Erik J. Lindbloom, MD, MSPH

BACKGROUND: A meta-analysis of 23 randomized trials published in 1996 found St. John’s wort (SJW) to be effective for treating depressive disorders. However, the trials have been criticized for such flaws as lack of standard diagnostic criteria, short duration, wide dose variation, failure to blind, lack of placebo use, and suboptimal doses of comparison antidepressants. This trial aimed to address those concerns.

POPULATION STUDIED: Patients with major depressive disorder according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition were recruited from 11 academic medical centers’ psychiatry outpatient clinics, and 200 met criteria for randomization. Treatment and control groups were similar, with a mean age of 41.4 years, 64% women, and 85% white. This was the first episode of major depression for 35% of the sample. Patients were excluded for risk of suicide, psychotropic medicine use, history of treatment-resistant depression, or recent enrollment in psychotherapy. Other conditions that led to exclusion were cognitive disorders, posttraumatic stress disorder, eating disorders, substance use disorder, panic disorder, bipolar or psychotic disorders, and borderline, antisocial, or schizotypal personality disorders.

STUDY DESIGN AND VALIDITY: This study was a multisite placebo-controlled trial. Allocation of assignment was concealed. The taste and smell of SJW were masked by using an odorless SJW extract. All patients received placebo for 1 week, and 16 patients were excluded either because they experienced a 25% improvement on the Hamilton Rating Scale for Depression (HAM-D) while taking placebo or had very low HAM-D scores after 1 week. Patients were then randomized to receive either 300 mg of SJW extract or an identical placebo tablet 3 times daily. At 4 weeks the dose increased to 4 times daily if no improvement occurred. The subjects were followed up for 8 weeks. The researchers addressed many of the concerns about previous studies by using standard diagnostic techniques and a standardized drug dose. The use of a placebo run-in period decreases the overall response rate of both groups. Therefore, it should not affect statistical significance in comparing the 2 groups, but the response rate may appear lower than the results seen in clinical practice. This study had the power to detect a 17.5% difference in response between SJW and placebo. Smaller differences may exist but may not be clinically meaningful.

OUTCOMES MEASURED: The researchers measured efficacy of treatment using standard assessment tools. The primary measure of efficacy was the difference in the rate of improvement between SJW and placebo on total HAM-D scores over 8 weeks. The researchers also looked for differences in response (50% improvement in HAM-D scores) and remission (a HAM-D score of ≤7 and a clinical global impression score of 1-2), and they did a subgroup analysis of patients with mild depression (HAM-D scores <23).

RESULTS: Of the 98 patients completing the placebo run-in and randomized to SJW, 80 completed the trial compared with 87 of 100 placebo-assigned patients. Both intention-to-treat and completer analysis were performed for all measures of effect. The rate of improvement over time was not significantly different between SJW and placebo (P=.58). The 26.5% clinical response for SJW was not significantly better at 8 weeks than the 18.6% response for placebo (P=.15). Remission rates were significantly higher for SJW compared with placebo in the intention-to-treat analysis (14.3%; 95% confidence interval [CI], 8.6%-22.8% vs 4.9%; 95% CI, 2.0%-11.3%, P=.02; number needed to treat=11). The only significant adverse outcome was headache, which occurred in 41% of patients taking SJW (number needed to harm=7).

BACKGROUND: A meta-analysis of 23 randomized trials published in 1996 found St. John’s wort (SJW) to be effective for treating depressive disorders. However, the trials have been criticized for such flaws as lack of standard diagnostic criteria, short duration, wide dose variation, failure to blind, lack of placebo use, and suboptimal doses of comparison antidepressants. This trial aimed to address those concerns.

POPULATION STUDIED: Patients with major depressive disorder according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition were recruited from 11 academic medical centers’ psychiatry outpatient clinics, and 200 met criteria for randomization. Treatment and control groups were similar, with a mean age of 41.4 years, 64% women, and 85% white. This was the first episode of major depression for 35% of the sample. Patients were excluded for risk of suicide, psychotropic medicine use, history of treatment-resistant depression, or recent enrollment in psychotherapy. Other conditions that led to exclusion were cognitive disorders, posttraumatic stress disorder, eating disorders, substance use disorder, panic disorder, bipolar or psychotic disorders, and borderline, antisocial, or schizotypal personality disorders.

STUDY DESIGN AND VALIDITY: This study was a multisite placebo-controlled trial. Allocation of assignment was concealed. The taste and smell of SJW were masked by using an odorless SJW extract. All patients received placebo for 1 week, and 16 patients were excluded either because they experienced a 25% improvement on the Hamilton Rating Scale for Depression (HAM-D) while taking placebo or had very low HAM-D scores after 1 week. Patients were then randomized to receive either 300 mg of SJW extract or an identical placebo tablet 3 times daily. At 4 weeks the dose increased to 4 times daily if no improvement occurred. The subjects were followed up for 8 weeks. The researchers addressed many of the concerns about previous studies by using standard diagnostic techniques and a standardized drug dose. The use of a placebo run-in period decreases the overall response rate of both groups. Therefore, it should not affect statistical significance in comparing the 2 groups, but the response rate may appear lower than the results seen in clinical practice. This study had the power to detect a 17.5% difference in response between SJW and placebo. Smaller differences may exist but may not be clinically meaningful.

OUTCOMES MEASURED: The researchers measured efficacy of treatment using standard assessment tools. The primary measure of efficacy was the difference in the rate of improvement between SJW and placebo on total HAM-D scores over 8 weeks. The researchers also looked for differences in response (50% improvement in HAM-D scores) and remission (a HAM-D score of ≤7 and a clinical global impression score of 1-2), and they did a subgroup analysis of patients with mild depression (HAM-D scores <23).

RESULTS: Of the 98 patients completing the placebo run-in and randomized to SJW, 80 completed the trial compared with 87 of 100 placebo-assigned patients. Both intention-to-treat and completer analysis were performed for all measures of effect. The rate of improvement over time was not significantly different between SJW and placebo (P=.58). The 26.5% clinical response for SJW was not significantly better at 8 weeks than the 18.6% response for placebo (P=.15). Remission rates were significantly higher for SJW compared with placebo in the intention-to-treat analysis (14.3%; 95% confidence interval [CI], 8.6%-22.8% vs 4.9%; 95% CI, 2.0%-11.3%, P=.02; number needed to treat=11). The only significant adverse outcome was headache, which occurred in 41% of patients taking SJW (number needed to harm=7).

BACKGROUND: A meta-analysis of 23 randomized trials published in 1996 found St. John’s wort (SJW) to be effective for treating depressive disorders. However, the trials have been criticized for such flaws as lack of standard diagnostic criteria, short duration, wide dose variation, failure to blind, lack of placebo use, and suboptimal doses of comparison antidepressants. This trial aimed to address those concerns.

POPULATION STUDIED: Patients with major depressive disorder according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition were recruited from 11 academic medical centers’ psychiatry outpatient clinics, and 200 met criteria for randomization. Treatment and control groups were similar, with a mean age of 41.4 years, 64% women, and 85% white. This was the first episode of major depression for 35% of the sample. Patients were excluded for risk of suicide, psychotropic medicine use, history of treatment-resistant depression, or recent enrollment in psychotherapy. Other conditions that led to exclusion were cognitive disorders, posttraumatic stress disorder, eating disorders, substance use disorder, panic disorder, bipolar or psychotic disorders, and borderline, antisocial, or schizotypal personality disorders.

STUDY DESIGN AND VALIDITY: This study was a multisite placebo-controlled trial. Allocation of assignment was concealed. The taste and smell of SJW were masked by using an odorless SJW extract. All patients received placebo for 1 week, and 16 patients were excluded either because they experienced a 25% improvement on the Hamilton Rating Scale for Depression (HAM-D) while taking placebo or had very low HAM-D scores after 1 week. Patients were then randomized to receive either 300 mg of SJW extract or an identical placebo tablet 3 times daily. At 4 weeks the dose increased to 4 times daily if no improvement occurred. The subjects were followed up for 8 weeks. The researchers addressed many of the concerns about previous studies by using standard diagnostic techniques and a standardized drug dose. The use of a placebo run-in period decreases the overall response rate of both groups. Therefore, it should not affect statistical significance in comparing the 2 groups, but the response rate may appear lower than the results seen in clinical practice. This study had the power to detect a 17.5% difference in response between SJW and placebo. Smaller differences may exist but may not be clinically meaningful.

OUTCOMES MEASURED: The researchers measured efficacy of treatment using standard assessment tools. The primary measure of efficacy was the difference in the rate of improvement between SJW and placebo on total HAM-D scores over 8 weeks. The researchers also looked for differences in response (50% improvement in HAM-D scores) and remission (a HAM-D score of ≤7 and a clinical global impression score of 1-2), and they did a subgroup analysis of patients with mild depression (HAM-D scores <23).

RESULTS: Of the 98 patients completing the placebo run-in and randomized to SJW, 80 completed the trial compared with 87 of 100 placebo-assigned patients. Both intention-to-treat and completer analysis were performed for all measures of effect. The rate of improvement over time was not significantly different between SJW and placebo (P=.58). The 26.5% clinical response for SJW was not significantly better at 8 weeks than the 18.6% response for placebo (P=.15). Remission rates were significantly higher for SJW compared with placebo in the intention-to-treat analysis (14.3%; 95% confidence interval [CI], 8.6%-22.8% vs 4.9%; 95% CI, 2.0%-11.3%, P=.02; number needed to treat=11). The only significant adverse outcome was headache, which occurred in 41% of patients taking SJW (number needed to harm=7).

BACKGROUND: The authors previously derived a simple clinical decision aid (CDA) to be used at the bedside for determining the prognosis of inpatients after resuscitation. The CDA was derived from data obtained from a population of 1077 inpatients who underwent resuscitation at 5 teaching hospitals. The authors observed that all resuscitated patients discharged from the hospital had a witnessed arrest, an initial cardiac rhythm of ventricular tachycardia or ventricular fibrillation, or a pulse within 10 minutes of chest compressions. They proposed that resuscitative efforts may be safely withdrawn if the patient does not meet at least 1 criterion. They noted that 100% of patients not meeting the CDA criteria died in the hospital. However, the 95% confidence interval for this figure ranged as low as 97.1%. The purpose of this study was to apply the CDA using data from a second set of patients to determine its usefulness.

POPULATION STUDIED: This validation study used a registry of data from 3960 attempted resuscitations at a 550-bed community teaching hospital. The investigators included 2181 arrests of inpatients 16 years and older who were pulseless at the start of resuscitation. They excluded patients who arrested in the operating room or neonatal intensive care unit; those who had an initial rhythm other than ventricular tachycardia, ventricular fibrillation, pulseless electrical activity, or asystole; those whose time to initial chest compressions exceeded 15 minutes; and those who received no chest compressions at all. Nearly 300 patients were also excluded because information needed to apply the CDA was missing.

STUDY DESIGN AND VALIDITY: The research team reviewed code sheets and records with hospital charges including cardioversion, defibrillation, or administration of epinephrine. Witnessed arrests were classified as those observed directly or on cardiac monitoring. They compared actual discharge status to that predicted by the CDA. Only 460 (21%) of the 2181 arrests were considered unwitnessed. No further details are given about the 7% who did not have adequate information to include in the study.

OUTCOMES MEASURED: The primary outcome was survival to discharge.

RESULTS: Fifteen percent (N=327) of the 2181 attempted resuscitations resulted in eventual discharge from the hospital. Of those 327 events, all but 3 were correctly predicted by the CDA (sensitivity=99.1%). Those 3 patients were among the 269 patients predicted by the CDA to have no chance of discharge (negative predictive value=98.9%). Because of the generally low success rate of attempted resuscitations, the specificity and positive predictive value of the CDA were low (14.4% and 17.0%, respectively). The negative likelihood ratio of this CDA was 0.064; this would lower the probability of surviving to discharge from 15% to 1.1% if the patient did not satisfy the CDA criteria. Of the 3 surviving patients predicted to have no chance of discharge, 2 were transferred to a nursing home, and 1 died 2 months after discharge.

BACKGROUND: The authors previously derived a simple clinical decision aid (CDA) to be used at the bedside for determining the prognosis of inpatients after resuscitation. The CDA was derived from data obtained from a population of 1077 inpatients who underwent resuscitation at 5 teaching hospitals. The authors observed that all resuscitated patients discharged from the hospital had a witnessed arrest, an initial cardiac rhythm of ventricular tachycardia or ventricular fibrillation, or a pulse within 10 minutes of chest compressions. They proposed that resuscitative efforts may be safely withdrawn if the patient does not meet at least 1 criterion. They noted that 100% of patients not meeting the CDA criteria died in the hospital. However, the 95% confidence interval for this figure ranged as low as 97.1%. The purpose of this study was to apply the CDA using data from a second set of patients to determine its usefulness.

POPULATION STUDIED: This validation study used a registry of data from 3960 attempted resuscitations at a 550-bed community teaching hospital. The investigators included 2181 arrests of inpatients 16 years and older who were pulseless at the start of resuscitation. They excluded patients who arrested in the operating room or neonatal intensive care unit; those who had an initial rhythm other than ventricular tachycardia, ventricular fibrillation, pulseless electrical activity, or asystole; those whose time to initial chest compressions exceeded 15 minutes; and those who received no chest compressions at all. Nearly 300 patients were also excluded because information needed to apply the CDA was missing.

STUDY DESIGN AND VALIDITY: The research team reviewed code sheets and records with hospital charges including cardioversion, defibrillation, or administration of epinephrine. Witnessed arrests were classified as those observed directly or on cardiac monitoring. They compared actual discharge status to that predicted by the CDA. Only 460 (21%) of the 2181 arrests were considered unwitnessed. No further details are given about the 7% who did not have adequate information to include in the study.

OUTCOMES MEASURED: The primary outcome was survival to discharge.

RESULTS: Fifteen percent (N=327) of the 2181 attempted resuscitations resulted in eventual discharge from the hospital. Of those 327 events, all but 3 were correctly predicted by the CDA (sensitivity=99.1%). Those 3 patients were among the 269 patients predicted by the CDA to have no chance of discharge (negative predictive value=98.9%). Because of the generally low success rate of attempted resuscitations, the specificity and positive predictive value of the CDA were low (14.4% and 17.0%, respectively). The negative likelihood ratio of this CDA was 0.064; this would lower the probability of surviving to discharge from 15% to 1.1% if the patient did not satisfy the CDA criteria. Of the 3 surviving patients predicted to have no chance of discharge, 2 were transferred to a nursing home, and 1 died 2 months after discharge.

BACKGROUND: The authors previously derived a simple clinical decision aid (CDA) to be used at the bedside for determining the prognosis of inpatients after resuscitation. The CDA was derived from data obtained from a population of 1077 inpatients who underwent resuscitation at 5 teaching hospitals. The authors observed that all resuscitated patients discharged from the hospital had a witnessed arrest, an initial cardiac rhythm of ventricular tachycardia or ventricular fibrillation, or a pulse within 10 minutes of chest compressions. They proposed that resuscitative efforts may be safely withdrawn if the patient does not meet at least 1 criterion. They noted that 100% of patients not meeting the CDA criteria died in the hospital. However, the 95% confidence interval for this figure ranged as low as 97.1%. The purpose of this study was to apply the CDA using data from a second set of patients to determine its usefulness.

POPULATION STUDIED: This validation study used a registry of data from 3960 attempted resuscitations at a 550-bed community teaching hospital. The investigators included 2181 arrests of inpatients 16 years and older who were pulseless at the start of resuscitation. They excluded patients who arrested in the operating room or neonatal intensive care unit; those who had an initial rhythm other than ventricular tachycardia, ventricular fibrillation, pulseless electrical activity, or asystole; those whose time to initial chest compressions exceeded 15 minutes; and those who received no chest compressions at all. Nearly 300 patients were also excluded because information needed to apply the CDA was missing.

STUDY DESIGN AND VALIDITY: The research team reviewed code sheets and records with hospital charges including cardioversion, defibrillation, or administration of epinephrine. Witnessed arrests were classified as those observed directly or on cardiac monitoring. They compared actual discharge status to that predicted by the CDA. Only 460 (21%) of the 2181 arrests were considered unwitnessed. No further details are given about the 7% who did not have adequate information to include in the study.

OUTCOMES MEASURED: The primary outcome was survival to discharge.

RESULTS: Fifteen percent (N=327) of the 2181 attempted resuscitations resulted in eventual discharge from the hospital. Of those 327 events, all but 3 were correctly predicted by the CDA (sensitivity=99.1%). Those 3 patients were among the 269 patients predicted by the CDA to have no chance of discharge (negative predictive value=98.9%). Because of the generally low success rate of attempted resuscitations, the specificity and positive predictive value of the CDA were low (14.4% and 17.0%, respectively). The negative likelihood ratio of this CDA was 0.064; this would lower the probability of surviving to discharge from 15% to 1.1% if the patient did not satisfy the CDA criteria. Of the 3 surviving patients predicted to have no chance of discharge, 2 were transferred to a nursing home, and 1 died 2 months after discharge.

BACKGROUND: Annual screening mammography is universally accepted as the standard of care in the United States for woman 50 years and older. Although evidence supports screening as effective in reducing breast cancer mortality, it is not known whether mammography plus a clinical breast examination (CBE) is more effective at reducing cancer mortality than a thorough CBE alone.

POPULATION STUDIED: A total of 39,459 Canadian women 50 to 59 years were recruited through general publicity, mailings, and physician referral. These women had not received a mammogram in the previous year and did not have a history of breast cancer.

STUDY DESIGN AND VALIDITY: The women were randomized to receive either 5 annual CBEs with mammography or a CBE alone annually for 5 years. Well-trained nurses using a visual inspection component and palpation in a radial pattern performed most of the breast examinations. Physicians performed the others. The examinations were very thorough and took approximately 10 minutes. Patients were also taught breast self-examination. Two-view mammograms were used and independently reviewed. Patients with abnormal findings were referred to the Canadian National Breast Screening Study (CNBSS) clinic for further evaluation by a surgeon. Breast cancers were identified through the CNBSS centers and the National Cancer Registry during the 13-year follow-up. The cause of death was identified through the participant’s family members, physicians, and the Canadian Mortality Data Base. Overall the study appeared valid. The 2 randomized groups seemed equal for breast cancer risk factors and other demographics. There was excellent follow-up and good compliance within each group. Randomization was not concealed. Previous scrutiny of this study centered on a change in mammography technique during the screening. Further analysis showed high sensitivity and expected cancer detection rates despite this change. The article does not mention what types of screening the participants underwent after the initial 5-year study period. This could potentially have an effect on the mortality numbers, if women decided to stop their screening after the study period ended. This study did not address differences in quality of life, such as discomfort from mammograms and additional procedures from false-positive screenings.

OUTCOMES MEASURED: Breast cancer mortality was the primary outcome. The tumor size and number of lymph node–positive cancers were also reported.

RESULTS: Only 54 of the original participants were excluded from the analysis. At the 13-year follow-up there were 107 breast cancer deaths in the combined mammography plus CBE group and 105 deaths in the CBE-only group (rate ratio=1.02; 95% confidence interval, 0.78-1.33). A total of 622 invasive and 71 in situ cancers were found in the combined group and 610 invasive and 16 in situ cancers were identified in the CBE-only group. Mammography was able to detect a cancer 2.1 years earlier than CBE alone. However, this lead time did not appear to improve survival. Overall, the tumors identified by mammography were smaller. There was no significant difference between the 2 groups in the number of lymph node–positive cancers detected by the end of the study. As expected, there were approximately 3 times as many biopsies and more diagnostic tests performed in the mammogram group.

BACKGROUND: Annual screening mammography is universally accepted as the standard of care in the United States for woman 50 years and older. Although evidence supports screening as effective in reducing breast cancer mortality, it is not known whether mammography plus a clinical breast examination (CBE) is more effective at reducing cancer mortality than a thorough CBE alone.

POPULATION STUDIED: A total of 39,459 Canadian women 50 to 59 years were recruited through general publicity, mailings, and physician referral. These women had not received a mammogram in the previous year and did not have a history of breast cancer.

STUDY DESIGN AND VALIDITY: The women were randomized to receive either 5 annual CBEs with mammography or a CBE alone annually for 5 years. Well-trained nurses using a visual inspection component and palpation in a radial pattern performed most of the breast examinations. Physicians performed the others. The examinations were very thorough and took approximately 10 minutes. Patients were also taught breast self-examination. Two-view mammograms were used and independently reviewed. Patients with abnormal findings were referred to the Canadian National Breast Screening Study (CNBSS) clinic for further evaluation by a surgeon. Breast cancers were identified through the CNBSS centers and the National Cancer Registry during the 13-year follow-up. The cause of death was identified through the participant’s family members, physicians, and the Canadian Mortality Data Base. Overall the study appeared valid. The 2 randomized groups seemed equal for breast cancer risk factors and other demographics. There was excellent follow-up and good compliance within each group. Randomization was not concealed. Previous scrutiny of this study centered on a change in mammography technique during the screening. Further analysis showed high sensitivity and expected cancer detection rates despite this change. The article does not mention what types of screening the participants underwent after the initial 5-year study period. This could potentially have an effect on the mortality numbers, if women decided to stop their screening after the study period ended. This study did not address differences in quality of life, such as discomfort from mammograms and additional procedures from false-positive screenings.

OUTCOMES MEASURED: Breast cancer mortality was the primary outcome. The tumor size and number of lymph node–positive cancers were also reported.

RESULTS: Only 54 of the original participants were excluded from the analysis. At the 13-year follow-up there were 107 breast cancer deaths in the combined mammography plus CBE group and 105 deaths in the CBE-only group (rate ratio=1.02; 95% confidence interval, 0.78-1.33). A total of 622 invasive and 71 in situ cancers were found in the combined group and 610 invasive and 16 in situ cancers were identified in the CBE-only group. Mammography was able to detect a cancer 2.1 years earlier than CBE alone. However, this lead time did not appear to improve survival. Overall, the tumors identified by mammography were smaller. There was no significant difference between the 2 groups in the number of lymph node–positive cancers detected by the end of the study. As expected, there were approximately 3 times as many biopsies and more diagnostic tests performed in the mammogram group.

BACKGROUND: Annual screening mammography is universally accepted as the standard of care in the United States for woman 50 years and older. Although evidence supports screening as effective in reducing breast cancer mortality, it is not known whether mammography plus a clinical breast examination (CBE) is more effective at reducing cancer mortality than a thorough CBE alone.

POPULATION STUDIED: A total of 39,459 Canadian women 50 to 59 years were recruited through general publicity, mailings, and physician referral. These women had not received a mammogram in the previous year and did not have a history of breast cancer.

STUDY DESIGN AND VALIDITY: The women were randomized to receive either 5 annual CBEs with mammography or a CBE alone annually for 5 years. Well-trained nurses using a visual inspection component and palpation in a radial pattern performed most of the breast examinations. Physicians performed the others. The examinations were very thorough and took approximately 10 minutes. Patients were also taught breast self-examination. Two-view mammograms were used and independently reviewed. Patients with abnormal findings were referred to the Canadian National Breast Screening Study (CNBSS) clinic for further evaluation by a surgeon. Breast cancers were identified through the CNBSS centers and the National Cancer Registry during the 13-year follow-up. The cause of death was identified through the participant’s family members, physicians, and the Canadian Mortality Data Base. Overall the study appeared valid. The 2 randomized groups seemed equal for breast cancer risk factors and other demographics. There was excellent follow-up and good compliance within each group. Randomization was not concealed. Previous scrutiny of this study centered on a change in mammography technique during the screening. Further analysis showed high sensitivity and expected cancer detection rates despite this change. The article does not mention what types of screening the participants underwent after the initial 5-year study period. This could potentially have an effect on the mortality numbers, if women decided to stop their screening after the study period ended. This study did not address differences in quality of life, such as discomfort from mammograms and additional procedures from false-positive screenings.

OUTCOMES MEASURED: Breast cancer mortality was the primary outcome. The tumor size and number of lymph node–positive cancers were also reported.

RESULTS: Only 54 of the original participants were excluded from the analysis. At the 13-year follow-up there were 107 breast cancer deaths in the combined mammography plus CBE group and 105 deaths in the CBE-only group (rate ratio=1.02; 95% confidence interval, 0.78-1.33). A total of 622 invasive and 71 in situ cancers were found in the combined group and 610 invasive and 16 in situ cancers were identified in the CBE-only group. Mammography was able to detect a cancer 2.1 years earlier than CBE alone. However, this lead time did not appear to improve survival. Overall, the tumors identified by mammography were smaller. There was no significant difference between the 2 groups in the number of lymph node–positive cancers detected by the end of the study. As expected, there were approximately 3 times as many biopsies and more diagnostic tests performed in the mammogram group.

BACKGROUND: Acute treatments for cluster headaches include oxygen, ergotamine derivatives, and intranasal or subcutaneous sumatriptan. Although up to 95% of acute cluster headache patients treated with subcutaneous sumatriptan experience pain relief within 15 minutes,¹ the route of administration and restrictions on recommended daily dosage may limit patient use of this therapy. Oxygen is effective as abortive therapy but is frequently unavailable in settings where acute cluster headaches are experienced. Rectal and oral ergotamine derivatives have poor bioavailability, and all ergot alkaloids have a high incidence of adverse effects. Oral zolmitriptan is efficacious in the acute treatment of migraine headache. However, no previous studies have evaluated the efficacy of oral triptans in the treatment of cluster headaches.

POPULATION STUDIED: The authors of this study included patients aged 18 to 65 years who were recruited from multiple specialty referral centers in Canada, the United Kingdom, and Sweden. All subjects had an established diagnosis of chronic or episodic cluster headache, described as headaches typically lasting 45 minutes or longer that were distinguishable from other types of episodic headaches, and had tolerated previous treatment with a 5-hydroxytryptamine (5-HT) agonist, such as sumatriptan or ergotamine. The study excluded patients with a history of basilar, ophthalmoplegic, or hemiplegic migraine, and those with risk factors contraindicating the use of 5-HT agonists.

STUDY DESIGN AND VALIDITY: This randomized double-blinded placebo-controlled crossover study compared 5-mg and 10-mg doses of zolmitriptan with placebo for the acute treatment of cluster headaches. Headache intensity was rated on a diary card with a 5-point severity scale (no, mild, moderate, severe, or very severe pain); only headaches of moderate to very severe intensity were treated. Subjects were required to take the study medication within 10 minutes of headache onset, were not permitted to take escape medications, such as oxygen or analgesics, within 30 minutes of taking study medications, and were not permitted to institute prophylactic treatment during the study period. Subjects whose cluster headache period ended before treatment or who had fewer than 3 headaches before the end of the study period were excluded from the analysis. Those who failed to comply with the strict requirements for medication use were noted, but were still included in the intention-to-treat analysis. This is a well-designed study, with no major threats to validity. Patients were selected from referral centers and thus may differ from cluster headache sufferers in a primary care clinic population.

OUTCOMES MEASURED: The primary outcome was headache improvement at 30 minutes, defined as a reduction in headache intensity of 2 or more points on the 5-point scale. Secondary treatment outcomes included the proportion of subjects experiencing any headache relief at 15 and 30 minutes, experiencing headache relief at any time, using escape medication 30 to 180 minutes after treatment, having mild or no pain 30 minutes after treatment, and obtaining relief of associated symptoms. Subjects in each study arm were also asked to indicate their preferred treatment.

RESULTS: Different treatment responses were found for episodic and chronic cluster headache subgroups (the latter patients had attacks for more than a year without remission). Chronic cluster headache subjects showed no statistically significant treatment response to zolmitriptan. Compared with placebo, a greater proportion of episodic cluster headache sufferers experienced a 2-point reduction in headache intensity after taking 10 mg of zolmitriptan (47% vs 29%). Six patients would need to be treated with this dose for 1 patient to improve this much (number needed to treat [NNT]=6). Use of 10 mg zolmitriptan was also associated with statistically significant improvement in all of the secondary outcomes. Patients treated with 5 mg zolmitriptan had improvement in only 3 secondary outcomes: headache relief at any time (NNT=6), lower likelihood of escape medication use (NNT=5), and mild or no pain at 30 minutes (NNT=7). Zolmitriptan was associated with a significantly greater incidence of medication-related adverse effects (number needed to harm=5 for the 10-mg dose). The most frequently described adverse effects were paresthesia, heaviness, asthenia, nausea, dizziness, and (nonchest) tightness. No medication-related events led to withdrawal from the study. Forty-five percent of subjects preferred the 10-mg dose compared with 29% who preferred the 5-mg dose, and 26% the placebo.

BACKGROUND: Acute treatments for cluster headaches include oxygen, ergotamine derivatives, and intranasal or subcutaneous sumatriptan. Although up to 95% of acute cluster headache patients treated with subcutaneous sumatriptan experience pain relief within 15 minutes,¹ the route of administration and restrictions on recommended daily dosage may limit patient use of this therapy. Oxygen is effective as abortive therapy but is frequently unavailable in settings where acute cluster headaches are experienced. Rectal and oral ergotamine derivatives have poor bioavailability, and all ergot alkaloids have a high incidence of adverse effects. Oral zolmitriptan is efficacious in the acute treatment of migraine headache. However, no previous studies have evaluated the efficacy of oral triptans in the treatment of cluster headaches.

POPULATION STUDIED: The authors of this study included patients aged 18 to 65 years who were recruited from multiple specialty referral centers in Canada, the United Kingdom, and Sweden. All subjects had an established diagnosis of chronic or episodic cluster headache, described as headaches typically lasting 45 minutes or longer that were distinguishable from other types of episodic headaches, and had tolerated previous treatment with a 5-hydroxytryptamine (5-HT) agonist, such as sumatriptan or ergotamine. The study excluded patients with a history of basilar, ophthalmoplegic, or hemiplegic migraine, and those with risk factors contraindicating the use of 5-HT agonists.

STUDY DESIGN AND VALIDITY: This randomized double-blinded placebo-controlled crossover study compared 5-mg and 10-mg doses of zolmitriptan with placebo for the acute treatment of cluster headaches. Headache intensity was rated on a diary card with a 5-point severity scale (no, mild, moderate, severe, or very severe pain); only headaches of moderate to very severe intensity were treated. Subjects were required to take the study medication within 10 minutes of headache onset, were not permitted to take escape medications, such as oxygen or analgesics, within 30 minutes of taking study medications, and were not permitted to institute prophylactic treatment during the study period. Subjects whose cluster headache period ended before treatment or who had fewer than 3 headaches before the end of the study period were excluded from the analysis. Those who failed to comply with the strict requirements for medication use were noted, but were still included in the intention-to-treat analysis. This is a well-designed study, with no major threats to validity. Patients were selected from referral centers and thus may differ from cluster headache sufferers in a primary care clinic population.

OUTCOMES MEASURED: The primary outcome was headache improvement at 30 minutes, defined as a reduction in headache intensity of 2 or more points on the 5-point scale. Secondary treatment outcomes included the proportion of subjects experiencing any headache relief at 15 and 30 minutes, experiencing headache relief at any time, using escape medication 30 to 180 minutes after treatment, having mild or no pain 30 minutes after treatment, and obtaining relief of associated symptoms. Subjects in each study arm were also asked to indicate their preferred treatment.

RESULTS: Different treatment responses were found for episodic and chronic cluster headache subgroups (the latter patients had attacks for more than a year without remission). Chronic cluster headache subjects showed no statistically significant treatment response to zolmitriptan. Compared with placebo, a greater proportion of episodic cluster headache sufferers experienced a 2-point reduction in headache intensity after taking 10 mg of zolmitriptan (47% vs 29%). Six patients would need to be treated with this dose for 1 patient to improve this much (number needed to treat [NNT]=6). Use of 10 mg zolmitriptan was also associated with statistically significant improvement in all of the secondary outcomes. Patients treated with 5 mg zolmitriptan had improvement in only 3 secondary outcomes: headache relief at any time (NNT=6), lower likelihood of escape medication use (NNT=5), and mild or no pain at 30 minutes (NNT=7). Zolmitriptan was associated with a significantly greater incidence of medication-related adverse effects (number needed to harm=5 for the 10-mg dose). The most frequently described adverse effects were paresthesia, heaviness, asthenia, nausea, dizziness, and (nonchest) tightness. No medication-related events led to withdrawal from the study. Forty-five percent of subjects preferred the 10-mg dose compared with 29% who preferred the 5-mg dose, and 26% the placebo.

BACKGROUND: Acute treatments for cluster headaches include oxygen, ergotamine derivatives, and intranasal or subcutaneous sumatriptan. Although up to 95% of acute cluster headache patients treated with subcutaneous sumatriptan experience pain relief within 15 minutes,¹ the route of administration and restrictions on recommended daily dosage may limit patient use of this therapy. Oxygen is effective as abortive therapy but is frequently unavailable in settings where acute cluster headaches are experienced. Rectal and oral ergotamine derivatives have poor bioavailability, and all ergot alkaloids have a high incidence of adverse effects. Oral zolmitriptan is efficacious in the acute treatment of migraine headache. However, no previous studies have evaluated the efficacy of oral triptans in the treatment of cluster headaches.

POPULATION STUDIED: The authors of this study included patients aged 18 to 65 years who were recruited from multiple specialty referral centers in Canada, the United Kingdom, and Sweden. All subjects had an established diagnosis of chronic or episodic cluster headache, described as headaches typically lasting 45 minutes or longer that were distinguishable from other types of episodic headaches, and had tolerated previous treatment with a 5-hydroxytryptamine (5-HT) agonist, such as sumatriptan or ergotamine. The study excluded patients with a history of basilar, ophthalmoplegic, or hemiplegic migraine, and those with risk factors contraindicating the use of 5-HT agonists.

STUDY DESIGN AND VALIDITY: This randomized double-blinded placebo-controlled crossover study compared 5-mg and 10-mg doses of zolmitriptan with placebo for the acute treatment of cluster headaches. Headache intensity was rated on a diary card with a 5-point severity scale (no, mild, moderate, severe, or very severe pain); only headaches of moderate to very severe intensity were treated. Subjects were required to take the study medication within 10 minutes of headache onset, were not permitted to take escape medications, such as oxygen or analgesics, within 30 minutes of taking study medications, and were not permitted to institute prophylactic treatment during the study period. Subjects whose cluster headache period ended before treatment or who had fewer than 3 headaches before the end of the study period were excluded from the analysis. Those who failed to comply with the strict requirements for medication use were noted, but were still included in the intention-to-treat analysis. This is a well-designed study, with no major threats to validity. Patients were selected from referral centers and thus may differ from cluster headache sufferers in a primary care clinic population.

OUTCOMES MEASURED: The primary outcome was headache improvement at 30 minutes, defined as a reduction in headache intensity of 2 or more points on the 5-point scale. Secondary treatment outcomes included the proportion of subjects experiencing any headache relief at 15 and 30 minutes, experiencing headache relief at any time, using escape medication 30 to 180 minutes after treatment, having mild or no pain 30 minutes after treatment, and obtaining relief of associated symptoms. Subjects in each study arm were also asked to indicate their preferred treatment.

RESULTS: Different treatment responses were found for episodic and chronic cluster headache subgroups (the latter patients had attacks for more than a year without remission). Chronic cluster headache subjects showed no statistically significant treatment response to zolmitriptan. Compared with placebo, a greater proportion of episodic cluster headache sufferers experienced a 2-point reduction in headache intensity after taking 10 mg of zolmitriptan (47% vs 29%). Six patients would need to be treated with this dose for 1 patient to improve this much (number needed to treat [NNT]=6). Use of 10 mg zolmitriptan was also associated with statistically significant improvement in all of the secondary outcomes. Patients treated with 5 mg zolmitriptan had improvement in only 3 secondary outcomes: headache relief at any time (NNT=6), lower likelihood of escape medication use (NNT=5), and mild or no pain at 30 minutes (NNT=7). Zolmitriptan was associated with a significantly greater incidence of medication-related adverse effects (number needed to harm=5 for the 10-mg dose). The most frequently described adverse effects were paresthesia, heaviness, asthenia, nausea, dizziness, and (nonchest) tightness. No medication-related events led to withdrawal from the study. Forty-five percent of subjects preferred the 10-mg dose compared with 29% who preferred the 5-mg dose, and 26% the placebo.

CLINICAL QUESTION: Should we screen for intracranial aneurysms in first-degree relatives of patients with subarachnoid hemorrhage?

BACKGROUND: A subarachnoid hemorrhage from a ruptured intracranial aneurysm is often a devastating event, with approximately 70% of affected patients dying or becoming functionally dependent. A family history of subarachnoid hemorrhage is a significant risk factor, associated with a 3- to 7-fold higher incidence. Previous studies have reported that intracranial aneurysms are found in 8% of persons with 2 relatives who have hemorrhaged. The investigators studied the risks and benefits of screening first-degree relatives (parents, siblings, or children) for aneurysms with magnetic resonance angiography (MRA).

POPULATION STUDIED: Index patients admitted for subarachnoid hemorrhage were consecutively identified at one of 2 Dutch academic health centers. The mean age of the index patients was 52 years, and 69% were women. One hundred seventy-two of 193 had living first-degree relatives and agreed to participate. Six hundred twenty-six of the 980 known relatives were screened; they were aged 20 to 70 years (mean = 41 years), and none had contraindications to MRA or surgery. The vast majority of screened relatives were either siblings or children of the index patients, and 52% were women.

STUDY DESIGN AND VALIDITY: If a definite aneurysm was seen with MRA, conventional angiography with neurosurgical consultation was recommended. Possible aneurysms were screened again with MRA 6 to 12 months later. The investigators reported the outcome of screening and surgical intervention in those that underwent surgery. No follow-up assessments were performed in relatives with normal findings or those with aneurysms who did not undergo surgery; this complicates the interpretation of the results. On the basis of previous studies, the authors also attempted to estimate the risk of rupture, disability, and mortality if the aneurysms had not been detected. There was no control group that did not undergo screening. This also weakens the interpretation of the reported functional changes.

OUTCOMES MEASURED: The authors of the article report the prevalence of intracranial aneurysms, and for those who underwent surgery it outlines the intervention performed, neurologic disability 6 months postoperatively estimated risk of hemorrhage without surgery, and estimated life expectancy with and without surgery.

RESULTS: Among screened relatives, 25 of 626 (4.0%) had unruptured aneurysms, and 18 of these 25 underwent conventional angiography and surgery. Surgery was not indicated in 4 relatives, and the other 3 refused intervention. In 11 of the 18 subjects who underwent conventional angiography and surgery, disability was higher 6 months postoperatively than before angiography. One of these 11 had severe complications from conventional angiography. Four patients had specific postoperative sequelae of partial hemianopia, unilateral visual loss, or anosmia. The remaining 6 had nonspecific symptoms such as headache, fatigue, impaired concentration, or emotional problems.

CLINICAL QUESTION: Should we screen for intracranial aneurysms in first-degree relatives of patients with subarachnoid hemorrhage?

BACKGROUND: A subarachnoid hemorrhage from a ruptured intracranial aneurysm is often a devastating event, with approximately 70% of affected patients dying or becoming functionally dependent. A family history of subarachnoid hemorrhage is a significant risk factor, associated with a 3- to 7-fold higher incidence. Previous studies have reported that intracranial aneurysms are found in 8% of persons with 2 relatives who have hemorrhaged. The investigators studied the risks and benefits of screening first-degree relatives (parents, siblings, or children) for aneurysms with magnetic resonance angiography (MRA).

POPULATION STUDIED: Index patients admitted for subarachnoid hemorrhage were consecutively identified at one of 2 Dutch academic health centers. The mean age of the index patients was 52 years, and 69% were women. One hundred seventy-two of 193 had living first-degree relatives and agreed to participate. Six hundred twenty-six of the 980 known relatives were screened; they were aged 20 to 70 years (mean = 41 years), and none had contraindications to MRA or surgery. The vast majority of screened relatives were either siblings or children of the index patients, and 52% were women.

STUDY DESIGN AND VALIDITY: If a definite aneurysm was seen with MRA, conventional angiography with neurosurgical consultation was recommended. Possible aneurysms were screened again with MRA 6 to 12 months later. The investigators reported the outcome of screening and surgical intervention in those that underwent surgery. No follow-up assessments were performed in relatives with normal findings or those with aneurysms who did not undergo surgery; this complicates the interpretation of the results. On the basis of previous studies, the authors also attempted to estimate the risk of rupture, disability, and mortality if the aneurysms had not been detected. There was no control group that did not undergo screening. This also weakens the interpretation of the reported functional changes.

OUTCOMES MEASURED: The authors of the article report the prevalence of intracranial aneurysms, and for those who underwent surgery it outlines the intervention performed, neurologic disability 6 months postoperatively estimated risk of hemorrhage without surgery, and estimated life expectancy with and without surgery.

RESULTS: Among screened relatives, 25 of 626 (4.0%) had unruptured aneurysms, and 18 of these 25 underwent conventional angiography and surgery. Surgery was not indicated in 4 relatives, and the other 3 refused intervention. In 11 of the 18 subjects who underwent conventional angiography and surgery, disability was higher 6 months postoperatively than before angiography. One of these 11 had severe complications from conventional angiography. Four patients had specific postoperative sequelae of partial hemianopia, unilateral visual loss, or anosmia. The remaining 6 had nonspecific symptoms such as headache, fatigue, impaired concentration, or emotional problems.

CLINICAL QUESTION: Should we screen for intracranial aneurysms in first-degree relatives of patients with subarachnoid hemorrhage?

BACKGROUND: A subarachnoid hemorrhage from a ruptured intracranial aneurysm is often a devastating event, with approximately 70% of affected patients dying or becoming functionally dependent. A family history of subarachnoid hemorrhage is a significant risk factor, associated with a 3- to 7-fold higher incidence. Previous studies have reported that intracranial aneurysms are found in 8% of persons with 2 relatives who have hemorrhaged. The investigators studied the risks and benefits of screening first-degree relatives (parents, siblings, or children) for aneurysms with magnetic resonance angiography (MRA).

POPULATION STUDIED: Index patients admitted for subarachnoid hemorrhage were consecutively identified at one of 2 Dutch academic health centers. The mean age of the index patients was 52 years, and 69% were women. One hundred seventy-two of 193 had living first-degree relatives and agreed to participate. Six hundred twenty-six of the 980 known relatives were screened; they were aged 20 to 70 years (mean = 41 years), and none had contraindications to MRA or surgery. The vast majority of screened relatives were either siblings or children of the index patients, and 52% were women.

STUDY DESIGN AND VALIDITY: If a definite aneurysm was seen with MRA, conventional angiography with neurosurgical consultation was recommended. Possible aneurysms were screened again with MRA 6 to 12 months later. The investigators reported the outcome of screening and surgical intervention in those that underwent surgery. No follow-up assessments were performed in relatives with normal findings or those with aneurysms who did not undergo surgery; this complicates the interpretation of the results. On the basis of previous studies, the authors also attempted to estimate the risk of rupture, disability, and mortality if the aneurysms had not been detected. There was no control group that did not undergo screening. This also weakens the interpretation of the reported functional changes.

OUTCOMES MEASURED: The authors of the article report the prevalence of intracranial aneurysms, and for those who underwent surgery it outlines the intervention performed, neurologic disability 6 months postoperatively estimated risk of hemorrhage without surgery, and estimated life expectancy with and without surgery.

RESULTS: Among screened relatives, 25 of 626 (4.0%) had unruptured aneurysms, and 18 of these 25 underwent conventional angiography and surgery. Surgery was not indicated in 4 relatives, and the other 3 refused intervention. In 11 of the 18 subjects who underwent conventional angiography and surgery, disability was higher 6 months postoperatively than before angiography. One of these 11 had severe complications from conventional angiography. Four patients had specific postoperative sequelae of partial hemianopia, unilateral visual loss, or anosmia. The remaining 6 had nonspecific symptoms such as headache, fatigue, impaired concentration, or emotional problems.