Clinical Inquiries

Evidence summary

Little evidence and no specific guidelines exist to guide the clinician in evaluating and managing exercise-induced amenorrhea. All athletes with amenorrhea should have a pregnancy test, because pregnancy is the most common cause of secondary amenorrhea.¹ After ruling it out, the clinician may choose to exclude other causes of secondary amenorrhea before presuming a diagnosis of hypothalamic amenorrhea.

Useful tests (TABLE) include:

• serum prolactin to rule out prolactinoma
• follicle-stimulating hormone to rule out premature ovarian failure
• thyroid-stimulating hormone to evaluate for thyroid problems.

If all these tests are negative, consider a progesterone challenge test.³ Typically, athletes with hypothalamic amenorrhea don’t experience withdrawal bleeding after progesterone challenge, because of inadequate endogenous estrogen stimulation.

Greater calorie and micronutrient intake—plus rest—is best

A 1999 study in the International Journal of Sport Nutrition found that chronic energy deficit in amenorrheic athletes (N=4) could be reversed in a 20-week program using a sport nutrition supplement, 1 rest day per week, and a dietician to help with food selection.⁴ A 2002 review similarly recommends 1 rest day per week, increasing caloric intake by 200 to 300 Kcal/d, and increasing intake of calcium, B vitamins, iron, and zinc.⁵

TABLE

Is it hypothalamic amenorrhea, or something else?

Oral contraceptives to prevent bone loss? Too little information

Bone loss in amenorrheic athletes may have long-term consequences, even if amenorrhea is only temporary. Some theoretical and disease-based research suggests a possible role for oral contraceptives to prevent bone loss in pre- and postmenopausal women,⁶ but little research has investigated younger women with hypothalamic amenorrhea. A recent open-label study that did examine bone mineral density (BMD) in women with hypothalamic amenorrhea before and after 13 cycles of oral contraceptives found a significant increase in BMD in the spine, but not at the hip.⁷

No published study has demonstrated clinically significant advantages for oral contraceptive therapy in women with secondary amenorrhea. These women should take adequate calcium and vitamin D. Bisphosphonates are not appropriate for women of reproductive age, because of their potential teratogenicity.¹

Recommendations

The Committee on Sports Medicine and Fitness of the American Academy of Pediatrics (AAP) encourages exercise to help maintain lean body mass and protect against obesity, diabetes, hypertension, and cardiovascular disease. Athletes with amenorrhea, however, may be at risk for sequelae such as osteopenia, fractures, and dyslipidemia. Amenorrhea during adolescence may inhibit the accretion of BMD, and the lost density may not be re-gained. Amenorrheic athletes are also at risk for the “female athlete triad”—disordered eating, amenorrhea, and osteoporosis.⁸

The potential negative sequelae of amenorrhea are best prevented with measures that restore physiologic menses.³ For exercise-induced hypothalamic bone loss, the AAP recommends decreased exercise, increased caloric intake, or both.

Evidence summary

Little evidence and no specific guidelines exist to guide the clinician in evaluating and managing exercise-induced amenorrhea. All athletes with amenorrhea should have a pregnancy test, because pregnancy is the most common cause of secondary amenorrhea.¹ After ruling it out, the clinician may choose to exclude other causes of secondary amenorrhea before presuming a diagnosis of hypothalamic amenorrhea.

Useful tests (TABLE) include:

• serum prolactin to rule out prolactinoma
• follicle-stimulating hormone to rule out premature ovarian failure
• thyroid-stimulating hormone to evaluate for thyroid problems.

If all these tests are negative, consider a progesterone challenge test.³ Typically, athletes with hypothalamic amenorrhea don’t experience withdrawal bleeding after progesterone challenge, because of inadequate endogenous estrogen stimulation.

Greater calorie and micronutrient intake—plus rest—is best

A 1999 study in the International Journal of Sport Nutrition found that chronic energy deficit in amenorrheic athletes (N=4) could be reversed in a 20-week program using a sport nutrition supplement, 1 rest day per week, and a dietician to help with food selection.⁴ A 2002 review similarly recommends 1 rest day per week, increasing caloric intake by 200 to 300 Kcal/d, and increasing intake of calcium, B vitamins, iron, and zinc.⁵

TABLE

Is it hypothalamic amenorrhea, or something else?

Oral contraceptives to prevent bone loss? Too little information

Bone loss in amenorrheic athletes may have long-term consequences, even if amenorrhea is only temporary. Some theoretical and disease-based research suggests a possible role for oral contraceptives to prevent bone loss in pre- and postmenopausal women,⁶ but little research has investigated younger women with hypothalamic amenorrhea. A recent open-label study that did examine bone mineral density (BMD) in women with hypothalamic amenorrhea before and after 13 cycles of oral contraceptives found a significant increase in BMD in the spine, but not at the hip.⁷

No published study has demonstrated clinically significant advantages for oral contraceptive therapy in women with secondary amenorrhea. These women should take adequate calcium and vitamin D. Bisphosphonates are not appropriate for women of reproductive age, because of their potential teratogenicity.¹

Recommendations

The Committee on Sports Medicine and Fitness of the American Academy of Pediatrics (AAP) encourages exercise to help maintain lean body mass and protect against obesity, diabetes, hypertension, and cardiovascular disease. Athletes with amenorrhea, however, may be at risk for sequelae such as osteopenia, fractures, and dyslipidemia. Amenorrhea during adolescence may inhibit the accretion of BMD, and the lost density may not be re-gained. Amenorrheic athletes are also at risk for the “female athlete triad”—disordered eating, amenorrhea, and osteoporosis.⁸

The potential negative sequelae of amenorrhea are best prevented with measures that restore physiologic menses.³ For exercise-induced hypothalamic bone loss, the AAP recommends decreased exercise, increased caloric intake, or both.

Evidence summary

Little evidence and no specific guidelines exist to guide the clinician in evaluating and managing exercise-induced amenorrhea. All athletes with amenorrhea should have a pregnancy test, because pregnancy is the most common cause of secondary amenorrhea.¹ After ruling it out, the clinician may choose to exclude other causes of secondary amenorrhea before presuming a diagnosis of hypothalamic amenorrhea.

Useful tests (TABLE) include:

• serum prolactin to rule out prolactinoma
• follicle-stimulating hormone to rule out premature ovarian failure
• thyroid-stimulating hormone to evaluate for thyroid problems.

If all these tests are negative, consider a progesterone challenge test.³ Typically, athletes with hypothalamic amenorrhea don’t experience withdrawal bleeding after progesterone challenge, because of inadequate endogenous estrogen stimulation.

Greater calorie and micronutrient intake—plus rest—is best

A 1999 study in the International Journal of Sport Nutrition found that chronic energy deficit in amenorrheic athletes (N=4) could be reversed in a 20-week program using a sport nutrition supplement, 1 rest day per week, and a dietician to help with food selection.⁴ A 2002 review similarly recommends 1 rest day per week, increasing caloric intake by 200 to 300 Kcal/d, and increasing intake of calcium, B vitamins, iron, and zinc.⁵

TABLE

Is it hypothalamic amenorrhea, or something else?

Oral contraceptives to prevent bone loss? Too little information

Bone loss in amenorrheic athletes may have long-term consequences, even if amenorrhea is only temporary. Some theoretical and disease-based research suggests a possible role for oral contraceptives to prevent bone loss in pre- and postmenopausal women,⁶ but little research has investigated younger women with hypothalamic amenorrhea. A recent open-label study that did examine bone mineral density (BMD) in women with hypothalamic amenorrhea before and after 13 cycles of oral contraceptives found a significant increase in BMD in the spine, but not at the hip.⁷

No published study has demonstrated clinically significant advantages for oral contraceptive therapy in women with secondary amenorrhea. These women should take adequate calcium and vitamin D. Bisphosphonates are not appropriate for women of reproductive age, because of their potential teratogenicity.¹

Recommendations

The Committee on Sports Medicine and Fitness of the American Academy of Pediatrics (AAP) encourages exercise to help maintain lean body mass and protect against obesity, diabetes, hypertension, and cardiovascular disease. Athletes with amenorrhea, however, may be at risk for sequelae such as osteopenia, fractures, and dyslipidemia. Amenorrhea during adolescence may inhibit the accretion of BMD, and the lost density may not be re-gained. Amenorrheic athletes are also at risk for the “female athlete triad”—disordered eating, amenorrhea, and osteoporosis.⁸

The potential negative sequelae of amenorrhea are best prevented with measures that restore physiologic menses.³ For exercise-induced hypothalamic bone loss, the AAP recommends decreased exercise, increased caloric intake, or both.

Evidence summary

The many definitions used to describe case management present a challenge in summarizing its effect.^1,2 A Cochrane review of case management by a “diabetes specialist nurse/nurse case manager” included 6 trials and 1382 patients with either type 1 or type 2 diabetes. It revealed a short-term benefit (lower HbA1c) in only 1 trial at 6 months and no difference in HbA1c or improvement in quality of life in any trial at 12 months.³

However, a review of 66 RCTs of case management for type 2 diabetes found a mean reduction in HbA1c of 0.52% (95% confidence interval [CI], 0.31-0.73) after adjusting for study size (smaller studies tended to report larger changes) and whether or not patients were “poorly controlled” at baseline (studies with higher HbA1c levels at baseline also reported larger effects).¹ The most striking HbA1c reduction occurred when case managers could make medication adjustments without physician approval (change in HbA1c=0.80%; 95% CI, 0.51-1.10). Moreover, using a multidisciplinary team reduced HbA1c by 0.37% more than interventions without such a team (95% CI, 0.16-0.58).

The authors of an earlier review of 15 case management studies for type 2 diabetes concluded that case management alone was beneficial, resulting in an HbA1c improvement of 0.40% (interquartile range=0.46-0.65).⁴ However, they further noted that studies that showed case management to be effective also involved disease management or included additional interventions such as education, reminders, or other supports.

But studies don’t always show robust outcomes

Outcomes in other studies often aren’t as robust. In the year-long Informatics for Diabetes Education and Telemedicine (IDEATel) project,⁵ for example, nurse case managers supervised by diabetologists and working with primary care physicians were able to direct care based on pre-established algorithms. Those in the intervention group with a baseline HbA1c >7 had an HbA1c reduction of 0.32% and small but statistically significant reductions in blood pressure (3.4 mm Hg systolic and 1.9 mm Hg diastolic) and low-density lipoprotein (9.5 mg/dL).

Intensive control produces positive results, a few harms

The Diabetes Control and Complications Trial (DCCT)⁶ showed that, in patients with type 1 diabetes, “intensive” diabetic control managed by a large team of health care providers for an average of 6.5 years reduced the development of retinopathy (number needed to treat [NNT]=6; 95% CI, 5-7), progression of retinopathy (NNT=5; 95% CI, 4-7), and development or progression of clinical neuropathy (NNT=13; 95% CI, 11-18).⁷ Intensive therapy also caused harms, including episodes of hypoglycemia (number needed to harm [NNH]=3), and “hypoglycemia requiring assistance” (NNH=36).

In the follow-up to DCCT—the Epidemiology of Diabetes Interventions and Complications study (EDIC)—93% of the patients in the original cohort were followed for an average of 17 years.⁸ The risk of developing any predetermined cardiovascular event was 42% less in the intervention group (NNT=14; 95% CI, 9-65), and the combined risk of death, nonfatal myocardial infarction, or stroke was 57% lower (NNT=10; 95% CI, 7-49). Harms, such as hypoglycemia, were not reported.

Recommendations

According to the American Diabetes Association, patients with diabetes should receive medical care from a physician-coordinated team, which may include nurse practitioners, physician’s assistants, nurses, dieticians, pharmacists, and mental health professionals.⁹

The Centers for Disease Control and Prevention strongly recommends that patients with diabetes be assigned “a case manager to plan, coordinate, and integrate care,” because case management improves glycemic control and physician monitoring.¹⁰

The American Association of Clinical Endocrinologists states: “Managing diabetes mellitus requires a team approach to patient care. However, because diabetes is primarily a self-managed disease, education in self-management skills is essential in implementing interventions.”¹¹

Evidence summary

The many definitions used to describe case management present a challenge in summarizing its effect.^1,2 A Cochrane review of case management by a “diabetes specialist nurse/nurse case manager” included 6 trials and 1382 patients with either type 1 or type 2 diabetes. It revealed a short-term benefit (lower HbA1c) in only 1 trial at 6 months and no difference in HbA1c or improvement in quality of life in any trial at 12 months.³

However, a review of 66 RCTs of case management for type 2 diabetes found a mean reduction in HbA1c of 0.52% (95% confidence interval [CI], 0.31-0.73) after adjusting for study size (smaller studies tended to report larger changes) and whether or not patients were “poorly controlled” at baseline (studies with higher HbA1c levels at baseline also reported larger effects).¹ The most striking HbA1c reduction occurred when case managers could make medication adjustments without physician approval (change in HbA1c=0.80%; 95% CI, 0.51-1.10). Moreover, using a multidisciplinary team reduced HbA1c by 0.37% more than interventions without such a team (95% CI, 0.16-0.58).

The authors of an earlier review of 15 case management studies for type 2 diabetes concluded that case management alone was beneficial, resulting in an HbA1c improvement of 0.40% (interquartile range=0.46-0.65).⁴ However, they further noted that studies that showed case management to be effective also involved disease management or included additional interventions such as education, reminders, or other supports.

But studies don’t always show robust outcomes

Outcomes in other studies often aren’t as robust. In the year-long Informatics for Diabetes Education and Telemedicine (IDEATel) project,⁵ for example, nurse case managers supervised by diabetologists and working with primary care physicians were able to direct care based on pre-established algorithms. Those in the intervention group with a baseline HbA1c >7 had an HbA1c reduction of 0.32% and small but statistically significant reductions in blood pressure (3.4 mm Hg systolic and 1.9 mm Hg diastolic) and low-density lipoprotein (9.5 mg/dL).

Intensive control produces positive results, a few harms

The Diabetes Control and Complications Trial (DCCT)⁶ showed that, in patients with type 1 diabetes, “intensive” diabetic control managed by a large team of health care providers for an average of 6.5 years reduced the development of retinopathy (number needed to treat [NNT]=6; 95% CI, 5-7), progression of retinopathy (NNT=5; 95% CI, 4-7), and development or progression of clinical neuropathy (NNT=13; 95% CI, 11-18).⁷ Intensive therapy also caused harms, including episodes of hypoglycemia (number needed to harm [NNH]=3), and “hypoglycemia requiring assistance” (NNH=36).

In the follow-up to DCCT—the Epidemiology of Diabetes Interventions and Complications study (EDIC)—93% of the patients in the original cohort were followed for an average of 17 years.⁸ The risk of developing any predetermined cardiovascular event was 42% less in the intervention group (NNT=14; 95% CI, 9-65), and the combined risk of death, nonfatal myocardial infarction, or stroke was 57% lower (NNT=10; 95% CI, 7-49). Harms, such as hypoglycemia, were not reported.

Recommendations

According to the American Diabetes Association, patients with diabetes should receive medical care from a physician-coordinated team, which may include nurse practitioners, physician’s assistants, nurses, dieticians, pharmacists, and mental health professionals.⁹

The Centers for Disease Control and Prevention strongly recommends that patients with diabetes be assigned “a case manager to plan, coordinate, and integrate care,” because case management improves glycemic control and physician monitoring.¹⁰

The American Association of Clinical Endocrinologists states: “Managing diabetes mellitus requires a team approach to patient care. However, because diabetes is primarily a self-managed disease, education in self-management skills is essential in implementing interventions.”¹¹

Evidence summary

The many definitions used to describe case management present a challenge in summarizing its effect.^1,2 A Cochrane review of case management by a “diabetes specialist nurse/nurse case manager” included 6 trials and 1382 patients with either type 1 or type 2 diabetes. It revealed a short-term benefit (lower HbA1c) in only 1 trial at 6 months and no difference in HbA1c or improvement in quality of life in any trial at 12 months.³

However, a review of 66 RCTs of case management for type 2 diabetes found a mean reduction in HbA1c of 0.52% (95% confidence interval [CI], 0.31-0.73) after adjusting for study size (smaller studies tended to report larger changes) and whether or not patients were “poorly controlled” at baseline (studies with higher HbA1c levels at baseline also reported larger effects).¹ The most striking HbA1c reduction occurred when case managers could make medication adjustments without physician approval (change in HbA1c=0.80%; 95% CI, 0.51-1.10). Moreover, using a multidisciplinary team reduced HbA1c by 0.37% more than interventions without such a team (95% CI, 0.16-0.58).

The authors of an earlier review of 15 case management studies for type 2 diabetes concluded that case management alone was beneficial, resulting in an HbA1c improvement of 0.40% (interquartile range=0.46-0.65).⁴ However, they further noted that studies that showed case management to be effective also involved disease management or included additional interventions such as education, reminders, or other supports.

But studies don’t always show robust outcomes

Outcomes in other studies often aren’t as robust. In the year-long Informatics for Diabetes Education and Telemedicine (IDEATel) project,⁵ for example, nurse case managers supervised by diabetologists and working with primary care physicians were able to direct care based on pre-established algorithms. Those in the intervention group with a baseline HbA1c >7 had an HbA1c reduction of 0.32% and small but statistically significant reductions in blood pressure (3.4 mm Hg systolic and 1.9 mm Hg diastolic) and low-density lipoprotein (9.5 mg/dL).

Intensive control produces positive results, a few harms

The Diabetes Control and Complications Trial (DCCT)⁶ showed that, in patients with type 1 diabetes, “intensive” diabetic control managed by a large team of health care providers for an average of 6.5 years reduced the development of retinopathy (number needed to treat [NNT]=6; 95% CI, 5-7), progression of retinopathy (NNT=5; 95% CI, 4-7), and development or progression of clinical neuropathy (NNT=13; 95% CI, 11-18).⁷ Intensive therapy also caused harms, including episodes of hypoglycemia (number needed to harm [NNH]=3), and “hypoglycemia requiring assistance” (NNH=36).

In the follow-up to DCCT—the Epidemiology of Diabetes Interventions and Complications study (EDIC)—93% of the patients in the original cohort were followed for an average of 17 years.⁸ The risk of developing any predetermined cardiovascular event was 42% less in the intervention group (NNT=14; 95% CI, 9-65), and the combined risk of death, nonfatal myocardial infarction, or stroke was 57% lower (NNT=10; 95% CI, 7-49). Harms, such as hypoglycemia, were not reported.

Recommendations

According to the American Diabetes Association, patients with diabetes should receive medical care from a physician-coordinated team, which may include nurse practitioners, physician’s assistants, nurses, dieticians, pharmacists, and mental health professionals.⁹

The Centers for Disease Control and Prevention strongly recommends that patients with diabetes be assigned “a case manager to plan, coordinate, and integrate care,” because case management improves glycemic control and physician monitoring.¹⁰

The American Association of Clinical Endocrinologists states: “Managing diabetes mellitus requires a team approach to patient care. However, because diabetes is primarily a self-managed disease, education in self-management skills is essential in implementing interventions.”¹¹

Evidence summary

Two nonoral estrogen-progestin contraceptives have been approved by the US Food and Drug Administration (FDA). OrthoEvra is a transdermal patch applied weekly for 3 consecutive weeks, followed by 1 patch-free week per cycle.¹ The NuvaRing is a vaginal ring worn for 3 consecutive weeks in a 4-week cycle.²

The patch causes greater estrogen exposure than OCs or the ring

In November 2005, the FDA issued an update to the labeling of the OrthoEvra contraceptive patch, reporting increased systemic estrogen exposure, which may increase the risk of blood clots.³ The FDA warned that the transdermal patch exposes the user to 60% more estrogen than the typical birth control pill containing 35 μg EE.³ In January 2008, the FDA approved an additional update to include the results of a new study that found users of the patch to be at higher risk of developing VTE than OC users.^3,4

One pharmacokinetic study found that exposure to EE differed among delivery systems. The area under the EE concentration-vs-time curve in the patch group was 1.6 times higher than in the OC group (P<.05) and 3.4 times higher than in the vaginal ring group (P<.05).²

So what’s the VTE risk? Two studies, contrasting conclusions

A nested case-control study—based on a Phar-Metrics longitudinal database of information from paid claims by managed care health plans—included 215,769 women between the ages of 15 and 44 years who had started using the patch or a norgestimate-EE combination OC since April 1, 2002, when OrthoEvra was first introduced on the US market.⁵ Investigators identified 68 diagnosed cases of VTE with no identifiable risk factors.

The overall incidence of VTE in this study was 52.8 per 100,000 women-years (95% confidence interval [CI], 35.8-74.9) among patch users and 41.8 per 100,000 women-years among OC users (95% CI, 29.4-57.6).⁵ The study concluded that the risk of nonfatal VTE for the patch isn’t higher than the risk for an OC containing 35 μg EE and norgestimate (odds ratio [OR]=0.9; 95% CI, 0.5-1.6; incidence rate ratio [IRR]=1.1; 95% CI, 0.7-1.8).

A recent update to the study evaluated an additional 17 months of data on new cases of women meeting the same criteria. The supplementary results proved consistent with earlier conclusions, indicating that the risk of nonfatal VTE for the patch is similar to the risk for the OC (OR=1.1; 95% CI, 0.6-2.1).⁶ Combined data from the original study and the update show that the OR for VTE is 1.0 (95% CI, 0.7-1.5) in users of the patch compared with users of the OC.⁶

Another nested case-control study—based on UnitedHealthcare insurance claims data and confirmatory chart reviews—showed contrasting results. The study included 340,377 women between the ages of 15 and 44 years who were new users of the patch or new and previous users of a norgestimate-EE combination OC from April 1, 2002 through December 31, 2004.³ Investigators verified 57 diagnoses of VTE, controlling for confounding factors. The incidence of VTE in this study was 40.8 per 100,000 women-years among patch users and 18.3 per 100,000 women-years among users of the norgestimate-35 μg EE OC. The study reported a more than 2-fold increased risk of VTE in patch users compared to OC users (OR=2.4; 95% CI, 1.1-5.5; IRR=2.2; 95% CI, 1.3-3.8).^3,7

Do the differences between studies make a difference?

The 2 studies appear similar in design but have 2 major identifiable differences:

• The first study verified VTE diagnoses by claims for systemic anticoagulants, whereas the second study expanded its analysis by performing confirmatory chart reviews for VTE diagnoses.
• The first study included only new OC and patch users as of April 1, 2002, whereas the second study included new and experienced users of the OC as of April 1, 2002.

The significance of the differences in these studies is debatable; the results have yielded controversial, conflicting evidence.

Safety and tolerability are similar for the vaginal ring and OCs

A 1-year, open-label, randomized Phase III study of 1030 women compared the NuvaRing with a combination OC containing levonorgestrel and 30 μg EE. One case of deep venous thrombosis occurred in the NuvaRing group.

In reviewing the data, the authors concluded that the NuvaRing demonstrated comparable safety and tolerability to the OC.⁸ NuvaRing users experienced similar side effects compared with OC users.⁹

Recommendations

The World Health Organization Medical Eligibility Criteria for Contraceptive Use (WHOMEC) reports that long-term safety data for the estrogen-progestin contraceptive patch are not available.¹⁰ However, the limited studies that are available suggest a safety profile similar to that of combination OCs with comparable hormone formulations.

WHOMEC suggests that the guidelines for combination OCs also should apply to the patch and the ring. Women shouldn’t use these contraceptive methods if they have a history of VTE or current VTE or if they are undergoing major surgery that may include prolonged immobilization.¹⁰

Evidence summary

Two nonoral estrogen-progestin contraceptives have been approved by the US Food and Drug Administration (FDA). OrthoEvra is a transdermal patch applied weekly for 3 consecutive weeks, followed by 1 patch-free week per cycle.¹ The NuvaRing is a vaginal ring worn for 3 consecutive weeks in a 4-week cycle.²

The patch causes greater estrogen exposure than OCs or the ring

In November 2005, the FDA issued an update to the labeling of the OrthoEvra contraceptive patch, reporting increased systemic estrogen exposure, which may increase the risk of blood clots.³ The FDA warned that the transdermal patch exposes the user to 60% more estrogen than the typical birth control pill containing 35 μg EE.³ In January 2008, the FDA approved an additional update to include the results of a new study that found users of the patch to be at higher risk of developing VTE than OC users.^3,4

One pharmacokinetic study found that exposure to EE differed among delivery systems. The area under the EE concentration-vs-time curve in the patch group was 1.6 times higher than in the OC group (P<.05) and 3.4 times higher than in the vaginal ring group (P<.05).²

So what’s the VTE risk? Two studies, contrasting conclusions

A nested case-control study—based on a Phar-Metrics longitudinal database of information from paid claims by managed care health plans—included 215,769 women between the ages of 15 and 44 years who had started using the patch or a norgestimate-EE combination OC since April 1, 2002, when OrthoEvra was first introduced on the US market.⁵ Investigators identified 68 diagnosed cases of VTE with no identifiable risk factors.

The overall incidence of VTE in this study was 52.8 per 100,000 women-years (95% confidence interval [CI], 35.8-74.9) among patch users and 41.8 per 100,000 women-years among OC users (95% CI, 29.4-57.6).⁵ The study concluded that the risk of nonfatal VTE for the patch isn’t higher than the risk for an OC containing 35 μg EE and norgestimate (odds ratio [OR]=0.9; 95% CI, 0.5-1.6; incidence rate ratio [IRR]=1.1; 95% CI, 0.7-1.8).

A recent update to the study evaluated an additional 17 months of data on new cases of women meeting the same criteria. The supplementary results proved consistent with earlier conclusions, indicating that the risk of nonfatal VTE for the patch is similar to the risk for the OC (OR=1.1; 95% CI, 0.6-2.1).⁶ Combined data from the original study and the update show that the OR for VTE is 1.0 (95% CI, 0.7-1.5) in users of the patch compared with users of the OC.⁶

Another nested case-control study—based on UnitedHealthcare insurance claims data and confirmatory chart reviews—showed contrasting results. The study included 340,377 women between the ages of 15 and 44 years who were new users of the patch or new and previous users of a norgestimate-EE combination OC from April 1, 2002 through December 31, 2004.³ Investigators verified 57 diagnoses of VTE, controlling for confounding factors. The incidence of VTE in this study was 40.8 per 100,000 women-years among patch users and 18.3 per 100,000 women-years among users of the norgestimate-35 μg EE OC. The study reported a more than 2-fold increased risk of VTE in patch users compared to OC users (OR=2.4; 95% CI, 1.1-5.5; IRR=2.2; 95% CI, 1.3-3.8).^3,7

Do the differences between studies make a difference?

The 2 studies appear similar in design but have 2 major identifiable differences:

• The first study verified VTE diagnoses by claims for systemic anticoagulants, whereas the second study expanded its analysis by performing confirmatory chart reviews for VTE diagnoses.
• The first study included only new OC and patch users as of April 1, 2002, whereas the second study included new and experienced users of the OC as of April 1, 2002.

The significance of the differences in these studies is debatable; the results have yielded controversial, conflicting evidence.

Safety and tolerability are similar for the vaginal ring and OCs

A 1-year, open-label, randomized Phase III study of 1030 women compared the NuvaRing with a combination OC containing levonorgestrel and 30 μg EE. One case of deep venous thrombosis occurred in the NuvaRing group.

In reviewing the data, the authors concluded that the NuvaRing demonstrated comparable safety and tolerability to the OC.⁸ NuvaRing users experienced similar side effects compared with OC users.⁹

Recommendations

The World Health Organization Medical Eligibility Criteria for Contraceptive Use (WHOMEC) reports that long-term safety data for the estrogen-progestin contraceptive patch are not available.¹⁰ However, the limited studies that are available suggest a safety profile similar to that of combination OCs with comparable hormone formulations.

WHOMEC suggests that the guidelines for combination OCs also should apply to the patch and the ring. Women shouldn’t use these contraceptive methods if they have a history of VTE or current VTE or if they are undergoing major surgery that may include prolonged immobilization.¹⁰

Evidence summary

Two nonoral estrogen-progestin contraceptives have been approved by the US Food and Drug Administration (FDA). OrthoEvra is a transdermal patch applied weekly for 3 consecutive weeks, followed by 1 patch-free week per cycle.¹ The NuvaRing is a vaginal ring worn for 3 consecutive weeks in a 4-week cycle.²

The patch causes greater estrogen exposure than OCs or the ring

In November 2005, the FDA issued an update to the labeling of the OrthoEvra contraceptive patch, reporting increased systemic estrogen exposure, which may increase the risk of blood clots.³ The FDA warned that the transdermal patch exposes the user to 60% more estrogen than the typical birth control pill containing 35 μg EE.³ In January 2008, the FDA approved an additional update to include the results of a new study that found users of the patch to be at higher risk of developing VTE than OC users.^3,4

One pharmacokinetic study found that exposure to EE differed among delivery systems. The area under the EE concentration-vs-time curve in the patch group was 1.6 times higher than in the OC group (P<.05) and 3.4 times higher than in the vaginal ring group (P<.05).²

So what’s the VTE risk? Two studies, contrasting conclusions

A nested case-control study—based on a Phar-Metrics longitudinal database of information from paid claims by managed care health plans—included 215,769 women between the ages of 15 and 44 years who had started using the patch or a norgestimate-EE combination OC since April 1, 2002, when OrthoEvra was first introduced on the US market.⁵ Investigators identified 68 diagnosed cases of VTE with no identifiable risk factors.

The overall incidence of VTE in this study was 52.8 per 100,000 women-years (95% confidence interval [CI], 35.8-74.9) among patch users and 41.8 per 100,000 women-years among OC users (95% CI, 29.4-57.6).⁵ The study concluded that the risk of nonfatal VTE for the patch isn’t higher than the risk for an OC containing 35 μg EE and norgestimate (odds ratio [OR]=0.9; 95% CI, 0.5-1.6; incidence rate ratio [IRR]=1.1; 95% CI, 0.7-1.8).

A recent update to the study evaluated an additional 17 months of data on new cases of women meeting the same criteria. The supplementary results proved consistent with earlier conclusions, indicating that the risk of nonfatal VTE for the patch is similar to the risk for the OC (OR=1.1; 95% CI, 0.6-2.1).⁶ Combined data from the original study and the update show that the OR for VTE is 1.0 (95% CI, 0.7-1.5) in users of the patch compared with users of the OC.⁶

Another nested case-control study—based on UnitedHealthcare insurance claims data and confirmatory chart reviews—showed contrasting results. The study included 340,377 women between the ages of 15 and 44 years who were new users of the patch or new and previous users of a norgestimate-EE combination OC from April 1, 2002 through December 31, 2004.³ Investigators verified 57 diagnoses of VTE, controlling for confounding factors. The incidence of VTE in this study was 40.8 per 100,000 women-years among patch users and 18.3 per 100,000 women-years among users of the norgestimate-35 μg EE OC. The study reported a more than 2-fold increased risk of VTE in patch users compared to OC users (OR=2.4; 95% CI, 1.1-5.5; IRR=2.2; 95% CI, 1.3-3.8).^3,7

Do the differences between studies make a difference?

The 2 studies appear similar in design but have 2 major identifiable differences:

• The first study verified VTE diagnoses by claims for systemic anticoagulants, whereas the second study expanded its analysis by performing confirmatory chart reviews for VTE diagnoses.
• The first study included only new OC and patch users as of April 1, 2002, whereas the second study included new and experienced users of the OC as of April 1, 2002.

The significance of the differences in these studies is debatable; the results have yielded controversial, conflicting evidence.

Safety and tolerability are similar for the vaginal ring and OCs

A 1-year, open-label, randomized Phase III study of 1030 women compared the NuvaRing with a combination OC containing levonorgestrel and 30 μg EE. One case of deep venous thrombosis occurred in the NuvaRing group.

In reviewing the data, the authors concluded that the NuvaRing demonstrated comparable safety and tolerability to the OC.⁸ NuvaRing users experienced similar side effects compared with OC users.⁹

Recommendations

The World Health Organization Medical Eligibility Criteria for Contraceptive Use (WHOMEC) reports that long-term safety data for the estrogen-progestin contraceptive patch are not available.¹⁰ However, the limited studies that are available suggest a safety profile similar to that of combination OCs with comparable hormone formulations.

WHOMEC suggests that the guidelines for combination OCs also should apply to the patch and the ring. Women shouldn’t use these contraceptive methods if they have a history of VTE or current VTE or if they are undergoing major surgery that may include prolonged immobilization.¹⁰

Evidence summary

Normal values for total or corrected serum calcium are 8.5-10.2 mg/dL and for ionized calcium, 4.4-5.4 mg/dL. Because total serum calcium is approximately 50% free (ionized) and 50% bound, primarily to albumin, the serum level must be “corrected” if hypoalbuminemia exists. Because serum calcium comprises less than 1% of body stores, severe total body deficiency of calcium can exist without hypocalcemia.^1,2

Ionized calcium is under tight physiologic control, monitored by calcium-sensing proteins in the parathyroid gland; low ionized calcium augments PTH secretion, which in turn has 3 primary actions:

• decreased calcium excretion by the kidneys
• increased activity of osteoclasts, leading to calcium release from bone
• increased activity of renal 25-OH vitamin D hydroxylase, resulting in elevated serum levels of calcitriol, the active form of vitamin D; elevated calcitriol in turn augments gastrointestinal absorption of calcium.

An adequate supply of 25-OH vitamin D to the kidneys requires adequate gastrointestinal absorption or sun-induced skin production of vitamin D and sufficient liver function to carry out the first of the 2 hydroxylation steps.^1,3

Common causes of hypocalcemia

We found no studies that established the frequency of various causes of hypocalcemia in the general population, but reviewers concurred that the most common specific causes, in order of frequency, are (TABLE):^2,3

• renal failure
• vitamin D deficiency
• hypomagnesemia
• pancreatitis
• hypoparathyroidism.

It is not surprising that renal failure is a common cause of hypocalcemia, given the high prevalence of chronic kidney disease in adults—11.2% of the total United States population older than 20 years has at least a mildly reduced glomerular filtration rate (stage 2, chronic kidney disease, with glomerular filtration rate <90 cc/min).⁴ Despite elevated PTH, serum calcium may be slightly reduced (and osteomalacia present) even in mild chronic kidney disease.^5,6 Only severe or end-stage chronic kidney disease (glomerular filtration rate <30 cc/min, 5.8% of population) is often associated with actual hypocalcemia.^5,6 Likewise, the prevalence of vitamin D deficiency (<15 ng/mL of 25-OH vitamin D) is 35% to 55% in the general population,^7,8 and 95% in institutionalized elderly patients.⁹

Chronic kidney disease (66%) and vitamin D deficiency (24%) were the most common causes of hypocalcemia in a study of 594 elderly general medicine inpatients.¹⁰ In a study of 62 hypocalcemic patients in a medical intensive care unit, the cause of the hypocalcemia could be determined in only 28 (45%); most of the cases were caused by hypomagnesemia (28%), renal insufficiency (8%), and pancreatitis (3%).¹¹

TABLE
Causes of hypocalcemia by key test results

Serious causes of hypocalcemia

The usual cause of critically low serum calcium (<7 mg/dL “corrected” or <3.2 mg/dL ionized) is parathyroidectomy or acute renal failure. Hypocalcemia resulting from partial parathyroidectomy or thyroidectomy (with inadvertent parathyroidectomy) occurs in approximately 5% of these surgeries; 99.5% of cases resolve completely within a year.¹²

Recommendations

Several reviewers recommend a similar workup and differential diagnosis for hypocalcemia. Unfortunately, none cites quantitative data on the prevalence of hypocalcemia and its causes.^2,13

Some authors recommend measuring 25-OH vitamin D in all hypocalcemia patients with elevated PTH without hyperphosphatemia to confirm vitamin D deficiency.^1,2 Others emphasize the importance of measuring ionized calcium to detect hypocalcemia, especially in critically ill patients, in whom many acute variables can decrease ionized calcium (alkalosis can increase protein binding, for example).^1,3,14

Although several reviewers present an algorithmic approach to determining the cause of hypocalcemia,³ we could find no data on the derivation or validation of the diagnostic effectiveness of these algorithms.

Evidence summary

Normal values for total or corrected serum calcium are 8.5-10.2 mg/dL and for ionized calcium, 4.4-5.4 mg/dL. Because total serum calcium is approximately 50% free (ionized) and 50% bound, primarily to albumin, the serum level must be “corrected” if hypoalbuminemia exists. Because serum calcium comprises less than 1% of body stores, severe total body deficiency of calcium can exist without hypocalcemia.^1,2

Ionized calcium is under tight physiologic control, monitored by calcium-sensing proteins in the parathyroid gland; low ionized calcium augments PTH secretion, which in turn has 3 primary actions:

• decreased calcium excretion by the kidneys
• increased activity of osteoclasts, leading to calcium release from bone
• increased activity of renal 25-OH vitamin D hydroxylase, resulting in elevated serum levels of calcitriol, the active form of vitamin D; elevated calcitriol in turn augments gastrointestinal absorption of calcium.

An adequate supply of 25-OH vitamin D to the kidneys requires adequate gastrointestinal absorption or sun-induced skin production of vitamin D and sufficient liver function to carry out the first of the 2 hydroxylation steps.^1,3

Common causes of hypocalcemia

We found no studies that established the frequency of various causes of hypocalcemia in the general population, but reviewers concurred that the most common specific causes, in order of frequency, are (TABLE):^2,3

• renal failure
• vitamin D deficiency
• hypomagnesemia
• pancreatitis
• hypoparathyroidism.

It is not surprising that renal failure is a common cause of hypocalcemia, given the high prevalence of chronic kidney disease in adults—11.2% of the total United States population older than 20 years has at least a mildly reduced glomerular filtration rate (stage 2, chronic kidney disease, with glomerular filtration rate <90 cc/min).⁴ Despite elevated PTH, serum calcium may be slightly reduced (and osteomalacia present) even in mild chronic kidney disease.^5,6 Only severe or end-stage chronic kidney disease (glomerular filtration rate <30 cc/min, 5.8% of population) is often associated with actual hypocalcemia.^5,6 Likewise, the prevalence of vitamin D deficiency (<15 ng/mL of 25-OH vitamin D) is 35% to 55% in the general population,^7,8 and 95% in institutionalized elderly patients.⁹

Chronic kidney disease (66%) and vitamin D deficiency (24%) were the most common causes of hypocalcemia in a study of 594 elderly general medicine inpatients.¹⁰ In a study of 62 hypocalcemic patients in a medical intensive care unit, the cause of the hypocalcemia could be determined in only 28 (45%); most of the cases were caused by hypomagnesemia (28%), renal insufficiency (8%), and pancreatitis (3%).¹¹

TABLE
Causes of hypocalcemia by key test results

Serious causes of hypocalcemia

The usual cause of critically low serum calcium (<7 mg/dL “corrected” or <3.2 mg/dL ionized) is parathyroidectomy or acute renal failure. Hypocalcemia resulting from partial parathyroidectomy or thyroidectomy (with inadvertent parathyroidectomy) occurs in approximately 5% of these surgeries; 99.5% of cases resolve completely within a year.¹²

Recommendations

Several reviewers recommend a similar workup and differential diagnosis for hypocalcemia. Unfortunately, none cites quantitative data on the prevalence of hypocalcemia and its causes.^2,13

Some authors recommend measuring 25-OH vitamin D in all hypocalcemia patients with elevated PTH without hyperphosphatemia to confirm vitamin D deficiency.^1,2 Others emphasize the importance of measuring ionized calcium to detect hypocalcemia, especially in critically ill patients, in whom many acute variables can decrease ionized calcium (alkalosis can increase protein binding, for example).^1,3,14

Although several reviewers present an algorithmic approach to determining the cause of hypocalcemia,³ we could find no data on the derivation or validation of the diagnostic effectiveness of these algorithms.

Evidence summary

Normal values for total or corrected serum calcium are 8.5-10.2 mg/dL and for ionized calcium, 4.4-5.4 mg/dL. Because total serum calcium is approximately 50% free (ionized) and 50% bound, primarily to albumin, the serum level must be “corrected” if hypoalbuminemia exists. Because serum calcium comprises less than 1% of body stores, severe total body deficiency of calcium can exist without hypocalcemia.^1,2

Ionized calcium is under tight physiologic control, monitored by calcium-sensing proteins in the parathyroid gland; low ionized calcium augments PTH secretion, which in turn has 3 primary actions:

• decreased calcium excretion by the kidneys
• increased activity of osteoclasts, leading to calcium release from bone
• increased activity of renal 25-OH vitamin D hydroxylase, resulting in elevated serum levels of calcitriol, the active form of vitamin D; elevated calcitriol in turn augments gastrointestinal absorption of calcium.

An adequate supply of 25-OH vitamin D to the kidneys requires adequate gastrointestinal absorption or sun-induced skin production of vitamin D and sufficient liver function to carry out the first of the 2 hydroxylation steps.^1,3

Common causes of hypocalcemia

We found no studies that established the frequency of various causes of hypocalcemia in the general population, but reviewers concurred that the most common specific causes, in order of frequency, are (TABLE):^2,3

• renal failure
• vitamin D deficiency
• hypomagnesemia
• pancreatitis
• hypoparathyroidism.

It is not surprising that renal failure is a common cause of hypocalcemia, given the high prevalence of chronic kidney disease in adults—11.2% of the total United States population older than 20 years has at least a mildly reduced glomerular filtration rate (stage 2, chronic kidney disease, with glomerular filtration rate <90 cc/min).⁴ Despite elevated PTH, serum calcium may be slightly reduced (and osteomalacia present) even in mild chronic kidney disease.^5,6 Only severe or end-stage chronic kidney disease (glomerular filtration rate <30 cc/min, 5.8% of population) is often associated with actual hypocalcemia.^5,6 Likewise, the prevalence of vitamin D deficiency (<15 ng/mL of 25-OH vitamin D) is 35% to 55% in the general population,^7,8 and 95% in institutionalized elderly patients.⁹

Chronic kidney disease (66%) and vitamin D deficiency (24%) were the most common causes of hypocalcemia in a study of 594 elderly general medicine inpatients.¹⁰ In a study of 62 hypocalcemic patients in a medical intensive care unit, the cause of the hypocalcemia could be determined in only 28 (45%); most of the cases were caused by hypomagnesemia (28%), renal insufficiency (8%), and pancreatitis (3%).¹¹

TABLE
Causes of hypocalcemia by key test results

Serious causes of hypocalcemia

The usual cause of critically low serum calcium (<7 mg/dL “corrected” or <3.2 mg/dL ionized) is parathyroidectomy or acute renal failure. Hypocalcemia resulting from partial parathyroidectomy or thyroidectomy (with inadvertent parathyroidectomy) occurs in approximately 5% of these surgeries; 99.5% of cases resolve completely within a year.¹²

Recommendations

Several reviewers recommend a similar workup and differential diagnosis for hypocalcemia. Unfortunately, none cites quantitative data on the prevalence of hypocalcemia and its causes.^2,13

Some authors recommend measuring 25-OH vitamin D in all hypocalcemia patients with elevated PTH without hyperphosphatemia to confirm vitamin D deficiency.^1,2 Others emphasize the importance of measuring ionized calcium to detect hypocalcemia, especially in critically ill patients, in whom many acute variables can decrease ionized calcium (alkalosis can increase protein binding, for example).^1,3,14

Although several reviewers present an algorithmic approach to determining the cause of hypocalcemia,³ we could find no data on the derivation or validation of the diagnostic effectiveness of these algorithms.

Evidence summary

The influence of cigarette smoking on the development of CHD has been well documented.^1,2 RR ranges from 1.5 to 3, depending on variables such as age, sex, and quantity of tobacco used.³ Quitting smoking reduces overall mortality more than other forms of secondary prevention, including aspirin, β-blockers, angiotensin-converting enzyme inhibitors, and cholesterol-lowering statins.³ In the wake of such evidence-based findings, the American Heart Association and American College of Cardiology Task Force developed clinical practice guidelines that recommend complete smoking cessation for secondary prevention of CHD in cardiac patients.⁴

0 cigarettes=lower mortality and morbidity

A Cochrane Heart Group meta-analysis examining all-cause CHD mortality in 20 cohort studies (n=12,603 patients), found a 36% reduction in mortality risk for CHD patients who quit smoking compared with those who didn’t (RR=0.64; 95% confidence interval [CI], 0.58-0.71).³ The review also noted a reduction in risk for nonfatal myocardial infarctions (RR=0.68; 95% CI, 0.57-0.82).³ The authors didn’t report how soon after smoking cessation mortality risk declined.

The authors acknowledge several limitations of the review, including the use of observational data and crude estimates, as well as potential publication bias and the misclassification of smoking status. Notably, however, their findings are consistent with the landmark prospective, community-based cohort Framingham Heart Study (N=1422), which indicates that smoking status predicts overall and morbidity-free survival at age 85.⁵

Smoking cessation has also been found to significantly affect morbidity among cardiac patients. Short-term benefits have been demonstrated in CHD patients after a myocardial infarction or coronary artery revascularization.⁶ Smoking status at 1-year follow-up was associated with a significant reduction in subsequent cardiac events (myocardial infarction, ischemic cerebrovascular event, revascularization, or death from CHD) when smokers who quit after an initial CHD event were compared with continuing smokers (odds ratio=0.71; 95% CI, 0.38-1.33).⁶

Going the distance is worth it

Regarding the role of extended abstinence on subsequent cardiac events, long-term quit status in post-coronary artery bypass graft (CABG) surgery patients has been found to predict decreased morbidity and lower rates of repeat revascularization surgery. Findings from the Coronary Artery Surgery Study show that, at 10-year follow-up, nonsmokers were more likely to be free of angina (54% of nonsmokers vs 42% of smokers; P=.02, NNT=8.3) and less likely to experience moderate to severe physical limitations (13% of non-smokers vs 24% of smokers; P=.0004; NNT=9.1). Nonsmokers also had fewer CHD-related admissions than smokers (2.6 vs 3.8; P<.0001).⁷

Another study found similar results at 20-year follow-up: Patients who had quit smoking underwent fewer repeat CABGs than smokers (RR=1.41; 95% CI, 1.02-1.94).⁸ The difference between post-CABG survival curves for quitters versus smokers increased from 3% at 5 years (98% vs 95%) to 15% at 15 years (70% vs 55%; P<.0001; NNT=6.7).⁸

Recommendations

The US Department of Health and Human Services recommends smoking cessation as an integral part of both primary and secondary prevention of CHD. Quitting reduces development of atherosclerosis and lowers the incidence of initial and recurrent myocardial infarction, thrombosis, cardiac arrhythmia, and death from cardiovascular causes.²

Evidence summary

The influence of cigarette smoking on the development of CHD has been well documented.^1,2 RR ranges from 1.5 to 3, depending on variables such as age, sex, and quantity of tobacco used.³ Quitting smoking reduces overall mortality more than other forms of secondary prevention, including aspirin, β-blockers, angiotensin-converting enzyme inhibitors, and cholesterol-lowering statins.³ In the wake of such evidence-based findings, the American Heart Association and American College of Cardiology Task Force developed clinical practice guidelines that recommend complete smoking cessation for secondary prevention of CHD in cardiac patients.⁴

0 cigarettes=lower mortality and morbidity

A Cochrane Heart Group meta-analysis examining all-cause CHD mortality in 20 cohort studies (n=12,603 patients), found a 36% reduction in mortality risk for CHD patients who quit smoking compared with those who didn’t (RR=0.64; 95% confidence interval [CI], 0.58-0.71).³ The review also noted a reduction in risk for nonfatal myocardial infarctions (RR=0.68; 95% CI, 0.57-0.82).³ The authors didn’t report how soon after smoking cessation mortality risk declined.

The authors acknowledge several limitations of the review, including the use of observational data and crude estimates, as well as potential publication bias and the misclassification of smoking status. Notably, however, their findings are consistent with the landmark prospective, community-based cohort Framingham Heart Study (N=1422), which indicates that smoking status predicts overall and morbidity-free survival at age 85.⁵

Smoking cessation has also been found to significantly affect morbidity among cardiac patients. Short-term benefits have been demonstrated in CHD patients after a myocardial infarction or coronary artery revascularization.⁶ Smoking status at 1-year follow-up was associated with a significant reduction in subsequent cardiac events (myocardial infarction, ischemic cerebrovascular event, revascularization, or death from CHD) when smokers who quit after an initial CHD event were compared with continuing smokers (odds ratio=0.71; 95% CI, 0.38-1.33).⁶

Going the distance is worth it

Regarding the role of extended abstinence on subsequent cardiac events, long-term quit status in post-coronary artery bypass graft (CABG) surgery patients has been found to predict decreased morbidity and lower rates of repeat revascularization surgery. Findings from the Coronary Artery Surgery Study show that, at 10-year follow-up, nonsmokers were more likely to be free of angina (54% of nonsmokers vs 42% of smokers; P=.02, NNT=8.3) and less likely to experience moderate to severe physical limitations (13% of non-smokers vs 24% of smokers; P=.0004; NNT=9.1). Nonsmokers also had fewer CHD-related admissions than smokers (2.6 vs 3.8; P<.0001).⁷

Another study found similar results at 20-year follow-up: Patients who had quit smoking underwent fewer repeat CABGs than smokers (RR=1.41; 95% CI, 1.02-1.94).⁸ The difference between post-CABG survival curves for quitters versus smokers increased from 3% at 5 years (98% vs 95%) to 15% at 15 years (70% vs 55%; P<.0001; NNT=6.7).⁸

Recommendations

The US Department of Health and Human Services recommends smoking cessation as an integral part of both primary and secondary prevention of CHD. Quitting reduces development of atherosclerosis and lowers the incidence of initial and recurrent myocardial infarction, thrombosis, cardiac arrhythmia, and death from cardiovascular causes.²

Evidence summary

The influence of cigarette smoking on the development of CHD has been well documented.^1,2 RR ranges from 1.5 to 3, depending on variables such as age, sex, and quantity of tobacco used.³ Quitting smoking reduces overall mortality more than other forms of secondary prevention, including aspirin, β-blockers, angiotensin-converting enzyme inhibitors, and cholesterol-lowering statins.³ In the wake of such evidence-based findings, the American Heart Association and American College of Cardiology Task Force developed clinical practice guidelines that recommend complete smoking cessation for secondary prevention of CHD in cardiac patients.⁴

0 cigarettes=lower mortality and morbidity

A Cochrane Heart Group meta-analysis examining all-cause CHD mortality in 20 cohort studies (n=12,603 patients), found a 36% reduction in mortality risk for CHD patients who quit smoking compared with those who didn’t (RR=0.64; 95% confidence interval [CI], 0.58-0.71).³ The review also noted a reduction in risk for nonfatal myocardial infarctions (RR=0.68; 95% CI, 0.57-0.82).³ The authors didn’t report how soon after smoking cessation mortality risk declined.

The authors acknowledge several limitations of the review, including the use of observational data and crude estimates, as well as potential publication bias and the misclassification of smoking status. Notably, however, their findings are consistent with the landmark prospective, community-based cohort Framingham Heart Study (N=1422), which indicates that smoking status predicts overall and morbidity-free survival at age 85.⁵

Smoking cessation has also been found to significantly affect morbidity among cardiac patients. Short-term benefits have been demonstrated in CHD patients after a myocardial infarction or coronary artery revascularization.⁶ Smoking status at 1-year follow-up was associated with a significant reduction in subsequent cardiac events (myocardial infarction, ischemic cerebrovascular event, revascularization, or death from CHD) when smokers who quit after an initial CHD event were compared with continuing smokers (odds ratio=0.71; 95% CI, 0.38-1.33).⁶

Going the distance is worth it

Regarding the role of extended abstinence on subsequent cardiac events, long-term quit status in post-coronary artery bypass graft (CABG) surgery patients has been found to predict decreased morbidity and lower rates of repeat revascularization surgery. Findings from the Coronary Artery Surgery Study show that, at 10-year follow-up, nonsmokers were more likely to be free of angina (54% of nonsmokers vs 42% of smokers; P=.02, NNT=8.3) and less likely to experience moderate to severe physical limitations (13% of non-smokers vs 24% of smokers; P=.0004; NNT=9.1). Nonsmokers also had fewer CHD-related admissions than smokers (2.6 vs 3.8; P<.0001).⁷

Another study found similar results at 20-year follow-up: Patients who had quit smoking underwent fewer repeat CABGs than smokers (RR=1.41; 95% CI, 1.02-1.94).⁸ The difference between post-CABG survival curves for quitters versus smokers increased from 3% at 5 years (98% vs 95%) to 15% at 15 years (70% vs 55%; P<.0001; NNT=6.7).⁸

Recommendations

The US Department of Health and Human Services recommends smoking cessation as an integral part of both primary and secondary prevention of CHD. Quitting reduces development of atherosclerosis and lowers the incidence of initial and recurrent myocardial infarction, thrombosis, cardiac arrhythmia, and death from cardiovascular causes.²

Evidence summary

As many as 25% of patients with GAS pharyngitis remain culture-positive after an adequate regimen of antibiotic therapy and are deemed GAS carriers.¹ Appropriate screening and management of asymptomatic carriers continues to cause confusion.

Routine treatment is usually unnecessary

The Infectious Diseases Society of America (IDSA) considers GAS carriers at low risk for developing complications and spreading infection to close contacts.² The 2002 IDSA practice guidelines recommend against routine screening for and treatment of GAS carriage except under the circumstances (2 through 7) outlined in the evidence-based answer.² It may be reasonable to treat patients whose carrier status is unknown when they have a second case of pharyngitis. For known GAS-positive patients, however, repeated episodes of pharyngitis over months or years should raise suspicion of intercurrent viral pharyngitis rather than true GAS pharyngitis.

When you should consider routine treatment

Some experts practicing in areas with a high prevalence of acute rheumatic fever take a different position: They favor routine treatment of patients with active pharyngitis and a positive throat culture, even if the patient is a known GAS carrier.³

No clear consensus on prophylaxis

In 1995, the Centers for Disease Control and Prevention convened a consensus group to address the issue of prophylaxis for people exposed to GAS-positive carriers, but the consensus group failed to reach a definitive conclusion.⁴

Clindamycin works; penicillin + rifampin is also effective

Most RCTs investigating effective antibiotic treatment of GAS target cases of acute pharyngitis. A wide variety of antibiotics have been studied, including cefadroxil, amoxicillin, amoxicillin/clavulanate, cefuroxime, azithromycin, cefprozil, and cephalexin. We evaluated 41 of 43 studies of treatment of acute GAS. Only 2 RCTs specifically address effective antibiotic regimens for treating GAS carriers.

The most recent study demonstrated a significantly greater eradication rate with oral clindamycin than penicillin plus rifampin (P<.025).⁵ Compared with penicillin plus rifampin after 3 weeks of therapy, the number needed to treat (NNT) for clindamycin was 4.⁵

An older study found intramuscular penicillin plus 4 days of oral rifampin superior to intramuscular penicillin alone (P<.005) or no treatment at all (P<.0005) for eradicating GAS in carriers.¹ Compared with placebo after 3 weeks of therapy, the NNT for penicillin plus rifampin was 2.¹

The IDSA recommends a 10-day course of amoxicillin/clavulanate as an alternative treatment option.²

Recommendations

The 2006 Red Book: Report of the Committee on Infectious Diseases notes 6 possible indications for treating GAS carriers; they’re nearly identical to circumstances 2 through 7 in the evidence-based answer.⁶ The Red Book also acknowledges several treatment options, including clindamycin, amoxicillin, azithromycin, and penicillin plus rifampin. A 10-day course of oral clindamycin, however, is the therapy of choice.⁶

Evidence summary

As many as 25% of patients with GAS pharyngitis remain culture-positive after an adequate regimen of antibiotic therapy and are deemed GAS carriers.¹ Appropriate screening and management of asymptomatic carriers continues to cause confusion.

Routine treatment is usually unnecessary

The Infectious Diseases Society of America (IDSA) considers GAS carriers at low risk for developing complications and spreading infection to close contacts.² The 2002 IDSA practice guidelines recommend against routine screening for and treatment of GAS carriage except under the circumstances (2 through 7) outlined in the evidence-based answer.² It may be reasonable to treat patients whose carrier status is unknown when they have a second case of pharyngitis. For known GAS-positive patients, however, repeated episodes of pharyngitis over months or years should raise suspicion of intercurrent viral pharyngitis rather than true GAS pharyngitis.

When you should consider routine treatment

Some experts practicing in areas with a high prevalence of acute rheumatic fever take a different position: They favor routine treatment of patients with active pharyngitis and a positive throat culture, even if the patient is a known GAS carrier.³

No clear consensus on prophylaxis

In 1995, the Centers for Disease Control and Prevention convened a consensus group to address the issue of prophylaxis for people exposed to GAS-positive carriers, but the consensus group failed to reach a definitive conclusion.⁴

Clindamycin works; penicillin + rifampin is also effective

Most RCTs investigating effective antibiotic treatment of GAS target cases of acute pharyngitis. A wide variety of antibiotics have been studied, including cefadroxil, amoxicillin, amoxicillin/clavulanate, cefuroxime, azithromycin, cefprozil, and cephalexin. We evaluated 41 of 43 studies of treatment of acute GAS. Only 2 RCTs specifically address effective antibiotic regimens for treating GAS carriers.

The most recent study demonstrated a significantly greater eradication rate with oral clindamycin than penicillin plus rifampin (P<.025).⁵ Compared with penicillin plus rifampin after 3 weeks of therapy, the number needed to treat (NNT) for clindamycin was 4.⁵

An older study found intramuscular penicillin plus 4 days of oral rifampin superior to intramuscular penicillin alone (P<.005) or no treatment at all (P<.0005) for eradicating GAS in carriers.¹ Compared with placebo after 3 weeks of therapy, the NNT for penicillin plus rifampin was 2.¹

The IDSA recommends a 10-day course of amoxicillin/clavulanate as an alternative treatment option.²

Recommendations

The 2006 Red Book: Report of the Committee on Infectious Diseases notes 6 possible indications for treating GAS carriers; they’re nearly identical to circumstances 2 through 7 in the evidence-based answer.⁶ The Red Book also acknowledges several treatment options, including clindamycin, amoxicillin, azithromycin, and penicillin plus rifampin. A 10-day course of oral clindamycin, however, is the therapy of choice.⁶

Evidence summary

As many as 25% of patients with GAS pharyngitis remain culture-positive after an adequate regimen of antibiotic therapy and are deemed GAS carriers.¹ Appropriate screening and management of asymptomatic carriers continues to cause confusion.

Routine treatment is usually unnecessary

The Infectious Diseases Society of America (IDSA) considers GAS carriers at low risk for developing complications and spreading infection to close contacts.² The 2002 IDSA practice guidelines recommend against routine screening for and treatment of GAS carriage except under the circumstances (2 through 7) outlined in the evidence-based answer.² It may be reasonable to treat patients whose carrier status is unknown when they have a second case of pharyngitis. For known GAS-positive patients, however, repeated episodes of pharyngitis over months or years should raise suspicion of intercurrent viral pharyngitis rather than true GAS pharyngitis.

When you should consider routine treatment

Some experts practicing in areas with a high prevalence of acute rheumatic fever take a different position: They favor routine treatment of patients with active pharyngitis and a positive throat culture, even if the patient is a known GAS carrier.³

No clear consensus on prophylaxis

In 1995, the Centers for Disease Control and Prevention convened a consensus group to address the issue of prophylaxis for people exposed to GAS-positive carriers, but the consensus group failed to reach a definitive conclusion.⁴

Clindamycin works; penicillin + rifampin is also effective

Most RCTs investigating effective antibiotic treatment of GAS target cases of acute pharyngitis. A wide variety of antibiotics have been studied, including cefadroxil, amoxicillin, amoxicillin/clavulanate, cefuroxime, azithromycin, cefprozil, and cephalexin. We evaluated 41 of 43 studies of treatment of acute GAS. Only 2 RCTs specifically address effective antibiotic regimens for treating GAS carriers.

The most recent study demonstrated a significantly greater eradication rate with oral clindamycin than penicillin plus rifampin (P<.025).⁵ Compared with penicillin plus rifampin after 3 weeks of therapy, the number needed to treat (NNT) for clindamycin was 4.⁵

An older study found intramuscular penicillin plus 4 days of oral rifampin superior to intramuscular penicillin alone (P<.005) or no treatment at all (P<.0005) for eradicating GAS in carriers.¹ Compared with placebo after 3 weeks of therapy, the NNT for penicillin plus rifampin was 2.¹

The IDSA recommends a 10-day course of amoxicillin/clavulanate as an alternative treatment option.²

Recommendations

The 2006 Red Book: Report of the Committee on Infectious Diseases notes 6 possible indications for treating GAS carriers; they’re nearly identical to circumstances 2 through 7 in the evidence-based answer.⁶ The Red Book also acknowledges several treatment options, including clindamycin, amoxicillin, azithromycin, and penicillin plus rifampin. A 10-day course of oral clindamycin, however, is the therapy of choice.⁶

Evidence summary

Although TSH followed by free T₄ remain the initial screening tests for thyroid disorders, adding thyroid autoantibodies may refine the diagnosis. Three principal thyroid antibodies—TPOAb, thyroglobulin, and TRAb—can be positive in a variety of autoimmune thyroid disorders. TPOAb represents a specific antigen of antimicrosomal antibody (AMA). It has largely replaced AMA testing in most laboratories and clinical settings.

Antibodies point to Graves’, autoimmune disorders

A cross-sectional study of 267 Singaporean patients with previously diagnosed thyroid disorders measured TRAb, AMA, and thyroglobulin (TABLE). TRAb levels >10 U/L were found to have a positive likelihood ratio (LR+) of 13 and a negative likelihood ratio (LR–) of 0.2 for Graves’ disease.¹

Two cross-sectional studies compared AMA to TPOAb in healthy patients and those with autoimmune thyroid and nonthyroid disorders. One study of 235 people in a university endocrinology department found that a TPOAb level >190 U/mL yielded an LR+ of 10.75 and an LR– of 0.15 for chronic autoimmune (Hashimoto’s) thyroiditis [CAHT]; the AMA-positive sera yielded an LR+ of 13.67 and an LR– of 0.19. Both TPOAb and AMA test characteristics were highly associated with CAHT (P<.001).

TABLE
Autoimmune markers in thyroid disorders

TPOAb is more sensitive than AMA and thyroglobulin

In the second study comparing AMA to TPOAb, the thyroid antibody test results of 32 healthy patients were compared with those of 262 clinic patients. In those with known thyroid dysfunction, TPOAb was found to be a more sensitive assay than AMA for autoimmune thyroid disorders. The sensitivity of TPOAb levels >3.1 U/mL was 88.1%; AMA sensitivity was 70.2% (P<.001).^2,3

A cross-sectional study (National Health and Nutrition Examination Survey [NHANES III]) evaluated the presence of thyroid antibodies in 17,353 people representing the geographic and ethnic distribution of the United States, 95% of whom were categorized as free of thyroid disease.⁴ The study found that TPOAb was more sensitive than thyroglobulin for diagnosing nonspecific thyroid disease. The diagnosis of thyroid disease was based on abnormal TSH and free T₄ levels. Abnormally high levels of TPOAb had an LR+ of 4.3 and LR– of 0.6 (P<.0001) for thyroid disease, compared with an LR+ of 3.4 and LR– of 0.7 (P<.01) for abnormally elevated thyroglobulin.

TSH + TPOAb more accurate than TSH in women

In the early 1970s, a cohort study of 2779 adults from Great Britain attempted to establish the incidence of thyroid disease in the general population by measuring TSH and TPOAb. Twenty years later, investigators restudied 1708 people from the original sample to determine the incidence of hypothyroidism and the prognostic value of these 2 biochemical markers for its development. At follow-up, the definition of a new case of hypothyroidism was based on an “intention to treat by the general practitioner by meeting clear biochemical criteria and/or symptoms.”

The initial presence of abnormally high serum TPOAb levels and TSH >2.0 mU/L predicted a 4.3% annual risk of developing hypothyroidism compared with a 2.6% annual risk with serum TSH >6.0 mU/L alone in women. This risk was not estimated for men because of the small number of cases.⁵

Recommendations

The American Association of Clinical Endocrinologists (AACE) makes no specific recommendations about laboratory testing of thyroid antibodies. Based on clinical judgment, the AACE states that antibodies may be considered in the workup of hyperthyroidism and hypothyroidism and to determine potential risk to the fetus in pregnant women diagnosed with Graves’ disease.⁶

The National Academy of Clinical Biochemistry (NACB) recommends TPOAb measurements in patients who have Down syndrome, are pregnant, or have miscarried or failed in vitro fertilization. The NACB also advocates measuring TPOAb before treatment with amiodarone, lithium, interferon-α, or interleukin-2.⁷

Evidence summary

Although TSH followed by free T₄ remain the initial screening tests for thyroid disorders, adding thyroid autoantibodies may refine the diagnosis. Three principal thyroid antibodies—TPOAb, thyroglobulin, and TRAb—can be positive in a variety of autoimmune thyroid disorders. TPOAb represents a specific antigen of antimicrosomal antibody (AMA). It has largely replaced AMA testing in most laboratories and clinical settings.

Antibodies point to Graves’, autoimmune disorders

A cross-sectional study of 267 Singaporean patients with previously diagnosed thyroid disorders measured TRAb, AMA, and thyroglobulin (TABLE). TRAb levels >10 U/L were found to have a positive likelihood ratio (LR+) of 13 and a negative likelihood ratio (LR–) of 0.2 for Graves’ disease.¹

Two cross-sectional studies compared AMA to TPOAb in healthy patients and those with autoimmune thyroid and nonthyroid disorders. One study of 235 people in a university endocrinology department found that a TPOAb level >190 U/mL yielded an LR+ of 10.75 and an LR– of 0.15 for chronic autoimmune (Hashimoto’s) thyroiditis [CAHT]; the AMA-positive sera yielded an LR+ of 13.67 and an LR– of 0.19. Both TPOAb and AMA test characteristics were highly associated with CAHT (P<.001).

TABLE
Autoimmune markers in thyroid disorders

TPOAb is more sensitive than AMA and thyroglobulin

In the second study comparing AMA to TPOAb, the thyroid antibody test results of 32 healthy patients were compared with those of 262 clinic patients. In those with known thyroid dysfunction, TPOAb was found to be a more sensitive assay than AMA for autoimmune thyroid disorders. The sensitivity of TPOAb levels >3.1 U/mL was 88.1%; AMA sensitivity was 70.2% (P<.001).^2,3

A cross-sectional study (National Health and Nutrition Examination Survey [NHANES III]) evaluated the presence of thyroid antibodies in 17,353 people representing the geographic and ethnic distribution of the United States, 95% of whom were categorized as free of thyroid disease.⁴ The study found that TPOAb was more sensitive than thyroglobulin for diagnosing nonspecific thyroid disease. The diagnosis of thyroid disease was based on abnormal TSH and free T₄ levels. Abnormally high levels of TPOAb had an LR+ of 4.3 and LR– of 0.6 (P<.0001) for thyroid disease, compared with an LR+ of 3.4 and LR– of 0.7 (P<.01) for abnormally elevated thyroglobulin.

TSH + TPOAb more accurate than TSH in women

In the early 1970s, a cohort study of 2779 adults from Great Britain attempted to establish the incidence of thyroid disease in the general population by measuring TSH and TPOAb. Twenty years later, investigators restudied 1708 people from the original sample to determine the incidence of hypothyroidism and the prognostic value of these 2 biochemical markers for its development. At follow-up, the definition of a new case of hypothyroidism was based on an “intention to treat by the general practitioner by meeting clear biochemical criteria and/or symptoms.”

The initial presence of abnormally high serum TPOAb levels and TSH >2.0 mU/L predicted a 4.3% annual risk of developing hypothyroidism compared with a 2.6% annual risk with serum TSH >6.0 mU/L alone in women. This risk was not estimated for men because of the small number of cases.⁵

Recommendations

The American Association of Clinical Endocrinologists (AACE) makes no specific recommendations about laboratory testing of thyroid antibodies. Based on clinical judgment, the AACE states that antibodies may be considered in the workup of hyperthyroidism and hypothyroidism and to determine potential risk to the fetus in pregnant women diagnosed with Graves’ disease.⁶

The National Academy of Clinical Biochemistry (NACB) recommends TPOAb measurements in patients who have Down syndrome, are pregnant, or have miscarried or failed in vitro fertilization. The NACB also advocates measuring TPOAb before treatment with amiodarone, lithium, interferon-α, or interleukin-2.⁷

Evidence summary

Although TSH followed by free T₄ remain the initial screening tests for thyroid disorders, adding thyroid autoantibodies may refine the diagnosis. Three principal thyroid antibodies—TPOAb, thyroglobulin, and TRAb—can be positive in a variety of autoimmune thyroid disorders. TPOAb represents a specific antigen of antimicrosomal antibody (AMA). It has largely replaced AMA testing in most laboratories and clinical settings.

Antibodies point to Graves’, autoimmune disorders

A cross-sectional study of 267 Singaporean patients with previously diagnosed thyroid disorders measured TRAb, AMA, and thyroglobulin (TABLE). TRAb levels >10 U/L were found to have a positive likelihood ratio (LR+) of 13 and a negative likelihood ratio (LR–) of 0.2 for Graves’ disease.¹

Two cross-sectional studies compared AMA to TPOAb in healthy patients and those with autoimmune thyroid and nonthyroid disorders. One study of 235 people in a university endocrinology department found that a TPOAb level >190 U/mL yielded an LR+ of 10.75 and an LR– of 0.15 for chronic autoimmune (Hashimoto’s) thyroiditis [CAHT]; the AMA-positive sera yielded an LR+ of 13.67 and an LR– of 0.19. Both TPOAb and AMA test characteristics were highly associated with CAHT (P<.001).

TABLE
Autoimmune markers in thyroid disorders

TPOAb is more sensitive than AMA and thyroglobulin

In the second study comparing AMA to TPOAb, the thyroid antibody test results of 32 healthy patients were compared with those of 262 clinic patients. In those with known thyroid dysfunction, TPOAb was found to be a more sensitive assay than AMA for autoimmune thyroid disorders. The sensitivity of TPOAb levels >3.1 U/mL was 88.1%; AMA sensitivity was 70.2% (P<.001).^2,3

A cross-sectional study (National Health and Nutrition Examination Survey [NHANES III]) evaluated the presence of thyroid antibodies in 17,353 people representing the geographic and ethnic distribution of the United States, 95% of whom were categorized as free of thyroid disease.⁴ The study found that TPOAb was more sensitive than thyroglobulin for diagnosing nonspecific thyroid disease. The diagnosis of thyroid disease was based on abnormal TSH and free T₄ levels. Abnormally high levels of TPOAb had an LR+ of 4.3 and LR– of 0.6 (P<.0001) for thyroid disease, compared with an LR+ of 3.4 and LR– of 0.7 (P<.01) for abnormally elevated thyroglobulin.

TSH + TPOAb more accurate than TSH in women

In the early 1970s, a cohort study of 2779 adults from Great Britain attempted to establish the incidence of thyroid disease in the general population by measuring TSH and TPOAb. Twenty years later, investigators restudied 1708 people from the original sample to determine the incidence of hypothyroidism and the prognostic value of these 2 biochemical markers for its development. At follow-up, the definition of a new case of hypothyroidism was based on an “intention to treat by the general practitioner by meeting clear biochemical criteria and/or symptoms.”

The initial presence of abnormally high serum TPOAb levels and TSH >2.0 mU/L predicted a 4.3% annual risk of developing hypothyroidism compared with a 2.6% annual risk with serum TSH >6.0 mU/L alone in women. This risk was not estimated for men because of the small number of cases.⁵

Recommendations

The American Association of Clinical Endocrinologists (AACE) makes no specific recommendations about laboratory testing of thyroid antibodies. Based on clinical judgment, the AACE states that antibodies may be considered in the workup of hyperthyroidism and hypothyroidism and to determine potential risk to the fetus in pregnant women diagnosed with Graves’ disease.⁶

The National Academy of Clinical Biochemistry (NACB) recommends TPOAb measurements in patients who have Down syndrome, are pregnant, or have miscarried or failed in vitro fertilization. The NACB also advocates measuring TPOAb before treatment with amiodarone, lithium, interferon-α, or interleukin-2.⁷

Evidence summary

Hypothyroidism is a common condition, affecting 4.6% of the population in the United States, according to the National Health and Nutrition Examination Survey (NHANES III).¹ A statewide study in Colorado found the prevalence of elevated TSH levels to be 9.5%.² The study population was older and had more women, Caucasians, and high school and college graduates than the general population. Among the general population, the prevalence of unsuspected overt hypothyroidism has been reported to be 0 to 18 cases per 1000.³

No randomized controlled trials or other high-quality studies have addressed the question of what laboratory tests are most useful to diagnose and monitor the treatment of hypothyroidism.

TSH is a cost-effective initial test, but has limitations

Experts recommend TSH level as the most cost-effective initial laboratory test for suspected primary hypothyroidism.⁴ TSH had a high sensitivity (98%) and specificity (92%) when used to confirm thyroid disease in patients referred to a specialty endocrine clinic, but its positive predictive value is low when used as a screening test in primary care.⁵

TSH is a poor measure of the clinical severity of hypothyroidism. In one study, no correlation was found between serum TSH and clinical and metabolic markers—such as clinical score, ankle reflex time, total cholesterol, and creatine kinase—when estimating the severity of primary thyroid failure.⁶

Uses of free T₄, T₃, and imaging

If TSH is elevated, a free T₄ level can help differentiate between central hyperthyroidism and much more common peripheral hypothyroidism (99% of patients). A T₃ level is necessary only if the TSH is undetectable and the free T₄ is normal.^7,8 Imaging the thyroid gland is reserved for evaluating structural abnormalities.

When to reassess TSH

In primary hypothyroidism, reassess TSH 6 weeks after the start of treatment or a change in replacement dose.⁴ This recommendation is based on the fact that levothyroxine has a half-life of about a week; a steady state would be achieved over the course of 5 half-lives. No direct patient-oriented evidence exists for this testing interval. Test free T₄ if you suspect excessive replacement or noncompliance.

Once TSH is in the normal range, experts recommend assessing the level after 6 months and then annually.⁴ A 2005 study suggested lowering the target TSH level for assessing adequate replacement in patients treated with standard levothyroxine because subtherapeutic T₃ levels were found despite normal TSH levels in these patients.⁹

TSH can’t be used to monitor therapy for central hypothyroidism. Follow both free T₄ and T₃ concentrations because elevated T₃ levels, indicative of overtreatment, can occur even when free T₄ measurements are normal in these patients.¹⁰

Recommendations

ACP Medicine recommends TSH as the initial test. If TSH is elevated, ACP Medicine advises confirmation with a repeat TSH plus a free T₄.¹¹

Evidence summary

Hypothyroidism is a common condition, affecting 4.6% of the population in the United States, according to the National Health and Nutrition Examination Survey (NHANES III).¹ A statewide study in Colorado found the prevalence of elevated TSH levels to be 9.5%.² The study population was older and had more women, Caucasians, and high school and college graduates than the general population. Among the general population, the prevalence of unsuspected overt hypothyroidism has been reported to be 0 to 18 cases per 1000.³

No randomized controlled trials or other high-quality studies have addressed the question of what laboratory tests are most useful to diagnose and monitor the treatment of hypothyroidism.

TSH is a cost-effective initial test, but has limitations

Experts recommend TSH level as the most cost-effective initial laboratory test for suspected primary hypothyroidism.⁴ TSH had a high sensitivity (98%) and specificity (92%) when used to confirm thyroid disease in patients referred to a specialty endocrine clinic, but its positive predictive value is low when used as a screening test in primary care.⁵

TSH is a poor measure of the clinical severity of hypothyroidism. In one study, no correlation was found between serum TSH and clinical and metabolic markers—such as clinical score, ankle reflex time, total cholesterol, and creatine kinase—when estimating the severity of primary thyroid failure.⁶

Uses of free T₄, T₃, and imaging

If TSH is elevated, a free T₄ level can help differentiate between central hyperthyroidism and much more common peripheral hypothyroidism (99% of patients). A T₃ level is necessary only if the TSH is undetectable and the free T₄ is normal.^7,8 Imaging the thyroid gland is reserved for evaluating structural abnormalities.

When to reassess TSH

In primary hypothyroidism, reassess TSH 6 weeks after the start of treatment or a change in replacement dose.⁴ This recommendation is based on the fact that levothyroxine has a half-life of about a week; a steady state would be achieved over the course of 5 half-lives. No direct patient-oriented evidence exists for this testing interval. Test free T₄ if you suspect excessive replacement or noncompliance.

Once TSH is in the normal range, experts recommend assessing the level after 6 months and then annually.⁴ A 2005 study suggested lowering the target TSH level for assessing adequate replacement in patients treated with standard levothyroxine because subtherapeutic T₃ levels were found despite normal TSH levels in these patients.⁹

TSH can’t be used to monitor therapy for central hypothyroidism. Follow both free T₄ and T₃ concentrations because elevated T₃ levels, indicative of overtreatment, can occur even when free T₄ measurements are normal in these patients.¹⁰

Recommendations

ACP Medicine recommends TSH as the initial test. If TSH is elevated, ACP Medicine advises confirmation with a repeat TSH plus a free T₄.¹¹

Evidence summary

Hypothyroidism is a common condition, affecting 4.6% of the population in the United States, according to the National Health and Nutrition Examination Survey (NHANES III).¹ A statewide study in Colorado found the prevalence of elevated TSH levels to be 9.5%.² The study population was older and had more women, Caucasians, and high school and college graduates than the general population. Among the general population, the prevalence of unsuspected overt hypothyroidism has been reported to be 0 to 18 cases per 1000.³

No randomized controlled trials or other high-quality studies have addressed the question of what laboratory tests are most useful to diagnose and monitor the treatment of hypothyroidism.

TSH is a cost-effective initial test, but has limitations

Experts recommend TSH level as the most cost-effective initial laboratory test for suspected primary hypothyroidism.⁴ TSH had a high sensitivity (98%) and specificity (92%) when used to confirm thyroid disease in patients referred to a specialty endocrine clinic, but its positive predictive value is low when used as a screening test in primary care.⁵

TSH is a poor measure of the clinical severity of hypothyroidism. In one study, no correlation was found between serum TSH and clinical and metabolic markers—such as clinical score, ankle reflex time, total cholesterol, and creatine kinase—when estimating the severity of primary thyroid failure.⁶

Uses of free T₄, T₃, and imaging

If TSH is elevated, a free T₄ level can help differentiate between central hyperthyroidism and much more common peripheral hypothyroidism (99% of patients). A T₃ level is necessary only if the TSH is undetectable and the free T₄ is normal.^7,8 Imaging the thyroid gland is reserved for evaluating structural abnormalities.

When to reassess TSH

In primary hypothyroidism, reassess TSH 6 weeks after the start of treatment or a change in replacement dose.⁴ This recommendation is based on the fact that levothyroxine has a half-life of about a week; a steady state would be achieved over the course of 5 half-lives. No direct patient-oriented evidence exists for this testing interval. Test free T₄ if you suspect excessive replacement or noncompliance.

Once TSH is in the normal range, experts recommend assessing the level after 6 months and then annually.⁴ A 2005 study suggested lowering the target TSH level for assessing adequate replacement in patients treated with standard levothyroxine because subtherapeutic T₃ levels were found despite normal TSH levels in these patients.⁹

TSH can’t be used to monitor therapy for central hypothyroidism. Follow both free T₄ and T₃ concentrations because elevated T₃ levels, indicative of overtreatment, can occur even when free T₄ measurements are normal in these patients.¹⁰

Recommendations

ACP Medicine recommends TSH as the initial test. If TSH is elevated, ACP Medicine advises confirmation with a repeat TSH plus a free T₄.¹¹

Evidence summary

rGH has been available since 1985. The Food and Drug Administration has approved it for such conditions as growth hormone deficiency, chronic renal insufficiency, Turner syndrome, small size for gestational age, and Prader-Willi syndrome.¹ The use of rGH to treat idiopathic short stature introduces many clinical, economic, and ethical questions. We have attempted to discern the clinical effectiveness of treatment by focusing on RCTs of rGH therapy while leaving the other substantive issues unexplored.

Final height is arguably the most important outcome measure for the effects of rGH and may be represented as actual height or as a standard deviation score (SDS)—actual height minus mean height for age divided by standard deviation of height for age.² This measure standardizes height comparisons for different age groups and is comparable to the percentile values on growth charts.

Growth hormone increases height in girls and boys

A 2003 Cochrane systematic review identified 9 RCTs that evaluated treatment with rGH in children with idiopathic short stature. Only 1 used near final height as its main outcome. Inclusion criteria for this RCT comprised prepubertal girls in the bottom third percentile for height without a known cause.

Of the 40 subjects, only 18 provided consent for randomization. Seven of the 10 girls randomized to the treatment group and 6 of the 8 randomized to the control group completed the study to final height measurement. The average age of the treated girls at the start of therapy was 8.07 years; the average duration of treatment was 6.2 years. All participants reached stage 4 breast development, menarche, and a growth velocity of <2 cm per year in the year preceding final height measurement. Mean final height in the treatment group was 155.3 cm compared to 147.8 cm in the control group—a 7.5-cm difference (95% confidence interval [CI], 3.14-11.86 cm).^2,3

A double-blind, placebo-controlled RCT published after the Cochrane review assessed final height in a peripubertal, predominantly male population with non-growth-hormone-deficient short stature.⁴ Inclusion criteria comprised a height SDS <–2.50, but 6 participants with a height SDS between –2.25 and –2.5 were included because of a change in the criteria.⁵ Sixty-eight children were initially randomized. Of the 37 randomized to treatment, 22 were available for final height measurement. The placebo group had a higher dropout rate—only 11 of 31 patients were available for final height measurement. In an attempt to reduce the dropout rate, the final height criterion for discontinuation of injections was changed from <0.5 to <1.5 cm per year. The mean age of the treatment group was 12.5 years at initiation of treatment; average duration of treatment was 4.6 years.

Intent-to-treat analysis of patients who received at least 6 months of treatment with final height assessment revealed a positive treatment effect on height (SDS) of 0.51. This is the equivalent of a 3.7-cm difference in final height for the treatment group compared with the placebo group (P<.02; 95% CI, 0.10-0.92 SDS).⁵

Recommendations

The FDA has approved rGH for use in children with height SDS ≤–2.25—equivalent to the lowest 1.2% of children. The Lawson-Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee states that rGH therapy should be considered only after accurate diagnosis, careful monitoring of growth velocity, and estimation of final height by a pediatric endocrinologist.^6,7

Evidence summary

rGH has been available since 1985. The Food and Drug Administration has approved it for such conditions as growth hormone deficiency, chronic renal insufficiency, Turner syndrome, small size for gestational age, and Prader-Willi syndrome.¹ The use of rGH to treat idiopathic short stature introduces many clinical, economic, and ethical questions. We have attempted to discern the clinical effectiveness of treatment by focusing on RCTs of rGH therapy while leaving the other substantive issues unexplored.

Final height is arguably the most important outcome measure for the effects of rGH and may be represented as actual height or as a standard deviation score (SDS)—actual height minus mean height for age divided by standard deviation of height for age.² This measure standardizes height comparisons for different age groups and is comparable to the percentile values on growth charts.

Growth hormone increases height in girls and boys

A 2003 Cochrane systematic review identified 9 RCTs that evaluated treatment with rGH in children with idiopathic short stature. Only 1 used near final height as its main outcome. Inclusion criteria for this RCT comprised prepubertal girls in the bottom third percentile for height without a known cause.

Of the 40 subjects, only 18 provided consent for randomization. Seven of the 10 girls randomized to the treatment group and 6 of the 8 randomized to the control group completed the study to final height measurement. The average age of the treated girls at the start of therapy was 8.07 years; the average duration of treatment was 6.2 years. All participants reached stage 4 breast development, menarche, and a growth velocity of <2 cm per year in the year preceding final height measurement. Mean final height in the treatment group was 155.3 cm compared to 147.8 cm in the control group—a 7.5-cm difference (95% confidence interval [CI], 3.14-11.86 cm).^2,3

A double-blind, placebo-controlled RCT published after the Cochrane review assessed final height in a peripubertal, predominantly male population with non-growth-hormone-deficient short stature.⁴ Inclusion criteria comprised a height SDS <–2.50, but 6 participants with a height SDS between –2.25 and –2.5 were included because of a change in the criteria.⁵ Sixty-eight children were initially randomized. Of the 37 randomized to treatment, 22 were available for final height measurement. The placebo group had a higher dropout rate—only 11 of 31 patients were available for final height measurement. In an attempt to reduce the dropout rate, the final height criterion for discontinuation of injections was changed from <0.5 to <1.5 cm per year. The mean age of the treatment group was 12.5 years at initiation of treatment; average duration of treatment was 4.6 years.

Intent-to-treat analysis of patients who received at least 6 months of treatment with final height assessment revealed a positive treatment effect on height (SDS) of 0.51. This is the equivalent of a 3.7-cm difference in final height for the treatment group compared with the placebo group (P<.02; 95% CI, 0.10-0.92 SDS).⁵

Recommendations

The FDA has approved rGH for use in children with height SDS ≤–2.25—equivalent to the lowest 1.2% of children. The Lawson-Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee states that rGH therapy should be considered only after accurate diagnosis, careful monitoring of growth velocity, and estimation of final height by a pediatric endocrinologist.^6,7

Evidence summary

rGH has been available since 1985. The Food and Drug Administration has approved it for such conditions as growth hormone deficiency, chronic renal insufficiency, Turner syndrome, small size for gestational age, and Prader-Willi syndrome.¹ The use of rGH to treat idiopathic short stature introduces many clinical, economic, and ethical questions. We have attempted to discern the clinical effectiveness of treatment by focusing on RCTs of rGH therapy while leaving the other substantive issues unexplored.

Final height is arguably the most important outcome measure for the effects of rGH and may be represented as actual height or as a standard deviation score (SDS)—actual height minus mean height for age divided by standard deviation of height for age.² This measure standardizes height comparisons for different age groups and is comparable to the percentile values on growth charts.

Growth hormone increases height in girls and boys

A 2003 Cochrane systematic review identified 9 RCTs that evaluated treatment with rGH in children with idiopathic short stature. Only 1 used near final height as its main outcome. Inclusion criteria for this RCT comprised prepubertal girls in the bottom third percentile for height without a known cause.

Of the 40 subjects, only 18 provided consent for randomization. Seven of the 10 girls randomized to the treatment group and 6 of the 8 randomized to the control group completed the study to final height measurement. The average age of the treated girls at the start of therapy was 8.07 years; the average duration of treatment was 6.2 years. All participants reached stage 4 breast development, menarche, and a growth velocity of <2 cm per year in the year preceding final height measurement. Mean final height in the treatment group was 155.3 cm compared to 147.8 cm in the control group—a 7.5-cm difference (95% confidence interval [CI], 3.14-11.86 cm).^2,3

A double-blind, placebo-controlled RCT published after the Cochrane review assessed final height in a peripubertal, predominantly male population with non-growth-hormone-deficient short stature.⁴ Inclusion criteria comprised a height SDS <–2.50, but 6 participants with a height SDS between –2.25 and –2.5 were included because of a change in the criteria.⁵ Sixty-eight children were initially randomized. Of the 37 randomized to treatment, 22 were available for final height measurement. The placebo group had a higher dropout rate—only 11 of 31 patients were available for final height measurement. In an attempt to reduce the dropout rate, the final height criterion for discontinuation of injections was changed from <0.5 to <1.5 cm per year. The mean age of the treatment group was 12.5 years at initiation of treatment; average duration of treatment was 4.6 years.

Intent-to-treat analysis of patients who received at least 6 months of treatment with final height assessment revealed a positive treatment effect on height (SDS) of 0.51. This is the equivalent of a 3.7-cm difference in final height for the treatment group compared with the placebo group (P<.02; 95% CI, 0.10-0.92 SDS).⁵

Recommendations

The FDA has approved rGH for use in children with height SDS ≤–2.25—equivalent to the lowest 1.2% of children. The Lawson-Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee states that rGH therapy should be considered only after accurate diagnosis, careful monitoring of growth velocity, and estimation of final height by a pediatric endocrinologist.^6,7

Evidence summary

Drug-seeking behaviors—known as aberrant behaviors in chronic pain literature—may suggest a substance abuse disorder (TABLE).² At least 4 validated screening tools are available for predicting or monitoring aberrant behaviors in patients with chronic, nonmalignant pain disorders who are being considered for, or receiving, opioid therapy:

The Screener and Opioid Assessment for Patients with Pain (SOAPP-R) is a 24-item, self-administered questionnaire that stratifies patients being considered for opioid therapy into lower or higher risk for future opioid-related aberrant behaviors.² Each item queries frequency of behaviors and emotions consistent with opioid misuse and can be scored as 0 (never) to 4 (very often). The items on the SOAPP-R were developed by a consensus panel of pain and addiction experts.

In a multidisciplinary pain center study, the SOAPP-R was administered to 283 chronic pain patients who were followed for 5 months. At a cutoff score of ≥18, the test had a positive likelihood ratio (LR+) of 3.80 and a negative likelihood ratio (LR–) of 0.29 for detecting opioid misuse. At this cutoff, the SOAPP-R was 81% sensitive and 68% specific for predicting patients at high risk for aberrant behavior.

The Opioid Risk Tool (ORT) is a self-administered, 5-item questionnaire used to predict and monitor aberrant behavior.³ Potential scores range from 0 to 26. When administered to 185 consecutive new patients at a chronic pain clinic, a score of <4 had an LR– of 0.08 and a score of ≥8 had an LR+ of 14 for manifesting opioid-related aberrant behaviors. Some ORT scoring criteria have not shown consistent results in other studies.⁴

The Current Opioid Misuse Measure (COMM) is used to monitor aberrant behaviors in patients on opioid therapy.⁵ Scoring for the 17-item, self-administered test is similar to the SOAPP-R. In a study of 86 patients at a multidisciplinary pain center, a score of ≥9 detected opioid misuse with an LR– of 0.08 and an LR+ of 3.48, at a sensitivity of 77% and specificity of 66%.

The Addiction Behaviors Checklist (ABC) is a 20-item Yes or No questionnaire administered by staff.⁶ At a cutoff score of 3 positive items, it had a sensitivity of 88% and specificity of 86% for detecting opioid misuse in 136 consecutive patients at a multidisciplinary pain center.

TABLE
Red flags for a substance abuse disorder

Limitations of the studies

These studies have several limitations. The investigators who validated or evaluated the SOAPP-R and ORT included only patients at chronic pain clinics, so the instruments may not be applicable to patients in primary care settings^2-4; the ORT study lacked standard measures of addiction³; and the ABC was tested in a population that was predominantly male.⁶

Recommendations

A 2006 guideline of the American Society of Interventional Pain Physicians describes behaviors that suggest abuse or misuse of opioid medication.⁷ These behaviors, which are similar to those listed in the TABLE, include failure to experience pain relief from high-dose opioids, lying to obtain opioids, obtaining drugs from multiple prescribers, functional deterioration or lack of functional improvement, exaggerating pain, and forgery. The guideline recommends monitoring patients for such behaviors.

Evidence summary

Drug-seeking behaviors—known as aberrant behaviors in chronic pain literature—may suggest a substance abuse disorder (TABLE).² At least 4 validated screening tools are available for predicting or monitoring aberrant behaviors in patients with chronic, nonmalignant pain disorders who are being considered for, or receiving, opioid therapy:

The Screener and Opioid Assessment for Patients with Pain (SOAPP-R) is a 24-item, self-administered questionnaire that stratifies patients being considered for opioid therapy into lower or higher risk for future opioid-related aberrant behaviors.² Each item queries frequency of behaviors and emotions consistent with opioid misuse and can be scored as 0 (never) to 4 (very often). The items on the SOAPP-R were developed by a consensus panel of pain and addiction experts.

In a multidisciplinary pain center study, the SOAPP-R was administered to 283 chronic pain patients who were followed for 5 months. At a cutoff score of ≥18, the test had a positive likelihood ratio (LR+) of 3.80 and a negative likelihood ratio (LR–) of 0.29 for detecting opioid misuse. At this cutoff, the SOAPP-R was 81% sensitive and 68% specific for predicting patients at high risk for aberrant behavior.

The Opioid Risk Tool (ORT) is a self-administered, 5-item questionnaire used to predict and monitor aberrant behavior.³ Potential scores range from 0 to 26. When administered to 185 consecutive new patients at a chronic pain clinic, a score of <4 had an LR– of 0.08 and a score of ≥8 had an LR+ of 14 for manifesting opioid-related aberrant behaviors. Some ORT scoring criteria have not shown consistent results in other studies.⁴

The Current Opioid Misuse Measure (COMM) is used to monitor aberrant behaviors in patients on opioid therapy.⁵ Scoring for the 17-item, self-administered test is similar to the SOAPP-R. In a study of 86 patients at a multidisciplinary pain center, a score of ≥9 detected opioid misuse with an LR– of 0.08 and an LR+ of 3.48, at a sensitivity of 77% and specificity of 66%.

The Addiction Behaviors Checklist (ABC) is a 20-item Yes or No questionnaire administered by staff.⁶ At a cutoff score of 3 positive items, it had a sensitivity of 88% and specificity of 86% for detecting opioid misuse in 136 consecutive patients at a multidisciplinary pain center.

TABLE
Red flags for a substance abuse disorder

Limitations of the studies

These studies have several limitations. The investigators who validated or evaluated the SOAPP-R and ORT included only patients at chronic pain clinics, so the instruments may not be applicable to patients in primary care settings^2-4; the ORT study lacked standard measures of addiction³; and the ABC was tested in a population that was predominantly male.⁶

Recommendations

A 2006 guideline of the American Society of Interventional Pain Physicians describes behaviors that suggest abuse or misuse of opioid medication.⁷ These behaviors, which are similar to those listed in the TABLE, include failure to experience pain relief from high-dose opioids, lying to obtain opioids, obtaining drugs from multiple prescribers, functional deterioration or lack of functional improvement, exaggerating pain, and forgery. The guideline recommends monitoring patients for such behaviors.

Evidence summary

Drug-seeking behaviors—known as aberrant behaviors in chronic pain literature—may suggest a substance abuse disorder (TABLE).² At least 4 validated screening tools are available for predicting or monitoring aberrant behaviors in patients with chronic, nonmalignant pain disorders who are being considered for, or receiving, opioid therapy:

The Screener and Opioid Assessment for Patients with Pain (SOAPP-R) is a 24-item, self-administered questionnaire that stratifies patients being considered for opioid therapy into lower or higher risk for future opioid-related aberrant behaviors.² Each item queries frequency of behaviors and emotions consistent with opioid misuse and can be scored as 0 (never) to 4 (very often). The items on the SOAPP-R were developed by a consensus panel of pain and addiction experts.

In a multidisciplinary pain center study, the SOAPP-R was administered to 283 chronic pain patients who were followed for 5 months. At a cutoff score of ≥18, the test had a positive likelihood ratio (LR+) of 3.80 and a negative likelihood ratio (LR–) of 0.29 for detecting opioid misuse. At this cutoff, the SOAPP-R was 81% sensitive and 68% specific for predicting patients at high risk for aberrant behavior.

The Opioid Risk Tool (ORT) is a self-administered, 5-item questionnaire used to predict and monitor aberrant behavior.³ Potential scores range from 0 to 26. When administered to 185 consecutive new patients at a chronic pain clinic, a score of <4 had an LR– of 0.08 and a score of ≥8 had an LR+ of 14 for manifesting opioid-related aberrant behaviors. Some ORT scoring criteria have not shown consistent results in other studies.⁴

The Current Opioid Misuse Measure (COMM) is used to monitor aberrant behaviors in patients on opioid therapy.⁵ Scoring for the 17-item, self-administered test is similar to the SOAPP-R. In a study of 86 patients at a multidisciplinary pain center, a score of ≥9 detected opioid misuse with an LR– of 0.08 and an LR+ of 3.48, at a sensitivity of 77% and specificity of 66%.

The Addiction Behaviors Checklist (ABC) is a 20-item Yes or No questionnaire administered by staff.⁶ At a cutoff score of 3 positive items, it had a sensitivity of 88% and specificity of 86% for detecting opioid misuse in 136 consecutive patients at a multidisciplinary pain center.

TABLE
Red flags for a substance abuse disorder

Limitations of the studies

These studies have several limitations. The investigators who validated or evaluated the SOAPP-R and ORT included only patients at chronic pain clinics, so the instruments may not be applicable to patients in primary care settings^2-4; the ORT study lacked standard measures of addiction³; and the ABC was tested in a population that was predominantly male.⁶

Recommendations

A 2006 guideline of the American Society of Interventional Pain Physicians describes behaviors that suggest abuse or misuse of opioid medication.⁷ These behaviors, which are similar to those listed in the TABLE, include failure to experience pain relief from high-dose opioids, lying to obtain opioids, obtaining drugs from multiple prescribers, functional deterioration or lack of functional improvement, exaggerating pain, and forgery. The guideline recommends monitoring patients for such behaviors.