ACE vs ARBACE vs ARBMetS/T2DM/HBPMetS/T2DM/HBP

Mario L Maiese DO FACC FACOIMario L Maiese DO FACC FACOIAssociate Professor UMDNJSOMAssociate Professor UMDNJSOM

SJHG SJHG www.sjhg.orgwww.sjhg.org maiese1@comcast.netmaiese1@comcast.net

EROCEROC April 1, 2005 April 1, 2005

Goals of Presentation:Goals of Presentation:

Understand the detrimental effects Understand the detrimental effects of AII.of AII.

Understand the beneficial effects of Understand the beneficial effects of AII blockade.AII blockade.

Evaluate therapeutic options Evaluate therapeutic options

Effects of Angiotensin II/HBP on Effects of Angiotensin II/HBP on the Heartthe Heart

VasoconstrictionVasoconstriction

Oxidative StressOxidative Stress

Cell GrowthCell Growth ProteinuriaProteinuria

LV remodelingLV remodeling

Vascular remodelingVascular remodeling

AngiotensinogenAngiotensinogen

Angiotensin IAngiotensin I

Angiotensin IIAngiotensin II

AT I receptorAT I receptor

ReninRenin

AngiotensinAngiotensinConvertingConverting

Enzyme (ACE)Enzyme (ACE)

Renin-Angiotensin-Aldosterone System Renin-Angiotensin-Aldosterone System (RAAS): (RAAS): Detrimental effectsDetrimental effects

AldosteroneAldosterone

Beneficial EffectsBeneficial Effects

AtherothrombosisAtherothrombosis

The HOPE Study Investigators.The HOPE Study Investigators. N Engl J Med. N Engl J Med. Jan 20 2000;342:145-153. Jan 20 2000;342:145-153.

26%P=0.0002

32%P=0.0002

20%P=0.0003

16%P=0.005

-35

-30

-25

-20

-15

-10

-5

0

% R

elat

ive

Ris

k R

educ

tion

CV DeathNonfatal

MIStrokeAll-CauseMortality*

Composite Outcome

22%P=0.0001

Health Outcomes Prevention Evaluation (HOPE) Study: 22% CV Risk Reduction

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

• Diuretics• Calcium channel blockers

Ramipril Benefit Beyond Standard Risk Reduction Therapies Alone

*Secondary end point

Data from: HOPE Study Investigators. Lancet. 2000;355:253-259.

HOPE for Patients with DiabetesHOPE for Patients with Diabetes

MICRO-HOPEMICRO-HOPE

Substudy of HOPE focusing on microalbuminuria, Substudy of HOPE focusing on microalbuminuria, cardiovascular, and renal outcomes in patients 55 or cardiovascular, and renal outcomes in patients 55 or older with diabetesolder with diabetes

Study objective: To assess whether the addition of Study objective: To assess whether the addition of ramipril to the current medical regimens of high-risk ramipril to the current medical regimens of high-risk patients with diabetes can reduce the risk of CV patients with diabetes can reduce the risk of CV eventsevents

97% of the patients in MICRO-HOPE had T2DM97% of the patients in MICRO-HOPE had T2DM

* 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*: Primary Outcome MICRO-HOPE*: Primary Outcome Reductions in Stroke, MI, and Reductions in Stroke, MI, and

CV DeathCV Death0.20

0.15

0.10

0.05

0

0 500 1,000 1,500

Days of Follow-Up

Pro

po

rtio

n o

f P

atie

nts

Rea

chin

g E

nd

Po

ints

Placebo

Ramipril

25% Reduction in Events P = 0.0004*

16% Reduction in Events at 1 Year

Data from: HOPE Study Investigators. Lancet 2000; 355: 253–259.

Stroke

33%*

22%†

NonfatalMI

TotalMortality

24%§

*P = 0.0074 †P = 0.01‡P = 0.0001 §P = 0.0004

Ris

k R

ed

uct

ion

(%

) 0

-5

-10

-15

-20

-30

-35

CVDeath

37%‡

-25

-40

Ramipril Effects Beyond Baseline Therapy• Aspirin

• Other Antiplatelet Agents• Lipid-Lowering Agents

• Diuretics• Beta-Blockers• Calcium-Channel Blockers

MICRO-HOPE: Ramipril Significantly MICRO-HOPE: Ramipril Significantly Reduces Cardiovascular MorbidityReduces Cardiovascular Morbidity

Effects of Ramipril: Effects of Ramipril: HOPE HOPE vs.vs. MICRO-HOPE MICRO-HOPE

Data from: HOPE Study Investigators. Lancet. 2000;355:253-259. HOPE Study Investigators. N Engl J Med 2000; 342: 145-153.

Stroke NonfatalMI

CV Death TotalMortality

0

5

10

15

20

25

30

35

40

32 33

20 22

26

37

16

24

Ris

k R

ed

uc t

ion

(%

)

HOPE MICRO-HOPE

MICRO-HOPEMICRO-HOPE

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

The EUROPA Study Investigators.The EUROPA Study Investigators. Lancet Lancet Sept 6 2003; 362: 782-788. Sept 6 2003; 362: 782-788.

14%Non-significant 22%

P=0.001

-35

-30

-25

-20

-15

-10

-5

0

% R

elat

ive

Ris

k R

educ

tion

CV DeathNonfatal

MI

Composite Outcome (CV death, MI & cardiac arrest)

20%P=0.0003

EUREURopean trial opean trial OOn reduction of cardiac events with n reduction of cardiac events with PPerindopril in stable Cerindopril in stable CAAD (D (EUROPAEUROPA):):

20% CV Risk Reduction

• Aspirin and other antiplatelets• Beta-blockers

• Lipid-lowering agents

Perindopril Benefit Beyond Standard Risk Reduction Therapies Alone

*Secondary end point

ACE-Inhibitors-Standard of CareACE-Inhibitors-Standard of Care….to decrease events….to decrease events

Atherothrombosis (atherosclerosis + Atherothrombosis (atherosclerosis + thrombosis), post MI.thrombosis), post MI.

LVSD/ HFLVSD/ HF

DiabetesDiabetes

?Hypertension?Hypertension

? Met S? Met S

ACE-Inhibitors-Standard of CareACE-Inhibitors-Standard of Care

Heart Outcomes Prevention Evaluation (Heart Outcomes Prevention Evaluation (HOPEHOPE) trial.) trial.

European Trial on Reduction of Cardiac events with European Trial on Reduction of Cardiac events with Perindopril in Stable CAD (Perindopril in Stable CAD (EUROPAEUROPA).).

Together 22,952 high risk patients with established Together 22,952 high risk patients with established vasc dx or DM randomized to ramipril 10mg or vasc dx or DM randomized to ramipril 10mg or perindopril 8mg vs placebo.perindopril 8mg vs placebo.

RR reduction of 20% and 22% in CV death, MI, stroke RR reduction of 20% and 22% in CV death, MI, stroke or cardiac arrest.or cardiac arrest.

HOPEHOPE:: N Engl J MedN Engl J Med 2000; 342: 145-153. 2000; 342: 145-153.

EUROPAEUROPA:: Lancet Lancet 2003; 362: 782-788. 2003; 362: 782-788.

ACE Inhibitors

Generic Trade Name G Avail Cost/MoGeneric Trade Name G Avail Cost/Mo

BenazeprilBenazepril Lotensin (Novartis)Lotensin (Novartis) nono $30$30

CaptoprilCaptopril Capoten (Bristol-Myers Squibb)Capoten (Bristol-Myers Squibb) yesyes $13$13

EnalaprilEnalapril Vasotec (Merck)Vasotec (Merck) yesyes $11$11

FosinoprilFosinopril Monopril (Bristol-Myers Squibb)Monopril (Bristol-Myers Squibb) nono $66$66

LisinoprilLisinopril Prinivil (Merck), Zestril (Zeneca)Prinivil (Merck), Zestril (Zeneca) yesyes $20$20

MoexiprilMoexipril Univasc (Schwarz Pharmaceuticals)Univasc (Schwarz Pharmaceuticals) nono $27$27

PerindoprilPerindopril Aceon (Solvay Pharmaceuticals)Aceon (Solvay Pharmaceuticals) nono $43$43

QuinaprilQuinapril Accupril (Pfizer)Accupril (Pfizer) nono $32$32

RamiprilRamipril Altace (Monarch Pharmaceuticals)Altace (Monarch Pharmaceuticals) nono $80$80

TrandolaprilTrandolapril Mavik (Knoll Pharmaceuticals)Mavik (Knoll Pharmaceuticals) nono $30$30

Ace inhibitors have the broadest Ace inhibitors have the broadest impact of any drug in CV medicine:impact of any drug in CV medicine:

Reduce risk of death, MI, stroke, diabetes Reduce risk of death, MI, stroke, diabetes and renal impairment.and renal impairment.

Benefit patients with HF or LV dysfunction, Benefit patients with HF or LV dysfunction, post MI, PAD, diabetes, stroke or TIA & post MI, PAD, diabetes, stroke or TIA & AAA and renal dysfunction.AAA and renal dysfunction.

ACE-Inhibitors-Standard of CareACE-Inhibitors-Standard of Care“WHOOPS”“WHOOPS”

Prevention of Events With Angiotensin-Prevention of Events With Angiotensin-Converting-enzyme Inhibition trial (Converting-enzyme Inhibition trial (PEACEPEACE). ).

Lower risk CAD patients - most post Lower risk CAD patients - most post revascularization on good risk reduction revascularization on good risk reduction treatment (antiplatelet therapy, beta-blockers treatment (antiplatelet therapy, beta-blockers and statins) on trandopril 4mg vs placebo.and statins) on trandopril 4mg vs placebo.

Resulted in no benefit.Resulted in no benefit.

N Engl J MedN Engl J Med 2004; 351; 2058-2068. 2004; 351; 2058-2068.

Comparison to HOPE & EUROPAComparison to HOPE & EUROPAThe patients enrolled in PEACE were at lower The patients enrolled in PEACE were at lower cardiovascular risk (annualized all-cause mortality in the cardiovascular risk (annualized all-cause mortality in the PEACE population was only 1.6%). PEACE population was only 1.6%). Normal mean serum creatinine and cholesterol levels Normal mean serum creatinine and cholesterol levels and their average blood pressure was the level achieved and their average blood pressure was the level achieved after use of an ACE inhibitor in HOPE and EUROPA. after use of an ACE inhibitor in HOPE and EUROPA. More patients in PEACE than in HOPE or EUROPA had More patients in PEACE than in HOPE or EUROPA had undergone coronary revascularization (73% vs 40% and undergone coronary revascularization (73% vs 40% and 54%, respectively).54%, respectively).More had received lipid-lowering therapy (70% vs 29% More had received lipid-lowering therapy (70% vs 29% and 56%). and as a consequence, their cardiovascular and 56%). and as a consequence, their cardiovascular event rate was lower than in HOPE and EUROPA. event rate was lower than in HOPE and EUROPA.

N Engl J MedN Engl J Med 2004; 351; 2058-2068. 2004; 351; 2058-2068.

Conclusions re PEACEConclusions re PEACE

Results of PEACE were entirely consistent Results of PEACE were entirely consistent with HOPE and EUROPA. with HOPE and EUROPA.

Underpowered (more patients and longer Underpowered (more patients and longer follow-up needed because better follow-up needed because better treatment resulted in lower risk).treatment resulted in lower risk).

Dosages of drugs are not comparable.Dosages of drugs are not comparable.

Absolute benefit obtained depends on Absolute benefit obtained depends on baseline risk. baseline risk.

AngiotensinogenAngiotensinogen

Angiotensin IAngiotensin I

Angiotensin IIAngiotensin II

AT I receptorAT I receptor

ReninRenin

AngiotensinAngiotensinConvertingConverting

Enzyme (ACE)Enzyme (ACE)

Medications that block the Medications that block the RAASRAAS

Renin blockers-Renin blockers-(Beta blockers)(Beta blockers)

ACE-inhibitorsACE-inhibitors

ARBsARBs

AldosteroneAldosteroneAldosteroneAldosterone

blockersblockers

A II BLOCKADEA II BLOCKADE It is no coincidence that:It is no coincidence that:

beta-blockers (renin inhibitors)beta-blockers (renin inhibitors)

angiotensin converting enzyme--(ACE) inhibitorsangiotensin converting enzyme--(ACE) inhibitors

angiotensin receptor blockers (ARBs)angiotensin receptor blockers (ARBs)

Aldosterone blockadeAldosterone blockade

— —all A II antagonistsall A II antagonists

↓↓ CV and CRD risk and decrease mortalityCV and CRD risk and decrease mortality

… …..improve outcomes!improve outcomes!

ConclusionConclusion

Angiotensin II Blockade is good.Angiotensin II Blockade is good.

ACEI apparently are very ACEI apparently are very effective with improved outcomes.effective with improved outcomes.

Always room for improvement!Always room for improvement!

The Question?The Question?

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

Blocking RAASBlocking RAASSuperior for risk reduction and less diabeto-genic than Superior for risk reduction and less diabeto-genic than “older” anti-hypertensive agents“older” anti-hypertensive agentsHOPEHOPE, , EUROPAEUROPA, , ALLHATALLHAT and and ANBP2ANBP2 trials have all trials have all shown decreases incidence of T2DM with ACE inhibition.shown decreases incidence of T2DM with ACE inhibition.Emerging evidence from the Emerging evidence from the LIFE LIFE and and CHARMCHARM trials have trials have shown respective 25% and 28% reductions in the shown respective 25% and 28% reductions in the incidence of DM with ARBsincidence of DM with ARBs..

HOPE HOPE – – HHeart eart OOutcomes utcomes PPrevention revention EEvaluation (Ramipril). valuation (Ramipril). N Engl J MedN Engl J Med 2000; 242: 145-153. 2000; 242: 145-153.

EUROPAEUROPA – – EUREURopean trial opean trial OOn reduction of cardiac events with n reduction of cardiac events with PPerindopril in stable Cerindopril in stable CAAD.D. Lancet Lancet 2003; 326: 782-788. 2003; 326: 782-788. ALLHATALLHAT – – AAntihypertensive and ntihypertensive and LLipid ipid LLowering Treatment to Prevent owering Treatment to Prevent HHeart eart AAttack ttack TTrial. rial. JAMAJAMA 2002; 288: 1981-1997. 2002; 288: 1981-1997. ANBP2ANBP2 – Second – Second AAustralian ustralian NNational ational BBlood lood PPressure Study. ressure Study. N Engl J MedN Engl J Med 2003; 348: 583-592. 2003; 348: 583-592. LIFE LIFE – Losarten Intervention for Endpoint Reduction (LIFE) Trial. – Losarten Intervention for Endpoint Reduction (LIFE) Trial. J Clin HypertensionJ Clin Hypertension 2002; 4: 301-305. 2002; 4: 301-305. CHARM CHARM – – CCandesartan in andesartan in HHeart Failure—eart Failure—AAssessment of ssessment of RReduction of eduction of MMortality and morbidity. ortality and morbidity. LancetLancet 2003; 326: 759-766. 2003; 326: 759-766.

ACE inhibitors and ARBsACE inhibitors and ARBs

Improve insulin sensitivityImprove insulin sensitivityUsage in various studies have shown Usage in various studies have shown decreased development of T2DMdecreased development of T2DMUnknown mechanismUnknown mechanism

? XX Induction of vascular insulin ? XX Induction of vascular insulin resistance on vsmc by A II…increased resistance on vsmc by A II…increased vasoconstriction, decreased NO, ED, vasoconstriction, decreased NO, ED, increased inflammation, insulin resistance increased inflammation, insulin resistance and increased prothrombotic state. and increased prothrombotic state.

Arguments Against ACEIArguments Against ACEI

Poor tolerabilityPoor tolerability

-- Cough 6% to 7% Cough 6% to 7%

-- Angioedema (1:1000) Angioedema (1:1000)

-- Angioedema requiring hospitalization Angioedema requiring hospitalization

(1: 10,000) (1: 10,000)

Arguments for ARBsArguments for ARBs

Beneficial in HF (Beneficial in HF (CHARM CHARM && ELITE II ELITE II).).

Beneficial post MI and better tolerated Beneficial post MI and better tolerated ((VALIANTVALIANT & & OPTIMAALOPTIMAAL).).

Shown to decrease progression of Shown to decrease progression of proteinuria and renal diseaseproteinuria and renal disease****..

Associated with decreased incidence of Associated with decreased incidence of DM (DM (LIFELIFE & & CHARMCHARM).).

Not associated with cough or angioedema.Not associated with cough or angioedema.

ARB DATAARB DATA

CHARMCHARM - - Lancet Lancet 2003; 326:759-66. 2003; 326:759-66.

ELITE IIELITE II – – LancetLancet 2000; 355: 1582-1587. 2000; 355: 1582-1587.

VALIANTVALIANT - - N Eng J MedN Eng J Med 2003; 349: 1893-1906. 2003; 349: 1893-1906.

OPTIMALOPTIMAL – – LancetLancet 2002; 360: 752-760. 2002; 360: 752-760.

LIFE LIFE – – HypertensionHypertension 2002; 4: 301-305. 2002; 4: 301-305.

Three recent studies show that ARBs can slow the Three recent studies show that ARBs can slow the progression of renal disease among patients with T2DM progression of renal disease among patients with T2DM

(with HBP and microalbuminuria). (with HBP and microalbuminuria).

Lewis EJ et al. Renoprotective effect of the angiotensin-Lewis EJ et al. Renoprotective effect of the angiotensin- receptor antagonist irbesartan in patients with receptor antagonist irbesartan in patients with nephropathy due to type II diabetes. nephropathy due to type II diabetes. N Enjl J MedN Enjl J Med 2001 Sep 20; 345: 852-60. 2001 Sep 20; 345: 852-60.

Brenner BM et al. Effects of losartan on renal andBrenner BM et al. Effects of losartan on renal and cardiovascular outcomes in patients with type II diabetes cardiovascular outcomes in patients with type II diabetes and nephropathy. and nephropathy. N Engl J MedN Engl J Med 2001 Sep 20; 345: 861-69. 2001 Sep 20; 345: 861-69.

Parving HH et al. The effect of irbesartan on Parving HH et al. The effect of irbesartan on development of diabetic nephropathy development of diabetic nephropathy in patients with type II diabetes. in patients with type II diabetes. N Engl J MedN Engl J Med 2001 Sep 20; 345: 870-78. 2001 Sep 20; 345: 870-78.

ARB vs ACE-I in T2DM + nephropathyARB vs ACE-I in T2DM + nephropathy

DETAIL study: comparison study with DETAIL study: comparison study with telmisartan vs enalapril.telmisartan vs enalapril.

Results: telmisartan is Results: telmisartan is not inferiornot inferior to to enalapril in providing renoprotection in enalapril in providing renoprotection in subjects with T2DM and mild nephropathy.subjects with T2DM and mild nephropathy.

N Engl J MedN Engl J Med Nov 4 2004; 351: 1952-1961. Nov 4 2004; 351: 1952-1961.

Evaluation of Therapeutic Options- Evaluation of Therapeutic Options- Criteria for Choice of Agent:Criteria for Choice of Agent:

Should have proven CV morbidity and Should have proven CV morbidity and mortalitymortality benefits. benefits. Should reduce BP over 24 hours (i.e. be long-Should reduce BP over 24 hours (i.e. be long-acting) in order to reduce end-organ damage acting) in order to reduce end-organ damage and the incidence of early morning and the incidence of early morning cardiovascular events. cardiovascular events. Should have direct protective properties on end Should have direct protective properties on end organs, such as the heart, brain and kidney.organs, such as the heart, brain and kidney.Should have a favorable interaction profile and Should have a favorable interaction profile and of course needs be well tolerated. of course needs be well tolerated.

ACE INHIB VS ARB for HBPACE INHIB VS ARB for HBP…Compelling Indications:…Compelling Indications:

Beneficial Effects of ACEI @ all Beneficial Effects of ACEI @ all stages (HBPstages (HBP→CAD→HF)→CAD→HF)

ImmediateImmediate Hemodynamic: Hemodynamic: ↓ BP↓ BP Preservation of bradykininPreservation of bradykinin ↑ ↑ nitric acidnitric acid ↓ ↓ superoxide productionsuperoxide production

Intermediate Intermediate Fibrinolytic stabilization Fibrinolytic stabilization ↓ ↓ PAI-1 PAI-1 ↑ ↑ PAPA ↓ ↓ platelet activatorplatelet activator

Late effectsLate effects ↓ cell migration ↓ cell migration ↓ ↓ cell proliferationcell proliferation Plaque stabilizationPlaque stabilization

Who should receive ACE-Who should receive ACE-inhibitors?inhibitors?

HF (LVEF < 40%)HF (LVEF < 40%)

CVD (CAD, PAD, carotid or cerebral vasc CVD (CAD, PAD, carotid or cerebral vasc dx, AAA)dx, AAA)

T2DMT2DM

Metabolic Syndrome (pre-diabetics)Metabolic Syndrome (pre-diabetics)

CRDCRD

HBPHBP

ConclusionsConclusions

No Evidence of superiority of ARBs Over ACEI.No Evidence of superiority of ARBs Over ACEI.

Should not replace comfort above efficacy and Should not replace comfort above efficacy and safety (ie ACEI the only agent with safety (ie ACEI the only agent with ↓ mortality ↓ mortality benefit.benefit.

Cost should always be part of the equation.Cost should always be part of the equation.

ACEI are still first choice but use ARBs in all ACEI are still first choice but use ARBs in all situations where ACEI cannot be tolerated…situations where ACEI cannot be tolerated…

… …and maybe as an add-on or in combo in patients and maybe as an add-on or in combo in patients

T2DM/microalbuminuria.T2DM/microalbuminuria.

Optimal TreatmentOptimal Treatment

T2DM/MetS/HBP/microalbuminuriaT2DM/MetS/HBP/microalbuminuria ACEI-First choice; ARBs-SecondACEI-First choice; ARBs-Second

- Poss consider both. - Poss consider both. Hctz &/or CoregHctz &/or Coreg ASAASA StatinStatin TLCTLC Control SugarsControl Sugars→ More drugs!!→ More drugs!!