ORIGINAL CONTRIBUTION
Association of Clopidogrel Treatment
With Risk of Mortality and Cardiovascular Events
Following Myocardial Infarction
in Patients With and Without Diabetes
Charlotte Andersson, MD, PhD
Stig Lyngbæk, MD
Cu Dinh Nguyen, MD
Mia Nielsen, MB
Gunnar H. Gislason, MD, PhD
Lars Køber, MD, DSc
Christian Torp-Pedersen, MD, DSc
P
ATIENTS WITH DIABETES HAVE AN
increased risk of ischemic ad-
verse events and death com-
pared with patients without dia-
betes.1-4 Some of this increase in risk may
relate to platelet hyperreactivity and al-
tered platelet receptor- and intracellular-
signaling pathways; including an up-
regulation of the P2Y12 pathway seen in
patients with diabetes.5 The P2Y12 path-
way is the therapeutic target used for in-
hibition of platelet activation in clopi-
dogrel treatment. Consequently, platelets
in patients with diabetes often display
persistently high platelet reactivity in
spite of clopidogrel treatment, as evalu-
ated by platelet function assays.6,7
High platelet reactivity during steady-
state treatment with clopidogrel has been
shown to increase the risk of major ad-
verse cardiovascular events in patients
with diabetes,8 but the overall clinical ef-
ficacy of clopidogrel treatment in pa-
tients with diabetes is not well investi-
gated. Data from a few randomized
clinical trials comparing dual antiplate-
let therapy with clopidogrel plus aspi-
rin, with aspirin as monotherapy in pa-
For editorial comment see p 921.
882 JAMA, September 5, 2012—Vol 308, No. 9
Downloaded from jamanetwork.com by Gulabi Pavan on 02/02/2024
Context Pharmacodynamic studies have shown that persistently high platelet reac-
tivity is common in patients with diabetes in spite of clopidogrel treatment. Clinical
trials have not convincingly demonstrated that clopidogrel benefits patients with dia-
betes as much patients without diabetes.
Objectives To estimate the clinical effectiveness associated with clopidogrel treat-
ment after myocardial infarction (MI) in patients with diabetes.
Design, Setting, and Patients By individual-level linkage of the Danish nationwide
administrative registries between 2002-2009, patients who were hospitalized with inci-
dent MI and who had survived and not undergone coronary artery bypass surgery 30
days after discharge were followed up for as long as 1 year (maximally until December
31, 2009). Adjusted for age, sex, comorbidity, calendar year, concomitant pharmaco-
therapy, and invasive interventions, hazard ratios that were associated with clopidogrel
in patients with and without diabetes were analyzed by Cox proportional-hazard models
and propensity score−matched models.
Main Outcome Measures All-cause mortality, cardiovascular mortality, and a com-
posite end point of recurrent MI and all-cause mortality.
Results Of the 58 851 patients included in the study, 7247 (12%) had diabetes and
35 380 (60%) received clopidogrel. In total, 1790 patients (25%) with diabetes and 7931
patients (15%) without diabetes met the composite end point. Of these, 1225 (17%)
with and 5377 (10%) without diabetes died. In total, 978 patients (80%) with and 4100
patients (76%) without diabetes died of events of cardiovascular origin. For patients with
diabetes who were treated with clopidogrel, the unadjusted mortality rates (events/100
person-years) were 13.4 (95% CI, 12.8-14.0) vs 29.3 (95% CI, 28.3-30.4) for those not
treated. For patients without diabetes who were treated with clopidogrel, the unadjusted
mortality rates were 6.4 (95% CI, 6.3-6.6) vs 21.3 (95% CI, 21.0-21.7) for those not
treated. However, among patients with diabetes vs those without diabetes, clopidogrel
was associated with less effectiveness for all-cause mortality (HR, 0.89 [95% CI, 0.79-
1.00] vs 0.75 [95% CI, 0.70-0.80]; P for interaction, .001) and for cardiovascular mor-
tality (HR, 0.93 [95% CI, 0.81-1.06] vs 0.77 [95% CI, 0.72-0.83]; P for interaction, .01)
but not for the composite end point (HR, 1.00 [95% CI, 0.91-1.10] vs 0.91 [95% CI,
0.87-0.96]; P for interaction, .08). Propensity score−matched models gave similar results.
Conclusion Among patients with diabetes compared with patients without diabe-
tes, the use of conventional clopidogrel treatment after MI was associated with lower
reduction in the risk of all-cause death and cardiovascular death.
JAMA. 2012;308(9):882-889 www.jama.com
Author Affiliations: Department of Cardiology,
tients at high risk of ischemic events, Gentofte Hospital (Drs Andersson, Lyngbæk, Nguyen,
Gislason, and Torp-Pedersen and Ms Nielsen) and The
have not convincingly demonstrated any Heart Center, Department of Cardiology (Dr Køber),
improvement in prognosis for patients Rigshospitalet, University of Copenhagen, Denmark.
Corresponding Author: Charlotte Andersson, MD, PhD,
with diabetes, as opposed to a clear re- DepartmentofCardiology,GentofteHospital,NielsAnder-
duction in event rates for patients with- sens vej 65, 2900 Hellerup, Denmark (ca@heart.dk).
©2012 American Medical Association. All rights reserved.

out diabetes, although no interactions
were presented.9-11
Currently,therearethienopyridineana-
loguesavailableonthemarketforsecond-
ary prevention of myocardial infarction
(MI) other than clopidogrel. Both prasu-
grel and ticagrelor have shown to cause
a greater inhibition of the P2Y12 pathway
than clopidogrel but have also shown to
cause more bleedings.12,13 Because future
selectionofantithromboticagentsmayde-
pend on the presence of diabetes, we ana-
lyzed the outcomes associated with clopi-
dogrel treatment after MI in patients with
andwithoutdiabetesusingthenationwide
administrative health care related regis-
tries available in Denmark.
METHODS
Registries
Danish health care is based on a tax-
financed system that provides all citi-
zens with equal access. Because indi-
viduals are given a personal and
permanent civil registration number at
the time of birth or immigration, ad-
ministrative nationwide registries al-
low data retrieval at the individual level.
All hospitalizations and invasive pro-
cedures have been registered since 1978
in the Danish National Patient Register.
Information includes dates and dis-
charge diagnoses (1 main diagnosis and
any bidiagnoses) registered according to
the International Classification of Dis-
eases (ICD) system. The MI diagnosis has
been validated with good sensitivity,
specificity, and positive predictive val-
ues.14 Dispensed prescriptions have con-
secutively been registered according to
the Anatomical Therapeutic Chemical
(ATC) classification system in the Dan-
ish Register of Medicinal Product Statis-
tics since 1995. The registry includes data
on amount and strength of dispensed tab-
lets as well as dispensing dates, which has
been shown to be accurate.15
All death certificates are registered in
the Danish National Causes of Deaths
register on immediate and contribut-
ing causes of deaths. The Danish Na-
tional Population registry updates in-
formation on vital status on all Danish
residents, and deaths are registered no
more than 2 weeks after occurrence.
©2012 American Medical Association. All rights reserved.
Downloaded from jamanetwork.com by Gulabi Pavan on 02/02/2024
CLOPIDOGREL, MORTALITY, CVD EVENTS, AND DIABETES
Population and Study
Outcome Measures
Through individual-level linkage of the
administrative registries, all patients who
were hospitalized with incident MI be-
tween 2002 and 2009 (main diagnoses;
ICD-10 codes I21 and I22) were identi-
fied. Study start was defined as 30 days
after discharge from index MI. This quar-
antine period was necessary to allow pa-
tients time for claiming a prescription for
clopidogrel and concomitant pharma-
cotherapy, thereby avoiding immortal-
time bias. Patients who had received a
coronary artery bypass graft (CABG) sur-
gery during this period were excluded be-
cause patients undergoing the proce-
dure are prone to stop clopidogrel
treatment after surgery.16
The following end points were de-
fined: all-cause mortality, cardiovascu-
lar mortality (immediate or contribut-
ing cause of death; ICD-10 code I00-
I99), and a combination of all-cause
mortality and recurrent MI (ICD-10 code
I21-I22). For analyses of the respective
end points, patients were followed up for
no longer than 365 days from study start
and were censored after 365 days, at the
time of an event, or at the end of 2009.
Comorbidity, Concomitant
Pharmacotherapy,
and Invasive Treatment
Comorbidity, defined as in the Ontario
acutemyocardialinfarctionmortalitypre-
diction rules,17 was identified by desig-
nated diagnoses at discharge from the in-
dex hospitalization and from other hos-
pitalizations up to a year before MI.
However, heart failure was not based on
hospitalizationdiagnosesbecauseofavery
low sensitivity in the registries (29%).18
Instead, loop diuretic dosages (ATC code
C03C) used at study baseline (ie, 30 days
after discharge) were used as a proxy for
heartfailureandheartfailureseverity.This
method has been used previously and has
shown to correlate well with New York
HeartAssociationfunctionalclassandthe
risk of mortality in patients with MI and
heart failure.19,20 Mean dosages were cal-
culated by dividing the amount of dis-
pensed tablets with the dispensing time
intervals, as described previously.19 Base-
line use and persistence rates of clopido-
grel(ATCcodeB01AC04)treatmentwere
also calculated by this method.21
Concomitant pharmacotherapy was
defined as at least 1 claimed prescrip-
tion of a specific agent between 90 days
prior to index hospitalization and 30 days
after discharge (ATC codes: ␤-blockers,
C07; statins, C10A; renin–angiotensin
system [RAS] inhibitors, C09; thia-
zides, C03A; spironolactone or epler-
enone, C03D; calcium-channel block-
ers, C08; digoxin, C01AA05; vitamin K
antagonists, B01AA0; aspirin, B01AC06;
metformin, A10BA02; sulfonylureas,
A10BB; and insulin, A10A). In accor-
dance with previous work,4 diabetes was
defined as at least 1 claimed prescrip-
tion of glucose-lowering medications
(ATC A10); for the present study at any
time between 90 days prior to hospital-
ization and 30 days after discharge.
Treatment with percutaneous coro-
nary intervention (PCI; procedure codes,
KFNG [Nordic classification system of
operations]) was identified as early (day
0-1) and late (days 2-30) after index MI.
Ethics
The study was approved by The Dan-
ish Data Protection Agency. Registries
were available at Statistics Denmark in
an anonymous set-up, disabling identi-
fication of individuals but enabling in-
dividual-level linkage between regis-
tries. In Denmark, retrospective registry-
based studies do not need ethical
approval or participant informed con-
sent. The Danish Data Protection Agency
has approved our use of registries.
Statistics
Tests for differences in baseline charac-
teristics between clopidogrel and non–
clopidogrel-treated individuals were per-
formed with ␹2 and t tests for discrete and
continuous variables, respectively. Mul-
tivariable Cox-proportional regression
analyses were used to calculate the haz-
ard ratios associated with clopidogrel
treatment in patients with and without
diabetes. Two different dummy vari-
ables according to clopidogrel treat-
ment were created; 1 for patients with
diabetes and 1 for patients without dia-
JAMA, September 5, 2012—Vol 308, No. 9 883
 CLOPIDOGREL, MORTALITY, CVD EVENTS, AND DIABETES
betes; enabling the whole population to
be analyzed in the same model. All mod-
els were adjusted for age, sex, concomi-
tant pharmacotherapy, heart failure se-
verity group, calendar year, average
income in a 5-year period prior to hos-
pitalization, comorbidity, PCI treat-
ment day 0 through 1, and PCI treat-
ment days 2 through 30. Tests for
differences in outcomes associated with
clopidogrel treatment in patients with
and without diabetes were performed by
inclusion of an interaction term in the
overall model. All tests were 2-sided and
P ⬍.05 was considered statistically
significant.
To ensure robustness of our findings,
additional propensity-based subgroup
analyseswereperformed.Inthese,patients
using clopidogrel were matched with pa-
tients not using clopidogrel (1:1) on all
baselinecharacteristicsfromTABLE 1using
the Greedy matching macro (http:
//mayoresearch.mayo.edu/mayo/research
/biostat/upload/gmatch.sas; accessed on
August 15, 2011). Finally, to ensure that
numbers were not affected by the use of
a 30-day quarantine period, all main
analyses were repeated with the use of a
7-day quarantine period. Cumulative in-
cidence curves and graphs over persis-
tence rates were generated using
the Kaplan-Meier method and test
for differences between strata were done
by log-rank test. Persistence curves were
divided into 2 periods because recom-
mended treatment length with clopido-
grel was changed from 6 months in 2002-
2003 to 12 months in 2004.22
All analyses were performed using
SAS version 9.2 (SAS Institute Inc).
RESULTS
Of the 58 851 patients—7247 of whom
(12%) had diabetes—who were in-
cluded in the analyses, 35 380 (60%) re-
ceived clopidogrel at study baseline.
Characteristics of patients with and with-
out diabetes stratified by clopidogrel
treatment are shown in Table 1. For both
groups, clopidogrel users were younger,
more often men, had lower prevalence
of comorbidity, and less often had heart
failure than the nonclopidogrel users.
Persistence rates of clopidogrel treat-
884 JAMA, September 5, 2012—Vol 308, No. 9
Downloaded from jamanetwork.com by Gulabi Pavan on 02/02/2024
ment were comparable in patients with
and without diabetes, eFigure 1 (avail-
able at http://www.jama.com).
Outcomes Associated With
Clopidogrel Treatment
Patients were followed up for a median
of 365 days (range, 0-365 days). In total,
1790 patients (25%) with and 7931 pa-
tients (15%) without diabetes met the
compositeendpoint.Ofthese,1225(17%)
with and 5377 (10%) without diabetes
died. In all, 978 patients (80%) with and
4100patients(76%)withoutdiabetesdied
because of cardiovascular-related events.
Crude incidence rates for the 3 de-
fined end points in patients with and
without diabetes stratified by clopido-
grel treatment are shown in TABLE 2.
Of patients with diabetes, those who
took clopidogrel had an all-cause mor-
tality per 100 person-years of 13.4 (95%
CI, 12.8-14.0) and those who were not
taking clopidogrel had an all-cause rate
of 29.3 (95% CI, 28.3-30.4). Of pa-
tients who did not have diabetes, those
who took clopidogrel had an all-cause
mortality of 6.4 (95% CI, 6.3-6.6) and
those who did not take clopidogrel had
an all-cause mortality of 21.3 (95% CI,
21.0-21.7). Adjusted for other vari-
ables (hazard ratios [HRs] associated
with other predictive variables are
shown in the eFigure 2), patients with
diabetes were found to have a smaller
relative risk reduction than patients
without diabetes (FIGURE 1).
Whenadjusted,thisfindingappliedfor
theall-causemortalityendpoint(HR,0.89
[95% CI, 0.79-1.00] for patients with dia-
betes vs HR, 0.75 [95% CI, 0.70-0.80] for
patients without diabetes, P for interac-
tion, .001) and the cardiovascular mor-
tality end point (HR, 0.93 [95% CI, 0.81-
1.06] for patients with vs HR, 0.77 [95%
CI, 0.72-0.83] for patients without dia-
betes, P for interaction, .01), but not for
the composite end point (HR, 1.00 [95%
CI, 0.91-1.10] vs 0.91 [0.87-0.96] P for
interaction,.08). Stratified according to
PCI treatment, similar (nonsignificant)
trends were seen for patients treated with
PCI and for those treated with colopido-
grel (FIGURE 2). There was no evidence
of a similar differential effectiveness as-
©2012 American Medical Association. All rights reserved.
sociated with aspirin treatment among
patients with and without diabetes (P for
interactions: .77 for all-cause mortality,
.67 for cardiovascular, and .66 for the
combined end point).
In subanalyses, there was no evi-
dence toward a differential effective-
ness of clopidogrel in patients with dia-
betes treated with and without
metformin (P for interactions: .63 for all-
cause mortality, .37 for cardiovascular
mortality, and .63 for the combined end
point), or with and without insulin (P for
interactions: .43 for all-cause mortality,
.34 for cardiovascular mortality, and .51
for the combined end point).
The propensity score−matching iden-
tified 4010 patients with diabetes, 2005
ofwhomweretreatedwithclopidogreland
2005 were not and found 22 820 patients
who did not have diabetes, 11 410 of
whom were treated with clopidogrel and
11 410 who were not. C statistics for
propensity-score models were 0.80 for
those with and 0.85 for those without dia-
betes. Baseline characteristics were com-
parable between patients treated with
clopidogrel and those who were not
(eTable). Similar to the main analysis,
these analyses revealed a diminished ef-
fectiveness associated with clopidogrel
treatment in patients with diabetes;
FIGURE 3.
Sensitivity Analysis
Starting the analyses only 7 days after dis-
charge instead of 30 days provided simi-
larresults.Hazardratiosforall-causemor-
tality for clopidogrel treatment were 0.80
(95% CI, 0.76-0.84) for patients with vs
0.62(95%CI,0.59-0.66)forpatientswith-
out diabetes (P for interaction, ⬍.001);
for cardiovascular mortality, 0.82 (95%
CI, 0.72-0.92) for patients with vs 0.62
(95% CI, 0.58-0.67) for patients without
diabetes(Pforinteraction,.0001);andfor
the combined end point, 0.80 (95% CI,
0.74-0.88) for patients with vs 0.72 (95%
CI, 0.69-0.75) for patients without dia-
betes (P for interaction, .02).
COMMENT
Using a cohort of nearly 60 000 patients
withfirst-timeMIbetween2002and2009,
the present analysis demonstrated a re-
 CLOPIDOGREL, MORTALITY, CVD EVENTS, AND DIABETES

duced 1-year clinical effectiveness asso- Clinical Effectiveness of Clopidogrel all-causemortalityinpatientswithoutdia-

ciated with clopidogrel treatment in pa-
tients with diabetes. This supports pre-
vious knowledge of platelets in diabetes
showing high platelet reactivity and di-
minished responsiveness to standard
clopidogrel treatment.
Treatment in Diabetes
In the present analysis, clopidogrel treat-
ment was associated with a relative risk
reduction of 25% for all-cause mortality,
23% for cardiovascular mortality, and 9%
for the combination of recurrent MI and
betes, and a relative risk reduction of 11%
for all-cause mortality but no significant
reduction in cardiovascular mortality or
the combined end point in patients with
diabetes.Thesenumberscorrespondwell
with the findings from randomized clini-

Table 1. Baseline Characteristics

Diabetes (n = 7247) No Diabetes (n = 51 604)
P Value for P Value for
Clopidogrel No Clopidogrel Difference Clopidogrel No Clopidogrel Difference
Total No. (%) of patients 4078 (56) 3169 (44) ⬍.001 31 302 (61) 20 302 (39) ⬍.001
Men, No. (%) 2615 (64) 1827 (58) ⬍.001 21 106 (67) 11 069 (55) ⬍.0001
Age, median (IQR), y 69 (60-78) 75 (65-82) ⬍.001 67 (57-77) 75 (63-83) ⬍.001
Average 5-y income, thousand kr, 136 (102-215) 121 (98-179) ⬍.001 170 (113-269) 129 (100-210) ⬍.001
median (IQR)
Year of hospitalization, No. (%)
2002-2003 828 (20) 1171 (37) 6282 (20) 8212 (40)
2004-2005 1078 (26) 792 (25) 8477 (27) 4989 (25)
⬍.001 ⬍.001
2006-2007 1086 (27) 636 (20) 8557 (27) 3726 (18)
2008-2009 1086 (27) 570 (18) 7987 (26) 3374 (17)
Comorbidity, No. (%)
A history of ischemic heart 1019 (25) 811 (26) .56 6400 (20) 4196 (21) .54
disease
COPD 240 (6) 286 (9) ⬍.001 1507 (5) 1865 (9) ⬍.001
Cerebral vascular disease 218 (5) 321 (10) ⬍.001 977 (3) 1466 (7) ⬍.001
Atrial fibrillation 303 (7) 462 (15) ⬍.001 1709 (6) 2498 (12) ⬍.001
Pulmonary edema 55 (1) 66 (2) .02 168 (0.5) 286 (1.4) ⬍.001
Peripheral vascular occlusive 124 (3) 177 (6) ⬍.001 283 (1) 343 (2) ⬍.001
disease
Cancer, any etiology 44 (1) 86 (3) ⬍.001 300 (1) 614 (3) ⬍.001
Renal disease 156 (4) 210 (7) ⬍.001 395 (1) 654 (3) ⬍.001
Heart failure severity
No heart failure, no loop diuretics 2346 (58) 1444 (46) 24 506 (78) 12 978 (64)
Mild heart failure, furosemide 453 (11) 407 (13) 2146 (7) 2132 (11)
ⱕ40 mg/d
Moderate heart failure, 623 (15) 570 (18) ⬍.001 2775 (9) 2719 (13) ⬍.001
furosemide ⬎40-80 mg/d
Severe heart failure, furosemide 250 (6) 283 (9) 895 (3) 1202 (6)
⬎80-159 mg/d
Very severe heart failure, 406 (10) 465 (15) 981 (3) 1270 (6)
furosemide ⱖ160 mg/d
Invasive treatment, No. (%)
PCI day 0-1 1127 (28) 157 (5) ⬍.001 12 698 (41) 1608 (8) ⬍.001
PCI day 2-30 1042 (26) 144 (5) ⬍.001 7846 (25) 1193 (6) ⬍.001
Concomitant pharmacotherapy, No. (%)
Aspirin 3218 (79) 2137 (67) ⬍.001 26 016 (83) 12 352 (61) ⬍.001
␤-Blockers 3450 (85) 2180 (69) ⬍.001 27 362 (87) 13 239 (65) ⬍.001
Calcium channel blockers 1394 (34) 1101 (35) .62 6738 (22) 4977 (25) ⬍.001
ACE-inhibitors and angiotensin 3198 (78) 2232 (70) ⬍.001 16 379 (52) 8936 (44) ⬍.001
II-blockers
Statins 3638 (89) 2107 (66) ⬍.001 28 196 (90) 10 858 (54) ⬍.0001
Thiazides 910 (22) 679 (21) .40 5164 (17) 4013 (20) ⬍.001
Spironolactone 550 (13) 590 (19) ⬍.001 2028 (6) 2116 (10) ⬍.001
Warfarin 317 (8) 413 (13) ⬍.001 1657 (5) 2133 (11) ⬍.001
Metformin 1842 (45) 1170 (37) ⬍.001
Insulin 1646 (40) 1352 (43) .05
Sulfonylureas 2049 (50) 1699 (54) ⬍.01
Abbreviations: ACE, angiotensin-converting enzyme; COPD, chronic obstructive pulmonary disease; PCI, percutaneous coronary intervention.

©2012 American Medical Association. All rights reserved. JAMA, September 5, 2012—Vol 308, No. 9 885

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 CLOPIDOGREL, MORTALITY, CVD EVENTS, AND DIABETES

cal trials, supporting the validity of our
registry-based analyses.10,11 Because pre-
vious randomized clinical trials were not
designed to investigate the relative effi-
cacy of standard clopidogrel treatment in
patients with diabetes, it has been impos-
sible to conclude definitively whether a
statistically significant diminished effec-
tivenessofclopidogreltreatmentispresent
for patients with diabetes or whether pre-
vious findings may be due to chance and
small numbers of patients in the diabe-
tes subgroups. This study supports the
conclusion that there may be a difference
of effect of clopidogrel among those with
diabetes compared with those without it.
Two large randomized clinical trials
investigating the long-term outcomes
of clopidogrel for patients at high risk of
cardiovascular events have presented
subgroup analyses of patients with dia-
betes, and neither of them have demon-
strated any clear beneficial effect of clopi-
dogrel treatment. The Clopidogrel for the
Reduction of Events During Observa-
tion (CREDO) trial evaluated the effect
of 75 mg of clopidogrel over placebo on
1-year incidence of the composite of
death, MI, or stroke in 2116 patients who
were planned for elective PCI or who had
a high likelihood of undergoing PCI.10
Subgroup analyses revealed no signifi-
cant effect of clopidogrel in the diabetes
subgroup (n=560; relative risk reduc-
tion, 11.2% [95% CI, −46.8% to 46.2%])
as opposed to a clear risk-reducing ef-
fect of clopidogrel in the nondiabetes
subgroup (relative risk reduction, 32.8%
[6.8%-51.6%]).10

Table 2. Unadjusted Incidence Rates a

Diabetes No Diabetes

Clopidogrel No Clopidogrel Clopidogrel No Clopidogrel

All-cause mortality
Events/total, No. (%) 472/4078 (12) 753/3169 (24) 1816/31 302 (6) 3661/20 302 (18)
Person-years 3518 2566 28 183 17 156
Crude incidence rates 13.4 (12.8-14.0) 29.3 (28.3-30.4) 6.4 (6.3-6.6) 21.3 (21.0-21.7)
Cardiovascular mortality
Events/total, No. (%) 388/4078 (10) 590/3169 (19) 1390/31 302 (4) 2710/20 302 (13)
Person-years 3518 2566 28 183 17 156
Crude incidence rates 11.0 (10.5-11.6) 23.0 (22.0-23.9) 4.9 (4.8-5.1) 15.8 (15.5-16.1)
Combined end point
Events/total, No. (%) 768/4078 (19) 1022/3169 (32) 3226/31 302 (10) 4705/20 302 (23)
Person-years 3305 2365 27 189 16 380
Crude incidence rates 23.2 (22.4-24.1) 43.2 (41.9-44.6) 11.9 (11.7-12.1) 28.7 (28.3-29.1)
PCI treated subgroup
All-cause mortality
Events/total, No. (%) 113/2183 (5) 33/303 (11) 530/20 595 (3) 201/2810 (7)
Person-years 1943 260 18 872 2468
Crude incidence rates 5.8 (5.3-6.4) 12.7 (10.5-14.9) 2.8 (2.7-2.9) 8.1 (7.6-8.7)
Cardiovascular mortality
Events/total, No. (%) 91/2183 (4) 30/303 (10) 380/20 595 (2) 164/2810 (6)
Person-years 1943 260 18 872 2468
Crude incidence rates 4.7 (4.2-5.2) 11.5 (9.4-13.6) 2.0 (1.9-2.1) 6.6 (6.1-7.2)
Combined end point
Events/total 183/2183 (8) 55/303 (18) 1067/20 595 (5) 283/2810 (10)
Person-years 1896 247 18 515 2406
Crude incidence rates 9.7 (8.9-10.4) 22.3 (19.3-25.3) 5.8 (5.6-5.9) 11.8 (11.1-12.5)
Medically treated subgroup
All-cause mortality
Events/total, No. (%) 359/1895 (19) 720/2866 (25) 1286/10 707 (12) 3460/17 492 (20)
Person-years 1574 2306 9310 14 688
Crude incidence rates 22.8 (21.6-24.0) 31.2 (30.1-32.4) 13.8 (13.4-14.2) 23.6 (23.2-24.0)
Cardiovascular mortality
Events/total, No. (%) 297/1895 (16) 560/2866 (20) 1010/10 707 (9) 2546/17 492 (15)
Person-years 1574 2306 9310 14 688
Crude incidence rates 18.9 (17.8-20.0) 24.3 (23.3-25.3) 10.8 (10.5-11.2) 17.3 (17.0-17.7)
Combined end point
Events/total, No. (%) 585/1895 (31) 967/2866 (34) 2159/10 707 (20) 4422/17 492 (25)
Person-years 1409 2118 8674 13 973
Crude incidence rates 41.5 (39.8-43.2) 45.7 (44.2-47.1) 24.9 (24.4-25.2) 31.6 (31.2-32.1)
Abbreviation: PCI, percutaneous intervention.
a Crude incidence rates are based on the number of events per 100 person-years. Combined end point refers to the first occurring of recurrent myocardial infarction or all-cause
mortality.

886 JAMA, September 5, 2012—Vol 308, No. 9 ©2012 American Medical Association. All rights reserved.

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 CLOPIDOGREL, MORTALITY, CVD EVENTS, AND DIABETES

The Clopidogrel for High Athero-
thrombotic Risk and Ischemic Stabili-
zation, Management, and Avoidance
(CHARISMA) trial enrolled 15 603 high-
risk patients without acute coronary syn-
drome, but with clinically evident car-
diovascular disease or multiple risk
factors.9 The study compared the effi-
cacy of 75 mg of clopidogrel to placebo
in addition to low-dose aspirin (75-
162 mg) on the risk of a composite end
point of stroke, MI, or cardiovascular
death.9 The trial showed no benefit of
75 mg of clopidogrel during 28 months
of follow-up. Interestingly, however,
subgroup analyses showed a clear trend
toward a risk-reducing effect of clopi-
dogrel in the nondiabetic subgroup as
opposed to a neutral outcome in the dia-
betes subgroup. Because diabetes was
prevalent in 43% of the total study popu-
lation, it may be speculated that exclu-
sion of patients with diabetes prior to en-
rollment would have resulted in a
significantly greater efficacy of clopido-
grel than aspirin.
Perspectives
and Clinical Implications
Current US guidelines recommend 12
than enhanced effects of prasugrel in
this particular subgroup.25 In this con-
text, prasugrel treatment has shown to
cause greater inhibition of platelet ag-
gregation and a lower rate of nonre-
sponders than clopidogrel.26
Although more study is needed, pra-
sugrel may constitute an attractive al-
ternative to clopidogrel in patients with
diabetes with acute coronary syn-
dromes, especially if recurrent ische-
mic events have occurred during clopi-
dogrel treatment. This is congruent with
recent European guidelines that rec-
ommend ticagrelor or prasugrel use be-
fore clopidogrel in acute coronary syn-
dromes.27 It is however still unknown
whether prasugrel and high doses of
Figure 1. Risk of Mortality and Recurrent Myocardial Infarction Among Patients With and
Without Diabetes After First-Time Myocardial Infarction and Based on Treatment
HR (95% CI)
All-cause mortality
No diabetes 0.75 (0.70-0.80)
Diabetes 0.89 (0.79-1.00)
Cardiovascular mortality
No diabetes 0.77 (0.72-0.83)
Diabetes 0.93 (0.81-1.06)
Combined end point
No diabetes 0.91 (0.87-0.96)
Diabetes 1.00 (0.91-1.10)
clopidogrel have comparable clinical ef-
ficacy in patients with diabetes be-
cause randomized studies with hard end
points comparing these 2 combina-
tions do not exist. Platelet inhibition
with high-dose clopidogrel (150 mg)
has been compared with standard
dose prasugrel (10 mg) in a cohort of
patients with planned PCI (30% of
whom had diabetes). In this study, pra-
sugrel was associated with more con-
sistent levels of platelet inhibition than
clopidogrel treatment, which may sup-
port the choice of prasugrel use before
clopidogrel for patients with diabetes,
but more studies are needed to estab-
lish the optimal antiplatelet treatment
strategy.28
Favors
Clopidogrel
Favors
No Clopidogrel
P for
Interaction
.001
.01
.08

months of dual platelet inhibition with 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4
a thienopyridine analogue (clopido- Hazard Ratio (95% CI)
grel or prasugrel) and aspirin after acute
coronary syndromes to prevent recur-
rent ischemic events but do not en- Figure 2. Adjusted Hazard Ratios Associated With Clopidogrel Treatment Stratified After PCI
Treatment
dorse one thienopyridine analogue over
another.23,24 The guidelines acknowl- No. of Events/Total No. of Patients
Favors Favors
edge the superiority of prasugrel over Clopidogrel No clopidogrel Clopidogrel No Clopidogrel
clopidogrel for reduction of adverse All-cause mortality
Medically treated
events overall but also emphasize the No diabetes 1286/10 707 3460/17 492
increased risk of bleedings associated Diabetes 359/1895 720/2866
PCI treated
with treatment with prasugrel.23,24 No diabetes 530/20 595 201/2810
Data from the Trial to Assess Im- Diabetes 113/2183 33/303
Cardiovascular mortality
provement in Therapeutic Outcomes by Medically treated
Optimizing Platelet Inhibition With No diabetes 1010/10 707 2546/17 492
Diabetes 297/1895 560/2866
Prasugrel-Thrombolysis in Myocar- PCI treated
dial Infarction 38 (TRITON-TIMI 38), No diabetes 380/20 595 164/2810
Diabetes 91/2183 30/303
a randomized clinical trial comparing Combined end point
clopidogrel with prasugrel after MI, in- Medically treated
No diabetes 2159/10 707 4422/17 492
dicated that treatment with prasugrel Diabetes 585/1895 967/2866
may have a greater clinical benefit in PCI treated
No diabetes 1067/20 595 283/2810
patients with diabetes compared with Diabetes 183/2183 55/303
patients without diabetes, which—
0.2 0.5 1.0 2.0
although speculative—could relate to Hazard Ratio (95% CI)
a limited effect of clopidogrel rather
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 CLOPIDOGREL, MORTALITY, CVD EVENTS, AND DIABETES

Limitations rather high mortality rates found in the enced the findings. Furthermore, no in-
We acknowledge that no definite con- present analyses compared with those formation was available on smoking
clusions on causal mechanisms can be seen in randomized trials, but it cannot status, which may influence the effi-
drawn from observational studies. Al- be excluded that some of the findings cacy of clopidogrel.29 Finally, the use of
though several differences between pa- may have related to confounding by in- loop diuretics as a proxy of heart failure
tients receiving and not receiving clopi- dication. Specifically, data on stents and and heart failure severity also com-
dogrel could be identified and adjusted stent types, body mass index, hematol- prises a limitation of the present study.
for in the present analyses, unmea- ogy and blood biochemistry, and left ven-
sured confounders may have influ- tricular ejection fraction were not avail- CONCLUSIONS
enced the results. Contrary to random- able, which—despite propensity In summary, data from previous clini-
ized clinical trials, the study population score−matched subgroup analyses re- cal trials and data from the present analy-
was unselected, which may explain the vealing similar results—may have influ- ses strongly suggest that patients with

Figure 3. Survival Curves of Patients With and Without Diabetes by Propensity-Score Matched Subgroup

No diabetes Diabetes

0.20 All-cause mortality All-cause mortality

Cumulative Mortality

0.15
Clopidogrel
Nonuser
0.10 User

0.05
P for difference < .0001 P for difference = .24
0
0 90 180 270 365 0 90 180 270 365
No. at risk Time, d Time, d
Nonuser 11 410 10 425 9777 9178 8680 2005 1782 1621 1516 1410
User 11 410 10 699 10 110 9635 9125 2005 1804 1685 1584 1456

0.20 Cardiovascular mortality Cardiovascular mortality

Cumulative Mortality

0.15

0.10

0.05
P for difference < .0001 P for difference = .74
0
0 90 180 270 365 0 90 180 270 365
No. at risk Time, d Time, d
Nonuser 11 410 11 425 9777 9178 8680 2005 1782 1621 1516 1410
User 11 410 11 669 10 110 9635 9125 2005 1804 1685 1584 1456

0.30 Combined end point Combined end point

0.25
Cumulative Mortality

0.20

0.15

0.10

0.05
P for difference < .01 P for difference = .90
0
0 90 180 270 365 0 90 180 270 365
Time, d Time, d
No. at risk
Nonuser 11 410 10 013 9263 8618 8089 2005 1658 1476 1351 1241
User 11 410 10 154 9491 8933 8378 2005 1669 1507 1442 1258

Kaplan-Meier curves for patients with and without use of clopidogrel: propensity score−matched sub-group analyses. C statistics for propensity-score models were 0.80 for
patients with diabetes and 0.85 for patients without diabetes. Diabetes-subgroup comprised 2005 clopidogrel-treated patients and 2005 non–clopidogrel-treated patients;
the nondiabetes subgroup comprised 11 410 clopidogrel-treated patients and 11 410 non–clopidogrel-treated patients. P for interaction was obtained from adjusted Cox re-
gression models between diabetes and nondiabetes subgroups: 0.02 for all-cause mortality, 0.01 for cardiovascular-related mortality, 0.09 for the combination end points.

888 JAMA, September 5, 2012—Vol 308, No. 9 ©2012 American Medical Association. All rights reserved.

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diabetes have a significantly dimin-
ished relative effectiveness of conven-
tional platelet-inhibition with clopido-
grel after MI compared with patients
without diabetes. It should however be
emphasized that considering the rela-
tively higher absolute risks found for pa-
tients with diabetes, use of clopidogrel
may still translate into a significant re-
duction in event rates for patients with
diabetes, which data from the sub-
group analyses supported. Available data
nevertheless raise a possibility that pa-
tients with diabetes may benefit from a
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CLOPIDOGREL, MORTALITY, CVD EVENTS, AND DIABETES
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to achieve a relative risk reduction simi-
lar to patients without diabetes.25
Author Contributions: Dr Anderson had full access to all
of the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data analysis.
Study concept and design: Lyngbaek, Gislason,
Torp-Pedersen, Andersson.
Analysis and interpretation of data: Lyngbaek, Nguyen,
Nielsen, Gislason, Køber, Torp-Pedersen, Andersson.
Drafting of the manuscript: Lyngbaek, Andersson.
Critical revision of the manuscript for important in-
tellectual content: Lyngbaek, Nguyen, Nielsen,
Gislason, Køber, Torp-Pedersen, Andersson.
Statistical analysis: Køber, Torp-Pedersen, Andersson.
Obtained funding: Torp-Pedersen.
Administrative, technical, or material support:
Torp-Pedersen.
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Conflict of Interest Disclosures: All authors have com-
pleted and submitted the ICMJE Form for Disclosure of
Potential Conflicts of Interest. Dr Køber reported that
he has received honorarium as speaker for Servier. Dr
Torp-Pedersen reported that he has served on advi-
sory boards and served on study steering committees
for Cardiome, Sanofi, and Merck; and has obtained re-
search grants from Bristol-Myers Squibb, and Sanofi. Dr
Andersson reported receiving a month’s salary for work
on the study.
Funding/Support: The study was founded by an in-
ternal research foundation at Department of Cardi-
ology, Gentofte Hospital.
Role of the Sponsor: The foundation had no influence
on design and conduct of the study; collection, man-
agement, analysis, and interpretation of the data; and
preparation, review, or approval of the manuscript.
Online-Only Material: The eTable and eFigures are
available at http://www.jama.com.
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