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Recommendations for the
pharmacological treatment of
atherosclerotic cardiovascular
disease based on clinical trials
Zofia Oko-Sarnowska
Department of Clinical Pharmacology
Differences between chronic and
acute atherosclerotic plaques
Chronic(stable)plaque Acute(unstable)plaque




Little lipide core
Thick fibrous cap
A low inflammatory
cells migration
A low MMP content




Big lipide core
Thin fibrous cap
A high inflammatory
cells migration
A high MMP content
Pharmacological methods of
stabilization of atherosclerotic plaque
APA
VPI
TNFαA
ACE-I
MMPI
BB
STATIN
Proven effect
Potencial effect
ARBs
AP
Stabilisation of atherosclerotic
plaque


Influence on outside risk factor of transition from
chronic to acute atherosclerosis
-reduction of sudden change of blood
pressure
-reduction of vasospastic reaction
-reduction of inflammatory process
Direct influence on atherosclerotic plaque
- decrease volume of lipid core
- reduction of inflammatory process in situ
- reduction of MMP concentration
Classes of recommendations
Class I
Evidence and/or general agreement that a given
diagnostic procedure/treatment is beneficial,
useful, and effective
Conflicting evidence and/or a divergence of
opinion about the usefulness/efficacy of the
treatment or procedure
Class IIa Weight of evidence/opinion is in favour of
usefullness/efficacy
Class IIb Usefullness/efficacy is less well established by
evidence/opinion
Class II
Class III
Evidence or general agreement that the
treatment or procedure is not useful/effective
and in some cases may be harmful
Levels of evidence
Level of evidence A
Data derived from
multiple randomized
clinical trials or metaanalyses
Level of evidence B
Data derived from a
single randomized
clinical trial or large
non-randomized studies
Level of evidence C
Consensus of opinion of
the experts and/or small
studies, retrospective
studies, registries
Pharmacological methods of
stabilization of atherosclerotic plaque
APA
VPI
TNFαA
ACE-I
MMPI
BB
STATIN
Proven effect
ARBs
AP
Angiotensin converting enzyme
inhibitors in cardiovacular disease






Heart failure (HF)
Asymptomatic left ventricular systolic
dysfunction (LVSD)
Diatolic failure
Acute myocardial infarction (AMI)
Hypertension (HT)
Secondary prevention and high-risk of
cardiovascular disease
Indication for ACE-I


Heart failure:
CONSENSUS, SAVE, VheFT-II
SOLVD Prevention, SOLVD Treatment
LVSD after MI (EF<40%)
Trial
ACE-I
n
NNT
Mortality
reduction
(RRR)
SAVE
kaptopril
2231
42
19%
AIRE
ramipril
2006
57
27%
TRACE
trandolapril
2606
76
22%
AIREX
ramipril
603
114
36%
Use of ACE-I in heart failure
Setting/indication
Class
Level
All patients with symptomatic HF and
reduced LVEF, NYHA II-IV
I
A
LVSD with/without symptoms after MI
I
A
LVSD (EF < 40-45%) without symptoms,
no previous MI
I
A
Diastolic HF
IIa
C
Use of ACE-I in myocardial
infarction
Setting/indication
Class
AMI, first 24h
risk (HF, LVD, no
reperfusion, large MI
Level
ISIS 4, GISSI-3, CCS-1,
CONSENSUS-2, SMILE
High
I
A
All
IIa
A
patients
Evolving AMI (>24h), Post MI
Clinical
HF, asymptomatic LVD
(EF<45%)
Diabetes
patients
or other high risk
SAVE, AIRE, TRACE,
I
A
I
A
Use of ACE-I in hypertension
Setting/indication
Class
Level
Trial
STOP-2,
UKPDS,
PROGRESS
To control blood pressure
I
A
Patients with HF, LVSD,
diabetics, previous MI or
stroke, high coronary
disease risk
I
A
CAPPP,
ABCD,
PROGRESS
Use of ACE-I in secondary prevention
and high-risk of cardiovacular disease
Setting/indication
High-risk patients
(evidence of
cardiovascular disease
or diabetes and one
other risk factor
Class
I
Level
Trial
A
QUIET,
PEACE,
HOPE,
EUROPA
ONTAGET
Hope study




Enrolled 9297 men and women
age > 55 years old
Indications:
1. confirmed arterial disease (CHD,
peripheral arterial disease, stroke
2. Diabetes and one other risk factor
(hypertension, cigarette smoking,
micoalbuminuria or dyslipidaemia)
Randomisation to ACE-I (ramipril 2,5-10mg) or
placebo
Follow-up: 5 years
Hope study
Results:
Primary end-point: death from
cardiovascular causes, MI or
stroke
Ramipril Placebo
14%
17,8%
NNT
26,3
RRR
22%
Secondary end-points
SCD
26%
Stroke
32%
Need for revascularisation
20%
Dabetic complications
16%
Onset of new diabetes
34%
Trials in low risk patients
n=13655
AP without HF
Perindopril 8mg/d Reduction of:
cardiovascular
mortality, MI, SCD
RRR= 20%
NNT = 50/4,2years
PEACE
Trandolapril
2-4mg/d
EUROPA
n=8290
CAD + EF> 40%
Reduction of
cardiovascular
mortality, non fatal
MI, need for
revascularisation
(NS)
Use of ACE-I to prevent sudden death


In patients with asymptomatic LV dysfunction,
moderate and advanced HF treatement with
ACE-I resulted in a reduction in mortality from
sudden cardiac death (SCD)
This reduction varied from 20-54% and was
statistically significant in some heart failure
studies, although SCD was not the primary endpoint in this trials.
Priori et al. For the Task Force on Sudden Cardiac Death of the ESC.
Eur Heart J 2001; 22: 1374-450
Update on the guidelines for SCD of the ESC. .Eur Heart J 2003; 24: 13-15
Use of ACE-I to prevent sudden death
Setting/indication
Class
Level
Patients with HF
I
A
Patients with previous
MI
I
A
Patients with dilated
cardiomyopathy
I
B
Pharmacological methods of
stabilization of atherosclerotic plaque
APA
VPI
TNFαA
ACE-I
MMPI
BB
STATIN
Proven effect
ARBs
AP
Usefulness of beta-adrenoceptor
antagonists in cardiovascular
disease
CAD
HF
H
DM
A
CAD – coranry artery disease, HF-heart failure, H - hypertension
DM - diabetes, A - arrythmia
Use of beta-adrenoceptor antagonists
in coronary heart disease







Acute myocardial infarction (AMI)
Post MI – secondary prevention
Acute coronary syndromes NSTEMI
Chronic, stable ischaemic heart disease
Heart failure (HF)
Arrythmias
Prevention of sudden cardiac death (SCD)
Use of beta-blockers in AMI
Setting/indication
Class
Level
For relief of ischaemic pain
I
B
To control hypertension, sinus tachycardia
I
B
Primary prevention of SCD
I
B
Sustained ventricular tachycardia
I
C
Supraventricular tachyarrythmias
I
C
To limit infarct size
IIa
A
All patients without contraindications
IIb
A
I
A
I.v.administration
Oral administration
All patients without contraindications
Use of beta-blockers in secondary
prevention after MI
Setting/indication
Class
Level
All patients without
contraindication, indefinitely
I
A
To improve survival
I
A
To prevent reinfarction
I
A
Primary prevention of SCD
I
A
To prevent/treat late ventricular
arrythmias
IIa
B
Use of beta-blockers in non-STsegment elevation ACS (NSTEMI ACS)
Setting/indication
Class
Level
Early benefit, reduction of ischaemia
I
B
Early benefit, prevention MI
I
B
Long-term secondary prevention
I
B
Use of beta-blockers in chronic, stable
ischaemic heart disease
Setting/indication
Class
Level
To improve survival
I
A
To reduce reinfarction
I
A
To prevent/control ischaemia
I
A
To improve survival
I
C
To reduce reinfarction
I
B
To prevent/control ischaemia
I
A
Previous infarction
No previous infarction
Usefulness of beta-blockers in CAD
based on clinical trials



Olson’s meta-analysis 1992 (5 trials with
metoprolol)
Yusuf’s meta-analysis 1998
(25 randomized studies)
Freemantle’s meta-analysis 1999 (82 trials post
MI)
23% reduction of overall mortality
despite ACE-I and ASA treatment
Use of beta-blockers in chronic
heart failure
Setting/indication
Class
Level
All stable patients, with symptomatic heart
failure and reduced LVEF, functional class II-IV
(to prolong survival)
I
A
LVSD without symptoms after AMI
I
A
LVSD without symptoms, no previous MI
I
B
Chronic HF with preserved systolic function (to
reduce heart rate)
IIa
C
Acute, compensated heart failure after AMI
IIa
B
Patient stable after acutely decompensated
chronic heart failure
I
A
Use of beta-adrenoceptor
antagonists in heart failure

Waagstein et al. – team from Gőteborg: the pioneers work on application
of beta-blockers (metoprolol) in the treatment of HF (1970y)

CIBIS I 1994 (bisoprolol).

USCP (US Carvedilol Programme) 1996 (carvedilol)

Australian/New Zealand Heart Failure Study 1997 (carvedilol)




CIBIS II (Cardiac Insufficiency Bisoprolol Study II) 1999
MERIT-HF 1999 (metoprolol CR)
COPERNICUS (Carvedilol Prospective Randomised Cumulative
Survival Study) 2001 (carvedilol)
CAPRICORN (Carvedilol Post-Infarct Survival Control in Left
Ventricular Dysfunction) 2001 (carvedilol)
Most importent trials in the
treatment of HF with beta-blockers
Trial
Agent
N
All-cause
mortality
RRR (%)
USCP
Carvedilol
451
65
27
CIBIS II
Bisoprolol
2647
35
15
MERIT-HF
Metoprolol
CR
3991
34
13
COPERNICUS
Carvedilol
2289
35
27
CV morbidity
RRR%
Use of beta-adrenoceptor
antagonists in heart failure


Beta-blockers should be considered for the treatment of
all patients (NYHA II-IV) with stable, mild, moderate,
and severe heart failure from ischaemic or nonischaemic cardiomyopathies and reduced LVEF on
standard treatment, including diuretics, and ACE-I,
unless there is a contraindication (Class I, level A)
Beta-blocking therapy reduces hospitalisations (all,
cardiovascular, and HF), improves the functional class
and leads to less worsening of HF. This beneficial effect
has been consistently observed in subgroups of different
age, gender, functional class, LVEF, and ischaemic or
non-ischaemic aetiology (Class I, level A)
Use of beta-adrenoceptor
antagonists in heart failure


In patients with LV systolic dysfunction, with or
without symptomatic HF, following an AMI
long-term beta-blockade is recommended in
addition to ACE inhibition to reduce mortality
(Class I, level B)
Differences in clinical effects may be present
between different beta-blockers in patients with
HF. Accordingly, only bisoprolol, carvedilol,
metoprolol succinate and nebivolol can be
recommended (Class I, level A)
Use of beta-adrenoceptor
antagonists in diabetes



Beta-blockers are particularly effective in
decreasing post-infarction mortality and new
infarcts in patients with a history of DM.
Thus, oral BBs are, in the absence of
contraindications, recommended for all diabetic
patients with ACS
(Class IIa, level B)
Furthermore, such patients are more prone to
develop heart failure and recent trials have
documented the beneficial effects of betablockade in HF patients.
Use of beta-blockers in diabetes


Selective beta-1-antagonist may be
preferred in case of insulin treatment
Alpha-1-beta-adrenergic antagonists such
as carvedilol may offer additional benefits
for patients with peripheral artery disease
or substantial insulin resistance.
Pharmacological methods of
stabilization of atherosclerotic plaque
APA
VPI
TNFαA
ACE-I
MMPI
BB
STATIN
Proven effect
ARBs
AP
Angiotensin II receptor blockers
(ARBs) – angioprotective action?

LIFE (losartan vs atenolol): 2002 N=9100; age>55lat
Hypertension with LVH
Results: Risk reduction of CV death, MI and stroke
Risk reduction of fatal nad non-fatal stroke
Decrease onset of new diabetes




SCOPE – beneficial effect of ARBs in primary prevention of stroke
MOSES – beneficial effect of ARBs in secondary prevention of
stroke
DETAIL (telmisartan vs enalapryl): similar nephroprotecive effects
in diabetes
VALUE – decrease onset of new diabetes
Use of angiotensin II receptor
blockers (ARBs) in heart failure


ARBs can be used as an alternative to ACE-I in
symptomatic patients intolerant to ACE-I to
improve morbidity and mortality (Class I, level
B) (ELITE II, OPTIMAAL)
ARBs and ACE-I seem to have similar efficiacy in
CHF on mortality and morbidity (Class IIa, level
B). In AMI with signs of HF or LVD ARBs and
ACE-I have similar or equivalent effects on
mortality (Class I, level B) (CHARM-Added)
CHARM Programme
3 component trials comparing candesartan to
placebo in patients with symptomatic heart failure
CHARM
Alternative
CHARM
Added
CHARM
Preserved
n=2028
n=2548
n=3025
LVEF 40%
ACE inhibitor
intolerant
LVEF 40%
ACE inhibitor
treated
LVEF >40%
ACE inhibitor
treated/not treated
Primary outcome for each trial: CV death or CHF hospitalisation
Primary outcome for Overall Programme: All-cause death
Pfeffer et al, Lancet 2003
CHARM-Alternative
Primary outcome, CV death or CHF
%
hospitalisation
50
406 (40%)
Placebo
40
334 (33%)
30
Candesartan
20
10
HR 0.77 (95% CI 0.67-0.89), p=0.0004
Adjusted HR 0.70, p<0.0001
0
Number at risk 0
Candesartan 1013
Placebo
1015
1
2
929
887
831
798
3
3.5 years
434 122
427 126
Granger et al, Lancet 2003
CHARM-Alternative
Conclusions


Despite prior intolerance to another
inhibitor of the renin-angiotensinaldosterone system, candesartan was
well tolerated
In patients with symptomatic CHF and
ACE inhibitor intolerance, candesartan
reduces cardiovascular mortality and
morbidity
Granger et al, Lancet 2003
CHARM-Added
Primary outcome, CV death or CHF
%
hospitalisation
50
538 (42.3%)
483 (37.9%)
Placebo
40
30
Candesartan
20
10
HR 0.85 (95% CI 0.75-0.96), p=0.011
Adjusted HR 0.85, p=0.010
0
Number at risk 0
Candesartan 1276
Placebo
1272
1
2
1176
1136
1063
1013
3
3.5 years
948 457
906 422
McMurray et al, Lancet 2003
CHARM-Added
Prespecified subgroups, CV death or CHF
hospitalisation
Candesartan
event/n
BetaYes
blocker
No
Recom.
Yes
dose of
No
ACE inhib
All patients
Placebo
event/n
223/702
260/574
232/643
251/633
274/711
264/561
275/648
263/624
483/1276
538/1272
p-value for
treatment
interaction
0.14
0.26
0.6
0.8
1.0
1.2
1.4
Candesartan Hazard
Placebo
better
ratio
better
McMurray et al, Lancet 2003
CHARM-Added
Conclusions



Addition of candesartan to an ACE inhibitor
(and beta-blocker) leads to a further and
clinically important reduction in CV mortality
and morbidity in patients with CHF
The benefit of candesartan corresponds to a
NNT of 23 (for a mean of 3.0 years) to prevent
one CV death or a first CHF hospitalisation
This benefit is obtained with relatively few
adverse effects, although there is an increased
risk of hypotension, hyperkalaemia and renal
dysfunction
McMurray et al, Lancet 2003
CHARM - Low EF trials: baseline characteristics
Candesartan
n=2289
Mean age (years)
Women (%)
NYHA class (%)
II
III
IV
Mean LVEF (%)
Medical history (%)
myocardial infarction
diabetes
hypertension
atrial fibrillation
Placebo
n=2287
65
26
65
26
35
62
3
29
34
62
4
29
59
29
48
26
58
29
50
26
Young et al, Circulation 2004
CHARM - Low EF trials
CV death or CHF hospitalisations
CV death or CHF hosp (%)
50
Placebo
944 (41.3%)
Two year HR 0.77
p<0.001
40
Candesartan
817 (35.7%)
One year HR 0.70
p<0.001
30
20
10
Hazard ratio 0.82 (95% CI 0.74 – 0.90),
p<0.001
0
Number at risk
Candesartan
Placebo
0
1
2289
2287
2105
2023
2
1894
1811
3
1382
1333
3.5 yrs
580
548
Young et al, Circulation 2004
CHARM-Low EF
Implications


Candesartan significantly reduces cardiovascular
death, hospital admission for heart failure, and
all-cause mortality in patients with CHF and
LVEF 40% when added to standard therapies
including ACE inhibitors, beta-blockers, and an
aldosterone antagonist
This approach offers the clinician an opportunity
to make additional improvements in the poor
prognosis of CHF patients when left ventricular
systolic dysfunction is present
Young et al, Circulation 2004
CHARM-Overall
%
50
CV death or CHF hospitalisation
40
1310 (34.5%)
1150 (30.2%)
Placebo
30
Candesartan
20
10
HR 0.84 (95% CI 0.77-0.91), p<0.0001
Adjusted HR 0.82, p<0.0001
0
0
Number at risk
Candesartan 3803
Placebo
3796
1
2
3
3563
3464
3271
3170
2215
2157
3.5 years
761
743
Pfeffer et al, Lancet 2003
CHARM-Overall
Conclusions
Treatment of a broad spectrum of patients
with symptomatic CHF with candesartan
resulted in a:




9% reduction in all cause deaths
(p=0.055, covariate adj. p=0.032)
12% reduction in CV mortality (p=0.012)
21% reduction in CHF hosp. (p<0.0001)
16% reduction in CV deaths or CHF hosp.
(p<0.0001)
Pfeffer et al, Lancet 2003
Use of angiotensin II receptor
blockers (ARBs) in heart failure


ARBs can be considered in combination with
ACE-I in patients who remain symptomatic, to
reduce mortality (Class IIa, level B) and hospital
admissions for HF (Class I, level A)
Concerns raised by initial studies about a
potential negative interaction between ARBs and
beta-blockers have not been confirmed by recent
studies in post-MI or CHF (Class I, level A)
Pharmacological methods of
stabilization of atherosclerotic plaque
APA
VPI
TNFαA
ACE-I
MMPI
BB
STATIN
Proven effect
ARBs
AP
Benefits of statin therapy
Angioprotective
effect
Secondary
prevention
of CVE
Dyslipidaemia
therapy
Significance of Scandinavian
Simvastatin Survival Study (4S) 1993




Simvastatin (10-40mg/d) vs placebo
Patients (n=4444) with CAD/post MI and total
cholesterol concentrations 5,5-8mmol/L
Prospective, randomized, double-blind, multicenter
study
Aim of study: to establish the benfit of simvastatin
therapy on cardiovascular morbidity and overall
mortality.
Significance of Scandinavian
Simvastatin Survival Study (4S)
Results: significant reduction of relative risk
Simvastatin vs placebo
RRR
Overall mortality
33%
CV death
42%
Serious cardiovascular events (AMI, SCD,
cardiovascular death)
34%
Need for revascularisation
37%
Cost of hospitalisation
32%
Beneficial effect was observed also in patients with diabetes
and in elderly
Pravastatin trials
LIPID 1995y



CARE 1996y.
Patients with CAD/MI
pravastatin 40mg/d vs placebo
N=9014
Results: reduction of RR
CV death
ovarall mortality
reinfarction
CABG
Stroke
25%
22%
29%
22%
19%



Patients post MI
pravastatin 40mg/d vs placebo
N=4159
Results: reduction of RR
CV death
reinfarction
CABG
PTCA
Stroke
TIA
24%
25%
26%
23%
32%
27%
Beneficial effects of statin despite
normal lipidogram?
HPS (Heart Protection Study) 2002
British multicenter study (55 hospitals)
 N=20536 patients (40-80 years old) with CAD
or AO
or after Stroke/TIA
or Diabetes (type 2)
 Total cholesterol concentration > 135mg%
 Follow-up: 5 years
 Arms of study: simvastatin vs placebo
simvastatin vs antioxidants
antioxidants vs placebo
placebo vs placebo
HPS (Heart Protection Study)
Results:


No effects on CV events after antioxidants
administration (Vit. C 250mg/d, vit. E 600mg/d,
beta-caroten 20mg/d)
Simvastatin therapy was associated with
significant risk reduction of:
CV death
18%
all-cause death
13%
overall death, MI, stroke,
need for revascularisation
24%
What LDL concentration is
optimal?
In the Pravastatin or Atorvastatin Evaluation and
Infection Therapy (PROVE-IT) trial, standard statin
therapy (pravastatin 40mg/d) was compared with
intensive therapy (atorvastatin 80mg/d)



Patients (n=4162) within 10 days of an ACS
Mean follow-up 24 months
Results: more intensive therapy (achived mean LDL
1,6mmol/L) was associated with a significant 16% risk
reduction in CVE, compred with standard therapy
(mean LDL 2,5mmol/l
Intensive vs standard statin therapy
Treat to New Targets Trial (TNT)



Comparision of intensive statin therapy
(atorvastain 80mg/d) and standard statin
therapy (atorvastain 10mg/d)
Patients (n=10001) with stable CAD
Results:
Mean LDL Ch
SCE
Atorvastatin 10mg/d
Atorvastatin 80mg/d
101mg/dL
77mg/dL
10,9%
8,7% (RRR=22%)
Pharmacological methods of
stabilization of atherosclerotic plaque
APA
VPI
TNFαA
ACE-I
MMPI
BB
STATIN
Proven effect
ARBs
AP
The use of aniplatelet agents in
patients with atherosclerotic
cardiovasular disease

ESC Expert Consensus Document
European Heart Journal 2004;25, 166-181

Sixth American College of Chest
Physicians (ACCP) Consensus Conference
on Antithrombotic Therapy
Chest 2001; 119: 39S-63S

Antithrombotic Trialists’ (ATT)
Collaboration
BMJ 2002; 324: 71-86
Antiplatelet drugs that may prevent
atherothrombosis



Approximately 20 different agents have been shown to
inhibit platelet aggregation through different mechanisms of
action
However, inhibition of platelet aggreagation does not
necessarily translate into prevention of atherothrombosis
Antiplatelet drugs that have been successfully tested against
placebo in adequately large randomized clinical trials
include:
* for chronic oral dosing: aspirin, ticlopidine and
clopidogrel
* for short-term intravenous administration: abciximab,
tirofiban and eptifibatide
Patients that may benefit from
antiplatelet therapy



Allocation of high-risk patients to a prolonged course of
antiplatelet therapy reduced the combined outcome of nonfatal
myocardial infarction, nonfatal stroke or vascular death (serious
vascular events-SVA) by about 25%
Absolute reductions in the risk of having a SVA:
36/1000
2 years
Previous myocardial infarction (MI)
38/1000
1 month
Acute myocardial infarction (AMI)
36/1000
2 years
Previous stroke/TIA
9/1000
1 month
Acute ischaemic stroke
22/1000
2 years
Stabile angina (AP), peripheral arterial
disease and atrial fibrillation (AF)
In each of these high-risk categories, the absolute benefits
substentially outweighed the absolute risk of major bleeding
complications
Clinical trial evidence in patients with
ischaemic heart disease



Ticlopidine and clopidogrel vs aspirin in patients with
AMI non-significantly lower rates of SVA in the aspirinetreated arm
In patients with chronic stable angina (AP), aspirin
(75mg/d) significantly reduced the occurence of the
primary end-point (MI, SCD) by 34% (median duration
of follow-up of 50 months)
In patients with unstable angina (API) aspirin (751300mg/d in 4 placebo-controlled trials) and ticlopidine
have been shown to reduce by~50% the rate of MI and
death
Clinical trial evidence in patients with
ischaemic heart disease


Aspirin + Clopidigrel produced additive effects in
patients with NSTEMI by reducing the rate of the first
primary outcome (a composite of cardiovascular death
(CVD), non fatal MI or stroke) by ~20% vs aspirin alone
(12months of follow-up)
The efficacy and safety of this combined antiplatelet
strategy is currently being tested in patients with AMI, a
clinical setting where aspirin alone (162,5mg started
within 24h of the onset of symptoms) reduced the
primary end-piont of CVD by ~23% and non-fatal SVA by
~50%
Anitiplatelet therapy in diabetic
patients with CAD


Aspirin should be given for the same indications
and in similar dosages to diabetic and nondiabetic patients
(Class IIa, level B)
ADP receptor-dependent platelet aggregation
inhibitor (clopidogrel) may be considered in
diabetic patients with ACS in addition to aspirin
(Class IIa, level C)
Guidelines on diabetes, pre-diabetes, and cardiovascular disease (ESC and EASD)
Eur Heart J 2007: 28, 88-136
Balance of benefits and risks of
antiplatelet therapy


The absolute benefits of aspirin therapy substantially
outweigh the absolute risks of major bleeding
[particulary, gastrointestinal (GI)] complications in a
variety of clinical settings characterized by moderate to
high risk of occlusive vascular events. However, in lowrisk individuals the benfit/risk profile of such a
preventive strategy is uncertain.
A meta-anlysis of four primary prevention trials suggests
that aspirin treatment is safe and worthwhile at coronary
event risk ≥ 1,5% per year
Recommendations concerning
individual antiplatelet agents






Aspirin
Ticlopidine
Clopidogrel
Dipyridamol
Abciximab, tirofiban, eptifibatide
Other antiplatelet drugs
ASPIRIN


Aspirin once daily is recommended in all clinical
conditions in wich antiplatelet prophylaxis has a
favourable benefit/risk profile.
Because of GI toxicity and its potential impact on
compliance, physicians are encouraged to use the lowest
dose of aspirin that was shown to be effective in each
clinical setting.
ASPIRIN


The available evidence supports daily dose od aspirin in
the range of 75-100 mg for the long term prevention of
SVE in high-risk patients (i.e. ≥ 3% per year).
In clinical situations where an immediate antithrombotic
effect is required (such as in ACS or acute ischaemic
stroke), a loading dose of 160 mg should be given at
diagnosis (rapid and complete inhibition of TXA2dependent platelet aggregation)!!!
ASPIRIN


No test of platelet function is recommended to assess the
antiplatelet effect of aspirin in the individual patient
The routine use of proton pump inhibitors or
cytoprtotecive agents is not recommended in patients
taking daily dose of aspirin in the range of 75-100 mg,
because of lack of randomized trials demonstrating the
efficiacy of such protective strategies in this setting
ASPIRIN


Non-steroidal anti-inflammatory drugs (NSAIDs) have
been investigated inadequately in terms of their potential
cardiovacular effects. Thus, physicians prescibing these
drugs to arthritic patients with prior vascular
complications should not discontinue treatment with
low-dose aspirin
Because of potential pharmacodynamic interactions
between traditional NSAIDs and aspirin, patients treated
with low-dose aspirin requiring NSAID therapy may
benfit from the use of selective COX-2 inhibitors.
TICLOPIDINE



The role of ticlopidine in the present therapeutic
armamentarium is uncertain. Now that ticlopidine is
available as a generic drug in many countries, its lower
cost as compared to clopidogrel is being emphasized
within a broad-cost containment strategy.
Although there are no large head-to-head comparisions
between the two thienopyridines, indirect comparisions
are highly suggestive of a lower burden of serious bonemarrow toxicity with clopidogrel as compared to
ticlopidine
In contrast to clopidogrel, ticlopidine does not have an
approved indication for patients with a AMI
CLOPIDOGREL


Although clopidogrel may be slightly more effecive than
aspirin, the size of any additional benefit is statistically
uncertain and the drug has not been granted a claim of
superiority vs aspirin by regulatory authorities.
Clopidogrel, 75mg daily, is an approppriate alternative
for high-risk patients with coronary, cerebrovascular or
peripheral arterial disease who have a contraindication
to low-dose aspirin
CLOPIDOGREL



The results of the CURE trial have led to approval of a
new indication for clopidogrel in patients with NSTEMI
ACS
A loading dose of 300 mg clopidogrel should be used in
this setting followed by 75 mg daily.
Revision of the existing guidelines will need a consensus
agreement by the experts with respect to timing of
percutaneous coronary intervention (PCI), length of
clopidogrel treatment, and combination with GPIIb/IIIa
anatagonists.
DIPYRIDAMOL


The combination of low-dose aspirin and extendedrelase dipyridamol (200mg bid) is considered an
acceptable option for initial therapy of patients with noncardioembolic cerebral ischaemic events.
(ESPS-2 trial)
There is no basis to recommend this combination in
patients with ischaemic heart disease.
Abciximab, eptifibatide and tirofiban


The benefit/risk profile of currently available GPIIb/IIIa
antagonists is substentially uncertain for patients with
ACS who are not routinely scheduled for early
revascularisation (GUSTO IV, ACS, PARAGON-B)
In contrast, for patients undergoing PCI, intensification
of antiplatelet therapy by adding an intravenous
GPIIb/IIIa blocker is an appropriate strategy to reduce
the risk of procedure-related thrombotic complications.
Other antiplatelet drugs


Indobufen, triflusal and picotamide are commercially
available in a few European countries, based on relatively
limited evidence for efficacy and safety.
Because of substantial statistical uncertainty
surrounding the direct randomized comparisions of
these agents vs aspirin and inadequate statistical power
of the studies to assess reliably any difference in SVE, the
use of indobufen, triflusal and picotamide instead of
aspirin is not recommended
ACS STEMI without PCI-secondary
prevention
STATIN
ACE-I
STEMI
ACS
ASA
BB
ACS STEMI post PCI (stent)
STATIN
clopidogrel
BB
STEMI
ACS
ACE-I
ASA
ACS NSTEMI with or without PCI
–secondary prevention
STATIN
clopidogrel
BB
NSTEMI
ACS
ACE-I
ASA
Stroke/TIA –secondary prevention
ACE-I
STROKE
APA
STATIN
Peripheral artery disease
–secondary prevention
ACE-I
PAD
APA
STATIN