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Clinical Case PresentationBB is a 62-year-old white male with no significant PMH who presents to the urgent care clinic withthe complaint of difficulty walking. The day prior to presentation the patient initially noticed that hewas limping on his right side later followed by difficulty using his right upper extremity. He thentook two aspirin and went to bed. The following morning he again experienced difficulty walkingand presented to clinic for evaluation. He denies headache, visual changes, dysphagia, dysarthria orsensory changes.PMH: None SH: Married, 4 children. Works as full-time professor. Prior tobacco use, quit 30 years ago. 2-3 glasses of wine/wk FH: Father deceased at age 73 of massive stroke. Mother deceased at age 101 of “old age”Meds: Multivitamin qd Allergies: NKDAROS: As above, otherwise negativePhysical Exam:T97.8 BP155/95 P78 R16General physical exam within normal limits. Neurologic exam: Pupils equal and reactive bilaterally,EOM full, facial strength and sensation intact, palate elevates symmetrically, tongue midline. Motorstrength 5/5 on left, 4-4+ on right. Coordination intact by rapid alternating movements, althoughslowed on the right . Sensation intact throughout to pinprick. DTRs 2+ throughout, toes downgoingbilaterally.Labs: CBC, BMP wnl. Head CT without contrast with mild atrophy, otherwise nl. ECG: NSR, noST/TW changes. LDL 110, HDL 34The patient was admitted to the hospital for one day and after having no further progression of hissymptoms was discharged home on aspirin 325mg daily, which had been initiated duringhospitalization. He had mild improvement in his weakness and was ambulatory with a cane upondischarge.The day following discharge the patient presented to the ED with worsening right-sided weakness,which was confirmed on neurologic examination. Repeat head CT was again negative. The patientwas re-admitted and started on clopidogrel 75mg daily. Carotid dopplers and TTE were normal. Thepatient’s symptoms remained stable for the next several days and he was discharged home oncontinued clopidogrel therapy in place of aspirin.Clinical Question: How effective is clopidogrel in secondary stroke prevention?
Background on StrokeStroke remains the third leading cause of death in the U.S. with an estimated 600,000 strokesannually, 500,000 of which are first attacks and 100,000 of which are recurrent strokes. It is theleading cause of disability in adults: of the approximately 300,000 stroke survivors each year, 30%require assistance with ADLs, 20% require assistance with ambulation, and 16% require institutionalcare. The estimated annual cost in 1999 was $51 billion. There are an estimated 4.6 million strokesurvivors in the U.S., highlighting the importance of secondary stroke prevention.Stroke is defined as a sudden focal neurologic deficit caused by a vascular event. There are two maintypes of stroke – ischemic and hemorrhagic. Ischemic strokes account for approximately 80-85% ofstrokes and hemorrhagic for 15-20%. A transient ischemic attack (TIA) is a focal neurologic deficitcaused by temporary interruption of the blood supply without permanent injury to brain tissue. TIAsare defined as lasting less than 24 hours however typically they last between five and twenty minutes,with most lasting less than one hour. Approximately 10-15% of individuals with stroke have priorTIAs and at least one-third of individuals with untreated TIAs will have a stroke within 5 years.Nonmodifiable and modifiable risk factors for ischemic stroke are listed in Table 1. The mostimportant nonmodifiable risk factor is increasing age, with a doubling of the stroke rate each 10 yearsafter age 55. Hypertension is the most important modifiable risk factor, increasing the relative riskthree-to fourfold.Table 1. Risk Factors for ischemic strokeNonmodifiable ModifiableAge HypertensionRace/ethnicity Prior stroke or TIAGender Cardiac diseaseFamily history Diabetes mellitus Hyperlipidemia Asymptomatic carotid stenosis Hyperhomocysteinemia Cigarette smoking Heavy alcohol use ObesityBackground on Stroke PreventionPrimary stroke prevention is oriented towards modification of the above factors. In regards tosecondary prevention, antiplatelet therapy has been shown to be of benefit in reducing vascularevents in those with a history of cerebrovascular or cardiovascular disease. The AntithromboticTrialists’ Collaboration (2002) performed a meta-analysis of 287 studies involving 135,000 patientsof antiplatelet therapy in reducing the endpoints of non-fatal MI, non-fatal stroke, or vascular death.Overall, antiplatelet therapy in patients with a history of atherosclerotic disease reduced the odds of asubsequent vascular event (non-fatal MI, non-fatal stroke, or vascular death) by 25%. Aspirin wasthe most widely tested in the trials evaluated and alone was also associated with an odds reduction of23% (SD 2%) in vascular events. More specifically related to stroke, the European Stroke Prevention
Study 2 (ESPS-2) trial found that in patients with a history of prior stroke or TIA, aspirin reduced therisk of stroke by 18% (P=0.013) when compared with placebo.For those patients that are either intolerant to aspirin or who fail aspirin treatment, alternativeantiplatelet therapy must be considered. Ticlopidine (Ticlid) and clopidogrel (Plavix) are in the classof thienopyridines and inhibit platelet activation by irreversibly inactivating ADP receptor functionand thereby preventing platelet aggregation by way of the GP IIb-IIIa complex. Clopidogrel ispreferred over ticlopidine secondary to having significantly fewer side effects, including rash,diarrhea, neutropenia, and TTP, which have been observed with ticlopidine. Clopidogrel is also thenewer of the two and therefore there are fewer studies evaluating its use.The Canadian American Ticlopidine Study (CATS) and the Ticlopidine Aspirin Stroke Study (TASS)are two studies which looked at the use of ticlopidine in the setting of stroke. The CATS was a trialof 1053 pts with recent thromboembolic stroke randomized to either ticlopidine or placebo andtreated for a mean duration of 1.5 yrs. The primary outcome was the composite of stroke, MI, orvascular death. By intention-to-treat analyses, ticlopidine resulted in a 23.3% relative risk reductionin the primary composite outcome (95% CI, 1.0-40.5%, P=0.02). The risk reduction in fatal andnonfatal stroke alone was not significant (P=0.063). The TASS was a trial of 3069 patients with oneor more of TIA, amaurosis fugax, RIND, or minor stroke (at least 80% recovery of function within 3wks) within 3 months prior to entry who were randomized to ticlopidine or aspirin for a meanduration of 2.1 yrs. The outcomes were death from all causes or nonfatal stroke. Ticlopidine resultedin a 21% relative risk reduction in fatal and nonfatal stroke compared to aspirin (95% CI, 4-38%,P=0.024) based on intention-to-treat analyses. There was a significantly higher incidence of adverseeffects including rash, diarrhea, and neutropenia associated with ticlopidine use in both studies. Bothstudies were limited by high rates (35-40%) of early discontinuation of study medication as well aswide confidence intervals. Conclusions from these studies are that, in patients with a history of priorstroke, ticlopidine compared with placebo reduces the risk of vascular events and compared withaspirin it reduces the risk of stroke, although both at the expense of an unfavorable side effect profile.Studies Evaluating the Use of Clopidogrel in Stroke PreventionClopidogrel vs. Aspirin in Patients at Risk of Ischemic Events (CAPRIE Steering Committee,1996)Study Design: Randomized, double-blinded trial to assess the relative efficacy of clopidogrel andaspirin in reducing the risk of the composite outcome of ischemic stroke, myocardial infarction, orvascular death in patients with atherosclerotic vascular disease manifested as either recent ischemicstroke, recent myocardial infarction, or symptomatic peripheral arterial diseaseParticipants: Patients with clinical evaluation establishing the diagnosis of ischemic stroke,myocardial infarction, or symptomatic atherosclerotic peripheral arterial disease. Inclusion criteriafor stroke participants: focal neurological deficit likely to be of atherothrombotic origin, onset > 1week and < 6 months before randomization, neurological signs persisting > 1 week from stroke onset,CT or MRI ruling out hemorrhage or non-relevant disease. Mean age 62, 72% male, 95% Caucasian,approximately 20% of pts with a history of prior TIA/strokeMethods: 19,185 patients from 384 clinical centers in 16 countries randomized over 3 year period toclopidogrel 75 mg qd plus aspirin placebo or 325 mg aspirin plus clopidogrel placebo. Follow up
visits montly for 4 months, then every 4 months for study duration. Compliance assessed with pillcounting.Outcomes: Primary: composite of ischemic stroke, MI, or vascular deathResults: Mean duration of follow-up 1.91 years. 22 pts in clopidogrel group and 20 in aspirin grouplost to follow-up. 21.3% of clopidogrel pts and 21.1% of aspirin pts had the study drug discontinuedearly for reasons other than an outcome event (most commonly secondary to adverse events). Meancompliance with clopidogrel and aspirin was 91%.Primary analysis by intention-to-treat based on incidence of first occurrence of ischemic stroke,myocardial infarction, or vascular death revealed an event rate per year of 5.32% in the clopidogrelgroup vs. 5.83% in the aspirin group, giving a relative risk reduction of 8.7% in favor of clopidogrel(95% CI 0.3-16.5%, P=0.043). Similar risk reductions seen in secondary outcome clusters, howeverthese were not statistically significant (P>0.05). Analysis of primary outcome cluster by subgroup,revealed 7.3% risk reduction for pts with stroke, which also was not statistically significant (95% CI–5.7-18.7, P=0.26). Significantly greater risk reduction was seen in pts with peripheral arterialdisease (23.8%), while those in the MI subgroup were found to have a relative risk increase of 3.7%,although this also was not statistically significant (Table 2). Further data analysis of those patientswith a history of MI revealed a 22.7% RRR (95% CI 4.9-37.2) in the composite outcome amongpatients with PAD and stroke with a history of MI and a 7.4% RRR (95% CI –5.2-18.6) among allpatients with a history of MI.Outcome event cluster and treatment First outcome events Event Relative-risk Pgroup rate per reduction (95% CI) Non-fatal Fatal Total yearIschaemic stroke, MI, or vascular death(primary cluster)Clopidogrel (nyrs=17636*) 631 308 939 5.32% 8.7% (0.3 to 16.5) 0.043Aspirin (nyrs=17519) 700 321 1021 5.83%Ischaemic stroke, MI, amputation, orvascular deathClopidogrel (nyrs=17594) 677 302 979 5.56% 7.6% (-0.8 to 15.3) 0.076Aspirin (nyrs=17482) 737 314 1051 6.01%Vascular deathClopidogrel (nyrs=17482) -- 350 350 1.90% 7.6% (-6.9 to 20.1) 0.29Aspirin (nyrs=17501) -- 378 378 2.06%Any stroke, MI, or death from any causeClopidogrel (nyrs=17622) 643 490 1133 6.43% 7.0% (-0.9 to 14.2) 0.081Aspirin (nyrs=17501) 720 487 1207 6.90%Death from any causeClopidogrel (nyrs=18377) -- 560 560 3.05% 2.2% (-9.9 to 12.9) 0.71Aspirin (nyrs=18354) -- 571 571 3.11%*Patient-years at risk for outcome clusterTable 2: Intention-to-treat analysis – primary and secondary outcome clusters
Adverse effects of rash and diarrhea were more frequent in the clopidogrel group, while GI effects(N/V, GIB) were more frequent in the aspirin group. Thrombocytopenia and neutropenia incidencewas low (0.26% and 0.05% respectively) and similar between the two groups.Conclusions: In patients at high risk for vascular events, clopidogrel provides risk reduction in thecomposite outcome of ischemic stroke, myocardial infarction, or vascular death compared withaspirin; clopidogrel was not associated with any increase in incidence of adverse effects compared toaspirinLimitations: 1. Only analyzed composite outcomes, did not look specifically at outcome of stroke alone 2. Primary composite outcome with wide confidence interval 3. Composite outcome risk reduction in subgroup of stroke patients not statistically significant 4. Study population primarily CaucasianReduction in the Need for Hospitalization for Recurrent Ischemic Events and Bleeding withClopidogrel Instead of Aspirin (Bhatt et al., 2000)Study Design: Analysis of data from the CAPRIE trial looking at clopidogrel vs. aspirin in reducingrehospitalization rates for ischemia and bleedingParticipants: Patients in the CAPRIE trialMethods: Rehospitalization rates for angina, TIA, limb ischemia, or bleeding were collected fromforms documenting significant adverse events which were required to be reported within 24 hours ofoccurrence. Rehospitalization was defined as a new hospitalization or extension of the duration of anexisting hospitalization. If two events began on the same day and both led to rehospitalization, theywere considered as one hospitalization.Results: There was a statistically significant decrease in the rate of rehospitalization for clopidogrelvs. aspirin for the outcomes of rehospitalization due to any ischemic or bleeding event (RRR 8.7%95% CI 1.7-15.2, P=0.015) and any ischemic event (RRR 7.7%, 95% CI 0.1-14.7, P=0.048). Withinsubgroups of ischemic events, there was a 25.6% RRR in rehospitalization for TIA (95% CI –0.6-45,P=0.054). Clopidogrel was also associated with decreased rates of rehospitalization forgastrointestinal bleeding compared to aspirin (RRR 31.8% 95% CI 7.9-49.5, P=0.012).Conclusions: In those patients with a recent ischemic event (stroke, MI, symptomatic peripheralarterial disease), clopidogrel resulted in a modest decrease in the risk of rehospitalization for furtherischemic events (angina, TIA, PAD) or gastrointestinal bleeding compared to aspirinLimitations: All rehospitalizations may not have been reported thereby affecting results. Wideconfidence intervals
Superiority of Clopidogrel Versus Aspirin in Patients with Prior Cardiac Surgery (Bhatt et al.,2001)Study Design: Analysis of data from the CAPRIE trial looking at those patients with a history ofprior cardiac surgery and the effectiveness of clopidogrel compared with aspirin in reducing recurrentischemic eventsParticipants: Patients in the CAPRIE trial with a history of cardiac surgeryMethods: Pts with a history of cardiac surgery were identified upon enrollment in the study. Pts witha history of valvular heart disease (9%) were excluded from the analysis in attempts to include onlythose with prior CABGOutcomes: 1. CAPRIE endpoint: vascular death, MI or ischemic stroke 2. Rehospitalization (all cause) 3. Rehospitalization (ischemic event or bleeding)Results: Event rate per year of composite outcome of vascular death, MI, or ischemic stroke inclopidogrel group 5.8% vs. 9.1% with aspirin, giving a RRR 36.3% (95% CI 13.4-53.1, P=0.004).For the outcome of all-cause death, MI, or all-cause stroke, there was a RRR 31.8% in favor ofclopidogrel (95% CI, 8.2-49.4, P=0.011). Clopidogrel was also associated with a decreased rate ofrehospitalization, principally for ischemic events (USA, TIA, or limb ischemia) with a RRR 21.3%(95% CI 1.2-37.4, P=0.038)Conclusions: Compared with aspirin, clopidogrel reduces the risk of the composite outcome ofvascular death, MI, and ischemic stroke and results in decreased rehospitalization rates in thosepatients with a history of atherosclerotic vascular disease and prior cardiac surgeryLimitations: Date and type of cardiac surgery not specified. Wide confidence intervals. Studyconcentrates on cardiac patients, limiting applicability to stroke populationEffects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromeswithout ST-Segment Elevation (CURE Trial Investigators, 2001)Study Design: Randomized, double-blinded, placebo-controlled trial assessing the efficacy andsafety of clopidogrel plus aspirin vs. aspirin alone in patients with acute coronary syndromes withoutST-segment elevationParticipants: Patients admitted to the hospital presenting with symptoms suggestive of acutecoronary syndrome within 24 hours of the onset of symptoms and without ST segment elevation>1mm. ECG changes compatible with new ischemia or elevated cardiac enzymes or tropinin I or Tto at least twice the upper limit of normal were required. Pts with severe heart failure (class IV),PTCA/stent or CABG within 3 months prior, or administration of glycoprotein IIb/IIIa inhibitorswithin 3 days prior were excluded. Mean age 64, 61% male, approximately 4% with prior history ofstroke
Methods: 12,562 patients from 482 clinical centers and 28 countries randomized to either clopidogrel300mg immediately, followed by 75mg qd (6259) or placebo (6303) over a period of 2 years.Aspirin (75-325mg) was started simultaneously with the study drug in both groups. Follow-upassessments at hospital discharge, one and three months, then every three months for the remainder ofthe study.Outcomes:Primary: 1. Composite of death from cardiovascular causes, nonfatal MI, or stroke 2. Composite of first primary outcome or refractory ischemiaSecondary: Severe ischemia, heart failure, and the need for revascularizationSafety Related: Bleeding complications (life threatening, major, minor)Results: Mean duration of treatment was 9 months. 46.2% of pts in clopidogrel group and 45.4% ofpts in placebo group discontinued study medication temporarily (>5 days), most commonlysecondary to the need for revascularization or another surgical procedure. 21.1% of pts inclopidogrel group and 18.8% in placebo group discontinued study medication permanently. 94-99%compliance with aspirin in both groups. Use of all medications other than lytics and IIb/IIIainhibitors similar between the two groups. Lytics used in 1.1% and 2.0% in clopidogrel and placebogroups respectively (P<0.001). IIb/IIIa inhibitor used in 5.9% and 7.2% in clopidogrel and placebogroups respectively (P=0.003). 21.2% of pts underwent PTCA and “vast majority” receivedthienopyridine-type antiplatelet drug for 2-4 weeks.The first primary outcome (cardiovascular death, nonfatal MI, or stroke) occurred in 9.3% ofclopidogrel group and 11.4% of placebo group (RR 0.80, 95% CI 0.72-0.90, P<0.001). The secondprimary outcome (first primary outcome or refractory ischemia) occurred in 16.5% of clopidogrelgroup and 18.8% of placebo group (RR 0.86, 95% CI 0.79-0.94, P<0.001). Within the subgroups ofprimary outcomes, stroke occurred in 1.2% of clopidogrel group and 1.4% in placebo group (RR0.82, 95% CI 0.63-1.18) (Table 3)Major and minor bleeding was significantly more common in the clopidogrel group compared withplacebo (3.7% vs. 2.7% and 5.1% vs. 2.4% respectively). The number of patients withthrombocytopenia (26 in clopidogrel group, 28 in placebo group) and neutropenia (8 and 5respectively) were similar in the two groups.
Table 3. Incidence of the Main Study Outcomes in CURE TrialConclusions: In patients presenting with acute coronary syndromes without ST-segment elevationtreatment with clopidogrel plus aspirin resulted in moderate reductions in the risk of the compositeoutcome of nonfatal MI, stroke, or death from cardiovascular causes as well as in the risk ofmyocardial infarction alone compared with aspirin. There was only a small reduction in stroke riskalone. Clopidogrel plus aspirin was also associated with an increased risk of bleeding complicationscompared with aspirin alone.Limitations: This study mainly looks at cardiac patients (only 4% with a history of prior stroke)therefore limiting applicability of this particular treatment (clopidogrel plus aspirin) in secondarystroke prevention. Breaks in treatment with temporary discontinuation of medication and use ofunknown thienopyridine following PTCA may have affected results. With regards to adverse effects,the study did not comment whether bleedings events occurred in association with other anticoagulantuse (heparin, IIb/IIIa inhibitors) or lytics.
Trial Therapy Outcome RRR (%) ARR (%) NNT (event rate/yr)ESPS-2 ASA vs. placebo Fatal/Nonfatal Stroke 18.3 1.3 76TASS Ticlop vs. ASA Fatal/Nonfatal Stroke 21.0 0.6 167CATS Ticlop vs. placebo Stroke, MI, vascular death 23.3 3.5 29CAPRIE Clopid vs. ASA Stroke, MI, vascular death 8.7 0.5 200CURE Clopid + ASA vs. ASA Stroke, nonfatal MI, 18.4 2.8 36 cardiovascular death Fatal/Nonfatal Stroke 14.3 0.2 413Table 4. Summary of results from selected antiplatelet trialsFINAL CONCLUSIONS: Aspirin’s effectiveness in reducing the risk of vascular events, includingstroke in patients with known atherosclerotic disease has been shown in many studies and remainsevident in a recent meta-analysis by the Antiplatelet Trialists Collaboration. The thienopyridinesticlopidine and clopidogrel also appear to be effective in secondary stroke prevention although whencompared with aspirin, the additional risk reduction is modest. Clopidogrel is the preferred agent,given its lower incidence of adverse effects compared to ticlopidine. The CAPRIE trial comparedclopidogrel with aspirin in pts with known vascular disease presenting with MI, stroke, or PAD. Thisagain revealed only modest risk reduction in the primary composite outcome of stroke, MI, andvascular death, with a RRR of 8.7% and number needed to treat (NNT) of 200. The reduction in riskwith stroke outcome alone was not statistically significant. Therefore, compared with aspirin, anadditional 200 pts would need to be treated with clopidogrel for one year to prevent one additionalvascular event. With an annual approximated cost of $800/pt this equates to $160,000 to prevent oneadditional event.The CURE trial provided evidence for a greater risk reduction with the combination of clopidogreland aspirin compared with aspirin alone. In the population studied (pts presenting with acutecoronary syndrome without ST elevation), clopidogrel plus aspirin compared to aspirin alone resultedin an 18% risk reduction in the composite outcome of stroke, nonfatal MI, and cardiovascular death(NNT 36). Application of these results to stroke prevention is limited by it being a study attractingprimarily cardiac pts with a low percentage of pts in the study with cerebrovascular disease (4% withhistory of prior stroke). This combination of antiplatelet therapy needs to be studied moreextensively in the stroke population with any benefit weighed against the potential increased risk ofbleeding which was observed in the CURE trial. A study is currently being done looking at aspirinplus clopidogrel vs. aspirin in patients with recent stroke/TIA (MATCH trial).Based on these results, with only a modest decrease in stroke risk with clopidogrel compared toaspirin and its significant cost, aspirin remains the first line agent for secondary prevention.Clopidogrel is an effective and safe alternative for those patients who are intolerant to aspirin, and itsuse should be considered in those patients with recurrent stroke or TIA while on aspirin therapy. Itsconcurrent use with aspirin requires further study in the stroke population. In addition to antiplatelettherapy, continued modification of risk factors should be emphasized. A limitation of the studiesdiscussed above is the lack of assessment of risk factor control, given that significant percentages of
the patients in these studies had histories of cardiac disease, diabetes, and hypertension. Furtherstudy of the effects of risk factor modification in conjunction with antiplatelet therapy in secondarystroke prevention is needed.REFERENCES1. American Heart Association. Stroke Statistics. http://www.americanheart.org/downloadable/heart/HS_State_02.pdf. Dallas, TX: American Heart Association; 2000.2. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomized trials of antiplatelet therapy – I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. British Med J 1994; 308:81-106.3. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. British Med J 2002; 324:71-86.4. Bhatt DL, Chew DP, Hirsch AT, Ringleb PA, Hacke W, Topol EJ. Superiority of Clopidogrel versus aspirin in patients with prior cardiac surgery. Circulation 2001; 103:363-8.5. Bhatt DL, Hirsch AT, Ringleb PA, Hacke W, Topol EJ. Reduction in the need for hospitalization for recurrent ischemic events and bleeding with clopidogrel instead of aspirin. American Heart J 2000; 140:67-73.6. Biller J, Love BB. Vascular Diseases of the Nervous System. In: Bradley WG, Daroff RB, Fenichel GM, Mardsen CD, eds. Neurology in Clinical Practice, 3rd edition. Boston: Butterworth Heinemann, 2000:1125-66.7. CAPRIE Steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348:1329-39.8. CURE Study Investigators. The clopidogrel in unstable angina to prevent recurrent events (CURE) trial programme: rationale, design and baseline characteristics including a meta- analysis of the effects of thienopyridines in vascular disease. European Heart J 2000; 20:2033-41.9. CURE study investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. New Engl J Med 2001; 245:494-502.10. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European stroke prevention study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sciences 1996; 143:1-13.
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