James McCormack

Seeing what you want to see in randomised controlled trials: versions and perversions of UKPDS data

Randomised controlled trials are objective, free of bias, and produce robust conclusions about the benefits and risks of treatment, and clinicians should be trained to rely on them; so says the gospel of evidence based practice. In this article we argue, using the United Kingdom prospective diabetes study (UKPDS) as an example, that there is one stage in the conduct of a randomised controlled trial—the interpretation and dissemination ofresults—that is open to several biases that can seriously distort the conclusions. By bias, we mean the epidemiological definition: anything that systematically distorts the comparisons between groups. We will argue that certain biases arise when different stakeholders assign their individual values to the interpretation of the final results of randomised controlled trials. #### Summary points Randomised trials are subject to interpretation bias as shown by the example of the UK prospective diabetes study The UK prospective diabetes study shows no benefit on macrovascular end points in patients with type 2 diabetes treated with sulphonylureas or insulin over 10 years The study shows a clinically important benefit on macrovascular end points from metformin in patients with type 2 diabetes that seems somewhat independent of the drugs ability to lower blood glucose concentrations Nevertheless, many authors, journal editors, and the wider scientific community interpreted the study as providing evidence of the benefit of intensive glucose control Journal editors should be aware of this important potential bias and encourage authors to present their results initially with a minimum of discussion so as to invite a range of comments and perspectives from readers Until 1998, type 2 diabetes had been treated for over 25 years with drugs such as the sulphonylureas, insulin, and metformin. Only one well designed, prospective clinical trial had evaluated the effect of these drugs on the development of microvascular and macrovascular disease. This was the …

Plasma concentrations after high-dose (45 mg · kg−1) rectal acetaminophen in children

Although the recommended dose of rectal acetaminophen (25–30 mg · kg−1) is twice that for oral administration (10–15 mg · kg−1), the literature justifies the use of a higher dose when acetaminophen is administered via the rectal route. We measured’ venous plasma acetaminophen concentrations resulting from 45 mg · kg−1 of rectal acetaminophen in ten ASA 1, 15 kg paediatric patients undergoing minor surgery with a standardized anaesthetic. After induction of anaesthesia, a single 650 mg suppository (Abenol®, SmithKline Beecham Pharma Inc.) was administered rectally. Plasma was sampled at t = 0, 15, 30, 45, 60, 90, 120, 180, 240 min in the first five patients and at t = 0, 30, 60, 90, 120, 180, 240, 300, 420 min in the subsequent five. Acetaminophen plasma concentrations were determined’ using a TDxFLx® fluorescence polarization immunoassay (Abbott Laboratories, Toronto, Ontario). The maximum plasma concentration was 88 ± 39 μmol · L−1 (13 ± 6 μg · ml−1) and the time of peak plasma concentration was 198 ± 70 min (mean ± SD). At 420 min, the mean plasma concentration was 46 ± 18 μmol · L−1 (7.0 ± 0.9 μg · ml−1). No plasma concentrations associated with toxicity (> 800 μmol · L−1) were identified. A 45 mg · kg−1 rectal dose of acetaminophen resulted in peak plasma concentrations comparable with those resulting from 10–15 mg · kg−1 of oral acetaminophen at three hours after suppository insertion. It is concluded that the delayed and erratic absorption of acetaminophen after rectal administration leads to unpredictable plasma concentrations. Rectal acetaminophen will not be consistently effective for providing rapid onset of analgesia in children.RésuméLa dose rectale d’acétaminophène conseillée (25–30 mg · kg−1) est le double de la dose orale (10–15 mg · kg−1); les publications confirment la pertinence de cette dose lorsque l’acétaminophène est administré par la voie rectale. Les auteurs ont mesuré la concentration plasmatique veineuse de l’acétaminophène 45 mg · kg−1 administré chez dix enfants ASA 1 de 15 kg soumis à une chirurgie mineure sous anesthésie standardisée. Après l’induction de l’anesthésie, un suppositoire de 650 mg d’acétaminophène (Abenol®, SmithKline Beecham Pharmacologique Inc.) est administré par la voie rectale. Le plasma est analysé au t = 0, 15, 30, 45, 60, 90, 120, 240 min chez les cinq premiers patients et au t = 30, 60, 90, 120, 180, 240, 300, 360, 420 min chez les cinq patients suivants. Les concentrations plasmatiques d’acétaminophène sont mesurées au moyen de l’épreuve d’immunofluorescence par polarisation TDxFLx® (Laboratoires Abbott, Toronto, Ontario). La concentration plasmatique maximale est de 88 ± 39 (13 ± 6 μg · ml−1) et elle survient à 198 ± 70 min (moyenne ± ET). A 420 min, la concentration plasmatique moyenne est de 46 ± 18 μmol · L−1 (7,0 ± 0,9 μg · ml−1). Aucune concentration plasmatique ne peut être associée au niveau toxique (> 800 μmol · L−1). La dose rectale de 45 mg · kg−1 d’acétaminop`ene produit des concentrations plasmatiques comparables à celles de la dose orale de 10–15 mg · kg−1 trois heures après l’insertion du suppositoire. Les auteurs concluent que l’absorption retardée et irrégulière de l’acétaminophène rectal entraîne des concentrations plasmatiques imprévisibles. L’acétaminophène rectal ne procure pas toujours un analgésie rectale efficace et rapide chez les enfants.

Metformin's contraindications should be contraindicated

Metformin has been used for over 40 years for patients with type 2 diabetes mellitus.[1][1] With over 40 million patient-years of use as of 1999,[1][1] there is now evidence that the drug decreases the risk of morbidity and death when used to treat type 2 diabetes.[2][2] However, concern remains

Influences of educational interventions and adverse news about calcium-channel blockers on first-line prescribing of antihypertensive drugs to elderly people in British Columbia

BACKGROUND The way in which dissemination of evidence changes medical practice needs to be better understood. Controversy about calcium-channel blockers (CCB) in the past 3 years has provided a natural experiment, enabling assessment of the impact of media stories, a national warning letter, a teleconference, small group workshops, and newsletters on first-line prescribing of antihypertensive drugs. METHODS We included all physicians (4403) in British Columbia who prescribed a thiazide diuretic, beta-blocker, inhibitor of angiotensin-converting enzyme (ACE), or CCB as the first antihypertensive agent for 36,507 residents aged 66 years and over, with no previous or concurrent sign of underlying cardiovascular disease. We used a database covering all prescriptions to elderly people to measure the change in proportion of newly treated patients who received each class of drug as first-line therapy. We used a matched cohort design for assessment of the teleconference and workshops, a randomised community design for the newsletters, and time-series analysis for the media impacts. FINDINGS The proportion of patients who received a CCB as first-line therapy declined gradually from 22% in early 1994 to 15% in late 1996. This proportion was not affected by two waves of adverse news about CCBs in 1995, but fell by 5% for 5 months and by 3% for 1 month after two waves in 1996. The proportion of patients who received either a CCB or an ACE inhibitor as first-line therapy, contrary to guidelines, was still 42% overall in 1996. The workshops and newsletters were followed by shifts from first-line CCB to first-line thiazide prescribing. INTERPRETATION Changes in prescribing practices occur gradually with the accumulation of small impacts from educational interventions and lay media attention.

Agreement among Cardiovascular Disease Risk Calculators

Background— Use of cardiovascular disease risk calculators is often recommended by guidelines, but research on consistency in risk assessment among calculators is limited. Method and Results— A search of PubMed and Google was performed. Five clinicians selected 25 calculators by independent review. Hypothetical patients were created with the use of 7 risk factors (age, sex, smoking, blood pressure, high-density lipoprotein, total cholesterol, and diabetes mellitus) dichotomized to high and low, generating 27 patients (128 total). These patients were assessed by each calculator by 2 clinicians. Risk estimates (and assigned risk categories) were compared among calculators. Selected calculators were from 8 countries, used 5- or 10-year predictions, and estimated either cardiovascular disease or coronary heart disease. With the use of 3 risk categories (low, medium, and high), the 25 calculators categorized each patient into a mean of 2.2 different categories, and 41% of unique patients were assigned across all 3 risk categories. Risk category agreement between pairs of calculators was 67%. This did not improve when analysis was limited to just the 10-year cardiovascular disease calculators. In nondiabetics, the highest calculated risk estimate from a calculator averaged 4.9 times higher (range, 1.9–13.3) than the lowest calculated risk estimate for the same patient. This did not change meaningfully for diabetics or when the analysis was limited to 10-year cardiovascular disease calculators. Conclusions— The decision as to which calculator to use for risk estimation has an important impact on both risk categorization and absolute risk estimates. This has broad implications for guidelines recommending therapies based on specific calculators.

Televised medical talk shows—what they recommend and the evidence to support their recommendations: a prospective observational study

Objective To determine the quality of health recommendations and claims made on popular medical talk shows. Design Prospective observational study. Setting Mainstream television media. Sources Internationally syndicated medical television talk shows that air daily (The Dr Oz Show and The Doctors). Interventions Investigators randomly selected 40 episodes of each of The Dr Oz Show and The Doctors from early 2013 and identified and evaluated all recommendations made on each program. A group of experienced evidence reviewers independently searched for, and evaluated as a team, evidence to support 80 randomly selected recommendations from each show. Main outcomes measures Percentage of recommendations that are supported by evidence as determined by a team of experienced evidence reviewers. Secondary outcomes included topics discussed, the number of recommendations made on the shows, and the types and details of recommendations that were made. Results We could find at least a case study or better evidence to support 54% (95% confidence interval 47% to 62%) of the 160 recommendations (80 from each show). For recommendations in The Dr Oz Show, evidence supported 46%, contradicted 15%, and was not found for 39%. For recommendations in The Doctors, evidence supported 63%, contradicted 14%, and was not found for 24%. Believable or somewhat believable evidence supported 33% of the recommendations on The Dr Oz Show and 53% on The Doctors. On average, The Dr Oz Show had 12 recommendations per episode and The Doctors 11. The most common recommendation category on The Dr Oz Show was dietary advice (39%) and on The Doctors was to consult a healthcare provider (18%). A specific benefit was described for 43% and 41% of the recommendations made on the shows respectively. The magnitude of benefit was described for 17% of the recommendations on The Dr Oz Show and 11% on The Doctors. Disclosure of potential conflicts of interest accompanied 0.4% of recommendations. Conclusions Recommendations made on medical talk shows often lack adequate information on specific benefits or the magnitude of the effects of these benefits. Approximately half of the recommendations have either no evidence or are contradicted by the best available evidence. Potential conflicts of interest are rarely addressed. The public should be skeptical about recommendations made on medical talk shows. Additional details of methods used and changes made to study protocol

Plasma concentrations of flumazenil following intranasal administration in children

Purpose: A pharmacokinetic study in children to determine plasma flumazenil concentrations after the intranasal administration of 40 µg·kg−1.Methods: Following institutional approval and informed written consent, II ASA physical status I–II patients, aged two to six years, undergoing general anesthesia for dental surgery were recruited. After induction, 40 µg·kg−1 flumazenil Anexate®, Roche, 0.1 mg·mL−1 (0.4 mL·kg−1)) were administered via a syringe as drops, prior to nasal intubation. Venous plasma samples were drawn prior to administration of flumazenil (t=0), and then at 2, 4, 6, 8, 10, 15, 20, 30, 40, 60, and 120 min thereafter. The plasma samples were immediately processed by the onsite laboratory and then stored at −70°C, before batch analysis via high performance liquid chromatography assay. Pharmacokinetic data calculations were performed using WinNonLin software (Scientific Consulting Inc.).Results: Eleven patients were studied, but data for one patient were discarded due to insufficient sampling. The median age was 4.3 yr (range 3 to 6), with a median weight of 18.9 kg (range 14.9 to 22.2). There were seven boys and three girls. Mean Cmax was 67.8 ng·mL−1 (SD 41.9), with Tmax at two minutes. The calculated half-life was 122 min (SD 99).Conclusion: The mean plasma concentrations of flumazenil attained were similar to those reported after intravenous administration, and may be sufficient to antagonize the side-effects of benzodiazepines. This route of administration may be useful when the intravenous route is not readily available.RésuméObjectif: Déterminer, par une étude pharmacocinétique chez des enfants, la concentration plasmatique de flumazénil après l’administration intranasale de 40 µg·kg−1.Méthode: Après avoir obtenu les autorisations écrites de l’institution et des parents, on a recruté II patients, d’état physique ASA I–II, âgés de deux à six ans, qui devaient subir une intervention dentaire sous anesthésie générale. À la suite de l’induction, 40µg·kg−1 de flumazénil (Anexate®, Roche, 0,1 mg·mL−1 (0,4 mL·kg−1)) ont été administrés en gouttelettes au moyen d’une seringue avant l’intubation nasale. Des échantillons plasmatiques veineux ont été pris avant l’administration de flumazénil (t=0), et ensuite à 2, 4, 6, 8, 10, 15, 20, 30, 40, 60, et 120 min. Les échantillons plasmatiques ont été immédiatement traités au laboratoire sur place et conservés à −70 °C, avant l’analyse du tout par chromatographie à haute performance. Les calculs pharmacocinétiques ont été réalisés avec le logiciel WinNonLin (Scientific Consulting Inc.).Résultats: Les données d’un seul patient sur II ont été refusées pour échantillons insuffisants. L’âge moyen des en fants, dont sept garçons et trois filles, était de 4,3 ans (limites de 3 à 6), et le poids moyen était de 18,9 kg (limites de 14,9 à 22,2). La Cmax moyenne était de 67,8 ng·mL−1 (écart type de 41,9), et un Tmax à deux minutes. La demi-vie était de 122 min (écart type de 99).Conclusion: Les concentrations plasmatiques moyennes de flumazénil obtenues ont été similaires à celles qui suivent l’administration intraveineuse et peuvent être suffisantes pour contrer les effets secondaires des benzodiazépines. L’administration par voie nasale peut se révéler utile lorsque la voie intraveineuse n’est pas facilement accessible.

How confidence intervals become confusion intervals.

BackgroundControversies are common in medicine. Some arise when the conclusions of research publications directly contradict each other, creating uncertainty for frontline clinicians.DiscussionIn this paper, we review how researchers can look at very similar data yet have completely different conclusions based purely on an over-reliance of statistical significance and an unclear understanding of confidence intervals. The dogmatic adherence to statistical significant thresholds can lead authors to write dichotomized absolute conclusions while ignoring the broader interpretations of very consistent findings. We describe three examples of controversy around the potential benefit of a medication, a comparison between new medications, and a medication with a potential harm. The examples include the highest levels of evidence, both meta-analyses and randomized controlled trials. We will show how in each case the confidence intervals and point estimates were very similar. The only identifiable differences to account for the contrasting conclusions arise from the serendipitous finding of confidence intervals that either marginally cross or just fail to cross the line of statistical significance.SummaryThese opposing conclusions are false disagreements that create unnecessary clinical uncertainty. We provide helpful recommendations in approaching conflicting conclusions when they are associated with remarkably similar results.

A comparison of regularly dosed oral morphine and on-demand intramuscular morphine in the treatment of postsurgical pain

A randomized, placebo-controlled, double-blind clinical trial was conducted to compare the use of regularly dosed po morphine and on-demand im morphine in 47 patients undergoing total hip arthroplasty. Patients were randomized to receive either 20 mg (initial dose) of regularly dosed morphine (every four hours po) plus breakthrough pain medication on-demand consisting of both 10 mg morphine po and placebo im, or an equivalent regularly dosed oral placebo (every four hours) with breakthrough pain medication consisting of oral placebo and 5–10 mg morphine im. Subsequent to each request for break-through pain medication, the next regularly dosed oral solution was increased by 5 mg (or equivalent volume of placebo) to a maximum of 40 mg po Q4H. Time-averaged pain scores were lower on both postoperative day 1 and 2 in the group receiving regularly dosed morphine po (P < 0.05). Fewer patients requested breakthrough pain medication on both days in the oral morphine group. The incidences of nausea and vomiting, and of decreased respiratory rates were similar in both groups. Regularly dosed oral morphine is inexpensive and should be compared to other methods of opioid delivery.RésuméUne étude randomisée, contrôlée avec placébo et à double insu est réalisée dans le but de comparer l’utilisation de morphine po avec la morphine sur demande im chez 47 patients après une arthroplastie totale de la hanche. La randomisation est effectuées de façon à ce que les patient reçoivent: soit morphine 20 mg po (dose initiale) répétée régulièrement (aux quatre heures) avec l’addition, pour les percées douloureuses sur demande de morphine 10 mg po ou d’un placébo im; soit un placébo oral administré avec la même régularité (aux quatre heures) avec l’addition pour les percées douloureuses de placébo po et morphine 5–10 mg im. Subsequemment à chaque demande supplémentaires pour des percées douloureuses, la dose régulière suivante est augmentée de 5 mg (ou d’un volume équivalent de placébo) jusqu’à un maximum de 40 mg po aux quatres heures. Les scores d’évaluation moyens sont plus bas pour les deux premiers jours postopératoires pour le groupe qui regoit de la morphine régulièrement (P < 0,05). Moins de patients reçoivent de la morphine pour des percées douloureuses pendant ces deux jours dans le groupe morphine po. L’incidence des nausées et vomissements et de bradypnée est la même dans les deux groupes. La morphine administrée po régulièrement coûte peu et devrait être comparée aux autres méthodes d’administration.

Drug concentration monitoring : an approach to rational use

ConclusionDrug concentration monitoring should currently be considered only as a tool to supplement clinical assessment of patient response. Consideration of appropriate drug selection, dosage and clinical monitoring of response is the most crucial component of patient therapy. Confirmation is required of the benefits of drug concentration monitoring in influencing patient outcome. Similarly, further research into methods of measuring drug concentrations at receptor sites, and the correlation of such concentration with outcome, would be a valuable addition to clinical assessment in adjusting drug therapy to achieve desirable patient outcomes. Until such data are available, only selective use of drug concentration monitoring is warranted in the appropriate clinical care of patients and to prevent inappropriate use of healthcare resources.