CVD Prevention for

Intermediate Risk Population:

Is statin a hope or foe?
Anwar Santoso


Dept. of Cardiology – Faculty of Medicine; University of Indonesia
National Cardiovascular Centre – Harapan Kita Hospital


President of Indonesian Heart Association
Jakarta - Indonesia
 The Magnitude of the Problem

❑ Hypertension is the single largest risk factor for

cardiovascular disease mortality, accounting for 45%
of all CVD deaths1
❑ INTERSTROKE Study concluded that hypertension
provides 34.6% of the population-attributable risk
(PAR) for stroke2, while INTERHEART found it
provides 17.9% of the PAR for myocardial infarction3
▪ The PAR is the reduction in incidence that would be observed if
the population were entirely unexposed (did not have
hypertension).
1. IOM (Institute of Medicine). 2010. A Population-Based Policy and Systems Change Approach to Prevent and Control Hypertension.
2. O’Donnell MJ, Xavier D, Liu L et al. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE
study): a case–control study. The Lancet 2010; 376:112–23
3. Salim Yusuf, Steven Hawken, Stephanie Ôunpuu, Tony Dans, Alvaro Avezum, Fernando Lanas, Matthew McQueen, Andrzej Budaj, Prem
Pais, John Varigos, Liu Lisheng, on behalf of the INTERHEART Study Investigators, Effect of potentially modifiable risk factors associated with
myocardial infarction in 52 countries (the INTERHEART study): case-control study, The Lancet, 2004: 9438, 11–17.
Relationship Between Proportional Reduction in Events and Mean
LDL-C Reduction at 1 Year

Major coronary events Major vascular events

50 50

40 40
Proportional reduction in event rate (%±SE)

Proportional reduction in event rate (%±SE)

30 30

20 20

10 10

0 0
0.5
 1.0
 1.5
 2.0

0.5
 1.0
 1.5
 2.0

(19) (38) (58) (77)
-10 -10 (19) (38) (58) (77)

Reduction in 
 Reduction in 

LDL-C mmol/L (mg/dL) LDL-C mmol/L (mg/dL)

CTT Collaborators. Lancet 2005;366:1267–1278.

 Relationship between LDL-C and 

Cardiovascular Event Rate

30
4S - Pl

Secondary Prevention
25 Rx - Statin therapy
Pl – Placebo
Pra – pravastatin
Atv - atorvastatin
Event rate (%)

4S - Rx
20

LIPID - Pl
15
CARE - Pl
LIPID - Rx
CARE - Rx Primary Prevention
HPS - Rx TNT – Atv10 HPS - Pl in high-risk subjects
10 PROVE-IT - Pra WOSCOPS – Pl
TNT – Atv80
PROVE-IT – Atv AFCAPS - Pl
6
5 AFCAPS - Rx WOSCOPS - Rx
ASCOT - Pl
ASCOT - Rx
0
40 60 80 100 120 140 160 180 200
(1.0) (1.6) (2.1) (2.6) (3.1) (3.6) (4.1) (4.7) (5.2)
LDL-C achieved mg/dL (mmol/L)

Rosenson RS. Exp Opin Emerg Drugs 2004;9(2):269-279, LaRosa JC et al. N Engl J Med 2005;352:1425-1435.
 Justification for CVD Prevention

• Graded increase in CVD risk with SBP >115 mmHg &

for LDL-C throughout documented ranges in
populations
• BP lowering trials indicate clear reductions in CVD in
those at high risk or with SBP≥160 mmHg
• Statins lower CVD in secondary prevention and in
primary prevention, studied mainly in European
populations with increased LDL-C, CRP, diabetes, or
hypertension

3
 Can we halve CVD mortality and 

cancer mortality?

UK: CVD mortality decreasing fast, due to

both prevention and treatment
 1980, M+F:
+ ← 16% dead
before 70

2010, M+F:
← 4% dead
before 70
Cardiac Rehabilitation and the ASCVD 

Prevention Pyramid

11
Sandesara PB, et al. J Am Coll Cardiol 2015; 65(4): 389 - 95
Distribution of population and CVD events by 10-
year CVD risk in men aged 35 – 69 years in Italy

15
Vanuzzo D & Giampaoli S. Primary prevention: principles and practice. In: Giellin S Textbook of Preventive Cardiology, 2015
 How to treat for intermediate risk
population without CVD?

• There is no straight forward recommendation!

 Intermediate-Risk Population
Inclusion Criteria (Target Risk 1.0%/yr)
Women ≥ 60 yrs, men ≥ 55 yrs with at least one additional
Risk Factor

• Increased WHR • Dysglycemia

• Smoking • Mild renal dysfunction

• Low HDL-C • Family history of CHD

Exclusion Criteria:
CVD or indication(s) or contraindication(s) to study drugs
No strict BP or LDL-C criteria for entry
Uncertainty principle 5
 Objectives

In an intermediate-risk population without CVD, to

evaluate the effects on CV events of:
1. BP lowering with a fixed dose combination of
Candesartan 16 mg and HCTZ 12.5 mg daily
2. Cholesterol lowering with Rosuvastatin 10 mg
daily
3. Combined BP and cholesterol lowering
Participants received lifestyle advice and
necessary therapies

4
 2 by 2 Factorial Design
14,682 Entered Single-blind 4 week Active Run-in
12,705 (87%) Randomized

Candesartan 16 mg +
Placebo
HCTZ 12.5 mg
n = 6,349
n= 6,356

Rosuvastatin Rosuvastatin
Rosuvastatin 

10 mg Cand+HCTZ
n = 3,181
n=6,361 n = 3,180

Placebo Cand+HCTZ Double Placebo

n = 6,344 n = 3,176 n = 3,168

Simple follow-up and few blood tests.

All reeived tailored lifestyle advice.
19
 Adherence and Follow-up

• Median Follow up: 5.6 years

• Participant Follow-up: 99.1%
• High adherence:

% on Study Drug
Cand + Double Double
Placebo Rosuva Placebo
HCTZ Active Placebo
1 Year 88 88 88 88 86 86
3 Years 84 83 83 83 81 81
Study End 77 76 77 75 75 72

8
 Outcomes

• Co-Primary 1
– Composite of CV death, MI, stroke (p<0.04)
• Co-Primary 2
– Composite 1 + resuscitated cardiac arrest, heart
failure, revascularizations (p<0.02)
• Secondary Outcomes
– Composite of Co-Primary 2 + angina with
objective ischemia
– Stroke

9
 Baseline Characteristics

12,705 randomized

Age (yrs) 66
Female 46%
Blood Pressure (mmHg) 138/82
LDL-Cholesterol (mg/dL) 128
LDL-Cholesterol (mmol/L) 3.3
Elevated waist-to-hip ratio 87%
hsCRP (g/L) median 2.0
Ethnicity
White Caucasian 20%
Latin American 28%
Chinese 29%
Other Asian 20%
Black African 2% 11
 BP Lowering vs. Placebo: 

140
Systolic Blood Pressure (mmHg) SBP Changes

Placebo
130 135

Candesartan + HCTZ
125

Δ BP=6.0/3.0 mmHg
120

0 1 2 3 4 5 6 7
Years

Cand/HCTZ 6356 5907 5667 5446 5213 3862 1437 350

Placebo 6347 5879 5623 5442 5186 3822 1424 334

12
 CV Death, MI, Stroke, Cardiac Arrest,
Revascularization, Heart Failure

0.10
HR (95% CI) = 0.95 (0.81-1.11)
0.08

P-value = 0.51
Cumulative Hazard Rates

0.06

Placebo
0.04

Candesartan + HCTZ
0.02
0.0

0 1 2 3 4 5 6 7

No. at Risk Years

Cand + HCTZ 6356 6272 6200 6103 5968 4969 2076 522
Placebo 6349 6270 6198 6096 5967 4970 2075 488
14
 Prespecified Subgroups: 

By Thirds of SBP
CV Death, MI, Stroke, Cardiac Arrest, Revasc, HF

SBP Placebo
HR (95% CI) P Trend
Cutoffs Mean Diff Event Rate%

≤131.5 122 6.1 3.5 1.25 (0.92-1.70) 0.009

131.6-143.5 138 5.6 4.6 1.02 (0.77-1.34)
>143.5 154 5.8 7.5 0.76 (0.60-0.96)

0.5 1.0 2.0

Candesartan + HCTZ Better Placebo Better

15
 Combination vs Double Placebo:

Change in SBP and LDL-C
140

Double placebo
135

Rosuva
SBP Mean Δ 6.2 mmHg
130

Cand + HTCZ
125

Combination

Double Placebo
120

Week 6

Rosuva.
0 Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7
Month 6 Cand+HCTZ
Combination
140

Cand + HCTZ
120

Double placebo

LDL-C Mean Δ 33.7 mg/dl

90 100

Rosuva

Combination
80

0 Year 1 Year 3 Study End

28
 CV Death, MI, Stroke, 

Cardiac Arrest, Revasc, Heart Failure
0.10

Double Placebo
0.08

Combination
Cumulative Hazard Rates

0.06
0.04
0.02

HR (95% CI) = 0.72 (0.57-0.89)

P-value = 0.0030
0.0

0 1 2 3 4 5 6 7
Years
Combination 3180 3063 1057
Rosuvastatin 3181 3061 1045
Candesartan/HCTZ 3176 3040 1019
Double Placebo 3168 3035 1030 30
 Coronary Heart Disease Stroke

0.005 0.010 0.015 0.020 0.025

0.05

HR (95% CI) = 0.62 (0.43-0.88) HR (95% CI) = 0.56 (0.36-0.87)

Cumulative Hazard Rates
0.04

P-value = 0.0085 P-value = 0.0094

0.03
0.02
0.01

0.0
0.0

0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7
Years Years

Double Placebo Combination

Coronary Heart Disease: Fatal/non-fatal MI, Coronary Revascularization

31
 RRR of Combination and Each 

Intervention vs Double Placebo
50%
Overall
Co-Primary 2 40%
28% 26%
30%

RRR 20%

10% 6%

0%
Combo Rosuva Cand + HCTZ
Only Only
50% Highest Third of SBP Lower Two Thirds of SBP
50%
40%
40%
40%
31%
30% 24% 30%
20% 19%
RRR

20% 20%

10% 10%
Cand + HCTZ Only

0% 0%
Combo Rosuva Cand+HCTZ Combo Rosuva Only
Only Only
-8% 32
 BP & Cholesterol Lowering vs 

Double Placebo: Conclusions

• About a 30% reduction in major vascular events

• Benefits of combined BP and cholesterol
lowering therapy:
– Largely seen in those in the upper third of
SBP (40% RRR in CVD)
– In lower two thirds the benefit is from
Rosuvastatin only (30% RRR in CVD)

34