This program will take 4-5 hours to complete, but is divided into a number of separate modules. The modules use an online presentation platform, and you will need a modern browser (e.g., Firefox 7+, Chrome 14+, Safari, Internet Explorer 9+) on a Windows PC or Mac. Your computer will need broadband internet access.

This program uses elements from the free online course; Understanding Evidence-Based Healthcare: A Foundation for Action – Course for Physicians, that is developed and maintained by the US Cochrane Center at the Johns Hopkins Bloomberg School of Public Health. Special acknowledgement must go to the Center who gave permission for their course to be used. You should feel free to complete the entire Cochrane Center course if you want more detailed teaching in evidence-based medicine.

The GP Synergy EBM Online Course can be found here: http://tiny.cc/ebm4gp

I welcome any comments that will help improve this teaching resource.

Abstract

Background

Medical educators at GP Synergy commenced a monthly evidence-based journal club as professional development activity in March 2011. Its goal was twofold: (i) to assist medical educators become aware of findings in the literature for both clinical medicine and medical education, and (ii) to have greater familiarity with the practice of evidence-based healthcare and to improve skills in critical evaluation of research.

Learning objectives

• learn how to facilitate an evidence-based journal club
• describe possible journal club formats
• able to briefly present and critically appraise a research paper
• develop journal clubs as an educational activity

Link: http://dx.doi.org/10.1056/NEJMoa0905561

Published: 17 September 2009

Evidence cookie says...

Dabigatran (Pradaxa) is non-inferior to warfarin for the prevention of strokes or systemic embolism, in non-valvular atrial fibrillation.  Its effectiveness and safety has not been demonstrated in patients with severe renal impairment or active liver disease (excluded). The benefits (↓ major bleeding and ↓ stroke) from dabigatran should be balanced against the harms (↑ myocardial infarction and ↑ gastrointestinal bleeding). The study design may have biased results favourably towards dabigatran. Note: dabigatran is not currently funded by the PBS for this indication.

Article details:

Study design:

multinational open label randomised controlled trial

Study aim:

To evaluate whether dabigatran (Pradaxa) is non-inferior to warfarin for the prevention of stroke or systemic embolism in patients with atrial fibrillation.

Study conclusion:

In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. ^[1]

Critical appraisal:

Methodology (PICO):

Note: the appraisal of this study was from the article ^[1], and also from a previous article describing the design fo the RE-LY trial ^[2].

Participants: who was studied?

• 18,113 patients
• enrolled between December 2005 and December 2007
• 951 clinical centres in 44 countries
• inclusion criteria:
  • ECG documented atrial fibrillation (AF), and
  • risk factor for stroke, and
  • age > 18 years at entry, and
  • written, informed consent
• exclusion criteria:
  • heart valve disorders
  • severe disabling stroke within previous 6 months, or any stroke within the previous 14 days
  • conditions associated with increased risk of bleeding
  • contraindication to warfarin treatment
  • reversible cause of atrial fibrillation
  • severe renal impairment (estimated creatinine clearance ≤ 30 mL/min)
  • active liver disease (persistent ALT, AST, alkaline phosphatase > 2 x ULN, or active viral hepatitis)
  • anaemia (Hb < 100g/L) or thrombocytopaenia (platelet < 100 x 10⁹/L)
  • patients considered unreliable by the investigator or have a life expectancy less than the expected duration of the trial because of concomitant disease
• participant characteristics:
  • mean age ~ 71 years, SD 8.7 years
  • mean weight ~ 83 kg
  • mean BP ~ 131/77
  • gender: 63.6% male
  • ~ one third of the participants had persistent AF, paroxysmal AF and permanent AF
  • ~ 20% with a previous stroke or TIA
  • ~ half were on long-term warfarin at baseline (prior to randomisation)
  • median duration of follow up was 2.0 years

Intervention: what was the exposure?

dabigatran 110 mg group:

• dabigatran capsules 110 mg twice daily (110 and 150 mg capsule groups were blinded to the dose)
• follow up visits at 14 days after randomisation, then 1 month, 3 months, and 3 monthly for the first year, and then every 4 months until study end

dabigatran 150 mg group:

• dabigatran capsules 150 mg twice daily (110 and 150 mg capsule groups were blinded to the dose)
• follow up schedule as above

Comparator: what was the control/alternative?

• warfarin (administered in an unblinded fashion)
• dose adjusted locally to an INR of 2.0 to 3.0
• INR measured at least monthly
• follow up visits otherwise as above
• the mean percentage of the study period during which the INR was within the therapeutic range was 64%

Outcomes: what was measured?

primary outcomes:

• study outcome: stroke or systemic embolism
• safety outcome: major haemorrhage

secondary outcomes:

• stroke
• systemic embolism
• death

Are the trial results valid?

Internal validity: Wikipedia

Was the assignment of patients to treatment randomised?

Yes.

• the patients were randomised by a central randomisation service

Were the groups similar at the start of the trial?

Yes.

• the patient characteristics were very similar between all three participant groups

Aside from the allocated treatment, were groups treated equally?

No, and unclear.

• the group randomised to warfarin had their INR locally monitored and doses adjusted; the dabigatran groups received no similar treatment
• it is unclear whether the open labelled nature in the treatment assignment between dabigatran and warfarin would have affected the follow up visits

Were all patients who entered the trial accounted for?

Yes.

• only 20 patients were lost to follow up (99.9% completed)
• analyses were performed by intention to treat principles

Were measures objective or were the patients and clinicians kept blind to which treatment was received?

Unclear.

• neither the patients nor clinicians were blinded to the allocation of dabigatran and warfarin
• given that this was a trial for a potential successor to warfarin, it is possible that there may have been an observer-expectancy effect (the clinician’s cognitive biases causes them to unconsciously influence the participants) and/or the Rosenthal effect (the greater expectation placed on the dabigatran group led to them performing better)
• it should be noted that the mean duration of the study period where the INR was not in the target range was over a third

What were the results?

Primary outcome

stroke or systemic embolism:

• dabigatran 110 mg group vs warfarin:
  • non-inferior to warfarin (P < 0.001)
  • relative risk: 0.91 (95% CI 0.74 to 1.11), P = 0.34
  • interpretation: no statistically significant difference was found between dabigatran 110 mg bd and warfarin for prevention of stroke and systemic emboli
• dabigatran 150 mg group vs warfarin:
  • non-inferior to warfarin
  • relative risk: 0.66 (95% CI 0.53 to 0.82), P < 0.001
  • interpretation: dabigatran 150 mg bd was associated with a 34% lower risk of stroke or systemic embolism (likely real value between 18% to 47%)

major bleeding:

• dabigatran 110 mg vs warfarin:
  • relative risk: 0.80 (95% CI 0.69 to 0.93), P = 0.003
  • interpretation: dabigatran 110 mg bd was associated with 20% fewer major bleeds compared to the warfarin group but the likely real value is in a relatively wide range (7% to 31%)
• dabigatran 150 mg vs warfarin:
  • relative risk: 0.93 (95% CI 0.81 to 1.07), P = 0.31
  • interpretation: there was no statistical significance in the rates of major bleeding between dabigatran 150 mg bd and warfarin

Other outcomes:

dabigatran as compared to warfarin:

• lower relative risk of haemorrhagic stroke
  • dabigatran 110 mg group: RR = 0.31 (0.17 to 0.56), P < 0.001
  • dabigatran 150 mg group: RR = 0.26 (0.14 to 0.49), P < 0.001
• higher relative risk of myocardial infarction
  • dabigatran 110 mg group: RR = 1.35 (0.98 to 1.87), P < 0.07
  • dabigatran 150 mg group: RR = 1.38 (1.00 to 1.91), P < 0.048
• no statistical significant difference in all cause mortality
• higher relative risk of gastrointestinal bleeding
  • dabigatran 110 mg group: RR = 1.10 (0.86 to 1.41), P < 0.43
  • dabigatran 150 mg group: RR = 1.50 (1.19 to 1.89), P < 0.001

Will the results help me care for my patient?

External validity: Wikipedia

Are the participants different to my patient?

• the participants in this study were older and had risks for stroke
• the exclusion criteria should be noted: there were no patients with valvular disease, severe renal impairment, persistent LFT dysfunction, or considered “unreliable” by the investigators

Is the treatment feasible?

• dabigatran is simpler to take and manage than warfarin in the community
• however, dabigatran is not funded (at the time of this article) by the PBS for the prevention of systemic embolism in patients with atrial fibrillation

Were all the clinically important outcomes considered?

Yes.

• the primary outcomes are those of most concern
• it should be noted that economic analyses were not a feature of this study

Are the treatment benefits worth the potential harms/costs?

Unclear.

• dabigatran 110 mg bd was associated with fewer bleeding complications than warfarin and non-inferior for strokes and systemic embolism
• dabigatran 150 mg bd was associated with superiority for strokes and systemic embolism and had a similar bleeding complication rate
• however, dabigatran was associated with a higher risk of myocardial and gastrointestinal bleeding and no benefit to all cause mortality

Study weaknesses (summary)

• a major weakness is that the study was open label, with regards to dabigatran and warfarin allocation
  • it is conceivable biases may have occurred that resulted in the dabigatran groups receiving better care
    • on average, INR was not within the target range over a third of the time; this was in a group where half were experienced in taking long term warfarin, and where “unreliable” participants were excluded
    • the rate of major bleeding with warfarin was higher than in other studies
  • biases in the design of the study are likely to benefit the dabigatran groups as compared to warfarin
  • note: it should be recognised that a double-blinded study would have been very difficult to perform as it would involve sham INR management
• little comment was made of the substantially higher discontinuation rate of dabigatran compared to warfarin (relative risk: 1.28)

Study strengths (summary)

• this was a very large trial over many centres and countries
• the statistical analyses were well designed and non-inferiority when compared to warfarin for strokes and systemic embolism seems well demonstrated

Biases and conflicts of interests

• This was a industry supported study.  It was funded by a grant from Boehringer Ingelheim, the manufacturer of dabigatran.
• All the main authors have received various fees and grants from Boehringer Ingelheim.
• The article describes results in a manner that minimises some of the adverse associations:
  • Major bleeding was characterised as the “primary safety outcome” in the section on “Outcomes” (p 1141) ^[1] but the relative risks of dabigatran compared to warfarin is not reported in the section on “Primary Outcome” (p 1142).  Rather, the relative risks of haemorrhagic stroke is given instead; this gives a misleading impression that dabigatran has a greater benefit to major bleeding than actually found.
  • There is little discussion on the higher discontinuation rate in the groups taking dabigatran compared to warfarin.
  • There is little discussion on the lack of benefit to all cause mortality.
  • The higher rates of myocardial infarction and gastrointestinal bleeding, though acknowledged, is not discussed in detail.

Clinical relevance to primary health care

Warfarin has been for decades the only oral anticoagulant available. It has clear benefits in patients with non-valvular atrial fibrillation; it reduces the risk of stroke by 68% ^[2].  However, management of warfarin involves substantial administrative time for the general practitioner in regular INR monitoring and dose titration.

Dabigatran (Pradaxa) is a direct thrombin (factor IIa) inhibitor ^[3] and is currently funded by the PBS on authority for prevention of venous thromboembolism in a patient undergoing total hip replacement or total knee replacement ^[4].  It has recently gained attention from the Pharmaceutical Benefits Advisory Committee’s (PBAC) positive recommendation for the authority to be extended to including the “prevention of stroke or systemic embolism in patients with non-valvular atrial fibrillation who are at moderate to high risk” ^[5].  Boehringer Ingelheim as been promoting dabigatran for this indication heavily.

This large study demonstrates that dabigatran 110 mg twice daily, or 150 mg twice daily is non-inferior to warfarin, for the prevention of stroke or systemic embolism.

The other potential (and advertised) benefits of dabigatran should be taken cautiously.  The lower dose of dabigatran was associated with less major bleeding and the higher dose was associated with lower risk of stroke or systemic embolism.  However, dabigatran was also associated with a higher risk of myocardial infarction and a higher risk of gastrointestinal bleeding.  It was associated with higher rates of discontinuation compared to warfarin.  There was no statistically significant effect on all cause mortality.  Potential study biases are likely to favour dabigatran over warfarin.

For the Australian general practitioner working in primary care, dabigatran appears to be an alternative to warfarin for the prevention of strokes in patients with non-valvular atrial fibrillation.

References

1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139-1151
2. Ezekowitz MD, Connolly S, Parekh A, et al. Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J 2009; 157: 805-10
3. Pradaxa.  MIMS Online Retrieved 18 June 2011.
4. Dabigatran etexilate. PBS Australian Government Website Retrieved 18 June 2011. http://pbs.gov.au/medicine/item/9319L-9323Q
5. March 2011 PBAC Outcomes – Positive Recommendations. PBS Australian Government Website Retrieved 18 June 2011. http://pbs.gov.au/info/industry/listing/elements/pbac-meetings/pbac-outcomes/2011-03/positive-recommendations

Link: http://dx.doi.org/10.3201/eid1610.100399

Published: October 2010

Evidence cookie says...

There may be an association between type 2 diabetes and malaria infection.  The evidence is low in quality and unreliable. Nevertheless, this finding reinforces current travel advice for travellers to malaria endemic regions (mosquito avoidance, protective clothing, chemoprophylaxis).

Article details:

Study design:

Study aim:

Study aim was not clearly stated, however implied it attempted to define “risk factors” for type 2 diabetes and hypertension.

Study conclusion:

This study provides evidence for increased risk for P. falciparum infection in patients with type 2 diabetes mellitus.

Critical appraisal:

Methodology:

Participants: who was studied?

• Total 1466 participants
• Patients with type 2 diabetes (n-495) and hypertension (n- 451) between August 2007- June 2008 in a teaching hospital in Ghana.
• Control group consisted of recruited community members, patient relatives or friends (n= 222); outpatient department patients (n= 150) and staff members (n= 148)

Outcomes: what was measured?

• History of fever or recent infection
• Microscopic blood film examination
• PCR for malarial parasites was performed
• secondary objectives: clinical and biochemical parameters

• participants were assessed with medical history, social history, physical examination, blood and urinary analysis.
• blood was tested for fasting plasma glucose, haemoglobin, malarial parasites
• statistics: comparisons between groups done using Mann-Whitney U, Chi squared and Fisher exact tests → odds ratios and confidence intervals were determined
• multivariate analysis was performed for glucose concentrations

Are the trial results valid?

Internal validity: Wikipedia

Was the defined representative sample of patients assembled at a common point in the course of their disease?

Unclear.

• the definitions used to define diabetes included being medicated with oral hypoglycaemics
• there was no indication of compliance with oral medications, stage of disease or length of diagnosis of diabetes

Were they representative?

• the population appears to be representative of the population in Ghana, but is not representative of the Australian community which is culturally heterogeneous, and with different prevalence of both diabetes and malaria

Were the groups similar at the start of the trial?

No.

• participants with type 2 diabetes were significantly more likely to have been:
  • older (54.7 vs 47.1 years)
  • illiterate (45.8 vs 26.1%)
  • having no formal education (35.7 vs 16.5%)
  • living in crowded conditions (26.7 vs 15.3%)
  • unemployed (36.9 vs 17.5%)

Was patient follow up sufficiently long and complete?

Unclear.

• there was no information provided about the follow up or subsequent treatment outcomes for those with malaria and diabetes
• this study does not shed light on whether the apparent association with asymptomatic carriage of malarial parasites is clinically significant and led/leads to malaria

If subgroups with different prognoses are identified, did adjustment for important prognostic factors take place?

Yes.

• subgroup analysis included a multivariate model examining incremental increases in blood glucose concentration versus risk of malaria
• it concluded that each mmol/L increase in blood glucose resulted in a 5% increased risk for P. falciparum infection, with a significant threshold reached at 8.6mmol/L

What were the results?

Outcome

• overall 0.9% of participants had malaria parasites seend on microscopy where as 14.1% were positive by PCR analysis
• statistically significant adjusted odds ratio (OR) was calculated between Type 2 diabetes group versus control group:
  • OR = 1.68, 95% CI 1.06-2.65

Will the results help me care for my patient?

External validity: Wikipedia

Are the participants different to my patient?

• homogeneous population in Ghana does not have broader applicability to Australian population (e.g., genetic factors may play a role in susceptibility to malaria; G6PD deficiency)
• this study was done in a country where malaria is endemic, in a population with constant exposure presumably some degree of baseline immunity
  • this may account for why those “infected” with malarial parasites were asymptomatic and afebrile
  • this may not be the case in the Australian population travelling to a malaria endemic country

Will this evidence make a clinically important impact on my conclusions about what to offer to tell my patients?

• this study describes an interesting observation: that people with Type 2 diabetes have an increased risk of malaria
• this may be of interest to diabetic travellers to a malaria endemic region, and reinforces the need for mosquito avoidance, mosquito repellent, protective clothing, and malaria prophylaxis

Study weaknesses (summary)

• screening in asymptomatic population may not reflect clinically significant infection
• there was a very low rate of positive malaria microscopiy of 0.9% overall, reflecting the low pre test probability in an asymptomatic population
• use of PCR to diagnose malaria is not the recommended diagnostic test, and may be overly sensitive in detection of malarial parasites.
• PCR may detect non viable malarial parasites, and may not reflect active disease
• there were substantial differences between the cases and their controls

Study strengths (summary)

• recruitment of cases and controls and the numbers achieved in the study considering the setting

Biases and conflicts of interests

• the study was supported by a grant from HemoCue, a manufacturer of diagnostic point of care devices

Clinical relevance to primary health care

This association between type 2 diabetes and Plasmodium falciparum infection in this study is interesting but hardly definitive.  The group with type 2 diabetes were substantially different to the control group without diabetes and many of these demographic factors are conceivably risk factors for malaria (older and greater socioeconomic disadvantage).  Causative conclusions cannot be made.

Nevertheless, the finding is of relevance to diabetic travellers to a malaria endemic region.  It reinforces current travel advice for mosquito avoidance, protective clothing and chemoprophylaxis.

References

1. Danquah I, Bedu-Addo G, Mockenhaupt F. Type 2 diabetes mellitus and increased risk for malaria infection. Emerg Inf Dis 2010; 16 (1): 1601-1604

Editor: Michael Tam

Link: http://dx.doi.org/10.1016/S0140-6736(10)62145-9

Published: 19 February 2011

Evidence cookie says...

Children with mild persistent asthma should be treated with regular inhaled corticosteroids.  Treatment with salbutamol (Ventolin) alone significantly increases the risk of exacerbations. Inhaled beclomethasone (Qvar) used as rescue therapy with salbutamol is likely better than salbutamol alone, for children with mild persistent asthma who do not take regular inhaled corticosteroids. Note: the study is relatively underpowered.

Article details:

Study design:

prospective, double-blind, randomised controlled trial

Study aim:

to assess the effectiveness of an inhaled corticosteroid, beclomethasone dipropionate (Qvar) as rescue treatment in children with mild persistent asthma

Study conclusion:

Children with mild persistent asthma should not be treated with rescue albuterol (Australia: salbutamol, Ventolin) alone and the most effective treatment to prevent exacerbations is daily inhaled corticosteroids (ICS). ICS as rescue medication with salbutamol might be an effective step-down strategy for children with well controlled, mild asthma because it is more effective at reducing exacerbations than is use of rescue salbutamol alone. Use of daily ICS treatment and related side-effects such as growth impairment can therefore be avoided. ^[1]

Critical appraisal:

Methodology (PICO):

Participants: who was studied?

• 288 children and adolescents:
  • 6 – 18 years
  • from five clinical centres in the USA
• January 2007 – May 2009
• history of mild persistent asthma during the previous 2 years, defined as:
  • on average, more than 2 days per week with symptoms (e.g., wheezing);
  • more than 2 days a week on which they had to use salbutamol to control symptoms;
  • more than two awakenings at night per month when not using controller medication; or
  • if they had to use daily controller treatment to keep their disorder well controlled
• qualified for interruption or discontinuation of controller treatment because their illness was well controlled (as defined in US National Asthma Education and Prevention Program asthma care guidelines)
• inclusion criteria:
  • naive to controller treatment;
  • history of one to two exacerbations in the previous year;
  • treated for the previous 8 weeks with a monotherapy other than inhaled corticosteroids; or
  • illness was controlled for the previous 8 weeks on low-dose corticosteroids as monotherapy (≤160 μg daily with a beclomethasone equivalent)
• exclusion criteria:
  • prebronchodilator FEV1 < 60% predicted at the first visit
  • admitted to hospital for asthma in the previous year
  • had any asthma exacerbation in the previous 3 months or more than two in the previous year
  • history of life-threatening asthma exacerbations that required intubation or mechanical ventilation, or that resulted in a hypoxic seizure
• Participants were included in the 44-week treatment phase only if their disease remained well controlled and they did not have any exacerbations during an initial 4-week run-in period

Intervention: what was the exposure?

• Combined group:
  • preventer = 1 puff (40 μg) twice daily beclomethasone
  • reliever = 2 puffs of beclomethasone (80 μg) plus salbutamol (180 μg) as needed
• Rescue ICS group:
  • preventer = twice daily placebo inhaler
  • reliever = 2 puffs of beclomethasone (80 μg) plus salbutamol (180 μg) as needed
• Daily ICS group:
  • preventer = 1 puff (40 μg) twice daily beclomethasone
  • reliever = 2 puffs of placebo plus salbutamol (180 μg) as neded

Comparator: what was the control/alternative?

• Placebo group:
  • preventer = twice daily placebo inhaler
  • reliever = 2 puffs of placebo plus salbutamol (180 μg) as needed

Outcomes: what was measured?

Primary outcome:

• the time to first exacerbation that required treatment with prednisone

Secondary outcomes:

• spirometry FEV1
• fractional exhaled nitric oxide (FENO)
• symptom diaries and control and quality of life questionnaires
• linear growth

Are the trial results valid?

Internal validity: Wikipedia

Were there sufficient participants in the trial?

Unclear.

• The target sample size was 280 randomised participants (70 per treatment group)
  • 90% statistical power for a two-sided, 0.05 significance level test, allowing for 10% withdrawals
  • to detect a hazard ratio of 0.5 in the time to first exacerbation for each main effect in the two by two factorial design
• The trial had a drop-out rate higher than the 10% (54 out of 288 patients, or 18.75%, dropped out)
• The detected magnitude of treatment effects were smaller than the HR of 0.5.

Was the assignment of patients to treatment randomised?

Yes.

• The randomisation sequence was stratified according to clinical centre and age group (6–11 years and 12-18 years), in blocks of four.

Were the groups similar at the start of the trial?

Yes.

• There were only minor differences between participant groups at baseline (see Table 1 ^[1])

Aside from the allocated treatment, were groups treated equally?

Yes.

Were all patients who entered the trial accounted for?

Yes.

• intention to treat analysis

Were measures objective or were the patients and clinicians kept blind to which treatment was received?

Yes.

• Both clinicians and participants were blinded.

What were the results?

Primary outcome

• Compared with the placebo group, the hazard ratios for asthma exacerbations were significantly lower in the daily ICS group,  and the combined group, but the difference was not significant in the rescue ICS group:
• Combined group vs placebo group:
  • HR = 0.56 (95% CI 0.32-0.96), P = 0.033
  • Interpretation:
    • use of corticosteroids both regularly and in rescue treatment was significantly associated with fewer exacerbations
    • note: there are wide-confidence intervals, the actual magnitude of the effect is unclear
• Daily ICS group vs placebo group:
  • HR = 0.49 (95% CI 0.28-0.85), P = 0.011
• Rescue ICS group vs placebo:
  • HR = 0.62 (95% CI 0.37-1.05), P = 0.073
  • Interpretation:
    • use of corticosteroids in rescue treatment only was associated with fewer exacerbations
    • however, this was not a statistically significant effect

Other outcomes:

Linear growth:

• Combined and daily ICS groups vs placebo group:
  • -1.1 cm (SD 0.3), P < 0.0001
  • Interpretation: children on daily inhaled beclomethasone on average grew 1.1 cm less than children in the placebo group
• Rescue ICS group vs placebo group:
  • -0.3 cm (SD 0.2), P = 0.26
  • Interpretation: children on the rescue ICS group grew 0.3 cm less but this result was not statistically significant

Will the results help me care for my patient?

External validity: Wikipedia

Are the participants different to my patient?

• study included only children with well controlled, mild persistent asthma
• they were mainly older children (mean age ~ 11 years)
• care needs to be taken in translating these results to intermittent asthma or asthma of greater severity

Is the treatment feasible?

Yes.

• The treatments studied were combinations of standard asthma treatments currently in use.

Were all the clinically important outcomes considered?

• the study focused on time to first exacerbation, and not necessarily long-term improvement in asthma severity

Are the treatment benefits worth the potential harms/costs?

Probably.

• rescue beclomethasone (compared to salbutamol alone) was associated with reduced exacerbations in children with mild persistent asthma
• rescue beclomethasone (without daily ICS use) was not associated with reduced linear growth, unlike daily corticosteroid use
• the results are arguably clinically significant despite the low statistical power and the lack of a statistically significant result for rescue beclomethasone for the primary outcome

Study weaknesses (summary)

The power of the study was reduced due to a number of factors:

• unanticipated subadditive interaction between treatments required a major deviation from the planned analysis
• instead of a two by two factorial analysis, the authors compared the effects recorded in the individual active treatment groups with the effects recorded in the placebo group.
• because the study was powered on the basis of a factorial design, such change in analysis decreased the study’s power substantially
• the recorded effects of the two groups in which rescue beclomethasone was used were less than those assumed when the study was planned

Study strengths (summary)

• first study to examine the use of ICS as rescue with salbutamol in school children, an age at which exacerbations play a major part in asthma morbidity
• otherwise well designed randomised controlled trial

Biases and conflicts of interests

• various authors have received consulting fees, research grants and honoria from major pharmaceutical companies that produce ICS
• the results of this study potentially support use of ICS in an expanded setting

Clinical relevance to primary health care

This study supports the use of regular inhaled corticosteroids (ICS) for children with mild persistent asthma.

Even though this study was relatively underpowered, it clearly demonstrates the superiority of daily inhaled beclomethasone (Qvar) for the primary outcome (time to first exacerbation that required treatment with prednisone).  Regular inhaled corticosteroids should still be considered the mainstay of therapy.

However, many children and their parents will resist long-term ICS therapy for mild persistent asthma.  In this setting, it might be reasonable to suggest ICS with salbutamol (Ventolin) for rescue therapy.  It appears to be associated with fewer exacerbations (when compared to salbutamol rescue/reliever therapy alone).  With regards to use of this strategy as  step-down management, the data from this study is suggestive but hardly definitive.

This study does not support the use of ICS in addition to salbutamol as a reliever where a regular ICS is already used.

References

1. Martinez FD, Chinchilli VM, Morgan WJ, et al. Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial. Lancet 2011; 377: 650–57

Editor: Michael Tam

Link: http://dx.doi.org/10.1002/14651858.CD001364.pub3

Published: 16 February 2011

Evidence cookie says...

Zinc administered within 24 hours of the symptoms of a common cold is associated with favourable outcomes but with some side-effects.  ↓ cold symptom duration by ~ 1 day ↓ cold symptom severity (minimal) ↑ side-effects: bad taste (NNH = 7) and nausea (NNH = 12) It is premature to routinely recommend zinc therapy for the common cold. It is reasonable to direct patients seeking community remedies towards zinc rather than other common treatments (echinacea, vitamin C). Note: there are limitations to the evidence. See below for more details.

Article details:

Study design:

systematic review of randomised controlled trials

Study aim:

to assess the effect of zinc on common cold symptoms

Study conclusion:

Zinc administered within 24 hours of onset of symptoms reduces the duration and severity of the common cold in health people. When supplemented for at least five months, it reduces cold incidence, school absenteeism and prescription of antibiotics in children. There is potential for zinc lozenges to produce side effects. In view of this and the differences in study populations, dosages, formulations and duration of treatment, it is difficult to make firm recommendations about the dose, formulation and duration that should be used ^[1].

Critical appraisal:

Are the trial results valid?

Internal validity: Wikipedia

Is it unlikely that important, relevant studies were missed?

Yes.

Extensive and detailed electronic searches performed. This systematic review builds on older versions of the same review with evidence from newer studies.

Were the criteria used to select articles for inclusion appropriate?

Yes.

• double-blind, placebo-controlled randomised controlled trials
• all participants in such trials
• therapeutic trials:
  • intervention commenced within three days of participants developing common cold symptoms
  • 1.5 to 2 hourly treatments with a zinc or placebo lozenge during waking hours (more than 6 hours a day)
  • at least 5 or more consecutive days
• prophylactic trials:
  • commenced and continued throughout cold season for at least five months
  • all zinc formulations considered

Were the included studies sufficiently valid for the type of question asked?

Yes.

• the review authors systematically and rigorously assessed the included studies for their methodological quality
• the majority were at low risk of bias on all items (adequate sequence generation? allocation concealment? blinding? incomplete outcome data addressed? free from selective reporting? free of other bias?)
• some studies were considered at high risk of bias on a few items

Were the results similar from study to study?

No / depended on outcome measure.

• there was large heterogeneity between the included trials
• this means that there is substantial uncertainty to the reliability of the pooled result
• I² statistic (the proportion that the differences in results are due to differences between the studies) for outcome measures:
  • duration of cold symptoms: 93%
  • severity of cold symptoms: 75%
  • incidence of common cold: 88%
  • any adverse event: 51%

What were the results?

Primary outcome

Duration of cold symptoms (zinc intervention administered within 24 hours of cold symptoms):

• placebo: mean duration of cold symptoms, 5.1 to 8.5 days
• zinc: standardised mean difference: -0.97 days (95% CI -1.56 to -0.38)
• interpretation: favourable result for zinc; on average the duration of symptoms was one day less, though the true value may conceivably lie anywhere from about 9 hours to 37 hours)

Severity of cold symptoms (score):

• placebo: mean severity of symptom score ranged from 0.4 to 5.61
• zinc: standardised mean difference: -0.39 (95% CI -0.77 to -0.02)
• interpretation: favourable results for zinc; though the heterogeneity (large range of mean symptom scores in the included studies) and very wide confidence intervals are problematic; nevertheless, the conceivable range of symptom improvement in the confidence interval ranges from no improvement to mild improvement
• note on symptom scoring:
  • 0 = no symptoms
  • 1 = mild symptoms
  • 2 = moderate symptoms
  • 3 = severe symptoms

Incidence of common cold (zinc treatment for over cold season for at least 5 months):

• placebo: 618 per 1000 person-time
• zinc: 382 per 1000 person-time (95% CI 354 to 431)
  • risk ratio (RR) = 0.64 (95% CI 0.47 – 0.88)
  • number needed to treat (NNT) = 4.2 (95% CI 3.8 – 5.3)
  • note: NNT calculated by Morsels of Evidence
  • interpretation: zinc therapy significantly decreased the incidence of the common cold

Other outcomes:

Any adverse events:

• placebo: 481 per 1000 person-time
• zinc: 562 per 1000 person-time (95% CI 252 to 898)
  • odds ratio (OR) = 1.59 (95% CI 0.97 – 2.58)
  • number needed to harm (NNH) = 12.3 (95% CI 2.4 to infinity)
  • note: NNH calculated by Morsels of Evidence
  • interpretation: zinc therapy was associated with more adverse events but the confidence interval was wide and the result was not statistically significant.  Nevertheless, it is likely that there is a real effect that is clinically significant but there is substantial uncertainty to the true value

Specific side-effects:

• bad taste:
  • suffered by 33.0% of the intervention group vs 18.6% of the placebo group
  • OR = 2.64 (CI 1.91 – 3.64)
  • NNH = 6.9 (CI 5.0 – 9.6)
• nausea:
  • suffered by 17.1% of the intervention group vs 8.9% of the placebo group
  • OR = 2.15 (CI 1.44 – 3.23)
  • NNH = 12.2 (CI 8.2 – 18.3)

Will the results help me care for my patient?

External validity: Wikipedia

Are the participants different to my patient?

• mixed group of adults and children
• subgroup analyses not possible due to limited number of participants
• no studies from low or middle income countries
• no studies in participants who may have a worse outcome with the common cold (chronic disease, immunodeficiency, asthma, etc.)

Is the treatment feasible?

Unclear.

• the therapy used in the zinc treatment group is possibly unrealistic in the primary health care setting (1.5 to 2 hourly zinc lozenges for at least 6 hours a day, for at least 5 days)
• the therapy used in the zinc prevention group is arguably infeasible in the primary health care setting (daily medication for almost half the year in otherwise healthy individuals to prevent an otherwise mild self-limiting infection)

Were all the clinically important outcomes considered?

• this study provided moderate level evidence for duration of cold symptoms, severity of cold symptoms, incidence of the common cold and adverse events
• a number of other important outcome measures were assessed but the level of evidence is low

Are the treatment benefits worth the potential harms/costs?

Unclear.

• zinc does appear to be associated with a clinically significant effect on the duration of a cold, reducing its length by on average a day
• even if the least favourable end of the confidence interval is true, it is still associated with a reduction of duration of approximately 9 hours, which is arguably meaningful
• zinc is associated with a statistically significant reduction in the severity of a cold, but the result is of questionable clinical significance
• zinc is associated with more side-effects with approximately 1 extra patient harmed for every 12 on zinc

Study weaknesses (summary)

• the weaknesses mostly relate to the limitations of the included studies:
  • substantial variations in study populations, the dosage, formulation of zinc, treatment duration
  • substantial heterogeneity between the results
• difficult to make any firm recommendations when applying the results to clinical populations

Study strengths (summary)

• rigorous systematic review
• detailed assessment of methodological quality of included trials

Biases and conflicts of interests

• nil declared and none seem obvious

Clinical relevance to primary health care

The common cold is one of the most common presentations to Australian general practice. Upper respiratory tract infections, the majority of which are colds, is the third most frequent problem managed; 5.8 cases per every 100 patient encounters ^[2]. There are no proven treatments for the common cold.

This well conducted systematic review demonstrates that zinc therapy is associated with favourable effects on the common cold.  Zinc therapy is associated with:

• reduced duration of cold symptoms
• reduced severity of symptoms
• reduced incidence of cold if used regularly throughout cold season

Zinc, however is associated with more side-effects. The reduction in cold symptom severity appears to be of minimal clinical significance. Moreover, it is questionable whether the intensity and frequency of the dosing schedule is realistic for patients suffering the cold in the primary health care setting. The substantial variability in study populations, dosage, formulation, treatment duration; and the large heterogeneity preclude any firm recommendation on who, when, and how to treat.

It is premature for Australian general practitioners to routinely recommend or prescribe zinc therapy for the treatment of the common cold for all patients. However, patients interested in trying over-the-counter remedies could be directed towards zinc, rather than other commonly used cold treatments with limited or inconsistent evidence (e.g., echinacea and vitamin C). Theses patients should be made aware of the dosing schedule used in the included studies (every 1.5 to 2 hourly, for at least 6 hours, for 5 days).

References

1. Singh M, Das RR. Zinc for the common cold. Cochrane Database of Systematic Reviews 2011, Issue 2. Art. No.: CD001364
2. Britt H, Miller GC, Charles J, et al. General practice activity in Australia 2006-07. Australian General Practice Statistics and Classification Centre, Australian Institute of Health and Welfare. 30 January 2008

Link: http://archinte.ama-assn.org/cgi/content/abstract/170/12/1024

Published: 28 June 2010

Evidence cookie says...

Statins were not associated with a benefit to all-cause mortality in a primary prevention setting. Although there is some ambiguity with the data, it is very unlikely that statins are of clinical benefit in patients with low and moderate absolute cardiovascular risk. Until more definitive evidence becomes available, statins in the primary prevention setting should be reserved for those patients who are at high risk according to the 2005 lipid management guidelines [2]

Article details:

Study design:

meta-analysis of randomised controlled trials

Study aim:

to reliably determine if statin therapy reduces all-cause mortality among intermediate to high-risk individuals without a history of cardiovascular disease

Study conclusion:

This literature-based meta-analysis did not find evidence for the benefit of statin therapy on all-cause mortality in a high-risk primary prevention set-up ^[1].

Critical appraisal:

Are the trial results valid?

Internal validity: Wikipedia

Is it unlikely that important, relevant studies were missed?

Yes.

• two major databases were searched (MEDLINE and the Cochrane Collaboration)
• bibliographies of retrieved studies were searched
• authors of further trials that included participants with cardiovascular disease at baseline, were asked for provide further information; to see if unpublished tabular information on the subset of participants without baseline cardiovascular disease was available

Were the criteria used to select articles for inclusion appropriate?

Yes.

Inclusion criteria were:

• randomised trials of statins vs placebo/control
• trials that collected information on all-cause mortality; and
• trials conducted among individuals without cardiovascular disease at baseline

Were the included studies sufficiently valid for the type of question asked?

Yes.

• the studies were all large randomised trials of statins vs placebo/control

Were the results similar from study to study?

Yes.

• there was only limited evidence of study heterogeneity in the correlation of statins on all-cause mortality
• I²=23%; (95% CI 0-61%), P = 0.23
• interpretation: only a mild (none to modest if considering the confidence interval) proportion of the variation of results is due to differences between the included studies; i.e., the studies were similar enough that it is valid to group the data together for analysis

What were the results?

Primary outcome

All-cause mortality:

• placebo/control group: 11.4 per 1000 person-years
• statin group: 10.7 per 1000 person-years
• Risk ratio (RR) for all-cause mortality associated with use of statins:
  • RR = 0.91 (95% CI 0.83 – 1.01)
  • interpretation: statin use was associated with a small relative risk reduction of all-cause mortality but this was not statistically significant
• Number needed to treat (NNT) (note: calculated by Morsels of Evidence):
  • treated with statin compared to placebo for 5 years to prevent one additional death:
  • NNT = 286 (95% CI 261 to infinity)
  • note: it should be reminded that the RR was not statistically significant so the 95% confidence interval for the real NNT includes infinity.

Other outcomes:

Relationship between lipid levels and all-cause mortality:

• no significant relationship was observed between the mean baseline levels of LDL-C and the relative reduction in all-cause mortality across studies (P = 0.97)

Will the results help me care for my patient?

External validity: Wikipedia

Are the participants different to my patient?

Study population:

• 65 229 subjects in predominantly Western populations
• no baseline cardiovascular disease
• some participants with type 2 diabetes mellitus
• mean age ranged from 51 to 75 years
• average baseline LDL-C was 3.6 mmol/L (138 mg/dL)
• relatively short mean follow up period, 3.7 years
• placebo/control group all-cause mortality rate:
  • 11.4 per 1000 person-years
  • 5.7% per 5-years
• it is not clear what the average absolute cardiovascular risk category these patients were in as it wasn’t a measured outcome
  • however, using the assumption that, (i) the majority of deaths are secondary to cardiovascular disease, and (ii) that at least half of those with cardiovascular disease would not have died, it can be inferred that that these patients had a moderate to high absolute 5-year risk of a cardiovascular event (> 10%)

Is the treatment feasible?

Yes.

• statin therapy in primary prevention is a potentially feasible treatment
• they are widely used for the treatment and prevention of cardiovascular disease both among individuals with established disease, and among high-risk healthy individuals
• it should be noted that in most situations, statins cannot be prescribed under the pharmaceutical benefits scheme (PBS) for primary prevention

Were all the clinically important outcomes considered?

No.

• the study does not measure the effects of statins on non-fatal cardiovascular outcomes

Are the treatment benefits worth the potential harms/costs?

Unclear, probably no.

• the benefits of statin therapy for all cause mortality in the primary prevention setting is possibly more modest than previously thought
• the population appears to be at high risk of death (5.7% risk over 5-years), but their absolutely cardiovascular risk can only be inferred (likely high)
• this study demonstrated a small, non-statistically significant benefit  to all-cause mortality
• even using results in the most favourable end of the confidence interval, the NNT with statin over placebo for 5-years is substantial (over 260)
• although no cost-effectiveness analysis was performed, it is very unlikely that statin therapy in primary prevention is cost-effective overall

Study weaknesses (summary)

• relatively short mean follow-up
• the study did not evaluate the effects of statins on cardiovascular mortality or non-fatal cardiovascular disease
• the study does not report the absolute cardiovascular risk of the study participants, and nor are there any results that divide the participants into groups according to baseline absolute cardiovascular risk
  • this would have improved the direct applicability of the results
• the lack of participant level data precludes any useful subgroup analyses
• authors attempted but were unable to obtain information from 4 published studies fulfilling the study criteria that would have contributed further information on approximately 3700 persons

Study strengths (summary)

• no material heterogeneity across the studies
• detailed protocol developed a priori, with thorough search of published and unpublished
• large number of participants
• authors obtained unpublished data from the authors of several original articles

Biases and conflicts of interests

• Ray KK (primary author) received honoraria for lectures and advisory boards from the majority of companies that market lipid-lowering agents
• various other authors received grants, fees, research support and honoraria from various pharmaceutical companies

Clinical relevance to primary health care

Statins are widely used for the treatment and prevention of cardiovascular disease, in individuals with established disease (secondary prevention), and in the primary prevention setting in individuals at an elevated risk of a cardiovascular event.

This study did not find statin therapy to be beneficial on all-cause mortality in a primary prevention setting, in a population without established cardiovascular disease but at an elevated risk of mortality (5.7% risk per 5-years). It is probable that any mortality benefits are likely to be more modest than previously perceived.

What do these results mean for Australian general practitioners?

• The grouped nature of these results, that the participants were not separated into 5-year absolute cardiovascular risk groups at baseline, and the necessary inferences on overall cardiovascular risk from the all-cause mortality rate; leads to increasing ambiguity in the validity of the findings when applied to patients at the highest cardiovascular risk.
• This study does not provide definitive evidence that overturns the current recommendation that individuals free from existing cardiovascular disease who nonetheless are at high risk of an event (i.e., 5-year absolute risk ≥ 15%, or, absolute risk 10-15% in family history of premature coronary heart disease or the metabolic syndrome) should have lipid-modifying therapy ^[2].

However, this study does support the notion that primary prevention of cardiovascular disease with statins in populations at moderate or low risk is of little or no benefit. Even if the number needed to treat (NNT) at the most favourable extent of the confidence interval is true, the average Australian GP will need to treat their entire patient base who are older than 50, who do not currently have established cardiovascular disease or other indications, with statins over 5-years to prevent a single death.

In the primary prevention setting, statins should be reserved for those patients who are at high risk according to the 2005 lipid management guidelines ^[2].

References

1. Ray KK, Seshasai SR, Erqou S, et al.  Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65 229 participants. Archives of Internal Medicine, 2010; 170(12): 1024-31
2. National Heart Foundation of Australia and the Cardiac Society of Australian and New Zealand. Position statement on lipid management – 2005. Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand, Elsevier Inc. 2005

Co-author: Michael Tam

Link: http://dx.doi.org/10.1038/ajg.2010.334

Published: 24 August 2010

Evidence cookie says...

Concurrent proton pump inhibitors (PPIs) may increase the risk of cardiovascular outcomes in patients taking clopidogrel. The results of this specific study are likely invalid due to methodological biases (see below for details). There is substantial uncertainty in the evidence base generally. GPs should be guided by a precautionary principle: it is reasonable to prescribe PPIs to those with clear indications new and ongoing therapy should be assessed from the perspective that PPIs might increase the risk of harm

Article details:

Study design:

retrospective cohort study

Study aim:

to investigate the association between the co-administration of a proton pump inhibitor (PPI) and clopidogrel (Plavix, Iscover), and the occurrence of cardiovascular (CV) and gastrointestinal (GI) events in a large cohort in the Netherlands

Study conclusion:

New clopidogrel users on PPIs are at an increased risk of cardiovascular and GI complications compared with those who are not using a PPI. The inferior cardiovascular profile of clopidogrel users on PPIs and the occurrence of channeling bias may be important factors underlying this observation ^[1].

Critical appraisal:

Methodology (PICO):

Participants: who was studied?

• 18,139 patients
  • data were collected from anonymised computerized databases of two Dutch health insurance companies
  • total pool of 4 million Dutch inhabitants (~ 25 % of the total population)
  • 1 January 2006 to 31 December 2007.
  • ≥ 18 years
  • ≥ 1 year of valid history available in the database
  • ≥ 1 prescription for clopidogrel
• PPI use:
  • ≥ 80% overlap between PPI and clopidogrel use
  • or, concurrent use of both medications within 7 days before or at the time of a possible event
• exclusions:
  • patients with documented use of clopidogrel in the 180 days before the index clopidogrel prescription date

Concurrent PPI and clopidogrel user group:

• 5,734 patients
• 58.5% male
• mean age: 68.6 years

Clopidogrel users without PPI group:

• 12,405 used clopidogrel without a PPI
• 66.9% male
• mean age: 66.1 years

Notable differences between groups:

• patients on concurrent PPIs were:
  • significantly older
  • had more comorbidities (including heart failure, history of unstable angina pectoris, chronic obstructive pulmonary disease and renal failure)
  • used more co-medications

Intervention: what was the exposure?

• clopidogrel, and
• PPI:
  • omeprazole (Losec, Acimax)
  • pantoprazole (Somac)
  • lansoprazole (Zoton)
  • rabeprazole (Pariet)
  • esomeprazole (Nexium)

Comparator: what was the control/alternative?

• clopidogrel

Outcomes: what was measured?

Primary outcome:

• composite of:
  • myocardial infarction
  • unstable angina pectoris
  • stroke
  • all-cause mortality
• during clopidogrel use or within 7 days of cessation

Secondary outcome:

• individual components of the primary outcome
• occurrence of peptic ulcer disease (PUD)
• during clopidogrel use or within 7 days of cessation

Are the trial results valid?

Internal validity: Wikipedia

Was the defined representative sample of patients assembled at a common point in the course of their disease?

Unclear.

• the number of subjects which formed the basis of the study was substantial; 4 million Dutch inhabitants
• however, as these were insured individuals (data through insurance company database), it is unclear whether these patients are representative of the overall population

Were the groups similar at the start of the trial?

No.

• there were substantial differences between the two groups
• the concurrent PPI and clopidogrel group were older and had more medical co-morbidities
• this is a serious threat to the internal validity of the study

Was patient follow up sufficiently long and complete?

N/A

Were outcome criteria either objective or applied in a blind fashion?

Yes.

• the composite outcome consisted of diagnoses that are objective made

If subgroups with different prognoses are identified, did adjustment for important prognostic factors take place?

Unclear, probably no.

• the authors provided results that were “adjusted for possible confounders” but did not explain which confounding factors
• it is highly probable that substantial residual confounding remains; the group receiving PPIs also were also at increased risk of PUD even with adjustment, contrary to data from randomised controlled trials
• this is another serious thread to internal validity

What were the results?

Primary outcome:

Composite outcome (myocardial infarction, unstable angina, stroke, all-cause mortality):

• PPI + clopidogrel group: 754 (13%)
• clopidogrel only group: 830 (7%)
• adjusted hazard ratio (HR), PPI + clopidogrel group vs clopidogrel-only group:
  • HR = 1.75 (95% CI 1.58-1.94)
  • interpretation: the PPI + clopidogrel group were at 75% higher risk of the primary outcome compared to the clopidogrel-only group
• mean time to the occurrence of cardiovascular event was 75 days

Other outcomes:

Complicated peptic ulcer disease, PPI + clopidogrel group vs clopidogrel-only group:

• HR = 4.76 (95% CI 1.18 – 19.17)

Will the results help me care for my patient?

External validity: Wikipedia

Are the participants different to my patient?

• older population; mean ages of 68.6 and 66.1 in the two groups studied
• roughly equal distribution between men and women
• approximately one third of patients had a history of myocardial infarction
• approximately one third of patients had a history of unstable angina pectoris
• the majority of patients were receiving: statins, β-blockers, ACE inhibitors, or aspirin, or a combination of these

Will this evidence make a clinically important impact on my conclusions about what to offer to tell my patients?

No.

• the evidence is too unreliable to be the basis of a change in management
• the risk, if any, of concurrent PPI in clopidogrel should be a reminder that PPIs should only be used if clinically indicated

Study weaknesses (summary)

• indication of what the authors term “channeling bias”; high likelihood that the concurrent PPI and clopidogrel group were less healthy
• the source database used did not contain information on important prognostic factors, e.g., smoking and obesity
  • the authors were unable to correct for these factors in their multivariate analysis
• it is probable that the magnitude of effect from the biases are substantially larger than studied effect (if it exists), invalidating the results

Study strengths (summary)

• first European cohort study investigating an association between concomitant use of clopidogrel and PPIs and the occurrence of cardiovascular events
• patients were censored after adverse events
• authors investigated the occurrence of GI events in this cohort, which was not done in the other similar studies
  • this gives an indication of the presence of unadjusted confounding
• large proportion (approximately 25%) of the Dutch population was included in the database

Biases and conflicts of interests

• van Boxel OS (primary author) was funded by an unrestricted grant from AstraZeneca (the manufacturer of omeprazole and esomeprazole)
• several other authors have served as consultants or received grants from various pharmaceutical companies including AstraZeneca
• the sponsors were not involved in the design, conduct, analysis, interpretation, review or approval of the study

Clinical relevance to primary health care

Clopidogrel (Plavix, Iscover) is widely used for the secondary prevention of cardiovascular disease in some settings (e.g., cerebrovascular disease, and myocardial infarction). To address the increased risk of gastrointestinal bleeding events in patients using clopidogrel, the American College of Cardiology recommends the use of prophylactic proton pump inhibitors (PPIs) in at-risk patients ^[2].

There is basic pharmacokinetic data that suggests that some PPIs decrease the actions of clopidogrel and several observational studies, including the described study, have demonstrated significant associations of harm.  However, in a recent trial, meta-analysis of randomised patients found no association of excess cardiovascular risk or overall mortality with concurrent PPI use ^[3]. The meta-analysis was limited by significant heterogeneity.

Australian general practitioners should consider the evidence base of increased cardiovascular risk from the use of PPIs in patients taking clopidogrel to be unclear. The nature of observational studies in general limits the causative statements that can be made. The results of this study in particular are probably invalid; there are indications that large confounding effects remain (even after adjustments, use of PPIs was still associated with almost a 5-fold increased risk of complicated peptic ulcer disease, completely contrary to the known empiric effects of PPIs and basic pathophysiology).

In the absence of definitive evidence, primary care physicians should be guided by a precautionary principle. It is reasonable to treat patients at high risk of gastrointestinal bleeding, or have other clear indications, with PPIs. The need for starting or ongoing PPIs should be assessed from the perspective that PPIs might increase the risk of cardiovascular outcomes ^[4].

References

1. van Boxel OS, van Oijen MGH, Hagenaars MP, et al. Cardiovascular and gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: results of a large Dutch cohort study.  Am J Gastroenterol 2010; 105: 2430–6
2. Bhatt DL , Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation 2008; 118: 1894–909.
3. Kwok CS, Loke YK. Meta-analysis: the effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel. Aliment Pharmacol Ther 2010; 31(8): 810–23
4. NPS Prescribing practice review 45: proton pump inhibitors: step-down to symptom control. National Prescribing Service Limited. 4 May 2009

Co-author: Michael Tam

Link: http://dx.doi.org/10.1111/j.1742-1241.2010.02352.x

Published: 16 June 2010

Evidence cookie says...

Chiropractic, specifically, high-velocity, short-lever thrusts of the upper spine with rotation is associated with numerous deaths. Most of the deaths were secondary to vascular accidents of the vertebrobasilar system. There is no good evidence for this therapy for any medical condition. General practitioners should advice their patients considering chiropractic therapy to avoid upper cervical manipulation.

Article details:

Study design:

systematic review of case studies

Study aim:

to summarise all cases in which chiropractic spinal manipulation was followed by death

Study conclusion:

Numerous deaths have occurred after chiropractic manipulations. The risks of this treatment by far outweigh its benefit. ^[1]

Critical appraisal:

Are the trial results valid?

Internal validity: Wikipedia

Is it unlikely that important, relevant studies were missed?

Yes.

• electronic searches of a number of databases
• bibliographies of articles searched
• several experts were contacted for further data

Were the criteria used to select articles for inclusion appropriate?

Yes.

• case reports included if they provided information on human patients who had died after receiving one or more treatments from a chiropractor

Were the included studies sufficiently valid for the type of question asked?

Yes.

• only qualitative exploration of the data was intended

Were the results similar from study to study?

N/A

What were the results?

Outcomes:

• 26 fatalities were published since 1934 (to September 2009)
• most of the victims were relatively young; 14 below the age of 40
• the type complication associated with death frequently related to a vascular accident leading to thrombosis and cerebral infarction
• the time between treatment and death ranged from 1 h to 58 days; in 10 cases, it was 1 day or less
• many other fatalities seem to have remain unpublished

Will the results help me care for my patient?

External validity: Wikipedia

Are the participants different to my patient?

• range of patients, many young receiving community chiropractic treatment

Is the treatment feasible?

N/A

Were all the clinically important outcomes considered?

• the cases looked specifically at death
• cerebrovascular accidents not resulting in death were not included in this systematic review
• it is probable that the systematic review substantially under-estimates the burden of death (due to unpublished reports) and serious adverse outcomes
• this limitation, however, strengthens rather than weakens the conclusion

Are the treatment benefits worth the potential harms/costs?

• chiropractic, specifically, high-velocity, short-lever thrusts of the upper spine with rotation is associated with numerous deaths
• there is no good evidence that it is effective therapy for any medical condition
• this particular form of therapy is not worth the potential harms

Study weaknesses (summary)

• published case studies likely grossly under-represent the true number of cases
• review of deaths following chiropractic only; other serious outcomes not resulting in death not reviewed
• study methodology cannot be used to calculate estimates of incidence
• although causation is implicated, it cannot be assumed by this review

Study strengths (summary)

• provides a summary of all the case reports in the medical literature
• the limitation of evidence is likely to be a gross under-estimate; the study conclusion is unlikely to be incorrect

Biases and conflicts of interests

• nil declared and none seem obvious

Clinical relevance to primary health care

Chiropractic treatment of the upper cervical spine, specifically, high-velocity, short-lever thrusts with rotation has been reportedly associated with vascular injury and occasionally death.

This systematic review of all published case studies of death following chiropractic, confirms this association. Almost all of the deaths resulted from a vascular accident of the vertebrobasilar system.  This study was not designed to estimate an incidence figure.

Given that there is no good evidence that chiropractic treatment of the upper cervical spine is effective therapy for any condition, the potential harm far outweighs the benefit.  General practitioners should advice their patients considering chiropractic therapy to avoid upper cervical manipulation.

References

1. Ernst E. Deaths after chiropractic: a review of published cases. Int J Clin Pract, July 2010; 64(8): 1162-5

Link: http://dx.doi.org/10.1136/bmj.d472

Published: 10 February 2011

Evidence cookie says...

The excess risk of childhood cancer from diagnostic imaging in utero and early infancy remains unclear. This study was underpowered for the results to be meaningful. Nevertheless, the results suggest that in utero ultrasound is unlikely to be associated with childhood cancer. Following a precautionary principle, the usual practice of avoiding diagnostic radiation in pregnant women and young children should continue.

Article details:

Study design:

analysis of data from a large multi-centre, case-control study

Study aim:

to examine the association between risk of childhood cancer and exposure to diagnostic radiation and ultrasound scans in utero and in early infancy (age 0-100 days)

Study conclusion:

Although the results for lymphoma need to be replicated, all of the findings indicate possible risks of cancer from radiation at doses lower than those associated with commonly used procedures such as computer tomography scans, suggesting the need for cautious use of diagnostic radiation imaging procedures to the abdomen/pelvis of the mother during pregnancy and in children at very young ages. ^[1]

Critical appraisal:

Methodology (PICO):

Participants: who was studied?

• review of data from the United Kingdom Childhood Cancer Study (UKCCS)
• children aged 14 years or younger in England, Wales and Scotland were eligible
• however, data not abstracted for participants from Scotland, Avon, Dorset and Sommerset so none of these children were included in analysis
• exclusions:
  • Down’s syndrome
  • radiotherapy
• cases:
  • diagnosed between 1992 and 1996 (year of birth 1976 to 1996) with a confirmed malignancy
  • 3133 were interviewed, 87% of eligible cases
  • 2690 had data abstracted from medical records, 60.1% of eligible cases
  • 2656 (60.0%) were included in analysis
• controls:
  • two controls selected from the same population register and matched on sex and date of birth (within one month)
  • if one eligible control refused interview, another eligible control was chosen until two controls participated per case
  • 7619 were interviewed, 64% of eligible controls
  • 4858 had data abstracted from medical records, 40.6% of eligible controls
  • 4854 (40.5%) were included in analysis
• baseline characteristics:
  • mean age: 5.6 years
  • 83.7% had birthweight between 2500 and 4000 g
  • mean maternal age: 27.8 years
  • notably: 1.3% of cases vs 0.1% of the control had Down’s syndrome (not included in analyses)

Intervention: what was the exposure?

• radiation from medical diagnostic procedures while mother pregnant
• ultrasound while mother pregnant
• radiation from medical diagnostic procedures on infant (aged 1-100 days)
• ultrasonographic procedures on infant (aged 1-100 days)

Comparator: what was the control/alternative?

N/A: see details on the control group in participants.

Outcomes: what was measured?

• odds ratios and 95% confidence intervals (CI) to examine the association between cancer and exposure to diagnostic radiation
• odds ratios and 95% CI to examine association between cancer and ultrasound
• final models adjusted for sex of child, age of diagnosis, study region, maternal age and birth weight
• Down’s syndrome excluded from the dataset; association with leukaemia and strong confounding in the dataset

Are the trial results valid?

Internal validity: Wikipedia

Was the defined representative sample of patients assembled at a common point in the course of their disease?

Unclear.

• controls were matched on sex and date of birth (within 1 month) from the same population register
• there were a substantial number of controls (36%) who refused to participate in the study, compared to 13% of cases → there may be issues with selection bias in the controls

Was patient follow up sufficiently long and complete?

N/A.

• cases chosen were those already with the outcome (paediatric cancer) and children up to the age of 14 years were included in the study

Were outcome criteria either objective or applied in a blind fashion?

Yes.

• diagnosis of cancer is objective
• the history of exposure to diagnostic imaging and ultrasound was from a review of medical records which is also objective

If subgroups with different prognoses are identified, did adjustment for important prognostic factors take place?

Yes.

• analyses were adjusted for sex of child, age of diagnosis, study region, maternal age and birth weight
• it is possible that other unidentified confounding exists

What were the results?

Outcomes:

Odds ratio (OR) (95% confidence interval) with in utero exposure:

• all cancers:
  • radiation exposure, OR = 1.14 (95% CI, 0.90 – 1.45)
  • ultrasound exposure, OR = 0.93 (95% CI, 0.79 – 1.09)
  • interpretation: no statistically significant result is detected

Odds ratio (95% confidence interval) in early infancy (0-100 days) exposure:

• all cancers:
  • radiation exposure, OR = 1.19 (95% CI, 0.82 – 1.74)
  • ultrasound exposure, OR = 1.55 (95% CI, 0.89 – 2.70)
  • interpretation: no statistically significant result is detected

Will the results help me care for my patient?

External validity: Wikipedia

Are the participants different to my patient?

• the children in the study were from the United Kingdom
• the study was performed in the 1990s; radiation doses from diagnostic imaging has decreased since that period
• the majority of radiation exposure in utero was in the form of pelvic, chest or abdominal x-ray (88% of procedures)
• only one mother received CT
• the majority of radiation exposure in early infancy was chest x-ray (72% of procedures)

Will this evidence make a clinically important impact on my conclusions about what to offer to tell my patients?

• the evidence is ambiguous as the study lacks sufficient power to make a meaningful interpretation

Study weaknesses (summary)

• the main weaknesses of this study is the lack of power
• effectively all important outcomes have wide confidence intervals that are not statistically significant
• there is a significant possibility of selection bias in the controls
• the conclusions made by the study authors demonstrate biases in interpretation:
  • “Exposure to diagnostic radiography in early infancy was associated with small, non-significant excess risks for all cancers and leukaemia, as well as increased risk of lymphoma on the basis of small numbers. We found no evidence of increased risk of childhood cancer with in utero exposure to ultrasound scans.” (pg. 5, “Discussion”) ^[1]
  • the increased risk of lymphoma is of questionable significance as it was on the basis of only 7 cases
  • moreover, the overall results are questionable: although an OR demonstrating a non-significant excess risk of 1.19 for early infancy radiation exposure, there was a greater magnitude excess risk with an OR of 1.55 for early infancy ultrasound
  • it is probable that random variation, or effects from unadjusted confounding factors are larger than any real effect if it exists

Study strengths (summary)

• use of medical records for assessment of exposure → likely to be more objective then previous studies based on parental memory

Biases and conflicts of interests

• none declared and none seem obvious

Clinical relevance to primary health care

There is a known probable association between in utero exposure to radiation, including diagnostic imaging, and the risk of childhood cancer. This study attempted to assess the risk between in utero and early childhood exposure of radiation and ultrasound.

It is the opinion of the author of this appraisal that this study is insufficiently powered to make a meaningful assessment of the risk. No statistically significant association of increased risk was found. The study does exclude very large excess risks but lower magnitude risks which are clinically significant remain possible. The exception is that in utero ultrasound exposure is unlikely to be associated with excess risk of childhood cancer; OR = 0.93 (95% CI, 0.79 – 1.09).

Australian general practitioners should follow a precautionary principle and avoid the use of diagnostic radiation in pregnant women and young infants where possible. The excess risk (if it exists) from simple x-rays in utero and in early childhood remains unclear.

References

1. Rajaraman P, Simpson J, Neta G, et al. Early life exposure to diagnostic radiation and ultrasound scans and risk of childhood cancer: case-control study. BMJ 2011; 342: d472