Mary Ann Moon

Major Finding: The hazard ratios for diabetes were 0.62 for patients taking TNF inhibitors and 0.54 for patients taking hydroxychloroquine, compared with patients taking nonbiologic DMARDs to treat their rheumatoid arthritis or psoriasis.

Data Source: A retrospective observational study involving 13,905 adults who had either RA or psoriasis, received a DMARD, and were followed for approximately 6 months for the development of diabetes. Participants were enrolled in one of two health care systems.

Disclosures: This study was supported by Amgen. Dr. Solomon reported ties to Abbott, Amgen, Bristol-Myers Squibb, and Pfizer, and his associates reported ties to numerous industry sources.

Some disease-modifying antirheumatic drugs that are taken for rheumatoid arthritis or psoriasis appear to reduce the rate of incident diabetes.

In a retrospective cohort study of patients who had RA or psoriasis, the use of a tumor necrosis factor (TNF) inhibitor or hydroxychloroquine to treat the systemic inflammatory disorder was associated with a reduced risk of developing diabetes, compared with the use of methotrexate or nonbiologic DMARDs, said Dr. Daniel H. Solomon of the divisions of phamacoepidemiology and rheumatology at Brigham and Women's Hospital, Boston, and his associates.

“Considering these results, in light of prior findings regarding improved insulin and glucose metabolism and reduced diabetes risk with hydroxychloroquine and TNF inhibitors, there is evidence suggesting a possible role for DMARDs and immunosuppression in diabetes prevention,” they noted.

The investigators assessed the relationship between DMARDs and the risk of new-onset diabetes because previous studies have demonstrated that inflammatory conditions such as RA and psoriasis predispose patients to insulin resistance, and that some of these anti-inflammatory medications appear to improve insulin resistance and prevent the onset of diabetes. They analyzed information from the databases of a Canadian health care system and a commercial U.S. health plan to identify 13,905 adults with RA or psoriasis who had filled at least one prescription for a DMARD and could be followed for approximately 6 months.

The DMARDs were divided into four mutually exclusive groups. The four groups were (1) TNF inhibitors such as adalimumab, etanercept, or infliximab; (2) methotrexate; (3) hydroxychloroquine; and (4) other nonbiologic DMARDs such as sulfasalazine, leflunomide, cyclosporine, azathioprine, cyclophosphamide, mycophenolate mofetil, 6-thioguanine, acitretin,

A total of 267 study subjects developed incident diabetes. The incidence was highest among patients who were taking nonbiologic DMARDs.

Patients taking a TNF inhibitor or hydroxychloroquine showed a reduced risk of diabetes, compared with patients taking any other agents.

After accounting for the effects of potentially confounding factors such as patient age, sex, and several clinical variables, investigators found that the hazard ratios for diabetes were 0.62 for TNF inhibitors and 0.54 for hydroxychloroquine, compared with the nonbiologic DMARDs, Dr. Solomon and his colleagues said (JAMA 2011;305:2525-31).

“These findings held up across a variety of sensitivity analyses,” they added.

“Taken in the context of prior research, [our] study supports the potential role for systemic immunosuppression in prevention and control of diabetes.

“If future studies show this convincingly, systemic immunosuppression in such situations would be predicated on a favorable risk-benefit profile.”

For example, the benefit of immunosuppression may outweigh the risk in a patient with a systemic rheumatic disease for which a DMARD is already indicated.

But immunosuppression may not outweigh the risk in a patient who already has diabetes and is prone to infection.

The investigators emphasized that this was an observational epidemiologic study without randomized-treatment assignment, so causation cannot be inferred.

“It is possible that patients receiving a TNF inhibitor or hydroxychloroquine were different from the reference group of other nonbiologic DMARD users in ways that went unmeasured, such as body mass index, exercise participation, family history, or disease severity,” they noted.

They added that the findings warrant confirmation in a randomized, controlled trial to test “the ability of these agents to prevent diabetes among participants with systemic inflammatory disorders.”

View on the News

Confirmation Still Needed

“Prospective trials are needed to confirm [these] observational data and clarify which patients may benefit from these possible pleiotropic effects of specific anti-inflammatories,” said Dr. Tim Bongartz and Dr. Yogish C. Kudva.

If TNF inhibitors or hydroxychloroquine prove to address two complex disease processes at once, “it will be crucial to investigate how much of their potential antidiabetic effects would add to good disease control, the durability of these effects, and the timing of treatment.”

Even if treatment of chronic inflammatory disease can reduce the risk of diabetes, “clinicians still will have to learn how to use specific anti-inflammatory agents to achieve optimal outcomes for both conditions,” they said.

DR. BONGARTZ is in the division of rheumatology and DR. KUDVA is in the division of endocrinology, diabetes, metabolism, and nutrition at the Mayo Clinic in Rochester, Minn. Dr. Bongartz reported ties to Wyeth and Abbott. Dr. Kudva reported no conflicts of interest. These remarks were taken from their editorial accompanying Dr. Solomon's report (JAMA 2011;305:2573-4).

Major Finding: The hazard ratios for diabetes were 0.62 for patients taking TNF inhibitors and 0.54 for patients taking hydroxychloroquine, compared with patients taking nonbiologic DMARDs to treat their rheumatoid arthritis or psoriasis.

Data Source: A retrospective observational study involving 13,905 adults who had either RA or psoriasis, received a DMARD, and were followed for approximately 6 months for the development of diabetes. Participants were enrolled in one of two health care systems.

Disclosures: This study was supported by Amgen. Dr. Solomon reported ties to Abbott, Amgen, Bristol-Myers Squibb, and Pfizer, and his associates reported ties to numerous industry sources.

Some disease-modifying antirheumatic drugs that are taken for rheumatoid arthritis or psoriasis appear to reduce the rate of incident diabetes.

In a retrospective cohort study of patients who had RA or psoriasis, the use of a tumor necrosis factor (TNF) inhibitor or hydroxychloroquine to treat the systemic inflammatory disorder was associated with a reduced risk of developing diabetes, compared with the use of methotrexate or nonbiologic DMARDs, said Dr. Daniel H. Solomon of the divisions of phamacoepidemiology and rheumatology at Brigham and Women's Hospital, Boston, and his associates.

“Considering these results, in light of prior findings regarding improved insulin and glucose metabolism and reduced diabetes risk with hydroxychloroquine and TNF inhibitors, there is evidence suggesting a possible role for DMARDs and immunosuppression in diabetes prevention,” they noted.

The investigators assessed the relationship between DMARDs and the risk of new-onset diabetes because previous studies have demonstrated that inflammatory conditions such as RA and psoriasis predispose patients to insulin resistance, and that some of these anti-inflammatory medications appear to improve insulin resistance and prevent the onset of diabetes. They analyzed information from the databases of a Canadian health care system and a commercial U.S. health plan to identify 13,905 adults with RA or psoriasis who had filled at least one prescription for a DMARD and could be followed for approximately 6 months.

The DMARDs were divided into four mutually exclusive groups. The four groups were (1) TNF inhibitors such as adalimumab, etanercept, or infliximab; (2) methotrexate; (3) hydroxychloroquine; and (4) other nonbiologic DMARDs such as sulfasalazine, leflunomide, cyclosporine, azathioprine, cyclophosphamide, mycophenolate mofetil, 6-thioguanine, acitretin,

A total of 267 study subjects developed incident diabetes. The incidence was highest among patients who were taking nonbiologic DMARDs.

Patients taking a TNF inhibitor or hydroxychloroquine showed a reduced risk of diabetes, compared with patients taking any other agents.

After accounting for the effects of potentially confounding factors such as patient age, sex, and several clinical variables, investigators found that the hazard ratios for diabetes were 0.62 for TNF inhibitors and 0.54 for hydroxychloroquine, compared with the nonbiologic DMARDs, Dr. Solomon and his colleagues said (JAMA 2011;305:2525-31).

“These findings held up across a variety of sensitivity analyses,” they added.

“Taken in the context of prior research, [our] study supports the potential role for systemic immunosuppression in prevention and control of diabetes.

“If future studies show this convincingly, systemic immunosuppression in such situations would be predicated on a favorable risk-benefit profile.”

For example, the benefit of immunosuppression may outweigh the risk in a patient with a systemic rheumatic disease for which a DMARD is already indicated.

But immunosuppression may not outweigh the risk in a patient who already has diabetes and is prone to infection.

The investigators emphasized that this was an observational epidemiologic study without randomized-treatment assignment, so causation cannot be inferred.

“It is possible that patients receiving a TNF inhibitor or hydroxychloroquine were different from the reference group of other nonbiologic DMARD users in ways that went unmeasured, such as body mass index, exercise participation, family history, or disease severity,” they noted.

They added that the findings warrant confirmation in a randomized, controlled trial to test “the ability of these agents to prevent diabetes among participants with systemic inflammatory disorders.”

View on the News

Confirmation Still Needed

“Prospective trials are needed to confirm [these] observational data and clarify which patients may benefit from these possible pleiotropic effects of specific anti-inflammatories,” said Dr. Tim Bongartz and Dr. Yogish C. Kudva.

If TNF inhibitors or hydroxychloroquine prove to address two complex disease processes at once, “it will be crucial to investigate how much of their potential antidiabetic effects would add to good disease control, the durability of these effects, and the timing of treatment.”

Even if treatment of chronic inflammatory disease can reduce the risk of diabetes, “clinicians still will have to learn how to use specific anti-inflammatory agents to achieve optimal outcomes for both conditions,” they said.

DR. BONGARTZ is in the division of rheumatology and DR. KUDVA is in the division of endocrinology, diabetes, metabolism, and nutrition at the Mayo Clinic in Rochester, Minn. Dr. Bongartz reported ties to Wyeth and Abbott. Dr. Kudva reported no conflicts of interest. These remarks were taken from their editorial accompanying Dr. Solomon's report (JAMA 2011;305:2573-4).

Major Finding: The hazard ratios for diabetes were 0.62 for patients taking TNF inhibitors and 0.54 for patients taking hydroxychloroquine, compared with patients taking nonbiologic DMARDs to treat their rheumatoid arthritis or psoriasis.

Data Source: A retrospective observational study involving 13,905 adults who had either RA or psoriasis, received a DMARD, and were followed for approximately 6 months for the development of diabetes. Participants were enrolled in one of two health care systems.

Disclosures: This study was supported by Amgen. Dr. Solomon reported ties to Abbott, Amgen, Bristol-Myers Squibb, and Pfizer, and his associates reported ties to numerous industry sources.

Some disease-modifying antirheumatic drugs that are taken for rheumatoid arthritis or psoriasis appear to reduce the rate of incident diabetes.

In a retrospective cohort study of patients who had RA or psoriasis, the use of a tumor necrosis factor (TNF) inhibitor or hydroxychloroquine to treat the systemic inflammatory disorder was associated with a reduced risk of developing diabetes, compared with the use of methotrexate or nonbiologic DMARDs, said Dr. Daniel H. Solomon of the divisions of phamacoepidemiology and rheumatology at Brigham and Women's Hospital, Boston, and his associates.

“Considering these results, in light of prior findings regarding improved insulin and glucose metabolism and reduced diabetes risk with hydroxychloroquine and TNF inhibitors, there is evidence suggesting a possible role for DMARDs and immunosuppression in diabetes prevention,” they noted.

The investigators assessed the relationship between DMARDs and the risk of new-onset diabetes because previous studies have demonstrated that inflammatory conditions such as RA and psoriasis predispose patients to insulin resistance, and that some of these anti-inflammatory medications appear to improve insulin resistance and prevent the onset of diabetes. They analyzed information from the databases of a Canadian health care system and a commercial U.S. health plan to identify 13,905 adults with RA or psoriasis who had filled at least one prescription for a DMARD and could be followed for approximately 6 months.

The DMARDs were divided into four mutually exclusive groups. The four groups were (1) TNF inhibitors such as adalimumab, etanercept, or infliximab; (2) methotrexate; (3) hydroxychloroquine; and (4) other nonbiologic DMARDs such as sulfasalazine, leflunomide, cyclosporine, azathioprine, cyclophosphamide, mycophenolate mofetil, 6-thioguanine, acitretin,

A total of 267 study subjects developed incident diabetes. The incidence was highest among patients who were taking nonbiologic DMARDs.

Patients taking a TNF inhibitor or hydroxychloroquine showed a reduced risk of diabetes, compared with patients taking any other agents.

After accounting for the effects of potentially confounding factors such as patient age, sex, and several clinical variables, investigators found that the hazard ratios for diabetes were 0.62 for TNF inhibitors and 0.54 for hydroxychloroquine, compared with the nonbiologic DMARDs, Dr. Solomon and his colleagues said (JAMA 2011;305:2525-31).

“These findings held up across a variety of sensitivity analyses,” they added.

“Taken in the context of prior research, [our] study supports the potential role for systemic immunosuppression in prevention and control of diabetes.

“If future studies show this convincingly, systemic immunosuppression in such situations would be predicated on a favorable risk-benefit profile.”

For example, the benefit of immunosuppression may outweigh the risk in a patient with a systemic rheumatic disease for which a DMARD is already indicated.

But immunosuppression may not outweigh the risk in a patient who already has diabetes and is prone to infection.

The investigators emphasized that this was an observational epidemiologic study without randomized-treatment assignment, so causation cannot be inferred.

“It is possible that patients receiving a TNF inhibitor or hydroxychloroquine were different from the reference group of other nonbiologic DMARD users in ways that went unmeasured, such as body mass index, exercise participation, family history, or disease severity,” they noted.

They added that the findings warrant confirmation in a randomized, controlled trial to test “the ability of these agents to prevent diabetes among participants with systemic inflammatory disorders.”

View on the News

Confirmation Still Needed

“Prospective trials are needed to confirm [these] observational data and clarify which patients may benefit from these possible pleiotropic effects of specific anti-inflammatories,” said Dr. Tim Bongartz and Dr. Yogish C. Kudva.

If TNF inhibitors or hydroxychloroquine prove to address two complex disease processes at once, “it will be crucial to investigate how much of their potential antidiabetic effects would add to good disease control, the durability of these effects, and the timing of treatment.”

Even if treatment of chronic inflammatory disease can reduce the risk of diabetes, “clinicians still will have to learn how to use specific anti-inflammatory agents to achieve optimal outcomes for both conditions,” they said.

DR. BONGARTZ is in the division of rheumatology and DR. KUDVA is in the division of endocrinology, diabetes, metabolism, and nutrition at the Mayo Clinic in Rochester, Minn. Dr. Bongartz reported ties to Wyeth and Abbott. Dr. Kudva reported no conflicts of interest. These remarks were taken from their editorial accompanying Dr. Solomon's report (JAMA 2011;305:2573-4).

The details of what is described as a profoundly unethical marketing ploy masquerading as a phase IV trial of gabapentin were reported June 27 in the Archives of Internal Medicine.

The Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) study was a so-called seeding trial, in which the stated objective was to assess the safety and efficacy of gabapentin, but the actual aim was to increase prescribing of the drug by duping the very physicians recruited to conduct the "trial," according to three medicolegal consultants involved in litigation against the drug’s manufacturer.

"Although STEPS was conducted 15 years ago, the ethical issues illustrated by the trial’s conduct, and the data gained from Parke-Davis’ marketing analyses, have tremendous relevance in today’s debates over the limits and consequences of pharmaceutical industry sponsorship of phase IV postmarketing clinical trials," wrote Samuel D. Krumholz, Dr. David S. Egilman, and Dr. Joseph S. Ross.

"Our analysis is only the second comprehensive account of a seeding trial based on primary source documents, and [it] clearly demonstrates how a clinical trial was designed, conducted, and explicitly used to promote marketing objectives, not science, without providing full informed consent to the patients and physicians who participated in the study," they noted.

Mr. Krumholz and Dr. Egilman are with Never Again Consulting, an independent Massachusetts firm that conducts research and analysis in support of occupational and environmental health. Dr. Egilman is also in the department of community health at Brown University, Providence, R.I., and Dr. Ross is at Yale–New Haven (Conn.) Hospital Center for Outcomes Research and Evaluation.

Their access to a complete set of documents and depositions produced during litigation against Parke-Davis (now a subsidiary of Pfizer) enabled them to analyze and expose seeding trials, which are "used to promote drugs recently approved or under review by the U.S. Food and Drug Administration by encouraging prescribers to use these medications under the guise of participating as an investigator in [the] trial."

The STEPS trial included the three key traits said to characterize seeding trials: involvement of the marketing department in study conception and design; involvement of the marketing department in data collection and analysis; and nondisclosure of the study’s true purpose from physicians, patients, and institutional review boards.

When asked to comment on the report, Pfizer spokesperson Christopher Loder wrote in an e-mail that "Neurontin is an important FDA-approved medicine that physicians have prescribed to treat millions of patients safely and effectively. Neurontin has been widely studied for more than 2 decades and there is an extensive body of publicly available literature on its safety and its use."

In the STEPS trial, Parke-Davis recruited 772 physicians to prescribe Neurontin (gabapentin) and titrate the dose upward in patients whose partial seizures were not completely controlled by other drugs. The drug company purposefully recruited "site investigators with little or no clinical trial experience [and] provided insufficient training," and limited enrollment to about four patients per investigator.

The study design was uncontrolled and unblinded, and its rigid titration protocol led to the exclusion of 87% of the study subjects. One institutional review board that twice rejected the STEPS application to be conducted at their medical center stated that "the entry criteria and outcome measures are too vague to allow any scientific conclusions to be reach[ed]."

Parke-Davis sales representatives collected and recorded individual subject data. In a clear example of data tampering, they not only attended epilepsy patients’ office visits (under the guise of "shadowing" the clinician), but also actively promoted the use of Neurontin and blocked the use of competing medications, particularly lamotrigine (Lamictal), at those visits. They also rewarded participating investigators with free lunches and dinners.

Without informing either patients or physicians, the drug company’s marketing department monitored each investigator’s prescribing practices. It documented a 38% increase in prescriptions of Neurontin after investigators attended an introductory briefing, as well as a 10% increase in the average prescribed dose. It also compared prescribing patterns between study investigators and a control group of nonparticipating neurologists, and documented increased prescribing of Neurontin only among the study participants.

In numerous internal documents, Parke-Davis described STEPS as a marketing strategy rather than a scientific study. The actual findings of the trial were immaterial; the strategy’s success in increasing market share in new prescriptions was paramount, the authors said (Arch. Intern. Med. 2011;171:1100-7).

"Our analysis provides critical evidence suggesting that seeding trials are used as a promotional strategy by pharmaceutical companies. Reform of the current IRB [institutional review board] system, as well as promoting better clinical trial practice in the human subjects research community, are necessary to prevent continued conduct of seeding trials by the pharmaceutical industry," they added.

Mr. Krumholz and his coauthors clearly demonstrate that the true intent of seeding trials is to introduce a new product and induce clinicians to use it, according to Dr. G. Caleb Alexander.

"Perhaps the greatest cause for concern is that these trials deceive investigators, clinicians, and patients, subverting the scientific process and violating ethical norms."

As others have noted, "Deception is not just an incidental part of a seeding trial, but rather the very success of the trial depends on such deception, since few institutional review boards, investigators, clinicians, or patients would willfully participate in a study with marketing objectives and little or no scientific value," Dr. Alexander wrote in commentary accompanying the report (Arch. Intern. Med. 2011;171:1107-8).

Because "there will continue to be a need for well designed, rigorously conducted phase 4 clinical trials," he noted that institutional review boards, clinical investigators, practicing clinicians, and other important stakeholders must increase their vigilance in order to prevent and recognize future seeding studies.

This analysis of the STEPS study was not directly supported by any grants or funds. Mr. Krumholz and Dr. Egilman are paid consultants for plaintiffs in litigation related to gabapentin against Pfizer Inc., and Dr. Ross is an unpaid consultant in the same litigation. Dr. Egilman and Dr. Ross were previously paid consultants for plaintiffs in litigation against Merck related to rofecoxib. Dr. Ross is supported by the National Institute on Aging and the American Federation of Aging Research.

Dr. Alexander is in the department of medicine at MacLean Center for Clinical Medical Ethics, University of Chicago Hospitals, and the department of pharmacy practice at the University of Illinois at Chicago School of Pharmacy. He is supported by the U.S. Agency for Healthcare Research and Quality, and he reported being a consultant for IMS Health.

The details of what is described as a profoundly unethical marketing ploy masquerading as a phase IV trial of gabapentin were reported June 27 in the Archives of Internal Medicine.

The Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) study was a so-called seeding trial, in which the stated objective was to assess the safety and efficacy of gabapentin, but the actual aim was to increase prescribing of the drug by duping the very physicians recruited to conduct the "trial," according to three medicolegal consultants involved in litigation against the drug’s manufacturer.

"Although STEPS was conducted 15 years ago, the ethical issues illustrated by the trial’s conduct, and the data gained from Parke-Davis’ marketing analyses, have tremendous relevance in today’s debates over the limits and consequences of pharmaceutical industry sponsorship of phase IV postmarketing clinical trials," wrote Samuel D. Krumholz, Dr. David S. Egilman, and Dr. Joseph S. Ross.

"Our analysis is only the second comprehensive account of a seeding trial based on primary source documents, and [it] clearly demonstrates how a clinical trial was designed, conducted, and explicitly used to promote marketing objectives, not science, without providing full informed consent to the patients and physicians who participated in the study," they noted.

Mr. Krumholz and Dr. Egilman are with Never Again Consulting, an independent Massachusetts firm that conducts research and analysis in support of occupational and environmental health. Dr. Egilman is also in the department of community health at Brown University, Providence, R.I., and Dr. Ross is at Yale–New Haven (Conn.) Hospital Center for Outcomes Research and Evaluation.

Their access to a complete set of documents and depositions produced during litigation against Parke-Davis (now a subsidiary of Pfizer) enabled them to analyze and expose seeding trials, which are "used to promote drugs recently approved or under review by the U.S. Food and Drug Administration by encouraging prescribers to use these medications under the guise of participating as an investigator in [the] trial."

The STEPS trial included the three key traits said to characterize seeding trials: involvement of the marketing department in study conception and design; involvement of the marketing department in data collection and analysis; and nondisclosure of the study’s true purpose from physicians, patients, and institutional review boards.

When asked to comment on the report, Pfizer spokesperson Christopher Loder wrote in an e-mail that "Neurontin is an important FDA-approved medicine that physicians have prescribed to treat millions of patients safely and effectively. Neurontin has been widely studied for more than 2 decades and there is an extensive body of publicly available literature on its safety and its use."

In the STEPS trial, Parke-Davis recruited 772 physicians to prescribe Neurontin (gabapentin) and titrate the dose upward in patients whose partial seizures were not completely controlled by other drugs. The drug company purposefully recruited "site investigators with little or no clinical trial experience [and] provided insufficient training," and limited enrollment to about four patients per investigator.

The study design was uncontrolled and unblinded, and its rigid titration protocol led to the exclusion of 87% of the study subjects. One institutional review board that twice rejected the STEPS application to be conducted at their medical center stated that "the entry criteria and outcome measures are too vague to allow any scientific conclusions to be reach[ed]."

Parke-Davis sales representatives collected and recorded individual subject data. In a clear example of data tampering, they not only attended epilepsy patients’ office visits (under the guise of "shadowing" the clinician), but also actively promoted the use of Neurontin and blocked the use of competing medications, particularly lamotrigine (Lamictal), at those visits. They also rewarded participating investigators with free lunches and dinners.

Without informing either patients or physicians, the drug company’s marketing department monitored each investigator’s prescribing practices. It documented a 38% increase in prescriptions of Neurontin after investigators attended an introductory briefing, as well as a 10% increase in the average prescribed dose. It also compared prescribing patterns between study investigators and a control group of nonparticipating neurologists, and documented increased prescribing of Neurontin only among the study participants.

In numerous internal documents, Parke-Davis described STEPS as a marketing strategy rather than a scientific study. The actual findings of the trial were immaterial; the strategy’s success in increasing market share in new prescriptions was paramount, the authors said (Arch. Intern. Med. 2011;171:1100-7).

"Our analysis provides critical evidence suggesting that seeding trials are used as a promotional strategy by pharmaceutical companies. Reform of the current IRB [institutional review board] system, as well as promoting better clinical trial practice in the human subjects research community, are necessary to prevent continued conduct of seeding trials by the pharmaceutical industry," they added.

Mr. Krumholz and his coauthors clearly demonstrate that the true intent of seeding trials is to introduce a new product and induce clinicians to use it, according to Dr. G. Caleb Alexander.

"Perhaps the greatest cause for concern is that these trials deceive investigators, clinicians, and patients, subverting the scientific process and violating ethical norms."

As others have noted, "Deception is not just an incidental part of a seeding trial, but rather the very success of the trial depends on such deception, since few institutional review boards, investigators, clinicians, or patients would willfully participate in a study with marketing objectives and little or no scientific value," Dr. Alexander wrote in commentary accompanying the report (Arch. Intern. Med. 2011;171:1107-8).

Because "there will continue to be a need for well designed, rigorously conducted phase 4 clinical trials," he noted that institutional review boards, clinical investigators, practicing clinicians, and other important stakeholders must increase their vigilance in order to prevent and recognize future seeding studies.

This analysis of the STEPS study was not directly supported by any grants or funds. Mr. Krumholz and Dr. Egilman are paid consultants for plaintiffs in litigation related to gabapentin against Pfizer Inc., and Dr. Ross is an unpaid consultant in the same litigation. Dr. Egilman and Dr. Ross were previously paid consultants for plaintiffs in litigation against Merck related to rofecoxib. Dr. Ross is supported by the National Institute on Aging and the American Federation of Aging Research.

Dr. Alexander is in the department of medicine at MacLean Center for Clinical Medical Ethics, University of Chicago Hospitals, and the department of pharmacy practice at the University of Illinois at Chicago School of Pharmacy. He is supported by the U.S. Agency for Healthcare Research and Quality, and he reported being a consultant for IMS Health.

The details of what is described as a profoundly unethical marketing ploy masquerading as a phase IV trial of gabapentin were reported June 27 in the Archives of Internal Medicine.

The Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) study was a so-called seeding trial, in which the stated objective was to assess the safety and efficacy of gabapentin, but the actual aim was to increase prescribing of the drug by duping the very physicians recruited to conduct the "trial," according to three medicolegal consultants involved in litigation against the drug’s manufacturer.

"Although STEPS was conducted 15 years ago, the ethical issues illustrated by the trial’s conduct, and the data gained from Parke-Davis’ marketing analyses, have tremendous relevance in today’s debates over the limits and consequences of pharmaceutical industry sponsorship of phase IV postmarketing clinical trials," wrote Samuel D. Krumholz, Dr. David S. Egilman, and Dr. Joseph S. Ross.

"Our analysis is only the second comprehensive account of a seeding trial based on primary source documents, and [it] clearly demonstrates how a clinical trial was designed, conducted, and explicitly used to promote marketing objectives, not science, without providing full informed consent to the patients and physicians who participated in the study," they noted.

Mr. Krumholz and Dr. Egilman are with Never Again Consulting, an independent Massachusetts firm that conducts research and analysis in support of occupational and environmental health. Dr. Egilman is also in the department of community health at Brown University, Providence, R.I., and Dr. Ross is at Yale–New Haven (Conn.) Hospital Center for Outcomes Research and Evaluation.

Their access to a complete set of documents and depositions produced during litigation against Parke-Davis (now a subsidiary of Pfizer) enabled them to analyze and expose seeding trials, which are "used to promote drugs recently approved or under review by the U.S. Food and Drug Administration by encouraging prescribers to use these medications under the guise of participating as an investigator in [the] trial."

The STEPS trial included the three key traits said to characterize seeding trials: involvement of the marketing department in study conception and design; involvement of the marketing department in data collection and analysis; and nondisclosure of the study’s true purpose from physicians, patients, and institutional review boards.

When asked to comment on the report, Pfizer spokesperson Christopher Loder wrote in an e-mail that "Neurontin is an important FDA-approved medicine that physicians have prescribed to treat millions of patients safely and effectively. Neurontin has been widely studied for more than 2 decades and there is an extensive body of publicly available literature on its safety and its use."

In the STEPS trial, Parke-Davis recruited 772 physicians to prescribe Neurontin (gabapentin) and titrate the dose upward in patients whose partial seizures were not completely controlled by other drugs. The drug company purposefully recruited "site investigators with little or no clinical trial experience [and] provided insufficient training," and limited enrollment to about four patients per investigator.

The study design was uncontrolled and unblinded, and its rigid titration protocol led to the exclusion of 87% of the study subjects. One institutional review board that twice rejected the STEPS application to be conducted at their medical center stated that "the entry criteria and outcome measures are too vague to allow any scientific conclusions to be reach[ed]."

Parke-Davis sales representatives collected and recorded individual subject data. In a clear example of data tampering, they not only attended epilepsy patients’ office visits (under the guise of "shadowing" the clinician), but also actively promoted the use of Neurontin and blocked the use of competing medications, particularly lamotrigine (Lamictal), at those visits. They also rewarded participating investigators with free lunches and dinners.

Without informing either patients or physicians, the drug company’s marketing department monitored each investigator’s prescribing practices. It documented a 38% increase in prescriptions of Neurontin after investigators attended an introductory briefing, as well as a 10% increase in the average prescribed dose. It also compared prescribing patterns between study investigators and a control group of nonparticipating neurologists, and documented increased prescribing of Neurontin only among the study participants.

In numerous internal documents, Parke-Davis described STEPS as a marketing strategy rather than a scientific study. The actual findings of the trial were immaterial; the strategy’s success in increasing market share in new prescriptions was paramount, the authors said (Arch. Intern. Med. 2011;171:1100-7).

"Our analysis provides critical evidence suggesting that seeding trials are used as a promotional strategy by pharmaceutical companies. Reform of the current IRB [institutional review board] system, as well as promoting better clinical trial practice in the human subjects research community, are necessary to prevent continued conduct of seeding trials by the pharmaceutical industry," they added.

Mr. Krumholz and his coauthors clearly demonstrate that the true intent of seeding trials is to introduce a new product and induce clinicians to use it, according to Dr. G. Caleb Alexander.

"Perhaps the greatest cause for concern is that these trials deceive investigators, clinicians, and patients, subverting the scientific process and violating ethical norms."

As others have noted, "Deception is not just an incidental part of a seeding trial, but rather the very success of the trial depends on such deception, since few institutional review boards, investigators, clinicians, or patients would willfully participate in a study with marketing objectives and little or no scientific value," Dr. Alexander wrote in commentary accompanying the report (Arch. Intern. Med. 2011;171:1107-8).

Because "there will continue to be a need for well designed, rigorously conducted phase 4 clinical trials," he noted that institutional review boards, clinical investigators, practicing clinicians, and other important stakeholders must increase their vigilance in order to prevent and recognize future seeding studies.

This analysis of the STEPS study was not directly supported by any grants or funds. Mr. Krumholz and Dr. Egilman are paid consultants for plaintiffs in litigation related to gabapentin against Pfizer Inc., and Dr. Ross is an unpaid consultant in the same litigation. Dr. Egilman and Dr. Ross were previously paid consultants for plaintiffs in litigation against Merck related to rofecoxib. Dr. Ross is supported by the National Institute on Aging and the American Federation of Aging Research.

Dr. Alexander is in the department of medicine at MacLean Center for Clinical Medical Ethics, University of Chicago Hospitals, and the department of pharmacy practice at the University of Illinois at Chicago School of Pharmacy. He is supported by the U.S. Agency for Healthcare Research and Quality, and he reported being a consultant for IMS Health.

The details of what is described as a profoundly unethical marketing ploy masquerading as a phase IV trial of gabapentin were reported June 27 in the Archives of Internal Medicine.

The Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) study was a so-called seeding trial, in which the stated objective was to assess the safety and efficacy of gabapentin, but the actual aim was to increase prescribing of the drug by duping the very physicians recruited to conduct the "trial," according to three medicolegal consultants involved in litigation against the drug’s manufacturer.

"Although STEPS was conducted 15 years ago, the ethical issues illustrated by the trial’s conduct, and the data gained from Parke-Davis’ marketing analyses, have tremendous relevance in today’s debates over the limits and consequences of pharmaceutical industry sponsorship of phase IV postmarketing clinical trials," wrote Samuel D. Krumholz, Dr. David S. Egilman, and Dr. Joseph S. Ross.

"Our analysis is only the second comprehensive account of a seeding trial based on primary source documents, and [it] clearly demonstrates how a clinical trial was designed, conducted, and explicitly used to promote marketing objectives, not science, without providing full informed consent to the patients and physicians who participated in the study," they noted.

Mr. Krumholz and Dr. Egilman are with Never Again Consulting, an independent Massachusetts firm that conducts research and analysis in support of occupational and environmental health. Dr. Egilman is also in the department of community health at Brown University, Providence, R.I., and Dr. Ross is at Yale–New Haven (Conn.) Hospital Center for Outcomes Research and Evaluation.

Their access to a complete set of documents and depositions produced during litigation against Parke-Davis (now a subsidiary of Pfizer) enabled them to analyze and expose seeding trials, which are "used to promote drugs recently approved or under review by the U.S. Food and Drug Administration by encouraging prescribers to use these medications under the guise of participating as an investigator in [the] trial."

The STEPS trial included the three key traits said to characterize seeding trials: involvement of the marketing department in study conception and design; involvement of the marketing department in data collection and analysis; and nondisclosure of the study’s true purpose from physicians, patients, and institutional review boards.

When asked to comment on the report, Pfizer spokesperson Christopher Loder wrote in an e-mail that "Neurontin is an important FDA-approved medicine that physicians have prescribed to treat millions of patients safely and effectively. Neurontin has been widely studied for more than 2 decades and there is an extensive body of publicly available literature on its safety and its use."

In the STEPS trial, Parke-Davis recruited 772 physicians to prescribe Neurontin (gabapentin) and titrate the dose upward in patients whose partial seizures were not completely controlled by other drugs. The drug company purposefully recruited "site investigators with little or no clinical trial experience [and] provided insufficient training," and limited enrollment to about four patients per investigator.

The study design was uncontrolled and unblinded, and its rigid titration protocol led to the exclusion of 87% of the study subjects. One institutional review board that twice rejected the STEPS application to be conducted at their medical center stated that "the entry criteria and outcome measures are too vague to allow any scientific conclusions to be reach[ed]."

Parke-Davis sales representatives collected and recorded individual subject data. In a clear example of data tampering, they not only attended epilepsy patients’ office visits (under the guise of "shadowing" the clinician), but also actively promoted the use of Neurontin and blocked the use of competing medications, particularly lamotrigine (Lamictal), at those visits. They also rewarded participating investigators with free lunches and dinners.

Without informing either patients or physicians, the drug company’s marketing department monitored each investigator’s prescribing practices. It documented a 38% increase in prescriptions of Neurontin after investigators attended an introductory briefing, as well as a 10% increase in the average prescribed dose. It also compared prescribing patterns between study investigators and a control group of nonparticipating neurologists, and documented increased prescribing of Neurontin only among the study participants.

In numerous internal documents, Parke-Davis described STEPS as a marketing strategy rather than a scientific study. The actual findings of the trial were immaterial; the strategy’s success in increasing market share in new prescriptions was paramount, the authors said (Arch. Intern. Med. 2011;171:1100-7).

"Our analysis provides critical evidence suggesting that seeding trials are used as a promotional strategy by pharmaceutical companies. Reform of the current IRB [institutional review board] system, as well as promoting better clinical trial practice in the human subjects research community, are necessary to prevent continued conduct of seeding trials by the pharmaceutical industry," they added.

Mr. Krumholz and his coauthors clearly demonstrate that the true intent of seeding trials is to introduce a new product and induce clinicians to use it, according to Dr. G. Caleb Alexander.

"Perhaps the greatest cause for concern is that these trials deceive investigators, clinicians, and patients, subverting the scientific process and violating ethical norms."

As others have noted, "Deception is not just an incidental part of a seeding trial, but rather the very success of the trial depends on such deception, since few institutional review boards, investigators, clinicians, or patients would willfully participate in a study with marketing objectives and little or no scientific value," Dr. Alexander wrote in commentary accompanying the report (Arch. Intern. Med. 2011;171:1107-8).

Because "there will continue to be a need for well designed, rigorously conducted phase 4 clinical trials," he noted that institutional review boards, clinical investigators, practicing clinicians, and other important stakeholders must increase their vigilance in order to prevent and recognize future seeding studies.

This analysis of the STEPS study was not directly supported by any grants or funds. Mr. Krumholz and Dr. Egilman are paid consultants for plaintiffs in litigation related to gabapentin against Pfizer Inc., and Dr. Ross is an unpaid consultant in the same litigation. Dr. Egilman and Dr. Ross were previously paid consultants for plaintiffs in litigation against Merck related to rofecoxib. Dr. Ross is supported by the National Institute on Aging and the American Federation of Aging Research.

Dr. Alexander is in the department of medicine at MacLean Center for Clinical Medical Ethics, University of Chicago Hospitals, and the department of pharmacy practice at the University of Illinois at Chicago School of Pharmacy. He is supported by the U.S. Agency for Healthcare Research and Quality, and he reported being a consultant for IMS Health.

The details of what is described as a profoundly unethical marketing ploy masquerading as a phase IV trial of gabapentin were reported June 27 in the Archives of Internal Medicine.

The Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) study was a so-called seeding trial, in which the stated objective was to assess the safety and efficacy of gabapentin, but the actual aim was to increase prescribing of the drug by duping the very physicians recruited to conduct the "trial," according to three medicolegal consultants involved in litigation against the drug’s manufacturer.

"Although STEPS was conducted 15 years ago, the ethical issues illustrated by the trial’s conduct, and the data gained from Parke-Davis’ marketing analyses, have tremendous relevance in today’s debates over the limits and consequences of pharmaceutical industry sponsorship of phase IV postmarketing clinical trials," wrote Samuel D. Krumholz, Dr. David S. Egilman, and Dr. Joseph S. Ross.

"Our analysis is only the second comprehensive account of a seeding trial based on primary source documents, and [it] clearly demonstrates how a clinical trial was designed, conducted, and explicitly used to promote marketing objectives, not science, without providing full informed consent to the patients and physicians who participated in the study," they noted.

Mr. Krumholz and Dr. Egilman are with Never Again Consulting, an independent Massachusetts firm that conducts research and analysis in support of occupational and environmental health. Dr. Egilman is also in the department of community health at Brown University, Providence, R.I., and Dr. Ross is at Yale–New Haven (Conn.) Hospital Center for Outcomes Research and Evaluation.

Their access to a complete set of documents and depositions produced during litigation against Parke-Davis (now a subsidiary of Pfizer) enabled them to analyze and expose seeding trials, which are "used to promote drugs recently approved or under review by the U.S. Food and Drug Administration by encouraging prescribers to use these medications under the guise of participating as an investigator in [the] trial."

The STEPS trial included the three key traits said to characterize seeding trials: involvement of the marketing department in study conception and design; involvement of the marketing department in data collection and analysis; and nondisclosure of the study’s true purpose from physicians, patients, and institutional review boards.

When asked to comment on the report, Pfizer spokesperson Christopher Loder wrote in an e-mail that "Neurontin is an important FDA-approved medicine that physicians have prescribed to treat millions of patients safely and effectively. Neurontin has been widely studied for more than 2 decades and there is an extensive body of publicly available literature on its safety and its use."

In the STEPS trial, Parke-Davis recruited 772 physicians to prescribe Neurontin (gabapentin) and titrate the dose upward in patients whose partial seizures were not completely controlled by other drugs. The drug company purposefully recruited "site investigators with little or no clinical trial experience [and] provided insufficient training," and limited enrollment to about four patients per investigator.

The study design was uncontrolled and unblinded, and its rigid titration protocol led to the exclusion of 87% of the study subjects. One institutional review board that twice rejected the STEPS application to be conducted at their medical center stated that "the entry criteria and outcome measures are too vague to allow any scientific conclusions to be reach[ed]."

Parke-Davis sales representatives collected and recorded individual subject data. In a clear example of data tampering, they not only attended epilepsy patients’ office visits (under the guise of "shadowing" the clinician), but also actively promoted the use of Neurontin and blocked the use of competing medications, particularly lamotrigine (Lamictal), at those visits. They also rewarded participating investigators with free lunches and dinners.

Without informing either patients or physicians, the drug company’s marketing department monitored each investigator’s prescribing practices. It documented a 38% increase in prescriptions of Neurontin after investigators attended an introductory briefing, as well as a 10% increase in the average prescribed dose. It also compared prescribing patterns between study investigators and a control group of nonparticipating neurologists, and documented increased prescribing of Neurontin only among the study participants.

In numerous internal documents, Parke-Davis described STEPS as a marketing strategy rather than a scientific study. The actual findings of the trial were immaterial; the strategy’s success in increasing market share in new prescriptions was paramount, the authors said (Arch. Intern. Med. 2011;171:1100-7).

"Our analysis provides critical evidence suggesting that seeding trials are used as a promotional strategy by pharmaceutical companies. Reform of the current IRB [institutional review board] system, as well as promoting better clinical trial practice in the human subjects research community, are necessary to prevent continued conduct of seeding trials by the pharmaceutical industry," they added.

Mr. Krumholz and his coauthors clearly demonstrate that the true intent of seeding trials is to introduce a new product and induce clinicians to use it, according to Dr. G. Caleb Alexander.

"Perhaps the greatest cause for concern is that these trials deceive investigators, clinicians, and patients, subverting the scientific process and violating ethical norms."

As others have noted, "Deception is not just an incidental part of a seeding trial, but rather the very success of the trial depends on such deception, since few institutional review boards, investigators, clinicians, or patients would willfully participate in a study with marketing objectives and little or no scientific value," Dr. Alexander wrote in commentary accompanying the report (Arch. Intern. Med. 2011;171:1107-8).

Because "there will continue to be a need for well designed, rigorously conducted phase 4 clinical trials," he noted that institutional review boards, clinical investigators, practicing clinicians, and other important stakeholders must increase their vigilance in order to prevent and recognize future seeding studies.

This analysis of the STEPS study was not directly supported by any grants or funds. Mr. Krumholz and Dr. Egilman are paid consultants for plaintiffs in litigation related to gabapentin against Pfizer Inc., and Dr. Ross is an unpaid consultant in the same litigation. Dr. Egilman and Dr. Ross were previously paid consultants for plaintiffs in litigation against Merck related to rofecoxib. Dr. Ross is supported by the National Institute on Aging and the American Federation of Aging Research.

Dr. Alexander is in the department of medicine at MacLean Center for Clinical Medical Ethics, University of Chicago Hospitals, and the department of pharmacy practice at the University of Illinois at Chicago School of Pharmacy. He is supported by the U.S. Agency for Healthcare Research and Quality, and he reported being a consultant for IMS Health.

The details of what is described as a profoundly unethical marketing ploy masquerading as a phase IV trial of gabapentin were reported June 27 in the Archives of Internal Medicine.

The Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) study was a so-called seeding trial, in which the stated objective was to assess the safety and efficacy of gabapentin, but the actual aim was to increase prescribing of the drug by duping the very physicians recruited to conduct the "trial," according to three medicolegal consultants involved in litigation against the drug’s manufacturer.

"Although STEPS was conducted 15 years ago, the ethical issues illustrated by the trial’s conduct, and the data gained from Parke-Davis’ marketing analyses, have tremendous relevance in today’s debates over the limits and consequences of pharmaceutical industry sponsorship of phase IV postmarketing clinical trials," wrote Samuel D. Krumholz, Dr. David S. Egilman, and Dr. Joseph S. Ross.

"Our analysis is only the second comprehensive account of a seeding trial based on primary source documents, and [it] clearly demonstrates how a clinical trial was designed, conducted, and explicitly used to promote marketing objectives, not science, without providing full informed consent to the patients and physicians who participated in the study," they noted.

Mr. Krumholz and Dr. Egilman are with Never Again Consulting, an independent Massachusetts firm that conducts research and analysis in support of occupational and environmental health. Dr. Egilman is also in the department of community health at Brown University, Providence, R.I., and Dr. Ross is at Yale–New Haven (Conn.) Hospital Center for Outcomes Research and Evaluation.

Their access to a complete set of documents and depositions produced during litigation against Parke-Davis (now a subsidiary of Pfizer) enabled them to analyze and expose seeding trials, which are "used to promote drugs recently approved or under review by the U.S. Food and Drug Administration by encouraging prescribers to use these medications under the guise of participating as an investigator in [the] trial."

The STEPS trial included the three key traits said to characterize seeding trials: involvement of the marketing department in study conception and design; involvement of the marketing department in data collection and analysis; and nondisclosure of the study’s true purpose from physicians, patients, and institutional review boards.

When asked to comment on the report, Pfizer spokesperson Christopher Loder wrote in an e-mail that "Neurontin is an important FDA-approved medicine that physicians have prescribed to treat millions of patients safely and effectively. Neurontin has been widely studied for more than 2 decades and there is an extensive body of publicly available literature on its safety and its use."

In the STEPS trial, Parke-Davis recruited 772 physicians to prescribe Neurontin (gabapentin) and titrate the dose upward in patients whose partial seizures were not completely controlled by other drugs. The drug company purposefully recruited "site investigators with little or no clinical trial experience [and] provided insufficient training," and limited enrollment to about four patients per investigator.

The study design was uncontrolled and unblinded, and its rigid titration protocol led to the exclusion of 87% of the study subjects. One institutional review board that twice rejected the STEPS application to be conducted at their medical center stated that "the entry criteria and outcome measures are too vague to allow any scientific conclusions to be reach[ed]."

Parke-Davis sales representatives collected and recorded individual subject data. In a clear example of data tampering, they not only attended epilepsy patients’ office visits (under the guise of "shadowing" the clinician), but also actively promoted the use of Neurontin and blocked the use of competing medications, particularly lamotrigine (Lamictal), at those visits. They also rewarded participating investigators with free lunches and dinners.

Without informing either patients or physicians, the drug company’s marketing department monitored each investigator’s prescribing practices. It documented a 38% increase in prescriptions of Neurontin after investigators attended an introductory briefing, as well as a 10% increase in the average prescribed dose. It also compared prescribing patterns between study investigators and a control group of nonparticipating neurologists, and documented increased prescribing of Neurontin only among the study participants.

In numerous internal documents, Parke-Davis described STEPS as a marketing strategy rather than a scientific study. The actual findings of the trial were immaterial; the strategy’s success in increasing market share in new prescriptions was paramount, the authors said (Arch. Intern. Med. 2011;171:1100-7).

"Our analysis provides critical evidence suggesting that seeding trials are used as a promotional strategy by pharmaceutical companies. Reform of the current IRB [institutional review board] system, as well as promoting better clinical trial practice in the human subjects research community, are necessary to prevent continued conduct of seeding trials by the pharmaceutical industry," they added.

Mr. Krumholz and his coauthors clearly demonstrate that the true intent of seeding trials is to introduce a new product and induce clinicians to use it, according to Dr. G. Caleb Alexander.

"Perhaps the greatest cause for concern is that these trials deceive investigators, clinicians, and patients, subverting the scientific process and violating ethical norms."

As others have noted, "Deception is not just an incidental part of a seeding trial, but rather the very success of the trial depends on such deception, since few institutional review boards, investigators, clinicians, or patients would willfully participate in a study with marketing objectives and little or no scientific value," Dr. Alexander wrote in commentary accompanying the report (Arch. Intern. Med. 2011;171:1107-8).

Because "there will continue to be a need for well designed, rigorously conducted phase 4 clinical trials," he noted that institutional review boards, clinical investigators, practicing clinicians, and other important stakeholders must increase their vigilance in order to prevent and recognize future seeding studies.

This analysis of the STEPS study was not directly supported by any grants or funds. Mr. Krumholz and Dr. Egilman are paid consultants for plaintiffs in litigation related to gabapentin against Pfizer Inc., and Dr. Ross is an unpaid consultant in the same litigation. Dr. Egilman and Dr. Ross were previously paid consultants for plaintiffs in litigation against Merck related to rofecoxib. Dr. Ross is supported by the National Institute on Aging and the American Federation of Aging Research.

Dr. Alexander is in the department of medicine at MacLean Center for Clinical Medical Ethics, University of Chicago Hospitals, and the department of pharmacy practice at the University of Illinois at Chicago School of Pharmacy. He is supported by the U.S. Agency for Healthcare Research and Quality, and he reported being a consultant for IMS Health.

The details of what is described as a profoundly unethical marketing ploy masquerading as a phase IV trial of gabapentin were reported June 27 in the Archives of Internal Medicine.

The Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) study was a so-called seeding trial, in which the stated objective was to assess the safety and efficacy of gabapentin, but the actual aim was to increase prescribing of the drug by duping the very physicians recruited to conduct the "trial," according to three medicolegal consultants involved in litigation against the drug’s manufacturer.

"Although STEPS was conducted 15 years ago, the ethical issues illustrated by the trial’s conduct, and the data gained from Parke-Davis’ marketing analyses, have tremendous relevance in today’s debates over the limits and consequences of pharmaceutical industry sponsorship of phase IV postmarketing clinical trials," wrote Samuel D. Krumholz, Dr. David S. Egilman, and Dr. Joseph S. Ross.

"Our analysis is only the second comprehensive account of a seeding trial based on primary source documents, and [it] clearly demonstrates how a clinical trial was designed, conducted, and explicitly used to promote marketing objectives, not science, without providing full informed consent to the patients and physicians who participated in the study," they noted.

Mr. Krumholz and Dr. Egilman are with Never Again Consulting, an independent Massachusetts firm that conducts research and analysis in support of occupational and environmental health. Dr. Egilman is also in the department of community health at Brown University, Providence, R.I., and Dr. Ross is at Yale–New Haven (Conn.) Hospital Center for Outcomes Research and Evaluation.

Their access to a complete set of documents and depositions produced during litigation against Parke-Davis (now a subsidiary of Pfizer) enabled them to analyze and expose seeding trials, which are "used to promote drugs recently approved or under review by the U.S. Food and Drug Administration by encouraging prescribers to use these medications under the guise of participating as an investigator in [the] trial."

The STEPS trial included the three key traits said to characterize seeding trials: involvement of the marketing department in study conception and design; involvement of the marketing department in data collection and analysis; and nondisclosure of the study’s true purpose from physicians, patients, and institutional review boards.

When asked to comment on the report, Pfizer spokesperson Christopher Loder wrote in an e-mail that "Neurontin is an important FDA-approved medicine that physicians have prescribed to treat millions of patients safely and effectively. Neurontin has been widely studied for more than 2 decades and there is an extensive body of publicly available literature on its safety and its use."

In the STEPS trial, Parke-Davis recruited 772 physicians to prescribe Neurontin (gabapentin) and titrate the dose upward in patients whose partial seizures were not completely controlled by other drugs. The drug company purposefully recruited "site investigators with little or no clinical trial experience [and] provided insufficient training," and limited enrollment to about four patients per investigator.

The study design was uncontrolled and unblinded, and its rigid titration protocol led to the exclusion of 87% of the study subjects. One institutional review board that twice rejected the STEPS application to be conducted at their medical center stated that "the entry criteria and outcome measures are too vague to allow any scientific conclusions to be reach[ed]."

Parke-Davis sales representatives collected and recorded individual subject data. In a clear example of data tampering, they not only attended epilepsy patients’ office visits (under the guise of "shadowing" the clinician), but also actively promoted the use of Neurontin and blocked the use of competing medications, particularly lamotrigine (Lamictal), at those visits. They also rewarded participating investigators with free lunches and dinners.

Without informing either patients or physicians, the drug company’s marketing department monitored each investigator’s prescribing practices. It documented a 38% increase in prescriptions of Neurontin after investigators attended an introductory briefing, as well as a 10% increase in the average prescribed dose. It also compared prescribing patterns between study investigators and a control group of nonparticipating neurologists, and documented increased prescribing of Neurontin only among the study participants.

In numerous internal documents, Parke-Davis described STEPS as a marketing strategy rather than a scientific study. The actual findings of the trial were immaterial; the strategy’s success in increasing market share in new prescriptions was paramount, the authors said (Arch. Intern. Med. 2011;171:1100-7).

"Our analysis provides critical evidence suggesting that seeding trials are used as a promotional strategy by pharmaceutical companies. Reform of the current IRB [institutional review board] system, as well as promoting better clinical trial practice in the human subjects research community, are necessary to prevent continued conduct of seeding trials by the pharmaceutical industry," they added.

Mr. Krumholz and his coauthors clearly demonstrate that the true intent of seeding trials is to introduce a new product and induce clinicians to use it, according to Dr. G. Caleb Alexander.

"Perhaps the greatest cause for concern is that these trials deceive investigators, clinicians, and patients, subverting the scientific process and violating ethical norms."

As others have noted, "Deception is not just an incidental part of a seeding trial, but rather the very success of the trial depends on such deception, since few institutional review boards, investigators, clinicians, or patients would willfully participate in a study with marketing objectives and little or no scientific value," Dr. Alexander wrote in commentary accompanying the report (Arch. Intern. Med. 2011;171:1107-8).

Because "there will continue to be a need for well designed, rigorously conducted phase 4 clinical trials," he noted that institutional review boards, clinical investigators, practicing clinicians, and other important stakeholders must increase their vigilance in order to prevent and recognize future seeding studies.

This analysis of the STEPS study was not directly supported by any grants or funds. Mr. Krumholz and Dr. Egilman are paid consultants for plaintiffs in litigation related to gabapentin against Pfizer Inc., and Dr. Ross is an unpaid consultant in the same litigation. Dr. Egilman and Dr. Ross were previously paid consultants for plaintiffs in litigation against Merck related to rofecoxib. Dr. Ross is supported by the National Institute on Aging and the American Federation of Aging Research.

Dr. Alexander is in the department of medicine at MacLean Center for Clinical Medical Ethics, University of Chicago Hospitals, and the department of pharmacy practice at the University of Illinois at Chicago School of Pharmacy. He is supported by the U.S. Agency for Healthcare Research and Quality, and he reported being a consultant for IMS Health.

The details of what is described as a profoundly unethical marketing ploy masquerading as a phase IV trial of gabapentin were reported June 27 in the Archives of Internal Medicine.

The Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) study was a so-called seeding trial, in which the stated objective was to assess the safety and efficacy of gabapentin, but the actual aim was to increase prescribing of the drug by duping the very physicians recruited to conduct the "trial," according to three medicolegal consultants involved in litigation against the drug’s manufacturer.

"Although STEPS was conducted 15 years ago, the ethical issues illustrated by the trial’s conduct, and the data gained from Parke-Davis’ marketing analyses, have tremendous relevance in today’s debates over the limits and consequences of pharmaceutical industry sponsorship of phase IV postmarketing clinical trials," wrote Samuel D. Krumholz, Dr. David S. Egilman, and Dr. Joseph S. Ross.

"Our analysis is only the second comprehensive account of a seeding trial based on primary source documents, and [it] clearly demonstrates how a clinical trial was designed, conducted, and explicitly used to promote marketing objectives, not science, without providing full informed consent to the patients and physicians who participated in the study," they noted.

Mr. Krumholz and Dr. Egilman are with Never Again Consulting, an independent Massachusetts firm that conducts research and analysis in support of occupational and environmental health. Dr. Egilman is also in the department of community health at Brown University, Providence, R.I., and Dr. Ross is at Yale–New Haven (Conn.) Hospital Center for Outcomes Research and Evaluation.

Their access to a complete set of documents and depositions produced during litigation against Parke-Davis (now a subsidiary of Pfizer) enabled them to analyze and expose seeding trials, which are "used to promote drugs recently approved or under review by the U.S. Food and Drug Administration by encouraging prescribers to use these medications under the guise of participating as an investigator in [the] trial."

The STEPS trial included the three key traits said to characterize seeding trials: involvement of the marketing department in study conception and design; involvement of the marketing department in data collection and analysis; and nondisclosure of the study’s true purpose from physicians, patients, and institutional review boards.

When asked to comment on the report, Pfizer spokesperson Christopher Loder wrote in an e-mail that "Neurontin is an important FDA-approved medicine that physicians have prescribed to treat millions of patients safely and effectively. Neurontin has been widely studied for more than 2 decades and there is an extensive body of publicly available literature on its safety and its use."

In the STEPS trial, Parke-Davis recruited 772 physicians to prescribe Neurontin (gabapentin) and titrate the dose upward in patients whose partial seizures were not completely controlled by other drugs. The drug company purposefully recruited "site investigators with little or no clinical trial experience [and] provided insufficient training," and limited enrollment to about four patients per investigator.

The study design was uncontrolled and unblinded, and its rigid titration protocol led to the exclusion of 87% of the study subjects. One institutional review board that twice rejected the STEPS application to be conducted at their medical center stated that "the entry criteria and outcome measures are too vague to allow any scientific conclusions to be reach[ed]."

Parke-Davis sales representatives collected and recorded individual subject data. In a clear example of data tampering, they not only attended epilepsy patients’ office visits (under the guise of "shadowing" the clinician), but also actively promoted the use of Neurontin and blocked the use of competing medications, particularly lamotrigine (Lamictal), at those visits. They also rewarded participating investigators with free lunches and dinners.

Without informing either patients or physicians, the drug company’s marketing department monitored each investigator’s prescribing practices. It documented a 38% increase in prescriptions of Neurontin after investigators attended an introductory briefing, as well as a 10% increase in the average prescribed dose. It also compared prescribing patterns between study investigators and a control group of nonparticipating neurologists, and documented increased prescribing of Neurontin only among the study participants.

In numerous internal documents, Parke-Davis described STEPS as a marketing strategy rather than a scientific study. The actual findings of the trial were immaterial; the strategy’s success in increasing market share in new prescriptions was paramount, the authors said (Arch. Intern. Med. 2011;171:1100-7).

"Our analysis provides critical evidence suggesting that seeding trials are used as a promotional strategy by pharmaceutical companies. Reform of the current IRB [institutional review board] system, as well as promoting better clinical trial practice in the human subjects research community, are necessary to prevent continued conduct of seeding trials by the pharmaceutical industry," they added.

Mr. Krumholz and his coauthors clearly demonstrate that the true intent of seeding trials is to introduce a new product and induce clinicians to use it, according to Dr. G. Caleb Alexander.

"Perhaps the greatest cause for concern is that these trials deceive investigators, clinicians, and patients, subverting the scientific process and violating ethical norms."

As others have noted, "Deception is not just an incidental part of a seeding trial, but rather the very success of the trial depends on such deception, since few institutional review boards, investigators, clinicians, or patients would willfully participate in a study with marketing objectives and little or no scientific value," Dr. Alexander wrote in commentary accompanying the report (Arch. Intern. Med. 2011;171:1107-8).

Because "there will continue to be a need for well designed, rigorously conducted phase 4 clinical trials," he noted that institutional review boards, clinical investigators, practicing clinicians, and other important stakeholders must increase their vigilance in order to prevent and recognize future seeding studies.

This analysis of the STEPS study was not directly supported by any grants or funds. Mr. Krumholz and Dr. Egilman are paid consultants for plaintiffs in litigation related to gabapentin against Pfizer Inc., and Dr. Ross is an unpaid consultant in the same litigation. Dr. Egilman and Dr. Ross were previously paid consultants for plaintiffs in litigation against Merck related to rofecoxib. Dr. Ross is supported by the National Institute on Aging and the American Federation of Aging Research.

Dr. Alexander is in the department of medicine at MacLean Center for Clinical Medical Ethics, University of Chicago Hospitals, and the department of pharmacy practice at the University of Illinois at Chicago School of Pharmacy. He is supported by the U.S. Agency for Healthcare Research and Quality, and he reported being a consultant for IMS Health.

The details of what is described as a profoundly unethical marketing ploy masquerading as a phase IV trial of gabapentin were reported June 27 in the Archives of Internal Medicine.

The Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) study was a so-called seeding trial, in which the stated objective was to assess the safety and efficacy of gabapentin, but the actual aim was to increase prescribing of the drug by duping the very physicians recruited to conduct the "trial," according to three medicolegal consultants involved in litigation against the drug’s manufacturer.

"Although STEPS was conducted 15 years ago, the ethical issues illustrated by the trial’s conduct, and the data gained from Parke-Davis’ marketing analyses, have tremendous relevance in today’s debates over the limits and consequences of pharmaceutical industry sponsorship of phase IV postmarketing clinical trials," wrote Samuel D. Krumholz, Dr. David S. Egilman, and Dr. Joseph S. Ross.

"Our analysis is only the second comprehensive account of a seeding trial based on primary source documents, and [it] clearly demonstrates how a clinical trial was designed, conducted, and explicitly used to promote marketing objectives, not science, without providing full informed consent to the patients and physicians who participated in the study," they noted.

Mr. Krumholz and Dr. Egilman are with Never Again Consulting, an independent Massachusetts firm that conducts research and analysis in support of occupational and environmental health. Dr. Egilman is also in the department of community health at Brown University, Providence, R.I., and Dr. Ross is at Yale–New Haven (Conn.) Hospital Center for Outcomes Research and Evaluation.

Their access to a complete set of documents and depositions produced during litigation against Parke-Davis (now a subsidiary of Pfizer) enabled them to analyze and expose seeding trials, which are "used to promote drugs recently approved or under review by the U.S. Food and Drug Administration by encouraging prescribers to use these medications under the guise of participating as an investigator in [the] trial."

The STEPS trial included the three key traits said to characterize seeding trials: involvement of the marketing department in study conception and design; involvement of the marketing department in data collection and analysis; and nondisclosure of the study’s true purpose from physicians, patients, and institutional review boards.

When asked to comment on the report, Pfizer spokesperson Christopher Loder wrote in an e-mail that "Neurontin is an important FDA-approved medicine that physicians have prescribed to treat millions of patients safely and effectively. Neurontin has been widely studied for more than 2 decades and there is an extensive body of publicly available literature on its safety and its use."

In the STEPS trial, Parke-Davis recruited 772 physicians to prescribe Neurontin (gabapentin) and titrate the dose upward in patients whose partial seizures were not completely controlled by other drugs. The drug company purposefully recruited "site investigators with little or no clinical trial experience [and] provided insufficient training," and limited enrollment to about four patients per investigator.

The study design was uncontrolled and unblinded, and its rigid titration protocol led to the exclusion of 87% of the study subjects. One institutional review board that twice rejected the STEPS application to be conducted at their medical center stated that "the entry criteria and outcome measures are too vague to allow any scientific conclusions to be reach[ed]."

Parke-Davis sales representatives collected and recorded individual subject data. In a clear example of data tampering, they not only attended epilepsy patients’ office visits (under the guise of "shadowing" the clinician), but also actively promoted the use of Neurontin and blocked the use of competing medications, particularly lamotrigine (Lamictal), at those visits. They also rewarded participating investigators with free lunches and dinners.

Without informing either patients or physicians, the drug company’s marketing department monitored each investigator’s prescribing practices. It documented a 38% increase in prescriptions of Neurontin after investigators attended an introductory briefing, as well as a 10% increase in the average prescribed dose. It also compared prescribing patterns between study investigators and a control group of nonparticipating neurologists, and documented increased prescribing of Neurontin only among the study participants.

In numerous internal documents, Parke-Davis described STEPS as a marketing strategy rather than a scientific study. The actual findings of the trial were immaterial; the strategy’s success in increasing market share in new prescriptions was paramount, the authors said (Arch. Intern. Med. 2011;171:1100-7).

"Our analysis provides critical evidence suggesting that seeding trials are used as a promotional strategy by pharmaceutical companies. Reform of the current IRB [institutional review board] system, as well as promoting better clinical trial practice in the human subjects research community, are necessary to prevent continued conduct of seeding trials by the pharmaceutical industry," they added.

Mr. Krumholz and his coauthors clearly demonstrate that the true intent of seeding trials is to introduce a new product and induce clinicians to use it, according to Dr. G. Caleb Alexander.

"Perhaps the greatest cause for concern is that these trials deceive investigators, clinicians, and patients, subverting the scientific process and violating ethical norms."

As others have noted, "Deception is not just an incidental part of a seeding trial, but rather the very success of the trial depends on such deception, since few institutional review boards, investigators, clinicians, or patients would willfully participate in a study with marketing objectives and little or no scientific value," Dr. Alexander wrote in commentary accompanying the report (Arch. Intern. Med. 2011;171:1107-8).

Because "there will continue to be a need for well designed, rigorously conducted phase 4 clinical trials," he noted that institutional review boards, clinical investigators, practicing clinicians, and other important stakeholders must increase their vigilance in order to prevent and recognize future seeding studies.

This analysis of the STEPS study was not directly supported by any grants or funds. Mr. Krumholz and Dr. Egilman are paid consultants for plaintiffs in litigation related to gabapentin against Pfizer Inc., and Dr. Ross is an unpaid consultant in the same litigation. Dr. Egilman and Dr. Ross were previously paid consultants for plaintiffs in litigation against Merck related to rofecoxib. Dr. Ross is supported by the National Institute on Aging and the American Federation of Aging Research.

Dr. Alexander is in the department of medicine at MacLean Center for Clinical Medical Ethics, University of Chicago Hospitals, and the department of pharmacy practice at the University of Illinois at Chicago School of Pharmacy. He is supported by the U.S. Agency for Healthcare Research and Quality, and he reported being a consultant for IMS Health.

Moderate and severe diastolic dysfunction in patients who have normal systolic function increased all-cause mortality, according to a report in the June 27 issue of the Archives of Internal Medicine.

Such diastolic dysfunction is usually preclinical and often is identified on outpatient echocardiography that was done to assess nonspecific symptoms, ventricular or valvular function, arrhythmia, or ECG abnormalities. Its clinical significance has not been documented until now, said Dr. Carmel M. Halley of the Heart and Vascular Institute at the Cleveland Clinic, and her associates.

"Because the use of echocardiography as a clinical tool in the outpatient setting continues to increase ... our study provides the physician with a prognostic context when diastolic dysfunction is reported, especially because most procedures are requested by noncardiologists," the researchers noted (Arch. Intern. Med. 2011;171:1082-7).

Dr. Halley and her colleagues examined diastolic dysfunction in the absence of systolic dysfunction, because the clinical relevance of the condition has been questioned. Many medical disorders associated with diastolic dysfunction, such as hypertension, coronary artery disease, obesity, and diabetes, are themselves predictors of increased mortality, so it was unclear whether diastolic dysfunction was an independent contributor.

The researchers reviewed the records of consecutive patients who underwent outpatient echocardiography at the Cleveland Clinic and its satellite facilities between 1996 and 2005. They identified 36,261 patients (65,696 echocardiographic tests) who had normal ejection fractions signaling preserved systolic function.

The mean patient age was 58 years, and slightly more than half of the study subjects were women. The subjects were typical of patients usually referred for echocardiography – they frequently had cardiovascular risk factors such as dyslipidemia (35%), hypertension (15%), and diabetes (12%), but usually did not have established CV disease, such as congestive heart failure (4%), peripheral vascular disease (1%), or coronary artery disease (0.6%).

The most frequent indications for ordering the echocardiography were symptom assessment, assessment of ventricular or valvular function, evaluation of suspected or known CAD, and assessment of arrhythmia or ECG abnormalities.

The prevalence of diastolic dysfunction was high, at 65%. The dysfunction was mild in the majority of patients (nearly 60%), moderate in 4.8%, and severe in 0.4%.

During an average follow-up of 6 years, there were 5,789 deaths. Unadjusted all-cause mortality was higher with any degree of diastolic dysfunction than with normal diastolic function: 21% with mild diastolic dysfunction, 24% with moderate diastolic dysfunction, and 39% with severe diastolic dysfunction, compared with 7% in patients who had normal diastolic function.

However, because comorbidities that could confound the analyses were more common among patients with more severe diastolic dysfunction, propensity matching and statistical controlling for comorbidities were performed. Subsequent analysis showed that only moderate and severe diastolic dysfunction raised mortality risk.

Eight-year survival estimates were 78% for patients with normal diastolic function and 72% for mild diastolic dysfunction, compared with 68% for moderate diastolic dysfunction and 58% for severe diastolic dysfunction.

"For the first time, to our knowledge, moderate and severe diastolic dysfunction have been shown to be independent predictors of mortality rate," Dr. Halley and her associates said.

The mechanisms by which diastolic dysfunction raises mortality are not yet known, nor is it known whether therapies targeting such dysfunction can be developed, or whether they would reduce mortality. "However, our results suggest that an increased awareness of the clinical significance of advanced diastolic dysfunction may lead to earlier identification of those patients who are at risk, especially at a preclinical stage," the investigators noted.

They added that this study was limited in that it was retrospective and involved only a single institution.

This new study provides "an important piece of the puzzle," shedding light on the continuum from mild and asymptomatic to severe and symptomatic diastolic dysfunction, said Dr. Ileana L. Piña in remarks taken from her invited commentary that accompanied Dr. Halley’s report (Arch. Intern. Med. 2011;171:1088-9).

The findings that diastolic dysfunction is so common – affecting 65% of this study cohort – and that physicians must be alert to the prognostic value of more severe dysfunction are "novel and important for physicians."

In the future, it will be critical to elucidate the missing link between diagnosis of diastolic dysfunction on echocardiography and the later presentation of older patients, particularly older women, with acute decompensated heart failure in which systolic function is preserved, Dr. Piña of the departments of epidemiology and biostatistics at Case Western Reserve University, Cleveland, added.

One of Dr. Halley’s associates reported ties to GE Healthcare, Philips Healthcare, and Siemens AG. Dr. Piña reported no financial disclosures.

Moderate and severe diastolic dysfunction in patients who have normal systolic function increased all-cause mortality, according to a report in the June 27 issue of the Archives of Internal Medicine.

Such diastolic dysfunction is usually preclinical and often is identified on outpatient echocardiography that was done to assess nonspecific symptoms, ventricular or valvular function, arrhythmia, or ECG abnormalities. Its clinical significance has not been documented until now, said Dr. Carmel M. Halley of the Heart and Vascular Institute at the Cleveland Clinic, and her associates.

"Because the use of echocardiography as a clinical tool in the outpatient setting continues to increase ... our study provides the physician with a prognostic context when diastolic dysfunction is reported, especially because most procedures are requested by noncardiologists," the researchers noted (Arch. Intern. Med. 2011;171:1082-7).

Dr. Halley and her colleagues examined diastolic dysfunction in the absence of systolic dysfunction, because the clinical relevance of the condition has been questioned. Many medical disorders associated with diastolic dysfunction, such as hypertension, coronary artery disease, obesity, and diabetes, are themselves predictors of increased mortality, so it was unclear whether diastolic dysfunction was an independent contributor.

The researchers reviewed the records of consecutive patients who underwent outpatient echocardiography at the Cleveland Clinic and its satellite facilities between 1996 and 2005. They identified 36,261 patients (65,696 echocardiographic tests) who had normal ejection fractions signaling preserved systolic function.

The mean patient age was 58 years, and slightly more than half of the study subjects were women. The subjects were typical of patients usually referred for echocardiography – they frequently had cardiovascular risk factors such as dyslipidemia (35%), hypertension (15%), and diabetes (12%), but usually did not have established CV disease, such as congestive heart failure (4%), peripheral vascular disease (1%), or coronary artery disease (0.6%).

The most frequent indications for ordering the echocardiography were symptom assessment, assessment of ventricular or valvular function, evaluation of suspected or known CAD, and assessment of arrhythmia or ECG abnormalities.

The prevalence of diastolic dysfunction was high, at 65%. The dysfunction was mild in the majority of patients (nearly 60%), moderate in 4.8%, and severe in 0.4%.

During an average follow-up of 6 years, there were 5,789 deaths. Unadjusted all-cause mortality was higher with any degree of diastolic dysfunction than with normal diastolic function: 21% with mild diastolic dysfunction, 24% with moderate diastolic dysfunction, and 39% with severe diastolic dysfunction, compared with 7% in patients who had normal diastolic function.

However, because comorbidities that could confound the analyses were more common among patients with more severe diastolic dysfunction, propensity matching and statistical controlling for comorbidities were performed. Subsequent analysis showed that only moderate and severe diastolic dysfunction raised mortality risk.

Eight-year survival estimates were 78% for patients with normal diastolic function and 72% for mild diastolic dysfunction, compared with 68% for moderate diastolic dysfunction and 58% for severe diastolic dysfunction.

"For the first time, to our knowledge, moderate and severe diastolic dysfunction have been shown to be independent predictors of mortality rate," Dr. Halley and her associates said.

The mechanisms by which diastolic dysfunction raises mortality are not yet known, nor is it known whether therapies targeting such dysfunction can be developed, or whether they would reduce mortality. "However, our results suggest that an increased awareness of the clinical significance of advanced diastolic dysfunction may lead to earlier identification of those patients who are at risk, especially at a preclinical stage," the investigators noted.

They added that this study was limited in that it was retrospective and involved only a single institution.

This new study provides "an important piece of the puzzle," shedding light on the continuum from mild and asymptomatic to severe and symptomatic diastolic dysfunction, said Dr. Ileana L. Piña in remarks taken from her invited commentary that accompanied Dr. Halley’s report (Arch. Intern. Med. 2011;171:1088-9).

The findings that diastolic dysfunction is so common – affecting 65% of this study cohort – and that physicians must be alert to the prognostic value of more severe dysfunction are "novel and important for physicians."

In the future, it will be critical to elucidate the missing link between diagnosis of diastolic dysfunction on echocardiography and the later presentation of older patients, particularly older women, with acute decompensated heart failure in which systolic function is preserved, Dr. Piña of the departments of epidemiology and biostatistics at Case Western Reserve University, Cleveland, added.

One of Dr. Halley’s associates reported ties to GE Healthcare, Philips Healthcare, and Siemens AG. Dr. Piña reported no financial disclosures.

Moderate and severe diastolic dysfunction in patients who have normal systolic function increased all-cause mortality, according to a report in the June 27 issue of the Archives of Internal Medicine.

Such diastolic dysfunction is usually preclinical and often is identified on outpatient echocardiography that was done to assess nonspecific symptoms, ventricular or valvular function, arrhythmia, or ECG abnormalities. Its clinical significance has not been documented until now, said Dr. Carmel M. Halley of the Heart and Vascular Institute at the Cleveland Clinic, and her associates.

"Because the use of echocardiography as a clinical tool in the outpatient setting continues to increase ... our study provides the physician with a prognostic context when diastolic dysfunction is reported, especially because most procedures are requested by noncardiologists," the researchers noted (Arch. Intern. Med. 2011;171:1082-7).

Dr. Halley and her colleagues examined diastolic dysfunction in the absence of systolic dysfunction, because the clinical relevance of the condition has been questioned. Many medical disorders associated with diastolic dysfunction, such as hypertension, coronary artery disease, obesity, and diabetes, are themselves predictors of increased mortality, so it was unclear whether diastolic dysfunction was an independent contributor.

The researchers reviewed the records of consecutive patients who underwent outpatient echocardiography at the Cleveland Clinic and its satellite facilities between 1996 and 2005. They identified 36,261 patients (65,696 echocardiographic tests) who had normal ejection fractions signaling preserved systolic function.

The mean patient age was 58 years, and slightly more than half of the study subjects were women. The subjects were typical of patients usually referred for echocardiography – they frequently had cardiovascular risk factors such as dyslipidemia (35%), hypertension (15%), and diabetes (12%), but usually did not have established CV disease, such as congestive heart failure (4%), peripheral vascular disease (1%), or coronary artery disease (0.6%).

The most frequent indications for ordering the echocardiography were symptom assessment, assessment of ventricular or valvular function, evaluation of suspected or known CAD, and assessment of arrhythmia or ECG abnormalities.

The prevalence of diastolic dysfunction was high, at 65%. The dysfunction was mild in the majority of patients (nearly 60%), moderate in 4.8%, and severe in 0.4%.

During an average follow-up of 6 years, there were 5,789 deaths. Unadjusted all-cause mortality was higher with any degree of diastolic dysfunction than with normal diastolic function: 21% with mild diastolic dysfunction, 24% with moderate diastolic dysfunction, and 39% with severe diastolic dysfunction, compared with 7% in patients who had normal diastolic function.

However, because comorbidities that could confound the analyses were more common among patients with more severe diastolic dysfunction, propensity matching and statistical controlling for comorbidities were performed. Subsequent analysis showed that only moderate and severe diastolic dysfunction raised mortality risk.

Eight-year survival estimates were 78% for patients with normal diastolic function and 72% for mild diastolic dysfunction, compared with 68% for moderate diastolic dysfunction and 58% for severe diastolic dysfunction.

"For the first time, to our knowledge, moderate and severe diastolic dysfunction have been shown to be independent predictors of mortality rate," Dr. Halley and her associates said.

The mechanisms by which diastolic dysfunction raises mortality are not yet known, nor is it known whether therapies targeting such dysfunction can be developed, or whether they would reduce mortality. "However, our results suggest that an increased awareness of the clinical significance of advanced diastolic dysfunction may lead to earlier identification of those patients who are at risk, especially at a preclinical stage," the investigators noted.

They added that this study was limited in that it was retrospective and involved only a single institution.

This new study provides "an important piece of the puzzle," shedding light on the continuum from mild and asymptomatic to severe and symptomatic diastolic dysfunction, said Dr. Ileana L. Piña in remarks taken from her invited commentary that accompanied Dr. Halley’s report (Arch. Intern. Med. 2011;171:1088-9).

The findings that diastolic dysfunction is so common – affecting 65% of this study cohort – and that physicians must be alert to the prognostic value of more severe dysfunction are "novel and important for physicians."

In the future, it will be critical to elucidate the missing link between diagnosis of diastolic dysfunction on echocardiography and the later presentation of older patients, particularly older women, with acute decompensated heart failure in which systolic function is preserved, Dr. Piña of the departments of epidemiology and biostatistics at Case Western Reserve University, Cleveland, added.

One of Dr. Halley’s associates reported ties to GE Healthcare, Philips Healthcare, and Siemens AG. Dr. Piña reported no financial disclosures.

Moderate and severe diastolic dysfunction in patients who have normal systolic function increased all-cause mortality, according to a report in the June 27 issue of the Archives of Internal Medicine.

Such diastolic dysfunction is usually preclinical and often is identified on outpatient echocardiography that was done to assess nonspecific symptoms, ventricular or valvular function, arrhythmia, or ECG abnormalities. Its clinical significance has not been documented until now, said Dr. Carmel M. Halley of the Heart and Vascular Institute at the Cleveland Clinic, and her associates.

"Because the use of echocardiography as a clinical tool in the outpatient setting continues to increase ... our study provides the physician with a prognostic context when diastolic dysfunction is reported, especially because most procedures are requested by noncardiologists," the researchers noted (Arch. Intern. Med. 2011;171:1082-7).

Dr. Halley and her colleagues examined diastolic dysfunction in the absence of systolic dysfunction, because the clinical relevance of the condition has been questioned. Many medical disorders associated with diastolic dysfunction, such as hypertension, coronary artery disease, obesity, and diabetes, are themselves predictors of increased mortality, so it was unclear whether diastolic dysfunction was an independent contributor.

The researchers reviewed the records of consecutive patients who underwent outpatient echocardiography at the Cleveland Clinic and its satellite facilities between 1996 and 2005. They identified 36,261 patients (65,696 echocardiographic tests) who had normal ejection fractions signaling preserved systolic function.

The mean patient age was 58 years, and slightly more than half of the study subjects were women. The subjects were typical of patients usually referred for echocardiography – they frequently had cardiovascular risk factors such as dyslipidemia (35%), hypertension (15%), and diabetes (12%), but usually did not have established CV disease, such as congestive heart failure (4%), peripheral vascular disease (1%), or coronary artery disease (0.6%).

The most frequent indications for ordering the echocardiography were symptom assessment, assessment of ventricular or valvular function, evaluation of suspected or known CAD, and assessment of arrhythmia or ECG abnormalities.

The prevalence of diastolic dysfunction was high, at 65%. The dysfunction was mild in the majority of patients (nearly 60%), moderate in 4.8%, and severe in 0.4%.

During an average follow-up of 6 years, there were 5,789 deaths. Unadjusted all-cause mortality was higher with any degree of diastolic dysfunction than with normal diastolic function: 21% with mild diastolic dysfunction, 24% with moderate diastolic dysfunction, and 39% with severe diastolic dysfunction, compared with 7% in patients who had normal diastolic function.

However, because comorbidities that could confound the analyses were more common among patients with more severe diastolic dysfunction, propensity matching and statistical controlling for comorbidities were performed. Subsequent analysis showed that only moderate and severe diastolic dysfunction raised mortality risk.

Eight-year survival estimates were 78% for patients with normal diastolic function and 72% for mild diastolic dysfunction, compared with 68% for moderate diastolic dysfunction and 58% for severe diastolic dysfunction.

"For the first time, to our knowledge, moderate and severe diastolic dysfunction have been shown to be independent predictors of mortality rate," Dr. Halley and her associates said.

The mechanisms by which diastolic dysfunction raises mortality are not yet known, nor is it known whether therapies targeting such dysfunction can be developed, or whether they would reduce mortality. "However, our results suggest that an increased awareness of the clinical significance of advanced diastolic dysfunction may lead to earlier identification of those patients who are at risk, especially at a preclinical stage," the investigators noted.

They added that this study was limited in that it was retrospective and involved only a single institution.

This new study provides "an important piece of the puzzle," shedding light on the continuum from mild and asymptomatic to severe and symptomatic diastolic dysfunction, said Dr. Ileana L. Piña in remarks taken from her invited commentary that accompanied Dr. Halley’s report (Arch. Intern. Med. 2011;171:1088-9).

The findings that diastolic dysfunction is so common – affecting 65% of this study cohort – and that physicians must be alert to the prognostic value of more severe dysfunction are "novel and important for physicians."

In the future, it will be critical to elucidate the missing link between diagnosis of diastolic dysfunction on echocardiography and the later presentation of older patients, particularly older women, with acute decompensated heart failure in which systolic function is preserved, Dr. Piña of the departments of epidemiology and biostatistics at Case Western Reserve University, Cleveland, added.

One of Dr. Halley’s associates reported ties to GE Healthcare, Philips Healthcare, and Siemens AG. Dr. Piña reported no financial disclosures.

Moderate and severe diastolic dysfunction in patients who have normal systolic function increased all-cause mortality, according to a report in the June 27 issue of the Archives of Internal Medicine.

Such diastolic dysfunction is usually preclinical and often is identified on outpatient echocardiography that was done to assess nonspecific symptoms, ventricular or valvular function, arrhythmia, or ECG abnormalities. Its clinical significance has not been documented until now, said Dr. Carmel M. Halley of the Heart and Vascular Institute at the Cleveland Clinic, and her associates.

"Because the use of echocardiography as a clinical tool in the outpatient setting continues to increase ... our study provides the physician with a prognostic context when diastolic dysfunction is reported, especially because most procedures are requested by noncardiologists," the researchers noted (Arch. Intern. Med. 2011;171:1082-7).

Dr. Halley and her colleagues examined diastolic dysfunction in the absence of systolic dysfunction, because the clinical relevance of the condition has been questioned. Many medical disorders associated with diastolic dysfunction, such as hypertension, coronary artery disease, obesity, and diabetes, are themselves predictors of increased mortality, so it was unclear whether diastolic dysfunction was an independent contributor.

The researchers reviewed the records of consecutive patients who underwent outpatient echocardiography at the Cleveland Clinic and its satellite facilities between 1996 and 2005. They identified 36,261 patients (65,696 echocardiographic tests) who had normal ejection fractions signaling preserved systolic function.

The mean patient age was 58 years, and slightly more than half of the study subjects were women. The subjects were typical of patients usually referred for echocardiography – they frequently had cardiovascular risk factors such as dyslipidemia (35%), hypertension (15%), and diabetes (12%), but usually did not have established CV disease, such as congestive heart failure (4%), peripheral vascular disease (1%), or coronary artery disease (0.6%).

The most frequent indications for ordering the echocardiography were symptom assessment, assessment of ventricular or valvular function, evaluation of suspected or known CAD, and assessment of arrhythmia or ECG abnormalities.

The prevalence of diastolic dysfunction was high, at 65%. The dysfunction was mild in the majority of patients (nearly 60%), moderate in 4.8%, and severe in 0.4%.

During an average follow-up of 6 years, there were 5,789 deaths. Unadjusted all-cause mortality was higher with any degree of diastolic dysfunction than with normal diastolic function: 21% with mild diastolic dysfunction, 24% with moderate diastolic dysfunction, and 39% with severe diastolic dysfunction, compared with 7% in patients who had normal diastolic function.

However, because comorbidities that could confound the analyses were more common among patients with more severe diastolic dysfunction, propensity matching and statistical controlling for comorbidities were performed. Subsequent analysis showed that only moderate and severe diastolic dysfunction raised mortality risk.

Eight-year survival estimates were 78% for patients with normal diastolic function and 72% for mild diastolic dysfunction, compared with 68% for moderate diastolic dysfunction and 58% for severe diastolic dysfunction.

"For the first time, to our knowledge, moderate and severe diastolic dysfunction have been shown to be independent predictors of mortality rate," Dr. Halley and her associates said.

The mechanisms by which diastolic dysfunction raises mortality are not yet known, nor is it known whether therapies targeting such dysfunction can be developed, or whether they would reduce mortality. "However, our results suggest that an increased awareness of the clinical significance of advanced diastolic dysfunction may lead to earlier identification of those patients who are at risk, especially at a preclinical stage," the investigators noted.

They added that this study was limited in that it was retrospective and involved only a single institution.

This new study provides "an important piece of the puzzle," shedding light on the continuum from mild and asymptomatic to severe and symptomatic diastolic dysfunction, said Dr. Ileana L. Piña in remarks taken from her invited commentary that accompanied Dr. Halley’s report (Arch. Intern. Med. 2011;171:1088-9).

The findings that diastolic dysfunction is so common – affecting 65% of this study cohort – and that physicians must be alert to the prognostic value of more severe dysfunction are "novel and important for physicians."

In the future, it will be critical to elucidate the missing link between diagnosis of diastolic dysfunction on echocardiography and the later presentation of older patients, particularly older women, with acute decompensated heart failure in which systolic function is preserved, Dr. Piña of the departments of epidemiology and biostatistics at Case Western Reserve University, Cleveland, added.

One of Dr. Halley’s associates reported ties to GE Healthcare, Philips Healthcare, and Siemens AG. Dr. Piña reported no financial disclosures.

Moderate and severe diastolic dysfunction in patients who have normal systolic function increased all-cause mortality, according to a report in the June 27 issue of the Archives of Internal Medicine.

Such diastolic dysfunction is usually preclinical and often is identified on outpatient echocardiography that was done to assess nonspecific symptoms, ventricular or valvular function, arrhythmia, or ECG abnormalities. Its clinical significance has not been documented until now, said Dr. Carmel M. Halley of the Heart and Vascular Institute at the Cleveland Clinic, and her associates.

"Because the use of echocardiography as a clinical tool in the outpatient setting continues to increase ... our study provides the physician with a prognostic context when diastolic dysfunction is reported, especially because most procedures are requested by noncardiologists," the researchers noted (Arch. Intern. Med. 2011;171:1082-7).

Dr. Halley and her colleagues examined diastolic dysfunction in the absence of systolic dysfunction, because the clinical relevance of the condition has been questioned. Many medical disorders associated with diastolic dysfunction, such as hypertension, coronary artery disease, obesity, and diabetes, are themselves predictors of increased mortality, so it was unclear whether diastolic dysfunction was an independent contributor.

The researchers reviewed the records of consecutive patients who underwent outpatient echocardiography at the Cleveland Clinic and its satellite facilities between 1996 and 2005. They identified 36,261 patients (65,696 echocardiographic tests) who had normal ejection fractions signaling preserved systolic function.

The mean patient age was 58 years, and slightly more than half of the study subjects were women. The subjects were typical of patients usually referred for echocardiography – they frequently had cardiovascular risk factors such as dyslipidemia (35%), hypertension (15%), and diabetes (12%), but usually did not have established CV disease, such as congestive heart failure (4%), peripheral vascular disease (1%), or coronary artery disease (0.6%).

The most frequent indications for ordering the echocardiography were symptom assessment, assessment of ventricular or valvular function, evaluation of suspected or known CAD, and assessment of arrhythmia or ECG abnormalities.

The prevalence of diastolic dysfunction was high, at 65%. The dysfunction was mild in the majority of patients (nearly 60%), moderate in 4.8%, and severe in 0.4%.

During an average follow-up of 6 years, there were 5,789 deaths. Unadjusted all-cause mortality was higher with any degree of diastolic dysfunction than with normal diastolic function: 21% with mild diastolic dysfunction, 24% with moderate diastolic dysfunction, and 39% with severe diastolic dysfunction, compared with 7% in patients who had normal diastolic function.

However, because comorbidities that could confound the analyses were more common among patients with more severe diastolic dysfunction, propensity matching and statistical controlling for comorbidities were performed. Subsequent analysis showed that only moderate and severe diastolic dysfunction raised mortality risk.

Eight-year survival estimates were 78% for patients with normal diastolic function and 72% for mild diastolic dysfunction, compared with 68% for moderate diastolic dysfunction and 58% for severe diastolic dysfunction.

"For the first time, to our knowledge, moderate and severe diastolic dysfunction have been shown to be independent predictors of mortality rate," Dr. Halley and her associates said.

The mechanisms by which diastolic dysfunction raises mortality are not yet known, nor is it known whether therapies targeting such dysfunction can be developed, or whether they would reduce mortality. "However, our results suggest that an increased awareness of the clinical significance of advanced diastolic dysfunction may lead to earlier identification of those patients who are at risk, especially at a preclinical stage," the investigators noted.

They added that this study was limited in that it was retrospective and involved only a single institution.

This new study provides "an important piece of the puzzle," shedding light on the continuum from mild and asymptomatic to severe and symptomatic diastolic dysfunction, said Dr. Ileana L. Piña in remarks taken from her invited commentary that accompanied Dr. Halley’s report (Arch. Intern. Med. 2011;171:1088-9).

The findings that diastolic dysfunction is so common – affecting 65% of this study cohort – and that physicians must be alert to the prognostic value of more severe dysfunction are "novel and important for physicians."

In the future, it will be critical to elucidate the missing link between diagnosis of diastolic dysfunction on echocardiography and the later presentation of older patients, particularly older women, with acute decompensated heart failure in which systolic function is preserved, Dr. Piña of the departments of epidemiology and biostatistics at Case Western Reserve University, Cleveland, added.

One of Dr. Halley’s associates reported ties to GE Healthcare, Philips Healthcare, and Siemens AG. Dr. Piña reported no financial disclosures.

Moderate and severe diastolic dysfunction in patients who have normal systolic function increased all-cause mortality, according to a report in the June 27 issue of the Archives of Internal Medicine.

Such diastolic dysfunction is usually preclinical and often is identified on outpatient echocardiography that was done to assess nonspecific symptoms, ventricular or valvular function, arrhythmia, or ECG abnormalities. Its clinical significance has not been documented until now, said Dr. Carmel M. Halley of the Heart and Vascular Institute at the Cleveland Clinic, and her associates.

"Because the use of echocardiography as a clinical tool in the outpatient setting continues to increase ... our study provides the physician with a prognostic context when diastolic dysfunction is reported, especially because most procedures are requested by noncardiologists," the researchers noted (Arch. Intern. Med. 2011;171:1082-7).

Dr. Halley and her colleagues examined diastolic dysfunction in the absence of systolic dysfunction, because the clinical relevance of the condition has been questioned. Many medical disorders associated with diastolic dysfunction, such as hypertension, coronary artery disease, obesity, and diabetes, are themselves predictors of increased mortality, so it was unclear whether diastolic dysfunction was an independent contributor.

The researchers reviewed the records of consecutive patients who underwent outpatient echocardiography at the Cleveland Clinic and its satellite facilities between 1996 and 2005. They identified 36,261 patients (65,696 echocardiographic tests) who had normal ejection fractions signaling preserved systolic function.

The mean patient age was 58 years, and slightly more than half of the study subjects were women. The subjects were typical of patients usually referred for echocardiography – they frequently had cardiovascular risk factors such as dyslipidemia (35%), hypertension (15%), and diabetes (12%), but usually did not have established CV disease, such as congestive heart failure (4%), peripheral vascular disease (1%), or coronary artery disease (0.6%).

The most frequent indications for ordering the echocardiography were symptom assessment, assessment of ventricular or valvular function, evaluation of suspected or known CAD, and assessment of arrhythmia or ECG abnormalities.

The prevalence of diastolic dysfunction was high, at 65%. The dysfunction was mild in the majority of patients (nearly 60%), moderate in 4.8%, and severe in 0.4%.

During an average follow-up of 6 years, there were 5,789 deaths. Unadjusted all-cause mortality was higher with any degree of diastolic dysfunction than with normal diastolic function: 21% with mild diastolic dysfunction, 24% with moderate diastolic dysfunction, and 39% with severe diastolic dysfunction, compared with 7% in patients who had normal diastolic function.

However, because comorbidities that could confound the analyses were more common among patients with more severe diastolic dysfunction, propensity matching and statistical controlling for comorbidities were performed. Subsequent analysis showed that only moderate and severe diastolic dysfunction raised mortality risk.

Eight-year survival estimates were 78% for patients with normal diastolic function and 72% for mild diastolic dysfunction, compared with 68% for moderate diastolic dysfunction and 58% for severe diastolic dysfunction.

"For the first time, to our knowledge, moderate and severe diastolic dysfunction have been shown to be independent predictors of mortality rate," Dr. Halley and her associates said.

The mechanisms by which diastolic dysfunction raises mortality are not yet known, nor is it known whether therapies targeting such dysfunction can be developed, or whether they would reduce mortality. "However, our results suggest that an increased awareness of the clinical significance of advanced diastolic dysfunction may lead to earlier identification of those patients who are at risk, especially at a preclinical stage," the investigators noted.

They added that this study was limited in that it was retrospective and involved only a single institution.

This new study provides "an important piece of the puzzle," shedding light on the continuum from mild and asymptomatic to severe and symptomatic diastolic dysfunction, said Dr. Ileana L. Piña in remarks taken from her invited commentary that accompanied Dr. Halley’s report (Arch. Intern. Med. 2011;171:1088-9).

The findings that diastolic dysfunction is so common – affecting 65% of this study cohort – and that physicians must be alert to the prognostic value of more severe dysfunction are "novel and important for physicians."

In the future, it will be critical to elucidate the missing link between diagnosis of diastolic dysfunction on echocardiography and the later presentation of older patients, particularly older women, with acute decompensated heart failure in which systolic function is preserved, Dr. Piña of the departments of epidemiology and biostatistics at Case Western Reserve University, Cleveland, added.

One of Dr. Halley’s associates reported ties to GE Healthcare, Philips Healthcare, and Siemens AG. Dr. Piña reported no financial disclosures.

Moderate and severe diastolic dysfunction in patients who have normal systolic function increased all-cause mortality, according to a report in the June 27 issue of the Archives of Internal Medicine.

Such diastolic dysfunction is usually preclinical and often is identified on outpatient echocardiography that was done to assess nonspecific symptoms, ventricular or valvular function, arrhythmia, or ECG abnormalities. Its clinical significance has not been documented until now, said Dr. Carmel M. Halley of the Heart and Vascular Institute at the Cleveland Clinic, and her associates.

"Because the use of echocardiography as a clinical tool in the outpatient setting continues to increase ... our study provides the physician with a prognostic context when diastolic dysfunction is reported, especially because most procedures are requested by noncardiologists," the researchers noted (Arch. Intern. Med. 2011;171:1082-7).

Dr. Halley and her colleagues examined diastolic dysfunction in the absence of systolic dysfunction, because the clinical relevance of the condition has been questioned. Many medical disorders associated with diastolic dysfunction, such as hypertension, coronary artery disease, obesity, and diabetes, are themselves predictors of increased mortality, so it was unclear whether diastolic dysfunction was an independent contributor.

The researchers reviewed the records of consecutive patients who underwent outpatient echocardiography at the Cleveland Clinic and its satellite facilities between 1996 and 2005. They identified 36,261 patients (65,696 echocardiographic tests) who had normal ejection fractions signaling preserved systolic function.

The mean patient age was 58 years, and slightly more than half of the study subjects were women. The subjects were typical of patients usually referred for echocardiography – they frequently had cardiovascular risk factors such as dyslipidemia (35%), hypertension (15%), and diabetes (12%), but usually did not have established CV disease, such as congestive heart failure (4%), peripheral vascular disease (1%), or coronary artery disease (0.6%).

The most frequent indications for ordering the echocardiography were symptom assessment, assessment of ventricular or valvular function, evaluation of suspected or known CAD, and assessment of arrhythmia or ECG abnormalities.

The prevalence of diastolic dysfunction was high, at 65%. The dysfunction was mild in the majority of patients (nearly 60%), moderate in 4.8%, and severe in 0.4%.

During an average follow-up of 6 years, there were 5,789 deaths. Unadjusted all-cause mortality was higher with any degree of diastolic dysfunction than with normal diastolic function: 21% with mild diastolic dysfunction, 24% with moderate diastolic dysfunction, and 39% with severe diastolic dysfunction, compared with 7% in patients who had normal diastolic function.

However, because comorbidities that could confound the analyses were more common among patients with more severe diastolic dysfunction, propensity matching and statistical controlling for comorbidities were performed. Subsequent analysis showed that only moderate and severe diastolic dysfunction raised mortality risk.

Eight-year survival estimates were 78% for patients with normal diastolic function and 72% for mild diastolic dysfunction, compared with 68% for moderate diastolic dysfunction and 58% for severe diastolic dysfunction.

"For the first time, to our knowledge, moderate and severe diastolic dysfunction have been shown to be independent predictors of mortality rate," Dr. Halley and her associates said.

The mechanisms by which diastolic dysfunction raises mortality are not yet known, nor is it known whether therapies targeting such dysfunction can be developed, or whether they would reduce mortality. "However, our results suggest that an increased awareness of the clinical significance of advanced diastolic dysfunction may lead to earlier identification of those patients who are at risk, especially at a preclinical stage," the investigators noted.

They added that this study was limited in that it was retrospective and involved only a single institution.

This new study provides "an important piece of the puzzle," shedding light on the continuum from mild and asymptomatic to severe and symptomatic diastolic dysfunction, said Dr. Ileana L. Piña in remarks taken from her invited commentary that accompanied Dr. Halley’s report (Arch. Intern. Med. 2011;171:1088-9).

The findings that diastolic dysfunction is so common – affecting 65% of this study cohort – and that physicians must be alert to the prognostic value of more severe dysfunction are "novel and important for physicians."

In the future, it will be critical to elucidate the missing link between diagnosis of diastolic dysfunction on echocardiography and the later presentation of older patients, particularly older women, with acute decompensated heart failure in which systolic function is preserved, Dr. Piña of the departments of epidemiology and biostatistics at Case Western Reserve University, Cleveland, added.

One of Dr. Halley’s associates reported ties to GE Healthcare, Philips Healthcare, and Siemens AG. Dr. Piña reported no financial disclosures.

Moderate and severe diastolic dysfunction in patients who have normal systolic function increased all-cause mortality, according to a report in the June 27 issue of the Archives of Internal Medicine.

Such diastolic dysfunction is usually preclinical and often is identified on outpatient echocardiography that was done to assess nonspecific symptoms, ventricular or valvular function, arrhythmia, or ECG abnormalities. Its clinical significance has not been documented until now, said Dr. Carmel M. Halley of the Heart and Vascular Institute at the Cleveland Clinic, and her associates.

"Because the use of echocardiography as a clinical tool in the outpatient setting continues to increase ... our study provides the physician with a prognostic context when diastolic dysfunction is reported, especially because most procedures are requested by noncardiologists," the researchers noted (Arch. Intern. Med. 2011;171:1082-7).

Dr. Halley and her colleagues examined diastolic dysfunction in the absence of systolic dysfunction, because the clinical relevance of the condition has been questioned. Many medical disorders associated with diastolic dysfunction, such as hypertension, coronary artery disease, obesity, and diabetes, are themselves predictors of increased mortality, so it was unclear whether diastolic dysfunction was an independent contributor.

The researchers reviewed the records of consecutive patients who underwent outpatient echocardiography at the Cleveland Clinic and its satellite facilities between 1996 and 2005. They identified 36,261 patients (65,696 echocardiographic tests) who had normal ejection fractions signaling preserved systolic function.

The mean patient age was 58 years, and slightly more than half of the study subjects were women. The subjects were typical of patients usually referred for echocardiography – they frequently had cardiovascular risk factors such as dyslipidemia (35%), hypertension (15%), and diabetes (12%), but usually did not have established CV disease, such as congestive heart failure (4%), peripheral vascular disease (1%), or coronary artery disease (0.6%).

The most frequent indications for ordering the echocardiography were symptom assessment, assessment of ventricular or valvular function, evaluation of suspected or known CAD, and assessment of arrhythmia or ECG abnormalities.

The prevalence of diastolic dysfunction was high, at 65%. The dysfunction was mild in the majority of patients (nearly 60%), moderate in 4.8%, and severe in 0.4%.

During an average follow-up of 6 years, there were 5,789 deaths. Unadjusted all-cause mortality was higher with any degree of diastolic dysfunction than with normal diastolic function: 21% with mild diastolic dysfunction, 24% with moderate diastolic dysfunction, and 39% with severe diastolic dysfunction, compared with 7% in patients who had normal diastolic function.

However, because comorbidities that could confound the analyses were more common among patients with more severe diastolic dysfunction, propensity matching and statistical controlling for comorbidities were performed. Subsequent analysis showed that only moderate and severe diastolic dysfunction raised mortality risk.

Eight-year survival estimates were 78% for patients with normal diastolic function and 72% for mild diastolic dysfunction, compared with 68% for moderate diastolic dysfunction and 58% for severe diastolic dysfunction.

"For the first time, to our knowledge, moderate and severe diastolic dysfunction have been shown to be independent predictors of mortality rate," Dr. Halley and her associates said.

The mechanisms by which diastolic dysfunction raises mortality are not yet known, nor is it known whether therapies targeting such dysfunction can be developed, or whether they would reduce mortality. "However, our results suggest that an increased awareness of the clinical significance of advanced diastolic dysfunction may lead to earlier identification of those patients who are at risk, especially at a preclinical stage," the investigators noted.

They added that this study was limited in that it was retrospective and involved only a single institution.

This new study provides "an important piece of the puzzle," shedding light on the continuum from mild and asymptomatic to severe and symptomatic diastolic dysfunction, said Dr. Ileana L. Piña in remarks taken from her invited commentary that accompanied Dr. Halley’s report (Arch. Intern. Med. 2011;171:1088-9).

The findings that diastolic dysfunction is so common – affecting 65% of this study cohort – and that physicians must be alert to the prognostic value of more severe dysfunction are "novel and important for physicians."

In the future, it will be critical to elucidate the missing link between diagnosis of diastolic dysfunction on echocardiography and the later presentation of older patients, particularly older women, with acute decompensated heart failure in which systolic function is preserved, Dr. Piña of the departments of epidemiology and biostatistics at Case Western Reserve University, Cleveland, added.

One of Dr. Halley’s associates reported ties to GE Healthcare, Philips Healthcare, and Siemens AG. Dr. Piña reported no financial disclosures.

French fries, potato chips, sugar-sweetened beverages, and red meat were linked to greater long-term weight gain in nonobese adults, while consumption of yogurt, nuts, fruits, and whole grains led to weight loss, according to an analysis in the June 23 issue of the New England Journal of Medicine.

But the relationships between dietary and activity factors on the one hand and weight gain on the other were complex, with certain foods and behaviors having a much greater impact than others on weight change over time, said Dr. Dariush Mozaffarian of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.

Photo credit: © Aleksandr Stennikov/Fotolia.com

"Our findings suggest that both individual and population-based strategies to help people consume fewer calories may be most effective when particular foods and beverages are targeted for decreased (or increased) consumption," they noted.

Healthy, normal-weight adults gained an average of approximately 3.5 pounds every 4 years in an analysis of data from three separate prospective cohort studies.

The investigators examined lifestyle changes and weight changes in 50,422 women participating in the Nurses Health Study, 47,898 women participating in the Nurses Health Study II, and 22,557 men participating in the Health Professionals Follow-Up Study. All of the study subjects were free of obesity and chronic diseases at baseline.

Weight changes were assessed at 4-year intervals. The average weight gain across all three cohorts was 3.35 pounds during each interval, for an overall gain of 16.8 pounds over 20 years.

"Average long-term weight gain in nonobese populations is gradual – in the cohorts we studied, about 0.8 pounds per year – but accumulated over time, even modest increases in weight have implications for long-term adiposity-related metabolic dysfunction, diabetes, cardiovascular disease, and cancer," the investigators said (N. Engl. J. Med. 2011;364:2392-404).

The relationships among dietary factors, physical activity, and weight change were comparable between men and women, attesting to the validity and generalizability of the findings.

Weight gain was significantly associated with consumption of starches, refined grains, and processed foods. Specifically, a 4-year weight gain correlated with higher intake of potato chips (gain of 1.69 pounds), sugar-sweetened drinks (gain of 1 pound), alcohol (0.41 pounds), unprocessed red meats (gain of 0.95 pounds), and processed meats (gain of 0.93 pounds).

Although potato consumption overall was associated with a 4-year weight gain of 1.28 pounds, french fries in particular were linked to greater 4-year weight gain (3.35 pounds) than were boiled, baked, or mashed potatoes (0.57 pounds). In fact, french fry consumption was associated with the greatest weight gain of any food in the study.

It seems likely that consumption of these foods is "less satiating, which increases subsequent hunger signals and total caloric intake, as compared with equivalent numbers of calories obtained from less processed, higher-fiber foods that also contain healthy fats and protein," Dr. Mozaffarian and his colleagues said.

In contrast, 4-year weight gain was inversely related to intake of vegetables (loss of 0.22 pounds), whole grains (loss of 0.37 pounds), fruits (loss of 0.49 pounds), nuts (loss of 0.57 pounds), and yogurt (loss of 0.82 pounds).This is likely because greater intake of these high-fiber, slower-to-digest foods is accompanied by less intake of starchy, processed foods.

Yogurt consumption was associated with less weight gain across all three cohorts. "Intriguing evidence suggests that changes in colonic bacteria might influence weight gain," the researchers said.

Increased intake of all liquids except milk was associated with weight gain. Other studies have suggested that liquids are less satiating than solid foods are, so people who drink a lot of liquids still eat the same amount of solid food, for an overall increase in total energy consumed.

There were no significant differences in weight gain between people who consumed skim or low-fat milk and those who consumed whole milk. In addition, there was a "relatively neutral association" between intake of most dairy foods and weight gain.

Changes in physical activity were independently associated with weight changes.

Specifically, increased television viewing correlated with weight gain (0.31 pounds), presumably because it is sedentary itself but also encourages snacking during such viewing and influences poor food choices at other times. Increased physical activity was associated with a decrease of nearly 2 pounds per 4-year interval.

Both increased and decreased sleep time – getting less than 6 hours or more than 8 hours of sleep per day – were associated with increased weight gain. This finding is similar to those from cross-sectional studies linking shorter sleep duration with obesity.

"A habitual energy imbalance of about 50-100 kcal/day may be sufficient to cause the gradual weight gain seen in most persons. This means that unintended weight gain occurs easily, but also that modest, sustained changes in lifestyle could mitigate or reverse such an energy imbalance," the researchers noted.

The National Institutes of Health and the Searle Scholars Program supported the study. Dr. Mozaffarian and his associates reported ties to Nutrition Impact, Foodminds, Aramark, Unilever, SPRIM, UpToDate, GlaxoSmithKline, Sigma-Tau, Pronova, Amgen, the Institute of Food Technologies, Merck, and the California Walnut Commission.

French fries, potato chips, sugar-sweetened beverages, and red meat were linked to greater long-term weight gain in nonobese adults, while consumption of yogurt, nuts, fruits, and whole grains led to weight loss, according to an analysis in the June 23 issue of the New England Journal of Medicine.

But the relationships between dietary and activity factors on the one hand and weight gain on the other were complex, with certain foods and behaviors having a much greater impact than others on weight change over time, said Dr. Dariush Mozaffarian of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.

Photo credit: © Aleksandr Stennikov/Fotolia.com

"Our findings suggest that both individual and population-based strategies to help people consume fewer calories may be most effective when particular foods and beverages are targeted for decreased (or increased) consumption," they noted.

Healthy, normal-weight adults gained an average of approximately 3.5 pounds every 4 years in an analysis of data from three separate prospective cohort studies.

The investigators examined lifestyle changes and weight changes in 50,422 women participating in the Nurses Health Study, 47,898 women participating in the Nurses Health Study II, and 22,557 men participating in the Health Professionals Follow-Up Study. All of the study subjects were free of obesity and chronic diseases at baseline.

Weight changes were assessed at 4-year intervals. The average weight gain across all three cohorts was 3.35 pounds during each interval, for an overall gain of 16.8 pounds over 20 years.

"Average long-term weight gain in nonobese populations is gradual – in the cohorts we studied, about 0.8 pounds per year – but accumulated over time, even modest increases in weight have implications for long-term adiposity-related metabolic dysfunction, diabetes, cardiovascular disease, and cancer," the investigators said (N. Engl. J. Med. 2011;364:2392-404).

The relationships among dietary factors, physical activity, and weight change were comparable between men and women, attesting to the validity and generalizability of the findings.

Weight gain was significantly associated with consumption of starches, refined grains, and processed foods. Specifically, a 4-year weight gain correlated with higher intake of potato chips (gain of 1.69 pounds), sugar-sweetened drinks (gain of 1 pound), alcohol (0.41 pounds), unprocessed red meats (gain of 0.95 pounds), and processed meats (gain of 0.93 pounds).

Although potato consumption overall was associated with a 4-year weight gain of 1.28 pounds, french fries in particular were linked to greater 4-year weight gain (3.35 pounds) than were boiled, baked, or mashed potatoes (0.57 pounds). In fact, french fry consumption was associated with the greatest weight gain of any food in the study.

It seems likely that consumption of these foods is "less satiating, which increases subsequent hunger signals and total caloric intake, as compared with equivalent numbers of calories obtained from less processed, higher-fiber foods that also contain healthy fats and protein," Dr. Mozaffarian and his colleagues said.

In contrast, 4-year weight gain was inversely related to intake of vegetables (loss of 0.22 pounds), whole grains (loss of 0.37 pounds), fruits (loss of 0.49 pounds), nuts (loss of 0.57 pounds), and yogurt (loss of 0.82 pounds).This is likely because greater intake of these high-fiber, slower-to-digest foods is accompanied by less intake of starchy, processed foods.

Yogurt consumption was associated with less weight gain across all three cohorts. "Intriguing evidence suggests that changes in colonic bacteria might influence weight gain," the researchers said.

Increased intake of all liquids except milk was associated with weight gain. Other studies have suggested that liquids are less satiating than solid foods are, so people who drink a lot of liquids still eat the same amount of solid food, for an overall increase in total energy consumed.

There were no significant differences in weight gain between people who consumed skim or low-fat milk and those who consumed whole milk. In addition, there was a "relatively neutral association" between intake of most dairy foods and weight gain.

Changes in physical activity were independently associated with weight changes.

Specifically, increased television viewing correlated with weight gain (0.31 pounds), presumably because it is sedentary itself but also encourages snacking during such viewing and influences poor food choices at other times. Increased physical activity was associated with a decrease of nearly 2 pounds per 4-year interval.

Both increased and decreased sleep time – getting less than 6 hours or more than 8 hours of sleep per day – were associated with increased weight gain. This finding is similar to those from cross-sectional studies linking shorter sleep duration with obesity.

"A habitual energy imbalance of about 50-100 kcal/day may be sufficient to cause the gradual weight gain seen in most persons. This means that unintended weight gain occurs easily, but also that modest, sustained changes in lifestyle could mitigate or reverse such an energy imbalance," the researchers noted.

The National Institutes of Health and the Searle Scholars Program supported the study. Dr. Mozaffarian and his associates reported ties to Nutrition Impact, Foodminds, Aramark, Unilever, SPRIM, UpToDate, GlaxoSmithKline, Sigma-Tau, Pronova, Amgen, the Institute of Food Technologies, Merck, and the California Walnut Commission.

French fries, potato chips, sugar-sweetened beverages, and red meat were linked to greater long-term weight gain in nonobese adults, while consumption of yogurt, nuts, fruits, and whole grains led to weight loss, according to an analysis in the June 23 issue of the New England Journal of Medicine.

But the relationships between dietary and activity factors on the one hand and weight gain on the other were complex, with certain foods and behaviors having a much greater impact than others on weight change over time, said Dr. Dariush Mozaffarian of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.

Photo credit: © Aleksandr Stennikov/Fotolia.com

"Our findings suggest that both individual and population-based strategies to help people consume fewer calories may be most effective when particular foods and beverages are targeted for decreased (or increased) consumption," they noted.

Healthy, normal-weight adults gained an average of approximately 3.5 pounds every 4 years in an analysis of data from three separate prospective cohort studies.

The investigators examined lifestyle changes and weight changes in 50,422 women participating in the Nurses Health Study, 47,898 women participating in the Nurses Health Study II, and 22,557 men participating in the Health Professionals Follow-Up Study. All of the study subjects were free of obesity and chronic diseases at baseline.

Weight changes were assessed at 4-year intervals. The average weight gain across all three cohorts was 3.35 pounds during each interval, for an overall gain of 16.8 pounds over 20 years.

"Average long-term weight gain in nonobese populations is gradual – in the cohorts we studied, about 0.8 pounds per year – but accumulated over time, even modest increases in weight have implications for long-term adiposity-related metabolic dysfunction, diabetes, cardiovascular disease, and cancer," the investigators said (N. Engl. J. Med. 2011;364:2392-404).

The relationships among dietary factors, physical activity, and weight change were comparable between men and women, attesting to the validity and generalizability of the findings.

Weight gain was significantly associated with consumption of starches, refined grains, and processed foods. Specifically, a 4-year weight gain correlated with higher intake of potato chips (gain of 1.69 pounds), sugar-sweetened drinks (gain of 1 pound), alcohol (0.41 pounds), unprocessed red meats (gain of 0.95 pounds), and processed meats (gain of 0.93 pounds).

Although potato consumption overall was associated with a 4-year weight gain of 1.28 pounds, french fries in particular were linked to greater 4-year weight gain (3.35 pounds) than were boiled, baked, or mashed potatoes (0.57 pounds). In fact, french fry consumption was associated with the greatest weight gain of any food in the study.

It seems likely that consumption of these foods is "less satiating, which increases subsequent hunger signals and total caloric intake, as compared with equivalent numbers of calories obtained from less processed, higher-fiber foods that also contain healthy fats and protein," Dr. Mozaffarian and his colleagues said.

In contrast, 4-year weight gain was inversely related to intake of vegetables (loss of 0.22 pounds), whole grains (loss of 0.37 pounds), fruits (loss of 0.49 pounds), nuts (loss of 0.57 pounds), and yogurt (loss of 0.82 pounds).This is likely because greater intake of these high-fiber, slower-to-digest foods is accompanied by less intake of starchy, processed foods.

Yogurt consumption was associated with less weight gain across all three cohorts. "Intriguing evidence suggests that changes in colonic bacteria might influence weight gain," the researchers said.

Increased intake of all liquids except milk was associated with weight gain. Other studies have suggested that liquids are less satiating than solid foods are, so people who drink a lot of liquids still eat the same amount of solid food, for an overall increase in total energy consumed.

There were no significant differences in weight gain between people who consumed skim or low-fat milk and those who consumed whole milk. In addition, there was a "relatively neutral association" between intake of most dairy foods and weight gain.

Changes in physical activity were independently associated with weight changes.

Specifically, increased television viewing correlated with weight gain (0.31 pounds), presumably because it is sedentary itself but also encourages snacking during such viewing and influences poor food choices at other times. Increased physical activity was associated with a decrease of nearly 2 pounds per 4-year interval.

Both increased and decreased sleep time – getting less than 6 hours or more than 8 hours of sleep per day – were associated with increased weight gain. This finding is similar to those from cross-sectional studies linking shorter sleep duration with obesity.

"A habitual energy imbalance of about 50-100 kcal/day may be sufficient to cause the gradual weight gain seen in most persons. This means that unintended weight gain occurs easily, but also that modest, sustained changes in lifestyle could mitigate or reverse such an energy imbalance," the researchers noted.

The National Institutes of Health and the Searle Scholars Program supported the study. Dr. Mozaffarian and his associates reported ties to Nutrition Impact, Foodminds, Aramark, Unilever, SPRIM, UpToDate, GlaxoSmithKline, Sigma-Tau, Pronova, Amgen, the Institute of Food Technologies, Merck, and the California Walnut Commission.

French fries, potato chips, sugar-sweetened beverages, and red meat were linked to greater long-term weight gain in nonobese adults, while consumption of yogurt, nuts, fruits, and whole grains led to weight loss, according to an analysis in the June 23 issue of the New England Journal of Medicine.

But the relationships between dietary and activity factors on the one hand and weight gain on the other were complex, with certain foods and behaviors having a much greater impact than others on weight change over time, said Dr. Dariush Mozaffarian of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.

Photo credit: © Aleksandr Stennikov/Fotolia.com

"Our findings suggest that both individual and population-based strategies to help people consume fewer calories may be most effective when particular foods and beverages are targeted for decreased (or increased) consumption," they noted.

Healthy, normal-weight adults gained an average of approximately 3.5 pounds every 4 years in an analysis of data from three separate prospective cohort studies.

The investigators examined lifestyle changes and weight changes in 50,422 women participating in the Nurses Health Study, 47,898 women participating in the Nurses Health Study II, and 22,557 men participating in the Health Professionals Follow-Up Study. All of the study subjects were free of obesity and chronic diseases at baseline.

Weight changes were assessed at 4-year intervals. The average weight gain across all three cohorts was 3.35 pounds during each interval, for an overall gain of 16.8 pounds over 20 years.

"Average long-term weight gain in nonobese populations is gradual – in the cohorts we studied, about 0.8 pounds per year – but accumulated over time, even modest increases in weight have implications for long-term adiposity-related metabolic dysfunction, diabetes, cardiovascular disease, and cancer," the investigators said (N. Engl. J. Med. 2011;364:2392-404).

The relationships among dietary factors, physical activity, and weight change were comparable between men and women, attesting to the validity and generalizability of the findings.

Weight gain was significantly associated with consumption of starches, refined grains, and processed foods. Specifically, a 4-year weight gain correlated with higher intake of potato chips (gain of 1.69 pounds), sugar-sweetened drinks (gain of 1 pound), alcohol (0.41 pounds), unprocessed red meats (gain of 0.95 pounds), and processed meats (gain of 0.93 pounds).

Although potato consumption overall was associated with a 4-year weight gain of 1.28 pounds, french fries in particular were linked to greater 4-year weight gain (3.35 pounds) than were boiled, baked, or mashed potatoes (0.57 pounds). In fact, french fry consumption was associated with the greatest weight gain of any food in the study.

It seems likely that consumption of these foods is "less satiating, which increases subsequent hunger signals and total caloric intake, as compared with equivalent numbers of calories obtained from less processed, higher-fiber foods that also contain healthy fats and protein," Dr. Mozaffarian and his colleagues said.

In contrast, 4-year weight gain was inversely related to intake of vegetables (loss of 0.22 pounds), whole grains (loss of 0.37 pounds), fruits (loss of 0.49 pounds), nuts (loss of 0.57 pounds), and yogurt (loss of 0.82 pounds).This is likely because greater intake of these high-fiber, slower-to-digest foods is accompanied by less intake of starchy, processed foods.

Yogurt consumption was associated with less weight gain across all three cohorts. "Intriguing evidence suggests that changes in colonic bacteria might influence weight gain," the researchers said.

Increased intake of all liquids except milk was associated with weight gain. Other studies have suggested that liquids are less satiating than solid foods are, so people who drink a lot of liquids still eat the same amount of solid food, for an overall increase in total energy consumed.

There were no significant differences in weight gain between people who consumed skim or low-fat milk and those who consumed whole milk. In addition, there was a "relatively neutral association" between intake of most dairy foods and weight gain.

Changes in physical activity were independently associated with weight changes.

Specifically, increased television viewing correlated with weight gain (0.31 pounds), presumably because it is sedentary itself but also encourages snacking during such viewing and influences poor food choices at other times. Increased physical activity was associated with a decrease of nearly 2 pounds per 4-year interval.

Both increased and decreased sleep time – getting less than 6 hours or more than 8 hours of sleep per day – were associated with increased weight gain. This finding is similar to those from cross-sectional studies linking shorter sleep duration with obesity.

"A habitual energy imbalance of about 50-100 kcal/day may be sufficient to cause the gradual weight gain seen in most persons. This means that unintended weight gain occurs easily, but also that modest, sustained changes in lifestyle could mitigate or reverse such an energy imbalance," the researchers noted.

The National Institutes of Health and the Searle Scholars Program supported the study. Dr. Mozaffarian and his associates reported ties to Nutrition Impact, Foodminds, Aramark, Unilever, SPRIM, UpToDate, GlaxoSmithKline, Sigma-Tau, Pronova, Amgen, the Institute of Food Technologies, Merck, and the California Walnut Commission.

French fries, potato chips, sugar-sweetened beverages, and red meat were linked to greater long-term weight gain in nonobese adults, while consumption of yogurt, nuts, fruits, and whole grains led to weight loss, according to an analysis in the June 23 issue of the New England Journal of Medicine.

But the relationships between dietary and activity factors on the one hand and weight gain on the other were complex, with certain foods and behaviors having a much greater impact than others on weight change over time, said Dr. Dariush Mozaffarian of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.

Photo credit: © Aleksandr Stennikov/Fotolia.com

"Our findings suggest that both individual and population-based strategies to help people consume fewer calories may be most effective when particular foods and beverages are targeted for decreased (or increased) consumption," they noted.

Healthy, normal-weight adults gained an average of approximately 3.5 pounds every 4 years in an analysis of data from three separate prospective cohort studies.

The investigators examined lifestyle changes and weight changes in 50,422 women participating in the Nurses Health Study, 47,898 women participating in the Nurses Health Study II, and 22,557 men participating in the Health Professionals Follow-Up Study. All of the study subjects were free of obesity and chronic diseases at baseline.

Weight changes were assessed at 4-year intervals. The average weight gain across all three cohorts was 3.35 pounds during each interval, for an overall gain of 16.8 pounds over 20 years.

"Average long-term weight gain in nonobese populations is gradual – in the cohorts we studied, about 0.8 pounds per year – but accumulated over time, even modest increases in weight have implications for long-term adiposity-related metabolic dysfunction, diabetes, cardiovascular disease, and cancer," the investigators said (N. Engl. J. Med. 2011;364:2392-404).

The relationships among dietary factors, physical activity, and weight change were comparable between men and women, attesting to the validity and generalizability of the findings.

Weight gain was significantly associated with consumption of starches, refined grains, and processed foods. Specifically, a 4-year weight gain correlated with higher intake of potato chips (gain of 1.69 pounds), sugar-sweetened drinks (gain of 1 pound), alcohol (0.41 pounds), unprocessed red meats (gain of 0.95 pounds), and processed meats (gain of 0.93 pounds).

Although potato consumption overall was associated with a 4-year weight gain of 1.28 pounds, french fries in particular were linked to greater 4-year weight gain (3.35 pounds) than were boiled, baked, or mashed potatoes (0.57 pounds). In fact, french fry consumption was associated with the greatest weight gain of any food in the study.

It seems likely that consumption of these foods is "less satiating, which increases subsequent hunger signals and total caloric intake, as compared with equivalent numbers of calories obtained from less processed, higher-fiber foods that also contain healthy fats and protein," Dr. Mozaffarian and his colleagues said.

In contrast, 4-year weight gain was inversely related to intake of vegetables (loss of 0.22 pounds), whole grains (loss of 0.37 pounds), fruits (loss of 0.49 pounds), nuts (loss of 0.57 pounds), and yogurt (loss of 0.82 pounds).This is likely because greater intake of these high-fiber, slower-to-digest foods is accompanied by less intake of starchy, processed foods.

Yogurt consumption was associated with less weight gain across all three cohorts. "Intriguing evidence suggests that changes in colonic bacteria might influence weight gain," the researchers said.

Increased intake of all liquids except milk was associated with weight gain. Other studies have suggested that liquids are less satiating than solid foods are, so people who drink a lot of liquids still eat the same amount of solid food, for an overall increase in total energy consumed.

There were no significant differences in weight gain between people who consumed skim or low-fat milk and those who consumed whole milk. In addition, there was a "relatively neutral association" between intake of most dairy foods and weight gain.

Changes in physical activity were independently associated with weight changes.

Specifically, increased television viewing correlated with weight gain (0.31 pounds), presumably because it is sedentary itself but also encourages snacking during such viewing and influences poor food choices at other times. Increased physical activity was associated with a decrease of nearly 2 pounds per 4-year interval.

Both increased and decreased sleep time – getting less than 6 hours or more than 8 hours of sleep per day – were associated with increased weight gain. This finding is similar to those from cross-sectional studies linking shorter sleep duration with obesity.

"A habitual energy imbalance of about 50-100 kcal/day may be sufficient to cause the gradual weight gain seen in most persons. This means that unintended weight gain occurs easily, but also that modest, sustained changes in lifestyle could mitigate or reverse such an energy imbalance," the researchers noted.

The National Institutes of Health and the Searle Scholars Program supported the study. Dr. Mozaffarian and his associates reported ties to Nutrition Impact, Foodminds, Aramark, Unilever, SPRIM, UpToDate, GlaxoSmithKline, Sigma-Tau, Pronova, Amgen, the Institute of Food Technologies, Merck, and the California Walnut Commission.

French fries, potato chips, sugar-sweetened beverages, and red meat were linked to greater long-term weight gain in nonobese adults, while consumption of yogurt, nuts, fruits, and whole grains led to weight loss, according to an analysis in the June 23 issue of the New England Journal of Medicine.

But the relationships between dietary and activity factors on the one hand and weight gain on the other were complex, with certain foods and behaviors having a much greater impact than others on weight change over time, said Dr. Dariush Mozaffarian of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.

Photo credit: © Aleksandr Stennikov/Fotolia.com

"Our findings suggest that both individual and population-based strategies to help people consume fewer calories may be most effective when particular foods and beverages are targeted for decreased (or increased) consumption," they noted.

Healthy, normal-weight adults gained an average of approximately 3.5 pounds every 4 years in an analysis of data from three separate prospective cohort studies.

The investigators examined lifestyle changes and weight changes in 50,422 women participating in the Nurses Health Study, 47,898 women participating in the Nurses Health Study II, and 22,557 men participating in the Health Professionals Follow-Up Study. All of the study subjects were free of obesity and chronic diseases at baseline.

Weight changes were assessed at 4-year intervals. The average weight gain across all three cohorts was 3.35 pounds during each interval, for an overall gain of 16.8 pounds over 20 years.

"Average long-term weight gain in nonobese populations is gradual – in the cohorts we studied, about 0.8 pounds per year – but accumulated over time, even modest increases in weight have implications for long-term adiposity-related metabolic dysfunction, diabetes, cardiovascular disease, and cancer," the investigators said (N. Engl. J. Med. 2011;364:2392-404).

The relationships among dietary factors, physical activity, and weight change were comparable between men and women, attesting to the validity and generalizability of the findings.

Weight gain was significantly associated with consumption of starches, refined grains, and processed foods. Specifically, a 4-year weight gain correlated with higher intake of potato chips (gain of 1.69 pounds), sugar-sweetened drinks (gain of 1 pound), alcohol (0.41 pounds), unprocessed red meats (gain of 0.95 pounds), and processed meats (gain of 0.93 pounds).

Although potato consumption overall was associated with a 4-year weight gain of 1.28 pounds, french fries in particular were linked to greater 4-year weight gain (3.35 pounds) than were boiled, baked, or mashed potatoes (0.57 pounds). In fact, french fry consumption was associated with the greatest weight gain of any food in the study.

It seems likely that consumption of these foods is "less satiating, which increases subsequent hunger signals and total caloric intake, as compared with equivalent numbers of calories obtained from less processed, higher-fiber foods that also contain healthy fats and protein," Dr. Mozaffarian and his colleagues said.

In contrast, 4-year weight gain was inversely related to intake of vegetables (loss of 0.22 pounds), whole grains (loss of 0.37 pounds), fruits (loss of 0.49 pounds), nuts (loss of 0.57 pounds), and yogurt (loss of 0.82 pounds).This is likely because greater intake of these high-fiber, slower-to-digest foods is accompanied by less intake of starchy, processed foods.

Yogurt consumption was associated with less weight gain across all three cohorts. "Intriguing evidence suggests that changes in colonic bacteria might influence weight gain," the researchers said.

Increased intake of all liquids except milk was associated with weight gain. Other studies have suggested that liquids are less satiating than solid foods are, so people who drink a lot of liquids still eat the same amount of solid food, for an overall increase in total energy consumed.

There were no significant differences in weight gain between people who consumed skim or low-fat milk and those who consumed whole milk. In addition, there was a "relatively neutral association" between intake of most dairy foods and weight gain.

Changes in physical activity were independently associated with weight changes.

Specifically, increased television viewing correlated with weight gain (0.31 pounds), presumably because it is sedentary itself but also encourages snacking during such viewing and influences poor food choices at other times. Increased physical activity was associated with a decrease of nearly 2 pounds per 4-year interval.

Both increased and decreased sleep time – getting less than 6 hours or more than 8 hours of sleep per day – were associated with increased weight gain. This finding is similar to those from cross-sectional studies linking shorter sleep duration with obesity.

"A habitual energy imbalance of about 50-100 kcal/day may be sufficient to cause the gradual weight gain seen in most persons. This means that unintended weight gain occurs easily, but also that modest, sustained changes in lifestyle could mitigate or reverse such an energy imbalance," the researchers noted.

The National Institutes of Health and the Searle Scholars Program supported the study. Dr. Mozaffarian and his associates reported ties to Nutrition Impact, Foodminds, Aramark, Unilever, SPRIM, UpToDate, GlaxoSmithKline, Sigma-Tau, Pronova, Amgen, the Institute of Food Technologies, Merck, and the California Walnut Commission.

Adding telaprevir to standard peginterferon-plus-ribavirin therapy markedly improves the sustained virologic response in patients with chronic hepatitis C infection, even in those who did not respond well to a previous course of standard treatment, according to two separate phase III clinical trials reported in the June 23 New England Journal of Medicine.

The addition of the HCV protease inhibitor allowed most patients to halve their duration of therapy, reducing total treatment time from 48 to 24 weeks, minimizing the therapy’s toxic effects, and decreasing the rate of treatment discontinuation.

In the first report, Dr. Stefan Zeuzem and his associates in the REALIZE study group assessed the benefit of adding telaprevir to the regimens of 662 patients from 17 countries who had previously shown no response (28%), a partial response (19%), or a relapse (53%) after standard peginterferon-plus-ribavirin therapy.

They also assessed whether using a 4-week lead-in phase of peginterferon plus ribavirin before the addition of telaprevir would reduce the emergence of protease-resistant variants, as had been suggested by a previous study using a different HCV protease inhibitor.

The rates of sustained virologic response proved to be significantly higher in subjects who received telaprevir, both with and without the lead-in period, than in those who did not. These rates were 64% without a lead-in period and 66% with a lead-in period, compared with only 17% in the control group, which received peginterferon plus ribavirin only.

Even patients who had previously shown a minimal response to earlier therapy showed a nearly sixfold increase in sustained virologic response when telaprevir was added to the regimen, the investigators said (N. Engl. J. Med. 2011;364:2417-28).

Telaprevir improved the rates of sustained virologic response across all subgroups of patients, regardless of their viral load at baseline or the presence and severity of liver fibrosis or cirrhosis, said Dr. Zeuzem of Johann Wolfgang Goethe University Hospital, Frankfurt, Germany, and his colleagues.

Telaprevir also raised the rate of adverse events, chiefly fatigue, pruritus, rash, nausea, anemia, and diarrhea. The number of grade 3 adverse events (mainly anemia, neutropenia, and leucopenia) also was increased with telaprevir (37%), compared with the control group (22%). The rate of adverse events leading to permanent discontinuation of the study drugs was 13% in subjects who received telaprevir, compared with 3% in the control group.

In the second report, Dr. Ira M. Jacobson and his associates in the ADVANCE study assessed the addition of telaprevir in 1,088 patients at 123 international sites. These study subjects had never received therapy for chronic HCV.

The objective was to adjust treatment guided by the patient’s response after 4 weeks. Earlier studies have shown "high rates of early viral suppression and low rates of relapse after cessation of telaprevir therapy, [suggesting] that therapy could potentially be shortened to 24 weeks in patients who have a rapid virologic response – that is, patients in whom HCV RNA is undetectable at week 4 of treatment," said Dr. Jacobson of Cornell University and the Center for the Study of Hepatitis C, both in New York, and his colleagues.

One group of subjects received telaprevir in addition to standard peginterferon-plus-ribavirin therapy for 12 weeks. If they showed a rapid virologic response at 4 and 12 weeks, telaprevir was withdrawn and standard therapy was continued for 12 more weeks, for a total of 24 weeks of treatment. If there was no rapid response, standard therapy was extended for the customary 36 weeks, for a total of 48 weeks of treatment.

A second group received telaprevir plus standard therapy for 8 weeks, followed by placebo plus standard therapy for 4 weeks; their response to treatment determined the same two alternative courses of therapy as in group 1. The control group received placebo plus standard therapy for 12 weeks, followed by standard therapy for 36 weeks, for the standard total of 48 weeks of therapy.

A total of 75% of group 1 and 69% of group 2 showed a rapid and sustained virologic response, allowing them to complete treatment in half the usual time. Relapse was "infrequent" in these patients, indicating that a total of 24 weeks of therapy is sufficient for rapid responders, Dr. Jacobson and his colleagues said (N. Engl. J. Med. 2011;364:2405-16).

In comparison, only 44% of the control group achieved a rapid and sustained virologic response.

The addition of telaprevir also substantially improved treatment response among patient groups who usually respond poorly to standard therapy, including those with fibrosis or cirrhosis, older patients, diabetics, and those with a high viral load at baseline. Telaprevir more than doubled treatment response among black patients, who typically show a very poor response to interferon that likely results from genetic factors, the researchers noted.

Both studies were funded by Tibotec and Vertex Pharmaceuticals, which both manufacture telaprevir. Dr. Zeuzem and Dr. Jacobson reported ties to Tibotec and Vertex, as well as to numerous other industry sources.

Adding telaprevir to standard peginterferon-plus-ribavirin therapy markedly improves the sustained virologic response in patients with chronic hepatitis C infection, even in those who did not respond well to a previous course of standard treatment, according to two separate phase III clinical trials reported in the June 23 New England Journal of Medicine.

The addition of the HCV protease inhibitor allowed most patients to halve their duration of therapy, reducing total treatment time from 48 to 24 weeks, minimizing the therapy’s toxic effects, and decreasing the rate of treatment discontinuation.

In the first report, Dr. Stefan Zeuzem and his associates in the REALIZE study group assessed the benefit of adding telaprevir to the regimens of 662 patients from 17 countries who had previously shown no response (28%), a partial response (19%), or a relapse (53%) after standard peginterferon-plus-ribavirin therapy.

They also assessed whether using a 4-week lead-in phase of peginterferon plus ribavirin before the addition of telaprevir would reduce the emergence of protease-resistant variants, as had been suggested by a previous study using a different HCV protease inhibitor.

The rates of sustained virologic response proved to be significantly higher in subjects who received telaprevir, both with and without the lead-in period, than in those who did not. These rates were 64% without a lead-in period and 66% with a lead-in period, compared with only 17% in the control group, which received peginterferon plus ribavirin only.

Even patients who had previously shown a minimal response to earlier therapy showed a nearly sixfold increase in sustained virologic response when telaprevir was added to the regimen, the investigators said (N. Engl. J. Med. 2011;364:2417-28).

Telaprevir improved the rates of sustained virologic response across all subgroups of patients, regardless of their viral load at baseline or the presence and severity of liver fibrosis or cirrhosis, said Dr. Zeuzem of Johann Wolfgang Goethe University Hospital, Frankfurt, Germany, and his colleagues.

Telaprevir also raised the rate of adverse events, chiefly fatigue, pruritus, rash, nausea, anemia, and diarrhea. The number of grade 3 adverse events (mainly anemia, neutropenia, and leucopenia) also was increased with telaprevir (37%), compared with the control group (22%). The rate of adverse events leading to permanent discontinuation of the study drugs was 13% in subjects who received telaprevir, compared with 3% in the control group.

In the second report, Dr. Ira M. Jacobson and his associates in the ADVANCE study assessed the addition of telaprevir in 1,088 patients at 123 international sites. These study subjects had never received therapy for chronic HCV.

The objective was to adjust treatment guided by the patient’s response after 4 weeks. Earlier studies have shown "high rates of early viral suppression and low rates of relapse after cessation of telaprevir therapy, [suggesting] that therapy could potentially be shortened to 24 weeks in patients who have a rapid virologic response – that is, patients in whom HCV RNA is undetectable at week 4 of treatment," said Dr. Jacobson of Cornell University and the Center for the Study of Hepatitis C, both in New York, and his colleagues.

One group of subjects received telaprevir in addition to standard peginterferon-plus-ribavirin therapy for 12 weeks. If they showed a rapid virologic response at 4 and 12 weeks, telaprevir was withdrawn and standard therapy was continued for 12 more weeks, for a total of 24 weeks of treatment. If there was no rapid response, standard therapy was extended for the customary 36 weeks, for a total of 48 weeks of treatment.

A second group received telaprevir plus standard therapy for 8 weeks, followed by placebo plus standard therapy for 4 weeks; their response to treatment determined the same two alternative courses of therapy as in group 1. The control group received placebo plus standard therapy for 12 weeks, followed by standard therapy for 36 weeks, for the standard total of 48 weeks of therapy.

A total of 75% of group 1 and 69% of group 2 showed a rapid and sustained virologic response, allowing them to complete treatment in half the usual time. Relapse was "infrequent" in these patients, indicating that a total of 24 weeks of therapy is sufficient for rapid responders, Dr. Jacobson and his colleagues said (N. Engl. J. Med. 2011;364:2405-16).

In comparison, only 44% of the control group achieved a rapid and sustained virologic response.

The addition of telaprevir also substantially improved treatment response among patient groups who usually respond poorly to standard therapy, including those with fibrosis or cirrhosis, older patients, diabetics, and those with a high viral load at baseline. Telaprevir more than doubled treatment response among black patients, who typically show a very poor response to interferon that likely results from genetic factors, the researchers noted.

Both studies were funded by Tibotec and Vertex Pharmaceuticals, which both manufacture telaprevir. Dr. Zeuzem and Dr. Jacobson reported ties to Tibotec and Vertex, as well as to numerous other industry sources.

Adding telaprevir to standard peginterferon-plus-ribavirin therapy markedly improves the sustained virologic response in patients with chronic hepatitis C infection, even in those who did not respond well to a previous course of standard treatment, according to two separate phase III clinical trials reported in the June 23 New England Journal of Medicine.

The addition of the HCV protease inhibitor allowed most patients to halve their duration of therapy, reducing total treatment time from 48 to 24 weeks, minimizing the therapy’s toxic effects, and decreasing the rate of treatment discontinuation.

In the first report, Dr. Stefan Zeuzem and his associates in the REALIZE study group assessed the benefit of adding telaprevir to the regimens of 662 patients from 17 countries who had previously shown no response (28%), a partial response (19%), or a relapse (53%) after standard peginterferon-plus-ribavirin therapy.

They also assessed whether using a 4-week lead-in phase of peginterferon plus ribavirin before the addition of telaprevir would reduce the emergence of protease-resistant variants, as had been suggested by a previous study using a different HCV protease inhibitor.

The rates of sustained virologic response proved to be significantly higher in subjects who received telaprevir, both with and without the lead-in period, than in those who did not. These rates were 64% without a lead-in period and 66% with a lead-in period, compared with only 17% in the control group, which received peginterferon plus ribavirin only.

Even patients who had previously shown a minimal response to earlier therapy showed a nearly sixfold increase in sustained virologic response when telaprevir was added to the regimen, the investigators said (N. Engl. J. Med. 2011;364:2417-28).

Telaprevir improved the rates of sustained virologic response across all subgroups of patients, regardless of their viral load at baseline or the presence and severity of liver fibrosis or cirrhosis, said Dr. Zeuzem of Johann Wolfgang Goethe University Hospital, Frankfurt, Germany, and his colleagues.

Telaprevir also raised the rate of adverse events, chiefly fatigue, pruritus, rash, nausea, anemia, and diarrhea. The number of grade 3 adverse events (mainly anemia, neutropenia, and leucopenia) also was increased with telaprevir (37%), compared with the control group (22%). The rate of adverse events leading to permanent discontinuation of the study drugs was 13% in subjects who received telaprevir, compared with 3% in the control group.

In the second report, Dr. Ira M. Jacobson and his associates in the ADVANCE study assessed the addition of telaprevir in 1,088 patients at 123 international sites. These study subjects had never received therapy for chronic HCV.

The objective was to adjust treatment guided by the patient’s response after 4 weeks. Earlier studies have shown "high rates of early viral suppression and low rates of relapse after cessation of telaprevir therapy, [suggesting] that therapy could potentially be shortened to 24 weeks in patients who have a rapid virologic response – that is, patients in whom HCV RNA is undetectable at week 4 of treatment," said Dr. Jacobson of Cornell University and the Center for the Study of Hepatitis C, both in New York, and his colleagues.

One group of subjects received telaprevir in addition to standard peginterferon-plus-ribavirin therapy for 12 weeks. If they showed a rapid virologic response at 4 and 12 weeks, telaprevir was withdrawn and standard therapy was continued for 12 more weeks, for a total of 24 weeks of treatment. If there was no rapid response, standard therapy was extended for the customary 36 weeks, for a total of 48 weeks of treatment.

A second group received telaprevir plus standard therapy for 8 weeks, followed by placebo plus standard therapy for 4 weeks; their response to treatment determined the same two alternative courses of therapy as in group 1. The control group received placebo plus standard therapy for 12 weeks, followed by standard therapy for 36 weeks, for the standard total of 48 weeks of therapy.

A total of 75% of group 1 and 69% of group 2 showed a rapid and sustained virologic response, allowing them to complete treatment in half the usual time. Relapse was "infrequent" in these patients, indicating that a total of 24 weeks of therapy is sufficient for rapid responders, Dr. Jacobson and his colleagues said (N. Engl. J. Med. 2011;364:2405-16).

In comparison, only 44% of the control group achieved a rapid and sustained virologic response.

The addition of telaprevir also substantially improved treatment response among patient groups who usually respond poorly to standard therapy, including those with fibrosis or cirrhosis, older patients, diabetics, and those with a high viral load at baseline. Telaprevir more than doubled treatment response among black patients, who typically show a very poor response to interferon that likely results from genetic factors, the researchers noted.

Both studies were funded by Tibotec and Vertex Pharmaceuticals, which both manufacture telaprevir. Dr. Zeuzem and Dr. Jacobson reported ties to Tibotec and Vertex, as well as to numerous other industry sources.