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Herbesser: Prevention of stroke!

No. of events /1000patients-years

Stroke & myocardial infarction


in 6 countries (areas)
16

Stroke
Myocardial Infarc

16

15
12.9
10.3

10

8.1
5.2
4.4

7.9
5.5
4
2

2.5

SHEP MRC Syst-EurSTONE


Syst-NICS-EH

China
1) JAMA,1991
USAEngland
Europe

China
China
Japan 2) Br Med J, 1985

3)
4)
5)
6)

Lancet, 1997
J Hypertens, 199
J Hypertens, 199
Hypertens Res, 2

StrokePreventionwithCCB
(vs.Conventionaltherapy)
STOP21)
INSIGHT2)
NORDIL3)

RR(95%CI)
0.88(0.731.06)
0.94(0.741.28)
0.80(0.650.99)

Pvalue
0.16
NA
0.04

Herbesserisasoleantihypertensiveagentto
reduceStrokesignificantlyvs.conventional
therapies.
1) Lancet,1999
2) Lancet, 2000
3) Lancet, 2000

Ref. Stroke reduction


Reduction in Odds

1999 WHO/ISH Hypertension


0
Guideline
-10
-20
-30
-40

NORDIL
39% reduction

-50(-blocker or Diuretics vs placebo)

0
-10
-20
-30 20%
-40
-50

further reduction !
With Diltiazem

Stroke Primary Prevention:


Modifiable risk factors
New ischemic stroke guideline issued by AHA!
Relative Risk (vs.
without)

Hypertension
Atrial fibrillation
Diabetes
Hypercholesterolemia
Asymptomatic Carotid Stenosis
Cigarette smoking

1.0 ~ 4.0
2.6 ~ 4.5
1.8 ~ 6
1.8 ~ 2.6
2.0
1.8
Stroke. 2001;32:280-299

Stroke prevention:
Diltiazem in NORDIL study
Diltiazem reduced stroke 20% more than Diuretics and -blocker.

Lancet 2000; 356: 359-65

Risk Factor 1: Hypertension


Mean BP reduction in NORDIL :
Diltiazem:
Diuretic and -blocker:

20.3/18.7 mmHg
23.3/18.7 mmHg

Lancet 2000; 356: 359-65

Risk Factor 2: Atrial fibrillation


Diltiazem: Reduction in atrial fibrillation in hypertension!
NORDIL results:
Occurrence of Atrial fibrillation
18% reduction
patient- years

Event rate per 1000

Diuretics and - blocker

Di Diltiazem

Relative risk (95% CI) = 0.82 (0.64-1.07) P = 0.14

Diltiazem reduced new atrial fibrillation by 18% compared


with Diuretics and -blocker
Lancet 2000; 356: 359-65

Ref: Diltiazem for Atrial fibrillation


Diltiazem improved in symptom in patients with atrial fibrillation.
Subject:
Method:
Drug:

252 patients with atrial fibrillation (7-360 days)


Randomized trial
Diltiazem po (n=125) mean dose 226, 234, 234 at 3, 6, 12th month
Amiodarone (n=127) mean dose 255, 204, 211 at 3, 6, 12th month

Results:
Symptomatic improvement (palpitation, dyspnoea, and dizziness) was similar
in both groups at any point during the course of the trial.
Exercise tolerance was better in amiodarone group.
Hospital admissions was significantly few in Diltiazem group.
Diltiazem*1 vs. Amiodarone*2 = 30/125 (24%) vs. 87/127 (69%), p=0.001
*1: mainly due to drug related side effect (68%, kind of side effect not mentioned)
*2: mainly due to electrical cardioversion (67%) or drug related side effect (27%,
kind of side effect not mentioned)
Lancet 2000; 356: 1789-94

Ref: Atrial fibrillation


How to induce stroke?
If you have atrial fibrillation, the upper left chamber (Atrium) of
your heart beats rapidly and unpredictably, making it hard for all
the blood in the chamber to empty. The remaining blood tends to
form clots that can travel to any part of your body. If they travel
to the brain, these clots can cause a stroke.
Blood circulation:
.. L. Atrium L. Ventricle Aorta Peripheral artery
clots

Risk Factor 3: Diabetes

Event rate per 1000 patient-years

Diltiazem: Reduction in Diabetes mellitus in hypertension!


NORDIL results:
Occurrence of Diabetes mellitus
11
10.5

13% reduction

10
9.5
9
8.5

Diuretics and -blocker

Diltiazem

Relative risk (95% CI) = 0.87 (0.73-1.04) P = 0.14

Diltiazem reduced new diabetes mellitus by 13% compared with


Diuretics and -blocker
Lancet 2000; 356: 359-65

Ref: Diltiazem for Diabetes


Diltiazem reduced proteinuria in hypertension with type 2 diabetes.
Effec t on Urinary prot ein excret ion
mg/day
1000
Nifedipine

600
Di

Diltiazem
* P < 0.05

200
Baseline

21 Months

Subject: 21 type-2 DM with hypertension and proteinuria


Drug:
Diltiazem OD (mean dose 43643 mg) vs. Nifedipine OD (mean dose 7812 mg)
Results: Both group reduced blood pressure significantly at similar level.
Only diltiazem reduced proteinuria significantly without change in GFR and PRF
Kidney International. 1998; 54: 889-896

Ref: Diabetes
How to induce stroke?
Diabetes

Hyperinsulinemia or insulin resistance (Syndrome X)

Hyperglycemia, High LDL, Low HDL and Hypertension

Stroke

Risk Factor 4: Hypercholesterolemia


Diltiazem: Increase in HDL and reduction in LDL/HDL ratio

LDL/HDL
HDL
1.1

** P < 0.001

4.4

** P < 0.001

Diltiazem
mmol/L

4.2

Atenolol

1.0

4.0

Atenolol

**

3.8

0.9
Randomization

1 year

Randomization

Diltiazem

1 year

T. Thulin et al, Int. J. Clin. Pharmacol. Ther. 1999;37:28-33

Summary
Diltiazem can reduce various risk factors for stroke!
Hypertension
Atrial fibrillation
Diabetes
Hypercholesterolemia

BP reduction
Occurrence reduced in HT (NORDIL)
AF related symptom improved.
Occurrence reduced in HT (NORDIL)
Proteinuria reduced in HT with DM
HDL increased and LDL/HDL ratio
decreased.