Is there evidence to justify different claims for different drug classes? Presentation to:

1. Is there evidence to justify different claims for different drug classes? Presentation to: Cardiovascular & Renal Drugs Advisory Committee Food & Drug Administration Rockville MD, June 15, 2005 Stephen W. MacMahon, B.Sc., Ph.D., M.P.H., F.A.C.C.

2. Blood Pressure Lowering Treatment Trialists’ Collaboration1995-2005Secretariat: The George Institute, University of Sydney & Royal Prince Alfred HospitalPrincipal sponsor: National Health & Medical Research Council of Australia

3. Analysis cycles • 1st cycle published Lancet 2000; 355:1955-64 • 2nd cycle published Lancet 2003; 362:1527-35 • 29 randomised trials • 162,341 patients • More than 700,000 patient years

4. Treatment comparisons • Active vs. control • ACE-I vs placebo • CA vs placebo • More intensive vs less intensive • ARB vs. other regimen • Active vs. active • ACE-I vs diuretic/beta-blocker* • CA vs diuretic/beta-blocker* • ACE-I vs CA

5. Treatment comparisons • Active vs. control • ACE-I vs placebo • CA vs placebo • More intensive vs less intensive • ARB vs. other regimen • Active vs. active • ACE-I vs diuretic/beta-blocker* • CA vs diuretic/beta-blocker* • ACE-I vs CA

6. Treatment comparisons • Most trials compared treatment regimens rather single drugs • Regimens were usually based on a specific agent with the addition of others as required for BP control • In active vs. active comparisons, the control condition was pre-specified as diuretic- or beta-blocker-based therapy (mostly diuretic)

7. ACE inhibitor vs.diuretic/beta-blocker

8. Calcium antagonist vs.diuretic/beta-blocker

9. ACE inhibitor vs.calcium antagonist

10. Active vs. activeStroke BP difference (mm Hg) Favours second listed Favours first listed RR (95% CI) 2/0 ACE vs. D/BB 1.09 (1.00,1.18) 1/0 CA vs. D/BB 0.93 (0.86,1.00) 1/1 ACE vs. CA 1.12 (1.01,1.25) 0.5 1.0 2.0 Relative Risk

11. Active vs. activeCoronary heart disease BP difference (mm Hg) Favours first listed Favours second listed RR (95% CI) 2/0 ACE vs. D/BB 0.98 (0.91,1.05) 1/0 CA vs. D/BB 1.01 (0.94,1.08) 1/1 ACE vs. CA 0.96 (0.88,1.04) 0.5 1.0 2.0 Relative Risk

12. Active vs. activeHeart failure BP difference (mm Hg) Favours first listed Favours second listed RR (95% CI) 2/0 ACE vs. D/BB 1.07 (0.96,1.19) 1/0 1.33 (1.21,1.47) CA vs. D/BB 1/1 ACE vs. CA 0.82 (0.73,0.92) 0.5 1.0 2.0 Relative Risk

13. Active vs. activeComposite major CVD events BP difference (mm Hg) Favours first listed Favours second listed RR (95% CI) 2/0 ACE vs. D/BB 1.02 (0.98,1.07) 1/0 1.04 (1.00,1.09) CA vs. D/BB ACE vs. CA 1/1 0.97 (0.92,1.03) 0.5 1.0 2.0 Relative Risk

14. Active vs. activeComposite major CVD events (diabetes subgroups) BP (mmHg) Favours first listed Favours second listed RR(95%CI) ACE-I vs. D/BB 0.90 (0.74,1.11) 2.2/0.3 Diabetes 1.04 (0.98,1.04) 1.4/0.2 No diabetes p homog =0.20 Overall CA vs. D/BB 0.7/-0.8 1.02 (0.95,1.10) Diabetes 1.04 (0.99,1.10) 1.1/-0.4 No diabetes p homog =0.83 Overall ACE-I vs. CA 0.92 (0.79,1.07) 1.6/1.2 Diabetes 0.99 (0.92,1.07) 1.3/0.9 No diabetes p homog =0.37 Overall 0.25 0.5 1 2 Risk ratio Arch Int Med 2005: in press

15. ARB-based regimens vs. othersComposite outcomes(diabetes subgroups) Favours ARB Favours Other BP (mmHg) RR(95%CI) Major CVD -2.1/-0.9 0.90 (0.82,0.99) Diabetes -1.4/-0.6 0.90 (0.81,1.00) No diabetes p homog=0.94 Overall CV deaths -2.1/-0.9 Diabetes 0.99 (0.77,1.28) -1.4/-0.6 No diabetes 0.95 (0.81,1.12) p homog=0.79 Overall Total mortality -2.1/-0.9 Diabetes 0.91 (0.75,1.10) -1.4/-0.6 No diabetes 0.97 (0.86,1.09) p homog=0.55 Overall 0.25 0.5 1 2 Arch Int Med 2005: in press

16. Conclusions • Calcium antagonist and D/BB-based regimens may be more effective than ACE inhibitors for stroke prevention • ACE inhibitors and D/BB regimens are more effectivethan CA-based regimens for heart failure prevention • No differences between regimens in effects on coronary heart disease

17. Conclusions • For total cardiovascular events, there were very similar effects of: • ACE inhibitor- • calcium antagonist- • D/BB-based regimens • ARB-based regimens also reduced total CV events • Effects of all drug classes similar in diabetic and non-diabetic patients

18. Independent drug effects? • Primary focus of debate for past decade, with no consensus • Main hypothesis concerns potential advantages of agents that inhibit the renin angiotensin system • Do ACE inhibitors and angiotensin receptor blockers confer benefits “beyond blood pressure reduction”

19. Effects of RAS inhibitors • In trials of active vs. active regimens • No clear advantage of ACE inhibitor-based regimens compared with D/BB-based regimens • But moderate differences between regimens in BP lowering effects • In trials of ARB-based regimens • Uncertainty as to whether benefits are greater than those expected given the reduction in BP

20. Effects of RAS inhibitors • New analysis • Effects of ACE-I and ARB-based regimen vs. any other comparator • Stratified by BP differences between randomized groups • Cause-specific outcomes: stroke, coronary heart disease, heart failure* *trials with calcium antagonist control treatment excluded from heart failure analyses, given clear evidence of differential effect of these agents

21. "This slide contains unpublished data. If you have any questions regarding these data, please contact Stephen W. MacMahon, B.Sc., Ph.D., M.P.H., F.A.C.C., Principal Director, Professor of Cardiovascular Medicine and Epidemiology, The George Institute for International Health, The University of Sydney."

22. "This slide contains unpublished data. If you have any questions regarding these data, please contact Stephen W. MacMahon, B.Sc., Ph.D., M.P.H., F.A.C.C., Principal Director, Professor of Cardiovascular Medicine and Epidemiology, The George Institute for International Health, The University of Sydney."

23. "This slide contains unpublished data. If you have any questions regarding these data, please contact Stephen W. MacMahon, B.Sc., Ph.D., M.P.H., F.A.C.C., Principal Director, Professor of Cardiovascular Medicine and Epidemiology, The George Institute for International Health, The University of Sydney."

24. "This slide contains unpublished data. If you have any questions regarding these data, please contact Stephen W. MacMahon, B.Sc., Ph.D., M.P.H., F.A.C.C., Principal Director, Professor of Cardiovascular Medicine and Epidemiology, The George Institute for International Health, The University of Sydney."

25. Conclusions • For all regimens, size of BP reduction directly related to size of risk reduction • For coronary heart disease, BP- independent effect of ACE inhibitor-based regimens (about 10%) • For stroke and heart failure, no clear evidence of BP-independent effects of either ACE-I or ARB-based regimens

26. Conclusions • In active vs. active comparisons, the independent effect of ACE-I-based regimens was obscured by weaker BP lowering properties • Because of this practical limitation, therapeutic relevance is uncertain • Combination therapy with an ACE inhibitor and other BP lowering agents may offer greatest protection

27. Acknowledgements • Coordinating center staff: • Fiona Turnbull MD MPH • Bruce Neal MD PhD MRCP • Charles Algert MPH • Mark Woodward PhD CStat • John Chalmers MD PhD FRACP