1. ACE INHIBITORS : FROM VENOM
TO DRUG
Dr Syed Raza
MD,MRCP(UK),CCT(UK),DIP.CARD(UK),FCCCP
Consultant Cardiologist

2. Objectives
• Overview of ACEI
• Indications and Uses
• Effectiveness and
• The Evidence

3. Franklin D Roosevelt – 1940s
Howard 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’’

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

5. Angiotensinogen
Renin
Angiotensin I Bradykinin
Non ACE ACE (-) ACEi (-)
Angiotensin II Inactive Metabolites
ARB
AT1 Receptor AT2 Receptor

6. ACE Inhibitor Groups
A. Sulfhydryl-containing agents:
– Captopril , the first ACE inhibitor
B. Dicarboxylate-containing agents:
– Enalapril
– Ramipril
– Quinapril
– Perindopril
– Lisinopril
– Benazepril
C. Phosphonate-containing agents:
– Fosinopril
– Trandolapril

7. Clinical Indications for ACEI
• Hypertension
• CHF
• Post MI
• Diabetes Mellitus
• Proteinuria
• Vascular Disease
• Post - transplant

8. Additional Benefits of ACEI
• Prevention of diabetes
• Prevention of stroke recurrence
• Prevention of atrial fibrillation

9. 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.

10. 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

11. 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.

12. 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

13. 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?

14. Concomitant Use of
Antihypertensive Drugs
Diuretics Beta Blockers
ACEIs Calcium
ARBs Channel
Blockers
α1-Receptor Blockers
Less effective Particularly effective
Adapted from Chalmers J. Clin Exp Hypertens. 1993;15:1299–1313.

15. 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

16. ALLHAT (JAMA 2002)
“The key message from ALLHAT is that what
matters most is getting blood pressure
controlled’’

17. The Heart Matters – the effect of ACEI
• Prevents cardiac hypertrophy
• Limits infarct size
• Improves cardiac function
• Improves cardiac metabolism

18. 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.

19. 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).

21. 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.

22. 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).

23. 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.

24. Landmark trials with ACE inhibitors in HF
Trial n EF% Drug Death Hospitalisation Follow up NNT
(death)
CONSENSUS 253 <35% enalapril 36 vs 50 reduced 1 year 6
1987 (IV)
SOLVD-P 4228 <35 enalapril trend to reduced 4 years 104
1992 (I) reduction
SOLVD – T 2500 < 40 enalapril 12.3 vs 15.5 reduced 3 years 31
1991 (II-III)
ATLAS 3164 <35 lisinopril no difference reduced 4 years -
1997 (II-IV)

25. • 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.

26. Type 2 diabetes
Management of cardiovascular risk factors
Lending our patients a hand

27. 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

28. 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

29. 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.

30. 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

31. Intensive Multiple Risk Factor Management Patients with
Type 2 Diabetes and Microalbuminuria
60 N=160; follow-up=7.8 years
Primary Composite Endpoint* (%)
Conventional Therapy
40 20% Absolute
Risk Reduction
20 Aggressive treatment of†:
– Microalbuminuria with
Intensive Therapy†
ACEIs, ARBs, or combination
– Hypertension
– Hyperglycemia
– Dyslipidemia
12 24 36 48 60 72 84 96 – Secondary prevention of CVD
Months of Follow-Up
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
artery disease.
†
Behavior modification and pharmacologic therapy.
Adapted from Gaede P, et al. N Eng J Med. 2003;348:383-393.
Med.

32. Vascular Protection
ACE inhibitor Trials
© Continuing Medical Implementation ® …...bridging the care gap

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

34. 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

35. 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

36. Study rationale and design

37. EUROPA
 Randomised 12,218 patients with stable coronary
artery disease (CAD) and a broad range of risk for
cardiovascular complications
 Showed the benefit of long-term (mean 4.2 years)
ACE-inhibition (perindopril 8 mg/day)

38. Study end points
Primary endpoint
 Non Fatal MI, Cardiac arrest and CV mortality
Secondary endpoints
 Heart failure
 Revascularisation (PCI/CABG)
 Stroke

39. Primary endpoint
% CV death, MI or cardiac arrest
14
12 RRR: 20% Placebo
p = 0.0003
10
Perindopril
8
6
4
2
0
0 1 2 3 4 5 Years
Placebo annual event rate: 2.4%

40. Primary endpoint
CV death, MI or cardiac arrest
RRR: 20% [95% CI : 9 - 29]
No events
700
9.9%
600
8.0% 603
500
400 488
300
200
100
0
Perindopril Placebo
(6 110) (6 108)

42. 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

43. 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.

44. 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

45. Change in Systolic Blood
Pressure
0
Pressure Change (mm Hg)
-1 ∆=-1.4
-2
-3
-4
-5
∆=-4.4, p<0.001
-6
0 1 2 3 4 5 6
Baseline= Time Since Randomization (Years)
133±17
Placebo Trandolapril

46. Change in Diastolic
Blood Pressure
0
Pressure Change (mm Hg)
-1
-2 ∆=-2.3
-3
-4
-5
∆=-3.6, p<0.001
-6
-7
0 1 2 3 4 5 6
Baseline= Time Since Randomization (Years)
78±10
Placebo Trandolapril

47. PEACE Trial: All Death
All-Cause Death
p = 0.13 • A slight reduction in all-
cause death seen in the
10 Trandolapril arm was not
statistically significant
8.1
8 7.2
6
4
2
0
Trandolapril Placebo
Presented at AHA 2004

48. PEACE Trial: Primary Endpoint
The individual components of the primary endpoint were also
equivalent in the Trandolapril and placebo groups
16 p=0.65
12.4 12.0
12 p=0.24
p=1.00
8 p=0.67 7.1
6.5
%
5.3 5.3
3.5 3.7
4
0
Cardio death Nonfatal MI CABG PCI
Trandolapril Placebo
Presented at AHA 2004

49. IMAGINE
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
CV death or cardiac arrest
•In patients at low risk of CV
(p = 0.57)
events after CABG, routine
early initiation of ACE
0.6
0.6 0.5
0.4
inhibitor therapy does not
0.4
0.4 appear to improve clinical
%
0.2
0.2 outcome up to 3 years after
CABG
Conclusions
00
Quinapril Placeb
(n = 1,280) o
(n =
1,273)

50. THANK YOU