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Anticoagulation Hub contains news and clinical review articles for physicians seeking the most up-to-date information on the rapidly evolving treatment options for preventing stroke, acute coronary events, deep vein thrombosis, and pulmonary embolism in at-risk patients. The Anticoagulation Hub is powered by Frontline Medical Communications.
Prescribers mostly ignore clopidogrel pharmacogenomic profiling
ANAHEIM, CALIF. – The boxed warning recommending pharmacogenomic testing of patients receiving clopidogrel to identify reduced metabolizers seems to be playing to a largely deaf audience.
Even when handed information on whether each clopidogrel-treated patient was a poor metabolizer of the drug, treating physicians usually did not switch them to a different antiplatelet drug, ticagrelor, that would be fully effective despite the patient’s reduced-metabolizer status. And clinicians who started patients on ticagrelor did not usually switch those with a good clopidogrel-metabolizing profile to the safer drug, clopidogrel, after learning that clopidogrel would be fully effective.
“Routine reporting of pharmacogenomics test results for acute coronary syndrome patients treated with P2Y12-inhibitor therapy had an uncertain yield and little impact on P2Y12-inhibitor switching,” E. Magnus Ohman, MBBS, said at the American Heart Association scientific sessions.
The study’s design gave each participating clinician free rein on whether to prescribe clopidogrel or ticagrelor (Brilinta) initially, and switching between the drugs was possible at any time after the initial prescription. At the trial’s start, 1,704 patients (56%) were on ticagrelor and 1,333 (44%) were on clopidogrel.
Pharmacogenomic testing showed that 34% of all patients were ultrametabolizers and 38% were extensive metabolizers. Patients in either of these categories metabolize enough clopidogrel into the active form to get full benefit from the drug and derive no additional efficacy benefit from switching to another P2Y12 inhibitor, such as ticagrelor or prasugrel (Effient) – drugs unaffected by metabolizer status. Testing also identified 25% of patients as intermediate metabolizers, who carry one loss-of-function allele for the CYP2C19 gene, and 3% were reduced metabolizers, who are homozygous for loss-of-function alleles. Standard practice is not to treat intermediate or reduced metabolizers with clopidogrel because they would not get an adequate antiplatelet effect; instead, these patients are usually treated with ticagrelor or with prasugrel when it’s an option.
After receiving the results regarding the clopidogrel-metabolizing status for each patient, attending physicians switched the drugs prescribed for only 7% of all patients: 9% of patients initially on ticagrelor and 4% of those initially on clopidogrel, reported Dr. Ohman, professor of medicine at Duke University in Durham, N.C. In addition, Dr. Ohman and his associates asked each participating physician who made a switch about his or her reasons for doing so. Of the patients who switched from clopidogrel to ticagrelor, only 23 were switched because of their pharmacogenomic results; this represents fewer than half of those who switched and only 2% of all patients who took clopidogrel. Only one patient changed from ticagrelor to clopidogrel based on pharmacogenomic results, representing 0.06% of all patients on ticagrelor.
“We believed the findings do not support the utility of mandatory testing in this context, as most did not act on the information,” Dr. Ohman said.
A major reason for the inertia, Dr. Gurbel suggested, may be the absence of any compelling data proving whether there’s any effect on clinical outcomes for switching reduced metabolizers off of clopidogrel or switching good metabolizers onto it.
“We have no large-scale, prospective data supporting pharmacogenomic-based personalization” of clopidogrel treatment leading to improved outcomes, but “we need to get over that,” he said. “It’s a challenge to get funding for this.” But “the answer is not to give ticagrelor or prasugrel to everyone because then the bleeding rate is too high.”
The findings Dr. Ohman reported came from the Study to Compare the Safety of Rivaroxaban Versus Acetylsalicylic Acid in Addition to Either Clopidogrel or Ticagrelor Therapy in Participants With Acute Coronary Syndrome (GEMINI-ACS-1), which had the primary goal of comparing the safety in acute coronary syndrome patients of a reduced dosage of rivaroxaban plus either clopidogrel or ticagrelor with the safety of aspirin plus one of these P2Y12 inhibitors. The primary endpoint was the rate of clinically significant bleeding events during a year of treatment. The study ran at 371 centers in 21 countries and showed similar bleeding rates in both treatment arms (Lancet. 2017 May 6; 389[10081]:1799-808).
The analysis also showed that patients identified as reduced metabolizers were fivefold more likely to be switched than patients identified as ultra metabolizers, and intermediate metabolizes had a 50% higher switching rate than ultra metabolizers. The rates of both ischemic and major bleeding outcomes were roughly similar across the spectrum of metabolizers, but Dr. Ohman cautioned that the trial was not designed to assess this. Dr. Gurbel urged the investigators to report on outcomes analyzed not just by metabolizer status but also by the treatment they received.
The boxed warning that clopidogrel received in 2010 regarding poor metabolizers led to “regulatory guidance” during design of the GEMINI-ACS-1 trial requiring routine pharmacogenomic testing for clopidogrel-metabolizing status, Dr. Ohman explained.
The trial was funded by Janssen and Bayer, the two companies that jointly market rivaroxaban (Xarelto). Dr. Ohman has been a consultant to Bayer and several other companies including AstraZeneca, the company that markets ticagrelor (Brilinta). He has also received research funding from Janssen, as well as Daiichi Sankyo and Gilead Sciences. Dr. Gurbel holds patents on platelet-function testing methods.
[email protected]
On Twitter @mitchelzoler
ANAHEIM, CALIF. – The boxed warning recommending pharmacogenomic testing of patients receiving clopidogrel to identify reduced metabolizers seems to be playing to a largely deaf audience.
Even when handed information on whether each clopidogrel-treated patient was a poor metabolizer of the drug, treating physicians usually did not switch them to a different antiplatelet drug, ticagrelor, that would be fully effective despite the patient’s reduced-metabolizer status. And clinicians who started patients on ticagrelor did not usually switch those with a good clopidogrel-metabolizing profile to the safer drug, clopidogrel, after learning that clopidogrel would be fully effective.
“Routine reporting of pharmacogenomics test results for acute coronary syndrome patients treated with P2Y12-inhibitor therapy had an uncertain yield and little impact on P2Y12-inhibitor switching,” E. Magnus Ohman, MBBS, said at the American Heart Association scientific sessions.
The study’s design gave each participating clinician free rein on whether to prescribe clopidogrel or ticagrelor (Brilinta) initially, and switching between the drugs was possible at any time after the initial prescription. At the trial’s start, 1,704 patients (56%) were on ticagrelor and 1,333 (44%) were on clopidogrel.
Pharmacogenomic testing showed that 34% of all patients were ultrametabolizers and 38% were extensive metabolizers. Patients in either of these categories metabolize enough clopidogrel into the active form to get full benefit from the drug and derive no additional efficacy benefit from switching to another P2Y12 inhibitor, such as ticagrelor or prasugrel (Effient) – drugs unaffected by metabolizer status. Testing also identified 25% of patients as intermediate metabolizers, who carry one loss-of-function allele for the CYP2C19 gene, and 3% were reduced metabolizers, who are homozygous for loss-of-function alleles. Standard practice is not to treat intermediate or reduced metabolizers with clopidogrel because they would not get an adequate antiplatelet effect; instead, these patients are usually treated with ticagrelor or with prasugrel when it’s an option.
After receiving the results regarding the clopidogrel-metabolizing status for each patient, attending physicians switched the drugs prescribed for only 7% of all patients: 9% of patients initially on ticagrelor and 4% of those initially on clopidogrel, reported Dr. Ohman, professor of medicine at Duke University in Durham, N.C. In addition, Dr. Ohman and his associates asked each participating physician who made a switch about his or her reasons for doing so. Of the patients who switched from clopidogrel to ticagrelor, only 23 were switched because of their pharmacogenomic results; this represents fewer than half of those who switched and only 2% of all patients who took clopidogrel. Only one patient changed from ticagrelor to clopidogrel based on pharmacogenomic results, representing 0.06% of all patients on ticagrelor.
“We believed the findings do not support the utility of mandatory testing in this context, as most did not act on the information,” Dr. Ohman said.
A major reason for the inertia, Dr. Gurbel suggested, may be the absence of any compelling data proving whether there’s any effect on clinical outcomes for switching reduced metabolizers off of clopidogrel or switching good metabolizers onto it.
“We have no large-scale, prospective data supporting pharmacogenomic-based personalization” of clopidogrel treatment leading to improved outcomes, but “we need to get over that,” he said. “It’s a challenge to get funding for this.” But “the answer is not to give ticagrelor or prasugrel to everyone because then the bleeding rate is too high.”
The findings Dr. Ohman reported came from the Study to Compare the Safety of Rivaroxaban Versus Acetylsalicylic Acid in Addition to Either Clopidogrel or Ticagrelor Therapy in Participants With Acute Coronary Syndrome (GEMINI-ACS-1), which had the primary goal of comparing the safety in acute coronary syndrome patients of a reduced dosage of rivaroxaban plus either clopidogrel or ticagrelor with the safety of aspirin plus one of these P2Y12 inhibitors. The primary endpoint was the rate of clinically significant bleeding events during a year of treatment. The study ran at 371 centers in 21 countries and showed similar bleeding rates in both treatment arms (Lancet. 2017 May 6; 389[10081]:1799-808).
The analysis also showed that patients identified as reduced metabolizers were fivefold more likely to be switched than patients identified as ultra metabolizers, and intermediate metabolizes had a 50% higher switching rate than ultra metabolizers. The rates of both ischemic and major bleeding outcomes were roughly similar across the spectrum of metabolizers, but Dr. Ohman cautioned that the trial was not designed to assess this. Dr. Gurbel urged the investigators to report on outcomes analyzed not just by metabolizer status but also by the treatment they received.
The boxed warning that clopidogrel received in 2010 regarding poor metabolizers led to “regulatory guidance” during design of the GEMINI-ACS-1 trial requiring routine pharmacogenomic testing for clopidogrel-metabolizing status, Dr. Ohman explained.
The trial was funded by Janssen and Bayer, the two companies that jointly market rivaroxaban (Xarelto). Dr. Ohman has been a consultant to Bayer and several other companies including AstraZeneca, the company that markets ticagrelor (Brilinta). He has also received research funding from Janssen, as well as Daiichi Sankyo and Gilead Sciences. Dr. Gurbel holds patents on platelet-function testing methods.
[email protected]
On Twitter @mitchelzoler
ANAHEIM, CALIF. – The boxed warning recommending pharmacogenomic testing of patients receiving clopidogrel to identify reduced metabolizers seems to be playing to a largely deaf audience.
Even when handed information on whether each clopidogrel-treated patient was a poor metabolizer of the drug, treating physicians usually did not switch them to a different antiplatelet drug, ticagrelor, that would be fully effective despite the patient’s reduced-metabolizer status. And clinicians who started patients on ticagrelor did not usually switch those with a good clopidogrel-metabolizing profile to the safer drug, clopidogrel, after learning that clopidogrel would be fully effective.
“Routine reporting of pharmacogenomics test results for acute coronary syndrome patients treated with P2Y12-inhibitor therapy had an uncertain yield and little impact on P2Y12-inhibitor switching,” E. Magnus Ohman, MBBS, said at the American Heart Association scientific sessions.
The study’s design gave each participating clinician free rein on whether to prescribe clopidogrel or ticagrelor (Brilinta) initially, and switching between the drugs was possible at any time after the initial prescription. At the trial’s start, 1,704 patients (56%) were on ticagrelor and 1,333 (44%) were on clopidogrel.
Pharmacogenomic testing showed that 34% of all patients were ultrametabolizers and 38% were extensive metabolizers. Patients in either of these categories metabolize enough clopidogrel into the active form to get full benefit from the drug and derive no additional efficacy benefit from switching to another P2Y12 inhibitor, such as ticagrelor or prasugrel (Effient) – drugs unaffected by metabolizer status. Testing also identified 25% of patients as intermediate metabolizers, who carry one loss-of-function allele for the CYP2C19 gene, and 3% were reduced metabolizers, who are homozygous for loss-of-function alleles. Standard practice is not to treat intermediate or reduced metabolizers with clopidogrel because they would not get an adequate antiplatelet effect; instead, these patients are usually treated with ticagrelor or with prasugrel when it’s an option.
After receiving the results regarding the clopidogrel-metabolizing status for each patient, attending physicians switched the drugs prescribed for only 7% of all patients: 9% of patients initially on ticagrelor and 4% of those initially on clopidogrel, reported Dr. Ohman, professor of medicine at Duke University in Durham, N.C. In addition, Dr. Ohman and his associates asked each participating physician who made a switch about his or her reasons for doing so. Of the patients who switched from clopidogrel to ticagrelor, only 23 were switched because of their pharmacogenomic results; this represents fewer than half of those who switched and only 2% of all patients who took clopidogrel. Only one patient changed from ticagrelor to clopidogrel based on pharmacogenomic results, representing 0.06% of all patients on ticagrelor.
“We believed the findings do not support the utility of mandatory testing in this context, as most did not act on the information,” Dr. Ohman said.
A major reason for the inertia, Dr. Gurbel suggested, may be the absence of any compelling data proving whether there’s any effect on clinical outcomes for switching reduced metabolizers off of clopidogrel or switching good metabolizers onto it.
“We have no large-scale, prospective data supporting pharmacogenomic-based personalization” of clopidogrel treatment leading to improved outcomes, but “we need to get over that,” he said. “It’s a challenge to get funding for this.” But “the answer is not to give ticagrelor or prasugrel to everyone because then the bleeding rate is too high.”
The findings Dr. Ohman reported came from the Study to Compare the Safety of Rivaroxaban Versus Acetylsalicylic Acid in Addition to Either Clopidogrel or Ticagrelor Therapy in Participants With Acute Coronary Syndrome (GEMINI-ACS-1), which had the primary goal of comparing the safety in acute coronary syndrome patients of a reduced dosage of rivaroxaban plus either clopidogrel or ticagrelor with the safety of aspirin plus one of these P2Y12 inhibitors. The primary endpoint was the rate of clinically significant bleeding events during a year of treatment. The study ran at 371 centers in 21 countries and showed similar bleeding rates in both treatment arms (Lancet. 2017 May 6; 389[10081]:1799-808).
The analysis also showed that patients identified as reduced metabolizers were fivefold more likely to be switched than patients identified as ultra metabolizers, and intermediate metabolizes had a 50% higher switching rate than ultra metabolizers. The rates of both ischemic and major bleeding outcomes were roughly similar across the spectrum of metabolizers, but Dr. Ohman cautioned that the trial was not designed to assess this. Dr. Gurbel urged the investigators to report on outcomes analyzed not just by metabolizer status but also by the treatment they received.
The boxed warning that clopidogrel received in 2010 regarding poor metabolizers led to “regulatory guidance” during design of the GEMINI-ACS-1 trial requiring routine pharmacogenomic testing for clopidogrel-metabolizing status, Dr. Ohman explained.
The trial was funded by Janssen and Bayer, the two companies that jointly market rivaroxaban (Xarelto). Dr. Ohman has been a consultant to Bayer and several other companies including AstraZeneca, the company that markets ticagrelor (Brilinta). He has also received research funding from Janssen, as well as Daiichi Sankyo and Gilead Sciences. Dr. Gurbel holds patents on platelet-function testing methods.
[email protected]
On Twitter @mitchelzoler
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: Physicians switched P2Y12 inhibitors for only 2% of patients on clopidogrel and only 0.06% on ticagrelor on the basis of their pharmacogenomic results.
Data source: GEMINI-ACS-1, a multicenter, prospective trial with 3,037 patients.
Disclosures: The GEMINI-ACS-1 trial was funded by Janssen and Bayer, the two companies that jointly market rivaroxaban (Xarelto). Dr. Ohman has been a consultant to Bayer and several other companies, including AstraZeneca, the company that markets ticagrelor (Brilinta). He has also received research funding from Janssen, as well as Daiichi Sankyo and Gilead Sciences. Dr. Gurbel holds patents on platelet-function testing methods.
Keep PCI patients on aspirin for noncardiac surgery
ANAHEIM, CALIF. – For every 1,000 patients with a history of percutaneous coronary intervention undergoing noncardiac surgery, perioperative aspirin would prevent 59 myocardial infarctions but cause 8 major/life-threatening bleeds, according to a substudy of the POISE-2 trial presented at the American Heart Association scientific sessions.
For patients with previous PCI undergoing noncardiac surgery, “I think aspirin will be more likely to benefit them than harm them,” so long as they are not having an operation where bleeding would be devastating.” These include “delicate neurosurgery in which, if you bleed into your spine, you end up paralyzed,” said lead investigator Michelle Graham, MD, an interventional cardiologist and professor of cardiology at the University of Alberta, Edmonton.
The original multisite POISE-2 trial (Perioperative Ischemic Evaluation 2) evaluated the effect of perioperative aspirin for noncardiac surgery. Patients were randomized to receive 200 mg aspirin or placebo within 4 hours of surgery and then 100 mg aspirin or placebo in the early postoperative period. There was no significant effect on the composite rate of death or myocardial infarction, but an increased risk of serious bleeding (N Engl J Med. 2014 Apr 17;370[16]:1494-503).
The new substudy focused on the 470 patients with previous PCIs, because such patients are known to have a higher risk for postop complications. More than half received bare-metal stents and a quarter got drug-eluting stents; in most of the rest, the stent type was not known. The median duration from PCI to noncardiac surgery was 64 months, ranging from 34 to 113 months. Patients with bare-metal stents placed within 6 weeks or drug-eluting stents within a year, were excluded.
Overall, 234 patients were randomized to the aspirin group, and 236 to placebo. Among those who came in on chronic, daily aspirin therapy – as almost all of the PCI subjects did – those who were randomized to perioperative aspirin stayed on daily 100 mg aspirin for a week postop, and then flipped back to whatever dose they were on at home. Likewise, placebo patients resumed their home aspirin after 1 week.
The results were very different from the main trial. At 30 days’ follow-up, just 6% of patients in the aspirin arm reached the primary endpoint of death or MI, versus 11.5% in the placebo group, a statistically significant 50% reduction.
This difference was driven almost entirely by a reduction in MIs. Whereas 5.1% of patients in the aspirin arm had MIs, 11% of the placebo group did, a significant 64% reduction. Meanwhile, the risk of major or life-threatening bleeding was not only similar between groups, but also to the overall trial, noted in 5.6% of aspirin and 4.2% of placebo subjects.
Over 75% of the participants were men, almost 60% were undergoing a major surgery, 30% had diabetes, and many had hypertension. Very few were on direct oral anticoagulants. The two arms were well matched, with a median age of about 68 years.
Simultaneously with Dr. Graham’s presentation, the results were published online (Ann Intern Med. 2017 Nov 14; doi: 10.7326/M17-2341)
The work was funded mostly by the Canadian Institutes of Health Research. Bayer supplied the aspirin. Dr. Graham has no industry disclosures.
ANAHEIM, CALIF. – For every 1,000 patients with a history of percutaneous coronary intervention undergoing noncardiac surgery, perioperative aspirin would prevent 59 myocardial infarctions but cause 8 major/life-threatening bleeds, according to a substudy of the POISE-2 trial presented at the American Heart Association scientific sessions.
For patients with previous PCI undergoing noncardiac surgery, “I think aspirin will be more likely to benefit them than harm them,” so long as they are not having an operation where bleeding would be devastating.” These include “delicate neurosurgery in which, if you bleed into your spine, you end up paralyzed,” said lead investigator Michelle Graham, MD, an interventional cardiologist and professor of cardiology at the University of Alberta, Edmonton.
The original multisite POISE-2 trial (Perioperative Ischemic Evaluation 2) evaluated the effect of perioperative aspirin for noncardiac surgery. Patients were randomized to receive 200 mg aspirin or placebo within 4 hours of surgery and then 100 mg aspirin or placebo in the early postoperative period. There was no significant effect on the composite rate of death or myocardial infarction, but an increased risk of serious bleeding (N Engl J Med. 2014 Apr 17;370[16]:1494-503).
The new substudy focused on the 470 patients with previous PCIs, because such patients are known to have a higher risk for postop complications. More than half received bare-metal stents and a quarter got drug-eluting stents; in most of the rest, the stent type was not known. The median duration from PCI to noncardiac surgery was 64 months, ranging from 34 to 113 months. Patients with bare-metal stents placed within 6 weeks or drug-eluting stents within a year, were excluded.
Overall, 234 patients were randomized to the aspirin group, and 236 to placebo. Among those who came in on chronic, daily aspirin therapy – as almost all of the PCI subjects did – those who were randomized to perioperative aspirin stayed on daily 100 mg aspirin for a week postop, and then flipped back to whatever dose they were on at home. Likewise, placebo patients resumed their home aspirin after 1 week.
The results were very different from the main trial. At 30 days’ follow-up, just 6% of patients in the aspirin arm reached the primary endpoint of death or MI, versus 11.5% in the placebo group, a statistically significant 50% reduction.
This difference was driven almost entirely by a reduction in MIs. Whereas 5.1% of patients in the aspirin arm had MIs, 11% of the placebo group did, a significant 64% reduction. Meanwhile, the risk of major or life-threatening bleeding was not only similar between groups, but also to the overall trial, noted in 5.6% of aspirin and 4.2% of placebo subjects.
Over 75% of the participants were men, almost 60% were undergoing a major surgery, 30% had diabetes, and many had hypertension. Very few were on direct oral anticoagulants. The two arms were well matched, with a median age of about 68 years.
Simultaneously with Dr. Graham’s presentation, the results were published online (Ann Intern Med. 2017 Nov 14; doi: 10.7326/M17-2341)
The work was funded mostly by the Canadian Institutes of Health Research. Bayer supplied the aspirin. Dr. Graham has no industry disclosures.
ANAHEIM, CALIF. – For every 1,000 patients with a history of percutaneous coronary intervention undergoing noncardiac surgery, perioperative aspirin would prevent 59 myocardial infarctions but cause 8 major/life-threatening bleeds, according to a substudy of the POISE-2 trial presented at the American Heart Association scientific sessions.
For patients with previous PCI undergoing noncardiac surgery, “I think aspirin will be more likely to benefit them than harm them,” so long as they are not having an operation where bleeding would be devastating.” These include “delicate neurosurgery in which, if you bleed into your spine, you end up paralyzed,” said lead investigator Michelle Graham, MD, an interventional cardiologist and professor of cardiology at the University of Alberta, Edmonton.
The original multisite POISE-2 trial (Perioperative Ischemic Evaluation 2) evaluated the effect of perioperative aspirin for noncardiac surgery. Patients were randomized to receive 200 mg aspirin or placebo within 4 hours of surgery and then 100 mg aspirin or placebo in the early postoperative period. There was no significant effect on the composite rate of death or myocardial infarction, but an increased risk of serious bleeding (N Engl J Med. 2014 Apr 17;370[16]:1494-503).
The new substudy focused on the 470 patients with previous PCIs, because such patients are known to have a higher risk for postop complications. More than half received bare-metal stents and a quarter got drug-eluting stents; in most of the rest, the stent type was not known. The median duration from PCI to noncardiac surgery was 64 months, ranging from 34 to 113 months. Patients with bare-metal stents placed within 6 weeks or drug-eluting stents within a year, were excluded.
Overall, 234 patients were randomized to the aspirin group, and 236 to placebo. Among those who came in on chronic, daily aspirin therapy – as almost all of the PCI subjects did – those who were randomized to perioperative aspirin stayed on daily 100 mg aspirin for a week postop, and then flipped back to whatever dose they were on at home. Likewise, placebo patients resumed their home aspirin after 1 week.
The results were very different from the main trial. At 30 days’ follow-up, just 6% of patients in the aspirin arm reached the primary endpoint of death or MI, versus 11.5% in the placebo group, a statistically significant 50% reduction.
This difference was driven almost entirely by a reduction in MIs. Whereas 5.1% of patients in the aspirin arm had MIs, 11% of the placebo group did, a significant 64% reduction. Meanwhile, the risk of major or life-threatening bleeding was not only similar between groups, but also to the overall trial, noted in 5.6% of aspirin and 4.2% of placebo subjects.
Over 75% of the participants were men, almost 60% were undergoing a major surgery, 30% had diabetes, and many had hypertension. Very few were on direct oral anticoagulants. The two arms were well matched, with a median age of about 68 years.
Simultaneously with Dr. Graham’s presentation, the results were published online (Ann Intern Med. 2017 Nov 14; doi: 10.7326/M17-2341)
The work was funded mostly by the Canadian Institutes of Health Research. Bayer supplied the aspirin. Dr. Graham has no industry disclosures.
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: For every 1,000 patients with a history of percutaneous coronary intervention undergoing noncardiac surgery, perioperative aspirin would prevent 59 myocardial infarctions but cause 8 major/life-threatening bleeds.
Data source: POISE-2, a randomized trial of 470 PCI patients.
Disclosures: The work was funded mostly by the Canadian Institutes of Health Research. Bayer supplied the aspirin. The lead investigator has no industry disclosures.
Targeting PCSK9 inhibitors to reap most benefit
ANAHEIM, CALIF. – Patients with symptomatic peripheral artery disease or a high-risk history of MI got the biggest bang for the buck from aggressive LDL cholesterol lowering with evolocumab in two new prespecified subgroup analyses from the landmark FOURIER trial presented at the American Heart Association scientific sessions.
“At the end of the day, not all of our patients with ASCVD [atherosclerotic cardiovascular disease] can have these expensive medications. These subgroup analyses will help clinicians to target use of PCSK9 inhibitors to the patients who will benefit the most,” Lynne T. Braun, PhD, commented in her role as discussant of the two secondary analyses, presented back to back in a late-breaking science session. Dr. Braun is a professor in the department of internal medicine at Rush University, Chicago.
The FOURIER trial included 27,564 high-risk patients with prior MI, stroke, and/or symptomatic peripheral arterial disease (PAD) who had an LDL cholesterol level of 70 mg/dL or more on high- or moderate-intensity statin therapy. They were randomized in double-blind fashion to add-on subcutaneous evolocumab (Repatha) at either 140 mg every 2 weeks or 420 mg/month or to placebo, for a median of 2.5 years of follow-up. The evolocumab group experienced a 59% reduction in LDL cholesterol, compared with the controls on background statin therapy plus placebo, down to a mean LDL cholesterol level of just 30 mg/dL.
As previously reported, the risk of the primary composite endpoint – comprising cardiovascular death, MI, stroke, unstable angina, or coronary revascularization – was reduced by 15% in the evolocumab group at 3 years. The secondary endpoint of cardiovascular death, MI, or stroke was reduced by 20%, from 9.9% to 7.9% (N Engl J Med. 2017;376:1713-22).
Evolocumab tamed PAD
At the AHA scientific sessions, Marc P. Bonaca, MD, presented a secondary analysis restricted to the 3,642 FOURIER participants with symptomatic PAD. The goal was to answer two unresolved questions: Does LDL cholesterol lowering beyond what’s achievable with a statin further reduce PAD patients’ cardiovascular risk? And does it reduce their risk of major adverse leg events (MALE), defined as a composite of acute limb ischemia, major amputation, and urgent revascularization?
The rate of the composite endpoint comprising cardiovascular death, MI, or stroke was 13% over 3 years in PAD patients randomized to placebo, which was 81% greater than the 7.6% rate in placebo-treated participants with a baseline history of stroke or MI but no PAD, in an analysis adjusted for demographics, cardiovascular risk factors, kidney function, body mass index, and prior revascularization.
The event rate was even higher in patients with PAD plus a history of MI or stroke, at 14.9%. Evolocumab reduced that risk by 27%, compared with placebo in patients with PAD, for an absolute risk reduction of 3.5% and a number-needed-to-treat (NNT) of 29 for 2.5 years.
The benefit of evolocumab was even more pronounced in the subgroup of 1,505 patients with baseline PAD but no prior MI or stroke: a 43% relative risk reduction, from 10.3% to 5.5%, for an absolute risk reduction of 4.8% and a NNT of 21.
A linear relationship was seen between the MALE rate during follow-up and LDL cholesterol level after 1 month of therapy, down to an LDL cholesterol level of less than 10 mg/dL. The clinically relevant composite endpoint of MACE (major adverse cardiovascular events – a composite of cardiovascular death, MI, and stroke) or MALE in patients with baseline PAD but no history of MI or stroke occurred in 12.8% of controls and 6.5% of the evolocumab group. This translated to a 48% relative risk reduction, a 6.3% absolute risk reduction, and a NNT of 16. The event curves in the evolocumab and control arms separated quite early, within the first 90 days of treatment.
The take home message: “LDL reduction to very low levels should be considered in patients with PAD, regardless of their history of MI or stroke, to reduce the risk of MACE [major adverse cardiovascular event] and MALE,” declared Dr. Bonaca of Brigham and Women’s Hospital and Harvard Medical School, both in Boston.
Spotting the patients with a history of MI who’re at highest risk
Marc S. Sabatine, MD, presented the subanalysis involving the 22,351 FOURIER patients with a prior MI. He and his coinvestigators identified three high-risk features within this group: an MI within the past 2 years, a history of two or more MIs, and residual multivessel CAD. Each of these three features was individually associated with a 34%-90% increased risk of MACE during follow-up. All told, 63% of FOURIER participants with prior MI had one or more of the high-risk features.
The use of evolocumab in patients with at least one of the three high-risk features was associated with a 22% relative risk reduction and an absolute 2.5% risk reduction, compared with placebo. The event curves diverged at about 6 months, and the gap between them steadily widened during follow-up. Extrapolating from this pattern, it’s likely that evolocumab would achieve an absolute 5% risk reduction in MACE, compared with placebo over 5 years, with an NNT of 20, according to Dr. Sabatine, professor of medicine at Harvard Medical School and chairman of the Thrombolysis in Myocardial Infarction (TIMI) Study Group.
Lingering questions
Dr. Braun was particularly impressed that the absolute risk reduction in MACE was even larger in patients with baseline PAD but no history of stroke or MI than in PAD patients with such a history. She added that, while she recognizes the value of selecting objectively assessable hard clinical MACE as the primary endpoint in FOURIER, her own patients care even more about other outcomes.
“What my patients with PAD care most about is whether profound LDL lowering translates to less claudication, improved quality of life, and greater physical activity tolerance. These were prespecified secondary outcomes in FOURIER, and I look forward to future reports addressing those issues,” she said.
Another unanswered question involves the mechanism by which intensive LDL cholesterol lowering results in fewer MACE and MALE events in high-risk subgroups. The possibilities include the plaque regression that was documented in the GLAGOV trial, an anti-inflammatory plaque-stabilizing effect being exerted through PCSK9 inhibition, or perhaps the PCSK9 inhibitors’ ability to moderately lower lipoprotein(a) cholesterol levels.
Simultaneous with Dr. Bonaca’s presentation at the AHA, the FOURIER PAD analysis was published online in Circulation (2017 Nov 13; doi: 10.1161/CIRCULATIONAHA.117.032235).
The FOURIER trial was sponsored by Amgen. Dr. Bonaca and Dr. Sabatine reported receiving research grants from and serving as consultants to Amgen and other companies.
ANAHEIM, CALIF. – Patients with symptomatic peripheral artery disease or a high-risk history of MI got the biggest bang for the buck from aggressive LDL cholesterol lowering with evolocumab in two new prespecified subgroup analyses from the landmark FOURIER trial presented at the American Heart Association scientific sessions.
“At the end of the day, not all of our patients with ASCVD [atherosclerotic cardiovascular disease] can have these expensive medications. These subgroup analyses will help clinicians to target use of PCSK9 inhibitors to the patients who will benefit the most,” Lynne T. Braun, PhD, commented in her role as discussant of the two secondary analyses, presented back to back in a late-breaking science session. Dr. Braun is a professor in the department of internal medicine at Rush University, Chicago.
The FOURIER trial included 27,564 high-risk patients with prior MI, stroke, and/or symptomatic peripheral arterial disease (PAD) who had an LDL cholesterol level of 70 mg/dL or more on high- or moderate-intensity statin therapy. They were randomized in double-blind fashion to add-on subcutaneous evolocumab (Repatha) at either 140 mg every 2 weeks or 420 mg/month or to placebo, for a median of 2.5 years of follow-up. The evolocumab group experienced a 59% reduction in LDL cholesterol, compared with the controls on background statin therapy plus placebo, down to a mean LDL cholesterol level of just 30 mg/dL.
As previously reported, the risk of the primary composite endpoint – comprising cardiovascular death, MI, stroke, unstable angina, or coronary revascularization – was reduced by 15% in the evolocumab group at 3 years. The secondary endpoint of cardiovascular death, MI, or stroke was reduced by 20%, from 9.9% to 7.9% (N Engl J Med. 2017;376:1713-22).
Evolocumab tamed PAD
At the AHA scientific sessions, Marc P. Bonaca, MD, presented a secondary analysis restricted to the 3,642 FOURIER participants with symptomatic PAD. The goal was to answer two unresolved questions: Does LDL cholesterol lowering beyond what’s achievable with a statin further reduce PAD patients’ cardiovascular risk? And does it reduce their risk of major adverse leg events (MALE), defined as a composite of acute limb ischemia, major amputation, and urgent revascularization?
The rate of the composite endpoint comprising cardiovascular death, MI, or stroke was 13% over 3 years in PAD patients randomized to placebo, which was 81% greater than the 7.6% rate in placebo-treated participants with a baseline history of stroke or MI but no PAD, in an analysis adjusted for demographics, cardiovascular risk factors, kidney function, body mass index, and prior revascularization.
The event rate was even higher in patients with PAD plus a history of MI or stroke, at 14.9%. Evolocumab reduced that risk by 27%, compared with placebo in patients with PAD, for an absolute risk reduction of 3.5% and a number-needed-to-treat (NNT) of 29 for 2.5 years.
The benefit of evolocumab was even more pronounced in the subgroup of 1,505 patients with baseline PAD but no prior MI or stroke: a 43% relative risk reduction, from 10.3% to 5.5%, for an absolute risk reduction of 4.8% and a NNT of 21.
A linear relationship was seen between the MALE rate during follow-up and LDL cholesterol level after 1 month of therapy, down to an LDL cholesterol level of less than 10 mg/dL. The clinically relevant composite endpoint of MACE (major adverse cardiovascular events – a composite of cardiovascular death, MI, and stroke) or MALE in patients with baseline PAD but no history of MI or stroke occurred in 12.8% of controls and 6.5% of the evolocumab group. This translated to a 48% relative risk reduction, a 6.3% absolute risk reduction, and a NNT of 16. The event curves in the evolocumab and control arms separated quite early, within the first 90 days of treatment.
The take home message: “LDL reduction to very low levels should be considered in patients with PAD, regardless of their history of MI or stroke, to reduce the risk of MACE [major adverse cardiovascular event] and MALE,” declared Dr. Bonaca of Brigham and Women’s Hospital and Harvard Medical School, both in Boston.
Spotting the patients with a history of MI who’re at highest risk
Marc S. Sabatine, MD, presented the subanalysis involving the 22,351 FOURIER patients with a prior MI. He and his coinvestigators identified three high-risk features within this group: an MI within the past 2 years, a history of two or more MIs, and residual multivessel CAD. Each of these three features was individually associated with a 34%-90% increased risk of MACE during follow-up. All told, 63% of FOURIER participants with prior MI had one or more of the high-risk features.
The use of evolocumab in patients with at least one of the three high-risk features was associated with a 22% relative risk reduction and an absolute 2.5% risk reduction, compared with placebo. The event curves diverged at about 6 months, and the gap between them steadily widened during follow-up. Extrapolating from this pattern, it’s likely that evolocumab would achieve an absolute 5% risk reduction in MACE, compared with placebo over 5 years, with an NNT of 20, according to Dr. Sabatine, professor of medicine at Harvard Medical School and chairman of the Thrombolysis in Myocardial Infarction (TIMI) Study Group.
Lingering questions
Dr. Braun was particularly impressed that the absolute risk reduction in MACE was even larger in patients with baseline PAD but no history of stroke or MI than in PAD patients with such a history. She added that, while she recognizes the value of selecting objectively assessable hard clinical MACE as the primary endpoint in FOURIER, her own patients care even more about other outcomes.
“What my patients with PAD care most about is whether profound LDL lowering translates to less claudication, improved quality of life, and greater physical activity tolerance. These were prespecified secondary outcomes in FOURIER, and I look forward to future reports addressing those issues,” she said.
Another unanswered question involves the mechanism by which intensive LDL cholesterol lowering results in fewer MACE and MALE events in high-risk subgroups. The possibilities include the plaque regression that was documented in the GLAGOV trial, an anti-inflammatory plaque-stabilizing effect being exerted through PCSK9 inhibition, or perhaps the PCSK9 inhibitors’ ability to moderately lower lipoprotein(a) cholesterol levels.
Simultaneous with Dr. Bonaca’s presentation at the AHA, the FOURIER PAD analysis was published online in Circulation (2017 Nov 13; doi: 10.1161/CIRCULATIONAHA.117.032235).
The FOURIER trial was sponsored by Amgen. Dr. Bonaca and Dr. Sabatine reported receiving research grants from and serving as consultants to Amgen and other companies.
ANAHEIM, CALIF. – Patients with symptomatic peripheral artery disease or a high-risk history of MI got the biggest bang for the buck from aggressive LDL cholesterol lowering with evolocumab in two new prespecified subgroup analyses from the landmark FOURIER trial presented at the American Heart Association scientific sessions.
“At the end of the day, not all of our patients with ASCVD [atherosclerotic cardiovascular disease] can have these expensive medications. These subgroup analyses will help clinicians to target use of PCSK9 inhibitors to the patients who will benefit the most,” Lynne T. Braun, PhD, commented in her role as discussant of the two secondary analyses, presented back to back in a late-breaking science session. Dr. Braun is a professor in the department of internal medicine at Rush University, Chicago.
The FOURIER trial included 27,564 high-risk patients with prior MI, stroke, and/or symptomatic peripheral arterial disease (PAD) who had an LDL cholesterol level of 70 mg/dL or more on high- or moderate-intensity statin therapy. They were randomized in double-blind fashion to add-on subcutaneous evolocumab (Repatha) at either 140 mg every 2 weeks or 420 mg/month or to placebo, for a median of 2.5 years of follow-up. The evolocumab group experienced a 59% reduction in LDL cholesterol, compared with the controls on background statin therapy plus placebo, down to a mean LDL cholesterol level of just 30 mg/dL.
As previously reported, the risk of the primary composite endpoint – comprising cardiovascular death, MI, stroke, unstable angina, or coronary revascularization – was reduced by 15% in the evolocumab group at 3 years. The secondary endpoint of cardiovascular death, MI, or stroke was reduced by 20%, from 9.9% to 7.9% (N Engl J Med. 2017;376:1713-22).
Evolocumab tamed PAD
At the AHA scientific sessions, Marc P. Bonaca, MD, presented a secondary analysis restricted to the 3,642 FOURIER participants with symptomatic PAD. The goal was to answer two unresolved questions: Does LDL cholesterol lowering beyond what’s achievable with a statin further reduce PAD patients’ cardiovascular risk? And does it reduce their risk of major adverse leg events (MALE), defined as a composite of acute limb ischemia, major amputation, and urgent revascularization?
The rate of the composite endpoint comprising cardiovascular death, MI, or stroke was 13% over 3 years in PAD patients randomized to placebo, which was 81% greater than the 7.6% rate in placebo-treated participants with a baseline history of stroke or MI but no PAD, in an analysis adjusted for demographics, cardiovascular risk factors, kidney function, body mass index, and prior revascularization.
The event rate was even higher in patients with PAD plus a history of MI or stroke, at 14.9%. Evolocumab reduced that risk by 27%, compared with placebo in patients with PAD, for an absolute risk reduction of 3.5% and a number-needed-to-treat (NNT) of 29 for 2.5 years.
The benefit of evolocumab was even more pronounced in the subgroup of 1,505 patients with baseline PAD but no prior MI or stroke: a 43% relative risk reduction, from 10.3% to 5.5%, for an absolute risk reduction of 4.8% and a NNT of 21.
A linear relationship was seen between the MALE rate during follow-up and LDL cholesterol level after 1 month of therapy, down to an LDL cholesterol level of less than 10 mg/dL. The clinically relevant composite endpoint of MACE (major adverse cardiovascular events – a composite of cardiovascular death, MI, and stroke) or MALE in patients with baseline PAD but no history of MI or stroke occurred in 12.8% of controls and 6.5% of the evolocumab group. This translated to a 48% relative risk reduction, a 6.3% absolute risk reduction, and a NNT of 16. The event curves in the evolocumab and control arms separated quite early, within the first 90 days of treatment.
The take home message: “LDL reduction to very low levels should be considered in patients with PAD, regardless of their history of MI or stroke, to reduce the risk of MACE [major adverse cardiovascular event] and MALE,” declared Dr. Bonaca of Brigham and Women’s Hospital and Harvard Medical School, both in Boston.
Spotting the patients with a history of MI who’re at highest risk
Marc S. Sabatine, MD, presented the subanalysis involving the 22,351 FOURIER patients with a prior MI. He and his coinvestigators identified three high-risk features within this group: an MI within the past 2 years, a history of two or more MIs, and residual multivessel CAD. Each of these three features was individually associated with a 34%-90% increased risk of MACE during follow-up. All told, 63% of FOURIER participants with prior MI had one or more of the high-risk features.
The use of evolocumab in patients with at least one of the three high-risk features was associated with a 22% relative risk reduction and an absolute 2.5% risk reduction, compared with placebo. The event curves diverged at about 6 months, and the gap between them steadily widened during follow-up. Extrapolating from this pattern, it’s likely that evolocumab would achieve an absolute 5% risk reduction in MACE, compared with placebo over 5 years, with an NNT of 20, according to Dr. Sabatine, professor of medicine at Harvard Medical School and chairman of the Thrombolysis in Myocardial Infarction (TIMI) Study Group.
Lingering questions
Dr. Braun was particularly impressed that the absolute risk reduction in MACE was even larger in patients with baseline PAD but no history of stroke or MI than in PAD patients with such a history. She added that, while she recognizes the value of selecting objectively assessable hard clinical MACE as the primary endpoint in FOURIER, her own patients care even more about other outcomes.
“What my patients with PAD care most about is whether profound LDL lowering translates to less claudication, improved quality of life, and greater physical activity tolerance. These were prespecified secondary outcomes in FOURIER, and I look forward to future reports addressing those issues,” she said.
Another unanswered question involves the mechanism by which intensive LDL cholesterol lowering results in fewer MACE and MALE events in high-risk subgroups. The possibilities include the plaque regression that was documented in the GLAGOV trial, an anti-inflammatory plaque-stabilizing effect being exerted through PCSK9 inhibition, or perhaps the PCSK9 inhibitors’ ability to moderately lower lipoprotein(a) cholesterol levels.
Simultaneous with Dr. Bonaca’s presentation at the AHA, the FOURIER PAD analysis was published online in Circulation (2017 Nov 13; doi: 10.1161/CIRCULATIONAHA.117.032235).
The FOURIER trial was sponsored by Amgen. Dr. Bonaca and Dr. Sabatine reported receiving research grants from and serving as consultants to Amgen and other companies.
EXPERT ANALYSIS FROM THE AHA SCIENTIFIC SESSIONS
Direct oral anticoagulants okay during AF device placement
ANAHEIM, CALIF. – Whether direct oral anticoagulants are continued or interrupted for device placement in atrial fibrillation patients, the risk of device pocket hematoma or stroke is very low, based on results of the BRUISE CONTROL–2 trial in more than 600 subjects.
Either strategy is reasonable depending on the clinical scenario, coprincipal investigator David Birnie, MD, said in presenting the results at the American Heart Association scientific sessions.
When atrial fibrillation (AF) patients on direct oral anticoagulants (DOACs) present for device surgery, there’s concern that keeping them on the drugs will increase the bleeding risk, but that taking them off will increase the stroke risk. “We sought to resolve this dilemma,” said Dr. Birnie, an electrophysiologist and director of the arrhythmia service at the University of Ottawa Heart Institute.
The subjects were on dabigatran, rivaroxaban, or apixaban, about a third in each group; 328 were randomized to continue their daily dosing, including on the day of surgery. The other 334 were randomized to interrupted treatment. For rivaroxaban and apixaban, that meant taking their last dose 2 days before surgery. Dabigatran patients discontinued the drug 1-2 days beforehand, depending on glomerular filtration rate. Patients resumed treatment about 24 hours after surgery. CHA2DS2-VASc scores were a mean of 3.9 in both arms, and at least 2 in all participants.
The rate of clinically significant hematoma – the primary outcome in the study, defined as a hematoma requiring prolonged hospitalization, interrupted postoperative anticoagulation, or reoperation to evacuate – was identical in both arms, 2.1% (seven patients each). There were two ischemic strokes, one in each arm. There was one delayed cardiac tamponade in the continuation arm and one pericardial effusion in the interrupted arm. The three deaths in the trial were not related to device placement.
So, what to do depends on the clinical scenario, Dr. Birnie said in an interview. If someone needs urgent placement and there’s no time to wait for DOAC washout, “it’s quite reasonable to go ahead.” Also, “if somebody is at extremely high risk for stroke, then it’s very reasonable to continue the drug.”
On the other hand, “if someone has a much lower stroke risk, then the risk-benefit ratio is probably in the opposite direction, so temporarily discontinuing the drug is the right thing to do,” he said.
Dr. Birnie cautioned that although continued DOAC may reduce the risk of thromboembolism, “this study was not designed with power to answer this.”
“We are already putting these findings into practice” in Ottawa, he said. “Our protocol” – as in many places – “ was always to stop anticoagulation for 2 or 3 days, but now, for very high-risk patients – high-risk AF, unstable temporary pacing, that type of thing – we are very comfortable continuing it,” he said. The study follows up a previous randomized trial by Dr. Birnie and his colleagues that pitted continued warfarin against heparin bridging for AF device placement. There were far fewer device pocket hematomas with uninterrupted warfarin (N Engl J Med. 2013 May 30;368[22]:2084-93).
The team wanted to repeat the study using DOACs, since their use has grown substantially, with the majority of AF patients now on them.
The arms in BRUISE CONTROL–2 (Strategy of Continued Versus Interrupted Novel Oral Anticoagulant at Time of Device Surgery in Patients With Moderate to High Risk of Arterial Thromboembolic Events) were well matched, with a mean age of about 74 years; men made up more than 70% of the subjects in both arms. About 17% of the participants were on chronic aspirin therapy and about 4% were on clopidogrel, in each arm. The uninterrupted DOAC group went about 14 hours between their last preop and first postop DOAC dose. The interrupted group went about 72 hours.
BRUISE CONTROL–2 was funded by the Heart and Stroke Foundation of Canada, Boehringer Ingelheim, Bayer, Pfizer, and Bristol-Myers Squibb, among others. Dr. Birnie had no relevant financial disclosures.
ANAHEIM, CALIF. – Whether direct oral anticoagulants are continued or interrupted for device placement in atrial fibrillation patients, the risk of device pocket hematoma or stroke is very low, based on results of the BRUISE CONTROL–2 trial in more than 600 subjects.
Either strategy is reasonable depending on the clinical scenario, coprincipal investigator David Birnie, MD, said in presenting the results at the American Heart Association scientific sessions.
When atrial fibrillation (AF) patients on direct oral anticoagulants (DOACs) present for device surgery, there’s concern that keeping them on the drugs will increase the bleeding risk, but that taking them off will increase the stroke risk. “We sought to resolve this dilemma,” said Dr. Birnie, an electrophysiologist and director of the arrhythmia service at the University of Ottawa Heart Institute.
The subjects were on dabigatran, rivaroxaban, or apixaban, about a third in each group; 328 were randomized to continue their daily dosing, including on the day of surgery. The other 334 were randomized to interrupted treatment. For rivaroxaban and apixaban, that meant taking their last dose 2 days before surgery. Dabigatran patients discontinued the drug 1-2 days beforehand, depending on glomerular filtration rate. Patients resumed treatment about 24 hours after surgery. CHA2DS2-VASc scores were a mean of 3.9 in both arms, and at least 2 in all participants.
The rate of clinically significant hematoma – the primary outcome in the study, defined as a hematoma requiring prolonged hospitalization, interrupted postoperative anticoagulation, or reoperation to evacuate – was identical in both arms, 2.1% (seven patients each). There were two ischemic strokes, one in each arm. There was one delayed cardiac tamponade in the continuation arm and one pericardial effusion in the interrupted arm. The three deaths in the trial were not related to device placement.
So, what to do depends on the clinical scenario, Dr. Birnie said in an interview. If someone needs urgent placement and there’s no time to wait for DOAC washout, “it’s quite reasonable to go ahead.” Also, “if somebody is at extremely high risk for stroke, then it’s very reasonable to continue the drug.”
On the other hand, “if someone has a much lower stroke risk, then the risk-benefit ratio is probably in the opposite direction, so temporarily discontinuing the drug is the right thing to do,” he said.
Dr. Birnie cautioned that although continued DOAC may reduce the risk of thromboembolism, “this study was not designed with power to answer this.”
“We are already putting these findings into practice” in Ottawa, he said. “Our protocol” – as in many places – “ was always to stop anticoagulation for 2 or 3 days, but now, for very high-risk patients – high-risk AF, unstable temporary pacing, that type of thing – we are very comfortable continuing it,” he said. The study follows up a previous randomized trial by Dr. Birnie and his colleagues that pitted continued warfarin against heparin bridging for AF device placement. There were far fewer device pocket hematomas with uninterrupted warfarin (N Engl J Med. 2013 May 30;368[22]:2084-93).
The team wanted to repeat the study using DOACs, since their use has grown substantially, with the majority of AF patients now on them.
The arms in BRUISE CONTROL–2 (Strategy of Continued Versus Interrupted Novel Oral Anticoagulant at Time of Device Surgery in Patients With Moderate to High Risk of Arterial Thromboembolic Events) were well matched, with a mean age of about 74 years; men made up more than 70% of the subjects in both arms. About 17% of the participants were on chronic aspirin therapy and about 4% were on clopidogrel, in each arm. The uninterrupted DOAC group went about 14 hours between their last preop and first postop DOAC dose. The interrupted group went about 72 hours.
BRUISE CONTROL–2 was funded by the Heart and Stroke Foundation of Canada, Boehringer Ingelheim, Bayer, Pfizer, and Bristol-Myers Squibb, among others. Dr. Birnie had no relevant financial disclosures.
ANAHEIM, CALIF. – Whether direct oral anticoagulants are continued or interrupted for device placement in atrial fibrillation patients, the risk of device pocket hematoma or stroke is very low, based on results of the BRUISE CONTROL–2 trial in more than 600 subjects.
Either strategy is reasonable depending on the clinical scenario, coprincipal investigator David Birnie, MD, said in presenting the results at the American Heart Association scientific sessions.
When atrial fibrillation (AF) patients on direct oral anticoagulants (DOACs) present for device surgery, there’s concern that keeping them on the drugs will increase the bleeding risk, but that taking them off will increase the stroke risk. “We sought to resolve this dilemma,” said Dr. Birnie, an electrophysiologist and director of the arrhythmia service at the University of Ottawa Heart Institute.
The subjects were on dabigatran, rivaroxaban, or apixaban, about a third in each group; 328 were randomized to continue their daily dosing, including on the day of surgery. The other 334 were randomized to interrupted treatment. For rivaroxaban and apixaban, that meant taking their last dose 2 days before surgery. Dabigatran patients discontinued the drug 1-2 days beforehand, depending on glomerular filtration rate. Patients resumed treatment about 24 hours after surgery. CHA2DS2-VASc scores were a mean of 3.9 in both arms, and at least 2 in all participants.
The rate of clinically significant hematoma – the primary outcome in the study, defined as a hematoma requiring prolonged hospitalization, interrupted postoperative anticoagulation, or reoperation to evacuate – was identical in both arms, 2.1% (seven patients each). There were two ischemic strokes, one in each arm. There was one delayed cardiac tamponade in the continuation arm and one pericardial effusion in the interrupted arm. The three deaths in the trial were not related to device placement.
So, what to do depends on the clinical scenario, Dr. Birnie said in an interview. If someone needs urgent placement and there’s no time to wait for DOAC washout, “it’s quite reasonable to go ahead.” Also, “if somebody is at extremely high risk for stroke, then it’s very reasonable to continue the drug.”
On the other hand, “if someone has a much lower stroke risk, then the risk-benefit ratio is probably in the opposite direction, so temporarily discontinuing the drug is the right thing to do,” he said.
Dr. Birnie cautioned that although continued DOAC may reduce the risk of thromboembolism, “this study was not designed with power to answer this.”
“We are already putting these findings into practice” in Ottawa, he said. “Our protocol” – as in many places – “ was always to stop anticoagulation for 2 or 3 days, but now, for very high-risk patients – high-risk AF, unstable temporary pacing, that type of thing – we are very comfortable continuing it,” he said. The study follows up a previous randomized trial by Dr. Birnie and his colleagues that pitted continued warfarin against heparin bridging for AF device placement. There were far fewer device pocket hematomas with uninterrupted warfarin (N Engl J Med. 2013 May 30;368[22]:2084-93).
The team wanted to repeat the study using DOACs, since their use has grown substantially, with the majority of AF patients now on them.
The arms in BRUISE CONTROL–2 (Strategy of Continued Versus Interrupted Novel Oral Anticoagulant at Time of Device Surgery in Patients With Moderate to High Risk of Arterial Thromboembolic Events) were well matched, with a mean age of about 74 years; men made up more than 70% of the subjects in both arms. About 17% of the participants were on chronic aspirin therapy and about 4% were on clopidogrel, in each arm. The uninterrupted DOAC group went about 14 hours between their last preop and first postop DOAC dose. The interrupted group went about 72 hours.
BRUISE CONTROL–2 was funded by the Heart and Stroke Foundation of Canada, Boehringer Ingelheim, Bayer, Pfizer, and Bristol-Myers Squibb, among others. Dr. Birnie had no relevant financial disclosures.
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: The rate of clinically significant hematoma was identical in both arms, at 2.1% (seven patients each).
Data source: BRUISE CONTROL-2, a randomized trial with more than 600 subjects.
Disclosures: The work was funded by the Heart and Stroke Foundation of Canada, Boehringer Ingelheim, Bayer, Pfizer, and Bristol-Myers Squibb, among others. The presenter had no relevant financial disclosures.
DAPT produces better CABG outcomes than aspirin alone
ANAHEIM, CALIF. – Treatment with dual-antiplatelet therapy following coronary artery bypass grafting with a saphenous vein maintained vein-graft patency better than aspirin alone in a randomized, multicenter trial with 500 patients.
After 1 year of dual-antiplatelet therapy (DAPT) with ticagrelor (Brilinta) and aspirin, 89% of saphenous-vein grafts remained patent, compared with a 77% patency rate in saphenous-vein grafts in patients treated with aspirin alone, a statistically significant difference for the study’s primary endpoint, Qiang Zhao, MD, said at the American Hart Association scientific sessions. The data, collected at six Chinese centers, also showed a nominal decrease in the combined rate of cardiovascular death, MI, and stroke: 2% with DAPT and 5% with aspirin alone. It further showed an increase in major or bypass-related bleeds: 2% with DAPT and none with aspirin alone, reported Dr. Zhao, professor and director of cardiac surgery at Ruijin Hospital in Shanghai, China.
“If this result were repeated in a larger study it would be important,” John H. Alexander, MD, professor of medicine at Duke University in Durham, N.C., commented in a video interview.
The Compare the Efficacy of Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Graft Surgery (DACAB) trial randomized patients who underwent coronary artery bypass grafting (CABG). They averaged about 64 years of age, and received an average of nearly four grafts each including an average of nearly three saphenous vein grafts. The study assigned patients to one of three treatment arms starting within 24 hours after surgery: 168 received ticagrelor 90 mg twice daily plus aspirin 100 mg once daily, 166 got ticagrelor alone, and 166 received aspirin alone. Treatment continued for 1 year.
“Some surgeons and physicians currently prescribe DAPT to CABG patients, but there is not much evidence of its benefit. The DACAB trial is useful, but you need to show that it does not just improve patency but that patients also have better outcomes. The excess of major bleeds is a big deal. It gives one pause about adopting DAPT as standard treatment,” Dr. Gardner said.
DACAB received no commercial funding. Dr. Zhao has been a speaker on behalf of and has received research funding from AstraZeneca, the company that markets ticagrelor (Brilinta). He has also been a speaker for Johnson & Johnson and Medtronic and has received research funding from Bayer, Novartis, and Sanofi. Dr. Gardner had no disclosures.
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On Twitter @mitchelzoler
Results from the DACAB trial showed that using aspirin and ticagrelor improved vein-graft patency, compared with using aspirin alone. It was a compelling result, but for the intermediate, imaging-based outcome of graft patency at 1 year after surgery. This finding is conclusive evidence that dual-antiplatelet therapy has some benefit.
But the findings from this trial, modestly sized with 500 patients, failed to prove that the clinical benefit from dual-antiplatelet therapy was worth the adverse effect of an increase in the rate of major and bypass-related bleeding. The study was underpowered to prove that dual-antiplatelet therapy had a clear beneficial impact on clinical outcomes such as cardiovascular death, MI, and stroke, although this combined rate went in the right direction with dual therapy, compared with aspirin alone. We need to see proof of a benefit for these clinical outcomes to justify using a treatment that causes an increase in major bleeds.
The DACAB results alone are not enough to justify a change in practice. It would be an important finding if the results could be replicated in a larger study. And if dual-antiplatelet therapy was proven to have a net clinical benefit for patients, we would still want to target it to patients with a higher ischemic risk and, in general, avoid using it in patients with a high bleeding risk.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
John H. Alexander, MD , is a cardiologist and professor of medicine at Duke University in Durham, N.C. He has been a consultant to and has received research funding from several companies, including AstraZeneca, the company that markets ticagrelor (Brilinta). He made these comments as designated discussant for the DACAB study and in a video interview .
Results from the DACAB trial showed that using aspirin and ticagrelor improved vein-graft patency, compared with using aspirin alone. It was a compelling result, but for the intermediate, imaging-based outcome of graft patency at 1 year after surgery. This finding is conclusive evidence that dual-antiplatelet therapy has some benefit.
But the findings from this trial, modestly sized with 500 patients, failed to prove that the clinical benefit from dual-antiplatelet therapy was worth the adverse effect of an increase in the rate of major and bypass-related bleeding. The study was underpowered to prove that dual-antiplatelet therapy had a clear beneficial impact on clinical outcomes such as cardiovascular death, MI, and stroke, although this combined rate went in the right direction with dual therapy, compared with aspirin alone. We need to see proof of a benefit for these clinical outcomes to justify using a treatment that causes an increase in major bleeds.
The DACAB results alone are not enough to justify a change in practice. It would be an important finding if the results could be replicated in a larger study. And if dual-antiplatelet therapy was proven to have a net clinical benefit for patients, we would still want to target it to patients with a higher ischemic risk and, in general, avoid using it in patients with a high bleeding risk.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
John H. Alexander, MD , is a cardiologist and professor of medicine at Duke University in Durham, N.C. He has been a consultant to and has received research funding from several companies, including AstraZeneca, the company that markets ticagrelor (Brilinta). He made these comments as designated discussant for the DACAB study and in a video interview .
Results from the DACAB trial showed that using aspirin and ticagrelor improved vein-graft patency, compared with using aspirin alone. It was a compelling result, but for the intermediate, imaging-based outcome of graft patency at 1 year after surgery. This finding is conclusive evidence that dual-antiplatelet therapy has some benefit.
But the findings from this trial, modestly sized with 500 patients, failed to prove that the clinical benefit from dual-antiplatelet therapy was worth the adverse effect of an increase in the rate of major and bypass-related bleeding. The study was underpowered to prove that dual-antiplatelet therapy had a clear beneficial impact on clinical outcomes such as cardiovascular death, MI, and stroke, although this combined rate went in the right direction with dual therapy, compared with aspirin alone. We need to see proof of a benefit for these clinical outcomes to justify using a treatment that causes an increase in major bleeds.
The DACAB results alone are not enough to justify a change in practice. It would be an important finding if the results could be replicated in a larger study. And if dual-antiplatelet therapy was proven to have a net clinical benefit for patients, we would still want to target it to patients with a higher ischemic risk and, in general, avoid using it in patients with a high bleeding risk.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
John H. Alexander, MD , is a cardiologist and professor of medicine at Duke University in Durham, N.C. He has been a consultant to and has received research funding from several companies, including AstraZeneca, the company that markets ticagrelor (Brilinta). He made these comments as designated discussant for the DACAB study and in a video interview .
ANAHEIM, CALIF. – Treatment with dual-antiplatelet therapy following coronary artery bypass grafting with a saphenous vein maintained vein-graft patency better than aspirin alone in a randomized, multicenter trial with 500 patients.
After 1 year of dual-antiplatelet therapy (DAPT) with ticagrelor (Brilinta) and aspirin, 89% of saphenous-vein grafts remained patent, compared with a 77% patency rate in saphenous-vein grafts in patients treated with aspirin alone, a statistically significant difference for the study’s primary endpoint, Qiang Zhao, MD, said at the American Hart Association scientific sessions. The data, collected at six Chinese centers, also showed a nominal decrease in the combined rate of cardiovascular death, MI, and stroke: 2% with DAPT and 5% with aspirin alone. It further showed an increase in major or bypass-related bleeds: 2% with DAPT and none with aspirin alone, reported Dr. Zhao, professor and director of cardiac surgery at Ruijin Hospital in Shanghai, China.
“If this result were repeated in a larger study it would be important,” John H. Alexander, MD, professor of medicine at Duke University in Durham, N.C., commented in a video interview.
The Compare the Efficacy of Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Graft Surgery (DACAB) trial randomized patients who underwent coronary artery bypass grafting (CABG). They averaged about 64 years of age, and received an average of nearly four grafts each including an average of nearly three saphenous vein grafts. The study assigned patients to one of three treatment arms starting within 24 hours after surgery: 168 received ticagrelor 90 mg twice daily plus aspirin 100 mg once daily, 166 got ticagrelor alone, and 166 received aspirin alone. Treatment continued for 1 year.
“Some surgeons and physicians currently prescribe DAPT to CABG patients, but there is not much evidence of its benefit. The DACAB trial is useful, but you need to show that it does not just improve patency but that patients also have better outcomes. The excess of major bleeds is a big deal. It gives one pause about adopting DAPT as standard treatment,” Dr. Gardner said.
DACAB received no commercial funding. Dr. Zhao has been a speaker on behalf of and has received research funding from AstraZeneca, the company that markets ticagrelor (Brilinta). He has also been a speaker for Johnson & Johnson and Medtronic and has received research funding from Bayer, Novartis, and Sanofi. Dr. Gardner had no disclosures.
[email protected]
On Twitter @mitchelzoler
ANAHEIM, CALIF. – Treatment with dual-antiplatelet therapy following coronary artery bypass grafting with a saphenous vein maintained vein-graft patency better than aspirin alone in a randomized, multicenter trial with 500 patients.
After 1 year of dual-antiplatelet therapy (DAPT) with ticagrelor (Brilinta) and aspirin, 89% of saphenous-vein grafts remained patent, compared with a 77% patency rate in saphenous-vein grafts in patients treated with aspirin alone, a statistically significant difference for the study’s primary endpoint, Qiang Zhao, MD, said at the American Hart Association scientific sessions. The data, collected at six Chinese centers, also showed a nominal decrease in the combined rate of cardiovascular death, MI, and stroke: 2% with DAPT and 5% with aspirin alone. It further showed an increase in major or bypass-related bleeds: 2% with DAPT and none with aspirin alone, reported Dr. Zhao, professor and director of cardiac surgery at Ruijin Hospital in Shanghai, China.
“If this result were repeated in a larger study it would be important,” John H. Alexander, MD, professor of medicine at Duke University in Durham, N.C., commented in a video interview.
The Compare the Efficacy of Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Graft Surgery (DACAB) trial randomized patients who underwent coronary artery bypass grafting (CABG). They averaged about 64 years of age, and received an average of nearly four grafts each including an average of nearly three saphenous vein grafts. The study assigned patients to one of three treatment arms starting within 24 hours after surgery: 168 received ticagrelor 90 mg twice daily plus aspirin 100 mg once daily, 166 got ticagrelor alone, and 166 received aspirin alone. Treatment continued for 1 year.
“Some surgeons and physicians currently prescribe DAPT to CABG patients, but there is not much evidence of its benefit. The DACAB trial is useful, but you need to show that it does not just improve patency but that patients also have better outcomes. The excess of major bleeds is a big deal. It gives one pause about adopting DAPT as standard treatment,” Dr. Gardner said.
DACAB received no commercial funding. Dr. Zhao has been a speaker on behalf of and has received research funding from AstraZeneca, the company that markets ticagrelor (Brilinta). He has also been a speaker for Johnson & Johnson and Medtronic and has received research funding from Bayer, Novartis, and Sanofi. Dr. Gardner had no disclosures.
[email protected]
On Twitter @mitchelzoler
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: The 1-year saphenous-vein graft patency rate was 89% with DAPT treatment and 77% with aspirin alone. Data source: DACAB, a multicenter, randomized trial with 500 Chinese patients.
Disclosures: DACAB received no commercial funding. Dr. Zhao has been a speaker on behalf of and has received research funding from AstraZeneca, the company that markets ticagrelor (Brilinta). He has also been a speaker for Johnson & Johnson and Medtronic and has received research funding from Bayer, Novartis, and Sanofi.
Delay predicting outcome in comatose cardiac arrest
ANAHEIM, CALIF. – Withdrawal of life-sustaining systemic therapies in comatose patients after out-of-hospital cardiac arrest as advised in current guidelines often occurs too early, resulting in the death of many patients who could potentially survive with good outcome, according to the results of NORCAST, the Norwegian Cardiorespiratory Arrest Study.
“The take-home message is to be patient and wait. Three days may be too early to make decisions on the patient,” Kjetil Sunde, MD, said in presenting the study findings at the Resuscitation Science Symposium held during the American Heart Association scientific sessions.
The European Resuscitation Council and European Society of Intensive Care Medicine have jointly recommended a prognostic algorithm in which a multimodal assessment is made on patients who are still comatose on day 3 after cardiac arrest. But this advice is based on expert opinion and has never been validated. This was the impetus for the prospective NORCAST study.
Current practice in the management of out-of-hospital cardiac arrest patients who are comatose upon hospital admission is to induce therapeutic hypothermia, with targeted temperature management to 33° C for 24 hours under deep sedation. The study hypothesis was that this strategy delays the time to awakening and that, as a consequence, the recommended prognostic tests that are usually done on day 3 after withdrawal of sedation are rendered insufficiently reliable. Thus, decisions to withdraw life-supporting therapies at that point will reduce the survival potential of this population, Dr. Sunde explained.
NORCAST was a prospective observational study that included 259 patients admitted to Oslo University Hospital in a comatose state after out-of-hospital cardiac arrest. In this unselected group, 81% had a cardiac cause for their arrest; the remainder had hypoxic arrest. All patients underwent therapeutic hypothermia, then a period of nonhypothermia followed by sedation withdrawal.
All of the widely used multimodal prognostic tests were ordered, including serial measurement of serum neuron-specific enolase; neurophysiologic testing using EEG and sensory-evoked potential readings obtained both during hypothermia and again at least 3 days after sedation withdrawal; a standardized clinical neurologic exam including assessment of brainstem reflexes and a Glasgow Coma Scale rating 3 days after sedation withdrawal; and a transcranial Doppler study and cerebral MRI on day 5-7. However, the treatment team was blinded to the results of these tests and was encouraged to delay withdrawal of life-supporting therapies as long as possible.
Key findings
Out of 259 patients who were comatose upon admission, 54% were alive at 6 months – and 91% of them had a CPC of 1 or 2.
The final tally at 6 months: 44% of patients were CPC 1, 5.5% were CPC 2, 4% were CPC 3, meaning severely disabled, and 46.5% were CPC 5, which is brain dead.
Withdrawal of life-supporting therapies occurred in 73 patients, or 28%, and 71% of those patients died, few of them in the early days.
Among patients with a CPC score of 1 or 2 at 6 months, only 20% were awake on day 1-3 following admission. Fifty-seven percent awoke on day 4-7, but importantly, 23% of patients with a good outcome at 6 months were not yet awake on day 8.
Three days after withdrawal of sedation, 49% of patients were rated as having a Glasgow Coma Scale score of 3-8, while 51% were Glasgow Coma Scale 9-15. Moreover, at that time 26% of patients with a good outcome as defined by a CPC of 1 or 2 at 6 months were still in a coma.
“So a lot of patients were still affected by their disease or by sedation at that point. That’s an important finding,” Dr. Sunde said.
Some prognostic tests were highly unreliable
A standout in poor performance was the widely utilized standard of a time to return of spontaneous circulation greater than 25 minutes as a predictor of poor cerebral outcome. In fact, it had a 34% false-positive rate.
“I think it’s really useless to use that. I would rather have return to spontaneous circulation after 40 minutes of good-quality CPR than not have it with 25 minutes of lesser-quality CPR,” he commented.
Similarly, a Glasgow Coma Scale score of 9 or less or a Glasgow Coma Scale-Motor score of 1-3 upon assessment 3 days after sedation withdrawal had false-positive rates of 30% and 34%, respectively.
During hypothermia, EEG abnormalities had a high false-positive rate, and sensory-evoked potential findings were difficult to interpret.
Predictors showing utility
Several clinical factors predicted poor cerebral outcome with low false-positive rates: Unwitnessed cardiac arrest had a false-positive rate of only 4%; initial presentation in asystole or with pulseless electrical activity had a false-positive rate of 6%; and no bystander CPR had a false-positive rate of 13%.
Abnormal sensory-evoked potential or EEG findings 3 days after sedation withdrawal had low false-positive rates as prognosticators of poor cerebral outcome. An EEG showing burst suppression or epileptiform activity had a “pretty good” false-positive rate of only 7%, Dr. Sunde noted. Bilaterally absent N20 sensory-evoked potential findings, while uncommon, had a false-positive rate of zero. A serum neuron-specific enolase level greater than 80 mcg/mL had a 3% false-positive rate, in sharp contrast to the previously recommended cutoff of more than 33 mcg/mL, which had an unacceptable 38% false-positive rate.
“We should avoid using single predictors in decision making and be patient, especially if we have a witnessed ventricular fibrillation with bystander CPR, independent of time to return of spontaneous circulation,” he concluded.
Dr. Sunde and his coinvestigators plan to present numerous further follow-up studies from NORCAST, including the results of comprehensive cognitive function testing 6-9 months after cardiac arrest in all survivors, coupled with interviews with their close relatives, as well as cognitive function and quality-of-life measurements 3-6 years after cardiac arrest along with interviews with relatives.
Several audience members rose to declare that they’ve been waiting for data such as this for a long time. Session chair Karl B. Kern, MD, professor of medicine at the University of Arizona, Tucson, and codirector of the University of Arizona Sarver Heart Center, commented, “We’ve been talking about whether 3 days is too early for a number of years, and clearly from your data it is. It was twice as long before most of them woke up.”
Dr. Sunde reported having no financial conflicts of interest regarding the NORCAST study, which was sponsored by Oslo University Hospital.
ANAHEIM, CALIF. – Withdrawal of life-sustaining systemic therapies in comatose patients after out-of-hospital cardiac arrest as advised in current guidelines often occurs too early, resulting in the death of many patients who could potentially survive with good outcome, according to the results of NORCAST, the Norwegian Cardiorespiratory Arrest Study.
“The take-home message is to be patient and wait. Three days may be too early to make decisions on the patient,” Kjetil Sunde, MD, said in presenting the study findings at the Resuscitation Science Symposium held during the American Heart Association scientific sessions.
The European Resuscitation Council and European Society of Intensive Care Medicine have jointly recommended a prognostic algorithm in which a multimodal assessment is made on patients who are still comatose on day 3 after cardiac arrest. But this advice is based on expert opinion and has never been validated. This was the impetus for the prospective NORCAST study.
Current practice in the management of out-of-hospital cardiac arrest patients who are comatose upon hospital admission is to induce therapeutic hypothermia, with targeted temperature management to 33° C for 24 hours under deep sedation. The study hypothesis was that this strategy delays the time to awakening and that, as a consequence, the recommended prognostic tests that are usually done on day 3 after withdrawal of sedation are rendered insufficiently reliable. Thus, decisions to withdraw life-supporting therapies at that point will reduce the survival potential of this population, Dr. Sunde explained.
NORCAST was a prospective observational study that included 259 patients admitted to Oslo University Hospital in a comatose state after out-of-hospital cardiac arrest. In this unselected group, 81% had a cardiac cause for their arrest; the remainder had hypoxic arrest. All patients underwent therapeutic hypothermia, then a period of nonhypothermia followed by sedation withdrawal.
All of the widely used multimodal prognostic tests were ordered, including serial measurement of serum neuron-specific enolase; neurophysiologic testing using EEG and sensory-evoked potential readings obtained both during hypothermia and again at least 3 days after sedation withdrawal; a standardized clinical neurologic exam including assessment of brainstem reflexes and a Glasgow Coma Scale rating 3 days after sedation withdrawal; and a transcranial Doppler study and cerebral MRI on day 5-7. However, the treatment team was blinded to the results of these tests and was encouraged to delay withdrawal of life-supporting therapies as long as possible.
Key findings
Out of 259 patients who were comatose upon admission, 54% were alive at 6 months – and 91% of them had a CPC of 1 or 2.
The final tally at 6 months: 44% of patients were CPC 1, 5.5% were CPC 2, 4% were CPC 3, meaning severely disabled, and 46.5% were CPC 5, which is brain dead.
Withdrawal of life-supporting therapies occurred in 73 patients, or 28%, and 71% of those patients died, few of them in the early days.
Among patients with a CPC score of 1 or 2 at 6 months, only 20% were awake on day 1-3 following admission. Fifty-seven percent awoke on day 4-7, but importantly, 23% of patients with a good outcome at 6 months were not yet awake on day 8.
Three days after withdrawal of sedation, 49% of patients were rated as having a Glasgow Coma Scale score of 3-8, while 51% were Glasgow Coma Scale 9-15. Moreover, at that time 26% of patients with a good outcome as defined by a CPC of 1 or 2 at 6 months were still in a coma.
“So a lot of patients were still affected by their disease or by sedation at that point. That’s an important finding,” Dr. Sunde said.
Some prognostic tests were highly unreliable
A standout in poor performance was the widely utilized standard of a time to return of spontaneous circulation greater than 25 minutes as a predictor of poor cerebral outcome. In fact, it had a 34% false-positive rate.
“I think it’s really useless to use that. I would rather have return to spontaneous circulation after 40 minutes of good-quality CPR than not have it with 25 minutes of lesser-quality CPR,” he commented.
Similarly, a Glasgow Coma Scale score of 9 or less or a Glasgow Coma Scale-Motor score of 1-3 upon assessment 3 days after sedation withdrawal had false-positive rates of 30% and 34%, respectively.
During hypothermia, EEG abnormalities had a high false-positive rate, and sensory-evoked potential findings were difficult to interpret.
Predictors showing utility
Several clinical factors predicted poor cerebral outcome with low false-positive rates: Unwitnessed cardiac arrest had a false-positive rate of only 4%; initial presentation in asystole or with pulseless electrical activity had a false-positive rate of 6%; and no bystander CPR had a false-positive rate of 13%.
Abnormal sensory-evoked potential or EEG findings 3 days after sedation withdrawal had low false-positive rates as prognosticators of poor cerebral outcome. An EEG showing burst suppression or epileptiform activity had a “pretty good” false-positive rate of only 7%, Dr. Sunde noted. Bilaterally absent N20 sensory-evoked potential findings, while uncommon, had a false-positive rate of zero. A serum neuron-specific enolase level greater than 80 mcg/mL had a 3% false-positive rate, in sharp contrast to the previously recommended cutoff of more than 33 mcg/mL, which had an unacceptable 38% false-positive rate.
“We should avoid using single predictors in decision making and be patient, especially if we have a witnessed ventricular fibrillation with bystander CPR, independent of time to return of spontaneous circulation,” he concluded.
Dr. Sunde and his coinvestigators plan to present numerous further follow-up studies from NORCAST, including the results of comprehensive cognitive function testing 6-9 months after cardiac arrest in all survivors, coupled with interviews with their close relatives, as well as cognitive function and quality-of-life measurements 3-6 years after cardiac arrest along with interviews with relatives.
Several audience members rose to declare that they’ve been waiting for data such as this for a long time. Session chair Karl B. Kern, MD, professor of medicine at the University of Arizona, Tucson, and codirector of the University of Arizona Sarver Heart Center, commented, “We’ve been talking about whether 3 days is too early for a number of years, and clearly from your data it is. It was twice as long before most of them woke up.”
Dr. Sunde reported having no financial conflicts of interest regarding the NORCAST study, which was sponsored by Oslo University Hospital.
ANAHEIM, CALIF. – Withdrawal of life-sustaining systemic therapies in comatose patients after out-of-hospital cardiac arrest as advised in current guidelines often occurs too early, resulting in the death of many patients who could potentially survive with good outcome, according to the results of NORCAST, the Norwegian Cardiorespiratory Arrest Study.
“The take-home message is to be patient and wait. Three days may be too early to make decisions on the patient,” Kjetil Sunde, MD, said in presenting the study findings at the Resuscitation Science Symposium held during the American Heart Association scientific sessions.
The European Resuscitation Council and European Society of Intensive Care Medicine have jointly recommended a prognostic algorithm in which a multimodal assessment is made on patients who are still comatose on day 3 after cardiac arrest. But this advice is based on expert opinion and has never been validated. This was the impetus for the prospective NORCAST study.
Current practice in the management of out-of-hospital cardiac arrest patients who are comatose upon hospital admission is to induce therapeutic hypothermia, with targeted temperature management to 33° C for 24 hours under deep sedation. The study hypothesis was that this strategy delays the time to awakening and that, as a consequence, the recommended prognostic tests that are usually done on day 3 after withdrawal of sedation are rendered insufficiently reliable. Thus, decisions to withdraw life-supporting therapies at that point will reduce the survival potential of this population, Dr. Sunde explained.
NORCAST was a prospective observational study that included 259 patients admitted to Oslo University Hospital in a comatose state after out-of-hospital cardiac arrest. In this unselected group, 81% had a cardiac cause for their arrest; the remainder had hypoxic arrest. All patients underwent therapeutic hypothermia, then a period of nonhypothermia followed by sedation withdrawal.
All of the widely used multimodal prognostic tests were ordered, including serial measurement of serum neuron-specific enolase; neurophysiologic testing using EEG and sensory-evoked potential readings obtained both during hypothermia and again at least 3 days after sedation withdrawal; a standardized clinical neurologic exam including assessment of brainstem reflexes and a Glasgow Coma Scale rating 3 days after sedation withdrawal; and a transcranial Doppler study and cerebral MRI on day 5-7. However, the treatment team was blinded to the results of these tests and was encouraged to delay withdrawal of life-supporting therapies as long as possible.
Key findings
Out of 259 patients who were comatose upon admission, 54% were alive at 6 months – and 91% of them had a CPC of 1 or 2.
The final tally at 6 months: 44% of patients were CPC 1, 5.5% were CPC 2, 4% were CPC 3, meaning severely disabled, and 46.5% were CPC 5, which is brain dead.
Withdrawal of life-supporting therapies occurred in 73 patients, or 28%, and 71% of those patients died, few of them in the early days.
Among patients with a CPC score of 1 or 2 at 6 months, only 20% were awake on day 1-3 following admission. Fifty-seven percent awoke on day 4-7, but importantly, 23% of patients with a good outcome at 6 months were not yet awake on day 8.
Three days after withdrawal of sedation, 49% of patients were rated as having a Glasgow Coma Scale score of 3-8, while 51% were Glasgow Coma Scale 9-15. Moreover, at that time 26% of patients with a good outcome as defined by a CPC of 1 or 2 at 6 months were still in a coma.
“So a lot of patients were still affected by their disease or by sedation at that point. That’s an important finding,” Dr. Sunde said.
Some prognostic tests were highly unreliable
A standout in poor performance was the widely utilized standard of a time to return of spontaneous circulation greater than 25 minutes as a predictor of poor cerebral outcome. In fact, it had a 34% false-positive rate.
“I think it’s really useless to use that. I would rather have return to spontaneous circulation after 40 minutes of good-quality CPR than not have it with 25 minutes of lesser-quality CPR,” he commented.
Similarly, a Glasgow Coma Scale score of 9 or less or a Glasgow Coma Scale-Motor score of 1-3 upon assessment 3 days after sedation withdrawal had false-positive rates of 30% and 34%, respectively.
During hypothermia, EEG abnormalities had a high false-positive rate, and sensory-evoked potential findings were difficult to interpret.
Predictors showing utility
Several clinical factors predicted poor cerebral outcome with low false-positive rates: Unwitnessed cardiac arrest had a false-positive rate of only 4%; initial presentation in asystole or with pulseless electrical activity had a false-positive rate of 6%; and no bystander CPR had a false-positive rate of 13%.
Abnormal sensory-evoked potential or EEG findings 3 days after sedation withdrawal had low false-positive rates as prognosticators of poor cerebral outcome. An EEG showing burst suppression or epileptiform activity had a “pretty good” false-positive rate of only 7%, Dr. Sunde noted. Bilaterally absent N20 sensory-evoked potential findings, while uncommon, had a false-positive rate of zero. A serum neuron-specific enolase level greater than 80 mcg/mL had a 3% false-positive rate, in sharp contrast to the previously recommended cutoff of more than 33 mcg/mL, which had an unacceptable 38% false-positive rate.
“We should avoid using single predictors in decision making and be patient, especially if we have a witnessed ventricular fibrillation with bystander CPR, independent of time to return of spontaneous circulation,” he concluded.
Dr. Sunde and his coinvestigators plan to present numerous further follow-up studies from NORCAST, including the results of comprehensive cognitive function testing 6-9 months after cardiac arrest in all survivors, coupled with interviews with their close relatives, as well as cognitive function and quality-of-life measurements 3-6 years after cardiac arrest along with interviews with relatives.
Several audience members rose to declare that they’ve been waiting for data such as this for a long time. Session chair Karl B. Kern, MD, professor of medicine at the University of Arizona, Tucson, and codirector of the University of Arizona Sarver Heart Center, commented, “We’ve been talking about whether 3 days is too early for a number of years, and clearly from your data it is. It was twice as long before most of them woke up.”
Dr. Sunde reported having no financial conflicts of interest regarding the NORCAST study, which was sponsored by Oslo University Hospital.
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: Patients with good cerebral function 6 months after admission in a comatose state stemming from out-of-hospital cardiac arrest awoke a mean of 6.2 days post cardiac arrest, far later than most prognostic assessments take place.
Data source: NORCAST, a prospective observational study, included 259 patients who were comatose upon hospital admission after out-of-hospital cardiac arrest.
Disclosures: NORCAST was sponsored by Oslo University Hospital. The presenter reported having no financial conflicts.
Genotype-guided warfarin dosing reduced adverse events in arthroplasty patients
The difference in the composite endpoint (major bleeding within 30 days, international normalized ratio [INR] of 4 or greater within 30 days, venous thromboembolism within 60 days, or death within 30 days) in the Genetic Informatics Trial of Warfarin to Prevent Deep Vein Thrombosis (GIFT) trial was mainly driven by a significant difference in episodes of elevated INR, reported Brian F. Gage, MD, and his colleagues (JAMA 2017;318[12]:1115-1124. doi: 10.1001/jama.2017.11469).
A total of 1,597 patients completed the trial. Of 808 patients in the genotype-guided group, 10.8% met one of the endpoints. Of 789 in the clinically guided warfarin dosing group, 14.7% met at least 1 of the endpoints. There were no deaths in the study.
“Widespread use of genotype-guided dosing will depend on reimbursement, regulations, and logistics. Although several commercial platforms for warfarin-related genes have been approved by the Food and Drug Administration and the European Medicines Agency, routine genotyping is not yet recommended,” wrote Dr. Gage of Washington University, St. Louis, and his coauthors.
The Centers for Medicare and Medicaid Services used its Coverage with Evidence Development program to fund genotyping in this trial and will review the results to determine future coverage, the researchers added.
In GIFT, patients were randomized to an 11-day regimen of warfarin guided either by a clinical algorithm or by their individual genotype. The team tested for four polymorphisms known to affect warfarin metabolism: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. The treatment goal was an INR of 1.8-2. After 11 days, physicians could administer warfarin according to their own judgment.
The absolute difference of 3.9% in the composite endpoint was largely driven by a 2.8% absolute difference in the rate of an INR of 4 or greater. The rate difference between the two groups was 0.8% for major bleeding, and 0.7% for VTE.
About 41% of the cohort was considered to be at high risk of bleeding complications, and this group accrued the highest benefit from genotype-based dosing. Among them, the composite endpoint was 11.5% compared with 15.2% in the clinical algorithm group – an absolute difference of 3.76%.
The benefit was consistent among black patients, and those with CYP2C9.
By day 90, one VTE had occurred in each group. An intracranial hemorrhage occurred in one patient in the clinically guided group, 2 months after stopping warfarin.
The clinical benefit of genotype-based dosing influenced 90-day outcomes as well, with the composite endpoint occurring in 11% of the genotype group and 15% of the clinically guided group (absolute difference 3.9%).
Among the 1,588 patients who had their percentage of time in the therapeutic range (PTTR) calculated, genotyping improved PTTR time by 3.4% overall. The effect was especially strong from days 4 to 14, when it improved PTTR by 5.7% relative to clinical guidance.
Three other studies have examined the effect of a genotype-based warfarin dosing regimen, Dr. Gage and his coauthors noted: Two found no benefit, and a third found that such guidance improved INR control. GIFT has several advantages over those trials, which the authors said lend credence to its results.
“Compared with previous studies, this trial was larger, used genotype-guided dosing for a longer duration, and incorporated more genes into the dosing algorithm …The longer period of genotype-guided dosing likely prevented cases of supratherapeutic INR that were common in these trials,” they wrote.
Dr. Gage reported no financial disclosures, but several coauthors reported ties with pharmaceutical and imaging companies.
Warfarin is the most commonly used anticoagulant in the world, and a significant cause of emergency department visits and hospitalizations, especially among older patients. Walking the fine line between dosing too little and too much is not an easy task – especially since warfarin response is influenced by diet, comorbidities, interactions with other medications and – as studies over the last 20 years have confirmed – many genetic variants.
Also, the practicality of genotyping every patient who needs anticoagulation therapy must be questioned. Based on the results of GIFT, 26 patients would need to be genotyped to prevent one event, typically an INR of 4 or greater. Although the cost of genotyping continues to decline, health insurers and publicly funded health systems have not yet been convinced that genotype-guided warfarin prescribing is a cost-effective strategy.
The benefits of genotyping would likely be less in patients with atrial fibrillation, for example, as they run a lower risk of VTE than do arthroplasty patients. The GIFT surgeries were all elective, so there was plenty of time to get back genotyping results before starting warfarin. That is a luxury not afforded to many patients in need of anticoagulation.
It’s possible, however, that the benefits of genotyping might be larger in the real world. GIFT was conducted at academic medical centers and used a clinical dosing algorithm as comparator. As a result, adverse event rates were likely lower in the comparison group than would be expected in other clinical settings with less-intense INR monitoring or empirically based initiation regimens.
Still, GIFT’s results are gaining global attention. Based on prepublication results of the GIFT trial, the Clinical Pharmacogenetics Implementation Consortium (CPIC), an international research network that develops consensus recommendations about the use of pharmacogenomic test results, recently published guidelines about genotype-guided dosing for warfarin. The group now recommends using genotype-guided warfarin dosing based on CYP2C9*2, CYP2C9*3, and VKORC1 variants for adult patients of non-African ancestry. It also recommends that patients with combinations of high-risk variants would benefit from an alternative anticoagulant strategy, because of likely greater risks of poor INR control and bleeding.
A single pharmacogenomic test covering many common variants relevant to multiple prescribing decisions over time is far more likely to be a cost-effective approach; however, there is no evidence for this proposition. Until then, it might be simpler and less expensive to use clinical dosing algorithms to reduce the risks of anticoagulation.
Jon D. Emery, PhD, is the Herman Professor of Primary Care Cancer Research at the University of Melbourne and Western Health, Melbourne. He made these remarks in an accompanying editorial (JAMA 2017;318;110-2 doi: 10.1001/jama.2017.11465 ).
Warfarin is the most commonly used anticoagulant in the world, and a significant cause of emergency department visits and hospitalizations, especially among older patients. Walking the fine line between dosing too little and too much is not an easy task – especially since warfarin response is influenced by diet, comorbidities, interactions with other medications and – as studies over the last 20 years have confirmed – many genetic variants.
Also, the practicality of genotyping every patient who needs anticoagulation therapy must be questioned. Based on the results of GIFT, 26 patients would need to be genotyped to prevent one event, typically an INR of 4 or greater. Although the cost of genotyping continues to decline, health insurers and publicly funded health systems have not yet been convinced that genotype-guided warfarin prescribing is a cost-effective strategy.
The benefits of genotyping would likely be less in patients with atrial fibrillation, for example, as they run a lower risk of VTE than do arthroplasty patients. The GIFT surgeries were all elective, so there was plenty of time to get back genotyping results before starting warfarin. That is a luxury not afforded to many patients in need of anticoagulation.
It’s possible, however, that the benefits of genotyping might be larger in the real world. GIFT was conducted at academic medical centers and used a clinical dosing algorithm as comparator. As a result, adverse event rates were likely lower in the comparison group than would be expected in other clinical settings with less-intense INR monitoring or empirically based initiation regimens.
Still, GIFT’s results are gaining global attention. Based on prepublication results of the GIFT trial, the Clinical Pharmacogenetics Implementation Consortium (CPIC), an international research network that develops consensus recommendations about the use of pharmacogenomic test results, recently published guidelines about genotype-guided dosing for warfarin. The group now recommends using genotype-guided warfarin dosing based on CYP2C9*2, CYP2C9*3, and VKORC1 variants for adult patients of non-African ancestry. It also recommends that patients with combinations of high-risk variants would benefit from an alternative anticoagulant strategy, because of likely greater risks of poor INR control and bleeding.
A single pharmacogenomic test covering many common variants relevant to multiple prescribing decisions over time is far more likely to be a cost-effective approach; however, there is no evidence for this proposition. Until then, it might be simpler and less expensive to use clinical dosing algorithms to reduce the risks of anticoagulation.
Jon D. Emery, PhD, is the Herman Professor of Primary Care Cancer Research at the University of Melbourne and Western Health, Melbourne. He made these remarks in an accompanying editorial (JAMA 2017;318;110-2 doi: 10.1001/jama.2017.11465 ).
Warfarin is the most commonly used anticoagulant in the world, and a significant cause of emergency department visits and hospitalizations, especially among older patients. Walking the fine line between dosing too little and too much is not an easy task – especially since warfarin response is influenced by diet, comorbidities, interactions with other medications and – as studies over the last 20 years have confirmed – many genetic variants.
Also, the practicality of genotyping every patient who needs anticoagulation therapy must be questioned. Based on the results of GIFT, 26 patients would need to be genotyped to prevent one event, typically an INR of 4 or greater. Although the cost of genotyping continues to decline, health insurers and publicly funded health systems have not yet been convinced that genotype-guided warfarin prescribing is a cost-effective strategy.
The benefits of genotyping would likely be less in patients with atrial fibrillation, for example, as they run a lower risk of VTE than do arthroplasty patients. The GIFT surgeries were all elective, so there was plenty of time to get back genotyping results before starting warfarin. That is a luxury not afforded to many patients in need of anticoagulation.
It’s possible, however, that the benefits of genotyping might be larger in the real world. GIFT was conducted at academic medical centers and used a clinical dosing algorithm as comparator. As a result, adverse event rates were likely lower in the comparison group than would be expected in other clinical settings with less-intense INR monitoring or empirically based initiation regimens.
Still, GIFT’s results are gaining global attention. Based on prepublication results of the GIFT trial, the Clinical Pharmacogenetics Implementation Consortium (CPIC), an international research network that develops consensus recommendations about the use of pharmacogenomic test results, recently published guidelines about genotype-guided dosing for warfarin. The group now recommends using genotype-guided warfarin dosing based on CYP2C9*2, CYP2C9*3, and VKORC1 variants for adult patients of non-African ancestry. It also recommends that patients with combinations of high-risk variants would benefit from an alternative anticoagulant strategy, because of likely greater risks of poor INR control and bleeding.
A single pharmacogenomic test covering many common variants relevant to multiple prescribing decisions over time is far more likely to be a cost-effective approach; however, there is no evidence for this proposition. Until then, it might be simpler and less expensive to use clinical dosing algorithms to reduce the risks of anticoagulation.
Jon D. Emery, PhD, is the Herman Professor of Primary Care Cancer Research at the University of Melbourne and Western Health, Melbourne. He made these remarks in an accompanying editorial (JAMA 2017;318;110-2 doi: 10.1001/jama.2017.11465 ).
The difference in the composite endpoint (major bleeding within 30 days, international normalized ratio [INR] of 4 or greater within 30 days, venous thromboembolism within 60 days, or death within 30 days) in the Genetic Informatics Trial of Warfarin to Prevent Deep Vein Thrombosis (GIFT) trial was mainly driven by a significant difference in episodes of elevated INR, reported Brian F. Gage, MD, and his colleagues (JAMA 2017;318[12]:1115-1124. doi: 10.1001/jama.2017.11469).
A total of 1,597 patients completed the trial. Of 808 patients in the genotype-guided group, 10.8% met one of the endpoints. Of 789 in the clinically guided warfarin dosing group, 14.7% met at least 1 of the endpoints. There were no deaths in the study.
“Widespread use of genotype-guided dosing will depend on reimbursement, regulations, and logistics. Although several commercial platforms for warfarin-related genes have been approved by the Food and Drug Administration and the European Medicines Agency, routine genotyping is not yet recommended,” wrote Dr. Gage of Washington University, St. Louis, and his coauthors.
The Centers for Medicare and Medicaid Services used its Coverage with Evidence Development program to fund genotyping in this trial and will review the results to determine future coverage, the researchers added.
In GIFT, patients were randomized to an 11-day regimen of warfarin guided either by a clinical algorithm or by their individual genotype. The team tested for four polymorphisms known to affect warfarin metabolism: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. The treatment goal was an INR of 1.8-2. After 11 days, physicians could administer warfarin according to their own judgment.
The absolute difference of 3.9% in the composite endpoint was largely driven by a 2.8% absolute difference in the rate of an INR of 4 or greater. The rate difference between the two groups was 0.8% for major bleeding, and 0.7% for VTE.
About 41% of the cohort was considered to be at high risk of bleeding complications, and this group accrued the highest benefit from genotype-based dosing. Among them, the composite endpoint was 11.5% compared with 15.2% in the clinical algorithm group – an absolute difference of 3.76%.
The benefit was consistent among black patients, and those with CYP2C9.
By day 90, one VTE had occurred in each group. An intracranial hemorrhage occurred in one patient in the clinically guided group, 2 months after stopping warfarin.
The clinical benefit of genotype-based dosing influenced 90-day outcomes as well, with the composite endpoint occurring in 11% of the genotype group and 15% of the clinically guided group (absolute difference 3.9%).
Among the 1,588 patients who had their percentage of time in the therapeutic range (PTTR) calculated, genotyping improved PTTR time by 3.4% overall. The effect was especially strong from days 4 to 14, when it improved PTTR by 5.7% relative to clinical guidance.
Three other studies have examined the effect of a genotype-based warfarin dosing regimen, Dr. Gage and his coauthors noted: Two found no benefit, and a third found that such guidance improved INR control. GIFT has several advantages over those trials, which the authors said lend credence to its results.
“Compared with previous studies, this trial was larger, used genotype-guided dosing for a longer duration, and incorporated more genes into the dosing algorithm …The longer period of genotype-guided dosing likely prevented cases of supratherapeutic INR that were common in these trials,” they wrote.
Dr. Gage reported no financial disclosures, but several coauthors reported ties with pharmaceutical and imaging companies.
The difference in the composite endpoint (major bleeding within 30 days, international normalized ratio [INR] of 4 or greater within 30 days, venous thromboembolism within 60 days, or death within 30 days) in the Genetic Informatics Trial of Warfarin to Prevent Deep Vein Thrombosis (GIFT) trial was mainly driven by a significant difference in episodes of elevated INR, reported Brian F. Gage, MD, and his colleagues (JAMA 2017;318[12]:1115-1124. doi: 10.1001/jama.2017.11469).
A total of 1,597 patients completed the trial. Of 808 patients in the genotype-guided group, 10.8% met one of the endpoints. Of 789 in the clinically guided warfarin dosing group, 14.7% met at least 1 of the endpoints. There were no deaths in the study.
“Widespread use of genotype-guided dosing will depend on reimbursement, regulations, and logistics. Although several commercial platforms for warfarin-related genes have been approved by the Food and Drug Administration and the European Medicines Agency, routine genotyping is not yet recommended,” wrote Dr. Gage of Washington University, St. Louis, and his coauthors.
The Centers for Medicare and Medicaid Services used its Coverage with Evidence Development program to fund genotyping in this trial and will review the results to determine future coverage, the researchers added.
In GIFT, patients were randomized to an 11-day regimen of warfarin guided either by a clinical algorithm or by their individual genotype. The team tested for four polymorphisms known to affect warfarin metabolism: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. The treatment goal was an INR of 1.8-2. After 11 days, physicians could administer warfarin according to their own judgment.
The absolute difference of 3.9% in the composite endpoint was largely driven by a 2.8% absolute difference in the rate of an INR of 4 or greater. The rate difference between the two groups was 0.8% for major bleeding, and 0.7% for VTE.
About 41% of the cohort was considered to be at high risk of bleeding complications, and this group accrued the highest benefit from genotype-based dosing. Among them, the composite endpoint was 11.5% compared with 15.2% in the clinical algorithm group – an absolute difference of 3.76%.
The benefit was consistent among black patients, and those with CYP2C9.
By day 90, one VTE had occurred in each group. An intracranial hemorrhage occurred in one patient in the clinically guided group, 2 months after stopping warfarin.
The clinical benefit of genotype-based dosing influenced 90-day outcomes as well, with the composite endpoint occurring in 11% of the genotype group and 15% of the clinically guided group (absolute difference 3.9%).
Among the 1,588 patients who had their percentage of time in the therapeutic range (PTTR) calculated, genotyping improved PTTR time by 3.4% overall. The effect was especially strong from days 4 to 14, when it improved PTTR by 5.7% relative to clinical guidance.
Three other studies have examined the effect of a genotype-based warfarin dosing regimen, Dr. Gage and his coauthors noted: Two found no benefit, and a third found that such guidance improved INR control. GIFT has several advantages over those trials, which the authors said lend credence to its results.
“Compared with previous studies, this trial was larger, used genotype-guided dosing for a longer duration, and incorporated more genes into the dosing algorithm …The longer period of genotype-guided dosing likely prevented cases of supratherapeutic INR that were common in these trials,” they wrote.
Dr. Gage reported no financial disclosures, but several coauthors reported ties with pharmaceutical and imaging companies.
FROM JAMA
Key clinical point:
Major finding: Genotype-guided dosing reduced adverse events – primarily elevated INRs – by almost 4% compared to clinically based warfarin dosing.
Data source: A randomized trial comprising 1,650 elderly patients undergoing elective knee or hip arthroplasty.
Disclosures: Dr. Gage had no financial disclosures, but several of his coauthors noted relationships with pharmaceutical and imaging companies.
Atrial fibrillation boosts VTE risk
BARCELONA – Atrial fibrillation is at least as strong a risk factor for venous thromboembolism as for ischemic stroke, Bjorn Hornestam, MD, asserted at the annual congress of the European Society of Cardiology.
This novel finding from a Swedish national registry study suggests it’s time for thoughtful consideration of a revision of risk scores in patients with atrial fibrillation (AF), according to Dr. Hornestam, director of cardiology at Sahlgrenska University Hospital in Gothenburg, Sweden.
“VTE risk is not included as an outcome in the CHA2DS2-VASc score, so we underestimate the total thromboembolic risk in AF patients,” he said.
Dr. Hornestam presented a Swedish registry study of 1.36 million patients, including 470,738 patients with new-onset AF and no previous diagnosis of VTE or ischemic stroke and twice as many controls without AF who were matched to the AF patients by age, gender, and county. 
The VTE risk was highest during the first 30 days after diagnosis of AF. Women with new-onset AF had an 8.3-fold increased risk of VTE compared with controls during this early period, by a margin of 55.8 versus 6.4 cases per 1,000 person-years. Men with newly diagnosed AF had a 7.2-fold increased risk of VTE in the first 30 days, reflecting a rate of 40.1 per 1,000 person-years compared to 5.6 per 1,000 in controls.
The VTE risk dropped off precipitously in men after the first month. The rate was cut in half by 2 months after AF diagnosis and was no different from that of controls by 9 months.
In women, too, the early elevated VTE risk was halved by 2 months out, but thereafter the rate of decline in VTE risk slowed. Even 10 years after AF diagnosis, women had a 21% greater VTE risk than did matched controls.
Of note, the risk of VTE during the first 12 months after diagnosis of AF was nearly twice as great in both men and women under age 65 than in those older than 75.
These data raise the question of whether standard therapy in AF patients needs to be modified, especially during what now appears to be the critical time frame of the first 3-6 months after diagnosis of the arrhythmia, Dr. Hornestam said.
He reported having no financial conflicts of interest regarding this study.
BARCELONA – Atrial fibrillation is at least as strong a risk factor for venous thromboembolism as for ischemic stroke, Bjorn Hornestam, MD, asserted at the annual congress of the European Society of Cardiology.
This novel finding from a Swedish national registry study suggests it’s time for thoughtful consideration of a revision of risk scores in patients with atrial fibrillation (AF), according to Dr. Hornestam, director of cardiology at Sahlgrenska University Hospital in Gothenburg, Sweden.
“VTE risk is not included as an outcome in the CHA2DS2-VASc score, so we underestimate the total thromboembolic risk in AF patients,” he said.
Dr. Hornestam presented a Swedish registry study of 1.36 million patients, including 470,738 patients with new-onset AF and no previous diagnosis of VTE or ischemic stroke and twice as many controls without AF who were matched to the AF patients by age, gender, and county.
The VTE risk was highest during the first 30 days after diagnosis of AF. Women with new-onset AF had an 8.3-fold increased risk of VTE compared with controls during this early period, by a margin of 55.8 versus 6.4 cases per 1,000 person-years. Men with newly diagnosed AF had a 7.2-fold increased risk of VTE in the first 30 days, reflecting a rate of 40.1 per 1,000 person-years compared to 5.6 per 1,000 in controls.
The VTE risk dropped off precipitously in men after the first month. The rate was cut in half by 2 months after AF diagnosis and was no different from that of controls by 9 months.
In women, too, the early elevated VTE risk was halved by 2 months out, but thereafter the rate of decline in VTE risk slowed. Even 10 years after AF diagnosis, women had a 21% greater VTE risk than did matched controls.
Of note, the risk of VTE during the first 12 months after diagnosis of AF was nearly twice as great in both men and women under age 65 than in those older than 75.
These data raise the question of whether standard therapy in AF patients needs to be modified, especially during what now appears to be the critical time frame of the first 3-6 months after diagnosis of the arrhythmia, Dr. Hornestam said.
He reported having no financial conflicts of interest regarding this study.
BARCELONA – Atrial fibrillation is at least as strong a risk factor for venous thromboembolism as for ischemic stroke, Bjorn Hornestam, MD, asserted at the annual congress of the European Society of Cardiology.
This novel finding from a Swedish national registry study suggests it’s time for thoughtful consideration of a revision of risk scores in patients with atrial fibrillation (AF), according to Dr. Hornestam, director of cardiology at Sahlgrenska University Hospital in Gothenburg, Sweden.
“VTE risk is not included as an outcome in the CHA2DS2-VASc score, so we underestimate the total thromboembolic risk in AF patients,” he said.
Dr. Hornestam presented a Swedish registry study of 1.36 million patients, including 470,738 patients with new-onset AF and no previous diagnosis of VTE or ischemic stroke and twice as many controls without AF who were matched to the AF patients by age, gender, and county.
The VTE risk was highest during the first 30 days after diagnosis of AF. Women with new-onset AF had an 8.3-fold increased risk of VTE compared with controls during this early period, by a margin of 55.8 versus 6.4 cases per 1,000 person-years. Men with newly diagnosed AF had a 7.2-fold increased risk of VTE in the first 30 days, reflecting a rate of 40.1 per 1,000 person-years compared to 5.6 per 1,000 in controls.
The VTE risk dropped off precipitously in men after the first month. The rate was cut in half by 2 months after AF diagnosis and was no different from that of controls by 9 months.
In women, too, the early elevated VTE risk was halved by 2 months out, but thereafter the rate of decline in VTE risk slowed. Even 10 years after AF diagnosis, women had a 21% greater VTE risk than did matched controls.
Of note, the risk of VTE during the first 12 months after diagnosis of AF was nearly twice as great in both men and women under age 65 than in those older than 75.
These data raise the question of whether standard therapy in AF patients needs to be modified, especially during what now appears to be the critical time frame of the first 3-6 months after diagnosis of the arrhythmia, Dr. Hornestam said.
He reported having no financial conflicts of interest regarding this study.
AT THE ESC CONGRESS 2017
Key clinical point:
Major finding: The risk of a first venous thromboembolism is increased 7.2- to 8.3-fold during the first 30 days following diagnosis of AF and remains moderately elevated in women even 10 years later.
Data source: An observational Swedish national registry study of more than 1.3 million patients, including 470,738 with newly diagnosed atrial fibrillation and their matched controls.
Disclosures: The presenter reported having no financial conflicts of interest regarding this study, which was conducted free of commercial support.
AF patients without oral anticoagulation face higher dementia risk
BARCELONA – The risk of developing dementia was reduced by 48% in patients with atrial fibrillation who were adherent to oral anticoagulation compared with those who were not, according to a Swedish propensity-matched registry study involving nearly 162,000 patients with the arrhythmia.
The study also addressed whether patients with atrial fibrillation (AF) are better off in terms of reducing their dementia risk if they’re on warfarin versus one of the novel oral anticoagulants. The answer is that it makes absolutely no difference, Leif Friberg, MD, reported at the annual congress of the European Society of Cardiology.
“We found no difference whatsoever in any of the subgroups. It appears that it is more important that you have some kind of oral treatment than exactly what kind to have,” said Dr. Friberg, a cardiologist at the Karolinska Institute in Stockholm.
It’s well established that AF is associated with increased risk of dementia, presumably because the arrhythmia kicks out microemboli that get distributed throughout the brain. But it has been unclear whether oral anticoagulation (OAC) prescribed for stroke prevention has the side benefit of reducing the elevated dementia risk.
“A randomized, controlled trial would be ideal to look at this, but it would be impractical and unethical. Second best [would be] a registry study with propensity matching,” according to Dr. Friberg.
And that’s just what he and his coinvestigators carried out. The study included 80,948 AF patients with no baseline diagnosis of dementia who were prescribed an OAC and an equal number of propensity-matched, dementia-free AF patients not on OAC therapy. During up to 8 years of follow-up, the unadjusted risk of a new diagnosis of dementia was 29% lower in the group on an OAC at baseline.
But the Swedish registries also enabled investigators to zero in on the impact of OAC in patients who were actually medication adherent over time. Dr. Friberg and his coworkers identified a subgroup of 50,406 AF patients who regularly filled their OAC prescriptions and took the medication at least 80% of the time, as well as 48,947 propensity-matched controls who never used OACs. In this on-treatment analysis, the OAC users had a robust 48% relative risk reduction in new diagnosis of dementia. The dementia curves diverged almost immediately and the gap between the two curves continued to widen throughout follow-up. All examined subgroups benefited, regardless of age, gender, AF duration, CHA2DS2-VASc score, or the presence or absence of diabetes, renal failure, or frequent falling.
“This is an important issue,” Dr. Friberg declared. “You may say, ‘What do we care about these findings? These patients are all supposed to be on an oral anticoagulant anyway.’ But you know, patients stop taking their oral anticoagulant. We’re pretty good at initiating treatment when we meet patients for the first time, if they have stroke risk factors, but annually, 10%-15% of patients drop out of treatment. And if patients aren’t concerned enough about their risk of stroke, they might be more concerned about the risk of becoming demented. So these data provide an additional argument for the need to persevere with oral anticoagulation therapy.”
Session cochair Gabriel Tatu-Chitoiu, MD, was skeptical.
“I’ve been working in the atrial fibrillation field for 40 years, and I have to say I haven’t seen a strong dementia possibility in my patients,” said Dr. Tatu-Chitoiu, a cardiologist in Bucharest, Romania, and immediate past president of the Romanian Cardiology Society.
Dr. Friberg replied that AF patients are elderly, and many of them may stop going to their cardiologist when they develop dementia.
“I don’t think you can make extensions from personal experience on this. You have to trust in statistical evidence,” he observed.
Dr. Friberg reported receiving research funding from Bayer, Bristol-Myers Squibb, Pfizer, and Sanofi. However, the registry study was carried out without commercial support.
BARCELONA – The risk of developing dementia was reduced by 48% in patients with atrial fibrillation who were adherent to oral anticoagulation compared with those who were not, according to a Swedish propensity-matched registry study involving nearly 162,000 patients with the arrhythmia.
The study also addressed whether patients with atrial fibrillation (AF) are better off in terms of reducing their dementia risk if they’re on warfarin versus one of the novel oral anticoagulants. The answer is that it makes absolutely no difference, Leif Friberg, MD, reported at the annual congress of the European Society of Cardiology.
“We found no difference whatsoever in any of the subgroups. It appears that it is more important that you have some kind of oral treatment than exactly what kind to have,” said Dr. Friberg, a cardiologist at the Karolinska Institute in Stockholm.
It’s well established that AF is associated with increased risk of dementia, presumably because the arrhythmia kicks out microemboli that get distributed throughout the brain. But it has been unclear whether oral anticoagulation (OAC) prescribed for stroke prevention has the side benefit of reducing the elevated dementia risk.
“A randomized, controlled trial would be ideal to look at this, but it would be impractical and unethical. Second best [would be] a registry study with propensity matching,” according to Dr. Friberg.
And that’s just what he and his coinvestigators carried out. The study included 80,948 AF patients with no baseline diagnosis of dementia who were prescribed an OAC and an equal number of propensity-matched, dementia-free AF patients not on OAC therapy. During up to 8 years of follow-up, the unadjusted risk of a new diagnosis of dementia was 29% lower in the group on an OAC at baseline.
But the Swedish registries also enabled investigators to zero in on the impact of OAC in patients who were actually medication adherent over time. Dr. Friberg and his coworkers identified a subgroup of 50,406 AF patients who regularly filled their OAC prescriptions and took the medication at least 80% of the time, as well as 48,947 propensity-matched controls who never used OACs. In this on-treatment analysis, the OAC users had a robust 48% relative risk reduction in new diagnosis of dementia. The dementia curves diverged almost immediately and the gap between the two curves continued to widen throughout follow-up. All examined subgroups benefited, regardless of age, gender, AF duration, CHA2DS2-VASc score, or the presence or absence of diabetes, renal failure, or frequent falling.
“This is an important issue,” Dr. Friberg declared. “You may say, ‘What do we care about these findings? These patients are all supposed to be on an oral anticoagulant anyway.’ But you know, patients stop taking their oral anticoagulant. We’re pretty good at initiating treatment when we meet patients for the first time, if they have stroke risk factors, but annually, 10%-15% of patients drop out of treatment. And if patients aren’t concerned enough about their risk of stroke, they might be more concerned about the risk of becoming demented. So these data provide an additional argument for the need to persevere with oral anticoagulation therapy.”
Session cochair Gabriel Tatu-Chitoiu, MD, was skeptical.
“I’ve been working in the atrial fibrillation field for 40 years, and I have to say I haven’t seen a strong dementia possibility in my patients,” said Dr. Tatu-Chitoiu, a cardiologist in Bucharest, Romania, and immediate past president of the Romanian Cardiology Society.
Dr. Friberg replied that AF patients are elderly, and many of them may stop going to their cardiologist when they develop dementia.
“I don’t think you can make extensions from personal experience on this. You have to trust in statistical evidence,” he observed.
Dr. Friberg reported receiving research funding from Bayer, Bristol-Myers Squibb, Pfizer, and Sanofi. However, the registry study was carried out without commercial support.
BARCELONA – The risk of developing dementia was reduced by 48% in patients with atrial fibrillation who were adherent to oral anticoagulation compared with those who were not, according to a Swedish propensity-matched registry study involving nearly 162,000 patients with the arrhythmia.
The study also addressed whether patients with atrial fibrillation (AF) are better off in terms of reducing their dementia risk if they’re on warfarin versus one of the novel oral anticoagulants. The answer is that it makes absolutely no difference, Leif Friberg, MD, reported at the annual congress of the European Society of Cardiology.
“We found no difference whatsoever in any of the subgroups. It appears that it is more important that you have some kind of oral treatment than exactly what kind to have,” said Dr. Friberg, a cardiologist at the Karolinska Institute in Stockholm.
It’s well established that AF is associated with increased risk of dementia, presumably because the arrhythmia kicks out microemboli that get distributed throughout the brain. But it has been unclear whether oral anticoagulation (OAC) prescribed for stroke prevention has the side benefit of reducing the elevated dementia risk.
“A randomized, controlled trial would be ideal to look at this, but it would be impractical and unethical. Second best [would be] a registry study with propensity matching,” according to Dr. Friberg.
And that’s just what he and his coinvestigators carried out. The study included 80,948 AF patients with no baseline diagnosis of dementia who were prescribed an OAC and an equal number of propensity-matched, dementia-free AF patients not on OAC therapy. During up to 8 years of follow-up, the unadjusted risk of a new diagnosis of dementia was 29% lower in the group on an OAC at baseline.
But the Swedish registries also enabled investigators to zero in on the impact of OAC in patients who were actually medication adherent over time. Dr. Friberg and his coworkers identified a subgroup of 50,406 AF patients who regularly filled their OAC prescriptions and took the medication at least 80% of the time, as well as 48,947 propensity-matched controls who never used OACs. In this on-treatment analysis, the OAC users had a robust 48% relative risk reduction in new diagnosis of dementia. The dementia curves diverged almost immediately and the gap between the two curves continued to widen throughout follow-up. All examined subgroups benefited, regardless of age, gender, AF duration, CHA2DS2-VASc score, or the presence or absence of diabetes, renal failure, or frequent falling.
“This is an important issue,” Dr. Friberg declared. “You may say, ‘What do we care about these findings? These patients are all supposed to be on an oral anticoagulant anyway.’ But you know, patients stop taking their oral anticoagulant. We’re pretty good at initiating treatment when we meet patients for the first time, if they have stroke risk factors, but annually, 10%-15% of patients drop out of treatment. And if patients aren’t concerned enough about their risk of stroke, they might be more concerned about the risk of becoming demented. So these data provide an additional argument for the need to persevere with oral anticoagulation therapy.”
Session cochair Gabriel Tatu-Chitoiu, MD, was skeptical.
“I’ve been working in the atrial fibrillation field for 40 years, and I have to say I haven’t seen a strong dementia possibility in my patients,” said Dr. Tatu-Chitoiu, a cardiologist in Bucharest, Romania, and immediate past president of the Romanian Cardiology Society.
Dr. Friberg replied that AF patients are elderly, and many of them may stop going to their cardiologist when they develop dementia.
“I don’t think you can make extensions from personal experience on this. You have to trust in statistical evidence,” he observed.
Dr. Friberg reported receiving research funding from Bayer, Bristol-Myers Squibb, Pfizer, and Sanofi. However, the registry study was carried out without commercial support.
AT THE ESC CONGRESS 2017
Key clinical point:
Major finding: The risk of new diagnosis of dementia during up to 8 years of follow-up was 48% lower in AF patients on an oral anticoagulant at least 80% of the time, compared with those not on the medication.
Data source: This was a Swedish registry study including nearly 162,000 propensity-matched patients with atrial fibrillation free of baseline dementia.
Disclosures: The study was conducted without commercial support.
Stroke cognitive outcomes found worse in Mexican Americans
SAN DIEGO – A new analysis shows that Mexican Americans (MAs) have worse cognitive outcomes a year after having a stroke than do non-Hispanic whites (NHWs).
The findings, which show that MAs had a mean score of 86 on the Modified Mini-Mental State Examination (3MSE; range: 0-100), compared with 92 for NHWs, come from a prospective study of MAs and NHWs in Corpus Christi, Texas, where both populations have long-established residencies.
After controlling for all factors, the researchers found a difference of –6.73 (95% confidence interval, –3.88 to –9.57; P less than .001).
“The Mexican-American population is growing quickly and aging. The cost of stroke-related cognitive impairment is high for patient, family, and society. Efforts to combat stroke-related cognitive decline are critical,” said Dr. Morgenstern, professor of neurology and epidemiology at the University of Michigan, Ann Arbor.
The study grew out of the Brain Attack Surveillance in Corpus Christi (BASIC) Project, which began in 1999 and is funded until 2019. It is the only ongoing stroke surveillance program that focuses on Mexican Americans, who comprise the largest segment of Hispanic Americans.
The researchers analyzed data encompassing all stroke patients in the BASIC Project from October 2014 through January 2016 (n = 227). They analyzed cognitive outcome data from 3 months, 6 months, and 12 months. MAs were younger on average than NHWs (median age 66 vs. 70; P = .018), and were more likely to have diabetes (54% vs. 36%; P less than .001). They were less likely to have atrial fibrillation (13% vs. 20%; P = .025).
At 12 months, MAs had a lower median 3MSE score of 86 (interquartile range, 73-93, compared with 92 in NHWs (IQR, 83-96; P less than .001). As the researchers adjusted for additional factors, the discrepancy became larger. Adjustment for age and sex revealed a difference of 6.88 (95% confidence interval, 4.15-9.60). Additional adjustment for prestroke condition showed a difference of 7.04. Additional adjustment for insurance led to the same differential of 7.04. Adjustment for diabetes and comorbidities pushed the difference to 7.11. Adjustment for stroke severity (National Institutes of Health Stroke Scale) revealed a difference of 6.73 (P less than .001).
Asked if the results were surprising, Dr. Morgenstern replied: “I think it’s always surprising to see one population of U.S. citizens who have more disease or a worse outcome than another when it’s not explained by the many possible factors we considered.” He also called for additional studies of cognitive dysfunction in Hispanic communities in other forms of dementia, such as Alzheimer’s disease and vascular dementia. “There’s very little of that,” he said.
The National Institutes of Health funded the study. Dr. Morgenstern reported having no financial disclosures.
SAN DIEGO – A new analysis shows that Mexican Americans (MAs) have worse cognitive outcomes a year after having a stroke than do non-Hispanic whites (NHWs).
The findings, which show that MAs had a mean score of 86 on the Modified Mini-Mental State Examination (3MSE; range: 0-100), compared with 92 for NHWs, come from a prospective study of MAs and NHWs in Corpus Christi, Texas, where both populations have long-established residencies.
After controlling for all factors, the researchers found a difference of –6.73 (95% confidence interval, –3.88 to –9.57; P less than .001).
“The Mexican-American population is growing quickly and aging. The cost of stroke-related cognitive impairment is high for patient, family, and society. Efforts to combat stroke-related cognitive decline are critical,” said Dr. Morgenstern, professor of neurology and epidemiology at the University of Michigan, Ann Arbor.
The study grew out of the Brain Attack Surveillance in Corpus Christi (BASIC) Project, which began in 1999 and is funded until 2019. It is the only ongoing stroke surveillance program that focuses on Mexican Americans, who comprise the largest segment of Hispanic Americans.
The researchers analyzed data encompassing all stroke patients in the BASIC Project from October 2014 through January 2016 (n = 227). They analyzed cognitive outcome data from 3 months, 6 months, and 12 months. MAs were younger on average than NHWs (median age 66 vs. 70; P = .018), and were more likely to have diabetes (54% vs. 36%; P less than .001). They were less likely to have atrial fibrillation (13% vs. 20%; P = .025).
At 12 months, MAs had a lower median 3MSE score of 86 (interquartile range, 73-93, compared with 92 in NHWs (IQR, 83-96; P less than .001). As the researchers adjusted for additional factors, the discrepancy became larger. Adjustment for age and sex revealed a difference of 6.88 (95% confidence interval, 4.15-9.60). Additional adjustment for prestroke condition showed a difference of 7.04. Additional adjustment for insurance led to the same differential of 7.04. Adjustment for diabetes and comorbidities pushed the difference to 7.11. Adjustment for stroke severity (National Institutes of Health Stroke Scale) revealed a difference of 6.73 (P less than .001).
Asked if the results were surprising, Dr. Morgenstern replied: “I think it’s always surprising to see one population of U.S. citizens who have more disease or a worse outcome than another when it’s not explained by the many possible factors we considered.” He also called for additional studies of cognitive dysfunction in Hispanic communities in other forms of dementia, such as Alzheimer’s disease and vascular dementia. “There’s very little of that,” he said.
The National Institutes of Health funded the study. Dr. Morgenstern reported having no financial disclosures.
SAN DIEGO – A new analysis shows that Mexican Americans (MAs) have worse cognitive outcomes a year after having a stroke than do non-Hispanic whites (NHWs).
The findings, which show that MAs had a mean score of 86 on the Modified Mini-Mental State Examination (3MSE; range: 0-100), compared with 92 for NHWs, come from a prospective study of MAs and NHWs in Corpus Christi, Texas, where both populations have long-established residencies.
After controlling for all factors, the researchers found a difference of –6.73 (95% confidence interval, –3.88 to –9.57; P less than .001).
“The Mexican-American population is growing quickly and aging. The cost of stroke-related cognitive impairment is high for patient, family, and society. Efforts to combat stroke-related cognitive decline are critical,” said Dr. Morgenstern, professor of neurology and epidemiology at the University of Michigan, Ann Arbor.
The study grew out of the Brain Attack Surveillance in Corpus Christi (BASIC) Project, which began in 1999 and is funded until 2019. It is the only ongoing stroke surveillance program that focuses on Mexican Americans, who comprise the largest segment of Hispanic Americans.
The researchers analyzed data encompassing all stroke patients in the BASIC Project from October 2014 through January 2016 (n = 227). They analyzed cognitive outcome data from 3 months, 6 months, and 12 months. MAs were younger on average than NHWs (median age 66 vs. 70; P = .018), and were more likely to have diabetes (54% vs. 36%; P less than .001). They were less likely to have atrial fibrillation (13% vs. 20%; P = .025).
At 12 months, MAs had a lower median 3MSE score of 86 (interquartile range, 73-93, compared with 92 in NHWs (IQR, 83-96; P less than .001). As the researchers adjusted for additional factors, the discrepancy became larger. Adjustment for age and sex revealed a difference of 6.88 (95% confidence interval, 4.15-9.60). Additional adjustment for prestroke condition showed a difference of 7.04. Additional adjustment for insurance led to the same differential of 7.04. Adjustment for diabetes and comorbidities pushed the difference to 7.11. Adjustment for stroke severity (National Institutes of Health Stroke Scale) revealed a difference of 6.73 (P less than .001).
Asked if the results were surprising, Dr. Morgenstern replied: “I think it’s always surprising to see one population of U.S. citizens who have more disease or a worse outcome than another when it’s not explained by the many possible factors we considered.” He also called for additional studies of cognitive dysfunction in Hispanic communities in other forms of dementia, such as Alzheimer’s disease and vascular dementia. “There’s very little of that,” he said.
The National Institutes of Health funded the study. Dr. Morgenstern reported having no financial disclosures.
AT ANA 2017
Key clinical point: In an analysis, cognitive outcomes were worse in Mexican-American stroke survivors despite researchers’ controlling for many factors.
Major finding: At 12 months, Mexican Americans scored 6 points lower on the Modified Mini-Mental State Examination compared with non-Hispanic whites.
Data source: Prospective analysis of 227 stroke patients in Corpus Christi, Texas.
Disclosures: The National Institutes of Health funded the study. Dr. Morgenstern reported having no financial disclosures.