Stopping
of Clopidogrel after Stent Implantation Causes Death/Mi
Jatin
Patel*, Jigna Shah, IS Anand and
CN Patel
Department of Clinical Pharmacy,
ABSTRACT
Clopidogrel is an oral antiplatelet agent
(thienopyridine class) to inhibit blood clots in coronary
artery disease, peripheral vascular disease, and cerebrovascular
disease. Clopidogrel keeps the platelets in your blood
from coagulating (clotting) to prevent unwanted blood clots that can occur with
certain heart or blood vessel conditions and is used to prevent blood clots
after a recent heart attack or stroke, and in people with certain disorders of
the heart or blood vessels. Here from the research article we found a
clustering of death and MI events in the initial 90-day period after
clopidogrel cessation, compared with subsequent follow-up intervals. Findings
were consistent among subgroups of patients who received shorter or longer
durations of clopidogrel therapy, patients with or without diabetes, and ACS
patients who underwent PCI. The rate of adverse events in the initial 90-day
interval after stopping clopidogrel was higher than the rate of adverse events
following hospital discharge while patients were still taking clopidogrel.
These findings support the hypothesis of a rebound hyperthrombotic period after
clopidogrel cessation. They also highlight the need for additional studies to
confirm these findings and to gain a deeper understanding of the
pathophysiology of this phenomenon as well as allowing identification of
strategies to attenuate this effect. We observed a clustering of adverse events in the initial 90
days after stopping clopidogrel among both medically treated and PCI-treated
patients with ACS, supporting the possibility of a clopidogrel rebound effect
KEY WORDS:
INTRODUCTION-
Clopidogrel is an oral antiplatelet agent
(thienopyridine class) to inhibit blood clots in coronary
artery disease, peripheral vascular disease, and cerebrovascular
disease. It is marketed by Bristol-Myers
Squibb and Sanofi-Aventis
under the trade
name Plavix, by Sun
Pharmaceuticals under the trade
name Clopilet, by Ranbaxy Laboratories
under the trade name Ceruvin. It works by irreversibly inhibiting a receptor
called P2Y12. Adverse effects include hemorrhage.1
Clopidogrel keeps the platelets in your blood from coagulating
(clotting) to prevent unwanted blood clots that can occur with certain heart or
blood vessel conditions.
Clopidogrel is used to prevent blood clots after a recent heart
attack or stroke, and in people with certain disorders of the heart or blood
vessels.
|
Clopidogrel |
|
Systematic (IUPAC) name |
|
(+)-(S)-methyl2- (2-chlorophenyl)- 2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate |
Clopidogrel is a pro-drug whose action may
be related to adenosine
diphosphate (ADP) receptor on platelet cell membranes.
The specific subtype of ADP receptor that clopidogrel irreversibly inhibits is P2Y12 and is important in
platelet aggregation and the cross-linking of platelets by fibrin. 3 The blockade of this
receptor inhibits platelet aggregation by blocking activation of the glycoprotein IIb/IIIa
pathway. The IIb/IIIa complex functions as a receptor mainly for fibrinogen and
vitronectin but also for fibronectin and von Willebrand factor. Activation of
this receptor complex is the "final common pathway" for platelet
aggregation, and is important in the cross-linking of platelets by fibrin.
Platelet inhibition can be demonstrated two
hours after a single dose of oral clopidogrel, but the onset of action is slow,
so that a loading-dose of 300-600 mg is usually administered.
Mechanism
of Action:-
Clopidogrel
is a prodrug,
one of whose metabolites is an inhibitor of platelet
aggregation. A variety of drugs that inhibit platelet
function have been shown to decrease morbid events in people with established cardiovascular
atherosclerotic
disease as evidenced by stroke
or transient ischemic attacks, myocardial
infarction, unstable angina
or the need for vascular
bypass
or angioplasty.
This indicates that platelets participate in the initiation and/or evolution
of these events and that inhibiting platelet function can reduce the event
rate.4
Clopidogrel
must be metabolized by CYP450 enzymes
to produce the active metabolite that inhibits platelet aggregation. The active
metabolite of clopidogrel selectively inhibits the binding of adenosine
diphosphate (ADP) to its platelet P2Y12 receptor
and the subsequent ADP-mediated activation of the glycoprotein
GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is
irreversible. Consequently, platelets exposed to clopidogrel's active
metabolite are affected for the remainder of their lifespan (about 7 to 10
days). Platelet aggregation induced by agonists other than ADP is also
inhibited by blocking the amplification
of platelet activation by released ADP.5
Because the
active metabolite is formed by CYP450 enzymes, some of which are polymorphic
or subject to inhibition by other drugs, not all patients will have adequate
platelet inhibition.
Clopidogrel
is indicated for: 6
·
Prevention
of vascular ischaemic events in
patients with symptomatic atherosclerosis
·
Acute
coronary syndrome without ST-segment elevation (NSTEMI),
·
ST
elevation MI (STEMI)
It is also used, along with aspirin, for the
prevention of thrombosis
after placement of intracoronary stent.6
International guidelines granted the highest
grade of recommendation for NSTE-ACS, PCI and stent,for Clopidogrel in addition
to Aspirin. Consensus-based therapeutic guidelines recommend also the use of
clopidogrel, instead of aspirin,
in patients requiring antiplatelet therapy but with a history of gastric
ulceration, as inhibition of the synthesis of prostaglandins by aspirin (acetylsalicylic
acid) can exacerbate this condition. A study has shown that in patients with
healed aspirin-induced ulcers, however, patients receiving aspirin plus the proton pump inhibitor esomeprazole had a lower
incidence of recurrent ulcer bleeding than patients receiving clopidogrel.7However,
a more recent study suggested that prophylaxis with proton pump inhibitors
along with clopidogrel following acute coronary syndrome
may increase adverse outcomes, possibly due to inhibition of CYP2C19 which is required for activation
of clopidogrel, itself a pro-drug.8
Clopidogrel
is a pro-drug activated
in the liver by cytochrome P450 enzymes, including CYP2C19. The active metabolite has an elimination
half-life of about 8 hours and acts by forming a disulfide bridge with the
platelet ADP receptor. Patients with a variant allele of CYP2C19 are 1.5 to 3.5
times more likely to die or have complications than patients with the
high-functioning allele.9-11Following an oral dose of 14C-labeled
clopidogrel in humans, approximately 50% was excreted in the urine and
approximately 46% in the feces in the 5 days after dosing.
Effect of Food:-
Administration of clopidogrel bisulfate
with meals did not significantly modify the bioavailability of
clopidogrel as assessed by the pharmacokinetics of the main circulating
metabolite. The effect
of food on the bioavailability of the parent compound or active metabolite is
currently not known.12
Absorption and Distribution:-
Clopidogrel is rapidly absorbed after oral administration of repeated doses of
75 mg clopidogrel (base), with peak plasma levels (appx. 3 mg/L) of the main
circulating metabolite occurring approximately 1 hour after dosing. The
pharmacokinetics of the main circulating metabolite are linear (plasma
concentrations increased in proportion to dose) in the dose range of 50 to 150
mg of clopidogrel. Absorption is at least 50% based on urinary excretion of
clopidogrel-related metabolites. Clopidogrel and the main circulating
metabolite bind reversibly in vitro to human plasma proteins
(98% and 94%, respectively). The binding is nonsaturable in vitro
up to a concentration of 110 μg/mL.
After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly
absorbed. Mean peak plasma levels of unchanged clopidogrel (approximately 2.2-2.5
ng/mL after a single 75-mg oral dose) occurred approximately 45 minutes after
dosing. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites. Clopidogrel and the
main circulating inactive metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively).13 The binding is
nonsaturable in
vitro up to a
concentration of 100 mcg/mL.
Metabolism: -In vitro and in vivo,
clopidogrel undergoes rapid hydrolysis into its carboxylic acid derivative. In plasma and
urine, the glucuronide of the carboxylic acid derivative is also observed. Clopidogrel is extensively metabolized by the liver. In vitro and in vivo, clopidogrel is metabolized
according to two main metabolic pathways: one mediated by esterases and leading to
hydrolysis into its inactive carboxylic acid derivative (85% of circulating
metabolites), and one mediated by multiple cytochromes P450. Cytochromes first
oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent
metabolism of the 2-oxo-clopidogrel intermediate metabolite results in
formation of the active metabolite, a thiol derivative of clopidogrel. In
vitro, this metabolic pathway is mediated by CYP3A4, CYP2C19, CYP1A2 and
CYP2B6. The active thiol metabolite which has been isolated in vitro, binds
rapidly and irreversibly to platelet receptors, thus inhibiting platelet
aggregation.14
Elimination:-
Following
an oral dose of 14C-labeled clopidogrel in humans, approximately 50% of total
radioactivity was excreted in urine and approximately 46% in feces
over the 5
days post-dosing. After a single, oral dose of 75 mg,15 clopidogrel
has a half-life of approximately 6 hours. The elimination half-life of the
inactive acid metabolite was 8 hours after single and repeated administration.
Covalent binding to platelets accounted for 2% of radiolabel with a half-life
of 11 days. In plasma and urine, the glucuronide of the carboxylic acid
derivative is also observed.
Note: Coronary artery stents: Duration of clopidogrel (in combination
with aspirin): According to the ACC/ AHA/SCAI guidelines, ideally 12 months
following drug-eluting stent (DES) placement in patients not at high risk for
bleeding; at a minimum, 1, 3, and 6 months for bare metal (BMS), sirolimus
eluting, and paclitaxel eluting stents, respectively, for uninterrupted therapy
(Smith, 2005). The 2008 Chest
guidelines recommend for patients who undergo PCI and receive a BMS (with
ongoing ACS) or a DES (with or without ongoing ACS) that clopidogrel be
continued for at least 12 months. In patients receiving a BMS without ongoing
ACS, clopidogrel may be continued for at least 1 month. In patients receiving a
DES, therapy with clopidogrel beyond 12 months may be considered in patients
without bleeding or tolerability issues (Becker, 2008). Premature interruption
of therapy may result in stent thrombosis with subsequent fatal and nonfatal
myocardial infarction. 17
Prevention
of coronary artery bypass graft closure (saphenous vein) [Chest guidelines, 2008]:
Aspirin-allergic patients (unlabeled use): Loading dose: 300 mg 6 hours
following procedure; maintenance: 75 mg/day
CYP2C19 is
an important drug-metabolizing enzyme that catalyzes the biotransformation of
many clinically useful drugs including antidepressants, barbituates, proton
pump inhibitors, antimalarial and antitumor drugs. Clopidogrel is one of the
drugs metabolized by this enzyme.
Several
recent landmark studies have proven the importance of 2C19 genotyping in
treatment using clopidogrel or Plavix. Researchers have found that patients
with variants in cytochrome P-450 2C19 (CYP2C19) have lower levels of the
active metabolite of clopidogrel, less inhibition of platelets, and a 3.58
times greater risk for major adverse cardiovascular events such as death, heart
attack, and stroke; the risk was greatest in CYP2C19 poor metabolizers. 18
Serious adverse drug reactions associated
with clopidogrel therapy include:
· Severe neutropenia
· Thrombotic thrombocytopenic purpura (TTP)
· Hemorrhage - The annual incidence of
hemorrhage may be increased by the co-administration of aspirin19
· Gastrointestinal Hemorrhage
· Cerebral Hemorrhage
· Use of non-steroidal anti-inflammatory drugs is
discouraged in those taking clopidogrel due to increased risk of digestive
tract hemorrhage
Most-Frequent:20
Abdominal Pain with Cramps, Arthralgia, Back Pain, Chest Pain, Dizziness,
Dyspepsia, Flu-Like Symptoms, Headache Disorder, Pain, Purpura, Upper
Respiratory.Infection
Less-Frequent:20
Anemia, Anxiety, Atrial Fibrillation, Bronchitis, Cataracts, Constipation,
Cough, Cramps in Legs, Depression, Diarrhea, Dyspnea, Eczema, Edema, Epistaxis,
Fainting, Fatigue, Gastrointestinal Hemorrhage, General Weakness, Gout,
Hypertension, Hypesthesia, Insomnia, Nausea, Palpitations, Paresthesia,
Pruritus of Skin, Rhinitis, SkinRash.
Rare:20
Abnormal Hepatic Function Tests, Acute Hepatic Failure, Acute Pancreatitis,
Agranulocytosis, Anaphylaxis, Angioedema, Aplastic Anemia, Bronchospastic
Pulmonary Disease, Bullous Dermatitis, Colitis, Conjunctival Hemorrhage,
Duodenal Ulcer, Dysgeusia, Erythema Multiforme, Fever, Gastric Ulcer,
Glomerulonephritis, Hallucinations, Hematoma, Hepatitis, Hypersensitivity Drug
Reactions, Hypotension, Impaired Cognition, Interstitial Pneumonitis,
Intracranial Bleeding, Leukopenia, Lichen Planus, Menorrhagia, Myalgia,
Neutropenic Disorder, Ocular Bleeding, Pancreatitis, Pancytopenia, Peptic
Ulcer, Renal Disease, Retinal Hemorrhage, Serum Sickness, Stevens-Johnson
Syndrome, Stomatitis, Thrombocytopenic Disorder, Thrombotic Thrombocytopenic
Purpura, Toxic Epidermal Necrolysis.
Clopidogrel
worldwide:-
Clopidogrel is marketed worldwide in nearly
110 countries, with sales of US$5.9 billion in 2005. 21 It had been
the 2nd top selling drug in the world for a few years as of 2007 22
and was still growing by over 20% in 2010.In 2006, generic clopidogrel was
briefly marketed by Apotex,
a Canadian generic pharmaceutical company
before a court order halted further production until resolution of a patent
infringement case brought by Bristol-Myers Squibb. 23
The court ruled that Bristol-Myers Squibb's patent was valid and provided
protection until November 2011. 24Generic clopidogrel is also produced
by several pharmaceutical companies in
Side
Effects:-25
General-Clopidogrel
has been evaluated for safety in more than 17,500 patients, including over
9,000 patients treated for 1 year or more. The overall tolerability of
clopidogrel in CAPRIE was similar to that of aspirin regardless of age, gender
and race, with an approximately equal incidence (13%) of patients withdrawing
from treatment because of adverse reactions.General complaints among at least
2.5% of treated patients in controlled trials have included chest pain,
influenza-like syndrome, general body pain, or fatigue. A causal relationship
has not been clearly demonstrated.
Cardiovascular:-Cardiovascular
side effects have included chest pain (8.3%), edema (4.1%), and hypertension
(4.3%) in treated patients during controlled trials (compared with 8.3%, 4.5%
and 5.1%, respectively, in patients who were given aspirin). Cardiovascular
adverse events that have occurred in 1.0% to 2.5% of patients included syncope,
palpitations, atrial fibrillation, and heart failure. Generalized edema has
been reported in less than 1% of treated patients. A relationship between these
adverse events and clopidogrel administration has not been clearly defined.
Similar rates were observed among patients treated with aspirin in controlled
trials.
Rarely, heart failure has been associated with the use of clopidogrel.
Vasculitis, angioedema, and hypotension have also been reported during postmarketing
experience.
Drug Interactions:-27
Anticoagulants: Antiplatelet Agents may enhance the
anticoagulant effect of Anticoagulants.
Antiplatelet Agents: May enhance the anticoagulant effect of
other Antiplatelet Agents.
Calcium Channel Blockers: May diminish the therapeutic effect
of Clopidogrel.
Dasatinib: May enhance the anticoagulant effect of
Antiplatelet Agents.
Drotrecogin Alfa: Antiplatelet Agents may enhance the
adverse/toxic effect of Drotrecogin Alfa. Bleeding may occur.
Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa,
Anise, Bilberry): May enhance the adverse/toxic effect of Antiplatelet Agents.
Bleeding may occur.
Ibritumomab: Antiplatelet Agents may enhance the
adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired
platelet function and an increased risk of bleeding.
Macrolide Antibiotics: May diminish the therapeutic effect of
Clopidogrel. Exceptions: Azithromycin;
Dirithromycin [Off Market]; Spiramycin.
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic
effect of Antiplatelet Agents. An increased risk of bleeding may occur.
Nonsteroidal Anti-Inflammatory Agents may diminish the cardioprotective effect
of Antiplatelet Agents. This interaction is likely specific to aspirin, and not
to other antiplatelet agents.
Omega-3-Acid Ethyl Esters: May enhance the antiplatelet
effect of Antiplatelet Agents.
Pentosan Polysulfate Sodium: May enhance the adverse/toxic
effect of Antiplatelet Agents. Specifically, the risk of bleeding may be
increased by concurrent use of these agents.
Prostacyclin Analogues: May enhance the antiplatelet effect
of Antiplatelet Agents.
Proton Pump Inhibitors: May diminish the therapeutic effect
of Clopidogrel. This appears to be due to reduced formation of the active
clopidogrel metabolite.
Rifamycin Derivatives: May enhance the therapeutic effect of
Clopidogrel.
Salicylates: Antiplatelet Agents may enhance the
adverse/toxic effect of Salicylates. Increased risk of bleeding may result.
Thrombolytic Agents: Antiplatelet Agents may enhance the
anticoagulant effect of Thrombolytic Agents.
Tositumomab and Iodine I 131 Tositumomab: Antiplatelet Agents
may enhance the adverse/toxic effect of Tositumomab and Iodine I 131
Tositumomab. Specifically, the risk of bleeding-related adverse events may be
increased.
Warfarin: Clopidogrel may enhance the anticoagulant effect of
Warfarin.
Moderate
Interaction with drugs: 26
Clopidogrel/Atorvastatin - Decreased
effect of the former drug
Platelet Aggregation Inhibitors/ Anticoagulants - Additive
side effects from both drugs
Ethanol/Nutrition/Herb
Interactions-Herb/Nutraceutical:
Avoid alfalfa, anise, bilberry, bladderwrack, bromelain, cat's claw, chamomile,
coleus, cordyceps, dong quai, evening primrose oil, fenugreek, feverfew,
garlic, ginger, ginkgo biloba, ginseng (American), ginseng (Panax), ginseng
(Siberian), grape seed, green tea, guggul, horse chestnut seed, horseradish,
licorice, prickly ash, red clover, reishi, SAMe (S-adenosylmethionine), sweet
clover, turmeric, white willow (all have additional antiplatelet activity). 26
Drug-Disease
Contraindications:- 27
Most Significant –
Gastrointestinal
Hemorrhage, Hemorrhage, Intracranial Bleeding
Significant –
Blood
Coagulation Disorder, Gastrointestinal Ulcer, Poor Metabolizer due to
Cytochrome p450 CYP2C19 Variant, Retinal Hemorrhage, Thrombotic
Thrombocytopenic Purpura
Possibly Significant –
Severe
Hepatic Disease, Severe Renal Disease, Surgical Procedure, Trauma
Anesthesia and Critical Care
Concerns/Other Considerations:-
Perioperative Management of
Clopidogrel:28-31
In patients with coronary stents, the risk of stent
thrombosis becomes elevated depending on the type of stent deployed (bare metal
vs drug-eluting stent) and the time from implantation. According to the
American College of Chest Physicians (Becker, 2008), the recommended length of
therapy for clopidogrel is at least 12 months in patients with ACS who undergo
PCI with a bare metal stent (BMS) or drug-eluting stent (DES). In patients
receiving a BMS without ongoing ACS, clopidogrel may be continued for at least
1 month. Early discontinuation of clopidogrel may result in stent thrombosis
leading to nonfatal and fatal myocardial infarction. The perioperative
recommendations for clopidogrel are below (Douketis, 2008):
Patients undergoing noncardiac
surgery (low risk of cardiac event without coronary stent): Clopidogrel and other antiplatelet agents should be
temporarily discontinued 5-10 days prior to surgery and resumed ~24 hours (or
the next morning) after the procedure when adequate hemostasis is achieved. Patients without coronary stent undergoing
cardiac surgery (eg, CABG) or noncardiac surgery (high risk of cardiac event):32,33
Discontinue clopidogrel at least 5 days and, preferably, 10 days prior to
surgery while continuing aspirin up to and beyond the time of surgery. If
aspirin is interrupted, it should be reinitiated 6-48 hours after surgery; may
resume clopidogrel ~24 hours (or the next morning) after the procedure when
adequate hemostasis is achieved. Patients
undergoing cardiac surgery (eg, CABG) or noncardiac surgery (with coronary
stent): Based on the risk of stent thrombosis, patients with a BMS who
require surgery within 6 weeks of implantation or with a DES who require
surgery within 12 months of implantation should continue on both aspirin and
clopidogrel during the perioperative period.
The AHA/ACC/SCAI/ACS/ADA Science Advisory (2007) published
recommendations (Circulation,
Cardiovascular Considerations:-
Acute Coronary Syndrome (ACS): The 2007 ACC/AHA guidelines for unstable
angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI) recommend
administration of clopidogrel to hospitalized patients who are unable to take
aspirin because of hypersensitivity or major gastrointestinal intolerance
(Class I; level of evidence: A). In certain situations, patients may even be
desensitized to aspirin so that they may receive aspirin and clopidogrel
concurrently. The CURE trial demonstrated that clopidogrel reduced major
cardiovascular events in patients with ACS without ST-segment elevation (Yusuf
S, 2001). In this trial, the risk of major bleeding was significantly increased
in the clopidogrel group although life-threatening bleeding and hemorrhagic
strokes were similar in both groups. In hospitalized UA/NSTEMI patients in whom
an early noninvasive strategy is planned, clopidogrel should be added to
aspirin and anticoagulant therapy as soon as possible (Class I, Level of
evidence A).
In UA/NSTEMI patients in whom an invasive strategy will be
employed, antiplatelet therapy should be initiated prior to diagnostic angiography.
This can be done with either clopidogrel or a glycoprotein IIb/IIIa inhibitor
(eg, eptifibatide) (Class I, Level of evidence A). The PCI-CURE trial, a
substudy of the CURE trial, suggested that in patients with ACS undergoing PCI
receiving aspirin, a strategy of clopidogrel pretreatment followed by long-term
therapy (9 months) is beneficial in reducing major cardiovascular events,
compared with placebo (Mehta SR, 2001). In the CREDO trial, long-term (1 year)
clopidogrel treatment (75 mg daily) following PCI, significantly reduced the
risk of adverse ischemic events (Steinhubl SR, 2002). In CREDO, the issue of
timing was evaluated and a 300 mg loading dose of clopidogrel must be given at
least 6 hours before PCI. More recently, however, a 600 mg loading dose of
clopidogrel was shown to result in maximal platelet inhibition at 2 hours
(Hochholzer W, 2005). In patients taking clopidogrel in whom elective CABG is
planned, clopidogrel should be withheld for 5-7 days before elective CABG. If
urgent CABG is required, the benefits of surgery should outweigh the risks of
incremental bleeding.
ST-Segment Elevation Myocardial
Infarction (STEMI):34,35 The COMMIT trial
(Chen ZM, 2005), randomized 45,852 patients with an acute MI (supporting ECG
abnormalities), presenting within 24 hours of onset of symptoms, to clopidogrel
75 mg daily or placebo. All patients received aspirin and standard medical care
(eg, thrombolytics if appropriate, ACEI). Clopidogrel was continued for 28 days
or until hospital discharge whichever came first. The primary outcome measure
was a composite of death, MI, or stroke. Patients in the clopidogrel arm had a
significantly lower death rate (7.5% clopidogrel, 8.1% placebo; p=0.002).The
CLARITY trial (Scirica BM, 2006) evaluated clopidogrel in the setting of
thrombolysis and its relationship to ST-segment resolution. The randomized,
double blind, placebo controlled trial included 3491 patients within 12 hours
of the onset of STEMI who were candidates for thrombolytic therapy. Patients were
randomized to receive clopidogrel (300 mg loading dose, then 75 mg daily) or
placebo until angioplasty, discharge, or Day 8. Patients also received aspirin
(loading dose followed by 75-162 mg/day). The ECG was monitored at baseline,
and 90- and 180 minutes after thrombolysis. There was no difference in ECG
resolution (none, partial, complete) between the groups at 90 minutes. Patients
with partial (30% to 70%) and complete (>70%) ST-segment resolution on
clopidogrel had significantly improved patency on discharge angiogram over
placebo patients with similar ST-segment resolution. The clopidogrel group with
partial ST segment resolution had a significantly lower rate of in-hospital
death and MI than their placebo counterparts. The clopidogrel group with complete
resolution of ST-segments showed a trend toward a reduction of in-hospital
death and MI but it was not statistically significant (p=0.056). Mortality was
followed for 30 days; the clopidogrel group with complete resolution of
ST-segment abnormalities had a significant reduction in the rate of death
compared to its placebo counterpart.
Percutaneous Coronary Intervention
(PCI)- The 2004 ACC/AHA guidelines for ST-elevation myocardial
infarction (STEMI) suggests that clopidogrel be continued for at least 1 month
after bare-metal stent implantation, for several months after drug-eluting
stent implantation (3 months for sirolimus, 6 months for paclitaxel), and
ideally for up to 12 months in patients who are not at high risk for bleeding.
Coronary Artery Stents:16-
The 2005 ACC/AHA/SCAI guidelines for PCI
recommends that along with aspirin, clopidogrel be continued for at least 1
month after bare-metal stent implantation, for several months after
drug-eluting stent implantation (3 months for sirolimus, 6 months for
paclitaxel), and ideally for up to 12 months in patients who are not at high
risk for bleeding. Clopidogrel is the preferred thienopyridine due to its lower
incidence of serious side effects (eg, neutropenia) as compared to ticlopidine.
The 2008 Chest guidelines recommend for patients who undergo PCI and
receive a BMS (with ongoing ACS) or a DES (with or without ongoing ACS) that
clopidogrel be continued for at least 12 months. In patients receiving a BMS
without ongoing ACS, clopidogrel may be continued for at least 1 month. In
patients receiving a DES, therapy with clopidogrel beyond 12 months may be
considered in patients without bleeding or tolerability issues (Becker, 2008).
The AHA/ACC/SCAI/ACS/ADA Science Advisory (2007) published
recommendations (Circulation,
High Cardiovascular-Event Risk
Patients- The CHARISMA trial (Bhatt DL, 2006) evaluated the use of
clopidogrel compared to placebo in 15,603 patients receiving low-dose aspirin
(75-162 mg/day) who were at high risk of future cardiovascular events. This
patient group included those with multiple atherothrombotic risk factors,
documented coronary, cerebrovascular, or peripheral vascular disease. The
primary outcome measure was a composite of myocardial infarction, stroke, or
death from cardiovascular causes. The primary outcome measure occurred in 6.8%
of patients receiving clopidogrel and aspirin vs. 7.3% with placebo and aspirin
(p=0.22). The rates of the secondary endpoints which included hospitalizations
for ischemic events, was 16.7% and 17.9% (p=0.04). The rate of GUSTO-defined
severe bleeding was 1.7% and 1.3% (p=0.09). A prespecified subgroup analysis
divided patients into a “symptomatic” group
(with documented cardiovascular disease) and an “asymptomatic” group (without
documented cardiovascular disease). In the patients considered symptomatic, the
primary event rate was lower in the clopidogrel group compared to placebo (6.9%
vs 7.9%, p=0.046). In patients considered asymptomatic, there was a 20%
relative increase in the primary event rate (6.6% vs 5.5%; p=0.20) if receiving
clopidogrel. The rate of death from cardiovascular causes was also higher in
this group (3.9% vs 2.2%, p=0.01). In summary, clopidogrel in addition to
low-dose aspirin is not significantly more effective than low-dose aspirin
alone in reducing the rate of MI, stroke, or death from cardiovascular causes.
Use of clopidogrel in addition to low-dose aspirin may be harmful in patients
with multiple atherothrombotic risk factors without cardiovascular disease. The
Clopidogrel:
Ongoing Safety Review - January 2009:
Special Alerts:-36-42
The U.S. Food and Drug Administration (FDA) is communicating
important information regarding an ongoing safety review of clopidogrel and its
effectiveness when used with proton pump inhibitors (PPIs).
Clopidogrel is a prodrug requiring
hepatic conversion via CYP3A4 and/or CYP2C19 to its active metabolite. Impaired
clopidogrel conversion to its active metabolite may be due to either CYP450
polymorphisms or drug-drug interactions resulting in suboptimal antiplatelet
activity.
A PPI is often prescribed with the combination of aspirin and
clopidogrel to prevent gastrointestinal bleeding. A number of PPIs are
available and include dexlansoprazole, esomeprazole, lansoprazole, omeprazole,
pantoprazole, and rabeprazole. Several studies have reported greater clinical
event rates (eg, myocardial infarction, death) or greater platelet reactivity
associated with concurrent use of clopidogrel and a PPI (Ho, 2008; Pezella,
2008; Gilard, 2006). Similarly, a prospective, randomized, double-blind trial
demonstrated a reduction in antiplatelet activity when omeprazole and
clopidogrel are used concurrently (Gilard, 2008). Another controlled trial with
the PPI lansoprazole also found evidence of a possible interaction resulting in
less antiplatelet activity (Small, 2008). This interaction is thought to result
from competitive inhibition of the CYP2C19-mediated activation of clopidogrel
by omeprazole and other PPIs, which are all metabolized to at least some degree
by CYP2C19. In contrast, one study with esomeprazole and pantoprazole did not
find evidence of reduced antiplatelet activity when administered with
clopidogrel (Siller-Matula, 2009), highlighting the need for additional studies
to determine the degree to which individual PPIs may differ in their potential
for interacting with clopidogrel.
The manufacturer of Plavix® has agreed
to conduct further studies to better understand the effect of other drugs
(including PPIs) and genetic factors on the effectiveness of clopidogrel. The
FDA is recommending that healthcare providers continue to prescribe clopidogrel
while reevaluating the need for prescription or over-the-counter (OTC) PPIs in
patients taking clopidogrel. Patients should continue taking clopidogrel as
directed. If taking a PPI with clopidogrel, patients should consult with their
healthcare provider.
International
Brand Names:-43
·
Ateplax
(PE)
·
Ceruvin
(MY)
·
Cloart
(KP)
·
Clopilet
(IN)
·
Clopivaz
(PH)
·
Deplat
(TW)
·
Iscover
(AR, AT, AU, BE, BG, CH, CO, CZ, DE, DK, ES, FI, FR, GB, GR, HN, IE, IT, NL,
NO, PT, RU, SE, TR)
·
Kovix
(KP)
·
Maxgrel
(KP)
·
Noclot
(PK)
·
Plagerine
(PH)
·
Plamed
(KP)
·
Plavitor
(KP)
·
Plavix
(AR, AT, AU, BB, BD, BE, BF, BG, BJ, BM, BO, BR, BS, BZ, CH, CI, CL, CN, CO,
CR, CZ, DE, DK, DO, EC, ES, ET, FI, FR, GB, GH, GM, GN, GR, GT, GY, HK, HN, ID,
IE, IL, IN, IT, JM, JP, KE, KP, LR, MA, ML, MR, MU, MW, MX, MY, NE, NG, NI, NL,
NO, PA, PE, PH, PK, PL, PR, PT, PY, RU, SC, SD, SE, SG, SL, SN, SR, SV, TH, TN,
TR, TT, TW, TZ, UG, UY, VE, ZA, ZM, ZW)
·
Q.O.L.
(KP)
SIMILAR
RESEARCH ARTICLES:
1-
Late Clinical Events After Clopidogrel Discontinuation May Limit the Benefit of
Drug-Eluting Stents 45
A consecutive
series of 746 nonselected patients with 1,133 stented lesions surviving 6
months without major events were followed for 1 year after the discontinuation
of clopidogrel. Patients were assigned randomly 2:1 to DES versus BMS in BASKET
(Basel Stent Kosten Effektivitäts Trial). The primary focus of this observation
was cardiac death/MI.
Rates of 18-month cardiac death/MI were not different
between DES and BMS patients. However, after the discontinuation of clopidogrel
(between months 7 and 18), these events occurred in 4.9% after DES versus 1.3%
after BMS implantation. Target vessel revascularization remained lower after DES, resulting in similar rates of all clinical
events for this time period (DES 9.3%, BMS 7.9%). Documented late stent
thrombosis and related death/target vessel MI were twice as frequent after DES
versus BMS (2.6% vs. 1.3%). Thrombosis-related events occurred between 15 and
362 days after the discontinuation of clopidogrel, presenting as MI or death in
88%.
After the discontinuation of
clopidogrel, the benefit of DES in reducing target vessel revascularization is
maintained but has to be balanced against an increase in late cardiac death or
nonfatal MI, possibly related to late stent thrombosis.
2- BASKET-LATE: Late Clinical Events Related to
Late Stent Thrombosis After Stopping Clopidogrel: Drug-Eluting vs Bare-Metal
Stenting 47
Between May 2003 and May 2004, patients
treated with percutaneous coronary intervention and stenting were enrolled in
the BASKET48 trial and randomized in a 2:1 fashion to receive DES or
BMS. Patients who remained event-free at 6-month follow-up were subsequently
enrolled in the BASKET-LATE trial. Patients were followed for an additional 12
months to determine the incidence of cardiac death or nonfatal myocardial
infarction (MI) (primary endpoint) and clinically driven restenosis-related
target vessel revascularization. Dual antiplatelet therapy was administered for
6 months in all patients regardless of stent type, and clopidogrel was
discontinued in all patients after 6 months.
After clopidogrel
discontinuation, late-stent thrombosis-related events were 2-3 times more
frequent among those who had received DES than among those who had received
BMS,carried 4 times higher risk of cardiac death/MI vs non-thrombosis-related
events,occurred up to 1 year after clopidogrel discontinuation, and were more
frequent in patients with prior MI, those who needed glycoprotein IIb/IIIa
inhibitors initially, or those who had received DES. From these results, the
authors calculated that real-world DES use in 100 patients avoids 5 target
vessel revascularization events at 6 months but leads to 3.3 late deaths or MI.
3- To Assess The Rates of
Adverse Events After Stopping Treatment With Clopidogrel in a National Sample
of Patients With Acute Coronary Syndrome (ACS).46
Design, Setting, and Patients: Retrospective cohort study of 3137 patients with ACS discharged from
127 Veterans Affairs hospitals between October 1, 2003, and March
31,2005,with,posthospital.treatment,with.clopidogrel.
Main Outcome Measure:
Rate of all-cause mortality or acute myocardial infarction (AMI) after. stopping.
treatment. with. clopidogrel.
Mean (SD)
follow-up after stopping treatment with clopidogrel was 196 (152) days for
medically treated patients with ACS without stents (n = 1568) and 203 (148) days
for patients with ACS treated with percutaneous coronary intervention (PCI) (n
= 1569). Among medically treated patients, mean (SD) duration of clopidogrel
treatment was 302 (151) days and death or AMI occurred in 17.1% (n = 268) of
patients, with 60.8% (n = 163) of events occurring during 0 to 90 days, 21.3%
(n = 57) during 91 to 180 days, and 9.7% (n = 26) during 181 to 270 days after
stopping treatment with clopidogrel. In multivariable analysis including
adjustment for duration of clopidogrel treatment, the first 90-day interval
after stopping treatment with clopidogrel was associated with a significantly
higher risk of adverse events (incidence rate ratio [IRR], 1.98; 95% confidence
interval [CI], 1.46-2.69 vs the interval of 91-180 days). Similarly, among
PCI-treated patients with ACS, mean (SD) duration of clopidogrel treatment was
278 (169) days and death or AMI occurred in 7.9% (n = 124) of patients, with
58.9% (n = 73) of events occurring during 0 to 90 days, 23.4% (n = 29) during
91 to 180 days, and 6.5% (n = 8) during 181 to 270 days after stopping
clopidogrel treatment.
CONCLUSIONS:
We observed a
clustering of adverse events in the initial 90 days after stopping clopidogrel
among both medically treated and PCI-treated patients with ACS, supporting the
possibility of a clopidogrel rebound effect. Additional studies are needed to
confirm the clustering of events after stopping clopidogrel, including
associations with cardiovascular mortality and reasons for stopping
clopidogrel, as well as to determine the mechanism of this phenomenon, and to
identify strategies to reduce early events after clopidogrel cessation.
DISCUSSION:
Here We found a clustering of death
and MI events in the initial 90-day period after clopidogrel cessation,
compared with subsequent follow-up intervals. Findings were consistent among
subgroups of patients who received shorter or longer durations of clopidogrel
therapy, patients with or without diabetes, and ACS patients who underwent PCI.
The rate of adverse events in the initial 90-day interval after stopping
clopidogrel was higher than the rate of adverse events following hospital
discharge while patients were still taking clopidogrel. These findings support
the hypothesis of a rebound hyperthrombotic period after clopidogrel cessation.
They also highlight the need for additional studies to confirm these findings
and to gain a deeper understanding of the pathophysiology of this phenomenon as
well as allowing identification of strategies to attenuate this effect. The
results of this study add to the literature supporting the hypothesis of a
rebound phenomenon following antiplatelet agent withdrawal In vitro and
physiologic evidence exist that support the notion of a short-term increase in
platelet activation and corresponding thrombotic risk immediately after
stopping antiplatelet therapy.''" Previous studies have shown that
discontinuation of aspirin therapy is associated with an increased short-term
risk of cerebrovascuiar and cardiac events compared with continuous aspirin use.
The STRATEGY (Single High- Dose Bolus Tirofiban and Sirolimus Eluting Stem
versus Abciximab and Bare Metal Stent in Acute Myocardial Infarction) study
reported a clustering of death or nonfatal MI within 30 days of stopping
thienopyridine therapy among patients treated with DES or BMS for ST-segment
elevation MF; however, a stent-related mechanism was identified as the likely
etiology for these events. We observed an increase in the incidence of adverse
events in nonstented, medically treated ACS patients following clopidogrel
cessation, implicating a mechanism unrelated to stenting. this study has
several potential implications. First, while the absolute rate of adverse
events was low, the relative increase in adverse events seen in the early
period after clopidogrel cessation was nearly twofold higher than in later
periods. The absolute number of adverse events attributable to this event
clustering is significant when extrapolated to a population level.These
findings do not necessarily offset the benefits of clopidogrel therapy for
patients with ACS. They do indicate, however, that additional studies are
urgently needed to confirm event clustering and understand the pathophysiology
of this phenomenon. Should these findings be confirmed, guideline recommendations
may need to be reconsidered regarding the duration of clopidogrel therapy and
possibly the means of clopidogrel cessation. Possibilities include continuing
clopidogrel for an extended period or indefinitely, although before
implementing this recommendation, the increased risk of bleeding with prolonged
dual antiplatelet therapy and the cost-effectiveness of such a strategy would
need to be considered tapering clopidogrel therapy; bridging clopidogrel
cessation with higher-dose aspirin for a given period; or using alternative
antiplatelet regimens. All these approaches would require formal study before
making a specific recommendation
REFERANCES:
1.
http://blog.adpharm.net/2009/09/plavix-living-proof/
Bal dit Sollier C, Mahe I, Berge N, et al, “Reduced Thrombus Cohesion in an ex vivo Human Model of Arterial
Thrombosis Induced by Clopidogrel Treatment: Kinetics of the Effect and
Influence of Single and Double Loading-Dose Regimens,” Thromb Res, 2003, 111(1-2):19-27.
2.
J. M.
Pereillo, M. Maftouh, A. Andrieu, M. F. Uzabiaga, O. Fedeli, P. Savi, M.
Pascal, J. M. Herbert, J. P. Maffrand, C. Picard (2002). "Structure and
stereochemistry of the active metabolite of clopidogrel". Drug Metab. Dispos. 30 (11):
1288-1295. doi:10.1124/dmd.30.11.1288. PMID 12386137. http://dmd.aspetjournals.org/cgi/reprint/30/11/1288.pdf.
3.
Savi,
P; Zachayus JL, Delesque-Touchard N et al. (July 2006). "The active
metabolite of Clopidogrel disrupts P2Y12 receptor oligomers and partitions them
out of lipid rafts". Proceedings
of the
4.
http://ventrilocontrolpanel.com/forum/viewtopic.php?f=2&t=68520
5.
http://packageinserts.bms.com/pi/pi_plavix.pdf.
Bal dit Sollier C, Mahe I, Berge N, et al, “Reduced Thrombus Cohesion in an ex vivo Human Model of Arterial
Thrombosis Induced by Clopidogrel Treatment: Kinetics of the Effect and
Influence of Single and Double Loading-Dose Regimens,” Thromb Res, 2003, 111(1-2):19-27.
6.
Rossi
S, editor. Australian
Medicines Handbook 2006.
7.
Chan
FK, Ching JY, Hung LC, et al.
(2005). "Clopidogrel versus aspirin and esomeprazole to prevent recurrent
ulcer bleeding". N. Engl. J. Med.
352
(3): 238-44. doi:10.1056/NEJMoa042087. PMID 15659723.
8.
Ho PM,
Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Rumsfeld JS. (2009).
"Risk of adverse outcomes associated with concomitant use of clopidogrel
and proton pump inhibitors following acute coronary syndrome.". JAMA. 301 (9): 937-44. PMID 19258584.
9.
Mega,
J. L. (2009). "Cytochrome P-450 Polymorphisms and Response to
Clopidogrel". New Engl. J. Med.
360:
354-362. doi:10.1056/NEJMoa0809171. PMID 19106084.
10. Simon, T. (2009). "Genetic Determinants
of Response to Clopidogrel and Cardiovascular Events". New Engl. J. Med. 360:
363-375. doi:10.1056/NEJMoa0808227. PMID 19106083.
11. Collet, J (2009). "Cytochrome P450 2C19
polymorphism in young patients treated with clopidogrel after myocardial infarction:
a cohort study". Lancet 373: 309. doi:10.1016/S0140-6736(08)61845-0.
12. unitcost.fda.moph.go.th/cl/.../document_20080131124726-1.pdf
–
13. http://plavix.legalview.info/wikipedia/Clopidogrel/
14. www.accessdata.fda.gov/drugsatfda_docs/.../020839s040ltr.pdf
–
15. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=11271, Small DS, Farid NA, Payne CD, et al,
“Effects of the Proton Pump Inhibitor Lansoprazole on the Pharmacokinetics and
Pharmacodynamics of Prasugrel and Clopidogrel,” J Clin Pharmacol, 2008, 48(4):475-84.
16. www.umm.edu/altmed/drugs/clopidogrel-030450.htm
17. http://74.125.153.132/search?q=cache:EMDV0XHAbg8J:www.merck.com/mmpe/lexicomp/clopidogrel.html
18. 9.PGxNews.Org (June 2009). "FDA updates
Plavix label with PGx data". PGxNews.Org. http://www.pgxnews.
org/web/the-news/1-latest-news/47-fda-updates-plavix-label-with-pgx-data.
Retrieved 2009-06-13.
19. 10.Diener HC, Bogousslavsky J, Brass LM, et al. (2004). "Aspirin and
clopidogrel compared with clopidogrel alone after recent ischaemic stroke or
transient ischaemic attack in high-risk patients (MATCH): randomised,
double-blind, placebo-controlled trial". Lancet
364
(9431): 331-7. doi:10.1016/S0140-6736(04)16721-4.
PMID 15276392
20. http://www.medscape.com/druginfo/dosage?drugid=5190&drugname=Clopidogrel+Oral&monotype=default
21. "New products
and markets fuel growth in 2005". IMS Health. http://www1.imshealth.com/web/content/0,3148,64576068_63872702_70260998_77974518,00.html.
Retrieved 2009-03-02.
22. "Top Ten
Global Products - 2007" (PDF). IMS Health. 2008-02-26. http://www.imshealth.com/deployedfiles/imshealth/Global/Content/StaticFile/Top_Line_Data/Top10GlobalProducts.pdf.
Retrieved 2009-03-02.
23. "Preliminary
Injunction Against Apotex Upheld on Appeal — Press Release". http://www.earthtimes.org/articles/show
/news_press_release,32577.shtml. Retrieved 2007-09-05.
24. "U.S. judge
upholds Bristol, Sanofi patent on Plavix". http://www.reuters.com/article/businessNews/idUSN1931607820070619?pageNumber=1.
Retrieved 2007-09-05.
25. http://www.drugs.com/sfx/clopidogrel-side-effects.html
26. http://www.mdconsult.com/das/pdxmd/body/167780134-2/0?type=med&eid=9-u1.0-_1_mt_5112401
27. http://www.medscape.com/druginfo/dosage?drugid=5190&drugname=Clopidogrel+Oral&monotype=default
28. “A Randomized, Blinded, Trial of Clopidogrel
Versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE). CAPRIE
Steering Committee,” Lancet,
1996, 348(9083):1329-39.
29. Adams HP, del Zoppo G,
Alberts MJ, et al, “Guidelines for the Early Management of Adults With Ischemic
Stroke: A Guideline from the American Heart Association/American Stroke
Association Stroke Council, Clinical Cardiology Council, Cardiovascular
Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular
Disease and Quality of Care Outcomes in Research Interdisciplinary Working
Groups,” Stroke, 2007,
38(5):1655-1711. Available at http://stroke.ahajournals.org/cgi/reprint/STROKEAHA.107.181486
30. Anderson JL, Adams CD, Antman EM, et al,
“ACC/AHA 2007 Guidelines for the Management of Patients With Unstable
Angina/Non ST-Elevation Myocardial Infarction: Executive Summary. A Report of
the American College of Cardiology/American Heart
31. Association Task Force on Practice
Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management
of Patients with Unstable Angina/Non ST-Elevation Myocardial Infarction)
Developed in Collaboration With the American College of Emergency Physicians,
The Society of Cardiovascular Angiography and Interventions, and the Society of
Thoracic Surgeons,” J Am Coll Cardiol,
2007, 50(7):1-157. Available at http://content.onlinejacc. org/cgi/reprint/50/7/e1
32. Antman EM, Anbe DT, Armstrong PW, et al.
“ACC/AHA 2007 Guidelines for the Management of Patients With ST-Elevation
Myocardial Infarction: A Report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines (Writing Committee to
Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial
Infarction),” J Am Coll Cardiol,
2004, 44(3):671-719. Available at http://www.acc.org/qualityand science/clinical/guidelines/stemi/Guideline1/index.htm
33. Bal dit Sollier C, Mahe I, Berge N, et al,
“Reduced Thrombus Cohesion in an ex
vivo Human Model of Arterial Thrombosis Induced by Clopidogrel
Treatment: Kinetics of the Effect and Influence of Single and Double Loading-Dose
Regimens,” Thromb Res, 2003,
111(1-2):19-27.
34. Sabatine MS, Cannon CP, Gibson CM, et al,
“Addition of Clopidogrel to Aspirin and Fibrinolytic Therapy for Myocardial
Infarction With ST-Segment Elevation,” N
Engl J Med, 2005, 352(12):1179-89.
35. Scirica BM, Sabatine MS, Morrow DA, et al.
“The Role of Clopidogrel in Early and Sustained Arterial Patency After
Fibrinolysis for ST-segment Elevation Myocardial Infarction. The ECG
Clarity-TIMI 28 Study,” J Am Coll
Cardiol, 2006, 48(1):37-42.
36. Ho PM, Maddox TM, Wang L, et al, “Risk of
Adverse Outcomes Associated With Concomitant Use of Clopidogrel and Proton Pump
Inhibitors Following Acute Coronary Syndrome,” JAMA, 2009, 301(9):937-44.
37. Pezalla E, Day D, and Pulliadath I, “Initial
Assessment of Clinical Impact of a Drug Interaction Between Clopidogrel and
Proton Pump Inhibitors,” J Am Coll
Cardiol, 2008, 52(12):1038-9.
38. Gilard M, Arnaud B, Le
Gal G, et al, “Influence of Omeprazol on the Antiplatelet Action of Clopidogrel
Associated to Aspirin,” J Thromb
Haemost, 2006, 4(11):2508-9.
39. Gilard M, Arnaud B, Cornily JC, et al,
“Influence of Omeprazole on the Antiplatelet Action of Clopidogrel Associated
With Aspirin: The Randomized, Double-Blind Ocla (Omeprazole Clopidogrel
Aspirin) Study,” J Am Coll Cardiol,
2008, 51(3):256-60.
40. Siller-Matula JM, Spiel AO, Lang IM, et al,
“Effects of Pantoprazole and Esomeprazole on Platelet Inhibition by
Clopidogrel,” Am Heart J, 2009,
157(1):148.e1-5.
41. Small DS, Farid NA, Payne CD, et al,
“Effects of the Proton Pump Inhibitor Lansoprazole on the Pharmacokinetics and
Pharmacodynamics of Prasugrel and Clopidogrel,” J Clin Pharmacol, 2008, 48(4):475-84.
42. Stanek EJ, Aubert RE, Flockhart DA, et al,
“A National Study of the Effect of Individual Proton Pump Inhibitors on
Cardiovascular Outcomes in Patients Treated With Clopidogrel Following Coronary
Stenting: The Clopidogrel Medco Outcomes Study,” Society for Cardiovascular
Angiography and Interventions 2009 Scientific Sessions; May 6, 2009; Las Vegas,
NV.
43. http://www.merck.com/mmpe/lexicomp/clopidogrel.html
44. http://www.liveinternet.ru/showjournal.php?journalid=2826971&tagid=1384740
45. ACP J Club.
2007 May-Jun;146(3):67. J Am Coll
Cardiol. 2006 Dec 19;48(12):2592-5.
46. http://jama.ama-assn.org/cgi/content/short/299/5/532
JAMA. 2008;299(5):532-539.
47. J Am Coll Cardiol, 2006; 48:2592-2595,
doi:10.1016/j.jacc.2006.10.025 (Published online
48. Kaiser C, Brunner-La Rocca HP, Buser PT, et
al; BASKET Investigators. Incremental cost-effectiveness of drug-eluting stents
compared with a third-generation bare-metal stent in a real-world setting:
randomised Basel Stent Kosten Effektivitats Trial (BASKET). Lancet.
2005;366:921-929.
Received on 30.12.2009
Accepted on 15.01.2010
© A&V Publication all right reserved
Research J. Pharmacology and
Pharmacodynamics 2(2): March –April 2010: 117-125