Endocrinology

PHILADELPHIA – Elagolix has emerged as an effective second-tier treatment option for patients with dysmenorrhea attributed to endometriosis, Charles E. Miller, MD, said at the annual meeting of the American Society for Reproductive Medicine.

Jeff Craven/MDedge News

Although clinicians need prior authorization and evidence of treatment failure before prescribing Elagolix, the drug is a viable option as a second-tier treatment for patients with endometriosis-associated dysmenorrhea, said Dr. Miller, director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital in Park Ridge, Ill. “We have a drug that is very effective, that has a very low adverse event profile, and is tolerated by the vast majority of our patients.”

First-line options

NSAIDs are first-line treatment for endometriosis-related dysmenorrhea, with acetaminophen used in cases where NSAIDs are contraindicated or cause side effects such as gastrointestinal issues. Hormonal contraceptives also can be used as first-line treatment, divided into estrogen/progestin and progestin-only options that can be combined. Evidence from the literature has shown oral pills decrease pain, compared with placebo, but the decrease is not dose dependent, said Dr. Miller.

“We also know that if you use it continuously or prolonged, we find that there is going to be greater success with dysmenorrhea, and that ultimately you would use a higher-dose pill because of the greater risk of breakthrough when using a lesser dose in a continuous fashion,” he said. “Obviously if you’re not having menses, you’re not going to have dysmenorrhea.”

Other estrogen/progestin hormonal contraception such as the vaginal ring or transdermal patch also have been shown to decrease dysmenorrhea from endometriosis, with one study showing a reduction from 17% to 6% in moderate to severe dysmenorrhea in patients using the vaginal ring, compared with patients receiving oral contraceptives. In a separate randomized, controlled trial, “dysmenorrhea was more common in patch users, so it doesn’t appear that the patch is quite as effective in terms of reducing dysmenorrhea,” said Dr. Miller (JAMA. 2001 May 9. doi: 10.1001/jama.285.18.2347).

Compared with combination hormone therapy, there has been less research conducted on progestin-only hormone contraceptives on reducing dysmenorrhea from endometriosis. For example, there is little evidence for depot medroxyprogesterone acetate in reducing dysmenorrhea, but rather with it causing amenorrhea; one study showed a 50% amenorrhea rate at 1 year. “The disadvantage, however, in our infertile population is ultimately getting the menses back,” said Dr. Miller.

IUDs using levonorgestrel appear comparable with gonadotropin-releasing hormone (GnRH) agonists in reducing endometriosis-related pain; in one study, most women treated with either of these had visual analogue scores of less than 3 at 6 months of treatment. Between 68% and 75% of women with dysmenorrhea who receive an implantable contraceptive device with etonogestrel report decreased pain, and one meta-analysis reported 75% of women had “complete resolution of dysmenorrhea.” Concerning progestin-only pills, they can be used for endometriosis-related dysmenorrhea, but they are “problematic in that there’s a lot of breakthrough bleeding, and often times that is associated with pain,” said Dr. Miller.

Second-tier options

Injectable GnRH agonists are effective options as second-tier treatments for endometriosis-related dysmenorrhea, but patients are at risk of developing postmenopausal symptoms such as hot flashes, insomnia, spotting, and decreased libido. “One advantage to that is, over the years and particularly something that I’ve done with my endometriosis-related dysmenorrhea, is to utilize add-back with these patients,” said Dr. Miller, who noted that patients on 2.5 mg of norethindrone acetate and 0.5 mg of ethinyl estradiol“do very well” with that combination of add-back therapy.

Elagolix is the most recent second-tier treatment option for these patients, and was studied in the Elaris EM-I and Elaris EM-II trials in a once-daily dose of 150 mg and a twice-daily dose of 200 mg. In Elaris EM-1, 76% of patients in the 200-mg elagolix group had a clinical response, compared with 46% in the 150-mg group and 20% in the placebo group (N Engl J Med. 2017 Jul 6. doi: 10.1056/NEJMoa1700089). However, patients should not be on elagolix at 200 mg for more than 6 months, while patients receiving elagolix at 150 mg can stay on the treatment for up to 2 years.

Patients taking elagolix also showed postmenopausal symptoms, with 24% in the 150-mg group and 46% in the 200-mg group experiencing hot flashes, compared with 9% of patients in the placebo group. While 6% of patients in the 150-mg group and 10% in the 200-mg group discontinued because of adverse events, 1% and 3% of patients in the 150-mg and 200-mg group discontinued because of hot flashes or night sweats, respectively. “Symptoms are well tolerated, far different than in comparison with leuprolide acetate and GnRH agonists,” said Dr. Miller.

There also is a benefit to how patients recover from bone mineral density (BMD) changes after remaining on elagolix, Dr. Miller noted. In patients who received elagolix for 12 months at doses of 150 mg and 200 mg, there was an increase in lumbar spine BMD recovered 6 months after discontinuation, with patients in the 150-mg group experiencing a recovery close to baseline BMD levels. Among patients who discontinued treatment, there also was a quick resumption in menses for both groups: 87% of patients in the 150 mg group and 88% of patients in the 200-mg group who discontinued treatment after 6 months had resumed menses by 2 months after discontinuation, while 95% of patients in the 150-mg and 91% in the 200-mg group who discontinued after 12 months resumed menses by 2 months after discontinuation.

Dr. Miller reported relationships with AbbVie, Allergan, Blue Seas Med Spa, Espiner Medical, Gynesonics, Halt Medical, Hologic, Karl Storz, Medtronic, and Richard Wolf in the form of consultancies, grants, speakers’ bureau appointments, stock options, royalties, and ownership interests.

PHILADELPHIA – Elagolix has emerged as an effective second-tier treatment option for patients with dysmenorrhea attributed to endometriosis, Charles E. Miller, MD, said at the annual meeting of the American Society for Reproductive Medicine.

Jeff Craven/MDedge News

Although clinicians need prior authorization and evidence of treatment failure before prescribing Elagolix, the drug is a viable option as a second-tier treatment for patients with endometriosis-associated dysmenorrhea, said Dr. Miller, director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital in Park Ridge, Ill. “We have a drug that is very effective, that has a very low adverse event profile, and is tolerated by the vast majority of our patients.”

First-line options

NSAIDs are first-line treatment for endometriosis-related dysmenorrhea, with acetaminophen used in cases where NSAIDs are contraindicated or cause side effects such as gastrointestinal issues. Hormonal contraceptives also can be used as first-line treatment, divided into estrogen/progestin and progestin-only options that can be combined. Evidence from the literature has shown oral pills decrease pain, compared with placebo, but the decrease is not dose dependent, said Dr. Miller.

“We also know that if you use it continuously or prolonged, we find that there is going to be greater success with dysmenorrhea, and that ultimately you would use a higher-dose pill because of the greater risk of breakthrough when using a lesser dose in a continuous fashion,” he said. “Obviously if you’re not having menses, you’re not going to have dysmenorrhea.”

Other estrogen/progestin hormonal contraception such as the vaginal ring or transdermal patch also have been shown to decrease dysmenorrhea from endometriosis, with one study showing a reduction from 17% to 6% in moderate to severe dysmenorrhea in patients using the vaginal ring, compared with patients receiving oral contraceptives. In a separate randomized, controlled trial, “dysmenorrhea was more common in patch users, so it doesn’t appear that the patch is quite as effective in terms of reducing dysmenorrhea,” said Dr. Miller (JAMA. 2001 May 9. doi: 10.1001/jama.285.18.2347).

Compared with combination hormone therapy, there has been less research conducted on progestin-only hormone contraceptives on reducing dysmenorrhea from endometriosis. For example, there is little evidence for depot medroxyprogesterone acetate in reducing dysmenorrhea, but rather with it causing amenorrhea; one study showed a 50% amenorrhea rate at 1 year. “The disadvantage, however, in our infertile population is ultimately getting the menses back,” said Dr. Miller.

IUDs using levonorgestrel appear comparable with gonadotropin-releasing hormone (GnRH) agonists in reducing endometriosis-related pain; in one study, most women treated with either of these had visual analogue scores of less than 3 at 6 months of treatment. Between 68% and 75% of women with dysmenorrhea who receive an implantable contraceptive device with etonogestrel report decreased pain, and one meta-analysis reported 75% of women had “complete resolution of dysmenorrhea.” Concerning progestin-only pills, they can be used for endometriosis-related dysmenorrhea, but they are “problematic in that there’s a lot of breakthrough bleeding, and often times that is associated with pain,” said Dr. Miller.

Second-tier options

Injectable GnRH agonists are effective options as second-tier treatments for endometriosis-related dysmenorrhea, but patients are at risk of developing postmenopausal symptoms such as hot flashes, insomnia, spotting, and decreased libido. “One advantage to that is, over the years and particularly something that I’ve done with my endometriosis-related dysmenorrhea, is to utilize add-back with these patients,” said Dr. Miller, who noted that patients on 2.5 mg of norethindrone acetate and 0.5 mg of ethinyl estradiol“do very well” with that combination of add-back therapy.

Elagolix is the most recent second-tier treatment option for these patients, and was studied in the Elaris EM-I and Elaris EM-II trials in a once-daily dose of 150 mg and a twice-daily dose of 200 mg. In Elaris EM-1, 76% of patients in the 200-mg elagolix group had a clinical response, compared with 46% in the 150-mg group and 20% in the placebo group (N Engl J Med. 2017 Jul 6. doi: 10.1056/NEJMoa1700089). However, patients should not be on elagolix at 200 mg for more than 6 months, while patients receiving elagolix at 150 mg can stay on the treatment for up to 2 years.

Patients taking elagolix also showed postmenopausal symptoms, with 24% in the 150-mg group and 46% in the 200-mg group experiencing hot flashes, compared with 9% of patients in the placebo group. While 6% of patients in the 150-mg group and 10% in the 200-mg group discontinued because of adverse events, 1% and 3% of patients in the 150-mg and 200-mg group discontinued because of hot flashes or night sweats, respectively. “Symptoms are well tolerated, far different than in comparison with leuprolide acetate and GnRH agonists,” said Dr. Miller.

There also is a benefit to how patients recover from bone mineral density (BMD) changes after remaining on elagolix, Dr. Miller noted. In patients who received elagolix for 12 months at doses of 150 mg and 200 mg, there was an increase in lumbar spine BMD recovered 6 months after discontinuation, with patients in the 150-mg group experiencing a recovery close to baseline BMD levels. Among patients who discontinued treatment, there also was a quick resumption in menses for both groups: 87% of patients in the 150 mg group and 88% of patients in the 200-mg group who discontinued treatment after 6 months had resumed menses by 2 months after discontinuation, while 95% of patients in the 150-mg and 91% in the 200-mg group who discontinued after 12 months resumed menses by 2 months after discontinuation.

Dr. Miller reported relationships with AbbVie, Allergan, Blue Seas Med Spa, Espiner Medical, Gynesonics, Halt Medical, Hologic, Karl Storz, Medtronic, and Richard Wolf in the form of consultancies, grants, speakers’ bureau appointments, stock options, royalties, and ownership interests.

PHILADELPHIA – Elagolix has emerged as an effective second-tier treatment option for patients with dysmenorrhea attributed to endometriosis, Charles E. Miller, MD, said at the annual meeting of the American Society for Reproductive Medicine.

Jeff Craven/MDedge News

Although clinicians need prior authorization and evidence of treatment failure before prescribing Elagolix, the drug is a viable option as a second-tier treatment for patients with endometriosis-associated dysmenorrhea, said Dr. Miller, director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital in Park Ridge, Ill. “We have a drug that is very effective, that has a very low adverse event profile, and is tolerated by the vast majority of our patients.”

First-line options

NSAIDs are first-line treatment for endometriosis-related dysmenorrhea, with acetaminophen used in cases where NSAIDs are contraindicated or cause side effects such as gastrointestinal issues. Hormonal contraceptives also can be used as first-line treatment, divided into estrogen/progestin and progestin-only options that can be combined. Evidence from the literature has shown oral pills decrease pain, compared with placebo, but the decrease is not dose dependent, said Dr. Miller.

“We also know that if you use it continuously or prolonged, we find that there is going to be greater success with dysmenorrhea, and that ultimately you would use a higher-dose pill because of the greater risk of breakthrough when using a lesser dose in a continuous fashion,” he said. “Obviously if you’re not having menses, you’re not going to have dysmenorrhea.”

Other estrogen/progestin hormonal contraception such as the vaginal ring or transdermal patch also have been shown to decrease dysmenorrhea from endometriosis, with one study showing a reduction from 17% to 6% in moderate to severe dysmenorrhea in patients using the vaginal ring, compared with patients receiving oral contraceptives. In a separate randomized, controlled trial, “dysmenorrhea was more common in patch users, so it doesn’t appear that the patch is quite as effective in terms of reducing dysmenorrhea,” said Dr. Miller (JAMA. 2001 May 9. doi: 10.1001/jama.285.18.2347).

Compared with combination hormone therapy, there has been less research conducted on progestin-only hormone contraceptives on reducing dysmenorrhea from endometriosis. For example, there is little evidence for depot medroxyprogesterone acetate in reducing dysmenorrhea, but rather with it causing amenorrhea; one study showed a 50% amenorrhea rate at 1 year. “The disadvantage, however, in our infertile population is ultimately getting the menses back,” said Dr. Miller.

IUDs using levonorgestrel appear comparable with gonadotropin-releasing hormone (GnRH) agonists in reducing endometriosis-related pain; in one study, most women treated with either of these had visual analogue scores of less than 3 at 6 months of treatment. Between 68% and 75% of women with dysmenorrhea who receive an implantable contraceptive device with etonogestrel report decreased pain, and one meta-analysis reported 75% of women had “complete resolution of dysmenorrhea.” Concerning progestin-only pills, they can be used for endometriosis-related dysmenorrhea, but they are “problematic in that there’s a lot of breakthrough bleeding, and often times that is associated with pain,” said Dr. Miller.

Second-tier options

Injectable GnRH agonists are effective options as second-tier treatments for endometriosis-related dysmenorrhea, but patients are at risk of developing postmenopausal symptoms such as hot flashes, insomnia, spotting, and decreased libido. “One advantage to that is, over the years and particularly something that I’ve done with my endometriosis-related dysmenorrhea, is to utilize add-back with these patients,” said Dr. Miller, who noted that patients on 2.5 mg of norethindrone acetate and 0.5 mg of ethinyl estradiol“do very well” with that combination of add-back therapy.

Elagolix is the most recent second-tier treatment option for these patients, and was studied in the Elaris EM-I and Elaris EM-II trials in a once-daily dose of 150 mg and a twice-daily dose of 200 mg. In Elaris EM-1, 76% of patients in the 200-mg elagolix group had a clinical response, compared with 46% in the 150-mg group and 20% in the placebo group (N Engl J Med. 2017 Jul 6. doi: 10.1056/NEJMoa1700089). However, patients should not be on elagolix at 200 mg for more than 6 months, while patients receiving elagolix at 150 mg can stay on the treatment for up to 2 years.

Patients taking elagolix also showed postmenopausal symptoms, with 24% in the 150-mg group and 46% in the 200-mg group experiencing hot flashes, compared with 9% of patients in the placebo group. While 6% of patients in the 150-mg group and 10% in the 200-mg group discontinued because of adverse events, 1% and 3% of patients in the 150-mg and 200-mg group discontinued because of hot flashes or night sweats, respectively. “Symptoms are well tolerated, far different than in comparison with leuprolide acetate and GnRH agonists,” said Dr. Miller.

There also is a benefit to how patients recover from bone mineral density (BMD) changes after remaining on elagolix, Dr. Miller noted. In patients who received elagolix for 12 months at doses of 150 mg and 200 mg, there was an increase in lumbar spine BMD recovered 6 months after discontinuation, with patients in the 150-mg group experiencing a recovery close to baseline BMD levels. Among patients who discontinued treatment, there also was a quick resumption in menses for both groups: 87% of patients in the 150 mg group and 88% of patients in the 200-mg group who discontinued treatment after 6 months had resumed menses by 2 months after discontinuation, while 95% of patients in the 150-mg and 91% in the 200-mg group who discontinued after 12 months resumed menses by 2 months after discontinuation.

Dr. Miller reported relationships with AbbVie, Allergan, Blue Seas Med Spa, Espiner Medical, Gynesonics, Halt Medical, Hologic, Karl Storz, Medtronic, and Richard Wolf in the form of consultancies, grants, speakers’ bureau appointments, stock options, royalties, and ownership interests.

CHICAGO – A large Danish registry-based study has confirmed an increased risk of acute pancreatitis for patients taking certain antithyroid drugs.

After 6 months of methimazole use, the odds ratio for acute pancreatitis was 2.02, with a nonsignificant risk elevation for propylthiouracil use after a similar duration, Laszlo Hegedüs, MD, reported at the annual meeting of the American Thyroid Association.

“Ongoing methimazole, but not propylthiouracil, use is associated with an increased risk of acute pancreatitis,” he said.

Dr. Hegedüs, professor of endocrinology and metabolism at the University of Southern Denmark, Odense, said that the European Medicines Agency has noted a few postmarketing reports of acute pancreatitis in patients who received the antithyroid drug methimazole, as well as its prodrug, carbimazole. The agency has accordingly contraindicated antithyroid drug use for patients who previously experienced acute pancreatitis after receiving this drug, advising that methimazole should be “discontinued immediately” should a patient develop acute pancreatitis.

However, investigation of the antithyroid drug–pancreatitis association had been limited to aggregating those case reports, so Dr. Hegedüs and colleagues decided to use Danish medical record and registry data to investigate the association in a nationwide, controlled study that looked at both duration of therapy and total antithyroid drug use.

During the period from 1995-2018, a total of 118,649 patients who used antithyroid drugs were found in the 5.5 million individuals in the Statistics Denmark registry. Dr. Hegedüs and his colleagues also pulled in patient registry and national prescription registry data, as well as civil vital statistics data.

Of those who used antithyroid drugs, 103,825 patients used methimazole, and 14,824 used propylthiouracil. The researchers found 43,580 instances of hospitalization for first-time acute pancreatitis in the pooled antithyroid drug data. Of those, however, just 226 (0.5%) occurred in patients using methimazole, and 19 (0.04%) in those using propylthiouracil at the time of pancreatitis onset.

To ascertain the risk of acute pancreatitis in patients using antithyroid drugs for various durations, Dr. Hegedüs and his colleagues used a case-crossover study design. In the case-crossover technique, patients served as their own controls, because each patient was both exposed and not exposed to antithyroid drugs at some point during the study period. Antithyroid drugs are well suited to this study design, explained Dr. Hegedüs, because they are given for a limited time. A case-crossover design can be used with a small sample size and effectively controls for potentially confounding variables.

The odds ratio for acute pancreatitis in methimazole users after 3 months of exposure was 1.51, with a 95% confidence interval of 1.12-2.02. After 3 months of propylthiouracil exposure, the odds ratio for acute pancreatitis was 1.16 (95% CI 0.46-2.3). At 6 months, the odds ratio of 2.02 for methimazole was similarly statistically significant (95% CI, 1.50-2.78), whereas the odds ratio of 1.40 for propylthiouracil use was not significant (95% CI, 0.58-3.34).

The researchers also wanted to find out whether the cumulative drug dose affected the risk of acute pancreatitis, so they drew from the antithyroid drug population to conduct a case-control study. Here, the investigators matched data from four control patients to each case of acute pancreatitis. The researchers also controlled for sex, age, comorbidities, and prior use of drugs associated with pancreatitis.

Overall, 20% of the 692 methimazole users and their controls were men, as were 16% of the 108 propylthiouracil users, in the case-control study.

Just more than half of patients overall had a total dose exposure of 200 to 1,200 defined daily dose (DDD) – a measure developed by the World Health Organization to denote the assumed average adult dose per day of a medication – with about a quarter of patients receiving a total antithyroid drug dose more than 1,200 DDD and about 20% receiving a dose exposure of less than 200 DDD. The risk of acute pancreatitis did not increase with increased total exposure to antithyroid drugs.

“There is no evidence of a cumulative dose effect of either methimazole or propylthiouracil on the risk of acute pancreatitis,” said Dr. Hegedüs. However, “the warning of the European Medicines Agency seems justified,” he added. “The frequency of acute pancreatitis in acute methimazole users is of a similar magnitude [to that] reported for agranulocytosis,” a known, dire complication of antithyroid drug use. Patients should be advised of the potential complication and informed of signs and symptoms of acute pancreatitis, he said.

Dr. Hegedüs noted that the study had the advantage of using validated epidemiologic methods to look at drug exposure and outcomes at a nationwide scale. However, the registries from which the data were drawn also have limitations. The investigators could not determine the severity of hyperthyroidism, he said, and the relatively rare occurrence of acute pancreatitis meant that there was not sufficient statistical power to look at the subgroup of individuals who had Graves disease and to compare them with those with nodular toxic goiter.

He advised conducting a confirmatory study in an independent cohort, as well as further investigating the yet unknown mechanism of action for the link between the antithyroid drug and acute pancreatitis.

Dr. Hegedüs reported that he had no relevant conflicts of interest and reported no outside sources of funding.
 

SOURCE: Hegedüs, L. et al. ATA 2019, Short Call Oral Abstract 6 .

CHICAGO – A large Danish registry-based study has confirmed an increased risk of acute pancreatitis for patients taking certain antithyroid drugs.

After 6 months of methimazole use, the odds ratio for acute pancreatitis was 2.02, with a nonsignificant risk elevation for propylthiouracil use after a similar duration, Laszlo Hegedüs, MD, reported at the annual meeting of the American Thyroid Association.

“Ongoing methimazole, but not propylthiouracil, use is associated with an increased risk of acute pancreatitis,” he said.

Dr. Hegedüs, professor of endocrinology and metabolism at the University of Southern Denmark, Odense, said that the European Medicines Agency has noted a few postmarketing reports of acute pancreatitis in patients who received the antithyroid drug methimazole, as well as its prodrug, carbimazole. The agency has accordingly contraindicated antithyroid drug use for patients who previously experienced acute pancreatitis after receiving this drug, advising that methimazole should be “discontinued immediately” should a patient develop acute pancreatitis.

However, investigation of the antithyroid drug–pancreatitis association had been limited to aggregating those case reports, so Dr. Hegedüs and colleagues decided to use Danish medical record and registry data to investigate the association in a nationwide, controlled study that looked at both duration of therapy and total antithyroid drug use.

During the period from 1995-2018, a total of 118,649 patients who used antithyroid drugs were found in the 5.5 million individuals in the Statistics Denmark registry. Dr. Hegedüs and his colleagues also pulled in patient registry and national prescription registry data, as well as civil vital statistics data.

Of those who used antithyroid drugs, 103,825 patients used methimazole, and 14,824 used propylthiouracil. The researchers found 43,580 instances of hospitalization for first-time acute pancreatitis in the pooled antithyroid drug data. Of those, however, just 226 (0.5%) occurred in patients using methimazole, and 19 (0.04%) in those using propylthiouracil at the time of pancreatitis onset.

To ascertain the risk of acute pancreatitis in patients using antithyroid drugs for various durations, Dr. Hegedüs and his colleagues used a case-crossover study design. In the case-crossover technique, patients served as their own controls, because each patient was both exposed and not exposed to antithyroid drugs at some point during the study period. Antithyroid drugs are well suited to this study design, explained Dr. Hegedüs, because they are given for a limited time. A case-crossover design can be used with a small sample size and effectively controls for potentially confounding variables.

The odds ratio for acute pancreatitis in methimazole users after 3 months of exposure was 1.51, with a 95% confidence interval of 1.12-2.02. After 3 months of propylthiouracil exposure, the odds ratio for acute pancreatitis was 1.16 (95% CI 0.46-2.3). At 6 months, the odds ratio of 2.02 for methimazole was similarly statistically significant (95% CI, 1.50-2.78), whereas the odds ratio of 1.40 for propylthiouracil use was not significant (95% CI, 0.58-3.34).

The researchers also wanted to find out whether the cumulative drug dose affected the risk of acute pancreatitis, so they drew from the antithyroid drug population to conduct a case-control study. Here, the investigators matched data from four control patients to each case of acute pancreatitis. The researchers also controlled for sex, age, comorbidities, and prior use of drugs associated with pancreatitis.

Overall, 20% of the 692 methimazole users and their controls were men, as were 16% of the 108 propylthiouracil users, in the case-control study.

Just more than half of patients overall had a total dose exposure of 200 to 1,200 defined daily dose (DDD) – a measure developed by the World Health Organization to denote the assumed average adult dose per day of a medication – with about a quarter of patients receiving a total antithyroid drug dose more than 1,200 DDD and about 20% receiving a dose exposure of less than 200 DDD. The risk of acute pancreatitis did not increase with increased total exposure to antithyroid drugs.

“There is no evidence of a cumulative dose effect of either methimazole or propylthiouracil on the risk of acute pancreatitis,” said Dr. Hegedüs. However, “the warning of the European Medicines Agency seems justified,” he added. “The frequency of acute pancreatitis in acute methimazole users is of a similar magnitude [to that] reported for agranulocytosis,” a known, dire complication of antithyroid drug use. Patients should be advised of the potential complication and informed of signs and symptoms of acute pancreatitis, he said.

Dr. Hegedüs noted that the study had the advantage of using validated epidemiologic methods to look at drug exposure and outcomes at a nationwide scale. However, the registries from which the data were drawn also have limitations. The investigators could not determine the severity of hyperthyroidism, he said, and the relatively rare occurrence of acute pancreatitis meant that there was not sufficient statistical power to look at the subgroup of individuals who had Graves disease and to compare them with those with nodular toxic goiter.

He advised conducting a confirmatory study in an independent cohort, as well as further investigating the yet unknown mechanism of action for the link between the antithyroid drug and acute pancreatitis.

Dr. Hegedüs reported that he had no relevant conflicts of interest and reported no outside sources of funding.
 

SOURCE: Hegedüs, L. et al. ATA 2019, Short Call Oral Abstract 6 .

CHICAGO – A large Danish registry-based study has confirmed an increased risk of acute pancreatitis for patients taking certain antithyroid drugs.

After 6 months of methimazole use, the odds ratio for acute pancreatitis was 2.02, with a nonsignificant risk elevation for propylthiouracil use after a similar duration, Laszlo Hegedüs, MD, reported at the annual meeting of the American Thyroid Association.

“Ongoing methimazole, but not propylthiouracil, use is associated with an increased risk of acute pancreatitis,” he said.

Dr. Hegedüs, professor of endocrinology and metabolism at the University of Southern Denmark, Odense, said that the European Medicines Agency has noted a few postmarketing reports of acute pancreatitis in patients who received the antithyroid drug methimazole, as well as its prodrug, carbimazole. The agency has accordingly contraindicated antithyroid drug use for patients who previously experienced acute pancreatitis after receiving this drug, advising that methimazole should be “discontinued immediately” should a patient develop acute pancreatitis.

However, investigation of the antithyroid drug–pancreatitis association had been limited to aggregating those case reports, so Dr. Hegedüs and colleagues decided to use Danish medical record and registry data to investigate the association in a nationwide, controlled study that looked at both duration of therapy and total antithyroid drug use.

During the period from 1995-2018, a total of 118,649 patients who used antithyroid drugs were found in the 5.5 million individuals in the Statistics Denmark registry. Dr. Hegedüs and his colleagues also pulled in patient registry and national prescription registry data, as well as civil vital statistics data.

Of those who used antithyroid drugs, 103,825 patients used methimazole, and 14,824 used propylthiouracil. The researchers found 43,580 instances of hospitalization for first-time acute pancreatitis in the pooled antithyroid drug data. Of those, however, just 226 (0.5%) occurred in patients using methimazole, and 19 (0.04%) in those using propylthiouracil at the time of pancreatitis onset.

To ascertain the risk of acute pancreatitis in patients using antithyroid drugs for various durations, Dr. Hegedüs and his colleagues used a case-crossover study design. In the case-crossover technique, patients served as their own controls, because each patient was both exposed and not exposed to antithyroid drugs at some point during the study period. Antithyroid drugs are well suited to this study design, explained Dr. Hegedüs, because they are given for a limited time. A case-crossover design can be used with a small sample size and effectively controls for potentially confounding variables.

The odds ratio for acute pancreatitis in methimazole users after 3 months of exposure was 1.51, with a 95% confidence interval of 1.12-2.02. After 3 months of propylthiouracil exposure, the odds ratio for acute pancreatitis was 1.16 (95% CI 0.46-2.3). At 6 months, the odds ratio of 2.02 for methimazole was similarly statistically significant (95% CI, 1.50-2.78), whereas the odds ratio of 1.40 for propylthiouracil use was not significant (95% CI, 0.58-3.34).

The researchers also wanted to find out whether the cumulative drug dose affected the risk of acute pancreatitis, so they drew from the antithyroid drug population to conduct a case-control study. Here, the investigators matched data from four control patients to each case of acute pancreatitis. The researchers also controlled for sex, age, comorbidities, and prior use of drugs associated with pancreatitis.

Overall, 20% of the 692 methimazole users and their controls were men, as were 16% of the 108 propylthiouracil users, in the case-control study.

Just more than half of patients overall had a total dose exposure of 200 to 1,200 defined daily dose (DDD) – a measure developed by the World Health Organization to denote the assumed average adult dose per day of a medication – with about a quarter of patients receiving a total antithyroid drug dose more than 1,200 DDD and about 20% receiving a dose exposure of less than 200 DDD. The risk of acute pancreatitis did not increase with increased total exposure to antithyroid drugs.

“There is no evidence of a cumulative dose effect of either methimazole or propylthiouracil on the risk of acute pancreatitis,” said Dr. Hegedüs. However, “the warning of the European Medicines Agency seems justified,” he added. “The frequency of acute pancreatitis in acute methimazole users is of a similar magnitude [to that] reported for agranulocytosis,” a known, dire complication of antithyroid drug use. Patients should be advised of the potential complication and informed of signs and symptoms of acute pancreatitis, he said.

Dr. Hegedüs noted that the study had the advantage of using validated epidemiologic methods to look at drug exposure and outcomes at a nationwide scale. However, the registries from which the data were drawn also have limitations. The investigators could not determine the severity of hyperthyroidism, he said, and the relatively rare occurrence of acute pancreatitis meant that there was not sufficient statistical power to look at the subgroup of individuals who had Graves disease and to compare them with those with nodular toxic goiter.

He advised conducting a confirmatory study in an independent cohort, as well as further investigating the yet unknown mechanism of action for the link between the antithyroid drug and acute pancreatitis.

Dr. Hegedüs reported that he had no relevant conflicts of interest and reported no outside sources of funding.
 

SOURCE: Hegedüs, L. et al. ATA 2019, Short Call Oral Abstract 6 .

PHILADELPHIA – The primary outcome results from the practice-changing DAPA-HF trial gave clinicians strong evidence that the diabetes drug dapagliflozin was equally effective at reducing cardiovascular death and acute exacerbations in patients with heart failure with reduced ejection fraction, whether or not they also had type 2 diabetes. More detailed findings from the 2,605 enrolled patients in DAPA-HF who lacked diabetes (55% of the total study population) have now sealed the deal.

Mitchel L. Zoler/MDedge News

“The relative and absolute reductions in cardiovascular death and hospitalizations or urgent visits for heart failure were substantial, clinically important, and consistent in patients with or without type 2 diabetes,” John McMurray, MD, declared at the American Heart Association scientific sessions as he summarized new trial results that confirmed the initial finding he reported previously.

While the initial report of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) by the study’s lead investigator, Dr. McMurray, was limited to the finding that the relative risk reduction for the study’s primary endpoint was a highly statistically significant 25% in heart failure patients with diabetes and an equally strongly significant 27% relative cut among patients without diabetes (N Engl J Med. 2019 Sep 19;doi: 10.1056/NEJMoa1911303), the new data showed that same consistency across the range of outcomes studied in the trial as well as across the range of glycosylated hemoglobin levels that patients had at study entry.

In an analysis that divided the entire study population of 4,744 patients with heart failure with reduced ejection fraction (HFrEF) into tertiles based on their entry blood level of hemoglobin A^1c, patients with a normal level at or below 5.6% had a 26% relative reduction in the study’s primary endpoint, essentially the same response as the 29% relative cut in adverse events in the tertile of patients with a glycosylated hemoglobin level of 5.7%-5.9% and the relative 28% relative reduction in events in patients diagnosed with type 2 diabetes and having a hemoglobin A_1c of 6.0% or greater, reported Dr. McMurray, professor of cardiology at the University of Glasgow. The results also showed a very benign safety profile in the patients without diabetes, similar to patients with diabetes and to placebo, and with no episodes of major hypoglycemia or diabetic ketoacidosis.

“It’s quite impressive that the result was consistent regardless of the level of hemoglobin A_1c,” commented Larry A. Allen, MD, professor of medicine at the University of Colorado in Aurora and designated discussant for the report. Even though the patients without diabetes constituted just over half of the full DAPA-HF enrollment, the comparison of the effect of dapagliflozin in patients with or without diabetes was prespecified in a trial that enrolled a relatively large number of patients into each of the two subgroups by diabetes status. “I think there a good chance dapagliflozin will get an indication” for treating HFrEF patients without diabetes, Dr. Allen suggested in a video interview.

If the DAPA-HF results persuade the U.S. Food and Drug Administration to grant a supplemental indication to dapagliflozin for use in cutting cardiovascular deaths and acute heart failure exacerbations in patients without diabetes, it would pave the way for health insurers to pay for the drug. Right now, even though Dr. Allen and other heart failure physicians have been impressed by the DAPA-HF findings and are eager to add the drug to the list of agents that HFrEF patients routinely receive, he’s been stymied so far by patients’ out-of pocket cost for using dapagliflozin off-label, roughly $500 a month.

“The DAPA-HF results suggest there is strong reason to consider dapagliflozin for patients without diabetes, and for payers to pay for it. I’m not prescribing dapagliflozin to HFrEF patients without diabetes right now; not because of the data, but because of noncoverage. Payers have not yet caught up with the data,” he said, and they likely will continue to not pay for the drug when used by patients without diabetes until a new labeled indication appears for those patients.

The immediate availability of dapagliflozin (Farxiga) and the two other approved members of the sodium-glucose co-transporter 2 inhibitor class of drugs, empagliflozin (Jardiance) and canagliflozin (Invokana), to treat patients with HFrEF, and the prospect of soon having dapagliflozin and possibly the other drugs in this class to treat patients with HFrEF but without diabetes also raises issues of drug sequencing in these patients and the overall number of drugs that HFrEF patients must now take to be on optimized medical therapy, Dr. Allen noted.

The already-existing lineup of medications for HFrEF patients includes starting on an ACE inhibitor or angiotensin receptor blocker and adding a beta-blocker, a mineralocorticoid receptor antagonist, then swapping out the initial renin-angiotensin system inhibitor for sacubitril/valsartan, and then, on top of all this, adding dapagliflozin or another drug in the same class. It raises questions of what is objectively the best way to introduce all these drugs into patients, and how to do it without subjecting patients to “financial toxicity,” Dr. Allen said during his discussion of the trial’s results.

DAPA-HF was sponsored by AstraZeneca, which markets dapagliflozin (Farxiga). The University of Glasgow received payment from AstraZeneca to compensate for the time Dr. McMurray spent running the study. Dr. Allen has been a consultant to ACI Clinical, Boston Scientific, and Janssen.

[email protected]

SOURCE: McMurray JJV. AHA 19, Late-Breaking Science 1.

PHILADELPHIA – The primary outcome results from the practice-changing DAPA-HF trial gave clinicians strong evidence that the diabetes drug dapagliflozin was equally effective at reducing cardiovascular death and acute exacerbations in patients with heart failure with reduced ejection fraction, whether or not they also had type 2 diabetes. More detailed findings from the 2,605 enrolled patients in DAPA-HF who lacked diabetes (55% of the total study population) have now sealed the deal.

Mitchel L. Zoler/MDedge News

“The relative and absolute reductions in cardiovascular death and hospitalizations or urgent visits for heart failure were substantial, clinically important, and consistent in patients with or without type 2 diabetes,” John McMurray, MD, declared at the American Heart Association scientific sessions as he summarized new trial results that confirmed the initial finding he reported previously.

While the initial report of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) by the study’s lead investigator, Dr. McMurray, was limited to the finding that the relative risk reduction for the study’s primary endpoint was a highly statistically significant 25% in heart failure patients with diabetes and an equally strongly significant 27% relative cut among patients without diabetes (N Engl J Med. 2019 Sep 19;doi: 10.1056/NEJMoa1911303), the new data showed that same consistency across the range of outcomes studied in the trial as well as across the range of glycosylated hemoglobin levels that patients had at study entry.

In an analysis that divided the entire study population of 4,744 patients with heart failure with reduced ejection fraction (HFrEF) into tertiles based on their entry blood level of hemoglobin A^1c, patients with a normal level at or below 5.6% had a 26% relative reduction in the study’s primary endpoint, essentially the same response as the 29% relative cut in adverse events in the tertile of patients with a glycosylated hemoglobin level of 5.7%-5.9% and the relative 28% relative reduction in events in patients diagnosed with type 2 diabetes and having a hemoglobin A_1c of 6.0% or greater, reported Dr. McMurray, professor of cardiology at the University of Glasgow. The results also showed a very benign safety profile in the patients without diabetes, similar to patients with diabetes and to placebo, and with no episodes of major hypoglycemia or diabetic ketoacidosis.

“It’s quite impressive that the result was consistent regardless of the level of hemoglobin A_1c,” commented Larry A. Allen, MD, professor of medicine at the University of Colorado in Aurora and designated discussant for the report. Even though the patients without diabetes constituted just over half of the full DAPA-HF enrollment, the comparison of the effect of dapagliflozin in patients with or without diabetes was prespecified in a trial that enrolled a relatively large number of patients into each of the two subgroups by diabetes status. “I think there a good chance dapagliflozin will get an indication” for treating HFrEF patients without diabetes, Dr. Allen suggested in a video interview.

If the DAPA-HF results persuade the U.S. Food and Drug Administration to grant a supplemental indication to dapagliflozin for use in cutting cardiovascular deaths and acute heart failure exacerbations in patients without diabetes, it would pave the way for health insurers to pay for the drug. Right now, even though Dr. Allen and other heart failure physicians have been impressed by the DAPA-HF findings and are eager to add the drug to the list of agents that HFrEF patients routinely receive, he’s been stymied so far by patients’ out-of pocket cost for using dapagliflozin off-label, roughly $500 a month.

“The DAPA-HF results suggest there is strong reason to consider dapagliflozin for patients without diabetes, and for payers to pay for it. I’m not prescribing dapagliflozin to HFrEF patients without diabetes right now; not because of the data, but because of noncoverage. Payers have not yet caught up with the data,” he said, and they likely will continue to not pay for the drug when used by patients without diabetes until a new labeled indication appears for those patients.

The immediate availability of dapagliflozin (Farxiga) and the two other approved members of the sodium-glucose co-transporter 2 inhibitor class of drugs, empagliflozin (Jardiance) and canagliflozin (Invokana), to treat patients with HFrEF, and the prospect of soon having dapagliflozin and possibly the other drugs in this class to treat patients with HFrEF but without diabetes also raises issues of drug sequencing in these patients and the overall number of drugs that HFrEF patients must now take to be on optimized medical therapy, Dr. Allen noted.

The already-existing lineup of medications for HFrEF patients includes starting on an ACE inhibitor or angiotensin receptor blocker and adding a beta-blocker, a mineralocorticoid receptor antagonist, then swapping out the initial renin-angiotensin system inhibitor for sacubitril/valsartan, and then, on top of all this, adding dapagliflozin or another drug in the same class. It raises questions of what is objectively the best way to introduce all these drugs into patients, and how to do it without subjecting patients to “financial toxicity,” Dr. Allen said during his discussion of the trial’s results.

DAPA-HF was sponsored by AstraZeneca, which markets dapagliflozin (Farxiga). The University of Glasgow received payment from AstraZeneca to compensate for the time Dr. McMurray spent running the study. Dr. Allen has been a consultant to ACI Clinical, Boston Scientific, and Janssen.

[email protected]

SOURCE: McMurray JJV. AHA 19, Late-Breaking Science 1.

PHILADELPHIA – The primary outcome results from the practice-changing DAPA-HF trial gave clinicians strong evidence that the diabetes drug dapagliflozin was equally effective at reducing cardiovascular death and acute exacerbations in patients with heart failure with reduced ejection fraction, whether or not they also had type 2 diabetes. More detailed findings from the 2,605 enrolled patients in DAPA-HF who lacked diabetes (55% of the total study population) have now sealed the deal.

Mitchel L. Zoler/MDedge News

“The relative and absolute reductions in cardiovascular death and hospitalizations or urgent visits for heart failure were substantial, clinically important, and consistent in patients with or without type 2 diabetes,” John McMurray, MD, declared at the American Heart Association scientific sessions as he summarized new trial results that confirmed the initial finding he reported previously.

While the initial report of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) by the study’s lead investigator, Dr. McMurray, was limited to the finding that the relative risk reduction for the study’s primary endpoint was a highly statistically significant 25% in heart failure patients with diabetes and an equally strongly significant 27% relative cut among patients without diabetes (N Engl J Med. 2019 Sep 19;doi: 10.1056/NEJMoa1911303), the new data showed that same consistency across the range of outcomes studied in the trial as well as across the range of glycosylated hemoglobin levels that patients had at study entry.

In an analysis that divided the entire study population of 4,744 patients with heart failure with reduced ejection fraction (HFrEF) into tertiles based on their entry blood level of hemoglobin A^1c, patients with a normal level at or below 5.6% had a 26% relative reduction in the study’s primary endpoint, essentially the same response as the 29% relative cut in adverse events in the tertile of patients with a glycosylated hemoglobin level of 5.7%-5.9% and the relative 28% relative reduction in events in patients diagnosed with type 2 diabetes and having a hemoglobin A_1c of 6.0% or greater, reported Dr. McMurray, professor of cardiology at the University of Glasgow. The results also showed a very benign safety profile in the patients without diabetes, similar to patients with diabetes and to placebo, and with no episodes of major hypoglycemia or diabetic ketoacidosis.

“It’s quite impressive that the result was consistent regardless of the level of hemoglobin A_1c,” commented Larry A. Allen, MD, professor of medicine at the University of Colorado in Aurora and designated discussant for the report. Even though the patients without diabetes constituted just over half of the full DAPA-HF enrollment, the comparison of the effect of dapagliflozin in patients with or without diabetes was prespecified in a trial that enrolled a relatively large number of patients into each of the two subgroups by diabetes status. “I think there a good chance dapagliflozin will get an indication” for treating HFrEF patients without diabetes, Dr. Allen suggested in a video interview.

If the DAPA-HF results persuade the U.S. Food and Drug Administration to grant a supplemental indication to dapagliflozin for use in cutting cardiovascular deaths and acute heart failure exacerbations in patients without diabetes, it would pave the way for health insurers to pay for the drug. Right now, even though Dr. Allen and other heart failure physicians have been impressed by the DAPA-HF findings and are eager to add the drug to the list of agents that HFrEF patients routinely receive, he’s been stymied so far by patients’ out-of pocket cost for using dapagliflozin off-label, roughly $500 a month.

“The DAPA-HF results suggest there is strong reason to consider dapagliflozin for patients without diabetes, and for payers to pay for it. I’m not prescribing dapagliflozin to HFrEF patients without diabetes right now; not because of the data, but because of noncoverage. Payers have not yet caught up with the data,” he said, and they likely will continue to not pay for the drug when used by patients without diabetes until a new labeled indication appears for those patients.

The immediate availability of dapagliflozin (Farxiga) and the two other approved members of the sodium-glucose co-transporter 2 inhibitor class of drugs, empagliflozin (Jardiance) and canagliflozin (Invokana), to treat patients with HFrEF, and the prospect of soon having dapagliflozin and possibly the other drugs in this class to treat patients with HFrEF but without diabetes also raises issues of drug sequencing in these patients and the overall number of drugs that HFrEF patients must now take to be on optimized medical therapy, Dr. Allen noted.

The already-existing lineup of medications for HFrEF patients includes starting on an ACE inhibitor or angiotensin receptor blocker and adding a beta-blocker, a mineralocorticoid receptor antagonist, then swapping out the initial renin-angiotensin system inhibitor for sacubitril/valsartan, and then, on top of all this, adding dapagliflozin or another drug in the same class. It raises questions of what is objectively the best way to introduce all these drugs into patients, and how to do it without subjecting patients to “financial toxicity,” Dr. Allen said during his discussion of the trial’s results.

DAPA-HF was sponsored by AstraZeneca, which markets dapagliflozin (Farxiga). The University of Glasgow received payment from AstraZeneca to compensate for the time Dr. McMurray spent running the study. Dr. Allen has been a consultant to ACI Clinical, Boston Scientific, and Janssen.

[email protected]

SOURCE: McMurray JJV. AHA 19, Late-Breaking Science 1.

Icosapent ethyl, a highly purified form of the ethyl ester of eicosapentaenoic acid, received unanimous backing from a Food and Drug Administration advisory panel for a new indication for reducing cardiovascular event risk.

Icosapent ethyl (Vascepa) received initial agency approval in 2012 for the indication of cutting triglyceride levels once they reached at least 500 mg/dL.

The target patient population for this new, cardiovascular-event protection role will reflect some or all of the types of patients enrolled in REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial), which tested icosapent ethyl in 8,179 patients with either established cardiovascular disease or diabetes and at least one additional cardiovascular disease risk factor. This study provided the bulk of the data considered by the FDA panel.

REDUCE-IT showed that, during a median of 4.9 years, patients who received icosapent ethyl had a statistically significant 25% relative risk reduction in the trial’s primary, composite endpoint (New Engl J Med. 2019 Jan 3;380[1]:11-22).

Icosapent ethyl “appeared effective and safe,” and would be a “useful, new, added agent for treating patients” like those enrolled in the trial, said Kenneth D. Burman, MD, professor and chief of endocrinology at Medstar Washington (D.C.) Hospital Center and chair of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee.

The advisory panel members appeared uniformly comfortable with recommending that the FDA add a cardiovascular disease indication based on the REDUCE-IT findings.

But while they agreed that icosapent ethyl should receive some type of indication for cardiovascular event reduction, the committee split over which patients the indication should include. Specifically, they diverged on the issue of primary prevention.

Some said that the patient enrollment that produced a positive result in REDUCE-IT should not be retrospectively subdivided, while others said that combining secondary- and primary-prevention patients in a single large trial inappropriately lumped together patients who would be better considered separately.

Committee members also expressed uncertainty over the appropriate triglyceride level to warrant treatment. The REDUCE-IT trial was designed to enroll patients with triglycerides of 135 mg/dL or greater, but several panel members suggested that, for labeling, the threshold should be at least 150 mg/dL, or even 200 mg/dL.

Safety was another aspect that generated a lot of panel discussion throughout their day-long discussion, with particular focus on a signal of a small but concerning increased rate of incident atrial fibrillation among patients who received icosapent ethyl, as well as a small but nearly significant increase in the rate of serious bleeds.

Further analyses presented during the meeting showed that an increased bleeding rate linked with icosapent ethyl was focused in patients who concurrently received one or more antiplatelet drugs or an anticoagulant.

However, panel members rejected the notion that these safety concerns warranted a boxed warning, agreeing that it could be managed with appropriate labeling information.

Clinician reaction

Clinicians who manage these types of patients viewed the prospect of an expanded indication for icosapent ethyl as an important advance.

The REDUCE-IT results by themselves “were convincing” for patients with established cardiovascular disease without need for a confirmatory trial, Robert H. Eckel, MD, an endocrinologist and professor of medicine at the University of Colorado at Denver, Aurora, said in an interview. But he remained unconvinced about efficacy for primary-prevention patients, or even for secondary-prevention patients with a triglyceride level below 150 mg/dL.

“Icosapent ethyl will clearly be a mainstay for managing high-risk patients. It gives us another treatment option,” Yehuda Handelsman, MD, an endocrinologist and medical director and principal investigator of the Metabolic Institute of America in Tarzana, Calif., said in an interview. “I do not see the atrial fibrillation or bleeding effects as reasons not to approve this drug. It should be a precaution. Overall, icosapent ethyl is one of the easier drugs for patients to take.”

Dr. Handelsman said it would be unethical to run a confirmatory trial and randomize patients to placebo. “Another trial makes no sense,” he said.

But the data from REDUCE-IT were “not as convincing” for primary-prevention patients, suggesting a need for caution about using icosapent ethyl for patients without established cardiovascular disease, Paul S. Jellinger, MD, an endocrinologist in Fort Lauderdale, Fla., said in an interview.

Cost-effectiveness

An analysis of the cost-effectiveness of icosapent ethyl as used in REDUCE-IT showed that the drug fell into the rare category of being a “dominant” treatment, meaning that it both improved patient outcomes and reduced medical costs. William S. Weintraub, MD, will report findings from this analysis on Nov. 16, 2019, at the annual scientific sessions of the American Heart Association.

The analysis used a wholesale acquisition cost for a 1-day dosage of icosapent ethyl of $4.16, derived from a commercial source for prescription-drug pricing and actual hospitalization costs for the patients in the trial.

Based on the REDUCE-IT outcomes, treatment with icosapent ethyl was linked with a boost in quality-adjusted life-years that extrapolated to an average 0.26 increase during the full lifetime of REDUCE-IT participants, at a cost that averaged $1,284 less per treated patient over their lifetime, according to Dr. Weintraub, director of Outcomes Research at Medstar Washington Hospital Center, Washington.

Although the 0.26 lifetime increase in quality-adjusted life-years may sound modest, “in the cost-effectiveness world, 0.26 is actually significant,” Dr. Weintraub said. He also highlighted how unusual it is to find a patented drug that improves quality of life and longevity while also saving money.

“I know of no other on-patent, branded pharmaceutical that is dominant,” he said.

Off-patent pharmaceuticals, like statins, can be quite inexpensive and may also be dominant, he noted. Being dominant for cost-effectiveness means that icosapent ethyl “provides good value and is worth what we pay for it, well within social thresholds of willingness to pay,” Dr. Weintraub said.

REDUCE-IT was sponsored by Amarin, the company that markets icosapent ethyl (Vascepa). Dr. Burman has received research funding from AstraZeneca, Eisai, and IBSA. Dr. Eckel has received personal fees from Kowa Pharmaceuticals, Merck, Novartis, and Sanofi/Regeneron, as well as research funding from Endece, Ionis Pharmaceuticals, and UniQure. Dr. Handelsman has been a consultant to and received research funding from Amarin and several other companies. Dr. Jellinger has been a speaker on behalf of Amarin, Amgen, and Regeneron. Dr. Weintraub has received honoraria and research support from Amarin, and honoraria from AstraZeneca.

[email protected]

Icosapent ethyl, a highly purified form of the ethyl ester of eicosapentaenoic acid, received unanimous backing from a Food and Drug Administration advisory panel for a new indication for reducing cardiovascular event risk.

Icosapent ethyl (Vascepa) received initial agency approval in 2012 for the indication of cutting triglyceride levels once they reached at least 500 mg/dL.

The target patient population for this new, cardiovascular-event protection role will reflect some or all of the types of patients enrolled in REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial), which tested icosapent ethyl in 8,179 patients with either established cardiovascular disease or diabetes and at least one additional cardiovascular disease risk factor. This study provided the bulk of the data considered by the FDA panel.

REDUCE-IT showed that, during a median of 4.9 years, patients who received icosapent ethyl had a statistically significant 25% relative risk reduction in the trial’s primary, composite endpoint (New Engl J Med. 2019 Jan 3;380[1]:11-22).

Icosapent ethyl “appeared effective and safe,” and would be a “useful, new, added agent for treating patients” like those enrolled in the trial, said Kenneth D. Burman, MD, professor and chief of endocrinology at Medstar Washington (D.C.) Hospital Center and chair of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee.

The advisory panel members appeared uniformly comfortable with recommending that the FDA add a cardiovascular disease indication based on the REDUCE-IT findings.

But while they agreed that icosapent ethyl should receive some type of indication for cardiovascular event reduction, the committee split over which patients the indication should include. Specifically, they diverged on the issue of primary prevention.

Some said that the patient enrollment that produced a positive result in REDUCE-IT should not be retrospectively subdivided, while others said that combining secondary- and primary-prevention patients in a single large trial inappropriately lumped together patients who would be better considered separately.

Committee members also expressed uncertainty over the appropriate triglyceride level to warrant treatment. The REDUCE-IT trial was designed to enroll patients with triglycerides of 135 mg/dL or greater, but several panel members suggested that, for labeling, the threshold should be at least 150 mg/dL, or even 200 mg/dL.

Safety was another aspect that generated a lot of panel discussion throughout their day-long discussion, with particular focus on a signal of a small but concerning increased rate of incident atrial fibrillation among patients who received icosapent ethyl, as well as a small but nearly significant increase in the rate of serious bleeds.

Further analyses presented during the meeting showed that an increased bleeding rate linked with icosapent ethyl was focused in patients who concurrently received one or more antiplatelet drugs or an anticoagulant.

However, panel members rejected the notion that these safety concerns warranted a boxed warning, agreeing that it could be managed with appropriate labeling information.

Clinician reaction

Clinicians who manage these types of patients viewed the prospect of an expanded indication for icosapent ethyl as an important advance.

The REDUCE-IT results by themselves “were convincing” for patients with established cardiovascular disease without need for a confirmatory trial, Robert H. Eckel, MD, an endocrinologist and professor of medicine at the University of Colorado at Denver, Aurora, said in an interview. But he remained unconvinced about efficacy for primary-prevention patients, or even for secondary-prevention patients with a triglyceride level below 150 mg/dL.

“Icosapent ethyl will clearly be a mainstay for managing high-risk patients. It gives us another treatment option,” Yehuda Handelsman, MD, an endocrinologist and medical director and principal investigator of the Metabolic Institute of America in Tarzana, Calif., said in an interview. “I do not see the atrial fibrillation or bleeding effects as reasons not to approve this drug. It should be a precaution. Overall, icosapent ethyl is one of the easier drugs for patients to take.”

Dr. Handelsman said it would be unethical to run a confirmatory trial and randomize patients to placebo. “Another trial makes no sense,” he said.

But the data from REDUCE-IT were “not as convincing” for primary-prevention patients, suggesting a need for caution about using icosapent ethyl for patients without established cardiovascular disease, Paul S. Jellinger, MD, an endocrinologist in Fort Lauderdale, Fla., said in an interview.

Cost-effectiveness

An analysis of the cost-effectiveness of icosapent ethyl as used in REDUCE-IT showed that the drug fell into the rare category of being a “dominant” treatment, meaning that it both improved patient outcomes and reduced medical costs. William S. Weintraub, MD, will report findings from this analysis on Nov. 16, 2019, at the annual scientific sessions of the American Heart Association.

The analysis used a wholesale acquisition cost for a 1-day dosage of icosapent ethyl of $4.16, derived from a commercial source for prescription-drug pricing and actual hospitalization costs for the patients in the trial.

Based on the REDUCE-IT outcomes, treatment with icosapent ethyl was linked with a boost in quality-adjusted life-years that extrapolated to an average 0.26 increase during the full lifetime of REDUCE-IT participants, at a cost that averaged $1,284 less per treated patient over their lifetime, according to Dr. Weintraub, director of Outcomes Research at Medstar Washington Hospital Center, Washington.

Although the 0.26 lifetime increase in quality-adjusted life-years may sound modest, “in the cost-effectiveness world, 0.26 is actually significant,” Dr. Weintraub said. He also highlighted how unusual it is to find a patented drug that improves quality of life and longevity while also saving money.

“I know of no other on-patent, branded pharmaceutical that is dominant,” he said.

Off-patent pharmaceuticals, like statins, can be quite inexpensive and may also be dominant, he noted. Being dominant for cost-effectiveness means that icosapent ethyl “provides good value and is worth what we pay for it, well within social thresholds of willingness to pay,” Dr. Weintraub said.

REDUCE-IT was sponsored by Amarin, the company that markets icosapent ethyl (Vascepa). Dr. Burman has received research funding from AstraZeneca, Eisai, and IBSA. Dr. Eckel has received personal fees from Kowa Pharmaceuticals, Merck, Novartis, and Sanofi/Regeneron, as well as research funding from Endece, Ionis Pharmaceuticals, and UniQure. Dr. Handelsman has been a consultant to and received research funding from Amarin and several other companies. Dr. Jellinger has been a speaker on behalf of Amarin, Amgen, and Regeneron. Dr. Weintraub has received honoraria and research support from Amarin, and honoraria from AstraZeneca.

[email protected]

Icosapent ethyl, a highly purified form of the ethyl ester of eicosapentaenoic acid, received unanimous backing from a Food and Drug Administration advisory panel for a new indication for reducing cardiovascular event risk.

Icosapent ethyl (Vascepa) received initial agency approval in 2012 for the indication of cutting triglyceride levels once they reached at least 500 mg/dL.

The target patient population for this new, cardiovascular-event protection role will reflect some or all of the types of patients enrolled in REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial), which tested icosapent ethyl in 8,179 patients with either established cardiovascular disease or diabetes and at least one additional cardiovascular disease risk factor. This study provided the bulk of the data considered by the FDA panel.

REDUCE-IT showed that, during a median of 4.9 years, patients who received icosapent ethyl had a statistically significant 25% relative risk reduction in the trial’s primary, composite endpoint (New Engl J Med. 2019 Jan 3;380[1]:11-22).

Icosapent ethyl “appeared effective and safe,” and would be a “useful, new, added agent for treating patients” like those enrolled in the trial, said Kenneth D. Burman, MD, professor and chief of endocrinology at Medstar Washington (D.C.) Hospital Center and chair of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee.

The advisory panel members appeared uniformly comfortable with recommending that the FDA add a cardiovascular disease indication based on the REDUCE-IT findings.

But while they agreed that icosapent ethyl should receive some type of indication for cardiovascular event reduction, the committee split over which patients the indication should include. Specifically, they diverged on the issue of primary prevention.

Some said that the patient enrollment that produced a positive result in REDUCE-IT should not be retrospectively subdivided, while others said that combining secondary- and primary-prevention patients in a single large trial inappropriately lumped together patients who would be better considered separately.

Committee members also expressed uncertainty over the appropriate triglyceride level to warrant treatment. The REDUCE-IT trial was designed to enroll patients with triglycerides of 135 mg/dL or greater, but several panel members suggested that, for labeling, the threshold should be at least 150 mg/dL, or even 200 mg/dL.

Safety was another aspect that generated a lot of panel discussion throughout their day-long discussion, with particular focus on a signal of a small but concerning increased rate of incident atrial fibrillation among patients who received icosapent ethyl, as well as a small but nearly significant increase in the rate of serious bleeds.

Further analyses presented during the meeting showed that an increased bleeding rate linked with icosapent ethyl was focused in patients who concurrently received one or more antiplatelet drugs or an anticoagulant.

However, panel members rejected the notion that these safety concerns warranted a boxed warning, agreeing that it could be managed with appropriate labeling information.

Clinician reaction

Clinicians who manage these types of patients viewed the prospect of an expanded indication for icosapent ethyl as an important advance.

The REDUCE-IT results by themselves “were convincing” for patients with established cardiovascular disease without need for a confirmatory trial, Robert H. Eckel, MD, an endocrinologist and professor of medicine at the University of Colorado at Denver, Aurora, said in an interview. But he remained unconvinced about efficacy for primary-prevention patients, or even for secondary-prevention patients with a triglyceride level below 150 mg/dL.

“Icosapent ethyl will clearly be a mainstay for managing high-risk patients. It gives us another treatment option,” Yehuda Handelsman, MD, an endocrinologist and medical director and principal investigator of the Metabolic Institute of America in Tarzana, Calif., said in an interview. “I do not see the atrial fibrillation or bleeding effects as reasons not to approve this drug. It should be a precaution. Overall, icosapent ethyl is one of the easier drugs for patients to take.”

Dr. Handelsman said it would be unethical to run a confirmatory trial and randomize patients to placebo. “Another trial makes no sense,” he said.

But the data from REDUCE-IT were “not as convincing” for primary-prevention patients, suggesting a need for caution about using icosapent ethyl for patients without established cardiovascular disease, Paul S. Jellinger, MD, an endocrinologist in Fort Lauderdale, Fla., said in an interview.

Cost-effectiveness

An analysis of the cost-effectiveness of icosapent ethyl as used in REDUCE-IT showed that the drug fell into the rare category of being a “dominant” treatment, meaning that it both improved patient outcomes and reduced medical costs. William S. Weintraub, MD, will report findings from this analysis on Nov. 16, 2019, at the annual scientific sessions of the American Heart Association.

The analysis used a wholesale acquisition cost for a 1-day dosage of icosapent ethyl of $4.16, derived from a commercial source for prescription-drug pricing and actual hospitalization costs for the patients in the trial.

Based on the REDUCE-IT outcomes, treatment with icosapent ethyl was linked with a boost in quality-adjusted life-years that extrapolated to an average 0.26 increase during the full lifetime of REDUCE-IT participants, at a cost that averaged $1,284 less per treated patient over their lifetime, according to Dr. Weintraub, director of Outcomes Research at Medstar Washington Hospital Center, Washington.

Although the 0.26 lifetime increase in quality-adjusted life-years may sound modest, “in the cost-effectiveness world, 0.26 is actually significant,” Dr. Weintraub said. He also highlighted how unusual it is to find a patented drug that improves quality of life and longevity while also saving money.

“I know of no other on-patent, branded pharmaceutical that is dominant,” he said.

Off-patent pharmaceuticals, like statins, can be quite inexpensive and may also be dominant, he noted. Being dominant for cost-effectiveness means that icosapent ethyl “provides good value and is worth what we pay for it, well within social thresholds of willingness to pay,” Dr. Weintraub said.

REDUCE-IT was sponsored by Amarin, the company that markets icosapent ethyl (Vascepa). Dr. Burman has received research funding from AstraZeneca, Eisai, and IBSA. Dr. Eckel has received personal fees from Kowa Pharmaceuticals, Merck, Novartis, and Sanofi/Regeneron, as well as research funding from Endece, Ionis Pharmaceuticals, and UniQure. Dr. Handelsman has been a consultant to and received research funding from Amarin and several other companies. Dr. Jellinger has been a speaker on behalf of Amarin, Amgen, and Regeneron. Dr. Weintraub has received honoraria and research support from Amarin, and honoraria from AstraZeneca.

[email protected]

CHICAGO – A new image-analysis algorithm for benign thyroid nodules that uses a technique similar to facial recognition showed good sensitivity and specificity, with the potential to reduce biopsies by more than 50%.

The negative predictive value of the ultrasound analysis algorithm was 93.2%, a figure approximating the false-negative rate of about 5% that is seen in fine-needle aspiration of thyroid nodules, said Johnson Thomas, MD, at the annual meeting of the American Thyroid Association.

“Millions of people have thyroid nodules,” many of which are detected incidentally, said Dr. Thomas, an endocrinologist with the Mercy health care system in Springfield, Mo. Fewer than 10% of thyroid nodules turn out to be malignant, but each year, millions of patients undergo biopsies to determine the status of their thyroid nodules.

Faced with evaluating a thyroid nodule, an endocrinologist can currently turn to a risk-stratification scheme, such as those developed by the American College of Radiology and the American Thyroid Association. However, there’s a big subjective component to risk stratification – significant inter- and intraobserver variation has been observed, said Dr. Thomas, and not all nodules are classifiable. The result is a system that still has low specificity and positive predictive value, he said.

Even after a decision to proceed to biopsy, one in seven thyroid nodule biopsies will not produce a definitive diagnosis, he said.

“We are doing millions of thyroid biopsies based on very subjective criteria to find thyroid cancer in a very small percentage of the population, with an invasive technique that may not be diagnostic one out of seven times,” Dr. Thomas said in summing up the current medical situation as he sees it.

Dr. Thomas, who writes his own computer code, said he was searching for a reliable and explainable noninvasive technique, and one that lacked subjective room for error, to address the thyroid nodule problem.

The question was whether an artificial intelligence (AI) algorithm could match radiologist performance in classifying thyroid nodules according to the characteristics of their ultrasound images.

Other algorithms use AI to predict which nodules are malignant, but they function as “black boxes” – a common criticism of AI. The outside observer cannot ordinarily see how the AI algorithm “knows” what it knows. This characteristic of AI poses at least a theoretical problem when such algorithms are used for diagnosis or medical decision making.

Dr. Thomas’s* approach was to use a set of training data to allow the algorithm he constructed to see 2,025 images from a total of 482 nodules. The thyroid nodules used for training had been subjected to biopsy or excised in surgery, so they all had a definitive status of being benign or malignant.

Then, after the algorithm was refined, a set of 103 nodules with known malignancy status was used to test the algorithm’s sensitivity and specificity.

The algorithm, dubbed AiBx, used a convolutional neural network to build a unique image vector for each nodule. The AiBx algorithm then looked at the training database to find the “nearest neighbors,” or the images it found to be the most similar to those of the nodule being examined.

For example, said Dr. Thomas, a test image of a benign nodule would have an output from the AiBx analysis of three similar images from the database – all benign. Hence, rather than making a black-box call of whether a nodule is benign or malignant, the algorithm merely says: “This nodule resembles a benign nodule in our database.” The interpreting physician can then use the algorithm as a decision aid with confidence.

The overall accuracy of AiBx was 81.5%, sensitivity was 87.8%, and specificity was 78.5%. Positive predictive value was 65.9%.

As more images are added to the database, AiBx can easily be retrained and refined, said Dr. Thomas.

“It’s intuitive and explainable,” he added, noting that the algorithm is also a good teaching tool for residents and fellows.

“This AI model can be deployed as an app, integrated with [medical imaging systems] or hosted as a website. By using image-similarity AI models we can eliminate subjectivity and decrease the number of unnecessary biopsies,” he explained in the abstract accompanying the presentation.

However, he said that the algorithm as it currently stands has limitations: It has been tested on only 103 images thus far, and there’s the potential for selection bias.

Dr. Thomas* reported that, although he developed the AiBx algorithm, he has not drawn income or royalties from it. He reported no other relevant conflicts of interest.
 

SOURCE: Thomas* J et al. ATA 2019, Oral Abstract 27.

*Correction, 21/11/2019: An earlier version of this story misstated Dr. Thomas's last name.

CHICAGO – A new image-analysis algorithm for benign thyroid nodules that uses a technique similar to facial recognition showed good sensitivity and specificity, with the potential to reduce biopsies by more than 50%.

The negative predictive value of the ultrasound analysis algorithm was 93.2%, a figure approximating the false-negative rate of about 5% that is seen in fine-needle aspiration of thyroid nodules, said Johnson Thomas, MD, at the annual meeting of the American Thyroid Association.

“Millions of people have thyroid nodules,” many of which are detected incidentally, said Dr. Thomas, an endocrinologist with the Mercy health care system in Springfield, Mo. Fewer than 10% of thyroid nodules turn out to be malignant, but each year, millions of patients undergo biopsies to determine the status of their thyroid nodules.

Faced with evaluating a thyroid nodule, an endocrinologist can currently turn to a risk-stratification scheme, such as those developed by the American College of Radiology and the American Thyroid Association. However, there’s a big subjective component to risk stratification – significant inter- and intraobserver variation has been observed, said Dr. Thomas, and not all nodules are classifiable. The result is a system that still has low specificity and positive predictive value, he said.

Even after a decision to proceed to biopsy, one in seven thyroid nodule biopsies will not produce a definitive diagnosis, he said.

“We are doing millions of thyroid biopsies based on very subjective criteria to find thyroid cancer in a very small percentage of the population, with an invasive technique that may not be diagnostic one out of seven times,” Dr. Thomas said in summing up the current medical situation as he sees it.

Dr. Thomas, who writes his own computer code, said he was searching for a reliable and explainable noninvasive technique, and one that lacked subjective room for error, to address the thyroid nodule problem.

The question was whether an artificial intelligence (AI) algorithm could match radiologist performance in classifying thyroid nodules according to the characteristics of their ultrasound images.

Other algorithms use AI to predict which nodules are malignant, but they function as “black boxes” – a common criticism of AI. The outside observer cannot ordinarily see how the AI algorithm “knows” what it knows. This characteristic of AI poses at least a theoretical problem when such algorithms are used for diagnosis or medical decision making.

Dr. Thomas’s* approach was to use a set of training data to allow the algorithm he constructed to see 2,025 images from a total of 482 nodules. The thyroid nodules used for training had been subjected to biopsy or excised in surgery, so they all had a definitive status of being benign or malignant.

Then, after the algorithm was refined, a set of 103 nodules with known malignancy status was used to test the algorithm’s sensitivity and specificity.

The algorithm, dubbed AiBx, used a convolutional neural network to build a unique image vector for each nodule. The AiBx algorithm then looked at the training database to find the “nearest neighbors,” or the images it found to be the most similar to those of the nodule being examined.

For example, said Dr. Thomas, a test image of a benign nodule would have an output from the AiBx analysis of three similar images from the database – all benign. Hence, rather than making a black-box call of whether a nodule is benign or malignant, the algorithm merely says: “This nodule resembles a benign nodule in our database.” The interpreting physician can then use the algorithm as a decision aid with confidence.

The overall accuracy of AiBx was 81.5%, sensitivity was 87.8%, and specificity was 78.5%. Positive predictive value was 65.9%.

As more images are added to the database, AiBx can easily be retrained and refined, said Dr. Thomas.

“It’s intuitive and explainable,” he added, noting that the algorithm is also a good teaching tool for residents and fellows.

“This AI model can be deployed as an app, integrated with [medical imaging systems] or hosted as a website. By using image-similarity AI models we can eliminate subjectivity and decrease the number of unnecessary biopsies,” he explained in the abstract accompanying the presentation.

However, he said that the algorithm as it currently stands has limitations: It has been tested on only 103 images thus far, and there’s the potential for selection bias.

Dr. Thomas* reported that, although he developed the AiBx algorithm, he has not drawn income or royalties from it. He reported no other relevant conflicts of interest.
 

SOURCE: Thomas* J et al. ATA 2019, Oral Abstract 27.

*Correction, 21/11/2019: An earlier version of this story misstated Dr. Thomas's last name.

CHICAGO – A new image-analysis algorithm for benign thyroid nodules that uses a technique similar to facial recognition showed good sensitivity and specificity, with the potential to reduce biopsies by more than 50%.

The negative predictive value of the ultrasound analysis algorithm was 93.2%, a figure approximating the false-negative rate of about 5% that is seen in fine-needle aspiration of thyroid nodules, said Johnson Thomas, MD, at the annual meeting of the American Thyroid Association.

“Millions of people have thyroid nodules,” many of which are detected incidentally, said Dr. Thomas, an endocrinologist with the Mercy health care system in Springfield, Mo. Fewer than 10% of thyroid nodules turn out to be malignant, but each year, millions of patients undergo biopsies to determine the status of their thyroid nodules.

Faced with evaluating a thyroid nodule, an endocrinologist can currently turn to a risk-stratification scheme, such as those developed by the American College of Radiology and the American Thyroid Association. However, there’s a big subjective component to risk stratification – significant inter- and intraobserver variation has been observed, said Dr. Thomas, and not all nodules are classifiable. The result is a system that still has low specificity and positive predictive value, he said.

Even after a decision to proceed to biopsy, one in seven thyroid nodule biopsies will not produce a definitive diagnosis, he said.

“We are doing millions of thyroid biopsies based on very subjective criteria to find thyroid cancer in a very small percentage of the population, with an invasive technique that may not be diagnostic one out of seven times,” Dr. Thomas said in summing up the current medical situation as he sees it.

Dr. Thomas, who writes his own computer code, said he was searching for a reliable and explainable noninvasive technique, and one that lacked subjective room for error, to address the thyroid nodule problem.

The question was whether an artificial intelligence (AI) algorithm could match radiologist performance in classifying thyroid nodules according to the characteristics of their ultrasound images.

Other algorithms use AI to predict which nodules are malignant, but they function as “black boxes” – a common criticism of AI. The outside observer cannot ordinarily see how the AI algorithm “knows” what it knows. This characteristic of AI poses at least a theoretical problem when such algorithms are used for diagnosis or medical decision making.

Dr. Thomas’s* approach was to use a set of training data to allow the algorithm he constructed to see 2,025 images from a total of 482 nodules. The thyroid nodules used for training had been subjected to biopsy or excised in surgery, so they all had a definitive status of being benign or malignant.

Then, after the algorithm was refined, a set of 103 nodules with known malignancy status was used to test the algorithm’s sensitivity and specificity.

The algorithm, dubbed AiBx, used a convolutional neural network to build a unique image vector for each nodule. The AiBx algorithm then looked at the training database to find the “nearest neighbors,” or the images it found to be the most similar to those of the nodule being examined.

For example, said Dr. Thomas, a test image of a benign nodule would have an output from the AiBx analysis of three similar images from the database – all benign. Hence, rather than making a black-box call of whether a nodule is benign or malignant, the algorithm merely says: “This nodule resembles a benign nodule in our database.” The interpreting physician can then use the algorithm as a decision aid with confidence.

The overall accuracy of AiBx was 81.5%, sensitivity was 87.8%, and specificity was 78.5%. Positive predictive value was 65.9%.

As more images are added to the database, AiBx can easily be retrained and refined, said Dr. Thomas.

“It’s intuitive and explainable,” he added, noting that the algorithm is also a good teaching tool for residents and fellows.

“This AI model can be deployed as an app, integrated with [medical imaging systems] or hosted as a website. By using image-similarity AI models we can eliminate subjectivity and decrease the number of unnecessary biopsies,” he explained in the abstract accompanying the presentation.

However, he said that the algorithm as it currently stands has limitations: It has been tested on only 103 images thus far, and there’s the potential for selection bias.

Dr. Thomas* reported that, although he developed the AiBx algorithm, he has not drawn income or royalties from it. He reported no other relevant conflicts of interest.
 

SOURCE: Thomas* J et al. ATA 2019, Oral Abstract 27.

*Correction, 21/11/2019: An earlier version of this story misstated Dr. Thomas's last name.

In honor of Diabetes Awareness Month, The Hospitalist spoke recently with Stephanie Dizon, PharmD, BCPS, director of pharmacy at Dignity Health Sequoia Hospital in Redwood City, Calif. Dr. Dizon was the project lead for Dignity Health Sequoia’s participation in the Society of Hospital Medicine’s Glycemic Control eQUIPS program. The Northern California hospital was recognized as a top performer in the program.

SHM’s eQUIPS offers a virtual library of resources, including a step-by-step implementation guide, that addresses various issues that range from subcutaneous insulin protocols to care coordination and good hypoglycemia management. In addition, the program offers access to a data center for performance tracking and benchmarking.

Dr. Dizon shared her experience as a participant in the program, and explained its impact on glycemic control at Dignity Health Sequoia Hospital.
 

Could you tell us about your personal involvement with SHM?

I started as the quality lead for glycemic control for Sequoia Hospital in 2017 while serving in the role as the clinical pharmacy manager. Currently, I am the director of pharmacy.

What inspired your institution to enroll in the GC eQUIPS program? What were the challenges it helped you address?

Sequoia Hospital started in this journey to improve overall glycemic control in a collaborative with eight other Dignity Health hospitals in 2011. At Sequoia Hospital, this effort was led by Karen Harrison, RN, MSN, CCRN. At the time, Dignity Health saw variations in insulin management and adverse events, and it inspired this group to review their practices and try to find a better way to standardize them. The hope was that sharing information and making efforts to standardize practices would lead to better glycemic control.

Enrollment in the GC eQUIPS program helped Sequoia Hospital efficiently analyze data that would otherwise be too large to manage. In addition, by tracking and trending these large data sets, it helped us not only to see where the hospital’s greatest challenges are in glycemic control but also observe what the impact is when making changes. We were part of a nine-site study that proved the effectiveness of GC eQUIPS and highlighted the collective success across the health system.
 

What did you find most useful in the suite of resources included in eQUIPS?

The benchmarking webinars and informational webinars that have been provided by Greg Maynard, MD, over the years have been especially helpful. They have broadened my understanding of glycemic control. The glucometrics database is especially helpful for tracking and trending – we share these reports on a monthly basis with nursing and provider leadership. In addition, being able to benchmark ourselves with other hospitals pushes us to improve and keep an eye on glycemic control.

Are there any other highlights from your participation– and your institution’s – in the program that you feel would be beneficial to others who may be considering enrollment?

Having access to the tools available in the GC eQUIPS program is very powerful for data analysis and benchmarking. As a result, it allows the people at an institution to focus on the day-to-day tasks, clinical initiatives, and building a culture that can make a program successful instead of focusing on data collection.

For more information on SHM’s Glycemic Control resources or to enroll in eQUIPS, visit hospitalmedicine.org/gc.

In honor of Diabetes Awareness Month, The Hospitalist spoke recently with Stephanie Dizon, PharmD, BCPS, director of pharmacy at Dignity Health Sequoia Hospital in Redwood City, Calif. Dr. Dizon was the project lead for Dignity Health Sequoia’s participation in the Society of Hospital Medicine’s Glycemic Control eQUIPS program. The Northern California hospital was recognized as a top performer in the program.

SHM’s eQUIPS offers a virtual library of resources, including a step-by-step implementation guide, that addresses various issues that range from subcutaneous insulin protocols to care coordination and good hypoglycemia management. In addition, the program offers access to a data center for performance tracking and benchmarking.

Dr. Dizon shared her experience as a participant in the program, and explained its impact on glycemic control at Dignity Health Sequoia Hospital.
 

Could you tell us about your personal involvement with SHM?

I started as the quality lead for glycemic control for Sequoia Hospital in 2017 while serving in the role as the clinical pharmacy manager. Currently, I am the director of pharmacy.

What inspired your institution to enroll in the GC eQUIPS program? What were the challenges it helped you address?

Sequoia Hospital started in this journey to improve overall glycemic control in a collaborative with eight other Dignity Health hospitals in 2011. At Sequoia Hospital, this effort was led by Karen Harrison, RN, MSN, CCRN. At the time, Dignity Health saw variations in insulin management and adverse events, and it inspired this group to review their practices and try to find a better way to standardize them. The hope was that sharing information and making efforts to standardize practices would lead to better glycemic control.

Enrollment in the GC eQUIPS program helped Sequoia Hospital efficiently analyze data that would otherwise be too large to manage. In addition, by tracking and trending these large data sets, it helped us not only to see where the hospital’s greatest challenges are in glycemic control but also observe what the impact is when making changes. We were part of a nine-site study that proved the effectiveness of GC eQUIPS and highlighted the collective success across the health system.
 

What did you find most useful in the suite of resources included in eQUIPS?

The benchmarking webinars and informational webinars that have been provided by Greg Maynard, MD, over the years have been especially helpful. They have broadened my understanding of glycemic control. The glucometrics database is especially helpful for tracking and trending – we share these reports on a monthly basis with nursing and provider leadership. In addition, being able to benchmark ourselves with other hospitals pushes us to improve and keep an eye on glycemic control.

Are there any other highlights from your participation– and your institution’s – in the program that you feel would be beneficial to others who may be considering enrollment?

Having access to the tools available in the GC eQUIPS program is very powerful for data analysis and benchmarking. As a result, it allows the people at an institution to focus on the day-to-day tasks, clinical initiatives, and building a culture that can make a program successful instead of focusing on data collection.

For more information on SHM’s Glycemic Control resources or to enroll in eQUIPS, visit hospitalmedicine.org/gc.

In honor of Diabetes Awareness Month, The Hospitalist spoke recently with Stephanie Dizon, PharmD, BCPS, director of pharmacy at Dignity Health Sequoia Hospital in Redwood City, Calif. Dr. Dizon was the project lead for Dignity Health Sequoia’s participation in the Society of Hospital Medicine’s Glycemic Control eQUIPS program. The Northern California hospital was recognized as a top performer in the program.

SHM’s eQUIPS offers a virtual library of resources, including a step-by-step implementation guide, that addresses various issues that range from subcutaneous insulin protocols to care coordination and good hypoglycemia management. In addition, the program offers access to a data center for performance tracking and benchmarking.

Dr. Dizon shared her experience as a participant in the program, and explained its impact on glycemic control at Dignity Health Sequoia Hospital.
 

Could you tell us about your personal involvement with SHM?

I started as the quality lead for glycemic control for Sequoia Hospital in 2017 while serving in the role as the clinical pharmacy manager. Currently, I am the director of pharmacy.

What inspired your institution to enroll in the GC eQUIPS program? What were the challenges it helped you address?

Sequoia Hospital started in this journey to improve overall glycemic control in a collaborative with eight other Dignity Health hospitals in 2011. At Sequoia Hospital, this effort was led by Karen Harrison, RN, MSN, CCRN. At the time, Dignity Health saw variations in insulin management and adverse events, and it inspired this group to review their practices and try to find a better way to standardize them. The hope was that sharing information and making efforts to standardize practices would lead to better glycemic control.

Enrollment in the GC eQUIPS program helped Sequoia Hospital efficiently analyze data that would otherwise be too large to manage. In addition, by tracking and trending these large data sets, it helped us not only to see where the hospital’s greatest challenges are in glycemic control but also observe what the impact is when making changes. We were part of a nine-site study that proved the effectiveness of GC eQUIPS and highlighted the collective success across the health system.
 

What did you find most useful in the suite of resources included in eQUIPS?

The benchmarking webinars and informational webinars that have been provided by Greg Maynard, MD, over the years have been especially helpful. They have broadened my understanding of glycemic control. The glucometrics database is especially helpful for tracking and trending – we share these reports on a monthly basis with nursing and provider leadership. In addition, being able to benchmark ourselves with other hospitals pushes us to improve and keep an eye on glycemic control.

Are there any other highlights from your participation– and your institution’s – in the program that you feel would be beneficial to others who may be considering enrollment?

Having access to the tools available in the GC eQUIPS program is very powerful for data analysis and benchmarking. As a result, it allows the people at an institution to focus on the day-to-day tasks, clinical initiatives, and building a culture that can make a program successful instead of focusing on data collection.

For more information on SHM’s Glycemic Control resources or to enroll in eQUIPS, visit hospitalmedicine.org/gc.

Data from more than 5 million individuals has been used to develop an equation for predicting the risk of incident chronic kidney disease (CKD) in people with or without diabetes, according to a presentation at Kidney Week 2019, sponsored by the American Society of Nephrology.

In a paper published simultaneously online in JAMA, researchers reported the outcome of an individual-level data analysis of 34 multinational cohorts involving 5,222,711 individuals – including 781,627 with diabetes – from 28 countries as part of the Chronic Kidney Disease Prognosis Consortium.

“An equation for kidney failure risk may help improve care for patients with established CKD, but relatively little work has been performed to develop predictive tools to identify those at increased risk of developing CKD – defined by reduced eGFR [estimated glomerular filtration rate], despite the high lifetime risk of CKD – which is estimated to be 59.1% in the United States,” wrote Robert G. Nelson, MD, PhD, from the National Institute of Diabetes and Digestive and Kidney Diseases in Phoenix and colleagues.

Over a mean follow-up of 4 years, 15% of individuals without diabetes and 40% of individuals with diabetes developed incident chronic kidney disease, defined as an eGFR below 60 mL/min per 1.73m².

The key risk factors were older age, female sex, black race, hypertension, history of cardiovascular disease, lower eGFR values, and higher urine albumin to creatinine ratio. Smoking was also significantly associated with reduced eGFR but only in cohorts without diabetes. In cohorts with diabetes, elevated hemoglobin A_1c and the presence and type of diabetes medication were also significantly associated with reduced eGFR.

Using this information, the researchers developed a prediction model built from weighted-average hazard ratios and validated it in nine external validation cohorts of 18 study populations involving a total of 2,253,540 individuals. They found that in 16 of the 18 study populations, the slope of observed to predicted risk ranged from 0.80 to 1.25.

Moreover, in the cohorts without diabetes, the risk equations had a median C-statistic for the 5-year predicted probability of 0.845 (interquartile range, 0.789-0.890) and of 0.801 (IQR, 0.750-0.819) in the cohorts with diabetes, the investigators reported.

“Several models have been developed for estimating the risk of prevalent and incident CKD and end-stage kidney disease, but even those with good discriminative performance have not always performed well for cohorts of people outside the original derivation cohort,” the authors wrote. They argued that their model “demonstrated high discrimination and variable calibration in diverse populations.”

However, they stressed that further study was needed to determine if use of the equations would actually lead to improvements in clinical care and patient outcomes. In an accompanying editorial, Sri Lekha Tummalapalli, MD, and Michelle M. Estrella, MD, of the Kidney Health Research Collaborative at the University of California, San Francisco, said the study and its focus on primary, rather than secondary, prevention of kidney disease is a critical step toward reducing the burden of that disease, especially given that an estimated 37 million people in the United States have chronic kidney disease.

It is also important, they added, that primary prevention of kidney disease is tailored to the individual patient’s risk because risk prediction and screening strategies are unlikely to improve outcomes if they are not paired with effective individualized interventions, such as lifestyle modification or management of blood pressure.

These risk equations could be more holistic by integrating the prediction of both elevated albuminuria and reduced eGFR because more than 40% of individuals with chronic kidney disease have increased albuminuria without reduced eGFR, they noted (JAMA. 2019 Nov 8. doi: 10.1001/jama.2019.17378).

The study and CKD Prognosis Consortium were supported by the U.S. National Kidney Foundation and the National Institute of Diabetes and Digestive and Kidney Diseases. One author was supported by a grant from the German Research Foundation. Nine authors declared grants, consultancies, and other support from the private sector and research organizations. No other conflicts of interest were declared. Dr. Tummalapalli and Dr. Estrella reported no conflicts of interest.

SOURCE: Nelson R et al. JAMA. 2019 Nov 8. doi: 10.1001/jama.2019.17379.

Data from more than 5 million individuals has been used to develop an equation for predicting the risk of incident chronic kidney disease (CKD) in people with or without diabetes, according to a presentation at Kidney Week 2019, sponsored by the American Society of Nephrology.

In a paper published simultaneously online in JAMA, researchers reported the outcome of an individual-level data analysis of 34 multinational cohorts involving 5,222,711 individuals – including 781,627 with diabetes – from 28 countries as part of the Chronic Kidney Disease Prognosis Consortium.

“An equation for kidney failure risk may help improve care for patients with established CKD, but relatively little work has been performed to develop predictive tools to identify those at increased risk of developing CKD – defined by reduced eGFR [estimated glomerular filtration rate], despite the high lifetime risk of CKD – which is estimated to be 59.1% in the United States,” wrote Robert G. Nelson, MD, PhD, from the National Institute of Diabetes and Digestive and Kidney Diseases in Phoenix and colleagues.

Over a mean follow-up of 4 years, 15% of individuals without diabetes and 40% of individuals with diabetes developed incident chronic kidney disease, defined as an eGFR below 60 mL/min per 1.73m².

The key risk factors were older age, female sex, black race, hypertension, history of cardiovascular disease, lower eGFR values, and higher urine albumin to creatinine ratio. Smoking was also significantly associated with reduced eGFR but only in cohorts without diabetes. In cohorts with diabetes, elevated hemoglobin A_1c and the presence and type of diabetes medication were also significantly associated with reduced eGFR.

Using this information, the researchers developed a prediction model built from weighted-average hazard ratios and validated it in nine external validation cohorts of 18 study populations involving a total of 2,253,540 individuals. They found that in 16 of the 18 study populations, the slope of observed to predicted risk ranged from 0.80 to 1.25.

Moreover, in the cohorts without diabetes, the risk equations had a median C-statistic for the 5-year predicted probability of 0.845 (interquartile range, 0.789-0.890) and of 0.801 (IQR, 0.750-0.819) in the cohorts with diabetes, the investigators reported.

“Several models have been developed for estimating the risk of prevalent and incident CKD and end-stage kidney disease, but even those with good discriminative performance have not always performed well for cohorts of people outside the original derivation cohort,” the authors wrote. They argued that their model “demonstrated high discrimination and variable calibration in diverse populations.”

However, they stressed that further study was needed to determine if use of the equations would actually lead to improvements in clinical care and patient outcomes. In an accompanying editorial, Sri Lekha Tummalapalli, MD, and Michelle M. Estrella, MD, of the Kidney Health Research Collaborative at the University of California, San Francisco, said the study and its focus on primary, rather than secondary, prevention of kidney disease is a critical step toward reducing the burden of that disease, especially given that an estimated 37 million people in the United States have chronic kidney disease.

It is also important, they added, that primary prevention of kidney disease is tailored to the individual patient’s risk because risk prediction and screening strategies are unlikely to improve outcomes if they are not paired with effective individualized interventions, such as lifestyle modification or management of blood pressure.

These risk equations could be more holistic by integrating the prediction of both elevated albuminuria and reduced eGFR because more than 40% of individuals with chronic kidney disease have increased albuminuria without reduced eGFR, they noted (JAMA. 2019 Nov 8. doi: 10.1001/jama.2019.17378).

The study and CKD Prognosis Consortium were supported by the U.S. National Kidney Foundation and the National Institute of Diabetes and Digestive and Kidney Diseases. One author was supported by a grant from the German Research Foundation. Nine authors declared grants, consultancies, and other support from the private sector and research organizations. No other conflicts of interest were declared. Dr. Tummalapalli and Dr. Estrella reported no conflicts of interest.

SOURCE: Nelson R et al. JAMA. 2019 Nov 8. doi: 10.1001/jama.2019.17379.

Data from more than 5 million individuals has been used to develop an equation for predicting the risk of incident chronic kidney disease (CKD) in people with or without diabetes, according to a presentation at Kidney Week 2019, sponsored by the American Society of Nephrology.

In a paper published simultaneously online in JAMA, researchers reported the outcome of an individual-level data analysis of 34 multinational cohorts involving 5,222,711 individuals – including 781,627 with diabetes – from 28 countries as part of the Chronic Kidney Disease Prognosis Consortium.

“An equation for kidney failure risk may help improve care for patients with established CKD, but relatively little work has been performed to develop predictive tools to identify those at increased risk of developing CKD – defined by reduced eGFR [estimated glomerular filtration rate], despite the high lifetime risk of CKD – which is estimated to be 59.1% in the United States,” wrote Robert G. Nelson, MD, PhD, from the National Institute of Diabetes and Digestive and Kidney Diseases in Phoenix and colleagues.

Over a mean follow-up of 4 years, 15% of individuals without diabetes and 40% of individuals with diabetes developed incident chronic kidney disease, defined as an eGFR below 60 mL/min per 1.73m².

The key risk factors were older age, female sex, black race, hypertension, history of cardiovascular disease, lower eGFR values, and higher urine albumin to creatinine ratio. Smoking was also significantly associated with reduced eGFR but only in cohorts without diabetes. In cohorts with diabetes, elevated hemoglobin A_1c and the presence and type of diabetes medication were also significantly associated with reduced eGFR.

Using this information, the researchers developed a prediction model built from weighted-average hazard ratios and validated it in nine external validation cohorts of 18 study populations involving a total of 2,253,540 individuals. They found that in 16 of the 18 study populations, the slope of observed to predicted risk ranged from 0.80 to 1.25.

Moreover, in the cohorts without diabetes, the risk equations had a median C-statistic for the 5-year predicted probability of 0.845 (interquartile range, 0.789-0.890) and of 0.801 (IQR, 0.750-0.819) in the cohorts with diabetes, the investigators reported.

“Several models have been developed for estimating the risk of prevalent and incident CKD and end-stage kidney disease, but even those with good discriminative performance have not always performed well for cohorts of people outside the original derivation cohort,” the authors wrote. They argued that their model “demonstrated high discrimination and variable calibration in diverse populations.”

However, they stressed that further study was needed to determine if use of the equations would actually lead to improvements in clinical care and patient outcomes. In an accompanying editorial, Sri Lekha Tummalapalli, MD, and Michelle M. Estrella, MD, of the Kidney Health Research Collaborative at the University of California, San Francisco, said the study and its focus on primary, rather than secondary, prevention of kidney disease is a critical step toward reducing the burden of that disease, especially given that an estimated 37 million people in the United States have chronic kidney disease.

It is also important, they added, that primary prevention of kidney disease is tailored to the individual patient’s risk because risk prediction and screening strategies are unlikely to improve outcomes if they are not paired with effective individualized interventions, such as lifestyle modification or management of blood pressure.

These risk equations could be more holistic by integrating the prediction of both elevated albuminuria and reduced eGFR because more than 40% of individuals with chronic kidney disease have increased albuminuria without reduced eGFR, they noted (JAMA. 2019 Nov 8. doi: 10.1001/jama.2019.17378).

The study and CKD Prognosis Consortium were supported by the U.S. National Kidney Foundation and the National Institute of Diabetes and Digestive and Kidney Diseases. One author was supported by a grant from the German Research Foundation. Nine authors declared grants, consultancies, and other support from the private sector and research organizations. No other conflicts of interest were declared. Dr. Tummalapalli and Dr. Estrella reported no conflicts of interest.

SOURCE: Nelson R et al. JAMA. 2019 Nov 8. doi: 10.1001/jama.2019.17379.

CHICAGO – Current dosing recommendations for thyroid replacement during immune checkpoint inhibitor therapy may overshoot the mark, both for patients with preexisting and de novo hypothyroidism.

Kari Oakes/MDedge News

The real-world data, presented by Megan Kristan, MD, at the annual meeting of the American Thyroid Association, refine recommendations for dosing by body weight for levothyroxine in patients receiving checkpoint inhibitor therapy.

Immune checkpoint inhibitors stand a good chance of turning the tide against melanoma, some lung cancers, and other malignancies that have long been considered lethal. However, as more patients are exposed to the therapies, endocrinologists are seeing a wave of thyroid abnormalities, and must decide when, and at what doses, to treat hypothyroidism, said Dr. Kristan, a diabetes, endocrinology, and nutrition fellow at the University of Maryland, Baltimore.

Six checkpoint inhibitors are currently approved to hit a variety of molecular targets, and the prevalence of thyroid toxicity and hypothyroidism across the drug class ranges from a reported 9% to 40%, said Dr. Kristan.

The acknowledged thyroid toxicity of these drugs led the American Society for Clinical Oncology (ASCO) to issue guidelines advising that oncologists obtain baseline thyroid function tests before initiating checkpoint inhibitors, and that values be rechecked frequently – every 4-6 weeks – during therapy.

The guidelines advise dosing levothyroxine at approximately 1.6 mcg/kg per day, based on ideal patient body weight. The recommendation is limited to patients without risk factors, and approximates full levothyroxine replacement.

However, some patients enter cancer treatment with hypothyroidism, and some develop it de novo after beginning checkpoint inhibitor therapy. It is not known how best to treat each group, said Dr. Kristan.

To help answer that question, she and her collaborators at Georgetown University Hospital, McLean, Va., made use of a database drawn from five hospitals to perform a retrospective chart review. They looked at 822 patients who had received checkpoint inhibitor therapy, and from those patients, they selected 118 who had a diagnosis of hypothyroidism, or who received a prescription for levothyroxine during the 8-year study period.

The investigators assembled all available relevant data for each patient, including thyroid function tests, levothyroxine dosing, type of cancer, and type of therapy. They sorted participants into those who had received a diagnosis of hypothyroidism before or after receiving the first dose of checkpoint inhibitor therapy.

At baseline, 81 patients had preexisting hypothyroidism and were receiving a mean levothyroxine dose of 88.2 mcg. After treatment, the mean dose was 94.3 mcg, a nonsignificant difference. The median dose for this group remained at 88 mcg through treatment.

For the 37 patients who developed hypothyroidism de novo during checkpoint inhibitor therapy, the final observed levothyroxine dose was 71.2 mcg.

The mean age of the patients at baseline was 69 years. About half were women, and 91% were white. Either nivolumab or pembrolizumab was used in 72% of patients, making them the most commonly used checkpoint inhibitors, though 90% of patients received combination therapy. Taken together, melanoma and lung cancer accounted for about two-thirds of the cancers seen.

For both groups, the on-treatment levothyroxine dose was considerably lower than the ASCO-recommended, weight-based dosing, which would have been 122.9 mcg for those with preexisting hypothyroidism and 115.7 mcg for those who developed hypothyroidism on treatment (P less than .001 for both).

Dr. Kristan noted that thyroid stimulating hormone (TSH) values for patients with pretreatment hypothyroidism peaked between weeks 12 and 20, though there was no preemptive adjustment of levothyroxine dosing.

For those who developed on-treatment hypothyroidism, TSH values peaked at a series of times, at about weeks 8, 16, and 32. These waves of TSH elevation, she said, support the 4- to 6-week follow-up interval recommended in the ASCO guidelines.

However, she said, patients with de novo hypothyroidism “should not be started on the 1.6-mcg/kg-a-day weight-based dosing.” The cohort with de novo hypothyroidism in Dr. Kristan’s analysis required a daily dose of about 1 mcg/kg, she said. These real-world results support the idea that many patients on checkpoint inhibitors retain some thyroid reserve.

Dr. Kristan said that based on these findings, she and her collaborators recommend monitoring thyroid function every 4-6 weeks for patients taking immune checkpoint inhibitors. Patients with preexisting thyroid disease should not have an empiric adjustment of levothyroxine dose on checkpoint inhibitor initiation. For patients who develop thyroiditis after starting therapy, initiating a dose at 1 mcg/kg per day of ideal body weight is a good place to start, and treatment response should be monitored.

The study was limited by its retrospective nature and the small sample size, acknowledged Dr. Kristan. In addition, there were confounding variables and different frequencies of testing across institutions, and antibody status was not available and may have affected the results. Testing was performable for all participants.

Dr. Kristan said that the analysis opens up areas for further study, such as which patient populations are at risk for developing thyroid toxicity, what baseline characteristics can help predict which patients develop toxicity, and whether particular checkpoint inhibitors are more likely to cause toxicity. In addition, she said, a subset of patients will develop hyperthyroidism on checkpoint inhibitor therapy, and little is known about how to treat that complication.

Dr. Kristan reported no conflicts of interest. The research she presented was completed during her residency at Georgetown University.
 

SOURCE: Kristan M et al. ATA 2019, Oral Abstract 25.

CHICAGO – Current dosing recommendations for thyroid replacement during immune checkpoint inhibitor therapy may overshoot the mark, both for patients with preexisting and de novo hypothyroidism.

Kari Oakes/MDedge News

The real-world data, presented by Megan Kristan, MD, at the annual meeting of the American Thyroid Association, refine recommendations for dosing by body weight for levothyroxine in patients receiving checkpoint inhibitor therapy.

Immune checkpoint inhibitors stand a good chance of turning the tide against melanoma, some lung cancers, and other malignancies that have long been considered lethal. However, as more patients are exposed to the therapies, endocrinologists are seeing a wave of thyroid abnormalities, and must decide when, and at what doses, to treat hypothyroidism, said Dr. Kristan, a diabetes, endocrinology, and nutrition fellow at the University of Maryland, Baltimore.

Six checkpoint inhibitors are currently approved to hit a variety of molecular targets, and the prevalence of thyroid toxicity and hypothyroidism across the drug class ranges from a reported 9% to 40%, said Dr. Kristan.

The acknowledged thyroid toxicity of these drugs led the American Society for Clinical Oncology (ASCO) to issue guidelines advising that oncologists obtain baseline thyroid function tests before initiating checkpoint inhibitors, and that values be rechecked frequently – every 4-6 weeks – during therapy.

The guidelines advise dosing levothyroxine at approximately 1.6 mcg/kg per day, based on ideal patient body weight. The recommendation is limited to patients without risk factors, and approximates full levothyroxine replacement.

However, some patients enter cancer treatment with hypothyroidism, and some develop it de novo after beginning checkpoint inhibitor therapy. It is not known how best to treat each group, said Dr. Kristan.

To help answer that question, she and her collaborators at Georgetown University Hospital, McLean, Va., made use of a database drawn from five hospitals to perform a retrospective chart review. They looked at 822 patients who had received checkpoint inhibitor therapy, and from those patients, they selected 118 who had a diagnosis of hypothyroidism, or who received a prescription for levothyroxine during the 8-year study period.

The investigators assembled all available relevant data for each patient, including thyroid function tests, levothyroxine dosing, type of cancer, and type of therapy. They sorted participants into those who had received a diagnosis of hypothyroidism before or after receiving the first dose of checkpoint inhibitor therapy.

At baseline, 81 patients had preexisting hypothyroidism and were receiving a mean levothyroxine dose of 88.2 mcg. After treatment, the mean dose was 94.3 mcg, a nonsignificant difference. The median dose for this group remained at 88 mcg through treatment.

For the 37 patients who developed hypothyroidism de novo during checkpoint inhibitor therapy, the final observed levothyroxine dose was 71.2 mcg.

The mean age of the patients at baseline was 69 years. About half were women, and 91% were white. Either nivolumab or pembrolizumab was used in 72% of patients, making them the most commonly used checkpoint inhibitors, though 90% of patients received combination therapy. Taken together, melanoma and lung cancer accounted for about two-thirds of the cancers seen.

For both groups, the on-treatment levothyroxine dose was considerably lower than the ASCO-recommended, weight-based dosing, which would have been 122.9 mcg for those with preexisting hypothyroidism and 115.7 mcg for those who developed hypothyroidism on treatment (P less than .001 for both).

Dr. Kristan noted that thyroid stimulating hormone (TSH) values for patients with pretreatment hypothyroidism peaked between weeks 12 and 20, though there was no preemptive adjustment of levothyroxine dosing.

For those who developed on-treatment hypothyroidism, TSH values peaked at a series of times, at about weeks 8, 16, and 32. These waves of TSH elevation, she said, support the 4- to 6-week follow-up interval recommended in the ASCO guidelines.

However, she said, patients with de novo hypothyroidism “should not be started on the 1.6-mcg/kg-a-day weight-based dosing.” The cohort with de novo hypothyroidism in Dr. Kristan’s analysis required a daily dose of about 1 mcg/kg, she said. These real-world results support the idea that many patients on checkpoint inhibitors retain some thyroid reserve.

Dr. Kristan said that based on these findings, she and her collaborators recommend monitoring thyroid function every 4-6 weeks for patients taking immune checkpoint inhibitors. Patients with preexisting thyroid disease should not have an empiric adjustment of levothyroxine dose on checkpoint inhibitor initiation. For patients who develop thyroiditis after starting therapy, initiating a dose at 1 mcg/kg per day of ideal body weight is a good place to start, and treatment response should be monitored.

The study was limited by its retrospective nature and the small sample size, acknowledged Dr. Kristan. In addition, there were confounding variables and different frequencies of testing across institutions, and antibody status was not available and may have affected the results. Testing was performable for all participants.

Dr. Kristan said that the analysis opens up areas for further study, such as which patient populations are at risk for developing thyroid toxicity, what baseline characteristics can help predict which patients develop toxicity, and whether particular checkpoint inhibitors are more likely to cause toxicity. In addition, she said, a subset of patients will develop hyperthyroidism on checkpoint inhibitor therapy, and little is known about how to treat that complication.

Dr. Kristan reported no conflicts of interest. The research she presented was completed during her residency at Georgetown University.
 

SOURCE: Kristan M et al. ATA 2019, Oral Abstract 25.

CHICAGO – Current dosing recommendations for thyroid replacement during immune checkpoint inhibitor therapy may overshoot the mark, both for patients with preexisting and de novo hypothyroidism.

Kari Oakes/MDedge News

The real-world data, presented by Megan Kristan, MD, at the annual meeting of the American Thyroid Association, refine recommendations for dosing by body weight for levothyroxine in patients receiving checkpoint inhibitor therapy.

Immune checkpoint inhibitors stand a good chance of turning the tide against melanoma, some lung cancers, and other malignancies that have long been considered lethal. However, as more patients are exposed to the therapies, endocrinologists are seeing a wave of thyroid abnormalities, and must decide when, and at what doses, to treat hypothyroidism, said Dr. Kristan, a diabetes, endocrinology, and nutrition fellow at the University of Maryland, Baltimore.

Six checkpoint inhibitors are currently approved to hit a variety of molecular targets, and the prevalence of thyroid toxicity and hypothyroidism across the drug class ranges from a reported 9% to 40%, said Dr. Kristan.

The acknowledged thyroid toxicity of these drugs led the American Society for Clinical Oncology (ASCO) to issue guidelines advising that oncologists obtain baseline thyroid function tests before initiating checkpoint inhibitors, and that values be rechecked frequently – every 4-6 weeks – during therapy.

The guidelines advise dosing levothyroxine at approximately 1.6 mcg/kg per day, based on ideal patient body weight. The recommendation is limited to patients without risk factors, and approximates full levothyroxine replacement.

However, some patients enter cancer treatment with hypothyroidism, and some develop it de novo after beginning checkpoint inhibitor therapy. It is not known how best to treat each group, said Dr. Kristan.

To help answer that question, she and her collaborators at Georgetown University Hospital, McLean, Va., made use of a database drawn from five hospitals to perform a retrospective chart review. They looked at 822 patients who had received checkpoint inhibitor therapy, and from those patients, they selected 118 who had a diagnosis of hypothyroidism, or who received a prescription for levothyroxine during the 8-year study period.

The investigators assembled all available relevant data for each patient, including thyroid function tests, levothyroxine dosing, type of cancer, and type of therapy. They sorted participants into those who had received a diagnosis of hypothyroidism before or after receiving the first dose of checkpoint inhibitor therapy.

At baseline, 81 patients had preexisting hypothyroidism and were receiving a mean levothyroxine dose of 88.2 mcg. After treatment, the mean dose was 94.3 mcg, a nonsignificant difference. The median dose for this group remained at 88 mcg through treatment.

For the 37 patients who developed hypothyroidism de novo during checkpoint inhibitor therapy, the final observed levothyroxine dose was 71.2 mcg.

The mean age of the patients at baseline was 69 years. About half were women, and 91% were white. Either nivolumab or pembrolizumab was used in 72% of patients, making them the most commonly used checkpoint inhibitors, though 90% of patients received combination therapy. Taken together, melanoma and lung cancer accounted for about two-thirds of the cancers seen.

For both groups, the on-treatment levothyroxine dose was considerably lower than the ASCO-recommended, weight-based dosing, which would have been 122.9 mcg for those with preexisting hypothyroidism and 115.7 mcg for those who developed hypothyroidism on treatment (P less than .001 for both).

Dr. Kristan noted that thyroid stimulating hormone (TSH) values for patients with pretreatment hypothyroidism peaked between weeks 12 and 20, though there was no preemptive adjustment of levothyroxine dosing.

For those who developed on-treatment hypothyroidism, TSH values peaked at a series of times, at about weeks 8, 16, and 32. These waves of TSH elevation, she said, support the 4- to 6-week follow-up interval recommended in the ASCO guidelines.

However, she said, patients with de novo hypothyroidism “should not be started on the 1.6-mcg/kg-a-day weight-based dosing.” The cohort with de novo hypothyroidism in Dr. Kristan’s analysis required a daily dose of about 1 mcg/kg, she said. These real-world results support the idea that many patients on checkpoint inhibitors retain some thyroid reserve.

Dr. Kristan said that based on these findings, she and her collaborators recommend monitoring thyroid function every 4-6 weeks for patients taking immune checkpoint inhibitors. Patients with preexisting thyroid disease should not have an empiric adjustment of levothyroxine dose on checkpoint inhibitor initiation. For patients who develop thyroiditis after starting therapy, initiating a dose at 1 mcg/kg per day of ideal body weight is a good place to start, and treatment response should be monitored.

The study was limited by its retrospective nature and the small sample size, acknowledged Dr. Kristan. In addition, there were confounding variables and different frequencies of testing across institutions, and antibody status was not available and may have affected the results. Testing was performable for all participants.

Dr. Kristan said that the analysis opens up areas for further study, such as which patient populations are at risk for developing thyroid toxicity, what baseline characteristics can help predict which patients develop toxicity, and whether particular checkpoint inhibitors are more likely to cause toxicity. In addition, she said, a subset of patients will develop hyperthyroidism on checkpoint inhibitor therapy, and little is known about how to treat that complication.

Dr. Kristan reported no conflicts of interest. The research she presented was completed during her residency at Georgetown University.
 

SOURCE: Kristan M et al. ATA 2019, Oral Abstract 25.

CHICAGO – Higher levels of triiodothyronine (T3) were seen in combatants with PTSD, compared with patients whose PTSD arose from other adverse experiences, according to findings from a systematic review and meta-analysis.

Patients with combat-related PTSD had higher levels of free T3 and total T3, compared with control participants who had experienced childhood or sexual abuse or were a wartime refugee without PTSD (FT3, 0.36 pg/mL higher, and total T3, 31.6 ng/mL higher, respectively; P = .0004 and P less than .00001).

“We found statistically higher free T3 and total T3 levels in patients with [combat-related] PTSD, compared with controls,” said Freddy J.K. Toloza, MD, in an interview during a poster session of the annual meeting of the American Thyroid Association.

However, he noted that there were no overall differences in thyroid-stimulating hormone, free tetraiodothyronine (T4), and total T4 levels between individuals with PTSD and the non-PTSD control participants. In addition, though free and total T3 levels were significantly higher for the overall PTSD cohort than for control participants, the differences were driven by the studies that included combat-exposed individuals.

Dr. Toloza and colleagues included 10 observational studies in their final review and meta-analysis. Five studies looked at war veterans; the others examined individuals who had experienced child abuse or sexual abuse, who were refugees, or who were from the general population.

For inclusion, the studies had to report both mean values and standard deviations for standard thyroid-hormone test values in patients with PTSD, compared with a non-PTSD control group. These included 373 patients with PTSD and 301 control participants. Just under half (47%) were women. None of the studies, wrote the investigators, “compared rates of overt/subclinical thyroid disease between groups.”

There are known links between many endocrine disorders and psychiatric conditions, said Dr. Toloza, but the interplay between disordered thyroid function and neuropsychiatric problems is still being examined. Looking at PTSD is important because it’s estimated that 6%-9% of the U.S. adult population has experienced PTSD over the course of a lifetime.

Levels of thyroid hormones in the systematic review and meta-analysis were still within normal range for the participants with PTSD, acknowledged Dr. Toloza, a research fellow in the division of endocrinology and metabolism at University of Arkansas for Medical Sciences, Little Rock.

However, even though there was no sign of frank thyroid disease in the PTSD population, the elevated T3 levels seen in the analysis are consistent with other studies showing a correlation between higher T3 levels and more-severe PTSD.

It is not known exactly why significant increases in the levels of total and free T3 were seen only in the combat-exposed PTSD population, Dr. Toloza said. “The type of trauma trigger may influence the adaptive responses to stress and might result in diverse thyroid alterations.”

Elevated catecholamine levels, seen in individuals with PTSD, can increase peripheral conversion of T4 to T3, explained Dr. Toloza. Ongoing catecholamine elevation may account for the isolated elevation in T3 levels in the PTSD population. Beta1-adrenergic blockade is an accepted pharmacologic strategy to help alleviate PTSD symptoms.

Dr. Toloza and coinvestigators did not have access to data that would have allowed them to ascertain what types of injuries were sustained by individuals with combat-related PTSD, but he noted in response to a question, that it would be worthwhile to see whether combatants who were blast exposed had different thyroid hormone values than those who were not, because hypothalamic injury is common in blast. This is a future direction Dr. Toloza wishes to pursue.

“Our findings add to the growing literature suggesting that thyroid function changes may be associated with PTSD,” the investigators wrote, but “further research is needed to ascertain the role of thyroid function alterations in PTSD.”

Dr. Toloza reported no financial disclosures or conflicts of interest.

CHICAGO – Higher levels of triiodothyronine (T3) were seen in combatants with PTSD, compared with patients whose PTSD arose from other adverse experiences, according to findings from a systematic review and meta-analysis.

Patients with combat-related PTSD had higher levels of free T3 and total T3, compared with control participants who had experienced childhood or sexual abuse or were a wartime refugee without PTSD (FT3, 0.36 pg/mL higher, and total T3, 31.6 ng/mL higher, respectively; P = .0004 and P less than .00001).

“We found statistically higher free T3 and total T3 levels in patients with [combat-related] PTSD, compared with controls,” said Freddy J.K. Toloza, MD, in an interview during a poster session of the annual meeting of the American Thyroid Association.

However, he noted that there were no overall differences in thyroid-stimulating hormone, free tetraiodothyronine (T4), and total T4 levels between individuals with PTSD and the non-PTSD control participants. In addition, though free and total T3 levels were significantly higher for the overall PTSD cohort than for control participants, the differences were driven by the studies that included combat-exposed individuals.

Dr. Toloza and colleagues included 10 observational studies in their final review and meta-analysis. Five studies looked at war veterans; the others examined individuals who had experienced child abuse or sexual abuse, who were refugees, or who were from the general population.

For inclusion, the studies had to report both mean values and standard deviations for standard thyroid-hormone test values in patients with PTSD, compared with a non-PTSD control group. These included 373 patients with PTSD and 301 control participants. Just under half (47%) were women. None of the studies, wrote the investigators, “compared rates of overt/subclinical thyroid disease between groups.”

There are known links between many endocrine disorders and psychiatric conditions, said Dr. Toloza, but the interplay between disordered thyroid function and neuropsychiatric problems is still being examined. Looking at PTSD is important because it’s estimated that 6%-9% of the U.S. adult population has experienced PTSD over the course of a lifetime.

Levels of thyroid hormones in the systematic review and meta-analysis were still within normal range for the participants with PTSD, acknowledged Dr. Toloza, a research fellow in the division of endocrinology and metabolism at University of Arkansas for Medical Sciences, Little Rock.

However, even though there was no sign of frank thyroid disease in the PTSD population, the elevated T3 levels seen in the analysis are consistent with other studies showing a correlation between higher T3 levels and more-severe PTSD.

It is not known exactly why significant increases in the levels of total and free T3 were seen only in the combat-exposed PTSD population, Dr. Toloza said. “The type of trauma trigger may influence the adaptive responses to stress and might result in diverse thyroid alterations.”

Elevated catecholamine levels, seen in individuals with PTSD, can increase peripheral conversion of T4 to T3, explained Dr. Toloza. Ongoing catecholamine elevation may account for the isolated elevation in T3 levels in the PTSD population. Beta1-adrenergic blockade is an accepted pharmacologic strategy to help alleviate PTSD symptoms.

Dr. Toloza and coinvestigators did not have access to data that would have allowed them to ascertain what types of injuries were sustained by individuals with combat-related PTSD, but he noted in response to a question, that it would be worthwhile to see whether combatants who were blast exposed had different thyroid hormone values than those who were not, because hypothalamic injury is common in blast. This is a future direction Dr. Toloza wishes to pursue.

“Our findings add to the growing literature suggesting that thyroid function changes may be associated with PTSD,” the investigators wrote, but “further research is needed to ascertain the role of thyroid function alterations in PTSD.”

Dr. Toloza reported no financial disclosures or conflicts of interest.

CHICAGO – Higher levels of triiodothyronine (T3) were seen in combatants with PTSD, compared with patients whose PTSD arose from other adverse experiences, according to findings from a systematic review and meta-analysis.

Patients with combat-related PTSD had higher levels of free T3 and total T3, compared with control participants who had experienced childhood or sexual abuse or were a wartime refugee without PTSD (FT3, 0.36 pg/mL higher, and total T3, 31.6 ng/mL higher, respectively; P = .0004 and P less than .00001).

“We found statistically higher free T3 and total T3 levels in patients with [combat-related] PTSD, compared with controls,” said Freddy J.K. Toloza, MD, in an interview during a poster session of the annual meeting of the American Thyroid Association.

However, he noted that there were no overall differences in thyroid-stimulating hormone, free tetraiodothyronine (T4), and total T4 levels between individuals with PTSD and the non-PTSD control participants. In addition, though free and total T3 levels were significantly higher for the overall PTSD cohort than for control participants, the differences were driven by the studies that included combat-exposed individuals.

Dr. Toloza and colleagues included 10 observational studies in their final review and meta-analysis. Five studies looked at war veterans; the others examined individuals who had experienced child abuse or sexual abuse, who were refugees, or who were from the general population.

For inclusion, the studies had to report both mean values and standard deviations for standard thyroid-hormone test values in patients with PTSD, compared with a non-PTSD control group. These included 373 patients with PTSD and 301 control participants. Just under half (47%) were women. None of the studies, wrote the investigators, “compared rates of overt/subclinical thyroid disease between groups.”

There are known links between many endocrine disorders and psychiatric conditions, said Dr. Toloza, but the interplay between disordered thyroid function and neuropsychiatric problems is still being examined. Looking at PTSD is important because it’s estimated that 6%-9% of the U.S. adult population has experienced PTSD over the course of a lifetime.

Levels of thyroid hormones in the systematic review and meta-analysis were still within normal range for the participants with PTSD, acknowledged Dr. Toloza, a research fellow in the division of endocrinology and metabolism at University of Arkansas for Medical Sciences, Little Rock.

However, even though there was no sign of frank thyroid disease in the PTSD population, the elevated T3 levels seen in the analysis are consistent with other studies showing a correlation between higher T3 levels and more-severe PTSD.

It is not known exactly why significant increases in the levels of total and free T3 were seen only in the combat-exposed PTSD population, Dr. Toloza said. “The type of trauma trigger may influence the adaptive responses to stress and might result in diverse thyroid alterations.”

Elevated catecholamine levels, seen in individuals with PTSD, can increase peripheral conversion of T4 to T3, explained Dr. Toloza. Ongoing catecholamine elevation may account for the isolated elevation in T3 levels in the PTSD population. Beta1-adrenergic blockade is an accepted pharmacologic strategy to help alleviate PTSD symptoms.

Dr. Toloza and coinvestigators did not have access to data that would have allowed them to ascertain what types of injuries were sustained by individuals with combat-related PTSD, but he noted in response to a question, that it would be worthwhile to see whether combatants who were blast exposed had different thyroid hormone values than those who were not, because hypothalamic injury is common in blast. This is a future direction Dr. Toloza wishes to pursue.

“Our findings add to the growing literature suggesting that thyroid function changes may be associated with PTSD,” the investigators wrote, but “further research is needed to ascertain the role of thyroid function alterations in PTSD.”

Dr. Toloza reported no financial disclosures or conflicts of interest.

Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Poor response to statins hikes risk of cardiovascular events

To take the posttest, go to: https://bit.ly/2MVHlDR
Expires April 17, 2020

2. Postvaccination febrile seizures are no more severe than other febrile seizures

To take the posttest, go to: https://bit.ly/2VUJzaE
Expires April 19, 2020

3. Hydroxychloroquine adherence in SLE: worse than you thought

To take the posttest, go to: https://bit.ly/2oT00Z9
Expires April 22, 2020

4. Long-term antibiotic use may heighten stroke, CHD risk

To take the posttest, go to: https://bit.ly/2OUUVu5
Expires April 28, 2020

5. Knowledge gaps about long-term osteoporosis drug therapy benefits, risks remain large

To take the posttest, go to: https://bit.ly/2Msgqkb
Expires May 1, 2020

Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Poor response to statins hikes risk of cardiovascular events

To take the posttest, go to: https://bit.ly/2MVHlDR
Expires April 17, 2020

2. Postvaccination febrile seizures are no more severe than other febrile seizures

To take the posttest, go to: https://bit.ly/2VUJzaE
Expires April 19, 2020

3. Hydroxychloroquine adherence in SLE: worse than you thought

To take the posttest, go to: https://bit.ly/2oT00Z9
Expires April 22, 2020

4. Long-term antibiotic use may heighten stroke, CHD risk

To take the posttest, go to: https://bit.ly/2OUUVu5
Expires April 28, 2020

5. Knowledge gaps about long-term osteoporosis drug therapy benefits, risks remain large

To take the posttest, go to: https://bit.ly/2Msgqkb
Expires May 1, 2020

Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Poor response to statins hikes risk of cardiovascular events

To take the posttest, go to: https://bit.ly/2MVHlDR
Expires April 17, 2020

2. Postvaccination febrile seizures are no more severe than other febrile seizures

To take the posttest, go to: https://bit.ly/2VUJzaE
Expires April 19, 2020

3. Hydroxychloroquine adherence in SLE: worse than you thought

To take the posttest, go to: https://bit.ly/2oT00Z9
Expires April 22, 2020

4. Long-term antibiotic use may heighten stroke, CHD risk

To take the posttest, go to: https://bit.ly/2OUUVu5
Expires April 28, 2020

5. Knowledge gaps about long-term osteoporosis drug therapy benefits, risks remain large

To take the posttest, go to: https://bit.ly/2Msgqkb
Expires May 1, 2020