Antiplatelet Therapy in Diabetes: Efficacy and Limitations of Current

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Bench to Clinic Symposia EDITORIAL REVIEW

Antiplatelet Therapy in Diabetes: Efﬁcacy and Limitations of Current Treatment Strategies and Future Directions

DOMINICK J. ANGIOLILLO, MD, PHD of low-dose aspirin (75–162 mg/day) as a primary prevention strategy in patients with type 1 or type 2 diabetes at increased Ͼ ardiovascular disease is the leading patients undergoing percutaneous coro- cardiovascular risk, including those 40 cause of morbidity and mortality in nary interventions (PCI) (4). However, years of age or who have additional risk C patients with diabetes (1). The con- these agents are available only for paren- factors (family history of cardiovascular comitant presence of multiple classical teral use and have a short duration of ac- disease, hypertension, smoking, dyslipi- cardiovascular risk factors in diabetic tion, which impedes their use for long- demia, or albuminuria) (8). However, subjects contributes to enhanced athero- term protection. The need for alternative aspirin therapy should not be recom- thrombotic risk (2). However, other risk antiplatelet treatment strategies led to the mended for patients aged Ͻ21 years be- factors may be important such as abnor- evaluation of effects obtained from a com- cause this may increase the risk of Reye’s mal platelet function (3). Platelets, in fact, bination of oral antiplatelet agents inhib- syndrome. The role of aspirin in diabetic play a key role in atherogenesis, and its iting other platelet-activating pathways. patients aged Ͻ30 years remains unclear thrombotic complications and measures, Ticlopidine is a first-generation thienopy- because it has not been investigated. which lead to blockade of one or multiple ridine, which irreversibly blocks the Several clinical trials have evaluated the efficacy of aspirin in diabetic patients pathways modulating platelet activation platelet ADP P2Y12 receptor (6). Its com- and aggregation processes, are pivotal in bination with aspirin is associated with a (9–12). Most of these studies showed a reducing ischemic risk in diabetic sub- more enhanced inhibition of platelet benefit of aspirin in diabetic patients (9– jects (4). This article reviews currently function and better clinical outcomes in 11). However, these outcomes were based available antiplatelet agents on ischemic patients undergoing coronary stenting on post hoc analyses because these trials events in diabetic patients, limitations of compared with aspirin monotherapy or were not specifically designed for diabetic currently available treatment strategies, aspirin plus warfarin (6). However, the patients. In addition, the obtained results and antiplatelet agents currently under limited safety profile of ticlopidine and its were based on small numbers of subjects, clinical development that may potentially inability to achieve antiplatelet effects which may explain why aspirin was not overcome these limitations. rapidly have led clopidogrel, a second- always shown to be beneficial in the pri- generation thienopyridine, to become the mary prevention setting in diabetic pa- Antiplatelet therapy ADP P2Y12 receptor antagonist of choice tients (12). There are three different classes of plate- (6–7). The Japanese Primary Prevention of let-inhibiting drugs: cyclooxygenase-1 Aspirin. Aspirin selectively acetylates Atherosclerosis With Aspirin for Diabetes (COX-1) inhibitors (aspirin), ADP P2Y12 the COX-1 enzyme, thereby blocking the (JPAD) trial (clinical trial reg. no. receptor antagonists (thienopyridines), formation of thromboxane A2 in platelets NCT00110448) was the first prospec- and platelet glycoprotein (GP) IIb/IIIa in- (5). This effect is irreversible because tively designed trial to evaluate the use of hibitors, which are mostly used for the platelets are enucleate and, thus, unable aspirin (81 mg or 100 mg) in the primary prevention and treatment of athero- to resynthesize COX-1. In addition to be- prevention of cardiovascular events in pa- thrombotic disorders (4) (Fig. 1). Aspirin ing the antiplatelet agent of choice for sec- tients with type 2 diabetes (n ϭ 2,539) inhibits the COX-1 enzyme and therefore ondary prevention of ischemic events in aged 30–85 years in Japan (13). After a blocks platelet thromboxane A2 synthesis patients with atherosclerotic disease, as- median follow-up of 4.37 years, there was (5). However, patients on aspirin therapy, pirin may also be used for primary pre- a 20% difference between the aspirin and particularly those at high risk, may con- vention of ischemic events. In fact, nonaspirin arms in the primary end point tinue to have recurrent thrombotic although this indication in the general (5.4 vs. 6.7%, respectively) that failed to events. GP IIb/IIIa inhibitors are very po- population is controversial, there is an ex- achieve statistical significance (P ϭ 0.16). tent antiplatelet agents, which exert ef- pert consensus for aspirin usage in the Among patients aged Ͼ65 years (n ϭ fects through inhibition of the final primary prevention setting in diabetic 1,363), aspirin was associated with a 32% common pathway that mediates platelet patients. reduction in the risk of the primary end aggregation processes, and have been Aspirin as a primary prevention strat- point (6.3 vs. 9.2%; P ϭ 0.047). Further- shown to be effective in preventing egy in diabetes. The American Diabetes more, in aspirin-treated patients, the thrombotic complications in high-risk Association (ADA) recommends the use incidence of fatal coronary and cerebro- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● vascular events (a secondary end point) From the Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida. was significantly lower by 90% (0.08 vs. Corresponding author: Dominick J. Angiolillo, [email protected]fl.edu. 0.8%; P ϭ 0.0037); however, there were Received 16 November 2008 and accepted 10 December 2008. no differences in nonfatal coronary and DOI: 10.2337/dc08-2064 © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly cerebrovascular events. Aspirin was well cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. tolerated, with no significant increase in org/licenses/by-nc-nd/3.0/ for details. the composite of hemorrhagic stroke and

DIABETES CARE, VOLUME 32, NUMBER 4, APRIL 2009 531 Antiplatelet therapy in diabetes

diovascular disease, including those with diabetes (15–16). The meta-analyses in- cluded 287 secondary prevention trials involving 212,000 high-risk patients with acute or prior vascular disease or another condition that increased their risk of vascular disease. Aspirin in doses ranging from 75 to 325 mg/day was the most frequently used antiplatelet agent. In the major high-risk groups (acute myocardial infarction, past history of myocardial infarction, past history of stroke or transient ischemic attack, acute stroke, and any other relevant history of vascular disease), antiplatelet therapy reduced the incidence of vascular events by 23%. Of note, a low dose of aspirin (75–150 mg/day) was found to be at least as effective as higher daily doses. Furthermore, bleeding complications were reduced with the lower doses. In more than 4,500 diabetic patients studied in the ATC, the incidence of vascular events was also reduced from

Figure 1— Mechanisms of action of antiplatelet agents. Aspirin inhibits thromboxane A2 (TXA2) 23.5 in the control group to 19.3% in the synthase through blockade of the COX-1 enzyme. Picotamide, ramatroban, and ridogrel inhibit group treated with antiplatelet therapy both TXA2 synthase and TXA2 receptors. Thienopyridines, ticlopidine, and clopidogrel are inhib- (P Ͻ 0.01) and from 17.2 to 13.7% in the itors of ADP P2Y12 receptor and block intracellular pathways leading to platelet activation. ϳ42,000 nondiabetic patients (P Ͻ Prasugrel, ticagrelor, cangrelor, and elinogrel are P2Y receptor antagonists currently under 12 0.00001). Although the overall incidence clinical investigation. Aspirin and P2Y12 receptor antagonists have synergistic effects in blocking the final common pathway leading to platelet aggregation represented by GP IIb/IIIa receptor, of vascular events was much higher in di- which may be directly inhibited by intravenous GP IIb/IIIa receptor antagonists. Cilostazol is an abetic patients, the benefit of antiplatelet inhibitor of phosphodiesterase (PDE) III, which inhibits platelets through an increase in in- therapy in both diabetic and nondiabetic traplatelet cAMP levels. E5555 and SCH 530348 are thrombin receptor antagonists that block the patients was consistent (42 vascular PAR-1 subtype. (Adapted from Schafer AI: Antiplatelet therapy. Am J Med 101:199–209, 1996.) events were prevented for every 1,000 diabetic patients and 35 events for every 1,000 nondiabetic patients). severe gastrointestinal bleeding. Limita- sure index Յ0.99 but no symptomatic tions of this trial include the open-label cardiovascular disease were randomized P2Y12 receptor antagonists assignment to aspirin and the low event to aspirin (100 mg) and antioxidants in a Clopidogrel is currently the thienopyri- rate. Therefore, the study may have been double-blind, 2 ϫ 2 factorial, placebo- dine of choice because it has a more favor- underpowered to demonstrate a signifi- controlled fashion. This trial failed to able safety profile compared with that of cant effect of aspirin on the primary end show any benefit with aspirin or antioxi- ticlopidine (6–7). The Clopidogrel versus point. The results of this trial have ques- dants in primary prevention of cardiovas- Aspirin in Patients at Risk of Ischemic tioned the validity of current guideline cular events. The overall small number of Events (CAPRIE) trial examined the ef- recommendations on aspirin usage in pri- patients with low event rates could have fects of clopidogrel (75 mg/day) versus mary prevention in diabetic patients. played a role in the outcomes of the study. aspirin (325 mg/day) in a large secondary However, there are other ongoing trials, Although patients in this trial were prevention population (n ϭ 19,185) of which will provide further insights to the asymptomatic, this should not be consid- patients with a history of recent myocar- appropriateness of aspirin usage in the ered a primary prevention study because dial infarction, recent ischemic stroke, or primary prevention setting in diabetic subjects had some degree of peripheral established PAD (17). The annual inci- subjects. These include A Study of Cardio- arterial disease (PAD). dence of the primary end point (com- vascular Events iN Diabetes (ASCEND) (clin- Aspirin as a secondary prevention bined incidence of vascular death, ical trial reg. no. NCT00135226) and Aspirin strategy in diabetes. ADA recommends myocardial infarction, or ischemic stroke) and Simvastatin Combination for Cardiovas- the use of low-dose aspirin (75–162 mg/ was 5.32% with clopidogrel and 5.83% cular Events Prevention Trial in Diabetes day) for secondary prevention of cerebro- with aspirin, representing an 8.7% rela- (ACCEPT-D) (clinical trial reg. no. IS- vascular and cardiovascular events in all tive risk reduction in favor of clopidogrel RCTN48110081). diabetic patients (8). This position is sup- (P ϭ 0.043). Bhatt et al. (18) retrospec- Recently, the results of the Prevention ported by the results of two large meta- tively analyzed the results of the diabetic Of Progression of Arterial Disease And Di- analyses of major secondary prevention subgroup in the CAPRIE study, which abetes (POPADAD) trial have been re- trials by the Antithrombotic Trialists’ Col- represented 20% of the study population. ported (14). In this trial, patients (n ϭ laboration (ATC), which showed oral an- The composite vascular primary end 1,276) with type 1 or type 2 diabetes aged tiplatelet agents, mostly aspirin, to be point occurred in 15.6 and 17.7% of pa- Ͼ40 years with an ankle-brachial pres- protective in patients at high risk for car- tients randomized to clopidogrel and as-

532 DIABETES CARE, VOLUME 32, NUMBER 4, APRIL 2009 Angiolillo pirin, respectively (P ϭ 0.042). For every tiplatelet treatment regimens, which may mortality was observed. Importantly, a 1,000 diabetic patients treated, this led to include more potent agents or a combina- large number of patients enrolled in this 21 vascular events prevented, which in- tion with other antiplatelet drugs, are latter subgroup had diabetes, as diabetes creased to 38 among insulin-treated dia- warranted in diabetic patients (20). diagnosis represented one of the key in- betic patients. Of note, the reduction in The current American College of clusion criteria. Therefore, dual antiplate- the composite vascular primary end point Cardiology (ACC)/American Heart As- let therapy with aspirin and clopidogrel with clopidogrel (11.8%) compared with sociation (AHA) guidelines for the should not be advocated in the primary pre- aspirin (12.7%) was not statistically sig- management of unstable angina and vention setting for diabetic individuals. nificant in nondiabetic patients. ADA cur- NSTEMI recommend the addition of clo- rently recommends the use of clopidogrel pidogrel (300 mg loading dose and 75 therapy in very high-risk diabetic patients mg/day maintenance dose) to aspirin in GP IIb/IIIa receptor antagonists or as an alternative therapy in aspirin- patients presenting with unstable angina Numerous studies have been performed intolerant patients (8). and NSTEMI (21). Recently, the use of comparing various GP IIb/IIIa inhibitors. The Clopidogrel in Unstable Angina clopidogrel in patients with ST-elevation Currently, three different GP IIb/IIIa in- to Prevent Recurrent Events (CURE) myocardial infarction (STEMI) has been hibitors (abciximab, eptifibatide, and ti- study examined outcomes with clopi- approved by the U.S. Food and Drug Ad- rofiban) are approved for clinical use. In a dogrel plus aspirin versus aspirin alone in ministration and endorsed by the current meta-analysis of six trials of intravenous patients (n ϭ 12,562) with unstable an- ACC/AHA guidelines on the management GP IIb/IIIa inhibitors in ACS patients, gina or non–ST-elevation myocardial in- of STEMI patients (22). In acute coronary 22% of whom had diabetes (n ϭ 6,458), farction (NSTEMI) (19). Patients were syndrome (ACS) patients, guidelines state GP IIb/IIIa blockers significantly reduced randomized to treatment with either clo- that clopidogrel should be used regard- mortality at 30 days from 6.2 to 4.6% pidogrel (300 mg loading dose and 75 less of the treatment strategy adopted (P ϭ 0.007) in diabetic patients (27). mg/day maintenance dose) or placebo in (invasive or noninvasive) and should, ide- Among more than 22,000 patients in addition to standard aspirin therapy (75– ally, be continued for up to 1 year. The these trials who did not have diabetes, GP 325 mg/day) for up to 1 year. Patients prognostic implications of compliance IIb/IIIa inhibitors did not improve sur- assigned to treatment with dual antiplate- with adjunctive clopidogrel therapy are vival. The effect of GP IIb/IIIa inhibitors in let therapy (aspirin and clopidogrel) had a underscored by a rebound increase in diabetic individuals was even greater in significant 20% relative reduction in the death and myocardial infarctions follow- 1,279 patients who underwent percuta- first primary outcome (composite vascu- ing its withdrawal (23). This phenome- neous coronary intervention during the lar death, myocardial infarction, or non is particularly apparent in diabetic index hospitalization; in these individu- stroke) compared with that in patients patients and may be attributed to a more als, GP IIb/IIIa inhibitors reduced 30-day treated solely with aspirin (9.3 vs. 11.4%, marked increase in platelet reactivity in mortality from 4 to 1.2% (P ϭ 0.002). Of respectively; P Ͻ 0.001). Although the these patients following clopidogrel with- note, these trials were performed in an era enhanced degree of platelet inhibition as- drawal (23–24). of limited use of clopidogrel that has chal- sociated with dual antiplatelet therapy In contrast to the clear benefit seen lenged the need for a GP IIb/IIIa receptor reduced ischemic events, this was associ- with dual antiplatelet therapy across the antagonist in diabetic patients. In fact, the ated with a higher incidence of major spectrum of patients with ACS, including Intracoronary Stenting and Antithrom- bleeding (3.7 vs. 2.7%; P ϭ 0.001). How- those undergoing PCI, the results of the botic Regimen: Is Abciximab a Superior ever, there were no significant differences Clopidogrel for High Atherothrombotic Way to Eliminate Elevated Thrombotic in life-threatening bleeding (2.2 vs. 1.8%; Risk and Ischemic Stabilization, Manage- Risk in Diabetics? (ISAR-SWEET) trial did P ϭ 0.13). In the CURE study, there were ment, and Avoidance (CHARISMA) trial not show any effect of abciximab on 2,840 diabetic patients who experienced showed that in high-risk but nonacute pa- 1-year risk of death and myocardial in- ϳ17% reduction in the first primary out- tients (n ϭ 15,603) with clinically evident farction in diabetic patients (n ϭ 701) un- come when treated with combined aspi- cardiovascular disease (n ϭ 12,153) or dergoing PCI after pretreatment with a rin and clopidogrel therapy compared multiple cardiovascular risk factors (n ϭ 600-mg loading dose of clopidogrel at with aspirin alone (14.2 vs. 16.7%). How- 3,284), treatment with clopidogrel plus least 2 h before the procedure (28). How- ever, the CI 0.70–1.02 shows that, al- aspirin was not significantly more effec- ever, the Intracoronary Stenting and An- though dual antiplatelet therapy with tive than that with aspirin alone in reduc- tithrombotic Regimen: Rapid Early aspirin and clopidogrel provided benefi- ing the rate of cardiovascular death, Action for Coronary Treatment 2 (ISAR- cial effects in the diabetic subgroup (as myocardial infarction, or stroke (6.8 vs. REACT 2) trial clearly showed that abcix- in the overall study population), this 7.3%, respectively; P ϭ 0.22) (25). Al- imab safely reduces the risk of adverse achieved a borderline statistical signifi- though a subgroup analysis in a higher- events in patients with NSTEMI ACS un- cance. It is important to note that the risk group (n ϭ 9,478) with prior dergoing PCI after pretreatment with 600 event rate was much higher in the diabetic myocardial infarction, ischemic stroke, or mg of clopidogrel, which was adminis- than in the nondiabetic subgroup despite symptomatic PAD (“CAPRIE-like” popu- tered to patients with elevated troponin more intense antiplatelet therapy with lation) showed a 17% relative risk reduc- levels but not to patients with electrocar- the adjunctive use of clopidogrel. In fact, tion (P ϭ 0.01) with dual antiplatelet diogram changes (29). The benefit was the primary composite cardiovascular therapy (26), the opposite findings were observed across all subgroups, includ- end point was almost twofold higher in observed in patients in the lower-risk co- ing patients with diabetes. Overall, in diabetic than in nondiabetic patients hort who were enrolled in the study based accordance with current guidelines, (14.2 vs. 7.9%, respectively) (19). These on the presence of multiple cardiovascu- these results continue to support the findings emphasize that more specific an- lar risk factors in which an increase in use of GP IIb/IIIa receptor antagonists

DIABETES CARE, VOLUME 32, NUMBER 4, APRIL 2009 533 Antiplatelet therapy in diabetes in ACS patients, in particular those with rial nature of atherothrombosis, which which are not blocked by aspirin. This diabetes (21). implies the existence of multiple mecha- becomes more evident when non–COX-1 Increased bleeding rates represent the nisms that can lead to recurrence of events. specific assays are used, and diabetic pa- major limitation of GP IIb/IIIa agents. Aspirin resistance. Numerous studies tients are more likely to be resistant using There is increasing evidence that bleeding have correlated aspirin resistance with these tests (34). has an important impact on prognosis, in- long-term adverse clinical outcomes not Only a limited number of studies cluding long-term mortality (30). Com- only in patients with coronary artery dis- have investigated the potential mecha- pared with GP IIb/IIIa inhibitors, ease but also in individuals with ischemic nisms of aspirin resistance intrinsic to di- bivalirudin (a direct thrombin inhibitor) stroke or peripheral arterial disease (33). abetic patients. Diabetic individuals are has been shown to provide similar protec- The prevalence of aspirin resistance de- characterized by increased platelet reac- tion from ischemic events with less major scribed in the literature varies consider- tivity and an increased level and activity of bleeding in ACS patients, resulting in a ably (in 0% of patients in some studies prothrombotic clotting factors (4), which significant reduction in net adverse clini- and Ͼ50% of patients in others); the dis- may explain their predisposition to inad- cal outcomes (31). These findings were parate findings can be attributed to differ- equate aspirin-induced effects. Hypergly- corroborated in a recent subgroup anal- ences in the definition of resistance, type cemia may be considered a diabetes- ysis of the Acute Catheterization and of assay used, dose of aspirin, and patient specific mechanism for inadequate Urgent Intervention Triage Strategy population under consideration. Many of aspirin-induced effects (40). In fact, an (ACUITY) trial performed in the diabetic the studies used assays that are not interaction between glycation and acety- cohort (n ϭ 3,852). In particular, biva- COX-1 specific (e.g., PFA-100, light lation has been repeatedly shown. Also, lirudin monotherapy compared with GP transmittance aggregometry using ago- increased glycation of platelet and coagu- IIb/IIIa plus heparin resulted in a similar nists other than arachidonic acid), and the lation factor proteins may interfere with rate of composite ischemia (7.9 vs. 8.9%, results obtained may be reflective of mul- the acetylation process, thereby contrib- respectively; P ϭ 0.39) and less major tiple platelet-signaling pathways. These uting to inadequate aspirin-induced anti- bleeding (3.7 vs. 7.1%; P Ͻ 0.001), yield- tests typically lead to a higher prevalence platelet effects in diabetic patients. ing fewer net adverse clinical outcomes of aspirin resistance, particularly in dia- However, it still remains undetermined (10.9 vs. 13.8%; P ϭ 0.02) (32). betic patients (34). There is accumulating whether improved glycemic control en- evidence, however, that when tests that hances the efficacy of aspirin or whether Limitations of currently available specifically assess COX-1 activity are used increased doses of aspirin are beneficial in antiplatelet drugs to determine aspirin responsiveness, aspi- the presence of poor glycemic control. Aspirin and clopidogrel represent the cor- rin resistance is encountered very infre- Clopidogrel resistance. Clopidogrel is nerstone of treatment for secondary pre- quently (in Ͻ5% of patients) (35–36). a specific, irreversible antagonist of the vention of ischemic events in patients, Even though the relevance of different as- platelet P2Y12 ADP receptor and, thus, in- including those with diabetes, presenting says testing aspirin sensitivity (specific hibits platelet activation in an entirely dis- with either stable or unstable atheroscle- and nonspecific for COX-1 inhibition) tinct manner compared with that of rotic cardiovascular disease. However, a still needs to be better defined, meta- aspirin. Similarly to aspirin, the preva- considerable number of patients continue analyses using various laboratory assays lence of clopidogrel resistance reported in to experience recurrent atherothrombotic support the poor prognostic implications the literature varies considerably and is events despite the use of these antiplatelet of inadequate aspirin-induced effects related to differences in the definitions agents. These observations have led over (37–38). However, there are no pub- used, type of assay used, dose of clopi- the course of recent years to the develop- lished studies specifically designed to dogrel, and patient population (41). ment of the concept of antiplatelet drug evaluate the implications of biochemical Nonetheless, interindividual variability in resistance. The term “resistance” derives aspirin resistance in diabetic patients. platelet response to clopidogrel is a well- from a laboratory finding consisting in The foremost reason for aspirin resis- established concept. Genetic, cellular, and failure of an antiplatelet agent to ade- tance when using COX-1–specific assays clinical causes can all contribute to inade- quately block its specific target on the is poor patient compliance (33,35). Inter- quate clopidogrel responsiveness (41). The platelet (33). Therefore, thrombotic actions with drugs, such as ibuprofen, presence of diabetes may contribute to in- events cannot be attributed to drug resis- that interfere with aspirin–induced adequate clopidogrel-induced effects tance if the efficacy of the antiplatelet COX-1 acetylation may also be a cause of through various mechanisms (Table 1). agent was not tested in affected patients. inadequate or absent effects of aspirin Clopidogrel nonresponsiveness is more For aspirin, resistance involves inade- (39). The latter may also be responsible prevalent in diabetic compared with non- quate or lack of inhibition of the COX-1– for an increased risk of ischemic events diabetic patients and is highest among pa- mediated thromboxane A2 pathway, despite aspirin use. In addition, the over- tients requiring insulin therapy (42–44) whereas for clopidogrel, resistance in- all prevalence of inadequate aspirin ef- (Fig. 2). These findings may explain why volves P2Y12 receptor signaling (33). An- fects may be influenced by the patient diabetic patients, particularly those at the tiplatelet drug resistance should not be population under investigation. Patients most advanced state of their disease (e.g., confused with treatment failure, which is with diabetes are typically characterized insulin-requiring diabetes), continue to defined by recurrence of an ischemic by platelet hyperreactivity. Although as- have recurrent atherothrombotic events, event despite treatment. Indeed, anti- pirin may lead to complete blockade of including stent thrombosis (41,45). platelet drug resistance can lead to a treat- COX-1 as assessed by assays specific to Platelet-function profiling performed ex- ment failure, but not all treatment failures this target, high residual platelet reactivity clusively in type 2 diabetic patients re- can be attributed to antiplatelet drug re- may persist in these patients as a result of ceiving aspirin and clopidogrel therapy sistance. This is in line with the multifacto- upregulation of other signaling pathways, has shown that even though these pa-

534 DIABETES CARE, VOLUME 32, NUMBER 4, APRIL 2009 Angiolillo

Table 1—Mechanisms of clopidogrel response variability patients were also characterized by a gen- Clinical factors eral dysfunctional status of their platelets, Failure to prescribe/poor compliance as revealed by the presence of high plate- Underdosing let reactivity using agonists testing for Poor absorption multiple signaling pathways. Drug–drug interactions involving intestinal P-glycoprotein (MDR1 gene product) Numerous mechanisms may account Drug–drug interactions involving CYP3A4 for inadequate clopidogrel response in di- Acute coronary syndrome abetic patients, in particular type 2 dia- Diabetes/insulin resistance* betic subjects. Human platelets are targets Elevated BMI* of insulin, which interacts with its own Cellular factors receptor on the surface of the platelet, Accelerated platelet turnover* leading to loss of Gi activity. This results Reduced CYP3A metabolic activity* in suppression of cAMP, inhibition of Increased ADP exposure* P2Y12 signaling, and reduced platelet re- Upregulation of the P2Y pathway* activity (47–48). However, platelets of 12 type 2 diabetic patients are also affected Upregulation of the P2Y1 pathway* Upregulation of P2Y-independent pathways* by the insulin resistance phenomenon Genetic factors that characterizes these patients, which Polymorphisms of CYP results in decreased sensitivity to insulin Polymorphisms of GPIa (9). This results in upregulation of the P2Y12 pathway and increased platelet re- Polymorphisms of P2Y12 Polymorphisms of GPIIIa activity. Other mechanisms linked to clo- Polymorphisms of MDR1 pidogrel nonresponsiveness in diabetic patients include increased exposure to *Factors potentially leading to reduced clopidogrel-induced effects in diabetic subjects. CYP, cythochrome P450; MDR1, multidrug resistance protein 1. (Adapted from ref. 41.) ADP, increased cytosolic levels of calcium, and increased platelet turnover (4,41). tients compared with nondiabetic sub- this cohort composed only of diabetic pa- jects have higher degrees of platelet tients, those with high platelet reactivity Future directions reactivity, there is still a broad range of had a more than threefold risk of long- The limitations of currently available an- responsiveness (46). Importantly, within term adverse events (Fig. 3) (46). These tiplatelet agents that are used for preven-

Figure 2— Platelet aggregation following ADP (20 ␮mol/l) stimuli in nondiabetic patients (NDM) (n ϭ 65), non–insulin-treated diabetic patients (NITDM) (n ϭ 133), and insulin-treated diabetic patients (ITDM) (n ϭ 68). Platelet aggregation is higher in diabetic than in nondiabetic patients, and insulin-treated diabetic patients have the highest degree of platelet reactivity. Platelet aggregation progressively increases across nondiabetic, non–insulin-treated, and insulin-treated patients, respectively. (Adapted from ref. 43.)

DIABETES CARE, VOLUME 32, NUMBER 4, APRIL 2009 535 Antiplatelet therapy in diabetes

Figure 3— Cumulative event-free survival from cardiovascular events in diabetic patients (n ϭ 173) with and without high platelet reactivity. The cutoff value to define high platelet reactivity using receiver operating characteristic analysis was 62% maximum ADP (20 ␮mol/l)-induced platelet aggregation (Aggmax). The major adverse cardiac event rate was significantly higher in patients with platelet reactivity above the cutoff value compared with those below this cutoff value (37.7 vs. 13.3%, respectively; odds ratio 3.96 [95% CI 1.8–8.7]; P Ͻ 0.0010). Multivariate Cox regression analyses showed high platelet reactivity (HR 3.35 [95% CI 1.68–6.66]; P ϭ 0.001) to be the strongest independent predictor of major adverse cardiac events. (Adapted from ref. 46.) tion of atherothrombotic events and that rather than an increase in a once-daily loading doses (53). A class IIb level of ev- have been shown to be of greater magni- dose may be more beneficial in these pa- idence C is available for 150-mg mainte- tude among diabetic patients underscore tients. Aspirin, in fact, has a very short nance dose. The ongoing Clopidogrel the need for more specific antiplatelet half-life and therefore will not achieve Optimal Loading Dose Usage to Reduce treatment regimens, particularly in these blockade of newly generated platelets. Recurrent EveNTs/Optimal Antiplatelet patients. Three strategies are proposed to However, the functional and clinical im- Strategy for InterventionS (CURRENT/ achieve this goal and include dose modi- plications of once-daily versus multiple OASIS7) trial will evaluate whether high fication, adjunctive antiplatelet drug us- daily aspirin administrations are un- loading and maintenance dosing of clopi- age, and use of newer agents. known. dogrel achieves better clinical outcomes Antiplatelet drug dose modification. Several studies have focused on how than standard dosing in ACS patients un- The rationale behind increasing the dose to overcome clopidogrel nonresponsive- dergoing PCI (clinical trial reg. no. of currently available antiplatelet agents is ness by increasing the dose (49–50). The NCT00335452). In addition, all patients that this strategy may potentially increase Optimizing Anti-Platelet Therapy in Dia- will be randomized to receive low (75– the bioavailability of the drug and there- betes MellitUS (OPTIMUS) study selec- 100 mg) or high (300–325 mg) doses of fore enhance platelet inhibition. The dose tively examined type 2 diabetic patients aspirin. of aspirin used in clinical practice broadly with high platelet reactivity in their Use of adjunctive antiplatelet agents. varies (75–325 mg/daily). Although there chronic phase of clopidogrel treatment Using additional antiplatelet therapy on are no randomized studies assessing (50). The use of a 150-mg clopidogrel top of therapies currently used for sec- which of these doses is most effective, the maintenance dose resulted in greater ondary prevention of ischemic events ATC clearly shows that higher aspirin platelet inhibition than use of a 75-mg may be a way of achieving enhanced doses are not associated with better clini- dose. Recent findings have shown that en- platelet inhibition in diabetic patients. cal outcomes (15–16). On the contrary, hanced P2Y12 inhibition achieved with However, there are limited options to aspirin dose is associated with a higher high-dose clopidogrel in diabetic patients reach this goal. GP IIb/IIIa inhibitors us- risk of adverse effects, mainly gastrointes- also reduces thrombin generation (51). age is limited to the acute phase of ther- tinal bleed (5). Although functional stud- However, despite this strategy, a signifi- apy. These drugs have been shown to be ies have shown that aspirin dosing may cant number of patients remained above particularly beneficial in ACS patients un- have an impact on its COX-1–indepen- the therapeutic threshold of posttreat- dergoing PCI, in particular diabetic pa- dent effects, the significance of which is ment platelet reactivity adopted in this tients (27). However, in the current era of unknown, this does not affect the degree study (50,52). Despite the lack of large- high-dose clopidogrel usage, GP IIb/IIIa of COX-1 blockade, which requires that scale clinical trial data sufficiently pow- inhibitors failed to show any clinical ben- low doses of aspirin be fully inhibited (5). ered to assess the safety and efficacy of efit in non-ACS settings, including in di- Given that diabetic platelets are character- high-dose clopidogrel, PCI guidelines abetic patients (28). It has been recently ized by increased turnover rates (4), it has provide a class I recommendation (level of suggested that GP IIb/IIIa inhibitors, been advocated that multiple daily dosing evidence C) for high (600 mg) clopidogrel however, may be beneficial in non-ACS

536 DIABETES CARE, VOLUME 32, NUMBER 4, APRIL 2009 Angiolillo settings in patients undergoing nonur- cantly lower among patients treated with tal stroke) occurred in 12.1 vs. 9.9% of gent PCI with aspirin or clopidogrel resis- picotamide (3.0%) than in those who re- clopidogrel- vs. prasugrel-treated pa- tance. However, a subgroup analysis of ceived aspirin (5.5%), with a relative risk tients, respectively (hazard ratio [HR] the Tailoring Treatment with Tirofiban in ratio for picotamide versus aspirin of 0.55 0.81; P Ͻ 0.001). However, there was an Patients Showing Resistance to Aspirin (95% CI 0.31–0.98). However, although increased risk of major bleeding observed and/or Resistance to Clopidogrel (3T/2R) the combined end point of mortality and in 2.4% of the patients receiving prasugrel study failed to show any significant differ- morbidity had a slightly lower incidence compared with 1.8% of the patients re- ences associated with this strategy among in the picotamide group, this difference ceiving clopidogrel (HR 1.32; P ϭ 0.03). diabetic subjects (54). Another approach did not reach statistical significance. Despite the increased bleeding risk, the to improve platelet inhibition in diabetic Other thromboxane inhibitors, such as prespecified net clinical benefit analysis, patients is with the adjunctive use of ramatroban, ridogrel, and S18886, are defined as the composite of efficacy and cilostazol, a phosphodiesterase III inhibi- also currently under clinical investigation bleeding end points, still favored prasug- tor (Fig. 1). Several studies have shown and may represent future treatment alter- rel (12.2 vs. 13.9% of prasugrel- and clo- the benefit of triple antiplatelet therapy natives (59) (Fig. 1). pidogrel-treated patients, respectively; ϭ with aspirin, clopidogrel, and cilostazol, There are several P2Y12 receptor an- HR 0.87; P 0.004). Of note, the patients particularly in diabetic patients treated tagonists under advanced clinical investi- who benefited most from prasugrel ther- with bare-metal as well as drug-eluting gation (60). These include prasugrel, apy were diabetic (63). There were 3,146 stents (55–56). These findings may be at- ticagrelor (AZD6140), cangrelor, and eli- subjects with a preexisting history of dia- tributed to a greater degree of platelet nogrel (PRT128) (Fig. 1). Prasugrel and betes, of whom 776 were receiving insu- inhibition achieved with adjunctive treat- ticagrelor are administered orally, cangre- lin therapy. The primary end point was ment with cilostazol in diabetic patients, lor is for intravenous use, and elinogrel reduced significantly with prasugrel in di- as shown in the OPTIMUS-2 study (57). can be administered via both routes. Pra- abetic subjects compared with patients This study showed that cilostazol, which sugrel is an irreversible agent, whereas ti- without diabetes (12.2 vs. 17.0%, respec- increases intraplatelet cAMP levels, en- cagrelor, cangrelor, and elinogrel are tively; HR 0.70; P Ͻ 0.001). A benefit of hances phosphorylation of vasodilator- reversible. All agents have increased po- prasugrel was observed in diabetic sub- stimulated phosphoprotein (VASP), tency and are associated with less re- jects on insulin (14.3 vs. 22.2%; HR 0.63; ϭ thereby increasing P2Y12 inhibitory ef- sponse variability compared with P 0.009) and those not on insulin (11.5 fects (57). However, the major drawback clopidogrel (60). The pharmacodynamic vs. 15.3%; HR 0.74; P ϭ 0.009) (Fig. 4). of cilostazol therapy is its high prevalence and pharmacokinetic profiles of these Myocardial infarction was reduced with of side effects (e.g., migraine, palpita- drugs and the preclinical and early-phase prasugrel by 40% in diabetic subjects (8.2 tions, and gastrointestinal disturbances), clinical data go beyond the scope of this vs. 13.2%; HR 0.60; P Ͻ 0.001). Similar which frequently lead to drug withdrawal review and are described in detail else- TIMI major hemorrhage rates were ob- (57). where (60). Encouraging clinical out- served in diabetic subjects receiving clo- Use of new agents. The development of come data from large-scale phase III pidogrel or prasugrel (2.6 vs. 2.5%, newer antiplatelet agents that can effec- testing is available for prasugrel (61). Pra- respectively; HR 1.06; P ϭ 0.81). The net tively and safely inhibit platelet activation sugrel is a third-generation thienopyri- clinical benefit with prasugrel was greater and aggregation processes appears to be dine that, like clopidogrel, selectively and for subjects with diabetes (14.6 vs. Ͻ the most promising strategy in view of a irreversibly blocks the ADP P2Y12 recep- 19.2%; HR 0.74; P 0.001) than without hypothetical future in which antiplatelet tor (62). However, prasugrel has a more diabetes (11.5 vs. 12.3%; HR 0.92; P ϭ drug regimens will be used according to favorable pharmacokinetic profile be- 0.16). The OPTIMUS-3 trial is currently individual need. This may imply use of cause, compared with clopidogrel, it is evaluating the pharmacodynamic differ- drugs that may target pathways that are more efficiently transformed into its ac- ences between prasugrel (60-mg loading dysfunctional in a particular patient pop- tive metabolite, which leads to more dose and 10-mg maintenance dose) and ulation, such as subjects with diabetes. prompt, potent, and predictable degrees clopidogrel (600-mg loading dose and Accordingly, picotamide has been sug- of platelet inhibition as shown in numer- 150-mg maintenance dose), specifically gested as a treatment alternative to aspirin ous pharmacodynamic studies even when in patients with type 2 diabetes (clinical (58). Picotamide, in fact, inhibits both compared with platelet inhibition associ- trial reg. no. NCT00642174). This study thromboxane A2 synthase and thrombox- ated with both high and maintenance will provide mechanistic insights into the ane A2 receptors and, therefore, is able to dosing of clopidogrel (62). The clinical clinical benefits achieved with clopi- block the effect of thromboxane A2 that is implications of these more favorable dogrel observed in the TRITON-TIMI 38 generated through COX-1 escape mecha- pharmacological properties were evalu- study, particularly in diabetic patients. nisms, which may represent a pathway ated in the Trial to Assess Improvement in Ultimately, antiplatelet agents that in- leading to an inadequate aspirin-induced Therapeutic Outcomes by Optimizing hibit targets other than COX-1 and P2Y12 effect in diabetic patients (Fig. 1). In the Platelet Inhibition with Prasugrel– are currently under advanced clinical de- Drug Evaluation in Atherosclerotic Vas- Thrombolysis in Myocardial Infarction 38 velopment. These are warranted in order cular Disease in Diabetics (DAVID) study, (TRITON-TIMI 38) comparing prasugrel to overcome the multitude of stimuli lead- a total of 1,209 adults aged 40–75 years with clopidogrel in patients (n ϭ 13,608) ing to enhanced platelet reactivity, which with type 2 diabetes and PAD were ran- with moderate- to high-risk ACS who un- characterizes diabetic patients. Thrombin domized to receive picotamide (600 mg derwent PCI (62). After a median dura- is the most potent platelet stimulus, and b.i.d.) or aspirin (320 mg o.d.) for 24 tion of 14.5 months, the primary end thrombin generation is pronounced in di- months (58). The cumulative incidence of point (composite of cardiovascular death, abetic patients. Several thrombin receptor the 2-year overall mortality was signifi- nonfatal myocardial infarction, or nonfa- antagonists that block the protease-

DIABETES CARE, VOLUME 32, NUMBER 4, APRIL 2009 537 Antiplatelet therapy in diabetes

Diabetes Obes 14:124–131, 2007 5. Patrono C, Garcia Rodriguez LA, Landolfi R et al.: Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 353:2373–2383, 2005 6. Savi P, Herbert JM: Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis. Semin Thromb Hemost 31:174–183, 2005 7. Bertrand ME, Rupprecht HJ, Urban P, et al.: Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international co- operative study (CLASSICS). Circulation 102:624–629, 2000 8. American Diabetes Association: Aspirin therapy in diabetes (Position Statement). Figure 4— The major adverse cardiac event (MACE) rate representing the primary end point Diabetes Care 27 (Suppl. 1):S72–S73, (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in the TRITON trial 2004 comparing prasugrel with clopidogrel in the overall study population according to the presence or 9. Steering Committee of the Physicians’ absence of diabetes (DM) and use of insulin therapy among diabetic patients. Health Study Research Group: Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl activated receptor (PAR)-1 subtype let treatment regimens in diabetic J Med 321:129–135, 1989 10. ETDRS Investigators: Aspirin effects on (E5555, SCH 530348) are currently un- patients. Novel and more potent anti- mortality and morbidity in patients with der clinical investigation (64) (Fig. 1). It is platelet agents currently under clinical diabetes mellitus. JAMA 268:1292–1300, important to emphasize that thrombotic development will be useful in efforts to 1992 processes are the result of not only plate- reach these therapeutic goals. 11. Hansson L, Zanchetti A, Carruthers SG, et lets but also plasmatic factors. Therefore, al.: Effects of intensive blood-pressure a better understanding of how these plas- lowering and low-dose aspirin in patients matic components contribute to adverse Acknowledgments— D.J.A. has received with hypertension: principal results of the outcomes in high-risk patients, including research grants from GlaxoSmithKline, Ot- Hypertension Optimal Treatment (HOT) those with diabetes, is pivotal for the de- suka, Eli Lilly, Daiichi Sankyo, The Medi- randomised trial. Lancet 351:1755-1762, cines Company, Portola Pharmaceuticals, velopment of tailored treatment strategies 1998 Accumetrics, Schering-Plough, AstraZen- 12. de Gaetano G; Collaborative Group of (65). Indeed, the large number of agents eca, and Eisai. D.J.A. has received honoraria the Primary Prevention Project: Low- specifically targeting various plasmatic and served on the advisory board for Bristol- dose aspirin and vitamin E in people at components involved in thrombotic pro- Myers Squibb, sanofi-aventis, Eli Lilly, Daii- cardiovascular risk: a randomized trial cesses will be useful as this field further chi Sankyo, The Medicines Company, in general practice. Lancet 357:89–95, develops. Portola Pharmaceuticals, Novartis, Medi- 2001 cure, Accumetrics, and Arena Pharmaceuti- 13. Ogawa H, Nakayama M, Morimoto T, et Conclusions cals. D.J.A. has received lecture honoraria al.: Low-dose aspirin for primary preven- Diabetic patients have an increased risk of from Bristol-Myers Squibb, sanofi-aventis, tion of atherosclerotic events in patients atherothrombotic events in part attrib- Eli Lilly, and Daiichi Sankyo. No other po- with type 2 diabetes: a randomized con- tential conflicts of interest relevant to this uted to platelet dysfunction, which char- trolled trial. JAMA 300:2134-2141, 2008 article were reported. 14. Belch J, MacCuish A, Campbell I, et al.: acterizes this patient population. In The prevention of progression of arterial particular, diabetic patients have in- disease and diabetes (POPADAD) trial: creased platelet reactivity warranting use References factorial randomised placebo controlled of platelet-inhibiting strategies in order to 1. King H, Aubert RE, Herman WH: Global trial of aspirin and antioxidants in pa- reduce their ischemic risk. Although cur- burden of diabetes, 1995–2025: preva- tients with diabetes and asymptomatic rently approved antiplatelet treatment lence, numerical estimates, and projec- peripheral arterial disease. BMJ 337: strategies have proven useful in improv- tions. Diabetes Care 21:1414–1431, 1998 a1840, 2008 ing outcomes, diabetic patients continue 2. 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Angiolillo DJ: Antiplatelet therapy in type Collaborative meta-analysis of random- score the need of individualized antiplate- 2 diabetes mellitus. Curr Opin Endocrinol ized trials of antiplatelet therapy for pre-

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