Curr Med Res Opin.
2005 Jan;21(1):101-12.
Modelling the long term cost effectiveness of clopidogrel for
the secondary prevention of occlusive vascular events in the UK.
Karnon J, Brennan A, Pandor A, Fowkes G, Lee A, Gray D, Coshall
C, Nicholls C, Akehurst R.
School of Health and Related Research (ScHARR), University of Sheffield,
Regent Court, 30 Regent Street, Sheffield, S1 4DA, UK. j.karnon@sheffield.ac.uk
OBJECTIVE: To assess the long term cost effectiveness of clopidogrel
monotherapy compared with acetylsalicylic acid (aspirin; ASA) monotherapy
in patients at risk of secondary occlusive vascular events (OVEs) in the
UK. DESIGN: Cost utility analysis based on clinical data from CAPRIE (a
multicentre randomised controlled trial, involving 19185 patients); long-term
effects were extrapolated beyond the trial period using a Markov model
populated with data from UK observational studies. Health economic evaluation
carried out from the perspective of the UK National Health Service. PARTICIPANTS:
A representative cohort of 1000 UK patients aged 60 years (approximate
mean age of the CAPRIE population), with the qualifying diagnoses of myocardial
infarction, ischaemic stroke and peripheral arterial disease, who are
at risk of secondary OVEs (non-fatal myocardial infarction, non-fatal
stroke or vascular death). INTERVENTIONS: Patients were assumed to receive
treatment with either clopidogrel (75 mg/day) for 2 years followed by
ASA (325 mg/day, average) for their remaining lifetime, or ASA alone (325
mg/day, average) for life. MAIN OUTCOME MEASURES: Incremental cost per
life year gained and incremental cost per quality-adjusted life year (QALY)
gained. RESULTS: In the base case, the incremental cost effectiveness
of clopidogrel versus ASA in this population is estimated at 18888 pounds
per life year gained and 21 489 pounds per QALY gained. Multiple deterministic
and probabilistic sensitivity analyses suggest the model is robust to
variations in a wide range of input parameters. CONCLUSION: Two years
of treatment with clopidogrel can be considered a cost effective intervention
in patients at risk of secondary OVEs in the UK.
Vascular. 2005 Jan-Feb;13(1):43-9.
Effect of clopidogrel on platelet aggregation and intimal hyperplasia
following carotid endarterectomy in the rat.
Bledsoe SL, Brown AT, Davis JA, Chen H, Eidt JF, Moursi MM.
Department of Surgery, Division of Vascular Surgery, University of
Arkansas for Medical Sciences, Central Arkansas Veterans Healthcare System,
Little Rock, AR, USA.
Intimal hyperplasia results in significant morbidity and mortality following
vascular intervention. Both platelets and elevated homocysteine have been
implicated in the development of intimal hyperplasia. We previously demonstrated
that a locally applied antiplatelet agent decreases the development of
intimal hyperplasia. We were therefore interested in a systemic antiplatelet
agent, clopidogrel. We hypothesized that clopidogrel would decrease platelet
aggregation and activity and intimal hyperplasia. Male Sprague-Dawley
rats underwent carotid endarterectomy (CEA) and treatment with either
placebo or varying regimens of clopidogrel, including chronic, pre-CEA
bolus, chronic plus pre-CEA bolus, and chronic plus post-CEA bolus; a
homocystine diet was used to elevate both plasma homocysteine and the
degree of intimal hyperplasia. Platelet aggregation, platelet activity,
and intimal hyperplasia were then assessed. Platelet aggregation was not
decreased with chronic clopidogrel; however, it was decreased with pre-CEA
bolus clopidogrel. Similarly, platelet activity was not inhibited by chronic
clopidogrel but was inhibited by pre-CEA and chronic plus pre-CEA bolus
clopidogrel. Neither chronic, pre-CEA bolus, chronic plus pre-CEA bolus,
nor chronic plus post-CEA bolus clopidogrel resulted in a decrease in
intimal hyperplasia. Although pre-CEA bolus clopidogrel resulted in a
decrease in both platelet aggregation and activity, it was unable to decrease
the development of intimal hyperplasia at any dose. Additional factors
must therefore contribute to the pathologic development of intimal hyperplasia.
Eur Heart J. 2005 Mar;26(6):576-83. Epub 2005 Feb 21.
Clopidogrel administration prior to coronary artery bypass grafting
surgery: the cardiologist's panacea or the surgeon's headache?
Kapetanakis EI, Medlam DA, Boyce SW, Haile E, Hill PC, Dullum MK, Bafi
AS, Petro KR, Corso PJ.
Section of Cardiac Surgery, Department of Surgery, Washington Hospital
Center, 106 Irving Street, NW, Suite 316, Washington, DC 20010-2975, USA.
AIMS: Thrombotic complications after percutaneous coronary intervention
procedures have decreased in past years mainly due to the use of clopidogrel
antiplatelet therapy. However, the risk of bleeding due to enhanced and
irreversible platelet inhibition in patients who will require surgical
coronary revascularization instead has not been adequately addressed in
the literature. The purpose of this study was to evaluate the effect of
pre-operative clopidrogel exposure in haemorrhage-related re-exploration
rates, peri-operative transfusion requirements, morbidity, and mortality
in patients undergoing coronary artery bypass grafting (CABG) surgery.
METHODS AND RESULTS: A study population of 2359 patients undergoing isolated
CABG between January 2000 and June 2002 was reviewed. Of these, 415 (17.6%)
received clopidogrel prior to CABG surgery, and 1944 (82.4%) did not.
A risk-adjusted logistic regression analysis was used to assess the association
between clopidogrel pre-medication (vs. no) and haemostatic re-operation,
intraoperative and post-operative blood transfusion rates, and multiple
transfusions received. Haemorrhage-related pre-operative risk factors
identified from the literature and those found significant in a univariate
model were used. Furthermore, a sub-cohort, matched-pair by propensity
scores analysis, was also conducted. The clopidogrel group had a higher
likelihood of haemostatic re-operation [OR=4.9, (95% CI, 2.63-8.97), P<0.01],
an increase in total packed red blood cell transfusions [OR=2.2, (95%
CI, 1.70-2.84), P<0.01], multiple unit blood transfusions [OR=1.9,
(95% CI, 1.33-2.75), P<0.01] and platelet transfusions [OR=2.6, (95%
CI, 1.95-3.56), P<0.01]. Surgical outcomes and operative mortality
[OR=1.5, (95% CI, 0.36-6.51), P=0.56] were not significantly different.
CONCLUSION: Pre-operative clopidogrel exposure increases the risk of haemostatic
re-operation and the requirements for blood and blood product transfusion
during, and after, CABG surgery.
Thromb Haemost. 2005 Mar;93(3):527-34.
Effects of aspirin, clopidogrel and dipyridamole administered
singly and in combination on platelet and leucocyte function in normal
volunteers and patients with prior ischaemic stroke.
Zhao L, Fletcher S, Weaver C, Leonardi-Bee J, May J, Fox S, Willmot M,
Heptinstal S, Bath P.
Division of Stroke Medicine, South Block, D Floor, Queen's Medical Centre,
Nottingham NG7 2UH UK, E-mail: philip.bath@nottingham.ac.uk.
The aim of this study was to assess whether triple antiplatelet therapy
is superior to dual and mono therapy in attenuating platelet and leucocyte
function. Aspirin (A), clopidogrel (C), and dipyridamole (D) were administered
singly and in various combinations (A, C, D,AC,AD, CD,ACD), each for two
weeks (without washout) to 11 healthy subjects and to 11 patients with
previous ischaemic stroke in two randomised multiway crossover trials.
At the end of each two-week period platelet aggregation, platelet-leucocyte
conjugate formation and leucocyte activation were measured ex vivo blinded
to treatment. Platelets were stimulated with collagen; additional measurements
were made with adenosine diphosphate (ADP), platelet activating factor
(PAF), adrenaline and the combination of, ADP, PAF and adrenaline. Results
show that in the presence of collagen, ACD was superior to all antagonists
or combinations, except AC, in reducing aggregation, platelet-leucocyte
conjugate formation, and monocyte activation (all p<0.05). ACD was
also more potent than other treatments, except AC, in inhibiting the aggregation
and platelet-monocyte conjugate formation induced by the combination of
ADP, PAF and adrenaline. The effects were similar in both volunteers and
stroke patients. No serious adverse events or major bleeding events occurred.
Triple antiplatelet therapy did not appear to be more effective than combined
aspirin and clopidogrel in moderating platelet and leucocyte function.
Any additional clinical benefit provided by dipyridamole may be through
other mechanisms of action.
Circulation. 2005 Mar 8;111(9):1153-9. Epub 2005 Feb 28.
Clopidogrel loading with eptifibatide to arrest the reactivity
of platelets: results of the Clopidogrel Loading With Eptifibatide to
Arrest the Reactivity of Platelets (CLEAR PLATELETS) study.
Gurbel PA, Bliden KP, Zaman KA, Yoho JA, Hayes KM, Tantry US.
Sinai Center for Thrombosis Research, Hoffberger Bldg, Suite 56, 2401
W Belvedere Ave, Baltimore, MD 21215, USA. pgurbel@lifebridgehealth.org
BACKGROUND: Pretreatment is not the most common strategy practiced for
clopidogrel administration in elective coronary stenting. Moreover, limited
information is available on the antiplatelet pharmacodynamics of a 300-mg
versus a 600-mg clopidogrel loading dose, and the comparative effect of
eptifibatide with these regimens is unknown. METHODS AND RESULTS: Patients
undergoing elective stenting (n=120) were enrolled in a 2x2 factorial
study (300 mg clopidogrel with or without eptifibatide; 600 mg clopidogrel
with or without eptifibatide) (Clopidogrel Loading With Eptifibatide to
Arrest the Reactivity of Platelets [CLEAR PLATELETS] Study). Clopidogrel
was administered immediately after stenting. Aggregometry and flow cytometry
were used to assess platelet reactivity. Eptifibatide added a > or
=2-fold increase in platelet inhibition to 600 mg clopidogrel alone at
3, 8, and 18 to 24 hours after stenting as measured by 5 micromol/L ADP-induced
aggregation (P<0.001). Without eptifibatide, 600 mg clopidogrel produced
better inhibition than 300 mg clopidogrel at all time points (P<0.001).
Glycoprotein IIb/IIIa (GPIIb/IIIa) blockade was associated with lower
cardiac marker release. Active GPIIb/IIIa expression was inhibited most
in the groups treated with eptifibatide (P<0.05). CONCLUSIONS: In elective
stenting without clopidogrel pretreatment, use of a GPIIb/IIIa inhibitor
produces superior platelet inhibition and lower myocardial necrosis compared
with high-dose (600 mg) or standard-dose (300 mg) clopidogrel loading
alone. In the absence of a GPIIb/IIIa inhibitor, 600 mg clopidogrel provides
better platelet inhibition than the standard 300-mg dose. These results
require confirmation in a large-scale clinical trial.
Eur Heart J. 2005 Feb 16.
Impact of combined pharmacologic treatment with clopidogrel and
a statin on outcomes of patients with non-ST-segment elevation acute coronary
syndromes: perspectives from a large multinational registry.
Lim MJ, Spencer FA, Gore JM, Dabbous OH, Agnelli G, Kline-Rogers EM, Dibenedetto
D, Eagle KA, Mehta RH.
Division of Cardiology, School of Medicine, Saint Louis University, St
Louis, MO, USA.
AIMS: To evaluate clinical outcomes associated with the combined use of clopidogrel and statins vs. clopidogrel alone on a background of aspirin therapy in patients with the spectrum of acute coronary syndromes (ACS). METHODS AND RESULTS: Utilizing data from the Global Registry of Acute Coronary Events, we studied 15 693 patients admitted with non-ST-segment elevation myocardial infarction (MI) or unstable angina, dividing them according to discharge medications: aspirin alone (group I); aspirin + clopidogrel (group II); aspirin + statin (group III); aspirin + clopidogrel + statin (group IV). Among the groups of patients in whom clopidogrel was used (groups II and IV), group II patients were older, more likely to have prior MI, but less likely to have a history of prior revascularization. In-hospital cardiac catheterization and revascularization rates were similar between groups II and IV. Importantly, Kaplan-Meier analysis showed that the 6 month mortality rate was lower in group IV (log-rank test 22.8, P < 0.0001). The hazard ratio for the 6 month mortality rate was adjusted using the Cox proportional hazard model for confounding variables and for propensity score, and the 6 month mortality rate for patients in group IV remained lower compared with those in group II [0.59 (0.41-0.86), P < 0.0001]. CONCLUSION: Our data suggest that the combination of clopidogrel with a statin has synergistic effects on the clinical outcomes of patients with non-ST-segment elevation ACS.
