ACE vs ARB MetS/T2DM/HBP

1
ACE vs ARBMetS/T2DM/HBP

• Mario L Maiese DO FACC FACOI
• Associate Professor UMDNJSOM
• SJHG www.sjhg.org
• maiese1_at_comcast.net
• EROC April 1, 2005

2
Goals of Presentation

• Understand the detrimental effects of AII.
• Understand the beneficial effects of AII
  blockade.
• Evaluate therapeutic options

3
Effects of Angiotensin II/HBP on the Heart
4
Renin-Angiotensin-Aldosterone System (RAAS)
Detrimental effects
Angiotensinogen
Renin
Angiotensin I
Angiotensin Converting Enzyme (ACE)
Angiotensin II
Aldosterone
AT I receptor
Vascular remodeling
Vasoconstriction
LV remodeling
Oxidative Stress
Cell Growth
Proteinuria
5
(No Transcript)
6
(No Transcript)
7
Beneficial Effects
8
Atherothrombosis
9
(No Transcript)
10
(No Transcript)
11
Health Outcomes Prevention Evaluation (HOPE)
Study 22 CV Risk Reduction
Ramipril Benefit Beyond Standard Risk Reduction
Therapies Alone

• Diuretics
• Calcium channel blockers

• Aspirin and other antiplatelets
• Beta-blockers
• Lipid-lowering agents

Composite Outcome
Nonfatal MI
All-Cause Mortality
CV Death
Stroke
0
-5
-10
-15
Relative Risk Reduction
16 P0.005
-20
20 P0.0003
22 P0.0001
-25
26 P0.0002
-30
Secondary end point
-35
32 P0.0002
The HOPE Study Investigators. N
Engl J Med. Jan 20 2000342145-153.
12
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.
2000355253-259.
13
MICRO-HOPE Primary Outcome Reductions in
Stroke, MI, and CV Death
Trial halted early because of
the highly significant risk reductions seen with
ramipril.
Data from HOPE Study Investigators. Lancet 2000
355 253-259.
14
MICRO-HOPE Ramipril Significantly Reduces
Cardiovascular Morbidity
Ramipril Effects Beyond Baseline Therapy
Data from HOPE Study Investigators. Lancet 2000
355 253259.
15
Effects of Ramipril HOPE vs. MICRO-HOPE
Data from HOPE Study Investigators. Lancet.
2000355253-259. HOPE Study Investigators. N
Engl J Med 2000 342 145-153.
16
MICRO-HOPE

• Only study to show improved outcomes in diabetics
  with A II Blockade.

17
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

• Lipid-lowering agents

• Aspirin and other antiplatelets
• Beta-blockers

Composite Outcome (CV death, MI cardiac arrest)
Nonfatal MI
CV Death
0
-5
-10
-15
Relative Risk Reduction
-20
14 Non-significant
20 P0.0003
-25
22 P0.001
-30
Secondary end point
-35
The EUROPA Study Investigators. Lancet Sept 6
2003 362 782-788.
18
ACE-Inhibitors-Standard of Care.to decrease
events

• Atherothrombosis (atherosclerosis thrombosis),
  post MI.
• LVSD/ HF
• Diabetes
• ?Hypertension
• ? Met S

19
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.

20
ACE Inhibitors
Generic Trade Name G Avail Cost/Mo

Benazepril 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
Perindopril Aceon (Solvay Pharmaceuticals) no 43
Quinapril Accupril (Pfizer) no 32
Ramipril Altace (Monarch Pharmaceuticals) no 80
Trandolapril Mavik (Knoll Pharmaceuticals) no 30
21
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.

22
ACE-Inhibitors-Standard of CareWHOOPS

• Prevention of Events With Angiotensin-Converting-e
  nzyme 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.

23
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.

24
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.

25
Medications that block the RAAS
Angiotensinogen
Renin
Renin blockers-(Beta blockers)
Angiotensin I
Angiotensin Converting Enzyme (ACE)
ACE-inhibitors
Angiotensin II
ARBs
Aldosterone
AT I receptor
Aldosterone blockers
26
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!

27
Conclusion

• Angiotensin II Blockade is good.
• ACEI apparently are very effective with improved
  outcomes.
• Always room for improvement!

28
(No Transcript)
29
The Question?

• Is an angiotensin receptor blocker (ARB) better
  then an ACEI because theoretically it would more
  completely block the effects of AII

30
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 FailureAssessment
  of Reduction of Mortality and morbidity. Lancet
  2003 326 759-766.

31
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 IIincreased
  vasoconstriction, decreased NO, ED, increased
  inflammation, insulin resistance and increased
  prothrombotic state.

32
Arguments Against ACEI

• Poor tolerability
• - Cough 6 to 7
• - Angioedema (11000)
• - Angioedema requiring hospitalization
• (1 10,000)

33
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.

34
ARB DATA

• CHARM - Lancet 2003 326759-66.
• 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.

35
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
  angiotensin- receptor 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.

36
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.

37
Evaluation of Therapeutic Options- Criteria for
Choice of Agent

• Should have proven CV morbidity and mortality
  benefits.
• Should reduce BP over 24 hours (i.e. be
  long-acting) 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.

38
ACE INHIB VS ARB for HBPCompelling Indications
39
Beneficial Effects of ACEI _at_ all stages
(HBP?CAD?HF)

• Immediate Hemodynamic ? BP
• Preservation of
  bradykinin
• ? nitric acid
• ? superoxide
  production
• Intermediate Fibrinolytic stabilization
• ? PAI-1
• ? PA
• ? platelet
  activator
• Late effects ? cell migration
• ? cell
  proliferation
• Plaque
  stabilization

40
Who should receive ACE-inhibitors?

• HF (LVEF lt 40)
• CVD (CAD, PAD, carotid or cerebral vasc dx, AAA)
• T2DM
• Metabolic Syndrome (pre-diabetics)
• CRD
• HBP

41
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.

42
(No Transcript)
43
Optimal Treatment

• T2DM/MetS/HBP/microalbuminuria
• ACEI-First choice ARBs-Second
• - Poss consider both.
  
• Hctz /or Coreg
• ASA
• Statin
• TLC
• Control Sugars? More drugs!!