Generic drug manufacturer Ranbaxy Laboratories Ltd. will have to withdraw all drug applications that contain data generated at one of its facilities in India and relinquish 180-day marketing exclusivity for three pending abbreviated New Drug Applications under a consent decree for permanent injunction filed Jan. 25 by the U.S. Department of Justice.

The decree follows a lengthy investigation by the DOJ and the U.S. Food and Drug Administration that found numerous problems at three Ranbaxy facilities in India and one facility in Gloversville, N.Y.

According to the DOJ, the problems with Ranbaxy’s drug manufacturing and testing include failure to keep records showing that drugs had been manufactured properly; failure to investigate evidence indicating that drugs did not meet their specifications; failure to adequately separate the manufacture of penicillin drugs from nonpenicillin drugs in order to prevent cross-contamination; lack of adequate procedures to prevent contamination of sterile drugs; and inadequate testing of drug to ensure that they maintained strength and effectiveness until their expiration date.

The government also said that Ranbaxy submitted false data in drug applications, including backdating tests and submitting test data for which no test samples existed.

The consent decree is unprecedented in its scope, according to DOJ officials.

"This action against Ranbaxy is groundbreaking in its international reach – it requires the company to make fundamental changes to its plants in both the United States and India," Assistant Attorney General Tony West said in a statement. "Submitting false data to the FDA in drug applications will not be tolerated."

Ranbaxy said in a statement that the consent decree would not affect the company’s recently launched generic atorvastatin, because it is not manufactured in the facilities cited in the decree.

"Today’s announcement is the next step in the process of finalizing our agreement with the FDA to resolve this legacy issue," according to Arun Sawhney, managing director of Ranbaxy Laboratories. "We are pleased with the progress we have made in upgrading and enhancing the quality of our business and manufacturing processes and remain committed to ensuring that all of our facilities and products meet the high standards that patients, prescribers and the public have come to expect from Ranbaxy."

Ranbaxy announced earlier that it had entered into the consent decree with the FDA and had set aside $500 million to settle the related DOJ investigation. The consent decree itself does not mention the size of the settlement, although it does note that "if defendants fail to comply with any provision of the law or this decree at any covered facility and/or with respect to any affected application, then [they] ... shall pay to the United States of America $15,000 in liquidated damages for each day such violation continues."

The company also agreed to relinquish the 180-day marketing exclusivity that it might have for three pending generic applications, but did not specify which drugs would be affected. The company also agreed to relinquish any 180-day marketing exclusivity that it may have for several additional generic applications if it fails to meet certain decree requirements by specified dates.

The manufacturing plants cited in the consent decree are the Paonta Sahib, Batamandi, and Dewas facilities, all in India, and the now-closed facility of Ranbaxy’s Ohm Laboratories subsidiary in Gloversville, N.Y. Import alerts for more than 30 products manufactured at the Paonta Sahib and Dewas sites have been in place since September 2008.

The consent decree also prevents Ranbaxy from manufacturing drugs for introduction to the U.S. market and for the President’s Emergency Plan for AIDS Relief Program at the four facilities.

Brenda Sandburg is a reporter for "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Generic drug manufacturer Ranbaxy Laboratories Ltd. will have to withdraw all drug applications that contain data generated at one of its facilities in India and relinquish 180-day marketing exclusivity for three pending abbreviated New Drug Applications under a consent decree for permanent injunction filed Jan. 25 by the U.S. Department of Justice.

The decree follows a lengthy investigation by the DOJ and the U.S. Food and Drug Administration that found numerous problems at three Ranbaxy facilities in India and one facility in Gloversville, N.Y.

According to the DOJ, the problems with Ranbaxy’s drug manufacturing and testing include failure to keep records showing that drugs had been manufactured properly; failure to investigate evidence indicating that drugs did not meet their specifications; failure to adequately separate the manufacture of penicillin drugs from nonpenicillin drugs in order to prevent cross-contamination; lack of adequate procedures to prevent contamination of sterile drugs; and inadequate testing of drug to ensure that they maintained strength and effectiveness until their expiration date.

The government also said that Ranbaxy submitted false data in drug applications, including backdating tests and submitting test data for which no test samples existed.

The consent decree is unprecedented in its scope, according to DOJ officials.

"This action against Ranbaxy is groundbreaking in its international reach – it requires the company to make fundamental changes to its plants in both the United States and India," Assistant Attorney General Tony West said in a statement. "Submitting false data to the FDA in drug applications will not be tolerated."

Ranbaxy said in a statement that the consent decree would not affect the company’s recently launched generic atorvastatin, because it is not manufactured in the facilities cited in the decree.

"Today’s announcement is the next step in the process of finalizing our agreement with the FDA to resolve this legacy issue," according to Arun Sawhney, managing director of Ranbaxy Laboratories. "We are pleased with the progress we have made in upgrading and enhancing the quality of our business and manufacturing processes and remain committed to ensuring that all of our facilities and products meet the high standards that patients, prescribers and the public have come to expect from Ranbaxy."

Ranbaxy announced earlier that it had entered into the consent decree with the FDA and had set aside $500 million to settle the related DOJ investigation. The consent decree itself does not mention the size of the settlement, although it does note that "if defendants fail to comply with any provision of the law or this decree at any covered facility and/or with respect to any affected application, then [they] ... shall pay to the United States of America $15,000 in liquidated damages for each day such violation continues."

The company also agreed to relinquish the 180-day marketing exclusivity that it might have for three pending generic applications, but did not specify which drugs would be affected. The company also agreed to relinquish any 180-day marketing exclusivity that it may have for several additional generic applications if it fails to meet certain decree requirements by specified dates.

The manufacturing plants cited in the consent decree are the Paonta Sahib, Batamandi, and Dewas facilities, all in India, and the now-closed facility of Ranbaxy’s Ohm Laboratories subsidiary in Gloversville, N.Y. Import alerts for more than 30 products manufactured at the Paonta Sahib and Dewas sites have been in place since September 2008.

The consent decree also prevents Ranbaxy from manufacturing drugs for introduction to the U.S. market and for the President’s Emergency Plan for AIDS Relief Program at the four facilities.

Brenda Sandburg is a reporter for "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Generic drug manufacturer Ranbaxy Laboratories Ltd. will have to withdraw all drug applications that contain data generated at one of its facilities in India and relinquish 180-day marketing exclusivity for three pending abbreviated New Drug Applications under a consent decree for permanent injunction filed Jan. 25 by the U.S. Department of Justice.

The decree follows a lengthy investigation by the DOJ and the U.S. Food and Drug Administration that found numerous problems at three Ranbaxy facilities in India and one facility in Gloversville, N.Y.

According to the DOJ, the problems with Ranbaxy’s drug manufacturing and testing include failure to keep records showing that drugs had been manufactured properly; failure to investigate evidence indicating that drugs did not meet their specifications; failure to adequately separate the manufacture of penicillin drugs from nonpenicillin drugs in order to prevent cross-contamination; lack of adequate procedures to prevent contamination of sterile drugs; and inadequate testing of drug to ensure that they maintained strength and effectiveness until their expiration date.

The government also said that Ranbaxy submitted false data in drug applications, including backdating tests and submitting test data for which no test samples existed.

The consent decree is unprecedented in its scope, according to DOJ officials.

"This action against Ranbaxy is groundbreaking in its international reach – it requires the company to make fundamental changes to its plants in both the United States and India," Assistant Attorney General Tony West said in a statement. "Submitting false data to the FDA in drug applications will not be tolerated."

Ranbaxy said in a statement that the consent decree would not affect the company’s recently launched generic atorvastatin, because it is not manufactured in the facilities cited in the decree.

"Today’s announcement is the next step in the process of finalizing our agreement with the FDA to resolve this legacy issue," according to Arun Sawhney, managing director of Ranbaxy Laboratories. "We are pleased with the progress we have made in upgrading and enhancing the quality of our business and manufacturing processes and remain committed to ensuring that all of our facilities and products meet the high standards that patients, prescribers and the public have come to expect from Ranbaxy."

Ranbaxy announced earlier that it had entered into the consent decree with the FDA and had set aside $500 million to settle the related DOJ investigation. The consent decree itself does not mention the size of the settlement, although it does note that "if defendants fail to comply with any provision of the law or this decree at any covered facility and/or with respect to any affected application, then [they] ... shall pay to the United States of America $15,000 in liquidated damages for each day such violation continues."

The company also agreed to relinquish the 180-day marketing exclusivity that it might have for three pending generic applications, but did not specify which drugs would be affected. The company also agreed to relinquish any 180-day marketing exclusivity that it may have for several additional generic applications if it fails to meet certain decree requirements by specified dates.

The manufacturing plants cited in the consent decree are the Paonta Sahib, Batamandi, and Dewas facilities, all in India, and the now-closed facility of Ranbaxy’s Ohm Laboratories subsidiary in Gloversville, N.Y. Import alerts for more than 30 products manufactured at the Paonta Sahib and Dewas sites have been in place since September 2008.

The consent decree also prevents Ranbaxy from manufacturing drugs for introduction to the U.S. market and for the President’s Emergency Plan for AIDS Relief Program at the four facilities.

Brenda Sandburg is a reporter for "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Comprehensive Management of Respiratory Symptoms in Patients with Advanced Lung Cancer

• Jessica McCannon, MD

  

  ^,

  

   [Author Vitae],
• Jennifer Temel, MD [Author Vitae]

• Pulmonary and Critical Care Medicine and Thoracic Oncology, Massachusetts General Hospital, Boston, Massachusetts

• Received 11 February 2011. Accepted 11 July 2011. Available online 12 October 2011.

• http://dx.doi.org/10.1016/j.suponc.2011.07.002, How to Cite or Link Using DOI

• Permissions & Reprints

Comprehensive Management of Respiratory Symptoms in Patients with Advanced Lung Cancer

• Jessica McCannon, MD

  

  ^,

  

   [Author Vitae],
• Jennifer Temel, MD [Author Vitae]

• Pulmonary and Critical Care Medicine and Thoracic Oncology, Massachusetts General Hospital, Boston, Massachusetts

• Received 11 February 2011. Accepted 11 July 2011. Available online 12 October 2011.

• http://dx.doi.org/10.1016/j.suponc.2011.07.002, How to Cite or Link Using DOI

• Permissions & Reprints

Comprehensive Management of Respiratory Symptoms in Patients with Advanced Lung Cancer

• Jessica McCannon, MD

  

  ^,

  

   [Author Vitae],
• Jennifer Temel, MD [Author Vitae]

• Pulmonary and Critical Care Medicine and Thoracic Oncology, Massachusetts General Hospital, Boston, Massachusetts

• Received 11 February 2011. Accepted 11 July 2011. Available online 12 October 2011.

• http://dx.doi.org/10.1016/j.suponc.2011.07.002, How to Cite or Link Using DOI

• Permissions & Reprints

Targeting the Symptoms of Lung Cancer, Not Just the Disease

• Steven I. Robinson, MBBS 
• Timothy J. Moynihan, MD

  

• Available online 23 September 2011.

• http://dx.doi.org/10.1016/j.suponc.2011.07.003

• Permissions & Reprints

Lung cancer accounts for a large percentage of cancer deaths worldwide. In the United States, an estimated 222,520 new diagnoses and 157,300 deaths associated with lung cancer were projected for 2010.¹ Even with the best approaches available to us today, median 5-year survival rates range from 10% to 15% in advanced disease.² The majority of our efforts have been aimed at prolonging survival, focusing on optimizing tumor-specific options. Unfortunately, we are prone to overlook symptoms that negatively impact quality of life. McCannon and Temel highlight approaches to managing the respiratory symptoms associated with advanced lung cancer, explaining the pathophysiology behind the common symptoms and critiquing the evidence behind these management approaches.

The authors emphasize the fact that multiple causes contribute to respiratory symptoms in patients with lung cancer. It is essential to perform a thorough history and clinical evaluation in order to elucidate the underlying insult(s) and not simply assume symptoms are due to progressive disease. The table gives an excellent framework to guide the approach to these patients. Reversible causes should always be sought and aggressively treated.

Targeting the Symptoms of Lung Cancer, Not Just the Disease

• Steven I. Robinson, MBBS 
• Timothy J. Moynihan, MD

  

• Available online 23 September 2011.

• http://dx.doi.org/10.1016/j.suponc.2011.07.003

• Permissions & Reprints

Lung cancer accounts for a large percentage of cancer deaths worldwide. In the United States, an estimated 222,520 new diagnoses and 157,300 deaths associated with lung cancer were projected for 2010.¹ Even with the best approaches available to us today, median 5-year survival rates range from 10% to 15% in advanced disease.² The majority of our efforts have been aimed at prolonging survival, focusing on optimizing tumor-specific options. Unfortunately, we are prone to overlook symptoms that negatively impact quality of life. McCannon and Temel highlight approaches to managing the respiratory symptoms associated with advanced lung cancer, explaining the pathophysiology behind the common symptoms and critiquing the evidence behind these management approaches.

The authors emphasize the fact that multiple causes contribute to respiratory symptoms in patients with lung cancer. It is essential to perform a thorough history and clinical evaluation in order to elucidate the underlying insult(s) and not simply assume symptoms are due to progressive disease. The table gives an excellent framework to guide the approach to these patients. Reversible causes should always be sought and aggressively treated.

Targeting the Symptoms of Lung Cancer, Not Just the Disease

• Steven I. Robinson, MBBS 
• Timothy J. Moynihan, MD

  

• Available online 23 September 2011.

• http://dx.doi.org/10.1016/j.suponc.2011.07.003

• Permissions & Reprints

Lung cancer accounts for a large percentage of cancer deaths worldwide. In the United States, an estimated 222,520 new diagnoses and 157,300 deaths associated with lung cancer were projected for 2010.¹ Even with the best approaches available to us today, median 5-year survival rates range from 10% to 15% in advanced disease.² The majority of our efforts have been aimed at prolonging survival, focusing on optimizing tumor-specific options. Unfortunately, we are prone to overlook symptoms that negatively impact quality of life. McCannon and Temel highlight approaches to managing the respiratory symptoms associated with advanced lung cancer, explaining the pathophysiology behind the common symptoms and critiquing the evidence behind these management approaches.

The authors emphasize the fact that multiple causes contribute to respiratory symptoms in patients with lung cancer. It is essential to perform a thorough history and clinical evaluation in order to elucidate the underlying insult(s) and not simply assume symptoms are due to progressive disease. The table gives an excellent framework to guide the approach to these patients. Reversible causes should always be sought and aggressively treated.

Respiratory Symptoms in Advanced Lung Cancer: A Persistent Challenge

• Ahmed Elsayem, MD

  

• Available online 23 November 2011.

• http://dx.doi.org/10.1016/j.suponc.2011.10.004

• Permissions & Reprints

Drs. McCannon and Temel have written an interesting review on the management of respiratory symptoms in advanced lung cancer patients. Their article is structured in a systematic, easy-to-follow format and will be a useful tool for physicians caring for patients with advanced lung cancer.

The authors reviewed up-to-date literature on frequent complications of advanced lung cancer such as pulmonary embolism, pleural effusion, pericardial tamponade, postobstructive pneumonia, and treatment-related pneumonitis (resulting from radiation therapy and certain types of chemotherapy). They also provide useful recommendations and suggest practical interventions which are supported by evidence from the literature. Clinicians caring for such patients must have a comprehensive knowledge of such complications to make a diagnosis and provide specific treatment.

Drs. McCannon and Temel address common symptoms associated with advanced lung cancer. In addition to their comprehensive review of the management of dyspnea, they address other symptoms such as cough and hemoptysis and provide specific recommendations on the management of each symptom with supportive evidence from the literature for each intervention.

Respiratory Symptoms in Advanced Lung Cancer: A Persistent Challenge

• Ahmed Elsayem, MD

  

• Available online 23 November 2011.

• http://dx.doi.org/10.1016/j.suponc.2011.10.004

• Permissions & Reprints

Drs. McCannon and Temel have written an interesting review on the management of respiratory symptoms in advanced lung cancer patients. Their article is structured in a systematic, easy-to-follow format and will be a useful tool for physicians caring for patients with advanced lung cancer.

The authors reviewed up-to-date literature on frequent complications of advanced lung cancer such as pulmonary embolism, pleural effusion, pericardial tamponade, postobstructive pneumonia, and treatment-related pneumonitis (resulting from radiation therapy and certain types of chemotherapy). They also provide useful recommendations and suggest practical interventions which are supported by evidence from the literature. Clinicians caring for such patients must have a comprehensive knowledge of such complications to make a diagnosis and provide specific treatment.

Drs. McCannon and Temel address common symptoms associated with advanced lung cancer. In addition to their comprehensive review of the management of dyspnea, they address other symptoms such as cough and hemoptysis and provide specific recommendations on the management of each symptom with supportive evidence from the literature for each intervention.

Respiratory Symptoms in Advanced Lung Cancer: A Persistent Challenge

• Ahmed Elsayem, MD

  

• Available online 23 November 2011.

• http://dx.doi.org/10.1016/j.suponc.2011.10.004

• Permissions & Reprints

Drs. McCannon and Temel have written an interesting review on the management of respiratory symptoms in advanced lung cancer patients. Their article is structured in a systematic, easy-to-follow format and will be a useful tool for physicians caring for patients with advanced lung cancer.

The authors reviewed up-to-date literature on frequent complications of advanced lung cancer such as pulmonary embolism, pleural effusion, pericardial tamponade, postobstructive pneumonia, and treatment-related pneumonitis (resulting from radiation therapy and certain types of chemotherapy). They also provide useful recommendations and suggest practical interventions which are supported by evidence from the literature. Clinicians caring for such patients must have a comprehensive knowledge of such complications to make a diagnosis and provide specific treatment.

Drs. McCannon and Temel address common symptoms associated with advanced lung cancer. In addition to their comprehensive review of the management of dyspnea, they address other symptoms such as cough and hemoptysis and provide specific recommendations on the management of each symptom with supportive evidence from the literature for each intervention.

After 13 years of follow-up, men who underwent annual screening for prostate cancer were no less likely to die of prostate cancer than were men who received usual care and opportunistic screening.

Cumulative mortality rates from prostate cancer differed by a statistically insignificant rate of 0.3 deaths per 10,000 person years in the intervention and usual-care arms of the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial, published online Jan. 6 in the Journal of the National Cancer Institute. Further, age, comorbidity status, and pretrial prostate-specific antigen (PSA) testing did not influence the results, wrote Dr. Gerald L. Andriole of Washington University, St. Louis, and his colleagues.

The PLCO trial randomly assigned 76,693 men, aged 55-74 years, to either 6 years of annual PSA screening in combination with 4 years of annual digital rectal examination (38,343) or to usual care (38,350), which included screening tests as recommended by physicians.

The goal was to evaluate the effect of adding annual screening and compare outcomes to the opportunistic screening already in place, the researchers said. It was expected that the impacts of earlier diagnosis and a persistent excess of cases because of annual screening in the intervention arm would exceed the impacts of opportunistic screening.

Prior to the study, 44% of all participants had undergone PSA screening. During the trial, 52% of the usual-care group, compared with the entire intervention group, underwent PSA testing.

The researchers had previously reported 7- and 10-year follow-up results. At 7 years of follow-up, yearly screening was associated with an increased incidence of prostate cancer diagnosis as compared with usual care. The rates of prostate cancer mortality and of all-cause mortality, however, were the same for both groups. Similarly, after 10 years of follow-up, no mortality benefit was observed for the intervention, the investigators reported previously (N. Engl. J. Med. 2009;360:1320-1328).

For the current study, Dr. Andriole and his associates ascertained all incident prostate cancer diagnoses and deaths through 13 years of follow-up or through December 31, 2009, and estimated relative risks as the ratio of observed rates of diagnoses and deaths in the intervention and control arms. They examined the interactions between prostate cancer mortality by trial arm and age, comorbidities, and pretrial PSA testing using Poisson regression modeling (J. Natl. Cancer Inst. 6 Jan. 2012 [doi: 10.1093/jnci/djr500]).

At 13 years, 4,250 of the 38,340 participants in the intervention arm had been diagnosed with prostate cancer, compared with 3,815 of the 38,345 control participants. "The cumulative incidence rates for prostate cancer in the intervention and control arms were 108.4 and 97.1 per 10,000 person-years, respectively, resulting in a statistically significant 12% relative increase in the intervention arm," the authors wrote. Of the prostate cancer diagnoses, 401 in the intervention arm and 454 in the usual care arm were high-grade prostate cancers with Gleason scores of 8-10.

At 13 years of follow-up, there were 158 deaths in the intervention arm and 145 deaths in the usual-care arm. "The cumulative mortality rates from prostate cancer were 3.7 and 3.4 deaths per 10,000 person-years, respectively, resulting in a non-statistically significant difference between the two arms," according to the authors. The examination of mortality rates per 10,000 person-years and relative risks of prostate cancer mortality by age, comorbidity, and pretrial PSA testing produced no statistically significant interactions.

Deaths from all causes other than prostate, lung, and colorectal cancers differed by a factor of "borderline" statistical significance, with 5,783 deaths in the intervention arm and 5,982 in the usual-care arm, Dr. Andriole and his associates wrote. "Intervention and control arms showed 23% and 22% deaths, respectively, from non-PLCO cancers, and 21% and 19% deaths, respectively, from ischemic heart disease."

The authors acknowledged limitations of the study, including the possibility that a reduction in prostate cancer mortality in the analysis has somehow been masked by "the sticking diagnosis effect." In other words, more deaths were attributed to prostate cancer in the intervention arm. This possibility is supported by the statistically significant lower all-cause mortality in the intervention group as compared with the usual-care group. The percentage of deaths from other causes was higher in the intervention arm, so an error in cause of death attribution likely does not account for the excess prostate cancer deaths in the intervention group, they concluded.

The investigators plan to update the mortality findings through 15 years of follow-up, when those data become available.

Some of the study authors report relationships with Amgen, Augmenix, Bayer, Cambridge Endo, Caris, Envisioneering Medical, France Foundation, GenProbe, GlaxoSmithKline, Human Genome Sciences, Myriad Genetics, Steba Biotech, Ortho Clinical Diagnostics, and Viking Medical.

After 13 years of follow-up, men who underwent annual screening for prostate cancer were no less likely to die of prostate cancer than were men who received usual care and opportunistic screening.

Cumulative mortality rates from prostate cancer differed by a statistically insignificant rate of 0.3 deaths per 10,000 person years in the intervention and usual-care arms of the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial, published online Jan. 6 in the Journal of the National Cancer Institute. Further, age, comorbidity status, and pretrial prostate-specific antigen (PSA) testing did not influence the results, wrote Dr. Gerald L. Andriole of Washington University, St. Louis, and his colleagues.

The PLCO trial randomly assigned 76,693 men, aged 55-74 years, to either 6 years of annual PSA screening in combination with 4 years of annual digital rectal examination (38,343) or to usual care (38,350), which included screening tests as recommended by physicians.

The goal was to evaluate the effect of adding annual screening and compare outcomes to the opportunistic screening already in place, the researchers said. It was expected that the impacts of earlier diagnosis and a persistent excess of cases because of annual screening in the intervention arm would exceed the impacts of opportunistic screening.

Prior to the study, 44% of all participants had undergone PSA screening. During the trial, 52% of the usual-care group, compared with the entire intervention group, underwent PSA testing.

The researchers had previously reported 7- and 10-year follow-up results. At 7 years of follow-up, yearly screening was associated with an increased incidence of prostate cancer diagnosis as compared with usual care. The rates of prostate cancer mortality and of all-cause mortality, however, were the same for both groups. Similarly, after 10 years of follow-up, no mortality benefit was observed for the intervention, the investigators reported previously (N. Engl. J. Med. 2009;360:1320-1328).

For the current study, Dr. Andriole and his associates ascertained all incident prostate cancer diagnoses and deaths through 13 years of follow-up or through December 31, 2009, and estimated relative risks as the ratio of observed rates of diagnoses and deaths in the intervention and control arms. They examined the interactions between prostate cancer mortality by trial arm and age, comorbidities, and pretrial PSA testing using Poisson regression modeling (J. Natl. Cancer Inst. 6 Jan. 2012 [doi: 10.1093/jnci/djr500]).

At 13 years, 4,250 of the 38,340 participants in the intervention arm had been diagnosed with prostate cancer, compared with 3,815 of the 38,345 control participants. "The cumulative incidence rates for prostate cancer in the intervention and control arms were 108.4 and 97.1 per 10,000 person-years, respectively, resulting in a statistically significant 12% relative increase in the intervention arm," the authors wrote. Of the prostate cancer diagnoses, 401 in the intervention arm and 454 in the usual care arm were high-grade prostate cancers with Gleason scores of 8-10.

At 13 years of follow-up, there were 158 deaths in the intervention arm and 145 deaths in the usual-care arm. "The cumulative mortality rates from prostate cancer were 3.7 and 3.4 deaths per 10,000 person-years, respectively, resulting in a non-statistically significant difference between the two arms," according to the authors. The examination of mortality rates per 10,000 person-years and relative risks of prostate cancer mortality by age, comorbidity, and pretrial PSA testing produced no statistically significant interactions.

Deaths from all causes other than prostate, lung, and colorectal cancers differed by a factor of "borderline" statistical significance, with 5,783 deaths in the intervention arm and 5,982 in the usual-care arm, Dr. Andriole and his associates wrote. "Intervention and control arms showed 23% and 22% deaths, respectively, from non-PLCO cancers, and 21% and 19% deaths, respectively, from ischemic heart disease."

The authors acknowledged limitations of the study, including the possibility that a reduction in prostate cancer mortality in the analysis has somehow been masked by "the sticking diagnosis effect." In other words, more deaths were attributed to prostate cancer in the intervention arm. This possibility is supported by the statistically significant lower all-cause mortality in the intervention group as compared with the usual-care group. The percentage of deaths from other causes was higher in the intervention arm, so an error in cause of death attribution likely does not account for the excess prostate cancer deaths in the intervention group, they concluded.

The investigators plan to update the mortality findings through 15 years of follow-up, when those data become available.

Some of the study authors report relationships with Amgen, Augmenix, Bayer, Cambridge Endo, Caris, Envisioneering Medical, France Foundation, GenProbe, GlaxoSmithKline, Human Genome Sciences, Myriad Genetics, Steba Biotech, Ortho Clinical Diagnostics, and Viking Medical.

After 13 years of follow-up, men who underwent annual screening for prostate cancer were no less likely to die of prostate cancer than were men who received usual care and opportunistic screening.

Cumulative mortality rates from prostate cancer differed by a statistically insignificant rate of 0.3 deaths per 10,000 person years in the intervention and usual-care arms of the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial, published online Jan. 6 in the Journal of the National Cancer Institute. Further, age, comorbidity status, and pretrial prostate-specific antigen (PSA) testing did not influence the results, wrote Dr. Gerald L. Andriole of Washington University, St. Louis, and his colleagues.

The PLCO trial randomly assigned 76,693 men, aged 55-74 years, to either 6 years of annual PSA screening in combination with 4 years of annual digital rectal examination (38,343) or to usual care (38,350), which included screening tests as recommended by physicians.

The goal was to evaluate the effect of adding annual screening and compare outcomes to the opportunistic screening already in place, the researchers said. It was expected that the impacts of earlier diagnosis and a persistent excess of cases because of annual screening in the intervention arm would exceed the impacts of opportunistic screening.

Prior to the study, 44% of all participants had undergone PSA screening. During the trial, 52% of the usual-care group, compared with the entire intervention group, underwent PSA testing.

The researchers had previously reported 7- and 10-year follow-up results. At 7 years of follow-up, yearly screening was associated with an increased incidence of prostate cancer diagnosis as compared with usual care. The rates of prostate cancer mortality and of all-cause mortality, however, were the same for both groups. Similarly, after 10 years of follow-up, no mortality benefit was observed for the intervention, the investigators reported previously (N. Engl. J. Med. 2009;360:1320-1328).

For the current study, Dr. Andriole and his associates ascertained all incident prostate cancer diagnoses and deaths through 13 years of follow-up or through December 31, 2009, and estimated relative risks as the ratio of observed rates of diagnoses and deaths in the intervention and control arms. They examined the interactions between prostate cancer mortality by trial arm and age, comorbidities, and pretrial PSA testing using Poisson regression modeling (J. Natl. Cancer Inst. 6 Jan. 2012 [doi: 10.1093/jnci/djr500]).

At 13 years, 4,250 of the 38,340 participants in the intervention arm had been diagnosed with prostate cancer, compared with 3,815 of the 38,345 control participants. "The cumulative incidence rates for prostate cancer in the intervention and control arms were 108.4 and 97.1 per 10,000 person-years, respectively, resulting in a statistically significant 12% relative increase in the intervention arm," the authors wrote. Of the prostate cancer diagnoses, 401 in the intervention arm and 454 in the usual care arm were high-grade prostate cancers with Gleason scores of 8-10.

At 13 years of follow-up, there were 158 deaths in the intervention arm and 145 deaths in the usual-care arm. "The cumulative mortality rates from prostate cancer were 3.7 and 3.4 deaths per 10,000 person-years, respectively, resulting in a non-statistically significant difference between the two arms," according to the authors. The examination of mortality rates per 10,000 person-years and relative risks of prostate cancer mortality by age, comorbidity, and pretrial PSA testing produced no statistically significant interactions.

Deaths from all causes other than prostate, lung, and colorectal cancers differed by a factor of "borderline" statistical significance, with 5,783 deaths in the intervention arm and 5,982 in the usual-care arm, Dr. Andriole and his associates wrote. "Intervention and control arms showed 23% and 22% deaths, respectively, from non-PLCO cancers, and 21% and 19% deaths, respectively, from ischemic heart disease."

The authors acknowledged limitations of the study, including the possibility that a reduction in prostate cancer mortality in the analysis has somehow been masked by "the sticking diagnosis effect." In other words, more deaths were attributed to prostate cancer in the intervention arm. This possibility is supported by the statistically significant lower all-cause mortality in the intervention group as compared with the usual-care group. The percentage of deaths from other causes was higher in the intervention arm, so an error in cause of death attribution likely does not account for the excess prostate cancer deaths in the intervention group, they concluded.

The investigators plan to update the mortality findings through 15 years of follow-up, when those data become available.

Some of the study authors report relationships with Amgen, Augmenix, Bayer, Cambridge Endo, Caris, Envisioneering Medical, France Foundation, GenProbe, GlaxoSmithKline, Human Genome Sciences, Myriad Genetics, Steba Biotech, Ortho Clinical Diagnostics, and Viking Medical.

SAN DIEGO – Insulinlike growth factor I level was not useful as a marker of growth hormone deficiency or altered body composition in a retrospective review of a large cohort of adult survivors of childhood cancers.

Late cancer treatment–related complications – metabolic syndrome, osteogenic side effects, thyroid dysfunction, and growth hormone deficiency – are increasing as a result of increased childhood cancer survivorship; 1 in 640 young adults is now a survivor of childhood cancer, she said.

Insulinlike growth factor I (IGF-I) is often used as a marker for growth hormone deficiency, said Dr. Blijdorp of the department of pediatric oncology at Erasmus University, Rotterdam, the Netherlands. Low IGF-I has been associated with a high body mass index and high visceral fat percentage, she said. Because BMI, dual x-ray absorptiometry (DXA), and waist-hip ratio are limited in their ability to determine body composition, "it would be useful to have an easy-to-measure serum marker, such as IGF-I, that predicts alterations in body composition, she added.

Dr. Blijdorp and her associates retrospectively reviewed 610 adult childhood cancer survivors who were treated at the university. Their median age at diagnosis was 6 years and the median follow-up time was 18 years. The researchers reviewed IGF-I z scores, anthropometrical measures, growth hormone–stimulation tests in patients with clinical suspicion of growth hormone deficiency, and measures of body composition on DXA.

About 30% of the patients had leukemia. Of the 610 survivors, 158 had cranial irradiation. A history of cranial irradiation was associated with a higher incidence of metabolic syndrome, with an increased BMI, waist-hip ratio, visceral fat percentage, and total body fat percentage, as well as lower lean body mass, Dr. Karin Blijdorp said at the annual meeting of the American Society of Hematology.

Significantly lower IGF-I z-scores (P less than .001) were noted in the acute leukemia survivors who had cranial irradiation (25 Gy; range, 24-25 Gy) and the brain tumor survivors who had local irradiation (42 Gy; range, 35-54 Gy). Compared with survivors who did not undergo cranial irradiation, survivors who underwent cranial irradiation also had lower height standard deviation scores (P less than .001), higher BMI (P less than .01), higher waist-hip ratios (P less than .001), higher visceral fat percentages (P less than .001), higher total body fat percentages (P less than .001), and lower lean body mass (P less than .001).

IGF-I was not strongly correlated with BMI (r = 0.12; P = .04), waist-hip ratio (r = 0.15; P = .01), total fat percentage (r = 0.14; P = .02), and lean body mass (r = 0.15; P = .01).

Among survivors who had low IGF-I levels and received growth hormone stimulation, IGF-I z scores did not did not significantly differ between those with and without severe growth hormone deficiency (P = .39).

Dr. Blijdorp said that she had no relevant financial conflicts to disclose.

SAN DIEGO – Insulinlike growth factor I level was not useful as a marker of growth hormone deficiency or altered body composition in a retrospective review of a large cohort of adult survivors of childhood cancers.

Late cancer treatment–related complications – metabolic syndrome, osteogenic side effects, thyroid dysfunction, and growth hormone deficiency – are increasing as a result of increased childhood cancer survivorship; 1 in 640 young adults is now a survivor of childhood cancer, she said.

Insulinlike growth factor I (IGF-I) is often used as a marker for growth hormone deficiency, said Dr. Blijdorp of the department of pediatric oncology at Erasmus University, Rotterdam, the Netherlands. Low IGF-I has been associated with a high body mass index and high visceral fat percentage, she said. Because BMI, dual x-ray absorptiometry (DXA), and waist-hip ratio are limited in their ability to determine body composition, "it would be useful to have an easy-to-measure serum marker, such as IGF-I, that predicts alterations in body composition, she added.

Dr. Blijdorp and her associates retrospectively reviewed 610 adult childhood cancer survivors who were treated at the university. Their median age at diagnosis was 6 years and the median follow-up time was 18 years. The researchers reviewed IGF-I z scores, anthropometrical measures, growth hormone–stimulation tests in patients with clinical suspicion of growth hormone deficiency, and measures of body composition on DXA.

About 30% of the patients had leukemia. Of the 610 survivors, 158 had cranial irradiation. A history of cranial irradiation was associated with a higher incidence of metabolic syndrome, with an increased BMI, waist-hip ratio, visceral fat percentage, and total body fat percentage, as well as lower lean body mass, Dr. Karin Blijdorp said at the annual meeting of the American Society of Hematology.

Significantly lower IGF-I z-scores (P less than .001) were noted in the acute leukemia survivors who had cranial irradiation (25 Gy; range, 24-25 Gy) and the brain tumor survivors who had local irradiation (42 Gy; range, 35-54 Gy). Compared with survivors who did not undergo cranial irradiation, survivors who underwent cranial irradiation also had lower height standard deviation scores (P less than .001), higher BMI (P less than .01), higher waist-hip ratios (P less than .001), higher visceral fat percentages (P less than .001), higher total body fat percentages (P less than .001), and lower lean body mass (P less than .001).

IGF-I was not strongly correlated with BMI (r = 0.12; P = .04), waist-hip ratio (r = 0.15; P = .01), total fat percentage (r = 0.14; P = .02), and lean body mass (r = 0.15; P = .01).

Among survivors who had low IGF-I levels and received growth hormone stimulation, IGF-I z scores did not did not significantly differ between those with and without severe growth hormone deficiency (P = .39).

Dr. Blijdorp said that she had no relevant financial conflicts to disclose.

SAN DIEGO – Insulinlike growth factor I level was not useful as a marker of growth hormone deficiency or altered body composition in a retrospective review of a large cohort of adult survivors of childhood cancers.

Late cancer treatment–related complications – metabolic syndrome, osteogenic side effects, thyroid dysfunction, and growth hormone deficiency – are increasing as a result of increased childhood cancer survivorship; 1 in 640 young adults is now a survivor of childhood cancer, she said.

Insulinlike growth factor I (IGF-I) is often used as a marker for growth hormone deficiency, said Dr. Blijdorp of the department of pediatric oncology at Erasmus University, Rotterdam, the Netherlands. Low IGF-I has been associated with a high body mass index and high visceral fat percentage, she said. Because BMI, dual x-ray absorptiometry (DXA), and waist-hip ratio are limited in their ability to determine body composition, "it would be useful to have an easy-to-measure serum marker, such as IGF-I, that predicts alterations in body composition, she added.

Dr. Blijdorp and her associates retrospectively reviewed 610 adult childhood cancer survivors who were treated at the university. Their median age at diagnosis was 6 years and the median follow-up time was 18 years. The researchers reviewed IGF-I z scores, anthropometrical measures, growth hormone–stimulation tests in patients with clinical suspicion of growth hormone deficiency, and measures of body composition on DXA.

About 30% of the patients had leukemia. Of the 610 survivors, 158 had cranial irradiation. A history of cranial irradiation was associated with a higher incidence of metabolic syndrome, with an increased BMI, waist-hip ratio, visceral fat percentage, and total body fat percentage, as well as lower lean body mass, Dr. Karin Blijdorp said at the annual meeting of the American Society of Hematology.

Significantly lower IGF-I z-scores (P less than .001) were noted in the acute leukemia survivors who had cranial irradiation (25 Gy; range, 24-25 Gy) and the brain tumor survivors who had local irradiation (42 Gy; range, 35-54 Gy). Compared with survivors who did not undergo cranial irradiation, survivors who underwent cranial irradiation also had lower height standard deviation scores (P less than .001), higher BMI (P less than .01), higher waist-hip ratios (P less than .001), higher visceral fat percentages (P less than .001), higher total body fat percentages (P less than .001), and lower lean body mass (P less than .001).

IGF-I was not strongly correlated with BMI (r = 0.12; P = .04), waist-hip ratio (r = 0.15; P = .01), total fat percentage (r = 0.14; P = .02), and lean body mass (r = 0.15; P = .01).

Among survivors who had low IGF-I levels and received growth hormone stimulation, IGF-I z scores did not did not significantly differ between those with and without severe growth hormone deficiency (P = .39).

Dr. Blijdorp said that she had no relevant financial conflicts to disclose.

SAN DIEGO – Patients who receive heparin bridging during an interruption of oral anticoagulation appear to be at a 5.4-fold increased risk of overall bleeding and a 3.6-fold increased risk of major bleeding, without a reduction in risk of thromboembolic events.

Those are key findings from a systematic review and meta-analysis of recently published medical literature presented by Dr. Jovana Yudin at the annual meeting of the American Society of Hematology.

Antithrombotic and thrombolytic therapy guidelines published by the American College of Chest Physicians in 2008 recommended bridging according to an individualized approach (Chest 2008;133[suppl. 6]:299S-339S).

"They suggested bridging according to patients’ bleeding and thromboembolic risk," said Dr. Yudin, a fellow in the hematology residency program at McMaster University, Hamilton, Ont. "Within the last decade, several new studies have been published using periprocedural bridging. In these studies, low-molecular-weight heparin has been used with increased frequency. However, optimal strategies for bridging remain unclear. Our objective was to do a systematic review and meta-analysis of bridging trials published in the last decade to look at thromboembolic risk as well as bleeding risk."

Dr. Yudin and her associates searched the MEDLINE, EMBASE, and Cochrane Collaboration databases for systematic reviews and meta-analyses of studies published between Jan. 1, 2001, and July 31, 2010, that examined bleeding and thromboembolic events in patients receiving bridging therapy during temporary oral anticoagulation interruption for elective surgical or invasive procedures. Studies were excluded if the reporting of thromboembolic or bleeding outcomes was unclear, or if they focused exclusively on patients with renal failure (ASH 2011; abstract 545). All studies were reviewed by two independent investigators.

The researchers identified and screened 1,164 studies for review. Of these, 35 studies that included 7,169 bridged patients were selected for the final review. Most of the studies (33) were observational, and only two were randomized. The median follow-up was 30 days.

The most common indication for anticoagulation was atrial fibrillation (44%), followed by mechanical valve (24%), prior venous thromboembolism (22%), and other (10%).

The most common preoperative strategy was to discontinue oral anticoagulation more than 3 days in advance. Low-molecular-weight heparin was most commonly used, both preoperatively and postoperatively.

Dr. Yudin reported that thromboembolic events, which were primarily arterial in nature, occurred in 73 of the 7,169 patients (mean rate, 0.96%). The mean rate of overall bleeding was 13.01%, whereas the mean rate of major bleeding was 4.32%.

Eight of the studies included in the final analysis had control groups from which the researchers were able to pull data to determine an odds ratio for thromboembolism with bridging vs. no bridging. These studies included 1,691 bridged patients and 3,493 nonbridged patients. The odds ratio for thromboembolic events was 0.80, with a 95% confidence interval (CI) of 0.42-1.54, "suggesting no risk reduction for thromboembolic events with heparin or low-molecular-weight bridging," Dr. Yudin said. "There was also no difference between these two groups in the risk for arterial or venous thromboembolism."

To determine the risk of overall bleeding, the researchers pulled data from 13 studies that included control groups. These studies included 1,935 bridged patients and 5,160 nonbridged patients. The odds ratio for overall bleeding with bridging was 5.40 (95% CI, 3.00-9.74). "This suggested an increased risk of overall bleeding with bridging anticoagulation, but there was significant heterogeneity noted across these studies."

For major bleeding, five studies with control groups were assessed. These included 1,397 bridged patients and 2,104 nonbridged patients. The odds ratio for major bleeding was 3.60 (95% CI, 1.52-8.50), "again suggesting an increased risk in major bleeding with bridging," she said. "There was significant heterogeneity noted across studies."

Dr. Yudin acknowledged that the review had certain limitations: Most of the studies included in the analysis were observational, and only about a third had control groups. "Our control groups consisted largely of low-thromboembolic-risk patients, or patients who were not chronically on vitamin K antagonists, suggesting that they had a different risk profile for thromboembolism than many of the bridged patients," she said.

The findings "underline the need for studies of higher [methodological] quality in periprocedural bridging," she concluded. "It also tells us that there is a need for standardized definitions in terms of outcomes. We suspect that much of our heterogeneity had to do with varying definitions for outcomes such as major bleeding."

Dr. Yudin said that she had no relevant financial conflicts to disclose.

SAN DIEGO – Patients who receive heparin bridging during an interruption of oral anticoagulation appear to be at a 5.4-fold increased risk of overall bleeding and a 3.6-fold increased risk of major bleeding, without a reduction in risk of thromboembolic events.

Those are key findings from a systematic review and meta-analysis of recently published medical literature presented by Dr. Jovana Yudin at the annual meeting of the American Society of Hematology.

Antithrombotic and thrombolytic therapy guidelines published by the American College of Chest Physicians in 2008 recommended bridging according to an individualized approach (Chest 2008;133[suppl. 6]:299S-339S).

"They suggested bridging according to patients’ bleeding and thromboembolic risk," said Dr. Yudin, a fellow in the hematology residency program at McMaster University, Hamilton, Ont. "Within the last decade, several new studies have been published using periprocedural bridging. In these studies, low-molecular-weight heparin has been used with increased frequency. However, optimal strategies for bridging remain unclear. Our objective was to do a systematic review and meta-analysis of bridging trials published in the last decade to look at thromboembolic risk as well as bleeding risk."

Dr. Yudin and her associates searched the MEDLINE, EMBASE, and Cochrane Collaboration databases for systematic reviews and meta-analyses of studies published between Jan. 1, 2001, and July 31, 2010, that examined bleeding and thromboembolic events in patients receiving bridging therapy during temporary oral anticoagulation interruption for elective surgical or invasive procedures. Studies were excluded if the reporting of thromboembolic or bleeding outcomes was unclear, or if they focused exclusively on patients with renal failure (ASH 2011; abstract 545). All studies were reviewed by two independent investigators.

The researchers identified and screened 1,164 studies for review. Of these, 35 studies that included 7,169 bridged patients were selected for the final review. Most of the studies (33) were observational, and only two were randomized. The median follow-up was 30 days.

The most common indication for anticoagulation was atrial fibrillation (44%), followed by mechanical valve (24%), prior venous thromboembolism (22%), and other (10%).

The most common preoperative strategy was to discontinue oral anticoagulation more than 3 days in advance. Low-molecular-weight heparin was most commonly used, both preoperatively and postoperatively.

Dr. Yudin reported that thromboembolic events, which were primarily arterial in nature, occurred in 73 of the 7,169 patients (mean rate, 0.96%). The mean rate of overall bleeding was 13.01%, whereas the mean rate of major bleeding was 4.32%.

Eight of the studies included in the final analysis had control groups from which the researchers were able to pull data to determine an odds ratio for thromboembolism with bridging vs. no bridging. These studies included 1,691 bridged patients and 3,493 nonbridged patients. The odds ratio for thromboembolic events was 0.80, with a 95% confidence interval (CI) of 0.42-1.54, "suggesting no risk reduction for thromboembolic events with heparin or low-molecular-weight bridging," Dr. Yudin said. "There was also no difference between these two groups in the risk for arterial or venous thromboembolism."

To determine the risk of overall bleeding, the researchers pulled data from 13 studies that included control groups. These studies included 1,935 bridged patients and 5,160 nonbridged patients. The odds ratio for overall bleeding with bridging was 5.40 (95% CI, 3.00-9.74). "This suggested an increased risk of overall bleeding with bridging anticoagulation, but there was significant heterogeneity noted across these studies."

For major bleeding, five studies with control groups were assessed. These included 1,397 bridged patients and 2,104 nonbridged patients. The odds ratio for major bleeding was 3.60 (95% CI, 1.52-8.50), "again suggesting an increased risk in major bleeding with bridging," she said. "There was significant heterogeneity noted across studies."

Dr. Yudin acknowledged that the review had certain limitations: Most of the studies included in the analysis were observational, and only about a third had control groups. "Our control groups consisted largely of low-thromboembolic-risk patients, or patients who were not chronically on vitamin K antagonists, suggesting that they had a different risk profile for thromboembolism than many of the bridged patients," she said.

The findings "underline the need for studies of higher [methodological] quality in periprocedural bridging," she concluded. "It also tells us that there is a need for standardized definitions in terms of outcomes. We suspect that much of our heterogeneity had to do with varying definitions for outcomes such as major bleeding."

Dr. Yudin said that she had no relevant financial conflicts to disclose.

SAN DIEGO – Patients who receive heparin bridging during an interruption of oral anticoagulation appear to be at a 5.4-fold increased risk of overall bleeding and a 3.6-fold increased risk of major bleeding, without a reduction in risk of thromboembolic events.

Those are key findings from a systematic review and meta-analysis of recently published medical literature presented by Dr. Jovana Yudin at the annual meeting of the American Society of Hematology.

Antithrombotic and thrombolytic therapy guidelines published by the American College of Chest Physicians in 2008 recommended bridging according to an individualized approach (Chest 2008;133[suppl. 6]:299S-339S).

"They suggested bridging according to patients’ bleeding and thromboembolic risk," said Dr. Yudin, a fellow in the hematology residency program at McMaster University, Hamilton, Ont. "Within the last decade, several new studies have been published using periprocedural bridging. In these studies, low-molecular-weight heparin has been used with increased frequency. However, optimal strategies for bridging remain unclear. Our objective was to do a systematic review and meta-analysis of bridging trials published in the last decade to look at thromboembolic risk as well as bleeding risk."

Dr. Yudin and her associates searched the MEDLINE, EMBASE, and Cochrane Collaboration databases for systematic reviews and meta-analyses of studies published between Jan. 1, 2001, and July 31, 2010, that examined bleeding and thromboembolic events in patients receiving bridging therapy during temporary oral anticoagulation interruption for elective surgical or invasive procedures. Studies were excluded if the reporting of thromboembolic or bleeding outcomes was unclear, or if they focused exclusively on patients with renal failure (ASH 2011; abstract 545). All studies were reviewed by two independent investigators.

The researchers identified and screened 1,164 studies for review. Of these, 35 studies that included 7,169 bridged patients were selected for the final review. Most of the studies (33) were observational, and only two were randomized. The median follow-up was 30 days.

The most common indication for anticoagulation was atrial fibrillation (44%), followed by mechanical valve (24%), prior venous thromboembolism (22%), and other (10%).

The most common preoperative strategy was to discontinue oral anticoagulation more than 3 days in advance. Low-molecular-weight heparin was most commonly used, both preoperatively and postoperatively.

Dr. Yudin reported that thromboembolic events, which were primarily arterial in nature, occurred in 73 of the 7,169 patients (mean rate, 0.96%). The mean rate of overall bleeding was 13.01%, whereas the mean rate of major bleeding was 4.32%.

Eight of the studies included in the final analysis had control groups from which the researchers were able to pull data to determine an odds ratio for thromboembolism with bridging vs. no bridging. These studies included 1,691 bridged patients and 3,493 nonbridged patients. The odds ratio for thromboembolic events was 0.80, with a 95% confidence interval (CI) of 0.42-1.54, "suggesting no risk reduction for thromboembolic events with heparin or low-molecular-weight bridging," Dr. Yudin said. "There was also no difference between these two groups in the risk for arterial or venous thromboembolism."

To determine the risk of overall bleeding, the researchers pulled data from 13 studies that included control groups. These studies included 1,935 bridged patients and 5,160 nonbridged patients. The odds ratio for overall bleeding with bridging was 5.40 (95% CI, 3.00-9.74). "This suggested an increased risk of overall bleeding with bridging anticoagulation, but there was significant heterogeneity noted across these studies."

For major bleeding, five studies with control groups were assessed. These included 1,397 bridged patients and 2,104 nonbridged patients. The odds ratio for major bleeding was 3.60 (95% CI, 1.52-8.50), "again suggesting an increased risk in major bleeding with bridging," she said. "There was significant heterogeneity noted across studies."

Dr. Yudin acknowledged that the review had certain limitations: Most of the studies included in the analysis were observational, and only about a third had control groups. "Our control groups consisted largely of low-thromboembolic-risk patients, or patients who were not chronically on vitamin K antagonists, suggesting that they had a different risk profile for thromboembolism than many of the bridged patients," she said.

The findings "underline the need for studies of higher [methodological] quality in periprocedural bridging," she concluded. "It also tells us that there is a need for standardized definitions in terms of outcomes. We suspect that much of our heterogeneity had to do with varying definitions for outcomes such as major bleeding."

Dr. Yudin said that she had no relevant financial conflicts to disclose.