Adult congenital heart disease significantly increases the risk of both hemorrhagic and ischemic stroke, particularly in individuals under 55 years of age, new data suggests.

A retrospective study of 29,638 adults aged 18-64 years with adult congenital heart disease (ACHD) showed that women aged 15-54 years with the disease were more than 12 times as likely to experience an ischemic stroke compared to the general population, while men had a nine-fold increase in risk.

Women aged over 55 years with ACHD had a four-fold higher risk of ischemic stroke, and men had a two-fold increase in risk, compared to the general population, according to a study published Nov. 23 in Circulation.

In the case of hemorrhagic stroke, women aged under 55 had a five-fold greater risk and men had a more than six-fold greater risk of ischemic stroke, while the risk for those older than 55 years was 2-3 times higher (Circulation 2015, November 23 [doi: 10.1161/CIRCULATIONAHA.115.011241]).

The risk of ischemic stroke increased significantly with heart failure, diabetes, or a recent myocardial infarction, and overall, 8.9% of men and 6.8% of women with ACHD who reached the age of 18 years had at least one stroke before age 65.

“Whether subgroups of patients with heart failure and sinus rhythm could benefit from an antithrombotic treatment is a matter of ongoing research in the general population and based on our findings may warrant further investigation in ACHD-patients,” wrote Dr. Jonas Lanz, from the McGill Adult Unit for Congenital Heart Disease Excellence, and co-authors.

The study was funded by the Heart and Stroke Foundation of Québec, the Fonds de Recherche en Santé Québec and the Canadian Institute of Health Research. There were no conflicts of interest declared.

Adult congenital heart disease significantly increases the risk of both hemorrhagic and ischemic stroke, particularly in individuals under 55 years of age, new data suggests.

A retrospective study of 29,638 adults aged 18-64 years with adult congenital heart disease (ACHD) showed that women aged 15-54 years with the disease were more than 12 times as likely to experience an ischemic stroke compared to the general population, while men had a nine-fold increase in risk.

Women aged over 55 years with ACHD had a four-fold higher risk of ischemic stroke, and men had a two-fold increase in risk, compared to the general population, according to a study published Nov. 23 in Circulation.

In the case of hemorrhagic stroke, women aged under 55 had a five-fold greater risk and men had a more than six-fold greater risk of ischemic stroke, while the risk for those older than 55 years was 2-3 times higher (Circulation 2015, November 23 [doi: 10.1161/CIRCULATIONAHA.115.011241]).

The risk of ischemic stroke increased significantly with heart failure, diabetes, or a recent myocardial infarction, and overall, 8.9% of men and 6.8% of women with ACHD who reached the age of 18 years had at least one stroke before age 65.

“Whether subgroups of patients with heart failure and sinus rhythm could benefit from an antithrombotic treatment is a matter of ongoing research in the general population and based on our findings may warrant further investigation in ACHD-patients,” wrote Dr. Jonas Lanz, from the McGill Adult Unit for Congenital Heart Disease Excellence, and co-authors.

The study was funded by the Heart and Stroke Foundation of Québec, the Fonds de Recherche en Santé Québec and the Canadian Institute of Health Research. There were no conflicts of interest declared.

Adult congenital heart disease significantly increases the risk of both hemorrhagic and ischemic stroke, particularly in individuals under 55 years of age, new data suggests.

A retrospective study of 29,638 adults aged 18-64 years with adult congenital heart disease (ACHD) showed that women aged 15-54 years with the disease were more than 12 times as likely to experience an ischemic stroke compared to the general population, while men had a nine-fold increase in risk.

Women aged over 55 years with ACHD had a four-fold higher risk of ischemic stroke, and men had a two-fold increase in risk, compared to the general population, according to a study published Nov. 23 in Circulation.

In the case of hemorrhagic stroke, women aged under 55 had a five-fold greater risk and men had a more than six-fold greater risk of ischemic stroke, while the risk for those older than 55 years was 2-3 times higher (Circulation 2015, November 23 [doi: 10.1161/CIRCULATIONAHA.115.011241]).

The risk of ischemic stroke increased significantly with heart failure, diabetes, or a recent myocardial infarction, and overall, 8.9% of men and 6.8% of women with ACHD who reached the age of 18 years had at least one stroke before age 65.

“Whether subgroups of patients with heart failure and sinus rhythm could benefit from an antithrombotic treatment is a matter of ongoing research in the general population and based on our findings may warrant further investigation in ACHD-patients,” wrote Dr. Jonas Lanz, from the McGill Adult Unit for Congenital Heart Disease Excellence, and co-authors.

The study was funded by the Heart and Stroke Foundation of Québec, the Fonds de Recherche en Santé Québec and the Canadian Institute of Health Research. There were no conflicts of interest declared.

Synovitis and effusion were associated with increases in pain sensitivity at the patella and wrist, respectively, in a study of 1,111 patients with or at risk of knee osteoarthritis (OA).

Radiographs and MRIs were taken of the patients’ knees, and the patients wrists and patellae were subjected to standardized quantitative sensory testing (QST) measures. The QST measures included temporal summation, which is a measure of central pain amplification based on “an augmented response to repetitive mechanical stimulation,” and pressure pain threshold (PPT), a measure of sensitivity to pain evoked by mechanical stimulation of nociceptors. (Lower PPTs represent a greater degree of sensitization or pain sensitivity.) All tests were conducted at baseline and 2 years later.

©KatarzynaBialasiewicz/ Thinkstock.com

Synovitis was associated with a significant decrease in PPT at the patella, while effusion was associated with a decrease in PPT at the wrist. Effusion was additionally associated with risk of incident temporal summation. In contrast to synovitis and effusion, bone marrow lesions were not associated with either temporal summation or decreased pressure pain threshold.

“Our findings support the potential relevance of inflammation in the development and heightening of sensitization in knee osteoarthritis in humans. We found that synovitis was associated with lower PPT and a decrease in PPT at the patella over time, indicating increased pain sensitization or sensitivity. Effusion was associated with development of new temporal summation at the patella, and with a decrease in PPT at the wrist, a site distant to the pathology; both findings suggest the involvement of central sensitization. Thus inflammation appears to influence the development of and perhaps amplification of sensitization,” said Dr. Tuhina Neogi, of the department of medicine at Boston University and her colleagues.

Read the full study in Arthritis & Rheumatology (doi: 10.1002/art.39488).

[email protected]

Synovitis and effusion were associated with increases in pain sensitivity at the patella and wrist, respectively, in a study of 1,111 patients with or at risk of knee osteoarthritis (OA).

Radiographs and MRIs were taken of the patients’ knees, and the patients wrists and patellae were subjected to standardized quantitative sensory testing (QST) measures. The QST measures included temporal summation, which is a measure of central pain amplification based on “an augmented response to repetitive mechanical stimulation,” and pressure pain threshold (PPT), a measure of sensitivity to pain evoked by mechanical stimulation of nociceptors. (Lower PPTs represent a greater degree of sensitization or pain sensitivity.) All tests were conducted at baseline and 2 years later.

©KatarzynaBialasiewicz/ Thinkstock.com

Synovitis was associated with a significant decrease in PPT at the patella, while effusion was associated with a decrease in PPT at the wrist. Effusion was additionally associated with risk of incident temporal summation. In contrast to synovitis and effusion, bone marrow lesions were not associated with either temporal summation or decreased pressure pain threshold.

“Our findings support the potential relevance of inflammation in the development and heightening of sensitization in knee osteoarthritis in humans. We found that synovitis was associated with lower PPT and a decrease in PPT at the patella over time, indicating increased pain sensitization or sensitivity. Effusion was associated with development of new temporal summation at the patella, and with a decrease in PPT at the wrist, a site distant to the pathology; both findings suggest the involvement of central sensitization. Thus inflammation appears to influence the development of and perhaps amplification of sensitization,” said Dr. Tuhina Neogi, of the department of medicine at Boston University and her colleagues.

Read the full study in Arthritis & Rheumatology (doi: 10.1002/art.39488).

[email protected]

Synovitis and effusion were associated with increases in pain sensitivity at the patella and wrist, respectively, in a study of 1,111 patients with or at risk of knee osteoarthritis (OA).

Radiographs and MRIs were taken of the patients’ knees, and the patients wrists and patellae were subjected to standardized quantitative sensory testing (QST) measures. The QST measures included temporal summation, which is a measure of central pain amplification based on “an augmented response to repetitive mechanical stimulation,” and pressure pain threshold (PPT), a measure of sensitivity to pain evoked by mechanical stimulation of nociceptors. (Lower PPTs represent a greater degree of sensitization or pain sensitivity.) All tests were conducted at baseline and 2 years later.

©KatarzynaBialasiewicz/ Thinkstock.com

Synovitis was associated with a significant decrease in PPT at the patella, while effusion was associated with a decrease in PPT at the wrist. Effusion was additionally associated with risk of incident temporal summation. In contrast to synovitis and effusion, bone marrow lesions were not associated with either temporal summation or decreased pressure pain threshold.

“Our findings support the potential relevance of inflammation in the development and heightening of sensitization in knee osteoarthritis in humans. We found that synovitis was associated with lower PPT and a decrease in PPT at the patella over time, indicating increased pain sensitization or sensitivity. Effusion was associated with development of new temporal summation at the patella, and with a decrease in PPT at the wrist, a site distant to the pathology; both findings suggest the involvement of central sensitization. Thus inflammation appears to influence the development of and perhaps amplification of sensitization,” said Dr. Tuhina Neogi, of the department of medicine at Boston University and her colleagues.

Read the full study in Arthritis & Rheumatology (doi: 10.1002/art.39488).

[email protected]

Both overweight and obese patients with knee osteoarthritis (OA) are more likely to get knee replacement surgery, compared with normal-weight patients with knee OA, results of a population-based cohort study of people in Catalonia, Spain, suggest.

The study included 105,189 patients, who had been diagnosed with knee OA between 2006 and 2011. Patients with a history of knee OA or knee replacement in either knee before Jan. 1, 2006, and patients with a history inflammatory arthritis were not included in the study.

© Kokhanchikov / fotolia.com

The patients were followed from the date of knee OA diagnosis until the date they underwent elective knee replacement surgery or until Dec. 31, 2011. (The researchers were unable to follow up with all individuals initially enrolled in the study.) The participants were broken up into the following categories based on their body mass index: normal (BMI was less than 25 kg/m²), overweight (BMI was 25 to less than 30 kg/m²), obese class I (BMI was 30 to less than 35 kg/m²), obese class II (BMI was 35 to less than 40 kg/m²), and obese class III (BMI was greater than or equal to 40 kg/m²).

The risk of knee replacement increased with BMI. For patients with a normal weight, the incidence rates of surgery were 1.35/100 person-years, compared with 3.49/100 person-years in patients in obese class III. Adjusted hazard ratios for knee replacement surgery were 1.41 for overweight, 1.97 for obese class I, 2.39 for obese class II, and 2.67 for obese class III, compared with normal-weight study participants.

An additional finding was a significant interaction between BMI and age on the risk of knee replacement (P is less than .001), with a higher relative hazard associated with obesity among patients aged less than 68 years.

“This research demonstrates that overweight and obesity are strong independent predictors of the clinical progression of knee OA, from disease onset/diagnosis to joint failure and subsequent [knee replacement]. Overweight subjects are at over 40% increased risk of surgery, and those who are obese have a more than doubled risk when compared to subjects with normal weight,” said Kristen M. Leyland, D.Phil., and her colleagues.

Read the full study in Arthritis & Rheumatology (doi: 10.1002/art.39486).

[email protected]

Both overweight and obese patients with knee osteoarthritis (OA) are more likely to get knee replacement surgery, compared with normal-weight patients with knee OA, results of a population-based cohort study of people in Catalonia, Spain, suggest.

The study included 105,189 patients, who had been diagnosed with knee OA between 2006 and 2011. Patients with a history of knee OA or knee replacement in either knee before Jan. 1, 2006, and patients with a history inflammatory arthritis were not included in the study.

© Kokhanchikov / fotolia.com

The patients were followed from the date of knee OA diagnosis until the date they underwent elective knee replacement surgery or until Dec. 31, 2011. (The researchers were unable to follow up with all individuals initially enrolled in the study.) The participants were broken up into the following categories based on their body mass index: normal (BMI was less than 25 kg/m²), overweight (BMI was 25 to less than 30 kg/m²), obese class I (BMI was 30 to less than 35 kg/m²), obese class II (BMI was 35 to less than 40 kg/m²), and obese class III (BMI was greater than or equal to 40 kg/m²).

The risk of knee replacement increased with BMI. For patients with a normal weight, the incidence rates of surgery were 1.35/100 person-years, compared with 3.49/100 person-years in patients in obese class III. Adjusted hazard ratios for knee replacement surgery were 1.41 for overweight, 1.97 for obese class I, 2.39 for obese class II, and 2.67 for obese class III, compared with normal-weight study participants.

An additional finding was a significant interaction between BMI and age on the risk of knee replacement (P is less than .001), with a higher relative hazard associated with obesity among patients aged less than 68 years.

“This research demonstrates that overweight and obesity are strong independent predictors of the clinical progression of knee OA, from disease onset/diagnosis to joint failure and subsequent [knee replacement]. Overweight subjects are at over 40% increased risk of surgery, and those who are obese have a more than doubled risk when compared to subjects with normal weight,” said Kristen M. Leyland, D.Phil., and her colleagues.

Read the full study in Arthritis & Rheumatology (doi: 10.1002/art.39486).

[email protected]

Both overweight and obese patients with knee osteoarthritis (OA) are more likely to get knee replacement surgery, compared with normal-weight patients with knee OA, results of a population-based cohort study of people in Catalonia, Spain, suggest.

The study included 105,189 patients, who had been diagnosed with knee OA between 2006 and 2011. Patients with a history of knee OA or knee replacement in either knee before Jan. 1, 2006, and patients with a history inflammatory arthritis were not included in the study.

© Kokhanchikov / fotolia.com

The patients were followed from the date of knee OA diagnosis until the date they underwent elective knee replacement surgery or until Dec. 31, 2011. (The researchers were unable to follow up with all individuals initially enrolled in the study.) The participants were broken up into the following categories based on their body mass index: normal (BMI was less than 25 kg/m²), overweight (BMI was 25 to less than 30 kg/m²), obese class I (BMI was 30 to less than 35 kg/m²), obese class II (BMI was 35 to less than 40 kg/m²), and obese class III (BMI was greater than or equal to 40 kg/m²).

The risk of knee replacement increased with BMI. For patients with a normal weight, the incidence rates of surgery were 1.35/100 person-years, compared with 3.49/100 person-years in patients in obese class III. Adjusted hazard ratios for knee replacement surgery were 1.41 for overweight, 1.97 for obese class I, 2.39 for obese class II, and 2.67 for obese class III, compared with normal-weight study participants.

An additional finding was a significant interaction between BMI and age on the risk of knee replacement (P is less than .001), with a higher relative hazard associated with obesity among patients aged less than 68 years.

“This research demonstrates that overweight and obesity are strong independent predictors of the clinical progression of knee OA, from disease onset/diagnosis to joint failure and subsequent [knee replacement]. Overweight subjects are at over 40% increased risk of surgery, and those who are obese have a more than doubled risk when compared to subjects with normal weight,” said Kristen M. Leyland, D.Phil., and her colleagues.

Read the full study in Arthritis & Rheumatology (doi: 10.1002/art.39486).

[email protected]

A prime-boost flu vaccination strategy proved effective in children and adolescents in an open-label phase III trial conducted by the vaccine manufacturer and reported online in the Pediatric Infectious Disease Journal.

This proof-of-concept result suggests that at the outbreak of the next flu pandemic, immediate priming with two doses of a subtype-matched flu vaccine, followed by boosting once a strain-matched vaccine becomes available, will offer the pediatric population better protection than simply waiting for adequate quantities of the strain-matched vaccine to be developed and marketed.

© mik38 - Fotolia.com

It is impossible to predict which specific viral strain will cause the next flu pandemic, but H5N1 is considered a likely candidate virus, “to the extent that vaccine manufacturers and regulatory authorities are actively developing H5N1 vaccines” for all age groups, said Dr. Patricia Izurieta of GlaxoSmithKline Vaccines, Belgium, and her associates.

Waiting for a pandemic to begin and then producing strain-specific vaccines could take as long as 6 months, and even then supplies probably would be limited. Experts have theorized that preemptive “priming” with already stockpiled H5N1 vaccines immediately after a pandemic begins may provide broad cross-protection that could mitigate the intensity of the subsequent pandemic, potentially reducing morbidity, mortality, and viral transmission.

To test this theory, Dr. Izurieta and her associates mimicked a potential flu pandemic by priming children and adolescents with two doses of an H5N1-AS03 vaccine, giving a booster dose of a specific H5N1 strain at 6 months, and assessing antibody response to all the vaccinations through 12 months. (Assessing actual vaccine efficacy was impossible because it would be unethical to determine this by exposing children to a flu virus.)

A total of 520 participants at a single medical center in the Philippines who were aged 3-18 years (mean age, 9 years) were assigned to two intervention groups and two control groups. Approximately half of these children and adolescents received the intervention – two priming doses of A/Indonesia/05/2005/H5N1-AS03B vaccine – while the control subjects received a single dose of hepatitis A vaccine. At day 182, half of the primed and half of the unprimed participants then received a booster dose of A/turkey/Turkey/01/2005-H5N1-As03B, while the remainder received the hepatitis A vaccine.

Compared with no priming, priming afforded superior seroconversion and putative seroprotection against the second, specific strain of H5N1. This robust protective effect was seen within 10 days after vaccination, occurred across all ages, and persisted through 12 months of follow-up, the investigators said (Ped Infect Dis J. 2015 Nov 6. [doi: 10.1097/INF.0000000000000968]).

Adverse events within 7 days of the priming vaccinations developed in 68%-76% of the intervention group, compared with only 37%-64% of the control group. Adverse events within 7 days of the booster vaccinations developed in 69% of the intervention group, compared with only 40% of the control group. The most common adverse events were upper respiratory tract infection (20% vs 14%), nasopharyngitis (4% vs 3%), and rhinitis (3% in both study groups). The most serious adverse events affected two children and were classified as grade 3.

The study results suggest that a prime-boost strategy can induce broad and long-lasting immunity and could be effectively employed in this age group in the prepandemic setting, Dr. Izurieta and her associates reported.

This trial was funded by GlaxoSmithKline, which also was involved in the design and conduct of the study, the data analysis, and the writing and publishing of the report. Dr. Izurieta and two of her associates are employed by GSK.

A prime-boost flu vaccination strategy proved effective in children and adolescents in an open-label phase III trial conducted by the vaccine manufacturer and reported online in the Pediatric Infectious Disease Journal.

This proof-of-concept result suggests that at the outbreak of the next flu pandemic, immediate priming with two doses of a subtype-matched flu vaccine, followed by boosting once a strain-matched vaccine becomes available, will offer the pediatric population better protection than simply waiting for adequate quantities of the strain-matched vaccine to be developed and marketed.

© mik38 - Fotolia.com

It is impossible to predict which specific viral strain will cause the next flu pandemic, but H5N1 is considered a likely candidate virus, “to the extent that vaccine manufacturers and regulatory authorities are actively developing H5N1 vaccines” for all age groups, said Dr. Patricia Izurieta of GlaxoSmithKline Vaccines, Belgium, and her associates.

Waiting for a pandemic to begin and then producing strain-specific vaccines could take as long as 6 months, and even then supplies probably would be limited. Experts have theorized that preemptive “priming” with already stockpiled H5N1 vaccines immediately after a pandemic begins may provide broad cross-protection that could mitigate the intensity of the subsequent pandemic, potentially reducing morbidity, mortality, and viral transmission.

To test this theory, Dr. Izurieta and her associates mimicked a potential flu pandemic by priming children and adolescents with two doses of an H5N1-AS03 vaccine, giving a booster dose of a specific H5N1 strain at 6 months, and assessing antibody response to all the vaccinations through 12 months. (Assessing actual vaccine efficacy was impossible because it would be unethical to determine this by exposing children to a flu virus.)

A total of 520 participants at a single medical center in the Philippines who were aged 3-18 years (mean age, 9 years) were assigned to two intervention groups and two control groups. Approximately half of these children and adolescents received the intervention – two priming doses of A/Indonesia/05/2005/H5N1-AS03B vaccine – while the control subjects received a single dose of hepatitis A vaccine. At day 182, half of the primed and half of the unprimed participants then received a booster dose of A/turkey/Turkey/01/2005-H5N1-As03B, while the remainder received the hepatitis A vaccine.

Compared with no priming, priming afforded superior seroconversion and putative seroprotection against the second, specific strain of H5N1. This robust protective effect was seen within 10 days after vaccination, occurred across all ages, and persisted through 12 months of follow-up, the investigators said (Ped Infect Dis J. 2015 Nov 6. [doi: 10.1097/INF.0000000000000968]).

Adverse events within 7 days of the priming vaccinations developed in 68%-76% of the intervention group, compared with only 37%-64% of the control group. Adverse events within 7 days of the booster vaccinations developed in 69% of the intervention group, compared with only 40% of the control group. The most common adverse events were upper respiratory tract infection (20% vs 14%), nasopharyngitis (4% vs 3%), and rhinitis (3% in both study groups). The most serious adverse events affected two children and were classified as grade 3.

The study results suggest that a prime-boost strategy can induce broad and long-lasting immunity and could be effectively employed in this age group in the prepandemic setting, Dr. Izurieta and her associates reported.

This trial was funded by GlaxoSmithKline, which also was involved in the design and conduct of the study, the data analysis, and the writing and publishing of the report. Dr. Izurieta and two of her associates are employed by GSK.

A prime-boost flu vaccination strategy proved effective in children and adolescents in an open-label phase III trial conducted by the vaccine manufacturer and reported online in the Pediatric Infectious Disease Journal.

This proof-of-concept result suggests that at the outbreak of the next flu pandemic, immediate priming with two doses of a subtype-matched flu vaccine, followed by boosting once a strain-matched vaccine becomes available, will offer the pediatric population better protection than simply waiting for adequate quantities of the strain-matched vaccine to be developed and marketed.

© mik38 - Fotolia.com

It is impossible to predict which specific viral strain will cause the next flu pandemic, but H5N1 is considered a likely candidate virus, “to the extent that vaccine manufacturers and regulatory authorities are actively developing H5N1 vaccines” for all age groups, said Dr. Patricia Izurieta of GlaxoSmithKline Vaccines, Belgium, and her associates.

Waiting for a pandemic to begin and then producing strain-specific vaccines could take as long as 6 months, and even then supplies probably would be limited. Experts have theorized that preemptive “priming” with already stockpiled H5N1 vaccines immediately after a pandemic begins may provide broad cross-protection that could mitigate the intensity of the subsequent pandemic, potentially reducing morbidity, mortality, and viral transmission.

To test this theory, Dr. Izurieta and her associates mimicked a potential flu pandemic by priming children and adolescents with two doses of an H5N1-AS03 vaccine, giving a booster dose of a specific H5N1 strain at 6 months, and assessing antibody response to all the vaccinations through 12 months. (Assessing actual vaccine efficacy was impossible because it would be unethical to determine this by exposing children to a flu virus.)

A total of 520 participants at a single medical center in the Philippines who were aged 3-18 years (mean age, 9 years) were assigned to two intervention groups and two control groups. Approximately half of these children and adolescents received the intervention – two priming doses of A/Indonesia/05/2005/H5N1-AS03B vaccine – while the control subjects received a single dose of hepatitis A vaccine. At day 182, half of the primed and half of the unprimed participants then received a booster dose of A/turkey/Turkey/01/2005-H5N1-As03B, while the remainder received the hepatitis A vaccine.

Compared with no priming, priming afforded superior seroconversion and putative seroprotection against the second, specific strain of H5N1. This robust protective effect was seen within 10 days after vaccination, occurred across all ages, and persisted through 12 months of follow-up, the investigators said (Ped Infect Dis J. 2015 Nov 6. [doi: 10.1097/INF.0000000000000968]).

Adverse events within 7 days of the priming vaccinations developed in 68%-76% of the intervention group, compared with only 37%-64% of the control group. Adverse events within 7 days of the booster vaccinations developed in 69% of the intervention group, compared with only 40% of the control group. The most common adverse events were upper respiratory tract infection (20% vs 14%), nasopharyngitis (4% vs 3%), and rhinitis (3% in both study groups). The most serious adverse events affected two children and were classified as grade 3.

The study results suggest that a prime-boost strategy can induce broad and long-lasting immunity and could be effectively employed in this age group in the prepandemic setting, Dr. Izurieta and her associates reported.

This trial was funded by GlaxoSmithKline, which also was involved in the design and conduct of the study, the data analysis, and the writing and publishing of the report. Dr. Izurieta and two of her associates are employed by GSK.

ORLANDO – The common challenge faced by clinicians in deciding whether or not to continue dual antiplatelet therapy beyond a year in a patient who underwent percutaneous coronary intervention has gotten easier.

Researchers have devised a simple, eight-element scoring system using information already available in a patient’s records to help determine whether an individual patient will be more likely to benefit from continuing or stopping dual antiplatelet therapy (DAPT).

Mitchel L. Zoler/Frontline Medical News

“The DAPT score may help clinicians decide who should and who should not be treated with extended DAPT,” Dr. Robert W. Yeh said at the American Heart Association Scientific Sessions.

“This is a step forward for an issue we deal with daily, balancing an individual patient’s risk from ischemia and bleeding,” commented Dr. Alice Jacobs, professor of medicine at Boston University and director of the cardiac catheterization laboratory and interventional cardiology at Boston Medical Center.

Dr. Yeh and his associates devised the DAPT score from the data collected in the DAPT study, which enrolled more than 25,000 patients and randomized about 10,000 to test whether patients fared better by stopping or continuing DAPT after completing their initial year of DAPT following percutaneous coronary intervention (PCI). The DAPT study results showed that after 18 additional months, continuing DAPT cut the rate of definite or probable stent thrombosis by 1 percentage point and the combined rate of death, MI, or stroke by 1.6 percentage points, both statistically significant differences, compared with patients randomized to treatment with aspirin plus placebo. The results also showed that continued DAPT increased GUSTO moderate or severe bleeding events by 1 percentage point, compared with the control patients (N Engl J Med. 2014 Dec 4;371[23]:2155-66).

The researchers used data collected in the DAPT study to build risk models using patient- and procedure-specific variables that predicted the ischemic and bleeding outcomes, and then combined the two into a single model. That meant abandoning some variables that had significant impact on both outcomes.

The result was a scoring system that includes eight variables that result in a score that ranges from –2 to 9. The analysis showed that a score of 1 or less identified patients for whom the risk for bleeding outweighs their potential gain by avoiding an ischemic event by about 2.5-fold, and hence likely would fare better by stopping DAPT. A score of 2 or higher flagged patients who benefited about eightfold more from avoided ischemic events, compared with their risk for a moderate or severe bleed.

Patient scores showed a classic bell-shaped curve, with roughly a quarter of the DAPT study patients having a score of 1 and about a quarter with a score of 2, about 16% had a score of 0 and about 16% had a score of 3, and about 8% had a score of –1 or –2, while about 9% had a score of 4 or more.

The investigators validated the scoring system using data collected in the PROTECT trial, which included 8,791 patients who underwent PCI during 2007-2008. Dr. Yeh acknowledged that the discrimination strength of the models he and his associated developed was “modest,” but added that its efficacy was greater than what has been shown in validation cohorts for the commonly used CH2ADS2-VASc and HAS-BLED scoring systems.

Dr. Yeh stressed that using the DAPT score “cannot trump clinical judgment.” He suggested that a clinician use the score to help facilitate a conversation with a PCI patient when the time comes to decide whether or not to continue DAPT beyond 1 year.

Other factors that could influence the decision include the length of the stented coronary lesions or prior radiation exposure to the patient’s coronary arteries, said Dr. Laura Mauri, who led the DAPT study and collaborated on developing the DAPT score. “It requires judgment to decide [on whether to continue DAPT] for patients who are on the borderline” for risk and benefit. “This gives patients a way to better understand what they might gain or lose” by continuing treatment. Without the quantification that the DAPT score provides, the balance of risk and benefit “is somewhat nebulous,” said Dr. Mauri, an interventional cardiologist and director of the Center for Clinical Biometrics in the division of cardiovascular medicine at Brigham and Women’s Hospital in Boston.

The investigators who ran the DAPT study realized several years before the study finished that development of the DAPT score was a critical part of applying the findings from the study into clinical practice, she said in an interview.

Dr. Yeh cautioned that the score is only appropriate for patients who match those enrolled into the DAPT study: patients who went through their first year post PCI on DAPT without having any ischemic or bleeding complications. For these patients, “we feel the DAPT score is incredibly valuable,” said Dr. Yeh, an interventional cardiologist and director of the Center for Outcomes Research in Cardiology at Beth Israel Deaconess Medical Center in Boston. He and his associates are now using data from the DAPT study to model bleeding and ischemia risks during the first year following PCI to try to come up with risk models that can address DAPT use during this period.

Dr. Yeh and Dr. Mauri have placed a link to the electronic DAPT score calculator on the website for the DAPT study (www.daptstudy.org), and Dr. Yeh said that an app version will soon become available. Interventionalists in the programs that Dr. Yeh and Mauri are affiliated with have recently begun using the DAPT score calculator in their routine practice, Dr. Yeh said.

The DAPT study received funding from Abbott, Boston Scientific, Cordis, Medtronic, Bristol-Myers Squib-Sanofi, Eli Lilly, and Daiichi Sankyo. Derivation of the DAPT score was funded by the National Institutes of Health. Dr. Yeh has received honoraria from Abbott, Boston Scientific, and Merck. Dr. Jacobs had no disclosures. Dr. Mauri has been a consultant to Biotronik, Medtronic, and St. Jude and has received research funding from several companies.

[email protected]

On Twitter @mitchelzoler

ORLANDO – The common challenge faced by clinicians in deciding whether or not to continue dual antiplatelet therapy beyond a year in a patient who underwent percutaneous coronary intervention has gotten easier.

Researchers have devised a simple, eight-element scoring system using information already available in a patient’s records to help determine whether an individual patient will be more likely to benefit from continuing or stopping dual antiplatelet therapy (DAPT).

Mitchel L. Zoler/Frontline Medical News

“The DAPT score may help clinicians decide who should and who should not be treated with extended DAPT,” Dr. Robert W. Yeh said at the American Heart Association Scientific Sessions.

“This is a step forward for an issue we deal with daily, balancing an individual patient’s risk from ischemia and bleeding,” commented Dr. Alice Jacobs, professor of medicine at Boston University and director of the cardiac catheterization laboratory and interventional cardiology at Boston Medical Center.

Dr. Yeh and his associates devised the DAPT score from the data collected in the DAPT study, which enrolled more than 25,000 patients and randomized about 10,000 to test whether patients fared better by stopping or continuing DAPT after completing their initial year of DAPT following percutaneous coronary intervention (PCI). The DAPT study results showed that after 18 additional months, continuing DAPT cut the rate of definite or probable stent thrombosis by 1 percentage point and the combined rate of death, MI, or stroke by 1.6 percentage points, both statistically significant differences, compared with patients randomized to treatment with aspirin plus placebo. The results also showed that continued DAPT increased GUSTO moderate or severe bleeding events by 1 percentage point, compared with the control patients (N Engl J Med. 2014 Dec 4;371[23]:2155-66).

The researchers used data collected in the DAPT study to build risk models using patient- and procedure-specific variables that predicted the ischemic and bleeding outcomes, and then combined the two into a single model. That meant abandoning some variables that had significant impact on both outcomes.

The result was a scoring system that includes eight variables that result in a score that ranges from –2 to 9. The analysis showed that a score of 1 or less identified patients for whom the risk for bleeding outweighs their potential gain by avoiding an ischemic event by about 2.5-fold, and hence likely would fare better by stopping DAPT. A score of 2 or higher flagged patients who benefited about eightfold more from avoided ischemic events, compared with their risk for a moderate or severe bleed.

Patient scores showed a classic bell-shaped curve, with roughly a quarter of the DAPT study patients having a score of 1 and about a quarter with a score of 2, about 16% had a score of 0 and about 16% had a score of 3, and about 8% had a score of –1 or –2, while about 9% had a score of 4 or more.

The investigators validated the scoring system using data collected in the PROTECT trial, which included 8,791 patients who underwent PCI during 2007-2008. Dr. Yeh acknowledged that the discrimination strength of the models he and his associated developed was “modest,” but added that its efficacy was greater than what has been shown in validation cohorts for the commonly used CH2ADS2-VASc and HAS-BLED scoring systems.

Dr. Yeh stressed that using the DAPT score “cannot trump clinical judgment.” He suggested that a clinician use the score to help facilitate a conversation with a PCI patient when the time comes to decide whether or not to continue DAPT beyond 1 year.

Other factors that could influence the decision include the length of the stented coronary lesions or prior radiation exposure to the patient’s coronary arteries, said Dr. Laura Mauri, who led the DAPT study and collaborated on developing the DAPT score. “It requires judgment to decide [on whether to continue DAPT] for patients who are on the borderline” for risk and benefit. “This gives patients a way to better understand what they might gain or lose” by continuing treatment. Without the quantification that the DAPT score provides, the balance of risk and benefit “is somewhat nebulous,” said Dr. Mauri, an interventional cardiologist and director of the Center for Clinical Biometrics in the division of cardiovascular medicine at Brigham and Women’s Hospital in Boston.

The investigators who ran the DAPT study realized several years before the study finished that development of the DAPT score was a critical part of applying the findings from the study into clinical practice, she said in an interview.

Dr. Yeh cautioned that the score is only appropriate for patients who match those enrolled into the DAPT study: patients who went through their first year post PCI on DAPT without having any ischemic or bleeding complications. For these patients, “we feel the DAPT score is incredibly valuable,” said Dr. Yeh, an interventional cardiologist and director of the Center for Outcomes Research in Cardiology at Beth Israel Deaconess Medical Center in Boston. He and his associates are now using data from the DAPT study to model bleeding and ischemia risks during the first year following PCI to try to come up with risk models that can address DAPT use during this period.

Dr. Yeh and Dr. Mauri have placed a link to the electronic DAPT score calculator on the website for the DAPT study (www.daptstudy.org), and Dr. Yeh said that an app version will soon become available. Interventionalists in the programs that Dr. Yeh and Mauri are affiliated with have recently begun using the DAPT score calculator in their routine practice, Dr. Yeh said.

The DAPT study received funding from Abbott, Boston Scientific, Cordis, Medtronic, Bristol-Myers Squib-Sanofi, Eli Lilly, and Daiichi Sankyo. Derivation of the DAPT score was funded by the National Institutes of Health. Dr. Yeh has received honoraria from Abbott, Boston Scientific, and Merck. Dr. Jacobs had no disclosures. Dr. Mauri has been a consultant to Biotronik, Medtronic, and St. Jude and has received research funding from several companies.

[email protected]

On Twitter @mitchelzoler

ORLANDO – The common challenge faced by clinicians in deciding whether or not to continue dual antiplatelet therapy beyond a year in a patient who underwent percutaneous coronary intervention has gotten easier.

Researchers have devised a simple, eight-element scoring system using information already available in a patient’s records to help determine whether an individual patient will be more likely to benefit from continuing or stopping dual antiplatelet therapy (DAPT).

Mitchel L. Zoler/Frontline Medical News

“The DAPT score may help clinicians decide who should and who should not be treated with extended DAPT,” Dr. Robert W. Yeh said at the American Heart Association Scientific Sessions.

“This is a step forward for an issue we deal with daily, balancing an individual patient’s risk from ischemia and bleeding,” commented Dr. Alice Jacobs, professor of medicine at Boston University and director of the cardiac catheterization laboratory and interventional cardiology at Boston Medical Center.

Dr. Yeh and his associates devised the DAPT score from the data collected in the DAPT study, which enrolled more than 25,000 patients and randomized about 10,000 to test whether patients fared better by stopping or continuing DAPT after completing their initial year of DAPT following percutaneous coronary intervention (PCI). The DAPT study results showed that after 18 additional months, continuing DAPT cut the rate of definite or probable stent thrombosis by 1 percentage point and the combined rate of death, MI, or stroke by 1.6 percentage points, both statistically significant differences, compared with patients randomized to treatment with aspirin plus placebo. The results also showed that continued DAPT increased GUSTO moderate or severe bleeding events by 1 percentage point, compared with the control patients (N Engl J Med. 2014 Dec 4;371[23]:2155-66).

The researchers used data collected in the DAPT study to build risk models using patient- and procedure-specific variables that predicted the ischemic and bleeding outcomes, and then combined the two into a single model. That meant abandoning some variables that had significant impact on both outcomes.

The result was a scoring system that includes eight variables that result in a score that ranges from –2 to 9. The analysis showed that a score of 1 or less identified patients for whom the risk for bleeding outweighs their potential gain by avoiding an ischemic event by about 2.5-fold, and hence likely would fare better by stopping DAPT. A score of 2 or higher flagged patients who benefited about eightfold more from avoided ischemic events, compared with their risk for a moderate or severe bleed.

Patient scores showed a classic bell-shaped curve, with roughly a quarter of the DAPT study patients having a score of 1 and about a quarter with a score of 2, about 16% had a score of 0 and about 16% had a score of 3, and about 8% had a score of –1 or –2, while about 9% had a score of 4 or more.

The investigators validated the scoring system using data collected in the PROTECT trial, which included 8,791 patients who underwent PCI during 2007-2008. Dr. Yeh acknowledged that the discrimination strength of the models he and his associated developed was “modest,” but added that its efficacy was greater than what has been shown in validation cohorts for the commonly used CH2ADS2-VASc and HAS-BLED scoring systems.

Dr. Yeh stressed that using the DAPT score “cannot trump clinical judgment.” He suggested that a clinician use the score to help facilitate a conversation with a PCI patient when the time comes to decide whether or not to continue DAPT beyond 1 year.

Other factors that could influence the decision include the length of the stented coronary lesions or prior radiation exposure to the patient’s coronary arteries, said Dr. Laura Mauri, who led the DAPT study and collaborated on developing the DAPT score. “It requires judgment to decide [on whether to continue DAPT] for patients who are on the borderline” for risk and benefit. “This gives patients a way to better understand what they might gain or lose” by continuing treatment. Without the quantification that the DAPT score provides, the balance of risk and benefit “is somewhat nebulous,” said Dr. Mauri, an interventional cardiologist and director of the Center for Clinical Biometrics in the division of cardiovascular medicine at Brigham and Women’s Hospital in Boston.

The investigators who ran the DAPT study realized several years before the study finished that development of the DAPT score was a critical part of applying the findings from the study into clinical practice, she said in an interview.

Dr. Yeh cautioned that the score is only appropriate for patients who match those enrolled into the DAPT study: patients who went through their first year post PCI on DAPT without having any ischemic or bleeding complications. For these patients, “we feel the DAPT score is incredibly valuable,” said Dr. Yeh, an interventional cardiologist and director of the Center for Outcomes Research in Cardiology at Beth Israel Deaconess Medical Center in Boston. He and his associates are now using data from the DAPT study to model bleeding and ischemia risks during the first year following PCI to try to come up with risk models that can address DAPT use during this period.

Dr. Yeh and Dr. Mauri have placed a link to the electronic DAPT score calculator on the website for the DAPT study (www.daptstudy.org), and Dr. Yeh said that an app version will soon become available. Interventionalists in the programs that Dr. Yeh and Mauri are affiliated with have recently begun using the DAPT score calculator in their routine practice, Dr. Yeh said.

The DAPT study received funding from Abbott, Boston Scientific, Cordis, Medtronic, Bristol-Myers Squib-Sanofi, Eli Lilly, and Daiichi Sankyo. Derivation of the DAPT score was funded by the National Institutes of Health. Dr. Yeh has received honoraria from Abbott, Boston Scientific, and Merck. Dr. Jacobs had no disclosures. Dr. Mauri has been a consultant to Biotronik, Medtronic, and St. Jude and has received research funding from several companies.

[email protected]

On Twitter @mitchelzoler

ORLANDO – Two guideline panels jointly upgraded percutaneous coronary interventions in noninfarct coronary arteries in patients with a recent MI, and downgraded manual aspiration thrombectomy in acute MI patients.

The panels, organized by the American College of Cardiology and the American Heart Association, cover, respectively, percutaneous coronary intervention (PCI) and ST-elevation MI (STEMI).

The revised guidance on percutaneous coronary intervention for multivessel coronary disease affects roughly half the patients with an acute ST-elevation MI, those who have significant stenoses in noninfarct coronaries. The 2011 guidelines from the PCI panel (J Am Coll Cardiol. 2011 Dec;58[24]:e44-122) and the 2013 guidelines from the STEMI committee (J Am Coll Cardiol. 2013 Jan;61[4]:e78-140) only endorsed revascularization of stenotic, noninfarct arteries in patients with cardiogenic shock or severe heart failure. Multivessel PCI for patients without hemodynamic compromise at the time of primary PCI was deemed a class III indication, “thought to confer harm,” based on the results of several observational studies, Dr. Patrick T. O’Gara said at the American Heart Association scientific sessions.

Mitchel L. Zoler/Frontline Medical News

After the 2013 STEMI guidelines came out, results from four studies showed either benefit or no harm from multivessel PCI in patients with appropriate anatomy performed either at the time of primary PCI or as a scheduled, staged procedure soon after primary PCI, said Dr. O’Gara, professor and director of clinical cardiology at Brigham and Women’s Hospital in Boston. Three of the four studies, PRAMI (N Engl J Med. 2013 Sept 19;369[12]:1115-23), CvLPRIT (J Am Coll Cardiol. 2015 March;65[10]:963-72), and DANAMI-3–PRIMULTI (Lancet. 2015 Aug 15;386[9994]:665-71), are published, while results from the fourth, PRAGUE-13, came out in a meeting report this year but as of mid-November had not been published.

Based on these data the two committees reset PCI of noninfarct arteries as a class IIb recommendation that “could be considered” in selected STEMI patients with multivessel disease who are hemodynamically stable.

The guidelines further said that “insufficient data exist to inform a recommendation” about the optimal time for this multivessel PCI, which could be coincident with primary PCI or 2 days, 3 days, a week, or even later after initial PCI, said Dr. O’Gara. “The writing committees do not advocate for routine use of multivessel PCI; clinical judgment is obviously needed,” he cautioned.

The two committees also reassessed manual aspiration thrombectomy during primary PCI for STEMI, which until now has been a class IIa recommendation, “reasonable” for STEMI patients undergoing primary PCI. But based on the neutral results for thrombectomy in the recent findings from the two largest randomized trials of thrombectomy, TOTAL (N Engl J Med. 2015 April 9;372[15]:1389-98) and TASTE (N Engl J Med. 2013 Oct 24;369[17]:1587-97), as well as a recent, 17-trial meta-analysis, the revised guidelines rate routine aspiration thrombectomy as class III, with “no benefit” and “not useful,” and selective and bailout thrombectomy as a class IIb recommendation, with usefulness that is “not well established.”

Selective use of thrombectomy will require good judgment, noted Dr. O’Gara, who added “it will be important to see what effect, if any, these observations, this evidence, and this distillation of the recommendations from the writing committees have on a change in practice” – using thrombectomy to treat STEMI patients.

Dr. O’Gara chairs the STEMI writing panel of the American College of Cardiology and American Heart Association.

[email protected]

On Twitter @mitchelzoler

ORLANDO – Two guideline panels jointly upgraded percutaneous coronary interventions in noninfarct coronary arteries in patients with a recent MI, and downgraded manual aspiration thrombectomy in acute MI patients.

The panels, organized by the American College of Cardiology and the American Heart Association, cover, respectively, percutaneous coronary intervention (PCI) and ST-elevation MI (STEMI).

The revised guidance on percutaneous coronary intervention for multivessel coronary disease affects roughly half the patients with an acute ST-elevation MI, those who have significant stenoses in noninfarct coronaries. The 2011 guidelines from the PCI panel (J Am Coll Cardiol. 2011 Dec;58[24]:e44-122) and the 2013 guidelines from the STEMI committee (J Am Coll Cardiol. 2013 Jan;61[4]:e78-140) only endorsed revascularization of stenotic, noninfarct arteries in patients with cardiogenic shock or severe heart failure. Multivessel PCI for patients without hemodynamic compromise at the time of primary PCI was deemed a class III indication, “thought to confer harm,” based on the results of several observational studies, Dr. Patrick T. O’Gara said at the American Heart Association scientific sessions.

Mitchel L. Zoler/Frontline Medical News

After the 2013 STEMI guidelines came out, results from four studies showed either benefit or no harm from multivessel PCI in patients with appropriate anatomy performed either at the time of primary PCI or as a scheduled, staged procedure soon after primary PCI, said Dr. O’Gara, professor and director of clinical cardiology at Brigham and Women’s Hospital in Boston. Three of the four studies, PRAMI (N Engl J Med. 2013 Sept 19;369[12]:1115-23), CvLPRIT (J Am Coll Cardiol. 2015 March;65[10]:963-72), and DANAMI-3–PRIMULTI (Lancet. 2015 Aug 15;386[9994]:665-71), are published, while results from the fourth, PRAGUE-13, came out in a meeting report this year but as of mid-November had not been published.

Based on these data the two committees reset PCI of noninfarct arteries as a class IIb recommendation that “could be considered” in selected STEMI patients with multivessel disease who are hemodynamically stable.

The guidelines further said that “insufficient data exist to inform a recommendation” about the optimal time for this multivessel PCI, which could be coincident with primary PCI or 2 days, 3 days, a week, or even later after initial PCI, said Dr. O’Gara. “The writing committees do not advocate for routine use of multivessel PCI; clinical judgment is obviously needed,” he cautioned.

The two committees also reassessed manual aspiration thrombectomy during primary PCI for STEMI, which until now has been a class IIa recommendation, “reasonable” for STEMI patients undergoing primary PCI. But based on the neutral results for thrombectomy in the recent findings from the two largest randomized trials of thrombectomy, TOTAL (N Engl J Med. 2015 April 9;372[15]:1389-98) and TASTE (N Engl J Med. 2013 Oct 24;369[17]:1587-97), as well as a recent, 17-trial meta-analysis, the revised guidelines rate routine aspiration thrombectomy as class III, with “no benefit” and “not useful,” and selective and bailout thrombectomy as a class IIb recommendation, with usefulness that is “not well established.”

Selective use of thrombectomy will require good judgment, noted Dr. O’Gara, who added “it will be important to see what effect, if any, these observations, this evidence, and this distillation of the recommendations from the writing committees have on a change in practice” – using thrombectomy to treat STEMI patients.

Dr. O’Gara chairs the STEMI writing panel of the American College of Cardiology and American Heart Association.

[email protected]

On Twitter @mitchelzoler

ORLANDO – Two guideline panels jointly upgraded percutaneous coronary interventions in noninfarct coronary arteries in patients with a recent MI, and downgraded manual aspiration thrombectomy in acute MI patients.

The panels, organized by the American College of Cardiology and the American Heart Association, cover, respectively, percutaneous coronary intervention (PCI) and ST-elevation MI (STEMI).

The revised guidance on percutaneous coronary intervention for multivessel coronary disease affects roughly half the patients with an acute ST-elevation MI, those who have significant stenoses in noninfarct coronaries. The 2011 guidelines from the PCI panel (J Am Coll Cardiol. 2011 Dec;58[24]:e44-122) and the 2013 guidelines from the STEMI committee (J Am Coll Cardiol. 2013 Jan;61[4]:e78-140) only endorsed revascularization of stenotic, noninfarct arteries in patients with cardiogenic shock or severe heart failure. Multivessel PCI for patients without hemodynamic compromise at the time of primary PCI was deemed a class III indication, “thought to confer harm,” based on the results of several observational studies, Dr. Patrick T. O’Gara said at the American Heart Association scientific sessions.

Mitchel L. Zoler/Frontline Medical News

After the 2013 STEMI guidelines came out, results from four studies showed either benefit or no harm from multivessel PCI in patients with appropriate anatomy performed either at the time of primary PCI or as a scheduled, staged procedure soon after primary PCI, said Dr. O’Gara, professor and director of clinical cardiology at Brigham and Women’s Hospital in Boston. Three of the four studies, PRAMI (N Engl J Med. 2013 Sept 19;369[12]:1115-23), CvLPRIT (J Am Coll Cardiol. 2015 March;65[10]:963-72), and DANAMI-3–PRIMULTI (Lancet. 2015 Aug 15;386[9994]:665-71), are published, while results from the fourth, PRAGUE-13, came out in a meeting report this year but as of mid-November had not been published.

Based on these data the two committees reset PCI of noninfarct arteries as a class IIb recommendation that “could be considered” in selected STEMI patients with multivessel disease who are hemodynamically stable.

The guidelines further said that “insufficient data exist to inform a recommendation” about the optimal time for this multivessel PCI, which could be coincident with primary PCI or 2 days, 3 days, a week, or even later after initial PCI, said Dr. O’Gara. “The writing committees do not advocate for routine use of multivessel PCI; clinical judgment is obviously needed,” he cautioned.

The two committees also reassessed manual aspiration thrombectomy during primary PCI for STEMI, which until now has been a class IIa recommendation, “reasonable” for STEMI patients undergoing primary PCI. But based on the neutral results for thrombectomy in the recent findings from the two largest randomized trials of thrombectomy, TOTAL (N Engl J Med. 2015 April 9;372[15]:1389-98) and TASTE (N Engl J Med. 2013 Oct 24;369[17]:1587-97), as well as a recent, 17-trial meta-analysis, the revised guidelines rate routine aspiration thrombectomy as class III, with “no benefit” and “not useful,” and selective and bailout thrombectomy as a class IIb recommendation, with usefulness that is “not well established.”

Selective use of thrombectomy will require good judgment, noted Dr. O’Gara, who added “it will be important to see what effect, if any, these observations, this evidence, and this distillation of the recommendations from the writing committees have on a change in practice” – using thrombectomy to treat STEMI patients.

Dr. O’Gara chairs the STEMI writing panel of the American College of Cardiology and American Heart Association.

[email protected]

On Twitter @mitchelzoler

ORLANDO – Considerable regional variation exists across the United States in outcomes, including survival and hospital charges following out-of-hospital cardiac arrest, Dr. Aiham Albaeni reported at the American Heart Association scientific sessions.

He presented an analysis of 155,592 adults who survived at least until hospital admission following non–trauma-related out-of-hospital cardiac arrest (OHCA) during 2002-2012. The data came from the Agency for Healthcare Research and Quality’s Nationwide Inpatient Sample, the largest all-payer U.S. inpatient database.

Bruce Jancin/Frontline Medical News

Mortality was lowest among patients whose OHCA occurred in the Midwest. Indeed, taking the Northeast region as the reference point in a multivariate analysis, the adjusted mortality risk was 14% lower in the Midwest and 9% lower in the South. There was no difference in survival rates between the West and Northeast in this analysis adjusted for age, gender, race, primary diagnosis, income, Charlson Comorbidity Index, primary payer, and hospital size and teaching status, reported Dr. Albaeni of Johns Hopkins University, Baltimore.

Total hospital charges for patients admitted following OHCA were far and away highest in the West, and this increased expenditure didn’t pay off in terms of a survival advantage. The Consumer Price Index–adjusted mean total hospital charges averaged $85,592 per patient in the West, $66,290 in the Northeast, $55,257 in the Midwest, and $54,878 in the South.

Outliers in terms of cost of care – that is, patients admitted with OHCA whose total hospital charges exceeded $109,000 per admission – were 85% more common in the West than the other three regions, he noted.

Hospital length of stay greater than 8 days occurred most often in the Northeast. These lengthier stays were 10%-12% less common in the other regions.

The explanation for the marked regional differences observed in this study remains unknown.

“These findings call for more efforts to identify a high-quality model of excellence that standardizes health care delivery and improves quality of care in low-performing regions,” said Dr. Albaeni.

He reported having no financial conflicts of interest regarding his study.

[email protected]

ORLANDO – Considerable regional variation exists across the United States in outcomes, including survival and hospital charges following out-of-hospital cardiac arrest, Dr. Aiham Albaeni reported at the American Heart Association scientific sessions.

He presented an analysis of 155,592 adults who survived at least until hospital admission following non–trauma-related out-of-hospital cardiac arrest (OHCA) during 2002-2012. The data came from the Agency for Healthcare Research and Quality’s Nationwide Inpatient Sample, the largest all-payer U.S. inpatient database.

Bruce Jancin/Frontline Medical News

Mortality was lowest among patients whose OHCA occurred in the Midwest. Indeed, taking the Northeast region as the reference point in a multivariate analysis, the adjusted mortality risk was 14% lower in the Midwest and 9% lower in the South. There was no difference in survival rates between the West and Northeast in this analysis adjusted for age, gender, race, primary diagnosis, income, Charlson Comorbidity Index, primary payer, and hospital size and teaching status, reported Dr. Albaeni of Johns Hopkins University, Baltimore.

Total hospital charges for patients admitted following OHCA were far and away highest in the West, and this increased expenditure didn’t pay off in terms of a survival advantage. The Consumer Price Index–adjusted mean total hospital charges averaged $85,592 per patient in the West, $66,290 in the Northeast, $55,257 in the Midwest, and $54,878 in the South.

Outliers in terms of cost of care – that is, patients admitted with OHCA whose total hospital charges exceeded $109,000 per admission – were 85% more common in the West than the other three regions, he noted.

Hospital length of stay greater than 8 days occurred most often in the Northeast. These lengthier stays were 10%-12% less common in the other regions.

The explanation for the marked regional differences observed in this study remains unknown.

“These findings call for more efforts to identify a high-quality model of excellence that standardizes health care delivery and improves quality of care in low-performing regions,” said Dr. Albaeni.

He reported having no financial conflicts of interest regarding his study.

[email protected]

ORLANDO – Considerable regional variation exists across the United States in outcomes, including survival and hospital charges following out-of-hospital cardiac arrest, Dr. Aiham Albaeni reported at the American Heart Association scientific sessions.

He presented an analysis of 155,592 adults who survived at least until hospital admission following non–trauma-related out-of-hospital cardiac arrest (OHCA) during 2002-2012. The data came from the Agency for Healthcare Research and Quality’s Nationwide Inpatient Sample, the largest all-payer U.S. inpatient database.

Bruce Jancin/Frontline Medical News

Mortality was lowest among patients whose OHCA occurred in the Midwest. Indeed, taking the Northeast region as the reference point in a multivariate analysis, the adjusted mortality risk was 14% lower in the Midwest and 9% lower in the South. There was no difference in survival rates between the West and Northeast in this analysis adjusted for age, gender, race, primary diagnosis, income, Charlson Comorbidity Index, primary payer, and hospital size and teaching status, reported Dr. Albaeni of Johns Hopkins University, Baltimore.

Total hospital charges for patients admitted following OHCA were far and away highest in the West, and this increased expenditure didn’t pay off in terms of a survival advantage. The Consumer Price Index–adjusted mean total hospital charges averaged $85,592 per patient in the West, $66,290 in the Northeast, $55,257 in the Midwest, and $54,878 in the South.

Outliers in terms of cost of care – that is, patients admitted with OHCA whose total hospital charges exceeded $109,000 per admission – were 85% more common in the West than the other three regions, he noted.

Hospital length of stay greater than 8 days occurred most often in the Northeast. These lengthier stays were 10%-12% less common in the other regions.

The explanation for the marked regional differences observed in this study remains unknown.

“These findings call for more efforts to identify a high-quality model of excellence that standardizes health care delivery and improves quality of care in low-performing regions,” said Dr. Albaeni.

He reported having no financial conflicts of interest regarding his study.

[email protected]

DALLAS—Positive data about the use of Exparel (bupivacaine liposome injectable suspension) as a postsurgical analgesic following total knee replacement surgery was presented at the 25th Annual Meeting of the American Association of Hip and Knee Surgeons.

The study, which compared the use of bupivacaine liposome injectable suspension infiltration to the standard of care in 1,110 patients, found that bupivacaine liposome injectable suspension was associated with significant improvements in a variety of patient and health economic outcomes, including opioid use, hospital stay, and readmission rate.

Patients who underwent total knee arthroplasty (TKA) received identical pre-, intra-, and postoperative pain management protocols, with the exception of 527 patients who received bupivacaine liposome injectable suspension infiltration in place of a femoral nerve block.

The study authors compared several patient and cost-related outcomes. Opioid use during hospitalization was statistically significantly reduced in the bupivacaine liposome injectable suspension group. Other key findings included:

• Shorter hospital length of stay (2.93 days for the bupivacaine liposome injectable suspension group vs 3.19 days for the femoral nerve block group, P<0.001)

• Increased rate of discharge to home (77.8% for the bupivacaine liposome injectable suspension group vs 72.21% for the femoral nerve block group, P=0.032)

• Reduced inpatient fall rate (0.56% for the bupivacaine liposome injectable suspension group vs 2.11% for the femoral nerve block group, P=0.03)

• Lower 30-day all-cause readmission rate (0.95% for the bupivacaine liposome injectable suspension group vs 2.57% for the femoral nerve block group, P=0.041)

“Based on our analysis, incorporating liposomal bupivacaine into the postsurgical analgesic protocol following total knee arthroplasty has significant and quantifiable benefits to both the patient and the institution,” said Richard Iorio, MD, Professor of Orthopaedic Surgery at NYU School of Medicine in New York. “The measurable opioid-sparing effect of this new regimen has enabled us to virtually eliminate intravenous patient-controlled analgesia, or PCA, devices from the standard of care in total joint arthroplasty patients, without compromising patient comfort. In addition, we found that the incremental cost of adding this new modality was offset by meaningful savings from shorter anesthesia induction time in the operating room, shorter hospital stays and lower rates of 30-day readmission.”

DALLAS—Positive data about the use of Exparel (bupivacaine liposome injectable suspension) as a postsurgical analgesic following total knee replacement surgery was presented at the 25th Annual Meeting of the American Association of Hip and Knee Surgeons.

The study, which compared the use of bupivacaine liposome injectable suspension infiltration to the standard of care in 1,110 patients, found that bupivacaine liposome injectable suspension was associated with significant improvements in a variety of patient and health economic outcomes, including opioid use, hospital stay, and readmission rate.

Patients who underwent total knee arthroplasty (TKA) received identical pre-, intra-, and postoperative pain management protocols, with the exception of 527 patients who received bupivacaine liposome injectable suspension infiltration in place of a femoral nerve block.

The study authors compared several patient and cost-related outcomes. Opioid use during hospitalization was statistically significantly reduced in the bupivacaine liposome injectable suspension group. Other key findings included:

• Shorter hospital length of stay (2.93 days for the bupivacaine liposome injectable suspension group vs 3.19 days for the femoral nerve block group, P<0.001)

• Increased rate of discharge to home (77.8% for the bupivacaine liposome injectable suspension group vs 72.21% for the femoral nerve block group, P=0.032)

• Reduced inpatient fall rate (0.56% for the bupivacaine liposome injectable suspension group vs 2.11% for the femoral nerve block group, P=0.03)

• Lower 30-day all-cause readmission rate (0.95% for the bupivacaine liposome injectable suspension group vs 2.57% for the femoral nerve block group, P=0.041)

“Based on our analysis, incorporating liposomal bupivacaine into the postsurgical analgesic protocol following total knee arthroplasty has significant and quantifiable benefits to both the patient and the institution,” said Richard Iorio, MD, Professor of Orthopaedic Surgery at NYU School of Medicine in New York. “The measurable opioid-sparing effect of this new regimen has enabled us to virtually eliminate intravenous patient-controlled analgesia, or PCA, devices from the standard of care in total joint arthroplasty patients, without compromising patient comfort. In addition, we found that the incremental cost of adding this new modality was offset by meaningful savings from shorter anesthesia induction time in the operating room, shorter hospital stays and lower rates of 30-day readmission.”

DALLAS—Positive data about the use of Exparel (bupivacaine liposome injectable suspension) as a postsurgical analgesic following total knee replacement surgery was presented at the 25th Annual Meeting of the American Association of Hip and Knee Surgeons.

The study, which compared the use of bupivacaine liposome injectable suspension infiltration to the standard of care in 1,110 patients, found that bupivacaine liposome injectable suspension was associated with significant improvements in a variety of patient and health economic outcomes, including opioid use, hospital stay, and readmission rate.

Patients who underwent total knee arthroplasty (TKA) received identical pre-, intra-, and postoperative pain management protocols, with the exception of 527 patients who received bupivacaine liposome injectable suspension infiltration in place of a femoral nerve block.

The study authors compared several patient and cost-related outcomes. Opioid use during hospitalization was statistically significantly reduced in the bupivacaine liposome injectable suspension group. Other key findings included:

• Shorter hospital length of stay (2.93 days for the bupivacaine liposome injectable suspension group vs 3.19 days for the femoral nerve block group, P<0.001)

• Increased rate of discharge to home (77.8% for the bupivacaine liposome injectable suspension group vs 72.21% for the femoral nerve block group, P=0.032)

• Reduced inpatient fall rate (0.56% for the bupivacaine liposome injectable suspension group vs 2.11% for the femoral nerve block group, P=0.03)

• Lower 30-day all-cause readmission rate (0.95% for the bupivacaine liposome injectable suspension group vs 2.57% for the femoral nerve block group, P=0.041)

“Based on our analysis, incorporating liposomal bupivacaine into the postsurgical analgesic protocol following total knee arthroplasty has significant and quantifiable benefits to both the patient and the institution,” said Richard Iorio, MD, Professor of Orthopaedic Surgery at NYU School of Medicine in New York. “The measurable opioid-sparing effect of this new regimen has enabled us to virtually eliminate intravenous patient-controlled analgesia, or PCA, devices from the standard of care in total joint arthroplasty patients, without compromising patient comfort. In addition, we found that the incremental cost of adding this new modality was offset by meaningful savings from shorter anesthesia induction time in the operating room, shorter hospital stays and lower rates of 30-day readmission.”

Leishmaniasis describes any disease caused by protozoan parasites of the genus Leishmania¹ and can manifest in 3 different forms: cutaneous (the most common); mucosal, a destructive metastatic sequela of the cutaneous form; and visceral, which is potentially fatal.² According to the World Health Organization, the leishmaniases are endemic in 88 countries.³ It is estimated that 95% of cutaneous cases occur in the Americas (most notably Central and South America), the Mediterranean basin, the Middle East, and Central Asia.² Most cutaneous cases diagnosed among nonmilitary personnel in the United States are acquired in Mexico and Central America.⁴ In Central and South America, the causative human pathogens include species of the Leishmania (Viannia) complex (eg, Leishmania panamensis, Leishmania braziliensis, Leishmania guyanensis, Leishmania peruviana) and the Leishmania mexicana complex (eg, Leishmania mexicana, Leishmania amazonensis, Leishmania venezuelensis). All of these species can cause localized cutaneous lesions, but only L panamensis, L braziliensis, and L guyanensis are associated with metastatic mucosal lesions. In Central and South Americas, only Leishmaniasis chagasi (also known as Leishmaniasis infantum) is known to cause visceral leishmaniasis.⁵

Case Report

A 26-year-old man was referred to the dermatology clinic by his primary care provider for evaluation of a nonhealing sore on the left volar forearm of 6 weeks’ duration. The patient described the initial lesion as a red bump resembling a mosquito bite. Over 6 weeks the papule evolved into an indurated plaque with painless ulceration. The patient’s primary care provider had prescribed antibiotics for a presumed Staphylococcus aureus infection of the skin 5 weeks prior to presentation; however, the lesion continued to enlarge in size, resulting in referral to our dermatology clinic.

Skin examination revealed a solitary, 4-cm, painless, ulcerated plaque on the left volar forearm (Figure 1). No lymphadenopathy was noted. The patient reported that he had returned from a mission trip to rural Costa Rica 2 weeks prior to the appearance of the lesion. His medical history was otherwise unremarkable and his vital signs were within normal limits. Our initial differential diagnosis included pyoderma gangrenosum, Sweet syndrome, cutaneous leishmaniasis, and an insect bite.

Histopathologic study of a 5-mm punch biopsy specimen from the lesion showed a dense nodular and diffuse lymphohistiocytic infiltrate containing foci of suppuration. Within these suppurative foci were histiocytes parasitized by intracellular organisms that appeared to be of uniform size and shape on Giemsa staining, all of which are considered to be pathognomonic features of cutaneous leishmaniasis⁶ (Figures 2 and 3). The dermatopathologist’s diagnosis of cutaneous leishmaniasis was confirmed by the Centers for Disease Control and Prevention. The species was identified by polymerase chain reaction (PCR) as L panamensis.

The patient was treated with intravenous sodium stibogluconate 20 mg/kg for 20 consecutive days as recommended by expert consensus. The decision to treat a frequently self-limited cutaneous lesion with a highly toxic systemic drug was based on the small but real risk of metastatic mucosal lesions, which is caused by the Viannia subgenus, including L panamensis. Of note, sodium stibogluconate and other antimony drugs are not sold in the United States. Sodium stibogluconate is approved by the US Food and Drug Administration to be distributed by the Centers for Disease Control and Prevention under a protocol requiring baseline and weekly electrocardiograms and monitoring of patients’ creatinine, transaminase, lipase, amylase, and complete blood count levels.⁷ Our patient tolerated treatment but experienced mild to moderate flulike symptoms. The patient experienced no remarkable sequelae other than scarring in the affected area. He was warned to notify his health care providers of any persistent nasal symptoms, including nasal stuffiness, mucosal bleeding, and increased secretions, heralding the possibility of mucosal metastasis.
 

Figure 2. Dense nodular and diffuse lymphohistiocytic infiltrate containing foci of suppuration (H&E, original magnification ×10).		Figure 3. Histiocytes parasitized by intracellular organisms of uniform shape and size on Giemsa staining (original magnification ×1000).

Comment

The true incidence of cutaneous leishmaniasis in American travelers returning from Mexico and South and Central Americas is not known. The best incidence estimates are based on the number of physician requests for sodium stibogluconate and travel surveillance data collected by the Centers for Disease Control and Prevention. One study estimated the incidence of cutaneous leishmaniasis in Americans to be 1 case per every 100,000 travelers to Mexico.⁹ Data on the incidence of cutaneous leishmaniasis in American travelers seen in travel clinics for skin lesions gives a different perspective.¹⁰ Leishmaniasis is one of the most common dermatologic diseases seen in patients (European, North American, and other) returning from South America, accounting for 143 of every 1000 patients diagnosed with a skin disease acquired in South America.

Although males are thought to be at higher risk for cutaneous leishmaniasis infection than females, other demographic and behavioral risk factors are not well defined. In a case series of US travelers diagnosed with cutaneous leishmaniasis between January 1985 and April 1990, Herwaldt et al⁹ found that 46% (27/59) were conducting field studies, while 39% (23/59) were tourists, visitors, or tour guides. At least 15 of the 58 travelers interviewed (26%) were in forested areas for 1 week or less, and of these 15 respondents, at least 6 had a maximum exposure of 2 days.⁹

Evidence suggests that cutaneous leishmaniasis is inefficiently diagnosed in the United States. One study showed that some patients may consult up to 7 physicians before a definitive diagnosis is made, and the median time from noticing eruption of the lesions to definitive treatment was 112 days.⁹ Several factors may contribute to delays and inefficiencies in diagnosis. First, the lesions of cutaneous leishmaniasis are varied in morphology, and although ulcers are thought to be the most commonly presenting lesions,¹¹ there are no specific morphologic features that are pathognomonic for cutaneous leishmaniasis. Second, the temporal association with travel to endemic countries is not necessarily apparent, with lesions developing gradually or weeks after the patient returns home. In the one study, 17% (10/58) of patients were home for more than 1 month before they noticed skin lesions.⁹ Finally, definitive diagnosis requires biopsy or scraping of the lesion followed by PCR, special histopathological staining (Giemsa), or culture. Polymerase chain reaction is currently the best means of identifying the causative Leishmania species.^12-14 However, since skin biopsies are not routine in primary care settings and few practitioners are familiar with PCR for identification of leishmaniasis, diagnosis is typically made only after referral to a specialist.

Leishmaniasis transmission occurs in diverse geographical settings though a variety of mechanisms (Figure 4). The morphology of cutaneous leishmaniasis varies and may include papules, nodules, psoriasiform plaques, or ulcers. The differential diagnosis may include staphylococcal skin infection, insect bite, cutaneous neoplasm, pyoderma gangrenosum, sporotrichosis, blastomycosis, chromomycosis, lobomycosis, cutaneous tuberculosis, atypical mycobacterial infection, syphilis, yaws, leprosy, Hansen disease, and sarcoidosis. A definitive diagnosis can be made only after identifying the causative parasite. A scraping or punch biopsy taken from a cleaned lesion provides an adequate sample. Identification can then be accomplished by histopathology, tissue culture, or PCR.⁵

We present a rhyme that can be used to promote greater awareness of cutaneous leishmaniasis among US health care practitioners:

Although clinical resolution of cutaneous leishmaniasis usually occurs over months to years, the unsightly appearance of the lesions as well as the potential for scarring and mucosal metastasis (associated with some species) drives medical treatment.¹⁵ Pentavalent antimonial drugs, which have been the mainstay of treatment for more than 50 years, remain the most popular treatment for cutaneous leishmaniasis. Two antimony compounds, sodium stibogluconate and meglumine antimoniate, often lead to clinical cure in less than 1 month⁷; however, these drugs are far from ideal because of the inconvenience of obtaining them, emerging parasite resistance, long treatment course, parenteral route of administration, and serious side effects including infusion reactions, arrhythmias, pancreatitis, and liver toxicity. Moreover, the subclinical persistence of cutaneous leishmaniasis years after treatment and clinical cure is common. There have been reports of spontaneous disease reactivation in immunocompromised individuals, and Leishmania has been detected in old cutaneous leishmaniasis scars on PCR testing.^16-18 Other therapies that have been used to treat cutaneous leishmaniasis include allopurinol, aminosidine sulphate, amphotericin B, the Bacillus Calmette–Guérin vaccine, cotrimoxazole, cryotherapy, dapsone, fluconazole, itraconazole, ketoconazole, laser therapy, metronidazole, miltefosine, paromomycin, pentamidine, pentoxifylline, photodynamic therapy, rifampicin, and surgical excision of the entire lesion.⁸ A 2009 Cochrane review of the various treatments for cutaneous leishmaniasis concluded that “no general consensus on optimal treatment has been achieved” and suggested “the creation of an international platform to improve the quality and standardization of future trials in order to develop a better evidence-based approach.”⁸

Conclusion

Cutaneous leishmaniasis should be included in the differential diagnosis for travelers returning from endemic areas who present with new skin lesions. Since no specific lesion types are pathognomonic for cutaneous leishmaniasis, tissue biopsy for histopathology and PCR are essential for diagnosis. Prevention of cutaneous leishmaniasis hinges on appropriate counseling of travelers to endemic regions.

Leishmaniasis describes any disease caused by protozoan parasites of the genus Leishmania¹ and can manifest in 3 different forms: cutaneous (the most common); mucosal, a destructive metastatic sequela of the cutaneous form; and visceral, which is potentially fatal.² According to the World Health Organization, the leishmaniases are endemic in 88 countries.³ It is estimated that 95% of cutaneous cases occur in the Americas (most notably Central and South America), the Mediterranean basin, the Middle East, and Central Asia.² Most cutaneous cases diagnosed among nonmilitary personnel in the United States are acquired in Mexico and Central America.⁴ In Central and South America, the causative human pathogens include species of the Leishmania (Viannia) complex (eg, Leishmania panamensis, Leishmania braziliensis, Leishmania guyanensis, Leishmania peruviana) and the Leishmania mexicana complex (eg, Leishmania mexicana, Leishmania amazonensis, Leishmania venezuelensis). All of these species can cause localized cutaneous lesions, but only L panamensis, L braziliensis, and L guyanensis are associated with metastatic mucosal lesions. In Central and South Americas, only Leishmaniasis chagasi (also known as Leishmaniasis infantum) is known to cause visceral leishmaniasis.⁵

Case Report

A 26-year-old man was referred to the dermatology clinic by his primary care provider for evaluation of a nonhealing sore on the left volar forearm of 6 weeks’ duration. The patient described the initial lesion as a red bump resembling a mosquito bite. Over 6 weeks the papule evolved into an indurated plaque with painless ulceration. The patient’s primary care provider had prescribed antibiotics for a presumed Staphylococcus aureus infection of the skin 5 weeks prior to presentation; however, the lesion continued to enlarge in size, resulting in referral to our dermatology clinic.

Skin examination revealed a solitary, 4-cm, painless, ulcerated plaque on the left volar forearm (Figure 1). No lymphadenopathy was noted. The patient reported that he had returned from a mission trip to rural Costa Rica 2 weeks prior to the appearance of the lesion. His medical history was otherwise unremarkable and his vital signs were within normal limits. Our initial differential diagnosis included pyoderma gangrenosum, Sweet syndrome, cutaneous leishmaniasis, and an insect bite.

Histopathologic study of a 5-mm punch biopsy specimen from the lesion showed a dense nodular and diffuse lymphohistiocytic infiltrate containing foci of suppuration. Within these suppurative foci were histiocytes parasitized by intracellular organisms that appeared to be of uniform size and shape on Giemsa staining, all of which are considered to be pathognomonic features of cutaneous leishmaniasis⁶ (Figures 2 and 3). The dermatopathologist’s diagnosis of cutaneous leishmaniasis was confirmed by the Centers for Disease Control and Prevention. The species was identified by polymerase chain reaction (PCR) as L panamensis.

The patient was treated with intravenous sodium stibogluconate 20 mg/kg for 20 consecutive days as recommended by expert consensus. The decision to treat a frequently self-limited cutaneous lesion with a highly toxic systemic drug was based on the small but real risk of metastatic mucosal lesions, which is caused by the Viannia subgenus, including L panamensis. Of note, sodium stibogluconate and other antimony drugs are not sold in the United States. Sodium stibogluconate is approved by the US Food and Drug Administration to be distributed by the Centers for Disease Control and Prevention under a protocol requiring baseline and weekly electrocardiograms and monitoring of patients’ creatinine, transaminase, lipase, amylase, and complete blood count levels.⁷ Our patient tolerated treatment but experienced mild to moderate flulike symptoms. The patient experienced no remarkable sequelae other than scarring in the affected area. He was warned to notify his health care providers of any persistent nasal symptoms, including nasal stuffiness, mucosal bleeding, and increased secretions, heralding the possibility of mucosal metastasis.
 

Figure 2. Dense nodular and diffuse lymphohistiocytic infiltrate containing foci of suppuration (H&E, original magnification ×10).		Figure 3. Histiocytes parasitized by intracellular organisms of uniform shape and size on Giemsa staining (original magnification ×1000).

Comment

The true incidence of cutaneous leishmaniasis in American travelers returning from Mexico and South and Central Americas is not known. The best incidence estimates are based on the number of physician requests for sodium stibogluconate and travel surveillance data collected by the Centers for Disease Control and Prevention. One study estimated the incidence of cutaneous leishmaniasis in Americans to be 1 case per every 100,000 travelers to Mexico.⁹ Data on the incidence of cutaneous leishmaniasis in American travelers seen in travel clinics for skin lesions gives a different perspective.¹⁰ Leishmaniasis is one of the most common dermatologic diseases seen in patients (European, North American, and other) returning from South America, accounting for 143 of every 1000 patients diagnosed with a skin disease acquired in South America.

Although males are thought to be at higher risk for cutaneous leishmaniasis infection than females, other demographic and behavioral risk factors are not well defined. In a case series of US travelers diagnosed with cutaneous leishmaniasis between January 1985 and April 1990, Herwaldt et al⁹ found that 46% (27/59) were conducting field studies, while 39% (23/59) were tourists, visitors, or tour guides. At least 15 of the 58 travelers interviewed (26%) were in forested areas for 1 week or less, and of these 15 respondents, at least 6 had a maximum exposure of 2 days.⁹

Evidence suggests that cutaneous leishmaniasis is inefficiently diagnosed in the United States. One study showed that some patients may consult up to 7 physicians before a definitive diagnosis is made, and the median time from noticing eruption of the lesions to definitive treatment was 112 days.⁹ Several factors may contribute to delays and inefficiencies in diagnosis. First, the lesions of cutaneous leishmaniasis are varied in morphology, and although ulcers are thought to be the most commonly presenting lesions,¹¹ there are no specific morphologic features that are pathognomonic for cutaneous leishmaniasis. Second, the temporal association with travel to endemic countries is not necessarily apparent, with lesions developing gradually or weeks after the patient returns home. In the one study, 17% (10/58) of patients were home for more than 1 month before they noticed skin lesions.⁹ Finally, definitive diagnosis requires biopsy or scraping of the lesion followed by PCR, special histopathological staining (Giemsa), or culture. Polymerase chain reaction is currently the best means of identifying the causative Leishmania species.^12-14 However, since skin biopsies are not routine in primary care settings and few practitioners are familiar with PCR for identification of leishmaniasis, diagnosis is typically made only after referral to a specialist.

Leishmaniasis transmission occurs in diverse geographical settings though a variety of mechanisms (Figure 4). The morphology of cutaneous leishmaniasis varies and may include papules, nodules, psoriasiform plaques, or ulcers. The differential diagnosis may include staphylococcal skin infection, insect bite, cutaneous neoplasm, pyoderma gangrenosum, sporotrichosis, blastomycosis, chromomycosis, lobomycosis, cutaneous tuberculosis, atypical mycobacterial infection, syphilis, yaws, leprosy, Hansen disease, and sarcoidosis. A definitive diagnosis can be made only after identifying the causative parasite. A scraping or punch biopsy taken from a cleaned lesion provides an adequate sample. Identification can then be accomplished by histopathology, tissue culture, or PCR.⁵

We present a rhyme that can be used to promote greater awareness of cutaneous leishmaniasis among US health care practitioners:

Although clinical resolution of cutaneous leishmaniasis usually occurs over months to years, the unsightly appearance of the lesions as well as the potential for scarring and mucosal metastasis (associated with some species) drives medical treatment.¹⁵ Pentavalent antimonial drugs, which have been the mainstay of treatment for more than 50 years, remain the most popular treatment for cutaneous leishmaniasis. Two antimony compounds, sodium stibogluconate and meglumine antimoniate, often lead to clinical cure in less than 1 month⁷; however, these drugs are far from ideal because of the inconvenience of obtaining them, emerging parasite resistance, long treatment course, parenteral route of administration, and serious side effects including infusion reactions, arrhythmias, pancreatitis, and liver toxicity. Moreover, the subclinical persistence of cutaneous leishmaniasis years after treatment and clinical cure is common. There have been reports of spontaneous disease reactivation in immunocompromised individuals, and Leishmania has been detected in old cutaneous leishmaniasis scars on PCR testing.^16-18 Other therapies that have been used to treat cutaneous leishmaniasis include allopurinol, aminosidine sulphate, amphotericin B, the Bacillus Calmette–Guérin vaccine, cotrimoxazole, cryotherapy, dapsone, fluconazole, itraconazole, ketoconazole, laser therapy, metronidazole, miltefosine, paromomycin, pentamidine, pentoxifylline, photodynamic therapy, rifampicin, and surgical excision of the entire lesion.⁸ A 2009 Cochrane review of the various treatments for cutaneous leishmaniasis concluded that “no general consensus on optimal treatment has been achieved” and suggested “the creation of an international platform to improve the quality and standardization of future trials in order to develop a better evidence-based approach.”⁸

Conclusion

Cutaneous leishmaniasis should be included in the differential diagnosis for travelers returning from endemic areas who present with new skin lesions. Since no specific lesion types are pathognomonic for cutaneous leishmaniasis, tissue biopsy for histopathology and PCR are essential for diagnosis. Prevention of cutaneous leishmaniasis hinges on appropriate counseling of travelers to endemic regions.

Leishmaniasis describes any disease caused by protozoan parasites of the genus Leishmania¹ and can manifest in 3 different forms: cutaneous (the most common); mucosal, a destructive metastatic sequela of the cutaneous form; and visceral, which is potentially fatal.² According to the World Health Organization, the leishmaniases are endemic in 88 countries.³ It is estimated that 95% of cutaneous cases occur in the Americas (most notably Central and South America), the Mediterranean basin, the Middle East, and Central Asia.² Most cutaneous cases diagnosed among nonmilitary personnel in the United States are acquired in Mexico and Central America.⁴ In Central and South America, the causative human pathogens include species of the Leishmania (Viannia) complex (eg, Leishmania panamensis, Leishmania braziliensis, Leishmania guyanensis, Leishmania peruviana) and the Leishmania mexicana complex (eg, Leishmania mexicana, Leishmania amazonensis, Leishmania venezuelensis). All of these species can cause localized cutaneous lesions, but only L panamensis, L braziliensis, and L guyanensis are associated with metastatic mucosal lesions. In Central and South Americas, only Leishmaniasis chagasi (also known as Leishmaniasis infantum) is known to cause visceral leishmaniasis.⁵

Case Report

A 26-year-old man was referred to the dermatology clinic by his primary care provider for evaluation of a nonhealing sore on the left volar forearm of 6 weeks’ duration. The patient described the initial lesion as a red bump resembling a mosquito bite. Over 6 weeks the papule evolved into an indurated plaque with painless ulceration. The patient’s primary care provider had prescribed antibiotics for a presumed Staphylococcus aureus infection of the skin 5 weeks prior to presentation; however, the lesion continued to enlarge in size, resulting in referral to our dermatology clinic.

Skin examination revealed a solitary, 4-cm, painless, ulcerated plaque on the left volar forearm (Figure 1). No lymphadenopathy was noted. The patient reported that he had returned from a mission trip to rural Costa Rica 2 weeks prior to the appearance of the lesion. His medical history was otherwise unremarkable and his vital signs were within normal limits. Our initial differential diagnosis included pyoderma gangrenosum, Sweet syndrome, cutaneous leishmaniasis, and an insect bite.

Histopathologic study of a 5-mm punch biopsy specimen from the lesion showed a dense nodular and diffuse lymphohistiocytic infiltrate containing foci of suppuration. Within these suppurative foci were histiocytes parasitized by intracellular organisms that appeared to be of uniform size and shape on Giemsa staining, all of which are considered to be pathognomonic features of cutaneous leishmaniasis⁶ (Figures 2 and 3). The dermatopathologist’s diagnosis of cutaneous leishmaniasis was confirmed by the Centers for Disease Control and Prevention. The species was identified by polymerase chain reaction (PCR) as L panamensis.

The patient was treated with intravenous sodium stibogluconate 20 mg/kg for 20 consecutive days as recommended by expert consensus. The decision to treat a frequently self-limited cutaneous lesion with a highly toxic systemic drug was based on the small but real risk of metastatic mucosal lesions, which is caused by the Viannia subgenus, including L panamensis. Of note, sodium stibogluconate and other antimony drugs are not sold in the United States. Sodium stibogluconate is approved by the US Food and Drug Administration to be distributed by the Centers for Disease Control and Prevention under a protocol requiring baseline and weekly electrocardiograms and monitoring of patients’ creatinine, transaminase, lipase, amylase, and complete blood count levels.⁷ Our patient tolerated treatment but experienced mild to moderate flulike symptoms. The patient experienced no remarkable sequelae other than scarring in the affected area. He was warned to notify his health care providers of any persistent nasal symptoms, including nasal stuffiness, mucosal bleeding, and increased secretions, heralding the possibility of mucosal metastasis.
 

Figure 2. Dense nodular and diffuse lymphohistiocytic infiltrate containing foci of suppuration (H&E, original magnification ×10).		Figure 3. Histiocytes parasitized by intracellular organisms of uniform shape and size on Giemsa staining (original magnification ×1000).

Comment

The true incidence of cutaneous leishmaniasis in American travelers returning from Mexico and South and Central Americas is not known. The best incidence estimates are based on the number of physician requests for sodium stibogluconate and travel surveillance data collected by the Centers for Disease Control and Prevention. One study estimated the incidence of cutaneous leishmaniasis in Americans to be 1 case per every 100,000 travelers to Mexico.⁹ Data on the incidence of cutaneous leishmaniasis in American travelers seen in travel clinics for skin lesions gives a different perspective.¹⁰ Leishmaniasis is one of the most common dermatologic diseases seen in patients (European, North American, and other) returning from South America, accounting for 143 of every 1000 patients diagnosed with a skin disease acquired in South America.

Although males are thought to be at higher risk for cutaneous leishmaniasis infection than females, other demographic and behavioral risk factors are not well defined. In a case series of US travelers diagnosed with cutaneous leishmaniasis between January 1985 and April 1990, Herwaldt et al⁹ found that 46% (27/59) were conducting field studies, while 39% (23/59) were tourists, visitors, or tour guides. At least 15 of the 58 travelers interviewed (26%) were in forested areas for 1 week or less, and of these 15 respondents, at least 6 had a maximum exposure of 2 days.⁹

Evidence suggests that cutaneous leishmaniasis is inefficiently diagnosed in the United States. One study showed that some patients may consult up to 7 physicians before a definitive diagnosis is made, and the median time from noticing eruption of the lesions to definitive treatment was 112 days.⁹ Several factors may contribute to delays and inefficiencies in diagnosis. First, the lesions of cutaneous leishmaniasis are varied in morphology, and although ulcers are thought to be the most commonly presenting lesions,¹¹ there are no specific morphologic features that are pathognomonic for cutaneous leishmaniasis. Second, the temporal association with travel to endemic countries is not necessarily apparent, with lesions developing gradually or weeks after the patient returns home. In the one study, 17% (10/58) of patients were home for more than 1 month before they noticed skin lesions.⁹ Finally, definitive diagnosis requires biopsy or scraping of the lesion followed by PCR, special histopathological staining (Giemsa), or culture. Polymerase chain reaction is currently the best means of identifying the causative Leishmania species.^12-14 However, since skin biopsies are not routine in primary care settings and few practitioners are familiar with PCR for identification of leishmaniasis, diagnosis is typically made only after referral to a specialist.

Leishmaniasis transmission occurs in diverse geographical settings though a variety of mechanisms (Figure 4). The morphology of cutaneous leishmaniasis varies and may include papules, nodules, psoriasiform plaques, or ulcers. The differential diagnosis may include staphylococcal skin infection, insect bite, cutaneous neoplasm, pyoderma gangrenosum, sporotrichosis, blastomycosis, chromomycosis, lobomycosis, cutaneous tuberculosis, atypical mycobacterial infection, syphilis, yaws, leprosy, Hansen disease, and sarcoidosis. A definitive diagnosis can be made only after identifying the causative parasite. A scraping or punch biopsy taken from a cleaned lesion provides an adequate sample. Identification can then be accomplished by histopathology, tissue culture, or PCR.⁵

We present a rhyme that can be used to promote greater awareness of cutaneous leishmaniasis among US health care practitioners:

Although clinical resolution of cutaneous leishmaniasis usually occurs over months to years, the unsightly appearance of the lesions as well as the potential for scarring and mucosal metastasis (associated with some species) drives medical treatment.¹⁵ Pentavalent antimonial drugs, which have been the mainstay of treatment for more than 50 years, remain the most popular treatment for cutaneous leishmaniasis. Two antimony compounds, sodium stibogluconate and meglumine antimoniate, often lead to clinical cure in less than 1 month⁷; however, these drugs are far from ideal because of the inconvenience of obtaining them, emerging parasite resistance, long treatment course, parenteral route of administration, and serious side effects including infusion reactions, arrhythmias, pancreatitis, and liver toxicity. Moreover, the subclinical persistence of cutaneous leishmaniasis years after treatment and clinical cure is common. There have been reports of spontaneous disease reactivation in immunocompromised individuals, and Leishmania has been detected in old cutaneous leishmaniasis scars on PCR testing.^16-18 Other therapies that have been used to treat cutaneous leishmaniasis include allopurinol, aminosidine sulphate, amphotericin B, the Bacillus Calmette–Guérin vaccine, cotrimoxazole, cryotherapy, dapsone, fluconazole, itraconazole, ketoconazole, laser therapy, metronidazole, miltefosine, paromomycin, pentamidine, pentoxifylline, photodynamic therapy, rifampicin, and surgical excision of the entire lesion.⁸ A 2009 Cochrane review of the various treatments for cutaneous leishmaniasis concluded that “no general consensus on optimal treatment has been achieved” and suggested “the creation of an international platform to improve the quality and standardization of future trials in order to develop a better evidence-based approach.”⁸

Conclusion

Cutaneous leishmaniasis should be included in the differential diagnosis for travelers returning from endemic areas who present with new skin lesions. Since no specific lesion types are pathognomonic for cutaneous leishmaniasis, tissue biopsy for histopathology and PCR are essential for diagnosis. Prevention of cutaneous leishmaniasis hinges on appropriate counseling of travelers to endemic regions.

 

 

Prescription medications

Photo by Steven Harbour

 

Health experts are calling on US lawmakers and regulators to “close loopholes” in the Orphan Drug Act.

The experts say the loopholes can provide pharmaceutical companies with millions of dollars in unintended subsidies and tax breaks and fuel skyrocketing medication costs.

They argue that companies are exploiting gaps in the law by claiming orphan status for drugs that end up being marketed for more common conditions.

“The industry has been gaming the system by slicing and dicing indications so that drugs qualify for lucrative orphan status benefits,” says Martin Makary, MD, of Johns Hopkins Hospital in Baltimore, Maryland.

“As a result, funding support intended for rare disease medicine is diverted to fund the development of blockbuster drugs.”

Dr Makary and his colleagues express this viewpoint in a commentary published in the American Journal of Clinical Oncology.

The US Food and Drug Administration (FDA) grants orphan designation to encourage the development of drugs for diseases that affect fewer than 200,000 people in the US. The Orphan Drug Act was enacted in 1983 to provide incentives for drug companies to develop treatments for so-called orphan diseases that would be unprofitable because of the limited market.

Dr Makary and his colleagues say the legislation has accomplished that mission and sparked the development of life-saving therapies for a range of rare disorders. However, the authors say the law has also invited abuse.

Under the terms of the act, companies can receive federal taxpayer subsidies of up to half a million dollars a year for up to 4 years per drug, large tax credits, and waivers of marketing application fees that can cost more than $2 million. In addition, the FDA can grant companies 7 years of marketing exclusivity for an orphan drug to ensure that companies recoup the costs of research and development.

Dr Makary says companies exploit the law by initially listing only a single indication for a drug’s use—one narrow enough to qualify for orphan disease benefits. After FDA approval, however, some such drugs are marketed and used off-label more broadly, thus turning large profits.

“This is a financially toxic practice that is also unethical,” says study author Michael Daniel, also of Johns Hopkins.

“It’s time to ensure that we also render it illegal. The practice inflates drug prices, and the costs are passed on to consumers in the form of higher health insurance premiums.”

For example, the drug rituximab was originally approved to treat follicular B-cell non-Hodgkin lymphoma, a disease that affects about 14,000 patients a year. Now, rituximab is also used to treat several other types of cancer, organ rejection following kidney transplant, and autoimmune diseases, including rheumatoid arthritis, which affects 1.3 million Americans.

Rituximab, marketed under several trade names, is the top-selling medication approved as an orphan drug, the 12th all-time drug best-seller in the US, and it generated $3.7 billion in domestic sales in 2014.

In fact, 7 of the top 10 best-selling drugs in the US for 2014 came on the market with an orphan designation, according to Dr Makary and his colleagues.

Of the 41 drugs approved by the FDA in 2014, 18 had orphan status designations. The authors predict that, in 2015, orphan drugs will generate sales totaling $107 billion. And that number is expected to reach $176 billion by 2020.

Dr Makary says this projection represents a yearly growth rate of nearly 11%, or double the growth rate of the overall prescription drug market. The authors also cite data showing that, by 2020, orphan drugs are expected to account for 19% of global prescription drug sales, up from 6% in the year 2000.

Although the reasons for this boom in orphan drugs are likely multifactorial, the exploitation of the orphan drug act is an important catalyst behind this trend, the authors say.

Because orphan designation guarantees a 7-year exclusivity deal to market the drug and protects it from generic competition, the price tags for such medications often balloon rapidly.

For example, the drug imatinib was initially priced at $30,000 per year in 2001. By 2012, it cost $92,000 a year.

The drug’s original designation was for chronic myelogenous leukemia, and it would therefore treat 9000 patients a year in the US. Subsequently, imatinib was given 6 additional orphan designations for various conditions, including gastric cancers and immune disorders.

Dr Makary says, in essence, the exclusivity clause guarantees a hyperextended government-sponsored monopoly. So it’s not surprising that the median cost for orphan drugs is more than $98,000 per patient per year, compared with a median cost of just over $5000 per patient per year for drugs without orphan status.

Overall, nearly 15% of already approved orphan drugs subsequently add far more common diseases to their treatment repertoires.

Dr Makary and his colleagues recommend that, once a drug exceeds the basic tenets of the act—to treat fewer than 200,000 people—it should no longer receive government support or marketing exclusivity.

This can be achieved, the authors say, through pricing negotiations, clauses that reduce marketing exclusivity, and leveling of taxes once a medication becomes a blockbuster treatment for conditions not listed in the original FDA approval.

They say such measures would ensure the spirit of the original act is followed while continuing to provide critical economic incentives for truly rare diseases.

 

 

Prescription medications

Photo by Steven Harbour

 

Health experts are calling on US lawmakers and regulators to “close loopholes” in the Orphan Drug Act.

The experts say the loopholes can provide pharmaceutical companies with millions of dollars in unintended subsidies and tax breaks and fuel skyrocketing medication costs.

They argue that companies are exploiting gaps in the law by claiming orphan status for drugs that end up being marketed for more common conditions.

“The industry has been gaming the system by slicing and dicing indications so that drugs qualify for lucrative orphan status benefits,” says Martin Makary, MD, of Johns Hopkins Hospital in Baltimore, Maryland.

“As a result, funding support intended for rare disease medicine is diverted to fund the development of blockbuster drugs.”

Dr Makary and his colleagues express this viewpoint in a commentary published in the American Journal of Clinical Oncology.

The US Food and Drug Administration (FDA) grants orphan designation to encourage the development of drugs for diseases that affect fewer than 200,000 people in the US. The Orphan Drug Act was enacted in 1983 to provide incentives for drug companies to develop treatments for so-called orphan diseases that would be unprofitable because of the limited market.

Dr Makary and his colleagues say the legislation has accomplished that mission and sparked the development of life-saving therapies for a range of rare disorders. However, the authors say the law has also invited abuse.

Under the terms of the act, companies can receive federal taxpayer subsidies of up to half a million dollars a year for up to 4 years per drug, large tax credits, and waivers of marketing application fees that can cost more than $2 million. In addition, the FDA can grant companies 7 years of marketing exclusivity for an orphan drug to ensure that companies recoup the costs of research and development.

Dr Makary says companies exploit the law by initially listing only a single indication for a drug’s use—one narrow enough to qualify for orphan disease benefits. After FDA approval, however, some such drugs are marketed and used off-label more broadly, thus turning large profits.

“This is a financially toxic practice that is also unethical,” says study author Michael Daniel, also of Johns Hopkins.

“It’s time to ensure that we also render it illegal. The practice inflates drug prices, and the costs are passed on to consumers in the form of higher health insurance premiums.”

For example, the drug rituximab was originally approved to treat follicular B-cell non-Hodgkin lymphoma, a disease that affects about 14,000 patients a year. Now, rituximab is also used to treat several other types of cancer, organ rejection following kidney transplant, and autoimmune diseases, including rheumatoid arthritis, which affects 1.3 million Americans.

Rituximab, marketed under several trade names, is the top-selling medication approved as an orphan drug, the 12th all-time drug best-seller in the US, and it generated $3.7 billion in domestic sales in 2014.

In fact, 7 of the top 10 best-selling drugs in the US for 2014 came on the market with an orphan designation, according to Dr Makary and his colleagues.

Of the 41 drugs approved by the FDA in 2014, 18 had orphan status designations. The authors predict that, in 2015, orphan drugs will generate sales totaling $107 billion. And that number is expected to reach $176 billion by 2020.

Dr Makary says this projection represents a yearly growth rate of nearly 11%, or double the growth rate of the overall prescription drug market. The authors also cite data showing that, by 2020, orphan drugs are expected to account for 19% of global prescription drug sales, up from 6% in the year 2000.

Although the reasons for this boom in orphan drugs are likely multifactorial, the exploitation of the orphan drug act is an important catalyst behind this trend, the authors say.

Because orphan designation guarantees a 7-year exclusivity deal to market the drug and protects it from generic competition, the price tags for such medications often balloon rapidly.

For example, the drug imatinib was initially priced at $30,000 per year in 2001. By 2012, it cost $92,000 a year.

The drug’s original designation was for chronic myelogenous leukemia, and it would therefore treat 9000 patients a year in the US. Subsequently, imatinib was given 6 additional orphan designations for various conditions, including gastric cancers and immune disorders.

Dr Makary says, in essence, the exclusivity clause guarantees a hyperextended government-sponsored monopoly. So it’s not surprising that the median cost for orphan drugs is more than $98,000 per patient per year, compared with a median cost of just over $5000 per patient per year for drugs without orphan status.

Overall, nearly 15% of already approved orphan drugs subsequently add far more common diseases to their treatment repertoires.

Dr Makary and his colleagues recommend that, once a drug exceeds the basic tenets of the act—to treat fewer than 200,000 people—it should no longer receive government support or marketing exclusivity.

This can be achieved, the authors say, through pricing negotiations, clauses that reduce marketing exclusivity, and leveling of taxes once a medication becomes a blockbuster treatment for conditions not listed in the original FDA approval.

They say such measures would ensure the spirit of the original act is followed while continuing to provide critical economic incentives for truly rare diseases.

 

 

Prescription medications

Photo by Steven Harbour

 

Health experts are calling on US lawmakers and regulators to “close loopholes” in the Orphan Drug Act.

The experts say the loopholes can provide pharmaceutical companies with millions of dollars in unintended subsidies and tax breaks and fuel skyrocketing medication costs.

They argue that companies are exploiting gaps in the law by claiming orphan status for drugs that end up being marketed for more common conditions.

“The industry has been gaming the system by slicing and dicing indications so that drugs qualify for lucrative orphan status benefits,” says Martin Makary, MD, of Johns Hopkins Hospital in Baltimore, Maryland.

“As a result, funding support intended for rare disease medicine is diverted to fund the development of blockbuster drugs.”

Dr Makary and his colleagues express this viewpoint in a commentary published in the American Journal of Clinical Oncology.

The US Food and Drug Administration (FDA) grants orphan designation to encourage the development of drugs for diseases that affect fewer than 200,000 people in the US. The Orphan Drug Act was enacted in 1983 to provide incentives for drug companies to develop treatments for so-called orphan diseases that would be unprofitable because of the limited market.

Dr Makary and his colleagues say the legislation has accomplished that mission and sparked the development of life-saving therapies for a range of rare disorders. However, the authors say the law has also invited abuse.

Under the terms of the act, companies can receive federal taxpayer subsidies of up to half a million dollars a year for up to 4 years per drug, large tax credits, and waivers of marketing application fees that can cost more than $2 million. In addition, the FDA can grant companies 7 years of marketing exclusivity for an orphan drug to ensure that companies recoup the costs of research and development.

Dr Makary says companies exploit the law by initially listing only a single indication for a drug’s use—one narrow enough to qualify for orphan disease benefits. After FDA approval, however, some such drugs are marketed and used off-label more broadly, thus turning large profits.

“This is a financially toxic practice that is also unethical,” says study author Michael Daniel, also of Johns Hopkins.

“It’s time to ensure that we also render it illegal. The practice inflates drug prices, and the costs are passed on to consumers in the form of higher health insurance premiums.”

For example, the drug rituximab was originally approved to treat follicular B-cell non-Hodgkin lymphoma, a disease that affects about 14,000 patients a year. Now, rituximab is also used to treat several other types of cancer, organ rejection following kidney transplant, and autoimmune diseases, including rheumatoid arthritis, which affects 1.3 million Americans.

Rituximab, marketed under several trade names, is the top-selling medication approved as an orphan drug, the 12th all-time drug best-seller in the US, and it generated $3.7 billion in domestic sales in 2014.

In fact, 7 of the top 10 best-selling drugs in the US for 2014 came on the market with an orphan designation, according to Dr Makary and his colleagues.

Of the 41 drugs approved by the FDA in 2014, 18 had orphan status designations. The authors predict that, in 2015, orphan drugs will generate sales totaling $107 billion. And that number is expected to reach $176 billion by 2020.

Dr Makary says this projection represents a yearly growth rate of nearly 11%, or double the growth rate of the overall prescription drug market. The authors also cite data showing that, by 2020, orphan drugs are expected to account for 19% of global prescription drug sales, up from 6% in the year 2000.

Although the reasons for this boom in orphan drugs are likely multifactorial, the exploitation of the orphan drug act is an important catalyst behind this trend, the authors say.

Because orphan designation guarantees a 7-year exclusivity deal to market the drug and protects it from generic competition, the price tags for such medications often balloon rapidly.

For example, the drug imatinib was initially priced at $30,000 per year in 2001. By 2012, it cost $92,000 a year.

The drug’s original designation was for chronic myelogenous leukemia, and it would therefore treat 9000 patients a year in the US. Subsequently, imatinib was given 6 additional orphan designations for various conditions, including gastric cancers and immune disorders.

Dr Makary says, in essence, the exclusivity clause guarantees a hyperextended government-sponsored monopoly. So it’s not surprising that the median cost for orphan drugs is more than $98,000 per patient per year, compared with a median cost of just over $5000 per patient per year for drugs without orphan status.

Overall, nearly 15% of already approved orphan drugs subsequently add far more common diseases to their treatment repertoires.

Dr Makary and his colleagues recommend that, once a drug exceeds the basic tenets of the act—to treat fewer than 200,000 people—it should no longer receive government support or marketing exclusivity.

This can be achieved, the authors say, through pricing negotiations, clauses that reduce marketing exclusivity, and leveling of taxes once a medication becomes a blockbuster treatment for conditions not listed in the original FDA approval.

They say such measures would ensure the spirit of the original act is followed while continuing to provide critical economic incentives for truly rare diseases.