tim mạch

1. To Optimize the Treatment of Hypertensive
Patients with Dyslipidaemia :
What scientific evidence shows?
Neil R Poulter
Co-Director International Centre for Circulatory Health
And Director Imperial Clinical Trials Unit
Imperial College London
President of the International Society of Hypertension
12th International meeting on Hypertension and Global
Cardiovascular Risk
Vilamoura, Portugal – 22nd February 2018

2. Disclosure of Interests
Neil Poulter has received financial support from several
pharmaceutical companies which manufacture either BP-
lowering or lipid lowering agents, or both, for consultancy fees
(Servier, Amgen), research projects and staff (Servier, Pfizer) and
for arranging and speaking at educational meetings
(AstraZeneca, Lri Therapharma, Napi, Servier and Pfizer). He
holds no stocks and shares in any such companies.

3. Health Statistics and Informatics
Deaths attributed to 19 leading factors,
by country income level, 2004

4. Most patients have
overlapping CV risk factors
Multiple comorbidities increase risk 400-700%
Of all people with hypertension:
• 65% have dyslipidaemia
• 16% have type 2 diabetes
• 45% are overweight/obese
Of all people with dyslipidaemia:
• 48% have hypertension
• 14% have type 2 diabetes
• 35% are overweight/obese
Of all people with type 2 diabetes:
• 60% have hypertension
• 60% have dyslipidaemia
• 90% are overweight/obese
Hypertensive
Dyslipidaemic Diabetes

5. Additive Effect of Cholesterol and Systolic BP on Risk of CHD Death
Neaton JD, et al. Arch Intern Med. 1992;152:56-64
142+
125-131
<182
182-202
203-220
221-244
<118
118-124
132-141
34
21
13
6
23
12
10
6
18
11
9
6
4
17
8
8
6
3
Deaths/10,000
patient-years
245+
14
5
6
3
12
17
N=316,099

6. LOWERING BP

7. Antihypertensive Treatment Reduces CV Events
17 trials, 47,653 patients, SBP diff 10–12 mmHg, DBP diff 5–6 mmHg
Total number of individuals affected
1,200
1,000
800
600
400
200
0
Reduction in
odds (SD) 38% (4%) 16% (4%) 21% (4%) 0% (6%)
p value <0.00001 <0.001 <0.00001 >0.5
MacMahon & Rodgers 1993
Stroke CHD Vascular All other
deaths deaths
Treatment
Control
Fatal events
Non-fatal events
T
C
T
C
T
C
T C
T
C

8. NICE ESH ESC ASH-ISH ‘JNC8’
A† + C§ A + C Black Black
A + D* A + C C + D
C + D A + D
C + D
Non-black Non-black
A + C A + C
A + D A + D
C + D
†: A = ACE-inhibitor or angiotensin receptor blocker
§: C = Calcium channel blocker
*: D = Diuretic (including thiazides or thiazide-like/type)
Recommended 2-drug combinations of antihypertensive drugs

9. A & C Trials
Trial VS
ASCOT - B+D
ACCOMPLISH - A+D

10. Step 4
Summary of
antihypertensive
drug treatment
Aged over 55 years
or black person of
African or Caribbean
family origin of any
age
Aged under
55 years
C*A
A + C*
A + C + D
Resistant hypertension
A + C + D + consider further diuretic
or alpha- or beta-blocker
Consider seeking expert advice
Step 1
Step 2
Step 3
Key
A – ACE inhibitor or low-cost
angiotensin II receptor
blocker (ARB)1
C – Calcium-channel
blocker (CCB)
*D – Thiazide-like diuretic

11. LIPID LOWERING

12. Key lesson from statin trials (> 160,000 patients)
lowering LDL reduces CV events
CTT Collaboration. Lancet 2010;376:1670–81.
Less statin
0.4 0.6 0.8 1 1.2 1.4
No. of events (% pa): Statin/
More statin
Control/ Relative risk (CI)
Statin/more
statin better
Control/less
statin better
Nonfatal MI
CHD death
Any major coronary event
CABG
PTCA
Unspecified
Any coronary revascularisation
Ischaemic stroke
Haemorrhagic stroke
Unknown stroke
Any stroke
Any major vascular event
3485 (1.0)
1887 (0.5)
5105 (1.4)
1453 (0.4)
1767 (0.5)
2133 (0.6)
5353 (1.5)
1427 (0.4)
257 (0.1)
618 (0.2)
2302 (0.6)
10973 (3.2)
4593 (1.3)
2281 (0.6)
6512 (1.9)
1857 (0.5)
2283 (0.7)
2667 (0.8)
6807 (2.0)
1751 (0.5)
220 (0.1)
709 (0.2)
2680 (0.8)
13350 (4.0)
0.71 (0.66 - 0.76)
0.78 (0.71 - 0.86)
0.73 (0.70 - 0.77)
0.71 (0.63 - 0.80)
0.72 (0.66 - 0.87)
0.77 (0.71 - 0.83)
0.75 (0.72 - 0.79)
0.80 (0.72 - 0.79)
1.15 (0.87 - 1.51)
0.88 (0.76 - 1.02)
0.85 (0.80 - 0.91)
0.78 (0.76 - 0.81)
99% or 95% CI

13. LOWERING
BP & LIPIDS

14. Study design
atenolol ±
bendroflumethiazide
amlodipine ±
perindopril
19,257
hypertensive
patients
PROBE
design
ASCOT-BPLA
Investigator-led, multinational
randomised controlled trial
placeboatorvastatin 10 mg Double-blind
ASCOT-LLA
10,305 patients
TC ≤ 6.5 mmol/L (250 mg/dL)

15. ASCOT-BPLA: summary of all end points
Dahlöf B, et al. Lancet. 2005;366:895-906.
amlodipine/perindopril better atenolol/thiazide better
0.50 0.70 1.00 1.45
Primary
Non-fatal MI (incl silent) + fatal CHD
Secondary
Non-fatal MI (exc. Silent) +fatal CHD
Total coronary end point
Total CV event and procedures
All-cause mortality
Cardiovascular mortality
Fatal and non-fatal stroke
Fatal and non-fatal heart failure
Tertiary
Silent MI
Unstable angina
Chronic stable angina
Peripheral arterial disease
Life-threatening arrhythmias
New-onset diabetes mellitus
New-onset renal impairment
Post hoc
Primary end point + coronary revasc procs
CV death + MI + stroke
2.00
Unadjusted HR (95% CI)
0.90 (0.79-1.02)
0.87 (0.76-1.00)
0.87 (0.79-0.96)
0.84 (0.78-0.90)
0.89 (0.81-0.99)
0.76 (0.65-0.90)
0.77 (0.66-0.89)
0.84 (0.66-1.05)
1.27 (0.80-2.00)
0.68 (0.51-0.92)
0.98 (0.81-1.19)
0.65 (0.52-0.81)
1.07 (0.62-1.85)
0.70 (0.63-.078)
0.85 (0.75-0.97)
0.86 (0.77-0.96)
0.84 (0.76-0.92)

16. Hazard Ratio
0.64 (0.50-0.83)
0.79 (0.69-0.90)
0.71 (0.59-0.86)
0.62 (0.47-0.81)
0.87 (0.71-1.06)
0.90 (0.66-1.23)
0.73 (0.56-0.96)
1.13 (0.73-1.78)
0.82 (0.40-1.66)
0.87 (0.49-1.57)
0.59 (0.38-0.90)
1.02 (0.66-1.57)
1.15 (0.91-1.44)
1.29 (0.76-2.19)
LLA : End Points
Area of squares is proportional to the amount of statistical information
0.5 1.0 1.5
Atorvastatin better Placebo better
Primary
Nonfatal MI (incl silent) + fatal CHD
Secondary
Total CV events and procedures
Total coronary events
Nonfatal MI (excl silent) + fatal CHD
All-cause mortality
Cardiovascular mortality
Fatal and nonfatal stroke
Fatal and nonfatal heart failure
Tertiary
Silent MI
Unstable angina
Chronic stable angina
Peripheral arterial disease
Development of diabetes mellitus
Development of renal impairment
Risk Ratio
Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

17. Amlodipine
 perindopril
Atenolol 
thiazide
Atorvastatin
Placebo
L
L
A
BPLA
1
2 or 3
2 or 3
4
ASCOT: BPLA and LLA combined: Insight into optimal
CV prevention (1)

18. ASCOT: BPLA and LLA combined:
Insight into optimal CV prevention (2)
Endpoint
Amlodipine 
perindopril +
atorvastatin
Atenolol 
thiazide +
placebo
Relative
risk
reduction
Non-fatal MI and fatal
CHD
4.8 9.2 48%
Fatal and non-fatal
stroke
4.6 8.2 44%
Rates / 1000 patient years

19. ASCOT-LLA
Primary endpoint: Non-fatal MI and fatal CHD
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
0.0
1.0
2.0
3.0
4.0
Years
Cumulativeincidence(%)
Atorvastatin
Placebo
53%
Amlodipine-based treatment
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
0.0
1.0
2.0
3.0
4.0
Years
Cumulativeincidence(%)
Atorvastatin
Placebo 16%
Atenolol-based treatment
HR=0.84 (0.60 - 1.17) p=0.30HR=0.47 (0.32 - 0.69) p<0.001

20. Long-standing guidelines for lipid lowering in patients with
hypertension ‘Thresholds’ in 1o prevention
“In view of the results of the ASCOT trial and other currently available
trial data, it seems reasonable, in the interests of simplicity, to treat
with a statin, all those patients at least up to the age of 80 years with
a total cholesterol ≥ 3.5mmol/l who have an estimated 10 year CVD
risk of 20% or more. In reality, this would mean considering statin
therapy in most hypertensive patients (especially men) over the age
of 50 years. As resources allow, a rationale for lowering this threshold
could be made on the basis of trial evidence.”
BHS IV (2004)
ESC-ESH (2003)

21. HOPE-3: Graded Effects on CV Outcomes
by Randomised Group
Rates (%) by group
OUTCOME BP & LIPID LIPID BP PLACEBO
Primary 1st † 3.6 3.8 4.6 5.0
2nd * 4.3 4.4 5.5 5.9
Secondary ‡ 4.6 5.0 5.9 6.5
F or NF MI 0.7 0.8 1.0 1.2
F or NF CVA 1.0 1.2 1.4 1.7
CV Death 2.4 2.5 2.5 2.9
† CV death + NF MI + NF CVA;
* Ist + C arrest, HF, revasc;
‡ 2nd + AP

22. CURRENT PRACTICE

23. Income level n Aware (%) Treated (%) Controlled
(%)
High 6263 49.0 46.7 19.0
Upper Middle 18123 52.5 48.3 15.6
Lower Middle 23269 43.6 36.9 9.9
Low 10185 40.8 31.7 12.7
Total 57840 46.5 40.6 13.2
Hypertension: Awareness, Treatment & Control†
by National Income: 2003 – 2009. PURE Study
† <140/90
Chow et al. JAMA 2013

24. Optimising Management
1.Awareness -Opportunistic, Standardised Screening
-ABPM
2.Treatment -When
-What with
-How far
-What else

26. Statins for all by the age of 50 years?
Statins could benefit health of millions
Medical journal says cholesterol-lowering pills
can reduce the risk of heart problems, especially
in the over-50s
On the one hand

27. Increasing publicity in the media and medical press
(BMJ 2013 two papers)
• Abrahamson et al. “Statin therapy has about an 18% risk of causing side effects that range
from minor and reversible to serious and irreversible”. Zhang is the only reference given in
support.
• Malhotra states that statins showed unacceptable side effects including myalgia,
gastrointestinal upset, sleep and disturbance and erectile dysfunction.
• Zhang reference is misquoted and some of alleged side effects not reported by Zhang.
• BMJ after review withdraws these claims.
On the other hand

28. Statin Discontinuation:
A Systematic Review of 39 Studies
Collectively, the results indicate that poor adherence and
withdrawal of statin therapy are linked to increased
cardiovascular events, cerebrovascular events, and mortality,
in both primary and secondary prevention, as well as in
perioperative populations. More specifically, the large majority of
papers found that statin nonadherence was significantly linked to
more adverse cardio- and cerebrovascular outcomes
Current Pharmaceutical Design, 2011

29. Summary
• Raised blood pressure and cholesterol are among the top contributors to global
mortality and burden of disease.
• These 2 risk factors coexist more frequently than chance would predict.
• Extensive RCT evidence show that both blood pressure-lowering and lipid
lowering generate large reductions in major adverse cardiovascular events.
• The ASCOT trial showed that lowering both blood pressure and lipids in
hypertensive patients generates at least additive benefits of the individual
interventions.
• Globally blood pressure-lowering is inadequate and lipid lowering has been
undermined by largely spurious concerns.