NEW ORLEANS — The presence of a favorable pattern of cerebral perfusion on magnetic resonance imaging may tell physicians which patients with acute ischemic stroke stand to benefit from thrombolysis even hours after the onset of symptoms.

Findings from two phase II studies using MRI show that some patients were able to safely receive a thrombolytic drug as long as 9 hours after the onset of their stroke symptoms. Results from the most recent of these studies were reported at the 30th International Stroke Conference.

“These are the first trials to test the hypothesis that selecting patients with favorable imaging patterns can extend treatment beyond the current 3-hour window,” said Anthony J. Furlan, M.D., head of the section of stroke and neurologic intensive care at the Cleveland Clinic and principal investigator of the new study. Results from the prior, European, study were published in January (Stroke 2005;36:66-73).

“If this hypothesis is borne out, it could have an enormous impact on how we use thrombolytic therapy for stroke,” he added. “It has the potential to at least triple the number of acute stroke patients who are eligible for thrombolytic therapy.”

Like the study done in Europe, Dr. Furlan's research used a combination of perfusion-weighted and diffusion-weighted imaging by MR to identify patients with at least a 20% mismatch between the two. The mismatch is a marker for patients with a significant penumbra region in their brain, tissue that might be salvageable by thrombolytic therapy because it is still viable despite being hypoperfused. “Most patients who made it to MR were eligible,” he said.

The other novel feature of both the European and U.S. studies was the thrombolytic drug used: desmoteplase, a plasminogen activator derived from vampire-bat saliva. Desmoteplase has several potential advantages over tissue plasminogen activator (TPA). In animal studies, desmoteplase showed no neurotoxicity, and it did not activate β-amyloid, a process that's been linked to an increased risk of intracranial hemorrhage.

Desmoteplase also has very high specificity and selectivity for fibrin and a long serum half-life of 4 hours. This last property means that it can be given as a bolus dose and may also help prevent acute reocclusion of newly opened arteries.

Desmoteplase is being developed in the United States by Forest Laboratories and in Europe by PAION, a German drug company. Dr. Furlan is a consultant to both companies, and he received compensation from both for acting as a principal investigator in these and ongoing studies.

The U.S. study involved enrollment of 37 patients who all met the entry MR criteria. After randomization, 14 patients were treated with 90 mcg/kg desmoteplase, 15 received 125 mcg/kg desmoteplase, and 8 received placebo. The average time to treatment was 7 hours. Although patients could enter treatment as long as 9 hours after the onset of their stroke symptoms, the top reason for excluding patients from the study was that they had gone beyond the 9-hour window.

The U.S. study's primary end point was the rate of symptomatic, intracranial hemorrhage (sICH), which occurred in none of the patients. In the prior European study, one sICH occurred among 15 patients treated with 90 mcg/kg and none among 15 patients treated with 125 mcg/kg. Thus, the overall rate of sICH in these two studies at these two doses was 1 among 59 treated patients, a 1.7% rate that was lower than the 6% rate with TPA in routine practice, noted Dr. Furlan at the conference, sponsored by the American Stroke Association.

In the European study, 30 patients received substantially higher doses of desmotoplase, and they had a 27% rate of sICH. In this higher-dose group, the lowest desmotoplase dose associated with intracranial hemorrhage was 294 mcg/kg.

The new study was not powered to show significant differences in clinical outcomes. The reperfusion rate was 38% in the control group, 18% in the 90-mcg/kg group, and 53% in the 125-mcg/kg group. Improved clinical outcomes at 90 days were seen in 25% of those in the placebo group, 29% of those in the low-dose arm, and 60% of those in the high-dose arm. There was no reduction of safety or efficacy in the patients treated 6-9 hours after their stroke onset, compared with those treated 3-6 hours after onset.

NEW ORLEANS — The presence of a favorable pattern of cerebral perfusion on magnetic resonance imaging may tell physicians which patients with acute ischemic stroke stand to benefit from thrombolysis even hours after the onset of symptoms.

Findings from two phase II studies using MRI show that some patients were able to safely receive a thrombolytic drug as long as 9 hours after the onset of their stroke symptoms. Results from the most recent of these studies were reported at the 30th International Stroke Conference.

“These are the first trials to test the hypothesis that selecting patients with favorable imaging patterns can extend treatment beyond the current 3-hour window,” said Anthony J. Furlan, M.D., head of the section of stroke and neurologic intensive care at the Cleveland Clinic and principal investigator of the new study. Results from the prior, European, study were published in January (Stroke 2005;36:66-73).

“If this hypothesis is borne out, it could have an enormous impact on how we use thrombolytic therapy for stroke,” he added. “It has the potential to at least triple the number of acute stroke patients who are eligible for thrombolytic therapy.”

Like the study done in Europe, Dr. Furlan's research used a combination of perfusion-weighted and diffusion-weighted imaging by MR to identify patients with at least a 20% mismatch between the two. The mismatch is a marker for patients with a significant penumbra region in their brain, tissue that might be salvageable by thrombolytic therapy because it is still viable despite being hypoperfused. “Most patients who made it to MR were eligible,” he said.

The other novel feature of both the European and U.S. studies was the thrombolytic drug used: desmoteplase, a plasminogen activator derived from vampire-bat saliva. Desmoteplase has several potential advantages over tissue plasminogen activator (TPA). In animal studies, desmoteplase showed no neurotoxicity, and it did not activate β-amyloid, a process that's been linked to an increased risk of intracranial hemorrhage.

Desmoteplase also has very high specificity and selectivity for fibrin and a long serum half-life of 4 hours. This last property means that it can be given as a bolus dose and may also help prevent acute reocclusion of newly opened arteries.

Desmoteplase is being developed in the United States by Forest Laboratories and in Europe by PAION, a German drug company. Dr. Furlan is a consultant to both companies, and he received compensation from both for acting as a principal investigator in these and ongoing studies.

The U.S. study involved enrollment of 37 patients who all met the entry MR criteria. After randomization, 14 patients were treated with 90 mcg/kg desmoteplase, 15 received 125 mcg/kg desmoteplase, and 8 received placebo. The average time to treatment was 7 hours. Although patients could enter treatment as long as 9 hours after the onset of their stroke symptoms, the top reason for excluding patients from the study was that they had gone beyond the 9-hour window.

The U.S. study's primary end point was the rate of symptomatic, intracranial hemorrhage (sICH), which occurred in none of the patients. In the prior European study, one sICH occurred among 15 patients treated with 90 mcg/kg and none among 15 patients treated with 125 mcg/kg. Thus, the overall rate of sICH in these two studies at these two doses was 1 among 59 treated patients, a 1.7% rate that was lower than the 6% rate with TPA in routine practice, noted Dr. Furlan at the conference, sponsored by the American Stroke Association.

In the European study, 30 patients received substantially higher doses of desmotoplase, and they had a 27% rate of sICH. In this higher-dose group, the lowest desmotoplase dose associated with intracranial hemorrhage was 294 mcg/kg.

The new study was not powered to show significant differences in clinical outcomes. The reperfusion rate was 38% in the control group, 18% in the 90-mcg/kg group, and 53% in the 125-mcg/kg group. Improved clinical outcomes at 90 days were seen in 25% of those in the placebo group, 29% of those in the low-dose arm, and 60% of those in the high-dose arm. There was no reduction of safety or efficacy in the patients treated 6-9 hours after their stroke onset, compared with those treated 3-6 hours after onset.

NEW ORLEANS — The presence of a favorable pattern of cerebral perfusion on magnetic resonance imaging may tell physicians which patients with acute ischemic stroke stand to benefit from thrombolysis even hours after the onset of symptoms.

Findings from two phase II studies using MRI show that some patients were able to safely receive a thrombolytic drug as long as 9 hours after the onset of their stroke symptoms. Results from the most recent of these studies were reported at the 30th International Stroke Conference.

“These are the first trials to test the hypothesis that selecting patients with favorable imaging patterns can extend treatment beyond the current 3-hour window,” said Anthony J. Furlan, M.D., head of the section of stroke and neurologic intensive care at the Cleveland Clinic and principal investigator of the new study. Results from the prior, European, study were published in January (Stroke 2005;36:66-73).

“If this hypothesis is borne out, it could have an enormous impact on how we use thrombolytic therapy for stroke,” he added. “It has the potential to at least triple the number of acute stroke patients who are eligible for thrombolytic therapy.”

Like the study done in Europe, Dr. Furlan's research used a combination of perfusion-weighted and diffusion-weighted imaging by MR to identify patients with at least a 20% mismatch between the two. The mismatch is a marker for patients with a significant penumbra region in their brain, tissue that might be salvageable by thrombolytic therapy because it is still viable despite being hypoperfused. “Most patients who made it to MR were eligible,” he said.

The other novel feature of both the European and U.S. studies was the thrombolytic drug used: desmoteplase, a plasminogen activator derived from vampire-bat saliva. Desmoteplase has several potential advantages over tissue plasminogen activator (TPA). In animal studies, desmoteplase showed no neurotoxicity, and it did not activate β-amyloid, a process that's been linked to an increased risk of intracranial hemorrhage.

Desmoteplase also has very high specificity and selectivity for fibrin and a long serum half-life of 4 hours. This last property means that it can be given as a bolus dose and may also help prevent acute reocclusion of newly opened arteries.

Desmoteplase is being developed in the United States by Forest Laboratories and in Europe by PAION, a German drug company. Dr. Furlan is a consultant to both companies, and he received compensation from both for acting as a principal investigator in these and ongoing studies.

The U.S. study involved enrollment of 37 patients who all met the entry MR criteria. After randomization, 14 patients were treated with 90 mcg/kg desmoteplase, 15 received 125 mcg/kg desmoteplase, and 8 received placebo. The average time to treatment was 7 hours. Although patients could enter treatment as long as 9 hours after the onset of their stroke symptoms, the top reason for excluding patients from the study was that they had gone beyond the 9-hour window.

The U.S. study's primary end point was the rate of symptomatic, intracranial hemorrhage (sICH), which occurred in none of the patients. In the prior European study, one sICH occurred among 15 patients treated with 90 mcg/kg and none among 15 patients treated with 125 mcg/kg. Thus, the overall rate of sICH in these two studies at these two doses was 1 among 59 treated patients, a 1.7% rate that was lower than the 6% rate with TPA in routine practice, noted Dr. Furlan at the conference, sponsored by the American Stroke Association.

In the European study, 30 patients received substantially higher doses of desmotoplase, and they had a 27% rate of sICH. In this higher-dose group, the lowest desmotoplase dose associated with intracranial hemorrhage was 294 mcg/kg.

The new study was not powered to show significant differences in clinical outcomes. The reperfusion rate was 38% in the control group, 18% in the 90-mcg/kg group, and 53% in the 125-mcg/kg group. Improved clinical outcomes at 90 days were seen in 25% of those in the placebo group, 29% of those in the low-dose arm, and 60% of those in the high-dose arm. There was no reduction of safety or efficacy in the patients treated 6-9 hours after their stroke onset, compared with those treated 3-6 hours after onset.

ORLANDO, FLA. — Prompt percutaneous intervention in acute MI patients who present more than 12 hours after onset of chest pain and are no longer symptomatic results in significantly reduced final infarct size, compared with standard medical management, according to the findings of the first randomized trial of an acute invasive strategy in such patients.

These late presenters make up roughly 20% of all acute MI patients. Current American College of Cardiology/American Heart Association guidelines don't recommend mechanical or fibrinolytic reperfusion in late presenters unless they show up with a stuttering course and persistent pain. But the guidelines ought to be changed in light of this new evidence supporting the benefit of mechanical reperfusion in asymptomatic patients—even when applied late, Adnan Kastrati, M.D., said at the annual meeting of the American College of Cardiology.

He presented the results of the Beyond 12 Hours Reperfusion Alternative Evaluation (BRAVE-2) trial. The study involved 365 acute MI patients who had become asymptomatic by the time they presented 12-48 hours after onset of chest pain. Participants were randomized to prompt percutaneous intervention or standard medical therapy at 16 medical centers in Germany, Italy, and Austria.

The primary end point in BRAVE-2 was infarct size as determined by technetium-99m sestamibi scintigraphy 5-10 days post randomization. The scans showed the infarct involved a mean 8% of the left ventricle in patients who underwent mechanical reperfusion, significantly less than the 13% in those managed medically, said Dr. Kastrati of the German Heart Center, Munich.

The secondary study end point, the 30-day combined rate of all-cause mortality or recurrent MI, was 4% in the invasive group and 6% in those managed conservatively, a nonsignificant difference. The disparity in the 30-day incidence of unplanned percutaneous intervention was far more dramatic: 1% in the invasive group vs. 33% in those who were managed conservatively.

Cindy L. Grines, M.D., a member of the task force responsible for the ACC/AHA guidelines for management of acute MI, said the reason for the recommendation that reperfusion therapy generally be given only within 12 hours of symptom onset is the persuasive evidence from fibrinolytic clinical trials that the benefit drops off sharply when this therapy is applied more than a few hours after MI onset. The same phenomenon has been shown in animal studies.

However, BRAVE-2 shows a “pretty striking” reduction in infarct size, and it's certainly plausible that late restoration of high-grade coronary blood flow—readily achievable with mechanical reperfusion but not with thrombolytic therapy—might revive hibernating myocardium as one potential explanation for this benefit, said Dr. Grines of William Beaumont Hospital in Royal Oak, Mich.

Before the guidelines are changed, however, it will be important to see a confirmatory study, preferably one that addresses the question of whether all asymptomatic late presenters ought to go to the catheterization laboratory, or just those who have larger infarcts. Another key question concerns how quickly these late presenters need to undergo mechanical reperfusion.

Noting that the mean time from randomization to coronary angiography in BRAVE-2 was a mere 1.5 hours, Dr. Grines commented, “I don't know about you, but I don't routinely get out of bed at 2 in the morning to do angioplasty in patients who are 36 hours into their infarct and totally asymptomatic. It would be nice to have some additional information from trials as to which patients are likely to benefit with a reduction in infarct size.”

BRAVE-2 was funded by the German Heart Center, Lilly Deutschland, and Guidant.

ORLANDO, FLA. — Prompt percutaneous intervention in acute MI patients who present more than 12 hours after onset of chest pain and are no longer symptomatic results in significantly reduced final infarct size, compared with standard medical management, according to the findings of the first randomized trial of an acute invasive strategy in such patients.

These late presenters make up roughly 20% of all acute MI patients. Current American College of Cardiology/American Heart Association guidelines don't recommend mechanical or fibrinolytic reperfusion in late presenters unless they show up with a stuttering course and persistent pain. But the guidelines ought to be changed in light of this new evidence supporting the benefit of mechanical reperfusion in asymptomatic patients—even when applied late, Adnan Kastrati, M.D., said at the annual meeting of the American College of Cardiology.

He presented the results of the Beyond 12 Hours Reperfusion Alternative Evaluation (BRAVE-2) trial. The study involved 365 acute MI patients who had become asymptomatic by the time they presented 12-48 hours after onset of chest pain. Participants were randomized to prompt percutaneous intervention or standard medical therapy at 16 medical centers in Germany, Italy, and Austria.

The primary end point in BRAVE-2 was infarct size as determined by technetium-99m sestamibi scintigraphy 5-10 days post randomization. The scans showed the infarct involved a mean 8% of the left ventricle in patients who underwent mechanical reperfusion, significantly less than the 13% in those managed medically, said Dr. Kastrati of the German Heart Center, Munich.

The secondary study end point, the 30-day combined rate of all-cause mortality or recurrent MI, was 4% in the invasive group and 6% in those managed conservatively, a nonsignificant difference. The disparity in the 30-day incidence of unplanned percutaneous intervention was far more dramatic: 1% in the invasive group vs. 33% in those who were managed conservatively.

Cindy L. Grines, M.D., a member of the task force responsible for the ACC/AHA guidelines for management of acute MI, said the reason for the recommendation that reperfusion therapy generally be given only within 12 hours of symptom onset is the persuasive evidence from fibrinolytic clinical trials that the benefit drops off sharply when this therapy is applied more than a few hours after MI onset. The same phenomenon has been shown in animal studies.

However, BRAVE-2 shows a “pretty striking” reduction in infarct size, and it's certainly plausible that late restoration of high-grade coronary blood flow—readily achievable with mechanical reperfusion but not with thrombolytic therapy—might revive hibernating myocardium as one potential explanation for this benefit, said Dr. Grines of William Beaumont Hospital in Royal Oak, Mich.

Before the guidelines are changed, however, it will be important to see a confirmatory study, preferably one that addresses the question of whether all asymptomatic late presenters ought to go to the catheterization laboratory, or just those who have larger infarcts. Another key question concerns how quickly these late presenters need to undergo mechanical reperfusion.

Noting that the mean time from randomization to coronary angiography in BRAVE-2 was a mere 1.5 hours, Dr. Grines commented, “I don't know about you, but I don't routinely get out of bed at 2 in the morning to do angioplasty in patients who are 36 hours into their infarct and totally asymptomatic. It would be nice to have some additional information from trials as to which patients are likely to benefit with a reduction in infarct size.”

BRAVE-2 was funded by the German Heart Center, Lilly Deutschland, and Guidant.

ORLANDO, FLA. — Prompt percutaneous intervention in acute MI patients who present more than 12 hours after onset of chest pain and are no longer symptomatic results in significantly reduced final infarct size, compared with standard medical management, according to the findings of the first randomized trial of an acute invasive strategy in such patients.

These late presenters make up roughly 20% of all acute MI patients. Current American College of Cardiology/American Heart Association guidelines don't recommend mechanical or fibrinolytic reperfusion in late presenters unless they show up with a stuttering course and persistent pain. But the guidelines ought to be changed in light of this new evidence supporting the benefit of mechanical reperfusion in asymptomatic patients—even when applied late, Adnan Kastrati, M.D., said at the annual meeting of the American College of Cardiology.

He presented the results of the Beyond 12 Hours Reperfusion Alternative Evaluation (BRAVE-2) trial. The study involved 365 acute MI patients who had become asymptomatic by the time they presented 12-48 hours after onset of chest pain. Participants were randomized to prompt percutaneous intervention or standard medical therapy at 16 medical centers in Germany, Italy, and Austria.

The primary end point in BRAVE-2 was infarct size as determined by technetium-99m sestamibi scintigraphy 5-10 days post randomization. The scans showed the infarct involved a mean 8% of the left ventricle in patients who underwent mechanical reperfusion, significantly less than the 13% in those managed medically, said Dr. Kastrati of the German Heart Center, Munich.

The secondary study end point, the 30-day combined rate of all-cause mortality or recurrent MI, was 4% in the invasive group and 6% in those managed conservatively, a nonsignificant difference. The disparity in the 30-day incidence of unplanned percutaneous intervention was far more dramatic: 1% in the invasive group vs. 33% in those who were managed conservatively.

Cindy L. Grines, M.D., a member of the task force responsible for the ACC/AHA guidelines for management of acute MI, said the reason for the recommendation that reperfusion therapy generally be given only within 12 hours of symptom onset is the persuasive evidence from fibrinolytic clinical trials that the benefit drops off sharply when this therapy is applied more than a few hours after MI onset. The same phenomenon has been shown in animal studies.

However, BRAVE-2 shows a “pretty striking” reduction in infarct size, and it's certainly plausible that late restoration of high-grade coronary blood flow—readily achievable with mechanical reperfusion but not with thrombolytic therapy—might revive hibernating myocardium as one potential explanation for this benefit, said Dr. Grines of William Beaumont Hospital in Royal Oak, Mich.

Before the guidelines are changed, however, it will be important to see a confirmatory study, preferably one that addresses the question of whether all asymptomatic late presenters ought to go to the catheterization laboratory, or just those who have larger infarcts. Another key question concerns how quickly these late presenters need to undergo mechanical reperfusion.

Noting that the mean time from randomization to coronary angiography in BRAVE-2 was a mere 1.5 hours, Dr. Grines commented, “I don't know about you, but I don't routinely get out of bed at 2 in the morning to do angioplasty in patients who are 36 hours into their infarct and totally asymptomatic. It would be nice to have some additional information from trials as to which patients are likely to benefit with a reduction in infarct size.”

BRAVE-2 was funded by the German Heart Center, Lilly Deutschland, and Guidant.

ORLANDO, FLA. — A 600-mg loading dose of clopidogrel was safe and more effective than the standard 300-mg dose prior to percutaneous coronary intervention in a study with 255 patients.

“Pretreatment with a 600-mg loading dose of clopidogrel given 6 hours before a percutaneous revascularization procedure reduced periprocedural myocardial infarctions and improved short-term prognosis,” Germano Di Sciascio, M.D., said at the annual meeting of the American College of Cardiology.

“This is the first study to compare a 600-mg loading dose of clopidogrel with any other dose based on clinical outcomes, and the results are sufficient to change clinical practice,” commented Peter Berger, M.D., director of interventional catheterization at Duke University Medical Center, Durham, N.C.

Many physicians already use a 600-mg loading dose, especially for high-risk patients, because it produces quicker and more complete inhibition of platelet activity, noted Dr. Di Sciascio, professor of medicine and chairman of the department of cardiology at the University of Rome. But until now, the safety and efficacy of this dose had not been proven in a clinical study, and official guidelines had continued to endorse a 300-mg loading dose.

The Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty (ARMYDA-2) study enrolled patients with effort angina and a positive stress test result or a recent ST-segment elevation acute MI who were scheduled to undergo coronary angiography. All patients underwent catheterization at either of two Italian hospitals: the Campus Bio-Medico of the University of Rome, or the Vito Fazzi Hospital in Lecce. The study received no external funding. Of 329 patients who had angiography, 255 had significant coronary artery disease and went on to have a percutaneous intervention.

An average of 6 hours before revascularization, patients were treated with either a 300-mg or 600-mg dose of clopidogrel. All patients also received aspirin and a weight-adjusted regimen of intravenous heparin. Treatment with a glycoprotein IIb/IIIa receptor antagonist could also be used at the operator's discretion. Following each procedure, all patients continued to receive a standard, daily regimen of aspirin and clopidogrel.

The study's primary end point was the combined rate of death, MI, and target-vessel revascularization at 30 days after the procedure. MI was defined as a postprocedural elevation of serum creatine kinase-MB (CK-MB) to more than three times the upper limit of normal.

This end point was reached in 4% of patients who received a 600-mg loading dose, compared with 12% of patients who received a 300-mg loading dose, a statistically significant difference. There were no deaths. One patient who received the 600-mg dose required revascularization, and five patients in the 600-mg group had an MI. A total of 15 patients in the 300-mg group had an MI.

Several secondary end points also favored the higher loading dose, including any rise in CK-MB above the upper limit of normal, and an increase in troponin I levels.

No patient in the study had a major bleed or needed a transfusion following revascularization.

In a multivariable analysis that controlled for possible confounding factors such as stent length, use of a IIb/IIIa inhibitor, and use of a statin starting before the procedure, treatment with the higher clopidogrel loading dose cut the incidence of periprocedural MI by 52%. Pretreatment with a statin was also associated with a significant 72% reduction in MIs. The effect of statin pretreatment and the 600-mg loading dose was additive: Patients who received both had an 80% reduced risk of a periprocedural MI, Dr. Di Sciascio said.

ORLANDO, FLA. — A 600-mg loading dose of clopidogrel was safe and more effective than the standard 300-mg dose prior to percutaneous coronary intervention in a study with 255 patients.

“Pretreatment with a 600-mg loading dose of clopidogrel given 6 hours before a percutaneous revascularization procedure reduced periprocedural myocardial infarctions and improved short-term prognosis,” Germano Di Sciascio, M.D., said at the annual meeting of the American College of Cardiology.

“This is the first study to compare a 600-mg loading dose of clopidogrel with any other dose based on clinical outcomes, and the results are sufficient to change clinical practice,” commented Peter Berger, M.D., director of interventional catheterization at Duke University Medical Center, Durham, N.C.

Many physicians already use a 600-mg loading dose, especially for high-risk patients, because it produces quicker and more complete inhibition of platelet activity, noted Dr. Di Sciascio, professor of medicine and chairman of the department of cardiology at the University of Rome. But until now, the safety and efficacy of this dose had not been proven in a clinical study, and official guidelines had continued to endorse a 300-mg loading dose.

The Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty (ARMYDA-2) study enrolled patients with effort angina and a positive stress test result or a recent ST-segment elevation acute MI who were scheduled to undergo coronary angiography. All patients underwent catheterization at either of two Italian hospitals: the Campus Bio-Medico of the University of Rome, or the Vito Fazzi Hospital in Lecce. The study received no external funding. Of 329 patients who had angiography, 255 had significant coronary artery disease and went on to have a percutaneous intervention.

An average of 6 hours before revascularization, patients were treated with either a 300-mg or 600-mg dose of clopidogrel. All patients also received aspirin and a weight-adjusted regimen of intravenous heparin. Treatment with a glycoprotein IIb/IIIa receptor antagonist could also be used at the operator's discretion. Following each procedure, all patients continued to receive a standard, daily regimen of aspirin and clopidogrel.

The study's primary end point was the combined rate of death, MI, and target-vessel revascularization at 30 days after the procedure. MI was defined as a postprocedural elevation of serum creatine kinase-MB (CK-MB) to more than three times the upper limit of normal.

This end point was reached in 4% of patients who received a 600-mg loading dose, compared with 12% of patients who received a 300-mg loading dose, a statistically significant difference. There were no deaths. One patient who received the 600-mg dose required revascularization, and five patients in the 600-mg group had an MI. A total of 15 patients in the 300-mg group had an MI.

Several secondary end points also favored the higher loading dose, including any rise in CK-MB above the upper limit of normal, and an increase in troponin I levels.

No patient in the study had a major bleed or needed a transfusion following revascularization.

In a multivariable analysis that controlled for possible confounding factors such as stent length, use of a IIb/IIIa inhibitor, and use of a statin starting before the procedure, treatment with the higher clopidogrel loading dose cut the incidence of periprocedural MI by 52%. Pretreatment with a statin was also associated with a significant 72% reduction in MIs. The effect of statin pretreatment and the 600-mg loading dose was additive: Patients who received both had an 80% reduced risk of a periprocedural MI, Dr. Di Sciascio said.

ORLANDO, FLA. — A 600-mg loading dose of clopidogrel was safe and more effective than the standard 300-mg dose prior to percutaneous coronary intervention in a study with 255 patients.

“Pretreatment with a 600-mg loading dose of clopidogrel given 6 hours before a percutaneous revascularization procedure reduced periprocedural myocardial infarctions and improved short-term prognosis,” Germano Di Sciascio, M.D., said at the annual meeting of the American College of Cardiology.

“This is the first study to compare a 600-mg loading dose of clopidogrel with any other dose based on clinical outcomes, and the results are sufficient to change clinical practice,” commented Peter Berger, M.D., director of interventional catheterization at Duke University Medical Center, Durham, N.C.

Many physicians already use a 600-mg loading dose, especially for high-risk patients, because it produces quicker and more complete inhibition of platelet activity, noted Dr. Di Sciascio, professor of medicine and chairman of the department of cardiology at the University of Rome. But until now, the safety and efficacy of this dose had not been proven in a clinical study, and official guidelines had continued to endorse a 300-mg loading dose.

The Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty (ARMYDA-2) study enrolled patients with effort angina and a positive stress test result or a recent ST-segment elevation acute MI who were scheduled to undergo coronary angiography. All patients underwent catheterization at either of two Italian hospitals: the Campus Bio-Medico of the University of Rome, or the Vito Fazzi Hospital in Lecce. The study received no external funding. Of 329 patients who had angiography, 255 had significant coronary artery disease and went on to have a percutaneous intervention.

An average of 6 hours before revascularization, patients were treated with either a 300-mg or 600-mg dose of clopidogrel. All patients also received aspirin and a weight-adjusted regimen of intravenous heparin. Treatment with a glycoprotein IIb/IIIa receptor antagonist could also be used at the operator's discretion. Following each procedure, all patients continued to receive a standard, daily regimen of aspirin and clopidogrel.

The study's primary end point was the combined rate of death, MI, and target-vessel revascularization at 30 days after the procedure. MI was defined as a postprocedural elevation of serum creatine kinase-MB (CK-MB) to more than three times the upper limit of normal.

This end point was reached in 4% of patients who received a 600-mg loading dose, compared with 12% of patients who received a 300-mg loading dose, a statistically significant difference. There were no deaths. One patient who received the 600-mg dose required revascularization, and five patients in the 600-mg group had an MI. A total of 15 patients in the 300-mg group had an MI.

Several secondary end points also favored the higher loading dose, including any rise in CK-MB above the upper limit of normal, and an increase in troponin I levels.

No patient in the study had a major bleed or needed a transfusion following revascularization.

In a multivariable analysis that controlled for possible confounding factors such as stent length, use of a IIb/IIIa inhibitor, and use of a statin starting before the procedure, treatment with the higher clopidogrel loading dose cut the incidence of periprocedural MI by 52%. Pretreatment with a statin was also associated with a significant 72% reduction in MIs. The effect of statin pretreatment and the 600-mg loading dose was additive: Patients who received both had an 80% reduced risk of a periprocedural MI, Dr. Di Sciascio said.

WASHINGTON — Patients on long-term clopidogrel treatment don't need to stop the drug before surgery, Richard E. Kuntz, M.D., said at a meeting sponsored by the Cardiovascular Research Institute at Washington Hospital Center.

“There is growing experience that it's safe to perform surgery on a patient taking clopidogrel. At our institution, surgeons will operate on these patients. There is no significant difference in morbidity and mortality” during surgery, said Dr. Kuntz, a cardiologist at Brigham and Women's Hospital in Boston.

This approach to dealing with patients on long-term treatment with the antiplatelet clopidogrel (Plavix) was endorsed also by Ron Waksman, M.D., of the division of cardiology at Washington Hospital Center. “If we push our surgeons, they'll do surgery without waiting to stop clopidogrel,” said Dr. Waksman, who chaired the meeting.

The issue of when to stop clopidogrel recently became critical for patients who take the drug after they have received drug-eluting coronary stents. A report last year detailed four anecdotal cases of patients who developed clinically significant coronary thrombosis within a drug-eluting stent after their clopidogrel and aspirin regimens were stopped (Lancet 2004;364:1519-21). In three of these cases, patients had stopped their antiplatelet medications before surgery.

These reports have made experts wary about stopping aspirin and clopidogrel in their patients.

Although standard practice when placing drug-eluting coronary stents is to treat patients with clopidogrel for 2-3 months (for sirolimus-eluting stents) or 6 months (for paclitaxel-eluting stents), Dr. Kuntz recommended continuing the drug even longer.

To prevent stent thrombosis, patients with a drug-eluting stent should continue clopidogrel “as long as possible, as long as they can afford it,” he said.

WASHINGTON — Patients on long-term clopidogrel treatment don't need to stop the drug before surgery, Richard E. Kuntz, M.D., said at a meeting sponsored by the Cardiovascular Research Institute at Washington Hospital Center.

“There is growing experience that it's safe to perform surgery on a patient taking clopidogrel. At our institution, surgeons will operate on these patients. There is no significant difference in morbidity and mortality” during surgery, said Dr. Kuntz, a cardiologist at Brigham and Women's Hospital in Boston.

This approach to dealing with patients on long-term treatment with the antiplatelet clopidogrel (Plavix) was endorsed also by Ron Waksman, M.D., of the division of cardiology at Washington Hospital Center. “If we push our surgeons, they'll do surgery without waiting to stop clopidogrel,” said Dr. Waksman, who chaired the meeting.

The issue of when to stop clopidogrel recently became critical for patients who take the drug after they have received drug-eluting coronary stents. A report last year detailed four anecdotal cases of patients who developed clinically significant coronary thrombosis within a drug-eluting stent after their clopidogrel and aspirin regimens were stopped (Lancet 2004;364:1519-21). In three of these cases, patients had stopped their antiplatelet medications before surgery.

These reports have made experts wary about stopping aspirin and clopidogrel in their patients.

Although standard practice when placing drug-eluting coronary stents is to treat patients with clopidogrel for 2-3 months (for sirolimus-eluting stents) or 6 months (for paclitaxel-eluting stents), Dr. Kuntz recommended continuing the drug even longer.

To prevent stent thrombosis, patients with a drug-eluting stent should continue clopidogrel “as long as possible, as long as they can afford it,” he said.

WASHINGTON — Patients on long-term clopidogrel treatment don't need to stop the drug before surgery, Richard E. Kuntz, M.D., said at a meeting sponsored by the Cardiovascular Research Institute at Washington Hospital Center.

“There is growing experience that it's safe to perform surgery on a patient taking clopidogrel. At our institution, surgeons will operate on these patients. There is no significant difference in morbidity and mortality” during surgery, said Dr. Kuntz, a cardiologist at Brigham and Women's Hospital in Boston.

This approach to dealing with patients on long-term treatment with the antiplatelet clopidogrel (Plavix) was endorsed also by Ron Waksman, M.D., of the division of cardiology at Washington Hospital Center. “If we push our surgeons, they'll do surgery without waiting to stop clopidogrel,” said Dr. Waksman, who chaired the meeting.

The issue of when to stop clopidogrel recently became critical for patients who take the drug after they have received drug-eluting coronary stents. A report last year detailed four anecdotal cases of patients who developed clinically significant coronary thrombosis within a drug-eluting stent after their clopidogrel and aspirin regimens were stopped (Lancet 2004;364:1519-21). In three of these cases, patients had stopped their antiplatelet medications before surgery.

These reports have made experts wary about stopping aspirin and clopidogrel in their patients.

Although standard practice when placing drug-eluting coronary stents is to treat patients with clopidogrel for 2-3 months (for sirolimus-eluting stents) or 6 months (for paclitaxel-eluting stents), Dr. Kuntz recommended continuing the drug even longer.

To prevent stent thrombosis, patients with a drug-eluting stent should continue clopidogrel “as long as possible, as long as they can afford it,” he said.

ORLANDO, FLA. — Stenting may have finally edged past coronary bypass surgery for treating multivessel coronary disease, according to the results from an uncontrolled series of 607 patients who underwent revascularization using drug-eluting stents.

One year after patients underwent multivessel revascularization with sirolimus-eluting (Cypher) coronary stents, their rate of major adverse events was better than the rate in a similar series of patients who underwent coronary bypass graft (CABG) surgery in the late 1990s, Patrick Serruys, M.D., said at the annual meeting of the American College of Cardiology.

“This study is a breakthrough,” commented Valentin Fuster, M.D., director of the cardiovascular institute at Mount Sinai Medical Center in New York. “Even though this was not a prospective, randomized, controlled study, I'm convinced that for patients with multivessel disease, drug-eluting stents may have more of an impact today on the rate of death and myocardial infarction than coronary artery bypass grafting.”

The biggest question remaining is whether surgery or drug-eluting-stent placement is the best treatment for such patients with diabetes. In the new study, 26% of enrolled patients had diabetes, so the applicability of the results to patients with diabetes remains unclear.

In this multicenter series, 54% of patients had triple-vessel disease, and 46% had two-vessel disease. All patients were treated with percutaneous coronary intervention using sirolimus-eluting coronary stents. The Arterial Revascularization Therapies Study Part II (ARTS II) was designed to test whether multivessel stenting was not inferior to CABG.

The study's primary end point was the combined rate of death, MI, stroke or transient ischemic attack, and need for revascularization 1 year after treatment. This combined rate was 10.4%, reported Dr. Serruys, chief of interventional cardiology at the thorax center of Erasmus University in Rotterdam, the Netherlands.

This rate was compared with the 11.7% rate in a very similar series of 605 patients who underwent CABG during the late 1990s in ARTS I, said Dr. Serruys.

In ARTS II, the incidence of death was 1.0%, the rate of cerebrovascular events was 0.8%, the rate of MI was 1.2%, and the rate of clinically necessary revascularization procedures was 7.4%. (See box.)

In the historic series of CABG patients, the 1-year rate of death was 2.7%, the rate of cerebrovascular events was 1.8%, the rate of MI was 3.5%, and the rate of clinically necessary revascularization was 3.7%.

Comparison of the combined adverse events showed that stenting was not inferior to CABG. The results further showed that stenting was statistically superior to bypass surgery after 1 year of follow-up, said Dr. Serruys.

After adjustment for baseline differences in the patients enrolled in both studies, the combined rate of major adverse events was 8.1% in the patients who underwent stenting and 13.1% among the patients who had bypass surgery.

The superiority of stenting with sirolimus-eluting stents in ARTS II contrasted with the results of the bare-metal-stent arm of ARTS I. In that series of 600 patients, done concurrently with the coronary bypass arm, the combined rate of major adverse events was 26.5% after 1 year, primarily because the rate of clinically necessary revascularization was 17.0%.

The difference in revascularization rates between ARTS I, with bare-metal stents, and ARTS II, with drug-eluting stents, “shows the difference that drug-eluting stents make,” commented Fayez Shamoon, M.D., a cardiologist at St. Michael's Medical Center in Newark, N.J. Based on the new results, “most interventional cardiologists would be willing to treat triple-vessel disease with a drug-eluting stent,” except in patients with diabetes, left main disease, or a left ventricular ejection fraction of 35% or less, he told this newspaper.

ORLANDO, FLA. — Stenting may have finally edged past coronary bypass surgery for treating multivessel coronary disease, according to the results from an uncontrolled series of 607 patients who underwent revascularization using drug-eluting stents.

One year after patients underwent multivessel revascularization with sirolimus-eluting (Cypher) coronary stents, their rate of major adverse events was better than the rate in a similar series of patients who underwent coronary bypass graft (CABG) surgery in the late 1990s, Patrick Serruys, M.D., said at the annual meeting of the American College of Cardiology.

“This study is a breakthrough,” commented Valentin Fuster, M.D., director of the cardiovascular institute at Mount Sinai Medical Center in New York. “Even though this was not a prospective, randomized, controlled study, I'm convinced that for patients with multivessel disease, drug-eluting stents may have more of an impact today on the rate of death and myocardial infarction than coronary artery bypass grafting.”

The biggest question remaining is whether surgery or drug-eluting-stent placement is the best treatment for such patients with diabetes. In the new study, 26% of enrolled patients had diabetes, so the applicability of the results to patients with diabetes remains unclear.

In this multicenter series, 54% of patients had triple-vessel disease, and 46% had two-vessel disease. All patients were treated with percutaneous coronary intervention using sirolimus-eluting coronary stents. The Arterial Revascularization Therapies Study Part II (ARTS II) was designed to test whether multivessel stenting was not inferior to CABG.

The study's primary end point was the combined rate of death, MI, stroke or transient ischemic attack, and need for revascularization 1 year after treatment. This combined rate was 10.4%, reported Dr. Serruys, chief of interventional cardiology at the thorax center of Erasmus University in Rotterdam, the Netherlands.

This rate was compared with the 11.7% rate in a very similar series of 605 patients who underwent CABG during the late 1990s in ARTS I, said Dr. Serruys.

In ARTS II, the incidence of death was 1.0%, the rate of cerebrovascular events was 0.8%, the rate of MI was 1.2%, and the rate of clinically necessary revascularization procedures was 7.4%. (See box.)

In the historic series of CABG patients, the 1-year rate of death was 2.7%, the rate of cerebrovascular events was 1.8%, the rate of MI was 3.5%, and the rate of clinically necessary revascularization was 3.7%.

Comparison of the combined adverse events showed that stenting was not inferior to CABG. The results further showed that stenting was statistically superior to bypass surgery after 1 year of follow-up, said Dr. Serruys.

After adjustment for baseline differences in the patients enrolled in both studies, the combined rate of major adverse events was 8.1% in the patients who underwent stenting and 13.1% among the patients who had bypass surgery.

The superiority of stenting with sirolimus-eluting stents in ARTS II contrasted with the results of the bare-metal-stent arm of ARTS I. In that series of 600 patients, done concurrently with the coronary bypass arm, the combined rate of major adverse events was 26.5% after 1 year, primarily because the rate of clinically necessary revascularization was 17.0%.

The difference in revascularization rates between ARTS I, with bare-metal stents, and ARTS II, with drug-eluting stents, “shows the difference that drug-eluting stents make,” commented Fayez Shamoon, M.D., a cardiologist at St. Michael's Medical Center in Newark, N.J. Based on the new results, “most interventional cardiologists would be willing to treat triple-vessel disease with a drug-eluting stent,” except in patients with diabetes, left main disease, or a left ventricular ejection fraction of 35% or less, he told this newspaper.

ORLANDO, FLA. — Stenting may have finally edged past coronary bypass surgery for treating multivessel coronary disease, according to the results from an uncontrolled series of 607 patients who underwent revascularization using drug-eluting stents.

One year after patients underwent multivessel revascularization with sirolimus-eluting (Cypher) coronary stents, their rate of major adverse events was better than the rate in a similar series of patients who underwent coronary bypass graft (CABG) surgery in the late 1990s, Patrick Serruys, M.D., said at the annual meeting of the American College of Cardiology.

“This study is a breakthrough,” commented Valentin Fuster, M.D., director of the cardiovascular institute at Mount Sinai Medical Center in New York. “Even though this was not a prospective, randomized, controlled study, I'm convinced that for patients with multivessel disease, drug-eluting stents may have more of an impact today on the rate of death and myocardial infarction than coronary artery bypass grafting.”

The biggest question remaining is whether surgery or drug-eluting-stent placement is the best treatment for such patients with diabetes. In the new study, 26% of enrolled patients had diabetes, so the applicability of the results to patients with diabetes remains unclear.

In this multicenter series, 54% of patients had triple-vessel disease, and 46% had two-vessel disease. All patients were treated with percutaneous coronary intervention using sirolimus-eluting coronary stents. The Arterial Revascularization Therapies Study Part II (ARTS II) was designed to test whether multivessel stenting was not inferior to CABG.

The study's primary end point was the combined rate of death, MI, stroke or transient ischemic attack, and need for revascularization 1 year after treatment. This combined rate was 10.4%, reported Dr. Serruys, chief of interventional cardiology at the thorax center of Erasmus University in Rotterdam, the Netherlands.

This rate was compared with the 11.7% rate in a very similar series of 605 patients who underwent CABG during the late 1990s in ARTS I, said Dr. Serruys.

In ARTS II, the incidence of death was 1.0%, the rate of cerebrovascular events was 0.8%, the rate of MI was 1.2%, and the rate of clinically necessary revascularization procedures was 7.4%. (See box.)

In the historic series of CABG patients, the 1-year rate of death was 2.7%, the rate of cerebrovascular events was 1.8%, the rate of MI was 3.5%, and the rate of clinically necessary revascularization was 3.7%.

Comparison of the combined adverse events showed that stenting was not inferior to CABG. The results further showed that stenting was statistically superior to bypass surgery after 1 year of follow-up, said Dr. Serruys.

After adjustment for baseline differences in the patients enrolled in both studies, the combined rate of major adverse events was 8.1% in the patients who underwent stenting and 13.1% among the patients who had bypass surgery.

The superiority of stenting with sirolimus-eluting stents in ARTS II contrasted with the results of the bare-metal-stent arm of ARTS I. In that series of 600 patients, done concurrently with the coronary bypass arm, the combined rate of major adverse events was 26.5% after 1 year, primarily because the rate of clinically necessary revascularization was 17.0%.

The difference in revascularization rates between ARTS I, with bare-metal stents, and ARTS II, with drug-eluting stents, “shows the difference that drug-eluting stents make,” commented Fayez Shamoon, M.D., a cardiologist at St. Michael's Medical Center in Newark, N.J. Based on the new results, “most interventional cardiologists would be willing to treat triple-vessel disease with a drug-eluting stent,” except in patients with diabetes, left main disease, or a left ventricular ejection fraction of 35% or less, he told this newspaper.

KEVIN FOLEY, RESEARCH/FORHAD S. HOSSAIN, DESIGN

KEVIN FOLEY, RESEARCH/FORHAD S. HOSSAIN, DESIGN

KEVIN FOLEY, RESEARCH/FORHAD S. HOSSAIN, DESIGN

ORLANDO, FLA. — Nearly half of patients hospitalized for acute coronary syndrome at one large HMO were rehospitalized for cardiovascular disease within the next 12 months, Stephen Sidney, M.D., reported at the annual meeting of the American College of Cardiology.

Within 12 months, 29% of the patients were readmitted for acute coronary syndrome (ACS). Adding in admissions for other manifestations of coronary heart disease along with those for heart failure and stroke, a total of 46% of patients were rehospitalized for cardiovascular disease (CVD) within 12 months of their index hospitalization for ACS.

Nearly 10% of patients were rehospitalized for coronary revascularization via coronary artery bypass graft surgery, and 7.4% were admitted for percutaneous intervention.

One-year mortality following the index hospitalization for ACS was 17.2%, and nearly two-thirds of the deaths were attributed to CVD, added Dr. Sidney of Kaiser Permanente in Oakland, Calif.

Few data are available on 1-year outcomes after hospital discharge for ACS, so Dr. Sidney and his coinvestigators analyzed computerized records for 14,852 patients admitted for ACS to Kaiser Permanente of Northern California hospitals during 1999-2000. The hospitalization rate for ACS was 5.7 cases per 1,000 person-years among subscribers to the prepaid health plan, which provides coverage to 30% of the population in the San Francisco Bay Area.

At the index ACS hospitalization, 31% of patients were hypertensive, 35% were diabetic, and 28% were hyperlipidemic. The relationships between these risk factors and the risks of rehospitalization for unstable angina and acute MI, respectively, differed in intriguing ways. For example, in a multivariate analysis, hyperlipidemic patients were 40% more likely to be rehospitalized for unstable angina within 12 months than were nonhyperlipidemic patients, but they were 32% less likely to experience MI.

In contrast, hypertension was associated with a 14% increased risk of rehospitalization for unstable angina but no significantly increased risk of rehospitalization for MI. Patients aged 65 or older were 16% more likely than were younger ACS patients to be rehospitalized for MI, but 12% less likely to be rehospitalized for unstable angina.

Diabetic patients had a 26% greater likelihood of being rehospitalized for MI and a 14% increased risk of rehospitalization for unstable angina compared with nondiabetics.

The Kaiser study was funded by Eli Lilly & Co.

ORLANDO, FLA. — Nearly half of patients hospitalized for acute coronary syndrome at one large HMO were rehospitalized for cardiovascular disease within the next 12 months, Stephen Sidney, M.D., reported at the annual meeting of the American College of Cardiology.

Within 12 months, 29% of the patients were readmitted for acute coronary syndrome (ACS). Adding in admissions for other manifestations of coronary heart disease along with those for heart failure and stroke, a total of 46% of patients were rehospitalized for cardiovascular disease (CVD) within 12 months of their index hospitalization for ACS.

Nearly 10% of patients were rehospitalized for coronary revascularization via coronary artery bypass graft surgery, and 7.4% were admitted for percutaneous intervention.

One-year mortality following the index hospitalization for ACS was 17.2%, and nearly two-thirds of the deaths were attributed to CVD, added Dr. Sidney of Kaiser Permanente in Oakland, Calif.

Few data are available on 1-year outcomes after hospital discharge for ACS, so Dr. Sidney and his coinvestigators analyzed computerized records for 14,852 patients admitted for ACS to Kaiser Permanente of Northern California hospitals during 1999-2000. The hospitalization rate for ACS was 5.7 cases per 1,000 person-years among subscribers to the prepaid health plan, which provides coverage to 30% of the population in the San Francisco Bay Area.

At the index ACS hospitalization, 31% of patients were hypertensive, 35% were diabetic, and 28% were hyperlipidemic. The relationships between these risk factors and the risks of rehospitalization for unstable angina and acute MI, respectively, differed in intriguing ways. For example, in a multivariate analysis, hyperlipidemic patients were 40% more likely to be rehospitalized for unstable angina within 12 months than were nonhyperlipidemic patients, but they were 32% less likely to experience MI.

In contrast, hypertension was associated with a 14% increased risk of rehospitalization for unstable angina but no significantly increased risk of rehospitalization for MI. Patients aged 65 or older were 16% more likely than were younger ACS patients to be rehospitalized for MI, but 12% less likely to be rehospitalized for unstable angina.

Diabetic patients had a 26% greater likelihood of being rehospitalized for MI and a 14% increased risk of rehospitalization for unstable angina compared with nondiabetics.

The Kaiser study was funded by Eli Lilly & Co.

ORLANDO, FLA. — Nearly half of patients hospitalized for acute coronary syndrome at one large HMO were rehospitalized for cardiovascular disease within the next 12 months, Stephen Sidney, M.D., reported at the annual meeting of the American College of Cardiology.

Within 12 months, 29% of the patients were readmitted for acute coronary syndrome (ACS). Adding in admissions for other manifestations of coronary heart disease along with those for heart failure and stroke, a total of 46% of patients were rehospitalized for cardiovascular disease (CVD) within 12 months of their index hospitalization for ACS.

Nearly 10% of patients were rehospitalized for coronary revascularization via coronary artery bypass graft surgery, and 7.4% were admitted for percutaneous intervention.

One-year mortality following the index hospitalization for ACS was 17.2%, and nearly two-thirds of the deaths were attributed to CVD, added Dr. Sidney of Kaiser Permanente in Oakland, Calif.

Few data are available on 1-year outcomes after hospital discharge for ACS, so Dr. Sidney and his coinvestigators analyzed computerized records for 14,852 patients admitted for ACS to Kaiser Permanente of Northern California hospitals during 1999-2000. The hospitalization rate for ACS was 5.7 cases per 1,000 person-years among subscribers to the prepaid health plan, which provides coverage to 30% of the population in the San Francisco Bay Area.

At the index ACS hospitalization, 31% of patients were hypertensive, 35% were diabetic, and 28% were hyperlipidemic. The relationships between these risk factors and the risks of rehospitalization for unstable angina and acute MI, respectively, differed in intriguing ways. For example, in a multivariate analysis, hyperlipidemic patients were 40% more likely to be rehospitalized for unstable angina within 12 months than were nonhyperlipidemic patients, but they were 32% less likely to experience MI.

In contrast, hypertension was associated with a 14% increased risk of rehospitalization for unstable angina but no significantly increased risk of rehospitalization for MI. Patients aged 65 or older were 16% more likely than were younger ACS patients to be rehospitalized for MI, but 12% less likely to be rehospitalized for unstable angina.

Diabetic patients had a 26% greater likelihood of being rehospitalized for MI and a 14% increased risk of rehospitalization for unstable angina compared with nondiabetics.

The Kaiser study was funded by Eli Lilly & Co.

ORLANDO, FLA. — The presence of inflammatory markers, a low hemoglobin level, or both is superior to traditional cardiovascular risk factors for predicting adverse cardiovascular outcomes in women under evaluation for suspected myocardial ischemia, Christopher B. Arant, M.D., said at the annual meeting of the American College of Cardiology.

The standard cardiovascular risk factors appear to considerably underestimate the true risk of cardiovascular events in women presenting with chest pain, added Dr. Arant, a cardiologist at the University of Florida, Gainesville.

He reported on 595 women, mean age 58 years, who underwent coronary angiography as part of an evaluation for suspected myocardial ischemia in the National Heart, Lung, and Blood Institute-sponsored Women and Ischemia Syndrome Evaluation (WISE).

During a mean 3.6 years of follow-up, all-cause mortality among the women was 7%, and the rate of an MI, heart failure, stroke, another vascular event, or death was 20%. Yet their predicted 10-year risk of a cardiovascular event based on their Framingham risk score was just 4.6%. This underestimate emphasizes the need to develop better methods of recognizing women at high risk, which is the mission of WISE.

Inflammation plays a key role in atherosclerosis and its related complications, perhaps even more so in women than in men. Dr. Arant and his coinvestigators previously examined the predictive power of three inflammatory markers—C-reactive protein, interleukin-6, and serum amyloid A—and showed that they were strong predictors of cardiovascular risk in the WISE cohort. They separately established that hemoglobin level was an independent predictor of adverse cardiovascular outcomes.

In their new study, they showed that adding a hemoglobin concentration below 12 g/dL to the three inflammatory markers created a four-biomarker combination that incrementally and independently predicted cardiovascular events in the WISE study women. (See above.)

In a Cox multivariate regression analysis, the only traditional risk factors that predicted cardiovascular events were diabetes, which was associated with a 79% increase in risk, and obstructive coronary artery disease on angiography, which conferred a 65% increased risk.

In contrast, the presence of any one of the four biomarkers was associated with a 90% increased risk of cardiovascular events during follow-up. Two positive biomarkers conferred a 192% increased risk. Women with three had a 368% increased risk, and those with four abnormal biomarkers had a 550% increased risk.

The same graded relationship held true between abnormal biomarkers and all-cause mortality. The risk of death increased 4.5-fold in women with one abnormal biomarker, compared with those with none, and 19.2-fold in subjects with four biomarkers.

The mean hemoglobin in the WISE cohort was 12.9 g/dL. Why a modest reduction to below 12 g/dL was predictive of cardiovascular events in the WISE population remains speculative. Hemoglobin is not an obvious marker of inflammation. Yet physicians have known for some time that low hemoglobin is an independent predictor of cardiovascular events in patients with heart failure, and more recent data suggest that the same applies in acute MI.

One possibility is that mild anemia may reflect bone marrow underproduction of red blood cells due to systemic inflammation. Thus, in that sense, a low hemoglobin may indeed be a surrogate marker for inflammation. However, the observation that adding hemoglobin to the three inflammatory markers yielded an incremental increase in event risk in WISE suggests a low hemoglobin may be acting directly to increase risk, Dr. Arant said.

Studies of sickle cell anemia patients suggest that hemoglobin may be important in the transport of nitric oxide, known to play a key role in endothelial function. Nearly two-thirds of women in WISE did not have obstructive coronary artery disease, instead presumably had what is often described as microvascular disease. Thus inadequate nitric oxide could exacerbate their endothelial dysfunction, which might explain the link between low hemoglobin and increased cardiovascular events, he said.

A clinical pearl from the WISE chest pain registry is that women with cardiac ischemia have a very high prevalence of atypical angina. “We like to say any pain above the waist in women who have risk factors requires a good history and physical exam and really needs to be considered as an anginal equivalent,” he said.

ORLANDO, FLA. — The presence of inflammatory markers, a low hemoglobin level, or both is superior to traditional cardiovascular risk factors for predicting adverse cardiovascular outcomes in women under evaluation for suspected myocardial ischemia, Christopher B. Arant, M.D., said at the annual meeting of the American College of Cardiology.

The standard cardiovascular risk factors appear to considerably underestimate the true risk of cardiovascular events in women presenting with chest pain, added Dr. Arant, a cardiologist at the University of Florida, Gainesville.

He reported on 595 women, mean age 58 years, who underwent coronary angiography as part of an evaluation for suspected myocardial ischemia in the National Heart, Lung, and Blood Institute-sponsored Women and Ischemia Syndrome Evaluation (WISE).

During a mean 3.6 years of follow-up, all-cause mortality among the women was 7%, and the rate of an MI, heart failure, stroke, another vascular event, or death was 20%. Yet their predicted 10-year risk of a cardiovascular event based on their Framingham risk score was just 4.6%. This underestimate emphasizes the need to develop better methods of recognizing women at high risk, which is the mission of WISE.

Inflammation plays a key role in atherosclerosis and its related complications, perhaps even more so in women than in men. Dr. Arant and his coinvestigators previously examined the predictive power of three inflammatory markers—C-reactive protein, interleukin-6, and serum amyloid A—and showed that they were strong predictors of cardiovascular risk in the WISE cohort. They separately established that hemoglobin level was an independent predictor of adverse cardiovascular outcomes.

In their new study, they showed that adding a hemoglobin concentration below 12 g/dL to the three inflammatory markers created a four-biomarker combination that incrementally and independently predicted cardiovascular events in the WISE study women. (See above.)

In a Cox multivariate regression analysis, the only traditional risk factors that predicted cardiovascular events were diabetes, which was associated with a 79% increase in risk, and obstructive coronary artery disease on angiography, which conferred a 65% increased risk.

In contrast, the presence of any one of the four biomarkers was associated with a 90% increased risk of cardiovascular events during follow-up. Two positive biomarkers conferred a 192% increased risk. Women with three had a 368% increased risk, and those with four abnormal biomarkers had a 550% increased risk.

The same graded relationship held true between abnormal biomarkers and all-cause mortality. The risk of death increased 4.5-fold in women with one abnormal biomarker, compared with those with none, and 19.2-fold in subjects with four biomarkers.

The mean hemoglobin in the WISE cohort was 12.9 g/dL. Why a modest reduction to below 12 g/dL was predictive of cardiovascular events in the WISE population remains speculative. Hemoglobin is not an obvious marker of inflammation. Yet physicians have known for some time that low hemoglobin is an independent predictor of cardiovascular events in patients with heart failure, and more recent data suggest that the same applies in acute MI.

One possibility is that mild anemia may reflect bone marrow underproduction of red blood cells due to systemic inflammation. Thus, in that sense, a low hemoglobin may indeed be a surrogate marker for inflammation. However, the observation that adding hemoglobin to the three inflammatory markers yielded an incremental increase in event risk in WISE suggests a low hemoglobin may be acting directly to increase risk, Dr. Arant said.

Studies of sickle cell anemia patients suggest that hemoglobin may be important in the transport of nitric oxide, known to play a key role in endothelial function. Nearly two-thirds of women in WISE did not have obstructive coronary artery disease, instead presumably had what is often described as microvascular disease. Thus inadequate nitric oxide could exacerbate their endothelial dysfunction, which might explain the link between low hemoglobin and increased cardiovascular events, he said.

A clinical pearl from the WISE chest pain registry is that women with cardiac ischemia have a very high prevalence of atypical angina. “We like to say any pain above the waist in women who have risk factors requires a good history and physical exam and really needs to be considered as an anginal equivalent,” he said.

ORLANDO, FLA. — The presence of inflammatory markers, a low hemoglobin level, or both is superior to traditional cardiovascular risk factors for predicting adverse cardiovascular outcomes in women under evaluation for suspected myocardial ischemia, Christopher B. Arant, M.D., said at the annual meeting of the American College of Cardiology.

The standard cardiovascular risk factors appear to considerably underestimate the true risk of cardiovascular events in women presenting with chest pain, added Dr. Arant, a cardiologist at the University of Florida, Gainesville.

He reported on 595 women, mean age 58 years, who underwent coronary angiography as part of an evaluation for suspected myocardial ischemia in the National Heart, Lung, and Blood Institute-sponsored Women and Ischemia Syndrome Evaluation (WISE).

During a mean 3.6 years of follow-up, all-cause mortality among the women was 7%, and the rate of an MI, heart failure, stroke, another vascular event, or death was 20%. Yet their predicted 10-year risk of a cardiovascular event based on their Framingham risk score was just 4.6%. This underestimate emphasizes the need to develop better methods of recognizing women at high risk, which is the mission of WISE.

Inflammation plays a key role in atherosclerosis and its related complications, perhaps even more so in women than in men. Dr. Arant and his coinvestigators previously examined the predictive power of three inflammatory markers—C-reactive protein, interleukin-6, and serum amyloid A—and showed that they were strong predictors of cardiovascular risk in the WISE cohort. They separately established that hemoglobin level was an independent predictor of adverse cardiovascular outcomes.

In their new study, they showed that adding a hemoglobin concentration below 12 g/dL to the three inflammatory markers created a four-biomarker combination that incrementally and independently predicted cardiovascular events in the WISE study women. (See above.)

In a Cox multivariate regression analysis, the only traditional risk factors that predicted cardiovascular events were diabetes, which was associated with a 79% increase in risk, and obstructive coronary artery disease on angiography, which conferred a 65% increased risk.

In contrast, the presence of any one of the four biomarkers was associated with a 90% increased risk of cardiovascular events during follow-up. Two positive biomarkers conferred a 192% increased risk. Women with three had a 368% increased risk, and those with four abnormal biomarkers had a 550% increased risk.

The same graded relationship held true between abnormal biomarkers and all-cause mortality. The risk of death increased 4.5-fold in women with one abnormal biomarker, compared with those with none, and 19.2-fold in subjects with four biomarkers.

The mean hemoglobin in the WISE cohort was 12.9 g/dL. Why a modest reduction to below 12 g/dL was predictive of cardiovascular events in the WISE population remains speculative. Hemoglobin is not an obvious marker of inflammation. Yet physicians have known for some time that low hemoglobin is an independent predictor of cardiovascular events in patients with heart failure, and more recent data suggest that the same applies in acute MI.

One possibility is that mild anemia may reflect bone marrow underproduction of red blood cells due to systemic inflammation. Thus, in that sense, a low hemoglobin may indeed be a surrogate marker for inflammation. However, the observation that adding hemoglobin to the three inflammatory markers yielded an incremental increase in event risk in WISE suggests a low hemoglobin may be acting directly to increase risk, Dr. Arant said.

Studies of sickle cell anemia patients suggest that hemoglobin may be important in the transport of nitric oxide, known to play a key role in endothelial function. Nearly two-thirds of women in WISE did not have obstructive coronary artery disease, instead presumably had what is often described as microvascular disease. Thus inadequate nitric oxide could exacerbate their endothelial dysfunction, which might explain the link between low hemoglobin and increased cardiovascular events, he said.

A clinical pearl from the WISE chest pain registry is that women with cardiac ischemia have a very high prevalence of atypical angina. “We like to say any pain above the waist in women who have risk factors requires a good history and physical exam and really needs to be considered as an anginal equivalent,” he said.

Supplement Editor:
Amir K. Jaffer, MD

Contents

A pharmacologic overview of current and emerging anticoagulants
Edith A. Nutescu, PharmD; Nancy L. Shapiro, PharmD; Aimee Chevalier, PharmD; and Alpesh N. Amin, MD, MBA

Prevention of venous thromboembolism in medical and surgical patients
Peter J. Kaboli, MD; Adam Brenner, BS; and Andrew S. Dunn, MD

Current and emerging options in the management of venous thromboembolism
Amir K. Jaffer, MD; Daniel J. Brotman, MD; and Franklin Michota, MD

Stroke prevention in atrial fibrillation: Current anticoagulation management and future directions
Benjamin T. Fitzgerald, MBBS; Steven L. Cohn, MD; and Allan L. Klein, MD

Heparin-induced thrombocytopenia: Principles for early recognition and management
John R. Bartholomew, MD; Susan M. Begelman, MD; and Amjad AlMahameed, MD

Anticoagulation in special patient populations: Are special dosing considerations required?
Franklin Michota, MD, and Geno Merli, MD

Cost considerations surrounding current and future anticoagulant therapies
Margaret C. Fang, MD, MPH; Tracy Minichiello, MD; and Andrew D. Auerbach, MD, MPH

Supplement Editor:
Amir K. Jaffer, MD

Contents

A pharmacologic overview of current and emerging anticoagulants
Edith A. Nutescu, PharmD; Nancy L. Shapiro, PharmD; Aimee Chevalier, PharmD; and Alpesh N. Amin, MD, MBA

Prevention of venous thromboembolism in medical and surgical patients
Peter J. Kaboli, MD; Adam Brenner, BS; and Andrew S. Dunn, MD

Current and emerging options in the management of venous thromboembolism
Amir K. Jaffer, MD; Daniel J. Brotman, MD; and Franklin Michota, MD

Stroke prevention in atrial fibrillation: Current anticoagulation management and future directions
Benjamin T. Fitzgerald, MBBS; Steven L. Cohn, MD; and Allan L. Klein, MD

Heparin-induced thrombocytopenia: Principles for early recognition and management
John R. Bartholomew, MD; Susan M. Begelman, MD; and Amjad AlMahameed, MD

Anticoagulation in special patient populations: Are special dosing considerations required?
Franklin Michota, MD, and Geno Merli, MD

Cost considerations surrounding current and future anticoagulant therapies
Margaret C. Fang, MD, MPH; Tracy Minichiello, MD; and Andrew D. Auerbach, MD, MPH

Supplement Editor:
Amir K. Jaffer, MD

Contents

A pharmacologic overview of current and emerging anticoagulants
Edith A. Nutescu, PharmD; Nancy L. Shapiro, PharmD; Aimee Chevalier, PharmD; and Alpesh N. Amin, MD, MBA

Prevention of venous thromboembolism in medical and surgical patients
Peter J. Kaboli, MD; Adam Brenner, BS; and Andrew S. Dunn, MD

Current and emerging options in the management of venous thromboembolism
Amir K. Jaffer, MD; Daniel J. Brotman, MD; and Franklin Michota, MD

Stroke prevention in atrial fibrillation: Current anticoagulation management and future directions
Benjamin T. Fitzgerald, MBBS; Steven L. Cohn, MD; and Allan L. Klein, MD

Heparin-induced thrombocytopenia: Principles for early recognition and management
John R. Bartholomew, MD; Susan M. Begelman, MD; and Amjad AlMahameed, MD

Anticoagulation in special patient populations: Are special dosing considerations required?
Franklin Michota, MD, and Geno Merli, MD

Cost considerations surrounding current and future anticoagulant therapies
Margaret C. Fang, MD, MPH; Tracy Minichiello, MD; and Andrew D. Auerbach, MD, MPH

Guest Editors:
Gurjit Kaur, DO, and Holly L. Thacker, MD

Contents

Recognizing and intervening in intimate partner violence
Gurjit Kaur, DO, and Linda Herbert, LISW

New cervical cancer screening strategy: Combined Pap and HPV testing
Xian Wen Jin, MD, PhD; Kristine Zanotti, MD; and Belinda Yen-Lieberman, PhD

Cardiovascular problems and pregnancy: An approach to management
Samuel Siu, MD, and Jack M. Colman, MD

Treatment options for menopausal hot flashes
Andrea Sikon, MD, and Holly L. Thacker, MD

Shared medical appointments: Increasing patient access without increasing physician hours
David L. Bronson, MD, and Richard A. Maxwell, MD

Premenstrual dysphoric disorder: A review for the treating practitioner
Gurjit Kaur, DO; Lilian Gonsalves, MD; and Holly L. Thacker, MD

Update on contraception: Benefits and risks of the new formulations
Pelin Batur, MD; Julie Elder, DO; and Mark Mayer, MD

DXA scanning to diagnose osteoporosis: Do you know what the results mean?
Bradford Richmond, MD

Culture, race, and disparities in health care
Charles S. Modlin, MD

Physician cultural competence: Cross-cultural communication improves care
Anita D. Misra-Hebert, MD

What are the key issues women face when ending hormone therapy?
Wulf H. Utian, MD, BCH, PhD

Vertebral compression fractures: Manage aggressively to prevent sequelae
Daniel J. Mazanec, MD; Alex Mompoint, MD; Vinod K. Podichetty, MD; and Amarish Potnis, MD

The HIP trial: Risedronate prevents hip fractures, but who should get therapy?
Chad L. Deal, MD

Discussing breast cancer and hormone therapy with women
Pelin Batur, MD; Holly L. Thacker, MD; and Halle C.F. Moore, MD

The case for hormone therapy: New studies that should inform the debate
Holly L. Thacker, MD
 

Guest Editors:
Gurjit Kaur, DO, and Holly L. Thacker, MD

Contents

Recognizing and intervening in intimate partner violence
Gurjit Kaur, DO, and Linda Herbert, LISW

New cervical cancer screening strategy: Combined Pap and HPV testing
Xian Wen Jin, MD, PhD; Kristine Zanotti, MD; and Belinda Yen-Lieberman, PhD

Cardiovascular problems and pregnancy: An approach to management
Samuel Siu, MD, and Jack M. Colman, MD

Treatment options for menopausal hot flashes
Andrea Sikon, MD, and Holly L. Thacker, MD

Shared medical appointments: Increasing patient access without increasing physician hours
David L. Bronson, MD, and Richard A. Maxwell, MD

Premenstrual dysphoric disorder: A review for the treating practitioner
Gurjit Kaur, DO; Lilian Gonsalves, MD; and Holly L. Thacker, MD

Update on contraception: Benefits and risks of the new formulations
Pelin Batur, MD; Julie Elder, DO; and Mark Mayer, MD

DXA scanning to diagnose osteoporosis: Do you know what the results mean?
Bradford Richmond, MD

Culture, race, and disparities in health care
Charles S. Modlin, MD

Physician cultural competence: Cross-cultural communication improves care
Anita D. Misra-Hebert, MD

What are the key issues women face when ending hormone therapy?
Wulf H. Utian, MD, BCH, PhD

Vertebral compression fractures: Manage aggressively to prevent sequelae
Daniel J. Mazanec, MD; Alex Mompoint, MD; Vinod K. Podichetty, MD; and Amarish Potnis, MD

The HIP trial: Risedronate prevents hip fractures, but who should get therapy?
Chad L. Deal, MD

Discussing breast cancer and hormone therapy with women
Pelin Batur, MD; Holly L. Thacker, MD; and Halle C.F. Moore, MD

The case for hormone therapy: New studies that should inform the debate
Holly L. Thacker, MD
 

Guest Editors:
Gurjit Kaur, DO, and Holly L. Thacker, MD

Contents

Recognizing and intervening in intimate partner violence
Gurjit Kaur, DO, and Linda Herbert, LISW

New cervical cancer screening strategy: Combined Pap and HPV testing
Xian Wen Jin, MD, PhD; Kristine Zanotti, MD; and Belinda Yen-Lieberman, PhD

Cardiovascular problems and pregnancy: An approach to management
Samuel Siu, MD, and Jack M. Colman, MD

Treatment options for menopausal hot flashes
Andrea Sikon, MD, and Holly L. Thacker, MD

Shared medical appointments: Increasing patient access without increasing physician hours
David L. Bronson, MD, and Richard A. Maxwell, MD

Premenstrual dysphoric disorder: A review for the treating practitioner
Gurjit Kaur, DO; Lilian Gonsalves, MD; and Holly L. Thacker, MD

Update on contraception: Benefits and risks of the new formulations
Pelin Batur, MD; Julie Elder, DO; and Mark Mayer, MD

DXA scanning to diagnose osteoporosis: Do you know what the results mean?
Bradford Richmond, MD

Culture, race, and disparities in health care
Charles S. Modlin, MD

Physician cultural competence: Cross-cultural communication improves care
Anita D. Misra-Hebert, MD

What are the key issues women face when ending hormone therapy?
Wulf H. Utian, MD, BCH, PhD

Vertebral compression fractures: Manage aggressively to prevent sequelae
Daniel J. Mazanec, MD; Alex Mompoint, MD; Vinod K. Podichetty, MD; and Amarish Potnis, MD

The HIP trial: Risedronate prevents hip fractures, but who should get therapy?
Chad L. Deal, MD

Discussing breast cancer and hormone therapy with women
Pelin Batur, MD; Holly L. Thacker, MD; and Halle C.F. Moore, MD

The case for hormone therapy: New studies that should inform the debate
Holly L. Thacker, MD