Friday, March 16, 2007

Lit Bits: March 16, 2007

From the recent medical literature...

1. Limitations of Angiography in Evaluation of Acute Coronary Syndrome

Karen Dente, MD. March 13, 2007 (Las Vegas) — Conventional diagnostic procedures such as stress-testing and coronary angiograms may no longer be the true gold standard for detecting coronary stenosis, according to an update on the new cardiology literature from 2006 presented here at the 13th annual scientific assembly of the American Academy of Emergency Medicine.

Reference was made to 2 issues of the Journal of the American College of Cardiology (vol 47, no. 8 and no. 10) reviewing the limitations of coronary angiography for detection of clinically significant coronary artery disease (CAD).

"Traditionally, it was assumed that plaques become vulnerable to rupture and cause acute myocardial infarction once they achieve stenosis greater than 70% of the coronary lumen," said Amal Mattu, MD, associate professor and program director of emergency medicine residency at the University of Maryland, who claims that notion to be outdated. "We now know that it is based on the composition of the plaque."

Plaques that are less than 50% occluded account for the majority (two thirds) of acute myocardial infarctions (AMIs). Rather than plaque size, it is plaque vulnerability that determines the likelihood of rupture with subsequent AMI, Dr. Mattu said.

A vulnerable plaque is usually made up of a large lipid core covered by a thin fibrous cap. A plaque with a thick fibrous cap is much less at risk for rupture than one covered by a thin layer of fiber.

In addition, the newer concept of coronary 'remodeling,' in which plaques grow into the vessel wall rather than into the lumen, has gained widespread recognition. Because the lumen is spared, a coronary angiogram may appear normal despite presence of a large intramural plaque, according to Dr. Mattu. The same holds true for a stress test that generally gives information about lumen patency rather than plaque composition, he said.

"Conventional stress-testing and angiogram gives you no information on whether a plaque is going to rupture," David DuBois, MD, an attendee at the symposium and emergency medicine specialist from Pinehurst, North Carolina, told Medscape. "[With these tests] there are a lot of false-positives and false-negatives," he said.

One of the hottest current discussions in the evaluation of acute coronary syndromes is centered around the use of computed tomography coronary angiography. "CT technology is advancing at a very fast rate," said Dr. Mattu, explaining the technology's improved detection in plaque composition and remodeling compared with conventional diagnostic tests.

"If you have a radiologist that can give you an accurate reading with the new 64-head multidetector CT scans, you can detect occlusions better," according to Dr. Dubois. But we are still a long way from having the new technology replace standard coronary angiography for the detection of large coronary stenoses, he said. "It is not going to change the [current] practice any time soon."

AAEM 13th Annual Scientific Assembly. Presented March 12, 2007.

2. Pulmonary Embolism an Uncommon Cause of COPD Flare

NEW YORK (Reuters Health) Mar 02 - The prevalence of unsuspected pulmonary embolism is "very low" in patients seen in the emergency department for acute exacerbation of chronic obstructive pulmonary disease (COPD), according to a study conducted in Switzerland.

In the study, 123 consecutive COPD patients presenting to the ED with acute disease exacerbation were investigated for pulmonary embolism -- whether or not it was clinically suspected.

Diagnostic evaluation including D-dimer testing and chest computed tomography scan of the lungs identified pulmonary embolism in only 4 patients (3%), Dr. Olivier T. Rutschmann of Geneva University Hospitals and colleagues report in the journal Thorax for February.

The prevalence of pulmonary embolism was 6.2% in the 48 patients who had a clinical suspicion of pulmonary embolism and 1.3% in those not suspected of having pulmonary embolism. These findings, the researchers say, indicate that pulmonary embolism is not a common finding in patients seen in the ED for an acute exacerbation of COPD.

"These results argue against a systematic examination for pulmonary embolism in this population," they conclude.

Co-authors of an editorial remind clinicians that "airway infection is the most common trigger for COPD exacerbation and strategies to reduce airway viruses and bacteria should be the most effective interventions to prevent or reduce these events."

Drs. J. A. Wedzicha and J. R. Hurst from University College London, UK, also make the point that some COPD flares "can have prolonged recovery periods, complicated by respiratory failure and co-morbidity, when the risk of pulmonary embolism may become greater."

Thorax 2007;62:103-104,121-125.

3. New Syncope Guidelines by ACEP, January 2007: Two Excerpts

…Few studies have directly evaluated risk stratification of syncope patients in the ED. In a Class I study, Martin et al studied 252 syncope patients to develop a risk classification system and then tested the system in a validation cohort of 374 patients. Predictors of arrhythmia or 1-year mortality in the validation cohort were found to be: (1) abnormal ECG result, (2) history of ventricular arrhythmia, (3) history of congestive heart failure, or (4) age more than 45 years.

The event rate (clinically significant arrhythmia or death) at 1 year in the validation cohort ranged from 0% for those with none of the 4 risk factors to 27% for those with 3 or 4 risk factors. In a similarly designed Class I study from Italy, Colivicchi et al derived risk factors for 1-year mortality (not arrhythmias) in 270 patients and then validated them on 328 patients and found an abnormal ECG result, a history of cardiovascular disease, lack of prodrome, and age older than 65 years to predict all deaths in the 2 cohorts.

These studies have determined that age, abnormal ECG result, lack of a prodrome, a history of cardiovascular disease, especially ventricular arrhythmia, and heart failure all appear to have predictive value in assessing 1-year risk of adverse outcomes in patients with syncope. A Class I study by Quinn et al, the San Francisco Syncope Study, examined short-term serious events in 684 ED patients presenting with syncope. Recursive partitioning techniques identified the following characteristics associated with a higher likelihood of an adverse event within 7 days of ED presentation: abnormal ECG result, shortness of breath, systolic blood pressure less than 90 mm Hg after arrival in the ED, hematocrit level less than 30%, and congestive heart failure by history or examination. This derivation set has now been prospectively validated. A prospective Class III study by Sarasin et al also found that an abnormal ECG result, history of congestive heart failure, and age more than 65 years were all risk factors for experiencing a serious arrhythmia.

Little literature exists to guide the clinician in cases of exertional syncope in young patients (age less than 35 years). This is an uncommon occurrence, usually with a very different etiology than syncope in an older patient. Possible etiologies include hypertrophic cardiomyopathy, coronary artery abnormalities, conduction abnormalities (long QT, preexcitation syndromes), and arrythmogenic cellular dysplasias. Cardiology consultation may be considered either as an inpatient or outpatient….

…Admit patients with syncope and evidence of heart failure or structural heart disease. Admit patients with syncope and other factors that lead to stratification as high-risk for adverse outcome. Factors that lead to stratification as high risk for adverse outcome:

(1) Older age and associated comorbidities. Note: Different studies use different ages as threshold for decisionmaking. Age is likely a continuous variable that reflects the cardiovascular health of the individual rather than an arbitrary value.
(2) Abnormal ECG, including acute ischemia, dysrhythmias, or significant conduction abnormalities.
(3) Hct less than 30 (if obtained).
(4) History or presence of heart failure, coronary artery disease, or structural heart disease.

The primary reason for admitting patients with syncope to an inpatient unit, observation unit, or other monitored area should be that the physician’s risk assessment indicates that a patient may be at risk for significant dysrrhythmia or sudden death and that observation might detect that event and enable an intervention. Problematic is the definition of short-term outcome, which is subjective and not clearly defined. Which patients will benefit from a 24- to 48-hour hospital admission or observation unit admission is not adequately described in the medical literature, nor has the value of admission in preventing a later adverse outcome been demonstrated.

Endpoints for patients followed up after an episode of syncope are typically reported at intervals of 6 months to 1 year or even longer. Only the San Francisco Syncope Rule, which used an endpoint of 7 days, has evaluated short-term risk of patients discharged from the ED. Other studies of ED patients have patient numbers that are too small for firm conclusions. The most rational approach to admission is to understand the specific risks for patients as stated in critical question 1, and make the admission decision in light of available literature. High-risk patients require hospital admission. However, one should also realize that the decision to admit patients often takes into consideration other symptoms, other medical problems, and social factors. Admission may also be initiated for additional testing and consultation or for anticipated therapy…


4. Recombinant Sepsis Drug, Approved for Adults, Fails in Children

A randomized, placebo-controlled trial failed to show efficacy of drotrecogin alfa (Xigris) in treating children with severe sepsis. (The drug, a recombinant form of human activated protein C, was approved in 2001 for use in adults.)

Researchers randomized nearly 500 children with sepsis-induced cardiovascular and respiratory failure to receive either a 4-day course of drotrecogin alfa or saline. They found no difference between the groups in the time to resolution of organ failure, the primary endpoint. There was also no difference in mortality, major amputations or adverse events.

A Lancet commentary called the latest results "profoundly disappointing" and questioned whether the positive adult results could "have been due to chance alone."

Drotrecogin alfa (activated) (DrotAA) is used for the treatment of adults with severe sepsis who have a high risk of dying. A phase 1b open-label study has indicated that the pharmacokinetics and pharmacodynamics of DrotAA are similar in children and adults. We initiated the RESOLVE (REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspectiVE) trial to investigate the efficacy and safety of the drug in children.

Children aged between 38 weeks' corrected gestational age and 17 years with sepsis-induced cardiovascular and respiratory failure were randomly assigned to receive placebo or DrotAA (24 μg/kg/h) for 96 h. We used a prospectively defined, novel primary endpoint of Composite Time to Complete Organ Failure Resolution (CTCOFR) score. Secondary endpoints were 28-day mortality, major amputations, and safety. Analysis was by intention-to-treat. This trial is registered with, number NCT00049764.

477 patients were enrolled; 237 received placebo, and 240 DrotAA. Our results showed no significant difference between groups in CTCOFR score (p=0·72) or in 28-day mortality (placebo 17·5%; DrotAA, 17·2%; p=0·93). Although there was no difference in overall serious bleeding events during the 28-day study period (placebo 6·8%; DrotAA 6·7%; p=0·97), there were numerically more instances of CNS bleeding in the DrotAA group (11 [4·6%], vs 5 [2·1%] in placebo, p=0·13), particularly in children younger than 60 days. For CTCOFR score days 1–14, correlation coefficient was −0·016 (95% CI −0·106 to 0·74); relative risk for 28-day mortality was 1·06 (95% CI 0·66 to 1·46) for DrotAA compared with placebo.

Although we did not record any efficacy of DrotAA in children with severe sepsis, serious bleeding events were similar between groups and the overall safety profile acceptable, except in children younger than 60 days. However, we gained important insights into clinical and laboratory characteristics of childhood severe sepsis, and have identified issues that need to be addressed in future trials in critically ill children.

Nadel S, et al. The Lancet 2007; 369:836-843

5. Stable VT: Procainamide Recommended over Amiodarone

The 2006 ACC/AHA/ESC Guidelines

“Intravenous amiodarone is not ideal for early conversion of stable monomorphic VT. Intravenous procainamide is more appropriate when early slowing of the VT rate and termination of monomorphic VT are desired. Close monitoring of blood pressure and cardiovascular status is recommended in the presence of congestive HF or severe LV dysfunction as intravenous procainamide can cause transient hypotension. Lidocaine is effective when VT is thought to be related to myocardial ischemia.”

Sustained Monomorphic Ventricular Tachycardia. Recommendations (page e416)

Class I

1. Wide-QRS tachycardia should be presumed to be VT if the diagnosis is unclear. (Level of Evidence: C)

2. Direct-current cardioversion with appropriate sedation is recommended at any point in the treatment cascade in patients with suspected sustained monomorphic VT with hemodynamic compromise. (Level of Evidence: C)

Class IIa

1. Intravenous procainamide (or ajmaline in some European countries) is reasonable for initial treatment of patients with stable sustained monomorphic VT. (Level of Evidence: B)

2. Intravenous amiodarone is reasonable for patients with sustained monomorphic VT that is hemodynamically unstable, refractory to conversion with countershock, or recurrent despite procainamide or other agents. (Level of Evidence: C)

J Amer Coll Cardiol 2006;48:e385-e484.

6. Less-than-Rapid Recovery of Consciousness After Febrile Seizures: Not Good

When a child with an untreated, apparent febrile seizure takes longer than 1 hour to recover, consider other etiologies.

Allen JE, et al. Archives of Disease in Childhood. 2007;92:39-42.

Objective: To investigate the duration of postictal impairment of consciousness and the factors that affect it.

Patients and methods: 90 children aged 1–16 years (37 male, 53 female, median age 6 years), attending the accident and emergency department, and inpatients of Leeds General Infirmary, Leeds, UK, who had experienced seizures involving impairment of consciousness. Interventions—hourly modified paediatric coma scores were determined, until a coma score of 15 was obtained. Linear regression analysis was used to determine the factors influencing recovery time.

Results: 49 children were excluded owing to incomplete coma scoring, lost notes and refusal of consent. Median time for full recovery of consciousness was 38 min (0.63 h, range 0.05–17 h). Median recovery time was 18 min (0.3 h, range 0.05–9 h) from febrile seizures, which was significantly shorter than for seizures of other aetiologies (p less than 0.05), 1.35 h (range 0.07–13.13 h) from idiopathic seizures, 1.25 h (0.07–12.1 h) from remote symptomatic seizures and 4.57 h (0.25–17 h) from acute symptomatic seizures. Median recovery time after the use of benzodiazepines was 3.46 h (range 0.08–14.25 h), and was significantly longer (p less than 0.05) than for seizures not treated with benzodiazepines (median 0.47 h, range 0.05–17 h). Age, sex, seizure type and duration did not significantly affect recovery time.

Conclusions: Most children experiencing febrile seizures recover within 30 min. An acute symptomatic aetiology should be considered if recovery takes greater than 1 h.

7. Study Finds Physicians Often Treat According to Patient Requests

Patients' stated wishes for specific tests, drugs, or referrals before a clinic visit are met by their clinicians most of the time, a study in Archives of Internal Medicine reports.

Researchers interviewed patients in waiting rooms just before their visits; those expressing a wish for a new drug, test, or referral were invited to participate by having their visit audiotaped. In 200 such clinical encounters, some 250 expectations were communicated and 67% were met. Expectations for drugs and tests were met more frequently (both about three-quarters of the time) than were referral requests (just over a third of the time).

Physicians, when asked on a post-visit questionnaire to report requests their patients had made, said that, had the patients not asked, they would not have fulfilled almost half of the 138 requests so reported. They said they felt "uncomfortable" about fulfilling 8 of the requests.

The authors comment that the unmet expectations did not seem to negatively affect patients' satisfaction or trust.


8. Atkins Bests Higher-Carbohydrate Diets in Year-Long Trial

In the short term, women can lose at least as much weight on the Atkins diet as on three higher-carbohydrate diets (LEARN, Ornish, and Zone), without increasing cardiovascular risks, a randomized trial in JAMA suggests.

The study included roughly 300 premenopausal, nondiabetic women, aged 25 to 50, who were obese or overweight. Women lost more weight over 1 year using the Atkins diet (mean, 4.7 kg) than they did using the other three diets (mean, 1.6 kg to 2.6 kg). The difference in weight loss was significant only between the Atkins diet and the Zone diet. Changes in HDL cholesterol, triglycerides, and mean blood pressure significantly favored Atkins over the other three diets.

Having observed that the weight loss achieved in all four groups was modest, the authors conclude: "Concerns about adverse metabolic effects of the Atkins diet were not substantiated within the 12-month study period."

Gardner CD, et al. Comparison of the Atkins, Zone, Ornish, and LEARN Diets for Change in Weight and Related Risk Factors Among Overweight Premenopausal Women: The A TO Z Weight Loss Study: A Randomized Trial. JAMA. 2007;297:969-977.

JAMA Abstract:

9. FDA Requests New Warnings on Sleep Aids

The FDA yesterday requested that the warning labeling be strengthened on 13 sedative-hypnotic sleep aids.

Risks to be highlighted include anaphylaxis, angioedema, and what the agency calls "complex sleep-related behaviors" such as driving, eating, and making phone calls while not fully awake. Manufacturers of the drugs -- which include Ambien, Halcion, Lunesta, and Sonata -- will begin sending out letters to healthcare providers this week discussing the new warnings, and will develop patient medication guides to be handed out when the drugs are dispensed.

The FDA has also recommended that manufacturers conduct studies to determine the risks for specific complex sleep behaviors on a drug-by-drug basis.

FDA Press Release:

10. FAST Is Less Accurate in the Presence of Major Pelvic Fracture

Taya VS, et al. J Trauma 2006;61:1453-1457.

Intro: Ultrasound (US) has been shown to be an accurate diagnostic test in the setting of blunt abdominal trauma for detecting clinically significant hemoperitoneum with sensitivity of 72% to 93% and specificity of 90% to 100%. Although the accuracy of abdominal ultrasound for free peritoneal fluid (FPF) in patients with major pelvic injury (MPI) is not known, previous reports have suggested that the presence of pelvic injury creates potential difficulties with the use of ultrasound for diagnosis and management of blunt abdominal trauma. Distortion of the bony pelvis and its associated vascular structures change the architecture of the pelvis and retroperitoneum and theoretically impact the utility of previously accepted diagnostic modalities such as ultrasound…

Background: Trauma ultrasound (US) utilizing the focused assessment with sonography in trauma (FAST) is often performed to detect traumatic free peritoneal fluid (FPF). Yet its accuracy is unclear in certain trauma subgroups such as those with major pelvic fractures whose emergent diagnostic and therapeutic needs are unique. We hypothesized that in patients with major pelvic injury (MPI) trauma ultrasound would perform with lower accuracy than has previously been reported.

Methods: Retrospective analysis of adult trauma patients with pelvic fractures seen at an urban Level I emergency department and trauma center. Patients were identified from the institutional trauma registry and ultrasound database from 1999 to 2003. All patients aged over 16 years with MPI (Tile classification A2, all type B and C pelvic fractures, and type C acetabular fractures determined by a blinded orthopedic traumatologist) and who had a trauma US performed during the initial emergency department evaluation were included. All ultrasounds were performed by emergency physicians or surgeons using the four-quadrant FAST evaluation. Results of US were compared with one of three reference standards: abdominal/pelvic computed tomography, diagnostic peritoneal tap, or exploratory laparotomy. Two-by-two tables were constructed for diagnostic indices.

Results: In all, 96 patients were eligible; 9 were excluded for indeterminate ultrasound results. Of the remaining 87 patients, the pelvic fracture types were distributed as follows: 9% type A2, 72% type B, 16% type C, and 3% type C acetabular fractures. Overall US sensitivity for detection of FPF was 80.8%, specificity was 86.9%, positive predictive value was 72.4%, and negative predictive value was 91.4%. Categorization of sensitivity according to pelvic ring fracture type is as follows: type A2 fractures: sensitivity and specificity, 75.0%; type B fractures: sensitivity, 73.3%, specificity, 85.1%; and type C fractures (pelvis and acetabulum): sensitivity and specificity, 100%. Of the true-positive US results, blood was the FPF in 16 of 21 (76%) and urine from intraperitoneal bladder rupture in 4 in 21 (19%) patients.

Conclusion: US in the initial evaluation of traumatic peritoneal fluid in major pelvic injury patients has lower sensitivity and specificity than previously reported for blunt trauma patients. Additionally, uroperitoneum comprises a substantial proportion of traumatic free peritoneal fluid in patients with MPI.

11. Ibuprofen Better Than Acetaminophen or Codeine for Pediatric Fracture Pain

Ibuprofen proved substantially better than acetaminophen or codeine at reducing pain in children with musculoskeletal injuries in a randomized trial published in the current Pediatrics.

Researchers randomized 300 children (ages 6 to 17) presenting at a children's emergency department with pain from a recent musculoskeletal injury to receive a single dose of either ibuprofen, acetaminophen, or codeine. One hour later, patients receiving ibuprofen showed significantly greater improvement from baseline in their pain scores (on a visual analog scale) than those receiving acetaminophen or codeine.

In subgroup analyses, ibuprofen was associated with significantly greater improvements in patients with fractures compared with the other two medications, but no differences among the three groups were detected in children with soft-tissue injuries.

The authors speculate that the anti-inflammatory properties of ibuprofen might be responsible for its superior pain relief, and note that "although ibuprofen was more efficacious in providing adequate analgesia, only 52% of children in this group could be defined as receiving 'adequate analgesia' at 60 minutes."

OBJECTIVE. Our goal was to determine which of 3 analgesics, acetaminophen, ibuprofen, or codeine, given as a single dose, provides the most efficacious analgesia for children presenting to the emergency department with pain from acute musculoskeletal injuries.

PATIENTS AND METHODS. Children 6 to 17 years old with pain from a musculoskeletal injury (to extremities, neck, and back) that occurred in the preceding 48 hours before presentation in the emergency department were randomly assigned to receive orally 15 mg/kg acetaminophen, 10 mg/kg ibuprofen, or 1 mg/kg codeine. Children, parents, and the research assistants were blinded to group assignment. The primary outcome was change in pain from baseline to 60 minutes after treatment with study medication as measured by using a visual analog scale.

RESULTS. A total of 336 patients were randomly assigned, and 300 were included in the analysis of the primary outcome (100 in the acetaminophen group, 100 in the ibuprofen group, and 100 in the codeine group). Study groups were similar in age, gender, final diagnosis, previous analgesic given, and baseline pain score. Patients in the ibuprofen group had a significantly greater improvement in pain score (mean decrease: 24 mm) than those in the codeine (mean decrease: 11 mm) and acetaminophen (mean decrease: 12 mm) groups at 60 minutes. In addition, at 60 minutes more patients in the ibuprofen group achieved adequate analgesia (as defined by a visual analog scale less than 30 mm) than the other 2 groups. There was no significant difference between patients in the codeine and acetaminophen groups in the change in pain score at any time period or in the number of patients achieving adequate analgesia.

CONCLUSIONS. For the treatment of acute traumatic musculoskeletal injuries, ibuprofen provides the best analgesia among the 3 study medications.

Clark E, et al. PEDIATRICS Vol. 119 No. 3 March 2007, pp. 460-467.

12. ED CHF Guidelines, ACEP, October 2006—The Questions Raised (and Answered!)

A. Does a B-type natriuretic polypeptide (BNP) or NT-ProBNP measurement improve the diagnostic accuracy over standard clinical judgment in the assessment of possible acute heart failure syndromes in the ED?

B. Is there a role for noninvasive positive-pressure ventilatory support in the ED management of patients with acute heart failure syndromes and respiratory distress?

C. Should vasodilator therapy (eg, nitrates, nesiritide, and ACE inhibitors) be prescribed in the ED management of patients with acute heart failure syndromes?

D. Should diuretic therapy be prescribed in the ED management of patients with acute heart failure syndromes?

Answers can be found on-line (Full-text is free):

13. FDA Approves First in New Class of Hypertension Drugs: Renin Inhibitor

The FDA this month approved Tekturna (aliskiren), the first antihypertensive drug that works by directly inhibiting renin. [HTN affects an estimated 25 percent of Americans!]

In clinical trials, Tekturna was shown to be effective in patients with mild-to-moderate hypertension, with slightly smaller blood pressure reductions for African Americans than for Caucasians and Asians. The drug's safety was assessed in almost 6500 patients, the FDA said; side effects were typically mild and brief, though rare allergic reactions were observed, and the drug is contraindicated in pregnancy.

The manufacturer expects the drug to be available this month as once-daily 150 mg and 300 mg tablets. It plans to conduct large outcome trials to evaluate the drug's long-term effects.

FDA Press Release:

14. Evidence Unclear on Treatment for Non-ST-Elevated Acute Coronary Syndrome

Long-term follow-up of patients with non-ST-elevation acute coronary syndrome (nSTE-ACS) showed no difference in mortality between more and less aggressive early treatments.

Researchers randomized 1200 nSTE-ACS patients with elevated cardiac troponin to early invasive treatment (immediate angiography followed when appropriate by percutaneous revascularization or cardiac surgery) or to selective invasive treatment (medical management only to start, with invasive procedures used in the event of cardiac instability). After 3 years, the combined primary endpoint of death, recurrent MI, or rehospitalization for angina did not differ between the two groups. MI was significantly more frequent with the early invasive strategy (an effect due to procedure-related MIs). There was no difference between the groups at the 4-year mark in all-cause mortality or cardiovascular mortality.

However, an editorialist argues that the available randomized trials "collectively show a significant improvement ... in patients with nSTE-ACS treated invasively rather than conservatively."

The ICTUS trial was a study that compared an early invasive with a selective invasive treatment strategy in patients with non-ST-elevation acute coronary syndrome (nSTE-ACS). The study reported no difference between the strategies for frequency of death, myocardial infarction, or rehospitalisation after 1 year. We did a follow-up study to assess the effects of these treatment strategies after 4 years.

1200 patients with nSTE-ACS and an elevated cardiac troponin were enrolled from 42 hospitals in the Netherlands. Patients were randomly assigned either to an early invasive strategy, including early routine catheterisation and revascularisation where appropriate, or to a more selective invasive strategy, where catheterisation was done if the patient had refractory angina or recurrent ischaemia. The main endpoints for the current follow-up study were death, recurrent myocardial infarction, or rehospitalisation for anginal symptoms within 3 years after randomisation, and cardiovascular mortality and all-cause mortality within 4 years. Analysis was by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN82153174.

The in-hospital revascularisation rate was 76% in the early invasive group and 40% in the selective invasive group. After 3 years, the cumulative rate for the combined endpoint was 30·0% in the early invasive group compared with 26·0% in the selective invasive group (hazard ratio 1·21; 95% CI 0·97–1·50; p=0·09). Myocardial infarction was more frequent in the early invasive strategy group (106 [18·3%] vs 69 [12·3%]; HR 1·61; 1·19–2·18; p=0·002). Rates of death or spontaneous myocardial infarction were not different (76 [14·3%] patients in the early invasive and 63 [11·2%] patients in the selective invasive strategy [HR 1·19; 0·86–1·67; p=0·30]). No difference in all-cause mortality (7·9% vs 7·7%; p=0·62) or cardiovascular mortality (4·5% vs 5·0%; p=0·97) was seen within 4 years.

Long-term follow-up of the ICTUS trial suggests that an early invasive strategy might not be better than a more selective invasive strategy in patients with nSTE-ACS and an elevated cardiac troponin, and implementation of either strategy might be acceptable in these patients.

Hirsch A, et al. The Lancet 2007; 369:827-835.

15. FDA to Review Children's Cold and Cough Drugs

The Food and Drug Administration will review over-the-counter cold and cough medications for children, with particular attention to use in children younger than 2 years, the New York Times reports.

Popular cold and cough remedies can cause cardiac problems when used at higher than recommended doses. Rarely, complications have been noted at standard doses. According to a recent CDC survey, some 1500 children were treated during 2004-2005 for adverse effects related to these drugs, including hypertension, arrhythmias, and stroke; three deaths in infants aged younger than 6 months were identified.

The Times reports that pediatricians and public health officials filed a petition yesterday asking the agency to stop manufacturers from marketing these products for children under age 6.

"We have no data on these agents of what's a safe and effective dose in children," the director of the FDA's office of nonprescription drugs told the newspaper.

NY Times article (one-time registration required):

16. Warfarin-Associated Intracerebral Hemorrhage is on the Rise

Flaherty ML, et al. Neurology 2007;68:116-121.

Intro: Community use of warfarin anticoagulation for stroke prevention in patients with atrial fibrillation became more common following publication of pivotal clinical trials in the 1990s. The risk-benefit ratio of warfarin treatment for atrial fibrillation is good among certain high-risk subgroups, including patients with prior thromboembolism, but is narrower when used for primary prevention among elderly subjects, where benefits may be offset by increased bleeding. Although intracranial bleeding is the most feared complication of warfarin use, anticoagulant-associated intracerebral hemorrhage (AAICH) has not been well studied in population-based settings.

Intracerebral hemorrhage (ICH) is conservatively estimated to occur in 67,000 persons in the United States annually; precise estimates of the incidence and demographic characteristics of AAICH are not available. We hypothesized that AAICH is increasing in frequency, and therefore studied the incidence of AAICH in three groups assembled from the same population before and after publication of important clinical trials of warfarin use for stroke prevention. To assess the potential benefit of warfarin in preventing ischemic stroke, we also determined incidence rates for patients hospitalized with ischemic stroke of cardioembolic mechanism during two of these periods.

Methods: We identified all patients hospitalized with first-ever intracerebral hemorrhage (ICH) in greater Cincinnati during 1988, from July 1993 through June 1994, and during 1999. AAICH was defined as ICH in patients receiving warfarin or heparin. Patients from the same region hospitalized with first-ever ischemic stroke of cardioembolic mechanism were identified during 1993/1994 and 1999. Incidence rates were calculated and adjusted to the 2000 US population. Estimates of warfarin distribution in the United States were obtained for the years 1988 through 2004.

Results: AAICH occurred in 9 of 184 ICH cases (5%) in 1988, 23 of 267 cases (9%) in 1993/1994, and 54 of 311 cases (17%) in 1999 (p less than 0.001). The annual incidence of AAICH per 100,000 persons was 0.8 (95% CI 0.3 to 1.3) in 1988, 1.9 (1.1 to 2.7) in 1993/1994, and 4.4 (3.2 to 5.5) in 1999 (p less than 0.001 for trend). Among persons aged 80 or older, the AAICH rate increased from 2.5 (0 to 7.4) in 1988 to 45.9 (25.6 to 66.2) in 1999 (p less than 0.001 for trend). Incidence rates of cardioembolic ischemic stroke were similar in 1993/1994 and 1999 (31.1 vs 30.4, p = 0.65). Warfarin distribution in the United States quadrupled on a per-capita basis between 1988 and 1999.

Conclusions: The incidence of anticoagulant-associated intracerebral hemorrhage quintupled in our population during the 1990s. The majority of this change can be explained by increasing warfarin use. Anticoagulant-associated intracerebral hemorrhage now occurs at a frequency comparable to subarachnoid hemorrhage.

17. Atorvastatin—Now Indicated for the Prevention of (almost!) Everything Cardiovascular

The FDA has approved five new indications for atorvastatin (Lipitor) in patients with cardiovascular disease, according to its manufacturer.

The company said in a press release March 7 that atorvastatin has now been approved for reducing the risks for nonfatal myocardial infarctions, fatal and nonfatal strokes, certain types of heart surgery, hospitalization for heart failure, and angina in patients with established coronary heart disease. This is the first statin to be approved for reducing the risk for hospitalization because of heart failure, according to the press release.

The company said that the approval was based on results from the Treating to New Targets (TNT) trial, published in the NEJM (2005) and the Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL) trial, published in JAMA (2005).

Pfizer Press Release:

18. New Guideline: Epidural Steroid Injections Limited in Treating Back Pain

ST. PAUL, MN -- March 5, 2007 -- A guideline developed by the American Academy of Neurology finds epidural steroid injections play a limited role in providing short-term pain relief for lower back pain that radiates down a leg, and do not provide long-term pain relief.

The guideline is published in the March 6, 2007, issue of Neurology, the scientific journal of the American Academy of Neurology. To develop the guideline, the authors analyzed scientific studies on the topic. According to the guideline, epidural steroid injections may provide some short-term pain relief between two and six weeks after injection, but the average amount of relief is small.

"While some pain relief is a positive result in and of itself, the extent of leg and back pain relief from epidural steroid injections, on the average, fell short of the values typically viewed as clinically meaningful," said lead author Carmel Armon, MD, MHS, Chief, Division of Neurology, with Bayside Medical Center in Springfield, Massachusetts, and Professor of Neurology at Tufts University School of Medicine in Boston, Massachusetts. Armon is also a Fellow member of the American Academy of Neurology.

The guideline also found epidural steroid injections usually did not help patients "buy time" to avoid surgery, or provide long-term pain relief beyond three months. Their routine use for these purposes is not recommended.

"The use of epidural steroid injections to treat chronic back pain is increasing over time despite limited quality data," said Armon. "Recent figures show 1999 Medicare Part B claims for lumbar epidural steroid injections were $49.9 million, for 40.4 million covered individuals."

In addition, the authors also found insufficient evidence to use epidural steroid injections to treat radicular cervical pain, or neck pain. Armon says the review was limited by the small number of high-quality scientific studies on epidural steroid injections, and further well-designed studies are needed to determine their effectiveness.

Armon C, et al. Neurology 2007;68;723-729

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19. ED Use and Subsequent Hospitalizations Among Members of a High-Deductible Health Plan

Wharam JF, et al. JAMA. 2007;297:1093-1102.

Context: Patients evaluated at emergency departments often present with nonemergency conditions that can be treated in other clinical settings. High-deductible health plans have been promoted as a means of reducing overutilization but could also be related to worse outcomes if patients defer necessary care.

Objectives: To determine the relationship between transition to a high-deductible health plan and emergency department use for low- and high-severity conditions and to examine changes in subsequent hospitalizations.

Design, Setting, and Participants: Analysis of emergency department visits and subsequent hospitalizations among 8724 individuals for 1 year before and after their employers mandated a switch from a traditional health maintenance organization plan to a high-deductible health plan, compared with 59 557 contemporaneous controls who remained in the traditional plan. All persons were aged 1 to 64 years and insured by a Massachusetts health plan between March 1, 2001, and June 30, 2005.

Main Outcome Measures: Rates of first and repeat emergency department visits classified as low, indeterminate, or high severity during the baseline and follow-up periods, as well as rates of inpatient admission after emergency department visits.

Results: Between the baseline and follow-up periods, emergency department visits among members who switched to high-deductible coverage decreased from 197.5 to 178.1 per 1000 members, while visits among controls remained at approximately 220 per 1000 (–10.0% adjusted difference in difference; 95% confidence interval [CI], –16.6% to –2.8%; P = .007). The high-deductible plan was not associated with a change in the rate of first visits occurring during the study period (–4.1% adjusted difference in difference; 95% CI, –11.8% to 4.3%). Repeat visits in the high-deductible group decreased from 334.6 to 255.3 visits per 1000 members and increased from 321.1 to 334.4 per 1000 members in controls (–24.9% difference in difference; 95% CI, –37.5% to –9.7%; P = .002). Low-severity repeat emergency department visits decreased in the high-deductible group from 142.5 to 92.1 per 1000 members and increased in controls from 128.0 to 132.5 visits per 1000 members (–36.4% adjusted difference in difference; 95% CI, –51.1% to –17.2%; P less than .001), whereas a small decrease in high-severity visits in the high-deductible group could not be excluded. The percentage of patients admitted from the emergency department in the high-deductible group decreased from 11.8 % to 10.9% and increased from 11.9% to 13.6% among controls (–24.7% adjusted difference in difference; 95% CI, –41.0% to –3.9%; P = .02).

Conclusions: Traditional health plan members who switched to high-deductible coverage visited the emergency department less frequently than controls, with reductions occurring primarily in repeat visits for conditions that were not classified as high severity, and had decreases in the rate of hospitalizations from the emergency department. Further research is needed to determine long-term health care utilization patterns under high-deductible coverage and to assess risks and benefits related to clinical outcomes.

20. Waiting for the Patient to "Sober Up": Effect of Alcohol Intoxication on Glasgow Coma Scale Score of Brain Injured Patients

Sperry JL, et al. J Trauma 2006;61:1305-1311.

Intro: The Glasgow Coma Scale (GCS) is a physiologic measure of level of consciousness. It is commonly used to assess severity of traumatic brain injury (TBI). A GCS score of 13 to 15 is considered a mild head injury, scores between 9 and 12 are considered moderate, whereas patients with a GCS score of 8 or less are considered to have severe TBI. Guidelines based upon these criteria are widely used for clinical decision making. Examples include an Advanced Trauma Life Support (ATLS) guideline for endotracheal intubation of trauma patients with GCS score of 8 or less, and the Brain Trauma Foundation's (BTF) management guidelines for intracranial pressure monitoring in patients with a GCS score of 8 or less and an abnormal head computed tomography scan. In addition, the GCS is also used to identify and enroll patients for participation in TBI-related research.

TBI is the most important determinant of GCS score. However, factors other than TBI may alter level of consciousness and GCS score. Alcohol intoxication, a central nervous depressant, is reported to be present in 35% to 50% of TBI patients. The effects of alcohol vary between individuals; however, in general, these effects appear dose dependent. Minor motor impairments occur at a blood alcohol concentration (BAC) of 80 mg/dL (the legal limit for driving is 80 mg/dL), gross motor impairment (balance and coordination) can occur at 150 mg/dL, and amnesia or coma may occur at levels greater than 200 mg/dL. These effects are at least partly attributable to a reduction in cerebral blood flow that occurs with alcohol intoxication. Although the effects of alcohol on level of consciousness alone would unlikely depress a patient's motor GCS score to the level of withdrawal or posturing, a patients motor GCS score already depressed by brain injury, could be depressed further because of the additive effects of intoxication.

The implications of whether alcohol confounds the GCS score of patients with brain injury are important. If alcohol intoxication decreases the GCS score of TBI patients, then the effect of alcohol needs to be accounted for, so that unnecessary interventions are not performed. Alternatively, if alcohol intoxication does not significantly decrease the GCS score of TBI patients, then a low GCS score should not be attributed to alcohol intoxication, and other causes should be aggressively sought so that a delay in needed interventions does not occur. Of equal importance, research protocols typically use GCS score to define severity of TBI. Alteration of the GCS score by alcohol may result in serious misclassification errors. For example, if alcohol significantly depresses the GCS score, patients with mild TBI but concomitant alcohol intoxication may be misclassified as severely brain injured…

Background: Between 35% to 50% of traumatic brain injury (TBI) patients are under the influence of alcohol. Alcohol intoxication may limit the ability of the Glasgow Coma Scale (GCS) to accurately assess severity of TBI. We hypothesized that alcohol intoxication significantly depresses GCS scores of TBI patients.

Methods: A 10-year, retrospective analysis of a Level I trauma center registry was undertaken. The study population consisted of all blunt injured TBI patients tested for blood alcohol concentration (BAC, n = 1,075). Patients were divided into two groups; intoxicated (mean BAC 202 +/- 77 mg/dL, n = 504) and nonintoxicated (BAC = 0, n = 571). TBI was classified using ICD-9 codes as concussion alone (ICD-9 850, n = 90) and intracranial injury (ICI, ICD-9 851-854, n = 985). Severity was further classified using the Abbreviated Injury Score (AIS). Mean GCS score was compared between the two groups. Patients who were either intubated or hypotensive upon arrival were analyzed separately to rule out confounding effects on GCS score. Severely intoxicated patients (BAC greater than 250 mg/dL, [mean +/- SD] 309 +/- 54 SD, n = 118) were similarly compared. Finally, multivariate linear regression analysis was undertaken to determine whether BAC level was an independent predictor of GCS score while controlling for confounding factors.

Results: Intoxicated and nonintoxicated TBI patients were clinically similar. Alcohol intoxication had little effect on GCS score, with less than a single point difference in all types of TBI, except the most severely injured (AIS 5 injuries, GCS score difference 1.4 points). These results were not altered by endotracheal intubation, systemic hypotension, or severe intoxication. Similarly, BAC was not a significant independent predictor of GCS score in a multivariate model.

Conclusion: Alcohol intoxication does not result in clinically significant changes in GCS score for patients with blunt TBI. Hence, alterations in GCS score after TBI should not be attributed to alcohol intoxication, as doing so might result in inappropriate delays in monitoring and therapeutic interventions.

21. Cell Phones Do Not Interfere with Hospital Equipment

Cell phones do not interfere with medical equipment when used normally in patient care areas of hospitals, according to a study in the Mayo Clinic Proceedings.

The investigators used phones from two different cellular carriers in patient rooms containing a total of 192 medical devices, such as ECG monitors, ventilators and ultrasound imaging machines. In 300 tests, they found no instances of interference. Two Blackberries tested 40 times near 24 medical devices caused no problems either.

"For institutions that have restricted cellular telephone use, these data support revision or abolition of the existing policy," the study concluded.

An editorialist suggests that "it would be appropriate for the FDA to take a more explicit stand that [interference] is unlikely to occur in a hospital setting and that internal regulations in health care facilities should reflect that fact."

OBJECTIVE: To determine whether cellular telephones used in a normal way would cause interference with medical devices located in patient care areas of hospitals.

METHODS: Two cellular telephones from different cellular carriers were tested in various patient care areas between February 15, 2006, and June 29, 2006. To monitor the medical devices and equipment in the patient care areas during testing, we observed the device displays and alarms.

RESULTS: Interference of any type occurred in 0 of the 75 patient care rooms during the 300 tests performed. These 300 tests involved a total of 192 medical devices. The incidence of clinically important interference was 0% (95% confidence interval, 0%-4.8%).

CONCLUSIONS: Although cellular telephone use in general has been prohibited in hospitals because of concerns that these telephones would interfere with medical devices, this study revealed that when cellular telephones are used in a normal way no noticeable interference or interactions occurred with the medical devices.

Tri JL, et al. Mayo Clin Proc. 2007;82(3):282-285