TREATMENT OF

ESSENTIAL HYPERTENSION WITH CCB:

WHAT IS THE PLACE OF LERCANIDIPINE?

ANTONIA ANNA LUKITO

DEPT KARDIOVASKULAR FKUPH/
RS SILOAM LIPPO VILLAGE
 CURRICULUM VITAE
Dr. dr. Antonia Anna Lukito, SpJP(K), FIHA, FAPSIC, FSCAI, FAsCC
EDUCATION:
•Medical Faculty, Airlangga University, 1988 (Hons)
•Cardiology Department, Indonesia University, 1997
•Doctoral Program, Hasanuddin University, 2012
•Advance Cardiology Course, Victoria Heart Center, Melbourne, Australia, 1996 & 2000
•Pacemaker & Interventional Cardiology, National Cardiac Center, 2004
•Cardiovascular CT Training, Cologne, Germany, 2005
•Advance Intervention Asia Crossroad Training program, Tokyo, 2009
•Carotid Intervention Training, NTUH, Taipei, 2012
•OCT training, Satakunta, Finland, 2012
•Rotablator & IVUS Tarining, Miyazaki, Japan,2013
ORGANIZATION:
•Committee of PERKI Pusat, PERKI Banten, InaSH, ISIC, IWoC, InaHRS
FELLOW:
•Fellow of Asia-Pacific Society of Interventional Cardiology (APSIC)
•Fellow of Asean College of Cardiology (AsCC)
•Fellow of Society for Cardivascular Angiography & Interventions (SCAI)
•Fellow of Indonesian Heart Association (IHA)
PROFESSIONAL EXPERIENCES:
•Heart Center, Siloam Hospitals, Lippo Village
•Head of Cardiovascular Dept of UPH medical Faculty
 NY S, 49 TAHUN

• Hipertensi diketahui sejak 7 tahun lalu

• Mengeluh kaki bengkak
• Rx. Amlodipine 1x5mg, Atenolol 1x50 mg
• Saat ini TD. 160/100 mmHg, Nadi. 55 x/menit
 HASIL PEMERIKSAAN

• EKG: LVH
• Foto Toraks : CTR 53%
• Lab: Ureum 29, Creatinin 0.79, eGFR 89, SGOT/SGPT . 20/23,
GD sewaktu 110 mg%, LDL-C. 132 mg%, ACR. 132.6 mg/g, Urin
lengkap: albumin (-)
 Burden of Hypertension
 77.9 million (1 in 3) US adults 20 years of
age and older have hypertension.
 69% of people who have a first heart
attack, 77% of those who have a first
stroke, and 74% of those who have heart
failure have a BP >140/90 mmHg.
 Hypertension is associated with shorter
overall life expectancy.

 Poor medication adherence is a major

barrier to effective BP control. only
about 57% remain adherent to their BP
medication at 2 years follow-up.
1. Mozaffarian D et al. Circulation 2015; 131: e29-322.
2. Roger VL, et al. Circulation. 2012;125:e2–e220.
3. Rapsomaniki, E et al. Lancet. 2014;383:1899-1911.
 Direct and indirect costs of CVD and stroke
United States, average annual 2012 to 2013

Direct and Indirect Costs

10%
11%
Heart disease

16% Hypertension
63%
Stroke
Other CVD

A Report From AHA: Heart Disease and Stroke Statistics—2017 Update

 Awareness of Hypertension Status

Normotensive and Hypertensive Unaware Aware No treatment Treated, BP Treated, BP

prehypertensive uncontrolled controlled

Olsen M.H., at al. Lancet. 2016;388;2665-2712.

Treating Hypertension: The Importance of Achieving
Target Blood Pressure
10 mmHg reduction in SBP is associated with
Coronary
All-cause heart disease Heart Renal
mortality Stroke failure failure
Relative Risk Reduction (%) 0

-5
-10

-13

-17
-20

-27 -28
-30

SBP= Systolic Blood Pressure

Ettehad D, at al. Lancet. 2016;387;957-367.

 Optimal Therapy Regimen in Hypertension

Lowering Blood Pressure

1

Reducing Cardiovascular Risk

2

Adherence on treatment
3

Kjeldsen S.E., et al. Drugs R D. 2014;14:31–43.

Peacock E., et al. Med Clin N Am. 2017;101:229–245.
 Blood Pressure Target and Stroke Prevention
in The ONTARGET Study
3
Visit with BP <130/80 mmHg
2.4
2.2 <25%
2 25-49%
50-74%
Stroke
≥75%
Incidence 1.2
(%) 1.1
1

0
N= 9141 4288 2282 1032
SBP 145 133 125 116
DBP 82 76 72 68

Mancia G et al. Circulation 2011; 124: 1727-1736.

 Initial Medications For
The Management of Hypertension (JNC 8)
Lifestyle Modification—
Especially Diet and Exercise

Thiazide-type
diuretic

-blockers should be included in the regimen if there is a

compelling indication for a -blocker

ACE-I
or CCB
ARB

James P. A. et al: JAMA. 2014;311(5):507–20.

 Absolute Risk Reduction of Various Outcomes Based on
Various Antihypertensive Drugs
Diuretics ACE Inhibitors ARBs CCBs
0

-2
-5
-5
-7 -7 -7
-10 -9 -9 -9
Absolute -12
Risk Reduction -15
-15
(%)
-17
-20

-25
-26
-30
Stroke CHD Heart Failure

Adapted from Thomopoulos C, et al. J Hypertens 2015;33:195-211.

 Common Reasons for Non-adherence

Side
effect
Not
understand Costly
instruction medication

Forgot to Drugs Taking to

Refill Rx Adherence many meds

Rx not Transportation
covered issues
Lack of
communi-
cation

Rx Outcomes Adviser - WordPress.com

 Prognostic of Poor Adherence to
Antihypertensive Therapy
p<0.001

1.00 0.87
1.0 (0.73-1.03)

0.8
0.50
0.6 (0.35-0.69)

0.4

0.2

0.0
Low (<40%) Medium (40-70%) High (≥80%)
Adherence within 6 months after diagnosis
Estimated by Cox proportional models

Mazzaglia et al. Circulation 2009;120:1598-605.

 Evolution of Dihydropyridine CCBs
Short-acting DHP
1st generation
eg, nifedipine

Modified formulation
2nd generation
eg, nifedipine GITS

Long plasma half-life

3rd generation
eg, amlodipine

Long receptor half-life

eg, lercanidipine

Borghi C. Vascular Health and Risk Management 2005:1(3) 173–182.

 Pharmacological Characteristics of
Lercanidipine
Highly selectivity on
1 Ca2+
Extra-Cellular Space
1 vascular

Highly lipophilic, better

2 penetration in cell
2 5 membranes

3 Gradually diffuses into

the calcium channels
3
4 Binding on calcium
channel receptors
4
5 Continuous and
ascending inhibition of
the calcium channel
Calcium Channel (VOC) Intra-Cellular Space

Burnier M, et al. Expert Opin Drug Metab Toxicol, 2009;5(8):981-987.

 24-hour Antihypertensive Efficacy:
Trough-to-Peak Ratio
Telmisartan

Irbesartan

Valsartan

Lisinopril

Captopril

Felodipine

Nifedipine GITS

Amlodipine

Lercanidipine

0 20 40 60 80 100
T/P Ratio (%)

1. Hernandez RH et al. Blood Press Monit. 2001;6(1):47-57. 4. Zannad F et al. Am J Hypertens. 1996;9(7):633-643.
2. McClellan KJ et al. Drugs. 2000;60(5):1123-1140. 5. Gradman AH, et al. Circulation. 2005;111:1012-1018.
3. Diamant M et al. J Hum Hypertens. 1999;13(6):405-412. 6. Hermida RC et al. Hypertens. 2003;42(3):283-290.
 Lercanidipine: Controlling BP over 24 hours
160
SYSTOLIC
BP (mmHg) 140

120

100
DIASTOLIC

80

60 Clock time (h)

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 1 2 3 4 5 6 7 8

Placebo Lercanidipine 20 mg OD Amlodipine 10 mg OD

BP= Blood Pressure

De Giorgio, et al. Curr Ther Res 1999; 60:511-520.

 ELYPSE Study:
Lercanidipine in Daily Clinical Practice
9,059 patients with a 3-month follow-up
80
68
Symptoms/adverse events (%)
70
60 Baseline
49
50 Lercanidipine 10 mg/day
40
30
21 19
20
12 11
10 6.6
3.0 0.6 0.3 1.2 1.2
0
Overall Headache Palpitations Asthenia Ankle edema Flushing

The ELYPSE study. Blood Pressure 2002; 11: 95–100.

 Incidence of Edema with Dihydropyridine CCBs

35 32.8 Amlodipine
30 28.9 Felodipine
Isradipine
25
22.0 Lacidipine
20 Nifedipine
17.6
15.1
16.2 Nitrendipine
15 13.8 14.2
Lercanidipine

10 9.3 8.6 8.2

5.7
5 3.9
2.2

0
Drop outs due to AEs Edema

Adapted from Papavassiliou MV, et al. Am J Hypertens. 2001;14:114A.

 Lercanidipine in Stable Effort Angina Patients
23 patients in a randomized, double-blind, parallel trial. Exercise was performed before (run-in placebo
period) & after 2-week treatment with lercanidipine 10 or 20 mg once daily.

Lercanidipine Lercanidipine Patients with angina during ETT

10 mg/day 20 mg/day Day 0 Day 14
0 100
ST segment depression (mm)

-0.15
-0.3 75

% of Patients
-0.3

-0.6
50
-0.9
25
-1.1 9
-1.2 1
-1.25 0
Lercanidipine Lercanidipine
-1.5
Day 0 Day 14 10 mg/day 20 mg/day

ETT= Exercise Treadmill Test

D. Acanfora D, et al. Am J Ther 2002;9:444-453.

 Lercanidipine in Type II Diabetic Patients
with Hypertension
8-week double-blind study, receiving lercanidipine 10 mg, up-titrated to 20 mg if
sufficient BP control was not achieved after 4 weeks.
Fasting blood glucose HbA1C
170 6.2
Baseline W4 W8 Baseline W4 W8

160
5.9 * *
*
150 * *
mg/dl

* 5.6

%
* *
140
5.3
130

5
120 Lercanidipine Lercanidipine
Lercanidipine Lercanidipine
10 mg/day 20 mg/day
10 mg/day 20 mg/day
N = 38 patients
*p < 0.001 vs. baseline.

Adapted from Viviani G.L. J Cardiovasc Pharmacol 2002; 40: 133-139.

 The DIAL Study:
Renal Protection with Lercanidipine
N=180, mild-to-moderate hypertension, type 2 diabetes, persistent microalbuminuria.
Mean blood pressure reduction Albumin excretion rate reduction
Lercanidipine Ramipril Lercanidipine Ramipril
0 0

-3
-5
-6

mg/day
mmHg

-9 -10

-12
-11.9 -15
-12.7
-15
-14.8
-17.4
-16.2
-18 -20
-19.7
SBP DBP
follow-up range was 9–12 months

Adapted from Dalla Vestra et al. Diabetes Nutr Metab 2004;17:259–66.

Antiproteinuria Effect of Lercanidipine in Patients Previously
Treated with ACE-I or ARB
1 month 3 month 6 month
0
-5
-10 -7.4
-10.4 -10.8
-15
-20
% -25
-30 -29
-35 -33
-40 Changes in mean SBP -37
-45 Changes on proteinuria N=68
-50

ACE-I = Angiotensin Converting Enzyme inhibitor, ARB = Angiotensin II Receptor Blocker

Robles NR, et al. Renal Failure 2010;32:192–197.

 NY S, 49 TAHUN

• Hipertensi diketahui sejak 7 tahun lalu

• Mengeluh kaki bengkak
• Rx. Amlodipine 1x5mg, Atenolol 1x50 mg
• Saat ini TD. 160/100 mmHg, Nadi. 56 x/menit
 HASIL PEMERIKSAAN

• EKG: LVH
• Foto Toraks : CTR 53%
• Lab: Ureum 29, Creatinin 0.79, eGFR 89, SGOT/SGPT . 20/23,
GD sewaktu 110 mg%, LDL-C. 132 mg%, ACR. 132.6 mg/g, Urin
lengkap.albumin (-)
 APA YANG AKAN DIBERIKAN?

1. Amlodipine 1x10mg, Irbesaran 1x150mg

2. Amlodipine 1x5mg, Irbesartan 1x300mg
3. Lercanidipine 1x10mg, Irbesartan 1x300mg
4. Lercaridipine 1x 20mg, Irbesartan 1x300mg
5. Atenolol 1x50mg, Irbesartan 1x 150mg
 FOLLOW UP

• Lercanidipine 1x20mg, Irbesartan 1x 300mg

• 2 bulan kemudian: kaki bengkak (-)
• TD. 130/80 mmHg, Nadi 62 x/menit, ACR 53 mg/g
• 5 bulan kemudian:
• TD. 120/80 mmHg, Nadi 63 x/menit, ACR 28 mg/g
 Summary
Hypertension is a disease needing life-long lifestyle modifications
and drug therapy.
Despite of many effective antihypertensive drugs, target blood
pressures are reached in only a minority of patients in clinical
practice.
Excellent adherence to drug therapy is necessary to achieve blood
pressure control.
The use of antihypertensive agents with a high efficacy in a broad
range of patient categories and a favorable tolerability profile is
important to improve adherence.
Lercanidipine is a third-generation calcium antagonist with a
proven antihypertensive efficacy and lower incidence of adverse
effects, in particular peripheral edema.
 BP Goals for Treatment of Hypertension

Chobanian AV. JAMA. 2017;317(6):579-580.