early repolarization on standard ecg is not an innocuous ... · early repolarization in inferior...

Early Repolarization on Standard ECG Is Not an Innocuous Finding

Long-Term Outcome Associated With Early Repolarization on Electrocardiography.

Tikkanen JT, Anttonen O, et al::

N Engl J Med 2009; 361 (December 24): 2529-2537

Early repolarization in inferior leads is associated with an increased risk of cardiac death in middle-aged adults.

Background: Early repolarization is an EGG finding characterized by elevation of the QRS-ST segment junction (J-point). This pattern has been considered a benign variant and is more common among young men, but recent observational studies have linked early repolarization in leads other than V1-V3 with an increased risk of ventricular fibrillation.

Objective: To determine the prevalence and prognosis of early repolarization in inferior and lateral leads in the general Finnish population.

Design: Retrospective analysis of data from the Coronary Heart Disease Study, a community-based cohort of 10,957 Finnish adults aged 30 to 59 years enrolled between 1966 and 1972.

Methods: Baseline ECG tracings for 10,864 patients (52% men; mean age, 44 years) were screened for early repolarization, left ventricular hypertrophy (LVH), and a prolonged QT-interval corrected for heart rate (QTc). The primary outcome measure was death from cardiac causes. Survival and causes of death were determined from death certificates kept by Statistics Finland. Secondary analyses compared the prognosis of early repolarization with that of prolonged QTc interval and LVH.

Results: After a mean follow-up of 30 years, vital statistics were available for 98% of subjects. Of the 6133 deaths overall, 1969 (32%) were from cardiac causes. Early repolarization in inferior or lateral leads was present in 630 subjects (5.8%); 65% of subjects with early repolarization were men. Compared to subjects without early repolarization, subjects with early repolarization of at least 0.1 mV in the inferior leads had a higher risk of cardiac death (adjusted relative risk [ARR], 1.28; 95% CI, 1.04 to 1.59; P =0.03) and death from arrhythmia (ARR, 1.43; 95% CI, 1.06 to 1.94). Early repolarization of >0.2 mV in inferior leads was present in only 36 subjects but was associated with a markedly increased risk of cardiac death (ARR, 2.98; 95% CI, 1.85 to 4.92) and death from arrhythmia (ARR, 2.92; 95% CI, 1.45 to 5.89). Early repolarization in lateral leads was associated with an increased risk of cardiac death (ARR, 1.34; 95% CI, 1.04 to 1.74) but not death from arrhythmia. The ARR of cardiac death among subjects with a prolonged QTc interval was 1.20 (95% CI, 1.02 to 1.42), and the ARR of cardiac death among subjects with LVH was 1.16 (95% CI, 1.05 to 1.27).

Conclusions: Early repolarization in the inferior leads is associated with an increased risk of death from cardiac causes in middle-aged subjects.

Reviewer's Comments: The take-home message from this study is that early repolarization (J-point elevation) in leads other than V1-V3 is associated with an increased risk of death from cardiac causes and can no longer be considered a benign variant in middle-aged patients. Early repolarization in inferior leads was associated with the most significant risk of cardiac death, and the magnitude of risk increased with more substantial J-point elevation. Future studies should determine the mechanisms underlying the early repolarization pattern and devise strategies to prevent cardiac death in patients with this pattern.

Additional Keywords: None

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CHD Risk in Patients With Stroke or TIA -- the SPARCL Trial

Coronary Heart Disease Risk in Patients With Stroke or Transient Attack and No Known Coronary Heart Disease:

Findings From the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial.

Amarenco P, Goldstein LB, et al::

Stroke 2010; 41 (March): 426-430

Stroke patients who are treated with atorvastatin have a reduced risk for CHD events, as well as recurrent stroke.

Background: 25% of patients with recent stroke have a history of known coronary artery disease and are at risk of further coronary events; however, data are limited on the risk of coronary events among stroke/transient ischemic attack (TIA) patients with no known history of clinical coronary heart disease (CHD).

Objective: To determine the risk of developing clinical CHD in subjects with recent stroke, TIA, or carotid atherosclerosis who were randomized to atorvastatin versus placebo in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial.

Design: Randomized controlled trial.

Methods: The SPARCL trial included subjects with recent stroke or TIA, diagnosed 1 to 6 months before randomization, who were free of known CHD regardless of the presence of atherosclerotic carotid disease. Stroke types were categorized as TIA/stroke unrelated to carotid disease (small vessel disease, ischemic stroke of unknown cause, hemorrhagic stroke) or stroke/TIA of carotid origin; 4731 patients (mean age, 63 years) were randomized to atorvastatin 80 mg a day or placebo and were followed up for the development of recurrent stroke/TIA, a major coronary event, any coronary event, and/or any revascularization procedure.

Results: After 4.9 years of follow-up, among the placebo group, 5.1% suffered a major coronary event and 8.6% suffered any CHD event (coronary events, revascularization, unstable angina, or angina/ischemia requiring hospitalization). Among patients taking atorvastatin, 3.4% suffered a major coronary event and 5.2% suffered any coronary event. The adjusted hazard ratio for atorvastatin versus placebo for any CHD event was 0.58 (95% CI, 0.46 to 0.73; P

Reviewer's Comments: Atorvastatin therapy was associated with a substantial decrease in the risk of a first coronary event in patients who had suffered a recent stroke or TIA, regardless of whether the event was due to carotid disease. This indicates that patients with small vessel cerebral vascular disease are at the same risk of CHD as those with carotid disease and should be treated similarly with regard to risk reduction. Patients who had a hemorrhagic stroke also benefitted from atorvastatin, but such patients were included in the trial only if they were deemed to be at high risk for ischemic stroke or CHD. The SPARCL trial was initially designed primarily to determine if atorvastatin was associated with a decreased incidence of stroke. The authors point out that the risk reduction of CHD events was double that of strokes.



Strict Rate Control Not Needed in AF Patients

Lenient Versus Strict Rate Control in Patients With Atrial Fibrillation.

Van Gelder IC, Groenveld HF, et al::

N Engl J Med 2010; March 15 (): epub ahead of print

A target HR of

Background: Rhythm control is often hard to achieve in patients with atrial fibrillation and does not improve outcomes compared to rate control treatment plans. Rate control can also be difficult due to medication side effects and effect on quality of life. It is unknown whether strict rate control improves outcomes compared to a strategy of more lenient heart rate (HR) goals.

Objective: To determine the noninferiority of a lenient rate control strategy compared to strict rate control in patients with atrial fibrillation.

Design: Multi-center, prospective, randomized, open-label, noninferiority trial.

Methods: The Rate Control Efficacy in Permanent Atrial Fibrillation: a Comparison between Lenient versus Strict Rate Control II (RACE II) study enrolled adult patients with permanent atrial fibrillation, on anticoagulation, with a baseline HR >80 beats per minute (bpm) from 33 centers in the Netherlands. Patients were randomized to a strict-control group (resting HR,

Results: 614 patients participated in the study; 65% were men, and the average age was 68 years. Most participants had a CHADS2 score of 0 or 1, and only 10% had previously been hospitalized for heart failure. At year 1 and 2 and at the end of trial follow-up, the lenient-control group had an average HR in the mid-80s, and the strict-control group had an average HR in the mid-70s. The primary outcome occurred in 38 patients randomized to lenient control and 43 patients with strict control. The estimated 3-year cumulative incidence was 12.9% for the lenient-control group and 14.9% for the strict-control group. There were no differences in secondary outcomes.

Conclusions: Lenient rate control is not inferior to strict rate control in preventing cardiovascular outcomes in patients with permanent atrial fibrillation.

Reviewer's Comments: Current guidelines recommend strict rate control based on experience, consensus, and plausible physiologic explanations. These parameters are often hard to achieve. This study suggests that more lenient HR parameters may lead to similar cardiovascular outcomes. It is worth noting that this study population was followed up for only 3 years. Perhaps the adverse effects of relative tachycardia take longer to manifest in this relative healthy population.



Is Coronary Angiography Used Too Often?

Low Diagnostic Yield of Elective Coronary Angiography.

Patel MR, Peterson ED, et al::

N Engl J Med 2010; 362 (March 11): 886-895

In patients without known coronary disease undergoing coronary angiography, nearly 40% have no evidence of obstructive disease.

Background: The American College of Cardiology sponsors a large, voluntary registry of clinical data and in-hospital outcomes of cardiac catheterizations from >600 sites in the United States. This database can serve as a tool to analyze patterns of angiography use.

Objective: (1) To better understand the use of coronary angiography in patients without known coronary artery disease, and (2) to investigate how risk factors, presenting symptoms, and results of previous testing relate to results of angiography.

Participants: Patients with no evidence of previously diagnosed coronary heart disease who underwent elective angiography were evaluated. To identify such patients, those with a history of myocardial infarction, percutaneous coronary intervention, cardiac transplantation, valve surgery, or coronary bypass were excluded.

Methods: In the database, available information included demographics, risk factors, symptoms, and results of noninvasive testing (which included resting electrocardiography, stress tests, echocardiography, and/or CT). Symptoms were defined as no symptoms, atypical chest pain, or stable angina. There was no specific information on the modality for noninvasive testing, which was simply reported as positive, negative, or equivocal. From available information, an estimate of the modified Framingham score was performed. Obstructive coronary disease was defined as a left main stenosis of ≥50% or a stenosis in the epicardial or branch vessel of ≥70%. The criteria for "no coronary disease" was stenosis of

Results: Nearly 400,000 patients were included. Median age was 61 years, and 47% were women; 20% were active smokers, 26% had diabetes, and 70% had hypertension. When Framingham scores were calculated, 29% of patients were low risk, 55% were intermediate risk, and 16% were high risk. As for clinical presentation, 30% had no angina, 37% had atypical symptoms, and 33% had stable angina. Obstructive coronary disease was identified in 38% of patients (41% if definition was modified to >50% lesion), and 39% had no obstructive disease. Patients with stable angina were found to have obstructive disease 44% of the time (32% in asymptomatic patients). In patients who underwent invasive testing (84%), those with positive findings were more likely to have obstructive disease than those with negative testing (41% vs 35%).

Conclusions: In patients without known coronary disease undergoing coronary angiography, many patients have no evidence of obstructive disease.

Reviewer's Comments: Clearly, our current strategies to identity patients who will benefit most from invasive cardiac testing is suboptimal. For instance, in this study, major risk factors were better at predicting angiography results than noninvasive testing. In addition, positive noninvasive imaging was only marginally more predictive than normal results. As the role of percutaneous coronary intervention in stable patients is primarily symptom management, we certainly need to look closely at those who were asymptomatic and develop better ways to choose invasive approaches.



Can Thyroid-Like Medications Lower Cholesterol?

Use of the Thyroid Hormone Analogue Eprotirome in Statin-Treated Dyslipidemia.

Ladenson PW, Kristensen JD, et al::

N Engl J Med 2010; 362 (March 11): 906-916

Eprotirome, a thyroid analog, lowers atherogenic lipoproteins in patients being treated with statins.

Background: Many patients with hyperlipidemia do not reach lipid targets with statins alone. Options for further lipid lowering are limited. Thyroid hormones have been shown to lower lipids. However, there has been considerable concern over adverse cardiovascular and bone effects. Eprotirome is a thyroid analog that has minimal uptake in non-hepatic tissues.

Objective: To determine if the addition of eprotirome to statin therapy would improve lipid parameters without adverse effects.

Design: Industry-sponsored, randomized, double-blind, placebo-controlled trial.

Participants: Patients aged 18 to 65 years on stable statin therapy who still had an LDL cholesterol level ≥116 mg/dL were included. There were numerous exclusion criteria, including thyroid disease, heart failure, beta-blocker use, stroke, percutaneous coronary intervention, and/or elevated liver enzymes.

Methods: After enrollment, patients were placed on an appropriate diet for 4 weeks. They were then randomized to eprotirome (25, 50, or 100 μg) or placebo for 12 weeks. The primary outcome was change in LDL cholesterol from baseline to week 12. Other lipid parameters were followed, including Lp(a) lipoprotein. To assess safety, thyroid, pituitary, and liver testing as well as heart rate, blood pressure, electrocardiography, and markers of bone turnover were measured.

Results: 184 patients were included in the efficacy analysis. The mean age was approximately 60 years, and LDL ranged from 138 to 144 mg/dL. Nearly all patients were receiving statin therapy for primary prevention. At week 12, in patients receiving placebo or 25, 50, or 100 µg of eprotirome, LDL levels had decreased by 7%, 22%, 28%, and 32%, respectively. The rates of patients who had achieved an LDL

Conclusions: Eprotirome, a thyroid analog, significantly lowered LDL cholesterol, triglycerides, and Lp(a).

Reviewer's Comments: As we have been reminded multiple times in the last few years, we need to be careful in interpreting the importance of surrogate markers. For instance, ezetimibe appears to be quite effective at lowering LDL cholesterol but, thus far, with no any clear impact on atherosclerosis. Therefore, when I look at this study, I am intrigued by the improvements seen in atherogenic lipoproteins. However, I am also reminded that this was a 12-week trial, and much longer study is needed to look at clinically meaningful end points and longer safety assessments.



Old Drug Improves Glycemic Control in Type 2 Diabetics

The Effects of Salsalate on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Trial.

Goldfine AB, Fonseca V, et al::

Ann Intern Med 2010; 152 (March 16): 346-357

Salsalate improves glycemic control with relative safety in healthy type 2 diabetics.

Background: In the late 1800s, sodium salicylate was noted to reduce glycosuria in diabetics. More recently, sodium salicylate was found to inhibit transcription factor nuclear-factor κB (NF-κB) which has been associated with insulin resistance and an increased risk of type 2 diabetes. Given these prior observations and a plausible biological mechanism, sodium salicylate may have a role in the treatment of diabetes. Salsalate, a sodium salicylate pro-drug, has been used safely for years in patients with arthritis.

Objective: To assess the efficacy and safety of salsalate in the treatment of type 2 diabetes.

Design: Randomized, double-blind, placebo-controlled, dose-ranging trial.

Methods: The Targeting Inflammation Using Salsalate in Type 2 Diabetes (the TINSAL-T2D) trial enrolled patients from 17 clinical sites in the United States. Participants were type 2 diabetics under the age of 75 years with a fasting glucose ≤225 mg/dL and HbA1c between 7.0% and 9.5% on diet, exercise, and/or oral medications. Medications were stable for at least 8 weeks before the trial. There were multiple exclusion criteria to avoid drug side effects or exacerbation of underlying disease. Patients were randomized to treatment with salsalate 3.0, 3.5, or 4.0 g/day or placebo divided into 3 daily doses for 14 weeks. The primary end point was change in HbA1c.

Results: 108 patients were randomized (27 in each group), with an average age of 55 years. Most of the patients were obese with mean body mass index of approximately 33 kg/m2 and a mean baseline HgA1c around 7.6%. Each group receiving salsalate had a statistically significant improvement in HgA1c compared to the placebo group: -0.36% at 3.0 g/day, -0.34% at 3.5 g/day, and -0.49% at 4.0 g/day. There were more mild hypoglycemic events, mild gastrointestinal symptoms, and tinnitus in patients receiving salsalate at any dose.

Conclusions: Salsalate lowers HgA1c over the short term in patients with type 2 diabetes with relative safety.

Reviewer's Comments: This early dosing and safety trial highlights the continued search for new ways to treat diabetes. Larger, longer trials will be needed to determine if a relatively healthy subset of diabetics will have a clinically relevant improvement in their glucose with this medication. Salsalate could become a useful drug for patients with mild diabetes who are intolerant to other medications, especially if they happen to have coexistent arthritis.



Lactic Acidosis Due to Metformin -- Is It a Myth?

Risk of Fatal and Nonfatal Lactic Acidosis With Metformin Use in Type 2 Diabetes Mellitus.

Salpeter SR, Greyber E, et al::

Cochrane Database Syst Rev 2010; 1 (January 10): CD002967

No cases of lactic acidosis due to metformin use were found in an analysis of 347 studies in which metformin was used.

Background: Metformin is a very helpful drug in the management of type 2 diabetes. It does not run the risk of hypoglycemia and does not promote weight gain. The main limitation has been the recommendation that it should not be used in patients with decreased creatinine clearance because of concern for the development of lactic acidosis. The drug phenformin was removed from the U.S. market in 1978 due to numerous fatal cases of lactic acidosis. Lactic acidosis occurred in 64 cases per 100,000 patients taking phenformin. Because metformin belongs to the same class as phenformin, there has always been concern that lactic acidosis could be a major problem with this drug.

Objective: To assess the incidence of fatal and non-fatal lactic acidosis in metformin users.

Methods: Comprehensive search of electronic databases looking at prospective trials and observational cohort studies of patients with type 2 diabetes treated with metformin. The studies were at least 2 months in duration and used metformin with or without other diabetes treatments.

Results: Data combined from 347 studies showed no cases of fatal or non-fatal lactic acidosis in 70,490 patient-years of metformin use and 55,451 patient-years of non-metformin therapies. There were no differences in lactate levels in the treated and non–metformin-treated patients. In 143 of the trials, patients with renal insufficiency were allowed into the studies.

Conclusions: Lactic acidosis did not occur in any of the patients enrolled in these 347 studies. If this condition is a complication of metformin use, it must be very, very rare.

Reviewer's Comments: This is an update on a previous Cochrane review from 2006. Lactic acidosis due to metformin is either remarkably rare or does not occur. The package insert for metformin recommends not using it in men who have a creatinine >1.5 and in women with a creatinine >1.4. This really restricts its use. Metformin has better survival data for the treatment of diabetes mellitus than other treatments, including in patients with congestive heart failure (CHF). Lactic acidosis does not appear to be a problem in patients on metformin who have CHF (even though the package insert says not to use it in CHF patients). Many physicians have liberalized their use of metformin in light of safety data such as that found in this review.



Long-Term Results of HAART Remain Good

Triple-Class Virologic Failure in HIV-Infected Patients Undergoing Antiretroviral Therapy for Up to 10 Years.

The Pursuing Later Treatment Options II Project Team for the Collaboration of Observational HIV Epidemiologic Research Europe::

Arch Intern Med 2010; 170 (March 8): 410-419

Less than 10% of patients receiving 3-drug HIV antiretroviral therapy develop drug resistance at 9 years.

Background: Since the advent of multi-drug highly active antiretroviral therapy (HAART) treatments for HIV patients, the life expectancy and functional capacity of patients with HIV disease has markedly improved. In groups of patients who adhere to HAART, life expectancy has been estimated to approach normal. The only way that life expectancy can approach that of the general population for patients with HIV disease is for patients to have long-term complete viral suppression.

Objective: To assess the rates of virologic failure with 3-drug HAART therapy over a prolonged period of time.

Methods: The Collaboration of Observational HIV Epidemiological Research Europe database was used to look at the rate of triple-drug virologic failure over time. Patients in this database were started on an antiretroviral therapy that consisted of nucleoside reverse transcriptase inhibitors (RTI) with either a non-nucleoside RTI or a ritonavir-boosted protease inhibitor (PI). The start of this data collection was in 1998.

Results: A total of 45,937 patients were followed up for a median of 3 years, with 980 (2.1%) developing resistance. At 5 years, 3.4% had developed resistance, and by 9 years, 8.6% had developed resistance. No difference was found in the risk of developing resistance whether the patient received a non-nucleoside or PI-containing initial regimen. The rates of subsequent resistance were much higher with the use of a PI containing second-line therapy for those who developed initial resistance to a non-nucleoside RTI-containing regimen (46% by 5 years). The risk of virologic failure was greatest in patients who had the lowest initial CD4 counts (CD4 count

Conclusions: Virologic failure of initial 3-drug therapy is low at 3 years, increasing to a level approaching 10% at 9 years. There is no significant difference in initial failure rates between a PI-inclusive regimen and a non-nucleoside RTI regimen.

Reviewer's Comments: This study provides a lot of useful information. It is a large trial with long-term data. Several key points are that there is no advantage to starting with a PI-containing regimen. This is important, since non-nucleoside RTI regimens avoid the metabolic consequences of PI therapy (increased lipids and impaired glucose tolerance). Younger individuals had a higher rate of developing resistance. I suspect this is due to less careful adherence to regimens in more youthful patients. The lower the CD4 count at which 3-drug therapy is started, the greater the risk for virologic failure. Overall, this study has very good news, showing that >90% of patients on triple therapy maintain viral loads



When Should We Start Antiretroviral Drugs During TB Therapy?

Timing of Initiation of Antiretroviral Drugs During Tuberculosis Therapy.

Karim SSA, Naidoo K, et al::

N Engl J Med 2010; 362 (February 25): 697-706

Initiating antiretroviral drugs during tuberculosis therapy significantly improves survival.

Background: Tuberculosis (TB) is a very common cause of death among African patients co-infected with HIV, but the optimal time to initiate antiretroviral treatment during TB therapy is unknown. Possible reasons to delay antiretroviral treatment during TB therapy include potential drug interactions between rifampin and several antiretroviral classes, immune reconstitution inflammatory syndromes (IRIS), drug toxicity, and the effect of a high pill burden on adherence.

Objective: To determine the optimal time to initiate antiretroviral therapy during TB therapy.

Design: Open-label, randomized, controlled trial conducted by the Centre for the AIDS Programme of Research in South Africa.

Methods: 642 HIV-infected adults with a CD4 count

Results: Patients in the integrated-therapy group initiated HAART a mean of 70 days after the start of TB therapy. Patients in the sequential-therapy group initiated HAART a mean of 260 days after starting TB therapy. After a planned interim analysis, the data and safety monitoring committee recommended that patients in the sequential-therapy group initiate HAART as soon as possible, because patients assigned to integrated-therapy had a 56% lower risk of death (HR in the integrated-therapy group, 0.44; 95% CI, 0.25 to 0.79; P =0.003). The 25 deaths in the integrated-therapy group represented a mortality rate of 5.4 per 100 person-years, while the 27 deaths in the sequential-therapy group represented a mortality rate of 12.1 per 100 person-years. IRIS occurred more commonly in the integrated-therapy group (12.4% vs 3.8%; P

Conclusions: The early initiation of antiretroviral drugs during TB therapy significantly improved survival.

Reviewer's Comments: This trial will be of landmark significance to providers who manage antiretroviral treatment of HIV infection. Unfortunately, too many patients are still being diagnosed with HIV infection at the time of presentation with an opportunistic illness, so the question of optimal timing of antiretroviral therapy comes up often. For physicians who do not manage HIV infection but wonder when to consult a colleague regarding HAART, the take-home message from this trial is simple and consistent with other recent developments. When it comes to treating HIV, earlier is better.



Uncomplicated UTI -- Which Treatment Works Best?

Effectiveness of Five Different Approaches in Management of Urinary Tract Infection: Randomised Controlled Trial.

Little P, Moore MV, et al::

BMJ 2010; 340 (): epub ahead of print

Midstream urinalysis has no added value in treatment of uncomplicated UTI, although basing antibiotic therapy on urine dipstick decreases antibiotic use.

Background: Empiric antibiotic therapy is the gold standard approach for patients with symptoms of uncomplicated urinary tract infections (UTIs). Recent trials suggest that clinical algorithms and urine dipsticks (Udips) are useful in targeting true UTIs for treatment with antibiotics; however, Udips have notoriously low negative predictive values (NPV), and many true UTIs could be missed.

Objective: To assess the efficacy of different management approaches for uncomplicated UTI treatment.

Design: Randomized, controlled trial.

Methods: 5 different methods for treatment of uncomplicated UTI in nonpregnant women were assessed, with the primary outcomes being frequency and severity on day 2 to 4, and duration and use of antibiotic therapy. A total of 309 subjects were randomized to empiric antibiotic treatment, symptom score (antibiotics were offered if patient had ≥2 symptoms: cloudy urine, malodorous urine, moderately severe dysuria, and/or nocturia), Udip (antibiotics were offered if patients had nitrites or leukocytes plus trace blood), midstream urinalysis, and delayed antibiotics were based on patient symptom perceptions. Symptom data were determined by patient symptom diary. Udips and midstream urinalysis were obtained at the providers' discretion, and antibiotics were available to all subjects upon request (independent of randomization).

Results: No significant differences were found in frequency or severity on day 2 to 4 among the 5 groups, correlating with a likelihood ratio of P =0.177. Antibiotic use was statistically lower in the delayed antibiotic group, 77% versus 80% for Udip and 81% for midstream urine) (compared to 97% in the immediate antibiotic group). Patients who waited >48 hours to start antibiotics had fewer re-consultations but had symptoms 37% longer than those taking immediate antibiotics. Obtaining Udip or midstream urinalysis varied among groups but did not affect the symptom severity, duration, or frequency.

Conclusions: There was no statistical difference in symptom control among the different treatment groups, and no clear advantage to sending midstream urinalysis. Delayed antibiotics and the use of back-up antibiotics based on Udip results reduced antibiotic use.

Reviewer's Comments: Since all treatment approaches had similar symptom outcomes, how do we decide the best approach? It's helpful to know that midstream urinalysis had no added value, and delaying therapy based on urinalysis correlated with poorer symptom control. Since Udips are immediately available, they are a reasonable approach. However, given the low negative predictive value, and observational studies showing significant symptom improvement in Udip-negative patients with UTI symptoms, it is important to provide back-up antibiotics based on the patient's perceptions of symptoms. In a paired publication in this same issue of BMJ, the authors reported that the Udip approach is the most cost effective. Empiric delay of antibiotics is an intriguing option and gives more autonomy to patients to determine if their symptoms warrant therapy. With increased patient education, such strategies that decrease overall antibiotic exposure might be increasingly valued by patients.



Is CEA Superior to Stenting for Symptomatic Carotid Artery Stenosis?

Short Term and Intermediate Term Comparison of Endarterectomy Versus Stenting for Carotid Artery Stenosis:

Systematic Review and Meta-Analysis of Randomised Controlled Clinical Trials.

Meier P, Knapp G, et al::

BMJ 2010; February 12 (): epub ahead of print

Carotid endarterectomy is superior to carotid artery stenting for symptomatic carotid stenosis, though carotid stenting should be considered for high-risk surgical patients.

Background: Carotid endarterectomy (CEA) is the gold standard therapy for significant carotid artery stenosis and has been shown to prevent stroke and mortality. Multiple studies have reported on carotid angioplasty and stenting compared to CEA, but the results have been mixed.

Objective: To evaluate the safety and efficacy of CEA and carotid artery stenting (CAS) for both short-term and intermediate-term outcomes.

Methods: A non-blinded systematic review and meta-analysis of randomized controlled trials since 1990 comparing CEA with CAS in symptomatic and asymptomatic patients with carotid stenosis was conducted. The primary outcome was a composite score of death and stroke. Secondary outcomes were stroke, death, myocardial infarction (MI), and cranial nerve injury, and a composite of disabling stroke and mortality. A total of 11 trials presenting 4796 patients were included.

Results: CEA had better short-term outcomes than CAS, but intermediate outcomes were not statistically different. The 30-day outcomes comparing CEA to CAS were: primary composite of death and stroke (OR, 0.67; absolute risk difference, 1.9%); stroke (OR, 0.65); mortality (OR, 1.14); and composite mortality and disabling stroke (OR, 0.74). MI and cranial nerve injuries were higher in CEA (OR, 2.69, and OR, 10.2, respectively). Intermediate-term outcomes were similar for CEA and CAS for the composite of stroke and death (HR, 1.1), stroke (HR, 0.86), and mortality (HR, 1.09).

Conclusions: The authors concluded that CEA is superior to CAS given the unacceptably high perioperative composite stroke and death rate of 7.3% for CAS compared to the accepted risk cut off of 6% for symptomatic patients. The authors believe CAS was an evolving technology that should be reserved for high-risk surgical patients.

Reviewer's Comments: Since the majority of patients included were symptomatic, caution should be used in extrapolating these results to asymptomatic patients. The primary outcome results may inflate the perception of harm for CAS as it was statistically driven by a higher amount of non-disabling strokes and not mortality. The authors postulated that the limited experience of 39% of operators in the CAS procedures, as well as the variable-use dual antiplatelet therapy and emboli protection devices, contributed to suboptimal outcomes for stenting. They felt the meta-analysis failed to show the improving trends in CAS outcomes over time (recent trials of 2000 and 4000 patient showed 30-day rates of stroke and death of 4.1% and 3.4%, respectively). While I would consider advising my high-risk surgical patients with symptomatic carotid artery stenosis to consider CAS as an option, I would also like to see a study comparing stenting to optimal medical management.



Obesity Increases Stroke Risk Regardless of Race, Gender

Race- and Sex-Specific Associations of Obesity Measures With Ischemic Stroke Incidence in the Atherosclerosis Risk in

Communities (ARIC) Study.

Yatsuya H, Folsom AR, et al::

Stroke 2010; 41 (March): 417-425

Obesity is associated with an increased risk of ischemic stroke in blacks and whites.

Background: Stroke is the third leading cause of death in the U.S. and causes significant morbidity. The incidence of stroke in blacks is approximately twice that of whites. Studies have shown that obesity is a risk factor for ischemic stroke in whites, but there are few studies among blacks, and results have been mixed.

Objective: To determine if obesity increases the risk of ischemic stroke in black and white men and women.

Design: Retrospective cohort study.

Methods: Body mass index (BMI), waist circumference, and waist-to-hip ratio (WHR) measurements were obtained from 13,549 black and white participants of the Atherosclerosis Risk in Communities (ARIC) study who were 45 to 65 years of age between 1987 and 1989. Participants were free of cardiovascular disease and cancer at baseline. Hospital records were reviewed to identify incident cases of ischemic stroke. Hazard ratios for ischemic stroke were determined by quintiles of obesity measures, according to sex and race, after adjusting for potential confounding variables.

Results: During a median of 16.9 years of follow-up, there were 598 incident strokes identified. The crude incidence of stroke per 1000 person-years for the lowest BMI quintile ranged from 1.2 in white women to 4.3 in black women, and for the highest BMI quintile, the crude incidence ranged from 2.2 in white women to 8.0 in black men. For waist circumference, the rates ranged from 1.1 for white women in the lowest quintile to 8.2 for black men in the highest quintile; for WHR, the rates ranged from 1.1 for white women in the lowest quintile to 8.2 for black women in the highest quintile. Adjusted hazard ratios for subjects in the highest versus lowest quintile for BMI, waist circumference, and WHR ranged from 1.43 to 3.19. Individuals in the highest BMI quintile had 1.43 to 2.12 times higher risk of stroke compared to the lowest BMI quintile. For waist circumference, the hazard ratios ranged from 1.65 in the lowest quintile to 3.19 in the highest quintile and for WHR from 1.69 in the lowest quintile to 2.55 in the highest quintile.

Conclusions: The relationship between the degree of obesity and ischemic stroke risk was positive and linear across all race and sex groups. Adjustment for hypertension and diabetes significantly weakened the associations.

Reviewer's Comments: For all 3 measures, the degree of obesity was associated with an increased incidence of ischemic stroke. Individuals in the highest quintile had approximately 2 times higher risk of stroke compared to the lowest quintile in each race-sex group. The consistency across all quintiles and across all measures of obesity for black and white men and women suggests that obesity is a significant modifiable risk factor regardless of gender and race. This study reinforces the message that controlling obesity, which may help prevent hypertension and diabetes, may reduce the risk for stroke.



ROSE -- Risk Stratification of Syncope in the Emergency Department

The ROSE (Risk Stratification of Syncope in the Emergency Department) Study.

Reed MJ, Newby DE, et al::

J Am Coll Cardiol 2010; 55 (February 23): 713-721

The ROSE CDR for patients with syncopal event is highly sensitive and reasonably specific. BNP as a part of this tool is a major predictor of serious cardiovascular event, including death.

Background: Although several risk stratification studies have been performed in patients who present to emergency departments (EDs) with syncope, most of them have been limited by small numbers or have not been validated. Syncope is a common and potentially serious medical concern; cardiac causes of syncope are known to have the worst outcomes.

Objective: To develop and validate a clinical decision rule (CDR) for patients presenting to the ED with syncope and for the prediction of short-term (1 month) serious outcomes.

Design: Single-center, prospective, observational study.

Methods: Predictor variables for the CDR were devised based on expert panel consensus; these included past medical and present illness historical elements, examination elements, electrocardiographic (EGG) findings, and B-type natriuretic peptide (BNP), which was felt to be understudied as a potential predictor in syncope outcome. The initial derivation cohort (n=550) was enrolled; then the CDR was tested in a validation cohort (n=550).

Results: 1-month serious outcomes (including arrhythmia, myocardial infarction, pulmonary embolism, gastrointestinal bleed, and death from any cause) occurred in 40 (7.3%) patients in the derivation cohort. Independent predictors included BNP ≥300 pg/mL (OR, 7.3), positive fecal occult blood test (OR, 13.2), hemoglobin ≤90 g/L (OR, 6.7), oxygen saturation ≤94% (OR, 3.0), and ECG with non-lead III Q-wave (OR, 2.8). In the validation cohort, 39 patients (7.1%) had a serious event. The ROSE rule had a sensitivity of 87.2% and specificity of 65.5%, with a negative predictive value of 98.5%. Elevated BNP was present prior to 8 of the 22 serious cardiovascular events (36%), and was present prior to the vast majority of deaths (8 of 9; 89%).

Conclusions: The ROSE CDR appears to be an excellent risk stratification tool for patients with syncope, with high sensitivity and excellent negative predictive value. Serum BNP is major predictor of serious cardiovascular outcomes and death.

Reviewer's Comments: This easy-to-use CDR needs to be externally validated (this study was performed at 1 major medical center in Scotland), but shows promise as a tool to assist with syncope evaluation. The pneumonic “BRACES” can help with remembering each component of the rule. If any of the below are positive, the ROSE suggests admission: B = BNP ≥300 pg/mL or bradycardia HR ≤50; R = rectal examination (if clinically indicated) with a positive fecal occult blood test; A = anemia, with hemoglobin ≤90 g/L (hematocrit less than approximately 27%); C = chest pain associated with syncope; E = ECG with Q-wave (non-lead III); and S = saturation of oxygen ≤94% on room air. In order for the BNP to be useful in this setting, it needs to be a rapid measurement (not yet available at many medical centers). This tool has the potential to help us avoid missing patients with syncope who are at highest risk of a serious outcome and avoid unnecessary admissions of patients who are lower risk.



Pipe, Cigar Smokers at Risk for COPD

The Association of Pipe and Cigar Use With Cotinine Levels, Lung Function, and Airflow Obstruction: A Cross-Sectional

Study.

Rodriguez J, Jiang R, et al::

Ann Intern Med 2010; 152 (February 16): 201-210

Pipe and cigar use increases cotinine levels and is associated with decreased lung function and increased odds of airflow obstruction.

Background: The potential harms of pipe and cigar smoking have not been well characterized.

Objective: To determine whether pipe and cigar smoking results in biological absorption of tobacco smoke, decreases lung function, and increases odds of airflow obstruction.

Design: Cross-sectional study.

Methods: Participants were a population-based sample of 3258 adults, aged 48 to 90 years, enrolled in the Multi-Ethnic Study of Atherosclerosis. Study measures included urine testing for cotinine and standard spirometry. Tobacco use was estimated by self-reported years of use multiplied by the number of pipe-bowls, cigars, or cigarette packs smoked per day.

Results: The mean age of participants was 66 years, and 51% were women. A broad range of ethnic groups was represented: 35% Caucasian, 26% African American, 22% Hispanic, and 17% Chinese. Self-reported tobacco use was: pipe smoking, 9% (median, 15 pipe-years); cigar smoking, 11% (median, 6 cigar-years); and cigarette smoking, 52% (median, 18 pack-years). A large proportion of pipe or cigar smokers also reported cigarette smoking (88%). Median urine cotinine levels were PP =0.039). Decrements in lung function were proportionate to cumulative tobacco use. The mean adjusted FEV1 among smokers of ≥50 pipe-years was 154 mL lower than that in never-smokers, and the mean adjusted FEV1-to-FVC ratio was 0.2 lower among smokers with ≥10 cigar-years than that in never-smokers although this association was weakened when restricted to cigar smokers who had never smoked cigarettes.

Conclusions: Pipe and cigar smoking increased urine cotinine levels and was associated with decreased lung function and increased odds of airflow obstruction.

Reviewer's Comments: Strengths of this analysis include the large, multi-ethnic sample of participants, demonstration of biologic plausibility via increased urine cotinine levels, and the association of an increased "dose" of pipe and cigar smoking with more significant lung damage. Major limitations of the study include its cross-sectional design and the difficulty determining the relative contribution to lung damage of pipe and cigar smoking versus cigarette smoking. The small number of participants who reported pipe or cigar smoking but not cigarette smoking made estimates of the lung damage less precise in this group, but the increased odds of airflow obstruction was statistically significant. Accordingly, this study makes it all the more reasonable to counsel patients who smoke pipes or cigars that they are at risk for COPD.



Is Tiotropium Safe in Patients With COPD?

Cardiovascular Safety of Tiotropium in Patients With COPD.

Celli B, Decramer M, et al::

Chest 2010; 137 (January): 20-30

Tiotropium is associated with reduced all-cause mortality, CV events, and CV mortality in patients with COPD.

Background: In patients with chronic obstructive pulmonary disease (COPD), randomized trials have shown that tiotropium improves FEV1, reduces exacerbations, and improves quality of life, but it is more expensive than ipratropium. Analyses of the cardiovascular (CV) safety of anticholinergic bronchodilators have yielded conflicting results. A meta-analysis by Singh (JAMA, 2008) that included placebo- and active-controlled trials of both ipratropium and tiotropium concluded that anticholinergic bronchodilator use was associated with increased risk of CV mortality (RR, 1.8). On the other hand, an analysis limited to 19 tiotropium trials conducted by Kesten (Chest, 2006) found that CV mortality was reduced 43%, and tiotropium reduced CV mortality 20% in UPLIFT (N Engl J Med 2009).

Objective: To determine the CV safety of tiotropium in patients with COPD.

Design: Pooled analysis of adverse events recorded in the tiotropium project database maintained by the drug manufacturer, Boehringer Ingelheim, which funded this study along with Pfizer.

Methods: Trials using a randomized, placebo-controlled, double-blind design enrolling COPD patients ≥40 years of age were eligible. Adverse events were reported by independent investigators to the drug manufacturer and recorded on standardized forms.

Results: 30 trials, enrolling 19,545 patients randomly assigned to tiotropium (n=10,846) or placebo (n=8,699), were included. Baseline characteristics were similar: mean age, 65 years; 76% male; mean FEV1, 1.5 L; and mean FEV1/FVC, 0.47. Tiotropium was associated with reduced risk of any serious adverse event (RR, 0.94; 95% CI, 0.89 to 0.998) and improved survival (RR for all-cause mortality, 0.88; 95% CI, 0.77 to 0.999). The incidence of most individual cardiac events was not different between groups, but the tiotropium group had reduced risk of a composite CV end point (RR, 0.83; 95% CI, 0.71 to 0.98) and CV mortality (RR, 0.77; 95% CI, 0.60 to 0.98).

Conclusions: Tiotropium was associated with reduced risk of all-cause mortality, CV events, and CV mortality in patients with COPD.

Reviewer's Comments: Smokers with COPD are at high risk of CV morbidity and mortality. Trials of tiotropium suggest it is safe in these patients. Although it is hard to understand why the effects of ipratropium would differ, pooled analyses have linked ipratropium with increased CV risk. Pooled analyses are susceptible to important limitations. Differences in patient populations, study design, data collection, publication bias, and the bias of the investigators who determine which trials to include can all affect the conclusions. Strengths of this pooled analysis include the large number of patients, similar trial design, and uniform data collection; however, the possibility of industry bias is worth noting. Each author has financial ties to the manufacturers of Spiriva. Three are employees of Boehringer Ingelheim, and the rest are members of speakers' bureaus and receive research funding from Boehringer Ingelheim and Pfizer. This study is probably not the final word on the subject, but for now, tiotropium appears to be a safer anticholinergic bronchodilator in patients with COPD.



Paroxetine Plus Tamoxifen Increases Breast Cancer-Related Death

Selective Serotonin Reuptake Inhibitors and Breast Cancer Mortality in Women Receiving Tamoxifen: A Population Based

Cohort Study.

Kelly CM, Juurlink DN, et al::


SSRIs that strongly inhibit CYP2D6 can decrease the effectiveness of tamoxifen for breast cancer treatment and are associated with increased breast cancer-related death.

Background: Tamoxifen is affective for treatment of early stage estrogen receptor-positive breast cancer, reducing the risk of breast cancer-related death by one third and the recurrence of breast cancer by one half. Breast cancer patients have almost double the rate of depression than the average population. Some selective serotonin reuptake inhibitors (SSRIs) are known to inhibit cytochrome P450 isoenzyme 2D6 (CYP2D6), which metabolizes tamoxifen to its active metabolite, but no studies to date have shown actual harm to patients.

Objective: To determine if SSRIs reduce tamoxifen effectiveness.

Design: Retrospective cohort.

Methods: Multiple Canadian national databases were used to identify women >65 years of age concurrently prescribed a single SSRI while taking tamoxifen for breast cancer therapy. Medications evaluated were paroxetine, fluoxetine, sertraline, citalopram, fluvoxamine, and venlafaxine. Analysis was adjusted multiple factors including treatment with other known CYP2D6 inhibitors. Subjects were excluded if they filled multiple SSRI prescriptions, had poor adherence to tamoxifen, or had an unknown cause of death.

Results: 2430 women were included; 374 died due to breast cancer. Adjusted HRs for 25%, 50%, and 75% concurrent exposure to the SSRI and tamoxifen therapy showed a statistically significant increased risk for paroxetine of 1.24, 1.54, and 1.91, respectively. Citalopram had a nonsignificant trend for increased risk (HR, 1.10, 1.21, 1.33), and venlafaxine showed a nonsignificant trend toward protection (HR, 0.67, 0.45, 0.30). Paroxetine showed a similar effect for the same exposure percentages for death from all-causes (including breast cancer) with an HR of 1.13, 1.28, and 1.46. Assuming the median amount of paroxetine overlap with tamoxifen of 41% seen in this study, the number needed to harm (NNH) for 1 death from breast cancer at 5 years is 19.7, and assuming 100% overlap, the NNH is 6.9.

Conclusions: The choice of antidepressants in women taking tamoxifen for breast cancer can negatively affect mortality by inhibiting CYP2D6. The authors recommend selection of SSRIs that do not have this effect.

Reviewer's Comments: The risk of medication interactions is ever present, but this study takes SSRI interactions with tamoxifen from a biologically plausible risk to clear evidence of harm. This well-done study directly opposes the conclusions of a case-control study that showed no harm with concurrent use of these medications, but the cohort design in this study is superior for assessing long-term risks. It is unclear why fluoxetine, another strong inhibitor of CYP2D6, was not associated with increased breast cancer deaths. The popular off label use of venlafaxine for hot flashes likely explains the strong trend toward protection, as hot flashes suggest increased efficacy of tamoxifen. I plan to avoid strong CYP2D6 inhibitors like paroxetine, fluoxetine, citalopram, bupropion and duloxetine in patients with breast cancer treated with tamoxifen.



Vitamin B6 May Lower Risk of Colorectal Cancer

Vitamin B6 and Risk of Colorectal Cancer: A Meta-Analysis of Prospective Studies.

Larsson SC, Orsini N, Wolk A::

JAMA 2010; 303 (March 17): 1077-1083

Colorectal cancer risk is inversely associated with serum levels of active vitamin B6 and possibly with vitamin B6 intake.

Background: Vitamin B6 is a frequent co-factor in the creation of amino acids and plays a role in DNA synthesis, methylation, and repair. Because of this, low vitamin B6 levels have been thought to result in increased colorectal cancer risk. Vitamin B6 consumption may be associated with lower colorectal cancer risk, as it has been shown to reduce cell proliferation, inflammation, oxidative stress, and nitric oxide synthesis.

Objective: To understand the association of the consumption of vitamin B6, or blood levels of its active form, pyridoxal 5'-phosphate (PLP), with the risk of colorectal cancer.

Design: Systematic review with meta-analysis of prospective studies.

Methods: Studies were identified by a search of MEDLINE and EMBASE databases until February 2010 without restrictions. Inclusion criteria were prospective studies, intake of vitamin B6 or plasma/serum PLP levels, outcome of interest to include colorectal, colon or rectal cancer, and report of relative risk estimates with 95% confidence intervals. Exclusion criteria were studies that duplicated data in >1 study.

Results: 9 studies reporting vitamin B6 intake (all dietary, not supplements) and 4 studies reporting PLP levels were included in the meta-analysis. The pooled relative risk (RR) of colorectal cancer for the highest versus the lowest category of vitamin B6 intake was 0.90 (95% CI, 0.75 to 1.07). For PLP levels, the pooled RR for the highest versus lowest category was 0.52 (95% CI, 0.38 to 0.71). Colorectal cancer risk decreased by 49% for every 100-pmol/mL increase in blood PLP levels. When a single study that contributed significantly to heterogeneity (with a very narrow range of vitamin B6 exposure) was omitted, the pooled RR for vitamin B6 intake was 0.80 (95% CI, 0.69 to 0.92).

Conclusions: Based on this fairly small meta-analysis, blood PLP levels are associated with lower colorectal cancer risk. A trend toward lower risk for colorectal cancer was seen in studies reporting higher vitamin B6 intake, though this was not statistically significant when all studies were included.

Reviewer's Comments: As with all meta-analyses, it is difficult to know how much of a role confounders play in the findings. Many of the studies did adjust for known risk factors for colorectal cancer; other unknown confounders may significantly bias the results. Vitamin B6 intake is associated with generally healthy behavior (such as exercise, less alcohol and tobacco, and higher folate intake). None of the articles included in this meta-analysis looked at vitamin B6 supplementation; all assessed dietary vitamin content. Common food sources of vitamin B6 include whole grains, fortified cereals, meats, fresh vegetables, and nuts. While the results of this study are not overwhelming, they do highlight one of the many potential benefits of consumption of whole, unprocessed foods.



Is Hormone Therapy as Bad as First Thought?

Coronary Heart Disease in Postmenopausal Recipients of Estrogen Plus Progestin Therapy: Does the Increased Risk

Ever Disappear? A Randomized Trial.

Toh S, Hernández-Díaz S, et al::

Ann Intern Med 2010; 152 (February 16): 211-217

Cardiovascular risks of hormone therapy may be less significant in women who initiate hormones within 10 years of menopause.

Background: Prior to the publication of the Women's Health Initiative (WHI) results in 2003, postmenopausal hormonal replacement therapy (HRT) was thought to reduce cardiovascular risk. The WHI was stopped early due to an increase in cardiovascular events in women taking postmenopausal combined hormone therapy. Subsequent studies have suggested that the cardiovascular effect of hormone therapy may vary depending on the time since menopause that hormones are initiated.

Objective: To evaluate the effect of continuous estrogen plus progestin therapy on cardiovascular risk expressed as length of time on hormones and time since menopause.

Design: Re-analysis of a randomized, placebo-controlled, double-blinded trial.

Methods: The WHI randomized 16,608 postmenopausal women aged 50 to 79 years to daily conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg or to placebo. The women were followed regularly, and adverse events and adherence to medications were carefully monitored. The primary outcome in the initial trial was the development of coronary heart disease (CHD). The current study is an adherence-adjusted rather than an intention-to-treat analysis. The data are presented as CHD-free survival curves, comparing women taking combined hormone therapy to placebo.

Results: During the first 2 years of follow-up, there was a significant increased risk of CHD in all women taking continuous hormone therapy versus placebo (HR, 2.36; 95% CI, 1.55 to 3.62). When the analysis is limited to women randomized to hormones

Conclusions: This analysis of WHI data showed increased CHD risk during the first 2 years in postmenopausal women taking continuous combined hormones. The increased risk was not as prominent in women initiating hormone therapy within 10 years of menopause. There is a suggestion that this subgroup, women who initiate continuous combined hormone therapy within 10 years of menopause, may begin to experience a cardioprotective effect from hormones after 6 years.

Reviewer's Comments: There are many problems inherent in secondary analyses of previously published trials. That being said, the WHI may be the largest trial we will ever have addressing the cardiovascular effects of combined postmenopausal HRT. Currently, HRT is used primarily in women around the time of menopause who are experiencing severe vasomotor symptoms. This group of patients may be at lower cardiovascular risk from hormones than the overall population in the WHI, and this risk may decline over time.



Lasofoxifene -- A Possible New SERM

Lasofoxifene in Postmenopausal Women With Osteoporosis.

Cummings SR, Ensrud K, et al::

N Engl J Med 2010; 362 (February 25): 686-696

In postmenopausal women with osteoporosis, lasofoxifene 0.5 mg daily decreases the rate of osteoporotic fractures, breast cancer, coronary events, and stroke but increases the rate of venous thromboembolism.

Background: Lasofoxifene, a selective estrogen-receptor modulator (SERM), has shown promise in reducing the risk of osteoporotic fractures. Although it has been approved in Europe, it has not received Food and Drug Administration (FDA) approval in the United States.

Objective: To determine the effect of lasofoxifene on fractures, breast cancer, and cardiovascular disease in postmenopausal women with osteoporosis.

Design: Industry-sponsored, multicenter, randomized, placebo-controlled trial.

Participants: Women in good or excellent health between 59 and 80 years of age, with a bone density T score of –2.5 or less were eligible. Exclusion criteria included a history of breast cancer, venous thromboembolic disease in the prior 5 years, stroke or myocardial infarction in prior 6 months, recent estrogen or raloxifene use, or bisphosphonate use in prior 2 years.

Methods: Women were randomized to 0.25 mg daily of lasofoxifene (lower-dose group), 0.5 mg daily of lasofoxifene (higher-dose group), or placebo for 5 years. Spine x-rays and mammography were obtained regularly. Fasting lipid panels were done at baseline and at 3 years The primary end points were vertebral fracture rate at 3 years and nonvertebral fracture and estrogen-receptor-positive breast cancer rates at 5 years.

Results: Over 8500 women were enrolled from 32 countries, with 77% completing 5 years. The mean age was 67 years, and roughly 75% were white. With the full dose of lasofoxifene, vertebral fracture rates were decreased by 42% (13.5 vs 23 fractures per 1000 patient-years, nonvertebral fractures by 24% (18.7 vs 24.5 fractures per 1000 patient-years), invasive breast cancer by 85% (0.2 vs 1.6 cases per 1000 patient-years), coronary events by 32% (5.1 vs 7.5 cases per 1000 patient-years), and stroke by 36% (2.4 vs 3.9 cases per 1000 patient-years). LDL-cholesterol decreased 16% while triglycerides increased 5%. Episodes of venous thromboembolism (VTE) were roughly 2.5 times more common in patients treated with lasofoxifene (3.8 vs 1.4 cases per 1000 patient-years). Other adverse events more common with lasofoxifene than with placebo included leg cramps and hot flushes. At the full dose, overall mortality was similar to placebo, but with the lower dose, there was a trend toward higher mortality than with placebo.

Conclusions: In postmenopausal women with osteoporosis, lasofoxifene 0.5 mg daily decreased the rate of osteoporotic fractures, breast cancer, coronary events, and stroke but increased the rate of venous thromboembolism.

Reviewer's Comments: Lasofoxifene has not been approved by the FDA, dating back to its original application in 2005. This industry-sponsored study certainly adds to our understanding of the risks and benefits associated with its use, and there certainly appear to be a number of attractive benefits. As to adverse effects, there was an expected increase in VTE but no evidence of excess endometrial cancer. It will be interesting to see if this impacts the approval process and, if so, how it will be incorporated into clinical use.



Contrast CT Not Needed to Diagnose Appendicitis in Adults

Diagnostic Accuracy of Noncontrast Computed Tomography for Appendicitis in Adults: A Systematic Review.

Hlibczuk V, Dattaro JA, et al::

Ann Emerg Med 2010; 55 (January): 51-59

Noncontrast CT of the abdomen is an excellent diagnostic test for the diagnosis of acute appendicitis in adults.

Background: Abdominal pain is commonly seen in the clinic and emergency department (ED) settings. The differential diagnosis is broad, and symptoms are often nonspecific. Appendicitis can be difficult to diagnose clinically because classic signs and symptoms are often absent. Short of surgical exploration, the best test to evaluate for acute appendicitis in adults is not agreed upon. Specifically, is noncontrast computed tomography (CT) adequate or should a contrast agent with inherent risks be added?

Objective: To determine the test characteristics of noncontrast CT for the diagnosis of acute appendicitis in adults.

Design: Systematic review.

Methods: Clinical databases were searched for clinical trials assessing the accuracy of noncontrast CT in the diagnosis of acute appendicitis in adults in the ED. Included studies addressed adult patients with suspected, but not confirmed, appendicitis who had surgical diagnostic confirmation or at least 2 weeks of clinical follow-up.

Results: 7 studies, representing 1060 patients, were included in the final analysis. The prevalence of appendicitis in the overall patient population was 39.3%. The combined test characteristics of noncontrast CT in the diagnosis of appendicitis had a sensitivity of 92.7% and a specificity of 96.1%. The positive likelihood ratio was 24 and the negative likelihood ratio was 0.08.

Conclusions: Noncontrast CT performs well in the diagnosis of acute appendicitis in adults in the ED. This procedure saves time, money, and patient complications when compared to contrast CT.

Reviewer's Comments: Acute appendicitis remains an important cause of abdominal pain in the adult population. Noncontrast CT of the abdomen, which requires no preprocedure testing and can be done quickly, performs well in the diagnosis of acute appendicitis. This review included only studies with the reasonable clinical standards of surgical intervention or at least 2 weeks of watching and waiting, thus mimicking the choices we make as practicing physicians.



Which Pressor Is Best in Shock?

Comparison of Dopamine and Norepinephrine in the Treatment of Shock.

De Backer D, Biston P, et al::

N Engl J Med 2010; 362 (March 4): 779-789

In patients with shock, those treated with dopamine have similar mortality to those treated with norepinephrine, but significantly more arrhythmias.

Background: Dopamine and norepinephrine are the most common vasopressors used for treating shock. Observational studies suggest that there may be a higher rate of death with the use of dopamine. However, there are few randomized data directly comparing these agents.

Objective: To determine if the initial choice of vasopressor (dopamine vs norepinephrine) affects the rate of death.

Design: Randomized, multicenter, double-blind trial.

Participants: Patients from 8 centers in Europe who were ≥18 years of age and required vasopressor treatment for shock were included. Shock was defined as a mean arterial pressure

Methods: Doctors and nurses administering the medications were unaware of the random treatment assignments. Initial dosing was weight-based, and blood pressure targets were determined by local physicians. The maximum doses for each agent were: dopamine, 20 µg/kg per minute and norepinephrine, 0.19 µg/kg per minute. If blood pressure targets were not met with the initial drug, open-label norepinephrine was used followed by rescue epinephrine or vasopressin. The primary end point was the rate of death at 28 days. Multiple secondary end points were also collected, including adverse events.

Results: 1679 patients, with a median age of 68 years, were enrolled. The cause of shock was sepsis in 62%, cardiogenic in 16%, hypovolemic in 16%, and other causes in 5% to 6%. The rate of death at 28 days was similar in both arms (dopamine, 52.5%; norepinephrine 48.5%; OR, 1.17; 95% CI, 0.97 to 1.42; P =0.10). Mortality rates for the hospital stay and out to 6 and 12 months were also similar. As for adverse events, arrhythmias were more common in the dopamine group (24% vs 12%), especially atrial fibrillation (20.5% vs 11%). In a preplanned subgroup analysis, the patients in cardiogenic shock had lower mortality when norepinephrine was used.

Conclusions: In patients with shock, the initial choice of vasopressor (dopamine or norepinephrine) does not appear to significantly affect either short- or long-term mortality. However, dopamine use leads to significantly more arrhythmias and does not seem as effective in patients with cardiogenic shock.

Reviewer's Comments: This study adds some data to the debate over the initial choice of vasopressor. Importantly, there was no difference in mortality seen, so for those inclined to use dopamine, this is reassuring. However, it does appear that dopamine may lead to significantly more rhythm abnormalities, especially atrial fibrillation. The data on cardiogenic shock are also interesting and, as the authors point out, may lead to reconsideration of dopamine as first-line agent in hypotensive patients with myocardial infarction.



Inverse Relationship Between Alcohol, Obesity

Alcohol Consumption, Weight Gain, and Risk of Becoming Overweight in Middle-Aged and Older Women.

Wang L, Lee I-M, et al::

Arch Intern Med 2010; 170 (March): 453-461

Light-to-moderate alcohol consumption in women is associated with a decreased risk of becoming overweight or obese.

Background: More than half of U.S. adults consume alcohol, and two-thirds are overweight (body mass index [BMI], ≥25). Alcohol consumption is a nontrivial source of energy intake and may contribute to the development of obesity. However, there are limited data on this relationship, and prior studies have revealed inconsistent results.

Design: Prospective cohort study.

Objective: To determine if moderate alcohol consumption is associated with an increased incidence of obesity in a cohort of U.S. women.

Participants/Methods: 19,220 U.S. women, who participated in the National Health and Nutrition Examination Survey, were aged ≥38.9 years, were free of cardiovascular disease, diabetes, or cancer, and had a baseline BMI of 18.5 to

Results: 7346 (38.2%) did not consume alcohol at baseline; 568 women (3.0%) consumed ≥30 g/day. A total of 7942 women (41.3%) who were initially normal weight became overweight or obese (732 women [3.8%] became obese). After adjusting for age, baseline BMI, smoking status, nonalcoholic energy intake, physical activity level, and other lifestyle/dietary factors, the relative risk of becoming overweight or obese decreased with increasing alcohol consumption, with a relative risk of 1.0 for 0 g/day, 0.96 for 0 to PPPP PP

Reviewer's Comments: Normal-weight women who consumed light to moderate amounts of alcohol, compared to those who did not consume alcohol, gained less weight and were at decreased risk of becoming overweight or obese. Alcohol consumption should not be recommended as a means to prevent weight gain, but for women who are light to moderate drinkers, the results of this study suggest that they are not at increased of becoming overweight or obese. The study did not address the effects of alcohol consumption on obesity in heavy drinkers.



Minorities Use Hospice Care for CHF Less Often Than Whites

Racial and Ethnic Differences in Hospice Use Among Patients With Heart Failure.

Givens JL, Tjia J, et al::

Arch Intern Med 2010; 170 (March): 427-432

Blacks and Hispanics use hospice for advanced heart failure at a rate of up to 50% less than whites, despite a markedly higher rate of incidence of this disease in these populations.

Background: Advanced congestive heart failure (CHF) is the most common non-cancer diagnosis for hospice referrals comprising 11.8% of hospice enrollees. Advanced CHF has a 1-year mortality of 50% to 70%, and hospice care is increasingly recommended as part of treatment guidelines. Studies have shown that blacks and other minorities use hospice services less frequently for cancer diagnoses, but there are little data on racial differences in hospice use for advanced CHF. Hospice is a Medicare benefit.

Objective: To determine racial and ethnic differences in hospice use for advanced CHF among Medicare beneficiaries.

Design: Prospective cohort study.

Participants/Methods: The study population consisted of a national sample of 98,258 Medicare beneficiaries who were not enrolled in Medicare managed care organizations, were ≥66 years of age on January 1, 2001, had a diagnosis of CHF, and had at least 1 hospitalization or 1 physician visit for CHF over the preceding year. The primary outcome was admission into a hospice with the diagnosis of CHF between January 1, 2001, and December 31, 2001. Data were obtained on race, ethnicity, socioeconomic factors, medical comorbidities, use of medical services (as a proxy for CHF severity), and geographic availability of hospice services.

Results: The sample population was 88.3% white, 8.5% black, 1.4% Hispanic and 1.8% other. Nonwhite participants were more likely to live in large metropolitan urban areas. Black and Hispanic beneficiaries had lower incomes and were younger than whites and others. In 2001, 3.9% of beneficiaries used hospice care, and of these, 18.2% were admitted to hospice for CHF. After adjusting for sociodemographics, urbanicity, comorbidities, severity of illness, and local density of hospice use, hospice care use was lower for minorities compared to whites. The adjusted OR was 0.49 (95% CI, 0.37 to 0.66) for Hispanics, 0.59 (95% CI, 0.47 to 0.73) for blacks, and 0.64 for other nonwhite beneficiaries.

Reviewer's Comments: In a sample of Medicare beneficiaries, blacks and Hispanics utilized hospice care for advanced CHF less frequently than did whites. Prior studies of hospice utilization revealed that geography plays an important role, with patients living in areas with a greater number of minority residents having less access to hospice services. This study took into account local patterns of hospice use and still found large racial differences in the use of hospice care. The differences may be due to patient preferences as well as physician referral patterns. The results of this study underscore the importance of ensuring that there is equal access to and culturally sensitive education about hospice care for racial and ethnic minorities.



Exercise Your Anxiety Away

The Effect of Exercise Training on Anxiety Symptoms Among Patients: A Systematic Review.

Herring MP, O'Connor PJ, Dishman RK::

Arch Intern Med 2010; 170 (February 22): 321-331

Exercise training is effective for the treatment of anxiety symptoms in chronically ill patients.

Background: Anxiety is common and can be debilitating, particularly in those with concomitant chronic illness. Exercise training has been shown to reduce depression, improve cognitive function, and improve quality of life. Exercise programs may also reduce anxiety symptoms.

Objective: To evaluate the effects of exercise training on anxiety symptoms among patients with chronic illness.

Design: Systematic review.

Methods: Articles published from 1995 through 2008 were identified using the Physical Activity Guidelines for Americans Scientific Database and several online databases (Google Scholar, MEDLINE, PsycINFO, PubMed, Web of Science). Inclusion criteria were English language articles, sedentary adult participants with chronic illness, random assignment of participants to either an exercise intervention or no exercise, and an anxiety outcome measured at baseline and after exercise training. Forty articles were identified. Participants in included articles were 33% women, with a mean age of 50 years. Exercise training averaged 3 sessions per week (42 minutes per session) for an average duration of 16 weeks.

Results: Exercise training significantly reduced anxiety symptoms by a mean effect Delta of 0.29 (95% CI, 0.23 to 0.36) as compared with no exercise. Longer session duration programs (at least 30 minutes) and programs lasting 3 to 12 weeks resulted in the largest improvements in anxiety.

Conclusions: Exercise training appears effective in reducing symptoms among sedentary patients with chronic illness.

Reviewer's Comments: This nicely done systematic review provides solid support for the benefits of exercise training on anxiety symptoms. It is most interesting that exercise programs of shorter total duration (3 to 12 weeks vs >12 weeks) resulted in significantly larger decreases in anxiety (Delta, 0.39 vs 0.23). This may be related to adherence; however, many studies included in this review did not report adherence, thus making it difficult to assess in this paper. Conversely, longer exercise session duration (>30 minutes vs 10 to 30 minutes) was associated with larger decreases in anxiety (Delta, 0.36 vs 0.22). The generalizability of this paper is limited to patients with chronic illness who have anxiety symptoms. The real question is, whether your patients with anxiety actually exercise. It certainly cannot hurt to share this paper with applicable patients and encourage exercise as a safe, nonpharmacologic intervention for anxiety symptoms.



XMRV Unlikely Cause of Most Chronic Fatigue Syndrome Cases

Prevalence of Xenotropic Murine Leukaemia Virus-Related Virus in Patients With Chronic Fatigue Syndrome in the

Netherlands: Retrospective Analysis of Samples From an Established Cohort.

van Kuppeveld FJM, de Jong AS, et al::


XMRV-related virus may have caused the outbreak of chronic fatigue syndrome in the Lombardi study, but it is unlikely to be the cause of most cases of chronic fatigue syndrome.

Background: Viruses such as Epstein-Barr virus have long been implicated in having a causative role in chronic fatigue syndrome (CFS). However, no credible evidence has been found to support a specific viral etiology until recently. The article by Lombardi et al in Science indicated that 67% of patients in their cohort of patients with chronic fatigue syndrome were found to have xenotropic murine leukemia virus-related virus (XMRV) in peripheral blood mononuclear cells.

Objectives: To repeat the same techniques used in the Lombardi trial to assess for the prevalence of XMRV in a cohort of Danish patients with known CFS and matched controls.

Methods: Blood samples from 32 patients with CFS and 43 neighborhood-matched controls were tested with a polymerase chain reaction assay targeting XMRV gene components. The study group had twice as many women as men, cases had an average age of 40, and the average duration of CFS was 5 to 7 years.

Results: No XMRV was found in the peripheral mononuclear cells of the CFS subjects or in the control group.

Conclusions: Despite the small size of this study, the authors felt that the absence of evidence of XMRV in both cases and controls strongly suggested that XMRV was unlikely to be associated with the majority of CFS cases.

Reviewer's Comments: The most interesting revelation in this paper was the authors' discussion of the population studied in the Lombardi study. At a 2009 Lisbon conference, it was disclosed that the study subjects with CFS in the Lombardi trial came from a 1984 to 1985 outbreak of chronic fatigue syndrome at Incline village near Lake Tahoe. The authors acknowledge that the Lombardi findings may have identified the particular viral cause of that specific outbreak. However, in light of the current study and a study conducted in the United Kingdom of 186 patients with CFS that also showed no XMRV in peripheral blood mononuclear cells, XMRV is unlikely to be a causative agent in the majority of CFS cases. It has been postulated that there are geographic differences in viral penetration that may account for these differences. In the United States, it is probably reasonable to assess for XMRV in community outbreaks of CFS. However, the bottom line for the majority of our patients with CFS is that the causative agent remains unclear, and while viral etiologies including Epstein-Barr virus and human herpes virus 6 have long been implicated, much research is still needed in this area.



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