Sherry Boschert

SAN FRANCISCO — A new analysis supports a controversial study that challenged the favored role of diuretics in combination therapy for hypertension, but some experts remain skeptical.

Dr. Kenneth Jamerson, lead investigator of the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial, said the results of a substudy he presented at the annual meeting of the American Society of Hypertension confirm that the main trial constitutes a paradigm shift in treating hypertension. His coinvestigator, Dr. George Bakris, director of the hypertension center and professor of medicine at the University of Chicago, echoed that assessment at a press conference.

The ACCOMPLISH trial's conclusion that a fixed-dose combination of an ACE inhibitor and a calcium channel blocker was superior to a combination of an ACE inhibitor and a diuretic for initial antihypertensive therapy “has huge implications for the millions of patients that are taking blood pressure medication,” said Dr. Jamerson, professor of medicine at the University of Michigan, Ann Arbor.

Other experts on a separate panel at the meeting were not convinced. Dr. William C. Cushman, chief of preventive medicine at the Memphis Veterans Affairs Medical Center and professor of preventive medicine at the University of Tennessee, Memphis, said the literature supports three drug classes as the mainstays of combination therapy for hypertension: diuretics, blockers of the renin-angiotensin-aldosterone system (RAAS), and calcium channel blockers.

“Based on all the data that we have, I would still put diuretics in a very favorable position in any combinations of these,” Dr. Cushman said.

Here's the back story: Diuretics have been a mainstay of antihypertensive therapy for half a century. Recent guidelines have promoted the use of combination therapy to treat hypertension rather than starting with a single agent in higher-risk patients. The double-blind, industry-sponsored ACCOMPLISH trial was the first to compare two antihypertensive combinations as initial therapy.

The study randomized 11,506 patients with hypertension who were at high risk for cardiovascular events to receive fixed-dose pills containing either the ACE inhibitor-diuretic combination of benazepril-hydrochlorothiazide (HCTZ) or benazepril plus amlodipine, a calcium channel blocker. After 36 months, the risk of cardiac events was significantly lower in the benazepril-amlodipine group (9.6%) compared with the benazepril-HCTZ group (11.8%), a 20% relative risk reduction (N. Engl. J. Med. 2008;359:2417–28).

Critics pounced on several aspects of the study, including the fact that the 0.9-mm Hg difference between groups in systolic blood pressure results was based on clinic measurements, which are less accurate than ambulatory blood pressure monitoring (N. Engl. J. Med. 2009;360:1147–50).

A new substudy of 573 ACCOMPLISH subjects who underwent 24-hour ambulatory blood pressure monitoring, however, showed good blood pressure control that was similar between groups and, if anything, may have been slightly better in the benazepril-HCTZ group, with a nonsignificant 1.6-mm Hg difference in mean 24-hour systolic pressures between groups, Dr. Jamerson reported at the meeting. (See box.)

The substudy confirms that the reduced cardiovascular risk seen with benazepril-amlodipine was due to other beneficial characteristics of this combination therapy and not driven by differences in blood pressures between groups, Dr. Jamerson said.

He has received funding from, or been a consultant and speaker for, Novartis Pharmaceuticals and other drug companies, and as president of the International Society of Hypertension in Blacks, he sought industry support for the organization. Novartis markets trade versions of the benazepril-amlodipine and benazepril-HCTZ combinations, and both combinations have generic versions on the market.

European guidelines on hypertension treatment favor combination therapy and suggest that combinations of ACE inhibitor with a diuretic or a calcium channel blocker are equally good. “We show evidence that they're not,” Dr. Jamerson said.

“They very likely may have to rethink their guidelines.” U.S. guidelines generally prefer combinations that include a diuretic, he added. “I think this directly challenges that. I consider it a paradigm shift. It's up to the entire community to decide.”

Dr. Bakris said that the subanalysis should pave the way for a change in recommendations. As editor of the hypertension portion of the electronic clinical resource tool UpToDate, he will be dropping a caveat about the ACCOMPLISH results and UpToDate will recommend the benazepril-amlodipine combination for initial therapy. Dr. Bakris has been a consultant, speaker, or adviser for Novartis and other pharmaceutical companies.

“The results of ACCOMPLISH may challenge current diuretic-based guidelines. I don't think this is absolutely clear,” Dr. Angela L. Brown said in the panel discussion. “I don't think we really know that yet just from this one trial,” said Dr. Brown of Washington University, St. Louis. She has been a consultant, adviser, or lecturer for Novartis, Boehringer Ingelheim, and Forest Laboratories.

The HCTZ dosage used in the ACCOMPLISH trial (12.5–25 mg/day) was lower than were dosages used in placebo-controlled studies that established the antihypertensive benefits of HCTZ, Dr. Cushman noted. Also, if the combined end points of death from cardiovascular causes, nonfatal MI or stroke, resuscitation after sudden cardiac arrest, hospitalization for angina, and coronary revascularization were reconfigured to exclude the angina and revascularization outcomes, there would have been no significant difference between groups in the primary combined outcome, he said.

One could interpret the ACCOMPLISH results to suggest that HCTZ doses of 25 mg/day or less are not as effective in preventing cardiovascular events as are full doses of amlodipine monotherapy or doses of diuretics used in previous trials, suggested Dr. Cushman, who has been a consultant, adviser, or lecturer for Novartis.

Dr. Louis Kuritzky suggested that results might have been different had ACCOMPLISH used the more potent diuretic chlorthalidone instead of HCTZ. In addition, it's unclear whether the results of the trial are generalizable, because the ACCOMPLISH cohort was older and more likely to have diabetes, dyslipidemia, and left ventricular hypertrophy than was the hypertensive population as a whole, said Dr. Kuritzky of the University of Florida, Gainesville.

He has been a consultant or speaker for Novartis and other drug companies but has no association with the company that markets chlorthalidone.

The ACCOMPLISH investigators chose HCTZ because it's the dominant diuretic used for hypertension. Choosing a different diuretic to combine with an ACE inhibitor would not provide the mechanistic synergy of a combined ACE inhibitor and calcium channel blocker that provides an antiatherosclerotic effect, Dr. Jamerson and his associates noted.

“It really does matter what agent you use,” he said.

The findings have “huge implications” for millions taking BP medication, Dr. Kenneth Jamerson said. Courtesy UM Photo Services, Martin Vloet

Ambulatory Monitoring Supports ACCOMPLISH Results

The initial analysis of ACCOMPLISH results reported mean systolic blood pressures of 131.6/73.3 mm Hg in the benazepril-amlodipine group and 132.5/74.4 mm Hg in the benazepril-HCTZ group using measurements taken predominantly in clinics.

The new analysis by Dr. Jamerson and associates studied 24-hour ambulatory blood pressure monitoring results in a subgroup of 573 patients, to provide a more accurate look at treatment effects on blood pressure.

After 2 years, the treatment groups did not differ significantly in 24-hour mean, daytime, or nighttime blood pressure levels. More than 80% in both groups achieved 24-hour blood pressure control (a mean systolic pressure less than 135 mm Hg over 24 hours). Rates of escape from control, morning surge in blood pressure, or dipping status did not differ significantly between groups, he reported.

Comparing the 288 patients on benazepril-amlodipine and 185 on benazepril-HCTZ, mean systolic pressures in clinic were 129.7 vs. 130.3 mm Hg and mean 24-hour measurements were 123.9 vs. 122.3 mm Hg, respectively. Mean daytime systolic pressures were 125.9 mm Hg vs. 124.1 mm Hg, and nighttime pressures were 118.1 vs. 116.9 mm Hg, respectively.

The proportion with a.m. dipping of systolic pressure comprised 29% of the benazepril-amlodipine group and 32% of the benazepril-HCTZ group, and 24-hour blood pressure control was achieved in 81% and 85%, respectively. Ten percent and 12% of the respective groups had any hourly mean systolic pressure above 160 mm Hg. Nighttime hypertension was seen in 19% on benazepril-amlodipine and 17% on benazepril-HCTZ. An a.m. surge (defined as greater than a 55- mm Hg rise between 6 and 10 a.m. compared with the lowest nighttime hourly mean) occurred in 3% and 4%, respectively.

The benazepril-amlodipine dosing was 20/5 mg once daily for 1 month, then 40/5 mg, followed by 40/10 mg if needed to achieve blood pressure goals. The benazepril-HCTZ group started with 20/12.5 mg once daily for 1 month, then 40/12.5 mg, followed by 40/25 mg if needed.

SAN FRANCISCO — A new analysis supports a controversial study that challenged the favored role of diuretics in combination therapy for hypertension, but some experts remain skeptical.

Dr. Kenneth Jamerson, lead investigator of the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial, said the results of a substudy he presented at the annual meeting of the American Society of Hypertension confirm that the main trial constitutes a paradigm shift in treating hypertension. His coinvestigator, Dr. George Bakris, director of the hypertension center and professor of medicine at the University of Chicago, echoed that assessment at a press conference.

The ACCOMPLISH trial's conclusion that a fixed-dose combination of an ACE inhibitor and a calcium channel blocker was superior to a combination of an ACE inhibitor and a diuretic for initial antihypertensive therapy “has huge implications for the millions of patients that are taking blood pressure medication,” said Dr. Jamerson, professor of medicine at the University of Michigan, Ann Arbor.

Other experts on a separate panel at the meeting were not convinced. Dr. William C. Cushman, chief of preventive medicine at the Memphis Veterans Affairs Medical Center and professor of preventive medicine at the University of Tennessee, Memphis, said the literature supports three drug classes as the mainstays of combination therapy for hypertension: diuretics, blockers of the renin-angiotensin-aldosterone system (RAAS), and calcium channel blockers.

“Based on all the data that we have, I would still put diuretics in a very favorable position in any combinations of these,” Dr. Cushman said.

Here's the back story: Diuretics have been a mainstay of antihypertensive therapy for half a century. Recent guidelines have promoted the use of combination therapy to treat hypertension rather than starting with a single agent in higher-risk patients. The double-blind, industry-sponsored ACCOMPLISH trial was the first to compare two antihypertensive combinations as initial therapy.

The study randomized 11,506 patients with hypertension who were at high risk for cardiovascular events to receive fixed-dose pills containing either the ACE inhibitor-diuretic combination of benazepril-hydrochlorothiazide (HCTZ) or benazepril plus amlodipine, a calcium channel blocker. After 36 months, the risk of cardiac events was significantly lower in the benazepril-amlodipine group (9.6%) compared with the benazepril-HCTZ group (11.8%), a 20% relative risk reduction (N. Engl. J. Med. 2008;359:2417–28).

Critics pounced on several aspects of the study, including the fact that the 0.9-mm Hg difference between groups in systolic blood pressure results was based on clinic measurements, which are less accurate than ambulatory blood pressure monitoring (N. Engl. J. Med. 2009;360:1147–50).

A new substudy of 573 ACCOMPLISH subjects who underwent 24-hour ambulatory blood pressure monitoring, however, showed good blood pressure control that was similar between groups and, if anything, may have been slightly better in the benazepril-HCTZ group, with a nonsignificant 1.6-mm Hg difference in mean 24-hour systolic pressures between groups, Dr. Jamerson reported at the meeting. (See box.)

The substudy confirms that the reduced cardiovascular risk seen with benazepril-amlodipine was due to other beneficial characteristics of this combination therapy and not driven by differences in blood pressures between groups, Dr. Jamerson said.

He has received funding from, or been a consultant and speaker for, Novartis Pharmaceuticals and other drug companies, and as president of the International Society of Hypertension in Blacks, he sought industry support for the organization. Novartis markets trade versions of the benazepril-amlodipine and benazepril-HCTZ combinations, and both combinations have generic versions on the market.

European guidelines on hypertension treatment favor combination therapy and suggest that combinations of ACE inhibitor with a diuretic or a calcium channel blocker are equally good. “We show evidence that they're not,” Dr. Jamerson said.

“They very likely may have to rethink their guidelines.” U.S. guidelines generally prefer combinations that include a diuretic, he added. “I think this directly challenges that. I consider it a paradigm shift. It's up to the entire community to decide.”

Dr. Bakris said that the subanalysis should pave the way for a change in recommendations. As editor of the hypertension portion of the electronic clinical resource tool UpToDate, he will be dropping a caveat about the ACCOMPLISH results and UpToDate will recommend the benazepril-amlodipine combination for initial therapy. Dr. Bakris has been a consultant, speaker, or adviser for Novartis and other pharmaceutical companies.

“The results of ACCOMPLISH may challenge current diuretic-based guidelines. I don't think this is absolutely clear,” Dr. Angela L. Brown said in the panel discussion. “I don't think we really know that yet just from this one trial,” said Dr. Brown of Washington University, St. Louis. She has been a consultant, adviser, or lecturer for Novartis, Boehringer Ingelheim, and Forest Laboratories.

The HCTZ dosage used in the ACCOMPLISH trial (12.5–25 mg/day) was lower than were dosages used in placebo-controlled studies that established the antihypertensive benefits of HCTZ, Dr. Cushman noted. Also, if the combined end points of death from cardiovascular causes, nonfatal MI or stroke, resuscitation after sudden cardiac arrest, hospitalization for angina, and coronary revascularization were reconfigured to exclude the angina and revascularization outcomes, there would have been no significant difference between groups in the primary combined outcome, he said.

One could interpret the ACCOMPLISH results to suggest that HCTZ doses of 25 mg/day or less are not as effective in preventing cardiovascular events as are full doses of amlodipine monotherapy or doses of diuretics used in previous trials, suggested Dr. Cushman, who has been a consultant, adviser, or lecturer for Novartis.

Dr. Louis Kuritzky suggested that results might have been different had ACCOMPLISH used the more potent diuretic chlorthalidone instead of HCTZ. In addition, it's unclear whether the results of the trial are generalizable, because the ACCOMPLISH cohort was older and more likely to have diabetes, dyslipidemia, and left ventricular hypertrophy than was the hypertensive population as a whole, said Dr. Kuritzky of the University of Florida, Gainesville.

He has been a consultant or speaker for Novartis and other drug companies but has no association with the company that markets chlorthalidone.

The ACCOMPLISH investigators chose HCTZ because it's the dominant diuretic used for hypertension. Choosing a different diuretic to combine with an ACE inhibitor would not provide the mechanistic synergy of a combined ACE inhibitor and calcium channel blocker that provides an antiatherosclerotic effect, Dr. Jamerson and his associates noted.

“It really does matter what agent you use,” he said.

The findings have “huge implications” for millions taking BP medication, Dr. Kenneth Jamerson said. Courtesy UM Photo Services, Martin Vloet

Ambulatory Monitoring Supports ACCOMPLISH Results

The initial analysis of ACCOMPLISH results reported mean systolic blood pressures of 131.6/73.3 mm Hg in the benazepril-amlodipine group and 132.5/74.4 mm Hg in the benazepril-HCTZ group using measurements taken predominantly in clinics.

The new analysis by Dr. Jamerson and associates studied 24-hour ambulatory blood pressure monitoring results in a subgroup of 573 patients, to provide a more accurate look at treatment effects on blood pressure.

After 2 years, the treatment groups did not differ significantly in 24-hour mean, daytime, or nighttime blood pressure levels. More than 80% in both groups achieved 24-hour blood pressure control (a mean systolic pressure less than 135 mm Hg over 24 hours). Rates of escape from control, morning surge in blood pressure, or dipping status did not differ significantly between groups, he reported.

Comparing the 288 patients on benazepril-amlodipine and 185 on benazepril-HCTZ, mean systolic pressures in clinic were 129.7 vs. 130.3 mm Hg and mean 24-hour measurements were 123.9 vs. 122.3 mm Hg, respectively. Mean daytime systolic pressures were 125.9 mm Hg vs. 124.1 mm Hg, and nighttime pressures were 118.1 vs. 116.9 mm Hg, respectively.

The proportion with a.m. dipping of systolic pressure comprised 29% of the benazepril-amlodipine group and 32% of the benazepril-HCTZ group, and 24-hour blood pressure control was achieved in 81% and 85%, respectively. Ten percent and 12% of the respective groups had any hourly mean systolic pressure above 160 mm Hg. Nighttime hypertension was seen in 19% on benazepril-amlodipine and 17% on benazepril-HCTZ. An a.m. surge (defined as greater than a 55- mm Hg rise between 6 and 10 a.m. compared with the lowest nighttime hourly mean) occurred in 3% and 4%, respectively.

The benazepril-amlodipine dosing was 20/5 mg once daily for 1 month, then 40/5 mg, followed by 40/10 mg if needed to achieve blood pressure goals. The benazepril-HCTZ group started with 20/12.5 mg once daily for 1 month, then 40/12.5 mg, followed by 40/25 mg if needed.

SAN FRANCISCO — A new analysis supports a controversial study that challenged the favored role of diuretics in combination therapy for hypertension, but some experts remain skeptical.

Dr. Kenneth Jamerson, lead investigator of the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial, said the results of a substudy he presented at the annual meeting of the American Society of Hypertension confirm that the main trial constitutes a paradigm shift in treating hypertension. His coinvestigator, Dr. George Bakris, director of the hypertension center and professor of medicine at the University of Chicago, echoed that assessment at a press conference.

The ACCOMPLISH trial's conclusion that a fixed-dose combination of an ACE inhibitor and a calcium channel blocker was superior to a combination of an ACE inhibitor and a diuretic for initial antihypertensive therapy “has huge implications for the millions of patients that are taking blood pressure medication,” said Dr. Jamerson, professor of medicine at the University of Michigan, Ann Arbor.

Other experts on a separate panel at the meeting were not convinced. Dr. William C. Cushman, chief of preventive medicine at the Memphis Veterans Affairs Medical Center and professor of preventive medicine at the University of Tennessee, Memphis, said the literature supports three drug classes as the mainstays of combination therapy for hypertension: diuretics, blockers of the renin-angiotensin-aldosterone system (RAAS), and calcium channel blockers.

“Based on all the data that we have, I would still put diuretics in a very favorable position in any combinations of these,” Dr. Cushman said.

Here's the back story: Diuretics have been a mainstay of antihypertensive therapy for half a century. Recent guidelines have promoted the use of combination therapy to treat hypertension rather than starting with a single agent in higher-risk patients. The double-blind, industry-sponsored ACCOMPLISH trial was the first to compare two antihypertensive combinations as initial therapy.

The study randomized 11,506 patients with hypertension who were at high risk for cardiovascular events to receive fixed-dose pills containing either the ACE inhibitor-diuretic combination of benazepril-hydrochlorothiazide (HCTZ) or benazepril plus amlodipine, a calcium channel blocker. After 36 months, the risk of cardiac events was significantly lower in the benazepril-amlodipine group (9.6%) compared with the benazepril-HCTZ group (11.8%), a 20% relative risk reduction (N. Engl. J. Med. 2008;359:2417–28).

Critics pounced on several aspects of the study, including the fact that the 0.9-mm Hg difference between groups in systolic blood pressure results was based on clinic measurements, which are less accurate than ambulatory blood pressure monitoring (N. Engl. J. Med. 2009;360:1147–50).

A new substudy of 573 ACCOMPLISH subjects who underwent 24-hour ambulatory blood pressure monitoring, however, showed good blood pressure control that was similar between groups and, if anything, may have been slightly better in the benazepril-HCTZ group, with a nonsignificant 1.6-mm Hg difference in mean 24-hour systolic pressures between groups, Dr. Jamerson reported at the meeting. (See box.)

The substudy confirms that the reduced cardiovascular risk seen with benazepril-amlodipine was due to other beneficial characteristics of this combination therapy and not driven by differences in blood pressures between groups, Dr. Jamerson said.

He has received funding from, or been a consultant and speaker for, Novartis Pharmaceuticals and other drug companies, and as president of the International Society of Hypertension in Blacks, he sought industry support for the organization. Novartis markets trade versions of the benazepril-amlodipine and benazepril-HCTZ combinations, and both combinations have generic versions on the market.

European guidelines on hypertension treatment favor combination therapy and suggest that combinations of ACE inhibitor with a diuretic or a calcium channel blocker are equally good. “We show evidence that they're not,” Dr. Jamerson said.

“They very likely may have to rethink their guidelines.” U.S. guidelines generally prefer combinations that include a diuretic, he added. “I think this directly challenges that. I consider it a paradigm shift. It's up to the entire community to decide.”

Dr. Bakris said that the subanalysis should pave the way for a change in recommendations. As editor of the hypertension portion of the electronic clinical resource tool UpToDate, he will be dropping a caveat about the ACCOMPLISH results and UpToDate will recommend the benazepril-amlodipine combination for initial therapy. Dr. Bakris has been a consultant, speaker, or adviser for Novartis and other pharmaceutical companies.

“The results of ACCOMPLISH may challenge current diuretic-based guidelines. I don't think this is absolutely clear,” Dr. Angela L. Brown said in the panel discussion. “I don't think we really know that yet just from this one trial,” said Dr. Brown of Washington University, St. Louis. She has been a consultant, adviser, or lecturer for Novartis, Boehringer Ingelheim, and Forest Laboratories.

The HCTZ dosage used in the ACCOMPLISH trial (12.5–25 mg/day) was lower than were dosages used in placebo-controlled studies that established the antihypertensive benefits of HCTZ, Dr. Cushman noted. Also, if the combined end points of death from cardiovascular causes, nonfatal MI or stroke, resuscitation after sudden cardiac arrest, hospitalization for angina, and coronary revascularization were reconfigured to exclude the angina and revascularization outcomes, there would have been no significant difference between groups in the primary combined outcome, he said.

One could interpret the ACCOMPLISH results to suggest that HCTZ doses of 25 mg/day or less are not as effective in preventing cardiovascular events as are full doses of amlodipine monotherapy or doses of diuretics used in previous trials, suggested Dr. Cushman, who has been a consultant, adviser, or lecturer for Novartis.

Dr. Louis Kuritzky suggested that results might have been different had ACCOMPLISH used the more potent diuretic chlorthalidone instead of HCTZ. In addition, it's unclear whether the results of the trial are generalizable, because the ACCOMPLISH cohort was older and more likely to have diabetes, dyslipidemia, and left ventricular hypertrophy than was the hypertensive population as a whole, said Dr. Kuritzky of the University of Florida, Gainesville.

He has been a consultant or speaker for Novartis and other drug companies but has no association with the company that markets chlorthalidone.

The ACCOMPLISH investigators chose HCTZ because it's the dominant diuretic used for hypertension. Choosing a different diuretic to combine with an ACE inhibitor would not provide the mechanistic synergy of a combined ACE inhibitor and calcium channel blocker that provides an antiatherosclerotic effect, Dr. Jamerson and his associates noted.

“It really does matter what agent you use,” he said.

The findings have “huge implications” for millions taking BP medication, Dr. Kenneth Jamerson said. Courtesy UM Photo Services, Martin Vloet

Ambulatory Monitoring Supports ACCOMPLISH Results

The initial analysis of ACCOMPLISH results reported mean systolic blood pressures of 131.6/73.3 mm Hg in the benazepril-amlodipine group and 132.5/74.4 mm Hg in the benazepril-HCTZ group using measurements taken predominantly in clinics.

The new analysis by Dr. Jamerson and associates studied 24-hour ambulatory blood pressure monitoring results in a subgroup of 573 patients, to provide a more accurate look at treatment effects on blood pressure.

After 2 years, the treatment groups did not differ significantly in 24-hour mean, daytime, or nighttime blood pressure levels. More than 80% in both groups achieved 24-hour blood pressure control (a mean systolic pressure less than 135 mm Hg over 24 hours). Rates of escape from control, morning surge in blood pressure, or dipping status did not differ significantly between groups, he reported.

Comparing the 288 patients on benazepril-amlodipine and 185 on benazepril-HCTZ, mean systolic pressures in clinic were 129.7 vs. 130.3 mm Hg and mean 24-hour measurements were 123.9 vs. 122.3 mm Hg, respectively. Mean daytime systolic pressures were 125.9 mm Hg vs. 124.1 mm Hg, and nighttime pressures were 118.1 vs. 116.9 mm Hg, respectively.

The proportion with a.m. dipping of systolic pressure comprised 29% of the benazepril-amlodipine group and 32% of the benazepril-HCTZ group, and 24-hour blood pressure control was achieved in 81% and 85%, respectively. Ten percent and 12% of the respective groups had any hourly mean systolic pressure above 160 mm Hg. Nighttime hypertension was seen in 19% on benazepril-amlodipine and 17% on benazepril-HCTZ. An a.m. surge (defined as greater than a 55- mm Hg rise between 6 and 10 a.m. compared with the lowest nighttime hourly mean) occurred in 3% and 4%, respectively.

The benazepril-amlodipine dosing was 20/5 mg once daily for 1 month, then 40/5 mg, followed by 40/10 mg if needed to achieve blood pressure goals. The benazepril-HCTZ group started with 20/12.5 mg once daily for 1 month, then 40/12.5 mg, followed by 40/25 mg if needed.

SAN FRANCISCO — Initial therapy with any antihypertensive medication is significantly better than placebo at preventing stroke, and any antihypertensive except an angiotensin receptor blocker is better than placebo for preventing heart disease, results of new meta-analyses show.

“Every time you turn on the news, every time you read USA Today, they're always complaining that some drug is not good,” Dr. William J. Elliott said at the annual meeting of the American Society of Hypertension. “Don't let patients tell you that 'I just read someplace that this drug is not good at preventing stroke.' In the aggregate, across all the data, that is not true. All the drugs, in fact, are superior to placebo” for the prevention of stroke.

For heart disease prevention, ARBs may have fallen short of superiority to placebo in patients with hypertension for reasons that are related to statistical power, he hypothesized. “ARBs have not been around as long as some of our more tried-and-true drugs” and thus have had fewer trials as initial hypertensive agents and fewer people in those trials develop coronary heart disease, said Dr. Elliott, professor of preventive medicine at Rush Medical College, Chicago.

He has been a consultant or speaker for companies that market antihypertensive drugs including ARBs. He also has received royalties from Elsevier, which owns this news organization.

The last major meta-analysis in 2003 of cardiovascular outcomes in hypertension treatment provided the basis for recommendations favoring low-dose diuretics as first-line antihypertensives to prevent cardiovascular disease in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7).

Since then, at least 25 more trials have been published, with stroke data on 269,180 more subjects and heart disease data on 276,396 more subjects who were included in the current meta-analyses.

Dr. Elliott and his associates conducted two types of meta-analyses on data from all published outcome-based clinical trials with a minimum 1-year follow-up in which all subjects had hypertension and in which a drug was the initial antihypertensive therapy. Results of both the “network meta-analyses” and “Bayesian meta-analyses” were strikingly consistent, he reported.

For stroke prevention, initial treatment for hypertension with a diuretic was no better than a calcium channel blocker (CCB) or ARB. All three were slightly but significantly better than a beta-blocker or ACE inhibitor in preventing stroke, Dr. Elliott reported. The risk for stroke was 56% higher on placebo than on a diuretic or a CCB. There were 9,351 strokes among subjects in 144 randomized arms in the trials.

Initial treatment with an ACE inhibitor was about 8% more effective than was a diuretic in reducing coronary heart disease events (defined as fatal or nonfatal MI or sudden cardiac death), though the difference was not statistically significant.

“Don't get too excited or too nervous. Don't give up your diuretic,” Dr. Elliott said. The finding is consistent with other suggestions in the literature that ACE inhibitors are better than diuretics at preventing heart disease, he added.

CCBs appeared to be as effective as diuretics for preventing heart disease, and beta-blockers were just behind. Both ARBs and placebos were statistically inferior to ACE inhibitors, diuretics, CCBs, and beta-blockers for preventing heart disease. The risk for coronary heart disease was 26%-28% higher on placebo than on an ACE inhibitor. There were 11,122 coronary heart disease events among subjects in 136 arms in the trials.

'All the drugs, in fact, are superior to placebo' for the prevention of stroke. DR. ELLIOTT

SAN FRANCISCO — Initial therapy with any antihypertensive medication is significantly better than placebo at preventing stroke, and any antihypertensive except an angiotensin receptor blocker is better than placebo for preventing heart disease, results of new meta-analyses show.

“Every time you turn on the news, every time you read USA Today, they're always complaining that some drug is not good,” Dr. William J. Elliott said at the annual meeting of the American Society of Hypertension. “Don't let patients tell you that 'I just read someplace that this drug is not good at preventing stroke.' In the aggregate, across all the data, that is not true. All the drugs, in fact, are superior to placebo” for the prevention of stroke.

For heart disease prevention, ARBs may have fallen short of superiority to placebo in patients with hypertension for reasons that are related to statistical power, he hypothesized. “ARBs have not been around as long as some of our more tried-and-true drugs” and thus have had fewer trials as initial hypertensive agents and fewer people in those trials develop coronary heart disease, said Dr. Elliott, professor of preventive medicine at Rush Medical College, Chicago.

He has been a consultant or speaker for companies that market antihypertensive drugs including ARBs. He also has received royalties from Elsevier, which owns this news organization.

The last major meta-analysis in 2003 of cardiovascular outcomes in hypertension treatment provided the basis for recommendations favoring low-dose diuretics as first-line antihypertensives to prevent cardiovascular disease in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7).

Since then, at least 25 more trials have been published, with stroke data on 269,180 more subjects and heart disease data on 276,396 more subjects who were included in the current meta-analyses.

Dr. Elliott and his associates conducted two types of meta-analyses on data from all published outcome-based clinical trials with a minimum 1-year follow-up in which all subjects had hypertension and in which a drug was the initial antihypertensive therapy. Results of both the “network meta-analyses” and “Bayesian meta-analyses” were strikingly consistent, he reported.

For stroke prevention, initial treatment for hypertension with a diuretic was no better than a calcium channel blocker (CCB) or ARB. All three were slightly but significantly better than a beta-blocker or ACE inhibitor in preventing stroke, Dr. Elliott reported. The risk for stroke was 56% higher on placebo than on a diuretic or a CCB. There were 9,351 strokes among subjects in 144 randomized arms in the trials.

Initial treatment with an ACE inhibitor was about 8% more effective than was a diuretic in reducing coronary heart disease events (defined as fatal or nonfatal MI or sudden cardiac death), though the difference was not statistically significant.

“Don't get too excited or too nervous. Don't give up your diuretic,” Dr. Elliott said. The finding is consistent with other suggestions in the literature that ACE inhibitors are better than diuretics at preventing heart disease, he added.

CCBs appeared to be as effective as diuretics for preventing heart disease, and beta-blockers were just behind. Both ARBs and placebos were statistically inferior to ACE inhibitors, diuretics, CCBs, and beta-blockers for preventing heart disease. The risk for coronary heart disease was 26%-28% higher on placebo than on an ACE inhibitor. There were 11,122 coronary heart disease events among subjects in 136 arms in the trials.

'All the drugs, in fact, are superior to placebo' for the prevention of stroke. DR. ELLIOTT

SAN FRANCISCO — Initial therapy with any antihypertensive medication is significantly better than placebo at preventing stroke, and any antihypertensive except an angiotensin receptor blocker is better than placebo for preventing heart disease, results of new meta-analyses show.

“Every time you turn on the news, every time you read USA Today, they're always complaining that some drug is not good,” Dr. William J. Elliott said at the annual meeting of the American Society of Hypertension. “Don't let patients tell you that 'I just read someplace that this drug is not good at preventing stroke.' In the aggregate, across all the data, that is not true. All the drugs, in fact, are superior to placebo” for the prevention of stroke.

For heart disease prevention, ARBs may have fallen short of superiority to placebo in patients with hypertension for reasons that are related to statistical power, he hypothesized. “ARBs have not been around as long as some of our more tried-and-true drugs” and thus have had fewer trials as initial hypertensive agents and fewer people in those trials develop coronary heart disease, said Dr. Elliott, professor of preventive medicine at Rush Medical College, Chicago.

He has been a consultant or speaker for companies that market antihypertensive drugs including ARBs. He also has received royalties from Elsevier, which owns this news organization.

The last major meta-analysis in 2003 of cardiovascular outcomes in hypertension treatment provided the basis for recommendations favoring low-dose diuretics as first-line antihypertensives to prevent cardiovascular disease in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7).

Since then, at least 25 more trials have been published, with stroke data on 269,180 more subjects and heart disease data on 276,396 more subjects who were included in the current meta-analyses.

Dr. Elliott and his associates conducted two types of meta-analyses on data from all published outcome-based clinical trials with a minimum 1-year follow-up in which all subjects had hypertension and in which a drug was the initial antihypertensive therapy. Results of both the “network meta-analyses” and “Bayesian meta-analyses” were strikingly consistent, he reported.

For stroke prevention, initial treatment for hypertension with a diuretic was no better than a calcium channel blocker (CCB) or ARB. All three were slightly but significantly better than a beta-blocker or ACE inhibitor in preventing stroke, Dr. Elliott reported. The risk for stroke was 56% higher on placebo than on a diuretic or a CCB. There were 9,351 strokes among subjects in 144 randomized arms in the trials.

Initial treatment with an ACE inhibitor was about 8% more effective than was a diuretic in reducing coronary heart disease events (defined as fatal or nonfatal MI or sudden cardiac death), though the difference was not statistically significant.

“Don't get too excited or too nervous. Don't give up your diuretic,” Dr. Elliott said. The finding is consistent with other suggestions in the literature that ACE inhibitors are better than diuretics at preventing heart disease, he added.

CCBs appeared to be as effective as diuretics for preventing heart disease, and beta-blockers were just behind. Both ARBs and placebos were statistically inferior to ACE inhibitors, diuretics, CCBs, and beta-blockers for preventing heart disease. The risk for coronary heart disease was 26%-28% higher on placebo than on an ACE inhibitor. There were 11,122 coronary heart disease events among subjects in 136 arms in the trials.

'All the drugs, in fact, are superior to placebo' for the prevention of stroke. DR. ELLIOTT

SAN FRANCISCO — Complications from a prolactinoma during pregnancy are best avoided by treating the adenoma before conception.

But with many women delaying pregnancy, it's not uncommon to see a woman in her late 30s with a macro-adenoma who says she wants to get pregnant soon and doesn't have the luxury of suppressing the tumor for a year or two on medical therapy before conception, Dr. J. Blake Tyrrell said at a conference on diabetes and advances in endocrinology and metabolism sponsored by the University of California, San Francisco.

The sparse data available to help guide the management of these patients suggest that suppressing prolactin-secreting adenomas with dopamine agonists reduces the effects of the tumor and allows the patient to get pregnant without increasing the risk of fetal loss or fetal abnormalities.

There is less experience with cabergoline, today's treatment of choice, than with the former first-line agent bromocriptine.

Whether the patient has a microadenoma or macroadenoma, Dr. Tyrrell prefers to treat with cabergoline to allow menstrual cycles to normalize. If the patient misses a period, test for pregnancy, and if she is pregnant discontinue cabergoline, advised Dr. Tyrrell, director of the endocrinology clinic at the university. With this method, fetal exposure to the drug should be no more than a couple of weeks, he said.

Once off of therapy, fewer than 2% of microadenomas will enlarge during pregnancy. Given this low risk, many providers choose to leave them alone during pregnancy. Dr. Tyrrell suggested following prolactin levels every 6 weeks, and if they get as high as 500 ng/mL, “I might get a bit concerned and ask the patient how she's doing,” he said.

Macroadenomas that are left untreated during pregnancy will enlarge in about 23% of cases and cause headache and visual field defects. “That's not a situation you want to get into,” he said. Only 3% of macroadenomas that were surgically debulked prior to conception enlarged during pregnancy, but medical therapy has largely replaced surgical treatment for prolactinomas.

In the management of macroadenomas during pregnancy, “we're on very thin ice” due to very limited data on the risks from taking dopamine agonists before or during pregnancy, he said.

One study reported on 86 women with macroadenomas who conceived after bromocriptine treatment, which was then stopped. Twenty women (23%) developed visual field defects during pregnancy. Four patients then underwent surgical treatment and 15 received bromocriptine therapy, and all 20 had successful pregnancy outcomes (Endocrinol. Metab. Clin. North Am. 2006;35:99–116).

Data from the early 1980s described 29 women with macroadenomas who were managed with continuous bromocriptine throughout pregnancy. Two developed visual field defects. All had successful pregnancy outcomes. Dr. Tyrrell noted that 7 of these 29 women probably had nonfunctional tumors because their serum prolactin levels were less than 200 ng/mL, which suggests that continuous drug therapy was associated with an even higher rate of visual field defects in women with functioning tumors (in 2 of 22) patients.

That's about the extent of the world literature on managing macroadenomas during pregnancy, which is “not very good considering that these drugs have been around for 30-plus years,” he said. There are no data on continuous cabergoline therapy during pregnancy.

In the worst-case scenario, a macro-adenoma may enlarge, usually during the second or third trimester, causing headache and visual field defects. A noncontrast MRI can be done safely during pregnancy to define the size.

If the tumor is enlarging, try medical therapy, and deliver the fetus early if it's viable. Surgery is a last resort, Dr. Tyrrell said. “Think about this if you can ahead of time to deal with the tumor before conception, before getting into trouble during pregnancy,” he concluded.

SAN FRANCISCO — Complications from a prolactinoma during pregnancy are best avoided by treating the adenoma before conception.

But with many women delaying pregnancy, it's not uncommon to see a woman in her late 30s with a macro-adenoma who says she wants to get pregnant soon and doesn't have the luxury of suppressing the tumor for a year or two on medical therapy before conception, Dr. J. Blake Tyrrell said at a conference on diabetes and advances in endocrinology and metabolism sponsored by the University of California, San Francisco.

The sparse data available to help guide the management of these patients suggest that suppressing prolactin-secreting adenomas with dopamine agonists reduces the effects of the tumor and allows the patient to get pregnant without increasing the risk of fetal loss or fetal abnormalities.

There is less experience with cabergoline, today's treatment of choice, than with the former first-line agent bromocriptine.

Whether the patient has a microadenoma or macroadenoma, Dr. Tyrrell prefers to treat with cabergoline to allow menstrual cycles to normalize. If the patient misses a period, test for pregnancy, and if she is pregnant discontinue cabergoline, advised Dr. Tyrrell, director of the endocrinology clinic at the university. With this method, fetal exposure to the drug should be no more than a couple of weeks, he said.

Once off of therapy, fewer than 2% of microadenomas will enlarge during pregnancy. Given this low risk, many providers choose to leave them alone during pregnancy. Dr. Tyrrell suggested following prolactin levels every 6 weeks, and if they get as high as 500 ng/mL, “I might get a bit concerned and ask the patient how she's doing,” he said.

Macroadenomas that are left untreated during pregnancy will enlarge in about 23% of cases and cause headache and visual field defects. “That's not a situation you want to get into,” he said. Only 3% of macroadenomas that were surgically debulked prior to conception enlarged during pregnancy, but medical therapy has largely replaced surgical treatment for prolactinomas.

In the management of macroadenomas during pregnancy, “we're on very thin ice” due to very limited data on the risks from taking dopamine agonists before or during pregnancy, he said.

One study reported on 86 women with macroadenomas who conceived after bromocriptine treatment, which was then stopped. Twenty women (23%) developed visual field defects during pregnancy. Four patients then underwent surgical treatment and 15 received bromocriptine therapy, and all 20 had successful pregnancy outcomes (Endocrinol. Metab. Clin. North Am. 2006;35:99–116).

Data from the early 1980s described 29 women with macroadenomas who were managed with continuous bromocriptine throughout pregnancy. Two developed visual field defects. All had successful pregnancy outcomes. Dr. Tyrrell noted that 7 of these 29 women probably had nonfunctional tumors because their serum prolactin levels were less than 200 ng/mL, which suggests that continuous drug therapy was associated with an even higher rate of visual field defects in women with functioning tumors (in 2 of 22) patients.

That's about the extent of the world literature on managing macroadenomas during pregnancy, which is “not very good considering that these drugs have been around for 30-plus years,” he said. There are no data on continuous cabergoline therapy during pregnancy.

In the worst-case scenario, a macro-adenoma may enlarge, usually during the second or third trimester, causing headache and visual field defects. A noncontrast MRI can be done safely during pregnancy to define the size.

If the tumor is enlarging, try medical therapy, and deliver the fetus early if it's viable. Surgery is a last resort, Dr. Tyrrell said. “Think about this if you can ahead of time to deal with the tumor before conception, before getting into trouble during pregnancy,” he concluded.

SAN FRANCISCO — Complications from a prolactinoma during pregnancy are best avoided by treating the adenoma before conception.

But with many women delaying pregnancy, it's not uncommon to see a woman in her late 30s with a macro-adenoma who says she wants to get pregnant soon and doesn't have the luxury of suppressing the tumor for a year or two on medical therapy before conception, Dr. J. Blake Tyrrell said at a conference on diabetes and advances in endocrinology and metabolism sponsored by the University of California, San Francisco.

The sparse data available to help guide the management of these patients suggest that suppressing prolactin-secreting adenomas with dopamine agonists reduces the effects of the tumor and allows the patient to get pregnant without increasing the risk of fetal loss or fetal abnormalities.

There is less experience with cabergoline, today's treatment of choice, than with the former first-line agent bromocriptine.

Whether the patient has a microadenoma or macroadenoma, Dr. Tyrrell prefers to treat with cabergoline to allow menstrual cycles to normalize. If the patient misses a period, test for pregnancy, and if she is pregnant discontinue cabergoline, advised Dr. Tyrrell, director of the endocrinology clinic at the university. With this method, fetal exposure to the drug should be no more than a couple of weeks, he said.

Once off of therapy, fewer than 2% of microadenomas will enlarge during pregnancy. Given this low risk, many providers choose to leave them alone during pregnancy. Dr. Tyrrell suggested following prolactin levels every 6 weeks, and if they get as high as 500 ng/mL, “I might get a bit concerned and ask the patient how she's doing,” he said.

Macroadenomas that are left untreated during pregnancy will enlarge in about 23% of cases and cause headache and visual field defects. “That's not a situation you want to get into,” he said. Only 3% of macroadenomas that were surgically debulked prior to conception enlarged during pregnancy, but medical therapy has largely replaced surgical treatment for prolactinomas.

In the management of macroadenomas during pregnancy, “we're on very thin ice” due to very limited data on the risks from taking dopamine agonists before or during pregnancy, he said.

One study reported on 86 women with macroadenomas who conceived after bromocriptine treatment, which was then stopped. Twenty women (23%) developed visual field defects during pregnancy. Four patients then underwent surgical treatment and 15 received bromocriptine therapy, and all 20 had successful pregnancy outcomes (Endocrinol. Metab. Clin. North Am. 2006;35:99–116).

Data from the early 1980s described 29 women with macroadenomas who were managed with continuous bromocriptine throughout pregnancy. Two developed visual field defects. All had successful pregnancy outcomes. Dr. Tyrrell noted that 7 of these 29 women probably had nonfunctional tumors because their serum prolactin levels were less than 200 ng/mL, which suggests that continuous drug therapy was associated with an even higher rate of visual field defects in women with functioning tumors (in 2 of 22) patients.

That's about the extent of the world literature on managing macroadenomas during pregnancy, which is “not very good considering that these drugs have been around for 30-plus years,” he said. There are no data on continuous cabergoline therapy during pregnancy.

In the worst-case scenario, a macro-adenoma may enlarge, usually during the second or third trimester, causing headache and visual field defects. A noncontrast MRI can be done safely during pregnancy to define the size.

If the tumor is enlarging, try medical therapy, and deliver the fetus early if it's viable. Surgery is a last resort, Dr. Tyrrell said. “Think about this if you can ahead of time to deal with the tumor before conception, before getting into trouble during pregnancy,” he concluded.

SAN FRANCISCO — How long to continue bisphosphonate therapy after the first few years is an open question, with some validity to each of the possible answers, according to Dr. Steven T. Harris.

“This is a hot-button issue. It comes up all the time,” he said at a meeting on diabetes and endocrinology sponsored by the University of California, San Francisco. There are limited data to guide clinicians on how long to extend bisphosphonate therapy, and whether it's risky for patients to interrupt treatment with a drug holiday.

“From my perspective, there is no clinical mandate that says after x number of safe years of therapy, you have to stop,” said Dr. Harris of the university. For some patients who have been on daily bisphosphonates for years and who are tired of coordinating their lives around taking the drug on an empty stomach with plain water, a drug holiday lasting a few years probably is acceptable, the data suggest.

Concerns about continuing bisphosphonates for decades revolve around the misconception that the drug “must be building bad bone or brittle bone or crummy bone—abnormal bone. That's absolutely not true,” said Dr. Harris, who has been a consultant for and received event funding from companies that make bisphosphonates. Bone biopsies done after 5 years of risedronate therapy or 10 years of alendronate therapy have shown histologically normal bone. More importantly, fracture rates remained lower than with placebo therapy after 7 years of risedronate therapy or 10 years of alendronate therapy, studies have shown. If bisphosphonates built abnormal bone, “you'd expect to see the fracture rates go up with extended therapy,” Dr. Harris explained.

For high-risk patients (however one defines that), it's reasonable to continue bisphosphonate therapy, he said. For example, for a 72-year-old patient with a T score of −3.4 who broke her wrist 3 years ago and has three compression fractures, “are you really going to stop her bisphosphonate after 5 years? I think not.”

On the issue of interrupting bisphosphonate therapy with a drug holiday, the key data come from the FLEX (Fracture Intervention Trial Long-Term Extension) study of 1,099 postmenopausal women who had taken alendronate for 3–6 years and were randomized to 5 more years of therapy (5 or 10 mg daily) or placebo (JAMA 2006;296:2927–38).

Those who continued alendronate had a significantly lower risk of having a clinical vertebral spine fracture, defined as a painful fracture causing someone to seek medical attention (relative risk, 0.45 compared with placebo). There were no significant differences between the groups in rates of morphometric spine fracture or nonspine fracture.

The gains in femoral neck and total hip densities that were seen in all patients during the first 3 years of bisphosphonate therapy remained stable in those who continued with the drug; however, the densities drifted down in those who were on placebo, so that there was a small but statistically significant difference between the groups 5 years after randomization.

Moreover, the difference between the groups in the number of clinical vertebral fractures amounted to an absolute relative risk reduction of 2.9%—from 5.3% in the placebo group to 2.4% in the alendronate group—for a relative risk reduction of 55%.

An unpublished subgroup analysis of the FLEX study data by other investigators showed that stopping or continuing alendronate made no difference in the risk for nonvertebral fractures in osteopenic patients (defined as those with a T score between −1 and −2.5) but that it did affect osteoporotic patients (those with a T score of −2.5 or lower at randomization). Osteoporotic patients were half as likely to develop nonvertebral fractures (absolute risk reduction, 13%) if they remained on the bisphosphonate, he said.

“If you have a low-risk patient who's been on therapy for years, I do think you can get away with stopping for awhile,” Dr. Harris said. Just don't expect the benefits to persist forever, he added, “though it's an issue that is admittedly a bit unsettled.”

'There is no clinical mandate that says after x number of safe years of therapy, you have to stop.' DR. HARRIS

SAN FRANCISCO — How long to continue bisphosphonate therapy after the first few years is an open question, with some validity to each of the possible answers, according to Dr. Steven T. Harris.

“This is a hot-button issue. It comes up all the time,” he said at a meeting on diabetes and endocrinology sponsored by the University of California, San Francisco. There are limited data to guide clinicians on how long to extend bisphosphonate therapy, and whether it's risky for patients to interrupt treatment with a drug holiday.

“From my perspective, there is no clinical mandate that says after x number of safe years of therapy, you have to stop,” said Dr. Harris of the university. For some patients who have been on daily bisphosphonates for years and who are tired of coordinating their lives around taking the drug on an empty stomach with plain water, a drug holiday lasting a few years probably is acceptable, the data suggest.

Concerns about continuing bisphosphonates for decades revolve around the misconception that the drug “must be building bad bone or brittle bone or crummy bone—abnormal bone. That's absolutely not true,” said Dr. Harris, who has been a consultant for and received event funding from companies that make bisphosphonates. Bone biopsies done after 5 years of risedronate therapy or 10 years of alendronate therapy have shown histologically normal bone. More importantly, fracture rates remained lower than with placebo therapy after 7 years of risedronate therapy or 10 years of alendronate therapy, studies have shown. If bisphosphonates built abnormal bone, “you'd expect to see the fracture rates go up with extended therapy,” Dr. Harris explained.

For high-risk patients (however one defines that), it's reasonable to continue bisphosphonate therapy, he said. For example, for a 72-year-old patient with a T score of −3.4 who broke her wrist 3 years ago and has three compression fractures, “are you really going to stop her bisphosphonate after 5 years? I think not.”

On the issue of interrupting bisphosphonate therapy with a drug holiday, the key data come from the FLEX (Fracture Intervention Trial Long-Term Extension) study of 1,099 postmenopausal women who had taken alendronate for 3–6 years and were randomized to 5 more years of therapy (5 or 10 mg daily) or placebo (JAMA 2006;296:2927–38).

Those who continued alendronate had a significantly lower risk of having a clinical vertebral spine fracture, defined as a painful fracture causing someone to seek medical attention (relative risk, 0.45 compared with placebo). There were no significant differences between the groups in rates of morphometric spine fracture or nonspine fracture.

The gains in femoral neck and total hip densities that were seen in all patients during the first 3 years of bisphosphonate therapy remained stable in those who continued with the drug; however, the densities drifted down in those who were on placebo, so that there was a small but statistically significant difference between the groups 5 years after randomization.

Moreover, the difference between the groups in the number of clinical vertebral fractures amounted to an absolute relative risk reduction of 2.9%—from 5.3% in the placebo group to 2.4% in the alendronate group—for a relative risk reduction of 55%.

An unpublished subgroup analysis of the FLEX study data by other investigators showed that stopping or continuing alendronate made no difference in the risk for nonvertebral fractures in osteopenic patients (defined as those with a T score between −1 and −2.5) but that it did affect osteoporotic patients (those with a T score of −2.5 or lower at randomization). Osteoporotic patients were half as likely to develop nonvertebral fractures (absolute risk reduction, 13%) if they remained on the bisphosphonate, he said.

“If you have a low-risk patient who's been on therapy for years, I do think you can get away with stopping for awhile,” Dr. Harris said. Just don't expect the benefits to persist forever, he added, “though it's an issue that is admittedly a bit unsettled.”

'There is no clinical mandate that says after x number of safe years of therapy, you have to stop.' DR. HARRIS

SAN FRANCISCO — How long to continue bisphosphonate therapy after the first few years is an open question, with some validity to each of the possible answers, according to Dr. Steven T. Harris.

“This is a hot-button issue. It comes up all the time,” he said at a meeting on diabetes and endocrinology sponsored by the University of California, San Francisco. There are limited data to guide clinicians on how long to extend bisphosphonate therapy, and whether it's risky for patients to interrupt treatment with a drug holiday.

“From my perspective, there is no clinical mandate that says after x number of safe years of therapy, you have to stop,” said Dr. Harris of the university. For some patients who have been on daily bisphosphonates for years and who are tired of coordinating their lives around taking the drug on an empty stomach with plain water, a drug holiday lasting a few years probably is acceptable, the data suggest.

Concerns about continuing bisphosphonates for decades revolve around the misconception that the drug “must be building bad bone or brittle bone or crummy bone—abnormal bone. That's absolutely not true,” said Dr. Harris, who has been a consultant for and received event funding from companies that make bisphosphonates. Bone biopsies done after 5 years of risedronate therapy or 10 years of alendronate therapy have shown histologically normal bone. More importantly, fracture rates remained lower than with placebo therapy after 7 years of risedronate therapy or 10 years of alendronate therapy, studies have shown. If bisphosphonates built abnormal bone, “you'd expect to see the fracture rates go up with extended therapy,” Dr. Harris explained.

For high-risk patients (however one defines that), it's reasonable to continue bisphosphonate therapy, he said. For example, for a 72-year-old patient with a T score of −3.4 who broke her wrist 3 years ago and has three compression fractures, “are you really going to stop her bisphosphonate after 5 years? I think not.”

On the issue of interrupting bisphosphonate therapy with a drug holiday, the key data come from the FLEX (Fracture Intervention Trial Long-Term Extension) study of 1,099 postmenopausal women who had taken alendronate for 3–6 years and were randomized to 5 more years of therapy (5 or 10 mg daily) or placebo (JAMA 2006;296:2927–38).

Those who continued alendronate had a significantly lower risk of having a clinical vertebral spine fracture, defined as a painful fracture causing someone to seek medical attention (relative risk, 0.45 compared with placebo). There were no significant differences between the groups in rates of morphometric spine fracture or nonspine fracture.

The gains in femoral neck and total hip densities that were seen in all patients during the first 3 years of bisphosphonate therapy remained stable in those who continued with the drug; however, the densities drifted down in those who were on placebo, so that there was a small but statistically significant difference between the groups 5 years after randomization.

Moreover, the difference between the groups in the number of clinical vertebral fractures amounted to an absolute relative risk reduction of 2.9%—from 5.3% in the placebo group to 2.4% in the alendronate group—for a relative risk reduction of 55%.

An unpublished subgroup analysis of the FLEX study data by other investigators showed that stopping or continuing alendronate made no difference in the risk for nonvertebral fractures in osteopenic patients (defined as those with a T score between −1 and −2.5) but that it did affect osteoporotic patients (those with a T score of −2.5 or lower at randomization). Osteoporotic patients were half as likely to develop nonvertebral fractures (absolute risk reduction, 13%) if they remained on the bisphosphonate, he said.

“If you have a low-risk patient who's been on therapy for years, I do think you can get away with stopping for awhile,” Dr. Harris said. Just don't expect the benefits to persist forever, he added, “though it's an issue that is admittedly a bit unsettled.”

'There is no clinical mandate that says after x number of safe years of therapy, you have to stop.' DR. HARRIS

SAN FRANCISCO — Initial therapy with any antihypertensive medication is significantly better than placebo at preventing stroke, and any antihypertensive except an angiotensin receptor blocker is better than placebo for preventing heart disease, results of new meta-analyses show.

“Don't let patients tell you, 'I just read someplace that this drug is not good at preventing stroke,'” Dr. William J. Elliott said at the annual meeting of the American Society of Hypertension. “All the drugs, in fact, are superior to placebo” in preventing stroke, he said.

For heart disease prevention, angiotensin receptor blockers (ARBs) may have fallen short of superiority to placebo in patients with hypertension for reasons related to statistical power, he hypothesized. “ARBs have not been around as long as some of our more tried-and-true drugs” and thus have had fewer trials as initial hypertensive agents, and fewer people in those trials develop coronary heart disease, said Dr. Elliott, professor of preventive medicine at Rush Medical College, Chicago.

The last major meta-analysis in 2003 of cardiovascular outcomes in hypertension treatment provided the basis for recommendations of low-dose diuretics as first-line antihypertensives to prevent cardiovascular disease in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7).

Since then, at least 25 more trials have been published, with stroke data on 269,180 more subjects and heart disease data on 276,396 more subjects who were included in the current meta-analyses.

Dr. Elliott and his associates conducted two types of meta-analyses on data from all published outcome-based clinical trials with a minimum 1-year follow-up in which all subjects had hypertension and in which a drug was the initial antihypertensive therapy. Results of both the “network” and “Bayesian” meta-analyses were strikingly consistent, he said

For stroke prevention, initial treatment for hypertension with a diuretic was no better than was a calcium channel blocker (CCB) or ARB. All three were slightly but significantly better than a beta-blocker or ACE inhibitor in preventing stroke, Dr. Elliott said. The risk for stroke was 56% higher on placebo than on a diuretic or a CCB. There were 9,351 strokes among subjects in 144 randomized arms in the trials.

Initial treatment with an ACE inhibitor was about 8% more effective than was a diuretic in reducing coronary heart disease events, though the difference was not statistically significant.

The finding is consistent with other suggestions in the literature that ACE inhibitors are better than diuretics at preventing heart disease, Dr. Elliott said.

Calcium channel blockers appeared to be as effective as diuretics for preventing heart disease, and beta-blockers were just behind. Both ARBs and placebos were statistically inferior to ACE inhibitors, diuretics, CCBs, and beta-blockers for preventing heart disease. The risk for coronary heart disease was 26%–28% higher on placebo than on an ACE inhibitor. There were 11,122 coronary heart disease events among subjects in 136 arms in the trials.

Dr. Elliott has been a consultant or speaker for Novartis Pharmaceuticals, Pfizer, Bristol-Myers Squibb/Sanofi-Synthelabo Partnership, and Sanofi-Aventis, some of which market antihypertensive drugs. He also has received royalties from Elsevier, which owns this news organization.

Antihypertensives are superior to placebo in stroke prevention, but ARBs fall short for heart disease prevention. DR. ELLIOTT

SAN FRANCISCO — Initial therapy with any antihypertensive medication is significantly better than placebo at preventing stroke, and any antihypertensive except an angiotensin receptor blocker is better than placebo for preventing heart disease, results of new meta-analyses show.

“Don't let patients tell you, 'I just read someplace that this drug is not good at preventing stroke,'” Dr. William J. Elliott said at the annual meeting of the American Society of Hypertension. “All the drugs, in fact, are superior to placebo” in preventing stroke, he said.

For heart disease prevention, angiotensin receptor blockers (ARBs) may have fallen short of superiority to placebo in patients with hypertension for reasons related to statistical power, he hypothesized. “ARBs have not been around as long as some of our more tried-and-true drugs” and thus have had fewer trials as initial hypertensive agents, and fewer people in those trials develop coronary heart disease, said Dr. Elliott, professor of preventive medicine at Rush Medical College, Chicago.

The last major meta-analysis in 2003 of cardiovascular outcomes in hypertension treatment provided the basis for recommendations of low-dose diuretics as first-line antihypertensives to prevent cardiovascular disease in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7).

Since then, at least 25 more trials have been published, with stroke data on 269,180 more subjects and heart disease data on 276,396 more subjects who were included in the current meta-analyses.

Dr. Elliott and his associates conducted two types of meta-analyses on data from all published outcome-based clinical trials with a minimum 1-year follow-up in which all subjects had hypertension and in which a drug was the initial antihypertensive therapy. Results of both the “network” and “Bayesian” meta-analyses were strikingly consistent, he said

For stroke prevention, initial treatment for hypertension with a diuretic was no better than was a calcium channel blocker (CCB) or ARB. All three were slightly but significantly better than a beta-blocker or ACE inhibitor in preventing stroke, Dr. Elliott said. The risk for stroke was 56% higher on placebo than on a diuretic or a CCB. There were 9,351 strokes among subjects in 144 randomized arms in the trials.

Initial treatment with an ACE inhibitor was about 8% more effective than was a diuretic in reducing coronary heart disease events, though the difference was not statistically significant.

The finding is consistent with other suggestions in the literature that ACE inhibitors are better than diuretics at preventing heart disease, Dr. Elliott said.

Calcium channel blockers appeared to be as effective as diuretics for preventing heart disease, and beta-blockers were just behind. Both ARBs and placebos were statistically inferior to ACE inhibitors, diuretics, CCBs, and beta-blockers for preventing heart disease. The risk for coronary heart disease was 26%–28% higher on placebo than on an ACE inhibitor. There were 11,122 coronary heart disease events among subjects in 136 arms in the trials.

Dr. Elliott has been a consultant or speaker for Novartis Pharmaceuticals, Pfizer, Bristol-Myers Squibb/Sanofi-Synthelabo Partnership, and Sanofi-Aventis, some of which market antihypertensive drugs. He also has received royalties from Elsevier, which owns this news organization.

Antihypertensives are superior to placebo in stroke prevention, but ARBs fall short for heart disease prevention. DR. ELLIOTT

SAN FRANCISCO — Initial therapy with any antihypertensive medication is significantly better than placebo at preventing stroke, and any antihypertensive except an angiotensin receptor blocker is better than placebo for preventing heart disease, results of new meta-analyses show.

“Don't let patients tell you, 'I just read someplace that this drug is not good at preventing stroke,'” Dr. William J. Elliott said at the annual meeting of the American Society of Hypertension. “All the drugs, in fact, are superior to placebo” in preventing stroke, he said.

For heart disease prevention, angiotensin receptor blockers (ARBs) may have fallen short of superiority to placebo in patients with hypertension for reasons related to statistical power, he hypothesized. “ARBs have not been around as long as some of our more tried-and-true drugs” and thus have had fewer trials as initial hypertensive agents, and fewer people in those trials develop coronary heart disease, said Dr. Elliott, professor of preventive medicine at Rush Medical College, Chicago.

The last major meta-analysis in 2003 of cardiovascular outcomes in hypertension treatment provided the basis for recommendations of low-dose diuretics as first-line antihypertensives to prevent cardiovascular disease in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7).

Since then, at least 25 more trials have been published, with stroke data on 269,180 more subjects and heart disease data on 276,396 more subjects who were included in the current meta-analyses.

Dr. Elliott and his associates conducted two types of meta-analyses on data from all published outcome-based clinical trials with a minimum 1-year follow-up in which all subjects had hypertension and in which a drug was the initial antihypertensive therapy. Results of both the “network” and “Bayesian” meta-analyses were strikingly consistent, he said

For stroke prevention, initial treatment for hypertension with a diuretic was no better than was a calcium channel blocker (CCB) or ARB. All three were slightly but significantly better than a beta-blocker or ACE inhibitor in preventing stroke, Dr. Elliott said. The risk for stroke was 56% higher on placebo than on a diuretic or a CCB. There were 9,351 strokes among subjects in 144 randomized arms in the trials.

Initial treatment with an ACE inhibitor was about 8% more effective than was a diuretic in reducing coronary heart disease events, though the difference was not statistically significant.

The finding is consistent with other suggestions in the literature that ACE inhibitors are better than diuretics at preventing heart disease, Dr. Elliott said.

Calcium channel blockers appeared to be as effective as diuretics for preventing heart disease, and beta-blockers were just behind. Both ARBs and placebos were statistically inferior to ACE inhibitors, diuretics, CCBs, and beta-blockers for preventing heart disease. The risk for coronary heart disease was 26%–28% higher on placebo than on an ACE inhibitor. There were 11,122 coronary heart disease events among subjects in 136 arms in the trials.

Dr. Elliott has been a consultant or speaker for Novartis Pharmaceuticals, Pfizer, Bristol-Myers Squibb/Sanofi-Synthelabo Partnership, and Sanofi-Aventis, some of which market antihypertensive drugs. He also has received royalties from Elsevier, which owns this news organization.

Antihypertensives are superior to placebo in stroke prevention, but ARBs fall short for heart disease prevention. DR. ELLIOTT

SAN FRANCISCO — A new analysis supports a controversial study that challenged the favored role of diuretics in combination therapy for hypertension, but some experts remain skeptical.

Dr. Kenneth Jamerson, lead investigator of the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial, said the results of a substudy he presented at the annual meeting of the American Society of Hypertension confirm that the main trial constitutes a paradigm shift in treating hypertension.

His coinvestigator, Dr. George Bakris, director of the hypertension center and professor of medicine at the University of Chicago, echoed that assessment at a press conference.

The ACCOMPLISH trial's conclusion that a fixed-dose combination of an ACE inhibitor and a calcium channel blocker was superior to a combination of an ACE inhibitor and a diuretic for initial antihypertensive therapy “has huge implications for the millions of patients who are taking blood pressure medication,” said Dr. Jamerson, professor of medicine at the University of Michigan, Ann Arbor.

Other experts on a separate panel at the meeting were not convinced.

Dr. William C. Cushman, chief of preventive medicine at the Memphis Veterans Affairs Medical Center and professor of preventive medicine at the University of Tennessee, Memphis, said the literature supports three drug classes as the mainstays of combination therapy for hypertension: diuretics, blockers of the renin-angiotensin-aldosterone system (RAAS), and calcium channel blockers.

“Based on all the data that we have, I would still put diuretics in a very favorable position in any combinations of these,” said Dr. Cushman, who has been a consultant, adviser, or lecturer for Novartis.

Diuretics have been a mainstay of antihypertensive therapy for half a century. Recent guidelines have promoted the use of combination therapy to treat hypertension rather than starting with a single agent in higher-risk patients.

The double-blind, industry-sponsored ACCOMPLISH trial was the first to compare two antihypertensive combinations as initial therapy.

The study randomized 11,506 patients with hypertension who were at high risk for cardiovascular events to receive fixed-dose pills containing either the ACE inhibitor-diuretic combination of benazepril-hydrochlorothiazide (HCTZ) or benazepril plus amlodipine, a calcium channel blocker.

After 36 months, the risk of cardiac events was significantly lower in the benazepril-amlodipine group (9.6%) compared with the benazepril-HCTZ group (11.8%), a 20% relative risk reduction (N. Engl. J. Med. 2008;359:2417–28).

Critics pounced on several aspects of the study, including the fact that the 0.9-mm Hg difference between groups in systolic blood pressure results was based on clinic measurements, which are less accurate than ambulatory blood pressure monitoring (N. Engl. J. Med. 2009;360:1147–50).

A new substudy of 573 ACCOMPLISH subjects who underwent 24-hour ambulatory blood pressure monitoring, however, showed good blood pressure control that was similar between groups and may have been better in the benazepril-HCTZ group, with a nonsignificant 1.6-mm Hg difference in mean 24-hour systolic pressures, Dr. Jamerson reported at the meeting.

The substudy confirms that the reduced cardiovascular risk seen with benazepril-amlodipine was due to other beneficial characteristics of this combination therapy and not driven by differences in blood pressures between groups, he said.

Dr. Jamerson has received funding from, or been a consultant and speaker for, Novartis Pharmaceuticals and other drug companies, and as president of the International Society of Hypertension in Blacks, he sought industry support for the organization. Novartis markets trade versions of the benazepril-amlodipine and benazepril-HCTZ combinations, and both combinations have generic versions on the market.

European guidelines on hypertension treatment favor combination therapy and suggest that combinations of ACE inhibitor with a diuretic or a calcium channel blocker are equally good.

“We show evidence that they're not,” Dr. Jamerson said. “They very likely may have to rethink their guidelines.” U.S. guidelines generally prefer combinations that include a diuretic, he added. “I think this directly challenges that. I consider it a paradigm shift. It's up to the entire community to decide.”

Dr. Bakris said the subanalysis should lead to a change in recommendations. Dr. Bakris has been a consultant, speaker, or adviser for Novartis and other pharmaceutical companies.

“The results of ACCOMPLISH may challenge current diuretic-based guidelines. I don't think this is absolutely clear,” Dr. Angela L. Brown said in the panel discussion.

“I don't think we really know that yet just from this one trial,” said Dr. Brown of Washington University, St. Louis. She has been a consultant, adviser, or lecturer for Novartis, Boehringer Ingelheim, and Forest Laboratories.

The HCTZ dosage used in the ACCOMPLISH trial (12.5–25 mg/day) was lower than were dosages used in placebo-controlled studies that established the antihypertensive benefits of HCTZ, Dr. Cushman noted.

Also, if the combined end points of death from cardiovascular causes, nonfatal MI or stroke, resuscitation after sudden cardiac arrest, hospitalization for angina, and coronary revascularization were reconfigured to exclude the angina and revascularization outcomes, there would have been no significant difference between groups in the primary combined outcome, he said.

The findings have 'huge implications for the millions of patients who are taking blood pressure medication.' DR. JAMERSON

'Based on all the data that we have, I would still put diuretics in a very favorable position in any combinations.' Dr. Cushman

SAN FRANCISCO — A new analysis supports a controversial study that challenged the favored role of diuretics in combination therapy for hypertension, but some experts remain skeptical.

Dr. Kenneth Jamerson, lead investigator of the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial, said the results of a substudy he presented at the annual meeting of the American Society of Hypertension confirm that the main trial constitutes a paradigm shift in treating hypertension.

His coinvestigator, Dr. George Bakris, director of the hypertension center and professor of medicine at the University of Chicago, echoed that assessment at a press conference.

The ACCOMPLISH trial's conclusion that a fixed-dose combination of an ACE inhibitor and a calcium channel blocker was superior to a combination of an ACE inhibitor and a diuretic for initial antihypertensive therapy “has huge implications for the millions of patients who are taking blood pressure medication,” said Dr. Jamerson, professor of medicine at the University of Michigan, Ann Arbor.

Other experts on a separate panel at the meeting were not convinced.

Dr. William C. Cushman, chief of preventive medicine at the Memphis Veterans Affairs Medical Center and professor of preventive medicine at the University of Tennessee, Memphis, said the literature supports three drug classes as the mainstays of combination therapy for hypertension: diuretics, blockers of the renin-angiotensin-aldosterone system (RAAS), and calcium channel blockers.

“Based on all the data that we have, I would still put diuretics in a very favorable position in any combinations of these,” said Dr. Cushman, who has been a consultant, adviser, or lecturer for Novartis.

Diuretics have been a mainstay of antihypertensive therapy for half a century. Recent guidelines have promoted the use of combination therapy to treat hypertension rather than starting with a single agent in higher-risk patients.

The double-blind, industry-sponsored ACCOMPLISH trial was the first to compare two antihypertensive combinations as initial therapy.

The study randomized 11,506 patients with hypertension who were at high risk for cardiovascular events to receive fixed-dose pills containing either the ACE inhibitor-diuretic combination of benazepril-hydrochlorothiazide (HCTZ) or benazepril plus amlodipine, a calcium channel blocker.

After 36 months, the risk of cardiac events was significantly lower in the benazepril-amlodipine group (9.6%) compared with the benazepril-HCTZ group (11.8%), a 20% relative risk reduction (N. Engl. J. Med. 2008;359:2417–28).

Critics pounced on several aspects of the study, including the fact that the 0.9-mm Hg difference between groups in systolic blood pressure results was based on clinic measurements, which are less accurate than ambulatory blood pressure monitoring (N. Engl. J. Med. 2009;360:1147–50).

A new substudy of 573 ACCOMPLISH subjects who underwent 24-hour ambulatory blood pressure monitoring, however, showed good blood pressure control that was similar between groups and may have been better in the benazepril-HCTZ group, with a nonsignificant 1.6-mm Hg difference in mean 24-hour systolic pressures, Dr. Jamerson reported at the meeting.

The substudy confirms that the reduced cardiovascular risk seen with benazepril-amlodipine was due to other beneficial characteristics of this combination therapy and not driven by differences in blood pressures between groups, he said.

Dr. Jamerson has received funding from, or been a consultant and speaker for, Novartis Pharmaceuticals and other drug companies, and as president of the International Society of Hypertension in Blacks, he sought industry support for the organization. Novartis markets trade versions of the benazepril-amlodipine and benazepril-HCTZ combinations, and both combinations have generic versions on the market.

European guidelines on hypertension treatment favor combination therapy and suggest that combinations of ACE inhibitor with a diuretic or a calcium channel blocker are equally good.

“We show evidence that they're not,” Dr. Jamerson said. “They very likely may have to rethink their guidelines.” U.S. guidelines generally prefer combinations that include a diuretic, he added. “I think this directly challenges that. I consider it a paradigm shift. It's up to the entire community to decide.”

Dr. Bakris said the subanalysis should lead to a change in recommendations. Dr. Bakris has been a consultant, speaker, or adviser for Novartis and other pharmaceutical companies.

“The results of ACCOMPLISH may challenge current diuretic-based guidelines. I don't think this is absolutely clear,” Dr. Angela L. Brown said in the panel discussion.

“I don't think we really know that yet just from this one trial,” said Dr. Brown of Washington University, St. Louis. She has been a consultant, adviser, or lecturer for Novartis, Boehringer Ingelheim, and Forest Laboratories.

The HCTZ dosage used in the ACCOMPLISH trial (12.5–25 mg/day) was lower than were dosages used in placebo-controlled studies that established the antihypertensive benefits of HCTZ, Dr. Cushman noted.

Also, if the combined end points of death from cardiovascular causes, nonfatal MI or stroke, resuscitation after sudden cardiac arrest, hospitalization for angina, and coronary revascularization were reconfigured to exclude the angina and revascularization outcomes, there would have been no significant difference between groups in the primary combined outcome, he said.

The findings have 'huge implications for the millions of patients who are taking blood pressure medication.' DR. JAMERSON

'Based on all the data that we have, I would still put diuretics in a very favorable position in any combinations.' Dr. Cushman

SAN FRANCISCO — A new analysis supports a controversial study that challenged the favored role of diuretics in combination therapy for hypertension, but some experts remain skeptical.

Dr. Kenneth Jamerson, lead investigator of the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial, said the results of a substudy he presented at the annual meeting of the American Society of Hypertension confirm that the main trial constitutes a paradigm shift in treating hypertension.

His coinvestigator, Dr. George Bakris, director of the hypertension center and professor of medicine at the University of Chicago, echoed that assessment at a press conference.

The ACCOMPLISH trial's conclusion that a fixed-dose combination of an ACE inhibitor and a calcium channel blocker was superior to a combination of an ACE inhibitor and a diuretic for initial antihypertensive therapy “has huge implications for the millions of patients who are taking blood pressure medication,” said Dr. Jamerson, professor of medicine at the University of Michigan, Ann Arbor.

Other experts on a separate panel at the meeting were not convinced.

Dr. William C. Cushman, chief of preventive medicine at the Memphis Veterans Affairs Medical Center and professor of preventive medicine at the University of Tennessee, Memphis, said the literature supports three drug classes as the mainstays of combination therapy for hypertension: diuretics, blockers of the renin-angiotensin-aldosterone system (RAAS), and calcium channel blockers.

“Based on all the data that we have, I would still put diuretics in a very favorable position in any combinations of these,” said Dr. Cushman, who has been a consultant, adviser, or lecturer for Novartis.

Diuretics have been a mainstay of antihypertensive therapy for half a century. Recent guidelines have promoted the use of combination therapy to treat hypertension rather than starting with a single agent in higher-risk patients.

The double-blind, industry-sponsored ACCOMPLISH trial was the first to compare two antihypertensive combinations as initial therapy.

The study randomized 11,506 patients with hypertension who were at high risk for cardiovascular events to receive fixed-dose pills containing either the ACE inhibitor-diuretic combination of benazepril-hydrochlorothiazide (HCTZ) or benazepril plus amlodipine, a calcium channel blocker.

After 36 months, the risk of cardiac events was significantly lower in the benazepril-amlodipine group (9.6%) compared with the benazepril-HCTZ group (11.8%), a 20% relative risk reduction (N. Engl. J. Med. 2008;359:2417–28).

Critics pounced on several aspects of the study, including the fact that the 0.9-mm Hg difference between groups in systolic blood pressure results was based on clinic measurements, which are less accurate than ambulatory blood pressure monitoring (N. Engl. J. Med. 2009;360:1147–50).

A new substudy of 573 ACCOMPLISH subjects who underwent 24-hour ambulatory blood pressure monitoring, however, showed good blood pressure control that was similar between groups and may have been better in the benazepril-HCTZ group, with a nonsignificant 1.6-mm Hg difference in mean 24-hour systolic pressures, Dr. Jamerson reported at the meeting.

The substudy confirms that the reduced cardiovascular risk seen with benazepril-amlodipine was due to other beneficial characteristics of this combination therapy and not driven by differences in blood pressures between groups, he said.

Dr. Jamerson has received funding from, or been a consultant and speaker for, Novartis Pharmaceuticals and other drug companies, and as president of the International Society of Hypertension in Blacks, he sought industry support for the organization. Novartis markets trade versions of the benazepril-amlodipine and benazepril-HCTZ combinations, and both combinations have generic versions on the market.

European guidelines on hypertension treatment favor combination therapy and suggest that combinations of ACE inhibitor with a diuretic or a calcium channel blocker are equally good.

“We show evidence that they're not,” Dr. Jamerson said. “They very likely may have to rethink their guidelines.” U.S. guidelines generally prefer combinations that include a diuretic, he added. “I think this directly challenges that. I consider it a paradigm shift. It's up to the entire community to decide.”

Dr. Bakris said the subanalysis should lead to a change in recommendations. Dr. Bakris has been a consultant, speaker, or adviser for Novartis and other pharmaceutical companies.

“The results of ACCOMPLISH may challenge current diuretic-based guidelines. I don't think this is absolutely clear,” Dr. Angela L. Brown said in the panel discussion.

“I don't think we really know that yet just from this one trial,” said Dr. Brown of Washington University, St. Louis. She has been a consultant, adviser, or lecturer for Novartis, Boehringer Ingelheim, and Forest Laboratories.

The HCTZ dosage used in the ACCOMPLISH trial (12.5–25 mg/day) was lower than were dosages used in placebo-controlled studies that established the antihypertensive benefits of HCTZ, Dr. Cushman noted.

Also, if the combined end points of death from cardiovascular causes, nonfatal MI or stroke, resuscitation after sudden cardiac arrest, hospitalization for angina, and coronary revascularization were reconfigured to exclude the angina and revascularization outcomes, there would have been no significant difference between groups in the primary combined outcome, he said.

The findings have 'huge implications for the millions of patients who are taking blood pressure medication.' DR. JAMERSON

'Based on all the data that we have, I would still put diuretics in a very favorable position in any combinations.' Dr. Cushman

Women diagnosed with gestational diabetes who gained more than 10 pounds after the pregnancy significantly increased their risk for a cesarean delivery at the next pregnancy, a study of 2,581 women found.

In the study, 5% of women who returned to their prepregnancy weight after being delivered vaginally of a live singleton, or whose prepregnancy weight decreased by more than 10 pounds by the time of their next pregnancy, were delivered by cesarean section in that subsequent pregnancy. Of women whose prepregnancy weights increased by more than 10 pounds, however, 10% had cesarean deliveries in the subsequent pregnancy, Dr. Pathmaja Paramsothy and associates reported (Obstet. Gynecol. 2009;113:817–23).

The risk for cesarean delivery was 70% higher in the weight-gain group after adjustment for the effects of confounding factors including maternal age, race/ethnicity, education, duration of birth interval, weight gain during each pregnancy, smoking, and year of birth, wrote Dr. Paramsothy and colleagues at the University of Washington, Seattle. The results were obtained in a retrospective analysis of linked birth-certificate data for women with at least two singleton births in Washington state from 1992 to 2005.

Of the 2,581 women studied, 35% were in the weight-gain group, 11% were in the weight-loss group, and 54% were in the weight-stable group.

Prepregnancy weight typically is measured at the first prenatal visit. The interpregnancy weight change was calculated by subtracting the prepregnancy weight for the subsequent pregnancy from the prepregnancy weight for the first pregnancy.

Previous studies have identified gestational diabetes, obesity, and excessive weight gain as independent risk factors for cesarean delivery and analyzed the effects of each separately. This may be the first study to look at the association between interpregnancy weight gain and subsequent cesarean delivery in women with gestational diabetes, a population that the investigators hypothesized would be at particularly high risk.

Women who gained more weight between pregnancies were more likely to deliver by cesarean at the subsequent pregnancy, with the risk increasing by 48%–136% depending on the number of pounds gained. Interpregnancy weight gain was more likely in women who were younger, African American or Hispanic, less educated, and more than 3 years from the initial pregnancy.

The rate of cesarean deliveries in the United States climbed from 6% in 1970 to 30% in 2005, potentially increasing the health risks for mothers and newborns and adding at least $15 billion in costs to the health care system, the authors noted. Delivering physicians should counsel women with gestational diabetes about weight management between pregnancies, Dr. Paramsothy and associates said.

Dr. Catherine Spong of the National Institute of Child Health and Human Development commented, “The take-home message from this is that interpregnancy weight gain is an important thing to keep in mind as you are managing patients with gestational diabetes.

“Not only do you want to test them for subsequent development of diabetes, but also monitor their weight gain to try to optimize subsequent pregnancy outcomes.”

New attention is being paid to questions about how much weight a woman can safely gain during or between pregnancies. Guidelines from the Institute of Medicine focus mainly on preventing low birth weight, and aim for at least a 10-pound maternal weight gain during pregnancy but don't address the upper limits of weight gain during or between pregnancies, Dr. Spong said in an interview.

“Now, really, low birth weight isn't particularly the issue. It's the obesity epidemic,” she said.

The Institute of Medicine is reviewing the guidelines and should produce new recommendations in the next few months that Dr. Spong hopes will also target obese and morbidly obese weight levels.

The investigators and Dr. Spong reported no conflicts of interest related to the study.

Women diagnosed with gestational diabetes who gained more than 10 pounds after the pregnancy significantly increased their risk for a cesarean delivery at the next pregnancy, a study of 2,581 women found.

In the study, 5% of women who returned to their prepregnancy weight after being delivered vaginally of a live singleton, or whose prepregnancy weight decreased by more than 10 pounds by the time of their next pregnancy, were delivered by cesarean section in that subsequent pregnancy. Of women whose prepregnancy weights increased by more than 10 pounds, however, 10% had cesarean deliveries in the subsequent pregnancy, Dr. Pathmaja Paramsothy and associates reported (Obstet. Gynecol. 2009;113:817–23).

The risk for cesarean delivery was 70% higher in the weight-gain group after adjustment for the effects of confounding factors including maternal age, race/ethnicity, education, duration of birth interval, weight gain during each pregnancy, smoking, and year of birth, wrote Dr. Paramsothy and colleagues at the University of Washington, Seattle. The results were obtained in a retrospective analysis of linked birth-certificate data for women with at least two singleton births in Washington state from 1992 to 2005.

Of the 2,581 women studied, 35% were in the weight-gain group, 11% were in the weight-loss group, and 54% were in the weight-stable group.

Prepregnancy weight typically is measured at the first prenatal visit. The interpregnancy weight change was calculated by subtracting the prepregnancy weight for the subsequent pregnancy from the prepregnancy weight for the first pregnancy.

Previous studies have identified gestational diabetes, obesity, and excessive weight gain as independent risk factors for cesarean delivery and analyzed the effects of each separately. This may be the first study to look at the association between interpregnancy weight gain and subsequent cesarean delivery in women with gestational diabetes, a population that the investigators hypothesized would be at particularly high risk.

Women who gained more weight between pregnancies were more likely to deliver by cesarean at the subsequent pregnancy, with the risk increasing by 48%–136% depending on the number of pounds gained. Interpregnancy weight gain was more likely in women who were younger, African American or Hispanic, less educated, and more than 3 years from the initial pregnancy.

The rate of cesarean deliveries in the United States climbed from 6% in 1970 to 30% in 2005, potentially increasing the health risks for mothers and newborns and adding at least $15 billion in costs to the health care system, the authors noted. Delivering physicians should counsel women with gestational diabetes about weight management between pregnancies, Dr. Paramsothy and associates said.

Dr. Catherine Spong of the National Institute of Child Health and Human Development commented, “The take-home message from this is that interpregnancy weight gain is an important thing to keep in mind as you are managing patients with gestational diabetes.

“Not only do you want to test them for subsequent development of diabetes, but also monitor their weight gain to try to optimize subsequent pregnancy outcomes.”

New attention is being paid to questions about how much weight a woman can safely gain during or between pregnancies. Guidelines from the Institute of Medicine focus mainly on preventing low birth weight, and aim for at least a 10-pound maternal weight gain during pregnancy but don't address the upper limits of weight gain during or between pregnancies, Dr. Spong said in an interview.

“Now, really, low birth weight isn't particularly the issue. It's the obesity epidemic,” she said.

The Institute of Medicine is reviewing the guidelines and should produce new recommendations in the next few months that Dr. Spong hopes will also target obese and morbidly obese weight levels.

The investigators and Dr. Spong reported no conflicts of interest related to the study.

Women diagnosed with gestational diabetes who gained more than 10 pounds after the pregnancy significantly increased their risk for a cesarean delivery at the next pregnancy, a study of 2,581 women found.

In the study, 5% of women who returned to their prepregnancy weight after being delivered vaginally of a live singleton, or whose prepregnancy weight decreased by more than 10 pounds by the time of their next pregnancy, were delivered by cesarean section in that subsequent pregnancy. Of women whose prepregnancy weights increased by more than 10 pounds, however, 10% had cesarean deliveries in the subsequent pregnancy, Dr. Pathmaja Paramsothy and associates reported (Obstet. Gynecol. 2009;113:817–23).

The risk for cesarean delivery was 70% higher in the weight-gain group after adjustment for the effects of confounding factors including maternal age, race/ethnicity, education, duration of birth interval, weight gain during each pregnancy, smoking, and year of birth, wrote Dr. Paramsothy and colleagues at the University of Washington, Seattle. The results were obtained in a retrospective analysis of linked birth-certificate data for women with at least two singleton births in Washington state from 1992 to 2005.

Of the 2,581 women studied, 35% were in the weight-gain group, 11% were in the weight-loss group, and 54% were in the weight-stable group.

Prepregnancy weight typically is measured at the first prenatal visit. The interpregnancy weight change was calculated by subtracting the prepregnancy weight for the subsequent pregnancy from the prepregnancy weight for the first pregnancy.

Previous studies have identified gestational diabetes, obesity, and excessive weight gain as independent risk factors for cesarean delivery and analyzed the effects of each separately. This may be the first study to look at the association between interpregnancy weight gain and subsequent cesarean delivery in women with gestational diabetes, a population that the investigators hypothesized would be at particularly high risk.

Women who gained more weight between pregnancies were more likely to deliver by cesarean at the subsequent pregnancy, with the risk increasing by 48%–136% depending on the number of pounds gained. Interpregnancy weight gain was more likely in women who were younger, African American or Hispanic, less educated, and more than 3 years from the initial pregnancy.

The rate of cesarean deliveries in the United States climbed from 6% in 1970 to 30% in 2005, potentially increasing the health risks for mothers and newborns and adding at least $15 billion in costs to the health care system, the authors noted. Delivering physicians should counsel women with gestational diabetes about weight management between pregnancies, Dr. Paramsothy and associates said.

Dr. Catherine Spong of the National Institute of Child Health and Human Development commented, “The take-home message from this is that interpregnancy weight gain is an important thing to keep in mind as you are managing patients with gestational diabetes.

“Not only do you want to test them for subsequent development of diabetes, but also monitor their weight gain to try to optimize subsequent pregnancy outcomes.”

New attention is being paid to questions about how much weight a woman can safely gain during or between pregnancies. Guidelines from the Institute of Medicine focus mainly on preventing low birth weight, and aim for at least a 10-pound maternal weight gain during pregnancy but don't address the upper limits of weight gain during or between pregnancies, Dr. Spong said in an interview.

“Now, really, low birth weight isn't particularly the issue. It's the obesity epidemic,” she said.

The Institute of Medicine is reviewing the guidelines and should produce new recommendations in the next few months that Dr. Spong hopes will also target obese and morbidly obese weight levels.

The investigators and Dr. Spong reported no conflicts of interest related to the study.

Many physicians think it's no big deal to schedule elective deliveries before 39 weeks' gestation—contrary to guidelines—but their minds and practices can be changed with concerted effort, according to a study at nine hospitals.

In a 5-year program, reeducation of physicians and nurses on the hazards of early-term elective delivery, combined with policing of their practices, reduced the rate of early elective deliveries from 28% of all elective deliveries in 1999–2000 to less than 10% within 6 months of program initiation. After 6 years with the program in place, the near-term elective delivery rate remained less than 3%, Dr. Bryan T. Oshiro and his associates reported (Obstet. Gynecol. 2009;113:804–11).

Those improvements did not come easily. It wasn't enough to remind physicians of American College of Obstetricians and Gynecologists guidelines recommending that elective deliveries not be performed before 39 weeks' gestation. Nor were their minds changed by national data showing greater perinatal morbidity in infants delivered before 39 weeks, including 8- to 23-fold higher incidences of severe respiratory distress syndrome with deliveries at 38 or 37 weeks, respectively.

The medical staff argued that their local patients were healthier than those reported in the literature. The physicians wanted to maintain autonomy in managing the timing of delivery. Nursing staff did not want to be responsible for enforcing a policy against early elective deliveries, which would put them in adversarial relationships with the doctors. “It was not until internal or local neonatal morbidity data were presented that significant initial buy-in by the medical staff was seen,” reported Dr. Oshiro of Loma Linda (Calif.) University.

The team who developed and administered the program within the Intermountain Healthcare network of hospitals in Utah and Southeast Idaho collected and presented data showing that their rate of neonatal ICU admissions for normal pregnancies increased from 3.3% for deliveries at 39 weeks to 4.5% for elective deliveries at 38 weeks and 8.9% for deliveries at 37 weeks. The rate of ventilator use for deliveries without complications increased from 0.3% for deliveries at 39 weeks to 0.5% for deliveries at 38 weeks and 1.4% for deliveries at 37 weeks. The in-hospital data were key to obtaining staff buy-in.

Concerns that delaying elective deliveries might increase morbidity were allayed by follow-up data showing significant declines in the rates of postpartum anemia, meconium aspiration, Apgar scores less than 5 at 1 minute, and cesarean deliveries due to fetal distress in infants delivered at 39–41 weeks' gestation in the period after the program was started, compared with the pre-program era. The rate of preeclampsia increased slightly, the study found.

Intermountain Healthcare is a vertically integrated health care system with 21 hospitals. The nine hospitals in the study use an electronic records system that allows identification and tracking of elective deliveries.

To overcome strong initial opposition to the program, the program managers conducted extensive education of the staff at each hospital. Physicians who wanted to schedule an early-term elective delivery were required to obtain permission from their hospital's ob.gyn. department chair or the attending perinatologist so that nursing staff would not have to be the ones enforcing the new policy. A new brochure helped explain the policy on early-term elective deliveries to patients.

Clinical program leaders monitor performance systemwide, at each facility, and for each practitioner, and regularly discuss the results with each hospital and sometimes with individual physicians. Hospital administrators were motivated to help the program succeed because part of their compensation depended on meeting the goal of decreasing early-term elective deliveries.

“They've done a really nice job showing that if you do bring attention to it, you can improve your rates” of elective delivery at appropriate gestational ages, Dr. Catherine Spong of the National Institute of Child Health and Human Development commented in an interview.

Requiring physicians to get permission for early elective deliveries “would make it more difficult for someone to just go ahead and deliver early,” she added.

The proportion of U.S. deliveries of live infants that occur between 37 and 38 weeks' gestation has increased to nearly 18% in the past decade. Separate data have shown that approximately one-third of elective repeat cesarean deliveries are performed before 39 weeks. The rate of late preterm deliveries (between 34 and 37 weeks' gestation) and the indications for those deliveries also have changed, Dr. Spong said. All of these “probably should be more closely evaluated.”

The majority of obstetric providers in the Intermountain Healthcare system are community physicians, most of whom could choose to do deliveries at nearby competing hospitals. “Thus we feel that this program could work in other hospitals and in other areas of the country,” the investigators concluded.

The authors and Dr. Spong reported no conflicts of interest related to this study.

Many physicians think it's no big deal to schedule elective deliveries before 39 weeks' gestation—contrary to guidelines—but their minds and practices can be changed with concerted effort, according to a study at nine hospitals.

In a 5-year program, reeducation of physicians and nurses on the hazards of early-term elective delivery, combined with policing of their practices, reduced the rate of early elective deliveries from 28% of all elective deliveries in 1999–2000 to less than 10% within 6 months of program initiation. After 6 years with the program in place, the near-term elective delivery rate remained less than 3%, Dr. Bryan T. Oshiro and his associates reported (Obstet. Gynecol. 2009;113:804–11).

Those improvements did not come easily. It wasn't enough to remind physicians of American College of Obstetricians and Gynecologists guidelines recommending that elective deliveries not be performed before 39 weeks' gestation. Nor were their minds changed by national data showing greater perinatal morbidity in infants delivered before 39 weeks, including 8- to 23-fold higher incidences of severe respiratory distress syndrome with deliveries at 38 or 37 weeks, respectively.

The medical staff argued that their local patients were healthier than those reported in the literature. The physicians wanted to maintain autonomy in managing the timing of delivery. Nursing staff did not want to be responsible for enforcing a policy against early elective deliveries, which would put them in adversarial relationships with the doctors. “It was not until internal or local neonatal morbidity data were presented that significant initial buy-in by the medical staff was seen,” reported Dr. Oshiro of Loma Linda (Calif.) University.

The team who developed and administered the program within the Intermountain Healthcare network of hospitals in Utah and Southeast Idaho collected and presented data showing that their rate of neonatal ICU admissions for normal pregnancies increased from 3.3% for deliveries at 39 weeks to 4.5% for elective deliveries at 38 weeks and 8.9% for deliveries at 37 weeks. The rate of ventilator use for deliveries without complications increased from 0.3% for deliveries at 39 weeks to 0.5% for deliveries at 38 weeks and 1.4% for deliveries at 37 weeks. The in-hospital data were key to obtaining staff buy-in.

Concerns that delaying elective deliveries might increase morbidity were allayed by follow-up data showing significant declines in the rates of postpartum anemia, meconium aspiration, Apgar scores less than 5 at 1 minute, and cesarean deliveries due to fetal distress in infants delivered at 39–41 weeks' gestation in the period after the program was started, compared with the pre-program era. The rate of preeclampsia increased slightly, the study found.

Intermountain Healthcare is a vertically integrated health care system with 21 hospitals. The nine hospitals in the study use an electronic records system that allows identification and tracking of elective deliveries.

To overcome strong initial opposition to the program, the program managers conducted extensive education of the staff at each hospital. Physicians who wanted to schedule an early-term elective delivery were required to obtain permission from their hospital's ob.gyn. department chair or the attending perinatologist so that nursing staff would not have to be the ones enforcing the new policy. A new brochure helped explain the policy on early-term elective deliveries to patients.

Clinical program leaders monitor performance systemwide, at each facility, and for each practitioner, and regularly discuss the results with each hospital and sometimes with individual physicians. Hospital administrators were motivated to help the program succeed because part of their compensation depended on meeting the goal of decreasing early-term elective deliveries.

“They've done a really nice job showing that if you do bring attention to it, you can improve your rates” of elective delivery at appropriate gestational ages, Dr. Catherine Spong of the National Institute of Child Health and Human Development commented in an interview.

Requiring physicians to get permission for early elective deliveries “would make it more difficult for someone to just go ahead and deliver early,” she added.

The proportion of U.S. deliveries of live infants that occur between 37 and 38 weeks' gestation has increased to nearly 18% in the past decade. Separate data have shown that approximately one-third of elective repeat cesarean deliveries are performed before 39 weeks. The rate of late preterm deliveries (between 34 and 37 weeks' gestation) and the indications for those deliveries also have changed, Dr. Spong said. All of these “probably should be more closely evaluated.”

The majority of obstetric providers in the Intermountain Healthcare system are community physicians, most of whom could choose to do deliveries at nearby competing hospitals. “Thus we feel that this program could work in other hospitals and in other areas of the country,” the investigators concluded.

The authors and Dr. Spong reported no conflicts of interest related to this study.

Many physicians think it's no big deal to schedule elective deliveries before 39 weeks' gestation—contrary to guidelines—but their minds and practices can be changed with concerted effort, according to a study at nine hospitals.

In a 5-year program, reeducation of physicians and nurses on the hazards of early-term elective delivery, combined with policing of their practices, reduced the rate of early elective deliveries from 28% of all elective deliveries in 1999–2000 to less than 10% within 6 months of program initiation. After 6 years with the program in place, the near-term elective delivery rate remained less than 3%, Dr. Bryan T. Oshiro and his associates reported (Obstet. Gynecol. 2009;113:804–11).

Those improvements did not come easily. It wasn't enough to remind physicians of American College of Obstetricians and Gynecologists guidelines recommending that elective deliveries not be performed before 39 weeks' gestation. Nor were their minds changed by national data showing greater perinatal morbidity in infants delivered before 39 weeks, including 8- to 23-fold higher incidences of severe respiratory distress syndrome with deliveries at 38 or 37 weeks, respectively.

The medical staff argued that their local patients were healthier than those reported in the literature. The physicians wanted to maintain autonomy in managing the timing of delivery. Nursing staff did not want to be responsible for enforcing a policy against early elective deliveries, which would put them in adversarial relationships with the doctors. “It was not until internal or local neonatal morbidity data were presented that significant initial buy-in by the medical staff was seen,” reported Dr. Oshiro of Loma Linda (Calif.) University.

The team who developed and administered the program within the Intermountain Healthcare network of hospitals in Utah and Southeast Idaho collected and presented data showing that their rate of neonatal ICU admissions for normal pregnancies increased from 3.3% for deliveries at 39 weeks to 4.5% for elective deliveries at 38 weeks and 8.9% for deliveries at 37 weeks. The rate of ventilator use for deliveries without complications increased from 0.3% for deliveries at 39 weeks to 0.5% for deliveries at 38 weeks and 1.4% for deliveries at 37 weeks. The in-hospital data were key to obtaining staff buy-in.

Concerns that delaying elective deliveries might increase morbidity were allayed by follow-up data showing significant declines in the rates of postpartum anemia, meconium aspiration, Apgar scores less than 5 at 1 minute, and cesarean deliveries due to fetal distress in infants delivered at 39–41 weeks' gestation in the period after the program was started, compared with the pre-program era. The rate of preeclampsia increased slightly, the study found.

Intermountain Healthcare is a vertically integrated health care system with 21 hospitals. The nine hospitals in the study use an electronic records system that allows identification and tracking of elective deliveries.

To overcome strong initial opposition to the program, the program managers conducted extensive education of the staff at each hospital. Physicians who wanted to schedule an early-term elective delivery were required to obtain permission from their hospital's ob.gyn. department chair or the attending perinatologist so that nursing staff would not have to be the ones enforcing the new policy. A new brochure helped explain the policy on early-term elective deliveries to patients.

Clinical program leaders monitor performance systemwide, at each facility, and for each practitioner, and regularly discuss the results with each hospital and sometimes with individual physicians. Hospital administrators were motivated to help the program succeed because part of their compensation depended on meeting the goal of decreasing early-term elective deliveries.

“They've done a really nice job showing that if you do bring attention to it, you can improve your rates” of elective delivery at appropriate gestational ages, Dr. Catherine Spong of the National Institute of Child Health and Human Development commented in an interview.

Requiring physicians to get permission for early elective deliveries “would make it more difficult for someone to just go ahead and deliver early,” she added.

The proportion of U.S. deliveries of live infants that occur between 37 and 38 weeks' gestation has increased to nearly 18% in the past decade. Separate data have shown that approximately one-third of elective repeat cesarean deliveries are performed before 39 weeks. The rate of late preterm deliveries (between 34 and 37 weeks' gestation) and the indications for those deliveries also have changed, Dr. Spong said. All of these “probably should be more closely evaluated.”

The majority of obstetric providers in the Intermountain Healthcare system are community physicians, most of whom could choose to do deliveries at nearby competing hospitals. “Thus we feel that this program could work in other hospitals and in other areas of the country,” the investigators concluded.

The authors and Dr. Spong reported no conflicts of interest related to this study.

Transferring one embryo at a time instead of two significantly improved the live-birth rate from assisted reproduction procedures and reduced costs, according to a report.

The success of elective single embryo transfer (eSET) in the study contrasts with findings from some earlier studies that reported lower birth rates using eSET. The difference can be explained in part by the eSET protocol at the Finnish clinic, which used frozen-thawed embryos if needed after the initial fresh embryo transfer, Dr. Zdravka Veleva of the University of Oulu (Finland) and associates reported.

Between 1995 and 2004, 1,510 women under age 40 underwent in vitro fertilization and/or intra-cytoplasmic sperm injection at Oulu University Hospital. Investigators compared clinical outcomes in two periods—1995–1999, when double embryo transfer (DET) was the norm and only 4% of women had eSET, and 2000–2004, when 46% of 684 women underwent eSET.

The findings—all of which were statistically significant between periods—included:

▸ The cumulative pregnancy rate per egg retrieval increased from 33% in the DET period to 38% in the eSET period.

▸ The cumulative term live birth rate per egg retrieval increased from 23% in the DET period to 28% in the eSET period.

▸ The cumulative term live birth rate per woman increased from 37% in the DET period to 42% in the eSET period.

▸ At the same time, the cumulative multiple birth rate declined from 20% in the DET period to 9% in the eSET period.

A higher proportion (49%) of deliveries in the eSET period occurred after frozen-thawed embryo transfer, compared with the DET period (35%), emphasizing the value of cryopreservation of embryos, “which until now has been underestimated in most countries,” they said.

In the current study, fresh embryos were transferred 2 or 3 days after oocyte collection, but previous data suggest that similar results could be expected if the embryos are transferred up to 5 days after oocyte collection, the researchers said.

Earlier studies included highly selected patient populations, while the current study included all consecutive patients at the clinic in the study period, providing more of a real-life setting that adds validity to the results (Hum. Reprod. doi:10.1093/humrep/).

Using eSET decreased the total treatment cost per woman by 5% compared with the DET period, according to an economic analysis in the current study. A term live birth in the eSET period cost 19,889 less than in the DET period. Dr. Veleva and associates suggested that infertility clinics focus their protocols for women under age 40 on single instead of double (or greater) embryo transfers. Insurers should consider not just the direct costs of treatment but also the costs associated with multiple births. Limiting the number of embryo transfer cycles eligible for reimbursement may result in greater use of multiple-embryo transfers, higher rates of multiple births, and higher total costs. The financial savings from switching to eSET instead of DET potentially could fund many more treatment cycles, they suggested.

The study was funded by the University of Oulu and the Sigrij Jusélius Foundation.

Transferring one embryo at a time instead of two significantly improved the live-birth rate from assisted reproduction procedures and reduced costs, according to a report.

The success of elective single embryo transfer (eSET) in the study contrasts with findings from some earlier studies that reported lower birth rates using eSET. The difference can be explained in part by the eSET protocol at the Finnish clinic, which used frozen-thawed embryos if needed after the initial fresh embryo transfer, Dr. Zdravka Veleva of the University of Oulu (Finland) and associates reported.

Between 1995 and 2004, 1,510 women under age 40 underwent in vitro fertilization and/or intra-cytoplasmic sperm injection at Oulu University Hospital. Investigators compared clinical outcomes in two periods—1995–1999, when double embryo transfer (DET) was the norm and only 4% of women had eSET, and 2000–2004, when 46% of 684 women underwent eSET.

The findings—all of which were statistically significant between periods—included:

▸ The cumulative pregnancy rate per egg retrieval increased from 33% in the DET period to 38% in the eSET period.

▸ The cumulative term live birth rate per egg retrieval increased from 23% in the DET period to 28% in the eSET period.

▸ The cumulative term live birth rate per woman increased from 37% in the DET period to 42% in the eSET period.

▸ At the same time, the cumulative multiple birth rate declined from 20% in the DET period to 9% in the eSET period.

A higher proportion (49%) of deliveries in the eSET period occurred after frozen-thawed embryo transfer, compared with the DET period (35%), emphasizing the value of cryopreservation of embryos, “which until now has been underestimated in most countries,” they said.

In the current study, fresh embryos were transferred 2 or 3 days after oocyte collection, but previous data suggest that similar results could be expected if the embryos are transferred up to 5 days after oocyte collection, the researchers said.

Earlier studies included highly selected patient populations, while the current study included all consecutive patients at the clinic in the study period, providing more of a real-life setting that adds validity to the results (Hum. Reprod. doi:10.1093/humrep/).

Using eSET decreased the total treatment cost per woman by 5% compared with the DET period, according to an economic analysis in the current study. A term live birth in the eSET period cost 19,889 less than in the DET period. Dr. Veleva and associates suggested that infertility clinics focus their protocols for women under age 40 on single instead of double (or greater) embryo transfers. Insurers should consider not just the direct costs of treatment but also the costs associated with multiple births. Limiting the number of embryo transfer cycles eligible for reimbursement may result in greater use of multiple-embryo transfers, higher rates of multiple births, and higher total costs. The financial savings from switching to eSET instead of DET potentially could fund many more treatment cycles, they suggested.

The study was funded by the University of Oulu and the Sigrij Jusélius Foundation.

Transferring one embryo at a time instead of two significantly improved the live-birth rate from assisted reproduction procedures and reduced costs, according to a report.

The success of elective single embryo transfer (eSET) in the study contrasts with findings from some earlier studies that reported lower birth rates using eSET. The difference can be explained in part by the eSET protocol at the Finnish clinic, which used frozen-thawed embryos if needed after the initial fresh embryo transfer, Dr. Zdravka Veleva of the University of Oulu (Finland) and associates reported.

Between 1995 and 2004, 1,510 women under age 40 underwent in vitro fertilization and/or intra-cytoplasmic sperm injection at Oulu University Hospital. Investigators compared clinical outcomes in two periods—1995–1999, when double embryo transfer (DET) was the norm and only 4% of women had eSET, and 2000–2004, when 46% of 684 women underwent eSET.

The findings—all of which were statistically significant between periods—included:

▸ The cumulative pregnancy rate per egg retrieval increased from 33% in the DET period to 38% in the eSET period.

▸ The cumulative term live birth rate per egg retrieval increased from 23% in the DET period to 28% in the eSET period.

▸ The cumulative term live birth rate per woman increased from 37% in the DET period to 42% in the eSET period.

▸ At the same time, the cumulative multiple birth rate declined from 20% in the DET period to 9% in the eSET period.

A higher proportion (49%) of deliveries in the eSET period occurred after frozen-thawed embryo transfer, compared with the DET period (35%), emphasizing the value of cryopreservation of embryos, “which until now has been underestimated in most countries,” they said.

In the current study, fresh embryos were transferred 2 or 3 days after oocyte collection, but previous data suggest that similar results could be expected if the embryos are transferred up to 5 days after oocyte collection, the researchers said.

Earlier studies included highly selected patient populations, while the current study included all consecutive patients at the clinic in the study period, providing more of a real-life setting that adds validity to the results (Hum. Reprod. doi:10.1093/humrep/).

Using eSET decreased the total treatment cost per woman by 5% compared with the DET period, according to an economic analysis in the current study. A term live birth in the eSET period cost 19,889 less than in the DET period. Dr. Veleva and associates suggested that infertility clinics focus their protocols for women under age 40 on single instead of double (or greater) embryo transfers. Insurers should consider not just the direct costs of treatment but also the costs associated with multiple births. Limiting the number of embryo transfer cycles eligible for reimbursement may result in greater use of multiple-embryo transfers, higher rates of multiple births, and higher total costs. The financial savings from switching to eSET instead of DET potentially could fund many more treatment cycles, they suggested.

The study was funded by the University of Oulu and the Sigrij Jusélius Foundation.

More than half of adults with heart disease also had arthritis, and they were 30% more likely to be physically inactive than were those with heart disease alone, judging from the findings of a survey of 757,959 Americans.

The Centers for Disease Control and Prevention analyzed data from all 50 states in the 2005 and 2007 Behavioral Risk Factor Surveillance System. In telephone interviews, 3% of respondents said they had been diagnosed with heart disease alone, 23% reported a diagnosis of arthritis alone, 4% said they had both, and 70% had neither.

Arthritis—defined as arthritis, rheumatoid arthritis, gout, lupus, or fibromyalgia—was present in 57% of the respondents with heart disease, compared with 27% of the total population (MMWR 2009;58:165-9).

In an interview, rheumatologist John A. Goldman, who was not involved with this study, said that getting patients with joint pain to increase activity is a priority for his colleagues who treat arthritis. “The CDC's recent slogan is 'Exercise, the Arthritis Pain Reliever.' Exercise is necessary. Working with physical therapists—especially trainers—on weight reduction; nonimpact, loading exercises; [and] bracing” can all help, said Dr. Goldman, who has a private rheumatology practice in Atlanta.

The investigators asked six questions about the frequency and duration of nonoccupational activities of moderate and vigorous activity; respondents who reported no participation in such activities were considered to be inactive.

People with heart disease and arthritis had the highest rate of inactivity (29%) compared with rates of 21% in people with heart disease alone, 18% in people with arthritis alone, and 11% in those who had neither heart disease nor arthritis, according to the MMWR report.

After adjustment for the effects of age, sex, education level, body mass index, and race or ethnicity, inactivity was 30% more likely in those with heart disease and arthritis, compared with people who had heart disease alone.

The risk of having one or both conditions increased with age. Men had a higher prevalence of heart disease alone (4%) or heart disease plus arthritis (4%) compared with women (2% and 3.5%, respectively). Women were more likely to have arthritis alone (27%) compared with men (19%). Whites were more likely than blacks to have one or both conditions. Each of these comparisons between subgroups was statistically significant.

According to Dr. Goldman, treating arthritis patients who are at risk for heart disease requires coordination with the patient's cardiologist and/or primary care physician. The use of anti-inflammatory disease-modifying antirheumatic drugs and also biologic therapies like methotrexate and tumor necrosis factor-alpha inhibitors decrease the risk of vascular disease, as do traditional cardiovascular drugs like statins, he said. Thus, treatment of both the RA and other inflammatory diseases, and also treatment for lipids, blood pressure, and diabetes mellitus need to be done in concert, he noted.

Associate Editor Denise Napoli contributed to this article.

ELSEVIER GLOBAL MEDICAL NEWS

More than half of adults with heart disease also had arthritis, and they were 30% more likely to be physically inactive than were those with heart disease alone, judging from the findings of a survey of 757,959 Americans.

The Centers for Disease Control and Prevention analyzed data from all 50 states in the 2005 and 2007 Behavioral Risk Factor Surveillance System. In telephone interviews, 3% of respondents said they had been diagnosed with heart disease alone, 23% reported a diagnosis of arthritis alone, 4% said they had both, and 70% had neither.

Arthritis—defined as arthritis, rheumatoid arthritis, gout, lupus, or fibromyalgia—was present in 57% of the respondents with heart disease, compared with 27% of the total population (MMWR 2009;58:165-9).

In an interview, rheumatologist John A. Goldman, who was not involved with this study, said that getting patients with joint pain to increase activity is a priority for his colleagues who treat arthritis. “The CDC's recent slogan is 'Exercise, the Arthritis Pain Reliever.' Exercise is necessary. Working with physical therapists—especially trainers—on weight reduction; nonimpact, loading exercises; [and] bracing” can all help, said Dr. Goldman, who has a private rheumatology practice in Atlanta.

The investigators asked six questions about the frequency and duration of nonoccupational activities of moderate and vigorous activity; respondents who reported no participation in such activities were considered to be inactive.

People with heart disease and arthritis had the highest rate of inactivity (29%) compared with rates of 21% in people with heart disease alone, 18% in people with arthritis alone, and 11% in those who had neither heart disease nor arthritis, according to the MMWR report.

After adjustment for the effects of age, sex, education level, body mass index, and race or ethnicity, inactivity was 30% more likely in those with heart disease and arthritis, compared with people who had heart disease alone.

The risk of having one or both conditions increased with age. Men had a higher prevalence of heart disease alone (4%) or heart disease plus arthritis (4%) compared with women (2% and 3.5%, respectively). Women were more likely to have arthritis alone (27%) compared with men (19%). Whites were more likely than blacks to have one or both conditions. Each of these comparisons between subgroups was statistically significant.

According to Dr. Goldman, treating arthritis patients who are at risk for heart disease requires coordination with the patient's cardiologist and/or primary care physician. The use of anti-inflammatory disease-modifying antirheumatic drugs and also biologic therapies like methotrexate and tumor necrosis factor-alpha inhibitors decrease the risk of vascular disease, as do traditional cardiovascular drugs like statins, he said. Thus, treatment of both the RA and other inflammatory diseases, and also treatment for lipids, blood pressure, and diabetes mellitus need to be done in concert, he noted.

Associate Editor Denise Napoli contributed to this article.

ELSEVIER GLOBAL MEDICAL NEWS

More than half of adults with heart disease also had arthritis, and they were 30% more likely to be physically inactive than were those with heart disease alone, judging from the findings of a survey of 757,959 Americans.

The Centers for Disease Control and Prevention analyzed data from all 50 states in the 2005 and 2007 Behavioral Risk Factor Surveillance System. In telephone interviews, 3% of respondents said they had been diagnosed with heart disease alone, 23% reported a diagnosis of arthritis alone, 4% said they had both, and 70% had neither.

Arthritis—defined as arthritis, rheumatoid arthritis, gout, lupus, or fibromyalgia—was present in 57% of the respondents with heart disease, compared with 27% of the total population (MMWR 2009;58:165-9).

In an interview, rheumatologist John A. Goldman, who was not involved with this study, said that getting patients with joint pain to increase activity is a priority for his colleagues who treat arthritis. “The CDC's recent slogan is 'Exercise, the Arthritis Pain Reliever.' Exercise is necessary. Working with physical therapists—especially trainers—on weight reduction; nonimpact, loading exercises; [and] bracing” can all help, said Dr. Goldman, who has a private rheumatology practice in Atlanta.

The investigators asked six questions about the frequency and duration of nonoccupational activities of moderate and vigorous activity; respondents who reported no participation in such activities were considered to be inactive.

People with heart disease and arthritis had the highest rate of inactivity (29%) compared with rates of 21% in people with heart disease alone, 18% in people with arthritis alone, and 11% in those who had neither heart disease nor arthritis, according to the MMWR report.

After adjustment for the effects of age, sex, education level, body mass index, and race or ethnicity, inactivity was 30% more likely in those with heart disease and arthritis, compared with people who had heart disease alone.

The risk of having one or both conditions increased with age. Men had a higher prevalence of heart disease alone (4%) or heart disease plus arthritis (4%) compared with women (2% and 3.5%, respectively). Women were more likely to have arthritis alone (27%) compared with men (19%). Whites were more likely than blacks to have one or both conditions. Each of these comparisons between subgroups was statistically significant.

According to Dr. Goldman, treating arthritis patients who are at risk for heart disease requires coordination with the patient's cardiologist and/or primary care physician. The use of anti-inflammatory disease-modifying antirheumatic drugs and also biologic therapies like methotrexate and tumor necrosis factor-alpha inhibitors decrease the risk of vascular disease, as do traditional cardiovascular drugs like statins, he said. Thus, treatment of both the RA and other inflammatory diseases, and also treatment for lipids, blood pressure, and diabetes mellitus need to be done in concert, he noted.

Associate Editor Denise Napoli contributed to this article.

ELSEVIER GLOBAL MEDICAL NEWS