Practice of EBM-Is Dual Anti-platelet Therapy vs.

Monotherapy Better for Secondary and Tertiary Prevention of CV events

PhD Student:Yi-Liang WuAdvisor: Prof. Meng-Chih Lee

Audit: Professor Long-Yau Lin, MD, Dr.PH

Backgrounds

Definitions• PRIMARY PREVENTION: Prevent the disease or injury from

actually occurring. In the case of CVDs, through actions such as a "Healthy Lifestyle" e.g., healthy diet, regular exercise, preventing overweight, control of stress, etc

• SECONDARY PREVENTION: Early detection and prompt treatment of disease. An example is medication to lower blood pressure

• TERTIARY PREVENTION (e.g. after myocardial infarction): Rehabilitation after a disease has occurred. Attempts are made to restore as much of a person's functions as possible e.g. revascularisation or even heart transplants for severe cases of CVDs

antiplatelet agents: inhibit platelet adhesion and aggregation

• cyclo-oxygenase inhibitors (e.g. acetylsalicylic acid -ASA)

• thienopyridine derivatives (e.g. ticlopidine, clopidogrel)

• phosphodiesterase inhibitors (e.g. dipyridamole)• thromboxane A2 antagonists• agents with direct effects on platelet membrane

receptors such as GP IIb/IIIa receptor and fibrinogen antagonists (e.g. defibrotide).

Major CV events • myocardial infarction, stroke, death from CV causes, heart

failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene

The possible indications for dual antiplatelet therapy include • coronary artery disease (CAD) stable CAD, non–ST-segment elevation myocardial infarction (MI) and/or unstable angina ST-segment elevation MI acute coronary syndrome (ACS) percutaneous coronary intervention (PCI)

• atherosclerotic ischemic stroke• atrial fibrillation.

執行 EBM 的五個步驟 ( I )

1.問問題（可以回答的問題）– Converting the need for information into an

answerable question.

2.找資料（可獲得最好的證據資訊）– Search the database and tracking down the

best evidence.

3.分析判斷（文獻的效度與重要性）– Critical appraising that evidence for its

validity and importance.

執行 EBM 的五個步驟 ( II )

4.臨床應用（整合三大層面）– Integrating the critical appraising with our

clinical expertise and our patient’s unique biology, values and circumstances.

5.評估成果（執行 EBM的效率）– Evaluating our effectiveness and efficiency

in executing step 1- 4 and seeking ways to improve them both for next time.

Step 1:Step 1: Formulating the management question to be answered

• P: patients who have coronary artery disease (CAD) or cerebral vascular disease (CVD) and those who have myocardial infarction (MI) or strokes

• I: dual antiplatelet therapy• C: monotherapy• O: (prevention of) CV events

Step 2Step 2:: Searching the literature and on-line databases for evidence to answer the questionevidence to answer the question

1.1. Search strategy: Cochrane Library, Pubmed, Search strategy: Cochrane Library, Pubmed, MedlineMedline

2.2. Search outcomeSearch outcome3.3. ReferencesReferences

Step 3Step 3:: Appraising the evidence

Cochrane library – dual antiplatelet

• Title: Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial.

• Author(s) Bhatt DL, Flather MD, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Fabry-Ribaudo L, Hu T, Topol EJ, Fox KA, CHARISMA Investigators

• Source: Journal of the American College of Cardiology Date of Publication 2007 May Volume 49 Issue 19 Pages 1982-8

• Abstract OBJECTIVES: The purpose of this study was to determine the possible benefit of dual antiplatelet therapy in patients with prior myocardial infarction (MI), ischemic stroke, or symptomatic peripheral arterial disease (PAD). BACKGROUND: Dual antiplatelet therapy with clopidogrel plus aspirin has been validated in the settings of acute coronary syndromes and coronary stenting. The value of this combination was recently evaluated in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial, where no statistically significant benefit was found in the overall broad population of stable patients studied. METHODS: We identified the subgroup in the CHARISMA trial who were enrolled with documented prior MI, ischemic stroke, or symptomatic PAD. RESULTS: A total of 9,478 patients met the inclusion criteria for this analysis. The median duration of follow-up was 27.6 months. The rate of cardiovascular death, MI, or stroke was significantly lower in the clopidogrel plus aspirin arm than in the placebo plus aspirin arm: 7.3% versus 8.8% (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.72 to 0.96, p = 0.01). Additionally, hospitalizations for ischemia were significantly decreased, 11.4% versus 13.2% (HR 0.86, 95% CI 0.76 to 0.96, p = 0.008). There was no significant difference in the rate of severe bleeding: 1.7% versus 1.5% (HR 1.12, 95% CI 0.81 to 1.53, p = 0.50); moderate bleeding was significantly increased: 2.0% versus 1.3% (HR 1.60, 95% CI 1.16 to 2.20, p = 0.004). CONCLUSIONS: In this analysis of the CHARISMA trial, the large number of patients with documented prior MI, ischemic stroke, or symptomatic PAD appeared to derive significant benefit from dual antiplatelet therapy with clopidogrel plus aspirin. Such patients may benefit from intensification of antithrombotic therapy beyond aspirin alone, a concept that future trials will need to validate.

1.Tertiary prevention ( s/p stroke and prior MI

2.Clopdogrel plus asprin better3.Subgroup analysis in a study with

no overall treatment effect

1.Tertiary prevention ( s/p stroke and prior MI

2.Clopdogrel plus asprin better3.Subgroup analysis in a study with

no overall treatment effect

• Title: Prolonged dual antiplatelet therapy after percutaneous coronary intervention reduces ischemic events without affecting the need for repeat revascularization: insights from the CREDO trial.

• Author(s) Brener SJ, Steinhubl SR, Berger PB, Brennan DM, Topol EJ, for the CREDO Investigators • Source: The Journal of invasive cardiology 2007 Jul Volume 19 Issue 7 Pages 287-90 • Abstract BACKGROUND: Dual antiplatelet therapy reduces ischemic events after percutaneous coronary

intervention (PCI) and in patients with acute coronary syndromes. The relationship between target vessel revascularization (TVR) and ischemic events in patients treated with aspirin and clopidogrel or aspirin alone from 1 month to 1 year after PCI has not been studied. METHODS: Patients enrolled in the CREDO trial were treated with aspirin and clopidogrel or aspirin and placebo for up to 1 year. We compared the rates of target vessel revascularization (TVR )and ischemic events (cardiac death, myocardial infarction or stroke) in the two groups, and modeled the effect of clopidogrel treatment on ischemic events after adjusting for relevant parameters. RESULTS One month after PCI, 1,955 patients have remained asymptomatic. By 1 year, ischemic events occurred in 5.3% of placebo- and 3.1% of clopidogrel-treated patients; p = 0.02. The rate of TVR was 11.9% and 12.2%, respectively; p = 0.82. Only 7 patients (clopidogrel: 3 and placebo: 4) experienced TVR within 7 days of an ischemic event. After adjustment, long-term dual antiplatelet therapy was associated with a 48% reduction in events; p = 0.01. Patients who experienced TVR had a significantly higher rate of ischemic events than those without TVR, regardless of treatment assignment: 12.3% vs. 3.1%, respectively; p < 0.001. CONCLUSION: Thus, after successful PCI, prolonged dual antiplatelet therapy reduces ischemic events without affecting TVR. Overall, patients with TVR experienced an ischemic event much more often that was not related to the PCI vessel. This suggests that the benefit of antiplatelet therapy after coronary revascularization is indexed to the patient's underlying atherothrombotic process, rather than the artery that underwent intervention.

1. A a randomized, double-blind, placebo-controlled trial

2. Clopdogrel plus asprin better3. Secondary prevention for

CAD with elective PCI

1. A a randomized, double-blind, placebo-controlled trial

2. Clopdogrel plus asprin better3. Secondary prevention for

CAD with elective PCI

• Title: Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. • Author(s) Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD,

Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ, CHARISMA Investigators

• Source: The New England journal of medicine Date of Publication 2006 Apr Volume 354 Issue 16 Pages 1706-17• Abstract BACKGROUND: Dual antiplatelet therapy with clopidogrel plus low-dose aspirin has not been studied in a

broad population of patients at high risk for atherothrombotic events. METHODS: We randomly assigned 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors to receive clopidogrel (75 mg per day) plus low-dose aspirin (75 to 162 mg per day) or placebo plus low-dose aspirin and followed them for a median of 28 months. The primary efficacy end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes. RESULTS: The rate of the primary efficacy end point was 6.8 percent with clopidogrel plus aspirin and 7.3 percent with placebo plus aspirin (relative risk, 0.93; 95 percent confidence interval, 0.83 to 1.05; P=0.22). The respective rate of the principal secondary efficacy end point, which included hospitalizations for ischemic events, was 16.7 percent and 17.9 percent (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.995; P=0.04), and the rate of severe bleeding was 1.7 percent and 1.3 percent (relative risk, 1.25; 95 percent confidence interval, 0.97 to 1.61 percent; P=0.09). The rate of the primary end point among patients with multiple risk factors was 6.6 percent with clopidogrel and 5.5 percent with placebo (relative risk, 1.2; 95 percent confidence interval, 0.91 to 1.59; P=0.20) and the rate of death from cardiovascular causes also was higher with clopidogrel (3.9 percent vs. 2.2 percent, P=0.01). In the subgroup with clinically evident atherothrombosis, the rate was 6.9 percent with clopidogrel and 7.9 percent with placebo (relative risk, 0.88; 95 percent confidence interval, 0.77 to 0.998; P=0.046). CONCLUSIONS: In this trial, there was a suggestion of benefit with clopidogrel treatment in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors. Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes.

1. Randomized contorlled trial2. Clopdogrel plus asprin not better

3. Secondary prevention of CAD

1. Randomized contorlled trial2. Clopdogrel plus asprin not better

3. Secondary prevention of CAD

• Title: Dual Antiplatelet Therapy With Clopidogrel and Aspirin in Symptomatic Carotid Stenosis Evaluated Using Doppler Embolic Signal Detection. The Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) Trial

• Authors: Hugh S. Markus FRCP*, Dirk W. Droste MD, Manfred Kaps MD, Vincent Larrue MD, Kennedy R. Lees FRCP, Mario Siebler MD, and E. Bernd Ringelstein

• Background--Evidence for efficacy of dual antiplatelet therapy in stroke is limited. Symptomatic carotid stenosis patients are at high risk of early recurrent stroke. In this group, asymptomatic microembolic signals (MES), detected by transcranial Doppler ultrasound (TCD), are markers of future stroke and transient ischemic attack (TIA) risk. They offer a surrogate marker to evaluate antiplatelet therapy, but no multicenter study has evaluated the feasibility of this approach.

• Methods and Results--Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) is a randomized, double-blind study in subjects with recently symptomatic 50% carotid stenosis. Patients were screened with TCD, and if MES were detected, they were randomized to clopidogrel and aspirin or aspirin monotherapy. Repeated TCD recordings were made on days 2 and 7. MES were detected in 110 of 230 patients by online analysis at baseline, of whom 107 were randomized. Intention-to-treat analysis revealed a significant

reduction in the primary end point: 43.8% of dual-therapy patients were MES positive on day 7, as compared with 72.7% of monotherapy patients (relative risk reduction 39.8%; 95% CI, 13.8 to 58.0; P=0.0046). The secondary end point of MES frequency per hour was reduced (compared with baseline) by 61.4% (95% CI, 31.6 to 78.2; P=0.0013) in the dual-therapy group at day 7 and by 61.6% (95% CI, 34.9 to 77.4; P=0.0005) on day 2. There were 4 recurrent strokes and 7 TIAs in the monotherapy group versus no stroke and 4 TIAs in the dual-therapy group that were treatment emergent and ipsilateral to the qualifying carotid stenosis; 2 additional ipsilateral TIAs occurred before treatment started. MES frequency was greater in the 17 patients with recurrent ipsilateral events compared with the 90 without (mean±SD: 24.4±27.7 versus 8.9±11.5 per hour; P=0.0003).

• Conclusions--In patients with recently symptomatic carotid stenosis, combination therapy with clopidogrel and aspirin is more effective than aspirin alone in reducing asymptomatic embolization. Doppler MES detection is a feasible method to evaluate the efficacy of antiplatelet therapy in multicenter studies.

1. randomized, double-blind study 2. clopidogrel and aspirin (better) or

aspirin3. Secondary prevention of

symptomatic carotid stneosis

1. randomized, double-blind study 2. clopidogrel and aspirin (better) or

aspirin3. Secondary prevention of

symptomatic carotid stneosis

Cochrane library – antiplatelet• Dipyridamole for preventing stroke and other vascular events in patients with vascular disease

Els De Schryver2, Ale Algra1, Jan van Gijn2

Cochrane Database of Systematic Reviews, Issue 4, 2008 (Status in this issue: Edited)Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.DOI: 10.1002/14651858.CD001820.pub3Abstract

Background• Patients with limited cerebral ischaemia of arterial origin are at risk of serious vascular events (4% to 11% annually). Aspirin reduces that risk by 13%. In one trial, adding dipyridamole to

aspirin was associated with a 22% risk reduction compared with aspirin alone. However, a systematic review of all trials of antiplatelet agents by the Antithrombotic Trialists' Collaboration showed that, in high-risk patients, there was virtually no difference between the aspirin-dipyridamole combination and aspirin alone.

Objectives• To assess the efficacy and safety of dipyridamole versus control in the secondary prevention of vascular events in patients with vascular disease.

Search strategy• We searched the Cochrane Stroke Group trials register (searched June 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2006), MEDLINE

(1966 to May 2006) and EMBASE (1980 to May 2006). We contacted authors and pharmaceutical companies in the search for further data on published and unpublished studies.

Selection criteria• We selected randomised long-term secondary prevention trials with concealed treatment allocation, treatment for more than one month, starting within six months after presentation

of an arterial vascular disease. Treatment consisted of dipyridamole with or without other antiplatelet drugs compared with no drug or an antiplatelet drug other than dipyridamole.

Data collection and analysis• Two review authors independently selected trials for inclusion, assessed trial quality and extracted data. Data were analysed according to the intention-to-treat principle.

Main results• Twenty-nine trials were included, with 23019 participants, among whom 1503 vascular deaths and 3438 fatal and non-fatal vascular events occurred during follow up. Compared with

control, dipyridamole had no clear effect on vascular death (relative risk (RR) 0.99, 95% confidence interval (CI) 0.87 to 1.12). This result was not influenced by the dose of dipyridamole or type of presenting vascular disease. Compared with control, dipyridamole appeared to reduce the risk of vascular events (RR 0.88, 95% CI 0.81 to 0.95). This effect was only statistically significant in patients presenting with cerebral ischaemia.

Authors' conclusions• For patients who presented with arterial vascular disease, there was no evidence that dipyridamole, in the presence or absence of another antiplatelet drug reduced the risk of vascular

death, though it reduces the risk of further vascular events. This benefit was found only in patients presenting after cerebral ischaemia. There was no evidence that dipyridamole alone was more efficacious than aspirin.

Plain language summary

Dipyridamole for preventing stroke and other vascular events in patients with vascular diseasePatients with symptoms of arterial disease have a high risk of getting a (possibly fatal) stroke or heart attack (myocardial infarction). Antiplatelet therapy with drugs like aspirin prevents blood clotting and reduces the risk of strokes, heart attacks, and death from vascular disease. Dipyridamole, another antiplatelet drug, given on its own or together with aspirin might reduce the risk even further. This review included 29 studies involving 23019 participants. When we compared the effects of dipyridamole (alone or together with aspirin) with aspirin alone there was no evidence of an effect on death from vascular causes. When we compared the effects on the occurrence of vascular events (strokes, heart attacks, and deaths from vascular diseases) the combination of aspirin and dipyridamole had an advantage over aspirin alone. This result holds particularly true for patients with ischaemic stroke.

1. Metaanalysis of randomised controlled long-term secondary prevention trials

2. aspirin and dipyridamole had an advantage over aspirin alone on the occurrence of

composite vascular events (strokes, heart attacks, and deaths from vascular diseases), but not on death from vascular causes, in patients

presenting with cerebral ischaemia.

• Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular diseaseTT Keller, A Squizzato, S Middeldorp

•Cochrane Database of Systematic Reviews 2008 Issue 4 (Status: Unchanged) Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.DOI: 10.1002/14651858.CD005158.pub2 This version first published online: 18 July 2007 in Issue 3, 2007

Background• Aspirin is the prophylactic antiplatelet drug of choice for people with cardiovascular disease. However, protection with antiplatelet therapy in people with a high risk of cardiovascular

disease is unsatisfactory in absolute terms. Adding a second antiplatelet drug to aspirin may produce additional benefit for those at high risk and those with established cardiovascular disease.

Objectives• To quantify the effects (both benefit and harm) of adding clopidogrel to standard long-term aspirin therapy for preventing cardiovascular events in people at high risk of cardiovascular

disease and those with established cardiovascular disease.

Search strategy• CENTRAL (Issue 2 2006), MEDLINE (2002 to May 2006) and EMBASE (2002 to May 2006) were searched. Online registers of ongoing trials and reference lists from original articles and

reviews were checked.

Selection criteria• All randomized controlled trials comparing long term (>30 days) use of aspirin plus clopidogrel with aspirin plus placebo or aspirin alone in patients with coronary disease, ischemic

cerebrovascular disease, peripheral arterial disease, or at high risk of atherothrombotic disease (with data for at least one of the outcomes) were included.

Data collection and analysis• Data were collected on the following outcomes and analysed where appropriate: mortality (from myocardial infarction, stroke, cardiovascular causes, all-causes), non-fatal myocardial

infarction, non-fatal stroke, unstable angina, heart failure, revascularizations, major and minor bleeding, and all adverse events. Quantitative analysis of outcome was based on an intention-to-treat principle. The overall treatment effect was estimated by the pooled odds ratio (OR) with 95% confidence interval (CI) using a fixed-effect model (Mantel-Haenszel).

Main results• Two RCTs were found. Patients enrolled in the CHARISMA study were at high risk for cardiovascular events, either with or without an established cardiovascular disease. Patients enrolled

in the CURE study had a recent non-ST segment elevation acute coronary syndrome. The use of clopidogrel plus aspirin, compared with placebo plus aspirin, was associated with a lower risk of cardiovascular events (OR: 0.87, 95% CI 0.81 to 0.94; P<0.01) and a higher risk of major bleeding (OR 1.34, 95% CI 1.14 to 1.57; P<0.01). Overall, we would expect 13 cardiovascular events to be prevented for every 1000 patients treated with the combination, but 6 major bleeds would be caused. Treatment effects differed in the two trials: the CURE trial, confined to people with acute non-ST segment coronary syndromes, showed definite evidence of benefit from treatment. For every 1000 people treated for an average of 9 months, 23 events would be avoided and 10 major bleeds would be caused. In the CHARISMA trial that randomized people at high cardiovascular risk defined either in terms of pre-existing cardiovascular diseases or risk factors, the effects of treatment were less marked and were consistent with the play of chance. For every 1000 people treated for an average of 28 months, 5 cardiovascular events would be avoided and 3 major bleeds would be caused.

Authors' conclusions• The available evidence demonstrates that the use of clopidogrel plus aspirin is associated with a reduction in the risk of cardiovascular events compared with aspirin alone in patients with

acute non-ST coronary syndrome. In patients at high risk of cardiovascular disease but not presenting acutely, there is only weak evidence of benefit and hazards of treatment almost match any benefit obtained.

Plain language summaryLow-dose aspirin as antiplatelet therapy is still the drug of choice for preventing cardiovascular events, but the protection aspirin gives to people at high risk of cardiovascular events is only relatively modest. This review of 28,165 people in two trials found that in patients with acute coronary syndromes the benefit - a reduction in cardiovascular events - outweighs the harm of major bleeding. However, clopidogrel plus aspirin has no clear positive risk-benefit profile in people at high risk of cardiovascular events (multiple atherothrombotic risk factors) or in people with established cardiovascular disease (known coronary disease, ischemic cerebrovascular disease or peripheral arterial disease) but not presenting with an acute coronary syndrome, and the combination should not be prescribed routinely to prevent cardiovascular disease.

1. Systematic review of 2 randomized controlled

trials 2. clopidogrel plus aspirin

better in in patients with acute non-ST coronary syndrome, not others

BJM clinical evidence - antiplatelet

In people with previous stroke or TIA: non-surgical preventionWeb publication date: 03 Sep 2008Summary• Cardiovascular events• Thienopyridines (ticlopidine or clopidogrel) compared with aspirin We don't know whether thienopyridines are

more effective than aspirin at reducing the risk of serious vascular events (stroke, MI, or vascular death) in people with a previous stroke or TIA ( low-quality evidence).

• Clopidogrel plus aspirin compared with aspirin alone: Clopidrogel plus aspirin increases the rate of severe bleeding, and is no more effective at reducing the risk of a primary composite end point of MI, stroke, or cardiovascular death at 28 months in people with ischaemic stroke or TIA or clinically evident CVD or multiple risk factors including previous stroke or TIA ( moderate-quality evidence).

• Clopidogrel plus aspirin compared with clopidrogel : Clopidogrel plus aspirin increases the rate of severe bleeding, and is no more effective at reducing a primary composite end point of ischaemic stroke, MI, vascular death, or rehospitalisation for acute ischaemia at 18 months in people with a recent ischaemic stroke or TIA ( high-quality evidence).

• Dipyridamole plus aspirin compared with aspirin alone: Dipyridamole plus aspirin is more effective than aspirin alone at reducing serious vascular events (stroke, MI) in people with a previous ischaemic stroke or TIA (moderate-quality evidence).

• Triflusal compared with aspirin: Triflusal and aspirin seem equally effective at reducing a primary outcome of ischaemic stroke, MI, or vascular death in people with a prior ischaemic stroke or TIA (moderate-quality evidence).

• Mortality• Dipyridamole plus aspirin compared with aspirin alone: Dipyridamole plus aspirin may be no more effective at

reducing vascular mortality or all-cause mortality in people with a previous stroke or TIA ( low-quality evidence)

1. Systematic review 2. Tertiary and secondary prevention of cerebrovascular

diseases3. Dipyridamole plus aspirin

(vs.aspirin) reduces serious vascular events (stroke, MI) ,but not mortality

1. Systematic review 2. Tertiary and secondary prevention of cerebrovascular

diseases3. Dipyridamole plus aspirin

(vs.aspirin) reduces serious vascular events (stroke, MI) ,but not mortality

Secondary prevention of ischaemic cardiac eventsWeb publication date: 01 Dec 2005SummaryMortality • Aspirin plus oral glycoprotein IIb/IIIa receptor inhibitor compared with aspirin alone: Aspirin plus

oral glycoprotein IIb/IIIa receptor inhibitor increases the risk of mortality at 2 years compared with aspirin alone ( high-quality evidence).

Cardiovascular events• Aspirin plus clopidogrel versus aspirin alone: Aspirin plus clopidogrel reduces cardiovascular

events at 9 months compared with aspirin plus placebo after acute coronary syndrome ( moderate-quality evidence).

• Aspirin plus oral glycoprotein IIb/IIIa receptor inhibitor versus aspirin alone: Aspirin plus oral glycoprotein IIb/IIIa receptor inhibitor is no more effective than aspirin alone at reducing cardiovascular events at 2 years (high-quality evidence).

Adverse effects: haemorrhage• Aspirin plus oral glycoprotein IIb/IIIa receptor inhibitor compared with aspirin alone: Aspirin plus

oral glycoprotein IIb/IIIa receptor inhibitor increases the risk of haemorrhage compared with aspirin alone at 2 years (high-quality evidence).

1. Aspirin plus oral glycoprotein IIb/IIIa receptor inhibitor : increases the risk of

mortality, increases the risk of haemorrhage, not more reduces

cardiovascular events 2. Aspirin plus clopidogrel: reduces cardiovascular events at 9 months after

acute coronary syndrome

1. Aspirin plus oral glycoprotein IIb/IIIa receptor inhibitor : increases the risk of

mortality, increases the risk of haemorrhage, not more reduces

cardiovascular events 2. Aspirin plus clopidogrel: reduces cardiovascular events at 9 months after

acute coronary syndrome

References

7. Yusuf S, Mehta SR, Zhao F, et al. Early and late effects of clopidogrel in patients with acute coronary syndromes. Circulation 2003;107:966–972. [PubMed]

8. Newby LK, Califf RM, White HD, et al. The failure of orally administered glycoprotein IIb/IIIa inhibitors to prevent recurrent cardiac events. Am J Med 2002;112:647–658. Search date 2001. [PubMed]

9. Topol EJ, Easton D, Harrington RA, et al. Randomized, double-blind, placebo-controlled, international trial of the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease. Circulation 2003;108:399–406. [PubMed]

UpToDate – antiplatelet

• Antiplatelet therapy for secondary prevention of stroke• Last literature review version 16.3: October 2008• Aspirin plus clopidogrel — Accumulating evidence suggests that aspirin and

clopidogrel in combination does not offer greater benefit for stroke prevention than either agent alone but does substantially increase the risk of bleeding complications.

• Aspirin plus dipyridamole — The beneficial effects of aspirin and dipyridamole for secondary stroke prevention appear to be additive such that the combination of aspirin and extended-release dipyridamole (ER-DP) is significantly more effective than aspirin alone for stroke prevention.

• Aspirin plus extended-release dipyridamole versus clopidogrel — The PRoFESS trial (Prevention Regimen for Effectively Avoiding Second Strokes) showed that clopidogrel monotherapy and aspirin plus ER-DP have similar risks and benefits for secondary stroke prevention.

1. Systematic review2. Secondary prevention of

stroke3. Aspirin plus clopidogrel:

increase bleeding4. clopidogrel = aspirin plus ER-

dipyridamole > aspirin alone

1. Systematic review2. Secondary prevention of

stroke3. Aspirin plus clopidogrel:

increase bleeding4. clopidogrel = aspirin plus ER-

dipyridamole > aspirin alone

• SUMMARY AND RECOMMENDATIONS • Aspirin, clopidogrel, and the combination of aspirin plus extended-release dipyridamole (ER-DP) (Aggrenox) are all

acceptable options for preventing recurrent noncardioembolic ischemic stroke.• For patients with a history of noncardioembolic stroke or transient ischemic attack (TIA) of atherothrombotic, lacunar

(small vessel occlusive type), or cryptogenic type, we recommend treatment with an antiplatelet agent (Grade 1A). We suggest initial antiplatelet therapy using either clopidogrel (75 mg daily) as monotherapy, or the combination of aspirin plus ER-DP (25 mg/200 mg twice a day), rather than aspirin (Grade 2A). The choice between clopidogrel and aspirin plus ER-DP is dependent mainly on patient tolerance and contraindications.

• These recommendations apply as long as the choice will not impose a substantial financial burden. Initial therapy with aspirin is appropriate for patients who cannot afford or cannot obtain the more effective antiplatelet agents (clopidogrel or aspirin plus ER-DP). (See "Aspirin" above and see "Clopidogrel" above and see "Aspirin plus dipyridamole" above).

• Although the optimal dose of aspirin is uncertain, there is no compelling evidence that any specific dose is more effective than another, and fewer gastrointestinal side effects and bleeding occur with lower doses (≤325 mg a day). We recommend a dose of 50 to 100 mg daily when using aspirin for the secondary prevention of ischemic stroke (Grade 1B). (See "Dose of aspirin" above).

• For patients having carotid endarterectomy, we recommend aspirin (81 to 325 mg daily) started before surgery and continued indefinitely in the absence of a contraindication (Grade 1A). (See "Carotid endarterectomy: Preoperative evaluation; surgical technique; and complications", section on Aspirin).

• Aggrenox contains aspirin and should not be used in patients who cannot tolerate aspirin. Clopidogrel (75 mg/day) is an obvious alternative for patients who cannot tolerate aspirin. Ticlopidine should be reserved for patients intolerant of aspirin and clopidogrel. (See "Aspirin plus dipyridamole" above, see "Clopidogrel" above, and see "Ticlopidine" above).

• For most patients with a noncardioembolic stroke or TIA, we recommend NOT using aspirin and clopidogrel in combination for long-term stroke prevention, given the lack of greater efficacy compared with clopidogrel alone and the substantially increased risk of bleeding complications (Grade 1A). (See "Aspirin plus clopidogrel" above).

• - However, select patients with a recent acute myocardial infarction, other acute coronary syndrome, or arterial stent placement may be treated with clopidogrel plus aspirin. Recommendations for combination antiplatelet therapy in these settings are discussed elsewhere. (See "Antiplatelet agents in acute ST elevation myocardial infarction" and see "Antiplatelet agents in unstable angina and acute non-ST elevation myocardial infarction" and see "Antithrombotic therapy for intracoronary stent implantation: General use" and see "Coronary artery stent thrombosis")

• We recommend oral anticoagulation for patients with atrial fibrillation and a recent stroke or TIA (Grade 1A). We recommend aspirin for patients with atrial fibrillation and cardioembolic stroke who have contraindications to anticoagulant therapy (Grade 1B). Prevention of recurrent stroke in patients with atrial fibrillation is discussed separately. (See "Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation").

PUBMed – dual antiplatelet

• Indications for Dual Antiplatelet Therapy with Aspirin and Clopidogrel: Evidence-Based Recommendations for Use • Kristen T Reaume, Randolph E Regal, and Michael P Dorsch• Ann Pharmacother 2008;42:550-7• OBJECTIVE: To thoroughly review the literature assessing dual antiplatelet therapy with aspirin and clopidogrel and

subsequently provide evidence-based recommendations for appropriate indications and length of therapy. DATA SOURCES: An English-language MEDLINE search (1950–December 2007) was conducted using the search terms antiplatelet, aspirin, thienopyridine, and clopidogrel to identify articles assessing dual antiplatelet therapy. Evaluation of references from identified trials for possible inclusion was also conducted. STUDY SELECTION AND DATA EXTRACTION: All studies that assessed treatment with the combination of aspirin and clopidogrel for any indication were included . DATA SYNTHESIS: Aspirin and clopidogrel have complementary mechanisms of action to inhibit platelet function. Indications that have been studied include coronary artery disease (CAD), atherosclerotic ischemic stroke, and atrial fibrillation. This combination has been beneficial in patients with acute coronary syndrome (ACS) with or without percutaneous coronary intervention (PCI), and in PCI patients without an acute event. There is a small but significant risk for increased bleeding with dual antiplatelet therapy for these indications. When used in patients with a history of atherosclerotic ischemic stroke or for prevention of cardioembolic stroke in patients with atrial fibrillation, this combination has been shown to increase bleeding, providing no clinical benefit, and to increase outcomes including stroke, myocardial infarction, and death, respectively.

• CONCLUSIONS: There is evidence to support use of aspirin in combination with clopidogrel for patients presenting with all ACS types, as well as for patients presenting with PCI for any indication. The treatment duration varies, but patients who have received stenting should receive at least 1 year of combination therapy. There is no evidence to support this combination for primary prevention of CAD or atherosclerotic ischemic events, secondary prevention of stable CAD, or prevention of cardioembolic stroke in patients with atrial fibrillation. The possible benefits of dual antiplatelet therapy also must be weighed against the risk of bleeding.

1. Systematic review of randomized, double-blind, and placebo-controlled study

1. Systematic review of randomized, double-blind, and placebo-controlled study

Step 4Step 4:: Integrating this appraisal with knowledge about the unique aspects of the patient (including preferences)

• For secondary and tertiary prevention of cerebrovascular disease (previous stoke or TIA or carotid stenting): dual antiplatelet therapy with aspirin and ER-dipyridamole or clopidogrel monotherapy is better than aspirin monotherapy

• For secondary and tertiary prevention of cardiovascular disease: dual antiplatelet therapy with aspirin and clopidogrel is better than monotherapy only in acute coronary syndrome

• Dual antiplatelet therapy with aspirin and oral glycoprotein IIb/IIIa receptor inhibitor increases mortality and bleeding

Step 5Step 5:: Evaluating our effectiveness and efficiency in Evaluating our effectiveness and efficiency in executing steps 1 - 4 and seek ways to improve them executing steps 1 - 4 and seek ways to improve them (Auditing performance in step 1-4 )(Auditing performance in step 1-4 )

•Secondary • Tertiary

prevention

•cyclo-oxygenase inhibitors•thienopyridine derivatives•phosphodiesterase inhibitors•thromboxane A2 antagonists• GP IIb/IIIa receptor inhibitor

•coronary artery diseasestable CAD, non–ST-segment elevation myocardial infarction (MI) and/or unstable angina ST-segment elevation MI acute coronary syndrome (ACS)percutaneous coronary intervention (PCI)•Cerebrovascular diseaseTIAStrokeCarotid artery stenosisIAStrokeCarotid artery stenosis

•CV events myocardial infarction, stroke, death from CV causes, heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene

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稽核 (Audit) 意見• 林隆堯 教授 :1. 步驟二直接進入 Cochrane Library 固然最有效率，

但可能遺漏最新的文獻，還是要上 PubMed 去搜尋

2. 步驟三並未列舉各搜索文獻之證據等級 ( 採Oxford 或 McMaster 之標準 )

• 李孟智 教授 :1. 步驟四除做結論外，應提出臨床實務建議2. 步驟四如有可能最好能計算 NNT 及 Cost-benefit3.EBM 最終目的還是要應用，並重新稽核其成果

感謝• 感謝 吳宜良同學之演練及學程老師和同學

之熱心參與• 期待我醫研所及老年照護學程師生均能重

視 EBM 並於日常診療中及學習中不斷演練

• 學程計畫主持人 李孟智 教授 敬上