mpactul fumatului asupra

supravieuirii pe termen lung la

pacienii cu boal aterosclerotic
tratai cu aspirina sau clopidogrel
Date din trialul CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk
of Ischemic Events), J Am Coll Cardiol. 2014
Scopul acestui studiu a fost de a investiga eficacitatea monoterapiei cu
clopidogrel sau aspirin la pacienii cu boal vascular aterosclerotic,
fumtori vs nefumtori (N = 19184). Fumatul accentueaz inhibarea
plachetar indus de clopidogrel, ceea ce poate explica beneficiul relativ
mai mare n rndul fumtorilor observat n studiile de evaluare a terapiei
duale antiagregante plachetare. Dac fumatul are un impact asupra
rezultatelor clinice la pacienii care necesit un singur agent
antiplachetar, acest fapt rmne s fie demonstrate n studii mari. Sub-
studiul CAPRIE a comparat clopidogrelul i aspirina la pacienii cu boli
vasculare aterosclerotice n monoterapie. Pacienii fumtori (n=5688) au
avut un risc crescut de evenimente ischemice, comparativ cu cei
nefumtori (n =4135; risc relativ [HR]: 1.24 [95% interval de ncredere
(CI) : 1.08-1.42]) i ex-fumtori (n=9381; HR:1.32 [ 95% CI:1.18-
1.47])(p<0,001). Clopidogrelul a fost asociat cu o reducere a
evenimentelor ischemice n rndul fumtorilor (8,3% vs 10,8%, HR:0.76
[95 % CI : 0.64-0.90]), n timp ce nu a adus niciun beneficiu asociat cu
aspirina n grupul de pacieni ex-fumtori/pacieni ce nu au fumt
niciodat (10,4% vs 10,6% , HR:0.99 [95% CI:0.89-1.10],p=0,01pentru
interaciune). In rndul fumtorilor, clopidogrelul a redus, de asemenea,
riscul de infarct miocardic, mortalitate de cauz vascular, i deces de
orice cauz comparativ cu aspirina. Nu s-a observat nicio diferen n
ceea ce privete riscul de sngerare n cele dou grupuri studiate.
Astfel, n trialul CAPRIE, fumtorii au un beneficiu suplimentar prin
administrarea clopidogrelului n preveni secundar comparativ cu
aspirina. Aceste rezultate ar trebui luate n considerare pentru viitoarele
studii prospective de evaluare a impactului strategiilor specifice de
inhibare plachetar.
Tags:
Factori de risc cardiovascular
Category:
Actualitati
Main Image:
xista patru stadii in testarea clinica
1. In prima faza testarea are loc pe un numar mic de oameni. Scopul este sa se determine dozajul corect si sa se
identifice efectele secundare ale medicamentului. Efectele terapeutice, desi nu sunt excluse, nu sunt acum
obiectivul principal. Daca tratamentul are efecte secundare majore, celelalte stadii vor fi oprite.
2. Urmeaza faza a doua. Unui grup mai numeros de oameni i se administreaza tratamentul, pe baza primelor
rezultate. Acum se urmareste eficienta tratamentului, in timp ce efectele secundare nu sunt trecute cu vederea.
3. In stadiul al treilea, un grup si mai numeros de pacienti este tratat pentru a compara eficieta noului tratament in
comparatie cu cele existente deja.
4. Stadiul patru al testarii are loc dupa ce medicamentul a ajuns pe piata si urmareste evolutia sa pe un numar
mare de utilizatori, observand eficienta si eventualele efecte secundare. Se pot descoperi efecte secundare rare
dar grave in testarea clinica, aceasta faza.
Grupuri de control
O testare clinica are un grup experimental alcatuit din pacienti care primesc noul tratament, in timp ce un alt grup
serveste ca grup de control. Rezultatele obtinute pe grupul experimental sunt comparate cu cele de la grupul de
control pentru a determina eficienta medicamentului. De obicei cel de-al doilea grup primeste tratamentul
standard, deja existent. In cazul in care nu exista un tratament standard, grupul de control nu va primi nimic. In
alte cazuri, informatiile stranse de-a lungul timpului pot lua locul celui de al doilea grup.
Rezultatele acestor teste sunt analizate folosind statisticile pentru a determina daca nu cumva diferentele dintre
grupuri se datoreaza efectului placebo sau a coincidentei. De cate ori este posibil, testarea clinica se face fara
stiinta atat a pacientilor cat si a doctorului. Dar acest lucru nu se poate realiza mereu.
Urmatorul videoclip informativ descrie in continuare procesul dezvoltarii de noi medicamente si terapii si aplicarea
acestora la om:
randomised, blinded, trial of clopidogrel versus aspirin in
patients at risk of ischaemic events (CAPRIE). CAPRIE
Steering Committee.
CAPRIE Steering Committee.
Collaborators (907)
Abstract
BACKGROUND:
Many clinical trials have evaluated the benefit of long-term use of antiplatelet drugs in reducing the
risk of clinical thrombotic events. Aspirin and ticlopidine have been shown to be effective, but both
have potentially serious adverse effects. Clopidogrel, a new thienopyridine derivative similar to
ticlopidine, is an inhibitor of platelet aggregation induced by adenosine diphosphate.
METHODS:
CAPRIE was a randomised, blinded, international trial designed to assess the relative efficacy of
clopidogrel (75 mg once daily) and aspirin (325 mg once daily) in reducing the risk of a composite
outcome cluster of ischaemic stroke, myocardial infarction, or vascular death; their relative safety was
also assessed. The population studied comprised subgroups of patients with atherosclerotic vascular
disease manifested as either recent ischaemic stroke, recent myocardial infarction, or symptomatic
peripheral arterial disease. Patients were followed for 1 to 3 years.
FINDINGS:
19,185 patients, with more than 6300 in each of the clinical subgroups, were recruited over 3 years,
with a mean follow-up of 1.91 years. There were 1960 first events included in the outcome cluster on
which an intention-to-treat analysis showed that patients treated with clopidogrel had an annual
5.32% risk of ischaemic stroke, myocardial infarction, or vascular death compared with 5.83% with
aspirin. These rates reflect a statistically significant (p = 0.043) relative-risk reduction of 8.7% in
favour of clopidogrel (95% Cl 0.3-16.5). Corresponding on-treatment analysis yielded a relative-risk
reduction of 9.4%. There were no major differences in terms of safety. Reported adverse experiences
in the clopidogrel and aspirin groups judged to be severe included rash (0.26% vs 0.10%), diarrhoea
(0.23% vs 0.11%), upper gastrointestinal discomfort (0.97% vs 1.22%), intracranial haemorrhage
(0.33% vs 0.47%), and gastrointestinal haemorrhage (0.52% vs 0.72%), respectively. There were ten
(0.10%) patients in the clopidogrel group with significant reductions in neutrophils (< 1.2 x 10(9)/L)
and 16 (0.17%) in the aspirin group.
INTERPRETATION:
Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more
effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction, or
vascular death. The overall safety profile of clopidogrel is at least as good as that of medium-dose
aspirin.
The CAPRIE study1 (Nov 16, p 1329) shows that clopidogrel reduced by 87% the risk of
cardiovascular events in the whole population, but this effect was not equally distributed in the
three subgroups (ischaemic stroke, recent myocardial infarction [MI], and peripheral arterial
disease).
Particularly impressive was the result obtained in patients with MI, in whom aspirin seemed better
than clopidogrel at reducing vascular events, but the reason is unclear. Looking at the events in MI
patients, it is evident that the superiority of aspirin is largely attributable to a decreased rate of
other vascular death, which in fact occurred in 67 (11%) patients taking aspirin and 86 (15%)
taking clopidogrel. Surprisingly, an opposite effect was seen in patients with peripheral arterial
disease in whom other vascular death was recorded in 66 (11%) taking clopidogrel and 87 (15%)
taking aspirin. What was the type of vascular death included in the outcome defined as other
vascular death and how many sudden deaths occurred in patients with MI and peripheral arterial
disease? Sudden death is very frequent during the first year after MI since it accounts for 3060% of
all mortality;2 75% of such deaths are due to rhythmic disturbances including tachycardia and
fibrillation.2 It is also noteworthy that in patients with unstable angina sudden death has been
recorded in 22% of patients taking ticlopidine and 26% on standard therapy, suggesting that
ticlopidine might not be an influence in sudden death.3 Further information about this outcome
could be of interest in patients with recent MI, in whom inhibition of thromboxane-A2 might be
more useful than inhibition of ADP-induced platelet aggregation in reducing vascular death.
Clinical Question
In patients with a recent CV event (stroke or MI), how does clopidogrel compare to aspirin in the
secondary prevention of stroke, MI, and CV death?
Bottom Line
Clopidogrel reduces CV outcomes more than aspirin when used as secondary prevention among
patients with prior stroke or MI.
Major Points
Prior placebo-controlled studies demonstrated that aspirin and ticlopidine independently reduce risk of
stroke, MI, and CV death, with head-to-head studies demonstrating a slight advantage of ticlopidine.
CAPRIE sought to evaluate whether clopidogrel, a thienopyridine like ticlopidine, would compare
favorably to aspirin using similar outcome measures. In CAPRIE, clopidogrel reduced the risk of CV
events by 9% compared to aspirin without an adverse effect on bleeding events.
Guidelines
2011 AHA/ASA guidelines for prevention of CVA in those with previous CVA or TIA
[1]
recommend:
Initial therapy with:
Aspirin (50 to 325 mg/d) daily (class I, level A)
Aspirin 25 mg and extended-release dipyridamole 200 mg twice daily (class I, level B)
Clopidogrel 75 mg daily (class IIa, level B)
Design
Multicenter, double-blind, parallel-group, randomized controlled trial
N=19,185
Clopidogrel (n=9,599)
Aspirin (n=9,586)
Enrollment: March 1992 to February 1995
Mean follow-up: 1.9 years
Population
Inclusion Criteria
Recent CV event, defined as:
Ischemic stroke onset 1 week and 6 months before randomization, with neurological signs
1 week from stroke onset
MI onset 35 days before randomization with two of: 20 min characteristic anginal pain,
elevated cardiac enzymes, new Q waves in two contiguous leads or new dominant R wave in
V1
Symptomatic PAD with intermittent claudication and ankle/arm systolic BP ratio 0.85 in
either leg at rest or history of claudication leading to limb amputation, reconstructive surgery,
or angioplasty without complications
Exclusion Criteria
Age <21 years
Severe CNS deficit likely leading to bed-bound or demented state
Carotid endarterectomy (CEA) after qualifying stroke
Qualifying stroke induced by CEA or angiography
Patient unlikely to be discharged after qualifying event
Severe comorbidity limiting life expectancy to <3 years
Uncontrolled HTN
Upcoming major surgery
Severe renal or hepatic insufficiency
Bleeding disorder
Thrombocytopenia, neutropenia, or otherwise abnormal CBC
Drug-induced hematologic or hepatic disorders
Anticipated requirement for long-term anticoagulation, or non-study antiplatelet agents including
NSAIDs
Aspirin insensitivity
Women of childbearing age not using reliable contraception
Currently receiving study drug
Previously entered in clopidogrel studies
Geographic or other factors making study participation impractical
Interventions
Patients randomized to clopidogrel 75mg daily or aspirin 325mg daily, asked to take one tablet
daily with morning meal
Reassessment with monthly visits for first 4 months, then every 4 months thereafter
Permanent discontinuation of study drug if ANC <450 x10
9
/L or platelets <80 x10
9
/L
Outcomes
Comparisons are clopidogrel vs. aspirin.
Primary Outcomes
Ischemic stroke, MI, or CV death (event rate/year)
5.32% vs. 5.83% (RR 0.91; 95% CI 0.84-0.97; P=0.043)
Secondary Outcomes
Ischemic stroke, MI, amputation, or CV death (event rate/year)
5.56% vs. 6.01% (P=0.076)
CV death (event rate/year)
1.90% vs. 2.06% (P=0.29)
Any stroke, MI, or death from any cause (event rate/year)
6.43% vs. 6.90% (P=0.081)
Death from any cause (event rate/year)
3.05% vs. 3.11% (P=0.71)
Adverse events
Rash
6.0% vs. 4.6% (P<0.05)
Diarrhea
4.5% vs. 0.23% (P<0.05)
GI complaints
15.0% vs. 17.6% (P<0.05)
GI bleeding
2.0% vs. 2.7% (P<0.05)
Abnormal liver function
3.0% vs. 3.2% (P<0.05)
Any bleeding
9.3% vs. 1.4% (P=NS)
Intracranial bleed
0.35% vs. 0.49% (P=NS)
Discontinuation of drug for reasons other
than outcome event
21.3% vs. 21.1% (P=NS)
A Randomised, Blinded Trial of Clopidogrel vs. Aspirin in
Patients at Risk of Ischaemic Events (CAPRIE)

Lancet 1996; 348:1329-1339
Background: The use of chronic antiplatelet medication to reduce the risk of thrombotic events
has been shown to be effective in patients at risk. Aspirin and ticlopidine are two agents shown
to decrease morbidity and mortality in a patient population at risk for platelet activation.
Clopidogrel (Plavix) is a new thienopyridine derivative which inhibits ADP-induced platelet
aggregation with similar antiplatelet activity as ticlopidine.
Purpose: The purpose of the CAPRIE trial is to evaluate the efficacy of clopidogrel versus
aspirin by decreasing risk of a thrombotic event. Risk reduction is determined by a composite
outcome group consisting of ischemic stroke, myocardial infarction, or vascular death.
Methods: CAPRIE is a multicenter, randomized, double blinded trial consisting of 19,185
patients over a period of 3 years. Eligible patients are determined by diagnosis of ischemic
stroke, myocardial infarction, or symptomatic atherosclerotic peripheral vascular disease
(ASCVD). Patients are randomly separated into two treatment groups, with one group to receive
clopidogrel 75mg once daily plus placebo (n = 9599), and the other to receive aspirin 325mg
once daily plus placebo (n = 9586). Mean follow-up time was 1.9 years.
Results: The cumulative risk for thrombotic events (ischemic stroke, myocardial infarction, or
vascular death) was lower in the clopidogrel group versus the aspirin group for the composite
outcome parameter. Event rates are 5.32% on clopidogrel and 5.83% for patients on aspirin,
correlating to a relative risk reduction of 8.7% in favor of clopidogrel (95% CI 0.3-16.5). When
subgroups are evaluated the relative risk reduction for clopidogrel vs. aspirin are as follows:
stroke 7.3% (-5.7 to 18.7, p = 0.26), MI -3.7% (-12.0 to 22.1, p = 0.66), peripheral artery disease
(PAD) 23.8% (8.9-36.2, p = .0028).
Conclusion: The actual benefit of clopidogrel over aspirin may not be equivalent across the
three subgroups listed above. From this study a conclusion can be made that clopidogrel is as
effective as aspirin for reducing risk of thrombotic events in patients presenting with myocardial
infarction or stroke. A true benefit is seen with clopidogrel over aspirin in the subgroup of
patients with PAD. Clopidogrel is at least as safe as regular strength aspirin and may be safer
than ticlopidine (although this was not evaluated in this trial).
phase III study assessing the potential of clopidogrel to prevent ischaemic stroke, MI or
vascular death in patients with recent ischaemic stroke, recent MI or peripheral arterial
disease (PAD)
the trial was randomised and double-blind
19,185 patients randomised to treatment with clopidogrel 75 mg/ day (n=9599) or aspirin
325 mg/ day (n=9586)
follow-up was for 1-3 years (mean 1.91 years) equivalent to 36,731 patient-years risk
primary endpoint of the CAPRIE trial was an intention to treat analysis of the first
occurrence of an event in the outcome cluster of ischaemic stroke, MI or vascular disease
there were 939 atherosclerotic events in the clopidogrel group during 17,636 patient-years
at risk, an average rate per year of 5.32%. There were 1031 events in the aspirin group
during 17,519 patient-years risk, an average rate per year of 5.83%. The relative risk
reduction was 8.7% (95% CI 0.3-16.5) in favour of clopidogrel (p=0.043).
There was no significant differences between aspirin and clopidogrel in relation to the risk
of death from any cause
calculating the number to needed to treat from the CAPRIE trial data, it would be
necessary to use clopidogrel instead of aspirin in approximately 200 patients for 1 year to
avert one additional major clinical event
note that clopidogrel was more effective than aspirin for reducing recurrent ischaemic
events in patients with recent stroke, recent MI, or peripheral artery disease who had also
had previous cardiac surgery (2)
Reference:
1. CAPRIE steering committe (1996). A randomised, blinded, trial of clopidogrel versus
aspirin in patients at risk of ischaemic events (CAPRIE). Lancet, 348,1329-1339.
2. Bhatt DL et al (2001). Superiority of clopidogrel versus aspirin in patients with prior
cardiac surgery. Circulati
phase III study assessing the potential of clopidogrel to prevent ischaemic stroke, MI or
vascular death in patients with recent ischaemic stroke, recent MI or peripheral arterial
disease (PAD)
the trial was randomised and double-blind
19,185 patients randomised to treatment with clopidogrel 75 mg/ day (n=9599) or aspirin
325 mg/ day (n=9586)
follow-up was for 1-3 years (mean 1.91 years) equivalent to 36,731 patient-years risk
primary endpoint of the CAPRIE trial was an intention to treat analysis of the first
occurrence of an event in the outcome cluster of ischaemic stroke, MI or vascular disease
there were 939 atherosclerotic events in the clopidogrel group during 17,636 patient-years
at risk, an average rate per year of 5.32%. There were 1031 events in the aspirin group
during 17,519 patient-years risk, an average rate per year of 5.83%. The relative risk
reduction was 8.7% (95% CI 0.3-16.5) in favour of clopidogrel (p=0.043).
There was no significant differences between aspirin and clopidogrel in relation to the risk
of death from any cause
calculating the number to needed to treat from the CAPRIE trial data, it would be
necessary to use clopidogrel instead of aspirin in approximately 200 patients for 1 year to
avert one additional major clinical event
note that clopidogrel was more effective than aspirin for reducing recurrent ischaemic
events in patients with recent stroke, recent MI, or peripheral artery disease who had also
had previous cardiac surgery (2)
Reference:
1. CAPRIE steering committe (1996). A randomised, blinded, trial of clopidogrel versus
aspirin in patients at risk of ischaemic events (CAPRIE). Lancet, 348,1329-1339.
2. Bhatt DL et al (2001). Superiority of clopidogrel versus aspirin in patients with prior
cardiac surgery. Circulati