CHICAGO — Mycophenolate mofetil may be eclipsing cyclophosphamide as the standard-of-care induction therapy for lupus nephritis, Jill P. Buyon, M.D., reported at a symposium sponsored by the American College of Rheumatology.

Although the role of mycophenolate mofetil (MMF) in maintenance therapy still needs to be defined, the immunosuppressive agent has generated a lot of excitement, she said.

“In patients who don't have rapidly escalating renal insufficiency and whose creatinines are less than 2, there is little question at this point in time that I would suggest MMF over IV Cytoxan [cyclophosphamide],” she said. “I think it's better tolerated.”

She cited results from the largest open-label, controlled study, led by Ellen M. Ginzler, M.D., of the State University of New York Downstate Medical Center, Brooklyn. In that investigation, Dr. Ginzler and colleagues randomly assigned 140 patients with class III, VI, or V lupus nephritis to MMF, starting at 1 g/day and escalating to 3 g, as tolerated, or to intravenous cyclophosphamide, dosed according to National Institutes of Health protocols. The treatment period was 24 weeks.

In all, 16 of the 71 patients initially assigned to the MMF group achieved complete remission of their nephritis, defined as normal serum creatinine level, inactive urine sediment, and proteinuria less than or equal to 500 mg/24 hours. By comparison, 4 of the 69 patients initially assigned to the cyclophosphamide group achieved this primary end point (Arthritis Rheum. 2003;48[9 suppl.]:S647[abstract 1690]).

MMF was well tolerated and appeared better accepted by participants than cyclophosphamide.

“This study has really changed the way I manage patients,” said Dr. Buyon, of the Hospital for Joint Diseases and professor of medicine at New York University. “I certainly call this to my patients' attention, and many, many patients prefer using MMF.”

Dr. Buyon starts patients on MMF 500 mg twice daily, titrating to a target dose of 3 g/day. Some patients may not be able to achieve the target dose because of GI intolerance.

All patients started on MMF also receive prednisone at approximately 60 mg daily, which is reduced over the course of 2-3 months to between 5 mg/day and 10 mg/day.

Dr. Buyon added that she also switches patients induced with cyclophosphamide to MMF if they are doing well at 6 months.

CHICAGO — Mycophenolate mofetil may be eclipsing cyclophosphamide as the standard-of-care induction therapy for lupus nephritis, Jill P. Buyon, M.D., reported at a symposium sponsored by the American College of Rheumatology.

Although the role of mycophenolate mofetil (MMF) in maintenance therapy still needs to be defined, the immunosuppressive agent has generated a lot of excitement, she said.

“In patients who don't have rapidly escalating renal insufficiency and whose creatinines are less than 2, there is little question at this point in time that I would suggest MMF over IV Cytoxan [cyclophosphamide],” she said. “I think it's better tolerated.”

She cited results from the largest open-label, controlled study, led by Ellen M. Ginzler, M.D., of the State University of New York Downstate Medical Center, Brooklyn. In that investigation, Dr. Ginzler and colleagues randomly assigned 140 patients with class III, VI, or V lupus nephritis to MMF, starting at 1 g/day and escalating to 3 g, as tolerated, or to intravenous cyclophosphamide, dosed according to National Institutes of Health protocols. The treatment period was 24 weeks.

In all, 16 of the 71 patients initially assigned to the MMF group achieved complete remission of their nephritis, defined as normal serum creatinine level, inactive urine sediment, and proteinuria less than or equal to 500 mg/24 hours. By comparison, 4 of the 69 patients initially assigned to the cyclophosphamide group achieved this primary end point (Arthritis Rheum. 2003;48[9 suppl.]:S647[abstract 1690]).

MMF was well tolerated and appeared better accepted by participants than cyclophosphamide.

“This study has really changed the way I manage patients,” said Dr. Buyon, of the Hospital for Joint Diseases and professor of medicine at New York University. “I certainly call this to my patients' attention, and many, many patients prefer using MMF.”

Dr. Buyon starts patients on MMF 500 mg twice daily, titrating to a target dose of 3 g/day. Some patients may not be able to achieve the target dose because of GI intolerance.

All patients started on MMF also receive prednisone at approximately 60 mg daily, which is reduced over the course of 2-3 months to between 5 mg/day and 10 mg/day.

Dr. Buyon added that she also switches patients induced with cyclophosphamide to MMF if they are doing well at 6 months.

CHICAGO — Mycophenolate mofetil may be eclipsing cyclophosphamide as the standard-of-care induction therapy for lupus nephritis, Jill P. Buyon, M.D., reported at a symposium sponsored by the American College of Rheumatology.

Although the role of mycophenolate mofetil (MMF) in maintenance therapy still needs to be defined, the immunosuppressive agent has generated a lot of excitement, she said.

“In patients who don't have rapidly escalating renal insufficiency and whose creatinines are less than 2, there is little question at this point in time that I would suggest MMF over IV Cytoxan [cyclophosphamide],” she said. “I think it's better tolerated.”

She cited results from the largest open-label, controlled study, led by Ellen M. Ginzler, M.D., of the State University of New York Downstate Medical Center, Brooklyn. In that investigation, Dr. Ginzler and colleagues randomly assigned 140 patients with class III, VI, or V lupus nephritis to MMF, starting at 1 g/day and escalating to 3 g, as tolerated, or to intravenous cyclophosphamide, dosed according to National Institutes of Health protocols. The treatment period was 24 weeks.

In all, 16 of the 71 patients initially assigned to the MMF group achieved complete remission of their nephritis, defined as normal serum creatinine level, inactive urine sediment, and proteinuria less than or equal to 500 mg/24 hours. By comparison, 4 of the 69 patients initially assigned to the cyclophosphamide group achieved this primary end point (Arthritis Rheum. 2003;48[9 suppl.]:S647[abstract 1690]).

MMF was well tolerated and appeared better accepted by participants than cyclophosphamide.

“This study has really changed the way I manage patients,” said Dr. Buyon, of the Hospital for Joint Diseases and professor of medicine at New York University. “I certainly call this to my patients' attention, and many, many patients prefer using MMF.”

Dr. Buyon starts patients on MMF 500 mg twice daily, titrating to a target dose of 3 g/day. Some patients may not be able to achieve the target dose because of GI intolerance.

All patients started on MMF also receive prednisone at approximately 60 mg daily, which is reduced over the course of 2-3 months to between 5 mg/day and 10 mg/day.

Dr. Buyon added that she also switches patients induced with cyclophosphamide to MMF if they are doing well at 6 months.

NEW YORK — New revelations about the complex cellular processes underlying scleroderma suggest that manipulating the immune system with thalidomide may offer a new means of targeting the disease, Stephen J. Oliver, M.D., said at a rheumatology meeting sponsored by New York University.

Scleroderma begins with inflammation and the production of cytokines, including transforming growth factor (TGF)-β and interleukin (IL)-4, both of which are profibrogenic and activate the fibroblast.

Once the fibroblast becomes activated, it produces its own TGF-β and other cytokines, such as connective tissue growth factor. This leads to further proliferation of fibroblasts and the production of collagen, Dr. Oliver explained.

“At this point, immunosuppression could theoretically act to shut off the production of cytokines and other exogenous activators of the fibroblast. But immune suppression has not been as effective in scleroderma as we would have liked it to be and, in fact, in many cases it hasn't been effective at all.” Early studies targeted TGF-β. However, this cytokine has multiple functions aside from its profibrogenic actions, “so blocking TGF-β systemically might not be such a great idea,” said Dr. Oliver of New York University, New York.

An alternative approach now being studied involves immune manipulation with thalidomide. In scleroderma, the T helper (Th)2 type of immune response is predominant, and laboratory investigations have revealed that thalidomide stimulates a Th1-type cellular response, causing increased production of interferon (IFN)-γ, IL-2, and IL-12 and enhancing the T-cell expression of the CD40 ligand.

Its potential applicability in scleroderma was suggested by the observation that this autoimmune disease shares many clinical features with graft-versus-host disease—a condition that sometimes responds to thalidomide.

In the first open-label study of the drug in scleroderma, 8 of 11 patients completed 12 weeks of treatment. The initial dosage was 50 mg/day; this was gradually increased to 400 mg/day, which is the maximum dosage used for the treatment of erythema nodosum leprosum.

Pruritus and dry skin were reported by seven of the eight patients, but there were no serious adverse events, such as the induction of renal disease, Dr. Oliver said.

Among the changes seen in patients in this preliminary study were increases in CD8 cells within the skin; this could offset the increased levels of CD4 cells that are associated with fibrosis of the skin, he said. Increases also were seen in tumor necrosis factor-α and IL-12. Moreover, there was a “striking clinical effect” in the healing of digital ulcers in four of five patients (Clin. Immunol. 2000;97:109-20).

Recruitment for a double-blind, placebo-controlled trial is under way. Dr. Oliver noted that he had no potential conflicts of interest.

Clinicians with patients who may be candidates for the New York University Scleroderma Trial can contact Dr. Oliver at 212-263-3874.

NEW YORK — New revelations about the complex cellular processes underlying scleroderma suggest that manipulating the immune system with thalidomide may offer a new means of targeting the disease, Stephen J. Oliver, M.D., said at a rheumatology meeting sponsored by New York University.

Scleroderma begins with inflammation and the production of cytokines, including transforming growth factor (TGF)-β and interleukin (IL)-4, both of which are profibrogenic and activate the fibroblast.

Once the fibroblast becomes activated, it produces its own TGF-β and other cytokines, such as connective tissue growth factor. This leads to further proliferation of fibroblasts and the production of collagen, Dr. Oliver explained.

“At this point, immunosuppression could theoretically act to shut off the production of cytokines and other exogenous activators of the fibroblast. But immune suppression has not been as effective in scleroderma as we would have liked it to be and, in fact, in many cases it hasn't been effective at all.” Early studies targeted TGF-β. However, this cytokine has multiple functions aside from its profibrogenic actions, “so blocking TGF-β systemically might not be such a great idea,” said Dr. Oliver of New York University, New York.

An alternative approach now being studied involves immune manipulation with thalidomide. In scleroderma, the T helper (Th)2 type of immune response is predominant, and laboratory investigations have revealed that thalidomide stimulates a Th1-type cellular response, causing increased production of interferon (IFN)-γ, IL-2, and IL-12 and enhancing the T-cell expression of the CD40 ligand.

Its potential applicability in scleroderma was suggested by the observation that this autoimmune disease shares many clinical features with graft-versus-host disease—a condition that sometimes responds to thalidomide.

In the first open-label study of the drug in scleroderma, 8 of 11 patients completed 12 weeks of treatment. The initial dosage was 50 mg/day; this was gradually increased to 400 mg/day, which is the maximum dosage used for the treatment of erythema nodosum leprosum.

Pruritus and dry skin were reported by seven of the eight patients, but there were no serious adverse events, such as the induction of renal disease, Dr. Oliver said.

Among the changes seen in patients in this preliminary study were increases in CD8 cells within the skin; this could offset the increased levels of CD4 cells that are associated with fibrosis of the skin, he said. Increases also were seen in tumor necrosis factor-α and IL-12. Moreover, there was a “striking clinical effect” in the healing of digital ulcers in four of five patients (Clin. Immunol. 2000;97:109-20).

Recruitment for a double-blind, placebo-controlled trial is under way. Dr. Oliver noted that he had no potential conflicts of interest.

Clinicians with patients who may be candidates for the New York University Scleroderma Trial can contact Dr. Oliver at 212-263-3874.

NEW YORK — New revelations about the complex cellular processes underlying scleroderma suggest that manipulating the immune system with thalidomide may offer a new means of targeting the disease, Stephen J. Oliver, M.D., said at a rheumatology meeting sponsored by New York University.

Scleroderma begins with inflammation and the production of cytokines, including transforming growth factor (TGF)-β and interleukin (IL)-4, both of which are profibrogenic and activate the fibroblast.

Once the fibroblast becomes activated, it produces its own TGF-β and other cytokines, such as connective tissue growth factor. This leads to further proliferation of fibroblasts and the production of collagen, Dr. Oliver explained.

“At this point, immunosuppression could theoretically act to shut off the production of cytokines and other exogenous activators of the fibroblast. But immune suppression has not been as effective in scleroderma as we would have liked it to be and, in fact, in many cases it hasn't been effective at all.” Early studies targeted TGF-β. However, this cytokine has multiple functions aside from its profibrogenic actions, “so blocking TGF-β systemically might not be such a great idea,” said Dr. Oliver of New York University, New York.

An alternative approach now being studied involves immune manipulation with thalidomide. In scleroderma, the T helper (Th)2 type of immune response is predominant, and laboratory investigations have revealed that thalidomide stimulates a Th1-type cellular response, causing increased production of interferon (IFN)-γ, IL-2, and IL-12 and enhancing the T-cell expression of the CD40 ligand.

Its potential applicability in scleroderma was suggested by the observation that this autoimmune disease shares many clinical features with graft-versus-host disease—a condition that sometimes responds to thalidomide.

In the first open-label study of the drug in scleroderma, 8 of 11 patients completed 12 weeks of treatment. The initial dosage was 50 mg/day; this was gradually increased to 400 mg/day, which is the maximum dosage used for the treatment of erythema nodosum leprosum.

Pruritus and dry skin were reported by seven of the eight patients, but there were no serious adverse events, such as the induction of renal disease, Dr. Oliver said.

Among the changes seen in patients in this preliminary study were increases in CD8 cells within the skin; this could offset the increased levels of CD4 cells that are associated with fibrosis of the skin, he said. Increases also were seen in tumor necrosis factor-α and IL-12. Moreover, there was a “striking clinical effect” in the healing of digital ulcers in four of five patients (Clin. Immunol. 2000;97:109-20).

Recruitment for a double-blind, placebo-controlled trial is under way. Dr. Oliver noted that he had no potential conflicts of interest.

Clinicians with patients who may be candidates for the New York University Scleroderma Trial can contact Dr. Oliver at 212-263-3874.

LONDON — The prognosis for patients with lupus nephritis who undergo renal transplantation today is good, with a low risk of recurrent renal flare and a decrease in lupus disease activity, Jo H. Berden, M.D., said at the Sixth European Lupus Meeting.

Uncertainty has existed as to whether outcomes among patients with systemic lupus erythematosus (SLE) would be equivalent to those seen among patients whose end-stage renal disease derives from another cause; studies have shown conflicting results and have been limited by confounding factors.

But a more comprehensive review of the European and U.S. experience has found no differences in graft or patient survival between lupus and nonlupus transplant recipients, said Dr. Berden of Radboud University, Nijmegen, the Netherlands.

An analysis based on European data for the years 1984 through 1992 provided by the Eurotransplant International Foundation, Leiden, the Netherlands, found no differences in either patient or graft survival when 165 lupus patients were compared with 20,000 nonlupus controls, Dr. Berden said at the meeting sponsored by the British Society for Rheumatology.

A larger analysis of data from the United States Renal Data System included 772 cadaveric transplants for lupus nephritis and 32,644 cadaveric transplants for other causes. This review also analyzed data from 390 lupus patients whose transplants had been from living donors and from 10,512 nonlupus patients whose transplants had been from living donors.

In an unadjusted analysis, patient survival was better in the lupus group, but graft survival was worse. Once adjustments were made for important confounding factors such as age and gender, however, there were no differences (Kidney Int. 2000;57:2136-43).

Nonlupus patients requiring renal transplantation tend to be male and older than the predominantly female lupus patients with this requirement.

Following transplantation, the incidence of renal flare in lupus patients is reported to be 2%-4% if clinical criteria are used and slightly higher if histologic criteria are used. This is a rather low incidence of recurrence, compared with that for other diseases, the nephrologist said.

Renal transplantation also confers nonrenal benefits to SLE patients. “In the Dutch Working Party on SLE, we found that most patients had severe disease before dialysis, intermediate disease during dialysis, and no extrarenal disease at all after transplantation. Apparently immune suppression that failed to control the disease initially was able to do so post transplantation,” he said.

The immunosuppressive regimen used for lupus patients after transplantation should take into account the heightened risk for cardiovascular disease in these patients, Dr. Berden cautioned. Among the immunosuppressant drugs, some, particularly cyclosporine, increase blood pressure. Sirolimus and cyclosporine raise cholesterol levels; tacrolimus and prednisone can induce or aggravate diabetes. In contrast, mycophenolate mofetil and azathioprine have little if any effect on blood pressure, cholesterol, or glucose levels. The long-term maintenance phase of immune suppression should therefore include one of these two less atherogenic agents, he said.

Experience also has taught that a careful evaluation before transplantation is essential for achieving the best outcome. “We screen all our candidates … for the presence of coronary abnormalities, even if there are no clinical symptoms,” he said. Because the exercise electrocardiogram is not sufficiently sensitive, a thallium scan or stress echocardiogram is recommended. “Until recently, we also did coronary angiography and if abnormalities were seen, revascularization was done,” he said. But recently a randomized clinical trial found no benefit for elective revascularization in asymptomatic patients awaiting major vascular surgery (N. Engl. J. Med. 2004;351:2795-804). “Therefore, there now is a question mark as to whether we should always advise revascularization,” he said.

Antiphospholipid antibodies, which are present in approximately one-third of lupus patients, present another unresolved issue. These antibodies signals an increased risk for acute graft thrombosis, so it remains unclear whether prolonged anticoagulation is needed following transplantation because there have been no randomized trials addressing this issue.

As with any patient approaching end-stage renal failure, “we should always consider preemptive living transplantation because the results are much better,” he said.

LONDON — The prognosis for patients with lupus nephritis who undergo renal transplantation today is good, with a low risk of recurrent renal flare and a decrease in lupus disease activity, Jo H. Berden, M.D., said at the Sixth European Lupus Meeting.

Uncertainty has existed as to whether outcomes among patients with systemic lupus erythematosus (SLE) would be equivalent to those seen among patients whose end-stage renal disease derives from another cause; studies have shown conflicting results and have been limited by confounding factors.

But a more comprehensive review of the European and U.S. experience has found no differences in graft or patient survival between lupus and nonlupus transplant recipients, said Dr. Berden of Radboud University, Nijmegen, the Netherlands.

An analysis based on European data for the years 1984 through 1992 provided by the Eurotransplant International Foundation, Leiden, the Netherlands, found no differences in either patient or graft survival when 165 lupus patients were compared with 20,000 nonlupus controls, Dr. Berden said at the meeting sponsored by the British Society for Rheumatology.

A larger analysis of data from the United States Renal Data System included 772 cadaveric transplants for lupus nephritis and 32,644 cadaveric transplants for other causes. This review also analyzed data from 390 lupus patients whose transplants had been from living donors and from 10,512 nonlupus patients whose transplants had been from living donors.

In an unadjusted analysis, patient survival was better in the lupus group, but graft survival was worse. Once adjustments were made for important confounding factors such as age and gender, however, there were no differences (Kidney Int. 2000;57:2136-43).

Nonlupus patients requiring renal transplantation tend to be male and older than the predominantly female lupus patients with this requirement.

Following transplantation, the incidence of renal flare in lupus patients is reported to be 2%-4% if clinical criteria are used and slightly higher if histologic criteria are used. This is a rather low incidence of recurrence, compared with that for other diseases, the nephrologist said.

Renal transplantation also confers nonrenal benefits to SLE patients. “In the Dutch Working Party on SLE, we found that most patients had severe disease before dialysis, intermediate disease during dialysis, and no extrarenal disease at all after transplantation. Apparently immune suppression that failed to control the disease initially was able to do so post transplantation,” he said.

The immunosuppressive regimen used for lupus patients after transplantation should take into account the heightened risk for cardiovascular disease in these patients, Dr. Berden cautioned. Among the immunosuppressant drugs, some, particularly cyclosporine, increase blood pressure. Sirolimus and cyclosporine raise cholesterol levels; tacrolimus and prednisone can induce or aggravate diabetes. In contrast, mycophenolate mofetil and azathioprine have little if any effect on blood pressure, cholesterol, or glucose levels. The long-term maintenance phase of immune suppression should therefore include one of these two less atherogenic agents, he said.

Experience also has taught that a careful evaluation before transplantation is essential for achieving the best outcome. “We screen all our candidates … for the presence of coronary abnormalities, even if there are no clinical symptoms,” he said. Because the exercise electrocardiogram is not sufficiently sensitive, a thallium scan or stress echocardiogram is recommended. “Until recently, we also did coronary angiography and if abnormalities were seen, revascularization was done,” he said. But recently a randomized clinical trial found no benefit for elective revascularization in asymptomatic patients awaiting major vascular surgery (N. Engl. J. Med. 2004;351:2795-804). “Therefore, there now is a question mark as to whether we should always advise revascularization,” he said.

Antiphospholipid antibodies, which are present in approximately one-third of lupus patients, present another unresolved issue. These antibodies signals an increased risk for acute graft thrombosis, so it remains unclear whether prolonged anticoagulation is needed following transplantation because there have been no randomized trials addressing this issue.

As with any patient approaching end-stage renal failure, “we should always consider preemptive living transplantation because the results are much better,” he said.

LONDON — The prognosis for patients with lupus nephritis who undergo renal transplantation today is good, with a low risk of recurrent renal flare and a decrease in lupus disease activity, Jo H. Berden, M.D., said at the Sixth European Lupus Meeting.

Uncertainty has existed as to whether outcomes among patients with systemic lupus erythematosus (SLE) would be equivalent to those seen among patients whose end-stage renal disease derives from another cause; studies have shown conflicting results and have been limited by confounding factors.

But a more comprehensive review of the European and U.S. experience has found no differences in graft or patient survival between lupus and nonlupus transplant recipients, said Dr. Berden of Radboud University, Nijmegen, the Netherlands.

An analysis based on European data for the years 1984 through 1992 provided by the Eurotransplant International Foundation, Leiden, the Netherlands, found no differences in either patient or graft survival when 165 lupus patients were compared with 20,000 nonlupus controls, Dr. Berden said at the meeting sponsored by the British Society for Rheumatology.

A larger analysis of data from the United States Renal Data System included 772 cadaveric transplants for lupus nephritis and 32,644 cadaveric transplants for other causes. This review also analyzed data from 390 lupus patients whose transplants had been from living donors and from 10,512 nonlupus patients whose transplants had been from living donors.

In an unadjusted analysis, patient survival was better in the lupus group, but graft survival was worse. Once adjustments were made for important confounding factors such as age and gender, however, there were no differences (Kidney Int. 2000;57:2136-43).

Nonlupus patients requiring renal transplantation tend to be male and older than the predominantly female lupus patients with this requirement.

Following transplantation, the incidence of renal flare in lupus patients is reported to be 2%-4% if clinical criteria are used and slightly higher if histologic criteria are used. This is a rather low incidence of recurrence, compared with that for other diseases, the nephrologist said.

Renal transplantation also confers nonrenal benefits to SLE patients. “In the Dutch Working Party on SLE, we found that most patients had severe disease before dialysis, intermediate disease during dialysis, and no extrarenal disease at all after transplantation. Apparently immune suppression that failed to control the disease initially was able to do so post transplantation,” he said.

The immunosuppressive regimen used for lupus patients after transplantation should take into account the heightened risk for cardiovascular disease in these patients, Dr. Berden cautioned. Among the immunosuppressant drugs, some, particularly cyclosporine, increase blood pressure. Sirolimus and cyclosporine raise cholesterol levels; tacrolimus and prednisone can induce or aggravate diabetes. In contrast, mycophenolate mofetil and azathioprine have little if any effect on blood pressure, cholesterol, or glucose levels. The long-term maintenance phase of immune suppression should therefore include one of these two less atherogenic agents, he said.

Experience also has taught that a careful evaluation before transplantation is essential for achieving the best outcome. “We screen all our candidates … for the presence of coronary abnormalities, even if there are no clinical symptoms,” he said. Because the exercise electrocardiogram is not sufficiently sensitive, a thallium scan or stress echocardiogram is recommended. “Until recently, we also did coronary angiography and if abnormalities were seen, revascularization was done,” he said. But recently a randomized clinical trial found no benefit for elective revascularization in asymptomatic patients awaiting major vascular surgery (N. Engl. J. Med. 2004;351:2795-804). “Therefore, there now is a question mark as to whether we should always advise revascularization,” he said.

Antiphospholipid antibodies, which are present in approximately one-third of lupus patients, present another unresolved issue. These antibodies signals an increased risk for acute graft thrombosis, so it remains unclear whether prolonged anticoagulation is needed following transplantation because there have been no randomized trials addressing this issue.

As with any patient approaching end-stage renal failure, “we should always consider preemptive living transplantation because the results are much better,” he said.

High-dose aspirin is just as effective as warfarin in treating intracranial arterial stenosis, and appears much safer, Marc Chimowitz, M.B., and colleagues have reported.

“The common practice of administering warfarin rather than aspirin for symptomatic intracranial arterial stenosis is not supported by the results of this trial,” said Dr. Chimowitz of Emory University, Atlanta.

Enrollment in the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial ended early because of the high rate of serious adverse events in the warfarin patients. In addition to being safer for patients, the researchers said, aspirin therapy did not require constant monitoring of international normalized ratios (INRs) and treatment of warfarin-associated bleeding. Aspirin also is much cheaper, they noted (N. Engl. J. Med. 2005;352:1305-16).

Ralph Sacco, M.D., an investigator in the Northern Manhattan Stroke Study, noted in an interview that the WASID trial's findings add to existing data to dispel beliefs about the benefit of warfarin for certain stroke populations.

The conclusion that warfarin provides no survival benefit over aspirin, but confers added risk, is more expensive, and requires intensive monitoring, should reshape its risk/benefit profile for some patients, said Dr. Sacco, professor of neurology and epidemiology at Columbia University, New York.

Dr. Chimowitz and his associates reported on the trial's final analysis that included 569 patients with symptomatic intracranial arterial stenosis who were randomized to either warfarin 5 mg daily or aspirin 650 mg twice daily.

The patients' mean age was about 63 years; about 61% were men. All had a history of either stroke or transient ischemic attack caused by 50%-90% stenosis of a major intracranial artery. The mean follow-up was 1.8 years.

The primary outcome—stroke, brain hemorrhage, or death from vascular causes other than stroke—occurred in 22% (62) of the aspirin patients and 21.8% (63) of the warfarin patients. Myocardial infarction or sudden death occurred significantly more often in the warfarin group than in the aspirin group (7.3% vs. 2.9%).

The overall rate of death was significantly higher in the warfarin group than in the aspirin group: 5.9% (17) vs. 4.3% (12). However, chance probably accounted for some of the deaths that were higher in the warfarin group, especially the six cancers. Major hemorrhages occurred significantly more often in the warfarin group (8.3% vs 3.2%).

Dr. Sacco noted that warfarin is “clearly indicated” for cardioembolic stroke. “This has been made clear in multiple studies, which were actually so positive that they were the springboard for these other studies looking at warfarin in different populations.”

High-dose aspirin is just as effective as warfarin in treating intracranial arterial stenosis, and appears much safer, Marc Chimowitz, M.B., and colleagues have reported.

“The common practice of administering warfarin rather than aspirin for symptomatic intracranial arterial stenosis is not supported by the results of this trial,” said Dr. Chimowitz of Emory University, Atlanta.

Enrollment in the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial ended early because of the high rate of serious adverse events in the warfarin patients. In addition to being safer for patients, the researchers said, aspirin therapy did not require constant monitoring of international normalized ratios (INRs) and treatment of warfarin-associated bleeding. Aspirin also is much cheaper, they noted (N. Engl. J. Med. 2005;352:1305-16).

Ralph Sacco, M.D., an investigator in the Northern Manhattan Stroke Study, noted in an interview that the WASID trial's findings add to existing data to dispel beliefs about the benefit of warfarin for certain stroke populations.

The conclusion that warfarin provides no survival benefit over aspirin, but confers added risk, is more expensive, and requires intensive monitoring, should reshape its risk/benefit profile for some patients, said Dr. Sacco, professor of neurology and epidemiology at Columbia University, New York.

Dr. Chimowitz and his associates reported on the trial's final analysis that included 569 patients with symptomatic intracranial arterial stenosis who were randomized to either warfarin 5 mg daily or aspirin 650 mg twice daily.

The patients' mean age was about 63 years; about 61% were men. All had a history of either stroke or transient ischemic attack caused by 50%-90% stenosis of a major intracranial artery. The mean follow-up was 1.8 years.

The primary outcome—stroke, brain hemorrhage, or death from vascular causes other than stroke—occurred in 22% (62) of the aspirin patients and 21.8% (63) of the warfarin patients. Myocardial infarction or sudden death occurred significantly more often in the warfarin group than in the aspirin group (7.3% vs. 2.9%).

The overall rate of death was significantly higher in the warfarin group than in the aspirin group: 5.9% (17) vs. 4.3% (12). However, chance probably accounted for some of the deaths that were higher in the warfarin group, especially the six cancers. Major hemorrhages occurred significantly more often in the warfarin group (8.3% vs 3.2%).

Dr. Sacco noted that warfarin is “clearly indicated” for cardioembolic stroke. “This has been made clear in multiple studies, which were actually so positive that they were the springboard for these other studies looking at warfarin in different populations.”

High-dose aspirin is just as effective as warfarin in treating intracranial arterial stenosis, and appears much safer, Marc Chimowitz, M.B., and colleagues have reported.

“The common practice of administering warfarin rather than aspirin for symptomatic intracranial arterial stenosis is not supported by the results of this trial,” said Dr. Chimowitz of Emory University, Atlanta.

Enrollment in the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial ended early because of the high rate of serious adverse events in the warfarin patients. In addition to being safer for patients, the researchers said, aspirin therapy did not require constant monitoring of international normalized ratios (INRs) and treatment of warfarin-associated bleeding. Aspirin also is much cheaper, they noted (N. Engl. J. Med. 2005;352:1305-16).

Ralph Sacco, M.D., an investigator in the Northern Manhattan Stroke Study, noted in an interview that the WASID trial's findings add to existing data to dispel beliefs about the benefit of warfarin for certain stroke populations.

The conclusion that warfarin provides no survival benefit over aspirin, but confers added risk, is more expensive, and requires intensive monitoring, should reshape its risk/benefit profile for some patients, said Dr. Sacco, professor of neurology and epidemiology at Columbia University, New York.

Dr. Chimowitz and his associates reported on the trial's final analysis that included 569 patients with symptomatic intracranial arterial stenosis who were randomized to either warfarin 5 mg daily or aspirin 650 mg twice daily.

The patients' mean age was about 63 years; about 61% were men. All had a history of either stroke or transient ischemic attack caused by 50%-90% stenosis of a major intracranial artery. The mean follow-up was 1.8 years.

The primary outcome—stroke, brain hemorrhage, or death from vascular causes other than stroke—occurred in 22% (62) of the aspirin patients and 21.8% (63) of the warfarin patients. Myocardial infarction or sudden death occurred significantly more often in the warfarin group than in the aspirin group (7.3% vs. 2.9%).

The overall rate of death was significantly higher in the warfarin group than in the aspirin group: 5.9% (17) vs. 4.3% (12). However, chance probably accounted for some of the deaths that were higher in the warfarin group, especially the six cancers. Major hemorrhages occurred significantly more often in the warfarin group (8.3% vs 3.2%).

Dr. Sacco noted that warfarin is “clearly indicated” for cardioembolic stroke. “This has been made clear in multiple studies, which were actually so positive that they were the springboard for these other studies looking at warfarin in different populations.”

NEW ORLEANS — A lower-than-usual intravenous dose of tissue plasminogen activator may still be effective for treating patients with acute stroke, according to a review of 83 patients.

“A low dose of 0.6 mg/kg was safe and effective,” Marilyn M. Rymer, M.D., and associates reported in a poster at the 30th International Stroke Conference.

The usual dose of intravenous tissue plasminogen activator (TPA) is 0.9 mg/kg, based on the regimen's safety and efficacy in the original thrombolytic therapy trial by the National Institute of Neurological Disorders and Stroke (NINDS) and reported in 1995, according to Dr. Rymer, medical director of the stroke center at Saint Luke's Hospital in Kansas City, Mo., and colleagues.

The idea of treating patients initially with a 0.6-mg/kg IV dose began with the Interventional Management of Stroke (IMS) trial, which reserved a 0.3-mg/kg dose for subsequent intraarterial delivery. Hospitals in the Mid America Brain and Stroke Institute (MABSI) regional network now routinely use the 0.6-mg/kg dose of intravenous TPA, and then send the patient by ambulance to a hospital or a referral center for further evaluation, Dr. Rymer and her associates reported in a poster at a conference sponsored by the American Stroke Association.

Dr. Rymer and her colleagues identified 83 patients who received the 0.6-mg/kg dose only in the MABSI database, as well as another 50 patients who received a 0.6-mg/kg dose initially that was later followed by intraarterial treatment with 0.3 mg/kg of TPA to assess in-hospital mortality and patients' NIH Stroke Scale (NIHSS) score at discharge. This analysis used a discharge NIHSS of 4 or less and 2 or less as criteria for good outcomes.

The in-hospital mortality rates were 6% in the 83 patients treated with 0.6 mg/kg of TPA only and 12% in all 133 patients in the MABSI database. The 90-day mortality rates were 17% in the original NINDS trial and 16% in the IMS trial.

At hospital discharge, 71% of the patients who received just the 0.6-mg/kg dose had an NIHSS of 4 or less, and 63% had a score of 2 or less. In the entire MABSI group, 62% had discharge scores of 4 or less and 48% had scores of 2 or less. In the NINDS and IMS studies, NIHSS were measured 90 days after treatment; 31% and 28% of patients, respectively, had scores of 1 or 0 at that time, the investigators reported.

NEW ORLEANS — A lower-than-usual intravenous dose of tissue plasminogen activator may still be effective for treating patients with acute stroke, according to a review of 83 patients.

“A low dose of 0.6 mg/kg was safe and effective,” Marilyn M. Rymer, M.D., and associates reported in a poster at the 30th International Stroke Conference.

The usual dose of intravenous tissue plasminogen activator (TPA) is 0.9 mg/kg, based on the regimen's safety and efficacy in the original thrombolytic therapy trial by the National Institute of Neurological Disorders and Stroke (NINDS) and reported in 1995, according to Dr. Rymer, medical director of the stroke center at Saint Luke's Hospital in Kansas City, Mo., and colleagues.

The idea of treating patients initially with a 0.6-mg/kg IV dose began with the Interventional Management of Stroke (IMS) trial, which reserved a 0.3-mg/kg dose for subsequent intraarterial delivery. Hospitals in the Mid America Brain and Stroke Institute (MABSI) regional network now routinely use the 0.6-mg/kg dose of intravenous TPA, and then send the patient by ambulance to a hospital or a referral center for further evaluation, Dr. Rymer and her associates reported in a poster at a conference sponsored by the American Stroke Association.

Dr. Rymer and her colleagues identified 83 patients who received the 0.6-mg/kg dose only in the MABSI database, as well as another 50 patients who received a 0.6-mg/kg dose initially that was later followed by intraarterial treatment with 0.3 mg/kg of TPA to assess in-hospital mortality and patients' NIH Stroke Scale (NIHSS) score at discharge. This analysis used a discharge NIHSS of 4 or less and 2 or less as criteria for good outcomes.

The in-hospital mortality rates were 6% in the 83 patients treated with 0.6 mg/kg of TPA only and 12% in all 133 patients in the MABSI database. The 90-day mortality rates were 17% in the original NINDS trial and 16% in the IMS trial.

At hospital discharge, 71% of the patients who received just the 0.6-mg/kg dose had an NIHSS of 4 or less, and 63% had a score of 2 or less. In the entire MABSI group, 62% had discharge scores of 4 or less and 48% had scores of 2 or less. In the NINDS and IMS studies, NIHSS were measured 90 days after treatment; 31% and 28% of patients, respectively, had scores of 1 or 0 at that time, the investigators reported.

NEW ORLEANS — A lower-than-usual intravenous dose of tissue plasminogen activator may still be effective for treating patients with acute stroke, according to a review of 83 patients.

“A low dose of 0.6 mg/kg was safe and effective,” Marilyn M. Rymer, M.D., and associates reported in a poster at the 30th International Stroke Conference.

The usual dose of intravenous tissue plasminogen activator (TPA) is 0.9 mg/kg, based on the regimen's safety and efficacy in the original thrombolytic therapy trial by the National Institute of Neurological Disorders and Stroke (NINDS) and reported in 1995, according to Dr. Rymer, medical director of the stroke center at Saint Luke's Hospital in Kansas City, Mo., and colleagues.

The idea of treating patients initially with a 0.6-mg/kg IV dose began with the Interventional Management of Stroke (IMS) trial, which reserved a 0.3-mg/kg dose for subsequent intraarterial delivery. Hospitals in the Mid America Brain and Stroke Institute (MABSI) regional network now routinely use the 0.6-mg/kg dose of intravenous TPA, and then send the patient by ambulance to a hospital or a referral center for further evaluation, Dr. Rymer and her associates reported in a poster at a conference sponsored by the American Stroke Association.

Dr. Rymer and her colleagues identified 83 patients who received the 0.6-mg/kg dose only in the MABSI database, as well as another 50 patients who received a 0.6-mg/kg dose initially that was later followed by intraarterial treatment with 0.3 mg/kg of TPA to assess in-hospital mortality and patients' NIH Stroke Scale (NIHSS) score at discharge. This analysis used a discharge NIHSS of 4 or less and 2 or less as criteria for good outcomes.

The in-hospital mortality rates were 6% in the 83 patients treated with 0.6 mg/kg of TPA only and 12% in all 133 patients in the MABSI database. The 90-day mortality rates were 17% in the original NINDS trial and 16% in the IMS trial.

At hospital discharge, 71% of the patients who received just the 0.6-mg/kg dose had an NIHSS of 4 or less, and 63% had a score of 2 or less. In the entire MABSI group, 62% had discharge scores of 4 or less and 48% had scores of 2 or less. In the NINDS and IMS studies, NIHSS were measured 90 days after treatment; 31% and 28% of patients, respectively, had scores of 1 or 0 at that time, the investigators reported.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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