Where is the evidence? PHRM2010

Judith Coombes

The University of Queensland/Princess Alexandra

Hospital

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)

A model of Evidence Based decisions

Patient ValuesClinical Expertise

Best research evidence

Decision

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

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

Answerable question

The patient-73 yr old female

main intervention-clopidogrel comparison treatment-aspirin clinical outcome-reduce mortality

1. search strategy; 2. search results; 3. the validity of this evidence; 4. the importance of this valid evidence; 5. can this valid, important evidence be applied to your patient; 6. your evaluation of this process.

Patient’s Name Learner:

Target Disorder:

Date and place to be filled:

Intervention (+/- comparison):

Outcome:

Does an intervention work?

Case reports Clinical experience Case series Case control study Cohort study Randomised, placebo controlled clinical

study

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

Find the best evidence

Merck Manual says Aspirin 650-1300mg no mention of clopidogrel

Cochrane database-1 review 2000 (amendment 2005) significant benefit but ? size

Clinical Evidence (BMJ) viewed 27.4.08 uses cochrane 2005 review says doubtful benefit

Medline-pubmed 66 clinical trials in English » CAPRIE 1996- significant difference» CHARISMA 2006- clopidogrel plus aspirin

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.

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

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

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

  

Cochrane Collaboration LOGO

Strength of evidence

I Strong evidence - at least one systematic review

II Strong evidence - at least one properly designed R.C.T.

III Evidence from well designed trials without randomisation

IV Evidence from well designed non-experimental studies (>1 group)

V Opinions based on clinical expertise

How to obtain access to systematic reviews

Internet sites» eg. www.clinicalevidence.com» www.cebm.utoronto.ca

The Australasian Cochrane Centre - Flinders University, SA » www.cochrane.org.au

Evidence Based Guidelines NPS (Aus) and NICE (UK)National Prescribing service NPSwww.NPS.org.auNational Institute of Clinical Excellencewww.NICE.org.uk

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

Now we have found some evidence. Can

we apply the evidence to this case?

Validity Impact applicability

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

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

Impact

Calculate the absolute benefit (or risk reduction)

Now the number needed treat (NNT) and for how long

calculate the absolute risk of harm

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

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

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 200+25 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

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.

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

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

Combined approaches

Evidence based Consensus Local guidelines Pharmacists can act as a focal or

facilitation point

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