SPC is important in management of hypertension

1. Azilsartan-CCB Combination :
A new frontier in Hypertension
Management
Dr. Praveen Nagula, MD,DM
Assistant Professor in Cardiology
Osmania General Hospital, Hyderabad
drpraveennagula@gmail.com
Twitter: @kizashipraveen

4. The Burden of Hypertension

5. Latest Hypertension Guidelines 2020 -ISH

12. AZILSARTAN

13. Differential pharmacology and benefit/risk of
Azilsartan compared to other Sartans
• FDA says , “it is the decrease in BP, rather than any other
property of (antihypertensive) drugs, that is largely responsible”
for their cardiovascular clinical benefits.
• Because the relationship between cardiovascular risk and BP is
monotonic with absolute risk decreasing progressively as BP
decreases towards recommended goals, the greater
antihypertensive effects of Azilsartan serve to justify clinical
interest in this recently approved ARB relative to other molecules
in the class with a lower capacity to reduce BP.
Ref-- Vascular Health and Risk Management 2012:8 133–143

14. Why Azilsartan is such a powerful BP medication ?
• Very tight binding to AT1 receptor provides prolonged efficacy
throughout the day
• Additional mechanism that appears to enhance Ang 1-7
vasodilatory action might add further efficacy
• Postulated effect of enhancing renal sodium excretion might also
contribute to BP effect

15. AZILSARTAN
“one who prevents bad things from happening to people”, “protector”, “guardian”

16. Response Rate with ARB Monotherapy
59
49
31
0
10
20
30
40
50
60
Azilsartan (80 mg) Olmesartan (40 mg) Telmisartan (80 mg)
ResponseRate(%)
A clinic SBP goal of < 140 mmHg and / or a > 20 mmHg reduction in SBP from
baseline
1. Hypertension. 2011;57(3):413–420 2. J Clin Hypertens. 2003;1:58–63

20. Trial/Observational Study Evidence

22. 22
Azilsartan - UACR Reduction
Azilsartan decreased blood pressure, UACR, and u-AGT more than the
other ARBs, and exerted depressor and reno-protective effects

23. Treatment of hypertension in CKD patients with
azilsartan/chlorthalidone vs
olmesartan/hydrochlorothiazide
The study of Bakris et al confirms that the AZL- M/CLD combination
pill is a safe and effective option in individuals with CKD 3 & hypertension
Conclusion-
The Study concluded that in one of the highest CV risk cohorts, ie, older persons with
CKD, use of AZL- M/CLD to achieve BP targets is safe and requires less dose titration
and fewer additional antihypertensive medications to achieve the BP target compared
to OLM/HCTZ.

24. No dose adjustment of AZL-M is required for
subjects with any degree of renal impairment,
including end-stage renal disease

25. Azilsartan+chlorthalidone Vs Azilsartan alone Vs
Chlorthalidone alone (Weber MA et al. JRAAS 2018; 16:1-13)
Clinic SBP (mm Hg) Clinic DBP (mm Hg)
AZL-M (40 mg) -23.3 -9.2
CLD (25 mg) -27.1 -9.2
AZL-M/CTD, 40/12.5mg -36.8 -15.6
AZL-M/CTD,40/25mg -39.5 -17
-23.3
-9.2
-27.1
-9.2
-36.8
-15.6
-39.5
-17
AXISTITLE
CLINIC BP (MMHG) REDUCTION
J Clin Hypertens (Greenwich). 2012; 14:284–292.
Vascular Health and Risk Management 2012:8 381–387. Table I

26. Primary Endpoint: Change in Clinic Systolic
BP
Week 12
-50
-40
-30
-20
-10
0
Baseline SBP: 164.6-165.0 mm Hg
*P<0.001 vs OLM/HCTZ
AZL-M/CLD
20/12.5 → 40/12.5
→ 40/25 mg
-42.5* -44.0*
-37.1
AZL-M/CLD
40/12.5 → 80/12.5
→ 80/25 mg
OLM/HCTZ
20/12.5 → 40/12.5
→ 40/25 mg
N=355 N=352 N=364
Cushman W et.al. Hypertension 2012;60:310

27. Azilsartan + chlorthalidone comb. Lowered systolic BP better
than olmesartan based comb.
The fall in clinical systolic BP
from the baseline was higher
in the chlorthalidone-based
regimen
W. C. Cushman et al. Hypertension, vol. 60, no. 2, pp. 310–318, 2012.

28. Place in therapy
• Azilsartan medoxomil, a new angiotensin receptor blocker, has superior ambulatory
and clinical BP-lowering effects compared with olmesartan and valsartan at their
highest clinically used doses and is well tolerated in patients with hypertension.
• BP control and response rates by this drug at its highest dose are greater than other
drugs in the same class by absolute rates of 8% to 10%.
• Azilsartan may be a useful treatment option to enhance blood pressure lowering for
patients in whom dual antihypertensive therapy with a generic ACEI or ARB, plus
either a calcium channel blocker (CCB) or diuretic has not reduced blood pressure to
the desired level, before trying triple antihypertensive therapy

29. * Hypertension.2018;72
Azilsartan provides additional 4 to 8 mmHg
further 24 hr SBP reduction over other ARBs
Olmesartan, Valsartan or ACE inhibitor -
Ramipril

30. CCBs in hypertension :
It’s time to look beyond the hypertension

36. Key Highlights –Cilnidipine

37. ESC TEXT BOOK OF
CARDIOVASCULAR
MEDICINE 2019
endorsed
CILNIDIPINE

39. Neutel & Smith. Cardiovascular Therapeutics. 2013 . 31 251-258.
CCB
INCREASED BP LOWERING ACTIVITY
ARB
SYNERGISTIC EFFECT
Decreased BP Decreased BP
Ca2+
Ca2+
Channel
receptor
Vaso-
dilation
Decreased
• Vasoconstriction
• Aldosterone secretion
• Catecholamine release
AT II
AT
receptor
*AT-Angiotensin
L & N type Ca2+
Channel
↓
Inhibit norepinephrine
release
↓
↓ Vasoconstriction
↓ Heart rate
↓ Renal blood flow
↓ Renin secretion
Cilnidipine
Azilsartan
39

40.  Slow onset
• For smooth reduction of blood pressure with less chances of hypotension
 Long Duration of Effect (24 hours)
• For better control of increased blood pressure especially during the
mornings
 Once daily administration for better compliance
 Suppresses Sympathetic Overactivity
• Less chances of Hypotension or Reflex Tachycardia
 Metabolically Neutral
• Minimal or negligible effect on glycemic or lipid metabolism for co-
administration in Diabetics and Dyslipidemic patients
 Pleiotrophic Effects
• Anti-inflammatory, antiproliferative or antioxidant properties

41. TRIAL EVIDENCE

42. 1st Indian data – Azilsartan +
Cilnidipine comb.
ABPM based trial

43. 1st Indian data – Azilsartan + Cilnidipine comb.
Objective - To evaluate the Efficacy, Safety and Tolerability of FDC of Azilsartan 40 mg +
Cilnidipine 5 mg /10 mg versus Azilsartan and Cilnidipine monotherapy in stage 2 hypertension.
Patient – 228 Stage 2 hypertensive patients with mean sitting SBP of ≥160 to ≤180 mmHg and
mean sitting DBP ≥100 to ≤110 mmHg between the age group of 18 to 65 years
Duration – 84 days
Dosage – Once a day
Result - FDC of Azilsartan 40 mg + Cilnidipine 10 mg produced statistically significant
reductions in seated SBP, DBP, 24 hour ABPM SBP and DBP when compared to Azilsartan
40 mg and Cilnidipine 10 mg monotherapy in stage 2 hypertension.

44. Significant reduction from baseline in SBP (164.1±15.3 to 139.2±15.3
mmHg, p<0.0001) & DBP (91.7±11.4 to 79.3±10.7 mmHg, p<0.0001).
Addition of cilnidipine to ARB monotherapy significantly reduces BP
Shinobu et al., Hypertens Res 2007; 30: 815-822.
After addition of cilnidipine
44

45. Patients achieved blood pressure goals at high rate after
addition of cilnidipine to ARB monotherapy
Blood Pressure Goals
% Patients Attaining
Blood Pressure Goals
≥65 years SBP:140/DBP:90 48.27%
<65 years SBP:130/DBP:85 19.78%
High-risk patients SBP:130/DBP:85 22.26%
Total patients attaining
blood pressure goals
31.39%
Shinobu et al., Hypertens Res 2007; 30: 815-822.
45

47. Azilsartan
 Eighth ARB to be approved for treatment of hypertension.
 24‐hour BP‐lowering activity.
 More effective than ARBs olmesartan & valsartan.
 In combination with calcium-channel blocker effective at lowering
SBP, with a reduced incidence of peripheral edema.
 In combination with thiazide-like diuretic chlorthalidone, more
effective in lowering SBP.
 Ideal in Salt sensitive Hypertension.
47

48. Cilnidipine
 4th generation calcium channel
blocker (CCB)
 Highly vaso-selective
 Blocks N-type channels to inhibit
release of norepinephrine at
sympathetic nerve endings
 Blocks L-type calcium channels to
stimulate vessel dilation
Takahara A. Cardiovascular Therapeutics. 2009. 27: 124-139.
48

49. Cilnidipine
 Causes less tachycardia
 Lower incidence of pedal
edema compared to amlodipine
 Has cardio,reno,neuro-
protective effect
 Improve insulin resistance
Takahara A. Cardiovascular Therapeutics. 2009. 27: 124-139.
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50. Thank You