent into the thrombus, along with aspiration or maceration of the thrombus. The goal of the treatment is to reduce the burden of thrombus, which in turn might reduce risk of the post-thrombotic syndrome.
However, in their randomized trial known as ATTRACT, which included 692 patients with an acute proximal DVT, rates of post-thrombotic syndrome between 6 to 24 months after intervention were 47% in the pharmacomechanical thrombolysis group and 48% in the control group (risk ratio, 0.96; 95% CI, 0.82-1.11; P = .56), according to the report (N Engl J Med. 2017;377:2240-52). Control group patients received no procedural intervention.
Major bleeds within 10 days of the intervention were 1.7% and 0.3% for the pharmacomechanical thrombolysis and control groups, respectively (P = .049).
By contrast, in the CAVENT trial, catheter-directed thrombolysis reduced the risk of the post-thrombotic syndrome over 5 years of follow-up (Lancet Haematol. 2016;3[2]:e64-71). Dr. Vedantham and his coauthors suggested that factors potentially explaining the difference in outcomes include the number of patients enrolled (692 in ATTRACT, versus 209 in CAVENT), or the greater use of mechanical therapies in ATTRACT versus longer recombinant tissue plasminogen activator infusions in CAVENT.
The study was supported by multiple sources, including the National Heart, Lung and Blood Institute (NHLBI), Boston Scientific, Covidien (now Medtronic), Genentech, and others. Dr. Vedantham reported receiving grant support from Cook Medical and Volcano. Some of the other authors reported financial ties to Abbott Vascular, Boston Scientific, Medtronic, and other pharmaceutical and device companies.
In patients with acute proximal deep vein thrombosis who were undergoing anticoagulation, adding pharmacomechanical catheter-directed thrombolysis did not reduce risk of the post-thrombotic syndrome, according to results of a phase 3, randomized, controlled trial.
Moreover, addition of pharmacomechanical thrombolysis increased risk of major bleeding risk, investigators wrote in a report published online Dec. 6 in the New England Journal of Medicine.
“Our trial, for uncertain reasons, did not confirm these findings,” wrote Suresh Vedantham, MD of Washington University, St. Louis, and his coauthors.
Post-thrombotic syndrome is associated with chronic limb swelling and pain, and can lead to leg ulcers, impaired quality of life, and major disability. About half of patients with proximal deep vein thrombosis (DVT) will develop the post-thrombotic syndrome within 2 years, despite use of anticoagulation therapy, Dr. Vedantham and his colleagues noted.
Pharmacomechanical thrombosis is the catheter-directed delivery of a fibrinolytic agent into the thrombus, along with aspiration or maceration of the thrombus. The goal of the treatment is to reduce the burden of thrombus, which in turn might reduce risk of the post-thrombotic syndrome.
However, in their randomized trial known as ATTRACT, which included 692 patients with an acute proximal DVT, rates of post-thrombotic syndrome between 6 to 24 months after intervention were 47% in the pharmacomechanical thrombolysis group and 48% in the control group (risk ratio, 0.96; 95% CI, 0.82-1.11; P = .56), according to the report (N Engl J Med. 2017;377:2240-52). Control group patients received no procedural intervention.
Major bleeds within 10 days of the intervention were 1.7% and 0.3% for the pharmacomechanical thrombolysis and control groups, respectively (P = .049).
By contrast, in the CAVENT trial, catheter-directed thrombolysis reduced the risk of the post-thrombotic syndrome over 5 years of follow-up (Lancet Haematol. 2016;3[2]:e64-71). Dr. Vedantham and his coauthors suggested that factors potentially explaining the difference in outcomes include the number of patients enrolled (692 in ATTRACT, versus 209 in CAVENT), or the greater use of mechanical therapies in ATTRACT versus longer recombinant tissue plasminogen activator infusions in CAVENT.
The study was supported by multiple sources, including the National Heart, Lung and Blood Institute (NHLBI), Boston Scientific, Covidien (now Medtronic), Genentech, and others. Dr. Vedantham reported receiving grant support from Cook Medical and Volcano. Some of the other authors reported financial ties to Abbott Vascular, Boston Scientific, Medtronic, and other pharmaceutical and device companies.
In patients with acute proximal deep vein thrombosis who were undergoing anticoagulation, adding pharmacomechanical catheter-directed thrombolysis did not reduce risk of the post-thrombotic syndrome, according to results of a phase 3, randomized, controlled trial.
Moreover, addition of pharmacomechanical thrombolysis increased risk of major bleeding risk, investigators wrote in a report published online Dec. 6 in the New England Journal of Medicine.
“Our trial, for uncertain reasons, did not confirm these findings,” wrote Suresh Vedantham, MD of Washington University, St. Louis, and his coauthors.
Post-thrombotic syndrome is associated with chronic limb swelling and pain, and can lead to leg ulcers, impaired quality of life, and major disability. About half of patients with proximal deep vein thrombosis (DVT) will develop the post-thrombotic syndrome within 2 years, despite use of anticoagulation therapy, Dr. Vedantham and his colleagues noted.
Pharmacomechanical thrombosis is the catheter-directed delivery of a fibrinolytic agent into the thrombus, along with aspiration or maceration of the thrombus. The goal of the treatment is to reduce the burden of thrombus, which in turn might reduce risk of the post-thrombotic syndrome.
However, in their randomized trial known as ATTRACT, which included 692 patients with an acute proximal DVT, rates of post-thrombotic syndrome between 6 to 24 months after intervention were 47% in the pharmacomechanical thrombolysis group and 48% in the control group (risk ratio, 0.96; 95% CI, 0.82-1.11; P = .56), according to the report (N Engl J Med. 2017;377:2240-52). Control group patients received no procedural intervention.
Major bleeds within 10 days of the intervention were 1.7% and 0.3% for the pharmacomechanical thrombolysis and control groups, respectively (P = .049).
By contrast, in the CAVENT trial, catheter-directed thrombolysis reduced the risk of the post-thrombotic syndrome over 5 years of follow-up (Lancet Haematol. 2016;3[2]:e64-71). Dr. Vedantham and his coauthors suggested that factors potentially explaining the difference in outcomes include the number of patients enrolled (692 in ATTRACT, versus 209 in CAVENT), or the greater use of mechanical therapies in ATTRACT versus longer recombinant tissue plasminogen activator infusions in CAVENT.
The study was supported by multiple sources, including the National Heart, Lung and Blood Institute (NHLBI), Boston Scientific, Covidien (now Medtronic), Genentech, and others. Dr. Vedantham reported receiving grant support from Cook Medical and Volcano. Some of the other authors reported financial ties to Abbott Vascular, Boston Scientific, Medtronic, and other pharmaceutical and device companies.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: Rates of post-thrombotic syndrome were 47% in the pharmacomechanical thrombolysis group, and 48% in the control group (risk ratio, 0.96; 95% CI, 0.82-1.11; P = .56).
Data source: A phase 3, multicenter, randomized, open-label, assessor-blinded, controlled clinical trial, including 692 patients with acute proximal deep vein thrombosis.
Disclosures: The study was supported by multiple sources, including the National Heart, Lung and Blood Institute (NHLBI), Boston Scientific, Covidien (now Medtronic), Genentech, and others. First author Suresh Vedantham, MD, reported receiving grant support from Cook Medical and Volcano. Some of the other authors reported financial ties to Abbott Vascular, Boston Scientific, Medtronic, and other pharmaceutical and device companies.
DAPT produces better CABG outcomes than aspirin alone
ANAHEIM, CALIF. – Treatment with dual-antiplatelet therapy following coronary artery bypass grafting with a saphenous vein maintained vein-graft patency better than aspirin alone in a randomized, multicenter trial with 500 patients.
After 1 year of dual-antiplatelet therapy (DAPT) with ticagrelor (Brilinta) and aspirin, 89% of saphenous-vein grafts remained patent, compared with a 77% patency rate in saphenous-vein grafts in patients treated with aspirin alone, a statistically significant difference for the study’s primary endpoint, Qiang Zhao, MD, said at the American Hart Association scientific sessions. The data, collected at six Chinese centers, also showed a nominal decrease in the combined rate of cardiovascular death, MI, and stroke: 2% with DAPT and 5% with aspirin alone. It further showed an increase in major or bypass-related bleeds: 2% with DAPT and none with aspirin alone, reported Dr. Zhao, professor and director of cardiac surgery at Ruijin Hospital in Shanghai, China.
“If this result were repeated in a larger study it would be important,” John H. Alexander, MD, professor of medicine at Duke University in Durham, N.C., commented in a video interview.
The Compare the Efficacy of Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Graft Surgery (DACAB) trial randomized patients who underwent coronary artery bypass grafting (CABG). They averaged about 64 years of age, and received an average of nearly four grafts each including an average of nearly three saphenous vein grafts. The study assigned patients to one of three treatment arms starting within 24 hours after surgery: 168 received ticagrelor 90 mg twice daily plus aspirin 100 mg once daily, 166 got ticagrelor alone, and 166 received aspirin alone. Treatment continued for 1 year.
“Some surgeons and physicians currently prescribe DAPT to CABG patients, but there is not much evidence of its benefit. The DACAB trial is useful, but you need to show that it does not just improve patency but that patients also have better outcomes. The excess of major bleeds is a big deal. It gives one pause about adopting DAPT as standard treatment,” Dr. Gardner said.
DACAB received no commercial funding. Dr. Zhao has been a speaker on behalf of and has received research funding from AstraZeneca, the company that markets ticagrelor (Brilinta). He has also been a speaker for Johnson & Johnson and Medtronic and has received research funding from Bayer, Novartis, and Sanofi. Dr. Gardner had no disclosures.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
Results from the DACAB trial showed that using aspirin and ticagrelor improved vein-graft patency, compared with using aspirin alone. It was a compelling result, but for the intermediate, imaging-based outcome of graft patency at 1 year after surgery. This finding is conclusive evidence that dual-antiplatelet therapy has some benefit.
But the findings from this trial, modestly sized with 500 patients, failed to prove that the clinical benefit from dual-antiplatelet therapy was worth the adverse effect of an increase in the rate of major and bypass-related bleeding. The study was underpowered to prove that dual-antiplatelet therapy had a clear beneficial impact on clinical outcomes such as cardiovascular death, MI, and stroke, although this combined rate went in the right direction with dual therapy, compared with aspirin alone. We need to see proof of a benefit for these clinical outcomes to justify using a treatment that causes an increase in major bleeds.
The DACAB results alone are not enough to justify a change in practice. It would be an important finding if the results could be replicated in a larger study. And if dual-antiplatelet therapy was proven to have a net clinical benefit for patients, we would still want to target it to patients with a higher ischemic risk and, in general, avoid using it in patients with a high bleeding risk.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
John H. Alexander, MD , is a cardiologist and professor of medicine at Duke University in Durham, N.C. He has been a consultant to and has received research funding from several companies, including AstraZeneca, the company that markets ticagrelor (Brilinta). He made these comments as designated discussant for the DACAB study and in a video interview .
Results from the DACAB trial showed that using aspirin and ticagrelor improved vein-graft patency, compared with using aspirin alone. It was a compelling result, but for the intermediate, imaging-based outcome of graft patency at 1 year after surgery. This finding is conclusive evidence that dual-antiplatelet therapy has some benefit.
But the findings from this trial, modestly sized with 500 patients, failed to prove that the clinical benefit from dual-antiplatelet therapy was worth the adverse effect of an increase in the rate of major and bypass-related bleeding. The study was underpowered to prove that dual-antiplatelet therapy had a clear beneficial impact on clinical outcomes such as cardiovascular death, MI, and stroke, although this combined rate went in the right direction with dual therapy, compared with aspirin alone. We need to see proof of a benefit for these clinical outcomes to justify using a treatment that causes an increase in major bleeds.
The DACAB results alone are not enough to justify a change in practice. It would be an important finding if the results could be replicated in a larger study. And if dual-antiplatelet therapy was proven to have a net clinical benefit for patients, we would still want to target it to patients with a higher ischemic risk and, in general, avoid using it in patients with a high bleeding risk.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
John H. Alexander, MD , is a cardiologist and professor of medicine at Duke University in Durham, N.C. He has been a consultant to and has received research funding from several companies, including AstraZeneca, the company that markets ticagrelor (Brilinta). He made these comments as designated discussant for the DACAB study and in a video interview .
Results from the DACAB trial showed that using aspirin and ticagrelor improved vein-graft patency, compared with using aspirin alone. It was a compelling result, but for the intermediate, imaging-based outcome of graft patency at 1 year after surgery. This finding is conclusive evidence that dual-antiplatelet therapy has some benefit.
But the findings from this trial, modestly sized with 500 patients, failed to prove that the clinical benefit from dual-antiplatelet therapy was worth the adverse effect of an increase in the rate of major and bypass-related bleeding. The study was underpowered to prove that dual-antiplatelet therapy had a clear beneficial impact on clinical outcomes such as cardiovascular death, MI, and stroke, although this combined rate went in the right direction with dual therapy, compared with aspirin alone. We need to see proof of a benefit for these clinical outcomes to justify using a treatment that causes an increase in major bleeds.
The DACAB results alone are not enough to justify a change in practice. It would be an important finding if the results could be replicated in a larger study. And if dual-antiplatelet therapy was proven to have a net clinical benefit for patients, we would still want to target it to patients with a higher ischemic risk and, in general, avoid using it in patients with a high bleeding risk.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
John H. Alexander, MD , is a cardiologist and professor of medicine at Duke University in Durham, N.C. He has been a consultant to and has received research funding from several companies, including AstraZeneca, the company that markets ticagrelor (Brilinta). He made these comments as designated discussant for the DACAB study and in a video interview .
ANAHEIM, CALIF. – Treatment with dual-antiplatelet therapy following coronary artery bypass grafting with a saphenous vein maintained vein-graft patency better than aspirin alone in a randomized, multicenter trial with 500 patients.
After 1 year of dual-antiplatelet therapy (DAPT) with ticagrelor (Brilinta) and aspirin, 89% of saphenous-vein grafts remained patent, compared with a 77% patency rate in saphenous-vein grafts in patients treated with aspirin alone, a statistically significant difference for the study’s primary endpoint, Qiang Zhao, MD, said at the American Hart Association scientific sessions. The data, collected at six Chinese centers, also showed a nominal decrease in the combined rate of cardiovascular death, MI, and stroke: 2% with DAPT and 5% with aspirin alone. It further showed an increase in major or bypass-related bleeds: 2% with DAPT and none with aspirin alone, reported Dr. Zhao, professor and director of cardiac surgery at Ruijin Hospital in Shanghai, China.
“If this result were repeated in a larger study it would be important,” John H. Alexander, MD, professor of medicine at Duke University in Durham, N.C., commented in a video interview.
The Compare the Efficacy of Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Graft Surgery (DACAB) trial randomized patients who underwent coronary artery bypass grafting (CABG). They averaged about 64 years of age, and received an average of nearly four grafts each including an average of nearly three saphenous vein grafts. The study assigned patients to one of three treatment arms starting within 24 hours after surgery: 168 received ticagrelor 90 mg twice daily plus aspirin 100 mg once daily, 166 got ticagrelor alone, and 166 received aspirin alone. Treatment continued for 1 year.
“Some surgeons and physicians currently prescribe DAPT to CABG patients, but there is not much evidence of its benefit. The DACAB trial is useful, but you need to show that it does not just improve patency but that patients also have better outcomes. The excess of major bleeds is a big deal. It gives one pause about adopting DAPT as standard treatment,” Dr. Gardner said.
DACAB received no commercial funding. Dr. Zhao has been a speaker on behalf of and has received research funding from AstraZeneca, the company that markets ticagrelor (Brilinta). He has also been a speaker for Johnson & Johnson and Medtronic and has received research funding from Bayer, Novartis, and Sanofi. Dr. Gardner had no disclosures.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
ANAHEIM, CALIF. – Treatment with dual-antiplatelet therapy following coronary artery bypass grafting with a saphenous vein maintained vein-graft patency better than aspirin alone in a randomized, multicenter trial with 500 patients.
After 1 year of dual-antiplatelet therapy (DAPT) with ticagrelor (Brilinta) and aspirin, 89% of saphenous-vein grafts remained patent, compared with a 77% patency rate in saphenous-vein grafts in patients treated with aspirin alone, a statistically significant difference for the study’s primary endpoint, Qiang Zhao, MD, said at the American Hart Association scientific sessions. The data, collected at six Chinese centers, also showed a nominal decrease in the combined rate of cardiovascular death, MI, and stroke: 2% with DAPT and 5% with aspirin alone. It further showed an increase in major or bypass-related bleeds: 2% with DAPT and none with aspirin alone, reported Dr. Zhao, professor and director of cardiac surgery at Ruijin Hospital in Shanghai, China.
“If this result were repeated in a larger study it would be important,” John H. Alexander, MD, professor of medicine at Duke University in Durham, N.C., commented in a video interview.
The Compare the Efficacy of Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Graft Surgery (DACAB) trial randomized patients who underwent coronary artery bypass grafting (CABG). They averaged about 64 years of age, and received an average of nearly four grafts each including an average of nearly three saphenous vein grafts. The study assigned patients to one of three treatment arms starting within 24 hours after surgery: 168 received ticagrelor 90 mg twice daily plus aspirin 100 mg once daily, 166 got ticagrelor alone, and 166 received aspirin alone. Treatment continued for 1 year.
“Some surgeons and physicians currently prescribe DAPT to CABG patients, but there is not much evidence of its benefit. The DACAB trial is useful, but you need to show that it does not just improve patency but that patients also have better outcomes. The excess of major bleeds is a big deal. It gives one pause about adopting DAPT as standard treatment,” Dr. Gardner said.
DACAB received no commercial funding. Dr. Zhao has been a speaker on behalf of and has received research funding from AstraZeneca, the company that markets ticagrelor (Brilinta). He has also been a speaker for Johnson & Johnson and Medtronic and has received research funding from Bayer, Novartis, and Sanofi. Dr. Gardner had no disclosures.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: The 1-year saphenous-vein graft patency rate was 89% with DAPT treatment and 77% with aspirin alone. Data source: DACAB, a multicenter, randomized trial with 500 Chinese patients.
Disclosures: DACAB received no commercial funding. Dr. Zhao has been a speaker on behalf of and has received research funding from AstraZeneca, the company that markets ticagrelor (Brilinta). He has also been a speaker for Johnson & Johnson and Medtronic and has received research funding from Bayer, Novartis, and Sanofi.
Genotype-guided warfarin dosing reduced adverse events in arthroplasty patients
The difference in the composite endpoint (major bleeding within 30 days, international normalized ratio [INR] of 4 or greater within 30 days, venous thromboembolism within 60 days, or death within 30 days) in the Genetic Informatics Trial of Warfarin to Prevent Deep Vein Thrombosis (GIFT) trial was mainly driven by a significant difference in episodes of elevated INR, reported Brian F. Gage, MD, and his colleagues (JAMA 2017;318[12]:1115-1124. doi: 10.1001/jama.2017.11469).
A total of 1,597 patients completed the trial. Of 808 patients in the genotype-guided group, 10.8% met one of the endpoints. Of 789 in the clinically guided warfarin dosing group, 14.7% met at least 1 of the endpoints. There were no deaths in the study.
“Widespread use of genotype-guided dosing will depend on reimbursement, regulations, and logistics. Although several commercial platforms for warfarin-related genes have been approved by the Food and Drug Administration and the European Medicines Agency, routine genotyping is not yet recommended,” wrote Dr. Gage of Washington University, St. Louis, and his coauthors.
The Centers for Medicare and Medicaid Services used its Coverage with Evidence Development program to fund genotyping in this trial and will review the results to determine future coverage, the researchers added.
In GIFT, patients were randomized to an 11-day regimen of warfarin guided either by a clinical algorithm or by their individual genotype. The team tested for four polymorphisms known to affect warfarin metabolism: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. The treatment goal was an INR of 1.8-2. After 11 days, physicians could administer warfarin according to their own judgment.
The absolute difference of 3.9% in the composite endpoint was largely driven by a 2.8% absolute difference in the rate of an INR of 4 or greater. The rate difference between the two groups was 0.8% for major bleeding, and 0.7% for VTE.
About 41% of the cohort was considered to be at high risk of bleeding complications, and this group accrued the highest benefit from genotype-based dosing. Among them, the composite endpoint was 11.5% compared with 15.2% in the clinical algorithm group – an absolute difference of 3.76%.
The benefit was consistent among black patients, and those with CYP2C9.
By day 90, one VTE had occurred in each group. An intracranial hemorrhage occurred in one patient in the clinically guided group, 2 months after stopping warfarin.
The clinical benefit of genotype-based dosing influenced 90-day outcomes as well, with the composite endpoint occurring in 11% of the genotype group and 15% of the clinically guided group (absolute difference 3.9%).
Among the 1,588 patients who had their percentage of time in the therapeutic range (PTTR) calculated, genotyping improved PTTR time by 3.4% overall. The effect was especially strong from days 4 to 14, when it improved PTTR by 5.7% relative to clinical guidance.
Three other studies have examined the effect of a genotype-based warfarin dosing regimen, Dr. Gage and his coauthors noted: Two found no benefit, and a third found that such guidance improved INR control. GIFT has several advantages over those trials, which the authors said lend credence to its results.
“Compared with previous studies, this trial was larger, used genotype-guided dosing for a longer duration, and incorporated more genes into the dosing algorithm …The longer period of genotype-guided dosing likely prevented cases of supratherapeutic INR that were common in these trials,” they wrote.
Dr. Gage reported no financial disclosures, but several coauthors reported ties with pharmaceutical and imaging companies.
Warfarin is the most commonly used anticoagulant in the world, and a significant cause of emergency department visits and hospitalizations, especially among older patients. Walking the fine line between dosing too little and too much is not an easy task – especially since warfarin response is influenced by diet, comorbidities, interactions with other medications and – as studies over the last 20 years have confirmed – many genetic variants.
Also, the practicality of genotyping every patient who needs anticoagulation therapy must be questioned. Based on the results of GIFT, 26 patients would need to be genotyped to prevent one event, typically an INR of 4 or greater. Although the cost of genotyping continues to decline, health insurers and publicly funded health systems have not yet been convinced that genotype-guided warfarin prescribing is a cost-effective strategy.
The benefits of genotyping would likely be less in patients with atrial fibrillation, for example, as they run a lower risk of VTE than do arthroplasty patients. The GIFT surgeries were all elective, so there was plenty of time to get back genotyping results before starting warfarin. That is a luxury not afforded to many patients in need of anticoagulation.
It’s possible, however, that the benefits of genotyping might be larger in the real world. GIFT was conducted at academic medical centers and used a clinical dosing algorithm as comparator. As a result, adverse event rates were likely lower in the comparison group than would be expected in other clinical settings with less-intense INR monitoring or empirically based initiation regimens.
Still, GIFT’s results are gaining global attention. Based on prepublication results of the GIFT trial, the Clinical Pharmacogenetics Implementation Consortium (CPIC), an international research network that develops consensus recommendations about the use of pharmacogenomic test results, recently published guidelines about genotype-guided dosing for warfarin. The group now recommends using genotype-guided warfarin dosing based on CYP2C9*2, CYP2C9*3, and VKORC1 variants for adult patients of non-African ancestry. It also recommends that patients with combinations of high-risk variants would benefit from an alternative anticoagulant strategy, because of likely greater risks of poor INR control and bleeding.
A single pharmacogenomic test covering many common variants relevant to multiple prescribing decisions over time is far more likely to be a cost-effective approach; however, there is no evidence for this proposition. Until then, it might be simpler and less expensive to use clinical dosing algorithms to reduce the risks of anticoagulation.
Jon D. Emery, PhD, is the Herman Professor of Primary Care Cancer Research at the University of Melbourne and Western Health, Melbourne. He made these remarks in an accompanying editorial (JAMA 2017;318;110-2 doi: 10.1001/jama.2017.11465 ).
Warfarin is the most commonly used anticoagulant in the world, and a significant cause of emergency department visits and hospitalizations, especially among older patients. Walking the fine line between dosing too little and too much is not an easy task – especially since warfarin response is influenced by diet, comorbidities, interactions with other medications and – as studies over the last 20 years have confirmed – many genetic variants.
Also, the practicality of genotyping every patient who needs anticoagulation therapy must be questioned. Based on the results of GIFT, 26 patients would need to be genotyped to prevent one event, typically an INR of 4 or greater. Although the cost of genotyping continues to decline, health insurers and publicly funded health systems have not yet been convinced that genotype-guided warfarin prescribing is a cost-effective strategy.
The benefits of genotyping would likely be less in patients with atrial fibrillation, for example, as they run a lower risk of VTE than do arthroplasty patients. The GIFT surgeries were all elective, so there was plenty of time to get back genotyping results before starting warfarin. That is a luxury not afforded to many patients in need of anticoagulation.
It’s possible, however, that the benefits of genotyping might be larger in the real world. GIFT was conducted at academic medical centers and used a clinical dosing algorithm as comparator. As a result, adverse event rates were likely lower in the comparison group than would be expected in other clinical settings with less-intense INR monitoring or empirically based initiation regimens.
Still, GIFT’s results are gaining global attention. Based on prepublication results of the GIFT trial, the Clinical Pharmacogenetics Implementation Consortium (CPIC), an international research network that develops consensus recommendations about the use of pharmacogenomic test results, recently published guidelines about genotype-guided dosing for warfarin. The group now recommends using genotype-guided warfarin dosing based on CYP2C9*2, CYP2C9*3, and VKORC1 variants for adult patients of non-African ancestry. It also recommends that patients with combinations of high-risk variants would benefit from an alternative anticoagulant strategy, because of likely greater risks of poor INR control and bleeding.
A single pharmacogenomic test covering many common variants relevant to multiple prescribing decisions over time is far more likely to be a cost-effective approach; however, there is no evidence for this proposition. Until then, it might be simpler and less expensive to use clinical dosing algorithms to reduce the risks of anticoagulation.
Jon D. Emery, PhD, is the Herman Professor of Primary Care Cancer Research at the University of Melbourne and Western Health, Melbourne. He made these remarks in an accompanying editorial (JAMA 2017;318;110-2 doi: 10.1001/jama.2017.11465 ).
Warfarin is the most commonly used anticoagulant in the world, and a significant cause of emergency department visits and hospitalizations, especially among older patients. Walking the fine line between dosing too little and too much is not an easy task – especially since warfarin response is influenced by diet, comorbidities, interactions with other medications and – as studies over the last 20 years have confirmed – many genetic variants.
Also, the practicality of genotyping every patient who needs anticoagulation therapy must be questioned. Based on the results of GIFT, 26 patients would need to be genotyped to prevent one event, typically an INR of 4 or greater. Although the cost of genotyping continues to decline, health insurers and publicly funded health systems have not yet been convinced that genotype-guided warfarin prescribing is a cost-effective strategy.
The benefits of genotyping would likely be less in patients with atrial fibrillation, for example, as they run a lower risk of VTE than do arthroplasty patients. The GIFT surgeries were all elective, so there was plenty of time to get back genotyping results before starting warfarin. That is a luxury not afforded to many patients in need of anticoagulation.
It’s possible, however, that the benefits of genotyping might be larger in the real world. GIFT was conducted at academic medical centers and used a clinical dosing algorithm as comparator. As a result, adverse event rates were likely lower in the comparison group than would be expected in other clinical settings with less-intense INR monitoring or empirically based initiation regimens.
Still, GIFT’s results are gaining global attention. Based on prepublication results of the GIFT trial, the Clinical Pharmacogenetics Implementation Consortium (CPIC), an international research network that develops consensus recommendations about the use of pharmacogenomic test results, recently published guidelines about genotype-guided dosing for warfarin. The group now recommends using genotype-guided warfarin dosing based on CYP2C9*2, CYP2C9*3, and VKORC1 variants for adult patients of non-African ancestry. It also recommends that patients with combinations of high-risk variants would benefit from an alternative anticoagulant strategy, because of likely greater risks of poor INR control and bleeding.
A single pharmacogenomic test covering many common variants relevant to multiple prescribing decisions over time is far more likely to be a cost-effective approach; however, there is no evidence for this proposition. Until then, it might be simpler and less expensive to use clinical dosing algorithms to reduce the risks of anticoagulation.
Jon D. Emery, PhD, is the Herman Professor of Primary Care Cancer Research at the University of Melbourne and Western Health, Melbourne. He made these remarks in an accompanying editorial (JAMA 2017;318;110-2 doi: 10.1001/jama.2017.11465 ).
The difference in the composite endpoint (major bleeding within 30 days, international normalized ratio [INR] of 4 or greater within 30 days, venous thromboembolism within 60 days, or death within 30 days) in the Genetic Informatics Trial of Warfarin to Prevent Deep Vein Thrombosis (GIFT) trial was mainly driven by a significant difference in episodes of elevated INR, reported Brian F. Gage, MD, and his colleagues (JAMA 2017;318[12]:1115-1124. doi: 10.1001/jama.2017.11469).
A total of 1,597 patients completed the trial. Of 808 patients in the genotype-guided group, 10.8% met one of the endpoints. Of 789 in the clinically guided warfarin dosing group, 14.7% met at least 1 of the endpoints. There were no deaths in the study.
“Widespread use of genotype-guided dosing will depend on reimbursement, regulations, and logistics. Although several commercial platforms for warfarin-related genes have been approved by the Food and Drug Administration and the European Medicines Agency, routine genotyping is not yet recommended,” wrote Dr. Gage of Washington University, St. Louis, and his coauthors.
The Centers for Medicare and Medicaid Services used its Coverage with Evidence Development program to fund genotyping in this trial and will review the results to determine future coverage, the researchers added.
In GIFT, patients were randomized to an 11-day regimen of warfarin guided either by a clinical algorithm or by their individual genotype. The team tested for four polymorphisms known to affect warfarin metabolism: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. The treatment goal was an INR of 1.8-2. After 11 days, physicians could administer warfarin according to their own judgment.
The absolute difference of 3.9% in the composite endpoint was largely driven by a 2.8% absolute difference in the rate of an INR of 4 or greater. The rate difference between the two groups was 0.8% for major bleeding, and 0.7% for VTE.
About 41% of the cohort was considered to be at high risk of bleeding complications, and this group accrued the highest benefit from genotype-based dosing. Among them, the composite endpoint was 11.5% compared with 15.2% in the clinical algorithm group – an absolute difference of 3.76%.
The benefit was consistent among black patients, and those with CYP2C9.
By day 90, one VTE had occurred in each group. An intracranial hemorrhage occurred in one patient in the clinically guided group, 2 months after stopping warfarin.
The clinical benefit of genotype-based dosing influenced 90-day outcomes as well, with the composite endpoint occurring in 11% of the genotype group and 15% of the clinically guided group (absolute difference 3.9%).
Among the 1,588 patients who had their percentage of time in the therapeutic range (PTTR) calculated, genotyping improved PTTR time by 3.4% overall. The effect was especially strong from days 4 to 14, when it improved PTTR by 5.7% relative to clinical guidance.
Three other studies have examined the effect of a genotype-based warfarin dosing regimen, Dr. Gage and his coauthors noted: Two found no benefit, and a third found that such guidance improved INR control. GIFT has several advantages over those trials, which the authors said lend credence to its results.
“Compared with previous studies, this trial was larger, used genotype-guided dosing for a longer duration, and incorporated more genes into the dosing algorithm …The longer period of genotype-guided dosing likely prevented cases of supratherapeutic INR that were common in these trials,” they wrote.
Dr. Gage reported no financial disclosures, but several coauthors reported ties with pharmaceutical and imaging companies.
The difference in the composite endpoint (major bleeding within 30 days, international normalized ratio [INR] of 4 or greater within 30 days, venous thromboembolism within 60 days, or death within 30 days) in the Genetic Informatics Trial of Warfarin to Prevent Deep Vein Thrombosis (GIFT) trial was mainly driven by a significant difference in episodes of elevated INR, reported Brian F. Gage, MD, and his colleagues (JAMA 2017;318[12]:1115-1124. doi: 10.1001/jama.2017.11469).
A total of 1,597 patients completed the trial. Of 808 patients in the genotype-guided group, 10.8% met one of the endpoints. Of 789 in the clinically guided warfarin dosing group, 14.7% met at least 1 of the endpoints. There were no deaths in the study.
“Widespread use of genotype-guided dosing will depend on reimbursement, regulations, and logistics. Although several commercial platforms for warfarin-related genes have been approved by the Food and Drug Administration and the European Medicines Agency, routine genotyping is not yet recommended,” wrote Dr. Gage of Washington University, St. Louis, and his coauthors.
The Centers for Medicare and Medicaid Services used its Coverage with Evidence Development program to fund genotyping in this trial and will review the results to determine future coverage, the researchers added.
In GIFT, patients were randomized to an 11-day regimen of warfarin guided either by a clinical algorithm or by their individual genotype. The team tested for four polymorphisms known to affect warfarin metabolism: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. The treatment goal was an INR of 1.8-2. After 11 days, physicians could administer warfarin according to their own judgment.
The absolute difference of 3.9% in the composite endpoint was largely driven by a 2.8% absolute difference in the rate of an INR of 4 or greater. The rate difference between the two groups was 0.8% for major bleeding, and 0.7% for VTE.
About 41% of the cohort was considered to be at high risk of bleeding complications, and this group accrued the highest benefit from genotype-based dosing. Among them, the composite endpoint was 11.5% compared with 15.2% in the clinical algorithm group – an absolute difference of 3.76%.
The benefit was consistent among black patients, and those with CYP2C9.
By day 90, one VTE had occurred in each group. An intracranial hemorrhage occurred in one patient in the clinically guided group, 2 months after stopping warfarin.
The clinical benefit of genotype-based dosing influenced 90-day outcomes as well, with the composite endpoint occurring in 11% of the genotype group and 15% of the clinically guided group (absolute difference 3.9%).
Among the 1,588 patients who had their percentage of time in the therapeutic range (PTTR) calculated, genotyping improved PTTR time by 3.4% overall. The effect was especially strong from days 4 to 14, when it improved PTTR by 5.7% relative to clinical guidance.
Three other studies have examined the effect of a genotype-based warfarin dosing regimen, Dr. Gage and his coauthors noted: Two found no benefit, and a third found that such guidance improved INR control. GIFT has several advantages over those trials, which the authors said lend credence to its results.
“Compared with previous studies, this trial was larger, used genotype-guided dosing for a longer duration, and incorporated more genes into the dosing algorithm …The longer period of genotype-guided dosing likely prevented cases of supratherapeutic INR that were common in these trials,” they wrote.
Dr. Gage reported no financial disclosures, but several coauthors reported ties with pharmaceutical and imaging companies.
FROM JAMA
Key clinical point:
Major finding: Genotype-guided dosing reduced adverse events – primarily elevated INRs – by almost 4% compared to clinically based warfarin dosing.
Data source: A randomized trial comprising 1,650 elderly patients undergoing elective knee or hip arthroplasty.
Disclosures: Dr. Gage had no financial disclosures, but several of his coauthors noted relationships with pharmaceutical and imaging companies.
VIDEO: Triple therapy study and new recommendations provide guidance on CAPS
MADRID – Catastrophic antiphospholipid syndrome (CAPS) is associated with a high mortality rate, but new research presented at the European Congress of Rheumatology shows that patient survival can be significantly improved by a triple therapy treatment approach.
Researchers at the Congress also presented clinical practice guidelines for the diagnosis and management of the rare disease, which accounts for just 1% of patients with antiphospholipid syndrome (APS).
CAPS is characterized by a fast onset of widespread thrombosis, mainly in the small vessels, and, often, microangiopathic hemolytic anemia is seen in the laboratory. If undiagnosed or left untreated, patients may present with multiorgan failure needing intensive care treatment, which can be fatal in up to 50% of cases.
At the Congress, Ignasi Rodríguez-Pintó, MD, presented new data from the CAPS Registry that looks at the combined effect of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins on the survival of patients with CAPS as well as the new clinical practice guidelines.
CAPS Registry study
The aim of the study Dr. Rodríguez-Pintó presented on behalf of the CAPS Registry Project Group was to determine what, if any, survival benefit would be incurred from a triple therapy approach when compared with other different combinations of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins, or none of these treatments.
Although the triple therapy treatment approach is already being used in practice, its use is largely empirical, Dr. Rodríguez-Pintó of the department of autoimmune disease at the Hospital Clinic, Barcelona, explained in a video interview.
The investigators derived their data from episodes of CAPS occurring in patients in the CAPS Registry from the European Forum on Antiphospholipid Antibodies. This international registry was set up in 2000 and has been assembling the clinical, laboratory, and therapeutic findings of patients with CAPS for almost 20 years.
“We observed 525 episodes of CAPS in 502 patients. That means that some patients had two to three episodes of CAPS,” Dr. Rodríguez-Pintó said. Data on 38 episodes of CAPS had to be excluded from the analysis because of missing information, which left 487 episodes occurring in 471 patients.
The mean age of the 471 patients included in the analysis was 38 years. The majority (67.9%) were female and had primary (68.8%) APS. Triple therapy was given to about 40% of patients who experienced CAPS, with about 57% receiving other combinations of drugs and 2.5% receiving no treatment for CAPS.
Overall, 177 of the 487 (36.3%) episodes of CAPS were fatal.
“Triple therapy was associated with a higher chance of survival when compared to other combinations or to none of these treatments,” Dr. Rodríguez-Pintó said.
While 28% of patients with CAPS died in the triple therapy group, mortality was 41% with other combinations of treatments and 75% with none of these treatments.
All-cause mortality was reduced by 47% with triple therapy, compared with none of these treatments. The adjusted odds ratio (aOR) when comparing survival between triple therapy and no treatment was 7.7, with a 95% confidence interval of 2.0 to 29.7. The aOR comparing other drug combinations versus none of these treatments was 6.8 (95% CI, 1.7-29.6).
“For a long time, we have been saying that triple therapy would probably be the best approach, but we had no firm evidence,” Dr. Rodríguez-Pintó said.
“So, this is the first time that we have clear clinical evidence of the benefit of these approaches, and I think that these results are important because they will give us more confidence in how we treat patients and help develop guidance on [the treatment’s] use in the future.”
Guidelines
A steering committee composed of representatives from the European Commission–funded RARE-BestPractices project and McMaster University in Hamilton, Ont., used GRADE methodology to develop the guidelines for CAPS diagnosis and management. The committee answered three diagnostic and seven treatment questions that originated from a panel of 19 international stakeholders, including Dr. Rodríguez-Pintó, through systematic reviews of the literature that used Cochrane criteria.
Although the review of studies did not include the study of CAPS Registry data that Dr. Rodríguez-Pintó and his colleagues conducted, he said that the recommendations still confirm the value of using a triple therapy approach to treatment.
The panel created three diagnostic recommendations for patients suspected of having CAPS, all of which were conditional and based on very low certainty of evidence: use preliminary CAPS classification criteria to diagnose CAPS; use or nonuse of biopsy, depending on the circumstances, because of its high specificity but possibly low sensitivity for thrombotic microangiopathy; and test for antiphospholipid antibodies, which should not delay initiation of treatment.
All seven first-line treatment recommendations that the panel developed relied on a very low certainty of evidence, and most were conditional:
- Triple therapy combination treatment with corticosteroids, heparin, and plasma exchange or intravenous immunoglobulins instead of a single agent or other combination treatments.
- Therapeutic dose anticoagulation was one of only two treatment recommendations to be considered “strong,” but use of direct oral anticoagulants is not advised.
- Therapeutic plasma exchange is recommended for use with other therapies and should be strongly considered for patients with microangiopathic hemolytic anemia.
- Intravenous immunoglobulin is advised for use in conjunction with other therapies and should be given special consideration for patients with immune thrombocytopenia or renal insufficiency.
- Antiplatelet agents are conditionally recommended as an add-on therapy, but their potential mortality benefit is tempered by increased risk of bleeding when used with anticoagulants. Strong consideration should be given to their use as an alternative therapy to anticoagulation when anticoagulation is contraindicated for a reason other than bleeding.
- Rituximab (Rituxan) should not be used because of little available data on its use, uncertainty regarding long-term consequences, and its expense – except for refractory cases where other therapies have been insufficient.
- Corticosteroids should not be used because of their lack of efficacy in CAPS when used alone and potential for adverse effects, except for certain circumstances where they may be indicated.
The authors of the guidelines emphasized that these recommendations are not meant to apply to every CAPS patient. They also noted that the available evidence did not allow for temporal analysis of treatments and that conclusions could not be drawn regarding “first-line” versus “second-line” therapies.
None of the authors of the registry study or the guidelines had relevant conflicts of interest to declare.
MADRID – Catastrophic antiphospholipid syndrome (CAPS) is associated with a high mortality rate, but new research presented at the European Congress of Rheumatology shows that patient survival can be significantly improved by a triple therapy treatment approach.
Researchers at the Congress also presented clinical practice guidelines for the diagnosis and management of the rare disease, which accounts for just 1% of patients with antiphospholipid syndrome (APS).
CAPS is characterized by a fast onset of widespread thrombosis, mainly in the small vessels, and, often, microangiopathic hemolytic anemia is seen in the laboratory. If undiagnosed or left untreated, patients may present with multiorgan failure needing intensive care treatment, which can be fatal in up to 50% of cases.
At the Congress, Ignasi Rodríguez-Pintó, MD, presented new data from the CAPS Registry that looks at the combined effect of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins on the survival of patients with CAPS as well as the new clinical practice guidelines.
CAPS Registry study
The aim of the study Dr. Rodríguez-Pintó presented on behalf of the CAPS Registry Project Group was to determine what, if any, survival benefit would be incurred from a triple therapy approach when compared with other different combinations of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins, or none of these treatments.
Although the triple therapy treatment approach is already being used in practice, its use is largely empirical, Dr. Rodríguez-Pintó of the department of autoimmune disease at the Hospital Clinic, Barcelona, explained in a video interview.
The investigators derived their data from episodes of CAPS occurring in patients in the CAPS Registry from the European Forum on Antiphospholipid Antibodies. This international registry was set up in 2000 and has been assembling the clinical, laboratory, and therapeutic findings of patients with CAPS for almost 20 years.
“We observed 525 episodes of CAPS in 502 patients. That means that some patients had two to three episodes of CAPS,” Dr. Rodríguez-Pintó said. Data on 38 episodes of CAPS had to be excluded from the analysis because of missing information, which left 487 episodes occurring in 471 patients.
The mean age of the 471 patients included in the analysis was 38 years. The majority (67.9%) were female and had primary (68.8%) APS. Triple therapy was given to about 40% of patients who experienced CAPS, with about 57% receiving other combinations of drugs and 2.5% receiving no treatment for CAPS.
Overall, 177 of the 487 (36.3%) episodes of CAPS were fatal.
“Triple therapy was associated with a higher chance of survival when compared to other combinations or to none of these treatments,” Dr. Rodríguez-Pintó said.
While 28% of patients with CAPS died in the triple therapy group, mortality was 41% with other combinations of treatments and 75% with none of these treatments.
All-cause mortality was reduced by 47% with triple therapy, compared with none of these treatments. The adjusted odds ratio (aOR) when comparing survival between triple therapy and no treatment was 7.7, with a 95% confidence interval of 2.0 to 29.7. The aOR comparing other drug combinations versus none of these treatments was 6.8 (95% CI, 1.7-29.6).
“For a long time, we have been saying that triple therapy would probably be the best approach, but we had no firm evidence,” Dr. Rodríguez-Pintó said.
“So, this is the first time that we have clear clinical evidence of the benefit of these approaches, and I think that these results are important because they will give us more confidence in how we treat patients and help develop guidance on [the treatment’s] use in the future.”
Guidelines
A steering committee composed of representatives from the European Commission–funded RARE-BestPractices project and McMaster University in Hamilton, Ont., used GRADE methodology to develop the guidelines for CAPS diagnosis and management. The committee answered three diagnostic and seven treatment questions that originated from a panel of 19 international stakeholders, including Dr. Rodríguez-Pintó, through systematic reviews of the literature that used Cochrane criteria.
Although the review of studies did not include the study of CAPS Registry data that Dr. Rodríguez-Pintó and his colleagues conducted, he said that the recommendations still confirm the value of using a triple therapy approach to treatment.
The panel created three diagnostic recommendations for patients suspected of having CAPS, all of which were conditional and based on very low certainty of evidence: use preliminary CAPS classification criteria to diagnose CAPS; use or nonuse of biopsy, depending on the circumstances, because of its high specificity but possibly low sensitivity for thrombotic microangiopathy; and test for antiphospholipid antibodies, which should not delay initiation of treatment.
All seven first-line treatment recommendations that the panel developed relied on a very low certainty of evidence, and most were conditional:
- Triple therapy combination treatment with corticosteroids, heparin, and plasma exchange or intravenous immunoglobulins instead of a single agent or other combination treatments.
- Therapeutic dose anticoagulation was one of only two treatment recommendations to be considered “strong,” but use of direct oral anticoagulants is not advised.
- Therapeutic plasma exchange is recommended for use with other therapies and should be strongly considered for patients with microangiopathic hemolytic anemia.
- Intravenous immunoglobulin is advised for use in conjunction with other therapies and should be given special consideration for patients with immune thrombocytopenia or renal insufficiency.
- Antiplatelet agents are conditionally recommended as an add-on therapy, but their potential mortality benefit is tempered by increased risk of bleeding when used with anticoagulants. Strong consideration should be given to their use as an alternative therapy to anticoagulation when anticoagulation is contraindicated for a reason other than bleeding.
- Rituximab (Rituxan) should not be used because of little available data on its use, uncertainty regarding long-term consequences, and its expense – except for refractory cases where other therapies have been insufficient.
- Corticosteroids should not be used because of their lack of efficacy in CAPS when used alone and potential for adverse effects, except for certain circumstances where they may be indicated.
The authors of the guidelines emphasized that these recommendations are not meant to apply to every CAPS patient. They also noted that the available evidence did not allow for temporal analysis of treatments and that conclusions could not be drawn regarding “first-line” versus “second-line” therapies.
None of the authors of the registry study or the guidelines had relevant conflicts of interest to declare.
MADRID – Catastrophic antiphospholipid syndrome (CAPS) is associated with a high mortality rate, but new research presented at the European Congress of Rheumatology shows that patient survival can be significantly improved by a triple therapy treatment approach.
Researchers at the Congress also presented clinical practice guidelines for the diagnosis and management of the rare disease, which accounts for just 1% of patients with antiphospholipid syndrome (APS).
CAPS is characterized by a fast onset of widespread thrombosis, mainly in the small vessels, and, often, microangiopathic hemolytic anemia is seen in the laboratory. If undiagnosed or left untreated, patients may present with multiorgan failure needing intensive care treatment, which can be fatal in up to 50% of cases.
At the Congress, Ignasi Rodríguez-Pintó, MD, presented new data from the CAPS Registry that looks at the combined effect of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins on the survival of patients with CAPS as well as the new clinical practice guidelines.
CAPS Registry study
The aim of the study Dr. Rodríguez-Pintó presented on behalf of the CAPS Registry Project Group was to determine what, if any, survival benefit would be incurred from a triple therapy approach when compared with other different combinations of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins, or none of these treatments.
Although the triple therapy treatment approach is already being used in practice, its use is largely empirical, Dr. Rodríguez-Pintó of the department of autoimmune disease at the Hospital Clinic, Barcelona, explained in a video interview.
The investigators derived their data from episodes of CAPS occurring in patients in the CAPS Registry from the European Forum on Antiphospholipid Antibodies. This international registry was set up in 2000 and has been assembling the clinical, laboratory, and therapeutic findings of patients with CAPS for almost 20 years.
“We observed 525 episodes of CAPS in 502 patients. That means that some patients had two to three episodes of CAPS,” Dr. Rodríguez-Pintó said. Data on 38 episodes of CAPS had to be excluded from the analysis because of missing information, which left 487 episodes occurring in 471 patients.
The mean age of the 471 patients included in the analysis was 38 years. The majority (67.9%) were female and had primary (68.8%) APS. Triple therapy was given to about 40% of patients who experienced CAPS, with about 57% receiving other combinations of drugs and 2.5% receiving no treatment for CAPS.
Overall, 177 of the 487 (36.3%) episodes of CAPS were fatal.
“Triple therapy was associated with a higher chance of survival when compared to other combinations or to none of these treatments,” Dr. Rodríguez-Pintó said.
While 28% of patients with CAPS died in the triple therapy group, mortality was 41% with other combinations of treatments and 75% with none of these treatments.
All-cause mortality was reduced by 47% with triple therapy, compared with none of these treatments. The adjusted odds ratio (aOR) when comparing survival between triple therapy and no treatment was 7.7, with a 95% confidence interval of 2.0 to 29.7. The aOR comparing other drug combinations versus none of these treatments was 6.8 (95% CI, 1.7-29.6).
“For a long time, we have been saying that triple therapy would probably be the best approach, but we had no firm evidence,” Dr. Rodríguez-Pintó said.
“So, this is the first time that we have clear clinical evidence of the benefit of these approaches, and I think that these results are important because they will give us more confidence in how we treat patients and help develop guidance on [the treatment’s] use in the future.”
Guidelines
A steering committee composed of representatives from the European Commission–funded RARE-BestPractices project and McMaster University in Hamilton, Ont., used GRADE methodology to develop the guidelines for CAPS diagnosis and management. The committee answered three diagnostic and seven treatment questions that originated from a panel of 19 international stakeholders, including Dr. Rodríguez-Pintó, through systematic reviews of the literature that used Cochrane criteria.
Although the review of studies did not include the study of CAPS Registry data that Dr. Rodríguez-Pintó and his colleagues conducted, he said that the recommendations still confirm the value of using a triple therapy approach to treatment.
The panel created three diagnostic recommendations for patients suspected of having CAPS, all of which were conditional and based on very low certainty of evidence: use preliminary CAPS classification criteria to diagnose CAPS; use or nonuse of biopsy, depending on the circumstances, because of its high specificity but possibly low sensitivity for thrombotic microangiopathy; and test for antiphospholipid antibodies, which should not delay initiation of treatment.
All seven first-line treatment recommendations that the panel developed relied on a very low certainty of evidence, and most were conditional:
- Triple therapy combination treatment with corticosteroids, heparin, and plasma exchange or intravenous immunoglobulins instead of a single agent or other combination treatments.
- Therapeutic dose anticoagulation was one of only two treatment recommendations to be considered “strong,” but use of direct oral anticoagulants is not advised.
- Therapeutic plasma exchange is recommended for use with other therapies and should be strongly considered for patients with microangiopathic hemolytic anemia.
- Intravenous immunoglobulin is advised for use in conjunction with other therapies and should be given special consideration for patients with immune thrombocytopenia or renal insufficiency.
- Antiplatelet agents are conditionally recommended as an add-on therapy, but their potential mortality benefit is tempered by increased risk of bleeding when used with anticoagulants. Strong consideration should be given to their use as an alternative therapy to anticoagulation when anticoagulation is contraindicated for a reason other than bleeding.
- Rituximab (Rituxan) should not be used because of little available data on its use, uncertainty regarding long-term consequences, and its expense – except for refractory cases where other therapies have been insufficient.
- Corticosteroids should not be used because of their lack of efficacy in CAPS when used alone and potential for adverse effects, except for certain circumstances where they may be indicated.
The authors of the guidelines emphasized that these recommendations are not meant to apply to every CAPS patient. They also noted that the available evidence did not allow for temporal analysis of treatments and that conclusions could not be drawn regarding “first-line” versus “second-line” therapies.
None of the authors of the registry study or the guidelines had relevant conflicts of interest to declare.
AT THE EULAR 2017 CONGRESS
Key clinical point:
Major finding: Mortality was 28% with triple therapy, 41% with other combinations of treatments, and 75% with none of these treatments.
Data source: A registry study of 471 CAPS patients and clinical practice guidelines for CAPS.
Disclosures: None of the authors of the registry study or the guidelines had relevant conflicts of interest to declare.