Jennie Smith

The American College of Cardiology Foundation and the American Heart Association have published updated guidelines for managing patients with unstable angina/non–ST elevation myocardial infarction, taking into consideration the use of a newer agent, prasugrel, as an alternative to clopidogrel, and recommending diagnostic angiography sooner for patients at high risk, among other changes.

The guidelines, published March 28 in the Journal of the American College of Cardiology (Am. J. Cardiol. 2011 March 28 [doi:10.1016/j.jacc.2011.02.009]) and based on the most recent clinical trial evidence available, update recommendations from 2007, and include several changes clinicians should be aware of, the guidelines’ lead author, Dr. R. Scott Wright of the Mayo Clinic in Rochester, Minn., said in an e-mail interview. These are, in order of importance:

• The timing of invasive therapy in medium- and high-risk patients.

• The role of triple- vs. dual-antiplatelet therapy in patients at medium and high risk.

• The role of invasive therapy in patients with chronic kidney disease.

• The importance of participating in quality improvement processes.

• The role of prasugrel in non–ST elevation acute coronary syndrome.

Clinicians face tough decisions about when to perform an invasive strategy such as diagnostic coronary angiography – whether within hours of presentation or days, Dr. Wright and his colleagues wrote in their analysis. Immediate catheterization with revascularization of unstable coronary lesions may prevent ischemic events that would otherwise occur during medical therapy – but pretreatment with antithrombotics "may diminish thrombus burden and ‘passivate’ unstable plaques," improving the safety of the procedure and reducing the risk of ischemic complications.

The new guidelines, based on findings from three randomized controlled trials evaluating the timing of angiography, recommend an early invasive strategy (12-24 hours after presentation) over a delayed invasive strategy (more than 24 hours after presentation) for initially stabilized high-risk patients with UA/NSTEMI.

"For patients not at high risk, a delayed invasive approach is also reasonable," Dr. Wright and his colleagues wrote.

Several changes to earlier recommendations for antiplatelet therapy are contained in the new guidelines, including altered loading doses for clopidogrel to counter the potential for the drug to be less effective in some patient groups, and the addition of prasugrel, which was approved by the Food and Drug Administration after the last guidelines were published.

Prasugrel, in a randomized controlled trial comparing it with clopidogrel, was shown to be superior in reducing clinical events but at the expense of an increased risk of bleeding, the guideline writers noted. In March 2010 the FDA issued a warning that in some patient groups clopidogrel is less effective than it should be because of a genetic variant that inhibits the body’s conversion of the prodrug to the drug.

However, Dr. Wright and his colleagues stopped short of endorsing prasugrel as a first choice over clopidogrel because of the higher bleeding risk and other considerations. People aged 75 years or older, those with a history of transient ischemic attack or stroke or with active pathological bleeding, and people weighing less than 60 kg saw no benefit and/or net harm from prasugrel, they noted.

Dr. Wright and his colleagues also changed recommendations involving glycoprotein IIB/IIIa inhibitors, noting that recent studies "more strongly support a strategy of selective rather than provisional use of GP IIb/IIIa inhibitor therapy as part of triple-antiplatelet therapy," due to concerns about the potential bleeding risks. Therefore, according to the new guidelines, for UA/NSTEMI patients who are at low risk of ischemic events or at high risk of bleeding and who are already receiving aspirin and clopidogrel, upstream GP IIb/IIIa inhibitors are not recommended.

People with kidney disease should receive adequate preparatory hydration before catheterization, say the new guidelines, which also tweak earlier recommendations about the contrast agents used in angiography. Finally, the guidelines recommend that clinicians and hospitals "participate in a standardized quality-of-care data registry designed to track and measure outcomes, complications, and adherence to evidence-based processes of care and quality improvement for UA/NSTEMI." No such recommendation had been included in the 2007 guidelines.

Dr. Wright declared no conflicts of interest. Several of Dr. Wright’s coauthors, including Dr. Jeffrey L. Anderson, the writing committee’s vice chair, disclosed consultant relationships with pharmaceutical firms Sanofi-Aventis, Bristol Myers-Squibb, Lilly, and Daiichi. Members with conflicts were not permitted to vote on recommended drug therapies.

The American College of Cardiology Foundation and the American Heart Association have published updated guidelines for managing patients with unstable angina/non–ST elevation myocardial infarction, taking into consideration the use of a newer agent, prasugrel, as an alternative to clopidogrel, and recommending diagnostic angiography sooner for patients at high risk, among other changes.

The guidelines, published March 28 in the Journal of the American College of Cardiology (Am. J. Cardiol. 2011 March 28 [doi:10.1016/j.jacc.2011.02.009]) and based on the most recent clinical trial evidence available, update recommendations from 2007, and include several changes clinicians should be aware of, the guidelines’ lead author, Dr. R. Scott Wright of the Mayo Clinic in Rochester, Minn., said in an e-mail interview. These are, in order of importance:

• The timing of invasive therapy in medium- and high-risk patients.

• The role of triple- vs. dual-antiplatelet therapy in patients at medium and high risk.

• The role of invasive therapy in patients with chronic kidney disease.

• The importance of participating in quality improvement processes.

• The role of prasugrel in non–ST elevation acute coronary syndrome.

Clinicians face tough decisions about when to perform an invasive strategy such as diagnostic coronary angiography – whether within hours of presentation or days, Dr. Wright and his colleagues wrote in their analysis. Immediate catheterization with revascularization of unstable coronary lesions may prevent ischemic events that would otherwise occur during medical therapy – but pretreatment with antithrombotics "may diminish thrombus burden and ‘passivate’ unstable plaques," improving the safety of the procedure and reducing the risk of ischemic complications.

The new guidelines, based on findings from three randomized controlled trials evaluating the timing of angiography, recommend an early invasive strategy (12-24 hours after presentation) over a delayed invasive strategy (more than 24 hours after presentation) for initially stabilized high-risk patients with UA/NSTEMI.

"For patients not at high risk, a delayed invasive approach is also reasonable," Dr. Wright and his colleagues wrote.

Several changes to earlier recommendations for antiplatelet therapy are contained in the new guidelines, including altered loading doses for clopidogrel to counter the potential for the drug to be less effective in some patient groups, and the addition of prasugrel, which was approved by the Food and Drug Administration after the last guidelines were published.

Prasugrel, in a randomized controlled trial comparing it with clopidogrel, was shown to be superior in reducing clinical events but at the expense of an increased risk of bleeding, the guideline writers noted. In March 2010 the FDA issued a warning that in some patient groups clopidogrel is less effective than it should be because of a genetic variant that inhibits the body’s conversion of the prodrug to the drug.

However, Dr. Wright and his colleagues stopped short of endorsing prasugrel as a first choice over clopidogrel because of the higher bleeding risk and other considerations. People aged 75 years or older, those with a history of transient ischemic attack or stroke or with active pathological bleeding, and people weighing less than 60 kg saw no benefit and/or net harm from prasugrel, they noted.

Dr. Wright and his colleagues also changed recommendations involving glycoprotein IIB/IIIa inhibitors, noting that recent studies "more strongly support a strategy of selective rather than provisional use of GP IIb/IIIa inhibitor therapy as part of triple-antiplatelet therapy," due to concerns about the potential bleeding risks. Therefore, according to the new guidelines, for UA/NSTEMI patients who are at low risk of ischemic events or at high risk of bleeding and who are already receiving aspirin and clopidogrel, upstream GP IIb/IIIa inhibitors are not recommended.

People with kidney disease should receive adequate preparatory hydration before catheterization, say the new guidelines, which also tweak earlier recommendations about the contrast agents used in angiography. Finally, the guidelines recommend that clinicians and hospitals "participate in a standardized quality-of-care data registry designed to track and measure outcomes, complications, and adherence to evidence-based processes of care and quality improvement for UA/NSTEMI." No such recommendation had been included in the 2007 guidelines.

Dr. Wright declared no conflicts of interest. Several of Dr. Wright’s coauthors, including Dr. Jeffrey L. Anderson, the writing committee’s vice chair, disclosed consultant relationships with pharmaceutical firms Sanofi-Aventis, Bristol Myers-Squibb, Lilly, and Daiichi. Members with conflicts were not permitted to vote on recommended drug therapies.

The American College of Cardiology Foundation and the American Heart Association have published updated guidelines for managing patients with unstable angina/non–ST elevation myocardial infarction, taking into consideration the use of a newer agent, prasugrel, as an alternative to clopidogrel, and recommending diagnostic angiography sooner for patients at high risk, among other changes.

The guidelines, published March 28 in the Journal of the American College of Cardiology (Am. J. Cardiol. 2011 March 28 [doi:10.1016/j.jacc.2011.02.009]) and based on the most recent clinical trial evidence available, update recommendations from 2007, and include several changes clinicians should be aware of, the guidelines’ lead author, Dr. R. Scott Wright of the Mayo Clinic in Rochester, Minn., said in an e-mail interview. These are, in order of importance:

• The timing of invasive therapy in medium- and high-risk patients.

• The role of triple- vs. dual-antiplatelet therapy in patients at medium and high risk.

• The role of invasive therapy in patients with chronic kidney disease.

• The importance of participating in quality improvement processes.

• The role of prasugrel in non–ST elevation acute coronary syndrome.

Clinicians face tough decisions about when to perform an invasive strategy such as diagnostic coronary angiography – whether within hours of presentation or days, Dr. Wright and his colleagues wrote in their analysis. Immediate catheterization with revascularization of unstable coronary lesions may prevent ischemic events that would otherwise occur during medical therapy – but pretreatment with antithrombotics "may diminish thrombus burden and ‘passivate’ unstable plaques," improving the safety of the procedure and reducing the risk of ischemic complications.

The new guidelines, based on findings from three randomized controlled trials evaluating the timing of angiography, recommend an early invasive strategy (12-24 hours after presentation) over a delayed invasive strategy (more than 24 hours after presentation) for initially stabilized high-risk patients with UA/NSTEMI.

"For patients not at high risk, a delayed invasive approach is also reasonable," Dr. Wright and his colleagues wrote.

Several changes to earlier recommendations for antiplatelet therapy are contained in the new guidelines, including altered loading doses for clopidogrel to counter the potential for the drug to be less effective in some patient groups, and the addition of prasugrel, which was approved by the Food and Drug Administration after the last guidelines were published.

Prasugrel, in a randomized controlled trial comparing it with clopidogrel, was shown to be superior in reducing clinical events but at the expense of an increased risk of bleeding, the guideline writers noted. In March 2010 the FDA issued a warning that in some patient groups clopidogrel is less effective than it should be because of a genetic variant that inhibits the body’s conversion of the prodrug to the drug.

However, Dr. Wright and his colleagues stopped short of endorsing prasugrel as a first choice over clopidogrel because of the higher bleeding risk and other considerations. People aged 75 years or older, those with a history of transient ischemic attack or stroke or with active pathological bleeding, and people weighing less than 60 kg saw no benefit and/or net harm from prasugrel, they noted.

Dr. Wright and his colleagues also changed recommendations involving glycoprotein IIB/IIIa inhibitors, noting that recent studies "more strongly support a strategy of selective rather than provisional use of GP IIb/IIIa inhibitor therapy as part of triple-antiplatelet therapy," due to concerns about the potential bleeding risks. Therefore, according to the new guidelines, for UA/NSTEMI patients who are at low risk of ischemic events or at high risk of bleeding and who are already receiving aspirin and clopidogrel, upstream GP IIb/IIIa inhibitors are not recommended.

People with kidney disease should receive adequate preparatory hydration before catheterization, say the new guidelines, which also tweak earlier recommendations about the contrast agents used in angiography. Finally, the guidelines recommend that clinicians and hospitals "participate in a standardized quality-of-care data registry designed to track and measure outcomes, complications, and adherence to evidence-based processes of care and quality improvement for UA/NSTEMI." No such recommendation had been included in the 2007 guidelines.

Dr. Wright declared no conflicts of interest. Several of Dr. Wright’s coauthors, including Dr. Jeffrey L. Anderson, the writing committee’s vice chair, disclosed consultant relationships with pharmaceutical firms Sanofi-Aventis, Bristol Myers-Squibb, Lilly, and Daiichi. Members with conflicts were not permitted to vote on recommended drug therapies.

A new, faster screening protocol can identify patients at a very low risk of cardiovascular events when they present to the emergency department with chest pain, allowing them to be safely discharged in 2 hours instead of the usual 6 or more, a New Zealand–based team of researchers has found.

The "accelerated diagnostic protocol," or ADP, evaluated in the study consists of three widely available measures: a patient’s thrombolysis in myocardial infarction, or TIMI, score; an electrocardiograph; and a biomarker panel of troponin, creatine kinase MB, and myoglobin. The current standard of care consists of serial sampling of cardiac troponin over 6 hours from the onset of symptoms.

In an article published March 23 in The Lancet (doi:10.1016/S01406736(11)603103), the Christchurch, New Zealand, team, led by Dr. Martin Than of Christchurch Hospital, investigated the protocol in the Asia-Pacific Evaluation of Chest Pain Trial (ASPECT), which included 3,582 consecutive patients presenting with chest pain suggestive of acute coronary syndromes at hospitals in nine countries in the Asia-Pacific region. All patients were followed up for a month. Study participants were mostly older, men, and either white or Chinese, they wrote.

Of the study subjects, just under a tenth (352) qualified for early discharge under the protocol. This meant that they had a TIMI risk score of 0 (out of 7), no ischemic ECG changes, and normal pointofcare triplemarker panels at presentation and 2 hours later.

The study’s primary end point was a major adverse cardiac event within the 30 days of follow-up, including death that was not clearly noncardiac, myocardial infarction, cardiogenic shock, and arrhythmia or atrioventricular block requiring intervention. A major adverse cardiac event occurred in three (0.9%) of the ADP-screened patients, Dr. Than and colleagues reported, giving the protocol a sensitivity of 99.3%, a negative predictive value of 99.1%, and a specificity of 11%.

"The near 10% possible reduction in patients needing prolonged assessment in this large patient group could reduce overcrowding in hospitals and emergency departments and provide earlier reassurance and greater convenience for patients," Dr. Than and colleagues wrote in discussing their findings.

They acknowledged as among the trial’s weaknesses its observational design and the protocol’s low specificity, which they described as commensurate with that of other diagnostic instruments to exclude acute coronary syndromes.

They also pointed out that "patients without chest pain but who presented with atypical symptoms (fatigue, nausea, vomiting, diaphoresis, faintness, and back pain) were not included in this trial," and that the researchers could not tell how many presented with those symptoms. "Thus," they wrote, "the applicability of the ADP is limited to the selected cohort of patients with chest pain (or discomfort) suggestive of acute coronary syndromes for whom the attending physician planned to investigate for these syndromes."

Dr. Than and six of his 26 coauthors disclosed having received grants and supplies, speaking honoraria, travel expenses or a combination of these from Alere Medical, a maker of diagnostic tests and equipment and the major funding source of the study. Eight other investigators received travel support from Alere to attend meetings.

In an editorial comment (Lancet 2011 March 23 [doi:10.1016/S01406736(11)603929]) accompanying Dr. Than and colleagues’ article, Dr. Richard Body of the Cardiovascular Research Group at the University of Manchester (England), noted that "the need for an effective rapid rule-out strategy to facilitate early discharge from the emergency department has been appreciated for over 20 years," and yet none has been widely adopted.

Dr. Body praised Dr. Than and colleagues’ study as "well designed to achieve its objectives," and showing "that it is possible to achieve an acceptably high sensitivity when triplemarker testing is used in the appropriate population."

However, he cautioned, the triple-marker testing alone had a sensitivity of only 82.9%. The overall sensitivity of the protocol "increased to an acceptable level because of the application of Bayesian principles, with biomarker testing only in patients with a low pretest probability of disease."

Most people "will probably consider this net risk to be statistically acceptable," Dr. Body wrote. "However, if properly informed, low-risk patients might feel differently about the relative merits of waiting for definitive 6h laboratory-based troponin testing or going home after 2 h on the basis of results from a test that correctly identifies serious coronary disease, when present, in just over eight of ten occasions."

Dr. Body advised that Dr. Than and colleagues’ findings be considered in light of other diagnostic tools. One newer troponin assay can detect with 90% sensitivity for acute myocardial infarction at presentation, he pointed out, and other "promising" biomarkers are being studied. "It therefore remains important that triplemarker testing is compared with some of these more recent alternatives," Dr. Body wrote.

Dr. Body disclosed having received past donations of research supplies from diagnostics firms owned by Roche, Siemens, and Alere, along with travel reimbursements from Roche and Randox.

The study was funded by Alere Medical, a maker of diagnostic tests and equipment, which provided grants and other direct funding to seven investigators and travel funding to eight others. Investigators in some countries received country-specific funding from other companies including Indonesian medical equipment maker, Medquest Jaya Global, and manufacturers Science International of Hong Kong, Bio Laboratories of Singapore and Progressive Group of Taiwan.

The sponsors had no role in the study or the report, the authors declared.

A new, faster screening protocol can identify patients at a very low risk of cardiovascular events when they present to the emergency department with chest pain, allowing them to be safely discharged in 2 hours instead of the usual 6 or more, a New Zealand–based team of researchers has found.

The "accelerated diagnostic protocol," or ADP, evaluated in the study consists of three widely available measures: a patient’s thrombolysis in myocardial infarction, or TIMI, score; an electrocardiograph; and a biomarker panel of troponin, creatine kinase MB, and myoglobin. The current standard of care consists of serial sampling of cardiac troponin over 6 hours from the onset of symptoms.

In an article published March 23 in The Lancet (doi:10.1016/S01406736(11)603103), the Christchurch, New Zealand, team, led by Dr. Martin Than of Christchurch Hospital, investigated the protocol in the Asia-Pacific Evaluation of Chest Pain Trial (ASPECT), which included 3,582 consecutive patients presenting with chest pain suggestive of acute coronary syndromes at hospitals in nine countries in the Asia-Pacific region. All patients were followed up for a month. Study participants were mostly older, men, and either white or Chinese, they wrote.

Of the study subjects, just under a tenth (352) qualified for early discharge under the protocol. This meant that they had a TIMI risk score of 0 (out of 7), no ischemic ECG changes, and normal pointofcare triplemarker panels at presentation and 2 hours later.

The study’s primary end point was a major adverse cardiac event within the 30 days of follow-up, including death that was not clearly noncardiac, myocardial infarction, cardiogenic shock, and arrhythmia or atrioventricular block requiring intervention. A major adverse cardiac event occurred in three (0.9%) of the ADP-screened patients, Dr. Than and colleagues reported, giving the protocol a sensitivity of 99.3%, a negative predictive value of 99.1%, and a specificity of 11%.

"The near 10% possible reduction in patients needing prolonged assessment in this large patient group could reduce overcrowding in hospitals and emergency departments and provide earlier reassurance and greater convenience for patients," Dr. Than and colleagues wrote in discussing their findings.

They acknowledged as among the trial’s weaknesses its observational design and the protocol’s low specificity, which they described as commensurate with that of other diagnostic instruments to exclude acute coronary syndromes.

They also pointed out that "patients without chest pain but who presented with atypical symptoms (fatigue, nausea, vomiting, diaphoresis, faintness, and back pain) were not included in this trial," and that the researchers could not tell how many presented with those symptoms. "Thus," they wrote, "the applicability of the ADP is limited to the selected cohort of patients with chest pain (or discomfort) suggestive of acute coronary syndromes for whom the attending physician planned to investigate for these syndromes."

Dr. Than and six of his 26 coauthors disclosed having received grants and supplies, speaking honoraria, travel expenses or a combination of these from Alere Medical, a maker of diagnostic tests and equipment and the major funding source of the study. Eight other investigators received travel support from Alere to attend meetings.

In an editorial comment (Lancet 2011 March 23 [doi:10.1016/S01406736(11)603929]) accompanying Dr. Than and colleagues’ article, Dr. Richard Body of the Cardiovascular Research Group at the University of Manchester (England), noted that "the need for an effective rapid rule-out strategy to facilitate early discharge from the emergency department has been appreciated for over 20 years," and yet none has been widely adopted.

Dr. Body praised Dr. Than and colleagues’ study as "well designed to achieve its objectives," and showing "that it is possible to achieve an acceptably high sensitivity when triplemarker testing is used in the appropriate population."

However, he cautioned, the triple-marker testing alone had a sensitivity of only 82.9%. The overall sensitivity of the protocol "increased to an acceptable level because of the application of Bayesian principles, with biomarker testing only in patients with a low pretest probability of disease."

Most people "will probably consider this net risk to be statistically acceptable," Dr. Body wrote. "However, if properly informed, low-risk patients might feel differently about the relative merits of waiting for definitive 6h laboratory-based troponin testing or going home after 2 h on the basis of results from a test that correctly identifies serious coronary disease, when present, in just over eight of ten occasions."

Dr. Body advised that Dr. Than and colleagues’ findings be considered in light of other diagnostic tools. One newer troponin assay can detect with 90% sensitivity for acute myocardial infarction at presentation, he pointed out, and other "promising" biomarkers are being studied. "It therefore remains important that triplemarker testing is compared with some of these more recent alternatives," Dr. Body wrote.

Dr. Body disclosed having received past donations of research supplies from diagnostics firms owned by Roche, Siemens, and Alere, along with travel reimbursements from Roche and Randox.

The study was funded by Alere Medical, a maker of diagnostic tests and equipment, which provided grants and other direct funding to seven investigators and travel funding to eight others. Investigators in some countries received country-specific funding from other companies including Indonesian medical equipment maker, Medquest Jaya Global, and manufacturers Science International of Hong Kong, Bio Laboratories of Singapore and Progressive Group of Taiwan.

The sponsors had no role in the study or the report, the authors declared.

A new, faster screening protocol can identify patients at a very low risk of cardiovascular events when they present to the emergency department with chest pain, allowing them to be safely discharged in 2 hours instead of the usual 6 or more, a New Zealand–based team of researchers has found.

The "accelerated diagnostic protocol," or ADP, evaluated in the study consists of three widely available measures: a patient’s thrombolysis in myocardial infarction, or TIMI, score; an electrocardiograph; and a biomarker panel of troponin, creatine kinase MB, and myoglobin. The current standard of care consists of serial sampling of cardiac troponin over 6 hours from the onset of symptoms.

In an article published March 23 in The Lancet (doi:10.1016/S01406736(11)603103), the Christchurch, New Zealand, team, led by Dr. Martin Than of Christchurch Hospital, investigated the protocol in the Asia-Pacific Evaluation of Chest Pain Trial (ASPECT), which included 3,582 consecutive patients presenting with chest pain suggestive of acute coronary syndromes at hospitals in nine countries in the Asia-Pacific region. All patients were followed up for a month. Study participants were mostly older, men, and either white or Chinese, they wrote.

Of the study subjects, just under a tenth (352) qualified for early discharge under the protocol. This meant that they had a TIMI risk score of 0 (out of 7), no ischemic ECG changes, and normal pointofcare triplemarker panels at presentation and 2 hours later.

The study’s primary end point was a major adverse cardiac event within the 30 days of follow-up, including death that was not clearly noncardiac, myocardial infarction, cardiogenic shock, and arrhythmia or atrioventricular block requiring intervention. A major adverse cardiac event occurred in three (0.9%) of the ADP-screened patients, Dr. Than and colleagues reported, giving the protocol a sensitivity of 99.3%, a negative predictive value of 99.1%, and a specificity of 11%.

"The near 10% possible reduction in patients needing prolonged assessment in this large patient group could reduce overcrowding in hospitals and emergency departments and provide earlier reassurance and greater convenience for patients," Dr. Than and colleagues wrote in discussing their findings.

They acknowledged as among the trial’s weaknesses its observational design and the protocol’s low specificity, which they described as commensurate with that of other diagnostic instruments to exclude acute coronary syndromes.

They also pointed out that "patients without chest pain but who presented with atypical symptoms (fatigue, nausea, vomiting, diaphoresis, faintness, and back pain) were not included in this trial," and that the researchers could not tell how many presented with those symptoms. "Thus," they wrote, "the applicability of the ADP is limited to the selected cohort of patients with chest pain (or discomfort) suggestive of acute coronary syndromes for whom the attending physician planned to investigate for these syndromes."

Dr. Than and six of his 26 coauthors disclosed having received grants and supplies, speaking honoraria, travel expenses or a combination of these from Alere Medical, a maker of diagnostic tests and equipment and the major funding source of the study. Eight other investigators received travel support from Alere to attend meetings.

In an editorial comment (Lancet 2011 March 23 [doi:10.1016/S01406736(11)603929]) accompanying Dr. Than and colleagues’ article, Dr. Richard Body of the Cardiovascular Research Group at the University of Manchester (England), noted that "the need for an effective rapid rule-out strategy to facilitate early discharge from the emergency department has been appreciated for over 20 years," and yet none has been widely adopted.

Dr. Body praised Dr. Than and colleagues’ study as "well designed to achieve its objectives," and showing "that it is possible to achieve an acceptably high sensitivity when triplemarker testing is used in the appropriate population."

However, he cautioned, the triple-marker testing alone had a sensitivity of only 82.9%. The overall sensitivity of the protocol "increased to an acceptable level because of the application of Bayesian principles, with biomarker testing only in patients with a low pretest probability of disease."

Most people "will probably consider this net risk to be statistically acceptable," Dr. Body wrote. "However, if properly informed, low-risk patients might feel differently about the relative merits of waiting for definitive 6h laboratory-based troponin testing or going home after 2 h on the basis of results from a test that correctly identifies serious coronary disease, when present, in just over eight of ten occasions."

Dr. Body advised that Dr. Than and colleagues’ findings be considered in light of other diagnostic tools. One newer troponin assay can detect with 90% sensitivity for acute myocardial infarction at presentation, he pointed out, and other "promising" biomarkers are being studied. "It therefore remains important that triplemarker testing is compared with some of these more recent alternatives," Dr. Body wrote.

Dr. Body disclosed having received past donations of research supplies from diagnostics firms owned by Roche, Siemens, and Alere, along with travel reimbursements from Roche and Randox.

The study was funded by Alere Medical, a maker of diagnostic tests and equipment, which provided grants and other direct funding to seven investigators and travel funding to eight others. Investigators in some countries received country-specific funding from other companies including Indonesian medical equipment maker, Medquest Jaya Global, and manufacturers Science International of Hong Kong, Bio Laboratories of Singapore and Progressive Group of Taiwan.

The sponsors had no role in the study or the report, the authors declared.

A new, faster screening protocol can identify patients at a very low risk of cardiovascular events when they present to the emergency department with chest pain, allowing them to be safely discharged in 2 hours instead of the usual 6 or more, a New Zealand–based team of researchers has found.

The "accelerated diagnostic protocol," or ADP, evaluated in the study consists of three widely available measures: a patient’s thrombolysis in myocardial infarction, or TIMI, score; an electrocardiograph; and a biomarker panel of troponin, creatine kinase MB, and myoglobin. The current standard of care consists of serial sampling of cardiac troponin over 6 hours from the onset of symptoms.

In an article published March 23 in The Lancet (doi:10.1016/S01406736(11)603103), the Christchurch, New Zealand, team, led by Dr. Martin Than of Christchurch Hospital, investigated the protocol in the Asia-Pacific Evaluation of Chest Pain Trial (ASPECT), which included 3,582 consecutive patients presenting with chest pain suggestive of acute coronary syndromes at hospitals in nine countries in the Asia-Pacific region. All patients were followed up for a month. Study participants were mostly older, men, and either white or Chinese, they wrote.

Of the study subjects, just under a tenth (352) qualified for early discharge under the protocol. This meant that they had a TIMI risk score of 0 (out of 7), no ischemic ECG changes, and normal pointofcare triplemarker panels at presentation and 2 hours later.

The study’s primary end point was a major adverse cardiac event within the 30 days of follow-up, including death that was not clearly noncardiac, myocardial infarction, cardiogenic shock, and arrhythmia or atrioventricular block requiring intervention. A major adverse cardiac event occurred in three (0.9%) of the ADP-screened patients, Dr. Than and colleagues reported, giving the protocol a sensitivity of 99.3%, a negative predictive value of 99.1%, and a specificity of 11%.

"The near 10% possible reduction in patients needing prolonged assessment in this large patient group could reduce overcrowding in hospitals and emergency departments and provide earlier reassurance and greater convenience for patients," Dr. Than and colleagues wrote in discussing their findings.

They acknowledged as among the trial’s weaknesses its observational design and the protocol’s low specificity, which they described as commensurate with that of other diagnostic instruments to exclude acute coronary syndromes.

They also pointed out that "patients without chest pain but who presented with atypical symptoms (fatigue, nausea, vomiting, diaphoresis, faintness, and back pain) were not included in this trial," and that the researchers could not tell how many presented with those symptoms. "Thus," they wrote, "the applicability of the ADP is limited to the selected cohort of patients with chest pain (or discomfort) suggestive of acute coronary syndromes for whom the attending physician planned to investigate for these syndromes."

Dr. Than and six of his 26 coauthors disclosed having received grants and supplies, speaking honoraria, travel expenses or a combination of these from Alere Medical, a maker of diagnostic tests and equipment and the major funding source of the study. Eight other investigators received travel support from Alere to attend meetings.

In an editorial comment (Lancet 2011 March 23 [doi:10.1016/S01406736(11)603929]) accompanying Dr. Than and colleagues’ article, Dr. Richard Body of the Cardiovascular Research Group at the University of Manchester (England), noted that "the need for an effective rapid rule-out strategy to facilitate early discharge from the emergency department has been appreciated for over 20 years," and yet none has been widely adopted.

Dr. Body praised Dr. Than and colleagues’ study as "well designed to achieve its objectives," and showing "that it is possible to achieve an acceptably high sensitivity when triplemarker testing is used in the appropriate population."

However, he cautioned, the triple-marker testing alone had a sensitivity of only 82.9%. The overall sensitivity of the protocol "increased to an acceptable level because of the application of Bayesian principles, with biomarker testing only in patients with a low pretest probability of disease."

Most people "will probably consider this net risk to be statistically acceptable," Dr. Body wrote. "However, if properly informed, low-risk patients might feel differently about the relative merits of waiting for definitive 6h laboratory-based troponin testing or going home after 2 h on the basis of results from a test that correctly identifies serious coronary disease, when present, in just over eight of ten occasions."

Dr. Body advised that Dr. Than and colleagues’ findings be considered in light of other diagnostic tools. One newer troponin assay can detect with 90% sensitivity for acute myocardial infarction at presentation, he pointed out, and other "promising" biomarkers are being studied. "It therefore remains important that triplemarker testing is compared with some of these more recent alternatives," Dr. Body wrote.

Dr. Body disclosed having received past donations of research supplies from diagnostics firms owned by Roche, Siemens, and Alere, along with travel reimbursements from Roche and Randox.

The study was funded by Alere Medical, a maker of diagnostic tests and equipment, which provided grants and other direct funding to seven investigators and travel funding to eight others. Investigators in some countries received country-specific funding from other companies including Indonesian medical equipment maker, Medquest Jaya Global, and manufacturers Science International of Hong Kong, Bio Laboratories of Singapore and Progressive Group of Taiwan.

The sponsors had no role in the study or the report, the authors declared.

A new, faster screening protocol can identify patients at a very low risk of cardiovascular events when they present to the emergency department with chest pain, allowing them to be safely discharged in 2 hours instead of the usual 6 or more, a New Zealand–based team of researchers has found.

The "accelerated diagnostic protocol," or ADP, evaluated in the study consists of three widely available measures: a patient’s thrombolysis in myocardial infarction, or TIMI, score; an electrocardiograph; and a biomarker panel of troponin, creatine kinase MB, and myoglobin. The current standard of care consists of serial sampling of cardiac troponin over 6 hours from the onset of symptoms.

In an article published March 23 in The Lancet (doi:10.1016/S01406736(11)603103), the Christchurch, New Zealand, team, led by Dr. Martin Than of Christchurch Hospital, investigated the protocol in the Asia-Pacific Evaluation of Chest Pain Trial (ASPECT), which included 3,582 consecutive patients presenting with chest pain suggestive of acute coronary syndromes at hospitals in nine countries in the Asia-Pacific region. All patients were followed up for a month. Study participants were mostly older, men, and either white or Chinese, they wrote.

Of the study subjects, just under a tenth (352) qualified for early discharge under the protocol. This meant that they had a TIMI risk score of 0 (out of 7), no ischemic ECG changes, and normal pointofcare triplemarker panels at presentation and 2 hours later.

The study’s primary end point was a major adverse cardiac event within the 30 days of follow-up, including death that was not clearly noncardiac, myocardial infarction, cardiogenic shock, and arrhythmia or atrioventricular block requiring intervention. A major adverse cardiac event occurred in three (0.9%) of the ADP-screened patients, Dr. Than and colleagues reported, giving the protocol a sensitivity of 99.3%, a negative predictive value of 99.1%, and a specificity of 11%.

"The near 10% possible reduction in patients needing prolonged assessment in this large patient group could reduce overcrowding in hospitals and emergency departments and provide earlier reassurance and greater convenience for patients," Dr. Than and colleagues wrote in discussing their findings.

They acknowledged as among the trial’s weaknesses its observational design and the protocol’s low specificity, which they described as commensurate with that of other diagnostic instruments to exclude acute coronary syndromes.

They also pointed out that "patients without chest pain but who presented with atypical symptoms (fatigue, nausea, vomiting, diaphoresis, faintness, and back pain) were not included in this trial," and that the researchers could not tell how many presented with those symptoms. "Thus," they wrote, "the applicability of the ADP is limited to the selected cohort of patients with chest pain (or discomfort) suggestive of acute coronary syndromes for whom the attending physician planned to investigate for these syndromes."

Dr. Than and six of his 26 coauthors disclosed having received grants and supplies, speaking honoraria, travel expenses or a combination of these from Alere Medical, a maker of diagnostic tests and equipment and the major funding source of the study. Eight other investigators received travel support from Alere to attend meetings.

In an editorial comment (Lancet 2011 March 23 [doi:10.1016/S01406736(11)603929]) accompanying Dr. Than and colleagues’ article, Dr. Richard Body of the Cardiovascular Research Group at the University of Manchester (England), noted that "the need for an effective rapid rule-out strategy to facilitate early discharge from the emergency department has been appreciated for over 20 years," and yet none has been widely adopted.

Dr. Body praised Dr. Than and colleagues’ study as "well designed to achieve its objectives," and showing "that it is possible to achieve an acceptably high sensitivity when triplemarker testing is used in the appropriate population."

However, he cautioned, the triple-marker testing alone had a sensitivity of only 82.9%. The overall sensitivity of the protocol "increased to an acceptable level because of the application of Bayesian principles, with biomarker testing only in patients with a low pretest probability of disease."

Most people "will probably consider this net risk to be statistically acceptable," Dr. Body wrote. "However, if properly informed, low-risk patients might feel differently about the relative merits of waiting for definitive 6h laboratory-based troponin testing or going home after 2 h on the basis of results from a test that correctly identifies serious coronary disease, when present, in just over eight of ten occasions."

Dr. Body advised that Dr. Than and colleagues’ findings be considered in light of other diagnostic tools. One newer troponin assay can detect with 90% sensitivity for acute myocardial infarction at presentation, he pointed out, and other "promising" biomarkers are being studied. "It therefore remains important that triplemarker testing is compared with some of these more recent alternatives," Dr. Body wrote.

Dr. Body disclosed having received past donations of research supplies from diagnostics firms owned by Roche, Siemens, and Alere, along with travel reimbursements from Roche and Randox.

The study was funded by Alere Medical, a maker of diagnostic tests and equipment, which provided grants and other direct funding to seven investigators and travel funding to eight others. Investigators in some countries received country-specific funding from other companies including Indonesian medical equipment maker, Medquest Jaya Global, and manufacturers Science International of Hong Kong, Bio Laboratories of Singapore and Progressive Group of Taiwan.

The sponsors had no role in the study or the report, the authors declared.

A new, faster screening protocol can identify patients at a very low risk of cardiovascular events when they present to the emergency department with chest pain, allowing them to be safely discharged in 2 hours instead of the usual 6 or more, a New Zealand–based team of researchers has found.

The "accelerated diagnostic protocol," or ADP, evaluated in the study consists of three widely available measures: a patient’s thrombolysis in myocardial infarction, or TIMI, score; an electrocardiograph; and a biomarker panel of troponin, creatine kinase MB, and myoglobin. The current standard of care consists of serial sampling of cardiac troponin over 6 hours from the onset of symptoms.

In an article published March 23 in The Lancet (doi:10.1016/S01406736(11)603103), the Christchurch, New Zealand, team, led by Dr. Martin Than of Christchurch Hospital, investigated the protocol in the Asia-Pacific Evaluation of Chest Pain Trial (ASPECT), which included 3,582 consecutive patients presenting with chest pain suggestive of acute coronary syndromes at hospitals in nine countries in the Asia-Pacific region. All patients were followed up for a month. Study participants were mostly older, men, and either white or Chinese, they wrote.

Of the study subjects, just under a tenth (352) qualified for early discharge under the protocol. This meant that they had a TIMI risk score of 0 (out of 7), no ischemic ECG changes, and normal pointofcare triplemarker panels at presentation and 2 hours later.

The study’s primary end point was a major adverse cardiac event within the 30 days of follow-up, including death that was not clearly noncardiac, myocardial infarction, cardiogenic shock, and arrhythmia or atrioventricular block requiring intervention. A major adverse cardiac event occurred in three (0.9%) of the ADP-screened patients, Dr. Than and colleagues reported, giving the protocol a sensitivity of 99.3%, a negative predictive value of 99.1%, and a specificity of 11%.

"The near 10% possible reduction in patients needing prolonged assessment in this large patient group could reduce overcrowding in hospitals and emergency departments and provide earlier reassurance and greater convenience for patients," Dr. Than and colleagues wrote in discussing their findings.

They acknowledged as among the trial’s weaknesses its observational design and the protocol’s low specificity, which they described as commensurate with that of other diagnostic instruments to exclude acute coronary syndromes.

They also pointed out that "patients without chest pain but who presented with atypical symptoms (fatigue, nausea, vomiting, diaphoresis, faintness, and back pain) were not included in this trial," and that the researchers could not tell how many presented with those symptoms. "Thus," they wrote, "the applicability of the ADP is limited to the selected cohort of patients with chest pain (or discomfort) suggestive of acute coronary syndromes for whom the attending physician planned to investigate for these syndromes."

Dr. Than and six of his 26 coauthors disclosed having received grants and supplies, speaking honoraria, travel expenses or a combination of these from Alere Medical, a maker of diagnostic tests and equipment and the major funding source of the study. Eight other investigators received travel support from Alere to attend meetings.

In an editorial comment (Lancet 2011 March 23 [doi:10.1016/S01406736(11)603929]) accompanying Dr. Than and colleagues’ article, Dr. Richard Body of the Cardiovascular Research Group at the University of Manchester (England), noted that "the need for an effective rapid rule-out strategy to facilitate early discharge from the emergency department has been appreciated for over 20 years," and yet none has been widely adopted.

Dr. Body praised Dr. Than and colleagues’ study as "well designed to achieve its objectives," and showing "that it is possible to achieve an acceptably high sensitivity when triplemarker testing is used in the appropriate population."

However, he cautioned, the triple-marker testing alone had a sensitivity of only 82.9%. The overall sensitivity of the protocol "increased to an acceptable level because of the application of Bayesian principles, with biomarker testing only in patients with a low pretest probability of disease."

Most people "will probably consider this net risk to be statistically acceptable," Dr. Body wrote. "However, if properly informed, low-risk patients might feel differently about the relative merits of waiting for definitive 6h laboratory-based troponin testing or going home after 2 h on the basis of results from a test that correctly identifies serious coronary disease, when present, in just over eight of ten occasions."

Dr. Body advised that Dr. Than and colleagues’ findings be considered in light of other diagnostic tools. One newer troponin assay can detect with 90% sensitivity for acute myocardial infarction at presentation, he pointed out, and other "promising" biomarkers are being studied. "It therefore remains important that triplemarker testing is compared with some of these more recent alternatives," Dr. Body wrote.

Dr. Body disclosed having received past donations of research supplies from diagnostics firms owned by Roche, Siemens, and Alere, along with travel reimbursements from Roche and Randox.

The study was funded by Alere Medical, a maker of diagnostic tests and equipment, which provided grants and other direct funding to seven investigators and travel funding to eight others. Investigators in some countries received country-specific funding from other companies including Indonesian medical equipment maker, Medquest Jaya Global, and manufacturers Science International of Hong Kong, Bio Laboratories of Singapore and Progressive Group of Taiwan.

The sponsors had no role in the study or the report, the authors declared.

A new, faster screening protocol can identify patients at a very low risk of cardiovascular events when they present to the emergency department with chest pain, allowing them to be safely discharged in 2 hours instead of the usual 6 or more, a New Zealand–based team of researchers has found.

The "accelerated diagnostic protocol," or ADP, evaluated in the study consists of three widely available measures: a patient’s thrombolysis in myocardial infarction, or TIMI, score; an electrocardiograph; and a biomarker panel of troponin, creatine kinase MB, and myoglobin. The current standard of care consists of serial sampling of cardiac troponin over 6 hours from the onset of symptoms.

In an article published March 23 in The Lancet (doi:10.1016/S01406736(11)603103), the Christchurch, New Zealand, team, led by Dr. Martin Than of Christchurch Hospital, investigated the protocol in the Asia-Pacific Evaluation of Chest Pain Trial (ASPECT), which included 3,582 consecutive patients presenting with chest pain suggestive of acute coronary syndromes at hospitals in nine countries in the Asia-Pacific region. All patients were followed up for a month. Study participants were mostly older, men, and either white or Chinese, they wrote.

Of the study subjects, just under a tenth (352) qualified for early discharge under the protocol. This meant that they had a TIMI risk score of 0 (out of 7), no ischemic ECG changes, and normal pointofcare triplemarker panels at presentation and 2 hours later.

The study’s primary end point was a major adverse cardiac event within the 30 days of follow-up, including death that was not clearly noncardiac, myocardial infarction, cardiogenic shock, and arrhythmia or atrioventricular block requiring intervention. A major adverse cardiac event occurred in three (0.9%) of the ADP-screened patients, Dr. Than and colleagues reported, giving the protocol a sensitivity of 99.3%, a negative predictive value of 99.1%, and a specificity of 11%.

"The near 10% possible reduction in patients needing prolonged assessment in this large patient group could reduce overcrowding in hospitals and emergency departments and provide earlier reassurance and greater convenience for patients," Dr. Than and colleagues wrote in discussing their findings.

They acknowledged as among the trial’s weaknesses its observational design and the protocol’s low specificity, which they described as commensurate with that of other diagnostic instruments to exclude acute coronary syndromes.

They also pointed out that "patients without chest pain but who presented with atypical symptoms (fatigue, nausea, vomiting, diaphoresis, faintness, and back pain) were not included in this trial," and that the researchers could not tell how many presented with those symptoms. "Thus," they wrote, "the applicability of the ADP is limited to the selected cohort of patients with chest pain (or discomfort) suggestive of acute coronary syndromes for whom the attending physician planned to investigate for these syndromes."

Dr. Than and six of his 26 coauthors disclosed having received grants and supplies, speaking honoraria, travel expenses or a combination of these from Alere Medical, a maker of diagnostic tests and equipment and the major funding source of the study. Eight other investigators received travel support from Alere to attend meetings.

In an editorial comment (Lancet 2011 March 23 [doi:10.1016/S01406736(11)603929]) accompanying Dr. Than and colleagues’ article, Dr. Richard Body of the Cardiovascular Research Group at the University of Manchester (England), noted that "the need for an effective rapid rule-out strategy to facilitate early discharge from the emergency department has been appreciated for over 20 years," and yet none has been widely adopted.

Dr. Body praised Dr. Than and colleagues’ study as "well designed to achieve its objectives," and showing "that it is possible to achieve an acceptably high sensitivity when triplemarker testing is used in the appropriate population."

However, he cautioned, the triple-marker testing alone had a sensitivity of only 82.9%. The overall sensitivity of the protocol "increased to an acceptable level because of the application of Bayesian principles, with biomarker testing only in patients with a low pretest probability of disease."

Most people "will probably consider this net risk to be statistically acceptable," Dr. Body wrote. "However, if properly informed, low-risk patients might feel differently about the relative merits of waiting for definitive 6h laboratory-based troponin testing or going home after 2 h on the basis of results from a test that correctly identifies serious coronary disease, when present, in just over eight of ten occasions."

Dr. Body advised that Dr. Than and colleagues’ findings be considered in light of other diagnostic tools. One newer troponin assay can detect with 90% sensitivity for acute myocardial infarction at presentation, he pointed out, and other "promising" biomarkers are being studied. "It therefore remains important that triplemarker testing is compared with some of these more recent alternatives," Dr. Body wrote.

Dr. Body disclosed having received past donations of research supplies from diagnostics firms owned by Roche, Siemens, and Alere, along with travel reimbursements from Roche and Randox.

The study was funded by Alere Medical, a maker of diagnostic tests and equipment, which provided grants and other direct funding to seven investigators and travel funding to eight others. Investigators in some countries received country-specific funding from other companies including Indonesian medical equipment maker, Medquest Jaya Global, and manufacturers Science International of Hong Kong, Bio Laboratories of Singapore and Progressive Group of Taiwan.

The sponsors had no role in the study or the report, the authors declared.

A new, faster screening protocol can identify patients at a very low risk of cardiovascular events when they present to the emergency department with chest pain, allowing them to be safely discharged in 2 hours instead of the usual 6 or more, a New Zealand–based team of researchers has found.

The "accelerated diagnostic protocol," or ADP, evaluated in the study consists of three widely available measures: a patient’s thrombolysis in myocardial infarction, or TIMI, score; an electrocardiograph; and a biomarker panel of troponin, creatine kinase MB, and myoglobin. The current standard of care consists of serial sampling of cardiac troponin over 6 hours from the onset of symptoms.

In an article published March 23 in The Lancet (doi:10.1016/S01406736(11)603103), the Christchurch, New Zealand, team, led by Dr. Martin Than of Christchurch Hospital, investigated the protocol in the Asia-Pacific Evaluation of Chest Pain Trial (ASPECT), which included 3,582 consecutive patients presenting with chest pain suggestive of acute coronary syndromes at hospitals in nine countries in the Asia-Pacific region. All patients were followed up for a month. Study participants were mostly older, men, and either white or Chinese, they wrote.

Of the study subjects, just under a tenth (352) qualified for early discharge under the protocol. This meant that they had a TIMI risk score of 0 (out of 7), no ischemic ECG changes, and normal pointofcare triplemarker panels at presentation and 2 hours later.

The study’s primary end point was a major adverse cardiac event within the 30 days of follow-up, including death that was not clearly noncardiac, myocardial infarction, cardiogenic shock, and arrhythmia or atrioventricular block requiring intervention. A major adverse cardiac event occurred in three (0.9%) of the ADP-screened patients, Dr. Than and colleagues reported, giving the protocol a sensitivity of 99.3%, a negative predictive value of 99.1%, and a specificity of 11%.

"The near 10% possible reduction in patients needing prolonged assessment in this large patient group could reduce overcrowding in hospitals and emergency departments and provide earlier reassurance and greater convenience for patients," Dr. Than and colleagues wrote in discussing their findings.

They acknowledged as among the trial’s weaknesses its observational design and the protocol’s low specificity, which they described as commensurate with that of other diagnostic instruments to exclude acute coronary syndromes.

They also pointed out that "patients without chest pain but who presented with atypical symptoms (fatigue, nausea, vomiting, diaphoresis, faintness, and back pain) were not included in this trial," and that the researchers could not tell how many presented with those symptoms. "Thus," they wrote, "the applicability of the ADP is limited to the selected cohort of patients with chest pain (or discomfort) suggestive of acute coronary syndromes for whom the attending physician planned to investigate for these syndromes."

Dr. Than and six of his 26 coauthors disclosed having received grants and supplies, speaking honoraria, travel expenses or a combination of these from Alere Medical, a maker of diagnostic tests and equipment and the major funding source of the study. Eight other investigators received travel support from Alere to attend meetings.

In an editorial comment (Lancet 2011 March 23 [doi:10.1016/S01406736(11)603929]) accompanying Dr. Than and colleagues’ article, Dr. Richard Body of the Cardiovascular Research Group at the University of Manchester (England), noted that "the need for an effective rapid rule-out strategy to facilitate early discharge from the emergency department has been appreciated for over 20 years," and yet none has been widely adopted.

Dr. Body praised Dr. Than and colleagues’ study as "well designed to achieve its objectives," and showing "that it is possible to achieve an acceptably high sensitivity when triplemarker testing is used in the appropriate population."

However, he cautioned, the triple-marker testing alone had a sensitivity of only 82.9%. The overall sensitivity of the protocol "increased to an acceptable level because of the application of Bayesian principles, with biomarker testing only in patients with a low pretest probability of disease."

Most people "will probably consider this net risk to be statistically acceptable," Dr. Body wrote. "However, if properly informed, low-risk patients might feel differently about the relative merits of waiting for definitive 6h laboratory-based troponin testing or going home after 2 h on the basis of results from a test that correctly identifies serious coronary disease, when present, in just over eight of ten occasions."

Dr. Body advised that Dr. Than and colleagues’ findings be considered in light of other diagnostic tools. One newer troponin assay can detect with 90% sensitivity for acute myocardial infarction at presentation, he pointed out, and other "promising" biomarkers are being studied. "It therefore remains important that triplemarker testing is compared with some of these more recent alternatives," Dr. Body wrote.

Dr. Body disclosed having received past donations of research supplies from diagnostics firms owned by Roche, Siemens, and Alere, along with travel reimbursements from Roche and Randox.

The study was funded by Alere Medical, a maker of diagnostic tests and equipment, which provided grants and other direct funding to seven investigators and travel funding to eight others. Investigators in some countries received country-specific funding from other companies including Indonesian medical equipment maker, Medquest Jaya Global, and manufacturers Science International of Hong Kong, Bio Laboratories of Singapore and Progressive Group of Taiwan.

The sponsors had no role in the study or the report, the authors declared.

A new, faster screening protocol can identify patients at a very low risk of cardiovascular events when they present to the emergency department with chest pain, allowing them to be safely discharged in 2 hours instead of the usual 6 or more, a New Zealand–based team of researchers has found.

The "accelerated diagnostic protocol," or ADP, evaluated in the study consists of three widely available measures: a patient’s thrombolysis in myocardial infarction, or TIMI, score; an electrocardiograph; and a biomarker panel of troponin, creatine kinase MB, and myoglobin. The current standard of care consists of serial sampling of cardiac troponin over 6 hours from the onset of symptoms.

In an article published March 23 in The Lancet (doi:10.1016/S01406736(11)603103), the Christchurch, New Zealand, team, led by Dr. Martin Than of Christchurch Hospital, investigated the protocol in the Asia-Pacific Evaluation of Chest Pain Trial (ASPECT), which included 3,582 consecutive patients presenting with chest pain suggestive of acute coronary syndromes at hospitals in nine countries in the Asia-Pacific region. All patients were followed up for a month. Study participants were mostly older, men, and either white or Chinese, they wrote.

Of the study subjects, just under a tenth (352) qualified for early discharge under the protocol. This meant that they had a TIMI risk score of 0 (out of 7), no ischemic ECG changes, and normal pointofcare triplemarker panels at presentation and 2 hours later.

The study’s primary end point was a major adverse cardiac event within the 30 days of follow-up, including death that was not clearly noncardiac, myocardial infarction, cardiogenic shock, and arrhythmia or atrioventricular block requiring intervention. A major adverse cardiac event occurred in three (0.9%) of the ADP-screened patients, Dr. Than and colleagues reported, giving the protocol a sensitivity of 99.3%, a negative predictive value of 99.1%, and a specificity of 11%.

"The near 10% possible reduction in patients needing prolonged assessment in this large patient group could reduce overcrowding in hospitals and emergency departments and provide earlier reassurance and greater convenience for patients," Dr. Than and colleagues wrote in discussing their findings.

They acknowledged as among the trial’s weaknesses its observational design and the protocol’s low specificity, which they described as commensurate with that of other diagnostic instruments to exclude acute coronary syndromes.

They also pointed out that "patients without chest pain but who presented with atypical symptoms (fatigue, nausea, vomiting, diaphoresis, faintness, and back pain) were not included in this trial," and that the researchers could not tell how many presented with those symptoms. "Thus," they wrote, "the applicability of the ADP is limited to the selected cohort of patients with chest pain (or discomfort) suggestive of acute coronary syndromes for whom the attending physician planned to investigate for these syndromes."

Dr. Than and six of his 26 coauthors disclosed having received grants and supplies, speaking honoraria, travel expenses or a combination of these from Alere Medical, a maker of diagnostic tests and equipment and the major funding source of the study. Eight other investigators received travel support from Alere to attend meetings.

In an editorial comment (Lancet 2011 March 23 [doi:10.1016/S01406736(11)603929]) accompanying Dr. Than and colleagues’ article, Dr. Richard Body of the Cardiovascular Research Group at the University of Manchester (England), noted that "the need for an effective rapid rule-out strategy to facilitate early discharge from the emergency department has been appreciated for over 20 years," and yet none has been widely adopted.

Dr. Body praised Dr. Than and colleagues’ study as "well designed to achieve its objectives," and showing "that it is possible to achieve an acceptably high sensitivity when triplemarker testing is used in the appropriate population."

However, he cautioned, the triple-marker testing alone had a sensitivity of only 82.9%. The overall sensitivity of the protocol "increased to an acceptable level because of the application of Bayesian principles, with biomarker testing only in patients with a low pretest probability of disease."

Most people "will probably consider this net risk to be statistically acceptable," Dr. Body wrote. "However, if properly informed, low-risk patients might feel differently about the relative merits of waiting for definitive 6h laboratory-based troponin testing or going home after 2 h on the basis of results from a test that correctly identifies serious coronary disease, when present, in just over eight of ten occasions."

Dr. Body advised that Dr. Than and colleagues’ findings be considered in light of other diagnostic tools. One newer troponin assay can detect with 90% sensitivity for acute myocardial infarction at presentation, he pointed out, and other "promising" biomarkers are being studied. "It therefore remains important that triplemarker testing is compared with some of these more recent alternatives," Dr. Body wrote.

Dr. Body disclosed having received past donations of research supplies from diagnostics firms owned by Roche, Siemens, and Alere, along with travel reimbursements from Roche and Randox.

The study was funded by Alere Medical, a maker of diagnostic tests and equipment, which provided grants and other direct funding to seven investigators and travel funding to eight others. Investigators in some countries received country-specific funding from other companies including Indonesian medical equipment maker, Medquest Jaya Global, and manufacturers Science International of Hong Kong, Bio Laboratories of Singapore and Progressive Group of Taiwan.

The sponsors had no role in the study or the report, the authors declared.

A new meta-analysis of observational studies suggests that rosiglitazone, the diabetes drug suspended last year by European regulators and severely restricted by the U.S. Food and Drug Administration over concerns of elevated cardiac risk, is associated with modest but statistically significant increases in the risk of heart attack, heart failure, and death, compared with pioglitazone, another drug in the same class.

The findings, derived from 16 studies (12 retrospective cohort studies and 4 case control studies), were published March 18 in BMJ (2011;342:d1309) and seem to add weight to the case against rosiglitazone’s cardiovascular safety relative to pioglitazone.

Rosiglitazone, the meta-analysis found, was associated with an approximately 16% higher heart attack risk, 22% higher congestive heart failure risk, and 14% higher mortality risk than pioglitazone among 810,000 patients with type 2 diabetes (429,000 taking rosiglitazone and 381,000 on pioglitazone). All differences were significantly different, reported Dr. Yoon Kong Loke of the University of East Anglia, Norwich, England. These numbers translate into 170 excess myocardial infarctions, 649 excess cases of heart failure, and 431 excess deaths for every 100,000 patients receiving rosiglitazone instead of pioglitazone, they explained.

The investigators chose to evaluate data from observational studies because of a lack of randomized controlled trials directly comparing the drugs, and because "clinical trials have strict selection criteria that may exclude participants at high risk of adverse events," they wrote, making cardiovascular events rarer than they would be in clinical practice.

Though Dr. Loke and his colleagues acknowledged that data from observational trials are susceptible to bias and confounding, they also argued that such data more likely reflected the results to be expected in real-world settings.

One clinician who remained unconvinced that Dr. Loke and his colleagues had demonstrated a significant risk difference was Dr. Sanjay Kaul, director of the Vascular Physiology and Thrombosis Research Laboratory at Cedars-Sinai Medical Center in Los Angeles and lead author of a 2010 American Heart Association Scientific Advisory on the two medications (Circulation 2010;121;1868-77). In the advisory, Dr. Kaul and his colleagues, citing a number of studies including a 2010 FDA meta-analysis of clinical trial data, determined that there were insufficient data to support pioglitazone over rosiglitazone based on cardiac risk.

In an interview, Dr. Kaul criticized Dr. Loke and his colleagues’ findings sharply, noting that meta-analyses of observational data are generally discouraged because they have been shown to produce "very precise but equally spurious" results that are seldom replicated in randomized trials.

Further, Dr. Kaul continued, Dr. Loke and his colleagues justified pooling "because of lack of statistical heterogeneity. However there is substantial clinical heterogeneity that arguably precludes pooling" – including differences in study design (such as case-control vs. cohort), treatment exposure, type of comparator (single vs. combined therapies), end points, method of analysis, matching technique, and effect size measure.

Dr. Kaul noted that, during a July 2010 FDA Advisory Panel meeting on rosiglitazone and cardiovascular safety, the agency’s statistical experts and reviewers had cautioned that because of such heterogeneity, estimates of association from observational studies should not be pooled into a single meta-analytic estimate.

The hypothesis of increased myocardial infarction risk raised was not validated in the four largest and highest-quality studies included in Dr. Loke and his colleagues’ meta-analysis, Dr. Kaul pointed out. Moreover, "The risk estimates for death or composite end points were all less than an odds ratio of less than 1.5. Effect sizes of this magnitude in epidemiologic studies are of questionable relevance and credibility," he said, adding that these should be considered as hypothesis generating at best and that randomized clinical trials would be required to confirm them.

Dr. Loke, in an interview, said that while he did not disagree that the design and data quality of the studies in his team’s meta-analysis were less than consistent, "Let’s face it, there’s never going to be a randomized controlled trial comparing [rosiglitazone and pioglitazone]. But, if I were a patient deciding, I’d want the available evidence."

Two editorialists suggested that the study was further evidence of misconduct by drug companies and regulators in pushing a treatment to market with questionable benefit and substantial evidence of harm. Dr. Victor M. Montori, professor of medicine, and Dr. Nilay D Shah of the department of health services research, both at the Mayo Clinic in Rochester, Minn., said the "rosiglitazone story says much about how health care has become less about promoting patients’ interests, alleviating illness, promoting function and independence, and curing disease, and much more about promoting other interests, including those of the drug industry. Has the corruption of health care advanced so far that it is unreasonable, even naive, to expect responsible drug companies, enlightened regulators, and thoughtful prescribers?" (BMJ 2011;342:d1354).

Dr. Loke and his colleagues declared no conflicts of interest in their meta-analysis. Dr. Montori and Dr. Shaw reported having no competing interests. Dr. Kaul also disclosed none related to his conclusions.

A new meta-analysis of observational studies suggests that rosiglitazone, the diabetes drug suspended last year by European regulators and severely restricted by the U.S. Food and Drug Administration over concerns of elevated cardiac risk, is associated with modest but statistically significant increases in the risk of heart attack, heart failure, and death, compared with pioglitazone, another drug in the same class.

The findings, derived from 16 studies (12 retrospective cohort studies and 4 case control studies), were published March 18 in BMJ (2011;342:d1309) and seem to add weight to the case against rosiglitazone’s cardiovascular safety relative to pioglitazone.

Rosiglitazone, the meta-analysis found, was associated with an approximately 16% higher heart attack risk, 22% higher congestive heart failure risk, and 14% higher mortality risk than pioglitazone among 810,000 patients with type 2 diabetes (429,000 taking rosiglitazone and 381,000 on pioglitazone). All differences were significantly different, reported Dr. Yoon Kong Loke of the University of East Anglia, Norwich, England. These numbers translate into 170 excess myocardial infarctions, 649 excess cases of heart failure, and 431 excess deaths for every 100,000 patients receiving rosiglitazone instead of pioglitazone, they explained.

The investigators chose to evaluate data from observational studies because of a lack of randomized controlled trials directly comparing the drugs, and because "clinical trials have strict selection criteria that may exclude participants at high risk of adverse events," they wrote, making cardiovascular events rarer than they would be in clinical practice.

Though Dr. Loke and his colleagues acknowledged that data from observational trials are susceptible to bias and confounding, they also argued that such data more likely reflected the results to be expected in real-world settings.

One clinician who remained unconvinced that Dr. Loke and his colleagues had demonstrated a significant risk difference was Dr. Sanjay Kaul, director of the Vascular Physiology and Thrombosis Research Laboratory at Cedars-Sinai Medical Center in Los Angeles and lead author of a 2010 American Heart Association Scientific Advisory on the two medications (Circulation 2010;121;1868-77). In the advisory, Dr. Kaul and his colleagues, citing a number of studies including a 2010 FDA meta-analysis of clinical trial data, determined that there were insufficient data to support pioglitazone over rosiglitazone based on cardiac risk.

In an interview, Dr. Kaul criticized Dr. Loke and his colleagues’ findings sharply, noting that meta-analyses of observational data are generally discouraged because they have been shown to produce "very precise but equally spurious" results that are seldom replicated in randomized trials.

Further, Dr. Kaul continued, Dr. Loke and his colleagues justified pooling "because of lack of statistical heterogeneity. However there is substantial clinical heterogeneity that arguably precludes pooling" – including differences in study design (such as case-control vs. cohort), treatment exposure, type of comparator (single vs. combined therapies), end points, method of analysis, matching technique, and effect size measure.

Dr. Kaul noted that, during a July 2010 FDA Advisory Panel meeting on rosiglitazone and cardiovascular safety, the agency’s statistical experts and reviewers had cautioned that because of such heterogeneity, estimates of association from observational studies should not be pooled into a single meta-analytic estimate.

The hypothesis of increased myocardial infarction risk raised was not validated in the four largest and highest-quality studies included in Dr. Loke and his colleagues’ meta-analysis, Dr. Kaul pointed out. Moreover, "The risk estimates for death or composite end points were all less than an odds ratio of less than 1.5. Effect sizes of this magnitude in epidemiologic studies are of questionable relevance and credibility," he said, adding that these should be considered as hypothesis generating at best and that randomized clinical trials would be required to confirm them.

Dr. Loke, in an interview, said that while he did not disagree that the design and data quality of the studies in his team’s meta-analysis were less than consistent, "Let’s face it, there’s never going to be a randomized controlled trial comparing [rosiglitazone and pioglitazone]. But, if I were a patient deciding, I’d want the available evidence."

Two editorialists suggested that the study was further evidence of misconduct by drug companies and regulators in pushing a treatment to market with questionable benefit and substantial evidence of harm. Dr. Victor M. Montori, professor of medicine, and Dr. Nilay D Shah of the department of health services research, both at the Mayo Clinic in Rochester, Minn., said the "rosiglitazone story says much about how health care has become less about promoting patients’ interests, alleviating illness, promoting function and independence, and curing disease, and much more about promoting other interests, including those of the drug industry. Has the corruption of health care advanced so far that it is unreasonable, even naive, to expect responsible drug companies, enlightened regulators, and thoughtful prescribers?" (BMJ 2011;342:d1354).

Dr. Loke and his colleagues declared no conflicts of interest in their meta-analysis. Dr. Montori and Dr. Shaw reported having no competing interests. Dr. Kaul also disclosed none related to his conclusions.

A new meta-analysis of observational studies suggests that rosiglitazone, the diabetes drug suspended last year by European regulators and severely restricted by the U.S. Food and Drug Administration over concerns of elevated cardiac risk, is associated with modest but statistically significant increases in the risk of heart attack, heart failure, and death, compared with pioglitazone, another drug in the same class.

The findings, derived from 16 studies (12 retrospective cohort studies and 4 case control studies), were published March 18 in BMJ (2011;342:d1309) and seem to add weight to the case against rosiglitazone’s cardiovascular safety relative to pioglitazone.

Rosiglitazone, the meta-analysis found, was associated with an approximately 16% higher heart attack risk, 22% higher congestive heart failure risk, and 14% higher mortality risk than pioglitazone among 810,000 patients with type 2 diabetes (429,000 taking rosiglitazone and 381,000 on pioglitazone). All differences were significantly different, reported Dr. Yoon Kong Loke of the University of East Anglia, Norwich, England. These numbers translate into 170 excess myocardial infarctions, 649 excess cases of heart failure, and 431 excess deaths for every 100,000 patients receiving rosiglitazone instead of pioglitazone, they explained.

The investigators chose to evaluate data from observational studies because of a lack of randomized controlled trials directly comparing the drugs, and because "clinical trials have strict selection criteria that may exclude participants at high risk of adverse events," they wrote, making cardiovascular events rarer than they would be in clinical practice.

Though Dr. Loke and his colleagues acknowledged that data from observational trials are susceptible to bias and confounding, they also argued that such data more likely reflected the results to be expected in real-world settings.

One clinician who remained unconvinced that Dr. Loke and his colleagues had demonstrated a significant risk difference was Dr. Sanjay Kaul, director of the Vascular Physiology and Thrombosis Research Laboratory at Cedars-Sinai Medical Center in Los Angeles and lead author of a 2010 American Heart Association Scientific Advisory on the two medications (Circulation 2010;121;1868-77). In the advisory, Dr. Kaul and his colleagues, citing a number of studies including a 2010 FDA meta-analysis of clinical trial data, determined that there were insufficient data to support pioglitazone over rosiglitazone based on cardiac risk.

In an interview, Dr. Kaul criticized Dr. Loke and his colleagues’ findings sharply, noting that meta-analyses of observational data are generally discouraged because they have been shown to produce "very precise but equally spurious" results that are seldom replicated in randomized trials.

Further, Dr. Kaul continued, Dr. Loke and his colleagues justified pooling "because of lack of statistical heterogeneity. However there is substantial clinical heterogeneity that arguably precludes pooling" – including differences in study design (such as case-control vs. cohort), treatment exposure, type of comparator (single vs. combined therapies), end points, method of analysis, matching technique, and effect size measure.

Dr. Kaul noted that, during a July 2010 FDA Advisory Panel meeting on rosiglitazone and cardiovascular safety, the agency’s statistical experts and reviewers had cautioned that because of such heterogeneity, estimates of association from observational studies should not be pooled into a single meta-analytic estimate.

The hypothesis of increased myocardial infarction risk raised was not validated in the four largest and highest-quality studies included in Dr. Loke and his colleagues’ meta-analysis, Dr. Kaul pointed out. Moreover, "The risk estimates for death or composite end points were all less than an odds ratio of less than 1.5. Effect sizes of this magnitude in epidemiologic studies are of questionable relevance and credibility," he said, adding that these should be considered as hypothesis generating at best and that randomized clinical trials would be required to confirm them.

Dr. Loke, in an interview, said that while he did not disagree that the design and data quality of the studies in his team’s meta-analysis were less than consistent, "Let’s face it, there’s never going to be a randomized controlled trial comparing [rosiglitazone and pioglitazone]. But, if I were a patient deciding, I’d want the available evidence."

Two editorialists suggested that the study was further evidence of misconduct by drug companies and regulators in pushing a treatment to market with questionable benefit and substantial evidence of harm. Dr. Victor M. Montori, professor of medicine, and Dr. Nilay D Shah of the department of health services research, both at the Mayo Clinic in Rochester, Minn., said the "rosiglitazone story says much about how health care has become less about promoting patients’ interests, alleviating illness, promoting function and independence, and curing disease, and much more about promoting other interests, including those of the drug industry. Has the corruption of health care advanced so far that it is unreasonable, even naive, to expect responsible drug companies, enlightened regulators, and thoughtful prescribers?" (BMJ 2011;342:d1354).

Dr. Loke and his colleagues declared no conflicts of interest in their meta-analysis. Dr. Montori and Dr. Shaw reported having no competing interests. Dr. Kaul also disclosed none related to his conclusions.

A new meta-analysis of observational studies suggests that rosiglitazone, the diabetes drug suspended last year by European regulators and severely restricted by the U.S. Food and Drug Administration over concerns of elevated cardiac risk, is associated with modest but statistically significant increases in the risk of heart attack, heart failure, and death, compared with pioglitazone, another drug in the same class.

The findings, derived from 16 studies (12 retrospective cohort studies and 4 case control studies), were published March 18 in BMJ (2011;342:d1309) and seem to add weight to the case against rosiglitazone’s cardiovascular safety relative to pioglitazone.

Rosiglitazone, the meta-analysis found, was associated with an approximately 16% higher heart attack risk, 22% higher congestive heart failure risk, and 14% higher mortality risk than pioglitazone among 810,000 patients with type 2 diabetes (429,000 taking rosiglitazone and 381,000 on pioglitazone). All differences were significantly different, reported Dr. Yoon Kong Loke of the University of East Anglia, Norwich, England. These numbers translate into 170 excess myocardial infarctions, 649 excess cases of heart failure, and 431 excess deaths for every 100,000 patients receiving rosiglitazone instead of pioglitazone, they explained.

The investigators chose to evaluate data from observational studies because of a lack of randomized controlled trials directly comparing the drugs, and because "clinical trials have strict selection criteria that may exclude participants at high risk of adverse events," they wrote, making cardiovascular events rarer than they would be in clinical practice.

Though Dr. Loke and his colleagues acknowledged that data from observational trials are susceptible to bias and confounding, they also argued that such data more likely reflected the results to be expected in real-world settings.

One clinician who remained unconvinced that Dr. Loke and his colleagues had demonstrated a significant risk difference was Dr. Sanjay Kaul, director of the Vascular Physiology and Thrombosis Research Laboratory at Cedars-Sinai Medical Center in Los Angeles and lead author of a 2010 American Heart Association Scientific Advisory on the two medications (Circulation 2010;121;1868-77). In the advisory, Dr. Kaul and his colleagues, citing a number of studies including a 2010 FDA meta-analysis of clinical trial data, determined that there were insufficient data to support pioglitazone over rosiglitazone based on cardiac risk.

In an interview, Dr. Kaul criticized Dr. Loke and his colleagues’ findings sharply, noting that meta-analyses of observational data are generally discouraged because they have been shown to produce "very precise but equally spurious" results that are seldom replicated in randomized trials.

Further, Dr. Kaul continued, Dr. Loke and his colleagues justified pooling "because of lack of statistical heterogeneity. However there is substantial clinical heterogeneity that arguably precludes pooling" – including differences in study design (such as case-control vs. cohort), treatment exposure, type of comparator (single vs. combined therapies), end points, method of analysis, matching technique, and effect size measure.

Dr. Kaul noted that, during a July 2010 FDA Advisory Panel meeting on rosiglitazone and cardiovascular safety, the agency’s statistical experts and reviewers had cautioned that because of such heterogeneity, estimates of association from observational studies should not be pooled into a single meta-analytic estimate.

The hypothesis of increased myocardial infarction risk raised was not validated in the four largest and highest-quality studies included in Dr. Loke and his colleagues’ meta-analysis, Dr. Kaul pointed out. Moreover, "The risk estimates for death or composite end points were all less than an odds ratio of less than 1.5. Effect sizes of this magnitude in epidemiologic studies are of questionable relevance and credibility," he said, adding that these should be considered as hypothesis generating at best and that randomized clinical trials would be required to confirm them.

Dr. Loke, in an interview, said that while he did not disagree that the design and data quality of the studies in his team’s meta-analysis were less than consistent, "Let’s face it, there’s never going to be a randomized controlled trial comparing [rosiglitazone and pioglitazone]. But, if I were a patient deciding, I’d want the available evidence."

Two editorialists suggested that the study was further evidence of misconduct by drug companies and regulators in pushing a treatment to market with questionable benefit and substantial evidence of harm. Dr. Victor M. Montori, professor of medicine, and Dr. Nilay D Shah of the department of health services research, both at the Mayo Clinic in Rochester, Minn., said the "rosiglitazone story says much about how health care has become less about promoting patients’ interests, alleviating illness, promoting function and independence, and curing disease, and much more about promoting other interests, including those of the drug industry. Has the corruption of health care advanced so far that it is unreasonable, even naive, to expect responsible drug companies, enlightened regulators, and thoughtful prescribers?" (BMJ 2011;342:d1354).

Dr. Loke and his colleagues declared no conflicts of interest in their meta-analysis. Dr. Montori and Dr. Shaw reported having no competing interests. Dr. Kaul also disclosed none related to his conclusions.

A new meta-analysis of observational studies suggests that rosiglitazone, the diabetes drug suspended last year by European regulators and severely restricted by the U.S. Food and Drug Administration over concerns of elevated cardiac risk, is associated with modest but statistically significant increases in the risk of heart attack, heart failure, and death, compared with pioglitazone, another drug in the same class.

The findings, derived from 16 studies (12 retrospective cohort studies and 4 case control studies), were published March 18 in BMJ (2011;342:d1309) and seem to add weight to the case against rosiglitazone’s cardiovascular safety relative to pioglitazone.

Rosiglitazone, the meta-analysis found, was associated with an approximately 16% higher heart attack risk, 22% higher congestive heart failure risk, and 14% higher mortality risk than pioglitazone among 810,000 patients with type 2 diabetes (429,000 taking rosiglitazone and 381,000 on pioglitazone). All differences were significantly different, reported Dr. Yoon Kong Loke of the University of East Anglia, Norwich, England. These numbers translate into 170 excess myocardial infarctions, 649 excess cases of heart failure, and 431 excess deaths for every 100,000 patients receiving rosiglitazone instead of pioglitazone, they explained.

The investigators chose to evaluate data from observational studies because of a lack of randomized controlled trials directly comparing the drugs, and because "clinical trials have strict selection criteria that may exclude participants at high risk of adverse events," they wrote, making cardiovascular events rarer than they would be in clinical practice.

Though Dr. Loke and his colleagues acknowledged that data from observational trials are susceptible to bias and confounding, they also argued that such data more likely reflected the results to be expected in real-world settings.

One clinician who remained unconvinced that Dr. Loke and his colleagues had demonstrated a significant risk difference was Dr. Sanjay Kaul, director of the Vascular Physiology and Thrombosis Research Laboratory at Cedars-Sinai Medical Center in Los Angeles and lead author of a 2010 American Heart Association Scientific Advisory on the two medications (Circulation 2010;121;1868-77). In the advisory, Dr. Kaul and his colleagues, citing a number of studies including a 2010 FDA meta-analysis of clinical trial data, determined that there were insufficient data to support pioglitazone over rosiglitazone based on cardiac risk.

In an interview, Dr. Kaul criticized Dr. Loke and his colleagues’ findings sharply, noting that meta-analyses of observational data are generally discouraged because they have been shown to produce "very precise but equally spurious" results that are seldom replicated in randomized trials.

Further, Dr. Kaul continued, Dr. Loke and his colleagues justified pooling "because of lack of statistical heterogeneity. However there is substantial clinical heterogeneity that arguably precludes pooling" – including differences in study design (such as case-control vs. cohort), treatment exposure, type of comparator (single vs. combined therapies), end points, method of analysis, matching technique, and effect size measure.

Dr. Kaul noted that, during a July 2010 FDA Advisory Panel meeting on rosiglitazone and cardiovascular safety, the agency’s statistical experts and reviewers had cautioned that because of such heterogeneity, estimates of association from observational studies should not be pooled into a single meta-analytic estimate.

The hypothesis of increased myocardial infarction risk raised was not validated in the four largest and highest-quality studies included in Dr. Loke and his colleagues’ meta-analysis, Dr. Kaul pointed out. Moreover, "The risk estimates for death or composite end points were all less than an odds ratio of less than 1.5. Effect sizes of this magnitude in epidemiologic studies are of questionable relevance and credibility," he said, adding that these should be considered as hypothesis generating at best and that randomized clinical trials would be required to confirm them.

Dr. Loke, in an interview, said that while he did not disagree that the design and data quality of the studies in his team’s meta-analysis were less than consistent, "Let’s face it, there’s never going to be a randomized controlled trial comparing [rosiglitazone and pioglitazone]. But, if I were a patient deciding, I’d want the available evidence."

Two editorialists suggested that the study was further evidence of misconduct by drug companies and regulators in pushing a treatment to market with questionable benefit and substantial evidence of harm. Dr. Victor M. Montori, professor of medicine, and Dr. Nilay D Shah of the department of health services research, both at the Mayo Clinic in Rochester, Minn., said the "rosiglitazone story says much about how health care has become less about promoting patients’ interests, alleviating illness, promoting function and independence, and curing disease, and much more about promoting other interests, including those of the drug industry. Has the corruption of health care advanced so far that it is unreasonable, even naive, to expect responsible drug companies, enlightened regulators, and thoughtful prescribers?" (BMJ 2011;342:d1354).

Dr. Loke and his colleagues declared no conflicts of interest in their meta-analysis. Dr. Montori and Dr. Shaw reported having no competing interests. Dr. Kaul also disclosed none related to his conclusions.

A new meta-analysis of observational studies suggests that rosiglitazone, the diabetes drug suspended last year by European regulators and severely restricted by the U.S. Food and Drug Administration over concerns of elevated cardiac risk, is associated with modest but statistically significant increases in the risk of heart attack, heart failure, and death, compared with pioglitazone, another drug in the same class.

The findings, derived from 16 studies (12 retrospective cohort studies and 4 case control studies), were published March 18 in BMJ (2011;342:d1309) and seem to add weight to the case against rosiglitazone’s cardiovascular safety relative to pioglitazone.

Rosiglitazone, the meta-analysis found, was associated with an approximately 16% higher heart attack risk, 22% higher congestive heart failure risk, and 14% higher mortality risk than pioglitazone among 810,000 patients with type 2 diabetes (429,000 taking rosiglitazone and 381,000 on pioglitazone). All differences were significantly different, reported Dr. Yoon Kong Loke of the University of East Anglia, Norwich, England. These numbers translate into 170 excess myocardial infarctions, 649 excess cases of heart failure, and 431 excess deaths for every 100,000 patients receiving rosiglitazone instead of pioglitazone, they explained.

The investigators chose to evaluate data from observational studies because of a lack of randomized controlled trials directly comparing the drugs, and because "clinical trials have strict selection criteria that may exclude participants at high risk of adverse events," they wrote, making cardiovascular events rarer than they would be in clinical practice.

Though Dr. Loke and his colleagues acknowledged that data from observational trials are susceptible to bias and confounding, they also argued that such data more likely reflected the results to be expected in real-world settings.

One clinician who remained unconvinced that Dr. Loke and his colleagues had demonstrated a significant risk difference was Dr. Sanjay Kaul, director of the Vascular Physiology and Thrombosis Research Laboratory at Cedars-Sinai Medical Center in Los Angeles and lead author of a 2010 American Heart Association Scientific Advisory on the two medications (Circulation 2010;121;1868-77). In the advisory, Dr. Kaul and his colleagues, citing a number of studies including a 2010 FDA meta-analysis of clinical trial data, determined that there were insufficient data to support pioglitazone over rosiglitazone based on cardiac risk.

In an interview, Dr. Kaul criticized Dr. Loke and his colleagues’ findings sharply, noting that meta-analyses of observational data are generally discouraged because they have been shown to produce "very precise but equally spurious" results that are seldom replicated in randomized trials.

Further, Dr. Kaul continued, Dr. Loke and his colleagues justified pooling "because of lack of statistical heterogeneity. However there is substantial clinical heterogeneity that arguably precludes pooling" – including differences in study design (such as case-control vs. cohort), treatment exposure, type of comparator (single vs. combined therapies), end points, method of analysis, matching technique, and effect size measure.

Dr. Kaul noted that, during a July 2010 FDA Advisory Panel meeting on rosiglitazone and cardiovascular safety, the agency’s statistical experts and reviewers had cautioned that because of such heterogeneity, estimates of association from observational studies should not be pooled into a single meta-analytic estimate.

The hypothesis of increased myocardial infarction risk raised was not validated in the four largest and highest-quality studies included in Dr. Loke and his colleagues’ meta-analysis, Dr. Kaul pointed out. Moreover, "The risk estimates for death or composite end points were all less than an odds ratio of less than 1.5. Effect sizes of this magnitude in epidemiologic studies are of questionable relevance and credibility," he said, adding that these should be considered as hypothesis generating at best and that randomized clinical trials would be required to confirm them.

Dr. Loke, in an interview, said that while he did not disagree that the design and data quality of the studies in his team’s meta-analysis were less than consistent, "Let’s face it, there’s never going to be a randomized controlled trial comparing [rosiglitazone and pioglitazone]. But, if I were a patient deciding, I’d want the available evidence."

Two editorialists suggested that the study was further evidence of misconduct by drug companies and regulators in pushing a treatment to market with questionable benefit and substantial evidence of harm. Dr. Victor M. Montori, professor of medicine, and Dr. Nilay D Shah of the department of health services research, both at the Mayo Clinic in Rochester, Minn., said the "rosiglitazone story says much about how health care has become less about promoting patients’ interests, alleviating illness, promoting function and independence, and curing disease, and much more about promoting other interests, including those of the drug industry. Has the corruption of health care advanced so far that it is unreasonable, even naive, to expect responsible drug companies, enlightened regulators, and thoughtful prescribers?" (BMJ 2011;342:d1354).

Dr. Loke and his colleagues declared no conflicts of interest in their meta-analysis. Dr. Montori and Dr. Shaw reported having no competing interests. Dr. Kaul also disclosed none related to his conclusions.

A new meta-analysis of observational studies suggests that rosiglitazone, the diabetes drug suspended last year by European regulators and severely restricted by the U.S. Food and Drug Administration over concerns of elevated cardiac risk, is associated with modest but statistically significant increases in the risk of heart attack, heart failure, and death, compared with pioglitazone, another drug in the same class.

The findings, derived from 16 studies (12 retrospective cohort studies and 4 case control studies), were published March 18 in BMJ (2011;342:d1309) and seem to add weight to the case against rosiglitazone’s cardiovascular safety relative to pioglitazone.

Rosiglitazone, the meta-analysis found, was associated with an approximately 16% higher heart attack risk, 22% higher congestive heart failure risk, and 14% higher mortality risk than pioglitazone among 810,000 patients with type 2 diabetes (429,000 taking rosiglitazone and 381,000 on pioglitazone). All differences were significantly different, reported Dr. Yoon Kong Loke of the University of East Anglia, Norwich, England. These numbers translate into 170 excess myocardial infarctions, 649 excess cases of heart failure, and 431 excess deaths for every 100,000 patients receiving rosiglitazone instead of pioglitazone, they explained.

The investigators chose to evaluate data from observational studies because of a lack of randomized controlled trials directly comparing the drugs, and because "clinical trials have strict selection criteria that may exclude participants at high risk of adverse events," they wrote, making cardiovascular events rarer than they would be in clinical practice.

Though Dr. Loke and his colleagues acknowledged that data from observational trials are susceptible to bias and confounding, they also argued that such data more likely reflected the results to be expected in real-world settings.

One clinician who remained unconvinced that Dr. Loke and his colleagues had demonstrated a significant risk difference was Dr. Sanjay Kaul, director of the Vascular Physiology and Thrombosis Research Laboratory at Cedars-Sinai Medical Center in Los Angeles and lead author of a 2010 American Heart Association Scientific Advisory on the two medications (Circulation 2010;121;1868-77). In the advisory, Dr. Kaul and his colleagues, citing a number of studies including a 2010 FDA meta-analysis of clinical trial data, determined that there were insufficient data to support pioglitazone over rosiglitazone based on cardiac risk.

In an interview, Dr. Kaul criticized Dr. Loke and his colleagues’ findings sharply, noting that meta-analyses of observational data are generally discouraged because they have been shown to produce "very precise but equally spurious" results that are seldom replicated in randomized trials.

Further, Dr. Kaul continued, Dr. Loke and his colleagues justified pooling "because of lack of statistical heterogeneity. However there is substantial clinical heterogeneity that arguably precludes pooling" – including differences in study design (such as case-control vs. cohort), treatment exposure, type of comparator (single vs. combined therapies), end points, method of analysis, matching technique, and effect size measure.

Dr. Kaul noted that, during a July 2010 FDA Advisory Panel meeting on rosiglitazone and cardiovascular safety, the agency’s statistical experts and reviewers had cautioned that because of such heterogeneity, estimates of association from observational studies should not be pooled into a single meta-analytic estimate.

The hypothesis of increased myocardial infarction risk raised was not validated in the four largest and highest-quality studies included in Dr. Loke and his colleagues’ meta-analysis, Dr. Kaul pointed out. Moreover, "The risk estimates for death or composite end points were all less than an odds ratio of less than 1.5. Effect sizes of this magnitude in epidemiologic studies are of questionable relevance and credibility," he said, adding that these should be considered as hypothesis generating at best and that randomized clinical trials would be required to confirm them.

Dr. Loke, in an interview, said that while he did not disagree that the design and data quality of the studies in his team’s meta-analysis were less than consistent, "Let’s face it, there’s never going to be a randomized controlled trial comparing [rosiglitazone and pioglitazone]. But, if I were a patient deciding, I’d want the available evidence."

Two editorialists suggested that the study was further evidence of misconduct by drug companies and regulators in pushing a treatment to market with questionable benefit and substantial evidence of harm. Dr. Victor M. Montori, professor of medicine, and Dr. Nilay D Shah of the department of health services research, both at the Mayo Clinic in Rochester, Minn., said the "rosiglitazone story says much about how health care has become less about promoting patients’ interests, alleviating illness, promoting function and independence, and curing disease, and much more about promoting other interests, including those of the drug industry. Has the corruption of health care advanced so far that it is unreasonable, even naive, to expect responsible drug companies, enlightened regulators, and thoughtful prescribers?" (BMJ 2011;342:d1354).

Dr. Loke and his colleagues declared no conflicts of interest in their meta-analysis. Dr. Montori and Dr. Shaw reported having no competing interests. Dr. Kaul also disclosed none related to his conclusions.

A new meta-analysis of observational studies suggests that rosiglitazone, the diabetes drug suspended last year by European regulators and severely restricted by the U.S. Food and Drug Administration over concerns of elevated cardiac risk, is associated with modest but statistically significant increases in the risk of heart attack, heart failure, and death, compared with pioglitazone, another drug in the same class.

The findings, derived from 16 studies (12 retrospective cohort studies and 4 case control studies), were published March 18 in BMJ (2011;342:d1309) and seem to add weight to the case against rosiglitazone’s cardiovascular safety relative to pioglitazone.

Rosiglitazone, the meta-analysis found, was associated with an approximately 16% higher heart attack risk, 22% higher congestive heart failure risk, and 14% higher mortality risk than pioglitazone among 810,000 patients with type 2 diabetes (429,000 taking rosiglitazone and 381,000 on pioglitazone). All differences were significantly different, reported Dr. Yoon Kong Loke of the University of East Anglia, Norwich, England. These numbers translate into 170 excess myocardial infarctions, 649 excess cases of heart failure, and 431 excess deaths for every 100,000 patients receiving rosiglitazone instead of pioglitazone, they explained.

The investigators chose to evaluate data from observational studies because of a lack of randomized controlled trials directly comparing the drugs, and because "clinical trials have strict selection criteria that may exclude participants at high risk of adverse events," they wrote, making cardiovascular events rarer than they would be in clinical practice.

Though Dr. Loke and his colleagues acknowledged that data from observational trials are susceptible to bias and confounding, they also argued that such data more likely reflected the results to be expected in real-world settings.

One clinician who remained unconvinced that Dr. Loke and his colleagues had demonstrated a significant risk difference was Dr. Sanjay Kaul, director of the Vascular Physiology and Thrombosis Research Laboratory at Cedars-Sinai Medical Center in Los Angeles and lead author of a 2010 American Heart Association Scientific Advisory on the two medications (Circulation 2010;121;1868-77). In the advisory, Dr. Kaul and his colleagues, citing a number of studies including a 2010 FDA meta-analysis of clinical trial data, determined that there were insufficient data to support pioglitazone over rosiglitazone based on cardiac risk.

In an interview, Dr. Kaul criticized Dr. Loke and his colleagues’ findings sharply, noting that meta-analyses of observational data are generally discouraged because they have been shown to produce "very precise but equally spurious" results that are seldom replicated in randomized trials.

Further, Dr. Kaul continued, Dr. Loke and his colleagues justified pooling "because of lack of statistical heterogeneity. However there is substantial clinical heterogeneity that arguably precludes pooling" – including differences in study design (such as case-control vs. cohort), treatment exposure, type of comparator (single vs. combined therapies), end points, method of analysis, matching technique, and effect size measure.

Dr. Kaul noted that, during a July 2010 FDA Advisory Panel meeting on rosiglitazone and cardiovascular safety, the agency’s statistical experts and reviewers had cautioned that because of such heterogeneity, estimates of association from observational studies should not be pooled into a single meta-analytic estimate.

The hypothesis of increased myocardial infarction risk raised was not validated in the four largest and highest-quality studies included in Dr. Loke and his colleagues’ meta-analysis, Dr. Kaul pointed out. Moreover, "The risk estimates for death or composite end points were all less than an odds ratio of less than 1.5. Effect sizes of this magnitude in epidemiologic studies are of questionable relevance and credibility," he said, adding that these should be considered as hypothesis generating at best and that randomized clinical trials would be required to confirm them.

Dr. Loke, in an interview, said that while he did not disagree that the design and data quality of the studies in his team’s meta-analysis were less than consistent, "Let’s face it, there’s never going to be a randomized controlled trial comparing [rosiglitazone and pioglitazone]. But, if I were a patient deciding, I’d want the available evidence."

Two editorialists suggested that the study was further evidence of misconduct by drug companies and regulators in pushing a treatment to market with questionable benefit and substantial evidence of harm. Dr. Victor M. Montori, professor of medicine, and Dr. Nilay D Shah of the department of health services research, both at the Mayo Clinic in Rochester, Minn., said the "rosiglitazone story says much about how health care has become less about promoting patients’ interests, alleviating illness, promoting function and independence, and curing disease, and much more about promoting other interests, including those of the drug industry. Has the corruption of health care advanced so far that it is unreasonable, even naive, to expect responsible drug companies, enlightened regulators, and thoughtful prescribers?" (BMJ 2011;342:d1354).

Dr. Loke and his colleagues declared no conflicts of interest in their meta-analysis. Dr. Montori and Dr. Shaw reported having no competing interests. Dr. Kaul also disclosed none related to his conclusions.

A new meta-analysis of observational studies suggests that rosiglitazone, the diabetes drug suspended last year by European regulators and severely restricted by the U.S. Food and Drug Administration over concerns of elevated cardiac risk, is associated with modest but statistically significant increases in the risk of heart attack, heart failure, and death, compared with pioglitazone, another drug in the same class.

The findings, derived from 16 studies (12 retrospective cohort studies and 4 case control studies), were published March 18 in BMJ (2011;342:d1309) and seem to add weight to the case against rosiglitazone’s cardiovascular safety relative to pioglitazone.

Rosiglitazone, the meta-analysis found, was associated with an approximately 16% higher heart attack risk, 22% higher congestive heart failure risk, and 14% higher mortality risk than pioglitazone among 810,000 patients with type 2 diabetes (429,000 taking rosiglitazone and 381,000 on pioglitazone). All differences were significantly different, reported Dr. Yoon Kong Loke of the University of East Anglia, Norwich, England. These numbers translate into 170 excess myocardial infarctions, 649 excess cases of heart failure, and 431 excess deaths for every 100,000 patients receiving rosiglitazone instead of pioglitazone, they explained.

The investigators chose to evaluate data from observational studies because of a lack of randomized controlled trials directly comparing the drugs, and because "clinical trials have strict selection criteria that may exclude participants at high risk of adverse events," they wrote, making cardiovascular events rarer than they would be in clinical practice.

Though Dr. Loke and his colleagues acknowledged that data from observational trials are susceptible to bias and confounding, they also argued that such data more likely reflected the results to be expected in real-world settings.

One clinician who remained unconvinced that Dr. Loke and his colleagues had demonstrated a significant risk difference was Dr. Sanjay Kaul, director of the Vascular Physiology and Thrombosis Research Laboratory at Cedars-Sinai Medical Center in Los Angeles and lead author of a 2010 American Heart Association Scientific Advisory on the two medications (Circulation 2010;121;1868-77). In the advisory, Dr. Kaul and his colleagues, citing a number of studies including a 2010 FDA meta-analysis of clinical trial data, determined that there were insufficient data to support pioglitazone over rosiglitazone based on cardiac risk.

In an interview, Dr. Kaul criticized Dr. Loke and his colleagues’ findings sharply, noting that meta-analyses of observational data are generally discouraged because they have been shown to produce "very precise but equally spurious" results that are seldom replicated in randomized trials.

Further, Dr. Kaul continued, Dr. Loke and his colleagues justified pooling "because of lack of statistical heterogeneity. However there is substantial clinical heterogeneity that arguably precludes pooling" – including differences in study design (such as case-control vs. cohort), treatment exposure, type of comparator (single vs. combined therapies), end points, method of analysis, matching technique, and effect size measure.

Dr. Kaul noted that, during a July 2010 FDA Advisory Panel meeting on rosiglitazone and cardiovascular safety, the agency’s statistical experts and reviewers had cautioned that because of such heterogeneity, estimates of association from observational studies should not be pooled into a single meta-analytic estimate.

The hypothesis of increased myocardial infarction risk raised was not validated in the four largest and highest-quality studies included in Dr. Loke and his colleagues’ meta-analysis, Dr. Kaul pointed out. Moreover, "The risk estimates for death or composite end points were all less than an odds ratio of less than 1.5. Effect sizes of this magnitude in epidemiologic studies are of questionable relevance and credibility," he said, adding that these should be considered as hypothesis generating at best and that randomized clinical trials would be required to confirm them.

Dr. Loke, in an interview, said that while he did not disagree that the design and data quality of the studies in his team’s meta-analysis were less than consistent, "Let’s face it, there’s never going to be a randomized controlled trial comparing [rosiglitazone and pioglitazone]. But, if I were a patient deciding, I’d want the available evidence."

Two editorialists suggested that the study was further evidence of misconduct by drug companies and regulators in pushing a treatment to market with questionable benefit and substantial evidence of harm. Dr. Victor M. Montori, professor of medicine, and Dr. Nilay D Shah of the department of health services research, both at the Mayo Clinic in Rochester, Minn., said the "rosiglitazone story says much about how health care has become less about promoting patients’ interests, alleviating illness, promoting function and independence, and curing disease, and much more about promoting other interests, including those of the drug industry. Has the corruption of health care advanced so far that it is unreasonable, even naive, to expect responsible drug companies, enlightened regulators, and thoughtful prescribers?" (BMJ 2011;342:d1354).

Dr. Loke and his colleagues declared no conflicts of interest in their meta-analysis. Dr. Montori and Dr. Shaw reported having no competing interests. Dr. Kaul also disclosed none related to his conclusions.

How do you solve a problem like Makena?

In February, when the Missouri-based pharmaceutical firm Ther-Rx received from the Food and Drug Administration the exclusive right to market a progesterone injection formerly known as 17P, maternal-fetal health advocates cheered.

The drug 17-alpha Hydroxyprogesterone caproate, or 17P, had originally received FDA approval in the 1950s for multiple indications, one of which was preventing preterm labor, but it came off the market in 2000 because of a manufacturing issue. After a publicly funded 2003 study of 463 women found weekly injections of 17P effective in preventing preterm labor among women at high risk (N. Engl. J. Med. 2003;348:2379-85), the drug gained widespread use, even though practitioners had to order it from compounding pharmacies.

In February, the March of Dimes lauded the FDA’s decision to approve 17P under its orphan drug program, guaranteeing market exclusivity to Ther-Rx, which will market 17P as Makena. The March of Dimes praised the FDA’s decision as likely to standardize the quality and consistency of the product and, presumably, to lessen the "logistical and financial barriers" to patient access, the organization said in a press statement.

And then everyone learned Makena’s price. This month, Ther-Rx revealed that each Makena shot would cost $1,500 – where it had previously cost between $10 and $50. The ideal treatment starts at approximately 16-18 weeks’ gestation and continues until 36 weeks’ gestation, so a woman might receive as many as 20 doses of 17P during her pregnancy. Although the company offered to offer the drug free to lower-income uninsured households, the full cost to insurers including Medicaid, according to an estimate provided by the American College of Obstetricians and Gynecologists, would be about $30,000 per pregnancy.

Dr. Christopher Harman, director of the Center for Advanced Fetal Care and chief of obstetrics and gynecology at the University of Maryland Medical Center, Baltimore, called Makena’s pricing "an outrage."

"This stuff is really cheap to make – this would be as if a brand-new company somehow got a patent on Tylenol or aspirin and decided to sell it at $100 a pill," said Dr. Harman. Makena’s pricing "strikes at the core of women at highest risk for preterm birth already" – young African American women. "We may remove their best hopes for having a close-to-term birth," he said in an interview.

Ther-Rx did not answer calls seeking comment. On its Web site, the company said: "We appreciate the concerns expressed by multiple audiences and are committed to working collaboratively with all interested parties to make this vital medication even more available and affordable to women across the country."

Dr. Harman said he has been using 17P for about 5 years in his patients, mostly low-income women in inner-city Maryland, and that between 100,000 and 140,000 women a year are probably eligible for treatment with 17P in the United States.

"Nobody is saying the company was out to deprive any group of women, but as often occurs when financial decisions are made, they have a disproportionate impact on the people who need the treatment the most," he said.

Other physicians were quick to express outrage online when they learned about the price – mostly at the manufacturer, but also at the March of Dimes for supporting Makena’s approval.

Dr. Jennifer Gunter, an ob.gyn, author, and pain physician at Kaiser Permanente in San Francisco, used her informational Web site, The Preemie Primer, to criticize what she considered to be March of Dimes’ naivete in celebrating the approval of Makena before learning of KV Pharmaceutical Company’s pricing intentions.

On March 11, three professional organizations, the American Academy of Pediatrics, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine, published a joint letter to Ther-Rx, a subsidiary of KV Pharmaceutical Company, critical of the pricing, stating that: "in our current climate of controlling health care costs in the United States an added cost of $30,000 for as many as 140,000 pregnancies per year, or 4.2 billion dollars, is a staggering figure."

Sen. Sherrod Brown (D-OH), slammed the pricing in his own letter to the company, stating that the $1,500 per shot price tag was "exorbitant," and that Ther-Rx was "taking advantage of FDA approval at the expense of women, children, and federal and state budgets." A spokesman for Sen. Brown said that, as of March 15, he had not received a response from the company.

Dr. Harman said the best people to pressure the FDA and government to reexamine the Makena decision were patients and the public. Last week, patients were among the most outspoken critics of Ther-Rx and KV Pharmaceutical Company, and to a lesser degree March of Dimes, which issued another statement March 14 in the form of a letter to the manufacturer saying that it was "deeply concerned that the cost of this lifesaving treatment could be put out of reach to thousands of women at risk for preterm delivery."

One patient group created a Facebook page specifically to shame the manufacturer. Sarah Vandermeulen, age 30 years, of Paducah, Ky., was quick to join up. Ms. Vandermeulen said that in 2000, she had delivered a 1 lb 3oz baby at 23 weeks’ gestation who did not survive. In 2009, she became pregnant again and had heard about 17P from members of an online support group "I promptly asked my doctor if this was for me, and she agreed I may benefit from taking 17P," she said in an interview. Ms. Vandermeulen delivered a healthy baby at 37 weeks’ gestation.

"I obviously have no comparison or scientific data, but I do believe that 17P at the very least delayed preterm labor," said Ms. Vandermeulen. "I know that other women are scared for their current and future pregnancies. Many swear they wouldn’t have carried to term without 17P and are terrified that they will be denied this treatment option. I can tell you that there are discussions taking place on what we can do to help change the price increase."

The same question is also vexing clinicians. Dr. Harman, whose university clinic handles about 1,500 high-risk babies per year and whose referring hospitals deliver a total of about 9,000, said that he was concerned that local compounding pharmacists would not make the medication now that it is FDA-approved. "We’re investigating our possibilities," he said. "We may end up a producer ourselves," he said, adding that this was only "anxious conversation" in the near term.

The compounding pharmacies for now are striking a defiant pose. On March 14, the International Academy of Compounding Pharmacists issued a statement to patients and providers saying that, although many pharmacies had received a warning letter dated Feb. 17 from Ther-Rx that they could no longer compound an FDA-approved medication to which Ther-Rx had exclusive marketing rights, "In our estimation, the letter is nothing more than a ‘scare tactic.’ ... Pharmacists can legally compound FDA approved products when a prescriber determines that the compounded preparation is more clinically appropriate for an individual patient."

David G. Miller, R.Ph., the group’s chief executive, said in an e-mail that the answer to the question of whether 17P can legally be compounded, in light of an FDA-approved product with market exclusivity, was "clear and simple."

"If a prescriber determines that a compounded preparation of a medication is in the best clinical interest of his or her patient and discusses the available options with a pharmacist, there are no statutory or regulatory prohibitions on that professional decision," Mr. Miller said.

One criticism raised by Mr. Miller and others was that Makena had received FDA approval in part as a way to offer 17P with guaranteed consistency across the market. However, Ther-Rx’s parent company, KV Pharmaceutical Company, has recently faced legal trouble over active-ingredient inconsistencies and false labeling of its FDA-approved products.

Just last week, KV Pharmaceutical Company’s former chief executive pleaded guilty to breaching federal food and drug statutes by selling oversized morphine tablets.

Dr. Harman said he had no relevant financial disclosures.

How do you solve a problem like Makena?

In February, when the Missouri-based pharmaceutical firm Ther-Rx received from the Food and Drug Administration the exclusive right to market a progesterone injection formerly known as 17P, maternal-fetal health advocates cheered.

The drug 17-alpha Hydroxyprogesterone caproate, or 17P, had originally received FDA approval in the 1950s for multiple indications, one of which was preventing preterm labor, but it came off the market in 2000 because of a manufacturing issue. After a publicly funded 2003 study of 463 women found weekly injections of 17P effective in preventing preterm labor among women at high risk (N. Engl. J. Med. 2003;348:2379-85), the drug gained widespread use, even though practitioners had to order it from compounding pharmacies.

In February, the March of Dimes lauded the FDA’s decision to approve 17P under its orphan drug program, guaranteeing market exclusivity to Ther-Rx, which will market 17P as Makena. The March of Dimes praised the FDA’s decision as likely to standardize the quality and consistency of the product and, presumably, to lessen the "logistical and financial barriers" to patient access, the organization said in a press statement.

And then everyone learned Makena’s price. This month, Ther-Rx revealed that each Makena shot would cost $1,500 – where it had previously cost between $10 and $50. The ideal treatment starts at approximately 16-18 weeks’ gestation and continues until 36 weeks’ gestation, so a woman might receive as many as 20 doses of 17P during her pregnancy. Although the company offered to offer the drug free to lower-income uninsured households, the full cost to insurers including Medicaid, according to an estimate provided by the American College of Obstetricians and Gynecologists, would be about $30,000 per pregnancy.

Dr. Christopher Harman, director of the Center for Advanced Fetal Care and chief of obstetrics and gynecology at the University of Maryland Medical Center, Baltimore, called Makena’s pricing "an outrage."

"This stuff is really cheap to make – this would be as if a brand-new company somehow got a patent on Tylenol or aspirin and decided to sell it at $100 a pill," said Dr. Harman. Makena’s pricing "strikes at the core of women at highest risk for preterm birth already" – young African American women. "We may remove their best hopes for having a close-to-term birth," he said in an interview.

Ther-Rx did not answer calls seeking comment. On its Web site, the company said: "We appreciate the concerns expressed by multiple audiences and are committed to working collaboratively with all interested parties to make this vital medication even more available and affordable to women across the country."

Dr. Harman said he has been using 17P for about 5 years in his patients, mostly low-income women in inner-city Maryland, and that between 100,000 and 140,000 women a year are probably eligible for treatment with 17P in the United States.

"Nobody is saying the company was out to deprive any group of women, but as often occurs when financial decisions are made, they have a disproportionate impact on the people who need the treatment the most," he said.

Other physicians were quick to express outrage online when they learned about the price – mostly at the manufacturer, but also at the March of Dimes for supporting Makena’s approval.

Dr. Jennifer Gunter, an ob.gyn, author, and pain physician at Kaiser Permanente in San Francisco, used her informational Web site, The Preemie Primer, to criticize what she considered to be March of Dimes’ naivete in celebrating the approval of Makena before learning of KV Pharmaceutical Company’s pricing intentions.

On March 11, three professional organizations, the American Academy of Pediatrics, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine, published a joint letter to Ther-Rx, a subsidiary of KV Pharmaceutical Company, critical of the pricing, stating that: "in our current climate of controlling health care costs in the United States an added cost of $30,000 for as many as 140,000 pregnancies per year, or 4.2 billion dollars, is a staggering figure."

Sen. Sherrod Brown (D-OH), slammed the pricing in his own letter to the company, stating that the $1,500 per shot price tag was "exorbitant," and that Ther-Rx was "taking advantage of FDA approval at the expense of women, children, and federal and state budgets." A spokesman for Sen. Brown said that, as of March 15, he had not received a response from the company.

Dr. Harman said the best people to pressure the FDA and government to reexamine the Makena decision were patients and the public. Last week, patients were among the most outspoken critics of Ther-Rx and KV Pharmaceutical Company, and to a lesser degree March of Dimes, which issued another statement March 14 in the form of a letter to the manufacturer saying that it was "deeply concerned that the cost of this lifesaving treatment could be put out of reach to thousands of women at risk for preterm delivery."

One patient group created a Facebook page specifically to shame the manufacturer. Sarah Vandermeulen, age 30 years, of Paducah, Ky., was quick to join up. Ms. Vandermeulen said that in 2000, she had delivered a 1 lb 3oz baby at 23 weeks’ gestation who did not survive. In 2009, she became pregnant again and had heard about 17P from members of an online support group "I promptly asked my doctor if this was for me, and she agreed I may benefit from taking 17P," she said in an interview. Ms. Vandermeulen delivered a healthy baby at 37 weeks’ gestation.

"I obviously have no comparison or scientific data, but I do believe that 17P at the very least delayed preterm labor," said Ms. Vandermeulen. "I know that other women are scared for their current and future pregnancies. Many swear they wouldn’t have carried to term without 17P and are terrified that they will be denied this treatment option. I can tell you that there are discussions taking place on what we can do to help change the price increase."

The same question is also vexing clinicians. Dr. Harman, whose university clinic handles about 1,500 high-risk babies per year and whose referring hospitals deliver a total of about 9,000, said that he was concerned that local compounding pharmacists would not make the medication now that it is FDA-approved. "We’re investigating our possibilities," he said. "We may end up a producer ourselves," he said, adding that this was only "anxious conversation" in the near term.

The compounding pharmacies for now are striking a defiant pose. On March 14, the International Academy of Compounding Pharmacists issued a statement to patients and providers saying that, although many pharmacies had received a warning letter dated Feb. 17 from Ther-Rx that they could no longer compound an FDA-approved medication to which Ther-Rx had exclusive marketing rights, "In our estimation, the letter is nothing more than a ‘scare tactic.’ ... Pharmacists can legally compound FDA approved products when a prescriber determines that the compounded preparation is more clinically appropriate for an individual patient."

David G. Miller, R.Ph., the group’s chief executive, said in an e-mail that the answer to the question of whether 17P can legally be compounded, in light of an FDA-approved product with market exclusivity, was "clear and simple."

"If a prescriber determines that a compounded preparation of a medication is in the best clinical interest of his or her patient and discusses the available options with a pharmacist, there are no statutory or regulatory prohibitions on that professional decision," Mr. Miller said.

One criticism raised by Mr. Miller and others was that Makena had received FDA approval in part as a way to offer 17P with guaranteed consistency across the market. However, Ther-Rx’s parent company, KV Pharmaceutical Company, has recently faced legal trouble over active-ingredient inconsistencies and false labeling of its FDA-approved products.

Just last week, KV Pharmaceutical Company’s former chief executive pleaded guilty to breaching federal food and drug statutes by selling oversized morphine tablets.

Dr. Harman said he had no relevant financial disclosures.

How do you solve a problem like Makena?

In February, when the Missouri-based pharmaceutical firm Ther-Rx received from the Food and Drug Administration the exclusive right to market a progesterone injection formerly known as 17P, maternal-fetal health advocates cheered.

The drug 17-alpha Hydroxyprogesterone caproate, or 17P, had originally received FDA approval in the 1950s for multiple indications, one of which was preventing preterm labor, but it came off the market in 2000 because of a manufacturing issue. After a publicly funded 2003 study of 463 women found weekly injections of 17P effective in preventing preterm labor among women at high risk (N. Engl. J. Med. 2003;348:2379-85), the drug gained widespread use, even though practitioners had to order it from compounding pharmacies.

In February, the March of Dimes lauded the FDA’s decision to approve 17P under its orphan drug program, guaranteeing market exclusivity to Ther-Rx, which will market 17P as Makena. The March of Dimes praised the FDA’s decision as likely to standardize the quality and consistency of the product and, presumably, to lessen the "logistical and financial barriers" to patient access, the organization said in a press statement.

And then everyone learned Makena’s price. This month, Ther-Rx revealed that each Makena shot would cost $1,500 – where it had previously cost between $10 and $50. The ideal treatment starts at approximately 16-18 weeks’ gestation and continues until 36 weeks’ gestation, so a woman might receive as many as 20 doses of 17P during her pregnancy. Although the company offered to offer the drug free to lower-income uninsured households, the full cost to insurers including Medicaid, according to an estimate provided by the American College of Obstetricians and Gynecologists, would be about $30,000 per pregnancy.

Dr. Christopher Harman, director of the Center for Advanced Fetal Care and chief of obstetrics and gynecology at the University of Maryland Medical Center, Baltimore, called Makena’s pricing "an outrage."

"This stuff is really cheap to make – this would be as if a brand-new company somehow got a patent on Tylenol or aspirin and decided to sell it at $100 a pill," said Dr. Harman. Makena’s pricing "strikes at the core of women at highest risk for preterm birth already" – young African American women. "We may remove their best hopes for having a close-to-term birth," he said in an interview.

Ther-Rx did not answer calls seeking comment. On its Web site, the company said: "We appreciate the concerns expressed by multiple audiences and are committed to working collaboratively with all interested parties to make this vital medication even more available and affordable to women across the country."

Dr. Harman said he has been using 17P for about 5 years in his patients, mostly low-income women in inner-city Maryland, and that between 100,000 and 140,000 women a year are probably eligible for treatment with 17P in the United States.

"Nobody is saying the company was out to deprive any group of women, but as often occurs when financial decisions are made, they have a disproportionate impact on the people who need the treatment the most," he said.

Other physicians were quick to express outrage online when they learned about the price – mostly at the manufacturer, but also at the March of Dimes for supporting Makena’s approval.

Dr. Jennifer Gunter, an ob.gyn, author, and pain physician at Kaiser Permanente in San Francisco, used her informational Web site, The Preemie Primer, to criticize what she considered to be March of Dimes’ naivete in celebrating the approval of Makena before learning of KV Pharmaceutical Company’s pricing intentions.

On March 11, three professional organizations, the American Academy of Pediatrics, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine, published a joint letter to Ther-Rx, a subsidiary of KV Pharmaceutical Company, critical of the pricing, stating that: "in our current climate of controlling health care costs in the United States an added cost of $30,000 for as many as 140,000 pregnancies per year, or 4.2 billion dollars, is a staggering figure."

Sen. Sherrod Brown (D-OH), slammed the pricing in his own letter to the company, stating that the $1,500 per shot price tag was "exorbitant," and that Ther-Rx was "taking advantage of FDA approval at the expense of women, children, and federal and state budgets." A spokesman for Sen. Brown said that, as of March 15, he had not received a response from the company.

Dr. Harman said the best people to pressure the FDA and government to reexamine the Makena decision were patients and the public. Last week, patients were among the most outspoken critics of Ther-Rx and KV Pharmaceutical Company, and to a lesser degree March of Dimes, which issued another statement March 14 in the form of a letter to the manufacturer saying that it was "deeply concerned that the cost of this lifesaving treatment could be put out of reach to thousands of women at risk for preterm delivery."

One patient group created a Facebook page specifically to shame the manufacturer. Sarah Vandermeulen, age 30 years, of Paducah, Ky., was quick to join up. Ms. Vandermeulen said that in 2000, she had delivered a 1 lb 3oz baby at 23 weeks’ gestation who did not survive. In 2009, she became pregnant again and had heard about 17P from members of an online support group "I promptly asked my doctor if this was for me, and she agreed I may benefit from taking 17P," she said in an interview. Ms. Vandermeulen delivered a healthy baby at 37 weeks’ gestation.

"I obviously have no comparison or scientific data, but I do believe that 17P at the very least delayed preterm labor," said Ms. Vandermeulen. "I know that other women are scared for their current and future pregnancies. Many swear they wouldn’t have carried to term without 17P and are terrified that they will be denied this treatment option. I can tell you that there are discussions taking place on what we can do to help change the price increase."

The same question is also vexing clinicians. Dr. Harman, whose university clinic handles about 1,500 high-risk babies per year and whose referring hospitals deliver a total of about 9,000, said that he was concerned that local compounding pharmacists would not make the medication now that it is FDA-approved. "We’re investigating our possibilities," he said. "We may end up a producer ourselves," he said, adding that this was only "anxious conversation" in the near term.

The compounding pharmacies for now are striking a defiant pose. On March 14, the International Academy of Compounding Pharmacists issued a statement to patients and providers saying that, although many pharmacies had received a warning letter dated Feb. 17 from Ther-Rx that they could no longer compound an FDA-approved medication to which Ther-Rx had exclusive marketing rights, "In our estimation, the letter is nothing more than a ‘scare tactic.’ ... Pharmacists can legally compound FDA approved products when a prescriber determines that the compounded preparation is more clinically appropriate for an individual patient."

David G. Miller, R.Ph., the group’s chief executive, said in an e-mail that the answer to the question of whether 17P can legally be compounded, in light of an FDA-approved product with market exclusivity, was "clear and simple."

"If a prescriber determines that a compounded preparation of a medication is in the best clinical interest of his or her patient and discusses the available options with a pharmacist, there are no statutory or regulatory prohibitions on that professional decision," Mr. Miller said.

One criticism raised by Mr. Miller and others was that Makena had received FDA approval in part as a way to offer 17P with guaranteed consistency across the market. However, Ther-Rx’s parent company, KV Pharmaceutical Company, has recently faced legal trouble over active-ingredient inconsistencies and false labeling of its FDA-approved products.

Just last week, KV Pharmaceutical Company’s former chief executive pleaded guilty to breaching federal food and drug statutes by selling oversized morphine tablets.

Dr. Harman said he had no relevant financial disclosures.

How do you solve a problem like Makena?

In February, when the Missouri-based pharmaceutical firm Ther-Rx received from the Food and Drug Administration the exclusive right to market a progesterone injection formerly known as 17P, maternal-fetal health advocates cheered.

The drug 17-alpha Hydroxyprogesterone caproate, or 17P, had originally received FDA approval in the 1950s for multiple indications, one of which was preventing preterm labor, but it came off the market in 2000 because of a manufacturing issue. After a publicly funded 2003 study of 463 women found weekly injections of 17P effective in preventing preterm labor among women at high risk (N. Engl. J. Med. 2003;348:2379-85), the drug gained widespread use, even though practitioners had to order it from compounding pharmacies.

In February, the March of Dimes lauded the FDA’s decision to approve 17P under its orphan drug program, guaranteeing market exclusivity to Ther-Rx, which will market 17P as Makena. The March of Dimes praised the FDA’s decision as likely to standardize the quality and consistency of the product and, presumably, to lessen the "logistical and financial barriers" to patient access, the organization said in a press statement.

And then everyone learned Makena’s price. This month, Ther-Rx revealed that each Makena shot would cost $1,500 – where it had previously cost between $10 and $50. The ideal treatment starts at approximately 16-18 weeks’ gestation and continues until 36 weeks’ gestation, so a woman might receive as many as 20 doses of 17P during her pregnancy. Although the company offered to offer the drug free to lower-income uninsured households, the full cost to insurers including Medicaid, according to an estimate provided by the American College of Obstetricians and Gynecologists, would be about $30,000 per pregnancy.

Dr. Christopher Harman, director of the Center for Advanced Fetal Care and chief of obstetrics and gynecology at the University of Maryland Medical Center, Baltimore, called Makena’s pricing "an outrage."

"This stuff is really cheap to make – this would be as if a brand-new company somehow got a patent on Tylenol or aspirin and decided to sell it at $100 a pill," said Dr. Harman. Makena’s pricing "strikes at the core of women at highest risk for preterm birth already" – young African American women. "We may remove their best hopes for having a close-to-term birth," he said in an interview.

Ther-Rx did not answer calls seeking comment. On its Web site, the company said: "We appreciate the concerns expressed by multiple audiences and are committed to working collaboratively with all interested parties to make this vital medication even more available and affordable to women across the country."

Dr. Harman said he has been using 17P for about 5 years in his patients, mostly low-income women in inner-city Maryland, and that between 100,000 and 140,000 women a year are probably eligible for treatment with 17P in the United States.

"Nobody is saying the company was out to deprive any group of women, but as often occurs when financial decisions are made, they have a disproportionate impact on the people who need the treatment the most," he said.

Other physicians were quick to express outrage online when they learned about the price – mostly at the manufacturer, but also at the March of Dimes for supporting Makena’s approval.

Dr. Jennifer Gunter, an ob.gyn, author, and pain physician at Kaiser Permanente in San Francisco, used her informational Web site, The Preemie Primer, to criticize what she considered to be March of Dimes’ naivete in celebrating the approval of Makena before learning of KV Pharmaceutical Company’s pricing intentions.

On March 11, three professional organizations, the American Academy of Pediatrics, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine, published a joint letter to Ther-Rx, a subsidiary of KV Pharmaceutical Company, critical of the pricing, stating that: "in our current climate of controlling health care costs in the United States an added cost of $30,000 for as many as 140,000 pregnancies per year, or 4.2 billion dollars, is a staggering figure."

Sen. Sherrod Brown (D-OH), slammed the pricing in his own letter to the company, stating that the $1,500 per shot price tag was "exorbitant," and that Ther-Rx was "taking advantage of FDA approval at the expense of women, children, and federal and state budgets." A spokesman for Sen. Brown said that, as of March 15, he had not received a response from the company.

Dr. Harman said the best people to pressure the FDA and government to reexamine the Makena decision were patients and the public. Last week, patients were among the most outspoken critics of Ther-Rx and KV Pharmaceutical Company, and to a lesser degree March of Dimes, which issued another statement March 14 in the form of a letter to the manufacturer saying that it was "deeply concerned that the cost of this lifesaving treatment could be put out of reach to thousands of women at risk for preterm delivery."

One patient group created a Facebook page specifically to shame the manufacturer. Sarah Vandermeulen, age 30 years, of Paducah, Ky., was quick to join up. Ms. Vandermeulen said that in 2000, she had delivered a 1 lb 3oz baby at 23 weeks’ gestation who did not survive. In 2009, she became pregnant again and had heard about 17P from members of an online support group "I promptly asked my doctor if this was for me, and she agreed I may benefit from taking 17P," she said in an interview. Ms. Vandermeulen delivered a healthy baby at 37 weeks’ gestation.

"I obviously have no comparison or scientific data, but I do believe that 17P at the very least delayed preterm labor," said Ms. Vandermeulen. "I know that other women are scared for their current and future pregnancies. Many swear they wouldn’t have carried to term without 17P and are terrified that they will be denied this treatment option. I can tell you that there are discussions taking place on what we can do to help change the price increase."

The same question is also vexing clinicians. Dr. Harman, whose university clinic handles about 1,500 high-risk babies per year and whose referring hospitals deliver a total of about 9,000, said that he was concerned that local compounding pharmacists would not make the medication now that it is FDA-approved. "We’re investigating our possibilities," he said. "We may end up a producer ourselves," he said, adding that this was only "anxious conversation" in the near term.

The compounding pharmacies for now are striking a defiant pose. On March 14, the International Academy of Compounding Pharmacists issued a statement to patients and providers saying that, although many pharmacies had received a warning letter dated Feb. 17 from Ther-Rx that they could no longer compound an FDA-approved medication to which Ther-Rx had exclusive marketing rights, "In our estimation, the letter is nothing more than a ‘scare tactic.’ ... Pharmacists can legally compound FDA approved products when a prescriber determines that the compounded preparation is more clinically appropriate for an individual patient."

David G. Miller, R.Ph., the group’s chief executive, said in an e-mail that the answer to the question of whether 17P can legally be compounded, in light of an FDA-approved product with market exclusivity, was "clear and simple."

"If a prescriber determines that a compounded preparation of a medication is in the best clinical interest of his or her patient and discusses the available options with a pharmacist, there are no statutory or regulatory prohibitions on that professional decision," Mr. Miller said.

One criticism raised by Mr. Miller and others was that Makena had received FDA approval in part as a way to offer 17P with guaranteed consistency across the market. However, Ther-Rx’s parent company, KV Pharmaceutical Company, has recently faced legal trouble over active-ingredient inconsistencies and false labeling of its FDA-approved products.

Just last week, KV Pharmaceutical Company’s former chief executive pleaded guilty to breaching federal food and drug statutes by selling oversized morphine tablets.

Dr. Harman said he had no relevant financial disclosures.

How do you solve a problem like Makena?

In February, when the Missouri-based pharmaceutical firm Ther-Rx received from the Food and Drug Administration the exclusive right to market a progesterone injection formerly known as 17P, maternal-fetal health advocates cheered.

The drug 17-alpha Hydroxyprogesterone caproate, or 17P, had originally received FDA approval in the 1950s for multiple indications, one of which was preventing preterm labor, but it came off the market in 2000 because of a manufacturing issue. After a publicly funded 2003 study of 463 women found weekly injections of 17P effective in preventing preterm labor among women at high risk (N. Engl. J. Med. 2003;348:2379-85), the drug gained widespread use, even though practitioners had to order it from compounding pharmacies.

In February, the March of Dimes lauded the FDA’s decision to approve 17P under its orphan drug program, guaranteeing market exclusivity to Ther-Rx, which will market 17P as Makena. The March of Dimes praised the FDA’s decision as likely to standardize the quality and consistency of the product and, presumably, to lessen the "logistical and financial barriers" to patient access, the organization said in a press statement.

And then everyone learned Makena’s price. This month, Ther-Rx revealed that each Makena shot would cost $1,500 – where it had previously cost between $10 and $50. The ideal treatment starts at approximately 16-18 weeks’ gestation and continues until 36 weeks’ gestation, so a woman might receive as many as 20 doses of 17P during her pregnancy. Although the company offered to offer the drug free to lower-income uninsured households, the full cost to insurers including Medicaid, according to an estimate provided by the American College of Obstetricians and Gynecologists, would be about $30,000 per pregnancy.

Dr. Christopher Harman, director of the Center for Advanced Fetal Care and chief of obstetrics and gynecology at the University of Maryland Medical Center, Baltimore, called Makena’s pricing "an outrage."

"This stuff is really cheap to make – this would be as if a brand-new company somehow got a patent on Tylenol or aspirin and decided to sell it at $100 a pill," said Dr. Harman. Makena’s pricing "strikes at the core of women at highest risk for preterm birth already" – young African American women. "We may remove their best hopes for having a close-to-term birth," he said in an interview.

Ther-Rx did not answer calls seeking comment. On its Web site, the company said: "We appreciate the concerns expressed by multiple audiences and are committed to working collaboratively with all interested parties to make this vital medication even more available and affordable to women across the country."

Dr. Harman said he has been using 17P for about 5 years in his patients, mostly low-income women in inner-city Maryland, and that between 100,000 and 140,000 women a year are probably eligible for treatment with 17P in the United States.

"Nobody is saying the company was out to deprive any group of women, but as often occurs when financial decisions are made, they have a disproportionate impact on the people who need the treatment the most," he said.

Other physicians were quick to express outrage online when they learned about the price – mostly at the manufacturer, but also at the March of Dimes for supporting Makena’s approval.

Dr. Jennifer Gunter, an ob.gyn, author, and pain physician at Kaiser Permanente in San Francisco, used her informational Web site, The Preemie Primer, to criticize what she considered to be March of Dimes’ naivete in celebrating the approval of Makena before learning of KV Pharmaceutical Company’s pricing intentions.

On March 11, three professional organizations, the American Academy of Pediatrics, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine, published a joint letter to Ther-Rx, a subsidiary of KV Pharmaceutical Company, critical of the pricing, stating that: "in our current climate of controlling health care costs in the United States an added cost of $30,000 for as many as 140,000 pregnancies per year, or 4.2 billion dollars, is a staggering figure."

Sen. Sherrod Brown (D-OH), slammed the pricing in his own letter to the company, stating that the $1,500 per shot price tag was "exorbitant," and that Ther-Rx was "taking advantage of FDA approval at the expense of women, children, and federal and state budgets." A spokesman for Sen. Brown said that, as of March 15, he had not received a response from the company.

Dr. Harman said the best people to pressure the FDA and government to reexamine the Makena decision were patients and the public. Last week, patients were among the most outspoken critics of Ther-Rx and KV Pharmaceutical Company, and to a lesser degree March of Dimes, which issued another statement March 14 in the form of a letter to the manufacturer saying that it was "deeply concerned that the cost of this lifesaving treatment could be put out of reach to thousands of women at risk for preterm delivery."

One patient group created a Facebook page specifically to shame the manufacturer. Sarah Vandermeulen, age 30 years, of Paducah, Ky., was quick to join up. Ms. Vandermeulen said that in 2000, she had delivered a 1 lb 3oz baby at 23 weeks’ gestation who did not survive. In 2009, she became pregnant again and had heard about 17P from members of an online support group "I promptly asked my doctor if this was for me, and she agreed I may benefit from taking 17P," she said in an interview. Ms. Vandermeulen delivered a healthy baby at 37 weeks’ gestation.

"I obviously have no comparison or scientific data, but I do believe that 17P at the very least delayed preterm labor," said Ms. Vandermeulen. "I know that other women are scared for their current and future pregnancies. Many swear they wouldn’t have carried to term without 17P and are terrified that they will be denied this treatment option. I can tell you that there are discussions taking place on what we can do to help change the price increase."

The same question is also vexing clinicians. Dr. Harman, whose university clinic handles about 1,500 high-risk babies per year and whose referring hospitals deliver a total of about 9,000, said that he was concerned that local compounding pharmacists would not make the medication now that it is FDA-approved. "We’re investigating our possibilities," he said. "We may end up a producer ourselves," he said, adding that this was only "anxious conversation" in the near term.

The compounding pharmacies for now are striking a defiant pose. On March 14, the International Academy of Compounding Pharmacists issued a statement to patients and providers saying that, although many pharmacies had received a warning letter dated Feb. 17 from Ther-Rx that they could no longer compound an FDA-approved medication to which Ther-Rx had exclusive marketing rights, "In our estimation, the letter is nothing more than a ‘scare tactic.’ ... Pharmacists can legally compound FDA approved products when a prescriber determines that the compounded preparation is more clinically appropriate for an individual patient."

David G. Miller, R.Ph., the group’s chief executive, said in an e-mail that the answer to the question of whether 17P can legally be compounded, in light of an FDA-approved product with market exclusivity, was "clear and simple."

"If a prescriber determines that a compounded preparation of a medication is in the best clinical interest of his or her patient and discusses the available options with a pharmacist, there are no statutory or regulatory prohibitions on that professional decision," Mr. Miller said.

One criticism raised by Mr. Miller and others was that Makena had received FDA approval in part as a way to offer 17P with guaranteed consistency across the market. However, Ther-Rx’s parent company, KV Pharmaceutical Company, has recently faced legal trouble over active-ingredient inconsistencies and false labeling of its FDA-approved products.

Just last week, KV Pharmaceutical Company’s former chief executive pleaded guilty to breaching federal food and drug statutes by selling oversized morphine tablets.

Dr. Harman said he had no relevant financial disclosures.

How do you solve a problem like Makena?

In February, when the Missouri-based pharmaceutical firm Ther-Rx received from the Food and Drug Administration the exclusive right to market a progesterone injection formerly known as 17P, maternal-fetal health advocates cheered.

The drug 17-alpha Hydroxyprogesterone caproate, or 17P, had originally received FDA approval in the 1950s for multiple indications, one of which was preventing preterm labor, but it came off the market in 2000 because of a manufacturing issue. After a publicly funded 2003 study of 463 women found weekly injections of 17P effective in preventing preterm labor among women at high risk (N. Engl. J. Med. 2003;348:2379-85), the drug gained widespread use, even though practitioners had to order it from compounding pharmacies.

In February, the March of Dimes lauded the FDA’s decision to approve 17P under its orphan drug program, guaranteeing market exclusivity to Ther-Rx, which will market 17P as Makena. The March of Dimes praised the FDA’s decision as likely to standardize the quality and consistency of the product and, presumably, to lessen the "logistical and financial barriers" to patient access, the organization said in a press statement.

And then everyone learned Makena’s price. This month, Ther-Rx revealed that each Makena shot would cost $1,500 – where it had previously cost between $10 and $50. The ideal treatment starts at approximately 16-18 weeks’ gestation and continues until 36 weeks’ gestation, so a woman might receive as many as 20 doses of 17P during her pregnancy. Although the company offered to offer the drug free to lower-income uninsured households, the full cost to insurers including Medicaid, according to an estimate provided by the American College of Obstetricians and Gynecologists, would be about $30,000 per pregnancy.

Dr. Christopher Harman, director of the Center for Advanced Fetal Care and chief of obstetrics and gynecology at the University of Maryland Medical Center, Baltimore, called Makena’s pricing "an outrage."

"This stuff is really cheap to make – this would be as if a brand-new company somehow got a patent on Tylenol or aspirin and decided to sell it at $100 a pill," said Dr. Harman. Makena’s pricing "strikes at the core of women at highest risk for preterm birth already" – young African American women. "We may remove their best hopes for having a close-to-term birth," he said in an interview.

Ther-Rx did not answer calls seeking comment. On its Web site, the company said: "We appreciate the concerns expressed by multiple audiences and are committed to working collaboratively with all interested parties to make this vital medication even more available and affordable to women across the country."

Dr. Harman said he has been using 17P for about 5 years in his patients, mostly low-income women in inner-city Maryland, and that between 100,000 and 140,000 women a year are probably eligible for treatment with 17P in the United States.

"Nobody is saying the company was out to deprive any group of women, but as often occurs when financial decisions are made, they have a disproportionate impact on the people who need the treatment the most," he said.

Other physicians were quick to express outrage online when they learned about the price – mostly at the manufacturer, but also at the March of Dimes for supporting Makena’s approval.

Dr. Jennifer Gunter, an ob.gyn, author, and pain physician at Kaiser Permanente in San Francisco, used her informational Web site, The Preemie Primer, to criticize what she considered to be March of Dimes’ naivete in celebrating the approval of Makena before learning of KV Pharmaceutical Company’s pricing intentions.

On March 11, three professional organizations, the American Academy of Pediatrics, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine, published a joint letter to Ther-Rx, a subsidiary of KV Pharmaceutical Company, critical of the pricing, stating that: "in our current climate of controlling health care costs in the United States an added cost of $30,000 for as many as 140,000 pregnancies per year, or 4.2 billion dollars, is a staggering figure."

Sen. Sherrod Brown (D-OH), slammed the pricing in his own letter to the company, stating that the $1,500 per shot price tag was "exorbitant," and that Ther-Rx was "taking advantage of FDA approval at the expense of women, children, and federal and state budgets." A spokesman for Sen. Brown said that, as of March 15, he had not received a response from the company.

Dr. Harman said the best people to pressure the FDA and government to reexamine the Makena decision were patients and the public. Last week, patients were among the most outspoken critics of Ther-Rx and KV Pharmaceutical Company, and to a lesser degree March of Dimes, which issued another statement March 14 in the form of a letter to the manufacturer saying that it was "deeply concerned that the cost of this lifesaving treatment could be put out of reach to thousands of women at risk for preterm delivery."

One patient group created a Facebook page specifically to shame the manufacturer. Sarah Vandermeulen, age 30 years, of Paducah, Ky., was quick to join up. Ms. Vandermeulen said that in 2000, she had delivered a 1 lb 3oz baby at 23 weeks’ gestation who did not survive. In 2009, she became pregnant again and had heard about 17P from members of an online support group "I promptly asked my doctor if this was for me, and she agreed I may benefit from taking 17P," she said in an interview. Ms. Vandermeulen delivered a healthy baby at 37 weeks’ gestation.

"I obviously have no comparison or scientific data, but I do believe that 17P at the very least delayed preterm labor," said Ms. Vandermeulen. "I know that other women are scared for their current and future pregnancies. Many swear they wouldn’t have carried to term without 17P and are terrified that they will be denied this treatment option. I can tell you that there are discussions taking place on what we can do to help change the price increase."

The same question is also vexing clinicians. Dr. Harman, whose university clinic handles about 1,500 high-risk babies per year and whose referring hospitals deliver a total of about 9,000, said that he was concerned that local compounding pharmacists would not make the medication now that it is FDA-approved. "We’re investigating our possibilities," he said. "We may end up a producer ourselves," he said, adding that this was only "anxious conversation" in the near term.

The compounding pharmacies for now are striking a defiant pose. On March 14, the International Academy of Compounding Pharmacists issued a statement to patients and providers saying that, although many pharmacies had received a warning letter dated Feb. 17 from Ther-Rx that they could no longer compound an FDA-approved medication to which Ther-Rx had exclusive marketing rights, "In our estimation, the letter is nothing more than a ‘scare tactic.’ ... Pharmacists can legally compound FDA approved products when a prescriber determines that the compounded preparation is more clinically appropriate for an individual patient."

David G. Miller, R.Ph., the group’s chief executive, said in an e-mail that the answer to the question of whether 17P can legally be compounded, in light of an FDA-approved product with market exclusivity, was "clear and simple."

"If a prescriber determines that a compounded preparation of a medication is in the best clinical interest of his or her patient and discusses the available options with a pharmacist, there are no statutory or regulatory prohibitions on that professional decision," Mr. Miller said.

One criticism raised by Mr. Miller and others was that Makena had received FDA approval in part as a way to offer 17P with guaranteed consistency across the market. However, Ther-Rx’s parent company, KV Pharmaceutical Company, has recently faced legal trouble over active-ingredient inconsistencies and false labeling of its FDA-approved products.

Just last week, KV Pharmaceutical Company’s former chief executive pleaded guilty to breaching federal food and drug statutes by selling oversized morphine tablets.

Dr. Harman said he had no relevant financial disclosures.

The clinical name "granulomatosis with polyangiitis (Wegener’s)" should replace "Wegener’s granulomatosis", according to a recommendation issued jointly by the American College of Rheumatology, the European League Against Rheumatism, and the American Society of Nephrology.

The new name may be expressed as its acronym, GPA, suggested Dr. Ronald J. Falk, the Doc J. Thurston Distinguished Professor of Medicine and chief of the division of nephrology and hypertension at the University of North Carolina, Chapel Hill, and his associates. The parenthetical would be dropped once enough time had passed that the old name was not longer used in the literature, according to the article published in the April issue of Arthritis & Rheumatism (doi:10.1002/art.30286).

The motivation behind the suggested change is a well-documented drive to move away from eponymous disease names in general and from those named after Nazis and other war criminals in particular.

The push to remove Wegener’s eponym began with the 2006 publication of an article by Dr. Alexander Woywodt of the University of Hanover, Germany (Lancet 2006;367:1296-7), and his colleagues, detailing what they had uncovered about Frederich Wegener’s activities during and after World War II.

Wegener, who died in 1990, was never tried for war crimes. However, Wegener had joined the Nazi paramilitary "Sturmabteilung," or brownshirts, in 1932, Dr. Woywodt and his colleagues learned, and retained his Nazi affiliations until the end of World War II. In 1938, Wegener became a lieutenant colonel in the medical corps and, in 1939, arrived in Lodz to serve as a military pathologist. Dr. Wegener later worked for the health office of the local civil municipal authority in Lodz, where his mentor was an ardent supporter of racial hygiene theory, according to Dr. Woywodt.

Dr. Woywodt and his colleagues had recommended that, in light of this finding, "Wegener’s granulomatosis" be changed to "ANCA-associated granulomatous vasculitis." The attempt at a name change has not caught on.

Wegener was not the only Nazi physician with an eponymous rheumatic disease: In 2003, journal editors agreed to stop using the term Reiter’s syndrome, which had been named after Hans Reiter, who was president of Nazi Germany’s Reich health ministry before and during World War II and oversaw human experiments at the Buchenwald concentration camp.

Over the past several years the discussion of tainted eponyms has been accompanied by a public debate over whether to abolish eponyms in disease altogether (BMJ 2007;335:424).

In an editorial accompanying Dr. Falk and his colleagues’ article, Dr. Eric L. Matteson, chair division of rheumatology at the Mayo Clinic in Rochester, Minn., and Dr. Richard S. Panush, chair of medicine at Saint Barnabas Medical Center in Livingston, N.J., take the abolitionist position, writing that rheumatologists "should lead the way in eliminating the use of eponymous titles for diseases. "They can reflect historical inaccuracies, jingoism, and political influence, and accord legitimacy to tainted and unethical research."

Other researchers with an interest in Nazi eponyms, including Dr. Rael Strous of Sackler Faculty of Medicine at Tel Aviv University, have not shared this view entirely. In a 2007 article cataloging diseases named in honor of Nazis and their victims (IMAJ 2007;9:207-14), Dr. Strous argued that the aggressors’ eponyms should be abolished. However, he noted, many diseases have also been named for physicians who became the Nazis’ victims.

The victims’ eponyms "should be strengthened and perpetuated," Dr. Strous wrote. "The maintenance of these eponyms would serve as a historical epithet for those who suffered."

The clinical name "granulomatosis with polyangiitis (Wegener’s)" should replace "Wegener’s granulomatosis", according to a recommendation issued jointly by the American College of Rheumatology, the European League Against Rheumatism, and the American Society of Nephrology.

The new name may be expressed as its acronym, GPA, suggested Dr. Ronald J. Falk, the Doc J. Thurston Distinguished Professor of Medicine and chief of the division of nephrology and hypertension at the University of North Carolina, Chapel Hill, and his associates. The parenthetical would be dropped once enough time had passed that the old name was not longer used in the literature, according to the article published in the April issue of Arthritis & Rheumatism (doi:10.1002/art.30286).

The motivation behind the suggested change is a well-documented drive to move away from eponymous disease names in general and from those named after Nazis and other war criminals in particular.

The push to remove Wegener’s eponym began with the 2006 publication of an article by Dr. Alexander Woywodt of the University of Hanover, Germany (Lancet 2006;367:1296-7), and his colleagues, detailing what they had uncovered about Frederich Wegener’s activities during and after World War II.

Wegener, who died in 1990, was never tried for war crimes. However, Wegener had joined the Nazi paramilitary "Sturmabteilung," or brownshirts, in 1932, Dr. Woywodt and his colleagues learned, and retained his Nazi affiliations until the end of World War II. In 1938, Wegener became a lieutenant colonel in the medical corps and, in 1939, arrived in Lodz to serve as a military pathologist. Dr. Wegener later worked for the health office of the local civil municipal authority in Lodz, where his mentor was an ardent supporter of racial hygiene theory, according to Dr. Woywodt.

Dr. Woywodt and his colleagues had recommended that, in light of this finding, "Wegener’s granulomatosis" be changed to "ANCA-associated granulomatous vasculitis." The attempt at a name change has not caught on.

Wegener was not the only Nazi physician with an eponymous rheumatic disease: In 2003, journal editors agreed to stop using the term Reiter’s syndrome, which had been named after Hans Reiter, who was president of Nazi Germany’s Reich health ministry before and during World War II and oversaw human experiments at the Buchenwald concentration camp.

Over the past several years the discussion of tainted eponyms has been accompanied by a public debate over whether to abolish eponyms in disease altogether (BMJ 2007;335:424).

In an editorial accompanying Dr. Falk and his colleagues’ article, Dr. Eric L. Matteson, chair division of rheumatology at the Mayo Clinic in Rochester, Minn., and Dr. Richard S. Panush, chair of medicine at Saint Barnabas Medical Center in Livingston, N.J., take the abolitionist position, writing that rheumatologists "should lead the way in eliminating the use of eponymous titles for diseases. "They can reflect historical inaccuracies, jingoism, and political influence, and accord legitimacy to tainted and unethical research."

Other researchers with an interest in Nazi eponyms, including Dr. Rael Strous of Sackler Faculty of Medicine at Tel Aviv University, have not shared this view entirely. In a 2007 article cataloging diseases named in honor of Nazis and their victims (IMAJ 2007;9:207-14), Dr. Strous argued that the aggressors’ eponyms should be abolished. However, he noted, many diseases have also been named for physicians who became the Nazis’ victims.

The victims’ eponyms "should be strengthened and perpetuated," Dr. Strous wrote. "The maintenance of these eponyms would serve as a historical epithet for those who suffered."

The clinical name "granulomatosis with polyangiitis (Wegener’s)" should replace "Wegener’s granulomatosis", according to a recommendation issued jointly by the American College of Rheumatology, the European League Against Rheumatism, and the American Society of Nephrology.

The new name may be expressed as its acronym, GPA, suggested Dr. Ronald J. Falk, the Doc J. Thurston Distinguished Professor of Medicine and chief of the division of nephrology and hypertension at the University of North Carolina, Chapel Hill, and his associates. The parenthetical would be dropped once enough time had passed that the old name was not longer used in the literature, according to the article published in the April issue of Arthritis & Rheumatism (doi:10.1002/art.30286).

The motivation behind the suggested change is a well-documented drive to move away from eponymous disease names in general and from those named after Nazis and other war criminals in particular.

The push to remove Wegener’s eponym began with the 2006 publication of an article by Dr. Alexander Woywodt of the University of Hanover, Germany (Lancet 2006;367:1296-7), and his colleagues, detailing what they had uncovered about Frederich Wegener’s activities during and after World War II.

Wegener, who died in 1990, was never tried for war crimes. However, Wegener had joined the Nazi paramilitary "Sturmabteilung," or brownshirts, in 1932, Dr. Woywodt and his colleagues learned, and retained his Nazi affiliations until the end of World War II. In 1938, Wegener became a lieutenant colonel in the medical corps and, in 1939, arrived in Lodz to serve as a military pathologist. Dr. Wegener later worked for the health office of the local civil municipal authority in Lodz, where his mentor was an ardent supporter of racial hygiene theory, according to Dr. Woywodt.

Dr. Woywodt and his colleagues had recommended that, in light of this finding, "Wegener’s granulomatosis" be changed to "ANCA-associated granulomatous vasculitis." The attempt at a name change has not caught on.

Wegener was not the only Nazi physician with an eponymous rheumatic disease: In 2003, journal editors agreed to stop using the term Reiter’s syndrome, which had been named after Hans Reiter, who was president of Nazi Germany’s Reich health ministry before and during World War II and oversaw human experiments at the Buchenwald concentration camp.

Over the past several years the discussion of tainted eponyms has been accompanied by a public debate over whether to abolish eponyms in disease altogether (BMJ 2007;335:424).

In an editorial accompanying Dr. Falk and his colleagues’ article, Dr. Eric L. Matteson, chair division of rheumatology at the Mayo Clinic in Rochester, Minn., and Dr. Richard S. Panush, chair of medicine at Saint Barnabas Medical Center in Livingston, N.J., take the abolitionist position, writing that rheumatologists "should lead the way in eliminating the use of eponymous titles for diseases. "They can reflect historical inaccuracies, jingoism, and political influence, and accord legitimacy to tainted and unethical research."

Other researchers with an interest in Nazi eponyms, including Dr. Rael Strous of Sackler Faculty of Medicine at Tel Aviv University, have not shared this view entirely. In a 2007 article cataloging diseases named in honor of Nazis and their victims (IMAJ 2007;9:207-14), Dr. Strous argued that the aggressors’ eponyms should be abolished. However, he noted, many diseases have also been named for physicians who became the Nazis’ victims.

The victims’ eponyms "should be strengthened and perpetuated," Dr. Strous wrote. "The maintenance of these eponyms would serve as a historical epithet for those who suffered."