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
Funding for the MRC/BHF Heart Protection Study

2. Heart Protection Study Collaborative Group University of Oxford UK
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

3. 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
BNP is secreted mainly in the ventricular myocardium, where it’s cleaved to the active peptide and the inactive amino terminal fragment, which we call NBNP or sometimes NT-proBNP.
The stimulus for its secretion is increased ventricular stretch and wall tension, and its main biological effects are the regulation of blood pressure, blood volume, and salt balance.

4. 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
The main clinical uses of N-BNP are that it provides a highly sensitive (and reasonably specific) test, for the diagnosis of heart failure and (probably) for pre-clinical ventricular dysfunction. This means that it can reliably be used to rule out heart failure as a possible diagnosis of breathlessness, in a primary care or emergency room setting.
It is also a powerful indicator of disease severity and prognosis in patients with heart failure, and so may be used as a guide for treatment decisions.
However, it’s role as a biomarker for vascular disease is less certain.

5. HPS: Randomised controlled trial of simvastatin 40mg daily vs placebo
20,536 patients aged 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
The Heart Protection Study, a randomised controlled trial of simvastatin 40mg daily versus placebo, was carried out in over 20,000 patients who were considered to be at high risk of vascular disease, either because of (in the case of two-thirds of them) a previous diagnosis of CHD or (for the remaining third) because of other vascular disease, diabetes, or in elderly men, because of treatment for hypertension.
Importantly, patients with heart failure WERE eligible for the study, providing they were not breathless at rest. Thus, the group of patients will have contained patients with mild-to-moderate heart failure. However, heart failure diagnosis was not recorded at entry into the trial.

6. HPS: Effect on major vascular events of reducing LDL cholesterol by 1 mmol/l
SIMVASTATIN
PLACEBO
Rate ratio & 95% CI
event
(10269)
(10267)
STATIN better
PLACEBO better
Major coronary
898
1212
Any stroke
444
585
Revascularisation
939
1205
ANY OF ABOVE
2033
2585
24% SE 3
(19.8%)
(25.2%)
reduction
The primary findings from HPS showed that reducing LDL cholesterol by an average of 1mmol/l over 5 years reduced the risk of a major coronary event (defined cardiac death or a non fatal myocardial infarction), reduced the risk of fatal or non-fatal stroke, and reduced the risk of any revascularisation procedure, each by around one quarter, so that, overall, the risk of ANY major vascular event, was also reduced by one quarter, from a five-year risk of around 25% to a five year risk of 20%.
(2P< )
0.4
0.6
0.8
1.0
1.2
1.4

7. HPS: Effect of simvastatin on major vascular events subdivided by other treatments
Baseline
SIMVASTATIN
PLACEBO
Rate ratio & 95% CI
treatment
(10269)
(10267)
STATIN better
PLACEBO better
Aspirin
Yes
1370
(21.1%)
1784
(27.4%) No
663
(17.5%)
801
(21.3%)
ACE inhibitor
Yes
495
(24.9%)
568
(28.5%) No
1538
(18.6%)
2017
(24.4%)
Beta-blocker
Yes
519
(19.5%)
705
(26.9%) No
1514
(19.9%)
1880
(24.6%)
Calcium antagonist
Because of the size of the study, HPS was also able to show that the benefits of simvastatin were similar in a variety of different groups of patients. For instance, this slide shows that lowering LDL cholesterol had the same proportional effect on major vascular event risk: in patients taking aspirin at baseline as in patients not taking aspirin, and in patients receiving a range of different blood pressure lowering drugs at baseline as in patients not receiving these drugs.
Now, one point to note is that in the mid 1990s when HPS was recruiting, ACE inhibitors were only being routinely used for the treatment of hypertension and heart failure (as the HOPE study wasn’t published until 2000). So, the observation that people taking ACE inhibitors experienced similar proportional reductions in vascular risk as other patients provides some indirect evidence, at least, of the possible benefits of cholesterol lowering in heart failure patients.
NB/ People not taking aspirin were mostly diabetics without prior vascular disease
Drug use increased generally throughout the study, but by the same amount in each treatment group.
e.g. ACE inhibitor use increased from around 25 to 35 percent.
Yes
788
(24.7%)
1023
(31.2%) No
1245
(17.6%)
1562
(22.4%)
ALL PATIENTS
2033
(19.8%)
2585
(25.2%)
24% SE 3
reduction
(2P< )
0.4
0.6
0.8
1.0
1.2
1.4

8. 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
So why have we measured NBNP in HPS? Well, this decision was motivated by the question of whether statins have similar benefits in heart failure as they do in other patients.
In a 2002 review article published in JACC, it was stated that “…the potential adverse effects of statins in heart failure include reduction in coenzyme Q10 and loss of the protection that lipoproteins may provide through binding and detoxifying endotoxins (the so-called endotoxin-lipoprotein hypothesis)…and that there was sufficient uncertainty to merit a definitive clinical trial”
And indeed, such a trial is underway. The CORONA trial is a PLACEBO-controlled study of Rosuvastatin 10mg in over 5000 elderly patients with chronic systolic heart failure of ischaemic aetiology.
In HPS, diagnoses of heart failure weren’t recorded at baseline, and so the effects of simvastatin in heart failure patients cannot be directly estimated.

9. 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.
Our aim was therefore to use N-BNP as a surrogate for pre-existing heart failure, and to estimate the effect of simvastatin on risk of major vascular events and heart failure hospitalisation or death, separately according to N-BNP level.
First however, the PREDICTIVE value of N-BNP for both the incidence of major vascular diseases and hospitalisation or death due to heart failure is examined from an epidemiological perspective.

10. HPS: Relationship of baseline N-BNP to other baseline characteristics
(fmol/ml)
<60
(n=6633)
60-188
(n=5400)
(n=4244)
(n=2773)
>954
(n=1486)
Mean age (years) 60 64 67 68 70
Mean LDL (mmol/l)*
3.4
3.3
Any CHD (%)* 47 65 74 80 81
ACEI (%)* 15 16 18 23 37
β blocker (%)* 11 32
Diuretic (%)* 17 20 24 30
This table shows people split into one of five groups based on their baseline N-BNP level. These groups were chosen so that an approximately equal number of subsequent major coronary events (rather than an equal number of people) are placed into each group, which allows for more precise estimates of risk differences between groups to be made.
It can be seen that there is a striking age gradient with increasing N-BNP level, with people in the top group being 10 years older, on average, than people in the lowest group. Even taking this age difference into account however, there was a strong positive gradient in baseline CHD (the age-adjusted baseline prevalence of CHD increased from 47% in the lowest group to over 80% in the top group). In addition, there were strong positive gradients between baseline N-BNP and the use of blood pressure lowering drugs, including (as we would expect) the use of ACE inhibitors.
However, there were no differences in LDL cholesterol level by N-BNP, and there were also no major differences in gender, blood pressure level or body mass index.
* adjusted for age and sex

11. HPS: N-BNP and vascular disease
These figures show the relationships between baseline N-BNP level and the subsequent INCIDENCE of disease ADJUSTED for differences in baseline characteristics. Thus, the risk relationships you see are NOT explained by age, sex, prior disease, drug use OR the main vascular risk factors.
For major coronary events, plotting N-BNP level and risk on a log scale, you can see that the relative risk of an event over the 5 years of the trial increased strongly with increasing N-BNP level. People in the highest group had 3.7 times the risk of people in the lowest group. To put the magnitude of this risk difference into perspective, this was over three times the size of the equivalent risk gradient observed when individuals were separated according to initial blood cholesterol level, blood pressure level, or cigarette smoking status.
For stroke, a similar but less strong relationship was observed, with people in the top group having nearly twice the stroke risk of people in the bottom group.
For major vascular events (which is the combination of major coronary events, strokes and also revascularisations [which are not shown here]), the relative risk for the top group compared with the bottom group was 2.4, with a similar graded increase in risk with increasing N-BNP level.
Finally for heart failure hospitalisation or death, unsurprisingly but reassuringly, there was a very strong, continuous, log-linear association between baseline N-BNP and risk. People with the highest N-BNP levels had 13 times the risk of heart failure hospitalisation or death compared with people with the lowest level.
NB/ To convert from fmol/ml to pg/ml multiply by 8.46.

12. HPS: Effect of simvastatin allocation on
major coronary events by baseline N-BNP
SIMVASTATIN
PLACEBO
Rate ratio & 95% CI
STATIN better
PLACEBO better
(10269)
(10267)
N-BNP (fmol/l)
<60
148
270
(4.5%)
(8.1%)
60 <188
176
242
(6.4%)
(9.1%)
188 <433
186
249
(8.8%)
(11.7%)
433 <954
185
233
(13.5%)
(16.6%)
954
203
218
(26.9%)
(29.9%)
ANY
898
1212
(11.8%)
27% SE 4
reduction
(2P< )
0.4
0.6
0.8
1.0
1.2
1.4
So N-BNP level is a very strong indicator of heart failure risk. The next question is does the proportional effect of simvastatin on vascular events differ by N-BNP level?
Separately people by N-BNP level as before, it can be seen that, for major coronary events, there is a significant trend towards lower proportional benefits in people with higher baseline N-BNP levels (albeit the absolute benefits are similar in each of the groups because of the higher absolute risk in people with higher N-BNP level). It should be noted that the LDL cholesterol reduction achieved in each of these groups was the same, so this cannot explain the trend.

13. HPS: Effect of simvastatin allocation on strokes by baseline N-BNP
PLACEBO
Rate ratio & 95% CI
STATIN better
PLACEBO better
(10269)
(10267)
N-BNP (fmol/l)
<60
109
133
(3.3%)
(4.0%)
60 <188
100
121
(3.6%)
(4.6%)
188 <433
111
141
(5.3%)
(6.6%)
433 <954 79
(5.8%)
(8.6%)
954 45 69
(6.0%)
(9.5%)
ANY
444
585
(4.3%)
(5.7%)
26% SE 5
reduction
(2P< )
0.4
0.6
0.8
1.0
1.2
1.4
For stroke however, there was a suggestion of an opposite trend, with the proportional reduction in risk from simvastatin being (if anything) greater in people with the highest N-BNP levels.

14. HPS: Effect of simvastatin allocation on
major vascular events by baseline N-BNP
SIMVASTATIN
PLACEBO
Rate ratio & 95% CI
STATIN better
PLACEBO better
(10269)
(10267)
N-BNP (fmol/l)
<60
448
649
(13.6%)
(19.4%)
60 <188
468
579
(17.0%)
(21.8%)
188 <433
460
561
(26.3%)
433 <954
377
479
(27.5%)
(34.2%)
954
280
317
(37.0%)
(43.4%)
ANY
2033
2585
(19.8%)
(25.2%)
24% SE 3
reduction
(2P< )
0.4
0.6
0.8
1.0
1.2
1.4
Combining major coronary events, strokes and revascularisation procedures (for which no trend was observed), it can be seen that the relative reduction in the risk of any major vascular event was the same irrespective of N-BNP level, with each group experiencing an approximate reduction in risk of around one quarter.

15. Effect of simvastatin allocation on heart failure hospitalisation or death
PLACEBO
Rate ratio & 95% CI
STATIN better
PLACEBO better
Baseline
feature
(10269)
(10267)
N-BNP (fmol/l)
<60 21 47
(0.6%)
(1.4%)
60 <188 55
(2.0%)
(2.1%)
188 <433 83 64
(3.9%)
(3.0%)
433 <954 81
114
(5.9%)
(8.1%)
954
125
(15.1%)
(17.1%)
ANY
354
405
(3.4%)
14% SE 7
reduction
(2P=0.05)
0.4
0.6
0.8
1.0
1.2
1.4
Finally, for heart failure hospitalisation or death, there was really too little data to be able to meaningfully examine the relative effects by N-BNP level. However, overall, reducing LDL cholesterol by 1mmol/l with simvastatin was associated with a nominally significant 14% reduction in the relative risk of heart failure.

16. 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
In conclusion, in people at high risk of vascular events, N-BNP is a strong independent predictor not only of heart failure, but also of major vascular events, while in patients with high N-BNP levels (consistent with heart failure), statins produce clear benefits, with no evidence of any significant hazard.

17. Slides will be available at:

18. HPS: Effect of simvastatin allocation on
vascular mortality by baseline N-BNP
SIMVASTATIN
PLACEBO
Rate ratio & 95% CI
STATIN better
PLACEBO better
Baseline
feature
(10269)
(10267)
N-BNP (fmol/l)
<60
106
128
(3.2%)
(3.8%)
60 <188
122
160
(4.4%)
(6.0%)
188 <433
161
200
(7.6%)
(9.4%)
433 <954
175
217
(12.8%)
(15.5%)
954
232
(28.7%)
(31.8%)
ANY
781
937
(9.1%)
17% SE 4
reduction
(2P<0.0001)
0.4
0.6
0.8
1.0
1.2
1.4

19. HPS: Effect of simvastatin allocation on
non-vascular mortality by baseline N-BNP
SIMVASTATIN
PLACEBO
Rate ratio & 95% CI
STATIN better
PLACEBO better
Baseline
feature
(10269)
(10267)
N-BNP (fmol/l)
<60
120
130
(3.7%)
(3.9%)
60 <188
134
152
(4.9%)
(5.7%)
188 <433
140
116
(6.6%)
(5.4%)
433 <954 97
107
(7.1%)
(7.6%)
954 56 65
(7.4%)
(8.9%)
ANY
547
570
(5.3%)
(5.6%)
5% SE 6
reduction
0.4
0.6
0.8
1.0
1.2
1.4