1. Where is the evidence? PHRM2010
Judith Coombes
The University of Queensland/Princess Alexandra Hospital
Introduce myself
1st year I spoke about quality
Next week about Drug Use Evaluation

2. What is evidence based medicine?
Evidence-based medicine(EBM) is the integration of best research evidence with clinical expertise and patient values (Sackett et al 1999)

3. A model of Evidence Based decisions
Clinical Expertise
Patient Values
Decision
Explain the definition of each circle here
To illustrate what I mean I will introduce Mrs R Stroke a 73 year old lady. Her doctor rings you because he was wondering if the drug Clopidogrel which everyone is using these days will be more effective in preventing a further stroke that the Aspirin she was taking before.
Best research evidence

4. Realisations Daily need for valid up to date information
Inadequacy of traditional resources
Gap between clinical judgment which  over time while up to date theoretical knowledge  over time
Time limitation for finding evidence
Inadequacy of Traditional resources
Texts-out of date
Journals –too many, too varied in validity
Experts- frequently wrong
CE-didactic is often ineffective- just in case when we want just in time

5. FIVE steps Convert information needs into an answerable question
Find the best evidence
Appraise validity, impact and applicability
Integrate appraisal with clinical expertise
Evaluate performance

6. Answerable question The patient-73 yr old female
main intervention-clopidogrel
comparison treatment-aspirin
clinical outcome-reduce mortality
The patient; Mrs Smith a 73 year old lady with a recent stroke
To illustrate what I mean I will introduce Mrs R Stroke a 73 year old lady. Her doctor rings you because he was wondering if the drug Clopidogrel which everyone is using these days will be more effective in preventing a further stroke than Aspirin.
The intervention Clopidogrel
The comparison aspirin
The clinical outcome reduced mortality
reduced stroke rate
no increase in bleeding
Mr A obese, 56yr male accountant, NIDDM diagnosed 11 years ago . On metformin bp 158/94 during past 3 visits he wants to know the benefit of your proposed treatment.
56yr male type 2 diabetes
does tight bp control reduce mortality and morbidity?
West of Scotland Study
Primary intervention

8. Does an intervention work?
Case reports
Clinical experience
Case series
Case control study
Cohort study
Randomised, placebo controlled clinical study
Having found some information which is the best and who should you believe.

9. FIVE steps Convert information needs into an answerable question
Find the best evidence
Appraise validity, impact and applicability
Integrate appraisal with clinical expertise
Evaluate performance

10. Find the best evidence
Merck Manual says Aspirin mg no mention of clopidogrel
Cochrane database-1 review 2000 (amendment 2005) significant benefit but ? size
Clinical Evidence (BMJ) viewed uses cochrane 2005 review says doubtful benefit
Medline-pubmed 66 clinical trials in English
CAPRIE significant difference
CHARISMA clopidogrel plus aspirin
Medline using stroke prevention and clopidogrel there was over 470 articles so limited to a clinical trial and found 55 articles of which one was refered to CAPRIE, CHARISMA is clopidogrel plus aspirin versus aspirin, as are CURE,CREDO, CARESS which are other patient groups
MATCH developed from cure added aspirin to clopidogrel –bleeds outweighed benefits.

11. Implications for practice
The cost of treating 100 patients for two years with clopidogrel, at about US$800 per patient per year, totals about $160,000 to prevent one vascular event. As this is likely to exceed the average cost of the vascular event prevented, it seems prudent, at this stage at least, to infer that thienopyridines should not replace aspirin as the first choice antiplatelet agent for all high vascular risk patients. However, clopidogrel would seem to have a role for patients who are intolerant of, or allergic to, aspirin, provided we accept the caveat that we do not have direct evidence of the relative effectiveness of thienopyridines compared with aspirin in these patients because they were excluded from the randomised trials.
Cochrane

12. Developments Strategies for finding and appraising evidence
Systematic reviews-Cochrane Collaboration
Evidence-based journals
Information systems bring info in seconds
Effective strategies for lifelong learning and improving clinical performance
EBM as a teaching/learning tool
Evidence based journals of secondary publication-publish 2% of valid and immediate clinical use
Can do EBM in just 30 minutes per week

13. Systematic reviews Different to conventional narrative reviews
Very useful way of presenting the accumulated results from primary research
Systematic approach used to minimise bias and random errors

14. Why do we need systematic reviews of the evidence?
No-one can possibly read, or find, all the trials and all the data about all specific clinical questions
Once found, trials may appear to give conflicting or contradictory results
Eg in 1994/1995 there were about 1000 papers a year being published studies on the treatment of stomach ulcer and H pylori eradication

15. Cochrane Collaboration LOGO
The logo represents 7 RCTs of a short course of corticosteroid given to women about to give birth prematurely.
1st line was in a short horizontal line showing a more certain result (mean and CI) than the next longer line.
Right of the line is more harm than good.
The logo shows the result if there was a systematic review in more good than harm but no review was published until more trials and obstetricians not realising that the odds of babies dying of complications of immaturity of 30-50%
WHAT HUMAN COST

16. Strength of evidence
CAUTION the order here is important not the number.

17. How to obtain access to systematic reviews
Internet sites
eg.
The Australasian Cochrane Centre - Flinders University, SA
Evidence Based Guidelines NPS (Aus) and NICE (UK)
National Prescribing service NPS
National Institute of Clinical Excellence

18. FIVE steps Convert information needs into an answerable question
Find the best evidence
Appraise validity, impact and applicability
Integrate appraisal with clinical expertise
Evaluate performance

19. Validity Impact applicability
Now we have found some evidence. Can we apply the evidence to this case?
Validity
Impact
applicability

20. Is the systematic review valid?
Is the review of randomised trials
do the methods describe-
finding and including all relevant trials
how validity of individual trials was assessed
were the results consistent from study to study

21. Validity (CAPRIE)
Was the assignment of patients to treatments randomised? YES
Was the randomisation list concealed? YES
Was follow-up of patients sufficiently long and complete? 1.91 yrs
Were all patients analysed in the groups to which they were randomised? Yes Were patients and clinicians kept “blind” to treatment? Yes
Were the groups treated equally, apart from the experimental treatment? YES
Were the groups similar at the start of the trial? YES

22. Impact Calculate the absolute benefit (or risk reduction)
Now the number needed treat (NNT) and for how long
calculate the absolute risk of harm
ISIS 2 acute MI aspirin after streptokinase CER 22%, EER 17%
RRR almost 30% ARR 5% 24 people for 2 years saves a life
WOSCOPSG non-fatal MI or death in hypercholesterolaemic men
CER 7.9% EER 5.5% RRR 30% BUT ARR 2.4% AND 44 men treated from years to avoid 1 event

23. Impact
Clopidogrel versus Aspirin Outcomes MI, STROKE, or vascular death combined
After 1 year
Relative risk reduction (RRR)
Absolute risk reduction (ARR)
Number needed to treat (NNT)
CER
EER
CER – EER CER
CER-EER 1
ARR
5.83%
5.32%
8.7%
0.51%
200
CER control event rate Annual risk
EER Experimental event rate-----Annual risk
They tell us 8.7% reduction but it is really only 0.51%
0.51/100 the inverse is 100/0.51 = 196 or 200
BACKGROUND: Many clinical trials have evaluated the benefit of long-term use of antiplatelet drugs in reducing the risk of clinical thrombotic events. Aspirin and ticlopidine have been shown to be effective, but both have potentially serious adverse effects. Clopidogrel, a new thienopyridine derivative similar to ticlopidine, is an inhibitor of platelet aggregation induced by adenosine diphosphate. METHODS: CAPRIE was a randomised, blinded, international trial designed to assess the relative efficacy of clopidogrel (75 mg once daily) and aspirin (325 mg once daily) in reducing the risk of a composite outcome cluster of ischaemic stroke, myocardial infarction, or vascular death; their relative safety was also assessed. The population studied comprised subgroups of patients with atherosclerotic vascular disease manifested as either recent ischaemic stroke, recent myocardial infarction, or symptomatic peripheral arterial disease. Patients were followed for 1 to 3 years. FINDINGS: 19,185 patients, with more than 6300 in each of the clinical subgroups, were recruited over 3 years, with a mean follow-up of 1.91 years. There were 1960 first events included in the outcome cluster on which an intention-to-treat analysis showed that patients treated with clopidogrel had an annual 5.32% risk of ischaemic stroke, myocardial infarction, or vascular death compared with 5.83% with aspirin. These rates reflect a statistically significant (p = 0.043) relative-risk reduction of 8.7% in favour of clopidogrel (95% Cl ). Corresponding on-treatment analysis yielded a relative-risk reduction of 9.4%. There were no major differences in terms of safety. Reported adverse experiences in the clopidogrel and aspirin groups judged to be severe included rash (0.26% vs 0.10%), diarrhoea (0.23% vs 0.11%), upper gastrointestinal discomfort (0.97% vs 1.22%), intracranial haemorrhage (0.33% vs 0.47%), and gastrointestinal haemorrhage (0.52% vs 0.72%), respectively. There were ten (0.10%) patients in the clopidogrel group with significant reductions in neutrophils (< 1.2 x 10(9)/L) and 16 (0.17%) in the aspirin group. INTERPRETATION: Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction, or vascular death. The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin.

24. Applicability
How is our patient different from the study patient –previous stroke subgroup didn’t do as well, 72% men mean age 62.5 yrs
Is this a treatment the patient will form a partnership with us to follow- WILL IT BE SUBSIDISED- it costs much more

25. eTG
For initial antiplatelet therapy, aspirin alone or the combination of aspirin plus dipyridamole (modified-release) are acceptable options:
aspirin 100 to 300 mg orally, daily (although doses down to 30 mg daily may be adequate)
   OR
dipyridamole (modified-release)+aspirin mg orally, twice daily. [Note 1]
     
Due to enhanced efficacy, the combination of dipyridamole+aspirin is preferred in patients with moderate or greater absolute risk of recurrent stroke events. It should also be considered in patients with recurrent stroke events despite aspirin therapy.
Headache is the most frequent adverse effect with combination therapy and may be overcome by initiating treatment with smaller doses.
Dipyridamole alone may be used in patients intolerant of both aspirin and clopidogrel

26. eTG
Clopidogrel, a platelet aggregation inhibitor, was shown in the CAPRIE trial to be modestly more effective than aspirin in the prevention of serious high-risk vascular outcomes (stroke, myocardial infarction, vascular death). This trial showed a relative risk reduction of 8.7% for clopidogrel over aspirin, with a similar magnitude of risk reduction seen for the outcome of stroke alone (7.3%). However, because of the small absolute risk reduction (approximately 0.5% per year) and the cost of the drug, clopidogrel is mainly used as second-line therapy in patients who are either intolerant of aspirin (eg those with gastrointestinal bleeding) or have developed recurrent cerebral ischaemic events while on aspirin (so-called aspirin failures). For such patients, use:
clopidogrel 75 mg orally, daily (blood monitoring is not necessary).
  More recently, clopidigrel has been tested in two clinical trials in combination with aspirin. The MATCH trial tested the addition of aspirin 75 mg daily to baseline clopidogrel in a stroke or TIA population comprising a high proportion of patients with small-vessel stroke syndromes associated with hypertension and diabetes. The addition of aspirin to clopidogrel did not significantly reduce the risk of the primary endpoint (a composite of ischaemic stroke, myocardial infarction, vascular death or rehospitalisation for acute ischaemia), but did result in significantly more life-threatening bleeds (2.6% versus 1.3%). The CHARISMA study tested the addition of clopidogrel 75 mg to baseline low-dose aspirin (75 to 162 mg) in two study populations—a ‘high-risk’ primary prevention group and a secondary prevention group combining patients with cardiovascular, cerebrovascular (approximately 35% of patients) and peripheral arterial disease. Overall there was no reduction in the primary end point of stroke, myocardial infarction or vascular death. Therefore, clopidogrel plus aspirin should not be used for long-term preventive therapy in patients with cerebrovascular disease.

27. Relevance of evidence based medicine to pharmacists
All areas of practice require decisions about optimal therapy (including no therapy) to improve patient outcomes
Information often comes to the pharmacist in an incomplete fashion
Pharmacists giving advice and being proactive in therapeutics need accurate information sources

28. Some limitations of evidence based medicine
Many questions do not have answers!
Evidence from populations - ?relevance to individual
Trials - not ‘real’ usage
Lack of local ownership of recommendations
Clinical effectiveness vs cost effectiveness
Coxibs examples

29. Combined approaches Evidence based Consensus Local guidelines
Pharmacists can act as a focal or facilitation point

30. Summary
Evidence based medicine is an effective tool to maximise optimal outcomes for our patients
Pharmacists need to learn how to incorporate evidence based principles in their practice
Pharmacists can contribute to local implementation of evidence based guidelines