1. CM-1 ACE Inhibitor Dosing Considerations in CHARM John J.V. McMurray, MD Professor of Medical Cardiology Western Infirmary Glasgow Scotland UK

2. CM-2 What is Optimal Treatment With an ACE Inhibitor? Which drug? What dose? The evidence-base: randomized controlled outcome trials Studies looking at higher than evidence- based doses?

3. CM-3 Which drug? The ACE inhibitors Used in Randomized Controlled Outcome Trials in Acute MI and CHF Captopril (SAVE) Ramipril (AIRE) Trandolapril (TRACE) Lisinopril (ATLAS, GISSI 3) Enalapril (CONSENSUS, SOLVD, VHeFT II) CHARM investigators were advised that these were the preferred ACE inhibitors – at investigator meetings and in study protocol

4. CM-4 Clinical Programme Protocol— CHARM Added Instructions to Investigators on Dosing of ACEi “… the investigator is asked to attempt to optimize therapy for each individual patient. In this component study baseline therapy with an ACE inhibitor is mandatory. No dose of an ACE inhibitor is, however, mandated. The investigator is free to choose the dose of ACE inhibitor that is optimum for each patient, based on tolerability (e.g. taking into account blood pressure, renal function etc.) and information from the large randomized trials. The investigator is reminded that these trials had target ACE inhibitor doses (Appendix 1) higher than those commonly used in clinical practice. Furthermore, the recent ATLAS study has also shown that larger ACE inhibitor doses reduce morbidity to a greater extent than lower doses.” 46 Clinical programme protocol-CHARM

5. CM-5 What dose? Randomized Controlled Outcome Trials Using Forced Titration of ACE Inhibitors in Acute MI and CHF Trial ACE inhibitor Target dose, mg Mean daily dose, mg SAVE (1992)captopril50 tid121 SOLVD-T (1991)enalapril10 bid16.6 AIRE (1993)ramipril5 bid8.7 TRACE (1995)trandolapril4 qd3 ATLAS (1999)lisinopril † 2.5 - 5.0 qd 32.5 - 35 qd 3.2 22.5 GISSI 3 (1994)lisinopril10 mg qdN/A These were the target doses CHARM investigators advised to aim for – at investigator meetings and in protocol † US and European guidelines recommend a target dose of 20 mg/d.

6. CM-6 Use of ACE Inhibitors: What happened in CHARM Added? Investigators were provided with a list of preferred ACE inhibitors and doses, based on randomized controlled outcome trials Investigators asked to ensure patients on “an individualized optimum” dose of ACE inhibitor at baseline Stable dose of ACEi for ≥ 30 days

7. CM-7 Which drug? The ACE inhibitors Used in Randomized Controlled Outcome Trials in Acute MI and CHF Captopril (SAVE) Ramipril (AIRE) Trandolapril (TRACE) Lisinopril (ATLAS, GISSI 3) Enalapril (CONSENSUS, SOLVD, VHeFT II) CHARM investigators were advised that these were the preferred ACE inhibitors. Approx. 80% of patients were treated with one of these evidence-based ACE inhibitors

8. CM-8 FDA Approved ACE Inhibitors For Heart Failure ACE inhibitorCHARM Added Proportion of patients at baseline, % FDA labeled HF dose Baseline mean dose mg/d Enalapril275 - 20 (40)17 Lisinopril195 - 40 (40)18 Captopril17150 - 300 (450)83 Ramipril11107 Trandolapril642 Perindopril † 6NA4 Quinapril520 - 4025 Fosinopril520 - 4020 Benazepril † 3NA26 Cilazapril †, Moexipril † 1NA– † NA = Not FDA approved for heart failure.

9. CM-9 Dose of ACE Inhibitor: What happened in CHARM Added? Investigators reported that 96% of patients were taking an individualized, optimum, dose of ACE inhibitor at baseline (CRF check box) Supporting evidence?

10. CM-10 Dose of ACE Inhibitor Achieved in CHARM Added Compared to Randomized Outcome Trials Using Forced Titration Trial ACE-inhibitor (% in CHARM Added) Mean dose in outcome trial (mg) Mean dose in CHARM-Added (mg) SOLVDEnalapril (27%)16.617.0 ATLASLisinopril (19%)3.2 † 22.5 † 17.7 GISSI 3LisinoprilN/A17.7 SAVECaptopril (17%)12182.5 AIRERamipril (11%)8.77.1 TRACETrandolapril (6%)3.02.5 † US and European guidelines recommend target dose of 20 mg/d.

11. CM-11 TrialN Target dose, mg Mean daily dose, mg CONSENSUS (1987)12720 bid18.4 SOLVD-T (1991) † 128410 bid16.6 SOLVD-P (1992)211110 bid16.7 V-HeFT II (1991)40310 bid15.0 OVERTURE (2002)288410 bid17.7 CARMEN (2004)190 E only 191 E+Carv 10 bid 16.8 14.9 CHARM Added680-17.0 Dose of ACE Inhibitor (Enalapril) Achieved in CHARM Added Compared to Randomized Outcome Trials Using Forced Titration † N.B. active run-in; 49% reached target dose.

12. CM-12 CHARM Investigators Did Optimize ACE Inhibitor Dose TrialMERIT-HF CIBIS-2 † RALES CHARM Added Enalapril1412.71517.0 Captopril6448.36282.5 Lisinopril16.512.814.317.7 Ramipril6.24.2-7.1 Daily dose of ACE inhibitor in CHARM Added compared to other outcome studies using “add-on” therapy † Personal communication.

13. CM-13 ACE Inhibitor Doses in CHF—CHARM Added Compared to Community and Hospital Practice Study/country/settingCaptoprilEnalaprilLisinoprilRamipril McGrae, et al, 1997 (US – hospital, n = 612) 217.7-- Smith, et al, 1998 (US – community [CVHS], n = 129) 548.911.7- McAlister, et al, 1999 (Canada – specialist HF clinic, n = 566) 62.110.710.3- Chen, et al, 2001 (US – hospital, n = 554) 58.812.010.0- EuroHF study, 2004 (Europe – hospital n = 11,304) 57.614.412.35.1 IMPROVEMENT-HF, 2002 (UK – Community, n = 599) 49.613.811.24.6 CHARM Added (n = 2548)82.517.017.77.1

14. CM-14 Would a Larger Than Evidence-Based Dose of an ACE Inhibitor Have Made a Difference? Many ACE inhibitor dose-response studies Most compared low dose(s) to a proven, evidence-based, dose (eg, NETWORK) or low dose(s) to a medium/high dose eg, (ATLAS) What about comparison of a proven, evidence- based, dose to an even higher dose? ACE inhibitor dose response studies

15. CM-15 Larger Than Evidence-Based Doses of ACE Inhibitors – Two Questions: Can they be achieved? Note: SOLVD-T target enalapril 10 mg bid 49% achieved target; mean dose achieved 16.6 mg CONSENSUS target 20 mg bid 22% achieved target; mean dose achieved 18.4 mg Is there additional benefit?

16. CM-16 Enalapril 20 mg/d vs 60 mg/d trial 248 patients with CHF (mean LVEF 19%) randomized to standard-dose (20 mg/d) or high-dose (60 mg/d) enalapril. 12 months follow-up Doses achieved: 17.9 mg/d and 42.5 mg/d, respectively 72.5% and 32.5%, respectively reached target dose by 3 months No statistically significant or clinically meaningful difference between groups for change in blood pressure, heart rate, LVEF or NYHA class No significant difference in any clinical outcome (but small numbers) Nanas J, et al. J Am Coll Cardiol. 2000;36:2090-2095.

17. CM-17 20 mg/d 60 mg/d Nanas J, et al. J Am Coll Cardiol. 2000;36:2090-2095. p = 0.645 Enalapril 20 mg/d vs 60 mg/d Trial: Death or HF Hospitalization—Event Free Survival 0246810 12 0 20 40 60 80 100 Freedom from death or HF hospitalization, % Time (months)

18. CM-18 Summary: Optimal ACE Inhibitor Treatment CHARM Added patients received Evidence-based ACE inhibitor (80% of patients) ACE inhibitor doses comparable to those achieved with forced titration (eg, 17 mg of enalapril) Higher doses of ACE inhibitor than in other recent “add-on” treatment trials Much higher doses of ACE inhibitor than in ordinary clinical practice No evidence that exceeding proven dose of ACE inhibitor is advantageous

19. CM-19 Conclusion: CHARM Added ACE Inhibitor Dosing Evidence-based treatment with ACE inhibitor advocated by protocol and used by investigators CHARM Added did test the hypothesis of whether adding an ARB to a evidence-based dose of ACE inhibitor would offer further clinical benefit