Presentation on theme: "Where is the evidence? PHRM2010"— Presentation transcript:
1 Where is the evidence? PHRM2010 Judith CoombesThe University of Queensland/Princess Alexandra HospitalIntroduce myself1st year I spoke about qualityNext 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 ExpertisePatient ValuesDecisionExplain the definition of each circle hereTo 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 resourcesGap between clinical judgment which over time while up to date theoretical knowledge over timeTime limitation for finding evidenceInadequacy of Traditional resourcesTexts-out of dateJournals –too many, too varied in validityExperts- frequently wrongCE-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 evidenceAppraise validity, impact and applicabilityIntegrate appraisal with clinical expertiseEvaluate performance
6 Answerable question The patient-73 yr old female main intervention-clopidogrelcomparison treatment-aspirinclinical outcome-reduce mortalityThe patient; Mrs Smith a 73 year old lady with a recent strokeTo 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 ClopidogrelThe comparison aspirinThe clinical outcome reduced mortalityreduced stroke rateno increase in bleedingMr 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 diabetesdoes tight bp control reduce mortality and morbidity?West of Scotland StudyPrimary intervention
8 Does an intervention work? Case reportsClinical experienceCase seriesCase control studyCohort studyRandomised, placebo controlled clinical studyHaving 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 evidenceAppraise validity, impact and applicabilityIntegrate appraisal with clinical expertiseEvaluate performance
10 Find the best evidenceMerck Manual says Aspirin mg no mention of clopidogrelCochrane database-1 review 2000 (amendment 2005) significant benefit but ? sizeClinical Evidence (BMJ) viewed uses cochrane 2005 review says doubtful benefitMedline-pubmed 66 clinical trials in EnglishCAPRIE significant differenceCHARISMA clopidogrel plus aspirinMedline 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 groupsMATCH 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 CollaborationEvidence-based journalsInformation systems bring info in secondsEffective strategies for lifelong learning and improving clinical performanceEBM as a teaching/learning toolEvidence based journals of secondary publication-publish 2% of valid and immediate clinical useCan 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 researchSystematic 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 questionsOnce found, trials may appear to give conflicting or contradictory resultsEg 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 evidenceCAUTION the order here is important not the number.
17 How to obtain access to systematic reviews Internet siteseg.The Australasian Cochrane Centre - Flinders University, SAEvidence Based Guidelines NPS (Aus) and NICE (UK)National Prescribing service NPSNational Institute of Clinical Excellence
18 FIVE steps Convert information needs into an answerable question Find the best evidenceAppraise validity, impact and applicabilityIntegrate appraisal with clinical expertiseEvaluate performance
19 Validity Impact applicability Now we have found some evidence. Can we apply the evidence to this case?ValidityImpactapplicability
20 Is the systematic review valid? Is the review of randomised trialsdo the methods describe-finding and including all relevant trialshow validity of individual trials was assessedwere the results consistent from study to study
21 Validity (CAPRIE)Was the assignment of patients to treatments randomised? YESWas the randomisation list concealed? YESWas follow-up of patients sufficiently long and complete? 1.91 yrsWere all patients analysed in the groups to which they were randomised? Yes Were patients and clinicians kept “blind” to treatment? YesWere the groups treated equally, apart from the experimental treatment? YESWere 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 longcalculate the absolute risk of harmISIS 2 acute MI aspirin after streptokinase CER 22%, EER 17%RRR almost 30% ARR 5% 24 people for 2 years saves a lifeWOSCOPSG non-fatal MI or death in hypercholesterolaemic menCER 7.9% EER 5.5% RRR 30% BUT ARR 2.4% AND 44 men treated from years to avoid 1 event
23 ImpactClopidogrel versus Aspirin Outcomes MI, STROKE, or vascular death combinedAfter 1 yearRelative risk reduction (RRR)Absolute risk reduction (ARR)Number needed to treat (NNT)CEREERCER – EER CERCER-EER1ARR5.83%5.32%8.7%0.51%200CER control event rate Annual riskEER Experimental event rate-----Annual riskThey tell us 8.7% reduction but it is really only 0.51%0.51/100 the inverse is 100/0.51 = 196 or 200BACKGROUND: 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 ApplicabilityHow is our patient different from the study patient –previous stroke subgroup didn’t do as well, 72% men mean age 62.5 yrsIs this a treatment the patient will form a partnership with us to follow- WILL IT BE SUBSIDISED- it costs much more
25 eTGFor 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) ORdipyridamole (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 eTGClopidogrel, 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 outcomesInformation often comes to the pharmacist in an incomplete fashionPharmacists 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 individualTrials - not ‘real’ usageLack of local ownership of recommendationsClinical effectiveness vs cost effectivenessCoxibs examples
29 Combined approaches Evidence based Consensus Local guidelines Pharmacists can act as a focal or facilitation point
30 SummaryEvidence based medicine is an effective tool to maximise optimal outcomes for our patientsPharmacists need to learn how to incorporate evidence based principles in their practicePharmacists can contribute to local implementation of evidence based guidelines