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What 2019’s top five CAD trials tell us
SNOWMASS, COLO. – A repeated theme threading through much of one prominent interventional cardiologist’s personal list of the top five coronary artery disease (CAD) trials of the past year is that aspirin is very often more trouble than it’s worth.
“For some years I’ve been concerned that the only thing that aspirin does [in patients after percutaneous coronary intervention] is increase your risk of bleeding. It doesn’t really provide any additional ischemic protection,” Malcolm R. Bell, MBBS, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“I’ll remind you that, when we go back to the early stent days, observed Dr. Bell, professor of medicine and vice chair of the department of cardiovascular medicine at the Mayo Clinic in Rochester, Minn.
Here are the key takeaway messages from his five most important randomized trials in CAD during the last year.
AUGUSTUS
For years, cardiologists have grappled with how to best manage high-cardiovascular-risk patients with atrial fibrillation who seem like they might benefit from triple-antithrombotic therapy. AUGUSTUS supplied the answer: Don’t do it. Skip the aspirin and turn instead to a P2Y12 inhibitor plus a non–vitamin K antagonist oral anticoagulant (NOAC), rather than warfarin.
“I would like you to think of triple therapy as a triple threat. That’s really what triple therapy is all about”– a three-pronged threat to patient safety, Dr. Bell commented.
In AUGUSTUS, 4,614 patients with atrial fibrillation and CAD with an acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) in 33 countries were placed on a P2Y12 inhibitor – most often clopidogrel – and randomized double blind to either apixaban (Eliquis) or warfarin, and further to aspirin or placebo, for 6 months of antithrombotic therapy. The strategy of a P2Y12 inhibitor and apixaban without aspirin was the clear winner, resulting in significantly less major bleeding, mortality, and hospitalizations than treatment with a P2Y12 inhibitor and warfarin, with or without aspirin. Most importantly, ischemic event rates didn’t differ between the apixaban and warfarin groups. And patients randomized to aspirin had rates of ischemic events and death or hospitalization similar to placebo-treated controls, meaning aspirin accomplished nothing (N Engl J Med. 2019 Apr 18;380[16]:1509-24).
Dr. Bell noted that a meta-analysis of AUGUSTUS and three smaller randomized trials including more than 10,000 AUGUSTUS-type patients with atrial fibrillation concluded that a treatment strategy utilizing a NOAC and a P2Y12 inhibitor resulted in less bleeding than warfarin plus DAPT, and at no cost in terms of excess ischemic events. Moreover, regimens without aspirin resulted in less intracranial and other major bleeding without any difference in major adverse cardiovascular events (JAMA Cardiol. 2019 Jun 19. doi: 10.1001/jamacardio.2019.1880).
A key message of these four trials is that a NOAC is preferable to warfarin, so much so that, in high-risk patients who are already on warfarin, it’s worth considering a switch to a NOAC.
“And we should really be avoiding DAPT,” Dr. Bell added.
How soon after an ACS and/or PCI should patients with atrial fibrillation stop taking aspirin?
“In AUGUSTUS, randomization occurred at a median of 6 days, so we know that half the patients stopped their aspirin by then. In our own practice, we’re just dropping the aspirin for the most part before the patient leaves the hospital. I think if you leave them with instructions to stop the aspirin in a week’s time or a month’s time it just leads to confusion. And we should also remember that half of the major bleeding after PCI or ACS happens in the first 30 days, so it doesn’t make a lot of sense to say that we should continue it for a month and then drop it,” according to the cardiologist.
SMART-CHOICE and STOPDAPT-2
These two large multicenter studies demonstrate that DAPT can safely be stopped early if needed. SMART-CHOICE from South Korea and STOPDAPT-2 from Japan each randomized roughly 3,000 patients undergoing PCI to 12 months of DAPT or to DAPT for only 3 months or 1 month, respectively, at which point the aspirin was dropped and patients in the abbreviated DAPT arm continued on P2Y12 inhibitor monotherapy, mostly clopidogrel, for the remainder of the 12 months. In the Japanese STOPDAPT-2 trial, 1 month of DAPT proved superior to 12 months of DAPT for the primary composite endpoint of cardiovascular death, MI, stroke, definite stent thrombosis, or major or minor bleeding at 12 months (JAMA. 2019 Jun 25;321[24]:2414-27). In the South Korean SMART-CHOICE trial, 3 months of DAPT was noninferior to 12 months for major adverse cardiac and cerebrovascular events, and superior in terms of bleeding risk (JAMA. 2019 Jun 25;321[24]:2428-37). Of note, roughly half of patients in the two trials were lower-risk individuals undergoing PCI for stable angina.
Dr. Bell noted that, while the TWILIGHT trial (Ticagrelor With or Without Aspirin in High-Risk Patients After PCI) didn’t make his top-five list, it certainly fits well with the two East Asian studies. The TWILIGHT investigators randomized more than 7,000 patients to 12 months of DAPT or discontinuation of aspirin after 3 months. The result: a lower incidence of clinically relevant bleeding with ticagrelor monotherapy, and with no increased risk of death, MI, or stroke, compared with 12 months of DAPT (N Engl J Med. 2019 Nov 21;381[21]:2032-42).
“Again, I would just question what the added value of aspirin is here,” Dr. Bell commented. “Many interventional cardiologists are absolutely terrified of their patients having stent thrombosis, but with second-generation drug-eluting stents – the stents we’re putting in day in and day out – the risk of stent thrombosis is less than 1%. And in these two trials it was less than 0.5%. There’s more risk of having major bleeding events than there is of ischemia, so I think the balance is in favor of preventing bleeding. We know that major bleeding predicts short- and long-term mortality.”
COLCOT
This double-blind trial randomized 4,745 patients within 30 days post MI to low-dose colchicine or placebo on top of excellent rates of background guideline-directed medical therapy. The goal was to see if this anti-inflammatory agent could reduce cardiovascular events independent of any lipid-lowering effect, as was earlier seen with canakinumab in the CANTOS trial. It did so to a statistically significant but relatively modest degree, with a 5.5% rate of the composite cardiovascular events endpoint in the colchicine group and 7.1% in placebo-treated controls (N Engl J Med. 2019 Dec 26;381[26]:2497-505). But Dr. Bell was unimpressed.
“All-cause mortality was identical at 1.8% in both groups. So colchicine is not saving lives. In fact, the only real differences were in stroke – but the study wasn’t powered to look at stroke – and in urgent hospitalization for angina leading to revascularization, which is a soft endpoint,” he observed.
Plus, 2.5% of patients were lost to follow-up, which Dr. Bell considers “a little concerning” in a trial conducted in the current era.
“In my opinion, the evidence that colchicine is effective is weak, and I don’t think really supports the drug’s routine use post MI. We already send these patients out on numerous medications. We have to think about cost/benefit, and if a patient asks me: ‘Is this going to prevent another heart attack or make me live longer?’ I think the unequivocal answer is no,” he said.
These days colchicine is no longer an inexpensive drug, either, at an average cost of $300-$400 per month, the cardiologist added.
COMPLETE
This study randomized more than 4,000 patients with ST-segment elevation MI (STEMI) and multivessel disease to primary PCI of the culprit lesion only or to staged complete revascularization via PCI of all angiographically significant nonculprit lesions. Complete revascularization proved to be the superior strategy, with a 26% reduction in the risk of the composite of cardiovascular death or MI at a median of 3 years (N Engl J Med. 2019 Oct 10;381[15]:1411-21).
The optimal timing of the staged procedure remains unclear, since the study didn’t specify a protocol.
“I’m still a bit uncomfortable doing multivessel PCI at 2 o’clock in the morning in the setting of STEMI in someone I’ve never met before. I don’t think there’s a rush to do anything then. Often in this middle-of-the-night stuff, we miss things or we overinterpret things. I think it’s better to let the patient cool down, get to know them,” according to Dr. Bell.
EXCEL
Publication of the 5-year outcomes of the largest-ever randomized trial of PCI versus coronary artery bypass grafting (CABG) for left main coronary disease has led to furious controversy, with a few of the surgeons involved in the study opting to publically broadcast allegations of misbehavior on the part of the interventional cardiologist study leadership, charges that have been strongly denied.
The actual results are in line with findings reported from smaller randomized trials. At 5 years in EXCEL, there was no significant difference between the PCI and CABG groups in the primary composite endpoint of death, cerebrovascular accident, or MI (N Engl J Med. 2019 Nov 7;381[19]:1820-30). The all-cause mortality rate was 13% in the PCI arm and 9.9% with CABG, but this finding comes with a caveat.
“I’ll emphasize this trial was never powered to look at mortality. Neither were any of the other randomized trials. On the other hand, I don’t think you can necessarily ignore the finding of an absolute 3.1% difference,” Dr. Bell said.
PCI and CABG are both very good, mature therapies for left main disease, in his view. In the setting of more-complex coronary disease in younger patients, he often views the complete revascularization offered by surgery as the preferred option. On the other hand, in an 80-year-old with severe comorbidities, clearly PCI is attractive.
He considers the highly public nature of this interspecialty spat a regrettable black eye for the entire field of cardiovascular medicine. And he predicted that an ongoing outside neutral-party review of the study data and procedures will conclude, as he has, “there was no malfeasance at all in the trial.”
Dr. Bell reported having no financial conflicts regarding his presentation.
SNOWMASS, COLO. – A repeated theme threading through much of one prominent interventional cardiologist’s personal list of the top five coronary artery disease (CAD) trials of the past year is that aspirin is very often more trouble than it’s worth.
“For some years I’ve been concerned that the only thing that aspirin does [in patients after percutaneous coronary intervention] is increase your risk of bleeding. It doesn’t really provide any additional ischemic protection,” Malcolm R. Bell, MBBS, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“I’ll remind you that, when we go back to the early stent days, observed Dr. Bell, professor of medicine and vice chair of the department of cardiovascular medicine at the Mayo Clinic in Rochester, Minn.
Here are the key takeaway messages from his five most important randomized trials in CAD during the last year.
AUGUSTUS
For years, cardiologists have grappled with how to best manage high-cardiovascular-risk patients with atrial fibrillation who seem like they might benefit from triple-antithrombotic therapy. AUGUSTUS supplied the answer: Don’t do it. Skip the aspirin and turn instead to a P2Y12 inhibitor plus a non–vitamin K antagonist oral anticoagulant (NOAC), rather than warfarin.
“I would like you to think of triple therapy as a triple threat. That’s really what triple therapy is all about”– a three-pronged threat to patient safety, Dr. Bell commented.
In AUGUSTUS, 4,614 patients with atrial fibrillation and CAD with an acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) in 33 countries were placed on a P2Y12 inhibitor – most often clopidogrel – and randomized double blind to either apixaban (Eliquis) or warfarin, and further to aspirin or placebo, for 6 months of antithrombotic therapy. The strategy of a P2Y12 inhibitor and apixaban without aspirin was the clear winner, resulting in significantly less major bleeding, mortality, and hospitalizations than treatment with a P2Y12 inhibitor and warfarin, with or without aspirin. Most importantly, ischemic event rates didn’t differ between the apixaban and warfarin groups. And patients randomized to aspirin had rates of ischemic events and death or hospitalization similar to placebo-treated controls, meaning aspirin accomplished nothing (N Engl J Med. 2019 Apr 18;380[16]:1509-24).
Dr. Bell noted that a meta-analysis of AUGUSTUS and three smaller randomized trials including more than 10,000 AUGUSTUS-type patients with atrial fibrillation concluded that a treatment strategy utilizing a NOAC and a P2Y12 inhibitor resulted in less bleeding than warfarin plus DAPT, and at no cost in terms of excess ischemic events. Moreover, regimens without aspirin resulted in less intracranial and other major bleeding without any difference in major adverse cardiovascular events (JAMA Cardiol. 2019 Jun 19. doi: 10.1001/jamacardio.2019.1880).
A key message of these four trials is that a NOAC is preferable to warfarin, so much so that, in high-risk patients who are already on warfarin, it’s worth considering a switch to a NOAC.
“And we should really be avoiding DAPT,” Dr. Bell added.
How soon after an ACS and/or PCI should patients with atrial fibrillation stop taking aspirin?
“In AUGUSTUS, randomization occurred at a median of 6 days, so we know that half the patients stopped their aspirin by then. In our own practice, we’re just dropping the aspirin for the most part before the patient leaves the hospital. I think if you leave them with instructions to stop the aspirin in a week’s time or a month’s time it just leads to confusion. And we should also remember that half of the major bleeding after PCI or ACS happens in the first 30 days, so it doesn’t make a lot of sense to say that we should continue it for a month and then drop it,” according to the cardiologist.
SMART-CHOICE and STOPDAPT-2
These two large multicenter studies demonstrate that DAPT can safely be stopped early if needed. SMART-CHOICE from South Korea and STOPDAPT-2 from Japan each randomized roughly 3,000 patients undergoing PCI to 12 months of DAPT or to DAPT for only 3 months or 1 month, respectively, at which point the aspirin was dropped and patients in the abbreviated DAPT arm continued on P2Y12 inhibitor monotherapy, mostly clopidogrel, for the remainder of the 12 months. In the Japanese STOPDAPT-2 trial, 1 month of DAPT proved superior to 12 months of DAPT for the primary composite endpoint of cardiovascular death, MI, stroke, definite stent thrombosis, or major or minor bleeding at 12 months (JAMA. 2019 Jun 25;321[24]:2414-27). In the South Korean SMART-CHOICE trial, 3 months of DAPT was noninferior to 12 months for major adverse cardiac and cerebrovascular events, and superior in terms of bleeding risk (JAMA. 2019 Jun 25;321[24]:2428-37). Of note, roughly half of patients in the two trials were lower-risk individuals undergoing PCI for stable angina.
Dr. Bell noted that, while the TWILIGHT trial (Ticagrelor With or Without Aspirin in High-Risk Patients After PCI) didn’t make his top-five list, it certainly fits well with the two East Asian studies. The TWILIGHT investigators randomized more than 7,000 patients to 12 months of DAPT or discontinuation of aspirin after 3 months. The result: a lower incidence of clinically relevant bleeding with ticagrelor monotherapy, and with no increased risk of death, MI, or stroke, compared with 12 months of DAPT (N Engl J Med. 2019 Nov 21;381[21]:2032-42).
“Again, I would just question what the added value of aspirin is here,” Dr. Bell commented. “Many interventional cardiologists are absolutely terrified of their patients having stent thrombosis, but with second-generation drug-eluting stents – the stents we’re putting in day in and day out – the risk of stent thrombosis is less than 1%. And in these two trials it was less than 0.5%. There’s more risk of having major bleeding events than there is of ischemia, so I think the balance is in favor of preventing bleeding. We know that major bleeding predicts short- and long-term mortality.”
COLCOT
This double-blind trial randomized 4,745 patients within 30 days post MI to low-dose colchicine or placebo on top of excellent rates of background guideline-directed medical therapy. The goal was to see if this anti-inflammatory agent could reduce cardiovascular events independent of any lipid-lowering effect, as was earlier seen with canakinumab in the CANTOS trial. It did so to a statistically significant but relatively modest degree, with a 5.5% rate of the composite cardiovascular events endpoint in the colchicine group and 7.1% in placebo-treated controls (N Engl J Med. 2019 Dec 26;381[26]:2497-505). But Dr. Bell was unimpressed.
“All-cause mortality was identical at 1.8% in both groups. So colchicine is not saving lives. In fact, the only real differences were in stroke – but the study wasn’t powered to look at stroke – and in urgent hospitalization for angina leading to revascularization, which is a soft endpoint,” he observed.
Plus, 2.5% of patients were lost to follow-up, which Dr. Bell considers “a little concerning” in a trial conducted in the current era.
“In my opinion, the evidence that colchicine is effective is weak, and I don’t think really supports the drug’s routine use post MI. We already send these patients out on numerous medications. We have to think about cost/benefit, and if a patient asks me: ‘Is this going to prevent another heart attack or make me live longer?’ I think the unequivocal answer is no,” he said.
These days colchicine is no longer an inexpensive drug, either, at an average cost of $300-$400 per month, the cardiologist added.
COMPLETE
This study randomized more than 4,000 patients with ST-segment elevation MI (STEMI) and multivessel disease to primary PCI of the culprit lesion only or to staged complete revascularization via PCI of all angiographically significant nonculprit lesions. Complete revascularization proved to be the superior strategy, with a 26% reduction in the risk of the composite of cardiovascular death or MI at a median of 3 years (N Engl J Med. 2019 Oct 10;381[15]:1411-21).
The optimal timing of the staged procedure remains unclear, since the study didn’t specify a protocol.
“I’m still a bit uncomfortable doing multivessel PCI at 2 o’clock in the morning in the setting of STEMI in someone I’ve never met before. I don’t think there’s a rush to do anything then. Often in this middle-of-the-night stuff, we miss things or we overinterpret things. I think it’s better to let the patient cool down, get to know them,” according to Dr. Bell.
EXCEL
Publication of the 5-year outcomes of the largest-ever randomized trial of PCI versus coronary artery bypass grafting (CABG) for left main coronary disease has led to furious controversy, with a few of the surgeons involved in the study opting to publically broadcast allegations of misbehavior on the part of the interventional cardiologist study leadership, charges that have been strongly denied.
The actual results are in line with findings reported from smaller randomized trials. At 5 years in EXCEL, there was no significant difference between the PCI and CABG groups in the primary composite endpoint of death, cerebrovascular accident, or MI (N Engl J Med. 2019 Nov 7;381[19]:1820-30). The all-cause mortality rate was 13% in the PCI arm and 9.9% with CABG, but this finding comes with a caveat.
“I’ll emphasize this trial was never powered to look at mortality. Neither were any of the other randomized trials. On the other hand, I don’t think you can necessarily ignore the finding of an absolute 3.1% difference,” Dr. Bell said.
PCI and CABG are both very good, mature therapies for left main disease, in his view. In the setting of more-complex coronary disease in younger patients, he often views the complete revascularization offered by surgery as the preferred option. On the other hand, in an 80-year-old with severe comorbidities, clearly PCI is attractive.
He considers the highly public nature of this interspecialty spat a regrettable black eye for the entire field of cardiovascular medicine. And he predicted that an ongoing outside neutral-party review of the study data and procedures will conclude, as he has, “there was no malfeasance at all in the trial.”
Dr. Bell reported having no financial conflicts regarding his presentation.
SNOWMASS, COLO. – A repeated theme threading through much of one prominent interventional cardiologist’s personal list of the top five coronary artery disease (CAD) trials of the past year is that aspirin is very often more trouble than it’s worth.
“For some years I’ve been concerned that the only thing that aspirin does [in patients after percutaneous coronary intervention] is increase your risk of bleeding. It doesn’t really provide any additional ischemic protection,” Malcolm R. Bell, MBBS, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“I’ll remind you that, when we go back to the early stent days, observed Dr. Bell, professor of medicine and vice chair of the department of cardiovascular medicine at the Mayo Clinic in Rochester, Minn.
Here are the key takeaway messages from his five most important randomized trials in CAD during the last year.
AUGUSTUS
For years, cardiologists have grappled with how to best manage high-cardiovascular-risk patients with atrial fibrillation who seem like they might benefit from triple-antithrombotic therapy. AUGUSTUS supplied the answer: Don’t do it. Skip the aspirin and turn instead to a P2Y12 inhibitor plus a non–vitamin K antagonist oral anticoagulant (NOAC), rather than warfarin.
“I would like you to think of triple therapy as a triple threat. That’s really what triple therapy is all about”– a three-pronged threat to patient safety, Dr. Bell commented.
In AUGUSTUS, 4,614 patients with atrial fibrillation and CAD with an acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) in 33 countries were placed on a P2Y12 inhibitor – most often clopidogrel – and randomized double blind to either apixaban (Eliquis) or warfarin, and further to aspirin or placebo, for 6 months of antithrombotic therapy. The strategy of a P2Y12 inhibitor and apixaban without aspirin was the clear winner, resulting in significantly less major bleeding, mortality, and hospitalizations than treatment with a P2Y12 inhibitor and warfarin, with or without aspirin. Most importantly, ischemic event rates didn’t differ between the apixaban and warfarin groups. And patients randomized to aspirin had rates of ischemic events and death or hospitalization similar to placebo-treated controls, meaning aspirin accomplished nothing (N Engl J Med. 2019 Apr 18;380[16]:1509-24).
Dr. Bell noted that a meta-analysis of AUGUSTUS and three smaller randomized trials including more than 10,000 AUGUSTUS-type patients with atrial fibrillation concluded that a treatment strategy utilizing a NOAC and a P2Y12 inhibitor resulted in less bleeding than warfarin plus DAPT, and at no cost in terms of excess ischemic events. Moreover, regimens without aspirin resulted in less intracranial and other major bleeding without any difference in major adverse cardiovascular events (JAMA Cardiol. 2019 Jun 19. doi: 10.1001/jamacardio.2019.1880).
A key message of these four trials is that a NOAC is preferable to warfarin, so much so that, in high-risk patients who are already on warfarin, it’s worth considering a switch to a NOAC.
“And we should really be avoiding DAPT,” Dr. Bell added.
How soon after an ACS and/or PCI should patients with atrial fibrillation stop taking aspirin?
“In AUGUSTUS, randomization occurred at a median of 6 days, so we know that half the patients stopped their aspirin by then. In our own practice, we’re just dropping the aspirin for the most part before the patient leaves the hospital. I think if you leave them with instructions to stop the aspirin in a week’s time or a month’s time it just leads to confusion. And we should also remember that half of the major bleeding after PCI or ACS happens in the first 30 days, so it doesn’t make a lot of sense to say that we should continue it for a month and then drop it,” according to the cardiologist.
SMART-CHOICE and STOPDAPT-2
These two large multicenter studies demonstrate that DAPT can safely be stopped early if needed. SMART-CHOICE from South Korea and STOPDAPT-2 from Japan each randomized roughly 3,000 patients undergoing PCI to 12 months of DAPT or to DAPT for only 3 months or 1 month, respectively, at which point the aspirin was dropped and patients in the abbreviated DAPT arm continued on P2Y12 inhibitor monotherapy, mostly clopidogrel, for the remainder of the 12 months. In the Japanese STOPDAPT-2 trial, 1 month of DAPT proved superior to 12 months of DAPT for the primary composite endpoint of cardiovascular death, MI, stroke, definite stent thrombosis, or major or minor bleeding at 12 months (JAMA. 2019 Jun 25;321[24]:2414-27). In the South Korean SMART-CHOICE trial, 3 months of DAPT was noninferior to 12 months for major adverse cardiac and cerebrovascular events, and superior in terms of bleeding risk (JAMA. 2019 Jun 25;321[24]:2428-37). Of note, roughly half of patients in the two trials were lower-risk individuals undergoing PCI for stable angina.
Dr. Bell noted that, while the TWILIGHT trial (Ticagrelor With or Without Aspirin in High-Risk Patients After PCI) didn’t make his top-five list, it certainly fits well with the two East Asian studies. The TWILIGHT investigators randomized more than 7,000 patients to 12 months of DAPT or discontinuation of aspirin after 3 months. The result: a lower incidence of clinically relevant bleeding with ticagrelor monotherapy, and with no increased risk of death, MI, or stroke, compared with 12 months of DAPT (N Engl J Med. 2019 Nov 21;381[21]:2032-42).
“Again, I would just question what the added value of aspirin is here,” Dr. Bell commented. “Many interventional cardiologists are absolutely terrified of their patients having stent thrombosis, but with second-generation drug-eluting stents – the stents we’re putting in day in and day out – the risk of stent thrombosis is less than 1%. And in these two trials it was less than 0.5%. There’s more risk of having major bleeding events than there is of ischemia, so I think the balance is in favor of preventing bleeding. We know that major bleeding predicts short- and long-term mortality.”
COLCOT
This double-blind trial randomized 4,745 patients within 30 days post MI to low-dose colchicine or placebo on top of excellent rates of background guideline-directed medical therapy. The goal was to see if this anti-inflammatory agent could reduce cardiovascular events independent of any lipid-lowering effect, as was earlier seen with canakinumab in the CANTOS trial. It did so to a statistically significant but relatively modest degree, with a 5.5% rate of the composite cardiovascular events endpoint in the colchicine group and 7.1% in placebo-treated controls (N Engl J Med. 2019 Dec 26;381[26]:2497-505). But Dr. Bell was unimpressed.
“All-cause mortality was identical at 1.8% in both groups. So colchicine is not saving lives. In fact, the only real differences were in stroke – but the study wasn’t powered to look at stroke – and in urgent hospitalization for angina leading to revascularization, which is a soft endpoint,” he observed.
Plus, 2.5% of patients were lost to follow-up, which Dr. Bell considers “a little concerning” in a trial conducted in the current era.
“In my opinion, the evidence that colchicine is effective is weak, and I don’t think really supports the drug’s routine use post MI. We already send these patients out on numerous medications. We have to think about cost/benefit, and if a patient asks me: ‘Is this going to prevent another heart attack or make me live longer?’ I think the unequivocal answer is no,” he said.
These days colchicine is no longer an inexpensive drug, either, at an average cost of $300-$400 per month, the cardiologist added.
COMPLETE
This study randomized more than 4,000 patients with ST-segment elevation MI (STEMI) and multivessel disease to primary PCI of the culprit lesion only or to staged complete revascularization via PCI of all angiographically significant nonculprit lesions. Complete revascularization proved to be the superior strategy, with a 26% reduction in the risk of the composite of cardiovascular death or MI at a median of 3 years (N Engl J Med. 2019 Oct 10;381[15]:1411-21).
The optimal timing of the staged procedure remains unclear, since the study didn’t specify a protocol.
“I’m still a bit uncomfortable doing multivessel PCI at 2 o’clock in the morning in the setting of STEMI in someone I’ve never met before. I don’t think there’s a rush to do anything then. Often in this middle-of-the-night stuff, we miss things or we overinterpret things. I think it’s better to let the patient cool down, get to know them,” according to Dr. Bell.
EXCEL
Publication of the 5-year outcomes of the largest-ever randomized trial of PCI versus coronary artery bypass grafting (CABG) for left main coronary disease has led to furious controversy, with a few of the surgeons involved in the study opting to publically broadcast allegations of misbehavior on the part of the interventional cardiologist study leadership, charges that have been strongly denied.
The actual results are in line with findings reported from smaller randomized trials. At 5 years in EXCEL, there was no significant difference between the PCI and CABG groups in the primary composite endpoint of death, cerebrovascular accident, or MI (N Engl J Med. 2019 Nov 7;381[19]:1820-30). The all-cause mortality rate was 13% in the PCI arm and 9.9% with CABG, but this finding comes with a caveat.
“I’ll emphasize this trial was never powered to look at mortality. Neither were any of the other randomized trials. On the other hand, I don’t think you can necessarily ignore the finding of an absolute 3.1% difference,” Dr. Bell said.
PCI and CABG are both very good, mature therapies for left main disease, in his view. In the setting of more-complex coronary disease in younger patients, he often views the complete revascularization offered by surgery as the preferred option. On the other hand, in an 80-year-old with severe comorbidities, clearly PCI is attractive.
He considers the highly public nature of this interspecialty spat a regrettable black eye for the entire field of cardiovascular medicine. And he predicted that an ongoing outside neutral-party review of the study data and procedures will conclude, as he has, “there was no malfeasance at all in the trial.”
Dr. Bell reported having no financial conflicts regarding his presentation.
REPORTING FROM ACC SNOWMASS 2020
Vigilance safely keeps AFib patients off anticoagulants post ablation
NATIONAL HARBOR, MD. – A pilot program of daily arrhythmia self-vigilance has allowed selected patients with no atrial fibrillation following a catheter ablation procedure to safely come off a regimen of daily oral anticoagulation despite having residual risk factors for ischemic stroke.
This program, which started several years ago at the University of Pennsylvania in Philadelphia, has now managed 190 patients and followed them for a median of just over 3 years, and during 576 patient-years of follow-up, just a single patient had an ischemic cerebrovascular event that occurred with no atrial fibrillation (AFib) recurrence and appeared to be caused by an atherosclerotic embolism, Francis E. Marchlinski, MD, said at the annual International AF Symposium.
Although this strategy has not yet been tested in a prospective, randomized trial, this anecdotal, single-center experience suggests that the approach is “safe and effective” for selected patients who are eager to come off of their anticoagulation regimen when they remain arrhythmia free following catheter ablation of their AFib, said Dr. Marchlinski, professor of medicine and director of electrophysiology at the University of Pennsylvania. He and his associates developed this strategy as a way to more safely allow these patients to stop taking a daily oral anticoagulant because he found that many patients were stopping on their own, with no safety strategy in place.
“Patients tell me they don’t want to be on an oral anticoagulant because a parent had a hemorrhagic stroke, and they say they’re willing to accept the risk” of having an ischemic stroke by coming off anticoagulation. “This is a way for them to do it safely,” Dr. Marchlinski said in an interview. He stressed that he only allows his patients to go this route if they understand the risk and accept their shared responsibility for vigilant, twice-daily pulse monitoring to detect resumption of an irregular heart beat.
Since 2011, Dr. Marchlinski’s program ablated 1,216 patients with AFib who then remained arrhythmia free during 3 weeks of continuous ECG monitoring following their procedure. Among these patients, 443 had a CHA2DS2-VAScscore of either 0 (men) or 1 (women) that indicated no ongoing need for oral anticoagulation according to current guidelines. Of the remaining 773 patients with a CHA2DS2-VASc score of at least 1 in men and 2 in women, the clinicians determined 583 to be ineligible for the program because of their unwillingness to accept the risk, unwillingness to comply with daily pulse checks, a history of asymptomatic AFib, a CHA2DS2-VASc score greater than 4, or a resting pulse above 90 beats per minute, leaving 190 patients eligible to participate. Among these patients, 105 (55%) had a CHA2DS2-VASc score of 2-4, which should prompt anticoagulation according to current guidelines.Participating patients committed to check their resting pulse by palpation at least twice daily and to contacting the program immediately if their resting rate spiked by more than 20 beats per minutes or in another way seemed irregular. Patients were also instructed to restart their oral anticoagulation immediately if they experienced AFib symptoms that persisted for more than 5 minutes. Many patients in the program also use a wearable device (usually a watch) to monitor their resting pulse and to generate a 30-second ECG recording that they can send as an electronic file to the University of Pennsylvania staff. “We embrace wearables,” Dr. Marchlinski said. Those without a wearable can undergo transtelephonic EEG monitoring to document a suspected arrhythmia recurrence, and all patients undergo annual monitoring by continuous ECG for at least 2 weeks.During follow-up, in addition to the 1 patient free from recurrent AFib who had an atherosclerotic embolism, 34 patients resumed anticoagulant treatment because of AFib recurrence; 12 withdrew from the program because of noncompliance or preference, or because an exclusion appeared; 29 resumed oral anticoagulation transiently but then discontinued the drug a second time when their AFib recurrence resolved; and 114 patients (60% of the starting cohort of 190) remained completely off anticoagulation during a median of 37 months. These data updated a published report from Dr. Marchlinski and his associates on their first 99 patients followed for a median of 30 months (J Cardiovasc Electrophysiol. 2019 May;30[5]:631-8).
This experience underscored the need for ongoing rhythm monitoring even in the absence of AFib symptoms, as six patients developed asymptomatic AFib detected by monitoring, including one patient whose recurrence occurred 30 months after the ablation procedure.
Dr. Marchlinski stressed the stringent selection process he applies to limit this approach to patients who are willing to faithfully monitor their pulse and symptoms daily, and who accept the risk that this approach may pose and their responsibility to stay in contact with the clinical team. The program calls patients at the 6-month mark between annual monitoring to remind them of their need for daily attention.
“Being off anticoagulants is very important to these patients,” he explained, and he highlighted the added workload this strategy places on his staff. “I think this has legs” for adoption by other cardiac arrhythmia programs, “but it depends on the time the staff is willing to spend” monitoring and following these patients, some of whom regularly send in ECG traces from their wearable devices for assessment. “It takes a village” to make this program work, he said.
Dr. Marchlinski has been a consultant to or has received honoraria from Abbott EP/St. Jude, Biosense Webster, Biotronik, Boston Scientific, and Medtronic.
NATIONAL HARBOR, MD. – A pilot program of daily arrhythmia self-vigilance has allowed selected patients with no atrial fibrillation following a catheter ablation procedure to safely come off a regimen of daily oral anticoagulation despite having residual risk factors for ischemic stroke.
This program, which started several years ago at the University of Pennsylvania in Philadelphia, has now managed 190 patients and followed them for a median of just over 3 years, and during 576 patient-years of follow-up, just a single patient had an ischemic cerebrovascular event that occurred with no atrial fibrillation (AFib) recurrence and appeared to be caused by an atherosclerotic embolism, Francis E. Marchlinski, MD, said at the annual International AF Symposium.
Although this strategy has not yet been tested in a prospective, randomized trial, this anecdotal, single-center experience suggests that the approach is “safe and effective” for selected patients who are eager to come off of their anticoagulation regimen when they remain arrhythmia free following catheter ablation of their AFib, said Dr. Marchlinski, professor of medicine and director of electrophysiology at the University of Pennsylvania. He and his associates developed this strategy as a way to more safely allow these patients to stop taking a daily oral anticoagulant because he found that many patients were stopping on their own, with no safety strategy in place.
“Patients tell me they don’t want to be on an oral anticoagulant because a parent had a hemorrhagic stroke, and they say they’re willing to accept the risk” of having an ischemic stroke by coming off anticoagulation. “This is a way for them to do it safely,” Dr. Marchlinski said in an interview. He stressed that he only allows his patients to go this route if they understand the risk and accept their shared responsibility for vigilant, twice-daily pulse monitoring to detect resumption of an irregular heart beat.
Since 2011, Dr. Marchlinski’s program ablated 1,216 patients with AFib who then remained arrhythmia free during 3 weeks of continuous ECG monitoring following their procedure. Among these patients, 443 had a CHA2DS2-VAScscore of either 0 (men) or 1 (women) that indicated no ongoing need for oral anticoagulation according to current guidelines. Of the remaining 773 patients with a CHA2DS2-VASc score of at least 1 in men and 2 in women, the clinicians determined 583 to be ineligible for the program because of their unwillingness to accept the risk, unwillingness to comply with daily pulse checks, a history of asymptomatic AFib, a CHA2DS2-VASc score greater than 4, or a resting pulse above 90 beats per minute, leaving 190 patients eligible to participate. Among these patients, 105 (55%) had a CHA2DS2-VASc score of 2-4, which should prompt anticoagulation according to current guidelines.Participating patients committed to check their resting pulse by palpation at least twice daily and to contacting the program immediately if their resting rate spiked by more than 20 beats per minutes or in another way seemed irregular. Patients were also instructed to restart their oral anticoagulation immediately if they experienced AFib symptoms that persisted for more than 5 minutes. Many patients in the program also use a wearable device (usually a watch) to monitor their resting pulse and to generate a 30-second ECG recording that they can send as an electronic file to the University of Pennsylvania staff. “We embrace wearables,” Dr. Marchlinski said. Those without a wearable can undergo transtelephonic EEG monitoring to document a suspected arrhythmia recurrence, and all patients undergo annual monitoring by continuous ECG for at least 2 weeks.During follow-up, in addition to the 1 patient free from recurrent AFib who had an atherosclerotic embolism, 34 patients resumed anticoagulant treatment because of AFib recurrence; 12 withdrew from the program because of noncompliance or preference, or because an exclusion appeared; 29 resumed oral anticoagulation transiently but then discontinued the drug a second time when their AFib recurrence resolved; and 114 patients (60% of the starting cohort of 190) remained completely off anticoagulation during a median of 37 months. These data updated a published report from Dr. Marchlinski and his associates on their first 99 patients followed for a median of 30 months (J Cardiovasc Electrophysiol. 2019 May;30[5]:631-8).
This experience underscored the need for ongoing rhythm monitoring even in the absence of AFib symptoms, as six patients developed asymptomatic AFib detected by monitoring, including one patient whose recurrence occurred 30 months after the ablation procedure.
Dr. Marchlinski stressed the stringent selection process he applies to limit this approach to patients who are willing to faithfully monitor their pulse and symptoms daily, and who accept the risk that this approach may pose and their responsibility to stay in contact with the clinical team. The program calls patients at the 6-month mark between annual monitoring to remind them of their need for daily attention.
“Being off anticoagulants is very important to these patients,” he explained, and he highlighted the added workload this strategy places on his staff. “I think this has legs” for adoption by other cardiac arrhythmia programs, “but it depends on the time the staff is willing to spend” monitoring and following these patients, some of whom regularly send in ECG traces from their wearable devices for assessment. “It takes a village” to make this program work, he said.
Dr. Marchlinski has been a consultant to or has received honoraria from Abbott EP/St. Jude, Biosense Webster, Biotronik, Boston Scientific, and Medtronic.
NATIONAL HARBOR, MD. – A pilot program of daily arrhythmia self-vigilance has allowed selected patients with no atrial fibrillation following a catheter ablation procedure to safely come off a regimen of daily oral anticoagulation despite having residual risk factors for ischemic stroke.
This program, which started several years ago at the University of Pennsylvania in Philadelphia, has now managed 190 patients and followed them for a median of just over 3 years, and during 576 patient-years of follow-up, just a single patient had an ischemic cerebrovascular event that occurred with no atrial fibrillation (AFib) recurrence and appeared to be caused by an atherosclerotic embolism, Francis E. Marchlinski, MD, said at the annual International AF Symposium.
Although this strategy has not yet been tested in a prospective, randomized trial, this anecdotal, single-center experience suggests that the approach is “safe and effective” for selected patients who are eager to come off of their anticoagulation regimen when they remain arrhythmia free following catheter ablation of their AFib, said Dr. Marchlinski, professor of medicine and director of electrophysiology at the University of Pennsylvania. He and his associates developed this strategy as a way to more safely allow these patients to stop taking a daily oral anticoagulant because he found that many patients were stopping on their own, with no safety strategy in place.
“Patients tell me they don’t want to be on an oral anticoagulant because a parent had a hemorrhagic stroke, and they say they’re willing to accept the risk” of having an ischemic stroke by coming off anticoagulation. “This is a way for them to do it safely,” Dr. Marchlinski said in an interview. He stressed that he only allows his patients to go this route if they understand the risk and accept their shared responsibility for vigilant, twice-daily pulse monitoring to detect resumption of an irregular heart beat.
Since 2011, Dr. Marchlinski’s program ablated 1,216 patients with AFib who then remained arrhythmia free during 3 weeks of continuous ECG monitoring following their procedure. Among these patients, 443 had a CHA2DS2-VAScscore of either 0 (men) or 1 (women) that indicated no ongoing need for oral anticoagulation according to current guidelines. Of the remaining 773 patients with a CHA2DS2-VASc score of at least 1 in men and 2 in women, the clinicians determined 583 to be ineligible for the program because of their unwillingness to accept the risk, unwillingness to comply with daily pulse checks, a history of asymptomatic AFib, a CHA2DS2-VASc score greater than 4, or a resting pulse above 90 beats per minute, leaving 190 patients eligible to participate. Among these patients, 105 (55%) had a CHA2DS2-VASc score of 2-4, which should prompt anticoagulation according to current guidelines.Participating patients committed to check their resting pulse by palpation at least twice daily and to contacting the program immediately if their resting rate spiked by more than 20 beats per minutes or in another way seemed irregular. Patients were also instructed to restart their oral anticoagulation immediately if they experienced AFib symptoms that persisted for more than 5 minutes. Many patients in the program also use a wearable device (usually a watch) to monitor their resting pulse and to generate a 30-second ECG recording that they can send as an electronic file to the University of Pennsylvania staff. “We embrace wearables,” Dr. Marchlinski said. Those without a wearable can undergo transtelephonic EEG monitoring to document a suspected arrhythmia recurrence, and all patients undergo annual monitoring by continuous ECG for at least 2 weeks.During follow-up, in addition to the 1 patient free from recurrent AFib who had an atherosclerotic embolism, 34 patients resumed anticoagulant treatment because of AFib recurrence; 12 withdrew from the program because of noncompliance or preference, or because an exclusion appeared; 29 resumed oral anticoagulation transiently but then discontinued the drug a second time when their AFib recurrence resolved; and 114 patients (60% of the starting cohort of 190) remained completely off anticoagulation during a median of 37 months. These data updated a published report from Dr. Marchlinski and his associates on their first 99 patients followed for a median of 30 months (J Cardiovasc Electrophysiol. 2019 May;30[5]:631-8).
This experience underscored the need for ongoing rhythm monitoring even in the absence of AFib symptoms, as six patients developed asymptomatic AFib detected by monitoring, including one patient whose recurrence occurred 30 months after the ablation procedure.
Dr. Marchlinski stressed the stringent selection process he applies to limit this approach to patients who are willing to faithfully monitor their pulse and symptoms daily, and who accept the risk that this approach may pose and their responsibility to stay in contact with the clinical team. The program calls patients at the 6-month mark between annual monitoring to remind them of their need for daily attention.
“Being off anticoagulants is very important to these patients,” he explained, and he highlighted the added workload this strategy places on his staff. “I think this has legs” for adoption by other cardiac arrhythmia programs, “but it depends on the time the staff is willing to spend” monitoring and following these patients, some of whom regularly send in ECG traces from their wearable devices for assessment. “It takes a village” to make this program work, he said.
Dr. Marchlinski has been a consultant to or has received honoraria from Abbott EP/St. Jude, Biosense Webster, Biotronik, Boston Scientific, and Medtronic.
REPORTING FROM THE AF SYMPOSIUM 2020
DOACs for treatment of cancer-associated venous thromboembolism
Bleeding risk may determine best option
Case
A 52-year-old female with past medical history of diabetes, hypertension, and stage 4 lung cancer on palliative chemotherapy presents with acute-onset dyspnea, pleuritic chest pain, and cough. Her exam is notable for tachycardia, hypoxemia, and diminished breath sounds. A CT pulmonary embolism study shows new left segmental thrombus. What is her preferred method of anticoagulation?
Brief overview of the issue
Venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a significant concern in the context of malignancy and is associated with higher rates of mortality at 1 year.
The standard of care in the recent past has relied on low-molecular-weight heparin (LMWH) after several trials showed decreased VTE recurrence in cancer patients, compared with vitamin K antagonist (VKA) treatment.1,2 LMWH has been recommended as a first-line treatment by clinical guidelines for cancer-related VTE given lower drug-drug interactions between LMWH and chemotherapy regimens, as compared with traditional VKAs, and it does not rely on intestinal absorption.3
In more recent years, the focus has shifted to direct oral anticoagulants (DOACs) as potential treatment options for cancer-related VTE given their ease of administration, low side-effect profile, and decreased cost. Until recently, studies have mainly been small and largely retrospective, however, several larger randomized control studies have recently been published.
Overview of the data
Several retrospective trials have investigated the use of DOACs in cancer-associated VTE. One study looking at VTE recurrence rates showed a trend towards lower rates with rivaroxaban, compared with LMWH at 6 months (13% vs. 17%) that was significantly lower at 12 months (16.5 % vs. 22%). Similar results were found when comparing rivaroxaban to warfarin. Major bleeding rates were similar among cohorts.4
Several other retrospective cohort studies looking at treatment of cancer-associated VTE treated with LMWH vs. DOACs found that overall patients treated with DOACs had cancers with lower risk for VTE and had lower burden of metastatic disease. When this was adjusted for, there was no significant difference in the rate of recurrent cancer-associated thrombosis or major bleeding.5,6
Recently several prospective studies have corroborated the noninferiority or slight superiority of DOACs when compared with LMWH in treatment of cancer-associated VTE, while showing similar rates of bleeding. These are summarized as follows: a prospective, open-label, randomized controlled (RCT), noninferiority trial of 1,046 patients with malignancy-related VTE assigned to either LMWH for at least 5 days, followed by oral edoxaban vs. subcutaneous dalteparin for at least 6 months and up to 12 months. Investigators found no significant difference in the rate of recurrent VTE in the edoxaban group (12.8%), as compared to the dalteparin group (13.5%, P = .006 for noninferiority). Risk of major bleeding was not significantly different between the groups.7
A small RCT of 203 patients comparing recurrent VTE rates with rivaroxaban vs. dalteparin found significantly fewer recurrent clots in the rivaroxaban group compared to the dalteparin group (11% vs 4%) with no significant difference in the 6-month cumulative rate of major bleeding, 4% in the dalteparin group and 6% for the rivaroxaban group.8 Preliminary results from the ADAM VTE trial comparing apixaban to dalteparin found significantly fewer recurrent VTE in the apixaban group (3.4% vs. 14.1%) with no significant difference in major bleeding events (0% vs 2.1%).9 The Caravaggio study is a large multinational randomized, controlled, open-label, noninferiority trial looking at apixaban vs. dalteparin with endpoints being 6-month recurrent VTE and bleeding risk that will likely report results soon.
Risk of bleeding is also a major consideration in VTE treatment as studies suggest that patients with metastatic cancer are at sixfold higher risk for anticoagulant-associated bleeding.3 Subgroup analysis of Hokusai VTE cancer study found that major bleeding occurred in 32 of 522 patients given edoxaban and 16 of 524 patients treated with dalteparin. Excess of major bleeding with edoxaban was confined to patients with GI cancer. However, rates of severe major bleeding at presentation were similar.10
Overall, the existing data suggests that DOACs may be a viable option in the treatment of malignancy-associated VTE given its similar efficacy in preventing recurrent VTE without significant increased risk of major bleeding. The 2018 International Society on Thrombosis and Haemostasis VTE in cancer guidelines have been updated to include rivaroxaban and edoxaban for use in patients at low risk of bleeding, but recommend an informed discussion between patients and clinicians in deciding between DOAC and LMWH.11 The Chest VTE guidelines have not been updated since 2016, prior to when the above mentioned DOAC studies were published.
Application of data to our patient
Compared with patients without cancer, anticoagulation in cancer patients with acute VTE is challenging because of higher rates of VTE recurrence and bleeding, as well as the potential for drug interactions with anticancer agents. Our patient is not at increased risk for gastrointestinal bleeding and no drug interactions exist between her current chemotherapy regimen and the available DOACs, therefore she is a candidate for treatment with a DOAC.
After an informed discussion, she chose to start rivaroxaban for treatment of her pulmonary embolism. While more studies are needed to definitively determine the best treatment for cancer-associated VTE, DOACs appear to be an attractive alternative to LMWH. Patient preferences of taking oral medications over injections as well as the significant cost savings of DOACs over LMWH will likely play into many patients’ and providers’ anticoagulant choices.
Bottom line
Direct oral anticoagulants are a treatment option for cancer-associated VTE in patients at low risk of bleeding complications. Patients at increased risk of bleeding (especially patients with GI malignancies) should continue to be treated with LMWH.
Dr. Spence is a hospitalist and palliative care physician at Denver Health, and an assistant professor of medicine at the University of Colorado at Denver, Aurora. Dr. Miller and Dr. Liu are hospitalists at Denver Health, and assistant professors of medicine at the University of Colorado at Denver.
References
1. Hull RD et al. Long term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patient with cancer. Am J Med. 2006;19(12):1062-72.
2. Lee AY et al. Low-molecular-weight heparin versus Coumadin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-53.
3. Ay C et al. Treatment of cancer-associated venous thromboembolism in the age of direct oral anticoagulants. Ann Oncol. 2019 Mar 27 [epub].
4. Streiff MB et al. Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer. Am J Hematol. 2018 May;93(5):664-71.
5. Phelps MK et al. A single center retrospective cohort study comparing low-molecular-weight heparins to direct oral anticoagulants for the treatment of venous thromboembolism in patients with cancer – A real-world experience. J Oncol Pharm Pract. 2019 Jun;25(4):793-800.
6. Simmons B et al. Efficacy and safety of rivaroxaban compared to enoxaparin in treatment of cancer-associated venous thromboembolism. Eur J Haematol. 2018 Apr 4. (Epub).
7. Raskob GE et al.; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-24.
8. Young AM et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-23.
9. McBane, RD et al. Apixaban, dalteparin, in active cancer associated venous thromboembolism, the ADAM VTE trial. Blood. 2018 Nov 29;132(suppl 1):421.
10. Kraaijpoel N et al. Clinical impact of bleeding in cancer-associated venous thromboembolism: Results from the Hokusai VTE cancer study. Thromb Haemost. 2018 Aug;118(8):1439-49.
11. Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: Guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Key points
- DOACs are a reasonable treatment option for malignancy-associated VTE in patients without GI tract malignancies and at low risk for bleeding complications.
- In patients with gastrointestinal malignancies or increased risk of bleeding, DOACs may have an increased bleeding risk and therefore LMWH is recommended.
- An informed discussion should occur between providers and patients to determine the best treatment option for cancer patients with VTE.
Additional reading
Dong Y et al. Efficacy and safety of direct oral anticoagulants versus low-molecular-weight heparin in patients with cancer: A systematic review and meta-analysis. J Thromb Thrombolysis. 2019 May 6.
Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Tritschler T et al. Venous thromboembolism advances in diagnosis and treatment. JAMA. 2018 Oct;320(15):1583-94.
Quiz
Which of the following is the recommended treatment of VTE in a patient with brain metastases?
A. Unfractionated heparin
B. Low molecular weight heparin
C. Direct oral anticoagulant
D. Vitamin K antagonist
The answer is B. Although there are very few data, LMWH is the recommended agent in patients with VTE and brain metastases.
A. LMWH has been shown to decrease mortality in patients with VTE and cancer, compared with unfractionated heparin (risk ratio, 0.66).
C. The safety of DOACs is not yet well established in patients with brain tumors. Antidotes and/or specific reversal agents for some DOACs are not available.
D. Vitamin K antagonists such as warfarin are not recommended in cancer patients because LMWH has a reduced risk of recurrent VTE without increased risk of bleeding.
Bleeding risk may determine best option
Bleeding risk may determine best option
Case
A 52-year-old female with past medical history of diabetes, hypertension, and stage 4 lung cancer on palliative chemotherapy presents with acute-onset dyspnea, pleuritic chest pain, and cough. Her exam is notable for tachycardia, hypoxemia, and diminished breath sounds. A CT pulmonary embolism study shows new left segmental thrombus. What is her preferred method of anticoagulation?
Brief overview of the issue
Venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a significant concern in the context of malignancy and is associated with higher rates of mortality at 1 year.
The standard of care in the recent past has relied on low-molecular-weight heparin (LMWH) after several trials showed decreased VTE recurrence in cancer patients, compared with vitamin K antagonist (VKA) treatment.1,2 LMWH has been recommended as a first-line treatment by clinical guidelines for cancer-related VTE given lower drug-drug interactions between LMWH and chemotherapy regimens, as compared with traditional VKAs, and it does not rely on intestinal absorption.3
In more recent years, the focus has shifted to direct oral anticoagulants (DOACs) as potential treatment options for cancer-related VTE given their ease of administration, low side-effect profile, and decreased cost. Until recently, studies have mainly been small and largely retrospective, however, several larger randomized control studies have recently been published.
Overview of the data
Several retrospective trials have investigated the use of DOACs in cancer-associated VTE. One study looking at VTE recurrence rates showed a trend towards lower rates with rivaroxaban, compared with LMWH at 6 months (13% vs. 17%) that was significantly lower at 12 months (16.5 % vs. 22%). Similar results were found when comparing rivaroxaban to warfarin. Major bleeding rates were similar among cohorts.4
Several other retrospective cohort studies looking at treatment of cancer-associated VTE treated with LMWH vs. DOACs found that overall patients treated with DOACs had cancers with lower risk for VTE and had lower burden of metastatic disease. When this was adjusted for, there was no significant difference in the rate of recurrent cancer-associated thrombosis or major bleeding.5,6
Recently several prospective studies have corroborated the noninferiority or slight superiority of DOACs when compared with LMWH in treatment of cancer-associated VTE, while showing similar rates of bleeding. These are summarized as follows: a prospective, open-label, randomized controlled (RCT), noninferiority trial of 1,046 patients with malignancy-related VTE assigned to either LMWH for at least 5 days, followed by oral edoxaban vs. subcutaneous dalteparin for at least 6 months and up to 12 months. Investigators found no significant difference in the rate of recurrent VTE in the edoxaban group (12.8%), as compared to the dalteparin group (13.5%, P = .006 for noninferiority). Risk of major bleeding was not significantly different between the groups.7
A small RCT of 203 patients comparing recurrent VTE rates with rivaroxaban vs. dalteparin found significantly fewer recurrent clots in the rivaroxaban group compared to the dalteparin group (11% vs 4%) with no significant difference in the 6-month cumulative rate of major bleeding, 4% in the dalteparin group and 6% for the rivaroxaban group.8 Preliminary results from the ADAM VTE trial comparing apixaban to dalteparin found significantly fewer recurrent VTE in the apixaban group (3.4% vs. 14.1%) with no significant difference in major bleeding events (0% vs 2.1%).9 The Caravaggio study is a large multinational randomized, controlled, open-label, noninferiority trial looking at apixaban vs. dalteparin with endpoints being 6-month recurrent VTE and bleeding risk that will likely report results soon.
Risk of bleeding is also a major consideration in VTE treatment as studies suggest that patients with metastatic cancer are at sixfold higher risk for anticoagulant-associated bleeding.3 Subgroup analysis of Hokusai VTE cancer study found that major bleeding occurred in 32 of 522 patients given edoxaban and 16 of 524 patients treated with dalteparin. Excess of major bleeding with edoxaban was confined to patients with GI cancer. However, rates of severe major bleeding at presentation were similar.10
Overall, the existing data suggests that DOACs may be a viable option in the treatment of malignancy-associated VTE given its similar efficacy in preventing recurrent VTE without significant increased risk of major bleeding. The 2018 International Society on Thrombosis and Haemostasis VTE in cancer guidelines have been updated to include rivaroxaban and edoxaban for use in patients at low risk of bleeding, but recommend an informed discussion between patients and clinicians in deciding between DOAC and LMWH.11 The Chest VTE guidelines have not been updated since 2016, prior to when the above mentioned DOAC studies were published.
Application of data to our patient
Compared with patients without cancer, anticoagulation in cancer patients with acute VTE is challenging because of higher rates of VTE recurrence and bleeding, as well as the potential for drug interactions with anticancer agents. Our patient is not at increased risk for gastrointestinal bleeding and no drug interactions exist between her current chemotherapy regimen and the available DOACs, therefore she is a candidate for treatment with a DOAC.
After an informed discussion, she chose to start rivaroxaban for treatment of her pulmonary embolism. While more studies are needed to definitively determine the best treatment for cancer-associated VTE, DOACs appear to be an attractive alternative to LMWH. Patient preferences of taking oral medications over injections as well as the significant cost savings of DOACs over LMWH will likely play into many patients’ and providers’ anticoagulant choices.
Bottom line
Direct oral anticoagulants are a treatment option for cancer-associated VTE in patients at low risk of bleeding complications. Patients at increased risk of bleeding (especially patients with GI malignancies) should continue to be treated with LMWH.
Dr. Spence is a hospitalist and palliative care physician at Denver Health, and an assistant professor of medicine at the University of Colorado at Denver, Aurora. Dr. Miller and Dr. Liu are hospitalists at Denver Health, and assistant professors of medicine at the University of Colorado at Denver.
References
1. Hull RD et al. Long term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patient with cancer. Am J Med. 2006;19(12):1062-72.
2. Lee AY et al. Low-molecular-weight heparin versus Coumadin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-53.
3. Ay C et al. Treatment of cancer-associated venous thromboembolism in the age of direct oral anticoagulants. Ann Oncol. 2019 Mar 27 [epub].
4. Streiff MB et al. Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer. Am J Hematol. 2018 May;93(5):664-71.
5. Phelps MK et al. A single center retrospective cohort study comparing low-molecular-weight heparins to direct oral anticoagulants for the treatment of venous thromboembolism in patients with cancer – A real-world experience. J Oncol Pharm Pract. 2019 Jun;25(4):793-800.
6. Simmons B et al. Efficacy and safety of rivaroxaban compared to enoxaparin in treatment of cancer-associated venous thromboembolism. Eur J Haematol. 2018 Apr 4. (Epub).
7. Raskob GE et al.; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-24.
8. Young AM et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-23.
9. McBane, RD et al. Apixaban, dalteparin, in active cancer associated venous thromboembolism, the ADAM VTE trial. Blood. 2018 Nov 29;132(suppl 1):421.
10. Kraaijpoel N et al. Clinical impact of bleeding in cancer-associated venous thromboembolism: Results from the Hokusai VTE cancer study. Thromb Haemost. 2018 Aug;118(8):1439-49.
11. Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: Guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Key points
- DOACs are a reasonable treatment option for malignancy-associated VTE in patients without GI tract malignancies and at low risk for bleeding complications.
- In patients with gastrointestinal malignancies or increased risk of bleeding, DOACs may have an increased bleeding risk and therefore LMWH is recommended.
- An informed discussion should occur between providers and patients to determine the best treatment option for cancer patients with VTE.
Additional reading
Dong Y et al. Efficacy and safety of direct oral anticoagulants versus low-molecular-weight heparin in patients with cancer: A systematic review and meta-analysis. J Thromb Thrombolysis. 2019 May 6.
Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Tritschler T et al. Venous thromboembolism advances in diagnosis and treatment. JAMA. 2018 Oct;320(15):1583-94.
Quiz
Which of the following is the recommended treatment of VTE in a patient with brain metastases?
A. Unfractionated heparin
B. Low molecular weight heparin
C. Direct oral anticoagulant
D. Vitamin K antagonist
The answer is B. Although there are very few data, LMWH is the recommended agent in patients with VTE and brain metastases.
A. LMWH has been shown to decrease mortality in patients with VTE and cancer, compared with unfractionated heparin (risk ratio, 0.66).
C. The safety of DOACs is not yet well established in patients with brain tumors. Antidotes and/or specific reversal agents for some DOACs are not available.
D. Vitamin K antagonists such as warfarin are not recommended in cancer patients because LMWH has a reduced risk of recurrent VTE without increased risk of bleeding.
Case
A 52-year-old female with past medical history of diabetes, hypertension, and stage 4 lung cancer on palliative chemotherapy presents with acute-onset dyspnea, pleuritic chest pain, and cough. Her exam is notable for tachycardia, hypoxemia, and diminished breath sounds. A CT pulmonary embolism study shows new left segmental thrombus. What is her preferred method of anticoagulation?
Brief overview of the issue
Venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a significant concern in the context of malignancy and is associated with higher rates of mortality at 1 year.
The standard of care in the recent past has relied on low-molecular-weight heparin (LMWH) after several trials showed decreased VTE recurrence in cancer patients, compared with vitamin K antagonist (VKA) treatment.1,2 LMWH has been recommended as a first-line treatment by clinical guidelines for cancer-related VTE given lower drug-drug interactions between LMWH and chemotherapy regimens, as compared with traditional VKAs, and it does not rely on intestinal absorption.3
In more recent years, the focus has shifted to direct oral anticoagulants (DOACs) as potential treatment options for cancer-related VTE given their ease of administration, low side-effect profile, and decreased cost. Until recently, studies have mainly been small and largely retrospective, however, several larger randomized control studies have recently been published.
Overview of the data
Several retrospective trials have investigated the use of DOACs in cancer-associated VTE. One study looking at VTE recurrence rates showed a trend towards lower rates with rivaroxaban, compared with LMWH at 6 months (13% vs. 17%) that was significantly lower at 12 months (16.5 % vs. 22%). Similar results were found when comparing rivaroxaban to warfarin. Major bleeding rates were similar among cohorts.4
Several other retrospective cohort studies looking at treatment of cancer-associated VTE treated with LMWH vs. DOACs found that overall patients treated with DOACs had cancers with lower risk for VTE and had lower burden of metastatic disease. When this was adjusted for, there was no significant difference in the rate of recurrent cancer-associated thrombosis or major bleeding.5,6
Recently several prospective studies have corroborated the noninferiority or slight superiority of DOACs when compared with LMWH in treatment of cancer-associated VTE, while showing similar rates of bleeding. These are summarized as follows: a prospective, open-label, randomized controlled (RCT), noninferiority trial of 1,046 patients with malignancy-related VTE assigned to either LMWH for at least 5 days, followed by oral edoxaban vs. subcutaneous dalteparin for at least 6 months and up to 12 months. Investigators found no significant difference in the rate of recurrent VTE in the edoxaban group (12.8%), as compared to the dalteparin group (13.5%, P = .006 for noninferiority). Risk of major bleeding was not significantly different between the groups.7
A small RCT of 203 patients comparing recurrent VTE rates with rivaroxaban vs. dalteparin found significantly fewer recurrent clots in the rivaroxaban group compared to the dalteparin group (11% vs 4%) with no significant difference in the 6-month cumulative rate of major bleeding, 4% in the dalteparin group and 6% for the rivaroxaban group.8 Preliminary results from the ADAM VTE trial comparing apixaban to dalteparin found significantly fewer recurrent VTE in the apixaban group (3.4% vs. 14.1%) with no significant difference in major bleeding events (0% vs 2.1%).9 The Caravaggio study is a large multinational randomized, controlled, open-label, noninferiority trial looking at apixaban vs. dalteparin with endpoints being 6-month recurrent VTE and bleeding risk that will likely report results soon.
Risk of bleeding is also a major consideration in VTE treatment as studies suggest that patients with metastatic cancer are at sixfold higher risk for anticoagulant-associated bleeding.3 Subgroup analysis of Hokusai VTE cancer study found that major bleeding occurred in 32 of 522 patients given edoxaban and 16 of 524 patients treated with dalteparin. Excess of major bleeding with edoxaban was confined to patients with GI cancer. However, rates of severe major bleeding at presentation were similar.10
Overall, the existing data suggests that DOACs may be a viable option in the treatment of malignancy-associated VTE given its similar efficacy in preventing recurrent VTE without significant increased risk of major bleeding. The 2018 International Society on Thrombosis and Haemostasis VTE in cancer guidelines have been updated to include rivaroxaban and edoxaban for use in patients at low risk of bleeding, but recommend an informed discussion between patients and clinicians in deciding between DOAC and LMWH.11 The Chest VTE guidelines have not been updated since 2016, prior to when the above mentioned DOAC studies were published.
Application of data to our patient
Compared with patients without cancer, anticoagulation in cancer patients with acute VTE is challenging because of higher rates of VTE recurrence and bleeding, as well as the potential for drug interactions with anticancer agents. Our patient is not at increased risk for gastrointestinal bleeding and no drug interactions exist between her current chemotherapy regimen and the available DOACs, therefore she is a candidate for treatment with a DOAC.
After an informed discussion, she chose to start rivaroxaban for treatment of her pulmonary embolism. While more studies are needed to definitively determine the best treatment for cancer-associated VTE, DOACs appear to be an attractive alternative to LMWH. Patient preferences of taking oral medications over injections as well as the significant cost savings of DOACs over LMWH will likely play into many patients’ and providers’ anticoagulant choices.
Bottom line
Direct oral anticoagulants are a treatment option for cancer-associated VTE in patients at low risk of bleeding complications. Patients at increased risk of bleeding (especially patients with GI malignancies) should continue to be treated with LMWH.
Dr. Spence is a hospitalist and palliative care physician at Denver Health, and an assistant professor of medicine at the University of Colorado at Denver, Aurora. Dr. Miller and Dr. Liu are hospitalists at Denver Health, and assistant professors of medicine at the University of Colorado at Denver.
References
1. Hull RD et al. Long term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patient with cancer. Am J Med. 2006;19(12):1062-72.
2. Lee AY et al. Low-molecular-weight heparin versus Coumadin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-53.
3. Ay C et al. Treatment of cancer-associated venous thromboembolism in the age of direct oral anticoagulants. Ann Oncol. 2019 Mar 27 [epub].
4. Streiff MB et al. Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer. Am J Hematol. 2018 May;93(5):664-71.
5. Phelps MK et al. A single center retrospective cohort study comparing low-molecular-weight heparins to direct oral anticoagulants for the treatment of venous thromboembolism in patients with cancer – A real-world experience. J Oncol Pharm Pract. 2019 Jun;25(4):793-800.
6. Simmons B et al. Efficacy and safety of rivaroxaban compared to enoxaparin in treatment of cancer-associated venous thromboembolism. Eur J Haematol. 2018 Apr 4. (Epub).
7. Raskob GE et al.; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-24.
8. Young AM et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-23.
9. McBane, RD et al. Apixaban, dalteparin, in active cancer associated venous thromboembolism, the ADAM VTE trial. Blood. 2018 Nov 29;132(suppl 1):421.
10. Kraaijpoel N et al. Clinical impact of bleeding in cancer-associated venous thromboembolism: Results from the Hokusai VTE cancer study. Thromb Haemost. 2018 Aug;118(8):1439-49.
11. Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: Guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Key points
- DOACs are a reasonable treatment option for malignancy-associated VTE in patients without GI tract malignancies and at low risk for bleeding complications.
- In patients with gastrointestinal malignancies or increased risk of bleeding, DOACs may have an increased bleeding risk and therefore LMWH is recommended.
- An informed discussion should occur between providers and patients to determine the best treatment option for cancer patients with VTE.
Additional reading
Dong Y et al. Efficacy and safety of direct oral anticoagulants versus low-molecular-weight heparin in patients with cancer: A systematic review and meta-analysis. J Thromb Thrombolysis. 2019 May 6.
Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Tritschler T et al. Venous thromboembolism advances in diagnosis and treatment. JAMA. 2018 Oct;320(15):1583-94.
Quiz
Which of the following is the recommended treatment of VTE in a patient with brain metastases?
A. Unfractionated heparin
B. Low molecular weight heparin
C. Direct oral anticoagulant
D. Vitamin K antagonist
The answer is B. Although there are very few data, LMWH is the recommended agent in patients with VTE and brain metastases.
A. LMWH has been shown to decrease mortality in patients with VTE and cancer, compared with unfractionated heparin (risk ratio, 0.66).
C. The safety of DOACs is not yet well established in patients with brain tumors. Antidotes and/or specific reversal agents for some DOACs are not available.
D. Vitamin K antagonists such as warfarin are not recommended in cancer patients because LMWH has a reduced risk of recurrent VTE without increased risk of bleeding.
The evolving landscape of complement inhibition therapy
The introduction of eculizumab, a monoclonal antibody targeting C5 of the complement cascade, revolutionized the treatment of paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disorder characterized by complement-mediated intravascular hemolysis, bone marrow failure, and thrombophilia. Treatment options for PNH were limited before eculizumab was approved by the Food and Drug Administration in 2007.
Its use resulted in the inhibition of intravascular hemolysis, hemoglobin stabilization, and substantial reductions in transfusion requirements. Moreover, eculizumab had the unexpected effect of reducing the risk of thromboembolic complications, the most severe complication of PNH. Patients treated with eculizumab experienced fewer thrombotic events (4%), compared with historical cohorts (27%). Importantly, 5-year overall survival rates for patients with PNH taking eculizumab improved more than 90%, compared wity the 80% reported historically.
More than 10 years later, we are tasked with assessing the impact of this drug. Unquestionably, eculizumab has done more for PNH than we could have hoped for. However, 10 years of additional data reveal the limitations of this groundbreaking therapy. Despite the overall sustained response and survival benefit, hematologic response remains variable. Complete normalization of hemoglobin occurs in less than one-third of patients. Transfusion requirements persist in many patients. Residual anemia during eculizumab therapy is at least partly attributed to bone marrow failure, a feature the complement inhibition does not address. Still, pharmacokinetic limitations of the drug also contribute to the lack of complete responses. There is residual intravascular hemolysis because of insufficient inhibition of C5 and the emergence of C3-mediated extravascular hemolysis constitutes an unanticipated mechanistic complication of all C5-mediated therapies.
The last few years have seen a surge in novel anticomplement agents, which improve upon the already well-established inhibition of C5 but also explore the efficacy of targeting earlier aspects of the complement pathway. During the American Society of Hematology (ASH) annual meeting, we had exciting updates on some of the promising new kids on the block.
Ravulizumab, the newest C5 monoclonal antibody approved by the FDA for PNH, displays more robust C5 inhibition, thereby reducing the breakthrough hemolysis still seen with eculizumab use. Crovalimab, also an anti-C5 humanized antibody, is engineered with Sequential Monoclonal Antibody Recycling Technology that improves the half-life of the drug and facilitates subcutaneous dosing while still achieving complete C5 inhibition. Some of the most exciting data is on danicopan, a small-molecule factor D inhibitor that targets the alternative pathway thereby inhibiting C3 convertase and blocking extravascular hemolysis. It has shown promise as a stand-alone agent, as well as with combined C5 inhibition, while promising safety, a reasonable concern as we explore the long-term risks of targeting the proximal complement pathway.
I was recently asked to comment on how the new complement inhibitors are addressing unmet needs in PNH. While the recent presentations at ASH demonstrate an improvement on the efficacy of C5 inhibition, pharmacokinetics, and drug delivery – all which translate to improved hemoglobin and reduced breakthrough hemolysis for PNH patients – I am most excited at the promise this new generation of drugs holds for other diseases. Since its approval for PNH, eculizumab has also been approved for use in atypical hemolytic uremic syndrome (aHUS), myasthenia gravis, and neuromyelitis optica spectrum disorder.
Perhaps the greatest potential I envision for the new generation of drugs is in aHUS, a chronic disease characterized by hemolytic anemia, thrombocytopenia, and end-stage renal disease that cannot be cured with renal transplantation. The pathophysiology involves dysregulation of complement activation because of genetic mutations or autoantibodies to key proteins in the complement cascade. Though we have experienced some success with eculizumab, responses can be incomplete, particularly in patients with C5 mutations. The newer drugs offer the opportunity to inhibit complement activation at both proximal and distal aspects of the cascade, which may prove ideal in a disease in which the affected protein is not consistent. Moreover, preclinical and clinical trials have shown promise for these novel complement inhibitors in other autoimmune diseases: antibody-mediated vasculitis, C3 glomerulopathy, catastrophic antibody syndrome, membranous nephropathy, and lupus nephritis.
The surge of new complement inhibitors could revolutionize our strategy for treatment of autoimmune-mediated diseases, in which downstream complement activation can manifest with life-threatening tissue injury. Inhibition of complement offers a promising strategy for blocking downstream immune-mediated effector mechanisms of injury common in several autoimmune diseases.
As the results from various clinical trials come to fruition, it will be exciting to determine how to best use this new generation of drugs to target new diseases and whether the next decade is poised to eclipse the progress in complement therapy already established by eculizumab.
Dr. Sosa is a benign hematologist at Fox Chase Cancer Center in Philadelphia. Her research interests are in thromboembolic disease, with a focus in racial and gender disparities.
The introduction of eculizumab, a monoclonal antibody targeting C5 of the complement cascade, revolutionized the treatment of paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disorder characterized by complement-mediated intravascular hemolysis, bone marrow failure, and thrombophilia. Treatment options for PNH were limited before eculizumab was approved by the Food and Drug Administration in 2007.
Its use resulted in the inhibition of intravascular hemolysis, hemoglobin stabilization, and substantial reductions in transfusion requirements. Moreover, eculizumab had the unexpected effect of reducing the risk of thromboembolic complications, the most severe complication of PNH. Patients treated with eculizumab experienced fewer thrombotic events (4%), compared with historical cohorts (27%). Importantly, 5-year overall survival rates for patients with PNH taking eculizumab improved more than 90%, compared wity the 80% reported historically.
More than 10 years later, we are tasked with assessing the impact of this drug. Unquestionably, eculizumab has done more for PNH than we could have hoped for. However, 10 years of additional data reveal the limitations of this groundbreaking therapy. Despite the overall sustained response and survival benefit, hematologic response remains variable. Complete normalization of hemoglobin occurs in less than one-third of patients. Transfusion requirements persist in many patients. Residual anemia during eculizumab therapy is at least partly attributed to bone marrow failure, a feature the complement inhibition does not address. Still, pharmacokinetic limitations of the drug also contribute to the lack of complete responses. There is residual intravascular hemolysis because of insufficient inhibition of C5 and the emergence of C3-mediated extravascular hemolysis constitutes an unanticipated mechanistic complication of all C5-mediated therapies.
The last few years have seen a surge in novel anticomplement agents, which improve upon the already well-established inhibition of C5 but also explore the efficacy of targeting earlier aspects of the complement pathway. During the American Society of Hematology (ASH) annual meeting, we had exciting updates on some of the promising new kids on the block.
Ravulizumab, the newest C5 monoclonal antibody approved by the FDA for PNH, displays more robust C5 inhibition, thereby reducing the breakthrough hemolysis still seen with eculizumab use. Crovalimab, also an anti-C5 humanized antibody, is engineered with Sequential Monoclonal Antibody Recycling Technology that improves the half-life of the drug and facilitates subcutaneous dosing while still achieving complete C5 inhibition. Some of the most exciting data is on danicopan, a small-molecule factor D inhibitor that targets the alternative pathway thereby inhibiting C3 convertase and blocking extravascular hemolysis. It has shown promise as a stand-alone agent, as well as with combined C5 inhibition, while promising safety, a reasonable concern as we explore the long-term risks of targeting the proximal complement pathway.
I was recently asked to comment on how the new complement inhibitors are addressing unmet needs in PNH. While the recent presentations at ASH demonstrate an improvement on the efficacy of C5 inhibition, pharmacokinetics, and drug delivery – all which translate to improved hemoglobin and reduced breakthrough hemolysis for PNH patients – I am most excited at the promise this new generation of drugs holds for other diseases. Since its approval for PNH, eculizumab has also been approved for use in atypical hemolytic uremic syndrome (aHUS), myasthenia gravis, and neuromyelitis optica spectrum disorder.
Perhaps the greatest potential I envision for the new generation of drugs is in aHUS, a chronic disease characterized by hemolytic anemia, thrombocytopenia, and end-stage renal disease that cannot be cured with renal transplantation. The pathophysiology involves dysregulation of complement activation because of genetic mutations or autoantibodies to key proteins in the complement cascade. Though we have experienced some success with eculizumab, responses can be incomplete, particularly in patients with C5 mutations. The newer drugs offer the opportunity to inhibit complement activation at both proximal and distal aspects of the cascade, which may prove ideal in a disease in which the affected protein is not consistent. Moreover, preclinical and clinical trials have shown promise for these novel complement inhibitors in other autoimmune diseases: antibody-mediated vasculitis, C3 glomerulopathy, catastrophic antibody syndrome, membranous nephropathy, and lupus nephritis.
The surge of new complement inhibitors could revolutionize our strategy for treatment of autoimmune-mediated diseases, in which downstream complement activation can manifest with life-threatening tissue injury. Inhibition of complement offers a promising strategy for blocking downstream immune-mediated effector mechanisms of injury common in several autoimmune diseases.
As the results from various clinical trials come to fruition, it will be exciting to determine how to best use this new generation of drugs to target new diseases and whether the next decade is poised to eclipse the progress in complement therapy already established by eculizumab.
Dr. Sosa is a benign hematologist at Fox Chase Cancer Center in Philadelphia. Her research interests are in thromboembolic disease, with a focus in racial and gender disparities.
The introduction of eculizumab, a monoclonal antibody targeting C5 of the complement cascade, revolutionized the treatment of paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disorder characterized by complement-mediated intravascular hemolysis, bone marrow failure, and thrombophilia. Treatment options for PNH were limited before eculizumab was approved by the Food and Drug Administration in 2007.
Its use resulted in the inhibition of intravascular hemolysis, hemoglobin stabilization, and substantial reductions in transfusion requirements. Moreover, eculizumab had the unexpected effect of reducing the risk of thromboembolic complications, the most severe complication of PNH. Patients treated with eculizumab experienced fewer thrombotic events (4%), compared with historical cohorts (27%). Importantly, 5-year overall survival rates for patients with PNH taking eculizumab improved more than 90%, compared wity the 80% reported historically.
More than 10 years later, we are tasked with assessing the impact of this drug. Unquestionably, eculizumab has done more for PNH than we could have hoped for. However, 10 years of additional data reveal the limitations of this groundbreaking therapy. Despite the overall sustained response and survival benefit, hematologic response remains variable. Complete normalization of hemoglobin occurs in less than one-third of patients. Transfusion requirements persist in many patients. Residual anemia during eculizumab therapy is at least partly attributed to bone marrow failure, a feature the complement inhibition does not address. Still, pharmacokinetic limitations of the drug also contribute to the lack of complete responses. There is residual intravascular hemolysis because of insufficient inhibition of C5 and the emergence of C3-mediated extravascular hemolysis constitutes an unanticipated mechanistic complication of all C5-mediated therapies.
The last few years have seen a surge in novel anticomplement agents, which improve upon the already well-established inhibition of C5 but also explore the efficacy of targeting earlier aspects of the complement pathway. During the American Society of Hematology (ASH) annual meeting, we had exciting updates on some of the promising new kids on the block.
Ravulizumab, the newest C5 monoclonal antibody approved by the FDA for PNH, displays more robust C5 inhibition, thereby reducing the breakthrough hemolysis still seen with eculizumab use. Crovalimab, also an anti-C5 humanized antibody, is engineered with Sequential Monoclonal Antibody Recycling Technology that improves the half-life of the drug and facilitates subcutaneous dosing while still achieving complete C5 inhibition. Some of the most exciting data is on danicopan, a small-molecule factor D inhibitor that targets the alternative pathway thereby inhibiting C3 convertase and blocking extravascular hemolysis. It has shown promise as a stand-alone agent, as well as with combined C5 inhibition, while promising safety, a reasonable concern as we explore the long-term risks of targeting the proximal complement pathway.
I was recently asked to comment on how the new complement inhibitors are addressing unmet needs in PNH. While the recent presentations at ASH demonstrate an improvement on the efficacy of C5 inhibition, pharmacokinetics, and drug delivery – all which translate to improved hemoglobin and reduced breakthrough hemolysis for PNH patients – I am most excited at the promise this new generation of drugs holds for other diseases. Since its approval for PNH, eculizumab has also been approved for use in atypical hemolytic uremic syndrome (aHUS), myasthenia gravis, and neuromyelitis optica spectrum disorder.
Perhaps the greatest potential I envision for the new generation of drugs is in aHUS, a chronic disease characterized by hemolytic anemia, thrombocytopenia, and end-stage renal disease that cannot be cured with renal transplantation. The pathophysiology involves dysregulation of complement activation because of genetic mutations or autoantibodies to key proteins in the complement cascade. Though we have experienced some success with eculizumab, responses can be incomplete, particularly in patients with C5 mutations. The newer drugs offer the opportunity to inhibit complement activation at both proximal and distal aspects of the cascade, which may prove ideal in a disease in which the affected protein is not consistent. Moreover, preclinical and clinical trials have shown promise for these novel complement inhibitors in other autoimmune diseases: antibody-mediated vasculitis, C3 glomerulopathy, catastrophic antibody syndrome, membranous nephropathy, and lupus nephritis.
The surge of new complement inhibitors could revolutionize our strategy for treatment of autoimmune-mediated diseases, in which downstream complement activation can manifest with life-threatening tissue injury. Inhibition of complement offers a promising strategy for blocking downstream immune-mediated effector mechanisms of injury common in several autoimmune diseases.
As the results from various clinical trials come to fruition, it will be exciting to determine how to best use this new generation of drugs to target new diseases and whether the next decade is poised to eclipse the progress in complement therapy already established by eculizumab.
Dr. Sosa is a benign hematologist at Fox Chase Cancer Center in Philadelphia. Her research interests are in thromboembolic disease, with a focus in racial and gender disparities.
Are providers asking about menstrual bleeding before/during anticoagulant therapy?
ORLANDO – A small study suggests health care providers may fail to ask patients about heavy menstrual bleeding before or during treatment with oral anticoagulants.
Researchers performed a chart review at a single center, which indicated that 60% of women were not asked about heavy menstrual bleeding before they were prescribed an oral anticoagulant.
Six months after the women started anticoagulant therapy, 29% required treatment for heavy menstrual bleeding. Charts for the remaining 71% of women contained no information about heavy menstrual bleeding.
“We were unable to distinguish between true absence of heavy menstrual bleeding and absence of reporting,” said Bethany T. Samuelson Bannow, MD, of Oregon Health & Science University, Portland.
Dr. Samuelson Bannow presented these findings at the annual meeting of the American Society of Hematology.
She explained that heavy menstrual bleeding is defined as more than 80 mL of blood loss per cycle. It affects 10%-15% of women in their lifetime, and anticoagulants increase the risk of heavy menstrual bleeding.
Studies have shown that heavy menstrual bleeding occurs in 22%-65% of women treated with vitamin K agonists and 20%-27% of women treated with rivaroxaban (Blood. 2017;130[24]:2603-9). However, many anticoagulant studies don’t include heavy menstrual bleeding as an outcome.
To gain more insight, Dr. Samuelson Bannow and colleagues conducted a chart review. Their study included 236 women of reproductive age treated at Oregon Health & Science University between Jan. 1, 2012, and Dec. 31, 2018.
The patients’ median age was 37 years (range, 18-50 years). Most patients (67%) were receiving an oral anticoagulant for venous thromboembolism. The rest were on anticoagulant therapy for arterial thrombosis (6%), atrial fibrillation (6%), a mechanical valve (1%), or “other” reasons (20%).
Dr. Samuelson Bannow said the other group was “almost exclusively women who were receiving prophylaxis” postoperatively or for travel. Most women in this group were receiving rivaroxaban.
Rivaroxaban was the most commonly prescribed anticoagulant in the entire cohort (41%), followed by warfarin (34%) and apixaban (25%).
At the time of anticoagulant prescription, 12% of women reported a history of heavy menstrual bleeding, and 28% did not. For most patients – 60% – there was no discussion of menstrual history documented.
Six months after starting oral anticoagulant therapy, 29% of patients required treatment for heavy menstrual bleeding. For 71% of patients, there was no documentation on the treatment of heavy menstrual bleeding.
Treatment for heavy menstrual bleeding was required in 33% of patients on rivaroxaban, 24% of those on apixaban, and 29% of those on warfarin, a significant difference (P less than .001).
“Rates of heavy menstrual bleeding … are higher in rivaroxaban users,” Dr. Samuelson Bannow said. “This is not the first study to demonstrate this. However, [the rate of heavy menstrual bleeding in this study] is still a lot lower than we would expect based on past levels with warfarin. This tells us we’re probably missing a lot of heavy menstrual bleeding. That’s not too surprising considering how few providers are actually asking about the menses.”
Dr. Samuelson Bannow and colleagues disclosed no conflicts of interest.
SOURCE: Samuelson Bannow BT et al. ASH 2019, Abstract 60.
ORLANDO – A small study suggests health care providers may fail to ask patients about heavy menstrual bleeding before or during treatment with oral anticoagulants.
Researchers performed a chart review at a single center, which indicated that 60% of women were not asked about heavy menstrual bleeding before they were prescribed an oral anticoagulant.
Six months after the women started anticoagulant therapy, 29% required treatment for heavy menstrual bleeding. Charts for the remaining 71% of women contained no information about heavy menstrual bleeding.
“We were unable to distinguish between true absence of heavy menstrual bleeding and absence of reporting,” said Bethany T. Samuelson Bannow, MD, of Oregon Health & Science University, Portland.
Dr. Samuelson Bannow presented these findings at the annual meeting of the American Society of Hematology.
She explained that heavy menstrual bleeding is defined as more than 80 mL of blood loss per cycle. It affects 10%-15% of women in their lifetime, and anticoagulants increase the risk of heavy menstrual bleeding.
Studies have shown that heavy menstrual bleeding occurs in 22%-65% of women treated with vitamin K agonists and 20%-27% of women treated with rivaroxaban (Blood. 2017;130[24]:2603-9). However, many anticoagulant studies don’t include heavy menstrual bleeding as an outcome.
To gain more insight, Dr. Samuelson Bannow and colleagues conducted a chart review. Their study included 236 women of reproductive age treated at Oregon Health & Science University between Jan. 1, 2012, and Dec. 31, 2018.
The patients’ median age was 37 years (range, 18-50 years). Most patients (67%) were receiving an oral anticoagulant for venous thromboembolism. The rest were on anticoagulant therapy for arterial thrombosis (6%), atrial fibrillation (6%), a mechanical valve (1%), or “other” reasons (20%).
Dr. Samuelson Bannow said the other group was “almost exclusively women who were receiving prophylaxis” postoperatively or for travel. Most women in this group were receiving rivaroxaban.
Rivaroxaban was the most commonly prescribed anticoagulant in the entire cohort (41%), followed by warfarin (34%) and apixaban (25%).
At the time of anticoagulant prescription, 12% of women reported a history of heavy menstrual bleeding, and 28% did not. For most patients – 60% – there was no discussion of menstrual history documented.
Six months after starting oral anticoagulant therapy, 29% of patients required treatment for heavy menstrual bleeding. For 71% of patients, there was no documentation on the treatment of heavy menstrual bleeding.
Treatment for heavy menstrual bleeding was required in 33% of patients on rivaroxaban, 24% of those on apixaban, and 29% of those on warfarin, a significant difference (P less than .001).
“Rates of heavy menstrual bleeding … are higher in rivaroxaban users,” Dr. Samuelson Bannow said. “This is not the first study to demonstrate this. However, [the rate of heavy menstrual bleeding in this study] is still a lot lower than we would expect based on past levels with warfarin. This tells us we’re probably missing a lot of heavy menstrual bleeding. That’s not too surprising considering how few providers are actually asking about the menses.”
Dr. Samuelson Bannow and colleagues disclosed no conflicts of interest.
SOURCE: Samuelson Bannow BT et al. ASH 2019, Abstract 60.
ORLANDO – A small study suggests health care providers may fail to ask patients about heavy menstrual bleeding before or during treatment with oral anticoagulants.
Researchers performed a chart review at a single center, which indicated that 60% of women were not asked about heavy menstrual bleeding before they were prescribed an oral anticoagulant.
Six months after the women started anticoagulant therapy, 29% required treatment for heavy menstrual bleeding. Charts for the remaining 71% of women contained no information about heavy menstrual bleeding.
“We were unable to distinguish between true absence of heavy menstrual bleeding and absence of reporting,” said Bethany T. Samuelson Bannow, MD, of Oregon Health & Science University, Portland.
Dr. Samuelson Bannow presented these findings at the annual meeting of the American Society of Hematology.
She explained that heavy menstrual bleeding is defined as more than 80 mL of blood loss per cycle. It affects 10%-15% of women in their lifetime, and anticoagulants increase the risk of heavy menstrual bleeding.
Studies have shown that heavy menstrual bleeding occurs in 22%-65% of women treated with vitamin K agonists and 20%-27% of women treated with rivaroxaban (Blood. 2017;130[24]:2603-9). However, many anticoagulant studies don’t include heavy menstrual bleeding as an outcome.
To gain more insight, Dr. Samuelson Bannow and colleagues conducted a chart review. Their study included 236 women of reproductive age treated at Oregon Health & Science University between Jan. 1, 2012, and Dec. 31, 2018.
The patients’ median age was 37 years (range, 18-50 years). Most patients (67%) were receiving an oral anticoagulant for venous thromboembolism. The rest were on anticoagulant therapy for arterial thrombosis (6%), atrial fibrillation (6%), a mechanical valve (1%), or “other” reasons (20%).
Dr. Samuelson Bannow said the other group was “almost exclusively women who were receiving prophylaxis” postoperatively or for travel. Most women in this group were receiving rivaroxaban.
Rivaroxaban was the most commonly prescribed anticoagulant in the entire cohort (41%), followed by warfarin (34%) and apixaban (25%).
At the time of anticoagulant prescription, 12% of women reported a history of heavy menstrual bleeding, and 28% did not. For most patients – 60% – there was no discussion of menstrual history documented.
Six months after starting oral anticoagulant therapy, 29% of patients required treatment for heavy menstrual bleeding. For 71% of patients, there was no documentation on the treatment of heavy menstrual bleeding.
Treatment for heavy menstrual bleeding was required in 33% of patients on rivaroxaban, 24% of those on apixaban, and 29% of those on warfarin, a significant difference (P less than .001).
“Rates of heavy menstrual bleeding … are higher in rivaroxaban users,” Dr. Samuelson Bannow said. “This is not the first study to demonstrate this. However, [the rate of heavy menstrual bleeding in this study] is still a lot lower than we would expect based on past levels with warfarin. This tells us we’re probably missing a lot of heavy menstrual bleeding. That’s not too surprising considering how few providers are actually asking about the menses.”
Dr. Samuelson Bannow and colleagues disclosed no conflicts of interest.
SOURCE: Samuelson Bannow BT et al. ASH 2019, Abstract 60.
REPORTING FROM ASH 2019
Bariatric surgery candidates show high prevalence of thrombophilia
LAS VEGAS – More than half the patients seeking laparoscopic sleeve gastrectomy at a pair of large U.S. programs tested positive for thrombophilia, and for most of these patients, their thrombophilia stemmed from an abnormally elevated level of clotting factor VIII. This thrombophilia seemed to link with a small, but potentially meaningful, excess of portomesenteric venous thrombosis that could warrant treating patients with an anticoagulation regimen for an extended, 30-day period post surgery, Manish S. Parikh, MD, said at a meeting presented by The Obesity Society and the American Society for Metabolic and Bariatric Surgery.
Although measurement of factor VIII excess can be done with a test that costs about $25, Dr. Parikh suggested that giving extended, 30-day anticoagulant prophylaxis to all patients undergoing laparoscopic sleeve gastrectomy (LSG) is a reasonable alternative to screening all patients first. “You could use our data to support 30-day prophylaxis for all LSG patients,” said Dr. Parikh, a metabolic and bariatric surgeon at NYU Langone Health in New York. He acknowledged that some logistic barriers can hamper the efficacy of extended prophylaxis.
The factor VIII elevations seen in many of these obese patients seeking metabolic surgery seems to be inherent and independent of their current weight. Although Dr. Parikh and his associates do not have long-term follow-up for all their LSG patients, “we’ve followed some patients, and their factor VIII is still elevated years later, after they’ve lost weight. We encourage lifelong anticoagulation [for these patients] because of their high risk for recurrent clot. This reflects their factor VIII and is independent of weight,” he said.
For their study, the researchers considered a factor VIII level above 150% of the normal level as abnormally elevated and prothrombotic.
The increased rate of portomesenteric venous thrombosis (PMVT) seen in the thrombophilic patients after LSG “is strongly related to the sleeve specifically,” added Dr. Parikh. He suggested that “something related to redirection of blood flow by taking the branches of the gastroepiploic arcade may lead to this.”
The interest of Dr. Parikh and his associates in thrombophilia and factor VIII excess began with a review they ran of more than 25,000 patients who underwent bariatric surgery at six U.S. centers during 2006-2016 that identified 40 patients who developed PMVT, all from the subgroup of nearly 10,000 patients who had LSG for their bariatric procedure. The prevalence of thrombophilia among those 40 patients with PMVT was 92%, with 76% having excess factor VIII (Surg Obes Relat Dis. 2017;13[11]:1835-9).
Based on those findings, the researchers began a practice of prospectively testing for thrombophilia in all patients who were assessed for LSG at two New York centers during August 2018–March 2019, a total of 1,075 patients, of whom 745 subsequently underwent the procedure. They tested the patients for factor VIII and four additional proteins in the clotting cascade that flag thrombophilia, a test panel that cost $103 per patient. That identified 563 surgery candidates (52%) with any thrombophilia, of whom 92% had excess factor VIII (48% of the total cohort of 1,075). Those patients received an extended, 30-day anticoagulant regimen.
To estimate the impact of this approach, the researchers compared the incidence of PMVT among the recent 745 patients who underwent LSG with a historic control group of 4,228 patients who underwent LSG at the two centers during the 4.5 years before routine thrombophilia screening. None of those 4,228 controls received extended anticoagulation.
During 30-day follow-up, 1 patient in the recent group of 745 patients (0.1%) developed PMVT, whereas 18 of the controls (0.4%) had PMVT. The incidence of bleeding was 0.6% in the recent patients and 0.4% in the controls. The researchers did not report a statistical analysis of these data, because the number of PMVT episodes was too small to allow reliable calculations, Dr. Parikh said. He also cautioned that the generalizability of the finding of thrombophilia prevalence is uncertain because the study population of 1,075 patients considering LSG was 84% Hispanic and 15% non-Hispanic African American.
Dr. Parikh had no disclosures.
SOURCE: Parikh MS et al. Obesity Week 2019, Abstract A109.
Vivek N. Prachand, MD , is professor of surgery and director of minimally invasive surgery at the University of Chicago. He had no disclosures. He made these comments as designated discussant for the report.
Vivek N. Prachand, MD , is professor of surgery and director of minimally invasive surgery at the University of Chicago. He had no disclosures. He made these comments as designated discussant for the report.
Vivek N. Prachand, MD , is professor of surgery and director of minimally invasive surgery at the University of Chicago. He had no disclosures. He made these comments as designated discussant for the report.
LAS VEGAS – More than half the patients seeking laparoscopic sleeve gastrectomy at a pair of large U.S. programs tested positive for thrombophilia, and for most of these patients, their thrombophilia stemmed from an abnormally elevated level of clotting factor VIII. This thrombophilia seemed to link with a small, but potentially meaningful, excess of portomesenteric venous thrombosis that could warrant treating patients with an anticoagulation regimen for an extended, 30-day period post surgery, Manish S. Parikh, MD, said at a meeting presented by The Obesity Society and the American Society for Metabolic and Bariatric Surgery.
Although measurement of factor VIII excess can be done with a test that costs about $25, Dr. Parikh suggested that giving extended, 30-day anticoagulant prophylaxis to all patients undergoing laparoscopic sleeve gastrectomy (LSG) is a reasonable alternative to screening all patients first. “You could use our data to support 30-day prophylaxis for all LSG patients,” said Dr. Parikh, a metabolic and bariatric surgeon at NYU Langone Health in New York. He acknowledged that some logistic barriers can hamper the efficacy of extended prophylaxis.
The factor VIII elevations seen in many of these obese patients seeking metabolic surgery seems to be inherent and independent of their current weight. Although Dr. Parikh and his associates do not have long-term follow-up for all their LSG patients, “we’ve followed some patients, and their factor VIII is still elevated years later, after they’ve lost weight. We encourage lifelong anticoagulation [for these patients] because of their high risk for recurrent clot. This reflects their factor VIII and is independent of weight,” he said.
For their study, the researchers considered a factor VIII level above 150% of the normal level as abnormally elevated and prothrombotic.
The increased rate of portomesenteric venous thrombosis (PMVT) seen in the thrombophilic patients after LSG “is strongly related to the sleeve specifically,” added Dr. Parikh. He suggested that “something related to redirection of blood flow by taking the branches of the gastroepiploic arcade may lead to this.”
The interest of Dr. Parikh and his associates in thrombophilia and factor VIII excess began with a review they ran of more than 25,000 patients who underwent bariatric surgery at six U.S. centers during 2006-2016 that identified 40 patients who developed PMVT, all from the subgroup of nearly 10,000 patients who had LSG for their bariatric procedure. The prevalence of thrombophilia among those 40 patients with PMVT was 92%, with 76% having excess factor VIII (Surg Obes Relat Dis. 2017;13[11]:1835-9).
Based on those findings, the researchers began a practice of prospectively testing for thrombophilia in all patients who were assessed for LSG at two New York centers during August 2018–March 2019, a total of 1,075 patients, of whom 745 subsequently underwent the procedure. They tested the patients for factor VIII and four additional proteins in the clotting cascade that flag thrombophilia, a test panel that cost $103 per patient. That identified 563 surgery candidates (52%) with any thrombophilia, of whom 92% had excess factor VIII (48% of the total cohort of 1,075). Those patients received an extended, 30-day anticoagulant regimen.
To estimate the impact of this approach, the researchers compared the incidence of PMVT among the recent 745 patients who underwent LSG with a historic control group of 4,228 patients who underwent LSG at the two centers during the 4.5 years before routine thrombophilia screening. None of those 4,228 controls received extended anticoagulation.
During 30-day follow-up, 1 patient in the recent group of 745 patients (0.1%) developed PMVT, whereas 18 of the controls (0.4%) had PMVT. The incidence of bleeding was 0.6% in the recent patients and 0.4% in the controls. The researchers did not report a statistical analysis of these data, because the number of PMVT episodes was too small to allow reliable calculations, Dr. Parikh said. He also cautioned that the generalizability of the finding of thrombophilia prevalence is uncertain because the study population of 1,075 patients considering LSG was 84% Hispanic and 15% non-Hispanic African American.
Dr. Parikh had no disclosures.
SOURCE: Parikh MS et al. Obesity Week 2019, Abstract A109.
LAS VEGAS – More than half the patients seeking laparoscopic sleeve gastrectomy at a pair of large U.S. programs tested positive for thrombophilia, and for most of these patients, their thrombophilia stemmed from an abnormally elevated level of clotting factor VIII. This thrombophilia seemed to link with a small, but potentially meaningful, excess of portomesenteric venous thrombosis that could warrant treating patients with an anticoagulation regimen for an extended, 30-day period post surgery, Manish S. Parikh, MD, said at a meeting presented by The Obesity Society and the American Society for Metabolic and Bariatric Surgery.
Although measurement of factor VIII excess can be done with a test that costs about $25, Dr. Parikh suggested that giving extended, 30-day anticoagulant prophylaxis to all patients undergoing laparoscopic sleeve gastrectomy (LSG) is a reasonable alternative to screening all patients first. “You could use our data to support 30-day prophylaxis for all LSG patients,” said Dr. Parikh, a metabolic and bariatric surgeon at NYU Langone Health in New York. He acknowledged that some logistic barriers can hamper the efficacy of extended prophylaxis.
The factor VIII elevations seen in many of these obese patients seeking metabolic surgery seems to be inherent and independent of their current weight. Although Dr. Parikh and his associates do not have long-term follow-up for all their LSG patients, “we’ve followed some patients, and their factor VIII is still elevated years later, after they’ve lost weight. We encourage lifelong anticoagulation [for these patients] because of their high risk for recurrent clot. This reflects their factor VIII and is independent of weight,” he said.
For their study, the researchers considered a factor VIII level above 150% of the normal level as abnormally elevated and prothrombotic.
The increased rate of portomesenteric venous thrombosis (PMVT) seen in the thrombophilic patients after LSG “is strongly related to the sleeve specifically,” added Dr. Parikh. He suggested that “something related to redirection of blood flow by taking the branches of the gastroepiploic arcade may lead to this.”
The interest of Dr. Parikh and his associates in thrombophilia and factor VIII excess began with a review they ran of more than 25,000 patients who underwent bariatric surgery at six U.S. centers during 2006-2016 that identified 40 patients who developed PMVT, all from the subgroup of nearly 10,000 patients who had LSG for their bariatric procedure. The prevalence of thrombophilia among those 40 patients with PMVT was 92%, with 76% having excess factor VIII (Surg Obes Relat Dis. 2017;13[11]:1835-9).
Based on those findings, the researchers began a practice of prospectively testing for thrombophilia in all patients who were assessed for LSG at two New York centers during August 2018–March 2019, a total of 1,075 patients, of whom 745 subsequently underwent the procedure. They tested the patients for factor VIII and four additional proteins in the clotting cascade that flag thrombophilia, a test panel that cost $103 per patient. That identified 563 surgery candidates (52%) with any thrombophilia, of whom 92% had excess factor VIII (48% of the total cohort of 1,075). Those patients received an extended, 30-day anticoagulant regimen.
To estimate the impact of this approach, the researchers compared the incidence of PMVT among the recent 745 patients who underwent LSG with a historic control group of 4,228 patients who underwent LSG at the two centers during the 4.5 years before routine thrombophilia screening. None of those 4,228 controls received extended anticoagulation.
During 30-day follow-up, 1 patient in the recent group of 745 patients (0.1%) developed PMVT, whereas 18 of the controls (0.4%) had PMVT. The incidence of bleeding was 0.6% in the recent patients and 0.4% in the controls. The researchers did not report a statistical analysis of these data, because the number of PMVT episodes was too small to allow reliable calculations, Dr. Parikh said. He also cautioned that the generalizability of the finding of thrombophilia prevalence is uncertain because the study population of 1,075 patients considering LSG was 84% Hispanic and 15% non-Hispanic African American.
Dr. Parikh had no disclosures.
SOURCE: Parikh MS et al. Obesity Week 2019, Abstract A109.
REPORTING FROM OBESITY WEEK 2019
ENGAGE AF-TIMI: Insulin linked to greater risk for stroke, CV death, bleeding
LOS ANGELES – Patients with diabetes had significantly higher adjusted risk of bleeding, cardiovascular-related death, and poorer net outcomes, particularly those treated with insulin, a subanalysis of the ENGAGE AF-TIMI 48 trial has shown.
In addition, the pharmacokinetic and pharmacodynamic profile of the study drug, edoxaban – a novel oral anticoagulant drug and a direct factor Xa inhibitor – was generally similar in patients with and without diabetes.
“We know that atrial fibrillation is associated with a fivefold increased risk of stroke,” Anna Plitt, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Type 2 diabetes is associated with a twofold increased risk of stroke, and longer duration of diabetes is associated with even higher ischemic event rates. The coexistence of [atrial fibrillation] and type 2 diabetes further increases thromboembolic risk.”
Dr. Plitt, a cardiology fellow at Mount Sinai Hospital, New York, noted that, although type 2 diabetes is characterized by a prothrombotic and inflammatory state, the mechanism of action by which hyperglycemia and/or insulin resistance leads to the development of atrial fibrillation (AFib) remains unknown. “Given the complex clinical interactions between AFib and type 2 diabetes, care for these patients remains challenging,” she said. “Recommendations for anticoagulation managements vary based on the presence of additional risk factors and which guidelines are followed.”
In the ENGAGE AF-TIMI 48 trial, 21,105 patients with documented AFib within the previous 12 months were randomized to standard-care warfarin or high-dose edoxaban (60 mg daily) or low-dose edoxaban (30 mg daily). The edoxaban dose was reduced by 50% if creatinine clearance reached 30-50 mL/min, patient weight reached 60 kg or less, or there was concomitant use of a P-glycoprotein inhibitor (N Engl J Med. 2013;369:2093-104). The median follow-up was 2.8 years, and the primary efficacy endpoint was stroke or systemic embolic events (SEEs). The primary safety endpoint was major bleeding, as defined by the International Society on Thrombosis and Haemostasis criteria.
The findings showed that edoxaban was noninferior to warfarin in preventing stroke/SEEs. It also significantly reduced major bleeding, cardiovascular death, and net outcomes. “Therefore, the higher dose of edoxaban was approved globally for treating patients with AFib,” Dr. Plitt said. “The lower-dose regimen was not approved because there was less protection from ischemic stroke, compared with warfarin.”
For the current subanalysis, Dr. Plitt and colleagues set out to further evaluate outcomes of patients enrolled in the ENGAGE AF-TIMI 48 trial, excluding those who were in the low-dose edoxaban group. The presence or absence of diabetes was determined by the local investigator at randomization. The investigators further stratified patients into insulin-treated and non–insulin treated groups and used multivariate Cox regression models to adjust for baseline characteristics across the groups stratified by diabetes status. Next, they analyzed edoxaban concentration, anti–factor Xa activity, and international normalized ratio data and compared outcomes of high-dose edoxaban with those of warfarin.
The primary endpoint and the primary safety endpoint of interest were the same as in the main ENGAGE AF-TIMI 48 trial. Key secondary endpoints included in the subanalysis were cardiovascular death, stroke/SEE, major adverse cardiovascular events (MACE, a composite of myocardial infarction, stroke, SEE, or death because of cardiovascular cause or bleeding), and all-cause death.
In all, 7,624 of the 21,105 patients in the ENGAGE AF-TIMI 48 trial had diabetes, for a rate of 36%. Most of the patients with diabetes did not require insulin (30%), while 6% did. There were fewer female patients with diabetes than without (37% vs. 39%, respectively). Of note was that history of prior stroke/transient ischemic attack was higher in the no-diabetes group than in the diabetes group (33% vs. 21%), as was congestive heart failure (63% vs. 48%).
The mean CHA2DS2-VASc score for predicting thromboembolic risk (0, low risk; greater than 1, high risk) was 4.6 in the diabetes group and 4.2 in the no-diabetes group. When diabetes was not included in the score, the mean CHA2DS2-VASc score was 3.6 in the diabetes group. “Because the trial entry criteria required a minimum CHADS2 score of 2, patients without diabetes were enriched with stroke risk factors other than diabetes,” Dr. Plitt said.
Adjusted outcomes from the subanalysis showed that the risk of stroke/SEE was similar between patients with and without diabetes (hazard ratio, 1.08). However, patients with diabetes were at higher adjusted risk for cardiovascular death than patients without diabetes (HR, 1.29), MACE (HR, 1.28), major bleed (HR, 1.28), and the net outcome of stroke, SEE, major bleed, or all-cause death (HR, 1.25).
The researchers also analyzed the pharmacodynamic and pharmacokinetic data of high-dose edoxaban, stratified by diabetes status. They found that the parameters were generally similar between patients with and without diabetes, including trough concentrations of edoxaban (34.3 and 37.2 ng/mL, respectively; P = .04), trough exogenous anti–factor Xa activity (0.59 and 0.68 IU/mL; P = .11), and the percentage change from baseline in the peak endogenous anti–factor Xa activity (P = .66). The percentage changes from baseline of the trough endogenous anti–factor Xa activity was slightly lower in patients with diabetes, compared with patients without diabetes (P less than .001). “However, these modest differences between the two groups are of unclear clinical significance,” Dr. Plitt said.
Results from the main ENGAGE AF-TIMI 48 showed that the rates of stroke/SEE were reduced by 13% on high-dose edoxaban. However, the subanalysis found no significant effect modification in the reduction in stroke/SEE with edoxaban, compared with warfarin, when stratified by diabetes status (reductions of 16% vs. 7% in the no-diabetes and diabetes groups, respectively; P for interaction = .54). The researchers also observed similar reductions with edoxaban in the risks of secondary outcomes when patients were stratified by diabetes status.
In another finding, patients with diabetes who were treated with insulin were at a higher adjusted risk for all outcomes, compared with those with diabetes who were not treated with insulin. This included stroke/SEE (HR, 1.44), cardiovascular-related death (HR, 1.83), MACE (HR, 1.78), major bleed (HR, 1.31), and net outcome (HR, 1.57).
Next, the researchers compared the study endpoints of high-dose edoxaban and warfarin, with and without insulin. “None of the efficacy, safety, or net outcomes demonstrated evidence of treatment effect modification related to the use of insulin among [patients with diabetes],” she said.
Dr. Plitt disclosed having received honoraria for educational activities from Bristol-Myers Squibb.
LOS ANGELES – Patients with diabetes had significantly higher adjusted risk of bleeding, cardiovascular-related death, and poorer net outcomes, particularly those treated with insulin, a subanalysis of the ENGAGE AF-TIMI 48 trial has shown.
In addition, the pharmacokinetic and pharmacodynamic profile of the study drug, edoxaban – a novel oral anticoagulant drug and a direct factor Xa inhibitor – was generally similar in patients with and without diabetes.
“We know that atrial fibrillation is associated with a fivefold increased risk of stroke,” Anna Plitt, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Type 2 diabetes is associated with a twofold increased risk of stroke, and longer duration of diabetes is associated with even higher ischemic event rates. The coexistence of [atrial fibrillation] and type 2 diabetes further increases thromboembolic risk.”
Dr. Plitt, a cardiology fellow at Mount Sinai Hospital, New York, noted that, although type 2 diabetes is characterized by a prothrombotic and inflammatory state, the mechanism of action by which hyperglycemia and/or insulin resistance leads to the development of atrial fibrillation (AFib) remains unknown. “Given the complex clinical interactions between AFib and type 2 diabetes, care for these patients remains challenging,” she said. “Recommendations for anticoagulation managements vary based on the presence of additional risk factors and which guidelines are followed.”
In the ENGAGE AF-TIMI 48 trial, 21,105 patients with documented AFib within the previous 12 months were randomized to standard-care warfarin or high-dose edoxaban (60 mg daily) or low-dose edoxaban (30 mg daily). The edoxaban dose was reduced by 50% if creatinine clearance reached 30-50 mL/min, patient weight reached 60 kg or less, or there was concomitant use of a P-glycoprotein inhibitor (N Engl J Med. 2013;369:2093-104). The median follow-up was 2.8 years, and the primary efficacy endpoint was stroke or systemic embolic events (SEEs). The primary safety endpoint was major bleeding, as defined by the International Society on Thrombosis and Haemostasis criteria.
The findings showed that edoxaban was noninferior to warfarin in preventing stroke/SEEs. It also significantly reduced major bleeding, cardiovascular death, and net outcomes. “Therefore, the higher dose of edoxaban was approved globally for treating patients with AFib,” Dr. Plitt said. “The lower-dose regimen was not approved because there was less protection from ischemic stroke, compared with warfarin.”
For the current subanalysis, Dr. Plitt and colleagues set out to further evaluate outcomes of patients enrolled in the ENGAGE AF-TIMI 48 trial, excluding those who were in the low-dose edoxaban group. The presence or absence of diabetes was determined by the local investigator at randomization. The investigators further stratified patients into insulin-treated and non–insulin treated groups and used multivariate Cox regression models to adjust for baseline characteristics across the groups stratified by diabetes status. Next, they analyzed edoxaban concentration, anti–factor Xa activity, and international normalized ratio data and compared outcomes of high-dose edoxaban with those of warfarin.
The primary endpoint and the primary safety endpoint of interest were the same as in the main ENGAGE AF-TIMI 48 trial. Key secondary endpoints included in the subanalysis were cardiovascular death, stroke/SEE, major adverse cardiovascular events (MACE, a composite of myocardial infarction, stroke, SEE, or death because of cardiovascular cause or bleeding), and all-cause death.
In all, 7,624 of the 21,105 patients in the ENGAGE AF-TIMI 48 trial had diabetes, for a rate of 36%. Most of the patients with diabetes did not require insulin (30%), while 6% did. There were fewer female patients with diabetes than without (37% vs. 39%, respectively). Of note was that history of prior stroke/transient ischemic attack was higher in the no-diabetes group than in the diabetes group (33% vs. 21%), as was congestive heart failure (63% vs. 48%).
The mean CHA2DS2-VASc score for predicting thromboembolic risk (0, low risk; greater than 1, high risk) was 4.6 in the diabetes group and 4.2 in the no-diabetes group. When diabetes was not included in the score, the mean CHA2DS2-VASc score was 3.6 in the diabetes group. “Because the trial entry criteria required a minimum CHADS2 score of 2, patients without diabetes were enriched with stroke risk factors other than diabetes,” Dr. Plitt said.
Adjusted outcomes from the subanalysis showed that the risk of stroke/SEE was similar between patients with and without diabetes (hazard ratio, 1.08). However, patients with diabetes were at higher adjusted risk for cardiovascular death than patients without diabetes (HR, 1.29), MACE (HR, 1.28), major bleed (HR, 1.28), and the net outcome of stroke, SEE, major bleed, or all-cause death (HR, 1.25).
The researchers also analyzed the pharmacodynamic and pharmacokinetic data of high-dose edoxaban, stratified by diabetes status. They found that the parameters were generally similar between patients with and without diabetes, including trough concentrations of edoxaban (34.3 and 37.2 ng/mL, respectively; P = .04), trough exogenous anti–factor Xa activity (0.59 and 0.68 IU/mL; P = .11), and the percentage change from baseline in the peak endogenous anti–factor Xa activity (P = .66). The percentage changes from baseline of the trough endogenous anti–factor Xa activity was slightly lower in patients with diabetes, compared with patients without diabetes (P less than .001). “However, these modest differences between the two groups are of unclear clinical significance,” Dr. Plitt said.
Results from the main ENGAGE AF-TIMI 48 showed that the rates of stroke/SEE were reduced by 13% on high-dose edoxaban. However, the subanalysis found no significant effect modification in the reduction in stroke/SEE with edoxaban, compared with warfarin, when stratified by diabetes status (reductions of 16% vs. 7% in the no-diabetes and diabetes groups, respectively; P for interaction = .54). The researchers also observed similar reductions with edoxaban in the risks of secondary outcomes when patients were stratified by diabetes status.
In another finding, patients with diabetes who were treated with insulin were at a higher adjusted risk for all outcomes, compared with those with diabetes who were not treated with insulin. This included stroke/SEE (HR, 1.44), cardiovascular-related death (HR, 1.83), MACE (HR, 1.78), major bleed (HR, 1.31), and net outcome (HR, 1.57).
Next, the researchers compared the study endpoints of high-dose edoxaban and warfarin, with and without insulin. “None of the efficacy, safety, or net outcomes demonstrated evidence of treatment effect modification related to the use of insulin among [patients with diabetes],” she said.
Dr. Plitt disclosed having received honoraria for educational activities from Bristol-Myers Squibb.
LOS ANGELES – Patients with diabetes had significantly higher adjusted risk of bleeding, cardiovascular-related death, and poorer net outcomes, particularly those treated with insulin, a subanalysis of the ENGAGE AF-TIMI 48 trial has shown.
In addition, the pharmacokinetic and pharmacodynamic profile of the study drug, edoxaban – a novel oral anticoagulant drug and a direct factor Xa inhibitor – was generally similar in patients with and without diabetes.
“We know that atrial fibrillation is associated with a fivefold increased risk of stroke,” Anna Plitt, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Type 2 diabetes is associated with a twofold increased risk of stroke, and longer duration of diabetes is associated with even higher ischemic event rates. The coexistence of [atrial fibrillation] and type 2 diabetes further increases thromboembolic risk.”
Dr. Plitt, a cardiology fellow at Mount Sinai Hospital, New York, noted that, although type 2 diabetes is characterized by a prothrombotic and inflammatory state, the mechanism of action by which hyperglycemia and/or insulin resistance leads to the development of atrial fibrillation (AFib) remains unknown. “Given the complex clinical interactions between AFib and type 2 diabetes, care for these patients remains challenging,” she said. “Recommendations for anticoagulation managements vary based on the presence of additional risk factors and which guidelines are followed.”
In the ENGAGE AF-TIMI 48 trial, 21,105 patients with documented AFib within the previous 12 months were randomized to standard-care warfarin or high-dose edoxaban (60 mg daily) or low-dose edoxaban (30 mg daily). The edoxaban dose was reduced by 50% if creatinine clearance reached 30-50 mL/min, patient weight reached 60 kg or less, or there was concomitant use of a P-glycoprotein inhibitor (N Engl J Med. 2013;369:2093-104). The median follow-up was 2.8 years, and the primary efficacy endpoint was stroke or systemic embolic events (SEEs). The primary safety endpoint was major bleeding, as defined by the International Society on Thrombosis and Haemostasis criteria.
The findings showed that edoxaban was noninferior to warfarin in preventing stroke/SEEs. It also significantly reduced major bleeding, cardiovascular death, and net outcomes. “Therefore, the higher dose of edoxaban was approved globally for treating patients with AFib,” Dr. Plitt said. “The lower-dose regimen was not approved because there was less protection from ischemic stroke, compared with warfarin.”
For the current subanalysis, Dr. Plitt and colleagues set out to further evaluate outcomes of patients enrolled in the ENGAGE AF-TIMI 48 trial, excluding those who were in the low-dose edoxaban group. The presence or absence of diabetes was determined by the local investigator at randomization. The investigators further stratified patients into insulin-treated and non–insulin treated groups and used multivariate Cox regression models to adjust for baseline characteristics across the groups stratified by diabetes status. Next, they analyzed edoxaban concentration, anti–factor Xa activity, and international normalized ratio data and compared outcomes of high-dose edoxaban with those of warfarin.
The primary endpoint and the primary safety endpoint of interest were the same as in the main ENGAGE AF-TIMI 48 trial. Key secondary endpoints included in the subanalysis were cardiovascular death, stroke/SEE, major adverse cardiovascular events (MACE, a composite of myocardial infarction, stroke, SEE, or death because of cardiovascular cause or bleeding), and all-cause death.
In all, 7,624 of the 21,105 patients in the ENGAGE AF-TIMI 48 trial had diabetes, for a rate of 36%. Most of the patients with diabetes did not require insulin (30%), while 6% did. There were fewer female patients with diabetes than without (37% vs. 39%, respectively). Of note was that history of prior stroke/transient ischemic attack was higher in the no-diabetes group than in the diabetes group (33% vs. 21%), as was congestive heart failure (63% vs. 48%).
The mean CHA2DS2-VASc score for predicting thromboembolic risk (0, low risk; greater than 1, high risk) was 4.6 in the diabetes group and 4.2 in the no-diabetes group. When diabetes was not included in the score, the mean CHA2DS2-VASc score was 3.6 in the diabetes group. “Because the trial entry criteria required a minimum CHADS2 score of 2, patients without diabetes were enriched with stroke risk factors other than diabetes,” Dr. Plitt said.
Adjusted outcomes from the subanalysis showed that the risk of stroke/SEE was similar between patients with and without diabetes (hazard ratio, 1.08). However, patients with diabetes were at higher adjusted risk for cardiovascular death than patients without diabetes (HR, 1.29), MACE (HR, 1.28), major bleed (HR, 1.28), and the net outcome of stroke, SEE, major bleed, or all-cause death (HR, 1.25).
The researchers also analyzed the pharmacodynamic and pharmacokinetic data of high-dose edoxaban, stratified by diabetes status. They found that the parameters were generally similar between patients with and without diabetes, including trough concentrations of edoxaban (34.3 and 37.2 ng/mL, respectively; P = .04), trough exogenous anti–factor Xa activity (0.59 and 0.68 IU/mL; P = .11), and the percentage change from baseline in the peak endogenous anti–factor Xa activity (P = .66). The percentage changes from baseline of the trough endogenous anti–factor Xa activity was slightly lower in patients with diabetes, compared with patients without diabetes (P less than .001). “However, these modest differences between the two groups are of unclear clinical significance,” Dr. Plitt said.
Results from the main ENGAGE AF-TIMI 48 showed that the rates of stroke/SEE were reduced by 13% on high-dose edoxaban. However, the subanalysis found no significant effect modification in the reduction in stroke/SEE with edoxaban, compared with warfarin, when stratified by diabetes status (reductions of 16% vs. 7% in the no-diabetes and diabetes groups, respectively; P for interaction = .54). The researchers also observed similar reductions with edoxaban in the risks of secondary outcomes when patients were stratified by diabetes status.
In another finding, patients with diabetes who were treated with insulin were at a higher adjusted risk for all outcomes, compared with those with diabetes who were not treated with insulin. This included stroke/SEE (HR, 1.44), cardiovascular-related death (HR, 1.83), MACE (HR, 1.78), major bleed (HR, 1.31), and net outcome (HR, 1.57).
Next, the researchers compared the study endpoints of high-dose edoxaban and warfarin, with and without insulin. “None of the efficacy, safety, or net outcomes demonstrated evidence of treatment effect modification related to the use of insulin among [patients with diabetes],” she said.
Dr. Plitt disclosed having received honoraria for educational activities from Bristol-Myers Squibb.
REPORTING FROM THE WCIRDC 2019
New ASH guideline: VTE prophylaxis after major surgery
ORLANDO – The latest American Society of Hematology guideline on venous thromboembolism (VTE) tackles 30 key questions regarding prophylaxis in hospitalized patients undergoing surgery, according to the chair of the guideline panel, who highlighted 9 of those questions during a special session at the society’s annual meeting.
The clinical practice guideline, published just about a week before the annual meeting of the American Society of Hematology, focuses mainly on pharmacologic prophylaxis in specific surgical settings, said David R. Anderson, MD, dean of the faculty of medicine of Dalhousie University, Halifax, N.S.
“Our guidelines focused upon clinically important symptomatic outcomes, with less emphasis being placed on asymptomatic deep vein thrombosis detected by screening tests,” Dr. Anderson said.
At the special education session, Dr. Anderson highlighted several specific recommendations on prophylaxis in surgical patients.
Pharmacologic prophylaxis is not recommended for patients experiencing major trauma deemed to be at high risk of bleeding. Its use does reduce risk of symptomatic pulmonary embolism (PE) and deep vein thrombosis (DVT) by about 10 events per 1,000 patients treated; however, Dr. Anderson said, the panel’s opinion was that this benefit was outweighed by increased risk of major bleeding, at 24 events per 1,000 patients treated.
“We do recommend, however that this risk of bleeding must be reevaluated over the course of recovery of patients, and this may change the decision around this intervention over time,” Dr. Anderson told attendees at the special session.
That’s because pharmacologic prophylaxis is recommended in surgical patients at low to moderate risk of bleeding. In this scenario, the incremental risk of major bleeding (14 events per 1,000 patients treated) is outweighed by the benefit of the reduction of symptomatic VTE events, according to Dr. Anderson.
When pharmacologic prophylaxis is used, the panel recommends combined prophylaxis – mechanical prophylaxis in addition to pharmacologic prophylaxis – especially in those patients at high or very high risk of VTE. Evidence shows that the combination approach significantly reduces risk of PE, and strongly suggests it may also reduce risk of symptomatic proximal DVT, Dr. Anderson said.
In surgical patients not receiving pharmacologic prophylaxis, mechanical prophylaxis is recommended over no mechanical prophylaxis, he added. Moreover, in those patients receiving mechanical prophylaxis, the ASH panel recommends use of intermittent compression devices over graduated compression stockings.
The panel comes out against prophylactic inferior vena cava (IVC) filter insertion in the guidelines. Dr. Anderson said that the “small reduction” in PE risk seen in observational studies is outweighed by increased risk of DVT, and a resulting trend for increased mortality, associated with insertion of the devices.
“We did not consider other risks of IVC filters such as filter embolization or perforation, which again would be complications that would support our recommendation against routine use of these devices in patients undergoing major surgery,” he said.
In terms of the type of pharmacologic prophylaxis to use, the panel said low-molecular-weight heparin or unfractionated heparin would be reasonable choices in this setting. Available data do not demonstrate any significant differences between these choices for major clinical outcomes, Dr. Anderson added.
The guideline also addresses duration of pharmacologic prophylaxis, stating that extended prophylaxis – of at least 3 weeks – is favored over short-term prophylaxis, or up to 2 weeks of treatment. The extended approach significantly reduces risk of symptomatic PE and proximal DVT, though most of the supporting data come from studies of major joint arthroplasty and major general surgical procedures for patients with cancer. “We need more studies in other clinical areas to examine this particular question,” Dr. Anderson said.
The guideline on prophylaxis in surgical patients was published in Blood Advances (2019 Dec 3;3[23]:3898-944). Six other ASH VTE guidelines, all published in 2018, covered prophylaxis in medical patients, diagnosis, VTE in pregnancy, optimal anticoagulation, heparin-induced thrombocytopenia, and pediatric considerations. The guidelines are available on the ASH website.
Dr. Anderson reported having no relevant conflicts of interest.
ORLANDO – The latest American Society of Hematology guideline on venous thromboembolism (VTE) tackles 30 key questions regarding prophylaxis in hospitalized patients undergoing surgery, according to the chair of the guideline panel, who highlighted 9 of those questions during a special session at the society’s annual meeting.
The clinical practice guideline, published just about a week before the annual meeting of the American Society of Hematology, focuses mainly on pharmacologic prophylaxis in specific surgical settings, said David R. Anderson, MD, dean of the faculty of medicine of Dalhousie University, Halifax, N.S.
“Our guidelines focused upon clinically important symptomatic outcomes, with less emphasis being placed on asymptomatic deep vein thrombosis detected by screening tests,” Dr. Anderson said.
At the special education session, Dr. Anderson highlighted several specific recommendations on prophylaxis in surgical patients.
Pharmacologic prophylaxis is not recommended for patients experiencing major trauma deemed to be at high risk of bleeding. Its use does reduce risk of symptomatic pulmonary embolism (PE) and deep vein thrombosis (DVT) by about 10 events per 1,000 patients treated; however, Dr. Anderson said, the panel’s opinion was that this benefit was outweighed by increased risk of major bleeding, at 24 events per 1,000 patients treated.
“We do recommend, however that this risk of bleeding must be reevaluated over the course of recovery of patients, and this may change the decision around this intervention over time,” Dr. Anderson told attendees at the special session.
That’s because pharmacologic prophylaxis is recommended in surgical patients at low to moderate risk of bleeding. In this scenario, the incremental risk of major bleeding (14 events per 1,000 patients treated) is outweighed by the benefit of the reduction of symptomatic VTE events, according to Dr. Anderson.
When pharmacologic prophylaxis is used, the panel recommends combined prophylaxis – mechanical prophylaxis in addition to pharmacologic prophylaxis – especially in those patients at high or very high risk of VTE. Evidence shows that the combination approach significantly reduces risk of PE, and strongly suggests it may also reduce risk of symptomatic proximal DVT, Dr. Anderson said.
In surgical patients not receiving pharmacologic prophylaxis, mechanical prophylaxis is recommended over no mechanical prophylaxis, he added. Moreover, in those patients receiving mechanical prophylaxis, the ASH panel recommends use of intermittent compression devices over graduated compression stockings.
The panel comes out against prophylactic inferior vena cava (IVC) filter insertion in the guidelines. Dr. Anderson said that the “small reduction” in PE risk seen in observational studies is outweighed by increased risk of DVT, and a resulting trend for increased mortality, associated with insertion of the devices.
“We did not consider other risks of IVC filters such as filter embolization or perforation, which again would be complications that would support our recommendation against routine use of these devices in patients undergoing major surgery,” he said.
In terms of the type of pharmacologic prophylaxis to use, the panel said low-molecular-weight heparin or unfractionated heparin would be reasonable choices in this setting. Available data do not demonstrate any significant differences between these choices for major clinical outcomes, Dr. Anderson added.
The guideline also addresses duration of pharmacologic prophylaxis, stating that extended prophylaxis – of at least 3 weeks – is favored over short-term prophylaxis, or up to 2 weeks of treatment. The extended approach significantly reduces risk of symptomatic PE and proximal DVT, though most of the supporting data come from studies of major joint arthroplasty and major general surgical procedures for patients with cancer. “We need more studies in other clinical areas to examine this particular question,” Dr. Anderson said.
The guideline on prophylaxis in surgical patients was published in Blood Advances (2019 Dec 3;3[23]:3898-944). Six other ASH VTE guidelines, all published in 2018, covered prophylaxis in medical patients, diagnosis, VTE in pregnancy, optimal anticoagulation, heparin-induced thrombocytopenia, and pediatric considerations. The guidelines are available on the ASH website.
Dr. Anderson reported having no relevant conflicts of interest.
ORLANDO – The latest American Society of Hematology guideline on venous thromboembolism (VTE) tackles 30 key questions regarding prophylaxis in hospitalized patients undergoing surgery, according to the chair of the guideline panel, who highlighted 9 of those questions during a special session at the society’s annual meeting.
The clinical practice guideline, published just about a week before the annual meeting of the American Society of Hematology, focuses mainly on pharmacologic prophylaxis in specific surgical settings, said David R. Anderson, MD, dean of the faculty of medicine of Dalhousie University, Halifax, N.S.
“Our guidelines focused upon clinically important symptomatic outcomes, with less emphasis being placed on asymptomatic deep vein thrombosis detected by screening tests,” Dr. Anderson said.
At the special education session, Dr. Anderson highlighted several specific recommendations on prophylaxis in surgical patients.
Pharmacologic prophylaxis is not recommended for patients experiencing major trauma deemed to be at high risk of bleeding. Its use does reduce risk of symptomatic pulmonary embolism (PE) and deep vein thrombosis (DVT) by about 10 events per 1,000 patients treated; however, Dr. Anderson said, the panel’s opinion was that this benefit was outweighed by increased risk of major bleeding, at 24 events per 1,000 patients treated.
“We do recommend, however that this risk of bleeding must be reevaluated over the course of recovery of patients, and this may change the decision around this intervention over time,” Dr. Anderson told attendees at the special session.
That’s because pharmacologic prophylaxis is recommended in surgical patients at low to moderate risk of bleeding. In this scenario, the incremental risk of major bleeding (14 events per 1,000 patients treated) is outweighed by the benefit of the reduction of symptomatic VTE events, according to Dr. Anderson.
When pharmacologic prophylaxis is used, the panel recommends combined prophylaxis – mechanical prophylaxis in addition to pharmacologic prophylaxis – especially in those patients at high or very high risk of VTE. Evidence shows that the combination approach significantly reduces risk of PE, and strongly suggests it may also reduce risk of symptomatic proximal DVT, Dr. Anderson said.
In surgical patients not receiving pharmacologic prophylaxis, mechanical prophylaxis is recommended over no mechanical prophylaxis, he added. Moreover, in those patients receiving mechanical prophylaxis, the ASH panel recommends use of intermittent compression devices over graduated compression stockings.
The panel comes out against prophylactic inferior vena cava (IVC) filter insertion in the guidelines. Dr. Anderson said that the “small reduction” in PE risk seen in observational studies is outweighed by increased risk of DVT, and a resulting trend for increased mortality, associated with insertion of the devices.
“We did not consider other risks of IVC filters such as filter embolization or perforation, which again would be complications that would support our recommendation against routine use of these devices in patients undergoing major surgery,” he said.
In terms of the type of pharmacologic prophylaxis to use, the panel said low-molecular-weight heparin or unfractionated heparin would be reasonable choices in this setting. Available data do not demonstrate any significant differences between these choices for major clinical outcomes, Dr. Anderson added.
The guideline also addresses duration of pharmacologic prophylaxis, stating that extended prophylaxis – of at least 3 weeks – is favored over short-term prophylaxis, or up to 2 weeks of treatment. The extended approach significantly reduces risk of symptomatic PE and proximal DVT, though most of the supporting data come from studies of major joint arthroplasty and major general surgical procedures for patients with cancer. “We need more studies in other clinical areas to examine this particular question,” Dr. Anderson said.
The guideline on prophylaxis in surgical patients was published in Blood Advances (2019 Dec 3;3[23]:3898-944). Six other ASH VTE guidelines, all published in 2018, covered prophylaxis in medical patients, diagnosis, VTE in pregnancy, optimal anticoagulation, heparin-induced thrombocytopenia, and pediatric considerations. The guidelines are available on the ASH website.
Dr. Anderson reported having no relevant conflicts of interest.
EXPERT ANALYSIS FROM ASH 2019
Aspirin plus a DOAC may do more harm than good in some
ORLANDO – in a large registry-based cohort.
The study, which involved a cohort of 2,045 patients who were followed at 6 anticoagulation clinics in Michigan during January 2009–June 2019, also found no apparent improvement in thrombosis incidence with the addition of aspirin, Jordan K. Schaefer, MD, reported during a press briefing at the annual meeting of the American Society of Hematology.
Of the cohort patients, 639 adults who received a DOAC plus aspirin after VTE or for NVAF without a clear indication were compared with 639 propensity-matched controls. The bleeding event rate per 100 patient years was 39.50 vs. 32.32 at an average of 15.2 months of follow-up in the combination therapy and DOAC monotherapy groups, respectively, said Dr. Schaefer of the division of hematology/oncology, department of internal medicine, University of Michigan, Ann Arbor.
“This result was statistically significant for clinically relevant non-major bleeding, with an 18.7 rate per 100 patient years, compared with 13.5 for DOAC monotherapy,” (P = .02), he said. “We also saw a significant increase in non-major bleeding with combination therapy, compared with direct oral anticoagulant monotherapy” (rate, 32.82 vs. 25.88; P =.04).
No significant difference was seen overall (P =.07) or for other specific types of bleeding, he noted.
The observed rates of thrombosis in the groups, respectively, were 2.35 and 2.23 per 100 patient years (P =.95), he said, noting that patients on combination therapy also had more emergency department visits and hospitalizations, but those differences were not statistically significant.
“Direct-acting oral anticoagulants, which include apixaban, dabigatran, edoxaban, and rivaroxaban, are increasingly used in clinical practice for indications that include the prevention of strokes for patients with nonvalvular atrial fibrillation, and the treatment and secondary prevention of venous thromboembolic disease,” Dr. Schaefer said.
Aspirin is commonly used in clinical practice for various indications, including primary prevention of heart attacks, strokes, and colorectal cancer, as well as for thromboprophylaxis in patients with certain blood disorders or with certain cardiac devices, he added.
“Aspirin is used for the secondary prevention of thrombosis for patients with known coronary artery disease, peripheral artery disease, or carotid artery disease,” he said. “And while adding aspirin to a DOAC is often appropriate after acute coronary syndromes or percutaneous coronary intervention, many patients receive the combination therapy without a clear indication, he said, noting that increasing evidence in recent years, largely from patients treated with warfarin and aspirin, suggest that the approach may do more harm than good for certain patients.
Specifically, there’s a question of whether aspirin is increasing the rates of bleeding without protecting patients from adverse thrombotic outcomes.
“This has specifically been a concern for patients who are on full-dose anticoagulation,” he said.
In the current study, patient demographics, comorbidities, and concurrent medications were well balanced in the treatment and control groups after propensity score matching, he said, noting that patients with a history of heart valve replacement, recent MI, or less than 3 months of follow-up were excluded.
“These findings need to be confirmed in larger studies, but until such data [are] available, clinicians and patients should continue to balance the relative risks and benefits of adding aspirin to their direct oral anticoagulant therapy,” Dr. Schaefer said. “Further research needs to evaluate key subgroups to see if any particular population may benefit from combination therapy compared to DOAC therapy alone.”
Dr. Schaefer reported having no disclosures.
SOURCE: Schaeffer J et al. ASH 2019. Abstract 787.
ORLANDO – in a large registry-based cohort.
The study, which involved a cohort of 2,045 patients who were followed at 6 anticoagulation clinics in Michigan during January 2009–June 2019, also found no apparent improvement in thrombosis incidence with the addition of aspirin, Jordan K. Schaefer, MD, reported during a press briefing at the annual meeting of the American Society of Hematology.
Of the cohort patients, 639 adults who received a DOAC plus aspirin after VTE or for NVAF without a clear indication were compared with 639 propensity-matched controls. The bleeding event rate per 100 patient years was 39.50 vs. 32.32 at an average of 15.2 months of follow-up in the combination therapy and DOAC monotherapy groups, respectively, said Dr. Schaefer of the division of hematology/oncology, department of internal medicine, University of Michigan, Ann Arbor.
“This result was statistically significant for clinically relevant non-major bleeding, with an 18.7 rate per 100 patient years, compared with 13.5 for DOAC monotherapy,” (P = .02), he said. “We also saw a significant increase in non-major bleeding with combination therapy, compared with direct oral anticoagulant monotherapy” (rate, 32.82 vs. 25.88; P =.04).
No significant difference was seen overall (P =.07) or for other specific types of bleeding, he noted.
The observed rates of thrombosis in the groups, respectively, were 2.35 and 2.23 per 100 patient years (P =.95), he said, noting that patients on combination therapy also had more emergency department visits and hospitalizations, but those differences were not statistically significant.
“Direct-acting oral anticoagulants, which include apixaban, dabigatran, edoxaban, and rivaroxaban, are increasingly used in clinical practice for indications that include the prevention of strokes for patients with nonvalvular atrial fibrillation, and the treatment and secondary prevention of venous thromboembolic disease,” Dr. Schaefer said.
Aspirin is commonly used in clinical practice for various indications, including primary prevention of heart attacks, strokes, and colorectal cancer, as well as for thromboprophylaxis in patients with certain blood disorders or with certain cardiac devices, he added.
“Aspirin is used for the secondary prevention of thrombosis for patients with known coronary artery disease, peripheral artery disease, or carotid artery disease,” he said. “And while adding aspirin to a DOAC is often appropriate after acute coronary syndromes or percutaneous coronary intervention, many patients receive the combination therapy without a clear indication, he said, noting that increasing evidence in recent years, largely from patients treated with warfarin and aspirin, suggest that the approach may do more harm than good for certain patients.
Specifically, there’s a question of whether aspirin is increasing the rates of bleeding without protecting patients from adverse thrombotic outcomes.
“This has specifically been a concern for patients who are on full-dose anticoagulation,” he said.
In the current study, patient demographics, comorbidities, and concurrent medications were well balanced in the treatment and control groups after propensity score matching, he said, noting that patients with a history of heart valve replacement, recent MI, or less than 3 months of follow-up were excluded.
“These findings need to be confirmed in larger studies, but until such data [are] available, clinicians and patients should continue to balance the relative risks and benefits of adding aspirin to their direct oral anticoagulant therapy,” Dr. Schaefer said. “Further research needs to evaluate key subgroups to see if any particular population may benefit from combination therapy compared to DOAC therapy alone.”
Dr. Schaefer reported having no disclosures.
SOURCE: Schaeffer J et al. ASH 2019. Abstract 787.
ORLANDO – in a large registry-based cohort.
The study, which involved a cohort of 2,045 patients who were followed at 6 anticoagulation clinics in Michigan during January 2009–June 2019, also found no apparent improvement in thrombosis incidence with the addition of aspirin, Jordan K. Schaefer, MD, reported during a press briefing at the annual meeting of the American Society of Hematology.
Of the cohort patients, 639 adults who received a DOAC plus aspirin after VTE or for NVAF without a clear indication were compared with 639 propensity-matched controls. The bleeding event rate per 100 patient years was 39.50 vs. 32.32 at an average of 15.2 months of follow-up in the combination therapy and DOAC monotherapy groups, respectively, said Dr. Schaefer of the division of hematology/oncology, department of internal medicine, University of Michigan, Ann Arbor.
“This result was statistically significant for clinically relevant non-major bleeding, with an 18.7 rate per 100 patient years, compared with 13.5 for DOAC monotherapy,” (P = .02), he said. “We also saw a significant increase in non-major bleeding with combination therapy, compared with direct oral anticoagulant monotherapy” (rate, 32.82 vs. 25.88; P =.04).
No significant difference was seen overall (P =.07) or for other specific types of bleeding, he noted.
The observed rates of thrombosis in the groups, respectively, were 2.35 and 2.23 per 100 patient years (P =.95), he said, noting that patients on combination therapy also had more emergency department visits and hospitalizations, but those differences were not statistically significant.
“Direct-acting oral anticoagulants, which include apixaban, dabigatran, edoxaban, and rivaroxaban, are increasingly used in clinical practice for indications that include the prevention of strokes for patients with nonvalvular atrial fibrillation, and the treatment and secondary prevention of venous thromboembolic disease,” Dr. Schaefer said.
Aspirin is commonly used in clinical practice for various indications, including primary prevention of heart attacks, strokes, and colorectal cancer, as well as for thromboprophylaxis in patients with certain blood disorders or with certain cardiac devices, he added.
“Aspirin is used for the secondary prevention of thrombosis for patients with known coronary artery disease, peripheral artery disease, or carotid artery disease,” he said. “And while adding aspirin to a DOAC is often appropriate after acute coronary syndromes or percutaneous coronary intervention, many patients receive the combination therapy without a clear indication, he said, noting that increasing evidence in recent years, largely from patients treated with warfarin and aspirin, suggest that the approach may do more harm than good for certain patients.
Specifically, there’s a question of whether aspirin is increasing the rates of bleeding without protecting patients from adverse thrombotic outcomes.
“This has specifically been a concern for patients who are on full-dose anticoagulation,” he said.
In the current study, patient demographics, comorbidities, and concurrent medications were well balanced in the treatment and control groups after propensity score matching, he said, noting that patients with a history of heart valve replacement, recent MI, or less than 3 months of follow-up were excluded.
“These findings need to be confirmed in larger studies, but until such data [are] available, clinicians and patients should continue to balance the relative risks and benefits of adding aspirin to their direct oral anticoagulant therapy,” Dr. Schaefer said. “Further research needs to evaluate key subgroups to see if any particular population may benefit from combination therapy compared to DOAC therapy alone.”
Dr. Schaefer reported having no disclosures.
SOURCE: Schaeffer J et al. ASH 2019. Abstract 787.
REPORTING FROM ASH 2019
Treating LDL to below 70 reduces recurrent stroke
PHILADELPHIA – Treating patients to a lower LDL target after an ischemic stroke of atherosclerotic origin resulted in fewer recurrent strokes or major cardiovascular events, compared with a higher LDL goal, even though the international trial was stopped early because of lack of funding.
“In the Treat Stroke to Target [TST] trial we showed that the group of patients with an atherosclerotic stroke achieving an LDL cholesterol of less than 70 mg/dL had 22% less recurrent ischemic stroke or other major vascular events than the group achieving a LDL cholesterol between 90 and 110 mg/dL,” lead author Pierre Amarenco, MD, chairman of the department of neurology and the stroke center at Bichat Hospital in Paris, said in an interview.
“We avoided more than one in recurrence in five,” he added.
The findings of the investigator-initiated trial were reported during a late-breaking research session at the American Heart Association scientific sessions and simultaneously published online Nov. 18 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1910355).
Discussant Mitchell S.V. Elkind, MD, president-elect of the American Heart Association, called the TST findings “practice confirming” of a strategy many cardiologists already follow for stroke patients.
“The TST study is only the second trial that was done in neurology for stroke prevention using statins and lipid-lowering therapy, and that’s what makes it a hopeful and real advance,” he said in an interview.
To achieve the LDL-lowering goal, two-thirds of patients received a high-dose statin therapy while the remainder received both high-dose statin and ezetimibe (Zetia, Merck). There were no significant increases in intracranial hemorrhage observed between lower- and higher-target groups.
“Now guidelines should move to recommending a target LDL cholesterol of less than 70 mg/dL in all patients with a proven ischemic stroke of atherosclerotic origin,” said Dr. Amarenco, who is also a professor of neurology at Denis Diderot Paris University.
Rare lipid study following stroke
American Heart Association/American Stroke Association guidelines recommend intense statin therapy after an atherothrombotic stroke “but no target level is given to the practitioners,” Dr. Amarenco said. “In reality, most patients receive a reduced dose of statin.”
For example, despite 70% of patients receiving a statin, the average LDL cholesterol level was 92 mg/dL in a real-world registry.
The TST trial is the first major study to evaluate treating to target LDL levels in the ischemic stroke population since the SPARCL trial in 2006. SPARCL was the first randomized, controlled clinical trial to evaluate whether daily statin therapy could reduce the risk of stroke in patients who had suffered a stroke or transient ischemic attack (TIA).
SPARCL demonstrated a 16% risk reduction with atorvastatin 80 mg daily versus placebo, and further risk reduction of 33% among those with carotid stenosis, over 5 years. There was some concern about safety for a time; post-hoc analysis showed what appeared to be an increased risk for intracranial hemorrhage with statin treatment. Subsequent analyses seemed to suggest the finding may have been a chance one, however.
For the TST study, Dr. Amarenco and colleagues enrolled participants between March 2010 and December 2018 at one of 61 centers in France. In 2015, the study expanded to include 16 sites in South Korea.
Investigators evaluated participants after an ischemic stroke or a TIA with evidence of atherosclerosis. Blood pressure, smoking cessation, and diabetes were well controlled, he said.
Dr. Amarenco and colleagues randomly assigned 1,430 participants to the low–LDL cholesterol target group, less than 70 mg/dL, and another 1,430 to a high-LDL group with a target of 100 mg/dL.
Assessments were every 6 months and up to 1 year after the last patient joined the study.
Treatment with any available statin on the market was allowed. Ezetimibe could be added on top of statin therapy as necessary. A total of 55% were statin naive at study entry.
Study stopped early
The trial was stopped in May 2019 after allocated funds ran out. At this point, researchers had 277 events to analyze, although their initial goal was to reach 385.
The primary endpoint of this event-driven trial was a composite of nonfatal stroke, nonfatal MI, and unstable angina followed by urgent coronary revascularization; TIA followed by urgent carotid revascularization; or cardiovascular death, including sudden deaths.
The endpoint was experienced by 8.5% of participants in the lower-target group versus 10.9% of those in the higher-target group. This translated to a 22% relative risk reduction (adjusted hazard ratio, 0.78; 95% confidence interval, 0.68-0.98; P =.04).
A total of 86% of participants had an ischemic stroke confirmed by brain MRI or CT scan. In this group, the relative risk reduction was 33% – “meaning that we could avoid one-third of recurrent major vascular events,” Dr. Amarenco said.
Furthermore, targeting the lower LDL levels was associated with a relative risk reduction of 40% among those with diabetes.
Secondary outcomes not significant
The investigators used hierarchical testing to compare two outcomes at a time in a prespecified order. They planned to continue this strategy until a comparison emerged as nonsignificant.
This occurred right away when their first composite secondary endpoint comparison between nonfatal MI and urgent revascularization was found to be not significantly different between groups (P = .12).
The early ending “weakened the results of the trial, and the results should be taken with caution because of that,” Dr. Amarenco said.
In addition, the number of hemorrhagic strokes did not differ significantly between groups. There were 18 of these events in the lower-target group and 13 in the higher-target cohort.
That numerical increase in intracranial hemorrhage was “driven by the Korean patients. … and that is something we will report soon,” Dr. Amarenco said.
Interestingly, the researchers also evaluated how much time participants spent within the target LDL cholesterol range, averaged by study site. They found that 53% of the lower–LDL target group, for example, was in the therapeutic range on average during the study.
When Dr. Amarenco and colleagues looked at participants who managed to spend 50%-100% in the target range, the relative risk reduction was 36%.
“So we can hypothesize that, if we had used a more potent drug like PCSK9 inhibitors to be closer to 100% in the therapeutic range, we may have had a greater effect size,” Dr. Amarenco said.
“Our results suggest that LDL cholesterol is causally related to atherosclerosis and confirm that the lower the LDL cholesterol the better,” Dr. Amarenco said.
“Future trials should explore the efficacy and safety of lowering LDL cholesterol to very low levels such as less than 55 mg/dL or even 30 mg/dL (as obtained in the FOURIER trial) by using PCSK9 inhibitors or equivalent in patients with an ischemic stroke due to atherosclerotic disease,” Dr. Amarenco said.
‘Practice-confirming’ findings
The findings are also in line with secondary analyses of the WASID (Neurology. 1995 Aug;45[8]:1488-93) and SAMMPRIS trials, which should dispel some concerns that persist about taking LDL to such low levels that it increases risk of intracerebral hemorrhage, Dr. Amarenco noted.
However, TST, he said, didn’t provide clear answers on what specific subgroups of patients with a stroke history would benefit from aggressive lipid lowering.
“What is stroke without atherosclerotic disease?” he said. “Some people say small-vessel disease is also a form of atherosclerosis, and most patients with atrial fibrillation, which is increasingly recognized as a cause of stroke, are also going to have atherosclerosis of the heart as well as the brain and blood vessels.
“Many, many stroke patients will fall into this category,” Dr. Elkind said, “and the question is, should they be treated more aggressively with lipid lowering?”
“The results of this study fit pretty nicely into the rubric of the AHA cholesterol guidelines,” said Donald M. Lloyd-Jones, MD, chairman, department of preventive medicine at Northwestern University Feinberg School of Medicine, Chicago, and chair of the AHA’s 2019 Council on Scientific Sessions Programming. Dr. Lloyd-Jones was also a member of the guideline committee.
Stroke patients are not “garden variety coronary patients,” he said. “The concern about intracerebral hemorrhage continues to be something that we wonder about: Should we be driving our stroke patients as low as our coronary patients? I think these data will certainly help us.”
Consideration for future guidelines
The study would have been more helpful if it provided more detail about the treatment regimens used, Jennifer Robinson, MD, director of the prevention intervention center, department of epidemiology, University of Iowa, said in an interview.
“What was the dose intensity of statins the patients were on?” Dr. Robinson said. “Part of our struggle has been to convince people to use high-intensity statins – get the maximum from statins that are generic now and cost saving in even very low-risk primary prevention patients.”
She said that a third of patients in TST also took ezetimibe with the statin “makes sense” because of its generic status.
Nonetheless, Dr. Robinson said, TST adds to the evidence that LDL of 100 mg/dL is not good enough, that high-intensity statin therapy is superior to a moderate regimen and that adding a nonstatin – ezetimibe in TST – can derive added benefit.
The TST findings may give guideline writers direction going forward, she said. “We really need to start thinking about the potential for net benefit from added therapy, whether it’s from intensifying LDL lowering, adding icosapent ethyl (Vascepa, Amarin), which seems to have remarkable benefits, or SGLT2 inhibitor,” she said.
“There are a lot of options,” Dr. Robinson said. “We need to have an outlook beyond just treating to target with what really is the best maximized accepted therapy.”
TST was funded primarily by French Government, but also with grants from Pfizer, Astra Zeneca and Merck. Dr. Amarenco disclosed that he is a consultant or advisor to Modest, Sanofi, Bristol-Myers Squibb, and Amgen; receives honoraria from Modest, Amgen, Kowa, Shing Poon, Kowa, Bayer, GSK, Fibrogen, and AstraZeneca. He also receives research grants from Pfizer, Astra Zeneca, Sanofi, BMS, Merck, Boston Scientific, and the French Government.
This article also appears on Medscape.com.
SOURCE: Amarenco P. ACC 2019, Late Breaking Science 6 session.
PHILADELPHIA – Treating patients to a lower LDL target after an ischemic stroke of atherosclerotic origin resulted in fewer recurrent strokes or major cardiovascular events, compared with a higher LDL goal, even though the international trial was stopped early because of lack of funding.
“In the Treat Stroke to Target [TST] trial we showed that the group of patients with an atherosclerotic stroke achieving an LDL cholesterol of less than 70 mg/dL had 22% less recurrent ischemic stroke or other major vascular events than the group achieving a LDL cholesterol between 90 and 110 mg/dL,” lead author Pierre Amarenco, MD, chairman of the department of neurology and the stroke center at Bichat Hospital in Paris, said in an interview.
“We avoided more than one in recurrence in five,” he added.
The findings of the investigator-initiated trial were reported during a late-breaking research session at the American Heart Association scientific sessions and simultaneously published online Nov. 18 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1910355).
Discussant Mitchell S.V. Elkind, MD, president-elect of the American Heart Association, called the TST findings “practice confirming” of a strategy many cardiologists already follow for stroke patients.
“The TST study is only the second trial that was done in neurology for stroke prevention using statins and lipid-lowering therapy, and that’s what makes it a hopeful and real advance,” he said in an interview.
To achieve the LDL-lowering goal, two-thirds of patients received a high-dose statin therapy while the remainder received both high-dose statin and ezetimibe (Zetia, Merck). There were no significant increases in intracranial hemorrhage observed between lower- and higher-target groups.
“Now guidelines should move to recommending a target LDL cholesterol of less than 70 mg/dL in all patients with a proven ischemic stroke of atherosclerotic origin,” said Dr. Amarenco, who is also a professor of neurology at Denis Diderot Paris University.
Rare lipid study following stroke
American Heart Association/American Stroke Association guidelines recommend intense statin therapy after an atherothrombotic stroke “but no target level is given to the practitioners,” Dr. Amarenco said. “In reality, most patients receive a reduced dose of statin.”
For example, despite 70% of patients receiving a statin, the average LDL cholesterol level was 92 mg/dL in a real-world registry.
The TST trial is the first major study to evaluate treating to target LDL levels in the ischemic stroke population since the SPARCL trial in 2006. SPARCL was the first randomized, controlled clinical trial to evaluate whether daily statin therapy could reduce the risk of stroke in patients who had suffered a stroke or transient ischemic attack (TIA).
SPARCL demonstrated a 16% risk reduction with atorvastatin 80 mg daily versus placebo, and further risk reduction of 33% among those with carotid stenosis, over 5 years. There was some concern about safety for a time; post-hoc analysis showed what appeared to be an increased risk for intracranial hemorrhage with statin treatment. Subsequent analyses seemed to suggest the finding may have been a chance one, however.
For the TST study, Dr. Amarenco and colleagues enrolled participants between March 2010 and December 2018 at one of 61 centers in France. In 2015, the study expanded to include 16 sites in South Korea.
Investigators evaluated participants after an ischemic stroke or a TIA with evidence of atherosclerosis. Blood pressure, smoking cessation, and diabetes were well controlled, he said.
Dr. Amarenco and colleagues randomly assigned 1,430 participants to the low–LDL cholesterol target group, less than 70 mg/dL, and another 1,430 to a high-LDL group with a target of 100 mg/dL.
Assessments were every 6 months and up to 1 year after the last patient joined the study.
Treatment with any available statin on the market was allowed. Ezetimibe could be added on top of statin therapy as necessary. A total of 55% were statin naive at study entry.
Study stopped early
The trial was stopped in May 2019 after allocated funds ran out. At this point, researchers had 277 events to analyze, although their initial goal was to reach 385.
The primary endpoint of this event-driven trial was a composite of nonfatal stroke, nonfatal MI, and unstable angina followed by urgent coronary revascularization; TIA followed by urgent carotid revascularization; or cardiovascular death, including sudden deaths.
The endpoint was experienced by 8.5% of participants in the lower-target group versus 10.9% of those in the higher-target group. This translated to a 22% relative risk reduction (adjusted hazard ratio, 0.78; 95% confidence interval, 0.68-0.98; P =.04).
A total of 86% of participants had an ischemic stroke confirmed by brain MRI or CT scan. In this group, the relative risk reduction was 33% – “meaning that we could avoid one-third of recurrent major vascular events,” Dr. Amarenco said.
Furthermore, targeting the lower LDL levels was associated with a relative risk reduction of 40% among those with diabetes.
Secondary outcomes not significant
The investigators used hierarchical testing to compare two outcomes at a time in a prespecified order. They planned to continue this strategy until a comparison emerged as nonsignificant.
This occurred right away when their first composite secondary endpoint comparison between nonfatal MI and urgent revascularization was found to be not significantly different between groups (P = .12).
The early ending “weakened the results of the trial, and the results should be taken with caution because of that,” Dr. Amarenco said.
In addition, the number of hemorrhagic strokes did not differ significantly between groups. There were 18 of these events in the lower-target group and 13 in the higher-target cohort.
That numerical increase in intracranial hemorrhage was “driven by the Korean patients. … and that is something we will report soon,” Dr. Amarenco said.
Interestingly, the researchers also evaluated how much time participants spent within the target LDL cholesterol range, averaged by study site. They found that 53% of the lower–LDL target group, for example, was in the therapeutic range on average during the study.
When Dr. Amarenco and colleagues looked at participants who managed to spend 50%-100% in the target range, the relative risk reduction was 36%.
“So we can hypothesize that, if we had used a more potent drug like PCSK9 inhibitors to be closer to 100% in the therapeutic range, we may have had a greater effect size,” Dr. Amarenco said.
“Our results suggest that LDL cholesterol is causally related to atherosclerosis and confirm that the lower the LDL cholesterol the better,” Dr. Amarenco said.
“Future trials should explore the efficacy and safety of lowering LDL cholesterol to very low levels such as less than 55 mg/dL or even 30 mg/dL (as obtained in the FOURIER trial) by using PCSK9 inhibitors or equivalent in patients with an ischemic stroke due to atherosclerotic disease,” Dr. Amarenco said.
‘Practice-confirming’ findings
The findings are also in line with secondary analyses of the WASID (Neurology. 1995 Aug;45[8]:1488-93) and SAMMPRIS trials, which should dispel some concerns that persist about taking LDL to such low levels that it increases risk of intracerebral hemorrhage, Dr. Amarenco noted.
However, TST, he said, didn’t provide clear answers on what specific subgroups of patients with a stroke history would benefit from aggressive lipid lowering.
“What is stroke without atherosclerotic disease?” he said. “Some people say small-vessel disease is also a form of atherosclerosis, and most patients with atrial fibrillation, which is increasingly recognized as a cause of stroke, are also going to have atherosclerosis of the heart as well as the brain and blood vessels.
“Many, many stroke patients will fall into this category,” Dr. Elkind said, “and the question is, should they be treated more aggressively with lipid lowering?”
“The results of this study fit pretty nicely into the rubric of the AHA cholesterol guidelines,” said Donald M. Lloyd-Jones, MD, chairman, department of preventive medicine at Northwestern University Feinberg School of Medicine, Chicago, and chair of the AHA’s 2019 Council on Scientific Sessions Programming. Dr. Lloyd-Jones was also a member of the guideline committee.
Stroke patients are not “garden variety coronary patients,” he said. “The concern about intracerebral hemorrhage continues to be something that we wonder about: Should we be driving our stroke patients as low as our coronary patients? I think these data will certainly help us.”
Consideration for future guidelines
The study would have been more helpful if it provided more detail about the treatment regimens used, Jennifer Robinson, MD, director of the prevention intervention center, department of epidemiology, University of Iowa, said in an interview.
“What was the dose intensity of statins the patients were on?” Dr. Robinson said. “Part of our struggle has been to convince people to use high-intensity statins – get the maximum from statins that are generic now and cost saving in even very low-risk primary prevention patients.”
She said that a third of patients in TST also took ezetimibe with the statin “makes sense” because of its generic status.
Nonetheless, Dr. Robinson said, TST adds to the evidence that LDL of 100 mg/dL is not good enough, that high-intensity statin therapy is superior to a moderate regimen and that adding a nonstatin – ezetimibe in TST – can derive added benefit.
The TST findings may give guideline writers direction going forward, she said. “We really need to start thinking about the potential for net benefit from added therapy, whether it’s from intensifying LDL lowering, adding icosapent ethyl (Vascepa, Amarin), which seems to have remarkable benefits, or SGLT2 inhibitor,” she said.
“There are a lot of options,” Dr. Robinson said. “We need to have an outlook beyond just treating to target with what really is the best maximized accepted therapy.”
TST was funded primarily by French Government, but also with grants from Pfizer, Astra Zeneca and Merck. Dr. Amarenco disclosed that he is a consultant or advisor to Modest, Sanofi, Bristol-Myers Squibb, and Amgen; receives honoraria from Modest, Amgen, Kowa, Shing Poon, Kowa, Bayer, GSK, Fibrogen, and AstraZeneca. He also receives research grants from Pfizer, Astra Zeneca, Sanofi, BMS, Merck, Boston Scientific, and the French Government.
This article also appears on Medscape.com.
SOURCE: Amarenco P. ACC 2019, Late Breaking Science 6 session.
PHILADELPHIA – Treating patients to a lower LDL target after an ischemic stroke of atherosclerotic origin resulted in fewer recurrent strokes or major cardiovascular events, compared with a higher LDL goal, even though the international trial was stopped early because of lack of funding.
“In the Treat Stroke to Target [TST] trial we showed that the group of patients with an atherosclerotic stroke achieving an LDL cholesterol of less than 70 mg/dL had 22% less recurrent ischemic stroke or other major vascular events than the group achieving a LDL cholesterol between 90 and 110 mg/dL,” lead author Pierre Amarenco, MD, chairman of the department of neurology and the stroke center at Bichat Hospital in Paris, said in an interview.
“We avoided more than one in recurrence in five,” he added.
The findings of the investigator-initiated trial were reported during a late-breaking research session at the American Heart Association scientific sessions and simultaneously published online Nov. 18 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1910355).
Discussant Mitchell S.V. Elkind, MD, president-elect of the American Heart Association, called the TST findings “practice confirming” of a strategy many cardiologists already follow for stroke patients.
“The TST study is only the second trial that was done in neurology for stroke prevention using statins and lipid-lowering therapy, and that’s what makes it a hopeful and real advance,” he said in an interview.
To achieve the LDL-lowering goal, two-thirds of patients received a high-dose statin therapy while the remainder received both high-dose statin and ezetimibe (Zetia, Merck). There were no significant increases in intracranial hemorrhage observed between lower- and higher-target groups.
“Now guidelines should move to recommending a target LDL cholesterol of less than 70 mg/dL in all patients with a proven ischemic stroke of atherosclerotic origin,” said Dr. Amarenco, who is also a professor of neurology at Denis Diderot Paris University.
Rare lipid study following stroke
American Heart Association/American Stroke Association guidelines recommend intense statin therapy after an atherothrombotic stroke “but no target level is given to the practitioners,” Dr. Amarenco said. “In reality, most patients receive a reduced dose of statin.”
For example, despite 70% of patients receiving a statin, the average LDL cholesterol level was 92 mg/dL in a real-world registry.
The TST trial is the first major study to evaluate treating to target LDL levels in the ischemic stroke population since the SPARCL trial in 2006. SPARCL was the first randomized, controlled clinical trial to evaluate whether daily statin therapy could reduce the risk of stroke in patients who had suffered a stroke or transient ischemic attack (TIA).
SPARCL demonstrated a 16% risk reduction with atorvastatin 80 mg daily versus placebo, and further risk reduction of 33% among those with carotid stenosis, over 5 years. There was some concern about safety for a time; post-hoc analysis showed what appeared to be an increased risk for intracranial hemorrhage with statin treatment. Subsequent analyses seemed to suggest the finding may have been a chance one, however.
For the TST study, Dr. Amarenco and colleagues enrolled participants between March 2010 and December 2018 at one of 61 centers in France. In 2015, the study expanded to include 16 sites in South Korea.
Investigators evaluated participants after an ischemic stroke or a TIA with evidence of atherosclerosis. Blood pressure, smoking cessation, and diabetes were well controlled, he said.
Dr. Amarenco and colleagues randomly assigned 1,430 participants to the low–LDL cholesterol target group, less than 70 mg/dL, and another 1,430 to a high-LDL group with a target of 100 mg/dL.
Assessments were every 6 months and up to 1 year after the last patient joined the study.
Treatment with any available statin on the market was allowed. Ezetimibe could be added on top of statin therapy as necessary. A total of 55% were statin naive at study entry.
Study stopped early
The trial was stopped in May 2019 after allocated funds ran out. At this point, researchers had 277 events to analyze, although their initial goal was to reach 385.
The primary endpoint of this event-driven trial was a composite of nonfatal stroke, nonfatal MI, and unstable angina followed by urgent coronary revascularization; TIA followed by urgent carotid revascularization; or cardiovascular death, including sudden deaths.
The endpoint was experienced by 8.5% of participants in the lower-target group versus 10.9% of those in the higher-target group. This translated to a 22% relative risk reduction (adjusted hazard ratio, 0.78; 95% confidence interval, 0.68-0.98; P =.04).
A total of 86% of participants had an ischemic stroke confirmed by brain MRI or CT scan. In this group, the relative risk reduction was 33% – “meaning that we could avoid one-third of recurrent major vascular events,” Dr. Amarenco said.
Furthermore, targeting the lower LDL levels was associated with a relative risk reduction of 40% among those with diabetes.
Secondary outcomes not significant
The investigators used hierarchical testing to compare two outcomes at a time in a prespecified order. They planned to continue this strategy until a comparison emerged as nonsignificant.
This occurred right away when their first composite secondary endpoint comparison between nonfatal MI and urgent revascularization was found to be not significantly different between groups (P = .12).
The early ending “weakened the results of the trial, and the results should be taken with caution because of that,” Dr. Amarenco said.
In addition, the number of hemorrhagic strokes did not differ significantly between groups. There were 18 of these events in the lower-target group and 13 in the higher-target cohort.
That numerical increase in intracranial hemorrhage was “driven by the Korean patients. … and that is something we will report soon,” Dr. Amarenco said.
Interestingly, the researchers also evaluated how much time participants spent within the target LDL cholesterol range, averaged by study site. They found that 53% of the lower–LDL target group, for example, was in the therapeutic range on average during the study.
When Dr. Amarenco and colleagues looked at participants who managed to spend 50%-100% in the target range, the relative risk reduction was 36%.
“So we can hypothesize that, if we had used a more potent drug like PCSK9 inhibitors to be closer to 100% in the therapeutic range, we may have had a greater effect size,” Dr. Amarenco said.
“Our results suggest that LDL cholesterol is causally related to atherosclerosis and confirm that the lower the LDL cholesterol the better,” Dr. Amarenco said.
“Future trials should explore the efficacy and safety of lowering LDL cholesterol to very low levels such as less than 55 mg/dL or even 30 mg/dL (as obtained in the FOURIER trial) by using PCSK9 inhibitors or equivalent in patients with an ischemic stroke due to atherosclerotic disease,” Dr. Amarenco said.
‘Practice-confirming’ findings
The findings are also in line with secondary analyses of the WASID (Neurology. 1995 Aug;45[8]:1488-93) and SAMMPRIS trials, which should dispel some concerns that persist about taking LDL to such low levels that it increases risk of intracerebral hemorrhage, Dr. Amarenco noted.
However, TST, he said, didn’t provide clear answers on what specific subgroups of patients with a stroke history would benefit from aggressive lipid lowering.
“What is stroke without atherosclerotic disease?” he said. “Some people say small-vessel disease is also a form of atherosclerosis, and most patients with atrial fibrillation, which is increasingly recognized as a cause of stroke, are also going to have atherosclerosis of the heart as well as the brain and blood vessels.
“Many, many stroke patients will fall into this category,” Dr. Elkind said, “and the question is, should they be treated more aggressively with lipid lowering?”
“The results of this study fit pretty nicely into the rubric of the AHA cholesterol guidelines,” said Donald M. Lloyd-Jones, MD, chairman, department of preventive medicine at Northwestern University Feinberg School of Medicine, Chicago, and chair of the AHA’s 2019 Council on Scientific Sessions Programming. Dr. Lloyd-Jones was also a member of the guideline committee.
Stroke patients are not “garden variety coronary patients,” he said. “The concern about intracerebral hemorrhage continues to be something that we wonder about: Should we be driving our stroke patients as low as our coronary patients? I think these data will certainly help us.”
Consideration for future guidelines
The study would have been more helpful if it provided more detail about the treatment regimens used, Jennifer Robinson, MD, director of the prevention intervention center, department of epidemiology, University of Iowa, said in an interview.
“What was the dose intensity of statins the patients were on?” Dr. Robinson said. “Part of our struggle has been to convince people to use high-intensity statins – get the maximum from statins that are generic now and cost saving in even very low-risk primary prevention patients.”
She said that a third of patients in TST also took ezetimibe with the statin “makes sense” because of its generic status.
Nonetheless, Dr. Robinson said, TST adds to the evidence that LDL of 100 mg/dL is not good enough, that high-intensity statin therapy is superior to a moderate regimen and that adding a nonstatin – ezetimibe in TST – can derive added benefit.
The TST findings may give guideline writers direction going forward, she said. “We really need to start thinking about the potential for net benefit from added therapy, whether it’s from intensifying LDL lowering, adding icosapent ethyl (Vascepa, Amarin), which seems to have remarkable benefits, or SGLT2 inhibitor,” she said.
“There are a lot of options,” Dr. Robinson said. “We need to have an outlook beyond just treating to target with what really is the best maximized accepted therapy.”
TST was funded primarily by French Government, but also with grants from Pfizer, Astra Zeneca and Merck. Dr. Amarenco disclosed that he is a consultant or advisor to Modest, Sanofi, Bristol-Myers Squibb, and Amgen; receives honoraria from Modest, Amgen, Kowa, Shing Poon, Kowa, Bayer, GSK, Fibrogen, and AstraZeneca. He also receives research grants from Pfizer, Astra Zeneca, Sanofi, BMS, Merck, Boston Scientific, and the French Government.
This article also appears on Medscape.com.
SOURCE: Amarenco P. ACC 2019, Late Breaking Science 6 session.
REPORTING FROM AHA 2019