JIKEI Satellite Meeting New Evidence in Management of High Risk Hypertension in Asian Population : Roles of ARB Can We Prevent Stroke for High Risk Hypertension Patients Beyond BP Reduction Associate Professor Somsak Tiamkao Division of Neurology, Department of Medicine Faculty of Medicine, Khon Kaen University E-mail : somtia@kku.ac.th ค าแน น า ก 25 November 2007 1 2 Fact Relationship between BP and occurrence of first stroke and effect of BP lowering treatment in preventing stroke well established ¾ of patient with acute stroke have high BP at presentation, 50% have history of HT BP declines spontaneously over first week in 2/3 of patients Fact There is no general agreement on BP management in acute phase Current opinions, SBP > 220 mmhg, DBP > 120 mmhg should treated Recommended cut off values for treat are lower in patients treated with rt PA 3 4 Purpose Role of BP in stroke Management of BP in acute ischemic stroke patients JIKEI Heart study: Personal views Conflict of interest No any research funding, joined meeting or conference, and clinical trials Never used ARB for ischemic stroke patients 5 6 1
Q U E S T I O N S? Question? Question? Question? 130/80 220/130 190/110 Question? Question? Question? CCB ACE-I ARB Question? Question? Question? Rx No Rx No answer Real life practice Women 51 yr, DM, HT, CKD On enalapril and diovan Sudden onset of left hemiparesis CT-brain: lacunar infarction BP 130/80 mmhg Left hemiparesis, fully of consciousness 7 8 Real life practice Female 65 yr old Underlying HT(Rx with ccb),dyslipidemia,dm Sudden developed right hemiplegia and global aphasia BP 200/100 mmhg CT brain showed normal study ( 4 hr after onset) How to manage these problems? What is a diagnosis? Treat or Not treat BP? How to treat? What is an anti HT drug? 9 10 Topics 1. Effect of BP in stroke patients 2. Role of antihypertensive drug in primary and secondary prevention 3. Management of BP in acute ischemic stroke 4. Personal views on JIKEI Heart study 11 http://www.cdc.gov/nchs/about/otheract/hp2000/hdspr/hdsprog.htm 2
Prevalence Stroke in Thailand Bangkok metropolis (1983) = 690 : 100,000 age over 20 (Viriyavejakul A, et al. 6 th Excerpta Medical No.22; 1983: 10) Stroke in the elderly (1998); overall 1.12% Central 1.99 North 0.6 South 1.5 Northeast 0.6 (Viriyavejakul A, et al. J Med Assoc Thai 1998; 81: 497-505) Thai Epidemiology Stroke Study (TES Study 2004): Stroke in age 45-80 years = 2.46% CINP Asia pacific Regional MeetngMarch 14-17, 2006, Pattaya, Thailand Abstracts P54-13 14 ก Stroke Stroke Mortality Rate by Age 1 Blood Pressure and Stroke Mortality ก 15 Stroke mort ality rate in each decade of age vs. usual blood pressure at the start of the decade. A meta-analysis involving 1 million participants in 61 cohort studies to determine the relevance of blood pressure to risk of disease in patients of different ages. 1. Prospective Studies Collaboration. Lancet 2002;360:1903-1913. 6 16 Trial HDFP trial MR C35-64 trial SHEP MR C65-74 trial 13 others All trials Primary prevention N of strokes 102:158 60:109 105:162 101:134 157:272 525:835 Odds ration (95% confidence intervals) Treatment better Treatment worse 37% (SD4) reduction P<0.00001 A net reduction of 5-6 mmhg DBP and 10-12 mmhg with a 38% reduction in the risk of fatal and non-fatal stroke PERINDOPRIL PROTECTION AGAINST RECURRENT STROKE STUDY The firs t randomized trial of ACE inhibitor-bas e d tre atment in patients with a his tory of c ere brovas cular dis e as e Neal B, MacMahon S. J Hypertens. 1995 ;13:1869-1873. Secondary prevention 18 3
Kaplan- Meier Rates Stroke: Survival Curve 0.06 Placebo 0.05 RRR 32% 0.04 0.03 0.02 Ramipril 0.01 0 0 500 1000 1500 Days of Follow-up P= 0.0002 RR= 0.68 BMJ ( 0.56-0.84) 08/2002 19 20 Proportion of patients with first event Reduction in the Risk of Stroke 1 8 7 5 4 2 6(% ) 3 1 Fatal and nonfatal stroke Atenolo l Losartan Adjusted risk reduction 24.9%, p = 0.0010 Unadjusted risk reduction 25.8%, p = 0.0006 0 0 6 12 18 24 30 36 42 48 54 60 66 Time (months) Number Losartan (n) 4605 4528 4469 4408 4332 4273 4224 4166 4117 3974 at risk 1928 925 Atenolol (n) 4588 4490 4424 4372 4317 4245 4180 4119 4055 3894 No significant difference in CV death and MI vs. atenolol. Risk reduction = relative risk vs. atenolol. 1901 897 161. Dahl?f B et al. Lancet 2002;359:995-1003. 21 Fact : Acute stroke Relationship between BP and occurrence of first stroke and effect of BP lowering treatment in preventing stroke well established ¾ of patient with acute stroke have high BP at presentation, 50% have history of HT BP declines spontaneously over first week in 2/3 of patients 22 Cerebral Blood Flow:CBF CBF of 50-70 ml/100g/min- normal CBF of 20-50 ml/100g/min- reduced flow CBF of 15-20 ml/100g/min- neuronal quiescence CBF <15mL/100g/min- neuronal death Equations MAP = 2/3 DBP + 1/3 SBP MAP = DBP+ 1/3(SBP-DBP) CPP = MAP ICP CBF = CPP/CVR Cerebral perfusion pressure (CPP) intracranial pressure (ICP) cerebrovascular resistance (CVR) 23 Mean arterial pressure (MAP) diastolic blood pressure (DBP) systolic blood pressure (SBP) 24 4
CBF: CPP/CVR Systemic hypertension in acute ischemic stroke is common Physiologic response for maintain adequate cerebral perfusion to ischemic penumbra Stroke Council of American Stroke Association Against treating HT in acute stroke Relationship between cerebral perfusion pressure and cerebral blood flow. 25 26 Do treat HT in acute cerebral infarction Decreased recurrent stroke, ICH Hypertensive encephalopathy may be associated with stroke Severe HT may cause acute cardiac strain HT may cause vasogenic brain edema Do treat HT in acute cerebral infarction rt-pa era after June 1996 Parenchymal bleeding, hemorrhagic transformation increasing in high BP Main motivation for BP management in acute phase 27 28 Do not treat HT in acute cerebral infarction Brain autoregulation for control CBF Impaired autoregulation in stroke Increased watershed infarction Increased turbulent flow of VV. 29 30 5
BP in the ED and on Admission to the Inpatient Clinic According to OCSP Classification Severity of Stroke on Admission to the Inpatient Clinic According to OCSP Classification Mean ± SD BP, mm Hg Mean ± SD Score OCSP Classification Systolic (ED) Diastolic (ED) Systolic (AD) Diastolic (AD) OCSP Classification NIH Scale GCS Barthel Index Rankin Modified Scale TACI (n = 16) PACI (n = 30) 160 ± 22 165 ± 26 79±13 85 ± 14 165±27 169 ± 28 88±17 90 ± 13 TACI (n = 16) PACI (n = 30) 19 ± 9 10 ± 5 11±2 13 ± 2 8±7 31 ± 35 5±0 4 ± 1 LACI (n = 34) POCI (n = 12) 170 ± 30 148 ± 46 90 ± 11 84 ± 18 181 ± 31 153 ± 42 96 ± 14 87 ± 21 LACI (n = 34) POCI (n = 14) 7 ± 7 27 ± 11 14 ± 2 8 ± 3 53 ± 36 4 ± 8 3 ±1 5 ±0 31 32 BP in the ED and on Admission to the Inpatient Clinic According to TOAST Classification Severity of Stroke on Admission to the Inpatient Clinic According to TOAST Classification TOAST Classification Cardioe (n = 28) LACI (n = 34) Systolic (ED) 157 ± 29 170 ± 30 Mean ± SD BP, mm Hg Diastolic (ED) 84±14 90 ± 11 Systolic (AD) 162± 28 181 ± 34 Diastolic (AD) 91±14 96 ± 14 TOAST Classification Cardioe (n = 28) LACI (n = 34) NIH Scale 17 ± 9 7 ± 7 GCS Mean ± SD Score Barthel Index 11±3 13±21 14 ± 2 53 ± 36 Rankin Modified Scale 4±1 3 ± 1 LVA (n = 29) 163 ± 33 81 ± 15 167 ± 34 86 ± 18 LVA (n = 29) 15 ± 11 12 ± 4 22 ± 34 4 ± 1 33 34 Systolic Mild Impairment Moderate Impairment Severe Impairment/Death Systolic Therapy Started or Increased Therapy Tapered or Stopped Therapy Unchanged No Therapy Diastolic Diastolic ED AD 24 Hours 4 Days Final ED AD 24 Hours 4 Days Final 35 36 6
Conclusion Highest BP at ED and 24 hr was seen in LACI LACI had less severe neurological deficit LVA and CE had a lower BP and more severe 37 38 Mortality rate (%) 80 70 60 50 40 30 20 10 0 Mortality rate at 1 month Mortality rate at 12 months <101 101-120 121-140 141-160 161-180 181-200 201-220 >220 Systolic BP on admission (mmhg) Mortality rate (%) 100 90 80 70 60 50 40 30 20 10 0 >61 61-70 71-80 81-90 91-100 101-110 111-120 >120 Diastolic BP on admission (mmhg) 39 40 Relationship between early or late stroke mortality and admission systolic blood pressure (SBP) values Outcome 1-month mortality 1-year mortality SBP (mmhg) 130 >130 130 >130 Hazard ratios (95% CI) 1.282 (1.086-1.513) 1.102 (1.042-1.166) 1.175 (1.031-1.340) 1.072 (1.022-1.123) P-value 0.003 0.001 0.016 0.004 Causes of death 1 month Neurological damage Cardiovascular disease Infections Other or unknown 12 month Neurological damage Cardiovascular disease Infections Other or unknown SBP 130 (n = 247) 13 (27.7) 14 (29.7) 13 (27.7) 7 (14.9) 14 (16.3) 27 (31.4) 22 (25.6) 23 (26.7) SBP > 130 (n = 883) 97 (50.5) 23 (12.4) 52 (28.0) 18 (09.1) 107 (37.8) 59 (20.8) 75 (26.5) 42 (14.9) P-value 0.005 0.004 0.968 0.246 0.001 0.043 0.865 0.011 41 42 7
Conclusion Every 10 mmhg rise in admission SBP above 130 mmhg, early and late mortality increase by 10.2, 7.2% Every 10 mmhg below SBP 130 mmhg, early and late mortality increase 28.2, 17.5% SBP 141-160 mmhg is optimal BP 43 44 45 46 Relationship between first BP variables and outcome: Rankin >3 vs 3 First BP-values (mm Hg) OR 95% CI P-value First SBP 130 (n = 97) vs 131-149 (n = 74) 1.10 0.43-2.83 NS 150 (n = 323) vs 131-149 1.38 0.58-3.31 NS First DBP 90 (n = 265) vs 91-109 (n = 92) 1.07 0.49-2.36 NS 110 (n = 46) vs 91-109 2.11 0.70-6.33 NS 47 48 8
The mean profiles of SBP with 95% CI according to favorable outcome (mrs 0 to 1) and unfavorable outcome (mrs 2 to 6) The mean profiles of SBP with 95% CI according to favorable outcome (mrs 0 to 1) and unfavorable outcome (mrs 2 to 6) Mean Systolic Blood Pressure (mmhg) Favorable outcome Unfavorable outcome Mean Systolic Blood Pressure (mmhg) Favorable outcome Unfavorable outcome Hours after Admission Hours after Admission 49 50 Mean value and 95% Cl of infarct volume on days 4 to 7 by SBP levels on admission Mean value and 95% Cl of infarct volume (cc) 51 52 Mean value and 95% Cl of infarct volume on days 4 to 7 by DBP levels on admission Mean value and 95% Cl of infarct volume (cc) Results U shaped effect Every 10 mmhg 180 mmhg SBP, 100 mm DBP neurological deterioration 6% poor outcome 25% mortality 7% mean infarct increased 7.3 cm 3 53 54 9
Results U shaped effect Every 10 mmhg > 180 mm SBP, > 100 DBP neurological deterioration 40% poor outcome 23% no effect on mortality mean infarct increased 5.5 cm3 55 56 Fact Previous data demonstrate the detriment effect of both low and high MAP in patient presenting with ischemic stroke Based on single BP at ER, mortality at 30-day Effect of change in SBP and DBP in 180 min Changes in Blood Pressure Between Admission and the First Day : Stroke Outcome Early neurological deterioration, % Poor neurological outcome, % Mortality at 3 months, % Volume of infarct, mean±sd, ml Systolic Blood Pressure Drop >20 mm Hg 54.4 (57) 90.2 (51) 23.5 (51) 133 ±66 (56) Drop 0-20 mm Hg 13.6 (177) 49.0 (151) 10.6 (151) 77 ±60 (147) Increase >0 mm Hg 30.3 (66) 57.4 (54) 13.0 (54) 108 ±73 (66) P Value <0.001 <0.001 0.066 <0.001 Diastolic Blood Pressure Drop >20 mm Hg 56.1 (50) 77.3 (44) 25.0 (44) 137 ±60 (49) Drop 0-20 mmhg 14.2 (197) 53.3 (167) 9.0 (167) 80 ±64 (195) Increase >0 mmhg 35.8 (53) 62.2 (45) 20.0 (45) 110 ±70 (52) P Value <0.001 0.014 0.009 <0.001 57 58 Comparison of BP values derived from measurements obtained during the first 180 minutes, patients with/ without 90-day mortality 90-day mortality Systolic BP, mm Hg Baseline Mean (SD) Median (IQR) Differential Mean (SD) Median (IQR) Yes, n=20 171.1 (31.8) 174.8 (146, 188) 50.8 (28.8) 47 (29, 70) No, n = 51 168.6 (35.9) 160 (143, 194) 37 (23.0) 30 (22, 50) Wilcoxon p value 0.91 0.047 Comparison of BP values derived from measurements obtained during the firs 180 minutes, patients with without 90-day mortality 90-day mortality Diastolic BP, mm Hg Baseline Mean (SD) Median (IQR) Differential Mean (SD) Median (IQR) Yes, n=20 86.4 (25.4) 90.5 (67, 100) 46 (20.7) 44.5 (31, 58) No, n = 51 80.2 (18.6) 80 (67.90) 27.3 (17.1) 25 (16,37) Wilcoxon p value 0.27 0.91 <0.001 59 60 10
Conclusion CBF in penumbra depends on systemic BP and collaterals until the occlude artery is recanalized Lower variability of DBP during 24hr with favorable outcome Reflect state of auto-regulation and BP control Benefit to keep BP at a reasonable lower overall level and less variable over time Sudden drop of BP with short half-life drug should avoided Conclusion Extreme variations in difference SBP/DBP in acute phrase are also predictive of a poor outcome Human brain has decreased ability to autoregulation Fluctuation in BP may lead to under-or overperfusion of delicate ischemic neurons Increased BP can lead edema and hemorrhage Decreased BP can lead infarction size 61 62 Objective BP in acute stroke Relationship with outcome Methods 17398 stroke, confirm with CT-brain Acute stroke within 48 hr 63 64 SBP (mmhg) <120 735 (4.2) 120-139 2476 (14.2) 140-159 4859 (27.9) 160-179 4541 (26.1) 180-199 2933 (16.9) >200 1854 (10.7) 65 66 11
Results U shaped Patients with SBP < 150 mmhg, every 10 mmhg fall in BP, increase risk of early death 17.9%, death or dependency at 6 months 3.6% Recurrent ischemic stroke within 14 days was increasing 4.2% every 10 mmhg increase in SBP 67 68 Low BP associated with early death from CAD Low BP could promote reduced CBP, cardiac perfusion, CAD CAD causes hypotension, low CBP, large infarction, poor outcome High BP caused cerebral edema, recurrent stroke Conclusion Patient with low BP might benefit from having it raised and cassation of prior antihypertensive drug Patient with high BP might have a better outcome if they continue prior antihypertensive drug or appropriate drug 69 70 Fact Antihypertensive drug indicate an emerging conceptual shift from lowering BP to specific organ protective effects Benefit beyond the effects of BP reduction ACE inhibitor, ARB showed protective against heart and renal ARB is protective against stroke 71 72 12
Patients Prospective, double-blind, placebo-controlled, RCT 500 patients with cerebral infarction within 36 hr BP 200 mmhg SBP and/or 110 mmhg DBP 6-24 hr BP 180 mmhg SBP and /or 105 mmhg DBP 24-36 hr Target reduction of BP was 10-15% within 24 hr 200/110 180/105 140/90 73 74 Baseline Characteristics on Admission, Barthel Index at 3 Months, Cumulative Mortality Until 12 Months, and Vascular Events Candesartan Cilexetil Placebo Blood pressure on admission, mm Hg 200 systolic Systolic Diastolic Blood pressure on study onset, mm Hg Systolic 196±23.1 103±14.0 188±20.9 199 ±22.9 102 ±14.9 190 ±19.7 150 100 50 0 diastolic Diastolic 99±14.9 99 ±13.0 75 76 Result Safety trial stopped premature, (342/500), because of an imbalance outcome 164/166 in placebo group was treated on day 7 (BP>140/90) Mortality rate 2.9 vs 7.2% Vascular event 9.8 vs 18.7% Baseline Characteristics on Admission, Barthel Index at 3 Months, Cumulative Mortality Until 12 Months, and Vascular Events Duration of symptoms until study onset, h Barthel Index day 0 Barthel Index 3 mo Cumulative 12-mo mortality Vascular events* Cardiovascular events (fatal and nonfatal) Cerebrovascular events (fatal and nonfatal) Noncardiovascular mortality Pulmonary embolism Candesartan Cilexetil 29.9 60.0±30.2 87.0±22.9 5 (2.9%) 17 (9.8)* 2 13 1 1 Placebo 29.7 64.1 ±27.5 88.9 ±19.9 12 (7.2%) 31 (18.7)* 10 19 1 1 77 78 13
Conclusion 7-day course of candesartan after acute ischemic stroke significantly improves cardiovascular morbi and morta However, favorable outcome is not achieved when started 7 days offer stroke Candesartan showed profoundly effect on cardiovascular, lower incidence of myocardial infarction Recurrent stroke did not difference Neurohumoral inhibition has benefit effect in cerebral and myocardial infarction 79 80 Fig. Automated brachial blood pressure and heart rate profile for 16 h after first dose. Lisinopril, n= 17; Placebo, n = 18. Data presented as mean± standard error bars. *Statistically significant BP reduction in lisinopril group compared to placebo for systolic (SBP), mean (MAP), and diastolic (DBP) blood pressure (p<.05) between hours 4 and 8 Fig. Automated brachial blood pressure and heart rate profiles for 16 h at baseline and day 14 of therapy. Lisinopril, n=12; Placebo, n= 16. Data presented as mean ± standard error bars. *Statistically significant BP reduction in lisionopril group compared to placebo for systolic (SBP), mean (MAP) (P>.01), and diastolic (DBP) blood pressure (P>.05) 81 82 Systolic Blood Pressure 175 170 165 160 D0 D1 D2 D3 D4 D5 D0 D1 D2 D3 D4 D5 mmhg 155 150 145 140 D0 D1 D2 D3 D4 D5 135 Placebo Low dose High dose 83 130 84 14
Diastolic Blood Pressure 100 95 Death or dependency Low-dose vs. Placebo Nimodipine n/n 71/93 Placebo n/n 62/92 Peto odds rations (95% C.I) Peto odds ratios (95% C.I) 1.55(0.82,2.94) 90 High-dose vs Placebo 72/83 62/92 3.69 (1.80,7.58) mm Hg 85 80 75 70 65 D0 D1 D2 D3 D4 D5 D0 D1 D2 D3 D4 D5 D0 D1 D2 D3 D4 D5 Placebo low-dose high-dose 85 Low-dose DBP change subgroups vs Placebo Unchanged/increased Slight decrease <10% Moderate decrease 10 to <20% Profound decrease >=20% 15/18 20/30 30/37 6/8 62/92 62/92 62/92 62/92 2.12(0.71,6.36) 0.97(0.40,2.32) 1.94(0.84,4.50) 1.41(0.30,6.60) 86 Death or dependency Nimodipine n/n High-dose DBP change subgroups vs. Placebo Placebo n/n Peto odds rations (95% C.I) Peto odds ratios (95% C.I) Unchanged/increased 8/10 62/92 1.79(0.44,7.24) Slight decrease <10% 14/16 62/92 2.60(0.82,8.27) Moderate decrease 10 to <20% 25/28 62/92 2.97(1.16,7.63) Profound decrease >=20% 25/26 62/92 4.36(1.63,11.7) 87 88 89 90 15
Fact USA guideline; SBP > 220, MAP > 130 mmhg 154 ischemic stroke 66% previous HT 51% use anti HT 10.71% severe HT on arrival Median BP 160/80 mmhg MAP 106 mmhg Fact (4 day hospitalization) 11% had hypotension (SBP < 120, MAP < 85 mmhg) 22% had one episode of severe HT 69% had one episode of hypotension Adherence to stroke guideline?? 91 92 Study Hypothesis Treatment with a valsartan-based therapy will The JIKEI HEART Study yield additional protective benefits, compared with conventional treatment, beyond those attributable to blood pressure (BP) control The First Large-scale Intervention Trial of an ARB in a Japanese Population 93 94 Study Endpoints Baseline Characteristics Primary endpoint: Combined endpoint of CV morbidity and mortality Hospitalization for stroke or TIA (Transient Ischemic Attack) Myocardial infarction (MI) Hospitalisation for congestive heart failure (CHF) Hospitalisation for angina pectoris Dissecting aneurysm of the aorta Doubling of serum creatinine or transition to dialysis Secondary Endpoints: Each component of the primary endpoint Death from any cause Clinical characteristics Male Female Age (years) Current smoker Systolic BP [SBP] (mmhg) Diastolic BP [DBP] (mmhg) Heart rate (beats/min) BMI (kg/cm 2 ) Valsartan arm (n=1,541) 1,020 (66%) 521 (34%) 65 (10) 259 (17%) 139.2 (11.4) 81.4 (10.5) 71 (11) 24(3) Non-ARB arm (n=1,540) 1,023 (66%) 517 (34%) 65 (10) 262 (17%) 138.8 (10.6) 81.4 (10.8) 72 (11) 24(3) 95 Note: Data are mean (Standard Deviation) or Number (%) 96 16
Medical History at Baseline Medications at Baseline Concomitant Diseases Valsartan arm (n=1,541) Non-ARB arm (n=1,540) CCB Valsartan arm (n=1,541) 1,041 (68%) Non-ARB arm (n=1,540) 1,011 (66%) Hypertension Coronary heart disease 1,358 (88%) 514 (33%) 1,341 (87%) 522 (34%) ACE Inhibitor β-blocker α-blocker 548 (36%) 486 (32%) 74 (5%) 525 (34%) 502 (33%) 93 (6%) Heart failure Hyperlipidaemia 176 (11%) 812 (53%) 174 (11%) 813 (53%) Thiazide Anti-aldosterone agent Other diuretics 29 (2%) 52 (3%) 117 (8%) 39 (3%) 64 (4%) 126 (8%) Diabetes mellitus 315 (20%) 314 (20%) Statin 461 (30%) 490 (32%) Fibrate 42 (3%) 37 (2%) 97 ACEI: angiotensin converting-enzyme inhibitor; CCB: calcium channel blocker 98 The JIKEI HEART Study was Halted Early Due to Unequivocal Benefit from Valsartan On a recommendation from the Data and Safety Monitoring Board (DSMB), the JIKEI HEART Study was halted early for ethical reasons, after 3.1 years because valsartan treatment was The JIKEI HEART Study associated with a reduction in the primary endpoint (combined Blood Pressure (BP) Results endpoint of cardiovascular morbidity and mortality) Originally, this study was planned to be conducted for 3.5 years 99 100 Primary Endpoint 15 Valsartan arm (92 events) Non-ARB arm (149 events) The JIKEI HEART Study Primary Endpoint Result Event rate (%) 10 5 39% HR=0.61, p=0.0002 95% CI 0.47 0.79 101 0 0 6 12 18 24 30 36 42 48 Number at risk Valsartan 1,541 1,504 1,441 1,257 1,092 855 689 368 368 Non-ARB 1,540 1,502 1,447 1,262 1,075 835 657 344 343 102 17
Effect of Treatment on Endpoints New or Recurrent Stroke Primary endpoint Composite endpoint Secondary endpoints Stroke/TIA Myocardial infarction Hospitalisation for angina pectoris Hospitalisation for Heart Failure Dissecting aortic aneurysm Transition to dialysis, doubling of serum creatinine levels All cause mortality Cardiovascular mortality Incidence of endpoint reduced TIA = transient ischaemic attack 0.125 0.25 0.5 1 2 4 P-value 0.0002 0.0280 0.7545 0.0001 0.0293 0.0340 0.8966 0.7537 0.9545 Incidence increased 103 Event rate (%) 3.5 3.0 2.5 2.0 1.5 1.0 0.5 Valsartan arm 29 events Non-ARB arm 48 events HR=0.60, p=0.028 95% CI 0.38 0.95 40% 0.0 0 6 12 18 24 30 36 42 48 Number at risk Valsartan 1,541 1,504 1,442 1,258 1,093 855 689 368 368 Non-ARB 1,540 1,502 1,450 1,266 1,079 836 656 343 343 TIA events: 4 in DIOVAN group; 5 in conventional group Source: Kaplan Meier Curve adopted from Dr Dahlof ESC 2006 Hotline presentation 104 JIKEI HEART Study: Main Results Blood Pressure Results The primary combined endpoint of cardiovascular morbidity and mortality was significantly reduced by 39% in those allocated to a valsartan-based regimen vs. those given conventional therapy Valsartan arm (n=1,541) Non-ARB arm (n=1,540) Reductions from baseline Valsartan Non-ARB 8.2/4.7 7.2/3.7 There were significant reductions in the following components of the primary endpoint among those receiving a valsartan-based regimen vs. those receiving conventional therapy 40% risk reduction in the incidences of new or recurrent stroke (p=0.028) 65% risk reduction in hospitalisation for angina pectoris (p=0.001) 47% risk reduction in hospitalisation for heart failure (p=0.0293) 81% risk reduction in dissecting aortic aneurysm (p=0.0340) mmhg 160 140 120 100 80 0 SBP DBP Mean SBP 131 vs. 132 mmhg Valsartan vs. non-arb n.s. Mean DBP 77 vs. 78 mmhg Valsartan vs. non-arb n.s. 0 6 12 18 24 30 36 42 Time (months) 105 Note: Data shown above as text is quoted in the Lancet publication text 106 Effect beyond HT Aggressive BP Control Rationale Anti-atherosclerotic effects Plaque rupture reduction Trial HOT CAPPP Journal Lancet 1998 Lancet 1999 Baseline 175/105 161/99 Study end 142/83 150/90 Improvement in vascular endothelial function Enhanced fibrinolysis Modulation of neurohormonally-induced arterial vasoconstriction Blood pressure lowering LV hypertrophy reduction Angiotensin II reduction / bradykinin increase 107 STOP-2 Lancet 1999 194/98 159/81 ALLHAT JAMA 2000 145/83 136/76 NORDIL Lancet 2000 173/106 151/88 INSIGHT Lancet 2000 173/99 138/82 LIFE Lancet 2002 174/98 145/81 VALUE Lancet 2004 154/88 138/79 ASCOT-BPLA Lancet 2005 164/95 137/78 JIKEI HEART Lancet 2007 139/81 131/77 Note: Data shown above is based on Dr Dahlof presentation at ESC 2006 108 18
Stroke out-come of ACE-I and ARB Rx Anti HT drug for first stroke prevention Clinical trial PROGRESS HOPE Medication Perindopril/diuretic Ramipril Stroke risk reduction 28.0 % RR 32.0 % RR DBP level (mmhg) 90-110 Number needed to treat 118 LIFE EUROPA Losartan Perindopril 25.8 % RR 20.0 % RR Up to 115 52 JIKEI SCOPE Valsartan Candesartan 40.0 % RR 28.0 % RR More than 115 29 109 110 Sartan= Result 4% discounting, prevention of stroke, gain of 3.7 life-year Losartan treatment was associated with 0.059 life year gained per patient treated Treatment with losartan compared with atenolol may well be a cost-effective 111 112 COST EFFECTIVENESS Losartan Atenolol Difference Costs (Euro) Medication 1265 138 1128 Stroke 3317 4393-1076 Net 4582 4531 51 Cumulative incidence of stroke at 5.5 yeas 0.049 0.065-0.016 What we learn from this topic Primary and secondary stroke prevention by control BP is essential Early and aggressive treatment high BP Cut-off level of high BP for start treatment in acute stroke should be more lower than present Target level of BP in primary and secondary prevention could be lower than present 113 114 19
Take home message Effect of anti HT beyond BP lowering Primary prevention is important ACE I and ARB showed more benefit in stroke management Early control BP in acute phase of acute stroke may be needed and useful by ARB Primary prevention is the best 115 116 ก Call EMS 34.65% Observe clinical 25.20% Call to family 26.20% Private clinic 16.54% Drugs store - Massage 19.69% Pre-test : World stroke day 25 May, 2007 at Khon Kaen, 127 elderly 117 118 Secondary prevention Smoking cessation ARR 2.3% NNT 43 0 12,700 Case discussion Female 65 yr old Underlying HT(Rx CCB),dyslipidemia,DM Sudden developed right hemiplegia and global aphasia BP 200/100 mmhg CT brain showed normal study ( 4 hr after onset) 119 120 20
How to manage these problem? What is a diagnosis? Treat or Not treat BP 200/100 mmhg? How to treat? What is an anti HT? Why you change your clinical practice? Case discussion Women 51 yr, DM, HT, CKD On enalapril and diovan Sudden onset of left hemiparesis CT-brain: lacunar infarction BP 130/80 mmhg Left hemiparesis, fully of consciousness 121 122 How to manage these problem? My brain mapping Acute ischemic stroke What is a diagnosis? Normal BP MAP 120 mmhg Treat or Not treat BP 130/80 mmhg? How to treat? What is an anti HT? Why you change your clinical practice? High BP All kinds anti HT Prefer ACE-I, ARB F/U Normal BP 130/80 mmhg Reduce BP 10-15% Within 24 hr No history of HT MAP 130 mmhg Stable, feed, oral ACE-I,ARB High BP Previous Rx HT MAP 140 mmhg NPO CCB,NTG,NPS 123 124 Sociopolitical influences CPG Political Personal ego Commercially fund Pharmaceutical industry References 1. Vemmos KN, Tsivgoulis G, Spengos K, et al. U-shaped relationship between mortality and admission blood pressure in patients with acute stroke. J Intern Med 2004;255:257-65. 2. Semplicini A, Maresca A, Boscolo G, et al. Hypertension in acute ischemic stroke. Arch Intern Med 2003;163:211-6. 3. Boersma C, Carides GW, Atthobari J, et al. An economic assessment of losartan-based versus atenolol-based therapy in patients with hypertension and left-ventricular hypertrophy: results from the losartan intervention for endpoint reduction (LIFE) study adapted to the Netherlands. Clinical Therapeutics 2007;29:963-71. 125 126 21
References 4. Schrader J, Luders S, Kulschewski A, et al. The ACCESS study evaluation of acute candesartan cilexetil therapy in stroke survivors. Stroke 2003;34:1699-703. 5. Leonardi-Bee J, Phillips SJ, Sandrcock AG, The IST Collaborative group. Blood pressure and clinical outcomes in the international stroke trial. Stroke 2002;33:1315-20. 6. Aslanyan S, Fazekas F, Weir CJ, et al. Effect of blood pressure during the acute period of ischemic stroke on stroke outcome a tertiary analysis of the GAIN international trial. Stroke 2003;34:2420-5. References 7. Lindenauer PK, Mathew MC, Ntuli TS, et al. Use of antihypertensive agents in the management of patients with acute ischemic stroke. Neurology 2004;63:318-23. 8. Boreas AMHP, Lodder J, Kessels F, et al. Prognostic value of blood pressure in acute stroke. Journal of Human Hypertension 2002;16:111-6. 9. Yamada K, Hirayama T, Hasegawa Y. Antiplatelet effect of losartan and telmisartan in patients with ischemic stroke. Journal of Stroke and Cerebrovascular Diseases 2007;16:225-31. 127 128 References 10. Yong M, Diener HC, Kaste M, et al. Characteristics of blood pressure profiles as predictors of long-term outcome after acute ischemic stroke. Stroke 2005;36:2619-25. 11. Castillo J, Leira R, Garcia MM, et al. Blood pressure decrease during the acute phase of ischemic stroke is associated with brain injury and poor stroke outcome. Stroke 2004;35:520-7. 12. Stead LG, Gilmore RM, Vedula KC, et al. Impact of acute blood pressure variability on ischemic stroke outcome. Neurology 2006;66:1878-81. 129 130 THANK YOU FOR YOUR ATTENTION 131 22