Researchers found a lower rate of pediatric fever after applying a standard definition of fever across three different clinical trials of pediatric patients receiving influenza vaccinations, according to research published in the Pediatric Infectious Disease Journal.

Yangna/Thinkstock

Investigators in future studies must adopt a standardized definition of pediatric fever after an influenza vaccination. “Our study demonstrates the variability in results which occur due to minor differences in the definition of fever, methods of analysis and reporting of results,” Jean Li-Kim-Moy, MBBS, of the University of Sydney, and colleagues wrote.

Dr. Li-Kim-Moy and colleagues analyzed pediatric datasets from three different clinical trials using trivalent influenza vaccine (TIV); the primary trial included 3,317 children aged 6-35 months who were randomized to receive Fluarix at 0.25 mL or 0.5 mL, or receive 0.25 mL of Fluzone. The other two trials studied children receiving TIV between 6 months–17 years and 3-17 years. The researchers also performed a multivariable regression analysis to determine the relationship between immunogenicity, antipyretic use, and postvaccination fever.

The primary study initially reported the fever rate 0 days–3 days after vaccination was between 6% and 7%. After reporting the rate of fever separately for each dose and changing the criteria to “defining fever as greater than or equal to 38.0°C by any route of measurement” for the primary study, the researchers found a rate of any-cause fever was 3%-4% for the first dose and 4%-5% for the second dose. The rate of vaccine-related fever in the primary study was 3% for the first dose and 3%-4% for the second dose, with researchers noting vaccine-related fever occurred significantly earlier compared with any-cause fever (mean 1 days vs. 2 days after vaccination; P equals .04).

Impact of fever, antipyretics

The researchers also performed a pooled immunogenicity analysis of 5,902 children from all three trials and found a strong association between fever after vaccination and increased geometric mean titer (GMT) ratios (1.21-1.39; P less than or equal to .01) and an association between antipyretic use and reduced GMT ratios (0.80-0.87; P less than .0006).

“Our pooled analysis of the three trials demonstrated highly significant associations, for all strains, between postvaccination fever and up to 39% higher GMT; this may suggest a close role between fever and the body’s immunologic response to the influenza antigens within the vaccine. Similarly, strong evidence of associations in the opposite direction was found between postvaccination antipyretic use (days 0-3), adjusting for all other factors including fever, and decreased immunogenicity against all vaccine strains in children,” Dr. Li-Kim-Moy and colleagues said.

Antipyretic use was common in the primary study, occurring in one in six of the children, they said. These findings of “significant associations between fever and increased vaccine immunogenicity, and between antipyretic use and reduced immunogenicity in children after influenza vaccination” suggest the need for further study, especially because parents often give antipyretics if their children are febrile after vaccinations.

“There is uncertainty whether our findings, and those of others, on immunogenicity translate into clinically significant effects,” they wrote. “However, the fact that influenza vaccine, unlike many routine childhood vaccines, is only moderately protective may mean that modest reductions in antibody response are more likely to correlate to less protection.”

Dr. Wood reported receiving a fellowship from the National Health and Medical Research Council (NHMRC) and being an investigator for GlaxoSmithKline trials. Dr. Booy reported being an advisor for influenza vaccine manufacturing, an advisory board member, on the speaker’s bureau, and a researcher of vaccines for several manufacturers. The other authors reported no relevant conflicts of interest.

SOURCE: Li-Kim-Moy J et al. Pediatr Infect Dis J. 2018 Oct;37(10):971-5.

Researchers found a lower rate of pediatric fever after applying a standard definition of fever across three different clinical trials of pediatric patients receiving influenza vaccinations, according to research published in the Pediatric Infectious Disease Journal.

Yangna/Thinkstock

Investigators in future studies must adopt a standardized definition of pediatric fever after an influenza vaccination. “Our study demonstrates the variability in results which occur due to minor differences in the definition of fever, methods of analysis and reporting of results,” Jean Li-Kim-Moy, MBBS, of the University of Sydney, and colleagues wrote.

Dr. Li-Kim-Moy and colleagues analyzed pediatric datasets from three different clinical trials using trivalent influenza vaccine (TIV); the primary trial included 3,317 children aged 6-35 months who were randomized to receive Fluarix at 0.25 mL or 0.5 mL, or receive 0.25 mL of Fluzone. The other two trials studied children receiving TIV between 6 months–17 years and 3-17 years. The researchers also performed a multivariable regression analysis to determine the relationship between immunogenicity, antipyretic use, and postvaccination fever.

The primary study initially reported the fever rate 0 days–3 days after vaccination was between 6% and 7%. After reporting the rate of fever separately for each dose and changing the criteria to “defining fever as greater than or equal to 38.0°C by any route of measurement” for the primary study, the researchers found a rate of any-cause fever was 3%-4% for the first dose and 4%-5% for the second dose. The rate of vaccine-related fever in the primary study was 3% for the first dose and 3%-4% for the second dose, with researchers noting vaccine-related fever occurred significantly earlier compared with any-cause fever (mean 1 days vs. 2 days after vaccination; P equals .04).

Impact of fever, antipyretics

The researchers also performed a pooled immunogenicity analysis of 5,902 children from all three trials and found a strong association between fever after vaccination and increased geometric mean titer (GMT) ratios (1.21-1.39; P less than or equal to .01) and an association between antipyretic use and reduced GMT ratios (0.80-0.87; P less than .0006).

“Our pooled analysis of the three trials demonstrated highly significant associations, for all strains, between postvaccination fever and up to 39% higher GMT; this may suggest a close role between fever and the body’s immunologic response to the influenza antigens within the vaccine. Similarly, strong evidence of associations in the opposite direction was found between postvaccination antipyretic use (days 0-3), adjusting for all other factors including fever, and decreased immunogenicity against all vaccine strains in children,” Dr. Li-Kim-Moy and colleagues said.

Antipyretic use was common in the primary study, occurring in one in six of the children, they said. These findings of “significant associations between fever and increased vaccine immunogenicity, and between antipyretic use and reduced immunogenicity in children after influenza vaccination” suggest the need for further study, especially because parents often give antipyretics if their children are febrile after vaccinations.

“There is uncertainty whether our findings, and those of others, on immunogenicity translate into clinically significant effects,” they wrote. “However, the fact that influenza vaccine, unlike many routine childhood vaccines, is only moderately protective may mean that modest reductions in antibody response are more likely to correlate to less protection.”

Dr. Wood reported receiving a fellowship from the National Health and Medical Research Council (NHMRC) and being an investigator for GlaxoSmithKline trials. Dr. Booy reported being an advisor for influenza vaccine manufacturing, an advisory board member, on the speaker’s bureau, and a researcher of vaccines for several manufacturers. The other authors reported no relevant conflicts of interest.

SOURCE: Li-Kim-Moy J et al. Pediatr Infect Dis J. 2018 Oct;37(10):971-5.

Researchers found a lower rate of pediatric fever after applying a standard definition of fever across three different clinical trials of pediatric patients receiving influenza vaccinations, according to research published in the Pediatric Infectious Disease Journal.

Yangna/Thinkstock

Investigators in future studies must adopt a standardized definition of pediatric fever after an influenza vaccination. “Our study demonstrates the variability in results which occur due to minor differences in the definition of fever, methods of analysis and reporting of results,” Jean Li-Kim-Moy, MBBS, of the University of Sydney, and colleagues wrote.

Dr. Li-Kim-Moy and colleagues analyzed pediatric datasets from three different clinical trials using trivalent influenza vaccine (TIV); the primary trial included 3,317 children aged 6-35 months who were randomized to receive Fluarix at 0.25 mL or 0.5 mL, or receive 0.25 mL of Fluzone. The other two trials studied children receiving TIV between 6 months–17 years and 3-17 years. The researchers also performed a multivariable regression analysis to determine the relationship between immunogenicity, antipyretic use, and postvaccination fever.

The primary study initially reported the fever rate 0 days–3 days after vaccination was between 6% and 7%. After reporting the rate of fever separately for each dose and changing the criteria to “defining fever as greater than or equal to 38.0°C by any route of measurement” for the primary study, the researchers found a rate of any-cause fever was 3%-4% for the first dose and 4%-5% for the second dose. The rate of vaccine-related fever in the primary study was 3% for the first dose and 3%-4% for the second dose, with researchers noting vaccine-related fever occurred significantly earlier compared with any-cause fever (mean 1 days vs. 2 days after vaccination; P equals .04).

Impact of fever, antipyretics

The researchers also performed a pooled immunogenicity analysis of 5,902 children from all three trials and found a strong association between fever after vaccination and increased geometric mean titer (GMT) ratios (1.21-1.39; P less than or equal to .01) and an association between antipyretic use and reduced GMT ratios (0.80-0.87; P less than .0006).

“Our pooled analysis of the three trials demonstrated highly significant associations, for all strains, between postvaccination fever and up to 39% higher GMT; this may suggest a close role between fever and the body’s immunologic response to the influenza antigens within the vaccine. Similarly, strong evidence of associations in the opposite direction was found between postvaccination antipyretic use (days 0-3), adjusting for all other factors including fever, and decreased immunogenicity against all vaccine strains in children,” Dr. Li-Kim-Moy and colleagues said.

Antipyretic use was common in the primary study, occurring in one in six of the children, they said. These findings of “significant associations between fever and increased vaccine immunogenicity, and between antipyretic use and reduced immunogenicity in children after influenza vaccination” suggest the need for further study, especially because parents often give antipyretics if their children are febrile after vaccinations.

“There is uncertainty whether our findings, and those of others, on immunogenicity translate into clinically significant effects,” they wrote. “However, the fact that influenza vaccine, unlike many routine childhood vaccines, is only moderately protective may mean that modest reductions in antibody response are more likely to correlate to less protection.”

Dr. Wood reported receiving a fellowship from the National Health and Medical Research Council (NHMRC) and being an investigator for GlaxoSmithKline trials. Dr. Booy reported being an advisor for influenza vaccine manufacturing, an advisory board member, on the speaker’s bureau, and a researcher of vaccines for several manufacturers. The other authors reported no relevant conflicts of interest.

SOURCE: Li-Kim-Moy J et al. Pediatr Infect Dis J. 2018 Oct;37(10):971-5.

SAN ANTONIO – A definitive laparotomy isn’t much more clinically costly than a damage-control procedure, but it can cost fewer resources: fewer days in intensive care, fewer days on a ventilator, and a shorter overall length of stay.

Among damage-control abdominal trauma cases that could have been closed, definitive laparotomy (DEF) was associated with a 56% probability of major abdominal complications – very close to the probability associated with damage-control closure, John Harvin, MD, said at the annual meeting of the American Association for the Surgery of Trauma.

Definitive closure was also associated with about a 72% chance of more ventilator- and hospital-free days and a 77% chance of more ICU-free days than damage-control closure, said Dr. Harvin of the University of Texas, Austin.

“Our analysis tells us that there’s a minimal chance of reducing complications with a definitive laparotomy, compared to leaving them open, but this also comes with more than a 70% chance of having a shorter hospital staying and getting off the ventilator faster.”

The data from a 2-year quality review process reaffirms what trauma surgeons have been seeing, and reporting, since damage-control closure became more popular in the past decade, said Peter Rhee, MD, commenting on the study.

Michele Sullivan/MDedge News

“There are three congregations in this faith of damage-control laparotomy,” said Dr. Rhee, a surgeon in Atlanta, Ga. “The first believes it should be the default for all these types of operations and that being preemptive is better than anything. The second believes that it doesn’t hurt the patient too much, and that it can be done when absolutely needed to save a life. The third belief is that there’s minimal data to support it, that it should rarely be used, and that it’s always costly. We all know that the pendulum of damage-control laparotomy is finally swinging back to the center.”

The study arose from an effort at the Red Duke Trauma Institute, Austin, Tex., to reduce its rate of damage-control laparotomy (DCL). Surgeons examined all emergent trauma laparotomies conducted from 2013 to 2015. They discussed each case and compared morbidity and mortality rates to a published control group. This work was published last year in the Journal of the American College of Surgeons.

By adopting this review procedure, the hospital was able to decrease its 39% DCL rate to 23% over 2 years (an absolute reduction of 68 cases) without any change in infection rates, fascial dehiscence, unplanned reoperation, or mortality. The improvements continued, Dr. Harvin noted, with a farther 17% reduction in DCL after the project concluded.

Dr. Harvin’s analysis looked at 44 of these procedures which, according to the adjudication panel, could have been managed by DEF. Each was matched to a DEF case, and the outcomes were calculated with a Bayesian statistical model.

The primary outcome was major abdominal complication, a composite measure of fascial dehiscence, organ or space surgical-site infection, reopening of fascia, and enteric suture line failure. Secondary outcomes were days off the ventilator and out of the ICU and hospital.

Of the 872 patients in the study, most (639; 73%) were managed by DEF; the rest (209; 24%) were managed by DCL. Of these, the panel agreed that 44 (22%) could have been safely closed at the time of surgery and survived at least 5 days. The propensity-matching scheme comprised 39 of these cases matched with 39 DEF cases.

Most were male (74%); the mean age was 38 years. Penetrating injuries were most common (54%). The abdominal Abbreviated Injury Score was 3. The mean Injury Severity Score was 22 in the DEF cases and 25 in the DCL cases, but this was not a significant difference. There were no differences in blood pressure at presentation or at the end of the surgery, no differences in blood transfusion needs, and no differences in body temperature.

A major abdominal complication occurred in 31% of the DEF cases and 21% of the DCL cases, a relative risk of 0.99. This amounted to a 56% posterior probability of a complication associated with DEF.

Comparing DCL cases with DEF cases, the mean number of hospital-free days was 15 vs.13; ICU-free days, 26 vs. 21; and ventilator-free days, 29 vs. 26. These differences amount to a 72% chance that DEL would result in more hospital-free days and more ventilator-free days, and a 77% chance that DEL would result in more ICU-free days.

The numbers underscore the need to rethink DCL for abdominal trauma, Dr. Rhee said.

“I too once believed in this procedure and used to do it all the time. After 2 decades, we now know that it contributed to the frozen bellies, abdominal wound hernias, fascial dehiscence, missed complications, and to the never-ending enteroatmospheric fistulas. If we want to reduce fistulas, we must first reduce damage-control laparotomy. Nurses will love you for not creating the narcotic-addicted, total parenteral nutrition–dependent patient with a fragrant open belly and a fistula.”

Neither Dr. Harvin nor Dr Rhee had any relevant financial disclosures.

[email protected]

SOURCE: Harvin L et al. AAST 2018, Oral paper 12.

SAN ANTONIO – A definitive laparotomy isn’t much more clinically costly than a damage-control procedure, but it can cost fewer resources: fewer days in intensive care, fewer days on a ventilator, and a shorter overall length of stay.

Among damage-control abdominal trauma cases that could have been closed, definitive laparotomy (DEF) was associated with a 56% probability of major abdominal complications – very close to the probability associated with damage-control closure, John Harvin, MD, said at the annual meeting of the American Association for the Surgery of Trauma.

Definitive closure was also associated with about a 72% chance of more ventilator- and hospital-free days and a 77% chance of more ICU-free days than damage-control closure, said Dr. Harvin of the University of Texas, Austin.

“Our analysis tells us that there’s a minimal chance of reducing complications with a definitive laparotomy, compared to leaving them open, but this also comes with more than a 70% chance of having a shorter hospital staying and getting off the ventilator faster.”

The data from a 2-year quality review process reaffirms what trauma surgeons have been seeing, and reporting, since damage-control closure became more popular in the past decade, said Peter Rhee, MD, commenting on the study.

Michele Sullivan/MDedge News

“There are three congregations in this faith of damage-control laparotomy,” said Dr. Rhee, a surgeon in Atlanta, Ga. “The first believes it should be the default for all these types of operations and that being preemptive is better than anything. The second believes that it doesn’t hurt the patient too much, and that it can be done when absolutely needed to save a life. The third belief is that there’s minimal data to support it, that it should rarely be used, and that it’s always costly. We all know that the pendulum of damage-control laparotomy is finally swinging back to the center.”

The study arose from an effort at the Red Duke Trauma Institute, Austin, Tex., to reduce its rate of damage-control laparotomy (DCL). Surgeons examined all emergent trauma laparotomies conducted from 2013 to 2015. They discussed each case and compared morbidity and mortality rates to a published control group. This work was published last year in the Journal of the American College of Surgeons.

By adopting this review procedure, the hospital was able to decrease its 39% DCL rate to 23% over 2 years (an absolute reduction of 68 cases) without any change in infection rates, fascial dehiscence, unplanned reoperation, or mortality. The improvements continued, Dr. Harvin noted, with a farther 17% reduction in DCL after the project concluded.

Dr. Harvin’s analysis looked at 44 of these procedures which, according to the adjudication panel, could have been managed by DEF. Each was matched to a DEF case, and the outcomes were calculated with a Bayesian statistical model.

The primary outcome was major abdominal complication, a composite measure of fascial dehiscence, organ or space surgical-site infection, reopening of fascia, and enteric suture line failure. Secondary outcomes were days off the ventilator and out of the ICU and hospital.

Of the 872 patients in the study, most (639; 73%) were managed by DEF; the rest (209; 24%) were managed by DCL. Of these, the panel agreed that 44 (22%) could have been safely closed at the time of surgery and survived at least 5 days. The propensity-matching scheme comprised 39 of these cases matched with 39 DEF cases.

Most were male (74%); the mean age was 38 years. Penetrating injuries were most common (54%). The abdominal Abbreviated Injury Score was 3. The mean Injury Severity Score was 22 in the DEF cases and 25 in the DCL cases, but this was not a significant difference. There were no differences in blood pressure at presentation or at the end of the surgery, no differences in blood transfusion needs, and no differences in body temperature.

A major abdominal complication occurred in 31% of the DEF cases and 21% of the DCL cases, a relative risk of 0.99. This amounted to a 56% posterior probability of a complication associated with DEF.

Comparing DCL cases with DEF cases, the mean number of hospital-free days was 15 vs.13; ICU-free days, 26 vs. 21; and ventilator-free days, 29 vs. 26. These differences amount to a 72% chance that DEL would result in more hospital-free days and more ventilator-free days, and a 77% chance that DEL would result in more ICU-free days.

The numbers underscore the need to rethink DCL for abdominal trauma, Dr. Rhee said.

“I too once believed in this procedure and used to do it all the time. After 2 decades, we now know that it contributed to the frozen bellies, abdominal wound hernias, fascial dehiscence, missed complications, and to the never-ending enteroatmospheric fistulas. If we want to reduce fistulas, we must first reduce damage-control laparotomy. Nurses will love you for not creating the narcotic-addicted, total parenteral nutrition–dependent patient with a fragrant open belly and a fistula.”

Neither Dr. Harvin nor Dr Rhee had any relevant financial disclosures.

[email protected]

SOURCE: Harvin L et al. AAST 2018, Oral paper 12.

SAN ANTONIO – A definitive laparotomy isn’t much more clinically costly than a damage-control procedure, but it can cost fewer resources: fewer days in intensive care, fewer days on a ventilator, and a shorter overall length of stay.

Among damage-control abdominal trauma cases that could have been closed, definitive laparotomy (DEF) was associated with a 56% probability of major abdominal complications – very close to the probability associated with damage-control closure, John Harvin, MD, said at the annual meeting of the American Association for the Surgery of Trauma.

Definitive closure was also associated with about a 72% chance of more ventilator- and hospital-free days and a 77% chance of more ICU-free days than damage-control closure, said Dr. Harvin of the University of Texas, Austin.

“Our analysis tells us that there’s a minimal chance of reducing complications with a definitive laparotomy, compared to leaving them open, but this also comes with more than a 70% chance of having a shorter hospital staying and getting off the ventilator faster.”

The data from a 2-year quality review process reaffirms what trauma surgeons have been seeing, and reporting, since damage-control closure became more popular in the past decade, said Peter Rhee, MD, commenting on the study.

Michele Sullivan/MDedge News

“There are three congregations in this faith of damage-control laparotomy,” said Dr. Rhee, a surgeon in Atlanta, Ga. “The first believes it should be the default for all these types of operations and that being preemptive is better than anything. The second believes that it doesn’t hurt the patient too much, and that it can be done when absolutely needed to save a life. The third belief is that there’s minimal data to support it, that it should rarely be used, and that it’s always costly. We all know that the pendulum of damage-control laparotomy is finally swinging back to the center.”

The study arose from an effort at the Red Duke Trauma Institute, Austin, Tex., to reduce its rate of damage-control laparotomy (DCL). Surgeons examined all emergent trauma laparotomies conducted from 2013 to 2015. They discussed each case and compared morbidity and mortality rates to a published control group. This work was published last year in the Journal of the American College of Surgeons.

By adopting this review procedure, the hospital was able to decrease its 39% DCL rate to 23% over 2 years (an absolute reduction of 68 cases) without any change in infection rates, fascial dehiscence, unplanned reoperation, or mortality. The improvements continued, Dr. Harvin noted, with a farther 17% reduction in DCL after the project concluded.

Dr. Harvin’s analysis looked at 44 of these procedures which, according to the adjudication panel, could have been managed by DEF. Each was matched to a DEF case, and the outcomes were calculated with a Bayesian statistical model.

The primary outcome was major abdominal complication, a composite measure of fascial dehiscence, organ or space surgical-site infection, reopening of fascia, and enteric suture line failure. Secondary outcomes were days off the ventilator and out of the ICU and hospital.

Of the 872 patients in the study, most (639; 73%) were managed by DEF; the rest (209; 24%) were managed by DCL. Of these, the panel agreed that 44 (22%) could have been safely closed at the time of surgery and survived at least 5 days. The propensity-matching scheme comprised 39 of these cases matched with 39 DEF cases.

Most were male (74%); the mean age was 38 years. Penetrating injuries were most common (54%). The abdominal Abbreviated Injury Score was 3. The mean Injury Severity Score was 22 in the DEF cases and 25 in the DCL cases, but this was not a significant difference. There were no differences in blood pressure at presentation or at the end of the surgery, no differences in blood transfusion needs, and no differences in body temperature.

A major abdominal complication occurred in 31% of the DEF cases and 21% of the DCL cases, a relative risk of 0.99. This amounted to a 56% posterior probability of a complication associated with DEF.

Comparing DCL cases with DEF cases, the mean number of hospital-free days was 15 vs.13; ICU-free days, 26 vs. 21; and ventilator-free days, 29 vs. 26. These differences amount to a 72% chance that DEL would result in more hospital-free days and more ventilator-free days, and a 77% chance that DEL would result in more ICU-free days.

The numbers underscore the need to rethink DCL for abdominal trauma, Dr. Rhee said.

“I too once believed in this procedure and used to do it all the time. After 2 decades, we now know that it contributed to the frozen bellies, abdominal wound hernias, fascial dehiscence, missed complications, and to the never-ending enteroatmospheric fistulas. If we want to reduce fistulas, we must first reduce damage-control laparotomy. Nurses will love you for not creating the narcotic-addicted, total parenteral nutrition–dependent patient with a fragrant open belly and a fistula.”

Neither Dr. Harvin nor Dr Rhee had any relevant financial disclosures.

[email protected]

SOURCE: Harvin L et al. AAST 2018, Oral paper 12.

MUNICH – A comprehensive home telemonitoring program paid off big for selected patients with heart failure in a large, German nationwide masked randomization trial.

Bruce Jancin/MDedge News

SOURCE: Koehler F et al. ESC Congress 2018. Lancet. 2018 Sep 22;392(10152):1047-57.

MUNICH – A comprehensive home telemonitoring program paid off big for selected patients with heart failure in a large, German nationwide masked randomization trial.

Bruce Jancin/MDedge News

SOURCE: Koehler F et al. ESC Congress 2018. Lancet. 2018 Sep 22;392(10152):1047-57.

MUNICH – A comprehensive home telemonitoring program paid off big for selected patients with heart failure in a large, German nationwide masked randomization trial.

Bruce Jancin/MDedge News

SOURCE: Koehler F et al. ESC Congress 2018. Lancet. 2018 Sep 22;392(10152):1047-57.

SAN DIEGO – Pulmonary artery denervation is efficacious for treating combined pre- and postcapillary pulmonary hypertension attributable to left heart failure, based on results of the Chinese PADN-5 trial reported at the Transcatheter Cardiovascular Therapeutics annual meeting.

Susan London/MDedge News

This ablative treatment has been studied among patients with pulmonary hypertension attributable to other etiologies, but not in randomized fashion among this population, noted lead investigator Shao-Liang Chen, MD, of Nanjing (China) First Hospital, Nanjing Medical University. The treatment is an attractive one, as medications recommended for pulmonary arterial hypertension are not recommended for joint pre- and postcapillary pulmonary hypertension (group II pulmonary hypertension).

In PADN-5, 98 patients were randomized to pulmonary artery denervation or to sham denervation plus open-label sildenafil (Viagra), which at the time of trial initiation was thought to be safe and potentially beneficial.

The trial’s main outcome, 6-minute walk distance at 6 months, improved in both groups, according to data reported at the meeting and simultaneously published in JACC Cardiovascular Interventions. But the improvement was about four times greater in the pulmonary artery denervation group. Secondary efficacy outcomes also favored that group, and the rate of fatal pulmonary embolism did not differ for the two groups.

“The PADN-5 trial demonstrates the benefits of pulmonary artery denervation for patients with combined pre- and postcapillary pulmonary hypertension. Patients with preserved and with reduced ejection fraction equally benefited,” summarized Dr. Chen, who pioneered this procedure about 7 years ago. “There was no sign of any harm of sildenafil in patients with combined pre- and postcapillary pulmonary hypertension.”
 

Trial critique

“This is a very difficult study to conduct, being able to recruit patients and actually have these procedures done,” commented press conference moderator Ori Ben-Yehuda, MD, professor of clinical medicine and director, coronary care unit, UC San Diego Medical Center.

At the same time, he expressed some reservations about the trial. “Sildenafil in the control group might actually be expected to ... decrease your effect size. Also, particularly in men, perhaps even in women, it might unblind them to which group they are in and undermine your sham design,” he noted. In addition, some hemodynamic changes after pulmonary artery denervation – a decrease in wedge pressure and an increase in ejection fraction – were puzzling.

“We need a lot more data here. There are some issues with this trial in terms of design, and we haven’t even gotten into the issue of whether there were core labs, whether the echoes, the hemodynamics, were read blindly,” Dr. Ben-Yehuda maintained. “This issue of secondary or group II pulmonary hypertension due to left heart failure is one that has been very frustrating in terms of actual PA-specific therapies. So this is an important step further, but it needs confirmation in truly sham-controlled trials that have no potential for unblinding.”

The catheter used in PADN-5 is available in China but has not received clearance in the United States, he pointed out. “There are alternative or competing technologies, one using ultrasound, for example, that has a very similar approach. … We’ll have to see how it ends up [performing].”
 

Trial details

Patients in the PADN-5 pulmonary artery denervation group underwent ablation only in the periconjunctional area between the distal main trunk and the left ostial branch with a multifunction catheter having premounted electrodes. Those in the control group underwent a sham procedure, with catheter positioning at the target sites and connection to a generator but no ablation, and were given open-label sildenafil. All additionally received standard heart failure medical therapy. (No sildenafil placebo was used in the denervation group.)

Trial results reported at the meeting, which is sponsored by the Cardiovascular Research Foundation, showed that most echocardiographic and hemodynamic measures improved more in the pulmonary artery denervation group.

The greater improvement in 6-minute walk test with denervation versus sham sildenafil at 6 months was evident in a variety of measures: absolute median distance walked (432.5 m vs. 358 m) and mean distance walked (434.6 m vs. 359.4 m), and absolute increase (80 m vs. 17.5 m) and relative increase (21.4% vs. 4.9%) The difference was significant for all measures at P less than .001.

The denervation group had a comparatively greater reduction of pulmonary vascular resistance (29.8% vs. 3.4%; P less than .001) and were less likely to experience clinical worsening (16.7% vs. 40.0%; P = .014).

There was a single fatal pulmonary embolism in each treatment group. Of the seven total deaths, two occurred in the denervation group (one attributable to pump failure, one a sudden death) and five occurred in the sham sildenafil group (all but one attributable to pump failure).

Dr. Chen disclosed that he had no relevant conflicts of interest. The trial was sponsored by Nanjing First Hospital, Nanjing Medical University.

SOURCE: Chen S-J et al. TCT 2018. JACC Cardiovasc Interv. 2018 Sep 23.

SAN DIEGO – Pulmonary artery denervation is efficacious for treating combined pre- and postcapillary pulmonary hypertension attributable to left heart failure, based on results of the Chinese PADN-5 trial reported at the Transcatheter Cardiovascular Therapeutics annual meeting.

Susan London/MDedge News

This ablative treatment has been studied among patients with pulmonary hypertension attributable to other etiologies, but not in randomized fashion among this population, noted lead investigator Shao-Liang Chen, MD, of Nanjing (China) First Hospital, Nanjing Medical University. The treatment is an attractive one, as medications recommended for pulmonary arterial hypertension are not recommended for joint pre- and postcapillary pulmonary hypertension (group II pulmonary hypertension).

In PADN-5, 98 patients were randomized to pulmonary artery denervation or to sham denervation plus open-label sildenafil (Viagra), which at the time of trial initiation was thought to be safe and potentially beneficial.

The trial’s main outcome, 6-minute walk distance at 6 months, improved in both groups, according to data reported at the meeting and simultaneously published in JACC Cardiovascular Interventions. But the improvement was about four times greater in the pulmonary artery denervation group. Secondary efficacy outcomes also favored that group, and the rate of fatal pulmonary embolism did not differ for the two groups.

“The PADN-5 trial demonstrates the benefits of pulmonary artery denervation for patients with combined pre- and postcapillary pulmonary hypertension. Patients with preserved and with reduced ejection fraction equally benefited,” summarized Dr. Chen, who pioneered this procedure about 7 years ago. “There was no sign of any harm of sildenafil in patients with combined pre- and postcapillary pulmonary hypertension.”
 

Trial critique

“This is a very difficult study to conduct, being able to recruit patients and actually have these procedures done,” commented press conference moderator Ori Ben-Yehuda, MD, professor of clinical medicine and director, coronary care unit, UC San Diego Medical Center.

At the same time, he expressed some reservations about the trial. “Sildenafil in the control group might actually be expected to ... decrease your effect size. Also, particularly in men, perhaps even in women, it might unblind them to which group they are in and undermine your sham design,” he noted. In addition, some hemodynamic changes after pulmonary artery denervation – a decrease in wedge pressure and an increase in ejection fraction – were puzzling.

“We need a lot more data here. There are some issues with this trial in terms of design, and we haven’t even gotten into the issue of whether there were core labs, whether the echoes, the hemodynamics, were read blindly,” Dr. Ben-Yehuda maintained. “This issue of secondary or group II pulmonary hypertension due to left heart failure is one that has been very frustrating in terms of actual PA-specific therapies. So this is an important step further, but it needs confirmation in truly sham-controlled trials that have no potential for unblinding.”

The catheter used in PADN-5 is available in China but has not received clearance in the United States, he pointed out. “There are alternative or competing technologies, one using ultrasound, for example, that has a very similar approach. … We’ll have to see how it ends up [performing].”
 

Trial details

Patients in the PADN-5 pulmonary artery denervation group underwent ablation only in the periconjunctional area between the distal main trunk and the left ostial branch with a multifunction catheter having premounted electrodes. Those in the control group underwent a sham procedure, with catheter positioning at the target sites and connection to a generator but no ablation, and were given open-label sildenafil. All additionally received standard heart failure medical therapy. (No sildenafil placebo was used in the denervation group.)

Trial results reported at the meeting, which is sponsored by the Cardiovascular Research Foundation, showed that most echocardiographic and hemodynamic measures improved more in the pulmonary artery denervation group.

The greater improvement in 6-minute walk test with denervation versus sham sildenafil at 6 months was evident in a variety of measures: absolute median distance walked (432.5 m vs. 358 m) and mean distance walked (434.6 m vs. 359.4 m), and absolute increase (80 m vs. 17.5 m) and relative increase (21.4% vs. 4.9%) The difference was significant for all measures at P less than .001.

The denervation group had a comparatively greater reduction of pulmonary vascular resistance (29.8% vs. 3.4%; P less than .001) and were less likely to experience clinical worsening (16.7% vs. 40.0%; P = .014).

There was a single fatal pulmonary embolism in each treatment group. Of the seven total deaths, two occurred in the denervation group (one attributable to pump failure, one a sudden death) and five occurred in the sham sildenafil group (all but one attributable to pump failure).

Dr. Chen disclosed that he had no relevant conflicts of interest. The trial was sponsored by Nanjing First Hospital, Nanjing Medical University.

SOURCE: Chen S-J et al. TCT 2018. JACC Cardiovasc Interv. 2018 Sep 23.

SAN DIEGO – Pulmonary artery denervation is efficacious for treating combined pre- and postcapillary pulmonary hypertension attributable to left heart failure, based on results of the Chinese PADN-5 trial reported at the Transcatheter Cardiovascular Therapeutics annual meeting.

Susan London/MDedge News

This ablative treatment has been studied among patients with pulmonary hypertension attributable to other etiologies, but not in randomized fashion among this population, noted lead investigator Shao-Liang Chen, MD, of Nanjing (China) First Hospital, Nanjing Medical University. The treatment is an attractive one, as medications recommended for pulmonary arterial hypertension are not recommended for joint pre- and postcapillary pulmonary hypertension (group II pulmonary hypertension).

In PADN-5, 98 patients were randomized to pulmonary artery denervation or to sham denervation plus open-label sildenafil (Viagra), which at the time of trial initiation was thought to be safe and potentially beneficial.

The trial’s main outcome, 6-minute walk distance at 6 months, improved in both groups, according to data reported at the meeting and simultaneously published in JACC Cardiovascular Interventions. But the improvement was about four times greater in the pulmonary artery denervation group. Secondary efficacy outcomes also favored that group, and the rate of fatal pulmonary embolism did not differ for the two groups.

“The PADN-5 trial demonstrates the benefits of pulmonary artery denervation for patients with combined pre- and postcapillary pulmonary hypertension. Patients with preserved and with reduced ejection fraction equally benefited,” summarized Dr. Chen, who pioneered this procedure about 7 years ago. “There was no sign of any harm of sildenafil in patients with combined pre- and postcapillary pulmonary hypertension.”
 

Trial critique

“This is a very difficult study to conduct, being able to recruit patients and actually have these procedures done,” commented press conference moderator Ori Ben-Yehuda, MD, professor of clinical medicine and director, coronary care unit, UC San Diego Medical Center.

At the same time, he expressed some reservations about the trial. “Sildenafil in the control group might actually be expected to ... decrease your effect size. Also, particularly in men, perhaps even in women, it might unblind them to which group they are in and undermine your sham design,” he noted. In addition, some hemodynamic changes after pulmonary artery denervation – a decrease in wedge pressure and an increase in ejection fraction – were puzzling.

“We need a lot more data here. There are some issues with this trial in terms of design, and we haven’t even gotten into the issue of whether there were core labs, whether the echoes, the hemodynamics, were read blindly,” Dr. Ben-Yehuda maintained. “This issue of secondary or group II pulmonary hypertension due to left heart failure is one that has been very frustrating in terms of actual PA-specific therapies. So this is an important step further, but it needs confirmation in truly sham-controlled trials that have no potential for unblinding.”

The catheter used in PADN-5 is available in China but has not received clearance in the United States, he pointed out. “There are alternative or competing technologies, one using ultrasound, for example, that has a very similar approach. … We’ll have to see how it ends up [performing].”
 

Trial details

Patients in the PADN-5 pulmonary artery denervation group underwent ablation only in the periconjunctional area between the distal main trunk and the left ostial branch with a multifunction catheter having premounted electrodes. Those in the control group underwent a sham procedure, with catheter positioning at the target sites and connection to a generator but no ablation, and were given open-label sildenafil. All additionally received standard heart failure medical therapy. (No sildenafil placebo was used in the denervation group.)

Trial results reported at the meeting, which is sponsored by the Cardiovascular Research Foundation, showed that most echocardiographic and hemodynamic measures improved more in the pulmonary artery denervation group.

The greater improvement in 6-minute walk test with denervation versus sham sildenafil at 6 months was evident in a variety of measures: absolute median distance walked (432.5 m vs. 358 m) and mean distance walked (434.6 m vs. 359.4 m), and absolute increase (80 m vs. 17.5 m) and relative increase (21.4% vs. 4.9%) The difference was significant for all measures at P less than .001.

The denervation group had a comparatively greater reduction of pulmonary vascular resistance (29.8% vs. 3.4%; P less than .001) and were less likely to experience clinical worsening (16.7% vs. 40.0%; P = .014).

There was a single fatal pulmonary embolism in each treatment group. Of the seven total deaths, two occurred in the denervation group (one attributable to pump failure, one a sudden death) and five occurred in the sham sildenafil group (all but one attributable to pump failure).

Dr. Chen disclosed that he had no relevant conflicts of interest. The trial was sponsored by Nanjing First Hospital, Nanjing Medical University.

SOURCE: Chen S-J et al. TCT 2018. JACC Cardiovasc Interv. 2018 Sep 23.

The U.S. Food and Drug Administration has approved cemiplimab-rwlc (Libtayo) for the treatment of metastatic or locally advanced cutaneous squamous cell carcinoma, the agency announced in a press release.

The U.S. Food and Drug Administration has approved cemiplimab-rwlc (Libtayo) for the treatment of metastatic or locally advanced cutaneous squamous cell carcinoma, the agency announced in a press release.

The U.S. Food and Drug Administration has approved cemiplimab-rwlc (Libtayo) for the treatment of metastatic or locally advanced cutaneous squamous cell carcinoma, the agency announced in a press release.

Across-the-board use of aspirin for primary prevention is “not justified” based on the results of ASPREE as well as the equivocal results from other recent primary prevention trials, according to Prakash C. Deedwania, MD, clinical professor of medicine and chief of the cardiology division at the Veterans Affairs Medical Center/University of California San Francisco Program in Fresno.

In ASPREE, a randomized, double-blind, placebo-controlled trial including nearly 20,000 participants, daily aspirin increased rates of major hemorrhage and did not significantly decrease risks of cardiovascular events, death, or other outcomes in healthy elderly individuals.

Aspirin did not prolong disability-free survival, a composite endpoint that included death, dementia, and permanent physical disability, according to one of three separate reports on ASPREE that were published in the New England Journal of Medicine.

Cardiovascular disease rates were likewise not significantly different between aspirin and placebo, with a hazard ratio that ruled out the possibility of a major protective effect, lead author John J. McNeil, MBBS, PhD, of Monash University, Melbourne, said in a second report on ASPREE.

All-cause mortality was actually higher in the aspirin arm versus the placebo arm, attributable largely to an excess of cancer-related deaths, Dr. McNeil and colleagues said in their third full report in the journal. However, that mortality finding needs to be interpreted with caution, they noted, given that previous investigations have shown a protective effect of aspirin on cancer-related death.
 

Potential harms of “innocuous” drug

The ASPREE (Aspirin in Reducing Events in the Elderly) study evaluated the use of aspirin as primary prevention in 19,114 healthy subjects, with a median age of 74 years, enrolled at 34 centers in Australia and the United States between 2010 and 2014.

The patients, who did not have cardiovascular disease, dementia, or disability at baseline, were randomized to daily 100-mg enteric-coated aspirin or placebo.

The rate of death, dementia, or disability was 21.5 events per 1,000 person-years in the aspirin group, and 21.2 events per 1,000 person-years in the placebo group, with a hazard ratio of 1.01 (95% confidence interval, 0.92-1.11; P = .79), Dr. McNeil and colleagues reported.

The rate of major hemorrhage was 8.6 events per 1,000 person-years for aspirin versus 6.2 events per 1,000 person years for placebo (HR, 1.38; 95% CI, 1.18-1.62; P less than .001), investigators found.
 

Cardiovascular outcomes: expectations vs. reality

Investigators said they thought they might see a significant cardiovascular benefit of aspirin in ASPREE based on earlier studies and meta-analyses that suggested a benefit in other populations. However, the rate of cardiovascular disease at 4.7 years of follow-up was 10.7 events per 1,000 person-years for aspirin, and 11.3 per 1,000 person years for placebo (HR, 0.95; 95% CI, 0.83-1.08).

That hazard ratio “rules out the possibility of a major protective effect of aspirin but is compatible with a more modest lowering of risk of up to 17%,” Dr. McNeil and colleagues wrote.

The results are consistent with those of a recent meta-analysis including eight primary prevention trials, mainly in adults under 70 years of age. That analysis found a 17% reduction in nonfatal myocardial infarction risk, a 14% reduction in stroke risk, and a higher risk of serious bleeding for aspirin versus control groups.

Results of ASPREE have to be interpreted in light of event rates, which were much lower than the expected 22.4 events per 1,000 person-years, they added. The low event rate probably reflects both the relatively good health of the study subjects, and the declining rates of cardiovascular disease in recent years, they said.

“Because of these factors, the absolute benefit that results from any proportionally lower rate of cardiovascular disease may be less than the benefit observed in studies from previous decades and is less likely than it had been to outweigh the risk of adverse events from aspirin,” investigators said in their report.

Current guidelines state that the evidence is limited for use of aspirin as primary prevention of cardiovascular disease in the elderly. “Nevertheless, many millions of relatively healthy older persons in the United States and Australia take low-dose aspirin with the assumption that it will reduce the likelihood of future cardiovascular disease and stroke,” study authors said in a discussion of the results.
 

Excess deaths explored

There were also no significant differences between arms for the endpoints of death, dementia, or disability evaluated separately. However, the rate of death by any cause was numerically higher in the aspirin group versus the placebo group, at 12.7 and 11.1 events per 1,000 person-years, respectively (HR, 1.14; 95% CI, 1.01-1.29).

Cancer was the major contributor to the imbalance in deaths, ASPREE results show, at 1.6 excess deaths per 1,000 person-years. A total of 3.1% of patients in the aspirin group had cancer-related deaths, compared with 2.3% in the placebo arm of the trial (HR, 1.31; 95% CI, 1.10-1.56).

Mortality related to major hemorrhage contributed “only minimally” to the excess in deaths, investigators added in their report.

The finding of excess deaths in the aspirin arm of ASPREE contrasts with meta-analyses of previous prevention trials. According to investigators, those studies show a protective effect of aspirin on cancer-related death that is apparent after 4-5 years of continuous treatment.

Various cellular and molecular pathways relevant to cancer development, progression, and spread are influenced by aspirin, previous studies show.

“Questions may therefore arise about whether the biology of cancer differs among age groups with regard to the frequency of common molecular patterns, metastatic behavior, and treatment responses,” Dr. McNeil and coauthors wrote in their report.

Dr. McNeil reported nonfinancial support from Bayer received during the conduct of the study.

SOURCE: McNeil JJ et al. N Engl J Med. 2018 Sep 16.

Across-the-board use of aspirin for primary prevention is “not justified” based on the results of ASPREE as well as the equivocal results from other recent primary prevention trials, according to Prakash C. Deedwania, MD, clinical professor of medicine and chief of the cardiology division at the Veterans Affairs Medical Center/University of California San Francisco Program in Fresno.

In ASPREE, a randomized, double-blind, placebo-controlled trial including nearly 20,000 participants, daily aspirin increased rates of major hemorrhage and did not significantly decrease risks of cardiovascular events, death, or other outcomes in healthy elderly individuals.

Aspirin did not prolong disability-free survival, a composite endpoint that included death, dementia, and permanent physical disability, according to one of three separate reports on ASPREE that were published in the New England Journal of Medicine.

Cardiovascular disease rates were likewise not significantly different between aspirin and placebo, with a hazard ratio that ruled out the possibility of a major protective effect, lead author John J. McNeil, MBBS, PhD, of Monash University, Melbourne, said in a second report on ASPREE.

All-cause mortality was actually higher in the aspirin arm versus the placebo arm, attributable largely to an excess of cancer-related deaths, Dr. McNeil and colleagues said in their third full report in the journal. However, that mortality finding needs to be interpreted with caution, they noted, given that previous investigations have shown a protective effect of aspirin on cancer-related death.
 

Potential harms of “innocuous” drug

The ASPREE (Aspirin in Reducing Events in the Elderly) study evaluated the use of aspirin as primary prevention in 19,114 healthy subjects, with a median age of 74 years, enrolled at 34 centers in Australia and the United States between 2010 and 2014.

The patients, who did not have cardiovascular disease, dementia, or disability at baseline, were randomized to daily 100-mg enteric-coated aspirin or placebo.

The rate of death, dementia, or disability was 21.5 events per 1,000 person-years in the aspirin group, and 21.2 events per 1,000 person-years in the placebo group, with a hazard ratio of 1.01 (95% confidence interval, 0.92-1.11; P = .79), Dr. McNeil and colleagues reported.

The rate of major hemorrhage was 8.6 events per 1,000 person-years for aspirin versus 6.2 events per 1,000 person years for placebo (HR, 1.38; 95% CI, 1.18-1.62; P less than .001), investigators found.
 

Cardiovascular outcomes: expectations vs. reality

Investigators said they thought they might see a significant cardiovascular benefit of aspirin in ASPREE based on earlier studies and meta-analyses that suggested a benefit in other populations. However, the rate of cardiovascular disease at 4.7 years of follow-up was 10.7 events per 1,000 person-years for aspirin, and 11.3 per 1,000 person years for placebo (HR, 0.95; 95% CI, 0.83-1.08).

That hazard ratio “rules out the possibility of a major protective effect of aspirin but is compatible with a more modest lowering of risk of up to 17%,” Dr. McNeil and colleagues wrote.

The results are consistent with those of a recent meta-analysis including eight primary prevention trials, mainly in adults under 70 years of age. That analysis found a 17% reduction in nonfatal myocardial infarction risk, a 14% reduction in stroke risk, and a higher risk of serious bleeding for aspirin versus control groups.

Results of ASPREE have to be interpreted in light of event rates, which were much lower than the expected 22.4 events per 1,000 person-years, they added. The low event rate probably reflects both the relatively good health of the study subjects, and the declining rates of cardiovascular disease in recent years, they said.

“Because of these factors, the absolute benefit that results from any proportionally lower rate of cardiovascular disease may be less than the benefit observed in studies from previous decades and is less likely than it had been to outweigh the risk of adverse events from aspirin,” investigators said in their report.

Current guidelines state that the evidence is limited for use of aspirin as primary prevention of cardiovascular disease in the elderly. “Nevertheless, many millions of relatively healthy older persons in the United States and Australia take low-dose aspirin with the assumption that it will reduce the likelihood of future cardiovascular disease and stroke,” study authors said in a discussion of the results.
 

Excess deaths explored

There were also no significant differences between arms for the endpoints of death, dementia, or disability evaluated separately. However, the rate of death by any cause was numerically higher in the aspirin group versus the placebo group, at 12.7 and 11.1 events per 1,000 person-years, respectively (HR, 1.14; 95% CI, 1.01-1.29).

Cancer was the major contributor to the imbalance in deaths, ASPREE results show, at 1.6 excess deaths per 1,000 person-years. A total of 3.1% of patients in the aspirin group had cancer-related deaths, compared with 2.3% in the placebo arm of the trial (HR, 1.31; 95% CI, 1.10-1.56).

Mortality related to major hemorrhage contributed “only minimally” to the excess in deaths, investigators added in their report.

The finding of excess deaths in the aspirin arm of ASPREE contrasts with meta-analyses of previous prevention trials. According to investigators, those studies show a protective effect of aspirin on cancer-related death that is apparent after 4-5 years of continuous treatment.

Various cellular and molecular pathways relevant to cancer development, progression, and spread are influenced by aspirin, previous studies show.

“Questions may therefore arise about whether the biology of cancer differs among age groups with regard to the frequency of common molecular patterns, metastatic behavior, and treatment responses,” Dr. McNeil and coauthors wrote in their report.

Dr. McNeil reported nonfinancial support from Bayer received during the conduct of the study.

SOURCE: McNeil JJ et al. N Engl J Med. 2018 Sep 16.

Across-the-board use of aspirin for primary prevention is “not justified” based on the results of ASPREE as well as the equivocal results from other recent primary prevention trials, according to Prakash C. Deedwania, MD, clinical professor of medicine and chief of the cardiology division at the Veterans Affairs Medical Center/University of California San Francisco Program in Fresno.

In ASPREE, a randomized, double-blind, placebo-controlled trial including nearly 20,000 participants, daily aspirin increased rates of major hemorrhage and did not significantly decrease risks of cardiovascular events, death, or other outcomes in healthy elderly individuals.

Aspirin did not prolong disability-free survival, a composite endpoint that included death, dementia, and permanent physical disability, according to one of three separate reports on ASPREE that were published in the New England Journal of Medicine.

Cardiovascular disease rates were likewise not significantly different between aspirin and placebo, with a hazard ratio that ruled out the possibility of a major protective effect, lead author John J. McNeil, MBBS, PhD, of Monash University, Melbourne, said in a second report on ASPREE.

All-cause mortality was actually higher in the aspirin arm versus the placebo arm, attributable largely to an excess of cancer-related deaths, Dr. McNeil and colleagues said in their third full report in the journal. However, that mortality finding needs to be interpreted with caution, they noted, given that previous investigations have shown a protective effect of aspirin on cancer-related death.
 

Potential harms of “innocuous” drug

The ASPREE (Aspirin in Reducing Events in the Elderly) study evaluated the use of aspirin as primary prevention in 19,114 healthy subjects, with a median age of 74 years, enrolled at 34 centers in Australia and the United States between 2010 and 2014.

The patients, who did not have cardiovascular disease, dementia, or disability at baseline, were randomized to daily 100-mg enteric-coated aspirin or placebo.

The rate of death, dementia, or disability was 21.5 events per 1,000 person-years in the aspirin group, and 21.2 events per 1,000 person-years in the placebo group, with a hazard ratio of 1.01 (95% confidence interval, 0.92-1.11; P = .79), Dr. McNeil and colleagues reported.

The rate of major hemorrhage was 8.6 events per 1,000 person-years for aspirin versus 6.2 events per 1,000 person years for placebo (HR, 1.38; 95% CI, 1.18-1.62; P less than .001), investigators found.
 

Cardiovascular outcomes: expectations vs. reality

Investigators said they thought they might see a significant cardiovascular benefit of aspirin in ASPREE based on earlier studies and meta-analyses that suggested a benefit in other populations. However, the rate of cardiovascular disease at 4.7 years of follow-up was 10.7 events per 1,000 person-years for aspirin, and 11.3 per 1,000 person years for placebo (HR, 0.95; 95% CI, 0.83-1.08).

That hazard ratio “rules out the possibility of a major protective effect of aspirin but is compatible with a more modest lowering of risk of up to 17%,” Dr. McNeil and colleagues wrote.

The results are consistent with those of a recent meta-analysis including eight primary prevention trials, mainly in adults under 70 years of age. That analysis found a 17% reduction in nonfatal myocardial infarction risk, a 14% reduction in stroke risk, and a higher risk of serious bleeding for aspirin versus control groups.

Results of ASPREE have to be interpreted in light of event rates, which were much lower than the expected 22.4 events per 1,000 person-years, they added. The low event rate probably reflects both the relatively good health of the study subjects, and the declining rates of cardiovascular disease in recent years, they said.

“Because of these factors, the absolute benefit that results from any proportionally lower rate of cardiovascular disease may be less than the benefit observed in studies from previous decades and is less likely than it had been to outweigh the risk of adverse events from aspirin,” investigators said in their report.

Current guidelines state that the evidence is limited for use of aspirin as primary prevention of cardiovascular disease in the elderly. “Nevertheless, many millions of relatively healthy older persons in the United States and Australia take low-dose aspirin with the assumption that it will reduce the likelihood of future cardiovascular disease and stroke,” study authors said in a discussion of the results.
 

Excess deaths explored

There were also no significant differences between arms for the endpoints of death, dementia, or disability evaluated separately. However, the rate of death by any cause was numerically higher in the aspirin group versus the placebo group, at 12.7 and 11.1 events per 1,000 person-years, respectively (HR, 1.14; 95% CI, 1.01-1.29).

Cancer was the major contributor to the imbalance in deaths, ASPREE results show, at 1.6 excess deaths per 1,000 person-years. A total of 3.1% of patients in the aspirin group had cancer-related deaths, compared with 2.3% in the placebo arm of the trial (HR, 1.31; 95% CI, 1.10-1.56).

Mortality related to major hemorrhage contributed “only minimally” to the excess in deaths, investigators added in their report.

The finding of excess deaths in the aspirin arm of ASPREE contrasts with meta-analyses of previous prevention trials. According to investigators, those studies show a protective effect of aspirin on cancer-related death that is apparent after 4-5 years of continuous treatment.

Various cellular and molecular pathways relevant to cancer development, progression, and spread are influenced by aspirin, previous studies show.

“Questions may therefore arise about whether the biology of cancer differs among age groups with regard to the frequency of common molecular patterns, metastatic behavior, and treatment responses,” Dr. McNeil and coauthors wrote in their report.

Dr. McNeil reported nonfinancial support from Bayer received during the conduct of the study.

SOURCE: McNeil JJ et al. N Engl J Med. 2018 Sep 16.

Maybe it is just me. It probably is. It seems I must have taken a wrong turn in practicing psychiatry somewhere along the line.

For whatever reason, I never truly saw and appreciated the seamlessness between the psychiatric problems children, adults, and the elderly have plaguing them. Of course, I always marveled at how a child who had honest-to-goodness autism could become a full-grown adult and have an adult psychiatrist diagnose that individual as having schizophrenia; why not an adult with autism? But that was the extent of my understanding of the seamlessness between childhood and adult diagnoses. Maybe it is because I was poorly trained and never bothered to get a childhood developmental from my adult psychiatric patients. When I would present a case to supervisors as an adult psychiatric resident, I recall never presenting a child developmental history as a part of the patient’s trajectory. It was as though since there was adult psychiatry and child psychiatry, then the disorders of adults and children should be separated as well.

I know many adult psychiatrists never ask their adult patients, “How old were you when you graduated high school?” although an answer of “I never graduated,” or I graduated at 19-20” should raise questions. When I was in community psychiatry residency, I had some training at the Institute for Juvenile Research (birthplace of child psychiatry), so I understood something about children and the problems they had. Of course, back then, child psychiatric diagnoses were not that good, but with the advent of the DSM-5, children’s psychiatric diagnoses became more precise. This was probably because of research and better epidemiologic data about the prevalence of the six major neurodevelopmental disorders (intellectual disability, attention-deficit/hyperactivity disorder, speech and language disorders, autism spectrum disorders, specific learning disorders, and motor disorders). Maybe I am too old to remember, but I don’t remember anyone with a serious focus on what happens to psychiatrically ill children when they grow up to be adults or what psychiatric problems adult psychiatric patients had when they were children.

In a brilliant article in the September issue of the American Journal of Psychiatry, Avshalom Caspi, PhD, and Terrie E. Moffitt, PhD, propose that there is a single dimension of psychopathology, or “p.” This is an article that everyone should read and study (Am J Psychiatry. 2018 Sep 1;175[9]:831-44).

The authors perceptively remind us that we characterize children’s psychopathology as internalizing and externalizing disorders (with a slight nod to psychotic disorders in children), but these features do not seem prominent or ubiquitous in adult psychiatry’s thinking about adult psychiatric patients. They do a great job at pointing out there is ample evidence of a great deal of comorbidity between “discrete” children’s and adults’ psychiatric disorders. We certainly learned this from the findings of the DSM-5’s Personality and Personality Disorders Work Group.

Their p suggests a common thread between various childhood psychiatric disorders and adult psychiatric disorders. Furthermore, Dr. Caspi’s and Dr. Moffitt’s assertion that longitudinal research identifying “poor childhood self-control” (a symptom of affect dysregulation) and poor executive functioning as a salient early developmental predictor of their p sounds a lot like fetal alcohol exposure to me (Fetal Alcohol Exposure Among African Americans). So does their declaration that individuals with higher levels of p have difficulty with attention, concentration, mental control, and visual-motor problems.

Maybe I have confirmational bias, as I have seen the common thread of fetal alcohol exposure run from childhood to adults, but many of my residents and students see it as well.

Accordingly, I think we have made mistakes in psychiatry when we ask (if we ask) the mother of our patients was she drinking when she was pregnant, and “Was the patient born low-birth weight and/or premature?” We should be asking – “When did you realize you were pregnant?” “Were you doing any social drinking before you knew you were pregnant?” Thus, we miss the common thread of fetal alcohol exposure in child and adult psychopathology.

I realize that a great many competing interests are trying to get our time and attention, and there is a lot to read and figure out. In our efforts to do no harm, do psychiatrists try to take their time to fully understand things before we act? Some aspects of our understanding seem to be “no brainers,” and the continuation of child neurodevelopmental disorders morphing into adult mental disorders should be obvious. But maybe we took a wrong turn – which is why it took me 45 years to figure out that fetal alcohol exposure in utero has a significant impact on adult psychiatric disorders.

Dr. Bell is staff psychiatrist at Jackson Park Hospital’s surgical-medical/psychiatric inpatient unit; clinical professor emeritus, department of psychiatry, University of Illinois at Chicago; former director of the Institute for Juvenile Research; and former president/CEO of the Community Mental Health Council, all in Chicago. He also serves as chair of psychiatry at Windsor University, St. Kitts.

Maybe it is just me. It probably is. It seems I must have taken a wrong turn in practicing psychiatry somewhere along the line.

For whatever reason, I never truly saw and appreciated the seamlessness between the psychiatric problems children, adults, and the elderly have plaguing them. Of course, I always marveled at how a child who had honest-to-goodness autism could become a full-grown adult and have an adult psychiatrist diagnose that individual as having schizophrenia; why not an adult with autism? But that was the extent of my understanding of the seamlessness between childhood and adult diagnoses. Maybe it is because I was poorly trained and never bothered to get a childhood developmental from my adult psychiatric patients. When I would present a case to supervisors as an adult psychiatric resident, I recall never presenting a child developmental history as a part of the patient’s trajectory. It was as though since there was adult psychiatry and child psychiatry, then the disorders of adults and children should be separated as well.

I know many adult psychiatrists never ask their adult patients, “How old were you when you graduated high school?” although an answer of “I never graduated,” or I graduated at 19-20” should raise questions. When I was in community psychiatry residency, I had some training at the Institute for Juvenile Research (birthplace of child psychiatry), so I understood something about children and the problems they had. Of course, back then, child psychiatric diagnoses were not that good, but with the advent of the DSM-5, children’s psychiatric diagnoses became more precise. This was probably because of research and better epidemiologic data about the prevalence of the six major neurodevelopmental disorders (intellectual disability, attention-deficit/hyperactivity disorder, speech and language disorders, autism spectrum disorders, specific learning disorders, and motor disorders). Maybe I am too old to remember, but I don’t remember anyone with a serious focus on what happens to psychiatrically ill children when they grow up to be adults or what psychiatric problems adult psychiatric patients had when they were children.

In a brilliant article in the September issue of the American Journal of Psychiatry, Avshalom Caspi, PhD, and Terrie E. Moffitt, PhD, propose that there is a single dimension of psychopathology, or “p.” This is an article that everyone should read and study (Am J Psychiatry. 2018 Sep 1;175[9]:831-44).

The authors perceptively remind us that we characterize children’s psychopathology as internalizing and externalizing disorders (with a slight nod to psychotic disorders in children), but these features do not seem prominent or ubiquitous in adult psychiatry’s thinking about adult psychiatric patients. They do a great job at pointing out there is ample evidence of a great deal of comorbidity between “discrete” children’s and adults’ psychiatric disorders. We certainly learned this from the findings of the DSM-5’s Personality and Personality Disorders Work Group.

Their p suggests a common thread between various childhood psychiatric disorders and adult psychiatric disorders. Furthermore, Dr. Caspi’s and Dr. Moffitt’s assertion that longitudinal research identifying “poor childhood self-control” (a symptom of affect dysregulation) and poor executive functioning as a salient early developmental predictor of their p sounds a lot like fetal alcohol exposure to me (Fetal Alcohol Exposure Among African Americans). So does their declaration that individuals with higher levels of p have difficulty with attention, concentration, mental control, and visual-motor problems.

Maybe I have confirmational bias, as I have seen the common thread of fetal alcohol exposure run from childhood to adults, but many of my residents and students see it as well.

Accordingly, I think we have made mistakes in psychiatry when we ask (if we ask) the mother of our patients was she drinking when she was pregnant, and “Was the patient born low-birth weight and/or premature?” We should be asking – “When did you realize you were pregnant?” “Were you doing any social drinking before you knew you were pregnant?” Thus, we miss the common thread of fetal alcohol exposure in child and adult psychopathology.

I realize that a great many competing interests are trying to get our time and attention, and there is a lot to read and figure out. In our efforts to do no harm, do psychiatrists try to take their time to fully understand things before we act? Some aspects of our understanding seem to be “no brainers,” and the continuation of child neurodevelopmental disorders morphing into adult mental disorders should be obvious. But maybe we took a wrong turn – which is why it took me 45 years to figure out that fetal alcohol exposure in utero has a significant impact on adult psychiatric disorders.

Dr. Bell is staff psychiatrist at Jackson Park Hospital’s surgical-medical/psychiatric inpatient unit; clinical professor emeritus, department of psychiatry, University of Illinois at Chicago; former director of the Institute for Juvenile Research; and former president/CEO of the Community Mental Health Council, all in Chicago. He also serves as chair of psychiatry at Windsor University, St. Kitts.

Maybe it is just me. It probably is. It seems I must have taken a wrong turn in practicing psychiatry somewhere along the line.

For whatever reason, I never truly saw and appreciated the seamlessness between the psychiatric problems children, adults, and the elderly have plaguing them. Of course, I always marveled at how a child who had honest-to-goodness autism could become a full-grown adult and have an adult psychiatrist diagnose that individual as having schizophrenia; why not an adult with autism? But that was the extent of my understanding of the seamlessness between childhood and adult diagnoses. Maybe it is because I was poorly trained and never bothered to get a childhood developmental from my adult psychiatric patients. When I would present a case to supervisors as an adult psychiatric resident, I recall never presenting a child developmental history as a part of the patient’s trajectory. It was as though since there was adult psychiatry and child psychiatry, then the disorders of adults and children should be separated as well.

I know many adult psychiatrists never ask their adult patients, “How old were you when you graduated high school?” although an answer of “I never graduated,” or I graduated at 19-20” should raise questions. When I was in community psychiatry residency, I had some training at the Institute for Juvenile Research (birthplace of child psychiatry), so I understood something about children and the problems they had. Of course, back then, child psychiatric diagnoses were not that good, but with the advent of the DSM-5, children’s psychiatric diagnoses became more precise. This was probably because of research and better epidemiologic data about the prevalence of the six major neurodevelopmental disorders (intellectual disability, attention-deficit/hyperactivity disorder, speech and language disorders, autism spectrum disorders, specific learning disorders, and motor disorders). Maybe I am too old to remember, but I don’t remember anyone with a serious focus on what happens to psychiatrically ill children when they grow up to be adults or what psychiatric problems adult psychiatric patients had when they were children.

In a brilliant article in the September issue of the American Journal of Psychiatry, Avshalom Caspi, PhD, and Terrie E. Moffitt, PhD, propose that there is a single dimension of psychopathology, or “p.” This is an article that everyone should read and study (Am J Psychiatry. 2018 Sep 1;175[9]:831-44).

The authors perceptively remind us that we characterize children’s psychopathology as internalizing and externalizing disorders (with a slight nod to psychotic disorders in children), but these features do not seem prominent or ubiquitous in adult psychiatry’s thinking about adult psychiatric patients. They do a great job at pointing out there is ample evidence of a great deal of comorbidity between “discrete” children’s and adults’ psychiatric disorders. We certainly learned this from the findings of the DSM-5’s Personality and Personality Disorders Work Group.

Their p suggests a common thread between various childhood psychiatric disorders and adult psychiatric disorders. Furthermore, Dr. Caspi’s and Dr. Moffitt’s assertion that longitudinal research identifying “poor childhood self-control” (a symptom of affect dysregulation) and poor executive functioning as a salient early developmental predictor of their p sounds a lot like fetal alcohol exposure to me (Fetal Alcohol Exposure Among African Americans). So does their declaration that individuals with higher levels of p have difficulty with attention, concentration, mental control, and visual-motor problems.

Maybe I have confirmational bias, as I have seen the common thread of fetal alcohol exposure run from childhood to adults, but many of my residents and students see it as well.

Accordingly, I think we have made mistakes in psychiatry when we ask (if we ask) the mother of our patients was she drinking when she was pregnant, and “Was the patient born low-birth weight and/or premature?” We should be asking – “When did you realize you were pregnant?” “Were you doing any social drinking before you knew you were pregnant?” Thus, we miss the common thread of fetal alcohol exposure in child and adult psychopathology.

I realize that a great many competing interests are trying to get our time and attention, and there is a lot to read and figure out. In our efforts to do no harm, do psychiatrists try to take their time to fully understand things before we act? Some aspects of our understanding seem to be “no brainers,” and the continuation of child neurodevelopmental disorders morphing into adult mental disorders should be obvious. But maybe we took a wrong turn – which is why it took me 45 years to figure out that fetal alcohol exposure in utero has a significant impact on adult psychiatric disorders.

Dr. Bell is staff psychiatrist at Jackson Park Hospital’s surgical-medical/psychiatric inpatient unit; clinical professor emeritus, department of psychiatry, University of Illinois at Chicago; former director of the Institute for Juvenile Research; and former president/CEO of the Community Mental Health Council, all in Chicago. He also serves as chair of psychiatry at Windsor University, St. Kitts.

The ClonoSEQ assay is the first next generation sequencing–based test to be granted marketing approval for detecting minimal residual disease in patients with acute lymphoblastic leukemia (ALL) or multiple myeloma, the U.S. Food and Drug Administration announced. Marketing authorization of the ClonoSEQ assay was granted to Adaptive Biotechnologies.

The ClonoSEQ assay is an in vitro diagnostic test that uses multiplex polymerase chain reaction and next-generation sequencing to identify and quantify certain gene sequences in DNA extracted from the bone marrow from patients with ALL or multiple myeloma. This is a single-site assay collected by the patient’s provider and sent to Adaptive Biotechnologies for evaluation.

The ClonoSEQ assay is capable of detecting minimal residual disease at levels below 1 in 1 million cells. Currently, providers test for MRD using flow cytometry assays or polymerase chain reaction–based assays. Those methods are usually capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.

“Determining whether a patient has residual cancer cells remaining after treatment provides information on how well a patient has responded to therapy and how long remission may last. Having a highly sensitive test available to measure minimal residual disease in ALL or multiple myeloma patients can help providers manage their patients’ care,” FDA Commissioner Scott Gottlieb, MD, said in a press release.

Along with this authorization, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the accuracy, reliability, and effectiveness of tests intended to be used as an aid to measure MRD to assess the change in burden of disease during and after treatment. These special controls, when met along with general controls, provide a reasonable assurance of safety and effectiveness for these tests, the agency said in the release. This action also creates a new regulatory classification, which means that subsequent devices of the same type with the same intended use may go through the FDA’s 510(k) process, whereby devices can obtain marketing authorization by demonstrating substantial equivalence to a previously approved device.

“The FDA is applying novel regulatory approaches to make sure that these rapidly evolving [next-generation sequencing] tests are accurate and reliable. At the same time, we’re seeing more and more laboratory-developed tests seek marketing authorization from the FDA,” he said, adding that the agency has put forward a plan to modernize the regulatory framework for all in vitro clinical tests.

The FDA evaluated data to demonstrate clinical validity from a retrospective analysis of samples obtained from three previously conducted clinical studies including 273 patients with ALL, an ongoing study of 323 patients with multiple myeloma, and a study of 706 patients with multiple myeloma, according to the FDA release.

For patients with ALL, the ClonoSEQ assay was used to assess MRD at various disease burden thresholds to show that the MRD level correlated with event-free survival – the length of time, after treatment, that the patient remains free of certain complications or events. Patients whose ClonoSEQ assay result was MRD negative had longer event-free survival, while patients with higher MRD assay results had lower event-free survival. Similar patterns of results were seen for progression-free and disease-free survival in patients with multiple myeloma.

[email protected]

The ClonoSEQ assay is the first next generation sequencing–based test to be granted marketing approval for detecting minimal residual disease in patients with acute lymphoblastic leukemia (ALL) or multiple myeloma, the U.S. Food and Drug Administration announced. Marketing authorization of the ClonoSEQ assay was granted to Adaptive Biotechnologies.

The ClonoSEQ assay is an in vitro diagnostic test that uses multiplex polymerase chain reaction and next-generation sequencing to identify and quantify certain gene sequences in DNA extracted from the bone marrow from patients with ALL or multiple myeloma. This is a single-site assay collected by the patient’s provider and sent to Adaptive Biotechnologies for evaluation.

The ClonoSEQ assay is capable of detecting minimal residual disease at levels below 1 in 1 million cells. Currently, providers test for MRD using flow cytometry assays or polymerase chain reaction–based assays. Those methods are usually capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.

“Determining whether a patient has residual cancer cells remaining after treatment provides information on how well a patient has responded to therapy and how long remission may last. Having a highly sensitive test available to measure minimal residual disease in ALL or multiple myeloma patients can help providers manage their patients’ care,” FDA Commissioner Scott Gottlieb, MD, said in a press release.

Along with this authorization, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the accuracy, reliability, and effectiveness of tests intended to be used as an aid to measure MRD to assess the change in burden of disease during and after treatment. These special controls, when met along with general controls, provide a reasonable assurance of safety and effectiveness for these tests, the agency said in the release. This action also creates a new regulatory classification, which means that subsequent devices of the same type with the same intended use may go through the FDA’s 510(k) process, whereby devices can obtain marketing authorization by demonstrating substantial equivalence to a previously approved device.

“The FDA is applying novel regulatory approaches to make sure that these rapidly evolving [next-generation sequencing] tests are accurate and reliable. At the same time, we’re seeing more and more laboratory-developed tests seek marketing authorization from the FDA,” he said, adding that the agency has put forward a plan to modernize the regulatory framework for all in vitro clinical tests.

The FDA evaluated data to demonstrate clinical validity from a retrospective analysis of samples obtained from three previously conducted clinical studies including 273 patients with ALL, an ongoing study of 323 patients with multiple myeloma, and a study of 706 patients with multiple myeloma, according to the FDA release.

For patients with ALL, the ClonoSEQ assay was used to assess MRD at various disease burden thresholds to show that the MRD level correlated with event-free survival – the length of time, after treatment, that the patient remains free of certain complications or events. Patients whose ClonoSEQ assay result was MRD negative had longer event-free survival, while patients with higher MRD assay results had lower event-free survival. Similar patterns of results were seen for progression-free and disease-free survival in patients with multiple myeloma.

[email protected]

The ClonoSEQ assay is the first next generation sequencing–based test to be granted marketing approval for detecting minimal residual disease in patients with acute lymphoblastic leukemia (ALL) or multiple myeloma, the U.S. Food and Drug Administration announced. Marketing authorization of the ClonoSEQ assay was granted to Adaptive Biotechnologies.

The ClonoSEQ assay is an in vitro diagnostic test that uses multiplex polymerase chain reaction and next-generation sequencing to identify and quantify certain gene sequences in DNA extracted from the bone marrow from patients with ALL or multiple myeloma. This is a single-site assay collected by the patient’s provider and sent to Adaptive Biotechnologies for evaluation.

The ClonoSEQ assay is capable of detecting minimal residual disease at levels below 1 in 1 million cells. Currently, providers test for MRD using flow cytometry assays or polymerase chain reaction–based assays. Those methods are usually capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.

“Determining whether a patient has residual cancer cells remaining after treatment provides information on how well a patient has responded to therapy and how long remission may last. Having a highly sensitive test available to measure minimal residual disease in ALL or multiple myeloma patients can help providers manage their patients’ care,” FDA Commissioner Scott Gottlieb, MD, said in a press release.

Along with this authorization, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the accuracy, reliability, and effectiveness of tests intended to be used as an aid to measure MRD to assess the change in burden of disease during and after treatment. These special controls, when met along with general controls, provide a reasonable assurance of safety and effectiveness for these tests, the agency said in the release. This action also creates a new regulatory classification, which means that subsequent devices of the same type with the same intended use may go through the FDA’s 510(k) process, whereby devices can obtain marketing authorization by demonstrating substantial equivalence to a previously approved device.

“The FDA is applying novel regulatory approaches to make sure that these rapidly evolving [next-generation sequencing] tests are accurate and reliable. At the same time, we’re seeing more and more laboratory-developed tests seek marketing authorization from the FDA,” he said, adding that the agency has put forward a plan to modernize the regulatory framework for all in vitro clinical tests.

The FDA evaluated data to demonstrate clinical validity from a retrospective analysis of samples obtained from three previously conducted clinical studies including 273 patients with ALL, an ongoing study of 323 patients with multiple myeloma, and a study of 706 patients with multiple myeloma, according to the FDA release.

For patients with ALL, the ClonoSEQ assay was used to assess MRD at various disease burden thresholds to show that the MRD level correlated with event-free survival – the length of time, after treatment, that the patient remains free of certain complications or events. Patients whose ClonoSEQ assay result was MRD negative had longer event-free survival, while patients with higher MRD assay results had lower event-free survival. Similar patterns of results were seen for progression-free and disease-free survival in patients with multiple myeloma.

[email protected]

Bone marrow aspirate Photo by Chad McNeeley

The U.S. Food and Drug Administration has authorized the first next-generation sequencing (NGS)-based assay to be marketed for minimal residual disease (MRD) testing in patients with acute lymphoblastic leukemia (ALL) or multiple myeloma (MM).

The assay, called clonoSEQ®, uses both polymerase chain reaction (PCR) and NGS to identify and quantify gene sequences in DNA from patients’ bone marrow.

ClonoSEQ Assay can detect MRD levels below 1 in 1 million cells. By comparison flow cytometry assays or PCR-based assays are capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.

The clonoSEQ Assay is marketed by Adaptive Biotechnologies.

The FDA based its authorization on data from three clinical studies, one with 273 ALL patients, an ongoing study of 323 MM patients, and another MM trial with 706 patients.

Validation in ALL

As described in the clonoSEQ Assay Technical Information, a subset of 273 patients originally enrolled in the Children’s Oncology Group AALL0232 (NCT00075725) and AALL0331 (NCT00103285) studies had left-over bone marrow specimens to evaluate the performance of the clonoSEQ Assay.

MRD as determined by MRD negativity at less than 10^-4 predicted improved event-free survival (EFS) irrespective of age. MRD-positive patients had a 2.74 higher event risk compared to MRD-negative patients.

Similar findings between MRD negativity and EFS in pediatric ALL using an earlier version of the assay were published in Blood.

Validation in MM

The ongoing phase 3 DFCI Study 10-106 (NCT01208662) is comparing conventional treatment with lenalidomide, bortezomib and dexamethasone to high-dose treatment with stem cell transplant as initial management of MM patients less than 65 years.

According to clonoSEQ’s technical information, bone marrow samples from 323 of the 720 patients originally enrolled were available and evaluable for MRD assessment.

ClonoSEQ measurements demonstrated that MRD status at a threshold of 10^-5 significantly predicts progression-free survival (PFS) in all patients (P=0.027).

And samples from 75 patients who had achieved complete remission (CR) showed a modest association with disease-free survival (DFS) and lower MRD levels (P=0.064).

In the phase 3 ALCYONE trial, investigators randomly assigned 706 treatment-naïve MM patients ineligible for hematopoietic stem cell transplant to bortezomib, melphalan, and prednisone with or without daratumumab.

MRD assessments were made using the clonoSEQ Assay at screening, at confirmation of CR or stringent CR, and at intervals after patients achieved a CR.

Patients who did not achieve CR were considered MRD positive. The threshold for the MRD analysis was 10^-5.

Investigators found that patients who were MRD negative by the clonoSEQ Assay had longer PFS compared to MRD-positive patients, regardless of treatment group.

For additional information on the clonoSEQ Assay consult the Technical Information available online. 

Bone marrow aspirate Photo by Chad McNeeley

The U.S. Food and Drug Administration has authorized the first next-generation sequencing (NGS)-based assay to be marketed for minimal residual disease (MRD) testing in patients with acute lymphoblastic leukemia (ALL) or multiple myeloma (MM).

The assay, called clonoSEQ®, uses both polymerase chain reaction (PCR) and NGS to identify and quantify gene sequences in DNA from patients’ bone marrow.

ClonoSEQ Assay can detect MRD levels below 1 in 1 million cells. By comparison flow cytometry assays or PCR-based assays are capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.

The clonoSEQ Assay is marketed by Adaptive Biotechnologies.

The FDA based its authorization on data from three clinical studies, one with 273 ALL patients, an ongoing study of 323 MM patients, and another MM trial with 706 patients.

Validation in ALL

As described in the clonoSEQ Assay Technical Information, a subset of 273 patients originally enrolled in the Children’s Oncology Group AALL0232 (NCT00075725) and AALL0331 (NCT00103285) studies had left-over bone marrow specimens to evaluate the performance of the clonoSEQ Assay.

MRD as determined by MRD negativity at less than 10^-4 predicted improved event-free survival (EFS) irrespective of age. MRD-positive patients had a 2.74 higher event risk compared to MRD-negative patients.

Similar findings between MRD negativity and EFS in pediatric ALL using an earlier version of the assay were published in Blood.

Validation in MM

The ongoing phase 3 DFCI Study 10-106 (NCT01208662) is comparing conventional treatment with lenalidomide, bortezomib and dexamethasone to high-dose treatment with stem cell transplant as initial management of MM patients less than 65 years.

According to clonoSEQ’s technical information, bone marrow samples from 323 of the 720 patients originally enrolled were available and evaluable for MRD assessment.

ClonoSEQ measurements demonstrated that MRD status at a threshold of 10^-5 significantly predicts progression-free survival (PFS) in all patients (P=0.027).

And samples from 75 patients who had achieved complete remission (CR) showed a modest association with disease-free survival (DFS) and lower MRD levels (P=0.064).

In the phase 3 ALCYONE trial, investigators randomly assigned 706 treatment-naïve MM patients ineligible for hematopoietic stem cell transplant to bortezomib, melphalan, and prednisone with or without daratumumab.

MRD assessments were made using the clonoSEQ Assay at screening, at confirmation of CR or stringent CR, and at intervals after patients achieved a CR.

Patients who did not achieve CR were considered MRD positive. The threshold for the MRD analysis was 10^-5.

Investigators found that patients who were MRD negative by the clonoSEQ Assay had longer PFS compared to MRD-positive patients, regardless of treatment group.

For additional information on the clonoSEQ Assay consult the Technical Information available online. 

Bone marrow aspirate Photo by Chad McNeeley

The U.S. Food and Drug Administration has authorized the first next-generation sequencing (NGS)-based assay to be marketed for minimal residual disease (MRD) testing in patients with acute lymphoblastic leukemia (ALL) or multiple myeloma (MM).

The assay, called clonoSEQ®, uses both polymerase chain reaction (PCR) and NGS to identify and quantify gene sequences in DNA from patients’ bone marrow.

ClonoSEQ Assay can detect MRD levels below 1 in 1 million cells. By comparison flow cytometry assays or PCR-based assays are capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.

The clonoSEQ Assay is marketed by Adaptive Biotechnologies.

The FDA based its authorization on data from three clinical studies, one with 273 ALL patients, an ongoing study of 323 MM patients, and another MM trial with 706 patients.

Validation in ALL

As described in the clonoSEQ Assay Technical Information, a subset of 273 patients originally enrolled in the Children’s Oncology Group AALL0232 (NCT00075725) and AALL0331 (NCT00103285) studies had left-over bone marrow specimens to evaluate the performance of the clonoSEQ Assay.

MRD as determined by MRD negativity at less than 10^-4 predicted improved event-free survival (EFS) irrespective of age. MRD-positive patients had a 2.74 higher event risk compared to MRD-negative patients.

Similar findings between MRD negativity and EFS in pediatric ALL using an earlier version of the assay were published in Blood.

Validation in MM

The ongoing phase 3 DFCI Study 10-106 (NCT01208662) is comparing conventional treatment with lenalidomide, bortezomib and dexamethasone to high-dose treatment with stem cell transplant as initial management of MM patients less than 65 years.

According to clonoSEQ’s technical information, bone marrow samples from 323 of the 720 patients originally enrolled were available and evaluable for MRD assessment.

ClonoSEQ measurements demonstrated that MRD status at a threshold of 10^-5 significantly predicts progression-free survival (PFS) in all patients (P=0.027).

And samples from 75 patients who had achieved complete remission (CR) showed a modest association with disease-free survival (DFS) and lower MRD levels (P=0.064).

In the phase 3 ALCYONE trial, investigators randomly assigned 706 treatment-naïve MM patients ineligible for hematopoietic stem cell transplant to bortezomib, melphalan, and prednisone with or without daratumumab.

MRD assessments were made using the clonoSEQ Assay at screening, at confirmation of CR or stringent CR, and at intervals after patients achieved a CR.

Patients who did not achieve CR were considered MRD positive. The threshold for the MRD analysis was 10^-5.

Investigators found that patients who were MRD negative by the clonoSEQ Assay had longer PFS compared to MRD-positive patients, regardless of treatment group.

For additional information on the clonoSEQ Assay consult the Technical Information available online.