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Combining ACEI and ARB
Therapy: The Next Step?
Pharmacokinetic rationale for combination
ACEI and ARB therapy
• Provides more complete RAAS blockade
• Improves BP control
• Preserves and increases tissue protective properties of bradykinin
• Averts negative consequences of “Ang II escape”
– Excess Ang II will stimulate AT2 receptors with potential for benefit
• Enhances vascular and metabolic pleiotropic effects of ACEIs
and ARBs
• Potential for additive clinical benefits in selected patients
Dzau V. J Hypertens. 2005;23(suppl 1):S9-17.
Unger T, Stoppelhaar M. Am J Cardiol. 2007;100(suppl):25J-31.
Key biochemical and hormonal effects of dual
RAAS blockade
ACEIs
ARBs
ACEIs + ARBs
Enzymes
Plasma/tissue ACE

---

Substrate
Bradykinin

---

Receptor stimulation
AT1R
AT2R
Bradykinin (B2)
----



--- or 
*

End products
Ang II
Non-ACE-induced Ang II
Aldosterone






 or --*

Miscellaneous
Tissue RAAS
Nitric oxide




*

*Theoretical
 = Increased,  = Decreased, --- = No change
 or  = Additive effect
Adapted from Azizi M, Ménard J. Circulation. 2004;109:2492-9.
ACEI-ARB combination vs ACEI monotherapy in
ambulatory SBP: Meta-analysis
Favors combination
Favors ACEI alone
Jacobsen 2002
Azizi 2000
Stergiou 2000
Agarwal 2001
Ferrari 2002
Rossing 2002
Jacobsen 2003
Jacobsen 2003a
Rossing 2003
Morgan 2004
Total
-10
-5
0
5
10
Δ SBP for combination vs ACEI alone
(mm Hg, 95% CI)
Doulton TWR et al. Hypertension. 2005;45:880-6.
ACEI-ARB combination vs ARB monotherapy in
ambulatory SBP: Meta-analysis
Favors combination
Favors ARB alone
Azizi 2000
Ferrari 2002
Jacobsen 2003
Morgan 2004
Overall effect
-10
-5
0
5
10
Δ SBP for combination vs ARB alone
(mm Hg, 95% CI)
Doulton TWR et al. Hypertension. 2005;45:880-6.
Meta-analysis: ACEI + ARB reduces proteinuria
compared with monotherapy (1 to 4 months)
Patients with microalbuminuria or proteinuria, with/without diabetes
ACEI + ARB
(n)
Comparator: ARB
(14 studies)
Comparator: ACEI
(21 studies)
254
418
Comparator
(n)
Favors
ACEI + ARB
Favors
comparator
234
0.76 (0.68-0.85)
417
0.78 (0.72-0.84)
-10
-5
0
5
10
Ratio of means (95% confidence interval)
Adapted from Kunz R et al. Ann Intern Med. 2008;148:30-8.
DETAIL: ARB and ACEI yield similar changes
in GFR
N = 250 with T2DM and early nephropathy, 5-year follow-up
5
Δ GFR at 5 years
0
Δ GFR
(mL/min
per 1.73 m2)
-5
Telmisartan: 17.5
Enalapril:
15.0
-10
GFR Treatment difference
-2.6 (-7.1 to 2.0)
-15
-20
-25
0
No. at risk (no. carried forward)
Enalapril
Telmisartan
1
2
3
4
5
113 (23)
102 (21)
113 (40)
102 (31)
113 (39)
103 (41)
Year
103 (0)
86 (0)
110 (22)
99 (23)
Telmisartan is not inferior to enalapril in providing long-term
renoprotection in persons with T2DM
GFR = glomerular filtration rate
Barnett AH et al. N Engl J Med. 2004;351:1952-61.
ACEI + ARB in HF
HF hospitalization
ARB + ACEI better
All-cause mortality
ARB + ACEI better
ACEI alone better
ACEI alone better
Val-HeFT
(HF)
CHARM
(HF)
VALIANT
(post MI + HF/LV dysfunction)
0.6
0.8
1.0
1.2
1.4
0.6
0.8
1.0
1.2
1.4
Odds ratio (95% CI)
Voors AA, van Veldhuisen DJ. Int J Cardiol. 2004;97:345-8.
ACEI + ARB enhances regression of LV
hypertrophy
N = 33 with T2DM and nephropathy
160
150
*
140
LVMI
(g/m2)
*
*
*
*†
130
*†
120
110
100
0
Losartan 100 mg
*P < 0.05 vs baseline, †P < 0.05 vs enalapril and losartan
LVMI = left ventricular mass index
6
Months
12
Enalapril 10 mg
Combination
Suzuki H et al. Ther Apher Dial. 2004;8:320-7.
RAAS inhibition in prevention of atrial fibrillation
ACE inhibitors
CAPP
GISSI
HOPE
SOLVD
STOP-H2
TRACE
Ueng
Van Den Berg
Subtotal
Favors treatment
Favors control
Captopril
Lisinopril
Ramipril
Enalapril
Enalapril
Trandolapril
Enalapril
Lisinopril
ARBs
CHARM
LIFE
Madrid
ValHeFT
Subtotal
Candesartan
Losartan
Irbesartan
Valsartan
Subtotal
Total
Total
0.1
0.2
0.5
1
2
RR (random)
95% CI
5
Salehian O et al. Am Heart J. 2007;154:448-53.
Healy JS et al. J Am Coll Cardiol. 2005;45:1832-9.
Meta-analysis: Adverse effects of ACEIs + ARBs
in symptomatic LV dysfunction (LVD)
VALIANT, CHARM-Added, Val-HeFT, RESOLVD; N = 17,337;
mean follow-up 25 months
Discontinued Rx for AE
Chronic HF
AMI with LVD
Worsening renal function
Chronic HF
AMI with LVD
Hyperkalemia
Chronic HF
AMI with LVD
Symptomatic hypotension
Chronic HF
AMI with LVD
Rx (%)
Control (%)
Relative risk (95% CI)
15
9.0
11
7.6
1.38 (1.22-1.55)
1.17 (1.03-1.34)
3.3
4.8
1.5
3.0
2.17 (1.59-2.97)
1.61 (1.31-1.98)
3.5
1.2
0.7
0.9
4.87 (2.39-9.94)
1.33 (0.90-1.98)
2.4
18.1
1.5
11.9
1.50 (1.09-2.07)
1.48 (1.33-3.18)
Phillips CO et al. Arch Intern Med. 2007;167:1930-6.
Risk of MI with ARBs vs ACEIs, other active
drugs, and placebo
Meta-analysis of 11 major ARB trials
Favors ARBs
Favors other drugs
ARBs vs ACEI
ARBs vs placebo and active drug
ARBs vs active drug
ARBs vs placebo
0.7
0.8
0.9
1.0
1.1
1.2
1.3
1.4
RR
(95% CI)
Volpe M et al. J Hypertens. 2005;23:2113-8.
ONTARGET/TRANSCEND trials: RAAS
modulation after HOPE—the next chapter
ONTARGET
TRANSCEND
730 centers, 40 countries
N = 25,620
Telmisartan
+
placebo
Noninferiority
Ramipril
+
placebo
N = 5776
Telmisartan
+
Ramipril
Telmisartan
Placebo
Superiority
Superiority
Primary outcome: CV death, MI,
stroke, hospitalization for HF
Follow-up
5.5 years
Primary outcome: CV death, MI,
stroke, hospitalization for HF
ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
ONTARGET/TRANSCEND: Substudies
ONTARGET
Overview
ONTARGET
TRANSCEND
Principle trial
Parallel trial
Substudies
Ambulatory BP monitoring
Cardiac MRI
OGTT
Erectile dysfunction
Health economics
Blood markers
Arterial stiffness
ONTARGET/TRANSCEND Investigators.
Am Heart J. 2004;148:52-61.
ONTARGET: Study design
Ongoing Telmisartan Alone and in Combination with Ramipril Global
Endpoint Trial
N = 25,620
≥55 Years with coronary, cerebrovascular, or peripheral vascular disease
or diabetes + end-organ damage
Ramipril 10 mg
Telmisartan 80 mg
Ramipril 10 mg +
telmisartan 80 mg
Primary outcome: CV death, MI, stroke, hosp for HF
Secondary outcomes: Newly diagnosed HF, T2DM,
or AF; revascularization procedures; development of
dementia/cognitive decline, nephropathy
ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
ONTARGET: Baseline medical conditions vs
HOPE
ONTARGET
HOPE
Hypertension
68.3
46.5
Diabetes
37.3
38.3
MI
48.7
52.8
Stable angina
34.8
55.8
Unstable angina
14.8
25.7
CABG
22.1
26.0
PCI
28.9
18.0
Stroke/TIA
20.7
10.8
Intermittent claudication
11.8
15.9
Peripheral artery surgery
5.8
6.2
Carotid endarterectomy
2.8
2.7
Current (%)
History (%)
ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
ONTARGET: Baseline medications vs HOPE
ONTARGET
HOPE
ACEIs
57.5
11.6
ARBs
8.6
–
-blockers
56.9
39.5
Statins
60.7
28.9
Aspirin
75.6
73.6
CCBs
33.5
47.6
Diuretics
27.9
15.1
Nitrates
29.2
31.1
Oral hypoglycemics
25.0
21.8
Insulin
10.4
11.7
Medications (%)
ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
ONTARGET: Time to primary outcome
0.20
0.15
Cumulative 0.10
hazard ratio
0.05
0.00
0
1
2
3
4
5
Follow-up (years)
Telmisartan
Ramipril
Telmisartan plus ramipril
ONTARGET Investigators. N Engl J Med. 2008;358:1547-59.
Primary outcome of ONTARGET compared
to HOPE
n
Ramipril
Telmisartan
n (%)
n (%)
8576
8542
1412 (16.5)
1423 (16.7)
Telmisartan vs ramipril
RR (95% CI)
P*
1.01 (0.94–1.09)
0.004
1.02 (0.95–1.10)
0.006
0.99 (0.91–1.07)
0.001
0.99 (0.91–1.07)
0.001
Primary outcome
CV death, MI, stroke,
HF hosp
(Adjusted for SBP)
HOPE primary outcome
CV death, MI, stroke
(Adjusted for SBP)
*P for noninferiority
1210 (14.1)
1190 (13.9)
ONTARGET Investigators. N Engl J Med. 2008;358:1547-59.
Yusuf S. www.clinicaltrialresults.org.
Telmisartan better
Primary composite outcome
CV death/MI/Stroke
(HOPE composite outcome)
0.8
*Comparison with noninferiority margin
Noninferiority margin
ONTARGET: Noninferiority comparison
Ramipril better
P = 0.004*
P = 0.001*
1.0
1.2
Relative risk (95% CI)
ONTARGET Investigators.
N Engl J Med. 2008;358:1547-59.
ONTARGET: Combination vs ramipril in
pre-specified subgroups
Incidence of primary
outcome in ramipril group (%)
Primary composite
16.5
Hx of CVD
No Hx of CVD
16.8
13.1
SBP ≤134 mm Hg
SBP 134 to ≤150 mm Hg
SBP >150 mm Hg
16.2
14.9
18.4
Diabetes
No Diabetes
20.7
14.0
HOPE low risk score
HOPE medium risk score
HOPE high risk score
10.1
15.0
24.4
Age <65 years
Age 65 to <75 years
Age ≥75 years
13.0
17.3
24.2
Male
Female
16.7
15.8
Telmisartan +
ramipril better
0.7
Ramipril
better
1.0
1.3
Relative risk (95% CI)
ONTARGET Investigators. N Engl J Med. 2008;358:1547-59.
ONTARGET: Effects of telmisartan, ramipril, and
combination on primary renal outcome
0.20
0.15
Cumulative incidence
of primary renal
0.10
outcome*
0.05
0
T vs R; P = 0.068
T+R vs R; P = 0.037
0
Telmisartan (T) + ramipril (R)
*Dialysis, doubling of serum creatinine, death
1
2
3
Follow-up (years)
Telmisartan
4
5
Ramipril
Mann JFE et al. Lancet.
2008;372:547-53.
ONTARGET: Relative risk of primary renal
outcome by subgroup: Ramipril vs telmisartan
n
Primary composite
Incidence of 10
outcome in
ramipril group (%)
Favors Favors
telmisartan ramipril
P for
interaction
17,118
13.4
6982
17.0
10,136
11.0
516
47.0
16,602
12.5
3819
9.0
13,299
14.7
2673
27.3
12,990
10.5
0.520
eGFR <60 mL/min per 1.73 m2
4046
19.2
0.836
eGFR ≥60 mL/min per 1.73 m2
12,945
11.4
History of hypertension
11,780
14.6
5333
10.8
Diabetes
No diabetes
Overt diabetic nephropathy
No overt diabetic nephropathy
No diabetes, no hypertension
Diabetes or hypertension
Micro- or macroalbuminuria
No micro- or macroalbuminuria
No history of hypertension
0.5
eGFR = estimated GFR
0.864
0.319
0.645
0.958
0.7
1.0
1.3
RR in telmisartan group (95% CI)
Mann JFE et al. Lancet. 2008;372:547-53.
ONTARGET: Relative risk of primary renal outcome
by subgroup: Ramipril vs ramipril plus telmisartan
n
Primary composite
Incidence of 10
outcome in
ramipril group (%)
17,078
13.4
6900
17.0
10,178
11.0
474
47.0
No overt diabetic nephropathy 16,604
12.5
No diabetes, no hypertension
3786
9.0
13,292
14.7
2648
27.3
No micro- or macroalbuminuria 12,981
10.5
eGFR <60 mL/min per 1.73 m2
3988
19.2
eGFR ≥60 mL/min per 1.73 m2
12,963
11.4
History of hypertension
11,745
14.6
5328
10.8
Diabetes
No diabetes
Overt diabetic nephropathy
Diabetes or hypertension
Micro- or macroalbuminuria
No history of hypertension
Favors
ramipril +
telmisartan
Favors
ramipril
P for
interaction
0.783
0.188
0.019
0.131
0.804
0.048
0.5
0.7
1.0
1.3
1.5
1.7
RR in ramipril + telmisartan group (95% CI)
Mann JFE et al. Lancet. 2008;372:547-53.
ONTARGET: Decline in eGFR with ramipril,
telmisartan, and combination
-6
-5
-4
Decrease in eGFR
from run-in
-3
-2
-1
0
Run-in
Week 6
Year 2
Time period
Telmisartan + ramipril
Telmisartan
Study
end
Ramipril
Mann JFE et al. Lancet. 2008;372:547-53.
ONTARGET: Time to permanent discontinuation
of study medication
0.4
0.3
Cumulative
0.2
hazard ratio
0.1
0.0
0
1
Telmisartan
2
3
Follow-up (years)
4
Ramipril
Yusuf S. www.clinicaltrialresults.org.
ONTARGET: Study medication discontinuation–
telmisartan vs ramipril
Reason for
permanent
discontinuation
Ramipril
(n = 8576)
n
Telmisartan
(n = 8542)
n
Hypotension
149
Syncope
Telmisartan vs ramipril
RR
P
229
1.54
<0.001
15
19
1.27
0.49
Cough
360
93
0.26
<0.001
Diarrhea
12
19
1.59
0.20
Angioedema
25
10
0.4
0.01
Renal Impairment
60
68
1.14
0.46
2099
1962
0.94
0.02
All discontinuations*
*Includes permanent and temporary discontinuations
ONTARGET Investigators.
N Engl J Med. 2008;358:1547-59.
ONTARGET: Study medication discontinuation–
ramipril vs combination
Reason for
permanent
discontinuation
Ramipril Combination
(n = 8576)
(n = 8502)
n
n
Combination vs ramipril
RR
P
Hypotension
149
406
2.75
<0.001
Syncope
15
29
1.95
0.03
Cough
360
392
1.10
0.19
Diarrhea
12
39
3.28
<0.001
Angioedema
25
18
0.73
0.30
Renal Impairment
60
94
1.58
<0.001
2099
2495
1.20
<0.001
All discontinuations*
*Includes permanent and temporary discontinuations
ONTARGET Investigators.
N Engl J Med. 2008;358:1547-59.
ONTARGET: Conclusions
• Telmisartan is noninferior to ramipril, with most
benefits preserved
– Primary composite outcome (P = 0.004)
– HOPE primary outcome (P = 0.001)
• Results are consistent over a range of secondary
outcomes and subgroup data
• Telmisartan exhibits slightly superior tolerability:
– Fewer discontinuations due to cough and angioedema
– More mild hypotensive symptoms, no difference in severe
hypotensive symptoms or syncope
Combination therapy vs ramipril:
Not more effective in reducing primary outcome
More adverse events
ONTARGET Investigators.
N Engl J Med. 2008;358:1547-59.
ONTARGET: Implications
• In patients with vascular disease or high-risk diabetes
and no heart failure, telmisartan is an equally effective
alternative to ramipril and less likely to cause
angioedema
• Risk/benefit ratios should be considered when guiding
optimal therapy in high-risk patients
ONTARGET Investigators.
N Engl J Med. 2008;358:1547-59.
TRANSCEND: Study design
N = 5776
≥55 Years with coronary, cerebrovascular, or peripheral vascular disease or
diabetes + end-organ damage; intolerant of ACEI
Telmisartan 80 mg
Placebo
Primary outcome: CV death, MI, stroke, hosp for HF
Secondary outcomes: Newly diagnosed HF, T2DM,
and AF; revascularization procedures; development
of dementia/cognitive decline, nephropathy
ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
TRANSCEND: Baseline medical conditions vs
HOPE
TRANSCEND
Telmisartan
Placebo
HOPE
Current (%)
Hypertension
Diabetes
76.5
35.8
76.3
35.6
46.5
38.3
History (%)
MI
Stable angina
Unstable angina
CABG
PCI
Stroke/TIA
Peripheral artery disease
46.8
37.0
15.9
19.2
26.5
21.9
11.8
45.8
37.3
14.6
18.5
25.8
22.0
10.9
52.8
55.8
25.7
26.0
18.0
10.8
15.9
ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
TRANSCEND Investigators. Lancet. 2008;372:1174-83.
TRANSCEND: Baseline medications vs HOPE
TRANSCEND
Telmisartan
Placebo
HOPE
ACEIs
–
–
11.6
ARBs
29.6
30.2
–
-blockers
59.3
57.2
39.5
Statins
55.7
54.7
28.9
Aspirin
75.0
74.4
73.6
Thienopyridines
10.8
10.6
–
Diuretics
33.2
32.8
15.1
CCBs
39.9
40.4
47.6
Medications (%)
ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
TRANSCEND Investigators. Lancet. 2008;372:1174-83.
TRANSCEND: Treatment effect on the primary
outcome
Hazard ratio 0.92 (95% CI 0.81-1.05)
P = 0.216
0.20
0.15
Cumulative
incidence (%)
0.10
0.05
0
0
1
2
3
4
5
Follow-up (years)
Placebo
Telmisartan
TRANSCEND Investigators. Lancet. 2008;372:1174-83.
TRANSCEND: Treatment effect on components
of primary outcome
Event rate (%)
Telmisartan
Placebo
HR (95% CI)
P
CV death
7.7
7.5
1.03
(0.85-1.24)
0.778
MI
3.9
5.0
0.79
(0.62-1.01)
0.059
Stroke
3.8
4.6
0.83
(0.64-1.06)
0.136
HF hosp
4.5
4.3
1.05
(0.82-1.34)
0.694
TRANSCEND Investigators. Lancet. 2008;372:1174-83.
TRANSCEND and PRoFESS combined results:
Evidence for delayed benefit
CV death, MI, stroke, HF hospitalization
Event rate (%)
Telmisartan
Placebo
HR (95% CI)
P
PRoFESS
13.5
14.4
0.93
(0.86-1.01)
0.067
TRANSCEND
15.7
17.0
0.91
(0.80-1.05)
0.205
Combined data
at ≤6 mo
4.2
3.7
1.12
(0.99-1.27)
0.075
Combined data
at >6 mo
10.3
11.7
0.86
(0.80-0.94)
<0.001
TRANSCEND Investigators. Lancet. 2008;372:1174-83.
TRANSCEND: Conclusions and implications
In a population of high-risk, ACEI-intolerant patients, treatment
with angiotensin receptor blockade (telmisartan)
• Was well tolerated
• Showed no effect vs placebo on hospitalizations for heart
failure, consistent with PRoFESS
• Demonstrated modest, nonsignificant reduction in MI and
stroke
• Analyses suggested greater benefit might have been achieved
with more prolonged treatment
Telmisartan is a potential treatment for patients with
vascular disease or high-risk diabetes,
if they are unable to tolerate an ACEI
TRANSCEND Investigators. Lancet. 2008;372:1174-83.
Evaluation of combined ACEI/ARB therapy:
What the evidence shows
BP reduction
Evidence for additive BP-lowering effects
Renal protection
Evidence for additive benefit in hypertensive renal disease
but not in atherosclerotic vascular disease or diabetes with
end-organ damage
Cardiac effects
Some evidence for additive benefit in HF/post MI LVD
but not in atherosclerotic vascular disease or diabetes
with end-organ damage
Doulton TWR et al. Hypertension. 2005.
Nakao N et al. Lancet. 2003.
Kasama S et al. J Nucl Med. 2003.
Voors AA, van Veldhuisen DJ. Int J Cardiol. 2004.
ONTARGET Investigators. N Engl J Med. 2008.
Mann JFE et al. Lancet. 2008.
TRANSCEND Investigators. Lancet. 2008.