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Genetic predisposition to hypercalcemia linked to CAD, MI
in a large mendelian randomization study published online July 25 in JAMA.
Each 0.5-mg rise in genetically predicted serum calcium concentration increased the odds of coronary artery disease (CAD) and myocardial infarction by about 25%, reported Susanna C. Larsson, Ph.D., of Karolinska Institutet in Stockholm, Sweden, and her associates. It remains unclear whether short- or medium-term calcium supplementation also increases the risk of these outcomes, they added.
Observational studies have linked high serum calcium with cardiovascular disease, but such studies are subject to confounding, the researchers noted. Randomized trials indicate that calcium supplementation might contribute to MI, but the trials are not designed to quantify long-term risks. Therefore, the investigators evaluated a proxy for lifelong hypercalcemia – six single nucleotide polymorphisms (SNPs) that have been linked to high serum calcium, but not to other CAD risk factors such as type 2 diabetes, fasting glucose and insulin levels, body mass index, waist-to-hip ratio, major lipids, or hypertension (JAMA. 2017 Jul 25;318[4]:371-80. doi: 10.1001/jama.2017.8981).
To examine how these SNPs affect the risk of CAD and MI, the researchers analyzed summary statistics for 184,305 individuals from a meta-analysis of CAD genome-wide association studies (Nat Genet. 2015;47:1121-30), including 60,801 cases (of whom about 70% also had MI) and 123,504 controls.
Together, these six SNPs explained about 0.8% of variations in serum calcium levels. Each 0.5-mg/dL (about one standard deviation) increase in genetically predicted serum calcium level significantly increased the risk of CAD (odds ratio, 1.25; 95% confidence interval, 1.08-1.45; P = .003) and MI (OR, 1.24; 95% CI, 1.05-1.46; P = .009). The genetic variant rs1801725 exerted the greatest effect on serum calcium levels, the investigators noted. This SNP affects the CASR gene, which encodes a calcium-sensing receptor that “plays a key role in calcium homeostasis.” However, four of the other five variants also had odds ratios above 1.0, and three had odds ratios above 1.25. A sensitivity analysis that excluded the CASR variant generated an identical odds ratio, although the confidence interval was wider. Studies of other risk factors for CAD have yielded odds ratios between 1.3 (triglyceride levels) and 1.7 (LDL cholesterol levels), the researchers noted.
A link between calcium supplementation and MI remains debatable. However, supplementation can lead to hypercalcemia and greater formation of insoluble calciprotein particles, the investigators said. Coronary artery disease might result from downstream effects on vascular calcification, vascular cells, blood coagulation pathways, or gene expression, but such mechanisms need more study, they added.
This analysis included men and women from the United States, Canada, the United Kingdom, Germany, Sweden, Ireland, the Netherlands, Finland, Iceland, Italy, Estonia, Lebanon, China, Korea, India, Pakistan and Greece. Participants tended to be men in their 50s and 60s, but more than half of studies lacked data on age and sex. Nearly all participants were of white European ancestry.
Karolinska Institutet supported Dr. Larsson. The investigators reported having no relevant conflicts of interest.
in a large mendelian randomization study published online July 25 in JAMA.
Each 0.5-mg rise in genetically predicted serum calcium concentration increased the odds of coronary artery disease (CAD) and myocardial infarction by about 25%, reported Susanna C. Larsson, Ph.D., of Karolinska Institutet in Stockholm, Sweden, and her associates. It remains unclear whether short- or medium-term calcium supplementation also increases the risk of these outcomes, they added.
Observational studies have linked high serum calcium with cardiovascular disease, but such studies are subject to confounding, the researchers noted. Randomized trials indicate that calcium supplementation might contribute to MI, but the trials are not designed to quantify long-term risks. Therefore, the investigators evaluated a proxy for lifelong hypercalcemia – six single nucleotide polymorphisms (SNPs) that have been linked to high serum calcium, but not to other CAD risk factors such as type 2 diabetes, fasting glucose and insulin levels, body mass index, waist-to-hip ratio, major lipids, or hypertension (JAMA. 2017 Jul 25;318[4]:371-80. doi: 10.1001/jama.2017.8981).
To examine how these SNPs affect the risk of CAD and MI, the researchers analyzed summary statistics for 184,305 individuals from a meta-analysis of CAD genome-wide association studies (Nat Genet. 2015;47:1121-30), including 60,801 cases (of whom about 70% also had MI) and 123,504 controls.
Together, these six SNPs explained about 0.8% of variations in serum calcium levels. Each 0.5-mg/dL (about one standard deviation) increase in genetically predicted serum calcium level significantly increased the risk of CAD (odds ratio, 1.25; 95% confidence interval, 1.08-1.45; P = .003) and MI (OR, 1.24; 95% CI, 1.05-1.46; P = .009). The genetic variant rs1801725 exerted the greatest effect on serum calcium levels, the investigators noted. This SNP affects the CASR gene, which encodes a calcium-sensing receptor that “plays a key role in calcium homeostasis.” However, four of the other five variants also had odds ratios above 1.0, and three had odds ratios above 1.25. A sensitivity analysis that excluded the CASR variant generated an identical odds ratio, although the confidence interval was wider. Studies of other risk factors for CAD have yielded odds ratios between 1.3 (triglyceride levels) and 1.7 (LDL cholesterol levels), the researchers noted.
A link between calcium supplementation and MI remains debatable. However, supplementation can lead to hypercalcemia and greater formation of insoluble calciprotein particles, the investigators said. Coronary artery disease might result from downstream effects on vascular calcification, vascular cells, blood coagulation pathways, or gene expression, but such mechanisms need more study, they added.
This analysis included men and women from the United States, Canada, the United Kingdom, Germany, Sweden, Ireland, the Netherlands, Finland, Iceland, Italy, Estonia, Lebanon, China, Korea, India, Pakistan and Greece. Participants tended to be men in their 50s and 60s, but more than half of studies lacked data on age and sex. Nearly all participants were of white European ancestry.
Karolinska Institutet supported Dr. Larsson. The investigators reported having no relevant conflicts of interest.
in a large mendelian randomization study published online July 25 in JAMA.
Each 0.5-mg rise in genetically predicted serum calcium concentration increased the odds of coronary artery disease (CAD) and myocardial infarction by about 25%, reported Susanna C. Larsson, Ph.D., of Karolinska Institutet in Stockholm, Sweden, and her associates. It remains unclear whether short- or medium-term calcium supplementation also increases the risk of these outcomes, they added.
Observational studies have linked high serum calcium with cardiovascular disease, but such studies are subject to confounding, the researchers noted. Randomized trials indicate that calcium supplementation might contribute to MI, but the trials are not designed to quantify long-term risks. Therefore, the investigators evaluated a proxy for lifelong hypercalcemia – six single nucleotide polymorphisms (SNPs) that have been linked to high serum calcium, but not to other CAD risk factors such as type 2 diabetes, fasting glucose and insulin levels, body mass index, waist-to-hip ratio, major lipids, or hypertension (JAMA. 2017 Jul 25;318[4]:371-80. doi: 10.1001/jama.2017.8981).
To examine how these SNPs affect the risk of CAD and MI, the researchers analyzed summary statistics for 184,305 individuals from a meta-analysis of CAD genome-wide association studies (Nat Genet. 2015;47:1121-30), including 60,801 cases (of whom about 70% also had MI) and 123,504 controls.
Together, these six SNPs explained about 0.8% of variations in serum calcium levels. Each 0.5-mg/dL (about one standard deviation) increase in genetically predicted serum calcium level significantly increased the risk of CAD (odds ratio, 1.25; 95% confidence interval, 1.08-1.45; P = .003) and MI (OR, 1.24; 95% CI, 1.05-1.46; P = .009). The genetic variant rs1801725 exerted the greatest effect on serum calcium levels, the investigators noted. This SNP affects the CASR gene, which encodes a calcium-sensing receptor that “plays a key role in calcium homeostasis.” However, four of the other five variants also had odds ratios above 1.0, and three had odds ratios above 1.25. A sensitivity analysis that excluded the CASR variant generated an identical odds ratio, although the confidence interval was wider. Studies of other risk factors for CAD have yielded odds ratios between 1.3 (triglyceride levels) and 1.7 (LDL cholesterol levels), the researchers noted.
A link between calcium supplementation and MI remains debatable. However, supplementation can lead to hypercalcemia and greater formation of insoluble calciprotein particles, the investigators said. Coronary artery disease might result from downstream effects on vascular calcification, vascular cells, blood coagulation pathways, or gene expression, but such mechanisms need more study, they added.
This analysis included men and women from the United States, Canada, the United Kingdom, Germany, Sweden, Ireland, the Netherlands, Finland, Iceland, Italy, Estonia, Lebanon, China, Korea, India, Pakistan and Greece. Participants tended to be men in their 50s and 60s, but more than half of studies lacked data on age and sex. Nearly all participants were of white European ancestry.
Karolinska Institutet supported Dr. Larsson. The investigators reported having no relevant conflicts of interest.
FROM JAMA
Key clinical point: Genetic predisposition to higher serum calcium levels was significantly associated with coronary artery disease and myocardial infarction.
Major finding: Each 0.5-mg per dL rise in serum calcium increased the odds of these outcomes by about 25% (odds ratios, 1.25 and 1.24, respectively).
Data source: A mendelian randomization study of 60,801 cases of coronary artery disease, 123,504 controls, and six single nucleotide polymorphisms linked to serum calcium but not to other risk factors for coronary artery disease.
Disclosures: Karolinska Institutet supported Dr. Larsson. The investigators reported having no relevant conflicts of interest.
Tramadol extended-release treated opioid withdrawal symptoms better than clonidine
For patients with opioid use disorders, a 7-day taper with up to 600 mg of extended-release tramadol per day suppressed withdrawal symptoms as well as buprenorphine and significantly better than clonidine, in a randomized, double-blind, double-dummy placebo-controlled trial of 103 patients.
Tramadol ER also produced less severe withdrawal symptoms after taper than did buprenorphine, reported Kelly E. Dunn, PhD, of Johns Hopkins University in Baltimore, and her associates. The study was published online July 12 in JAMA Psychiatry.
“Tramadol ER is a schedule V medication that can be administered once a day and has lower abuse liability than other opioid agonists,” the researchers wrote. “These data suggest that tramadol ER is a promising and valuable medication for the management of opioid withdrawal in patients undergoing treatment for opioid use disorder.”
Successful opioid detoxification hinges on managing withdrawal symptoms, often with clonidine, which is an unscheduled adrenergic agonist, or buprenorphine HCl, which is a partial mu and opioid receptor like–1 receptor agonist and kappa antagonist. Clonidine has low abuse potential, but must be given several times daily, can cause sedation and hypotension, and is less effective than buprenorphine, which is a schedule III drug that requires a specialized waiver to prescribe. In contrast, tramadol ER has lower abuse potential (schedule V), a low affinity for mu, kappa, and delta opioid receptors, and an elimination half-life compatible with once-daily dosing, the investigators reported (JAMA Psychiatry. 2017 Jul 12. doi: 10.1001/jamapsychiatry.2017.1838).
Their study included three phases. First, participants were stabilized with subcutaneous morphine injections four times daily for 7-10 days. Next, they started a 7-day taper with buprenorphine (31 individuals), clonidine (36 individuals), or tramadol ER (36 individuals). Then they crossed over to a 7-day double-blind placebo period. The researchers measured withdrawal symptoms on the 11-item Clinical Opiate Withdrawal Scale (COWS) and the 16-item, 5-point Subjective Opiate Withdrawal Scale (SOWS).
For all three medications, average COWS and SOWS scores rose at the start of taper and subsequently dropped. For example, buprenorphine patients averaged higher SOWS scores after taper (7.2) than did clonidine (3.2) or tramadol ER patients (2.8), but the differences were not statistically significant. Post hoc analyses of SOWS scores linked clonidine with significantly worse withdrawal symptoms than tramadol ER (P = .02) or buprenorphine (P less than .001) during taper.
Patients also reported significant lessening of withdrawal symptoms after tapering off clonidine (P less than .001) and tramadol ER (P = .03), but not buprenorphine. Average pupil diameters increased only after stopping buprenorphine but rose slightly while tapering off the other medications. Patients also used significantly more concomitant medication after stopping buprenorphine. “Together, these findings suggest that buprenorphine participants experienced continued withdrawal following the removal of buprenorphine,” the researchers wrote. “Although a delayed onset of withdrawal has been previously reported following buprenorphine withdrawal, it is notable that this pattern was not observed in the other groups.”
In all, 85% of study participants were male, 42% were white, and the average age was 29 years. Retention rates were 66% for clonidine, 72% for tramadol ER, and 90% for buprenorphine. About half of patients reported adverse effects, and those rates were similar among the groups. Most of the adverse effects were related to opioid withdrawal, and no severe adverse events were reported.
The study “shows that tramadol extended-release suppressed withdrawal more than clonidine and comparably to buprenorphine during a double-blind taper, and did not produce a delayed onset of opioid withdrawal after the taper,” the researchers wrote. However, the findings “are tempered by the high rates of relapse generally associated with supervised withdrawal relative to maintenance treatments, and epidemiologic evidence that tramadol is abusable.” Tramadol ER was previously unscheduled but now is a schedule V medication, which “adds complexity in its use for opioid withdrawal suppression,” they noted. They recommended more studies in patients with worse withdrawal symptoms, outpatient settings, and extended care to prevent overdose.
The National Institute on Drug Abuse funded the work. Reckitt Benckiser Pharmaceuticals provided buprenorphine and placebo tablets and reviewed the report for scientific accuracy. Dr. Dunn and one coinvestigator had no disclosures. The senior author, Eric C. Strain, MD, and another coinvestigator disclosed ties to Indivior Pharmaceuticals, Egalet, and several other pharmaceutical companies.
For patients with opioid use disorders, a 7-day taper with up to 600 mg of extended-release tramadol per day suppressed withdrawal symptoms as well as buprenorphine and significantly better than clonidine, in a randomized, double-blind, double-dummy placebo-controlled trial of 103 patients.
Tramadol ER also produced less severe withdrawal symptoms after taper than did buprenorphine, reported Kelly E. Dunn, PhD, of Johns Hopkins University in Baltimore, and her associates. The study was published online July 12 in JAMA Psychiatry.
“Tramadol ER is a schedule V medication that can be administered once a day and has lower abuse liability than other opioid agonists,” the researchers wrote. “These data suggest that tramadol ER is a promising and valuable medication for the management of opioid withdrawal in patients undergoing treatment for opioid use disorder.”
Successful opioid detoxification hinges on managing withdrawal symptoms, often with clonidine, which is an unscheduled adrenergic agonist, or buprenorphine HCl, which is a partial mu and opioid receptor like–1 receptor agonist and kappa antagonist. Clonidine has low abuse potential, but must be given several times daily, can cause sedation and hypotension, and is less effective than buprenorphine, which is a schedule III drug that requires a specialized waiver to prescribe. In contrast, tramadol ER has lower abuse potential (schedule V), a low affinity for mu, kappa, and delta opioid receptors, and an elimination half-life compatible with once-daily dosing, the investigators reported (JAMA Psychiatry. 2017 Jul 12. doi: 10.1001/jamapsychiatry.2017.1838).
Their study included three phases. First, participants were stabilized with subcutaneous morphine injections four times daily for 7-10 days. Next, they started a 7-day taper with buprenorphine (31 individuals), clonidine (36 individuals), or tramadol ER (36 individuals). Then they crossed over to a 7-day double-blind placebo period. The researchers measured withdrawal symptoms on the 11-item Clinical Opiate Withdrawal Scale (COWS) and the 16-item, 5-point Subjective Opiate Withdrawal Scale (SOWS).
For all three medications, average COWS and SOWS scores rose at the start of taper and subsequently dropped. For example, buprenorphine patients averaged higher SOWS scores after taper (7.2) than did clonidine (3.2) or tramadol ER patients (2.8), but the differences were not statistically significant. Post hoc analyses of SOWS scores linked clonidine with significantly worse withdrawal symptoms than tramadol ER (P = .02) or buprenorphine (P less than .001) during taper.
Patients also reported significant lessening of withdrawal symptoms after tapering off clonidine (P less than .001) and tramadol ER (P = .03), but not buprenorphine. Average pupil diameters increased only after stopping buprenorphine but rose slightly while tapering off the other medications. Patients also used significantly more concomitant medication after stopping buprenorphine. “Together, these findings suggest that buprenorphine participants experienced continued withdrawal following the removal of buprenorphine,” the researchers wrote. “Although a delayed onset of withdrawal has been previously reported following buprenorphine withdrawal, it is notable that this pattern was not observed in the other groups.”
In all, 85% of study participants were male, 42% were white, and the average age was 29 years. Retention rates were 66% for clonidine, 72% for tramadol ER, and 90% for buprenorphine. About half of patients reported adverse effects, and those rates were similar among the groups. Most of the adverse effects were related to opioid withdrawal, and no severe adverse events were reported.
The study “shows that tramadol extended-release suppressed withdrawal more than clonidine and comparably to buprenorphine during a double-blind taper, and did not produce a delayed onset of opioid withdrawal after the taper,” the researchers wrote. However, the findings “are tempered by the high rates of relapse generally associated with supervised withdrawal relative to maintenance treatments, and epidemiologic evidence that tramadol is abusable.” Tramadol ER was previously unscheduled but now is a schedule V medication, which “adds complexity in its use for opioid withdrawal suppression,” they noted. They recommended more studies in patients with worse withdrawal symptoms, outpatient settings, and extended care to prevent overdose.
The National Institute on Drug Abuse funded the work. Reckitt Benckiser Pharmaceuticals provided buprenorphine and placebo tablets and reviewed the report for scientific accuracy. Dr. Dunn and one coinvestigator had no disclosures. The senior author, Eric C. Strain, MD, and another coinvestigator disclosed ties to Indivior Pharmaceuticals, Egalet, and several other pharmaceutical companies.
For patients with opioid use disorders, a 7-day taper with up to 600 mg of extended-release tramadol per day suppressed withdrawal symptoms as well as buprenorphine and significantly better than clonidine, in a randomized, double-blind, double-dummy placebo-controlled trial of 103 patients.
Tramadol ER also produced less severe withdrawal symptoms after taper than did buprenorphine, reported Kelly E. Dunn, PhD, of Johns Hopkins University in Baltimore, and her associates. The study was published online July 12 in JAMA Psychiatry.
“Tramadol ER is a schedule V medication that can be administered once a day and has lower abuse liability than other opioid agonists,” the researchers wrote. “These data suggest that tramadol ER is a promising and valuable medication for the management of opioid withdrawal in patients undergoing treatment for opioid use disorder.”
Successful opioid detoxification hinges on managing withdrawal symptoms, often with clonidine, which is an unscheduled adrenergic agonist, or buprenorphine HCl, which is a partial mu and opioid receptor like–1 receptor agonist and kappa antagonist. Clonidine has low abuse potential, but must be given several times daily, can cause sedation and hypotension, and is less effective than buprenorphine, which is a schedule III drug that requires a specialized waiver to prescribe. In contrast, tramadol ER has lower abuse potential (schedule V), a low affinity for mu, kappa, and delta opioid receptors, and an elimination half-life compatible with once-daily dosing, the investigators reported (JAMA Psychiatry. 2017 Jul 12. doi: 10.1001/jamapsychiatry.2017.1838).
Their study included three phases. First, participants were stabilized with subcutaneous morphine injections four times daily for 7-10 days. Next, they started a 7-day taper with buprenorphine (31 individuals), clonidine (36 individuals), or tramadol ER (36 individuals). Then they crossed over to a 7-day double-blind placebo period. The researchers measured withdrawal symptoms on the 11-item Clinical Opiate Withdrawal Scale (COWS) and the 16-item, 5-point Subjective Opiate Withdrawal Scale (SOWS).
For all three medications, average COWS and SOWS scores rose at the start of taper and subsequently dropped. For example, buprenorphine patients averaged higher SOWS scores after taper (7.2) than did clonidine (3.2) or tramadol ER patients (2.8), but the differences were not statistically significant. Post hoc analyses of SOWS scores linked clonidine with significantly worse withdrawal symptoms than tramadol ER (P = .02) or buprenorphine (P less than .001) during taper.
Patients also reported significant lessening of withdrawal symptoms after tapering off clonidine (P less than .001) and tramadol ER (P = .03), but not buprenorphine. Average pupil diameters increased only after stopping buprenorphine but rose slightly while tapering off the other medications. Patients also used significantly more concomitant medication after stopping buprenorphine. “Together, these findings suggest that buprenorphine participants experienced continued withdrawal following the removal of buprenorphine,” the researchers wrote. “Although a delayed onset of withdrawal has been previously reported following buprenorphine withdrawal, it is notable that this pattern was not observed in the other groups.”
In all, 85% of study participants were male, 42% were white, and the average age was 29 years. Retention rates were 66% for clonidine, 72% for tramadol ER, and 90% for buprenorphine. About half of patients reported adverse effects, and those rates were similar among the groups. Most of the adverse effects were related to opioid withdrawal, and no severe adverse events were reported.
The study “shows that tramadol extended-release suppressed withdrawal more than clonidine and comparably to buprenorphine during a double-blind taper, and did not produce a delayed onset of opioid withdrawal after the taper,” the researchers wrote. However, the findings “are tempered by the high rates of relapse generally associated with supervised withdrawal relative to maintenance treatments, and epidemiologic evidence that tramadol is abusable.” Tramadol ER was previously unscheduled but now is a schedule V medication, which “adds complexity in its use for opioid withdrawal suppression,” they noted. They recommended more studies in patients with worse withdrawal symptoms, outpatient settings, and extended care to prevent overdose.
The National Institute on Drug Abuse funded the work. Reckitt Benckiser Pharmaceuticals provided buprenorphine and placebo tablets and reviewed the report for scientific accuracy. Dr. Dunn and one coinvestigator had no disclosures. The senior author, Eric C. Strain, MD, and another coinvestigator disclosed ties to Indivior Pharmaceuticals, Egalet, and several other pharmaceutical companies.
FROM JAMA PSYCHIATRY
Key clinical point:
Major finding: Withdrawal symptoms were significantly worse during taper with clonidine than with tramadol ER (P = .02) or buprenorphine (P less than .001), in post hoc analyses of the 5-point Subjective Opiate Withdrawal Scale. Retention rates also were lowest with clonidine (66%).
Data source: A randomized, double-blind, double-dummy placebo-controlled study of 103 patients with opioid use disorder.
Disclosures: The National Institute on Drug Abuse funded the study. Reckitt Benckiser Pharmaceuticals provided the buprenorphine and placebo tablets and reviewed the report for scientific accuracy. Dr. Dunn and one coinvestigator had no disclosures. The senior author, Eric C. Strain, MD, and another coinvestigator disclosed ties to Indivior Pharmaceuticals, Egalet Corporation, and several other pharmaceutical companies.
Idarucizumab reversed dabigatran completely and rapidly in study
One IV 5-g dose of idarucizumab completely, rapidly, and safely reversed the anticoagulant effect of dabigatran, according to final results for 503 patients in the multicenter, prospective, open-label, uncontrolled RE-VERSE AD study.
Uncontrolled bleeding stopped a median of 2.5 hours after 134 patients received idarucizumab. In a separate group of 202 patients, 197 were able to undergo urgent procedures after a median of 1.6 hours, Charles V. Pollack Jr., MD, and his associates reported at the International Society on Thrombosis and Haemostasis congress. The report was simultaneously published in the New England Journal of Medicine.
Idarucizumab was specifically developed to reverse the anticoagulant effect of dabigatran. Many countries have already licensed the humanized monoclonal antibody fragment based on interim results for the first 90 patients enrolled in the Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) study (NCT02104947), noted Dr. Pollack, of Thomas Jefferson University, Philadelphia.
The final RE-VERSE AD cohort included 301 patients with uncontrolled gastrointestinal, intracranial, or trauma-related bleeding and 202 patients who needed urgent procedures. Participants from both groups typically were white, in their late 70s (age range, 21-96 years), and receiving 110 mg (75-150 mg) dabigatran twice daily. The primary endpoint was maximum percentage reversal within 4 hours after patients received idarucizumab, based on diluted thrombin time and ecarin clotting time.
The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100% to 100%) in more than 98% of patients, and the effect usually lasted 24 hours. Among patients who underwent procedures, intraprocedural hemostasis was considered normal in 93% of cases, mildly abnormal in 5% of cases, and moderately abnormal in 2% of cases, the researchers noted. Seven patients received another dose of idarucizumab after developing recurrent or postoperative bleeding.
A total of 24 patients had an adjudicated thrombotic event within 30 days after receiving idarucizumab. These events included pulmonary embolism, systemic embolism, ischemic stroke, deep vein thrombosis, and myocardial infarction. The fact that many patients did not restart anticoagulation could have contributed to these thrombotic events, the researchers asserted. They noted that idarucizumab had no procoagulant activity in studies of animals and healthy human volunteers.
About 19% of patients in both groups died within 90 days. “Patients enrolled in this study were elderly, had numerous coexisting conditions, and presented with serious index events, such as intracranial hemorrhage, multiple trauma, sepsis, acute abdomen, or open fracture,” the investigators wrote. “Most of the deaths that occurred within 5 days after enrollment appeared to be related to the severity of the index event or to coexisting conditions, such as respiratory failure or multiple organ failure, whereas deaths that occurred after 30 days were more likely to be independent events or related to coexisting conditions.”
Boehringer Ingelheim Pharmaceuticals provided funding. Dr. Pollack disclosed grant support from Boehringer Ingelheim during the course of the study and ties to Daiichi Sankyo, Portola, CSL Behring, Bristol-Myers Squibb/Pfizer, Janssen Pharma, and AstraZeneca. Eighteen coinvestigators also disclosed ties to Boehringer Ingelheim and a number of other pharmaceutical companies. Two coinvestigators had no relevant financial disclosures.
One IV 5-g dose of idarucizumab completely, rapidly, and safely reversed the anticoagulant effect of dabigatran, according to final results for 503 patients in the multicenter, prospective, open-label, uncontrolled RE-VERSE AD study.
Uncontrolled bleeding stopped a median of 2.5 hours after 134 patients received idarucizumab. In a separate group of 202 patients, 197 were able to undergo urgent procedures after a median of 1.6 hours, Charles V. Pollack Jr., MD, and his associates reported at the International Society on Thrombosis and Haemostasis congress. The report was simultaneously published in the New England Journal of Medicine.
Idarucizumab was specifically developed to reverse the anticoagulant effect of dabigatran. Many countries have already licensed the humanized monoclonal antibody fragment based on interim results for the first 90 patients enrolled in the Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) study (NCT02104947), noted Dr. Pollack, of Thomas Jefferson University, Philadelphia.
The final RE-VERSE AD cohort included 301 patients with uncontrolled gastrointestinal, intracranial, or trauma-related bleeding and 202 patients who needed urgent procedures. Participants from both groups typically were white, in their late 70s (age range, 21-96 years), and receiving 110 mg (75-150 mg) dabigatran twice daily. The primary endpoint was maximum percentage reversal within 4 hours after patients received idarucizumab, based on diluted thrombin time and ecarin clotting time.
The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100% to 100%) in more than 98% of patients, and the effect usually lasted 24 hours. Among patients who underwent procedures, intraprocedural hemostasis was considered normal in 93% of cases, mildly abnormal in 5% of cases, and moderately abnormal in 2% of cases, the researchers noted. Seven patients received another dose of idarucizumab after developing recurrent or postoperative bleeding.
A total of 24 patients had an adjudicated thrombotic event within 30 days after receiving idarucizumab. These events included pulmonary embolism, systemic embolism, ischemic stroke, deep vein thrombosis, and myocardial infarction. The fact that many patients did not restart anticoagulation could have contributed to these thrombotic events, the researchers asserted. They noted that idarucizumab had no procoagulant activity in studies of animals and healthy human volunteers.
About 19% of patients in both groups died within 90 days. “Patients enrolled in this study were elderly, had numerous coexisting conditions, and presented with serious index events, such as intracranial hemorrhage, multiple trauma, sepsis, acute abdomen, or open fracture,” the investigators wrote. “Most of the deaths that occurred within 5 days after enrollment appeared to be related to the severity of the index event or to coexisting conditions, such as respiratory failure or multiple organ failure, whereas deaths that occurred after 30 days were more likely to be independent events or related to coexisting conditions.”
Boehringer Ingelheim Pharmaceuticals provided funding. Dr. Pollack disclosed grant support from Boehringer Ingelheim during the course of the study and ties to Daiichi Sankyo, Portola, CSL Behring, Bristol-Myers Squibb/Pfizer, Janssen Pharma, and AstraZeneca. Eighteen coinvestigators also disclosed ties to Boehringer Ingelheim and a number of other pharmaceutical companies. Two coinvestigators had no relevant financial disclosures.
One IV 5-g dose of idarucizumab completely, rapidly, and safely reversed the anticoagulant effect of dabigatran, according to final results for 503 patients in the multicenter, prospective, open-label, uncontrolled RE-VERSE AD study.
Uncontrolled bleeding stopped a median of 2.5 hours after 134 patients received idarucizumab. In a separate group of 202 patients, 197 were able to undergo urgent procedures after a median of 1.6 hours, Charles V. Pollack Jr., MD, and his associates reported at the International Society on Thrombosis and Haemostasis congress. The report was simultaneously published in the New England Journal of Medicine.
Idarucizumab was specifically developed to reverse the anticoagulant effect of dabigatran. Many countries have already licensed the humanized monoclonal antibody fragment based on interim results for the first 90 patients enrolled in the Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) study (NCT02104947), noted Dr. Pollack, of Thomas Jefferson University, Philadelphia.
The final RE-VERSE AD cohort included 301 patients with uncontrolled gastrointestinal, intracranial, or trauma-related bleeding and 202 patients who needed urgent procedures. Participants from both groups typically were white, in their late 70s (age range, 21-96 years), and receiving 110 mg (75-150 mg) dabigatran twice daily. The primary endpoint was maximum percentage reversal within 4 hours after patients received idarucizumab, based on diluted thrombin time and ecarin clotting time.
The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100% to 100%) in more than 98% of patients, and the effect usually lasted 24 hours. Among patients who underwent procedures, intraprocedural hemostasis was considered normal in 93% of cases, mildly abnormal in 5% of cases, and moderately abnormal in 2% of cases, the researchers noted. Seven patients received another dose of idarucizumab after developing recurrent or postoperative bleeding.
A total of 24 patients had an adjudicated thrombotic event within 30 days after receiving idarucizumab. These events included pulmonary embolism, systemic embolism, ischemic stroke, deep vein thrombosis, and myocardial infarction. The fact that many patients did not restart anticoagulation could have contributed to these thrombotic events, the researchers asserted. They noted that idarucizumab had no procoagulant activity in studies of animals and healthy human volunteers.
About 19% of patients in both groups died within 90 days. “Patients enrolled in this study were elderly, had numerous coexisting conditions, and presented with serious index events, such as intracranial hemorrhage, multiple trauma, sepsis, acute abdomen, or open fracture,” the investigators wrote. “Most of the deaths that occurred within 5 days after enrollment appeared to be related to the severity of the index event or to coexisting conditions, such as respiratory failure or multiple organ failure, whereas deaths that occurred after 30 days were more likely to be independent events or related to coexisting conditions.”
Boehringer Ingelheim Pharmaceuticals provided funding. Dr. Pollack disclosed grant support from Boehringer Ingelheim during the course of the study and ties to Daiichi Sankyo, Portola, CSL Behring, Bristol-Myers Squibb/Pfizer, Janssen Pharma, and AstraZeneca. Eighteen coinvestigators also disclosed ties to Boehringer Ingelheim and a number of other pharmaceutical companies. Two coinvestigators had no relevant financial disclosures.
FROM 2017 ISTH CONGRESS
Key clinical point:
Major finding: Uncontrolled bleeding stopped a median of 2.5 hours after 134 patients received idarucizumab. In a separate group, 197 patients were able to undergo urgent procedures after a median of 1.6 hours.
Data source: A multicenter, prospective, open-label study of 503 patients (RE-VERSE AD).
Disclosures: Boehringer Ingelheim Pharmaceuticals provided funding. Dr. Pollack disclosed grant support from Boehringer Ingelheim during the course of the study and ties to Daiichi Sankyo, Portola, CSL Behring, BMS/Pfizer, Janssen Pharma, and AstraZeneca. Eighteen coinvestigators disclosed ties to Boehringer Ingelheim and a number of other pharmaceutical companies. Two coinvestigators had no relevant financial disclosures.
R-CHOP matched more intense regimens for overall survival in high-risk, untreated DLBCL
High-dose chemotherapy with upfront autologous stem cell transplantation did not meaningfully improve survival at 5 years in a phase 3 trial of 399 patients under age 66 years with intermediate to high– or high-risk untreated diffuse large B-cell lymphoma.
Rates of treatment failure-free survival at 2 years were 71% for patients who received rituximab dose–dense chemotherapy followed by autologous stem cell transplantation (ASCT) and 62% for patients who received only the rituximab regimen (hazard ratio, 0.65; 95% confidence interval, 0.47-0.91; P = .01), Annalisa Chiappella, MD, of Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino (Italy) reported with her associates in Lancet Oncology.
Patients with diffuse large B-cell lymphoma, whose age-adjusted International Prognostic Index (aa-IPI) scores are 2 or 3 (intermediate to high or high risk), have a poor prognosis despite standard treatment with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone). Given a historic lack of late-phase studies of this population, the researchers designed a multicenter, open-label, randomized phase 3 trial comparing rituximab dose–dense chemotherapy without ASCT with a shorter rituximab regimen followed by consolidation with R-MAD (rituximab plus high-dose cytarabine plus mitoxantrone plus dexamethasone) and high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) plus ASCT in untreated patients aged 18-65 years.
Rituximab-based chemotherapy consisted of 14-day cycles of either standard R-CHOP or an intensified R-CHOP–like regimen that increased the doses of cyclophosphamide (1200 mg/m2) and doxorubicin (70 mg/m2), the investigators noted (Lancet Oncol. 2017 Jun 28. doi: 10.1016/S1470-2045[17]30444-8).
In all, 96 patients were assigned to receive only standard R-CHOP (eight cycles), 100 patients were assigned to high-dose R-CHOP (six cycles), 103 patients were assigned to standard R-CHOP (four cycles) plus R-MAD (2 cycles) plus BEAM plus ASCT, and 96 patients were assigned to high-dose R-CHOP (four cycles) plus the same sequence of R-MAD, BEAM, and ASCT. A total of 325 (81%) patients completed treatment, and the median follow-up period was 72 months (interquartile range, 57 to 88 months). There was no evidence that treatment efficacy varied by age, sex, bone marrow involvement, or other histology results, but only the intermediate-high risk patients experienced a benefit in terms of failure-free survival.
Grade 3 or higher adverse hematologic events affected 183 (92%) ASCT recipients and 135 (68%) patients who received only R-CHOP or high-dose R-CHOP. Nonhematologic adverse events affected 45% and 16% of patients, respectively, and were mostly gastrointestinal in nature. Of recipients of ASCT, 12 stopped treatment because of infections, prolonged neutropenia, gastrointestinal symptoms, or cardiac abnormalities, and two patients who did not undergo ASCT stopped treatment because of infections or prolonged neutropenia. Three (13%) patients died from treatment-related causes, including eight patients in the transplantation groups and five of the other patients.
Previous studies have reported benefits from intensified R-CHOP–like regimens in diffuse large B-cell lymphoma, but these trials included low-risk patients.
“Our study enrolled only intermediate to high–risk or high-risk patients, and the findings do not support the hypothesis that increasing the dose of R-CHOP improves outcomes in patients with diffuse large B-cell lymphoma who are at high risk,” they wrote. “The addition of novel drugs, such as lenalidomide, ibrutinib, bortezomib, and others, to standard R-CHOP regimens has been reported in phase 1 or 2 studies with promising results in high-risk patients, leading to ongoing phase 3 randomized trials to assess the efficacy of these strategies. While awaiting the results of these randomized studies, the standard treatment in patients with diffuse large B-cell lymphoma at intermediate to high and high risk remains chemoimmunotherapy based on the standard R-CHOP regimen.”
Fondazione Italiana Linfomi funded the study. Dr. Chiappelli and several coinvestigators disclosed ties to Amgen, Celgene, Janssen, Nanostring, Pfizer, and other companies.
High-dose chemotherapy with upfront autologous stem cell transplantation did not meaningfully improve survival at 5 years in a phase 3 trial of 399 patients under age 66 years with intermediate to high– or high-risk untreated diffuse large B-cell lymphoma.
Rates of treatment failure-free survival at 2 years were 71% for patients who received rituximab dose–dense chemotherapy followed by autologous stem cell transplantation (ASCT) and 62% for patients who received only the rituximab regimen (hazard ratio, 0.65; 95% confidence interval, 0.47-0.91; P = .01), Annalisa Chiappella, MD, of Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino (Italy) reported with her associates in Lancet Oncology.
Patients with diffuse large B-cell lymphoma, whose age-adjusted International Prognostic Index (aa-IPI) scores are 2 or 3 (intermediate to high or high risk), have a poor prognosis despite standard treatment with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone). Given a historic lack of late-phase studies of this population, the researchers designed a multicenter, open-label, randomized phase 3 trial comparing rituximab dose–dense chemotherapy without ASCT with a shorter rituximab regimen followed by consolidation with R-MAD (rituximab plus high-dose cytarabine plus mitoxantrone plus dexamethasone) and high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) plus ASCT in untreated patients aged 18-65 years.
Rituximab-based chemotherapy consisted of 14-day cycles of either standard R-CHOP or an intensified R-CHOP–like regimen that increased the doses of cyclophosphamide (1200 mg/m2) and doxorubicin (70 mg/m2), the investigators noted (Lancet Oncol. 2017 Jun 28. doi: 10.1016/S1470-2045[17]30444-8).
In all, 96 patients were assigned to receive only standard R-CHOP (eight cycles), 100 patients were assigned to high-dose R-CHOP (six cycles), 103 patients were assigned to standard R-CHOP (four cycles) plus R-MAD (2 cycles) plus BEAM plus ASCT, and 96 patients were assigned to high-dose R-CHOP (four cycles) plus the same sequence of R-MAD, BEAM, and ASCT. A total of 325 (81%) patients completed treatment, and the median follow-up period was 72 months (interquartile range, 57 to 88 months). There was no evidence that treatment efficacy varied by age, sex, bone marrow involvement, or other histology results, but only the intermediate-high risk patients experienced a benefit in terms of failure-free survival.
Grade 3 or higher adverse hematologic events affected 183 (92%) ASCT recipients and 135 (68%) patients who received only R-CHOP or high-dose R-CHOP. Nonhematologic adverse events affected 45% and 16% of patients, respectively, and were mostly gastrointestinal in nature. Of recipients of ASCT, 12 stopped treatment because of infections, prolonged neutropenia, gastrointestinal symptoms, or cardiac abnormalities, and two patients who did not undergo ASCT stopped treatment because of infections or prolonged neutropenia. Three (13%) patients died from treatment-related causes, including eight patients in the transplantation groups and five of the other patients.
Previous studies have reported benefits from intensified R-CHOP–like regimens in diffuse large B-cell lymphoma, but these trials included low-risk patients.
“Our study enrolled only intermediate to high–risk or high-risk patients, and the findings do not support the hypothesis that increasing the dose of R-CHOP improves outcomes in patients with diffuse large B-cell lymphoma who are at high risk,” they wrote. “The addition of novel drugs, such as lenalidomide, ibrutinib, bortezomib, and others, to standard R-CHOP regimens has been reported in phase 1 or 2 studies with promising results in high-risk patients, leading to ongoing phase 3 randomized trials to assess the efficacy of these strategies. While awaiting the results of these randomized studies, the standard treatment in patients with diffuse large B-cell lymphoma at intermediate to high and high risk remains chemoimmunotherapy based on the standard R-CHOP regimen.”
Fondazione Italiana Linfomi funded the study. Dr. Chiappelli and several coinvestigators disclosed ties to Amgen, Celgene, Janssen, Nanostring, Pfizer, and other companies.
High-dose chemotherapy with upfront autologous stem cell transplantation did not meaningfully improve survival at 5 years in a phase 3 trial of 399 patients under age 66 years with intermediate to high– or high-risk untreated diffuse large B-cell lymphoma.
Rates of treatment failure-free survival at 2 years were 71% for patients who received rituximab dose–dense chemotherapy followed by autologous stem cell transplantation (ASCT) and 62% for patients who received only the rituximab regimen (hazard ratio, 0.65; 95% confidence interval, 0.47-0.91; P = .01), Annalisa Chiappella, MD, of Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino (Italy) reported with her associates in Lancet Oncology.
Patients with diffuse large B-cell lymphoma, whose age-adjusted International Prognostic Index (aa-IPI) scores are 2 or 3 (intermediate to high or high risk), have a poor prognosis despite standard treatment with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone). Given a historic lack of late-phase studies of this population, the researchers designed a multicenter, open-label, randomized phase 3 trial comparing rituximab dose–dense chemotherapy without ASCT with a shorter rituximab regimen followed by consolidation with R-MAD (rituximab plus high-dose cytarabine plus mitoxantrone plus dexamethasone) and high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) plus ASCT in untreated patients aged 18-65 years.
Rituximab-based chemotherapy consisted of 14-day cycles of either standard R-CHOP or an intensified R-CHOP–like regimen that increased the doses of cyclophosphamide (1200 mg/m2) and doxorubicin (70 mg/m2), the investigators noted (Lancet Oncol. 2017 Jun 28. doi: 10.1016/S1470-2045[17]30444-8).
In all, 96 patients were assigned to receive only standard R-CHOP (eight cycles), 100 patients were assigned to high-dose R-CHOP (six cycles), 103 patients were assigned to standard R-CHOP (four cycles) plus R-MAD (2 cycles) plus BEAM plus ASCT, and 96 patients were assigned to high-dose R-CHOP (four cycles) plus the same sequence of R-MAD, BEAM, and ASCT. A total of 325 (81%) patients completed treatment, and the median follow-up period was 72 months (interquartile range, 57 to 88 months). There was no evidence that treatment efficacy varied by age, sex, bone marrow involvement, or other histology results, but only the intermediate-high risk patients experienced a benefit in terms of failure-free survival.
Grade 3 or higher adverse hematologic events affected 183 (92%) ASCT recipients and 135 (68%) patients who received only R-CHOP or high-dose R-CHOP. Nonhematologic adverse events affected 45% and 16% of patients, respectively, and were mostly gastrointestinal in nature. Of recipients of ASCT, 12 stopped treatment because of infections, prolonged neutropenia, gastrointestinal symptoms, or cardiac abnormalities, and two patients who did not undergo ASCT stopped treatment because of infections or prolonged neutropenia. Three (13%) patients died from treatment-related causes, including eight patients in the transplantation groups and five of the other patients.
Previous studies have reported benefits from intensified R-CHOP–like regimens in diffuse large B-cell lymphoma, but these trials included low-risk patients.
“Our study enrolled only intermediate to high–risk or high-risk patients, and the findings do not support the hypothesis that increasing the dose of R-CHOP improves outcomes in patients with diffuse large B-cell lymphoma who are at high risk,” they wrote. “The addition of novel drugs, such as lenalidomide, ibrutinib, bortezomib, and others, to standard R-CHOP regimens has been reported in phase 1 or 2 studies with promising results in high-risk patients, leading to ongoing phase 3 randomized trials to assess the efficacy of these strategies. While awaiting the results of these randomized studies, the standard treatment in patients with diffuse large B-cell lymphoma at intermediate to high and high risk remains chemoimmunotherapy based on the standard R-CHOP regimen.”
Fondazione Italiana Linfomi funded the study. Dr. Chiappelli and several coinvestigators disclosed ties to Amgen, Celgene, Janssen, Nanostring, Pfizer, and other companies.
FROM LANCET ONCOLOGY
Key clinical point: Pending phase 3 trial results for novel drugs, R-CHOP should remain the standard treatment for high-risk diffuse large B-cell lymphoma.
Major finding: For patients given rituximab dose-dense chemotherapy followed by chemoimmunotherapy consolidation and autologous stem cell transplantation, versus rituximab dose-dense chemotherapy alone, 5-year rates of overall survival were 78% and 77%, respectively,
Data source: A randomized, open-label, phase 3 study of 399 patients, aged 18-65 years.
Disclosures: Fondazione Italiana Linfomi funded the study. Dr. Chiappelli and several coinvestigators disclosed ties to Amgen, Celgene, Janssen, Nanostring, Pfizer, and other companies.
Monthly fitusiran showed promise in small phase I hemophilia trial
and increased thrombin production, according to the results of a small phase I dose-escalation study.
Compared with baseline, levels of antithrombin dropped by 70%-89%, K. John Pasi, MB, ChB, PhD, of the Royal London Haemophilia Centre and the London School of Medicine and Dentistry and his associates reported at the International Society on Thrombosis and Haemostasis congress and simultaneously in the New England Journal of Medicine. There were no thromboembolic events during the study, and the most common adverse events were mild injection-site reactions, they added.
Patients with hemophilia typically need frequent infusions of clotting factors, creating an urgent need for new therapies. Fitusiran is an investigational RNA interference (RNAi) therapy that targets antithrombin. This multicenter, open-label, phase I study included four healthy volunteers and 25 patients with moderate or severe hemophilia A or B without inhibitors. The healthy participants received a single subcutaneous injection of fitusiran (0.03 mg/kg) or placebo. The hemophilia patients received three injections of fitusiran either once weekly (0.015, 0.045, or 0.075 mg/kg) or once monthly (0.225, 0.45, 0.9, or 1.8 mg/kg, or a fixed dose of 80 mg (N Engl J Med. 2017 July 10. doi: 10.1056/NEJMoa1616569).
The single fitusiran dose and the weekly treatment regimens both produced consistent, sustained drops in plasma antithrombin levels, which supported a longer interval between doses, the researchers said. A monthly dose of 0.225 mg/kg cut antithrombin levels by about 70%, compared with baseline (standard deviation, ±9%), while a monthly dose of 1.8 mg/kg produced about an 89% (standard deviation, ±1%) drop in antithrombin levels. The fixed 80-mg dose consistently lowered antithrombin levels by about 87%, compared with baseline. The decreases in antithrombin varied little during the weeks between doses and were associated with increased thrombin generation, regardless of whether patients had hemophilia A or B, Dr. Pasi and his associates said.
One patient stopped treatment because of severe chest pain, but the investigators ruled out thrombosis as a cause. Fitusiran targets the liver, and 36% of patients developed transient increases in liver aminotransferase levels, they noted. Most of these patients had a history of hepatitis C virus infection. An extension study (NCT02554773) is ongoing to assess longer-term safety and efficacy findings. The investigators also are studying fitusiran in patients with inhibitory alloantibodies.
Alnylam Pharmaceuticals provided funding. Dr. Pasi disclosed research funding, advisory board fees, and travel grants from Alnylam and Genzyme. Four coinvestigators also disclosed receiving support from Alnylam during the conduct of the study.
and increased thrombin production, according to the results of a small phase I dose-escalation study.
Compared with baseline, levels of antithrombin dropped by 70%-89%, K. John Pasi, MB, ChB, PhD, of the Royal London Haemophilia Centre and the London School of Medicine and Dentistry and his associates reported at the International Society on Thrombosis and Haemostasis congress and simultaneously in the New England Journal of Medicine. There were no thromboembolic events during the study, and the most common adverse events were mild injection-site reactions, they added.
Patients with hemophilia typically need frequent infusions of clotting factors, creating an urgent need for new therapies. Fitusiran is an investigational RNA interference (RNAi) therapy that targets antithrombin. This multicenter, open-label, phase I study included four healthy volunteers and 25 patients with moderate or severe hemophilia A or B without inhibitors. The healthy participants received a single subcutaneous injection of fitusiran (0.03 mg/kg) or placebo. The hemophilia patients received three injections of fitusiran either once weekly (0.015, 0.045, or 0.075 mg/kg) or once monthly (0.225, 0.45, 0.9, or 1.8 mg/kg, or a fixed dose of 80 mg (N Engl J Med. 2017 July 10. doi: 10.1056/NEJMoa1616569).
The single fitusiran dose and the weekly treatment regimens both produced consistent, sustained drops in plasma antithrombin levels, which supported a longer interval between doses, the researchers said. A monthly dose of 0.225 mg/kg cut antithrombin levels by about 70%, compared with baseline (standard deviation, ±9%), while a monthly dose of 1.8 mg/kg produced about an 89% (standard deviation, ±1%) drop in antithrombin levels. The fixed 80-mg dose consistently lowered antithrombin levels by about 87%, compared with baseline. The decreases in antithrombin varied little during the weeks between doses and were associated with increased thrombin generation, regardless of whether patients had hemophilia A or B, Dr. Pasi and his associates said.
One patient stopped treatment because of severe chest pain, but the investigators ruled out thrombosis as a cause. Fitusiran targets the liver, and 36% of patients developed transient increases in liver aminotransferase levels, they noted. Most of these patients had a history of hepatitis C virus infection. An extension study (NCT02554773) is ongoing to assess longer-term safety and efficacy findings. The investigators also are studying fitusiran in patients with inhibitory alloantibodies.
Alnylam Pharmaceuticals provided funding. Dr. Pasi disclosed research funding, advisory board fees, and travel grants from Alnylam and Genzyme. Four coinvestigators also disclosed receiving support from Alnylam during the conduct of the study.
and increased thrombin production, according to the results of a small phase I dose-escalation study.
Compared with baseline, levels of antithrombin dropped by 70%-89%, K. John Pasi, MB, ChB, PhD, of the Royal London Haemophilia Centre and the London School of Medicine and Dentistry and his associates reported at the International Society on Thrombosis and Haemostasis congress and simultaneously in the New England Journal of Medicine. There were no thromboembolic events during the study, and the most common adverse events were mild injection-site reactions, they added.
Patients with hemophilia typically need frequent infusions of clotting factors, creating an urgent need for new therapies. Fitusiran is an investigational RNA interference (RNAi) therapy that targets antithrombin. This multicenter, open-label, phase I study included four healthy volunteers and 25 patients with moderate or severe hemophilia A or B without inhibitors. The healthy participants received a single subcutaneous injection of fitusiran (0.03 mg/kg) or placebo. The hemophilia patients received three injections of fitusiran either once weekly (0.015, 0.045, or 0.075 mg/kg) or once monthly (0.225, 0.45, 0.9, or 1.8 mg/kg, or a fixed dose of 80 mg (N Engl J Med. 2017 July 10. doi: 10.1056/NEJMoa1616569).
The single fitusiran dose and the weekly treatment regimens both produced consistent, sustained drops in plasma antithrombin levels, which supported a longer interval between doses, the researchers said. A monthly dose of 0.225 mg/kg cut antithrombin levels by about 70%, compared with baseline (standard deviation, ±9%), while a monthly dose of 1.8 mg/kg produced about an 89% (standard deviation, ±1%) drop in antithrombin levels. The fixed 80-mg dose consistently lowered antithrombin levels by about 87%, compared with baseline. The decreases in antithrombin varied little during the weeks between doses and were associated with increased thrombin generation, regardless of whether patients had hemophilia A or B, Dr. Pasi and his associates said.
One patient stopped treatment because of severe chest pain, but the investigators ruled out thrombosis as a cause. Fitusiran targets the liver, and 36% of patients developed transient increases in liver aminotransferase levels, they noted. Most of these patients had a history of hepatitis C virus infection. An extension study (NCT02554773) is ongoing to assess longer-term safety and efficacy findings. The investigators also are studying fitusiran in patients with inhibitory alloantibodies.
Alnylam Pharmaceuticals provided funding. Dr. Pasi disclosed research funding, advisory board fees, and travel grants from Alnylam and Genzyme. Four coinvestigators also disclosed receiving support from Alnylam during the conduct of the study.
FROM THE 2017 ISTH CONGRESS
Key clinical point: Once-monthly subcutaneous treatment with fitusiran led to dose-dependent lowering of antithrombin levels and increased thrombin production among patients with hemophilia A or B without inhibitors.
Major finding: Compared with baseline, levels of antithrombin dropped by 70%-89%. There were no episodes of thrombosis, and the most common adverse events were injection-site reactions.
Data source: A phase I dose-escalation study.
Disclosures: Alnylam Pharmaceuticals provided funding. Dr. Pasi disclosed research funding, advisory board fees, and travel grants from Alnylam and Genzyme. Four coinvestigators also disclosed receiving support from Alnylam during the conduct of the study.
Prophylactic emicizumab cut bleeds by 87% in hemophilia A with inhibitors
Once-weekly prophylactic therapy with emicizumab (ACE910) was associated an 87% lower rate of treated bleeding than no prophylaxis among patients with hemophilia A with inhibitors in the open-label, phase III HAVEN 1 trial.
After a median 24 weeks of treatment (range, 3-48 weeks), the 35 patients who were randomly assigned to prophylactic emicizumab (3.0 mg per kg for 4 weeks, followed by 1.5 mg per kg) had an annualized bleeding rate of 2.9 events, compared with an annualized rate of 23.3 events among the 18 patients who received no prophylaxis. The difference was statistically significant, reported Johannes Oldenburg, MD, PhD, and his associates at the International Society on Thrombosis and Haemostasis congress and simultaneously in the New England Journal of Medicine (N Engl J Med. 2017 Jul 10. doi: 10.1056/NEJMoa1703068).
In addition, 63% of patients who received prophylactic emicizumab had no bleeding events, compared with only 6% of the comparison group, said Dr. Oldenburg of Universitaetsklinikum Bonn, Germany. Emicizumab also was associated with a 79% lower rate of treated bleeds, compared with the historic rate among 24 patients who previously had been on prophylactic bypassing agents (P less than .001). No patient developed detectable antidrug antibodies.
The most common adverse events were injection site reactions (15% of patients), followed by headache, upper respiratory tract infection, arthralgia, and fatigue. Four patients developed thrombotic microangiopathy or cavernous sinus thrombosis and skin necrosis, all of whom had experienced breakthrough bleeding for which they had received multiple infusions of activated prothrombin complex concentrate at doses averaging more than 100 U per kg per day.
Patients with severe hemophilia A typically require prophylactic factor VIII infusions two to three times a week, but 30% develop neutralizing antibodies against factor VIII (inhibitors), which increases care burden, costs, and complication rates.
Emicizumab is a recombinant humanized bispecific monoclonal antibody that restores the function of missing active factor VIII by bridging activated factor IX and factor X, the investigators noted. A phase I study linked once-weekly emicizumab prophylaxis to markedly lower bleeding rates without dose-limiting toxicities (N Engl J Med 2016;374:2044-53). Subsequently, the phase III HAVEN 1 study (NCT02622321) compared once-weekly subcutaneous prophylactic emicizumab with on-demand (episodic) and prophylactic use of bypassing agents (BPAs) in 109 adults and adolescents (12 years and older) with hemophilia A with inhibitors. The primary endpoint was the difference in rates of treated bleeds between the groups. Patients had a median age of 28 years, all were male, and most had severe hemophilia at baseline. They typically had more than nine bleeding events in the 6 months before enrollment, with bleeding in more than one target joint and factor VIII titers of 180 Bethesda units per mL.
HAVEN 1 was funded by F. Hoffmann-La Roche and Chugai Pharmaceutical. Dr. Oldenburg and 13 coinvestigators disclosed ties to Chugai, Roche, and other pharmaceutical companies. The remaining coinvestigator had no disclosures.
The results of this phase III trial are of great importance to patients with for hemophilia A, offering “an elegant new solution for treatment.” Although it is not clear how best to treat the infrequent events of breakthrough bleeding when administering emicizumab, it is evident that repeated high doses of activated prothrombin complex concentrate should be avoided. Also, how to integrate emicizumab prophylaxis with current schedules for the induction of immune tolerance to factor VIII remains to be seen.
Meanwhile, weekly subcutaneous emicizumab prophylaxis offer great reductions in bleeding rates and improve quality of life “for this very challenging patient group.” Additional studies already are underway to ascertain the benefit of emicizumab prophylaxis in children with hemophilia with inhibitors, and a study for patients with hemophilia A without inhibitors is planned.
“These are extraordinary times for innovation in hemophilia therapy, and the introduction of emicizumab represents a major contribution toward achieving an enhanced standard of care for this lifelong bleeding disorder.”
David Lillicrap, MD, is with the department of pathology and molecular medicine at Queen’s University, Kingston, Ontario. He reported having no relevant conflicts of interest. These comments are from his accompanying editorial (N Engl J Med. 2017 June 10. doi: 10.1056/NEJMe1707802).
The results of this phase III trial are of great importance to patients with for hemophilia A, offering “an elegant new solution for treatment.” Although it is not clear how best to treat the infrequent events of breakthrough bleeding when administering emicizumab, it is evident that repeated high doses of activated prothrombin complex concentrate should be avoided. Also, how to integrate emicizumab prophylaxis with current schedules for the induction of immune tolerance to factor VIII remains to be seen.
Meanwhile, weekly subcutaneous emicizumab prophylaxis offer great reductions in bleeding rates and improve quality of life “for this very challenging patient group.” Additional studies already are underway to ascertain the benefit of emicizumab prophylaxis in children with hemophilia with inhibitors, and a study for patients with hemophilia A without inhibitors is planned.
“These are extraordinary times for innovation in hemophilia therapy, and the introduction of emicizumab represents a major contribution toward achieving an enhanced standard of care for this lifelong bleeding disorder.”
David Lillicrap, MD, is with the department of pathology and molecular medicine at Queen’s University, Kingston, Ontario. He reported having no relevant conflicts of interest. These comments are from his accompanying editorial (N Engl J Med. 2017 June 10. doi: 10.1056/NEJMe1707802).
The results of this phase III trial are of great importance to patients with for hemophilia A, offering “an elegant new solution for treatment.” Although it is not clear how best to treat the infrequent events of breakthrough bleeding when administering emicizumab, it is evident that repeated high doses of activated prothrombin complex concentrate should be avoided. Also, how to integrate emicizumab prophylaxis with current schedules for the induction of immune tolerance to factor VIII remains to be seen.
Meanwhile, weekly subcutaneous emicizumab prophylaxis offer great reductions in bleeding rates and improve quality of life “for this very challenging patient group.” Additional studies already are underway to ascertain the benefit of emicizumab prophylaxis in children with hemophilia with inhibitors, and a study for patients with hemophilia A without inhibitors is planned.
“These are extraordinary times for innovation in hemophilia therapy, and the introduction of emicizumab represents a major contribution toward achieving an enhanced standard of care for this lifelong bleeding disorder.”
David Lillicrap, MD, is with the department of pathology and molecular medicine at Queen’s University, Kingston, Ontario. He reported having no relevant conflicts of interest. These comments are from his accompanying editorial (N Engl J Med. 2017 June 10. doi: 10.1056/NEJMe1707802).
Once-weekly prophylactic therapy with emicizumab (ACE910) was associated an 87% lower rate of treated bleeding than no prophylaxis among patients with hemophilia A with inhibitors in the open-label, phase III HAVEN 1 trial.
After a median 24 weeks of treatment (range, 3-48 weeks), the 35 patients who were randomly assigned to prophylactic emicizumab (3.0 mg per kg for 4 weeks, followed by 1.5 mg per kg) had an annualized bleeding rate of 2.9 events, compared with an annualized rate of 23.3 events among the 18 patients who received no prophylaxis. The difference was statistically significant, reported Johannes Oldenburg, MD, PhD, and his associates at the International Society on Thrombosis and Haemostasis congress and simultaneously in the New England Journal of Medicine (N Engl J Med. 2017 Jul 10. doi: 10.1056/NEJMoa1703068).
In addition, 63% of patients who received prophylactic emicizumab had no bleeding events, compared with only 6% of the comparison group, said Dr. Oldenburg of Universitaetsklinikum Bonn, Germany. Emicizumab also was associated with a 79% lower rate of treated bleeds, compared with the historic rate among 24 patients who previously had been on prophylactic bypassing agents (P less than .001). No patient developed detectable antidrug antibodies.
The most common adverse events were injection site reactions (15% of patients), followed by headache, upper respiratory tract infection, arthralgia, and fatigue. Four patients developed thrombotic microangiopathy or cavernous sinus thrombosis and skin necrosis, all of whom had experienced breakthrough bleeding for which they had received multiple infusions of activated prothrombin complex concentrate at doses averaging more than 100 U per kg per day.
Patients with severe hemophilia A typically require prophylactic factor VIII infusions two to three times a week, but 30% develop neutralizing antibodies against factor VIII (inhibitors), which increases care burden, costs, and complication rates.
Emicizumab is a recombinant humanized bispecific monoclonal antibody that restores the function of missing active factor VIII by bridging activated factor IX and factor X, the investigators noted. A phase I study linked once-weekly emicizumab prophylaxis to markedly lower bleeding rates without dose-limiting toxicities (N Engl J Med 2016;374:2044-53). Subsequently, the phase III HAVEN 1 study (NCT02622321) compared once-weekly subcutaneous prophylactic emicizumab with on-demand (episodic) and prophylactic use of bypassing agents (BPAs) in 109 adults and adolescents (12 years and older) with hemophilia A with inhibitors. The primary endpoint was the difference in rates of treated bleeds between the groups. Patients had a median age of 28 years, all were male, and most had severe hemophilia at baseline. They typically had more than nine bleeding events in the 6 months before enrollment, with bleeding in more than one target joint and factor VIII titers of 180 Bethesda units per mL.
HAVEN 1 was funded by F. Hoffmann-La Roche and Chugai Pharmaceutical. Dr. Oldenburg and 13 coinvestigators disclosed ties to Chugai, Roche, and other pharmaceutical companies. The remaining coinvestigator had no disclosures.
Once-weekly prophylactic therapy with emicizumab (ACE910) was associated an 87% lower rate of treated bleeding than no prophylaxis among patients with hemophilia A with inhibitors in the open-label, phase III HAVEN 1 trial.
After a median 24 weeks of treatment (range, 3-48 weeks), the 35 patients who were randomly assigned to prophylactic emicizumab (3.0 mg per kg for 4 weeks, followed by 1.5 mg per kg) had an annualized bleeding rate of 2.9 events, compared with an annualized rate of 23.3 events among the 18 patients who received no prophylaxis. The difference was statistically significant, reported Johannes Oldenburg, MD, PhD, and his associates at the International Society on Thrombosis and Haemostasis congress and simultaneously in the New England Journal of Medicine (N Engl J Med. 2017 Jul 10. doi: 10.1056/NEJMoa1703068).
In addition, 63% of patients who received prophylactic emicizumab had no bleeding events, compared with only 6% of the comparison group, said Dr. Oldenburg of Universitaetsklinikum Bonn, Germany. Emicizumab also was associated with a 79% lower rate of treated bleeds, compared with the historic rate among 24 patients who previously had been on prophylactic bypassing agents (P less than .001). No patient developed detectable antidrug antibodies.
The most common adverse events were injection site reactions (15% of patients), followed by headache, upper respiratory tract infection, arthralgia, and fatigue. Four patients developed thrombotic microangiopathy or cavernous sinus thrombosis and skin necrosis, all of whom had experienced breakthrough bleeding for which they had received multiple infusions of activated prothrombin complex concentrate at doses averaging more than 100 U per kg per day.
Patients with severe hemophilia A typically require prophylactic factor VIII infusions two to three times a week, but 30% develop neutralizing antibodies against factor VIII (inhibitors), which increases care burden, costs, and complication rates.
Emicizumab is a recombinant humanized bispecific monoclonal antibody that restores the function of missing active factor VIII by bridging activated factor IX and factor X, the investigators noted. A phase I study linked once-weekly emicizumab prophylaxis to markedly lower bleeding rates without dose-limiting toxicities (N Engl J Med 2016;374:2044-53). Subsequently, the phase III HAVEN 1 study (NCT02622321) compared once-weekly subcutaneous prophylactic emicizumab with on-demand (episodic) and prophylactic use of bypassing agents (BPAs) in 109 adults and adolescents (12 years and older) with hemophilia A with inhibitors. The primary endpoint was the difference in rates of treated bleeds between the groups. Patients had a median age of 28 years, all were male, and most had severe hemophilia at baseline. They typically had more than nine bleeding events in the 6 months before enrollment, with bleeding in more than one target joint and factor VIII titers of 180 Bethesda units per mL.
HAVEN 1 was funded by F. Hoffmann-La Roche and Chugai Pharmaceutical. Dr. Oldenburg and 13 coinvestigators disclosed ties to Chugai, Roche, and other pharmaceutical companies. The remaining coinvestigator had no disclosures.
From 2017 ISTH CONGRESS
Key clinical point: .
Major finding: After a median 24 weeks of treatment, the intervention group averaged 2.9 bleeds per year vs. 23.3 events in the control group.
Data source: A phase III randomized multicenter open-label trial of 109 male adolescents and adults with hemophilia A and factor VIII inhibitors.
Disclosures: HAVEN 1 was funded by F. Hoffmann-La Roche and Chugai Pharmaceutical. Dr. Oldenburg and 13 coinvestigators disclosed ties to Chugai, Roche, and other pharmaceutical companies. The remaining coinvestigator had no disclosures.
FDA approves first new drug for sickle cell in nearly 20 years
The approval was based on placebo-controlled phase II and phase III trials suggesting that L-glutamate offered moderate benefit to patients with this rare, serious, and potentially fatal blood disorder.
L-glutamine oral powder will be marketed under the brand name Endari by Emmaus Medical. The FDA granted the approval through its orphan drug pathway, which is reserved for treatments of rare diseases or conditions. The National Institutes of Health estimates that sickle cell disorder affects approximately 100,000 individuals in the United States. Previously, the only drug approved for treating sickle cell disorder was hydroxyurea, which the FDA green-lighted in 1998.
The randomized, placebo-controlled, phase III trial on which the approval of L-glutamine was based (GLUSCC09-01) comprised patients aged 5-58 years with sickle cell disease or beta-0 thalassemia who had at least two episodes of painful crises during the 12 months before screening. A total of 152 patients were randomly assigned to receive oral L-glutamine (0.3 mg/kg per day) for 48 weeks followed by a 3-week tapering period, while 78 patients received placebo. Patients who received L-glutamine averaged three hospital visits for painful crises for which they received parenteral narcotics or ketorolac, while the placebo group averaged four such hospital visits. Additionally, the time to second crisis was delayed by 79 days in the treatment group, compared with the placebo group (hazard ratio, 0.68).
L-glutamine also was associated with fewer hospital days (median 6.5 vs. 11 days) and fewer occurrences of potentially life-threatening acute chest syndrome (8.6% vs. 23.1%), investigators reported to the FDA’s Oncologic Drugs Advisory Committee during a meeting on May 24.
Safety studies of L-glutamine included phase II and phase III data from 187 patients who received L-glutamine and 111 patients who received placebo, the investigators reported. Based on these analyses, rates of sickle cell anemia with crisis were 66% in the treatment population and 72% in placebo recipients. Rates of acute chest syndrome were 7% and 19%, respectively. Treatment-emergent adverse events led patients to drop out of the studies in 2.7% and 0.9% of cases. The most common adverse events of L-glutamine therapy were constipation, nausea, headache, cough, pain in the extremities, back pain, chest pain, and abdominal pain.
The FDA advisory committee voted 10-3 in favor of approving L-glutamate after hearing from industry and FDA representatives, physicians who treat patients with sickle cell disorder, and patients and their family members at the May 24 meeting. “No” voters expressed concerns about differing drop-out rates between the study groups, but other committee members emphasized the severe impact of sickle cell disorder on quality of life and the crucial need for more treatments.
The FDA Orphan Products Grants Program provided some of the funding to develop the drug. The FDA committee members had no relevant conflicts of interests.
The approval was based on placebo-controlled phase II and phase III trials suggesting that L-glutamate offered moderate benefit to patients with this rare, serious, and potentially fatal blood disorder.
L-glutamine oral powder will be marketed under the brand name Endari by Emmaus Medical. The FDA granted the approval through its orphan drug pathway, which is reserved for treatments of rare diseases or conditions. The National Institutes of Health estimates that sickle cell disorder affects approximately 100,000 individuals in the United States. Previously, the only drug approved for treating sickle cell disorder was hydroxyurea, which the FDA green-lighted in 1998.
The randomized, placebo-controlled, phase III trial on which the approval of L-glutamine was based (GLUSCC09-01) comprised patients aged 5-58 years with sickle cell disease or beta-0 thalassemia who had at least two episodes of painful crises during the 12 months before screening. A total of 152 patients were randomly assigned to receive oral L-glutamine (0.3 mg/kg per day) for 48 weeks followed by a 3-week tapering period, while 78 patients received placebo. Patients who received L-glutamine averaged three hospital visits for painful crises for which they received parenteral narcotics or ketorolac, while the placebo group averaged four such hospital visits. Additionally, the time to second crisis was delayed by 79 days in the treatment group, compared with the placebo group (hazard ratio, 0.68).
L-glutamine also was associated with fewer hospital days (median 6.5 vs. 11 days) and fewer occurrences of potentially life-threatening acute chest syndrome (8.6% vs. 23.1%), investigators reported to the FDA’s Oncologic Drugs Advisory Committee during a meeting on May 24.
Safety studies of L-glutamine included phase II and phase III data from 187 patients who received L-glutamine and 111 patients who received placebo, the investigators reported. Based on these analyses, rates of sickle cell anemia with crisis were 66% in the treatment population and 72% in placebo recipients. Rates of acute chest syndrome were 7% and 19%, respectively. Treatment-emergent adverse events led patients to drop out of the studies in 2.7% and 0.9% of cases. The most common adverse events of L-glutamine therapy were constipation, nausea, headache, cough, pain in the extremities, back pain, chest pain, and abdominal pain.
The FDA advisory committee voted 10-3 in favor of approving L-glutamate after hearing from industry and FDA representatives, physicians who treat patients with sickle cell disorder, and patients and their family members at the May 24 meeting. “No” voters expressed concerns about differing drop-out rates between the study groups, but other committee members emphasized the severe impact of sickle cell disorder on quality of life and the crucial need for more treatments.
The FDA Orphan Products Grants Program provided some of the funding to develop the drug. The FDA committee members had no relevant conflicts of interests.
The approval was based on placebo-controlled phase II and phase III trials suggesting that L-glutamate offered moderate benefit to patients with this rare, serious, and potentially fatal blood disorder.
L-glutamine oral powder will be marketed under the brand name Endari by Emmaus Medical. The FDA granted the approval through its orphan drug pathway, which is reserved for treatments of rare diseases or conditions. The National Institutes of Health estimates that sickle cell disorder affects approximately 100,000 individuals in the United States. Previously, the only drug approved for treating sickle cell disorder was hydroxyurea, which the FDA green-lighted in 1998.
The randomized, placebo-controlled, phase III trial on which the approval of L-glutamine was based (GLUSCC09-01) comprised patients aged 5-58 years with sickle cell disease or beta-0 thalassemia who had at least two episodes of painful crises during the 12 months before screening. A total of 152 patients were randomly assigned to receive oral L-glutamine (0.3 mg/kg per day) for 48 weeks followed by a 3-week tapering period, while 78 patients received placebo. Patients who received L-glutamine averaged three hospital visits for painful crises for which they received parenteral narcotics or ketorolac, while the placebo group averaged four such hospital visits. Additionally, the time to second crisis was delayed by 79 days in the treatment group, compared with the placebo group (hazard ratio, 0.68).
L-glutamine also was associated with fewer hospital days (median 6.5 vs. 11 days) and fewer occurrences of potentially life-threatening acute chest syndrome (8.6% vs. 23.1%), investigators reported to the FDA’s Oncologic Drugs Advisory Committee during a meeting on May 24.
Safety studies of L-glutamine included phase II and phase III data from 187 patients who received L-glutamine and 111 patients who received placebo, the investigators reported. Based on these analyses, rates of sickle cell anemia with crisis were 66% in the treatment population and 72% in placebo recipients. Rates of acute chest syndrome were 7% and 19%, respectively. Treatment-emergent adverse events led patients to drop out of the studies in 2.7% and 0.9% of cases. The most common adverse events of L-glutamine therapy were constipation, nausea, headache, cough, pain in the extremities, back pain, chest pain, and abdominal pain.
The FDA advisory committee voted 10-3 in favor of approving L-glutamate after hearing from industry and FDA representatives, physicians who treat patients with sickle cell disorder, and patients and their family members at the May 24 meeting. “No” voters expressed concerns about differing drop-out rates between the study groups, but other committee members emphasized the severe impact of sickle cell disorder on quality of life and the crucial need for more treatments.
The FDA Orphan Products Grants Program provided some of the funding to develop the drug. The FDA committee members had no relevant conflicts of interests.
July 2017: Click for Credit
Here are 6 articles in the July issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. High-dose Oral Vitamin D3 Significantly Reduced Effects of Sunburn
To take the posttest, go to: http://bit.ly/2tmDiKc
Expires May 23, 2018
2. Women Less Likely to Be Diagnosed With Sleep Disorders
To take the posttest, go to: http://bit.ly/2rgLdne
Expires May 30, 2018
3. RA Treatment Delays Raise Risk for Long-term Disability
To take the posttest, go to: http://bit.ly/2tC0IGF
Expires May 30, 2018
4. Target Self-medication of Mood and Anxiety Symptoms
To take the posttest, go to: http://bit.ly/2vy5jel
Expires May 2, 2018
5. Two New Biomarkers for Breast Cancer Show Validity
To take the posttest, go to: http://bit.ly/2ve9H2L
Expires May 2, 2018
6. Time to Therapy for Gram-positive Bacteremia Reduced From 60 Hours to 4 Hours
To take the posttest, go to: http://bit.ly/2ssacIf
Expires May 25, 2018
Here are 6 articles in the July issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. High-dose Oral Vitamin D3 Significantly Reduced Effects of Sunburn
To take the posttest, go to: http://bit.ly/2tmDiKc
Expires May 23, 2018
2. Women Less Likely to Be Diagnosed With Sleep Disorders
To take the posttest, go to: http://bit.ly/2rgLdne
Expires May 30, 2018
3. RA Treatment Delays Raise Risk for Long-term Disability
To take the posttest, go to: http://bit.ly/2tC0IGF
Expires May 30, 2018
4. Target Self-medication of Mood and Anxiety Symptoms
To take the posttest, go to: http://bit.ly/2vy5jel
Expires May 2, 2018
5. Two New Biomarkers for Breast Cancer Show Validity
To take the posttest, go to: http://bit.ly/2ve9H2L
Expires May 2, 2018
6. Time to Therapy for Gram-positive Bacteremia Reduced From 60 Hours to 4 Hours
To take the posttest, go to: http://bit.ly/2ssacIf
Expires May 25, 2018
Here are 6 articles in the July issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. High-dose Oral Vitamin D3 Significantly Reduced Effects of Sunburn
To take the posttest, go to: http://bit.ly/2tmDiKc
Expires May 23, 2018
2. Women Less Likely to Be Diagnosed With Sleep Disorders
To take the posttest, go to: http://bit.ly/2rgLdne
Expires May 30, 2018
3. RA Treatment Delays Raise Risk for Long-term Disability
To take the posttest, go to: http://bit.ly/2tC0IGF
Expires May 30, 2018
4. Target Self-medication of Mood and Anxiety Symptoms
To take the posttest, go to: http://bit.ly/2vy5jel
Expires May 2, 2018
5. Two New Biomarkers for Breast Cancer Show Validity
To take the posttest, go to: http://bit.ly/2ve9H2L
Expires May 2, 2018
6. Time to Therapy for Gram-positive Bacteremia Reduced From 60 Hours to 4 Hours
To take the posttest, go to: http://bit.ly/2ssacIf
Expires May 25, 2018
VIDEO: Autoimmune hepatitis with cirrhosis tied to hepatocellular carcinoma
The presence of cirrhosis in patients with autoimmune hepatitis markedly increased their risk of hepatocellular carcinoma, according to a systematic review and meta-analysis of 25 cohort studies and 6,528 patients.
Estimated rates of hepatocellular carcinoma (HCC) were 10.1 (6.9-14.7) cases per 1,000 person-years in these patients versus 1.1 (0.6-2.2) cases per 1,000 person-years in patients without cirrhosis at diagnosis, Aylin Tansel, MD, of Baylor College of Medicine in Houston, and associates reported in Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.02.006). Thus, surveillance for HCC “might be cost effective in this population,” they wrote. “However, patients with AIH [autoimmune hepatitis] without cirrhosis at index diagnosis, particularly those identified from general populations, are at an extremely low risk of HCC.”
Source: American Gastroenterological Association
Autoimmune hepatitis may be asymptomatic at presentation or may cause severe acute hepatitis or even fulminant liver failure. Even with immunosuppressive therapy, patients progress to cirrhosis at reported annual rates of 0.1%-8%. HCC is the fastest-growing cause of cancer mortality, and the American Association for the Study of Liver Diseases (AASLD) recommends enhanced surveillance for this disease in patients whose annual estimated risk is at least 1.5%. Although the European Association for the Study of Liver Diseases recommends screening for HCC in patients with autoimmune hepatitis and cirrhosis, AASLD makes no such recommendation, the reviewers noted. To study the risk of HCC in patients with autoimmune hepatitis, they searched PubMed, Embase, and reference lists for relevant cohort studies published through June 2016. This work yielded 20 papers and five abstracts with a pooled median follow-up period of 8 years.
The overall pooled incidence of HCC was 3.1 (95% confidence interval, 2.2-4.2) cases per 1,000 person-years, or 1.007% per year, the reviewers wrote. However, the 95% confidence interval for the annual incidence rate nearly encompassed the 1.5% cutoff recommended by AASLD, they said. Furthermore, 5 of 16 studies that investigated the risk of HCC in patients with concurrent cirrhosis reported incidence rates above 1.5%. Among 93 patients who developed HCC in the meta-analysis, only 1 did not have cirrhosis by the time autoimmune hepatitis was diagnosed.
The meta-analysis also linked HCC to older age and Asian ethnicity among patients with autoimmune hepatitis, as has been reported before. Male sex only slightly increased the risk of HCC, but the studies included only about 1,130 men, the reviewers noted. Although the severity of autoimmune hepatitis varied among studies, higher rates of relapse predicted HCC in two cohorts. Additionally, one study linked alcohol abuse to a sixfold higher risk of HCC among patients with autoimmune hepatitis. “These data support careful monitoring of patients with autoimmune hepatitis, particularly older men, patients with multiple autoimmune hepatitis relapses, and those with ongoing alcohol abuse,” the investigators wrote.
They found no evidence of publication bias, but each individual study included at most 15 cases of HCC, so pooled incidence rates were probably imprecise, especially for subgroups, they said. Studies also inconsistently reported HCC risk factors, often lacked comparison groups, and usually did not report the effects of surveillance for HCC.
Dr. Tansel reported receiving support from the National Institutes of Health. The reviewers had no conflicts of interest.
Serial imaging surveillance facilitates detection of hepatocellular carcinoma (HCC) at a stage amenable to potentially curative resection or liver transplantation. The AASLD, EASL, and APASL recommend surveillance for cirrhotic patients; however, the AASLD stipulates that the incidence of HCC exceed the threshold of cost-effectiveness of 1.5% per year. Whether HCC surveillance in cirrhotic patients with autoimmune hepatitis (AIH) is cost effective remains controversial. The systematic review and meta-analysis by Tansel et al. of 25 rigorously selected cohort studies of AIH addresses this question by calculating incidence rates of HCC per 1,000 person-years using 95% confidence intervals derived from event rates in relation to the duration of follow-up. 
John M. Vierling, MD, FACP, FAASLD, is professor of medicine and surgery, chief of hepatology, Baylor College of Medicine, Houston. He has received grant support from Taiwan J and Novartis and is on the scientific advisory board for Novartis.
Serial imaging surveillance facilitates detection of hepatocellular carcinoma (HCC) at a stage amenable to potentially curative resection or liver transplantation. The AASLD, EASL, and APASL recommend surveillance for cirrhotic patients; however, the AASLD stipulates that the incidence of HCC exceed the threshold of cost-effectiveness of 1.5% per year. Whether HCC surveillance in cirrhotic patients with autoimmune hepatitis (AIH) is cost effective remains controversial. The systematic review and meta-analysis by Tansel et al. of 25 rigorously selected cohort studies of AIH addresses this question by calculating incidence rates of HCC per 1,000 person-years using 95% confidence intervals derived from event rates in relation to the duration of follow-up.
John M. Vierling, MD, FACP, FAASLD, is professor of medicine and surgery, chief of hepatology, Baylor College of Medicine, Houston. He has received grant support from Taiwan J and Novartis and is on the scientific advisory board for Novartis.
Serial imaging surveillance facilitates detection of hepatocellular carcinoma (HCC) at a stage amenable to potentially curative resection or liver transplantation. The AASLD, EASL, and APASL recommend surveillance for cirrhotic patients; however, the AASLD stipulates that the incidence of HCC exceed the threshold of cost-effectiveness of 1.5% per year. Whether HCC surveillance in cirrhotic patients with autoimmune hepatitis (AIH) is cost effective remains controversial. The systematic review and meta-analysis by Tansel et al. of 25 rigorously selected cohort studies of AIH addresses this question by calculating incidence rates of HCC per 1,000 person-years using 95% confidence intervals derived from event rates in relation to the duration of follow-up.
John M. Vierling, MD, FACP, FAASLD, is professor of medicine and surgery, chief of hepatology, Baylor College of Medicine, Houston. He has received grant support from Taiwan J and Novartis and is on the scientific advisory board for Novartis.
The presence of cirrhosis in patients with autoimmune hepatitis markedly increased their risk of hepatocellular carcinoma, according to a systematic review and meta-analysis of 25 cohort studies and 6,528 patients.
Estimated rates of hepatocellular carcinoma (HCC) were 10.1 (6.9-14.7) cases per 1,000 person-years in these patients versus 1.1 (0.6-2.2) cases per 1,000 person-years in patients without cirrhosis at diagnosis, Aylin Tansel, MD, of Baylor College of Medicine in Houston, and associates reported in Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.02.006). Thus, surveillance for HCC “might be cost effective in this population,” they wrote. “However, patients with AIH [autoimmune hepatitis] without cirrhosis at index diagnosis, particularly those identified from general populations, are at an extremely low risk of HCC.”
Source: American Gastroenterological Association
Autoimmune hepatitis may be asymptomatic at presentation or may cause severe acute hepatitis or even fulminant liver failure. Even with immunosuppressive therapy, patients progress to cirrhosis at reported annual rates of 0.1%-8%. HCC is the fastest-growing cause of cancer mortality, and the American Association for the Study of Liver Diseases (AASLD) recommends enhanced surveillance for this disease in patients whose annual estimated risk is at least 1.5%. Although the European Association for the Study of Liver Diseases recommends screening for HCC in patients with autoimmune hepatitis and cirrhosis, AASLD makes no such recommendation, the reviewers noted. To study the risk of HCC in patients with autoimmune hepatitis, they searched PubMed, Embase, and reference lists for relevant cohort studies published through June 2016. This work yielded 20 papers and five abstracts with a pooled median follow-up period of 8 years.
The overall pooled incidence of HCC was 3.1 (95% confidence interval, 2.2-4.2) cases per 1,000 person-years, or 1.007% per year, the reviewers wrote. However, the 95% confidence interval for the annual incidence rate nearly encompassed the 1.5% cutoff recommended by AASLD, they said. Furthermore, 5 of 16 studies that investigated the risk of HCC in patients with concurrent cirrhosis reported incidence rates above 1.5%. Among 93 patients who developed HCC in the meta-analysis, only 1 did not have cirrhosis by the time autoimmune hepatitis was diagnosed.
The meta-analysis also linked HCC to older age and Asian ethnicity among patients with autoimmune hepatitis, as has been reported before. Male sex only slightly increased the risk of HCC, but the studies included only about 1,130 men, the reviewers noted. Although the severity of autoimmune hepatitis varied among studies, higher rates of relapse predicted HCC in two cohorts. Additionally, one study linked alcohol abuse to a sixfold higher risk of HCC among patients with autoimmune hepatitis. “These data support careful monitoring of patients with autoimmune hepatitis, particularly older men, patients with multiple autoimmune hepatitis relapses, and those with ongoing alcohol abuse,” the investigators wrote.
They found no evidence of publication bias, but each individual study included at most 15 cases of HCC, so pooled incidence rates were probably imprecise, especially for subgroups, they said. Studies also inconsistently reported HCC risk factors, often lacked comparison groups, and usually did not report the effects of surveillance for HCC.
Dr. Tansel reported receiving support from the National Institutes of Health. The reviewers had no conflicts of interest.
The presence of cirrhosis in patients with autoimmune hepatitis markedly increased their risk of hepatocellular carcinoma, according to a systematic review and meta-analysis of 25 cohort studies and 6,528 patients.
Estimated rates of hepatocellular carcinoma (HCC) were 10.1 (6.9-14.7) cases per 1,000 person-years in these patients versus 1.1 (0.6-2.2) cases per 1,000 person-years in patients without cirrhosis at diagnosis, Aylin Tansel, MD, of Baylor College of Medicine in Houston, and associates reported in Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.02.006). Thus, surveillance for HCC “might be cost effective in this population,” they wrote. “However, patients with AIH [autoimmune hepatitis] without cirrhosis at index diagnosis, particularly those identified from general populations, are at an extremely low risk of HCC.”
Source: American Gastroenterological Association
Autoimmune hepatitis may be asymptomatic at presentation or may cause severe acute hepatitis or even fulminant liver failure. Even with immunosuppressive therapy, patients progress to cirrhosis at reported annual rates of 0.1%-8%. HCC is the fastest-growing cause of cancer mortality, and the American Association for the Study of Liver Diseases (AASLD) recommends enhanced surveillance for this disease in patients whose annual estimated risk is at least 1.5%. Although the European Association for the Study of Liver Diseases recommends screening for HCC in patients with autoimmune hepatitis and cirrhosis, AASLD makes no such recommendation, the reviewers noted. To study the risk of HCC in patients with autoimmune hepatitis, they searched PubMed, Embase, and reference lists for relevant cohort studies published through June 2016. This work yielded 20 papers and five abstracts with a pooled median follow-up period of 8 years.
The overall pooled incidence of HCC was 3.1 (95% confidence interval, 2.2-4.2) cases per 1,000 person-years, or 1.007% per year, the reviewers wrote. However, the 95% confidence interval for the annual incidence rate nearly encompassed the 1.5% cutoff recommended by AASLD, they said. Furthermore, 5 of 16 studies that investigated the risk of HCC in patients with concurrent cirrhosis reported incidence rates above 1.5%. Among 93 patients who developed HCC in the meta-analysis, only 1 did not have cirrhosis by the time autoimmune hepatitis was diagnosed.
The meta-analysis also linked HCC to older age and Asian ethnicity among patients with autoimmune hepatitis, as has been reported before. Male sex only slightly increased the risk of HCC, but the studies included only about 1,130 men, the reviewers noted. Although the severity of autoimmune hepatitis varied among studies, higher rates of relapse predicted HCC in two cohorts. Additionally, one study linked alcohol abuse to a sixfold higher risk of HCC among patients with autoimmune hepatitis. “These data support careful monitoring of patients with autoimmune hepatitis, particularly older men, patients with multiple autoimmune hepatitis relapses, and those with ongoing alcohol abuse,” the investigators wrote.
They found no evidence of publication bias, but each individual study included at most 15 cases of HCC, so pooled incidence rates were probably imprecise, especially for subgroups, they said. Studies also inconsistently reported HCC risk factors, often lacked comparison groups, and usually did not report the effects of surveillance for HCC.
Dr. Tansel reported receiving support from the National Institutes of Health. The reviewers had no conflicts of interest.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: Patients with autoimmune hepatitis and cirrhosis are at increased risk of hepatocellular carcinoma.
Major finding: For every 1,000 person-years, there were 3.1 (95% CI, 2.2-4.2) cases of hepatocellular carcinoma overall, 10.1 (6.9-14.7) cases in patients who also had cirrhosis at diagnosis, and 1.1 (0.6-2.2) cases in patients who did not have cirrhosis at diagnosis.
Data source: A systematic review and meta-analysis of 25 studies of 6,528 patients with autoimmune hepatitis.
Disclosures: Dr. Tansel reported receiving support from the National Institutes of Health. The investigators disclosed no conflicts.
VIDEO: Meta-analysis favors anticoagulation for patients with cirrhosis and portal vein thrombosis
Patients with cirrhosis and portal vein thrombosis (PVT) who received anticoagulation therapy had nearly fivefold greater odds of recanalization compared with untreated patients, and were no more likely to experience major or minor bleeding, in a pooled analysis of eight studies published in the August issue of Gastroenterology (doi: 10.1053/j.gastro.2017.04.042).
Rates of any recanalization were 71% in treated patients and 42% in untreated patients (P less than .0001), wrote Lorenzo Loffredo, MD, of Sapienza University, Rome, and his coinvestigators. Rates of complete recanalization were 53% and 33%, respectively (P = .002), rates of spontaneous variceal bleeding were 2% and 12% (P = .04), and bleeding affected 11% of patients in each group. Together, the findings “show that anticoagulants are efficacious and safe for treatment of portal vein thrombosis in cirrhotic patients,” although larger, interventional clinical trials are needed to pinpoint the clinical role of anticoagulation in cirrhotic patients with PVT, the reviewers reported.
Source: American Gastroenterological Association
Bleeding from portal hypertension is a major complication in cirrhosis, but PVT affects about 20% of patients and predicts poor outcomes, they noted. Anticoagulation in this setting can be difficult because patients often have concurrent coagulopathies that are hard to assess with standard techniques, such as PT-INR (international normalized ratio). Although some studies support anticoagulating these patients, data are limited. Therefore, the reviewers searched PubMed, the ISI Web of Science, SCOPUS, and the Cochrane database through Feb. 14, 2017, for trials comparing anticoagulation with no treatment in patients with cirrhosis and PVT.
This search yielded eight trials of 353 patients who received low-molecular-weight heparin, warfarin, or no treatment for about 6 months, with a typical follow-up period of 2 years. The reviewers found no evidence of publication bias or significant heterogeneity among the trials. Six studies evaluated complete recanalization, another set of six studies tracked progression of PVT, a third set of six studies evaluated major or minor bleeding events, and four studies evaluated spontaneous variceal bleeding. Compared with no treatment, anticoagulation was tied to a significantly greater likelihood of complete recanalization (pooled odds ratio, 3.4; 95% confidence interval, 1.5-7.4; P = .002), a significantly lower chance of PVT progressing (9% vs. 33%; pooled odds ratio, 0.14; 95% CI, 0.06-0.31; P less than .0001), no difference in bleeding rates (11% in each pooled group), and a significantly lower risk of spontaneous variceal bleeding (OR, 0.23; 95% CI, 0.06-0.94; P = .04).
“Metaregression analysis showed that duration of anticoagulation did not influence outcomes,” the reviewers wrote. “Low-molecular-weight heparin, but not warfarin, was significantly associated with a complete PVT resolution as compared to untreated patients, while both low-molecular-weight heparin and warfarin were effective in reducing PVT progression.” That finding merits careful interpretation, however, because most studies on warfarin were retrospective and lacked data on the quality of anticoagulation, they added.
“It is a challenge to treat patients with cirrhosis using anticoagulants because of the perception that the coexistent coagulopathy could promote bleeding,” the researchers wrote. Nonetheless, their analysis suggests that anticoagulation has significant benefits and does not increase bleeding risk, regardless of the severity of liver failure, they concluded.
The reviewers reported having no funding sources or conflicts of interest.
Patients with cirrhosis and portal vein thrombosis (PVT) who received anticoagulation therapy had nearly fivefold greater odds of recanalization compared with untreated patients, and were no more likely to experience major or minor bleeding, in a pooled analysis of eight studies published in the August issue of Gastroenterology (doi: 10.1053/j.gastro.2017.04.042).
Rates of any recanalization were 71% in treated patients and 42% in untreated patients (P less than .0001), wrote Lorenzo Loffredo, MD, of Sapienza University, Rome, and his coinvestigators. Rates of complete recanalization were 53% and 33%, respectively (P = .002), rates of spontaneous variceal bleeding were 2% and 12% (P = .04), and bleeding affected 11% of patients in each group. Together, the findings “show that anticoagulants are efficacious and safe for treatment of portal vein thrombosis in cirrhotic patients,” although larger, interventional clinical trials are needed to pinpoint the clinical role of anticoagulation in cirrhotic patients with PVT, the reviewers reported.
Source: American Gastroenterological Association
Bleeding from portal hypertension is a major complication in cirrhosis, but PVT affects about 20% of patients and predicts poor outcomes, they noted. Anticoagulation in this setting can be difficult because patients often have concurrent coagulopathies that are hard to assess with standard techniques, such as PT-INR (international normalized ratio). Although some studies support anticoagulating these patients, data are limited. Therefore, the reviewers searched PubMed, the ISI Web of Science, SCOPUS, and the Cochrane database through Feb. 14, 2017, for trials comparing anticoagulation with no treatment in patients with cirrhosis and PVT.
This search yielded eight trials of 353 patients who received low-molecular-weight heparin, warfarin, or no treatment for about 6 months, with a typical follow-up period of 2 years. The reviewers found no evidence of publication bias or significant heterogeneity among the trials. Six studies evaluated complete recanalization, another set of six studies tracked progression of PVT, a third set of six studies evaluated major or minor bleeding events, and four studies evaluated spontaneous variceal bleeding. Compared with no treatment, anticoagulation was tied to a significantly greater likelihood of complete recanalization (pooled odds ratio, 3.4; 95% confidence interval, 1.5-7.4; P = .002), a significantly lower chance of PVT progressing (9% vs. 33%; pooled odds ratio, 0.14; 95% CI, 0.06-0.31; P less than .0001), no difference in bleeding rates (11% in each pooled group), and a significantly lower risk of spontaneous variceal bleeding (OR, 0.23; 95% CI, 0.06-0.94; P = .04).
“Metaregression analysis showed that duration of anticoagulation did not influence outcomes,” the reviewers wrote. “Low-molecular-weight heparin, but not warfarin, was significantly associated with a complete PVT resolution as compared to untreated patients, while both low-molecular-weight heparin and warfarin were effective in reducing PVT progression.” That finding merits careful interpretation, however, because most studies on warfarin were retrospective and lacked data on the quality of anticoagulation, they added.
“It is a challenge to treat patients with cirrhosis using anticoagulants because of the perception that the coexistent coagulopathy could promote bleeding,” the researchers wrote. Nonetheless, their analysis suggests that anticoagulation has significant benefits and does not increase bleeding risk, regardless of the severity of liver failure, they concluded.
The reviewers reported having no funding sources or conflicts of interest.
Patients with cirrhosis and portal vein thrombosis (PVT) who received anticoagulation therapy had nearly fivefold greater odds of recanalization compared with untreated patients, and were no more likely to experience major or minor bleeding, in a pooled analysis of eight studies published in the August issue of Gastroenterology (doi: 10.1053/j.gastro.2017.04.042).
Rates of any recanalization were 71% in treated patients and 42% in untreated patients (P less than .0001), wrote Lorenzo Loffredo, MD, of Sapienza University, Rome, and his coinvestigators. Rates of complete recanalization were 53% and 33%, respectively (P = .002), rates of spontaneous variceal bleeding were 2% and 12% (P = .04), and bleeding affected 11% of patients in each group. Together, the findings “show that anticoagulants are efficacious and safe for treatment of portal vein thrombosis in cirrhotic patients,” although larger, interventional clinical trials are needed to pinpoint the clinical role of anticoagulation in cirrhotic patients with PVT, the reviewers reported.
Source: American Gastroenterological Association
Bleeding from portal hypertension is a major complication in cirrhosis, but PVT affects about 20% of patients and predicts poor outcomes, they noted. Anticoagulation in this setting can be difficult because patients often have concurrent coagulopathies that are hard to assess with standard techniques, such as PT-INR (international normalized ratio). Although some studies support anticoagulating these patients, data are limited. Therefore, the reviewers searched PubMed, the ISI Web of Science, SCOPUS, and the Cochrane database through Feb. 14, 2017, for trials comparing anticoagulation with no treatment in patients with cirrhosis and PVT.
This search yielded eight trials of 353 patients who received low-molecular-weight heparin, warfarin, or no treatment for about 6 months, with a typical follow-up period of 2 years. The reviewers found no evidence of publication bias or significant heterogeneity among the trials. Six studies evaluated complete recanalization, another set of six studies tracked progression of PVT, a third set of six studies evaluated major or minor bleeding events, and four studies evaluated spontaneous variceal bleeding. Compared with no treatment, anticoagulation was tied to a significantly greater likelihood of complete recanalization (pooled odds ratio, 3.4; 95% confidence interval, 1.5-7.4; P = .002), a significantly lower chance of PVT progressing (9% vs. 33%; pooled odds ratio, 0.14; 95% CI, 0.06-0.31; P less than .0001), no difference in bleeding rates (11% in each pooled group), and a significantly lower risk of spontaneous variceal bleeding (OR, 0.23; 95% CI, 0.06-0.94; P = .04).
“Metaregression analysis showed that duration of anticoagulation did not influence outcomes,” the reviewers wrote. “Low-molecular-weight heparin, but not warfarin, was significantly associated with a complete PVT resolution as compared to untreated patients, while both low-molecular-weight heparin and warfarin were effective in reducing PVT progression.” That finding merits careful interpretation, however, because most studies on warfarin were retrospective and lacked data on the quality of anticoagulation, they added.
“It is a challenge to treat patients with cirrhosis using anticoagulants because of the perception that the coexistent coagulopathy could promote bleeding,” the researchers wrote. Nonetheless, their analysis suggests that anticoagulation has significant benefits and does not increase bleeding risk, regardless of the severity of liver failure, they concluded.
The reviewers reported having no funding sources or conflicts of interest.
FROM GASTROENTEROLOGY
Key clinical point: Anticoagulation produced favorable outcomes with no increase in bleeding risk in patients with cirrhosis and portal vein thrombosis.
Major finding: Rates of any recanalization were 71% in treated patients and 42% in untreated patients (P less than .0001); rates of complete recanalization were 53% and 33%, respectively (P = .002), rates of spontaneous variceal bleeding were 2% and 12% (P = .04), and bleeding affected 11% of patients in each group.
Data source: A systematic review and meta-analysis of eight studies of 353 patients with cirrhosis and portal vein thrombosis.
Disclosures: The reviewers reported having no funding sources or conflicts of interest.
