Journal of Clinical Outcomes Management

Women whose rheumatoid arthritis is carefully managed before and during pregnancy have a significantly lower risk of adverse pregnancy outcomes, including miscarriage or perinatal death, new research suggests.

zoranm/Getty Images

A study published in Arthritis Care & Research presents the outcomes of a retrospective, observational study examining health care data from 443 first pregnancies in women with RA and 6,097 women without the disease.

First author Alessandra Bortoluzzi, MD, PhD, from the Rheumatology Unit at the University of Ferrara (Italy) and coauthors looked at seven diagnostic, therapeutic, and follow-up health care quality indicators during the prepregnancy and perinatal period. They included having at least one blood test in the 18 months before conception and during pregnancy, preconception musculoskeletal imaging, no exposure or wash-out from teratogenic drugs, and no exposure to biologic drugs between conception and delivery or end of pregnancy.

An ideal clinical pathway included at least one element from each of the diagnostic, therapeutic, and prenatal follow-up quality indicators.

Overall, women with RA had a significantly higher rate of thyroid diseases, adverse pregnancy outcomes, and miscarriage or perinatal death when compared with controls. However, those who followed the ideal clinical pathway for management of their disease during pregnancy had a 40% lower odds of adverse pregnancy outcomes (odds ratio, 0.60; 95% confidence interval, 0.39-0.94) and a 60% lower odds of miscarriage or perinatal death (OR, 0.40; 95% CI, 0.24-0.69) in comparison with women with RA who were not managed to the same standard. The researchers adjusted both comparisons for age, Charlson comorbidity index, and thyroid diseases.

Women with RA who met diagnostic, therapeutic, and prenatal follow-up quality indicators showed no significant differences from the general population in terms of the risk of adverse pregnancy outcomes, miscarriage, or perinatal death after adjusting for hypertension in addition to the same variables as before.

When researchers looked at some of the individual health care quality indicators, they found that testing for antiphospholipid (aPL) antibodies within 18 months of conception or pregnancy was associated with a 44% lower rate of adverse pregnancy outcomes. Similarly, antinuclear antibody or anti–extractable nuclear antigen antibody testing was associated with 36% lower odds of adverse pregnancy outcomes.

Dr. Bortoluzzi and her coauthors wrote that their findings pointed to the value of testing for aPL antibodies in women with RA who wish to get pregnant.

“In fact, despite the absence of formal recommendation or validated health care quality indicators focused on stratification of preconceptional obstetric risk in patients with RA, we started from the basic and universally accepted assumption that aPL antibodies are pathogenic autoantibodies and therefore recognized risk factors for adverse pregnancy outcome,” they wrote.

Women with RA who had either no exposure to methotrexate or leflunomide or who had a washout period from 6 months prior to conception had 72% lower odds of adverse pregnancy outcomes.

The authors also looked at the effects of drugs such as aspirin, glucocorticoids, and low-molecular-weight heparin that are used during pregnancy. They found that the relative risk of adverse pregnancy outcomes was 40% higher in women with RA who were taking glucocorticoids, compared with those with the disease but not taking that type of medication. However, low-molecular-weight heparin use was associated with an 80% lower relative risk of miscarriage or perinatal death in comparison with those not taking it. Researchers saw no significant effects of aspirin or conventional synthetic disease-modifying antirheumatic drugs on either adverse pregnancy outcomes or the risk of miscarriage or perinatal death.

“This reinforces the importance of adjustment of therapy for RA before conception and throughout pregnancy, because medication use could affect pregnancy course not only influencing maternal disease activity but also the gestational outcome,” the authors wrote. “Although this is a study conducted on administrative data, we can hypothesize that exposure to therapy represents a marker of high RA disease activity and severity. In our setting, it is possible that, the more active the disease, the greater the probability of being included in the ideal clinical pathway, but in any case, this resulted in a lower odds ratio of adverse pregnancy outcome and miscarriage/perinatal death.”

The study was supported by the Italian Society for Rheumatology. No conflicts of interest were declared.

SOURCE: Bortoluzzi A et al. Arthritis Care Res. 2020 Jan 8. doi: 10.1002/ACR.24116.

Women whose rheumatoid arthritis is carefully managed before and during pregnancy have a significantly lower risk of adverse pregnancy outcomes, including miscarriage or perinatal death, new research suggests.

zoranm/Getty Images

A study published in Arthritis Care & Research presents the outcomes of a retrospective, observational study examining health care data from 443 first pregnancies in women with RA and 6,097 women without the disease.

First author Alessandra Bortoluzzi, MD, PhD, from the Rheumatology Unit at the University of Ferrara (Italy) and coauthors looked at seven diagnostic, therapeutic, and follow-up health care quality indicators during the prepregnancy and perinatal period. They included having at least one blood test in the 18 months before conception and during pregnancy, preconception musculoskeletal imaging, no exposure or wash-out from teratogenic drugs, and no exposure to biologic drugs between conception and delivery or end of pregnancy.

An ideal clinical pathway included at least one element from each of the diagnostic, therapeutic, and prenatal follow-up quality indicators.

Overall, women with RA had a significantly higher rate of thyroid diseases, adverse pregnancy outcomes, and miscarriage or perinatal death when compared with controls. However, those who followed the ideal clinical pathway for management of their disease during pregnancy had a 40% lower odds of adverse pregnancy outcomes (odds ratio, 0.60; 95% confidence interval, 0.39-0.94) and a 60% lower odds of miscarriage or perinatal death (OR, 0.40; 95% CI, 0.24-0.69) in comparison with women with RA who were not managed to the same standard. The researchers adjusted both comparisons for age, Charlson comorbidity index, and thyroid diseases.

Women with RA who met diagnostic, therapeutic, and prenatal follow-up quality indicators showed no significant differences from the general population in terms of the risk of adverse pregnancy outcomes, miscarriage, or perinatal death after adjusting for hypertension in addition to the same variables as before.

When researchers looked at some of the individual health care quality indicators, they found that testing for antiphospholipid (aPL) antibodies within 18 months of conception or pregnancy was associated with a 44% lower rate of adverse pregnancy outcomes. Similarly, antinuclear antibody or anti–extractable nuclear antigen antibody testing was associated with 36% lower odds of adverse pregnancy outcomes.

Dr. Bortoluzzi and her coauthors wrote that their findings pointed to the value of testing for aPL antibodies in women with RA who wish to get pregnant.

“In fact, despite the absence of formal recommendation or validated health care quality indicators focused on stratification of preconceptional obstetric risk in patients with RA, we started from the basic and universally accepted assumption that aPL antibodies are pathogenic autoantibodies and therefore recognized risk factors for adverse pregnancy outcome,” they wrote.

Women with RA who had either no exposure to methotrexate or leflunomide or who had a washout period from 6 months prior to conception had 72% lower odds of adverse pregnancy outcomes.

The authors also looked at the effects of drugs such as aspirin, glucocorticoids, and low-molecular-weight heparin that are used during pregnancy. They found that the relative risk of adverse pregnancy outcomes was 40% higher in women with RA who were taking glucocorticoids, compared with those with the disease but not taking that type of medication. However, low-molecular-weight heparin use was associated with an 80% lower relative risk of miscarriage or perinatal death in comparison with those not taking it. Researchers saw no significant effects of aspirin or conventional synthetic disease-modifying antirheumatic drugs on either adverse pregnancy outcomes or the risk of miscarriage or perinatal death.

“This reinforces the importance of adjustment of therapy for RA before conception and throughout pregnancy, because medication use could affect pregnancy course not only influencing maternal disease activity but also the gestational outcome,” the authors wrote. “Although this is a study conducted on administrative data, we can hypothesize that exposure to therapy represents a marker of high RA disease activity and severity. In our setting, it is possible that, the more active the disease, the greater the probability of being included in the ideal clinical pathway, but in any case, this resulted in a lower odds ratio of adverse pregnancy outcome and miscarriage/perinatal death.”

The study was supported by the Italian Society for Rheumatology. No conflicts of interest were declared.

SOURCE: Bortoluzzi A et al. Arthritis Care Res. 2020 Jan 8. doi: 10.1002/ACR.24116.

Women whose rheumatoid arthritis is carefully managed before and during pregnancy have a significantly lower risk of adverse pregnancy outcomes, including miscarriage or perinatal death, new research suggests.

zoranm/Getty Images

A study published in Arthritis Care & Research presents the outcomes of a retrospective, observational study examining health care data from 443 first pregnancies in women with RA and 6,097 women without the disease.

First author Alessandra Bortoluzzi, MD, PhD, from the Rheumatology Unit at the University of Ferrara (Italy) and coauthors looked at seven diagnostic, therapeutic, and follow-up health care quality indicators during the prepregnancy and perinatal period. They included having at least one blood test in the 18 months before conception and during pregnancy, preconception musculoskeletal imaging, no exposure or wash-out from teratogenic drugs, and no exposure to biologic drugs between conception and delivery or end of pregnancy.

An ideal clinical pathway included at least one element from each of the diagnostic, therapeutic, and prenatal follow-up quality indicators.

Overall, women with RA had a significantly higher rate of thyroid diseases, adverse pregnancy outcomes, and miscarriage or perinatal death when compared with controls. However, those who followed the ideal clinical pathway for management of their disease during pregnancy had a 40% lower odds of adverse pregnancy outcomes (odds ratio, 0.60; 95% confidence interval, 0.39-0.94) and a 60% lower odds of miscarriage or perinatal death (OR, 0.40; 95% CI, 0.24-0.69) in comparison with women with RA who were not managed to the same standard. The researchers adjusted both comparisons for age, Charlson comorbidity index, and thyroid diseases.

Women with RA who met diagnostic, therapeutic, and prenatal follow-up quality indicators showed no significant differences from the general population in terms of the risk of adverse pregnancy outcomes, miscarriage, or perinatal death after adjusting for hypertension in addition to the same variables as before.

When researchers looked at some of the individual health care quality indicators, they found that testing for antiphospholipid (aPL) antibodies within 18 months of conception or pregnancy was associated with a 44% lower rate of adverse pregnancy outcomes. Similarly, antinuclear antibody or anti–extractable nuclear antigen antibody testing was associated with 36% lower odds of adverse pregnancy outcomes.

Dr. Bortoluzzi and her coauthors wrote that their findings pointed to the value of testing for aPL antibodies in women with RA who wish to get pregnant.

“In fact, despite the absence of formal recommendation or validated health care quality indicators focused on stratification of preconceptional obstetric risk in patients with RA, we started from the basic and universally accepted assumption that aPL antibodies are pathogenic autoantibodies and therefore recognized risk factors for adverse pregnancy outcome,” they wrote.

Women with RA who had either no exposure to methotrexate or leflunomide or who had a washout period from 6 months prior to conception had 72% lower odds of adverse pregnancy outcomes.

The authors also looked at the effects of drugs such as aspirin, glucocorticoids, and low-molecular-weight heparin that are used during pregnancy. They found that the relative risk of adverse pregnancy outcomes was 40% higher in women with RA who were taking glucocorticoids, compared with those with the disease but not taking that type of medication. However, low-molecular-weight heparin use was associated with an 80% lower relative risk of miscarriage or perinatal death in comparison with those not taking it. Researchers saw no significant effects of aspirin or conventional synthetic disease-modifying antirheumatic drugs on either adverse pregnancy outcomes or the risk of miscarriage or perinatal death.

“This reinforces the importance of adjustment of therapy for RA before conception and throughout pregnancy, because medication use could affect pregnancy course not only influencing maternal disease activity but also the gestational outcome,” the authors wrote. “Although this is a study conducted on administrative data, we can hypothesize that exposure to therapy represents a marker of high RA disease activity and severity. In our setting, it is possible that, the more active the disease, the greater the probability of being included in the ideal clinical pathway, but in any case, this resulted in a lower odds ratio of adverse pregnancy outcome and miscarriage/perinatal death.”

The study was supported by the Italian Society for Rheumatology. No conflicts of interest were declared.

SOURCE: Bortoluzzi A et al. Arthritis Care Res. 2020 Jan 8. doi: 10.1002/ACR.24116.

In males but not females, hyperinsulinemia, insulin resistance, and metabolic syndrome are independently associated with a higher risk of Barrett’s esophagus (BE), based on a recent case-control study.

These findings offer some insight into why men have higher rates of BE and esophageal adenocarcinoma than do women, reported lead author Bradley J. Kendall, MBBS, PhD, of the University of Queensland in Brisbane, Australia, and colleagues.

“Esophageal adenocarcinoma (EA) and its precursor lesion, Barrett’s esophagus (BE), are more common in males than females,” the investigators wrote in the Journal of Clinical Gastroenterology. “In contrast, gastroesophageal reflux (GER), the major risk factor for BE and EA occurs at similar frequencies in both sexes. In addition, 10% to 20% of BE and EA cases report no history of GER symptoms. This suggests that non-GER factors are important in the development of BE and EA.”

To examine risk factors more closely, the investigators enrolled 227 patients with BE and 241 age- and sex-matched controls. Data were drawn from self-reported questionnaires, interviews, blood pressure readings, and anthropometric measurements, the latter of which included weight, height, and waist circumference. These patient characteristics were supplemented with fasted blood assays. The investigators looked for associations between BE and insulin level, Homeostatic Model Assessment of Insulin Resistance, metabolic syndrome, type 2 diabetes mellitus, insulin-like growth factors, and interleukin-6 (IL-6).

Across the entire population, independent associations were detected between BE and hyperinsulinemia (highest vs. lowest tertile; odds ratio, 1.9; P = .003), insulin resistance (OR, 1.9; P = .006) and metabolic syndrome (OR, 1.8; P = .004). For those with metabolic syndrome, risk of BE increased by 20% for each additional syndrome criterion (P = .02).

When stratifying by sex, however, all of the above risk factors remained statistically significant in men, but not in women. For male patients, compared with the population as a whole, risks were relatively higher for all three factors: hyperinsulinemia (OR, 2.1; P = .007), insulin resistance (OR, 2.1; P = .01), and metabolic syndrome (OR, 2.3; P = .001). Similarly, for men with metabolic syndrome, each additional syndrome criterion increased risk of BE by 40% (P = .005).

Regardless of sex stratification, the other evaluated characteristics (type 2 diabetes mellitus, insulin-like growth factors, and IL-6) were not associated with BE risk.

The investigators offered some possible mechanistic explanations for their findings.

“Hyperinsulinemia ... can result in increased insulin signaling, increased cellular proliferation, reduced apoptosis, oncogenic pathway activation, and enhanced cellular invasion,” they wrote. “In addition, abdominal obesity, which is the driver of these disorders of insulin homeostasis, also alters adipocytokine profiles and induces a chronic systemic inflammatory state. The inflammatory state can result in oncoprotein activation, angiogenesis, cellular proliferation, apoptosis, and metastasis.”

Concerning the difference between sexes, the investigators pointed to patterns of abdominal obesity. “[A]bdominal obesity and the associated metabolic sequelae are more common in males than females,” they wrote. “These observations give rise to the notion that the metabolic syndrome potentiates the inflammatory effects of the gastric refluxate in the distal esophagus and this may play a role in the male predominance of BE and EA.”

While these findings offer insight into the underlying processes that precipitate BE, the investigators suggested that more research is needed.

“The interactions of obesity hormones, GER, and the cells of the esophageal mucosa warrant further investigation,” they concluded.

The study was funded by the Queensland Cancer Fund, Queensland Government Smart State Fund, and the Princess Alexandra Hospital Research Foundation, and others. The investigators reported no disclosures.

SOURCE: Kendall BJ et al. J Clin Gastroenterol. 2019 Dec 24. doi: 10.1097/MCG.0000000000001307.

In males but not females, hyperinsulinemia, insulin resistance, and metabolic syndrome are independently associated with a higher risk of Barrett’s esophagus (BE), based on a recent case-control study.

These findings offer some insight into why men have higher rates of BE and esophageal adenocarcinoma than do women, reported lead author Bradley J. Kendall, MBBS, PhD, of the University of Queensland in Brisbane, Australia, and colleagues.

“Esophageal adenocarcinoma (EA) and its precursor lesion, Barrett’s esophagus (BE), are more common in males than females,” the investigators wrote in the Journal of Clinical Gastroenterology. “In contrast, gastroesophageal reflux (GER), the major risk factor for BE and EA occurs at similar frequencies in both sexes. In addition, 10% to 20% of BE and EA cases report no history of GER symptoms. This suggests that non-GER factors are important in the development of BE and EA.”

To examine risk factors more closely, the investigators enrolled 227 patients with BE and 241 age- and sex-matched controls. Data were drawn from self-reported questionnaires, interviews, blood pressure readings, and anthropometric measurements, the latter of which included weight, height, and waist circumference. These patient characteristics were supplemented with fasted blood assays. The investigators looked for associations between BE and insulin level, Homeostatic Model Assessment of Insulin Resistance, metabolic syndrome, type 2 diabetes mellitus, insulin-like growth factors, and interleukin-6 (IL-6).

Across the entire population, independent associations were detected between BE and hyperinsulinemia (highest vs. lowest tertile; odds ratio, 1.9; P = .003), insulin resistance (OR, 1.9; P = .006) and metabolic syndrome (OR, 1.8; P = .004). For those with metabolic syndrome, risk of BE increased by 20% for each additional syndrome criterion (P = .02).

When stratifying by sex, however, all of the above risk factors remained statistically significant in men, but not in women. For male patients, compared with the population as a whole, risks were relatively higher for all three factors: hyperinsulinemia (OR, 2.1; P = .007), insulin resistance (OR, 2.1; P = .01), and metabolic syndrome (OR, 2.3; P = .001). Similarly, for men with metabolic syndrome, each additional syndrome criterion increased risk of BE by 40% (P = .005).

Regardless of sex stratification, the other evaluated characteristics (type 2 diabetes mellitus, insulin-like growth factors, and IL-6) were not associated with BE risk.

The investigators offered some possible mechanistic explanations for their findings.

“Hyperinsulinemia ... can result in increased insulin signaling, increased cellular proliferation, reduced apoptosis, oncogenic pathway activation, and enhanced cellular invasion,” they wrote. “In addition, abdominal obesity, which is the driver of these disorders of insulin homeostasis, also alters adipocytokine profiles and induces a chronic systemic inflammatory state. The inflammatory state can result in oncoprotein activation, angiogenesis, cellular proliferation, apoptosis, and metastasis.”

Concerning the difference between sexes, the investigators pointed to patterns of abdominal obesity. “[A]bdominal obesity and the associated metabolic sequelae are more common in males than females,” they wrote. “These observations give rise to the notion that the metabolic syndrome potentiates the inflammatory effects of the gastric refluxate in the distal esophagus and this may play a role in the male predominance of BE and EA.”

While these findings offer insight into the underlying processes that precipitate BE, the investigators suggested that more research is needed.

“The interactions of obesity hormones, GER, and the cells of the esophageal mucosa warrant further investigation,” they concluded.

The study was funded by the Queensland Cancer Fund, Queensland Government Smart State Fund, and the Princess Alexandra Hospital Research Foundation, and others. The investigators reported no disclosures.

SOURCE: Kendall BJ et al. J Clin Gastroenterol. 2019 Dec 24. doi: 10.1097/MCG.0000000000001307.

In males but not females, hyperinsulinemia, insulin resistance, and metabolic syndrome are independently associated with a higher risk of Barrett’s esophagus (BE), based on a recent case-control study.

These findings offer some insight into why men have higher rates of BE and esophageal adenocarcinoma than do women, reported lead author Bradley J. Kendall, MBBS, PhD, of the University of Queensland in Brisbane, Australia, and colleagues.

“Esophageal adenocarcinoma (EA) and its precursor lesion, Barrett’s esophagus (BE), are more common in males than females,” the investigators wrote in the Journal of Clinical Gastroenterology. “In contrast, gastroesophageal reflux (GER), the major risk factor for BE and EA occurs at similar frequencies in both sexes. In addition, 10% to 20% of BE and EA cases report no history of GER symptoms. This suggests that non-GER factors are important in the development of BE and EA.”

To examine risk factors more closely, the investigators enrolled 227 patients with BE and 241 age- and sex-matched controls. Data were drawn from self-reported questionnaires, interviews, blood pressure readings, and anthropometric measurements, the latter of which included weight, height, and waist circumference. These patient characteristics were supplemented with fasted blood assays. The investigators looked for associations between BE and insulin level, Homeostatic Model Assessment of Insulin Resistance, metabolic syndrome, type 2 diabetes mellitus, insulin-like growth factors, and interleukin-6 (IL-6).

Across the entire population, independent associations were detected between BE and hyperinsulinemia (highest vs. lowest tertile; odds ratio, 1.9; P = .003), insulin resistance (OR, 1.9; P = .006) and metabolic syndrome (OR, 1.8; P = .004). For those with metabolic syndrome, risk of BE increased by 20% for each additional syndrome criterion (P = .02).

When stratifying by sex, however, all of the above risk factors remained statistically significant in men, but not in women. For male patients, compared with the population as a whole, risks were relatively higher for all three factors: hyperinsulinemia (OR, 2.1; P = .007), insulin resistance (OR, 2.1; P = .01), and metabolic syndrome (OR, 2.3; P = .001). Similarly, for men with metabolic syndrome, each additional syndrome criterion increased risk of BE by 40% (P = .005).

Regardless of sex stratification, the other evaluated characteristics (type 2 diabetes mellitus, insulin-like growth factors, and IL-6) were not associated with BE risk.

The investigators offered some possible mechanistic explanations for their findings.

“Hyperinsulinemia ... can result in increased insulin signaling, increased cellular proliferation, reduced apoptosis, oncogenic pathway activation, and enhanced cellular invasion,” they wrote. “In addition, abdominal obesity, which is the driver of these disorders of insulin homeostasis, also alters adipocytokine profiles and induces a chronic systemic inflammatory state. The inflammatory state can result in oncoprotein activation, angiogenesis, cellular proliferation, apoptosis, and metastasis.”

Concerning the difference between sexes, the investigators pointed to patterns of abdominal obesity. “[A]bdominal obesity and the associated metabolic sequelae are more common in males than females,” they wrote. “These observations give rise to the notion that the metabolic syndrome potentiates the inflammatory effects of the gastric refluxate in the distal esophagus and this may play a role in the male predominance of BE and EA.”

While these findings offer insight into the underlying processes that precipitate BE, the investigators suggested that more research is needed.

“The interactions of obesity hormones, GER, and the cells of the esophageal mucosa warrant further investigation,” they concluded.

The study was funded by the Queensland Cancer Fund, Queensland Government Smart State Fund, and the Princess Alexandra Hospital Research Foundation, and others. The investigators reported no disclosures.

SOURCE: Kendall BJ et al. J Clin Gastroenterol. 2019 Dec 24. doi: 10.1097/MCG.0000000000001307.

ORLANDO – Anti-CD5 chimeric antigen receptor (CAR) T cells can produce complete responses (CRs) in patients with relapsed or refractory T-cell malignancies, according to findings from a phase 1 trial.

Jennifer Smith/MDedge News

Three of 11 patients achieved a CR after CAR T-cell therapy, and one patient achieved a mixed response that deepened to a CR after transplant. Three responders, all of whom had T-cell lymphoma, were still alive and in CR at last follow-up.

There were no cases of severe cytokine release syndrome (CRS) or severe neurotoxicity, no serious infectious complications, and no nonhematologic grade 4 adverse events in this trial.

LaQuisa C. Hill, MD, of Baylor College of Medicine, Houston, presented these results at the annual meeting of the American Society of Hematology.

“While CD19 CAR T cells have revolutionized the treatment of relapsed/refractory B-cell malignancies, development of CAR T-cell platforms targeting T-cell-driven malignancies have been hindered by three main factors: CAR T-cell fratricide due to shared expression of target antigens leading to impaired expansion, ablation of normal T cells continuing to cause profound immunodeficiency, and the potential of transduced tumor cells providing a means of tumor escape,” Dr. Hill said.

Researchers have theorized that anti-CD5 CAR T cells can overcome these obstacles. In preclinical studies, anti-CD5 CAR T cells eliminated malignant blasts in vitro and in vivo and resulted in “limited and transient” fratricide (Blood. 2015 Aug 20;126[8]:983-92).

With this in mind, Dr. Hill and her colleagues tested CD5.28z CAR T cells in a phase 1 trial (NCT03081910). Eleven patients have been treated thus far – five with T-cell acute lymphoblastic leukemia (T-ALL), three with peripheral T-cell lymphoma (PTCL), two with angioimmunoblastic T-cell lymphoma (AITL), and one with Sézary syndrome.

The patients’ median age at baseline was 62 years (range, 21-71 years), and 63% were men. They had received a median of 5 prior therapies (range, 3-18). Two patients had relapsed after allogeneic hematopoietic stem cell transplant (HSCT), three had relapsed after autologous HSCT, and five were primary refractory.

Patients underwent lymphodepletion with fludarabine and cyclophosphamide, then received CAR T cells at doses of 1 x 10⁷ or 5 x 10⁷.
 

Response

Three lymphoma patients – two with AITL and one with PTCL – were still alive and in CR at last follow-up. The PTCL patient achieved a CR after CAR T-cell therapy and declined a subsequent HSCT. The patient has not received additional therapy and has retained the CR for 7 months.

One AITL patient achieved a CR and declined transplant as well. He relapsed after 7 months but received subsequent therapy and achieved another CR. The other AITL patient had a mixed response to CAR T-cell therapy but proceeded to allogeneic HSCT and achieved a CR that has lasted 9 months.

The remaining three lymphoma patients – two with PTCL and one with Sézary syndrome – progressed and died.

One T-ALL patient achieved a CR lasting 6 weeks, but the patient died while undergoing transplant workup. Two T-ALL patients did not respond to treatment and died. The remaining two patients progressed, and one of them died. The other patient who progressed is still alive and in CR after receiving subsequent therapy.

Factors associated with response

Dr. Hill said a shortened manufacturing process may be associated with enhanced response, as all responders received CAR T cells produced via a shorter manufacturing process. The shortened process involves freezing cells on day 4-5 post transduction, as opposed to day 7.

“While the numbers are too small to make any definitive conclusions, this seems to correlate with less terminal differentiation, which might improve potency,” Dr. Hill said. “However, additional analyses are ongoing.”

Dr. Hill also pointed out that CAR T-cell expansion was observed in all patients, with higher peak levels observed at the higher dose. In addition, CAR T-cell persistence was durable at both dose levels.

“We have been able to detect the CAR transgene at all follow-up time points, out to 9 months for some patients,” Dr. Hill said. “While limited persistence may play a role in nonresponders, it does not appear to be the only factor.”

Safety

“Surprisingly, no selective ablation of normal T cells has been observed,” Dr. Hill said. “As CAR T cells dwindled [after infusion], we were able to see recovery of normal T cells, all of which expressed normal levels of CD5. This was observed in all patients on study, except for one patient who had prolonged pancytopenia.”

Cytopenias were the most common grade 3/4 adverse events, including neutropenia (n = 8), anemia (n = 7), and thrombocytopenia (n = 5). Other grade 3/4 events included elevated aspartate aminotransferase (n = 2), hypoalbuminemia (n = 1), hyponatremia (n = 1), hypophosphatemia (n = 1), and elevated alanine aminotransferase (n = 1). There were no grade 5 adverse events.

Two patients developed grade 1 CRS, and two had grade 2 CRS. Both patients with grade 2 CRS were treated with tocilizumab, and their symptoms resolved.

One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome, but this resolved with supportive care.

One patient had a central line–associated bloodstream infection (coagulase-negative staphylococci), and one had cytomegalovirus and BK virus reactivation. There were no fungal infections.

“We have demonstrated that CD5 CAR T cells can be manufactured from heavily pretreated patients with T-cell malignancies, and therapy is well tolerated,” Dr. Hill said. “We have seen strong and promising activity in T-cell lymphoma, which we hope to be able to translate to T-ALL as well.”

Dr. Hill said she and her colleagues hope to improve upon these results with a higher dose level of CD5 CAR T cells (1 x 10⁸), which the team plans to start testing soon. The researchers may also investigate other target antigens, such as CD7, as well as the use of donor-derived CAR T cells for patients who have relapsed after allogeneic HSCT.

Dr. Hill said she has no relevant disclosures. Baylor College of Medicine is sponsoring this trial.

[email protected]

SOURCE: Hill L et al. ASH 2019. Abstract 199.

ORLANDO – Anti-CD5 chimeric antigen receptor (CAR) T cells can produce complete responses (CRs) in patients with relapsed or refractory T-cell malignancies, according to findings from a phase 1 trial.

Jennifer Smith/MDedge News

Three of 11 patients achieved a CR after CAR T-cell therapy, and one patient achieved a mixed response that deepened to a CR after transplant. Three responders, all of whom had T-cell lymphoma, were still alive and in CR at last follow-up.

There were no cases of severe cytokine release syndrome (CRS) or severe neurotoxicity, no serious infectious complications, and no nonhematologic grade 4 adverse events in this trial.

LaQuisa C. Hill, MD, of Baylor College of Medicine, Houston, presented these results at the annual meeting of the American Society of Hematology.

“While CD19 CAR T cells have revolutionized the treatment of relapsed/refractory B-cell malignancies, development of CAR T-cell platforms targeting T-cell-driven malignancies have been hindered by three main factors: CAR T-cell fratricide due to shared expression of target antigens leading to impaired expansion, ablation of normal T cells continuing to cause profound immunodeficiency, and the potential of transduced tumor cells providing a means of tumor escape,” Dr. Hill said.

Researchers have theorized that anti-CD5 CAR T cells can overcome these obstacles. In preclinical studies, anti-CD5 CAR T cells eliminated malignant blasts in vitro and in vivo and resulted in “limited and transient” fratricide (Blood. 2015 Aug 20;126[8]:983-92).

With this in mind, Dr. Hill and her colleagues tested CD5.28z CAR T cells in a phase 1 trial (NCT03081910). Eleven patients have been treated thus far – five with T-cell acute lymphoblastic leukemia (T-ALL), three with peripheral T-cell lymphoma (PTCL), two with angioimmunoblastic T-cell lymphoma (AITL), and one with Sézary syndrome.

The patients’ median age at baseline was 62 years (range, 21-71 years), and 63% were men. They had received a median of 5 prior therapies (range, 3-18). Two patients had relapsed after allogeneic hematopoietic stem cell transplant (HSCT), three had relapsed after autologous HSCT, and five were primary refractory.

Patients underwent lymphodepletion with fludarabine and cyclophosphamide, then received CAR T cells at doses of 1 x 10⁷ or 5 x 10⁷.
 

Response

Three lymphoma patients – two with AITL and one with PTCL – were still alive and in CR at last follow-up. The PTCL patient achieved a CR after CAR T-cell therapy and declined a subsequent HSCT. The patient has not received additional therapy and has retained the CR for 7 months.

One AITL patient achieved a CR and declined transplant as well. He relapsed after 7 months but received subsequent therapy and achieved another CR. The other AITL patient had a mixed response to CAR T-cell therapy but proceeded to allogeneic HSCT and achieved a CR that has lasted 9 months.

The remaining three lymphoma patients – two with PTCL and one with Sézary syndrome – progressed and died.

One T-ALL patient achieved a CR lasting 6 weeks, but the patient died while undergoing transplant workup. Two T-ALL patients did not respond to treatment and died. The remaining two patients progressed, and one of them died. The other patient who progressed is still alive and in CR after receiving subsequent therapy.

Factors associated with response

Dr. Hill said a shortened manufacturing process may be associated with enhanced response, as all responders received CAR T cells produced via a shorter manufacturing process. The shortened process involves freezing cells on day 4-5 post transduction, as opposed to day 7.

“While the numbers are too small to make any definitive conclusions, this seems to correlate with less terminal differentiation, which might improve potency,” Dr. Hill said. “However, additional analyses are ongoing.”

Dr. Hill also pointed out that CAR T-cell expansion was observed in all patients, with higher peak levels observed at the higher dose. In addition, CAR T-cell persistence was durable at both dose levels.

“We have been able to detect the CAR transgene at all follow-up time points, out to 9 months for some patients,” Dr. Hill said. “While limited persistence may play a role in nonresponders, it does not appear to be the only factor.”

Safety

“Surprisingly, no selective ablation of normal T cells has been observed,” Dr. Hill said. “As CAR T cells dwindled [after infusion], we were able to see recovery of normal T cells, all of which expressed normal levels of CD5. This was observed in all patients on study, except for one patient who had prolonged pancytopenia.”

Cytopenias were the most common grade 3/4 adverse events, including neutropenia (n = 8), anemia (n = 7), and thrombocytopenia (n = 5). Other grade 3/4 events included elevated aspartate aminotransferase (n = 2), hypoalbuminemia (n = 1), hyponatremia (n = 1), hypophosphatemia (n = 1), and elevated alanine aminotransferase (n = 1). There were no grade 5 adverse events.

Two patients developed grade 1 CRS, and two had grade 2 CRS. Both patients with grade 2 CRS were treated with tocilizumab, and their symptoms resolved.

One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome, but this resolved with supportive care.

One patient had a central line–associated bloodstream infection (coagulase-negative staphylococci), and one had cytomegalovirus and BK virus reactivation. There were no fungal infections.

“We have demonstrated that CD5 CAR T cells can be manufactured from heavily pretreated patients with T-cell malignancies, and therapy is well tolerated,” Dr. Hill said. “We have seen strong and promising activity in T-cell lymphoma, which we hope to be able to translate to T-ALL as well.”

Dr. Hill said she and her colleagues hope to improve upon these results with a higher dose level of CD5 CAR T cells (1 x 10⁸), which the team plans to start testing soon. The researchers may also investigate other target antigens, such as CD7, as well as the use of donor-derived CAR T cells for patients who have relapsed after allogeneic HSCT.

Dr. Hill said she has no relevant disclosures. Baylor College of Medicine is sponsoring this trial.

[email protected]

SOURCE: Hill L et al. ASH 2019. Abstract 199.

ORLANDO – Anti-CD5 chimeric antigen receptor (CAR) T cells can produce complete responses (CRs) in patients with relapsed or refractory T-cell malignancies, according to findings from a phase 1 trial.

Jennifer Smith/MDedge News

Three of 11 patients achieved a CR after CAR T-cell therapy, and one patient achieved a mixed response that deepened to a CR after transplant. Three responders, all of whom had T-cell lymphoma, were still alive and in CR at last follow-up.

There were no cases of severe cytokine release syndrome (CRS) or severe neurotoxicity, no serious infectious complications, and no nonhematologic grade 4 adverse events in this trial.

LaQuisa C. Hill, MD, of Baylor College of Medicine, Houston, presented these results at the annual meeting of the American Society of Hematology.

“While CD19 CAR T cells have revolutionized the treatment of relapsed/refractory B-cell malignancies, development of CAR T-cell platforms targeting T-cell-driven malignancies have been hindered by three main factors: CAR T-cell fratricide due to shared expression of target antigens leading to impaired expansion, ablation of normal T cells continuing to cause profound immunodeficiency, and the potential of transduced tumor cells providing a means of tumor escape,” Dr. Hill said.

Researchers have theorized that anti-CD5 CAR T cells can overcome these obstacles. In preclinical studies, anti-CD5 CAR T cells eliminated malignant blasts in vitro and in vivo and resulted in “limited and transient” fratricide (Blood. 2015 Aug 20;126[8]:983-92).

With this in mind, Dr. Hill and her colleagues tested CD5.28z CAR T cells in a phase 1 trial (NCT03081910). Eleven patients have been treated thus far – five with T-cell acute lymphoblastic leukemia (T-ALL), three with peripheral T-cell lymphoma (PTCL), two with angioimmunoblastic T-cell lymphoma (AITL), and one with Sézary syndrome.

The patients’ median age at baseline was 62 years (range, 21-71 years), and 63% were men. They had received a median of 5 prior therapies (range, 3-18). Two patients had relapsed after allogeneic hematopoietic stem cell transplant (HSCT), three had relapsed after autologous HSCT, and five were primary refractory.

Patients underwent lymphodepletion with fludarabine and cyclophosphamide, then received CAR T cells at doses of 1 x 10⁷ or 5 x 10⁷.
 

Response

Three lymphoma patients – two with AITL and one with PTCL – were still alive and in CR at last follow-up. The PTCL patient achieved a CR after CAR T-cell therapy and declined a subsequent HSCT. The patient has not received additional therapy and has retained the CR for 7 months.

One AITL patient achieved a CR and declined transplant as well. He relapsed after 7 months but received subsequent therapy and achieved another CR. The other AITL patient had a mixed response to CAR T-cell therapy but proceeded to allogeneic HSCT and achieved a CR that has lasted 9 months.

The remaining three lymphoma patients – two with PTCL and one with Sézary syndrome – progressed and died.

One T-ALL patient achieved a CR lasting 6 weeks, but the patient died while undergoing transplant workup. Two T-ALL patients did not respond to treatment and died. The remaining two patients progressed, and one of them died. The other patient who progressed is still alive and in CR after receiving subsequent therapy.

Factors associated with response

Dr. Hill said a shortened manufacturing process may be associated with enhanced response, as all responders received CAR T cells produced via a shorter manufacturing process. The shortened process involves freezing cells on day 4-5 post transduction, as opposed to day 7.

“While the numbers are too small to make any definitive conclusions, this seems to correlate with less terminal differentiation, which might improve potency,” Dr. Hill said. “However, additional analyses are ongoing.”

Dr. Hill also pointed out that CAR T-cell expansion was observed in all patients, with higher peak levels observed at the higher dose. In addition, CAR T-cell persistence was durable at both dose levels.

“We have been able to detect the CAR transgene at all follow-up time points, out to 9 months for some patients,” Dr. Hill said. “While limited persistence may play a role in nonresponders, it does not appear to be the only factor.”

Safety

“Surprisingly, no selective ablation of normal T cells has been observed,” Dr. Hill said. “As CAR T cells dwindled [after infusion], we were able to see recovery of normal T cells, all of which expressed normal levels of CD5. This was observed in all patients on study, except for one patient who had prolonged pancytopenia.”

Cytopenias were the most common grade 3/4 adverse events, including neutropenia (n = 8), anemia (n = 7), and thrombocytopenia (n = 5). Other grade 3/4 events included elevated aspartate aminotransferase (n = 2), hypoalbuminemia (n = 1), hyponatremia (n = 1), hypophosphatemia (n = 1), and elevated alanine aminotransferase (n = 1). There were no grade 5 adverse events.

Two patients developed grade 1 CRS, and two had grade 2 CRS. Both patients with grade 2 CRS were treated with tocilizumab, and their symptoms resolved.

One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome, but this resolved with supportive care.

One patient had a central line–associated bloodstream infection (coagulase-negative staphylococci), and one had cytomegalovirus and BK virus reactivation. There were no fungal infections.

“We have demonstrated that CD5 CAR T cells can be manufactured from heavily pretreated patients with T-cell malignancies, and therapy is well tolerated,” Dr. Hill said. “We have seen strong and promising activity in T-cell lymphoma, which we hope to be able to translate to T-ALL as well.”

Dr. Hill said she and her colleagues hope to improve upon these results with a higher dose level of CD5 CAR T cells (1 x 10⁸), which the team plans to start testing soon. The researchers may also investigate other target antigens, such as CD7, as well as the use of donor-derived CAR T cells for patients who have relapsed after allogeneic HSCT.

Dr. Hill said she has no relevant disclosures. Baylor College of Medicine is sponsoring this trial.

[email protected]

SOURCE: Hill L et al. ASH 2019. Abstract 199.

PHILADELPHIA – Treatment with the PCSK9 inhibitor alirocumab linked with a significant cut in the rates of peripheral artery disease events and ischemic strokes without increasing the rate of hemorrhagic strokes, and alirocumab treatment also showed a trend toward an association with a reduced rate of venous thromboembolic events in prespecified, ancillary analyses of data collected from more than 18,000 patients in the ODYSSEY Outcomes trial.

Mitchel L. Zoler/MDedge News

The analyses that looked at peripheral artery disease (PAD) events and venous thromboembolism (VTE) events also suggested that the apparent ability of alirocumab to reduce their incidence may have been largely mediated through a reduction in Lp(a) lipoprotein, with less of a contribution from the drug’s primary action of reducing LDL cholesterol, Gregory G. Schwartz, MD, said at the American Heart Association scientific sessions.

When used on top of intensive statin treatment, as in the ODYSSEY Outcomes trial, treatment with the PCSK9 inhibitor alirocumab “may be useful to prevent PAD events, particularly in patients with high levels of Lp(a),” said Dr. Schwartz, professor of medicine at the University of Colorado Denver in Aurora. In the analysis he reported, patients treated with alirocumab for a median of 2.8 years had a statistically significant 31% reduced rate of PAD or VTE event and a significant 31% reduced rate of PAD events alone, compared with control patients who received placebo, he reported. Alirocumab treatment was also associated with a 33% lower rate of VTE events only, but the overall rate of these events was low, and this difference just missed statistical significance with a P value of .06.

“Levels of Lp(a), but not LDL cholesterol, predicted the risk of PAD events,” and in patients on alirocumab treatment “the magnitude of Lp(a) reduction, but not LDL-cholesterol reduction, was associated with a reduction in PAD events and VTE.” The reduction in PAD events linked with alirocumab treatment “may be related to Lp(a) lowering,” Dr. Schwartz suggested.

The link between alirocumab treatment and a reduction in ischemic stroke with no increase in hemorrhagic strokes appeared in a separate prespecified analysis from ODYSSEY Outcomes that looked at the rates of ischemic stroke, hemorrhagic stroke, and their combined incidence during the median 2.8 year of study follow-up. Patients treated with alirocumab had a statistically significant 27% reduction in their rate of ischemic strokes compared with patients on placebo, and a statistically significant 28% relative reduction in the rate of any stroke with alirocumab treatment, J. Wouter Jukema, MD, said in a separate report at the meeting. The rate of hemorrhagic strokes was small, and showed a nominal 17% reduction in patients treated with alirocumab, compared with controls, a difference that was not statistically significant.

Mitchel L. Zoler/MDedge News

Further analysis of the stroke outcomes also showed that these reductions in total strokes occurred with alirocumab treatment at roughly similar rates regardless of baseline level of LDL cholesterol or history of a prior cerebrovascular event. Analysis also showed that the rate of hemorrhagic strokes was consistently low regardless of the on-treatment level of LDL cholesterol. Even among patients whose LDL cholesterol level fell below 25 mg/dL on alirocumab treatment, the incidence of hemorrhagic strokes during follow-up was 0.1%, “a very reassuring finding,” said Dr. Jukema, professor of cardiology at Leiden (The Netherlands) University. The stroke analyses did not examine possible linkages of these effects with changes in level of Lp(a).

ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) included 18,924 patients who had experienced an acute coronary syndrome event within the prior 12 months and had an LDL cholesterol level of at least 70 mg/dL despite maximally tolerated statin treatment and randomized them to treatment with alirocumab or placebo. The primary endpoint was the combination of coronary heart disease death, nonfatal MI, ischemic stroke, and hospitalization for unstable angina, which alirocumab effectively reduced compared with placebo (N Engl J Med. 2018 Nov 29;379[22]:2097-107).

The PAD analysis tallied the combined rate of acute limb ischemia, revascularization, or amputation related to PAD, and the VTE cases included patients who developed deep vein thrombosis or pulmonary embolism. All cases were nonadjudicated reports from participating investigators. Because Lp(a) makes up a portion of LDL cholesterol, Dr. Schwartz and associates calculated adjusted values for LDL cholesterol that were independent of Lp(a).

In a multivariable analysis that adjusted for demographic and clinical characteristics as well as baseline Lp(a) and the calculated level of LDL cholesterol, every 1 mg/dL decrease in Lp(a) linked with a statistically significant, nearly 1% decrease in the rate of either a PAD or VTE event, while the change in LDL cholesterol had no significant relationship with this endpoint, said Dr. Schwartz.

The impact of Lp(a) lowering was most dramatic among the subgroups of patients who entered the study with the highest levels of Lp(a). “In the lowest quartile [for baseline level of Lp(a)] the effect of treatment [with alirocumab] was inconsequential; all of the action was in the upper two quartiles,” he said. Dr. Schwartz highlighted that 90% of patients in the study were on an “intense” statin dosage, and 97% received some statin treatment. Against that treatment background, the findings showed that patients still had residual cardiovascular disease risk that did not appear to respond to changes in LDL cholesterol but which did appear to respond to a reduction in Lp(a) produced by alirocumab. Dr. Schwartz further suggested that alirocumab’s reduction of Lp(a) might also mediate the drug’s apparent effect on reducing VTE incidence, possibly because Lp(a) is structurally similar to plasminogen and hence can have prothrombotic effects.

ODYSSEY Outcomes was sponsored by Sanofi and Regeneron, the companies that market alirocumab (Praluent). Dr. Schwartz has received research support from Sanofi and from Resverlogix, Roche, and The Medicines Company. Dr. Jukema has been a speaker for and received research support from Sanofi Regeneron, and has also been a speaker for Amgen, MSD, and Roche and has also received research support from Biotronik

[email protected]

SOURCE: Schwartz GG et al. AHA 2019, Abstract 309; Jukema JW et al. AHA 2019, Abstract 334.

PHILADELPHIA – Treatment with the PCSK9 inhibitor alirocumab linked with a significant cut in the rates of peripheral artery disease events and ischemic strokes without increasing the rate of hemorrhagic strokes, and alirocumab treatment also showed a trend toward an association with a reduced rate of venous thromboembolic events in prespecified, ancillary analyses of data collected from more than 18,000 patients in the ODYSSEY Outcomes trial.

Mitchel L. Zoler/MDedge News

The analyses that looked at peripheral artery disease (PAD) events and venous thromboembolism (VTE) events also suggested that the apparent ability of alirocumab to reduce their incidence may have been largely mediated through a reduction in Lp(a) lipoprotein, with less of a contribution from the drug’s primary action of reducing LDL cholesterol, Gregory G. Schwartz, MD, said at the American Heart Association scientific sessions.

When used on top of intensive statin treatment, as in the ODYSSEY Outcomes trial, treatment with the PCSK9 inhibitor alirocumab “may be useful to prevent PAD events, particularly in patients with high levels of Lp(a),” said Dr. Schwartz, professor of medicine at the University of Colorado Denver in Aurora. In the analysis he reported, patients treated with alirocumab for a median of 2.8 years had a statistically significant 31% reduced rate of PAD or VTE event and a significant 31% reduced rate of PAD events alone, compared with control patients who received placebo, he reported. Alirocumab treatment was also associated with a 33% lower rate of VTE events only, but the overall rate of these events was low, and this difference just missed statistical significance with a P value of .06.

“Levels of Lp(a), but not LDL cholesterol, predicted the risk of PAD events,” and in patients on alirocumab treatment “the magnitude of Lp(a) reduction, but not LDL-cholesterol reduction, was associated with a reduction in PAD events and VTE.” The reduction in PAD events linked with alirocumab treatment “may be related to Lp(a) lowering,” Dr. Schwartz suggested.

The link between alirocumab treatment and a reduction in ischemic stroke with no increase in hemorrhagic strokes appeared in a separate prespecified analysis from ODYSSEY Outcomes that looked at the rates of ischemic stroke, hemorrhagic stroke, and their combined incidence during the median 2.8 year of study follow-up. Patients treated with alirocumab had a statistically significant 27% reduction in their rate of ischemic strokes compared with patients on placebo, and a statistically significant 28% relative reduction in the rate of any stroke with alirocumab treatment, J. Wouter Jukema, MD, said in a separate report at the meeting. The rate of hemorrhagic strokes was small, and showed a nominal 17% reduction in patients treated with alirocumab, compared with controls, a difference that was not statistically significant.

Mitchel L. Zoler/MDedge News

Further analysis of the stroke outcomes also showed that these reductions in total strokes occurred with alirocumab treatment at roughly similar rates regardless of baseline level of LDL cholesterol or history of a prior cerebrovascular event. Analysis also showed that the rate of hemorrhagic strokes was consistently low regardless of the on-treatment level of LDL cholesterol. Even among patients whose LDL cholesterol level fell below 25 mg/dL on alirocumab treatment, the incidence of hemorrhagic strokes during follow-up was 0.1%, “a very reassuring finding,” said Dr. Jukema, professor of cardiology at Leiden (The Netherlands) University. The stroke analyses did not examine possible linkages of these effects with changes in level of Lp(a).

ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) included 18,924 patients who had experienced an acute coronary syndrome event within the prior 12 months and had an LDL cholesterol level of at least 70 mg/dL despite maximally tolerated statin treatment and randomized them to treatment with alirocumab or placebo. The primary endpoint was the combination of coronary heart disease death, nonfatal MI, ischemic stroke, and hospitalization for unstable angina, which alirocumab effectively reduced compared with placebo (N Engl J Med. 2018 Nov 29;379[22]:2097-107).

The PAD analysis tallied the combined rate of acute limb ischemia, revascularization, or amputation related to PAD, and the VTE cases included patients who developed deep vein thrombosis or pulmonary embolism. All cases were nonadjudicated reports from participating investigators. Because Lp(a) makes up a portion of LDL cholesterol, Dr. Schwartz and associates calculated adjusted values for LDL cholesterol that were independent of Lp(a).

In a multivariable analysis that adjusted for demographic and clinical characteristics as well as baseline Lp(a) and the calculated level of LDL cholesterol, every 1 mg/dL decrease in Lp(a) linked with a statistically significant, nearly 1% decrease in the rate of either a PAD or VTE event, while the change in LDL cholesterol had no significant relationship with this endpoint, said Dr. Schwartz.

The impact of Lp(a) lowering was most dramatic among the subgroups of patients who entered the study with the highest levels of Lp(a). “In the lowest quartile [for baseline level of Lp(a)] the effect of treatment [with alirocumab] was inconsequential; all of the action was in the upper two quartiles,” he said. Dr. Schwartz highlighted that 90% of patients in the study were on an “intense” statin dosage, and 97% received some statin treatment. Against that treatment background, the findings showed that patients still had residual cardiovascular disease risk that did not appear to respond to changes in LDL cholesterol but which did appear to respond to a reduction in Lp(a) produced by alirocumab. Dr. Schwartz further suggested that alirocumab’s reduction of Lp(a) might also mediate the drug’s apparent effect on reducing VTE incidence, possibly because Lp(a) is structurally similar to plasminogen and hence can have prothrombotic effects.

ODYSSEY Outcomes was sponsored by Sanofi and Regeneron, the companies that market alirocumab (Praluent). Dr. Schwartz has received research support from Sanofi and from Resverlogix, Roche, and The Medicines Company. Dr. Jukema has been a speaker for and received research support from Sanofi Regeneron, and has also been a speaker for Amgen, MSD, and Roche and has also received research support from Biotronik

[email protected]

SOURCE: Schwartz GG et al. AHA 2019, Abstract 309; Jukema JW et al. AHA 2019, Abstract 334.

PHILADELPHIA – Treatment with the PCSK9 inhibitor alirocumab linked with a significant cut in the rates of peripheral artery disease events and ischemic strokes without increasing the rate of hemorrhagic strokes, and alirocumab treatment also showed a trend toward an association with a reduced rate of venous thromboembolic events in prespecified, ancillary analyses of data collected from more than 18,000 patients in the ODYSSEY Outcomes trial.

Mitchel L. Zoler/MDedge News

The analyses that looked at peripheral artery disease (PAD) events and venous thromboembolism (VTE) events also suggested that the apparent ability of alirocumab to reduce their incidence may have been largely mediated through a reduction in Lp(a) lipoprotein, with less of a contribution from the drug’s primary action of reducing LDL cholesterol, Gregory G. Schwartz, MD, said at the American Heart Association scientific sessions.

When used on top of intensive statin treatment, as in the ODYSSEY Outcomes trial, treatment with the PCSK9 inhibitor alirocumab “may be useful to prevent PAD events, particularly in patients with high levels of Lp(a),” said Dr. Schwartz, professor of medicine at the University of Colorado Denver in Aurora. In the analysis he reported, patients treated with alirocumab for a median of 2.8 years had a statistically significant 31% reduced rate of PAD or VTE event and a significant 31% reduced rate of PAD events alone, compared with control patients who received placebo, he reported. Alirocumab treatment was also associated with a 33% lower rate of VTE events only, but the overall rate of these events was low, and this difference just missed statistical significance with a P value of .06.

“Levels of Lp(a), but not LDL cholesterol, predicted the risk of PAD events,” and in patients on alirocumab treatment “the magnitude of Lp(a) reduction, but not LDL-cholesterol reduction, was associated with a reduction in PAD events and VTE.” The reduction in PAD events linked with alirocumab treatment “may be related to Lp(a) lowering,” Dr. Schwartz suggested.

The link between alirocumab treatment and a reduction in ischemic stroke with no increase in hemorrhagic strokes appeared in a separate prespecified analysis from ODYSSEY Outcomes that looked at the rates of ischemic stroke, hemorrhagic stroke, and their combined incidence during the median 2.8 year of study follow-up. Patients treated with alirocumab had a statistically significant 27% reduction in their rate of ischemic strokes compared with patients on placebo, and a statistically significant 28% relative reduction in the rate of any stroke with alirocumab treatment, J. Wouter Jukema, MD, said in a separate report at the meeting. The rate of hemorrhagic strokes was small, and showed a nominal 17% reduction in patients treated with alirocumab, compared with controls, a difference that was not statistically significant.

Mitchel L. Zoler/MDedge News

Further analysis of the stroke outcomes also showed that these reductions in total strokes occurred with alirocumab treatment at roughly similar rates regardless of baseline level of LDL cholesterol or history of a prior cerebrovascular event. Analysis also showed that the rate of hemorrhagic strokes was consistently low regardless of the on-treatment level of LDL cholesterol. Even among patients whose LDL cholesterol level fell below 25 mg/dL on alirocumab treatment, the incidence of hemorrhagic strokes during follow-up was 0.1%, “a very reassuring finding,” said Dr. Jukema, professor of cardiology at Leiden (The Netherlands) University. The stroke analyses did not examine possible linkages of these effects with changes in level of Lp(a).

ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) included 18,924 patients who had experienced an acute coronary syndrome event within the prior 12 months and had an LDL cholesterol level of at least 70 mg/dL despite maximally tolerated statin treatment and randomized them to treatment with alirocumab or placebo. The primary endpoint was the combination of coronary heart disease death, nonfatal MI, ischemic stroke, and hospitalization for unstable angina, which alirocumab effectively reduced compared with placebo (N Engl J Med. 2018 Nov 29;379[22]:2097-107).

The PAD analysis tallied the combined rate of acute limb ischemia, revascularization, or amputation related to PAD, and the VTE cases included patients who developed deep vein thrombosis or pulmonary embolism. All cases were nonadjudicated reports from participating investigators. Because Lp(a) makes up a portion of LDL cholesterol, Dr. Schwartz and associates calculated adjusted values for LDL cholesterol that were independent of Lp(a).

In a multivariable analysis that adjusted for demographic and clinical characteristics as well as baseline Lp(a) and the calculated level of LDL cholesterol, every 1 mg/dL decrease in Lp(a) linked with a statistically significant, nearly 1% decrease in the rate of either a PAD or VTE event, while the change in LDL cholesterol had no significant relationship with this endpoint, said Dr. Schwartz.

The impact of Lp(a) lowering was most dramatic among the subgroups of patients who entered the study with the highest levels of Lp(a). “In the lowest quartile [for baseline level of Lp(a)] the effect of treatment [with alirocumab] was inconsequential; all of the action was in the upper two quartiles,” he said. Dr. Schwartz highlighted that 90% of patients in the study were on an “intense” statin dosage, and 97% received some statin treatment. Against that treatment background, the findings showed that patients still had residual cardiovascular disease risk that did not appear to respond to changes in LDL cholesterol but which did appear to respond to a reduction in Lp(a) produced by alirocumab. Dr. Schwartz further suggested that alirocumab’s reduction of Lp(a) might also mediate the drug’s apparent effect on reducing VTE incidence, possibly because Lp(a) is structurally similar to plasminogen and hence can have prothrombotic effects.

ODYSSEY Outcomes was sponsored by Sanofi and Regeneron, the companies that market alirocumab (Praluent). Dr. Schwartz has received research support from Sanofi and from Resverlogix, Roche, and The Medicines Company. Dr. Jukema has been a speaker for and received research support from Sanofi Regeneron, and has also been a speaker for Amgen, MSD, and Roche and has also received research support from Biotronik

[email protected]

SOURCE: Schwartz GG et al. AHA 2019, Abstract 309; Jukema JW et al. AHA 2019, Abstract 334.

WASHINGTON – Research on pravastatin for the prevention of preeclampsia is moving along after “reassuring” data from pilot studies, with a large National Institutes of Health–funded trial currently recruiting women with a prior history of the disorder with preterm delivery at less than 34 weeks, Maged Costantine, MD, said at the biennial Diabetes in Pregnancy Study Group of North America meeting.

Creatas Images

More should be learned about low-dose aspirin, in the meantime, once the outcomes of a global study involving first-trimester initiation are published, said another speaker, Cynthia Gyamfi-Bannerman, MD, MS. Low-dose aspirin currently is recommended for preeclampsia prevention starting between 12 and 28 weeks, optimally before 16 weeks.

The biological plausibility of using pravastatin for preeclampsia prevention stems from the overlapping pathophysiology of preeclampsia with atherosclerotic cardiovascular disease – endothelial dysfunction and inflammation are common key mechanisms – as well as common risk factors, including diabetes and obesity, said Dr. Costantine, director of the division of maternal-fetal medicine at Ohio State University, Columbus, who is chairing the study.

In animal models of preeclampsia, pravastatin has been shown to upregulate placental growth factor, reduce antiangiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1), and upregulate endothelial nitric oxide synthase. Mice have shown improved vascular reactivity, decreased proteinuria, decreased oxidative stress, and other positive effects, without any detrimental outcomes.

A pilot randomized controlled trial conducted with the Obstetric-Fetal Pharmacology Research Units Network and published in the American Journal of Obstetrics and Gynecology in 2016 assigned 10 women to 10 mg daily pravastatin and 10 women to placebo. The drug reduced maternal cholesterol concentrations but there were no differences in birth weight or umbilical cord cholesterol concentrations between the two groups.

Women in the pravastatin group were less likely to develop preeclampsia (none, compared with four in the placebo group), less likely to have an indicated preterm delivery (one, compared with five in the placebo group), and less likely to have their neonates admitted to the neonatal ICU.

There were no differences in side effects, congenital anomalies, or other adverse events. Dr. Costantine, principal investigator of the pilot study, and his colleagues wrote in the paper that the “favorable risk-benefit analysis justifies continued research with a dose escalation” (Am J Obstet Gynecol. 2016 Jun;214[6]:720.e1-17).

The new multicenter randomized controlled trial is randomizing 1,550 women to either 20 mg pravastatin or placebo starting between 12 weeks 0 days and 16 weeks 6 days. The primary outcome is a composite of preeclampsia, maternal death, or fetal loss. Secondary outcomes include a composite of severe maternal morbidity and various measures representing preeclampsia severity and complications, as well as preterm delivery less than 37 weeks and less than 34 weeks and various fetal/neonatal outcomes.

“In addition, we’ll look at development,” Dr. Costantine said, with offspring assessed at 2 and 5 years of age. The trial is sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute.

In the meantime, he said, the use of pravastatin to ameliorate early-onset preeclampsia is being tested in a small European proof-of-concept trial that has randomized women with early-onset preeclampsia (between 24 and 31 6/7 weeks) to 40 mg pravastatin or placebo. The primary outcome is reduction of antiangiogenic markers. Results are expected in another year or 2, he said.

The aspirin trial referred to by Dr. Gyamfi-Bannerman has been looking at the 81-mg dose of aspirin initiated between 6 0/7 and 13 6/7 weeks in nulliparous women who had no more than two previous pregnancy losses. The key question of the Aspirin Supplementation for Pregnancy Indicated Risk Reduction in Nulliparas (ASPIRIN) trial – conducted in the NICHD Global Network for Women’s and Children’s Health – is whether low-dose aspirin can reduce the rate of preterm birth. Preeclampsia is a secondary outcome (https://clinicaltrials.gov/ct2/show/NCT02409680).

“It may eventually be that the use of baby aspirin is further expanded to reduce the risk of preterm birth,” she said.

Overall, “we need more data on first-trimester use [of low-dose aspirin] and long-term outcomes,” Dr. Gyamfi-Bannerman said. And with respect to preeclampsia prevention specifically, more research is needed looking at risk reduction levels within specific groups of patients.

Since 2014, the U.S. Preventive Services Task Force (USPSTF) has called for low-dose aspirin at 81 mg/day in women who have one or more high-risk factors for preeclampsia (including type 1 or type 2 diabetes mellitus), and consideration of such treatment in patients with several moderate-risk factors. The American College of Obstetricians and Gynecologists’ recommendation varies slightly in that it advises treatment in patients with more than one (versus several) moderate-level risk factors (Obstet Gynecol. 2018;132[1]:e44-52).

Moderate-level risk factors include nulliparity, obesity, family history of preeclampsia, a baseline demographic risk (African-American or low socioeconomic status), and prior poor history (intrauterine growth restriction/small-for-gestational-age, previous poor outcome). “This is just about everyone I see,” Dr. Gyamfi-Bannerman said.

Dr. Gyamfi-Bannerman said she’d “love to see more data on higher doses” of low-dose aspirin – data that compares 81 mg/day with 150 mg/day, for instance.

A study published in 2017 in the New England Journal of Medicine randomized 1,776 women at high risk for preeclampsia to 150 mg/day or placebo and found a significant reduction in preterm preeclampsia (4.3% vs. 1.6%) in the aspirin group. Women in this European trial were deemed to be at high risk, however, based on a first-trimester screening algorithm that incorporated serum markers (maternal serum pregnancy-associated plasma protein A and placental growth factor) and uterine artery Doppler measures (N Engl J Med. 2017 Aug 17;377[7]:613-22).

“So it was a very interesting study, very provocative, but it’s hard to know how it would translate to the U.S. population [given that such screening practices] are not the way most of us are practicing here,” said Dr. Gyamfi-Bannerman, codirector of the Preterm Birth Prevention Center at Columbia University, New York, and professor of obstetrics and gynecology at the university.

The USPSTF based its recommendations on a systematic review that pooled data from 15 high-quality randomized controlled trials, including 13 that reported preeclampsia incidence among women at highest risk of disease. They found a 24% reduction in preeclampsia, but the actual risk reduction depends on the baseline population risk and may be closer to 10%, she said.

In a presentation on gaps in knowledge, Leslie Myatt, PhD, of the department of obstetrics and gynecology at Oregon Health and Science University, Portland, emphasized that preeclampsia is a syndrome with a heterogeneity of presentation and pathophysiology. “We don’t completely understand the pathophysiology,” he said.

Research needs to be “directed at the existence of multiple pathways [and subtypes],” he said, such that future therapies can be targeted and personalized.

Dr. Costantine did not report any disclosures. Dr. Gyamfi-Bannerman reported a Society of Maternal Fetal Medicine/AMAG Pharmaceuticals unrestricted grant and Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Heart, Lung and Blood Institute funding. Dr. Myatt reported that he has no financial or other ties that pose a conflict of interest.

WASHINGTON – Research on pravastatin for the prevention of preeclampsia is moving along after “reassuring” data from pilot studies, with a large National Institutes of Health–funded trial currently recruiting women with a prior history of the disorder with preterm delivery at less than 34 weeks, Maged Costantine, MD, said at the biennial Diabetes in Pregnancy Study Group of North America meeting.

Creatas Images

More should be learned about low-dose aspirin, in the meantime, once the outcomes of a global study involving first-trimester initiation are published, said another speaker, Cynthia Gyamfi-Bannerman, MD, MS. Low-dose aspirin currently is recommended for preeclampsia prevention starting between 12 and 28 weeks, optimally before 16 weeks.

The biological plausibility of using pravastatin for preeclampsia prevention stems from the overlapping pathophysiology of preeclampsia with atherosclerotic cardiovascular disease – endothelial dysfunction and inflammation are common key mechanisms – as well as common risk factors, including diabetes and obesity, said Dr. Costantine, director of the division of maternal-fetal medicine at Ohio State University, Columbus, who is chairing the study.

In animal models of preeclampsia, pravastatin has been shown to upregulate placental growth factor, reduce antiangiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1), and upregulate endothelial nitric oxide synthase. Mice have shown improved vascular reactivity, decreased proteinuria, decreased oxidative stress, and other positive effects, without any detrimental outcomes.

A pilot randomized controlled trial conducted with the Obstetric-Fetal Pharmacology Research Units Network and published in the American Journal of Obstetrics and Gynecology in 2016 assigned 10 women to 10 mg daily pravastatin and 10 women to placebo. The drug reduced maternal cholesterol concentrations but there were no differences in birth weight or umbilical cord cholesterol concentrations between the two groups.

Women in the pravastatin group were less likely to develop preeclampsia (none, compared with four in the placebo group), less likely to have an indicated preterm delivery (one, compared with five in the placebo group), and less likely to have their neonates admitted to the neonatal ICU.

There were no differences in side effects, congenital anomalies, or other adverse events. Dr. Costantine, principal investigator of the pilot study, and his colleagues wrote in the paper that the “favorable risk-benefit analysis justifies continued research with a dose escalation” (Am J Obstet Gynecol. 2016 Jun;214[6]:720.e1-17).

The new multicenter randomized controlled trial is randomizing 1,550 women to either 20 mg pravastatin or placebo starting between 12 weeks 0 days and 16 weeks 6 days. The primary outcome is a composite of preeclampsia, maternal death, or fetal loss. Secondary outcomes include a composite of severe maternal morbidity and various measures representing preeclampsia severity and complications, as well as preterm delivery less than 37 weeks and less than 34 weeks and various fetal/neonatal outcomes.

“In addition, we’ll look at development,” Dr. Costantine said, with offspring assessed at 2 and 5 years of age. The trial is sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute.

In the meantime, he said, the use of pravastatin to ameliorate early-onset preeclampsia is being tested in a small European proof-of-concept trial that has randomized women with early-onset preeclampsia (between 24 and 31 6/7 weeks) to 40 mg pravastatin or placebo. The primary outcome is reduction of antiangiogenic markers. Results are expected in another year or 2, he said.

The aspirin trial referred to by Dr. Gyamfi-Bannerman has been looking at the 81-mg dose of aspirin initiated between 6 0/7 and 13 6/7 weeks in nulliparous women who had no more than two previous pregnancy losses. The key question of the Aspirin Supplementation for Pregnancy Indicated Risk Reduction in Nulliparas (ASPIRIN) trial – conducted in the NICHD Global Network for Women’s and Children’s Health – is whether low-dose aspirin can reduce the rate of preterm birth. Preeclampsia is a secondary outcome (https://clinicaltrials.gov/ct2/show/NCT02409680).

“It may eventually be that the use of baby aspirin is further expanded to reduce the risk of preterm birth,” she said.

Overall, “we need more data on first-trimester use [of low-dose aspirin] and long-term outcomes,” Dr. Gyamfi-Bannerman said. And with respect to preeclampsia prevention specifically, more research is needed looking at risk reduction levels within specific groups of patients.

Since 2014, the U.S. Preventive Services Task Force (USPSTF) has called for low-dose aspirin at 81 mg/day in women who have one or more high-risk factors for preeclampsia (including type 1 or type 2 diabetes mellitus), and consideration of such treatment in patients with several moderate-risk factors. The American College of Obstetricians and Gynecologists’ recommendation varies slightly in that it advises treatment in patients with more than one (versus several) moderate-level risk factors (Obstet Gynecol. 2018;132[1]:e44-52).

Moderate-level risk factors include nulliparity, obesity, family history of preeclampsia, a baseline demographic risk (African-American or low socioeconomic status), and prior poor history (intrauterine growth restriction/small-for-gestational-age, previous poor outcome). “This is just about everyone I see,” Dr. Gyamfi-Bannerman said.

Dr. Gyamfi-Bannerman said she’d “love to see more data on higher doses” of low-dose aspirin – data that compares 81 mg/day with 150 mg/day, for instance.

A study published in 2017 in the New England Journal of Medicine randomized 1,776 women at high risk for preeclampsia to 150 mg/day or placebo and found a significant reduction in preterm preeclampsia (4.3% vs. 1.6%) in the aspirin group. Women in this European trial were deemed to be at high risk, however, based on a first-trimester screening algorithm that incorporated serum markers (maternal serum pregnancy-associated plasma protein A and placental growth factor) and uterine artery Doppler measures (N Engl J Med. 2017 Aug 17;377[7]:613-22).

“So it was a very interesting study, very provocative, but it’s hard to know how it would translate to the U.S. population [given that such screening practices] are not the way most of us are practicing here,” said Dr. Gyamfi-Bannerman, codirector of the Preterm Birth Prevention Center at Columbia University, New York, and professor of obstetrics and gynecology at the university.

The USPSTF based its recommendations on a systematic review that pooled data from 15 high-quality randomized controlled trials, including 13 that reported preeclampsia incidence among women at highest risk of disease. They found a 24% reduction in preeclampsia, but the actual risk reduction depends on the baseline population risk and may be closer to 10%, she said.

In a presentation on gaps in knowledge, Leslie Myatt, PhD, of the department of obstetrics and gynecology at Oregon Health and Science University, Portland, emphasized that preeclampsia is a syndrome with a heterogeneity of presentation and pathophysiology. “We don’t completely understand the pathophysiology,” he said.

Research needs to be “directed at the existence of multiple pathways [and subtypes],” he said, such that future therapies can be targeted and personalized.

Dr. Costantine did not report any disclosures. Dr. Gyamfi-Bannerman reported a Society of Maternal Fetal Medicine/AMAG Pharmaceuticals unrestricted grant and Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Heart, Lung and Blood Institute funding. Dr. Myatt reported that he has no financial or other ties that pose a conflict of interest.

WASHINGTON – Research on pravastatin for the prevention of preeclampsia is moving along after “reassuring” data from pilot studies, with a large National Institutes of Health–funded trial currently recruiting women with a prior history of the disorder with preterm delivery at less than 34 weeks, Maged Costantine, MD, said at the biennial Diabetes in Pregnancy Study Group of North America meeting.

Creatas Images

More should be learned about low-dose aspirin, in the meantime, once the outcomes of a global study involving first-trimester initiation are published, said another speaker, Cynthia Gyamfi-Bannerman, MD, MS. Low-dose aspirin currently is recommended for preeclampsia prevention starting between 12 and 28 weeks, optimally before 16 weeks.

The biological plausibility of using pravastatin for preeclampsia prevention stems from the overlapping pathophysiology of preeclampsia with atherosclerotic cardiovascular disease – endothelial dysfunction and inflammation are common key mechanisms – as well as common risk factors, including diabetes and obesity, said Dr. Costantine, director of the division of maternal-fetal medicine at Ohio State University, Columbus, who is chairing the study.

In animal models of preeclampsia, pravastatin has been shown to upregulate placental growth factor, reduce antiangiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1), and upregulate endothelial nitric oxide synthase. Mice have shown improved vascular reactivity, decreased proteinuria, decreased oxidative stress, and other positive effects, without any detrimental outcomes.

A pilot randomized controlled trial conducted with the Obstetric-Fetal Pharmacology Research Units Network and published in the American Journal of Obstetrics and Gynecology in 2016 assigned 10 women to 10 mg daily pravastatin and 10 women to placebo. The drug reduced maternal cholesterol concentrations but there were no differences in birth weight or umbilical cord cholesterol concentrations between the two groups.

Women in the pravastatin group were less likely to develop preeclampsia (none, compared with four in the placebo group), less likely to have an indicated preterm delivery (one, compared with five in the placebo group), and less likely to have their neonates admitted to the neonatal ICU.

There were no differences in side effects, congenital anomalies, or other adverse events. Dr. Costantine, principal investigator of the pilot study, and his colleagues wrote in the paper that the “favorable risk-benefit analysis justifies continued research with a dose escalation” (Am J Obstet Gynecol. 2016 Jun;214[6]:720.e1-17).

The new multicenter randomized controlled trial is randomizing 1,550 women to either 20 mg pravastatin or placebo starting between 12 weeks 0 days and 16 weeks 6 days. The primary outcome is a composite of preeclampsia, maternal death, or fetal loss. Secondary outcomes include a composite of severe maternal morbidity and various measures representing preeclampsia severity and complications, as well as preterm delivery less than 37 weeks and less than 34 weeks and various fetal/neonatal outcomes.

“In addition, we’ll look at development,” Dr. Costantine said, with offspring assessed at 2 and 5 years of age. The trial is sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute.

In the meantime, he said, the use of pravastatin to ameliorate early-onset preeclampsia is being tested in a small European proof-of-concept trial that has randomized women with early-onset preeclampsia (between 24 and 31 6/7 weeks) to 40 mg pravastatin or placebo. The primary outcome is reduction of antiangiogenic markers. Results are expected in another year or 2, he said.

The aspirin trial referred to by Dr. Gyamfi-Bannerman has been looking at the 81-mg dose of aspirin initiated between 6 0/7 and 13 6/7 weeks in nulliparous women who had no more than two previous pregnancy losses. The key question of the Aspirin Supplementation for Pregnancy Indicated Risk Reduction in Nulliparas (ASPIRIN) trial – conducted in the NICHD Global Network for Women’s and Children’s Health – is whether low-dose aspirin can reduce the rate of preterm birth. Preeclampsia is a secondary outcome (https://clinicaltrials.gov/ct2/show/NCT02409680).

“It may eventually be that the use of baby aspirin is further expanded to reduce the risk of preterm birth,” she said.

Overall, “we need more data on first-trimester use [of low-dose aspirin] and long-term outcomes,” Dr. Gyamfi-Bannerman said. And with respect to preeclampsia prevention specifically, more research is needed looking at risk reduction levels within specific groups of patients.

Since 2014, the U.S. Preventive Services Task Force (USPSTF) has called for low-dose aspirin at 81 mg/day in women who have one or more high-risk factors for preeclampsia (including type 1 or type 2 diabetes mellitus), and consideration of such treatment in patients with several moderate-risk factors. The American College of Obstetricians and Gynecologists’ recommendation varies slightly in that it advises treatment in patients with more than one (versus several) moderate-level risk factors (Obstet Gynecol. 2018;132[1]:e44-52).

Moderate-level risk factors include nulliparity, obesity, family history of preeclampsia, a baseline demographic risk (African-American or low socioeconomic status), and prior poor history (intrauterine growth restriction/small-for-gestational-age, previous poor outcome). “This is just about everyone I see,” Dr. Gyamfi-Bannerman said.

Dr. Gyamfi-Bannerman said she’d “love to see more data on higher doses” of low-dose aspirin – data that compares 81 mg/day with 150 mg/day, for instance.

A study published in 2017 in the New England Journal of Medicine randomized 1,776 women at high risk for preeclampsia to 150 mg/day or placebo and found a significant reduction in preterm preeclampsia (4.3% vs. 1.6%) in the aspirin group. Women in this European trial were deemed to be at high risk, however, based on a first-trimester screening algorithm that incorporated serum markers (maternal serum pregnancy-associated plasma protein A and placental growth factor) and uterine artery Doppler measures (N Engl J Med. 2017 Aug 17;377[7]:613-22).

“So it was a very interesting study, very provocative, but it’s hard to know how it would translate to the U.S. population [given that such screening practices] are not the way most of us are practicing here,” said Dr. Gyamfi-Bannerman, codirector of the Preterm Birth Prevention Center at Columbia University, New York, and professor of obstetrics and gynecology at the university.

The USPSTF based its recommendations on a systematic review that pooled data from 15 high-quality randomized controlled trials, including 13 that reported preeclampsia incidence among women at highest risk of disease. They found a 24% reduction in preeclampsia, but the actual risk reduction depends on the baseline population risk and may be closer to 10%, she said.

In a presentation on gaps in knowledge, Leslie Myatt, PhD, of the department of obstetrics and gynecology at Oregon Health and Science University, Portland, emphasized that preeclampsia is a syndrome with a heterogeneity of presentation and pathophysiology. “We don’t completely understand the pathophysiology,” he said.

Research needs to be “directed at the existence of multiple pathways [and subtypes],” he said, such that future therapies can be targeted and personalized.

Dr. Costantine did not report any disclosures. Dr. Gyamfi-Bannerman reported a Society of Maternal Fetal Medicine/AMAG Pharmaceuticals unrestricted grant and Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Heart, Lung and Blood Institute funding. Dr. Myatt reported that he has no financial or other ties that pose a conflict of interest.

PHILADELPHIA – The American Heart Association and American College of Cardiology took a big step toward facilitating widespread U.S. application of the hypertension management guideline that the societies issued in 2017 by releasing a set of performance and quality measures for adults with high blood pressure based on the 2017 guideline.

Mitchel L. Zoler/MDedge News

This guideline notably set a treatment target for patients diagnosed with hypertension of less than 130/80 mg/dL, and also lowered the threshold for diagnosing stage 1 hypertension to a blood pressure at or above 130/80 mm Hg, adding in a stroke about 31 million adults with hypertension to the U.S. total.

Having performance and quality measures based on the guideline is “critical, because how else would you know whether you’re having an effect on accurately diagnosing and properly controlling hypertension?” said Donald E. Casey Jr., MD, chair of the performance measures writing committee. The next step is field testing of the measures “to show they are reliable and effective,” as well as other steps to encourage widespread U.S. uptake of the performance and quality measures and the specifics of the 2017 guideline, Dr. Casey said during a presentation of the revised measures at the American Heart Association scientific sessions.

He especially highlighted the important role of Target: BP, an education, recognition, and quality improvement program run by the AHA and American Medical Association, as a tool that medical practices, health systems, and even payers and employers can use to begin to apply the new performance and quality measures (J Am Coll Cardiol. 2019 Nov 26;74[21]:2661-706) and better align with the recommendations of the 2017 high blood pressure guideline (J Am Coll Cardiol. 2018 May;71[19]:e127-248).

“We’re trying now to promote Target: BP; it’s something you can take off the shelf and get going if it’s embedded in a real-life delivery model. I think Target: BP is the secret sauce. It will be the way we’ll convince people to adopt this,” said Dr. Casey, principal and founder of IPO 4 Health, a Chicago-based health care consulting firm.

He also advised practices and health systems not to feel compelled to introduce all of the specific performance and quality measures at once. “We don’t believe everyone has the resources to do all of it at once; the point is to move toward this system of care. We understand that people don’t have the resources to get it all done” immediately, Dr. Casey said in an interview.

Mitchel L. Zoler/MDedge News

A report during another session at the meeting documented the potential impact that Target: BP can have on blood pressure control within a health system. The Trinity Health of New England medical group based in Springfield, Mass., a system with about 140,000 patients – including 20,000 adults diagnosed with hypertension – and served by 230 health care providers in 13 offices in western Massachusetts, began using Target: BP’s MAP improvement program in its practices in November 2018. (MAP stands for measure accurately, act rapidly, and partner with patients.) Just before the MAP program began, 72% of patients diagnosed with hypertension in the medical group were at their goal blood pressure. Less than a year later, in September 2019, the hypertension control rate had jumped to 84%, a 12 percentage point improvement in control in practices that already had been doing a relatively good job, said Daniel W. Weiswasser, MD, director of quality and clinical informatics at Trinity Health of New England. Based on this success, Trinity Health plans to next involve the remaining regions of Trinity Health of New England in Target: BP, followed by the other regions of Trinity’s national organization, which operates in 21 states with nearly 4,000 staff physicians and about half a million patients diagnosed with hypertension, Dr. Weiswasser said.

Mitchel L. Zoler/MDedge News

“If clinicians do the three steps of the MAP then we will see substantial drops in blood pressures. It will occur,” declared Brent M. Egan, MD, vice president for cardiovascular disease prevention of the AMA in Greenville, S.C.

The new report includes six performance measures based on the strongest guideline recommendations and designed to document adherence levels for the purposes of public reporting and pay-for-performance programs. It also includes 16 quality measures designed for local quality review purposes, with 6 process quality measures and 10 structural quality measures. The report spells out that the authors designed the performance measures for use by major national organizations such as the Centers for Medicare & Medicaid Services and the National Committee for Quality Assurance (NCQA), while the quality measures are designed to support quality improvement efforts in any care-delivery setting.

The authors said that the writing committee is sensitive to the fact that the 2019 performance measures for controlling high blood pressure developed by the NCQA for the Healthcare Effectiveness Data and Information Set and currently in use in 2019 by CMS also does not incorporate the 2017 Hypertension Clinical Practice Guidelines classification scheme. “It is well understood that these measures are already in widespread use, especially for quality-related payment programs promulgated by CMS, such as the Medicare Advantage ‘Stars’ ratings, the Medicare Shared Savings Program, and the Physician Quality Payment Program, as well as many other programs promoted by commercial health insurers. In particular, the widespread use of the 2017 Hypertension Clinical Practice Guidelines classification scheme will also help to guide decision making about when to prescribe antihypertensive medications in accordance with its current recommendations for the ACC/AHA “stages” of stage 1 and stage 2 hypertension and elevated blood pressure,” they added.

The report also says that “the writing committee was sensitive to the fact that there is currently not complete consensus among other guidelines from the American College of Physicians and the American Academy of Family Physicians, and also the European Society of Cardiology and the European Society of Hypertension. Nonetheless, despite this ongoing debate, the writing committee felt strongly that it is now time to move the U.S. health care system ahead to reflect these differing points of view and expects that widespread use of this new measure set will help to achieve this goal.” The new report revises hypertension performance measures developed by the ACC and AHA in 2011 (J Am Coll Cardiol. 2011 Jul 12;58[3]: 316-36).

In short, the performance and quality measures give all the diverse components of the U.S. health care delivery system a road map for implementing the 2017 High Blood Pressure Guideline in a format that depends on those components electing to adopt and adhere to the 2017 guideline. (Although one of the new performance measures, 1a, harmonizes with an existing and widely applied performance measure.)

“Who is the audience for this, and how will they respond? These performance measures need to be appropriated” by health systems and by performance-assessment groups. “I hope the NCQA will adopt it,” said William C. Cushman, MD, professor of preventive medicine at the University of Tennessee Health Science Center in Memphis, and chief of preventive medicine at the Memphis Veterans Affairs Medical Center. “There are some negatives to performance measures, but on balance they have done good things and led to better care.” Dr. Cushman also approved of several specific performance and quality measures included in the report. “Most of what they emphasized is good,” particularly the importance of accurate pressure measurement, he said in an interview.

“Process drives outcomes” in hypertension management, and the new performance and quality measures “have some very good process metrics,” commented Dr. Egan. “I’d encourage health systems to select two or three measures that are key to what they do and make sense in their setting rather than try to implement it all at once,” he advised, echoing what Dr. Casey had suggested. “It’s ideal to do everything, but we know that if you give physicians a long list of performance measures they just get overwhelmed. The nice thing about hypertension is that we know that process drives outcomes. In the past, we’ve had some process metrics that did not drive outcomes. Getting these processes implemented will lead to better patient outcomes and save a ton of money.”

Mitchel L. Zoler/MDedge News

“We have introduced the 2017 guideline recommendations throughout Target: BP, but like any quality improvement program there is a question of how does it spread,” said Gregory Wozniak, PhD, director of outcomes analytics for the AMA in Chicago. “Our goal for Target: BP is to be impacting 20 million patients by 2021.”

Dr. Casey, Dr. Weiswasser, and Dr. Wozniak had no disclosures. Dr. Cushman has received honoraria as a speaker from Arbor and Sanofi-Aventis, and travel and research support from Eli Lilly. Dr. Egan has been a consultant to and speaker on behalf of Merck and a speaker for Emcure.

[email protected]

SOURCE: Casey DE et al. J Am Coll Cardiol. 2019 Nov 26;74[21]: 2661-706.

PHILADELPHIA – The American Heart Association and American College of Cardiology took a big step toward facilitating widespread U.S. application of the hypertension management guideline that the societies issued in 2017 by releasing a set of performance and quality measures for adults with high blood pressure based on the 2017 guideline.

Mitchel L. Zoler/MDedge News

This guideline notably set a treatment target for patients diagnosed with hypertension of less than 130/80 mg/dL, and also lowered the threshold for diagnosing stage 1 hypertension to a blood pressure at or above 130/80 mm Hg, adding in a stroke about 31 million adults with hypertension to the U.S. total.

Having performance and quality measures based on the guideline is “critical, because how else would you know whether you’re having an effect on accurately diagnosing and properly controlling hypertension?” said Donald E. Casey Jr., MD, chair of the performance measures writing committee. The next step is field testing of the measures “to show they are reliable and effective,” as well as other steps to encourage widespread U.S. uptake of the performance and quality measures and the specifics of the 2017 guideline, Dr. Casey said during a presentation of the revised measures at the American Heart Association scientific sessions.

He especially highlighted the important role of Target: BP, an education, recognition, and quality improvement program run by the AHA and American Medical Association, as a tool that medical practices, health systems, and even payers and employers can use to begin to apply the new performance and quality measures (J Am Coll Cardiol. 2019 Nov 26;74[21]:2661-706) and better align with the recommendations of the 2017 high blood pressure guideline (J Am Coll Cardiol. 2018 May;71[19]:e127-248).

“We’re trying now to promote Target: BP; it’s something you can take off the shelf and get going if it’s embedded in a real-life delivery model. I think Target: BP is the secret sauce. It will be the way we’ll convince people to adopt this,” said Dr. Casey, principal and founder of IPO 4 Health, a Chicago-based health care consulting firm.

He also advised practices and health systems not to feel compelled to introduce all of the specific performance and quality measures at once. “We don’t believe everyone has the resources to do all of it at once; the point is to move toward this system of care. We understand that people don’t have the resources to get it all done” immediately, Dr. Casey said in an interview.

Mitchel L. Zoler/MDedge News

A report during another session at the meeting documented the potential impact that Target: BP can have on blood pressure control within a health system. The Trinity Health of New England medical group based in Springfield, Mass., a system with about 140,000 patients – including 20,000 adults diagnosed with hypertension – and served by 230 health care providers in 13 offices in western Massachusetts, began using Target: BP’s MAP improvement program in its practices in November 2018. (MAP stands for measure accurately, act rapidly, and partner with patients.) Just before the MAP program began, 72% of patients diagnosed with hypertension in the medical group were at their goal blood pressure. Less than a year later, in September 2019, the hypertension control rate had jumped to 84%, a 12 percentage point improvement in control in practices that already had been doing a relatively good job, said Daniel W. Weiswasser, MD, director of quality and clinical informatics at Trinity Health of New England. Based on this success, Trinity Health plans to next involve the remaining regions of Trinity Health of New England in Target: BP, followed by the other regions of Trinity’s national organization, which operates in 21 states with nearly 4,000 staff physicians and about half a million patients diagnosed with hypertension, Dr. Weiswasser said.

Mitchel L. Zoler/MDedge News

“If clinicians do the three steps of the MAP then we will see substantial drops in blood pressures. It will occur,” declared Brent M. Egan, MD, vice president for cardiovascular disease prevention of the AMA in Greenville, S.C.

The new report includes six performance measures based on the strongest guideline recommendations and designed to document adherence levels for the purposes of public reporting and pay-for-performance programs. It also includes 16 quality measures designed for local quality review purposes, with 6 process quality measures and 10 structural quality measures. The report spells out that the authors designed the performance measures for use by major national organizations such as the Centers for Medicare & Medicaid Services and the National Committee for Quality Assurance (NCQA), while the quality measures are designed to support quality improvement efforts in any care-delivery setting.

The authors said that the writing committee is sensitive to the fact that the 2019 performance measures for controlling high blood pressure developed by the NCQA for the Healthcare Effectiveness Data and Information Set and currently in use in 2019 by CMS also does not incorporate the 2017 Hypertension Clinical Practice Guidelines classification scheme. “It is well understood that these measures are already in widespread use, especially for quality-related payment programs promulgated by CMS, such as the Medicare Advantage ‘Stars’ ratings, the Medicare Shared Savings Program, and the Physician Quality Payment Program, as well as many other programs promoted by commercial health insurers. In particular, the widespread use of the 2017 Hypertension Clinical Practice Guidelines classification scheme will also help to guide decision making about when to prescribe antihypertensive medications in accordance with its current recommendations for the ACC/AHA “stages” of stage 1 and stage 2 hypertension and elevated blood pressure,” they added.

The report also says that “the writing committee was sensitive to the fact that there is currently not complete consensus among other guidelines from the American College of Physicians and the American Academy of Family Physicians, and also the European Society of Cardiology and the European Society of Hypertension. Nonetheless, despite this ongoing debate, the writing committee felt strongly that it is now time to move the U.S. health care system ahead to reflect these differing points of view and expects that widespread use of this new measure set will help to achieve this goal.” The new report revises hypertension performance measures developed by the ACC and AHA in 2011 (J Am Coll Cardiol. 2011 Jul 12;58[3]: 316-36).

In short, the performance and quality measures give all the diverse components of the U.S. health care delivery system a road map for implementing the 2017 High Blood Pressure Guideline in a format that depends on those components electing to adopt and adhere to the 2017 guideline. (Although one of the new performance measures, 1a, harmonizes with an existing and widely applied performance measure.)

“Who is the audience for this, and how will they respond? These performance measures need to be appropriated” by health systems and by performance-assessment groups. “I hope the NCQA will adopt it,” said William C. Cushman, MD, professor of preventive medicine at the University of Tennessee Health Science Center in Memphis, and chief of preventive medicine at the Memphis Veterans Affairs Medical Center. “There are some negatives to performance measures, but on balance they have done good things and led to better care.” Dr. Cushman also approved of several specific performance and quality measures included in the report. “Most of what they emphasized is good,” particularly the importance of accurate pressure measurement, he said in an interview.

“Process drives outcomes” in hypertension management, and the new performance and quality measures “have some very good process metrics,” commented Dr. Egan. “I’d encourage health systems to select two or three measures that are key to what they do and make sense in their setting rather than try to implement it all at once,” he advised, echoing what Dr. Casey had suggested. “It’s ideal to do everything, but we know that if you give physicians a long list of performance measures they just get overwhelmed. The nice thing about hypertension is that we know that process drives outcomes. In the past, we’ve had some process metrics that did not drive outcomes. Getting these processes implemented will lead to better patient outcomes and save a ton of money.”

Mitchel L. Zoler/MDedge News

“We have introduced the 2017 guideline recommendations throughout Target: BP, but like any quality improvement program there is a question of how does it spread,” said Gregory Wozniak, PhD, director of outcomes analytics for the AMA in Chicago. “Our goal for Target: BP is to be impacting 20 million patients by 2021.”

Dr. Casey, Dr. Weiswasser, and Dr. Wozniak had no disclosures. Dr. Cushman has received honoraria as a speaker from Arbor and Sanofi-Aventis, and travel and research support from Eli Lilly. Dr. Egan has been a consultant to and speaker on behalf of Merck and a speaker for Emcure.

[email protected]

SOURCE: Casey DE et al. J Am Coll Cardiol. 2019 Nov 26;74[21]: 2661-706.

PHILADELPHIA – The American Heart Association and American College of Cardiology took a big step toward facilitating widespread U.S. application of the hypertension management guideline that the societies issued in 2017 by releasing a set of performance and quality measures for adults with high blood pressure based on the 2017 guideline.

Mitchel L. Zoler/MDedge News

This guideline notably set a treatment target for patients diagnosed with hypertension of less than 130/80 mg/dL, and also lowered the threshold for diagnosing stage 1 hypertension to a blood pressure at or above 130/80 mm Hg, adding in a stroke about 31 million adults with hypertension to the U.S. total.

Having performance and quality measures based on the guideline is “critical, because how else would you know whether you’re having an effect on accurately diagnosing and properly controlling hypertension?” said Donald E. Casey Jr., MD, chair of the performance measures writing committee. The next step is field testing of the measures “to show they are reliable and effective,” as well as other steps to encourage widespread U.S. uptake of the performance and quality measures and the specifics of the 2017 guideline, Dr. Casey said during a presentation of the revised measures at the American Heart Association scientific sessions.

He especially highlighted the important role of Target: BP, an education, recognition, and quality improvement program run by the AHA and American Medical Association, as a tool that medical practices, health systems, and even payers and employers can use to begin to apply the new performance and quality measures (J Am Coll Cardiol. 2019 Nov 26;74[21]:2661-706) and better align with the recommendations of the 2017 high blood pressure guideline (J Am Coll Cardiol. 2018 May;71[19]:e127-248).

“We’re trying now to promote Target: BP; it’s something you can take off the shelf and get going if it’s embedded in a real-life delivery model. I think Target: BP is the secret sauce. It will be the way we’ll convince people to adopt this,” said Dr. Casey, principal and founder of IPO 4 Health, a Chicago-based health care consulting firm.

He also advised practices and health systems not to feel compelled to introduce all of the specific performance and quality measures at once. “We don’t believe everyone has the resources to do all of it at once; the point is to move toward this system of care. We understand that people don’t have the resources to get it all done” immediately, Dr. Casey said in an interview.

Mitchel L. Zoler/MDedge News

A report during another session at the meeting documented the potential impact that Target: BP can have on blood pressure control within a health system. The Trinity Health of New England medical group based in Springfield, Mass., a system with about 140,000 patients – including 20,000 adults diagnosed with hypertension – and served by 230 health care providers in 13 offices in western Massachusetts, began using Target: BP’s MAP improvement program in its practices in November 2018. (MAP stands for measure accurately, act rapidly, and partner with patients.) Just before the MAP program began, 72% of patients diagnosed with hypertension in the medical group were at their goal blood pressure. Less than a year later, in September 2019, the hypertension control rate had jumped to 84%, a 12 percentage point improvement in control in practices that already had been doing a relatively good job, said Daniel W. Weiswasser, MD, director of quality and clinical informatics at Trinity Health of New England. Based on this success, Trinity Health plans to next involve the remaining regions of Trinity Health of New England in Target: BP, followed by the other regions of Trinity’s national organization, which operates in 21 states with nearly 4,000 staff physicians and about half a million patients diagnosed with hypertension, Dr. Weiswasser said.

Mitchel L. Zoler/MDedge News

“If clinicians do the three steps of the MAP then we will see substantial drops in blood pressures. It will occur,” declared Brent M. Egan, MD, vice president for cardiovascular disease prevention of the AMA in Greenville, S.C.

The new report includes six performance measures based on the strongest guideline recommendations and designed to document adherence levels for the purposes of public reporting and pay-for-performance programs. It also includes 16 quality measures designed for local quality review purposes, with 6 process quality measures and 10 structural quality measures. The report spells out that the authors designed the performance measures for use by major national organizations such as the Centers for Medicare & Medicaid Services and the National Committee for Quality Assurance (NCQA), while the quality measures are designed to support quality improvement efforts in any care-delivery setting.

The authors said that the writing committee is sensitive to the fact that the 2019 performance measures for controlling high blood pressure developed by the NCQA for the Healthcare Effectiveness Data and Information Set and currently in use in 2019 by CMS also does not incorporate the 2017 Hypertension Clinical Practice Guidelines classification scheme. “It is well understood that these measures are already in widespread use, especially for quality-related payment programs promulgated by CMS, such as the Medicare Advantage ‘Stars’ ratings, the Medicare Shared Savings Program, and the Physician Quality Payment Program, as well as many other programs promoted by commercial health insurers. In particular, the widespread use of the 2017 Hypertension Clinical Practice Guidelines classification scheme will also help to guide decision making about when to prescribe antihypertensive medications in accordance with its current recommendations for the ACC/AHA “stages” of stage 1 and stage 2 hypertension and elevated blood pressure,” they added.

The report also says that “the writing committee was sensitive to the fact that there is currently not complete consensus among other guidelines from the American College of Physicians and the American Academy of Family Physicians, and also the European Society of Cardiology and the European Society of Hypertension. Nonetheless, despite this ongoing debate, the writing committee felt strongly that it is now time to move the U.S. health care system ahead to reflect these differing points of view and expects that widespread use of this new measure set will help to achieve this goal.” The new report revises hypertension performance measures developed by the ACC and AHA in 2011 (J Am Coll Cardiol. 2011 Jul 12;58[3]: 316-36).

In short, the performance and quality measures give all the diverse components of the U.S. health care delivery system a road map for implementing the 2017 High Blood Pressure Guideline in a format that depends on those components electing to adopt and adhere to the 2017 guideline. (Although one of the new performance measures, 1a, harmonizes with an existing and widely applied performance measure.)

“Who is the audience for this, and how will they respond? These performance measures need to be appropriated” by health systems and by performance-assessment groups. “I hope the NCQA will adopt it,” said William C. Cushman, MD, professor of preventive medicine at the University of Tennessee Health Science Center in Memphis, and chief of preventive medicine at the Memphis Veterans Affairs Medical Center. “There are some negatives to performance measures, but on balance they have done good things and led to better care.” Dr. Cushman also approved of several specific performance and quality measures included in the report. “Most of what they emphasized is good,” particularly the importance of accurate pressure measurement, he said in an interview.

“Process drives outcomes” in hypertension management, and the new performance and quality measures “have some very good process metrics,” commented Dr. Egan. “I’d encourage health systems to select two or three measures that are key to what they do and make sense in their setting rather than try to implement it all at once,” he advised, echoing what Dr. Casey had suggested. “It’s ideal to do everything, but we know that if you give physicians a long list of performance measures they just get overwhelmed. The nice thing about hypertension is that we know that process drives outcomes. In the past, we’ve had some process metrics that did not drive outcomes. Getting these processes implemented will lead to better patient outcomes and save a ton of money.”

Mitchel L. Zoler/MDedge News

“We have introduced the 2017 guideline recommendations throughout Target: BP, but like any quality improvement program there is a question of how does it spread,” said Gregory Wozniak, PhD, director of outcomes analytics for the AMA in Chicago. “Our goal for Target: BP is to be impacting 20 million patients by 2021.”

Dr. Casey, Dr. Weiswasser, and Dr. Wozniak had no disclosures. Dr. Cushman has received honoraria as a speaker from Arbor and Sanofi-Aventis, and travel and research support from Eli Lilly. Dr. Egan has been a consultant to and speaker on behalf of Merck and a speaker for Emcure.

[email protected]

SOURCE: Casey DE et al. J Am Coll Cardiol. 2019 Nov 26;74[21]: 2661-706.

LAS VEGAS – Nearly a quarter of American adults are on a prescription drug that often produces obesity as a side effect, and use of such obesogenic drugs was significantly higher among patients who already are obese, based on national U.S. data collected during 2013-2016.

Mitchel L. Zoler/MDedge News

The Endocrine Society, the STOP Obesity Alliance, and other medical societies have recommended that clinicians try to minimize use of obesogenic drugs and focus on prescribing agents that are weight neutral or that trigger weight loss when those options are available and appropriate, and the new findings add further evidence that clinicians need to be more mindful of this issue, Craig M. Hales, MD, said at a meeting presented by the Obesity Society and the American Society for Metabolic and Bariatric Surgery.

Among the American adults interviewed for the survey, 40% of those on at least one prescription medication were on at least one drug that is considered obesogenic, said Dr. Hales, a medical epidemiologist at the Centers for Disease Control and Prevention in Hyattsville, Md.

According to practice guidelines published by the Endocrine Society, all drugs in the classes of glucocorticoids, beta-blockers, and antihistamines are obesogenic, as well as selected agents in the classes of antidepressant drugs, antipsychotics, antidepressants, antidiabetics, and contraceptives that are progestin only, said Dr. Hales (J Clin Endocrinol Metab. 2015 Feb;100[2]:342-62).

The data he reported came from the National Health and Nutrition Examination Survey (NHANES) run by the CDC during 2013-2016 that included 11,055 adults who were at least 20 years old. The findings showed that 23% of those adults had taken at least one drug that was considered obesogenic during the 30 days preceding the survey date. By comparison, 35% of the same adults had taken any type of prescription drug during the previous 30 days. That meant that overall, 40% of surveyed adults who had recently used any prescription medication had taken an obesogenic drug.

The 23% prevalence of recent obesogenic drug use was fairly stable at that level during several preceding NHANES surveys going back to 2001, suggesting that the increasing use of obesogenic drugs during the period since 2001 was not a factor in the recent increased prevalence of obesity among U.S. residents, added Dr. Hales.

The 2013-2016 analysis also showed a strong link between obesogenic drug use and increasing obesity severity. Among survey participants with a body mass index (BMI) in the normal range (18.5-24 kg/m²), 16% had recent use of an obesogenic drug. This prevalence increased to 22% among those who were overweight (BMI, 25-29 kg/m²), 29% among those with class 1 or 2 obesity (BMI, 30-39 kg/m²), and 33% among those with class 3 obesity (BMI, 40 kg/m² or greater).

In contrast, recent use of prescription medications that do not contribute to obesity showed no significant relationship with BMI, with rates that ranged from 34% among those with a normal BMI, to 37% among those with class 3 obesity.

As an example of this relationship for a specific obesogenic drug class, the prevalence of beta-blocker use was about 7% among people with a normal BMI, about 10% among those who were overweight, about 14% among people with class 1 or 2 obesity, and about 17% among people with class 3 obesity, a statistically significant link suggesting that the relationship between use of obesogenic drugs and obesity is “bidirectional,” Dr. Hales said, in that increasing obesogenic drug use likely contributes to obesity, while simultaneously, the more obese people become, the more likely they are to take additional prescription drugs, particularly those that are obesogenic.

NHANES is run by the CDC and receives no commercial funding. The authors reported no conflicts of interest.

[email protected]

SOURCE: Hales CM et al. Obesity Week 2019, Abstract T-OR-2037.

LAS VEGAS – Nearly a quarter of American adults are on a prescription drug that often produces obesity as a side effect, and use of such obesogenic drugs was significantly higher among patients who already are obese, based on national U.S. data collected during 2013-2016.

Mitchel L. Zoler/MDedge News

The Endocrine Society, the STOP Obesity Alliance, and other medical societies have recommended that clinicians try to minimize use of obesogenic drugs and focus on prescribing agents that are weight neutral or that trigger weight loss when those options are available and appropriate, and the new findings add further evidence that clinicians need to be more mindful of this issue, Craig M. Hales, MD, said at a meeting presented by the Obesity Society and the American Society for Metabolic and Bariatric Surgery.

Among the American adults interviewed for the survey, 40% of those on at least one prescription medication were on at least one drug that is considered obesogenic, said Dr. Hales, a medical epidemiologist at the Centers for Disease Control and Prevention in Hyattsville, Md.

According to practice guidelines published by the Endocrine Society, all drugs in the classes of glucocorticoids, beta-blockers, and antihistamines are obesogenic, as well as selected agents in the classes of antidepressant drugs, antipsychotics, antidepressants, antidiabetics, and contraceptives that are progestin only, said Dr. Hales (J Clin Endocrinol Metab. 2015 Feb;100[2]:342-62).

The data he reported came from the National Health and Nutrition Examination Survey (NHANES) run by the CDC during 2013-2016 that included 11,055 adults who were at least 20 years old. The findings showed that 23% of those adults had taken at least one drug that was considered obesogenic during the 30 days preceding the survey date. By comparison, 35% of the same adults had taken any type of prescription drug during the previous 30 days. That meant that overall, 40% of surveyed adults who had recently used any prescription medication had taken an obesogenic drug.

The 23% prevalence of recent obesogenic drug use was fairly stable at that level during several preceding NHANES surveys going back to 2001, suggesting that the increasing use of obesogenic drugs during the period since 2001 was not a factor in the recent increased prevalence of obesity among U.S. residents, added Dr. Hales.

The 2013-2016 analysis also showed a strong link between obesogenic drug use and increasing obesity severity. Among survey participants with a body mass index (BMI) in the normal range (18.5-24 kg/m²), 16% had recent use of an obesogenic drug. This prevalence increased to 22% among those who were overweight (BMI, 25-29 kg/m²), 29% among those with class 1 or 2 obesity (BMI, 30-39 kg/m²), and 33% among those with class 3 obesity (BMI, 40 kg/m² or greater).

In contrast, recent use of prescription medications that do not contribute to obesity showed no significant relationship with BMI, with rates that ranged from 34% among those with a normal BMI, to 37% among those with class 3 obesity.

As an example of this relationship for a specific obesogenic drug class, the prevalence of beta-blocker use was about 7% among people with a normal BMI, about 10% among those who were overweight, about 14% among people with class 1 or 2 obesity, and about 17% among people with class 3 obesity, a statistically significant link suggesting that the relationship between use of obesogenic drugs and obesity is “bidirectional,” Dr. Hales said, in that increasing obesogenic drug use likely contributes to obesity, while simultaneously, the more obese people become, the more likely they are to take additional prescription drugs, particularly those that are obesogenic.

NHANES is run by the CDC and receives no commercial funding. The authors reported no conflicts of interest.

[email protected]

SOURCE: Hales CM et al. Obesity Week 2019, Abstract T-OR-2037.

LAS VEGAS – Nearly a quarter of American adults are on a prescription drug that often produces obesity as a side effect, and use of such obesogenic drugs was significantly higher among patients who already are obese, based on national U.S. data collected during 2013-2016.

Mitchel L. Zoler/MDedge News

The Endocrine Society, the STOP Obesity Alliance, and other medical societies have recommended that clinicians try to minimize use of obesogenic drugs and focus on prescribing agents that are weight neutral or that trigger weight loss when those options are available and appropriate, and the new findings add further evidence that clinicians need to be more mindful of this issue, Craig M. Hales, MD, said at a meeting presented by the Obesity Society and the American Society for Metabolic and Bariatric Surgery.

Among the American adults interviewed for the survey, 40% of those on at least one prescription medication were on at least one drug that is considered obesogenic, said Dr. Hales, a medical epidemiologist at the Centers for Disease Control and Prevention in Hyattsville, Md.

According to practice guidelines published by the Endocrine Society, all drugs in the classes of glucocorticoids, beta-blockers, and antihistamines are obesogenic, as well as selected agents in the classes of antidepressant drugs, antipsychotics, antidepressants, antidiabetics, and contraceptives that are progestin only, said Dr. Hales (J Clin Endocrinol Metab. 2015 Feb;100[2]:342-62).

The data he reported came from the National Health and Nutrition Examination Survey (NHANES) run by the CDC during 2013-2016 that included 11,055 adults who were at least 20 years old. The findings showed that 23% of those adults had taken at least one drug that was considered obesogenic during the 30 days preceding the survey date. By comparison, 35% of the same adults had taken any type of prescription drug during the previous 30 days. That meant that overall, 40% of surveyed adults who had recently used any prescription medication had taken an obesogenic drug.

The 23% prevalence of recent obesogenic drug use was fairly stable at that level during several preceding NHANES surveys going back to 2001, suggesting that the increasing use of obesogenic drugs during the period since 2001 was not a factor in the recent increased prevalence of obesity among U.S. residents, added Dr. Hales.

The 2013-2016 analysis also showed a strong link between obesogenic drug use and increasing obesity severity. Among survey participants with a body mass index (BMI) in the normal range (18.5-24 kg/m²), 16% had recent use of an obesogenic drug. This prevalence increased to 22% among those who were overweight (BMI, 25-29 kg/m²), 29% among those with class 1 or 2 obesity (BMI, 30-39 kg/m²), and 33% among those with class 3 obesity (BMI, 40 kg/m² or greater).

In contrast, recent use of prescription medications that do not contribute to obesity showed no significant relationship with BMI, with rates that ranged from 34% among those with a normal BMI, to 37% among those with class 3 obesity.

As an example of this relationship for a specific obesogenic drug class, the prevalence of beta-blocker use was about 7% among people with a normal BMI, about 10% among those who were overweight, about 14% among people with class 1 or 2 obesity, and about 17% among people with class 3 obesity, a statistically significant link suggesting that the relationship between use of obesogenic drugs and obesity is “bidirectional,” Dr. Hales said, in that increasing obesogenic drug use likely contributes to obesity, while simultaneously, the more obese people become, the more likely they are to take additional prescription drugs, particularly those that are obesogenic.

NHANES is run by the CDC and receives no commercial funding. The authors reported no conflicts of interest.

[email protected]

SOURCE: Hales CM et al. Obesity Week 2019, Abstract T-OR-2037.

The 2019-2020 flu season took a big jump in severity during the last full week of 2019, according to the Centers for Disease Control and Prevention.

For the week ending Dec. 28, 6.9% of all outpatient visits to health care providers were for influenza-like illness (ILI), the CDC’s influenza division reported Jan. 3. That is up from 5.1% the previous week and is the highest rate recorded in December since 2003. During the flu pandemic season of 2009-2010, the rate peaked in October and dropped to relatively normal levels by the end of November, CDC data show.

This marks the eighth consecutive week that the outpatient visit rate has been at or above the nation’s baseline level of 2.4%, but the data for this week “may in part be influenced by changes in healthcare-seeking behavior that can occur during the holidays,” the CDC suggested.

All those outpatient visits mean that the ILI activity map is getting quite red. Thirty states, as well as the District of Columbia and Puerto Rico, were at the highest level on the CDC’s 1-10 activity scale during the week ending Dec. 28, compared with 20 the week before. Four states were categorized in the “high” range with activity levels of 8 and 9.

There have been approximately 6.4 million flu illnesses so far this season, the CDC estimated, along with 55,000 hospitalizations, although the ILI admission rate of 9.2 per 100,000 population is fairly typical for this time of year.

The week of Dec. 28 also brought reports of five more ILI-related pediatric deaths, which all occurred in the two previous weeks. A total of 27 children have died from the flu so far during the 2019-2020 season, the CDC said.

[email protected]

The 2019-2020 flu season took a big jump in severity during the last full week of 2019, according to the Centers for Disease Control and Prevention.

For the week ending Dec. 28, 6.9% of all outpatient visits to health care providers were for influenza-like illness (ILI), the CDC’s influenza division reported Jan. 3. That is up from 5.1% the previous week and is the highest rate recorded in December since 2003. During the flu pandemic season of 2009-2010, the rate peaked in October and dropped to relatively normal levels by the end of November, CDC data show.

This marks the eighth consecutive week that the outpatient visit rate has been at or above the nation’s baseline level of 2.4%, but the data for this week “may in part be influenced by changes in healthcare-seeking behavior that can occur during the holidays,” the CDC suggested.

All those outpatient visits mean that the ILI activity map is getting quite red. Thirty states, as well as the District of Columbia and Puerto Rico, were at the highest level on the CDC’s 1-10 activity scale during the week ending Dec. 28, compared with 20 the week before. Four states were categorized in the “high” range with activity levels of 8 and 9.

There have been approximately 6.4 million flu illnesses so far this season, the CDC estimated, along with 55,000 hospitalizations, although the ILI admission rate of 9.2 per 100,000 population is fairly typical for this time of year.

The week of Dec. 28 also brought reports of five more ILI-related pediatric deaths, which all occurred in the two previous weeks. A total of 27 children have died from the flu so far during the 2019-2020 season, the CDC said.

[email protected]

The 2019-2020 flu season took a big jump in severity during the last full week of 2019, according to the Centers for Disease Control and Prevention.

For the week ending Dec. 28, 6.9% of all outpatient visits to health care providers were for influenza-like illness (ILI), the CDC’s influenza division reported Jan. 3. That is up from 5.1% the previous week and is the highest rate recorded in December since 2003. During the flu pandemic season of 2009-2010, the rate peaked in October and dropped to relatively normal levels by the end of November, CDC data show.

This marks the eighth consecutive week that the outpatient visit rate has been at or above the nation’s baseline level of 2.4%, but the data for this week “may in part be influenced by changes in healthcare-seeking behavior that can occur during the holidays,” the CDC suggested.

All those outpatient visits mean that the ILI activity map is getting quite red. Thirty states, as well as the District of Columbia and Puerto Rico, were at the highest level on the CDC’s 1-10 activity scale during the week ending Dec. 28, compared with 20 the week before. Four states were categorized in the “high” range with activity levels of 8 and 9.

There have been approximately 6.4 million flu illnesses so far this season, the CDC estimated, along with 55,000 hospitalizations, although the ILI admission rate of 9.2 per 100,000 population is fairly typical for this time of year.

The week of Dec. 28 also brought reports of five more ILI-related pediatric deaths, which all occurred in the two previous weeks. A total of 27 children have died from the flu so far during the 2019-2020 season, the CDC said.

[email protected]

Even on-time pneumococcal vaccines don’t completely protect children with asthma from developing invasive pneumococcal disease, a meta-analysis has determined.

Despite receiving pneumococcal valent 7, 10, or 13, children with asthma were still almost twice as likely to develop the disease as were children without asthma, Jose A. Castro-Rodriguez, MD, PhD, and colleagues reported in Pediatrics (2020 Jan. doi: 10.1542/peds.2019-1200). None of the studies included rates for those who received the pneumococcal polysaccharide vaccine (PPSV23).

“For the first time, this meta-analysis reveals 90% increased odds of invasive pneumococcal disease (IPD) among [vaccinated] children with asthma,” said Dr. Castro-Rodriguez, of Pontificia Universidad Católica de Chile, Santiago, and colleagues. “If confirmed, these findings will bear clinical and public health importance,” they noted, because guidelines now recommend PPSV23 after age 2 in children with asthma only if they’re treated with prolonged high-dose oral corticosteroids.

However, because the analysis comprised only four studies, the authors cautioned that the results aren’t enough to justify changes to practice recommendations.

Asthma treatment with inhaled corticosteroids (ICS) may be driving the increased risk, Dr. Castro-Rodriguez and his coauthors suggested. ICS deposition in the oropharynx could boost oropharyngeal candidiasis risk by weakening the mucosal immune response, the researchers noted. And that same process may be at work with Streptococcus pneumoniae.

A prior study found that children with asthma who received ICS for at least 1 month were almost four times more likely to have oropharyngeal colonization by S. pneumoniae as were those who didn’t get the drugs. Thus, a higher carrier rate of S. pneumoniae in the oropharynx, along with asthma’s impaired airway clearance, might increase the risk of pneumococcal diseases, the investigators explained.

Dr. Castro-Rodriguez and colleagues analyzed four studies with more than 4,000 cases and controls, and about 26 million person-years of follow-up.

Rates and risks of IPD in the four studies were as follows:

• Among those with IPD, 27% had asthma, with 18% of those without, an adjusted odds ratio (aOR) of 1.8.
• In a European of patients who received at least 3 doses of PCV7, IPD rates per 100,000 person-years for 5-year-olds were 11.6 for children with asthma and 7.3 for those without. For 5- to 17-year-olds with and without asthma, the rates were 2.3 and 1.6, respectively.
• In 2001, a Korean found an aOR of 2.08 for IPD in children with asthma, compared with those without. In 2010, the aOR was 3.26. No vaccine types were reported in the study.
• of IPD were 3.7 per 100,000 person-years for children with asthma, compared with 2.5 for healthy controls – an adjusted relative risk of 1.5.

The pooled estimate of the four studies revealed an aOR of 1.9 for IPD among children with asthma, compared with those without, Dr. Castro-Rodriguez and his team concluded.

None of the studies reported hospital admissions, mortality, length of hospital stay, intensive care admission, invasive respiratory support, or additional medication use.

One, however, did find asthma severity was significantly associated with increasing IPD treatment costs per 100,000 person-years: $72,581 for healthy controls, compared with $100,020 for children with mild asthma, $172,002 for moderate asthma, and $638,452 for severe asthma.

In addition, treating all-cause pneumonia was more expensive in children with asthma. For all-cause pneumonia, the researchers found that estimated costs per 100,000 person-years for mild, moderate, and severe asthma were $7.5 million, $14.6 million, and $46.8 million, respectively, compared with $1.7 million for healthy controls.

The authors had no relevant financial disclosures.

[email protected]

SOURCE: Castro-Rodriguez J et al. Pediatrics. 2020 Jan. doi: 10.1542/peds.2019-1200.

Even on-time pneumococcal vaccines don’t completely protect children with asthma from developing invasive pneumococcal disease, a meta-analysis has determined.

Despite receiving pneumococcal valent 7, 10, or 13, children with asthma were still almost twice as likely to develop the disease as were children without asthma, Jose A. Castro-Rodriguez, MD, PhD, and colleagues reported in Pediatrics (2020 Jan. doi: 10.1542/peds.2019-1200). None of the studies included rates for those who received the pneumococcal polysaccharide vaccine (PPSV23).

“For the first time, this meta-analysis reveals 90% increased odds of invasive pneumococcal disease (IPD) among [vaccinated] children with asthma,” said Dr. Castro-Rodriguez, of Pontificia Universidad Católica de Chile, Santiago, and colleagues. “If confirmed, these findings will bear clinical and public health importance,” they noted, because guidelines now recommend PPSV23 after age 2 in children with asthma only if they’re treated with prolonged high-dose oral corticosteroids.

However, because the analysis comprised only four studies, the authors cautioned that the results aren’t enough to justify changes to practice recommendations.

Asthma treatment with inhaled corticosteroids (ICS) may be driving the increased risk, Dr. Castro-Rodriguez and his coauthors suggested. ICS deposition in the oropharynx could boost oropharyngeal candidiasis risk by weakening the mucosal immune response, the researchers noted. And that same process may be at work with Streptococcus pneumoniae.

A prior study found that children with asthma who received ICS for at least 1 month were almost four times more likely to have oropharyngeal colonization by S. pneumoniae as were those who didn’t get the drugs. Thus, a higher carrier rate of S. pneumoniae in the oropharynx, along with asthma’s impaired airway clearance, might increase the risk of pneumococcal diseases, the investigators explained.

Dr. Castro-Rodriguez and colleagues analyzed four studies with more than 4,000 cases and controls, and about 26 million person-years of follow-up.

Rates and risks of IPD in the four studies were as follows:

• Among those with IPD, 27% had asthma, with 18% of those without, an adjusted odds ratio (aOR) of 1.8.
• In a European of patients who received at least 3 doses of PCV7, IPD rates per 100,000 person-years for 5-year-olds were 11.6 for children with asthma and 7.3 for those without. For 5- to 17-year-olds with and without asthma, the rates were 2.3 and 1.6, respectively.
• In 2001, a Korean found an aOR of 2.08 for IPD in children with asthma, compared with those without. In 2010, the aOR was 3.26. No vaccine types were reported in the study.
• of IPD were 3.7 per 100,000 person-years for children with asthma, compared with 2.5 for healthy controls – an adjusted relative risk of 1.5.

The pooled estimate of the four studies revealed an aOR of 1.9 for IPD among children with asthma, compared with those without, Dr. Castro-Rodriguez and his team concluded.

None of the studies reported hospital admissions, mortality, length of hospital stay, intensive care admission, invasive respiratory support, or additional medication use.

One, however, did find asthma severity was significantly associated with increasing IPD treatment costs per 100,000 person-years: $72,581 for healthy controls, compared with $100,020 for children with mild asthma, $172,002 for moderate asthma, and $638,452 for severe asthma.

In addition, treating all-cause pneumonia was more expensive in children with asthma. For all-cause pneumonia, the researchers found that estimated costs per 100,000 person-years for mild, moderate, and severe asthma were $7.5 million, $14.6 million, and $46.8 million, respectively, compared with $1.7 million for healthy controls.

The authors had no relevant financial disclosures.

[email protected]

SOURCE: Castro-Rodriguez J et al. Pediatrics. 2020 Jan. doi: 10.1542/peds.2019-1200.

Even on-time pneumococcal vaccines don’t completely protect children with asthma from developing invasive pneumococcal disease, a meta-analysis has determined.

Despite receiving pneumococcal valent 7, 10, or 13, children with asthma were still almost twice as likely to develop the disease as were children without asthma, Jose A. Castro-Rodriguez, MD, PhD, and colleagues reported in Pediatrics (2020 Jan. doi: 10.1542/peds.2019-1200). None of the studies included rates for those who received the pneumococcal polysaccharide vaccine (PPSV23).

“For the first time, this meta-analysis reveals 90% increased odds of invasive pneumococcal disease (IPD) among [vaccinated] children with asthma,” said Dr. Castro-Rodriguez, of Pontificia Universidad Católica de Chile, Santiago, and colleagues. “If confirmed, these findings will bear clinical and public health importance,” they noted, because guidelines now recommend PPSV23 after age 2 in children with asthma only if they’re treated with prolonged high-dose oral corticosteroids.

However, because the analysis comprised only four studies, the authors cautioned that the results aren’t enough to justify changes to practice recommendations.

Asthma treatment with inhaled corticosteroids (ICS) may be driving the increased risk, Dr. Castro-Rodriguez and his coauthors suggested. ICS deposition in the oropharynx could boost oropharyngeal candidiasis risk by weakening the mucosal immune response, the researchers noted. And that same process may be at work with Streptococcus pneumoniae.

A prior study found that children with asthma who received ICS for at least 1 month were almost four times more likely to have oropharyngeal colonization by S. pneumoniae as were those who didn’t get the drugs. Thus, a higher carrier rate of S. pneumoniae in the oropharynx, along with asthma’s impaired airway clearance, might increase the risk of pneumococcal diseases, the investigators explained.

Dr. Castro-Rodriguez and colleagues analyzed four studies with more than 4,000 cases and controls, and about 26 million person-years of follow-up.

Rates and risks of IPD in the four studies were as follows:

• Among those with IPD, 27% had asthma, with 18% of those without, an adjusted odds ratio (aOR) of 1.8.
• In a European of patients who received at least 3 doses of PCV7, IPD rates per 100,000 person-years for 5-year-olds were 11.6 for children with asthma and 7.3 for those without. For 5- to 17-year-olds with and without asthma, the rates were 2.3 and 1.6, respectively.
• In 2001, a Korean found an aOR of 2.08 for IPD in children with asthma, compared with those without. In 2010, the aOR was 3.26. No vaccine types were reported in the study.
• of IPD were 3.7 per 100,000 person-years for children with asthma, compared with 2.5 for healthy controls – an adjusted relative risk of 1.5.

The pooled estimate of the four studies revealed an aOR of 1.9 for IPD among children with asthma, compared with those without, Dr. Castro-Rodriguez and his team concluded.

None of the studies reported hospital admissions, mortality, length of hospital stay, intensive care admission, invasive respiratory support, or additional medication use.

One, however, did find asthma severity was significantly associated with increasing IPD treatment costs per 100,000 person-years: $72,581 for healthy controls, compared with $100,020 for children with mild asthma, $172,002 for moderate asthma, and $638,452 for severe asthma.

In addition, treating all-cause pneumonia was more expensive in children with asthma. For all-cause pneumonia, the researchers found that estimated costs per 100,000 person-years for mild, moderate, and severe asthma were $7.5 million, $14.6 million, and $46.8 million, respectively, compared with $1.7 million for healthy controls.

The authors had no relevant financial disclosures.

[email protected]

SOURCE: Castro-Rodriguez J et al. Pediatrics. 2020 Jan. doi: 10.1542/peds.2019-1200.

BALTIMORE – Monitoring children who have tuberous sclerosis with EEG and treating them with vigabatrin (Sabril) at the first sign of preseizure abnormalities, rather than the usual practice of no surveillance and waiting until they have seizures, prevents epilepsy and cognitive decline, according to European investigators.

M. Alexander Otto/MDedge News

Early surveillance is recommended and standard practice in Europe. That’s not the case in the United States, but might be someday pending the results of the PREVENT trial (Preventing Epilepsy Using Vigabatrin In Infants With Tuberous Sclerosis Complex), an ongoing, National Institute of Neurological Disorders and Stroke–funded study to confirm the European findings.

“We are trying to convince doctors” in the United States and other “countries to do this. If you are not convinced to do early treatment,” at least “do surveillance with EEG. You will diagnose epilepsy earlier, and treat earlier, and children will do much better,” said Sergiusz Jozwiak, MD, PhD, head of pediatric neurology at Warsaw Medical University and recipient of an award from the U.S. Tuberous Sclerosis Alliance for his pioneering work.

Some U.S. physicians are already doing preventive treatment, but it’s hit and miss. “We are talking about monitoring children below the age of 2 years,” when seizures are associated with cognitive decline, he noted at the annual meeting of the American Epilepsy Society.

Dr. Jozwiak presented a follow-up at the meeting to his 2011 investigation, the first prevention study in tuberous sclerosis. Fourteen infants diagnosed within 2 months of birth underwent video-EEG monitoring every 4-6 weeks until age 2 years and were treated with vigabatrin 100-150 mg/kg per day when multifocal epileptiform discharges – a sign of impending seizures – were detected. Outcomes were compared with infants treated traditionally, with no EEG monitoring and vigabatrin only after they seized.

The children are about 9 years old now; the median IQ in the prevention arm is 94 versus 46 in the control group (P less than .03). Seven of the 14 prevention children (50%) never had a clinical seizure, while all but 1 of 25 (96%) in the control arm did (P = .001). Six of 11 prevention children (55%) versus 4 of 24 in the control group (17%), were able to come off antiepileptic drugs altogether, with no seizures (P less than .03). The work was published shortly before the epilepsy meeting.

The original 2011 report, which had similarly favorable outcomes when the children were 2 years old, led directly to the EpiStop trial, conducted at 16 mostly European centers and also reported at the meeting. Dr. Jozwiak was the senior investigator.

The design was different; all of the infants had EEG monitoring every 4 weeks until month 6, then every 6 weeks until age 12 months, then every 2 months until age 2 years. At the first detection of multifocal epileptiform discharges, infants were randomized 1:1 to vigabatrin or to the control group, with further monitoring followed by vigabatrin at the first seizure on EEG or first clinical seizure. An additional group of children – the open-label arm – also had EEG monitoring, but when to start vigabatrin was left up to the study site.

M. Alexander Otto/MDedge News

Only 50 of the original 94 children completed the trial to the full 2 years; tuberous sclerosis comorbidities drove many of them out, said lead investigator Katarzyna Kotulska-Jozwiak, MD, PhD, head of neurology at Children’s Memorial Health Institute, Warsaw.

Even so, the 25 children treated preventively in the randomized and open-label cohorts were more than three times as likely to be seizure free at 2 years (P = .01), and 74% less likely to develop drug-resistant epilepsy (P = .013). None of the prevention children developed infantile spasms versus 10 controls (40%) treated at first clinical or EEG seizure.

The incidence of neurodevelopmental delay was 34%, and autism 33%, at 24 months, and did not differ between prevention and control subjects. It’s probably because even children in the control group benefited from EEG surveillance and early treatment, the investigators said.

Historically, the rate of intellectual disability with usual treatment is around 60%, Dr. Kotulska-Jozwiak noted.

Overall, Dr. Jozwiak said that European physicians are more comfortable using vigabatrin than U.S. doctors, where the drug hasn’t been on the market as long and carries a Food and Drug Administration boxed warning of visual impairment. Its indications in the United States include infantile spasms in children 1-24 months old.

Levetiracetam (Keppra) is another option, but it’s not as effective in tuberous sclerosis. The PREVENT trial is using vigabatrin, and some U.S. doctors “are changing their minds, but it takes time,” Dr. Jozwiak said.

He noted that TSC is increasingly being diagnosed in utero, which gives a leg up on early diagnosis and prevention. The giveaways are heart tumors on ECG and cortical tubers on fetal MRI.

Dr. Jozwiak thinks the prevention approach might also help in other early seizure disorders, such as Sturge-Weber syndrome.

The work was funded by the European Commission and Polish government. Dr. Jozwiak and Dr. Kotulska-Jozwiak didn’t have any disclosures.
 

[email protected]

SOURCES: Jozwiak S et al. AES 2019, Abstract 1.218; Kotulska-Jozwiak K et al. AES 2019, Abstract 2.121.

BALTIMORE – Monitoring children who have tuberous sclerosis with EEG and treating them with vigabatrin (Sabril) at the first sign of preseizure abnormalities, rather than the usual practice of no surveillance and waiting until they have seizures, prevents epilepsy and cognitive decline, according to European investigators.

M. Alexander Otto/MDedge News

Early surveillance is recommended and standard practice in Europe. That’s not the case in the United States, but might be someday pending the results of the PREVENT trial (Preventing Epilepsy Using Vigabatrin In Infants With Tuberous Sclerosis Complex), an ongoing, National Institute of Neurological Disorders and Stroke–funded study to confirm the European findings.

“We are trying to convince doctors” in the United States and other “countries to do this. If you are not convinced to do early treatment,” at least “do surveillance with EEG. You will diagnose epilepsy earlier, and treat earlier, and children will do much better,” said Sergiusz Jozwiak, MD, PhD, head of pediatric neurology at Warsaw Medical University and recipient of an award from the U.S. Tuberous Sclerosis Alliance for his pioneering work.

Some U.S. physicians are already doing preventive treatment, but it’s hit and miss. “We are talking about monitoring children below the age of 2 years,” when seizures are associated with cognitive decline, he noted at the annual meeting of the American Epilepsy Society.

Dr. Jozwiak presented a follow-up at the meeting to his 2011 investigation, the first prevention study in tuberous sclerosis. Fourteen infants diagnosed within 2 months of birth underwent video-EEG monitoring every 4-6 weeks until age 2 years and were treated with vigabatrin 100-150 mg/kg per day when multifocal epileptiform discharges – a sign of impending seizures – were detected. Outcomes were compared with infants treated traditionally, with no EEG monitoring and vigabatrin only after they seized.

The children are about 9 years old now; the median IQ in the prevention arm is 94 versus 46 in the control group (P less than .03). Seven of the 14 prevention children (50%) never had a clinical seizure, while all but 1 of 25 (96%) in the control arm did (P = .001). Six of 11 prevention children (55%) versus 4 of 24 in the control group (17%), were able to come off antiepileptic drugs altogether, with no seizures (P less than .03). The work was published shortly before the epilepsy meeting.

The original 2011 report, which had similarly favorable outcomes when the children were 2 years old, led directly to the EpiStop trial, conducted at 16 mostly European centers and also reported at the meeting. Dr. Jozwiak was the senior investigator.

The design was different; all of the infants had EEG monitoring every 4 weeks until month 6, then every 6 weeks until age 12 months, then every 2 months until age 2 years. At the first detection of multifocal epileptiform discharges, infants were randomized 1:1 to vigabatrin or to the control group, with further monitoring followed by vigabatrin at the first seizure on EEG or first clinical seizure. An additional group of children – the open-label arm – also had EEG monitoring, but when to start vigabatrin was left up to the study site.

M. Alexander Otto/MDedge News

Only 50 of the original 94 children completed the trial to the full 2 years; tuberous sclerosis comorbidities drove many of them out, said lead investigator Katarzyna Kotulska-Jozwiak, MD, PhD, head of neurology at Children’s Memorial Health Institute, Warsaw.

Even so, the 25 children treated preventively in the randomized and open-label cohorts were more than three times as likely to be seizure free at 2 years (P = .01), and 74% less likely to develop drug-resistant epilepsy (P = .013). None of the prevention children developed infantile spasms versus 10 controls (40%) treated at first clinical or EEG seizure.

The incidence of neurodevelopmental delay was 34%, and autism 33%, at 24 months, and did not differ between prevention and control subjects. It’s probably because even children in the control group benefited from EEG surveillance and early treatment, the investigators said.

Historically, the rate of intellectual disability with usual treatment is around 60%, Dr. Kotulska-Jozwiak noted.

Overall, Dr. Jozwiak said that European physicians are more comfortable using vigabatrin than U.S. doctors, where the drug hasn’t been on the market as long and carries a Food and Drug Administration boxed warning of visual impairment. Its indications in the United States include infantile spasms in children 1-24 months old.

Levetiracetam (Keppra) is another option, but it’s not as effective in tuberous sclerosis. The PREVENT trial is using vigabatrin, and some U.S. doctors “are changing their minds, but it takes time,” Dr. Jozwiak said.

He noted that TSC is increasingly being diagnosed in utero, which gives a leg up on early diagnosis and prevention. The giveaways are heart tumors on ECG and cortical tubers on fetal MRI.

Dr. Jozwiak thinks the prevention approach might also help in other early seizure disorders, such as Sturge-Weber syndrome.

The work was funded by the European Commission and Polish government. Dr. Jozwiak and Dr. Kotulska-Jozwiak didn’t have any disclosures.
 

[email protected]

SOURCES: Jozwiak S et al. AES 2019, Abstract 1.218; Kotulska-Jozwiak K et al. AES 2019, Abstract 2.121.

BALTIMORE – Monitoring children who have tuberous sclerosis with EEG and treating them with vigabatrin (Sabril) at the first sign of preseizure abnormalities, rather than the usual practice of no surveillance and waiting until they have seizures, prevents epilepsy and cognitive decline, according to European investigators.

M. Alexander Otto/MDedge News

Early surveillance is recommended and standard practice in Europe. That’s not the case in the United States, but might be someday pending the results of the PREVENT trial (Preventing Epilepsy Using Vigabatrin In Infants With Tuberous Sclerosis Complex), an ongoing, National Institute of Neurological Disorders and Stroke–funded study to confirm the European findings.

“We are trying to convince doctors” in the United States and other “countries to do this. If you are not convinced to do early treatment,” at least “do surveillance with EEG. You will diagnose epilepsy earlier, and treat earlier, and children will do much better,” said Sergiusz Jozwiak, MD, PhD, head of pediatric neurology at Warsaw Medical University and recipient of an award from the U.S. Tuberous Sclerosis Alliance for his pioneering work.

Some U.S. physicians are already doing preventive treatment, but it’s hit and miss. “We are talking about monitoring children below the age of 2 years,” when seizures are associated with cognitive decline, he noted at the annual meeting of the American Epilepsy Society.

Dr. Jozwiak presented a follow-up at the meeting to his 2011 investigation, the first prevention study in tuberous sclerosis. Fourteen infants diagnosed within 2 months of birth underwent video-EEG monitoring every 4-6 weeks until age 2 years and were treated with vigabatrin 100-150 mg/kg per day when multifocal epileptiform discharges – a sign of impending seizures – were detected. Outcomes were compared with infants treated traditionally, with no EEG monitoring and vigabatrin only after they seized.

The children are about 9 years old now; the median IQ in the prevention arm is 94 versus 46 in the control group (P less than .03). Seven of the 14 prevention children (50%) never had a clinical seizure, while all but 1 of 25 (96%) in the control arm did (P = .001). Six of 11 prevention children (55%) versus 4 of 24 in the control group (17%), were able to come off antiepileptic drugs altogether, with no seizures (P less than .03). The work was published shortly before the epilepsy meeting.

The original 2011 report, which had similarly favorable outcomes when the children were 2 years old, led directly to the EpiStop trial, conducted at 16 mostly European centers and also reported at the meeting. Dr. Jozwiak was the senior investigator.

The design was different; all of the infants had EEG monitoring every 4 weeks until month 6, then every 6 weeks until age 12 months, then every 2 months until age 2 years. At the first detection of multifocal epileptiform discharges, infants were randomized 1:1 to vigabatrin or to the control group, with further monitoring followed by vigabatrin at the first seizure on EEG or first clinical seizure. An additional group of children – the open-label arm – also had EEG monitoring, but when to start vigabatrin was left up to the study site.

M. Alexander Otto/MDedge News

Only 50 of the original 94 children completed the trial to the full 2 years; tuberous sclerosis comorbidities drove many of them out, said lead investigator Katarzyna Kotulska-Jozwiak, MD, PhD, head of neurology at Children’s Memorial Health Institute, Warsaw.

Even so, the 25 children treated preventively in the randomized and open-label cohorts were more than three times as likely to be seizure free at 2 years (P = .01), and 74% less likely to develop drug-resistant epilepsy (P = .013). None of the prevention children developed infantile spasms versus 10 controls (40%) treated at first clinical or EEG seizure.

The incidence of neurodevelopmental delay was 34%, and autism 33%, at 24 months, and did not differ between prevention and control subjects. It’s probably because even children in the control group benefited from EEG surveillance and early treatment, the investigators said.

Historically, the rate of intellectual disability with usual treatment is around 60%, Dr. Kotulska-Jozwiak noted.

Overall, Dr. Jozwiak said that European physicians are more comfortable using vigabatrin than U.S. doctors, where the drug hasn’t been on the market as long and carries a Food and Drug Administration boxed warning of visual impairment. Its indications in the United States include infantile spasms in children 1-24 months old.

Levetiracetam (Keppra) is another option, but it’s not as effective in tuberous sclerosis. The PREVENT trial is using vigabatrin, and some U.S. doctors “are changing their minds, but it takes time,” Dr. Jozwiak said.

He noted that TSC is increasingly being diagnosed in utero, which gives a leg up on early diagnosis and prevention. The giveaways are heart tumors on ECG and cortical tubers on fetal MRI.

Dr. Jozwiak thinks the prevention approach might also help in other early seizure disorders, such as Sturge-Weber syndrome.

The work was funded by the European Commission and Polish government. Dr. Jozwiak and Dr. Kotulska-Jozwiak didn’t have any disclosures.
 

[email protected]

SOURCES: Jozwiak S et al. AES 2019, Abstract 1.218; Kotulska-Jozwiak K et al. AES 2019, Abstract 2.121.