Platelets play a central role in the pathobiology of atherogenesis and atherothrombosis. Therefore therapies that are directed toward platelet inhibition are widely used in patients with established coronary heart disease (CHD) or in moderate- to high-risk individuals for primary prevention of cardiovascular (CV) events. As our armamentarium of potent antiplatelet therapies continues to expand, there is growing interest in identifying the appropriate groups of patients who will derive the greatest benefit from more potent therapies. To that end, several studies over the past few decades have highlighted that individuals with diabetes mellitus (DM) exhibit abnormalities in platelet function that place them at increased risk of adverse outcomes, as compared with their nondiabetic counterparts (see also Chapter 10 ). Although the mechanisms that contribute to platelet hyperreactivity in patients with diabetes continue to be elucidated, it appears that diabetic platelets are characterized by the dysregulation of several signaling pathways that occur both at the level of the platelet receptor and with subsequent downstream signaling. In addition, glycosylation may impair endothelial function and promote oxidative stress, thereby further promoting platelet reactivity and procoagulant activity. There is therefore a priori biologic plausibility to support the concept that patients with diabetes may derive enhanced benefit from particular therapies directed toward blocking the platelet. However, differences in platelet biology in patients with diabetes may also contribute to diminished antiplatelet drug responsiveness. This chapter reviews the use of established and novel oral antiplatelet therapies in patients with diabetes for use in primary or secondary prevention of CV events.
ACETYLSALICYLIC ACID
Acetylsalicylic acid (ASA) selectively acetylates the hydroxyl group of a serine residue leading to irreversible inhibition of the cyclooxygenase-1 (COX-1) enzyme. In turn, inhibition of the COX-1 enzyme blocks downstream production of thromboxane A 2 (TXA 2 ; Fig. 20.1 ), thereby preventing thromboxane-mediated platelet aggregation and vasoconstriction. Because the platelet is enucleate, it is unable to resynthesize COX-1 and the effects of ASA persist throughout the lifetime of the platelet.
The platelet has multiple ligands that contribute to pathways leading to platelet activation including thrombin, adenosine diphosphate (ADP), von Willebrand factor, and thromboxane A 2 (TXA 2 ). The activated platelet then releases prothrombotic factors, including ADP and TXA 2 , thereby further amplifying platelet activation. A platelet latticework is formed when fibrinogen cross-links activated platelets via the glycoprotein IIb/IIIa receptor. The P2Y12 subtype of the ADP receptor is the site of action for established and novel compounds, including ticlopidine, clopidogrel, prasugrel, ticagrelor, and cangrelor.
Modified from Bhatt DL. Intensifying platelet inhibition—navigating between Scylla and Charybdis, N Engl J Med. 2007;357:2078–2081.
Acetylsalicylic Acid in Persons Without Known Atherosclerotic Cardiovascular Disease
Although its role in persons with atherosclerotic cardiovascular disease (ASCVD) is well established, the net clinical benefit of ASA in those without known atherosclerosis continues to be debated. Several large trials of ASA have been conducted in the general population without known ASCVD, and investigators have subsequently evaluated the benefit of ASA within their diabetic subgroups. Although limited by small numbers of patients with diabetes and by post hoc design, many trials were able to demonstrate a consistent benefit of ASA in the prevention of first CV events for both patients with and without diabetes. These results were supported by the Early Treatment Diabetic Retinopathy Study (ETDRS), which included a mixed population of 3711 patients with DM with or without a history of CHD who were randomized to ASA 650 mg daily or placebo. Although ASA did not reduce the primary endpoint of all-cause death (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.75–1.11), a favorable trend was observed toward a reduction in fatal or nonfatal myocardial infarction (MI) at 5 years that did not achieve statistical significance (HR, 0.83; 95% CI, 0.66–1.04).
In contrast, a benefit for ASA could not be definitively demonstrated in patients with diabetes enrolled in the Primary Prevention Project (PPP), a randomized trial of low-dose ASA (100 mg daily) versus a placebo in 4495 patients with one or more CV risk factors. Although underpowered to detect a significant benefit within the diabetic subgroup ( n = 1031), the investigators were unable to demonstrate a significant reduction in CV death, MI, or stroke in patients with diabetes (HR, 0.90; 95% CI, 0.50–1.62) or in total CV events (HR, 0.89; 95% CI, 0.62–1.26). Moreover, an unfavorable trend was observed toward an increased risk of CV death (HR, 1.23; 95% CI, 0.69–2.19) in ASA-treated patients with diabetes. In contrast, a more consistent benefit was seen with ASA in patients without diabetes with regard to reduction in the risk of CV death, MI, or stroke (HR, 0.59; 95% CI, 0.37–0.94); total CV events (HR, 0.69; 95% CI, 0.53–0.90); and CV death (HR, 0.32; 95% CI, 0.14–0.72).
Because subgroup analyses from randomized trials may yield spurious results, dedicated trials of ASA for primary prevention in patients with diabetes have since been completed. The Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) study was the first prospectively designed trial to evaluate the use of low-dose ASA (81 or 100 mg daily) versus a placebo in 2539 type 2 patients with diabetes in Japan aged 30 to 85 years and without a known history of ASCVD. After a median of 4.37 years, only 154 atherosclerotic events (including fatal or nonfatal ischemic heart disease, fatal or nonfatal stroke, and peripheral arterial disease [PAD]) occurred during follow-up and the trial was therefore unable to demonstrate clinical efficacy with ASA in patients with diabetes despite a directional trend (HR, 0.80; 95% CI, 0.58–1.10; P = 0.16). In addition to being underpowered, other limitations of the trial included its open-label design, which introduced the possibility of bias. However, among the subgroup of patients older than 65 years, ASA reduced the risk of atherosclerotic events by 32% ( P = 0.047). The incidence of hemorrhagic stroke or gastrointestinal (GI) bleeding was low and did not differ significantly between groups.
Subsequently, the Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial evaluated the efficacy of low-dose ASA (100 mg daily) versus a placebo in 1276 adults in Scotland older than 40 years with type 1 or type 2 diabetes and an ankle brachial pressure index below 0.99 in the absence of symptomatic CV disease. Although the trial was relatively small, the incidence of CV events (death from congestive heart failure [CHF] or stroke, nonfatal MI or stroke, or amputation because of critical limb ischemia) was almost identical between treatment arms during a median of 6.7 years of follow-up (116 vs. 117 events; HR, 0.98, 95% CI, 0.76–1.26). ASA did not reduce the risk of death from CHD or stroke (HR, 1.23; 95% CI, 0.79–1.93). GI bleeding was infrequent, and its incidence did not differ between groups.
The Japanese Primary Prevention Project (JPPP) was an open-label trial that randomized 14,464 patients in Japan aged 60 to 85 years with hypertension, dyslipidemia, or diabetes mellitus to enteric-coated ASA (100 mg/d) or none. The trial was stopped for futility after a median follow-up of ~5 years. The primary outcome of CV death, MI, or stroke was neutral (HR, 0.94; 95% CI, 0.77–1.15; P = 0.54), despite a significant reduction in MI (HR, 0.53; 95% CI, 0.31–0.91; P = 0.02) and TIA (HR, 0.57; 95% CI, 0.32–0.99; P = 0.04). There was an observed increase in extracranial hemorrhage requiring transfusion or hospitalization (HR, 1.85; 95% CI, 1.22–2.81; P = 0.004).
Although not a dedicated trial for individuals with diabetes mellitus, the use of ASA in older persons without known ASCVD was more broadly challenged by the results of the ASPREE (Aspirin in Reducing Events in the Elderly) trial. The trial randomized 19,114 participants from Australia or the United States aged ≥70 years old (≥65 years old for Hispanic and African American patients within the United States) without life-limiting chronic illness, dementia, physical disability, or documented cardiovascular or cerebrovascular disease (11% with diabetes mellitus) to ASA 100 mg daily or placebo. After a median follow-up of 4.7 years, the trial was stopped early for futility. The primary endpoint of disability-free survival (survival free from dementia or persistent physical disability) was not reduced with ASA (HR, 1.01; 95% CI, 0.92–1.11; P = 0.79), nor was the risk of CV events. ASA increased the risk of major bleeding (HR, 1.38; 95% CI, 1.18–1.62; P < 0.001). A higher risk of all-cause mortality was observed with ASA, mainly due to cancer-related mortality, although no longer significant after statistical correction for multiple comparisons.
In contrast, the ASCEND (A Study of Cardiovascular Events in Diabetes) trial randomized 15,480 patients with DM and without known occlusive arterial disease to 100 mg of ASA daily versus a placebo. After a mean follow-up of 7.4 years, ASA was shown to marginally reduce the risk of the primary endpoint (nonfatal MI, nonfatal stroke or transient ischemic attack, or death from any vascular cause; HR, 0.88; 95% CI, 0.79–0.97, P = 0.01), but again at the price of increased risk of major bleeding (RR, 1.29; 95% CI, 1.09–1.52; P = 0.003). Fatal and intracranial hemorrhage were infrequent and similar between groups.
In an updated meta-analysis of 13 trials enrolling 164,225 participants without known cardiovascular disease, ASA use reduced CV death, MI, or stroke but was associated with an increased risk of major bleeding, intracranial bleeding, and major GI bleeding with comparable absolute risk estimates. Among the 30,448 with DM, ASA use was associated with a reduction in major adverse cardiovascular event (MACE (HR, 0.90; 95% CI, 0.82–1.00; number-needed-to-treat (NNT) = 153). ASA use was associated with an increase in major bleeding (HR, 1.29; 95% CI, 1.11–1.51; number-needed-to-harm (NNH) = 121) and major GI bleeding (HR, 1.35; 95% CI, 1.05–1.75; number-needed-to-harm = 243) in participants with diabetes, but no excess in intracranial bleeding.
In summary, the evidence suggests that any signal suggesting efficacy must be weighed against the potential risks of treatment. As such, many guidelines, including those by the ACC/AHA and American Diabetes Association, have evolved toward a strategy of a shared decision-making approach involving clinicians and patients, in which the trade-off between ischemic event reduction and increased bleeding risk with ASA can be considered ( Table 20.1 ). Algorithms have therefore been proposed to guide ASA therapy use in persons without known ASCVD and with diabetes mellitus, incorporating an estimation of their CV risk.
Table 20.1
Summary of Recommendations Regarding the Use of Aspirin in Primary Prevention
| ORGANIZATION | YEAR | RECOMMENDATION |
|---|---|---|
| American Diabetes Association | 2018 | Aspirin therapy (75–162 mg/day) may be considered as a primary prevention strategy in those with type 1 or type 2 diabetes who are at increased CV risk. This includes most men and women with diabetes aged ≥50 years who have at least one additional major risk factor (family history of premature atherosclerotic cardiovascular disease, hypertension, dyslipidemia, smoking, or albuminuria) and are not at increased risk of bleeding. |
| American College of Cardiology/ American Heart Association | 2019 | Low-dose aspirin use (75–100 mg/d) might be considered for the primary prevention of ASCVD among adults aged 40–70 years at higher CVD risk but not at increased risk of bleeding. Low-dose aspirin use is not recommended on a routine basis for primary prevention of CVD in adults older than 70 years or among adults of any age who are at increased risk of bleeding |
| US Preventive Services Task Force | 2022 | Aspirin use for the primary prevention of CVD events in adults aged 40–59 years who have a 10% or greater 10-year CVD risk has a small net benefit. Aspirin use for the primary prevention of CVD events in adults 60 years or older has no net benefit. |
| ESC Task Force for CV disease prevention with representatives from 12 medical societies, including European Association of Preventive Cardiology (EAPC) | 2021 | Antiplatelet therapy is not recommended in low/middle-risk patients due to increased risk of major bleeding. Evidence is lacking in higher-risk patients. |
| The Task Force for diabetes, prediabetes, and cardiovascular diseases of the European Society of Cardiology and the European Association for the Study of Diabetes (EASD) | 2019 | Patients with DM and high/very high risk of CV disease can be considered for aspirin therapy (75–100 mg daily) for primary prevention in the absence of clear contraindications. Its use is not endorsed in patients at low or moderate risk of CV disease. The use of proton pump inhibitors is advised in combination with low-dose aspirin. |
ASCVD , Atherosclerotic cardiovascular diseases; CV , cardiovascular; CVD, cardiovascular disease; DM , diabetes mellitus.
The updated guidelines of the European Society of Cardiology in 2019 advised that ASA for prevention of a first CV event is not be used in individuals with DM who are only at low or moderate risk of ASCVD. The European guidelines acknowledge that there continues to exist a relative paucity of data for patients at higher risk, and therefore note ASA can be considered in high- and very high-risk patients with again a shared approach toward decision making.
The US Preventive Services Task Force states that the use of ASA for the prevention of CV disease in adults aged 40 to 59 years who have a 10% or greater 10-year CVD risk should be an individual one, but states that the net benefit in this group is small. However, their recommendations now state that the use of low-dose ASA in primary prevention is not recommended in adults 60 years or older largely based on the results of the ASPREE trial that suggested net harm from in older individuals.
Acetylsalicylic Acid in Persons With Known Atherosclerotic Cardiovascular Disease
Although the role of aspirin for prevention of a first CV event continues to be investigated, the use of ASA in stable and unstable ASCVD is well established. Whereas smaller studies had been suggestive, the first randomized trial that definitively demonstrated ASA’s efficacy in patients with acute MI was the Second International Study of Infarct Survival (ISIS-2), which demonstrated a 23% reduction in the odds of vascular death with ASA at 5 weeks when compared with a placebo. Subsequent trials have since demonstrated a consistent benefit for ASA across the spectrum of acute coronary syndrome (ACS; see also Chapter 21 ).
The Antithrombotic Trialists’ Collaboration (ATC) combined data from 287 secondary prevention studies of oral antiplatelet agents, mostly ASA, and included a total of 212,000 individuals with acute vascular disease, established vascular disease, or risk factors for vascular disease. Overall, in patients with established CV disease, antiplatelet therapy reduced the odds of recurrent CV events by 22% and of nonfatal stroke by 25%. Although individuals with DM had a higher absolute event rate than patients without diabetes, the relative benefit of antiplatelet therapy toward reducing vascular events was consistent across patient groups. For every 1000 patients with diabetes treated with ASA, it was estimated that 42 vascular events could be prevented with the use of antiplatelet therapy.
Of note, it was observed in the ATC analysis that lower doses of ASA (75–150 mg/day) appeared to be as efficacious as high doses of ASA (>150 mg/day). Furthermore, the use of lower doses of ASA was associated with a reduced risk of bleeding complications as compared with higher doses. The evidence to support the use of lower doses of ASA was also supported by an observational analysis from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial that demonstrated that ASA doses exceeding 100 mg daily were not associated with increased efficacy as compared with lower doses in patients with stable CV disease or CV risk factors. Moreover, there was an unfavorable trend toward a higher risk of CV death, MI, or stroke (adjusted HR, 1.16; 95% CI, 0.93–1.14) and increased risk of severe or life-threatening bleeding (adjusted HR, 1.30; 95% CI, 0.83–2.04) when ASA doses above 100 mg daily were combined with clopidogrel. The question of optimal ASA dosage was directly addressed in a randomized clinical trial of low-dose (325 mg loading dose, 75–100 mg daily) versus higher-dose ASA (325 mg loading dose, 300–325 mg daily) in patients with ACS in the CURRENT-OASIS-7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events−Seventh Organization to Assess Strategies in Ischemic Syndromes) trial. The use of higher-dose ASA did not reduce the risk of CV death, MI, or stroke (HR, 0.97; 95% CI, 0.86–1.09) as compared with low-dose ASA after 30 days, but increased the risk of minor bleeding by 13% (HR, 1.13; 95% CI, 1.00–1.27; P = 0.04). This was supported by the open-label, pragmatic ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) trial that studied low-dose (81 mg daily) versus full-dose (325 mg daily) ASA in patients with established ASCVD. Substantial dose switching occurred between groups, but ultimately no significant differences were seen in efficacy or safety. Results did not differ between patients with (~38%) or without diabetes.
The ADA currently recommends the use of low-dose ASA (75–162 mg/day) for patients with established ASCVD (including ischemic stroke) in all patients with diabetes without contraindication. Following an initial loading dose, the use of low-dose ASA is recommended by existing guidelines in the acute phase of an acute coronary syndrome and after percutaneous coronary intervention. However, its long-term use in patients with established ASCVD may be influenced by other mitigating factors, including perceived ischemic versus bleeding risk, use of a P2Y12 inhibitor, and/or use of an oral anticoagulant (see also Chapter 21 ).
ORAL P2Y12 RECEPTOR ANTAGONISTS
Although CV events are not always platelet mediated, platelet activation and aggregation may occur in the presence of ASA through pathways unrelated to TXA 2 (see Fig. 20.1 ). Therefore this unmet need has prompted the development of alternate oral antiplatelet drugs to use in combination with or as a substitute for ASA. The P2Y1 and P2Y12 receptors on the platelet cell surface play a tandem role in contributing to platelet activation and aggregation via adenosine diphosphate (ADP)–dependent pathways. The P2Y1 receptor is responsible for an initial weak and transient phase of platelet aggregation, whereas ADP signaling pathways mediated by G i -coupled P2Y12 receptor activation lead to sustained platelet aggregation and stabilization of the platelet aggregate. The P2Y12 receptor is the target for many antiplatelet agents, including ticlopidine, clopidogrel, prasugrel, ticagrelor, and intravenous cangrelor.
Clopidogrel
The efficacy of clopidogrel monotherapy (75 mg/day) versus ASA (325 mg/day) in persons with ASCVD was evaluated in the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial. The CAPRIE trial compared clopidogrel (75 mg/day) versus ASA (325 mg/day) in 19,185 patients with recent MI, recent stroke, or symptomatic PAD. Overall, clopidogrel monotherapy significantly reduced the risk of vascular death, MI, or ischemic stroke by 8.7% compared with ASA alone ( P = 0.043) and reduced the risk of GI bleeding ( P = 0.05). Patients with DM in the trial ( n = 3866) were observed to have approximately a threefold higher event rate compared with their nondiabetic counterparts. Overall, the relative risk reduction (RRR) of clopidogrel versus ASA for reducing vascular events was statistically similar in patients with and without diabetes (12.5% vs. 6.1%, respectively, P for interaction = 0.36). However, because of the higher absolute event rate in patients with diabetes and the trend toward a greater RRR, clopidogrel conferred a greater absolute benefit in patients with diabetes. To that end, the number of events (vascular death, MI, stroke, rehospitalization with ischemia, bleeding) prevented per 1000 patients per year was 21 in patients with diabetes versus 9 in patients without diabetes treated with clopidogrel as compared with ASA. The absolute benefit of clopidogrel further improved to 38 events prevented per 1000 patients per year in insulin-treated patients with diabetes treated with clopidogrel as compared with ASA ( Fig. 20.2 ). Following the publication of the CAPRIE findings, the ADA issued recommendations that clopidogrel be used as monotherapy in very high-risk patients with diabetes and as an alternative to ASA in intolerant patients. More recently these findings were supported by an open-label trial that demonstrated that patients treated with clopidogrel monotherapy had a lower risk of MACE and bleeding events (including GI bleeds) when compared to ASA monotherapy 6 to 18 months after percutaneous coronary intervention (PCI).
The number of events (vascular death, myocardial infarction [MI], stroke, or rehospitalization for ischemia or bleeding) prevented per 1000 patients per year treated with clopidogrel instead of aspirin in patients without diabetes mellitus (DM), patients with DM, and patients with DM treated with insulin in the CAPRIE trial.
Modified from Bhatt DL, Marso SP, Hirsch AT, et al. Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus, Am J Cardiol. 2002;90:625–628.
Although individuals with DM have higher platelet reactivity, randomized trials have been unable to demonstrate a greater relative benefit for clopidogrel in patients with versus without diabetes. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial enrolled 12,562 patients with non-ST-elevation ACS and randomized them to clopidogrel versus placebo on a background of ASA for up to 1 year. After a mean of 9 months, clopidogrel reduced the risk of vascular death, MI, or stroke by 20% compared with placebo (HR 0.80, 95% CI 0.72-0.90). This clinical benefit was associated with a 38% increase in the risk of major bleeding (3.7% vs. 2.7%, P < 0.001) but no increase in the risk of fatal bleeding. The benefit of clopidogrel appeared early but was maintained beyond 30 days (HR 0.82; 95% CI 0.70–0.95). Consistent with prior studies, patients with diabetes in the trial ( n = 2840) were observed to have almost a two-fold higher rate of CV events (14.2% vs. 7.9%) as compared with their nondiabetic counterparts, thereby translating into a greater absolute benefit from clopidogrel. However, the relative benefit of clopidogrel was grossly similar in patients with and without diabetes with an approximate 17% RRR in the primary endpoint in patients with diabetes, as compared with 20% in the overall population.
There are mechanistic data to suggest that clopidogrel may have diminished efficacy in patients with diabetes. Pharmacodynamic studies have demonstrated that almost two thirds of patients with diabetes have an inadequate response to clopidogrel. Moreover, platelet aggregation on dual antiplatelet therapy is even further heightened in insulin-treated patients with diabetes, as compared with those who do not require insulin therapy ( Fig. 20.3 ). The latter finding is perhaps explained by the fact that insulin inhibits platelet aggregation by suppressing the P2Y12 pathway. Because patients with diabetes have a loss of responsiveness to insulin, there is subsequent upregulation of the P2Y12 pathway, leading to heightened platelet reactivity and diminished response to antiplatelet agents.
Platelet aggregation after stimulation with 6 μM and 20 μM adenosine diphosphate (ADP) in patients without diabetes mellitus (DM), noninsulin-treated patients with DM, and insulin-dependent patients with DM on stable doses of dual anti-platelet therapy.
Modified from Angiolillo DJ, Bernardo E, Ramirez C, et al. Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment. J Am Coll Cardiol. 2006;48:298–304.
Higher loading (600 mg) and maintenance doses (150 mg daily for 6 days) of clopidogrel were compared with standard doses of clopidogrel in patients after ACS in the Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events—Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS 7) trial (see also Chapter 21 ). Although double-dosing did not reduce the risk of 30-day CV events in the overall study population (HR 0.94, 95% CI 0.83–1.06), the higher-dose regimen was associated with a reduced risk of CV death, MI, or stroke (HR 0.86, 95% CI 0.74-0.99) in the cohort of patients who underwent PCI. However, the higher dose of clopidogrel also increased the risk of major bleeding by 42% (HR 1.42, 95% CI 1.09–1.83). There was no evidence of heterogeneity by DM status for the primary efficacy endpoint ( P for interaction =.32).
The use of dual antiplatelet therapy in stable patients with ASCVD or at high-risk for ASCVD was evaluated in the CHARISMA trial. Overall, clopidogrel did not reduce the risk of CV events when compared with placebo, and there was no evidence of interaction by DM status. In a post hoc analysis, the subgroup of patients with prior MI, ischemic stroke, or symptomatic peripheral arterial disease (PAD) showed a 17% RRR with dual antiplatelet therapy. In contrast, there was no clear benefit and an increased risk of bleeding in high-risk patients in the absence of established vascular disease ( Fig. 20.4 ). Of note, the cohort of patients without ASCVD was enriched with patients with diabetes based on the entry criteria. Therefore the results of the CHARISMA trial do not support the use of dual antiplatelet therapy in patients with diabetes without known atherosclerosis, but ongoing trials may demonstrate a benefit for more prolonged dual antiplatelet therapy in patients with established vascular disease.
The relative effect (hazard ratio [HR], 95% confidence interval [CI]) of clopidogrel versus a placebo in patients with symptomatic atherosclerotic disease or multiple risk factors in the CHARISMA trial. In subgroup analyses, clopidogrel reduced the risk of cardiovascular (CV) death, myocardial infarction (MI), or stroke in patients with symptomatic atherosclerotic disease, but not in patients who only had multiple risk factors in the absence of symptoms. Persons with diabetes mellitus (DM) were enriched in the latter group. CAD , Coronary artery disease; CVA , cerebrovascular accident; PAD , peripheral arterial disease.
Modified from Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354:1706–1717.
Clopidogrel Response Variability
There exists significant interindividual variability in pharmacodynamic response to clopidogrel. In turn, patients with diabetes with an inadequate response to clopidogrel are at increased risk of CV events. The estimated prevalence of individuals with an inadequate response to clopidogrel varies considerably depending on the applied definitions, type of assay, dose of clopidogrel, and patient population. In patients undergoing elective PCI, it has been described that approximately 31% of individuals will have less than 10% inhibition of platelet aggregation (IPA) at 24 hours as measured by light transmission aggregometry after a 300-mg loading dose of clopidogrel. It is important to note there is evidence that the prevalence of clopidogrel hyporesponders is higher in patients with DM and is highest in patients requiring insulin therapy (see Fig. 20.3 ). In the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) trial, individuals with DM had higher baseline platelet reactivity, and almost two-thirds of patients with diabetes were demonstrated to have an inadequate response to clopidogrel. Higher baseline platelet reactivity and diminished response to clopidogrel may therefore in part explain the persistent risk of CV events that is observed in patients with diabetes.
Regardless of DM status, several studies have demonstrated that clopidogrel-treated patients with at least one copy of a reduced-function CYP2C19 allele have an increased risk of CV events after undergoing PCI ; however, genotype appears to explain only a small fraction of observed interpatient variability. In patients with diabetes, in the setting of excess insulin, there is evidence to suggest that platelets develop insulin resistance leading to upregulation of the P2Y12 receptor and heightened platelet reactivity. Additional cellular factors that may contribute to the observed attenuation in response in patients with diabetes include alterations in calcium metabolism, increased ADP exposure, and accelerated platelet turnover.
Prasugrel
Prasugrel is a third-generation thienopyridine that irreversibly binds to the P2Y12 receptor to inhibit platelet activation and aggregation. Although the active metabolites of both clopidogrel and prasugrel have similar affinity for the P2Y12 receptor in vitro, prasugrel achieves more rapid and more potent IPA than clopidogrel due to its more efficient pathway of drug metabolism and activation. Clopidogrel requires two separate CYP-dependent oxidative steps to form its active metabolite, and most of the prodrug is metabolized by esterases that shunt the drug toward a dead-end inactive pathway. In contrast, esterases assist with activation of the prasugrel prodrug, and prasugrel is oxidized to its active metabolite in a single CYP-dependent step. After a 60-mg loading dose, prasugrel has been shown to significantly inhibit platelets within 30 minutes of ingestion. In contrast, a 300-mg loading dose of clopidogrel requires approximately 6 hours to achieve steady state, and a 600-mg loading dose takes approximately 2 hours to demonstrate clinically relevant antiplatelet effects. In addition to its enhanced potency, prasugrel demonstrates diminished interpatient variability as compared with clopidogrel.
The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel—Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 enrolled 13,608 patients with ACS and undergoing PCI to prasugrel (60-mg loading dose, 10 mg daily) or clopidogrel (300-mg loading dose, 75 mg daily) on a background of ASA (see also Chapter 21 ). After a median of 14.5 months, prasugrel significantly reduced the risk of CV death, MI, or stroke by 19% as compared with clopidogrel (HR, 0.81; 95% CI, 0.73–0.90). Furthermore, prasugrel significantly reduced the risk of MI (9.7% vs. 7.4%; P < 0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; P < 0.001), and stent thrombosis (2.4% vs. 1.1%; P < 0.001). The benefit of prasugrel appeared early, and landmark analyses demonstrated that the benefit appeared to persist over time. Although the incidence of bleeding was low, prasugrel significantly increased the risk of non-coronary artery bypass graft (CABG) surgery-related TIMI major bleeding by 32%, including a significant increase in the risk of life-threatening and fatal bleeding. Subsequent post hoc analyses demonstrated the patients with a history of stroke or TIA do not appear to benefit from prasugrel and may incur harm from more potent antiplatelet therapy. In addition, a net clinical benefit was not observed in patients aged older than 75 years or weighing less than 60 kg.
Of interest, the balance between efficacy and safety for prasugrel compared with clopidogrel appeared most favorable in patients with diabetes enrolled in the TRITON-TIMI 38 trial with DM. Of the 3146 patients with DM, prasugrel significantly reduced the risk of CV death, MI, or stroke by 30% (HR, 0.70; 95% CI, 0.58–0.85; P < 0.001, P interaction = 0.09) and this benefit was further increased to 37% in insulin-treated patients (HR, 0.63; 95% CI, 0.44–0.89; Fig. 20.5 ). Prasugrel reduced the risk of MI by 40% in patients with diabetes (HR, 0.60; 95% CI, 0.48–0.76), as opposed to by 18% in patients without diabetes (HR, 0.82; 95% CI, 0.72–0.95; P interaction = 0.02). Also, prasugrel reduced the risk of stent thrombosis in the overall diabetic cohort (3.6% vs. 2.0%; HR, 0.52; 95% CI, 0.33–0.84), and this benefit was further enhanced in patients with diabetes requiring insulin (5.7% vs. 1.8%; HR, 0.31; 95% CI, 0.12–0.77). Although patients with diabetes had a higher absolute rate of bleeding, prasugrel did not appear to substantially increase the risk of major bleeding as compared with clopidogrel in this high-risk patient group (2.6% vs. 2.5%; HR, 1.06; 95% CI, 0.66–1.69). Because of the higher event rate and greater benefit of prasugrel in insulin-treated patients, the absolute risk reduction in CV events with prasugrel was 8%, indicating that only 13 insulin-treated patients with diabetes would need to be treated to prevent one ischemic event, contrasted with a number-needed-to-treat of 26 for DM patients not on insulin. The observations from the diabetic subgroup of the TRITON-TIMI 38 trial therefore support the hypothesis that the achieved degree of platelet reactivity is an important predictor of outcome. Because individuals with DM have higher baseline platelet reactivity and diminished pharmacodynamic response to clopidogrel, it is plausible that patients with diabetes derive enhanced benefit from this more potent antiplatelet therapy that is able to attain lower levels of on-treatment platelet reactivity.
Clinical events and relative benefit (hazard ratio [HR], 95% confidence interval [CI]) of prasugrel versus clopidogrel for patients without diabetes mellitus (DM), patients with diabetes not treated with insulin, and insulin-treated patients with diabetes in the TRITON-TIMI 38 trial. The relative benefit of prasugrel versus clopidogrel appeared to be enhanced in patients with diabetes, and further benefit was observed in those patients requiring insulin therapy. CV , Cardiovascular; MI , myocardial infarction.
Modified from Wiviott SD, Braunwald E, Angiolillo DJ, et al. 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. Circulation. 2008;118:1626–1636.
The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation—Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) trial was a two-phase study of 201 patients undergoing PCI that compared the pharmacodynamic response to prasugrel (60-mg loading dose, 10 mg daily) with higher-dose clopidogrel (600-mg loading dose, 150 mg daily). Prasugrel achieved greater IPA as compared with higher-dose clopidogrel in both the loading dose and maintenance dose phases. The rate of patients who were hyporesponsive to clopidogrel (IPA ≤20% in response to 20 μM ADP) was higher in patients with diabetes than in those without diabetes at all timepoints. In contrast, no hyporesponders were observed for patients on prasugrel at 6 hours, regardless of diabetes status. Consistent findings were observed in the OPTIMUS-3 trial, which exclusively enrolled patients with DM. In OPTIMUS-3, individuals with DM and coronary artery disease (CAD) were randomized to prasugrel (60-mg loading dose, 10 mg daily) or clopidogrel (600-mg loading dose, 150 mg daily) over two 1-week treatment periods separated by a 2-week washout. Prasugrel achieved greater platelet inhibition than high-dose clopidogrel at 4 hours after a loading dose. This difference was maintained throughout the loading dose and maintenance phase (from 1 hour through 7 days; P < 0.001). Prasugrel reduced the number of patients with diabetes with an inadequate response to thienopyridine therapy as compared with high-dose clopidogrel.
After the publication of the TRITON-TIMI 38 trial findings, the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial compared the long-term efficacy of prasugrel (10 mg daily) versus clopidogrel (75 mg daily) in 7243 patients with ACS who were managed medically without coronary revascularization (see also Chapter 21 ). A lower dose of prasugrel (5 mg daily) was used in patients who weighed less than 60 kg or were older than 75 years. The primary analysis was restricted to patients younger than 75 years. In this patient group, prasugrel did not significantly reduce the risk of CV death, MI, or stroke as compared with clopidogrel (HR, 0.91; 95% CI, 0.79–1.05). The findings were consistent in the subset of 2811 patients with DM (HR, 0.90; 95% CI, 0.73–1.09; P interaction = 0.71). The prespecified analysis of first or recurrent ischemic events (all components of the primary endpoint) suggested a lower risk for prasugrel among patients under the age of 75 years (HR, 0.85; 95% CI, 0.72–1.00; P = 0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups. Therefore the findings of the TRILOGY ACS trial do not support the use of prasugrel in patients who are managed without coronary revascularization.
The 2025 AHA/ACC Guidelines for the Management of Patients with ACS offers a class I recommendation for the use of clopidogrel, prasugrel, or ticagrelor (see later) on a background of ASA in patients with ACS who are undergoing PCI, with consideration to be given to preferential use of prasugrel or ticagrelor as a class I recommendation. There is no distinction in the recommendations with regard to drug of choice based on DM status (see also Chapter 21). If prasugrel is used, it should be given promptly and no later than 1 hour after PCI once the coronary anatomy is defined and the decision is made to proceed with PCI (see also Chapters 17 and 22). There is no apparent benefit and possible risk of harm if prasugrel is administered prior to coronary catheterization in patients with non-ST-elevation acute coronary syndromes. Based on the findings from TRITON-TIMI 38, prasugrel should not be administered to patients with a history of stroke or transient ischemic attack (TIA). In patients over the age of 75 years, the use of prasugrel is generally not recommended but may be considered in high-risk patients such as those with DM. A lower dose of 5 mg daily can be considered in patients over the age of 75 or who weigh less than 60 kg. It is generally recommended that prasugrel be continued for at least 12 months in ACS patients who undergo PCI. Earlier discontinuation of ASA or a P2Y12 receptor inhibitor or “de-escalation” of prasugrel or ticagrelor to clopidogrel can be considered in patients in whom the anticipated morbidity from bleeding exceeds its benefits.
Ticagrelor
Ticagrelor is the first reversibly binding oral P2Y12 receptor antagonist. It is a nonthienopyridine and does not require metabolism to form its active metabolite. It has been shown to bind the P2Y12 receptor with a noncompetitive binding mechanism toward ADP. Similar to prasugrel, ticagrelor demonstrates rapid onset of action and decreased interpatient variability as compared with clopidogrel. Because of an elimination half-life of 7 hours and its reversible binding characteristics, it is administered twice daily. However, its antiplatelet effects have been shown to extend to approximately 120 hours. Although it is more potent than clopidogrel, its ability to inhibit platelet aggregation is roughly equivalent to that of clopidogrel at 24 hours after drug discontinuation because of its faster offset kinetics. Ticagrelor may therefore be less likely than clopidogrel to increase the risk of bleeding in patients who require surgery 48 to 120 hours after the last dose.
The Study of Platelet Inhibition and Patient Outcomes (PLATO) trial evaluated the safety and efficacy of ticagrelor in 18,624 patients across the spectrum of ACS (see also Chapter 21 ). Patients were randomized to clopidogrel (300- to 600-mg loading dose, 75 mg daily) or ticagrelor (180-mg loading dose, 90 mg daily). At 12 months, ticagrelor reduced the risk of vascular death, MI, or stroke by 16% (HR, 0.84; 95% CI, 0.77–0.92), as compared with clopidogrel. In addition, ticagrelor reduced the risk of death from vascular causes (4.0% vs. 5.1%; P = 0.001) and all-cause mortality (4.5% vs. 5.9% with clopidogrel; P < 0.001), but increased the risk of non-CABG-related Thrombolysis in Myocardial Infarction (TIMI) major bleeding by 25% ( P = 0.03). Of the P2Y12 inhibitors that have been evaluated to date, ticagrelor is the only drug to have demonstrated a mortality benefit across the spectrum of ACS. However, ticagrelor did not increase the risk of fatal bleeding ( P = 0.66) or CABG-related major bleeding ( P = 0.32).
The relative benefit of ticagrelor appeared to be comparable in patients with and without diabetes in PLATO, although the absolute benefits were greater in insulin-treated patients with diabetes. Ticagrelor reduced the risk of vascular death, MI, or stroke by 12% in patients with diabetes (HR, 0.88; 95% CI, 0.76–1.03) versus 17% in patients without diabetes (HR, 0.83; 95% CI, 0.74–0.92; P interaction = 0.49; Fig. 20.6 ). Similarly, in patients with diabetes, ticagrelor reduced the risk of all-cause mortality (HR, 0.82; 95% CI, 0.66–1.01) and stent thrombosis (HR, 0.65; 95% CI, 0.36–1.17) to an extent that was consistent with the overall cohort. Ticagrelor tended to increase non–CABG-related PLATO major bleeding in both patients with and without diabetes (HR, 1.13; 95% CI, 0.86–1.49; HR, 1.22; 95% CI, 1.01–1.46, respectively; P interaction = 0.69). There was no heterogeneity in the efficacy or safety of ticagrelor with regard to patients who were or were not treated with insulin.
Clinical events and comparative efficacy (hazard ratio [HR], 95% confidence interval [CI]) of ticagrelor versus clopidogrel for patients without diabetes mellitus (DM), patients with diabetes not treated with insulin, and patients with diabetes treated with insulin in the PLATO trial. The absolute benefit of ticagrelor appeared largest in patients with diabetes treated with insulin, although the relative benefits were similar in all three groups. CV , Cardiovascular; MI , myocardial infarction.
Modified from James S, Angiolillo DJ, Cornel JH, et al. Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J. 2010;31:3006–3016.
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