Lit Bits: May 23, 2006

From the recent medical literature...

1. Are Lifestyle Measures Effective in Patients With GERD?

An Evidence-Based Approach by Tonya Kaltenbach, MD; et al. Arch Intern Med. 2006;166:965-971.

Lifestyle modifications are first-line therapy for patients with gastroesophageal reflux disease (GERD). We applied an evidence-based approach to determine the efficacy of lifestyle measures for GERD management. We used PubMed and Ovid to perform a search of the literature published between 1975 and 2004 using the key words heartburn, GERD, smoking, alcohol, obesity, weight loss, caffeine or coffee, citrus, chocolate, spicy food, head of bed elevation, and late-evening meal.

Each study was reviewed by 2 reviewers who assigned one of the following ratings: evidence A, randomized clinical trials; evidence B, cohort or case-control studies; evidence C, case reports or flawed clinical trials; evidence D, investigator experience; or evidence E, insufficient information. We screened 2039 studies and identified 100 that were relevant. Only 16 clinical trials examined the impact on GERD (by change in symptoms, esophageal pH variables, or lower esophageal sphincter pressure) of the lifestyle measure. Although there was physiologic evidence that exposure to tobacco, alcohol, chocolate, and high-fat meals decreases lower esophageal sphincter pressure, there was no published evidence of the efficacy of dietary measures.

Neither tobacco nor alcohol cessation was associated with improvement in esophageal pH profiles or symptoms (evidence B). Head of bed elevation and left lateral decubitus position improved the overall time that the esophageal pH was less than 4.0 (evidence B). Weight loss improved pH profiles and symptoms (evidence B). Weight loss and head of bed elevation are effective lifestyle interventions for GERD. There is no evidence supporting an improvement in GERD measures after cessation of tobacco, alcohol, or other dietary interventions.

2. Is There Cross-Reactivity Between Penicillins and Cephalosporins?

Apter AJ, et al. Am J Med. 2006; 119: 354.e11-354.e19 (April 2006)

Abstract
Background
We sought to determine the risk of an allergic reaction to a cephalosporin exposure in those with prior penicillin reactions.

Methods
We conducted a retrospective cohort study using the United Kingdom General Practice Research Database. We selected all patients receiving a prescription for penicillin followed by a prescription for a cephalosporin and identified allergic-like events within 30 days after each prescription. Allergic events were defined by 2 sets of codes: 1 more restrictive, 1 more inclusive. Comparison was made with a population of patients receiving a prescription for a penicillin followed by a prescription for a sulfonamide antibiotic.

Results
A total of 3 375 162 patients received a penicillin; 506 679 (15%) received a subsequent cephalosporin. Among patients receiving a penicillin followed by a cephalosporin, the unadjusted risk ratio of an allergic-like event for those who had a prior event, compared with those who had no such prior event, narrowly defined, was 10.1 (confidence interval 7.4-13.8). The absolute risk of anaphylaxis after a cephalosporin was less than 0.001%. The unadjusted risk ratio for sulfonamide antibiotic, rather than cephalosporin after penicillin allergic-like events was 7.2 (confidence interval 3.8-13.5).

Conclusion
Patients with allergic-like events after penicillin had a markedly increased risk of events after either subsequent cephalosporins or sulfonamide antibiotics. Cross-reactivity is not an adequate explanation for this increased risk, and the risk of anaphylaxis is very low. Thus, our data indicate that cephalosporins can be considered for patients with penicillin allergy.

3. How Thrombogenic Is Hypoxia of Air Travel? …NOT!

Effect of Hypobaric Hypoxia, Simulating Conditions During Long-Haul Air
Travel, on Coagulation, Fibrinolysis, Platelet Function, and Endothelial
Activation. William D. Toff; et al. JAMA 2006;295 2251-2261

Conclusion: Our findings do not support the hypothesis that hypobaric hypoxia, of the degree that might be encountered during long-haul air travel, is associated with prothrombotic alterations in the hemostatic system in healthy individuals at low risk of venous thromboembolism.

Abstract: http://jama.ama-assn.org/cgi/content/abstract/295/19/2251?etoc

Review in Science: http://sciencenow.sciencemag.org/cgi/content/full/2006/516/3 (for subscribers only, I think).

4. Can sutures get wet? …YES!

Prospective randomised controlled trial of wound management in general practice. Clare Heal, et al. BMJ 2006;332:1053-1056.

Guidelines for managing surgical wounds that are closed primarily (that is, those with the skin edges re-approximated at the end of the procedure) instruct that patients should keep their wounds dry and covered for 24-48 hours. Before our study, the four participating general practices were implementing these guidelines and advising patients to keep their wounds dry and covered for 48 hours after minor excisions. For patients living in the tropics of North Queensland, with increased heat and humidity, this recommendation is impractical and a nuisance.

Literature on wound management is sparse. As regards wetting sutures, previous studies have compared standard management (keeping wounds dry) with washing with soap and water in the first 48 hours after minor skin excisions or compared standard management with early showering after more major surgery. These relatively few published studies suggest that getting sutures wet does not increase the infection rate. However, numbers of patients studied have been small, and only one previous study was randomised. No previous studies have been done in the general practice setting.

As regards uncovering sutures, some evidence shows that no difference exists in the incidence of infection between wounds left without dressings and those covered with a dry dressing in the early postoperative period. Again, no previous studies had been done in a general practice setting.

As the two factors, wetting and uncovering, are difficult to separate in the immediate postoperative period, we decided to assess these factors together. We proposed to look at the effects of allowing patients to uncover and wet their wounds during the first 48 hours after minor skin excision, hypothesising that infection rates would be non-inferior compared with a control group following the dry wound management recommendations.

Objective To compare standard management of keeping wounds dry and covered with allowing wounds to be uncovered and wet in the first 48 hours after minor skin excision.

Design Prospective, randomised controlled, multicentre trial testing for equivalence of infection rates.

Setting Primary care in regional centre, Queensland, Australia.

Participants 857 patients randomised to either keep their wound dry and covered (n = 442) or remove the dressing and wet the wound (n = 415).

Results The incidence of infection in the intervention group (8.4%) was not inferior to the incidence in the control group (8.9%) (P < 0.05). The one sided 95% confidence interval for the difference of infection rates was to 0.028.
Conclusion These results indicate that wounds can be uncovered and allowed to get wet in the first 48 hours after minor skin excision without increasing the incidence of infection.

5. Race Influences Side Effects of Cardiovascular Drugs

NEW YORK (Reuters Health) May 04 - Compared with patients of other ethnicities, black and East Asian patients are at increased risk for various adverse reactions when taking cardiovascular drugs, according to a report in the May 4th online issue of the British Medical Journal.

Ethnic group "may be one determinant of harms of a given treatment in the individual patient, either because it acts as a surrogate measure of genetic make up or because cultural factors alter the risk," senior author Dr. Robin E. Ferner and colleagues note.

Dr. Ferner, from City Hospital in Birmingham, UK, and colleagues examined ethnic differences in the side effects of cardiovascular agents by conducting a meta-analysis of data from 24 studies identified through a Medline and Embase search.

On pooled analysis, black patients taking ACE inhibitors were three times more likely to develop angioedema than their non-black counterparts. In addition, black ethnicity raised the risk of intracranial hemorrhage from thrombolytic therapy by 50%.

East Asian patients were also at heightened risk for side effects when taking cardiovascular drugs. In particular, they were 2.7-times more likely to experience cough with ACE inhibitor therapy than were white patients. The authors conclude that future studies looking at cardiovascular agents should taking into account the potential for different side effect profiles based on race.
BMJ 2006.

6. Goth subculture is strongly linked with self harm and attempted suicide

Identification with the Goth youth subculture is strongly associated with self harm and attempted suicide. A longitudinal cohort study by Young and colleagues (BMJ 2006;332:1058-1061) of 1258 people aged 19 who had been followed up since they were 11, found that the prevalence of self harm and attempted suicide were 53% and 47% respectively among the participants who identified mostly strongly with the Goth subculture. Prevalences of self harm and attempted suicide in the whole sample were 7% and 6%.

Abstract: http://bmj.bmjjournals.com/cgi/content/abstract/332/7549/1058

7. High-Dose Corticosteroids Tied to Increased Risk of Atrial Fibrillation

By Megan Rauscher. NEW YORK (Reuters Health) May 09 - Results of a population-based cohort study strongly suggest that treatment with high doses of corticosteroids, regardless of the indication, increases the risk of new-onset atrial fibrillation.

"We suspected this from case reports," Dr. Bruno H. Ch. Stricker from Erasmus University Medical Center, Rotterdam, told Reuters Health. "The effect was, however, higher than anticipated."

In the May 8th Archives of Internal Medicine, Dr. Stricker and colleagues report that among 7,983 adults in the Rotterdam Study who were 55 or older in 1990, 385 developed new-onset atrial fibrillation during an 8-year follow-up period. According to the team, the risk of new-onset atrial fibrillation was significantly higher in individuals who received a corticosteroid prescription within 1 month of the index date (odds ratio, 3.75).

However, only high-dose corticosteroid use -- defined as oral or parenteral steroid at a daily dose of 7.5 mg/day or more of prednisone equivalents -- was associated with increased risk (odds ratio, 6.07). Low- or intermediate-dose corticosteroid use was not associated with increased risk of atrial fibrillation (odds ratio, 1.42). As mentioned, the association of atrial fibrillation with high-dose corticosteroid use was largely independent of the indication for corticosteroid treatment, the authors note.

Clinicians, said Dr. Stricker, need to "be aware that high-dose corticosteroids may increase the risk of atrial fibrillation." High doses of corticosteroids may affect the balance of potassium in cardiac muscle cells, which may induce arrhythmia, the team notes, or may cause sodium and fluid retention, leading to hypertension, left atrial enlargement and congestive heart failure -- all known risk factors for atrial fibrillation.

For individuals on high-dose corticosteroids, careful monitoring "by clinical examination and by performing an electrocardiogram before and after high-dose (pulse) therapy could increase the chances to diagnose and treat this serious arrhythmia as soon as possible," the investigators advise.

Arch Intern Med 2006;165:1016-1020.

8. Elderly Not Adherent to Concomitant Antihypertensive and Lipid-Lowering Therapy

By Martha Kerr. NEW YORK (Reuters Health) May 10 - A retrospective study of elderly patients shows that only 32.9% took concomitant antihypertensive and lipid-lowering medication as prescribed.

"This study emphasizes the importance of considering adherence when caring for high-risk older patients," Dr. Richard H. Chapman commented to Reuters Health. "Despite the relatively high cardiovascular risk of these patients with both hypertension and dyslipidemia, surprisingly few patients were adherent to prescribed medications."

Dr. Chapman of ValuMedics Research in Falls Church, Virginia, and colleagues conducted an analysis of data on 4,052 patients aged 65 and older enrolled in the Protocare Sciences Managed Care Database. Antihypertensive therapy and lipid-lowering agents were initially prescribed within a 90-day period.

The researchers defined adherence as filling prescriptions to cover at least 80% of days for anti-hypertensives and for lipid-lowering therapies. Adherence was evaluated at three-month intervals, and mean follow-up was 19.5 months. The team reported the results at the American Heart Association's 7th Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Diseases and Stroke, being held in Washington, D.C.

Dr. Chapman reported that adherence to both classes of drugs fell rapidly to 40.5% at the 3-month mark, then to 32.7% at 6 months, and stabilized at 32.9% at 1 year. Patients took more of one class of drug or the other, with an additional 27.8% to 35.0% adherent to one medication at each time point over the estimates of adherence for both. Adherence to antihypertensive therapy was higher than with statin therapy.

"From the data in this study we cannot say why adherence was lower with lipid-lowering agents," Dr. Chapman said. "Such differences could be due to differences in side effects or other factors ... For example, patients may believe that their high blood pressure is more of a problem than their high cholesterol." However, "we have no way to tell this for sure from this study."

The researchers found that if both drugs were prescribed at the same time, adherence to both was higher, with an adjusted odds ratio of 1.13. Patients with existing heart disease were more motivated to take medications as prescribed, with an adjusted odds ratio of 1.27 for adherence to both. The factor associated with the lowest adherence to both drugs, with an odds ratio 0.43, was having multiple prescriptions for additional medications.

Based on these findings, Dr. Chapman said that adherence could be improved by initiating antihypertensive and lipid-lowering therapies at the same time if possible. In addition, "attention to polypharmacy is a particularly important issue in the care of older patients," he commented.

9. Codeine Seen to Have No Antitussive Effect in COPD Patients

May 12, 2006 — In patients with stable chronic obstructive pulmonary disease (COPD), codeine treatment had no more effect on cough than did placebo, UK researchers report.

In the April issue of the Journal of Allergy and Clinical Immunology, Dr. Jacyln Smith of South Manchester University Hospital Trusts and colleagues note that codeine is the standard antitussive agent to which others are compared. Laboratory studies suggest it is effective in cough of mixed etiology, but little is known about its impact on cough in COPD patients.

To investigate further, the researchers conducted a double-blind, randomized placebo-controlled study of 21 such patients with stable disease who complained of cough.

They underwent citric acid cough challenge. On two separate occasions after the cough challenge, the subjects were given 60 mg of codeine phosphate or placebo 1 hour before at-home 10-hour daytime ambulatory and 10-hour overnight digital audio recording was started. A lapel microphone was used to capture the sounds of "explosive" coughing.

At baseline, subjects experienced a median of 8.27 seconds of coughing per hour. After placebo this fell to 7.22 seconds per hour. After codeine, it dropped to 6.41 seconds per hour. Although the time spent coughing was significantly less after codeine than at baseline (p = 0.02), there was no significant duration difference between codeine and placebo (p = 0.52) — despite the fact that the dose of codeine used "far exceeds that in over-the-counter cough remedies and is in excess of that used in many previous studies," the researchers note.

They conclude that the findings are "consistent with the view that any antitussive effect of codeine is attributable to a placebo effect." Dr. Smith and colleagues say that studies of cough in other clinical situations are "urgently needed" if codeine is to continue to be used as a cough remedy.

J Allergy Clin Immunol. 2006;117:831-835

10. ST Elevation in Precordial Leads (I)

From Medscape Cardiology. Posted 05/02/2006

For Tracing and Discussion: http://www.medscape.com/viewarticle/530410

11. Signatures Submitted for Tobacco Tax Measure

Source: California Healthline (http://www.californiahealthline.org)
Date: May 5, 2006

Supporters of an initiative to increase the cigarette tax by $2.60 per pack to fund health programs submitted an estimated 1.1 million signatures to county registrars earlier this month to qualify the measure for the November ballot, the Riverside Press-Enterprise reports. The tax, which would raise the combined per-pack tax to $3.47, is expected to generate about $2.1 billion annually. However, that estimate likely will decline as more people stop using tobacco, according to the Legislative Analyst's Office. The initiative calls for:

52.75% of the revenue to be used to fund hospital emergency services, nurse education, community health clinics and tobacco cessation programs;

42.25% to be used for children's health insurance, including an expansion of the Healthy Kids program; smoking prevention campaigns; and cancer, heart, asthma and other disease research; and

5% to be used for cancer- and tobacco disease-related research.

The measure is supported by the Coalition for a Healthy California, which includes the American Lung Association, the California Hospital Association, Children Now and the American Heart Association. Tobacco companies are expected to oppose the measure.

More info? See:
http://www.californiahealthline.org/index.cfm?action=dspItem&itemID=121159&changedID=121113

12. Fever in 2- to 6-Month-Old Infants

Although the pneumococcal and Haemophilus influenzae type B conjugate vaccines have reduced risk for serious bacterial infection in infants, they have changed the landscape of fever management, especially in infants older than 2 months. Investigators at one institution in Connecticut prospectively evaluated 429 consecutive febrile infants (age, 57–180 days) who presented to the emergency department. Evaluation included routine blood and urine laboratory tests and diagnostic tests for viral infection.

Forty-four infants (10.3%) had test results consistent with serious bacterial infections (40 had urinary tract infections, 3 had bacteremia, 1 had both). None of the 58 infants who underwent lumbar puncture had bacterial meningitis. The 163 infants with viral infections were significantly less likely to have serious bacterial infections than the 251 infants without viral infections (4.9% vs. 13.5%). The incidence of urinary tract infections was identical in males and females (9.7%). Among males with known circumcision status, 36% (of 50) uncircumcised infants had UTIs compared with 1.6% (of 128) circumcised infants.

Comment: The 10% incidence of serious bacterial infection in infants older than 2 months is surprisingly high, but considering that their parents had either sought care in or were referred to the ED, the infants in this study likely were sicker than those seen in practice. Clinicians should be aware of the risk for serious bacterial infections, particularly UTIs, in infants who are 2 to 6 months old.

— Howard Bauchner, MD. Published in Journal Watch May 16, 2006. Source: Hsiao AL et al. Incidence and predictors of serious bacterial infections among 57- to 180-day-old infants. Pediatrics 2006 May; 117:1695-701.

13. Industry-Supported Clinical Trials More Likely to Favor Newer Treatments

NEW YORK (Reuters Health) May 16 - Compared with trials funded by nonprofit organizations, industry-supported studies tend to result in favorable outcomes for new treatments, researchers report in the Journal of the American Medical Association for May 17.

Trials that use surrogate end points, such as serum biomarkers or functional measures, instead of clinical endpoints are also more likely to yield positive findings, add Dr. Paul M. Ridker and Jose Torres of Harvard Medical School in Boston.

Surveys of randomized trials published between 1990 and 2000 showed that research funding affected reported outcomes, the researchers note. Proposals to ensure more reliable reporting included improved academic oversight and required registration and publication of all clinical trials.

To see if these recommendations have altered trial reporting, Dr. Ridker and Torres reviewed 324 human clinical trials of cardiovascular medications and devices published between 2000 and 2005 in JAMA, The Lancet or The New England Journal of Medicine, thus limiting their analysis to "trials considered to be of high quality on the basis of prior rigorous peer and editorial review."

They found that 49% of not-for-profit trials, 56.5% of jointly funded trials, and 67.2% of industry-funded trials significantly favored newer treatments (p for trend = 0.005). Similar patterns were observed for trials of drugs, devices and hard clinical end points. As noted, trials with clinical end points, regardless of funding source, were more likely to report positive findings than those using surrogate end points (67% versus 54.1%).

When similar findings were reported prior to 2000, the discrepancies were blamed on bias, data suppression, and differential data quality, Dr. Ridker and Mr. Torres note. Their current report, on the other hand, shows that trials "funded by for-profit organizations tend to have greater sample size, were more likely to be multicentered, and less likely to use surrogate end points, all characteristics typically associated with high quality."

The findings also show that the direction of effect is not always predictable, with some major industry-funded trials showing superiority of a competing manufacturer's product.

Another explanation for the differences between funding sources is that initial negative results for novel therapy are less likely to receive further funding at all, whereas continued research into positive results will probably be supported by industry.

Other factors affecting outcomes include industry's interest in evaluating proven therapies in previously understudied patient populations, while older therapies in common use often fail to be effective when tested rigorously by not-for-profit organizations.

In conclusion, the authors write, "our observations... strongly reinforce the need for physician decision-making and Food and Drug Administration approval to remain on the basis of clinical rather than surrogate end points."

JAMA 2006;295:2270-2274.

14. Acetaminophen/Paracetamol Analgesia Blocked by (Newer) Anti-Emetic Drugs

NEW YORK (Reuters Health) May 22 - Results of a French study provide the first evidence in humans that co-administration of the anti-emetics tropisetron or granisetron with acetaminophen (also known as paracetamol) blocks the analgesic action of acetaminophen.

This is a potentially important observation, investigators say, given that the anti-emetics are frequently used concomitantly with acetaminophen in patients with cancer.

The interaction between these agents "needs to be evaluated in the clinic to determine whether it is of clinical importance," write Dr. Gisele Pickering from Centre Hospitalier Universitaire in Clermont-Ferrand, France and colleagues in the April issue of Clinical Pharmacology and Therapeutics. Using an experimental electrical stimulus pain model in 26 volunteers, the team showed that the pain-relieving effect of acetaminophen was totally inhibited by co-administration of tropisetron or granisetron, two serotonin antagonists primarily used in the prevention of chemotherapy-induced nausea and vomiting.

These observations in humans support preclinical studies, which have suggested that acetaminophen "involves endogenous serotonin to exert its antinociceptive effects," the authors note.

Dr. Pickering's team also points out that the antagonism of acetaminophen analgesia by the anti-emetics was not a result of a pharmacokinetic interaction, because plasma levels were unchanged when tropisetron or granisetron was given concomitantly with acetaminophen. Rather, the results favor a pharmacodynamic interaction between acetaminophen and tropisetron and granisetron - one that needs to be studied further, the authors conclude.

Clin Pharmacol Ther 2006;79:371-378.

15. Flu Vaccine Recommended for More Americans in 2006-7 Season
By Maggie Fox. WASHINGTON (Reuters) May 19 - The U.S. Centers for Disease Control and Prevention is preparing its broadest and most ambitious vaccination effort yet for the coming influenza season, experts said during a briefing on Thursday.

The new recommendations will cover 218 million Americans, or 73% of the population, for the 2006-2007 influenza season. The hope is to both reduce flu deaths -- 36,000 every year on average -- and to coax vaccine makers back into the uncertain U.S. market.

There will not be enough vaccine for this many people, but historically most Americans who should be vaccinated do not. Furthermore, the CDC expects a record number of doses to be available -- up to 120 million, said Dr. Nicole Smith of the CDC's influenza division. The most ever available before has been 95 million doses.

Smith said the CDC was expected to extend its recommendations to include children aged up to 5 years and all their contacts -- including siblings, parents and caregivers. Last year only children aged 6 months to 2 years were on the priority list. There is also talk of adding all children to the list. Vaccinating schoolchildren could provide indirect protection to other groups via the herd effect, Smith added, including the elderly.

One question was whether to go ahead and recommend that everyone be vaccinated, or concentrate on getting more members of higher-risk groups vaccinated, Smith told the briefing, sponsored by The National Foundation for Infectious Diseases.

Dr. Ardis Hoven, a member of the American Medical Association's Board of Trustees, noted that only 40% of health-care professionals, including doctors, nurses and technicians, get vaccinated against flu every year. At Hoven's hospital at the University of Kentucky College of Medicine, 1,000 doses of flu vaccine went unused last year and had to be sent back to the manufacturer.

Part of the problem is that makers cannot deliver all their influenza vaccine doses right at the start of flu season in October. If people ask for a vaccine and cannot get it immediately, they often fail to come back looking for one later.

Interest in vaccination tends to wane after the Thanksgiving holiday at the end of November, Hoven said, even though the flu season has not even properly geared up. "We know that it peaks in February, but we are seeing cases in March, we are seeing cases in April," she said.

The CDC and NFID say people benefit from getting vaccinated as late as February.

Hoven and the other experts hope that having more vaccine available, and getting more Americans vaccinated, will encourage drug companies to make flu vaccines. Currently just four companies supply the U.S. market, and there have been severe shortages in the past five years. "We have got to increase the number of manufacturers and we have got to stabilize the vaccine supply," Hoven said.

16. Highlights From MMWR: Pre-Transport Stroke Death Rate Remains High

Yael Waknine. May 19, 2006 — The US Centers for Disease Control and Prevention (CDC) reported in the May 19 issue of the Morbidity and Mortality Weekly Report on the continued high prevalence of pre-transport stroke deaths; a link between physical dating violence in teens and risk behaviors such as sexual activity and fighting; and primary diagnoses most commonly associated with hospital admission of patients arriving by emergency transport.

Continued High Rate of Pre-Transport Stroke Deaths Underscores Need for Early Recognition and Timely Response

Approximately half of all stroke deaths occur prior to hospital transport, according to an analysis of 1999-2002 death-certificate data from all 50 states and the District of Columbia. The study found that 49.2% of stroke victims in 2002 died before emergency transportation, while 0.4% were dead on arrival (DOA), and 50.3% died after emergency transportation.

A significant proportion of pre-transport stroke deaths occurred in nursing homes (35.4%) rather than in the home or other place (13.8%), and mortality rates increased with age (particularly among nursing home residents), female sex, and non-Hispanic origin. The most common causes included sequelae of cerebrovascular diseases (72.1%) and other cerebrovascular conditions (69.5%), followed by unspecified stroke (54.5%), cerebral infarction (53.2%), and hemorrhagic stroke (14.2%).

Post-transport deaths were more likely to occur after admission to the hospital than in the emergency department (47.0% vs 3.3%) and were most commonly associated with hemorrhagic stroke (79.6%).

The CDC notes that although the national age-adjusted stroke death rate per 100,000 population decreased from 1999 to 2002 (61.6 vs 56.2 people), overall trends and characteristics associated with place of death among decedents remained consistent during this period, and with 1998 data (pre-transport deaths, 46.1%; DOA, 0.6%; hospital deaths, 49.5%).

According to CDC, the findings highlight the need for early patient and bystander recognition of stroke symptoms and improved emergency response times to reduce the continued high rate of pre-transport deaths and serious sequelae that can lead to severe disabilities.

MMWR. 2006;55:529-550

17. Accuracy of B-Type Natriuretic Peptide Tests to Exclude Congestive Heart Failure: Systematic Review of Test Accuracy Studies

Markus Battaglia; et al. Arch Intern Med. 2006;166:1073-1080.

Background Congestive heart failure (CHF) is a major public health problem. The use of B-type natriuretic peptide (BNP) tests shows promising diagnostic accuracy. Herein, we summarize the evidence on the accuracy of BNP tests in the diagnosis of CHF and compare the performance of rapid enzyme-linked immunosorbent assay (ELISA) and standard radioimmunosorbent assay (RIA) tests.

Methods We searched electronic databases and the reference lists of included studies, and we contacted experts. Data were extracted on the study population, the type of test used, and methods. Receiver operating characteristic (ROC) plots and summary ROC curves were produced and negative likelihood ratios pooled. Random-effect meta-analysis and metaregression were used to combine data and explore sources of between-study heterogeneity.

Results Nineteen studies describing 22 patient populations (9 ELISA and 13 RIA) and 9093 patients were included. The diagnosis of CHF was verified by echocardiography, radionuclide scan, or echocardiography combined with clinical criteria. The pooled negative likelihood ratio overall from random-effect meta-analysis was 0.18 (95% confidence interval [CI], 0.13-0.23). It was lower for the ELISA test (0.12; 95% CI, 0.09-0.16) than for the RIA test (0.23; 95% CI, 0.16-0.32). For a pretest probability of 20%, which is typical for patients with suspected CHF in primary care, a negative result of the ELISA test would produce a posttest probability of 2.9%; a negative RIA test, a posttest probability of 5.4%.

Conclusions The use of BNP tests to rule out CHF in primary care settings could reduce demand for echocardiography. The advantages of rapid ELISA tests need to be balanced against their higher cost.

18. Aspirin Plus Dipyridamole Better Than Aspirin Alone for Secondary Stroke Prevention

News Author: Laurie Barclay, MD. May 22, 2006 -- Aspirin plus dipyridamole is better than aspirin alone for secondary prevention of stroke in patients who have had transient ischemic attacks or small strokes, according to the results of a randomized trial reported in the May 20 issue of The Lancet. The editorialist agrees and also comments on the importance of other interventions including lifestyle changes.

"Results of trials of aspirin and dipyridamole combined versus aspirin alone for the secondary prevention of vascular events after ischaemic stroke of presumed arterial origin are inconsistent," write A. Algra, MD, from University Medical Center Utrecht in the Netherlands, and colleagues from the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) Study Group. "Because of these conflicting results, the routine use of the combination of dipyridamole and aspirin in the secondary prevention of vascular events after ischaemic stroke of presumed arterial origin is controversial."

Within 6 months of a transient ischemic attack or minor stroke of presumed arterial origin, patients were randomized to aspirin (30 - 325 mg daily) with (n = 1363) or without (n = 1376) dipyridamole (200 mg twice daily). The main outcome was the composite of death from all vascular causes, nonfatal stroke, nonfatal myocardial infarction, or major bleeding complication or whichever occurred first. Treatment was open, but auditing of outcome events was blinded, and primary analysis was by intent-to-treat. Mean follow-up was 3.5 ± 2.0 years.

Median aspirin dose was 75 mg in both treatment groups (range, 30 - 325), and 1131 patients (83%) on the combination regimen used extended-release dipyridamole. Primary outcome events occurred in 173 patients (13%) receiving aspirin and dipyridamole and in 216 patients (16%) taking aspirin alone (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.66 - 0.98; absolute risk reduction, 1.0% per year; 95% CI, 0.1 - 1.8).

Adding the ESPRIT data to the meta-analysis of previous trials yielded an overall risk ratio for the composite of vascular death, stroke, or myocardial infarction of 0.82 (95% CI, 0.74 - 0.91). Patients taking aspirin and dipyridamole discontinued trial medication more often than those taking aspirin alone (470 vs 184) primarily because of headache.

"The ESPRIT results, combined with the results of previous trials, provide sufficient evidence to prefer the combination regimen of aspirin plus dipyridamole over aspirin alone as antithrombotic therapy after cerebral ischaemia of arterial origin," the authors write.

Study limitations include lack of blinding, long duration but relatively large proportion of patients with incomplete follow-up, no firm restrictions as to the dose of aspirin prescribed, lower than anticipated rate of primary outcome events in the aspirin group, exclusion of 24 patients from one hospital because of incomplete data, and classification of large and small vessel disease based on clinical features.

The Council of Singapore, European Commission, Janivo Foundation, French Ministry of Health, Netherlands Heart Foundation, Thrombosis Foundation, and University Medical Center Utrecht sponsored this study. The authors have disclosed no relevant financial relationships.

In an accompanying editorial, Bo Norrving, MD, from University Hospital in Lund, Sweden, notes that therapy with dipyridamole and aspirin is difficult to maintain in the long term and that one third of the patients discontinued therapy mainly because of headaches.

"With today's report dual dipyridamole and aspirin therapy joins the podium of well-established interventions to be applied in routine clinical practice in secondary stroke prevention," Dr Norrving writes. "In clinical practice, secondary stroke prevention is still far from being ideal. Antiplatelet therapy, even if dual, is far from being the sole panacea for stroke prevention: risk factor and lifestyle modification should not be forgotten." Dr Norrving has disclosed no relevant financial relationships.

Lancet. 2006;367:1638-1639, 1665-1673.