“Hypertension Update: From Guideline to Clinical Practise”

Fix-Dose Combination Therapy in Hypertension:

Focus on ARB and Diuretic.

Dr. Heru Prasanto, SpPD-KGH, FINASIM

Division of Nephrology, Internal Medicine Department, Faculty of Medicine,
Universitas Gadjah Mada / Dr. Sardjito General Hospital.
Yogyakarta.
 Pendahuluan
• Hipertensi sering disebut sebagai “The Silent Killer”
 sering tanpa keluhan, tidak menimbulkan gejala yang spesifik
 menyebabkan banyak penderita hipertensi yang tidak diobati.

• Hipertensi  kontributor utama untuk penyakit jantung, gagal ginjal,

dan stroke di Indonesia.
• Diagnosis hipertensi jika hasil pengukuran tekanan darah menunjukkan
hasil tekanan sistol ≥ 140 mmHg dan/atau tekanan diastol ≥ 90 mmHg
pada lebih dari 1(satu) kali kunjungan.
 Pendahuluan
• Komplikasi hipertensi dapat mengenai berbagai organ target, seperti
penyakit jantung iskemik, hipertrofi ventrikel kiri, gagal jantung, stroke,
gagal ginjal, retinopati.
• Kerusakan organ-organ tersebut berhubungan dengan tingginya tekanan
darah pasien dan berapa lama tekanan darah tinggi tersebut tidak terkontrol
dan tidak diobati.

 Prevalensi hipertensi merupakan masalah diseluruh dunia.

 Secara global disebutkan , prevalensi hipertensi sebesar 26,4% dan akan
menjadi 29,2% ditahun 2025.
RISKESDAS 2018
RISKESDAS 2018
RISKESDAS 2018
RISKESDAS 2018
Hypertension & Cardiovascular Risk Classification

Different grades of hypertension

and the presence of CV risk factors,
HMOD or comorbidities could
impact the progression of the
stages of hypertension-associated
disease (from uncomplicated
through to asymptomatic or
established disease).

William B, et al. 2018 ESC-ESH Guidelines for the management of arterial hypertension, European Heart Journal (2018) 39, 3021–3104
 Dalam sebuah studi meta analisis yang mencakup 61 studi obervasional prospekti
pada 1 juta pasien, yang setara dengan 12,7 juta person-years, ditemukan bahwa:
 penurunan rerata tekanan darah sistolik sebesar 2 mmHg
 dapat menurunkan risiko mortalitas akibat penyakit jantung iskemik
sebesar 7% dan
 menurunkan risiko mortalitas akibat stroke sebesar 10%.

Tercapainya target penurunan tekanan darah sangat penting untuk

menurunkan kejadian komplikasi kardiovaskuler pada pasien hipertensi.
Lewington S, Clarke R, Qizilbash N, peto R, Collins R, Prospective Studies Collaboration. age-specific relevance of usual blood
pressure to vascular mortality: A meta-analysis of individual data for one million adults in 61 prospective studies . Lancet. 2002, 360(9349):
1903-13.
Penanganan hipertensi pd bbrp guideline dimulai dengan modifikasi gaya hidup,
upaya awal ini diketahui dapat menghambat progresivitas hipertensi.

Namun, sebagian besar pasien memerlukan obat anti hipertensi seumur hidup
bahkan tidak hanya satu jenis obat tetapi dengan kombinasi lebih dari satu obat.
 Panduan/Guideline Terapi Hipertensi

Penanganan hipertensi pd bbrp guideline dimulai dengan modifikasi gaya hidup,

upaya awal ini diketahui dapat menghambat progresivitas hipertensi.

 JNC8 2014 (dengan 140/90 mmHg sebagai batasan untuk hipertensi) digunakan
untuk menentukan prevalensi, kesadaran, pengobatan, dan pengendalian hipertensi.

 ACC/AHA 2017 untuk Pencegahan, Deteksi, Evaluasi, dan Manajemen, target

Tekanan Darah Tinggi pada Orang Dewasa dengan batas 130/80 mmHg
JAMA February 5, 2014 Volume 311, Number
5
 The concept of initial combination therapy is not
new because one of the first large clinical trials
published in the late 1960s, the Veteran Affairs
Cooperative Study, showed reduced morbidity with
improved BP control using triple therapy
combination.

Veterans Administration Cooperative Study Group on Antihypertensive Agents, Effects of

Treatment on Morbidity in Hypertension, JAMA, Dec 11, 1967 ● Vol 202, No.11
 Evolution of Antihypertensive Combination Therapy

• The use of combination therapies started in the 1950s, when pills containing reserpine were introduced.
• Followed in the 1960s and 1970s by availability of other formulations:
o triple combination hydralazine, HCT and reserpine
o combination potassium-sparing diuretics, beta-blockers, and clonidine
• In the 1980s, thiazides combined with ACE-inhibitors
• In the 1990s, a combination of an ACE inhibitor and CCB

Yamout H, et al. Use of Combination Therapies,

Illustration Of Various Drug Class Combinations To Lower Blood Pressure
Blood Pressure Goal in Special Population

The ESC/ESH guideline supports a BP

between 130/70 and 139/79 mm Hg,

while the ACC/AHA guideline

recommends <130/80 mm Hg for those
older than 65 years.

Bakris J, et al. ACC-AHA Versus ESC-ESH on Hypertension Guidelines JACC Guideline Comparison, J Am Coll Cardiol
2019;73:3018–26
Treatment algorithm JNC 8
 Concepts of Blood Pressure Management

William B, et al. 2018 ESC-ESH Guidelines for the management of arterial hypertension, European Heart Journal (2018) 39, 3021–3104
 Hypertension Drug Treatment Strategy

William B, et al. 2018 ESC-ESH Guidelines for the management of arterial hypertension, European Heart Journal (2018) 39, 3021–3104
 Drug Treatment Strategy For Uncomplicated Hypertension

William B, et al. 2018 ESC-ESH Guidelines for the management of arterial hypertension, European Heart Journal (2018) 39, 3021–
3104
Rationale For Initial Combination Therapy:
Multifactorial Causes High Blood Pressure
There are multiple systems that regulate BP (sympathetic nervous
system (SNS), renin-angiotensin system (RAS), and volume
modulators from the kidney and heart like natriuretic peptides)

It is difficult to determine with certainty which system

The use of different classes of medications will increase the

chance of controlling BP faster and more effectively

An increase dose of a single agent is less likely to achieve BP

control than adding lower doses of a second agent.
Yamout H, et al. Use of Combination Therapies,
 Combination Therapy vs. Monotherapy
In Reducing Blood Pressure
Comparison of observed versus expected effects of a single pill combination
versus doubling the dose of an antihypertensive medication

Use of combination therapy

improves BP control with fewer
adverse events compared with
doubling the dose of a single pill.

Addition of an antihypertensive
agent from a different class is five
times more effective in improving
BP control than doubling the dose
of a single drug.

Improvement in BP control occurs

when even half the dose of the
individual drugs are used in a
combination pill compared with
full doses of each as monotherapy.
Yamout H, et al. Use of Combination Therapies,
 Adherence in Single Pill Combination
Adherence with single pill combinations compared with free-drug combinations.

Even when the same two drugs are given

as individual pills, adherence rates with
combination therapy are significantly
higher and can reduce non-adherence by
up to 24%.

Yamout H, et al. Use of Combination Therapies,

Rationale For Initial Two-drug Combination Therapy

• Greater BP reduction vs monotherapy

• Reduced heterogenicity of the BP response
• No/small increase in hypotensive episodes
• More frequents BP control after 1 year
- Better adherence to treatment
- Reduced therapeutic inertia
• Reduced CV events
Abbreviations: ACE, 1 angiotensin-converting enzyme; RCT, eviden
evidence-based dose that balances efficacy and safety is 25-50 mg daily.
 The mean change in blood pressure from baseline was 27.8
mmHg [95 % confidence interval (CI) 26.4–29.1 mmHg; p<0.001]
systolic and 13.5 mmHg (95 % CI 12.6–14.4 mmHg; p<0.001)
diastolic.

The fixed irbesartan/ hydrochlorothiazide combination may

control blood pressure to the target level in about 60 % of
patients with moderate to severe hypertension, with an
acceptable safety profile.

Mean changes from baseline in systolic and diastolic blood

pressure in the intention to- treat analysis
COSIMA study was designed to establish whether the fixed
combination with hydrochlorothiazide (HCTZ) would blunt the
differences in BP-lowering efficacy observed between irbesartan
and valsartan monotherapy.

The percentage of patients with normalized BP at the final

visit HBPM was higher in the irbesartan/HCTZ group than in
the valsartan/HCTZ group: respectively 50.2% v 33.2%
(P=.0003) in the ITT population.

The percentage of patients with normalized BP at the final

visit Office was also higher in the irbesartan/HCTZ group
than in the valsartan/HCTZ group: respectively 51.4 v 41.9%
(P=.0436) in the ITT population.

The COSIMA study demonstrates that in hypertensive patients

who remain uncontrolled with HCTZ 12.5 mg monotherapy, a
fixed regimen combining irbesartan/HCTZ (150/12.5 mg) for 8
weeks is more effective in reducing BP than a fixed regimen
combining valsartan/HCTZ (80/12.5 mg).
To evaluate the efficacy of combination of ARB with HCTZ compared
to ARB alone in patients with uncontrolled hypertension via a
systematic review and meta-analysis.

Methods. We searched databases till July 2019 using relevant search

terms. We included articles that were randomised controlled trials
(RCTs) comparing ARB/HCTZ with ARB for a duration of at least 4
weeks and reported on the efficacy or safety. Meta-analyses for
efficacy outcomes were performed.

Conclusion:
Using a combination of ARB with a low concentration of HCTZ
afforded better BP control without additional AEs compared with
using ARB alone in patients with uncontrolled

International Journal of Hypertension, Volume 2021

Conclusion:
Using a combination of ARB with a low concentration of HCTZ afforded better BP control without additional AEs compared
with using ARB alone in patients with uncontrolled

International Journal of Hypertension, Volume 2021

The FLASH study involving 780 patients investigated the efficacy and
safety of a single-pill combination BP-lowering therapy including HCTZ
and irbesartan in subjects with moderate or severe hypertension, one third
previously untreated and two thirds in whom prior therapy had not been
sufficient to reach the target BP.

FIGURE 1. Average systolic and diastolic BP at baseline and follow-up

visit.
BP, Blood Pressure; HCTZ, Hydrochlorothiazide.
Mean reductions in systolic/diastolic BP after 8 weeks were 23.7 ±
13.7/11.7 ± 8.5 mmHg vs. baseline, with a reduction of 26.9 ±
14.1/13.0 ± 8.8 mmHg or 21.8 ± 13.1/11.0 ± 8.3 mmHg when the
single-pill combination was given as first line or replacement
treatment, respectively

Conclusions: The single-pill combination of irbesartan/HCTZ

was well-tolerated and achieved substantial reductions in both
systolic and diastolic BP. The SBP control rate was greater
when the combination was prescribed as first line treatment as
suggested by recent ESC/ESH guidelines.
 Key Points
A SPC treatment strategy with preferred use of two-drug combination
therapy is recommended for the initial treatment of most patients with
hypertension, the use of different classes of medications will increase the
chance of controlling BP faster and more effectively

The use of diuretic and RAAS blocker combination counteract the body
response to diuretic (that activate the RAS) and are complementary to
diuretic action to low BP.

Diuretic and RAS combination give vascular dilation in volume retension

type hypertension (nocturnal hypertension, CKD, CHF) with decreasing
plasma and extracellular volume.

The fixed irbesartan/ hydrochlorothiazidecombination may control blood

pressure to the target level in about 60 % of patients with moderate to
severe hypertension, with an acceptable safety profile.
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