Hypertension and stroke

1. BREAKING THE SILENCE
ON THE SILENT KILLERS
Understanding Stroke from the lens
of hypertension

2. Hypertension and Stroke: WHO
Hypertension causes 10%
death in India
• 51% death due to CVA
• 45% due to CAD
Stroke >25 years
• 34% men
• 32% women
Preventable by Rx
• 35-45% Stroke
• 25% CAD

4. Diastolic BP as Risk Factor of Stroke
Eastern Stroke and Coronary Heart
Disease Collaborative Research
Group
• Diastolic BP 110 mmHg had
13 times risk of stroke as compared
to <79 mmHg
60
50
40
30
20
10
0
Stroke Prevention
MacMohan
Stroke
Prevention

6. Age and Stroke with Hypertension
 Elevated BP and risk of stroke is weaker
in older age compared to middle age
 The Asia Pacific Cohort Studies
Collaboration (APCSC)
Treating BP is still important due to
increased incidence of stroke with aging
60
50
40
30
20
10
0
Stroke after 10mmHg
Decrease of Systolic BP
Stroke
Prevention

7. During 2-year to 7-year follow-ups of the participants, researchers found those who had
nighttime systolic blood pressure that was 20 millimeters of mercury (mm Hg) above their
daytime systolic reading were significantly more likely to experience atherosclerotic
cardiovascular disease and heart failure.

8. Cerebral Ischemic Stroke
10
Time in hours
CBF
(ml/100g
brain)
Low flow, raised O2 extraction, normal
function
1 2 3 4 5
Synaptic transmission
failure
Membrane pump failure
20
50
CBF
(ml/100g
brain)
Time in hours

9. Morning BP Surge and Stroke Risk in Elderly hypertension
(Matching for age and 24-hour SBP)
JMS ABPM Study Wave 1

10. Relationship between morning home systolic BP and stroke/coronary
event (Spline regression analysis)

11. Pathophysiology of altered
diurnal BP variation and
nocturnal hypertension
The Multi-factorial
pathophysiology of
nocturnal BP increase

12. Circadian BP pattern is determined by the percentage of BP drop during
the night in comparison with diurnal BP. Four BP patterns could be defined:
extreme dipping (>20% BP drop), dipping (10% <BP drop ≤20%), nondipping
(0% <BP drop ≤10%), and inverse dipping or rising (BP drop ≤0%).
Pathophysiology of altered
diurnal BP variation and
nocturnal hypertension

13. 1. Large vessel Atherosclerosis
2. Medium vessel Arteriosclerosis
3. Small Vessel Lipohyalanosis
4. Cardioembolic stroke
Pathogenesis of Stroke due to Hypertension

14. Blood Pressure in Acute Ischemic Stroke
 Systolic blood pressure on arrival at Emergency
• >139 mm Hg in 77%
• >184 mm Hg in 15%
 The blood pressure is often higher in acute stroke patients with
a history of hypertension
 Blood pressure decreases spontaneously within 90 minutes
after onset

15. Evaluation of Nocturnal BP
Evaluation of nocturnal BP can be achieved only by ABPM
Method of determining the times of waking and sleeping is to assess this information
using a sleep diary that includes information about whether the patient had taken
daytime naps, which otherwise might contribute to a misclassification of the nocturnal
BP dipping status.
Nocturnal BP is considered within the normal range if the average of nighttime values is
lower than 120/70 mm Hg, whereas values higher than 125/75 mm Hg are deemed
abnormal
Each 10-mm Hg increase in nocturnal systolic BP were 1.16 or 1.14 for total mortality
and 1.19 or 1.15 for cardiovascular morbidity in hypertensive patients or the general
population, respectively
Evaluation of Nocturnal BP

16. Effect of a Novel CCB – Cilnidipine on Abnormal Nocturnal Blood pressure in Hypertensive
patients

18. A 12‐week treatment with cilnidipine significantly reduced 24‐hour BP in all groups.
Changes in nocturnal systolic BP (SBP) from baseline were −17.9 mm Hg from 154.6 mm Hg in
risers and −11.9 mm Hg from 142.1 mm Hg, −6.6 mm Hg from 128.5 mm Hg, and 0.1 mm Hg
from 115.8 mm Hg in nondippers, dippers, and extreme dippers, respectively.
Changes from baseline in nocturnal SBP reduction rate were 8.2% in risers but −7.0% in
extreme dippers (P<.001), while no change was observed in the nighttime SBP reduction rate
for the total patients
Cilnidipine partially, but significantly, restored abnormal nocturnal dipping status
toward a normal dipping pattern in hypertensive patients.
J Clin Hypertens (Greenwich). 2013 Jul; 15(7): 465–472.

19. Cilnidipine – Role in post-stroke patients
CA-ATTEND, 2017
(N = 2667)
CA-ATTEND (Subset)
(N = 603)
Journal of Stroke, 2015
(N = 309)
Among the calcium channel blockers, cilnidipine may
be more favorable than other calcium channel
blockers for blood pressure management in patients
with cerebrovascular disease
Cilnidipine was effective in treating uncontrolled
blood pressure and was well tolerated in Japanese
post-stroke hypertensive patients in a real-world
clinical setting
Cilnidipine promoted the regression of common
carotid IMT in post-stroke hypertensive patients,
especially in the thick group. Cilnidipine also reduced
the IAD in both normal and thick groups.

20. The growing
significance of
ABPM in
detection and
diagnosis of
HTN
The use of 24-h ABPM was introduced in the late 1970s. In the
beginning, the devices were large, heavy, and cumbersome, but today
the devices are lightweight and nearly all of them use an oscillometric
measurement method to compute BP levels.
Additionally, 24-h ABPM provides information on BP variability, circadian
changes, and the effects of environmental and emotional conditions on
BP levels.
Advantages of ABPM over office measurements:
• Prediction of Cardiovascular events
• Comparison of ambulatory BP measurements with home
measurements.
• Identification of white coat HTN.
• Identification of masked hypertension
• Nocturnal BP
• ABPM guiding management of HTN
• Additional information derived from ABPM. – helps to identify
secondary hypertension, sleep apnea, resistant hypertension
Diabetes Care. 2013 Aug; 36(Suppl 2): S307–S311.

21. European heart journal. 2018 Sep 1;39(33):3021-104.
HTN Management

22. Focus on Calcium
Channel Blockers
(CCBs)

23. Calcium Channels Blocked & Clinical Significance

24. 26-12-2023
L, N, T- Calcium Channels

25. Comparison – DHP CCBs
Journal of Geriatric Cardiology (2017) 14: 67 72

26. 26-12-2023
The Evolution of Calcium Channel Blockers
N-channel
blockade

27. Cilnidipine
The Choice of
CCB
Clinical Studies
12/26/2023 27

28. Morning blood pressure (BP) level plays an important role in the incidence of cardiovascular
disease. Kario, et al proposed the usefulness of ME difference (morning minus evening systolic
BP) and ME average (average of morning and evening systolic BP) for the evaluation of
antihypertensive treatment.
Cilnidipine is a novel calcium channel blocker (CCB) that exerts inhibitory actions not only on L-
type but also on N-type calcium channels.

29. This study investigated the
effect of bedtime
administration of cilnidipine
(10 mg) in addition to the
antihypertensive treatment for
uncontrolled morning
hypertension.
Twenty-three hypertensive
outpatients (13 males and 10
females; mean age, 66.9 years)
with stable antihypertensive
medication and uncontrolled
morning BP were studied using
self-measured BP monitoring
in the morning and evening.
• Morning SBP and DBP decreased significantly
from 150.2 ± 8.7 and 87.8 ± 9.3 to 132.7 ± 7.4
and 77.5 ± 8.5 mmHg, respectively, after the
addition of cilnidipine.
• Morning heart rate did not change (63.3 ± 7.0
to 64.1 ± 9.4).
• The evening SBP, but not DBP, decreased
significantly after treatment.
• Both the ME average and ME difference
significantly decreased from 143.0 ± 9.2 and
14.3 ± 12.4 to 131.3 ± 7.2 and 2.8 ± 9.2 mmHg
after treatment, respectively.
• The microalbuminuria decreased from 39.6
± 13.2 to 27.3 ± 8.4 mg/g Cr.
• Cilnidipine may be useful for patients with
uncontrollable morning hypertension by
reducing both ME average and ME

30. J-Stroke, 2015
N= 309
24-hour blood pressure
variability was measured, in
309 patients with a history
of cerebrovascular disease
treated with angiotensin-
converting enzyme inhibitor,
angiotensin receptor blocker,
β blocker, or calcium channel
blocker.

31. Conclusions:
From the results, it is suggested that angiotensin receptor blocker and calcium
channel blockers rather than β blockers may be more favorable for blood pressure
management in patients with cerebrovascular disease. Among the calcium
channel blockers, cilnidipine may be more favorable than other calcium channel
blockers.
J-Stroke, 2015

32. CA-ATTEND, 2017
N = 2667
Cilnidipine treatment caused a decrease in both clinic and home blood pressures
2 months after the beginning of treatment, and the decreased blood pressure
was maintained until the end of 12 months' observation.
The proportion of patients in whom clinic blood pressure was well controlled
(<140/90 mmHg) increased from 21.5% to 65.3% in cilnidipine treatment, with no
differences in effectiveness among the various clinical subtypes of stroke

33. CA-ATTEND Study: Post-
stroke HTN
• Existing Baseline and 12 month
• CCB: 6.3% -> 11.3%
• ARB: 41.1% -> 89.7%
• ACE inhibitor: 2.9% -> 5.4%
• α-blocker: 1.9% -> 4.1%
• β-blocker: 3.3% -> 7.4%
• Diuretics: 8.1%-> 18.9%
Time-course of changes in blood pressure and pulse rate
Clinical and Experimental Hypertension. 2017;39:3, 225-234,

34. CA-ATTEND Study: Post-stroke HTN
Clinical and Experimental Hypertension. 2017; 39:3, 225-234,

35. Although several
antihypertensive agents reduced
the carotid intima-media
thickness (IMT), it remains
unclear whether those agents
affect the inter-adventitial
diameter (IAD). Researchers
aimed to examine whether
cilnidipine, an L/N-type calcium
channel blocker, reduced the
common carotid IMT or IAD in
CA-ATTEND (subset), 2018
N = 603
The mean max-IMT from baseline to 12 months did
not change in the normal, whereas a significant
reduction was observed in the thick group (－0.09
mm, 95% CI －0.13 to －0.05, n=156).
The mean IAD was significantly reduced during the
study period in the normal group (－0.14 mm, 95%
CI －0.22 to －0.05) as well as in the thick group (－
0.12 mm, 95% CI －0.21 to －0.03).

36. Cilnidipine promoted the regression of common carotid IMT in
post-stroke hypertensive patients, especially in the thick
group. Cilnidipine also reduced the IAD in both normal and
thick groups.
Changes in IAD and LD at the quartile of max-IMT in the
carotid arteries.
The increasing trend of LD or IAD in the quartile of max-
IMT was analyzed using the Jonckheere–Terpstra test. The
difference in IAD was calculated using Dunnett's test.

37. The association between the changes in max-IMT and
baseline max-IMT.
Pearson's correlation coefficient (r) and the
associated p value are shown for all subjects (n = 326).
Abbreviation: IMT, intima-media thickness.
Supplementary Fig.. The association between the
changes in IAD and baseline IAD.
Pearson's correlation coefficient (r) and the
associated p value are shown for all subjects (n = 326).
Abbreviation: IAD, interadventitial diameter.

39. Amlodipine 5-7.5 mg/day, or
cilnidipine 5-10 mg/day was
administered to 78 hypertensive
subjects (greater than 140
mmHg systolic, or 90 mmHg
diastolic) undergoing outpatient
treatment.
Amlodipine or cilnidipine was
also administered similarly, to 30
subjects having hypertension
associated with a cerebral infarct
which occurred more than one
month earlier due to cerebral
thrombosis or embolism.
After 3 months administration,
the subjects’ blood pressures
and pulse rates were recorded
with an ambulatory blood
pressure monitor over 24 hours

40. No difference was recognized in patient
age, gender, and systolic and diastolic
blood pressure before treatment
between the groups.
In the cilnidipine groups, no difference in
average 24-hour or waking systolic blood
pressure values was seen between
cerebrovascular disease (CVD) subjects
and non-CVD subjects, although in the
amlodipine groups, CVD subjects had
significantly higher blood pressure
values than non- CVD subjects.
In the cilnidipine group, the coefficient
of variation values of pulse rate were
significantly higher in CVD subjects than
in non-CVD subjects (p<0.05) .

41. Comparison of H/M ratio
MIBG uptake and washout
rate before and 3 months
after drug treatment in
hypertensive patients
treated with amlodipine

42. Conclusion
In patients with recent stroke, a Ca antagonist with no sympathetic nerve
suppression had weaker blood pressure-lowering effects. Significantly increased
pulse rate variability, shown in the CVD subjects administered cilnidipine,
suggests that cilnidipine enhanced the parasympathetic function in hypertensive
patients with CVD.

43. Cilnidipine – Reduces Arterial Stiffness & Central Aortic
pressures
Year: 2015 INDIAN STUDY (Andhra Pradesh)
An Open Label Parallel Group Study to Assess the Effects of Amlodipine and
Cilnidipine on Pulse Wave Velocity and Augmentation Pressures in Mild to
Moderate Essential Hypertensive Patients
No. of Patients: 60 patients Duration: 8 weeks
AIM: Study was designed to compare the effects of 8 weeks blood pressure control using
Amlodipine and Cilnidipine on hemodynamic parameters and vascular indices in mild to
moderate hypertensive patients.
J Clin Diagn Res. 2015 Nov; 9(11): FC13–FC16

44. Cilnidipine – Reduces Arterial Stiffness & Central Aortic
pressures
The mean change in the central artery stiffness from baseline to week-8 in the
Amlodipine group as compared to Cilnidipine group
cf Pulse Wave Velocity -139.3±27.7 vs. -234.1±74.8 cm/s
Aortic Arterial Pressure -3.8±1.5 vs. -5.6±3.3 mm of Hg
Augmentation Index -6.8±2.4 vs. -10.8±4.4 %
J Clin Diagn Res. 2015 Nov; 9(11): FC13–FC16

45. The mean change in the AoAP was -3.8±1.5 (Amlodipine) vs. -
5.6±3.3 mm of Hg (Cilnidipine)
Cilnidipine – Reduces Arterial Stiffness & Central Aortic
pressures and
J Clin Diagn Res. 2015 Nov; 9(11): FC13–
FC16

46. “To better prevent the occurrence of fatal stroke, antihypertensive
treatment should preferentially target drugs able to intrinsically reduce
aortic stiffness, i.e., drugs that have demonstrated their efficacy in
reducing PWV independently of the reduction in MBP”
Stroke, Volume 34, Issue 5, 1 May 2003; Pages 1203-1206
https://doi.org/10.1161/01.STR.0000065428.03209.64
Study suggests that…..

47. Morimoto et al. Journal of hypertension. 2007;25(10):2178-83.
N= 50
 Patients with untreated hypertension
 SBP/DBP of ≥140/90 mmHg
 Cilnidipine 10 mg
 Once daily in morning
 Amlodipine 5 mg
 Once daily in morning
1:1
Treatment duration: 24 weeks
Parameter of arterial stiffness
 Brachial-ankle pulse wave velocity (baPWV)
Cilnidipine Effectively Improves Arterial Stiffness
more than Amlodipine
baPWV Change in baPWV
Decrease of brachial-ankle pulse
wave velocity was significantly
larger in cilnidipine group than in
amlodipine group.

48. Effects of anti-hypertensive drugs on Blood pressure variability

49. Summary
Hypertension is a gateway to many chronic diseases including CVDs and stroke
Nocturnal Hypertension plays an important role in morning stroke attacks
Effective antihypertensive therapy is the cornerstone for prevention and management of
hypertensive strokes
Cilnidipine among the other CCBs is a molecule that has recently shown beneficial effects in
post-stroke patients in large patient Japanese studies
Cilnidipine reduces the c-IMT and IAD, decreases the arterial stiffness and the central aortic
pressures and is overall well tolerated in uncontrolled hypertensive patients
With studies in the Journal of Stroke, Cilnidipine as a molecule is being more explored for its
beneficial role in post-stroke patients