Role of RAAS inhibition Role of RAAS inhibition in the Management of in the Management of Hypertension Hypertension Dr KyawSoe Win MBBS, M Med Sc (Int Med), MRCPUK, FRCPE, FAsCC, FAPSIC Asso: Prof / Senoir Consultant Cardiologist Department of Cardiovascular Medicine Mandalay General Hospital Hot Topic In Hypertension 2013 12 th January 2013
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Role of raas inhibition in management of hypertension
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Role of RAAS inhibition Role of RAAS inhibition in the Management of in the Management of
HypertensionHypertension
Dr KyawSoe WinMBBS, M Med Sc (Int Med), MRCPUK, FRCPE, FAsCC, FAPSIC
Asso: Prof / Senoir Consultant CardiologistDepartment of Cardiovascular Medicine
Mandalay General Hospital
Hot Topic In Hypertension 2013
12th January 2013
RAAS: Central Role in the Pathogenesis
of Cardiovascular Disease
Ang II effect in target organ damage
McFarlane SI et al. Am J Cardiol. 2003;91(suppl):30H-7.
Perindopril 8 mg CAD No heart failure Age ≥18 years
CV death, MI, cardiac arrest
PEACE N = 8290 (4.8 years)
Trandolapril 4 mg CAD LVEF ≥40% Age ≥50 years
CV death, MI, coronary revascularization
QUIET N = 1750 (2.25 years)
Quinapril 20 mg PTCA, atherectomy Normal LVEF
CV death, MI, coronary revasc, cardiac arrest, hosp for angina
EUROPA Investigators. Lancet. 2003;362:782-8.HOPE Study Investigators. N Engl J Med. 2000;342:145-53.
PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.Pitt B et al. Am J Cardiol. 2001;87:1058-63.
ACEI outcome trials in CAD patients without HF
HOPE N = 9297 (4.5 years)
Ramipril 10 mg Vascular disease (80% had CAD) LVEF ≥40%, or No heart failure Age ≥55 years
CV death, MI, stroke
ACEI outcome trials in CAD patients without HF: Totality of trial evidence
MI
Stroke
All-cause death
Event rate (%)
Favors ACEIACEI
Revascularization
Favors placeboPlacebo
7.5
6.4
2.1
15.5
8.9
7.7
2.7
16.3
0.86
0.86
0.77
0.93
0.0004
0.0004
0.0004
0.025
0.5 0.75 1.251Odds ratio
P
Pepine CJ, Probstfield JL. Vasc Bio Clin Pract. CME Monograph; UF College of Medicine. 2004;6(3).
HOPE, EUROPA, PEACE, QUIET
HOPE, EUROPA, PEACE: Benefit of ACEIs across broad spectrum of risk
Dagenais GR et al. Lancet. 2006;368:581-8.
TrialPatients
(n)Annual rates in placebo groups
OR(95% CI) P
-5 20 405 3015 35Odds reduction (%)
25100
PEACE 8290 2.13 7 (-8 to 19) 0.328
HOPE total 9297 3.95 25 (16 to 32) 0.0001HOPE lower risk 3083 2.17 18 (-4 to 35)HOPE med risk 3100 3.58 20 (3 to 33)HOPE high risk 3114 5.98 24 (12 to 34)
EUROPA total 12,218 2.60 19 (8 to 28) 0.0007
EUROPA lower risk 3976 1.40 19 (-5 to 38)EUROPA med risk 3975 2.41 28 (11 to 41)EUROPA high risk 3975 4.00 10 (-4 to 22)
AIRE 1986 22.6 24 (7 to 38) 0.0068
TRACE 1749 17.0 25 (9 to 33) 0.0028
SOLVD-P 4228 7.4 15 (2 to 27) 0.0252SOLVD-T 2569 13.1 23 (10 to 33) 0.0009SAVE 2231 9.8 20 (4 to 33) 0.0168
CV death,* nonfatal MI or strokeACEI worse
ACEI better
*Or total mortality in AIRE, TRACE, SOLVD, SAVE trials
HOPE Study Investigators. N Engl J Med. 2000;342:145-53. EUROPA Investigators. Lancet. 2003;362:782-8.
PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.Pitt B et al. Am J Cardiol. 2001;87:1058-63.
ACEI outcome trials in CAD patients without HF: Differences in baseline CV risk
HOPE EUROPA PEACE
Annualizedevent rate in placebo group
(%/yr)
CV death Nonfatal MIQUIET
1.8
1.00.8 0.7
2.7
1.5
1.1
2.0
0.0
1.0
2.0
3.0
EUROPA: EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease
EUROPA Investigators. Lancet. 2003;362:782-8.
Objective: Assess effects of the ACEI perindopril on CV risk in a broad-spectrum population with stable CAD and without HF
Design: N = 12,218, age ≥18 years, with CAD/without HF at randomization
EUROPA • Age ≥18 years• Females: 15% • No clinical HF• Documented CAD including
– Previous MI, PCI/CABG– Angiographic evidence of
CAD with/without previous coronary event
– Positive stress test (men)
EUROPA Investigators. Lancet. 2003;362:782-8.HOPE Study Investigators. N Engl J Med. 2000;342:145-53.
HOPE patients were at higher risk than EUROPAHOPE patients were at higher risk than EUROPA
EUROPA vs HOPE: Event rates in placebo groups reflect differences in baseline risk
80% higher annual rate of CV and total mortality in HOPE80% higher annual rate of CV and total mortality in HOPE
EUROPA Investigators. Lancet. 2003;362:782-8.HOPE Study Investigators. N Engl J Med. 2000;342:145-53.
CV mortality Total mortality
Annualizedevent ratein placebo
groups(%)
HOPEEUROPA
1.8
2.7
1.0
1.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Are all ACEIs the same: Survival post-MI by ACEI at discharge
P < 0.001 log-rank
100
90
80
70121086420
Months
Captopril
Ramipril
Quinapril
Fosinopril
Lisinopril
Enalapril
Perindopril
Unadjusted cumulative
survival(%)
N = 7512
Pilote L et al. Ann Intern Med. 2004;141:102-12.
n = 421
n = 905
n = 276
n = 889
n = 2201
n = 2577
n = 243
Factors that may lead to divergent results in ACEI trials
• Underdosing – Dose-related effects on vascular and myocardial tissue
– Dose for CAD patients can’t be predicted from studies in HF or hypertension
• Differences may exist among ACEIs
• Differences in baseline risk (age, diabetes, HTN, PAD)
• Inclusion of revascularization in primary outcome
• Lack of power
• Poor adherence to assigned treatmentPitt B et al. Am J Cardiol. 2004;87:1058-63.
Yusuf S, Pogue J. N Engl J Med. 2005;352:937-8.Pitt B. N Engl J Med. 2004;351:2115-7.
Pepine CJ, Probstfield JL. Vasc Bio Clin Pract. CME Monograph; UF College of Medicine. 2004;6(3).
• Cumulative evidence supports ACE inhibitors for stable CAD patients with/without clinical signs of HF
• Not all ACE inhibitors can be assumed to have comparable effects for all indications – Dose and individual properties of ACEIs are important
• Benefit may depend on risk level – Benefit may be less in patients with well controlled risk factors
• Randomized clinical trial evidence and guidelines should guide selection of effective ACE inhibitor and dose for CAD patients without HF
Pitt B. N Engl J Med. 2004;351:2115-7.
ACEI outcome trials in CAD patients without HF: Clinical implications
• Totality of clinical trial evidence supports ACEI for treatment of stable CAD patients with/without HF
• Benefits have been shown in patients at all levels of risk
• All ACEIs may not have comparable effects for all indications
• Consider evidence and guidelines in selection of an ACEI and dose.
• Both ramipril and perindopril reduce risk of CV events in stable CAD patients without HF
– Ramipril 10 mg has proven efficacy in CAD patients ≥55 yrs
– Perindopril 8 mg has proven efficacy in CAD patients ≥18 yrs
Pitt B. N Engl J Med. 2004;351:2115-7.EUROPA Investigators. Lancet. 2003;362:782-8.
HOPE Study Investigators. N Engl J Med. 2000;342:145-53.PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.
Should all patients with stable CAD without HF receive an ACEI? Interpreting evidence
Evidence-based medicine: Updated guide-lines for ACEI in CAD patients without HF
“ACE inhibitors should be used as routine secondary prevention for patients with known CAD, particularly in diabetics without severe renal disease.” . . . R.J. Gibbons et al.
“The HOPE trial…confirms that the ACE inhibitor ramipril reduced CV death, MI, and stroke in patients who were at high risk for, or had, vascular disease in the absence ofheart failure.” . . . R.J. Gibbons et al.
EUROPA “showed that an ACE inhibitor can have a vasculoprotective effect in patients at lower risk than those enrolled in the HOPE study.” . . . V. Snow et al.
Gibbons RJ et al. 2002 ACC/AHA Practice Guidelines. www.acc.org; July 2005.Snow V et al. Ann Intern Med. 2004;141:562-7.
Role of RAAS Modulation in
CAD Patients with heart failure
ACE inhibition in CAD: Short-term trials in acute MI
Odds ratio (95% CI)
220/3044 (7.23%)
570/9682 (5.89%)
2035/29,028 (7.01%)
676/7460 (9.06%)
CONSENSUS-II*
Test for Heterogeneity: χ2 5.8 (2p = 0.1) df = 3
Deaths (n)/Randomized (n)
GISSI-3
ISIS-4
CCS-1
Total
Control O-E Variance
1.0 1.25 1.50.750.5
727/7489 (9.71%)
650/9712(6.69%)
192/3046(6.30%)
2171/29,022(7.48%)
3501/49,214(7.11%)
3740/49,269(7.59%)
14.07
–39.06
–68.22
–24.14
–117.35
96.05
285.83
975.33
317.85
1675.06
ACEI
ACEI better Control better
Odds reduction (± SD)7 ± 2
Treat Eff: χ2 (2p = 0.004)
ACE Inhibitor MI Collaborative Group. Circulation. 1998;97:2202-12.*IV infusion followed by oral therapy
ACE inhibition in CAD: Long-term trials in post-MI LV dysfunction and HF
AIRE Study Investigators. Lancet. 1993;342:821-8.Køber L et al. N Engl J Med. 1995;333:1670-6.
SOLVD Investigators. N Engl J Med. 1991;325:293-302.SOLVD Investigators. N Engl J Med. 1992;327:685-91.
Pfeffer MA et al. N Engl J Med. 1992;327:669-77.
AIRE
TRACE
SOLVD(Treatment)
SAVE
0.002
0.001
0.0036
0.019
0 5 10 15 20 25
Risk reduction in total mortality (%)
P
30
SOLVD(Prevention)
0.30
27%
22%
8%
16%
19%
Aldosterone blockade and AT1 receptor blockade: Trials in post-MI/LV dysfunction or HF
Pitt B et al. N Eng J Med. 1999;341:709-17.Pitt B et al. N Eng J Med. 2003;348:1309-21.
Pitt B et al. N Eng J Med. 2003;349:1893-906.
VALIANT
Months
CaptoprilValsartan
0.4
0.1
0.2
6 12 24 30 36
0.3
0.0
Probability of event
0% RR V vs CHR 1.00 (0.90–1.11)
P = 0.98
RALES
0.75
0.60
1.00
0
Placebo
Spironolactone
Months
Probability of survival
24 366
30% Risk reductionRR 0.70 (0.60–0.82)
P < 0.001
300.00
12 18
0.90
0.45
180
Valsartan/captopril
22
10
2
6 24 300
Eplerenone
Months
18
14
6
3612
EPHESUS15% Risk reductionRR 0.85 (0.75–0.96)
P = 0.008
Cumulativeincidence
(%)
Placebo
018
2% RR V/C vs CHR 0.98 (0.89–1.09)
P = 0.73)
EPHESUS: New subgroup analysis
Pitt B et al. Am J Cardiol. 2006;97(suppl):26F-33F.
N = 6632 with post-MI LVSD, mean follow-up 16 months
Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study
History of hypertensionAll-cause mortalityCV mortality/hospitalizationSudden cardiac death
History of diabetesAll-cause mortalityCV mortality/hospitalizationSudden cardiac death
LVEF ≤30%All-cause mortalityCV mortality/hospitalizationSudden cardiac death
P
0.0010.0020.022
0.1270.03
0.641
0.0120.001
0.010.2 1.0 1.2 1.8
Eplerenone better Placebo better
1.4 1.60.4 0.6 0.8Odds ratio (95% Cl)
Greenberg B et al. Am J Cardiol. 2006;97(suppl):34F-40F.
EMPHASIS-HF: Study design
Eplerenone+ standard therapy
N = 2584 with NYHA class II chronic systolic HF
Results in 2010
Placebo+ standard therapy
Primary end point:CV death, hosp for HF
Follow-up: 4 years
Effect of Eplerenone in Chronic Systolic Heart Failure
EMPHASIS-HF: Major results
EMPHASIS-HF
Outcome Eplerenone (%) Placebo (%) Adjusted hazard ratio (95% CI)
– Determined the mechanisms by which the ACEI perindopril improved outcomes in patients with stable coronary artery disease
• PERFECT: PERindopril-Function of the Endothelium in Coronary artery disease Trial
– Evaluated whether long-term administration of perindopril improves endothelial dysfunction
Ferrari R. ESC 2004; Munich.Bots ML et al. Cardiovasc Drugs Ther. 2002;16:227-36.
PERTINENT: Study design
Endothelial cell (EC) studiesEndothelial cell (EC) studiesECs incubated with serum from CAD ECs incubated with serum from CAD patients at baseline and at 1 year* patients at baseline and at 1 year*
Plasma studiesPlasma studiesMeasure substances in plasma that Measure substances in plasma that
modulate ecNOS and apoptosismodulate ecNOS and apoptosis
*Human umbilical vein ECsecNOS = EC nitric oxide synthase Ferrari R. ESC 2004; Munich.
Levels measured at baseline vs 1 year
Objective: Objective: Evaluate effects of perindopril on endothelial function and markers of Evaluate effects of perindopril on endothelial function and markers of inflammation and thrombosis in EUROPA subgroup of CAD patientsinflammation and thrombosis in EUROPA subgroup of CAD patients
EUROPA substudy
↑ ecNOS activity
↓ Endothelial cell apoptosis
↓ Ang II
↑ Bradykinin
↓ TNF-α↓ von Willebrand factor
Ferrari R. ESC 2004; Munich.*Incubated with patients’ serum
Endothelial cells* Patients’ plasma
EUROPA substudy
• The only significant correlation was between bradykinin and ecNOS
• Results suggest perindopril modifies inflammation and thrombosis and endothelial function through bradykinin-dependent mechanisms
PERTINENT: Effects of treatment with perindopril for 1 year
PERFECT: Study design
Objective: Determine effect of perindopril on brachial artery endothelial function in patients with stable CAD and without clinical HF
Design: Double-blind randomized controlled trial
Population: N = 333 at 20 centers
Treatment: Perindopril 8 mg or placebo
Follow-up: 3 years
Primary outcome: Change in flow-mediated vasodilation of
brachial artery assessed over 36 months
EUROPA substudy
Bots ML et al. J Am Coll Cardiol. 2005;45A(suppl):409A.Bots ML et al. Cardiovasc Drugs Ther. 2002;16:227-36.
• Mean FMD* increased (baseline vs 36 months) Perindopril 2.7% to 3.3% (+37%)Placebo 2.8% to 3.0% (+7%)
• Endothelial function (rate of change per 6 months) Perindopril 0.14% (P < 0.05 vs baseline) Placebo 0.02% (P = 0.74 vs baseline) (P = 0.07 for perindopril vs placebo)
• Conclusion: Part of the beneficial effect of perindopril on CV morbidity and mortality in the EUROPA study may be explained by improvement in endothelial function
*Brachial artery vasodilation in response to reactive hyperemia Bots ML et al. J Am Coll Cardiol. 2005;45A(suppl A):409A.
PERFECT: ACEI and endothelial functionEUROPA substudy
Effects of ARBs in type 2 diabetes: Renal and CV outcomes
Lewis EJ et al. N Engl J Med. 2001;345:851-60.Brenner BM et al. N Engl J Med. 2001;345:861-9.Parving HH et al. N Engl J Med. 2001;345:870-8.
*Doubling of baseline serum creatinine, end-stage renal disease (IDNT, RENAAL): progression to
diabetic nephropathy (IRMA-2)
Study(N) ARB
Primary outcome: Renal disease progression*
Secondaryoutcomes
(CV)
Average duration(years)
IDNT (N = 1715)
Irbesartan 300 mg/d vs amlodipine 10 mg
↓20% vs placebo, (P = 0.02) and ↓23% vs amlodipine (P = 0.006)
↓39% with 150 mg (P = 0.08)↓70% with 300 mg (P < 0.001)
Nonfatal CV events: NS
2
Clinical trials of ARBs: CV outcomes
Similar ↓
Greater ↓ with amlodipine (2.0/1.6 mm Hg)
Losartan vs atenolol
Valsartan vs amlodipine
Essential HTN
N = 9193
(4.8 years)
Essential HTN, high CV risk
N = 15,245
(4.3 years)
LIFE (2002)
VALUE (2004)
BPTreatment
Patients
(Follow-up)Trial (year)
HTN = hypertension
13% ↓ in primary outcome (CV death, MI, stroke) with ARB (P = 0.021) driven by 25% ↓ in stroke (P = 0.001)
No difference in CV death/MI
CV outcomes
Primary outcome similar at study end
Trend favors amlodipine at 3 and 6 months
Difficult to interpret due to BP difference
Dahlöf B et al. Lancet. 2002;359:995-1003. Julius S et al. Lancet. 2004;363:2022-31.
LIFE: Effects of ARB vs β-blockade on primary outcome and components
Dahlöf B et al. Lancet. 2002;359:995-1003.
N = 9193 with hypertension and ECG-LVH
LIFE = Losartan Intervention for Endpoint Reduction in Hypertension
16
Proportionof patientswith first
event (%)
12
8
4
0
60 18 30 5442 66
AtenololLosartan
Primary composite endpoint(CV death/MI/stroke)
Adjusted RR 13.0%P = 0.021
(losartan vs atenolol)
Time (months)
5
10Risk
increase(%)
0
5
10
15
20
25
Primary outcome components
(Losartan vs atenolol)
Riskreduction
(%)
P = 0.206
CV death
P = 0.491
Stroke
MI
P = 0.001
LIFE: Comparison of treatment effects in overall population vs with diabetes
Patients with hypertension and LVH
Dahlöf B et al. Lancet. 2002;359:995-1003. Lindholm LH et al. Lancet. 2002;359:1004-10.
0.5 1.0 1.5
Overall (n = 9193)
Diabetes (n = 1195)0.206
0.028
0.001
0.204
0.491
0.373
Favors losartan50–100 mg
Favors atenolol50–100 mg
P
CV death
Stroke
MI
Hazard ratio
VALUE: Similar treatment effectson primary outcome at study end
14
4
2
0
Proportionof patientswith first
event (%)
0 12 3018 24 54 60 66
Time (months)
6
8
10
12
6 36 42 48
HR = 1.03; 95% CI 0.94–1.14; P = 0.49
Valsartan-based regimen
Amlodipine-based regimen
Julius S et al. Lancet. 2004;363:2049-51
Timeinterval(mos)
∆ SBP(mm Hg)
Odds ratio Odds ratio
Favorsvalsartan
Favorsamlodipine
Favorsvalsartan
Favorsamlodipine
Primary outcome Myocardial infarction
0.5 1.0 2.0 4.0 0.5 1.0 2.0 4.0
All study 2.20–3 3.83–6 2.36–12 2.012–24 1.824–36 1.6
Study end 1.736–48 1.4
Julius S et al. Lancet. 2004;363:2022-31.
VALUE: SBP and outcome differences during consecutive time periods
VALUE = Valsartan Antihypertensive Long-Term Use Evaluation
Direct Renin InhibitorAliskerin
pre-clinical data
Aliskerin preclinical dataSummary
• Aliskerin demonstrates organ protective effects in animal models
• Renoprotection comparable with ACEIs and ARBs
• LVH reductions comparable with ARBs• Suppresses markers of renal damage in
diabetic nephropathy• Atherogenesis prevention
Direct Renin InhibitorAliskerin
Clinical data
Direct Renin InhibitorAliskerin
Outcome data
EFFECT OF THE DIRECT RENIN INHIBITOR ALISKIREN ON LEFT VENTRICULAR
REMODELING FOLLOWING MYOCARDIAL INFARCTION WITH LEFT VENTRICULAR
DYSFUNCTION
ASPIRE TrialScott D. Solomon, MD, FACC, Sung Hee Shin, MD, Amil Shah, MD, Lars Kober, MD, Aldo P.
Maggioni, MD, Jean Rouleau, MD, FACC, John J. V. McMurray, MD, FACC, Roxzana Kelly, Allen Hester, Marc A. Pfeffer, MD, PhD, FACC for the Aliskiren Study in Post-MI Patients to Reduce
Remodeling (ASPIRE) investigators
Brigham and Women’s Hospital, Boston, MA; Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark; ANMCO Research Center, Firenze, Italy; University of Montreal, Montreal,
Canada; Western Infirmary, Glasgow, Scotland; Novartis Pharmaceuticals, East Hanover, NJ
Cardiovascular Outcomes ASPIRE Trial
EndpointPlacebo
n=397n (%)
Aliskiren n=423n (%)
CV Death 6 (1.5) 13 (3.1)
Resuscitated Sudden Death 4 (1.0) 1 (0.2)
HF Hospitalization 17 (4.3) 12 (2.8)
Myocardial Infarction 16 (4.0) 11 (2.6)
Stroke 2 (0.5) 7 (1.7)
Any of the above 34 (8.6) 39 (9.2)
No Significant between group differences
Conclusions ASPIRE Trial
• In high risk post-MI patients with LV systolic dysfunction, the addition of aliskiren to a standard optimal medical regimen, including an ACE-I or an ARB, did not result in benefit with respect to ventricular remodeling compared to placebo and was associated with more adverse events
• Although ASPIRE utilized a surrogate endpoint, and was not powered to assess hard clinical outcomes, these results do not provide support for testing the use of aliskiren in a morbidity and mortality trial in the high-risk post-MI population
• Ongoing outcomes trials with aliskiren in patients with heart failure and diabetic kidney disease are well underway and will further assess the role for direct renin inhibition in these populations
Evidence of Dual RAA inhibition
RAAS: Pathways of ACE inhibition and angiotensin receptor blockade
Dzau V. J Hypertens. 2005;23(suppl 1):S9-S17.
ACE inhibitor
Bradykinin/NO
Inactivefragments
Chymase,tPA,
cathepsin
‘Angiotensin IIescape’
ARB
AT1 receptor AT2 receptor
Angiotensin I
Angiotensin II
ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
ONTARGET: Study design
Ramipril 10 mg Telmisartan 80 mg
N = 25,620≥55 years with coronary, cerebrovascular, or peripheral vascular disease,
or diabetes + end-organ damage
Results in 2007
Ramipril 10 mg + telmisartan 80 mg
Primary end point:CV death, MI, stroke, hosp for HF
Secondary end point:Newly diagnosed diabetes
ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial
ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
TRANSCEND: Study design
Telmisartan 80 mg
N = 5776 ACEI-intolerant≥55 years with coronary, cerebrovascular, or peripheral vascular disease,
or diabetes + end-organ damage
Results in 2007
Placebo
Primary end point:CV death, MI, stroke, hosp for HF
Secondary end point:Newly diagnosed diabetes
Telmisartan Randomized AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease
Yusuf S et al. N Engl J Med 2008: 358:1547-1559.
ONTARGET: Key results Outcome Ramipril,
n=8576 (%)Telmisartan, n=8542 (%)
Combination, n=8502 (%)
CV death/MI/stroke/ CHF hospitalizationa
16.5 16.7 16.3
CV death/MI/strokeb 14.1 13.9 14.1
MI 4.8 5.2 5.2
Stroke 4.7 4.3 4.4
CHF hospitalization 4.1 4.6 3.9
CV death 7.0 7.0 7.3
Any death 11.8 11.6 12.5
Renal impairment 10.2 10.6 13.5
a. Primary end pointb. Primary end point in the HOPE trial
Yusuf S et al. N Engl J Med 2008: 358:1547-1559.
ONTARGET: Key results Outcome Risk ratio (95% CI),
telmisartan vs ramipril Risk ratio (95% CI), combination therapy vs ramipril
a. Primary end pointb. Primary end point in the HOPE trial
ONTARGET: Reasons for permanent discontinuations
Yusuf S et al. N Engl J Med 2008: 358:1547-1559.
Outcome Ramipril (%)
Telmisartan (%)
Combination (%)
p, telmisartan vs ramipril
p, combination therapy vs ramipril
Hypotensive symptoms
1.7 2.7 4.8 <0.001 <0.001
Syncope 0.2 0.2 0.3 0.49 0.03
Cough 4.2 1.1 4.6 <0.001 0.19
Diarrhea 0.1 0.2 0.5 0.20 <0.001
Angioedema 0.3 0.1 0.2 0.01 0.30
Renal impairment
0.7 0.8 1.1 0.46 <0.001
Conclusions: Telmisartan vs. Ramipril
1. Telmisartan is clearly “non-inferior” to ramipril,with most ( 95-100%) of the benefits preserved
2. Consistent results on a range of:• Secondary outcomes• Subgroups
3. Telmisartan exhibits slightly superior overall tolerability:
• Less cough and angioneurotic edema• More mild hypotensive symptoms, but no
difference in severe hypotensive symptoms, such as syncope
Conclusions: Telmisartan plus Ramipril vs. Ramipril
1. Combination therapy does not reduce the primary outcome to a greater extent compared to ramipril alone and has higher adverse events.
Implications• Telmisartan is as effective as ramipril, with a slightly
better tolerability.
• Combination therapy is not superior to ramipril, and has increased side effects.
•The combination of aliskiren (Rasilez) with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) has been associated with serious adverse cardiovascular and renal outcomes in a recent large clinical trial (ALTITUDE). •This combination is now contraindicated in: diabetic patients (type I or type II); and non-diabetic patients with an estimated glomerular filtration rate (eGFR) <60 mL/min per 1•73 m2
•In all other patient groups, aliskiren in combination with an ACE inhibitor or an ARB is not recommended•Any use of aliskiren (either as monotherapy or in combination with other medicines) is no longer recommended in any patient with severe renal impairment: eGFR <30 mL/min per 1•73 m2
RAA inhibition
? ACEI? ARB? DRI
Evidences from Recent Analysis
Aliskiren in HypertensionClinical summary
•Aliskerin provides long- term suppression of PRA
•Aliskerin effectively reduces PRA from baseline as monotherapy, and blocks the rise in PRA seen during treatment with other antihypertensives such as ARB
•Aliskerin monotherapy provides dose-dependent reductions in DBP and SBP
•Additional BP lowering when combined with other antihypertensives but more side effects
Meta-analyses show consistency of ACEI benefit in preventing CV events
No. of trials N
Relative risk reduction (%)
CV death MI
Danchin, 2006 7 33,960 19 18
Al-Mallah, 2006 6 33,500 17 16
Dagenais, 2006 3 29,805 18 18
Danchin N et al. Arch Intern Med. 2006.Al-Mallah MH et al. J Am Coll Cardiol. 2006.
Dagenais GR et al. Lancet. 2006.
Randomized, placebo-controlled trials in patients with CAD without HF or LV dysfunction
Meta-analysis of trials comparing ARB vs placebo, non-ACEI comparators, or ACEI
Strauss MH, Hall AS. Circulation. 2006;114:838-54.
Van Vark LC, Bertrand M, Fox K, Mourad JJ, Boersma E, et al. Eur Heart J 2012; published online April 17.
All-cause mortality: effect of ACE inhibitors
ASCOT-BPLA
ADVANCE
HYVET
Overall
1.03 (0.90-1.15)
0.90 (0.75-1.09)
0.99 (0.62-1.58)
1.32 (0.61-2.86)
0.89 (0.81-0.99)
0.86 (0.75-0.98)
0.79 (0.65-0.95)
0.90 (0.84-0.97)
ACE inhibitor better Control better
Random effects model HR (95% CI) P
N= 76 6150.50 0.75 1.33 2.01HR (log scale)
0.03
0.03
0.02
0.87(0.81-0.93)
0.004
<0.001
ALLHAT (lisinopril)
ANBP-2 (enalapril)
pilot HYVET (lisinopril)
JMIC-B (lisinopril, enalapril)
(perindopril)
Van Vark LC, Bertrand M, Fox K, Mourad JJ, Boersma E, et al. Eur Heart J 2012; published online April 17.
All-cause mortality: effect of ARBs
RENAAL (losartan)
IDNT (irbesartan)
LIFE (losartan)
SCOPE (candesartan)
VALUE (valsartan)
MOSES (eprosartan)
JIKEI HEART (valsartan)
PRoFESS (telmisartan)
TRANSCEND (telmisartan)CASE-J (candesartan)
HIJ-CREATE (candesartan)
KYOTO HEART (valsartan)
NAVIGATOR (valsartan)
Overall
HR (log scale) Control betterARB better0.50 0.75 1.33 2.01
1.03 (0.83-1.29)
0.92 (0.69-1.23)
0.88 (0.77-1.01)
0.96 (0.81-1.14)
1.04 (0.94-1.14)
1.07 (0.73-1.57)
1.09 (0.64-1.85)
1.03 (0.93-1.14)
1.05 (0.91-1.22)
0.85 (0.62-1.16)
1.18 (0.83-1.67)
0.76 (0.40-1.30)
0.90 (0.77-1.05)
0.99 (0.94-1.04)
Random effects model HR (95% CI) P
N=82 383
0.683
Van Vark LC, Bertrand M, Fox K, Mourad JJ, Boersma E, et al. Eur Heart J 2012; published online April 17.
Among RAAS inhibitors, only ACE inhibitors have demonstrateda significant 10% mortality reduction in hypertensive patients (P=0.004).
No significant reduction in all-cause mortality could be demonstrated with ARBs (HR, 0.99 (0.95-1.04); P=0.683).
The difference in treatment effect between ACE inhibitors and ARBs was statistically significant (P-value for interaction 0.036).
The largest mortality reductions were observed in ASCOT-BPLA, ADVANCE, and HYVET, which studied the ACE inhibitor perindopril (pooled HR, 0.87 [0.81-0.93]; P<0.001).
Because of the high prevalence of hypertension, the widespread use of ACE inhibitors may result in an important gain in lives saved.
Van Vark LC, Bertrand M, Fox K, Mourad JJ, Boersma E, et al. Eur Heart J 2012; published online April 17.
Savarese G,et al.J Am Coll Cardiol.In press.doi:10.1016/i.iacc.2012.10.011
Savarese G,et al.J Am Coll Cardiol.In press.doi:10.1016/i.iacc.2012.10.011
Savarese G,et al.J Am Coll Cardiol.In press.doi:10.1016/i.iacc.2012.10.011
Conclusion From Saverese G,et al Conclusion From Saverese G,et al Meta-analysisMeta-analysis
End Points ACEI ARB
Composite outcome
-14.9%p=0.001
-7%p=0.005
CV death -10%p=0.112
No benefit
MI -17.7%p<0.001
-9.5%NS
Stroke -19.6%p=0.004
-9.1%p=0.011
All cause death -8.3%p=0.008
No benefit
New-onset HF -20.5%p=0.001
No benefit
New-onset DM -13.7%p=0.012
-10.6%P<0.001
RAAS modulation in high-risk patients: Summary
• Opportunity for greater use of RAAS modulation in patients at high risk for CV events
• ACEIs reduce CV death, MI, HF, and stroke across a broad range of patients with vascular disease– With/without LVSD or HF– With/without other proven CV therapies– Annual event rates of 1.4%–22.6% in untreated
groups• ARBs reduce HF and stroke• ACEIs may be considered in all patients with
vascular disease• ARBs are an alternative in ACEI-intolerant patients• Dual RAAS inhibition is not better than single
therapy and causes more side effects
AHA/ACC secondary-prevention guidelines: ACEIs and ARBs
ACEIs• All patients with LVEF ≤40%, hypertension, diabetes,
or chronic kidney disease (IA)• Consider for all other patients (IB)• Optional: Lower-risk, post-revascularization patients
with normal LVEF and well-controlled risk factors (IIaB)
ARBs• ACEI-intolerant patients with HF or post-MI LVEF
≤40% (IA)• Consider in DM and other ACEI-intolerant patients
(IB)• Consider use in combination with ACEIs in systolic