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Guidelines emphasize testing early and often for renal impairment in multiple myeloma
Renal status should be evaluated at diagnosis and follow-up in all myeloma patients, according to new guidance from the International Myeloma Working Group published online in the Journal of Clinical Oncology.
Renal impairment (RI) affects up to half of patients with multiple myeloma, and severe RI predicts early death, noted Dr. Meletios Dimopoulos of National and Kapodistrian University of Athens and his associates. Novel therapies have substantially increased survival for myeloma with less severe kidney disease, underscoring the importance of early treatment. To develop the guidelines, the authors reviewed all evidence from randomized trials, systematic reviews, meta-analyses, and prospective and observational studies published through December 2015 (J Clin Oncol. 2016 Mar 14. doi: 10.1200/JCO.2015.65.0044).
Grade A recommendations (evidence obtained from meta-analysis of multiple well-designed, randomized controlled trials) include the following:
Evaluate serum creatinine, estimated glomerular filtration rate, and electrolytes at initial diagnosis and follow-up assessments. Also perform the serum free light chain test, if available, and electrophoresis of a 24-hour urine specimen.
In patients with stabilized serum creatinine, evaluate GFR using the Chronic Kidney Disease Epidemiology Collaboration (preferred) or the Modification of Diet in Renal Disease formulas.
Based on GFR, determine stage of chronic kidney disease (ranging from 1, kidney damage with normal or elevated GFR, to 5, renal failure).
Bortezomib remains the foundational treatment for myeloma-related renal impairment, the authors emphasized. This 26S proteasome inhibitor should be started at the standard dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of a 3-week cycle.
Another option for patients with creatinine clearance above 15 mL/min is carfilzomib, which needs no dose modification and yields similar results regardless of RI status. However, more data are needed on its renal safety, the authors said.
Patients with creatinine clearance above 30 mL/min can safely receive ixazomib in combination with lenalidomide and dexamethasone.
Those with creatinine clearance above 45 mL/min should receive pomalidomide at a dose of 4 mg/day; it is not yet clear whether the dose should be cut for more severe renal impairment.
Hypercalcemia can be treated with bisphosphonates, but patients with creatinine clearance below 30 mL/min should not receive pamidronate or zoledronic acid.
Avoid nephrotoxic agents, such as as aminoglycosides, furosemide, and contrast agents, in all patients with multiple myeloma and RI.
Dr. Dimopoulos reported receiving honoraria or financial support related to travel, accommodations, or expenses from Amgen, Celgene, Onyx Pharmaceuticals, Janssen-Cilag, Bristol-Myers Squibb, Novartis, and Genesis Pharmaceuticals. Seventeen coauthors also reported financial relationships with a number of pharmaceutical companies. The remaining three coauthors had no disclosures.
Renal status should be evaluated at diagnosis and follow-up in all myeloma patients, according to new guidance from the International Myeloma Working Group published online in the Journal of Clinical Oncology.
Renal impairment (RI) affects up to half of patients with multiple myeloma, and severe RI predicts early death, noted Dr. Meletios Dimopoulos of National and Kapodistrian University of Athens and his associates. Novel therapies have substantially increased survival for myeloma with less severe kidney disease, underscoring the importance of early treatment. To develop the guidelines, the authors reviewed all evidence from randomized trials, systematic reviews, meta-analyses, and prospective and observational studies published through December 2015 (J Clin Oncol. 2016 Mar 14. doi: 10.1200/JCO.2015.65.0044).
Grade A recommendations (evidence obtained from meta-analysis of multiple well-designed, randomized controlled trials) include the following:
Evaluate serum creatinine, estimated glomerular filtration rate, and electrolytes at initial diagnosis and follow-up assessments. Also perform the serum free light chain test, if available, and electrophoresis of a 24-hour urine specimen.
In patients with stabilized serum creatinine, evaluate GFR using the Chronic Kidney Disease Epidemiology Collaboration (preferred) or the Modification of Diet in Renal Disease formulas.
Based on GFR, determine stage of chronic kidney disease (ranging from 1, kidney damage with normal or elevated GFR, to 5, renal failure).
Bortezomib remains the foundational treatment for myeloma-related renal impairment, the authors emphasized. This 26S proteasome inhibitor should be started at the standard dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of a 3-week cycle.
Another option for patients with creatinine clearance above 15 mL/min is carfilzomib, which needs no dose modification and yields similar results regardless of RI status. However, more data are needed on its renal safety, the authors said.
Patients with creatinine clearance above 30 mL/min can safely receive ixazomib in combination with lenalidomide and dexamethasone.
Those with creatinine clearance above 45 mL/min should receive pomalidomide at a dose of 4 mg/day; it is not yet clear whether the dose should be cut for more severe renal impairment.
Hypercalcemia can be treated with bisphosphonates, but patients with creatinine clearance below 30 mL/min should not receive pamidronate or zoledronic acid.
Avoid nephrotoxic agents, such as as aminoglycosides, furosemide, and contrast agents, in all patients with multiple myeloma and RI.
Dr. Dimopoulos reported receiving honoraria or financial support related to travel, accommodations, or expenses from Amgen, Celgene, Onyx Pharmaceuticals, Janssen-Cilag, Bristol-Myers Squibb, Novartis, and Genesis Pharmaceuticals. Seventeen coauthors also reported financial relationships with a number of pharmaceutical companies. The remaining three coauthors had no disclosures.
Renal status should be evaluated at diagnosis and follow-up in all myeloma patients, according to new guidance from the International Myeloma Working Group published online in the Journal of Clinical Oncology.
Renal impairment (RI) affects up to half of patients with multiple myeloma, and severe RI predicts early death, noted Dr. Meletios Dimopoulos of National and Kapodistrian University of Athens and his associates. Novel therapies have substantially increased survival for myeloma with less severe kidney disease, underscoring the importance of early treatment. To develop the guidelines, the authors reviewed all evidence from randomized trials, systematic reviews, meta-analyses, and prospective and observational studies published through December 2015 (J Clin Oncol. 2016 Mar 14. doi: 10.1200/JCO.2015.65.0044).
Grade A recommendations (evidence obtained from meta-analysis of multiple well-designed, randomized controlled trials) include the following:
Evaluate serum creatinine, estimated glomerular filtration rate, and electrolytes at initial diagnosis and follow-up assessments. Also perform the serum free light chain test, if available, and electrophoresis of a 24-hour urine specimen.
In patients with stabilized serum creatinine, evaluate GFR using the Chronic Kidney Disease Epidemiology Collaboration (preferred) or the Modification of Diet in Renal Disease formulas.
Based on GFR, determine stage of chronic kidney disease (ranging from 1, kidney damage with normal or elevated GFR, to 5, renal failure).
Bortezomib remains the foundational treatment for myeloma-related renal impairment, the authors emphasized. This 26S proteasome inhibitor should be started at the standard dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of a 3-week cycle.
Another option for patients with creatinine clearance above 15 mL/min is carfilzomib, which needs no dose modification and yields similar results regardless of RI status. However, more data are needed on its renal safety, the authors said.
Patients with creatinine clearance above 30 mL/min can safely receive ixazomib in combination with lenalidomide and dexamethasone.
Those with creatinine clearance above 45 mL/min should receive pomalidomide at a dose of 4 mg/day; it is not yet clear whether the dose should be cut for more severe renal impairment.
Hypercalcemia can be treated with bisphosphonates, but patients with creatinine clearance below 30 mL/min should not receive pamidronate or zoledronic acid.
Avoid nephrotoxic agents, such as as aminoglycosides, furosemide, and contrast agents, in all patients with multiple myeloma and RI.
Dr. Dimopoulos reported receiving honoraria or financial support related to travel, accommodations, or expenses from Amgen, Celgene, Onyx Pharmaceuticals, Janssen-Cilag, Bristol-Myers Squibb, Novartis, and Genesis Pharmaceuticals. Seventeen coauthors also reported financial relationships with a number of pharmaceutical companies. The remaining three coauthors had no disclosures.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
PSA screens could be cost effective if low-risk cases went untreated
Given current treatment practices, prostate-specific antigen (PSA) screening is not cost effective unless performed every 4 years in men aged 55-69 years, and with a biopsy threshold of 10.0 ng/mL, researchers reported online in JAMA Oncology.
But several less conservative testing strategies could be cost effective if patients with Gleason scores under 7 and clinical T2a stage cancer or lower are not treated unless they clinically progress, said Joshua A. Roth, Ph.D., of Fred Hutchinson Cancer Research Center in Seattle and his associates.
The study has “clear implications for the future of PSA screening in the United States,” the investigators wrote (JAMA Oncol. Mar 24. doi: 10.1001/jamaoncol.2015.6275). “Rather than stopping PSA screening, as recommended by the U.S. Preventive Services Task Force, implementation of strategies that extend the screening interval and/or use higher PSA biopsy thresholds have the potential to preserve substantial benefit, while controlling harm and costs.”
The investigators constructed a hypothetical group of men in the United States who underwent 18 different PSA screening strategies starting at age 40. Under the current treatment paradigm, PSA screening increased years of life by 3%-6%, with a cost of $7,335-$21,649 for each extra year of life. Quality years of life rose only if the strategy included a narrower age range for testing or a biopsy threshold of 10.0 ng/mL.
If the more selective treatment model was used, screening 55- to 69-year-old men every 4 years and using a PSA biopsy threshold of 3.0 ng/mL was not only potentially cost effective, but also increased quality years of life. The same was true for quadrennial screening of men aged 50-74 years with a biopsy threshold of 4.0 ng/mL.
“Our work adds to a growing consensus that highly conservative use of the PSA test and biopsy referral is necessary if PSA screening is to be cost effective,” the researchers concluded. Less frequent screening and stricter biopsy criteria for biopsy were most likely to make screening cost effective, especially if physicians do not immediately treat low-risk cases, they added.
The study was supported by the National Cancer Institute, the Centers for Disease Control and Prevention, and the Agency for Healthcare Research and Quality. The investigators had no disclosures.
This study forces us to change the debate from “Should we screen?” to “How can we get physicians to follow best practice?” I have heard it said that the professional, financial, and malpractice incentives to screen and then treat low-risk cancer are too overwhelming to allow for significant practice change. But this is clearly disconfirmed by the literature. Use of active surveillance for low-risk prostate cancer has increased fourfold in the past few years; PSA testing in older men has also fallen recently. Rates of unnecessary treatment still remain much too high (about 60%) as does screening of older men (about 35% for those aged 75 years and older). More work needs to be done, and much more change needs to happen.
 |
Andrew J. Vickers, Ph.D. |
Based on these results, if we follow the literature on how to screen with PSA and which screen-detected prostate cancers to treat, we will likely do more good than harm. If we simply carry on with common practice – screening older men, aggressively treating low-risk disease – then we should call for PSA screening to end.
Andrew J. Vickers, Ph.D., is at Memorial Sloan Kettering Cancer Center, New York. He reported being named on a patent application for a statistical method to detect prostate cancer; receiving royalties from sales of the test; and having stock options in OPKO Health, which commercialized the test. These comments are from his editorial (JAMA Oncol. 2016 Mar 24 doi: 10.1001/jamaoncol.2015.6276).
This study forces us to change the debate from “Should we screen?” to “How can we get physicians to follow best practice?” I have heard it said that the professional, financial, and malpractice incentives to screen and then treat low-risk cancer are too overwhelming to allow for significant practice change. But this is clearly disconfirmed by the literature. Use of active surveillance for low-risk prostate cancer has increased fourfold in the past few years; PSA testing in older men has also fallen recently. Rates of unnecessary treatment still remain much too high (about 60%) as does screening of older men (about 35% for those aged 75 years and older). More work needs to be done, and much more change needs to happen.
|
Andrew J. Vickers, Ph.D. |
Based on these results, if we follow the literature on how to screen with PSA and which screen-detected prostate cancers to treat, we will likely do more good than harm. If we simply carry on with common practice – screening older men, aggressively treating low-risk disease – then we should call for PSA screening to end.
Andrew J. Vickers, Ph.D., is at Memorial Sloan Kettering Cancer Center, New York. He reported being named on a patent application for a statistical method to detect prostate cancer; receiving royalties from sales of the test; and having stock options in OPKO Health, which commercialized the test. These comments are from his editorial (JAMA Oncol. 2016 Mar 24 doi: 10.1001/jamaoncol.2015.6276).
This study forces us to change the debate from “Should we screen?” to “How can we get physicians to follow best practice?” I have heard it said that the professional, financial, and malpractice incentives to screen and then treat low-risk cancer are too overwhelming to allow for significant practice change. But this is clearly disconfirmed by the literature. Use of active surveillance for low-risk prostate cancer has increased fourfold in the past few years; PSA testing in older men has also fallen recently. Rates of unnecessary treatment still remain much too high (about 60%) as does screening of older men (about 35% for those aged 75 years and older). More work needs to be done, and much more change needs to happen.
|
Andrew J. Vickers, Ph.D. |
Based on these results, if we follow the literature on how to screen with PSA and which screen-detected prostate cancers to treat, we will likely do more good than harm. If we simply carry on with common practice – screening older men, aggressively treating low-risk disease – then we should call for PSA screening to end.
Andrew J. Vickers, Ph.D., is at Memorial Sloan Kettering Cancer Center, New York. He reported being named on a patent application for a statistical method to detect prostate cancer; receiving royalties from sales of the test; and having stock options in OPKO Health, which commercialized the test. These comments are from his editorial (JAMA Oncol. 2016 Mar 24 doi: 10.1001/jamaoncol.2015.6276).
Given current treatment practices, prostate-specific antigen (PSA) screening is not cost effective unless performed every 4 years in men aged 55-69 years, and with a biopsy threshold of 10.0 ng/mL, researchers reported online in JAMA Oncology.
But several less conservative testing strategies could be cost effective if patients with Gleason scores under 7 and clinical T2a stage cancer or lower are not treated unless they clinically progress, said Joshua A. Roth, Ph.D., of Fred Hutchinson Cancer Research Center in Seattle and his associates.
The study has “clear implications for the future of PSA screening in the United States,” the investigators wrote (JAMA Oncol. Mar 24. doi: 10.1001/jamaoncol.2015.6275). “Rather than stopping PSA screening, as recommended by the U.S. Preventive Services Task Force, implementation of strategies that extend the screening interval and/or use higher PSA biopsy thresholds have the potential to preserve substantial benefit, while controlling harm and costs.”
The investigators constructed a hypothetical group of men in the United States who underwent 18 different PSA screening strategies starting at age 40. Under the current treatment paradigm, PSA screening increased years of life by 3%-6%, with a cost of $7,335-$21,649 for each extra year of life. Quality years of life rose only if the strategy included a narrower age range for testing or a biopsy threshold of 10.0 ng/mL.
If the more selective treatment model was used, screening 55- to 69-year-old men every 4 years and using a PSA biopsy threshold of 3.0 ng/mL was not only potentially cost effective, but also increased quality years of life. The same was true for quadrennial screening of men aged 50-74 years with a biopsy threshold of 4.0 ng/mL.
“Our work adds to a growing consensus that highly conservative use of the PSA test and biopsy referral is necessary if PSA screening is to be cost effective,” the researchers concluded. Less frequent screening and stricter biopsy criteria for biopsy were most likely to make screening cost effective, especially if physicians do not immediately treat low-risk cases, they added.
The study was supported by the National Cancer Institute, the Centers for Disease Control and Prevention, and the Agency for Healthcare Research and Quality. The investigators had no disclosures.
Given current treatment practices, prostate-specific antigen (PSA) screening is not cost effective unless performed every 4 years in men aged 55-69 years, and with a biopsy threshold of 10.0 ng/mL, researchers reported online in JAMA Oncology.
But several less conservative testing strategies could be cost effective if patients with Gleason scores under 7 and clinical T2a stage cancer or lower are not treated unless they clinically progress, said Joshua A. Roth, Ph.D., of Fred Hutchinson Cancer Research Center in Seattle and his associates.
The study has “clear implications for the future of PSA screening in the United States,” the investigators wrote (JAMA Oncol. Mar 24. doi: 10.1001/jamaoncol.2015.6275). “Rather than stopping PSA screening, as recommended by the U.S. Preventive Services Task Force, implementation of strategies that extend the screening interval and/or use higher PSA biopsy thresholds have the potential to preserve substantial benefit, while controlling harm and costs.”
The investigators constructed a hypothetical group of men in the United States who underwent 18 different PSA screening strategies starting at age 40. Under the current treatment paradigm, PSA screening increased years of life by 3%-6%, with a cost of $7,335-$21,649 for each extra year of life. Quality years of life rose only if the strategy included a narrower age range for testing or a biopsy threshold of 10.0 ng/mL.
If the more selective treatment model was used, screening 55- to 69-year-old men every 4 years and using a PSA biopsy threshold of 3.0 ng/mL was not only potentially cost effective, but also increased quality years of life. The same was true for quadrennial screening of men aged 50-74 years with a biopsy threshold of 4.0 ng/mL.
“Our work adds to a growing consensus that highly conservative use of the PSA test and biopsy referral is necessary if PSA screening is to be cost effective,” the researchers concluded. Less frequent screening and stricter biopsy criteria for biopsy were most likely to make screening cost effective, especially if physicians do not immediately treat low-risk cases, they added.
The study was supported by the National Cancer Institute, the Centers for Disease Control and Prevention, and the Agency for Healthcare Research and Quality. The investigators had no disclosures.
FROM JAMA ONCOLOGY
Key clinical point: A modeling study found that screening for prostate-specific antigen could be cost effective if low-risk cases are not treated unless they progress.
Major finding: Screening 55- to 69-year-old men every 4 years and using a PSA biopsy threshold of 3.0 ng/mL was potentially cost effective and also increased quality years of life. The same was true for quadrennial screening of men aged 50-74 years with a biopsy threshold of 4.0 ng/mL.
Data source: A microsimulation model of prostate cancer incidence and mortality.
Disclosures: The study was supported by the National Cancer Institute, the Centers for Disease Control and Prevention, and the Agency for Healthcare Research and Quality. The investigators had no disclosures.
Gefitinib missed noninferiority endpoint vs. erlotinib in lung cancer trial
Gefitinib failed to meet its noninferiority endpoint, compared with erlotinib, but was significantly less likely to cause grade 3 rash in a multicenter, randomized phase III trial of patients with advanced, pretreated lung adenocarcinoma.
“Subset analysis including mutation status did not reveal any populations with noteworthy differences in clinical efficacy between gefitinib and erlotinib,” said Dr. Yoshiko Urata at Hyogo Cawncer Center in Akashi, Japan, and associates. Nonetheless, gefitinib could be a therapeutic option, given its milder adverse effects in this patient population, the investigators reported online in the Journal of Clinical Oncology.
Both gefitinib and erlotinib are first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Gefitinib had a higher response rate in Japanese patients than in non-Japanese patients in a prior phase II trial. Erlotinib yielded better survival results than gefitinib in subsequent trials, but the two agents had never been compared directly in a phase III trial, according to the investigators (J. Clin. Oncol. 2016 Mar. 28. doi: 10.1200/JCO.2015.63.4154).
Their study included 561 patients, of whom 401 had the EGFR mutation. Baseline factors except performance status were balanced between the randomization arms. Erlotinib was dosed at 150 mg/day, and gefitinib at 250 mg/day. In the event of toxicities, erlotinib could be lowered to 100 mg and 50 mg, and gefitinib to 250 mg on alternate days and 250 mg once every 3 days.
The median progression-free survival (PFS) was 6.5 months for gefitinib and 7.5 months for erlotinib (hazard ratio, 1.1; 95% confidence interval, 0.9-1.4; P = .26). The median PFS also did not statistically differ according to treatment in patients with the EGFR mutation (8.3 and 10.0 months, respectively; HR, 1.1; 95% CI, 0.9-1.4). The median overall survival was 22.8 months for gefitinib and 24.5 months for erlotinib (HR, 1.04; 95% CI, 0.833-1.29). The response rates were 45.9% and 44.1%, respectively.
The most common grade 3-4 toxicities included rash and increases in liver enzymes, said the researchers. Notably, grade 3 rash affected 18% of erlotinib patients and only 2% of gefitinib patients; no patients had grade 4 rash. Gefitinib was linked to three to four times the rate of increased liver enzymes, but an overall analysis of adverse effects nonetheless favored gefitinib (P less than .001).
Gefitinib failed to meet its noninferiority endpoint, compared with erlotinib, but was significantly less likely to cause grade 3 rash in a multicenter, randomized phase III trial of patients with advanced, pretreated lung adenocarcinoma.
“Subset analysis including mutation status did not reveal any populations with noteworthy differences in clinical efficacy between gefitinib and erlotinib,” said Dr. Yoshiko Urata at Hyogo Cawncer Center in Akashi, Japan, and associates. Nonetheless, gefitinib could be a therapeutic option, given its milder adverse effects in this patient population, the investigators reported online in the Journal of Clinical Oncology.
Both gefitinib and erlotinib are first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Gefitinib had a higher response rate in Japanese patients than in non-Japanese patients in a prior phase II trial. Erlotinib yielded better survival results than gefitinib in subsequent trials, but the two agents had never been compared directly in a phase III trial, according to the investigators (J. Clin. Oncol. 2016 Mar. 28. doi: 10.1200/JCO.2015.63.4154).
Their study included 561 patients, of whom 401 had the EGFR mutation. Baseline factors except performance status were balanced between the randomization arms. Erlotinib was dosed at 150 mg/day, and gefitinib at 250 mg/day. In the event of toxicities, erlotinib could be lowered to 100 mg and 50 mg, and gefitinib to 250 mg on alternate days and 250 mg once every 3 days.
The median progression-free survival (PFS) was 6.5 months for gefitinib and 7.5 months for erlotinib (hazard ratio, 1.1; 95% confidence interval, 0.9-1.4; P = .26). The median PFS also did not statistically differ according to treatment in patients with the EGFR mutation (8.3 and 10.0 months, respectively; HR, 1.1; 95% CI, 0.9-1.4). The median overall survival was 22.8 months for gefitinib and 24.5 months for erlotinib (HR, 1.04; 95% CI, 0.833-1.29). The response rates were 45.9% and 44.1%, respectively.
The most common grade 3-4 toxicities included rash and increases in liver enzymes, said the researchers. Notably, grade 3 rash affected 18% of erlotinib patients and only 2% of gefitinib patients; no patients had grade 4 rash. Gefitinib was linked to three to four times the rate of increased liver enzymes, but an overall analysis of adverse effects nonetheless favored gefitinib (P less than .001).
Gefitinib failed to meet its noninferiority endpoint, compared with erlotinib, but was significantly less likely to cause grade 3 rash in a multicenter, randomized phase III trial of patients with advanced, pretreated lung adenocarcinoma.
“Subset analysis including mutation status did not reveal any populations with noteworthy differences in clinical efficacy between gefitinib and erlotinib,” said Dr. Yoshiko Urata at Hyogo Cawncer Center in Akashi, Japan, and associates. Nonetheless, gefitinib could be a therapeutic option, given its milder adverse effects in this patient population, the investigators reported online in the Journal of Clinical Oncology.
Both gefitinib and erlotinib are first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Gefitinib had a higher response rate in Japanese patients than in non-Japanese patients in a prior phase II trial. Erlotinib yielded better survival results than gefitinib in subsequent trials, but the two agents had never been compared directly in a phase III trial, according to the investigators (J. Clin. Oncol. 2016 Mar. 28. doi: 10.1200/JCO.2015.63.4154).
Their study included 561 patients, of whom 401 had the EGFR mutation. Baseline factors except performance status were balanced between the randomization arms. Erlotinib was dosed at 150 mg/day, and gefitinib at 250 mg/day. In the event of toxicities, erlotinib could be lowered to 100 mg and 50 mg, and gefitinib to 250 mg on alternate days and 250 mg once every 3 days.
The median progression-free survival (PFS) was 6.5 months for gefitinib and 7.5 months for erlotinib (hazard ratio, 1.1; 95% confidence interval, 0.9-1.4; P = .26). The median PFS also did not statistically differ according to treatment in patients with the EGFR mutation (8.3 and 10.0 months, respectively; HR, 1.1; 95% CI, 0.9-1.4). The median overall survival was 22.8 months for gefitinib and 24.5 months for erlotinib (HR, 1.04; 95% CI, 0.833-1.29). The response rates were 45.9% and 44.1%, respectively.
The most common grade 3-4 toxicities included rash and increases in liver enzymes, said the researchers. Notably, grade 3 rash affected 18% of erlotinib patients and only 2% of gefitinib patients; no patients had grade 4 rash. Gefitinib was linked to three to four times the rate of increased liver enzymes, but an overall analysis of adverse effects nonetheless favored gefitinib (P less than .001).
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Gefitinib failed to meet its noninferiority endpoint, compared with erlotinib, in patients with advanced, pretreated lung adenocarcinoma.
Major finding: The median PFS was 6.5 months for gefitinib and 7.5 months for erlotinib (hazard ratio, 1.1; 95% confidence interval, 0.9-1.4; P = .26).
Data source: A multicenter, randomized, phase III trial of 561 patients with advanced, pretreated lung adenocarcinoma.
Disclosures: The study was funded by West Japan Oncology Group, a nonprofit organization supported by unrestricted donations from several pharmaceutical companies. Dr. Urata reported receiving honoraria from AstraZeneca, Chugai Pharma, Eli Lilly, Astellas Pharma, and Novartis. Sixteen coinvestigators reported financial relationships with numerous pharmaceutical companies.
Losmapimod failed to beat placebo in acute MI trial
Twelve weeks of treatment with the anti-inflammatory drug losmapimod did not prevent cardiovascular death, myocardial infarction, or severe recurrent ischemia in patients hospitalized with acute MI, based on the results of LATITUDE-TIMI 60, a multicenter placebo-controlled phase 3 trial.
Losmapimod also did not significantly affect secondary outcomes such as all-cause mortality, said Dr. Michelle O’Donoghue at Brigham and Women’s Hospital in Boston and her associates.
“The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population,” they concluded at the annual meeting of the American College of Cardiology and in a report published online April 4 in JAMA.
Losmapimod selectively inhibits pro-inflammatory p38 mitogen-activated protein kinase, which contributes to atherosclerosis and plaque destabilization and is activated by stressors such as oxidized low-density lipoprotein cholesterol, hypertension, ischemia, and volume overload. In a prior 12-week phase 2 study, losmapimod failed to reduce inflammatory biomarker levels or myonecrosis, but showed a trend toward lower rates of mortality, MI, recurrent ischemia, stroke, and heart failure, as well as improved left ventricular function.
Based on those observations, Dr. O’Donoghue and her associates randomly assigned 3,503 hospitalized patients with acute MI and at least one other cardiovascular risk factor to receive either losmapimod (7.5 mg twice daily) or placebo, along with guideline-recommended therapy for 12 weeks. Patients averaged 66 years old, about 90% were white, and about 30% were women. The primary endpoint was a composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization (JAMA 2016 April 4 doi: 10.1001/jama.2016.3609).
The endpoint was met for 139 (8.1%) losmapimod patients and 123 (7%) placebo patients, for a non-significant hazard ratio of 1.16, said the researchers. Losmapimod was, however, associated with significant decreases in levels of high-sensitivity C-reactive protein and N-terminal pro-brain natriuretic peptide as compared with placebo, with durable effects at 12 weeks. Serious adverse events affected 16% of losmapimod patients and 14% of placebo patients, and rates of premature treatment discontinuation were 15.5% with losmapimod and nearly 14% with placebo. Losmapimod did not appear to increase the risk of infections compared with placebo at week 12, but did show a non-significant trend toward mildly increased hepatic transaminases.
“Because inflammation is believed to play a key role in atherogenesis, there remains intense interest to identify an anti-inflammatory therapeutic that will reduce the risk of cardiovascular events,” the researchers noted. “However, because inflammation acts along multiple redundant and interconnected pathways, the identification of an appropriate target may be difficult, and it is challenging to predict clinical efficacy prior to phase 3 testing. Ongoing clinical trials are currently evaluating additional anti-inflammatory therapeutics in patients with atherosclerosis, and will provide further insight into pathways that contribute to vascular disease.”
Pharmacodynamic data on losmapimod do not suggest that its anti-inflammatory effects increase at higher doses, the researchers also noted.
GlaxoSmithKline developed losmapimod and funded the study. Dr. O’Donoghue reported grant funding from Eisai, Merck, and AstraZeneca. The senior author and several coinvestigators disclosed relationships with numerous pharmaceutical companies.
Twelve weeks of treatment with the anti-inflammatory drug losmapimod did not prevent cardiovascular death, myocardial infarction, or severe recurrent ischemia in patients hospitalized with acute MI, based on the results of LATITUDE-TIMI 60, a multicenter placebo-controlled phase 3 trial.
Losmapimod also did not significantly affect secondary outcomes such as all-cause mortality, said Dr. Michelle O’Donoghue at Brigham and Women’s Hospital in Boston and her associates.
“The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population,” they concluded at the annual meeting of the American College of Cardiology and in a report published online April 4 in JAMA.
Losmapimod selectively inhibits pro-inflammatory p38 mitogen-activated protein kinase, which contributes to atherosclerosis and plaque destabilization and is activated by stressors such as oxidized low-density lipoprotein cholesterol, hypertension, ischemia, and volume overload. In a prior 12-week phase 2 study, losmapimod failed to reduce inflammatory biomarker levels or myonecrosis, but showed a trend toward lower rates of mortality, MI, recurrent ischemia, stroke, and heart failure, as well as improved left ventricular function.
Based on those observations, Dr. O’Donoghue and her associates randomly assigned 3,503 hospitalized patients with acute MI and at least one other cardiovascular risk factor to receive either losmapimod (7.5 mg twice daily) or placebo, along with guideline-recommended therapy for 12 weeks. Patients averaged 66 years old, about 90% were white, and about 30% were women. The primary endpoint was a composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization (JAMA 2016 April 4 doi: 10.1001/jama.2016.3609).
The endpoint was met for 139 (8.1%) losmapimod patients and 123 (7%) placebo patients, for a non-significant hazard ratio of 1.16, said the researchers. Losmapimod was, however, associated with significant decreases in levels of high-sensitivity C-reactive protein and N-terminal pro-brain natriuretic peptide as compared with placebo, with durable effects at 12 weeks. Serious adverse events affected 16% of losmapimod patients and 14% of placebo patients, and rates of premature treatment discontinuation were 15.5% with losmapimod and nearly 14% with placebo. Losmapimod did not appear to increase the risk of infections compared with placebo at week 12, but did show a non-significant trend toward mildly increased hepatic transaminases.
“Because inflammation is believed to play a key role in atherogenesis, there remains intense interest to identify an anti-inflammatory therapeutic that will reduce the risk of cardiovascular events,” the researchers noted. “However, because inflammation acts along multiple redundant and interconnected pathways, the identification of an appropriate target may be difficult, and it is challenging to predict clinical efficacy prior to phase 3 testing. Ongoing clinical trials are currently evaluating additional anti-inflammatory therapeutics in patients with atherosclerosis, and will provide further insight into pathways that contribute to vascular disease.”
Pharmacodynamic data on losmapimod do not suggest that its anti-inflammatory effects increase at higher doses, the researchers also noted.
GlaxoSmithKline developed losmapimod and funded the study. Dr. O’Donoghue reported grant funding from Eisai, Merck, and AstraZeneca. The senior author and several coinvestigators disclosed relationships with numerous pharmaceutical companies.
Twelve weeks of treatment with the anti-inflammatory drug losmapimod did not prevent cardiovascular death, myocardial infarction, or severe recurrent ischemia in patients hospitalized with acute MI, based on the results of LATITUDE-TIMI 60, a multicenter placebo-controlled phase 3 trial.
Losmapimod also did not significantly affect secondary outcomes such as all-cause mortality, said Dr. Michelle O’Donoghue at Brigham and Women’s Hospital in Boston and her associates.
“The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population,” they concluded at the annual meeting of the American College of Cardiology and in a report published online April 4 in JAMA.
Losmapimod selectively inhibits pro-inflammatory p38 mitogen-activated protein kinase, which contributes to atherosclerosis and plaque destabilization and is activated by stressors such as oxidized low-density lipoprotein cholesterol, hypertension, ischemia, and volume overload. In a prior 12-week phase 2 study, losmapimod failed to reduce inflammatory biomarker levels or myonecrosis, but showed a trend toward lower rates of mortality, MI, recurrent ischemia, stroke, and heart failure, as well as improved left ventricular function.
Based on those observations, Dr. O’Donoghue and her associates randomly assigned 3,503 hospitalized patients with acute MI and at least one other cardiovascular risk factor to receive either losmapimod (7.5 mg twice daily) or placebo, along with guideline-recommended therapy for 12 weeks. Patients averaged 66 years old, about 90% were white, and about 30% were women. The primary endpoint was a composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization (JAMA 2016 April 4 doi: 10.1001/jama.2016.3609).
The endpoint was met for 139 (8.1%) losmapimod patients and 123 (7%) placebo patients, for a non-significant hazard ratio of 1.16, said the researchers. Losmapimod was, however, associated with significant decreases in levels of high-sensitivity C-reactive protein and N-terminal pro-brain natriuretic peptide as compared with placebo, with durable effects at 12 weeks. Serious adverse events affected 16% of losmapimod patients and 14% of placebo patients, and rates of premature treatment discontinuation were 15.5% with losmapimod and nearly 14% with placebo. Losmapimod did not appear to increase the risk of infections compared with placebo at week 12, but did show a non-significant trend toward mildly increased hepatic transaminases.
“Because inflammation is believed to play a key role in atherogenesis, there remains intense interest to identify an anti-inflammatory therapeutic that will reduce the risk of cardiovascular events,” the researchers noted. “However, because inflammation acts along multiple redundant and interconnected pathways, the identification of an appropriate target may be difficult, and it is challenging to predict clinical efficacy prior to phase 3 testing. Ongoing clinical trials are currently evaluating additional anti-inflammatory therapeutics in patients with atherosclerosis, and will provide further insight into pathways that contribute to vascular disease.”
Pharmacodynamic data on losmapimod do not suggest that its anti-inflammatory effects increase at higher doses, the researchers also noted.
GlaxoSmithKline developed losmapimod and funded the study. Dr. O’Donoghue reported grant funding from Eisai, Merck, and AstraZeneca. The senior author and several coinvestigators disclosed relationships with numerous pharmaceutical companies.
FROM ACC 16
Key clinical point: The anti-inflammatory drug losmapimod missed its composite primary endpoint in a phase 3 study of patients with acute myocardial infarction.
Major finding: At week 12, there was no significant effect on cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization.
Data source: A multicenter randomized phase 3 trial of 3,503 hospitalized adults with acute MI and at least one other cardiovascular risk factor.
Disclosures: GlaxoSmithKline developed losmapimod and funded the study. Dr. O’Donoghue reported grant funding from Eisai, Merck, and AstraZeneca. The senior author and several coinvestigators disclosed relationships with numerous pharmaceutical companies.
Adding mitral valve repair to CABG found risky, with limited benefits
In patients with moderate ischemic mitral regurgitation, adding mitral valve repair to coronary artery bypass graft did not significantly affect the extent of left ventricular remodeling at 2 years, according to a randomized multicenter trial.
Compared with revascularization alone, the combined procedure was associated with a two-thirds lower rate of moderate to severe mitral regurgitation at the end of year 2, reported Dr. Robert Michler at Albert Einstein College of Medicine, New York, together with his associates. But improved durability did not translate to better survival or lower rates of major adverse cardiac and cerebrovascular events, heart failure, or hospital readmissions, they said. Furthermore, adding mitral valve repair to CABG was linked to higher rates of postoperative neurologic events and supraventricular arrhythmias than for CABG alone, the investigators reported at the annual meeting of the American College of Cardiology and simultaneously online April 3 in the New England Journal of Medicine.
Surgeons have debated whether to add restrictive mitral annuloplasty to CABG in patients with moderate ischemic mitral regurgitation. The combined approach requires open-heart exposure and longer aortic cross-clamping and cardiopulmonary bypass time, all of which increase perioperative risk, the researchers noted. To explore the risk-benefit balance of these approaches, they randomly assigned 301 patients to either revascularization alone or to the combined procedure, and assessed clinical and echocardiographic outcomes over 2 years (New Engl. J. Med. 2016 April 3 doi: 10.1056/NEJMoa1602003).
At year 1, the arms resembled each other in terms of survival, rates of major adverse cardiac or cerebrovascular events (MACCEs), and left ventricular reverse remodeling, as measured by left ventricular end-systolic volume index (LVESVI), said the investigators. At year 2, the extent of remodeling remained similar between the arms, with mean LVESVIs of 41.2 mL (standard deviation, 20.0 mL) per square meter of body surface area in the CABG-only group and 43.2 mL (SD, 20.6 mL) in the combined procedure group, for a mean decrease from baseline of 14.1 and 14.6 mL, respectively. About two-thirds of improvements in LVESI occurred during year 1 regardless of procedure type, the researchers noted.
About a third of CABG-only patients had moderate to severe mitral regurgitation at 2 years, compared with only 11% of patients who underwent the combined procedure (P less than .001). Patients who had mild or no mitral regurgitation had more than twice the percentage improvement in the global wall motion index and in the inferior-posterior-lateral regional wall motion score, compared with patients with moderate to severe regurgitation. Although both groups improved on several quality-of-life indices, the combined-procedure group scored more than 5 points higher on the Duke Activity Status Index, which measures self-reported exercise capacity. That difference was not only clinically meaningful, but resembled the increase in peak myocardial oxygen consumption in a similar, smaller trial (New Engl. J. Med. 2016 Jan. 28 doi: 10.1056/NEJMoa151291), the investigators noted.
However, mortality rates were similar between the arms at 2 years – 10.6% for CABG only and 10% for the combined procedure, for a non-significant hazard ratio of 0.9. Likewise, rates of heart failure and other serious adverse events were similar between the arms, while the combined-procedure arm had more than three times more postoperative neurologic events and more than twice as many occurrences of supraventricular arrhythmia. Therefore, treatment choice requires “balancing the risks of adverse perioperative events against the uncertain benefits of a lower incidence of postoperative moderate or severe mitral regurgitation,” said the researchers. “Effective revascularization, as reflected in improved regional and global left ventricular function, plays an important role independent of mitral valve repair.”
The National Institutes of Health and the Canadian Institutes of Health Research funded the study. Disclosures were reported separately at nejm.org.
In patients with moderate ischemic mitral regurgitation, adding mitral valve repair to coronary artery bypass graft did not significantly affect the extent of left ventricular remodeling at 2 years, according to a randomized multicenter trial.
Compared with revascularization alone, the combined procedure was associated with a two-thirds lower rate of moderate to severe mitral regurgitation at the end of year 2, reported Dr. Robert Michler at Albert Einstein College of Medicine, New York, together with his associates. But improved durability did not translate to better survival or lower rates of major adverse cardiac and cerebrovascular events, heart failure, or hospital readmissions, they said. Furthermore, adding mitral valve repair to CABG was linked to higher rates of postoperative neurologic events and supraventricular arrhythmias than for CABG alone, the investigators reported at the annual meeting of the American College of Cardiology and simultaneously online April 3 in the New England Journal of Medicine.
Surgeons have debated whether to add restrictive mitral annuloplasty to CABG in patients with moderate ischemic mitral regurgitation. The combined approach requires open-heart exposure and longer aortic cross-clamping and cardiopulmonary bypass time, all of which increase perioperative risk, the researchers noted. To explore the risk-benefit balance of these approaches, they randomly assigned 301 patients to either revascularization alone or to the combined procedure, and assessed clinical and echocardiographic outcomes over 2 years (New Engl. J. Med. 2016 April 3 doi: 10.1056/NEJMoa1602003).
At year 1, the arms resembled each other in terms of survival, rates of major adverse cardiac or cerebrovascular events (MACCEs), and left ventricular reverse remodeling, as measured by left ventricular end-systolic volume index (LVESVI), said the investigators. At year 2, the extent of remodeling remained similar between the arms, with mean LVESVIs of 41.2 mL (standard deviation, 20.0 mL) per square meter of body surface area in the CABG-only group and 43.2 mL (SD, 20.6 mL) in the combined procedure group, for a mean decrease from baseline of 14.1 and 14.6 mL, respectively. About two-thirds of improvements in LVESI occurred during year 1 regardless of procedure type, the researchers noted.
About a third of CABG-only patients had moderate to severe mitral regurgitation at 2 years, compared with only 11% of patients who underwent the combined procedure (P less than .001). Patients who had mild or no mitral regurgitation had more than twice the percentage improvement in the global wall motion index and in the inferior-posterior-lateral regional wall motion score, compared with patients with moderate to severe regurgitation. Although both groups improved on several quality-of-life indices, the combined-procedure group scored more than 5 points higher on the Duke Activity Status Index, which measures self-reported exercise capacity. That difference was not only clinically meaningful, but resembled the increase in peak myocardial oxygen consumption in a similar, smaller trial (New Engl. J. Med. 2016 Jan. 28 doi: 10.1056/NEJMoa151291), the investigators noted.
However, mortality rates were similar between the arms at 2 years – 10.6% for CABG only and 10% for the combined procedure, for a non-significant hazard ratio of 0.9. Likewise, rates of heart failure and other serious adverse events were similar between the arms, while the combined-procedure arm had more than three times more postoperative neurologic events and more than twice as many occurrences of supraventricular arrhythmia. Therefore, treatment choice requires “balancing the risks of adverse perioperative events against the uncertain benefits of a lower incidence of postoperative moderate or severe mitral regurgitation,” said the researchers. “Effective revascularization, as reflected in improved regional and global left ventricular function, plays an important role independent of mitral valve repair.”
The National Institutes of Health and the Canadian Institutes of Health Research funded the study. Disclosures were reported separately at nejm.org.
In patients with moderate ischemic mitral regurgitation, adding mitral valve repair to coronary artery bypass graft did not significantly affect the extent of left ventricular remodeling at 2 years, according to a randomized multicenter trial.
Compared with revascularization alone, the combined procedure was associated with a two-thirds lower rate of moderate to severe mitral regurgitation at the end of year 2, reported Dr. Robert Michler at Albert Einstein College of Medicine, New York, together with his associates. But improved durability did not translate to better survival or lower rates of major adverse cardiac and cerebrovascular events, heart failure, or hospital readmissions, they said. Furthermore, adding mitral valve repair to CABG was linked to higher rates of postoperative neurologic events and supraventricular arrhythmias than for CABG alone, the investigators reported at the annual meeting of the American College of Cardiology and simultaneously online April 3 in the New England Journal of Medicine.
Surgeons have debated whether to add restrictive mitral annuloplasty to CABG in patients with moderate ischemic mitral regurgitation. The combined approach requires open-heart exposure and longer aortic cross-clamping and cardiopulmonary bypass time, all of which increase perioperative risk, the researchers noted. To explore the risk-benefit balance of these approaches, they randomly assigned 301 patients to either revascularization alone or to the combined procedure, and assessed clinical and echocardiographic outcomes over 2 years (New Engl. J. Med. 2016 April 3 doi: 10.1056/NEJMoa1602003).
At year 1, the arms resembled each other in terms of survival, rates of major adverse cardiac or cerebrovascular events (MACCEs), and left ventricular reverse remodeling, as measured by left ventricular end-systolic volume index (LVESVI), said the investigators. At year 2, the extent of remodeling remained similar between the arms, with mean LVESVIs of 41.2 mL (standard deviation, 20.0 mL) per square meter of body surface area in the CABG-only group and 43.2 mL (SD, 20.6 mL) in the combined procedure group, for a mean decrease from baseline of 14.1 and 14.6 mL, respectively. About two-thirds of improvements in LVESI occurred during year 1 regardless of procedure type, the researchers noted.
About a third of CABG-only patients had moderate to severe mitral regurgitation at 2 years, compared with only 11% of patients who underwent the combined procedure (P less than .001). Patients who had mild or no mitral regurgitation had more than twice the percentage improvement in the global wall motion index and in the inferior-posterior-lateral regional wall motion score, compared with patients with moderate to severe regurgitation. Although both groups improved on several quality-of-life indices, the combined-procedure group scored more than 5 points higher on the Duke Activity Status Index, which measures self-reported exercise capacity. That difference was not only clinically meaningful, but resembled the increase in peak myocardial oxygen consumption in a similar, smaller trial (New Engl. J. Med. 2016 Jan. 28 doi: 10.1056/NEJMoa151291), the investigators noted.
However, mortality rates were similar between the arms at 2 years – 10.6% for CABG only and 10% for the combined procedure, for a non-significant hazard ratio of 0.9. Likewise, rates of heart failure and other serious adverse events were similar between the arms, while the combined-procedure arm had more than three times more postoperative neurologic events and more than twice as many occurrences of supraventricular arrhythmia. Therefore, treatment choice requires “balancing the risks of adverse perioperative events against the uncertain benefits of a lower incidence of postoperative moderate or severe mitral regurgitation,” said the researchers. “Effective revascularization, as reflected in improved regional and global left ventricular function, plays an important role independent of mitral valve repair.”
The National Institutes of Health and the Canadian Institutes of Health Research funded the study. Disclosures were reported separately at nejm.org.
FROM ACC 16
Key clinical point: In patients with moderate ischemic mitral regurgitation, adding mitral valve repair to coronary artery bypass graft did not significantly affect left ventricular remodeling at two years.
Major finding: Mean decreases in left ventricular end systolic volume index were 14.1 mL and 14.6 mL, respectively.
Data source: A multicenter randomized trial of 301 patients with moderate to severe baseline mitral regurgitation.
Disclosures: The National Institutes of Health and the Canadian Institutes of Health Research funded the study. Disclosures were reported separately at nejm.org.
Women With Suspected CAD Classified as Lower Risk Than Men
Women with suspected coronary artery disease had similar symptoms and more heart disease risk factors, compared with men, but were assessed as lower risk by their providers and on all standard risk scores, according to a secondary analysis of the PROMISE trial.
The results “highlight the need for sex-specific approaches to coronary artery disease evaluation and testing,” said Kshipra Hemal at Duke Clinical Research Institute in Durham, N.C., and her associates. The findings will be presented April 3 at the annual meeting of the American College of Cardiology and were published online March 23 in the Journal of the American College of Cardiology: Cardiovascular Imaging.
The PROMISE (Prospective Multicenter Imaging Study for the Evaluation of Chest Pain) trial is one of the largest contemporary trials of symptomatic, nonacute suspected CAD. The study included 10,003 stable outpatients, nearly half of whom were women. The researchers calculated the 2008 Framingham score, 2013 Atherosclerotic Cardiovascular Disease score, 1979 Diamond and Forrester score, modified 2011 Diamond and Forrester score, and 2012 combined Diamond-Forrester and Coronary Artery Surgery Study scores for all patients. Patients also were randomly assigned to either anatomical testing with CT angiography or to functional testing with exercise electrocardiogram, stress nuclear imaging, or stress echocardiogram (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.001).
Women in the study were an average of 3 years older than the men and were significantly more likely to be hypertensive (67% vs. 63%), dyslipidemic (69% vs. 66%), and to have a family history of premature CAD (35% vs. 29%; P less than .01 for all comparisons), the researchers reported. Nonetheless, all five risk scores characterized women as lower risk than men (P less than .001 for mean differences). Moreover, before testing, providers characterized 41% of women having a low (less than 30%) likelihood of CAD, compared with 34% of men (P less than .001).
Women were more likely than men to be referred for stress echocardiography or nuclear stress test, but only 9.7% had a positive noninvasive test, compared with 15% of men (P less than .001), the researchers also reported. “A number of characteristics predicted positive test results, and many characteristics were similar between the sexes,” they added. “However, in multivariable models, key predictors of test positivity were few and varied by sex.” Body mass index and Framingham risk score predicted a positive test for women, while both the Framingham and modified Diamond-Forrester risk scores predicted a positive test for men.
Chest pain was the most common primary symptom reported by nearly three-quarters of women and men and was described as “crushing/pressure/squeezing/tightness” 53% and 46% of the time, respectively (P less than .001). Dyspnea was the second most frequent primary symptom at 15% for both sexes. Women were more likely than men to describe back pain, neck or jaw pain, or palpitations, but only 0.6% to 2.7% of patients ranked these among their main symptoms.
“Further studies are warranted to examine the underlying pathophysiology and implications for clinical care of the sex-based clinical differences observed along the entire diagnostic pathway of suspected CAD, including risk factor burden, presenting symptoms, and testing results,” the researchers concluded.
The PROMISE study was funded by the National Heart, Lung, and Blood Institute. Ms. Hemal had no disclosures. Senior author Dr. Pamela S. Douglas disclosed grant support from HeartFlow and having served on a data and safety monitoring board for General Electric Healthcare. Two of the other 15 coinvestigators also disclosed relationships with industry; the rest had no disclosures.
Despite symptomatic presentation, greater family history of premature coronary artery disease, and higher risk factor burden, including older age and greater prevalence of hypertension and dyslipidemia, the women in PROMISE were more likely to be characterized as low risk based on standard cardiovascular risk assessment scores and thus, not surprisingly, also were considered to be at lower risk by their providers. These findings add credence to the ongoing concerns that women are preferentially likely to receive less intensive management of CAD than their male counterparts.
The 2014 American Heart Association Consensus Statement on noninvasive diagnostic testing in women with suspected ischemic heart disease highlighted the development of novel diagnostic tools that have an expanded role in the evaluation of symptomatic female patients to detect not only focal epicardial coronary stenosis, but also nonobstructive atherosclerosis as well as the identification of ischemia resulting from microvascular dysfunction. Such methods using advanced imaging are making steady progress in the understanding of microvascular disease and its consequences.
We agree with the PROMISE investigators that focused sex-specific diagnostic strategies are needed to reduce the cardiovascular mortality and morbidity in women. With emerging data on the full pathophysiologic spectrum of ischemic heart disease in women, diagnostic algorithms must include functional and anatomic cardiac tests as well as physiologic assessments of endothelial and microvascular function, for accurately establishing the diagnosis and prognosis of women with suspected IHD.
Dr. Jennifer H. Mieres is with Hofstra University, Hempstead, N.Y. Dr. Robert O. Bonow is with Northwestern University, Chicago. They had no disclosures. These comments are from their editorial (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.0089).
Despite symptomatic presentation, greater family history of premature coronary artery disease, and higher risk factor burden, including older age and greater prevalence of hypertension and dyslipidemia, the women in PROMISE were more likely to be characterized as low risk based on standard cardiovascular risk assessment scores and thus, not surprisingly, also were considered to be at lower risk by their providers. These findings add credence to the ongoing concerns that women are preferentially likely to receive less intensive management of CAD than their male counterparts.
The 2014 American Heart Association Consensus Statement on noninvasive diagnostic testing in women with suspected ischemic heart disease highlighted the development of novel diagnostic tools that have an expanded role in the evaluation of symptomatic female patients to detect not only focal epicardial coronary stenosis, but also nonobstructive atherosclerosis as well as the identification of ischemia resulting from microvascular dysfunction. Such methods using advanced imaging are making steady progress in the understanding of microvascular disease and its consequences.
We agree with the PROMISE investigators that focused sex-specific diagnostic strategies are needed to reduce the cardiovascular mortality and morbidity in women. With emerging data on the full pathophysiologic spectrum of ischemic heart disease in women, diagnostic algorithms must include functional and anatomic cardiac tests as well as physiologic assessments of endothelial and microvascular function, for accurately establishing the diagnosis and prognosis of women with suspected IHD.
Dr. Jennifer H. Mieres is with Hofstra University, Hempstead, N.Y. Dr. Robert O. Bonow is with Northwestern University, Chicago. They had no disclosures. These comments are from their editorial (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.0089).
Despite symptomatic presentation, greater family history of premature coronary artery disease, and higher risk factor burden, including older age and greater prevalence of hypertension and dyslipidemia, the women in PROMISE were more likely to be characterized as low risk based on standard cardiovascular risk assessment scores and thus, not surprisingly, also were considered to be at lower risk by their providers. These findings add credence to the ongoing concerns that women are preferentially likely to receive less intensive management of CAD than their male counterparts.
The 2014 American Heart Association Consensus Statement on noninvasive diagnostic testing in women with suspected ischemic heart disease highlighted the development of novel diagnostic tools that have an expanded role in the evaluation of symptomatic female patients to detect not only focal epicardial coronary stenosis, but also nonobstructive atherosclerosis as well as the identification of ischemia resulting from microvascular dysfunction. Such methods using advanced imaging are making steady progress in the understanding of microvascular disease and its consequences.
We agree with the PROMISE investigators that focused sex-specific diagnostic strategies are needed to reduce the cardiovascular mortality and morbidity in women. With emerging data on the full pathophysiologic spectrum of ischemic heart disease in women, diagnostic algorithms must include functional and anatomic cardiac tests as well as physiologic assessments of endothelial and microvascular function, for accurately establishing the diagnosis and prognosis of women with suspected IHD.
Dr. Jennifer H. Mieres is with Hofstra University, Hempstead, N.Y. Dr. Robert O. Bonow is with Northwestern University, Chicago. They had no disclosures. These comments are from their editorial (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.0089).
Women with suspected coronary artery disease had similar symptoms and more heart disease risk factors, compared with men, but were assessed as lower risk by their providers and on all standard risk scores, according to a secondary analysis of the PROMISE trial.
The results “highlight the need for sex-specific approaches to coronary artery disease evaluation and testing,” said Kshipra Hemal at Duke Clinical Research Institute in Durham, N.C., and her associates. The findings will be presented April 3 at the annual meeting of the American College of Cardiology and were published online March 23 in the Journal of the American College of Cardiology: Cardiovascular Imaging.
The PROMISE (Prospective Multicenter Imaging Study for the Evaluation of Chest Pain) trial is one of the largest contemporary trials of symptomatic, nonacute suspected CAD. The study included 10,003 stable outpatients, nearly half of whom were women. The researchers calculated the 2008 Framingham score, 2013 Atherosclerotic Cardiovascular Disease score, 1979 Diamond and Forrester score, modified 2011 Diamond and Forrester score, and 2012 combined Diamond-Forrester and Coronary Artery Surgery Study scores for all patients. Patients also were randomly assigned to either anatomical testing with CT angiography or to functional testing with exercise electrocardiogram, stress nuclear imaging, or stress echocardiogram (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.001).
Women in the study were an average of 3 years older than the men and were significantly more likely to be hypertensive (67% vs. 63%), dyslipidemic (69% vs. 66%), and to have a family history of premature CAD (35% vs. 29%; P less than .01 for all comparisons), the researchers reported. Nonetheless, all five risk scores characterized women as lower risk than men (P less than .001 for mean differences). Moreover, before testing, providers characterized 41% of women having a low (less than 30%) likelihood of CAD, compared with 34% of men (P less than .001).
Women were more likely than men to be referred for stress echocardiography or nuclear stress test, but only 9.7% had a positive noninvasive test, compared with 15% of men (P less than .001), the researchers also reported. “A number of characteristics predicted positive test results, and many characteristics were similar between the sexes,” they added. “However, in multivariable models, key predictors of test positivity were few and varied by sex.” Body mass index and Framingham risk score predicted a positive test for women, while both the Framingham and modified Diamond-Forrester risk scores predicted a positive test for men.
Chest pain was the most common primary symptom reported by nearly three-quarters of women and men and was described as “crushing/pressure/squeezing/tightness” 53% and 46% of the time, respectively (P less than .001). Dyspnea was the second most frequent primary symptom at 15% for both sexes. Women were more likely than men to describe back pain, neck or jaw pain, or palpitations, but only 0.6% to 2.7% of patients ranked these among their main symptoms.
“Further studies are warranted to examine the underlying pathophysiology and implications for clinical care of the sex-based clinical differences observed along the entire diagnostic pathway of suspected CAD, including risk factor burden, presenting symptoms, and testing results,” the researchers concluded.
The PROMISE study was funded by the National Heart, Lung, and Blood Institute. Ms. Hemal had no disclosures. Senior author Dr. Pamela S. Douglas disclosed grant support from HeartFlow and having served on a data and safety monitoring board for General Electric Healthcare. Two of the other 15 coinvestigators also disclosed relationships with industry; the rest had no disclosures.
Women with suspected coronary artery disease had similar symptoms and more heart disease risk factors, compared with men, but were assessed as lower risk by their providers and on all standard risk scores, according to a secondary analysis of the PROMISE trial.
The results “highlight the need for sex-specific approaches to coronary artery disease evaluation and testing,” said Kshipra Hemal at Duke Clinical Research Institute in Durham, N.C., and her associates. The findings will be presented April 3 at the annual meeting of the American College of Cardiology and were published online March 23 in the Journal of the American College of Cardiology: Cardiovascular Imaging.
The PROMISE (Prospective Multicenter Imaging Study for the Evaluation of Chest Pain) trial is one of the largest contemporary trials of symptomatic, nonacute suspected CAD. The study included 10,003 stable outpatients, nearly half of whom were women. The researchers calculated the 2008 Framingham score, 2013 Atherosclerotic Cardiovascular Disease score, 1979 Diamond and Forrester score, modified 2011 Diamond and Forrester score, and 2012 combined Diamond-Forrester and Coronary Artery Surgery Study scores for all patients. Patients also were randomly assigned to either anatomical testing with CT angiography or to functional testing with exercise electrocardiogram, stress nuclear imaging, or stress echocardiogram (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.001).
Women in the study were an average of 3 years older than the men and were significantly more likely to be hypertensive (67% vs. 63%), dyslipidemic (69% vs. 66%), and to have a family history of premature CAD (35% vs. 29%; P less than .01 for all comparisons), the researchers reported. Nonetheless, all five risk scores characterized women as lower risk than men (P less than .001 for mean differences). Moreover, before testing, providers characterized 41% of women having a low (less than 30%) likelihood of CAD, compared with 34% of men (P less than .001).
Women were more likely than men to be referred for stress echocardiography or nuclear stress test, but only 9.7% had a positive noninvasive test, compared with 15% of men (P less than .001), the researchers also reported. “A number of characteristics predicted positive test results, and many characteristics were similar between the sexes,” they added. “However, in multivariable models, key predictors of test positivity were few and varied by sex.” Body mass index and Framingham risk score predicted a positive test for women, while both the Framingham and modified Diamond-Forrester risk scores predicted a positive test for men.
Chest pain was the most common primary symptom reported by nearly three-quarters of women and men and was described as “crushing/pressure/squeezing/tightness” 53% and 46% of the time, respectively (P less than .001). Dyspnea was the second most frequent primary symptom at 15% for both sexes. Women were more likely than men to describe back pain, neck or jaw pain, or palpitations, but only 0.6% to 2.7% of patients ranked these among their main symptoms.
“Further studies are warranted to examine the underlying pathophysiology and implications for clinical care of the sex-based clinical differences observed along the entire diagnostic pathway of suspected CAD, including risk factor burden, presenting symptoms, and testing results,” the researchers concluded.
The PROMISE study was funded by the National Heart, Lung, and Blood Institute. Ms. Hemal had no disclosures. Senior author Dr. Pamela S. Douglas disclosed grant support from HeartFlow and having served on a data and safety monitoring board for General Electric Healthcare. Two of the other 15 coinvestigators also disclosed relationships with industry; the rest had no disclosures.
FROM ACC 16
Women With Suspected CAD Classified as Lower Risk Than Men
Women with suspected coronary artery disease had similar symptoms and more heart disease risk factors, compared with men, but were assessed as lower risk by their providers and on all standard risk scores, according to a secondary analysis of the PROMISE trial.
The results “highlight the need for sex-specific approaches to coronary artery disease evaluation and testing,” said Kshipra Hemal at Duke Clinical Research Institute in Durham, N.C., and her associates. The findings will be presented April 3 at the annual meeting of the American College of Cardiology and were published online March 23 in the Journal of the American College of Cardiology: Cardiovascular Imaging.
The PROMISE (Prospective Multicenter Imaging Study for the Evaluation of Chest Pain) trial is one of the largest contemporary trials of symptomatic, nonacute suspected CAD. The study included 10,003 stable outpatients, nearly half of whom were women. The researchers calculated the 2008 Framingham score, 2013 Atherosclerotic Cardiovascular Disease score, 1979 Diamond and Forrester score, modified 2011 Diamond and Forrester score, and 2012 combined Diamond-Forrester and Coronary Artery Surgery Study scores for all patients. Patients also were randomly assigned to either anatomical testing with CT angiography or to functional testing with exercise electrocardiogram, stress nuclear imaging, or stress echocardiogram (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.001).
Women in the study were an average of 3 years older than the men and were significantly more likely to be hypertensive (67% vs. 63%), dyslipidemic (69% vs. 66%), and to have a family history of premature CAD (35% vs. 29%; P less than .01 for all comparisons), the researchers reported. Nonetheless, all five risk scores characterized women as lower risk than men (P less than .001 for mean differences). Moreover, before testing, providers characterized 41% of women having a low (less than 30%) likelihood of CAD, compared with 34% of men (P less than .001).
Women were more likely than men to be referred for stress echocardiography or nuclear stress test, but only 9.7% had a positive noninvasive test, compared with 15% of men (P less than .001), the researchers also reported. “A number of characteristics predicted positive test results, and many characteristics were similar between the sexes,” they added. “However, in multivariable models, key predictors of test positivity were few and varied by sex.” Body mass index and Framingham risk score predicted a positive test for women, while both the Framingham and modified Diamond-Forrester risk scores predicted a positive test for men.
Chest pain was the most common primary symptom reported by nearly three-quarters of women and men and was described as “crushing/pressure/squeezing/tightness” 53% and 46% of the time, respectively (P less than .001). Dyspnea was the second most frequent primary symptom at 15% for both sexes. Women were more likely than men to describe back pain, neck or jaw pain, or palpitations, but only 0.6% to 2.7% of patients ranked these among their main symptoms.
“Further studies are warranted to examine the underlying pathophysiology and implications for clinical care of the sex-based clinical differences observed along the entire diagnostic pathway of suspected CAD, including risk factor burden, presenting symptoms, and testing results,” the researchers concluded.
The PROMISE study was funded by the National Heart, Lung, and Blood Institute. Ms. Hemal had no disclosures. Senior author Dr. Pamela S. Douglas disclosed grant support from HeartFlow and having served on a data and safety monitoring board for General Electric Healthcare. Two of the other 15 coinvestigators also disclosed relationships with industry; the rest had no disclosures.
Despite symptomatic presentation, greater family history of premature coronary artery disease, and higher risk factor burden, including older age and greater prevalence of hypertension and dyslipidemia, the women in PROMISE were more likely to be characterized as low risk based on standard cardiovascular risk assessment scores and thus, not surprisingly, also were considered to be at lower risk by their providers. These findings add credence to the ongoing concerns that women are preferentially likely to receive less intensive management of CAD than their male counterparts.
The 2014 American Heart Association Consensus Statement on noninvasive diagnostic testing in women with suspected ischemic heart disease highlighted the development of novel diagnostic tools that have an expanded role in the evaluation of symptomatic female patients to detect not only focal epicardial coronary stenosis, but also nonobstructive atherosclerosis as well as the identification of ischemia resulting from microvascular dysfunction. Such methods using advanced imaging are making steady progress in the understanding of microvascular disease and its consequences.
We agree with the PROMISE investigators that focused sex-specific diagnostic strategies are needed to reduce the cardiovascular mortality and morbidity in women. With emerging data on the full pathophysiologic spectrum of ischemic heart disease in women, diagnostic algorithms must include functional and anatomic cardiac tests as well as physiologic assessments of endothelial and microvascular function, for accurately establishing the diagnosis and prognosis of women with suspected IHD.
Dr. Jennifer H. Mieres is with Hofstra University, Hempstead, N.Y. Dr. Robert O. Bonow is with Northwestern University, Chicago. They had no disclosures. These comments are from their editorial (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.0089).
Despite symptomatic presentation, greater family history of premature coronary artery disease, and higher risk factor burden, including older age and greater prevalence of hypertension and dyslipidemia, the women in PROMISE were more likely to be characterized as low risk based on standard cardiovascular risk assessment scores and thus, not surprisingly, also were considered to be at lower risk by their providers. These findings add credence to the ongoing concerns that women are preferentially likely to receive less intensive management of CAD than their male counterparts.
The 2014 American Heart Association Consensus Statement on noninvasive diagnostic testing in women with suspected ischemic heart disease highlighted the development of novel diagnostic tools that have an expanded role in the evaluation of symptomatic female patients to detect not only focal epicardial coronary stenosis, but also nonobstructive atherosclerosis as well as the identification of ischemia resulting from microvascular dysfunction. Such methods using advanced imaging are making steady progress in the understanding of microvascular disease and its consequences.
We agree with the PROMISE investigators that focused sex-specific diagnostic strategies are needed to reduce the cardiovascular mortality and morbidity in women. With emerging data on the full pathophysiologic spectrum of ischemic heart disease in women, diagnostic algorithms must include functional and anatomic cardiac tests as well as physiologic assessments of endothelial and microvascular function, for accurately establishing the diagnosis and prognosis of women with suspected IHD.
Dr. Jennifer H. Mieres is with Hofstra University, Hempstead, N.Y. Dr. Robert O. Bonow is with Northwestern University, Chicago. They had no disclosures. These comments are from their editorial (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.0089).
Despite symptomatic presentation, greater family history of premature coronary artery disease, and higher risk factor burden, including older age and greater prevalence of hypertension and dyslipidemia, the women in PROMISE were more likely to be characterized as low risk based on standard cardiovascular risk assessment scores and thus, not surprisingly, also were considered to be at lower risk by their providers. These findings add credence to the ongoing concerns that women are preferentially likely to receive less intensive management of CAD than their male counterparts.
The 2014 American Heart Association Consensus Statement on noninvasive diagnostic testing in women with suspected ischemic heart disease highlighted the development of novel diagnostic tools that have an expanded role in the evaluation of symptomatic female patients to detect not only focal epicardial coronary stenosis, but also nonobstructive atherosclerosis as well as the identification of ischemia resulting from microvascular dysfunction. Such methods using advanced imaging are making steady progress in the understanding of microvascular disease and its consequences.
We agree with the PROMISE investigators that focused sex-specific diagnostic strategies are needed to reduce the cardiovascular mortality and morbidity in women. With emerging data on the full pathophysiologic spectrum of ischemic heart disease in women, diagnostic algorithms must include functional and anatomic cardiac tests as well as physiologic assessments of endothelial and microvascular function, for accurately establishing the diagnosis and prognosis of women with suspected IHD.
Dr. Jennifer H. Mieres is with Hofstra University, Hempstead, N.Y. Dr. Robert O. Bonow is with Northwestern University, Chicago. They had no disclosures. These comments are from their editorial (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.0089).
Women with suspected coronary artery disease had similar symptoms and more heart disease risk factors, compared with men, but were assessed as lower risk by their providers and on all standard risk scores, according to a secondary analysis of the PROMISE trial.
The results “highlight the need for sex-specific approaches to coronary artery disease evaluation and testing,” said Kshipra Hemal at Duke Clinical Research Institute in Durham, N.C., and her associates. The findings will be presented April 3 at the annual meeting of the American College of Cardiology and were published online March 23 in the Journal of the American College of Cardiology: Cardiovascular Imaging.
The PROMISE (Prospective Multicenter Imaging Study for the Evaluation of Chest Pain) trial is one of the largest contemporary trials of symptomatic, nonacute suspected CAD. The study included 10,003 stable outpatients, nearly half of whom were women. The researchers calculated the 2008 Framingham score, 2013 Atherosclerotic Cardiovascular Disease score, 1979 Diamond and Forrester score, modified 2011 Diamond and Forrester score, and 2012 combined Diamond-Forrester and Coronary Artery Surgery Study scores for all patients. Patients also were randomly assigned to either anatomical testing with CT angiography or to functional testing with exercise electrocardiogram, stress nuclear imaging, or stress echocardiogram (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.001).
Women in the study were an average of 3 years older than the men and were significantly more likely to be hypertensive (67% vs. 63%), dyslipidemic (69% vs. 66%), and to have a family history of premature CAD (35% vs. 29%; P less than .01 for all comparisons), the researchers reported. Nonetheless, all five risk scores characterized women as lower risk than men (P less than .001 for mean differences). Moreover, before testing, providers characterized 41% of women having a low (less than 30%) likelihood of CAD, compared with 34% of men (P less than .001).
Women were more likely than men to be referred for stress echocardiography or nuclear stress test, but only 9.7% had a positive noninvasive test, compared with 15% of men (P less than .001), the researchers also reported. “A number of characteristics predicted positive test results, and many characteristics were similar between the sexes,” they added. “However, in multivariable models, key predictors of test positivity were few and varied by sex.” Body mass index and Framingham risk score predicted a positive test for women, while both the Framingham and modified Diamond-Forrester risk scores predicted a positive test for men.
Chest pain was the most common primary symptom reported by nearly three-quarters of women and men and was described as “crushing/pressure/squeezing/tightness” 53% and 46% of the time, respectively (P less than .001). Dyspnea was the second most frequent primary symptom at 15% for both sexes. Women were more likely than men to describe back pain, neck or jaw pain, or palpitations, but only 0.6% to 2.7% of patients ranked these among their main symptoms.
“Further studies are warranted to examine the underlying pathophysiology and implications for clinical care of the sex-based clinical differences observed along the entire diagnostic pathway of suspected CAD, including risk factor burden, presenting symptoms, and testing results,” the researchers concluded.
The PROMISE study was funded by the National Heart, Lung, and Blood Institute. Ms. Hemal had no disclosures. Senior author Dr. Pamela S. Douglas disclosed grant support from HeartFlow and having served on a data and safety monitoring board for General Electric Healthcare. Two of the other 15 coinvestigators also disclosed relationships with industry; the rest had no disclosures.
Women with suspected coronary artery disease had similar symptoms and more heart disease risk factors, compared with men, but were assessed as lower risk by their providers and on all standard risk scores, according to a secondary analysis of the PROMISE trial.
The results “highlight the need for sex-specific approaches to coronary artery disease evaluation and testing,” said Kshipra Hemal at Duke Clinical Research Institute in Durham, N.C., and her associates. The findings will be presented April 3 at the annual meeting of the American College of Cardiology and were published online March 23 in the Journal of the American College of Cardiology: Cardiovascular Imaging.
The PROMISE (Prospective Multicenter Imaging Study for the Evaluation of Chest Pain) trial is one of the largest contemporary trials of symptomatic, nonacute suspected CAD. The study included 10,003 stable outpatients, nearly half of whom were women. The researchers calculated the 2008 Framingham score, 2013 Atherosclerotic Cardiovascular Disease score, 1979 Diamond and Forrester score, modified 2011 Diamond and Forrester score, and 2012 combined Diamond-Forrester and Coronary Artery Surgery Study scores for all patients. Patients also were randomly assigned to either anatomical testing with CT angiography or to functional testing with exercise electrocardiogram, stress nuclear imaging, or stress echocardiogram (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.001).
Women in the study were an average of 3 years older than the men and were significantly more likely to be hypertensive (67% vs. 63%), dyslipidemic (69% vs. 66%), and to have a family history of premature CAD (35% vs. 29%; P less than .01 for all comparisons), the researchers reported. Nonetheless, all five risk scores characterized women as lower risk than men (P less than .001 for mean differences). Moreover, before testing, providers characterized 41% of women having a low (less than 30%) likelihood of CAD, compared with 34% of men (P less than .001).
Women were more likely than men to be referred for stress echocardiography or nuclear stress test, but only 9.7% had a positive noninvasive test, compared with 15% of men (P less than .001), the researchers also reported. “A number of characteristics predicted positive test results, and many characteristics were similar between the sexes,” they added. “However, in multivariable models, key predictors of test positivity were few and varied by sex.” Body mass index and Framingham risk score predicted a positive test for women, while both the Framingham and modified Diamond-Forrester risk scores predicted a positive test for men.
Chest pain was the most common primary symptom reported by nearly three-quarters of women and men and was described as “crushing/pressure/squeezing/tightness” 53% and 46% of the time, respectively (P less than .001). Dyspnea was the second most frequent primary symptom at 15% for both sexes. Women were more likely than men to describe back pain, neck or jaw pain, or palpitations, but only 0.6% to 2.7% of patients ranked these among their main symptoms.
“Further studies are warranted to examine the underlying pathophysiology and implications for clinical care of the sex-based clinical differences observed along the entire diagnostic pathway of suspected CAD, including risk factor burden, presenting symptoms, and testing results,” the researchers concluded.
The PROMISE study was funded by the National Heart, Lung, and Blood Institute. Ms. Hemal had no disclosures. Senior author Dr. Pamela S. Douglas disclosed grant support from HeartFlow and having served on a data and safety monitoring board for General Electric Healthcare. Two of the other 15 coinvestigators also disclosed relationships with industry; the rest had no disclosures.
FROM ACC 16
Women with suspected CAD classified as lower risk than men
Women with suspected coronary artery disease had similar symptoms and more heart disease risk factors, compared with men, but were assessed as lower risk by their providers and on all standard risk scores, according to a secondary analysis of the PROMISE trial.
The results “highlight the need for sex-specific approaches to coronary artery disease evaluation and testing,” said Kshipra Hemal at Duke Clinical Research Institute in Durham, N.C., and her associates. The findings will be presented April 3 at the annual meeting of the American College of Cardiology and were published online March 23 in the Journal of the American College of Cardiology: Cardiovascular Imaging.
The PROMISE (Prospective Multicenter Imaging Study for the Evaluation of Chest Pain) trial is one of the largest contemporary trials of symptomatic, nonacute suspected CAD. The study included 10,003 stable outpatients, nearly half of whom were women. The researchers calculated the 2008 Framingham score, 2013 Atherosclerotic Cardiovascular Disease score, 1979 Diamond and Forrester score, modified 2011 Diamond and Forrester score, and 2012 combined Diamond-Forrester and Coronary Artery Surgery Study scores for all patients. Patients also were randomly assigned to either anatomical testing with CT angiography or to functional testing with exercise electrocardiogram, stress nuclear imaging, or stress echocardiogram (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.001).
Women in the study were an average of 3 years older than the men and were significantly more likely to be hypertensive (67% vs. 63%), dyslipidemic (69% vs. 66%), and to have a family history of premature CAD (35% vs. 29%; P less than .01 for all comparisons), the researchers reported. Nonetheless, all five risk scores characterized women as lower risk than men (P less than .001 for mean differences). Moreover, before testing, providers characterized 41% of women having a low (less than 30%) likelihood of CAD, compared with 34% of men (P less than .001).
Women were more likely than men to be referred for stress echocardiography or nuclear stress test, but only 9.7% had a positive noninvasive test, compared with 15% of men (P less than .001), the researchers also reported. “A number of characteristics predicted positive test results, and many characteristics were similar between the sexes,” they added. “However, in multivariable models, key predictors of test positivity were few and varied by sex.” Body mass index and Framingham risk score predicted a positive test for women, while both the Framingham and modified Diamond-Forrester risk scores predicted a positive test for men.
Chest pain was the most common primary symptom reported by nearly three-quarters of women and men and was described as “crushing/pressure/squeezing/tightness” 53% and 46% of the time, respectively (P less than .001). Dyspnea was the second most frequent primary symptom at 15% for both sexes. Women were more likely than men to describe back pain, neck or jaw pain, or palpitations, but only 0.6% to 2.7% of patients ranked these among their main symptoms.
“Further studies are warranted to examine the underlying pathophysiology and implications for clinical care of the sex-based clinical differences observed along the entire diagnostic pathway of suspected CAD, including risk factor burden, presenting symptoms, and testing results,” the researchers concluded.
The PROMISE study was funded by the National Heart, Lung, and Blood Institute. Ms. Hemal had no disclosures. Senior author Dr. Pamela S. Douglas disclosed grant support from HeartFlow and having served on a data and safety monitoring board for General Electric Healthcare. Two of the other 15 coinvestigators also disclosed relationships with industry; the rest had no disclosures.
Despite symptomatic presentation, greater family history of premature coronary artery disease, and higher risk factor burden, including older age and greater prevalence of hypertension and dyslipidemia, the women in PROMISE were more likely to be characterized as low risk based on standard cardiovascular risk assessment scores and thus, not surprisingly, also were considered to be at lower risk by their providers. These findings add credence to the ongoing concerns that women are preferentially likely to receive less intensive management of CAD than their male counterparts.
The 2014 American Heart Association Consensus Statement on noninvasive diagnostic testing in women with suspected ischemic heart disease highlighted the development of novel diagnostic tools that have an expanded role in the evaluation of symptomatic female patients to detect not only focal epicardial coronary stenosis, but also nonobstructive atherosclerosis as well as the identification of ischemia resulting from microvascular dysfunction. Such methods using advanced imaging are making steady progress in the understanding of microvascular disease and its consequences.
We agree with the PROMISE investigators that focused sex-specific diagnostic strategies are needed to reduce the cardiovascular mortality and morbidity in women. With emerging data on the full pathophysiologic spectrum of ischemic heart disease in women, diagnostic algorithms must include functional and anatomic cardiac tests as well as physiologic assessments of endothelial and microvascular function, for accurately establishing the diagnosis and prognosis of women with suspected IHD.
Dr. Jennifer H. Mieres is with Hofstra University, Hempstead, N.Y. Dr. Robert O. Bonow is with Northwestern University, Chicago. They had no disclosures. These comments are from their editorial (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.0089).
Despite symptomatic presentation, greater family history of premature coronary artery disease, and higher risk factor burden, including older age and greater prevalence of hypertension and dyslipidemia, the women in PROMISE were more likely to be characterized as low risk based on standard cardiovascular risk assessment scores and thus, not surprisingly, also were considered to be at lower risk by their providers. These findings add credence to the ongoing concerns that women are preferentially likely to receive less intensive management of CAD than their male counterparts.
The 2014 American Heart Association Consensus Statement on noninvasive diagnostic testing in women with suspected ischemic heart disease highlighted the development of novel diagnostic tools that have an expanded role in the evaluation of symptomatic female patients to detect not only focal epicardial coronary stenosis, but also nonobstructive atherosclerosis as well as the identification of ischemia resulting from microvascular dysfunction. Such methods using advanced imaging are making steady progress in the understanding of microvascular disease and its consequences.
We agree with the PROMISE investigators that focused sex-specific diagnostic strategies are needed to reduce the cardiovascular mortality and morbidity in women. With emerging data on the full pathophysiologic spectrum of ischemic heart disease in women, diagnostic algorithms must include functional and anatomic cardiac tests as well as physiologic assessments of endothelial and microvascular function, for accurately establishing the diagnosis and prognosis of women with suspected IHD.
Dr. Jennifer H. Mieres is with Hofstra University, Hempstead, N.Y. Dr. Robert O. Bonow is with Northwestern University, Chicago. They had no disclosures. These comments are from their editorial (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.0089).
Despite symptomatic presentation, greater family history of premature coronary artery disease, and higher risk factor burden, including older age and greater prevalence of hypertension and dyslipidemia, the women in PROMISE were more likely to be characterized as low risk based on standard cardiovascular risk assessment scores and thus, not surprisingly, also were considered to be at lower risk by their providers. These findings add credence to the ongoing concerns that women are preferentially likely to receive less intensive management of CAD than their male counterparts.
The 2014 American Heart Association Consensus Statement on noninvasive diagnostic testing in women with suspected ischemic heart disease highlighted the development of novel diagnostic tools that have an expanded role in the evaluation of symptomatic female patients to detect not only focal epicardial coronary stenosis, but also nonobstructive atherosclerosis as well as the identification of ischemia resulting from microvascular dysfunction. Such methods using advanced imaging are making steady progress in the understanding of microvascular disease and its consequences.
We agree with the PROMISE investigators that focused sex-specific diagnostic strategies are needed to reduce the cardiovascular mortality and morbidity in women. With emerging data on the full pathophysiologic spectrum of ischemic heart disease in women, diagnostic algorithms must include functional and anatomic cardiac tests as well as physiologic assessments of endothelial and microvascular function, for accurately establishing the diagnosis and prognosis of women with suspected IHD.
Dr. Jennifer H. Mieres is with Hofstra University, Hempstead, N.Y. Dr. Robert O. Bonow is with Northwestern University, Chicago. They had no disclosures. These comments are from their editorial (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.0089).
Women with suspected coronary artery disease had similar symptoms and more heart disease risk factors, compared with men, but were assessed as lower risk by their providers and on all standard risk scores, according to a secondary analysis of the PROMISE trial.
The results “highlight the need for sex-specific approaches to coronary artery disease evaluation and testing,” said Kshipra Hemal at Duke Clinical Research Institute in Durham, N.C., and her associates. The findings will be presented April 3 at the annual meeting of the American College of Cardiology and were published online March 23 in the Journal of the American College of Cardiology: Cardiovascular Imaging.
The PROMISE (Prospective Multicenter Imaging Study for the Evaluation of Chest Pain) trial is one of the largest contemporary trials of symptomatic, nonacute suspected CAD. The study included 10,003 stable outpatients, nearly half of whom were women. The researchers calculated the 2008 Framingham score, 2013 Atherosclerotic Cardiovascular Disease score, 1979 Diamond and Forrester score, modified 2011 Diamond and Forrester score, and 2012 combined Diamond-Forrester and Coronary Artery Surgery Study scores for all patients. Patients also were randomly assigned to either anatomical testing with CT angiography or to functional testing with exercise electrocardiogram, stress nuclear imaging, or stress echocardiogram (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.001).
Women in the study were an average of 3 years older than the men and were significantly more likely to be hypertensive (67% vs. 63%), dyslipidemic (69% vs. 66%), and to have a family history of premature CAD (35% vs. 29%; P less than .01 for all comparisons), the researchers reported. Nonetheless, all five risk scores characterized women as lower risk than men (P less than .001 for mean differences). Moreover, before testing, providers characterized 41% of women having a low (less than 30%) likelihood of CAD, compared with 34% of men (P less than .001).
Women were more likely than men to be referred for stress echocardiography or nuclear stress test, but only 9.7% had a positive noninvasive test, compared with 15% of men (P less than .001), the researchers also reported. “A number of characteristics predicted positive test results, and many characteristics were similar between the sexes,” they added. “However, in multivariable models, key predictors of test positivity were few and varied by sex.” Body mass index and Framingham risk score predicted a positive test for women, while both the Framingham and modified Diamond-Forrester risk scores predicted a positive test for men.
Chest pain was the most common primary symptom reported by nearly three-quarters of women and men and was described as “crushing/pressure/squeezing/tightness” 53% and 46% of the time, respectively (P less than .001). Dyspnea was the second most frequent primary symptom at 15% for both sexes. Women were more likely than men to describe back pain, neck or jaw pain, or palpitations, but only 0.6% to 2.7% of patients ranked these among their main symptoms.
“Further studies are warranted to examine the underlying pathophysiology and implications for clinical care of the sex-based clinical differences observed along the entire diagnostic pathway of suspected CAD, including risk factor burden, presenting symptoms, and testing results,” the researchers concluded.
The PROMISE study was funded by the National Heart, Lung, and Blood Institute. Ms. Hemal had no disclosures. Senior author Dr. Pamela S. Douglas disclosed grant support from HeartFlow and having served on a data and safety monitoring board for General Electric Healthcare. Two of the other 15 coinvestigators also disclosed relationships with industry; the rest had no disclosures.
Women with suspected coronary artery disease had similar symptoms and more heart disease risk factors, compared with men, but were assessed as lower risk by their providers and on all standard risk scores, according to a secondary analysis of the PROMISE trial.
The results “highlight the need for sex-specific approaches to coronary artery disease evaluation and testing,” said Kshipra Hemal at Duke Clinical Research Institute in Durham, N.C., and her associates. The findings will be presented April 3 at the annual meeting of the American College of Cardiology and were published online March 23 in the Journal of the American College of Cardiology: Cardiovascular Imaging.
The PROMISE (Prospective Multicenter Imaging Study for the Evaluation of Chest Pain) trial is one of the largest contemporary trials of symptomatic, nonacute suspected CAD. The study included 10,003 stable outpatients, nearly half of whom were women. The researchers calculated the 2008 Framingham score, 2013 Atherosclerotic Cardiovascular Disease score, 1979 Diamond and Forrester score, modified 2011 Diamond and Forrester score, and 2012 combined Diamond-Forrester and Coronary Artery Surgery Study scores for all patients. Patients also were randomly assigned to either anatomical testing with CT angiography or to functional testing with exercise electrocardiogram, stress nuclear imaging, or stress echocardiogram (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.001).
Women in the study were an average of 3 years older than the men and were significantly more likely to be hypertensive (67% vs. 63%), dyslipidemic (69% vs. 66%), and to have a family history of premature CAD (35% vs. 29%; P less than .01 for all comparisons), the researchers reported. Nonetheless, all five risk scores characterized women as lower risk than men (P less than .001 for mean differences). Moreover, before testing, providers characterized 41% of women having a low (less than 30%) likelihood of CAD, compared with 34% of men (P less than .001).
Women were more likely than men to be referred for stress echocardiography or nuclear stress test, but only 9.7% had a positive noninvasive test, compared with 15% of men (P less than .001), the researchers also reported. “A number of characteristics predicted positive test results, and many characteristics were similar between the sexes,” they added. “However, in multivariable models, key predictors of test positivity were few and varied by sex.” Body mass index and Framingham risk score predicted a positive test for women, while both the Framingham and modified Diamond-Forrester risk scores predicted a positive test for men.
Chest pain was the most common primary symptom reported by nearly three-quarters of women and men and was described as “crushing/pressure/squeezing/tightness” 53% and 46% of the time, respectively (P less than .001). Dyspnea was the second most frequent primary symptom at 15% for both sexes. Women were more likely than men to describe back pain, neck or jaw pain, or palpitations, but only 0.6% to 2.7% of patients ranked these among their main symptoms.
“Further studies are warranted to examine the underlying pathophysiology and implications for clinical care of the sex-based clinical differences observed along the entire diagnostic pathway of suspected CAD, including risk factor burden, presenting symptoms, and testing results,” the researchers concluded.
The PROMISE study was funded by the National Heart, Lung, and Blood Institute. Ms. Hemal had no disclosures. Senior author Dr. Pamela S. Douglas disclosed grant support from HeartFlow and having served on a data and safety monitoring board for General Electric Healthcare. Two of the other 15 coinvestigators also disclosed relationships with industry; the rest had no disclosures.
FROM ACC 16
Key clinical point: Women with suspected coronary artery disease had similar symptoms and more risk factors for coronary artery disease, compared with men, but were classified as lower risk on risk scores and by providers.
Major finding: All risk scores assessed women as being at lower risk than men. Providers characterized 41% of pretest women and 34% of men as low risk (P less than .001).
Data source: A prospective, multicenter, randomized trial of 10,003 symptomatic outpatients with suspected coronary artery disease.
Disclosures: The PROMISE study was funded by the National Heart, Lung, and Blood Institute. Dr. Hemal had no disclosures. Senior author Dr. Pamela Douglas disclosed grant support from HeartFlow and having served on a data and safety monitoring board for General Electric Healthcare. Two of the other 15 coinvestigators also disclosed relationships with industry; the rest had no disclosures.
Large cohort study confirms link between pioglitazone, bladder cancer
Pioglitazone was linked to a 63% increase in bladder cancer risk, compared with other noninsulin antidiabetic drugs in a large population-based cohort study.
Furthermore, incidence rose the longer patients took pioglitazone and the higher their dose, according to Dr. Marco Tuccori at Jewish General Hospital in Montreal, and his associates. “Rosiglitazone was not associated with an increased risk of bladder cancer in any analysis, suggesting the risk is drug-specific and not a class effect,” they wrote online March 30 in BMJ.
Both pioglitazone and rosiglitazone are thiazolidinediones that help treat insulin resistance in patients with type 2 diabetes. In 2005, Proactive trial investigators reported that patients were more likely to develop bladder cancer on pioglitazone, compared with placebo. But later observational studies reported mixed associations between pioglitazone and bladder cancer, perhaps because of biases and other methodological shortcomings, the researchers said (BMJ. 2016. doi: 10.1136/bmj.i1541).
Dr. Tuccori and his colleagues studied 145,806 patients with newly diagnosed type 2 diabetes, defined as a first-ever prescription for thiazolidinediones, metformin, sulfonylureas, prandial glucose regulators, acarbose, dipeptidyl peptidase-4 inhibitors, glucagonlike peptide agonists, or sodium-glucose cotransporter-2 inhibitors. The investigators excluded patients with any history of bladder cancer or less than a year of follow-up, and set a lag period of 1 year to help control for bladder cancer cases that were undiagnosed at study entry. The study included data for 2000-2013 from a national primary care registry that correlated well with the national cancer registry, the investigators said.
In all, 622 patients were diagnosed with bladder cancer (90 cases per 100,000 person-years), with a median of 4.4 years between study entry and cancer diagnosis (interquartile range, 2.5-6.5 years). Pioglitazone was associated with 121 cases of bladder cancer for every 100,000 person-years, compared with only 89 cases per 100,000 person-years for other antidiabetic drugs (hazard ratio, 1.6; 95% confidence interval, 1.2-2.2). Patients were no more likely to develop bladder cancer on rosiglitazone than other antidiabetic drugs (86.2 and 88.9 cases per 100,000 person-years of exposure, respectively; HR, 1.1; 95% CI, 0.8-1.5). Furthermore, pioglitazone was linked to nearly a 50% greater risk of bladder cancer, compared with rosiglitazone in a head-to-head comparison.
Not only did the link between pioglitazone and bladder cancer hold up in nine sensitivity analyses, but the hazard ratio increased to 1.73 when the researchers increased the required lag period to 2 years. Pharmacologic differences between pioglitazone and rosiglitazone might explain their distinct risk profiles in terms of bladder cancer, the investigators noted. Rosiglitazone is selective for peroxisome proliferator-activated receptor (PPAR) gamma, while pioglitazone has dual PPAR alpha/gamma activity. Only the latter increased expression of carcinogenic bladder biomarkers in rat models, they noted. This mechanism needs more exploration, they added.
The Canadian Institutes of Health Research funded the study. The researchers had no disclosures.
The results of such a large study are troubling Although it represents a retroactive observational assessment of the risk of bladder cancer from pioglitazone rather than a prospective randomized trial, the large number of patients gives this study strength. Yet, it is at odds, as the authors themselves point out, with other published studies like the Kaiser Permanente Northern California study. That study used the same cohort with follow-up extended to 10 years, and the use of pioglitazone was no longer significantly associated with an increased risk of bladder cancer. It is important to note that, although the authors show an increased risk for bladder cancer, the numbers are very small. I wish the authors would balance the risk in their study with potential benefit in the same cohort. They did cite the recently published Insulin Resistance Intervention after Stroke (IRIS) trial, which randomized 3,895 people. After a similar median follow-up of 4.8 years (4.7 years in the United Kingdom study), pioglitazone was associated with a decreased risk of a composite endpoint of stroke or myocardial infarction. In the IRIS study, there was an increased number of bladder cancer events in the pioglitazone group: 12 vs. 8 in the placebo group. In IRIS we see a clear benefit-risk ratio. By prescribing pioglitazone, there is significant cardiovascular risk improvement, while the number of cancer cases was quite small. In summary, continued prescribing of pioglitazone seems reasonable, and although the controversy has not been resolved, it seems that benefit-risk ratio favors prescribing pioglitazone. It makes sense, however, to exercise caution and follow the recommendations of the Food and Drug Administration in patients with a high risk for bladder cancer.
Dr. Yehuda Handelsman is medical director and principal investigator, Metabolic Institute of America, Tarzana, Calif., and immediate past president, American College of Endocrinology.
The results of such a large study are troubling Although it represents a retroactive observational assessment of the risk of bladder cancer from pioglitazone rather than a prospective randomized trial, the large number of patients gives this study strength. Yet, it is at odds, as the authors themselves point out, with other published studies like the Kaiser Permanente Northern California study. That study used the same cohort with follow-up extended to 10 years, and the use of pioglitazone was no longer significantly associated with an increased risk of bladder cancer. It is important to note that, although the authors show an increased risk for bladder cancer, the numbers are very small. I wish the authors would balance the risk in their study with potential benefit in the same cohort. They did cite the recently published Insulin Resistance Intervention after Stroke (IRIS) trial, which randomized 3,895 people. After a similar median follow-up of 4.8 years (4.7 years in the United Kingdom study), pioglitazone was associated with a decreased risk of a composite endpoint of stroke or myocardial infarction. In the IRIS study, there was an increased number of bladder cancer events in the pioglitazone group: 12 vs. 8 in the placebo group. In IRIS we see a clear benefit-risk ratio. By prescribing pioglitazone, there is significant cardiovascular risk improvement, while the number of cancer cases was quite small. In summary, continued prescribing of pioglitazone seems reasonable, and although the controversy has not been resolved, it seems that benefit-risk ratio favors prescribing pioglitazone. It makes sense, however, to exercise caution and follow the recommendations of the Food and Drug Administration in patients with a high risk for bladder cancer.
Dr. Yehuda Handelsman is medical director and principal investigator, Metabolic Institute of America, Tarzana, Calif., and immediate past president, American College of Endocrinology.
The results of such a large study are troubling Although it represents a retroactive observational assessment of the risk of bladder cancer from pioglitazone rather than a prospective randomized trial, the large number of patients gives this study strength. Yet, it is at odds, as the authors themselves point out, with other published studies like the Kaiser Permanente Northern California study. That study used the same cohort with follow-up extended to 10 years, and the use of pioglitazone was no longer significantly associated with an increased risk of bladder cancer. It is important to note that, although the authors show an increased risk for bladder cancer, the numbers are very small. I wish the authors would balance the risk in their study with potential benefit in the same cohort. They did cite the recently published Insulin Resistance Intervention after Stroke (IRIS) trial, which randomized 3,895 people. After a similar median follow-up of 4.8 years (4.7 years in the United Kingdom study), pioglitazone was associated with a decreased risk of a composite endpoint of stroke or myocardial infarction. In the IRIS study, there was an increased number of bladder cancer events in the pioglitazone group: 12 vs. 8 in the placebo group. In IRIS we see a clear benefit-risk ratio. By prescribing pioglitazone, there is significant cardiovascular risk improvement, while the number of cancer cases was quite small. In summary, continued prescribing of pioglitazone seems reasonable, and although the controversy has not been resolved, it seems that benefit-risk ratio favors prescribing pioglitazone. It makes sense, however, to exercise caution and follow the recommendations of the Food and Drug Administration in patients with a high risk for bladder cancer.
Dr. Yehuda Handelsman is medical director and principal investigator, Metabolic Institute of America, Tarzana, Calif., and immediate past president, American College of Endocrinology.
Pioglitazone was linked to a 63% increase in bladder cancer risk, compared with other noninsulin antidiabetic drugs in a large population-based cohort study.
Furthermore, incidence rose the longer patients took pioglitazone and the higher their dose, according to Dr. Marco Tuccori at Jewish General Hospital in Montreal, and his associates. “Rosiglitazone was not associated with an increased risk of bladder cancer in any analysis, suggesting the risk is drug-specific and not a class effect,” they wrote online March 30 in BMJ.
Both pioglitazone and rosiglitazone are thiazolidinediones that help treat insulin resistance in patients with type 2 diabetes. In 2005, Proactive trial investigators reported that patients were more likely to develop bladder cancer on pioglitazone, compared with placebo. But later observational studies reported mixed associations between pioglitazone and bladder cancer, perhaps because of biases and other methodological shortcomings, the researchers said (BMJ. 2016. doi: 10.1136/bmj.i1541).
Dr. Tuccori and his colleagues studied 145,806 patients with newly diagnosed type 2 diabetes, defined as a first-ever prescription for thiazolidinediones, metformin, sulfonylureas, prandial glucose regulators, acarbose, dipeptidyl peptidase-4 inhibitors, glucagonlike peptide agonists, or sodium-glucose cotransporter-2 inhibitors. The investigators excluded patients with any history of bladder cancer or less than a year of follow-up, and set a lag period of 1 year to help control for bladder cancer cases that were undiagnosed at study entry. The study included data for 2000-2013 from a national primary care registry that correlated well with the national cancer registry, the investigators said.
In all, 622 patients were diagnosed with bladder cancer (90 cases per 100,000 person-years), with a median of 4.4 years between study entry and cancer diagnosis (interquartile range, 2.5-6.5 years). Pioglitazone was associated with 121 cases of bladder cancer for every 100,000 person-years, compared with only 89 cases per 100,000 person-years for other antidiabetic drugs (hazard ratio, 1.6; 95% confidence interval, 1.2-2.2). Patients were no more likely to develop bladder cancer on rosiglitazone than other antidiabetic drugs (86.2 and 88.9 cases per 100,000 person-years of exposure, respectively; HR, 1.1; 95% CI, 0.8-1.5). Furthermore, pioglitazone was linked to nearly a 50% greater risk of bladder cancer, compared with rosiglitazone in a head-to-head comparison.
Not only did the link between pioglitazone and bladder cancer hold up in nine sensitivity analyses, but the hazard ratio increased to 1.73 when the researchers increased the required lag period to 2 years. Pharmacologic differences between pioglitazone and rosiglitazone might explain their distinct risk profiles in terms of bladder cancer, the investigators noted. Rosiglitazone is selective for peroxisome proliferator-activated receptor (PPAR) gamma, while pioglitazone has dual PPAR alpha/gamma activity. Only the latter increased expression of carcinogenic bladder biomarkers in rat models, they noted. This mechanism needs more exploration, they added.
The Canadian Institutes of Health Research funded the study. The researchers had no disclosures.
Pioglitazone was linked to a 63% increase in bladder cancer risk, compared with other noninsulin antidiabetic drugs in a large population-based cohort study.
Furthermore, incidence rose the longer patients took pioglitazone and the higher their dose, according to Dr. Marco Tuccori at Jewish General Hospital in Montreal, and his associates. “Rosiglitazone was not associated with an increased risk of bladder cancer in any analysis, suggesting the risk is drug-specific and not a class effect,” they wrote online March 30 in BMJ.
Both pioglitazone and rosiglitazone are thiazolidinediones that help treat insulin resistance in patients with type 2 diabetes. In 2005, Proactive trial investigators reported that patients were more likely to develop bladder cancer on pioglitazone, compared with placebo. But later observational studies reported mixed associations between pioglitazone and bladder cancer, perhaps because of biases and other methodological shortcomings, the researchers said (BMJ. 2016. doi: 10.1136/bmj.i1541).
Dr. Tuccori and his colleagues studied 145,806 patients with newly diagnosed type 2 diabetes, defined as a first-ever prescription for thiazolidinediones, metformin, sulfonylureas, prandial glucose regulators, acarbose, dipeptidyl peptidase-4 inhibitors, glucagonlike peptide agonists, or sodium-glucose cotransporter-2 inhibitors. The investigators excluded patients with any history of bladder cancer or less than a year of follow-up, and set a lag period of 1 year to help control for bladder cancer cases that were undiagnosed at study entry. The study included data for 2000-2013 from a national primary care registry that correlated well with the national cancer registry, the investigators said.
In all, 622 patients were diagnosed with bladder cancer (90 cases per 100,000 person-years), with a median of 4.4 years between study entry and cancer diagnosis (interquartile range, 2.5-6.5 years). Pioglitazone was associated with 121 cases of bladder cancer for every 100,000 person-years, compared with only 89 cases per 100,000 person-years for other antidiabetic drugs (hazard ratio, 1.6; 95% confidence interval, 1.2-2.2). Patients were no more likely to develop bladder cancer on rosiglitazone than other antidiabetic drugs (86.2 and 88.9 cases per 100,000 person-years of exposure, respectively; HR, 1.1; 95% CI, 0.8-1.5). Furthermore, pioglitazone was linked to nearly a 50% greater risk of bladder cancer, compared with rosiglitazone in a head-to-head comparison.
Not only did the link between pioglitazone and bladder cancer hold up in nine sensitivity analyses, but the hazard ratio increased to 1.73 when the researchers increased the required lag period to 2 years. Pharmacologic differences between pioglitazone and rosiglitazone might explain their distinct risk profiles in terms of bladder cancer, the investigators noted. Rosiglitazone is selective for peroxisome proliferator-activated receptor (PPAR) gamma, while pioglitazone has dual PPAR alpha/gamma activity. Only the latter increased expression of carcinogenic bladder biomarkers in rat models, they noted. This mechanism needs more exploration, they added.
The Canadian Institutes of Health Research funded the study. The researchers had no disclosures.
FROM BMJ
Key clinical point: Pioglitazone exposure increased the risk of bladder cancer by 63%, compared with other antidiabetic drugs in a large observational study.
Major finding: Pioglitazone was associated with 121 cases of bladder cancer for every 100,000 person-years, compared with 89 cases for every 100,000 person-years for other drugs (HR, 1.63; 95% CI, 1.22-2.19).
Data source: A population-based cohort study of 145,806 patients newly treated with antidiabetic drugs between 2000 and 2013.
Disclosures: The Canadian Institutes of Health Research funded the study. The researchers had no disclosures.
Statins inversely linked to colorectal cancer in patients with IBD
Patients with inflammatory bowel disease who were prescribed statins had 65% lower odds of subsequent colorectal cancer, compared with other IBD patients, even after controlling for multiple potential confounders, researchers reported in Clinical Gastroenterology and Hepatology.
“Further confirmation from other cohorts may provide support for the use of statins as a chemopreventive in patients with IBD,” said Dr. Ashwin Ananthakrishnan of Massachusetts General Hospital in Boston, and his associates.
Patients with long-standing ulcerative colitis or colonic Crohn’s disease have about twice the risk of colorectal cancer (CRC), compared with the general population, and up to an 18% lifetime risk of CRC by 30 years after diagnosis, the researchers noted. Early results supporting mesalamine as chemoprophylaxis did not hold up in later trials. Although several studies suggested that statins might help prevent sporadic colon cancer, the only such study in IBD patients was small and did not control for key covariates such as smoking, the investigators added. Therefore, they collected data from 11,001 patients with IBD who were seen at Boston area hospitals between 1998 and 2010. They identified CRC diagnoses based on ICD-9 codes, and analyzed electronic prescriptions to see whether and when patients had used statins (Clin Gastroenterol Hepatol. 2016 Feb 21. doi: 10.1016/j.cgh.2016.02.017).
A total of 1,376 patients (12.5%) were prescribed at least one statin. Over 9 years of follow-up, 2% of statin users developed CRC, compared with 3% of nonusers (age-adjusted odds ratio, 0.35; 95% confidence interval, 0.24-0.53). Statin users were more likely to be older, male, white, smokers, and had more comorbidities than nonusers. Nonetheless, the protective effect of statins remained significant after controlling for demographic factors, smoking status, number of colonoscopies, use of steroids and immunomodulators, the presence of primary sclerosing cholangitis, and increases in inflammatory biomarkers (OR, 0.42; 95% CI, 0.28-0.62). The effect occurred for both Crohn’s disease and ulcerative colitis. Notably, the inverse association was even stronger among patients who had been prescribed at least two statins or who had at least a 2-year interval between statin use and CRC diagnosis.
Statins might help prevent CRC through HMG-CoA reductase inhibition and other mechanisms, according to the researchers. By inhibiting HMG-CoA reductase, statins lower production of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which are needed for post-translational activation of Ras, Rho, and other proteins that are overexpressed in CRC and that have been linked to tumor invasion. Statins also might help prevent CRC through antioxidant effects or by inhibiting inflammation, cell adhesion, and angiogenesis, the investigators added. “Although we did not see a difference in median C-reactive protein levels between statin users and nonusers, statin users were less likely to require immunomodulator or biologic therapy for their IBD, supporting a potential anti-inflammatory role for statins.”
Because patients mainly were treated at two tertiary referral hospitals, they may have had more severe disease than the general population of patients with IBD, the investigators acknowledged. They noted that in some meta-analyses, referral center studies yielded chemopreventive effects that did not hold up in population-based cohorts.
The study was funded by the National Institutes of Health, the American Gastroenterological Association, and the Harold and Duval Bowen Fund. The researchers had no disclosures.
Patients with inflammatory bowel disease who were prescribed statins had 65% lower odds of subsequent colorectal cancer, compared with other IBD patients, even after controlling for multiple potential confounders, researchers reported in Clinical Gastroenterology and Hepatology.
“Further confirmation from other cohorts may provide support for the use of statins as a chemopreventive in patients with IBD,” said Dr. Ashwin Ananthakrishnan of Massachusetts General Hospital in Boston, and his associates.
Patients with long-standing ulcerative colitis or colonic Crohn’s disease have about twice the risk of colorectal cancer (CRC), compared with the general population, and up to an 18% lifetime risk of CRC by 30 years after diagnosis, the researchers noted. Early results supporting mesalamine as chemoprophylaxis did not hold up in later trials. Although several studies suggested that statins might help prevent sporadic colon cancer, the only such study in IBD patients was small and did not control for key covariates such as smoking, the investigators added. Therefore, they collected data from 11,001 patients with IBD who were seen at Boston area hospitals between 1998 and 2010. They identified CRC diagnoses based on ICD-9 codes, and analyzed electronic prescriptions to see whether and when patients had used statins (Clin Gastroenterol Hepatol. 2016 Feb 21. doi: 10.1016/j.cgh.2016.02.017).
A total of 1,376 patients (12.5%) were prescribed at least one statin. Over 9 years of follow-up, 2% of statin users developed CRC, compared with 3% of nonusers (age-adjusted odds ratio, 0.35; 95% confidence interval, 0.24-0.53). Statin users were more likely to be older, male, white, smokers, and had more comorbidities than nonusers. Nonetheless, the protective effect of statins remained significant after controlling for demographic factors, smoking status, number of colonoscopies, use of steroids and immunomodulators, the presence of primary sclerosing cholangitis, and increases in inflammatory biomarkers (OR, 0.42; 95% CI, 0.28-0.62). The effect occurred for both Crohn’s disease and ulcerative colitis. Notably, the inverse association was even stronger among patients who had been prescribed at least two statins or who had at least a 2-year interval between statin use and CRC diagnosis.
Statins might help prevent CRC through HMG-CoA reductase inhibition and other mechanisms, according to the researchers. By inhibiting HMG-CoA reductase, statins lower production of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which are needed for post-translational activation of Ras, Rho, and other proteins that are overexpressed in CRC and that have been linked to tumor invasion. Statins also might help prevent CRC through antioxidant effects or by inhibiting inflammation, cell adhesion, and angiogenesis, the investigators added. “Although we did not see a difference in median C-reactive protein levels between statin users and nonusers, statin users were less likely to require immunomodulator or biologic therapy for their IBD, supporting a potential anti-inflammatory role for statins.”
Because patients mainly were treated at two tertiary referral hospitals, they may have had more severe disease than the general population of patients with IBD, the investigators acknowledged. They noted that in some meta-analyses, referral center studies yielded chemopreventive effects that did not hold up in population-based cohorts.
The study was funded by the National Institutes of Health, the American Gastroenterological Association, and the Harold and Duval Bowen Fund. The researchers had no disclosures.
Patients with inflammatory bowel disease who were prescribed statins had 65% lower odds of subsequent colorectal cancer, compared with other IBD patients, even after controlling for multiple potential confounders, researchers reported in Clinical Gastroenterology and Hepatology.
“Further confirmation from other cohorts may provide support for the use of statins as a chemopreventive in patients with IBD,” said Dr. Ashwin Ananthakrishnan of Massachusetts General Hospital in Boston, and his associates.
Patients with long-standing ulcerative colitis or colonic Crohn’s disease have about twice the risk of colorectal cancer (CRC), compared with the general population, and up to an 18% lifetime risk of CRC by 30 years after diagnosis, the researchers noted. Early results supporting mesalamine as chemoprophylaxis did not hold up in later trials. Although several studies suggested that statins might help prevent sporadic colon cancer, the only such study in IBD patients was small and did not control for key covariates such as smoking, the investigators added. Therefore, they collected data from 11,001 patients with IBD who were seen at Boston area hospitals between 1998 and 2010. They identified CRC diagnoses based on ICD-9 codes, and analyzed electronic prescriptions to see whether and when patients had used statins (Clin Gastroenterol Hepatol. 2016 Feb 21. doi: 10.1016/j.cgh.2016.02.017).
A total of 1,376 patients (12.5%) were prescribed at least one statin. Over 9 years of follow-up, 2% of statin users developed CRC, compared with 3% of nonusers (age-adjusted odds ratio, 0.35; 95% confidence interval, 0.24-0.53). Statin users were more likely to be older, male, white, smokers, and had more comorbidities than nonusers. Nonetheless, the protective effect of statins remained significant after controlling for demographic factors, smoking status, number of colonoscopies, use of steroids and immunomodulators, the presence of primary sclerosing cholangitis, and increases in inflammatory biomarkers (OR, 0.42; 95% CI, 0.28-0.62). The effect occurred for both Crohn’s disease and ulcerative colitis. Notably, the inverse association was even stronger among patients who had been prescribed at least two statins or who had at least a 2-year interval between statin use and CRC diagnosis.
Statins might help prevent CRC through HMG-CoA reductase inhibition and other mechanisms, according to the researchers. By inhibiting HMG-CoA reductase, statins lower production of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which are needed for post-translational activation of Ras, Rho, and other proteins that are overexpressed in CRC and that have been linked to tumor invasion. Statins also might help prevent CRC through antioxidant effects or by inhibiting inflammation, cell adhesion, and angiogenesis, the investigators added. “Although we did not see a difference in median C-reactive protein levels between statin users and nonusers, statin users were less likely to require immunomodulator or biologic therapy for their IBD, supporting a potential anti-inflammatory role for statins.”
Because patients mainly were treated at two tertiary referral hospitals, they may have had more severe disease than the general population of patients with IBD, the investigators acknowledged. They noted that in some meta-analyses, referral center studies yielded chemopreventive effects that did not hold up in population-based cohorts.
The study was funded by the National Institutes of Health, the American Gastroenterological Association, and the Harold and Duval Bowen Fund. The researchers had no disclosures.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: Preliminary evidence suggests that statins might help prevent colorectal cancer in patients with inflammatory bowel disease.
Major finding: A total of 2% of statin users developed CRC over 9 years of follow-up, compared with 3% of nonusers (age-adjusted odds ratio, 0.35).
Data source: An analysis of ICD-9 codes and electronic prescription data for 11,001 patients with IBD.
Disclosures: The study was funded by the National Institutes of Health, the American Gastroenterological Association, and the Harold and Duval Bowen Fund. The researchers had no disclosures.
