Women with early breast cancer and a high genetic risk for recurrence at a distant site achieved greater freedom from recurrence when treated with chemoendocrine therapy than with endocrine therapy alone in a study of 1,389 women with hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer.

“The 21-gene recurrence score (RS) assay provides prognostic information for distant recurrence in hormone-receptor–positive, ERBB2-negative early breast cancer that is independent of clinicopathologic features and is also predictive of chemotherapy benefit when the RS is high,” wrote Joseph A. Sparano, MD, of Montefiore Medical Center, New York, and his colleagues. However, little is known about how this risk score applies to women with hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer, they said.

In the study published in JAMA Oncology, they identified 1,389 women with a recurrence score of 26-100 (the definition of a high recurrence risk). The average age of the patients was 56 years, and 71% were postmenopausal.

In addition to receiving endocrine therapy, the women were randomized to no chemotherapy (89 patients) or one of several chemotherapy regimens including docetaxel/cyclophosphamide (589 patients), anthracycline without a taxane (334 patients), an anthracycline and taxane (244 patients), cyclophosphamide/methotrexate/5-fluorouracil (52 patients), and other regimens (81 patients). Among those treated with chemotherapy, overall survival (OS) at 5 years was 96% and estimated rates of freedom from recurrence of breast cancer at a distant site, and from a distant and/or local regional site, at 5 years were 93% and 91%, respectively. At 5 years, the estimated rate of invasive disease–free survival (IDFS) was 88%.

When broken down by chemotherapy regimen, 5-year rates of freedom from recurrence of breast cancer at a distant site ranged from 92.3% to 95.5%, except for 88.5% for the cyclophosphamide/methotrexate/5-fluorouracil (CMF) group; the rate was 92.6% for patients in the no-chemotherapy group.

The 5-year rates of IDFS ranged from 84% to 91.3% in the chemotherapy groups, compared with 79.7% in the no-chemotherapy group.

The expected rates of distant recurrence in the overall patient population if treated with endocrine therapy alone was 78.8% at 5 years and 65.4% at 9 years, the researchers said. Rates among the patients with an RS of 26-30 if treated with endocrine therapy alone were 89.6% at 5 years and 80.6% at 9 years; rates for those with an RS of 31-100 were 70.7% and 54% for 5 and 9 years, respectively.

The study findings were limited by several factors including a lack of randomization to endocrine therapy alone and the relatively short follow-up period, the researchers noted. However, strengths include the large sample size and high rate of compliance with chemotherapy.

The results support data from previous studies and “add to the evidence base supporting the use of the 21-gene RS assay to guide the use of adjuvant chemotherapy in patients with hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer,” they concluded.

The study was supported in part by the National Cancer Institute, the Canadian Cancer Society Research Institute, the Breast Cancer Research Foundation, the Komen Foundation, and the Breast Cancer Research Stamp issued by the United States Postal Service. Dr. Sparano disclosed grants from the National Cancer Institute. Of the remaining authors, several disclosed receiving personal or speaker fees from the assay manufacturer, Genomic Health; one author received funding from the company during the study.

SOURCE: Sparano J et al. JAMA Oncol. 2019 Sep 30. doi: 10.1001/jamaoncol.2019.4794.

Women with early breast cancer and a high genetic risk for recurrence at a distant site achieved greater freedom from recurrence when treated with chemoendocrine therapy than with endocrine therapy alone in a study of 1,389 women with hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer.

“The 21-gene recurrence score (RS) assay provides prognostic information for distant recurrence in hormone-receptor–positive, ERBB2-negative early breast cancer that is independent of clinicopathologic features and is also predictive of chemotherapy benefit when the RS is high,” wrote Joseph A. Sparano, MD, of Montefiore Medical Center, New York, and his colleagues. However, little is known about how this risk score applies to women with hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer, they said.

In the study published in JAMA Oncology, they identified 1,389 women with a recurrence score of 26-100 (the definition of a high recurrence risk). The average age of the patients was 56 years, and 71% were postmenopausal.

In addition to receiving endocrine therapy, the women were randomized to no chemotherapy (89 patients) or one of several chemotherapy regimens including docetaxel/cyclophosphamide (589 patients), anthracycline without a taxane (334 patients), an anthracycline and taxane (244 patients), cyclophosphamide/methotrexate/5-fluorouracil (52 patients), and other regimens (81 patients). Among those treated with chemotherapy, overall survival (OS) at 5 years was 96% and estimated rates of freedom from recurrence of breast cancer at a distant site, and from a distant and/or local regional site, at 5 years were 93% and 91%, respectively. At 5 years, the estimated rate of invasive disease–free survival (IDFS) was 88%.

When broken down by chemotherapy regimen, 5-year rates of freedom from recurrence of breast cancer at a distant site ranged from 92.3% to 95.5%, except for 88.5% for the cyclophosphamide/methotrexate/5-fluorouracil (CMF) group; the rate was 92.6% for patients in the no-chemotherapy group.

The 5-year rates of IDFS ranged from 84% to 91.3% in the chemotherapy groups, compared with 79.7% in the no-chemotherapy group.

The expected rates of distant recurrence in the overall patient population if treated with endocrine therapy alone was 78.8% at 5 years and 65.4% at 9 years, the researchers said. Rates among the patients with an RS of 26-30 if treated with endocrine therapy alone were 89.6% at 5 years and 80.6% at 9 years; rates for those with an RS of 31-100 were 70.7% and 54% for 5 and 9 years, respectively.

The study findings were limited by several factors including a lack of randomization to endocrine therapy alone and the relatively short follow-up period, the researchers noted. However, strengths include the large sample size and high rate of compliance with chemotherapy.

The results support data from previous studies and “add to the evidence base supporting the use of the 21-gene RS assay to guide the use of adjuvant chemotherapy in patients with hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer,” they concluded.

The study was supported in part by the National Cancer Institute, the Canadian Cancer Society Research Institute, the Breast Cancer Research Foundation, the Komen Foundation, and the Breast Cancer Research Stamp issued by the United States Postal Service. Dr. Sparano disclosed grants from the National Cancer Institute. Of the remaining authors, several disclosed receiving personal or speaker fees from the assay manufacturer, Genomic Health; one author received funding from the company during the study.

SOURCE: Sparano J et al. JAMA Oncol. 2019 Sep 30. doi: 10.1001/jamaoncol.2019.4794.

Women with early breast cancer and a high genetic risk for recurrence at a distant site achieved greater freedom from recurrence when treated with chemoendocrine therapy than with endocrine therapy alone in a study of 1,389 women with hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer.

“The 21-gene recurrence score (RS) assay provides prognostic information for distant recurrence in hormone-receptor–positive, ERBB2-negative early breast cancer that is independent of clinicopathologic features and is also predictive of chemotherapy benefit when the RS is high,” wrote Joseph A. Sparano, MD, of Montefiore Medical Center, New York, and his colleagues. However, little is known about how this risk score applies to women with hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer, they said.

In the study published in JAMA Oncology, they identified 1,389 women with a recurrence score of 26-100 (the definition of a high recurrence risk). The average age of the patients was 56 years, and 71% were postmenopausal.

In addition to receiving endocrine therapy, the women were randomized to no chemotherapy (89 patients) or one of several chemotherapy regimens including docetaxel/cyclophosphamide (589 patients), anthracycline without a taxane (334 patients), an anthracycline and taxane (244 patients), cyclophosphamide/methotrexate/5-fluorouracil (52 patients), and other regimens (81 patients). Among those treated with chemotherapy, overall survival (OS) at 5 years was 96% and estimated rates of freedom from recurrence of breast cancer at a distant site, and from a distant and/or local regional site, at 5 years were 93% and 91%, respectively. At 5 years, the estimated rate of invasive disease–free survival (IDFS) was 88%.

When broken down by chemotherapy regimen, 5-year rates of freedom from recurrence of breast cancer at a distant site ranged from 92.3% to 95.5%, except for 88.5% for the cyclophosphamide/methotrexate/5-fluorouracil (CMF) group; the rate was 92.6% for patients in the no-chemotherapy group.

The 5-year rates of IDFS ranged from 84% to 91.3% in the chemotherapy groups, compared with 79.7% in the no-chemotherapy group.

The expected rates of distant recurrence in the overall patient population if treated with endocrine therapy alone was 78.8% at 5 years and 65.4% at 9 years, the researchers said. Rates among the patients with an RS of 26-30 if treated with endocrine therapy alone were 89.6% at 5 years and 80.6% at 9 years; rates for those with an RS of 31-100 were 70.7% and 54% for 5 and 9 years, respectively.

The study findings were limited by several factors including a lack of randomization to endocrine therapy alone and the relatively short follow-up period, the researchers noted. However, strengths include the large sample size and high rate of compliance with chemotherapy.

The results support data from previous studies and “add to the evidence base supporting the use of the 21-gene RS assay to guide the use of adjuvant chemotherapy in patients with hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer,” they concluded.

The study was supported in part by the National Cancer Institute, the Canadian Cancer Society Research Institute, the Breast Cancer Research Foundation, the Komen Foundation, and the Breast Cancer Research Stamp issued by the United States Postal Service. Dr. Sparano disclosed grants from the National Cancer Institute. Of the remaining authors, several disclosed receiving personal or speaker fees from the assay manufacturer, Genomic Health; one author received funding from the company during the study.

SOURCE: Sparano J et al. JAMA Oncol. 2019 Sep 30. doi: 10.1001/jamaoncol.2019.4794.

Researchers have found that patients with heart disease have an increased risk of hospitalization for severe cutaneous adverse reactions to allopurinol, with factors like chronic kidney disease and high initial dosage adding to that risk.

“Physicians who prescribe allopurinol should look for these risk factors so that they may consider initiating lower-dosage allopurinol and other precautions, which may prevent this rare but serious adverse reaction,” Chio Yokose, MD, of Massachusetts General Hospital in Boston and coauthors wrote in the Canadian Medical Association Journal.

To further investigate known associations between heart disease and severe cutaneous adverse reactions to allopurinol – including Stevens-Johnson syndrome and toxic epidermal necrolysis – the researchers used an administrative database known as Population Data BC to conduct a cohort study of allopurinol initiators in British Columbia between 1997 and 2015. Individuals with a history of severe cutaneous adverse reactions before starting allopurinol were excluded.

Of the 130,325 allopurinol users identified, 109 were hospitalized for allopurinol-associated severe cutaneous adverse reactions within 3 months of starting the drug. One in 655 allopurinol users with heart disease were admitted to the hospital for allopurinol-associated severe cutaneous adverse reaction (risk ratio = 1.53 per 1,000; 95% confidence interval, 1.10-2.06), compared with 1 in 1,548 allopurinol users without heart disease (risk ratio = 0.65 per 1,000; 95% CI, 0.50-0.82).

After multivariable analysis, other significant associations with hospital admission included chronic kidney disease (relative risk, 1.88; 95% CI, 1.17-3.02) and an initial allopurinol dosage greater than 100 mg/day (RR, 2.78; 95% CI, 1.75-4.43). In addition, patients with heart disease, chronic kidney disease, and an initial dosage greater than 100 mg/day had an 11-fold higher risk of hospital admission (RR, 11.13; 95% CI, 4.66-26.58).

The authors acknowledged their study’s limitations, including potential misclassification of reactions and comorbidities that can stem from a reliance on ICD codes. However, they also noted that “any misclassification is expected to be nondifferential” and bias results toward the null accordingly.

The study was funded by the Canadian Institutes of Health Research. One author reported receiving a grant from the National Institutes of Health and research support from AstraZeneca, along with consulting fees from Takeda, Selecta Biosciences, and Horizon. No other conflicts of interest were reported.

SOURCE: Yokose C et al. CMAJ. 2019 Sep 30. doi: 10.1503/cmaj.190339.

Researchers have found that patients with heart disease have an increased risk of hospitalization for severe cutaneous adverse reactions to allopurinol, with factors like chronic kidney disease and high initial dosage adding to that risk.

“Physicians who prescribe allopurinol should look for these risk factors so that they may consider initiating lower-dosage allopurinol and other precautions, which may prevent this rare but serious adverse reaction,” Chio Yokose, MD, of Massachusetts General Hospital in Boston and coauthors wrote in the Canadian Medical Association Journal.

To further investigate known associations between heart disease and severe cutaneous adverse reactions to allopurinol – including Stevens-Johnson syndrome and toxic epidermal necrolysis – the researchers used an administrative database known as Population Data BC to conduct a cohort study of allopurinol initiators in British Columbia between 1997 and 2015. Individuals with a history of severe cutaneous adverse reactions before starting allopurinol were excluded.

Of the 130,325 allopurinol users identified, 109 were hospitalized for allopurinol-associated severe cutaneous adverse reactions within 3 months of starting the drug. One in 655 allopurinol users with heart disease were admitted to the hospital for allopurinol-associated severe cutaneous adverse reaction (risk ratio = 1.53 per 1,000; 95% confidence interval, 1.10-2.06), compared with 1 in 1,548 allopurinol users without heart disease (risk ratio = 0.65 per 1,000; 95% CI, 0.50-0.82).

After multivariable analysis, other significant associations with hospital admission included chronic kidney disease (relative risk, 1.88; 95% CI, 1.17-3.02) and an initial allopurinol dosage greater than 100 mg/day (RR, 2.78; 95% CI, 1.75-4.43). In addition, patients with heart disease, chronic kidney disease, and an initial dosage greater than 100 mg/day had an 11-fold higher risk of hospital admission (RR, 11.13; 95% CI, 4.66-26.58).

The authors acknowledged their study’s limitations, including potential misclassification of reactions and comorbidities that can stem from a reliance on ICD codes. However, they also noted that “any misclassification is expected to be nondifferential” and bias results toward the null accordingly.

The study was funded by the Canadian Institutes of Health Research. One author reported receiving a grant from the National Institutes of Health and research support from AstraZeneca, along with consulting fees from Takeda, Selecta Biosciences, and Horizon. No other conflicts of interest were reported.

SOURCE: Yokose C et al. CMAJ. 2019 Sep 30. doi: 10.1503/cmaj.190339.

Researchers have found that patients with heart disease have an increased risk of hospitalization for severe cutaneous adverse reactions to allopurinol, with factors like chronic kidney disease and high initial dosage adding to that risk.

“Physicians who prescribe allopurinol should look for these risk factors so that they may consider initiating lower-dosage allopurinol and other precautions, which may prevent this rare but serious adverse reaction,” Chio Yokose, MD, of Massachusetts General Hospital in Boston and coauthors wrote in the Canadian Medical Association Journal.

To further investigate known associations between heart disease and severe cutaneous adverse reactions to allopurinol – including Stevens-Johnson syndrome and toxic epidermal necrolysis – the researchers used an administrative database known as Population Data BC to conduct a cohort study of allopurinol initiators in British Columbia between 1997 and 2015. Individuals with a history of severe cutaneous adverse reactions before starting allopurinol were excluded.

Of the 130,325 allopurinol users identified, 109 were hospitalized for allopurinol-associated severe cutaneous adverse reactions within 3 months of starting the drug. One in 655 allopurinol users with heart disease were admitted to the hospital for allopurinol-associated severe cutaneous adverse reaction (risk ratio = 1.53 per 1,000; 95% confidence interval, 1.10-2.06), compared with 1 in 1,548 allopurinol users without heart disease (risk ratio = 0.65 per 1,000; 95% CI, 0.50-0.82).

After multivariable analysis, other significant associations with hospital admission included chronic kidney disease (relative risk, 1.88; 95% CI, 1.17-3.02) and an initial allopurinol dosage greater than 100 mg/day (RR, 2.78; 95% CI, 1.75-4.43). In addition, patients with heart disease, chronic kidney disease, and an initial dosage greater than 100 mg/day had an 11-fold higher risk of hospital admission (RR, 11.13; 95% CI, 4.66-26.58).

The authors acknowledged their study’s limitations, including potential misclassification of reactions and comorbidities that can stem from a reliance on ICD codes. However, they also noted that “any misclassification is expected to be nondifferential” and bias results toward the null accordingly.

The study was funded by the Canadian Institutes of Health Research. One author reported receiving a grant from the National Institutes of Health and research support from AstraZeneca, along with consulting fees from Takeda, Selecta Biosciences, and Horizon. No other conflicts of interest were reported.

SOURCE: Yokose C et al. CMAJ. 2019 Sep 30. doi: 10.1503/cmaj.190339.

BARCELONA – Patients with newly diagnosed metastatic non–small cell lung cancer (NSCLC) had better overall survival with a first-line therapy combination of nivolumab (Opdivo) and low-dose ipilimumab (Yervoy) than patients treated with chemotherapy, reported investigators in the Checkmate 227 trial.

Neil Osterweil/MDedge News

Among 793 patients with treatment-naive metastatic NSCLC with programmed death-ligand 1 (PD-L1) expression of at least 1%, median overall survival (OS) was 17.1 months for patients treated with the combination versus 14.9 months for patients treated with chemotherapy, a difference that translated into a hazard ratio with the combination of 0.79 (P = .007). Two-year overall survival rates were 40% and 32.8%, respectively.

The improvement in OS with the combination occurred regardless of PD-L1 status, suggesting that it can be a chemotherapy-free option for patients with previously untreated metastatic NSCLC, Solange Peters, MD, of Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said at the European Society for Medical Oncology Congress.

Checkmate 227 “is the first phase 3 study proving the concept in an evidence-based fashion of the combination of CTLA4 and anti–PD-1/PD-L1 in non–small cell lung cancer,” Dr. Peters said at a briefing prior to her presentation of the data in a symposium.

CheckMate 227 investigators enrolled patients with stage IV or recurrent NSCLC who had not received any treatment previously. Part one of the multipart study was designed to compare different nivolumab-based regimens versus chemotherapy in patients with PD-L1 expression of 1% or greater, or less than 1%.

The trial has two independent primary endpoints, the first of which, progression-free survival (PFS) with nivolumab and ipilimumab versus chemotherapy, was reported at the 2018 annual meeting of the American Association for Cancer Research.

Dr. Peters presented the overall survival endpoint at ESMO 2019. Results of the study were published simultaneously in the New England Journal of Medicine (2019 Sep 28. doi: 10.1056/NEJMoa1910231).

In part one of the trial, patients with PD-L1 expression of at least 1% (1,189 patients) were randomized on a 1:1:1 basis to one of three treatment options: nivolumab plus low-dose ipilimumab, nivolumab alone, or histology-based chemotherapy. Patients with PD-L1 expression less than 1% (550 patients) were randomized to nivolumab plus low-dose ipilimumab, nivolumab plus chemotherapy, or chemotherapy.

The survival benefit seen with the immunotherapy combination was durable, with 2-year OS rates of 40% for nivolumab/ipilimumab versus 32.8% for chemotherapy. The median durations of response were 23.2 months vs. 6.2 months, respectively.

Patients with low or no PD-L1 expression levels also benefited from the immunotherapy combination, with a median OS of 17.2 months with nivolumab plus ipilimumab, compared with 12.2 months with chemotherapy.

Among all enrolled patients, the median OS duration was 17.1 months with nivolumab plus ipilimumab versus 13.9 months with chemotherapy.

Grade 3 or 4 treatment-related adverse events in the overall study population occurred in 32.8% of patients treated with combined immunotherapy and in 36% of those treated with chemotherapy.

“A key question remains: Is the addition of ipilimumab providing additional benefit on top of nivolumab?” Dr. Peters asked. The answer to that question appears to be “yes,” she said, pointing to a comparison of OS among patients with PD-L1 expression below 1%. Although this subanalysis was not powered for statistical significance, the survival curves indicated a significant advantage for the combination, compared with nivolumab alone or chemotherapy, with respective median OS rates of 17.2, 15.2, and 12.2 months.

“What have we learned from Checkmate 227 so far? Caveat emptor – buyer beware. Beware of the adverse event profile for this doublet chemotherapy combination,” said Sanjay Popat, MD, PhD, of the Royal Marsden Hospital in London, who was the invited discussant at the symposium.

He noted that among PD-L1–positive patients, the OS benefit appears to be driven by patients with high levels of PD-L1 expression (50% or greater).

Additional questions that need addressing, he said, include how immune-related adverse events evolve over time; whether the combination can be made less toxic without impairing efficacy; and what is the optimum duration, dosing, and scheduling of ipilimumab.

Neil Osterweil/MDedge News

“What is the promise of [Checkmate] 227? The promise of the 227 is to have long-lasting responses. That means long life for our patients with a chemo-sparing regimen,” commented Marina Garassino, MD, from the Istituto Nazionale dei Tumori in Milan, who was the invited discussant at the presymposium briefing.

“At the same time, we have to go back to the bench, to the scientists, and to ask the scientists to [help us] understand who are the patients to be treated with the combination of immunotherapy and immunotherapy, with the combination of chemotherapy and immunotherapy, and just with a single agent,” she said.

The study was funded by Bristol-Myers Squibb. Dr. Peters reported a consultant/advisory role, speakers bureau activity, and research support from BMS and others. Dr. Popat disclosed honoraria from BMS and others. Dr. Garrassino disclosed personal fees from BMS and others.

SOURCE: Hellmann MD et al. ESMO 2019. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910231.

BARCELONA – Patients with newly diagnosed metastatic non–small cell lung cancer (NSCLC) had better overall survival with a first-line therapy combination of nivolumab (Opdivo) and low-dose ipilimumab (Yervoy) than patients treated with chemotherapy, reported investigators in the Checkmate 227 trial.

Neil Osterweil/MDedge News

Among 793 patients with treatment-naive metastatic NSCLC with programmed death-ligand 1 (PD-L1) expression of at least 1%, median overall survival (OS) was 17.1 months for patients treated with the combination versus 14.9 months for patients treated with chemotherapy, a difference that translated into a hazard ratio with the combination of 0.79 (P = .007). Two-year overall survival rates were 40% and 32.8%, respectively.

The improvement in OS with the combination occurred regardless of PD-L1 status, suggesting that it can be a chemotherapy-free option for patients with previously untreated metastatic NSCLC, Solange Peters, MD, of Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said at the European Society for Medical Oncology Congress.

Checkmate 227 “is the first phase 3 study proving the concept in an evidence-based fashion of the combination of CTLA4 and anti–PD-1/PD-L1 in non–small cell lung cancer,” Dr. Peters said at a briefing prior to her presentation of the data in a symposium.

CheckMate 227 investigators enrolled patients with stage IV or recurrent NSCLC who had not received any treatment previously. Part one of the multipart study was designed to compare different nivolumab-based regimens versus chemotherapy in patients with PD-L1 expression of 1% or greater, or less than 1%.

The trial has two independent primary endpoints, the first of which, progression-free survival (PFS) with nivolumab and ipilimumab versus chemotherapy, was reported at the 2018 annual meeting of the American Association for Cancer Research.

Dr. Peters presented the overall survival endpoint at ESMO 2019. Results of the study were published simultaneously in the New England Journal of Medicine (2019 Sep 28. doi: 10.1056/NEJMoa1910231).

In part one of the trial, patients with PD-L1 expression of at least 1% (1,189 patients) were randomized on a 1:1:1 basis to one of three treatment options: nivolumab plus low-dose ipilimumab, nivolumab alone, or histology-based chemotherapy. Patients with PD-L1 expression less than 1% (550 patients) were randomized to nivolumab plus low-dose ipilimumab, nivolumab plus chemotherapy, or chemotherapy.

The survival benefit seen with the immunotherapy combination was durable, with 2-year OS rates of 40% for nivolumab/ipilimumab versus 32.8% for chemotherapy. The median durations of response were 23.2 months vs. 6.2 months, respectively.

Patients with low or no PD-L1 expression levels also benefited from the immunotherapy combination, with a median OS of 17.2 months with nivolumab plus ipilimumab, compared with 12.2 months with chemotherapy.

Among all enrolled patients, the median OS duration was 17.1 months with nivolumab plus ipilimumab versus 13.9 months with chemotherapy.

Grade 3 or 4 treatment-related adverse events in the overall study population occurred in 32.8% of patients treated with combined immunotherapy and in 36% of those treated with chemotherapy.

“A key question remains: Is the addition of ipilimumab providing additional benefit on top of nivolumab?” Dr. Peters asked. The answer to that question appears to be “yes,” she said, pointing to a comparison of OS among patients with PD-L1 expression below 1%. Although this subanalysis was not powered for statistical significance, the survival curves indicated a significant advantage for the combination, compared with nivolumab alone or chemotherapy, with respective median OS rates of 17.2, 15.2, and 12.2 months.

“What have we learned from Checkmate 227 so far? Caveat emptor – buyer beware. Beware of the adverse event profile for this doublet chemotherapy combination,” said Sanjay Popat, MD, PhD, of the Royal Marsden Hospital in London, who was the invited discussant at the symposium.

He noted that among PD-L1–positive patients, the OS benefit appears to be driven by patients with high levels of PD-L1 expression (50% or greater).

Additional questions that need addressing, he said, include how immune-related adverse events evolve over time; whether the combination can be made less toxic without impairing efficacy; and what is the optimum duration, dosing, and scheduling of ipilimumab.

Neil Osterweil/MDedge News

“What is the promise of [Checkmate] 227? The promise of the 227 is to have long-lasting responses. That means long life for our patients with a chemo-sparing regimen,” commented Marina Garassino, MD, from the Istituto Nazionale dei Tumori in Milan, who was the invited discussant at the presymposium briefing.

“At the same time, we have to go back to the bench, to the scientists, and to ask the scientists to [help us] understand who are the patients to be treated with the combination of immunotherapy and immunotherapy, with the combination of chemotherapy and immunotherapy, and just with a single agent,” she said.

The study was funded by Bristol-Myers Squibb. Dr. Peters reported a consultant/advisory role, speakers bureau activity, and research support from BMS and others. Dr. Popat disclosed honoraria from BMS and others. Dr. Garrassino disclosed personal fees from BMS and others.

SOURCE: Hellmann MD et al. ESMO 2019. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910231.

BARCELONA – Patients with newly diagnosed metastatic non–small cell lung cancer (NSCLC) had better overall survival with a first-line therapy combination of nivolumab (Opdivo) and low-dose ipilimumab (Yervoy) than patients treated with chemotherapy, reported investigators in the Checkmate 227 trial.

Neil Osterweil/MDedge News

Among 793 patients with treatment-naive metastatic NSCLC with programmed death-ligand 1 (PD-L1) expression of at least 1%, median overall survival (OS) was 17.1 months for patients treated with the combination versus 14.9 months for patients treated with chemotherapy, a difference that translated into a hazard ratio with the combination of 0.79 (P = .007). Two-year overall survival rates were 40% and 32.8%, respectively.

The improvement in OS with the combination occurred regardless of PD-L1 status, suggesting that it can be a chemotherapy-free option for patients with previously untreated metastatic NSCLC, Solange Peters, MD, of Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said at the European Society for Medical Oncology Congress.

Checkmate 227 “is the first phase 3 study proving the concept in an evidence-based fashion of the combination of CTLA4 and anti–PD-1/PD-L1 in non–small cell lung cancer,” Dr. Peters said at a briefing prior to her presentation of the data in a symposium.

CheckMate 227 investigators enrolled patients with stage IV or recurrent NSCLC who had not received any treatment previously. Part one of the multipart study was designed to compare different nivolumab-based regimens versus chemotherapy in patients with PD-L1 expression of 1% or greater, or less than 1%.

The trial has two independent primary endpoints, the first of which, progression-free survival (PFS) with nivolumab and ipilimumab versus chemotherapy, was reported at the 2018 annual meeting of the American Association for Cancer Research.

Dr. Peters presented the overall survival endpoint at ESMO 2019. Results of the study were published simultaneously in the New England Journal of Medicine (2019 Sep 28. doi: 10.1056/NEJMoa1910231).

In part one of the trial, patients with PD-L1 expression of at least 1% (1,189 patients) were randomized on a 1:1:1 basis to one of three treatment options: nivolumab plus low-dose ipilimumab, nivolumab alone, or histology-based chemotherapy. Patients with PD-L1 expression less than 1% (550 patients) were randomized to nivolumab plus low-dose ipilimumab, nivolumab plus chemotherapy, or chemotherapy.

The survival benefit seen with the immunotherapy combination was durable, with 2-year OS rates of 40% for nivolumab/ipilimumab versus 32.8% for chemotherapy. The median durations of response were 23.2 months vs. 6.2 months, respectively.

Patients with low or no PD-L1 expression levels also benefited from the immunotherapy combination, with a median OS of 17.2 months with nivolumab plus ipilimumab, compared with 12.2 months with chemotherapy.

Among all enrolled patients, the median OS duration was 17.1 months with nivolumab plus ipilimumab versus 13.9 months with chemotherapy.

Grade 3 or 4 treatment-related adverse events in the overall study population occurred in 32.8% of patients treated with combined immunotherapy and in 36% of those treated with chemotherapy.

“A key question remains: Is the addition of ipilimumab providing additional benefit on top of nivolumab?” Dr. Peters asked. The answer to that question appears to be “yes,” she said, pointing to a comparison of OS among patients with PD-L1 expression below 1%. Although this subanalysis was not powered for statistical significance, the survival curves indicated a significant advantage for the combination, compared with nivolumab alone or chemotherapy, with respective median OS rates of 17.2, 15.2, and 12.2 months.

“What have we learned from Checkmate 227 so far? Caveat emptor – buyer beware. Beware of the adverse event profile for this doublet chemotherapy combination,” said Sanjay Popat, MD, PhD, of the Royal Marsden Hospital in London, who was the invited discussant at the symposium.

He noted that among PD-L1–positive patients, the OS benefit appears to be driven by patients with high levels of PD-L1 expression (50% or greater).

Additional questions that need addressing, he said, include how immune-related adverse events evolve over time; whether the combination can be made less toxic without impairing efficacy; and what is the optimum duration, dosing, and scheduling of ipilimumab.

Neil Osterweil/MDedge News

“What is the promise of [Checkmate] 227? The promise of the 227 is to have long-lasting responses. That means long life for our patients with a chemo-sparing regimen,” commented Marina Garassino, MD, from the Istituto Nazionale dei Tumori in Milan, who was the invited discussant at the presymposium briefing.

“At the same time, we have to go back to the bench, to the scientists, and to ask the scientists to [help us] understand who are the patients to be treated with the combination of immunotherapy and immunotherapy, with the combination of chemotherapy and immunotherapy, and just with a single agent,” she said.

The study was funded by Bristol-Myers Squibb. Dr. Peters reported a consultant/advisory role, speakers bureau activity, and research support from BMS and others. Dr. Popat disclosed honoraria from BMS and others. Dr. Garrassino disclosed personal fees from BMS and others.

SOURCE: Hellmann MD et al. ESMO 2019. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910231.

BARCELONA – Adding olaparib to bevacizumab as maintenance after first-line platinum-based chemotherapy for advanced ovarian cancer provided a significant and clinically meaningful progression-free survival (PFS) benefit in the phase 3 PAOLA-1/ENGOT-ov25 trial.

The benefit was particularly pronounced in patients with a tumor BRCA mutation (tBRCAm), and in those with homologous recombination deficiency (HRD)–positive disease, Isabelle Ray-Coquard, MD, PhD, reported at the European Society for Medical Oncology Congress.

Investigator-assessed median PFS was 22.1 months in 537 patients randomized to receive the poly adenosine diphosphate–ribose polymerase (PARP) inhibitor olaparib plus bevacizumab maintenance, compared with 16.6 months in 269 patients who received placebo plus bevacizumab in the randomized, double-blind trial.

The difference was statistically significant (hazard ratio, 0.59; P = .0001), said Dr. Ray-Coquard, a medical oncologist at Centre Léon Bérard and a professor of medical oncology at the Université Claude Bernard, Lyon, France.

In patients with tBRCAm, the median PFS in the olaparib and placebo arms, respectively, was 37.2 vs. 21.7 months (HR, 0.31); in HRD-positive patients – inclusive of those with tBRCAm – median PFS was 37.2 vs. 17.7 months, respectively; and in HRD-positive patients without tBRCAm, median PFS was 28.1 and 16.6 months, respectively (HR, 0.43), she said.

“So PAOLA-1 met its primary endpoint of a statistically significant improvement in PFS in the [intent-to-treat] population, in favor of the olaparib arm,” Dr. Ray-Coquard said. “What does that mean? For advanced ovarian cancer ... a benefit of a median time of nearly 30 months without relapse.”

The findings of the subgroup analysis showing an even stronger association between combination olaparib and bevacizumab and improved PFS in patients with tBRCAm are similar to those reported from the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer, she noted.

“It is interesting to note that our PFS in the control arm is longer than [that seen] in the SOLO1 trial, which is probably due to the use of bevacizumab” in PAOLA-1, she said.

Additionally, a “new population of patients was identified: HRD-positive [patients] without BRCA mutation,” who experienced a PFS improvement of almost 1 year with olaparib versus placebo, Dr. Ray-Coquard noted.

Patients enrolled in the international trial – the first randomized trial to explore the efficacy and safety of maintenance olaparib plus bevacizumab in this setting and in patients with or without tBRCAm – had newly diagnosed stage III-IV, high-grade serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer; had undergone upfront or interval surgery; had received platinum-taxane–based chemotherapy; and had received at least three cycles of bevacizumab. They were randomized 2:1 to receive maintenance therapy with 300-mg olaparib tablets given twice daily for up to 24 months along with bevacizumab at a dose of 15 mg/kg on day 1 every 3 weeks for 15 months (including when combined with platinum-based chemotherapy), or placebo plus bevacizumab.

The current standard of care for most patients with newly diagnosed advanced ovarian cancer is surgery and platinum-based chemotherapy combined with bevacizumab, followed by bevacizumab alone for maintenance.

Patient characteristics in the two arms were well balanced, Dr. Ray-Coquard said. “The PAOLA-1 population is representative of the majority of patients with advanced ovarian cancer, as the patient selection was not restricted by surgical outcome or BRCA mutation,” she commented, adding that the safety profile of the olaparib-bevacizumab combination was generally consistent with that seen in previous trials.

The addition of olaparib did not appear to affect bevacizumab tolerability or quality of life, she noted.

During a press briefing at the congress, Susan Banerjee, MBBS, PhD, who reported the SOLO1 results at the 2018 ESMO Congress, said that “PARP inhibitors have revolutionized the treatment landscape in ovarian cancer,” and have been approved in the recurrent ovarian cancer setting.

“But if we’re really going to have a chance to increase overall survival, and hopefully [have] more women cured, we need to bring these treatments into the first-line setting,” said Dr. Banerjee, consultant medical oncologist and research lead for the gynecology unit of the Royal Marsden Hospital, NHS Foundation Trust, London.

Given these and other recent findings, answers to the key question of how to improve outcomes in the first-line setting – and in patients beyond those with BRCA mutations – are emerging and showing that more women with ovarian cancer can benefit from PARP inhibitors.

“We know now ... that we can use PARP inhibitors in the first-line setting, beyond women with BRCA mutations,” Dr. Banerjee said. “The key question, really, is ‘What about patients that don’t have HRD deficiency? We do know that patients with BRCA mutations and who are HRD-positive have the greatest benefit with either a PARP inhibitor alone or, indeed, in combination with bevacizumab.”

In an ESMO press release about the PAOLA-1 and other related data presented at the congress, Ana Oaknin, MD, of Vall D’Hebron Institute of Oncology in Barcelona, stated that “the main goal in ovarian cancer is to avoid relapse after first-line therapy because otherwise the probability of cure is quite low.”

Combination olaparib and bevacizumab for first-line maintenance therapy “should become a new standard of care for patients with advanced ovarian cancer,” she said, noting that, while the PAOLA-1/ENGOT-ov25 trial did not include patients with no response to first-line chemotherapy (who comprise a small group of ovarian cancer patients), the trial is “a significant step forward in treatment for these women.”

In the context of other positive trial findings, including those from SOLO1 and other studies of PARP inhibition in this setting, the results represent a milestone, Dr. Oaknin said. “After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression-free survival, and hopefully we will improve long-term outcome.”

As for the “next priority for research in this field, Dr. Oaknin said that strategies are needed to improve the current 45% 5-year overall survival rate for ovarian cancer. “I think the next approach is to incorporate immunotherapy as part of first-line therapy; ongoing trials are expected to report in 2-3 years,” she commented.

The PAOLA-1/ENGOT-ov25 trial was funded by ARCAGY Research, AstraZeneca, and Roche. Dr. Ray-Coquard reported relationships with AstraZeneca, Clovis Oncology, Tesaro, Pharma Mar, Roche, and Genmab, including receiving honoraria, travel/accommodations/expenses, and/or research grant funding, and/or serving as an advisor or consultant. Dr. Banerjee is a lecturer and/or advisory board member for AstraZeneca, Clovis, Gamamabs, Merck Serono, Pharmamar, Seattle Genetics, Roche, and Tesaro, and has received a travel grant from Nucana. Dr. Oaknin reported having no disclosures.

[email protected]

SOURCE: Ray-Coquard I et al. ESMO 2019, Abstract LBA2. Ann Oncol. 19;30:suppl 9.
 

BARCELONA – Adding olaparib to bevacizumab as maintenance after first-line platinum-based chemotherapy for advanced ovarian cancer provided a significant and clinically meaningful progression-free survival (PFS) benefit in the phase 3 PAOLA-1/ENGOT-ov25 trial.

The benefit was particularly pronounced in patients with a tumor BRCA mutation (tBRCAm), and in those with homologous recombination deficiency (HRD)–positive disease, Isabelle Ray-Coquard, MD, PhD, reported at the European Society for Medical Oncology Congress.

Investigator-assessed median PFS was 22.1 months in 537 patients randomized to receive the poly adenosine diphosphate–ribose polymerase (PARP) inhibitor olaparib plus bevacizumab maintenance, compared with 16.6 months in 269 patients who received placebo plus bevacizumab in the randomized, double-blind trial.

The difference was statistically significant (hazard ratio, 0.59; P = .0001), said Dr. Ray-Coquard, a medical oncologist at Centre Léon Bérard and a professor of medical oncology at the Université Claude Bernard, Lyon, France.

In patients with tBRCAm, the median PFS in the olaparib and placebo arms, respectively, was 37.2 vs. 21.7 months (HR, 0.31); in HRD-positive patients – inclusive of those with tBRCAm – median PFS was 37.2 vs. 17.7 months, respectively; and in HRD-positive patients without tBRCAm, median PFS was 28.1 and 16.6 months, respectively (HR, 0.43), she said.

“So PAOLA-1 met its primary endpoint of a statistically significant improvement in PFS in the [intent-to-treat] population, in favor of the olaparib arm,” Dr. Ray-Coquard said. “What does that mean? For advanced ovarian cancer ... a benefit of a median time of nearly 30 months without relapse.”

The findings of the subgroup analysis showing an even stronger association between combination olaparib and bevacizumab and improved PFS in patients with tBRCAm are similar to those reported from the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer, she noted.

“It is interesting to note that our PFS in the control arm is longer than [that seen] in the SOLO1 trial, which is probably due to the use of bevacizumab” in PAOLA-1, she said.

Additionally, a “new population of patients was identified: HRD-positive [patients] without BRCA mutation,” who experienced a PFS improvement of almost 1 year with olaparib versus placebo, Dr. Ray-Coquard noted.

Patients enrolled in the international trial – the first randomized trial to explore the efficacy and safety of maintenance olaparib plus bevacizumab in this setting and in patients with or without tBRCAm – had newly diagnosed stage III-IV, high-grade serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer; had undergone upfront or interval surgery; had received platinum-taxane–based chemotherapy; and had received at least three cycles of bevacizumab. They were randomized 2:1 to receive maintenance therapy with 300-mg olaparib tablets given twice daily for up to 24 months along with bevacizumab at a dose of 15 mg/kg on day 1 every 3 weeks for 15 months (including when combined with platinum-based chemotherapy), or placebo plus bevacizumab.

The current standard of care for most patients with newly diagnosed advanced ovarian cancer is surgery and platinum-based chemotherapy combined with bevacizumab, followed by bevacizumab alone for maintenance.

Patient characteristics in the two arms were well balanced, Dr. Ray-Coquard said. “The PAOLA-1 population is representative of the majority of patients with advanced ovarian cancer, as the patient selection was not restricted by surgical outcome or BRCA mutation,” she commented, adding that the safety profile of the olaparib-bevacizumab combination was generally consistent with that seen in previous trials.

The addition of olaparib did not appear to affect bevacizumab tolerability or quality of life, she noted.

During a press briefing at the congress, Susan Banerjee, MBBS, PhD, who reported the SOLO1 results at the 2018 ESMO Congress, said that “PARP inhibitors have revolutionized the treatment landscape in ovarian cancer,” and have been approved in the recurrent ovarian cancer setting.

“But if we’re really going to have a chance to increase overall survival, and hopefully [have] more women cured, we need to bring these treatments into the first-line setting,” said Dr. Banerjee, consultant medical oncologist and research lead for the gynecology unit of the Royal Marsden Hospital, NHS Foundation Trust, London.

Given these and other recent findings, answers to the key question of how to improve outcomes in the first-line setting – and in patients beyond those with BRCA mutations – are emerging and showing that more women with ovarian cancer can benefit from PARP inhibitors.

“We know now ... that we can use PARP inhibitors in the first-line setting, beyond women with BRCA mutations,” Dr. Banerjee said. “The key question, really, is ‘What about patients that don’t have HRD deficiency? We do know that patients with BRCA mutations and who are HRD-positive have the greatest benefit with either a PARP inhibitor alone or, indeed, in combination with bevacizumab.”

In an ESMO press release about the PAOLA-1 and other related data presented at the congress, Ana Oaknin, MD, of Vall D’Hebron Institute of Oncology in Barcelona, stated that “the main goal in ovarian cancer is to avoid relapse after first-line therapy because otherwise the probability of cure is quite low.”

Combination olaparib and bevacizumab for first-line maintenance therapy “should become a new standard of care for patients with advanced ovarian cancer,” she said, noting that, while the PAOLA-1/ENGOT-ov25 trial did not include patients with no response to first-line chemotherapy (who comprise a small group of ovarian cancer patients), the trial is “a significant step forward in treatment for these women.”

In the context of other positive trial findings, including those from SOLO1 and other studies of PARP inhibition in this setting, the results represent a milestone, Dr. Oaknin said. “After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression-free survival, and hopefully we will improve long-term outcome.”

As for the “next priority for research in this field, Dr. Oaknin said that strategies are needed to improve the current 45% 5-year overall survival rate for ovarian cancer. “I think the next approach is to incorporate immunotherapy as part of first-line therapy; ongoing trials are expected to report in 2-3 years,” she commented.

The PAOLA-1/ENGOT-ov25 trial was funded by ARCAGY Research, AstraZeneca, and Roche. Dr. Ray-Coquard reported relationships with AstraZeneca, Clovis Oncology, Tesaro, Pharma Mar, Roche, and Genmab, including receiving honoraria, travel/accommodations/expenses, and/or research grant funding, and/or serving as an advisor or consultant. Dr. Banerjee is a lecturer and/or advisory board member for AstraZeneca, Clovis, Gamamabs, Merck Serono, Pharmamar, Seattle Genetics, Roche, and Tesaro, and has received a travel grant from Nucana. Dr. Oaknin reported having no disclosures.

[email protected]

SOURCE: Ray-Coquard I et al. ESMO 2019, Abstract LBA2. Ann Oncol. 19;30:suppl 9.
 

BARCELONA – Adding olaparib to bevacizumab as maintenance after first-line platinum-based chemotherapy for advanced ovarian cancer provided a significant and clinically meaningful progression-free survival (PFS) benefit in the phase 3 PAOLA-1/ENGOT-ov25 trial.

The benefit was particularly pronounced in patients with a tumor BRCA mutation (tBRCAm), and in those with homologous recombination deficiency (HRD)–positive disease, Isabelle Ray-Coquard, MD, PhD, reported at the European Society for Medical Oncology Congress.

Investigator-assessed median PFS was 22.1 months in 537 patients randomized to receive the poly adenosine diphosphate–ribose polymerase (PARP) inhibitor olaparib plus bevacizumab maintenance, compared with 16.6 months in 269 patients who received placebo plus bevacizumab in the randomized, double-blind trial.

The difference was statistically significant (hazard ratio, 0.59; P = .0001), said Dr. Ray-Coquard, a medical oncologist at Centre Léon Bérard and a professor of medical oncology at the Université Claude Bernard, Lyon, France.

In patients with tBRCAm, the median PFS in the olaparib and placebo arms, respectively, was 37.2 vs. 21.7 months (HR, 0.31); in HRD-positive patients – inclusive of those with tBRCAm – median PFS was 37.2 vs. 17.7 months, respectively; and in HRD-positive patients without tBRCAm, median PFS was 28.1 and 16.6 months, respectively (HR, 0.43), she said.

“So PAOLA-1 met its primary endpoint of a statistically significant improvement in PFS in the [intent-to-treat] population, in favor of the olaparib arm,” Dr. Ray-Coquard said. “What does that mean? For advanced ovarian cancer ... a benefit of a median time of nearly 30 months without relapse.”

The findings of the subgroup analysis showing an even stronger association between combination olaparib and bevacizumab and improved PFS in patients with tBRCAm are similar to those reported from the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer, she noted.

“It is interesting to note that our PFS in the control arm is longer than [that seen] in the SOLO1 trial, which is probably due to the use of bevacizumab” in PAOLA-1, she said.

Additionally, a “new population of patients was identified: HRD-positive [patients] without BRCA mutation,” who experienced a PFS improvement of almost 1 year with olaparib versus placebo, Dr. Ray-Coquard noted.

Patients enrolled in the international trial – the first randomized trial to explore the efficacy and safety of maintenance olaparib plus bevacizumab in this setting and in patients with or without tBRCAm – had newly diagnosed stage III-IV, high-grade serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer; had undergone upfront or interval surgery; had received platinum-taxane–based chemotherapy; and had received at least three cycles of bevacizumab. They were randomized 2:1 to receive maintenance therapy with 300-mg olaparib tablets given twice daily for up to 24 months along with bevacizumab at a dose of 15 mg/kg on day 1 every 3 weeks for 15 months (including when combined with platinum-based chemotherapy), or placebo plus bevacizumab.

The current standard of care for most patients with newly diagnosed advanced ovarian cancer is surgery and platinum-based chemotherapy combined with bevacizumab, followed by bevacizumab alone for maintenance.

Patient characteristics in the two arms were well balanced, Dr. Ray-Coquard said. “The PAOLA-1 population is representative of the majority of patients with advanced ovarian cancer, as the patient selection was not restricted by surgical outcome or BRCA mutation,” she commented, adding that the safety profile of the olaparib-bevacizumab combination was generally consistent with that seen in previous trials.

The addition of olaparib did not appear to affect bevacizumab tolerability or quality of life, she noted.

During a press briefing at the congress, Susan Banerjee, MBBS, PhD, who reported the SOLO1 results at the 2018 ESMO Congress, said that “PARP inhibitors have revolutionized the treatment landscape in ovarian cancer,” and have been approved in the recurrent ovarian cancer setting.

“But if we’re really going to have a chance to increase overall survival, and hopefully [have] more women cured, we need to bring these treatments into the first-line setting,” said Dr. Banerjee, consultant medical oncologist and research lead for the gynecology unit of the Royal Marsden Hospital, NHS Foundation Trust, London.

Given these and other recent findings, answers to the key question of how to improve outcomes in the first-line setting – and in patients beyond those with BRCA mutations – are emerging and showing that more women with ovarian cancer can benefit from PARP inhibitors.

“We know now ... that we can use PARP inhibitors in the first-line setting, beyond women with BRCA mutations,” Dr. Banerjee said. “The key question, really, is ‘What about patients that don’t have HRD deficiency? We do know that patients with BRCA mutations and who are HRD-positive have the greatest benefit with either a PARP inhibitor alone or, indeed, in combination with bevacizumab.”

In an ESMO press release about the PAOLA-1 and other related data presented at the congress, Ana Oaknin, MD, of Vall D’Hebron Institute of Oncology in Barcelona, stated that “the main goal in ovarian cancer is to avoid relapse after first-line therapy because otherwise the probability of cure is quite low.”

Combination olaparib and bevacizumab for first-line maintenance therapy “should become a new standard of care for patients with advanced ovarian cancer,” she said, noting that, while the PAOLA-1/ENGOT-ov25 trial did not include patients with no response to first-line chemotherapy (who comprise a small group of ovarian cancer patients), the trial is “a significant step forward in treatment for these women.”

In the context of other positive trial findings, including those from SOLO1 and other studies of PARP inhibition in this setting, the results represent a milestone, Dr. Oaknin said. “After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression-free survival, and hopefully we will improve long-term outcome.”

As for the “next priority for research in this field, Dr. Oaknin said that strategies are needed to improve the current 45% 5-year overall survival rate for ovarian cancer. “I think the next approach is to incorporate immunotherapy as part of first-line therapy; ongoing trials are expected to report in 2-3 years,” she commented.

The PAOLA-1/ENGOT-ov25 trial was funded by ARCAGY Research, AstraZeneca, and Roche. Dr. Ray-Coquard reported relationships with AstraZeneca, Clovis Oncology, Tesaro, Pharma Mar, Roche, and Genmab, including receiving honoraria, travel/accommodations/expenses, and/or research grant funding, and/or serving as an advisor or consultant. Dr. Banerjee is a lecturer and/or advisory board member for AstraZeneca, Clovis, Gamamabs, Merck Serono, Pharmamar, Seattle Genetics, Roche, and Tesaro, and has received a travel grant from Nucana. Dr. Oaknin reported having no disclosures.

[email protected]

SOURCE: Ray-Coquard I et al. ESMO 2019, Abstract LBA2. Ann Oncol. 19;30:suppl 9.
 

PHILADELPHIA – While immune checkpoint inhibitors were not significantly more cardiotoxic than other lung cancer treatments, major adverse cardiac events (MACE) did occur earlier, and occurred more frequently in patients with elevated biomarkers, in a retrospective cohort study reported at the annual scientific meeting of the Heart Failure Society of America.

Andrew D. Bowser/MDedge News

The findings support monitoring of cardiac biomarkers in the initial phase of checkpoint inhibitor treatment to identify patient at high cardiac risk, according to Kalyan R. Chitturi, DO, a resident physician with the DeBakey Heart and Vascular Center, Houston Methodist Hospital, who presented the results.

“It’s the early period that warrants the closest monitoring, as within the first 30-40 days, there’s higher risk,” Dr. Chitturi said in an interview. “When there was a biomarker elevation, it markedly increased the risk of MACE, warranting a closer vigilance during that time period.”

The retrospective study conducted by Dr. Chitturi and colleagues included a total of 252 patients with lung cancer who had been treated at one of seven different sites in Houston Methodist Cancer Center between Aug. 1, 2015, and Aug. 1, 2018.

Immune checkpoint inhibitors did not significantly increase the risk of MACE, compared with other lung cancer therapies, with incidences of 13.3% and 10.3%, respectively (P = .632), the investigators found.

However, MACE did occur earlier in the checkpoint inhibitor group, at a median time to event of 40 days, compared with 118 days in the patients not treated with checkpoint inhibitors, they found.

Risk of MACE with checkpoint inhibitor treatment was increased in patients with elevated troponin (hazard ratio, 2.48; 95% confidence interval, 1.18-5.21; P = .017) or elevated brain natriuretic peptide (HR, 5.77; 95% CI, 2.70-12.35; P less than .001), according to multivariate logistic regression analysis results.

These results suggest biomarkers such as cardiac troponin and brain natriuretic peptide are warranted to monitor patients in the early phase of checkpoint inhibitor treatment, according to Dr. Chitturi. “In the cost-benefit ratio of often-lethal MACE, it’s well worth it to collect these,” he said in the interview.

The results corroborate findings from some other recent studies, he noted. These include a recent study that linked elevated serum troponin to myocarditis in patients treated with immune checkpoint inhibitors (J Am Coll Cardiol. 2018 Apr 24;71[16]:1755-64).

Dr. Chitturi and coauthors reported no disclosures related to their presentation at the HFSA meeting.

SOURCE: Chitturi KR et al. HFSA 2019, Abstract 127.

PHILADELPHIA – While immune checkpoint inhibitors were not significantly more cardiotoxic than other lung cancer treatments, major adverse cardiac events (MACE) did occur earlier, and occurred more frequently in patients with elevated biomarkers, in a retrospective cohort study reported at the annual scientific meeting of the Heart Failure Society of America.

Andrew D. Bowser/MDedge News

The findings support monitoring of cardiac biomarkers in the initial phase of checkpoint inhibitor treatment to identify patient at high cardiac risk, according to Kalyan R. Chitturi, DO, a resident physician with the DeBakey Heart and Vascular Center, Houston Methodist Hospital, who presented the results.

“It’s the early period that warrants the closest monitoring, as within the first 30-40 days, there’s higher risk,” Dr. Chitturi said in an interview. “When there was a biomarker elevation, it markedly increased the risk of MACE, warranting a closer vigilance during that time period.”

The retrospective study conducted by Dr. Chitturi and colleagues included a total of 252 patients with lung cancer who had been treated at one of seven different sites in Houston Methodist Cancer Center between Aug. 1, 2015, and Aug. 1, 2018.

Immune checkpoint inhibitors did not significantly increase the risk of MACE, compared with other lung cancer therapies, with incidences of 13.3% and 10.3%, respectively (P = .632), the investigators found.

However, MACE did occur earlier in the checkpoint inhibitor group, at a median time to event of 40 days, compared with 118 days in the patients not treated with checkpoint inhibitors, they found.

Risk of MACE with checkpoint inhibitor treatment was increased in patients with elevated troponin (hazard ratio, 2.48; 95% confidence interval, 1.18-5.21; P = .017) or elevated brain natriuretic peptide (HR, 5.77; 95% CI, 2.70-12.35; P less than .001), according to multivariate logistic regression analysis results.

These results suggest biomarkers such as cardiac troponin and brain natriuretic peptide are warranted to monitor patients in the early phase of checkpoint inhibitor treatment, according to Dr. Chitturi. “In the cost-benefit ratio of often-lethal MACE, it’s well worth it to collect these,” he said in the interview.

The results corroborate findings from some other recent studies, he noted. These include a recent study that linked elevated serum troponin to myocarditis in patients treated with immune checkpoint inhibitors (J Am Coll Cardiol. 2018 Apr 24;71[16]:1755-64).

Dr. Chitturi and coauthors reported no disclosures related to their presentation at the HFSA meeting.

SOURCE: Chitturi KR et al. HFSA 2019, Abstract 127.

PHILADELPHIA – While immune checkpoint inhibitors were not significantly more cardiotoxic than other lung cancer treatments, major adverse cardiac events (MACE) did occur earlier, and occurred more frequently in patients with elevated biomarkers, in a retrospective cohort study reported at the annual scientific meeting of the Heart Failure Society of America.

Andrew D. Bowser/MDedge News

The findings support monitoring of cardiac biomarkers in the initial phase of checkpoint inhibitor treatment to identify patient at high cardiac risk, according to Kalyan R. Chitturi, DO, a resident physician with the DeBakey Heart and Vascular Center, Houston Methodist Hospital, who presented the results.

“It’s the early period that warrants the closest monitoring, as within the first 30-40 days, there’s higher risk,” Dr. Chitturi said in an interview. “When there was a biomarker elevation, it markedly increased the risk of MACE, warranting a closer vigilance during that time period.”

The retrospective study conducted by Dr. Chitturi and colleagues included a total of 252 patients with lung cancer who had been treated at one of seven different sites in Houston Methodist Cancer Center between Aug. 1, 2015, and Aug. 1, 2018.

Immune checkpoint inhibitors did not significantly increase the risk of MACE, compared with other lung cancer therapies, with incidences of 13.3% and 10.3%, respectively (P = .632), the investigators found.

However, MACE did occur earlier in the checkpoint inhibitor group, at a median time to event of 40 days, compared with 118 days in the patients not treated with checkpoint inhibitors, they found.

Risk of MACE with checkpoint inhibitor treatment was increased in patients with elevated troponin (hazard ratio, 2.48; 95% confidence interval, 1.18-5.21; P = .017) or elevated brain natriuretic peptide (HR, 5.77; 95% CI, 2.70-12.35; P less than .001), according to multivariate logistic regression analysis results.

These results suggest biomarkers such as cardiac troponin and brain natriuretic peptide are warranted to monitor patients in the early phase of checkpoint inhibitor treatment, according to Dr. Chitturi. “In the cost-benefit ratio of often-lethal MACE, it’s well worth it to collect these,” he said in the interview.

The results corroborate findings from some other recent studies, he noted. These include a recent study that linked elevated serum troponin to myocarditis in patients treated with immune checkpoint inhibitors (J Am Coll Cardiol. 2018 Apr 24;71[16]:1755-64).

Dr. Chitturi and coauthors reported no disclosures related to their presentation at the HFSA meeting.

SOURCE: Chitturi KR et al. HFSA 2019, Abstract 127.

SAN FRANCISCO – It took about 50 MitraClip cases for operator outcomes to start improving, and outcomes were still improving at 200 cases, in a study reviewing 14,923 MitraClip procedures in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry from November 2013 to March 2018.

“These findings demonstrate the key role of operator experience in optimizing outcomes” of transcatheter mitral valve repair (TMVr) with MitraClip (Abbott Structural), said investigators, led by Adnan Chhatriwalla, MD, an interventional cardiologist at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.

“New operators may experience a ‘learning curve’ irrespective of the overall site experience or experience of other members of the Heart Team,” they wrote in the study (JACC Cardiovasc Interv. 2019 Sep 27. doi: 10.1016/j.jacc.2019.09.014).

“As TMVr becomes more prevalent in the U.S., it may be prudent for less experienced operators to be cognizant of where they sit on the ‘learning curve’ and to pay particular attention to case selection in their early experience, considering that more complex patients may be referred to more experienced centers for treatment when prudent,” they noted.

“The overall duration of the learning curve may exceed 200 cases,” Dr. Chhatriwalla said at the Transcatheter Cardiovascular Therapeutics annual meeting in a presentation that coincided with the study’s publication.

“This is a more complex procedure than [transcatheter aortic valve replacement], and the volume/outcome relationship is stronger. We are seeing issues that are related to early experience in low-volume programs. Public reporting so consumers can determine how many cases a center does is going to be critical,” said cardiothoracic surgeon Michael Mack, MD, director of the cardiovascular service line at a health system in Dallas, after the talk. He was one of the authors of the study.

The investigators compared outcomes among 549 operators who had done 1-25 MitraClip cases, 230 who had performed 26-50 cases, and 116 who had performed 50 or more.

Optimal procedural success – defined as less than or equal to 1+ residual mitral regurgitation (MR) without death or cardiac surgery – was 63.9%, 68.4%, and 75.1%, respectively, across the three groups (P less than .001). The “acceptable” procedural success rate – less than or equal to 2+ residual MR without death or cardiac surgery – was 91.4%, 92.4%, and 93.8% (P less than .001). No interaction was observed between the mechanism of mitral valve regurgitation and procedural outcomes.

Procedure time decreased as operators gained experience (145, 118, and 99 minutes), and atrial septal defect closure rates increased (0.9%, 1.4%, and 2.2%, respectively).

Composite complications rates also fell (9.7%, 8.1%, and 7.3%), driven mostly by less frequent cardiac perforation (1.0%, 1.1%, and 0.4%) and less frequent blood transfusion (9.6%, 8.6%, and 6.5%). The results were statistically significant.

“Adjusted learning curves for procedural success were visually evident after approximately 50 cases, and continued improvement in clinical outcomes was observed for the entire case sequence up to 200 cases,” the investigators wrote. The improvements could not be attributed to patient selection alone, they said.

More experienced operators were more likely to use more than one clip per case, and more frequently treated central and medial, as opposed to lateral, pathology. Operators with more than 50 cases were less likely to treat patients who had preexisting mitral stenosis or required home oxygen, and experienced operators were more likely to perform the procedure in unstable patients, when appropriate. The proportion of patients with functional MR – as opposed to degenerative disease – increased with increasing experience.

There were no statistically significant differences across the groups in stroke rates (P = .26), single-leaflet device attachments (P = .11), trans-septal complications (P = .25), urgent cardiac surgery (P = .42), or in-hospital mortality (P = .55).

Patients were a median of 81 years old, and most were white; 93% had 3+ or 4+ MR at baseline, and 86.3% had degenerative mitral disease. Two-thirds had atrial fibrillation/flutter.

The work was supported by the ACC/STS TVT Registry. Dr. Chhatriwalla is a proctor for Edwards Lifesciences and Medtronic, and is a speaker for Abbott, Edwards Lifesciences, and Medtronic. Dr. Mack has served as an investigator for Edwards Lifesciences and Abbott, and as a study chair for Medtronic. Other investigators reported similar industry disclosures.

The meeting is sponsored by the Cardiovascular Research Foundation.

[email protected]

SOURCE: Chhatriwalla A et. al. JACC Cardiovasc Interv. 2019 Sep 27. doi: 10.1016/j.jacc.2019.09.014.

SAN FRANCISCO – It took about 50 MitraClip cases for operator outcomes to start improving, and outcomes were still improving at 200 cases, in a study reviewing 14,923 MitraClip procedures in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry from November 2013 to March 2018.

“These findings demonstrate the key role of operator experience in optimizing outcomes” of transcatheter mitral valve repair (TMVr) with MitraClip (Abbott Structural), said investigators, led by Adnan Chhatriwalla, MD, an interventional cardiologist at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.

“New operators may experience a ‘learning curve’ irrespective of the overall site experience or experience of other members of the Heart Team,” they wrote in the study (JACC Cardiovasc Interv. 2019 Sep 27. doi: 10.1016/j.jacc.2019.09.014).

“As TMVr becomes more prevalent in the U.S., it may be prudent for less experienced operators to be cognizant of where they sit on the ‘learning curve’ and to pay particular attention to case selection in their early experience, considering that more complex patients may be referred to more experienced centers for treatment when prudent,” they noted.

“The overall duration of the learning curve may exceed 200 cases,” Dr. Chhatriwalla said at the Transcatheter Cardiovascular Therapeutics annual meeting in a presentation that coincided with the study’s publication.

“This is a more complex procedure than [transcatheter aortic valve replacement], and the volume/outcome relationship is stronger. We are seeing issues that are related to early experience in low-volume programs. Public reporting so consumers can determine how many cases a center does is going to be critical,” said cardiothoracic surgeon Michael Mack, MD, director of the cardiovascular service line at a health system in Dallas, after the talk. He was one of the authors of the study.

The investigators compared outcomes among 549 operators who had done 1-25 MitraClip cases, 230 who had performed 26-50 cases, and 116 who had performed 50 or more.

Optimal procedural success – defined as less than or equal to 1+ residual mitral regurgitation (MR) without death or cardiac surgery – was 63.9%, 68.4%, and 75.1%, respectively, across the three groups (P less than .001). The “acceptable” procedural success rate – less than or equal to 2+ residual MR without death or cardiac surgery – was 91.4%, 92.4%, and 93.8% (P less than .001). No interaction was observed between the mechanism of mitral valve regurgitation and procedural outcomes.

Procedure time decreased as operators gained experience (145, 118, and 99 minutes), and atrial septal defect closure rates increased (0.9%, 1.4%, and 2.2%, respectively).

Composite complications rates also fell (9.7%, 8.1%, and 7.3%), driven mostly by less frequent cardiac perforation (1.0%, 1.1%, and 0.4%) and less frequent blood transfusion (9.6%, 8.6%, and 6.5%). The results were statistically significant.

“Adjusted learning curves for procedural success were visually evident after approximately 50 cases, and continued improvement in clinical outcomes was observed for the entire case sequence up to 200 cases,” the investigators wrote. The improvements could not be attributed to patient selection alone, they said.

More experienced operators were more likely to use more than one clip per case, and more frequently treated central and medial, as opposed to lateral, pathology. Operators with more than 50 cases were less likely to treat patients who had preexisting mitral stenosis or required home oxygen, and experienced operators were more likely to perform the procedure in unstable patients, when appropriate. The proportion of patients with functional MR – as opposed to degenerative disease – increased with increasing experience.

There were no statistically significant differences across the groups in stroke rates (P = .26), single-leaflet device attachments (P = .11), trans-septal complications (P = .25), urgent cardiac surgery (P = .42), or in-hospital mortality (P = .55).

Patients were a median of 81 years old, and most were white; 93% had 3+ or 4+ MR at baseline, and 86.3% had degenerative mitral disease. Two-thirds had atrial fibrillation/flutter.

The work was supported by the ACC/STS TVT Registry. Dr. Chhatriwalla is a proctor for Edwards Lifesciences and Medtronic, and is a speaker for Abbott, Edwards Lifesciences, and Medtronic. Dr. Mack has served as an investigator for Edwards Lifesciences and Abbott, and as a study chair for Medtronic. Other investigators reported similar industry disclosures.

The meeting is sponsored by the Cardiovascular Research Foundation.

[email protected]

SOURCE: Chhatriwalla A et. al. JACC Cardiovasc Interv. 2019 Sep 27. doi: 10.1016/j.jacc.2019.09.014.

SAN FRANCISCO – It took about 50 MitraClip cases for operator outcomes to start improving, and outcomes were still improving at 200 cases, in a study reviewing 14,923 MitraClip procedures in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry from November 2013 to March 2018.

“These findings demonstrate the key role of operator experience in optimizing outcomes” of transcatheter mitral valve repair (TMVr) with MitraClip (Abbott Structural), said investigators, led by Adnan Chhatriwalla, MD, an interventional cardiologist at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.

“New operators may experience a ‘learning curve’ irrespective of the overall site experience or experience of other members of the Heart Team,” they wrote in the study (JACC Cardiovasc Interv. 2019 Sep 27. doi: 10.1016/j.jacc.2019.09.014).

“As TMVr becomes more prevalent in the U.S., it may be prudent for less experienced operators to be cognizant of where they sit on the ‘learning curve’ and to pay particular attention to case selection in their early experience, considering that more complex patients may be referred to more experienced centers for treatment when prudent,” they noted.

“The overall duration of the learning curve may exceed 200 cases,” Dr. Chhatriwalla said at the Transcatheter Cardiovascular Therapeutics annual meeting in a presentation that coincided with the study’s publication.

“This is a more complex procedure than [transcatheter aortic valve replacement], and the volume/outcome relationship is stronger. We are seeing issues that are related to early experience in low-volume programs. Public reporting so consumers can determine how many cases a center does is going to be critical,” said cardiothoracic surgeon Michael Mack, MD, director of the cardiovascular service line at a health system in Dallas, after the talk. He was one of the authors of the study.

The investigators compared outcomes among 549 operators who had done 1-25 MitraClip cases, 230 who had performed 26-50 cases, and 116 who had performed 50 or more.

Optimal procedural success – defined as less than or equal to 1+ residual mitral regurgitation (MR) without death or cardiac surgery – was 63.9%, 68.4%, and 75.1%, respectively, across the three groups (P less than .001). The “acceptable” procedural success rate – less than or equal to 2+ residual MR without death or cardiac surgery – was 91.4%, 92.4%, and 93.8% (P less than .001). No interaction was observed between the mechanism of mitral valve regurgitation and procedural outcomes.

Procedure time decreased as operators gained experience (145, 118, and 99 minutes), and atrial septal defect closure rates increased (0.9%, 1.4%, and 2.2%, respectively).

Composite complications rates also fell (9.7%, 8.1%, and 7.3%), driven mostly by less frequent cardiac perforation (1.0%, 1.1%, and 0.4%) and less frequent blood transfusion (9.6%, 8.6%, and 6.5%). The results were statistically significant.

“Adjusted learning curves for procedural success were visually evident after approximately 50 cases, and continued improvement in clinical outcomes was observed for the entire case sequence up to 200 cases,” the investigators wrote. The improvements could not be attributed to patient selection alone, they said.

More experienced operators were more likely to use more than one clip per case, and more frequently treated central and medial, as opposed to lateral, pathology. Operators with more than 50 cases were less likely to treat patients who had preexisting mitral stenosis or required home oxygen, and experienced operators were more likely to perform the procedure in unstable patients, when appropriate. The proportion of patients with functional MR – as opposed to degenerative disease – increased with increasing experience.

There were no statistically significant differences across the groups in stroke rates (P = .26), single-leaflet device attachments (P = .11), trans-septal complications (P = .25), urgent cardiac surgery (P = .42), or in-hospital mortality (P = .55).

Patients were a median of 81 years old, and most were white; 93% had 3+ or 4+ MR at baseline, and 86.3% had degenerative mitral disease. Two-thirds had atrial fibrillation/flutter.

The work was supported by the ACC/STS TVT Registry. Dr. Chhatriwalla is a proctor for Edwards Lifesciences and Medtronic, and is a speaker for Abbott, Edwards Lifesciences, and Medtronic. Dr. Mack has served as an investigator for Edwards Lifesciences and Abbott, and as a study chair for Medtronic. Other investigators reported similar industry disclosures.

The meeting is sponsored by the Cardiovascular Research Foundation.

[email protected]

SOURCE: Chhatriwalla A et. al. JACC Cardiovasc Interv. 2019 Sep 27. doi: 10.1016/j.jacc.2019.09.014.

SAN FRANCISCO – After 3 months of ticagrelor (Brilinta) plus aspirin following cardiac stenting, stopping the aspirin but continuing the ticagrelor resulted in less bleeding with no increase in ischemic events in a randomized trial with more than 7,000 drug-eluting stent patients at high risk for both.

“This was a superior therapy” to staying on both drugs, the more usual approach, said lead investigator Roxana Mehran, MD, director of interventional cardiovascular research and clinical trials at the Icahn School of Medicine at Mount Sinai, New York.

“We can’t say this is for all comers, but for patients whose physician felt comfortable putting them on aspirin and ticagrelor,” who tolerated it well for the first 3 months, and who had clinical and angiographic indications of risk, “I think these patients can be peeled away” from aspirin, she said in a presentation at the Transcatheter Cardiovascular Therapeutics annual meeting that coincided with publication of the trial, dubbed TWILIGHT (Ticagrelor with Aspirin or Alone in High-Risk Patients after Coronary Intervention).

Interventional cardiologists have long sought the sweet spot for dual-antiplatelet therapy (DAPT) after stenting; the idea is to maximize thrombosis prevention while minimizing bleeding risk. The trial supports the trend in recent years towards shorter DAPT. Often, however, it’s the P2Y12 inhibitor – ticagrelor, clopidogrel (Plavix), or prasugrel (Effient) – that goes first, not the aspirin.

Responding to an audience question about why the trial didn’t include an aspirin monotherapy arm, Dr. Mehran said that aspirin alone wouldn’t have been sufficient in high-risk patients “in whom you have almost 70% acute coronary syndrome.” She added that her team has data showing that aspirin itself doesn’t have much effect on blood thrombogenicity.

The 7,119 patients in TWILIGHT were on ticagrelor 90 mg twice daily and aspirin 81-100 mg daily for 3 months, then evenly randomized to continued treatment or ticagrelor plus an aspirin placebo for a year.

Subjects had to have at least one clinical and angiographic finding that put them at high risk for bleeding or an ischemic event, such as chronic kidney disease, acute coronary syndrome, diabetes, or a bifurcated target lesion treated with two stents.

One year after randomization, 4% in the ticagrelor monotherapy group versus 7.1% in the ticagrelor plus aspirin arm reached the primary end point, actionable (type 2), severe (type 3), or fatal (type 5) bleeding on the Bleeding Academic Research Consortium scale (hazard ratio, 0.56; 95% confidence interval, 0.45 - 0.68, P less than .001).

The incidence of death from any cause, nonfatal myocardial infarction, or nonfatal stroke was 3.9% in both groups (HR, 0.99; 95% CI, 0.78-1.25; P less than .001 for noninferiority).

There were more ischemic strokes in the ticagrelor monotherapy arm (0.5% versus 0.2%). All-cause mortality (1.3% versus 1%) and stent thrombosis (0.6% versus 0.4%) were more frequent in the ticagrelor/aspirin group, but the differences were not statistically significant.

The two groups were well balanced. The mean age was 65 years, 23.8% of the patients were female, 37% had diabetes, and 65% had percutaneous coronary intervention for an acute coronary syndrome. Almost two-thirds had multivessel disease. Mean stent length was about 40 mm. The trial excluded patients with prior strokes.

Almost 2,000 patients originally enrolled in the trial never made it to randomization because they had a major bleeding or ischemic event in the 3-month run up, or dyspnea or some other reaction to ticagrelor.

The recent STOPDAPT-2 trial had a similar outcome – less bleeding with no increase in ischemic events – with clopidogrel monotherapy after a month-long run in of dual therapy with aspirin, versus continued treatment with both, in patients at low risk for ischemic events after stenting (JAMA. 2019 Jun 25;321[24]:2414-27).

Another recent study, GLOBAL LEADERS, concluded that 1 month of DAPT followed by ticagrelor monotherapy for 23 months was not superior to 12 months of DAPT followed by a year of aspirin. There was a numerical advantage for solo ticagrelor on death, myocardial infarction, and bleeding, but it did not reach statistical significance (Lancet. 2018 Sep 15;392[10151]:940-9).

The work was funded by ticagrelor’s maker, AstraZeneca. Dr. Mehran reported consulting and other relationships with Abbott, Janssen, and other companies.

[email protected]

SOURCE: Mehran A et al. N Engl J Med. 2019 Sep 26. doi: 10.1056/NEJMoa1908419.

SAN FRANCISCO – After 3 months of ticagrelor (Brilinta) plus aspirin following cardiac stenting, stopping the aspirin but continuing the ticagrelor resulted in less bleeding with no increase in ischemic events in a randomized trial with more than 7,000 drug-eluting stent patients at high risk for both.

“This was a superior therapy” to staying on both drugs, the more usual approach, said lead investigator Roxana Mehran, MD, director of interventional cardiovascular research and clinical trials at the Icahn School of Medicine at Mount Sinai, New York.

“We can’t say this is for all comers, but for patients whose physician felt comfortable putting them on aspirin and ticagrelor,” who tolerated it well for the first 3 months, and who had clinical and angiographic indications of risk, “I think these patients can be peeled away” from aspirin, she said in a presentation at the Transcatheter Cardiovascular Therapeutics annual meeting that coincided with publication of the trial, dubbed TWILIGHT (Ticagrelor with Aspirin or Alone in High-Risk Patients after Coronary Intervention).

Interventional cardiologists have long sought the sweet spot for dual-antiplatelet therapy (DAPT) after stenting; the idea is to maximize thrombosis prevention while minimizing bleeding risk. The trial supports the trend in recent years towards shorter DAPT. Often, however, it’s the P2Y12 inhibitor – ticagrelor, clopidogrel (Plavix), or prasugrel (Effient) – that goes first, not the aspirin.

Responding to an audience question about why the trial didn’t include an aspirin monotherapy arm, Dr. Mehran said that aspirin alone wouldn’t have been sufficient in high-risk patients “in whom you have almost 70% acute coronary syndrome.” She added that her team has data showing that aspirin itself doesn’t have much effect on blood thrombogenicity.

The 7,119 patients in TWILIGHT were on ticagrelor 90 mg twice daily and aspirin 81-100 mg daily for 3 months, then evenly randomized to continued treatment or ticagrelor plus an aspirin placebo for a year.

Subjects had to have at least one clinical and angiographic finding that put them at high risk for bleeding or an ischemic event, such as chronic kidney disease, acute coronary syndrome, diabetes, or a bifurcated target lesion treated with two stents.

One year after randomization, 4% in the ticagrelor monotherapy group versus 7.1% in the ticagrelor plus aspirin arm reached the primary end point, actionable (type 2), severe (type 3), or fatal (type 5) bleeding on the Bleeding Academic Research Consortium scale (hazard ratio, 0.56; 95% confidence interval, 0.45 - 0.68, P less than .001).

The incidence of death from any cause, nonfatal myocardial infarction, or nonfatal stroke was 3.9% in both groups (HR, 0.99; 95% CI, 0.78-1.25; P less than .001 for noninferiority).

There were more ischemic strokes in the ticagrelor monotherapy arm (0.5% versus 0.2%). All-cause mortality (1.3% versus 1%) and stent thrombosis (0.6% versus 0.4%) were more frequent in the ticagrelor/aspirin group, but the differences were not statistically significant.

The two groups were well balanced. The mean age was 65 years, 23.8% of the patients were female, 37% had diabetes, and 65% had percutaneous coronary intervention for an acute coronary syndrome. Almost two-thirds had multivessel disease. Mean stent length was about 40 mm. The trial excluded patients with prior strokes.

Almost 2,000 patients originally enrolled in the trial never made it to randomization because they had a major bleeding or ischemic event in the 3-month run up, or dyspnea or some other reaction to ticagrelor.

The recent STOPDAPT-2 trial had a similar outcome – less bleeding with no increase in ischemic events – with clopidogrel monotherapy after a month-long run in of dual therapy with aspirin, versus continued treatment with both, in patients at low risk for ischemic events after stenting (JAMA. 2019 Jun 25;321[24]:2414-27).

Another recent study, GLOBAL LEADERS, concluded that 1 month of DAPT followed by ticagrelor monotherapy for 23 months was not superior to 12 months of DAPT followed by a year of aspirin. There was a numerical advantage for solo ticagrelor on death, myocardial infarction, and bleeding, but it did not reach statistical significance (Lancet. 2018 Sep 15;392[10151]:940-9).

The work was funded by ticagrelor’s maker, AstraZeneca. Dr. Mehran reported consulting and other relationships with Abbott, Janssen, and other companies.

[email protected]

SOURCE: Mehran A et al. N Engl J Med. 2019 Sep 26. doi: 10.1056/NEJMoa1908419.

SAN FRANCISCO – After 3 months of ticagrelor (Brilinta) plus aspirin following cardiac stenting, stopping the aspirin but continuing the ticagrelor resulted in less bleeding with no increase in ischemic events in a randomized trial with more than 7,000 drug-eluting stent patients at high risk for both.

“This was a superior therapy” to staying on both drugs, the more usual approach, said lead investigator Roxana Mehran, MD, director of interventional cardiovascular research and clinical trials at the Icahn School of Medicine at Mount Sinai, New York.

“We can’t say this is for all comers, but for patients whose physician felt comfortable putting them on aspirin and ticagrelor,” who tolerated it well for the first 3 months, and who had clinical and angiographic indications of risk, “I think these patients can be peeled away” from aspirin, she said in a presentation at the Transcatheter Cardiovascular Therapeutics annual meeting that coincided with publication of the trial, dubbed TWILIGHT (Ticagrelor with Aspirin or Alone in High-Risk Patients after Coronary Intervention).

Interventional cardiologists have long sought the sweet spot for dual-antiplatelet therapy (DAPT) after stenting; the idea is to maximize thrombosis prevention while minimizing bleeding risk. The trial supports the trend in recent years towards shorter DAPT. Often, however, it’s the P2Y12 inhibitor – ticagrelor, clopidogrel (Plavix), or prasugrel (Effient) – that goes first, not the aspirin.

Responding to an audience question about why the trial didn’t include an aspirin monotherapy arm, Dr. Mehran said that aspirin alone wouldn’t have been sufficient in high-risk patients “in whom you have almost 70% acute coronary syndrome.” She added that her team has data showing that aspirin itself doesn’t have much effect on blood thrombogenicity.

The 7,119 patients in TWILIGHT were on ticagrelor 90 mg twice daily and aspirin 81-100 mg daily for 3 months, then evenly randomized to continued treatment or ticagrelor plus an aspirin placebo for a year.

Subjects had to have at least one clinical and angiographic finding that put them at high risk for bleeding or an ischemic event, such as chronic kidney disease, acute coronary syndrome, diabetes, or a bifurcated target lesion treated with two stents.

One year after randomization, 4% in the ticagrelor monotherapy group versus 7.1% in the ticagrelor plus aspirin arm reached the primary end point, actionable (type 2), severe (type 3), or fatal (type 5) bleeding on the Bleeding Academic Research Consortium scale (hazard ratio, 0.56; 95% confidence interval, 0.45 - 0.68, P less than .001).

The incidence of death from any cause, nonfatal myocardial infarction, or nonfatal stroke was 3.9% in both groups (HR, 0.99; 95% CI, 0.78-1.25; P less than .001 for noninferiority).

There were more ischemic strokes in the ticagrelor monotherapy arm (0.5% versus 0.2%). All-cause mortality (1.3% versus 1%) and stent thrombosis (0.6% versus 0.4%) were more frequent in the ticagrelor/aspirin group, but the differences were not statistically significant.

The two groups were well balanced. The mean age was 65 years, 23.8% of the patients were female, 37% had diabetes, and 65% had percutaneous coronary intervention for an acute coronary syndrome. Almost two-thirds had multivessel disease. Mean stent length was about 40 mm. The trial excluded patients with prior strokes.

Almost 2,000 patients originally enrolled in the trial never made it to randomization because they had a major bleeding or ischemic event in the 3-month run up, or dyspnea or some other reaction to ticagrelor.

The recent STOPDAPT-2 trial had a similar outcome – less bleeding with no increase in ischemic events – with clopidogrel monotherapy after a month-long run in of dual therapy with aspirin, versus continued treatment with both, in patients at low risk for ischemic events after stenting (JAMA. 2019 Jun 25;321[24]:2414-27).

Another recent study, GLOBAL LEADERS, concluded that 1 month of DAPT followed by ticagrelor monotherapy for 23 months was not superior to 12 months of DAPT followed by a year of aspirin. There was a numerical advantage for solo ticagrelor on death, myocardial infarction, and bleeding, but it did not reach statistical significance (Lancet. 2018 Sep 15;392[10151]:940-9).

The work was funded by ticagrelor’s maker, AstraZeneca. Dr. Mehran reported consulting and other relationships with Abbott, Janssen, and other companies.

[email protected]

SOURCE: Mehran A et al. N Engl J Med. 2019 Sep 26. doi: 10.1056/NEJMoa1908419.

BARCELONA – In patients with advanced, treatment-naive non–small cell lung cancer (NSCLC), therapy with osimertinib (Tagrisso) is associated with a significant and clinically meaningful improvement in overall survival, compared with other agents targeted against NSCLC with epidermal growth factor–receptor (EGFR) mutations, investigators for the FLAURA trial reported.

Neil Osterweil/MDedge News

After median follow-up ranging from 27 to 35.8 months, the median overall survival was 38.6 months for patients randomized to osimertinib, compared with 31.8 months for patients assigned to either of two comparator tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or erlotinib (Tarceva).

The hazard ratio for death with osimertinib was 0.799 (P = .0462), reported Suresh Ramalingam, MD, director of the lung cancer program at Winship Cancer Institute of Emory University, Atlanta.

“I’m excited that the new milestone accomplished with osimertinib in this trial will serve as the platform to build on in our efforts to improve the lives of patients with lung cancer,” he said at the European Society for Medical Oncology Congress.

Osimertinib is the first TKI to show improvement in overall survival over another TKI in the treatment of advanced stage cancers, he noted.

Overall survival was a secondary endpoint of the FLAURA trial. As previously reported, FLAURA met its primary endpoint of improvement in progression-free survival (PFS) in an interim analysis presented at ESMO 2017. In that analysis, osimertinib cut the risk of disease progression by 54%, compared with gefitinib or erlotinib.

Among 279 patients with EGFR-mutated locally advanced or metastatic NSCLC treated with osimertinib, the median PFS was 18.9 months, compared with 10.2 months for 277 patients treated with the standard of care, which translated into a HR of 0.46 (P less than .0001).

The FLAURA results supported Food and Drug Administration approval of osimertinib in April 2018 for first-line treatment of patients with metastatic NSCLC with EGFR mutations as detected by an FDA-approved test.

The current overall survival analysis, although not powered to show differences among patient subgroups, showed trends favoring osimertinib over a comparator TKI among both men and women, older and younger patients, patients with central nervous system metastases at trial entry, and patients with the EGFR exon 19 deletion at randomization.

The 31.8 month median overall survival for the control (comparator-TKI) arm is among the highest reported for patients with EGFR-mutated NSCLC, Dr. Ramalingam noted.

“That is because a lot of patients crossed over from the control group to receive osimertinib on progression,” he said, adding that the magnitude of benefit from osimertinib was greater among non-Asian patients, compared with Asians.
 

FLAURA details

In the phase 3 FLAURA trial, investigators stratified patients with previously untreated NSCLC positive for EGFR resistance mutations according to mutation status (exon 19 deletion or the L858R amino acid substitution in exon 21) and race (Asian or non-Asian).

Patients were randomly assigned to treatment with either oral osimertinib 80 mg daily or an EGFR TKI, either oral gefitinib 250 mg or erlotinib 150 mg daily.

The patients were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) every 6 weeks until objective disease progression.

Patients assigned to the standard-of-care arm who had central confirmation of progression and T790M positivity were allowed to cross over to open-label osimertinib.

PFS, the primary endpoint, was also significantly better with osimertinib than with either of the comparator TKIs in patients with and without central nervous system metastases at study entry (HR, 0.47; P = .0009 for patients with CNS metastases; HR, 0.46; P less than .0001 for patients with no CNS metastases).

Neil Osterweil/MDedge News

“For clinicians, for patients, and also for our health authorities, the results in terms of overall survival are really relevant, and this is why this study is so important, knowing this secondary endpoint from a statistical point of view. The study is statistically significant and clinically relevant,” commented Pilar Garrido, MD, from the department of medical oncology, Hospital Universitario Ramón y Cajal in Madrid, the invited discussant at a briefing where Dr. Ramalingam outlined the study findings prior to his presentation of the data in a symposium.

“What’s the future of EGFR mutant lung cancer? Well, I think we should be done with single-agent EGFR-TKI comparisons: We have a clear agent that’s associated with an improvement in survival. I think our focus needs to shift to building on or adding to osimertinib,” commented Pasi A Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute in Boston, the invited discussant at the symposium.

He said that the challenge for clinicians will be to identify high- and low-risk EGFR-mutant NSCLC, and to determine which patients could be treated with a single agent, and which may require a combination therapy approach.

FLAURA was sponsored by AstraZeneca. Dr. Ramalingam disclosed honoraria, an advisory or consulting role, and research funding from that company and others. Dr. Garrido disclosed a speaker and advisory role for AstraZeneca and others. Dr. Jänne disclosed prior consulting for AstraZeneca.

SOURCE: Ramalingam S et al. ESMO 2019. Abstract LBA5_PR.

BARCELONA – In patients with advanced, treatment-naive non–small cell lung cancer (NSCLC), therapy with osimertinib (Tagrisso) is associated with a significant and clinically meaningful improvement in overall survival, compared with other agents targeted against NSCLC with epidermal growth factor–receptor (EGFR) mutations, investigators for the FLAURA trial reported.

Neil Osterweil/MDedge News

After median follow-up ranging from 27 to 35.8 months, the median overall survival was 38.6 months for patients randomized to osimertinib, compared with 31.8 months for patients assigned to either of two comparator tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or erlotinib (Tarceva).

The hazard ratio for death with osimertinib was 0.799 (P = .0462), reported Suresh Ramalingam, MD, director of the lung cancer program at Winship Cancer Institute of Emory University, Atlanta.

“I’m excited that the new milestone accomplished with osimertinib in this trial will serve as the platform to build on in our efforts to improve the lives of patients with lung cancer,” he said at the European Society for Medical Oncology Congress.

Osimertinib is the first TKI to show improvement in overall survival over another TKI in the treatment of advanced stage cancers, he noted.

Overall survival was a secondary endpoint of the FLAURA trial. As previously reported, FLAURA met its primary endpoint of improvement in progression-free survival (PFS) in an interim analysis presented at ESMO 2017. In that analysis, osimertinib cut the risk of disease progression by 54%, compared with gefitinib or erlotinib.

Among 279 patients with EGFR-mutated locally advanced or metastatic NSCLC treated with osimertinib, the median PFS was 18.9 months, compared with 10.2 months for 277 patients treated with the standard of care, which translated into a HR of 0.46 (P less than .0001).

The FLAURA results supported Food and Drug Administration approval of osimertinib in April 2018 for first-line treatment of patients with metastatic NSCLC with EGFR mutations as detected by an FDA-approved test.

The current overall survival analysis, although not powered to show differences among patient subgroups, showed trends favoring osimertinib over a comparator TKI among both men and women, older and younger patients, patients with central nervous system metastases at trial entry, and patients with the EGFR exon 19 deletion at randomization.

The 31.8 month median overall survival for the control (comparator-TKI) arm is among the highest reported for patients with EGFR-mutated NSCLC, Dr. Ramalingam noted.

“That is because a lot of patients crossed over from the control group to receive osimertinib on progression,” he said, adding that the magnitude of benefit from osimertinib was greater among non-Asian patients, compared with Asians.
 

FLAURA details

In the phase 3 FLAURA trial, investigators stratified patients with previously untreated NSCLC positive for EGFR resistance mutations according to mutation status (exon 19 deletion or the L858R amino acid substitution in exon 21) and race (Asian or non-Asian).

Patients were randomly assigned to treatment with either oral osimertinib 80 mg daily or an EGFR TKI, either oral gefitinib 250 mg or erlotinib 150 mg daily.

The patients were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) every 6 weeks until objective disease progression.

Patients assigned to the standard-of-care arm who had central confirmation of progression and T790M positivity were allowed to cross over to open-label osimertinib.

PFS, the primary endpoint, was also significantly better with osimertinib than with either of the comparator TKIs in patients with and without central nervous system metastases at study entry (HR, 0.47; P = .0009 for patients with CNS metastases; HR, 0.46; P less than .0001 for patients with no CNS metastases).

Neil Osterweil/MDedge News

“For clinicians, for patients, and also for our health authorities, the results in terms of overall survival are really relevant, and this is why this study is so important, knowing this secondary endpoint from a statistical point of view. The study is statistically significant and clinically relevant,” commented Pilar Garrido, MD, from the department of medical oncology, Hospital Universitario Ramón y Cajal in Madrid, the invited discussant at a briefing where Dr. Ramalingam outlined the study findings prior to his presentation of the data in a symposium.

“What’s the future of EGFR mutant lung cancer? Well, I think we should be done with single-agent EGFR-TKI comparisons: We have a clear agent that’s associated with an improvement in survival. I think our focus needs to shift to building on or adding to osimertinib,” commented Pasi A Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute in Boston, the invited discussant at the symposium.

He said that the challenge for clinicians will be to identify high- and low-risk EGFR-mutant NSCLC, and to determine which patients could be treated with a single agent, and which may require a combination therapy approach.

FLAURA was sponsored by AstraZeneca. Dr. Ramalingam disclosed honoraria, an advisory or consulting role, and research funding from that company and others. Dr. Garrido disclosed a speaker and advisory role for AstraZeneca and others. Dr. Jänne disclosed prior consulting for AstraZeneca.

SOURCE: Ramalingam S et al. ESMO 2019. Abstract LBA5_PR.

BARCELONA – In patients with advanced, treatment-naive non–small cell lung cancer (NSCLC), therapy with osimertinib (Tagrisso) is associated with a significant and clinically meaningful improvement in overall survival, compared with other agents targeted against NSCLC with epidermal growth factor–receptor (EGFR) mutations, investigators for the FLAURA trial reported.

Neil Osterweil/MDedge News

After median follow-up ranging from 27 to 35.8 months, the median overall survival was 38.6 months for patients randomized to osimertinib, compared with 31.8 months for patients assigned to either of two comparator tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or erlotinib (Tarceva).

The hazard ratio for death with osimertinib was 0.799 (P = .0462), reported Suresh Ramalingam, MD, director of the lung cancer program at Winship Cancer Institute of Emory University, Atlanta.

“I’m excited that the new milestone accomplished with osimertinib in this trial will serve as the platform to build on in our efforts to improve the lives of patients with lung cancer,” he said at the European Society for Medical Oncology Congress.

Osimertinib is the first TKI to show improvement in overall survival over another TKI in the treatment of advanced stage cancers, he noted.

Overall survival was a secondary endpoint of the FLAURA trial. As previously reported, FLAURA met its primary endpoint of improvement in progression-free survival (PFS) in an interim analysis presented at ESMO 2017. In that analysis, osimertinib cut the risk of disease progression by 54%, compared with gefitinib or erlotinib.

Among 279 patients with EGFR-mutated locally advanced or metastatic NSCLC treated with osimertinib, the median PFS was 18.9 months, compared with 10.2 months for 277 patients treated with the standard of care, which translated into a HR of 0.46 (P less than .0001).

The FLAURA results supported Food and Drug Administration approval of osimertinib in April 2018 for first-line treatment of patients with metastatic NSCLC with EGFR mutations as detected by an FDA-approved test.

The current overall survival analysis, although not powered to show differences among patient subgroups, showed trends favoring osimertinib over a comparator TKI among both men and women, older and younger patients, patients with central nervous system metastases at trial entry, and patients with the EGFR exon 19 deletion at randomization.

The 31.8 month median overall survival for the control (comparator-TKI) arm is among the highest reported for patients with EGFR-mutated NSCLC, Dr. Ramalingam noted.

“That is because a lot of patients crossed over from the control group to receive osimertinib on progression,” he said, adding that the magnitude of benefit from osimertinib was greater among non-Asian patients, compared with Asians.
 

FLAURA details

In the phase 3 FLAURA trial, investigators stratified patients with previously untreated NSCLC positive for EGFR resistance mutations according to mutation status (exon 19 deletion or the L858R amino acid substitution in exon 21) and race (Asian or non-Asian).

Patients were randomly assigned to treatment with either oral osimertinib 80 mg daily or an EGFR TKI, either oral gefitinib 250 mg or erlotinib 150 mg daily.

The patients were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) every 6 weeks until objective disease progression.

Patients assigned to the standard-of-care arm who had central confirmation of progression and T790M positivity were allowed to cross over to open-label osimertinib.

PFS, the primary endpoint, was also significantly better with osimertinib than with either of the comparator TKIs in patients with and without central nervous system metastases at study entry (HR, 0.47; P = .0009 for patients with CNS metastases; HR, 0.46; P less than .0001 for patients with no CNS metastases).

Neil Osterweil/MDedge News

“For clinicians, for patients, and also for our health authorities, the results in terms of overall survival are really relevant, and this is why this study is so important, knowing this secondary endpoint from a statistical point of view. The study is statistically significant and clinically relevant,” commented Pilar Garrido, MD, from the department of medical oncology, Hospital Universitario Ramón y Cajal in Madrid, the invited discussant at a briefing where Dr. Ramalingam outlined the study findings prior to his presentation of the data in a symposium.

“What’s the future of EGFR mutant lung cancer? Well, I think we should be done with single-agent EGFR-TKI comparisons: We have a clear agent that’s associated with an improvement in survival. I think our focus needs to shift to building on or adding to osimertinib,” commented Pasi A Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute in Boston, the invited discussant at the symposium.

He said that the challenge for clinicians will be to identify high- and low-risk EGFR-mutant NSCLC, and to determine which patients could be treated with a single agent, and which may require a combination therapy approach.

FLAURA was sponsored by AstraZeneca. Dr. Ramalingam disclosed honoraria, an advisory or consulting role, and research funding from that company and others. Dr. Garrido disclosed a speaker and advisory role for AstraZeneca and others. Dr. Jänne disclosed prior consulting for AstraZeneca.

SOURCE: Ramalingam S et al. ESMO 2019. Abstract LBA5_PR.

SAN FRANCISCO – The prevalence of hypoattenuated leaflet thickening (HALT) and reduced leaflet motion among patients undergoing transcatheter aortic valve replacement (TAVR) with SAPIEN 3 or surgery was 10% at 30 days and increased to 24% at 1 year, results from a PARTNER 3 substudy demonstrated.

Doug Brunk/MDedge News

However, the lack of a clear association with serious clinical events such as death, MI, and stroke “does not justify the routine prophylactic use of anticoagulation [following TAVR] in all patients,” lead study investigator Raj R. Makkar, MD, said during a press briefing at the Transcatheter Cardiovascular Therapeutics annual meeting.

“Subclinical leaflet thrombosis characterized by hypoattenuated leaflet thickening and reduced leaflet motion has been frequently observed in transcatheter and surgical aortic bioprosthetic valves,” said Dr. Makkar, director of the interventional cardiology division, Cedars-Sinai Medical Center, Los Angeles. “Thrombus on bioprosthetic valves can present as a spectrum: HALT with relatively normal leaflet motion, HALT with reduced leaflet motion but normal gradients, and clinical valve thrombosis with elevated gradients.”

The primary objective of the current Food and Drug Administration–mandated study, known as the PARTNER 3 Low-Risk Computed Tomography Sub-study, was to evaluate HALT and reduced leaflet motion in terms of differences in transcatheter and surgical bioprosthetic aortic valves among patients enrolled in the randomized PARTNER 3 cohort, to understand the natural history of HALT and reduced leaflet motion in the absence of anticoagulation, and to understand its impact on valve hemodynamics and clinical outcomes. Patients underwent specialized serial CTs at 30 days and at 1 year post TAVR or surgical aortic valve replacement (SAVR). All scans were analyzed by a CT core lab blinded to patient information or time of the scans, and the treating investigators were blinded to the results of the 30-day and 1-year CT scans. A clinical events committee adjudicated key clinical events.

Dr. Makkar reported outcomes from 408 patients: 213 who underwent TAVR and 195 who underwent surgery. There were 348 evaluable serial CT scans at 30 days and 312 at 1 year. The incidence of HALT at 30 days was 13.3% in the TAVR group and 5% in the surgery group, a difference that reached statistical significance (P = .03). At 1 year, however, the difference was not significant (27.5% vs. 20.2%, respectively; P = .19). In the overall cohort, he said, the incidence of HALT was 10% at 30 days and increased to 24% at 1 year.

The researchers also found that HALT was dynamic and spontaneously resolved in 56% of patients in the absence of anticoagulation at 30 days, while new HALT appeared in 21% of patients at 1 year.

“In terms of its impact on valve gradient, the impact was minimal,” Dr. Makkar said. “There was an increase of 1-2 mm Hg in patients who had HALT and in patients who had reduced leaflet motion.”

As for impact on clinical outcomes, the researchers observed no deaths or any myocardial infarction at any time point in patients who had HALT. “There were four cases of valve thrombosis, three of which occurred in patients who had HALT,” Dr. Makkar said at the meeting, sponsored by the Cardiovascular Research Foundation. “One stroke occurred in each group. TIA [transient ischemic attack] occurred in 1 patient out of 35 in the HALT group and 3 out of 311 in the no-HALT group. There was one case of retinal artery embolism in each group.”

In a pooled analysis of clinical events, he and his colleagues observed a numerical increase in death, stroke, TIA, and thrombotic events in patients who had HALT at 30 days, compared with those who did not (8.6% vs. 2.9%, respectively), but the difference did not reach statistical significance (P = .11). “However, given the low total number of events, the data are inconclusive and only hypothesis generating,” he said. “A longer-term follow-up and [a] larger data set will further clarify the impact on clinical outcomes.”

Dr. Makkar emphasized that routine post–TAVR/SAVR CT scans outside of research protocols are not indicated. “CTs should be prompted by increased gradients or thromboembolic events,” he said.

One of the discussants at the briefing, Michael J. Mack, MD, chair of the cardiovascular service line at Baylor Scott and White Health in Dallas and primary author of the PARTNER 3 study, said that prior to the substudy results, “I’ve always thought that the incidence of valve thrombosis would be higher with TAVR than with surgery. So the fact that it was higher at 30 days didn’t surprise me. One of the reasons is that you lose the backwashing effect by changing flow dynamics in the aortic route. What did surprise me is the percent that resolved without anticoagulation.”

He added, “The impact of all this is that we are not justified recommending routine anticoagulation [after bioprosthetic aortic valve replacement surgery]. I think it does call into question the guidelines for surgical valves, because we did that based on smaller observational studies. Now that we have routine surveillance of surgical valves, I think it calls into question the class IIa recommendation for 3 months of anticoagulation. It’s what we’ve always done, and we’ll probably stop doing it on the basis of this. The other shoe that hasn’t dropped is its effect on long-term structural valve deterioration. I do think that early HALT does explain premature structural valve deterioration.”

The trial was sponsored by Edwards Lifesciences. Dr. Makkar disclosed that he is a consultant for and has received research grants from Edwards Lifesciences, Abbott, Medtronic, and Boston Scientific. Dr. Mack is a consultant to Gore and an investigator for Abbott, Edwards Lifesciences, and Medtronic.

[email protected]

SAN FRANCISCO – The prevalence of hypoattenuated leaflet thickening (HALT) and reduced leaflet motion among patients undergoing transcatheter aortic valve replacement (TAVR) with SAPIEN 3 or surgery was 10% at 30 days and increased to 24% at 1 year, results from a PARTNER 3 substudy demonstrated.

Doug Brunk/MDedge News

However, the lack of a clear association with serious clinical events such as death, MI, and stroke “does not justify the routine prophylactic use of anticoagulation [following TAVR] in all patients,” lead study investigator Raj R. Makkar, MD, said during a press briefing at the Transcatheter Cardiovascular Therapeutics annual meeting.

“Subclinical leaflet thrombosis characterized by hypoattenuated leaflet thickening and reduced leaflet motion has been frequently observed in transcatheter and surgical aortic bioprosthetic valves,” said Dr. Makkar, director of the interventional cardiology division, Cedars-Sinai Medical Center, Los Angeles. “Thrombus on bioprosthetic valves can present as a spectrum: HALT with relatively normal leaflet motion, HALT with reduced leaflet motion but normal gradients, and clinical valve thrombosis with elevated gradients.”

The primary objective of the current Food and Drug Administration–mandated study, known as the PARTNER 3 Low-Risk Computed Tomography Sub-study, was to evaluate HALT and reduced leaflet motion in terms of differences in transcatheter and surgical bioprosthetic aortic valves among patients enrolled in the randomized PARTNER 3 cohort, to understand the natural history of HALT and reduced leaflet motion in the absence of anticoagulation, and to understand its impact on valve hemodynamics and clinical outcomes. Patients underwent specialized serial CTs at 30 days and at 1 year post TAVR or surgical aortic valve replacement (SAVR). All scans were analyzed by a CT core lab blinded to patient information or time of the scans, and the treating investigators were blinded to the results of the 30-day and 1-year CT scans. A clinical events committee adjudicated key clinical events.

Dr. Makkar reported outcomes from 408 patients: 213 who underwent TAVR and 195 who underwent surgery. There were 348 evaluable serial CT scans at 30 days and 312 at 1 year. The incidence of HALT at 30 days was 13.3% in the TAVR group and 5% in the surgery group, a difference that reached statistical significance (P = .03). At 1 year, however, the difference was not significant (27.5% vs. 20.2%, respectively; P = .19). In the overall cohort, he said, the incidence of HALT was 10% at 30 days and increased to 24% at 1 year.

The researchers also found that HALT was dynamic and spontaneously resolved in 56% of patients in the absence of anticoagulation at 30 days, while new HALT appeared in 21% of patients at 1 year.

“In terms of its impact on valve gradient, the impact was minimal,” Dr. Makkar said. “There was an increase of 1-2 mm Hg in patients who had HALT and in patients who had reduced leaflet motion.”

As for impact on clinical outcomes, the researchers observed no deaths or any myocardial infarction at any time point in patients who had HALT. “There were four cases of valve thrombosis, three of which occurred in patients who had HALT,” Dr. Makkar said at the meeting, sponsored by the Cardiovascular Research Foundation. “One stroke occurred in each group. TIA [transient ischemic attack] occurred in 1 patient out of 35 in the HALT group and 3 out of 311 in the no-HALT group. There was one case of retinal artery embolism in each group.”

In a pooled analysis of clinical events, he and his colleagues observed a numerical increase in death, stroke, TIA, and thrombotic events in patients who had HALT at 30 days, compared with those who did not (8.6% vs. 2.9%, respectively), but the difference did not reach statistical significance (P = .11). “However, given the low total number of events, the data are inconclusive and only hypothesis generating,” he said. “A longer-term follow-up and [a] larger data set will further clarify the impact on clinical outcomes.”

Dr. Makkar emphasized that routine post–TAVR/SAVR CT scans outside of research protocols are not indicated. “CTs should be prompted by increased gradients or thromboembolic events,” he said.

One of the discussants at the briefing, Michael J. Mack, MD, chair of the cardiovascular service line at Baylor Scott and White Health in Dallas and primary author of the PARTNER 3 study, said that prior to the substudy results, “I’ve always thought that the incidence of valve thrombosis would be higher with TAVR than with surgery. So the fact that it was higher at 30 days didn’t surprise me. One of the reasons is that you lose the backwashing effect by changing flow dynamics in the aortic route. What did surprise me is the percent that resolved without anticoagulation.”

He added, “The impact of all this is that we are not justified recommending routine anticoagulation [after bioprosthetic aortic valve replacement surgery]. I think it does call into question the guidelines for surgical valves, because we did that based on smaller observational studies. Now that we have routine surveillance of surgical valves, I think it calls into question the class IIa recommendation for 3 months of anticoagulation. It’s what we’ve always done, and we’ll probably stop doing it on the basis of this. The other shoe that hasn’t dropped is its effect on long-term structural valve deterioration. I do think that early HALT does explain premature structural valve deterioration.”

The trial was sponsored by Edwards Lifesciences. Dr. Makkar disclosed that he is a consultant for and has received research grants from Edwards Lifesciences, Abbott, Medtronic, and Boston Scientific. Dr. Mack is a consultant to Gore and an investigator for Abbott, Edwards Lifesciences, and Medtronic.

[email protected]

SAN FRANCISCO – The prevalence of hypoattenuated leaflet thickening (HALT) and reduced leaflet motion among patients undergoing transcatheter aortic valve replacement (TAVR) with SAPIEN 3 or surgery was 10% at 30 days and increased to 24% at 1 year, results from a PARTNER 3 substudy demonstrated.

Doug Brunk/MDedge News

However, the lack of a clear association with serious clinical events such as death, MI, and stroke “does not justify the routine prophylactic use of anticoagulation [following TAVR] in all patients,” lead study investigator Raj R. Makkar, MD, said during a press briefing at the Transcatheter Cardiovascular Therapeutics annual meeting.

“Subclinical leaflet thrombosis characterized by hypoattenuated leaflet thickening and reduced leaflet motion has been frequently observed in transcatheter and surgical aortic bioprosthetic valves,” said Dr. Makkar, director of the interventional cardiology division, Cedars-Sinai Medical Center, Los Angeles. “Thrombus on bioprosthetic valves can present as a spectrum: HALT with relatively normal leaflet motion, HALT with reduced leaflet motion but normal gradients, and clinical valve thrombosis with elevated gradients.”

The primary objective of the current Food and Drug Administration–mandated study, known as the PARTNER 3 Low-Risk Computed Tomography Sub-study, was to evaluate HALT and reduced leaflet motion in terms of differences in transcatheter and surgical bioprosthetic aortic valves among patients enrolled in the randomized PARTNER 3 cohort, to understand the natural history of HALT and reduced leaflet motion in the absence of anticoagulation, and to understand its impact on valve hemodynamics and clinical outcomes. Patients underwent specialized serial CTs at 30 days and at 1 year post TAVR or surgical aortic valve replacement (SAVR). All scans were analyzed by a CT core lab blinded to patient information or time of the scans, and the treating investigators were blinded to the results of the 30-day and 1-year CT scans. A clinical events committee adjudicated key clinical events.

Dr. Makkar reported outcomes from 408 patients: 213 who underwent TAVR and 195 who underwent surgery. There were 348 evaluable serial CT scans at 30 days and 312 at 1 year. The incidence of HALT at 30 days was 13.3% in the TAVR group and 5% in the surgery group, a difference that reached statistical significance (P = .03). At 1 year, however, the difference was not significant (27.5% vs. 20.2%, respectively; P = .19). In the overall cohort, he said, the incidence of HALT was 10% at 30 days and increased to 24% at 1 year.

The researchers also found that HALT was dynamic and spontaneously resolved in 56% of patients in the absence of anticoagulation at 30 days, while new HALT appeared in 21% of patients at 1 year.

“In terms of its impact on valve gradient, the impact was minimal,” Dr. Makkar said. “There was an increase of 1-2 mm Hg in patients who had HALT and in patients who had reduced leaflet motion.”

As for impact on clinical outcomes, the researchers observed no deaths or any myocardial infarction at any time point in patients who had HALT. “There were four cases of valve thrombosis, three of which occurred in patients who had HALT,” Dr. Makkar said at the meeting, sponsored by the Cardiovascular Research Foundation. “One stroke occurred in each group. TIA [transient ischemic attack] occurred in 1 patient out of 35 in the HALT group and 3 out of 311 in the no-HALT group. There was one case of retinal artery embolism in each group.”

In a pooled analysis of clinical events, he and his colleagues observed a numerical increase in death, stroke, TIA, and thrombotic events in patients who had HALT at 30 days, compared with those who did not (8.6% vs. 2.9%, respectively), but the difference did not reach statistical significance (P = .11). “However, given the low total number of events, the data are inconclusive and only hypothesis generating,” he said. “A longer-term follow-up and [a] larger data set will further clarify the impact on clinical outcomes.”

Dr. Makkar emphasized that routine post–TAVR/SAVR CT scans outside of research protocols are not indicated. “CTs should be prompted by increased gradients or thromboembolic events,” he said.

One of the discussants at the briefing, Michael J. Mack, MD, chair of the cardiovascular service line at Baylor Scott and White Health in Dallas and primary author of the PARTNER 3 study, said that prior to the substudy results, “I’ve always thought that the incidence of valve thrombosis would be higher with TAVR than with surgery. So the fact that it was higher at 30 days didn’t surprise me. One of the reasons is that you lose the backwashing effect by changing flow dynamics in the aortic route. What did surprise me is the percent that resolved without anticoagulation.”

He added, “The impact of all this is that we are not justified recommending routine anticoagulation [after bioprosthetic aortic valve replacement surgery]. I think it does call into question the guidelines for surgical valves, because we did that based on smaller observational studies. Now that we have routine surveillance of surgical valves, I think it calls into question the class IIa recommendation for 3 months of anticoagulation. It’s what we’ve always done, and we’ll probably stop doing it on the basis of this. The other shoe that hasn’t dropped is its effect on long-term structural valve deterioration. I do think that early HALT does explain premature structural valve deterioration.”

The trial was sponsored by Edwards Lifesciences. Dr. Makkar disclosed that he is a consultant for and has received research grants from Edwards Lifesciences, Abbott, Medtronic, and Boston Scientific. Dr. Mack is a consultant to Gore and an investigator for Abbott, Edwards Lifesciences, and Medtronic.

[email protected]

SAN FRANCISCO – A postmarket analysis of the coronary intravascular lithotripsy (IVL) system validated the safety and utility of the procedure first described in the Disrupt CAD I study.

“We now have an efficient technology to treat calcium that is safe to use, simple to learn, and able to achieve 100% success in delivering stents, with low final residual stenosis (7.8%),” Carlo Di Mario, MD, said in an interview in advance of the Transcatheter Cardiovascular Therapeutics annual meeting. “This was accomplished with a low rate of complications.”

Developed by Shockwave Medical, coronary IVL is an innovative lesion preparation tool designed to fracture challenging calcium using sonic pressure waves in order to facilitate stent delivery, deployment, and optimal expansion. In a feasibility study known as DISRUPT CAD I, Dr. Di Mario, director of structural interventional cardiology at Careggi University Hospital in Florence, Italy, and his colleagues performed the procedure in 60 patients (Circulation 2019;139:834-6). Clinical success, defined as residual stenosis of less than 50% post PCI with no evidence of in-hospital major adverse cardiac events (MACE), was 95%, while device success, defined as successful delivery and IVL treatment at target lesion, reached 98.3%.

In an effort to ensure that results of DISRUPT CAD 1 were generalizable to a broader population, Dr. Di Mario and his colleagues enrolled 120 subjects at 15 sites in nine European countries into DISRUPT CAD II, a postmarket, single-arm study. They underwent vessel preparation for stent implantation with IVL, and the primary endpoint was in-hospital MACE, defined as cardiac death, myocardial infarction, or target vessel revascularization. The researchers also performed an optical coherence tomography (OCT) substudy to evaluate the mechanism of action of IVL and to quantify coronary artery calcium characteristics and calcium plaque fracture.

The mean age of the 120 patients was 72 years, 78% were male, 80% had hypertension, 72% had hyperlipidemia, 32% had diabetes, and 65% had class I or II angina. Most of the patients (94%) had severe calcification, with a mean lesion length of about 26 mm. The lesions were concentric in 70% of cases, and 30% had side-branch involvement.

Dr. Di Mario and his associates reported that IVL was delivered successfully in all cases. It also delivered stents successfully in all cases, with a high acute luminal gain (a mean of 1.7 mm²), and low residual stenosis (7.8%). The primary endpoint occurred in 5.8% of patients, consisting of seven non–Q-wave myocardial infarctions. The IVL mechanism of action was shown to be intraplaque calcium fracture, which occurred in about 80% of lesions analyzed by OCT.

“Based on my previous experience with IVL, I was confident that it could modify the calcium, but the results of the OCT substudy of the Disrupt CAD II utilizing OCT to evaluate the mechanism of action was clearly more positive than expected,” said Dr. Di Mario, who was a coprincipal investigator for the trial. “It demonstrated that IVL creates visible calcium fractures in the majority of cases and confirmed that full stent expansion secondary to the circumferential calcium modification is achievable, despite that nearly all the patients (94%) had severe coronary artery calcification. We know from previous work that full stent expansion is required to minimize complications and improve clinical outcomes, which was not always achievable before IVL.”

He acknowledged certain limitations of the study, including the fact that it lacked a concurrent control group, “but it was run very carefully with complete monitoring of events and core lab and CEC [clinical endpoint committee] adjudication,” he said. “Also, the study was used to confirm short-term safety, and as such, did not include long term follow-up.”

In an interview at the meeting, Ajay J. Kirtane, MD, an interventional cardiologist at Columbia University Medical Center, New York, called the findings “reassuring,” but said that he looks forward to results from the trial of the system currently under way in the United States known as the DISRUPT CAD III IDE Study. “The technology is accessible to many physicians because it’s a balloon-based technology,” he said. “Yet in terms of performance, we need to not only evaluate short-term outcomes, we need to see long-term outcomes as well, to make sure there are no untoward effects.”

Shockwave C² Coronary IVL catheters are commercially available for the treatment of de novo coronary artery disease in Europe and other select countries; in the United States they are limited to investigational use within the DISRUPT CAD III IDE Study.

At the meeting, Ziad A. Ali, MD, an interventional cardiologist at Columbia University/New York–Presbyterian Hospital, presented results from Disrupt CAD II, and the content was published online at the time of presentation. The meeting was sponsored by the Cardiovascular Research Foundation. Dr. Di Mario disclosed that Shockwave Medical provided a grant for the study to Careggi University Hospital. Dr. Ali reported having personal equity and fees from Shockwave Medical, as well as grants from other companies outside the scope of the study.

[email protected]

SOURCE: Di Mario C et al. Circ Cardiovasc Interv. 2019 Sep 25 doi: 10.1161/CIRCINTERVENTIONS.119.008434.

SAN FRANCISCO – A postmarket analysis of the coronary intravascular lithotripsy (IVL) system validated the safety and utility of the procedure first described in the Disrupt CAD I study.

“We now have an efficient technology to treat calcium that is safe to use, simple to learn, and able to achieve 100% success in delivering stents, with low final residual stenosis (7.8%),” Carlo Di Mario, MD, said in an interview in advance of the Transcatheter Cardiovascular Therapeutics annual meeting. “This was accomplished with a low rate of complications.”

Developed by Shockwave Medical, coronary IVL is an innovative lesion preparation tool designed to fracture challenging calcium using sonic pressure waves in order to facilitate stent delivery, deployment, and optimal expansion. In a feasibility study known as DISRUPT CAD I, Dr. Di Mario, director of structural interventional cardiology at Careggi University Hospital in Florence, Italy, and his colleagues performed the procedure in 60 patients (Circulation 2019;139:834-6). Clinical success, defined as residual stenosis of less than 50% post PCI with no evidence of in-hospital major adverse cardiac events (MACE), was 95%, while device success, defined as successful delivery and IVL treatment at target lesion, reached 98.3%.

In an effort to ensure that results of DISRUPT CAD 1 were generalizable to a broader population, Dr. Di Mario and his colleagues enrolled 120 subjects at 15 sites in nine European countries into DISRUPT CAD II, a postmarket, single-arm study. They underwent vessel preparation for stent implantation with IVL, and the primary endpoint was in-hospital MACE, defined as cardiac death, myocardial infarction, or target vessel revascularization. The researchers also performed an optical coherence tomography (OCT) substudy to evaluate the mechanism of action of IVL and to quantify coronary artery calcium characteristics and calcium plaque fracture.

The mean age of the 120 patients was 72 years, 78% were male, 80% had hypertension, 72% had hyperlipidemia, 32% had diabetes, and 65% had class I or II angina. Most of the patients (94%) had severe calcification, with a mean lesion length of about 26 mm. The lesions were concentric in 70% of cases, and 30% had side-branch involvement.

Dr. Di Mario and his associates reported that IVL was delivered successfully in all cases. It also delivered stents successfully in all cases, with a high acute luminal gain (a mean of 1.7 mm²), and low residual stenosis (7.8%). The primary endpoint occurred in 5.8% of patients, consisting of seven non–Q-wave myocardial infarctions. The IVL mechanism of action was shown to be intraplaque calcium fracture, which occurred in about 80% of lesions analyzed by OCT.

“Based on my previous experience with IVL, I was confident that it could modify the calcium, but the results of the OCT substudy of the Disrupt CAD II utilizing OCT to evaluate the mechanism of action was clearly more positive than expected,” said Dr. Di Mario, who was a coprincipal investigator for the trial. “It demonstrated that IVL creates visible calcium fractures in the majority of cases and confirmed that full stent expansion secondary to the circumferential calcium modification is achievable, despite that nearly all the patients (94%) had severe coronary artery calcification. We know from previous work that full stent expansion is required to minimize complications and improve clinical outcomes, which was not always achievable before IVL.”

He acknowledged certain limitations of the study, including the fact that it lacked a concurrent control group, “but it was run very carefully with complete monitoring of events and core lab and CEC [clinical endpoint committee] adjudication,” he said. “Also, the study was used to confirm short-term safety, and as such, did not include long term follow-up.”

In an interview at the meeting, Ajay J. Kirtane, MD, an interventional cardiologist at Columbia University Medical Center, New York, called the findings “reassuring,” but said that he looks forward to results from the trial of the system currently under way in the United States known as the DISRUPT CAD III IDE Study. “The technology is accessible to many physicians because it’s a balloon-based technology,” he said. “Yet in terms of performance, we need to not only evaluate short-term outcomes, we need to see long-term outcomes as well, to make sure there are no untoward effects.”

Shockwave C² Coronary IVL catheters are commercially available for the treatment of de novo coronary artery disease in Europe and other select countries; in the United States they are limited to investigational use within the DISRUPT CAD III IDE Study.

At the meeting, Ziad A. Ali, MD, an interventional cardiologist at Columbia University/New York–Presbyterian Hospital, presented results from Disrupt CAD II, and the content was published online at the time of presentation. The meeting was sponsored by the Cardiovascular Research Foundation. Dr. Di Mario disclosed that Shockwave Medical provided a grant for the study to Careggi University Hospital. Dr. Ali reported having personal equity and fees from Shockwave Medical, as well as grants from other companies outside the scope of the study.

[email protected]

SOURCE: Di Mario C et al. Circ Cardiovasc Interv. 2019 Sep 25 doi: 10.1161/CIRCINTERVENTIONS.119.008434.

SAN FRANCISCO – A postmarket analysis of the coronary intravascular lithotripsy (IVL) system validated the safety and utility of the procedure first described in the Disrupt CAD I study.

“We now have an efficient technology to treat calcium that is safe to use, simple to learn, and able to achieve 100% success in delivering stents, with low final residual stenosis (7.8%),” Carlo Di Mario, MD, said in an interview in advance of the Transcatheter Cardiovascular Therapeutics annual meeting. “This was accomplished with a low rate of complications.”

Developed by Shockwave Medical, coronary IVL is an innovative lesion preparation tool designed to fracture challenging calcium using sonic pressure waves in order to facilitate stent delivery, deployment, and optimal expansion. In a feasibility study known as DISRUPT CAD I, Dr. Di Mario, director of structural interventional cardiology at Careggi University Hospital in Florence, Italy, and his colleagues performed the procedure in 60 patients (Circulation 2019;139:834-6). Clinical success, defined as residual stenosis of less than 50% post PCI with no evidence of in-hospital major adverse cardiac events (MACE), was 95%, while device success, defined as successful delivery and IVL treatment at target lesion, reached 98.3%.

In an effort to ensure that results of DISRUPT CAD 1 were generalizable to a broader population, Dr. Di Mario and his colleagues enrolled 120 subjects at 15 sites in nine European countries into DISRUPT CAD II, a postmarket, single-arm study. They underwent vessel preparation for stent implantation with IVL, and the primary endpoint was in-hospital MACE, defined as cardiac death, myocardial infarction, or target vessel revascularization. The researchers also performed an optical coherence tomography (OCT) substudy to evaluate the mechanism of action of IVL and to quantify coronary artery calcium characteristics and calcium plaque fracture.

The mean age of the 120 patients was 72 years, 78% were male, 80% had hypertension, 72% had hyperlipidemia, 32% had diabetes, and 65% had class I or II angina. Most of the patients (94%) had severe calcification, with a mean lesion length of about 26 mm. The lesions were concentric in 70% of cases, and 30% had side-branch involvement.

Dr. Di Mario and his associates reported that IVL was delivered successfully in all cases. It also delivered stents successfully in all cases, with a high acute luminal gain (a mean of 1.7 mm²), and low residual stenosis (7.8%). The primary endpoint occurred in 5.8% of patients, consisting of seven non–Q-wave myocardial infarctions. The IVL mechanism of action was shown to be intraplaque calcium fracture, which occurred in about 80% of lesions analyzed by OCT.

“Based on my previous experience with IVL, I was confident that it could modify the calcium, but the results of the OCT substudy of the Disrupt CAD II utilizing OCT to evaluate the mechanism of action was clearly more positive than expected,” said Dr. Di Mario, who was a coprincipal investigator for the trial. “It demonstrated that IVL creates visible calcium fractures in the majority of cases and confirmed that full stent expansion secondary to the circumferential calcium modification is achievable, despite that nearly all the patients (94%) had severe coronary artery calcification. We know from previous work that full stent expansion is required to minimize complications and improve clinical outcomes, which was not always achievable before IVL.”

He acknowledged certain limitations of the study, including the fact that it lacked a concurrent control group, “but it was run very carefully with complete monitoring of events and core lab and CEC [clinical endpoint committee] adjudication,” he said. “Also, the study was used to confirm short-term safety, and as such, did not include long term follow-up.”

In an interview at the meeting, Ajay J. Kirtane, MD, an interventional cardiologist at Columbia University Medical Center, New York, called the findings “reassuring,” but said that he looks forward to results from the trial of the system currently under way in the United States known as the DISRUPT CAD III IDE Study. “The technology is accessible to many physicians because it’s a balloon-based technology,” he said. “Yet in terms of performance, we need to not only evaluate short-term outcomes, we need to see long-term outcomes as well, to make sure there are no untoward effects.”

Shockwave C² Coronary IVL catheters are commercially available for the treatment of de novo coronary artery disease in Europe and other select countries; in the United States they are limited to investigational use within the DISRUPT CAD III IDE Study.

At the meeting, Ziad A. Ali, MD, an interventional cardiologist at Columbia University/New York–Presbyterian Hospital, presented results from Disrupt CAD II, and the content was published online at the time of presentation. The meeting was sponsored by the Cardiovascular Research Foundation. Dr. Di Mario disclosed that Shockwave Medical provided a grant for the study to Careggi University Hospital. Dr. Ali reported having personal equity and fees from Shockwave Medical, as well as grants from other companies outside the scope of the study.

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SOURCE: Di Mario C et al. Circ Cardiovasc Interv. 2019 Sep 25 doi: 10.1161/CIRCINTERVENTIONS.119.008434.