1、STROKE: SECONDARY PREVENTION THE WHO PREMISE STUDYMARGARITA E. DAZCENTRE FOR ACADEMIC MEDICAL RESEARCHMontevideo UruguayDEFINITIONStroke is defined as an episode of focal or global neurological deficit of rapid onset and lasting over 24 hours or leading to death, with no cause apparent other than a

2、vascular one. IS STROKE A FREQUENT PHENOMENON?WORLDWIDE PERCENTAGES OF DEATHS Stroke 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 3rd most common cause of death50 million have suffered a

3、stroke5 million die each year because of a strokeWORLDWIDE IMPACT OF STROKEWORLDWIDE CONSEQUENCES OF STROKEAlmost 33 % of those who present a stroke die in 3 weeks50 % of survivors are left with physical and/or mental disability20 % of survivors suffer another stroke within 5 yearsPREVALENCE OF RECU

4、RRENT STROKEHier DB et al Stroke 1991; 22: 155-161.Onset6 months1 year0.000.020.040.060.080.100.120.1418 months2 yearsCumulativedistributionTime after first strokeWHO PREMISE Study of secondary prevention of strokeCauses of stroke and its established risk factorsNon-modifiable and modifiable risk fa

5、ctorsResults 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 interventionClin

6、ical trials with universal treatmentSpecific treatment according to diagnosis: isquemic/hemorrhaegic strokeComplianceWHO PREMISE Study of secondary prevention of strokeCauses of stroke and its established risk factorsNon-modifiable and modifiable risk factorsResults of the WHO PREMISE StudyPrevalenc

7、e 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 tre

8、atment according to diagnosis: isquemic/hemorrhaegic strokeComplianceNON-MODIFIABLE RISKFACTORS FOR STROKE Age sex Heredity Ethnicity Previous strokeESTABILISHED MODIFIABLE RISK FACTORS FOR STROKEHypertensionChronic renal insufficiencyCarotid stenosisSmokingHeavy alcohol consumptionPhysical inactivi

9、tyDyslipidaemiaDiabetes mellitusCANDIDATE RISK FACTORSFOR STROKE MigraineOral contraceptivesSleep apnoeaCocaine and amphetaminesCertain infectionsElevated homocysteineMODIFIABLE CARDIACRISK FACTORS FOR STROKE Coronary heart diseaseMyocardial infarctionCongestive heart failureLeft ventricular disfunc

10、tion/ mural thrombusMitral stenosisAtrial fibrillationRATES of MORTALITY for CEREBROVASCULAR DISEASE by age and sex group, CanadaHealth Canada, 1999TOTAL NUMBER OF PARTICIPANTS OF CHD AND STROKEBY AGE AND SEX IN THE WHO-PREMISE STUDYCeVD: Cerebrovascular disease REPORTED HISTORY OF RISK FACTORS IN P

11、ERCENTAGES AMONG ALL CVD PATIENTSWHO-PREMISE STUDYHBP: High blood pressure - HBS High blood sugar - HC High blood cholesterolCLUSTERING OF RISK FACTORS IN PERCENTAGES AMONG ALL CVD PATIENTSWHO-PREMISE STUDY0 FR1 FR2 FR3 FR4 FRLYFESTYLE CHANGES HAVE A MAJOR IMPACT ON SECONDARY PREVENTONWHO PREMISE St

12、udy 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

13、 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 MEDICATIONS IN ALL CeV

14、D PATIENTS n =10 855WHO-PREMISE STUDYUSE OF MEDICATIONS IN PERCENTAGESBY REPORTED RISK FACTORS AMONG ALL CVD PATIENTSASPIRIN(%) BLOCKERS(%) ACE inhibitor(%) STATINS(%)HBP n= 6 73086.654.953.624.1HBC n= 4 01286.155.950.740.2HBS n= 3 13387.450.847.925.4Current Smokersn= 1 24589.258.548.722.3HBP: High

15、blood pressure HBC: High blood cholesterol HBS: High blood sugar WHO-PREMISE STUDYUSE OF MEDICATIONS IN PERCENTAGES BYSOCIO-DEMOGRAPHIC CHARACTERISTICS AMONG ALL CVD PATIENTSASPIRIN(%) BLOCKERS(%)ACE inhibitor(%)STATINS(%) GENDERMales87544826Females47514721p0.0010.070.7760 years85515021p0.940.030.00

16、10.001EDUCATIONPrimary85534722Secondary and more86524927p 0.160.450.030.001WHO-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

17、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 diag

18、nosis: isquemic/hemorrhaegic strokeCompliance Hypertensive 163/1464 235/1452 Non hypertensive 144/1587 185/1602 Total stroke 307/3051 420/3054 Major vascular events Hypertensive 240/1464 331/1452 Non hypertensive 218/1587 273/1602 Total events 458/3051 604/3054 Events/patients Active* PlaceboFavorsa

19、ctiveFavorsplaceboRisk reduction(95%CI)StrokeRISK REDUCTION IN HYPERTENSIVE VS 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,

20、5 mgRandomized, double-blind placebo-control trial of 4 years durationNo blood pressure (BP) entry criteria 762 patients received ACE-inhibitor perindopril (diuretic: indapamide) 758 patients on placebo Baseline mean BP was reduced by 14/6 mm Hg in the active treatment group compared to the placebo

21、groupAlso a reduction by 55 % (p0.01) in the stroke recurrence (8.8 % vs 19.4 %) in the active treatment group with or without hypertensionSource: Liu LS; Gong LS, Wang W Blood Pressure Lowering to Prevent Recurrent Stroke Study Group Zhonghua Xin Xue Guan Bing Za Zhi. 2005 Jul;33(7):613-7.EFFECTS O

22、F BLOOD PRESSURE LOWERING TREATMENT ON STROKE RECURRENCEANTICOAGULATION RECOMMENDATIONSfor PRIMARY PREVENTION of STROKEin PATIENTS with ATRIAL FIBRILATIONAgeRisk factorsRecommendations 75 yearsNo or yesWarfarinRisk factors: History of cerebrovascular disease or TIA, left ventricular dysfunction , va

23、lvular hearth disease, congestive heart failure, systolic blood pressure 160 mmHg.Source: EAFT (European Atrial Fibrillation Trial) Study GroupSTUDY OF DRUG COMPLIANCE IN SECONDARY PREVENTION OF STROKE - TIANTAN HOSPITAL PATIENTS OF CAPITAL UNIVERSITY OF MEDICAL SCIENCES, BEIJING, CHINA.Objective: I

24、dentify rate of Compliance for secondary prevention according to the prevalence of risk factorsTelephone interview of 296 consecutive patients entering the Neurology Department October-02 to April-03Treatment Compliance: Hypertension: 78 % Diabetes: 80 % Hyperlipidoemia: 48 % Antithrombotic drugs: 3

25、5 %+ Compliance: Medical insurance and free medical care OD 2.12 (95 % CI: 1.17-3.82)- Compliance: Use of antithrombotic drugs other than aspirin OD 0.35 (95 % CI: 0.15-0.81) and lower living ability (62.5 13.3 p0.001)Comments: Incorrect discontinuation of drugs or change and reduction of dosage ref

26、lect a need of clear guidelines for patientsSource: Wu D, Ma RH, Wang YL, Wang YJ. Zhonghua Nei Ke Za Zhi. 2005.LOOKING INTO PERSPECTIVESecondary prevention of strokePrimary prevention of stroke Secondary prevention of myocardial infarctionNew mechanisms of the physiopathology and pathogenesis of th

27、e recurrent stroke 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 CONTROL OF HYPERTENSIONLowering blood pressure

28、 has proved to be the best therapeutic tool to prevent a stroke.Primary prevention has demonstrated that Amlodipine or slow release calcium antagonist are, together with diuretics useful and better than beta-blockers and ACE inhibitors (Lisinopril in the ALLHAT study) once an equal hipotensive effec

29、t is obtain, is this the case for secondary prevention? ACE inhibitors (Perindopril + Indapamide 2.5) have proven to be effective in secondary prevention of stroke, are they more effective than slow release calcium antagonists or diuretics? Angiotensin II antagonists and Aldosterone antagonists need

30、 to be tried and compared with drugs that have already shown a benefit at least in primary prevention of stroke.HOW TO OPTIMIZE ANTITHROMBOTIC THERAPY - LIMITED TO PATIENTS WHOSE FIRST STROKE WAS UNEQUIVOCALLY ISQUAEMICPatients with atrial fibrillation and/or cardiac emboli have proven to be better

31、treated with Warfarin. The data of primary and secondary prevention of myocardial infarction has shown that Aspirin (low dose) and Clopidogrel are the best combination, and better than a single drug. Aspirin has not proven to be as good for prevention of brain damage as it has at heart level. Is the

32、 combination with Clopidogrel an option in this case? Are they applicable for secondary stroke prevention patients? It is in order to investigate whether antithrombins (eg.: Ximelagatran) merits dedicated research in patients with and without atrial fibrillation.ROLE OF CHOLESTEROL LOWERING DRUGSIN

33、SECONDARY PREVENTION OF STROKEStatins have shown to be effective in primary prevention of stroke, though their therapeutic mechanism of action which apparently exceeds the one obtained with the inhibition of the HMG Ca reductase in the initial stroke - is still unknown. Are statins useful in secondary prevention? Do they do so through the same or other mechanisms? And do the fibrates