Implementing Single Pill

Combination Therapy for

Hypertension

Dr Tunggul D Situmorang,SpPD,KGH,FINASIM
22 Juli 2024
 Tailoring Antihypertensive Treatment

The activity of the renin system decreases with advancing age and is
lower in Blacks compared with Whites.
These pathophysiological principles explain why guidelines, with the
exception of the 2018 European and the 2020 International guidelines
recommend to start antihypertensive drug treatment with ACE
inhibitors or ARBs below age 55 and with thiazide diuretics (TDs) or
dihydropyridine CCBs (calcium-channel blockers) in older patients and
in Blacks across the adult age range.
Isolated systolic hypertension, which in its initial course is not
associated with increased peripheral resistance, but is caused by
stiffening of the large arteries is an indication for TDs or CCBs.

https://doi.org/10.1161/HYPERTENSIONAHA.120.12858Hypertension. 2021;77:788–798
(ESC / ESH / InaSH) 2018/2019
(I S H)
2020
 TALES OF HYPERTENSION
GUIDELINES
ALTITUDE ACCOMPLISH

ON
TARGET ACCF/AHA
HYVET
REIN-2 ESH/ESC ACCORD-BP ESC/ESH

CAMELOTACC/AHA NICE ASH-ISH SPRINT

2003 2005 2007 2009 201 2014 2017 2018 2020

1
JNC 7 JNC 8 ACC/AHA ESC/ESH ISH
• valsartan/amlodipine;
• valsartan/hydrochlorothiazide;
• indapamide/amlodipine;
• olmesartan/amlodipine;
• amlodipine/valsartan/hydrochlorothiazide;
• atorvastatin/perindopril/amlodipine;
• olmesartan/amlodipine/hydrochlorothiazide.
 Glob Heart. 2022; 17(1): 6.

Published online 2022 Jan 25. doi: 10.5334/gh.1087

• THE USE OF SINGLE PILL COMBINATION IN TREATMENT OF HYPERTENSION
AMONG DALMATIAN PATIENTS IN NEPHROLOGY OUTPATIENT CLINIC
Radic, J.1,2; Milin, S.1; Novak, I.1; Culjak, Z. 3

The study included 201 subjects, 112 (55.7%) men aged 68.5 (59.3 – 75.8) years and 89 (44.3%) women aged 68 (59.5 - 73)
years. Data for age, gender, type and number of antihypertensive drugs were recorded. Serum values of urea, creatinine,
haemoglobin and potassium have been measured and glomerular filtration rate (GFR) was calculated for each patient.
Results:
67 (33.3%) patient were taking single pill combination. Those patients with single pill combination had statistically lower urea
(8.1 (6–2–10.6) vs. 10 (7–15.93), p = 0.01), creatinine (101 (76 - 139) vs. 134 (89.75 – 198.75), p = <0.001) and statistically
higher haemoglobin level (141 (131 - 152) vs. 132 (119 - 146), p = 0.04) and GFR (61.5 (42.6 - 82) vs. 39.45 (25.4 – 69.65), p =
<0.001) than those patient without single pill combination. Statistically significant difference in potassium level and measured
blood pressure parameters was not found among these two group of patients.

Conclusions:
Low proportion of hypertensive patients were taking single pill combination. Possible explanation for this finding could be
statistically higher creatinine level and low GFR in those patients without single pill combination. Chronic kidney disease
among hypertensive patients in nephrology outpatient clinic could be possible reason for not prescribing single pill
combination, especially those single pill combination with angiotensin-converting enzyme inhibitors or angiotensin II receptor
blockers.

Journal of Hypertension 37():p e252, July 2019. | DOI: 10.1097/01.hjh.0000573224.34237.ea

 A Systematic Review and Meta-Analysis

Gianfranco Parati. Hypertension. Adherence to Single-Pill Versus

Free-Equivalent Combination Therapy in Hypertension, Volume: 77,
Issue: 2, Pages: 692-705, DOI:
(10.1161/HYPERTENSIONAHA.120.15781) © 2020 American Heart Association, Inc.
 Olmesartan provides improved early BP reductions
compared
with other ARBs
Seated DBP Seated SBP

Mean change in BP at 2 weeks (mmHg)

OLM LOS VAL IRB OLM LOS VAL IRB
20 mg 50 mg 80 mg 150 mg 20 mg 50 mg 80 mg 150 mg

n=14 n=14 n=14 n=14 n=14 n=14 n=14 n=14

5 6 2 5 5 6 2 5

*p≤0.05; **p≤0.005; ***p≤0.0005 vs OLM.

ARB, angiotensin II receptor blocker; BP, blood pressure; DBP, diastolic blood pressure; IRB, irbesartan;
LOS, losartan potassium; OLM, olmesartan medoxomil; SBP, systolic blood pressure; VAL, valsartan. Oparil S, et al. J Clin Hypertens 2001;3:283–291.

• When comparing the early reductions in blood pressure associated with angiotensin II receptor blocker (ARB)
therapy, olmesartan medoxomil has been shown to provide significantly greater reductions in both systolic and
diastolic blood pressure within 2 weeks of initiating treatment compared with other ARBs.
 Olmesartan achieves greater reductions in 24-hour ABP
at 8 weeks versus other ARBs
DBP SBP
OLM LOS VAL IRB OLM LOS VAL IRB
20 mg 50 mg 80 mg 150 mg 20 mg 50 mg 80 mg 150 mg

Mean change in BP at 8 weeks (mmHg)

n=14 n=14 n=14 n=14 n=14 n=14 n=14 n=14
5 6 2 5 5 6 2 5

**p≤0.005; ***p≤0.0005 vs OLM.

ABP, ambulatory blood pressure; ARB, angiotensin II receptor blocker; BP, blood pressure; DBP, diastolic blood pressure;
Oparil S, et al. J Clin Hypertens 2001;3:283–291.
IRB, irbesartan; LOS, losartan potassium; OLM, olmesartan medoxomil; SBP, systolic blood pressure; VAL, valsartan.

• After 8 weeks of treatment, olmesartan medoxomil provides significantly greater reductions in both systolic
and diastolic 24-hour mean ambulatory blood pressure compared with the other angiotensin II receptor
blockers losartan and valsartan.
Olmesartan achieves greater reductions in 24-hour ABP
at 8 weeks versus other ARBs
Oparil et al.1a Smith et al.2b Brunner et al.3c Giles et al. 4a
LOS
50/100 mg
OLM LOS VAL IRB OLM LOS VAL IRB OLM CAN OLM VAL
20 mg 50 mg 80 mg 150 mg 20 mg 50 mg 80 mg 150 mg 20 mg 8 mg 20/40 mg 80/160 mg

Patients achieving BP goal (%)

14 14 142 14 136 134 130 134 31 32 18 19 18

5 6 5 2 3 9 2 9 n
*p<0.05; **p<0.01; ***p<0.001 vs OLM.
a
BP goal <140/90 mmHg; bBP goal <130/80 mmHg; cBP goal <125/80 mmHg;
ABP, ambulatory blood pressure; ARB, angiotensin II receptor blocker; BP, blood pressure; 1. Oparil S, et al. Am J Hypertens 2005;18:287–294; 2. Smith DHG, et al. Am J Cardiovasc Drugs 2005;5:41–50;
IRB, irbesartan; LOS, losartan potassium; OLM, olmesartan medoxomil; VAL, valsartan. 3. Brunner HR, et al. Clin Drug Invest 2006;26:185–193; 4. Giles TD, et al. J Clin Hypertens 2007;9:187–195.

• Several studies have demonstrated that, after 8 weeks of treatment, a significantly greater
proportion of patients administered olmesartan medoxomil achieve their blood pressure goal
compared with other angiotensin II receptor blockers.1-4
Olmesartan has a favourable tolerability profile compared with
other ARBs
Adverse effects* Losartan Valsartan Irbesartan Candesartan Telmisartan Eprosartan Olmesartan
n=1,075 n=2,316 n=1,965 n=2,350 n=1,455 n=1,202 n=3,278
Dizziness 3.5% – – 4% – – 3%
Fatigue – 2% 4% – – 2% –
Diarrhoea 2.4% – 3% – 3% – –
Dyspepsia 1.3% – 2% – – – –
Abdominal pain – 2% – – – 2% –
MSK arthralgia – – – – – 2% –
MSK pain – – – 3% 1–3% – –
URTI 7.9% – 9% 6% 7% 8% –
Cough 3.4% – 2.8% – – 4% –
Sinusitis – – – – 3% – –
Viral infection – 3% – – – 2% –

*Occurred in ≥2% of patients.

ARB, angiotensin II receptor blocker; MSK, musculoskeletal; URTI, upper respiratory tract infection. Barreras A, et al. Proc (Bayl Univ Med Cent)
2003;16:123–126.

• Olmesartan has a favourable safety profile compared with other angiotensin receptor blockers.
• Dizziness is a common adverse event associated with therapies that lower blood pressure; Olmesartan
exhibited numerically lower rates of dizziness than other angiotensin II receptor blockers.
• Olmesartan has a lower risk of muscle pain, fatigue, gastrointestinal adverse events and infection than other
angiotensin II receptor blockers.
Possible combinations of classes
of antihypertensive drugs

ESC-ESH Guideine, 2013

 Adding olmesartan to amlodipine increases BP reductions
Mean seSBP reductions at 8 weeks in the overall population
Placeb AML 5 AML 10 OLM 20 OLM 40 AZOR 5/20 AZOR 10/40
o mg mg mg mg mg mg
n=16 n=16 n=15 n=16 n=16
Mean change in SeSBP from

n=16 n=16
0 1 3 9 0 0 1
baseline (mmHg)

Mean BP baseline values were: placebo=167/102 mmHg; AML 5 mg=163/102 mmHg; AML 10 mg=164/102 mmHg; OLM 20 mg=164/102 mmHg;
OLM 40 mg=163/101 mmHg; AZOR 5/20 mg=164/102 mmHg; AZOR 10/40 mg=166/102 mmHg. Mean SeDBP reductions were: placebo=3 mmHg;
AML 5 mg=9 mmHg; AML 10 mg=13 mmHg; OLM 20 mg=9 mmHg; OLM 40 mg=10 mmHg; AZOR 5/20 mg=14 mmHg; AZOR 10/40 mg=19 mmHg.
*p<0.05 vs baseline; **p<0.001 vs baseline.
AML, amlodipine; AZOR, amlodipine, olmesartan medoxomil; BP, blood pressure; OLM, olmesartan medoxomil; SeSBP, seated systolic blood pressure.

• The COACH study was a pivotal trial that demonstrated significantly greater blood pressure reductions with AZOR
(amlodipine plus olmesartan medoxomil) than with either amlodipine or olmesartan monotherapy.

Chrysant SG, et al. Clin Ther 2008;30:587–604.

 Adding olmesartan to amlodipine improves BP control
BP goal: <140/90 mmHg (<130/80 mmHg for diabetics)

Patients reaching BP goal

at 8 weeks (%)

n=18 n=18 n=18

4 7 6
AML 5 20/5 40/5
mg mg mg

AZ
*p<0.0001 vs. AML 5 mg monotherapy.
AML, amlodipine; AZOR, amlodipine; olmesartan medoxomil; BP, blood pressure. OR
• After 8 weeks of treatment, combination therapy with AZOR (amlodipine plus olmesartan medoxomil) helped significantly
more patients with hypertension reach their blood pressure goal compared with amlodipine (5 mg) monotherapy.

Volpe M, et al. Clin Drug Invest 2009;29:11–25.

 Olmesartan and amlodipine in combination
helps more patients achieve their BP goal than
olmesartan alone
BP goal: <140/90 mmHg (<130/80 mmHg for diabetics)

*
Patients reaching BP goal

* *
at 8 weeks (%)

n=15 n=16 n=16 n=15

9 0 0 7
OLM 20 OLM 40 20/5 40/5
mg mg mg mg
*p<0.001 vs OLM 20 mg monotherapy; **p<0.005 vs OLM 40 mg monotherapy.
AZOR, amlodipine, olmesartan medoxomil; BP, blood pressure; OLM, olmesartan medoxomil.
AZ Chrysant SG, et al. Clin Ther 2008;30:587–604.

OR
• After 8 weeks of treatment, combination therapy with AZOR (amlodipine plus olmesartan medoxomil) helped
significantly more patients with hypertension reach their blood pressure goal compared with Olmesartan monotherapy.
 Combining olmesartan and amlodipine reduces BP in elderly
patients
<65 ≥65
PL yearsOLM
AML AZOR PL AMLyears
OLM AZOR
128 131 129 128 32 32 31 33 n
0
baseline at 8 weeks

-10 *
*
Change from

(mmHg)

-20
*
†
-30
‡
† §
-40
‡
*p<0.05 vs baseline; **p<0.01 vs baseline;
†p<0.0001 vs both monotherapy components; ‡p<0.0001 vs OLM; §p<0.025 vs AML.
SeSB SeDBP
AML, amlodipine 10 mg; AZOR, amlodipine 10 mg, olmesartan medoxomil 40 mg; BP, blood
pressure;
P
Chrysant SG, et al. J Hum Hypertens 2010;24:730–738.
OLM, olmesartan medoxomil 40 mg; PL, placebo; SeDBP, seated diastolic blood pressure; SeSBP,
seated systolic blood pressure.

• Amlodipine and olmesartan medoxomil both decrease blood pressure as monotherapies but are more effective in
combination than in monotherapy in elderly patients.
 Combining olmesartan and amlodipine reduces BP in patients with type
2 diabetes
Diab No
PL etes OLM
AML AZOR PL AMLdiabete
OLM AZOR
23 23 21 24 137 140 139 137 n
0 s
* *
Change from baseline
at 8 weeks (mmHg)

-10
*
-20 *
** * ‡ †
-30
* §
‡ †
-40
§
*p<0.05 vs baseline; **p<0.01 vs baseline; ***p<0.001 vs baseline;
SeSB SeDBP
†p<0.0001 vs both monotherapy components; ‡p<0.0001 vs OLM; §p<0.01 vs AML.
AML, amlodipine 10 mg; AZOR, amlodipine 10 mg, olmesartan medoxomil 40 mg; BP, blood pressure;
P Chrysant SG, et al. J Hum Hypertens 2010;24:730–738.
OLM, olmesartan medoxomil 40 mg; PL, placebo; SeDBP, seated diastolic blood pressure; SeSBP, seated
systolic blood pressure.

• In hypertensive patients with type 2 diabetes, amlodipine and olmesartan medoxomil both decrease blood pressure as
monotherapies but are more effective in combination than in monotherapy.
 Combining olmesartan and amlodipine reduces BP in obese patients
<30 ≥30
2 2
PL kg/mOLM
AML AZOR PL AMLkg/m
OLM AZOR
23 23 21 24 137 140 139 137 n
0
baseline at 8 weeks

-10 * **
*
Change from

*
(mmHg)

-20 *
†
†
-30

‡ †
-40

*p<0.05 vs baseline; **p<0.01 vs baseline; ***p<0.001 vs baseline;

§ SeSB SeDBP
†p<0.0001 vs both monotherapy components; ‡p<0.01 vs OLM; §p<0.001 vs AML.
AML, amlodipine 10 mg; AZOR, amlodipine 10 mg, olmesartan medoxomil 40 mg; BP, blood pressure; P Chrysant SG, et al. J Hum Hypertens 2010;24:730–738.
OLM, olmesartan medoxomil 40 mg; PL, placebo; SeDBP, seated diastolic blood pressure; SeSBP, seated systolic
blood pressure.

• In hypertensive patients with obesity, amlodipine and olmesartan medoxomil both decrease blood pressure as
monotherapies but are more effective in combination than in monotherapy.
 Olmesartan plus amlodipine therapy
maintains BP control over 24 hours
160
Mean 24-hour SBP:

Mean SBP (mmHg)

150 144.8 mmHg

140 Baseline

130
Mean 24-hour SBP:
123.5 mmHg
120
End of Study
110
0 4 8 12 16 20 24

90
Mean 24-hour DBP:
Mean DBP (mmHg)

Baseline 85.7 mmHg

80

70
Mean 24-hour DBP:
End of Study
73.0 mmHg
60
0 4 8 12 16 20 24
Time (hours)
N=185
BP, blood pressure; DBP, diastolic blood pressure; SBP, systolic blood pressure. Punzi H, et al. Ther Adv Cardiovasc Dis 2010;4:209.
 Combining an ARB with a CCB
reduces the risk of cardiovascular
events

N=1,164; *Olmesartan 40 mg/day; **Olmesartan 20 mg/day + amlodipine (2.5 or 5 mg/day) or Ogawa H, et al. Am J Med 2012;125:981–990.
azelnidipine (8 or 16 mg/day).
ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; CI, confidence interval; HR, hazard ratio.

• Patients treated with a high-dose angiotensin II receptor blocker alone may be more than 60% more likely to experience a major
adverse cardiovascular event than patients administered a combination of an angiotensin II receptor blocker and a calcium channel
blocker.
 Olmesartan plus amlodipine is an effective antihypertensive combination
therapy
Blood pressure reduction,
Patient, Mean dose, mg mmHg I p
(95%Cl) 2
n (SD)
Olmesartan/amlodipine 1,82 35.0/9.2 SBP: -23.7 (-32.6, 71. <0.00
7 (6.3/1.2) -9.4) 3 1
DBP: -17.4 (-20.2, 97. <0.00
Olmesartan/HCTZ 2,55 26.2/17.8 SBP:
-14.4)-22.2 (-25.7, 93.
5 <0.00
1
7 (3.1/1.6) -18.1) 0 1
DBP: -14.7 (-20.2, 61. <0.01
Felodipine/metoprolol 1,08 10/100 SBP:
-7.2) -20.8 (-30.6, 96.
1 <0.00
5 (0/0) -0.8) 2 1
DBP: -13.3 (-16.5, 93. <0.00
Valsartan/HCTZ 3,86 189.1/16.3 SBP:
-9.4) -20.2 (-23.0, 51.
8 0.
1 1
8 (22.8/1.7) -17.2) 4 <0.00
DBP: -11.8 (-14.0, 64. 1
Perindopril/indapamide 1,24 3.6/1.0 SBP:
-9.6) -15.1 (-18.9, 63.
5 <0.00
6 (0.7/0.1) -10.9) 7 1
DBP: -10.7 (-12.8, 68. <0.00
Losartan/HCTZ 2,70 100/25 SBP:
-8.7) -14.4 (-17.8, 68.
4 <0.00
1
5 (0/0) -10.7) 9 1
DBP: -13.2 (-20.9, 80. <0.00
Valsartan/amlodipine 2,77 156.5/4.2 SBP:
-3.6) -13.0 (-21.9, 94.
2 <0.00
1
7 (38.8/0.8) -7.5) 7 1
DBP: -5.4 (-11.5, 88. <0.00
31,49 -0.9)
SBP: -20.2 (-23.4, 1
89. 1
0.00
All combinations
7 -16.7) 4 1
SBP 3 2 2 1 1 5 0 DBP: -12.8 (-1.8, 81. 0.03
0 5 0 5 0 54. 0.6
DBP -10.8) in forest plot
All combinations included 5
Blood Pressure reduction in 9 <0.0
mmHg
CI, confidence interval; DBP, diastolic blood pressure; HCTZ, hydrochlorothiazide; SBP, systolic blood pressure; 82. 5
Paz SG, et al. Medicine (Baltimore) 2016;95:e4071.
SD, standard deviation. 6
 Summary and Conclusion
❖ Awareness, Diagnosis & Best antihypertensive which prevent target organ
complications will save lives !
❖ Achieving Blood Pressure Control goal is a mandatory in hypertensive
patients management
❖ Combination Theraphy
❖ Combination Therapy is a Practical Necessity, base on Right Combination
for the Right Condition and more effective, higher BP control rates
❖ Single Pill Combination (SPC) of ARBs + CCBs recommended by
guidelines as initial treatment of hypertension
❖ Hypertension emergencies can be life-threatening and require
immediate intervention to lower BP, usually with intravenous (i.v.)
therapy