aggrenox slide kit

Aggrenox/Asasantin

Slide Kit

Prevention of Recurrent Stroke and TIA

Please note that the results discussed herein may go beyond the licenced indications of the drugs.

The data presented in this slide kit are for scientific education only. They do not intend to suggest a use of the drug in a particular way.

Therefore, please contact the Boehringer Ingelheim affiliate in your country in order to obtain the information relevant for your country.Disclaimer

Chapters

1.Background Information on Stroke / TIA2.1.Antithrombotic / Antiplatelet Therapy2.2.Meta-Analyses for Antiplatelet Therapy in Ischaemic Stroke2.3.PRoFESS The Largest Trial in Recurrent Stroke Prevention2.4.SafetyGuidelines & RecommendationsPrescribing Information

Background Information on Stroke / TIA

1. Background Information on Stroke / TIA

1.1. Pathophysiology1.2. Epidemiology1.3. Costs

Pathological mechanisms contributingto cardio- and cerebrovascular eventsAtherosclerosis, Cardio- and Cerebrovascular EventsHowever, stroke and MI patients differ in the risk of subsequent vascular eventsAtheroma formation and rupture in coronariesEmbolism and impaired vasoreactivity in brain circulationEndothelialDysfunction

Hadi et al. Vascular Health and Risk Management 2005; 1(3): 183-198. Glasser et al. Am Heart J 1996; 131: 379384.

Treatment of atherothrombosisNeed for acuteantiplatelet treatmentNeed for chronic antithrombotic, anti-inflammatory and vessel wall treatmentEisert et al. In Michelson AD, 2nd ed. Chap 63. Platelets Amsterdam: Elsevier 2007: 11651179.Pleiotropic effects of dipyridamole add to inhibition of platelets

Stroke types and incidenceIschaemic stroke 88%Haemorrhagic stroke 12%Other 5% Cryptogenic 30%Cardiogenic embolism 20%Small vesseldiseaselacunes 25%Atheroscleroticcerebrovasculardisease20%Albers et al. Chest 2004; 126 (3 Suppl): 438S512S.Thom et al. American Heart Association. Circulation 2006; 113: e85e151.

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Haemorrhagic stroke12

Atherosclerotic cerebrovascular disease20

Small vessel disease lacunes25

Cardiogenic embolism20

Cryptogenic30

Other5

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Risk factors and predictors of strokeNon-modifiable risk factorsOlder ageMale genderNon-white ethnicityFamily historyPrevious strokeModifiable risk factorsCigarette smokingObesityHigh alcohol consumptionLow physical activityElevated blood pressureDiabetes mellitusHyperlipidaemiaAtrial fibrillation Carotid artery diseaseCardiac diseasePrevious stroke or TIA is one of the most importantrisk factors for strokeJohnston et al. Lancet 2007; 369: 283-292.Coull et al. BMJ 2004; 328: 326-328.Hankey. Cerebrovasc Dis 2003; 16 (Suppl 1): 1419. Sacco et al. Stroke 1997; 28: 15071517.

Stroke begets strokeAlbers. Neurology 2000; 54: 10221028.n=6,431Stroke patients are most at risk of another strokePercentage (%) of stroke patients with subsequent eventsCATS0246810121416TASSCAPRIE*ESPS 214%3%13%7%10%2%13%3%TrialsMyocardial InfarctionStrokePercentages rounded up

Transient ischaemic attack (TIA)Aetiology no different from definite stroke.A TIA is a "warning stroke" or "mini-stroke with stroke-like symptoms persisting less than 24 hours, that clears without residual disability.Prompt evaluation (hospital or stroke specialist) is necessary to identify the cause and determine appropriate therapy.TIA and stroke have the identical risk for early recurrent stroke up to 14% within the first 2 weeks.About one-third of those who have a TIA will have an acute stroke some time in the future.

Johnston et al. JAMA 2000; 284: 29012906.Warach, Kidwell. Neurology 2004; 62: 359360.Mohr. Neurology 2004; 62 (8 Suppl 6): S3S6.

Stroke and TIA patients are at high risk of a recurrent event within 3 months052015107-daystroke risk30-daystroke risk3-monthstroke risk%052015107-daystroke risk30-daystroke risk3-monthstroke risk%Stroke patients: risk of recurrent eventTIA patients: risk of recurrent eventCoull et al. BMJ 2004; 328: 326.11.515.018.58.011.517.3

Early treatment of TIA or minor stroke reduces risk of recurrent strokeMany patients with a TIA or minor stroke experience delays in assessment and treatment.Because symptoms are not long-term, patients are often not admitted to a hospital.TIAs and minor strokes should be considered as medical emergencies.Early initiation of preventative treatment can reduce the risk of early recurrent stroke by 80%.For patients with a TIA, evaluation and initiation of treatment in a specialised outpatient clinic is associated with a reduced risk of subsequent stroke. Lavalle et al. Lancet Neurol 2007; 6: 953-960.Rothwell et al. Lancet 2007; 370: 1432-1442.

Stroke morbidity and mortalityEach year stroke causes about 5.54 million deaths worldwide and the estimated costs in 2007 amounted to 57.9 billion US$.Stroke is the second leading cause of mortality worldwide and the third most common cause in more developed countries.Stroke is the major cause of long-term disability in adults.Without urgent action, deaths from stroke will increase over the next decade by 12% globally and 20% in resource-poor countries.Compared with conventional ward care, stroke unit care is associated with a reduced probability of death or disablement.

The advent of thrombolytic therapy together with development of stroke units has led to a reduction of mortality and disability caused by stroke.

Sarti et al. Stroke 2000; 31: 15881601. Murray et al. Lancet 1997; 349: 12691276.WHO neurological disorders report 2007: 151163.Feigin et al. Lancet Neurology, 2003; 2: 4353.Candelise et al. Lancet 2007; 369: 299-305.

Total costs of stroke in the US (billion US $), 2008Estimated at 65.5 billion US $Rosamond et al. American Heart Association. Circulation 2008; 117: e25e146. Direct costs43.7 bn US $Indirect costs21.8 bn US $Home healthcare4.2Medical durables1.3Physicians3.6Lost productivity/morbidity6.7Lost productivity/mortality15.1Totals do not add up because of rounding and overlap.

2.1. Antithrombotic / Antiplatelet Therapy

2.1. Antithrombotic / Antiplatelet Therapy 2.1.1. Aspirin (ASA)2.1.2. Clopidogrel2.1.3. Extended-Release Dipyridamole + Aspirin

Efficacy of ASA in the prevention of recurrent strokeAlgra, van Gijn. J Neurol Surg Psychat 1996; 60: 197199.Algra, van Gijn. JNNP 1999; 66: 255.He et al. 1998. JAMA 1998; 280: 19301935.Johnson et al. Arch Intern Med 1999; 159: 12481253. Albers, Tijssen. Neurology 1999; 53 (7 Suppl 4): S25S31.In patients with an ischaemic stroke or TIA, there is a:13% RRR in the combined endpoint of MI/stroke/vascular disease RRR of 18% in patients with ischaemic stroke, completely independent of dosage

Many studies have shown the efficacy of low-dose ASA for the prevention of vascular events

Prevention of vascular events in stroke/TIApatients with ASA following first stroke12% relative risk reduction in ESPS 2 (ASA 50 mg/d vs. placebo)Albers, Tijssen. Neurology 1999; 53 (7 Suppl 4): S25S31.ASA vs. placebo: efficacy by doseA meta-analysis of 10 controlled trials (n=9,173)ASA dose Relative risk (stroke, MI or vascular death)1,0001,300 mg/d300 mg/d5075 mg/dOverall0.8 (20% relative risk reduction)ASA betterPlacebo better

CAPRIE Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events

Primary outcome: cumulative risk of ischaemic stroke, myocardial infarction, or vascular deathCAPRIE Steering Committee. Lancet 1996; 348: 13291339. Time since randomisation (months) 03691215182124273033 Cumulative risk (%) 05101520Clopidogrel 75 mg/day ASA 325 mg/day RRR: 8.7% (p=0.043, n=19,185)36n=19,185

StrokeMIASA

Clopidogrel

8% RRR* (ns) 15% RRR* (ns)CAPRIE Steering Committee. Lancet 1996; 348: 13291339.Total number (n) of events (2 yr follow-up)33851315440100200300400Results for stroke patient subgroup analysis: non-significant prevention of vascular events with clopidogrel*RRR = Relative Risk ReductionThe RRR* of vascular events was 7.3% in favour of clopidogrel (p=0.26)n=6,431

Composition of the Aggrenox/Asasantin retard capsuleProven combination antiplatelet therapyThree primary mechanisms of actionprevents platelet aggregationantithrombotic effects on the endotheliumanti-inflammatory effectsImproved absorption through extended-release form (for subjects with increased gastric pH)ASADipyridamole extended-release pelletsDipyridamoleHP cellulose protective filmRetard coating Tartaric acid:Intermediator DPDerendorf et al. J Clin Pharmacol 2005;45: 845850.Eisert et al. In Michelson AD, 2nd ed. Chap 63. Platelets Amsterdam: Elsevier 2007: 11651179.Diener et al. J Neurol Sci 1996; 143: 113.

Derendorf et al. J Clin Pharmacol 2005; 45 (7): 845850.200 mg ER-DP + 25 mg IR-ASAIR-DP 100 mg dose at 0 and 6 hours, where the first dose was co-administered with an 81 mg delayed release ASA tabletImproved absorption with extended-release dipyridamole formulation17501500125010007505002500024681012Time (h)Concentration (ng/mL)DP bioavailability from the ER-DP tablet was approximately twice that of the IR-DP tabletPeak DP plasma concentrations were 57% lower with the IR-DP tabletGastric pH was increased (pH > 4.0) in 20 healthy subjects with lansoprazole

Aggrenox Mode of ActionEisert et al. In Michelson AD, 2nd ed. Chap 63. Platelets Amsterdam: Elsevier 2007: 11651179. Platelets:Vessel wall:multiple protective effectsantiinflammatoryantioxidativeantiproliferativeantithrombotic effect

Effects of ER-DP: benefits beyond platelet inhibitionPlatelet inhibition (adenosine)Thrombin receptor density reductionAdditional effects at the vessel wall:Potentiates nitric oxide effectsAnti-inflammatoryAnti-oxidantCell membrane protectionAntiproliferativeTissue preconditioningEisert et al. In Michelson AD, 2nd ed. Chap 63. Platelets Amsterdam: Elsevier 2007: 11651179.Weyrich et al. Circulation 2005; 111: 633642.Aktas et al. Stroke 2003; 34: 764769.

ESPS 2 The European Stroke Prevention Study 2

ESPS 2: effects on stroke relative risk reductionDiener et al. J Neurol Sci 1996; 143 (12): 113.ER-DP + ASA vs. placebo ER-DP vs. placebo ASA vs. placeboER-DP + ASA vs. ASA Relative Risk Reduction (%)Pairwise comparisons:ER-DP + ASA is significantly more effective than ASA or ER-DP alone

ESPS 2, combined endpoint (stroke or death): 24% RRR ER-DP+ASA vs. placeboCombined endpoint (stroke or death): 24% RRR ER-DP+ASA vs. placebo30Time (months)252015105006121824PlaceboASAER-DPER-DP+ASAp

0624PlaceboASAER-DPER-DP+ASAp

ESPS 2: efficacy of ER-DP + ASATotal number (n) of events (2 yr follow-up)StrokeMIstatistically significant 23% RRR 10% RRR2063915735050100150200250Diener et al. J Neurol Sci 1997; 151 (Suppl): S1S77..

ESPRIT The European/Australasian Stroke Prevention in Reversible Ischaemia Trial

DisclaimerESPRIT is an independent investigator initiated studyESPRIT describes the use in a composite endpoint which is not part of the Aggrenox (Asasantin Retard) labelThe dose range of ASA in ESPRIT was between 30 and 325mg/day; in average less than 75mg/day83% of the patients received extended-release dipyridamole, 8% the fixed-dose combination ER-DP + ASA 200/25mg twice daily, marketed as Aggrenox (Asasantin Retard)

Time to event curves for primary outcome event and all ischaemic eventsTime from randomisation (years)Time from randomisation (years)ASADP + ASACumulative event rate (%)012345012345Primary outcome event (death from all vascular causes, non-fatal stroke / MI, or major bleeding)All ischaemic events The ESPRIT Study Group. Lancet 2006; 367: 1665-1673.RRR: 20%RRR: 19%2520151050

2.2. Meta-Analyses for Antiplatelet Therapy in Ischaemic Stroke

2.2. Meta-Analyses for Antiplatelet Therapy in Ischaemic Stroke 2.2.1. Halkes et al. 2008(JNNP 2008; ePub ahead of print)

2.2.2. Verro et al. 2008(Stroke 2008;39:13581363)

2.2.3. Thijs et al. 2008(European Heart Journal 2008;29(9):1086-92)

Results of a meta-analysis by Halkes et al on stroke patients comparing DP + ASA vs. ASA aloneHalkes et al. JNNP 2008; ePub ahead of print.4754343583418117557952836018742987DP + ASA (n=3,800)ASA (n=3,812)Stroke, MI, vascular deathStroke, vascular deathMIStrokeVasculardeathAlldeathEvents (n)HR 0.81(*0.72-0.92)HR 0.82(*0.72-0.92)HR 1.01(*0.87-1.17)HR 0.96 (*0.78-1.18)HR 0.78(*0.68-0.90)HR 0.94(*0.69-1.27)*95% Confidence Interval

Results SubgroupsOutcome: vascular death, non-fatal stroke, non-fatal MI, HR (95% Confidence Interval)Halkes et al. JNNP 2008; ePub ahead of print.

Verro et al. Stroke 2008; 39: 13581363.Outcome non-fatal stroke0.010.030.100.321.003.50Risk Ratio (95% CI)Favours aspirin+ dipyridamoleFavours aspirin0.77 (0.67-0.89)0.79 (0.61-1.01)0.74 (0.60-0.91)0.83 (0.55-1.26)0.98 (0.50-1.91)0.27 (0.03-2.37)0.64 (0.15-2.72)Relative Risk (95% CI)Caneschi*Guiraud-ChaumeilAICLAACCSGESPS-2ESPRITSummary* Data for stroke alone endpoint only

Composite outcome of non-fatal stroke, non-fatal myocardial infarction, and vascular deathGuiraud-ChaumeilAICLAACCSGESPS-2ESPRITSummaryFavours aspirin+ dipyridamoleFavoursaspirin0.50.71.01.41.92.6Risk Ratio (95% CI)0.95 (0.60-1.51)1.17 (0.53-2.56)0.92 (0.70-1.21)0.85 (0.73-0.98)0.78 (0.64-0.96)0.85 (0.76-0.94)Relative Risk (95% CI)Verro et al. Stroke 2008; 39: 13581363.

Results for direct comparison and network meta-analysisDirectMeta- analysisSimultaneous meta-analysis of common antiplatelet regimens after TIA or stroke(42,688 patients) on the combination of vascular death, stroke or MI.Thijs et al. Eur Heart J 2008; Mar 17; 29(9):1086-92.Each cell gives an odds ratio (and 95% confidence interval); in the lower diagonal part, this OR compares the row condition with the column condition, and in the upper diagonal part, the OR compares the column condition with the row condition.

PlaceboASAThieno-pyridinesASA + DP Thieno pyridines + ASA

Placebo0.86 (0.780.96)0.77 (0.581.03)0.65 (0.570.76)No direct comparisonASA 0.85 (0.780.93)0.94 (0.851.04) 0.79 (0.700.90) 0.83 (0.671.03)Thienopyridines0.79 (0.700.89) 0.93 (0.851.02) No direct comparison0.97 (0.841.10)ASA + DP 0.67 (0.600.75)0.78 (0.700.87)0.84 (0.730.97) No direct comparisonThienopyridines + ASA 0.75 (0.640.88)0.88 (0.771.00)0.95 (0.841.07)1.12 (0.951.33)

2.3. PRoFESS The largest trial inrecurrent stroke prevention

The PRoFESS Trial Prevention Regimen For Effectively avoiding Second Strokes

the worlds largest trial inprevention of recurrent strokeDiener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380.Participating countriesNon-participating countries

*Objectives:

To compare the efficacy and safety of the combination of extended-release dipyridamole and aspirin to clopidogrelTo compare telmisartan to placebo in the prevention of recurrent stroke

PlaceboTelmisartan(80 mg)*Initially ASA plus clopidogrel trial design2x2 factorial design involving 20,332 stroke patientsDiener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380.BI data on file 2008.*changed in May 2004 from clopidogrel + ASA

ER-DP + ASA(400 mg/50 mg)Clopidogrel*(75 mg)

ER-DP + ASA+ TelmisartanClopidogrel* + Telmisartan

ER-DP + ASA + PlaceboClopidogrel* +Placebo

55 years AND ischaemic stroke within 90 days of the eventOR50-54 years AND/OR after 90-120 days of the qualifying stroke,provided the patient had at least two of the following risk factors:Diabetes mellitusHypertensionSmoker at time of qualifying strokeObesityVascular disease prior to qualifying strokeEnd-organ damageHyperlipidaemiaDiener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380.

exclusion criteriaHaemorrhagic stroke Congestive heart failureUnstable anginaDementiaModified Rankin Scale >4Hepatic and renal insufficiencyHistory of thrombocytopeniaUncontrolled hypertension (systolic BP >180 mmHg, or diastolic BP > 110 mmHg)Ongoing treatment with an ARBDiener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380.

endpoint definitionPrimary endpointStroke, MI or vascular deathStroke, MI, vascular death or congestive heart failureNew onset diabetesSecondary endpointsRecurrent stroke (ischaemic, haemorrhagic, or undefined)Diener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380.

other endpointsPrespecified analysesStroke or major haemorrhagic eventHaemorrhagic eventsOther designated vascular eventsAll deathsNew or worsening congestive heart failureThrombotic thrombocytopenic purpuraNeutropenia Diener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380.

The trial was designed to detect a 13% RRR of ER-DP + ASA vs. clopidogrel at 82% power (1,715 recurrent strokes)

The Steering Committee recommended a sequential approach to analysis of non-inferiority followed by superiority statistical design

sequential statistical analysisAssuming ER-DP + ASA has 6.5% risk reduction over clopidogrel (risk ratio=0.935) with one-sided =0.025Non-inferiority =1.075 (risk ratio)Upper limit of 95% confidence interval is less than the non-inferiority =1.075Non-inferiority0.7750.850.92511.0751.15Hazard RatioER-DP + ASA betterCP betterUpper limit of 95% CI

substudiesFour main substudies were approved as part of the PRoFESS trial:The cognitive substudy will examine whether study medication can reduce the rate of cognitive decline.The haemodynamic substudy will investigate the central and peripheral haemodynamic effects of the study drugs, including central compliance, central blood pressure, myocardial perfusion (Buckberg index) and various 24-hour ambulatory blood pressure measures.The magnetic resonance imaging substudy will determine whether patients with silent brain infarcts have a higher risk of recurrent stroke, and whether patients with white matter lesions at study entry are developing vascular dementia more frequently. The biomarker and genetic analysis substudy will perform these analyses on blood samples collected at baseline and at 2 years.Diener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380.

PRoFESS Baseline data

Diener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380. age, gender, BMI, blood pressure

Mean SBPmmHgMean DBPmmHg14484

Mean BMIMean abdominal girthcm26.896.5

Mean Age yrsMale66.164.0 %

regional distributionDiener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380.

Race or ethnic group%

European/Caucasian57.3Chinese18.0South Asian8.4Japanese1.1Malaysian0.6Other Asian4.6Black African/African American4.0Native Latin4.5Caribbean/Hispanic0.3Arab, Persian0.2Other0.8

medical historyDiener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380.

MMSE* at 30 days* Mini Mental State ExaminationDiener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380.* Numbers rounded off

MMSE*

Median28

modified Rankin ScaleMostly mildly impaired patients took part in the trial, which is typical for recurrent stroke prevention trials.Diener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380.

TOAST criteria*Diener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380.* Numbers rounded offLarge-artery Atherosclerotic29%Undetermined aetiology16%Cardioembolism2%Small-artery Occlusion52%Other determined aetiology2%

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time to randomisationDiener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380.PRoFESS

Median time from qualifying event to randomisation was 15 days40% of patients were randomised within 10 daysWith over 8,000 patients enrolled within 10 days, PRoFESS will provide important data regarding the efficacy of starting antiplatelet regimens early after stroke onset

medication at baselineDiener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380.* Numbers rounded off

Concomitant medication%*

ACE inhibitors37Statins47Calcium channel blockers24ARBs5Beta blockers21Loop active diuretics3Thiazide diuretics17Potassium-sparing diuretics2Insulin6Oral hypoglycaemic drugs19

summary trial designPRoFESS

is one of the worlds largest trials in prevention of recurrent stroke with 20,332 patients enrolledis the first head-to-head comparison of antiplatelet treatment for recurrent stroke prevention (ER-dipyridamole + ASA or clopidogrel)compares telmisartan vs. placebo on top of antiplatelet therapyuses a 2 x 2 factorial trial design that allows assessment of the contribution of each treatment tested

Diener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380.Sacco RL, Diener HC, Yusuf S et al. N Engl J Med 2008; 359:1238-51.

summary baseline dataPRoFESSis a multinational trial with substantial representation of all continents and racessucceeded to enrol more than 2/3 of patients within 30 days of stroke onsethas enrolled a wide spectrum of patients with different ischaemic stroke subtypes (small vessel as well as large artery disease) and stroke severity (modified Rankin Scale 05)patients represent a high-risk patient cohort with 30% of patients having concomitant cardiovascular disease other than stroke; nearly 1/3 are diabetic and more than 2/3 are hypertensivepatients receive state of the art cardiovascular treatment (statin use in 47% of patients, BP well controlled at baseline with a mean BP of 144/84 mmHg)Diener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380.

PRoFESS Results

primary outcome: stroke recurrenceYears since randomisation* Covariates in Cox model are age, baseline ACE-inhibitor use, modified Rankin, and baseline diabetes status.Sacco RL, Diener HC, Yusuf S et al. N Engl J Med 2008; 359:1238-51.0 321Clopidogrel ER-DP+ASA0.51.52.53.5Cumulative Probability of Recurrent Stroke0.000.040.060.080.100.120.140.02Please note: ER DP + ASA did not meet the predefined statistical non-inferiority vs clopidogrel.Both regimens show comparable efficacy.

No. at risk:ER-DP+ASA101819715943191466970442623321060Clopidogrel101519677937191376934443523311037

ER-DP + ASAClopidogrelHR95% CIp-value916 (9.0%)898 (8.8%)1.010.92, 1.110.783

% of Patients0ER-DP + ASA12345678910916 (9.0%)898 (8.8%)780 (7.7 %)83 (0.8%)53 (0.5%)805 (7.9%)45 (0.4%)48 (0.5%)ClopidogrelIschaemicHaemorrhagicOther or unknown characterisation of first recurrent strokeSacco RL, Diener HC, Yusuf S et al. N Engl J Med 2008; 359:1238-51.

secondary outcome: stroke, MI, vascular deathCumulative Probability of Stroke, MI, or Death from Vascular Causes0.000.040.060.080 321ClopidogrelER-DP+ASAYears since randomisation0.51.52.50.100.160.180.02* Covariates in Cox model are age, baseline ACE-inhibitor use, modified Rankin score, and baseline diabetes status.3.50.120.14Sacco RL, Diener HC, Yusuf S et al. N Engl J Med 2008; 359:1238-51.


ER-DP + ASAClopidogrelHR95% CIp-value1,333 (13.1%)1,333 (13.1%)0.990.92, 1.070.829

tertiary outcomesSacco RL, Diener HC, Yusuf S et al. N Engl J Med 2008; 359:1238-51.

ER-DP + ASAClopidogrelHR(ER-DP + ASA)95% CI

Number of randomised patients10,18110,151Tertiary outcomesMI178 (1.7%)197 (1.9%)0.900.73, 1.10New/worsening CHF144 (1.4%)182 (1.8%)0.780.62, 0.96Death739 (7.3%)756 (7.4%)0.970.87, 1.07Other designated vascular event533 (5.2%)517 (5.1%)1.030.91, 1.16

new or worsening CHF* Covariates in Cox model are age, baseline ACE-inhibitor use, modified Rankin, and baseline diabetes status.Events (%)0.0000.0050.0100.0150 321ClopidogrelER-DP+ASAYears since randomisation0.51.52.53.50.0200.0250.030BI data on file 2008

ER-DP + ASAClopidogrelHR95% CIp-value144 (1.4%)182 (1.8%)0.780.62 - 0.960.022


adverse events leading to permanent discontinuationSacco RL, Diener HC, Yusuf S et al. N Engl J Med 2008; 359:1238-51.

ER-DP + ASAClopidogrel

Patients receiving antiplatelet medication10,055 (100.0%)10,040 (100.0%)Patients with adverse events leading to treatment discontinuation1,650 (16.4%)1,069 (10.6%)Headache593 (5.9%)87 (0.9%)Vomiting158 (1.6%)37 (0.4%)Nausea155 (1.5%)58 (0.6%)Dizziness134 (1.3%)52 (0.5%)Atrial fibrillation122 (1.2%)143 (1.4%)Diarrhea102 (1.0%)42 (0.4%)Hypotension54 (0.5%)35 (0.3%)

conclusions of the antiplatelet armPRoFESS was not able to meet the pre-specified non-inferiority criteria for ER-DP + ASA vs. clopidogrel

ER-DP + ASA and clopidogrel had similar rates of recurrentstroke

The composite outcome of stroke, MI or vascular death rateswere identical in the two groups

Major haemorrhagic events, including intracranial bleeds, weremore frequent among those treated with ER-DP + ASA, but theabsolute risks were low and partially offset by fewer ischaemicevents

Net benefit/risks were similar with ER DP + ASA vs clopidogrel*

*defined as the combination of recurrent stroke and major haemorrhageSacco RL, Diener HC, Yusuf S et al. N Engl J Med 2008; 359:1238-51.

2.4. Safety

2.4. Safety

2.4.1. Cardiac Safety 2.4.2. Headache

ER-DP for the prevention of recurrent stroke does not lead to angina pectoris, MI, or increased mortality in patients with prior CHD or MI

Diener et al. Int J Clin Pract 2001; 55: 162163.Cardiac safety in ESPS 2: no increased risk of angina pectoris or myocardial infarctionNew symptoms of angina pectoris during follow-up%0246810*p

2.4. Safety

2.4.1. Cardiac Safety 2.4.2. Headache

ESPS 2: adverse eventsThe ESPS 2 Study Group. J Neurol Sci 1997; 151 (Suppl): S1S77.

ESPS 2Dyspepsia (%)Headache(%)

ER-DP + ASA17.638.2Placebo16.132.4ASA17.233.1ER-DP16.637.2

Week 1Week 2p=0.0002 for week 1 vs. 2n=36Two 7 day periods taking Aggrenox twice daily on days 1-4, am day 5, washout days 6 and 7 (healthy volunteers):Headache severity:Theis JG et al. Br J Clin Pharmacol 1999;48:750-755.Theis, 1999 shift of headache severity towards no headache27.2%40.5%20.5%11.8%70%22.9%5%2.1%

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Cumulative severity x durationDay 1Day 2Day 3Day 4Week 1Week 2Theis JG et al. Br J Clin Pharmacol 1999;48:750-755.Theis, 1999 cumulative severity of headache x duration per day in each periodDay 1Day 2Day 3Day 4

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512.25185.59383.5

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Composite profile of the frequency and severity of headacheChua et al. Neurol J Southeast Asia 2003; 8: 913.256323231557745344214504030201023456789101112131418201417162071010913FrequencySevereModerateMildDays of treatment4 01105 Filipinos, 18 years old or above,with TIA or complete stroke within past 3 months

3213

Most Aggrenox-associated headaches resolve quickly on continued administration

2 hours post-AggrenoxIn a study of 513 healthy volunteers given Aggrenox, 39.7% reported moderate to severe headache after 2 hours. This group was randomised to receive paracetamol or placebo.2 hours post-randomisationWithin 2 hours of receiving paracetamol or placebo, 72.4% of the headache group had a mild or no headache.There was no statistical difference between headache rates with paracetamol or placebo.On day 7Patients continued to take Aggrenox and study medication for 7 days.On the 7th day, 82.1% of the headache group had a mild or no headache.Lipton et al. Neurology 2004; 63: 10991101.Headache need not disrupt effective recurrent stroke prevention

Headache need not disrupt effective recurrent stroke prevention In the ESPRIT trial, headache was at least partly responsible for the 26% of patients who discontinued the combination.Taiwanese titration headache trial*Initial reduced-dose treatment with ER-DP + ASA causes significantly fewer headaches than regular dosing.

Chang et al. Cerebrovasc Dis 2006; 22: 258262. The ESPRIT Study Group. Lancet 2006; 367: 16651673.

Population:Intent-to-treatPlacebo(n = 46)Reduced dose(n = 45)Regular dose(n = 49)p-value

Headache7 (15.2%)7 (15.6%)19 (38.8%)0.011*

Titration scheme regimen in case of intolerable headachesFDA approved label:

In the event of intolerable headaches during initial treatment, switch to one capsule at bedtime and low-dose acetylsalicylic acid (ASA) in the morning. Because there are no outcome data with this regimen and headaches become less of a problem as treatment continues, patients should return to the usual regimen as soon as possible, usually within one week.FDA revised January 31, 2007, NDA 20-84/S-012: Page 16.

Safety summaryNo significant change in cardiac mortality or morbidity on Aggrenox

Most Aggrenox-associated headaches resolve quickly with continued administration

Titration improves toleranceDiener et al. J Neurological Sci 1996; 143: 113. Diener et al. Int J Clin Pract 2001; 55: 162163.Lipton et al. Neurology 2004; 63: 10991101.Chang et al. Cerebrovasc Dis 2006; 22: 258262.

3. Guidelines & Recommendations

International guidelines on prevention of recurrent stroke* old recommendation: Class IIa, Level AER-DP = extended-release dipyridamole; ASA = aspirin; CP = clopidogrelNICE. TA90. 2005.Diener et al. Akt Neurol 2007; 34: 8-12.Adams et al. Stroke 2008; 39: 1647-1652].Albers et al. Chest 2004; 126 (3 Suppl): 483S-512S. ESO Guidelines 2008. Publication pending in Cerebrovasc Dis.

ASA/AHAACCPESONICEDSG/DGN

ASAacceptable option 50 325 mgClass I, Level A*50 325 mgGrade 1A50 325 mgClass I, Level A50 150 mgGrade Arecurrent risk 4%: ER-DP + ASA better than ASA alone Grade AER-DPreduces stroke recurrence with similar efficacy to ASAlong-term therapy with low-dose ASA for ER-DP intoleranceClopidogrelacceptable option Class I, Level A*may be considered over aspirin alone on the basis of direct-comparison trials Class Iib, Level B75 mgGrade 1Abetter than ASA Grade 2Bis slightly more effective than ASA in prevention of vascular eventsClass I, Level Afor intolerance of low-dose ASA or PAOD75 mg Grade Arecurrent risk >4% and symptomatic PAOD: Grade Cfor contraindications or intolerance of ASA Grade A


3.1.American Stroke Association / American Heart Association (ASA/AHA) 3.2.National Institute for Health and Clinical Excellence (NICE)

ASA/AHA Guidelines for prevention of stroke in patients with ischaemic stroke or TIA (2008)Adams et al. Stroke 2008; 39: 1647-1652.

RecommendationClass/Level of Evidence*

For patients with noncardioembolic stroke or TIA, antiplatelet agents rather than oral anticoagulation are recommended to reduce the risk of recurrent stroke and other cardiovascular events.Class I, Level AAspirin (50 to 325 mg/d) monotherapy, the combination of aspirin and extended-release dipyridamole, and clopidogrel monotherapy are all acceptable options for initial therapy.*Class I, Level AThe combination of aspirin and extended-release dipyridamole is recommended over aspirin alone.Class I, Level BClopidogrel may be considered over aspirin alone on the basis of direct-comparison trials. Class IIb, Level BAddition of aspirin to clopidogrel increases the risk of haemorrhage and is not routinely recommended for ischaemic stroke or TIA patients unless they have a specific indication for this therapy (ie, coronary stent or acute coronary syndrome).Class IIIFor patients allergic to aspirin, clopidogrel is reasonable.Class IIa, Level BFor patients who have an ischaemic cerebrovascular event while taking aspirin, there is no evidence that increasing the dose of aspirin provides additional benefit. Although alternative antiplatelet agents are often considered for non-cardioembolic patients, no single agent or combination has been well studied in patients who have an event while receiving aspirin.


3.1.American Stroke Association / American Heart Association (ASA/AHA) 3.2.National Institute for Health and Clinical Excellence (NICE)

NICE Recommendations for the prevention of occlusive vascular events (2005)As part of the prevention of occlusive vascular events, the NICEguidance states that for all stroke and TIA patients: The combination of (MR) dipyridamole and aspirin is recommended for people who have had an ischaemic stroke or transient ischaemic attack within a period of 2 years from the most recent event. Thereafter, or if (MR) dipyridamole is not tolerated, preventive therapy should revert to standard care (including long-term treatment with low-dose aspirin).Clopidogrel alone (with its licensed indications) is recommended for people who are intolerant of low-dose aspirin and either have experienced an occlusive vascular event or have symptomatic peripheral arterial disease.

NICE. Technical Appraisal 90. 2005.

4. Prescribing Information (UK)


4.1.Aggrenox /Asasantin Retard(ER-DP plus ASA) 4.2. Persantin Retard(dipyridamole 200mg)

Prescribing Information (UK)Aggrenox /Asasantin Retard (ER-dipyridamole plus aspirin)Asasantin Retard (dipyridamole and aspirin)Capsules containing dipyridamole 200mg (modified release) and aspirin 25mg (standard release). Indication: Secondary prevention of ischaemic stroke and transient ischaemic attacks. Dose: Adults only: 1 capsule twice daily, with meals. Contraindications: hypersensitivity to any component or salicylates; active gastric or duodenal ulcers or bleeding disorders. Precautions: Severe coronary artery disease, subvalvular aortic stenosis, haemodynamic instability; coagulation disorders; asthma, allergic rhinitis, nasal polyps, chronic or recurring gastric or duodenal complaints, impaired renal or hepatic function or G6PD deficiency; hypersensitivity to NSAIDs; patients should not receive additional intravenous dipyridamole. Do not give to children aged under 16 years unless specifically indicated (eg. Kawasaki disease). Interactions: adenosine, hypotensive agents, cholinesterase inhibitors, anticoagulants, NSAIDs particularly ibuprofen, corticosteroids, hypoglycaemic agents, methotrexate, spironolactone, uricosuric agents. Pregnancy and lactation: avoid in 3rd trimester, caution at other times. Side effects: Vomiting, diarrhoea, dizziness, nausea, dyspepsia, headache, myalgia; hypotension, hot flushes, tachycardia, and rarely, worsening of the symptoms of coronary heart disease; prolonged bleeding time and, rarely, increased bleeding during or after surgery; epigastric distress, gastro or duodenal ulcers and erosive gastritis which may lead to serious GI bleeding; occult GI bleeding may result in iron deficiency anaemia; occasional hypersensitivity such as rash, angioedema, bronchoconstriction; very rarely, thrombocytopenia; dizziness and tinnitus suggest aspirin overdosage. Prescribers should consult the Summary of Product Characteristics in relation to other side-effects. Pack size and NHS price: 60 capsules 8.20. PL 00015/0224 POM Product licence holder: Boehringer Ingelheim Ltd, Ellesfield Avenue, Bracknell RG12 8YS. For full prescribing information please see Summary of Product Characteristics. Date of Preparation: February 2007.


4.1.Aggrenox /Asasantin Retard(ER-DP plus ASA) 4.2. Persantin Retard(dipyridamole 200mg)

Persantin Retard (dipyridamole) 200mgPrescribing Information (as approved for the United Kingdom)Aggrenox Asasantin Retard (dipyridamole and aspirin)Capsules containing dipyridamole 200mg (modified release) and aspirin 25mg (standard release). Indication:Secondary prevention of ischaemic stroke and transient ischaemic attacks. Dose: Adults only: 1 capsule twice daily, with meals. Contraindications: hypersensitivity to any component or salicylates; active gastric or duodenal ulcers or bleeding disorders. Patients in the last trimester of pregnancy. Patients with rare hereditary fructose intolerance, galactose intolerance, the lapp lactase deficiency, glucose-galactose malabsorption or sucrose-isomaltase insufficiency. Precautions: Severe coronary artery disease, left ventricular outflow obstruction, haemodynamic instability; coagulation disorders; asthma, allergic rhinitis, nasal polyps, chronic or recurring gastric or duodenal complaints, impaired renal (avoid if severe) or hepatic function or G6PD deficiency; hypersensitivity to NSAIDs; patients should not receive additional intravenous dipyridamole; see SPC for advice on stress testing. Concomitant medication which may increase the risk of bleeding. Do not give to children aged under 16 years unless specifically indicated (eg. Kawasaki disease). Interactions: adenosine, hypotensive agents, cholinesterase inhibitors, anticoagulants, antiplatelet agents, SSRIs, NSAIDs particularly ibuprofen, chronic alcohol use, corticosteroids, hypoglycaemic agents, methotrexate, spironolactone, uricosuric agents, valproic acid. Pregnancy and lactation: contraindicated in 3rd trimester, caution at other times. Side effects: Vomiting, diarrhoea, dizziness, nausea, dyspepsia, headache (may be migraine-like), myalgia; hypotension, hot flushes, tachycardia, worsening of the symptoms of coronary heart disease; prolonged bleeding time and, rarely, increased bleeding during or after surgery; epigastric distress, gastric or duodenal ulcers and erosive gastritis which may lead to serious GI bleeding; occult GI bleeding may result in iron deficiency anaemia; occasional hypersensitivity such as rash, urticaria, angioedema, severe bronchospasm, rhinitis, severe skin eruptions; very rarely, thrombocytopenia; skin haemorrhages such as contusion, ecchymosis and haematoma. Dizziness and tinnitus suggest aspirin overdosage. Prescribers should consult the Summary of Product Characteristics in relation to other side-effects. For full prescribing information please see Summary of Product Characteristics. Date of Preparation: January 2008.

Please be advisedThis slide kit is intended for all international markets. This being the case, please be aware that there may be some differences between countries regarding specific medical information including licensed uses and national guidelines. Please take this into account when referring to the material, and always check the statement you are planning against the jurisdiction in your country, because this may differ from country to country.

For product use, please check the local SPC of the country you live in.

ImpressumPublished byBoehringer Ingelheim GmbH www.aggrenox-asasantin.comRealisationinfill Kommunikation GmbH www.infill.comTeamSupervisor Ingo BarmsenMedical EditingKonrad BeckerMedical Writing & Proof Reading Emma Raderschadt, MDTechnical Support Christian Guhlke, Dominique Jppner

***Endothelial cell dysfunction is associated with atherosclerosis and is thought to contribute to cardio- and cerebrovascular events such as ischaemic stroke, myocardial infarction, etc. Antithrombotic mechanisms in the vessel wall may play an important role in preventing cerebrovascular disease. Mechanisms beyond platelet inhibition are now being discussed as a means of reducing the risk of a recurrent stroke.

Hadi et al. Vascular Health and Risk Management 2005; 1(3): 183-198 [Ref. 1, 183, Abstract; 184, 1, Fig 1] Glasser et al. Am Heart J 1996; 131: 379384. [Ref.3,380, 2, 5; 381, 1, 3] *During acute thrombosis over limited time intervals (weeks to months) treatment of atherothrombosis is aimed at substantial inhibition of platelets. Chronic prevention of thromboembolism and atherosclerosis may require differentiated therapeutic approaches directed toward endothelial and vessel wall dysfunction.Perfusion of microvessels seems to be of particular importance. Dipyridamoles pleiotropic antithrombotic, antioxidant, and anti-inflammatory effects add to platelet inhibition and may intervene in disease progression at earlier stages of vascular disease and thrombosis.

Eisert et al. In Michelson AD, 2nd ed. Chap 63. Platelets Amsterdam: Elsevier 2007: 11651179. [Ref. 5, 1166, Fig 63-1]

***Bleeding, as well as ischaemia, can be the cause of a cerebrovascular disorder. 812% of ischaemic strokes and 37.5% of haemorrhagic strokes result in death within 30 days.

In thrombolysis trials, the representation of small vessel disease was often lower than is indicated here. In addition, the number of patients who are considered to have stroke of other or unknown cause may vary from centre to centre and is largely dependent on the perception of the individual physician, and whether he has identified the reason for the stroke or not.

Albers et al. Chest 2004; 126 (3 Suppl): 438S512S. [Ref. 6, 484S, Fig 2] Thom et al. American Heart Association. Circulation 2006; 113: e85e151. [Ref. 7, 19, 3] **With an aging population, prevention of stroke and recurrent stroke is a major healthcare priority. Medical treatment of modifiable risk factors, such as high blood pressure, diabetes mellitus and hyperlipidaemia, has been shown to reduce the frequency of stroke and remains an important mainstay of preventive treatment.Since previous stroke is one of the most important risk factors for a subsequent stroke, the use of agents in recurrent stroke prevention is particularly important.

Johnston et al. Lancet 2007; 369: 283-292. [Ref. 9, 285, 2; 290, 6] Coull et al. BMJ 2004; 328: 326-328. [Ref. 15, 327, 2] Hankey. Cerebrovasc Dis 2003; 16 (Suppl 1): 1419. [Ref. 8, 18, Table 4; 19 2] Sacco et al. Stroke 1997; 28: 15071517. [Ref. 10, 2, 3+5, Table 1; 9, 2] **The relative efficacies of different antiplatelet agents for prevention of a recurrent stroke are unknown because of differences in clinical trial design, a lack of direct comparisons between individual agents, and differences in the choice of primary endpoints. For patients with stroke or TIA, the single outcome of stroke is particularly important because these patients have a higher risk of recurrent stroke than any other vascular outcome during the initial years after a stroke.

This data was also confirmed in ESPRIT, where 116/1,376 stroke patients (8.4%) suffered a subsequent stroke and 60/1,376 stroke patients (4.4%) suffered subsequent cardiac events in the aspirin alone group.

Albers. Neurology 2000; 54: 10221028. [Ref. 11, 1026, Figure]

The ESPRIT Study Group. Lancet 2006; 367: 1665-1673. [Ref. 32, 1669, Table 3]**While in earlier times, stroke and TIA were considered to be different entities, nowadays the concept of TIA being a mild subtype of stroke with complete clinical recovery prevails. Recently, new guidelines for the diagnosis of TIAs were developed. In addition, many TIA victims may show morphological changes on CT or MRI despite complete recovery, proving that clinical outcome is not completely linked to absence of infarcted tissue. Therefore, even after TIA symptoms have completely resolved, patients should still be considered emergencies and sent to a hospital, where fast evaluation of TIA symptoms, and CT or MRI scanning and ultrasound can be accomplished. TIA is a predictor for subsequent stroke, and a subsequent stroke is more likely in the first days and weeks after TIA.

Johnston et al. JAMA 2000; 284: 29012906. [Ref. 12, 2902, 2; 2904, 6; 2905, 3] Warach, Kidwell. Neurology 2004; 62: 359360. [Ref. 13, 359, 3, 7] Mohr. Neurology 2004; 62 (8 Suppl 6): S3S6. [Ref. 14, 5, 2; 4, 7]

**Irrespective of whether a patient had a stroke or a TIA, the risk of a recurrent cerebrovascular event is almost equally high.

Coull et al. BMJ 2004;328:326. [Ref. 15, 327, 2]

**A prospective study (EXPRESS Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke) was a prospective before (phase 1) versus after (phase 2) study of the effect of assessment and treatment of acute stroke patients in a clinic rather than in primary care. The risk of recurrent stroke was significantly higher in the first 90 days after a TIA or minor stroke for the entire study population. (p2). Compared with conventional ward care, admission to a stroke unit was associated with a reduced probability of death or disablement (OR 0.81, 95% CI 0.72-0.91; p=0.0001). The investigators concluded that all patients with acute stroke should be admitted to a stroke unit within 48 hours of the onset of symptoms.

Sarti et al. Stroke 2000; 31: 15881601. [Ref. 16,1588, 1] Murray et al. Lancet 1997; 349: 12691276. [Ref. 17,1274, Table 3] WHO neurological disorders report 2007: 151163. [Ref. 18, 154, 3; 156, 1-2; 162, Conclusion] Feigin et al. Lancet Neurology, 2003; 2: 4353. [Ref. 19, 43, 1]Candelise et al. Lancet 2007; 369: 299-305. [Ref. 33, 299, Summary] ***The costs of stroke amounted to 65.5 billion US $. The health expenditures contain the direct costs for physicians and other professionals, hospital and nursing home services, medications, home healthcare, and the indirect costs resulting from morbidity and mortality.

Rosamond et al. American Heart Association. Circulation 2008; 117: e25e146. [Ref. 20, e137, Table 19-1]

*****Many studies have shown the efficacy of low-dose ASA for the prevention of vascular events. Algra and van Gijn (1996) demonstrated that ASA reduces the risk of myocardial infarction, stroke or vascular mortality after preliminary stroke or TIA by about 13% compared with placebo. The relative risk reduction is completely independent of dosage: the high (> 900 mg), medium (300 mg) and low (< 100 mg) daily doses reduced the relative risk by 14%, 9% and 13%, respectively, showing no significant differences. These results were confirmed by a further analysis of stroke studies, which showed an almost identical reduction in the risk of vascular events at high, medium and low doses of ASA (Albers, Tijssen 1999).

An 18% reduction in the risk of ischaemic stroke with ASA was demonstrated by He et al. (1998), and this effect was independent of ASA dosage (50-1,500 mg/day) in a metaregression analysis of the dose-response effect of ASA in stroke (Johnson et al. 1999).

The dose-independent relative risk reduction of the combined endpoint of stroke, myocardial infarction and vascular mortality with ASA was also shown in a meta-analysis by Albers and Tijssen (1999).

Algra, van Gijn. J Neurol Surg Psychat 1996; 60: 197199. [Ref. 21, Abstract] He et al. 1998. JAMA 1998; 280: 19301935. [Ref. 22, 1932, 2] Johnson et al. Arch Intern Med 1999; 159: 12481253. [Ref. 23, 1248, Abstract; 1251, 1] Albers, Tijssen. Neurology 1999; 53 (7 Suppl 4): S25S31. [Ref. 24,27, 2]

**Presented here are the results from a meta-analysis of the efficacy of acetylsalicylic acid (ASA) in preventing stroke, myocardial infarction or vascular death, combining the results according to the ASA dose used. The relative risks and 95% CI for the three dose categories (1,0001,300 mg/d; 300 mg/d; 5075 mg/d) of ASA and for all doses combined are shown. The relationship between the benefit of ASA and the dose showed that the relative risk is identical in all 3 dose categories. In each case, the relative risk is about 0.87, corresponding to a 13% relative risk reduction.

Outcomes of two single trials that directly compared different doses of ASA strongly suggest that the benefit of ASA is independent of dose in this patient population. Lower doses are now recommended because of their more favourable side effect profiles.

Albers, Tijssen. Neurology 1999; 53 (7Suppl 4):S25-S31. [Ref. 24, S26, 4-5; S27, 2, Fig 2]

***Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events **CAPRIE (n=19,185) The largest thienopyridine trial Patients at risk of ischaemic events due to previous MI, ischaemic stroke or peripheral artery disease (PAD) 8.7% RRR of the major outcomes (MI, ischaemic stroke and vascular death) within a mean follow-up of 1.9 years

CAPRIE Steering Committee. Lancet 1996; 348: 13291339. [Ref. 25, 1329, 2; 1333, Fig 3, 7]

**Analysing the results for the stroke subgroup only, there was no significant difference between clopidogrel and ASA in reducing the risk of stroke. The average event rate per year was 7.15% in the clopidogrel group and was 7.71% in the ASA group, a non-significant (p=0.26) relative risk reduction of 7.3% (-5.718.7).

CAPRIE Steering Committee. Lancet 1996; 348: 13291339. [Ref. 25, 1334, Table 7, 4]

**Aggrenox inhibits the aggregation of platelets, improves the antithrombotic properties of the vascular wall, controls smooth muscle cell proliferation, improves tolerance of tissue to hypoxia, and increases perfusion under chronic ischaemic conditions. Thus dipyridamole shows antithrombotic, anti-inflammatory, and, potentially anti-atherosclerotic benefit.

Derendorf et al. J Clin Pharmacol 2005;45: 845850. [Ref. 28, 848, 1] Eisert et al. In Michelson AD, 2nd ed. Chap 63. Platelets Amsterdam: Elsevier 2007: 11651179. [Ref. 5, 1167, Fig 3, 1] Diener et al. J Neurol Sci 1996; 143: 113. [Ref. 29, 9, 4]

**Dipyridamole relative bioavailability was reduced to 53% with conventional tablets compared to the composite buffered extended-release capsule in reduced gastric acid conditions. Peak dipyridamole plasma concentrations were 57% lower with immediate-release tablets compared to the composite formulation with high stomach pH. Substituting generic dipyridamole plus low-dose ASA may be less effective than the buffered dipyridamole composite product in patients with concomitant antacid therapies.

Derendorf et al. J Clin Pharmacol 2005;45: 845850. [Ref. 28, 845, Summary, 1; 848, Fig 1]

*The antithrombotic action of the acetylsalicylic acid/dipyridamole combination is based on the different biochemical mechanisms involved.Acetylsalicylic acid inactivates irreversibly the enzyme cyclo-oxygenase in platelets thus preventing the production of thromboxane A2, a powerful inducer of platelet aggregation and vasoconstriction.Dipyridamole inhibits the uptake of adenosine into erythrocytes, platelets and endothelial cells in vitro and in vivo; the inhibition amounts to approximately 80% at its maximum and occurs dose-dependently at therapeutic concentrations (0.5 2 mcg/ml). Consequently, there is an increased concentration of adenosine locally to act on the platelet A2-receptor, stimulating platelet adenylate cyclase, thereby increasing platelet cAMP levels. Thus, platelet aggregation in response to various stimuli such as platelet activating factor (PAF), collagen and adenosine diphosphate (ADP) is inhibited. Reduced platelet aggregation reduces platelet consumption towards normal levels. In addition, adenosine has a vasodilator effect and this is one of the mechanisms by which dipyridamole produces vasodilation.Dipyridamole has also been shown to reduce the density of prothrombotic surface proteins (PAR-1: Thrombin receptor) on platelets as well as to reduce levels of c-reactive protein (CRP) and von Willebrand Factor (vWF) in stroke patients. In-vitro investigations have shown that dipyridamole selectively inhibits inflammatory cytokines (MCP-1 and MMP-9) arising from platelet-monocyte interaction.Dipyridamole inhibits phosphodiesterase (PDE) in various tissues.Whilst the inhibition of cAMP-PDE is weak, therapeutic levels of dipyridamole inhibit cGMP-PDE, thereby augmenting the increase in cGMP produced by EDRF (endothelium-derived relaxing factor, identified as nitric oxide (NO)).Dipyridamole increases the release of t-PA from microvascular endothelial cells and was shown to amplify the antithrombotic properties of endothelial cells on thrombus formation on adjacent subendothelial matrix in a dose dependent manner. Dipyridamole is a potent radical scavenger for oxy- and peroxy-radicals.Dipyridamole also stimulates the biosynthesis and release of prostacyclin by the endothelium and reduces the thrombogenicity of subendothelial structures by increasing the concentration of the protective mediator 13-HODE (13-hydroxyoctadecadienic acid). Whereas acetylsalicylic acid inhibits only platelet aggregation, dipyridamole in addition inhibits platelet activation and adhesion. Therefore an additional benefit from combining both drugs can be expected.

Eisert et al. In Michelson AD, 2nd ed. Chap 63. Platelets Amsterdam: Elsevier 2007: 11651179. [Ref. 5, 1165, col 2, 1; 1167, 1, 1170, 3; col 2, 2]

*

Eisert et al. In Michelson AD, 2nd ed. Chap 63. Platelets Amsterdam: Elsevier 2007: 11651179. [Ref. 5, 1165, 2; 1166, 1; 1167, 1; 1169, 5; 1174, 5] Weyrich et al. Circulation 2005; 111: 633642. [Ref. 30, 633, Summary] Aktas et al. Stroke 2003; 34: 764769. [Ref. 31, 764, Summary]

****Extended-release dipyridamole (ER-DP) and ASA seem to have an additive effect on the prevention of stroke, as indicated by results from pairwise comparisons of relative risk reduction. Treatment with ASA alone and with ER-DP alone lead to a similar risk reduction of 18.1% and 16.3%, respectively. Combined therapy with ER-DP + ASA showed significantly better stroke prevention vs. placebo (37.0%) as well as vs. ASA alone (23.1%).

ESPS 2 shows ER-DP 400 mg daily to be as effective as ASA when given alone, and the combination of ER-DP + ASA to be statistically more effective than either component alone.

Diener et al. J Neurol Sci 1996; 143 (12): 113. [Ref. 29, 5, 3; 6, 1; 9, 4]

***Modified from Diener et al. J Neurol Sci 1996; 143 (12): 113. [Ref. 29, 5, Fig 1b]**A comparison of ER-DP + ASA vs. ASA alone revealed that an additional 30 strokes per 1,000 patients were prevented by the combination therapy with ER-DP + ASA. These numbers reflect all strokes, fatal or otherwise.

Modified from Diener et al. J Neurol Sci 1996; 143 (12): 113. [Ref. 29, 5, Fig 1a; 7, Table 4]

**The results of ESPS 2 clearly show that the combination treatment of ER-DP + ASA is significantly superior to ASA alone (RRR 23.1%, p 30)Vascular disease (stroke, myocardial infarction, or peripheral artery disease) prior to qualifying strokeEnd-organ damage (retinopathy, left-ventricular hypertrophy, or microalbuminuria)Stroke is defined as a new focal neurological deficit of vascular origin lasting more than 24 hours, or where there is evidence of a new brain infarct upon brain imaging.The diagnosis of the ischaemic stroke is based upon the clinical judgement of the investigator supplemented with evidence on a computerised tomography (CT) scan or other imaging modality, e.g., magnetic resonance imaging (MRI) of the brain. The patients neurological and clinical condition following the qualifying stroke must have stabilised in the opinion of the investigator, i.e., the patient is not deteriorating or showing evidence of a progressive stroke or other condition.

Diener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380. [Ref. 37, 372, Table 2; 371, 1]

***Exclusion criteria:Patients presenting with a primary haemorrhagic stroke (intracerebral haemorrhage or subarachnoid haemorrhage) are excluded. Haemorrhagic stroke must be excluded by means of appropriate brain imaging (e.g., CT scan, MRI).Current congestive heart failure (CHF), defined as a previous definitive diagnosis, or present symptoms of at least Category II of the NYHA classification system for CHF.Patients whose qualifying stroke had been induced by a surgical or cardiovascular procedure such as carotid endarterectomy, angiogram, or cardiac surgery.Also excluded were patients who had had an MI within the last 3 months, or those requiring long-term treatment with anticoagulants, antithrombotics, or an angiotensin receptor blocker.

Diener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380. [Ref. 37, 372, Table 2]

***The PRoFESS study focussed primarily on the recurrent stroke rate among patients randomised to ER-DP + ASA or to clopidogrel, and telmisartan or matching placebo. Stroke is defined as a new focal neurological deficit of vascular origin lasting more than 24 h, or evidence of a new brain infarct upon brain imaging. The stroke can be of any type. Vascular events is a composite outcome defined as time to the first stroke (non-fatal or fatal), or myocardial infarction (non-fatal or fatal), or vascular death.

Diener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380. [Ref. 37, 370, Table 1; 371, 1; 376, 5]***Stroke or major haemorrhagic event is a composite outcome. Major haemorrhagic events include those that result in significant disability, symptomatic intracranial haemorrhage, intraocular bleeding causing loss of vision, the need for a transfusion of 2 units of red blood cells or equivalent whole blood, or hospitalisation.

Other designated vascular events is a composite outcome defined as the time to the first pulmonary embolism, or retinal vascular accident, or deep vein thrombosis, or peripheral arterial occlusion, or transient ischaemic attack

New or worsening congestive heart failure (CHF) is defined as any of the following: The patient is hospitalised for CHF symptoms. The patient is seen in the Emergency Room for symptoms of CHF. The patient is treated with an intravenous diuretic.


PRoFESS was designed with an assumption that Aggrenox was superior to clopidogrel (13% risk reduction). It was adequately powered to show non-inferiority only if the risk reduction was as low as 6.5% - meaning that the anticipated width of the confidence interval would most likely lie completely below the non-inferiority delta if PRoFESS was 6.5% better than clopidogrel. If the initial assumption was that Aggrenox and clopidogrel had equal stroke rates, we would have needed many more patients and/or events (2 to 3 times what we had) to produce the narrower confidence interval (i.e., give us the statistical power) needed to demonstrate non-inferiority.Sequential testing was performed to determine whether ER-DP + ASA was non-inferior and then superior to clopidogrel in the prevention of the primary endpoint of recurrent stroke. **The purpose of a typical non-inferiority trial is to show that two seemingly equally effective medications are in fact statistically similar (this is done statistically by proving that the 95% confidence interval lies completely below the non-inferiority delta). **

Diener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380. [Ref. 37, 376, 2]

****Abdominal girth is more important as a risk factor for stroke than BMI.

Many PRoFESS patients had concomitant vascular disease and risk factors typical for this population. The mean blood pressure was 144/84 mm Hg.

Diener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380. [Ref. 37, 375, Table 4; 376, 3]

**PRoFESS is a multinational trial with a homogenous mixed proportion of all continents and races. Thus, aetiologies of stroke, risk factors, and effects of treatment can be compared between different countries and races.


**Concomitant vascular disease and risk factors were considered typical of this patient population. 4,129 patients (20.3%) had at least one cardiac condition (Boehringer Ingelheim data on file 2008).

Diener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380. [Ref. 37, 375, Table 4]Boehringer Ingelheim. Data on file 2008. **Although the Mini Mental State Examination (MMSE) is not very sophisticated, it is sensitive and easy to apply internationally. MMSE was performed on the second visit at one month (then later at 2 years and 4 years).

Diener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380. [Ref. 37, 374, Table 3; 375, Table 4]

**The modified Rankin score was that seen on recruitment to the trial.


**Some regional differences were observed in TOAST classifications of qualifying strokes. However, even within geographic regions there was often heterogeneity among countries. While there were some regional differences in demographics such as age and gender, and in certain risk factors such as hypertension, hyperlipidaemia, diabetes and tobacco use, these did not account for the regional differences observed in TOAST classifications.

There may be significant differences between countries and regions in stroke subtype when recruiting patients to trials of recurrent stroke prevention. The reasons for these differences need to be explored to determine whether they reflect real differences in stroke subtype proportions or other factors such as differences in physician classification criteria and patterns.

Diener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380. [Ref. 37, 375, Table 4]Donnan et al. Poster presented at the American Stroke Association International Stroke Conference, San Francisco, USA, 79 February 2007. [Ref. 33, column 2-4]

**

Diener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380. [Ref. 37, 376, 3; 375, Table 4; 376, 4]

**The most commonly used concomitant medications at randomisation were statins (47.2%), ACE inhibitors (36.8%), calcium channel blockers (24.2%), and beta-blockers (20.7%).Only a relatively small proportion of patients had severe diabetes.


**PRoFESS is a multinational, double-blind, double-dummy, active and placebo controlled, randomised, parallel group study with a 2 x 2 factorial design. The total duration of the trial is projected to be 4years, depending upon how long it takes for a total of 2170*, strokes (of any type) to occur among recruited patients. This is the number of strokes that must occur in the patient population in order to attain statistical power. Extended-release dipyridamole + ASA (ER-DP + ASA), clopidogrel, and ASA alone are each separately approved for prevention of stroke in those who have suffered a recent stroke. The ESPS 2 study demonstrated that each component of dipyridamole + ASA reduced the risk of stroke in patients who had suffered a previous stroke or TIA. Furthermore, the combination of dipyridamole + ASA produced greater risk reduction than either component alone, with the effects being essentially additive. Originally designed to compare ASA + ER-DP with clopidogrel + ASA, in the light of the results from the MATCH trial, which showed the combination of ASA + clopidogrel to be little better than clopidogrel alone, but to have an increased risk of bleeding, the study design was altered. The PRoFESS study is therefore designed to make a direct comparison between ER-DP + ASA and clopidogrel in the reduction of recurrent stroke in patients who have recently suffered a stroke.

Although telmisartan is not approved for the prevention of stroke, there is a strong rationale based on studies such as LIFE to believe that this angiotensin receptor blocker (ARB) will provide additional benefit, beyond its blood pressure lowering effect, in preventing recurrent stroke by blockade of the actions of angiotensin II through the AT1 receptor. PRoFESS will therefore also investigate the potential cerebrovascular protection with telmisartan in reducing the risk of recurrent stroke.

Diener, Sacco, Yusuf. Cerebrovasc Dis 2007; 23: 368380. [Ref. 368-369, Abstract; 370, Fig. 1, 1]BI, data on file. [Ref. 38, pending 2008]Dahlf et al. Lancet 2002; 359: 995-1003. [Ref. 39, 999, Fig. 5]

**


***The occurrence of new or worsening CHF (one of the tertiary endpoints in PRoFESS) was significantly lower (1.4%) in the ER-DP + ASA group compared to the clopidogrel group {(1.8%) HR 0.78; 95% CI 0.62-0.96; p=0.022}. This provides further evidence in favour of the safety of ER-DP + ASA for prevention of recurrent stroke in cardiac patients or those at risk of cardiac disease.*The occurrence of new or worsening CHF (one of the tertiary endpoints in PRoFESS) was significantly lower (1.4%) in the ER-DP + ASA group compared to the clopidogrel group {(1.8%) HR 0.78; 95% CI 0.62-0.96; p=0.022}. This provides further evidence in favour of the safety of ER-DP + ASA for prevention of recurrent stroke in cardiac patients or those at risk of cardiac disease.**The occurrence of new or worsening CHF (one of the tertiary endpoints in PRoFESS) was significantly lower (1.4%) in the ER-DP + ASA group compared to the clopidogrel group {(1.8%) HR 0.78; 95% CI 0.62-0.96; p=0.022}. This provides further evidence in favour of the safety of ER-DP + ASA for prevention of recurrent stroke in cardiac patients or those at risk of cardiac disease.*Headache, a known side effect of dipyridamole, resulted more commonly in discontinuation in the ER-DP + ASA group than in the clopidogrel group. Dizziness and syncope were also more frequently reported in the ER-DP + ASA group.******The post hoc analysis of the ESPS 2 data demonstrates that ER-DP for stroke prevention does not lead to an increased risk of angina pectoris or MI in patients with prior coronary heart disease (CHD) or MI.No statistically significant difference between dipyridamole-treated patients and ASA-treated patients was observed. After 2 years of follow-up, the number of myocardial infarctions was not significantly increased after ER-DP treatment.

Diener et al. Int J Clin Pract 2001; 55: 162163. [Ref. 50, 163, 1, 5, Table 2]***This shows the excellent record of safety of ASA + ER-DP, summarising the incidences of the most common adverse events reported in the 4 study groups. Dyspepsia, gastrointestinal bleedings, and headache were the most frequently reported adverse events, including the placebo group. Gastrointestinal events were comparable to ASA. The incidence of dyspepsia with ASA + ER-DP was similar to that with ASA alone (18.4% vs. 18.1%). The incidence of GI bleeding with ASA + ER-DP was comparable to ASA (4.1% vs. 3.2%).

The most common adverse event with ASA + ER-DP was headache: (39.2% vs. 29.9% vs. placebo). Headache was more frequent at the onset of therapy, but diminished over time. In healthy volunteers, tolerance developed in a few days, and rates fell by half on the second day of dosing, and by the 11th day were 312%. Patients with a known migraine with multiple attacks per month may experience longer lasting or persisting headaches that may cause the need for discontinuation of ASA + ER-DP

It has been suggested to initiate ASA + ER-DP therapy using half the dose (one tablet at night) and just giving ASA in the morning. After some days, the dose can be increased to twice daily.

The ESPS 2 Study Group. J Neurol Sci 1997; 151 (Suppl): S1S77. [Ref. 49, S43, Table 29A]

FDA revised January 31, 2007, NDA 20-84/S-012: Page 16. [Ref. 55, 16, 2]

* Bioequivalence study of Aggrenox due to minor changes in production process. No pharmacokinetic difference in results between batches, so headache data shown together. During the entire trial at least one episode of headaches was reported by 72% of the volunteers. All patients recovered fully from the headache episodes. The most likely explanation for the extremely high incidence of headaches in this trial is the health and young age of the trial population. In contrast to elderly patients and especially to stroke patients these young healthy volunteers are likely to have a much higher cerebral vasodilator capacitance allowing for increased vasodilator headaches.

Theis JG et al. Br J Clin Pharmacol 1999;48:750-755. [Ref. 51, 752, Table 1]Theis JG et al. Br J Clin Pharmacol 1999;48:750-755. [Ref. 51, 753, Table 2]***Open non-comparative study carried out among 105 Filipinos, 18 years old or above with transient ischaemic attack or completed stroke within past 3 months. Patients with history of peptic ulcer disease, gastrointestinal bleeding or hypersensitivity to study drugs were excluded. Subjects were given 25 mg of acetylsalicylic acid and 200 mg of dipyridamole twice a day for 2 weeks. Number of dropouts due to headache was the primary outcome measure. Incidence, severity, duration and timing of headaches and the need for an analgesic were documented in patients diary. Evaluation was done after 7 and 14 days of treatment.

The slide describes the composite profile of the frequency and severity of headache among patients who experienced headache during the 14-day treatment period.Chua et al. Neurol J Southeast Asia 2003; 8: 913. [Ref. 52, 11, Fig 1]**In the ESPS 2 trial, Aggrenox-related headache was reported by 38.2 % of patients (compared with 32.4 % for placebo) with only 8 % discontinuation due to headache.

The study by Lipton et al supports the concept that headache attributed to ER-DP+ASA is self-limited, tending to spontaneous remission in most patients. ER-DP+ASA is effective in the prevention of recurrent stroke and TIA, and headache should not be a reason for non-adherence in the majority of the patients. Clinicians should advise patients about headache and its benign nature following ER-DP+ASA, with special caution if they fall into one of the higher risk subgroups. As the headaches are mild and usually disappear with the chronic use of ER-DP+ASA, acute and pre-emptive treatments may not be necessary in most patients.

Lipton et al. Neurology 2004; 63: 10991101. [Ref. 53,1100, Fig 1, Fig 2, col 2, 2]**Combination of low-dose aspirin and modified-release dipyridamole (ASA + ER-DP) provides a significantly increased benefit in stroke prevention over aspirin alone. However, headaches were reported in more patients receiving dipyridamole-containing agents than in those receiving placebo.The authors undertook a randomised, double-blind, placebo-controlled trial to evaluate which dosing regimens of ASA + ER-DP have better tolerance. 146 patients with a history of ischaemic cerebrovascular disease were randomised into three groups: placebo (days 1-28), reduced dose (placebo on days 1-4, ASA + ER-DP once daily before bed during days 5-14, and b.i.d. on days 15-28), and regular dose (placebo on days 1-4, and ASA + ER-DP b.i.d. on days 5-28). Using Chinese Diary Cards, headache was assessed as mean cumulated headache (Sigma frequency x intensity/occurrence days x study days) over the study period, and was graded 0-4 according to Cancer Therapy Evaluation Program, Common Toxicity Criteria, Version 2.0.Intent-to-treat patients after randomisation was 46 in placebo group, 45, reduced dose, and 49, regular dose. Among commonly reported adverse effects, headache of any grade occurred significantly more in the regular dose group (38.8%), as compared to the other two groups (p < 0.05). Mean cumulated headache was higher (p < 0.05) in the regular dose group than in the reduced group during days 5-14. Of 27 patients who dropped out, 15 (55.6%) were due to headache, which was substantially more in regular dose (8, 53.3%), though the difference was statistically insignificant.The authors concluded that Initial reduced dose treatment with ASA + ER-DP causes fewer headaches than regular dosing, and seems to be better tolerated by those susceptible to phosphodiesterase inhibitor-induced headache.

Chang et al. Cerebrovasc Dis 2006; 22: 258262. [Ref.54, 260, Table 2]The ESPRIT Study Group. Lancet 2006; 367: 16651673. [Ref. 32,1669, 2]*FDA revised January 31, 2007, NDA 20-84/S-012: Page 16. [Ref. 55, 16, 2]**Diener et al. J Neurological Sci 1996; 143: 113. [Ref. 29, 8, Table 8] Diener et al. Int J Clin Pract 2001; 55: 162163. [Ref. 50, 163, 5]Lipton et al. Neurology 2004; 63: 10991101. [Ref. 53,1101, col 2, last ]Chang et al. Cerebrovasc Dis 2006; 22: 258262. [Ref.54, 261, 3]

****Aggrenox is a first-line treatment option in the guidelines of the American College of Chest Physicians (ACCP), the European Stroke Organisation (ESO), the National Institute for Clinical Excellence (NICE) and the German Stroke Society (DSG).AHA/ASA, 2008: For patients who have an ischemic cerebrovascular event while taking aspirin, there is no evidence that increasing the dose of aspirin provides additional benefit. Class II: For patients allergic to ASA, clopidogrel is reasonable (Class IIa, Level B). Class III: The addition of ASA to clopidogrel increases the risk of haemorrhage. Combination therapy of ASA and clopidogrel is not routinely recommended for ischaemic stroke or TIA patients unless they have a specific indication for this therapy (i.e., coronary stent or acute coronary syndrome). NICE. Technical Appraisal 90. 2005. [Ref. 58, 4, 1.1.1 1.1.2.]Adams et al. Stroke 2008; 39: 1647-1652. [Ref. 57, 2, Table 1]Albers. Chest 2004; 126 (3 Suppl): 483S-512S. [Ref. 60, 500S-502S, Recommendations]ESO Guidelines 2008. Publication pending. [Ref. 61, publication ending]Diener et al. Akt Neurol 2007; 34: 8-12. [Ref. 62, 9-10, Bisherige Empfehlung; Modifizierte Empfehlung] ***The aim of the AHA's new statement is to provide comprehensive and timely evidence-based recommendations on the prevention of ischaemic stroke among survivors of ischaemic stroke or transient ischaemic attack.2

Definition of Classes and Levels of Evidence Used in AHA Recommendations: Class I Conditions for which there is evidence for and/or general agreement that the procedure or treatment is useful and effective. Class II Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatment. Class IIa Weight of evidence or opinion is in favour of the procedure or treatment. Class IIb Usefulness/efficacy is less well established by evidence or opinion. Class III Conditions for which there is evidence and/or general agreement that the procedure or treatment is not useful/effective and in some cases may be harmful. Level of Evidence A Data derived from multiple randomised clinical trials Level of Evidence B Data derived from a single randomised trial or non-randomised studies Level of Evidence C Expert opinion or case studies

Adams et al. Stroke 2008 [Epub ahead of print]. [Ref. 57, 2, Table 1] ***

NICE. Technical Appraisal 90. 2005. [Ref. 58, 4, 1.1.1 1.1.2.]********In patients who cannot be treated with, or who have contraindications for ASA, clopidogrel is recommended (Grade A). Higher doses of ASA (> 150 mg) will result in a higher risk of bleeds.**

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