Hypertension and Stroke: new data

Transcription

1 Hypertension and Stroke: new data Antonio Coca, MD, PhD, FRCP Hypertension Unit. Institute of Internal Medicine and Dermatology. Hospital Clínic (IDIBAPS). University of Barcelona, Spain WG Seminars. Hellenic Society of Cardiology Thessaloniki, February 18th, 2012

2 Contents Stroke as leading cause of morbidity and mortality in Europe Primary prevention - Antihypertensive drugs - Statins Secondary Prevention - Statins Treatment in the acute phase

3 Albania Andorra Austria Azerbaijan Belarus Belgium Bosnia and Herzegovina Bulgaria Croatia Cyprus Czech Republic Denmark Estonia Finland France Georgia Germany Greece Hungary Iceland Ireland Israel Italy Kazakhstan Kyrgyzstan Latvia Lithuania Luxembourg Malta Monaco Netherlands Norway Poland Portugal Republic of Moldova Romania Russian Federation San Marino Serbia and Montenegro Slovakia Slovenia Spain Sweden Switzerland Turkey Ukraine United Kingdom Columna2 Europe average Stroke mortality in European Countries: WHO 2002 Yearly adjusted mortality rate by 100,000 inhabitants 300,0 250,0 n= ,0 150,0 100,0 50,0 - n= 14 n= 14 Redon J, Coca A et al, Eur Heart J 2011;32:

4 Trends in Stroke Mortality Risk from by Country group (WHO) in Europe Age-adjusted stroke mortality rates per 100,000 inhabitants Group of Countries Males Females Group A (Very low child and adult mortality) Group B (Low child and adult mortality) Group C (Low child and high adult mortality) Mean (95% CI) 93.9 ( ) ( ) ( ) ( ) ( ) ( ) Group A: Greece and Portugal had rates twice the group average Group B: Bulgaria and Romania had the highest rates Group C: Latvia and Russian Federation had the highest rates Redon J, Coca A et al, Eur Heart J 2011;32:

5 Age-adjusted rates per 100,000 men Age-adjusted rates per 100,000 men Trends in Stroke Mortality Rate from by Country group (WHO) in Europe Mean trend for mortality rates for each of the country groups Men Women Group C Group C Group B 150 Group B Group A 50 Group A Redon J, Coca A et al, Eur Heart J 2011;32:

6 Contents Stroke as leading cause of morbidity and mortality in Europe Primary prevention - Antihypertensive drugs - Statins Secondary Prevention - Statins Treatment in the acute phase

7 Is there a lower BP limit below which there is no benefit or even an increased risk? J Curve Events What are the lower limits for BP reduction in stroke? Nadir Blood Pressure Reappraisal ESH/ESC Guidelines. J Hypertens 2009; 27:

8 Blood Pressure Achieved in ACCORD Study patients with DM-2 treated for 8 years Adjusted incidence per 1000 subjects/year (%) Macrovascular complications (MI, Stroke, CV death) 10 0 Estand SBP (mmhg) N Eng J Med 2010; 362:

9 Blood Pressure Achieved in ACCORD Study Adjusted incidence per 1000 subjects/year (%) Intensivo Estand SBP (mmhg) 4733 patients with DM-2 treated for 8 years Macrovascular complications (MI, Stroke, CV death) SBP difference between strategies mmhg N Eng J Med 2010; 362:

10 Patients with Events (%) Patients with Events (%) Blood Pressure Achieved and Cardiovascular Prevention in ACCORD Study Primary Outcome Nonfatal MI, Nonfatal Stroke or CVD Death HR = % CI ( ) 11% Secondary outcome Total Stroke HR = % CI ( ) NNT for 5 years = 89 Standard Intensive Years Post-Randomization Standard Intensive % Years Post-Randomization N Eng J Med 2010; 362:

11 Blood Pressure Targets and Stroke Prevention in the ONTARGET Study Incidence of stroke to the % of in-treatment visits in which BP was found to be reduced to < 130/80 mmhg Stroke Incidence (%) n= SBP DBP Visits with BP<130/80 mmhg <25% 25-49% 50-74% 75% Include patients with baseline SBP 130 and 7 intreatment visits before the endpoint Mancia et al. Circulation 2011; 124:

12 Events (%) ONTARGET Study: Stroke Incidence Related to In-treatment SBP in Patients with Diabetes 10 Diabetic (n= 9,603) Non-diabetic (n= 15,981) In-treatment SBP deciles (mmhg) Redón et al. JACC 2012; 59: 74-78

13 Statins and Intracerebral Hemorrhage Hackam et al. Circulation 2011; 124:

14 Statins and Intracerebral Hemorrhage Trial RR (95% Cl) 4D 0.64 (0.21 to 1.96) ACAPS 0.14 (0.01 to 2.75) AFCAPS 3.00 (0.12 to 3.62) ALERT 0.59 (0.27 to 1.28) ALLHAT 3.42 (1.26 to 9.27) ASCOT 0.55 (0.26 to 1.14) ASPEN 1.98 (0.36 to 10.9) AURORA 1.04 (0.57 to 1.91) Bone et al 0.74 (0.03 to 18.3) CARE 0.33 (0.07 to 1.65) CLAPT 0.34 (0.01 to 8.34) CORONA 1.66 (0.72 to 3.80) GISSI-HF 3.69 (1.03 to 13.2) JUPITER 0.67 (0.24 to 1.87) LIPID 1.89 (0.84 to 4.24) MEGA 1.09 (0.56 to 2.11) MIRACL 0.14 (0.01 to 2.78) PROSPER 0.81 (0.32 to 2.04) SPARCL 1.69 (1.09 to 2.60) SSSS 1.75 (0.51 to 6.00) Overall 1.10 (0.86 to 1.42) Conclusions: We found no evidence that statins were associated with intracerebral hemorrage: if such a risk is present, its absolute magnitude is likely to be small and outweighed by the other cardiovascular benefits of these drugs Hackam et al. Circulation 2011; 124:

15 Statins in Primary Prevention of Major Cerebrovascular Events AFCAPS/TexCAPS ALLHAT-LLT * ASCOT-LLA CARDS PROSPER WOSCOPS RR: 0.82 [ ] RR: 0.91 [ ] RR: 0.73 [ ] RR: 0.59 [ ] RR: 1.03 [ ] RR: 0.90 [ ] Todos RR: 0.86; p= 0.02 *Comparison with usual care Statin better Placebo better Thavendiranathan et al. Arch Intern Med. 2006;166:

16 Statins in Primary Prevention of Stroke: JUPITER Study Incidence of fatal and non-fatal stroke (Ischemic, hemorrhagic, unknown type)) HR 0.52 (95% CI P= Placebo 48% Cumulative Incidence Rosuvastatin Follow-up (years) Everet et al. Circulation 2010; 121:

17 Statins in Primary Prevention of Stroke Risk of stroke in four statin primary prevention trials Hazard Ratio [95% CI] WOSCOPS AFCAPS/TexCAPS MEGA JUPITER RR: 0.89 [ ] RR: 0.82 [ ] RR: 0.83 [ ] RR: 0.52 [ ] All RR: 0.75 [ ]; p= Statin better Placebo better Everet et al. Circulation 2010; 121:

18 Contents Stroke as leading cause of morbidity and mortality in Europe Primary prevention - Antihypertensive drugs - Statins Secondary Prevention - Statins Treatment in the acute phase

19 Statins in Secondary Prevention of Stroke: SPARCL Study Cumulated incidence (%) 8 Atorvastatin 80 mg Placebo Fatal and non-fatal stroke RRR 16% 4 0 P= 0.03 Adjusted RR*= 0.84 [IC 95% ] Time (years) since randomization The SPARCL Investigators. N Engl J Med. 2006; 355:

20 Statin Treatment and Functional Outcome after Acute Ischemic Stroke STUDY Meta-Analysis Forest Plot OR (95% CI OR) Weight (%) Reeves 1.35 (0.97, 1.87) Greisengger 2.27 (1.09, 4.74) 3.94 Yu 2.00 (1.00, 4.00) 4.41 Yoon 2.90 (1.23, 6.85) 2.96 Arboix 1.32 (1.01, 1.73) MGH (Present Study) 1.51 (0.94, 2.43) 8.49 Moonis 1.57 (1.04, 2.38) Goldstein 1.50 (1.01, 2.23) Martinez-Sanchez 2.08 (1.39, 3.11) Elkind 3.33 (1.00, 11.04) 1.57 Marti-Fabregas 5.55 (1.57, 19.65) 1.41 Jonsson 1.42 (0.90, 2.23) 9.29 Random Effects Model P< ( ) Better statin nonuser (n= 9682) Better statin user (n= 2013) Biffi et al. Stroke 2011; 42:

21 Proportion Surviving Statin Use During Ischemic Stroke Hospitalization and Survival 12,689 patients with ischemic stroke in 17 hospitals operated by Kaiser Permanente Northern California between January 2000 December Statin use before stroke HR 0.85 (95% CI ) p< Statin use before & during stroke HR 0.59 (95% CI ) p< Statin Statin Statin Statin n= 3,749 (29.5%) No statin n= 8,940 (70.5%) 0.6 Statin n= 6,294 (49.6%) No statin n= 6,395 (50.4%) - Statin Days after stroke onset Days after stroke onset Flint et al. Stroke 2012; 43:

22 Proportion Surviving Statin Use During Ischemic Stroke Hospitalization and Survival 12,689 patients with ischemic stroke in 17 hospitals operated by Kaiser Permanente Northern California between January 2000 December Statin use before stroke HR 0.85 (95% CI ) p< Statin use before & during stroke HR 0.59 (95% CI ) p< mg/d mg/d 0.8 <60mg/d 0.8 <60mg/d statin 60 mg/d n= 655 (5.2%) <60 mg/d n= 3,094 (24.4%) No statin n= 8,940 (70.4%) Days after stroke onset statin 60 mg/d n= 549 (6.4%) <60 mg/d n= 2,154 (25.0%) No statin n= 5,911 (68.6%) Days after stroke onset Flint et al. Stroke 2012; 43:

23 Statin Use During Ischemic Stroke Hospitalization and Mortality Hazard Ratio for death Increasing HR of death with delayed in-hospital statin treatment among patients not taking statin before stroke hospitalization or restarting previous statin treatment Cox regression model P< for trend Day 1 Day 2 Day 3 Timing of statin initiation P< for trend Day 1 Day 2 Day 3 Timing of statin restart Flint et al. Stroke 2012; 43:

24 Contents Stroke as leading cause of morbidity and mortality in Europe Primary prevention - Antihypertensive drugs - Statins Secondary Prevention - Statins Treatment in the acute phase

25 High BP Treatment in the Acute Stroke Phase Elevations in SBP > 160 mmhg are detected in more than 60% of patients with acute stroke, and are associated with poor outcome after stroke For every 10 mmhg increase over SBP 180 mmhg, the risk of neurological deterioration increased by 40% and the risk of poor outcome increased by 23% Theoretical reasons for lowering BP include reducing the formation of brain edema, lessening the risk of hemorrhagic transformation of the infarction, preventing further vascular damage, and forestalling early recurrent stroke Adams et al. AHA/ASA Guidelines. Stroke 2007; 38:

26 Treatment of High Blood Pressure in the Acute Phase of Stroke In a majority of patients, a decline in BP occurs within the first hours after stroke even without any specific medical treatment Aggressive treatment of initial high BP may lead to neurological worsening by reducing perfusion pressure to ischemic areas of the brain Adams et al. AHA/ASA Guidelines. Stroke 2007; 38:

27 Treatment of High Blood Pressure in the Acute Phase of Stroke Questions to be answered Should BP be lowered in all patients with acute ischemic stroke and high BP values? Should patients previously taking antihypertensive drugs continue taking them in the first hours of stroke? When should treatment be started? How much should BP be reduced? Which drug classes and formulations should be used? Coca A. J Hyperrtens 2003; 21: 1-2

28 SCAST Study Sandset et al. Lancet 2011;377;

29 SCAST Study Group 146 centres, 9 European countries Norway Denmark Sweden Finland Estonia Lithuania 2,029 pts with acute stroke and elevated blood pressure ( ) Recruitment was stopped early on administrative grounds (target: 2,500 pts) Belgium Germany Poland Sandset et al. Lancet 2011;377;

30 Central randomisation Study Treatment Candesartan/placebo for 7 days (doses increasing from 4 to 16 mg during first 3 days) Treatment in follow-up period left to discretion of clinician (candesartan provided free of charge) Candesartan Placebo 0 7 d 180 d Sandset et al. Lancet 2011;377;

31 SCAST Study: Inclusion Criteria Clinical diagnosis of stroke (ischaemic or haemorrhagic) Systolic blood pressure 140 mm Hg Treatment possible within 30 hours of symptom onset Age 18 years or older Sandset et al. Lancet 2011;377;

32 SCAST Study: Two Co-primary Effect Variables Composite vascular endpoint during first 6 months: vascular death, myocardial infarction and stroke Functional outcome at 6 months (as measured by the modified Rankin Scale) Sandset et al. Lancet 2011;377;

33 SCAST Study: Trial Profile 2029 patients randomised 1017 allocated candesartan 20 with SSS consciousness score 2 11 without stroke (8 with TIA) 5 with pre-morbid mrs score 4 1 with symptom duration >30 hrs 1 with on-going treatment with ARB 16 not given treatment per protocol 1012 allocated placebo 20 with SSS consciousness score 2 11 without stroke (5 with TIA) 2 with pre-morbid mrs score 4 1 with symptom duration >30 hrs 2 with on-going treatment with ARB 8 not given treatment per protocol 1 lost to follow-up 16 withdrew consent 3 lost to follow-up 5 withdrew consent 1017 included in analysis of composite end-point 1000 included in analysis of functional outcome at 6 months 1012 included in analysis of composite end-point 1004 included in analysis of functional outcome at 6 months Sandset et al. Lancet 2011;377;

34 SCAST Study: Baseline Characteristics Candesartan n = 1,017 Placebo n = 1,012 Female gender, n (%) 405 (40) 448 (44) Age, years (mean, SD) Systolic blood pressure, mm Hg (mean, SD) Diastolic blood pressure, mm Hg (mean, SD) Duration of symptoms, hrs (mean, SD) SSS score (mean, SD) Qualifying event Ischaemic stroke, n (%) 862 (85) 871 (86) Haemorrhagic stroke, n (%) 144 (14) 130 (13) Other, n (%) 9 (1) 11 (1) Unknown, n (%) 2 0 Medical history Hypertension, n (%) 676 (69) 670 (70) Diabetes mellitus, n (%) 163 (16) 157 (16) Atrial fibrillation, n (%) 190 (19) 186 (19) Previous stroke or TIA, n (%) 252 (25) 204 (21) Thrombolytic treatment before inclusion 69 (8) 82 (9) Sandset et al. Lancet 2011;377;

35 Blood Pressure in Treatment Period 180 SBP mm Hg DBP Candesartan Placebo Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day ΔSBP P-value <0 001 <0 001 <0 001 <0 001 <0 001 Sandset et al. Lancet 2011;377;

36 Composite Vascular Endpoint (Vascular Death, Myocardial Infarction or Stroke) Candesartan: 120 (11.7%) Placebo: 111 (11.3%) Adjusted HR 1.09 [95% CI ] p=0.52

37 Functional Outcome (mrs) = Independent 6 = Dead Candesartan Placebo % 20 % 40 % 60 % 80 % 100 % Adjusted common OR 1.17, 95% CI ; p=0.048 (non-significant, due to the use of two co-primary effect variables) Sandset et al. Lancet 2011;377;

38 Recurrent Stroke Candesartan: 69 (6.8%) Placebo: 59 (5.8%) Adjusted HR 1.18 [95% CI ] p=0.35 Sandset et al. Lancet 2011;377;

39 SCAST Study: Summary SCAST is the first, large trial of BP lowering treatment in patients with acute stroke and elevated BP Candesartan gave a small blood pressure reduction already on day 2, and a modest reduction was seen from day 4 No significant differences were observed for the two co-primary effect variables: i) composite vascular endpoint, and ii) functional outcome. If anything, the outcome data points towards a harmful effect Sandset et al. Lancet 2011;377;

40 Blood Pressure Changes in the Acute Phase of Stroke 240 first-ever ischemic or haemorrhagic stroke patients recruited within first 3 h 24-h BP values measured at 15 min intervals. No antihypertensive treatment permitted CT scan obtained within 24h from stroke and 5 days later to assess brain oedema Vemmos et al. J Hypertens 2003; 21:

41 Blood Pressure Changes in the Acute Phase of Stroke SBP (mmhg) h BP associated with brain edema (p< 0.019) OR 1.25 (95% CI ) for brain edema with each 10 mmhg SBP increase Patients with brain edema (n= 78; 32.5%) Patients with absence of brain swelling (n= 162; 67.5%) 3h 4h 5h 6h 7h 8h 9h 10h 11h 12h 13h 14h 15h 16h 17h 18h 19h 20h 21h 22h 23h 24h 25h 26h 27h Time from stroke onset Vemmos et al. J Hypertens 2003; 21:

42 Treatment of High Blood Pressure in the Acute Phase of Stroke Management of BP during the first 6 hours after stroke in the absence of other organ dysfunction requiring rapid BP lowering or need for thrombolytic therapy - BP level to start: SBP >220 mmhg or DBP >120 mmhg - BP goal: lower BP by 15% to 25% of baseline level within the first day - Antihypertensive agent: No specific drug recommendation Select on a case-by-case basis - Timing to start treatment for secondary prevention: ~ 1 day Adams et al. AHA/ASA Guidelines. Stroke 2007; 38:

43 Treatment of High Blood Pressure in the Acute Phase of Stroke If the patient is eligible for intravenous rtpa BP level to start: SBP >185 mmhg or DBP >110 mmhg - Labetalol 10 to 20 mg IV over 1-2 minutes - Nitropaste 1 to 2 inches - Nicardipine infusion 5 mg/h (titrate up by 2.5 mg/h at 5 to 15 minute intervals..) If BP doest not decline and remains > 185/110 mmhg, do not administer rtpa Adams et al. AHA/ASA Guidelines. Stroke 2007; 38: