Impact of Resting Heart Rate on Mortality, Disability and Cognitive - - PowerPoint PPT Presentation

• M. Böhm

Daniel Cotton, Lydia Foster, Florian Custodis, Ulrich Laufs, Ralph Sacco, Philip Barth, Salim Yusuf Hans-Christoph Diener

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

Data from PROFESS

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

Disclosures

Rosengren et al, Lancet 364 (2004): 953-962

Background: Psychosocial Stress is CV Risk Indicator

Background: Stress Produces a Vascular Phenotype

Custodis et al, Stroke 42: 1742-1749, 2011

• 125
• 10

10 20 30 40 50 60 70 80 90 100 110 300 350 400 450 500 550 600 650 700 750 800 220

time [min] Heart rate [bpm]

60 80 100 120 140 160 180

• 125
• 10

10 20 30 40 50 60 70 80 90 100 110 220

time [min] MABP [mmHg]

Control Ivabradine Tail Suspension

Custodis et al, Stroke 42: 1742-1749, 2011

Background: Stress Reaction Involves Heart Rate

Cerebral infarct volume [mm³]

naive vehicle naive iva stress vehicle stress iva

5 10 15 20 25 30 35 40

* **

• * p<0.05 vs. naive vehicle
• ** p<0.05 vs. stress vehicle

Background: Stroke Size in Chronic Stress is HR Dependent

*

Custodis et al, Stroke 42: 1742-1749, 2011

20,332 pts Telmisartan placebo Telmisartan 2x2 Factorial design 20,332 stroke patients over age 50 ER-DP+ASA Clopidogrel* ER-DP+ASA + clopidogrel placebo + Telmisartan Clopidogrel + ER-DP+ASA placebo + Telmisartan ER-DP+ASA + clopidogrel placebo + Telmisartan placebo Clopidogrel + ER-DP+ASA placebo + Telmisartan placebo

Study Design

Diener et al., Cerebrovasc Dis 17: 253-261, 2004

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)

** Covariates in Cox model are age, baseline ACE-inhibitor use, Modified Rankin, and baseline diabetes status.

Telmisarta n Placebo HR 95% CI p-value 880 (8.7%) 934 (9.2%) 0.9 5 0.86, 1.04 0.231

Primary Outcome: Recurrent Stroke

ASA+ER-DP Clopidogre l HR 95% CI p-value 916 (9.0%) 898 (8.8%) 1.01 0.92, 1.11 0.783

Yusuf et al., NEJM 359: 1225-1237 , 2008 Sacco et al., NEJM 359: 1238-1251, 2008

8,4 7,9 24,3 25,4 17 18,4 18,1 15 14,8 5,2 4,9 15,3 13,6 11,7 0% 20% 40% 60% 80% 100% Telmisartan Placebo 1 2 3 4 5 6

mRS Among Subjects with Recurrent Strokes – ARB Comparison

Baseline 3 months post recurrent stroke

* From Cochran-Armitage test for linear trend.

p=0.612*

10,9 11,6 35,5 34,5 25,1 26,3 18,4 17,3 10,1 10,3 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Telmisartan Placebo 1 2 3 4

Diener et al., Lanct Neurol 7: 875-884, 2008

• 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

Objectives of Current Analysis (1)

• 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) Association of Resting Heart Rate to

• Recurrent Stroke, Myocardial Infarction and CHF
• Total CV and non CV-Mortality

Objectives of Current Analysis (2)

According to: Cummings, JAMA 269 (1993): 2420-2421 ; Crum et al, JAMA 269 (1993): 2386-2391 Mahoney and Barthel, Maryland State Medical Journal 21 (1965): 61-65

Definitions and Methods

Statistical Analysis:

• 20,165 Pts, 695 centers, 35 countries
• differences tested by Chi-square (categorical) or

Kruskal Wallis test (continuous)

• Cox propotional hazard model
• multiple regression
• p<0.01

Baseline Characteristics Divided by Quintiles of Heart Rate

Age in years Female sex (%) Hypertension (%) Diabetes mellitus (%) Hyperlipidemia (%) Use of Statin (%) Use of Diuretic (%) Use of Beta-blocker (%) Baseline SBP 67.36 (8.50) 30.82 75.68 21.80 50.49 51.23 23.10 35.76 145.42 (17.15)

Q1 (≤ 64)

66.19 (8.48) 34.62 72.53 25.85 45.86 46.37 20.97 21.45 143.45 (16.40)

Q2 (65 to ≤ 70)

65.90 (8.55) 38.05 73.87 29.04 46.08 45.14 20.35 17.19 143.73 (16.25)

Q3 (71 to ≤ 76)

65.46 (8.52) 37.25 73.07 30.92 44.40 44.74 18.50 14.79 143.64 (15.95)

Q4 (77 to ≤ 82)

65.46 (8.63) 40.05 74.48 35.43 45.21 47.76 20.85 10.81 143.93 (16.70)

Q5 (> 82)

<0.0001 <0.0001 0.0095 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001

P

Baseline Characteristics Divided by Quintiles of Heart Rate

TOAST classification Large-artery atherosclerosis Modified Ranking scale score 0 – 2 Baseline NIHSS score 0 – 1 MMSE score at 1 month 27.36 81.43 45.60 27.16 (3.77)

Q1 (≤ 64)

28.69 77.55 40.27 27.14 (3.86)

Q2 (65 to ≤ 70)

26.65 77.86 40.08 27.05 (3.98)

Q3 (71 to ≤ 76)

29.67 73.55 35.77 26.86 (4.35)

Q4 (77 to ≤ 82)

31.31 69.24 35.04 26.54 (4.61)

Q5 (> 82)

<0.0001 <0.0001 <0.0001 <0.0001

P

0.000

Probability of Death

1750 Days 1500 1250 1000 750 500 250

0.025 0.050 0.075 0.100 0.125 0.150 0.175

1750 Days 1500 1250 1000 750 500 250 1750 Days 1500 1250 1000 750 500 250

(A) Death (B) CV Death (C) Non CV Death

Q4 Q5 Q3 Q2 Q1

4835 3772 4236 3509 3813 750 464 554 376 379 1901 1415 1554 1119 1276 3565 2727 2952 2408 2621 4668 3639 4054 3346 3578 4745 3704 4142 3431 3686 4835 3772 4236 3509 3813 544 464 491 376 379 1856 1379 1356 1119 1128 3566 2616 2952 2408 2552 4667 3639 4054 3346 3578 4745 3704 4142 3431 3684 4835 3772 4236 3509 3813 750 459 554 356 312 1901 1415 1554 965 1276 3566 2727 2943 2400 2621 4668 3638 4053 3344 3576 4744 3699 4140 3427 3686 Q1 Q2 Q3 Q4 Q5

Log rank p<0.0001 Log rank p<0.0001 Log rank p=0.0016

Numbers at Risk

Cardiovascular Outcomes

(A) Total Death

1.0 2.0 1.8 1.4 0.8 1.6 1.2

(B) CV-Death

1.0 2.2 2.0 1.6 0.8 1.8 1.4

(C) Non CV-Death

1.2 1.0 2.2 2.0 1.6 0.8 1.8 1.4 1.2 0.6

1.74 (1.48-2.06) 1.42 (1.19-1.69) 1.32 (1.11-1.56) 1.11 (0.93-1.33) 1.00 1.78 (1.44-2.22) 1.51 (1.20-1.90) 1.39 (1.11-1.74) 1.20 (0.95-1.52) 1.00 1.66 (1.29-2.13) 1.25 (0.95-1.64) 1.19 (0.92-1.53) 0.99 (0.75-1.30) 1.00

Q5

(>82)

Q4

(77 to ≤82)

Q3

(71 to ≤76)

Q2

(65 to ≤70)

Q1

(≤64)

Cardiovascular Outcomes

0.000

1750 Days 1500 1250 1000 750 500 250

0.250

1750 Days 1500 1250 1000 750 500 250

0.025

1750 Days 1500 1250 1000 750 500 250

(A) Stroke (B) Myocardial Infarction (C) Major CV Outcome

Q4 Q5 Q3 Q2 Q1

4835 3772 4236 3509 3813 496 359 315 249 360 1740 1075 1378 987 1084 3300 2547 2735 2273 2441 4418 3450 3841 3182 3376 4584 3570 3998 3313 3539 4835 3772 4236 3509 3813 683 430 381 371 1887 1287 1494 836 907 3526 2690 2895 2197 2585 4619 3606 4008 3320 3553 4716 3684 4125 3417 3667 4835 3772 4236 3509 3813 485 417 425 341 294 1727 1256 1368 1033 1076 3282 2518 2698 2248 2423 4372 3428 3805 3158 3357 4555 3555 3985 3303 3527 Q1 Q2 Q3 Q4 Q5 Numbers at Risk

Log rank p=0.1379 Log rank p=0.7084 Log rank p=0.0042

0.075 0.050 0.100 0.125 0.175 0.150 0.200 0.225

Probability of Death

Cardiovascular Outcomes

(A) Recurrent Stroke

1.0 1.3 1.2 1.1 0.9 0.8

(B) Myocardial Infarction

1.0 1.6 1.4 1.2 0.8 0.6 1.8

Q5

(>82)

Q4

(77 to ≤82)

Q3

(71 to ≤76)

Q2

(65 to ≤70)

Q1

(≤64)

1.11 (0.96-1.29) 0.96 (0.82-1.12) 1.05 (0.91-1.22) 0.98 (0.84-1.14) 1.00 1.30 (0.93-1.81) 1.05 (0.74-1.49) 1.18 (0.86-1.60) 1.20 (0.76-1.45) 1.00

Cardiovascular 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)

Neurological Outcomes

According to: Cummings, JAMA 269 (1993): 2420-2421 ; Crum et al, JAMA 269 (1993): 2386-2391 Mahoney and Barthel, Maryland State Medical Journal 21 (1965): 61-65

At Baseline

10

Percentage

40 60 80 90 100 70 50 30 20

Q1

(≤64)

Q2

(65 to ≤70)

Q3

(71 to ≤76)

Q4

(77 to ≤82)

Q5

(>82)

3 Months After Recurrent Stroke

10

Percentage

40 60 80 90 100 70 50 30 20 1 2 3 4 5 6

Modified Rankin Scale Scores

p<0.001 (ANOVA) p=0.0002 (ANOVA)

Q1

(≤64)

Q2

(65 to ≤70)

Q3

(71 to ≤76)

Q4

(77 to ≤82)

Q5

(>82)

Barthel Index (Self Care) After Recurrent Stroke

74 75

Score

76 77 78 79

Q1

(≤64)

Q2

(65 to ≤70)

Q3

(71 to ≤76)

Q4

(77 to ≤82)

Q5

(>82)

p=0.0002 (Kruskal Wallis) Quintiles

(Heart Rate)

Mini Mental State Exam (MMSE) ≤ 24 (Dementia)

13

Patients (%)

Q1

(≤64)

Q2

(65 to ≤70)

Q3

(71 to ≤76)

Q4

(77 to ≤82)

Q5

(>82)

19 21 15 17 13

Q1

(≤64)

Q2

(65 to ≤70)

Q3

(71 to ≤76)

Q4

(77 to ≤82)

Q5

(>82)

19 21 15 17

Patients (%)

MMSE at month 1 MMSE from month 1 to penultimate visit

p<0.0001 (Chi-Square) p<0.0001 (Chi-Square)

> 2pt Decrease in Mini Mental State Exam (MMSE) (One Month vs. Penultimate)

17

Patients (%)

21

Q1

(≤64)

Q2

(65 to ≤70)

Q3

(71 to ≤76)

Q4

(77 to ≤82)

Q5

(>82)

20 19 18

p=0.0319 (Chi-Square)

• 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

Cardiovascular Outcomes Conclusion (1)

Conclusion (2)

• 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

Measures of neuroprotection are associated to low resting HR

naive vehicle stress vehicle stress iva Custodis et al, Stroke 42: 1742-1749, 2011

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.

• M. Böhm

Innere Medizin III (Kardiologie / Angiologie / Internistische Intensivmedizin) Universitätsklinikum des Saarlandes Homburg/Saar

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