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Funding to Oxford University for MRC/BHF Heart Protection Study

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.

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Funding to Oxford University for MRC/BHF Heart Protection Study

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  1. Funding to Oxford Universityfor 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

  2. 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 GroupUniversity 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

  4. 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

  5. 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

  6. HPS: Effect on major vascular events of reducing LDL cholesterol by 1 mmol/l Vascular 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 reduction (19.8%) (25.2%) (2P<0.00001) 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 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<0.00001) 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

  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.

  10. HPS: Relationship of baseline N-BNP to other baseline characteristics * adjusted for age and sex

  11. HPS: N-BNP and vascular disease

  12. SIMVASTATIN PLACEBO Rate ratio & 95% CI N-BNP (fmol/l) (10269) (10267) STATIN better PLACEBO better <60 148 (4.5%) 270 (8.1%) ³ 60 <188 176 (6.4%) 242 (9.1%) ³ 188 <433 186 (8.8%) 249 (11.7%) ³ 433 <954 185 (13.5%) 233 (16.6%) ³ 954 203 (26.9%) 218 (29.9%) 27% SE 4 ANY 898 (8.8%) 1212 (11.8%) reduction (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4 HPS: Effect of simvastatin allocation on major coronary events by baseline N-BNP

  13. SIMVASTATIN PLACEBO Rate ratio & 95% CI N-BNP (fmol/l) (10269) (10267) STATIN better PLACEBO better <60 109 (3.3%) 133 (4.0%) ³ 60 <188 100 (3.6%) 121 (4.6%) ³ 188 <433 111 (5.3%) 141 (6.6%) ³ 433 <954 79 (5.8%) 121 (8.6%) ³ 954 45 (6.0%) 69 (9.5%) 26% SE 5 ANY 444 (4.3%) 585 (5.7%) reduction (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4 HPS: Effect of simvastatin allocation on strokes by baseline N-BNP

  14. SIMVASTATIN PLACEBO Rate ratio & 95% CI N-BNP (fmol/l) (10269) (10267) STATIN better PLACEBO better <60 448 (13.6%) 649 (19.4%) ³ 60 <188 468 (17.0%) 579 (21.8%) ³ 188 <433 460 (21.8%) 561 (26.3%) ³ 433 <954 377 (27.5%) 479 (34.2%) ³ 954 280 (37.0%) 317 (43.4%) 24% SE 3 ANY 2033 (19.8%) 2585 (25.2%) reduction (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4 HPS: Effect of simvastatin allocation on major vascular events by baseline N-BNP

  15. Baseline SIMVASTATIN PLACEBO Rate ratio & 95% CI feature (10269) (10267) STATIN better PLACEBO better N-BNP (fmol/l) <60 21 (0.6%) 47 (1.4%) ³ 60 <188 55 (2.0%) 55 (2.1%) ³ 188 <433 83 (3.9%) 64 (3.0%) ³ 433 <954 81 (5.9%) 114 (8.1%) ³ 954 114 (15.1%) 125 (17.1%) 14% SE 7 ANY 354 (3.4%) 405 (3.9%) reduction (2P=0.05) 0.4 0.6 0.8 1.0 1.2 1.4 Effect of simvastatin allocation on heart failure hospitalisation or death

  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

  17. Slides will be available at: www.hpsinfo.org

  18. Baseline SIMVASTATIN PLACEBO Rate ratio & 95% CI feature (10269) (10267) STATIN better PLACEBO better N-BNP (fmol/l) <60 106 (3.2%) 128 (3.8%) ³ 60 <188 122 (4.4%) 160 (6.0%) ³ 188 <433 161 (7.6%) 200 (9.4%) ³ 433 <954 175 (12.8%) 217 (15.5%) ³ 954 217 (28.7%) 232 (31.8%) 17% SE 4 ANY 781 (7.6%) 937 (9.1%) reduction (2P<0.0001) 0.4 0.6 0.8 1.0 1.2 1.4 HPS: Effect of simvastatin allocation on vascular mortality by baseline N-BNP

  19. Baseline SIMVASTATIN PLACEBO Rate ratio & 95% CI feature (10269) (10267) STATIN better PLACEBO better N-BNP (fmol/l) <60 120 (3.7%) 130 (3.9%) ³ 60 <188 134 (4.9%) 152 (5.7%) ³ 188 <433 140 (6.6%) 116 (5.4%) ³ 433 <954 97 (7.1%) 107 (7.6%) ³ 954 56 (7.4%) 65 (8.9%) 5% SE 6 ANY 547 (5.3%) 570 (5.6%) reduction 0.4 0.6 0.8 1.0 1.2 1.4 HPS: Effect of simvastatin allocation on non-vascular mortality by baseline N-BNP

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