CM-1
ACE Inhibitor Dosing
Considerations in CHARM
John J.V. McMurray, MD
Professor of Medical Cardiology
Western 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?
Which drug? The ACE inhibitors Used in CM-3
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-4
46
Clinical Programme Protocol—
CHARM Added
Clinical programme protocol-CHARM
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.‖
What dose? Randomized Controlled CM-5
Outcome Trials Using Forced Titration of
ACE Inhibitors in Acute MI and CHF
ACE Target dose, Mean daily
Trial inhibitor mg 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 3.2
32.5 - 35 qd 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
Which drug? The ACE inhibitors Used in CM-7
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 FDA labeled Baseline
of patients HF dose mean dose
at baseline, % 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?
Dose of ACE Inhibitor Achieved in CM-10
CHARM Added Compared to Randomized
Outcome Trials Using Forced Titration
ACE-inhibitor Mean dose in Mean dose in
Trial (% in CHARM outcome trial CHARM-Added
Added) (mg) (mg)
SOLVD Enalapril (27%) 16.6 17.0
ATLAS Lisinopril (19%) 3.2† 17.7
22.5†
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
Dose of ACE Inhibitor (Enalapril) Achieved in
CHARM Added Compared to Randomized
Outcome Trials Using Forced Titration
Target dose, Mean daily
Trial N mg 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 10 bid 16.8
191 E+Carv 10 bid 14.9
CHARM Added 680 - 17.0
† N.B. active run-in; 49% reached target dose.
CM-12
CHARM Investigators Did Optimize
ACE Inhibitor Dose
Daily dose of ACE inhibitor in CHARM Added compared
to other outcome studies using ―add-on‖ therapy
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
† 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 21 7.7 - -
(US – hospital, n = 612)
Smith, et al, 1998 54 8.9 11.7 -
(US – community [CVHS], n = 129)
McAlister, et al, 1999 (Canada – 62.1 10.7 10.3 -
specialist HF clinic, n = 566)
Chen, et al, 2001 58.8 12.0 10.0 -
(US – hospital, n = 554)
EuroHF study, 2004 (Europe – 57.6 14.4 12.3 5.1
hospital n = 11,304)
IMPROVEMENT-HF, 2002 (UK – 49.6 13.8 11.2 4.6
Community, n = 599)
CHARM Added (n = 2548) 82.5 17.0 17.7 7.1
Would a Larger Than Evidence-Based CM-14
Dose of an ACE Inhibitor Have Made a
Difference?
ACE inhibitor dose response studies
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?
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.
Enalapril 20 mg/d vs 60 mg/d Trial: CM-17
Death or HF Hospitalization—Event
Free Survival
100
Freedom from death or HF
80
hospitalization, %
20 mg/d
60 60 mg/d
40
20
p = 0.645
0
0 2 4 6 8 10 12
Time (months)
Nanas J, et al. J Am Coll Cardiol. 2000;36:2090-2095.
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