The document discusses optimizing treatment of hypertension with angiotensin receptor blockers (ARBs) in combination therapy. It provides guidelines on when combination therapy is needed, such as for patients at high cardiovascular risk or those requiring tight blood pressure control. It evaluates ARBs as the preferred combination, noting their efficacy in lowering blood pressure and reducing cardiovascular risk based on clinical trial evidence, as well as their better tolerability profile compared to other drug classes. The document recommends ARB/calcium channel blocker combination therapy as the optimal approach.
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Tối Ưu Hóa Điều Trị Tăng Huyết Áp với Thuốc chẹn thụ thể AT1
1. Tối Ưu Hóa Điều Trị Tăng Huyết Áp với
Thuốc chẹn thụ thể AT1 trong
Liệu Pháp Phối Hợp Thuốc Cùng Viên
PGS.TS. Phạm Mạnh Hùng
Tổng thư ký – Hội Tim Mạch Việt nam
2. Khi nào cần phối hợp thuốc?
• Bệnh nhân có nguy cơ tim mạch cao
– Nhiều yếu tố nguy cơ, ĐTĐ
– Tiền sử có bệnh tim mạch
• Tăng huyết áp (> 160/100)
• Huyết áp mục tiêu thấp
– ĐTĐ, Bệnh thận mạn, tiền sử Đột quị, Nhồi máu
cơ tim
• Tất cả các yếu tố trên
3. Eur Heart J 2007;28:1462-1536
Phân tầng nguy cơ tim mạch và
chọn lựa chiến lược điều trị
Mức huyết áp
Bênh/Nguy
cơ
tim
mạch
Lựa chọn thuốc kiểm soat huyết áp
tốt và kéo dài
Lựa
chọn
thuốc
giảm
các
biến
cố
tim
mạch
ESC Guidelines 2007
Kiểm soát huyết áp hiệu quả
Giảm
nguy
cơ
4. Tiêu chí của
thuốc lý tưởng
Risk Factors
Diabetes
Hypertension
Hyperlipidemia
Smoking
Atherosclerosis
and LVH
Ventricular
Dilatation
Chronic
Heart
Failure
End-Stage
Heart Disease
Myocardial
Infarction
Remodelling
Death
1. ARB có phải là “thuốc lý tưởng”?
2. Phối hợp thuốc ARB có phải là the “phối hợp tối
ưu”, khi bệnh nhân cần hạ áp thêm?
3. Phối hợp nào của ARB sẽ là “Phối hợp tối ưu”?
4. Dạng thuốc phối hợp (SPC) nào sẽ là “phối hợp tối ưu” ?
5. Eur Heart J 2007;28:1462-1536
Chiến lược điều trị
ESC Guidelines 2007
Effectively lower BP
Lower
CV
risk 2 Thuốc
???ARB
?SPC
7. Lợi ích của thuốc ức chế men chuyển
(ACEi) trên chuỗi bệnh lý tim mạch đã
được khẳng định rõ
Risk Factors
Diabetes
Hypertension
Atherosclerosis
and LVH
Myocardial
Infarction
Remodelling
Ventricular
Dilatation
Chronic
Heart
Failure
End-Stage
Heart Disease
and Death
Death
CONSENSUS
SOLVD
SAVE ,AIRE
TRACE,SMILE
ISIS 4
GISSI 3
HOPE
CAPP
EUROPA
9. BP Lowering Efficacy Cough
Tỷ lệ ngưng thuốc do tác dụng phụ
Ann Intern Med. 2008;148:16-29.
ARBs hạ huyết áp tương đương nhưng
dung nạp tốt hơn ACEi
10. 10
* Relative to ACE-I after 1 y of treatment
0.5 1.0 2.0
Diuretics
βB
α-blockers
CCBs
ACE-Is
ARBs
1.83
1.64
1.23
1.08
1.00
0.92
- +
Cause-specific HR (95% CI) for discontinuation*
ARBs là thuốc có tỷ lệ tuân trị cao nhất
Corrrao et al. J Hypertens. 2008;26:819–824.
11. Survival,
%
Impact of Medication Therapy Discontinuation on Mortality
Không tuân thủ điều trị là yếu tố gia tăng
nguy cơ tử vong cho bệnh nhân
Discontinuation one month after
myocardial infarction vs.
continued use of at least one
medication
> 10%
Ho et al. Arch Intern Med 166 (2006): 1842-1847
0 1 3 6 9 12
50
55
60
65
70
75
80
85
90
95
100
(n=1521) (n=1509) (n=1487) (n=1475) (n=1450)
Months
Any Medications
0 Medications
12. 12
Heart failure
Hypertension
LIFE
VALUE
VALIANT
CHARM
Val-HeFT
ELITE II
Dzau et al. Circulation. 2006;114:2850–2870; Dzau, Braunwald. Am Heart J. 1991;121:1244–1263;
Yusuf et al. Lancet. 2004;364:937–952; The ONTARGET Investigators. N Engl J Med. 2008;358:1547–1559.
Các bằng chứng về lợi ích của ARB
trên chuỗi bệnh lý tim mạch và thận
CV high risk
ONTARGET® trial programme
Remodelling
MI and
stroke
Cardio/
cerebrovascular
death
ESRD
Nephrotic
proteinuria
Macro-
proteinuria
Micro-
albuminuria
Endothelial
dysfunction
Atherosclerosis
and LVH
Ventricular dilation/
cognitive dysfunction
CHF/
secondary stroke
Risk factors:
hypertension, diabetes,
obesity, smoking, age
1. Sử dụng
ACEi
2. Nếu không
dung nạp
ACEi , sử
dụng các
thuốc ARB
có chỉ định
trên bệnh
nhân sau
MI , Suy
tim
ARB!!!
13. Bài học từ N/C HOPE và
ONTARGET
• Nghiên cứu HOPE chứng minh Ramipril giảm các biến cố tim
mạch độc lập với tác dụng hạ huyết áp
• Nghiên cứu ONTARGET chứng minh Telmisartan giảm biến cố
tim mạch không thua kém Ramipril trên bệnh nhân nguy cơ
tim mạch cao
Ramipril, n=4,645
Placebo, n=4,652
Death from
CV causes MI Stroke
%
risk
reduction
(treatment
vs.
placebo)
–32%
p<0.001
–22%
p<0.001
–26%
p<0.001
–20%
p<0.001
0
–4
–8
–12
–16
–20
–24
–28
–32
–36
–40
Composite
CV endpoint†
High-risk patients; mean baseline SBP/DBP 139/79 mmHg
Years of
follow-up
0.20
0.15
0.05
0.10
0
0 1 2 3 4 5
Cumulative
Hazard
Ratio
Telmisartan
Ramipril
Telmisartan
Ramipril
HOPE ONTARGET
HOPE Study Invest 2000 NEJM (342) 145-53 ONTARGET Investigators. NEJM. 2008;358(15):1547-59.
14. Dữ liệu về lợi ích lâm sàng của chẹn
kênh Ca ( đại diện: Amlodipine )
1Pitt et al. Circulation 2000;102:1503–10; 2Nissen et al. JAMA 2004;292:2217–26; 3Dahlof et al. Lancet 2005;366:895–906;
4Williams et al. Circulation 2006;113:1213–25; 5Leenen et al. Hypertension 2006;48:374–84
PREVENT1
825 coronary heart disease (CAD) patients (≥30%):
Multicentre, randomized, placebo controlled
Primary outcome: No difference in mean 3 yr coronary
angiographic changes vs placebo
35% hospitalization for HF + angina
43% revascularization procedures
CAMELOT2
1,991 CAD patients (>20%): Double-blind,
randomized study vs placebo and enalapril 20 mg
Primary outcome: 31% in CV events vs placebo
42% hospitalization for angina
27% coronary revascularization
ASCOT-BPLA/CAFE3,4
19,257 hypertensive patients: Multicentre,
randomized, prospective study vs atenolol
Primary outcome: 10% in non-fatal MI & fatal CHD
16% total CV events and procedures
30% new-onset diabetes
23% stroke
11% all-cause mortality
central aortic pressure by 4.3 mmHg
ALLHAT5
18,102 hypertensive patients: Randomized,
prospective study vs lisinopril
Primary outcome: No difference in composite of fatal
CHD + non-fatal MI vs lisinopril
6% combined CV disease
23% stroke
15. 15
Lý do của việc phối hợp ARB và CCB trong
điêuc trị bệnh nhân THA
A powerful, complementary combination of 2 proven MOAs
MOA=mechanism of action; ARB=angiotensin II receptor blocker; CCB=calcium channel blocker; BP=blood pressure; Ca=calcium;
RAAS=renin-angiotensin-aldosterone system.
Oparil S and Weber M. Postgrad Med. 2009;121:25-39.
21. ACCOMPLISH: Lợi ích của phối hợp chẹn
RAAS và CCB so với chẹn RAAS và lợi tiểu
Months 0 6 12 18 24 30 36 42
0.16
0.12
0.08
0.04
0
Cumulative
event
rate
0 182 366 547 731 912 1,096 1,277
Benazepril/amlodipine (552 patients with events: 9.6%)
Benazepril/HCTZ (679 patients with events: 11.8%)
Time to first CV mortality/morbidity (days)
HR 0.80 (95%CI 0.72–0.90); p<0.001
Jamerson et al. N Engl J Med 2008;359:241728
20%
Giảm nguy
cơ tương đối
ACCOMPLISH = Avoiding Cardiovascular events through COMbination
therapy in Patients LIving with Systolic Hypertension
22. ACCOMPLISH: Hiệu quả hạ áp trong nghiên cứu
Benazepril/HCTZ
Benazepril/amlodipine
160
140
120
100
80
60
mmHg
0 3 6 12 18 14 30 36 42
Months
N=11,506 (n=5,744 benazepril/amlodipine; n=5,762 benazepril/HCTZ)
The mean SBP/DBP following titration was 131.6/73.3 mmHg in the benazepril/amlodipine group and 132.5/74.4 mmHg
in the benazepril/HCTZ group. The mean difference in SBP/DBP between the 2 groups was 0.9/1.1 mmHg (p<0.001)
Jamerson et al. N Engl J Med 2008;359:241728
? Lợi ích độc lập với hiệu quả hạ
huyết áp ?
23. Thuốc chẹn thụ thể AT1(ARB) giảm hiện
tượng phù ngoại vi do chẹn kênh Ca (CCB)
Opie et al. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:42–73; White et al. Clin Pharmacol Ther. 1986;39:43–48;
Gustaffson. J Cardiovasc Pharmacol. 1987;10:S121–S131; Messerli et al. Am J Cardiol. 2000;86:11821187.
CCB
+ ARB
24. 24
Telmisartan / Amlodipine : phối hợp thuốc làm
giảm phù ngoại vi do CCB
5.2
1.7
17.8
0
5
10
15
20
A10
(n = 124)
T40–80+A5
(n = 264)
Patients
with
peripheral
oedema
(%)
T40–80+A5–A10
(n = 543)
p < 0.0001
p < 0.0001
–90% –71%
Littlejohn et al. J Clin Hypertens. 2009;11:207–213.
25. 2009 Reappraisal of European guidelines on hypertension management:
A ESH Task Force Document. J Hypertens 2009
26. NICE clinical guideline : Clinical management of primary hypertension in adults: updated August 2011
NICE 2011
28. Sự phối hợp “Đúng” !!!
• Phải có tác động hiệp đồng hạ huyết áp
• Giảm được tác dụng phụ
– Cân bằng điện giải (ARB + diuretic)
– Giảm phù (ARB + CCB)
• Mỗi thành phần phải có bằng chứng lâm sàng
giảm các biến cố tim mạch
• Đặc biệt việc kết hợp có thể được trong cùng
một viên thuốc “Single Pill Combination”
(SPC)
29. Compliance: extent to which a patient acts in accordance with the prescribed
interval and dose of dosing regimen (synonym: adherence)
Persistence: accumulation of time from initiation to discontinuation of therapy
Định nghĩa về Sự Tuân Thủ Điều trị
(Compliance) và Khả năng duy trì
điều trị (Persistence)
Prescribed regimen for 12 months
Fully compliant for 12 months
Fully persistent for 12 months
Partial compliance
Non-persistent (stop therapy before 12 months)
Non-compliant and non-persistent
Non-acceptance (does not start therapy)
Timeline
MedicationCompliance and Persistence Special InterestGroup. International Society of
Pharmacoeconomics and Outcomes Research (ISPOR)
30. †Defined as the total number of days of therapy for
medication dispensed/365 days of study follow-up
Gerbino & Shoheiber. Am J Health System Pharm 2007;64:1279–83
Single-pill combination
(amlodipine/benazepril)
(n=2,839)
Free combination
(ACEI + CCB)
(n=3,367)
Medication possession ratio (MPR)†
p<0.0001
88.0%
69.0%
0% 20% 40% 60% 80% 100%
31. Dạng thuốc phối hợp cố định liều
và tuân thủ điều trị của bệnh nhân
Gupta et al. Hypertension 2010;55:399407
Meta-analysis of 15 studies. 3 cohort studies (n=17,642) and two trials (n=357)
reported data on compliance. FDC=fixed-dose combination
Dạng phối hợp cố định liều giúp tăng 21% tỷ lệ
tuân trị của bệnh nhân so với phối hợp các
thuốc riêng rẽ
32. Tính tuân thủ điều trị của các dạng phối
hợp cố định liều
Wanovich et al. Am J Hypertens 2004;17:223A (poster)
Medication-possession ratio
*p<0.0001
* * *
* * * *
Number of concomitant drugs
33. Dạng thuốc phối hợp cùng một viên làm tăng
tuân thủ điều trị trên mọi lứa tuổi
Age group
*p<0.001
Taylor et al. Congest Heart Fail 2003;9:324–32
A large managed care database analysis (n=5,732)
*
*
*
*
Medication
possession
ratio
(%)
34. Hiệu quả giảm huyết áp tốt hơn trên
bệnh nhân tuân thủ điều trị
*p<0.05 vs non-persistent; **p<0.0005 vs non-compliant
§Medication-possession ratio ≥80%; §§Remaining on therapy for 12 months
¶Vs non-compliant or non-persistent patients, respectively
N=982; BP = blood pressure
*
**
*
Additional
reduction
in
BP
¶
(mmHg)
Compliant1§ (n=556) Persistent2§§ (n=862)
Systolic BP
Diastolic BP
1Halpern et al. J Hypertens 2006;24(Suppl. 4):S154
2Halpern et al. J Hypertens 2006;24(Suppl. 4):S182
0.0
–0.5
–1.0
–1.5
–2.0
–2.5
–3.0
–3.5
–4.0
–4.5
35. Compliance with Antihypertensive Therapy
Results in More Patients Achieving Blood
Pressure (BP) Goal (<140/90 mmHg)
Yiannakopoulou et al. Eur J Cardiovasc Prev Rehabil 2005;12:243–9
Compliant Non-compliant
Observational, cross-sectional study (n=1,000)
p<0.005
Patients
achieving
BP
<140/90
mmHg
(%)
36. Nguy cơ tuơng đối của biến cố tim mạch
Tỷ lệ tuân trị
Bệnh nhân tuân trị tốt làm giảm
các biến cố tim mạch
Mazzaglia et al. Circulation 2009;120:1598-1605
50% lower risk of a CV event
(n = 7,624)
(n = 9,666) (n = 1,516)
37. Có thể giảm chi phí y tế khi sử dụng dạng
thuốc phối hợp cố định liều
334 402
1,120 1,322
3,179
410
1,229
1,646
1,952
5,236
0
1000
2000
3000
4000
5000
6000
Hospital
Single-pill combinations (n=2,336)
Free-combination therapy (n=3,368)
Healthcare
costs
(US$)
Other Ambulatory Drug Total
P<0.0001
P<0.0001
P<0.0001
P<0.0001
Not significant
• Total healthcare costs and ambulatory, drug and other costs were all lower among
patients receiving single-pill combination therapy versus free-combination therapy
(P<0.0001)
Dickson M & Plauschinat CA. Am J Cardiovasc Drugs 2008;8:45–50.
38. ACCOMPLISH: Thiết kế nghiên cứu
Benazepril 20 mg +
Amlodipine 5 mg
Free add-on*
Free add-on*
–2 Weeks Day 1 Month 1 Month 2 Year 5
Month 3
Screening
11,506 patients
Forced
titration
*Beta blockers; alpha blockers; clonidine; loop diuretics; HCTZ = hydrochlorothiazide
Target BP <140/90 mmHg;
<130/80 mmHg in patients
with diabetes or renal
insufficiency
Randomization
Follow up at 6 months and
every 6 months thereafter
Prospective, randomized, double-blind,
event-driven trial
Benazepril 40 mg +
Amlodipine 5 mg
Benazepril 40 mg +
Amlodipine 10 mg
Benazepril 20 mg +
HCTZ 12.5 mg
Benazepril 40 mg +
HCTZ 12.5 mg
Benazepril 40 mg +
HCTZ 25 mg
Jamerson et al. J Clin Hypertens 2003;5(4 Suppl 3):29–35
Jamerson et al. Am J Hypertens 2004;17:793–801; Jamerson et al. Blood Press 2007;16:80–6
39. ACCOMPLISH: hiệu quả kiểm soát hiệu áp
tốt của liệu pháp phối hợp
Benazepril/HCTZ
n=5,762
Benazepril/amlodipine
n=5,744
90
80
70
60
50
40
30
20
10
37%
Controlled at
randomization
72%
‡
75%
‡
*Control defined as BP <140/90 mmHg
‡Values calculated from mean BP after titration and mean BP
control rate over the duration of the study.
ACCOMPLISH = Avoiding Cardiovascular events through
COMbination therapy in Patients LIving with Systolic Hypertension
Mean
BP
control
rate
after
titration
(%
patients
<140/90
mmHg)
Jamerson et al. N Engl J Med 2008;359:241728
Jamerson et al. Presented at ACC 2008
38%
Controlled at
randomization
40. Ưu điểm dạng thuốc phối hợp
cùng viên
• Giảm gánh nặng dùng nhiều viên thuốc
– SPC giảm số viên thuốc phải dùng -> cải thiện khả năng
tuân thủ điều trị
– Một số bàn cãi ở các nước đang phát triển về việc viên
thuốc phối hợp (polypill): cần đánh giá lại cost-effective
trong cộng đồng
• Hiệu quả hơn Cải thiện tiên lượng/chất lượng
• Giảm các tác dụng phụ
– SPC khống chế các tác dụng phụ của các nhóm thuốc khác
nhau
• Cải thiện tính cân bằng Cost - Effectiveness
Bangalore S. Current Hypertension Reports 2007, 9:184–189
41. • 2009 European guidelines state:
‘The combination of two antihypertensive drugs
may offer advantages also for treatment initiation,
particularly in patients at high cardiovascular risk in
which early BP control may be desirable’
‘Whenever possible, use of fixed dose (or single
pill) combinations should be preferred, because
simplification of treatment carries advantages for
compliance to treatment’
European Guidelines now Recommend
use of Single-pill Combination Therapy
Mancia et al. Blood Press 2009;18:308–47
42. 43
Các thử nghiệm lâm sàng phối hợp
thuốc giữa Losartan + Amlodipine
Camsylate
43. 44
Losartan + Amlodipine Camsylate FDC*
1.Dose-Finding Study
2.Uncontrolled on Losartan 100 mg* Study
3.Uncontrolled on Amlodipine 5 mg* Study
4.Uncontrolled on Amlodipine 5 mg* Study in Korean patients
* COZAAR XQ, MSD
44. 45
Primary Endpoint
Mean change in siDBP
at 8 weeks
Selected 2nd Endpoints
Mean change in siSBP
at 8 weeks
Response* rates
Safety profile
Losartan + Amlodipine FDC: Dose-Finding Study
Study Design
Objective
Compare the dose-response and efficacy/safety of amlodipine or losartan
monotherapy, and their combination in patients with essential hypertension
Study Design
8-week, phase II, multicenter, randomized, double-blind, factorial design
Data on file, MSD.
2–4 week
placebo
run-in
period
siDBP = sitting diastolic blood pressure
siSBP = sitting systolic blood pressure
Patients
(N = 320)
Adults 18-75 years of age
Mild to moderate essential
hypertension
8 weeks randomized,
double-blind period
Amlo/Losartan FDC
5/50 mg (n = 38)
10/50 mg (n = 43)
5/100 mg (n = 41)
10/100 mg (n = 41)
Amlodipine mono
5 mg (n = 40)
10 mg (n = 39)
Losartan
50 mg (n = 38)
100 mg (n = 40)
*Defined as siSBP<140 mm Hg or
siDBP<90 mm Hg, or change in
siSBP>20 mm Hg from baseline,
or change in siDBP>10 mm Hg
from baseline.
45. 46
Losartan + Amlodipine FDC : Dose-Finding Study
Inclusion and Exclusion Criteria
Data on file, MSD.
Selected Inclusion Criteria
– Adult subjects 18–75 years of age with essential hypertension (DBP ≥95
mm Hg and <115 mm Hg)
Selected Exclusion Criteria
– A difference in sitting systolic BP measurements ≥20 mm Hg or diastolic
BP ≥10 mm Hg between the highest and lowest measurements after 3
measurements
– Systolic BP ≥200 mm Hg
– Known hypersensitivity to dihydropyridine CCBs or ARBs
– Known or suspected secondary hypertension
– Been continuously administered drugs for more than 3 months (other than
anti-hypertensive drugs) that could have affected blood pressure
– Received drugs with possible drug interactions with study drugs
– Diabetes, severe heart disease, renal or liver disease, or other medical
conditions that the investigator deemed could significantly affect the
outcome of the study
– Women who were pregnant or nursing
46. 47
Losartan + Amlodipine FDC* : Dose-Finding Study
Primary Endpoint Results
The change from baseline blood pressure at 8 weeks was P < 0.0001 in each of these 8 treatment arms.
Data on file, MSD
* COZAAR XQ, MSD
–11.7
Amlo/Losartan FDC*
5/50 mg 5/100 mg
–15.6A,B
Mean
change,
mm
Hg
–16.1C,D
–10.5
–16.4
Losartan
50 mg 100 mg
-7
A P < 0.0001 vs losartan 50 mg; B P = 0.0390 vs amlodipine 5 mg;
C P = 0.0027 vs losartan 100 mg; D P = 0.0143 vs amlodipine 5 mg
Amlodipine
5 mg 10 mg
Mean DBP Reductions at 8 weeks (n=320)
Amlo/Losartan FDC*
10/50 mg 10/100 mg
–18.3
–20.8
-20
-16
-12
-8
-4
0
47. 48
The change from baseline blood pressure at 8 weeks was P < 0.0001 in each of the 8 treatment arms.
Data on file, MSD
* COZAAR XQ, MSD
Mean SBP Reductions at 8 weeks (n=320)
Losartan + Amlodipine FDC*: Dose-Finding Study
Additional Efficacy Results
–7
–15.5
–25.7A,B
Mean
change,
mm
Hg
A P < 0.0001 vs losartan 50 mg; B P = 0.0035 vs amlodipine 5 mg;
C P = 0.0229 vs losartan 100 mg; D P = 0.0092 vs amlodipine 5 mg
–24C,D
–23.6
–25.9
–28.7
–16
Amlo/Losartan FDC*
5/50 mg 5/100 mg
Losartan
50 mg 100 mg
Amlodipine
5 mg 10 mg
Amlo/Losartan FDC*
10/50 mg 10/100 mg
-30
-24
-18
-12
-6
0
48. 49
Losartan + Amlodipine FDC*: Dose-Finding Study
Additional Efficacy Results
*The rate of patients who achieved any of the following predefined targets:
1) SBP <140 mm Hg or DBP <90 mm Hg,
2) A reduction in SBP >20 mm Hg from baseline, or a reduction in DBP >10 mm Hg from baseline
Data on file, MSD
* COZAAR XQ, MSD
Response Rates FDC vs. Monotherapies
Amlodipin/Losartan FDC 5/50 mg
(n=38)
86.8%
p-value vs.
components
Amlodipine 5 mg (n=40) 77.5% p=0.3794
Losartan 50 mg (n=38) 50% p=0.0011
Amlodipin/Losartan FDC 5/100 mg
(n=41)
92.7%
p-value vs.
components
Amlodipine 5 mg (n=40) 77.5% p=0.0667
Losartan 100 mg (n=40) 72.5% p=0.0201
50. 51
Losartan + Amlodipine FDC* in Uncontrolled on Losartan 100 mg
Study Design
Objective
Evaluate the efficacy and safety of Amlodipine/Losartan FDC 5/100 mg vs.
losartan 100 mg in patients with essential hypertension inadequately controlled on
losartan 100 mg
Study Design
8-week, multicenter, randomized, double-blind phase III clinical study
Data on file, MSD
*COZAAR XQ, MSD
*siDBP ≥ 90 mm Hg if drug-treated
or ≥ 95 mm Hg if drug-naïve
siDBP = sitting diastolic blood pressure
siSBP = sitting systolic blood pressure
**Defined as siSBP<140 mm Hg or
siDBP<90 mm Hg, or change in siSBP
>20 mm Hg from baseline, or change in
siDBP>10 mm Hg from baseline.
32 days run-in
treatment
period
(losartan 100
mg once daily)
8 weeks randomized,
double-blind period
Patients
(N = 142)
Adults ≥18 years with
essential hypertension
Not controlled* on
losartan 100 mg
monotherapy
Losartan 100 mg
(n = 72)
once daily
Amlo/Losartan FDC
5/100 mg (n = 70)
once daily
Primary Endpoint
Mean change in siDBP
at 8 weeks
Selected 2nd Endpoints
Mean change in siSBP
at 8 weeks
Response** rates
Safety profile
51. 52
Data on file, MSD
Losartan + Amlodipine FDC in Uncontrolled on Losartan 100 mg
Inclusion and Exclusion Criteria
Selected Inclusion Criteria
– Patients 18 years of age or older with essential hypertension (DBP ≥ 90 mm
Hg if drug-treated or ≥ 95 mm Hg if drug-naïve).
– Non-responders to 4 weeks of treatment with losartan 100 mg monotherapy
(sitting DBP≥ 90).
Selected Exclusion Criteria
– Secondary hypertension
– A difference in sitting systolic BP measurements ≥20 mm Hg or diastolic BP
≥10 mm Hg between the highest and lowest measurements after 3
measurements
– Known hypersensitivity to dihydropyridine CCBs or ARBs
– Mean sitting SBP ≥ 200 mm Hg or mean sitting DBP ≥ 120 mm Hg at
screening and mean siSBP ≥ 180 mm Hg or mean sitting DBP ≥ 120 mm Hg
after 4 weeks of losartan potassium 100 mg treatment.
– Clinically significant renal, metabolic, or hepatic disease
– Severe heart disease or severe neurovascular disease
– Uncontrolled diabetes mellitus
– Pregnant or nursing women
52. 53
Data on file, MSD
*COZAAR XQ, MSD
-15
-9
-3
Mean
change
(mm
Hg)
P < 0.0001
–11.7
–3.2 –3.4
–13.4
P < 0.0001
Losartan + Amlodipine FDC* in Uncontrolled on Losartan 100 mg
Mean Reductions in DBP (Primary Endpoint) and SBP
Mean SBP Reductions
Losartan
100 mg
Mean BP Reductions at 8 weeks (N=142)
Losartan
100 mg
Mean DBP Reductions
Amlo/Losartan FDC
5/100 mg
Amlo/Losartan FDC
5/100 mg
53. 54
*The rate of patients who achieved any of the following predefined targets: 1) systolic BP <140 mm Hg or diastolic BP
<90 mm Hg, 2) a reduction in systolic BP >20 mm Hg from baseline, or 3) a reduction in diastolic BP >10 mm Hg from baseline.
Data on file, MSD
*COZAAR XQ, MSD
Losartan + Amlodipine FDC* in Uncontrolled on Losartan 100 mg
Losartan 100 mg Additional Efficacy Results
90%
Losartan
100 mg
66.7%
Amlo/ Losartan FDC
5/100 mg
Patients,
%
Blood Pressure Response Rates*
P < 0.0008
0
20
40
60
80
100
54. 55
Losartan + Amlodipine FDC* in Uncontrolled on Losartan 100 mg
Safety Profile Results (After Randomization)
Amlo/Losartan
FDC 5/100 mg
(n=70)
Losartan
100 mg
(n=72)
P value
Subjects with AEs 21 (30.0%) 16 (22.2%) 0.2911
Number of AEs 25 25
Number of serious AEs 0 1 (1.4%) 0.2306
Severity of AEs
Mild 19 (27.1%) 15 (20.8%) 0.5294
Moderate 2 (2.9%) 1 (1.4%)
Severe 0 0
AEs leading to discontinuation 1 (1.4%) 0 0.4930
Drug-related AEs 5 (7.1%) 9 (12.5%) 0.2844
Deaths 0 0
Data on file, MSD
*COZAAR XQ, MSD
55. 56
Losartan + Amlodipine FDC* in Uncontrolled on Amlodipine 5 mg
Study Design
Objective
Compared the efficacy and safety of Amlodipine/Losartan FDC 5/50 mg to
amlodipine 10 mg in patients with essential hypertension inadequately controlled
on amlodipine 5 mg
Study Design
8-week, multicenter, randomized, double-blind phase III clinical study
Kang S-M et al. Clin Ther 2011;33(12):1953-1963.
*COZAAR XQ, MSD
32 days run-in
treatment period
(amlodipine
camsylate
5 mg daily)
*siDBP ≥ 90 mm Hg if drug-treated or ≥
95 mm Hg if drug-naïve
8 weeks randomized,
double-blind period
siDBP = sitting diastolic blood pressure
siSBP = sitting systolic blood pressure
**Defined as siSBP<140 mm Hg or
siDBP<90 mm Hg, or change in siSBP
>20 mm Hg from baseline, or change in
siDBP>10 mm Hg from baseline.
Amlo/Losartan
5/50 mg (n = 92)
once daily
Primary Endpoint
Mean change in siDBP
at 8 weeks
Selected 2nd Endpoints
Mean change in siSBP
at 8 weeks
Response** rates
Safety profile
Patients
(N = 184)
Adults ≥18 years with
essential hypertension
Not controlled* on
amlodipine
5 mg monotherapy
Amlodipine 10 mg
(n = 92)
once daily
56. 57
Data on file, MSD
Losartan + Amlodipine FDC* in Uncontrolled on Amlodipine 5 mg
Inclusion and Exclusion Criteria
Selected Inclusion Criteria
– Adults aged 18 or older with essential hypertension with uncontrolled essential
hypertension [a sitting DBP ≥90 mm Hg in drug-treated patients and ≥95 mm Hg in
drug-naïve patients]
– Non-responders to 4 weeks of treatment with open-label amlodipine 5 mg
monotherapy (DBP ≥90 mm Hg)
Selected Exclusion Criteria
– Secondary hypertension
– A difference in sitting systolic BP measurements ≥20 mm Hg or diastolic BP
≥10 mm Hg between the highest and lowest measurements after 3 measurements
– Known hypersensitivity to dihydropyridine CCBs or ARBs
– Mean sitting SBP ≥ 200 mm Hg or mean sitting DBP ≥ 120 mm Hg at screening and
mean siSBP ≥ 180 mm Hg or mean sitting DBP ≥ 120 mm Hg after 4 weeks of
amlodipine 5 mg treatment.
– Clinically significant renal, metabolic, or hepatic disease
– Severe heart disease or severe neurovascular disease
– Uncontrolled diabetes mellitus
– Pregnant or nursing women
Kang S-M et al. Clin Ther 2011;33(12):1953-1963.
57. 58
–13.4
Mean
change
(mm
Hg)
Mean DBP Reductions
P = NS
Mean SBP Reductions
Mean BP Reductions at 8 weeks (N=183)
Amlodipine
10 mg
Amlo/Losartan FDC
5/50 mg
Amlodipine
10 mg
Amlo/Losartan FDC
5/50 mg
–8.9
–12.2
–9.4
P = NS
Losartan + Amlodipine FDC* in Uncontrolled on Amlodipine 5 mg
Mean Reductions in DBP (Primary Endpoint) and SBP
-15
-9
-3
Kang S-M et al. Clin Ther 2011;33(12):1953-1963
*COZAAR XQ, MSD
58. 59
*The rate of patients who achieved any of the following predefined targets: 1) systolic BP <140 mm Hg or diastolic BP <90 mm Hg,
2) a reduction in systolic BP >20 mm Hg from baseline, or 3) a reduction in diastolic BP >10 mm Hg from baseline.
89.1%
Amlodipine
10 mg
Patients,
%
Blood Pressure Response Rates*
P < 0. 07960
87.9%
Losartan + Amlodipine FDC* in Uncontrolled on Amlodipine 5 mg
Additional Efficacy Results
0
20
40
60
80
100
Kang S-M et al. Clin Ther 2011;33(12):1953-1963.
Amlo/Losartan FDC
5/50 mg
59. 60
Losartan + Amlodipine FDC* in Uncontrolled on Amlodipine 5 mg
Safety Profile Results
Amlo/Losartan FDC
5/50 mg
(n=92)
Amlodipine
10 mg
(n=92)
P value
Subjects with AEs 20 (21.7%) 24 (26.1%) 0.49
Number of AEs 38 31 -
Number of serious AEs 1 (1.1%) 1 (1.1%) 1.00
Severity of AEs 0.6907
Mild 15 (16.3%) 21 (22.8%)
Moderate 3 (3.3%) 2 (2.2%)
Severe 2 (2.2%) 1 (1.1%)
AEs leading to discontinuation 0 2 (2.2%) 0.50
Drug-related AEs 6 (6.5%) 10 (10.9%) 0.30
Deaths 0 0
Kang S-M et al. Clin Ther 2011;33(12):1953-1963.
60. Thuốc chẹn thụ thể AT1 trong liệu
pháp phối hợp thuốc: Kết luận
• Cần kiểm soát huyết áp tốt /mục tiêu huyết áp thấp hơn trên
bệnh nhân nguy cơ tim mạch cao như ĐTĐ , tiền sử bệnh tim
mạch .
• Liệu pháp phối hơp thuốc ( ngay từ đầu) giúp cho kiểm soát
huyết áp tốt trên những bệnh nhân nguy cơ cao.
• Phối hợp của chẹn thụ thể AT1 (ARB)là lựa chọn tối ưu( đặc biệt
là phối hợp giữa ARB + CCB)
• Tiêu chí lựa chọn phối hợp giữa ARB và CCB gồm
– Dung nạp tốt
– Hiệu quả kiểm soát huyết áp 24h
– Đã có chứng minh về hiệu quả bảo vệ tim mạch của cac thuốc trong thành
phần phối hợp.
61. Làm thế nào tối ưu hóa liệu pháp chẹn thụ thể
AT1 trên bệnh nhân tăng huyết áp?: Kết luận
Dạng thuốc phối hợp cố định liều là bước tiến trong
quản lý tăng huyết áp trong thập niên vừa qua.
Phối hợp thuốc cùng viên (SPC) là một “bước
nhảy vọt” duy nhất trong điều trị THA thời
gian qua:
chiến lược duy nhất được chứng minh làm giảm huyết áp
hơn nữa
thông qua cơ chế compliance/persistence
giảm giá thành / nhập viện
giảm các biến cố tim mạch !!!!!!