1. Pgs.TS. NguyÔn Quang TuÊn, FACC, fscai ViÖn tim m¹ch ViÖt nam
TĂNG HUYẾT ÁP VÀ
BỆNH ĐỘNG MẠCH VÀNH
This presentation aims at reviewing the available information about the cardiovascular tolerability of Procoralan, the first selective and specific If inhibitor. As we will see, the majority of the studies included have been performed in well-adapted and validated animal models, to assess the optimal preservation of cardiovascular function with Procoralan treatment.
Pgs.TS. NguyÔn Quang TuÊn, FACC, fscai
ViÖn tim m¹ch ViÖt nam

2. THA gánh nặng toàn cầu 333 413 639 1.15B 300 400 500 600 700 1.15 B
Developed Countries
Developing Countries
2000
2025 (projected)
Millions
24% increase
60% increase
Kearney PM et al. Lancet. 2005;365:

3. Peripheral vascular disease
Biến chứng của THA
Hypertension
TIA, stroke
LVH, CHD, HF
Retinopathy
Renal failure
Peripheral vascular disease
Valsartan, valsartan + HCTZ, and amlodipine besylate/benazepril HCl are not indicated for the treatment or prevention of target organ damage.
Hypertension is an important contributing risk factor for end-organ damage and subsequent increases in morbidity and mortality. The goal in treating hypertension is to prevent CV and renal complications. Even small elevations above optimal BP values (< 120/80 mm Hg) increase the likelihood of developing hypertension (BP ≥ 140/90 mm Hg) and incurring target organ damage.
Chronic elevations of BP lead to target-organ damage and the development of CV and renal diseases, including retinopathy, peripheral vascular disease, stroke, CHD, heart failure, left ventricular hypertrophy, and renal failure.
Signs of target organ damage herald a poorer prognosis and may present in the heart, blood vessels, kidneys, brain, or eyes. Later consequences include cardiac, cerebrovascular, vascular, and renal morbidities, and death.
Because of the complex nature of hypertension, it is not surprising that single antihypertensive agents normalize BP for less than a majority of hypertensive patients.
Reference
Cushman WC. J Clin Hypertens. 2003;5(suppl):14-22.
Cushman WC. J Clin Hypertens. 2003;5(suppl):14-22.

4. Nguy c¬ bÞ bÖnh §MV thÊp h¬n ë bÖnh nh©n ®­îc ®iÒu trÞ THA
Veterans Administration, 1967
Veterans Administration, 1970
Hypertension Stroke Study, 1974
USPHS Study, 1977
EWPHE Study, 1985
Coope and Warrender, 1986
SHEP Study, 1991
STOP-Hypertension Study, 1991
MRC Study, 1992
Syst-Eur Study, 1997
Total
0.79 (0.69 to 0.90)
0.5
1.0
1.5
2.0
Tèt h¬n gi¶ d­îc
KÐm h¬n gi¶ d­îc
He J et al. Am Heart J 1999; 138:

5. với tỷ lệ tử vong do bệnh ĐMV
Liên quan giữa HA
với tỷ lệ tử vong do bệnh ĐMV
SBP
DBP
Age at risk:
256
256
80-89 y
128
128
70-79 y 64 64
60-69 y 32 32
IHD mortality
(floating absolute risk and 95% CI)
50-59 y 16 16
40-49 y 8 8 4 4 2 2 1 1
120
140
160
180 70 80 90
100
110
Usual SBP (mm Hg)
Usual DBP (mm Hg)
IHD, ischemic heart disease.
Prospective Studies Collaboration. Lancet. 2002;360:

6. THA là một trong các bội số quan trọng của nguy cơ tim mạch
Huyết áp >140/90 mmHg làm xuất hiện:
69% NMCT lần đầu tiên
74% số ca bệnh tim do mạch vành
77% đột quỵ lần đầu
91% số ca suy tim
tử vong năm 2003
$63,5 tỷ hàng năm (chi phí trực tiếp/gián tiếp)
Valsartan, valsartan + HCTZ, and amlodipine besylate/benazepril HCl are not indicated for the treatment or prevention of target organ damage.
Hypertension is an important contributing risk factor for end-organ damage and subsequent increases in morbidity and mortality. The goal in treating hypertension is to prevent CV and renal complications. Even small elevations above optimal BP values (< 120/80 mm Hg) increase the likelihood of developing hypertension (BP ≥ 140/90 mm Hg) and incurring target organ damage.
Chronic elevations of BP lead to target-organ damage and the development of CV and renal diseases, including retinopathy, peripheral vascular disease, stroke, CHD, heart failure, left ventricular hypertrophy, and renal failure.
Signs of target organ damage herald a poorer prognosis and may present in the heart, blood vessels, kidneys, brain, or eyes. Later consequences include cardiac, cerebrovascular, vascular, and renal morbidities, and death.
Because of the complex nature of hypertension, it is not surprising that single antihypertensive agents normalize BP for less than a majority of hypertensive patients.
Reference
Cushman WC. J Clin Hypertens. 2003;5(suppl):14-22.
Adapted from Thom T et al. Circulation. 2006;113:e85–e151.

7. Thật vậy, những biểu đồ này cho thấy nhịp tim tăng sẽ kéo theo sư tăng mức tiêu thụ oxy của cơ tim đồng thời làm giảm thời gian tưới máu thì tâm trương. Mà chúng ta đều biết, sự tưới máu cho mạch vành chỉ xảy ra trong thời kỳ tâm trương. Do đó thời gian tâm trương giảm sẽ dẫn đến việc cung cấp oxy cho cơ tim cũng giảm theo rõ rệt.

8. Hạ huyết áp là vấn đề then chốt
[1/Lewington/ p 1912/C 1/P2/ ln 7-24, p 1903/C 2/p 1/ln 1-3, P 2/ln 1-2, Appendix A, References to Studies]
Meta-analysis of 61 prospective, observational studies*
1 million adults
12.7 million person-years
Giảm 7% nguy cơ tử vong bệnh tim thiếu máu cục bộ
Giảm 2 mm Hg HATTh trung bình
Giảm 10% nguy cơ tử vong do đột quỵ
SLIDE SUMMARY: BP REDUCTION IS IMPORTANT; EVEN A LITTLE GOES A LONG WAY
Perhaps most striking are the practical implications of these data: even a small, 2 mm Hg fall in mean systolic BP would be associated with large absolute reductions in premature deaths and disabling strokes.1 As shown here, a 2 mm Hg lower mean systolic BP could lead to a 7% lower risk of IHD death and a 10% lower risk of stroke death1
Data from a meta-analysis of 61 prospective, observational studies provide powerful evidence that throughout middle and old age, BP is strongly and directly related to vascular mortality.1 For example, a 10 mm Hg lower systolic BP is associated over the long term with a 40% lower risk of stroke death and a 30% lower risk of death from ischemic heart disease (IHD) or other vascular causes1
Within each decade of life between 40 and 89 years, the proportional difference in the risk of vascular death associated with a given absolute difference in mean BP is roughly equivalent down to at least 115 mm Hg for systolic BP and 75 mm Hg for diastolic BP (below this level there is little evidence). Thus, there was no evidence of a J curve across all middle and older age groups1
The investigators included studies in data on blood pressure, blood cholesterol, date of birth (or age) and sex had been recorded at baseline and in which a cause and date of death had been sought by study screeners. 33 of the studies were done in Europe (eg, the British Regional Heart Study, the Scottish Heart Health Study, the Tromso Study, assessing the association between blood pressure and serum lipids) 18 in North American or Australia (eg, the Atherosclerotic Risk in Communities Study, the Minnesota Heart Health Program) and 10 studies in China or Japan (eg, the Seven Cities China study on stroke prevention)1
[1/Lewington/ p 1912/C 1/P2/ ln 7-24]
[1/Lewington/ p 1903/Abstract/ Findings]
*Epidemiologic studies, not clinical trials of HTN agents.
BP, blood pressure; IHD, ischemic heart disease.
Lewington S et al. Lancet 2002;360:
[1/Lewington/p 1904/C 1/P 3/ln2-6,
/Appendix A, Table A]
Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. 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:

9. Môc tiªu: <140/90 mmHg hoÆc <130/80 nÕu §T§ hay suy thËn m¹n
KiÓm so¸t huyÕt ¸p
Môc tiªu: <140/90 mmHg hoÆc <130/80 nÕu §T§ hay suy thËn m¹n
HuyÕt ¸p  120/80 mmHg:
B¾t ®Çu vµ duy tr× thay ®æi lèi sèng: kiÓm so¸t träng l­îng c¬ thÓ , t¨ng ho¹t ®éng thÓ lùc, uèng r­îu võa ph¶i, ¨n nh¹t, ¨n nhiÒu rau qu¶ t­¬i vµ c¸c s¶n phÈm Ýt chÊt bÐo.
Smoking: Goal complete cessation. No exposure to environmental tobacco smoke.
· Ask about tobacco use status at every visit. I (B)
· Advise every tobacco user to quit. I (B)
· Assess the tobacco user’s willingness to quit. I (B)
· Assist by counseling and developing a plan for quitting. I (B)
· Arrange follow-up, referral to special programs, or pharmacotherapy (including nicotine
replacement and buproprion). I (B)
· Urge avoidance of exposure to environmental tobacco smoke at work and home. I (B)
HuyÕt ¸p  140/90 mmHg (hoÆc130/80 ë bÖnh nh©n §T§ hay suy thËn m¹n)
B¾t ®Çu ®iÒu trÞ b»ng thuèc chÑn bªta vµ/hoÆc ¦CMC cã thÓ phèi hîp thªm c¸c thuèc kh¸c nh­ lîi tiÓu thiazides nÕu cÇn ®Ó ®¹t ®­îc huyÕt ¸p môc tiªu.

10. Thay ®æi lèi sèng trong kiÓm so¸t HA
Môc tiªu
¦íc tÝnh thay ®æi HA t©m thu
Gi¶m c©n
Duy tr× träng l­îng c¬ thÓ hîp lý (BMI=18,5-22,9)
5-20 mmHg/10 kg
ChÕ ®é ¨n
ChÕ ®é ¨n giµu ra qu¶, Ýt chÊt bÐo
8-14 mmHg
Gi¶m muèi
<2,4 gram muèi mçi ngµy
2-8 mmHg
Ho¹t ®éng thÓ lùc
TËp luyÖn thÓ lùc Ýt nhÊt 30 phót mçi ngµy, Ýt nhÊt 5 ngµy mçi tuÇn
4-9 mmHg
Uèng r­îu võa ph¶i
<2 ly r­îu/ngµy víi nam giíi vµ <1 ly r­îu/ngµy víi n÷ giíi
2-4 mmHg
Chobanian AV et al. JAMA. 2003;289:

11. Các thuốc điều trị THA Hiệu quả và sự dung nạp
1940’s ’s 1970’s 1980’s 1990’s 2000
Peripheral sympatholytics
Ganglion blockers
Veratrum alkaloids
Direct vasodilators
Thiazide diuretics
Central 2 agonists
Calcium antagonists-non-DHPs
Beta-blockers
Alpha- blockers
Calcium antagonists- DHPs
ACE inhibitors
ARBs
Based on the clearly established need to control BP in hypertensive patients, there has been an evolution of antihypertensive medications, starting with vasodilators and diuretics and leading to the more recent development of agents that directly inhibit the renin-angiotensin-aldosterone system, such as ACE inhibitors and angiotensin II receptor blockers (ARBs).
The more recently developed agents have generally proven to be better tolerated than older agents while still maintaining a high degree of efficacy, thus potentially leading to increased control rates among patients with hypertension. ARBs have demonstrated placebo-like tolerability.
DHP, dihydropyridine; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker

12. Blood Pressure Lowering Treatment Trialists Collaboration (BPLTTC)
Institute
for
International
Health

13. Trials Contributing to Meta-Regressions
29 trials, n= 162,341
AASK
ABCD (H)
ABCD (N)
ALLHAT
ANBP2
CAPPP
CONVINCE
ELSA
HOPE
HOT
IDNT
INSIGHT
JMIC-B
LIFE
NICOLE
NICS-EH
NORDIL
PART-2
PREVENT
PROGRESS
QUIET
RENAAL
SCAT
SCOPE
SHELL
STOP-2
SYST-EUR
UKPDS-HDS
VHAS
Turnbull F. Lancet. 2003;362:1527–35.

14. BPLTTC: Tãm l¹i
Similar net effects on total cardio-vascular events of:
ACE inhibitors
Calcium antagonists
Diuretics/beta-blockers
ARBs also effective in reducing total cardiovascular events.
Turnbull F. Lancet. 2003;362:1527–35.

15. Blood Pressure Lowering Treatment Trialists’ Collaboration Second cycle of overview analyses
Meta-regressionsTrials
including randomisation to an ACE inhibitor arm or an ARB arm
Strauss MH et al. Eur Heart J. 2005;362:2351–53

16. Trials Contributing to Meta-Regressions
21 studies, 137,356 participants
RENAAL
SCAT
SCOPE
STOP-2
UKPDS-HDS
VALUE
PEACE
DIAB-HYCAR
EUROPA
HOPE
IDNT
JMIC-B
LIFE
PART-2
AASK
ABCD (H)
ABCD (N)
ALLHAT
ANBP2
CAPPP
PROGRESS
Strauss MH et al. Eur Heart J. 2005;362:2351–53

17. B»ng chøng tõ c¸c ph©n tÝch tæng hîp
William J. Elliott et al. Circulation. 2006;113:

18. B»ng chøng tõ c¸cph©n tÝch tæng hîp
Martin H.Strauss et al. Circulation 2006;114:

19. B»ng chøng tõ c¸c ph©n tÝch tæng hîp BP-independent effect
ACE-Is
BP-independent effect
Stroke
RRR = -2% (8% to -13%) HF
RRR = 5% (15% to -5%)
Stroke p=0.6
CHD
RRR = 9% (14% to 3%)
ARBs
HF p=0.6
CHD
p=0.002
Stroke
RRR = 1% (18% to -20%) HF
RRR = 17% (38% to -12%)
CHD
RRR = -8% (17% to -39%)
30%
20%
10% 0%
10%
20%
30%
Risk Decrease
Risk Increase
Adapted from JHypertens.2007;25:

20. Sripal Bangalore et al., BMJ 2011; 342:d2234
doi: /bmj.d2234

21. KHUYẾN CÁO THUỐC ƯCMC
Bệnh nhân BMV có THA, suy tim, RL chức năng thất trái, tiền sử NMCT hay ĐTĐ (class I, level of evidence A)
Tất cả bệnh nhân ĐTN và có BMV dựa trên lợi ích mang lại so với giá thành và nguy cơ bị tác dụng phụ (class IIa, level of evidence B)
Nên sử dụng các thuốc và liều đã được chứng minh là có hiệu quả trong phòng ngừa thứ phát.
Guidelines on the management of stable angina. Eur Heart J 2006;27:

22. But more importantly this analysis showed a significant 46% reduction in all-cause mortality in comparison of Cov + CCB vs CCB alone.
(n.b. comparison of patients receiving placebo/placebo vs CCB + Coversyl had a 64% reduction of mortality)
Bertrand ME, Ferrari R, Remme WJ, Simoons ML, Deckers JW, Fox KM. Clinical synergy of perindopril and calcium-channel blocker in the prevention of cardiac events and mortality in patients with coronary artery disease. Post hoc analysis of the EUROPA study. Am Heart J. 2010;159:

23. Giảm tử vong trên bệnh nhân sau NMCT
Keát quaû toát töø:
Metoprolol
p=0.024
Placebo 10 20 30 40 50 60 70 80 90
Day after entry
Cumulative number of
deaths
- Metoprolol study, Sweden
Hjalmarson et al, Lancet 1981
0.25
0.05
0.10
0.15
0.20
Cumulative Mortality Rate 6 36 30 24 18 12
Months of Follow-up
Placebo
Timolol
p=0.0001
- Timolol study, Norway
Norwegian Study Group, N Engl J Med 1981 36
Cumulative Mortality Rate (%) 30 24 18 12 6 14 4 8 10 2
Months of Follow-up
Placebo
Propranolol
p=0.005
- Propranolol study, USA
BHAT Research group, JAMA 1982
(taát caû caùc öùc cheá beta aùi môõ)

24. Nghieân cöùu MAPHY Toång töû vong Ñoät töû Giaûm nguy cô 22%
Töû vong coäng doàn
Töû vong coäng doàn 90 50
Lôïi tieåu
Lôïi tieåu
p=0.028 70 40
p=0.017
Metoprolol
Metoprolol 30 50 20
Giaûm nguy cô 22%
Giaûm nguy cô 30% 20 10 5 10 5 10
Thôøi gian (naêm)
Thôøi gian (naêm)
Wikstrand J et al JAMA 1988
Olsson G et alAm J Hypertens 1991

25. Nghieân cöùu MAPHY
Bieán coá töû vong + khoâng töû vong (thôøi gian ñeán bieán coá ñaàu tieân)
160 40 20 60
100 80
120
140
Bieán coá maïch vaønh
Lôïi tieåu
p=0.0010
Metoprolol
Giaûm nguy cô 24%
Töû vong coäng doàn
Bieán coá ñoät quî
Lôïi tieåu
Metoprolol 5 10
Thôøi gian, naêm
Wikstrand et al, Hypertension 1991;17;579-88

26. Giảm ĐỘT TỬ sau NMCT với METOPROLOL
[Tổng hợp từ 5 nghiên cứu Amsterdam, Belfast, Gothenburg, Stockholm and LIT (n=5474)]
120 90 80
Placebo 70
100
(n=2721) 60 50 40
p=0.002 80 30
Nam (n=4353) 20
Tử vong cộng dồn 10
Metoprolol 60
(n=2753) 1 2 3 20 40
Trên bệnh nhân NMCT, trong 1 nghiên cứu gộp từ 5 nghiên cứu của Metoprolol trên gần bệnh nhân đã cho thấy, Metoprolol giúp giảm tỉ lệ đột rất có ý nghĩa thông kê so với nhóm giả dược.
Kết quả của nghiên cứu gộp cho thấy, Metoprolol giúp giảm tử vong và biến cố tim mạch trong phòng ngừa thứ phát bệnh mạch vành 15 20 10 5
Nữ (n=1121) 1 2 3
Năm 1 2 3
Olsson G et al, Eur Heart J 1992;13:28-32 26

27. Tæng hîp c¸c nghiªn cøu phßng ngõa thø ph¸t cña thuèc chÑn bªta
Tæng sè BN
RR (95% CI)
Trong giai
®o¹n cÊp
28.970
0,87 (0,77-0,98)
Sau NMCT
24.298
0,77 (0,70-0,84)
Chung
53.268
0,81 (0,75-0,87)
0,5
1,0
2,0
Nguy c¬ t­¬ng ®èi bÞ TV
ChÑn bªta tèt h¬n
Gi¶ d­îc tèt h¬n
Antman E, Braunwald E. Acute Myocardial Infarction. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease: A textbook of Cardiovascular Medicine, 6th ed., Philadelphia, PA: W.B. Sanders, 2001, 1168.

28. Bệnh động mạch vành Cung Cầu Khẩu kính ĐMV Tần số tim Áp lực tưới máu
Nồng độ Hb
Thời gian TTr
Cầu
Tần số tim
Co bóp cơ tim
Tiền gánh
Hậu gánh

29. Lîi Ých cña gi¶m tÇn sè tim
ë bÖnh nh©n MV
As you know, heart rate reduction is beneficial for patients with stable angina. By reducing heart rate, the oxygen consumption is decreased and also oxygen supply increased, at peak exercise, as you can see on the slide.
Kop W, et al. J Am Coll Cardiol. 2001;38:742.

30. Lîi Ých cña gi¶m tÇn sè tim ®èi víi tiªn l­îng bÖnh nh©n MV
 Taàn soá tim
Löïc caêng thaønh ñoäng maïch
Hình thaønh caùc sang thöông xô vöõa ñoäng maïch veà laâu daøi
Vôõ maûng xô vöõa
Ces observations peuvent s’expliquer par l’amélioration de la balance apports/besoins myocardiques en oxygène, mais également par le mécanisme suivant:
On sait qu’une augmentation de la fréquence cardiaque augmente le stress pariétal subi par les artères, notamment coronaires. Ceci concoure au développement de lésions athéroscléreuses au long cours, responsables de la maladie ischémique chronique (l’angor stable).
L’augmentation du stress sur les parois artérielles est également responsable de ruptures ou fissurations de plaques d’athérome, à l’origine d’un syndrome coronaire aigu (infarctus du myocarde ou angor instable).
Ainsi, la réduction de la fréquence cardiaque, en plus d’améliorer la balance apports/besoins myocardiques en oxygène, va diminuer le stress subi par les parois artérielles. Ce qui va être bénéfique dans la maladie ischémique chronique et sur le risque de syndrome coronaire aigu.
Beänh tim TMCB maïn
(ÑTN oån ñònh)
Hoäi chöùng maïch vaønh caáp
(NMCT, ÑTN khoâng oån ñònh)
Palatini P. Eur Heart J supplements 1999 (Suppl B):B3-B9

31. Gi¶m tÇn sè tim sÏ lµm gi¶m tö vong do tim
Post-MI
Gi¶m tÇn sè tim sÏ lµm gi¶m
tö vong do tim
A meta-regression of randomized clinical trials
This meta-regression analysis includes randomised trials in post-MI patients treated with beta-blockers for duration of 9 months to 2 years. HR reduction was significantly associated with reduction in the odds ratio of cardiac death (figure), sudden death (p<0.01) and reinfarction (p<0.01). This data robustly demonstrate that the beneficial effect of beta blockers in post MI is related to HR reduction and is proportional to the extent of HR reduction.
Each 10 bpm HR reduction = 26% cardiac death reduction
Cucherat M et al. Eur Heart J. 2006, 27(Abstract Suppl):590.

32. In the treatment of stable angina,
it is conventional to adjust the dose of beta-blockers to reduce heart rate at rest to 55 to 60 beats per min.
ACC/AHA Guideline for
the Management of Chronic Stable Angina
J AM Coll Cardiol. 2003;41:

33. Thoái triển = Phòng ngừa
Liên quan giữa tiến triển của xơ vữa động mạch khảo sát qua IVUS và các biến chứng tim mạch 60
Thoái triển = Phòng ngừa 50 40 30 20
Annualized Change in Plaque + Media Cross-Sectional Area (%) 10
-10
-20
-30
Key Point: In this serial IVUS study, patients with adverse CV events (eg, MI, unstable angina, or percutaneous intervention [PCI] of new lesion) had more annual plaque progression compared with patients who experienced no adverse CV events.
Currently, data linking changes in IVUS parameters with clinical outcomes are limited. In this serial IVUS study, von Birgelen and colleagues compared the rate of atherosclerotic progression assessed by serial IVUS evaluations and the estimated risk scores for clinical events in 56 patients with established atherosclerosis. Information on the rate of adverse CV events in these patients was also collected, which is the focus of this slide.
During a mean 18 months of follow-up, 5 patients had an acute MI, 7 had unstable angina, and 6 had PCI of new de novo lesions. This slide illustrates the annual changes in plaque plus media cross-sectional area and the reports of adverse CV events for each of the 56 patients. The 18 patients who experienced adverse events had more atherosclerotic progression than the rest of the population (25.2% vs 5.9%, P<0.001) but showed no difference in the length of follow-up.
-40
Individual Patients (n=56)
Myocardial infarction (n=5)
PCI of new de-novo lesion (n=6)
Unstable angina (n=7)
No events (n=36)
Observational study of plaques in left main coronary arteries of patients with established atherosclerosis. PCI=percutaneous catheter intervention. Adapted with permission from von Birgelen C, et al. Circulation. 2004;110:
Reference
von Birgelen C, Hartmann M, Mintz GS, et al. Relationship between cardiovascular risk as predicted by established risk scores versus plaque progression as measured by serial intravascular ultrasound in left main coronary arteries. Circulation. 2004;110:

34. Thoái triển = Phòng ngừa
~Sub analysis of Extended-ESTABLISH study~
Cumulative event free survival in patients with ACS
1.0
0.9
0.8
0.7
0.6
Cumulative event free survival
0.5
Long-rank test: P=0.032
0.4
0.3
regression group
progression group
0.2
0.1
0.0
This is a sub analysis of the Extended-ESTABLISH study. The purpose of the ESTABLISH study was to investigate the atherosclerosis regression effect of aggressive lipid-lowering therapy by atrovastatin in Japanese ACS patients. As a result. aggressive lipid-lowering therapy could induce a significant reduction in plaque volume. The results of this study were published in Circulation in 2004.
The Extended-ESTABLISH study is a follow-up study of ESTABLISH study which investigates how changes in plaque volume such as progression or regression determined by IVUS influences clinical outcomes after ACS.
In this follow-up study, patients were divided into either regression or progression. As a result of analysis. it became clear that coronary plaque regression or progression influenced clinical outcomes. These data also show that regressing atherosclerosis is important to prevent CV events .
This messages is similar to Steve Nicholls’s report, but the ESTABLISH study is an “of Japanese, by Japanese, for Japanese”study !
To sum up, I have to say that regression of atherosclerosis is needed to prevent CV events for all Japanese people.
500
1000
1500
2000
2500
Days of Follow-up
The patients were enrolled if a change of 6 months in the site of the proximal reference from an ACS culprit lesion could be precisely measured by IVUS. The exclusion criteria were death and cardiovascular events before follow-up IVUS and repeat revascularization therapy at follow-up IVUS.
〔Daida H. et al,2009〕

35. Thoái triển = Phòng ngừa
A direct relationship was observed between the burden of coronary atherosclerosis
Baseline plague volume
1.3 Q1 Q2 Q3 Q4
Lowest ↑ ↓
Highest
1.2
1.1
More MACE
Odds ratio
1.0
Fewer MACE
0.9
Athero
regression
Athero
progression
Đây là bài báo mới nhất của Steve Nicholls công bố trên tạp chí JACC của Mỹ năm 2010.
Bài báo này là một phân tích gộp dữ kiện của 6 thử nghiệm lâm sàng khảo sát xơ vữa động mạch bằng IVUS trên tổng số 4,000 bệnh nhân nhằm tìm hiểu mối liên hệ giữa xơ vữa động mạch và kết cục lâm sàng.
Biểu đồ trên cho thấy rằng sự thoái triển mảng xơ vữa đóng vai trò quan trọng trong phòng ngừa biến cố tim mạch ! Không những vậy, những bệnh nhân nằm trong nhóm tứ phân vị Q1 hưởng lợi nhiều hơn nhiều hơn nhóm Q4 ! Điều này có nghĩa là không chỉ thoái triển mảng xơ vữa mà can thiệp điều trị mảng xơ vữa sớm rất quan trọng trong việc phòng ngừa biến cố tim mạch !
Như vậy, xin nhắc lại một nguyên lý tuy đã cũ nhưng vẫn còn rất hợp thời : điều trị xơ vữa động mạch “càng thấp và càng sớm thì càng tốt”
Cho đến nghiên cứu này của Nicholls, các dữ liệu về mối liên hệ giữa tiến trình xơ vữa động mạch và kết cục lâm sàng mặc dù đã có và khá thuyết phục nhưng vẫn còn khá ít. Tuy nhiên, một điều rõ ràng là các nghiên cứu đó cùng với nghiên cứu này của Nicholls đã chứng minh được mối liên hệ giữa điều trị tích cực hạ LDL, tăng HDL sẽ giúp đẩy lùi và thoái triển mảng xơ vữa, cải thiện được dự hậu lâm sàng.
As you know, This is the latest report published by Steve Nicholls two months ago.
This report presents pooled data from 6 IVUS clinical trials involving about 4,000 patients and explores relationships between atherosclerosis and CV events.
This data shows that regressing atherosclerosis is very important to prevent CV events ! Moreover, patients in the lowest quartiles of baseline PAV(Q1) gain greater risk reduction rate than Q4 ! It means that not only regressing atherosclerosis but also early intervention in plaque is very important for preventing CV events !
To sum up, starting Atherosclerosis Regression Therapy is “the earlier & the sooner , the better ”
Until this report, there have been few data about the relationships between atherosclerosis and CV events. We have been looking forward to seeing new data such as this for a long time.
We believe this manuscript will be very useful for getting agreement from Drs that atherosclerosis regression is needed to prevent CV events. Actually, a lot of Japanese KOLs are interested in this ! But unfortunately this is a Western report. Of course, Japanese Drs require Japanese data such as this.
Next, I’ll introduce some Japanese data that shows a relationship between atherosclerosis and CV events among Japanese people.
0.8 -4 -2 2 4
Annual Change Percent Atheroma Volume （％）
Nicholls SJ et al. J Am Coll Cardiol. 2010;55:

36. Baèng chöùng cô baûn cuûa thuoác öùc cheá beâta Caùc thöû nghieäm sieâu aâm noäi maïch
REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) study
CAMELOT (Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis) IVUS study
ACTIVATE study (ACAT Intravascular Atherosclerosis Treatment Evaluation)
ASTEROID study (A Study To Evaluate the Effect of Rosuvastatin On Intravascular Ultrasound-Derived Coronary Atheroma Burden)
REVERSAL evaluated the effects of moderate vs. intensive lipid lowering with statins, the CAMELOT IVUS study examined the effects of a calcium-channel blocker (amlodipine) and an angiotensin-converting enzyme inhibitor (enalapril), ACTIVATE evauluated the effect of the acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, pactimibe and ASTEROID evaluated the effect of very-high intensity lipid-lowering with rosuvastatin on the progression rate of coronary atherosclerosis. However, no study has systematically evaluated the potential coronary anti-atherosclerotic effects of ß-blockers utilizing IVUS or any other modality allowing the direct quantification of plaque volume over-time.

37. Söû duïng thuoác öùc cheá beâta trong caùc thöû nghieäm
Khoâng öùc cheá beâ-ta
Giaù trò P
REVERSAL
0.82
Atorvastatin 80 mg/ngaøy
176 (71.5%)
70 (28.5%)
Pravastatin 40 mg/ngaøy
179 (72.5%)
68 (27.5%)
Total (n=493)
355 (72%)
138 (28%)
CAMELOT IVUS Substudy
0.44
Amlodipine 10 mg/ngaøy
73 (80.2%)
18 (19.8%)
Enalapril 20 mg/ngaøy
70 (79.5%)
18 (20.5%)
Placebo
81 (86.2%)
13 (13.8%)
Toång coäng (n=273)
224 (82.1%)
49 (17.9%)
ACTIVATE
0.98
Pactimibe 100 mg/ngaøy
150 (74.3%)
52 (25.7%)
148 (74.4%)
51 (25.6%)
Toång coäng (n=401)
298 (74.3%)
103 (25.7%)
ASTEROID
N/A
Rosuvastat 40 mg/ngaøy (n=348)
277 (79.6%)
71 (20.4%)
Coäng 4 thöû nghieäm (n=1515)
1154 (76.2%)
361 (23.8%)
Of the total study population comprised of 1515 patients, 76% were on concomitant ß-blocker treatment during the trials (72% in REVERSAL, 82% in CAMELOT IVUS study, 74% in ACTIVATE and 80% in ASTEROID). The frequency of concomitant ß-blocker treatment was not significantly different in the different arms of individual studies Metoprolol was the most commonly used ß-blocker in all four studies about 50%( followed by atenolol (about 25%).
Ann Intern Med. 2007;147:10-18.

38. Coù öùc cheá ß so vôùi khoâng öùc cheá ß Caùc keát quaû sieâu aâm noäi maïch
ÖÙc cheá ß (n=1154)
Khoâng öùc cheá ß (n=361)
Giaù trò P
Theå tích khoái xô vöõa ban ñaàu (mm3)
Trung bình ± ÑLC
198.4±84.3
199.5±84.8
0.77*
Theå tích khoái xô vöõa qua theo doõi (mm3)
194.7±82.6
199.2±83.3
0.016†
Giaù tri P (so vôùi ban ñaàu)
<0.0001†
0.86†
Thay ñoåi veà theå tích khoái xô vöõa (mm3/naêm)
Trung bình bình phöông toái thieåu ± ÑLC
-2.4±0.5
-0.4±0.9
0.034‡
* Mann-Whitney test
† Linear regression model with baseline values and histories of hypertension, angina, and myocardial infarction as covariates
‡ Linear mixed-effects model with histories of hypertension, angina, and myocardial infarction as covariates.
Ann Intern Med. 2007;147:10-18.

39. Clinical Investigation and Reports
Lieàu thaáp Metoprolol CR/XL vaø Fluvastatin laøm chaäm tieán trieån ñoä daøy lôùp noäi trung maïc ñoäng maïch caûnh keát quaû chính töø nghieân cöùu öùc cheá beâta laøm giaûm cholesterol, maûng xô vöõa ôû ngöôøi chöa coù trieäu chöùng (BCAPS) Main Results From the -Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS)
17. BCAPS is a very large-scale intervention study performed as a one-centre study in Malmö, Sweden. It was published in CIRCULATION in 2001.
B. Hedblad, MD, PhD; J. Wikstrand, MD, PhD; L. Janzon, MD,PhD;
H. Wedel, PhD; G. Berglund, MD, PhD
Hedblad et al, Circulation 2001;103:

40. BCAPS (n = 793) Daân soá nghieân cöùu Thieát keá nghieân cöùu
Nam, nöõ, chöa coù trieäu chöùng beänh maïch vaønh
Tuoåi: 49-70
Coù maûng xô vöõa treân ñoäng maïch caûnh phaûi
Thieát keá nghieân cöùu
Ngaãu nhieân, muø ñoâi, coù kieåm chöùng vôùi giaû döôïc, moät trung taâm, theo doõi 3 naêm, lieàu metoprolol succinate 25mg (CR/XL) ngaøy moät laàn1
1 Factorial design with fluvastatin
Hedblad B et al. Circulation 2001;103:

41. Nhịp tim: Nhịp tim giảm 2,5 bpm Huyết áp tâm thu không đổi
BCAPS – Kết quả sau 3 năm
Nhịp tim: Nhịp tim giảm 2,5 bpm
Huyết áp tâm thu không đổi
Slide 10
Compared with the placebo group, mean heart rate (HR) decreased in the metoprolol CR/XL group by 2.5 beats/min (95% CI, -4.2 to -0.7; p=0.006) after 36 months.
Systolic blood pressure (SBP) was not significantly changed in the metoprolol CR/XL group compared with the placebo group after 36 months (-1.3 mm Hg; 95% CI, -4.2 to 1.6; p=0.372).

42. TÖÛ VONG DO CAÙC NGUYEÂN NHAÂN HOAËC NMCT/ÑOÄT QUÎ)
(thôøi gian ñeán bieán coá ñaàu tieân)
Phaàn traêm 5
Placebo 4
Giảm 58% (p=0,031) 3
Metoprolol CR/XL
25 mg o.d. 2 1 6 12 18 24 30 36
Thaùng theo doõi
Hedblad B et al. Circulation 2001;103:

43. THAY ÑOÅI ÑOÄ DAØY MAÛNG XÔ VÖÕA trong suoát thôøi gian nghieân cöùu
(IMTmax xoang ñoäng maïch caûnh)
Taát caû beänh nhaân (n = 793)
mm
0.35
0.30
p=0,018
0.25
0.20
p<0,001
Thay ñoåi xoang ñoäng maïch caûnh
0.15
0.10
0.05
Theo doõi:
18 thaùng
36 thaùng
Placebo
Metoprolol CR/XL
Hedblad B et al. Circulation 2001;103:

44. THAY ÑOÅI ÑOÄ DAØY MAÛNG XÔ VÖÕA trong suoát thôøi gian nghieân cöùu
(IMTmax xoang ñoäng maïch caûnh)
Nhoùm BN coù toång cholesterol >6.5 mmol/L (n = 270)
mm
p=0,002
0.35
0.30
0.25
p=0,002
0.20
Thay ñoåi xoang ñoäng maïch caûnh
0.15
0.10
0.05
Theo doõi:
18 thaùng
36 thaùng
Placebo
Metoprolol CR/XL
Hedblad B et al. Circulation 2001;103:

45. HuyÕt ¸p cµng thÊp cµng tèt
Lower is Better
Age at Risk (Y)
Age at Risk (Y)
80-89
80-89
256
128 64 32 16 8 4 2 1
256
128 64 32 16 8 4 2 1
70-79
70-79
60-69
60-69
50-59
50-59
Tû lÖ tö vong do BTTMCB
Tû lÖ tö vong do BTTMCB
40-49
40-49
120
140
160
180 80 90
100
110 70
Usual Systolic BP (mm Hg)
Usual Diastolic BP (mm Hg)
Prospective Studies Collaboration. Lancet. 2002;360:

46. HOT Trial: Kiểm soát HA làm giảm biến cố tim mạch
Nhóm Bn ĐTĐ 30
P<0.005
Mục tiêu điều trị: HATTR đích
24.4 25
90 mm Hg (n=501) 20
18.8
85 mm Hg (n=501)
NMCT, ĐQ, tử vong tim mạch/1000 BN-năm
80 mm Hg (n=499) 15
The Hypertension Optimal Treatment (HOT) trial (1998) demonstrated fewer CV events with tighter control of BP in patients with diabetes. Target goals and achieved levels of diastolic BP are depicted on the right of the slide.
One objective of the HOT trial was to assess the optimum target diastolic BP in the treatment of hypertension. In the subgroup of patients with diabetes, there was a 51% reduction in major CV events in the target 80-mm Hg group compared with the target 90-mm Hg (P=0.005) group.
11.9
Đạt được 10
 mm Hg
 mm Hg
 mm Hg 5
Hansson et al. Lancet. 1998;351:1755.
Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351:

47. HA bình thường cao không thể gọi là “lành tính”
Nghiên cứu Framingham
Nam
1.6-lần nguy cơ nhiều hơn†
Bình thường
-cao
BT cao = /85-89 mm Hg
Cao = /80-84 mm Hg
Tối ưu = < 120/< 80 mm Hg
Bình thường
Tỷ suất tích luỹ mới mắc các biến cố tim mạch * (%)
Tối ưu
The category of pre-hypertension was created on the basis of new data, such as that from the Framingham study, which demonstrated a substantially increased risk of CVD in persons with BP of /85-89 mm Hg, a category previously referred to as high-normal.
In 6859 individuals free from hypertension and CVD at baseline, the 10-year cumulative incidence of a first CV event among men was 10.1% in subjects with BP of /85-89 mm Hg and 7.6% in those with BP of /80-84 mm Hg (normal). This corresponded to a hazard ratio of 1.6 (adjusted for concomitant CV risk factors).
Reference
Vasan RS et al. N Engl J Med. 2001;345:
Thời gian (năm)
*Tử vong do tim mạch, nhồi máu cơ tim, đột quị, suy tim
†Được hiệu chỉnh cho các yếu tố nguy cơ tim mạch kèm theo.
Vasan RS et al. N Engl J Med. 2001;345:

48. (International Verapamil-Trandolapril Study)
Nghiªn cøu INVEST
(International Verapamil-Trandolapril Study)
Nghiªn cøu ®a trung t©m: 862 trung t©m t¹i 14 n­íc.
®èi t­îng nghiªn cøu: bao gåm bÖnh nh©n THA vµ bÖnh MV.
Môc tiªu nghiªn cøu: ®Ó x¸c ®Þnh xem liÖu viÖc h¹ huyÕt ¸p thÊp cã lµm t¨ng tû lÖ tö vong vµ biÕn chøng hay kh«ng? (tö vong, NMCT kh«ng tö vong)
Franz H et al. Ann Intern Med. 2006; 144:

49. 49

50. Nguyeân taéc ñieàu trò THA caáp cöùu
Cho BN nhaäp ICU
Theo doõi HA tröïc tieáp trong ñoäng maïch (neáu ñöôïc).
Haï HA ngay baèng thuoác truyeàn TM.
Haï HA 20-25% trong voøng 1-2 giôø ñaàu; Neáu tình traïng beänh nhaân oån, tieáp tuïc haï HA xuoáng möùc 160/100 mmHg trong voøng 2-6 giôø vaø xuoáng möùc bình thöôøng trong voøng giôø.
ESH Scientific Newsletter 2006;7:No.28

51. KẾT LUẬN THA là yếu tố nguy cơ quan trọng của BMV.
ƯCMC, chẹn beta giao cảm và chẹn kênh canci là lựa chọn hàng đầu.
Cùng với việc điều trị THA phải điều trị các yếu tố nguy cơ tim mạch khác.
Không nên hạ HA quá nhiều.