ACE vs ARB
MetS/T2DM/HBP
Mario L Maiese DO FACC FACOI
Associate Professor UMDNJSOM
SJHG
www.sjhg.org
maiese1@comcast.net
EROC April 1, 2005
Goals of Presentation:
Understand the detrimental
effects of AII.
Understand the beneficial effects
of AII blockade.
Evaluate therapeutic options
Effects of Angiotensin II/HBP on
the Heart
Renin-Angiotensin-Aldosterone System
(RAAS): Detrimental effects
Angiotensinogen
Renin
Angiotensin I
Angiotensin
Converting
Enzyme (ACE)
Angiotensin II
Aldosterone
AT I receptor
Vasoconstriction
Oxidative Stress
Cell Growth
Vascular remodeling
LV remodeling
Proteinuria
Beneficial Effects
Atherothrombosis
Health Outcomes Prevention Evaluation (HOPE)
Study: 22% CV Risk Reduction
Ramipril Benefit Beyond Standard Risk Reduction Therapies Alone
% Relative Risk Reduction
• Aspirin and other antiplatelets
• Beta-blockers
• Lipid-lowering agents
Composite
Outcome
0
Stroke
• Diuretics
• Calcium channel blockers
CV Death
Nonfatal
MI
All-Cause
Mortality*
-5
-10
-15
-20
-25
-30
-35
22%
P=0.0001
32%
P=0.0002
26%
P=0.0002
20%
P=0.0003
16%
P=0.005
*Secondary
end point
The HOPE Study Investigators. N Engl J Med. Jan 20 2000;342:145-153.
HOPE for Patients with Diabetes
MICRO-HOPE
Substudy of HOPE focusing on
microalbuminuria, cardiovascular, and renal
outcomes in patients 55 or older with diabetes
Study objective: To assess whether the addition
of ramipril to the current medical regimens of
high-risk patients with diabetes can reduce the
risk of CV events
97% of the patients in MICRO-HOPE had T2DM
Data from: HOPE Study Investigators. Lancet. 2000;355:253-259.
MICRO-HOPE*: Primary Outcome
Reductions in Stroke, MI, and
CV Death
Proportion of Patients
Reaching End Points
0.20
25%
Reduction
in Events
0.15
Placebo
P = 0.0004*
Ramipril
0.10
16%
Reduction
in Events
at 1 Year
0.05
0
0
500
1,000
1,500
Days of Follow-Up
*Trial halted early because of the highly significant risk reductions seen with ramipril.
Data from: HOPE Study Investigators. Lancet 2000; 355: 253-259.
MICRO-HOPE: Ramipril Significantly
Reduces Cardiovascular Morbidity
Ramipril Effects Beyond Baseline Therapy
• Aspirin
• Other Antiplatelet Agents
• Lipid-Lowering Agents
Risk Reduction (%)
Stroke
0
Nonfatal
MI
• Diuretics
• Beta-Blockers
• Calcium-Channel Blockers
CV
Death
Total
Mortality
-5
-10
-15
-20
22%
-25
†
-30
-35
-40
24%
§
33%
*
37%
*P
= 0.0074
†P = 0.01
‡P = 0.0001
§P = 0.0004
‡
Data from: HOPE Study Investigators. Lancet 2000; 355: 253–259.
Effects of Ramipril:
HOPE vs. MICRO-HOPE
HOPE
40
35
30
25
20
15
10
5
0
MICRO-HOPE
37
32
33
26
20
24
22
16
Stroke
Nonfatal
MI
CV Death
Total
Mortality
Data from: HOPE Study Investigators. Lancet. 2000;355:253-259.
HOPE Study Investigators. N Engl J Med 2000; 342: 145-153.
MICRO-HOPE
Only study to show improved
outcomes in diabetics with A II
Blockade.
EURopean trial On reduction of cardiac events with
Perindopril in stable CAD (EUROPA):
20% CV Risk Reduction
Perindopril Benefit Beyond Standard Risk Reduction Therapies Alone
• Aspirin and other antiplatelets
• Beta-blockers
% Relative Risk Reduction
Composite Outcome
(CV death, MI &
cardiac arrest)
• Lipid-lowering agents
CV Death
0
Nonfatal
MI
-5
-10
-15
-20
-25
-30
-35
20%
P=0.0003
14%
Non-significant
22%
P=0.001
*Secondary
end point
The EUROPA Study Investigators. Lancet Sept 6 2003; 362: 782-788.
ACE-Inhibitors-Standard of Care
….to decrease events
Atherothrombosis (atherosclerosis +
thrombosis), post MI.
LVSD/ HF
Diabetes
?Hypertension
? Met S
ACE-Inhibitors-Standard of Care
Heart Outcomes Prevention Evaluation (HOPE) trial.
European Trial on Reduction of Cardiac events with
Perindopril in Stable CAD (EUROPA).
Together 22,952 high risk patients with established
vasc dx or DM randomized to ramipril 10mg or
perindopril 8mg vs placebo.
RR reduction of 20% and 22% in CV death, MI, stroke
or cardiac arrest.
HOPE: N Engl J Med 2000; 342: 145-153.
EUROPA: Lancet 2003; 362: 782-788.
ACE Inhibitors
Generic
Benazepril
Trade Name
G Avail
Cost/Mo
Lotensin (Novartis)
no
$30
Captopril
Capoten (Bristol-Myers Squibb)
yes
$13
Enalapril
Vasotec (Merck)
yes
$11
Fosinopril
Monopril (Bristol-Myers Squibb)
no
$66
Lisinopril
Prinivil (Merck), Zestril (Zeneca)
yes
$20
Moexipril
Univasc (Schwarz Pharmaceuticals)
no
$27
Aceon (Solvay Pharmaceuticals)
no
$43
Quinapril
Accupril (Pfizer)
no
$32
Ramipril
Altace (Monarch Pharmaceuticals)
no
$80
Mavik (Knoll Pharmaceuticals)
no
$30
Perindopril
Trandolapril
Ace inhibitors have the broadest
impact of any drug in CV medicine:
Reduce risk of death, MI, stroke, diabetes
and renal impairment.
Benefit patients with HF or LV dysfunction,
post MI, PAD, diabetes, stroke or TIA &
AAA and renal dysfunction.
ACE-Inhibitors-Standard of Care
“WHOOPS”
Prevention of Events With AngiotensinConverting-enzyme Inhibition trial (PEACE).
Lower risk CAD patients - most post
revascularization on good risk reduction
treatment (antiplatelet therapy, beta-blockers
and statins) on trandopril 4mg vs placebo.
Resulted in no benefit.
N Engl J Med 2004; 351; 2058-2068.
Comparison to HOPE & EUROPA
The patients enrolled in PEACE were at lower
cardiovascular risk (annualized all-cause mortality in the
PEACE population was only 1.6%).
Normal mean serum creatinine and cholesterol levels
and their average blood pressure was the level achieved
after use of an ACE inhibitor in HOPE and EUROPA.
More patients in PEACE than in HOPE or EUROPA had
undergone coronary revascularization (73% vs 40% and
54%, respectively).
More had received lipid-lowering therapy (70% vs 29%
and 56%). and as a consequence, their cardiovascular
event rate was lower than in HOPE and EUROPA.
N Engl J Med 2004; 351; 2058-2068.
Conclusions re PEACE
Results of PEACE were entirely consistent
with HOPE and EUROPA.
Underpowered (more patients and longer
follow-up needed because better
treatment resulted in lower risk).
Dosages of drugs are not comparable.
Absolute benefit obtained depends on
baseline risk.
Medications that block the
RAAS
Angiotensinogen
Renin
Angiotensin
Converting
Enzyme (ACE)
Renin blockers(Beta blockers)
Angiotensin I
ACE-inhibitors
Angiotensin II
ARBs
AT I receptor
Aldosterone
Aldosterone
blockers
A II BLOCKADE
It is no coincidence that:
beta-blockers (renin inhibitors)
angiotensin converting enzyme--(ACE)
inhibitors
angiotensin receptor blockers (ARBs)
Aldosterone blockade
—all A II antagonists
↓ CV and CRD risk and decrease mortality
….improve outcomes!
Conclusion
Angiotensin II Blockade is good.
ACEI apparently are very effective
with improved outcomes.
Always room for improvement!
The Question?
Is an angiotensin receptor blocker (ARB)
better then an ACEI because theoretically
it would more completely block the effects
of AII
Blocking RAAS
Superior for risk reduction and less diabeto-genic than
“older” anti-hypertensive agents
HOPE, EUROPA, ALLHAT and ANBP2 trials have all
shown decreases incidence of T2DM with ACE inhibition.
Emerging evidence from the LIFE and CHARM trials have
shown respective 25% and 28% reductions in the
incidence of DM with ARBs.
HOPE – Heart Outcomes Prevention Evaluation (Ramipril). N Engl J Med 2000; 242: 145-153.
EUROPA – EURopean trial On reduction of cardiac events with Perindopril in stable CAD. Lancet 2003; 326: 782-788.
ALLHAT – Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial. JAMA 2002; 288: 1981-1997.
ANBP2 – Second Australian National Blood Pressure Study. N Engl J Med 2003; 348: 583-592.
LIFE – Losarten Intervention for Endpoint Reduction (LIFE) Trial. J Clin Hypertension 2002; 4: 301-305.
CHARM – Candesartan in Heart Failure—Assessment of Reduction of Mortality and morbidity. Lancet 2003; 326: 759-766.
ACE inhibitors and ARBs
Improve insulin sensitivity
Usage in various studies have shown
decreased development of T2DM
Unknown mechanism
? XX Induction of vascular insulin
resistance on vsmc by A II…increased
vasoconstriction, decreased NO, ED,
increased inflammation, insulin resistance
and increased prothrombotic state.
Arguments Against ACEI
Poor tolerability
- Cough 6% to 7%
- Angioedema (1:1000)
- Angioedema requiring hospitalization
(1: 10,000)
Arguments for ARBs
Beneficial in HF (CHARM & ELITE II).
Beneficial post MI and better tolerated
(VALIANT & OPTIMAAL).
Shown to decrease progression of
proteinuria and renal disease**.
Associated with decreased incidence of
DM (LIFE & CHARM).
Not associated with cough or angioedema.
ARB DATA
CHARM - Lancet 2003; 326:759-66.
ELITE II – Lancet 2000; 355: 1582-1587.
VALIANT - N Eng J Med 2003; 349: 1893-1906.
OPTIMAL – Lancet 2002; 360: 752-760.
LIFE – Hypertension 2002; 4: 301-305.
Three recent studies show that ARBs can slow the
progression of renal disease among patients with T2DM
(with HBP and microalbuminuria).
Lewis EJ et al. Renoprotective effect of the angiotensinreceptor antagonist irbesartan in patients with
nephropathy due to type II diabetes.
N Enjl J Med 2001 Sep 20; 345: 852-60.
Brenner BM et al. Effects of losartan on renal and
cardiovascular outcomes in patients with type II diabetes
and nephropathy.
N Engl J Med 2001 Sep 20; 345: 861-69.
Parving HH et al. The effect of irbesartan on
development of diabetic nephropathy
in patients with type II diabetes.
N Engl J Med 2001 Sep 20; 345: 870-78.
ARB vs ACE-I in T2DM + nephropathy
DETAIL study: comparison study with
telmisartan vs enalapril.
Results: telmisartan is not inferior to
enalapril in providing renoprotection in
subjects with T2DM and mild nephropathy.
N Engl J Med Nov 4 2004; 351: 1952-1961.
Evaluation of Therapeutic OptionsCriteria for Choice of Agent:
Should have proven CV morbidity and mortality
benefits.
Should reduce BP over 24 hours (i.e. be longacting) in order to reduce end-organ damage
and the incidence of early morning
cardiovascular events.
Should have direct protective properties on end
organs, such as the heart, brain and kidney.
Should have a favorable interaction profile and
of course needs be well tolerated.
ACE INHIB VS ARB for HBP
…Compelling Indications:
Beneficial Effects of ACEI @ all
stages (HBP→CAD→HF)
Immediate
Intermediate
Late effects
Hemodynamic: ↓ BP
Preservation of bradykinin
↑ nitric acid
↓ superoxide production
Fibrinolytic stabilization
↓ PAI-1
↑ PA
↓ platelet activator
↓ cell migration
↓ cell proliferation
Plaque stabilization
Who should receive ACEinhibitors?
HF (LVEF < 40%)
CVD (CAD, PAD, carotid or cerebral vasc
dx, AAA)
T2DM
Metabolic Syndrome (pre-diabetics)
CRD
HBP
Conclusions
No Evidence of superiority of ARBs Over ACEI.
Should not replace comfort above efficacy and
safety (ie ACEI the only agent with ↓ mortality
benefit.
Cost should always be part of the equation.
ACEI are still first choice but use ARBs in all
situations where ACEI cannot be tolerated…
…and maybe as an add-on or in combo in patients
T2DM/microalbuminuria.
Optimal Treatment
T2DM/MetS/HBP/microalbuminuria
ACEI-First choice; ARBs-Second
- Poss consider both.
Hctz &/or Coreg
ASA
Statin
TLC
Control Sugars→ More drugs!!