CM-1

ACE Inhibitor Dosing Considerations in CHARM

John J.V. McMurray, MD

Professor of Medical CardiologyWestern Infirmary

Glasgow

Scotland

UK

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?

CM-3Which 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

CM-4Clinical Programme Protocol—CHARM AddedInstructions 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.”

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CM-5What dose? Randomized Controlled Outcome Trials Using Forced Titration of ACE Inhibitors in Acute MI and CHF

TrialACEinhibitor

Target dose, mg

Mean daily dose, mg

SAVE (1992) captopril 50 tid 121

SOLVD-T (1991) enalapril 10 bid 16.6

AIRE (1993) ramipril 5 bid 8.7

TRACE (1995) trandolapril 4 qd 3

ATLAS (1999) lisinopril† 2.5 - 5.0 qd

32.5 - 35 qd

3.2

22.5

GISSI 3 (1994) lisinopril 10 mg qd N/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.

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

CM-7Which 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

CM-8

FDA Approved ACE Inhibitors For Heart Failure

ACE inhibitor CHARM Added

Proportion of patients

at baseline, %

FDA labeled HF dose

Baseline mean dose

mg/d mg/d

Enalapril 27 5 - 20 (40) 17

Lisinopril 19 5 - 40 (40) 18

Captopril 17 150 - 300 (450) 83

Ramipril 11 10 7

Trandolapril 6 4 2

Perindopril† 6 NA 4

Quinapril 5 20 - 40 25

Fosinopril 5 20 - 40 20

Benazepril† 3 NA 26

Cilazapril†, Moexipril† 1 NA –

† NA = Not FDA approved for heart failure.

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?

CM-10Dose of ACE Inhibitor Achieved in CHARM Added Compared to Randomized Outcome Trials Using Forced Titration

TrialACE-inhibitor

(% in CHARM Added)

Mean dose in outcome trial

(mg)

Mean dose in CHARM-Added

(mg)

SOLVD Enalapril (27%) 16.6 17.0

ATLAS Lisinopril (19%) 3.2†

22.5†

17.7

GISSI 3 Lisinopril N/A 17.7

SAVE Captopril (17%) 121 82.5

AIRE Ramipril (11%) 8.7 7.1

TRACE Trandolapril (6%) 3.0 2.5

† US and European guidelines recommend target dose of 20 mg/d.

CM-11

Trial NTarget dose,

mgMean daily dose, mg

CONSENSUS (1987) 127 20 bid 18.4

SOLVD-T (1991)† 1284 10 bid 16.6

SOLVD-P (1992) 2111 10 bid 16.7

V-HeFT II (1991) 403 10 bid 15.0

OVERTURE (2002) 2884 10 bid 17.7

CARMEN (2004) 190 E only

191 E+Carv

10 bid

10 bid

16.8

14.9

CHARM Added 680 - 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.

CM-12

CHARM Investigators Did Optimize ACE Inhibitor Dose

Trial MERIT-HF CIBIS-2† RALES CHARM Added

Enalapril 14 12.7 15 17.0

Captopril 64 48.3 62 82.5

Lisinopril 16.5 12.8 14.3 17.7

Ramipril 6.2 4.2 - 7.1

Daily dose of ACE inhibitor in CHARM Added compared to other outcome studies using “add-on” therapy

† Personal communication.

CM-13

ACE Inhibitor Doses in CHF—CHARM Added Compared to Community and Hospital Practice

Study/country/setting Captopril Enalapril Lisinopril Ramipril

McGrae, et al, 1997 (US – hospital, n = 612)

21 7.7 - -

Smith, et al, 1998 (US – community [CVHS], n = 129)

54 8.9 11.7 -

McAlister, et al, 1999 (Canada – specialist HF clinic, n = 566)

62.1 10.7 10.3 -

Chen, et al, 2001 (US – hospital, n = 554)

58.8 12.0 10.0 -

EuroHF study, 2004 (Europe – hospital n = 11,304)

57.6 14.4 12.3 5.1

IMPROVEMENT-HF, 2002 (UK –Community, n = 599)

49.6 13.8 11.2 4.6

CHARM Added (n = 2548) 82.5 17.0 17.7 7.1

CM-14Would 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

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?

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.

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

0 2 4 6 8 10 120

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60

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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

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