The document discusses the challenges of managing uncontrolled hypertension, noting that control rates are particularly low in low-income countries. It highlights the efficacy of triple combination therapy as a necessary approach for most hypertensive patients to achieve target blood pressure, while emphasizing the importance of elements like drug adherence and the benefits of using single-pill combinations. Additionally, it presents cilnidipine as a promising treatment option, particularly for younger patients and those at risk for chronic kidney disease.

1. Triple Combination is the era in
Uncontrolled Hypertension Management:
Why is it so ?

2. WHO Report : September 2023

3. Major complications of
uncontrolled / difficult
to manage BP
3
Increase in BP increases risk for
kidney disease progression

4. BP Control Rates are Suboptimal
• Despite the clear benefits of reducing BP to target level,
rate of BP control are suboptimal in most countries
• BP control rates are particularly poor in low-income
Countries
• BP control rate are <30% in several Asia-Pacific Countries

5. Get The Pressure Down!!
Awareness, Diagnosis & Best
antihypertensive which
prevent complications will
save lives !
Of Deaths
from Stroke
51%
Of Deaths
from Coronary
Heart Disease
45%
Deaths due to
HT
7.5 million
Total global
deaths
13%
http://www.who.int/gho/ncd/risk_factors/blood_pressure_prevalence_text/en/

6. Diseases Attributable to Hypertension
Hypertension
Heart failure
Stroke
Coronary heart disease
Myocardial infarction
Left ventricular
hypertrophy
Aortic aneurysm
Retinopathy
Peripheral vascular disease
Hypertensive
encephalopathy
Chronic kidney failure
Cerebral hemorrhage
http://www.mayoclinic.org/diseases-conditions/high-blood-pressure/in-
depth/high-blood-pressure/art-20045868.
All
Vascular

7. CV
mortality
risk
SBP/DBP (mm Hg)
0
1
2
3
4
5
6
7
8
115/75 135/85 155/95 175/105
CV Mortality Risk Doubles With
Each 20/10 mm Hg BP Increment*
Assadi F. Prehypertension: Int J Prev Med. 2014 Mar;5(Suppl 1):S4-9.

8. Reasons for Not Achieving BP Control
 Poor adherence and persistence with therapy.
 Physicians’ reluctance to switch to an alternative treatment
and/or increase doses if BP remains uncontrolled.
 Selected antihypertensive drug does not target the
mechanism causing the patient’s hypertension.
http://www.mayoclinic.org/diseases-conditions/high-blood-
pressure/basics/treatment/con-20019580 accessed on 9-oct-2015

9. Need for Combination Therapy
Clinical Evidences

10. Combination Therapy: A Practical Necessity
 Required in ~ 75% of hypertensives to achieve target BP
 Greater efficacy
 Faster achievement of target BP
 Higher response rates
 May make therapy effective in broader population
 Additive antihypertensive effects through complimentary pharmacologic
mechanisms
 In some cases, improved side effect profile
•Gradman AH, Basile JN, Carter BL, et al. J Clin Hypertens (Greenwich).
2011;13:146–154.

11. Combination Therapy is More Effective Than
High Dose Monotherapy
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
Thiazide Beta-blocker ACEI CCB All classes
Combination Double dose
Incremental
SBP
reduction
ratio
of
observed
to
expected
additive
effects
Wald DS, et al. Am J Med 2009;122:290-300

12. Higher BP Control Rates Are Achieved With Single Pill
Combinations
26
55
0
10
20
30
40
50
60
Freecombination Singlepill
12
Change
in
proportion
of
patients
achieving
BP
goals
relative
to
monotherapy
(%)
Patients receiving a single pill combination are more likely to
achieve BP goals than those receiving free combinations or
monotherapy
Gu Q, et al. Circulation 2012;126:2105-14
*p<0.05 vs monotherapy
**p<0.01 vs. monotherapy
Regional guidelines on combination therapy| March 2013

13. Single Pill Combinations are
Recommended by Guidelines
 Single pill combinations (SPCs) or fixed-dose combinations have
numerous advantages over multiple drug combination therapy
 Current hypertension guidelines generally recommend SPCs over
multiple drug treatment with their individual components
1. Gupta AK, et al. Hypertension 2010;55:399-407
2. Bangalore S, et al. Am J Med 2007;120:713-9
3. Dusig R. VHRM 2010;6:321-5
4. Mancia G, et al. J Hypertens 2009;27:2121-58

14. Comparison of Monotherapy and Free and Single Pill
Combinations
Monotherapy Free
combination
Single pill
combination
Convenience ✔ ✗ ✔✔a
Adherence − − ✔
Efficacy ✗ ✔ ✔
Tolerability ✗ ✔ ✔b
Flexibility ✔✔ ✔✔ ✔c
a Switching and dose titration less likely to be required than for monotherapy
b Single pill may be better tolerated as doses tend to be lower than in free combinations
c Flexibility with single pill combinations is increasing as the range of doses increases
Xinhuan Wana et al., Asian Journal of Pharmaceutical Sciences Volume 9, Issue 1, February
2014, 1–7

15. TRIPLE COMBINATION THERAPY – ESH 2023 New guidelines

16. 16
Restores the podocin
and nephrin
expression, protects
the podocytes
Afferent and Efferent
arterioles (L&N
channel blocking), thus
reduced glomerular
pressure
Ameliorates urinary
albumin excretion and
decreases urinary 8-
OHdG and L-FABP
Cilnidipine has multiple approaches in reno-protection
J Hypertens. 2010 May; 28(5): 1034–1043.
Hypertens Res. 2012 Nov;35(11):1058-62. doi: 10.1038/hr.2012.96.

17. Change in pulse rate (PR) after Amlodipine and
Cilnidipine treatment compared to the
pretreatment value
Change in urinary protein/creatinine ratio during the 6-
month treatment period in the Amlodipine and
Cilnidipine group
Cilnidipine significantly reduces HR and UACR, Amlodipine increases
Zaman ZA et al. Int J Basic Clin Pharmacol. 2013 Apr;2(2):160-164

18. 18
Mega-Trial of Cilnidipine proves it reduces HR by 9.7 bpm, effective in morning hypertension
ACHIEVE-One study
These effects of cilnidipine are new features not known in conventional L‐type Ca channel
blockers
Cilnidipine reduces HR better when it is higher than 85bpm
• Generally, morning hypertension involves increased
sympathetic activity, and the renin‐angiotensin
system (RAS).
• Cilnidipine reduced MSBP and MPR even in patients
who had already been administrated β‐blockers or
RAS inhibitors (including ARBs and ACE inhibitors).
• These additive BP‐ and PR‐lowering effects of
cilnidipine may be a reflection of dual L‐and N‐type
Ca channel–blocking actions differing from
β‐adrenergic receptor blocking and RAS‐inhibiting
actions
“High-rate morning hypertension”
characterized by high MSBP and MPR.
Cilnidipine is the optimal CCB in
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034443/

19. 19

20. J Clin Pharmacol. 1998;38(6):477–491.
J Clin Pharmacol. 1995;35(11):1060–1066. Am J
Cardiol. 1995;76(8):595–597.

21. 21
ESC/ ESH HYPERTENSION
GUIDELINE RECOMMENDS
DUAL COMBINATION
THERAPY AS A INITIAL
THERAPY
First look at the new 2018 European Guidelines for the treatment ofhigh blood pressure. 2018 ESC and ESH joint guidelines for
themanagement of arterial hypertension. Available from URL:http://www.eshonline.org/esh-annual-meeting/

22. 22
TRIPLE DRUG COMBINATION
• About 24% to 32% of patients with HTN will require more than two
drugs to achieve their BP target.
• A rational combination in this setting would be an RAAS inhibitor, a
CCB, and a diuretic.

23. 23
Single-pill triple combinations of different classes of drugs with complementary
mechanisms of action help to treat patients to goal with improved efficacy and better
adherence to treatment
Triple drug fixed dose combination of Telmisartan, Amlodipine and hydrochlorothiazide
was found to be effective and safe option for the optimal management of hypertension.

24. 24
TRIPLE DRUG COMBINATION
• Triple fixed-dose drug combinations should be reserved only for patients with uncontrolled
BP with 2 agents, poor adherence in complex therapeutic regimens or on inappropriate free-
drug combinations.
• Triple therapy may help overcome clinical inertia by prescribing more potent antihypertensive
formulations in one pill.
• Beyond the choice between different triple fixed-dose combinations it is important to
evaluate at shortterm whether BP is controlled within target and whether the administered
fixed-dose treatment is associated with good compliance

25. 25
Curr Vasc Pharmacol.
2017;16(1):61-65.

26. 26
How to build up appropriate triple drug combinations.
Curr Vasc Pharmacol. 2017;16(1):61-65.

27. 27
CHANGING TRENDS IN PHARMACOTHERAPY FOR
HYPERTENSION IN INDIA
47
53
0
10
20
30
40
50
60
70
Mono Combo
Malhotra et al. Eur J Clin Pharm.
2001;57:535
49
51
0
10
20
30
40
50
60
70
Mono Combo
Sreedharan et al. Int J Clin Pharm Ther.
2011;49:277
27
73
0
10
20
30
40
50
60
70
Mono Combo
Gupta R, et al.
2018. Unpublished.

29. 29
Summary
• Within a population of 30% affected by hypertension, 72% of the patients remain
uncontrolled in India
• The reasons for uncontrolled hypertension are varied including ignorance, mis-diagnosis /
underdiagnosis, and undertreatment, patient adherence is also a key factor
• Guidelines recommend triple combinations for uncontrolled hypertension to improve
outcomes and patient adherence
• Cilnidipine a novel CCB , well established in India in hypertension management also offers
reno-protective benefits in uncontrolled hypertensives who are at high risk for CKD
• Also, sympatholytic activities of cilnidipine make it the choice of CCB in youngsters as well for
HTN control and reduction of HR
• Hypertension is a multi-dimensional disease, which has moved beyond just control of
numbers , the major focus is on end-organ protection in the long term
• Wise choice of molecules can help patients with the best outcomes in their hypertensive
journey and improve adherence as well

30. 30