The Impact of Cigarette Smoking on Clopidogrel Induced Platelet Inhibition in Saudi Patients with Acute Coronary Syndrome Underwent Coronary Stenting
Hassan Khalaf1*, Ahmed Al Meman1*, Seemab Rasool1 and Giuseppe Gullace2
1Prince Sultan Cardiac Center, Qassim & Genetic laboratory at Qassim University, Kingdom of Saudi Arabia
2Multimedica Hospital Group, Italy
Submission: October 25, 2016; Published: November 10, 2016
*Corresponding author: Hassan Khalaf and Ahmed Al Meman, Prince Sultan Cardiac Center at Qassim, Saudi Arabia, Email: [email protected]
How to cite this article: Hassan K, Ahmed Al M, Seemab R, Giuseppe G. BThe Impact of Cigarette Smoking on Clopidogrel Induced Platelet Inhibition in Saudi Patients with Acute Coronary Syndrome Underwent Coronary Stenting. J Cardiol & Cardiovasc Ther. 2016; 2(1): 555578. DOI: 10.19080/JOCCT.2016.02.555578
Purpose: The variable response to clopidogrel is multi-factorial; cigarette smoking is thought to be one of these factors as smoking is a known inducer of CYP1A2, one of the predominant isoenzymes responsible for activation of clopidogrel. The Purpose of this study is to finds out the impact of cigarette smoking on clopidogrel-induced platelet inhibition.
Methodology: retrospective analysis of a prospective cohort of 90 Saudi patients with acute coronary syndrome who underwent coronary angioplasty with drug eluting stents. Pre-procedure arterial blood sample was taken from every patient for assessment of platelet function (Verify Now P2Y12 point-of-care assay.
Results: Of these ninety patients, 26 (28.8%) patients were smokers. Patients received clopidogre l300 mg or 600mg as loading and 75mg per day as maintenance dose. The Inhibition of platelet aggregation percent (IPA %) was lower in non smokers (12.9 ± 13.1) as compared to smokers (23.8 ± 18.3) by two sample T test with p value =0.01. The mean P2Y12 reaction units (PRU) was found to be significantly higher in non smokers at 213±72 than in smokers who had mean PRU of 152 ± 66 (p>0.001). One in-hospital clinical event was encountered, with documented sub acute stent thrombosis.
Conclusion: The platelets inhibition in response to clopidogrel was lower in non smoker compared with smoker in Saudi patients who presented with acute coronary syndrome and underwent coronary stenting.
Keywords: Clopidogrel; Smoking; Platelet Function Test; Acute Coronary Syndrome
Antiplatelet therapy reduces ischemic events in a wide range of patients with coronary artery disease. Efficacy of dual-antiplatelet therapy with a thienopyridine plus aspirin is well demonstrated in major randomized controlled trials of coronary stenting . Clopidogrel is a prodrug, metabolized by two consecutive cytochrome P450 (CYP)-dependent steps to its active metabolite, which binds irreversibly to the platelet P2Y12 receptor. The hepatic enzymes involved in the metabolism of clopidogrel include CYP1A2, 2B6, 2C9, 2 C19, and 3A 4/5 .The variability of response to clopidogrel is thought to be multi-factorial, mainly variable Genetic and environmental influences on CYP450 enzyme activity [3-6]. This great inter-patient variability to Clopidogrel response has been shown in multiple
clinical trials [7-9]. Hypo-responsiveness to clopidogrel after
drug eluting stent (DES) may be detrimental to patients as is
evidenced by the large-scale, prospective ADAPT-DES study ,
in which on-treatment hypo-responsiveness was an independent
predictor of 1-year stent thrombosis and myocardial infarction.
However, inhibitory response to clopidogrel varies considerably
An impaired response to Clopidogrel therapy as measured
by ADP-induced platelet reactivity on light transmittance
aggregometry (LTA) has been associated with adverse outcomes
after percutaneous coronary intervention (PCI) . LTA as well
as the phosphorylation assay (VASP) require special training to
perform, and are not commonly used . Another method to
assess the effect of clopidogrel on platelet reactivity is the pointof-
care test with the Verify Now P2Y12 assay (Accumetrics Inc.)
[13-15].The Verify Now instrument measures platelet-induced
aggregation as an increase in light transmittance and utilizes a
proprietary algorithm to report values in P2Y12 reaction units
(PRU).The results of this assay have been shown to be well
correlated with ADP-induced platelet aggregation by LTA .
Recent studies have investigated Cigarette smoking and its effect
on thepharmacokinetics and pharmacodynamics of clopidogrel.
Cigarette smoking seems to positively modify the beneficial
effect of clopidogrel .
The aim of this study is to find out the impact of cigarette
smoking on clopidogrel-induced platelet inhibition in Saudi
patients presented with acute coronary syndrome and
underwent coronary angioplasty with drug eluting stents.
Our study was conducted in prince Sultan cardiac center,
Qassim, at central provence in Saudi Arabia. Ninety Saudi
patients were enrolled including those admitted to our center
from Emergency room or refered from other hospitals or health
facilities. A retrospective analysis of the prospective cohort was
conducted to investigate the impact of smoking on clopidogrel
induced platelet inhibition. The study was approved by the
ethical institutional review committee in King Fahad Specialist
Hospital for which the center belongs. An informed consent was
obtained from all patients prior to the study.
Saudi patients were eligible for enrolment if they had
acute coronary syndrome including unstable angina, non ST
elevation myocardial infarction or Recent STEMI and undergone
PCI with deployment of at least a single Drug Eluting Stent.
Patients received a loading dose of clopidogrel300 mg or
600mg (as per preference of the primary physatain) and
maintained on 75mg per day. Patients presented with Acute STEMI who underwent primary PCI were excluded. Patients
with hemodynamic instability were also excluded. Patients who
received glycoprotein inhibitors, heparin or thrombolysis within
24 hours before the blood sample taken were also excluded (due
to potential interference with theP2Y12 assay) .
An arterial blood sample was collected via the procedure
access (Femoral or radial artery) after the diagnostic angiography
and before giving heparin for a planned PCI. The inhibitory
effect of clopidogrel was measured using the Verify Now P2Y12
assay (Accumetrics Inc.) not less than 20 minutes and not more
than 2 hours. The Verify Now P2Y12 assay includes 2 channels
in the device. One contains adenosine diphosphate (ADP) and
prostaglandin E1 (PGE1); the measurement from this channel
is reported as P2Y12 reaction units (PRU). A higher PRU result
reflects greater platelet reactivity mediated by P2Y12 activation.
The second channel contains iso-thrombin receptor activating
peptide [iso-TRAP: protease-activated receptor (PAR)-1 agonist]
and PAR-4 activating peptide (PAR-4 AP). The measurement from
this channel estimates maximal platelet function independent of
P2Y12 receptor blockade and is reported as BASE. Inhibition of
platelet aggregation (IPA %) is calculated as follows:
IPA (%) = 100% × [(BASE - PRU)/BASE].
In our study we measured both the percent of IPA % as well
as the PRU.
Follow up: patients were observed during hospital
stay and at one month clinic visit for major cardiovascular
events including death, myocardial infarction, and stroke or
Statistics: Data was stored and analyzed in Mini tab
15® to generate all statistical results. Patients were divided
into two groups based on their smoking history. Student’s-ttest
was used to spot potential differences in platelet function
test and Chi-square test to find potential association. The
level of significance (α) was determined to be 0.05 and a
P-value of 5 percent.
Results: A total of 90 Saudi patients with acute coronary
syndrome were included in the analysis and divided into two
groups smokers (all cigarette smokers) 26 patients (28.9%)
and non smokers 64 patients ( 69.1%).patient characteristics
of the two groups were shown in (Table 1).
In our study, the smoker groups were all males with higher
incidence of hypertension and present mostly with recent STEMI
at younger age compared with non smokers. The mean time on
clopidogrel (hours) was42 ± 27 in smoker group versus 49 ± 25
in non smoker group (p <0.5). The mean Inhibition of platelet
aggregation percent (IPA %) was higher in smokers (23.8 ± 18.3).
as compared to non smokers (12.9 ± 13.1) with a P value<0.01.
Similarly, the mean P2Y12 reaction units (PRU) was found to be
significantly higher in non smokers at (213 ± 72) than in smokers
who had mean PRU of (152 ± 66) with a P value <0.001 (Table2).
In hospital clinical events: Only one event was observed during
the one month follow up, which was a documented case of subacute
Patients with Acute coronary syndrome are expected to
have a higher platelet activity and might respond to clopideogrel
differently compared with stable coronary artery disease. Our
study cohorts of acute coronary syndrome Saudi patients were
mostly male which consists with the higher prevalence of the
disease in men. Smoking is rarely reported in Saudi females.
Smokers mostly present with STEMI at younger age compared
with non smokers which reflect the deleterious effect of smoking
resulting in coronary thrombosis. Smoking is more prevalent as
sole risk factors in myocardial infarction in young. The patient’s
characteristics of the two groups (smokers versus non smokers)
were comparable apart from the age, gender and hypertension
and all has no known impact on platelet function.
Hypertension was more prevalent in nonsmoker group
probably because of their higher age. In our study, we found
that clopidogrel-induced Inhibition of platelet aggregation
percent (IPA %) is more significant in smoker patients (23.8 ±
18.3) compared with non smokers (12.9 ± 13.1) with a P value
<0.01. Likewise, the P2Y12 reaction units (PRU) of the smokers
is significantly low (152±66) compared with non-smokers
(213±72) with p value <0; 001. Both readings confirm the high
and rapid response of smokers to clopidogrel. Our results are
in consistence with several studies that report a greater platelet
inhibition demonstrated in smoker patients compared with
non smokers . In the recent “PARADOX” trial, smoking was
found to influence pharmacokinetics and pharmacodynamics of
clopidogrel, in contrary toprasugrel and nonsmokers were found
to have reduced responsiveness to clopidogrel compared with
The result of our study might be explaned by Cigarette
smoking is an inducer of CYP1A221, a hepatic enzyme involved
in the metabolism of clopidogrel. CYP1A2 is responsible for
the first oxidative step in the conversion of clopidogrel to its
active metabolite. Accelerating the first step would help prevent
the pro-drug from being shunted down an esterase-mediated
pathway that leads to pharmacologically inactive metabolites. An
alternative explanation for the association between smoking and
enhanced clopidogrel effect may be the lower release of tissue
plasminogen activator in current smokers . Current smokers
with impaired endogenous fibrinolysis may benefit most from
antiplatelet therapy, an observation noted in thrombolytic
therapy and coined the “smoker’s paradox” .
However, cigarette smoking has a number of adverse effects
which influence the cardiovascular system and overall health
. Smoking causes endothelial dysfunction and increased
platelet activation leading to a prothrombotic state [23,24]. Our
results do not mean that you encourage people to smoke!! Rather
than highlight the lack of response in the non smoker group of
patients. The clinical value of this observation still uncertain. In
our cohort we encountered only one event of stent thrombosis
which occurred in a non smoker.
Our study limitations include small sample size, comparison
of surrogate end points rather than clinical ones. A study with
large sample size with clinical end points is required.