ace inhibitor
DESCRIPTION
TRANSCRIPT
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
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