Clinical Inquiries

Evidence summary

The only studies of hand paresthesias that we found pertained to of CTS. A consensus statement on CTS listed intermittent numbness, tingling, and pain along the sensory distribution of the median nerve as diagnostic criteria for CTS.¹ Patients often report that these symptoms awaken them at night. Shaking the hand may relieve the discomfort. Commonly, the pain is burning in nature and worsens with use during the day. Repetitive trauma or mechanical stress related to workplace tasks is associated with CTS.

A meta-analysis of studies reviewing the precision and accuracy of the history and physical examination in the diagnosis of CTS in adults found that hypoalgesia (LR+, 3.1), classic or probable hand diagram results (LR+ 2.4, LR- 0.2), and weak thumb abduction strength (weakness of resisted movement of the thumb at right angles to the palm; LR+ 1.8, LR- 0.5) best distinguish those with and those without CTS.² A hand diagram is a graphical depiction of the distribution of tingling created by the patient; a classical distribution is in that of the median nerve, while a probable distribution involves the entire palmar surface. The reference standard for these studies was a nerve conduction study. Nocturnal paresthesias, Phalen and Tinel signs, and thenar atrophy had little or no diagnostic utility.

Recommendations from others

Collins³ recommends the following approach to paresthesias of the upper extremity. If the paresthesias are symmetric, consider peripheral neuropathy, Raynaud’s, or multiple sclerosis. If asymmetric, evaluate for radiculopathy with a neurological examination. If pain is radicular, and neurologic findings are consistent, consider spinal cord or nerve root compression. If the examination is normal, consider a plexopathy or herpes zoster. If there is no radiculopathy, the following maneuvers may suggest a cause. A positive Adson’s maneuver is consistent with thoracic outlet syndrome, a Tinel’s or Phalen’s sign at the wrist suggests carpal tunnel syndrome, or Tinel’s sign at the elbow suggests ulnar neuropathy. Note that the latter signs are not well validated by good quality diagnostic test studies.

Clinical Commentary by Peter Danis, MD, at http://www.fpin.org.

Evidence summary

The only studies of hand paresthesias that we found pertained to of CTS. A consensus statement on CTS listed intermittent numbness, tingling, and pain along the sensory distribution of the median nerve as diagnostic criteria for CTS.¹ Patients often report that these symptoms awaken them at night. Shaking the hand may relieve the discomfort. Commonly, the pain is burning in nature and worsens with use during the day. Repetitive trauma or mechanical stress related to workplace tasks is associated with CTS.

A meta-analysis of studies reviewing the precision and accuracy of the history and physical examination in the diagnosis of CTS in adults found that hypoalgesia (LR+, 3.1), classic or probable hand diagram results (LR+ 2.4, LR- 0.2), and weak thumb abduction strength (weakness of resisted movement of the thumb at right angles to the palm; LR+ 1.8, LR- 0.5) best distinguish those with and those without CTS.² A hand diagram is a graphical depiction of the distribution of tingling created by the patient; a classical distribution is in that of the median nerve, while a probable distribution involves the entire palmar surface. The reference standard for these studies was a nerve conduction study. Nocturnal paresthesias, Phalen and Tinel signs, and thenar atrophy had little or no diagnostic utility.

Recommendations from others

Collins³ recommends the following approach to paresthesias of the upper extremity. If the paresthesias are symmetric, consider peripheral neuropathy, Raynaud’s, or multiple sclerosis. If asymmetric, evaluate for radiculopathy with a neurological examination. If pain is radicular, and neurologic findings are consistent, consider spinal cord or nerve root compression. If the examination is normal, consider a plexopathy or herpes zoster. If there is no radiculopathy, the following maneuvers may suggest a cause. A positive Adson’s maneuver is consistent with thoracic outlet syndrome, a Tinel’s or Phalen’s sign at the wrist suggests carpal tunnel syndrome, or Tinel’s sign at the elbow suggests ulnar neuropathy. Note that the latter signs are not well validated by good quality diagnostic test studies.

Clinical Commentary by Peter Danis, MD, at http://www.fpin.org.

Evidence summary

The only studies of hand paresthesias that we found pertained to of CTS. A consensus statement on CTS listed intermittent numbness, tingling, and pain along the sensory distribution of the median nerve as diagnostic criteria for CTS.¹ Patients often report that these symptoms awaken them at night. Shaking the hand may relieve the discomfort. Commonly, the pain is burning in nature and worsens with use during the day. Repetitive trauma or mechanical stress related to workplace tasks is associated with CTS.

A meta-analysis of studies reviewing the precision and accuracy of the history and physical examination in the diagnosis of CTS in adults found that hypoalgesia (LR+, 3.1), classic or probable hand diagram results (LR+ 2.4, LR- 0.2), and weak thumb abduction strength (weakness of resisted movement of the thumb at right angles to the palm; LR+ 1.8, LR- 0.5) best distinguish those with and those without CTS.² A hand diagram is a graphical depiction of the distribution of tingling created by the patient; a classical distribution is in that of the median nerve, while a probable distribution involves the entire palmar surface. The reference standard for these studies was a nerve conduction study. Nocturnal paresthesias, Phalen and Tinel signs, and thenar atrophy had little or no diagnostic utility.

Recommendations from others

Collins³ recommends the following approach to paresthesias of the upper extremity. If the paresthesias are symmetric, consider peripheral neuropathy, Raynaud’s, or multiple sclerosis. If asymmetric, evaluate for radiculopathy with a neurological examination. If pain is radicular, and neurologic findings are consistent, consider spinal cord or nerve root compression. If the examination is normal, consider a plexopathy or herpes zoster. If there is no radiculopathy, the following maneuvers may suggest a cause. A positive Adson’s maneuver is consistent with thoracic outlet syndrome, a Tinel’s or Phalen’s sign at the wrist suggests carpal tunnel syndrome, or Tinel’s sign at the elbow suggests ulnar neuropathy. Note that the latter signs are not well validated by good quality diagnostic test studies.

Clinical Commentary by Peter Danis, MD, at http://www.fpin.org.

Evidence summary

Current studies regarding urodynamic testing in older adults with incontinence are limited by multiple factors, including inherent gender bias, poor reproducibility, and small study populations. Moreover, the lack of a reference standard has contributed to difficulty in assessing outcome measures. No published study to date has convincingly supported a role for advanced urodynamic testing (leak point pressure measurement, pressure flow studies, electromyelography, etc.) in the evaluation of routine urinary incontinence. Simple cystometry, (measuring post-void residuals and determining bladder capacity), has proved particularly useful in detecting abnormalities of detrusor compliance and contractility, especially when the cause of incontinence is unclear.^1,2

One well designed retrospective cohort study of 950 women found that the positive predictive value of clinical symptoms in urinary incontinence alone (74% in the context of a 53% prevalence of incontinence) was not accurate enough to rely on for decisions about surgery.³ This study supports the need for urodynamic evaluation in most women prior to surgical incontinence treatment.

Another recent small RCT (n=87) found that, of patients with previous genitourinary surgery or more severe stress incontinence, about one quarter were more likely to have their management revised after urodynamic studies.⁴ Patients who demonstrated little or no improvement during the first few months of conservative treatment also ran a higher risk of misdiagnosis. Despite these findings, no difference in treatment outcomes was detected for women randomized to urodynamic testing.

Two additional RCTs suggest that, despite the wide use of urodynamic testing, reproducibility is limited and may lack sufficient sensitivity and specificity to identify underlying pathology.^5,6 Specific concerns raised in these studies included test-retest variation, as well as concerns about possible interpretation error of urodynamic testing.

Recommendations from others

In its 1996 Clinical Practice Guideline Update, the Agency for Healthcare Research and Quality (AHRQ) recommended a focused history and targeted examination (including urinalysis and post-void residual measurement) in order to detect reversible causes of urinary incontinence.¹ The guideline stresses that urodynamic testing is invasive and expensive, and it should be reserved for those situations when the patient desires such evaluation and the information gathered would potentially change management. Although AHRQ considers this guideline too old to direct current medical practice, we found little recent evidence to refute these recommendations.

TABLE
Indications for urodynamic evaluation in older adults

Clinical Commentary by John Gazewood, MD, at http://www.fpin.org.

Evidence summary

Current studies regarding urodynamic testing in older adults with incontinence are limited by multiple factors, including inherent gender bias, poor reproducibility, and small study populations. Moreover, the lack of a reference standard has contributed to difficulty in assessing outcome measures. No published study to date has convincingly supported a role for advanced urodynamic testing (leak point pressure measurement, pressure flow studies, electromyelography, etc.) in the evaluation of routine urinary incontinence. Simple cystometry, (measuring post-void residuals and determining bladder capacity), has proved particularly useful in detecting abnormalities of detrusor compliance and contractility, especially when the cause of incontinence is unclear.^1,2

One well designed retrospective cohort study of 950 women found that the positive predictive value of clinical symptoms in urinary incontinence alone (74% in the context of a 53% prevalence of incontinence) was not accurate enough to rely on for decisions about surgery.³ This study supports the need for urodynamic evaluation in most women prior to surgical incontinence treatment.

Another recent small RCT (n=87) found that, of patients with previous genitourinary surgery or more severe stress incontinence, about one quarter were more likely to have their management revised after urodynamic studies.⁴ Patients who demonstrated little or no improvement during the first few months of conservative treatment also ran a higher risk of misdiagnosis. Despite these findings, no difference in treatment outcomes was detected for women randomized to urodynamic testing.

Two additional RCTs suggest that, despite the wide use of urodynamic testing, reproducibility is limited and may lack sufficient sensitivity and specificity to identify underlying pathology.^5,6 Specific concerns raised in these studies included test-retest variation, as well as concerns about possible interpretation error of urodynamic testing.

Recommendations from others

In its 1996 Clinical Practice Guideline Update, the Agency for Healthcare Research and Quality (AHRQ) recommended a focused history and targeted examination (including urinalysis and post-void residual measurement) in order to detect reversible causes of urinary incontinence.¹ The guideline stresses that urodynamic testing is invasive and expensive, and it should be reserved for those situations when the patient desires such evaluation and the information gathered would potentially change management. Although AHRQ considers this guideline too old to direct current medical practice, we found little recent evidence to refute these recommendations.

TABLE
Indications for urodynamic evaluation in older adults

Clinical Commentary by John Gazewood, MD, at http://www.fpin.org.

Evidence summary

Current studies regarding urodynamic testing in older adults with incontinence are limited by multiple factors, including inherent gender bias, poor reproducibility, and small study populations. Moreover, the lack of a reference standard has contributed to difficulty in assessing outcome measures. No published study to date has convincingly supported a role for advanced urodynamic testing (leak point pressure measurement, pressure flow studies, electromyelography, etc.) in the evaluation of routine urinary incontinence. Simple cystometry, (measuring post-void residuals and determining bladder capacity), has proved particularly useful in detecting abnormalities of detrusor compliance and contractility, especially when the cause of incontinence is unclear.^1,2

One well designed retrospective cohort study of 950 women found that the positive predictive value of clinical symptoms in urinary incontinence alone (74% in the context of a 53% prevalence of incontinence) was not accurate enough to rely on for decisions about surgery.³ This study supports the need for urodynamic evaluation in most women prior to surgical incontinence treatment.

Another recent small RCT (n=87) found that, of patients with previous genitourinary surgery or more severe stress incontinence, about one quarter were more likely to have their management revised after urodynamic studies.⁴ Patients who demonstrated little or no improvement during the first few months of conservative treatment also ran a higher risk of misdiagnosis. Despite these findings, no difference in treatment outcomes was detected for women randomized to urodynamic testing.

Two additional RCTs suggest that, despite the wide use of urodynamic testing, reproducibility is limited and may lack sufficient sensitivity and specificity to identify underlying pathology.^5,6 Specific concerns raised in these studies included test-retest variation, as well as concerns about possible interpretation error of urodynamic testing.

Recommendations from others

In its 1996 Clinical Practice Guideline Update, the Agency for Healthcare Research and Quality (AHRQ) recommended a focused history and targeted examination (including urinalysis and post-void residual measurement) in order to detect reversible causes of urinary incontinence.¹ The guideline stresses that urodynamic testing is invasive and expensive, and it should be reserved for those situations when the patient desires such evaluation and the information gathered would potentially change management. Although AHRQ considers this guideline too old to direct current medical practice, we found little recent evidence to refute these recommendations.

TABLE
Indications for urodynamic evaluation in older adults

Clinical Commentary by John Gazewood, MD, at http://www.fpin.org.

Evidence summary

A systematic review of 5 RCTs (N=274) confirmed clinically and statistically significant prevention of bone loss at the lumbar spine for patients receiving glucocorticoids who also received calcium (500–1000 mg daily) and vitamin D (400–800 IU) daily.¹ A systematic review found that patients receiving steroids longer than 3 months gained bone mass when placed on a bisphosphonate.² A two-year RCT of 208 patients receiving steroids who also received alendronate or placebo demonstrated an incidence of vertebral fracture of 0.7% and 6.8% (NNT=16; RRR=90%; ARR = 5.9%; P= .026), respectively.³ A 48-week RCT involving 477 patients receiving steroids who also received alendronate or placebo demonstrated a 2.3% and 3.7% in incidence of vertebral fracture, respectively (RRR = 38%; ARR = 1.4%; P= NS).⁴ A 1-year RCT of 184 men on or off steroids using risedronate found an 82.4% decreased incidence of vertebral fractures compared with those who received placebo (NNT = 5; P= .008).⁵

In hypogonadal patients, several small studies have shown that replacement of sex hormones (estrogen in women and testosterone in men) increases lumbar spine BMD (women 2% and 3–4%; men 5%; all P< .05). Fracture reduction and risk of long-term use were not studied.^6-8 In a systematic review of 9 RCTs, including 441 patients, calcitonin preserved bone mass in the lumbar spine but not the femoral neck during the first year of steroid therapy. Lumbar spine BMD values with calcitonin were significantly higher than with placebo at 6 and 12 months, but were similar at 24 months.⁹

Recommendations from others

The American College of Rheumatology recommends calcium and vitamin D be offered to all patients initiating a regimen of prednisone 5 mg/d or its equivalent with expected duration of longer than 3 months. Bisphosphonates should be prescribed for all patients starting steroids and for patients receiving steroids with a T-score less than -1.0; however they should be used with caution in pre-menopausal women.⁸ A leading researcher states the rank order for prevention is a bisphosphonate followed by a vitamin D metabolite or hormone replacement.¹⁰

Clinical Commentary by Michael Fisher, MD, at http://www.fpin.org.

Evidence summary

A systematic review of 5 RCTs (N=274) confirmed clinically and statistically significant prevention of bone loss at the lumbar spine for patients receiving glucocorticoids who also received calcium (500–1000 mg daily) and vitamin D (400–800 IU) daily.¹ A systematic review found that patients receiving steroids longer than 3 months gained bone mass when placed on a bisphosphonate.² A two-year RCT of 208 patients receiving steroids who also received alendronate or placebo demonstrated an incidence of vertebral fracture of 0.7% and 6.8% (NNT=16; RRR=90%; ARR = 5.9%; P= .026), respectively.³ A 48-week RCT involving 477 patients receiving steroids who also received alendronate or placebo demonstrated a 2.3% and 3.7% in incidence of vertebral fracture, respectively (RRR = 38%; ARR = 1.4%; P= NS).⁴ A 1-year RCT of 184 men on or off steroids using risedronate found an 82.4% decreased incidence of vertebral fractures compared with those who received placebo (NNT = 5; P= .008).⁵

In hypogonadal patients, several small studies have shown that replacement of sex hormones (estrogen in women and testosterone in men) increases lumbar spine BMD (women 2% and 3–4%; men 5%; all P< .05). Fracture reduction and risk of long-term use were not studied.^6-8 In a systematic review of 9 RCTs, including 441 patients, calcitonin preserved bone mass in the lumbar spine but not the femoral neck during the first year of steroid therapy. Lumbar spine BMD values with calcitonin were significantly higher than with placebo at 6 and 12 months, but were similar at 24 months.⁹

Recommendations from others

The American College of Rheumatology recommends calcium and vitamin D be offered to all patients initiating a regimen of prednisone 5 mg/d or its equivalent with expected duration of longer than 3 months. Bisphosphonates should be prescribed for all patients starting steroids and for patients receiving steroids with a T-score less than -1.0; however they should be used with caution in pre-menopausal women.⁸ A leading researcher states the rank order for prevention is a bisphosphonate followed by a vitamin D metabolite or hormone replacement.¹⁰

Clinical Commentary by Michael Fisher, MD, at http://www.fpin.org.

Evidence summary

A systematic review of 5 RCTs (N=274) confirmed clinically and statistically significant prevention of bone loss at the lumbar spine for patients receiving glucocorticoids who also received calcium (500–1000 mg daily) and vitamin D (400–800 IU) daily.¹ A systematic review found that patients receiving steroids longer than 3 months gained bone mass when placed on a bisphosphonate.² A two-year RCT of 208 patients receiving steroids who also received alendronate or placebo demonstrated an incidence of vertebral fracture of 0.7% and 6.8% (NNT=16; RRR=90%; ARR = 5.9%; P= .026), respectively.³ A 48-week RCT involving 477 patients receiving steroids who also received alendronate or placebo demonstrated a 2.3% and 3.7% in incidence of vertebral fracture, respectively (RRR = 38%; ARR = 1.4%; P= NS).⁴ A 1-year RCT of 184 men on or off steroids using risedronate found an 82.4% decreased incidence of vertebral fractures compared with those who received placebo (NNT = 5; P= .008).⁵

In hypogonadal patients, several small studies have shown that replacement of sex hormones (estrogen in women and testosterone in men) increases lumbar spine BMD (women 2% and 3–4%; men 5%; all P< .05). Fracture reduction and risk of long-term use were not studied.^6-8 In a systematic review of 9 RCTs, including 441 patients, calcitonin preserved bone mass in the lumbar spine but not the femoral neck during the first year of steroid therapy. Lumbar spine BMD values with calcitonin were significantly higher than with placebo at 6 and 12 months, but were similar at 24 months.⁹

Recommendations from others

The American College of Rheumatology recommends calcium and vitamin D be offered to all patients initiating a regimen of prednisone 5 mg/d or its equivalent with expected duration of longer than 3 months. Bisphosphonates should be prescribed for all patients starting steroids and for patients receiving steroids with a T-score less than -1.0; however they should be used with caution in pre-menopausal women.⁸ A leading researcher states the rank order for prevention is a bisphosphonate followed by a vitamin D metabolite or hormone replacement.¹⁰

Clinical Commentary by Michael Fisher, MD, at http://www.fpin.org.

EVIDENCE-BASED ANSWER

Antioxidant supplements of vitamins E and C do not reduce cardiovascular death in people with coronary artery disease. Vitamin E supplementation, in a variety of doses, does not decrease the incidence of cardiovascular or all-cause mortality (grade of recommendation: A, 4 high quality randomized controlled trials [RCTs]). There is no evidence that vitamin C decreases mortality in patients at risk for coronary disease (grade of recommendation: A, meta-analysis of 3 small RCTs). Combination antioxidant regimens (Vitamins E, C, and betacarotene) seem safe, but do not decrease mortality or incidence of major coronary and vascular events (grade recommendation: A, 1 high-quality RCT).

Evidence summary

Four large, well-designed RCTs with a combined enrollment of nearly 25,000 individuals with known coronary artery disease (CAD) or high risk for CAD receiving vitamin E (50–800 IU/d) collectively demonstrated no change in all-cause mortality or incidence of total cardiovascular events.¹ Three of these studies were double-blind, placebo-controlled and the fourth was an open-label design with central randomization and 4 treatment arms.^2-5 Two of the studies did suggest that vitamin E may reduce the incidence of non-fatal myocardial infarctions. One study of 2002 persons receiving 400–800 IU/d showed a statistically significant reduction of non-fatal coronary events (relative risk [RR], 0.62)² In a subgroup analysis of another, 1862 men with history of MI also had reduced risk of non-fatal MI (RR, 0.23).³ However, in both of these groups, the increase in coronary death was not significant.¹

Three small RCTs enrolling a total of 1034 geriatric patients, with follow-up of less than 2 years, evaluated vitamin C (50–200 mg/d) versus placebo and showed no mortality benefit.¹ Meta-analysis of these studies showed a non-significant increase in the relative risk of death (RR, 1.08).⁶

A randomized, placebo-controlled study of simvastatin 40 mg and antioxidants (vitamin E 600 mg, vitamin C 250 mg, beta-carotene 20 mg) enrolled 20,536 adults aged 40 to 80 years with known CAD or high risk for CAD. No significant difference was found in all-cause mortality (RR, 1.04), major coronary events (RR, 1.02), any stroke (RR, 0.99), or any major vascular event (RR, 1.00).⁷ The investigators found no evidence of an adverse affect of the antioxidants on the substantial outcome benefits demonstrated with 40 mg daily of simvastatin. This finding eases some concern from a smaller prior study, which had suggested a negative interaction between simvastatin plus niacin and antioxidant supplementation (composed of vitamins E and C, beta-carotene, and selenium).⁸

Recommendations from others

A 2002 systematic review of antioxidant vitamins (carotene, tocopherol, and ascorbic acid) in primary and secondary prevention of cardiovascular disease concluded simply that “antioxidant vitamins as food supplements cannot be recommended in the primary or secondary prevention against cardiovascular disease.”⁹

The American Heart Association guidelines do not advocate antioxidant vitamin supplements, rather a well-balanced diet “with emphasis on anti-oxidant rich fruits and vegetables and whole grains.”¹⁰

EVIDENCE-BASED ANSWER

Antioxidant supplements of vitamins E and C do not reduce cardiovascular death in people with coronary artery disease. Vitamin E supplementation, in a variety of doses, does not decrease the incidence of cardiovascular or all-cause mortality (grade of recommendation: A, 4 high quality randomized controlled trials [RCTs]). There is no evidence that vitamin C decreases mortality in patients at risk for coronary disease (grade of recommendation: A, meta-analysis of 3 small RCTs). Combination antioxidant regimens (Vitamins E, C, and betacarotene) seem safe, but do not decrease mortality or incidence of major coronary and vascular events (grade recommendation: A, 1 high-quality RCT).

Evidence summary

Four large, well-designed RCTs with a combined enrollment of nearly 25,000 individuals with known coronary artery disease (CAD) or high risk for CAD receiving vitamin E (50–800 IU/d) collectively demonstrated no change in all-cause mortality or incidence of total cardiovascular events.¹ Three of these studies were double-blind, placebo-controlled and the fourth was an open-label design with central randomization and 4 treatment arms.^2-5 Two of the studies did suggest that vitamin E may reduce the incidence of non-fatal myocardial infarctions. One study of 2002 persons receiving 400–800 IU/d showed a statistically significant reduction of non-fatal coronary events (relative risk [RR], 0.62)² In a subgroup analysis of another, 1862 men with history of MI also had reduced risk of non-fatal MI (RR, 0.23).³ However, in both of these groups, the increase in coronary death was not significant.¹

Three small RCTs enrolling a total of 1034 geriatric patients, with follow-up of less than 2 years, evaluated vitamin C (50–200 mg/d) versus placebo and showed no mortality benefit.¹ Meta-analysis of these studies showed a non-significant increase in the relative risk of death (RR, 1.08).⁶

A randomized, placebo-controlled study of simvastatin 40 mg and antioxidants (vitamin E 600 mg, vitamin C 250 mg, beta-carotene 20 mg) enrolled 20,536 adults aged 40 to 80 years with known CAD or high risk for CAD. No significant difference was found in all-cause mortality (RR, 1.04), major coronary events (RR, 1.02), any stroke (RR, 0.99), or any major vascular event (RR, 1.00).⁷ The investigators found no evidence of an adverse affect of the antioxidants on the substantial outcome benefits demonstrated with 40 mg daily of simvastatin. This finding eases some concern from a smaller prior study, which had suggested a negative interaction between simvastatin plus niacin and antioxidant supplementation (composed of vitamins E and C, beta-carotene, and selenium).⁸

Recommendations from others

A 2002 systematic review of antioxidant vitamins (carotene, tocopherol, and ascorbic acid) in primary and secondary prevention of cardiovascular disease concluded simply that “antioxidant vitamins as food supplements cannot be recommended in the primary or secondary prevention against cardiovascular disease.”⁹

The American Heart Association guidelines do not advocate antioxidant vitamin supplements, rather a well-balanced diet “with emphasis on anti-oxidant rich fruits and vegetables and whole grains.”¹⁰

EVIDENCE-BASED ANSWER

Antioxidant supplements of vitamins E and C do not reduce cardiovascular death in people with coronary artery disease. Vitamin E supplementation, in a variety of doses, does not decrease the incidence of cardiovascular or all-cause mortality (grade of recommendation: A, 4 high quality randomized controlled trials [RCTs]). There is no evidence that vitamin C decreases mortality in patients at risk for coronary disease (grade of recommendation: A, meta-analysis of 3 small RCTs). Combination antioxidant regimens (Vitamins E, C, and betacarotene) seem safe, but do not decrease mortality or incidence of major coronary and vascular events (grade recommendation: A, 1 high-quality RCT).

Evidence summary

Four large, well-designed RCTs with a combined enrollment of nearly 25,000 individuals with known coronary artery disease (CAD) or high risk for CAD receiving vitamin E (50–800 IU/d) collectively demonstrated no change in all-cause mortality or incidence of total cardiovascular events.¹ Three of these studies were double-blind, placebo-controlled and the fourth was an open-label design with central randomization and 4 treatment arms.^2-5 Two of the studies did suggest that vitamin E may reduce the incidence of non-fatal myocardial infarctions. One study of 2002 persons receiving 400–800 IU/d showed a statistically significant reduction of non-fatal coronary events (relative risk [RR], 0.62)² In a subgroup analysis of another, 1862 men with history of MI also had reduced risk of non-fatal MI (RR, 0.23).³ However, in both of these groups, the increase in coronary death was not significant.¹

Three small RCTs enrolling a total of 1034 geriatric patients, with follow-up of less than 2 years, evaluated vitamin C (50–200 mg/d) versus placebo and showed no mortality benefit.¹ Meta-analysis of these studies showed a non-significant increase in the relative risk of death (RR, 1.08).⁶

A randomized, placebo-controlled study of simvastatin 40 mg and antioxidants (vitamin E 600 mg, vitamin C 250 mg, beta-carotene 20 mg) enrolled 20,536 adults aged 40 to 80 years with known CAD or high risk for CAD. No significant difference was found in all-cause mortality (RR, 1.04), major coronary events (RR, 1.02), any stroke (RR, 0.99), or any major vascular event (RR, 1.00).⁷ The investigators found no evidence of an adverse affect of the antioxidants on the substantial outcome benefits demonstrated with 40 mg daily of simvastatin. This finding eases some concern from a smaller prior study, which had suggested a negative interaction between simvastatin plus niacin and antioxidant supplementation (composed of vitamins E and C, beta-carotene, and selenium).⁸

Recommendations from others

A 2002 systematic review of antioxidant vitamins (carotene, tocopherol, and ascorbic acid) in primary and secondary prevention of cardiovascular disease concluded simply that “antioxidant vitamins as food supplements cannot be recommended in the primary or secondary prevention against cardiovascular disease.”⁹

The American Heart Association guidelines do not advocate antioxidant vitamin supplements, rather a well-balanced diet “with emphasis on anti-oxidant rich fruits and vegetables and whole grains.”¹⁰

EVIDENCE-BASED ANSWER

Healthy women who urinate within 15 minutes of sexual intercourse may be slightly less likely to develop a urinary tract infection (UTI) than women who do not urinate afterward (grade of recommendation: D, extrapolation of single case-control study with nonsignificant findings).

Evidence summary

A literature review revealed only 1 small case-control study. The goal of this study was to identify possible risk factors for developing UTIs among young, healthy women who presented to the University of California at Los Angeles student health center.¹ A total of 225 women were enrolled in the study. Exclusion criteria included pregnancy, diabetes, vaginitis, can-didiasis, a history of more than 1 prior UTI, hospitalization, or catheterization 4 weeks before study enrollment. The women were surveyed regarding their dietary habits, clothing, sexual and urinary habits, and birth control methods used. From mid-stream urine samples, the authors identified 44 cases of UTI and 181 controls presenting to the health center without urinary symptoms or a history of UTI. A UTI was defined as the presence of more than 50,000 colony forming units of a single species of bacteria per milliliter of urine and the report of 1 or more of the following symptoms: painful urination, frequent urination, urination at night, and urgent need to urinate, or blood in the urine. A primary UTI case was further defined as a not having had a prior history of UTI; a secondary UTI case was defined as a patient who reported 1 prior UTI.

Women who urinated < 15 minutes after intercourse had an estimated relative risk (RR) of 0.40 (95% confidence interval [CI], 0.09–2.17) for developing a primary case of UTI, and an estimated RR of 0.92 (95% CI, 0.18–4.88) for developing a secondary UTI. These findings were not statistically significant, but the power was too low to rule out a potential effect.

This single small case-control study had several limitations. It was not a randomized controlled trial, which would be required to prove that post-coital voiding is an effective intervention. The study included only young, healthy women and excluded women with recurrent UTIs, a subpopulation of sexually active patients who may particularly benefit from the intervention. Finally, the study lacked adequate sample size to detect a small-to-moderate effect of postcoital voiding.

Recommendations from others

A major urology text does not specifically address the prevention strategy of postcoital voiding.² However, Griffith’s 5 Minute Clinical Consult recommends that women with frequent or intercourse related UTIs should “empty [their] bladder immediately before and following intercourse and consider post-coital antibiotic treatment.”³ Furthermore, the American College of Obstetricians and Gynecologists District II NYS recommends urinating after sexual intercourse to prevent recurrent cystitis.⁴

Read a Clinical Commentary by Jay Moreland, MD, online at http://www.FPIN.org.

EVIDENCE-BASED ANSWER

Healthy women who urinate within 15 minutes of sexual intercourse may be slightly less likely to develop a urinary tract infection (UTI) than women who do not urinate afterward (grade of recommendation: D, extrapolation of single case-control study with nonsignificant findings).

Evidence summary

A literature review revealed only 1 small case-control study. The goal of this study was to identify possible risk factors for developing UTIs among young, healthy women who presented to the University of California at Los Angeles student health center.¹ A total of 225 women were enrolled in the study. Exclusion criteria included pregnancy, diabetes, vaginitis, can-didiasis, a history of more than 1 prior UTI, hospitalization, or catheterization 4 weeks before study enrollment. The women were surveyed regarding their dietary habits, clothing, sexual and urinary habits, and birth control methods used. From mid-stream urine samples, the authors identified 44 cases of UTI and 181 controls presenting to the health center without urinary symptoms or a history of UTI. A UTI was defined as the presence of more than 50,000 colony forming units of a single species of bacteria per milliliter of urine and the report of 1 or more of the following symptoms: painful urination, frequent urination, urination at night, and urgent need to urinate, or blood in the urine. A primary UTI case was further defined as a not having had a prior history of UTI; a secondary UTI case was defined as a patient who reported 1 prior UTI.

Women who urinated < 15 minutes after intercourse had an estimated relative risk (RR) of 0.40 (95% confidence interval [CI], 0.09–2.17) for developing a primary case of UTI, and an estimated RR of 0.92 (95% CI, 0.18–4.88) for developing a secondary UTI. These findings were not statistically significant, but the power was too low to rule out a potential effect.

This single small case-control study had several limitations. It was not a randomized controlled trial, which would be required to prove that post-coital voiding is an effective intervention. The study included only young, healthy women and excluded women with recurrent UTIs, a subpopulation of sexually active patients who may particularly benefit from the intervention. Finally, the study lacked adequate sample size to detect a small-to-moderate effect of postcoital voiding.

Recommendations from others

A major urology text does not specifically address the prevention strategy of postcoital voiding.² However, Griffith’s 5 Minute Clinical Consult recommends that women with frequent or intercourse related UTIs should “empty [their] bladder immediately before and following intercourse and consider post-coital antibiotic treatment.”³ Furthermore, the American College of Obstetricians and Gynecologists District II NYS recommends urinating after sexual intercourse to prevent recurrent cystitis.⁴

Read a Clinical Commentary by Jay Moreland, MD, online at http://www.FPIN.org.

EVIDENCE-BASED ANSWER

Healthy women who urinate within 15 minutes of sexual intercourse may be slightly less likely to develop a urinary tract infection (UTI) than women who do not urinate afterward (grade of recommendation: D, extrapolation of single case-control study with nonsignificant findings).

Evidence summary

A literature review revealed only 1 small case-control study. The goal of this study was to identify possible risk factors for developing UTIs among young, healthy women who presented to the University of California at Los Angeles student health center.¹ A total of 225 women were enrolled in the study. Exclusion criteria included pregnancy, diabetes, vaginitis, can-didiasis, a history of more than 1 prior UTI, hospitalization, or catheterization 4 weeks before study enrollment. The women were surveyed regarding their dietary habits, clothing, sexual and urinary habits, and birth control methods used. From mid-stream urine samples, the authors identified 44 cases of UTI and 181 controls presenting to the health center without urinary symptoms or a history of UTI. A UTI was defined as the presence of more than 50,000 colony forming units of a single species of bacteria per milliliter of urine and the report of 1 or more of the following symptoms: painful urination, frequent urination, urination at night, and urgent need to urinate, or blood in the urine. A primary UTI case was further defined as a not having had a prior history of UTI; a secondary UTI case was defined as a patient who reported 1 prior UTI.

Women who urinated < 15 minutes after intercourse had an estimated relative risk (RR) of 0.40 (95% confidence interval [CI], 0.09–2.17) for developing a primary case of UTI, and an estimated RR of 0.92 (95% CI, 0.18–4.88) for developing a secondary UTI. These findings were not statistically significant, but the power was too low to rule out a potential effect.

This single small case-control study had several limitations. It was not a randomized controlled trial, which would be required to prove that post-coital voiding is an effective intervention. The study included only young, healthy women and excluded women with recurrent UTIs, a subpopulation of sexually active patients who may particularly benefit from the intervention. Finally, the study lacked adequate sample size to detect a small-to-moderate effect of postcoital voiding.

Recommendations from others

A major urology text does not specifically address the prevention strategy of postcoital voiding.² However, Griffith’s 5 Minute Clinical Consult recommends that women with frequent or intercourse related UTIs should “empty [their] bladder immediately before and following intercourse and consider post-coital antibiotic treatment.”³ Furthermore, the American College of Obstetricians and Gynecologists District II NYS recommends urinating after sexual intercourse to prevent recurrent cystitis.⁴

Read a Clinical Commentary by Jay Moreland, MD, online at http://www.FPIN.org.

EVIDENCE-BASED ANSWER

Most recent randomized controlled clinical trials have not found a benefit in antioxidants (vitamin C, vitamin E, and/or beta-carotene) for preventing cardiovascular disease, including stroke. These recent clinical studies have not confirmed earlier observational studies that suggested a benefit. No studies have assessed only stroke patients and stroke outcomes. (Grade of recommendation: A, based on randomized controlled clinical trials and a systematic review of antioxidants and cardiovascular disease.)

Evidence summary

The Heart Outcomes Prevention Evaluation (HOPE) trial was a 4.5-year randomized controlled clinical trial of vitamin E or placebo in 9541 patients aged 55 years or older with a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes and other cardiovascular disease risk factors. No difference was noted between vitamin E and placebo for the outcomes of stroke, death, or other cardiac outcomes for these high-risk patients.¹ In a randomized controlled clinical trial of 29,133 Finnish male smokers, the overall net stroke morbidity and mortality with antioxidants was not significantly different from placebo. However, a trend toward higher rates of subarachnoid hemorrhages was found (relative risk [RR] = 1.5; 95% confidence interval [CI], 0.97–2.32; numbers needed to harm [NNH] = 833), while the cerebral infarction rate was decreased (RR = 0.86; 95% CI, 0.75–0.99; numbers needed to treat = 239) by vitamin E. Beta-carotene increased intracerebral hemorrhage (RR = 1.61; 95% CI, 1.10–2.36; NNH = 546).² Subsequent subgroup analysis showed a significant decrease in cerebral infarction (RR = 0.33; 95% CI, 0.14–0.78) without increasing subarachnoid hemorrhage in hypertensive, diabetic men taking vitamin E.³ Given the inherent methodological perils of subgroup analysis, this association requires further study before clinical implementation.

The Italian GISSI study of 11,324 patients with a recent myocardial infarction showed no effect of vitamin E on the combined outcomes of death, myocardial infarction, and stroke.⁴ In the Heart Protection Study, 20,536 adults between the ages of 40 and 80 years with cardiovascular disease, stroke, or diabetes were given vitamin E, vitamin C, beta-carotene, or placebo for 5 years. No significant differences were noted between vitamins and placebo in fatal or nonfatal stroke (RR = 0.99; 95% CI, 0.87–1.12).⁵

Although prior observational studies have hinted at a link between antioxidants and improved cardiovascular outcomes, the recently published Health Professionals Follow-up Study found no benefit to vitamin C or E in preventing strokes, based on the dietary assessment of 43,738 men, aged 40 to 75 years, who were not known to have cardiovascular disease or diabetes.⁶

Recommendations from others

The American Heart Association Science Advisory and Coordinating Committee commented on antioxidant use in 1999. While their emphasis was on coronary heart disease, they concluded that the general population should “consume a balanced diet with emphasis on antioxidant-rich fruits and vegetables and whole grains,” noting that “the absence of efficacy and safety data from randomized trials precludes the establishment of population-wide recommendations regarding vitamin E supplementation.”⁷ Some authors argue that the failure to demonstrate a benefit from antioxidants is due to inadequate antioxidant dosing, treatment length, or type of antioxidant.⁸

Read a Clinical Commentary by Dan Sontheimer, MD, MBA, online at http://www.FPIN.org.

EVIDENCE-BASED ANSWER

Most recent randomized controlled clinical trials have not found a benefit in antioxidants (vitamin C, vitamin E, and/or beta-carotene) for preventing cardiovascular disease, including stroke. These recent clinical studies have not confirmed earlier observational studies that suggested a benefit. No studies have assessed only stroke patients and stroke outcomes. (Grade of recommendation: A, based on randomized controlled clinical trials and a systematic review of antioxidants and cardiovascular disease.)

Evidence summary

The Heart Outcomes Prevention Evaluation (HOPE) trial was a 4.5-year randomized controlled clinical trial of vitamin E or placebo in 9541 patients aged 55 years or older with a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes and other cardiovascular disease risk factors. No difference was noted between vitamin E and placebo for the outcomes of stroke, death, or other cardiac outcomes for these high-risk patients.¹ In a randomized controlled clinical trial of 29,133 Finnish male smokers, the overall net stroke morbidity and mortality with antioxidants was not significantly different from placebo. However, a trend toward higher rates of subarachnoid hemorrhages was found (relative risk [RR] = 1.5; 95% confidence interval [CI], 0.97–2.32; numbers needed to harm [NNH] = 833), while the cerebral infarction rate was decreased (RR = 0.86; 95% CI, 0.75–0.99; numbers needed to treat = 239) by vitamin E. Beta-carotene increased intracerebral hemorrhage (RR = 1.61; 95% CI, 1.10–2.36; NNH = 546).² Subsequent subgroup analysis showed a significant decrease in cerebral infarction (RR = 0.33; 95% CI, 0.14–0.78) without increasing subarachnoid hemorrhage in hypertensive, diabetic men taking vitamin E.³ Given the inherent methodological perils of subgroup analysis, this association requires further study before clinical implementation.

The Italian GISSI study of 11,324 patients with a recent myocardial infarction showed no effect of vitamin E on the combined outcomes of death, myocardial infarction, and stroke.⁴ In the Heart Protection Study, 20,536 adults between the ages of 40 and 80 years with cardiovascular disease, stroke, or diabetes were given vitamin E, vitamin C, beta-carotene, or placebo for 5 years. No significant differences were noted between vitamins and placebo in fatal or nonfatal stroke (RR = 0.99; 95% CI, 0.87–1.12).⁵

Although prior observational studies have hinted at a link between antioxidants and improved cardiovascular outcomes, the recently published Health Professionals Follow-up Study found no benefit to vitamin C or E in preventing strokes, based on the dietary assessment of 43,738 men, aged 40 to 75 years, who were not known to have cardiovascular disease or diabetes.⁶

Recommendations from others

The American Heart Association Science Advisory and Coordinating Committee commented on antioxidant use in 1999. While their emphasis was on coronary heart disease, they concluded that the general population should “consume a balanced diet with emphasis on antioxidant-rich fruits and vegetables and whole grains,” noting that “the absence of efficacy and safety data from randomized trials precludes the establishment of population-wide recommendations regarding vitamin E supplementation.”⁷ Some authors argue that the failure to demonstrate a benefit from antioxidants is due to inadequate antioxidant dosing, treatment length, or type of antioxidant.⁸

Read a Clinical Commentary by Dan Sontheimer, MD, MBA, online at http://www.FPIN.org.

EVIDENCE-BASED ANSWER

Most recent randomized controlled clinical trials have not found a benefit in antioxidants (vitamin C, vitamin E, and/or beta-carotene) for preventing cardiovascular disease, including stroke. These recent clinical studies have not confirmed earlier observational studies that suggested a benefit. No studies have assessed only stroke patients and stroke outcomes. (Grade of recommendation: A, based on randomized controlled clinical trials and a systematic review of antioxidants and cardiovascular disease.)

Evidence summary

The Heart Outcomes Prevention Evaluation (HOPE) trial was a 4.5-year randomized controlled clinical trial of vitamin E or placebo in 9541 patients aged 55 years or older with a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes and other cardiovascular disease risk factors. No difference was noted between vitamin E and placebo for the outcomes of stroke, death, or other cardiac outcomes for these high-risk patients.¹ In a randomized controlled clinical trial of 29,133 Finnish male smokers, the overall net stroke morbidity and mortality with antioxidants was not significantly different from placebo. However, a trend toward higher rates of subarachnoid hemorrhages was found (relative risk [RR] = 1.5; 95% confidence interval [CI], 0.97–2.32; numbers needed to harm [NNH] = 833), while the cerebral infarction rate was decreased (RR = 0.86; 95% CI, 0.75–0.99; numbers needed to treat = 239) by vitamin E. Beta-carotene increased intracerebral hemorrhage (RR = 1.61; 95% CI, 1.10–2.36; NNH = 546).² Subsequent subgroup analysis showed a significant decrease in cerebral infarction (RR = 0.33; 95% CI, 0.14–0.78) without increasing subarachnoid hemorrhage in hypertensive, diabetic men taking vitamin E.³ Given the inherent methodological perils of subgroup analysis, this association requires further study before clinical implementation.

The Italian GISSI study of 11,324 patients with a recent myocardial infarction showed no effect of vitamin E on the combined outcomes of death, myocardial infarction, and stroke.⁴ In the Heart Protection Study, 20,536 adults between the ages of 40 and 80 years with cardiovascular disease, stroke, or diabetes were given vitamin E, vitamin C, beta-carotene, or placebo for 5 years. No significant differences were noted between vitamins and placebo in fatal or nonfatal stroke (RR = 0.99; 95% CI, 0.87–1.12).⁵

Although prior observational studies have hinted at a link between antioxidants and improved cardiovascular outcomes, the recently published Health Professionals Follow-up Study found no benefit to vitamin C or E in preventing strokes, based on the dietary assessment of 43,738 men, aged 40 to 75 years, who were not known to have cardiovascular disease or diabetes.⁶

Recommendations from others

The American Heart Association Science Advisory and Coordinating Committee commented on antioxidant use in 1999. While their emphasis was on coronary heart disease, they concluded that the general population should “consume a balanced diet with emphasis on antioxidant-rich fruits and vegetables and whole grains,” noting that “the absence of efficacy and safety data from randomized trials precludes the establishment of population-wide recommendations regarding vitamin E supplementation.”⁷ Some authors argue that the failure to demonstrate a benefit from antioxidants is due to inadequate antioxidant dosing, treatment length, or type of antioxidant.⁸

Read a Clinical Commentary by Dan Sontheimer, MD, MBA, online at http://www.FPIN.org.

EVIDENCE-BASED ANSWER

Vitamin B6 (50–100 mg/d) and elemental calcium (1200 mg/d) are safe, inexpensive, and moderately effective (Table) (grade of recommendation: B). Selective serotonin reuptake inhibitors (SSRIs) and some other antidepressants are more effective, but are also more costly and more likely to cause side effects or treatment dropout (grade of recommendation: A). Antidepressant dosing only during the luteal phase may be effective and more tolerable (grade of recommendation: B). Alprazolam (generally 0.25–0.5 mg 3 times a day during luteal phase) may be effective for treating mood or anxiety symptoms (grade of recommendation: B). Hormonal therapies (oral contraceptives, gonadotropin-releasing hormone agonists, danazol, estrogen) lack convincing evidence of efficacy and cause many side effects; progesterone is no more beneficial than placebo (grade of recommendation: B). There is no convincing evidence of benefit from diuretics, magnesium, beta-blockers, or lithium (grade of recommendation: C).

TABLE

Agents for treating symptoms of premenstrual syndrome

Evidence summary

Pooled results of 9, generally poor-quality studies of Vitamin B6 show some benefit.¹ Doses higher than 100 mg/d may cause peripheral neuropathy. Three small studies in the 1980s suggested possible benefit of Vitamin E; however, these studies have not been further replicated. One well-designed, randomized controlled trial of calcium therapy showed > 50% decrease in symptom complex scores after 3 months in more than half of subjects taking 1200 mg/d supplemental elemental calcium (NNT=6).²

Among SSRIs, fluoxetine (20 mg/d) is well-studied and effective.³ Other SSRIs, including sertraline, paroxetine, fluvoxamine, and venlafaxine, and clomipramine (a tricyclic with serotonin reuptake inhibitor activity), also show benefit but are less well studied. Luteal phase-only dosing may be equally or more effective than continuous dosing for some SSRIs. Benzodiazepines have shown mixed results in treating PMS, and overall their benefit appears smaller than that of SSRIs.⁴ Luteal phase-only dosing theoretically reduces the risk of benzodiazepine withdrawal or dependence, but published data are rare.

Gonadotropin-releasing hormone agonists may be effective, but troublesome anti-estrogenic side effects limit their utility. Estrogen and progesterone “add-back” therapy to counter side effects further complicates this approach. The gonadotropin inhibitor danazol has a high treatment dropout rate at higher doses (200–400 mg/d continuously), but can be effective in individuals who are able to tolerate it^3,5 ; however, danazol is expensive and causes significant androgenic side effects. Lower-dose danazol (200 mg/d luteal phase only) is better tolerated but ineffective.⁶ A meta-analysis of progesterone found no evidence to support its efficacy.⁷ Oral contraceptives are ineffective for global symptoms, and may actually cause PMS symptoms in some women.

Recommendations from others

The American College of Obstetricians and Gynecologists recommend that patients with mild to moderate PMS should receive supportive, lifestyle, and dietary interventions. For severe PMS, SSRIs are the initial drug of choice. Alprazolam may be useful when these interventions are ineffective. Consider oral contraceptives for primarily physical symptoms and reserve gonadotropin-releasing hormone for severe cases unresponsive to other treatments.⁸

Clinical Commentary by Peter Danis, MD, at http://www.fpin.org.

EVIDENCE-BASED ANSWER

Vitamin B6 (50–100 mg/d) and elemental calcium (1200 mg/d) are safe, inexpensive, and moderately effective (Table) (grade of recommendation: B). Selective serotonin reuptake inhibitors (SSRIs) and some other antidepressants are more effective, but are also more costly and more likely to cause side effects or treatment dropout (grade of recommendation: A). Antidepressant dosing only during the luteal phase may be effective and more tolerable (grade of recommendation: B). Alprazolam (generally 0.25–0.5 mg 3 times a day during luteal phase) may be effective for treating mood or anxiety symptoms (grade of recommendation: B). Hormonal therapies (oral contraceptives, gonadotropin-releasing hormone agonists, danazol, estrogen) lack convincing evidence of efficacy and cause many side effects; progesterone is no more beneficial than placebo (grade of recommendation: B). There is no convincing evidence of benefit from diuretics, magnesium, beta-blockers, or lithium (grade of recommendation: C).

TABLE

Agents for treating symptoms of premenstrual syndrome

Evidence summary

Pooled results of 9, generally poor-quality studies of Vitamin B6 show some benefit.¹ Doses higher than 100 mg/d may cause peripheral neuropathy. Three small studies in the 1980s suggested possible benefit of Vitamin E; however, these studies have not been further replicated. One well-designed, randomized controlled trial of calcium therapy showed > 50% decrease in symptom complex scores after 3 months in more than half of subjects taking 1200 mg/d supplemental elemental calcium (NNT=6).²

Among SSRIs, fluoxetine (20 mg/d) is well-studied and effective.³ Other SSRIs, including sertraline, paroxetine, fluvoxamine, and venlafaxine, and clomipramine (a tricyclic with serotonin reuptake inhibitor activity), also show benefit but are less well studied. Luteal phase-only dosing may be equally or more effective than continuous dosing for some SSRIs. Benzodiazepines have shown mixed results in treating PMS, and overall their benefit appears smaller than that of SSRIs.⁴ Luteal phase-only dosing theoretically reduces the risk of benzodiazepine withdrawal or dependence, but published data are rare.

Gonadotropin-releasing hormone agonists may be effective, but troublesome anti-estrogenic side effects limit their utility. Estrogen and progesterone “add-back” therapy to counter side effects further complicates this approach. The gonadotropin inhibitor danazol has a high treatment dropout rate at higher doses (200–400 mg/d continuously), but can be effective in individuals who are able to tolerate it^3,5 ; however, danazol is expensive and causes significant androgenic side effects. Lower-dose danazol (200 mg/d luteal phase only) is better tolerated but ineffective.⁶ A meta-analysis of progesterone found no evidence to support its efficacy.⁷ Oral contraceptives are ineffective for global symptoms, and may actually cause PMS symptoms in some women.

Recommendations from others

The American College of Obstetricians and Gynecologists recommend that patients with mild to moderate PMS should receive supportive, lifestyle, and dietary interventions. For severe PMS, SSRIs are the initial drug of choice. Alprazolam may be useful when these interventions are ineffective. Consider oral contraceptives for primarily physical symptoms and reserve gonadotropin-releasing hormone for severe cases unresponsive to other treatments.⁸

Clinical Commentary by Peter Danis, MD, at http://www.fpin.org.

EVIDENCE-BASED ANSWER

Vitamin B6 (50–100 mg/d) and elemental calcium (1200 mg/d) are safe, inexpensive, and moderately effective (Table) (grade of recommendation: B). Selective serotonin reuptake inhibitors (SSRIs) and some other antidepressants are more effective, but are also more costly and more likely to cause side effects or treatment dropout (grade of recommendation: A). Antidepressant dosing only during the luteal phase may be effective and more tolerable (grade of recommendation: B). Alprazolam (generally 0.25–0.5 mg 3 times a day during luteal phase) may be effective for treating mood or anxiety symptoms (grade of recommendation: B). Hormonal therapies (oral contraceptives, gonadotropin-releasing hormone agonists, danazol, estrogen) lack convincing evidence of efficacy and cause many side effects; progesterone is no more beneficial than placebo (grade of recommendation: B). There is no convincing evidence of benefit from diuretics, magnesium, beta-blockers, or lithium (grade of recommendation: C).

TABLE

Agents for treating symptoms of premenstrual syndrome

Evidence summary

Pooled results of 9, generally poor-quality studies of Vitamin B6 show some benefit.¹ Doses higher than 100 mg/d may cause peripheral neuropathy. Three small studies in the 1980s suggested possible benefit of Vitamin E; however, these studies have not been further replicated. One well-designed, randomized controlled trial of calcium therapy showed > 50% decrease in symptom complex scores after 3 months in more than half of subjects taking 1200 mg/d supplemental elemental calcium (NNT=6).²

Among SSRIs, fluoxetine (20 mg/d) is well-studied and effective.³ Other SSRIs, including sertraline, paroxetine, fluvoxamine, and venlafaxine, and clomipramine (a tricyclic with serotonin reuptake inhibitor activity), also show benefit but are less well studied. Luteal phase-only dosing may be equally or more effective than continuous dosing for some SSRIs. Benzodiazepines have shown mixed results in treating PMS, and overall their benefit appears smaller than that of SSRIs.⁴ Luteal phase-only dosing theoretically reduces the risk of benzodiazepine withdrawal or dependence, but published data are rare.

Gonadotropin-releasing hormone agonists may be effective, but troublesome anti-estrogenic side effects limit their utility. Estrogen and progesterone “add-back” therapy to counter side effects further complicates this approach. The gonadotropin inhibitor danazol has a high treatment dropout rate at higher doses (200–400 mg/d continuously), but can be effective in individuals who are able to tolerate it^3,5 ; however, danazol is expensive and causes significant androgenic side effects. Lower-dose danazol (200 mg/d luteal phase only) is better tolerated but ineffective.⁶ A meta-analysis of progesterone found no evidence to support its efficacy.⁷ Oral contraceptives are ineffective for global symptoms, and may actually cause PMS symptoms in some women.

Recommendations from others

The American College of Obstetricians and Gynecologists recommend that patients with mild to moderate PMS should receive supportive, lifestyle, and dietary interventions. For severe PMS, SSRIs are the initial drug of choice. Alprazolam may be useful when these interventions are ineffective. Consider oral contraceptives for primarily physical symptoms and reserve gonadotropin-releasing hormone for severe cases unresponsive to other treatments.⁸

Clinical Commentary by Peter Danis, MD, at http://www.fpin.org.

EVIDENCE-BASED ANSWER

Efforts to increase physical activity or decrease sedentary activities have shown some short-term benefit, and adding dietary changes may be more effective. Aiming interventions at parents, intensive family therapy, comprehensive school-based programs, and selecting motivated children for subspecialty care may improve success. (Grade of recommendation: B, based on poor-quality randomized controlled trials [RCTs] and heterogeneous systematic reviews.) Other potentially effective short-term strategies include screening with body mass index (BMI) for age (grade of recommendation: C, extrapolation from cohort studies and ecological research) or dietary counseling (grade of recommendation: D, conflicting poor-quality RCTs). No drugs are currently approved for pediatric obesity therapy in the United States.

Evidence summary

Pediatric obesity increases the risk of adverse outcomes in adulthood, independent of adult BMI.¹ Trials aiming to reduce childhood obesity suffer from serious methodological constraints. No long-term (> 2 years) evidence is available. Many apparently efficacious interventions are beyond the scope of primary care physicians. A detailed summary is available online at http://www.FPIN.org.

Several studies have examined the value of isolated changes in either diet or activity level. Randomized controlled trials and retrospective cohort studies of dietary advice alone show short-term efficacy (weeks to months).¹ Most involve intensive subspecialty care for extremely obese children who are 120% to 140% over their ideal body weight. Trials without careful selection of motivated children had dropout rates up to 87%. One Italian RCT showed a 12% reduction in the number of obese children in schools receiving multimedia dietary advice compared with a 5% to 6% increase in those schools receiving only written or no advice.² Several RCTs reduced obesity by introducing or improving school-based physical activity.¹ Two RCTs that discouraged sedentary activity through counseling or school-based programs also reduced obesity.^3,4

Two larger trials integrated diet and exercise advice into school curricula. One study emphasized improving school menus, but no difference was observed because children compensated by overeating at home.⁵ The other emphasized reducing sedentary activities and found lower obesity rates in the intervention schools, but only for girls.⁶ A third trial provided family-based dietary and behavior counseling, but emphasized either increasing physical activity or decreasing sedentary activity.⁷ Both strategies resulted in reduced obesity compared with controls. A systematic review supported the combined approach of these trials, finding diet and exercise interventions superior to diet interventions alone.⁸

Some evidence supports focusing on the family rather than just the child. A systematic review found that family therapy prevented pediatric obesity.⁹ An RCT found that focusing on parents as the sole change agent was superior to targeting the child.¹⁰

Recommendations from others

Expert consensus promotes screening because of obesity’s increasing incidence and associated morbidity and mortality.¹¹ The Maternal and Child Health Bureau recommends a primary goal of healthy eating and activity. They recommend treating when the body mass index is >95th percentile, and assessing the child and family’s willingness to change. Primary strategies are to begin early, involve the family, promote parenting skills, and increase activity and reduce high-calorie food intake. They also recommend ongoing support to maintain weight loss.⁹

Clinical Commentary by Tess Bobo, MD, at http://www.fpin.org.

EVIDENCE-BASED ANSWER

Efforts to increase physical activity or decrease sedentary activities have shown some short-term benefit, and adding dietary changes may be more effective. Aiming interventions at parents, intensive family therapy, comprehensive school-based programs, and selecting motivated children for subspecialty care may improve success. (Grade of recommendation: B, based on poor-quality randomized controlled trials [RCTs] and heterogeneous systematic reviews.) Other potentially effective short-term strategies include screening with body mass index (BMI) for age (grade of recommendation: C, extrapolation from cohort studies and ecological research) or dietary counseling (grade of recommendation: D, conflicting poor-quality RCTs). No drugs are currently approved for pediatric obesity therapy in the United States.

Evidence summary

Pediatric obesity increases the risk of adverse outcomes in adulthood, independent of adult BMI.¹ Trials aiming to reduce childhood obesity suffer from serious methodological constraints. No long-term (> 2 years) evidence is available. Many apparently efficacious interventions are beyond the scope of primary care physicians. A detailed summary is available online at http://www.FPIN.org.

Several studies have examined the value of isolated changes in either diet or activity level. Randomized controlled trials and retrospective cohort studies of dietary advice alone show short-term efficacy (weeks to months).¹ Most involve intensive subspecialty care for extremely obese children who are 120% to 140% over their ideal body weight. Trials without careful selection of motivated children had dropout rates up to 87%. One Italian RCT showed a 12% reduction in the number of obese children in schools receiving multimedia dietary advice compared with a 5% to 6% increase in those schools receiving only written or no advice.² Several RCTs reduced obesity by introducing or improving school-based physical activity.¹ Two RCTs that discouraged sedentary activity through counseling or school-based programs also reduced obesity.^3,4

Two larger trials integrated diet and exercise advice into school curricula. One study emphasized improving school menus, but no difference was observed because children compensated by overeating at home.⁵ The other emphasized reducing sedentary activities and found lower obesity rates in the intervention schools, but only for girls.⁶ A third trial provided family-based dietary and behavior counseling, but emphasized either increasing physical activity or decreasing sedentary activity.⁷ Both strategies resulted in reduced obesity compared with controls. A systematic review supported the combined approach of these trials, finding diet and exercise interventions superior to diet interventions alone.⁸

Some evidence supports focusing on the family rather than just the child. A systematic review found that family therapy prevented pediatric obesity.⁹ An RCT found that focusing on parents as the sole change agent was superior to targeting the child.¹⁰

Recommendations from others

Expert consensus promotes screening because of obesity’s increasing incidence and associated morbidity and mortality.¹¹ The Maternal and Child Health Bureau recommends a primary goal of healthy eating and activity. They recommend treating when the body mass index is >95th percentile, and assessing the child and family’s willingness to change. Primary strategies are to begin early, involve the family, promote parenting skills, and increase activity and reduce high-calorie food intake. They also recommend ongoing support to maintain weight loss.⁹

Clinical Commentary by Tess Bobo, MD, at http://www.fpin.org.

EVIDENCE-BASED ANSWER

Efforts to increase physical activity or decrease sedentary activities have shown some short-term benefit, and adding dietary changes may be more effective. Aiming interventions at parents, intensive family therapy, comprehensive school-based programs, and selecting motivated children for subspecialty care may improve success. (Grade of recommendation: B, based on poor-quality randomized controlled trials [RCTs] and heterogeneous systematic reviews.) Other potentially effective short-term strategies include screening with body mass index (BMI) for age (grade of recommendation: C, extrapolation from cohort studies and ecological research) or dietary counseling (grade of recommendation: D, conflicting poor-quality RCTs). No drugs are currently approved for pediatric obesity therapy in the United States.

Evidence summary

Pediatric obesity increases the risk of adverse outcomes in adulthood, independent of adult BMI.¹ Trials aiming to reduce childhood obesity suffer from serious methodological constraints. No long-term (> 2 years) evidence is available. Many apparently efficacious interventions are beyond the scope of primary care physicians. A detailed summary is available online at http://www.FPIN.org.

Several studies have examined the value of isolated changes in either diet or activity level. Randomized controlled trials and retrospective cohort studies of dietary advice alone show short-term efficacy (weeks to months).¹ Most involve intensive subspecialty care for extremely obese children who are 120% to 140% over their ideal body weight. Trials without careful selection of motivated children had dropout rates up to 87%. One Italian RCT showed a 12% reduction in the number of obese children in schools receiving multimedia dietary advice compared with a 5% to 6% increase in those schools receiving only written or no advice.² Several RCTs reduced obesity by introducing or improving school-based physical activity.¹ Two RCTs that discouraged sedentary activity through counseling or school-based programs also reduced obesity.^3,4

Two larger trials integrated diet and exercise advice into school curricula. One study emphasized improving school menus, but no difference was observed because children compensated by overeating at home.⁵ The other emphasized reducing sedentary activities and found lower obesity rates in the intervention schools, but only for girls.⁶ A third trial provided family-based dietary and behavior counseling, but emphasized either increasing physical activity or decreasing sedentary activity.⁷ Both strategies resulted in reduced obesity compared with controls. A systematic review supported the combined approach of these trials, finding diet and exercise interventions superior to diet interventions alone.⁸

Some evidence supports focusing on the family rather than just the child. A systematic review found that family therapy prevented pediatric obesity.⁹ An RCT found that focusing on parents as the sole change agent was superior to targeting the child.¹⁰

Recommendations from others

Expert consensus promotes screening because of obesity’s increasing incidence and associated morbidity and mortality.¹¹ The Maternal and Child Health Bureau recommends a primary goal of healthy eating and activity. They recommend treating when the body mass index is >95th percentile, and assessing the child and family’s willingness to change. Primary strategies are to begin early, involve the family, promote parenting skills, and increase activity and reduce high-calorie food intake. They also recommend ongoing support to maintain weight loss.⁹

Clinical Commentary by Tess Bobo, MD, at http://www.fpin.org.

EVIDENCE-BASED ANSWER

Large published randomized controlled trials (RCTs) show that pravastatin and simvastatin are well-tolerated and reduce major coronary events such as death, myocardial infarction, and revascularization by about 25%. The Heart Protection Study suggested this benefit is noted even among individuals with pretreatment low-density lipoprotein (LDL) cholesterol of less than 100 mg/dL. Fluvastatin reduces major coronary events, but current studies are too small to prove reduced overall mortality. The best evidence to date suggests that most patients at significant risk for major coronary events should be given pravastatin or simvastatin 40 mg daily, without concern for the initial or follow-up LDL levels. (Grade of recommendation: A, based on large randomized trials.)

Evidence summary

The evidence is solid to support the use of HMG–CoA reductase inhibitors (statins) for patients with coronary artery disease (CAD). The Scandinavian Simvastatin Survival study used simvastatin 20 mg daily unless total cholesterol levels did not decrease to less than 200 mg/dL.¹ The Long-Term Intervention with Pravastatin in Ischaemic Disease study randomized patients to pravastatin 40 mg daily or placebo, without titration.² The intervention arm in the Cholesterol and Recurrent Events trial was also pravastatin 40 mg daily, with cholestyramine added if the LDL level remained higher than 175 mg/dL.³ The Lescol Intervention Prevention study randomized patients after angioplasty to fluvastatin 40 mg twice daily or placebo.⁴ The Heart Protection Study used simvastatin 40 mg daily, without titration.⁵ No RCTs have evaluated the clinical benefit of adding medications to adequate doses of statins to lower LDL to less than 175 mg/dL. See Table of major RCTs with clinical outcomes.

Subgroup analyses of earlier major RCTs had suggested that patients with CAD and low initial LDL levels (< 125 mg/dL) have little to gain from pravastatin.^2,3 However, the Heart Protection Study enrolled 20,000 people with CAD or equivalent (diabetes, peripheral vascular disease, stroke, etc).⁵ The study demonstrated a reduction of major coronary events with simvastatin, with numbers needed to treat (NNT) of 19 (P < .0001); the NNT for reduction in all-cause mortality was 55 (P = .0003). The benefit of simvastatin was noted in virtually every predefined subgroup, including individuals older than 70 years, women, and patients without known CAD (but with CAD equivalents). Notably, no difference in benefit was found between patients with different pretreatment LDL levels. A significant reduction in major vascular events was noted even for the 3400 subjects with pretreatment LDL levels of less than 100 mg/dL (NNT = 22, P = .0006). A greater percentage reduction in LDL with medication did not predict better clinical outcomes.⁵

TABLE

LDL levels and relative risk of major coronary events after treatment

Recommendations from others

The National Cholesterol Education Project (NCEP) recommends that patients with CAD and an LDL of more than 130 mg/dL adopt therapeutic lifestyle changes and start LDL-lowering medication, usually a statin. For patients with LDL between 100 and 130 mg/dL, the NCEP recommends therapeutic lifestyle changes, with the option of adding a statin. For patients with LDL less than 100 mg/dL, maintenance of LDL control is recommended with therapeutic lifestyle changes. For patients with high initial LDL levels that stay above 100 mg/dL on statin therapy, the NCEP recommends that additional medications, such as nicotinic acid or fibrates, as well as intensive therapeutic lifestyle changes, be considered.⁶

Clinical Commentary by William Chavey, MD, at http://www.fpin.org.

EVIDENCE-BASED ANSWER

Large published randomized controlled trials (RCTs) show that pravastatin and simvastatin are well-tolerated and reduce major coronary events such as death, myocardial infarction, and revascularization by about 25%. The Heart Protection Study suggested this benefit is noted even among individuals with pretreatment low-density lipoprotein (LDL) cholesterol of less than 100 mg/dL. Fluvastatin reduces major coronary events, but current studies are too small to prove reduced overall mortality. The best evidence to date suggests that most patients at significant risk for major coronary events should be given pravastatin or simvastatin 40 mg daily, without concern for the initial or follow-up LDL levels. (Grade of recommendation: A, based on large randomized trials.)

Evidence summary

The evidence is solid to support the use of HMG–CoA reductase inhibitors (statins) for patients with coronary artery disease (CAD). The Scandinavian Simvastatin Survival study used simvastatin 20 mg daily unless total cholesterol levels did not decrease to less than 200 mg/dL.¹ The Long-Term Intervention with Pravastatin in Ischaemic Disease study randomized patients to pravastatin 40 mg daily or placebo, without titration.² The intervention arm in the Cholesterol and Recurrent Events trial was also pravastatin 40 mg daily, with cholestyramine added if the LDL level remained higher than 175 mg/dL.³ The Lescol Intervention Prevention study randomized patients after angioplasty to fluvastatin 40 mg twice daily or placebo.⁴ The Heart Protection Study used simvastatin 40 mg daily, without titration.⁵ No RCTs have evaluated the clinical benefit of adding medications to adequate doses of statins to lower LDL to less than 175 mg/dL. See Table of major RCTs with clinical outcomes.

Subgroup analyses of earlier major RCTs had suggested that patients with CAD and low initial LDL levels (< 125 mg/dL) have little to gain from pravastatin.^2,3 However, the Heart Protection Study enrolled 20,000 people with CAD or equivalent (diabetes, peripheral vascular disease, stroke, etc).⁵ The study demonstrated a reduction of major coronary events with simvastatin, with numbers needed to treat (NNT) of 19 (P < .0001); the NNT for reduction in all-cause mortality was 55 (P = .0003). The benefit of simvastatin was noted in virtually every predefined subgroup, including individuals older than 70 years, women, and patients without known CAD (but with CAD equivalents). Notably, no difference in benefit was found between patients with different pretreatment LDL levels. A significant reduction in major vascular events was noted even for the 3400 subjects with pretreatment LDL levels of less than 100 mg/dL (NNT = 22, P = .0006). A greater percentage reduction in LDL with medication did not predict better clinical outcomes.⁵

TABLE

LDL levels and relative risk of major coronary events after treatment

Recommendations from others

The National Cholesterol Education Project (NCEP) recommends that patients with CAD and an LDL of more than 130 mg/dL adopt therapeutic lifestyle changes and start LDL-lowering medication, usually a statin. For patients with LDL between 100 and 130 mg/dL, the NCEP recommends therapeutic lifestyle changes, with the option of adding a statin. For patients with LDL less than 100 mg/dL, maintenance of LDL control is recommended with therapeutic lifestyle changes. For patients with high initial LDL levels that stay above 100 mg/dL on statin therapy, the NCEP recommends that additional medications, such as nicotinic acid or fibrates, as well as intensive therapeutic lifestyle changes, be considered.⁶

Clinical Commentary by William Chavey, MD, at http://www.fpin.org.

EVIDENCE-BASED ANSWER

Large published randomized controlled trials (RCTs) show that pravastatin and simvastatin are well-tolerated and reduce major coronary events such as death, myocardial infarction, and revascularization by about 25%. The Heart Protection Study suggested this benefit is noted even among individuals with pretreatment low-density lipoprotein (LDL) cholesterol of less than 100 mg/dL. Fluvastatin reduces major coronary events, but current studies are too small to prove reduced overall mortality. The best evidence to date suggests that most patients at significant risk for major coronary events should be given pravastatin or simvastatin 40 mg daily, without concern for the initial or follow-up LDL levels. (Grade of recommendation: A, based on large randomized trials.)

Evidence summary

The evidence is solid to support the use of HMG–CoA reductase inhibitors (statins) for patients with coronary artery disease (CAD). The Scandinavian Simvastatin Survival study used simvastatin 20 mg daily unless total cholesterol levels did not decrease to less than 200 mg/dL.¹ The Long-Term Intervention with Pravastatin in Ischaemic Disease study randomized patients to pravastatin 40 mg daily or placebo, without titration.² The intervention arm in the Cholesterol and Recurrent Events trial was also pravastatin 40 mg daily, with cholestyramine added if the LDL level remained higher than 175 mg/dL.³ The Lescol Intervention Prevention study randomized patients after angioplasty to fluvastatin 40 mg twice daily or placebo.⁴ The Heart Protection Study used simvastatin 40 mg daily, without titration.⁵ No RCTs have evaluated the clinical benefit of adding medications to adequate doses of statins to lower LDL to less than 175 mg/dL. See Table of major RCTs with clinical outcomes.

Subgroup analyses of earlier major RCTs had suggested that patients with CAD and low initial LDL levels (< 125 mg/dL) have little to gain from pravastatin.^2,3 However, the Heart Protection Study enrolled 20,000 people with CAD or equivalent (diabetes, peripheral vascular disease, stroke, etc).⁵ The study demonstrated a reduction of major coronary events with simvastatin, with numbers needed to treat (NNT) of 19 (P < .0001); the NNT for reduction in all-cause mortality was 55 (P = .0003). The benefit of simvastatin was noted in virtually every predefined subgroup, including individuals older than 70 years, women, and patients without known CAD (but with CAD equivalents). Notably, no difference in benefit was found between patients with different pretreatment LDL levels. A significant reduction in major vascular events was noted even for the 3400 subjects with pretreatment LDL levels of less than 100 mg/dL (NNT = 22, P = .0006). A greater percentage reduction in LDL with medication did not predict better clinical outcomes.⁵

TABLE

LDL levels and relative risk of major coronary events after treatment

Recommendations from others

The National Cholesterol Education Project (NCEP) recommends that patients with CAD and an LDL of more than 130 mg/dL adopt therapeutic lifestyle changes and start LDL-lowering medication, usually a statin. For patients with LDL between 100 and 130 mg/dL, the NCEP recommends therapeutic lifestyle changes, with the option of adding a statin. For patients with LDL less than 100 mg/dL, maintenance of LDL control is recommended with therapeutic lifestyle changes. For patients with high initial LDL levels that stay above 100 mg/dL on statin therapy, the NCEP recommends that additional medications, such as nicotinic acid or fibrates, as well as intensive therapeutic lifestyle changes, be considered.⁶

Clinical Commentary by William Chavey, MD, at http://www.fpin.org.