RATIONALE FOR THE USE OF SINGLE

PILL COMBINATION
Dr S.N Cookey
Consultant Cardiologist BMSH
 Adapted slide

Evolution of antihypertensive drugs

Eplerenone
CCB 1995
amlodipine
1992
-blockers
β-blockers DRI aliskiren
ARB 2007
Reserpine 1994/95
ACEIs
CCB 1981
verapamil
Thiazides
Rauwolfia 1963
1958
alkaloids

ACE=angiotensin-converting-enzyme inhibitors; ARB=angiotensin receptor blocker;

CCB=calcium channel blocker; DRI=direct renin inhibitor Düsing. Expert Rev Clin Pharmacol 2010;3:739
 BP control rates in hypertensive patients in
developing economies

24% 37% 2129%

China*1 Thailand*2 Taiwan†3

20% 24% 27%

Philippines*4 Turkey*5 Malaysia*6

BP controlled BP uncontrolled
*Treated population 1
Wu et al. Circulation 2008;118:2679–86; 2Aekplakorn et al. J Hypertens 2008;26:191–8;
†Control rate: 21% in males, 29% in females 3
Chiang et al. J Formos Med Assoc 2010;109:740–3; 4Sison et al. PJC 2007;35:1–9;
BP=blood pressure 5
Erem et al. J Public Health 2009;31:47–58; 6Rampal et al. Public Health 2008;122:11–18
 Number of antihypertensive drugs in
intervention studies
Study (systolic BP achieved)
MDRD (132 mmHg)
HOT (138 mmHg)
RENAAL (141 mmHg)
AASK (128 mmHg)
ABCD (132 mmHg)
IDNT (138 mmHg)
UKPDS (144 mmHg)
ASCOT-BPLA (136.9 mmHg)
ALLHAT (138 mmHg)
ACCOMPLISH (132 mmHg)
1 2 3 4
Average number of antihypertensive drugs
Bakris et al. Am J Med 2004;116(5A):30S–8; Dahlöf et al. Lancet 2005;366:895–906;
Jamerson et al. Blood Press 2007;16:806; Jamerson et al. N Engl J Med 2008;359:2417–28
 Number of antihypertensive drugs in
intervention studies
Study (systolic BP achieved)
MDRD (132 mmHg)
HOT (138 mmHg)
RENAAL (141 mmHg)
AASK (1281/3
mmHg)normalized with 1 agent
ABCD (1321/3
mmHg)normalized with 2 agents
IDNT (1381/3
mmHg)normalized with ≥3 agents*
UKPDS (144 mmHg)
ASCOT-BPLA (136.9 mmHg)
ALLHAT (138 mmHg)
ACCOMPLISH (132 mmHg)
1 2 3 4
Average number of antihypertensive drugs
*32.3% in ACCOMPLISH
Düsing. Vasc Health Risk Manag 2010;6:1
 New slide

American Heart Association 2013

Medication adherence – taking your

meds as directed

It is estimated that three out of four Americans do not take their

medication as directed

Poor medication adherence takes the lives of 125,000 Americans

annually

…costs the health care system nearly $300 billion a year in

additional doctor visits, emergency department visits and
hospitalizations

Available at: http://www.heart.org/HEARTORG/Conditions/More/ConsumerHealthCare/Medication-Adherence-

Taking-Your-Meds-as-Directed_UCM_453329_Article.jsp
 Single-Pill Combinations Have Several Advantages Versus
Free Combinations of Two or More Antihypertensive Drugs
Single pill Free

Simplicity of treatment + –

Compliance + –

Efficacy + +

Tolerability +* –

Price + –

Flexibility +** ++
*Lower doses generally used in single-pill combinations
**An increasing number of single-pill combinations are becoming available with a range of doses
+ = potential advantage
Burnier, et al. Am J Hypertens 2006;19:1190–6;
Neutel. Hypertension . Companion to Brenner & Rector’s
The Kidney. 2nd ed. Philadelphia: Elsevier Saunders, 2005. p. 522–9
 Guidelines: fixed-dose (single pill) combinations
ESH/ESC (2013)1 Europe
…the 2013 ESH/ESC guidelines favour the use of combinations of antihypertensive drugs at fixed
doses in a single tablet, because reducing the number of pills to be taken daily improves
adherence…

ASH/ISH (2013)2 USA (Endorsed by the Asia Pacific Society of Hypertension)

…the use of a combination product with two appropriate medications in a single tablet can simplify
treatment for patients

CHEP (2014)3 Canada

Single pill combinations help achieve BP control

JSH (2014)4 Japan

…using fixed-combination drugs is useful for improving adherence and controlling BP

1
ESH/ESC. J Hypertens 2013;31:1281–135;
ASH=American Society of Hypertension; CHEP=Canadian Hypertension Education 2
ASH/ISH. J Hypertens 2014;32:3–15;
Program; ESH=European Society of Hypertension; ESC=European Society of Cardiology; 3
www.hypertension.ca/en/chep;
ISH=International Society of Hypertension; JHS=Japanese Society of Hypertension 4
Shimamoto et al. Hypertens Res 2014;37:253–392
2003

Dual
combination
“Usually thiazide-type diuretic and ACEI,
or ARB, or BB, or CCB”
Monotherapy

“Thiazide-type diuretics”

Triple
combination
“Optimize dosage or add additional
drugs…”

BB=beta blocker
 New slide
ESH/ESC 2007: first-line antihypertensives and
combination therapy
Diuretics

β-blockers ARB

Triple-combination:
no recommendation

-blockers CCB

ACEIs
Most rational combinations
ESH/ESC. J Hypertens 2007;25:1105–87
 New slide

Question 1

In the past, ESH-ESC hypertension guidelines did not recommend

specific antihypertensive triple combinations1

Recent hypertension guidelines recommend which combination for

patients whose BP is not normalized on dual antihypertensive
therapy

1 ACEI + thiazide diuretic + CCB

2 ARB + thiazide diuretic + β-blocker
3 RAS blocker + thiazide diuretic + CCB
4 RAS blocker + thiazide diuretic + spironolactone

RAS=renin-angiotensin system ESH/ESC. J Hypertens 2007;25:1105–87

 New slide
Evolution of the BHS and NICE
hypertension guidelines: triple therapy
<55 years ≥55 years
1. step A or B C or D
BHS 2004

2. step A or B + C or D
3. step A or B + C+D

1. step A C or D
BHS 2006

2. step A + C or D
3. step A+C+D

1. step A C
BHS 2011

2. step A+C
3. step A+C+D

BHS=British Hypertension Society;

NICE=National Institute for Clinical Excellence Adapted from Düsing. Dtsch Med Wochenschr 2011;136:2378
 Adapted slide
ESH/ESC 2013 and JNC 8:* initial monotherapy,
dual and triple combinations

Diuretics ARB
 If goal BP is not reached… add a
second drug from one of these Not a recommended
classes: thiazide-type diuretic, combination
CCB, ACEI, or ARB
 If goal BP cannot be reached with
two drugs, add…a third drug from
the list provided
 Do not use an ACEI and an ARB
together in the same patient

ACEI CCB

*Report of the panel appointed to the

8th Joint National Committee. Not NHLBI endorsed ESH/ESC. J Hypertens 2013;31:1281–357;
NHLBI=National Heart, Lung, and Blood Institute JNC 8. JAMA 2014;311:507
 Adapted slide

Algorithm of antihypertensive drug treatment

BHS 2006/2011, ASH/ISH 2013,
ESH/ESC 2013, JNC 8 2013*

Diuretic RAAS blocker CCB

RAAS blocker RAAS blocker Diuretic

+ diuretic + CCB + CCB

RAAS blocker
+ CCB Düsing 2014
+ diuretic Adapted from:
James et al. (JNC8). JAMA 2014;311:507–20;
Weber et al. (ASH/ISH). J Hypertens 2014;32:3–15;
Go et a.l (AHA). J Am Coll Cardiol. 2014;63:1230–8;
*Report of the panel appointed to the 8th Joint National Committee. NICE guideline (CG34) 2006 (www.nice.org.uk);
Not NHLBI endorsed NICE guidelines (CG127) 2011 (www.nice.org.uk);
JNC=Joint National Committee Mancia et al. (ESH/ESC). J Hypertens 2013;31:1281–357
 Adapted slide

Algorithm of antihypertensive drug treatment

BHS 2006/2011, ASH/ISH 2013, ESH/ESC 2013, JNC 8 2013*

Diuretic RAAS blocker CCB

RAAS blocker RAAS blocker Diuretic

+ diuretic + CCB + CCB
Preferentially as
SPC
RAAS blocker
+ CCB
+ diuretic Düsing 2014
Adapted from:
James et al (JNC8). JAMA 2014;311:507–20;
Weber et al (ASH/ISH). J Hypertens 2014;32:3–15;
Go et al (AHA). J Am Coll Cardiol. 2014;63:1230–8;
*Report of the panel appointed to the 8th Joint National Committee. NICE guideline (CG34) 2006 (www.nice.org.uk);
Not NHLBI endorsed NICE guidelines (CG127) 2011 (www.nice.org.uk);
SPC=single-pill combination Mancia et al (ESH/ESC). J Hypertens 2013;31:1281–357
 New slide

Evolution of antihypertensive drugs

Eplerenone
CCB 1995
RAAS amlodipine
CCB
1992
blocker
-Blockers
β-Blockers DRI aliskiren
ARBs 2007
Reserpine 1994/95

Diuretic
CCB
ACEIs
1981
verapamil
Thiazides
Rauwolfia 1963
1958
alkaloids

Düsing. Expert Rev Clin Pharmacol 2010;3:739

 Treatment algorithm

 Heart failure/impaired
ventricular function
 Unstable CHD, MI
 Oedema RAAS blocker All others

RAAS blocker RAAS blocker +

+ diuretic CCB

CHD=coronary heart disease; MI=myocardial infarction www.nice.org.uk (May 2011)

 Rationale for ARB/ACEI + HCT + CCB combination

Diuretic CCB

Na+-loss and volume

Vasodilatation
contraction

Activation of RAAS

Addition of RAAS blocker

Increased BP lowering

Stanton et al. J Hum Hypertens 2002;16:75–8;

HCT=hydrochlorothiazide Jamerson et al. Am J Hypertens 2004;17:793–801
 Study design: triple combination
amlo/val/HCT
8-week, multicentre, multinational, randomized trial
Design: parallel, 4 treatment groups
Randomization

Amlo/HCT Amlo/HCT
5/12.5 mg 10/25 mg

Val/HCT Val/HCT
Placebo 160/12.5 mg 320/25 mg
“run-in” Amlo/val Amlo/val
5/160 mg 10/320 mg

Val/HCT Amlo/val/HCT Amlo/val/HCT

160/12.5 mg 5/160/12.5 mg 10/320/25 mg

4 weeks 1 week 1 week 6 weeks

 Inclusion criteria: Stage 2 hypertension (Grade 2 and 3 according to ESH)

 2,271 patients; average age 53 years; BP at randomization: 170/107 mmHg

Amlo=amlodipine; val=valsartan Calhoun et al. Hypertension 2009;54:32–9

 High dose triple-combination (amlo/val/HCT): BP

e ek 8
W
Amlo/val/HCT Val/HCT Amlo/val HCT/amlo
10/320/25 mg 320/25 mg 10/320 mg 25/10 mg
0
n=583 n=559 n=568 n=561
–10
Change in SBP (mmHg)

–20
–32 –33.5 –31.5
–30
31.5
32.0 33.5
–39.7*
–40
39.7*
Δ 7.6 mmHg
–50 Δ 6.2 mmHg
Δ 8.2 mmHg
*p<0.0001 vs dual combinations
SBP=systolic blood pressure Calhoun et al. Hypertension 2009;54:32–9
 Triple combination therapy with amlo/val/HCT
increases proportion of patients achieving BP goal
Multicentre, randomized, double-blind, parallel-group, 8-week study in
e ek 8 2,271 patients with moderate or severe hypertension
W
80
70.8 *
70
(<140/90 mmHg) at study end (%)

60
Patients achieving BP control

54.1
50 48.3
44.8
40

30

20

10
n=559 n=568 n=561 n=583
0
Val/HCT
Series1 Amlo/val Amlo/HCT Amlo/val/
320/25 mg 10/320 mg 10/25 mg HCT 10/320/25 mg

*p<0.0001 vs each dual combination treatment

Titration to target dose occurred during Week 3 Calhoun et al. Hypertension 2009;54:32–9
 New slide
Triple combination therapy vs dual therapy
in patients with severe hypertension‡

Amlo/val/
HCT Val/HCT Amlo/val HCT/amlo
10/320/25 mg 320/25 mg 10/320 mg 25/10 mg
0
n=168 n=155 n=155 n=168
Change in SBP (mmHg)

–10

–20

–30
–39.9 –43.6 –31.5
–40
–49.6
–50 p<0.0001
p<0.0009
p<0.0001

Calhoun et al. Hypertension 2009;54:32–9;

‡
Defined as SBP ≥180 mmHg at baseline Lacourciere et al. J Hypertens 2009;27(Suppl 4):S119 [Abstract]
 New slide
Amlo/val/HCT provides powerful
SBP reductions over 24 hours
170

160
Baseline data
150
ASBP (mmHg)

140

130 24-hour
treatment data
120

110

100
Amlo/val/HCT 10/320/25 mg Amlo/val 10/320 mg
Val/HCT 320/25 mg Amlo/HCT 10/25 mg

0 4 8 12 16 20 24
Hours after dosing

ASBP=ambulatory systolic blood pressure Lacourcière et al. J Hum Hypertens 2011;25:615

 Amlo/val/HCT: safety and tolerability

Adverse events % Amlo/val/HCT Val/HCT Amlo/val HCT/amlo

All 45.2 45.3 44.9 48.3

Dizziness 7.7 7.0 2.3 3.9

Peripheral oedema 4.5 0.9 8.5 8.9

Headaches 4.3 5.4 4.9 7.0

Hypotension 1.5 1.4 0.4 0.0

Calhoun et al. Hypertension 2009;54:32–9

The addition of valsartan to amlodipine + HCT provided a greater
BP reduction than the addition of olmesartan

Fogari et al. Expert Opin Pharmacother 2012;13:629–36

 Mean ambulatory BP reduction with triple combination
therapy: valsartan vs olmesartan
Olmesartan Valsartan
24 h Daytime Night-time 24 h Daytime Night-time
0 0
Change in SBP (mmHg)

Change in DBP (mmHg)

–7 –7

p<0.01
p<0.01
p=0.02 p<0.01
p=0.03 p<0.01

–14 –14

Patients with uncontrolled BP on amlodipine (5 mg) + HCT (12.5 mg) (4 weeks) were randomized
to addition of either valsartan 160 mg or olmesartan 20 mg (4 weeks)
End of dual combination versus end of study
Fogari et al. Expert Opin Pharmacother 2012;13:629–36
 EXCITE*: study design
Prospective, multinational, ‘real-world’ study
*The clinical EXperienCe of amlodIpine and valsarTan in hypErtension (EXCITE) study
• Adult patients (10,000 from 13 countries) with hypertension receiving SPC treatment with amlodipine/valsartan
or amlodipine/valsartan/HCT as part of routine care, and according to the local prescribing information in the
respective participating countries enrolled in the study
• The interim analysis evaluated data from 5,674 patients from 10 countries

Non-interventional, observational study where study participation was

separate from the treatment decision made by the physician #

Amlodipine/valsartan† OR Amlodipine/valsartan/HCT†

Visit 1 Visit 2–13 wks Visit 3–26 wks

Baseline End of study
Observational period of 26 weeks ± 8 weeks ‡

#
Therapy was prescribed according to the treating clinician and was clearly separated
from the decision to include the patient in the study; †Prescribed at any dosage in
compliance with local prescribing information for arterial hypertension, administered
as single therapy, or as add-on therapy to diuretics, β-blockers, CCBs, ACEIs or ARBs;
‡
Only data from routine medical practice collected – no imposed visit schedule, or
required diagnostic or therapeutic procedures or tests Sison et al. Curr Med Res Opin 2014;30:1937–45
 EXCITE: incremental BP reductions with amlo/val/HCT
across prior antihypertensive dual therapy classes
Prior antihypertensive dual Overall ACEI+CCB ARB+CCB ACEI+Diu ARB+Diu
therapy (n=235) (n=54) (n=54) (n=20) (n=90)
BL msSBP/msDBP 161.9/96.0 160.9/94.7 162.3/96.4 164.6/95.8 161.6/97.1
(mmHg) 0

–5

–10
Change in mean sitting

–15
BP (mmHg)

–15.3 –14.6 –14.3 –15.3

–20 –18.4
–25

–30
–30.7
–35 –32.7 –33.0 –32.3

–40 –37.4

95% CI (LL, UL) Overall ACEI+CCB ARB+CCB ACEI+Diu ARB+Diu

msSBP –34.80, –30.62 –35.48, –25.85 –37.41, –28.63 –45.82, –28.88 –35.31, –29.20
msDBP –16.49, –14.16 –17.21, –12.05 –16.89, –11.78 –23.66, –13.04 –16.95, –13.56
Post-hoc analysis. Baseline defined as prior to start of amlo/val/HCT. End of study defined as Visit 3 (Week 26). Included only patients who
did not take any antihypertensive medication during the observational period, in addition to amlo/val/HCT, and did not switch to amlo/val.
No additional treatment prior to study entry was received

Amlo/val/HCT=amlodipine+valsartan+hydrochlorothiazide combination; Sison et al. Abstract 109 presented at the 5th International Conference on
BL msSBP/msDBP=mean sitting systolic/diastolic blood pressure at baseline; Fixed Combination in the Treatment of Hypertension, Dyslipidemia and
Diu=diuretic; LL=lower limit; UL=upper limit Diabetes Mellitus, Bangkok, Thailand, 21–24 November 2013
 Adapted slide
EXCITE: meaningful BP reductions from baseline
across all hypertension severities
Amlo/val/HCT
140 to <160 160 to <180 ≥180
BL msSBP (mmHg) (n=302) (n=529) (n=276)
BL msSBP/msDBP
(mmHg) 148.9/94.2 165.8/97.4 188.3/103.6
0

–10

–14.0
–20
–18.5
–20.5 –22.0
–30

–40 –37.6

–50

–60 –55.7
140−<160 160−<180 ≥180
msSBP −21.68, −19.35 −38.51, −36.60 −57.42, −54.02
msDBP −15.01, −13.05 −19.31, −17.73 −23.28, −20.70

n=number of patients from which change in BP was calculated (full analysis set:
all patients with at least one baseline and post-baseline BP assessment, last observation
carried forward) Sison et al. Curr Med Res Opin 2014;30:1937–45
 Summary
 Antihypertensive monotherapy can control BP in one-third of patients with
hypertension
 Combination therapy with two and more drugs required in the majority of patients
 Complexity of therapy represents an important underlying factor for non-compliance
 Most guidelines recommend the use of single-pill combinations (whenever possible) to
improve treatment compliance
 ≥3 drugs required for BP control in approximately 1/3 of hypertensive patients
 When triple therapy is required, (all) guidelines recommend a combination of RAAS
blocker plus diuretic plus CCB
 Amlodipine/valsartan/HCT first of such single-pill triple combinations
 Allows to control BP in up to 90% of hypertensive patients with a single-pill strategy