Activation of the interferon-α pathway identifies a subgroup of lupus erythematosus patients with distinct serologic features and more active disease, according to Kyriakos A. Kirou, M.D.

There is no consensus in the current literature regarding the most useful or accurate marker of lupus disease activity, thus the use of increased interferon-inducible gene expression as a potential biomarker of active disease could prove valuable to clinicians and researchers.

The investigators subjected freshly isolated peripheral blood mononuclear cells from 77 patients with systemic lupus erythematosus (SLE), 22 disease controls with either rheumatoid arthritis or inflammatory uveitis, and 28 healthy donors to real-time polymerase chain reaction for three genes (PRKR, IFIT1, and IF144) that are preferentially induced by interferon-α. The results were used to determine an IFN-α score for all participants.

SLE patients with a high IFN-α score had a significantly higher prevalence of renal disease, a greater number of American College of Rheumatology criteria for SLE, and a higher Systemic Lupus International Collaborating Clinics damage index (SDI) score than did patients with a low IFN-α score (Arthritis Rheum. 2005;52:1491–503).

Patients with high IFN-α scores also showed increased disease activity, as measured by lower serum C3 levels, hemoglobin levels, absolute lymphocyte counts, and albumin levels, and a higher anti-double-stranded DNA (dsDNA) titer, erythrocyte sedimentation rate, and SLE Disease Activity Index 2000 score.

“Our most striking data, and that which may provide us new clues regarding underlying disease mechanisms, came from analysis of the serologic profiles of the SLE patients,” wrote Dr. Kirou and colleagues at the Hospital for Special Surgery in New York.

The investigators found that the presence of antibodies specific for RNA-binding protein (RBP), including Ro, U1 ribonucleoprotein (RNP), and Sm, was significantly associated with a high IFN-α score.

Logistic regression analysis confirmed that the presence of renal disease, low complement levels, autoantibodies specific for RBP (but not anti-dsDNA or antiphospholipid autoantibodies), and higher SDI scores, all independently increased the likelihood of having a high IFN-α score.

“Activation of the IFN-α pathway could be an important mediator of the immune system alterations that confer tissue damage in SLE,” the authors wrote.

Additionally, activation of the IFN-α pathway may also contribute to production of pathogenic autoantibodies by direct and indirect effects on B cells, resulting in differentiation and Ig class switching to IgG and IgA isotypes.

Prospective longitudinal studies are needed to assess the role of interferon-inducible genes in monitoring disease activity, they concluded.

Activation of the interferon-α pathway identifies a subgroup of lupus erythematosus patients with distinct serologic features and more active disease, according to Kyriakos A. Kirou, M.D.

There is no consensus in the current literature regarding the most useful or accurate marker of lupus disease activity, thus the use of increased interferon-inducible gene expression as a potential biomarker of active disease could prove valuable to clinicians and researchers.

The investigators subjected freshly isolated peripheral blood mononuclear cells from 77 patients with systemic lupus erythematosus (SLE), 22 disease controls with either rheumatoid arthritis or inflammatory uveitis, and 28 healthy donors to real-time polymerase chain reaction for three genes (PRKR, IFIT1, and IF144) that are preferentially induced by interferon-α. The results were used to determine an IFN-α score for all participants.

SLE patients with a high IFN-α score had a significantly higher prevalence of renal disease, a greater number of American College of Rheumatology criteria for SLE, and a higher Systemic Lupus International Collaborating Clinics damage index (SDI) score than did patients with a low IFN-α score (Arthritis Rheum. 2005;52:1491–503).

Patients with high IFN-α scores also showed increased disease activity, as measured by lower serum C3 levels, hemoglobin levels, absolute lymphocyte counts, and albumin levels, and a higher anti-double-stranded DNA (dsDNA) titer, erythrocyte sedimentation rate, and SLE Disease Activity Index 2000 score.

“Our most striking data, and that which may provide us new clues regarding underlying disease mechanisms, came from analysis of the serologic profiles of the SLE patients,” wrote Dr. Kirou and colleagues at the Hospital for Special Surgery in New York.

The investigators found that the presence of antibodies specific for RNA-binding protein (RBP), including Ro, U1 ribonucleoprotein (RNP), and Sm, was significantly associated with a high IFN-α score.

Logistic regression analysis confirmed that the presence of renal disease, low complement levels, autoantibodies specific for RBP (but not anti-dsDNA or antiphospholipid autoantibodies), and higher SDI scores, all independently increased the likelihood of having a high IFN-α score.

“Activation of the IFN-α pathway could be an important mediator of the immune system alterations that confer tissue damage in SLE,” the authors wrote.

Additionally, activation of the IFN-α pathway may also contribute to production of pathogenic autoantibodies by direct and indirect effects on B cells, resulting in differentiation and Ig class switching to IgG and IgA isotypes.

Prospective longitudinal studies are needed to assess the role of interferon-inducible genes in monitoring disease activity, they concluded.

Activation of the interferon-α pathway identifies a subgroup of lupus erythematosus patients with distinct serologic features and more active disease, according to Kyriakos A. Kirou, M.D.

There is no consensus in the current literature regarding the most useful or accurate marker of lupus disease activity, thus the use of increased interferon-inducible gene expression as a potential biomarker of active disease could prove valuable to clinicians and researchers.

The investigators subjected freshly isolated peripheral blood mononuclear cells from 77 patients with systemic lupus erythematosus (SLE), 22 disease controls with either rheumatoid arthritis or inflammatory uveitis, and 28 healthy donors to real-time polymerase chain reaction for three genes (PRKR, IFIT1, and IF144) that are preferentially induced by interferon-α. The results were used to determine an IFN-α score for all participants.

SLE patients with a high IFN-α score had a significantly higher prevalence of renal disease, a greater number of American College of Rheumatology criteria for SLE, and a higher Systemic Lupus International Collaborating Clinics damage index (SDI) score than did patients with a low IFN-α score (Arthritis Rheum. 2005;52:1491–503).

Patients with high IFN-α scores also showed increased disease activity, as measured by lower serum C3 levels, hemoglobin levels, absolute lymphocyte counts, and albumin levels, and a higher anti-double-stranded DNA (dsDNA) titer, erythrocyte sedimentation rate, and SLE Disease Activity Index 2000 score.

“Our most striking data, and that which may provide us new clues regarding underlying disease mechanisms, came from analysis of the serologic profiles of the SLE patients,” wrote Dr. Kirou and colleagues at the Hospital for Special Surgery in New York.

The investigators found that the presence of antibodies specific for RNA-binding protein (RBP), including Ro, U1 ribonucleoprotein (RNP), and Sm, was significantly associated with a high IFN-α score.

Logistic regression analysis confirmed that the presence of renal disease, low complement levels, autoantibodies specific for RBP (but not anti-dsDNA or antiphospholipid autoantibodies), and higher SDI scores, all independently increased the likelihood of having a high IFN-α score.

“Activation of the IFN-α pathway could be an important mediator of the immune system alterations that confer tissue damage in SLE,” the authors wrote.

Additionally, activation of the IFN-α pathway may also contribute to production of pathogenic autoantibodies by direct and indirect effects on B cells, resulting in differentiation and Ig class switching to IgG and IgA isotypes.

Prospective longitudinal studies are needed to assess the role of interferon-inducible genes in monitoring disease activity, they concluded.

WASHINGTON — By the first few months of this year, drug-eluting coronary stents had become more cost effective than ever before.

Based on the price of drug-eluting stents, the average number of stents used per patient, and their efficacy at cutting the rate of restenosis, drug-eluting stents are now cost effective in any patient who would have a risk of restenosis of 10% or more if treated with bare-metal stents, David J. Cohen, M.D., said at a meeting sponsored by the Cardiovascular Research Institute of the Washington Hospital Center.

In contrast, based on last year's averages, drug-eluting stents were cost effective whenever the restenosis rate with bare-metal stents was 12% or greater (CARDIOLOGY NEWS, March 2005, p. 7).

The upshot is that drug-eluting stents now make economic sense in wider coronary arteries and in vessels with shorter lesions. It is reasonable from an economic standpoint to use drug-eluting stents in most patients with coronary artery disease, said Dr. Cohen, associate director of interventional cardiology at Beth Israel Deaconess Medical Center in Boston.

By early 2005, the two types of drug-eluting stents sold in the United States (sirolimus-eluting and paclitaxel-eluting) cost an average of $2,300 per stent, down from an average of $2,700 last year and $3,100 in 2003. In early 2005, the difference in cost of a drug-eluting coronary stent over a comparable bare-metal stent had dropped to $1,600, down by $300 from the year before.

At Dr. Cohen's center, patients who had drug-eluting coronary stents placed in late 2004 received an average of 1.6 stents each. And the most current data from studies that compared drug-eluting stents with bare-metal stents showed that drug-eluting stents cut the need for target vessel revascularization by about 82%.

One additional issue for a cost-effectiveness calculation is that patients who receive drug-eluting stents require daily treatment with clopidogrel for several months, a regimen that costs about $120 per month.

Crunching all of these cost-adding and -saving numbers together yields the estimate that placement of a drug-eluting stent adds no incremental cost when used in patients with an expected restenosis rate with bare-metal stents of at least 10%, he said.

Based on an analysis done by Dr. Cohen and his associates in the late 1990s, virtually all patients with diabetes have a restenosis rate of 10% or greater with bare-metal stents. The only exceptions are patients with lesions that are less than 30 mm in length that are in coronary arteries that are at least 4.0 mm in diameter. Among patients without diabetes, a restenosis rate of less than 10% with bare-metal stents occurs in all coronary arteries that are 4.0 mm in diameter or greater, regardless of lesion length, and in vessels that are 3.5 mm in diameter or greater if the lesion length is less than 25 mm.

WASHINGTON — By the first few months of this year, drug-eluting coronary stents had become more cost effective than ever before.

Based on the price of drug-eluting stents, the average number of stents used per patient, and their efficacy at cutting the rate of restenosis, drug-eluting stents are now cost effective in any patient who would have a risk of restenosis of 10% or more if treated with bare-metal stents, David J. Cohen, M.D., said at a meeting sponsored by the Cardiovascular Research Institute of the Washington Hospital Center.

In contrast, based on last year's averages, drug-eluting stents were cost effective whenever the restenosis rate with bare-metal stents was 12% or greater (CARDIOLOGY NEWS, March 2005, p. 7).

The upshot is that drug-eluting stents now make economic sense in wider coronary arteries and in vessels with shorter lesions. It is reasonable from an economic standpoint to use drug-eluting stents in most patients with coronary artery disease, said Dr. Cohen, associate director of interventional cardiology at Beth Israel Deaconess Medical Center in Boston.

By early 2005, the two types of drug-eluting stents sold in the United States (sirolimus-eluting and paclitaxel-eluting) cost an average of $2,300 per stent, down from an average of $2,700 last year and $3,100 in 2003. In early 2005, the difference in cost of a drug-eluting coronary stent over a comparable bare-metal stent had dropped to $1,600, down by $300 from the year before.

At Dr. Cohen's center, patients who had drug-eluting coronary stents placed in late 2004 received an average of 1.6 stents each. And the most current data from studies that compared drug-eluting stents with bare-metal stents showed that drug-eluting stents cut the need for target vessel revascularization by about 82%.

One additional issue for a cost-effectiveness calculation is that patients who receive drug-eluting stents require daily treatment with clopidogrel for several months, a regimen that costs about $120 per month.

Crunching all of these cost-adding and -saving numbers together yields the estimate that placement of a drug-eluting stent adds no incremental cost when used in patients with an expected restenosis rate with bare-metal stents of at least 10%, he said.

Based on an analysis done by Dr. Cohen and his associates in the late 1990s, virtually all patients with diabetes have a restenosis rate of 10% or greater with bare-metal stents. The only exceptions are patients with lesions that are less than 30 mm in length that are in coronary arteries that are at least 4.0 mm in diameter. Among patients without diabetes, a restenosis rate of less than 10% with bare-metal stents occurs in all coronary arteries that are 4.0 mm in diameter or greater, regardless of lesion length, and in vessels that are 3.5 mm in diameter or greater if the lesion length is less than 25 mm.

WASHINGTON — By the first few months of this year, drug-eluting coronary stents had become more cost effective than ever before.

Based on the price of drug-eluting stents, the average number of stents used per patient, and their efficacy at cutting the rate of restenosis, drug-eluting stents are now cost effective in any patient who would have a risk of restenosis of 10% or more if treated with bare-metal stents, David J. Cohen, M.D., said at a meeting sponsored by the Cardiovascular Research Institute of the Washington Hospital Center.

In contrast, based on last year's averages, drug-eluting stents were cost effective whenever the restenosis rate with bare-metal stents was 12% or greater (CARDIOLOGY NEWS, March 2005, p. 7).

The upshot is that drug-eluting stents now make economic sense in wider coronary arteries and in vessels with shorter lesions. It is reasonable from an economic standpoint to use drug-eluting stents in most patients with coronary artery disease, said Dr. Cohen, associate director of interventional cardiology at Beth Israel Deaconess Medical Center in Boston.

By early 2005, the two types of drug-eluting stents sold in the United States (sirolimus-eluting and paclitaxel-eluting) cost an average of $2,300 per stent, down from an average of $2,700 last year and $3,100 in 2003. In early 2005, the difference in cost of a drug-eluting coronary stent over a comparable bare-metal stent had dropped to $1,600, down by $300 from the year before.

At Dr. Cohen's center, patients who had drug-eluting coronary stents placed in late 2004 received an average of 1.6 stents each. And the most current data from studies that compared drug-eluting stents with bare-metal stents showed that drug-eluting stents cut the need for target vessel revascularization by about 82%.

One additional issue for a cost-effectiveness calculation is that patients who receive drug-eluting stents require daily treatment with clopidogrel for several months, a regimen that costs about $120 per month.

Crunching all of these cost-adding and -saving numbers together yields the estimate that placement of a drug-eluting stent adds no incremental cost when used in patients with an expected restenosis rate with bare-metal stents of at least 10%, he said.

Based on an analysis done by Dr. Cohen and his associates in the late 1990s, virtually all patients with diabetes have a restenosis rate of 10% or greater with bare-metal stents. The only exceptions are patients with lesions that are less than 30 mm in length that are in coronary arteries that are at least 4.0 mm in diameter. Among patients without diabetes, a restenosis rate of less than 10% with bare-metal stents occurs in all coronary arteries that are 4.0 mm in diameter or greater, regardless of lesion length, and in vessels that are 3.5 mm in diameter or greater if the lesion length is less than 25 mm.

ORLANDO, FLA. — A new type of drug-eluting coronary stent was safe and effective in its first phase III clinical trial, compared with a similar bare-metal stent in about 1,200 patients.

But the results also raised novel issues on how effective drug-eluting stents must be at stopping the growth of coronary artery endothelium in order to prevent restenosis and the need for revascularization. That's because the new stent, brand named Endeavor and coated with a sirolimus-like drug called ABT-578, was successful at capping the target-lesion revascularization rate at 4.6% after 9 months, despite allowing a surprisingly high average late lumen loss of 0.62 mm within stented coronary arteries.

“The current paradigm is that inflating a balloon leads to a vascular response to injury that then produces intimal proliferation, restenosis, and [cardiac] events; but it didn't work that way” in this study, commented Lloyd W. Klein, M.D., at the annual meeting of the American College of Cardiology. “It makes you wonder if we have the right paradigm. Patients don't care about their intimal thickness; they care about whether they need to come back to the cath lab,” said Dr. Klein of Gottlieb Memorial Hospital in Melrose, Ill.

In the study, named ENDEAVOR II, 1,197 patients were enrolled at 72 centers in Europe, Asia, and Oceania. About 20% of patients had diabetes.

The study's primary end point was the composite incidence of cardiac death, nonfatal myocardial infarction, or need for target-vessel revascularization during 9 months of follow-up. The incidence of this composite end point was 8.1% in patients who received the drug-eluting stent and 15.4% in patients who received a comparable bare-metal stent (Driver), reported William Wijns, M.D., codirector of the Cardiovascular Centre at OLV Hospital in Aalst, Belgium. The study was sponsored by Medtronic Inc., which makes both the Endeavor and Driver stents.

Two other studies, both funded by Medtronic and now in progress, are comparing the Endeavor stent with the two competing drug-eluting stents on the U.S. market. One study matches the Endeavor and sirolimus-eluting (Cypher) stents; the other matches the Endeavor and paclitaxel-eluting (Taxus) stents. Medtronic will not seek U.S. marketing approval for the Endeavor stent until results from these studies are in.

In the current study, the ABT-578-eluting stent also looked good by other clinical end points: the 4.6% rate of target-lesion revascularization with the drug-eluting stent, compared with a 12.1% rate with the bare-metal stent; and the 0.5% rate of stent thrombosis during 9 months with the drug-eluting stent, compared with 1.2% with the bare-metal stent.

But this drug-eluting stent was less successful by the angiographic measures that were collected in 89% of the first 600 patients enrolled in the study. Although the mean late loss of 0.62 mm in the drug-eluting stents improved on the 1.03-mm rate of late loss with the bare-metal stent, it's a higher rate than has been seen in prior studies with other types of drug-eluting stents. Similarly, the in-stent binary restenosis rate of 9.5% with Endeavor in this study improved on the 32.7% rate with bare-metal stents, and was a higher restenosis rate than in earlier studies with other brands of drug-eluting stents.

In recent pivotal studies, the late-loss rate following coronary artery stenting averaged 0.17 mm with the sirolimus-eluting stent and 0.39 mm with the paclitaxel-eluting stent, said Gregg W. Stone, M.D., of Columbia University in New York. When compared with the 0.62-mm late loss with the ABT-578-eluting stent, these findings show “a striking difference in biologic potency” between the three drug-eluting stents.

But it's a different story for the target-lesion revascularization rates, the “purest surrogate measure of efficacy for drug-eluting stents.” These rates were 4.1% with the sirolimus-eluting stent and 3.0% with the paclitaxel-eluting stent, not substantially better than the 4.6% rate with the ABT-578-eluting stent in the new study.

“We go from a marked difference in biologic response to no difference in clinical results,” said Dr. Stone, although he also warned that these data were collected in three different studies, and comparisons across studies must be done cautiously.

What explains this apparent paradox? He hypothesized that the difference in late-loss rates may stem from differences in drug-elution rates. “You wouldn't expect such a difference in biologic responses based on any difference in the drugs.” But 75% of the sirolimus on a Cypher stent elutes in 10 days, and it takes 30 days for all of the drug to come off. In contrast, 75% of ABT-578 is off the Endeavor stent within 2 days after a stent is placed in a coronary artery, and 100% is off within 10 days. “It's plausible that the difference in elution rates at least partially explains the difference in vascular effects between the two stents,” he said.

When it comes to their clinical effect, “we know that most patients can accommodate a certain amount of stenosis before it overwhelms their coronary flow reserve,” said Dr. Stone. “The target lesion revascularization rate is only 7% when late loss is 0.70 mm. A 0.62-mm late-loss rate would not be expected to cause much target-lesion revascularization,” he said.

“Late loss is significantly greater [with the Endeavor stent] than with other drug-eluting stents, but it is still low enough to produce excellent freedom from restenosis,” Dr. Stone concluded.

Another factor is that the ENDEAVOR II study mostly used patients with a low relative risk for target-lesion restenosis. If the stent is tested in higher-risk patients or in higher-risk lesions, such as those in narrow coronary arteries, it's possible that the higher rate of late loss will make a clinical difference, commented Laura Mauri, M.D., a cardiologist at Brigham and Women's Hospital in Boston.

Nonetheless, the Endeavor stent may have other attributes that make it an attractive option. The Driver bare-metal stent that's the platform for the ABT-578-eluting stent is widely regarded as easy to use. Plus, the Endeavor stent uses a biocompatible phosphorylcholine coating that binds the drug layer to the metal stent. The sirolimus- and paclitaxel-eluting stents use a polymer coating. The phosphorylcholine coating may explain why the rate of late thrombosis in the ENDEAVOR II study was so low, 0.5%. The polymer coats on the other drug-eluting stents may, in part, be why they have led to some problems with late thrombosis, Dr. Mauri said. But a study designed to definitively show whether these stents differ in their rate of late thrombosis would require several thousand patients.

ORLANDO, FLA. — A new type of drug-eluting coronary stent was safe and effective in its first phase III clinical trial, compared with a similar bare-metal stent in about 1,200 patients.

But the results also raised novel issues on how effective drug-eluting stents must be at stopping the growth of coronary artery endothelium in order to prevent restenosis and the need for revascularization. That's because the new stent, brand named Endeavor and coated with a sirolimus-like drug called ABT-578, was successful at capping the target-lesion revascularization rate at 4.6% after 9 months, despite allowing a surprisingly high average late lumen loss of 0.62 mm within stented coronary arteries.

“The current paradigm is that inflating a balloon leads to a vascular response to injury that then produces intimal proliferation, restenosis, and [cardiac] events; but it didn't work that way” in this study, commented Lloyd W. Klein, M.D., at the annual meeting of the American College of Cardiology. “It makes you wonder if we have the right paradigm. Patients don't care about their intimal thickness; they care about whether they need to come back to the cath lab,” said Dr. Klein of Gottlieb Memorial Hospital in Melrose, Ill.

In the study, named ENDEAVOR II, 1,197 patients were enrolled at 72 centers in Europe, Asia, and Oceania. About 20% of patients had diabetes.

The study's primary end point was the composite incidence of cardiac death, nonfatal myocardial infarction, or need for target-vessel revascularization during 9 months of follow-up. The incidence of this composite end point was 8.1% in patients who received the drug-eluting stent and 15.4% in patients who received a comparable bare-metal stent (Driver), reported William Wijns, M.D., codirector of the Cardiovascular Centre at OLV Hospital in Aalst, Belgium. The study was sponsored by Medtronic Inc., which makes both the Endeavor and Driver stents.

Two other studies, both funded by Medtronic and now in progress, are comparing the Endeavor stent with the two competing drug-eluting stents on the U.S. market. One study matches the Endeavor and sirolimus-eluting (Cypher) stents; the other matches the Endeavor and paclitaxel-eluting (Taxus) stents. Medtronic will not seek U.S. marketing approval for the Endeavor stent until results from these studies are in.

In the current study, the ABT-578-eluting stent also looked good by other clinical end points: the 4.6% rate of target-lesion revascularization with the drug-eluting stent, compared with a 12.1% rate with the bare-metal stent; and the 0.5% rate of stent thrombosis during 9 months with the drug-eluting stent, compared with 1.2% with the bare-metal stent.

But this drug-eluting stent was less successful by the angiographic measures that were collected in 89% of the first 600 patients enrolled in the study. Although the mean late loss of 0.62 mm in the drug-eluting stents improved on the 1.03-mm rate of late loss with the bare-metal stent, it's a higher rate than has been seen in prior studies with other types of drug-eluting stents. Similarly, the in-stent binary restenosis rate of 9.5% with Endeavor in this study improved on the 32.7% rate with bare-metal stents, and was a higher restenosis rate than in earlier studies with other brands of drug-eluting stents.

In recent pivotal studies, the late-loss rate following coronary artery stenting averaged 0.17 mm with the sirolimus-eluting stent and 0.39 mm with the paclitaxel-eluting stent, said Gregg W. Stone, M.D., of Columbia University in New York. When compared with the 0.62-mm late loss with the ABT-578-eluting stent, these findings show “a striking difference in biologic potency” between the three drug-eluting stents.

But it's a different story for the target-lesion revascularization rates, the “purest surrogate measure of efficacy for drug-eluting stents.” These rates were 4.1% with the sirolimus-eluting stent and 3.0% with the paclitaxel-eluting stent, not substantially better than the 4.6% rate with the ABT-578-eluting stent in the new study.

“We go from a marked difference in biologic response to no difference in clinical results,” said Dr. Stone, although he also warned that these data were collected in three different studies, and comparisons across studies must be done cautiously.

What explains this apparent paradox? He hypothesized that the difference in late-loss rates may stem from differences in drug-elution rates. “You wouldn't expect such a difference in biologic responses based on any difference in the drugs.” But 75% of the sirolimus on a Cypher stent elutes in 10 days, and it takes 30 days for all of the drug to come off. In contrast, 75% of ABT-578 is off the Endeavor stent within 2 days after a stent is placed in a coronary artery, and 100% is off within 10 days. “It's plausible that the difference in elution rates at least partially explains the difference in vascular effects between the two stents,” he said.

When it comes to their clinical effect, “we know that most patients can accommodate a certain amount of stenosis before it overwhelms their coronary flow reserve,” said Dr. Stone. “The target lesion revascularization rate is only 7% when late loss is 0.70 mm. A 0.62-mm late-loss rate would not be expected to cause much target-lesion revascularization,” he said.

“Late loss is significantly greater [with the Endeavor stent] than with other drug-eluting stents, but it is still low enough to produce excellent freedom from restenosis,” Dr. Stone concluded.

Another factor is that the ENDEAVOR II study mostly used patients with a low relative risk for target-lesion restenosis. If the stent is tested in higher-risk patients or in higher-risk lesions, such as those in narrow coronary arteries, it's possible that the higher rate of late loss will make a clinical difference, commented Laura Mauri, M.D., a cardiologist at Brigham and Women's Hospital in Boston.

Nonetheless, the Endeavor stent may have other attributes that make it an attractive option. The Driver bare-metal stent that's the platform for the ABT-578-eluting stent is widely regarded as easy to use. Plus, the Endeavor stent uses a biocompatible phosphorylcholine coating that binds the drug layer to the metal stent. The sirolimus- and paclitaxel-eluting stents use a polymer coating. The phosphorylcholine coating may explain why the rate of late thrombosis in the ENDEAVOR II study was so low, 0.5%. The polymer coats on the other drug-eluting stents may, in part, be why they have led to some problems with late thrombosis, Dr. Mauri said. But a study designed to definitively show whether these stents differ in their rate of late thrombosis would require several thousand patients.

ORLANDO, FLA. — A new type of drug-eluting coronary stent was safe and effective in its first phase III clinical trial, compared with a similar bare-metal stent in about 1,200 patients.

But the results also raised novel issues on how effective drug-eluting stents must be at stopping the growth of coronary artery endothelium in order to prevent restenosis and the need for revascularization. That's because the new stent, brand named Endeavor and coated with a sirolimus-like drug called ABT-578, was successful at capping the target-lesion revascularization rate at 4.6% after 9 months, despite allowing a surprisingly high average late lumen loss of 0.62 mm within stented coronary arteries.

“The current paradigm is that inflating a balloon leads to a vascular response to injury that then produces intimal proliferation, restenosis, and [cardiac] events; but it didn't work that way” in this study, commented Lloyd W. Klein, M.D., at the annual meeting of the American College of Cardiology. “It makes you wonder if we have the right paradigm. Patients don't care about their intimal thickness; they care about whether they need to come back to the cath lab,” said Dr. Klein of Gottlieb Memorial Hospital in Melrose, Ill.

In the study, named ENDEAVOR II, 1,197 patients were enrolled at 72 centers in Europe, Asia, and Oceania. About 20% of patients had diabetes.

The study's primary end point was the composite incidence of cardiac death, nonfatal myocardial infarction, or need for target-vessel revascularization during 9 months of follow-up. The incidence of this composite end point was 8.1% in patients who received the drug-eluting stent and 15.4% in patients who received a comparable bare-metal stent (Driver), reported William Wijns, M.D., codirector of the Cardiovascular Centre at OLV Hospital in Aalst, Belgium. The study was sponsored by Medtronic Inc., which makes both the Endeavor and Driver stents.

Two other studies, both funded by Medtronic and now in progress, are comparing the Endeavor stent with the two competing drug-eluting stents on the U.S. market. One study matches the Endeavor and sirolimus-eluting (Cypher) stents; the other matches the Endeavor and paclitaxel-eluting (Taxus) stents. Medtronic will not seek U.S. marketing approval for the Endeavor stent until results from these studies are in.

In the current study, the ABT-578-eluting stent also looked good by other clinical end points: the 4.6% rate of target-lesion revascularization with the drug-eluting stent, compared with a 12.1% rate with the bare-metal stent; and the 0.5% rate of stent thrombosis during 9 months with the drug-eluting stent, compared with 1.2% with the bare-metal stent.

But this drug-eluting stent was less successful by the angiographic measures that were collected in 89% of the first 600 patients enrolled in the study. Although the mean late loss of 0.62 mm in the drug-eluting stents improved on the 1.03-mm rate of late loss with the bare-metal stent, it's a higher rate than has been seen in prior studies with other types of drug-eluting stents. Similarly, the in-stent binary restenosis rate of 9.5% with Endeavor in this study improved on the 32.7% rate with bare-metal stents, and was a higher restenosis rate than in earlier studies with other brands of drug-eluting stents.

In recent pivotal studies, the late-loss rate following coronary artery stenting averaged 0.17 mm with the sirolimus-eluting stent and 0.39 mm with the paclitaxel-eluting stent, said Gregg W. Stone, M.D., of Columbia University in New York. When compared with the 0.62-mm late loss with the ABT-578-eluting stent, these findings show “a striking difference in biologic potency” between the three drug-eluting stents.

But it's a different story for the target-lesion revascularization rates, the “purest surrogate measure of efficacy for drug-eluting stents.” These rates were 4.1% with the sirolimus-eluting stent and 3.0% with the paclitaxel-eluting stent, not substantially better than the 4.6% rate with the ABT-578-eluting stent in the new study.

“We go from a marked difference in biologic response to no difference in clinical results,” said Dr. Stone, although he also warned that these data were collected in three different studies, and comparisons across studies must be done cautiously.

What explains this apparent paradox? He hypothesized that the difference in late-loss rates may stem from differences in drug-elution rates. “You wouldn't expect such a difference in biologic responses based on any difference in the drugs.” But 75% of the sirolimus on a Cypher stent elutes in 10 days, and it takes 30 days for all of the drug to come off. In contrast, 75% of ABT-578 is off the Endeavor stent within 2 days after a stent is placed in a coronary artery, and 100% is off within 10 days. “It's plausible that the difference in elution rates at least partially explains the difference in vascular effects between the two stents,” he said.

When it comes to their clinical effect, “we know that most patients can accommodate a certain amount of stenosis before it overwhelms their coronary flow reserve,” said Dr. Stone. “The target lesion revascularization rate is only 7% when late loss is 0.70 mm. A 0.62-mm late-loss rate would not be expected to cause much target-lesion revascularization,” he said.

“Late loss is significantly greater [with the Endeavor stent] than with other drug-eluting stents, but it is still low enough to produce excellent freedom from restenosis,” Dr. Stone concluded.

Another factor is that the ENDEAVOR II study mostly used patients with a low relative risk for target-lesion restenosis. If the stent is tested in higher-risk patients or in higher-risk lesions, such as those in narrow coronary arteries, it's possible that the higher rate of late loss will make a clinical difference, commented Laura Mauri, M.D., a cardiologist at Brigham and Women's Hospital in Boston.

Nonetheless, the Endeavor stent may have other attributes that make it an attractive option. The Driver bare-metal stent that's the platform for the ABT-578-eluting stent is widely regarded as easy to use. Plus, the Endeavor stent uses a biocompatible phosphorylcholine coating that binds the drug layer to the metal stent. The sirolimus- and paclitaxel-eluting stents use a polymer coating. The phosphorylcholine coating may explain why the rate of late thrombosis in the ENDEAVOR II study was so low, 0.5%. The polymer coats on the other drug-eluting stents may, in part, be why they have led to some problems with late thrombosis, Dr. Mauri said. But a study designed to definitively show whether these stents differ in their rate of late thrombosis would require several thousand patients.

SAN FRANCISCO — Use of the Gore TAG thoracic endograft markedly reduced morbidity and mortality, compared with open repair through 2 years of follow-up, R. Scott Mitchell, M.D., said at the annual meeting of the American Association for Thoracic Surgery.

Earlier this year, the catheter-delivered Gore TAG device was approved as the first stent graft for treating descending thoracic aortic aneurysms. It consists of a Teflon tube covered by a nitinol exoskeleton. Although several endovascular devices for treatment of abdominal aortic aneurysms are on the market, endoprostheses for the less frequent thoracic aortic aneurysms has been slower to develop. The Gore TAG was the first such device to enter clinical trials, which were halted for 2 years upon discovery that it was prone to asymptomatic stent fractures along the graft spine.

The 17-center prospective nonrandomized trial compared outcomes in 140 patients with endovascular repair using the Gore TAG and a historical control group of 94 patients with a conventional open repair.

Mean estimated procedural blood loss was 472 mL in the Gore TAG group vs. 2,402 mL with open surgery. Temporary or permanent paraplegia occurred within 30 days in 3% of the Gore TAG group and 14% of controls. Early mortality in the Gore TAG group was 2%, compared with 6% in controls. The 3.5% perioperative stroke rate in the Gore TAG group was significantly lower than in controls. Rates of renal dysfunction and cardiac complications were also lower. ICU time and hospital length of stay were markedly shorter in the Gore TAG patients, who were able to return to normal activities in an average of 30 days, vs. 78 days in the open-surgery patients.

The rate of 2-year freedom from aneurysm-related mortality was 98% in the stent group and 91% in controls. However, all-cause mortality was similar in the two groups, at about 25%, according to Dr. Mitchell, professor of cardiovascular surgery at Stanford (Calif.) University and co-principal investigator in the trial.

Over 2 years of follow-up, 15% of Gore TAG-treated patients had an endoleak, for which four underwent endovascular revision; one required an open conversion.

During follow-up, the aneurysm sac decreased in size by more than 5 mm in 24 patients and grew by more than 5 mm in 11 patients. There have been no late aneurysm ruptures.

“I think these complications will be ongoing. Hopefully they'll be decreasing with time. But we don't know that, so these patients will require lifelong follow-up,” the surgeon stressed.

The device is not for everyone. It requires access vessels that allow passage of a 20–24 French sheath. The patient must have a minimum 2-cm landing zone of normal thoracic aorta free of thrombus or calcification proximal and distal to the aneurysm. Patients with Marfan syndrome and other connective tissue disorders were excluded from the trial, and Dr. Mitchell urged that the same policy be followed in clinical practice because the device is unlikely to be effective in that population.

Roughly 10,000–15,000 thoracic aortic aneurysms are diagnosed annually, often in elderly patients who are not good surgical candidates. The Gore TAG device, which spares patients the large chest incision and prolonged aortic clamping entailed in open surgery, could expand the pool of patients who can undergo repair.

Recognizing this, discussant Joseph S. Coselli, M.D., of Baylor College of Medicine in Houston, predicted, “this technology will forever alter how we approach descending thoracic aortic aneurysm pathology.” He added, however, that many participants in the control group for this trial were retrospectively acquired.

“It's not the best control group. We admit that,” said Dr. Mitchell. “But I think all of us are aware of the difficulties in trying to get a very aware public to enroll in a randomized trial.”

He is a consultant to W.L. Gore & Associates Inc., the study sponsor.

SAN FRANCISCO — Use of the Gore TAG thoracic endograft markedly reduced morbidity and mortality, compared with open repair through 2 years of follow-up, R. Scott Mitchell, M.D., said at the annual meeting of the American Association for Thoracic Surgery.

Earlier this year, the catheter-delivered Gore TAG device was approved as the first stent graft for treating descending thoracic aortic aneurysms. It consists of a Teflon tube covered by a nitinol exoskeleton. Although several endovascular devices for treatment of abdominal aortic aneurysms are on the market, endoprostheses for the less frequent thoracic aortic aneurysms has been slower to develop. The Gore TAG was the first such device to enter clinical trials, which were halted for 2 years upon discovery that it was prone to asymptomatic stent fractures along the graft spine.

The 17-center prospective nonrandomized trial compared outcomes in 140 patients with endovascular repair using the Gore TAG and a historical control group of 94 patients with a conventional open repair.

Mean estimated procedural blood loss was 472 mL in the Gore TAG group vs. 2,402 mL with open surgery. Temporary or permanent paraplegia occurred within 30 days in 3% of the Gore TAG group and 14% of controls. Early mortality in the Gore TAG group was 2%, compared with 6% in controls. The 3.5% perioperative stroke rate in the Gore TAG group was significantly lower than in controls. Rates of renal dysfunction and cardiac complications were also lower. ICU time and hospital length of stay were markedly shorter in the Gore TAG patients, who were able to return to normal activities in an average of 30 days, vs. 78 days in the open-surgery patients.

The rate of 2-year freedom from aneurysm-related mortality was 98% in the stent group and 91% in controls. However, all-cause mortality was similar in the two groups, at about 25%, according to Dr. Mitchell, professor of cardiovascular surgery at Stanford (Calif.) University and co-principal investigator in the trial.

Over 2 years of follow-up, 15% of Gore TAG-treated patients had an endoleak, for which four underwent endovascular revision; one required an open conversion.

During follow-up, the aneurysm sac decreased in size by more than 5 mm in 24 patients and grew by more than 5 mm in 11 patients. There have been no late aneurysm ruptures.

“I think these complications will be ongoing. Hopefully they'll be decreasing with time. But we don't know that, so these patients will require lifelong follow-up,” the surgeon stressed.

The device is not for everyone. It requires access vessels that allow passage of a 20–24 French sheath. The patient must have a minimum 2-cm landing zone of normal thoracic aorta free of thrombus or calcification proximal and distal to the aneurysm. Patients with Marfan syndrome and other connective tissue disorders were excluded from the trial, and Dr. Mitchell urged that the same policy be followed in clinical practice because the device is unlikely to be effective in that population.

Roughly 10,000–15,000 thoracic aortic aneurysms are diagnosed annually, often in elderly patients who are not good surgical candidates. The Gore TAG device, which spares patients the large chest incision and prolonged aortic clamping entailed in open surgery, could expand the pool of patients who can undergo repair.

Recognizing this, discussant Joseph S. Coselli, M.D., of Baylor College of Medicine in Houston, predicted, “this technology will forever alter how we approach descending thoracic aortic aneurysm pathology.” He added, however, that many participants in the control group for this trial were retrospectively acquired.

“It's not the best control group. We admit that,” said Dr. Mitchell. “But I think all of us are aware of the difficulties in trying to get a very aware public to enroll in a randomized trial.”

He is a consultant to W.L. Gore & Associates Inc., the study sponsor.

SAN FRANCISCO — Use of the Gore TAG thoracic endograft markedly reduced morbidity and mortality, compared with open repair through 2 years of follow-up, R. Scott Mitchell, M.D., said at the annual meeting of the American Association for Thoracic Surgery.

Earlier this year, the catheter-delivered Gore TAG device was approved as the first stent graft for treating descending thoracic aortic aneurysms. It consists of a Teflon tube covered by a nitinol exoskeleton. Although several endovascular devices for treatment of abdominal aortic aneurysms are on the market, endoprostheses for the less frequent thoracic aortic aneurysms has been slower to develop. The Gore TAG was the first such device to enter clinical trials, which were halted for 2 years upon discovery that it was prone to asymptomatic stent fractures along the graft spine.

The 17-center prospective nonrandomized trial compared outcomes in 140 patients with endovascular repair using the Gore TAG and a historical control group of 94 patients with a conventional open repair.

Mean estimated procedural blood loss was 472 mL in the Gore TAG group vs. 2,402 mL with open surgery. Temporary or permanent paraplegia occurred within 30 days in 3% of the Gore TAG group and 14% of controls. Early mortality in the Gore TAG group was 2%, compared with 6% in controls. The 3.5% perioperative stroke rate in the Gore TAG group was significantly lower than in controls. Rates of renal dysfunction and cardiac complications were also lower. ICU time and hospital length of stay were markedly shorter in the Gore TAG patients, who were able to return to normal activities in an average of 30 days, vs. 78 days in the open-surgery patients.

The rate of 2-year freedom from aneurysm-related mortality was 98% in the stent group and 91% in controls. However, all-cause mortality was similar in the two groups, at about 25%, according to Dr. Mitchell, professor of cardiovascular surgery at Stanford (Calif.) University and co-principal investigator in the trial.

Over 2 years of follow-up, 15% of Gore TAG-treated patients had an endoleak, for which four underwent endovascular revision; one required an open conversion.

During follow-up, the aneurysm sac decreased in size by more than 5 mm in 24 patients and grew by more than 5 mm in 11 patients. There have been no late aneurysm ruptures.

“I think these complications will be ongoing. Hopefully they'll be decreasing with time. But we don't know that, so these patients will require lifelong follow-up,” the surgeon stressed.

The device is not for everyone. It requires access vessels that allow passage of a 20–24 French sheath. The patient must have a minimum 2-cm landing zone of normal thoracic aorta free of thrombus or calcification proximal and distal to the aneurysm. Patients with Marfan syndrome and other connective tissue disorders were excluded from the trial, and Dr. Mitchell urged that the same policy be followed in clinical practice because the device is unlikely to be effective in that population.

Roughly 10,000–15,000 thoracic aortic aneurysms are diagnosed annually, often in elderly patients who are not good surgical candidates. The Gore TAG device, which spares patients the large chest incision and prolonged aortic clamping entailed in open surgery, could expand the pool of patients who can undergo repair.

Recognizing this, discussant Joseph S. Coselli, M.D., of Baylor College of Medicine in Houston, predicted, “this technology will forever alter how we approach descending thoracic aortic aneurysm pathology.” He added, however, that many participants in the control group for this trial were retrospectively acquired.

“It's not the best control group. We admit that,” said Dr. Mitchell. “But I think all of us are aware of the difficulties in trying to get a very aware public to enroll in a randomized trial.”

He is a consultant to W.L. Gore & Associates Inc., the study sponsor.

ORLANDO, FLA. — Early angiography is associated with improved survival in women presenting with acute coronary syndrome, Rasha N. Bazari, M.D., reported at an international conference on women, heart disease, and stroke.

Women who underwent coronary angiography within 2 days of presenting with ACS had a significantly lower 3-year mortality rates than did those who had later procedures (a difference of 7% vs. 20%), said Dr. Bazari of the Henry Ford Heart and Vascular Institute, Detroit.

Angiography beyond 48 hours after presentation was the most significant predictor of mortality, after adjustment for confounding variables (odds ratio 3.7).

Marginal predictors of mortality included older age and lower diastolic blood pressure, she said.

Dr. Bazari and associates reviewed the records of 836 patients (350 women and 486 men) admitted to the hospital during 1997–2000 who underwent angiography during their stay.

The study also showed that fewer women than men admitted during the study period underwent early coronary angiography (63% vs. 74%), she noted.

“Gender should not be a reason to delay early angiography” Dr. Bazari said.

ORLANDO, FLA. — Early angiography is associated with improved survival in women presenting with acute coronary syndrome, Rasha N. Bazari, M.D., reported at an international conference on women, heart disease, and stroke.

Women who underwent coronary angiography within 2 days of presenting with ACS had a significantly lower 3-year mortality rates than did those who had later procedures (a difference of 7% vs. 20%), said Dr. Bazari of the Henry Ford Heart and Vascular Institute, Detroit.

Angiography beyond 48 hours after presentation was the most significant predictor of mortality, after adjustment for confounding variables (odds ratio 3.7).

Marginal predictors of mortality included older age and lower diastolic blood pressure, she said.

Dr. Bazari and associates reviewed the records of 836 patients (350 women and 486 men) admitted to the hospital during 1997–2000 who underwent angiography during their stay.

The study also showed that fewer women than men admitted during the study period underwent early coronary angiography (63% vs. 74%), she noted.

“Gender should not be a reason to delay early angiography” Dr. Bazari said.

ORLANDO, FLA. — Early angiography is associated with improved survival in women presenting with acute coronary syndrome, Rasha N. Bazari, M.D., reported at an international conference on women, heart disease, and stroke.

Women who underwent coronary angiography within 2 days of presenting with ACS had a significantly lower 3-year mortality rates than did those who had later procedures (a difference of 7% vs. 20%), said Dr. Bazari of the Henry Ford Heart and Vascular Institute, Detroit.

Angiography beyond 48 hours after presentation was the most significant predictor of mortality, after adjustment for confounding variables (odds ratio 3.7).

Marginal predictors of mortality included older age and lower diastolic blood pressure, she said.

Dr. Bazari and associates reviewed the records of 836 patients (350 women and 486 men) admitted to the hospital during 1997–2000 who underwent angiography during their stay.

The study also showed that fewer women than men admitted during the study period underwent early coronary angiography (63% vs. 74%), she noted.

“Gender should not be a reason to delay early angiography” Dr. Bazari said.

ORLANDO, FLA. — Women presenting with myocardial infarction continue to receive less intensive treatment and have higher mortality than men with similar presentations, but the gender gap in medical interventions prescribed at hospital discharge may be narrowing, according to studies presented at an international conference on women, heart disease, and stroke.

One retrospective study included nearly 26,700 Swedish patients who were treated for ST-elevation myocardial infarction (STEMI) at cardiac intensive care units during 1997–2001. Reperfusion therapy was administered to 71% of the 17,243 men in the study, compared with 62% of the 9,455 women who participated in the study, Sofia Sederholm Lavesson, M.D., reported.

Men, compared with women, had lower in-hospital mortality (9% vs. 16%), 30-day mortality (11% vs. 18%), and 1-year mortality (16% vs. 25%), said Dr. Lavesson of Linköping (Sweden) University.

After adjustment for numerous confounding factors, women remained significantly less likely than men to receive reperfusion therapy (odds ratio 0.83) and to survive while in the hospital (OR 1.23), she said, noting that the differences between men and women cannot be fully explained by differences in age and comorbidities. “[Greater] age is the main explanation for the higher mortality in women, but less intensive treatment also appears to contribute,” she said.

A similar conclusion was reached in a study of more than 55,000 patients who were admitted to any of 153 different hospitals with a primary diagnosis of Q-wave acute MI during January 2000-June 2004.

Mortality was 13% in the 19,034 women in the study, compared with 7% in the 35,969 men.

Even after adjustment for a total of 24 variables, including age, various comorbidities, and the type of hospital setting that provided the treatment (heart surgery hospital, cath lab hospital, or a hospital with neither a heart surgery or cath lab), men were still shown to be less likely than women to die (OR 0.71).

Additionally, men were more likely than women to be transferred for further treatment (OR 1.24), receive thrombolytics (OR 1.16), receive percutaneous coronary intervention (OR 1.12), and/or receive coronary artery bypass grafting (OR 1.64), reported Allan L. Anderson, M.D., a cardiologist at the Medical City Dallas Hospital.

“Women with Q-wave acute MI continue to have significantly worse mortality rates and receive less revascularization than men,” he concluded, noting that additional research is needed to determine how women with MI can obtain clinical parity with men.

But such parity is being achieved when it comes to the prescribing of medical interventions at hospital discharge in patients who present with heart attack or chest pain, a third study suggests.

That ongoing study showed such men and women are being prescribed appropriate drug interventions at the about the same frequency.

The subanalysis of a National Institutes of Health-funded study of 177 men and 35 women with acute coronary syndrome showed that women were prescribed aspirin, β-blockers, and statins as frequently as men.

However, it also showed that 10% of women with acute coronary syndrome didn't receive aspirin or β-blockers and that more than 30% didn't receive statins, Shu-Fen Wung, Ph.D., and Heather Hiscox of the University of Arizona, Tucson, reported in a poster.

Also, women in this study lived significantly longer than men following their hospitalization (179 days vs. 156 days), with both age and gender showing a significant association with 6-month survival, the investigators noted.

The findings suggest that more people are following the guidelines of the American Heart Association and American College of Cardiology, and that progress is being made in the treatment of both men and women, Dr. Wung said in a statement.

ORLANDO, FLA. — Women presenting with myocardial infarction continue to receive less intensive treatment and have higher mortality than men with similar presentations, but the gender gap in medical interventions prescribed at hospital discharge may be narrowing, according to studies presented at an international conference on women, heart disease, and stroke.

One retrospective study included nearly 26,700 Swedish patients who were treated for ST-elevation myocardial infarction (STEMI) at cardiac intensive care units during 1997–2001. Reperfusion therapy was administered to 71% of the 17,243 men in the study, compared with 62% of the 9,455 women who participated in the study, Sofia Sederholm Lavesson, M.D., reported.

Men, compared with women, had lower in-hospital mortality (9% vs. 16%), 30-day mortality (11% vs. 18%), and 1-year mortality (16% vs. 25%), said Dr. Lavesson of Linköping (Sweden) University.

After adjustment for numerous confounding factors, women remained significantly less likely than men to receive reperfusion therapy (odds ratio 0.83) and to survive while in the hospital (OR 1.23), she said, noting that the differences between men and women cannot be fully explained by differences in age and comorbidities. “[Greater] age is the main explanation for the higher mortality in women, but less intensive treatment also appears to contribute,” she said.

A similar conclusion was reached in a study of more than 55,000 patients who were admitted to any of 153 different hospitals with a primary diagnosis of Q-wave acute MI during January 2000-June 2004.

Mortality was 13% in the 19,034 women in the study, compared with 7% in the 35,969 men.

Even after adjustment for a total of 24 variables, including age, various comorbidities, and the type of hospital setting that provided the treatment (heart surgery hospital, cath lab hospital, or a hospital with neither a heart surgery or cath lab), men were still shown to be less likely than women to die (OR 0.71).

Additionally, men were more likely than women to be transferred for further treatment (OR 1.24), receive thrombolytics (OR 1.16), receive percutaneous coronary intervention (OR 1.12), and/or receive coronary artery bypass grafting (OR 1.64), reported Allan L. Anderson, M.D., a cardiologist at the Medical City Dallas Hospital.

“Women with Q-wave acute MI continue to have significantly worse mortality rates and receive less revascularization than men,” he concluded, noting that additional research is needed to determine how women with MI can obtain clinical parity with men.

But such parity is being achieved when it comes to the prescribing of medical interventions at hospital discharge in patients who present with heart attack or chest pain, a third study suggests.

That ongoing study showed such men and women are being prescribed appropriate drug interventions at the about the same frequency.

The subanalysis of a National Institutes of Health-funded study of 177 men and 35 women with acute coronary syndrome showed that women were prescribed aspirin, β-blockers, and statins as frequently as men.

However, it also showed that 10% of women with acute coronary syndrome didn't receive aspirin or β-blockers and that more than 30% didn't receive statins, Shu-Fen Wung, Ph.D., and Heather Hiscox of the University of Arizona, Tucson, reported in a poster.

Also, women in this study lived significantly longer than men following their hospitalization (179 days vs. 156 days), with both age and gender showing a significant association with 6-month survival, the investigators noted.

The findings suggest that more people are following the guidelines of the American Heart Association and American College of Cardiology, and that progress is being made in the treatment of both men and women, Dr. Wung said in a statement.

ORLANDO, FLA. — Women presenting with myocardial infarction continue to receive less intensive treatment and have higher mortality than men with similar presentations, but the gender gap in medical interventions prescribed at hospital discharge may be narrowing, according to studies presented at an international conference on women, heart disease, and stroke.

One retrospective study included nearly 26,700 Swedish patients who were treated for ST-elevation myocardial infarction (STEMI) at cardiac intensive care units during 1997–2001. Reperfusion therapy was administered to 71% of the 17,243 men in the study, compared with 62% of the 9,455 women who participated in the study, Sofia Sederholm Lavesson, M.D., reported.

Men, compared with women, had lower in-hospital mortality (9% vs. 16%), 30-day mortality (11% vs. 18%), and 1-year mortality (16% vs. 25%), said Dr. Lavesson of Linköping (Sweden) University.

After adjustment for numerous confounding factors, women remained significantly less likely than men to receive reperfusion therapy (odds ratio 0.83) and to survive while in the hospital (OR 1.23), she said, noting that the differences between men and women cannot be fully explained by differences in age and comorbidities. “[Greater] age is the main explanation for the higher mortality in women, but less intensive treatment also appears to contribute,” she said.

A similar conclusion was reached in a study of more than 55,000 patients who were admitted to any of 153 different hospitals with a primary diagnosis of Q-wave acute MI during January 2000-June 2004.

Mortality was 13% in the 19,034 women in the study, compared with 7% in the 35,969 men.

Even after adjustment for a total of 24 variables, including age, various comorbidities, and the type of hospital setting that provided the treatment (heart surgery hospital, cath lab hospital, or a hospital with neither a heart surgery or cath lab), men were still shown to be less likely than women to die (OR 0.71).

Additionally, men were more likely than women to be transferred for further treatment (OR 1.24), receive thrombolytics (OR 1.16), receive percutaneous coronary intervention (OR 1.12), and/or receive coronary artery bypass grafting (OR 1.64), reported Allan L. Anderson, M.D., a cardiologist at the Medical City Dallas Hospital.

“Women with Q-wave acute MI continue to have significantly worse mortality rates and receive less revascularization than men,” he concluded, noting that additional research is needed to determine how women with MI can obtain clinical parity with men.

But such parity is being achieved when it comes to the prescribing of medical interventions at hospital discharge in patients who present with heart attack or chest pain, a third study suggests.

That ongoing study showed such men and women are being prescribed appropriate drug interventions at the about the same frequency.

The subanalysis of a National Institutes of Health-funded study of 177 men and 35 women with acute coronary syndrome showed that women were prescribed aspirin, β-blockers, and statins as frequently as men.

However, it also showed that 10% of women with acute coronary syndrome didn't receive aspirin or β-blockers and that more than 30% didn't receive statins, Shu-Fen Wung, Ph.D., and Heather Hiscox of the University of Arizona, Tucson, reported in a poster.

Also, women in this study lived significantly longer than men following their hospitalization (179 days vs. 156 days), with both age and gender showing a significant association with 6-month survival, the investigators noted.

The findings suggest that more people are following the guidelines of the American Heart Association and American College of Cardiology, and that progress is being made in the treatment of both men and women, Dr. Wung said in a statement.

ORLANDO, FLA. — One in 12 patients with acute MI presents with a concomitant acute potentially life-threatening noncardiac condition at admission, Judith H. Lichtman, Ph.D., reported at the annual meeting of the American College of Cardiology.

None of the current risk-adjustment models for MI patients that are widely used to guide clinical care and benchmark hospital and physician performance take account of these life-threatening noncardiac conditions.

Instead, the prognostic models are restricted to variables that are directly related to the patient's cardiovascular disease. That's largely because the models were developed using data from randomized clinical trials from which patients with significant comorbidities are generally excluded.

As a consequence, the risk-adjustment models fail to account for much of the variation in short-term outcomes in MI patients, explained Dr. Lichtman of Yale University, New Haven.

This is a glaring oversight, she stressed, because those 1 in 12 MI patients who have a dueling potentially life-threatening acute noncardiac condition account for a disproportionate share of total inpatient deaths.

Indeed, in the Prospective Registry Evaluating Outcomes After Myocardial Infarction: Events and Recovery (PREMIER) study such patients had an in-hospital mortality of 20%, compared with 3% in MI patients without such comorbidities.

“We feel that in this study we've identified a very important subgroup of acute MI patients at increased risk for mortality that have really not been previously described in the literature,” Dr. Lichtman added.

The PREMIER registry involved 3,948 acute myocardial infarction patients prospectively enrolled at 19 participating U.S. medical centers during 2003–2004. Chart review showed that 8% of these patients enrolled had an acute potentially life-threatening noncardiac condition present at the time of their admission.

These were not chronic conditions such as arthritis or seizure disorders. The most common of these conditions included severe pneumonia requiring intubation, trauma, stroke, sepsis, severe GI bleeding, and hip fracture.

Patients who present with one of these conditions in addition to an acute MI typically have been found to require care from multiple specialists, including both cardiovascular and noncardiovascular.

The MI patients with acute potentially life-threatening noncardiac conditions in PREMIER presented differently from those with MI alone. They were older—a mean age of 62 years compared with 56—and more likely to be women and nonwhite.

They also were more likely to have diabetes and hypertension and less likely to present with ST-elevation MI. And they were less likely to receive early therapy with aspirin, fibrinolytic agents, and β-blockers, as recommended in national guidelines.

After adjustment for the lesser use of guideline-based initial therapies for MI in the patients with potentially life-threatening comorbid conditions, along with differences in demographics, prior history, and clinical presentation, the patients still had a 4.9-fold increased risk of in-hospital mortality.

“I think this underscores a strong need to adopt a broader perspective of the clinical factors that contribute to the initial assessment, process of care, and outcomes for acute MI patients. … These factors need to be put on the radar of these risk-adjustment models,” Dr. Lichtman concluded.

Session cochair Eric D. Peterson, M.D., of Duke University in Durham, N.C., who was a coinvestigator in the PREMIER registry, said that while most MI patients with an acute potentially life-threatening noncardiac condition are routinely admitted to coronary care units, it might make more sense for them to go directly to the intensive care unit, where the caregivers are experienced in managing a wider array of very serious medical conditions.

ORLANDO, FLA. — One in 12 patients with acute MI presents with a concomitant acute potentially life-threatening noncardiac condition at admission, Judith H. Lichtman, Ph.D., reported at the annual meeting of the American College of Cardiology.

None of the current risk-adjustment models for MI patients that are widely used to guide clinical care and benchmark hospital and physician performance take account of these life-threatening noncardiac conditions.

Instead, the prognostic models are restricted to variables that are directly related to the patient's cardiovascular disease. That's largely because the models were developed using data from randomized clinical trials from which patients with significant comorbidities are generally excluded.

As a consequence, the risk-adjustment models fail to account for much of the variation in short-term outcomes in MI patients, explained Dr. Lichtman of Yale University, New Haven.

This is a glaring oversight, she stressed, because those 1 in 12 MI patients who have a dueling potentially life-threatening acute noncardiac condition account for a disproportionate share of total inpatient deaths.

Indeed, in the Prospective Registry Evaluating Outcomes After Myocardial Infarction: Events and Recovery (PREMIER) study such patients had an in-hospital mortality of 20%, compared with 3% in MI patients without such comorbidities.

“We feel that in this study we've identified a very important subgroup of acute MI patients at increased risk for mortality that have really not been previously described in the literature,” Dr. Lichtman added.

The PREMIER registry involved 3,948 acute myocardial infarction patients prospectively enrolled at 19 participating U.S. medical centers during 2003–2004. Chart review showed that 8% of these patients enrolled had an acute potentially life-threatening noncardiac condition present at the time of their admission.

These were not chronic conditions such as arthritis or seizure disorders. The most common of these conditions included severe pneumonia requiring intubation, trauma, stroke, sepsis, severe GI bleeding, and hip fracture.

Patients who present with one of these conditions in addition to an acute MI typically have been found to require care from multiple specialists, including both cardiovascular and noncardiovascular.

The MI patients with acute potentially life-threatening noncardiac conditions in PREMIER presented differently from those with MI alone. They were older—a mean age of 62 years compared with 56—and more likely to be women and nonwhite.

They also were more likely to have diabetes and hypertension and less likely to present with ST-elevation MI. And they were less likely to receive early therapy with aspirin, fibrinolytic agents, and β-blockers, as recommended in national guidelines.

After adjustment for the lesser use of guideline-based initial therapies for MI in the patients with potentially life-threatening comorbid conditions, along with differences in demographics, prior history, and clinical presentation, the patients still had a 4.9-fold increased risk of in-hospital mortality.

“I think this underscores a strong need to adopt a broader perspective of the clinical factors that contribute to the initial assessment, process of care, and outcomes for acute MI patients. … These factors need to be put on the radar of these risk-adjustment models,” Dr. Lichtman concluded.

Session cochair Eric D. Peterson, M.D., of Duke University in Durham, N.C., who was a coinvestigator in the PREMIER registry, said that while most MI patients with an acute potentially life-threatening noncardiac condition are routinely admitted to coronary care units, it might make more sense for them to go directly to the intensive care unit, where the caregivers are experienced in managing a wider array of very serious medical conditions.

ORLANDO, FLA. — One in 12 patients with acute MI presents with a concomitant acute potentially life-threatening noncardiac condition at admission, Judith H. Lichtman, Ph.D., reported at the annual meeting of the American College of Cardiology.

None of the current risk-adjustment models for MI patients that are widely used to guide clinical care and benchmark hospital and physician performance take account of these life-threatening noncardiac conditions.

Instead, the prognostic models are restricted to variables that are directly related to the patient's cardiovascular disease. That's largely because the models were developed using data from randomized clinical trials from which patients with significant comorbidities are generally excluded.

As a consequence, the risk-adjustment models fail to account for much of the variation in short-term outcomes in MI patients, explained Dr. Lichtman of Yale University, New Haven.

This is a glaring oversight, she stressed, because those 1 in 12 MI patients who have a dueling potentially life-threatening acute noncardiac condition account for a disproportionate share of total inpatient deaths.

Indeed, in the Prospective Registry Evaluating Outcomes After Myocardial Infarction: Events and Recovery (PREMIER) study such patients had an in-hospital mortality of 20%, compared with 3% in MI patients without such comorbidities.

“We feel that in this study we've identified a very important subgroup of acute MI patients at increased risk for mortality that have really not been previously described in the literature,” Dr. Lichtman added.

The PREMIER registry involved 3,948 acute myocardial infarction patients prospectively enrolled at 19 participating U.S. medical centers during 2003–2004. Chart review showed that 8% of these patients enrolled had an acute potentially life-threatening noncardiac condition present at the time of their admission.

These were not chronic conditions such as arthritis or seizure disorders. The most common of these conditions included severe pneumonia requiring intubation, trauma, stroke, sepsis, severe GI bleeding, and hip fracture.

Patients who present with one of these conditions in addition to an acute MI typically have been found to require care from multiple specialists, including both cardiovascular and noncardiovascular.

The MI patients with acute potentially life-threatening noncardiac conditions in PREMIER presented differently from those with MI alone. They were older—a mean age of 62 years compared with 56—and more likely to be women and nonwhite.

They also were more likely to have diabetes and hypertension and less likely to present with ST-elevation MI. And they were less likely to receive early therapy with aspirin, fibrinolytic agents, and β-blockers, as recommended in national guidelines.

After adjustment for the lesser use of guideline-based initial therapies for MI in the patients with potentially life-threatening comorbid conditions, along with differences in demographics, prior history, and clinical presentation, the patients still had a 4.9-fold increased risk of in-hospital mortality.

“I think this underscores a strong need to adopt a broader perspective of the clinical factors that contribute to the initial assessment, process of care, and outcomes for acute MI patients. … These factors need to be put on the radar of these risk-adjustment models,” Dr. Lichtman concluded.

Session cochair Eric D. Peterson, M.D., of Duke University in Durham, N.C., who was a coinvestigator in the PREMIER registry, said that while most MI patients with an acute potentially life-threatening noncardiac condition are routinely admitted to coronary care units, it might make more sense for them to go directly to the intensive care unit, where the caregivers are experienced in managing a wider array of very serious medical conditions.

NEW ORLEANS — The benefits of emboli protection devices clearly outweigh the risks, with most major centers and trials reporting a 50% reduction in strokes during carotid artery stenting, Alex Abou-Chebl, M.D., reported during the joint annual meeting of the American Association of Neurological Surgeons and the American Society of Interventional and Therapeutic Neuroradiology.

Further, newer generation devices are easier to use, said Dr. Abou-Chebl, an interventional neurologist with the Cleveland Clinic department of neurology.

Transcranial Doppler studies have shown that all patients who undergo angioplasty or stenting of the carotid arteries have emboli. The greatest number of emboli is during the actual intervention, and not during guidewire placement.

Since the filter device is the first to pass through the lesion, it has the potential to trap many emboli and thereby reduce intraoperative events, Dr. Abou-Chebl said. The 30-day stroke rate in most stenting and angioplasty trials before the filter devices were available was quite high, between 5% and 8%.

“We use these devices not because we are going to cause stroke in 100% of patients, but because we are going to cause stroke in 5%–8% of patients, and in these patients we want to have these devices there to help us out,” Dr. Abou-Chebl said.

Newer-generation devices are smaller and generally better tolerated. But the devices can be difficult to deliver in some lesions, increase the complexity of surgery, cause vasospasm and dissection, and fail. Vasospasm discontinues when the device is removed, and although serious, dissection occurs in less than 1% of patients and can be treated, Dr. Abou-Chebl said.

Critics have argued that the devices catch only platelet aggregation and thrombus formation on top of the device. Clinical experience suggests that the majority of particles are thrombotically formed from the carotid plaque, and range in size from 1.1 μm to 5 mm, Dr. Abou-Chebl said.

Dr. Abou-Chebl has placed stents in 187 patients with a filter device and captured particles as large as 4.5 by 5 mm.

Large particles are trapped, but it's the smaller particles that come out of the plaque that mandate the use of some protection device, Lee R. Guterman, M.D., of the department of neurosurgery at the State University of New York at Buffalo said during the same scientific session.

“They cause either permanent or transient neurologic deficit,” said Dr. Guterman, who has participated in all of the major stenting trials.

Emboli protection devices have been added to major angioplasty and stenting trials with consistently better results, with the exception of the Acculink for Revascularization of Carotids in High-Risk Patients (ARCHER) trial.

Dr. Abou-Chebl said he could not explain the ARCHER results, which showed a 30-day all-stroke rate of 7.6% in the first phase without protection, 8.6% in the second phase with embolic protection, and 8.3% in the third phase using the rapid exchange versions of the devices.

Comparatively, data from the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial showed a 98.6% successful placement rate for the device and an overall stroke and death rate of 3.7% in a high-risk population.

The filter captures particles as large as 4.5 by 5 mm and reduces intraoperative events. Courtesy Dr. Alex Abou-Chebl

NEW ORLEANS — The benefits of emboli protection devices clearly outweigh the risks, with most major centers and trials reporting a 50% reduction in strokes during carotid artery stenting, Alex Abou-Chebl, M.D., reported during the joint annual meeting of the American Association of Neurological Surgeons and the American Society of Interventional and Therapeutic Neuroradiology.

Further, newer generation devices are easier to use, said Dr. Abou-Chebl, an interventional neurologist with the Cleveland Clinic department of neurology.

Transcranial Doppler studies have shown that all patients who undergo angioplasty or stenting of the carotid arteries have emboli. The greatest number of emboli is during the actual intervention, and not during guidewire placement.

Since the filter device is the first to pass through the lesion, it has the potential to trap many emboli and thereby reduce intraoperative events, Dr. Abou-Chebl said. The 30-day stroke rate in most stenting and angioplasty trials before the filter devices were available was quite high, between 5% and 8%.

“We use these devices not because we are going to cause stroke in 100% of patients, but because we are going to cause stroke in 5%–8% of patients, and in these patients we want to have these devices there to help us out,” Dr. Abou-Chebl said.

Newer-generation devices are smaller and generally better tolerated. But the devices can be difficult to deliver in some lesions, increase the complexity of surgery, cause vasospasm and dissection, and fail. Vasospasm discontinues when the device is removed, and although serious, dissection occurs in less than 1% of patients and can be treated, Dr. Abou-Chebl said.

Critics have argued that the devices catch only platelet aggregation and thrombus formation on top of the device. Clinical experience suggests that the majority of particles are thrombotically formed from the carotid plaque, and range in size from 1.1 μm to 5 mm, Dr. Abou-Chebl said.

Dr. Abou-Chebl has placed stents in 187 patients with a filter device and captured particles as large as 4.5 by 5 mm.

Large particles are trapped, but it's the smaller particles that come out of the plaque that mandate the use of some protection device, Lee R. Guterman, M.D., of the department of neurosurgery at the State University of New York at Buffalo said during the same scientific session.

“They cause either permanent or transient neurologic deficit,” said Dr. Guterman, who has participated in all of the major stenting trials.

Emboli protection devices have been added to major angioplasty and stenting trials with consistently better results, with the exception of the Acculink for Revascularization of Carotids in High-Risk Patients (ARCHER) trial.

Dr. Abou-Chebl said he could not explain the ARCHER results, which showed a 30-day all-stroke rate of 7.6% in the first phase without protection, 8.6% in the second phase with embolic protection, and 8.3% in the third phase using the rapid exchange versions of the devices.

Comparatively, data from the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial showed a 98.6% successful placement rate for the device and an overall stroke and death rate of 3.7% in a high-risk population.

The filter captures particles as large as 4.5 by 5 mm and reduces intraoperative events. Courtesy Dr. Alex Abou-Chebl

NEW ORLEANS — The benefits of emboli protection devices clearly outweigh the risks, with most major centers and trials reporting a 50% reduction in strokes during carotid artery stenting, Alex Abou-Chebl, M.D., reported during the joint annual meeting of the American Association of Neurological Surgeons and the American Society of Interventional and Therapeutic Neuroradiology.

Further, newer generation devices are easier to use, said Dr. Abou-Chebl, an interventional neurologist with the Cleveland Clinic department of neurology.

Transcranial Doppler studies have shown that all patients who undergo angioplasty or stenting of the carotid arteries have emboli. The greatest number of emboli is during the actual intervention, and not during guidewire placement.

Since the filter device is the first to pass through the lesion, it has the potential to trap many emboli and thereby reduce intraoperative events, Dr. Abou-Chebl said. The 30-day stroke rate in most stenting and angioplasty trials before the filter devices were available was quite high, between 5% and 8%.

“We use these devices not because we are going to cause stroke in 100% of patients, but because we are going to cause stroke in 5%–8% of patients, and in these patients we want to have these devices there to help us out,” Dr. Abou-Chebl said.

Newer-generation devices are smaller and generally better tolerated. But the devices can be difficult to deliver in some lesions, increase the complexity of surgery, cause vasospasm and dissection, and fail. Vasospasm discontinues when the device is removed, and although serious, dissection occurs in less than 1% of patients and can be treated, Dr. Abou-Chebl said.

Critics have argued that the devices catch only platelet aggregation and thrombus formation on top of the device. Clinical experience suggests that the majority of particles are thrombotically formed from the carotid plaque, and range in size from 1.1 μm to 5 mm, Dr. Abou-Chebl said.

Dr. Abou-Chebl has placed stents in 187 patients with a filter device and captured particles as large as 4.5 by 5 mm.

Large particles are trapped, but it's the smaller particles that come out of the plaque that mandate the use of some protection device, Lee R. Guterman, M.D., of the department of neurosurgery at the State University of New York at Buffalo said during the same scientific session.

“They cause either permanent or transient neurologic deficit,” said Dr. Guterman, who has participated in all of the major stenting trials.

Emboli protection devices have been added to major angioplasty and stenting trials with consistently better results, with the exception of the Acculink for Revascularization of Carotids in High-Risk Patients (ARCHER) trial.

Dr. Abou-Chebl said he could not explain the ARCHER results, which showed a 30-day all-stroke rate of 7.6% in the first phase without protection, 8.6% in the second phase with embolic protection, and 8.3% in the third phase using the rapid exchange versions of the devices.

Comparatively, data from the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial showed a 98.6% successful placement rate for the device and an overall stroke and death rate of 3.7% in a high-risk population.

The filter captures particles as large as 4.5 by 5 mm and reduces intraoperative events. Courtesy Dr. Alex Abou-Chebl

1. Esper F, Shapiro ED, Weibel C, et al. Association between a novel human coronavirus and Kawasaki disease. J Infect Dis. 2005;191:499-502.

Kawasaki disease, a systemic vasculitis of childhood, is the most common cause of childhood acquired heart disease in developed countries and frequently a diagnosis made in the inpatient setting. Although the etiology of Kawasaki disease is not known, there is evidence to suggest the disease may be triggered by an infectious agent. This evidence includes wavelike spread in countries, seasonal epidemics, and the rarity of Kawasaki disease in adults and infants less than 3 months old. Even more compelling is the recent identification by Rowley et al. Of an antigen of unknown origin in respiratory epithelial cells and macrophages from children with Kawasaki disease (1).

Despite suggestion that retroviruses, Epstein–Barr virus, parvovirus B19, or chlamydia may be important in the pathogenesis of Kawasaki disease, no infectious etiology has been proven. In this brief report, Esper et al. document the interesting finding of a novel human coronavirus, “New Haven coronavirus” (HCoVNH), in the respiratory secretions of a 6-month old infant diagnosed with Kawasaki disease. Subsequently, the authors performed a retrospective, case-controlled study of 11 Kawasaki disease patients less than 5 years of age from whom respiratory secretions were archived but had tested negative for respiratory syncytial virus, influenza viruses A and B, parainfluenza viruses 1–3, and adenovirus by direct fluorescent antibody assay. These patients were matched with 2 control subjects. Eight (72.7%) of 11 case subjects and 1 (4.5%) of the 22 control subjects tested positive for HCoVNH by reverse transcriptase polymerase chain reaction (p=.0015). Further studies are needed to determine the precise role this, or other infectious pathogens, may have in the pathogenesis of the disease.

Reference

1. Rowley AH, Baker SC, Shulman ST, et al. Detection of antigen in bronchial epithelium and macrophages in acute Kawasaki disease by use of synthetic antibody. J Infect Dis. 2004;190:856-65.

2. Eyaid WM, AlNouri DM, Rashed MS, et al. An inborn error of metabolism presenting as hypoxicischemic insult. Pediatr Neurol. 2005;32:134-6.

Inborn error of metabolism is frequently on the “bottom” of many differential diagnoses lists for common pediatric presenting complaints. Relative infrequency coupled with the occasional difficulty of making an accurate diagnosis presents unique challenges. Nonetheless, the importance of making this diagnosis is essential, given the frequent opportunity for pharmacologic and/ or dietary intervention to be therapeutic.

These authors present an interesting case of siblings presenting with seizures and central nervous system imaging consistent with hypoxicischemic insult who were subsequently diagnosed with isolated sulfite oxidase deficiency.

1. Esper F, Shapiro ED, Weibel C, et al. Association between a novel human coronavirus and Kawasaki disease. J Infect Dis. 2005;191:499-502.

Kawasaki disease, a systemic vasculitis of childhood, is the most common cause of childhood acquired heart disease in developed countries and frequently a diagnosis made in the inpatient setting. Although the etiology of Kawasaki disease is not known, there is evidence to suggest the disease may be triggered by an infectious agent. This evidence includes wavelike spread in countries, seasonal epidemics, and the rarity of Kawasaki disease in adults and infants less than 3 months old. Even more compelling is the recent identification by Rowley et al. Of an antigen of unknown origin in respiratory epithelial cells and macrophages from children with Kawasaki disease (1).

Despite suggestion that retroviruses, Epstein–Barr virus, parvovirus B19, or chlamydia may be important in the pathogenesis of Kawasaki disease, no infectious etiology has been proven. In this brief report, Esper et al. document the interesting finding of a novel human coronavirus, “New Haven coronavirus” (HCoVNH), in the respiratory secretions of a 6-month old infant diagnosed with Kawasaki disease. Subsequently, the authors performed a retrospective, case-controlled study of 11 Kawasaki disease patients less than 5 years of age from whom respiratory secretions were archived but had tested negative for respiratory syncytial virus, influenza viruses A and B, parainfluenza viruses 1–3, and adenovirus by direct fluorescent antibody assay. These patients were matched with 2 control subjects. Eight (72.7%) of 11 case subjects and 1 (4.5%) of the 22 control subjects tested positive for HCoVNH by reverse transcriptase polymerase chain reaction (p=.0015). Further studies are needed to determine the precise role this, or other infectious pathogens, may have in the pathogenesis of the disease.

Reference

1. Rowley AH, Baker SC, Shulman ST, et al. Detection of antigen in bronchial epithelium and macrophages in acute Kawasaki disease by use of synthetic antibody. J Infect Dis. 2004;190:856-65.

2. Eyaid WM, AlNouri DM, Rashed MS, et al. An inborn error of metabolism presenting as hypoxicischemic insult. Pediatr Neurol. 2005;32:134-6.

Inborn error of metabolism is frequently on the “bottom” of many differential diagnoses lists for common pediatric presenting complaints. Relative infrequency coupled with the occasional difficulty of making an accurate diagnosis presents unique challenges. Nonetheless, the importance of making this diagnosis is essential, given the frequent opportunity for pharmacologic and/ or dietary intervention to be therapeutic.

These authors present an interesting case of siblings presenting with seizures and central nervous system imaging consistent with hypoxicischemic insult who were subsequently diagnosed with isolated sulfite oxidase deficiency.

1. Esper F, Shapiro ED, Weibel C, et al. Association between a novel human coronavirus and Kawasaki disease. J Infect Dis. 2005;191:499-502.

Kawasaki disease, a systemic vasculitis of childhood, is the most common cause of childhood acquired heart disease in developed countries and frequently a diagnosis made in the inpatient setting. Although the etiology of Kawasaki disease is not known, there is evidence to suggest the disease may be triggered by an infectious agent. This evidence includes wavelike spread in countries, seasonal epidemics, and the rarity of Kawasaki disease in adults and infants less than 3 months old. Even more compelling is the recent identification by Rowley et al. Of an antigen of unknown origin in respiratory epithelial cells and macrophages from children with Kawasaki disease (1).

Despite suggestion that retroviruses, Epstein–Barr virus, parvovirus B19, or chlamydia may be important in the pathogenesis of Kawasaki disease, no infectious etiology has been proven. In this brief report, Esper et al. document the interesting finding of a novel human coronavirus, “New Haven coronavirus” (HCoVNH), in the respiratory secretions of a 6-month old infant diagnosed with Kawasaki disease. Subsequently, the authors performed a retrospective, case-controlled study of 11 Kawasaki disease patients less than 5 years of age from whom respiratory secretions were archived but had tested negative for respiratory syncytial virus, influenza viruses A and B, parainfluenza viruses 1–3, and adenovirus by direct fluorescent antibody assay. These patients were matched with 2 control subjects. Eight (72.7%) of 11 case subjects and 1 (4.5%) of the 22 control subjects tested positive for HCoVNH by reverse transcriptase polymerase chain reaction (p=.0015). Further studies are needed to determine the precise role this, or other infectious pathogens, may have in the pathogenesis of the disease.

Reference

1. Rowley AH, Baker SC, Shulman ST, et al. Detection of antigen in bronchial epithelium and macrophages in acute Kawasaki disease by use of synthetic antibody. J Infect Dis. 2004;190:856-65.

2. Eyaid WM, AlNouri DM, Rashed MS, et al. An inborn error of metabolism presenting as hypoxicischemic insult. Pediatr Neurol. 2005;32:134-6.

Inborn error of metabolism is frequently on the “bottom” of many differential diagnoses lists for common pediatric presenting complaints. Relative infrequency coupled with the occasional difficulty of making an accurate diagnosis presents unique challenges. Nonetheless, the importance of making this diagnosis is essential, given the frequent opportunity for pharmacologic and/ or dietary intervention to be therapeutic.

These authors present an interesting case of siblings presenting with seizures and central nervous system imaging consistent with hypoxicischemic insult who were subsequently diagnosed with isolated sulfite oxidase deficiency.

Calicitonin Precusors and IL-8 as a Screen Panel for Bacterial Sepsis

Stryjewski GR, Nylen ES, Bell MJ, et al. Interleukin-6, interleukin-8, and a rapid and sensitive assay for calcitonin precursors for the determination of bacterial sepsis in febrile neutropenic children. Pediatr Crit Care Med. 2005;6:129-35.

Identification of sensitive and specific markers for serious bacterial infection (SBI) in children has commanded significant attention in recent literature. These researchers present a prospective cohort study of 56 children aged 5 months to 17 years (median 6.7 years) with fever (axillary temperature ≥37.5°C or oral temperature ≥38°C) and neutropenia (absolute neutrophil count ≤500/mm³) admitted to Children’s National Medical Center during a 15-month period. Researchers hypothesized that a highly sensitive assay for calcitonin precursors (CTpr) would detect levels of CTpr early in the course of illness, and that these levels in conjunction with measured levels of the cytokines interleukin (IL)-6 and IL-8 would provide a sensitive and specific set of markers for diagnosing bacterial sepsis in the study population. Markers were measured at admission, at 24 hours and at 48 hours. CTpr at 24 hours (adjusted odds ratio [95% confidence interval], 1.8 [1.2–2.8], p=.001) and IL8 (at 48 hours 1.08 [1.2–2.8], p=.02) were found to have association with bacterial sepsis. The authors conclude that based on the data generated, using cutoff values of 500 pg/mL for CTpr at 24 hours and 20 pg/mL for IL-8 at 48 hours would provide a sensitivity of 94% and specificity of 90%. Reliable biochemical markers that are highly associated with SBI and/or sepsis will likely improve the care of pediatric patients by guiding more specific therapy and potentially limiting exposure to unnecessary antibiotic . The results of this study cannot be generalized to all pediatric patients with fever and risk for SBI, due to the unique attributes of the study population. However, the study does provide information for future research into the development of markers and/or scoring systems to aid in the early diagnosis of SBI/sepsis in the general pediatric population.

Which Tests are Helpful and Cost-Effective in the Evaluation of Pediatric Syncope?

Steinberg LA, Knilans TK. Syncope in children: diagnostic tests have a high cost and low yield. J Pediatr. 2005;146:355-8.

Evaluation of syncope in children is not uncommon. This evaluation can often include multiple expensive tests, and evidence defining the most efficacious and cost-effective course of evaluation is lacking. Researchers from the Children’s Heart Center at St. Vincent Hospital in Indianapolis and the Division of Cardiology at Children’s Hospital Medical Center in Cincinnati present a retrospective review of 169 patients aged 4.5 to 18.7 years (mean, 13.1 ± 3.6) presenting to a tertiary care center for evaluation of transient loss of consciousness associated with loss of postural tone to describe the cost and utility of testing used to make a diagnosis. Costs were based on hospital costs for 1999 and did not include professional fees, the cost of clinic evaluations, or hospital admissions. There are significant limitations in the study design, and these are adequately discussed by the authors. A diagnosis was established in 128 patients (76%), and neurocardiogenic syncope was the most common diagnosis occurring in 116 patients (68%). Other diagnoses included seizure disorder (3 patients), pseudoseizure (2), anxiety disorder (2), psychogenic syncope (2) and 1 patient each with breathholding spells, long QT syndrome, and exertonal ventricular tachycardia. Tilt-testing had the highest diagnostic yield, although the researchers aptly point out that in the literature the specificity of tilt-testing ranges from 48 to 100% and that this test is rarely required to diagnose neurocardiogenic syncope, the most frequent diagnosis in this review. Loop memory cardiac monitoring had the lowest cost per diagnostic result. Electrocardiography had the lowest diagnostic yield and highest cost per test. Echocardiogram, chest radiograph, cardiac catheterization, electrophysiology studies, and evaluation of serum and body fluids were not diagnostic in this series. This respective review highlights the need for a consistent, evidence-based approach to this common presenting problem while emphasizing the importance of judicious testing guided by a thorough history and physical exam.

An Increase in Severe Community Acquired MRSA Infections in Texas

Gonzales BE, Martinez-Aguilar G, Hulten KG, et al. Severe staphylococcal sepsis in adolescents in the era of community-acquired methicillin-resistant Staphylococcus aureus. Pediatrics. 2005;115:642-8.

Gonzales et al. describe data prospectively gathered since August 1, 2001, showing an increase in the number of severely ill patients with community acquired (CA) Staphylococcus aureus infections. Fourteen patients with a mean age of 12.9 years (range: 10–15 years) were admitted to the PICU with sepsis. Twelve patients had CA methicillin-resistant S. aureus (CAMRSA). Thirteen patients (93%) had bone and joint infections. Thirteen patients had pulmonary involvement. Acute prerenal failure and peripheral vascular thrombosis were present in 50% and 29% of patients, respectively. Thirteen patients were bacteremic. All CAMRSA isolates were resistant to erythromycin, without inducible resistance to clindamycin. The review is interesting in light of the other literature reviewed by the authors suggesting a trend toward more severe infections caused by CAMRSA.

TheoPhylline vs. Terubutaline in Critically III Asthmatics

Wheeler DS, Jacobs BR, Kenreigh CA, et al. Theophylline versus terbutaline in treating critically ill children with status asthmaticus: A prospective, randomized, controlled trial. Pediatr Crit Care Med. 2005;6:142-7.

Status asthmaticus is a common diagnosis on the pediatric inpatient unit and in the pediatric intensive care unit (PICU). Inhaled beta-2 agonists, systemic corticosteroids, and supplemental oxygen are accepted as the standard of care for children with status asthmaticus who require admission. For critically ill children who are poorly responsive to the aforementioned triad of therapy, both theophylline and terbutaline are considered possible adjunctive therapies. Wheeler et al. suggest that the many studies failing to demonstrate added benefit of theophylline in non–critically ill patients has decreased the use of theophylline in the critical care setting, but point out that recent studies involving critically ill populations with status asthmaticus treated with theophylline have suggested benefit with comparison to placebo. Therefore, these researchers present a randomized, prospective, controlled, double-blind trial comparing the efficacy of theophylline alone, terbutaline alone, and theophylline and terbutaline together in critically ill pediatric patients receiving continuous nebulized albuterol and intravenous steroids. Forty patients with impending respiratory failure between the ages of 3 and 15 years were randomized to 1 of 3 groups: theophylline plus placebo (group 1), terbutaline plus placebo (group 2), or theophylline and terbutaline together (group 3). Thirty-six patients completed the study; 3 patients from group 1 were withdrawn due to parental request secondary to agitation (2 patients) and being inadvertently placed on a terbutaline infusion (1 patient). One patient from group 3 was withdrawn by the treating physician due to lack of improvement. All study participants, with the exception of the study pharmacist, were blinded to group assignment. Adjunctive therapies, including magnesium, ipatropium bromide and ketamine, were utilized at the discretion of the treating physician and were not controlled for. The primary outcome variable was change in a clinical scoring tool. Secondary outcomes variables included time to a specific clinical score, length of stay in the PICU, progression to mechanical ventilation, and incidence of adverse events. In addition, a cost analysis was performed isolating the 3 groups based on fiscal year 2003 cost estimates for theophylline and terbutaline. Results demonstrated no difference in the primary or secondary clinical outcome measures, with the exception of a higher incidence of nausea in group 3. The hospital costs were significantly lower in group 1 compared with groups 2 and 3 ($280 vs. $3,908 vs. $4,045, respectively, p<.0001). Significant limitations to the study include the lack of control of adjunctive therapies, a small sample size that confounds the ability to conclude no clinical difference between groups, and a baseline Pediatric Risk of Mortality (PRISM) Score in group 3 compared with groups 1 and 2. Despite these limitations the researchers suggest that the addition of intravenous theophylline to continuous nebulized albuterol and corticosteroids in the management of critically ill children with status asthmaticus is as safe and effective as adding intravenous terbutaline while being more cost-effective. Subsequent larger, well-controlled studies are required to support this conclusion.

Can Computerized Physician Ordering Create Errors?

Koppel R, Metlay JP, Cohen A, et al. Role of computerized physician order entry systems in facilitating medication errors. JAMA. 2005;293:1197-203.

Adverse drug events are a frequent etiology of inpatient morbidity and prescribing errors are the most frequent source. Computerized physician order entry (CPOE) is touted as a potential remedy for some types of adverse drug events. Few studies have investigated the potential for novel medication errors generated by a change to CPOE from conventional ordering. Koppel et al. present a quantitative and qualitative study of medication errors caused or exacerbated by a CPOE system. Interviews, surveys, and focus groups were the primary means of data collection. Housestaff who typically enter more than 9 orders per month were the primary study population, but data collection also included pharmacists, nursing staff , information technology managers, and attending physicians. The study was conducted in a tertiary-care teaching hospital between 2002 and 2004 utilizing a CPOE system in place since 1997. The CPOE system utilized is described as “monochromatic” and having “pre-Windows interfaces.” While not integrated with all hospital functions, the system was integrated with pharmacy and nursing medication lists. Researchers grouped errors into two broad categories: (1) information errors (fragmentation and systems integration failure) and (2) human-machine interface flaws (machine rules that do not correspond to work organization or usual behaviors). In total, 22 types of errors were recorded.

An example of an “information error” is assumed and incorrect dose information based on viewing doses intended only to describe pharmacy stocking practice―i.e. assuming that because the pharmacy stocks a 10mg dose of a medication, 10mg is an appropriate “minimally effective” dose. A “human-machine interface error” example is selecting an incorrect patient for ordering due to properties of the CPOE screen, such as the patient name not appearing on all screens. There are several important limitations to this study, but perhaps most important is the inability to generalize this data to other settings with potentially different physician users and software. Also important is a lack of description regarding physician user training and/or correlation of errors with amount of training or frequency of use, considering that the study population was defined as housestaff who may only use the system for 9 orders each . Despite these limitations, the study represents a requisite component to the growing trend toward the complete electronic record―namely, the use of objective investigations to study the safety and effectiveness of CPOE and the electronic record to promote the most optimal implementation and evolution of this new clinical tool.

Single-Dose Azithromycin for Acute Otitis Media

Arguedas A, Emparanza P, Schwartz RH, et al. A randomized, multicenter, double blind, double dummy trial of single dose azithromycin versus high dose amoxicillin for treatment of uncomplicated acute otitis media. Pediatr Infect Dis J. 2005;24: 153-61.

Acute otitis media is a common comorbid condition in pediatric inpatients. Patients at risk of having AOM with drug-resistant Streptococcus pneumoniae can be treated with high-dose amoxicillin as a first-line therapy according to recent American Academy of Pediatrics (AAP) recommendations. Despite this recommendation, there is evidence of reduced in vitro activity of amoxicillin against β-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis, as well as a lack of data from controlled and blinded studies demonstrating efficacy, adverse events and compliance for high-dose regimens. Azithromycin has in vitro activity against the 4 pathogens of clinical significance in AOM, and studies have shown that a single-dose regimen of azithromycin by the oral route is pharmacokinetically feasible, safe, and comparable in success rate to 3- and 5-day azithromycin regimens. With these considerations in mind, Arguedas et al. designed this study to compare single-dose (30 mg/kg) azithromycin with high-dose (90 mg/kg/day) amoxicillin in uncomplicated AOM.

In this double-blind, double-dummy, multinational, clinical trial, children between the ages of 6 and 30 months with uncomplicated AOM were randomized to treatment with single-dose azithromycin or high-dose amoxicillin (90 mg/kg/day, in 2 div doses) for 10 days. The primary outcome measure was clinical efficacy assessed at the end of treatment on the basis of a modified intent-to-treat (MITT) population. Secondary outcomes were analyses of safety and compliance. Three hundred thirteen patients were enrolled, of whom 83% were <2 years old, with 158 patients randomized to receive azithromycin and 154 to receive amoxicillin. Tympanocentesis was performed at baseline, and clinical responses were assessed at days 12–14 (end of therapy) and 25–28 (end of study). A middle-ear pathogen was detected in 212 patients (68%). H. Influenzae was the most common pathogen isolated (96 cases), followed by S. pneumoniae (92), M. catarrhalis (23), and S. pyogenes (23). At the end of therapy, clinical success rates for azithromycin and amoxicillin were comparable for all patients (84% and 84%, respectively) and for children <2 years of age (82% and 82%, respectively). At the end of the study, clinical efficacies among all microbiologic modified intent-to-treat evaluable subjects were comparable for patients treated with azithro(80%) and patients treated with amoxicillin (83%). The rates of adverse events for azithromycin and amoxicillin were 20% and 29%, respectively (p=.064). Diarrhea was more common in the amoxicillin group (17.5%) as compared to the azithromycin group (8.2%) (p=.017). Compliance, defined as completion of >80% of the study medications, was higher in the azithromycin group (100%) then in the amoxicillin group (90%) (p=.001). For practitioners ordering medications, compliance and efficacy are uppermost considerations. Single-dose azithromycin ensured 100% compliance, decreased adverse reactions, and equal efficacy, compared to high-dose amoxicillin in this well designed, randomized, controlled trial. (Jadad Score = 4/5) all patients (84% and 84%, respectively) and for children <2 years of age (82% and 82%, respectively). At the end of the study, clinical efficacies among all microbiologic modified intent-to-treat evaluable subjects were comparable for patients treated with azithromycin (80%) and patients treated with amoxicillin (83%). The rates of adverse events for azithromycin and amoxicillin were 20% and 29%, respectively

(p=.064). Diarrhea was more common in the amoxicillin group (17.5%) as compared to the azithromycin group (8.2%) (p=.017). Compliance, defined as completion of >80% of the study medications, was higher in the azithromycin group (100%) then in the amoxicillin group (90%) (p=.001). For practitioners ordering medications, compliance and efficacy are uppermost considerations. Single-dose azithromycin ensured 100% compliance, decreased adverse reactions, and equal efficacy, compared to high-dose amoxicillin in this well-designed, randomized, controlled trial. (Jadad Score = 4/5)

Calicitonin Precusors and IL-8 as a Screen Panel for Bacterial Sepsis

Stryjewski GR, Nylen ES, Bell MJ, et al. Interleukin-6, interleukin-8, and a rapid and sensitive assay for calcitonin precursors for the determination of bacterial sepsis in febrile neutropenic children. Pediatr Crit Care Med. 2005;6:129-35.

Identification of sensitive and specific markers for serious bacterial infection (SBI) in children has commanded significant attention in recent literature. These researchers present a prospective cohort study of 56 children aged 5 months to 17 years (median 6.7 years) with fever (axillary temperature ≥37.5°C or oral temperature ≥38°C) and neutropenia (absolute neutrophil count ≤500/mm³) admitted to Children’s National Medical Center during a 15-month period. Researchers hypothesized that a highly sensitive assay for calcitonin precursors (CTpr) would detect levels of CTpr early in the course of illness, and that these levels in conjunction with measured levels of the cytokines interleukin (IL)-6 and IL-8 would provide a sensitive and specific set of markers for diagnosing bacterial sepsis in the study population. Markers were measured at admission, at 24 hours and at 48 hours. CTpr at 24 hours (adjusted odds ratio [95% confidence interval], 1.8 [1.2–2.8], p=.001) and IL8 (at 48 hours 1.08 [1.2–2.8], p=.02) were found to have association with bacterial sepsis. The authors conclude that based on the data generated, using cutoff values of 500 pg/mL for CTpr at 24 hours and 20 pg/mL for IL-8 at 48 hours would provide a sensitivity of 94% and specificity of 90%. Reliable biochemical markers that are highly associated with SBI and/or sepsis will likely improve the care of pediatric patients by guiding more specific therapy and potentially limiting exposure to unnecessary antibiotic . The results of this study cannot be generalized to all pediatric patients with fever and risk for SBI, due to the unique attributes of the study population. However, the study does provide information for future research into the development of markers and/or scoring systems to aid in the early diagnosis of SBI/sepsis in the general pediatric population.

Which Tests are Helpful and Cost-Effective in the Evaluation of Pediatric Syncope?

Steinberg LA, Knilans TK. Syncope in children: diagnostic tests have a high cost and low yield. J Pediatr. 2005;146:355-8.

Evaluation of syncope in children is not uncommon. This evaluation can often include multiple expensive tests, and evidence defining the most efficacious and cost-effective course of evaluation is lacking. Researchers from the Children’s Heart Center at St. Vincent Hospital in Indianapolis and the Division of Cardiology at Children’s Hospital Medical Center in Cincinnati present a retrospective review of 169 patients aged 4.5 to 18.7 years (mean, 13.1 ± 3.6) presenting to a tertiary care center for evaluation of transient loss of consciousness associated with loss of postural tone to describe the cost and utility of testing used to make a diagnosis. Costs were based on hospital costs for 1999 and did not include professional fees, the cost of clinic evaluations, or hospital admissions. There are significant limitations in the study design, and these are adequately discussed by the authors. A diagnosis was established in 128 patients (76%), and neurocardiogenic syncope was the most common diagnosis occurring in 116 patients (68%). Other diagnoses included seizure disorder (3 patients), pseudoseizure (2), anxiety disorder (2), psychogenic syncope (2) and 1 patient each with breathholding spells, long QT syndrome, and exertonal ventricular tachycardia. Tilt-testing had the highest diagnostic yield, although the researchers aptly point out that in the literature the specificity of tilt-testing ranges from 48 to 100% and that this test is rarely required to diagnose neurocardiogenic syncope, the most frequent diagnosis in this review. Loop memory cardiac monitoring had the lowest cost per diagnostic result. Electrocardiography had the lowest diagnostic yield and highest cost per test. Echocardiogram, chest radiograph, cardiac catheterization, electrophysiology studies, and evaluation of serum and body fluids were not diagnostic in this series. This respective review highlights the need for a consistent, evidence-based approach to this common presenting problem while emphasizing the importance of judicious testing guided by a thorough history and physical exam.

An Increase in Severe Community Acquired MRSA Infections in Texas

Gonzales BE, Martinez-Aguilar G, Hulten KG, et al. Severe staphylococcal sepsis in adolescents in the era of community-acquired methicillin-resistant Staphylococcus aureus. Pediatrics. 2005;115:642-8.

Gonzales et al. describe data prospectively gathered since August 1, 2001, showing an increase in the number of severely ill patients with community acquired (CA) Staphylococcus aureus infections. Fourteen patients with a mean age of 12.9 years (range: 10–15 years) were admitted to the PICU with sepsis. Twelve patients had CA methicillin-resistant S. aureus (CAMRSA). Thirteen patients (93%) had bone and joint infections. Thirteen patients had pulmonary involvement. Acute prerenal failure and peripheral vascular thrombosis were present in 50% and 29% of patients, respectively. Thirteen patients were bacteremic. All CAMRSA isolates were resistant to erythromycin, without inducible resistance to clindamycin. The review is interesting in light of the other literature reviewed by the authors suggesting a trend toward more severe infections caused by CAMRSA.

TheoPhylline vs. Terubutaline in Critically III Asthmatics

Wheeler DS, Jacobs BR, Kenreigh CA, et al. Theophylline versus terbutaline in treating critically ill children with status asthmaticus: A prospective, randomized, controlled trial. Pediatr Crit Care Med. 2005;6:142-7.

Status asthmaticus is a common diagnosis on the pediatric inpatient unit and in the pediatric intensive care unit (PICU). Inhaled beta-2 agonists, systemic corticosteroids, and supplemental oxygen are accepted as the standard of care for children with status asthmaticus who require admission. For critically ill children who are poorly responsive to the aforementioned triad of therapy, both theophylline and terbutaline are considered possible adjunctive therapies. Wheeler et al. suggest that the many studies failing to demonstrate added benefit of theophylline in non–critically ill patients has decreased the use of theophylline in the critical care setting, but point out that recent studies involving critically ill populations with status asthmaticus treated with theophylline have suggested benefit with comparison to placebo. Therefore, these researchers present a randomized, prospective, controlled, double-blind trial comparing the efficacy of theophylline alone, terbutaline alone, and theophylline and terbutaline together in critically ill pediatric patients receiving continuous nebulized albuterol and intravenous steroids. Forty patients with impending respiratory failure between the ages of 3 and 15 years were randomized to 1 of 3 groups: theophylline plus placebo (group 1), terbutaline plus placebo (group 2), or theophylline and terbutaline together (group 3). Thirty-six patients completed the study; 3 patients from group 1 were withdrawn due to parental request secondary to agitation (2 patients) and being inadvertently placed on a terbutaline infusion (1 patient). One patient from group 3 was withdrawn by the treating physician due to lack of improvement. All study participants, with the exception of the study pharmacist, were blinded to group assignment. Adjunctive therapies, including magnesium, ipatropium bromide and ketamine, were utilized at the discretion of the treating physician and were not controlled for. The primary outcome variable was change in a clinical scoring tool. Secondary outcomes variables included time to a specific clinical score, length of stay in the PICU, progression to mechanical ventilation, and incidence of adverse events. In addition, a cost analysis was performed isolating the 3 groups based on fiscal year 2003 cost estimates for theophylline and terbutaline. Results demonstrated no difference in the primary or secondary clinical outcome measures, with the exception of a higher incidence of nausea in group 3. The hospital costs were significantly lower in group 1 compared with groups 2 and 3 ($280 vs. $3,908 vs. $4,045, respectively, p<.0001). Significant limitations to the study include the lack of control of adjunctive therapies, a small sample size that confounds the ability to conclude no clinical difference between groups, and a baseline Pediatric Risk of Mortality (PRISM) Score in group 3 compared with groups 1 and 2. Despite these limitations the researchers suggest that the addition of intravenous theophylline to continuous nebulized albuterol and corticosteroids in the management of critically ill children with status asthmaticus is as safe and effective as adding intravenous terbutaline while being more cost-effective. Subsequent larger, well-controlled studies are required to support this conclusion.

Can Computerized Physician Ordering Create Errors?

Koppel R, Metlay JP, Cohen A, et al. Role of computerized physician order entry systems in facilitating medication errors. JAMA. 2005;293:1197-203.

Adverse drug events are a frequent etiology of inpatient morbidity and prescribing errors are the most frequent source. Computerized physician order entry (CPOE) is touted as a potential remedy for some types of adverse drug events. Few studies have investigated the potential for novel medication errors generated by a change to CPOE from conventional ordering. Koppel et al. present a quantitative and qualitative study of medication errors caused or exacerbated by a CPOE system. Interviews, surveys, and focus groups were the primary means of data collection. Housestaff who typically enter more than 9 orders per month were the primary study population, but data collection also included pharmacists, nursing staff , information technology managers, and attending physicians. The study was conducted in a tertiary-care teaching hospital between 2002 and 2004 utilizing a CPOE system in place since 1997. The CPOE system utilized is described as “monochromatic” and having “pre-Windows interfaces.” While not integrated with all hospital functions, the system was integrated with pharmacy and nursing medication lists. Researchers grouped errors into two broad categories: (1) information errors (fragmentation and systems integration failure) and (2) human-machine interface flaws (machine rules that do not correspond to work organization or usual behaviors). In total, 22 types of errors were recorded.

An example of an “information error” is assumed and incorrect dose information based on viewing doses intended only to describe pharmacy stocking practice―i.e. assuming that because the pharmacy stocks a 10mg dose of a medication, 10mg is an appropriate “minimally effective” dose. A “human-machine interface error” example is selecting an incorrect patient for ordering due to properties of the CPOE screen, such as the patient name not appearing on all screens. There are several important limitations to this study, but perhaps most important is the inability to generalize this data to other settings with potentially different physician users and software. Also important is a lack of description regarding physician user training and/or correlation of errors with amount of training or frequency of use, considering that the study population was defined as housestaff who may only use the system for 9 orders each . Despite these limitations, the study represents a requisite component to the growing trend toward the complete electronic record―namely, the use of objective investigations to study the safety and effectiveness of CPOE and the electronic record to promote the most optimal implementation and evolution of this new clinical tool.

Single-Dose Azithromycin for Acute Otitis Media

Arguedas A, Emparanza P, Schwartz RH, et al. A randomized, multicenter, double blind, double dummy trial of single dose azithromycin versus high dose amoxicillin for treatment of uncomplicated acute otitis media. Pediatr Infect Dis J. 2005;24: 153-61.

Acute otitis media is a common comorbid condition in pediatric inpatients. Patients at risk of having AOM with drug-resistant Streptococcus pneumoniae can be treated with high-dose amoxicillin as a first-line therapy according to recent American Academy of Pediatrics (AAP) recommendations. Despite this recommendation, there is evidence of reduced in vitro activity of amoxicillin against β-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis, as well as a lack of data from controlled and blinded studies demonstrating efficacy, adverse events and compliance for high-dose regimens. Azithromycin has in vitro activity against the 4 pathogens of clinical significance in AOM, and studies have shown that a single-dose regimen of azithromycin by the oral route is pharmacokinetically feasible, safe, and comparable in success rate to 3- and 5-day azithromycin regimens. With these considerations in mind, Arguedas et al. designed this study to compare single-dose (30 mg/kg) azithromycin with high-dose (90 mg/kg/day) amoxicillin in uncomplicated AOM.

In this double-blind, double-dummy, multinational, clinical trial, children between the ages of 6 and 30 months with uncomplicated AOM were randomized to treatment with single-dose azithromycin or high-dose amoxicillin (90 mg/kg/day, in 2 div doses) for 10 days. The primary outcome measure was clinical efficacy assessed at the end of treatment on the basis of a modified intent-to-treat (MITT) population. Secondary outcomes were analyses of safety and compliance. Three hundred thirteen patients were enrolled, of whom 83% were <2 years old, with 158 patients randomized to receive azithromycin and 154 to receive amoxicillin. Tympanocentesis was performed at baseline, and clinical responses were assessed at days 12–14 (end of therapy) and 25–28 (end of study). A middle-ear pathogen was detected in 212 patients (68%). H. Influenzae was the most common pathogen isolated (96 cases), followed by S. pneumoniae (92), M. catarrhalis (23), and S. pyogenes (23). At the end of therapy, clinical success rates for azithromycin and amoxicillin were comparable for all patients (84% and 84%, respectively) and for children <2 years of age (82% and 82%, respectively). At the end of the study, clinical efficacies among all microbiologic modified intent-to-treat evaluable subjects were comparable for patients treated with azithro(80%) and patients treated with amoxicillin (83%). The rates of adverse events for azithromycin and amoxicillin were 20% and 29%, respectively (p=.064). Diarrhea was more common in the amoxicillin group (17.5%) as compared to the azithromycin group (8.2%) (p=.017). Compliance, defined as completion of >80% of the study medications, was higher in the azithromycin group (100%) then in the amoxicillin group (90%) (p=.001). For practitioners ordering medications, compliance and efficacy are uppermost considerations. Single-dose azithromycin ensured 100% compliance, decreased adverse reactions, and equal efficacy, compared to high-dose amoxicillin in this well designed, randomized, controlled trial. (Jadad Score = 4/5) all patients (84% and 84%, respectively) and for children <2 years of age (82% and 82%, respectively). At the end of the study, clinical efficacies among all microbiologic modified intent-to-treat evaluable subjects were comparable for patients treated with azithromycin (80%) and patients treated with amoxicillin (83%). The rates of adverse events for azithromycin and amoxicillin were 20% and 29%, respectively

(p=.064). Diarrhea was more common in the amoxicillin group (17.5%) as compared to the azithromycin group (8.2%) (p=.017). Compliance, defined as completion of >80% of the study medications, was higher in the azithromycin group (100%) then in the amoxicillin group (90%) (p=.001). For practitioners ordering medications, compliance and efficacy are uppermost considerations. Single-dose azithromycin ensured 100% compliance, decreased adverse reactions, and equal efficacy, compared to high-dose amoxicillin in this well-designed, randomized, controlled trial. (Jadad Score = 4/5)

Calicitonin Precusors and IL-8 as a Screen Panel for Bacterial Sepsis

Stryjewski GR, Nylen ES, Bell MJ, et al. Interleukin-6, interleukin-8, and a rapid and sensitive assay for calcitonin precursors for the determination of bacterial sepsis in febrile neutropenic children. Pediatr Crit Care Med. 2005;6:129-35.

Identification of sensitive and specific markers for serious bacterial infection (SBI) in children has commanded significant attention in recent literature. These researchers present a prospective cohort study of 56 children aged 5 months to 17 years (median 6.7 years) with fever (axillary temperature ≥37.5°C or oral temperature ≥38°C) and neutropenia (absolute neutrophil count ≤500/mm³) admitted to Children’s National Medical Center during a 15-month period. Researchers hypothesized that a highly sensitive assay for calcitonin precursors (CTpr) would detect levels of CTpr early in the course of illness, and that these levels in conjunction with measured levels of the cytokines interleukin (IL)-6 and IL-8 would provide a sensitive and specific set of markers for diagnosing bacterial sepsis in the study population. Markers were measured at admission, at 24 hours and at 48 hours. CTpr at 24 hours (adjusted odds ratio [95% confidence interval], 1.8 [1.2–2.8], p=.001) and IL8 (at 48 hours 1.08 [1.2–2.8], p=.02) were found to have association with bacterial sepsis. The authors conclude that based on the data generated, using cutoff values of 500 pg/mL for CTpr at 24 hours and 20 pg/mL for IL-8 at 48 hours would provide a sensitivity of 94% and specificity of 90%. Reliable biochemical markers that are highly associated with SBI and/or sepsis will likely improve the care of pediatric patients by guiding more specific therapy and potentially limiting exposure to unnecessary antibiotic . The results of this study cannot be generalized to all pediatric patients with fever and risk for SBI, due to the unique attributes of the study population. However, the study does provide information for future research into the development of markers and/or scoring systems to aid in the early diagnosis of SBI/sepsis in the general pediatric population.

Which Tests are Helpful and Cost-Effective in the Evaluation of Pediatric Syncope?

Steinberg LA, Knilans TK. Syncope in children: diagnostic tests have a high cost and low yield. J Pediatr. 2005;146:355-8.

Evaluation of syncope in children is not uncommon. This evaluation can often include multiple expensive tests, and evidence defining the most efficacious and cost-effective course of evaluation is lacking. Researchers from the Children’s Heart Center at St. Vincent Hospital in Indianapolis and the Division of Cardiology at Children’s Hospital Medical Center in Cincinnati present a retrospective review of 169 patients aged 4.5 to 18.7 years (mean, 13.1 ± 3.6) presenting to a tertiary care center for evaluation of transient loss of consciousness associated with loss of postural tone to describe the cost and utility of testing used to make a diagnosis. Costs were based on hospital costs for 1999 and did not include professional fees, the cost of clinic evaluations, or hospital admissions. There are significant limitations in the study design, and these are adequately discussed by the authors. A diagnosis was established in 128 patients (76%), and neurocardiogenic syncope was the most common diagnosis occurring in 116 patients (68%). Other diagnoses included seizure disorder (3 patients), pseudoseizure (2), anxiety disorder (2), psychogenic syncope (2) and 1 patient each with breathholding spells, long QT syndrome, and exertonal ventricular tachycardia. Tilt-testing had the highest diagnostic yield, although the researchers aptly point out that in the literature the specificity of tilt-testing ranges from 48 to 100% and that this test is rarely required to diagnose neurocardiogenic syncope, the most frequent diagnosis in this review. Loop memory cardiac monitoring had the lowest cost per diagnostic result. Electrocardiography had the lowest diagnostic yield and highest cost per test. Echocardiogram, chest radiograph, cardiac catheterization, electrophysiology studies, and evaluation of serum and body fluids were not diagnostic in this series. This respective review highlights the need for a consistent, evidence-based approach to this common presenting problem while emphasizing the importance of judicious testing guided by a thorough history and physical exam.

An Increase in Severe Community Acquired MRSA Infections in Texas

Gonzales BE, Martinez-Aguilar G, Hulten KG, et al. Severe staphylococcal sepsis in adolescents in the era of community-acquired methicillin-resistant Staphylococcus aureus. Pediatrics. 2005;115:642-8.

Gonzales et al. describe data prospectively gathered since August 1, 2001, showing an increase in the number of severely ill patients with community acquired (CA) Staphylococcus aureus infections. Fourteen patients with a mean age of 12.9 years (range: 10–15 years) were admitted to the PICU with sepsis. Twelve patients had CA methicillin-resistant S. aureus (CAMRSA). Thirteen patients (93%) had bone and joint infections. Thirteen patients had pulmonary involvement. Acute prerenal failure and peripheral vascular thrombosis were present in 50% and 29% of patients, respectively. Thirteen patients were bacteremic. All CAMRSA isolates were resistant to erythromycin, without inducible resistance to clindamycin. The review is interesting in light of the other literature reviewed by the authors suggesting a trend toward more severe infections caused by CAMRSA.

TheoPhylline vs. Terubutaline in Critically III Asthmatics

Wheeler DS, Jacobs BR, Kenreigh CA, et al. Theophylline versus terbutaline in treating critically ill children with status asthmaticus: A prospective, randomized, controlled trial. Pediatr Crit Care Med. 2005;6:142-7.

Status asthmaticus is a common diagnosis on the pediatric inpatient unit and in the pediatric intensive care unit (PICU). Inhaled beta-2 agonists, systemic corticosteroids, and supplemental oxygen are accepted as the standard of care for children with status asthmaticus who require admission. For critically ill children who are poorly responsive to the aforementioned triad of therapy, both theophylline and terbutaline are considered possible adjunctive therapies. Wheeler et al. suggest that the many studies failing to demonstrate added benefit of theophylline in non–critically ill patients has decreased the use of theophylline in the critical care setting, but point out that recent studies involving critically ill populations with status asthmaticus treated with theophylline have suggested benefit with comparison to placebo. Therefore, these researchers present a randomized, prospective, controlled, double-blind trial comparing the efficacy of theophylline alone, terbutaline alone, and theophylline and terbutaline together in critically ill pediatric patients receiving continuous nebulized albuterol and intravenous steroids. Forty patients with impending respiratory failure between the ages of 3 and 15 years were randomized to 1 of 3 groups: theophylline plus placebo (group 1), terbutaline plus placebo (group 2), or theophylline and terbutaline together (group 3). Thirty-six patients completed the study; 3 patients from group 1 were withdrawn due to parental request secondary to agitation (2 patients) and being inadvertently placed on a terbutaline infusion (1 patient). One patient from group 3 was withdrawn by the treating physician due to lack of improvement. All study participants, with the exception of the study pharmacist, were blinded to group assignment. Adjunctive therapies, including magnesium, ipatropium bromide and ketamine, were utilized at the discretion of the treating physician and were not controlled for. The primary outcome variable was change in a clinical scoring tool. Secondary outcomes variables included time to a specific clinical score, length of stay in the PICU, progression to mechanical ventilation, and incidence of adverse events. In addition, a cost analysis was performed isolating the 3 groups based on fiscal year 2003 cost estimates for theophylline and terbutaline. Results demonstrated no difference in the primary or secondary clinical outcome measures, with the exception of a higher incidence of nausea in group 3. The hospital costs were significantly lower in group 1 compared with groups 2 and 3 ($280 vs. $3,908 vs. $4,045, respectively, p<.0001). Significant limitations to the study include the lack of control of adjunctive therapies, a small sample size that confounds the ability to conclude no clinical difference between groups, and a baseline Pediatric Risk of Mortality (PRISM) Score in group 3 compared with groups 1 and 2. Despite these limitations the researchers suggest that the addition of intravenous theophylline to continuous nebulized albuterol and corticosteroids in the management of critically ill children with status asthmaticus is as safe and effective as adding intravenous terbutaline while being more cost-effective. Subsequent larger, well-controlled studies are required to support this conclusion.

Can Computerized Physician Ordering Create Errors?

Koppel R, Metlay JP, Cohen A, et al. Role of computerized physician order entry systems in facilitating medication errors. JAMA. 2005;293:1197-203.

Adverse drug events are a frequent etiology of inpatient morbidity and prescribing errors are the most frequent source. Computerized physician order entry (CPOE) is touted as a potential remedy for some types of adverse drug events. Few studies have investigated the potential for novel medication errors generated by a change to CPOE from conventional ordering. Koppel et al. present a quantitative and qualitative study of medication errors caused or exacerbated by a CPOE system. Interviews, surveys, and focus groups were the primary means of data collection. Housestaff who typically enter more than 9 orders per month were the primary study population, but data collection also included pharmacists, nursing staff , information technology managers, and attending physicians. The study was conducted in a tertiary-care teaching hospital between 2002 and 2004 utilizing a CPOE system in place since 1997. The CPOE system utilized is described as “monochromatic” and having “pre-Windows interfaces.” While not integrated with all hospital functions, the system was integrated with pharmacy and nursing medication lists. Researchers grouped errors into two broad categories: (1) information errors (fragmentation and systems integration failure) and (2) human-machine interface flaws (machine rules that do not correspond to work organization or usual behaviors). In total, 22 types of errors were recorded.

An example of an “information error” is assumed and incorrect dose information based on viewing doses intended only to describe pharmacy stocking practice―i.e. assuming that because the pharmacy stocks a 10mg dose of a medication, 10mg is an appropriate “minimally effective” dose. A “human-machine interface error” example is selecting an incorrect patient for ordering due to properties of the CPOE screen, such as the patient name not appearing on all screens. There are several important limitations to this study, but perhaps most important is the inability to generalize this data to other settings with potentially different physician users and software. Also important is a lack of description regarding physician user training and/or correlation of errors with amount of training or frequency of use, considering that the study population was defined as housestaff who may only use the system for 9 orders each . Despite these limitations, the study represents a requisite component to the growing trend toward the complete electronic record―namely, the use of objective investigations to study the safety and effectiveness of CPOE and the electronic record to promote the most optimal implementation and evolution of this new clinical tool.

Single-Dose Azithromycin for Acute Otitis Media

Arguedas A, Emparanza P, Schwartz RH, et al. A randomized, multicenter, double blind, double dummy trial of single dose azithromycin versus high dose amoxicillin for treatment of uncomplicated acute otitis media. Pediatr Infect Dis J. 2005;24: 153-61.

Acute otitis media is a common comorbid condition in pediatric inpatients. Patients at risk of having AOM with drug-resistant Streptococcus pneumoniae can be treated with high-dose amoxicillin as a first-line therapy according to recent American Academy of Pediatrics (AAP) recommendations. Despite this recommendation, there is evidence of reduced in vitro activity of amoxicillin against β-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis, as well as a lack of data from controlled and blinded studies demonstrating efficacy, adverse events and compliance for high-dose regimens. Azithromycin has in vitro activity against the 4 pathogens of clinical significance in AOM, and studies have shown that a single-dose regimen of azithromycin by the oral route is pharmacokinetically feasible, safe, and comparable in success rate to 3- and 5-day azithromycin regimens. With these considerations in mind, Arguedas et al. designed this study to compare single-dose (30 mg/kg) azithromycin with high-dose (90 mg/kg/day) amoxicillin in uncomplicated AOM.

In this double-blind, double-dummy, multinational, clinical trial, children between the ages of 6 and 30 months with uncomplicated AOM were randomized to treatment with single-dose azithromycin or high-dose amoxicillin (90 mg/kg/day, in 2 div doses) for 10 days. The primary outcome measure was clinical efficacy assessed at the end of treatment on the basis of a modified intent-to-treat (MITT) population. Secondary outcomes were analyses of safety and compliance. Three hundred thirteen patients were enrolled, of whom 83% were <2 years old, with 158 patients randomized to receive azithromycin and 154 to receive amoxicillin. Tympanocentesis was performed at baseline, and clinical responses were assessed at days 12–14 (end of therapy) and 25–28 (end of study). A middle-ear pathogen was detected in 212 patients (68%). H. Influenzae was the most common pathogen isolated (96 cases), followed by S. pneumoniae (92), M. catarrhalis (23), and S. pyogenes (23). At the end of therapy, clinical success rates for azithromycin and amoxicillin were comparable for all patients (84% and 84%, respectively) and for children <2 years of age (82% and 82%, respectively). At the end of the study, clinical efficacies among all microbiologic modified intent-to-treat evaluable subjects were comparable for patients treated with azithro(80%) and patients treated with amoxicillin (83%). The rates of adverse events for azithromycin and amoxicillin were 20% and 29%, respectively (p=.064). Diarrhea was more common in the amoxicillin group (17.5%) as compared to the azithromycin group (8.2%) (p=.017). Compliance, defined as completion of >80% of the study medications, was higher in the azithromycin group (100%) then in the amoxicillin group (90%) (p=.001). For practitioners ordering medications, compliance and efficacy are uppermost considerations. Single-dose azithromycin ensured 100% compliance, decreased adverse reactions, and equal efficacy, compared to high-dose amoxicillin in this well designed, randomized, controlled trial. (Jadad Score = 4/5) all patients (84% and 84%, respectively) and for children <2 years of age (82% and 82%, respectively). At the end of the study, clinical efficacies among all microbiologic modified intent-to-treat evaluable subjects were comparable for patients treated with azithromycin (80%) and patients treated with amoxicillin (83%). The rates of adverse events for azithromycin and amoxicillin were 20% and 29%, respectively

(p=.064). Diarrhea was more common in the amoxicillin group (17.5%) as compared to the azithromycin group (8.2%) (p=.017). Compliance, defined as completion of >80% of the study medications, was higher in the azithromycin group (100%) then in the amoxicillin group (90%) (p=.001). For practitioners ordering medications, compliance and efficacy are uppermost considerations. Single-dose azithromycin ensured 100% compliance, decreased adverse reactions, and equal efficacy, compared to high-dose amoxicillin in this well-designed, randomized, controlled trial. (Jadad Score = 4/5)