Umang Sharma, MD

ILLUSTRATIVE CASES

• A 60-year-old man has struggled to get his BP under control despite the use of 3 anti-hypertensives. Is there anything you can recommend to improve his BP control and lower his cardiovascular risk?
• You prescribe hydrochlorothiazide for a 55-year-old woman with newly diagnosed hypertension. What can you tell her about how to take the medication to maximize its beneficial effects?

Management of hypertension often centers around BP measurements taken in a doctor’s office during the day, although both BP and metabolism fluctuate with circadian rhythms. Most people experience an increase in pressure during the day, with peaks in the morning and evening, followed by a decline in BP while they sleep at night.³

The focus belongs on nighttime BP
Sleeping BP is getting considerable attention, particularly the phenomenon of nondipping. Commonly defined as a <10% decline in systolic pressure during sleep, nondipping is associated with an increased risk of cardiovascular events, such as heart attack and stroke.⁴ What’s more, mean BP during the night is a better predictor of cardiovascular disease (CVD) risk than BP while the patient is awake.^5,6

Evidence suggests that taking an anti-hypertensive medication at night increases its therapeutic effect,⁷ yet most patients take it in the morning.⁸ The study detailed in this PURL was designed to investigate whether bedtime dosing significantly affects BP control and CVD risk.

STUDY SUMMARY: Bedtime dosing benefits patients, and there’s no downside

The MAPEC study was an open-label RCT conducted at a single center in Spain.¹ Patients were enrolled if they had a diagnosis of either untreated hypertension (based on ambulatory BP monitoring [ABPM] criteria) or resistant hypertension (uncontrolled on ≥3 optimally dosed antihypertensive medications). Exclusion criteria included pregnancy, a history of drug/alcohol abuse, night shift work, acquired immune deficiency syndrome, type 1 diabetes, secondary hypertension, and a previous CVD diagnosis.

Patients were randomly assigned to one of 2 time-of-day dosing groups: morning dosing of all their BP medications (n=1109) or dosing of ≥1 BP medications at bedtime (n=1092). ABPM—in which patients wore a monitor that recorded their BP every 20 minutes during the day and every 30 minutes at night for 48 hours—was conducted once a year, or more frequently when medication adjustments occurred. The use of a specific drug was not required, but physicians were instructed to adjust medications according to a study-specific ABPM protocol.

Patients were followed for a mean of 5.6 years for the endpoints of CVD events and mortality. These endpoints were assessed by researchers blinded to patients’ treatment assignment.

At baseline, the 2 groups were similar in age (mean of 55 years), percentage of men (48%), presence of comorbidities, and baseline clinic and ambulatory BP. Throughout the study, patients in the bedtime dosing group had lower mean asleep systolic and diastolic BP, a lower prevalence of a non-dipping pattern, and a higher prevalence of controlled ambulatory BP. The bedtime group also had a lower risk of total CVD events (relative risk [RR]=0.39; 95% confidence interval [CI], 0.29-0.51; P<.001) and major CVD events (RR=0.33; 95% CI, 0.19-0.55; P<.001), and fewer overall deaths (4.16/1000 vs 2.11/1000 patient-years; P=.008) (TABLE). To prevent one CVD event, 63 patients would need to take their BP medication at bedtime instead of in the morning for one year. To prevent one death, 488 patient would need to adhere to the nighttime schedule for one year.

A subgroup analysis of patients with type 2 diabetes (n=448)² had similar results: For this population, too, bedtime dosing led to lower asleep BP, a lower prevalence of a non-dipping pattern, and a higher prevalence of controlled ambulatory BP, as well as a lower risk of total CVD events, major CVD events, and CVD-related death. The differences persisted after correction for the use of statins and aspirin. Among those in this subgroup analysis, 29 patients would need to take their BP medications at bedtime for one year to prevent one CVD event, and 263 patients would need to be treated for one year to prevent one death.

TABLE
Dosing of BP meds: A look at outcomes

WHAT’S NEW: Advantages of preventing nondipping are clearly established

We’ve known that a nondipping pattern is associated with higher cardiovascular risks and that taking antihypertensives at bedtime decreases the prevalence of nondipping patterns. The MAPEC study, however, is the first prospective trial to show that bedtime dosing of BP medications lowers the risk of CVD events and death.

CAVEATS: Methodology, non-US guidelines raise questions about applicability here

MAPEC was an open-label study, meaning that the physicians adjusting BP medications were aware of the treatment groups to which their patients were allocated. Physicians were given guidelines for the titration of medications, but it is unclear whether they treated patients in both treatment groups identically. Patients were also aware of their treatment group, which creates the potential for bias if one group adhered to their medications more closely than the other.

The study was a single-center trial conducted in Spain, which may limit its generalizability to the United States. Notably, Spain’s medication guidelines differ from ours, with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and calcium channel blockers as first-line medications and hydrochlorothiazide as a second-line option.

While ABPM appears to be a better indicator of CVD risk compared with clinic BP monitoring, most US physicians still rely on readings taken in their office for diagnosing and managing hypertension. How ambulatory BP translates to clinic BP is somewhat unclear.

CHALLENGES TO IMPLEMENTATION: Some patients and providers may resist the switch

We see few challenges to implementing bedtime dosing of BP medications for patients with uncontrolled hypertension. It is possible, however, that patients who have a long-standing routine of taking their medications in the morning may be resistant to change. Also, pharmacists and nurses, as well as some physicians, may continue recommending morning dosing, which could be confusing for patients.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASES

• A 60-year-old man has struggled to get his BP under control despite the use of 3 anti-hypertensives. Is there anything you can recommend to improve his BP control and lower his cardiovascular risk?
• You prescribe hydrochlorothiazide for a 55-year-old woman with newly diagnosed hypertension. What can you tell her about how to take the medication to maximize its beneficial effects?

Management of hypertension often centers around BP measurements taken in a doctor’s office during the day, although both BP and metabolism fluctuate with circadian rhythms. Most people experience an increase in pressure during the day, with peaks in the morning and evening, followed by a decline in BP while they sleep at night.³

The focus belongs on nighttime BP
Sleeping BP is getting considerable attention, particularly the phenomenon of nondipping. Commonly defined as a <10% decline in systolic pressure during sleep, nondipping is associated with an increased risk of cardiovascular events, such as heart attack and stroke.⁴ What’s more, mean BP during the night is a better predictor of cardiovascular disease (CVD) risk than BP while the patient is awake.^5,6

Evidence suggests that taking an anti-hypertensive medication at night increases its therapeutic effect,⁷ yet most patients take it in the morning.⁸ The study detailed in this PURL was designed to investigate whether bedtime dosing significantly affects BP control and CVD risk.

STUDY SUMMARY: Bedtime dosing benefits patients, and there’s no downside

The MAPEC study was an open-label RCT conducted at a single center in Spain.¹ Patients were enrolled if they had a diagnosis of either untreated hypertension (based on ambulatory BP monitoring [ABPM] criteria) or resistant hypertension (uncontrolled on ≥3 optimally dosed antihypertensive medications). Exclusion criteria included pregnancy, a history of drug/alcohol abuse, night shift work, acquired immune deficiency syndrome, type 1 diabetes, secondary hypertension, and a previous CVD diagnosis.

Patients were randomly assigned to one of 2 time-of-day dosing groups: morning dosing of all their BP medications (n=1109) or dosing of ≥1 BP medications at bedtime (n=1092). ABPM—in which patients wore a monitor that recorded their BP every 20 minutes during the day and every 30 minutes at night for 48 hours—was conducted once a year, or more frequently when medication adjustments occurred. The use of a specific drug was not required, but physicians were instructed to adjust medications according to a study-specific ABPM protocol.

Patients were followed for a mean of 5.6 years for the endpoints of CVD events and mortality. These endpoints were assessed by researchers blinded to patients’ treatment assignment.

At baseline, the 2 groups were similar in age (mean of 55 years), percentage of men (48%), presence of comorbidities, and baseline clinic and ambulatory BP. Throughout the study, patients in the bedtime dosing group had lower mean asleep systolic and diastolic BP, a lower prevalence of a non-dipping pattern, and a higher prevalence of controlled ambulatory BP. The bedtime group also had a lower risk of total CVD events (relative risk [RR]=0.39; 95% confidence interval [CI], 0.29-0.51; P<.001) and major CVD events (RR=0.33; 95% CI, 0.19-0.55; P<.001), and fewer overall deaths (4.16/1000 vs 2.11/1000 patient-years; P=.008) (TABLE). To prevent one CVD event, 63 patients would need to take their BP medication at bedtime instead of in the morning for one year. To prevent one death, 488 patient would need to adhere to the nighttime schedule for one year.

A subgroup analysis of patients with type 2 diabetes (n=448)² had similar results: For this population, too, bedtime dosing led to lower asleep BP, a lower prevalence of a non-dipping pattern, and a higher prevalence of controlled ambulatory BP, as well as a lower risk of total CVD events, major CVD events, and CVD-related death. The differences persisted after correction for the use of statins and aspirin. Among those in this subgroup analysis, 29 patients would need to take their BP medications at bedtime for one year to prevent one CVD event, and 263 patients would need to be treated for one year to prevent one death.

TABLE
Dosing of BP meds: A look at outcomes

WHAT’S NEW: Advantages of preventing nondipping are clearly established

We’ve known that a nondipping pattern is associated with higher cardiovascular risks and that taking antihypertensives at bedtime decreases the prevalence of nondipping patterns. The MAPEC study, however, is the first prospective trial to show that bedtime dosing of BP medications lowers the risk of CVD events and death.

CAVEATS: Methodology, non-US guidelines raise questions about applicability here

MAPEC was an open-label study, meaning that the physicians adjusting BP medications were aware of the treatment groups to which their patients were allocated. Physicians were given guidelines for the titration of medications, but it is unclear whether they treated patients in both treatment groups identically. Patients were also aware of their treatment group, which creates the potential for bias if one group adhered to their medications more closely than the other.

The study was a single-center trial conducted in Spain, which may limit its generalizability to the United States. Notably, Spain’s medication guidelines differ from ours, with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and calcium channel blockers as first-line medications and hydrochlorothiazide as a second-line option.

While ABPM appears to be a better indicator of CVD risk compared with clinic BP monitoring, most US physicians still rely on readings taken in their office for diagnosing and managing hypertension. How ambulatory BP translates to clinic BP is somewhat unclear.

CHALLENGES TO IMPLEMENTATION: Some patients and providers may resist the switch

We see few challenges to implementing bedtime dosing of BP medications for patients with uncontrolled hypertension. It is possible, however, that patients who have a long-standing routine of taking their medications in the morning may be resistant to change. Also, pharmacists and nurses, as well as some physicians, may continue recommending morning dosing, which could be confusing for patients.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASES

• A 60-year-old man has struggled to get his BP under control despite the use of 3 anti-hypertensives. Is there anything you can recommend to improve his BP control and lower his cardiovascular risk?
• You prescribe hydrochlorothiazide for a 55-year-old woman with newly diagnosed hypertension. What can you tell her about how to take the medication to maximize its beneficial effects?

Management of hypertension often centers around BP measurements taken in a doctor’s office during the day, although both BP and metabolism fluctuate with circadian rhythms. Most people experience an increase in pressure during the day, with peaks in the morning and evening, followed by a decline in BP while they sleep at night.³

The focus belongs on nighttime BP
Sleeping BP is getting considerable attention, particularly the phenomenon of nondipping. Commonly defined as a <10% decline in systolic pressure during sleep, nondipping is associated with an increased risk of cardiovascular events, such as heart attack and stroke.⁴ What’s more, mean BP during the night is a better predictor of cardiovascular disease (CVD) risk than BP while the patient is awake.^5,6

Evidence suggests that taking an anti-hypertensive medication at night increases its therapeutic effect,⁷ yet most patients take it in the morning.⁸ The study detailed in this PURL was designed to investigate whether bedtime dosing significantly affects BP control and CVD risk.

STUDY SUMMARY: Bedtime dosing benefits patients, and there’s no downside

The MAPEC study was an open-label RCT conducted at a single center in Spain.¹ Patients were enrolled if they had a diagnosis of either untreated hypertension (based on ambulatory BP monitoring [ABPM] criteria) or resistant hypertension (uncontrolled on ≥3 optimally dosed antihypertensive medications). Exclusion criteria included pregnancy, a history of drug/alcohol abuse, night shift work, acquired immune deficiency syndrome, type 1 diabetes, secondary hypertension, and a previous CVD diagnosis.

Patients were randomly assigned to one of 2 time-of-day dosing groups: morning dosing of all their BP medications (n=1109) or dosing of ≥1 BP medications at bedtime (n=1092). ABPM—in which patients wore a monitor that recorded their BP every 20 minutes during the day and every 30 minutes at night for 48 hours—was conducted once a year, or more frequently when medication adjustments occurred. The use of a specific drug was not required, but physicians were instructed to adjust medications according to a study-specific ABPM protocol.

Patients were followed for a mean of 5.6 years for the endpoints of CVD events and mortality. These endpoints were assessed by researchers blinded to patients’ treatment assignment.

At baseline, the 2 groups were similar in age (mean of 55 years), percentage of men (48%), presence of comorbidities, and baseline clinic and ambulatory BP. Throughout the study, patients in the bedtime dosing group had lower mean asleep systolic and diastolic BP, a lower prevalence of a non-dipping pattern, and a higher prevalence of controlled ambulatory BP. The bedtime group also had a lower risk of total CVD events (relative risk [RR]=0.39; 95% confidence interval [CI], 0.29-0.51; P<.001) and major CVD events (RR=0.33; 95% CI, 0.19-0.55; P<.001), and fewer overall deaths (4.16/1000 vs 2.11/1000 patient-years; P=.008) (TABLE). To prevent one CVD event, 63 patients would need to take their BP medication at bedtime instead of in the morning for one year. To prevent one death, 488 patient would need to adhere to the nighttime schedule for one year.

A subgroup analysis of patients with type 2 diabetes (n=448)² had similar results: For this population, too, bedtime dosing led to lower asleep BP, a lower prevalence of a non-dipping pattern, and a higher prevalence of controlled ambulatory BP, as well as a lower risk of total CVD events, major CVD events, and CVD-related death. The differences persisted after correction for the use of statins and aspirin. Among those in this subgroup analysis, 29 patients would need to take their BP medications at bedtime for one year to prevent one CVD event, and 263 patients would need to be treated for one year to prevent one death.

TABLE
Dosing of BP meds: A look at outcomes

WHAT’S NEW: Advantages of preventing nondipping are clearly established

We’ve known that a nondipping pattern is associated with higher cardiovascular risks and that taking antihypertensives at bedtime decreases the prevalence of nondipping patterns. The MAPEC study, however, is the first prospective trial to show that bedtime dosing of BP medications lowers the risk of CVD events and death.

CAVEATS: Methodology, non-US guidelines raise questions about applicability here

MAPEC was an open-label study, meaning that the physicians adjusting BP medications were aware of the treatment groups to which their patients were allocated. Physicians were given guidelines for the titration of medications, but it is unclear whether they treated patients in both treatment groups identically. Patients were also aware of their treatment group, which creates the potential for bias if one group adhered to their medications more closely than the other.

The study was a single-center trial conducted in Spain, which may limit its generalizability to the United States. Notably, Spain’s medication guidelines differ from ours, with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and calcium channel blockers as first-line medications and hydrochlorothiazide as a second-line option.

While ABPM appears to be a better indicator of CVD risk compared with clinic BP monitoring, most US physicians still rely on readings taken in their office for diagnosing and managing hypertension. How ambulatory BP translates to clinic BP is somewhat unclear.

CHALLENGES TO IMPLEMENTATION: Some patients and providers may resist the switch

We see few challenges to implementing bedtime dosing of BP medications for patients with uncontrolled hypertension. It is possible, however, that patients who have a long-standing routine of taking their medications in the morning may be resistant to change. Also, pharmacists and nurses, as well as some physicians, may continue recommending morning dosing, which could be confusing for patients.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

CASE: Ms. K, a 68-year-old woman diagnosed with osteoporosis on a screening DXA scan a year ago, has been taking a bisphosphonate ever since. She’s anxious to know whether the medication is working and asks if it’s time for a repeat DXA scan. What should you tell her?

Fragility fractures from osteoporosis are common in postmenopausal women. In the year 2000 alone, an estimated 9 million such fractures occurred worldwide.² Treatment with bisphosphonates has been found to reduce the risk of fragility fractures,³ and the United States Preventive Services Task Force (USPSTF) recommends a DXA scan to screen for osteoporosis in women older than 65 years and some younger women at increased risk.⁴

Monitoring treatment: How often?

Although recommendations for how often to monitor bone mineral density (BMD) after initiating treatment vary, the consensus has been that periodic monitoring is useful. But there have been no randomized trials evaluating BMD testing in patients taking bisphosphonates.

The use of DXA scans to identify osteoporosis has been shown to be a cost-effective strategy in women older than 65 years,⁵ but there has not been a cost/benefit analysis of follow-up DXA scanning after initiating treatment. The cost of a scan ranges from about $150 to $300, and it is not known how many patients undergo repeat DXA scanning after starting treatment.

STUDY SUMMARY: Yearly scans are not helpful

The study we report on here is a secondary analysis of data from the Fracture Intervention Trial (FIT).⁶ In 1993, FIT randomized 6457 US women ages 55 to 80 years with low hip bone density to either alendronate or placebo. The initial dose of alendronate was 5 mg/d, but was later increased to 10 mg/d when other studies found that the higher dose was more effective. FIT showed that alendronate increased BMD and decreased the risk of vertebral fracture.⁷

Bell et al¹ used a mixed-model statistical analysis to compare “within-person variation” in BMD (variation in DXA results over time in individuals) and “between-person variation” in BMD (variation in DXA results over time in the population of patients). The BMD of all FIT participants in both the control and treatment groups was measured at baseline and at the 1-, 2-, and 3-year marks. Each individual was always tested on the same scanner to minimize differences in machinery.

Individual results vary from year to year. The researchers found that the within-person variation was about 10 times greater than the between-person variation. This finding suggests that the precision of DXA scan measurements is not that reliable from 1 test to another.

The average annual increase in BMD in patients in the alendronate group was 0.0085 g/cm²—which is smaller than the typical year-to-year (within-person) variation of 0.013 g/cm². It would therefore be difficult to differentiate the medication’s effect from the random variation inherent in DXA scans.

Response is favorable after 3 years of treatment. While there is variation in test results from year to year, longer-term findings are more reliable. After 3 years of treatment, 97.5% of patients taking alendronate had an increase in hip BMD of at least 0.019 g/cm², with a strong correlation between hip and spine measurements. Although this represents a relatively small change in Z and T scores, this increase in hip BMD is considered a favorable response that warrants continued treatment. These findings are consistent with a previous analysis of BMD monitoring in women taking bisphosphonates, in which those who had the largest drop in BMD after the first year of treatment typically had a large gain over the second year.⁸

WHAT’S NEW: Now we know early testing is unnecessary

Not many studies are available to provide guidance about the interval between BMD measurements after starting a bisphosphonate. This study advises us that it is not necessary to recheck BMD for at least 3 years after starting treatment. Elimination of early repeat DXA testing could result in significant cost savings.

CAVEATS: Findings contradict usual recommendations

Physicians should be aware that the conclusion of this study is not in line with recommendations from a number of prominent organizations. The American Association of Clinical Endocrinology,⁹ the National Osteoporosis Foundation,¹⁰ and the North American Menopause Society¹¹ all recommend follow-up DXA testing in 1 or 2 years.

High-risk patient exception. The delay in repeat DXA testing may not be appropriate for patients at higher risk of bone density loss. However, a separate analysis of higher-risk groups was not done.

Finally, while the findings of Bell et al suggest that we should wait at least 3 years before retesting, it is still not clear whether there is any benefit to repeat DXA testing at any interval, given the nearly universal response rate. It is also possible that advances in DXA technology will reduce some of the variation in BMD results.

CHALLENGES TO IMPLEMENTATION: Anxious patients

Patients like Ms. K may ask their physicians to retest well before 3 years. Yet those who undergo scanning after a shorter interval may be discouraged by early results. Advising patients that the treatment is almost uniformly effective in increasing BMD should reassure them that sticking with treatment is worthwhile.

Acknowledgment

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

CASE: Ms. K, a 68-year-old woman diagnosed with osteoporosis on a screening DXA scan a year ago, has been taking a bisphosphonate ever since. She’s anxious to know whether the medication is working and asks if it’s time for a repeat DXA scan. What should you tell her?

Fragility fractures from osteoporosis are common in postmenopausal women. In the year 2000 alone, an estimated 9 million such fractures occurred worldwide.² Treatment with bisphosphonates has been found to reduce the risk of fragility fractures,³ and the United States Preventive Services Task Force (USPSTF) recommends a DXA scan to screen for osteoporosis in women older than 65 years and some younger women at increased risk.⁴

Monitoring treatment: How often?

Although recommendations for how often to monitor bone mineral density (BMD) after initiating treatment vary, the consensus has been that periodic monitoring is useful. But there have been no randomized trials evaluating BMD testing in patients taking bisphosphonates.

The use of DXA scans to identify osteoporosis has been shown to be a cost-effective strategy in women older than 65 years,⁵ but there has not been a cost/benefit analysis of follow-up DXA scanning after initiating treatment. The cost of a scan ranges from about $150 to $300, and it is not known how many patients undergo repeat DXA scanning after starting treatment.

STUDY SUMMARY: Yearly scans are not helpful

The study we report on here is a secondary analysis of data from the Fracture Intervention Trial (FIT).⁶ In 1993, FIT randomized 6457 US women ages 55 to 80 years with low hip bone density to either alendronate or placebo. The initial dose of alendronate was 5 mg/d, but was later increased to 10 mg/d when other studies found that the higher dose was more effective. FIT showed that alendronate increased BMD and decreased the risk of vertebral fracture.⁷

Bell et al¹ used a mixed-model statistical analysis to compare “within-person variation” in BMD (variation in DXA results over time in individuals) and “between-person variation” in BMD (variation in DXA results over time in the population of patients). The BMD of all FIT participants in both the control and treatment groups was measured at baseline and at the 1-, 2-, and 3-year marks. Each individual was always tested on the same scanner to minimize differences in machinery.

Individual results vary from year to year. The researchers found that the within-person variation was about 10 times greater than the between-person variation. This finding suggests that the precision of DXA scan measurements is not that reliable from 1 test to another.

The average annual increase in BMD in patients in the alendronate group was 0.0085 g/cm²—which is smaller than the typical year-to-year (within-person) variation of 0.013 g/cm². It would therefore be difficult to differentiate the medication’s effect from the random variation inherent in DXA scans.

Response is favorable after 3 years of treatment. While there is variation in test results from year to year, longer-term findings are more reliable. After 3 years of treatment, 97.5% of patients taking alendronate had an increase in hip BMD of at least 0.019 g/cm², with a strong correlation between hip and spine measurements. Although this represents a relatively small change in Z and T scores, this increase in hip BMD is considered a favorable response that warrants continued treatment. These findings are consistent with a previous analysis of BMD monitoring in women taking bisphosphonates, in which those who had the largest drop in BMD after the first year of treatment typically had a large gain over the second year.⁸

WHAT’S NEW: Now we know early testing is unnecessary

Not many studies are available to provide guidance about the interval between BMD measurements after starting a bisphosphonate. This study advises us that it is not necessary to recheck BMD for at least 3 years after starting treatment. Elimination of early repeat DXA testing could result in significant cost savings.

CAVEATS: Findings contradict usual recommendations

Physicians should be aware that the conclusion of this study is not in line with recommendations from a number of prominent organizations. The American Association of Clinical Endocrinology,⁹ the National Osteoporosis Foundation,¹⁰ and the North American Menopause Society¹¹ all recommend follow-up DXA testing in 1 or 2 years.

High-risk patient exception. The delay in repeat DXA testing may not be appropriate for patients at higher risk of bone density loss. However, a separate analysis of higher-risk groups was not done.

Finally, while the findings of Bell et al suggest that we should wait at least 3 years before retesting, it is still not clear whether there is any benefit to repeat DXA testing at any interval, given the nearly universal response rate. It is also possible that advances in DXA technology will reduce some of the variation in BMD results.

CHALLENGES TO IMPLEMENTATION: Anxious patients

Patients like Ms. K may ask their physicians to retest well before 3 years. Yet those who undergo scanning after a shorter interval may be discouraged by early results. Advising patients that the treatment is almost uniformly effective in increasing BMD should reassure them that sticking with treatment is worthwhile.

Acknowledgment

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

CASE: Ms. K, a 68-year-old woman diagnosed with osteoporosis on a screening DXA scan a year ago, has been taking a bisphosphonate ever since. She’s anxious to know whether the medication is working and asks if it’s time for a repeat DXA scan. What should you tell her?

Fragility fractures from osteoporosis are common in postmenopausal women. In the year 2000 alone, an estimated 9 million such fractures occurred worldwide.² Treatment with bisphosphonates has been found to reduce the risk of fragility fractures,³ and the United States Preventive Services Task Force (USPSTF) recommends a DXA scan to screen for osteoporosis in women older than 65 years and some younger women at increased risk.⁴

Monitoring treatment: How often?

Although recommendations for how often to monitor bone mineral density (BMD) after initiating treatment vary, the consensus has been that periodic monitoring is useful. But there have been no randomized trials evaluating BMD testing in patients taking bisphosphonates.

The use of DXA scans to identify osteoporosis has been shown to be a cost-effective strategy in women older than 65 years,⁵ but there has not been a cost/benefit analysis of follow-up DXA scanning after initiating treatment. The cost of a scan ranges from about $150 to $300, and it is not known how many patients undergo repeat DXA scanning after starting treatment.

STUDY SUMMARY: Yearly scans are not helpful

The study we report on here is a secondary analysis of data from the Fracture Intervention Trial (FIT).⁶ In 1993, FIT randomized 6457 US women ages 55 to 80 years with low hip bone density to either alendronate or placebo. The initial dose of alendronate was 5 mg/d, but was later increased to 10 mg/d when other studies found that the higher dose was more effective. FIT showed that alendronate increased BMD and decreased the risk of vertebral fracture.⁷

Bell et al¹ used a mixed-model statistical analysis to compare “within-person variation” in BMD (variation in DXA results over time in individuals) and “between-person variation” in BMD (variation in DXA results over time in the population of patients). The BMD of all FIT participants in both the control and treatment groups was measured at baseline and at the 1-, 2-, and 3-year marks. Each individual was always tested on the same scanner to minimize differences in machinery.

Individual results vary from year to year. The researchers found that the within-person variation was about 10 times greater than the between-person variation. This finding suggests that the precision of DXA scan measurements is not that reliable from 1 test to another.

The average annual increase in BMD in patients in the alendronate group was 0.0085 g/cm²—which is smaller than the typical year-to-year (within-person) variation of 0.013 g/cm². It would therefore be difficult to differentiate the medication’s effect from the random variation inherent in DXA scans.

Response is favorable after 3 years of treatment. While there is variation in test results from year to year, longer-term findings are more reliable. After 3 years of treatment, 97.5% of patients taking alendronate had an increase in hip BMD of at least 0.019 g/cm², with a strong correlation between hip and spine measurements. Although this represents a relatively small change in Z and T scores, this increase in hip BMD is considered a favorable response that warrants continued treatment. These findings are consistent with a previous analysis of BMD monitoring in women taking bisphosphonates, in which those who had the largest drop in BMD after the first year of treatment typically had a large gain over the second year.⁸

WHAT’S NEW: Now we know early testing is unnecessary

Not many studies are available to provide guidance about the interval between BMD measurements after starting a bisphosphonate. This study advises us that it is not necessary to recheck BMD for at least 3 years after starting treatment. Elimination of early repeat DXA testing could result in significant cost savings.

CAVEATS: Findings contradict usual recommendations

Physicians should be aware that the conclusion of this study is not in line with recommendations from a number of prominent organizations. The American Association of Clinical Endocrinology,⁹ the National Osteoporosis Foundation,¹⁰ and the North American Menopause Society¹¹ all recommend follow-up DXA testing in 1 or 2 years.

High-risk patient exception. The delay in repeat DXA testing may not be appropriate for patients at higher risk of bone density loss. However, a separate analysis of higher-risk groups was not done.

Finally, while the findings of Bell et al suggest that we should wait at least 3 years before retesting, it is still not clear whether there is any benefit to repeat DXA testing at any interval, given the nearly universal response rate. It is also possible that advances in DXA technology will reduce some of the variation in BMD results.

CHALLENGES TO IMPLEMENTATION: Anxious patients

Patients like Ms. K may ask their physicians to retest well before 3 years. Yet those who undergo scanning after a shorter interval may be discouraged by early results. Advising patients that the treatment is almost uniformly effective in increasing BMD should reassure them that sticking with treatment is worthwhile.

Acknowledgment

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 44-year-old woman with a family history of early CHD is considering hysterectomy for painful uterine fibroids. She’s thinking about undergoing concurrent bilateral oophorectomy to prevent ovarian cancer and asks for your input. How would you advise her?

Hysterectomy is the most common gynecologic surgery in the United States. In 2003, more than 600,000 hysterectomies were performed; 89% were not associated with malignancies.²

Ovarian conservation is not the norm

Data from the University Health-System Consortium Clinical Database indicate that between 2002 and 2008, about 55% of women who had a hysterectomy that was not cancer-related underwent oophorectomy. Rates of concurrent oophorectomy included:

• 68% of women ages 65 and older
• 77% of women ages 51 to 64
• 48% of women ages 31 to 50
• 3% of women ages 18 to 30.

A recent analysis from the Centers for Disease Control and Prevention found that among women who underwent hysterectomy for any reason between 1994 and 1998, 55% also had their ovaries removed.³

Hormones and CHD: An unanswered question

Over the last several decades, there has been a great deal of interest in the relationship between hormones and CHD, much of it stemming from the controversy about hormone replacement therapy (HRT). The findings of the Women’s Health Initiative implicated combined exogenous hormones (estrogen and progestin) as a risk factor for CHD.⁴ Endogenous hormone production, however, may protect against CHD; some studies have demonstrated a decreased risk of cardiovascular death with later age of menopause.^5,6

Current oophorectomy recommendations are age-specific. The American College of Obstetricians and Gynecologists (ACOG) recommends that strong consideration be given to ovarian conservation in premenopausal women who are not at risk for ovarian cancer. For postmenopausal women, however, ACOG recommends consideration of oophorectomy as prophylaxis.⁷ These recommendations are based on expert opinion. Previous studies suggest that ovarian conservation may improve survival in specific age groups.^8,9 The large, high-quality observational study reviewed here provides further guidance about the role of ovarian conservation across all age groups.

STUDY SUMMARY: Oophorectomy increases risk of CHD and death

This observational study¹ was part of the Nurses’ Health Study. It included 29,380 women, of which 16,345 (55.6%) underwent hysterectomy with bilateral oophorectomy and 13,035 (44.4%) had hysterectomy with ovarian conservation. Women with unilateral oophorectomy were excluded, as were those who had a history of CHD or stroke, and women for whom pertinent data, such as age, were missing. A follow-up survey was sent to participants every 2 years for 24 years, with an average return rate of 90%.

Women who had undergone bilateral oophorectomy had an increased risk of CHD and all-cause mortality ( TABLE ). The authors estimated that with a postsurgical life span of approximately 35 years, every 9 oophorectomies would result in 1 additional death. The authors also pointed out there were no age exceptions: Ovarian-sparing surgery was linked to improved survival in every age group.

Oophorectomy did have a protective effect against breast cancer, ovarian cancer (number needed to treat=220), and total cancer incidence, but it was associated with an increased incidence of lung cancer (number needed to harm=190) and total cancer mortality. There was no significant difference in rates of stroke, pulmonary embolus, colorectal cancer, or hip fracture.

TABLE
Oophorectomy (vs ovarian conservation) increases key risks¹

WHAT’S NEW: Ovarian conservation: Better for all ages

The evidence is clear: Conserving the ovaries, rather than removing them, during hysterectomy is associated with a lower risk of CHD and both all-cause and cancer-related mortality.

What about the patient’s age? A 2005 analysis suggested that ovarian conservation conferred a survival benefit compared to oophorectomy in women <65 years.⁸ Similarly, a 2006 cohort study found increased mortality in women <45 years who underwent concurrent oophorectomy.⁹ But this is the first study to demonstrate that ovarian-sparing surgery is associated with improved survival in women of every age group.

CAVEATS: Study sample and HRT use could affect outcome

The average age of patients in the treatment (oophorectomy) arm was higher than that of patients in the control group; the women in the treatment group were older at the time of hysterectomy (46.8 vs 43.3 years), as well. This should not bias the results, which were adjusted by age and many other variables.

Nonrepresentative sample. This group of nurses is not representative of the general population in several important aspects, including socioeconomic status, educational level, and race (94% Caucasian). This may limit the generalizability of the findings.

Study design. The observational design and the fact that the patients themselves decided whether or not to undergo oophorectomy also raise the possibility of unmeasured confounding factors.

Cancer risk. Women with known BRCA mutations were not studied separately, but the results were adjusted for family history of breast or ovarian cancer. The authors stated that a subgroup analysis of women with a family history of ovarian cancer had similar outcomes, although the data were not included

HRT use. As might be expected, patients in the oophorectomy arm of the study were more likely to use HRT. Since the completion of the study in 2000, practice recommendations have shifted against combined HRT use. Unopposed estrogen, which is not thought to increase the incidence of cardiovascular disease, remains a treatment option for women who have undergone hysterectomy and oophorectomy. But the overall effect of unopposed estrogen on survival is still uncertain.⁴ It is unclear how the recent decline in the use of exogenous hormones would affect these results.

BARRIERS TO IMPLEMENTATION: FP-GYN communication can be difficult

This study provides important information for primary care physicians to discuss with female patients and their gynecologists. However, some doctors may not have relationships with the gynecologists in their community, or have limited (or no) influence or input into which specialists their patients see. In addition, some gynecologists may hesitate to perform hysterectomy without oophorectomy in some cases for technical reasons.¹⁰

Concern about prevention of ovarian cancer must be balanced with increased risk of mortality and CHD events. It may be helpful to tell patients who are about to undergo hysterectomy for a benign condition that women are nearly 30 times more likely to die of cardiovascular disease (CHD or stroke) than ovarian cancer (413,800/year vs 14,700/year).¹¹

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

The authors wish to acknowledge Sofia Medvedev, PhD, of the University HealthSystem Consortium in Oak Brook, Ill, for analysis of the National Ambulatory Medical Care Survey data and the UHC Clinical Database.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 44-year-old woman with a family history of early CHD is considering hysterectomy for painful uterine fibroids. She’s thinking about undergoing concurrent bilateral oophorectomy to prevent ovarian cancer and asks for your input. How would you advise her?

Hysterectomy is the most common gynecologic surgery in the United States. In 2003, more than 600,000 hysterectomies were performed; 89% were not associated with malignancies.²

Ovarian conservation is not the norm

Data from the University Health-System Consortium Clinical Database indicate that between 2002 and 2008, about 55% of women who had a hysterectomy that was not cancer-related underwent oophorectomy. Rates of concurrent oophorectomy included:

• 68% of women ages 65 and older
• 77% of women ages 51 to 64
• 48% of women ages 31 to 50
• 3% of women ages 18 to 30.

A recent analysis from the Centers for Disease Control and Prevention found that among women who underwent hysterectomy for any reason between 1994 and 1998, 55% also had their ovaries removed.³

Hormones and CHD: An unanswered question

Over the last several decades, there has been a great deal of interest in the relationship between hormones and CHD, much of it stemming from the controversy about hormone replacement therapy (HRT). The findings of the Women’s Health Initiative implicated combined exogenous hormones (estrogen and progestin) as a risk factor for CHD.⁴ Endogenous hormone production, however, may protect against CHD; some studies have demonstrated a decreased risk of cardiovascular death with later age of menopause.^5,6

Current oophorectomy recommendations are age-specific. The American College of Obstetricians and Gynecologists (ACOG) recommends that strong consideration be given to ovarian conservation in premenopausal women who are not at risk for ovarian cancer. For postmenopausal women, however, ACOG recommends consideration of oophorectomy as prophylaxis.⁷ These recommendations are based on expert opinion. Previous studies suggest that ovarian conservation may improve survival in specific age groups.^8,9 The large, high-quality observational study reviewed here provides further guidance about the role of ovarian conservation across all age groups.

STUDY SUMMARY: Oophorectomy increases risk of CHD and death

This observational study¹ was part of the Nurses’ Health Study. It included 29,380 women, of which 16,345 (55.6%) underwent hysterectomy with bilateral oophorectomy and 13,035 (44.4%) had hysterectomy with ovarian conservation. Women with unilateral oophorectomy were excluded, as were those who had a history of CHD or stroke, and women for whom pertinent data, such as age, were missing. A follow-up survey was sent to participants every 2 years for 24 years, with an average return rate of 90%.

Women who had undergone bilateral oophorectomy had an increased risk of CHD and all-cause mortality ( TABLE ). The authors estimated that with a postsurgical life span of approximately 35 years, every 9 oophorectomies would result in 1 additional death. The authors also pointed out there were no age exceptions: Ovarian-sparing surgery was linked to improved survival in every age group.

Oophorectomy did have a protective effect against breast cancer, ovarian cancer (number needed to treat=220), and total cancer incidence, but it was associated with an increased incidence of lung cancer (number needed to harm=190) and total cancer mortality. There was no significant difference in rates of stroke, pulmonary embolus, colorectal cancer, or hip fracture.

TABLE
Oophorectomy (vs ovarian conservation) increases key risks¹

WHAT’S NEW: Ovarian conservation: Better for all ages

The evidence is clear: Conserving the ovaries, rather than removing them, during hysterectomy is associated with a lower risk of CHD and both all-cause and cancer-related mortality.

What about the patient’s age? A 2005 analysis suggested that ovarian conservation conferred a survival benefit compared to oophorectomy in women <65 years.⁸ Similarly, a 2006 cohort study found increased mortality in women <45 years who underwent concurrent oophorectomy.⁹ But this is the first study to demonstrate that ovarian-sparing surgery is associated with improved survival in women of every age group.

CAVEATS: Study sample and HRT use could affect outcome

The average age of patients in the treatment (oophorectomy) arm was higher than that of patients in the control group; the women in the treatment group were older at the time of hysterectomy (46.8 vs 43.3 years), as well. This should not bias the results, which were adjusted by age and many other variables.

Nonrepresentative sample. This group of nurses is not representative of the general population in several important aspects, including socioeconomic status, educational level, and race (94% Caucasian). This may limit the generalizability of the findings.

Study design. The observational design and the fact that the patients themselves decided whether or not to undergo oophorectomy also raise the possibility of unmeasured confounding factors.

Cancer risk. Women with known BRCA mutations were not studied separately, but the results were adjusted for family history of breast or ovarian cancer. The authors stated that a subgroup analysis of women with a family history of ovarian cancer had similar outcomes, although the data were not included

HRT use. As might be expected, patients in the oophorectomy arm of the study were more likely to use HRT. Since the completion of the study in 2000, practice recommendations have shifted against combined HRT use. Unopposed estrogen, which is not thought to increase the incidence of cardiovascular disease, remains a treatment option for women who have undergone hysterectomy and oophorectomy. But the overall effect of unopposed estrogen on survival is still uncertain.⁴ It is unclear how the recent decline in the use of exogenous hormones would affect these results.

BARRIERS TO IMPLEMENTATION: FP-GYN communication can be difficult

This study provides important information for primary care physicians to discuss with female patients and their gynecologists. However, some doctors may not have relationships with the gynecologists in their community, or have limited (or no) influence or input into which specialists their patients see. In addition, some gynecologists may hesitate to perform hysterectomy without oophorectomy in some cases for technical reasons.¹⁰

Concern about prevention of ovarian cancer must be balanced with increased risk of mortality and CHD events. It may be helpful to tell patients who are about to undergo hysterectomy for a benign condition that women are nearly 30 times more likely to die of cardiovascular disease (CHD or stroke) than ovarian cancer (413,800/year vs 14,700/year).¹¹

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

The authors wish to acknowledge Sofia Medvedev, PhD, of the University HealthSystem Consortium in Oak Brook, Ill, for analysis of the National Ambulatory Medical Care Survey data and the UHC Clinical Database.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 44-year-old woman with a family history of early CHD is considering hysterectomy for painful uterine fibroids. She’s thinking about undergoing concurrent bilateral oophorectomy to prevent ovarian cancer and asks for your input. How would you advise her?

Hysterectomy is the most common gynecologic surgery in the United States. In 2003, more than 600,000 hysterectomies were performed; 89% were not associated with malignancies.²

Ovarian conservation is not the norm

Data from the University Health-System Consortium Clinical Database indicate that between 2002 and 2008, about 55% of women who had a hysterectomy that was not cancer-related underwent oophorectomy. Rates of concurrent oophorectomy included:

• 68% of women ages 65 and older
• 77% of women ages 51 to 64
• 48% of women ages 31 to 50
• 3% of women ages 18 to 30.

A recent analysis from the Centers for Disease Control and Prevention found that among women who underwent hysterectomy for any reason between 1994 and 1998, 55% also had their ovaries removed.³

Hormones and CHD: An unanswered question

Over the last several decades, there has been a great deal of interest in the relationship between hormones and CHD, much of it stemming from the controversy about hormone replacement therapy (HRT). The findings of the Women’s Health Initiative implicated combined exogenous hormones (estrogen and progestin) as a risk factor for CHD.⁴ Endogenous hormone production, however, may protect against CHD; some studies have demonstrated a decreased risk of cardiovascular death with later age of menopause.^5,6

Current oophorectomy recommendations are age-specific. The American College of Obstetricians and Gynecologists (ACOG) recommends that strong consideration be given to ovarian conservation in premenopausal women who are not at risk for ovarian cancer. For postmenopausal women, however, ACOG recommends consideration of oophorectomy as prophylaxis.⁷ These recommendations are based on expert opinion. Previous studies suggest that ovarian conservation may improve survival in specific age groups.^8,9 The large, high-quality observational study reviewed here provides further guidance about the role of ovarian conservation across all age groups.

STUDY SUMMARY: Oophorectomy increases risk of CHD and death

This observational study¹ was part of the Nurses’ Health Study. It included 29,380 women, of which 16,345 (55.6%) underwent hysterectomy with bilateral oophorectomy and 13,035 (44.4%) had hysterectomy with ovarian conservation. Women with unilateral oophorectomy were excluded, as were those who had a history of CHD or stroke, and women for whom pertinent data, such as age, were missing. A follow-up survey was sent to participants every 2 years for 24 years, with an average return rate of 90%.

Women who had undergone bilateral oophorectomy had an increased risk of CHD and all-cause mortality ( TABLE ). The authors estimated that with a postsurgical life span of approximately 35 years, every 9 oophorectomies would result in 1 additional death. The authors also pointed out there were no age exceptions: Ovarian-sparing surgery was linked to improved survival in every age group.

Oophorectomy did have a protective effect against breast cancer, ovarian cancer (number needed to treat=220), and total cancer incidence, but it was associated with an increased incidence of lung cancer (number needed to harm=190) and total cancer mortality. There was no significant difference in rates of stroke, pulmonary embolus, colorectal cancer, or hip fracture.

TABLE
Oophorectomy (vs ovarian conservation) increases key risks¹

WHAT’S NEW: Ovarian conservation: Better for all ages

The evidence is clear: Conserving the ovaries, rather than removing them, during hysterectomy is associated with a lower risk of CHD and both all-cause and cancer-related mortality.

What about the patient’s age? A 2005 analysis suggested that ovarian conservation conferred a survival benefit compared to oophorectomy in women <65 years.⁸ Similarly, a 2006 cohort study found increased mortality in women <45 years who underwent concurrent oophorectomy.⁹ But this is the first study to demonstrate that ovarian-sparing surgery is associated with improved survival in women of every age group.

CAVEATS: Study sample and HRT use could affect outcome

The average age of patients in the treatment (oophorectomy) arm was higher than that of patients in the control group; the women in the treatment group were older at the time of hysterectomy (46.8 vs 43.3 years), as well. This should not bias the results, which were adjusted by age and many other variables.

Nonrepresentative sample. This group of nurses is not representative of the general population in several important aspects, including socioeconomic status, educational level, and race (94% Caucasian). This may limit the generalizability of the findings.

Study design. The observational design and the fact that the patients themselves decided whether or not to undergo oophorectomy also raise the possibility of unmeasured confounding factors.

Cancer risk. Women with known BRCA mutations were not studied separately, but the results were adjusted for family history of breast or ovarian cancer. The authors stated that a subgroup analysis of women with a family history of ovarian cancer had similar outcomes, although the data were not included

HRT use. As might be expected, patients in the oophorectomy arm of the study were more likely to use HRT. Since the completion of the study in 2000, practice recommendations have shifted against combined HRT use. Unopposed estrogen, which is not thought to increase the incidence of cardiovascular disease, remains a treatment option for women who have undergone hysterectomy and oophorectomy. But the overall effect of unopposed estrogen on survival is still uncertain.⁴ It is unclear how the recent decline in the use of exogenous hormones would affect these results.

BARRIERS TO IMPLEMENTATION: FP-GYN communication can be difficult

This study provides important information for primary care physicians to discuss with female patients and their gynecologists. However, some doctors may not have relationships with the gynecologists in their community, or have limited (or no) influence or input into which specialists their patients see. In addition, some gynecologists may hesitate to perform hysterectomy without oophorectomy in some cases for technical reasons.¹⁰

Concern about prevention of ovarian cancer must be balanced with increased risk of mortality and CHD events. It may be helpful to tell patients who are about to undergo hysterectomy for a benign condition that women are nearly 30 times more likely to die of cardiovascular disease (CHD or stroke) than ovarian cancer (413,800/year vs 14,700/year).¹¹

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

The authors wish to acknowledge Sofia Medvedev, PhD, of the University HealthSystem Consortium in Oak Brook, Ill, for analysis of the National Ambulatory Medical Care Survey data and the UHC Clinical Database.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

Evidence summary

Clinical evaluation with medical history and physical exam, chest radiography, and selected sputum sampling to exclude active tuberculosis are part of the recommended algorithm for all patients who develop a positive PPD (FIGURE).^1-3 These recommendations are derived from expert opinion, and their usefulness has not been evaluated in any population-based study of asymptomatic PPD-positive patients.

A comprehensive review of RCTs from the 1950s and 1960s demonstrated that INH treatment of patients with latent tuberculosis infection is effective in decreasing the progression to active tuberculosis.⁴ A series of double-blinded RCTs performed by the US Public Health Service included 25,923 patients with latent tuberculosis who were randomized to receive either daily INH or placebo for 1 year with 6- to 10-year follow-up. Groups studied included household contacts of patients with active tuberculosis (rate of progression to active disease in placebo group [baseline rate]=27/1000, relative risk with INH [RR]=0.4, number needed to treat [NNT]=63), patients in mental institutions (baseline rate=12/1000, RR=0.3, NNT=121), and patients with x-ray findings of healed tuberculosis (baseline rate=69/1000, RR=0.4, NNT=23).

The optimal length of treatment for PPD-positive patients without active disease was evaluated through 1 double-blinded RCT enrolling 28,000 patients with 5-year follow-up after 12, 24, or 52 weeks of INH or placebo. Active TB developed in 0.35% (24/6919) after 52 weeks of INH compared with 0.49% (34/6965) after 24 weeks (RR=1.4, NNT=708).⁵ Incidence in the placebo group was 1.4%. Subgroup analysis determined that maximum efficacy with fewest side effects was achieved at 9 months.⁶ Nine months of INH is also recommended for HIV-positive patients, based on extrapolations from these and other studies.³

INH monotherapy was compared with combination INH and rifampin in a 2005 meta-analysis of 5 RCTs of variable quality involving 1926 patients.⁷ This meta-analysis found equivalency in risk of active TB and mortality between INH monotherapy for 6 to 12 months and the combination of rifampin and INH for 3 months (pooled risk difference=0%; 95% confidence interval [CI], –1% to 2%). This study also showed similar rates of adverse events in both groups (pooled risk difference=–1%; 95% CI, –7% to 5%). Short-course combination rifampin and pyrazinamide is no longer recommended after an open-label RCT with 589 patients demonstrated severe hepatoxicity in 7.7% (16/207) on a 2-month course of pyrazinamide and rifampin, compared with 1% (2/204) on 6 months of INH (RR=7.9, number needed to harm=15).⁸ Rifampin monotherapy has only been studied in patients with silicosis in a RCT enrolling 652 participants with latent tuberculosis. A 12-week course of rifampin (600 mg daily) was as effective as 6 months of INH in preventing development of active TB over the next 5 years.⁹

FIGURE
Suggested workup of asymptomatic, HIV-negative patients with a positive PPD

Recommendations from others

Centers for Disease Control and Prevention, American Thoracic Society, and Infectious Disease Society of America guidelines recommend targeted screening of high-risk persons followed by further clinical evaluation of all those with a reactive PPD (FIGURE).^2,10 The recommended treatment regimen for latent TB is daily INH for 9 months. Less preferable regimens are daily INH for 6 months, or daily rifampin for 4 months in patients who cannot tolerate INH. A 2-month course of rifampin and pyrazinamide is no longer recommended. The recent meta-analysis supporting a 3-month regimen of combination INH and rifampin has not been incorporated into expert guidelines.⁷

Evidence summary

Clinical evaluation with medical history and physical exam, chest radiography, and selected sputum sampling to exclude active tuberculosis are part of the recommended algorithm for all patients who develop a positive PPD (FIGURE).^1-3 These recommendations are derived from expert opinion, and their usefulness has not been evaluated in any population-based study of asymptomatic PPD-positive patients.

A comprehensive review of RCTs from the 1950s and 1960s demonstrated that INH treatment of patients with latent tuberculosis infection is effective in decreasing the progression to active tuberculosis.⁴ A series of double-blinded RCTs performed by the US Public Health Service included 25,923 patients with latent tuberculosis who were randomized to receive either daily INH or placebo for 1 year with 6- to 10-year follow-up. Groups studied included household contacts of patients with active tuberculosis (rate of progression to active disease in placebo group [baseline rate]=27/1000, relative risk with INH [RR]=0.4, number needed to treat [NNT]=63), patients in mental institutions (baseline rate=12/1000, RR=0.3, NNT=121), and patients with x-ray findings of healed tuberculosis (baseline rate=69/1000, RR=0.4, NNT=23).

The optimal length of treatment for PPD-positive patients without active disease was evaluated through 1 double-blinded RCT enrolling 28,000 patients with 5-year follow-up after 12, 24, or 52 weeks of INH or placebo. Active TB developed in 0.35% (24/6919) after 52 weeks of INH compared with 0.49% (34/6965) after 24 weeks (RR=1.4, NNT=708).⁵ Incidence in the placebo group was 1.4%. Subgroup analysis determined that maximum efficacy with fewest side effects was achieved at 9 months.⁶ Nine months of INH is also recommended for HIV-positive patients, based on extrapolations from these and other studies.³

INH monotherapy was compared with combination INH and rifampin in a 2005 meta-analysis of 5 RCTs of variable quality involving 1926 patients.⁷ This meta-analysis found equivalency in risk of active TB and mortality between INH monotherapy for 6 to 12 months and the combination of rifampin and INH for 3 months (pooled risk difference=0%; 95% confidence interval [CI], –1% to 2%). This study also showed similar rates of adverse events in both groups (pooled risk difference=–1%; 95% CI, –7% to 5%). Short-course combination rifampin and pyrazinamide is no longer recommended after an open-label RCT with 589 patients demonstrated severe hepatoxicity in 7.7% (16/207) on a 2-month course of pyrazinamide and rifampin, compared with 1% (2/204) on 6 months of INH (RR=7.9, number needed to harm=15).⁸ Rifampin monotherapy has only been studied in patients with silicosis in a RCT enrolling 652 participants with latent tuberculosis. A 12-week course of rifampin (600 mg daily) was as effective as 6 months of INH in preventing development of active TB over the next 5 years.⁹

FIGURE
Suggested workup of asymptomatic, HIV-negative patients with a positive PPD

Recommendations from others

Centers for Disease Control and Prevention, American Thoracic Society, and Infectious Disease Society of America guidelines recommend targeted screening of high-risk persons followed by further clinical evaluation of all those with a reactive PPD (FIGURE).^2,10 The recommended treatment regimen for latent TB is daily INH for 9 months. Less preferable regimens are daily INH for 6 months, or daily rifampin for 4 months in patients who cannot tolerate INH. A 2-month course of rifampin and pyrazinamide is no longer recommended. The recent meta-analysis supporting a 3-month regimen of combination INH and rifampin has not been incorporated into expert guidelines.⁷

Evidence summary

Clinical evaluation with medical history and physical exam, chest radiography, and selected sputum sampling to exclude active tuberculosis are part of the recommended algorithm for all patients who develop a positive PPD (FIGURE).^1-3 These recommendations are derived from expert opinion, and their usefulness has not been evaluated in any population-based study of asymptomatic PPD-positive patients.

A comprehensive review of RCTs from the 1950s and 1960s demonstrated that INH treatment of patients with latent tuberculosis infection is effective in decreasing the progression to active tuberculosis.⁴ A series of double-blinded RCTs performed by the US Public Health Service included 25,923 patients with latent tuberculosis who were randomized to receive either daily INH or placebo for 1 year with 6- to 10-year follow-up. Groups studied included household contacts of patients with active tuberculosis (rate of progression to active disease in placebo group [baseline rate]=27/1000, relative risk with INH [RR]=0.4, number needed to treat [NNT]=63), patients in mental institutions (baseline rate=12/1000, RR=0.3, NNT=121), and patients with x-ray findings of healed tuberculosis (baseline rate=69/1000, RR=0.4, NNT=23).

The optimal length of treatment for PPD-positive patients without active disease was evaluated through 1 double-blinded RCT enrolling 28,000 patients with 5-year follow-up after 12, 24, or 52 weeks of INH or placebo. Active TB developed in 0.35% (24/6919) after 52 weeks of INH compared with 0.49% (34/6965) after 24 weeks (RR=1.4, NNT=708).⁵ Incidence in the placebo group was 1.4%. Subgroup analysis determined that maximum efficacy with fewest side effects was achieved at 9 months.⁶ Nine months of INH is also recommended for HIV-positive patients, based on extrapolations from these and other studies.³

INH monotherapy was compared with combination INH and rifampin in a 2005 meta-analysis of 5 RCTs of variable quality involving 1926 patients.⁷ This meta-analysis found equivalency in risk of active TB and mortality between INH monotherapy for 6 to 12 months and the combination of rifampin and INH for 3 months (pooled risk difference=0%; 95% confidence interval [CI], –1% to 2%). This study also showed similar rates of adverse events in both groups (pooled risk difference=–1%; 95% CI, –7% to 5%). Short-course combination rifampin and pyrazinamide is no longer recommended after an open-label RCT with 589 patients demonstrated severe hepatoxicity in 7.7% (16/207) on a 2-month course of pyrazinamide and rifampin, compared with 1% (2/204) on 6 months of INH (RR=7.9, number needed to harm=15).⁸ Rifampin monotherapy has only been studied in patients with silicosis in a RCT enrolling 652 participants with latent tuberculosis. A 12-week course of rifampin (600 mg daily) was as effective as 6 months of INH in preventing development of active TB over the next 5 years.⁹

FIGURE
Suggested workup of asymptomatic, HIV-negative patients with a positive PPD

Recommendations from others

Centers for Disease Control and Prevention, American Thoracic Society, and Infectious Disease Society of America guidelines recommend targeted screening of high-risk persons followed by further clinical evaluation of all those with a reactive PPD (FIGURE).^2,10 The recommended treatment regimen for latent TB is daily INH for 9 months. Less preferable regimens are daily INH for 6 months, or daily rifampin for 4 months in patients who cannot tolerate INH. A 2-month course of rifampin and pyrazinamide is no longer recommended. The recent meta-analysis supporting a 3-month regimen of combination INH and rifampin has not been incorporated into expert guidelines.⁷