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 Indicator of disease severity and prognosis in patients with heart failure –Target for treatment titration in heart failure Possible risk prediction for vascular disease 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

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

HPS: Effect on major vascular events of reducing LDL cholesterol by 1 mmol/l (10269)(10267) SIMVASTATINPLACEBORate ratio & 95% CI STATIN betterPLACEBO better Vascular event Major coronary Any stroke Revascularisation (19.8%)(25.2%) 24% SE 3 reduction (2P< ) ANY OF ABOVE

HPS: Effect of simvastatin on major vascular events subdivided by other treatments (10269)(10267) SIMVASTATINPLACEBORate ratio & 95% CI STATIN betterPLACEBO better Baseline treatment Aspirin (21.1%)(27.4%) Yes (17.5%)(21.3%) No ACE inhibitor (24.9%)(28.5%) Yes (18.6%)(24.4%) No Beta-blocker (19.5%)(26.9%) Yes (19.9%)(24.6%) No Calcium antagonist (24.7%)(31.2%) Yes (17.6%)(22.4%) No 24% SE 3 reduction (2P< ) (19.8%)(25.2%)ALL 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 Why measure N-BNP in HPS: Do statins have similar benefits in heart failure as in other patients?

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) (n=5400) (n=4244) (n=2773) >954 (n=1486) Mean age (years) Mean LDL (mmol/l)* Any CHD (%)* ACEI (%)* β blocker (%)* Diuretic (%)* * adjusted for age and sex

HPS: N-BNP and vascular disease

HPS: Effect of simvastatin allocation on major coronary events by baseline N-BNP SIMVASTATINPLACEBORate ratio & 95% CI STATIN betterPLACEBO better(10269)(10267) N-BNP (fmol/l) < (4.5%)(8.1%)  60 < (6.4%)(9.1%)  188 < (8.8%)(11.7%)  433 < (13.5%)(16.6%)  (26.9%)(29.9%) ANY (8.8%)(11.8%) 27% SE 4 reduction (2P< )

SIMVASTATINPLACEBORate ratio & 95% CI STATIN betterPLACEBO better(10269)(10267) N-BNP (fmol/l) < (3.3%)(4.0%)  60 < (3.6%)(4.6%)  188 < (5.3%)(6.6%)  433 < (5.8%)(8.6%)  (6.0%)(9.5%) ANY444585(4.3%)(5.7%) 26% SE 5 reduction (2P< ) HPS: Effect of simvastatin allocation on strokes by baseline N-BNP

SIMVASTATINPLACEBORate ratio & 95% CI STATIN betterPLACEBO better(10269)(10267) N-BNP (fmol/l) < (13.6%)(19.4%)  60 < (17.0%)(21.8%)  188 < (21.8%)(26.3%)  433 < (27.5%)(34.2%)  (37.0%)(43.4%) ANY (19.8%)(25.2%) 24% SE 3 reduction (2P< ) HPS: Effect of simvastatin allocation on major vascular events by baseline N-BNP

Effect of simvastatin allocation on heart failure hospitalisation or death SIMVASTATINPLACEBORate ratio & 95% CI STATIN betterPLACEBO better Baseline feature (10269)(10267) N-BNP (fmol/l) <602147(0.6%)(1.4%)  60 <18855 (2.0%)(2.1%)  188 < (3.9%)(3.0%)  433 < (5.9%)(8.1%)  (15.1%)(17.1%) ANY354405(3.4%)(3.9%) 14% SE 7 reduction (2P=0.05)

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:

HPS: Effect of simvastatin allocation on vascular mortality by baseline N-BNP SIMVASTATINPLACEBORate ratio & 95% CI STATIN betterPLACEBO better Baseline feature (10269)(10267) N-BNP (fmol/l) < (3.2%)(3.8%)  60 < (4.4%)(6.0%)  188 < (7.6%)(9.4%)  433 < (12.8%)(15.5%)  (28.7%)(31.8%) ANY781937(7.6%)(9.1%) 17% SE 4 reduction (2P<0.0001)

HPS: Effect of simvastatin allocation on non-vascular mortality by baseline N-BNP SIMVASTATINPLACEBORate ratio & 95% CI STATIN betterPLACEBO better Baseline feature (10269)(10267) N-BNP (fmol/l) < (3.7%)(3.9%)  60 < (4.9%)(5.7%)  188 < (6.6%)(5.4%)  433 < (7.1%)(7.6%)  (7.4%)(8.9%) ANY547570(5.3%)(5.6%) 5% SE 6 reduction