Impact of Resting Heart Rate on Mortality, Disability and Cognitive Decline in Patients after Ischemic Stroke

Transcription

1 Impact of Resting Heart Rate on Mortality, Disability and Cognitive Decline in Patients after Ischemic Stroke Data from PROFESS M. Böhm Daniel Cotton, Lydia Foster, Florian Custodis, Ulrich Laufs, Ralph Sacco, Philip Barth, Salim Yusuf Hans-Christoph Diener

2 Disclosures Authors were members of the PROfESS Steering Committee or received honoraria and research grants from Boehringer Ingelheim as well as fees from other major cardovascular pharmaceutical companies

3 Background: Psychosocial Stress is CV Risk Indicator Rosengren et al, Lancet 364 (24):

4 Background: Stress Produces a Vascular Phenotype Custodis et al, Stroke 42: , 211

5 Background: Stress Reaction Involves Heart Rate Tail Suspension Control Ivabradine Heart rate [bpm] MABP [mmhg] time [min] time [min] Custodis et al, Stroke 42: , 211

6 Background: Stroke Size in Chronic Stress is HR Dependent Cerebral infarct volume [mm³] * * * p<.5 vs. naive vehicle ** p<.5 vs. stress vehicle ** naive vehicle naive iva stress vehicle stress iva Custodis et al, Stroke 42: , 211

7 Study Design 2x2 Factorial design 2,332 stroke patients over age 5 Telmisartan Telmisartan placebo ER-DP+ASA ER-DP+ASA + clopidogrel placebo + Telmisartan ER-DP+ASA + clopidogrel placebo + Telmisartan placebo Clopidogrel* Clopidogrel + ER-DP+ASA placebo + Telmisartan Clopidogrel + ER-DP+ASA placebo + Telmisartan placebo 2,332 pts Diener et al., Cerebrovasc Dis 17: , 24

8 Objectives: To compare the efficacy and safety of the combination of extended-release dipyridamole and aspirin to clopidogrel (non-inferiority first then superiority) To compare telmisartan to placebo in the prevention of recurrent stroke (superiority)

9 Primary Outcome: Recurrent Stroke ** Covariates in Cox model are age, baseline ACE-inhibitor use, Modified Rankin, and baseline diabetes status. Telmisarta n 88 (8.7%) Placebo HR 95% CI p-value 934 (9.2%) , ASA+ER-DP Clopidogre l HR 95% CI p-value 916 (9.%) 898 (8.8%) , Yusuf et al., NEJM 359: , 28 Sacco et al., NEJM 359: , 28

10 Baseline mrs Among Subjects with Recurrent Strokes ARB Comparison Placebo 11,6 34,5 26,3 17,3 1,3 Telmisartan 1,9 35,5 25,1 18,4 1,1 % 1% 2% 3% 4% 5% 6% 7% 8% 9% 1% 3 months post recurrent stroke Placebo 7,9 25,4 18, ,8 4,9 13,6 Telmisartan 8,4 24, ,1 11,7 5,2 15,3 p=.612* % 2% 4% 6% 8% 1% * From Cochran-Armitage test for linear trend Diener et al., Lanct Neurol 7: , 28

11 Objectives of Current Analysis (1) HR predict CV events along the cardiovascular continuum In stress models, HR reduction reduces stroke size It s not known whether HR in patients after stroke - predicts recurrent stroke, MI, CHF or death after stroke - is associated with functional outcome or cognitve decline after recurrent stroke

12 Mahoney and Barthel, Maryland State Medical Journal 21 (1965): Objectives of Current Analysis (2) Association of Resting Heart Rate to - Recurrent Stroke, Myocardial Infarction and CHF - Total CV and non CV-Mortality Disability after recurrent stroke as measured by mrs Disability of recurrent stroke as measured by Barthel Index Decline in cognitive function as measured by Mini Mental State Examination (MMSE) According to: Cummings, JAMA 269 (1993): ; Crum et al, JAMA 269 (1993):

13 Definitions and Methods Statistical Analysis: - 2,165 Pts, 695 centers, 35 countries - differences tested by Chi-square (categorical) or Kruskal Wallis test (continuous) - Cox propotional hazard model - multiple regression - p<.1

14 Baseline Characteristics Divided by Quintiles of Heart Rate Q1 ( 64) Q2 (65 to 7) Q3 (71 to 76) Q4 (77 to 82) Q5 (> 82) P Age in years (8.5) (8.48) 65.9 (8.55) (8.52) (8.63) <.1 Female sex (%) <.1 Hypertension (%) Diabetes mellitus (%) <.1 Hyperlipidemia (%) <.1 Use of Statin (%) <.1 Use of Diuretic (%) <.1 Use of Beta-blocker (%) <.1 Baseline SBP (17.15) (16.4) (16.25) (15.95) (16.7) <.1

15 Baseline Characteristics Divided by Quintiles of Heart Rate Q1 ( 64) Q2 (65 to 7) Q3 (71 to 76) Q4 (77 to 82) Q5 (> 82) P TOAST classification Large-artery atherosclerosis <.1 Modified Ranking scale score <.1 Baseline NIHSS score <.1 MMSE score at 1 month (3.77) (3.86) 27.5 (3.98) (4.35) (4.61) <.1

16 Cardiovascular Outcomes.175 (A) Death (B) CV Death (C) Non CV Death Log rank p<.1 Log rank p<.1 Log rank p= Probability of Death Numbers at Risk Q Q Q Q4 359 Q Days Days Days Q1 Q2 Q3 Q4 Q5

17 Cardiovascular Outcomes (A) Total Death (B) CV-Death (C) Non CV-Death Q1 ( 64) Q2 (65 to 7) 1.11 ( ) 1.2 ( ).99 ( ) Q3 (71 to 76) 1.32 ( ) 1.39 ( ) 1.19 ( ) Q4 (77 to 82) 1.42 ( ) 1.51 ( ) 1.25 ( ) Q5 (>82) 1.74 ( ) 1.78 ( ) 1.66 ( )

18 Cardiovascular Outcomes (A) Stroke (B) Myocardial Infarction (C) Major CV Outcome Log rank p=.1379 Log rank p=.784 Log rank p=.42.2 Probability of Death Numbers at Risk Q Q Q Q4 359 Q Days Days Days Q1 Q2 Q3 Q4 Q5

19 Cardiovascular Outcomes (A) Recurrent Stroke (B) Myocardial Infarction Q1 ( 64) Q2 (65 to 7).98 ( ) 1.2 ( ) Q3 (71 to 76) 1.5 ( ) 1.18 ( ) Q4 (77 to 82).96 ( ) 1.5 ( ) Q5 (>82) 1.11 ( ) 1.3 ( )

20 Neurological Outcomes Disability after recurrent stroke as measured by mrs Disability of recurrent stroke as measured by Barthel Index Decline in cognitive function as measured by Mini Mental State Examination (MMSE) According to: Cummings, JAMA 269 (1993): ; Crum et al, JAMA 269 (1993): Mahoney and Barthel, Maryland State Medical Journal 21 (1965): 61-65

21 Modified Rankin Scale Scores At Baseline p<.1 (ANOVA) 3 Months After Recurrent Stroke p=.2 (ANOVA) Q5 (>82) Q5 (>82) Q4 (77 to 82) Q4 (77 to 82) Q3 (71 to 76) Q3 (71 to 76) Q2 (65 to 7) Q2 (65 to 7) Q1 ( 64) Q1 ( 64) Percentage Percentage

22 Barthel Index (Self Care) After Recurrent Stroke 79 p=.2 (Kruskal Wallis) 78 Score Q1 ( 64) Q2 (65 to 7) Q3 (71 to 76) Q4 (77 to 82) Q5 (>82) Quintiles (Heart Rate)

23 Mini Mental State Exam (MMSE) 24 (Dementia) MMSE at month 1 MMSE from month 1 to penultimate visit p<.1 (Chi-Square) p<.1 (Chi-Square) Patients (%) Patients (%) Q1 ( 64) Q2 (65 to 7) Q3 (71 to 76) Q4 (77 to 82) Q5 (>82) 13 Q1 ( 64) Q2 (65 to 7) Q3 (71 to 76) Q4 (77 to 82) Q5 (>82)

24 > 2pt Decrease in Mini Mental State Exam (MMSE) (One Month vs. Penultimate) 21 p=.319 (Chi-Square) Patients (%) Q1 ( 64) Q2 (65 to 7) Q3 (71 to 76) Q4 (77 to 82) Q5 (>82)

25 Conclusion (1) Cardiovascular Outcomes No association of resting heart rate to recurrent stroke and myocardial infarction Resting heart rate is predictive of mortality after a first stroke total CV and non CV-mortality have different heart rate thresholds

26 Conclusion (2) Measures of neuroprotection are associated to low resting HR Disability after recurrent stroke as measured by mrs Disability of recurrent stroke as measured by Barthel Index Decline in cognitive function as measured by Mini Mental State Examination (MMSE) i.e. less patients > 26 or 2 Pts decline

27 Custodis et al, Stroke 42: , 211 Interpretation - Low heart rates might be associated to smaller strokes rather then to lower numbers of recurrent strokes to improve functional outcomes. - Heart rate could be a therapeutic target after a first stroke. naive vehicle stress vehicle stress iva

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29 Thank You! M. Böhm Innere Medizin III (Kardiologie / Angiologie / Internistische Intensivmedizin) Universitätsklinikum des Saarlandes Homburg/Saar