Published online before print August 31, 2008, doi: 10.1161/CIRCULATIONAHA.108.791061
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(Circulation. 2008;118:1626-1636.)
© 2008 American Heart Association, Inc.
Coronary Heart Disease |
Greater Clinical Benefit of More Intensive Oral Antiplatelet Therapy With Prasugrel in Patients With Diabetes Mellitus in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38
From the TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass (S.D.W., E.B., S.A.M. C.H.M., E.M.A.); University of Florida College of Medicine, Jacksonville (D.J.A.); Hillel Yaffe Medical Center, Hadera, Israel (S.M.); St Michael’s Hospital, University of Toronto, and Canadian Heart Research Center, Toronto, Ontario, Canada (S.G.G.); Millpark Hospital, Johannesburg, South Africa (A.J.D.); Department of Cardiology, University Hospital Nijmegen, Nijmegen, the Netherlands (F.W.A.V.); Department of Cardiology, Catholic University School of Medicine, Santiago, Chile (R.C.); and Black Hills Cardiovascular Research Group, Black Hills, SD (D.A.P.).
Reprint requests to Dr S.D. Wiviott, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail swiviott{at}partners.org
Received May 7, 2008; accepted August 7, 2008.
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Abstract |
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Background— Patients with diabetes mellitus (DM) are at high risk for recurrent cardiovascular events after acute coronary syndromes, in part because of increased platelet reactivity. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) showed an overall reduction in ischemic events with more intensive antiplatelet therapy with prasugrel than with clopidogrel but with more bleeding. We compared prasugrel with clopidogrel among subjects with DM in TRITON-TIMI 38.
Methods and Results— We classified 13 608 subjects on the basis of preexisting history of DM and further according to insulin use. Prespecified analyses of the primary (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and key secondary end points, including net clinical benefit (death, nonfatal myocardial infarction, nonfatal stroke, and nonfatal TIMI major bleeding) were compared by use of the log-rank test. We found that 3146 subjects had a preexisting history of DM, including 776 receiving insulin. The primary end point was reduced significantly with prasugrel among subjects without DM (9.2% versus 10.6%; hazard ratio [HR], 0.86; P=0.02) and with DM (12.2% versus 17.0%; HR, 0.70; P<0.001, Pinteraction=0.09). A benefit for prasugrel was observed among DM subjects on insulin (14.3% versus 22.2%; HR, 0.63; P=0.009) and those not on insulin (11.5% versus 15.3%; HR, 0.74; P=0.009). Myocardial infarction was reduced with prasugrel by 18% among subjects without DM (7.2% versus 8.7%; HR, 0.82; P=0.006) and by 40% among subjects with DM (8.2% versus 13.2%; HR, 0.60; P<0.001, Pinteraction=0.02). Although TIMI major hemorrhage was increased among subjects without DM on prasugrel (1.6% versus 2.4%; HR, 1.43; P=0.02), the rates were similar among subjects with DM for clopidogrel and prasugrel (2.6% versus 2.5%; HR, 1.06; P=0.81, Pinteraction=0.29). Net clinical benefit with prasugrel was greater for subjects with DM (14.6% versus 19.2%; HR, 0.74; P=0.001) than for subjects without DM (11.5% versus 12.3%; HR, 0.92; P=0.16, Pinteraction=0.05).
Conclusions— Subjects with DM tended to have a greater reduction in ischemic events without an observed increase in TIMI major bleeding and therefore a greater net treatment benefit with prasugrel compared with clopidogrel. These data demonstrate that the more intensive oral antiplatelet therapy provided with prasugrel is of particular benefit to patients with DM.
Key Words: angioplasty • anticoagulants • myocardial infarction • platelets • diabetes mellitus
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Introduction |
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The global prevalence of diabetes mellitus (DM) has been estimated at >170 million individuals and is rapidly increasing, with projections of >350 million by 2030.1 With improved control over other cardiovascular risk factors, the burden of cardiovascular disease attributable to DM is increasing.2,3 Among patients with acute coronary syndromes (ACS), those with DM are at higher risk for subsequent events, including death, independent of other comorbidities4; indeed, patients with DM but without known cardiovascular disease are at a risk of morbidity and mortality after ACS similar to that of patients without DM but with known cardiovascular disease.5 Several mechanisms may play roles in the increased risk of events in patients with DM, including greater frequency of other cardiac risk factors, a greater burden of atherosclerotic disease, hyperglycemia, inflammation, and a greater tendency toward thrombosis.6–8 Despite initial favorable data, results of definitive studies of insulin therapy in patients with ACS have not demonstrated benefit.9–11
Platelet activation and aggregation are key factors in the development of ACS and its complications. It has been known for decades that platelets from patients with DM are characterized by increased reactivity.12,13 Intensive intravenous blockade of platelet aggregation in subjects with ACS using glycoprotein IIb/IIIa receptor inhibitors (GPIs) appears to be of particular benefit among subjects with DM.7,14 A meta-analysis of >30 000 subjects from the acute GPI trials revealed a significant 26% relative reduction in mortality among subjects with DM, a significant 70% relative mortality reduction among diabetic subjects undergoing percutaneous coronary intervention (PCI), and no mortality benefit among subjects without DM.7,14
Editorial p 1607
Clinical Perspective p 1636
Prasugrel is a third-generation thienopyridine antiplatelet agent that, like clopidogrel, exerts its antiplatelet effect by P2Y12 receptor blockade.15 Treatment with prasugrel results in higher and more consistent levels of platelet inhibition than standard- or higher-dose clopidogrel.16,17 In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial 38 (TRITON-TIMI 38), treatment with prasugrel compared with clopidogrel resulted in a 19% lower incidence in cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke but with more bleeding among patients with ACS in whom PCI was planned.18 Several studies using multiple methods of measurement of platelet function have demonstrated less inhibition and greater rates of poor antiplatelet response to clopidogrel among subjects with DM.19–23 We hypothesized that because of the increased platelet reactivity and higher reported rates of poor response to clopidogrel among patients with DM, we would observe a greater benefit for prasugrel compared with clopidogrel among subjects with DM in TRITON-TIMI 38.
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Methods |
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Study Population
This analysis includes all 13 608 subjects randomized into the TRITON-TIMI 38 trial stratified by DM status, a prespecified subgroup. Inclusion and exclusion criteria for the main trial have previously been published in detail.24 Briefly, subjects were eligible for enrollment if they had moderate- to high-risk unstable angina (UA/NSTEMI), after medical treatment for ST-segment elevation MI (STEMI) with coronary anatomy known to be suitable for PCI, or before cardiac catheterization with planned primary PCI for STEMI. Key exclusion criteria included increased risk of bleeding and any thienopyridine within 5 days before enrollment. A history of DM for each subject was established from the report of the local investigator on the case record form. Subjects were classified on the basis of treatment with insulin before enrollment in TRITON-TIMI 38.
End Points
End-point definitions for TRITON-TIMI 38 have been published previously and were used for this analysis.18,24 All components of the end points were adjudicated by a clinical events committee blinded to treatment assignment. The primary end point of TRITON-TIMI 38 and this analysis was the composite of cardiovascular death, nonfatal MI, or nonfatal stroke. Additional efficacy end points examined included the individual assessment of cardiovascular death, MI, or stent thrombosis using the definite/probable Academic Research Consortium definition.25,26 The key safety end point was non–coronary artery bypass grafting (CABG)–related TIMI major bleeding; secondary analysis was of non–CABG-related TIMI major or minor bleeding as previously defined.24 Net clinical benefit was defined as the composite of all-cause mortality, nonfatal MI, nonfatal stroke, or nonfatal TIMI major bleeding not related to CABG.18 Efficacy event rates are calculated from intention-to-treat analyses, and safety analyses are based on the safety cohort.18
Statistical Analysis
Baseline characteristics of subjects with and without DM were compared by the 
2 test for categorical variables and the Wilcoxon rank-sum test for continuous variables. Because randomization was not stratified by DM status, baseline characteristics were compared among subjects with and without DM by treatment assignment. Survival analysis methods were used to compare outcomes by treatment assignment (prasugrel versus clopidogrel) and to compare outcomes by presence or absence of DM. Event rates are reported using Kaplan–Meier estimates at 450 days. Comparisons are expressed as hazard ratios (HRs) and 95% CIs including the entire duration of follow-up. Testing for an interaction between the efficacy of prasugrel compared with clopidogrel and diabetic status was performed by constructing a Cox proportional-hazards model using terms for both the main effect and the interaction. Given the number of subjects enrolled, the proportion of subjects with DM, and the overall reduction in the primary end point with prasugrel in the total cohort, there was 80% power at an 
level of 0.05 to detect an interaction HR (ie, the ratio of the HRs for benefit of prasugrel in the DM and non-DM groups) of 0.70; assuming an =0.10, there was 80% power to detect an interaction HR of 0.73. For all analyses, values of P<0.05 were considered significant. All analyses were performed with STATA/SE 9.2 (STATA Corp, College Station, Tex).
The sponsors of TRITON-TIMI 38 supported the design and implementation of the main trial from which these results are obtained. All analyses were performed by the TIMI Study Group using an independent copy of the complete clinical trial database. The authors wrote all drafts of the article and take responsibility for its content. The sponsors had the opportunity to review and comment on this article but had no editorial authority.
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Results |
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Baseline and Procedural Characteristics
Of 13 608 subjects randomized into TRITON-TIMI 38, 3146 (23%) had DM, with 776 (6%) reporting treatment with insulin. Baseline characteristics by diabetic status are shown in Table 1. Subjects with DM were more likely to have UA/NSTEMI, to be older, to more often be female, and to have a higher body mass index. DM subjects were more often from North America, had more frequent prior MI and prior CABG, and were more likely to have hypertension or hyperlipidemia but were less likely to be smokers. There was no difference in the frequency of PCI at the time of enrollment. For the index PCI, subjects with DM were more likely to have multivessel PCI and were more likely to have received at least 1 drug-eluting stent than subjects without DM. Subjects with DM were more likely to receive treatment with an angiotensin-converting enzyme inhibitor, an angiotensin receptor blocker, or a calcium channel blocker but had similar rates of use of GPIs, statins, and aspirin. Baseline characteristics were well matched within the randomized treatment assignments (prasugrel versus clopidogrel). The only significant differences between treatment groups were that among subjects with DM more women were randomized to clopidogrel than prasugrel (36% versus 31%; P=0.004) and that among nondiabetics slightly more subjects randomized to prasugrel had prior CABG (7% versus 6%; P=0.03).
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Compared with subjects with DM not on insulin (Table I of the online Data Supplement), DM subjects on insulin were slightly younger, more often female, heavier, and more often enrolled in North America and more often had prior MI, prior CABG, prior stroke, and renal dysfunction. Subjects on insulin were less likely to receive only bare metal stents but otherwise had similar adjunctive therapies.
Outcomes by Diabetic Status
Rates of thrombotic events were higher among subjects with DM than subjects without DM (Table 2). The primary end point was observed in 14.6% of subjects with and 9.9% of subjects without DM (HR, 1.45; 95% CI, 1.29 to 1.62; P<0.0001). A significantly increasing gradient of higher event rates was observed with a progression across cohorts from no DM to DM without insulin to DM on insulin (Table 3). The primary end point was seen in 9.9% of subjects without DM, 13.4% of subjects with DM without insulin therapy, and 18.3% of subjects with insulin therapy (P for trend <0.0001). MI was observed in 8.0% of subjects without DM and 10.7% of subjects with DM (HR, 1.30; 95% CI, 1.14 to 1.49; P=0.0001), with a similar gradient observed in the 3-stratum comparison (Table 3). Subjects with DM had a higher rate of stent thrombosis than those without DM (2.8% versus 1.4%; HR, 1.95; 95% CI, 1.47 to 2.59; P<0.0001), with highest rates among subjects treated with insulin. After baseline demographic and treatment differences were controlled for, DM remained an independent predictor of ischemic outcomes, including the primary end point, MI, stent thrombosis, and net clinical benefit.
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Overall, major bleeding rates (2.6% versus 2.0%; HR, 1.28; P=0.08) and major or minor bleeding rates (4.8% versus 4.2%; HR, 1.15; 95% CI, 0.95 to 1.4; P=0.15) were similar between subjects with and without DM, respectively, regardless of diabetes treatment.
Prasugrel Compared With Clopidogrel by Diabetes Status
A significant 14% overall reduction in the primary end point (Table 4 and Figure 1
A) was seen with prasugrel among subjects without DM (P=0.02). Among subjects with DM, a 30% reduction in the primary end point was observed with prasugrel (P<0.001, Pinteraction=0.09). As a result of the relative benefits and event rates, the number needed to treat with prasugrel to prevent 1 primary end-point event among subjects with DM was 21 compared with 71 subjects without DM. The reduction in the primary end point among subjects with DM was consistent across major subgroups (Figure 2). There were no significant interactions between treatment effect among patients with DM and presenting syndrome (UA/NSTEMI versus STEMI), gender, age, use of GPI, renal function, or stent type. The reduction in the primary end point with prasugrel was driven largely by a lower incidence of MI (Figure 1B). A highly significant 18% reduction in MI among subjects without DM (P=0.006) was observed, and there was a statistically greater 40% reduction in MI in subjects with DM (P<0.001, Pinteraction=0.02). The substantial reduction in stent thrombosis (Figure 1C) with prasugrel was similar regardless of diabetic status, including 55% among those without DM (2.0% versus 0.9%; P<0.001) and 48% among subjects with DM (3.6% versus 2.0%; P=0.007, Pinteraction=0.63). Among patients with DM, stent thrombosis was reduced to a similar extent with prasugrel in the 1605 patients treated with a drug-eluting stent only (2.0% with prasugrel versus 3.5% with clopidogrel; HR, 0.53; 95% CI, 0.28 to 1.02; P=0.054) and the 1327 patients with bare metal stents only (1.9% versus 3.8%; HR, 0.52; 95% CI, 0.26 to 1.04; P=0.06, Pinteraction=0.95).
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Among subjects without DM, prasugrel treatment was associated with a 43% increase in non–CABG-related TIMI major hemorrhage (P=0.02). Although no significant difference was seen in major hemorrhage in those with DM, no interaction between treatment and DM status was observed for major hemorrhage (Figure 1
D). Among patients without DM, TIMI major or minor bleeding not related to CABG was observed in 4.9% with prasugrel and 3.6% with clopidogrel (HR, 1.32; 95% CI, 1.08 to 1.61; P=0.006). Among patients with DM, TIMI major or minor bleeding was observed in 5.3% with prasugrel and 4.3% with clopidogrel (HR, 1.30; 95% CI, 0.92 to 1.82; P=0.13, Pinteraction=0.93).
The combination of a relatively greater reduction in ischemic end points and no increase in major bleeding among subjects with DM led to a statistically greater net clinical benefit for prasugrel among subjects with DM (Figure 1E). Specifically, among subjects without DM, a nonsignificant 8% reduction in the composite of all-cause mortality, nonfatal MI, nonfatal stroke, or nonfatal major bleeding (P=0.16) was observed, whereas a statistically greater 26% reduction in this composite outcome was seen for subjects with DM (P=0.001, Pinteraction=0.05).
Prasugrel Compared With Clopidogrel by Diabetes Treatment Type
The relative benefit of prasugrel compared with clopidogrel for the reduction of ischemic end points was consistent across the different treatment subgroups of diabetes (insulin versus no insulin; Table 5 and Figure 3). Among insulin-treated and non–insulin-treated diabetics, highly significant relative reductions in the primary end point (37% and 26%, respectively) were observed. This resulted in a number needed to treat of 13 subjects with DM on insulin and 26 with DM not on insulin to prevent 1 primary end-point event. Substantial benefits in ischemic events, including a 44% relative reduction in MI (9.9% versus 17.3%; P=0.005) for DM on insulin and a 38% relative reduction for MI in DM without insulin (11.9% versus 7.7%; P<0.001), plus a 69% relative reduction in stent thrombosis for DM on insulin (1.8% versus 5.7%; P=0.008) and a 34% reduction among subjects with DM without insulin therapy (2.0% versus 3.0%; P=0.14), were observed. Hemorrhage rates were similar regardless of DM treatment type. As a result, a net clinical benefit of 34% was seen among subjects with DM on insulin (P=0.01) and a 22% net clinical benefit among subjects with DM not on insulin (P=0.02).
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Discussion |
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We demonstrated in TRITON-TIMI 38 that more intensive and consistent antiplatelet therapy with a third-generation thienopyridine (prasugrel) plus aspirin in subjects with ACS undergoing PCI resulted in a reduction in ischemic events compared with standard dual antiplatelet therapy but with more bleeding and, on balance, an improved net clinical benefit.18 The present analysis examined the effect of DM on outcomes and the relative efficacy of prasugrel compared with clopidogrel. Our data extend previous observations regarding worse clinical outcomes of subjects with DM across the spectrum of ACS.4 We observed that despite modern coronary intervention with stenting and high levels of guideline-based medical care, DM had an independent adverse effect on clinical outcome. In addition, we observed that subjects with DM treated with insulin at the time of enrollment had very high rates of ischemic events.
Prasugrel was especially efficacious in patients with DM. Although key ischemic end points, including the primary end point and MI, were significantly reduced among subjects both with and without DM, a greater relative reduction was seen in favor of prasugrel among subjects with DM, including a 40% relative reduction in MI. In addition, when both ischemic events and bleeding are integrated into a net clinical benefit composite end point, a significantly greater relative improvement was observed with prasugrel in subjects with DM than without DM (26% versus 8%). This combination of higher clinical event rates and greater relative treatment effect in subjects with DM led to markedly greater absolute event reductions in subjects with DM. Although these results were consistent regardless of whether subjects with DM were treated with insulin, the higher event rates for subjects with DM on insulin result in an even greater absolute benefit. Compared with standard clopidogrel, to prevent 1 cardiovascular death, nonfatal MI, or nonfatal stroke, 13 patients with DM on insulin, 26 patients with DM not on insulin, and 71 patients without DM would need to be treated with prasugrel.
The present data also build on previous observations regarding intensive antiplatelet therapy among subjects with DM.27 The particular benefit of GPIs among patients with DM has led to the support in clinical guidelines for their use in patients with DM undergoing PCI.28 Speculation regarding the mechanisms of the apparent increased benefit of antiplatelet therapy has centered on increased platelet reactivity with DM.6,7,29 Several studies have identified differences in platelet reactivity among subjects with and without DM, with greater response to platelet agonists among the former.6,12,13,19,22,30,31 Potential mechanisms to explain this difference in platelet activity include direct platelet effects such as glycosylation of platelet membrane proteins, leading to alterations in receptor function and signaling pathways, and nonplatelet effects such as increased oxidative stress and impaired endothelial function, resulting in a procoagulant milieu.6 Physiologically, insulin reduces platelet aggregation by inhibiting the P2Y12 receptor, although this inhibition is absent in subjects with DM and insulin resistance.32,33 In previous mechanistic studies, insulin-treated subjects had higher levels of platelet aggregation after dual antiplatelet therapy than subjects with DM not treated with insulin, indicating that treatment with insulin may identify a group of subjects at particular risk for poor response to clopidogrel.22 We did not collect age of onset (juvenile versus adult) or duration of diabetes, both factors that may influence insulin use. These data do not necessarily imply that insulin use was causally related to higher rates of adverse outcomes but are compatible with the notion that insulin use identifies a high-risk subgroup.
Given the potential role of stimulation of the P2Y12 receptor in platelet activation seen in subjects with DM, a particular benefit of thienopyridines seen in this subgroup is biologically plausible. Indeed, in the Clopidogrel Versus Aspirin in Patients at Risk for Ischemic Events (CAPRIE) trial comparing aspirin with clopidogrel in the secondary prevention of vascular disease events, a greater benefit of clopidogrel among subjects with DM was noted.34 However, in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial of subjects with ACS, dual antiplatelet therapy with aspirin and clopidogrel was associated with a similar benefit regardless of DM, although event rates were higher among subjects with DM.35
One factor that may have limited the ability to observe a greater effect among subjects with DM and ACS in CURE is hyporesponsiveness to clopidogrel. Intersubject variability of response to clopidogrel is a well-described laboratory phenomenon, with growing evidence for poor response to clopidogrel being associated with worse clinical outcomes.17,36,37 Clinical factors associated with impaired response to clopidogrel include both ACS and DM, placing the subjects with these 2 features at especially high risk for a diminished response to clopidogrel.37 Clopidogrel responsiveness has been specifically tested in subjects with DM and has been observed to be related to clinical outcomes. Diabetic subjects with higher posttreatment platelet reactivity are at higher risk for adverse events after coronary stenting.38 As a result of these observations, investigators have examined the effects of higher (150-mg) maintenance20 doses of clopidogrel on platelet function in subjects with DM and found improved response, but they also noted the persistence of a high proportion of subjects not achieving predefined goals for platelet inhibition.20 The results observed in this DM subgroup analysis of TRITON-TIMI 38, however, are the first demonstration in a trial adequately sized for clinical outcomes that more intensive oral antiplatelet therapy (in this case, with prasugrel) improved clinical outcomes compared with standard-dose clopidogrel in diabetic subjects. Although the data presented here do not address the question of whether prasugrel would have been superior to higher-dose clopidogrel, prasugrel at the doses used in TRITON-TIMI 38 has been shown to provide superior antiplatelet effects to higher loading (600 mg) and maintenance (150 mg) doses of clopidogrel in patients undergoing elective PCI in the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation–Thrombolysis in Myocardial Infarction 44 trial (PRINCIPLE-TIMI 44) study.17 The Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events–Optimal Antiplatelet Strategy for Interventions (CURRENT-OASIS 7) trial (NCT00335452) is comparing the clinical efficacy of high- and standard-dose clopidogrel; the results of the diabetic patients in this trial will be of great interest in determining whether a smaller difference in the intensity of platelet inhibition will result in improved clinical outcomes similar to those observed in TRITON-TIMI 38.
The greater relative effect of prasugrel compared with clopidogrel among subjects with DM that we observed in this analysis supports the hypothesis that greater platelet inhibition among patients with DM results in improved outcomes. Whether the differential effects between prasugrel and clopidogrel result from a greater level of inhibition of platelet aggregation on a population level or a greater proportion of subjects reaching a specific threshold cannot be determined from these data. That the benefit was consistent among subjects with DM across a broad spectrum of characteristics, including UA/NSTEMI or STEMI, gender, and age, suggests that there is a relationship between DM per se and greater relative benefit with prasugrel. That a greater absolute benefit is seen among insulin-treated subjects with DM also supports this hypothesis. Of note, in the presence or absence of GPI, the benefit of prasugrel compared with clopidogrel was still observed, indicating that blocking the P2Y12 receptor in patients with DM is an important target beyond potent inhibition of platelet aggregation.
It is of interest that subjects with DM had similar TIMI major bleeding rates regardless of treatment with prasugrel or clopidogrel. This may relate to the higher body weight of diabetics or greater baseline platelet reactivity among diabetics, or because the probability value for interaction with the entire cohort is nonsignificant, this observation may simply have been the play of chance. The latter explanation is supported by the similar relative increase in the combination of major or minor bleeding among subjects with and without DM and the higher major bleeding rate among diabetics compared with nondiabetics on clopidogrel, a finding that would be unexpected if this difference were related only to platelet activity.
The combination of higher ischemic event rates with greater reductions with prasugrel and similar major bleeding rates leads to a significantly greater net benefit of prasugrel compared with clopidogrel among subjects with DM. In choosing antiplatelet therapies for management of patients with ACS undergoing PCI, the treating physician needs to weigh the competing risks of recurrent thrombosis and bleeding. Previously, subgroups have been identified that had limited net benefit with prasugrel from TRITON-TIMI 38, including those with prior stroke or low body weight or the elderly.18 These data demonstrate that patients with DM, seen in increasing frequency with ACS, derive a particular benefit from a more intensive oral antiplatelet strategy with acceptable safety.
Study Limitations
This was a prespecified subgroup analysis of prasugrel versus clopidogrel among diabetics. Information regarding diabetes type was posthoc and should be considered exploratory. Comparisons between the outcomes of subjects by diabetic status (diabetes versus no diabetes or diabetic subtype) are subject to the influence of differing baseline characteristics, and diabetes is being used as a marker to represent these differing characteristics. Although diabetics had similar baseline characteristics between treatment groups (prasugrel versus clopidogrel) and the size of this subgroup was robust (n=3146), randomization was not stratified by diabetic status, and the possibility of an unidentified imbalance between treatment groups exists. The results are strengthened by biological plausibility, a gradient of effect with disease severity, and consistency with previous data for intensive platelet inhibition in patients with DM. We did not measure hemoglobin A1c or have another measure of DM severity or its medical control to better characterize the DM subgroup, although it would be expected that misidentification would be unusual and would only serve to bias the results toward the null. Finally, the absence of a large-scale platelet function study in subjects with DM in TRITON-TIMI 38 does not allow elucidation of the direct relationships between prasugrel, clopidogrel, platelet function, and outcomes. However, our study shows that an agent that achieves greater antiplatelet effect on a population basis had a larger effect on outcomes among subjects with than without DM.
Conclusions
In this analysis from TRITON-TIMI 38, we have demonstrated that DM has an independent adverse association with ischemic outcomes in subjects undergoing PCI for ACS, including a gradient from no DM to DM without insulin therapy to DM with insulin therapy. We have also shown that compared with standard clopidogrel therapy, intensive oral platelet inhibition with prasugrel resulted in greater benefit in reducing ischemic events and improving net outcomes among subjects with DM than in those without DM. These data demonstrate that intensive oral antiplatelet therapy is of particular benefit to patients with DM with ACS and planned PCI, and diabetes status should be considered when therapeutic options are weighed.
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Acknowledgments |
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Disclosures
The TRITON-TIMI 38 trial was supported by Daiichi Sankyo Co, Ltd, and Eli Lilly and Co. Dr Wiviott, Dr Braunwald, C.H. McCabe, S.A. Murphy, and Dr Antman report receiving research grants from Daiichi Sankyo, Eli Lilly, and Sanofi-Aventis. In addition, Dr Wiviott reports receiving consulting or advisory board fees from Sanofi-Aventis and lecture fees from Eli Lilly and Daiichi Sankyo; Dr Braunwald reports receiving consulting or paid advisory board fees from Daiichi Sankyo and Sanofi-Aventis and lecture fees from Eli Lilly and Sanofi-Aventis; Dr Antman reports receiving consulting or advisory board fees from Sanofi-Aventis and lecture fees from Eli Lilly and Sanofi-Aventis. Dr Angiolillo reports research grant support from Glaxo Smith Kline and consulting, speakers bureau, or advisory board fees from Daiichi Sankyo, Eli Lilly, Bristol-Myers Squibb, Sanofi-Aventis, Novartis, and Portola. Dr Goodman reports receiving research grant support, speaker honoraria, or consulting income from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Schering Plough, and The Medicines Co. The other authors report no conflicts.
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Footnotes |
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Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.
The online Data Supplement can be found with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.791061/DC1.
Guest Editor for this article was Valentin Fuster, MD.
Clinical trial registration information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00097591.
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Circulation 2008 118: 1605-1606.
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