Patrick G. O'Malley

Treatment of Fibromyalgia with Antidepressants: A Meta-analysis

AbstractBACKGROUND: Fibromyalgia is a common, poorly understood musculoskeletal pain syndrome with limited therapeutic options. OBJECTIVE: To systematically review the efficacy of antidepressants in the treatment of fibromyalgia and examine whether this effect was independent of depression. DESIGN: Meta-analysis of English-language, randomized, placebo-controlled trials. Studies were obtained from searching medline, embase, and psyclit (1966-1999), the Cochrane Library, unpublished literature, and bibliographies. We performed independent duplicate review of each study for both inclusion and data extraction. MAIN RESULTS: Sixteen randomized, placebo-controlled trials were identified, of which 13 were appropriate for data extraction. There were 3 classes of antidepressants evaluated: tricyclics (9 trials), selective serotonin reuptake inhibitors (3 trials), and S-adenosylmethionine (2 trials). Overall, the quality of the studies was good (mean score 5.6, scale 0–8). The odds ratio for improvement with therapy was 4.2 (95% confidence interval [95% CI], 2.6 to 6.8). The pooled risk difference for these studies was 0.25 (95% CI, 0.16 to 0.34), which calculates to 4 (95% CI, 2.9 to 6.3) individuals needing treatment for 1 patient to experience symptom improvement. When the effect on individual symptoms was combined, anti-depressants improved sleep, fatigue, pain, and well-being, but not trigger points. In the 5 studies where there was adequate assessment for an effect independent of depression, only 1 study found a correlation between symptom improvement and depression scores. Outcomes were not affected by class of agent or quality score using meta-regression. CONCLUSION: Antidepressants are efficacious in treating many of the symptoms of fibromyalgia. Patients were more than 4 times as likely to report overall improvement, and reported moderate reductions in individual symptoms, particularly pain. Whether this effect is independent of depression needs further study.

Meta-analysis : The effect of statins on albuminuria

Context Albuminuria is a marker of endothelial dysfunction and is a risk factor for cardiovascular disease. We do not know whether or to what degree statins affect albuminuria. Contribution This meta-analysis of 15 randomized, placebo-controlled trials found that statins reduced albuminuria and proteinuria. Studies with greater baseline albuminuria showed greater reductions. Cautions Studies were small, showed heterogeneous effects, and were often of poor quality. Implications Statins might reduce albuminuria. We need larger, better studies to confirm these findings and to determine whether reducing albuminuria affects the incidence of end-stage renal disease or cardiovascular disease. The Editors Amarker of endothelial dysfunction, albuminuria has long been recognized as a risk factor for progression to end-stage renal disease. More recently, however, albuminuria has been recognized as an independent risk factor for cardiovascular morbidity and mortality (14). Beyond angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker therapies, therapeutic options to affect the progression of albuminuria are limited. One therapeutic option may be 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). The beneficial effects of statins on cardiovascular morbidity and mortality cannot be explained solely by their effect on low-density lipoprotein (LDL) cholesterol levels (57) and may involve an independent effect on endothelial dysfunction. Some investigators have noted that the effects of statins exceed those expected from simply lowering LDL cholesterol levels and occur too early in treatment to be due to the lowering of LDL cholesterol levels (8). The nonlipid mechanisms that may be involved are called pleiotropic effects, such as lipid-independent plaque stabilization, reduced inflammation, decreased thrombogenicity, increased arterial compliance, and improved endothelial function (7, 912). We systematically reviewed the literature to determine whether and to what degree statins affect albuminuria or proteinuria. Methods Literature Search We searched the PubMed, MEDLINE, EMBASE, BIOSIS, SciSearch, PASCAL, and International Pharmaceutical Abstracts (IPA) databases, as well as the Cochrane Central Register of Controlled Trials, for all relevant articles published in any language between January 1974 and November 2005. We used the following Medical Subject Headings (MeSH) and text words: proteinuria, urinary protein excretion, albuminuria, urinary albumin excretion, pitavastatin, mevastatin, fluvastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, lovastatin, and rosuvastatin. We limited our searches to randomized, placebo-controlled trials in adults (age >18 years). Study Selection Two investigators independently screened the titles and abstracts of potentially relevant studies before retrieving the full-text articles. When investigators doubted a studys eligibility for inclusion, they obtained the full-text article. We included randomized, controlled trials that studied adults and had both a statin group and a placebo group. We considered the end point to be appropriate if proteinuria or albuminuria was measured either by timed urine collections to measure 24-hour excretion or by untimed specimens to calculate albumin-to-creatinine ratios. We complemented the database searches by reviewing the a priori end points of major lipid-lowering trials and the reference lists from original research articles, review articles, and previous meta-analyses. We focused exclusively on published data and did not contact authors of trials that met selection criteria but did not have data on albuminuria or proteinuria. Validity Assessment Two reviewers independently assessed study quality by using the Jadad rating instrument (13), complemented by an assessment of the intention-to-treat analysis, loss to follow-up, and industry sponsorship. Jadad scores are based on the description of randomization, blinding, inclusion and exclusion criteria, withdrawals, and method to assess adverse events. Scores can range from 0 to 8, and higher scores indicate better methodologic quality. We calculated interrater agreement, and we resolved differences by consensus. Data Extraction We extracted characteristics of the study (author, year, country, design, duration, statin and dosage, and sample size) and the participants (age, sex, presence and type of renal disease, proportion with diabetes, proportion with hypertension, baseline and follow-up cholesterol levels, baseline and follow-up urinary albumin and protein excretion rates, angiotensin-converting enzyme inhibitor use, angiotensin II receptor blocker use, and calcium-channel blocker use). If data could not be extracted or calculated from the manuscript with confidence, no data were entered. Two reviewers independently extracted data, and we resolved disagreements by consensus. Quantitative Data Synthesis The principal measure of effect was the weighted mean difference in the proportional change from baseline to follow-up albuminuria (or proteinuria) between the statin and placebo groups. We pooled the results by using a random-effects model to obtain the summary weighted mean difference with confidence interval. To avoid bias from carryover effects, we used data from only the first phase of crossover studies for the analysis when possible. We replaced missing means with the reported medians for calculating the weighted mean difference. We imputed missing SDs on the basis of reported P values, if available. We performed these imputations conservatively to err on the side of underestimating the statistical significance of positive studies. Specifically, we approximated imputed values to just reach statistical significance (for example, if the reported P value was less than 0.050, we imputed a value that would yield a P value of 0.049). When P values were not available, we imputed the SDs by using the mean proportional SD of the other studies. Both baseline and follow-up SDs were weighted by sample size and were averaged before inclusion in the random-effects model. We conducted sensitivity analyses for the imputed values. We assessed heterogeneity by using the I2 statistic (14). The I2 statistic is an estimate of the amount of variance due to heterogeneity rather than chance and is based on the traditional measure of variance, the Cochran Q statistic. We assessed the sources of heterogeneity by performing stratified analyses (15). We considered a P value less than 0.050 to indicate statistically significant heterogeneity. We performed 2 subgroup analyses for the variables that we deemed most likely to be the potential sources of statistical heterogeneity and for which data were complete. These variables included the baseline level of urinary excretion (calculated as the weighted average of statin and placebo group data and reflecting the presence and severity of disease and the likelihood of benefit from therapy) and loss to follow-up (the quality measure exhibiting the most variation across studies). The cut-points used for urinary excretion level were less than 30 mg/d (n= 3), corresponding to nonpathologic levels; 30 to 299 mg/d (n= 6), corresponding to microalbuminuric levels; and 300 mg/d or greater (n= 6), corresponding to macroalbuminuric levels. For losses to follow-up, we used cut-points of more than 20% (n= 3) and 5% or less (n= 12), which may represent excessive and minimal bias, respectively. Publication Bias We assessed publication bias by using the Begg method with funnel plot analysis (16). Sensitivity Analyses To exclude the possibility that any one study was exerting excessive influence on the results, we conducted a sensitivity analysis by systematically excluding each study and then reanalyzing the data to assess the change in effect size. In addition, because gross proteinuria might reflect tubular dysfunction rather than endothelial glomerular dysfunction, we conducted a sensitivity analysis by excluding the 4 studies that measured only gross proteinuria. We performed all analyses with Stata software, version 8.2 (Stata Corp., College Station, Texas). We considered P values less than 0.050 to be statistically significant. We used the Quality of Reports of Meta-analyses (QUOROM) statement to guide both our reporting and our discussion of the results of our meta-analysis (17). Role of the Funding Source No funding was received in support of our study. Results Literature Search Figure 1 shows the literature search and selection flow chart. Figure 1. Study flow diagram. Study and Patient Characteristics Our final pool of eligible studies included 15 randomized, placebo-controlled trials involving 1384 participants (1832). Studies originated from 10 different countries. Most studies were performed in Europe (53%), and only 1 study was performed in the United States. All studies measured the outcome by using a 24-hour urine collection. Three studies enrolled participants with normal albumin excretion (<30 mg/d), 6 studies enrolled participants with microalbuminuria (30 to 299 mg/d), and 6 studies enrolled participants with gross albuminuria (n= 2) or proteinuria (n= 4) (300 mg/d). The median number of participants in each study was 36 (range, 18 to 864 participants). Statins were (in order of decreasing frequency) simvastatin (5 studies), pravastatin (4 studies), fluvastatin and cerivastatin (2 studies each), and atorvastatin and lovastatin (1 study each). The median reduction in LDL cholesterol level was 26% (range, 10% to 51%). Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers were used concurrently in 7 studies and were prohibited in 4 studies. We could not determine their use for the remaining 4 studies. Except for 1 study (26), which measured albuminuria as a potential adverse event, all studies measured either albuminuria (n= 10) or proteinuria (n= 4) as an a priori efficacy outcome. The median duration of f

Lack of Correlation between Psychological Factors and Subclinical Coronary Artery Disease

BACKGROUND The relation between psychological variables and clinically evident coronary artery disease has been studied extensively, although the potential mechanisms of such a relation remain speculative. We studied the relation between multiple psychological variables and subclinical coronary artery disease to assess the possible role of such variables in atherogenesis. METHODS We conducted a prospective study of 630 consecutive consenting, active-duty U.S. Army personnel, 39 to 45 years of age, without known coronary artery disease. Each participant was assessed for depression, anxiety, somatization, hostility, and stress. Subclinical coronary artery disease was identified by electron-beam computed tomography. RESULTS The mean (+/-SD) age of the subjects was 42+/-2 years; 82 percent were male, and 72 percent were white. The prevalence of coronary-artery calcification was 17.6 percent (mean calcification score, 10+/-49). The prevalence of prior or current psychiatric disorders was 12.7 percent. There was no correlation between the coronary-calcification score and the scores measuring depression (r= -0.07, P=0.08), anxiety (r=-0.07, P=0.10), hostility (r=-0.07, P=0.10), or stress (r=-0.002, P=0.96). Somatization (the number and severity of durable physical symptoms) was inversely correlated with calcification scores (r=-0.12, P=0.003), even after we controlled for age and sex. In multivariate logistic-regression models, a somatization score greater than 4 (out of a possible 26) was independently associated with the absence of any coronary-artery calcification (odds ratio, 0.49; 95 percent confidence interval, 0.25 to 0.96). CONCLUSIONS Our data suggest that depression, anxiety, hostility, and stress are not related to coronary-artery calcification and that somatization is associated with the absence of calcification.

Tricyclic antidepressants and headaches: systematic review and meta-analysis

Objective To evaluate the efficacy and relative adverse effects of tricyclic antidepressants in the treatment of migraine, tension-type, and mixed headaches. Design Meta-analysis. Data sources Medline, Embase, the Cochrane Trials Registry, and PsycLIT. Studies reviewed Randomised trials of adults receiving tricyclics as only treatment for a minimum of four weeks. Data extraction Frequency of headaches (number of headache attacks for migraine and number of days with headache for tension-type headaches), intensity of headache, and headache index. Results 37 studies met the inclusion criteria. Tricyclics significantly reduced the number of days with tension-type headache and number of headache attacks from migraine than placebo (average standardised mean difference −1.29, 95% confidence interval −2.18 to −0.39 and −0.70, −0.93 to −0.48) but not compared with selective serotonin reuptake inhibitors (−0.80, −2.63 to 0.02 and −0.20, −0.60 to 0.19). The effect of tricyclics increased with longer duration of treatment (β=−0.11, 95% confidence interval −0.63 to −0.15; P<0.0005). Tricyclics were also more likely to reduce the intensity of headaches by at least 50% than either placebo (tension-type: relative risk 1.41, 95% confidence interval 1.02 to 1.89; migraine: 1.80, 1.24 to 2.62) or selective serotonin reuptake inhibitors (1.73, 1.34 to 2.22 and 1.72, 1.15 to 2.55). Tricyclics were more likely to cause adverse effects than placebo (1.53, 95% confidence interval 1.11 to 2.12) and selective serotonin reuptake inhibitors (2.22, 1.52 to 3.32), including dry mouth (P<0.0005 for both), drowsiness (P<0.0005 for both), and weight gain (P<0.001 for both), but did not increase dropout rates (placebo: 1.22, 0.83 to 1.80, selective serotonin reuptake inhibitors: 1.16, 0.81 to 2.97). Conclusions Tricyclic antidepressants are effective in preventing migraine and tension-type headaches and are more effective than selective serotonin reuptake inhibitors, although with greater adverse effects. The effectiveness of tricyclics seems to increase over time.

Relationship Between Depression and C-reactive Protein in a Screening Population

Background: Both depression and C-reactive protein (CRP) are markers of increased risk for cardiovascular events. This study examined the relationship between CRP and depression in a cohort of participants undergoing a periodic physical to assess potential for interaction as either mediation or confounding of effect on cardiovascular risk. Methods: We conducted a cross-sectional study of a cohort of 696 consenting, active duty US Army personnel undergoing a periodic physical. We measured depression using the Patient Health Questionnaire-9, the depression module of the self-administered version of the Primary Care Evaluation of Mental Disorders (PRIME-MD). We used a highly sensitive assay to measure CRP. Results: The mean age in the cohort was 44 years (SD ± 3; 82% male). The mean CRP level was 1.7 mg/l (range, 0.3–9.9; SD ± 1.6 mg/l). Depression scores ranged from 0 to 26 with a mean of 2 (SD ± 3). Depression scores correlated with prevalences of major depressive disorder and of any depressive disorder of 3.3% and 15%, respectively. Depression scores correlated positively with CRP levels (r = 0.085; p = .028), as did other variables known to be associated with CRP: body mass index (BMI; r = 0.36), insulin levels (r = 0.22), mean arterial pressure (r = 0.21), triglycerides (r = 0.18), exercise (r = −0.12), female sex (r = 0.097), current smoking status (r = 0.08), and high density lipoprotein (r = −0.09). After controlling only for BMI, the relationship between depression and CRP lost statistical significance among women (adjusted r = 0.08; p = .37), among men (adjusted r = −0.11; p = .8), and overall (adjusted r = 0.047; p = .219). Conclusion: Depressive symptoms are only weakly correlated with CRP. However, after adjusting for BMI, we found no significant relationship between CRP and depression. The relationship between depression and clinical coronary disease is unlikely to be explained through direct effects on CRP levels, but may be mediated by BMI. CRP = C-reactive protein; BMI = body mass index; PHQ-9 = 9-question depression module of the Patient Health Questionnaire.

Treatment of Excessive Anticoagulation With Phytonadione (Vitamin K): A Meta-analysis

BACKGROUND Patients taking oral anticoagulants with an international normalized ratio (INR) greater than 4.0 are at increased risk for bleeding. We performed a meta-analysis to determine the effectiveness of phytonadione (vitamin K) in treating excessive anticoagulation. METHODS The MEDLINE, EMBASE, and Cochrane Library databases were searched (without language restrictions) for articles published between January 1985 and September 2004. Randomized controlled trials or prospective, nonrandomized trials that used vitamin K to treat patients without major hemorrhage with an INR greater than 4.0 due to oral anticoagulant use were included. The primary outcome was achievement of the target INR (1.8-4.0) at 24 hours after vitamin K administration. Summary estimates were calculated using a random effects model. RESULTS Twenty-one studies (10 randomized and 11 prospective trials) were included. Among oral vitamin K treatment arms (4, n = 75), the proportion with a target INR at 24 hours was 82% (95% confidence interval [CI], 70%-93%), which was similar to intravenous vitamin K treatment arms (6, n = 69; target INR, 77%; 95% CI, 60%-95%). Treatment arms of subcutaneous vitamin K (3, n = 58; 31%; 95% CI, 7%-55%) and placebo/observation (2, n = 27; 20%; 95% CI, 0%-47%) were less likely to achieve target INR at 24 hours. Only 1 of 21 trials appropriately assessed for adverse events, so a summary estimate for bleeding risk could not be generated. CONCLUSIONS Limited evidence suggests that oral and intravenous vitamin K are equivalent and more effective for excessive anticoagulation than simply withholding warfarin sodium. Subcutaneous vitamin K, however, is inferior to oral and intravenous vitamin K for this indication and is similar to placebo. Whether treatment with vitamin K decreases hemorrhagic events cannot be determined from the published literature.

Faculty Development Seminars Based on the One‐Minute Preceptor Improve Feedback in the Ambulatory Setting

OBJECTIVE: While several models of medical student instruction in the ambulatory setting exist, few have been formally studied. We wished to assess the impact of a faculty development workshop based on the One-Minute Preceptor model on the amount and quality of feedback in the outpatient setting.DESIGN: Ambulatory teaching behaviors were studied during consecutive outpatient precepting sessions before and after 3 faculty development workshops. Student-teacher interactions were assessed using audiotapes of teaching encounters coded through qualitative techniques, and surveys of teacher, learner, and patient satisfaction.SETTING: Ambulatory internal medicine clinic in a tertiary care medical center.PATIENTS/PARTICIPANTS: Nine board-certified internist faculty preceptors and 44 third-year medical students.INTERVENTIONS: Three 90-minute faculty development seminars based on the One-Minute Preceptor teaching model.MEASUREMENTS AND MAIN RESULTS: Ninety-four encounters with 18,577 utterances were recorded, half before and half after the seminars. After the workshops, the proportion of utterances that contained feedback increased from 17% to 22% (P=.09) and was more likely to be specific (9% vs 15%; P=.02). After the workshops, teachers reported that the learning encounters were more successful (P=.03) and that they were better at letting the students reach their own conclusions (P=.001), at evaluating the learners (P=.03), and at creating plans for post-encounter learning (P=.02). The workshops had no effect on the duration of the student-teacher encounter or on student or patient satisfaction with the encounters.CONCLUSIONS: Brief, interactive, faculty development workshops based on the One-Minute Preceptor model of clinical teaching resulted in modest improvements in the quality of feedback delivered in the ambulatory setting.

Association between C-reactive protein and hypertension in healthy middle-aged men and women

ObjectiveTo ascertain whether C-reactive protein (CRP), an inflammatory marker related to increased cardiovascular risk, is associated with blood pressure in a sample of healthy, middle-aged people. Methods and resultsA case–control study among 904 participants, 39–50 years old, from a cardiovascular risk screening study. Participants with systolic blood pressure ≥140 mmHg or diastolic blood pressure≥90 mmHg (n=120) were considered as case participants and all others as control participants (n=784). Exposure was defined using quintiles of high-sensitivity CRP among control participants. A continuous increase in blood pressure was observed across CRP quintiles. Systolic blood pressure increased 1.17 mmHg [95% confidence interval (CI), 0.60–1.74] and diastolic blood pressure 1.04 mmHg (95% CI, 0.64–1.45) from one quintile to the next. The prevalence of hypertension was 13.3% and it increased with CRP exposure: Q1, 8.9%; Q2, 11.9%; Q3, 12.2%; Q4, 14.3%; and Q5, 18.6%. After adjustment for sex, obesity, race, serum insulin level and family history of coronary heart disease, odds ratios for hypertension increased progressively across CRP quintiles. Participants in the highest CRP quintile were 2.35 times more likely to have hypertension than those in the lowest quintile (P=0.03, trend test P=0.04). ConclusionThese results are consistent with a continuous, independent association between serum CRP and elevated blood pressure.

Vitamin K1 intake and coronary calcification.

ObjectivesThe activity of matrix Gla-protein (MGP), a potent inhibitor of vascular calcification, is dependent on carboxylation using vitamin K as a co-factor. In animals, low intake of total vitamin K has been shown to accelerate vascular calcification via the MGP mechanism. This has led to the hypothesis that low levels of dietary vitamin K intake may be a risk factor for accelerated vascular calcification in humans due to decreased MGP activity. Additionally, some authors have suggested that current recommended daily intake values for vitamin K might be insufficient to fully inhibit vascular calcification via the MGP mechanism. The aim of this study was to examine the relationship between dietary vitamin K1 (the most prevalent dietary form of vitamin K) intake and premature coronary artery calcification (CAC) in an asymptomatic screening population. MethodsWe conducted a prospective study of 807 consecutive active-duty US Army personnel, 39–45 years of age, without known coronary heart disease. Vitamin K1 intake was measured with the Block Dietary Questionnaire and CAC was identified using electron-beam computed tomography (EBCT). ResultsWe found no significant correlation between CAC score and vitamin K1 intake (r=0.132, P=0.106). Multivariate analysis with adjustment for cardiac risk factors showed no association between dietary vitamin K1 intake and CAC. ConclusionsDietary vitamin K1 (phylloquinone) intake appears to be unrelated to premature coronary calcification in a screening population. Further investigation into the relationship of vascular calcification and other forms of vitamin K1 (menaquinones) is indicated.

Physical activity and the presence and extent of calcified coronary atherosclerosis

PURPOSE Regular physical activity leads to a more favorable cardiovascular risk factor profile and a lower risk of developing incident coronary heart disease (CHD). These correlations suggest that higher levels of physical activity should also attenuate the presence and extent of coronary atherosclerosis. METHODS Physical activity was measured using the Baecke Physical Activity Index in 630 consecutive asymptomatic men and women ages 39-45 without known heart disease. The degree of physical activity was compared with the cardiovascular risk factor profile and the presence and extent of subclinical atherosclerosis measured using electron beam computed tomography. RESULTS Sports-related physical activity was associated with lower body mass index (r = -0.11; P = 0.001), higher high-density lipoprotein (HDL) cholesterol (r = 0.13; P = 0.003) and less glucose resistance as assessed by fasting serum insulin levels (r = -0.16; P = 0.001). Leisure-time and work-related physical activity were unrelated to any coronary risk variables. Calcified subclinical atherosclerosis was unrelated to all physical activity dimensions. Comparing the most sedentary (lowest quartile) and most active (highest quartile) patients, the prevalence of coronary calcium (17.0% vs 18.5%; P = 0.92) and mean coronary calcium scores (8 +/- 31 vs 5 +/- 15; P = 0.87) were similar. In a multivariate model controlling for standard cardiovascular risk factors and physical activity level, only low-density lipoprotein (LDL) cholesterol was associated with the presence of coronary calcium. CONCLUSION Physical activity, particularly high-intensity exercise in sports-related activities, promotes a healthy cardiovascular risk profile, including lower body mass index and insulin resistance, but is unrelated to coronary calcification. This suggests that the risk reduction associated with physical activity is mediated by factors other than retarding the development of calcified atherosclerosis.