STROKE: SECONDARY PREVENTION THE WHO PREMISE STUDYMARGARITA E. DAZCENTRE FOR ACADEMIC MEDICAL RESEARCHCENTRE FOR ACADEMIC MEDICAL RESEARCHMontevideo UruguayMontevideo UruguayDEFINITIONDEFINITIONStroke is defined as an episode of focal or global Stroke is defined as an episode of focal or global neurological deficit of rapid onset and lasting over neurological deficit of rapid onset and lasting over 24 hours or leading to death, with no cause 24 hours or leading to death, with no cause apparent other than a vascular one.apparent other than a vascular one. IS STROKE A FREQUENT PHENOMENON?WORLDWIDE PERCENTAGES OF DEATHS WORLDWIDE PERCENTAGES OF DEATHS Stroke and other leading causes 2002Stroke and other leading causes 2002Source Mackay, J, Mensah, G. The Atlas of Heart Disease and Stroke.WHO-CDC, 2004.Total number of Deaths: 57 millionStroke is the 3Stroke is the 3rdrd most common cause of death most common cause of death50 million have suffered a stroke50 million have suffered a stroke5 million die each year because of a stroke5 million die each year because of a strokeWORLDWIDE IMPACT OF STROKEWORLDWIDE IMPACT OF STROKEWORLDWIDE CONSEQUENCES OF STROKEWORLDWIDE CONSEQUENCES OF STROKEAlmost 33 % of those who present a stroke die in 3 weeksAlmost 33 % of those who present a stroke die in 3 weeks50 % of survivors are left with physical and/or mental disability50 % of survivors are left with physical and/or mental disability20 % of survivors suffer another stroke within 5 years20 % of survivors suffer another stroke within 5 yearsPREVALENCE OF RECURRENT STROKEPREVALENCE OF RECURRENT STROKEHierHier DB et al Stroke 1991; 22: 155-161. DB et al Stroke 1991; 22: 155-161.Onset6 months1 year0.000.020.040.060.080.100.120.1418 months2 yearsCumulativedistributionTime Time after first strokeafter first strokeWHO PREMISE Study of secondary prevention of strokeCauses of stroke and its established risk factorsNon-modifiable and modifiable risk factorsResults of the WHO PREMISE Study Prevalence of the most important risk factorsUse of medication from the WHO PREMISE Study By socio-demographic characteristicsAccording to risk factorsBy clinical characteristicsPredictors for the use of medicationPerspectives of pharmacological interventionClinical trials with universal treatmentSpecific treatment according to diagnosis: isquemic/hemorrhaegic strokeComplianceOBJECTIVES OF THE WHO PREMISE STUDYOBJECTIVES OF THE WHO PREMISE STUDYPHASE 1 PHASE 1 To assess current practice patterns related to secondary To assess current practice patterns related to secondary prevention of coronary heart disease and prevention of coronary heart disease and cerebrovascularcerebrovascular disease (disease (CeVDCeVD) in primary, secondary and tertiary health care ) in primary, secondary and tertiary health care settingssettingsLearn about patient behaviour and compliance in the 3 years Learn about patient behaviour and compliance in the 3 years after an eventafter an eventImplement strategies to strengthen the health care system with Implement strategies to strengthen the health care system with interventions based in primary care and community based interventions based in primary care and community based actionactionCRUDE PREVALENCE OF STROKE IN THE PARTICIPATING CRUDE PREVALENCE OF STROKE IN THE PARTICIPATING COUNTRIES IN THE WHO-PREMISE STUDYCOUNTRIES IN THE WHO-PREMISE STUDYn=10 855n=10 855Population Population In Millions In Millions (2002)(2002)Sample sizeSample size(n)(n)PrevalencePrevalenceof stroke (%)of stroke (%)BrazilBrazil18018099699616.116.1EgyptEgypt717199699621.321.3India India 1 0001 0001 0131 0138.08.0IndonesiaIndonesia23423499999944.344.3IranIran68689169164.44.4PakistanPakistan1561561 0071 00713.213.2RussiaRussia1431439939937.57.5Sri LankaSri Lanka19191 0381 03824.024.0TunisiaTunisia9 99999995.55.5TurkeyTurkey68681 0001 0006.06.0UruguayUruguay3 389889825.025.0WHO PREMISE Study of secondary prevention of strokeCauses of stroke and its established risk factorsNon-modifiable and modifiable risk factorsResults of the WHO PREMISE StudyPrevalence of the most important risk factorsUse of medication from the WHO PREMISE StudyBy socio-demographic characteristicsAccording to risk factorsBy clinical characteristicsPredictors for the use of medicationPerspectives of pharmacological interventionClinical trials with universal treatmentSpecific treatment according to diagnosis: isquemic/hemorrhaegic strokeComplianceNON-MODIFIABLE RISKNON-MODIFIABLE RISKFACTORS FOR STROKEFACTORS FOR STROKEl l Age Age l l sex sexl l Heredity Heredityl l Ethnicity Ethnicityl l Previous stroke Previous strokeESTABILISHED MODIFIABLE ESTABILISHED MODIFIABLE RISK FACTORS FOR STROKERISK FACTORS FOR STROKEHypertensionHypertensionChronic renal insufficiencyChronic renal insufficiencyCarotid Carotid stenosisstenosisSmokingSmokingHeavy alcohol consumptionHeavy alcohol consumptionPhysical inactivityPhysical inactivityDyslipidaemiaDyslipidaemiaDiabetes mellitusDiabetes mellitusCANDIDATE RISK FACTORSCANDIDATE RISK FACTORSFOR STROKE FOR STROKE MigraineMigraineOral contraceptivesOral contraceptivesSleep Sleep apnoeaapnoeaCocaine and amphetaminesCocaine and amphetaminesCertain infectionsCertain infectionsElevated Elevated homocysteinehomocysteineMODIFIABLE CARDIACMODIFIABLE CARDIACRISK FACTORS FOR STROKE RISK FACTORS FOR STROKE Coronary heart diseaseCoronary heart diseaseMyocardial infarctionMyocardial infarctionCongestive heart failureCongestive heart failureLeft ventricular Left ventricular disfunctiondisfunction/ mural / mural thrombusthrombusMitralMitral stenosisstenosisAtrialAtrial fibrillation fibrillationRATES of MORTALITY for CEREBROVASCULAR DISEASE RATES of MORTALITY for CEREBROVASCULAR DISEASE by age and sex group, Canadaby age and sex group, CanadaHealth Canada, 1999Health Canada, 1999PREDICTORS OF DEATH FROM STROKE IN ITALYPREDICTORS OF DEATH FROM STROKE IN ITALY Percentage increased risk of death from strokePercentage increased risk of death from stroke in people aged 65 years and above, 2001 in people aged 65 years and above, 2001Number of deaths from Stroke in 2002 : 69.075Source Mackay, J, Mensah, G. The Atlas of Heart Disease and Stroke.WHO-CDC, 2004.WHO PREMISE Study of secondary prevention of strokeCauses of stroke and its established risk factorsNon-modifiable and modifiable risk factorsResults of the WHO-PREMISE StudyPrevalence of the most important risk factorsUse of medication from the WHO PREMISE StudyBy socio-demographic characteristicsAccording to risk factorsBy clinical characteristicsPredictors for the use of medicationPerspectives of pharmacological interventionClinical trials with universal treatmentSpecific treatment according to diagnosis: isquemic / hemorrhaegic strokeComplianceTOTAL NUMBER OF PARTICIPANTSTOTAL NUMBER OF PARTICIPANTS OF CORONARYOF CORONARYHEART DISEASE (CHD) AND STROKEHEART DISEASE (CHD) AND STROKEIN THE WHO-PREMISE STUDYIN THE WHO-PREMISE STUDYAGE GROUPS FOR MALES AND FEMALESTOTAL NUMBER OF PARTICIPANTS OF CHD AND STROKEBY AGE AND SEX IN THE WHO-PREMISE STUDYIN THE WHO-PREMISE STUDYCeVD: Cerebrovascular disease REPORTED HISTORY OF RISK FACTORS IN REPORTED HISTORY OF RISK FACTORS IN PERCENTAGES AMONG ALL CVD PATIENTSPERCENTAGES AMONG ALL CVD PATIENTSWHO-PREMISE STUDYHBP: High blood pressure - HBS High blood sugar - HC High blood cholesterolHBP: High blood pressure - HBS High blood sugar - HC High blood cholesterolCLUSTERING OF RISK FACTORS IN PERCENTAGES CLUSTERING OF RISK FACTORS IN PERCENTAGES AMONG ALL CVD PATIENTSAMONG ALL CVD PATIENTSWHO-PREMISE STUDY0 FR1 FR2 FR3 FR4 FRLYFESTYLE CHANGES HAVE A MAJOR LYFESTYLE CHANGES HAVE A MAJOR IMPACT ON SECONDARY PREVENTONIMPACT ON SECONDARY PREVENTONANTIHYPERTENSIVE TREATMENT IS 510 TIMES ANTIHYPERTENSIVE TREATMENT IS 510 TIMES MORE SUCCESSFUL IN ELDERLY PATIENTS THAN IN MORE SUCCESSFUL IN ELDERLY PATIENTS THAN IN MIDDLE-AGED PATIENTS WITH MILD HYPERTENSIONMIDDLE-AGED PATIENTS WITH MILD HYPERTENSION(1000 pts/5 years)(1000 pts/5 years) expected prevented expected prevented expected prevented expected preventedMildMildHypertensionHypertensionEventsEventshypertensionhypertensionin the elderlyin the elderlyCardiovascularCardiovascular15154-54-51201204040deathsdeathsStrokesStrokes151510101231234949Coronary eventsCoronary events30302-32-397971414Holzgreve and Middeke, 1994WHO PREMISE Study of secondary prevention of strokeCauses of stroke and its established risk factorsNon-modifiable and modifiable risk factorsResults of the WHO-PREMISE StudyPrevalence of the most important risk factorsUse of medication in the WHO PREMISE StudyBy socio-demographic characteristicsAccording to risk factorsBy clinical characteristicsPredictors for the use of medicationPerspectives of pharmacological interventionClinical trials with universal treatmentSpecific treatment according to diagnosis: isquemic/hemorrhaegic strokeCompliancePERCENTAGE OF PATIENTS WITH STROKE TAKING PERCENTAGE OF PATIENTS WITH STROKE TAKING MEDICATIONS IN ALL CeVD PATIENTSMEDICATIONS IN ALL CeVD PATIENTS n =10 855n =10 855WHO-PREMISE STUDYUSE OF MEDICATIONS IN USE OF MEDICATIONS IN PERCENTAGESPERCENTAGESB BY REPORTED RISK FACTORS Y REPORTED RISK FACTORS AMONG ALL CVD PATIENTSAMONG ALL CVD PATIENTSASPIRINASPIRIN(%)(%) BLOCKERS BLOCKERS(%) (%) ACE inhibitorACE inhibitor(%) (%) STATINSSTATINS(%)(%)HBP HBP n n= = 6 7306 73086.686.654.954.953.653.624.124.1HBC HBC n=n= 4 0124 01286.186.155.955.950.750.740.240.2HBS HBS n= 3 133n= 3 13387.487.450.850.847.947.925.425.4Current Current SmokersSmokersn= 1 245n= 1 24589.289.258.558.548.748.722.322.3HBP: High blood pressure HBC: High blood cholesterol HBS: High blood sugar WHO-PREMISE STUDYUSE OF MEDICATIONS IN PERCENTAGES BYUSE OF MEDICATIONS IN PERCENTAGES BYSOCIO-DEMOGRAPHIC CHARACTERISTICS AMONG SOCIO-DEMOGRAPHIC CHARACTERISTICS AMONG ALL CVD PATIENTSALL CVD PATIENTSASPIRINASPIRIN(%) (%) BLOCKERS BLOCKERS(%)(%)ACE inhibitorACE inhibitor(%)(%)STATINSSTATINS(%) (%) GENDERGENDERMalesMales8787545448482626FemalesFemales4747515147472121p p0.0010.0010.070.070.770.770.00160 years60 years8585515150502121p p0.940.940.030.030.0010.0010.0010.001EDUCATIONEDUCATIONPrimaryPrimary8585535347472222Secondary Secondary and moreand more8686525249492727p p 0.160.160.450.450.030.030.0010.001WHO-PREMISE STUDYWHO PREMISE Study of secondary prevention of strokeCauses of stroke and its established risk factorsNon-modifiable and modifiable risk factorsResults of the WHO PREMISE Study Prevalence of the most important risk factorsUse of medication from the WHO PREMISE StudyBy socio-demographic characteristicsAccording to risk factorsBy clinical characteristicsPredictors for the use of medicationPerspectives of pharmacological interventionClinical trials with universal treatmentSpecific treatment according to diagnosis: isquemic/hemorrhaegic strokeCompliance Hypertensive 163/1464 235/1452Hypertensive 163/1464 235/1452 Non hypertensive 144/1587 185/1602 Non hypertensive 144/1587 185/1602 Total stroke 307/3051 420/3054 Major vascular events HypertensiveHypertensive 240/1464 331/1452 240/1464 331/1452 Non hypertensive 218/1587 273/1602 Non hypertensive 218/1587 273/1602 Total events 458/3051 604/3054 Events/patients Active* PlaceboFavorsactiveFavorsplaceboRisk reduction(95%CI)StrokeRISK REDUCTION IN HYPERTENSIVE RISK REDUCTION IN HYPERTENSIVE VS NORMOTENSIVE PATIENTSVS NORMOTENSIVE PATIENTS 32% (17 to 44) 27% (8 to 42) 28% (17 to 38) 29% (16 to 40) 24% (9 to 37) 26% (16 to 34)0.52.0 Hazard ratio1.0Reference: Progress Study.Lancet 2001; 358: 1033-41*Active: Perindopril 4 mg Indapamide 2,5 mgRandomizedRandomized, double-blind placebo-control trial of 4 years duration, double-blind placebo-control trial of 4 years durationNo blood pressure (BP) entry criteriaNo blood pressure (BP) entry criterian n 762 patients received ACE-inhibitor 762 patients received ACE-inhibitor perindoprilperindopril ( ( diuretic: diuretic: indapamideindapamide) )n n 758 patients on placebo 758 patients on placebo Baseline mean BP was reduced by 14/6 mm Hg in the active Baseline mean BP was reduced by 14/6 mm Hg in the active treatment group compared to the placebo grouptreatment group compared to the placebo groupAlso a reduction by 55 % (p0.01) in the stroke recurrence (8.8 % Also a reduction by 55 % (p0.01) in the stroke recurrence (8.8 % vsvs 19.4 %) in the active treatment group with or without hypertension19.4 %) in the active treatment group with or without hypertensionSource: Liu LS; Gong LS, Wang W Blood Pressure Lowering to Prevent Recurrent Stroke Study Source: Liu LS; Gong LS, Wang W Blood Pressure Lowering to Prevent Recurrent Stroke Study Group Group ZhonghuaZhonghua XinXin XueXue Guan Guan Bing Za Bing Za ZhiZhi. 2005 Jul;33(7):613-7. 2005 Jul;33(7):613-7.EFFECTS OF BLOOD PRESSURE LOWERING TREATMENT EFFECTS OF BLOOD PRESSURE LOWERING TREATMENT ON STROKE RECURRENCEON STROKE RECURRENCEANTICOAGULATION RECOMMENDATIONSANTICOAGULATION RECOMMENDATIONSfor PRIMARY PREVENTION of STROKEfor PRIMARY PREVENTION of STROKEin PATIENTS with ATRIAL FIBRILATIONin PATIENTS with ATRIAL FIBRILATIONAgeAgeRisk factorsRisk factorsRecommendationsRecommendations 65 years 75 years 75 yearsNo or yesNo or yesWarfarinWarfarinRisk factors: History of Risk factors: History of cerebrovascularcerebrovascular disease or TIA, left ventricular disease or TIA, left ventricular dysfunction , dysfunction , valvularvalvular hearth disease, congestive heart failure, systolic blood hearth disease, congestive heart failure, systolic blood pressure pressure 160 mmHg.160 mmHg.Source: EAFT (European Atrial Fibrillation Trial) Study GroupSTUDY OF DRUG COMPLIANCE IN SECONDARY PREVENTION OF STUDY OF DRUG COMPLIANCE IN SECONDARY PREVENTION OF STROKE - TIANTAN HOSPITAL PATIENTS OF STROKE - TIANTAN HOSPITAL PATIENTS OF CAPITAL CAPITAL UNIVERSITY OF MEDICAL SCIENCES, BEIJING, CHINA.UNIVERSITY OF MEDICAL SCIENCES, BEIJING, CHINA.Objective: Identify rate of Compliance for secondary prevention according to the Objective: Identify rate of Compliance for secondary prevention according to the prevalence of risk factorsprevalence of risk factorsTelephone interview of 296 consecutive patients entering the Neurology Telephone interview of 296 consecutive patients entering the Neurology Department October-02 to April-03Department October-02 to April-03Treatment Compliance: Treatment Compliance: Hypertension: Hypertension: 78 % 78 % Diabetes: Diabetes: 80 %80 % HyperlipidoemiaHyperlipidoemia: : 48 % 48 % AntithromboticAntithrombotic drugs: drugs: 35 %35 %+ Compliance+ Compliance: Medical insurance and free medical care : Medical insurance and free medical care OD 2.12OD 2.12 (95 % CI: 1.17-3.82) (95 % CI: 1.17-3.82)- Compliance- Compliance: Use of : Use of antithromboticantithrombotic drugs other than aspirin drugs other than aspirin OD 0.35OD 0.35 (95 % CI: 0.15-0.81) and lower living ability (62.5 (95 % CI: 0.15-0.81) and lower living ability (62.5 13.3 p0.001) 13.3 p0.001)Comments: Incorrect discontinuation of drugs or change and reduction of Comments: Incorrect discontinuation of drugs or change and reduction of dosage reflect a need of clear guidelines for patientsdosage reflect a need of clear guidelines for patientsSource:Source: Wu D, Ma RH, Wang YL, Wang YJ. Wu D, Ma RH, Wang YL, Wang YJ. ZhonghuaZhonghua NeiNei KeKe ZaZa ZhiZhi. 2005. 2005.LOOKING INTO PERSPECTIVELOOKING INTO PERSPECTIVESecondary prevention of strokeSecondary prevention of strokePrimary prevention of stroke Primary prevention of stroke Secondary prevention of myocardial infarctionSecondary prevention of myocardial infarctionNew mechanisms of theNew mechanisms of the physiopathology physiopathology and and pathogenesis of the recurrent stroke pathogenesis of the recurrent stroke New drugs and known drugs with unknown mechanisms New drugs and known drugs with unknown mechanisms Considerations of available information on the following items permit to outline high-priority research questions on the secondary prevention of stroke:WHAT NEEDS TO BE KNOWN ABOUT THE WHAT NEEDS TO BE KNOWN ABOUT THE CONTROL OF HYPERTENSIONCONTROL OF HYPERTENSIONLowering blood pressure has proved to be the best therapeutic tool to Lowering blood pressure has proved to be the best therapeutic tool to prevent a stroke.prevent a stroke.Primary prevention has demonstrated that Primary prevention has demonstrated that AmlodipineAmlodipine or slow release or slow release calcium antagonist are, together with diuretics useful and better than beta-calcium antagonist are, together with diuretics useful and better than beta-blockers and ACE inhibitors (blockers and ACE inhibitors (LisinoprilLisinopril in the ALLHAT study) once an in the ALLHAT study) once an equal equal hipotensivehipotensive effect is obtain, effect is obtain, is this the case for secondary is this the case for secondary prevention?prevention? ACE inhibitors (ACE inhibitors (PerindoprilPerindopril + + IndapamideIndapamide 2.5) have proven to be effective 2.5) have proven to be effective in secondary prevention of stroke, in secondary prevention of stroke, are they more effective than slow are they more effective than slow release calcium antagonists or diuretics?release calcium antagonists or diuretics? AngiotensinAngiotensin II antagonists and II antagonists and AldosteroneAldosterone antagonists antagonists need to be tried need to be tried and comparedand compared with drugs that have already shown a benefit at least in with drugs that have already shown a benefit at least in primary prevention of stroke.primary prevention of stroke.HOW TO OPTIMIZE ANTITHROMBOTIC THERAPY HOW TO OPTIMIZE ANTITHROMBOTIC THERAPY - - LIMITED TO PATIENTS WHOSE FIRST STROKE WAS LIMITED TO PATIENTS WHOSE FIRST STROKE WAS UNEQUIVOCALLY ISQUAEMICUNEQUIVOCALLY ISQUAEMICPatients with Patients with atrialatrial fibrillation and/or cardiac emboli have proven to be fibrillation and/or cardiac emboli have proven to be better treated with better treated with WarfarinWarfarin. . The data of primary and secondary prevention of myocardial infarction has The data of primary and secondary prevention of myocardial infarction has shown that Aspirin (low dose) and shown that Aspirin (low dose) and ClopidogrelClopidogrel are the best combination, are the best combination, and better than a single drug. and better than a single drug. Aspirin has not proven to be as good for prevention of brain damage as it Aspirin has not proven to be as good for prevention of brain damage as it has at heart level. has at heart level. Is the combination with Is the combination with ClopidogrelClopidogrel an option in this an option in this case? Are they applicable for secondary stroke prevention patients? case? Are they applicable for secondary stroke prevention patients? It is in order to investigate whether It is in order to investigate whether antithrombinsantithrombins ( (egeg.: .: XimelagatranXimelagatran) merits ) merits dedicated research in patients with and without dedicated research in patients with and without atrialatrial fibrillation. fibrillation.ROLE OF CHOLESTEROL LOWERING DRUGSROLE OF CHOLESTEROL LOWERING DRUGSIN SECONDARY PREVENTION OF STROKEIN SECONDARY PREVENTION OF STROKEStatinsStatins have shown to be effective in primary prevention of have shown to be effective in primary prevention of stroke, though their therapeutic mechanism of action which stroke, though their therapeutic mechanism of action which apparently exceeds the one obtained with the inhibition of the apparently exceeds the one obtained with the inhibition of the HMG Ca HMG Ca reductasereductase in the initial stroke - is still unknown. in the initial stroke - is still unknown. Are Are statinsstatins useful in secondary prevention? Do they do so useful in secondary prevention? Do they do so through the same or other mechanisms? And do the through the same or other mechanisms? And do the fibratesfibrates and new drugs - which act upon the plasma lipid profile - have a and new drugs - which act upon the plasma lipid profile - have a preventive role as well?preventive role as well?DRUGS TARGETING VASCULAR OR NEUROLOGIC DRUGS TARGETING VASCULAR OR NEUROLOGIC PROCESSES LINKED TO STROKE:PROCESSES LINKED TO STROKE:INFLAMMATION AND OXIDATIVE STRESS INFLAMMATION AND OXIDATIVE STRESS Anti cytokine agentsAnti cytokine agentsDrugs which reduce oxidative stressDrugs which reduce oxidative stress: : Reduce the generation of reactive substances (e.g.: NDPH Reduce the generation of reactive substances (e.g.: NDPH oxidazeoxidaze inhibitors) inhibitors)Increase the antioxidant defense e.g.: low sodium diet, low Increase the antioxidant defense e.g.: low sodium diet, low dose aspirin and low dose diuretics, all of which diminish dose aspirin and low dose diuretics, all of which diminish uricosuriauricosuria and increase the plasmatic uric acid and increase the plasmatic uric acid CONCLUSIONSTherapeutic objectives depend on each individuals risk factors and existing pathology.There is a wide consensus on:Treating patients with atrial fibrillation with anticoagulantsWhen anticoagulation is not possible due to socio-economic factors or clinically contraindicated - antiplatlet therapy should be usedLowering blood pressure is the most important risk factor goal to achieve Patients education and physicians dedication to improve treatment and prevention through non-pharmacologic and pharmacologic treatment is essential to improve complianceCENTRE FOR ACADEMIC MEDICAL RESEARCHCENTRE FOR ACADEMIC MEDICAL RESEARCHMONTEVIDEO, URUGUAYMONTEVIDEO, URUGUAY