ACE INHIBITORS : FROM VENOMTO DRUGDr Syed Raza

MD,MRCP(UK),CCT(UK),DIP.CARD(UK),FCCCP

Consultant Cardiologist

Objectives

• Overview of ACEI• Indications and Uses• Effectiveness and • The Evidence

Franklin D Roosevelt – 1940sHoward Bruenn lamented in the Annals of Internal Medicine, "I have often wondered what turn the subsequent course of history might have taken if the modern methods for the control of hypertension had been available’’

Originally synthesized from compounds found in pit viper venom(Sir John Vane -1960s)

Angiotensinogen

Angiotensin I

Angiotensin II

AT1 Receptor AT2 Receptor

Bradykinin

Inactive Metabolites

Renin

ACE

ARB

Non ACE ACEi(-) (-)

ACE Inhibitor GroupsA. Sulfhydryl-containing agents:

– Captopril , the first ACE inhibitor B. Dicarboxylate-containing agents:

– Enalapril – Ramipril – Quinapril – Perindopril – Lisinopril – Benazepril

C. Phosphonate-containing agents: – Fosinopril– Trandolapril

Clinical Indications for ACEI

• Hypertension• CHF• Post MI• Diabetes Mellitus• Proteinuria• Vascular Disease• Post - transplant

Additional Benefits of ACEI

• Prevention of diabetes• Prevention of stroke recurrence• Prevention of atrial fibrillation

How ACEI is useful in hypertension?

• ACE inhibitors block the conversion of angiotensin I to angiotensin II

• Lower arteriolar and renovascular resistance • Increase venous capacity,• Increase cardiac output, cardiac index and

stroke volume.

Which antihypertensive?NICE Diabetes Clinical Guideline 66;May 2008. NICE Full Diabetes Guideline;2008

• First-line BP lowering therapy should be a once-daily, generic ACE inhibitor

• Exceptions to this are:

– People of African-Caribbean descent– Women for whom there is a possibility of

becoming pregnant– For a person with continuing intolerance to an

ACE inhibitor

Choice of antihypertensive agents

When implementing blockade of the renin–

angiotensin system start treatment with an ACE inhibitor first then move to an ARB if the ACE inhibitor is not tolerated.

Pharmacotherapy –BP Control

• In people without CKD aim to keep the systolic blood pressure below 140 mmHg (target range 120–139 mmHg) and the diastolic blood pressure below 90 mmHg.

• In people with CKD and diabetes with urinary protein excretion 1 g/24 h or more) aim to keep the systolic blood pressure below 130 mmHg (target range 120–129 mmHg) and the diastolic blood pressure below 80 mmHg

Fixed Drug Combination

► To achieve recommended blood pressure goals, it is often necessary to combine two or more antihypertensive agents. Is there a preferred combination?

► To achieve recommended blood pressure goals, it is often necessary to combine two or more antihypertensive agents. Is there a preferred combination?

Less effective

Diuretics Beta Blockers

ACEIsARBsACEIsARBs

CalciumChannelBlockers

CalciumChannelBlockers

1-Receptor BlockersParticularly effective

Adapted from Chalmers J. Clin Exp Hypertens. 1993;15:1299–1313.

Concomitant Use of Antihypertensive Drugs

The Moral of the Tale

As long as we reach the objective BP below 140/90 (130/80), it doesn’t matter how we get there

ALLHAT (JAMA 2002)

“The key message from ALLHAT is that what matters most is getting blood pressure controlled’’

The Heart Matters – the effect of ACEI

• Prevents cardiac hypertrophy• Limits infarct size• Improves cardiac function• Improves cardiac metabolism

ACEI in Heart Failure

• ACE inhibitors are recommended to treat HF due to systolic dysfunction.

• The benefit of ACE inhibitors has been demonstrated in all severities of symptomatic HF and in patients with asymptomatic left ventricular (LV) dysfunction.

ACE in Heart Failure: the evidence

A meta-analysis evaluated five trials • Improvement in symptoms• A lower total mortality. • A lower rate of readmission for HF).

ACE Inhibitors for ‘Diastolic’ Heart Failure?

• Guidelines for the management of heart failure focus on patients with left ventricular systolic dysfunction.

• However, guidelines make no recommendation for their use in patients with heart failure and preserved left ventricular systolic function.

ACE inhibitors versus ARBs: comparison of practice guidelines and treatment selection

• ACC/AHA Heart Failure guidelines 2005. ACE inhibitors should be prescribed to all patients with left ventricular systolic dysfunction HF (class IA recommendation).

• They recommend ARBs as a "reasonable alternative" first-line therapy (class IIA recommendation).

ACE inhibitors versus ARBs: comparison of practice guidelines : Contd

• ACEI more cost effective• ARB better tolerated than ACEI• Deciding factor may be largely patient-

specific.

Landmark trials with ACE inhibitors in HF

Trial n EF% Drug Death Hospitalisation Follow up NNT(death)

CONSENSUS1987

253 <35%(IV)

enalapril 36 vs 50 reduced 1 year 6

SOLVD-P1992

4228 <35(I)

enalapril trend toreduction

reduced 4 years 104

SOLVD – T1991

2500 < 40(II-III)

enalapril 12.3 vs 15.5 reduced 3 years 31

ATLAS1997

3164 <35(II-IV)

lisinopril no difference reduced 4 years -

• The ACE inhibitor Enalapril has also been shown to reduce cardiac cachexia in patients with chronic heart failure

• Cachexia is a poor prognostic sign in patients with chronic heart failure. ACE inhibitors are now used to reverse frailty and muscle wasting in elderly patients without heart failure.

Type 2 diabetes Management of cardiovascular risk factors

Lending our patients a hand

Can ACEI prevent Diabetes ?

• Several recent studies indicate that ACE inhibitor therapy reduces the development of type 2 diabetes in persons with essential hypertension.

• HOPE, CAPPP, SOLVD, and ALLHAT • DREAM & ONTARGET = more recent

Path physiology

• Exact mechanism is not known• ACEI reduces oxidative stress• Increases insulin sensitivity in the liver• Reduces Insulin resistance in muscles• Helps in the preservation of islet cells of

pancreas

ACEI and the Kidneys

Clinical studies have shown ACE inhibitors

reduce the progress of diabetic nephropathy independently from their blood pressure-lowering effect.

This action of ACE inhibitors is used in the prevention of diabetic renal failure.

ACEI and the Kidneys – Contd:

• Decreases Proteinuria (DM and Non-DM)• Beneficial effect on permeability• Beneficial effect on size selectivity• Slow the Rate of GFR Decline

Primary composite endpoint: conventional therapy (44%) and intensive therapy (24%).Primary composite endpoint: conventional therapy (44%) and intensive therapy (24%).**Death from CV causes, nonfatal MI, CABG, PCI, nonfatal stroke, amputation, or surgery for peripheral atherosclerotic Death from CV causes, nonfatal MI, CABG, PCI, nonfatal stroke, amputation, or surgery for peripheral atherosclerotic

artery disease.artery disease.††Behavior modification and pharmacologic therapy.Behavior modification and pharmacologic therapy.

Adapted from Gaede P, et al. Adapted from Gaede P, et al. N Eng J MedN Eng J Med. 2003;348:383-393. . 2003;348:383-393.

Prim

ary

Com

posi

te E

ndpo

int*

(%

)P

rimar

y C

ompo

site

End

poin

t* (

%)

Months of Follow-UpMonths of Follow-Up

6060

4040

2020

1212 2424 3636 4848 6060 7272 8484 9696

Conventional TherapyConventional TherapyConventional TherapyConventional Therapy

Intensive TherapyIntensive Therapy††Intensive TherapyIntensive Therapy††

20% Absolute 20% Absolute Risk ReductionRisk Reduction20% Absolute 20% Absolute Risk ReductionRisk Reduction

N=160; follow-up=7.8 yearsN=160; follow-up=7.8 years

Aggressive treatment ofAggressive treatment of††::– Microalbuminuria with Microalbuminuria with ACEIs, ARBs, or combinationACEIs, ARBs, or combination– HypertensionHypertension– HyperglycemiaHyperglycemia– DyslipidemiaDyslipidemia– Secondary prevention of CVDSecondary prevention of CVD

Aggressive treatment ofAggressive treatment of††::– Microalbuminuria with Microalbuminuria with ACEIs, ARBs, or combinationACEIs, ARBs, or combination– HypertensionHypertension– HyperglycemiaHyperglycemia– DyslipidemiaDyslipidemia– Secondary prevention of CVDSecondary prevention of CVD

Intensive Multiple Risk Factor Management Patients with Type 2 Diabetes and Microalbuminuria

© Continuing Medical Implementation ® ….. .bridging the care gap

Vascular Protection ACE inhibitor Trials

HOPE (Heart Outcome Prevention Evaluation)

• 9297 Patients• Age >55• DM + 1 other CV factor• Normal EF (>40%)• Ramipril (10mg) vs. Placebo

HOPE (Primary endpoints)

• Death (CV) - 6.1 vs 8.1 P<0.001 RR=0.75

• MI - 9.9 vs 12.2 P<0.001 RR=0.80

• Stroke - 3.4 vs 4.9 P<0.001 RR=0.69

HOPE (secondary endpts.)

• Death 10.4 vs 12.2• Revascularization 16.0 vs 18.6• Cardiac arrest 0.8 vs 1.2• Heart Failure 7.4 vs 9.4• DM complications 6.2 vs 7.4

* all statistically significant

EUROPA

Randomised 12,218 patients with stable coronaryartery disease (CAD) and a broad range of risk forcardiovascular complications

Showed the benefit of long-term (mean 4.2 years)

ACE-inhibition (perindopril 8 mg/day)

Study end points

Non Fatal MI, Cardiac arrest and CV mortality Non Fatal MI, Cardiac arrest and CV mortality

Primary endpointPrimary endpoint

Secondary endpointsSecondary endpoints

Heart failureHeart failure Revascularisation (PCI/CABG)Revascularisation (PCI/CABG) StrokeStroke

Primary endpoint% CV death, MI or cardiac arrest% CV death, MI or cardiac arrest

Placebo annual event rate: 2.4%Placebo annual event rate: 2.4%

Perindopril Perindopril

PlaceboPlacebop = 0.0003p = 0.0003RRR: RRR: 20%20%

YearsYears00

22

44

66

88

1010

1212

1414

00 11 22 33 44 55

Primary endpoint

RRR: 20% [95% CI : 9 - 29]RRR: 20% [95% CI : 9 - 29]CV death, MI or cardiac arrestCV death, MI or cardiac arrest

00

100100

200200

300300

400400

500500

600600

700700

No eventsNo events

PerindoprilPerindopril(6 110)(6 110)

8.0%8.0%

488488

PlaceboPlacebo(6 108)(6 108)

9.9%9.9%

603603

The Prevention of Events with Angiotensin Converting Enzyme

Inhibition (PEACE) Trial A double-blind, placebo-controlled, randomized trial

Sponsored by the National Heart, Lung, and Blood Institute

Hypothesis

To test whether ACE inhibitor therapy, when added to modern conventional therapy, reduces CV mortality, MI, or coronary revascularization in low-risk,

stable CAD patients with normal or mildly reduced LV function.

Inclusion Criteria

• Age 50 years• Coronary artery disease

– MI, or– CABG or PCI, or– Coronary angiogram with obstruction of 50%

luminal diameter in at least one native vessel• LVEF > 40%• Tolerated 2 week run-in of 2 mg/day

trandolapril

Change in Systolic Blood Pressure

-6

-5

-4

-3

-2

-1

0

0 1 2 3 4 5 6

Time Since Randomization (Years)

Pre

ssur

e C

hang

e (m

m H

g)

Placebo Trandolapril

Baseline= 13317

=-1.4

=-4.4, p<0.001

Change in Diastolic Blood Pressure

-7

-6

-5

-4

-3

-2

-1

0

0 1 2 3 4 5 6

Time Since Randomization (Years)

Pre

ssur

e C

hang

e (m

m H

g)

Placebo Trandolapril

Baseline= 7810

=-2.3

=-3.6, p<0.001

PEACE Trial: All Death

7.28.1

0

2

4

6

8

10

Trandolapril Placebo

7.28.1

0

2

4

6

8

10

Trandolapril Placebo

• A slight reduction in all-cause death seen in the Trandolapril arm was not statistically significant

All-Cause Death

p = 0.13

Presented at AHA 2004Presented at AHA 2004

PEACE Trial: Primary Endpoint

3.5

5.36.5

12.4

3.7

5.3

7.1

12.0

0

4

8

12

16

Cardio death Nonfatal MI CABG PCI

Trandolapril Placebo

3.5

5.36.5

12.4

3.7

5.3

7.1

12.0

0

4

8

12

16

Cardio death Nonfatal MI CABG PCI

Trandolapril Placebo

%

Presented at AHA 2004Presented at AHA 2004

p=0.67

p=1.00p=0.24

p=0.65

The individual components of the primary endpoint were also equivalent in the Trandolapril and placebo groups

IMAGINE

•In patients at low risk of CV events after CABG, routine early initiation of ACE inhibitor therapy does not appear to improve clinical outcome up to 3 years after CABG

Trial design: IMAGINE was a double-blinded, randomized, placebo-controlled trial designed to test the effects of early ACE inhibitor initiation (quinapril 10 or 20 mg/day within 7 to 10 days) after CABG in patients with preserved LV function, and no clear indication for ACE inhibitor therapy.

CONCLUSION

Conclusions

CV death or cardiac arrest

(p = 0.57)

Quinapril(n = 1,280)

%

0

0.2

0.4

0.6 0.50.4

Placebo

(n = 1,273)

0.6

0.4

0.2

0

THANK YOU