Major CV Events Not Decreased With Vytorin

Combined simvastatin plus ezetimibe treatment not only failed to reduce major cardiovascular events, but also was linked to an increase in cancer deaths among asymptomatic patients with aortic stenosis, according to the first report of a randomized, placebo-controlled, phase III trial.

The only positive outcome of the 1,873-patient SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study was in the secondary end point of reduced ischemic events. Relative risk fell 22% in patients treated with the drug combination, which is marketed as Vytorin in the United States.

Concern over the unexpected increase in cancer deaths prompted an immediate independent analysis of cancer incidence and mortality among 20,000 patients treated so far in two other ongoing Vytorin trials: SHARP (the Study of Heart and Renal Protection) and IMPROVE-IT (the Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

Dr. Richard Peto of the clinical trial service unit at the University of Oxford (England) and his colleagues found no increased cancer risk in those studies, and concluded that “the SEAS, SHARP, and IMPROVE-IT trials do not provide credible evidence of any adverse effect on cancer.”

“Even if you add them together, the total evidence of adverse effect is no more surprising than getting heads if you toss a coin,” Dr. Peto, a professor of medical statistics and epidemiology at the university, said in a Webcast presentation of SEAS results and the analysis.

Dr. Terje R. Pedersen, chairman of the SEAS trial, said the investigators would have preferred to report the data at a scientific meeting, but intense interest made secrecy difficult. “There were a lot of rumors out there,” said Dr. Pedersen, professor of medicine and head of the center for preventive medicine at Ullevål University Hospital, Oslo.

Merck Sharp & Dohme and Schering-Plough Corp. (companies that market the two drugs as Vytorin) funded the SEAS study. Starting in 2001, investigators enrolled 1,873 patients with mild to moderate symptoms of aortic stenosis at 173 centers in seven countries in Northern Europe.

The population was randomized to 40 mg of simvastatin (Zocor) plus 10 mg of ezetimibe (Zetia) daily, or to placebo. Data collection ended June 30, 2008, after the last patient had been followed for 4 years. As expected, Vytorin reduced LDL cholesterol significantly, from 140 mg/dL at baseline to 52 mg/dL at 8 weeks; little change was seen in the placebo group.

The combination failed to meet the primary end point of significantly fewer major cardiovascular events. These occurred in 355 patients on placebo and 333 in the Vytorin group. A secondary end point of fewer aortic valve events also did not show a significant difference (326 events with placebo vs. 308 with Vytorin).

Ischemic cardiovascular events were significantly reduced, occurring in 187 patients on placebo and 148 in the Vytorin group. Dr. Pedersen attributed this to fewer coronary artery bypass grafting procedures when aortic stenosis patients underwent cardiac surgery.

In the safety analysis, significantly more placebo patients developed cancer during the study: 93 (9.85%) vs. 65 (7.0 %) in the treatment group. More cancer deaths occurred, however, in the Vytorin cohort vs. the placebo group: 39 (4.13%) vs. 23 (2.48%), a nonsignificant difference.

Dr. Peto used different figures, reporting the total number of patients with cancer as 102 in the treatment group and 67 in the control group. He reported that “no overall increase” in incidence was found in the combined SHARP and IMPROVE-IT data, in which 313 treated patients and 326 controls had cancer.

Other factors arguing against increased risk, he said, were that the cancers did not concentrate in any one anatomical site and that relative risk did not increase significantly over time in all three studies. Based on cancer incidence, the relative risk with treatment went from 0.95 in the first year to 1.15 in the second year, to 1.17 in the third year, and to 1.01 in the fourth year.

“Likewise, nor does the relative risk for cancer mortality increase with time,” he said.

Summarizing the SEAS findings, Dr. Pedersen called the combined treatment “safe and well tolerated.”

In a subsequent interview, Dr. Richard Steingart, chief of cardiology at Memorial Sloan-Kettering Cancer Center, New York, challenged the SEAS hypothesis that Vytorin could slow aortic stenosis. “I think that was a bit of a reach anyway, and it turned out it didn't,” he said.

Moreover, SEAS did not answer questions raised by the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial, according to Dr. Steingart and Dr. Harlan M. Krumholz, a professor of internal medicine, epidemiology, and public health at Yale University in New Haven, Conn. As designed, it could not tease out whether ezetimibe adds any benefit when combined with a statin.

“The SEAS study provides no evidence to support the use of Vytorin, and raises a concern that is hard to dismiss,” Dr. Krumholz said in a separate interview. “For me,” he added, “the bottom line is this: If you can take a statin and be treated adequately, you should not be on this drug.”

Although Dr. Krumholz said he awaits the two larger trials to settle questions of benefit and safety, an added concern for Dr. Steingart is that these trials may not resolve the issue. The approval and ensuing widespread use of ezetimibe based on surrogate end points may make it impossible to determine clinical end points, he warned.

Moreover, the cancer data in SEAS could discourage patients from enrolling in IMPROVE-IT. “If I were recruiting for this trial, I would think these issues would make it very difficult,” he said.

The unusual reporting of results by Webcast instead of peer review also is an issue. “I don't think this is a great precedent,” Dr. Steingart said, adding that although he found the cancer analysis reassuring, it would not deter inquiry into a possible cancer link.

“How could they be so confident?” Dr. Krumholz asked, agreeing that Vytorin's causing cancer is unlikely but not ruled out by the hasty analysis. “I just don't know why they rushed as opposed to deliberating.”

Lee A. Davies, director of global product communications and advocacy relations for Schering-Plough, said that fuller results may be presented as soon as the European Society for Cardiology convenes this month. “Nonetheless, given the confluence of our earnings release, the findings in the study, and the importance of restoring confidence in the transparency of the pharmaceutical industry, we felt strongly that it was important to disseminate the results now and to provide our view of them,” he said.

The company has posted a letter to physicians at www.msppharma.com

Combined simvastatin plus ezetimibe treatment not only failed to reduce major cardiovascular events, but also was linked to an increase in cancer deaths among asymptomatic patients with aortic stenosis, according to the first report of a randomized, placebo-controlled, phase III trial.

The only positive outcome of the 1,873-patient SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study was in the secondary end point of reduced ischemic events. Relative risk fell 22% in patients treated with the drug combination, which is marketed as Vytorin in the United States.

Concern over the unexpected increase in cancer deaths prompted an immediate independent analysis of cancer incidence and mortality among 20,000 patients treated so far in two other ongoing Vytorin trials: SHARP (the Study of Heart and Renal Protection) and IMPROVE-IT (the Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

Dr. Richard Peto of the clinical trial service unit at the University of Oxford (England) and his colleagues found no increased cancer risk in those studies, and concluded that “the SEAS, SHARP, and IMPROVE-IT trials do not provide credible evidence of any adverse effect on cancer.”

“Even if you add them together, the total evidence of adverse effect is no more surprising than getting heads if you toss a coin,” Dr. Peto, a professor of medical statistics and epidemiology at the university, said in a Webcast presentation of SEAS results and the analysis.

Dr. Terje R. Pedersen, chairman of the SEAS trial, said the investigators would have preferred to report the data at a scientific meeting, but intense interest made secrecy difficult. “There were a lot of rumors out there,” said Dr. Pedersen, professor of medicine and head of the center for preventive medicine at Ullevål University Hospital, Oslo.

Merck Sharp & Dohme and Schering-Plough Corp. (companies that market the two drugs as Vytorin) funded the SEAS study. Starting in 2001, investigators enrolled 1,873 patients with mild to moderate symptoms of aortic stenosis at 173 centers in seven countries in Northern Europe.

The population was randomized to 40 mg of simvastatin (Zocor) plus 10 mg of ezetimibe (Zetia) daily, or to placebo. Data collection ended June 30, 2008, after the last patient had been followed for 4 years. As expected, Vytorin reduced LDL cholesterol significantly, from 140 mg/dL at baseline to 52 mg/dL at 8 weeks; little change was seen in the placebo group.

The combination failed to meet the primary end point of significantly fewer major cardiovascular events. These occurred in 355 patients on placebo and 333 in the Vytorin group. A secondary end point of fewer aortic valve events also did not show a significant difference (326 events with placebo vs. 308 with Vytorin).

Ischemic cardiovascular events were significantly reduced, occurring in 187 patients on placebo and 148 in the Vytorin group. Dr. Pedersen attributed this to fewer coronary artery bypass grafting procedures when aortic stenosis patients underwent cardiac surgery.

In the safety analysis, significantly more placebo patients developed cancer during the study: 93 (9.85%) vs. 65 (7.0 %) in the treatment group. More cancer deaths occurred, however, in the Vytorin cohort vs. the placebo group: 39 (4.13%) vs. 23 (2.48%), a nonsignificant difference.

Dr. Peto used different figures, reporting the total number of patients with cancer as 102 in the treatment group and 67 in the control group. He reported that “no overall increase” in incidence was found in the combined SHARP and IMPROVE-IT data, in which 313 treated patients and 326 controls had cancer.

Other factors arguing against increased risk, he said, were that the cancers did not concentrate in any one anatomical site and that relative risk did not increase significantly over time in all three studies. Based on cancer incidence, the relative risk with treatment went from 0.95 in the first year to 1.15 in the second year, to 1.17 in the third year, and to 1.01 in the fourth year.

“Likewise, nor does the relative risk for cancer mortality increase with time,” he said.

Summarizing the SEAS findings, Dr. Pedersen called the combined treatment “safe and well tolerated.”

In a subsequent interview, Dr. Richard Steingart, chief of cardiology at Memorial Sloan-Kettering Cancer Center, New York, challenged the SEAS hypothesis that Vytorin could slow aortic stenosis. “I think that was a bit of a reach anyway, and it turned out it didn't,” he said.

Moreover, SEAS did not answer questions raised by the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial, according to Dr. Steingart and Dr. Harlan M. Krumholz, a professor of internal medicine, epidemiology, and public health at Yale University in New Haven, Conn. As designed, it could not tease out whether ezetimibe adds any benefit when combined with a statin.

“The SEAS study provides no evidence to support the use of Vytorin, and raises a concern that is hard to dismiss,” Dr. Krumholz said in a separate interview. “For me,” he added, “the bottom line is this: If you can take a statin and be treated adequately, you should not be on this drug.”

Although Dr. Krumholz said he awaits the two larger trials to settle questions of benefit and safety, an added concern for Dr. Steingart is that these trials may not resolve the issue. The approval and ensuing widespread use of ezetimibe based on surrogate end points may make it impossible to determine clinical end points, he warned.

Moreover, the cancer data in SEAS could discourage patients from enrolling in IMPROVE-IT. “If I were recruiting for this trial, I would think these issues would make it very difficult,” he said.

The unusual reporting of results by Webcast instead of peer review also is an issue. “I don't think this is a great precedent,” Dr. Steingart said, adding that although he found the cancer analysis reassuring, it would not deter inquiry into a possible cancer link.

“How could they be so confident?” Dr. Krumholz asked, agreeing that Vytorin's causing cancer is unlikely but not ruled out by the hasty analysis. “I just don't know why they rushed as opposed to deliberating.”

Lee A. Davies, director of global product communications and advocacy relations for Schering-Plough, said that fuller results may be presented as soon as the European Society for Cardiology convenes this month. “Nonetheless, given the confluence of our earnings release, the findings in the study, and the importance of restoring confidence in the transparency of the pharmaceutical industry, we felt strongly that it was important to disseminate the results now and to provide our view of them,” he said.

The company has posted a letter to physicians at www.msppharma.com

Combined simvastatin plus ezetimibe treatment not only failed to reduce major cardiovascular events, but also was linked to an increase in cancer deaths among asymptomatic patients with aortic stenosis, according to the first report of a randomized, placebo-controlled, phase III trial.

The only positive outcome of the 1,873-patient SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study was in the secondary end point of reduced ischemic events. Relative risk fell 22% in patients treated with the drug combination, which is marketed as Vytorin in the United States.

Concern over the unexpected increase in cancer deaths prompted an immediate independent analysis of cancer incidence and mortality among 20,000 patients treated so far in two other ongoing Vytorin trials: SHARP (the Study of Heart and Renal Protection) and IMPROVE-IT (the Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

Dr. Richard Peto of the clinical trial service unit at the University of Oxford (England) and his colleagues found no increased cancer risk in those studies, and concluded that “the SEAS, SHARP, and IMPROVE-IT trials do not provide credible evidence of any adverse effect on cancer.”

“Even if you add them together, the total evidence of adverse effect is no more surprising than getting heads if you toss a coin,” Dr. Peto, a professor of medical statistics and epidemiology at the university, said in a Webcast presentation of SEAS results and the analysis.

Dr. Terje R. Pedersen, chairman of the SEAS trial, said the investigators would have preferred to report the data at a scientific meeting, but intense interest made secrecy difficult. “There were a lot of rumors out there,” said Dr. Pedersen, professor of medicine and head of the center for preventive medicine at Ullevål University Hospital, Oslo.

Merck Sharp & Dohme and Schering-Plough Corp. (companies that market the two drugs as Vytorin) funded the SEAS study. Starting in 2001, investigators enrolled 1,873 patients with mild to moderate symptoms of aortic stenosis at 173 centers in seven countries in Northern Europe.

The population was randomized to 40 mg of simvastatin (Zocor) plus 10 mg of ezetimibe (Zetia) daily, or to placebo. Data collection ended June 30, 2008, after the last patient had been followed for 4 years. As expected, Vytorin reduced LDL cholesterol significantly, from 140 mg/dL at baseline to 52 mg/dL at 8 weeks; little change was seen in the placebo group.

The combination failed to meet the primary end point of significantly fewer major cardiovascular events. These occurred in 355 patients on placebo and 333 in the Vytorin group. A secondary end point of fewer aortic valve events also did not show a significant difference (326 events with placebo vs. 308 with Vytorin).

Ischemic cardiovascular events were significantly reduced, occurring in 187 patients on placebo and 148 in the Vytorin group. Dr. Pedersen attributed this to fewer coronary artery bypass grafting procedures when aortic stenosis patients underwent cardiac surgery.

In the safety analysis, significantly more placebo patients developed cancer during the study: 93 (9.85%) vs. 65 (7.0 %) in the treatment group. More cancer deaths occurred, however, in the Vytorin cohort vs. the placebo group: 39 (4.13%) vs. 23 (2.48%), a nonsignificant difference.

Dr. Peto used different figures, reporting the total number of patients with cancer as 102 in the treatment group and 67 in the control group. He reported that “no overall increase” in incidence was found in the combined SHARP and IMPROVE-IT data, in which 313 treated patients and 326 controls had cancer.

Other factors arguing against increased risk, he said, were that the cancers did not concentrate in any one anatomical site and that relative risk did not increase significantly over time in all three studies. Based on cancer incidence, the relative risk with treatment went from 0.95 in the first year to 1.15 in the second year, to 1.17 in the third year, and to 1.01 in the fourth year.

“Likewise, nor does the relative risk for cancer mortality increase with time,” he said.

Summarizing the SEAS findings, Dr. Pedersen called the combined treatment “safe and well tolerated.”

In a subsequent interview, Dr. Richard Steingart, chief of cardiology at Memorial Sloan-Kettering Cancer Center, New York, challenged the SEAS hypothesis that Vytorin could slow aortic stenosis. “I think that was a bit of a reach anyway, and it turned out it didn't,” he said.

Moreover, SEAS did not answer questions raised by the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial, according to Dr. Steingart and Dr. Harlan M. Krumholz, a professor of internal medicine, epidemiology, and public health at Yale University in New Haven, Conn. As designed, it could not tease out whether ezetimibe adds any benefit when combined with a statin.

“The SEAS study provides no evidence to support the use of Vytorin, and raises a concern that is hard to dismiss,” Dr. Krumholz said in a separate interview. “For me,” he added, “the bottom line is this: If you can take a statin and be treated adequately, you should not be on this drug.”

Although Dr. Krumholz said he awaits the two larger trials to settle questions of benefit and safety, an added concern for Dr. Steingart is that these trials may not resolve the issue. The approval and ensuing widespread use of ezetimibe based on surrogate end points may make it impossible to determine clinical end points, he warned.

Moreover, the cancer data in SEAS could discourage patients from enrolling in IMPROVE-IT. “If I were recruiting for this trial, I would think these issues would make it very difficult,” he said.

The unusual reporting of results by Webcast instead of peer review also is an issue. “I don't think this is a great precedent,” Dr. Steingart said, adding that although he found the cancer analysis reassuring, it would not deter inquiry into a possible cancer link.

“How could they be so confident?” Dr. Krumholz asked, agreeing that Vytorin's causing cancer is unlikely but not ruled out by the hasty analysis. “I just don't know why they rushed as opposed to deliberating.”

Lee A. Davies, director of global product communications and advocacy relations for Schering-Plough, said that fuller results may be presented as soon as the European Society for Cardiology convenes this month. “Nonetheless, given the confluence of our earnings release, the findings in the study, and the importance of restoring confidence in the transparency of the pharmaceutical industry, we felt strongly that it was important to disseminate the results now and to provide our view of them,” he said.

The company has posted a letter to physicians at www.msppharma.com