Christine Kilgore

Discussing the risks of the human papillomavirus and the value of HPV vaccination is no easy feat for physicians who are seeing preteen and teenage girls and trying to institute national vaccination recommendations.

Especially in the 11- to 12-year-old population – the age group for whom the vaccine is recommended as part of the regular immunization schedule – how to best address HPV risk is still "a million dollar question," said Dr. Charles Wibbelsman, a pediatrician who is chief of adolescent medicine at Kaiser Permanente in San Francisco and a former member of the American Academy of Pediatrics’ committee on adolescents.

Uptake of the vaccine has been slower and lower than it has been for other vaccines, experts say, and both surveys and interviews with physicians around the country indicate that physicians face a host of moral, ethical, and safety concerns from parents, even though almost 5 years have passed since Gardasil – the first of two HPV vaccines – was licensed.

A survey of more than 1,500 parents published last April, for instance, showed that the HPV vaccine was the most commonly refused pediatric vaccine. Almost 80% of the parents who refused said they believed there had not been enough research on it, 51% said it challenged their belief systems, 59% said they believed their children were at low risk for contracting the sexually transmitted disease, and 37% said they did "not believe the vaccine is effective in preventing the disease" (Pediatrics 2010:125:654-9).

Physicians who spoke with this news organization said that understanding and anticipating these common reasons for refusal of the vaccine are key to an efficient and meaningful discussion of HPV risks. So is the use of affirmative, matter-of-fact statements about HPV vaccination.

"If you approach it by saying ‘It’s time to receive your HPV vaccine,’ there’s often no need to go any further, other than providing parents with the appropriate information pamphlet" from the Centers for Disease Control and Prevention, said Dr. Michael E. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute and a pediatrician in private practice in that city.

"If you start out, on the other hand, by saying ‘It’s time to discuss the possibility of your daughter receiving the HPV vaccine,’ immediately that sends a very different message," said Dr. Pichichero, who has served as a consultant for both Merck and GlaxoSmithKline, the manufacturers of Gardasil and Cervarix, respectively.

"Parents have never heard this type of approach used with a vaccine before," he said.

It is important to tailor one’s approach to the fact that "there isn’t as immediate a preventive effect that parents can appreciate, compared with other vaccines," said Dr. Gary L. Freed, immediate past chairman of the National Vaccine Advisory Committee and director of the division of general pediatrics and the child health evaluation and research unit at the University of Michigan in Ann Arbor.

"We can do better at being straightforward in addressing the issues of HPV, with both children and their parents," he said.

The following are some of the suggestions offered and experiences shared by these physicians and others:

• The "Why Now" Factor. As with other sensitive issues, pediatricians have to tailor the depth of discussion about HPV infection to the maturity of the child and values of the family.

"But when a parent [of an 11- to 12-year-old] says, ‘I want to have this discussion 2 years from now,’ I think it’s our responsibility to share data about the risk, and to convey the fact that we want to provide universal protection at an age when we know the child will respond effectively to the vaccine by developing a strong immune response ... and at an age that is prior to the risk," said Dr. Joseph Bocchini, immediate past chairman of the American Academy of Pediatrics’ committee on infectious diseases and chairman of the department of pediatrics at the Louisiana State University Health Sciences Center in Shreveport.

Both parents and pediatricians underestimate the likelihood that their child or patient is sexually active or about to become sexually active, said Dr. Bocchini, who also serves on the HPV working group of the CDC’s Advisory Committee on Immunization Practices (ACIP).

In all, 20% of adolescents are infected with HPV within 2 years of the onset of sexual activity, he said, which for the majority of girls occurs during their teenage years.

Although physicians should not shy away from discussing HPV infection as a sexually transmitted disease – indeed, it is the most commonly occurring STD – they should nevertheless take care to emphasize the overall goal of vaccination: the prevention of cervical cancer.

"Most mothers aren’t ready to deal with the possibility of their daughter becoming sexually active, so they tie together the vaccine with more or less an acknowledgement that their daughter is about to become sexually active, whether or not that’s true," said Dr. Pichichero.

That’s why it’s important, he and others said, to emphasize that vaccination is not about sexual readiness, but about preventing cervical cancer. Providing the vaccine has not been shown in any way to increase sexual activity, he and other physicians said. And, Dr. Pichichero added, "studies show, without a doubt, that when you vaccinate at a younger age, you get much higher immunity levels."

Kaiser’s Dr. Wibbelsman said he tells parents that at least "10,000 women die each year of cervical cancer and countless others have cervical cancer, and that HPV causes cervical cancer."

Dr. Stan Block, who practices in a six-pediatrician group in Bardstown, Ky., with a large adolescent population, said that "numbers give parents something concrete to hang their hats on." He tells many parents that "the lifetime risk of getting cervical, anal, vaginal, or vulvar precancer or cancer goes from about 1 in 20 without vaccination to 1 in 50 with vaccination," and that the risk of venereal warts similarly drops from 1 in 10 without vaccination with Gardasil to about 1 in 100 with vaccination.

"We explain that even precancerous lesions can have serious consequences, like surgery and the inability to have children," said Dr. Block, who estimates that his practice has an 85%-90% HPV vaccination rate in female patients. "You have to test the waters, the comfort level of the child ... but whenever possible, I lay all this out."

When parents refuse the vaccine, he either tells them that he is documenting the refusal in their child’s chart or asks them to sign a form to document that they acknowledge the risk of refusing vaccination. "Without a doubt, it’s a malpractice risk," he said. Sometimes, he added, such a statement or request results in parents’ changing their minds.

• Safety. At least several studies have shown that the vaccine would receive greater acceptance if it was perceived to be safe.

"I tell parents that the vaccine has now been received by literally hundreds of thousands in this country, and that there are no serious adverse events associated with the vaccine," said Dr. Freed. "Then I say that in the same time period, there likely have been at least several thousand young women who have been infected with HPV who will develop precancerous cervical lesions and may go on to develop cervical cancer."

Others said they refer parents to the CDC’s Web site for vaccine safety profiles (www.cdc.gov/vaccinesafety/vaccines/hpv). "This way, it’s not me talking, and not the manufacturer, but a body with a lot of credibility," said Dr. Stanley Gall, professor of ob.gyn at the University of Louisville (Ky.) and a member of ACIP’s HPV working group.

According to the CDC Web site, approximately 32 million doses of Gardasil were distributed in the United States from the time the vaccine was licensed in 2006 until September 2010. All serious adverse event reports that were made to the Vaccine Adverse Event Reporting System have been fully investigated, with staff finding "no pattern or clustering ... to suggest they were caused by the HPV vaccination," the site says.

Syncope and fainting are common in preteens and teens after injections, the CDC notes, making the recommended 15-minute postvaccination observation period extremely important. Patients should lie down or sit for this period of time.

• Duration of efficacy. Manufacturers have tracked vaccine recipients for up to 8-10 years at this point, with no "breakthrough cases" of HPV infection, sources said.

"We can tell parents that – as with any new vaccine – we can’t say how long efficacy will last, but that we do know the vaccine is highly immunogenic, that we’re seeing no breakthrough cases in the recipients being followed, and that we know protection will last at least 7.5 years and likely significantly longer," said Dr. Bocchini. If needed in the future, a booster dose will become available.

• Vaccine differences. The most important facts for parents to know, several pediatricians said, is that both Gardasil and Cervarix protect against the two strains of HPV (types 16 and 18) that are believed to cause 70% of all cervical cancers, and that Gardasil also protects against HPV-6 and -11, the most common cause of genital warts.

Parents and older teens should know the value of protecting against genital warts, they said. "There are about a million new cases of genital warts each year in this country, and the amount of money spent treating them is equivalent to the amount of money spent treating cervical cancer," not to mention the fact that genital warts cause significant anguish, Dr. Gall said.

Dr. Pichichero, however, said that Cervarix contains a novel adjuvant that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and -18, compared with Gardasil. Higher antibody titers may translate into a longer duration of protection, he said.

Cervarix also has been shown, he said, to afford some level of cross-protection against other HPV strains that are responsible for a small yet significant proportion of cervical cancer cases. Although such differences should be weighed in the long term, right now it seems that parents are more concerned about safety and experience with the vaccines, and physicians should focus on this, he said.

Dr. Pichichero said he has served as a consultant to Merck and GlaxoSmithKline on their "National Advisory Boards for periodic 1-day consulting." Dr. Block said he has done research for both companies and is on the speakers bureau for Gardasil. Dr. Gall said he was working on clinical trials and is a speaker for GlaxoSmithKline and Merck. The other physicians reported no disclosures.

Discussing the risks of the human papillomavirus and the value of HPV vaccination is no easy feat for physicians who are seeing preteen and teenage girls and trying to institute national vaccination recommendations.

Especially in the 11- to 12-year-old population – the age group for whom the vaccine is recommended as part of the regular immunization schedule – how to best address HPV risk is still "a million dollar question," said Dr. Charles Wibbelsman, a pediatrician who is chief of adolescent medicine at Kaiser Permanente in San Francisco and a former member of the American Academy of Pediatrics’ committee on adolescents.

Uptake of the vaccine has been slower and lower than it has been for other vaccines, experts say, and both surveys and interviews with physicians around the country indicate that physicians face a host of moral, ethical, and safety concerns from parents, even though almost 5 years have passed since Gardasil – the first of two HPV vaccines – was licensed.

A survey of more than 1,500 parents published last April, for instance, showed that the HPV vaccine was the most commonly refused pediatric vaccine. Almost 80% of the parents who refused said they believed there had not been enough research on it, 51% said it challenged their belief systems, 59% said they believed their children were at low risk for contracting the sexually transmitted disease, and 37% said they did "not believe the vaccine is effective in preventing the disease" (Pediatrics 2010:125:654-9).

Physicians who spoke with this news organization said that understanding and anticipating these common reasons for refusal of the vaccine are key to an efficient and meaningful discussion of HPV risks. So is the use of affirmative, matter-of-fact statements about HPV vaccination.

"If you approach it by saying ‘It’s time to receive your HPV vaccine,’ there’s often no need to go any further, other than providing parents with the appropriate information pamphlet" from the Centers for Disease Control and Prevention, said Dr. Michael E. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute and a pediatrician in private practice in that city.

"If you start out, on the other hand, by saying ‘It’s time to discuss the possibility of your daughter receiving the HPV vaccine,’ immediately that sends a very different message," said Dr. Pichichero, who has served as a consultant for both Merck and GlaxoSmithKline, the manufacturers of Gardasil and Cervarix, respectively.

"Parents have never heard this type of approach used with a vaccine before," he said.

It is important to tailor one’s approach to the fact that "there isn’t as immediate a preventive effect that parents can appreciate, compared with other vaccines," said Dr. Gary L. Freed, immediate past chairman of the National Vaccine Advisory Committee and director of the division of general pediatrics and the child health evaluation and research unit at the University of Michigan in Ann Arbor.

"We can do better at being straightforward in addressing the issues of HPV, with both children and their parents," he said.

The following are some of the suggestions offered and experiences shared by these physicians and others:

• The "Why Now" Factor. As with other sensitive issues, pediatricians have to tailor the depth of discussion about HPV infection to the maturity of the child and values of the family.

"But when a parent [of an 11- to 12-year-old] says, ‘I want to have this discussion 2 years from now,’ I think it’s our responsibility to share data about the risk, and to convey the fact that we want to provide universal protection at an age when we know the child will respond effectively to the vaccine by developing a strong immune response ... and at an age that is prior to the risk," said Dr. Joseph Bocchini, immediate past chairman of the American Academy of Pediatrics’ committee on infectious diseases and chairman of the department of pediatrics at the Louisiana State University Health Sciences Center in Shreveport.

Both parents and pediatricians underestimate the likelihood that their child or patient is sexually active or about to become sexually active, said Dr. Bocchini, who also serves on the HPV working group of the CDC’s Advisory Committee on Immunization Practices (ACIP).

In all, 20% of adolescents are infected with HPV within 2 years of the onset of sexual activity, he said, which for the majority of girls occurs during their teenage years.

Although physicians should not shy away from discussing HPV infection as a sexually transmitted disease – indeed, it is the most commonly occurring STD – they should nevertheless take care to emphasize the overall goal of vaccination: the prevention of cervical cancer.

"Most mothers aren’t ready to deal with the possibility of their daughter becoming sexually active, so they tie together the vaccine with more or less an acknowledgement that their daughter is about to become sexually active, whether or not that’s true," said Dr. Pichichero.

That’s why it’s important, he and others said, to emphasize that vaccination is not about sexual readiness, but about preventing cervical cancer. Providing the vaccine has not been shown in any way to increase sexual activity, he and other physicians said. And, Dr. Pichichero added, "studies show, without a doubt, that when you vaccinate at a younger age, you get much higher immunity levels."

Kaiser’s Dr. Wibbelsman said he tells parents that at least "10,000 women die each year of cervical cancer and countless others have cervical cancer, and that HPV causes cervical cancer."

Dr. Stan Block, who practices in a six-pediatrician group in Bardstown, Ky., with a large adolescent population, said that "numbers give parents something concrete to hang their hats on." He tells many parents that "the lifetime risk of getting cervical, anal, vaginal, or vulvar precancer or cancer goes from about 1 in 20 without vaccination to 1 in 50 with vaccination," and that the risk of venereal warts similarly drops from 1 in 10 without vaccination with Gardasil to about 1 in 100 with vaccination.

"We explain that even precancerous lesions can have serious consequences, like surgery and the inability to have children," said Dr. Block, who estimates that his practice has an 85%-90% HPV vaccination rate in female patients. "You have to test the waters, the comfort level of the child ... but whenever possible, I lay all this out."

When parents refuse the vaccine, he either tells them that he is documenting the refusal in their child’s chart or asks them to sign a form to document that they acknowledge the risk of refusing vaccination. "Without a doubt, it’s a malpractice risk," he said. Sometimes, he added, such a statement or request results in parents’ changing their minds.

• Safety. At least several studies have shown that the vaccine would receive greater acceptance if it was perceived to be safe.

"I tell parents that the vaccine has now been received by literally hundreds of thousands in this country, and that there are no serious adverse events associated with the vaccine," said Dr. Freed. "Then I say that in the same time period, there likely have been at least several thousand young women who have been infected with HPV who will develop precancerous cervical lesions and may go on to develop cervical cancer."

Others said they refer parents to the CDC’s Web site for vaccine safety profiles (www.cdc.gov/vaccinesafety/vaccines/hpv). "This way, it’s not me talking, and not the manufacturer, but a body with a lot of credibility," said Dr. Stanley Gall, professor of ob.gyn at the University of Louisville (Ky.) and a member of ACIP’s HPV working group.

According to the CDC Web site, approximately 32 million doses of Gardasil were distributed in the United States from the time the vaccine was licensed in 2006 until September 2010. All serious adverse event reports that were made to the Vaccine Adverse Event Reporting System have been fully investigated, with staff finding "no pattern or clustering ... to suggest they were caused by the HPV vaccination," the site says.

Syncope and fainting are common in preteens and teens after injections, the CDC notes, making the recommended 15-minute postvaccination observation period extremely important. Patients should lie down or sit for this period of time.

• Duration of efficacy. Manufacturers have tracked vaccine recipients for up to 8-10 years at this point, with no "breakthrough cases" of HPV infection, sources said.

"We can tell parents that – as with any new vaccine – we can’t say how long efficacy will last, but that we do know the vaccine is highly immunogenic, that we’re seeing no breakthrough cases in the recipients being followed, and that we know protection will last at least 7.5 years and likely significantly longer," said Dr. Bocchini. If needed in the future, a booster dose will become available.

• Vaccine differences. The most important facts for parents to know, several pediatricians said, is that both Gardasil and Cervarix protect against the two strains of HPV (types 16 and 18) that are believed to cause 70% of all cervical cancers, and that Gardasil also protects against HPV-6 and -11, the most common cause of genital warts.

Parents and older teens should know the value of protecting against genital warts, they said. "There are about a million new cases of genital warts each year in this country, and the amount of money spent treating them is equivalent to the amount of money spent treating cervical cancer," not to mention the fact that genital warts cause significant anguish, Dr. Gall said.

Dr. Pichichero, however, said that Cervarix contains a novel adjuvant that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and -18, compared with Gardasil. Higher antibody titers may translate into a longer duration of protection, he said.

Cervarix also has been shown, he said, to afford some level of cross-protection against other HPV strains that are responsible for a small yet significant proportion of cervical cancer cases. Although such differences should be weighed in the long term, right now it seems that parents are more concerned about safety and experience with the vaccines, and physicians should focus on this, he said.

Dr. Pichichero said he has served as a consultant to Merck and GlaxoSmithKline on their "National Advisory Boards for periodic 1-day consulting." Dr. Block said he has done research for both companies and is on the speakers bureau for Gardasil. Dr. Gall said he was working on clinical trials and is a speaker for GlaxoSmithKline and Merck. The other physicians reported no disclosures.

Discussing the risks of the human papillomavirus and the value of HPV vaccination is no easy feat for physicians who are seeing preteen and teenage girls and trying to institute national vaccination recommendations.

Especially in the 11- to 12-year-old population – the age group for whom the vaccine is recommended as part of the regular immunization schedule – how to best address HPV risk is still "a million dollar question," said Dr. Charles Wibbelsman, a pediatrician who is chief of adolescent medicine at Kaiser Permanente in San Francisco and a former member of the American Academy of Pediatrics’ committee on adolescents.

Uptake of the vaccine has been slower and lower than it has been for other vaccines, experts say, and both surveys and interviews with physicians around the country indicate that physicians face a host of moral, ethical, and safety concerns from parents, even though almost 5 years have passed since Gardasil – the first of two HPV vaccines – was licensed.

A survey of more than 1,500 parents published last April, for instance, showed that the HPV vaccine was the most commonly refused pediatric vaccine. Almost 80% of the parents who refused said they believed there had not been enough research on it, 51% said it challenged their belief systems, 59% said they believed their children were at low risk for contracting the sexually transmitted disease, and 37% said they did "not believe the vaccine is effective in preventing the disease" (Pediatrics 2010:125:654-9).

Physicians who spoke with this news organization said that understanding and anticipating these common reasons for refusal of the vaccine are key to an efficient and meaningful discussion of HPV risks. So is the use of affirmative, matter-of-fact statements about HPV vaccination.

"If you approach it by saying ‘It’s time to receive your HPV vaccine,’ there’s often no need to go any further, other than providing parents with the appropriate information pamphlet" from the Centers for Disease Control and Prevention, said Dr. Michael E. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute and a pediatrician in private practice in that city.

"If you start out, on the other hand, by saying ‘It’s time to discuss the possibility of your daughter receiving the HPV vaccine,’ immediately that sends a very different message," said Dr. Pichichero, who has served as a consultant for both Merck and GlaxoSmithKline, the manufacturers of Gardasil and Cervarix, respectively.

"Parents have never heard this type of approach used with a vaccine before," he said.

It is important to tailor one’s approach to the fact that "there isn’t as immediate a preventive effect that parents can appreciate, compared with other vaccines," said Dr. Gary L. Freed, immediate past chairman of the National Vaccine Advisory Committee and director of the division of general pediatrics and the child health evaluation and research unit at the University of Michigan in Ann Arbor.

"We can do better at being straightforward in addressing the issues of HPV, with both children and their parents," he said.

The following are some of the suggestions offered and experiences shared by these physicians and others:

• The "Why Now" Factor. As with other sensitive issues, pediatricians have to tailor the depth of discussion about HPV infection to the maturity of the child and values of the family.

"But when a parent [of an 11- to 12-year-old] says, ‘I want to have this discussion 2 years from now,’ I think it’s our responsibility to share data about the risk, and to convey the fact that we want to provide universal protection at an age when we know the child will respond effectively to the vaccine by developing a strong immune response ... and at an age that is prior to the risk," said Dr. Joseph Bocchini, immediate past chairman of the American Academy of Pediatrics’ committee on infectious diseases and chairman of the department of pediatrics at the Louisiana State University Health Sciences Center in Shreveport.

Both parents and pediatricians underestimate the likelihood that their child or patient is sexually active or about to become sexually active, said Dr. Bocchini, who also serves on the HPV working group of the CDC’s Advisory Committee on Immunization Practices (ACIP).

In all, 20% of adolescents are infected with HPV within 2 years of the onset of sexual activity, he said, which for the majority of girls occurs during their teenage years.

Although physicians should not shy away from discussing HPV infection as a sexually transmitted disease – indeed, it is the most commonly occurring STD – they should nevertheless take care to emphasize the overall goal of vaccination: the prevention of cervical cancer.

"Most mothers aren’t ready to deal with the possibility of their daughter becoming sexually active, so they tie together the vaccine with more or less an acknowledgement that their daughter is about to become sexually active, whether or not that’s true," said Dr. Pichichero.

That’s why it’s important, he and others said, to emphasize that vaccination is not about sexual readiness, but about preventing cervical cancer. Providing the vaccine has not been shown in any way to increase sexual activity, he and other physicians said. And, Dr. Pichichero added, "studies show, without a doubt, that when you vaccinate at a younger age, you get much higher immunity levels."

Kaiser’s Dr. Wibbelsman said he tells parents that at least "10,000 women die each year of cervical cancer and countless others have cervical cancer, and that HPV causes cervical cancer."

Dr. Stan Block, who practices in a six-pediatrician group in Bardstown, Ky., with a large adolescent population, said that "numbers give parents something concrete to hang their hats on." He tells many parents that "the lifetime risk of getting cervical, anal, vaginal, or vulvar precancer or cancer goes from about 1 in 20 without vaccination to 1 in 50 with vaccination," and that the risk of venereal warts similarly drops from 1 in 10 without vaccination with Gardasil to about 1 in 100 with vaccination.

"We explain that even precancerous lesions can have serious consequences, like surgery and the inability to have children," said Dr. Block, who estimates that his practice has an 85%-90% HPV vaccination rate in female patients. "You have to test the waters, the comfort level of the child ... but whenever possible, I lay all this out."

When parents refuse the vaccine, he either tells them that he is documenting the refusal in their child’s chart or asks them to sign a form to document that they acknowledge the risk of refusing vaccination. "Without a doubt, it’s a malpractice risk," he said. Sometimes, he added, such a statement or request results in parents’ changing their minds.

• Safety. At least several studies have shown that the vaccine would receive greater acceptance if it was perceived to be safe.

"I tell parents that the vaccine has now been received by literally hundreds of thousands in this country, and that there are no serious adverse events associated with the vaccine," said Dr. Freed. "Then I say that in the same time period, there likely have been at least several thousand young women who have been infected with HPV who will develop precancerous cervical lesions and may go on to develop cervical cancer."

Others said they refer parents to the CDC’s Web site for vaccine safety profiles (www.cdc.gov/vaccinesafety/vaccines/hpv). "This way, it’s not me talking, and not the manufacturer, but a body with a lot of credibility," said Dr. Stanley Gall, professor of ob.gyn at the University of Louisville (Ky.) and a member of ACIP’s HPV working group.

According to the CDC Web site, approximately 32 million doses of Gardasil were distributed in the United States from the time the vaccine was licensed in 2006 until September 2010. All serious adverse event reports that were made to the Vaccine Adverse Event Reporting System have been fully investigated, with staff finding "no pattern or clustering ... to suggest they were caused by the HPV vaccination," the site says.

Syncope and fainting are common in preteens and teens after injections, the CDC notes, making the recommended 15-minute postvaccination observation period extremely important. Patients should lie down or sit for this period of time.

• Duration of efficacy. Manufacturers have tracked vaccine recipients for up to 8-10 years at this point, with no "breakthrough cases" of HPV infection, sources said.

"We can tell parents that – as with any new vaccine – we can’t say how long efficacy will last, but that we do know the vaccine is highly immunogenic, that we’re seeing no breakthrough cases in the recipients being followed, and that we know protection will last at least 7.5 years and likely significantly longer," said Dr. Bocchini. If needed in the future, a booster dose will become available.

• Vaccine differences. The most important facts for parents to know, several pediatricians said, is that both Gardasil and Cervarix protect against the two strains of HPV (types 16 and 18) that are believed to cause 70% of all cervical cancers, and that Gardasil also protects against HPV-6 and -11, the most common cause of genital warts.

Parents and older teens should know the value of protecting against genital warts, they said. "There are about a million new cases of genital warts each year in this country, and the amount of money spent treating them is equivalent to the amount of money spent treating cervical cancer," not to mention the fact that genital warts cause significant anguish, Dr. Gall said.

Dr. Pichichero, however, said that Cervarix contains a novel adjuvant that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and -18, compared with Gardasil. Higher antibody titers may translate into a longer duration of protection, he said.

Cervarix also has been shown, he said, to afford some level of cross-protection against other HPV strains that are responsible for a small yet significant proportion of cervical cancer cases. Although such differences should be weighed in the long term, right now it seems that parents are more concerned about safety and experience with the vaccines, and physicians should focus on this, he said.

Dr. Pichichero said he has served as a consultant to Merck and GlaxoSmithKline on their "National Advisory Boards for periodic 1-day consulting." Dr. Block said he has done research for both companies and is on the speakers bureau for Gardasil. Dr. Gall said he was working on clinical trials and is a speaker for GlaxoSmithKline and Merck. The other physicians reported no disclosures.

WASHINGTON – Aan investigational paclitaxel-coated balloon catheter resulted in significant reductions in late lumen loss at 6 months compared with standard balloon angioplasty in a randomized study of 101 patients with femoropopliteal disease.

Tthe LEVANT I study randomized1patients to angioplasty – with or without stenting – using a regular angioplasty balloon catheter or the Moxy (Lutonix) paclitaxel-coated balloon catheter.

Six-month late lumen loss, the primary end point, was 0.46 mm in the paclitaxel-coated balloon group and 1.09 in the traditional angioplasty group, a statistically significant difference, reported Dr. Dierk Scheinert of the Heart Center Leipzig/Park Hospital, Germany.

Late lumen loss was reduced with the paclitaxel-coated balloon catheter in both the stented and nonstented patients. There also was a trend toward lower target lesion revascularization among patients who received treatment with the Moxy balloon catheter.

The paclitaxel-coated balloon catheter appears to have a “strong biologic effect … on the inhibition of neointimal hyperplasia,” Dr. Scheinert said at the meeting, sponsored by the Cardiovascular Research Foundation.

The study suggests that a shorter duration of antiplatelet therapy is feasible in the peripheral vasculature when such treatment is employed, he noted. Patients who were not stented were prescribed 1 month of a dual-antiplatelet regimen. Those who were stented were prescribed 3 months of the regimen.

The Moxy device is designed so that paclitaxel is retained during transit of the balloon catheter and is delivered during the 30- to 60-second inflation time. A larger and longer prospective randomized trial to look at primary patency of the target lesion and various clinical end points – LEVANT II – was pending approval, Dr. Scheinert said.

The trial was sponsored by Lutonix Inc., maker of the Moxy catheter. Dr. Scheinert had no disclosures.

WASHINGTON – Aan investigational paclitaxel-coated balloon catheter resulted in significant reductions in late lumen loss at 6 months compared with standard balloon angioplasty in a randomized study of 101 patients with femoropopliteal disease.

Tthe LEVANT I study randomized1patients to angioplasty – with or without stenting – using a regular angioplasty balloon catheter or the Moxy (Lutonix) paclitaxel-coated balloon catheter.

Six-month late lumen loss, the primary end point, was 0.46 mm in the paclitaxel-coated balloon group and 1.09 in the traditional angioplasty group, a statistically significant difference, reported Dr. Dierk Scheinert of the Heart Center Leipzig/Park Hospital, Germany.

Late lumen loss was reduced with the paclitaxel-coated balloon catheter in both the stented and nonstented patients. There also was a trend toward lower target lesion revascularization among patients who received treatment with the Moxy balloon catheter.

The paclitaxel-coated balloon catheter appears to have a “strong biologic effect … on the inhibition of neointimal hyperplasia,” Dr. Scheinert said at the meeting, sponsored by the Cardiovascular Research Foundation.

The study suggests that a shorter duration of antiplatelet therapy is feasible in the peripheral vasculature when such treatment is employed, he noted. Patients who were not stented were prescribed 1 month of a dual-antiplatelet regimen. Those who were stented were prescribed 3 months of the regimen.

The Moxy device is designed so that paclitaxel is retained during transit of the balloon catheter and is delivered during the 30- to 60-second inflation time. A larger and longer prospective randomized trial to look at primary patency of the target lesion and various clinical end points – LEVANT II – was pending approval, Dr. Scheinert said.

The trial was sponsored by Lutonix Inc., maker of the Moxy catheter. Dr. Scheinert had no disclosures.

WASHINGTON – Aan investigational paclitaxel-coated balloon catheter resulted in significant reductions in late lumen loss at 6 months compared with standard balloon angioplasty in a randomized study of 101 patients with femoropopliteal disease.

Tthe LEVANT I study randomized1patients to angioplasty – with or without stenting – using a regular angioplasty balloon catheter or the Moxy (Lutonix) paclitaxel-coated balloon catheter.

Six-month late lumen loss, the primary end point, was 0.46 mm in the paclitaxel-coated balloon group and 1.09 in the traditional angioplasty group, a statistically significant difference, reported Dr. Dierk Scheinert of the Heart Center Leipzig/Park Hospital, Germany.

Late lumen loss was reduced with the paclitaxel-coated balloon catheter in both the stented and nonstented patients. There also was a trend toward lower target lesion revascularization among patients who received treatment with the Moxy balloon catheter.

The paclitaxel-coated balloon catheter appears to have a “strong biologic effect … on the inhibition of neointimal hyperplasia,” Dr. Scheinert said at the meeting, sponsored by the Cardiovascular Research Foundation.

The study suggests that a shorter duration of antiplatelet therapy is feasible in the peripheral vasculature when such treatment is employed, he noted. Patients who were not stented were prescribed 1 month of a dual-antiplatelet regimen. Those who were stented were prescribed 3 months of the regimen.

The Moxy device is designed so that paclitaxel is retained during transit of the balloon catheter and is delivered during the 30- to 60-second inflation time. A larger and longer prospective randomized trial to look at primary patency of the target lesion and various clinical end points – LEVANT II – was pending approval, Dr. Scheinert said.

The trial was sponsored by Lutonix Inc., maker of the Moxy catheter. Dr. Scheinert had no disclosures.

For years, the Nobel Committee for Physiology or Medicine passed over in vitro fertilization.

Its members were urged by obstetricians and gynecologists, among others, to award the Nobel Prize to British biologist Robert G. Edwards, Ph.D., and to recognize IVF for its reach and impact. Yet for years – for reasons which are discussed but may never be fully detailed – the committee made other choices, leaving in vitro fertilization and its main visionary to continue waiting in the wings.

In October, after Dr. Edwards’ wife was informed that her 85-year-old husband was being awarded the Nobel Prize for the decades of work he spent developing IVF; committee members explained that the time was right. And infertility specialists and other ob.gyns. felt vindicated.

“One to two percent of all newborns are conceived through IVF,” said Professor Göran K. Hansson, secretary of the committee, in announcing the decision. “IVF children are as healthy as other children … and many of the IVF children born in the 1980s now have children of their own, conceived without the help of IVF.”

Reproductive endocrinologists who are now active leaders in their field have called the award “gratifying,” “exciting,” and “long overdue” at a time when some 4 million babies worldwide have been conceived with IVF. For many of them, the 1978 birth in England of Louise Brown, the first child conceived through IVF, either drew them into the specialty, or propelled them forward with new or renewed drive.

They practiced amidst a steady stream of ethical and moral questions, and watched the technology go from one that, in many quarters, including some within their own profession, was vilified and considered a threat to humanity, to one that – while not without controversy, cost, and complexity – is now widely accepted as a key treatment for infertility.

They experienced the succession of developments that improved the success rates and possibilities of IVF – from the first birth of a baby conceived with a donated egg in 1983 and the first successful use of a frozen embryo in 1984, to the development of preimplantation genetics diagnosis (PGD) in 1990 and the development of intracytoplasmic sperm injection (ICSI) in 1991.

“IVF has enabled us to dissect the human reproductive processes in a way we weren’t able to do in the past. … There are very few things in medicine that have changed not only how we look at reproduction but life itself,” said Dr. Zev Rosenwaks, director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Cornell University and the New York Presbyterian Hospital, both in New York.

“From a social, ethical, human, medical, and scientific point of view,” the award was well deserved and long overdue, he said.

A Progression of Advances

In comments made after the Nobel Prize announcement, Professor Christer Höög, a member of the Nobel Committee for Physiology or Medicine, said that the prize was given to Dr. Edwards alone because “he had the vision [for IVF]. Others assisted … but it was really Dr. Edwards who saw the vision and made it happen.”

Some believe, however, that if his collaborator Dr. Patrick Steptoe were alive (he died in 1988), he might have shared the prize. Dr. Edwards, now a professor emeritus at the University of Cambridge, England, had called Dr. Steptoe to ask him for his help in 1968, after reading of his work with laparoscopy and having come to appreciate the fragility of in vitro–matured oocytes.

“Then the world’s master of this method, he could easily aspirate [matured] oocytes from their follicles. We teamed up for IVF and discussed in detail the safety of our proposed procedures, and the underlying ethics,” Dr. Edwards wrote in 2001 (Nature Medicine 2001;7:1091-4). “We agreed to work together as equals, pursue our work carefully, and stop if any danger emerged to patients or children, but not for vague religious or political reasons. We stayed together for 20 years, until his death. I reckon he taught me medicine.”

Dr. Alan H. DeCherney, editor in chief of the journal Fertility and Sterility, heard Dr. Steptoe present their experience with the first IVF baby at a conference in Venice, Italy, held shortly after Louise Brown’s birth. “People knew about it, but this was the first scientific presentation,” he recalled. “I thought, this is the future, and when I returned to Yale – where I was at the time – we immediately starting putting together an IVF program.”

It took 2 years to hire the right people, get IRB (institutional review board) approval, and treat their first patient – and even longer to achieve their first birth, Dr. DeCherney recalled.

In the meantime, the first birth outside England of a child conceived through IVF was reported in 1980 in Australia. In 1981, the first IVF baby in the United States, Elizabeth Carr, was born in Norfolk, Va., after the in vitro technique was performed at the Eastern Virginia Medical School there, now home of the Jones Institute for Reproductive Medicine. During 1982 and 1983, IVF births were reported at Yale University, New Haven, Conn., other U.S. institutions, and in other countries. By the end of 1983, 150 IVF babies had been born.

The early 1980s were full of continual improvements in clinical IVF – the improvement of embryo culture conditions and transfer techniques, for example, as well as the cryopreservation of surplus embryos, oocyte and embryo donation, and the development of ovarian stimulation regimens using various compounds during the follicular, mid-cycle, and luteal phase.

“There were constantly changes in the lab,” Dr. DeCherney said in an interview. “And switching from laparoscopy to [transvaginal] ultrasound [which also occurred in the early 1980s] was a very big change.”

Dr. G. David Adamson, who did his first IVF procedures in the mid-1980s at Stanford (Calif.) University before starting his own fertility practice in Palo Alto and San Jose, Calif., recalled how “a program with a 10% live birth rate was doing very well at that point.”

Then, “in the early 1990s, there was another rapid increase in the quality of the labs, and ICSI [intracytoplasmic sperm injections] was developed – this made a huge difference in pregnancy rates. … and there was a rapid increase in the number of programs,” said Dr. Adamson, who became interested in IVF in 1976, when, as a resident, he read Dr. Edwards’ and Dr. Steptoe’s report on the first ectopic IVF pregnancy, published as a letter in the British Medical Journal.

In 1986, when Dr. Adamson began doing IVF procedures in Stanford’s new program, the number of IVF babies born worldwide was 2,000. Almost a decade and a half later, by the year 2000, that number had soared to 1 million.

The problem was, with the focus on raising pregnancy rates and the simultaneous improvements in technique, the rate of multiple pregnancies as a result of IVF soared. In 1997 and 1998, the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technologies (SART), respectively, published their first guidelines recommending maximal number of embryos for transfer, according to the women’s age, embryo quality, and the opportunity for cryopreservation. The guidelines were amended in 1999 to include a new category called “most favorable” for which the transfer of no more than two embryos is recommended.

In 2004, fertility researchers announced success in significantly reducing the number of triplet and higher-order multiple births without hurting pregnancy rates (N. Engl. J. Med. 2004;350:1639-45), and just last year, the ASRM released even tighter guidelines, specifying that even in exceptions of patients with a “less favorable” prognosis, only one more embryo than called for in the guidelines should be transferred.

A Future of Challenges

Despite efforts to rein in multiple pregnancies and encourage more single-embryo transfers, multiple-embryo transfer is still the most common practice in the United States, and twin pregnancies – including what experts say is a substantial number of risky pregnancies – continue to increase. Fertility specialists still feel the tug between the need to control the multiple birth rate on one hand, and the principle of patient autonomy and free enterprise on the other, said Dr. Bradley J. Van Voorhis, who directs the IVF program at the University of Iowa Hospitals and Clinics in Iowa City. Too often, he said, patient autonomy still wins over.

“In many cases, the reason for implanting multiple embryos is that ‘that’s what the patient wanted,’ ” he said. “I’m not sure that’s a good answer anymore.”

Efforts to further reduce multiples and improve pregnancy rates with single-embryo transfers might be boosted in the future by further improvements in culturing and embryo transfer techniques, leaders say, but it is embryo selection – finding the healthy, most viable embryos, those most likely to implant – that they are pinning their hopes on.

“Without question,” said Dr. Rosenwaks, a former director of the Jones Institute for Reproductive Medicine, “identifying a viable embryo is one of the greatest challenges for IVF in the future.”

Dr. Edwards, who had lamented in 2001 that, “something must be fundamentally flawed with a reproductive system that allows only 20% of embryos to implant,” would likely agree (Nature Medicine 2001;7:1091-4).

Still, other leaders say they’re optimistic. “I think there will be more breakthroughs with this,” said Dr. Van Voorhis, who was in medical school when Louise Brown was born. (He said he was swayed into the specialty of ob.gyn. and then reproductive endocrinology, by the early IVF successes.)

There were high hopes that preimplantation genetics diagnosis would serve as a useful tool in identifying healthy embryos, but so far there is little data that PGD improves outcomes. “None of the methods utilized thus far have been able to predict implantation 100%,” Dr. Rosenwaks said. “At best, the ability to predict implantation is between 70% and 80%, even in the most optimistic and enthusiastic circles.”

The long-term health outcomes for children who were conceived through IVF are still an open question, moreover.

“What remains to be seen are things like, will they be more prone to cancer? Are there epigenetic changes that might manifest themselves in the future?” Dr. Van Voorhis said.

Epidemiologic studies have suggested that IVF babies are more likely to have certain birth defects than are babies conceived naturally (it is unclear whether the increase is a treatment effect or brought about by characteristics of the underlying population), but so far, longer-term developmental and neurologic outcomes are encouraging.

Indeed, Nobel Prize committee member Dr. Höög said the committee was influenced by “several [recently reported] long-term studies of the children,” as well as the fact that some of the IVF children have had healthy children themselves. The time seemed right, he said, because of “all these things coming together.”

More than 30 years have passed since Louise Brown was born, but the milestone in 1978 was the culmination of many more prior decades of painstaking research. Research on animal embryos goes back to the last century. In 1959, Dr. Min-Chueh Chang, an embryologist working at Harvard Medical School, Boston, reported the first successful in vitro fertilization in the rabbit. And in 1966, Dr. Edwards, who had begun his work in the 1950s, performed the first fertilization of a human egg in vitro.

“In terms of the development of IVF, many of the things that have come about were not particularly surprising because, early on [in their collaboration], Edwards and Steptoe had predicted many of the things that IVF would allow us to learn about, many of the things that have come to be,” said Dr. Rosenwaks, a past president of the SART and the Society for Reproductive Endocrinology and Infertility.

“They’d predicted, for example, that one would be able to do egg donation and that one would be able to do genetic testing on embryos,” and they knew that the types of ethical controversies they faced early on would continue and that new controversial advances, such as cloning, would evolve, he said.

Dr. Rosenwaks recalls following the IVF developments and anticipating the first successful birth as he pursued his fellowship from 1976 to 1978. “We began treating women who traditionally would have had their gonads removed for cancer, or whatever reason, more conservatively, leaving the uterus in. We definitely considered the coming of IVF in our deliberations. We knew that someday soon, they’d be able to try to conceive with IVF and egg donation.”

For years, the Nobel Committee for Physiology or Medicine passed over in vitro fertilization.

Its members were urged by obstetricians and gynecologists, among others, to award the Nobel Prize to British biologist Robert G. Edwards, Ph.D., and to recognize IVF for its reach and impact. Yet for years – for reasons which are discussed but may never be fully detailed – the committee made other choices, leaving in vitro fertilization and its main visionary to continue waiting in the wings.

In October, after Dr. Edwards’ wife was informed that her 85-year-old husband was being awarded the Nobel Prize for the decades of work he spent developing IVF; committee members explained that the time was right. And infertility specialists and other ob.gyns. felt vindicated.

“One to two percent of all newborns are conceived through IVF,” said Professor Göran K. Hansson, secretary of the committee, in announcing the decision. “IVF children are as healthy as other children … and many of the IVF children born in the 1980s now have children of their own, conceived without the help of IVF.”

Reproductive endocrinologists who are now active leaders in their field have called the award “gratifying,” “exciting,” and “long overdue” at a time when some 4 million babies worldwide have been conceived with IVF. For many of them, the 1978 birth in England of Louise Brown, the first child conceived through IVF, either drew them into the specialty, or propelled them forward with new or renewed drive.

They practiced amidst a steady stream of ethical and moral questions, and watched the technology go from one that, in many quarters, including some within their own profession, was vilified and considered a threat to humanity, to one that – while not without controversy, cost, and complexity – is now widely accepted as a key treatment for infertility.

They experienced the succession of developments that improved the success rates and possibilities of IVF – from the first birth of a baby conceived with a donated egg in 1983 and the first successful use of a frozen embryo in 1984, to the development of preimplantation genetics diagnosis (PGD) in 1990 and the development of intracytoplasmic sperm injection (ICSI) in 1991.

“IVF has enabled us to dissect the human reproductive processes in a way we weren’t able to do in the past. … There are very few things in medicine that have changed not only how we look at reproduction but life itself,” said Dr. Zev Rosenwaks, director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Cornell University and the New York Presbyterian Hospital, both in New York.

“From a social, ethical, human, medical, and scientific point of view,” the award was well deserved and long overdue, he said.

A Progression of Advances

In comments made after the Nobel Prize announcement, Professor Christer Höög, a member of the Nobel Committee for Physiology or Medicine, said that the prize was given to Dr. Edwards alone because “he had the vision [for IVF]. Others assisted … but it was really Dr. Edwards who saw the vision and made it happen.”

Some believe, however, that if his collaborator Dr. Patrick Steptoe were alive (he died in 1988), he might have shared the prize. Dr. Edwards, now a professor emeritus at the University of Cambridge, England, had called Dr. Steptoe to ask him for his help in 1968, after reading of his work with laparoscopy and having come to appreciate the fragility of in vitro–matured oocytes.

“Then the world’s master of this method, he could easily aspirate [matured] oocytes from their follicles. We teamed up for IVF and discussed in detail the safety of our proposed procedures, and the underlying ethics,” Dr. Edwards wrote in 2001 (Nature Medicine 2001;7:1091-4). “We agreed to work together as equals, pursue our work carefully, and stop if any danger emerged to patients or children, but not for vague religious or political reasons. We stayed together for 20 years, until his death. I reckon he taught me medicine.”

Dr. Alan H. DeCherney, editor in chief of the journal Fertility and Sterility, heard Dr. Steptoe present their experience with the first IVF baby at a conference in Venice, Italy, held shortly after Louise Brown’s birth. “People knew about it, but this was the first scientific presentation,” he recalled. “I thought, this is the future, and when I returned to Yale – where I was at the time – we immediately starting putting together an IVF program.”

It took 2 years to hire the right people, get IRB (institutional review board) approval, and treat their first patient – and even longer to achieve their first birth, Dr. DeCherney recalled.

In the meantime, the first birth outside England of a child conceived through IVF was reported in 1980 in Australia. In 1981, the first IVF baby in the United States, Elizabeth Carr, was born in Norfolk, Va., after the in vitro technique was performed at the Eastern Virginia Medical School there, now home of the Jones Institute for Reproductive Medicine. During 1982 and 1983, IVF births were reported at Yale University, New Haven, Conn., other U.S. institutions, and in other countries. By the end of 1983, 150 IVF babies had been born.

The early 1980s were full of continual improvements in clinical IVF – the improvement of embryo culture conditions and transfer techniques, for example, as well as the cryopreservation of surplus embryos, oocyte and embryo donation, and the development of ovarian stimulation regimens using various compounds during the follicular, mid-cycle, and luteal phase.

“There were constantly changes in the lab,” Dr. DeCherney said in an interview. “And switching from laparoscopy to [transvaginal] ultrasound [which also occurred in the early 1980s] was a very big change.”

Dr. G. David Adamson, who did his first IVF procedures in the mid-1980s at Stanford (Calif.) University before starting his own fertility practice in Palo Alto and San Jose, Calif., recalled how “a program with a 10% live birth rate was doing very well at that point.”

Then, “in the early 1990s, there was another rapid increase in the quality of the labs, and ICSI [intracytoplasmic sperm injections] was developed – this made a huge difference in pregnancy rates. … and there was a rapid increase in the number of programs,” said Dr. Adamson, who became interested in IVF in 1976, when, as a resident, he read Dr. Edwards’ and Dr. Steptoe’s report on the first ectopic IVF pregnancy, published as a letter in the British Medical Journal.

In 1986, when Dr. Adamson began doing IVF procedures in Stanford’s new program, the number of IVF babies born worldwide was 2,000. Almost a decade and a half later, by the year 2000, that number had soared to 1 million.

The problem was, with the focus on raising pregnancy rates and the simultaneous improvements in technique, the rate of multiple pregnancies as a result of IVF soared. In 1997 and 1998, the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technologies (SART), respectively, published their first guidelines recommending maximal number of embryos for transfer, according to the women’s age, embryo quality, and the opportunity for cryopreservation. The guidelines were amended in 1999 to include a new category called “most favorable” for which the transfer of no more than two embryos is recommended.

In 2004, fertility researchers announced success in significantly reducing the number of triplet and higher-order multiple births without hurting pregnancy rates (N. Engl. J. Med. 2004;350:1639-45), and just last year, the ASRM released even tighter guidelines, specifying that even in exceptions of patients with a “less favorable” prognosis, only one more embryo than called for in the guidelines should be transferred.

A Future of Challenges

Despite efforts to rein in multiple pregnancies and encourage more single-embryo transfers, multiple-embryo transfer is still the most common practice in the United States, and twin pregnancies – including what experts say is a substantial number of risky pregnancies – continue to increase. Fertility specialists still feel the tug between the need to control the multiple birth rate on one hand, and the principle of patient autonomy and free enterprise on the other, said Dr. Bradley J. Van Voorhis, who directs the IVF program at the University of Iowa Hospitals and Clinics in Iowa City. Too often, he said, patient autonomy still wins over.

“In many cases, the reason for implanting multiple embryos is that ‘that’s what the patient wanted,’ ” he said. “I’m not sure that’s a good answer anymore.”

Efforts to further reduce multiples and improve pregnancy rates with single-embryo transfers might be boosted in the future by further improvements in culturing and embryo transfer techniques, leaders say, but it is embryo selection – finding the healthy, most viable embryos, those most likely to implant – that they are pinning their hopes on.

“Without question,” said Dr. Rosenwaks, a former director of the Jones Institute for Reproductive Medicine, “identifying a viable embryo is one of the greatest challenges for IVF in the future.”

Dr. Edwards, who had lamented in 2001 that, “something must be fundamentally flawed with a reproductive system that allows only 20% of embryos to implant,” would likely agree (Nature Medicine 2001;7:1091-4).

Still, other leaders say they’re optimistic. “I think there will be more breakthroughs with this,” said Dr. Van Voorhis, who was in medical school when Louise Brown was born. (He said he was swayed into the specialty of ob.gyn. and then reproductive endocrinology, by the early IVF successes.)

There were high hopes that preimplantation genetics diagnosis would serve as a useful tool in identifying healthy embryos, but so far there is little data that PGD improves outcomes. “None of the methods utilized thus far have been able to predict implantation 100%,” Dr. Rosenwaks said. “At best, the ability to predict implantation is between 70% and 80%, even in the most optimistic and enthusiastic circles.”

The long-term health outcomes for children who were conceived through IVF are still an open question, moreover.

“What remains to be seen are things like, will they be more prone to cancer? Are there epigenetic changes that might manifest themselves in the future?” Dr. Van Voorhis said.

Epidemiologic studies have suggested that IVF babies are more likely to have certain birth defects than are babies conceived naturally (it is unclear whether the increase is a treatment effect or brought about by characteristics of the underlying population), but so far, longer-term developmental and neurologic outcomes are encouraging.

Indeed, Nobel Prize committee member Dr. Höög said the committee was influenced by “several [recently reported] long-term studies of the children,” as well as the fact that some of the IVF children have had healthy children themselves. The time seemed right, he said, because of “all these things coming together.”

More than 30 years have passed since Louise Brown was born, but the milestone in 1978 was the culmination of many more prior decades of painstaking research. Research on animal embryos goes back to the last century. In 1959, Dr. Min-Chueh Chang, an embryologist working at Harvard Medical School, Boston, reported the first successful in vitro fertilization in the rabbit. And in 1966, Dr. Edwards, who had begun his work in the 1950s, performed the first fertilization of a human egg in vitro.

“In terms of the development of IVF, many of the things that have come about were not particularly surprising because, early on [in their collaboration], Edwards and Steptoe had predicted many of the things that IVF would allow us to learn about, many of the things that have come to be,” said Dr. Rosenwaks, a past president of the SART and the Society for Reproductive Endocrinology and Infertility.

“They’d predicted, for example, that one would be able to do egg donation and that one would be able to do genetic testing on embryos,” and they knew that the types of ethical controversies they faced early on would continue and that new controversial advances, such as cloning, would evolve, he said.

Dr. Rosenwaks recalls following the IVF developments and anticipating the first successful birth as he pursued his fellowship from 1976 to 1978. “We began treating women who traditionally would have had their gonads removed for cancer, or whatever reason, more conservatively, leaving the uterus in. We definitely considered the coming of IVF in our deliberations. We knew that someday soon, they’d be able to try to conceive with IVF and egg donation.”

For years, the Nobel Committee for Physiology or Medicine passed over in vitro fertilization.

Its members were urged by obstetricians and gynecologists, among others, to award the Nobel Prize to British biologist Robert G. Edwards, Ph.D., and to recognize IVF for its reach and impact. Yet for years – for reasons which are discussed but may never be fully detailed – the committee made other choices, leaving in vitro fertilization and its main visionary to continue waiting in the wings.

In October, after Dr. Edwards’ wife was informed that her 85-year-old husband was being awarded the Nobel Prize for the decades of work he spent developing IVF; committee members explained that the time was right. And infertility specialists and other ob.gyns. felt vindicated.

“One to two percent of all newborns are conceived through IVF,” said Professor Göran K. Hansson, secretary of the committee, in announcing the decision. “IVF children are as healthy as other children … and many of the IVF children born in the 1980s now have children of their own, conceived without the help of IVF.”

Reproductive endocrinologists who are now active leaders in their field have called the award “gratifying,” “exciting,” and “long overdue” at a time when some 4 million babies worldwide have been conceived with IVF. For many of them, the 1978 birth in England of Louise Brown, the first child conceived through IVF, either drew them into the specialty, or propelled them forward with new or renewed drive.

They practiced amidst a steady stream of ethical and moral questions, and watched the technology go from one that, in many quarters, including some within their own profession, was vilified and considered a threat to humanity, to one that – while not without controversy, cost, and complexity – is now widely accepted as a key treatment for infertility.

They experienced the succession of developments that improved the success rates and possibilities of IVF – from the first birth of a baby conceived with a donated egg in 1983 and the first successful use of a frozen embryo in 1984, to the development of preimplantation genetics diagnosis (PGD) in 1990 and the development of intracytoplasmic sperm injection (ICSI) in 1991.

“IVF has enabled us to dissect the human reproductive processes in a way we weren’t able to do in the past. … There are very few things in medicine that have changed not only how we look at reproduction but life itself,” said Dr. Zev Rosenwaks, director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Cornell University and the New York Presbyterian Hospital, both in New York.

“From a social, ethical, human, medical, and scientific point of view,” the award was well deserved and long overdue, he said.

A Progression of Advances

In comments made after the Nobel Prize announcement, Professor Christer Höög, a member of the Nobel Committee for Physiology or Medicine, said that the prize was given to Dr. Edwards alone because “he had the vision [for IVF]. Others assisted … but it was really Dr. Edwards who saw the vision and made it happen.”

Some believe, however, that if his collaborator Dr. Patrick Steptoe were alive (he died in 1988), he might have shared the prize. Dr. Edwards, now a professor emeritus at the University of Cambridge, England, had called Dr. Steptoe to ask him for his help in 1968, after reading of his work with laparoscopy and having come to appreciate the fragility of in vitro–matured oocytes.

“Then the world’s master of this method, he could easily aspirate [matured] oocytes from their follicles. We teamed up for IVF and discussed in detail the safety of our proposed procedures, and the underlying ethics,” Dr. Edwards wrote in 2001 (Nature Medicine 2001;7:1091-4). “We agreed to work together as equals, pursue our work carefully, and stop if any danger emerged to patients or children, but not for vague religious or political reasons. We stayed together for 20 years, until his death. I reckon he taught me medicine.”

Dr. Alan H. DeCherney, editor in chief of the journal Fertility and Sterility, heard Dr. Steptoe present their experience with the first IVF baby at a conference in Venice, Italy, held shortly after Louise Brown’s birth. “People knew about it, but this was the first scientific presentation,” he recalled. “I thought, this is the future, and when I returned to Yale – where I was at the time – we immediately starting putting together an IVF program.”

It took 2 years to hire the right people, get IRB (institutional review board) approval, and treat their first patient – and even longer to achieve their first birth, Dr. DeCherney recalled.

In the meantime, the first birth outside England of a child conceived through IVF was reported in 1980 in Australia. In 1981, the first IVF baby in the United States, Elizabeth Carr, was born in Norfolk, Va., after the in vitro technique was performed at the Eastern Virginia Medical School there, now home of the Jones Institute for Reproductive Medicine. During 1982 and 1983, IVF births were reported at Yale University, New Haven, Conn., other U.S. institutions, and in other countries. By the end of 1983, 150 IVF babies had been born.

The early 1980s were full of continual improvements in clinical IVF – the improvement of embryo culture conditions and transfer techniques, for example, as well as the cryopreservation of surplus embryos, oocyte and embryo donation, and the development of ovarian stimulation regimens using various compounds during the follicular, mid-cycle, and luteal phase.

“There were constantly changes in the lab,” Dr. DeCherney said in an interview. “And switching from laparoscopy to [transvaginal] ultrasound [which also occurred in the early 1980s] was a very big change.”

Dr. G. David Adamson, who did his first IVF procedures in the mid-1980s at Stanford (Calif.) University before starting his own fertility practice in Palo Alto and San Jose, Calif., recalled how “a program with a 10% live birth rate was doing very well at that point.”

Then, “in the early 1990s, there was another rapid increase in the quality of the labs, and ICSI [intracytoplasmic sperm injections] was developed – this made a huge difference in pregnancy rates. … and there was a rapid increase in the number of programs,” said Dr. Adamson, who became interested in IVF in 1976, when, as a resident, he read Dr. Edwards’ and Dr. Steptoe’s report on the first ectopic IVF pregnancy, published as a letter in the British Medical Journal.

In 1986, when Dr. Adamson began doing IVF procedures in Stanford’s new program, the number of IVF babies born worldwide was 2,000. Almost a decade and a half later, by the year 2000, that number had soared to 1 million.

The problem was, with the focus on raising pregnancy rates and the simultaneous improvements in technique, the rate of multiple pregnancies as a result of IVF soared. In 1997 and 1998, the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technologies (SART), respectively, published their first guidelines recommending maximal number of embryos for transfer, according to the women’s age, embryo quality, and the opportunity for cryopreservation. The guidelines were amended in 1999 to include a new category called “most favorable” for which the transfer of no more than two embryos is recommended.

In 2004, fertility researchers announced success in significantly reducing the number of triplet and higher-order multiple births without hurting pregnancy rates (N. Engl. J. Med. 2004;350:1639-45), and just last year, the ASRM released even tighter guidelines, specifying that even in exceptions of patients with a “less favorable” prognosis, only one more embryo than called for in the guidelines should be transferred.

A Future of Challenges

Despite efforts to rein in multiple pregnancies and encourage more single-embryo transfers, multiple-embryo transfer is still the most common practice in the United States, and twin pregnancies – including what experts say is a substantial number of risky pregnancies – continue to increase. Fertility specialists still feel the tug between the need to control the multiple birth rate on one hand, and the principle of patient autonomy and free enterprise on the other, said Dr. Bradley J. Van Voorhis, who directs the IVF program at the University of Iowa Hospitals and Clinics in Iowa City. Too often, he said, patient autonomy still wins over.

“In many cases, the reason for implanting multiple embryos is that ‘that’s what the patient wanted,’ ” he said. “I’m not sure that’s a good answer anymore.”

Efforts to further reduce multiples and improve pregnancy rates with single-embryo transfers might be boosted in the future by further improvements in culturing and embryo transfer techniques, leaders say, but it is embryo selection – finding the healthy, most viable embryos, those most likely to implant – that they are pinning their hopes on.

“Without question,” said Dr. Rosenwaks, a former director of the Jones Institute for Reproductive Medicine, “identifying a viable embryo is one of the greatest challenges for IVF in the future.”

Dr. Edwards, who had lamented in 2001 that, “something must be fundamentally flawed with a reproductive system that allows only 20% of embryos to implant,” would likely agree (Nature Medicine 2001;7:1091-4).

Still, other leaders say they’re optimistic. “I think there will be more breakthroughs with this,” said Dr. Van Voorhis, who was in medical school when Louise Brown was born. (He said he was swayed into the specialty of ob.gyn. and then reproductive endocrinology, by the early IVF successes.)

There were high hopes that preimplantation genetics diagnosis would serve as a useful tool in identifying healthy embryos, but so far there is little data that PGD improves outcomes. “None of the methods utilized thus far have been able to predict implantation 100%,” Dr. Rosenwaks said. “At best, the ability to predict implantation is between 70% and 80%, even in the most optimistic and enthusiastic circles.”

The long-term health outcomes for children who were conceived through IVF are still an open question, moreover.

“What remains to be seen are things like, will they be more prone to cancer? Are there epigenetic changes that might manifest themselves in the future?” Dr. Van Voorhis said.

Epidemiologic studies have suggested that IVF babies are more likely to have certain birth defects than are babies conceived naturally (it is unclear whether the increase is a treatment effect or brought about by characteristics of the underlying population), but so far, longer-term developmental and neurologic outcomes are encouraging.

Indeed, Nobel Prize committee member Dr. Höög said the committee was influenced by “several [recently reported] long-term studies of the children,” as well as the fact that some of the IVF children have had healthy children themselves. The time seemed right, he said, because of “all these things coming together.”

More than 30 years have passed since Louise Brown was born, but the milestone in 1978 was the culmination of many more prior decades of painstaking research. Research on animal embryos goes back to the last century. In 1959, Dr. Min-Chueh Chang, an embryologist working at Harvard Medical School, Boston, reported the first successful in vitro fertilization in the rabbit. And in 1966, Dr. Edwards, who had begun his work in the 1950s, performed the first fertilization of a human egg in vitro.

“In terms of the development of IVF, many of the things that have come about were not particularly surprising because, early on [in their collaboration], Edwards and Steptoe had predicted many of the things that IVF would allow us to learn about, many of the things that have come to be,” said Dr. Rosenwaks, a past president of the SART and the Society for Reproductive Endocrinology and Infertility.

“They’d predicted, for example, that one would be able to do egg donation and that one would be able to do genetic testing on embryos,” and they knew that the types of ethical controversies they faced early on would continue and that new controversial advances, such as cloning, would evolve, he said.

Dr. Rosenwaks recalls following the IVF developments and anticipating the first successful birth as he pursued his fellowship from 1976 to 1978. “We began treating women who traditionally would have had their gonads removed for cancer, or whatever reason, more conservatively, leaving the uterus in. We definitely considered the coming of IVF in our deliberations. We knew that someday soon, they’d be able to try to conceive with IVF and egg donation.”

For years, the Nobel Committee for Physiology or Medicine passed over in vitro fertilization.

Its members were urged by obstetricians and gynecologists, among others, to award the Nobel Prize to British biologist Robert G. Edwards, Ph.D., and to recognize IVF for its reach and impact. Yet for years – for reasons that are discussed but may never be fully detailed – the committee made other choices, leaving in vitro fertilization and its main visionary to continue waiting in the wings.

Last month, after Dr. Edwards' wife was informed that her 85-year-old husband was being awarded the Nobel Prize for the decades of work he spent developing IVF, committee members explained that the time was right. And infertility specialists and other ob.gyns. felt vindicated.

“One to two percent of all newborns are conceived through IVF,” said Prof. Göran K. Hansson, secretary of the committee, in announcing the decision. “IVF children are as healthy as other children … and many of the IVF children born in the 1980s now have children of their own, conceived without the help of IVF.”

Reproductive endocrinologists who are now active leaders in their field have called the award “gratifying,” “exciting,” and “long overdue” at a time when some 4 million babies worldwide have been conceived with IVF. For many of them, the 1978 birth in England of Louise Brown, the first child conceived through IVF, either drew them into the specialty, or propelled them forward with new or renewed drive.

They practiced amidst a steady stream of ethical and moral questions, and watched the technology go from one that, in many quarters, including some within their own profession, was vilified and considered a threat to humanity, to one that – while not without controversy, cost, and complexity – is now widely accepted as a key treatment for infertility.

They experienced a succession of developments that improved the success rates of IVF – from the first birth of a baby conceived with a donated egg in 1983 and the first successful use of a frozen embryo in 1984, to the development of preimplantation genetics diagnosis in 1990 and the development of intracytoplasmic sperm injection in 1991.

“IVF has enabled us to dissect the human reproductive processes in a way we weren't able to do in the past. … There are very few things in medicine that have changed not only how we look at reproduction but life itself,” said Dr. Zev Rosenwaks, director of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Cornell University and the New York Presbyterian Hospital, both in New York.

“From a social, ethical, human, medical, and scientific point of view,” the award was well deserved and long overdue, he said.

In comments made after the Nobel Prize announcement, Prof. Christer Höög, a member of the Nobel Committee for Physiology or Medicine, said that the prize was given to Dr. Edwards alone because “he had the vision [for IVF]. Others assisted … but it was really Dr. Edwards who saw the vision and made it happen.”

Some believe, however, that if his collaborator Dr. Patrick Steptoe were alive (he died in 1988), he might have shared the prize. Dr. Edwards, now a professor emeritus at the University of Cambridge, England, had called Dr. Steptoe to ask him for his help in 1968, after reading of his work with laparoscopy and having come to appreciate the fragility of in vitro–matured oocytes.

“Then the world's master of this method, he could easily aspirate [matured] oocytes from their follicles. We teamed up for IVF and discussed in detail the safety of our proposed procedures, and the underlying ethics,” Dr. Edwards wrote in 2001 (Nat. Med. 2001;7:1091-4). “We agreed to work together as equals, pursue our work carefully, and stop if any danger emerged to patients or children, but not for vague religious or political reasons. We stayed together for 20 years, until his death. I reckon he taught me medicine.”

Dr. Alan H. DeCherney, editor in chief of the journal Fertility and Sterility, heard Dr. Steptoe present their experience with the first IVF baby at a conference in Venice, Italy, held shortly after Louise Brown's birth. “I thought, this is the future, and when I returned to Yale – where I was at the time – we immediately starting putting together an IVF program.”

In the meantime, the first birth outside England of a child conceived through IVF was reported in 1980 in Australia. In 1981, the first IVF baby in the United States, Elizabeth Carr, was born in Norfolk, Va. By the end of 1983, 150 IVF babies had been born worldwide. Through continual improvements in clinical IVF, the number of live births worldwide soared, to 1 million in 2000.

The problem was, with the focus on raising pregnancy rates and the simultaneous improvements in technique, the rate of multiple pregnancies as a result of IVF skyrocketed. Reproductive specialty organizations set standards for maximal embryo transfers. The efforts have paid off in terms of triplet and higher-order multiple births, but twin pregnancies continue to rise.

Fertility specialists still feel the tug between the need to control the multiple birth rate on one hand, and the principle of patient autonomy and free enterprise on the other, said Dr. Bradley J. Van Voorhis, who directs the IVF program at the University of Iowa Hospitals and Clinics in Iowa City.

To resolve this dilemma, many in the field are pinning their hopes on embryo selection – finding the healthiest, most viable embryos, those most likely to implant. “Without question,” said Dr. Rosenwaks, “identifying a viable embryo is one of the greatest challenges for IVF in the future.”

Dr. Robert G. Edwards in 1998 with 'test-tube babies' Jack and Sophie Emery.

Source ©AP Photo/Alastair Grant

For years, the Nobel Committee for Physiology or Medicine passed over in vitro fertilization.

Its members were urged by obstetricians and gynecologists, among others, to award the Nobel Prize to British biologist Robert G. Edwards, Ph.D., and to recognize IVF for its reach and impact. Yet for years – for reasons that are discussed but may never be fully detailed – the committee made other choices, leaving in vitro fertilization and its main visionary to continue waiting in the wings.

Last month, after Dr. Edwards' wife was informed that her 85-year-old husband was being awarded the Nobel Prize for the decades of work he spent developing IVF, committee members explained that the time was right. And infertility specialists and other ob.gyns. felt vindicated.

“One to two percent of all newborns are conceived through IVF,” said Prof. Göran K. Hansson, secretary of the committee, in announcing the decision. “IVF children are as healthy as other children … and many of the IVF children born in the 1980s now have children of their own, conceived without the help of IVF.”

Reproductive endocrinologists who are now active leaders in their field have called the award “gratifying,” “exciting,” and “long overdue” at a time when some 4 million babies worldwide have been conceived with IVF. For many of them, the 1978 birth in England of Louise Brown, the first child conceived through IVF, either drew them into the specialty, or propelled them forward with new or renewed drive.

They practiced amidst a steady stream of ethical and moral questions, and watched the technology go from one that, in many quarters, including some within their own profession, was vilified and considered a threat to humanity, to one that – while not without controversy, cost, and complexity – is now widely accepted as a key treatment for infertility.

They experienced a succession of developments that improved the success rates of IVF – from the first birth of a baby conceived with a donated egg in 1983 and the first successful use of a frozen embryo in 1984, to the development of preimplantation genetics diagnosis in 1990 and the development of intracytoplasmic sperm injection in 1991.

“IVF has enabled us to dissect the human reproductive processes in a way we weren't able to do in the past. … There are very few things in medicine that have changed not only how we look at reproduction but life itself,” said Dr. Zev Rosenwaks, director of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Cornell University and the New York Presbyterian Hospital, both in New York.

“From a social, ethical, human, medical, and scientific point of view,” the award was well deserved and long overdue, he said.

In comments made after the Nobel Prize announcement, Prof. Christer Höög, a member of the Nobel Committee for Physiology or Medicine, said that the prize was given to Dr. Edwards alone because “he had the vision [for IVF]. Others assisted … but it was really Dr. Edwards who saw the vision and made it happen.”

Some believe, however, that if his collaborator Dr. Patrick Steptoe were alive (he died in 1988), he might have shared the prize. Dr. Edwards, now a professor emeritus at the University of Cambridge, England, had called Dr. Steptoe to ask him for his help in 1968, after reading of his work with laparoscopy and having come to appreciate the fragility of in vitro–matured oocytes.

“Then the world's master of this method, he could easily aspirate [matured] oocytes from their follicles. We teamed up for IVF and discussed in detail the safety of our proposed procedures, and the underlying ethics,” Dr. Edwards wrote in 2001 (Nat. Med. 2001;7:1091-4). “We agreed to work together as equals, pursue our work carefully, and stop if any danger emerged to patients or children, but not for vague religious or political reasons. We stayed together for 20 years, until his death. I reckon he taught me medicine.”

Dr. Alan H. DeCherney, editor in chief of the journal Fertility and Sterility, heard Dr. Steptoe present their experience with the first IVF baby at a conference in Venice, Italy, held shortly after Louise Brown's birth. “I thought, this is the future, and when I returned to Yale – where I was at the time – we immediately starting putting together an IVF program.”

In the meantime, the first birth outside England of a child conceived through IVF was reported in 1980 in Australia. In 1981, the first IVF baby in the United States, Elizabeth Carr, was born in Norfolk, Va. By the end of 1983, 150 IVF babies had been born worldwide. Through continual improvements in clinical IVF, the number of live births worldwide soared, to 1 million in 2000.

The problem was, with the focus on raising pregnancy rates and the simultaneous improvements in technique, the rate of multiple pregnancies as a result of IVF skyrocketed. Reproductive specialty organizations set standards for maximal embryo transfers. The efforts have paid off in terms of triplet and higher-order multiple births, but twin pregnancies continue to rise.

Fertility specialists still feel the tug between the need to control the multiple birth rate on one hand, and the principle of patient autonomy and free enterprise on the other, said Dr. Bradley J. Van Voorhis, who directs the IVF program at the University of Iowa Hospitals and Clinics in Iowa City.

To resolve this dilemma, many in the field are pinning their hopes on embryo selection – finding the healthiest, most viable embryos, those most likely to implant. “Without question,” said Dr. Rosenwaks, “identifying a viable embryo is one of the greatest challenges for IVF in the future.”

Dr. Robert G. Edwards in 1998 with 'test-tube babies' Jack and Sophie Emery.

Source ©AP Photo/Alastair Grant

For years, the Nobel Committee for Physiology or Medicine passed over in vitro fertilization.

Its members were urged by obstetricians and gynecologists, among others, to award the Nobel Prize to British biologist Robert G. Edwards, Ph.D., and to recognize IVF for its reach and impact. Yet for years – for reasons that are discussed but may never be fully detailed – the committee made other choices, leaving in vitro fertilization and its main visionary to continue waiting in the wings.

Last month, after Dr. Edwards' wife was informed that her 85-year-old husband was being awarded the Nobel Prize for the decades of work he spent developing IVF, committee members explained that the time was right. And infertility specialists and other ob.gyns. felt vindicated.

“One to two percent of all newborns are conceived through IVF,” said Prof. Göran K. Hansson, secretary of the committee, in announcing the decision. “IVF children are as healthy as other children … and many of the IVF children born in the 1980s now have children of their own, conceived without the help of IVF.”

Reproductive endocrinologists who are now active leaders in their field have called the award “gratifying,” “exciting,” and “long overdue” at a time when some 4 million babies worldwide have been conceived with IVF. For many of them, the 1978 birth in England of Louise Brown, the first child conceived through IVF, either drew them into the specialty, or propelled them forward with new or renewed drive.

They practiced amidst a steady stream of ethical and moral questions, and watched the technology go from one that, in many quarters, including some within their own profession, was vilified and considered a threat to humanity, to one that – while not without controversy, cost, and complexity – is now widely accepted as a key treatment for infertility.

They experienced a succession of developments that improved the success rates of IVF – from the first birth of a baby conceived with a donated egg in 1983 and the first successful use of a frozen embryo in 1984, to the development of preimplantation genetics diagnosis in 1990 and the development of intracytoplasmic sperm injection in 1991.

“IVF has enabled us to dissect the human reproductive processes in a way we weren't able to do in the past. … There are very few things in medicine that have changed not only how we look at reproduction but life itself,” said Dr. Zev Rosenwaks, director of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Cornell University and the New York Presbyterian Hospital, both in New York.

“From a social, ethical, human, medical, and scientific point of view,” the award was well deserved and long overdue, he said.

In comments made after the Nobel Prize announcement, Prof. Christer Höög, a member of the Nobel Committee for Physiology or Medicine, said that the prize was given to Dr. Edwards alone because “he had the vision [for IVF]. Others assisted … but it was really Dr. Edwards who saw the vision and made it happen.”

Some believe, however, that if his collaborator Dr. Patrick Steptoe were alive (he died in 1988), he might have shared the prize. Dr. Edwards, now a professor emeritus at the University of Cambridge, England, had called Dr. Steptoe to ask him for his help in 1968, after reading of his work with laparoscopy and having come to appreciate the fragility of in vitro–matured oocytes.

“Then the world's master of this method, he could easily aspirate [matured] oocytes from their follicles. We teamed up for IVF and discussed in detail the safety of our proposed procedures, and the underlying ethics,” Dr. Edwards wrote in 2001 (Nat. Med. 2001;7:1091-4). “We agreed to work together as equals, pursue our work carefully, and stop if any danger emerged to patients or children, but not for vague religious or political reasons. We stayed together for 20 years, until his death. I reckon he taught me medicine.”

Dr. Alan H. DeCherney, editor in chief of the journal Fertility and Sterility, heard Dr. Steptoe present their experience with the first IVF baby at a conference in Venice, Italy, held shortly after Louise Brown's birth. “I thought, this is the future, and when I returned to Yale – where I was at the time – we immediately starting putting together an IVF program.”

In the meantime, the first birth outside England of a child conceived through IVF was reported in 1980 in Australia. In 1981, the first IVF baby in the United States, Elizabeth Carr, was born in Norfolk, Va. By the end of 1983, 150 IVF babies had been born worldwide. Through continual improvements in clinical IVF, the number of live births worldwide soared, to 1 million in 2000.

The problem was, with the focus on raising pregnancy rates and the simultaneous improvements in technique, the rate of multiple pregnancies as a result of IVF skyrocketed. Reproductive specialty organizations set standards for maximal embryo transfers. The efforts have paid off in terms of triplet and higher-order multiple births, but twin pregnancies continue to rise.

Fertility specialists still feel the tug between the need to control the multiple birth rate on one hand, and the principle of patient autonomy and free enterprise on the other, said Dr. Bradley J. Van Voorhis, who directs the IVF program at the University of Iowa Hospitals and Clinics in Iowa City.

To resolve this dilemma, many in the field are pinning their hopes on embryo selection – finding the healthiest, most viable embryos, those most likely to implant. “Without question,” said Dr. Rosenwaks, “identifying a viable embryo is one of the greatest challenges for IVF in the future.”

Dr. Robert G. Edwards in 1998 with 'test-tube babies' Jack and Sophie Emery.

Source ©AP Photo/Alastair Grant

Major Finding: At 2 years, treatment with the everolimus-eluting Xience V stent rather than the paclitaxel-eluting Taxus stent resulted in a 30% relative reduction in target lesion failure, a 34% relative reduction in ischemia-driven target lesion revascularization, and a 64% relative reduction in stent thrombosis. Between 1 and 2 years in the COMPARE trial, there was a 77% reduction in very late definite or probable stent thrombosis in favor of Xience V.

Data Source: SPIRIT IV: a randomized prospective study of 3,687 patients treated at 66 U.S. medical centers. COMPARE: a randomized single-center trial of 1,800 patients.

Disclosures: The SPIRIT IV trial is sponsored by Abbott Vascular; the COMPARE trial is funded by Abbott Vascular and Boston Scientific. Dr. Stone disclosed that he sits on the advisory boards for, and receives honoraria from, Abbott Vascular and Boston Scientific. Dr. Smits disclosed that he received a speaking fee from Abbott Vascular and that his cardiology department has received unrestricted research grants from Abbott Vascular and Boston Scientific.

WASHINGTON – The benefits seen 1 year after percutaneous coronary intervention with the everolimus-eluting Xience V stent compared with the paclitaxel-eluting Taxus stent were sustained at 2 years of follow-up in two very different types of randomized studies.

And in the case of stent thrombosis in particular, the benefits of the everolimus-eluting stent appear to have intensified at 2 years, investigators reported at the meeting.

The new 2-year findings from both the SPIRIT IV trial, a large study involving 66 U.S. sites, and the COMPARE trial, a small, single-center, “all-comers” trial in Europe, confirm the superiority of the everolimus-eluting stent in patients – except in patients with diabetes, the investigators and other discussants said.

In patients with diabetes, no significant differences in the risk of major adverse cardiac events (MACE) were observed with either stent in either trial at 1 or 2 years after PCI, a finding that led experts at the meeting to surmise that diabetic patients may fare equally well with both stents.

“We've seen this now in almost every trial” comparing these drug-eluting stents. “There is no difference in MACE rates,” Dr. Gregg W. Stone of Columbia University College of Physicians and Surgeons, New York, said in a session announcing the new SPIRIT IV findings.

“In my mind, this lack of benefit [to the Xience V stent] in diabetics means without any doubt that there's a difference in the mechanistic response of diabetics versus nondiabetics … to these types of drugs,” he said. Dr. Stone is principal investigator for Spirit IV and codirector of medical research and education at the Cardiovascular Research Foundation, which sponsored the TCT meeting.

The 3,687 patients in the industry-sponsored SPIRIT IV trial, including 1,185 with diabetes, were randomized in 2:1 fashion to receive either the everolimus-eluting Xience V stent (Abbott Vascular) or the first-generation paclitaxel-eluting Taxus Express stent (Boston Scientific). The patients had up to three untreated coronary artery lesions that were as long as 28 mm, in vessels with a diameter of 2.5–3.75 mm.

At 2 years, treatment with Xience V resulted in a relative 30% reduction (and a 3% absolute decline) in target lesion failure compared with treatment with the Taxus stent, with target lesion failure occurring in about 6.9% and 9.9% of the patients, respectively. (The rates of this primary end point after 1 year were 4.0% and 6.9%, respectively.)

The relative reduction in target lesion failure was 39% in patients without diabetes, but in diabetic patients there was little difference between the two groups. Target lesion failure is a composite end point reflecting cardiac death, target-vessel myocardial infarction, or ischemia-driven target lesion revascularization.

Ischemia-driven target lesion revascularization, a secondary end point, occurred at a rate of 4.5% at 2 years in the Xience group, compared with 6.9% in the Taxus group, for an absolute reduction of 2.4% and a relative reduction of 34%. The rates of this secondary outcome after 1 year were 2.4% compared with 4.6%.

While there were no mortality differences, target-vessel MI also occurred at a significantly reduced rate in the Xience group at both 1 and 2 years (2.3% v. 3.5% at 2 years), said Dr. Stone.

The rates in stent thrombosis in both studies, in fact, drew significant attention at the meeting. At 2 years after intervention in SPIRIT IV, 1.2% in the Taxus group had developed definite/probable stent thrombosis according to definitions of the Academic Research Consortium (ARC), compared with 0.4% in the Xience arm.

This translates into a 64% relative risk reduction for stent thrombosis (a 0.8% absolute reduction) that occurred during each period – early (the first 30 days), late (31 days to 1 year) and very late period (over 1 year).

The 2-year reductions in stent thrombosis reported from the COMPARE trial were even more striking, discussants said at the meeting.

In this trial, 1,800 consecutive patients undergoing PCI at one center in Rotterdam, the Netherlands, were randomly assigned in 1:1 fashion to treatment with the Xience V stent or the Taxus Liberté stent, a second-generation paclitaxel-eluting stent.

(The Taxus Express stent used in SPIRIT IV is no longer commercially available, according to a spokesperson for Boston Scientific. The Taxus Liberté stent, which uses the same polymer but a different stent platform, is currently available in the United States and in Europe, he said.)

The rate of definite/probable stent thrombosis (again, by ARC definition) at 2 years in the COMPARE trial was 0.9% in the Xience V group and 3.9% in the Taxus group – higher rates than found in SPIRIT IV. Most notable, however, was a 77% reduction in very late definite/probable stent thrombosis in the Xience V arm. The rate of this outcome was 0.3% in the Xience V group and 1.5% in the Taxus Liberté group, reported Dr. Peter Smits of Maasstad Ziekenhuis.

This difference is especially notable because the vast majority of patients were no longer taking dual antiplatelet therapy at 2 years, said Dr. Smits, principal investigator of COMPARE. In contrast, more than 70% of patients in each arm of the SPIRIT IV trial remained on dual antiplatelet therapy at 2 years.

Unlike the SPIRIT design, the COMPARE trial was designed to be an “all-comer, real-world study” without exclusions for complex patients. At 2 years, the superiority of the Xience V stent for the primary end point – a composite of all mortality, nonfatal MI, and target vessel revascularization (MACE) – was maintained, with larger absolute differences between the stents than at 12 months.

At 1 year, this primary end point had occurred in 6.2% and 9.1% in the Xience V and Taxus groups, respectively, for an absolute difference of 2.9%. At 2 years, these rates rose to 9.0% and 13.7%, for an absolute difference of 4.7%. There were similar reductions in secondary end points. As in SPIRIT IV, there were no benefits of the Xience V stent for diabetic patients.

Both studies are still ongoing and will conclude with 5-year analyses.

The lack of benefit of the Xience V stent in diabetics means there is a difference in their mechanistic response.

Source DR. STONE

Major Finding: At 2 years, treatment with the everolimus-eluting Xience V stent rather than the paclitaxel-eluting Taxus stent resulted in a 30% relative reduction in target lesion failure, a 34% relative reduction in ischemia-driven target lesion revascularization, and a 64% relative reduction in stent thrombosis. Between 1 and 2 years in the COMPARE trial, there was a 77% reduction in very late definite or probable stent thrombosis in favor of Xience V.

Data Source: SPIRIT IV: a randomized prospective study of 3,687 patients treated at 66 U.S. medical centers. COMPARE: a randomized single-center trial of 1,800 patients.

Disclosures: The SPIRIT IV trial is sponsored by Abbott Vascular; the COMPARE trial is funded by Abbott Vascular and Boston Scientific. Dr. Stone disclosed that he sits on the advisory boards for, and receives honoraria from, Abbott Vascular and Boston Scientific. Dr. Smits disclosed that he received a speaking fee from Abbott Vascular and that his cardiology department has received unrestricted research grants from Abbott Vascular and Boston Scientific.

WASHINGTON – The benefits seen 1 year after percutaneous coronary intervention with the everolimus-eluting Xience V stent compared with the paclitaxel-eluting Taxus stent were sustained at 2 years of follow-up in two very different types of randomized studies.

And in the case of stent thrombosis in particular, the benefits of the everolimus-eluting stent appear to have intensified at 2 years, investigators reported at the meeting.

The new 2-year findings from both the SPIRIT IV trial, a large study involving 66 U.S. sites, and the COMPARE trial, a small, single-center, “all-comers” trial in Europe, confirm the superiority of the everolimus-eluting stent in patients – except in patients with diabetes, the investigators and other discussants said.

In patients with diabetes, no significant differences in the risk of major adverse cardiac events (MACE) were observed with either stent in either trial at 1 or 2 years after PCI, a finding that led experts at the meeting to surmise that diabetic patients may fare equally well with both stents.

“We've seen this now in almost every trial” comparing these drug-eluting stents. “There is no difference in MACE rates,” Dr. Gregg W. Stone of Columbia University College of Physicians and Surgeons, New York, said in a session announcing the new SPIRIT IV findings.

“In my mind, this lack of benefit [to the Xience V stent] in diabetics means without any doubt that there's a difference in the mechanistic response of diabetics versus nondiabetics … to these types of drugs,” he said. Dr. Stone is principal investigator for Spirit IV and codirector of medical research and education at the Cardiovascular Research Foundation, which sponsored the TCT meeting.

The 3,687 patients in the industry-sponsored SPIRIT IV trial, including 1,185 with diabetes, were randomized in 2:1 fashion to receive either the everolimus-eluting Xience V stent (Abbott Vascular) or the first-generation paclitaxel-eluting Taxus Express stent (Boston Scientific). The patients had up to three untreated coronary artery lesions that were as long as 28 mm, in vessels with a diameter of 2.5–3.75 mm.

At 2 years, treatment with Xience V resulted in a relative 30% reduction (and a 3% absolute decline) in target lesion failure compared with treatment with the Taxus stent, with target lesion failure occurring in about 6.9% and 9.9% of the patients, respectively. (The rates of this primary end point after 1 year were 4.0% and 6.9%, respectively.)

The relative reduction in target lesion failure was 39% in patients without diabetes, but in diabetic patients there was little difference between the two groups. Target lesion failure is a composite end point reflecting cardiac death, target-vessel myocardial infarction, or ischemia-driven target lesion revascularization.

Ischemia-driven target lesion revascularization, a secondary end point, occurred at a rate of 4.5% at 2 years in the Xience group, compared with 6.9% in the Taxus group, for an absolute reduction of 2.4% and a relative reduction of 34%. The rates of this secondary outcome after 1 year were 2.4% compared with 4.6%.

While there were no mortality differences, target-vessel MI also occurred at a significantly reduced rate in the Xience group at both 1 and 2 years (2.3% v. 3.5% at 2 years), said Dr. Stone.

The rates in stent thrombosis in both studies, in fact, drew significant attention at the meeting. At 2 years after intervention in SPIRIT IV, 1.2% in the Taxus group had developed definite/probable stent thrombosis according to definitions of the Academic Research Consortium (ARC), compared with 0.4% in the Xience arm.

This translates into a 64% relative risk reduction for stent thrombosis (a 0.8% absolute reduction) that occurred during each period – early (the first 30 days), late (31 days to 1 year) and very late period (over 1 year).

The 2-year reductions in stent thrombosis reported from the COMPARE trial were even more striking, discussants said at the meeting.

In this trial, 1,800 consecutive patients undergoing PCI at one center in Rotterdam, the Netherlands, were randomly assigned in 1:1 fashion to treatment with the Xience V stent or the Taxus Liberté stent, a second-generation paclitaxel-eluting stent.

(The Taxus Express stent used in SPIRIT IV is no longer commercially available, according to a spokesperson for Boston Scientific. The Taxus Liberté stent, which uses the same polymer but a different stent platform, is currently available in the United States and in Europe, he said.)

The rate of definite/probable stent thrombosis (again, by ARC definition) at 2 years in the COMPARE trial was 0.9% in the Xience V group and 3.9% in the Taxus group – higher rates than found in SPIRIT IV. Most notable, however, was a 77% reduction in very late definite/probable stent thrombosis in the Xience V arm. The rate of this outcome was 0.3% in the Xience V group and 1.5% in the Taxus Liberté group, reported Dr. Peter Smits of Maasstad Ziekenhuis.

This difference is especially notable because the vast majority of patients were no longer taking dual antiplatelet therapy at 2 years, said Dr. Smits, principal investigator of COMPARE. In contrast, more than 70% of patients in each arm of the SPIRIT IV trial remained on dual antiplatelet therapy at 2 years.

Unlike the SPIRIT design, the COMPARE trial was designed to be an “all-comer, real-world study” without exclusions for complex patients. At 2 years, the superiority of the Xience V stent for the primary end point – a composite of all mortality, nonfatal MI, and target vessel revascularization (MACE) – was maintained, with larger absolute differences between the stents than at 12 months.

At 1 year, this primary end point had occurred in 6.2% and 9.1% in the Xience V and Taxus groups, respectively, for an absolute difference of 2.9%. At 2 years, these rates rose to 9.0% and 13.7%, for an absolute difference of 4.7%. There were similar reductions in secondary end points. As in SPIRIT IV, there were no benefits of the Xience V stent for diabetic patients.

Both studies are still ongoing and will conclude with 5-year analyses.

The lack of benefit of the Xience V stent in diabetics means there is a difference in their mechanistic response.

Source DR. STONE

Major Finding: At 2 years, treatment with the everolimus-eluting Xience V stent rather than the paclitaxel-eluting Taxus stent resulted in a 30% relative reduction in target lesion failure, a 34% relative reduction in ischemia-driven target lesion revascularization, and a 64% relative reduction in stent thrombosis. Between 1 and 2 years in the COMPARE trial, there was a 77% reduction in very late definite or probable stent thrombosis in favor of Xience V.

Data Source: SPIRIT IV: a randomized prospective study of 3,687 patients treated at 66 U.S. medical centers. COMPARE: a randomized single-center trial of 1,800 patients.

Disclosures: The SPIRIT IV trial is sponsored by Abbott Vascular; the COMPARE trial is funded by Abbott Vascular and Boston Scientific. Dr. Stone disclosed that he sits on the advisory boards for, and receives honoraria from, Abbott Vascular and Boston Scientific. Dr. Smits disclosed that he received a speaking fee from Abbott Vascular and that his cardiology department has received unrestricted research grants from Abbott Vascular and Boston Scientific.

WASHINGTON – The benefits seen 1 year after percutaneous coronary intervention with the everolimus-eluting Xience V stent compared with the paclitaxel-eluting Taxus stent were sustained at 2 years of follow-up in two very different types of randomized studies.

And in the case of stent thrombosis in particular, the benefits of the everolimus-eluting stent appear to have intensified at 2 years, investigators reported at the meeting.

The new 2-year findings from both the SPIRIT IV trial, a large study involving 66 U.S. sites, and the COMPARE trial, a small, single-center, “all-comers” trial in Europe, confirm the superiority of the everolimus-eluting stent in patients – except in patients with diabetes, the investigators and other discussants said.

In patients with diabetes, no significant differences in the risk of major adverse cardiac events (MACE) were observed with either stent in either trial at 1 or 2 years after PCI, a finding that led experts at the meeting to surmise that diabetic patients may fare equally well with both stents.

“We've seen this now in almost every trial” comparing these drug-eluting stents. “There is no difference in MACE rates,” Dr. Gregg W. Stone of Columbia University College of Physicians and Surgeons, New York, said in a session announcing the new SPIRIT IV findings.

“In my mind, this lack of benefit [to the Xience V stent] in diabetics means without any doubt that there's a difference in the mechanistic response of diabetics versus nondiabetics … to these types of drugs,” he said. Dr. Stone is principal investigator for Spirit IV and codirector of medical research and education at the Cardiovascular Research Foundation, which sponsored the TCT meeting.

The 3,687 patients in the industry-sponsored SPIRIT IV trial, including 1,185 with diabetes, were randomized in 2:1 fashion to receive either the everolimus-eluting Xience V stent (Abbott Vascular) or the first-generation paclitaxel-eluting Taxus Express stent (Boston Scientific). The patients had up to three untreated coronary artery lesions that were as long as 28 mm, in vessels with a diameter of 2.5–3.75 mm.

At 2 years, treatment with Xience V resulted in a relative 30% reduction (and a 3% absolute decline) in target lesion failure compared with treatment with the Taxus stent, with target lesion failure occurring in about 6.9% and 9.9% of the patients, respectively. (The rates of this primary end point after 1 year were 4.0% and 6.9%, respectively.)

The relative reduction in target lesion failure was 39% in patients without diabetes, but in diabetic patients there was little difference between the two groups. Target lesion failure is a composite end point reflecting cardiac death, target-vessel myocardial infarction, or ischemia-driven target lesion revascularization.

Ischemia-driven target lesion revascularization, a secondary end point, occurred at a rate of 4.5% at 2 years in the Xience group, compared with 6.9% in the Taxus group, for an absolute reduction of 2.4% and a relative reduction of 34%. The rates of this secondary outcome after 1 year were 2.4% compared with 4.6%.

While there were no mortality differences, target-vessel MI also occurred at a significantly reduced rate in the Xience group at both 1 and 2 years (2.3% v. 3.5% at 2 years), said Dr. Stone.

The rates in stent thrombosis in both studies, in fact, drew significant attention at the meeting. At 2 years after intervention in SPIRIT IV, 1.2% in the Taxus group had developed definite/probable stent thrombosis according to definitions of the Academic Research Consortium (ARC), compared with 0.4% in the Xience arm.

This translates into a 64% relative risk reduction for stent thrombosis (a 0.8% absolute reduction) that occurred during each period – early (the first 30 days), late (31 days to 1 year) and very late period (over 1 year).

The 2-year reductions in stent thrombosis reported from the COMPARE trial were even more striking, discussants said at the meeting.

In this trial, 1,800 consecutive patients undergoing PCI at one center in Rotterdam, the Netherlands, were randomly assigned in 1:1 fashion to treatment with the Xience V stent or the Taxus Liberté stent, a second-generation paclitaxel-eluting stent.

(The Taxus Express stent used in SPIRIT IV is no longer commercially available, according to a spokesperson for Boston Scientific. The Taxus Liberté stent, which uses the same polymer but a different stent platform, is currently available in the United States and in Europe, he said.)

The rate of definite/probable stent thrombosis (again, by ARC definition) at 2 years in the COMPARE trial was 0.9% in the Xience V group and 3.9% in the Taxus group – higher rates than found in SPIRIT IV. Most notable, however, was a 77% reduction in very late definite/probable stent thrombosis in the Xience V arm. The rate of this outcome was 0.3% in the Xience V group and 1.5% in the Taxus Liberté group, reported Dr. Peter Smits of Maasstad Ziekenhuis.

This difference is especially notable because the vast majority of patients were no longer taking dual antiplatelet therapy at 2 years, said Dr. Smits, principal investigator of COMPARE. In contrast, more than 70% of patients in each arm of the SPIRIT IV trial remained on dual antiplatelet therapy at 2 years.

Unlike the SPIRIT design, the COMPARE trial was designed to be an “all-comer, real-world study” without exclusions for complex patients. At 2 years, the superiority of the Xience V stent for the primary end point – a composite of all mortality, nonfatal MI, and target vessel revascularization (MACE) – was maintained, with larger absolute differences between the stents than at 12 months.

At 1 year, this primary end point had occurred in 6.2% and 9.1% in the Xience V and Taxus groups, respectively, for an absolute difference of 2.9%. At 2 years, these rates rose to 9.0% and 13.7%, for an absolute difference of 4.7%. There were similar reductions in secondary end points. As in SPIRIT IV, there were no benefits of the Xience V stent for diabetic patients.

Both studies are still ongoing and will conclude with 5-year analyses.

The lack of benefit of the Xience V stent in diabetics means there is a difference in their mechanistic response.

Source DR. STONE

Major Finding: At 9 months, the rate of MACE was 4.9% in the 1,390 Xience-treated patients and 5.2% in 1,384 Cypher-treated patients in ISAR-TEST 4. At 2 years, target lesion revascularization was 16% with Xience and 18.8% with Cypher in SORT OUT 4.

Data Source: Two prospective, randomized industry-independent studies conducted in Europe: ISAR-TEST 4 and SORT OUT 4.

Disclosures: Dr. Jensen reported that she has a financial interest/arrangement or affiliation with Cordis, Johnson & Johnson, and Abbott. Dr. Byrne reported that he had no relevant disclosures.

WASHINGTON – Two European head-to-head comparisons of the second-generation everolimus-eluting stent with the first-generation sirolimus-eluting stent have failed to detect any significant clinical differences between the two stents in patients with coronary artery disease, investigators reported.

“The sirolimus-eluting stent demonstrated the least amount of late lumen loss among previously released first-generation drug-eluting stents, but its efficacy and safety have not [previously] been compared head-to-head with the second-generation everolimus-eluting stent,” Dr. Lisette Okkels Jensen said in describing the rationale for her team's SORT OUT IV trial.

Nine-month data from this prospective randomized study, which involved patients in a population-based health care setting and was powered to detect noninferiority, show that the everolimus-eluting Xience V stent (Abbott Vascular) was noninferior to the sirolimus-eluting Cypher Select Plus stent (Cordis) when it came to the primary end point of major adverse cardiac events (MACE) – a composite of cardiac death, myocardial infarction, definite stent thrombosis, and target vessel revascularization.

The rate of MACE was 4.9% in the 1,390 Xience-treated patients and 5.2% in the 1,384 Cypher-treated patients, reported Dr. Jensen of Odense (Denmark) University.

Approximately 55% of the patients in each arm had stable angina, and almost 33% in each arm had NSTEMI/unstable angina. In most of the remaining patients, STEMI drove the need for percutaneous coronary intervention.

The other head-to-head drug-eluting stent comparison was part of the larger randomized, two-center ISAR-TEST 4 trial designed to compare a biodegradable polymer DES with permanent polymer stents. Within the permanent polymer arm of 1,304 subjects, patients were randomized 1:1 to receive either the Xience or Cypher stent.

At 2 years – a longer follow-up period than in SORT OUT I – there were no significant differences in the combined primary end point of cardiac death, target-vessel–related myocardial infarction, and target lesion revascularization (16% in Xience-treated patients and 18.8% in Cypher-treated patients), reported Dr. Robert A. Byrne of Deutsches Herzzentrum in Munich.

The rates of definite or probable stent thrombosis at 2 years – the secondary, safety end point of the study – were also similar (1.4% in those who received the everolimus-eluting stent and 1.9% in patients treated with the sirolimus-eluting stent).

There was a trend toward superior antirestenotic efficacy with the Xience stent, but “specifically powered studies are needed to evaluate the clinical significance of this finding,” said Dr. Byrne. (Target lesion revascularization occurred in 9.9% of Xience-treated patients and 13.5% of the Cypher-treated patients.)

The Cypher Select Plus sirolimus-eluting stent that was used in the SORT OUT IV trial is a version of the Cypher stent that is not commercially available in the United States. U.S. physicians who discussed the trial said they have no reason to believe results would be different with other Cypher stent products.

Major Finding: At 9 months, the rate of MACE was 4.9% in the 1,390 Xience-treated patients and 5.2% in 1,384 Cypher-treated patients in ISAR-TEST 4. At 2 years, target lesion revascularization was 16% with Xience and 18.8% with Cypher in SORT OUT 4.

Data Source: Two prospective, randomized industry-independent studies conducted in Europe: ISAR-TEST 4 and SORT OUT 4.

Disclosures: Dr. Jensen reported that she has a financial interest/arrangement or affiliation with Cordis, Johnson & Johnson, and Abbott. Dr. Byrne reported that he had no relevant disclosures.

WASHINGTON – Two European head-to-head comparisons of the second-generation everolimus-eluting stent with the first-generation sirolimus-eluting stent have failed to detect any significant clinical differences between the two stents in patients with coronary artery disease, investigators reported.

“The sirolimus-eluting stent demonstrated the least amount of late lumen loss among previously released first-generation drug-eluting stents, but its efficacy and safety have not [previously] been compared head-to-head with the second-generation everolimus-eluting stent,” Dr. Lisette Okkels Jensen said in describing the rationale for her team's SORT OUT IV trial.

Nine-month data from this prospective randomized study, which involved patients in a population-based health care setting and was powered to detect noninferiority, show that the everolimus-eluting Xience V stent (Abbott Vascular) was noninferior to the sirolimus-eluting Cypher Select Plus stent (Cordis) when it came to the primary end point of major adverse cardiac events (MACE) – a composite of cardiac death, myocardial infarction, definite stent thrombosis, and target vessel revascularization.

The rate of MACE was 4.9% in the 1,390 Xience-treated patients and 5.2% in the 1,384 Cypher-treated patients, reported Dr. Jensen of Odense (Denmark) University.

Approximately 55% of the patients in each arm had stable angina, and almost 33% in each arm had NSTEMI/unstable angina. In most of the remaining patients, STEMI drove the need for percutaneous coronary intervention.

The other head-to-head drug-eluting stent comparison was part of the larger randomized, two-center ISAR-TEST 4 trial designed to compare a biodegradable polymer DES with permanent polymer stents. Within the permanent polymer arm of 1,304 subjects, patients were randomized 1:1 to receive either the Xience or Cypher stent.

At 2 years – a longer follow-up period than in SORT OUT I – there were no significant differences in the combined primary end point of cardiac death, target-vessel–related myocardial infarction, and target lesion revascularization (16% in Xience-treated patients and 18.8% in Cypher-treated patients), reported Dr. Robert A. Byrne of Deutsches Herzzentrum in Munich.

The rates of definite or probable stent thrombosis at 2 years – the secondary, safety end point of the study – were also similar (1.4% in those who received the everolimus-eluting stent and 1.9% in patients treated with the sirolimus-eluting stent).

There was a trend toward superior antirestenotic efficacy with the Xience stent, but “specifically powered studies are needed to evaluate the clinical significance of this finding,” said Dr. Byrne. (Target lesion revascularization occurred in 9.9% of Xience-treated patients and 13.5% of the Cypher-treated patients.)

The Cypher Select Plus sirolimus-eluting stent that was used in the SORT OUT IV trial is a version of the Cypher stent that is not commercially available in the United States. U.S. physicians who discussed the trial said they have no reason to believe results would be different with other Cypher stent products.

Major Finding: At 9 months, the rate of MACE was 4.9% in the 1,390 Xience-treated patients and 5.2% in 1,384 Cypher-treated patients in ISAR-TEST 4. At 2 years, target lesion revascularization was 16% with Xience and 18.8% with Cypher in SORT OUT 4.

Data Source: Two prospective, randomized industry-independent studies conducted in Europe: ISAR-TEST 4 and SORT OUT 4.

Disclosures: Dr. Jensen reported that she has a financial interest/arrangement or affiliation with Cordis, Johnson & Johnson, and Abbott. Dr. Byrne reported that he had no relevant disclosures.

WASHINGTON – Two European head-to-head comparisons of the second-generation everolimus-eluting stent with the first-generation sirolimus-eluting stent have failed to detect any significant clinical differences between the two stents in patients with coronary artery disease, investigators reported.

“The sirolimus-eluting stent demonstrated the least amount of late lumen loss among previously released first-generation drug-eluting stents, but its efficacy and safety have not [previously] been compared head-to-head with the second-generation everolimus-eluting stent,” Dr. Lisette Okkels Jensen said in describing the rationale for her team's SORT OUT IV trial.

Nine-month data from this prospective randomized study, which involved patients in a population-based health care setting and was powered to detect noninferiority, show that the everolimus-eluting Xience V stent (Abbott Vascular) was noninferior to the sirolimus-eluting Cypher Select Plus stent (Cordis) when it came to the primary end point of major adverse cardiac events (MACE) – a composite of cardiac death, myocardial infarction, definite stent thrombosis, and target vessel revascularization.

The rate of MACE was 4.9% in the 1,390 Xience-treated patients and 5.2% in the 1,384 Cypher-treated patients, reported Dr. Jensen of Odense (Denmark) University.

Approximately 55% of the patients in each arm had stable angina, and almost 33% in each arm had NSTEMI/unstable angina. In most of the remaining patients, STEMI drove the need for percutaneous coronary intervention.

The other head-to-head drug-eluting stent comparison was part of the larger randomized, two-center ISAR-TEST 4 trial designed to compare a biodegradable polymer DES with permanent polymer stents. Within the permanent polymer arm of 1,304 subjects, patients were randomized 1:1 to receive either the Xience or Cypher stent.

At 2 years – a longer follow-up period than in SORT OUT I – there were no significant differences in the combined primary end point of cardiac death, target-vessel–related myocardial infarction, and target lesion revascularization (16% in Xience-treated patients and 18.8% in Cypher-treated patients), reported Dr. Robert A. Byrne of Deutsches Herzzentrum in Munich.

The rates of definite or probable stent thrombosis at 2 years – the secondary, safety end point of the study – were also similar (1.4% in those who received the everolimus-eluting stent and 1.9% in patients treated with the sirolimus-eluting stent).

There was a trend toward superior antirestenotic efficacy with the Xience stent, but “specifically powered studies are needed to evaluate the clinical significance of this finding,” said Dr. Byrne. (Target lesion revascularization occurred in 9.9% of Xience-treated patients and 13.5% of the Cypher-treated patients.)

The Cypher Select Plus sirolimus-eluting stent that was used in the SORT OUT IV trial is a version of the Cypher stent that is not commercially available in the United States. U.S. physicians who discussed the trial said they have no reason to believe results would be different with other Cypher stent products.

WASHINGTON – Treating symptomatic femoropopliteal artery disease with a paclitaxel-eluting peripheral stent beat both percutaneous transluminal angioplasty and provisional bare-metal stenting in achieving vessel patency rates at 12 months in a prospective, randomized trial.

With the increasing development of dedicated devices for peripheral lesions, more interventional cardiologists have become interested in peripheral interventions. Other drug-eluting stents that were tested in previous trials failed, however, to show significant differences in outcome, compared with those of bare-metal stenting.

This trial was different. In one major finding of the multitiered study, patency rates at 12 months were 83.1% with Cook Medical Inc.’s paclitaxel-eluting Zilver stent and 67% with “standard” care (angioplasty with provisional bare-metal stenting). And in a head-to-head comparison of provisional stenting, the patency rate was 89.9% with the Zilver PTX stent and 73% with the bare-metal stent.

“This is the largest randomized trial ever performed for the endovascular management of peripheral artery disease,” said principal investigator Dr. Michael D. Dake, who presented the results of the industry-sponsored Zilver PTX trial at the Transcatheter Cardiovascular Therapeutics 2010.

“I think it’s a signal that it’s possible to improve the results of current therapies for PAD with a combination of both drugs and mechanical devices,” he said in a press conference.

The trial enrolled 479 patients at 55 sites in the United States, Germany, and Japan. Patients had symptomatic disease of the above-the-knee femoropopliteal artery (most were moderately to severely symptomatic), as well as lesions up to 14 cm. The average lesion length was 6.6 cm, and vessel diameter was 4-9 mm.

In the first of two randomization protocols, patients were randomized to treatment with either conventional percutaneous transluminal angioplasty (PTA) or with the Zilver PTX stent, a self-expanding nitinol stent with a polymer-free paclitaxel coating. After 1 year, 83.1% of the vessels that were treated with the paclitaxel-eluting stent were still patent, compared with 32.8% of the vessels in the PTA-treated group.

Patency was defined as peak systolic velocity ratio less than 2.0 as measured by duplex ultrasonography, or diameter stenosis less than 50% as determined by angiography.

However, PTA failed to restore primary patency in approximately half of the patients in the PTA group – a rate seen in other trials. When the Zilver PTX stent was compared with “optimal” PTA (only those who achieved optimal results after primary PTA), the Zilver stent still performed significantly better, at 83.1% vs. 65.3%.

In the secondary randomization, the “suboptimal” PTA group (those who failed primary PTA) was randomized again to receive either a bare-metal Zilver stent or the paclitaxel-eluting version. In this comparison of provisional stenting, 12-month patency rates were 89.9% in the Zilver PTX group and 73% in the bare-metal stent group.

In other words, the 12-month restenosis rates were 10.1% with the Zilver PTX stent and 27% with the bare-metal stent, said Dr. Dake of Stanford (Calif.) University.

In another analysis crossing both tiers, the investigators compared primary use of the paclitaxel-eluting stent with the “real-world standard of care” in a group that comprised patients whose PTA treatment was optimal as well as those who received bare-metal stents after their PTA had failed. This “standard of care” group had a patency rate of 67%, significantly less than the 83.1% patency rate of the primary Zilver PTX group.

The primary safety end point was 12-month, event-free survival, which included freedom from amputation, target lesion revascularization, and significant worsening of claudication. Event-free survival was 90.4% in the patients who were initially randomized for treatment with the Zilver PTX stent and 82.6% in the PTA group.

There was “only a 0.9% stent fracture rate through 12 months,” and none of the four stent fractures that occurred had any clinical sequelae, said Dr. Dake.

Moreover, subgroup studies with intravascular ultrasound and angiography showed “no evidence of untoward effects [of the drug] or complications of the device,” and there were no cases of acute stent thrombosis, he reported. Patients in the trial were on a dual antiplatelet regimen for at least 2 months. At 12 months, “61% of patients had remained on it,” Dr. Dake said.

Dr. John Laird of the University of California, Davis, Medical Center said that longer-term results are critical since “there’s potential for late restenosis” resulting from the “chronic injury and chronic irritation” caused by stents. “The big difference here is that there’s no polymer on the stent to be a source of irritation as well,” he said.

It is also uncertain whether the patency results can be replicated with the longer lesions that are typically seen in PAD in the “real world,” panelists said.

(Investigators in the current randomized trial were limited, per the Food and Drug Administration–approved study protocol, to treat lesions that were no longer than 14 cm, Dr. Dake said.)

Dr. Hans Krankenberg of the cardiovascular center at the University of Hamburg (Germany) said that an ongoing international Zilver PTX registry is showing, thus far, that “the findings from this trial can be transferred to almost all [other lesions].”

Patients in the randomized trial had an average age of 68 years, and almost half had diabetes.

Clinical outcomes, which will be presented later, mirror the patency findings, Dr. Dake said. There will be ongoing follow-up through 5 years.

Dr. William A. Gray, director of endovascular services at Columbia University Medical Center, New York, who moderated a discussion of the study at the meeting, noted that the Zilver PTX trial followed both the SIROCCO trial, which tested a sirolimus-eluting, durable polymer–coated SMART stent against a bare-metal stent in patients with femoropopliteal disease, and the STRIDES trial, which tested an everolimus-eluting, durable polymer–coated ABSOLUTE stent. Both studies failed to show any real efficacy at reducing restenosis.

The Zilver PTX stent lacks a durable polymer and delivers paclitaxel rather than a limus drug, which raises questions about the causal mechanisms for its unprecedented success, Dr. Gray said. There are also questions about how its effectiveness in the shorter lesions in this trial can be extrapolated to real-world lesion lengths of 20 cm and even 30 cm. Nevertheless, he noted, this positive trial is a critically important proof of concept, and potentially groundbreaking in the way superficial femoral artery disease and popliteal treatment will be viewed from now on.

The Zilver PTX stent is currently available in Europe. In the United States, Cook Medical has submitted a premarket approval application to the FDA, a company spokesperson said.

The trial was sponsored by Cook Medical, which manufactures the Zilver PTX stent. Dr. Dake disclosed that he had clinical trial support from Cook Medical, consulting fees/honoraria from W.L. Gore and Abbott Vascular, and equity interest/stock options in various device companies. Dr. Gray is a consultant for Cook Medical, which manufactures the Zilver PTX stent, as well as Abbott Vascular and Cordis/Johnson and Johnson.

* Correction, Oct. 20, 2010: The original version of this article incorrectly referred to Zilver PTX as Zenith PTX on several references. This version has been updated. 

WASHINGTON – Treating symptomatic femoropopliteal artery disease with a paclitaxel-eluting peripheral stent beat both percutaneous transluminal angioplasty and provisional bare-metal stenting in achieving vessel patency rates at 12 months in a prospective, randomized trial.

With the increasing development of dedicated devices for peripheral lesions, more interventional cardiologists have become interested in peripheral interventions. Other drug-eluting stents that were tested in previous trials failed, however, to show significant differences in outcome, compared with those of bare-metal stenting.

This trial was different. In one major finding of the multitiered study, patency rates at 12 months were 83.1% with Cook Medical Inc.’s paclitaxel-eluting Zilver stent and 67% with “standard” care (angioplasty with provisional bare-metal stenting). And in a head-to-head comparison of provisional stenting, the patency rate was 89.9% with the Zilver PTX stent and 73% with the bare-metal stent.

“This is the largest randomized trial ever performed for the endovascular management of peripheral artery disease,” said principal investigator Dr. Michael D. Dake, who presented the results of the industry-sponsored Zilver PTX trial at the Transcatheter Cardiovascular Therapeutics 2010.

“I think it’s a signal that it’s possible to improve the results of current therapies for PAD with a combination of both drugs and mechanical devices,” he said in a press conference.

The trial enrolled 479 patients at 55 sites in the United States, Germany, and Japan. Patients had symptomatic disease of the above-the-knee femoropopliteal artery (most were moderately to severely symptomatic), as well as lesions up to 14 cm. The average lesion length was 6.6 cm, and vessel diameter was 4-9 mm.

In the first of two randomization protocols, patients were randomized to treatment with either conventional percutaneous transluminal angioplasty (PTA) or with the Zilver PTX stent, a self-expanding nitinol stent with a polymer-free paclitaxel coating. After 1 year, 83.1% of the vessels that were treated with the paclitaxel-eluting stent were still patent, compared with 32.8% of the vessels in the PTA-treated group.

Patency was defined as peak systolic velocity ratio less than 2.0 as measured by duplex ultrasonography, or diameter stenosis less than 50% as determined by angiography.

However, PTA failed to restore primary patency in approximately half of the patients in the PTA group – a rate seen in other trials. When the Zilver PTX stent was compared with “optimal” PTA (only those who achieved optimal results after primary PTA), the Zilver stent still performed significantly better, at 83.1% vs. 65.3%.

In the secondary randomization, the “suboptimal” PTA group (those who failed primary PTA) was randomized again to receive either a bare-metal Zilver stent or the paclitaxel-eluting version. In this comparison of provisional stenting, 12-month patency rates were 89.9% in the Zilver PTX group and 73% in the bare-metal stent group.

In other words, the 12-month restenosis rates were 10.1% with the Zilver PTX stent and 27% with the bare-metal stent, said Dr. Dake of Stanford (Calif.) University.

In another analysis crossing both tiers, the investigators compared primary use of the paclitaxel-eluting stent with the “real-world standard of care” in a group that comprised patients whose PTA treatment was optimal as well as those who received bare-metal stents after their PTA had failed. This “standard of care” group had a patency rate of 67%, significantly less than the 83.1% patency rate of the primary Zilver PTX group.

The primary safety end point was 12-month, event-free survival, which included freedom from amputation, target lesion revascularization, and significant worsening of claudication. Event-free survival was 90.4% in the patients who were initially randomized for treatment with the Zilver PTX stent and 82.6% in the PTA group.

There was “only a 0.9% stent fracture rate through 12 months,” and none of the four stent fractures that occurred had any clinical sequelae, said Dr. Dake.

Moreover, subgroup studies with intravascular ultrasound and angiography showed “no evidence of untoward effects [of the drug] or complications of the device,” and there were no cases of acute stent thrombosis, he reported. Patients in the trial were on a dual antiplatelet regimen for at least 2 months. At 12 months, “61% of patients had remained on it,” Dr. Dake said.

Dr. John Laird of the University of California, Davis, Medical Center said that longer-term results are critical since “there’s potential for late restenosis” resulting from the “chronic injury and chronic irritation” caused by stents. “The big difference here is that there’s no polymer on the stent to be a source of irritation as well,” he said.

It is also uncertain whether the patency results can be replicated with the longer lesions that are typically seen in PAD in the “real world,” panelists said.

(Investigators in the current randomized trial were limited, per the Food and Drug Administration–approved study protocol, to treat lesions that were no longer than 14 cm, Dr. Dake said.)

Dr. Hans Krankenberg of the cardiovascular center at the University of Hamburg (Germany) said that an ongoing international Zilver PTX registry is showing, thus far, that “the findings from this trial can be transferred to almost all [other lesions].”

Patients in the randomized trial had an average age of 68 years, and almost half had diabetes.

Clinical outcomes, which will be presented later, mirror the patency findings, Dr. Dake said. There will be ongoing follow-up through 5 years.

Dr. William A. Gray, director of endovascular services at Columbia University Medical Center, New York, who moderated a discussion of the study at the meeting, noted that the Zilver PTX trial followed both the SIROCCO trial, which tested a sirolimus-eluting, durable polymer–coated SMART stent against a bare-metal stent in patients with femoropopliteal disease, and the STRIDES trial, which tested an everolimus-eluting, durable polymer–coated ABSOLUTE stent. Both studies failed to show any real efficacy at reducing restenosis.

The Zilver PTX stent lacks a durable polymer and delivers paclitaxel rather than a limus drug, which raises questions about the causal mechanisms for its unprecedented success, Dr. Gray said. There are also questions about how its effectiveness in the shorter lesions in this trial can be extrapolated to real-world lesion lengths of 20 cm and even 30 cm. Nevertheless, he noted, this positive trial is a critically important proof of concept, and potentially groundbreaking in the way superficial femoral artery disease and popliteal treatment will be viewed from now on.

The Zilver PTX stent is currently available in Europe. In the United States, Cook Medical has submitted a premarket approval application to the FDA, a company spokesperson said.

The trial was sponsored by Cook Medical, which manufactures the Zilver PTX stent. Dr. Dake disclosed that he had clinical trial support from Cook Medical, consulting fees/honoraria from W.L. Gore and Abbott Vascular, and equity interest/stock options in various device companies. Dr. Gray is a consultant for Cook Medical, which manufactures the Zilver PTX stent, as well as Abbott Vascular and Cordis/Johnson and Johnson.

* Correction, Oct. 20, 2010: The original version of this article incorrectly referred to Zilver PTX as Zenith PTX on several references. This version has been updated. 

WASHINGTON – Treating symptomatic femoropopliteal artery disease with a paclitaxel-eluting peripheral stent beat both percutaneous transluminal angioplasty and provisional bare-metal stenting in achieving vessel patency rates at 12 months in a prospective, randomized trial.

With the increasing development of dedicated devices for peripheral lesions, more interventional cardiologists have become interested in peripheral interventions. Other drug-eluting stents that were tested in previous trials failed, however, to show significant differences in outcome, compared with those of bare-metal stenting.

This trial was different. In one major finding of the multitiered study, patency rates at 12 months were 83.1% with Cook Medical Inc.’s paclitaxel-eluting Zilver stent and 67% with “standard” care (angioplasty with provisional bare-metal stenting). And in a head-to-head comparison of provisional stenting, the patency rate was 89.9% with the Zilver PTX stent and 73% with the bare-metal stent.

“This is the largest randomized trial ever performed for the endovascular management of peripheral artery disease,” said principal investigator Dr. Michael D. Dake, who presented the results of the industry-sponsored Zilver PTX trial at the Transcatheter Cardiovascular Therapeutics 2010.

“I think it’s a signal that it’s possible to improve the results of current therapies for PAD with a combination of both drugs and mechanical devices,” he said in a press conference.

The trial enrolled 479 patients at 55 sites in the United States, Germany, and Japan. Patients had symptomatic disease of the above-the-knee femoropopliteal artery (most were moderately to severely symptomatic), as well as lesions up to 14 cm. The average lesion length was 6.6 cm, and vessel diameter was 4-9 mm.

In the first of two randomization protocols, patients were randomized to treatment with either conventional percutaneous transluminal angioplasty (PTA) or with the Zilver PTX stent, a self-expanding nitinol stent with a polymer-free paclitaxel coating. After 1 year, 83.1% of the vessels that were treated with the paclitaxel-eluting stent were still patent, compared with 32.8% of the vessels in the PTA-treated group.

Patency was defined as peak systolic velocity ratio less than 2.0 as measured by duplex ultrasonography, or diameter stenosis less than 50% as determined by angiography.

However, PTA failed to restore primary patency in approximately half of the patients in the PTA group – a rate seen in other trials. When the Zilver PTX stent was compared with “optimal” PTA (only those who achieved optimal results after primary PTA), the Zilver stent still performed significantly better, at 83.1% vs. 65.3%.

In the secondary randomization, the “suboptimal” PTA group (those who failed primary PTA) was randomized again to receive either a bare-metal Zilver stent or the paclitaxel-eluting version. In this comparison of provisional stenting, 12-month patency rates were 89.9% in the Zilver PTX group and 73% in the bare-metal stent group.

In other words, the 12-month restenosis rates were 10.1% with the Zilver PTX stent and 27% with the bare-metal stent, said Dr. Dake of Stanford (Calif.) University.

In another analysis crossing both tiers, the investigators compared primary use of the paclitaxel-eluting stent with the “real-world standard of care” in a group that comprised patients whose PTA treatment was optimal as well as those who received bare-metal stents after their PTA had failed. This “standard of care” group had a patency rate of 67%, significantly less than the 83.1% patency rate of the primary Zilver PTX group.

The primary safety end point was 12-month, event-free survival, which included freedom from amputation, target lesion revascularization, and significant worsening of claudication. Event-free survival was 90.4% in the patients who were initially randomized for treatment with the Zilver PTX stent and 82.6% in the PTA group.

There was “only a 0.9% stent fracture rate through 12 months,” and none of the four stent fractures that occurred had any clinical sequelae, said Dr. Dake.

Moreover, subgroup studies with intravascular ultrasound and angiography showed “no evidence of untoward effects [of the drug] or complications of the device,” and there were no cases of acute stent thrombosis, he reported. Patients in the trial were on a dual antiplatelet regimen for at least 2 months. At 12 months, “61% of patients had remained on it,” Dr. Dake said.

Dr. John Laird of the University of California, Davis, Medical Center said that longer-term results are critical since “there’s potential for late restenosis” resulting from the “chronic injury and chronic irritation” caused by stents. “The big difference here is that there’s no polymer on the stent to be a source of irritation as well,” he said.

It is also uncertain whether the patency results can be replicated with the longer lesions that are typically seen in PAD in the “real world,” panelists said.

(Investigators in the current randomized trial were limited, per the Food and Drug Administration–approved study protocol, to treat lesions that were no longer than 14 cm, Dr. Dake said.)

Dr. Hans Krankenberg of the cardiovascular center at the University of Hamburg (Germany) said that an ongoing international Zilver PTX registry is showing, thus far, that “the findings from this trial can be transferred to almost all [other lesions].”

Patients in the randomized trial had an average age of 68 years, and almost half had diabetes.

Clinical outcomes, which will be presented later, mirror the patency findings, Dr. Dake said. There will be ongoing follow-up through 5 years.

Dr. William A. Gray, director of endovascular services at Columbia University Medical Center, New York, who moderated a discussion of the study at the meeting, noted that the Zilver PTX trial followed both the SIROCCO trial, which tested a sirolimus-eluting, durable polymer–coated SMART stent against a bare-metal stent in patients with femoropopliteal disease, and the STRIDES trial, which tested an everolimus-eluting, durable polymer–coated ABSOLUTE stent. Both studies failed to show any real efficacy at reducing restenosis.

The Zilver PTX stent lacks a durable polymer and delivers paclitaxel rather than a limus drug, which raises questions about the causal mechanisms for its unprecedented success, Dr. Gray said. There are also questions about how its effectiveness in the shorter lesions in this trial can be extrapolated to real-world lesion lengths of 20 cm and even 30 cm. Nevertheless, he noted, this positive trial is a critically important proof of concept, and potentially groundbreaking in the way superficial femoral artery disease and popliteal treatment will be viewed from now on.

The Zilver PTX stent is currently available in Europe. In the United States, Cook Medical has submitted a premarket approval application to the FDA, a company spokesperson said.

The trial was sponsored by Cook Medical, which manufactures the Zilver PTX stent. Dr. Dake disclosed that he had clinical trial support from Cook Medical, consulting fees/honoraria from W.L. Gore and Abbott Vascular, and equity interest/stock options in various device companies. Dr. Gray is a consultant for Cook Medical, which manufactures the Zilver PTX stent, as well as Abbott Vascular and Cordis/Johnson and Johnson.

* Correction, Oct. 20, 2010: The original version of this article incorrectly referred to Zilver PTX as Zenith PTX on several references. This version has been updated. 

WASHINGTON – Treating symptomatic femoropopliteal artery disease with a paclitaxel-eluting peripheral stent beat both percutaneous transluminal angioplasty and provisional bare-metal stenting in achieving vessel patency rates at 12 months in a prospective, randomized trial.

With the increasing development of dedicated devices for peripheral lesions, more interventional cardiologists have become interested in peripheral interventions. Other drug-eluting stents that were tested in previous trials failed, however, to show significant differences in outcome, compared with those of bare-metal stenting.

This trial was different. In one major finding of the multitiered study, patency rates at 12 months were 83.1% with Cook Medical Inc.’s paclitaxel-eluting Zilver stent and 67% with “standard” care (angioplasty with provisional bare-metal stenting). And in a head-to-head comparison of provisional stenting, the patency rate was 89.9% with the Zilver PTX stent and 73% with the bare-metal stent.

“This is the largest randomized trial ever performed for the endovascular management of peripheral artery disease,” said principal investigator Dr. Michael D. Dake, who presented the results of the industry-sponsored Zilver PTX trial at the Transcatheter Cardiovascular Therapeutics 2010.

“I think it’s a signal that it’s possible to improve the results of current therapies for PAD with a combination of both drugs and mechanical devices,” he said in a press conference.

The trial enrolled 479 patients at 55 sites in the United States, Germany, and Japan. Patients had symptomatic disease of the above-the-knee femoropopliteal artery (most were moderately to severely symptomatic), as well as lesions up to 14 cm. The average lesion length was 6.6 cm, and vessel diameter was 4-9 mm.

In the first of two randomization protocols, patients were randomized to treatment with either conventional percutaneous transluminal angioplasty (PTA) or with the Zilver PTX stent, a self-expanding nitinol stent with a polymer-free paclitaxel coating. After 1 year, 83.1% of the vessels that were treated with the paclitaxel-eluting stent were still patent, compared with 32.8% of the vessels in the PTA-treated group.

Patency was defined as peak systolic velocity ratio less than 2.0 as measured by duplex ultrasonography, or diameter stenosis less than 50% as determined by angiography.

However, PTA failed to restore primary patency in approximately half of the patients in the PTA group – a rate seen in other trials. When the Zilver PTX stent was compared with “optimal” PTA (only those who achieved optimal results after primary PTA), the Zilver stent still performed significantly better, at 83.1% vs. 65.3%.

In the secondary randomization, the “suboptimal” PTA group (those who failed primary PTA) was randomized again to receive either a bare-metal Zilver stent or the paclitaxel-eluting version. In this comparison of provisional stenting, 12-month patency rates were 89.9% in the Zilver PTX group and 73% in the bare-metal stent group.

In other words, the 12-month restenosis rates were 10.1% with the Zilver PTX stent and 27% with the bare-metal stent, said Dr. Dake of Stanford (Calif.) University.

In another analysis crossing both tiers, the investigators compared primary use of the paclitaxel-eluting stent with the “real-world standard of care” in a group that comprised patients whose PTA treatment was optimal as well as those who received bare-metal stents after their PTA had failed. This “standard of care” group had a patency rate of 67%, significantly less than the 83.1% patency rate of the primary Zilver PTX group.

The primary safety end point was 12-month, event-free survival, which included freedom from amputation, target lesion revascularization, and significant worsening of claudication. Event-free survival was 90.4% in the patients who were initially randomized for treatment with the Zilver PTX stent and 82.6% in the PTA group.

There was “only a 0.9% stent fracture rate through 12 months,” and none of the four stent fractures that occurred had any clinical sequelae, said Dr. Dake.

Moreover, subgroup studies with intravascular ultrasound and angiography showed “no evidence of untoward effects [of the drug] or complications of the device,” and there were no cases of acute stent thrombosis, he reported. Patients in the trial were on a dual antiplatelet regimen for at least 2 months. At 12 months, “61% of patients had remained on it,” Dr. Dake said.

Dr. John Laird of the University of California, Davis, Medical Center said that longer-term results are critical since “there’s potential for late restenosis” resulting from the “chronic injury and chronic irritation” caused by stents. “The big difference here is that there’s no polymer on the stent to be a source of irritation as well,” he said.

It is also uncertain whether the patency results can be replicated with the longer lesions that are typically seen in PAD in the “real world,” panelists said.

(Investigators in the current randomized trial were limited, per the Food and Drug Administration–approved study protocol, to treat lesions that were no longer than 14 cm, Dr. Dake said.)

Dr. Hans Krankenberg of the cardiovascular center at the University of Hamburg (Germany) said that an ongoing international Zilver PTX registry is showing, thus far, that “the findings from this trial can be transferred to almost all [other lesions].”

Patients in the randomized trial had an average age of 68 years, and almost half had diabetes.

Clinical outcomes, which will be presented later, mirror the patency findings, Dr. Dake said. There will be ongoing follow-up through 5 years.

Dr. William A. Gray, director of endovascular services at Columbia University Medical Center, New York, who moderated a discussion of the study at the meeting, noted that the Zilver PTX trial followed both the SIROCCO trial, which tested a sirolimus-eluting, durable polymer–coated SMART stent against a bare-metal stent in patients with femoropopliteal disease, and the STRIDES trial, which tested an everolimus-eluting, durable polymer–coated ABSOLUTE stent. Both studies failed to show any real efficacy at reducing restenosis.

The Zilver PTX stent lacks a durable polymer and delivers paclitaxel rather than a limus drug, which raises questions about the causal mechanisms for its unprecedented success, Dr. Gray said. There are also questions about how its effectiveness in the shorter lesions in this trial can be extrapolated to real-world lesion lengths of 20 cm and even 30 cm. Nevertheless, he noted, this positive trial is a critically important proof of concept, and potentially groundbreaking in the way superficial femoral artery disease and popliteal treatment will be viewed from now on.

The Zilver PTX stent is currently available in Europe. In the United States, Cook Medical has submitted a premarket approval application to the FDA, a company spokesperson said.

The trial was sponsored by Cook Medical, which manufactures the Zilver PTX stent. Dr. Dake disclosed that he had clinical trial support from Cook Medical, consulting fees/honoraria from W.L. Gore and Abbott Vascular, and equity interest/stock options in various device companies. Dr. Gray is a consultant for Cook Medical, which manufactures the Zilver PTX stent, as well as Abbott Vascular and Cordis/Johnson and Johnson.

* Correction, Oct. 20, 2010: The original version of this article incorrectly referred to Zilver PTX as Zenith PTX on several references. This version has been updated. 

WASHINGTON – Treating symptomatic femoropopliteal artery disease with a paclitaxel-eluting peripheral stent beat both percutaneous transluminal angioplasty and provisional bare-metal stenting in achieving vessel patency rates at 12 months in a prospective, randomized trial.

With the increasing development of dedicated devices for peripheral lesions, more interventional cardiologists have become interested in peripheral interventions. Other drug-eluting stents that were tested in previous trials failed, however, to show significant differences in outcome, compared with those of bare-metal stenting.

This trial was different. In one major finding of the multitiered study, patency rates at 12 months were 83.1% with Cook Medical Inc.’s paclitaxel-eluting Zilver stent and 67% with “standard” care (angioplasty with provisional bare-metal stenting). And in a head-to-head comparison of provisional stenting, the patency rate was 89.9% with the Zilver PTX stent and 73% with the bare-metal stent.

“This is the largest randomized trial ever performed for the endovascular management of peripheral artery disease,” said principal investigator Dr. Michael D. Dake, who presented the results of the industry-sponsored Zilver PTX trial at the Transcatheter Cardiovascular Therapeutics 2010.

“I think it’s a signal that it’s possible to improve the results of current therapies for PAD with a combination of both drugs and mechanical devices,” he said in a press conference.

The trial enrolled 479 patients at 55 sites in the United States, Germany, and Japan. Patients had symptomatic disease of the above-the-knee femoropopliteal artery (most were moderately to severely symptomatic), as well as lesions up to 14 cm. The average lesion length was 6.6 cm, and vessel diameter was 4-9 mm.

In the first of two randomization protocols, patients were randomized to treatment with either conventional percutaneous transluminal angioplasty (PTA) or with the Zilver PTX stent, a self-expanding nitinol stent with a polymer-free paclitaxel coating. After 1 year, 83.1% of the vessels that were treated with the paclitaxel-eluting stent were still patent, compared with 32.8% of the vessels in the PTA-treated group.

Patency was defined as peak systolic velocity ratio less than 2.0 as measured by duplex ultrasonography, or diameter stenosis less than 50% as determined by angiography.

However, PTA failed to restore primary patency in approximately half of the patients in the PTA group – a rate seen in other trials. When the Zilver PTX stent was compared with “optimal” PTA (only those who achieved optimal results after primary PTA), the Zilver stent still performed significantly better, at 83.1% vs. 65.3%.

In the secondary randomization, the “suboptimal” PTA group (those who failed primary PTA) was randomized again to receive either a bare-metal Zilver stent or the paclitaxel-eluting version. In this comparison of provisional stenting, 12-month patency rates were 89.9% in the Zilver PTX group and 73% in the bare-metal stent group.

In other words, the 12-month restenosis rates were 10.1% with the Zilver PTX stent and 27% with the bare-metal stent, said Dr. Dake of Stanford (Calif.) University.

In another analysis crossing both tiers, the investigators compared primary use of the paclitaxel-eluting stent with the “real-world standard of care” in a group that comprised patients whose PTA treatment was optimal as well as those who received bare-metal stents after their PTA had failed. This “standard of care” group had a patency rate of 67%, significantly less than the 83.1% patency rate of the primary Zilver PTX group.

The primary safety end point was 12-month, event-free survival, which included freedom from amputation, target lesion revascularization, and significant worsening of claudication. Event-free survival was 90.4% in the patients who were initially randomized for treatment with the Zilver PTX stent and 82.6% in the PTA group.

There was “only a 0.9% stent fracture rate through 12 months,” and none of the four stent fractures that occurred had any clinical sequelae, said Dr. Dake.

Moreover, subgroup studies with intravascular ultrasound and angiography showed “no evidence of untoward effects [of the drug] or complications of the device,” and there were no cases of acute stent thrombosis, he reported. Patients in the trial were on a dual antiplatelet regimen for at least 2 months. At 12 months, “61% of patients had remained on it,” Dr. Dake said.

Dr. John Laird of the University of California, Davis, Medical Center said that longer-term results are critical since “there’s potential for late restenosis” resulting from the “chronic injury and chronic irritation” caused by stents. “The big difference here is that there’s no polymer on the stent to be a source of irritation as well,” he said.

It is also uncertain whether the patency results can be replicated with the longer lesions that are typically seen in PAD in the “real world,” panelists said.

(Investigators in the current randomized trial were limited, per the Food and Drug Administration–approved study protocol, to treat lesions that were no longer than 14 cm, Dr. Dake said.)

Dr. Hans Krankenberg of the cardiovascular center at the University of Hamburg (Germany) said that an ongoing international Zilver PTX registry is showing, thus far, that “the findings from this trial can be transferred to almost all [other lesions].”

Patients in the randomized trial had an average age of 68 years, and almost half had diabetes.

Clinical outcomes, which will be presented later, mirror the patency findings, Dr. Dake said. There will be ongoing follow-up through 5 years.

Dr. William A. Gray, director of endovascular services at Columbia University Medical Center, New York, who moderated a discussion of the study at the meeting, noted that the Zilver PTX trial followed both the SIROCCO trial, which tested a sirolimus-eluting, durable polymer–coated SMART stent against a bare-metal stent in patients with femoropopliteal disease, and the STRIDES trial, which tested an everolimus-eluting, durable polymer–coated ABSOLUTE stent. Both studies failed to show any real efficacy at reducing restenosis.

The Zilver PTX stent lacks a durable polymer and delivers paclitaxel rather than a limus drug, which raises questions about the causal mechanisms for its unprecedented success, Dr. Gray said. There are also questions about how its effectiveness in the shorter lesions in this trial can be extrapolated to real-world lesion lengths of 20 cm and even 30 cm. Nevertheless, he noted, this positive trial is a critically important proof of concept, and potentially groundbreaking in the way superficial femoral artery disease and popliteal treatment will be viewed from now on.

The Zilver PTX stent is currently available in Europe. In the United States, Cook Medical has submitted a premarket approval application to the FDA, a company spokesperson said.

The trial was sponsored by Cook Medical, which manufactures the Zilver PTX stent. Dr. Dake disclosed that he had clinical trial support from Cook Medical, consulting fees/honoraria from W.L. Gore and Abbott Vascular, and equity interest/stock options in various device companies. Dr. Gray is a consultant for Cook Medical, which manufactures the Zilver PTX stent, as well as Abbott Vascular and Cordis/Johnson and Johnson.

* Correction, Oct. 20, 2010: The original version of this article incorrectly referred to Zilver PTX as Zenith PTX on several references. This version has been updated. 

WASHINGTON – Treating symptomatic femoropopliteal artery disease with a paclitaxel-eluting peripheral stent beat both percutaneous transluminal angioplasty and provisional bare-metal stenting in achieving vessel patency rates at 12 months in a prospective, randomized trial.

With the increasing development of dedicated devices for peripheral lesions, more interventional cardiologists have become interested in peripheral interventions. Other drug-eluting stents that were tested in previous trials failed, however, to show significant differences in outcome, compared with those of bare-metal stenting.

This trial was different. In one major finding of the multitiered study, patency rates at 12 months were 83.1% with Cook Medical Inc.’s paclitaxel-eluting Zilver stent and 67% with “standard” care (angioplasty with provisional bare-metal stenting). And in a head-to-head comparison of provisional stenting, the patency rate was 89.9% with the Zilver PTX stent and 73% with the bare-metal stent.

“This is the largest randomized trial ever performed for the endovascular management of peripheral artery disease,” said principal investigator Dr. Michael D. Dake, who presented the results of the industry-sponsored Zilver PTX trial at the Transcatheter Cardiovascular Therapeutics 2010.

“I think it’s a signal that it’s possible to improve the results of current therapies for PAD with a combination of both drugs and mechanical devices,” he said in a press conference.

The trial enrolled 479 patients at 55 sites in the United States, Germany, and Japan. Patients had symptomatic disease of the above-the-knee femoropopliteal artery (most were moderately to severely symptomatic), as well as lesions up to 14 cm. The average lesion length was 6.6 cm, and vessel diameter was 4-9 mm.

In the first of two randomization protocols, patients were randomized to treatment with either conventional percutaneous transluminal angioplasty (PTA) or with the Zilver PTX stent, a self-expanding nitinol stent with a polymer-free paclitaxel coating. After 1 year, 83.1% of the vessels that were treated with the paclitaxel-eluting stent were still patent, compared with 32.8% of the vessels in the PTA-treated group.

Patency was defined as peak systolic velocity ratio less than 2.0 as measured by duplex ultrasonography, or diameter stenosis less than 50% as determined by angiography.

However, PTA failed to restore primary patency in approximately half of the patients in the PTA group – a rate seen in other trials. When the Zilver PTX stent was compared with “optimal” PTA (only those who achieved optimal results after primary PTA), the Zilver stent still performed significantly better, at 83.1% vs. 65.3%.

In the secondary randomization, the “suboptimal” PTA group (those who failed primary PTA) was randomized again to receive either a bare-metal Zilver stent or the paclitaxel-eluting version. In this comparison of provisional stenting, 12-month patency rates were 89.9% in the Zilver PTX group and 73% in the bare-metal stent group.

In other words, the 12-month restenosis rates were 10.1% with the Zilver PTX stent and 27% with the bare-metal stent, said Dr. Dake of Stanford (Calif.) University.

In another analysis crossing both tiers, the investigators compared primary use of the paclitaxel-eluting stent with the “real-world standard of care” in a group that comprised patients whose PTA treatment was optimal as well as those who received bare-metal stents after their PTA had failed. This “standard of care” group had a patency rate of 67%, significantly less than the 83.1% patency rate of the primary Zilver PTX group.

The primary safety end point was 12-month, event-free survival, which included freedom from amputation, target lesion revascularization, and significant worsening of claudication. Event-free survival was 90.4% in the patients who were initially randomized for treatment with the Zilver PTX stent and 82.6% in the PTA group.

There was “only a 0.9% stent fracture rate through 12 months,” and none of the four stent fractures that occurred had any clinical sequelae, said Dr. Dake.

Moreover, subgroup studies with intravascular ultrasound and angiography showed “no evidence of untoward effects [of the drug] or complications of the device,” and there were no cases of acute stent thrombosis, he reported. Patients in the trial were on a dual antiplatelet regimen for at least 2 months. At 12 months, “61% of patients had remained on it,” Dr. Dake said.

Dr. John Laird of the University of California, Davis, Medical Center said that longer-term results are critical since “there’s potential for late restenosis” resulting from the “chronic injury and chronic irritation” caused by stents. “The big difference here is that there’s no polymer on the stent to be a source of irritation as well,” he said.

It is also uncertain whether the patency results can be replicated with the longer lesions that are typically seen in PAD in the “real world,” panelists said.

(Investigators in the current randomized trial were limited, per the Food and Drug Administration–approved study protocol, to treat lesions that were no longer than 14 cm, Dr. Dake said.)

Dr. Hans Krankenberg of the cardiovascular center at the University of Hamburg (Germany) said that an ongoing international Zilver PTX registry is showing, thus far, that “the findings from this trial can be transferred to almost all [other lesions].”

Patients in the randomized trial had an average age of 68 years, and almost half had diabetes.

Clinical outcomes, which will be presented later, mirror the patency findings, Dr. Dake said. There will be ongoing follow-up through 5 years.

Dr. William A. Gray, director of endovascular services at Columbia University Medical Center, New York, who moderated a discussion of the study at the meeting, noted that the Zilver PTX trial followed both the SIROCCO trial, which tested a sirolimus-eluting, durable polymer–coated SMART stent against a bare-metal stent in patients with femoropopliteal disease, and the STRIDES trial, which tested an everolimus-eluting, durable polymer–coated ABSOLUTE stent. Both studies failed to show any real efficacy at reducing restenosis.

The Zilver PTX stent lacks a durable polymer and delivers paclitaxel rather than a limus drug, which raises questions about the causal mechanisms for its unprecedented success, Dr. Gray said. There are also questions about how its effectiveness in the shorter lesions in this trial can be extrapolated to real-world lesion lengths of 20 cm and even 30 cm. Nevertheless, he noted, this positive trial is a critically important proof of concept, and potentially groundbreaking in the way superficial femoral artery disease and popliteal treatment will be viewed from now on.

The Zilver PTX stent is currently available in Europe. In the United States, Cook Medical has submitted a premarket approval application to the FDA, a company spokesperson said.

The trial was sponsored by Cook Medical, which manufactures the Zilver PTX stent. Dr. Dake disclosed that he had clinical trial support from Cook Medical, consulting fees/honoraria from W.L. Gore and Abbott Vascular, and equity interest/stock options in various device companies. Dr. Gray is a consultant for Cook Medical, which manufactures the Zilver PTX stent, as well as Abbott Vascular and Cordis/Johnson and Johnson.

* Correction, Oct. 20, 2010: The original version of this article incorrectly referred to Zilver PTX as Zenith PTX on several references. This version has been updated. 

WASHINGTON – The benefits seen 1 year after percutaneous coronary intervention with the everolimus-eluting Xience V stent compared with the paclitaxel-eluting Taxus stent were sustained at 2 years of follow-up in two very different types of randomized studies.

And in the case of stent thrombosis in particular, the benefits of the everolimus-eluting stent appear to have intensified at 2 years, investigators reported at Transcatheter Cardiovascular Therapeutics 2010.

The new 2-year findings from both the SPIRIT IV trial, a large study involving 66 U.S. sites, and the COMPARE trial, a small, single-center, “all-comers” trial in Europe, confirm the superiority of the everolimus-eluting stent in patients – except in patients with diabetes, the investigators and other discussants said.

In patients with diabetes, no significant differences in the risk of major adverse cardiac events (MACE) were observed with either stent in either trial at 1 or 2 years after PCI, a finding that led experts at the meeting to surmise that diabetic patients may fare equally well with both stents.

“We’ve seen this now in almost every trial” comparing these drug-eluting stents. “There is no difference in MACE rates,” Dr. Gregg W. Stone of Columbia University College of Physicians and Surgeons, New York, said in a session announcing the new SPIRIT IV findings.

“In my mind, this lack of benefit [to the Xience V stent] in diabetics means without any doubt that there’s a difference in the mechanistic response of diabetics versus nondiabetics ... to these types of drugs,” he said. Dr. Stone is principal investigator for Spirit IV and codirector of medical research and education at the Cardiovascular Research Foundation, which sponsored the TCT meeting.

The 3,687 patients in the industry-sponsored SPIRIT IV trial, including 1,185 with diabetes, were randomized in 2:1 fashion to receive either the everolimus-eluting Xience V stent (Abbott Vascular) or the first-generation paclitaxel-eluting Taxus Express stent (Boston Scientific). The patients had up to three untreated coronary artery lesions that were as long as 28 mm, in vessels with a diameter of 2.5-3.75 mm.

At 2 years, treatment with Xience V resulted in a relative 30% reduction (and a 3% absolute decline) in target lesion failure compared with treatment with the Taxus stent, with target lesion failure occurring in about 6.9% and 9.9% of the patients, respectively. (The rates of this primary end point after 1 year were 4.0% and 6.9%, respectively.)

The relative reduction in target lesion failure was 39% in patients without diabetes, but in diabetic patients there was little difference between the two groups. Target lesion failure is a composite end point reflecting cardiac death, target-vessel myocardial infarction, or ischemia-driven target lesion revascularization.

Ischemia-driven target lesion revascularization, a secondary end point, occurred at a rate of 4.5% at 2 years in the Xience group compared with 6.9% in the Taxus group, for an absolute reduction of 2.4% and a relative reduction of 34%. The rates of this secondary outcome after 1 year were 2.4% compared with 4.6%.

While there were no mortality differences, target-vessel MI also occurred at a significantly reduced rate in the Xience group at both 1 and 2 years (2.3% v. 3.5% at 2 years), said Dr. Stone.

At a press conference, Dr. Dean Kereiakes said in his presentation of the 2-year SPIRIT IV findings that for every 1 million patients treated with the everolimus-eluting stent, there would be 24,000 fewer repeat revascularization procedures.

“And for every 1 million patients treated (with Xience V), there would be more than 8,000 stent thromboses prevented,” said Dr. Kereiakes of the Christ Hospital Ohio Heart and Vascular Center in Cincinnati.

The rates in stent thrombosis in both studies, in fact, drew significant attention at the meeting. At 2 years after intervention in SPIRIT IV, 1.2% in the Taxus group had developed definite/probable stent thrombosis according to definitions of the Academic Research Consortium (ARC), compared with 0.4% in the Xience arm.

This translates into a 64% relative risk reduction for stent thrombosis (a 0.8% absolute reduction) that occurred during each period – early (the first 30 days), late (31 days to 1 year) and very late period (over 1 year).

The 2-year reductions in stent thrombosis reported from the COMPARE trial were even more striking, discussants said at the meeting.

In this trial, 1,800 consecutive patients undergoing PCI at one center in Rotterdam, the Netherlands, were randomly assigned in 1:1 fashion to treatment with the Xience V stent or the Taxus Libert? stent, a second-generation paclitaxel-eluting stent.

(The Taxus Express stent used in SPIRIT IV is no longer commercially available, according to a spokesperson for Boston Scientific. The Taxus Libert? stent, which uses the same polymer but a different stent platform, is currently available in the United States and in Europe, he said.)

The rate of definite/probable stent thrombosis (again, by ARC definition) at 2 years in the COMPARE trial was 0.9% in the Xience V group and 3.9% in the Taxus group – higher rates than found in SPIRIT IV. Most notable, however, was a 77% reduction in very late definite/probable stent thrombosis in the Xience V arm. The rate of this outcome was 0.3% in the Xience V group and 1.5% in the Taxus Libert? group, reported Dr. Peter Smits of Maasstad Ziekenhuis.

This difference is especially notable because the vast majority of patients were no longer taking dual antiplatelet therapy at 2 years, said Dr. Smits, principal investigator of COMPARE. In contrast, more than 70% of patients in each arm of the SPIRIT IV trial remained on dual antiplatelet therapy at 2 years.

Unlike the SPIRIT design, the COMPARE trial was designed to be an “all-comer, real-world study” without exclusions for complex patients. At 2 years, the superiority of the Xience V stent for the primary end point – a composite of all mortality, nonfatal MI, and target vessel revascularization (MACE) – was maintained, with larger absolute differences between the stents than at 12 months.

At 1 year, this primary end point had occurred in 6.2% and 9.1% in the Xience V and Taxus groups, respectively, for an absolute difference of 2.9%. At 2 years, these rates rose to 9.0% and 13.7%, for an absolute difference of 4.7%. There were similar reductions in secondary end points. As in SPIRIT IV, there were no benefits of the Xience V stent for diabetic patients.

Both studies are still ongoing and will conclude with 5-year analyses.

The SPIRIT IV trial is sponsored by Abbott Vascular, and the COMPARE trial is funded by Abbott Vascular and Boston Scientific. Dr. Stone disclosed that he sits on the advisory boards for, and receives honoraria from, Abbott Vascular and Boston Scientific. Dr. Smits disclosed that he received a speaking fee from Abbott Vascular and that his cardiology department has received unrestricted research grants from Abbott Vascular and Boston Scientific. Dr. Kereiakes disclosed that he has received honoraria and grant support from both Abbott Vascular and Boston Scientific.

WASHINGTON – The benefits seen 1 year after percutaneous coronary intervention with the everolimus-eluting Xience V stent compared with the paclitaxel-eluting Taxus stent were sustained at 2 years of follow-up in two very different types of randomized studies.

And in the case of stent thrombosis in particular, the benefits of the everolimus-eluting stent appear to have intensified at 2 years, investigators reported at Transcatheter Cardiovascular Therapeutics 2010.

The new 2-year findings from both the SPIRIT IV trial, a large study involving 66 U.S. sites, and the COMPARE trial, a small, single-center, “all-comers” trial in Europe, confirm the superiority of the everolimus-eluting stent in patients – except in patients with diabetes, the investigators and other discussants said.

In patients with diabetes, no significant differences in the risk of major adverse cardiac events (MACE) were observed with either stent in either trial at 1 or 2 years after PCI, a finding that led experts at the meeting to surmise that diabetic patients may fare equally well with both stents.

“We’ve seen this now in almost every trial” comparing these drug-eluting stents. “There is no difference in MACE rates,” Dr. Gregg W. Stone of Columbia University College of Physicians and Surgeons, New York, said in a session announcing the new SPIRIT IV findings.

“In my mind, this lack of benefit [to the Xience V stent] in diabetics means without any doubt that there’s a difference in the mechanistic response of diabetics versus nondiabetics ... to these types of drugs,” he said. Dr. Stone is principal investigator for Spirit IV and codirector of medical research and education at the Cardiovascular Research Foundation, which sponsored the TCT meeting.

The 3,687 patients in the industry-sponsored SPIRIT IV trial, including 1,185 with diabetes, were randomized in 2:1 fashion to receive either the everolimus-eluting Xience V stent (Abbott Vascular) or the first-generation paclitaxel-eluting Taxus Express stent (Boston Scientific). The patients had up to three untreated coronary artery lesions that were as long as 28 mm, in vessels with a diameter of 2.5-3.75 mm.

At 2 years, treatment with Xience V resulted in a relative 30% reduction (and a 3% absolute decline) in target lesion failure compared with treatment with the Taxus stent, with target lesion failure occurring in about 6.9% and 9.9% of the patients, respectively. (The rates of this primary end point after 1 year were 4.0% and 6.9%, respectively.)

The relative reduction in target lesion failure was 39% in patients without diabetes, but in diabetic patients there was little difference between the two groups. Target lesion failure is a composite end point reflecting cardiac death, target-vessel myocardial infarction, or ischemia-driven target lesion revascularization.

Ischemia-driven target lesion revascularization, a secondary end point, occurred at a rate of 4.5% at 2 years in the Xience group compared with 6.9% in the Taxus group, for an absolute reduction of 2.4% and a relative reduction of 34%. The rates of this secondary outcome after 1 year were 2.4% compared with 4.6%.

While there were no mortality differences, target-vessel MI also occurred at a significantly reduced rate in the Xience group at both 1 and 2 years (2.3% v. 3.5% at 2 years), said Dr. Stone.

At a press conference, Dr. Dean Kereiakes said in his presentation of the 2-year SPIRIT IV findings that for every 1 million patients treated with the everolimus-eluting stent, there would be 24,000 fewer repeat revascularization procedures.

“And for every 1 million patients treated (with Xience V), there would be more than 8,000 stent thromboses prevented,” said Dr. Kereiakes of the Christ Hospital Ohio Heart and Vascular Center in Cincinnati.

The rates in stent thrombosis in both studies, in fact, drew significant attention at the meeting. At 2 years after intervention in SPIRIT IV, 1.2% in the Taxus group had developed definite/probable stent thrombosis according to definitions of the Academic Research Consortium (ARC), compared with 0.4% in the Xience arm.

This translates into a 64% relative risk reduction for stent thrombosis (a 0.8% absolute reduction) that occurred during each period – early (the first 30 days), late (31 days to 1 year) and very late period (over 1 year).

The 2-year reductions in stent thrombosis reported from the COMPARE trial were even more striking, discussants said at the meeting.

In this trial, 1,800 consecutive patients undergoing PCI at one center in Rotterdam, the Netherlands, were randomly assigned in 1:1 fashion to treatment with the Xience V stent or the Taxus Libert? stent, a second-generation paclitaxel-eluting stent.

(The Taxus Express stent used in SPIRIT IV is no longer commercially available, according to a spokesperson for Boston Scientific. The Taxus Libert? stent, which uses the same polymer but a different stent platform, is currently available in the United States and in Europe, he said.)

The rate of definite/probable stent thrombosis (again, by ARC definition) at 2 years in the COMPARE trial was 0.9% in the Xience V group and 3.9% in the Taxus group – higher rates than found in SPIRIT IV. Most notable, however, was a 77% reduction in very late definite/probable stent thrombosis in the Xience V arm. The rate of this outcome was 0.3% in the Xience V group and 1.5% in the Taxus Libert? group, reported Dr. Peter Smits of Maasstad Ziekenhuis.

This difference is especially notable because the vast majority of patients were no longer taking dual antiplatelet therapy at 2 years, said Dr. Smits, principal investigator of COMPARE. In contrast, more than 70% of patients in each arm of the SPIRIT IV trial remained on dual antiplatelet therapy at 2 years.

Unlike the SPIRIT design, the COMPARE trial was designed to be an “all-comer, real-world study” without exclusions for complex patients. At 2 years, the superiority of the Xience V stent for the primary end point – a composite of all mortality, nonfatal MI, and target vessel revascularization (MACE) – was maintained, with larger absolute differences between the stents than at 12 months.

At 1 year, this primary end point had occurred in 6.2% and 9.1% in the Xience V and Taxus groups, respectively, for an absolute difference of 2.9%. At 2 years, these rates rose to 9.0% and 13.7%, for an absolute difference of 4.7%. There were similar reductions in secondary end points. As in SPIRIT IV, there were no benefits of the Xience V stent for diabetic patients.

Both studies are still ongoing and will conclude with 5-year analyses.

The SPIRIT IV trial is sponsored by Abbott Vascular, and the COMPARE trial is funded by Abbott Vascular and Boston Scientific. Dr. Stone disclosed that he sits on the advisory boards for, and receives honoraria from, Abbott Vascular and Boston Scientific. Dr. Smits disclosed that he received a speaking fee from Abbott Vascular and that his cardiology department has received unrestricted research grants from Abbott Vascular and Boston Scientific. Dr. Kereiakes disclosed that he has received honoraria and grant support from both Abbott Vascular and Boston Scientific.

WASHINGTON – The benefits seen 1 year after percutaneous coronary intervention with the everolimus-eluting Xience V stent compared with the paclitaxel-eluting Taxus stent were sustained at 2 years of follow-up in two very different types of randomized studies.

And in the case of stent thrombosis in particular, the benefits of the everolimus-eluting stent appear to have intensified at 2 years, investigators reported at Transcatheter Cardiovascular Therapeutics 2010.

The new 2-year findings from both the SPIRIT IV trial, a large study involving 66 U.S. sites, and the COMPARE trial, a small, single-center, “all-comers” trial in Europe, confirm the superiority of the everolimus-eluting stent in patients – except in patients with diabetes, the investigators and other discussants said.

In patients with diabetes, no significant differences in the risk of major adverse cardiac events (MACE) were observed with either stent in either trial at 1 or 2 years after PCI, a finding that led experts at the meeting to surmise that diabetic patients may fare equally well with both stents.

“We’ve seen this now in almost every trial” comparing these drug-eluting stents. “There is no difference in MACE rates,” Dr. Gregg W. Stone of Columbia University College of Physicians and Surgeons, New York, said in a session announcing the new SPIRIT IV findings.

“In my mind, this lack of benefit [to the Xience V stent] in diabetics means without any doubt that there’s a difference in the mechanistic response of diabetics versus nondiabetics ... to these types of drugs,” he said. Dr. Stone is principal investigator for Spirit IV and codirector of medical research and education at the Cardiovascular Research Foundation, which sponsored the TCT meeting.

The 3,687 patients in the industry-sponsored SPIRIT IV trial, including 1,185 with diabetes, were randomized in 2:1 fashion to receive either the everolimus-eluting Xience V stent (Abbott Vascular) or the first-generation paclitaxel-eluting Taxus Express stent (Boston Scientific). The patients had up to three untreated coronary artery lesions that were as long as 28 mm, in vessels with a diameter of 2.5-3.75 mm.

At 2 years, treatment with Xience V resulted in a relative 30% reduction (and a 3% absolute decline) in target lesion failure compared with treatment with the Taxus stent, with target lesion failure occurring in about 6.9% and 9.9% of the patients, respectively. (The rates of this primary end point after 1 year were 4.0% and 6.9%, respectively.)

The relative reduction in target lesion failure was 39% in patients without diabetes, but in diabetic patients there was little difference between the two groups. Target lesion failure is a composite end point reflecting cardiac death, target-vessel myocardial infarction, or ischemia-driven target lesion revascularization.

Ischemia-driven target lesion revascularization, a secondary end point, occurred at a rate of 4.5% at 2 years in the Xience group compared with 6.9% in the Taxus group, for an absolute reduction of 2.4% and a relative reduction of 34%. The rates of this secondary outcome after 1 year were 2.4% compared with 4.6%.

While there were no mortality differences, target-vessel MI also occurred at a significantly reduced rate in the Xience group at both 1 and 2 years (2.3% v. 3.5% at 2 years), said Dr. Stone.

At a press conference, Dr. Dean Kereiakes said in his presentation of the 2-year SPIRIT IV findings that for every 1 million patients treated with the everolimus-eluting stent, there would be 24,000 fewer repeat revascularization procedures.

“And for every 1 million patients treated (with Xience V), there would be more than 8,000 stent thromboses prevented,” said Dr. Kereiakes of the Christ Hospital Ohio Heart and Vascular Center in Cincinnati.

The rates in stent thrombosis in both studies, in fact, drew significant attention at the meeting. At 2 years after intervention in SPIRIT IV, 1.2% in the Taxus group had developed definite/probable stent thrombosis according to definitions of the Academic Research Consortium (ARC), compared with 0.4% in the Xience arm.

This translates into a 64% relative risk reduction for stent thrombosis (a 0.8% absolute reduction) that occurred during each period – early (the first 30 days), late (31 days to 1 year) and very late period (over 1 year).

The 2-year reductions in stent thrombosis reported from the COMPARE trial were even more striking, discussants said at the meeting.

In this trial, 1,800 consecutive patients undergoing PCI at one center in Rotterdam, the Netherlands, were randomly assigned in 1:1 fashion to treatment with the Xience V stent or the Taxus Libert? stent, a second-generation paclitaxel-eluting stent.

(The Taxus Express stent used in SPIRIT IV is no longer commercially available, according to a spokesperson for Boston Scientific. The Taxus Libert? stent, which uses the same polymer but a different stent platform, is currently available in the United States and in Europe, he said.)

The rate of definite/probable stent thrombosis (again, by ARC definition) at 2 years in the COMPARE trial was 0.9% in the Xience V group and 3.9% in the Taxus group – higher rates than found in SPIRIT IV. Most notable, however, was a 77% reduction in very late definite/probable stent thrombosis in the Xience V arm. The rate of this outcome was 0.3% in the Xience V group and 1.5% in the Taxus Libert? group, reported Dr. Peter Smits of Maasstad Ziekenhuis.

This difference is especially notable because the vast majority of patients were no longer taking dual antiplatelet therapy at 2 years, said Dr. Smits, principal investigator of COMPARE. In contrast, more than 70% of patients in each arm of the SPIRIT IV trial remained on dual antiplatelet therapy at 2 years.

Unlike the SPIRIT design, the COMPARE trial was designed to be an “all-comer, real-world study” without exclusions for complex patients. At 2 years, the superiority of the Xience V stent for the primary end point – a composite of all mortality, nonfatal MI, and target vessel revascularization (MACE) – was maintained, with larger absolute differences between the stents than at 12 months.

At 1 year, this primary end point had occurred in 6.2% and 9.1% in the Xience V and Taxus groups, respectively, for an absolute difference of 2.9%. At 2 years, these rates rose to 9.0% and 13.7%, for an absolute difference of 4.7%. There were similar reductions in secondary end points. As in SPIRIT IV, there were no benefits of the Xience V stent for diabetic patients.

Both studies are still ongoing and will conclude with 5-year analyses.

The SPIRIT IV trial is sponsored by Abbott Vascular, and the COMPARE trial is funded by Abbott Vascular and Boston Scientific. Dr. Stone disclosed that he sits on the advisory boards for, and receives honoraria from, Abbott Vascular and Boston Scientific. Dr. Smits disclosed that he received a speaking fee from Abbott Vascular and that his cardiology department has received unrestricted research grants from Abbott Vascular and Boston Scientific. Dr. Kereiakes disclosed that he has received honoraria and grant support from both Abbott Vascular and Boston Scientific.

WASHINGTON – The benefits seen 1 year after percutaneous coronary intervention with the everolimus-eluting Xience V stent compared with the paclitaxel-eluting Taxus stent were sustained at 2 years of follow-up in two very different types of randomized studies.

And in the case of stent thrombosis in particular, the benefits of the everolimus-eluting stent appear to have intensified at 2 years, investigators reported at Transcatheter Cardiovascular Therapeutics 2010.

The new 2-year findings from both the SPIRIT IV trial, a large study involving 66 U.S. sites, and the COMPARE trial, a small, single-center, “all-comers” trial in Europe, confirm the superiority of the everolimus-eluting stent in patients – except in patients with diabetes, the investigators and other discussants said.

In patients with diabetes, no significant differences in the risk of major adverse cardiac events (MACE) were observed with either stent in either trial at 1 or 2 years after PCI, a finding that led experts at the meeting to surmise that diabetic patients may fare equally well with both stents.

“We’ve seen this now in almost every trial” comparing these drug-eluting stents. “There is no difference in MACE rates,” Dr. Gregg W. Stone of Columbia University College of Physicians and Surgeons, New York, said in a session announcing the new SPIRIT IV findings.

“In my mind, this lack of benefit [to the Xience V stent] in diabetics means without any doubt that there’s a difference in the mechanistic response of diabetics versus nondiabetics ... to these types of drugs,” he said. Dr. Stone is principal investigator for Spirit IV and codirector of medical research and education at the Cardiovascular Research Foundation, which sponsored the TCT meeting.

The 3,687 patients in the industry-sponsored SPIRIT IV trial, including 1,185 with diabetes, were randomized in 2:1 fashion to receive either the everolimus-eluting Xience V stent (Abbott Vascular) or the first-generation paclitaxel-eluting Taxus Express stent (Boston Scientific). The patients had up to three untreated coronary artery lesions that were as long as 28 mm, in vessels with a diameter of 2.5-3.75 mm.

At 2 years, treatment with Xience V resulted in a relative 30% reduction (and a 3% absolute decline) in target lesion failure compared with treatment with the Taxus stent, with target lesion failure occurring in about 6.9% and 9.9% of the patients, respectively. (The rates of this primary end point after 1 year were 4.0% and 6.9%, respectively.)

The relative reduction in target lesion failure was 39% in patients without diabetes, but in diabetic patients there was little difference between the two groups. Target lesion failure is a composite end point reflecting cardiac death, target-vessel myocardial infarction, or ischemia-driven target lesion revascularization.

Ischemia-driven target lesion revascularization, a secondary end point, occurred at a rate of 4.5% at 2 years in the Xience group compared with 6.9% in the Taxus group, for an absolute reduction of 2.4% and a relative reduction of 34%. The rates of this secondary outcome after 1 year were 2.4% compared with 4.6%.

While there were no mortality differences, target-vessel MI also occurred at a significantly reduced rate in the Xience group at both 1 and 2 years (2.3% v. 3.5% at 2 years), said Dr. Stone.

At a press conference, Dr. Dean Kereiakes said in his presentation of the 2-year SPIRIT IV findings that for every 1 million patients treated with the everolimus-eluting stent, there would be 24,000 fewer repeat revascularization procedures.

“And for every 1 million patients treated (with Xience V), there would be more than 8,000 stent thromboses prevented,” said Dr. Kereiakes of the Christ Hospital Ohio Heart and Vascular Center in Cincinnati.

The rates in stent thrombosis in both studies, in fact, drew significant attention at the meeting. At 2 years after intervention in SPIRIT IV, 1.2% in the Taxus group had developed definite/probable stent thrombosis according to definitions of the Academic Research Consortium (ARC), compared with 0.4% in the Xience arm.

This translates into a 64% relative risk reduction for stent thrombosis (a 0.8% absolute reduction) that occurred during each period – early (the first 30 days), late (31 days to 1 year) and very late period (over 1 year).

The 2-year reductions in stent thrombosis reported from the COMPARE trial were even more striking, discussants said at the meeting.

In this trial, 1,800 consecutive patients undergoing PCI at one center in Rotterdam, the Netherlands, were randomly assigned in 1:1 fashion to treatment with the Xience V stent or the Taxus Libert? stent, a second-generation paclitaxel-eluting stent.

(The Taxus Express stent used in SPIRIT IV is no longer commercially available, according to a spokesperson for Boston Scientific. The Taxus Libert? stent, which uses the same polymer but a different stent platform, is currently available in the United States and in Europe, he said.)

The rate of definite/probable stent thrombosis (again, by ARC definition) at 2 years in the COMPARE trial was 0.9% in the Xience V group and 3.9% in the Taxus group – higher rates than found in SPIRIT IV. Most notable, however, was a 77% reduction in very late definite/probable stent thrombosis in the Xience V arm. The rate of this outcome was 0.3% in the Xience V group and 1.5% in the Taxus Libert? group, reported Dr. Peter Smits of Maasstad Ziekenhuis.

This difference is especially notable because the vast majority of patients were no longer taking dual antiplatelet therapy at 2 years, said Dr. Smits, principal investigator of COMPARE. In contrast, more than 70% of patients in each arm of the SPIRIT IV trial remained on dual antiplatelet therapy at 2 years.

Unlike the SPIRIT design, the COMPARE trial was designed to be an “all-comer, real-world study” without exclusions for complex patients. At 2 years, the superiority of the Xience V stent for the primary end point – a composite of all mortality, nonfatal MI, and target vessel revascularization (MACE) – was maintained, with larger absolute differences between the stents than at 12 months.

At 1 year, this primary end point had occurred in 6.2% and 9.1% in the Xience V and Taxus groups, respectively, for an absolute difference of 2.9%. At 2 years, these rates rose to 9.0% and 13.7%, for an absolute difference of 4.7%. There were similar reductions in secondary end points. As in SPIRIT IV, there were no benefits of the Xience V stent for diabetic patients.

Both studies are still ongoing and will conclude with 5-year analyses.

The SPIRIT IV trial is sponsored by Abbott Vascular, and the COMPARE trial is funded by Abbott Vascular and Boston Scientific. Dr. Stone disclosed that he sits on the advisory boards for, and receives honoraria from, Abbott Vascular and Boston Scientific. Dr. Smits disclosed that he received a speaking fee from Abbott Vascular and that his cardiology department has received unrestricted research grants from Abbott Vascular and Boston Scientific. Dr. Kereiakes disclosed that he has received honoraria and grant support from both Abbott Vascular and Boston Scientific.

WASHINGTON – The benefits seen 1 year after percutaneous coronary intervention with the everolimus-eluting Xience V stent compared with the paclitaxel-eluting Taxus stent were sustained at 2 years of follow-up in two very different types of randomized studies.

And in the case of stent thrombosis in particular, the benefits of the everolimus-eluting stent appear to have intensified at 2 years, investigators reported at Transcatheter Cardiovascular Therapeutics 2010.

The new 2-year findings from both the SPIRIT IV trial, a large study involving 66 U.S. sites, and the COMPARE trial, a small, single-center, “all-comers” trial in Europe, confirm the superiority of the everolimus-eluting stent in patients – except in patients with diabetes, the investigators and other discussants said.

In patients with diabetes, no significant differences in the risk of major adverse cardiac events (MACE) were observed with either stent in either trial at 1 or 2 years after PCI, a finding that led experts at the meeting to surmise that diabetic patients may fare equally well with both stents.

“We’ve seen this now in almost every trial” comparing these drug-eluting stents. “There is no difference in MACE rates,” Dr. Gregg W. Stone of Columbia University College of Physicians and Surgeons, New York, said in a session announcing the new SPIRIT IV findings.

“In my mind, this lack of benefit [to the Xience V stent] in diabetics means without any doubt that there’s a difference in the mechanistic response of diabetics versus nondiabetics ... to these types of drugs,” he said. Dr. Stone is principal investigator for Spirit IV and codirector of medical research and education at the Cardiovascular Research Foundation, which sponsored the TCT meeting.

The 3,687 patients in the industry-sponsored SPIRIT IV trial, including 1,185 with diabetes, were randomized in 2:1 fashion to receive either the everolimus-eluting Xience V stent (Abbott Vascular) or the first-generation paclitaxel-eluting Taxus Express stent (Boston Scientific). The patients had up to three untreated coronary artery lesions that were as long as 28 mm, in vessels with a diameter of 2.5-3.75 mm.

At 2 years, treatment with Xience V resulted in a relative 30% reduction (and a 3% absolute decline) in target lesion failure compared with treatment with the Taxus stent, with target lesion failure occurring in about 6.9% and 9.9% of the patients, respectively. (The rates of this primary end point after 1 year were 4.0% and 6.9%, respectively.)

The relative reduction in target lesion failure was 39% in patients without diabetes, but in diabetic patients there was little difference between the two groups. Target lesion failure is a composite end point reflecting cardiac death, target-vessel myocardial infarction, or ischemia-driven target lesion revascularization.

Ischemia-driven target lesion revascularization, a secondary end point, occurred at a rate of 4.5% at 2 years in the Xience group compared with 6.9% in the Taxus group, for an absolute reduction of 2.4% and a relative reduction of 34%. The rates of this secondary outcome after 1 year were 2.4% compared with 4.6%.

While there were no mortality differences, target-vessel MI also occurred at a significantly reduced rate in the Xience group at both 1 and 2 years (2.3% v. 3.5% at 2 years), said Dr. Stone.

At a press conference, Dr. Dean Kereiakes said in his presentation of the 2-year SPIRIT IV findings that for every 1 million patients treated with the everolimus-eluting stent, there would be 24,000 fewer repeat revascularization procedures.

“And for every 1 million patients treated (with Xience V), there would be more than 8,000 stent thromboses prevented,” said Dr. Kereiakes of the Christ Hospital Ohio Heart and Vascular Center in Cincinnati.

The rates in stent thrombosis in both studies, in fact, drew significant attention at the meeting. At 2 years after intervention in SPIRIT IV, 1.2% in the Taxus group had developed definite/probable stent thrombosis according to definitions of the Academic Research Consortium (ARC), compared with 0.4% in the Xience arm.

This translates into a 64% relative risk reduction for stent thrombosis (a 0.8% absolute reduction) that occurred during each period – early (the first 30 days), late (31 days to 1 year) and very late period (over 1 year).

The 2-year reductions in stent thrombosis reported from the COMPARE trial were even more striking, discussants said at the meeting.

In this trial, 1,800 consecutive patients undergoing PCI at one center in Rotterdam, the Netherlands, were randomly assigned in 1:1 fashion to treatment with the Xience V stent or the Taxus Libert? stent, a second-generation paclitaxel-eluting stent.

(The Taxus Express stent used in SPIRIT IV is no longer commercially available, according to a spokesperson for Boston Scientific. The Taxus Libert? stent, which uses the same polymer but a different stent platform, is currently available in the United States and in Europe, he said.)

The rate of definite/probable stent thrombosis (again, by ARC definition) at 2 years in the COMPARE trial was 0.9% in the Xience V group and 3.9% in the Taxus group – higher rates than found in SPIRIT IV. Most notable, however, was a 77% reduction in very late definite/probable stent thrombosis in the Xience V arm. The rate of this outcome was 0.3% in the Xience V group and 1.5% in the Taxus Libert? group, reported Dr. Peter Smits of Maasstad Ziekenhuis.

This difference is especially notable because the vast majority of patients were no longer taking dual antiplatelet therapy at 2 years, said Dr. Smits, principal investigator of COMPARE. In contrast, more than 70% of patients in each arm of the SPIRIT IV trial remained on dual antiplatelet therapy at 2 years.

Unlike the SPIRIT design, the COMPARE trial was designed to be an “all-comer, real-world study” without exclusions for complex patients. At 2 years, the superiority of the Xience V stent for the primary end point – a composite of all mortality, nonfatal MI, and target vessel revascularization (MACE) – was maintained, with larger absolute differences between the stents than at 12 months.

At 1 year, this primary end point had occurred in 6.2% and 9.1% in the Xience V and Taxus groups, respectively, for an absolute difference of 2.9%. At 2 years, these rates rose to 9.0% and 13.7%, for an absolute difference of 4.7%. There were similar reductions in secondary end points. As in SPIRIT IV, there were no benefits of the Xience V stent for diabetic patients.

Both studies are still ongoing and will conclude with 5-year analyses.

The SPIRIT IV trial is sponsored by Abbott Vascular, and the COMPARE trial is funded by Abbott Vascular and Boston Scientific. Dr. Stone disclosed that he sits on the advisory boards for, and receives honoraria from, Abbott Vascular and Boston Scientific. Dr. Smits disclosed that he received a speaking fee from Abbott Vascular and that his cardiology department has received unrestricted research grants from Abbott Vascular and Boston Scientific. Dr. Kereiakes disclosed that he has received honoraria and grant support from both Abbott Vascular and Boston Scientific.

WASHINGTON – The benefits seen 1 year after percutaneous coronary intervention with the everolimus-eluting Xience V stent compared with the paclitaxel-eluting Taxus stent were sustained at 2 years of follow-up in two very different types of randomized studies.

And in the case of stent thrombosis in particular, the benefits of the everolimus-eluting stent appear to have intensified at 2 years, investigators reported at Transcatheter Cardiovascular Therapeutics 2010.

The new 2-year findings from both the SPIRIT IV trial, a large study involving 66 U.S. sites, and the COMPARE trial, a small, single-center, “all-comers” trial in Europe, confirm the superiority of the everolimus-eluting stent in patients – except in patients with diabetes, the investigators and other discussants said.

In patients with diabetes, no significant differences in the risk of major adverse cardiac events (MACE) were observed with either stent in either trial at 1 or 2 years after PCI, a finding that led experts at the meeting to surmise that diabetic patients may fare equally well with both stents.

“We’ve seen this now in almost every trial” comparing these drug-eluting stents. “There is no difference in MACE rates,” Dr. Gregg W. Stone of Columbia University College of Physicians and Surgeons, New York, said in a session announcing the new SPIRIT IV findings.

“In my mind, this lack of benefit [to the Xience V stent] in diabetics means without any doubt that there’s a difference in the mechanistic response of diabetics versus nondiabetics ... to these types of drugs,” he said. Dr. Stone is principal investigator for Spirit IV and codirector of medical research and education at the Cardiovascular Research Foundation, which sponsored the TCT meeting.

The 3,687 patients in the industry-sponsored SPIRIT IV trial, including 1,185 with diabetes, were randomized in 2:1 fashion to receive either the everolimus-eluting Xience V stent (Abbott Vascular) or the first-generation paclitaxel-eluting Taxus Express stent (Boston Scientific). The patients had up to three untreated coronary artery lesions that were as long as 28 mm, in vessels with a diameter of 2.5-3.75 mm.

At 2 years, treatment with Xience V resulted in a relative 30% reduction (and a 3% absolute decline) in target lesion failure compared with treatment with the Taxus stent, with target lesion failure occurring in about 6.9% and 9.9% of the patients, respectively. (The rates of this primary end point after 1 year were 4.0% and 6.9%, respectively.)

The relative reduction in target lesion failure was 39% in patients without diabetes, but in diabetic patients there was little difference between the two groups. Target lesion failure is a composite end point reflecting cardiac death, target-vessel myocardial infarction, or ischemia-driven target lesion revascularization.

Ischemia-driven target lesion revascularization, a secondary end point, occurred at a rate of 4.5% at 2 years in the Xience group compared with 6.9% in the Taxus group, for an absolute reduction of 2.4% and a relative reduction of 34%. The rates of this secondary outcome after 1 year were 2.4% compared with 4.6%.

While there were no mortality differences, target-vessel MI also occurred at a significantly reduced rate in the Xience group at both 1 and 2 years (2.3% v. 3.5% at 2 years), said Dr. Stone.

At a press conference, Dr. Dean Kereiakes said in his presentation of the 2-year SPIRIT IV findings that for every 1 million patients treated with the everolimus-eluting stent, there would be 24,000 fewer repeat revascularization procedures.

“And for every 1 million patients treated (with Xience V), there would be more than 8,000 stent thromboses prevented,” said Dr. Kereiakes of the Christ Hospital Ohio Heart and Vascular Center in Cincinnati.

The rates in stent thrombosis in both studies, in fact, drew significant attention at the meeting. At 2 years after intervention in SPIRIT IV, 1.2% in the Taxus group had developed definite/probable stent thrombosis according to definitions of the Academic Research Consortium (ARC), compared with 0.4% in the Xience arm.

This translates into a 64% relative risk reduction for stent thrombosis (a 0.8% absolute reduction) that occurred during each period – early (the first 30 days), late (31 days to 1 year) and very late period (over 1 year).

The 2-year reductions in stent thrombosis reported from the COMPARE trial were even more striking, discussants said at the meeting.

In this trial, 1,800 consecutive patients undergoing PCI at one center in Rotterdam, the Netherlands, were randomly assigned in 1:1 fashion to treatment with the Xience V stent or the Taxus Libert? stent, a second-generation paclitaxel-eluting stent.

(The Taxus Express stent used in SPIRIT IV is no longer commercially available, according to a spokesperson for Boston Scientific. The Taxus Libert? stent, which uses the same polymer but a different stent platform, is currently available in the United States and in Europe, he said.)

The rate of definite/probable stent thrombosis (again, by ARC definition) at 2 years in the COMPARE trial was 0.9% in the Xience V group and 3.9% in the Taxus group – higher rates than found in SPIRIT IV. Most notable, however, was a 77% reduction in very late definite/probable stent thrombosis in the Xience V arm. The rate of this outcome was 0.3% in the Xience V group and 1.5% in the Taxus Libert? group, reported Dr. Peter Smits of Maasstad Ziekenhuis.

This difference is especially notable because the vast majority of patients were no longer taking dual antiplatelet therapy at 2 years, said Dr. Smits, principal investigator of COMPARE. In contrast, more than 70% of patients in each arm of the SPIRIT IV trial remained on dual antiplatelet therapy at 2 years.

Unlike the SPIRIT design, the COMPARE trial was designed to be an “all-comer, real-world study” without exclusions for complex patients. At 2 years, the superiority of the Xience V stent for the primary end point – a composite of all mortality, nonfatal MI, and target vessel revascularization (MACE) – was maintained, with larger absolute differences between the stents than at 12 months.

At 1 year, this primary end point had occurred in 6.2% and 9.1% in the Xience V and Taxus groups, respectively, for an absolute difference of 2.9%. At 2 years, these rates rose to 9.0% and 13.7%, for an absolute difference of 4.7%. There were similar reductions in secondary end points. As in SPIRIT IV, there were no benefits of the Xience V stent for diabetic patients.

Both studies are still ongoing and will conclude with 5-year analyses.

The SPIRIT IV trial is sponsored by Abbott Vascular, and the COMPARE trial is funded by Abbott Vascular and Boston Scientific. Dr. Stone disclosed that he sits on the advisory boards for, and receives honoraria from, Abbott Vascular and Boston Scientific. Dr. Smits disclosed that he received a speaking fee from Abbott Vascular and that his cardiology department has received unrestricted research grants from Abbott Vascular and Boston Scientific. Dr. Kereiakes disclosed that he has received honoraria and grant support from both Abbott Vascular and Boston Scientific.