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ICYMI: Noninferior tuberculosis prevention in HIV has shorter duration
The primary endpoint – first case of tuberculosis or death from tuberculosis or unknown cause among patients with HIV – was reported in 2% of both arms in the open-label, phase 3, noninferiority trial BRIEF TB (NCT01404312).
In the New England Journal of Medicine (2019 Mar 14;380[11]:1001-11), 3,000 patients with HIV were randomized to receive either 1 month of rifapentine/isoniazid or 9 months of isoniazid monotherapy for prevention of tuberculosis. Although safety was also similar between arms, the completion rate was significantly higher in the combination treatment arm, compared with the monotherapy arm (97% vs. 90%; P less than .001).
We covered this story at the annual Conference on Retroviruses & Opportunistic Infections. See our coverage at the link below.
The primary endpoint – first case of tuberculosis or death from tuberculosis or unknown cause among patients with HIV – was reported in 2% of both arms in the open-label, phase 3, noninferiority trial BRIEF TB (NCT01404312).
In the New England Journal of Medicine (2019 Mar 14;380[11]:1001-11), 3,000 patients with HIV were randomized to receive either 1 month of rifapentine/isoniazid or 9 months of isoniazid monotherapy for prevention of tuberculosis. Although safety was also similar between arms, the completion rate was significantly higher in the combination treatment arm, compared with the monotherapy arm (97% vs. 90%; P less than .001).
We covered this story at the annual Conference on Retroviruses & Opportunistic Infections. See our coverage at the link below.
The primary endpoint – first case of tuberculosis or death from tuberculosis or unknown cause among patients with HIV – was reported in 2% of both arms in the open-label, phase 3, noninferiority trial BRIEF TB (NCT01404312).
In the New England Journal of Medicine (2019 Mar 14;380[11]:1001-11), 3,000 patients with HIV were randomized to receive either 1 month of rifapentine/isoniazid or 9 months of isoniazid monotherapy for prevention of tuberculosis. Although safety was also similar between arms, the completion rate was significantly higher in the combination treatment arm, compared with the monotherapy arm (97% vs. 90%; P less than .001).
We covered this story at the annual Conference on Retroviruses & Opportunistic Infections. See our coverage at the link below.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Bempedoic acid safely dropped LDL, now seeks FDA approval
Based on its performance, bempedoic acid seems on track for agency approval.
Aside from demonstrating safety, the efficacy goal of the CLEAR Harmony (Evaluation of Long-Term Safety and Tolerability of ETC-1002 in High-Risk Patients With Hyperlipidemia and High CV Risk) trial was to cut LDL cholesterol as an add-on to maximally tolerated statin treatment, as well as discretionary use of other lipid-lowering agents in patients with atherosclerotic cardiovascular disease.
That goal appeared to be met by the CLEAR Harmony results, as well as the results from four other studies that contributed data to the approval application filed for bempedoic acid. A clinical outcomes study is underway with more than 12,000 patients aimed at showing incremental clinical benefit from bempedoic acid on top of approved treatments for lowering LDL cholesterol, but those results are not expected until 2022. Until then, the application’s data focus on the evidence that the new drug safely lowers LDL cholesterol when used on top of existing treatments.
“Bempedoic acid provides an additional therapeutic option to safely lower LDL cholesterol in patients with high risk for atherosclerotic cardiovascular disease already treated with a statin,” Kausik K. Ray, MD, said when he first reported these findings during the annual meeting of the European Society of Cardiology last August in Munich. The same results appeared in a newly released article (N Engl J Med. 2019 Mar 14;380[11]:1022-32).
Maximum recommended statin dosages exist because, for every doubling of the statin dosage, LDL cholesterol levels drop by about another 6%, but adverse events grow more common. Because bempedoic acid and other ATP citrate lyase inhibitors work via the same metabolic pathway as that of statins – HMG CoA reductase inhibitors – “we did not know whether squeezing another 20% of LDL cholesterol lowering would be tolerated. What we have clearly and reassuringly shown is it is well tolerated,” said Dr. Ray, a cardiologist and professor of public health at Imperial College, London.
The CLEAR Harmony results showed in 2,230 randomized patients that treatment with bempedoic acid cut LDL cholesterol levels by an average of 18% more compared with placebo in the intention-to-treat analysis, and by 20% in an on-treatment analysis.
By seeking U.S. marketing approval for bempedoic acid based on LDL-lowering and safety only, but without data on clinical endpoints, the company developing the drug is following a path already established by several other lipid-lowering drug classes.
“Statins, ezetimibe and the PCSK9 inhibitors were all approved based on clinical trial results that showed LDL-cholesterol reductions with what the FDA judged to be acceptable safety, but without results from completed outcomes trials,” Christie M. Ballantyne, MD, a coauthor of the CLEAR Harmony study and professor and chief of cardiology at Baylor College of Medicine in Houston, said in an interview.
Stephen Nicholls, MD, professor of cardiology at Monash University in Melbourne, added in an interview that “the precedent has been to conditionally approve LDL cholesterol–lowering drugs at this stage of development, based on the large body of evidence demonstrating that LDL cholesterol–lowering consistently produces clinical benefit.”
To gain more confidence that treatment with bempedoic acid exerts a benefit to patients prior to availability of clinical-outcome results, the developing company sponsored a genetic and epidemiologic study that looked at the association between naturally occurring mutations that dampen the activity of ATP citrate lyase, an enzyme that metabolically sits just upstream from HMG CoA reductase, the enzyme that statins target. Dr. Nicholls, Dr. Ray, and several other collaborators devised “genetic scores” that took into account variants of the gene that codes for ATP citrate lyase, and a separate score for HMG CoA reductase variants. Each score estimated a person’s activity for each of these enzymes. The researchers then used the scores to classify enzymatic activity in more than 650,000 people in several different databases, including more than 100,000 people with a history of major cardiovascular events.
The results showed that “genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action. They were associated with nearly identical effects on the risk of cardiovascular disease and cancer per unit decrease in the LDL cholesterol level,” the investigators said in an article published concurrently with the CLEAR Harmony results (N Engl J Med. 2019 March 14;380[11]:1033-42).
This finding “strengthens the likelihood that an outcome trial will show benefits,” Steven E. Nissen, MD, chairman of cardiovascular medicine at the Cleveland Clinic Foundation, and a lead investigator in the bempedoic acid outcomes trial, CLEAR Outcomes, said in an interview.
Dr. Nicholls noted that, on the basis of the genetic study’s results “it would seem very reasonable to extrapolate and expect that bempedoic acid should reduce cardiovascular events.”
The data reported by Dr. Ray and his associates from the CLEAR Harmony trial showed that overall, the adverse-event rates associated with bempedoic acid treatment were similar to the rates seen in patients who received placebo. But Michael V. Holmes, MD, who wrote an editorial that accompanied both reports, highlighted a few differences in the adverse event rates that concerned him. These were a statistically significant higher rate of gout and blood uric acid levels on bempedoic acid treatment compared with controls, a significantly higher rate of discontinuations because of adverse events, and nominally higher rates of death, cardiovascular death, and heart failure hospitalization, said Dr. Holmes, an epidemiologist at the University of Oxford, England.
But Dr. Nissen said that “the safety ‘signals’ involve very small numbers of patients and do not raise major concerns. The increases in gout and uric acid are worth noting, but are less weighty than the disease the drug is intended to treat: major cardiovascular events.”
Dr. Nichols added that “the large cardiovascular outcome trial will provide the opportunity to further study safety and potential side effects. I’m hesitant to overinterpret event data from a relatively small clinical trial that primarily focused on the lipid effects.”
Despite recent success of the PCSK9 inhibitors as an add-on or substitute for statin treatment of elevated LDL cholesterol, the cost of the drugs in this class has made the cardiovascular disease community eager for another alternative to statins.
“The PCSK9 inhibitors are extremely effective, but uptake has been slow due to their cost and formulary restrictions,” said Dr. Ballantyne. “Many high-risk patients continue to have persistently elevated levels of LDL cholesterol.” Bempedoic acid is “a new therapy that can help people who continue to have elevations of LDL cholesterol despite current therapies.”
CLEAR Harmony and the genetic study were sponsored by Esperion, the company developing bempedoic acid. Dr. Ray has been a consultant to several drug companies but had no other financial relationship to Esperion. Dr. Ballantyne and Dr. Nicholls have been consultants to and have received research funding from Esperion and from several other companies. Dr. Nissen is leading an Esperion-sponsored study but has no financial relationships with the company or with other companies.
SOURCEs: N Engl J Med. 2019 Mar 14;380[11]:1022-32 and 1033-42.
The primary endpoint of bempedoic acid’s safety, assessed by means of the incidence of adverse events and changes in safety laboratory variables during the CLEAR Harmony trial, did not differ meaningfully between the bempedoic acid group and the placebo group. However, patients in the bempedoic acid group had an excess risk of adverse events leading to discontinuation of the blinded trial regimen, an excess risk of gout, and higher blood concentrations of uric acid than those in the placebo group.
In further analyses of nonprimary and secondary endpoints, there were additional potentially troubling signals, although the 95% confidence intervals were wide: 0.9% of the patients treated with bempedoic acid died, compared with 0.3% of those in the placebo group; 0.4% and 0.1%, respectively, died from adjudicated cardiovascular disease; and 0.6% and 0.1%, respectively, were hospitalized for heart failure. Although the findings are potentially alarming, the imprecision that is reflected in the 95% confidence intervals renders the relative risk values virtually meaningless, but can these effect estimates be unseen?
The cumulative data from randomized treatment trials and from studies of human genetics say that, for a given reduction in the LDL cholesterol level, drugs that inhibit ATP citrate lyase and do not have off-target effects ought to yield reductions in the risk of cardiovascular disease that are similar to those achieved with statins. However, analysis of endpoints in treatment trials for which there is marginal statistical power is best avoided. Fortunately for bempedoic acid, an ongoing phase 3, cardiovascular outcome trial will provide additional information.
More broadly, the genetic characterization of drug targets is set to revolutionize how we develop medicines.
Michael V. Holmes, MD, is an epidemiologist at the University of Oxford, England. He made these comments in a published editorial (N Engl J Med. 2019 Mar 14;380[11]:1076-9). He had no disclosures.
The primary endpoint of bempedoic acid’s safety, assessed by means of the incidence of adverse events and changes in safety laboratory variables during the CLEAR Harmony trial, did not differ meaningfully between the bempedoic acid group and the placebo group. However, patients in the bempedoic acid group had an excess risk of adverse events leading to discontinuation of the blinded trial regimen, an excess risk of gout, and higher blood concentrations of uric acid than those in the placebo group.
In further analyses of nonprimary and secondary endpoints, there were additional potentially troubling signals, although the 95% confidence intervals were wide: 0.9% of the patients treated with bempedoic acid died, compared with 0.3% of those in the placebo group; 0.4% and 0.1%, respectively, died from adjudicated cardiovascular disease; and 0.6% and 0.1%, respectively, were hospitalized for heart failure. Although the findings are potentially alarming, the imprecision that is reflected in the 95% confidence intervals renders the relative risk values virtually meaningless, but can these effect estimates be unseen?
The cumulative data from randomized treatment trials and from studies of human genetics say that, for a given reduction in the LDL cholesterol level, drugs that inhibit ATP citrate lyase and do not have off-target effects ought to yield reductions in the risk of cardiovascular disease that are similar to those achieved with statins. However, analysis of endpoints in treatment trials for which there is marginal statistical power is best avoided. Fortunately for bempedoic acid, an ongoing phase 3, cardiovascular outcome trial will provide additional information.
More broadly, the genetic characterization of drug targets is set to revolutionize how we develop medicines.
Michael V. Holmes, MD, is an epidemiologist at the University of Oxford, England. He made these comments in a published editorial (N Engl J Med. 2019 Mar 14;380[11]:1076-9). He had no disclosures.
The primary endpoint of bempedoic acid’s safety, assessed by means of the incidence of adverse events and changes in safety laboratory variables during the CLEAR Harmony trial, did not differ meaningfully between the bempedoic acid group and the placebo group. However, patients in the bempedoic acid group had an excess risk of adverse events leading to discontinuation of the blinded trial regimen, an excess risk of gout, and higher blood concentrations of uric acid than those in the placebo group.
In further analyses of nonprimary and secondary endpoints, there were additional potentially troubling signals, although the 95% confidence intervals were wide: 0.9% of the patients treated with bempedoic acid died, compared with 0.3% of those in the placebo group; 0.4% and 0.1%, respectively, died from adjudicated cardiovascular disease; and 0.6% and 0.1%, respectively, were hospitalized for heart failure. Although the findings are potentially alarming, the imprecision that is reflected in the 95% confidence intervals renders the relative risk values virtually meaningless, but can these effect estimates be unseen?
The cumulative data from randomized treatment trials and from studies of human genetics say that, for a given reduction in the LDL cholesterol level, drugs that inhibit ATP citrate lyase and do not have off-target effects ought to yield reductions in the risk of cardiovascular disease that are similar to those achieved with statins. However, analysis of endpoints in treatment trials for which there is marginal statistical power is best avoided. Fortunately for bempedoic acid, an ongoing phase 3, cardiovascular outcome trial will provide additional information.
More broadly, the genetic characterization of drug targets is set to revolutionize how we develop medicines.
Michael V. Holmes, MD, is an epidemiologist at the University of Oxford, England. He made these comments in a published editorial (N Engl J Med. 2019 Mar 14;380[11]:1076-9). He had no disclosures.
Based on its performance, bempedoic acid seems on track for agency approval.
Aside from demonstrating safety, the efficacy goal of the CLEAR Harmony (Evaluation of Long-Term Safety and Tolerability of ETC-1002 in High-Risk Patients With Hyperlipidemia and High CV Risk) trial was to cut LDL cholesterol as an add-on to maximally tolerated statin treatment, as well as discretionary use of other lipid-lowering agents in patients with atherosclerotic cardiovascular disease.
That goal appeared to be met by the CLEAR Harmony results, as well as the results from four other studies that contributed data to the approval application filed for bempedoic acid. A clinical outcomes study is underway with more than 12,000 patients aimed at showing incremental clinical benefit from bempedoic acid on top of approved treatments for lowering LDL cholesterol, but those results are not expected until 2022. Until then, the application’s data focus on the evidence that the new drug safely lowers LDL cholesterol when used on top of existing treatments.
“Bempedoic acid provides an additional therapeutic option to safely lower LDL cholesterol in patients with high risk for atherosclerotic cardiovascular disease already treated with a statin,” Kausik K. Ray, MD, said when he first reported these findings during the annual meeting of the European Society of Cardiology last August in Munich. The same results appeared in a newly released article (N Engl J Med. 2019 Mar 14;380[11]:1022-32).
Maximum recommended statin dosages exist because, for every doubling of the statin dosage, LDL cholesterol levels drop by about another 6%, but adverse events grow more common. Because bempedoic acid and other ATP citrate lyase inhibitors work via the same metabolic pathway as that of statins – HMG CoA reductase inhibitors – “we did not know whether squeezing another 20% of LDL cholesterol lowering would be tolerated. What we have clearly and reassuringly shown is it is well tolerated,” said Dr. Ray, a cardiologist and professor of public health at Imperial College, London.
The CLEAR Harmony results showed in 2,230 randomized patients that treatment with bempedoic acid cut LDL cholesterol levels by an average of 18% more compared with placebo in the intention-to-treat analysis, and by 20% in an on-treatment analysis.
By seeking U.S. marketing approval for bempedoic acid based on LDL-lowering and safety only, but without data on clinical endpoints, the company developing the drug is following a path already established by several other lipid-lowering drug classes.
“Statins, ezetimibe and the PCSK9 inhibitors were all approved based on clinical trial results that showed LDL-cholesterol reductions with what the FDA judged to be acceptable safety, but without results from completed outcomes trials,” Christie M. Ballantyne, MD, a coauthor of the CLEAR Harmony study and professor and chief of cardiology at Baylor College of Medicine in Houston, said in an interview.
Stephen Nicholls, MD, professor of cardiology at Monash University in Melbourne, added in an interview that “the precedent has been to conditionally approve LDL cholesterol–lowering drugs at this stage of development, based on the large body of evidence demonstrating that LDL cholesterol–lowering consistently produces clinical benefit.”
To gain more confidence that treatment with bempedoic acid exerts a benefit to patients prior to availability of clinical-outcome results, the developing company sponsored a genetic and epidemiologic study that looked at the association between naturally occurring mutations that dampen the activity of ATP citrate lyase, an enzyme that metabolically sits just upstream from HMG CoA reductase, the enzyme that statins target. Dr. Nicholls, Dr. Ray, and several other collaborators devised “genetic scores” that took into account variants of the gene that codes for ATP citrate lyase, and a separate score for HMG CoA reductase variants. Each score estimated a person’s activity for each of these enzymes. The researchers then used the scores to classify enzymatic activity in more than 650,000 people in several different databases, including more than 100,000 people with a history of major cardiovascular events.
The results showed that “genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action. They were associated with nearly identical effects on the risk of cardiovascular disease and cancer per unit decrease in the LDL cholesterol level,” the investigators said in an article published concurrently with the CLEAR Harmony results (N Engl J Med. 2019 March 14;380[11]:1033-42).
This finding “strengthens the likelihood that an outcome trial will show benefits,” Steven E. Nissen, MD, chairman of cardiovascular medicine at the Cleveland Clinic Foundation, and a lead investigator in the bempedoic acid outcomes trial, CLEAR Outcomes, said in an interview.
Dr. Nicholls noted that, on the basis of the genetic study’s results “it would seem very reasonable to extrapolate and expect that bempedoic acid should reduce cardiovascular events.”
The data reported by Dr. Ray and his associates from the CLEAR Harmony trial showed that overall, the adverse-event rates associated with bempedoic acid treatment were similar to the rates seen in patients who received placebo. But Michael V. Holmes, MD, who wrote an editorial that accompanied both reports, highlighted a few differences in the adverse event rates that concerned him. These were a statistically significant higher rate of gout and blood uric acid levels on bempedoic acid treatment compared with controls, a significantly higher rate of discontinuations because of adverse events, and nominally higher rates of death, cardiovascular death, and heart failure hospitalization, said Dr. Holmes, an epidemiologist at the University of Oxford, England.
But Dr. Nissen said that “the safety ‘signals’ involve very small numbers of patients and do not raise major concerns. The increases in gout and uric acid are worth noting, but are less weighty than the disease the drug is intended to treat: major cardiovascular events.”
Dr. Nichols added that “the large cardiovascular outcome trial will provide the opportunity to further study safety and potential side effects. I’m hesitant to overinterpret event data from a relatively small clinical trial that primarily focused on the lipid effects.”
Despite recent success of the PCSK9 inhibitors as an add-on or substitute for statin treatment of elevated LDL cholesterol, the cost of the drugs in this class has made the cardiovascular disease community eager for another alternative to statins.
“The PCSK9 inhibitors are extremely effective, but uptake has been slow due to their cost and formulary restrictions,” said Dr. Ballantyne. “Many high-risk patients continue to have persistently elevated levels of LDL cholesterol.” Bempedoic acid is “a new therapy that can help people who continue to have elevations of LDL cholesterol despite current therapies.”
CLEAR Harmony and the genetic study were sponsored by Esperion, the company developing bempedoic acid. Dr. Ray has been a consultant to several drug companies but had no other financial relationship to Esperion. Dr. Ballantyne and Dr. Nicholls have been consultants to and have received research funding from Esperion and from several other companies. Dr. Nissen is leading an Esperion-sponsored study but has no financial relationships with the company or with other companies.
SOURCEs: N Engl J Med. 2019 Mar 14;380[11]:1022-32 and 1033-42.
Based on its performance, bempedoic acid seems on track for agency approval.
Aside from demonstrating safety, the efficacy goal of the CLEAR Harmony (Evaluation of Long-Term Safety and Tolerability of ETC-1002 in High-Risk Patients With Hyperlipidemia and High CV Risk) trial was to cut LDL cholesterol as an add-on to maximally tolerated statin treatment, as well as discretionary use of other lipid-lowering agents in patients with atherosclerotic cardiovascular disease.
That goal appeared to be met by the CLEAR Harmony results, as well as the results from four other studies that contributed data to the approval application filed for bempedoic acid. A clinical outcomes study is underway with more than 12,000 patients aimed at showing incremental clinical benefit from bempedoic acid on top of approved treatments for lowering LDL cholesterol, but those results are not expected until 2022. Until then, the application’s data focus on the evidence that the new drug safely lowers LDL cholesterol when used on top of existing treatments.
“Bempedoic acid provides an additional therapeutic option to safely lower LDL cholesterol in patients with high risk for atherosclerotic cardiovascular disease already treated with a statin,” Kausik K. Ray, MD, said when he first reported these findings during the annual meeting of the European Society of Cardiology last August in Munich. The same results appeared in a newly released article (N Engl J Med. 2019 Mar 14;380[11]:1022-32).
Maximum recommended statin dosages exist because, for every doubling of the statin dosage, LDL cholesterol levels drop by about another 6%, but adverse events grow more common. Because bempedoic acid and other ATP citrate lyase inhibitors work via the same metabolic pathway as that of statins – HMG CoA reductase inhibitors – “we did not know whether squeezing another 20% of LDL cholesterol lowering would be tolerated. What we have clearly and reassuringly shown is it is well tolerated,” said Dr. Ray, a cardiologist and professor of public health at Imperial College, London.
The CLEAR Harmony results showed in 2,230 randomized patients that treatment with bempedoic acid cut LDL cholesterol levels by an average of 18% more compared with placebo in the intention-to-treat analysis, and by 20% in an on-treatment analysis.
By seeking U.S. marketing approval for bempedoic acid based on LDL-lowering and safety only, but without data on clinical endpoints, the company developing the drug is following a path already established by several other lipid-lowering drug classes.
“Statins, ezetimibe and the PCSK9 inhibitors were all approved based on clinical trial results that showed LDL-cholesterol reductions with what the FDA judged to be acceptable safety, but without results from completed outcomes trials,” Christie M. Ballantyne, MD, a coauthor of the CLEAR Harmony study and professor and chief of cardiology at Baylor College of Medicine in Houston, said in an interview.
Stephen Nicholls, MD, professor of cardiology at Monash University in Melbourne, added in an interview that “the precedent has been to conditionally approve LDL cholesterol–lowering drugs at this stage of development, based on the large body of evidence demonstrating that LDL cholesterol–lowering consistently produces clinical benefit.”
To gain more confidence that treatment with bempedoic acid exerts a benefit to patients prior to availability of clinical-outcome results, the developing company sponsored a genetic and epidemiologic study that looked at the association between naturally occurring mutations that dampen the activity of ATP citrate lyase, an enzyme that metabolically sits just upstream from HMG CoA reductase, the enzyme that statins target. Dr. Nicholls, Dr. Ray, and several other collaborators devised “genetic scores” that took into account variants of the gene that codes for ATP citrate lyase, and a separate score for HMG CoA reductase variants. Each score estimated a person’s activity for each of these enzymes. The researchers then used the scores to classify enzymatic activity in more than 650,000 people in several different databases, including more than 100,000 people with a history of major cardiovascular events.
The results showed that “genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action. They were associated with nearly identical effects on the risk of cardiovascular disease and cancer per unit decrease in the LDL cholesterol level,” the investigators said in an article published concurrently with the CLEAR Harmony results (N Engl J Med. 2019 March 14;380[11]:1033-42).
This finding “strengthens the likelihood that an outcome trial will show benefits,” Steven E. Nissen, MD, chairman of cardiovascular medicine at the Cleveland Clinic Foundation, and a lead investigator in the bempedoic acid outcomes trial, CLEAR Outcomes, said in an interview.
Dr. Nicholls noted that, on the basis of the genetic study’s results “it would seem very reasonable to extrapolate and expect that bempedoic acid should reduce cardiovascular events.”
The data reported by Dr. Ray and his associates from the CLEAR Harmony trial showed that overall, the adverse-event rates associated with bempedoic acid treatment were similar to the rates seen in patients who received placebo. But Michael V. Holmes, MD, who wrote an editorial that accompanied both reports, highlighted a few differences in the adverse event rates that concerned him. These were a statistically significant higher rate of gout and blood uric acid levels on bempedoic acid treatment compared with controls, a significantly higher rate of discontinuations because of adverse events, and nominally higher rates of death, cardiovascular death, and heart failure hospitalization, said Dr. Holmes, an epidemiologist at the University of Oxford, England.
But Dr. Nissen said that “the safety ‘signals’ involve very small numbers of patients and do not raise major concerns. The increases in gout and uric acid are worth noting, but are less weighty than the disease the drug is intended to treat: major cardiovascular events.”
Dr. Nichols added that “the large cardiovascular outcome trial will provide the opportunity to further study safety and potential side effects. I’m hesitant to overinterpret event data from a relatively small clinical trial that primarily focused on the lipid effects.”
Despite recent success of the PCSK9 inhibitors as an add-on or substitute for statin treatment of elevated LDL cholesterol, the cost of the drugs in this class has made the cardiovascular disease community eager for another alternative to statins.
“The PCSK9 inhibitors are extremely effective, but uptake has been slow due to their cost and formulary restrictions,” said Dr. Ballantyne. “Many high-risk patients continue to have persistently elevated levels of LDL cholesterol.” Bempedoic acid is “a new therapy that can help people who continue to have elevations of LDL cholesterol despite current therapies.”
CLEAR Harmony and the genetic study were sponsored by Esperion, the company developing bempedoic acid. Dr. Ray has been a consultant to several drug companies but had no other financial relationship to Esperion. Dr. Ballantyne and Dr. Nicholls have been consultants to and have received research funding from Esperion and from several other companies. Dr. Nissen is leading an Esperion-sponsored study but has no financial relationships with the company or with other companies.
SOURCEs: N Engl J Med. 2019 Mar 14;380[11]:1022-32 and 1033-42.
Key clinical point: Bempedoic acid safely lowed LDL cholesterol levels in a pivotal trial.
Major finding: In the intention-to-treat analysis, bempedoic acid cut LDL cholesterol by 18%; by 20% in an on-treatment analysis.
Study details: CLEAR Harmony, a multicenter, randomized trial with 2,230 patients.
Disclosures: CLEAR Harmony and the genetic study were sponsored by Esperion, the company developing bempedoic acid. Dr. Ray has been a consultant to several drug companies but had no other financial relationship to Esperion. Dr. Ballantyne and Dr. Nicholls have been consultants to and have received research funding from Esperion and from several other companies. Dr. Nissen is leading an Esperion-sponsored study but has no financial relationships with the company or with other companies.
Sources: N Engl J Med. 2019 Mar 14;380[11]:1022-32 and 1033-42.
Endovascular device sustains blood pressure control after 3 years
WASHINGTON – As a result of remarkably sustained antihypertensive effect, interest is intensifying in the potential for a pivotal trial to associate a novel endovascular device with unprecedented blood pressure control in patients with treatment-resistant hypertension, according to an update presented at CRT 2019, sponsored by MedStar Heart & Vascular Institute.
With up to 3 years of follow-up, “systolic blood pressures have remained persistently reduced by as much as 24 mm Hg,” reported John P. Reilly, MD, an interventional cardiologist in Southampton, N.Y., who presented follow-up data for some of those enrolled in the first-in-human study of this device.
When the stent-like device is placed in the carotid artery, it alters its geometric shape, which increases pulsatile wall strain. The increase on wall strain alters an afferent signaling loop controlled by carotid baroreceptors that inhibits sympathetic outflow to lower blood pressure.
In the proof-of-principle, first-in-human CALM study, 47 patients were implanted with the device (MobiusHD, Vascular Dynamics). The initial study enrolled 30 subjects in Europe and 17 in the United States. Initial findings in the cohort of European patients, which included a mean 21–mm Hg reduction in systolic blood pressure and a 12–mm Hg reduction in diastolic blood pressure measured by ambulatory monitoring at 6 months, were published in the Lancet (2017 Dec 16;390[10113]:2655-661).
The patients enrolled in the proof-of-principle CALM trial were required to have highly-treatment-resistant hypertension, defined as a systolic blood pressure greater than or equal to 160 mm Hg despite at least three antihypertensive medications. The average number of medications was 4.4, according to Dr. Reilly. The mean blood pressure at entry was 165/98 mm Hg. Nearly 20% had previously undergone renal denervation.
The device was successfully deployed in all of the patients who participated in the open-label CALM study. Most of the 10 serious adverse events were related to hypotension, according to Dr. Reilly. Others included a wound infection and a case of intermittent claudication. Two instances of neurologic complaints, such as numbness and weakness, experienced within a day of device placement were considered potential transient ischemic attacks, but these resolved completely and no defects were observed on imaging.
In an update on CALM, Dr. Reilly reported that the large reductions in blood pressure previously reported at 6 months have been sustained. Follow-up is approximately 3 years in most patients, and the reductions previously reported have persisted in responders. When a clinically significant response is defined as a 10–mm Hg or more reduction in office blood pressure or 5–mm Hg or more reduction in ambulatory blood pressure, 75% of patients enrolled are still responding, but the more important point is that there has been no substantial reduction in blood pressure control over time in responders, according to Dr. Reilly.
When patients were stratified by a pulse pressure of greater or less than 70 mm Hg at study entry, response rates have been similar, he added.
The long-term responses are significant because there was concern about tachyphylaxis. In fact, coronary stents also produce a reduction in blood pressure immediately after placement that is likely caused by the same effect, but that effect “peters out in a day or 2,” noted Dr. Reilly. As opposed to the round shape of coronary stents, the rectangular shape of the novel device produces “an increase in the perceived strain on the carotid body” that does not appear to diminish over time.
CALM-2, which is designed to be a pivotal trial to support regulatory approval of the device, began enrolling in September 2018. An enrollment of 300 patients with treatment-resistant hypertension is planned. Participants will be randomized to receive the device or a sham procedure consisting of a carotid artery angiogram, according to Dr. Reilly. Although the initial CALM trial was small, open label, and conducted without a control, the persistent benefit over extended follow-up is driving excitement about the potential of this device.
“These are some of the greatest sustained reductions in ambulatory blood pressure we have ever seen,” according to Vasilios Papademetriou, MD, PhD, a professor of medicine at Georgetown University, Washington. Impressed by undiminished blood pressure control observed so far, he characterized the promise of this device as “very compelling.”
Dr. Reilly disclosed that he was a stockholder in Johnson & Johnson.
WASHINGTON – As a result of remarkably sustained antihypertensive effect, interest is intensifying in the potential for a pivotal trial to associate a novel endovascular device with unprecedented blood pressure control in patients with treatment-resistant hypertension, according to an update presented at CRT 2019, sponsored by MedStar Heart & Vascular Institute.
With up to 3 years of follow-up, “systolic blood pressures have remained persistently reduced by as much as 24 mm Hg,” reported John P. Reilly, MD, an interventional cardiologist in Southampton, N.Y., who presented follow-up data for some of those enrolled in the first-in-human study of this device.
When the stent-like device is placed in the carotid artery, it alters its geometric shape, which increases pulsatile wall strain. The increase on wall strain alters an afferent signaling loop controlled by carotid baroreceptors that inhibits sympathetic outflow to lower blood pressure.
In the proof-of-principle, first-in-human CALM study, 47 patients were implanted with the device (MobiusHD, Vascular Dynamics). The initial study enrolled 30 subjects in Europe and 17 in the United States. Initial findings in the cohort of European patients, which included a mean 21–mm Hg reduction in systolic blood pressure and a 12–mm Hg reduction in diastolic blood pressure measured by ambulatory monitoring at 6 months, were published in the Lancet (2017 Dec 16;390[10113]:2655-661).
The patients enrolled in the proof-of-principle CALM trial were required to have highly-treatment-resistant hypertension, defined as a systolic blood pressure greater than or equal to 160 mm Hg despite at least three antihypertensive medications. The average number of medications was 4.4, according to Dr. Reilly. The mean blood pressure at entry was 165/98 mm Hg. Nearly 20% had previously undergone renal denervation.
The device was successfully deployed in all of the patients who participated in the open-label CALM study. Most of the 10 serious adverse events were related to hypotension, according to Dr. Reilly. Others included a wound infection and a case of intermittent claudication. Two instances of neurologic complaints, such as numbness and weakness, experienced within a day of device placement were considered potential transient ischemic attacks, but these resolved completely and no defects were observed on imaging.
In an update on CALM, Dr. Reilly reported that the large reductions in blood pressure previously reported at 6 months have been sustained. Follow-up is approximately 3 years in most patients, and the reductions previously reported have persisted in responders. When a clinically significant response is defined as a 10–mm Hg or more reduction in office blood pressure or 5–mm Hg or more reduction in ambulatory blood pressure, 75% of patients enrolled are still responding, but the more important point is that there has been no substantial reduction in blood pressure control over time in responders, according to Dr. Reilly.
When patients were stratified by a pulse pressure of greater or less than 70 mm Hg at study entry, response rates have been similar, he added.
The long-term responses are significant because there was concern about tachyphylaxis. In fact, coronary stents also produce a reduction in blood pressure immediately after placement that is likely caused by the same effect, but that effect “peters out in a day or 2,” noted Dr. Reilly. As opposed to the round shape of coronary stents, the rectangular shape of the novel device produces “an increase in the perceived strain on the carotid body” that does not appear to diminish over time.
CALM-2, which is designed to be a pivotal trial to support regulatory approval of the device, began enrolling in September 2018. An enrollment of 300 patients with treatment-resistant hypertension is planned. Participants will be randomized to receive the device or a sham procedure consisting of a carotid artery angiogram, according to Dr. Reilly. Although the initial CALM trial was small, open label, and conducted without a control, the persistent benefit over extended follow-up is driving excitement about the potential of this device.
“These are some of the greatest sustained reductions in ambulatory blood pressure we have ever seen,” according to Vasilios Papademetriou, MD, PhD, a professor of medicine at Georgetown University, Washington. Impressed by undiminished blood pressure control observed so far, he characterized the promise of this device as “very compelling.”
Dr. Reilly disclosed that he was a stockholder in Johnson & Johnson.
WASHINGTON – As a result of remarkably sustained antihypertensive effect, interest is intensifying in the potential for a pivotal trial to associate a novel endovascular device with unprecedented blood pressure control in patients with treatment-resistant hypertension, according to an update presented at CRT 2019, sponsored by MedStar Heart & Vascular Institute.
With up to 3 years of follow-up, “systolic blood pressures have remained persistently reduced by as much as 24 mm Hg,” reported John P. Reilly, MD, an interventional cardiologist in Southampton, N.Y., who presented follow-up data for some of those enrolled in the first-in-human study of this device.
When the stent-like device is placed in the carotid artery, it alters its geometric shape, which increases pulsatile wall strain. The increase on wall strain alters an afferent signaling loop controlled by carotid baroreceptors that inhibits sympathetic outflow to lower blood pressure.
In the proof-of-principle, first-in-human CALM study, 47 patients were implanted with the device (MobiusHD, Vascular Dynamics). The initial study enrolled 30 subjects in Europe and 17 in the United States. Initial findings in the cohort of European patients, which included a mean 21–mm Hg reduction in systolic blood pressure and a 12–mm Hg reduction in diastolic blood pressure measured by ambulatory monitoring at 6 months, were published in the Lancet (2017 Dec 16;390[10113]:2655-661).
The patients enrolled in the proof-of-principle CALM trial were required to have highly-treatment-resistant hypertension, defined as a systolic blood pressure greater than or equal to 160 mm Hg despite at least three antihypertensive medications. The average number of medications was 4.4, according to Dr. Reilly. The mean blood pressure at entry was 165/98 mm Hg. Nearly 20% had previously undergone renal denervation.
The device was successfully deployed in all of the patients who participated in the open-label CALM study. Most of the 10 serious adverse events were related to hypotension, according to Dr. Reilly. Others included a wound infection and a case of intermittent claudication. Two instances of neurologic complaints, such as numbness and weakness, experienced within a day of device placement were considered potential transient ischemic attacks, but these resolved completely and no defects were observed on imaging.
In an update on CALM, Dr. Reilly reported that the large reductions in blood pressure previously reported at 6 months have been sustained. Follow-up is approximately 3 years in most patients, and the reductions previously reported have persisted in responders. When a clinically significant response is defined as a 10–mm Hg or more reduction in office blood pressure or 5–mm Hg or more reduction in ambulatory blood pressure, 75% of patients enrolled are still responding, but the more important point is that there has been no substantial reduction in blood pressure control over time in responders, according to Dr. Reilly.
When patients were stratified by a pulse pressure of greater or less than 70 mm Hg at study entry, response rates have been similar, he added.
The long-term responses are significant because there was concern about tachyphylaxis. In fact, coronary stents also produce a reduction in blood pressure immediately after placement that is likely caused by the same effect, but that effect “peters out in a day or 2,” noted Dr. Reilly. As opposed to the round shape of coronary stents, the rectangular shape of the novel device produces “an increase in the perceived strain on the carotid body” that does not appear to diminish over time.
CALM-2, which is designed to be a pivotal trial to support regulatory approval of the device, began enrolling in September 2018. An enrollment of 300 patients with treatment-resistant hypertension is planned. Participants will be randomized to receive the device or a sham procedure consisting of a carotid artery angiogram, according to Dr. Reilly. Although the initial CALM trial was small, open label, and conducted without a control, the persistent benefit over extended follow-up is driving excitement about the potential of this device.
“These are some of the greatest sustained reductions in ambulatory blood pressure we have ever seen,” according to Vasilios Papademetriou, MD, PhD, a professor of medicine at Georgetown University, Washington. Impressed by undiminished blood pressure control observed so far, he characterized the promise of this device as “very compelling.”
Dr. Reilly disclosed that he was a stockholder in Johnson & Johnson.
REPORTING FROM CRT 2019
Weekly turoctocog alfa pegol is feasible for hemophilia A
FROM HAEMOPHILIA
Some patients with severe hemophilia A can be managed with weekly injections of the recombinant factor VIII (rFVIII) product turoctocog alfa pegol (N8-GP), based on results from an extension of the pathfinder 2 trial.
In patients who had two or fewer bleeding episodes during the preceding 6 months, N8-GP was effective for prophylaxis and treating bleeding episodes without causing inhibitor development, reported lead author Nicola Curry, MD, of the Oxford (England) Haemophilia and Thrombosis Centre at Churchill Hospital and her colleagues.
The trial exemplifies an ongoing effort to reduce frequency of prophylaxis in hemophilia A.
N8-GP, given every 4 days (or twice weekly in children), was approved by the Food and Drug Administration in February 2019; however, the investigators hypothesized that dose frequency could be stepped down in those who responded well to initial treatment.
“Many patients struggle to integrate prophylactic schedules into their daily lives, leading to missed injections and increased bleeding episodes,” the investigators wrote in a Haemophilia. “Therefore, prophylactic strategies offering effective haemostatic coverage with more convenient administration schedules are needed.”
To this end, the investigators identified 55 patients (at least 12 years old) from the pathfinder 2 trial who had two or fewer bleeding episodes during the preceding 6 months. From this group, 17 patients continued to receive 50 IU/kg of N8-GP every 4 days, as they had done during the main trial, while 38 patients received a higher dose – 75 IU/kg – every 7 days.
When necessary, N8-GP was used to treat bleeding episodes. Primary coendpoints were immunogenicity and efficacy, while all secondary endpoints were safety measures.
For both cohorts, median annualized bleeding rate (ABR) was 0.00 days, and greater than 50% of patients experienced no bleeds (53% every 4 days vs. 58% weekly). No inhibitors developed during the extension phase of the trial.
Along with strong support for weekly prophylaxis, N8-GP demonstrated efficiency in treating bleeding episodes; 87.5% of episodes were controlled with just one injection. This rate increased to 94.7% when including two or fewer injections.
During the study, 108 adverse events were reported in 65.5% of patients, although almost all were mild or moderate in severity, and unrelated to N8-GP. Five adverse events in five patients were related to treatment, including rash, headache, purpura, increased aspartate aminotransferase, and thrombocytopenia. No thromboembolic events were reported.
“These findings suggest that weekly N8-GP may provide effective prophylaxis with a reduced treatment burden for a selected subset of low-bleeding patients with severe haemophilia A,” the investigators wrote.
The study was funded by Novo Nordisk. The investigators reported financial relationships with Bayer, CSL, Novo Nordisk, Octapharma, Genentech, Shire, and others.
SOURCE: Curry N et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13712.
FROM HAEMOPHILIA
Some patients with severe hemophilia A can be managed with weekly injections of the recombinant factor VIII (rFVIII) product turoctocog alfa pegol (N8-GP), based on results from an extension of the pathfinder 2 trial.
In patients who had two or fewer bleeding episodes during the preceding 6 months, N8-GP was effective for prophylaxis and treating bleeding episodes without causing inhibitor development, reported lead author Nicola Curry, MD, of the Oxford (England) Haemophilia and Thrombosis Centre at Churchill Hospital and her colleagues.
The trial exemplifies an ongoing effort to reduce frequency of prophylaxis in hemophilia A.
N8-GP, given every 4 days (or twice weekly in children), was approved by the Food and Drug Administration in February 2019; however, the investigators hypothesized that dose frequency could be stepped down in those who responded well to initial treatment.
“Many patients struggle to integrate prophylactic schedules into their daily lives, leading to missed injections and increased bleeding episodes,” the investigators wrote in a Haemophilia. “Therefore, prophylactic strategies offering effective haemostatic coverage with more convenient administration schedules are needed.”
To this end, the investigators identified 55 patients (at least 12 years old) from the pathfinder 2 trial who had two or fewer bleeding episodes during the preceding 6 months. From this group, 17 patients continued to receive 50 IU/kg of N8-GP every 4 days, as they had done during the main trial, while 38 patients received a higher dose – 75 IU/kg – every 7 days.
When necessary, N8-GP was used to treat bleeding episodes. Primary coendpoints were immunogenicity and efficacy, while all secondary endpoints were safety measures.
For both cohorts, median annualized bleeding rate (ABR) was 0.00 days, and greater than 50% of patients experienced no bleeds (53% every 4 days vs. 58% weekly). No inhibitors developed during the extension phase of the trial.
Along with strong support for weekly prophylaxis, N8-GP demonstrated efficiency in treating bleeding episodes; 87.5% of episodes were controlled with just one injection. This rate increased to 94.7% when including two or fewer injections.
During the study, 108 adverse events were reported in 65.5% of patients, although almost all were mild or moderate in severity, and unrelated to N8-GP. Five adverse events in five patients were related to treatment, including rash, headache, purpura, increased aspartate aminotransferase, and thrombocytopenia. No thromboembolic events were reported.
“These findings suggest that weekly N8-GP may provide effective prophylaxis with a reduced treatment burden for a selected subset of low-bleeding patients with severe haemophilia A,” the investigators wrote.
The study was funded by Novo Nordisk. The investigators reported financial relationships with Bayer, CSL, Novo Nordisk, Octapharma, Genentech, Shire, and others.
SOURCE: Curry N et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13712.
FROM HAEMOPHILIA
Some patients with severe hemophilia A can be managed with weekly injections of the recombinant factor VIII (rFVIII) product turoctocog alfa pegol (N8-GP), based on results from an extension of the pathfinder 2 trial.
In patients who had two or fewer bleeding episodes during the preceding 6 months, N8-GP was effective for prophylaxis and treating bleeding episodes without causing inhibitor development, reported lead author Nicola Curry, MD, of the Oxford (England) Haemophilia and Thrombosis Centre at Churchill Hospital and her colleagues.
The trial exemplifies an ongoing effort to reduce frequency of prophylaxis in hemophilia A.
N8-GP, given every 4 days (or twice weekly in children), was approved by the Food and Drug Administration in February 2019; however, the investigators hypothesized that dose frequency could be stepped down in those who responded well to initial treatment.
“Many patients struggle to integrate prophylactic schedules into their daily lives, leading to missed injections and increased bleeding episodes,” the investigators wrote in a Haemophilia. “Therefore, prophylactic strategies offering effective haemostatic coverage with more convenient administration schedules are needed.”
To this end, the investigators identified 55 patients (at least 12 years old) from the pathfinder 2 trial who had two or fewer bleeding episodes during the preceding 6 months. From this group, 17 patients continued to receive 50 IU/kg of N8-GP every 4 days, as they had done during the main trial, while 38 patients received a higher dose – 75 IU/kg – every 7 days.
When necessary, N8-GP was used to treat bleeding episodes. Primary coendpoints were immunogenicity and efficacy, while all secondary endpoints were safety measures.
For both cohorts, median annualized bleeding rate (ABR) was 0.00 days, and greater than 50% of patients experienced no bleeds (53% every 4 days vs. 58% weekly). No inhibitors developed during the extension phase of the trial.
Along with strong support for weekly prophylaxis, N8-GP demonstrated efficiency in treating bleeding episodes; 87.5% of episodes were controlled with just one injection. This rate increased to 94.7% when including two or fewer injections.
During the study, 108 adverse events were reported in 65.5% of patients, although almost all were mild or moderate in severity, and unrelated to N8-GP. Five adverse events in five patients were related to treatment, including rash, headache, purpura, increased aspartate aminotransferase, and thrombocytopenia. No thromboembolic events were reported.
“These findings suggest that weekly N8-GP may provide effective prophylaxis with a reduced treatment burden for a selected subset of low-bleeding patients with severe haemophilia A,” the investigators wrote.
The study was funded by Novo Nordisk. The investigators reported financial relationships with Bayer, CSL, Novo Nordisk, Octapharma, Genentech, Shire, and others.
SOURCE: Curry N et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13712.
Bleeding disorders don’t carry increased risks for patients undergoing endoscopy
When managed by an experienced team, patients with inherited bleeding disorders undergoing gastrointestinal endoscopy are not at increased bleeding risk, according to researchers reporting the largest series of such patients to date.
The postendoscopy bleeding rate was less than 1% for the patients in this series, many of whom underwent high-risk procedures or had comorbid conditions putting them at risk of bleeding, the researchers reported.
The rate of colonoscopic postpolypectomy bleeding was less than 5%, which is comparable to the general population rate for such high-risk procedures, said investigator Marcel Tomaszewski, MD, of McGill University, Montreal, and colleagues.
Those results favor the use of the “interdisciplinary approach provided by a hemophilia treatment center, communication between services, and the use of periprocedure prophylaxis including tranexamic acid,” Dr. Tomaszewski and coinvestigators said in their report in Haemophilia.
The study cohort included 48 individuals undergoing a total of 104 endoscopies, which is believed to be the largest case series of digestive endoscopy procedures ever reported in patients with congenital bleeding disorders, according to the researchers.
Hemophilia A and von Willebrand disease were the most common bleeding disorders among these patients, accounting for 49 and 40 of the 104 procedures, respectively. The remaining 17 procedures were performed in patients with factor XI deficiency, hemophilia B, or factor VII deficiency.
Before their endoscopies, patients received bleeding prophylaxis, which consisted of combinations of recombinant factor for hemophilia patients, plasma-derived factor for von Willebrand disease patients, desmopressin, and tranexamic acid.
The rate of bleeding within 72 hours of the endoscopic procedure was 0.96% (95% confidence interval, 0.17%-5.25%). The bleeding rate for hemophilia A patients, regardless of severity, was 2.2%, while the rate for hemophilia B, von Willebrand disease, factor VII deficiency and factor XI deficiency was 0%.
The only endoscopic procedures associated with bleeding were colonoscopy, with a bleeding rate of 2%, and colonoscopy with polypectomy, which had a 4.8% bleeding rate, they added, noting that the reported rate of postpolypectomy bleeding in the general population ranges between 0.3% and 10%.
“The very low incidence of bleeding adverse events limited further planned inferential statistical analysis,” the researchers wrote.
These findings stand in contrast to some previous reports, including one series of 19 patients with hemophilia in which 31% experienced gastrointestinal bleeding after colonoscopy polypectomy, despite preprocedure prophylaxis.
“Our approach, particularly with the addition of tranexamic acid, and our patient mix may explain the lower bleeding rate,” they wrote.
The most common indications for endoscopy in the present report were anemia, colorectal cancer screening or polyp surveillance, upper GI symptoms, and screening or surveillance of varices.
Many patients had conditions that might predispose them to bleeding, investigators said. Most commonly, those conditions included hepatitis C virus infection, cirrhosis, esophageal varices, and previous gastrointestinal bleeding.
Dr. Tomaszewski reported that he had no potential conflicts of interest related to the research. Coauthors reported financial disclosures related to AbbVie, Pfizer, Takeda, Janssen, and others.
SOURCE: Tomaszewski M et al. Haemophilia. 2019 Feb 12. doi: 10.1111/hae.13691
When managed by an experienced team, patients with inherited bleeding disorders undergoing gastrointestinal endoscopy are not at increased bleeding risk, according to researchers reporting the largest series of such patients to date.
The postendoscopy bleeding rate was less than 1% for the patients in this series, many of whom underwent high-risk procedures or had comorbid conditions putting them at risk of bleeding, the researchers reported.
The rate of colonoscopic postpolypectomy bleeding was less than 5%, which is comparable to the general population rate for such high-risk procedures, said investigator Marcel Tomaszewski, MD, of McGill University, Montreal, and colleagues.
Those results favor the use of the “interdisciplinary approach provided by a hemophilia treatment center, communication between services, and the use of periprocedure prophylaxis including tranexamic acid,” Dr. Tomaszewski and coinvestigators said in their report in Haemophilia.
The study cohort included 48 individuals undergoing a total of 104 endoscopies, which is believed to be the largest case series of digestive endoscopy procedures ever reported in patients with congenital bleeding disorders, according to the researchers.
Hemophilia A and von Willebrand disease were the most common bleeding disorders among these patients, accounting for 49 and 40 of the 104 procedures, respectively. The remaining 17 procedures were performed in patients with factor XI deficiency, hemophilia B, or factor VII deficiency.
Before their endoscopies, patients received bleeding prophylaxis, which consisted of combinations of recombinant factor for hemophilia patients, plasma-derived factor for von Willebrand disease patients, desmopressin, and tranexamic acid.
The rate of bleeding within 72 hours of the endoscopic procedure was 0.96% (95% confidence interval, 0.17%-5.25%). The bleeding rate for hemophilia A patients, regardless of severity, was 2.2%, while the rate for hemophilia B, von Willebrand disease, factor VII deficiency and factor XI deficiency was 0%.
The only endoscopic procedures associated with bleeding were colonoscopy, with a bleeding rate of 2%, and colonoscopy with polypectomy, which had a 4.8% bleeding rate, they added, noting that the reported rate of postpolypectomy bleeding in the general population ranges between 0.3% and 10%.
“The very low incidence of bleeding adverse events limited further planned inferential statistical analysis,” the researchers wrote.
These findings stand in contrast to some previous reports, including one series of 19 patients with hemophilia in which 31% experienced gastrointestinal bleeding after colonoscopy polypectomy, despite preprocedure prophylaxis.
“Our approach, particularly with the addition of tranexamic acid, and our patient mix may explain the lower bleeding rate,” they wrote.
The most common indications for endoscopy in the present report were anemia, colorectal cancer screening or polyp surveillance, upper GI symptoms, and screening or surveillance of varices.
Many patients had conditions that might predispose them to bleeding, investigators said. Most commonly, those conditions included hepatitis C virus infection, cirrhosis, esophageal varices, and previous gastrointestinal bleeding.
Dr. Tomaszewski reported that he had no potential conflicts of interest related to the research. Coauthors reported financial disclosures related to AbbVie, Pfizer, Takeda, Janssen, and others.
SOURCE: Tomaszewski M et al. Haemophilia. 2019 Feb 12. doi: 10.1111/hae.13691
When managed by an experienced team, patients with inherited bleeding disorders undergoing gastrointestinal endoscopy are not at increased bleeding risk, according to researchers reporting the largest series of such patients to date.
The postendoscopy bleeding rate was less than 1% for the patients in this series, many of whom underwent high-risk procedures or had comorbid conditions putting them at risk of bleeding, the researchers reported.
The rate of colonoscopic postpolypectomy bleeding was less than 5%, which is comparable to the general population rate for such high-risk procedures, said investigator Marcel Tomaszewski, MD, of McGill University, Montreal, and colleagues.
Those results favor the use of the “interdisciplinary approach provided by a hemophilia treatment center, communication between services, and the use of periprocedure prophylaxis including tranexamic acid,” Dr. Tomaszewski and coinvestigators said in their report in Haemophilia.
The study cohort included 48 individuals undergoing a total of 104 endoscopies, which is believed to be the largest case series of digestive endoscopy procedures ever reported in patients with congenital bleeding disorders, according to the researchers.
Hemophilia A and von Willebrand disease were the most common bleeding disorders among these patients, accounting for 49 and 40 of the 104 procedures, respectively. The remaining 17 procedures were performed in patients with factor XI deficiency, hemophilia B, or factor VII deficiency.
Before their endoscopies, patients received bleeding prophylaxis, which consisted of combinations of recombinant factor for hemophilia patients, plasma-derived factor for von Willebrand disease patients, desmopressin, and tranexamic acid.
The rate of bleeding within 72 hours of the endoscopic procedure was 0.96% (95% confidence interval, 0.17%-5.25%). The bleeding rate for hemophilia A patients, regardless of severity, was 2.2%, while the rate for hemophilia B, von Willebrand disease, factor VII deficiency and factor XI deficiency was 0%.
The only endoscopic procedures associated with bleeding were colonoscopy, with a bleeding rate of 2%, and colonoscopy with polypectomy, which had a 4.8% bleeding rate, they added, noting that the reported rate of postpolypectomy bleeding in the general population ranges between 0.3% and 10%.
“The very low incidence of bleeding adverse events limited further planned inferential statistical analysis,” the researchers wrote.
These findings stand in contrast to some previous reports, including one series of 19 patients with hemophilia in which 31% experienced gastrointestinal bleeding after colonoscopy polypectomy, despite preprocedure prophylaxis.
“Our approach, particularly with the addition of tranexamic acid, and our patient mix may explain the lower bleeding rate,” they wrote.
The most common indications for endoscopy in the present report were anemia, colorectal cancer screening or polyp surveillance, upper GI symptoms, and screening or surveillance of varices.
Many patients had conditions that might predispose them to bleeding, investigators said. Most commonly, those conditions included hepatitis C virus infection, cirrhosis, esophageal varices, and previous gastrointestinal bleeding.
Dr. Tomaszewski reported that he had no potential conflicts of interest related to the research. Coauthors reported financial disclosures related to AbbVie, Pfizer, Takeda, Janssen, and others.
SOURCE: Tomaszewski M et al. Haemophilia. 2019 Feb 12. doi: 10.1111/hae.13691
FROM HAEMOPHILIA
Erectile dysfunction appears prevalent with hemophilia
Erectile dysfunction (ED) appears prevalent among men with hemophilia and becomes increasingly common with age, according to results from a recent survey.
Although the findings may not be generalizable because of small sample size (44 respondents), the survey offers a general sense of the sexual health of patients with hemophilia, which is a minimally researched topic, reported lead author Ming Yang, PhD, of the British Columbia Provincial Bleeding Disorders Program at St. Paul’s Hospital in Vancouver and colleagues.
Such data become increasingly important as new hemophilia therapies further extend the lifespan of patients, which thereby exposes them to diseases of old age, the investigators noted in Haemophilia.
Additionally, ED is considered an early sign of endothelial dysfunction in the general population, but data are lacking for patients with hemophilia.
Among the 56 men with hemophilia A or B who were surveyed with the International Index of Erectile Function (IIEF) questionnaire, 44 completed the survey (median age, 49 years). Specifically, respondents completed the “erectile function” component of the questionnaire because this is the only domain that has been validated.
To assess associations between ED and well-established risk factors, the investigators recorded prior surgeries, medications, atherosclerotic diseases, viral infections, and hemophilia-specific factors. To better characterize the population and look for other associations, the investigators had patients undergo baseline laboratory testing and measurements of blood pressure, anthropomorphic indexes, and endothelial function.
According to the IIEF, 38.6% of patients had ED, which was subcategorized as mild and mild to moderate in 4.5% of patients, moderate in 18.2%, and severe in 15.9%.
The investigators found significant associations between ED and coronary artery disease, hypertension, smoking, higher waist/hip ratio, homocysteine level, and age. However, on multivariable analysis, only age was correlated with ED domain score (P = .03). No associations between ED and endothelial dysfunction were reported.
While the findings may offer a rare look at ED rates in patients with hemophilia, they are insufficient for comparisons and generalizations, the investigators cautioned.
“Without comparative studies within the haemophilia population in Canada or elsewhere and due to limited sample size and non‐normalized distribution of our age group, this prevalence cannot reasonably be generalized to the entire haemophilia population,” the investigators wrote.
Instead, the investigators suggested that more studies are needed, especially ones involving customized questionnaires.
The study was funded by Pfizer. Dr. Yang reported having no conflicts of interest. One coauthor reported an unrestricted educational award from the Association of Hemophilia Clinic Directors of Canada/Baxter Canadian Hemostasis Fellowship, and another coauthor reported research funding from Pfizer.
SOURCE: Yang M et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13707.
Erectile dysfunction (ED) appears prevalent among men with hemophilia and becomes increasingly common with age, according to results from a recent survey.
Although the findings may not be generalizable because of small sample size (44 respondents), the survey offers a general sense of the sexual health of patients with hemophilia, which is a minimally researched topic, reported lead author Ming Yang, PhD, of the British Columbia Provincial Bleeding Disorders Program at St. Paul’s Hospital in Vancouver and colleagues.
Such data become increasingly important as new hemophilia therapies further extend the lifespan of patients, which thereby exposes them to diseases of old age, the investigators noted in Haemophilia.
Additionally, ED is considered an early sign of endothelial dysfunction in the general population, but data are lacking for patients with hemophilia.
Among the 56 men with hemophilia A or B who were surveyed with the International Index of Erectile Function (IIEF) questionnaire, 44 completed the survey (median age, 49 years). Specifically, respondents completed the “erectile function” component of the questionnaire because this is the only domain that has been validated.
To assess associations between ED and well-established risk factors, the investigators recorded prior surgeries, medications, atherosclerotic diseases, viral infections, and hemophilia-specific factors. To better characterize the population and look for other associations, the investigators had patients undergo baseline laboratory testing and measurements of blood pressure, anthropomorphic indexes, and endothelial function.
According to the IIEF, 38.6% of patients had ED, which was subcategorized as mild and mild to moderate in 4.5% of patients, moderate in 18.2%, and severe in 15.9%.
The investigators found significant associations between ED and coronary artery disease, hypertension, smoking, higher waist/hip ratio, homocysteine level, and age. However, on multivariable analysis, only age was correlated with ED domain score (P = .03). No associations between ED and endothelial dysfunction were reported.
While the findings may offer a rare look at ED rates in patients with hemophilia, they are insufficient for comparisons and generalizations, the investigators cautioned.
“Without comparative studies within the haemophilia population in Canada or elsewhere and due to limited sample size and non‐normalized distribution of our age group, this prevalence cannot reasonably be generalized to the entire haemophilia population,” the investigators wrote.
Instead, the investigators suggested that more studies are needed, especially ones involving customized questionnaires.
The study was funded by Pfizer. Dr. Yang reported having no conflicts of interest. One coauthor reported an unrestricted educational award from the Association of Hemophilia Clinic Directors of Canada/Baxter Canadian Hemostasis Fellowship, and another coauthor reported research funding from Pfizer.
SOURCE: Yang M et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13707.
Erectile dysfunction (ED) appears prevalent among men with hemophilia and becomes increasingly common with age, according to results from a recent survey.
Although the findings may not be generalizable because of small sample size (44 respondents), the survey offers a general sense of the sexual health of patients with hemophilia, which is a minimally researched topic, reported lead author Ming Yang, PhD, of the British Columbia Provincial Bleeding Disorders Program at St. Paul’s Hospital in Vancouver and colleagues.
Such data become increasingly important as new hemophilia therapies further extend the lifespan of patients, which thereby exposes them to diseases of old age, the investigators noted in Haemophilia.
Additionally, ED is considered an early sign of endothelial dysfunction in the general population, but data are lacking for patients with hemophilia.
Among the 56 men with hemophilia A or B who were surveyed with the International Index of Erectile Function (IIEF) questionnaire, 44 completed the survey (median age, 49 years). Specifically, respondents completed the “erectile function” component of the questionnaire because this is the only domain that has been validated.
To assess associations between ED and well-established risk factors, the investigators recorded prior surgeries, medications, atherosclerotic diseases, viral infections, and hemophilia-specific factors. To better characterize the population and look for other associations, the investigators had patients undergo baseline laboratory testing and measurements of blood pressure, anthropomorphic indexes, and endothelial function.
According to the IIEF, 38.6% of patients had ED, which was subcategorized as mild and mild to moderate in 4.5% of patients, moderate in 18.2%, and severe in 15.9%.
The investigators found significant associations between ED and coronary artery disease, hypertension, smoking, higher waist/hip ratio, homocysteine level, and age. However, on multivariable analysis, only age was correlated with ED domain score (P = .03). No associations between ED and endothelial dysfunction were reported.
While the findings may offer a rare look at ED rates in patients with hemophilia, they are insufficient for comparisons and generalizations, the investigators cautioned.
“Without comparative studies within the haemophilia population in Canada or elsewhere and due to limited sample size and non‐normalized distribution of our age group, this prevalence cannot reasonably be generalized to the entire haemophilia population,” the investigators wrote.
Instead, the investigators suggested that more studies are needed, especially ones involving customized questionnaires.
The study was funded by Pfizer. Dr. Yang reported having no conflicts of interest. One coauthor reported an unrestricted educational award from the Association of Hemophilia Clinic Directors of Canada/Baxter Canadian Hemostasis Fellowship, and another coauthor reported research funding from Pfizer.
SOURCE: Yang M et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13707.
FROM HAEMOPHILIA
Haplo-HSCT bests chemotherapy for MRD-positive adult ALL
HOUSTON – Haploidentical stem cell transplantation (Haplo-HSCT) outperforms chemotherapy for the treatment of adults with acute lymphoblastic leukemia (ALL) in first complete remission, findings from a prospective multicenter trial suggest.
The 2-year leukemia-free survival (LFS) was about 70% in 49 patients in first remission who received haplo-HSCT vs. 40% in 40 patients who received chemotherapy, and 2-year overall survival (OS) was about 80% vs. 50% in the groups, respectively, Meng Lv, MD, PhD, of Peking University People’s Hospital in Beijing reported at the Transplantation & Cellular Therapy Meetings.
“This result is comparable to results of our previous reports,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
He noted that the findings also support those from other institutions.
Study subjects initially included 112 newly diagnosed standard-risk ALL patients aged 18-39 years without high-risk features who achieved complete remission (CR) after one or two cycles of induction. They were consecutively enrolled at five centers in China, including high-volume centers, between July 2014 and June 2017 and were followed for a median of 24.6 months.
Subjects without a suitable HLA-matched sibling donor (MSD) or HLA-matched unrelated donor after two cycles of consolidation with hyper-CVAD chemotherapy were eligible for haplo-HSCT or further hyper-CVAD chemotherapy.
The final analysis included 89 patients after 23 were excluded because of early relapse (6 patients) or a decision to undergo MSD HSCT (16 patients), or unrelated donor-HSCT (1 patient), Dr. Lv said, noting that landmark analysis was used when comparing the outcomes of patients receiving haplo-HSCT with those receiving chemotherapy.
Multivariate analysis with adjustment for a propensity score calculated for each patient showed that treatment (haplo-HSCT vs. chemotherapy) independently predicted LFS (hazard ratio, 0.388), OS (HR, 0.346), and cumulative incidence of relapse (CIR; HR, 0.247). Minimal residual disease (MRD) positivity after the first consolidation was an independent risk factor for LFS (HR, 2.162) and CIR (HR, 3.667). Additionally, diagnosis (T- vs. B-cell) was an independent risk factor for OS (HR, 2.267), Dr. Lv said, adding that nonrelapse mortality was similar in the groups in the propensity score–adjusted analysis.
The findings overall show that haplo-HSCT has variable impact on survival in standard-risk ALL, when compared with traditional chemotherapy, with subgroup analyses showing MRD-positive patients deriving the greatest benefit, he said. Future studies are planned to look more closely at MRD-positive disease and the possible benefits of postponing transplant until the second CR.
At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
Dr. Lv reported having no financial disclosures.
SOURCE: Lv M et al. TCT 2019, Abstract 8.
HOUSTON – Haploidentical stem cell transplantation (Haplo-HSCT) outperforms chemotherapy for the treatment of adults with acute lymphoblastic leukemia (ALL) in first complete remission, findings from a prospective multicenter trial suggest.
The 2-year leukemia-free survival (LFS) was about 70% in 49 patients in first remission who received haplo-HSCT vs. 40% in 40 patients who received chemotherapy, and 2-year overall survival (OS) was about 80% vs. 50% in the groups, respectively, Meng Lv, MD, PhD, of Peking University People’s Hospital in Beijing reported at the Transplantation & Cellular Therapy Meetings.
“This result is comparable to results of our previous reports,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
He noted that the findings also support those from other institutions.
Study subjects initially included 112 newly diagnosed standard-risk ALL patients aged 18-39 years without high-risk features who achieved complete remission (CR) after one or two cycles of induction. They were consecutively enrolled at five centers in China, including high-volume centers, between July 2014 and June 2017 and were followed for a median of 24.6 months.
Subjects without a suitable HLA-matched sibling donor (MSD) or HLA-matched unrelated donor after two cycles of consolidation with hyper-CVAD chemotherapy were eligible for haplo-HSCT or further hyper-CVAD chemotherapy.
The final analysis included 89 patients after 23 were excluded because of early relapse (6 patients) or a decision to undergo MSD HSCT (16 patients), or unrelated donor-HSCT (1 patient), Dr. Lv said, noting that landmark analysis was used when comparing the outcomes of patients receiving haplo-HSCT with those receiving chemotherapy.
Multivariate analysis with adjustment for a propensity score calculated for each patient showed that treatment (haplo-HSCT vs. chemotherapy) independently predicted LFS (hazard ratio, 0.388), OS (HR, 0.346), and cumulative incidence of relapse (CIR; HR, 0.247). Minimal residual disease (MRD) positivity after the first consolidation was an independent risk factor for LFS (HR, 2.162) and CIR (HR, 3.667). Additionally, diagnosis (T- vs. B-cell) was an independent risk factor for OS (HR, 2.267), Dr. Lv said, adding that nonrelapse mortality was similar in the groups in the propensity score–adjusted analysis.
The findings overall show that haplo-HSCT has variable impact on survival in standard-risk ALL, when compared with traditional chemotherapy, with subgroup analyses showing MRD-positive patients deriving the greatest benefit, he said. Future studies are planned to look more closely at MRD-positive disease and the possible benefits of postponing transplant until the second CR.
At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
Dr. Lv reported having no financial disclosures.
SOURCE: Lv M et al. TCT 2019, Abstract 8.
HOUSTON – Haploidentical stem cell transplantation (Haplo-HSCT) outperforms chemotherapy for the treatment of adults with acute lymphoblastic leukemia (ALL) in first complete remission, findings from a prospective multicenter trial suggest.
The 2-year leukemia-free survival (LFS) was about 70% in 49 patients in first remission who received haplo-HSCT vs. 40% in 40 patients who received chemotherapy, and 2-year overall survival (OS) was about 80% vs. 50% in the groups, respectively, Meng Lv, MD, PhD, of Peking University People’s Hospital in Beijing reported at the Transplantation & Cellular Therapy Meetings.
“This result is comparable to results of our previous reports,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
He noted that the findings also support those from other institutions.
Study subjects initially included 112 newly diagnosed standard-risk ALL patients aged 18-39 years without high-risk features who achieved complete remission (CR) after one or two cycles of induction. They were consecutively enrolled at five centers in China, including high-volume centers, between July 2014 and June 2017 and were followed for a median of 24.6 months.
Subjects without a suitable HLA-matched sibling donor (MSD) or HLA-matched unrelated donor after two cycles of consolidation with hyper-CVAD chemotherapy were eligible for haplo-HSCT or further hyper-CVAD chemotherapy.
The final analysis included 89 patients after 23 were excluded because of early relapse (6 patients) or a decision to undergo MSD HSCT (16 patients), or unrelated donor-HSCT (1 patient), Dr. Lv said, noting that landmark analysis was used when comparing the outcomes of patients receiving haplo-HSCT with those receiving chemotherapy.
Multivariate analysis with adjustment for a propensity score calculated for each patient showed that treatment (haplo-HSCT vs. chemotherapy) independently predicted LFS (hazard ratio, 0.388), OS (HR, 0.346), and cumulative incidence of relapse (CIR; HR, 0.247). Minimal residual disease (MRD) positivity after the first consolidation was an independent risk factor for LFS (HR, 2.162) and CIR (HR, 3.667). Additionally, diagnosis (T- vs. B-cell) was an independent risk factor for OS (HR, 2.267), Dr. Lv said, adding that nonrelapse mortality was similar in the groups in the propensity score–adjusted analysis.
The findings overall show that haplo-HSCT has variable impact on survival in standard-risk ALL, when compared with traditional chemotherapy, with subgroup analyses showing MRD-positive patients deriving the greatest benefit, he said. Future studies are planned to look more closely at MRD-positive disease and the possible benefits of postponing transplant until the second CR.
At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
Dr. Lv reported having no financial disclosures.
SOURCE: Lv M et al. TCT 2019, Abstract 8.
REPORTING FROM TCT 2019
FXIII replacement may improve hemostasis in acquired hemophilia A
Measurement of factor XIII levels, followed by replacing deficiencies if found, may help to achieve sustained hemostasis in the management of bleeding in patients with acquired hemophilia A.
Jameel Abdulrehman, MD, of the University of Toronto in Ontario and his colleagues retrospectively reviewed cases of acquired hemophilia A with bleeding at a large hospital from 2015-2016. The findings were published in a letter to the editor in Haemophilia.
The researchers reported that depletion of Factor XIII (FXIII) in the setting of acquired hemophilia A has only been reported in a single case. In the present analysis, the researchers identified a total of seven patients with acquired hemophilia A from 2015-2016. FXIII antigen levels were measured in five cases and were found to be low in four cases, and three patients required FXIII replacement to secure hemostasis.
The relationship between acquired hemophilia A and FXIII deficiency was evaluated using descriptive case analysis.
After analysis, the team reported that measuring FXIII levels may be useful in refractory patients, in whom bleeding remains uncontrolled despite the use of standard therapy. Additionally, the results supported FXIII supplementation if a deficiency is detected.
“FXIII replacement was not complicated by any infusion reactions or thromboembolic events,” they wrote.
The replaced FXIII levels dropped more rapidly than expected, the researchers noted. The established half-life of pd-XIII is 6.6 days plus or minus 2.29 days; however, in the most severe of the cases reported, it was depleted “within a few days,” they wrote. “This is compatible with either consumption of FXIII or inhibition/clearance by an autoantibody.”
Dr. Abdulrehman and his colleagues acknowledged that FXIII deficiency can be challenging to identify because the majority of coagulation assays do not measure FXIII levels.
“As we gain a greater appreciation for the role of FXIII in various pathological states, access to accurate FXIII testing will become increasingly important,” they added.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: Abdulrehman J et al. Haemophilia. 2019 Mar 7. doi: 10.1111/hae.13690.
Measurement of factor XIII levels, followed by replacing deficiencies if found, may help to achieve sustained hemostasis in the management of bleeding in patients with acquired hemophilia A.
Jameel Abdulrehman, MD, of the University of Toronto in Ontario and his colleagues retrospectively reviewed cases of acquired hemophilia A with bleeding at a large hospital from 2015-2016. The findings were published in a letter to the editor in Haemophilia.
The researchers reported that depletion of Factor XIII (FXIII) in the setting of acquired hemophilia A has only been reported in a single case. In the present analysis, the researchers identified a total of seven patients with acquired hemophilia A from 2015-2016. FXIII antigen levels were measured in five cases and were found to be low in four cases, and three patients required FXIII replacement to secure hemostasis.
The relationship between acquired hemophilia A and FXIII deficiency was evaluated using descriptive case analysis.
After analysis, the team reported that measuring FXIII levels may be useful in refractory patients, in whom bleeding remains uncontrolled despite the use of standard therapy. Additionally, the results supported FXIII supplementation if a deficiency is detected.
“FXIII replacement was not complicated by any infusion reactions or thromboembolic events,” they wrote.
The replaced FXIII levels dropped more rapidly than expected, the researchers noted. The established half-life of pd-XIII is 6.6 days plus or minus 2.29 days; however, in the most severe of the cases reported, it was depleted “within a few days,” they wrote. “This is compatible with either consumption of FXIII or inhibition/clearance by an autoantibody.”
Dr. Abdulrehman and his colleagues acknowledged that FXIII deficiency can be challenging to identify because the majority of coagulation assays do not measure FXIII levels.
“As we gain a greater appreciation for the role of FXIII in various pathological states, access to accurate FXIII testing will become increasingly important,” they added.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: Abdulrehman J et al. Haemophilia. 2019 Mar 7. doi: 10.1111/hae.13690.
Measurement of factor XIII levels, followed by replacing deficiencies if found, may help to achieve sustained hemostasis in the management of bleeding in patients with acquired hemophilia A.
Jameel Abdulrehman, MD, of the University of Toronto in Ontario and his colleagues retrospectively reviewed cases of acquired hemophilia A with bleeding at a large hospital from 2015-2016. The findings were published in a letter to the editor in Haemophilia.
The researchers reported that depletion of Factor XIII (FXIII) in the setting of acquired hemophilia A has only been reported in a single case. In the present analysis, the researchers identified a total of seven patients with acquired hemophilia A from 2015-2016. FXIII antigen levels were measured in five cases and were found to be low in four cases, and three patients required FXIII replacement to secure hemostasis.
The relationship between acquired hemophilia A and FXIII deficiency was evaluated using descriptive case analysis.
After analysis, the team reported that measuring FXIII levels may be useful in refractory patients, in whom bleeding remains uncontrolled despite the use of standard therapy. Additionally, the results supported FXIII supplementation if a deficiency is detected.
“FXIII replacement was not complicated by any infusion reactions or thromboembolic events,” they wrote.
The replaced FXIII levels dropped more rapidly than expected, the researchers noted. The established half-life of pd-XIII is 6.6 days plus or minus 2.29 days; however, in the most severe of the cases reported, it was depleted “within a few days,” they wrote. “This is compatible with either consumption of FXIII or inhibition/clearance by an autoantibody.”
Dr. Abdulrehman and his colleagues acknowledged that FXIII deficiency can be challenging to identify because the majority of coagulation assays do not measure FXIII levels.
“As we gain a greater appreciation for the role of FXIII in various pathological states, access to accurate FXIII testing will become increasingly important,” they added.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: Abdulrehman J et al. Haemophilia. 2019 Mar 7. doi: 10.1111/hae.13690.
FROM HAEMOPHILIA
Injectable nimodipine does not improve outcomes of subarachnoid hemorrhage
HONOLULU – according to a study presented at the International Stroke Conference sponsored by the American Heart Association. However, the treatment does reduce the rate of angiographic vasospasm significantly and does not raise significant safety concerns.
Approximately 70% of patients with subarachnoid hemorrhage develop vasospasm, which can in turn cause delayed cerebral ischemia. The only evidence-based treatment for ischemia of the brain resulting from vasospasm is nimodipine, which has been the standard of care for more than a decade.
EG-1962 was developed to deliver higher amounts of nimodipine to the CNS and spastic vessels than oral nimodipine. The formulation contains 50-mcm particles of nimodipine combined with a biodegradable polymer. Pharmacokinetic studies indicate that EG-1962 successfully delivers higher amounts of nimodipine to the CNS than the oral formulation does.
A multisite, phase 3 trial
Stephan A. Mayer, MD, William T. Gossett Endowed Chair of Neurology at the Henry Ford Health System in Detroit, presented the trial results. He and his colleagues conducted NEWTON2, a phase 3 trial to evaluate the safety and efficacy of a single 600-mg intraventricular dose of EG-1962 in patients with aneurysmal subarachnoid hemorrhage, compared with those of oral nimodipine. Eligible participants had a World Federation of Neurosurgeons Score (WFNS) of 2-4, Glasgow Coma Scale scores of 7-14, and an indication for placement of an external ventricular drain (such as hydrocephalus). All patients had their aneurysms clipped or coiled.
On the first day after the operation, the investigators randomized patients in equal groups to EG-1962 plus oral placebo or oral nimodipine plus placebo injection. Patients in the EG-1962 arm received a 600-mg injection of nimodipine into the ventricular system. The primary endpoint was the proportion of subjects with an extended Glasgow Outcome Scale (eGOS) score of 6-8 (that is, minimal or mild disability) at day 90. The main secondary endpoint was the proportion of subjects with a Montreal Cognitive Assessment (MOCA) score of 26 or greater (indicating no important cognitive disability) at day 90. Safety outcomes included cerebral infarction, hypotension, and ventriculitis.
Dr. Mayer and his colleagues conducted the study at 65 centers in 11 countries. They planned to enroll 374 patients and conduct an interim analysis after the first 210 participants had their 90-day follow-up. An independent data monitoring committee reviewed the safety data as it was collected. The investigators stopped the study for futility after the preplanned interim analysis was completed.
The challenge of identifying responders
The two study arms were well matched on age and gender. The proportion of patients with poor WFNS was 45% in the EG-1962 arm and 53% in the oral nimodipine arm.
The rate of any vasospasm (such as symptomatic or by imaging) was 56% in the intervention group and 70% in the oral nimodipine group, a statistically significant difference. Follow-up angiography showed vasospasm in 50% of the intervention group, compared with 63% of the oral nimodipine group, which was also statistically significant.
When the investigators examined the primary endpoint, they found that 46% of patients who received EG-1962 had a favorable outcome, compared with 43% of patients who received oral nimodipine, a nonsignificant difference. If the investigators had defined a favorable outcome as an eGOS score of 4 or greater, “there would have been a more favorable effect,” said Dr. Mayer. The investigators found no difference between groups in MOCA score at day 90.
Subgroup analyses produced “puzzling” results, said Dr. Mayer. For example, more patients with poor-grade WFNS had a favorable outcome at 3 months in the EG-1962 group than in the nimodipine group, but fewer patients with good-grade WFNS had a favorable outcome at 3 months in the EG-1962 group than in the nimodipine group. In addition, the treatment effect was more evident in the United States than abroad.
The safety analysis indicated a trend toward less rescue therapy – defined as hypertensive therapy or any interventional approach – in the EG-1962 group (27%), compared with the oral nimodipine group (35%). The rate of hypotension was slightly lower in the EG-1962 group. The rates of treatment-emergent serious adverse events and hydrocephalus were not significantly different between groups.
The results may encourage neurologists to treat “extremely sick patients with highly refractory vasospasms,” said Dr. Mayer. “We have a biologically active agent. The problem is, though, that it’s very hard ... to prove efficacy in trials, because we do not fully understand who the responders were going to be.”
Dr. Mayer reported receiving consulting fees from Edge Therapeutics, the company that developed EG-1962, in the past for activities unrelated to this study. Other investigators are employees of Edge Therapeutics.
SOURCE: Mayer SA et al. ISC 2019, Abstract LB15.
HONOLULU – according to a study presented at the International Stroke Conference sponsored by the American Heart Association. However, the treatment does reduce the rate of angiographic vasospasm significantly and does not raise significant safety concerns.
Approximately 70% of patients with subarachnoid hemorrhage develop vasospasm, which can in turn cause delayed cerebral ischemia. The only evidence-based treatment for ischemia of the brain resulting from vasospasm is nimodipine, which has been the standard of care for more than a decade.
EG-1962 was developed to deliver higher amounts of nimodipine to the CNS and spastic vessels than oral nimodipine. The formulation contains 50-mcm particles of nimodipine combined with a biodegradable polymer. Pharmacokinetic studies indicate that EG-1962 successfully delivers higher amounts of nimodipine to the CNS than the oral formulation does.
A multisite, phase 3 trial
Stephan A. Mayer, MD, William T. Gossett Endowed Chair of Neurology at the Henry Ford Health System in Detroit, presented the trial results. He and his colleagues conducted NEWTON2, a phase 3 trial to evaluate the safety and efficacy of a single 600-mg intraventricular dose of EG-1962 in patients with aneurysmal subarachnoid hemorrhage, compared with those of oral nimodipine. Eligible participants had a World Federation of Neurosurgeons Score (WFNS) of 2-4, Glasgow Coma Scale scores of 7-14, and an indication for placement of an external ventricular drain (such as hydrocephalus). All patients had their aneurysms clipped or coiled.
On the first day after the operation, the investigators randomized patients in equal groups to EG-1962 plus oral placebo or oral nimodipine plus placebo injection. Patients in the EG-1962 arm received a 600-mg injection of nimodipine into the ventricular system. The primary endpoint was the proportion of subjects with an extended Glasgow Outcome Scale (eGOS) score of 6-8 (that is, minimal or mild disability) at day 90. The main secondary endpoint was the proportion of subjects with a Montreal Cognitive Assessment (MOCA) score of 26 or greater (indicating no important cognitive disability) at day 90. Safety outcomes included cerebral infarction, hypotension, and ventriculitis.
Dr. Mayer and his colleagues conducted the study at 65 centers in 11 countries. They planned to enroll 374 patients and conduct an interim analysis after the first 210 participants had their 90-day follow-up. An independent data monitoring committee reviewed the safety data as it was collected. The investigators stopped the study for futility after the preplanned interim analysis was completed.
The challenge of identifying responders
The two study arms were well matched on age and gender. The proportion of patients with poor WFNS was 45% in the EG-1962 arm and 53% in the oral nimodipine arm.
The rate of any vasospasm (such as symptomatic or by imaging) was 56% in the intervention group and 70% in the oral nimodipine group, a statistically significant difference. Follow-up angiography showed vasospasm in 50% of the intervention group, compared with 63% of the oral nimodipine group, which was also statistically significant.
When the investigators examined the primary endpoint, they found that 46% of patients who received EG-1962 had a favorable outcome, compared with 43% of patients who received oral nimodipine, a nonsignificant difference. If the investigators had defined a favorable outcome as an eGOS score of 4 or greater, “there would have been a more favorable effect,” said Dr. Mayer. The investigators found no difference between groups in MOCA score at day 90.
Subgroup analyses produced “puzzling” results, said Dr. Mayer. For example, more patients with poor-grade WFNS had a favorable outcome at 3 months in the EG-1962 group than in the nimodipine group, but fewer patients with good-grade WFNS had a favorable outcome at 3 months in the EG-1962 group than in the nimodipine group. In addition, the treatment effect was more evident in the United States than abroad.
The safety analysis indicated a trend toward less rescue therapy – defined as hypertensive therapy or any interventional approach – in the EG-1962 group (27%), compared with the oral nimodipine group (35%). The rate of hypotension was slightly lower in the EG-1962 group. The rates of treatment-emergent serious adverse events and hydrocephalus were not significantly different between groups.
The results may encourage neurologists to treat “extremely sick patients with highly refractory vasospasms,” said Dr. Mayer. “We have a biologically active agent. The problem is, though, that it’s very hard ... to prove efficacy in trials, because we do not fully understand who the responders were going to be.”
Dr. Mayer reported receiving consulting fees from Edge Therapeutics, the company that developed EG-1962, in the past for activities unrelated to this study. Other investigators are employees of Edge Therapeutics.
SOURCE: Mayer SA et al. ISC 2019, Abstract LB15.
HONOLULU – according to a study presented at the International Stroke Conference sponsored by the American Heart Association. However, the treatment does reduce the rate of angiographic vasospasm significantly and does not raise significant safety concerns.
Approximately 70% of patients with subarachnoid hemorrhage develop vasospasm, which can in turn cause delayed cerebral ischemia. The only evidence-based treatment for ischemia of the brain resulting from vasospasm is nimodipine, which has been the standard of care for more than a decade.
EG-1962 was developed to deliver higher amounts of nimodipine to the CNS and spastic vessels than oral nimodipine. The formulation contains 50-mcm particles of nimodipine combined with a biodegradable polymer. Pharmacokinetic studies indicate that EG-1962 successfully delivers higher amounts of nimodipine to the CNS than the oral formulation does.
A multisite, phase 3 trial
Stephan A. Mayer, MD, William T. Gossett Endowed Chair of Neurology at the Henry Ford Health System in Detroit, presented the trial results. He and his colleagues conducted NEWTON2, a phase 3 trial to evaluate the safety and efficacy of a single 600-mg intraventricular dose of EG-1962 in patients with aneurysmal subarachnoid hemorrhage, compared with those of oral nimodipine. Eligible participants had a World Federation of Neurosurgeons Score (WFNS) of 2-4, Glasgow Coma Scale scores of 7-14, and an indication for placement of an external ventricular drain (such as hydrocephalus). All patients had their aneurysms clipped or coiled.
On the first day after the operation, the investigators randomized patients in equal groups to EG-1962 plus oral placebo or oral nimodipine plus placebo injection. Patients in the EG-1962 arm received a 600-mg injection of nimodipine into the ventricular system. The primary endpoint was the proportion of subjects with an extended Glasgow Outcome Scale (eGOS) score of 6-8 (that is, minimal or mild disability) at day 90. The main secondary endpoint was the proportion of subjects with a Montreal Cognitive Assessment (MOCA) score of 26 or greater (indicating no important cognitive disability) at day 90. Safety outcomes included cerebral infarction, hypotension, and ventriculitis.
Dr. Mayer and his colleagues conducted the study at 65 centers in 11 countries. They planned to enroll 374 patients and conduct an interim analysis after the first 210 participants had their 90-day follow-up. An independent data monitoring committee reviewed the safety data as it was collected. The investigators stopped the study for futility after the preplanned interim analysis was completed.
The challenge of identifying responders
The two study arms were well matched on age and gender. The proportion of patients with poor WFNS was 45% in the EG-1962 arm and 53% in the oral nimodipine arm.
The rate of any vasospasm (such as symptomatic or by imaging) was 56% in the intervention group and 70% in the oral nimodipine group, a statistically significant difference. Follow-up angiography showed vasospasm in 50% of the intervention group, compared with 63% of the oral nimodipine group, which was also statistically significant.
When the investigators examined the primary endpoint, they found that 46% of patients who received EG-1962 had a favorable outcome, compared with 43% of patients who received oral nimodipine, a nonsignificant difference. If the investigators had defined a favorable outcome as an eGOS score of 4 or greater, “there would have been a more favorable effect,” said Dr. Mayer. The investigators found no difference between groups in MOCA score at day 90.
Subgroup analyses produced “puzzling” results, said Dr. Mayer. For example, more patients with poor-grade WFNS had a favorable outcome at 3 months in the EG-1962 group than in the nimodipine group, but fewer patients with good-grade WFNS had a favorable outcome at 3 months in the EG-1962 group than in the nimodipine group. In addition, the treatment effect was more evident in the United States than abroad.
The safety analysis indicated a trend toward less rescue therapy – defined as hypertensive therapy or any interventional approach – in the EG-1962 group (27%), compared with the oral nimodipine group (35%). The rate of hypotension was slightly lower in the EG-1962 group. The rates of treatment-emergent serious adverse events and hydrocephalus were not significantly different between groups.
The results may encourage neurologists to treat “extremely sick patients with highly refractory vasospasms,” said Dr. Mayer. “We have a biologically active agent. The problem is, though, that it’s very hard ... to prove efficacy in trials, because we do not fully understand who the responders were going to be.”
Dr. Mayer reported receiving consulting fees from Edge Therapeutics, the company that developed EG-1962, in the past for activities unrelated to this study. Other investigators are employees of Edge Therapeutics.
SOURCE: Mayer SA et al. ISC 2019, Abstract LB15.
REPORTING FROM ISC 2019
Descovy noninferior to Truvada for PrEP
SEATTLE – Descovy [emtricitabine/tenofovir alafenamide (F/TAF]) was noninferior to Truvada [emtricitabine/tenofovir disoproxil fumarate (F/TDF)] for preexposure HIV prophylaxis in a blinded, randomized trial involving more than 5,000 men at high risk for the infection.
Both nucleotide reverse transcriptase inhibitors are made by Gilead, and the company funded the trial.
F/TDF (Truvada) has been a blockbuster for the company, both for HIV treatment and, since 2012, for preexposure prophylaxis (PrEP); it’s the only medication to carry the indication. However, F/TDF is set to go off patent in 2021, so the company has turned its development efforts to a successor, F/TAF (Descovy), a prodrug of tenofovir that is already approved for HIV treatment.
The new study builds a case for F/TAF for PrEP, but whether the results are strong enough to persuade people to opt for it over a much less expensive generic version of F/TDF remains to be seen.
The trial randomized 2,694 men who have sex with men to F/TAF, and 2,693 to F/TDF for up to 96 weeks. Entrance criteria included at least two episodes of unprotected anal sex in the previous 12 weeks, or a diagnosis of rectal gonorrhea, chlamydia, or syphilis in the previous 6 months.
More than half the men contracted at least one sexually transmitted infection during the trial, “which indicated to us that these were the right patients to be enrolled in the study,” lead investigator Charles Hare, MD, an infectious disease specialist at the University of California, San Francisco, said at the Conference on Retroviruses and Opportunistic Infections.
There were 15 new HIV infections in the F/TDF group (0.34 per 100 person-years), versus 7 in the F/TAF group (0.16 per 100 person-years). Almost all of the new infections were due to poor adherence – as proven by blood levels and dry blood spot testing – and most of the rest were in men who probably entered the trial with newly acquired HIV.
When those subjects were excluded, there were just two new onset HIV cases in subjects adherent to dosing, one in each arm. Infection rates were far lower than would have been expected had the subjects not been on PrEP.
One of Gilead’s main selling points for F/TAF over F/TDF is that the newer drug has better bone and renal safety, and there were slight biomarker differences in the trial that supported the assertion.
For instance, spine bone mineral density decreased 3% or greater from baseline in 10 F/TAF patients, but 27 men on F/TDF (P less than .001). Results were similar with hip bone density.
On the renal front, estimated glomerular filtration rates fell a median of 2.3 mL/min per 1.73 m2 in the F/TDF arm, but rose 1.8 mL/min per 1.73 m2 in men on F/TAF (P less than .001). Proximal tubular protein to creatinine ratios were largely unchanged from baseline with F/TAF, but slightly higher in the F/TDF group, at 48 weeks.
There were no statistically significant differences on actual safety outcomes – as opposed to biomarkers – between the two drugs or discontinuations due to side effects, which were rare and most often due to gastrointestinal issues. F/TAF patients gained about 1.1 kg in the trial, while weight held steady in the F/TDF arm. The study team plans to analyze lipid profile differences between the groups, since concern has been raised about F/TAF’s effect on them.
In a press conference at the conference, there was quite a bit of discussion about whether the results would justify using F/TAF for PrEP when less expensive generic versions of F/TDF become available.
“That’s a great question,” Dr. Hare said. “Both drugs actually performed quite well,” and both “do pretty well in terms of safety in this population.”
It’s not known at this point if the biomarker differences will prove to be clinically relevant. Hip fractures, kidney failure, and other problems are so rare in young, relatively healthy PrEP users that a trial to demonstrate clinical relevance would have to be huge, with years-long follow-up, Dr. Hare noted.
The average age of the men in this study was 36 years. Most were white, and about 60% lived in the United States. Other participants were from Canada or Europe.
The work was funded by Gilead; five investigators, including the senior investigator, were employees. Dr. Hare is an investigator for the company.
SOURCE: Hare CB et al. CROI 2019, Abstract 104 LB.
SEATTLE – Descovy [emtricitabine/tenofovir alafenamide (F/TAF]) was noninferior to Truvada [emtricitabine/tenofovir disoproxil fumarate (F/TDF)] for preexposure HIV prophylaxis in a blinded, randomized trial involving more than 5,000 men at high risk for the infection.
Both nucleotide reverse transcriptase inhibitors are made by Gilead, and the company funded the trial.
F/TDF (Truvada) has been a blockbuster for the company, both for HIV treatment and, since 2012, for preexposure prophylaxis (PrEP); it’s the only medication to carry the indication. However, F/TDF is set to go off patent in 2021, so the company has turned its development efforts to a successor, F/TAF (Descovy), a prodrug of tenofovir that is already approved for HIV treatment.
The new study builds a case for F/TAF for PrEP, but whether the results are strong enough to persuade people to opt for it over a much less expensive generic version of F/TDF remains to be seen.
The trial randomized 2,694 men who have sex with men to F/TAF, and 2,693 to F/TDF for up to 96 weeks. Entrance criteria included at least two episodes of unprotected anal sex in the previous 12 weeks, or a diagnosis of rectal gonorrhea, chlamydia, or syphilis in the previous 6 months.
More than half the men contracted at least one sexually transmitted infection during the trial, “which indicated to us that these were the right patients to be enrolled in the study,” lead investigator Charles Hare, MD, an infectious disease specialist at the University of California, San Francisco, said at the Conference on Retroviruses and Opportunistic Infections.
There were 15 new HIV infections in the F/TDF group (0.34 per 100 person-years), versus 7 in the F/TAF group (0.16 per 100 person-years). Almost all of the new infections were due to poor adherence – as proven by blood levels and dry blood spot testing – and most of the rest were in men who probably entered the trial with newly acquired HIV.
When those subjects were excluded, there were just two new onset HIV cases in subjects adherent to dosing, one in each arm. Infection rates were far lower than would have been expected had the subjects not been on PrEP.
One of Gilead’s main selling points for F/TAF over F/TDF is that the newer drug has better bone and renal safety, and there were slight biomarker differences in the trial that supported the assertion.
For instance, spine bone mineral density decreased 3% or greater from baseline in 10 F/TAF patients, but 27 men on F/TDF (P less than .001). Results were similar with hip bone density.
On the renal front, estimated glomerular filtration rates fell a median of 2.3 mL/min per 1.73 m2 in the F/TDF arm, but rose 1.8 mL/min per 1.73 m2 in men on F/TAF (P less than .001). Proximal tubular protein to creatinine ratios were largely unchanged from baseline with F/TAF, but slightly higher in the F/TDF group, at 48 weeks.
There were no statistically significant differences on actual safety outcomes – as opposed to biomarkers – between the two drugs or discontinuations due to side effects, which were rare and most often due to gastrointestinal issues. F/TAF patients gained about 1.1 kg in the trial, while weight held steady in the F/TDF arm. The study team plans to analyze lipid profile differences between the groups, since concern has been raised about F/TAF’s effect on them.
In a press conference at the conference, there was quite a bit of discussion about whether the results would justify using F/TAF for PrEP when less expensive generic versions of F/TDF become available.
“That’s a great question,” Dr. Hare said. “Both drugs actually performed quite well,” and both “do pretty well in terms of safety in this population.”
It’s not known at this point if the biomarker differences will prove to be clinically relevant. Hip fractures, kidney failure, and other problems are so rare in young, relatively healthy PrEP users that a trial to demonstrate clinical relevance would have to be huge, with years-long follow-up, Dr. Hare noted.
The average age of the men in this study was 36 years. Most were white, and about 60% lived in the United States. Other participants were from Canada or Europe.
The work was funded by Gilead; five investigators, including the senior investigator, were employees. Dr. Hare is an investigator for the company.
SOURCE: Hare CB et al. CROI 2019, Abstract 104 LB.
SEATTLE – Descovy [emtricitabine/tenofovir alafenamide (F/TAF]) was noninferior to Truvada [emtricitabine/tenofovir disoproxil fumarate (F/TDF)] for preexposure HIV prophylaxis in a blinded, randomized trial involving more than 5,000 men at high risk for the infection.
Both nucleotide reverse transcriptase inhibitors are made by Gilead, and the company funded the trial.
F/TDF (Truvada) has been a blockbuster for the company, both for HIV treatment and, since 2012, for preexposure prophylaxis (PrEP); it’s the only medication to carry the indication. However, F/TDF is set to go off patent in 2021, so the company has turned its development efforts to a successor, F/TAF (Descovy), a prodrug of tenofovir that is already approved for HIV treatment.
The new study builds a case for F/TAF for PrEP, but whether the results are strong enough to persuade people to opt for it over a much less expensive generic version of F/TDF remains to be seen.
The trial randomized 2,694 men who have sex with men to F/TAF, and 2,693 to F/TDF for up to 96 weeks. Entrance criteria included at least two episodes of unprotected anal sex in the previous 12 weeks, or a diagnosis of rectal gonorrhea, chlamydia, or syphilis in the previous 6 months.
More than half the men contracted at least one sexually transmitted infection during the trial, “which indicated to us that these were the right patients to be enrolled in the study,” lead investigator Charles Hare, MD, an infectious disease specialist at the University of California, San Francisco, said at the Conference on Retroviruses and Opportunistic Infections.
There were 15 new HIV infections in the F/TDF group (0.34 per 100 person-years), versus 7 in the F/TAF group (0.16 per 100 person-years). Almost all of the new infections were due to poor adherence – as proven by blood levels and dry blood spot testing – and most of the rest were in men who probably entered the trial with newly acquired HIV.
When those subjects were excluded, there were just two new onset HIV cases in subjects adherent to dosing, one in each arm. Infection rates were far lower than would have been expected had the subjects not been on PrEP.
One of Gilead’s main selling points for F/TAF over F/TDF is that the newer drug has better bone and renal safety, and there were slight biomarker differences in the trial that supported the assertion.
For instance, spine bone mineral density decreased 3% or greater from baseline in 10 F/TAF patients, but 27 men on F/TDF (P less than .001). Results were similar with hip bone density.
On the renal front, estimated glomerular filtration rates fell a median of 2.3 mL/min per 1.73 m2 in the F/TDF arm, but rose 1.8 mL/min per 1.73 m2 in men on F/TAF (P less than .001). Proximal tubular protein to creatinine ratios were largely unchanged from baseline with F/TAF, but slightly higher in the F/TDF group, at 48 weeks.
There were no statistically significant differences on actual safety outcomes – as opposed to biomarkers – between the two drugs or discontinuations due to side effects, which were rare and most often due to gastrointestinal issues. F/TAF patients gained about 1.1 kg in the trial, while weight held steady in the F/TDF arm. The study team plans to analyze lipid profile differences between the groups, since concern has been raised about F/TAF’s effect on them.
In a press conference at the conference, there was quite a bit of discussion about whether the results would justify using F/TAF for PrEP when less expensive generic versions of F/TDF become available.
“That’s a great question,” Dr. Hare said. “Both drugs actually performed quite well,” and both “do pretty well in terms of safety in this population.”
It’s not known at this point if the biomarker differences will prove to be clinically relevant. Hip fractures, kidney failure, and other problems are so rare in young, relatively healthy PrEP users that a trial to demonstrate clinical relevance would have to be huge, with years-long follow-up, Dr. Hare noted.
The average age of the men in this study was 36 years. Most were white, and about 60% lived in the United States. Other participants were from Canada or Europe.
The work was funded by Gilead; five investigators, including the senior investigator, were employees. Dr. Hare is an investigator for the company.
SOURCE: Hare CB et al. CROI 2019, Abstract 104 LB.
REPORTING FROM CROI 2019