Transcript Slide 1

Funding to Oxford University
for MRC/BHF Heart Protection Study
•
Medical Research Council $14M
•
British Heart Foundation
$2M
•
Merck
$8M
•
Roche Vitamins
$8M
Designed, conducted & analysed
independently of all sources of support
N-Terminal Pro-B-Type Natriuretic Peptide
and Vascular Disease among 20,536
Patients in the MRC/BHF Heart Protection
Study
Heart Protection Study Collaborative Group
University of Oxford
UK
BNP and N-BNP
• Prohormone released in
ventricular myocardium,
cleaved to active peptide
(BNP) and inactive
amino-terminal fragment
(N-BNP)
• Stimulus for secretion:
increased ventricular
stretch and wall tension
• Biological effects:
regulation of blood
pressure, blood volume
and sodium balance
Clinical uses of N-BNP measurement
• Provides a highly sensitive (and reasonably
specific) test for diagnosis of heart failure and
pre-clinical ventricular dysfunction
– e.g. differential diagnosis of breathlessness in primary
care and emergency room
• Indicator of disease severity and prognosis in
patients with heart failure
– Target for treatment titration in heart failure
• Possible risk prediction for vascular disease
HPS: Randomised controlled trial of
simvastatin 40mg daily vs placebo
• 20,536 patients aged 40-80 years at “high risk”
of vascular disease:
– 13,386 (65%) with prior CHD
– 7,150 (35%) with no CHD but with other vascular
disease, diabetes or (men aged over 65 only) treated
hypertension
• Patients with heart failure were eligible provided
they were not breathless at rest, but diagnosis of
heart failure was not recorded at baseline
HPS: Effect on major vascular events of
reducing LDL cholesterol by 1 mmol/l
Vascular
event
SIMVASTATIN PLACEBO
(10269)
(10267)
Major coronary
898
1212
Any stroke
444
585
Revascularisation
939
1205
2033
(19.8%)
2585
(25.2%)
ANY OF ABOVE
Rate ratio & 95% CI
STATIN better PLACEBO better
24% SE 3
reduction
(2P<0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
HPS: Effect of simvastatin on major vascular
events subdivided by other treatments
Baseline
treatment
SIMVASTATIN
(10269)
PLACEBO
(10267)
Aspirin
Yes
No
1370 (21.1%) 1784 (27.4%)
663 (17.5%)
801 (21.3%)
ACE inhibitor
Yes
No
495 (24.9%)
568 (28.5%)
1538 (18.6%) 2017 (24.4%)
Beta-blocker
Yes
No
519 (19.5%)
705 (26.9%)
1514 (19.9%) 1880 (24.6%)
Calcium antagonist
Yes
No
788 (24.7%) 1023 (31.2%)
1245 (17.6%) 1562 (22.4%)
ALL PATIENTS
2033 (19.8%) 2585 (25.2%)
0.4
Rate ratio & 95% CI
STATIN better PLACEBO better
24% SE 3
reduction
(2P<0.00001)
0.6
0.8
1.0
1.2
1.4
Why measure N-BNP in HPS: Do statins
have similar benefits in heart failure as in
other patients?
“….The potential adverse effects of statins in CHF (heart
failure) include reduction in coenzyme Q10 and loss of
the protection that lipoproteins may provide through
binding and detoxifying endotoxins…sufficient
uncertainty to merit a definitive clinical trial.”
Krum et al. JACC 2002
• CORONA: placebo-controlled trial of rosuvastatin 10mg
among ~5000 elderly patients with symptomatic systolic
heart failure of ischaemic aetiology
Aims
• To estimate the effect of simvastatin on risk of
major vascular events and heart failure
hospitalisation or death, separately according to
N-BNP level.
• To examine the epidemiological relationship
between N-BNP and the risk of major vascular
events and hospitalisation or death due to heart
failure.
HPS: Relationship of baseline N-BNP to
other baseline characteristics
N-BNP
(fmol/ml)
<60
(n=6633)
60-188
(n=5400)
188-433
(n=4244)
433-954
(n=2773)
>954
(n=1486)
Mean age
(years)
60
64
67
68
70
Mean LDL
(mmol/l)*
3.4
3.4
3.4
3.4
3.3
Any CHD (%)*
47
65
74
80
81
ACEI (%)*
15
16
18
23
37
β blocker (%)*
11
23
32
37
32
Diuretic (%)*
17
20
24
30
47
* adjusted for age and sex
HPS: N-BNP and vascular disease
HPS: Effect of simvastatin allocation on
major coronary events by baseline N-BNP
N-BNP (fmol/l)
SIMVASTATIN PLACEBO
Rate ratio & 95% CI
(10269)
(10267) STATIN better PLACEBO better
<60
148 (4.5%)
270 (8.1%)
60 <188
176 (6.4%)
242 (9.1%)
188 <433
186 (8.8%)
249 (11.7%)
433 <954
185 (13.5%)
233 (16.6%)
954
203 (26.9%)
218 (29.9%)
ANY
898 (8.8%)
27% SE 4
reduction
(2P<0.00001)
1212 (11.8%)
0.4
0.6
0.8
1.0
1.2
1.4
HPS: Effect of simvastatin allocation on
strokes by baseline N-BNP
N-BNP (fmol/l)
SIMVASTATIN PLACEBO
Rate ratio & 95% CI
(10269)
(10267) STATIN better PLACEBO better
<60
109 (3.3%)
133 (4.0%)
60 <188
100 (3.6%)
121 (4.6%)
188 <433
111 (5.3%)
141 (6.6%)
433 <954
79 (5.8%)
121 (8.6%)
954
45 (6.0%)
69 (9.5%)
444 (4.3%)
585 (5.7%)
ANY
0.4
26% SE 5
reduction
(2P<0.00001)
0.6
0.8
1.0
1.2
1.4
HPS: Effect of simvastatin allocation on
major vascular events by baseline N-BNP
N-BNP (fmol/l)
SIMVASTATIN PLACEBO
Rate ratio & 95% CI
(10269)
(10267) STATIN better PLACEBO better
<60
448 (13.6%)
649 (19.4%)
60 <188
468 (17.0%)
579 (21.8%)
188 <433
460 (21.8%)
561 (26.3%)
433 <954
377 (27.5%)
479 (34.2%)
954
280 (37.0%)
317 (43.4%)
ANY
24% SE 3
reduction
(2P<0.00001)
2033 (19.8%) 2585 (25.2%)
0.4
0.6
0.8
1.0
1.2
1.4
Effect of simvastatin allocation on heart
failure hospitalisation or death
Baseline
feature
SIMVASTATIN PLACEBO
Rate ratio & 95% CI
(10269)
(10267) STATIN better PLACEBO better
N-BNP (fmol/l)
<60
21 (0.6%)
47 (1.4%)
60 <188
55 (2.0%)
55 (2.1%)
188 <433
83 (3.9%)
64 (3.0%)
433 <954
81 (5.9%)
114 (8.1%)
114 (15.1%)
125 (17.1%)
354 (3.4%)
405 (3.9%)
954
ANY
0.4
14% SE 7
reduction
(2P=0.05)
0.6
0.8
1.0
1.2
1.4
HPS: Conclusions for heart failure and
statins
• In people at risk of vascular events, N-BNP is a
strong independent predictor not only of heart
failure, but also of major vascular events
• In patients with high N-BNP levels (consistent
with heart failure), statins produce clear benefits,
with no evidence of any significant hazard
Slides will be available at:
www.hpsinfo.org
HPS: Effect of simvastatin allocation on
vascular mortality by baseline N-BNP
Baseline
feature
SIMVASTATIN PLACEBO
Rate ratio & 95% CI
(10269)
(10267) STATIN better PLACEBO better
N-BNP (fmol/l)
<60
106 (3.2%)
128 (3.8%)
60 <188
122 (4.4%)
160 (6.0%)
188 <433
161 (7.6%)
200 (9.4%)
433 <954
175 (12.8%)
217 (15.5%)
954
217 (28.7%)
232 (31.8%)
781 (7.6%)
937 (9.1%)
ANY
0.4
17% SE 4
reduction
(2P<0.0001)
0.6
0.8
1.0
1.2
1.4
HPS: Effect of simvastatin allocation on
non-vascular mortality by baseline N-BNP
Baseline
feature
SIMVASTATIN PLACEBO
Rate ratio & 95% CI
(10269)
(10267) STATIN better PLACEBO better
N-BNP (fmol/l)
<60
120 (3.7%)
130 (3.9%)
60 <188
134 (4.9%)
152 (5.7%)
188 <433
140 (6.6%)
116 (5.4%)
433 <954
97 (7.1%)
107 (7.6%)
954
56 (7.4%)
65 (8.9%)
547 (5.3%)
570 (5.6%)
ANY
0.4
5% SE 6
reduction
0.6
0.8
1.0
1.2
1.4