Download Concomitant Administration of Clopidogrel With Statins or Calcium

JACC: CARDIOVASCULAR INTERVENTIONS
VOL. 6, NO. 12, 2013
ª 2013 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER INC.
ISSN 1936-8798/$36.00
http://dx.doi.org/10.1016/j.jcin.2013.06.014
Concomitant Administration of Clopidogrel
With Statins or Calcium-Channel Blockers
Insights From the TRITON–TIMI 38 (Trial to Assess Improvement in
Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–
Thrombolysis In Myocardial Infarction 38)
Oluseyi Ojeifo, MD,* Stephen D. Wiviott, MD,y Elliott M. Antman, MD,y
Sabina A. Murphy, MPH,y Jacob A. Udell, MD,z Eric R. Bates, MD,x
Jessica L. Mega, MD, MPH,y Marc S. Sabatine, MD, MPH,y
Michelle L. O’Donoghue, MD, MPHy
Boston, Massachusetts; Toronto, Ontario, Canada; and Ann Arbor, Michigan
Objectives This study sought to evaluate the clinical relevance of potential clopidogrel drug–drug
interactions.
Background Some studies have demonstrated that statins and calcium-channel blockers (CCBs) may
attenuate the pharmacodynamic effects of clopidogrel.
Methods The TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38) enrolled 13,608 patients
with an acute coronary syndrome (ACS) and planned percutaneous coronary intervention (PCI), and
randomized them to clopidogrel or prasugrel. Use of a statin or CCB was left to the discretion of the
treating physician. A multivariable Cox model with propensity score was employed to evaluate the
association between statin or CCB use and clinical outcomes.
Results Of the 6,795 subjects assigned to clopidogrel, 4,794 (70.6%) were on a CYP3A4-metabolized
statin, and 966 (14.2%) were on a CCB at randomization. The risk of cardiovascular (CV) death,
myocardial infarction (MI), or stroke was similar regardless of baseline use of statins (adjusted hazard
ratio [HR]: 1.02, 95% confidence interval [CI]: 0.85 to 1.22) or CCBs (adjusted HR: 1.16; 95% CI: 0.94 to
1.43) in clopidogrel-treated patients. Further, the combined use of a CCB and atorvastatin 80 mg daily
(adjusted HR: 0.82; 95% CI: 0.37 to 1.84), or a CCB, statin, and proton pump inhibitor (adjusted HR: 1.04;
95% CI: 0.70 to 1.54) were not associated with an increased risk of CV death, MI, or stroke. The use of
statins or CCBs did not modify the relative efficacy of prasugrel versus clopidogrel for the primary
endpoint (p for interaction ¼ 0.43, 0.55, respectively).
Conclusions In patients with ACS undergoing PCI, the use of statins or CCBs was not associated with
an increased risk of CV events in clopidogrel-treated patients. Consistent results were observed when
the drugs were administered alone, together, or in combination with proton pump inhibitors. (J Am
Coll Cardiol Intv 2013;6:1275–81) ª 2013 by the American College of Cardiology Foundation
From the *Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; yTIMI Study Group, Cardiovascular
Division, Brigham and Women’s Hospital, Boston, Massachusetts; zDivision of Cardiology, Women’s College Hospital, University of
Toronto, Toronto, Ontario, Canada; and the xDepartment of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
Dr. Wiviott is a consultant for Angelmed, Eisai, Aegerion, Janssen Pharmaceuticals, St. Jude Medical, and Xoma; and has received research
funding from Merck & Co., Eisai, AstraZeneca, and Eli Lilly and Company/Daichi Sankyo. Dr. Antman has received research funding
from Eli Lilly and Company and Daiichi Sankyo. Ms. Murphy has received research funding from Eli Lilly and Company. Dr. Bates is on
the advisory boards of Daichi Sankyo, AstraZeneca, Eli Lilly and Company, and Sanofi-aventis. Dr. Mega has received research funding
from Jannsen Pharmaceuticals, Bayer HealthCare, AstraZeneca, Eli Lilly and Company, Daiichi Sankyo, Bristol-Myers Squibb, and Sanofiaventis; and is a consultant for Boehringer Ingelheim and Janssen Pharmaceuticals. Dr. Sabatine has received research funding through
Brigham and Women’s Hospital from Abbott Laboratories, Amgen, AstraZeneca, AstraZeneca/Bristol-Myers Squibb Alliance, Critical
Diagnostics, Daiichi-Sankyo, Eisai, Genzyme, GlaxoSmithKline, Intarcia, Merck, Roche Diagnostics, Sanofi-aventis, and Takeda; and is a
consultant for Aegerion, Amgen, AstraZeneca/Bristol-Myers Squibb Alliance, Intarcia, Pfizer, Sanofi-aventis, and Vertex. Dr. O’Donoghue
has received research funding from GlaxoSmithKline and AstraZeneca and is a consultant for Aegerion. All other authors have reported that
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Ojeifo et al.
Clopidogrel and Drug Interactions
Statins and calcium-channel blockers (CCBs) are frequently
co-administered with clopidogrel after an acute coronary
syndrome (ACS). Because clopidogrel requires hepatic metabolism via the cytochrome P450 (CYP) enzyme system to
form its active metabolite, there exists concern that certain
drugs, such as statins or CCBs, that are metabolized by or
inhibit isoenzymes along this pathway, can interfere with the
clinical efficacy of clopidogrel.
See page 1282
These concerns are supported by studies that have
demonstrated that atorvastatin (1–3) or CCBs (4–6) can
attenuate the pharmacodynamic effects of clopidogrel in
vitro; however, the results from pharmacodynamic studies
remain mixed (7) and the clinical implications of these
findings remain unclear. We therefore assessed whether
statins or CCBs interfere with the clinical efficacy of clopidogrel in a large trial population of patients with ACS
undergoing percutaneous coronary intervention (PCI). FurAbbreviations
and Acronyms
ther, we assessed the relative
efficacy and safety of prasugrel
ACS = acute coronary
versus clopidogrel in those
syndrome
subjects who were treated with
CCB = calcium-channel
statins or CCBs.
blocker
CI = confidence interval
CV = cardiovascular
Methods
HR = hazard ratio
The TRITON–TIMI 38 (Trial
to Assess Improvement in TherPCI = percutaneous coronary
apeutic Outcomes by Optimizintervention
ing Platelet Inhibition With
Prasugrel–Thrombolysis in Myocardial Infarction 38) study was a double-blind, phase 3 trial
that enrolled 13,608 patients with moderate-to-high-risk
ACS undergoing planned PCI, and randomized them to
prasugrel (60-mg loading dose, 10 mg a day maintenance dose)
or clopidogrel (300-mg loading dose, 75 mg a day maintenance
dose) for a median duration of 14.5 months (8). The primary
endpoint of the TRITON–TIMI 38 trial was the composite of
cardiovascular (CV) death, nonfatal myocardial infarction
(MI), or nonfatal stroke. Relevant exclusions to participation
in the trial included an increased risk of bleeding, a history
of anemia, thrombocytopenia, or pathological intracranial
findings.
Statin or CCB use. The decision to treat with a statin or
CCB was left to the discretion of the treating physician. The
names (brand name or generic), doses, and start and stop
MI = myocardial infarction
they have no relationships relevant to the contents of this paper to disclose. The
TRITON–TIMI 38 trial was sponsored by Daiichi Sankyo and Eli Lilly and
Company. The current analysis received no sources of external funding. The TIMI
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DECEMBER 2013:1275–81
dates of concomitant medications were captured on the case
report forms at patient visits. For the current analysis, we
defined statin use as all statins that were known to be
metabolized by the CYP3A4 enzyme system, including
atorvastatin, simvastatin, cerivastatin, and lovastatin. On
the basis of prior pharmacodynamic studies (1–3), we
also examined atorvastatin use individually in a sensitivity
analysis. CCB use was defined as any of the following
subtypes that are metabolized by or inhibit the CYP3A4
isoenzyme, including diltiazem, verapamil, nifedipine, felodipine, amlodipine, nisoldipine, isradipine, nimodipine,
nicardipine, lercanidipine, nitrendipine, bepridil, lacidipine,
barnidipine, and azelnidipine.
All primary efficacy and key safety endpoints were adjudicated by an independent clinical events committee who
were unaware of the assigned treatment; however, the use of
concomitant medications including CCBs and statins was
not concealed. For the current analysis, stent thrombosis was
defined according to the Academic Research Consortium
(ARC) definite or probable definitions (9).
Statistical analysis. Baseline characteristics are presented as
medians (interquartile ranges) for continuous variables and
frequencies for categorical variables. Comparisons for baseline characteristics were made with Wilcoxon rank sum tests
for continuous variables and chi-square tests for categorical
variables.
Multivariable Cox proportional hazards model was used
to examine the independent association between use of
a statin and/or CCB and the risk of adverse outcomes for
patients on clopidogrel. Using logistic regression modeling
with a forward selection algorithm (p for inclusion < 0.20),
propensity scores were developed to account for the clinician’s decision to treat with a statin or CCB. The final
variables included in each propensity score and multivariable
models are included in the Online Appendix. Because
patients could start or stop medications during the course of
study, we conducted sensitivity analyses that were restricted to
those subjects on a concomitant medication of interest both at
randomization and at the end of the study.
All efficacy analyses comparing prasugrel with clopidogrel
were conducted according to the intention-to-treat principle. Rates of endpoints are expressed as Kaplan-Meier
estimates at 450 days. All tests were 2-sided with a significance value of p < 0.05. Analyses were performed with Stata
version 9.2 (Stata Corp., College Station, Texas).
Results
Of the 13,608 patients enrolled in the TRITON–TIMI
38 trial, 9,580 (70.4%) were recorded to be taking
Study Group has an independent copy of the trial database and conducted the current
analysis.
Manuscript received April 29, 2013; accepted June 21, 2013.
Ojeifo et al.
Clopidogrel and Drug Interactions
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Table 1. Baseline Characteristics Stratified by Use of a CYP3A4-Metabolized Statin or CCB
CCB at
Randomization
(n ¼ 1,972)
No CCB at
Randomization
(n ¼ 11,636)
p Value
Statin at
Randomization
(n ¼ 9,580)
No Statin at
Randomization
(n ¼ 4,028)
p Value
Age 75 yrs
19.2
Male
70.7
12.3
<0.001
12.2
16.0
<0.001
74.7
<0.001
74.8
72.5
White race
91.4
<0.001
92.7
0.054
91.9
94.0
<0.001
30.6
34.2
<0.001
Region
North America
40.9
30.1
<0.001
South America
2.4
4.2
4.4
2.8
Western Europe
20.8
27.0
24.7
29.6
Eastern Europe
15.2
26.0
24.7
23.7
Rest of the World
20.7
12.7
15.7
9.7
28.7 (25.7–32.2)
27.7 (25.1–30.9)
<0.001
27.8 (25.2–31.2)
27.6 (24.9–30.8)
Current tobacco use
30.8
39.4
<0.001
38.4
37.6
0.38
Hypertension
82.4
61.2
<0.001
64.6
63.3
0.15
BMI, kg/m2
<0.001
Hypercholesterolemia
64.6
54.2
<0.001
59.1
47.6
<0.001
Diabetes mellitus
31.5
21.7
<0.001
24.1
20.7
<0.001
Peptic ulcer disease
6.3
5.9
0.48
6.2
5.5
0.11
Carotid or vertebral arterial disease
4.7
2.6
<0.001
2.8
3.1
0.36
History stroke or TIA
6.2
3.4
<0.001
3.8
3.9
0.65
History of peripheral arterial disease
8.8
4.6
<0.001
5.4
4.9
0.32
Prior MI
23.9
16.9
<0.001
19.1
15.0
<0.001
Prior CABG
12.2
6.9
<0.0001
8.2
6.3
<0.001
Creatinine clearance <60 ml/min/m2
15.2
10.4
<0.001
10.3
13.2
<0.001
Index diagnosis of NSTEMI or UA
85.2
72.1
<0.001
75.2
71.2
<0.001
ACEI/ARB at randomization
68.3
54.1
<0.001
60.8
45.0
<0.001
Beta-blocker at randomization
70.7
74.5
<0.001
77.5
65.5
<0.001
Aspirin at randomization
97.3
96.6
0.12
97.6
94.6
<0.001
Randomized to prasugrel
51.0
49.9
0.36
50.0
50.3
0.70
Values are % or median (interquartile range).
ACEI ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; BMI ¼ body mass index; CABG ¼ coronary artery bypass graft
surgery; CCB ¼ calcium-channel blocker; MI ¼ myocardial infarction; NSTEMI ¼ non–ST-segment elevation myocardial infarction; PCI ¼ percutaneous
coronary intervention; TIA ¼ transient ischemic attack; UA ¼ unstable angina.
a CYP3A4-metabolized statin, and 1,972 (14.5%) were
recorded to be taking a CCB at the time of randomization.
The baseline characteristics for patients who were or were not
taking statins or CCBs are shown in Table 1. The frequency
of use of the different types of CYP3A4-metabolized statins
and CCBs is included in Online Tables 1 and 2.
Patients on a CYP3A4-metabolized statin were more likely
to be younger, male, and have an index diagnosis of a non–
ST-segment elevation ACS compared with patients not on
a statin (Table 1). Subjects treated with a statin were more
likely to have a history of hyperlipidemia, diabetes mellitus,
and prior MI or coronary artery bypass graft surgery, but were
less likely to have a reduced creatinine clearance (Table 1).
Patients treated with a CCB were more likely to be older,
female, and have additional risk factors including hypertension, hyperlipidemia, diabetes, prior MI, family history of
CAD, cerebrovascular disease, peripheral arterial disease,
and congestive heart failure.
Statins and clinical outcomes. For patients randomized to
clopidogrel, the Kaplan-Meier rate of the primary endpoint
through long-term follow-up was similar for patients who
were (11.9%) or were not (12.4%) on a CYP3A4-metabolized statin (unadjusted hazard ratio [HR]: 0.94; 95%
confidence interval [CI]: 0.81 to 1.10; p ¼ 0.43) (Fig. 1).
After multivariable adjustment including the propensity to
be treated with a statin, there remained no significant
association between statin use and the risk of CV death, MI,
or stroke for patients on clopidogrel (adjusted HR: 1.02;
95% CI: 0.85 to 1.22; p ¼ 0.83) (Table 2). Similarly, statin
use was also not associated with an increased risk of CV
death or MI (adjusted HR: 1.02; 95% CI: 0.85 to 1.23;
p ¼ 0.84) (Table 2).
Because patients could start or stop a statin during the
course of follow-up, we examined those clopidogrel-treated
patients who were recorded to be consistently taking
a CYP3A4-metabolized statin both at randomization and at
the end of the study (n ¼ 3,841, 56.5%). The consistent use
of statins was not associated with an increased risk of CV
death, MI, or stroke (adjusted HR: 0.96; 95% CI: 0.74 to
1.25; p ¼ 0.78) or CV death or MI (adjusted HR: 0.95; 95%
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Clopidogrel and Drug Interactions
Figure 1. Risk of CV Events for Clopidogrel-Treated Patients With or
Without a Statin
Unadjusted Kaplan-Meier curves for risk of cardiovascular (CV) death,
myocardial infarction (MI), or stroke for clopidogrel-treated patients who were
(blue line) or were not (red line) on a CYP3A4-metabolized statin at
randomization. The risk of CV events was similar for clopidogrel-treated
patients regardless of background use of a statin.
CI: 0.72 to 1.24; p ¼ 0.70), as compared with those patients
not consistently on a statin.
As a sensitivity analysis, we examined the association
between the use of atorvastatin and the risk of CV events for
patients on clopidogrel, because some studies have only
shown a pharmacodynamic interaction with clopidogrel for
this particular statin type. When atorvastatin was examined
individually, its use was also not associated with an increased
risk of CV death or MI (HR: 1.07; 95% CI: 0.92 to 1.25;
p ¼ 0.39) or stent thrombosis (HR: 0.99; 95% CI: 0.69 to
1.40; p ¼ 0.93) in clopidogrel-treated patients.
The efficacy of prasugrel versus clopidogrel was similar for
patients who were (HR: 0.79; 95% CI: 0.70 to 0.90) or were
not (HR: 0.86; 95% CI: 0.72 to 1.04) on a statin (p for
interaction ¼ 0.43) (Fig. 2). Prasugrel significantly reduced
the risk of stent thrombosis by 48% to 60% for patients who
were (HR: 0.52; 95% CI: 0.37 to 0.74) or were not (HR: 0.40;
95% CI: 0.24 to 0.66) on a statin (p for interaction ¼ 0.39).
CCBs and clinical outcomes. Before multivariable adjustment,
patients on a CCB had a higher risk of CV death, MI, or
stroke through long-term follow-up, regardless of whether
they were on clopidogrel or prasugrel. For patients randomized
to clopidogrel, the rate of the primary endpoint throughout
long-term follow-up was 15.7% for patients on a CCB versus
11.5% for those not a CCB (unadjusted HR: 1.38; 95% CI:
1.15 to 1.65; p ¼ 0.001). However, after adjusting for baseline
differences and the propensity to treat with a CCB, use of
a CCB was no longer associated with an increased risk of CV
death, MI, or stroke in clopidogrel-treated patients (adjusted
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HR: 1.16; 95% CI: 0.94 to 1.43; p ¼ 0.18) or CV death or
MI (adjusted HR: 1.17; 95% CI: 0.93 to 1.45; p ¼ 0.17)
(Table 2).
For those clopidogrel-treated patients who were recorded
to be taking a CCB both at the start and end of the study
(n ¼ 582, 10.5%), the consistent use of CCBs was not
associated with an increased risk of CV death, MI, or stroke
(adjusted HR: 1.06; 95% CI: 0.80 to 1.40; p ¼ 0.71) or CV
death or MI (adjusted HR: 1.02; 95% CI: 0.77 to 1.37;
p ¼ 0.87).
Patients on a CCB had a comparable reduction in CV
death, MI, or stroke with prasugrel versus clopidogrel (HR:
0.87; 95% CI: 0.68 to 1.10), as compared with those patients
not on a CCB (HR: 0.80; 95% CI: 0.71 to 0.90, p for
interaction ¼ 0.55) (Fig. 2). Prasugrel also significantly
reduced the risk of stent thrombosis for patients who were
(HR: 0.30; 95% CI: 0.16 to 0.58) or were not (HR: 0.53;
95% CI: 0.39 to 0.74) on a CCB (p for interaction ¼ 0.13).
Concomitant use of multiple CYP450-metabolized medications.
In the event that a clinical threshold effect may exist for the
pharmacodynamic effects of clopidogrel, we examined CV
risk in those patients who were treated simultaneously with 2
or more medications that have been hypothesized to interfere
with the conversion of clopidogrel to its active metabolite. In
clopidogrel-treated patients, 694 individuals were simultaneously on a CYP3A4-metabolized statin and a CCB at
randomization. Within this group of patients on 2 CYP3A4metabolized medications, there remained no significant
association between combined drug use and the risk of CV
death, MI, or stroke (adjusted HR: 1.19; 95% CI: 0.93 to
1.51), as compared with those patients not on either a statin
or CCB. Similarly, there was not an increased risk of CV
death, MI, or stroke for those patients simultaneously on
atorvastatin 80 mg daily and a CCB (adjusted HR: 0.82; 95%
CI: 0.37 to 1.84).
Only 236 clopidogrel-treated subjects were on a combination of a CCB, statin, and a proton pump inhibitor
at randomization. Within this group of subjects, the
concomitant use of 3 drugs that could interfere with the
hepatic metabolism of clopidogrel was not associated with an
increased risk of CV death, MI, or stroke (adjusted HR:
1.04; 95% CI: 0.70 to 1.54) when compared with patients
on none of these medications.
Discussion
In a large population of patients with ACS, we found that the
use of statins, CCBs, or a combination of both these medications did not appear to interfere with the clinical efficacy
of clopidogrel. These findings are clinically relevant in light
of prior pharmacodynamic studies that have shown conflicting results as to whether statins or CCBs may attenuate
the acute antiplatelet effects of clopidogrel (1–6). Therefore,
Ojeifo et al.
Clopidogrel and Drug Interactions
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Table 2. Kaplan-Meier Event Rates Through Long-Term Follow-Up Stratified by the Use of a Statin or CCB at Randomization for Patients
Treated With Clopidogrel
Statin
CCB
Treated
Not Treated
Adjusted HR
(95% CI)
Treated vs. Nontreated*
Treated
Not Treated
Adjusted HR
(95% CI)
Treated vs. Nontreated
CV death, MI, or stroke
11.9% (542/4,794)
12.4% (239/2,001)
1.02 (0.85–1.22)
15.7% (142/966)
11.5% (639/5,829)
1.16 (0.94–1.43)
CV death or MI
11.0% (503/4,794)
11.7% (225/2,001)
1.02 (0.85–1.23)
14.4% (131/966)
10.7% (597/5,829)
1.17 (0.93–1.45)
Values are % (n/N). Adjusted hazard ratios (HRs) (95% confidence intervals [CI]) reflect the association between subjects treated with a CYP3A4-metabolized statin or calcium-channel blocker (CCB) use (as
compared with those subjects not treated with a CYP3A4-metabolized statin or CCB) and the risk of clinical outcomes after adjusting for potential confounders and the propensity to treat with the drug.
CV ¼ cardiovascular; MI ¼ myocardial infarction.
this information provides important reassurance to clinicians
that these classes of drugs can be safely combined.
Both clopidogrel and prasugrel are pro-drugs that require
biotransformation via the CYP enzyme system to form their
active metabolites. Before undergoing hepatic metabolism,
85% of the clopidogrel pro-drug is converted to inactive
esterases and therefore unable to undergo hepatic metabolism. By contrast, the metabolism of prasugrel appears to be
more efficient because it involves a single CYP-dependent
step, and the pro-drug is not shunted down a dead-end
pathway (10). Although several CYP enzymes contribute to
the 2-step metabolism of clopidogrel, it has been suggested
that the greatest contribution is from the CYP3A4,
CYP3A5, and CYP2C19 isoenzymes (11). Supporting
the concept that CYP3A4 plays a key role in the conversion
of clopidogrel to its active metabolite, CYP3A4 enzyme
activity has been shown to be inversely correlated to the
pharmacodynamic response to clopidogrel (12). Although
the relative contribution of different CYP450 isoenzymes to
the metabolism of clopidogrel remains unclear, 1 in vitro
study using human microsomes containing CYP3A4 and
CYP3A5 suggested that these 2 isoenzymes are primarily
responsible for the conversion of clopidogrel to its active
metabolite (13). A second study demonstrated that the
CYP2C19 isoenzyme contributes substantially to both
bio-oxidative steps, whereas CYP3A4 is integral to the
second bio-oxidative step (11).
Lipophilic statins, including atorvastatin, simvastatin, and
lovastatin, are metabolized by CYP3A4 and therefore compete
with clopidogrel for its substrate. In ex vivo experiments, when
clopidogrel and atorvastatin were exposed in equimolar
amounts to human microsomes containing CYP3A4, clopidogrel metabolism was inhibited by >90% (13). Further,
studies have shown that atorvastatin may attenuate the antiplatelet effects of clopidogrel (1,2). These results were subsequently validated by a prospective randomized trial that
showed an interaction between atorvastatin and a 300-mg (but
not a 600-mg) loading dose of clopidogrel as assessed by lighttransmission aggregometry (3). By contrast, several studies
have since been unable to demonstrate a definitive interaction
between these classes of drugs (7). These discrepancies might
in part be explained by marked differences in study designs,
population size, clopidogrel dosing, platelet function
testing methodology, and concomitant medications (7). To
date, the clinical relevance of these findings has been
evaluated in several observational studies that have failed to
demonstrate that CYP3A4-metabolized statins interfere
with the clinical efficacy of clopidogrel (14–19).
Because of their common requirement for CYP3A4
metabolism, there exists similar concern that CCBs might
Figure 2. Efficacy of Prasugrel Versus Clopidogrel for Patients on a Statin or CCB
The relative efficacy of prasugrel versus clopidogrel for patients on a background of CYP3A4-metabolized statins or calcium-channel blockers (CCBs). Hazard ratios
(HRs) (95% confidence interval [CI]) reflect the relative risk of CV death, MI, or stroke for patients treated with prasugrel as compared with those patients treated with
clopidogrel. Abbreviations as in Figure 1.
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Clopidogrel and Drug Interactions
interact with clopidogrel. This concern is supported by
several studies that have shown that CCBs attenuate the
antiplatelet effects of clopidogrel (4–6). However, as with
statins, some studies have failed to observe a pharmacodynamic interaction between these classes of drugs (20,21). To
date, there exist limited data to determine whether use of
a CCB increases CV risk in clopidogrel-treated patients. In
a Danish registry of patients after MI, patients on a CCB
were observed to have an increased risk of CV events
regardless of whether or not they were treated with clopidogrel, thereby suggesting the increase in risk was likely
explained by unidentified confounders (22). More recently,
there was no evidence of an interaction between clopidogrel
and CCB use in a post hoc analysis of 2,116 subjects in
a randomized trial of 2 dosage regimens of clopidogrel postPCI (23) or in 1,608 subjects after placement of a drugeluting stent (21).
In the current analysis of 13,608 subjects with ACS, we
did not find that CYP3A4-metabolized statins, CCBs, or
concomitant use of both medications attenuated the clinical
efficacy of clopidogrel. Moreover, the combination of
a proton pump inhibitor with 2 CYP3A4-metabolized drugs
also did not demonstrate an increased risk of CV events.
These data represent one of the largest study populations to
address the question of a possible drug–drug interaction
between these classes of drugs. Because the study population
was drawn from a clinical trial database, we were able to
carefully adjust for baseline differences and the propensity to
treat with either a statin or CCB. Although patients on
a CCB were found to be at increased risk of CV events, this
excess in CV risk did not persist after multivariable adjustment in clopidogrel-treated patients; thereby highlighting
that CCB use was associated with a higher-risk patient
population rather than interfering with the efficacy of clopidogrel. Further, the relative efficacy of prasugrel versus
clopidogrel was similar regardless of background use of
statins or CCBs, again suggesting that the clinical efficacy of
clopidogrel was not attenuated in patients prescribed
CYP3A4-metabolized drugs.
Therefore, despite the previously reported in vitro interaction that was observed in some studies between clopidogrel and CYP3A4-metabolized statins or CCBs, we did
not observe concomitant use of these classes of drugs to be
associated with an increased risk of CV events. These
findings highlight that there is still more to learn regarding
the relationship between platelet reactivity and clinical
outcomes. Further, an ex vivo measure of platelet function
may not reliably reflect the in vivo complexity of thrombosis,
inflammation, and endothelial function. Although a pharmacodynamic interaction has been reported for some types
of proton pump inhibitors when combined with clopidogrel
(7), several outcome studies, including an analysis from the
TRITON–TIMI 38 trial, did not confirm an increase in CV
events when these drug classes are combined (24,25). If
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DECEMBER 2013:1275–81
a pharmacodynamic interaction indeed exists between clopidogrel and CCBs or statins, it is plausible that this
interaction is too weak to translate into CV harm (26).
However, we still observed no signal toward increased risk
when multiple drugs that interfere with the CYP450 enzyme
system were combined.
Study limitations. Limitations to the current analysis include
the fact that use of statins and CCBs were not randomized,
thereby increasing the risk of confounding by indication or
by other unassessed variables, and therefore, causality cannot
be definitively determined. However, we performed extensive multivariable adjustment for baseline differences and
included a propensity score to be treated with a statin or
CCB in our models. The use of concomitant medications
was captured at randomization and may have changed
because statins and CCBs could have been started or stopped
during the course of the trial. Because DNA samples were
only available in a subset of the TRITON–TIMI 38 population, our study was insufficiently powered to determine
whether an interaction might exist between CYP3A4metabolized medications and carriers of a reduced-function
CYP2C19 allele. Although loss-of-function variants in the
CYP3A4 gene exist, they are rare.
Conclusions
Overall, in patients with an ACS undergoing PCI, the
clinical efficacy of clopidogrel did not appear to be significantly modified by concomitant CCB and/or statin use.
Further, the use of statins and CCBs did not influence the
relative efficacy or safety of prasugrel as compared with
clopidogrel. Although only a randomized trial can definitively establish the clinical implications of combining statins
or CCBs with clopidogrel, the results of this study do not
support the need to avoid concomitant use of statins or
CCBs in patients receiving clopidogrel.
Reprint requests and correspondence: Dr. Michelle L. O’Donoghue, Cardiovascular Division, Brigham and Women’s Hospital,
TIMI Study Group, 350 Longwood Avenue, 1st Floor, Boston,
Massachusetts 02115. E-mail: [email protected].
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Key Words: clopidogrel - clopidogrel response variability - drug–drug interactions - drug metabolism prasugrel.
APPENDIX
For supplementary tables and expanded Methods section, please see the
online version of this paper.