Herbesser: Prevention of stroke!

Stroke & myocardial infarction in 6 countries (areas)

No. of events /1000patients-years
16 15 12.9 10 5.2 4.4 10.3 8.1 7.9 5.5 4 2 0 2.5

Stroke 16 Myocardial Infarction

SHEP MRC Syst-EurSTONE Syst- NICS-EH China 1) JAMA,1991 2) Br USA England Europe China Med J, 1985 China Japan

3) 4) 5) 6)

Lancet, 1997 J Hypertens, 1996 J Hypertens, 1998 Hypertens Res, 2000

Stroke Prevention with CCB (vs. Conventional therapy)

STOP-2 1) INSIGHT 2) NORDIL 3) RR (95% CI) 0.88 (0.73-1.06) 0.94 (0.74-1.28) 0.80 (0.65-0.99) P value 0.16 NA 0.04

Herbesser is a sole antihypertensive agent to reduce Stroke significantly vs. 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
0 -10 -20

(-blocker or Diuretics vs placebo) -50

20% -30
-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
6 Event rate per 1000 patient- years

18% reduction
5

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

Diltiazem: Reduction in Diabetes mellitus in hypertension! NORDIL Occurrence of Diabetes mellitus results:
Event rate per 1000 patient-years 11 10.5 10 9.5 9 8.5

13% reduction

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.
m g/ day 1000 Nifedipine Effect on Urinary protein excretion

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 Diltiazem ** P < 0.001

4.4 4.2

** P < 0.001 Atenolol **

Randomization 1 year

mmol/L

1.0 Atenolol 0.9 Randomization 1 year

4.0 3.8

Diltiazem

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.