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Effect of Antiplatelet Therapy on Coronary Heart Disease Risk in Patients with Diabetes Mellitus
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 diabetic patients 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 diabetic patients may derive enhanced benefit from particular therapies directed toward blocking the platelet. However, differences in platelet biology in diabetic patients may also contribute to diminished antiplatelet drug responsiveness. This chapter reviews the use of established and novel oral antiplatelet therapies in diabetic patients for use in primary or secondary prevention of CV events.
Aspirin
To date, aspirin remains the cornerstone of antiplatelet therapy in the primary and secondary prevention of CV events. Aspirin 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. 16-1 ), thereby preventing thromboxane-mediated platelet aggregation and vasoconstriction. Because the platelet is enucleate, it is unable to resynthesize COX-1 and the effects of aspirin persist throughout the lifetime of the platelet.
Aspirin in Primary Prevention
Although its role in secondary prevention is well established, the clinical efficacy of aspirin in primary prevention remains an ongoing area of investigation. Several large primary prevention trials of aspirin have been conducted in the general population, and investigators have subsequently evaluated the benefit of aspirin within their diabetic subgroups. Although limited by small numbers of diabetic patients and by post hoc design, many trials were able to demonstrate a consistent benefit of aspirin in the primary prevention of CV events for both their diabetic and nondiabetic patients. , 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 aspirin 650 mg daily or placebo. Although aspirin 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 aspirin could not be definitively demonstrated in diabetic patients enrolled in the Primary Prevention Project (PPP), a randomized trial of low-dose aspirin (100 mg daily) versus 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 diabetic patients (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 aspirin-treated diabetic patients. In contrast, a more consistent benefit was seen with aspirin in nondiabetic patients 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 individual trials of aspirin therapy in primary prevention enrolled relatively few diabetic patients, De Berardis and colleagues combined data from six trials and 10,117 patients to examine the clinical efficacy of aspirin to reduce major CV events in primary prevention. The meta-analysis demonstrated a benefit of aspirin in the overall study population, yet the authors were unable to identify a statistically significant benefit in the diabetic subgroup. Although a directional trend was observed, aspirin did not significantly reduce the risk of major CV events in diabetic patients as compared with placebo (HR 0.90, 95% CI 0.81-1.00). Furthermore, aspirin did not reduce either CV mortality (HR 0.94, 95% CI 0.72-1.23) or all-cause mortality (HR 0.93, 95% CI 0.82-1.05) in diabetic patients. However, limitations of the meta-analysis included evidence of significant heterogeneity across trials for key endpoints including MI. To that end, aspirin significantly reduced the risk of MI in men (HR 0.57, 95% CI 0.34-0.94), but did not reduce the risk of MI in women (HR 1.08, 95% CI 0.71-1.65; P for interaction = 0.056). Because women had a higher prevalence of DM, sex-restricted enrollment in some of the trials may have contributed to the observed heterogeneity. , Consistent findings were observed in an updated meta-analysis that included individuals with DM across nine trials of aspirin in primary prevention. Aspirin reduced the risk of CHD events by 9%, but the results were not statistically significant (relative risk 0.91, 95% CI 0.79 -1.05). Similarly, the use of aspirin was associated with a nonsignificant 10% reduction in the risk of stroke (relative risk 0.90, 95% CI 0.71-1.13; Fig. 16-2 ). These findings therefore raised concerns that the antiplatelet effects of aspirin were insufficient to attenuate risk of CV events in diabetic patients with baseline abnormalities in platelet function.
Because subgroup analyses from randomized trials may yield spurious results, dedicated trials of aspirin for primary prevention in diabetic patients have since been completed or are still ongoing. 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 aspirin (81 or 100 mg daily) versus placebo in 2539 type 2 diabetic patients in Japan aged 30 to 85 years and without a known history of atherosclerotic disease. 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 aspirin in diabetic patients 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, aspirin 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 aspirin (100 mg daily) versus placebo in 1276 adults in Scotland older than 40 years with type 1 or type 2 DM 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 follow-up (116 versus 117 events; HR 0.98, 95% CI 0.76-1.26). Aspirin 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.
In light of these conflicting data, the use of aspirin in primary prevention continues to be a topic of debate. In particular, any signal suggesting efficacy must be weighed against the potential risks of treatment. In a large population-based cohort of individuals in Italy, the use of aspirin was associated with a relative 55% increased incidence of major bleeding over a median of 5.7 years in the overall cohort, as compared with patients not taking aspirin. The risk of bleeding was increased in individuals over the age of 70, those with a higher risk of GI disease, and by concomitant use of NSAIDs. Irrespective of aspirin use, patients with DM were observed to have a 36% higher incidence of major bleeding episodes, including an increased risk of GI and intracranial bleeding, as compared with nondiabetic patients. Of interest, the use of aspirin did not appear to be associated with an increased risk of bleeding for diabetic patients. However, it remains unknown whether the absence of a bleeding signal with aspirin in diabetic patients might be explained by a diminished pharmacodynamic response to aspirin in diabetic patients with abnormal platelet biology, or attributable to other factors.
Based on the weight of the evidence to date, the American Diabetes Association (ADA) updated its recommendations in 2010 to consider low-dose aspirin therapy (75 to 162 mg/day) in primary prevention in diabetic individuals (men older than 50 years, women older than 60 years) at increased CV risk (10-year risk greater than 10%) with at least one or more major CV risk factor including family history of CV disease, hypertension, albuminuria, dyslipidemia, or current tobacco use ( Table 16-1 ). In 2010, an expert panel that included representatives from the ADA, the American College of Cardiology Foundation (ACCF), and the American Heart Association (AHA) issued similar recommendations that included the use of aspirin (75 to 162 mg/day) in individuals (men older than 50 years, women older than 60 years) at increased CV risk (10-year risk > 10%) and with established CV risk factors, who were not believed to be at increased risk of bleeding. They also noted that low-dose (75-162 mg/day) aspirin could be considered for those with DM at intermediate CVD risk (younger patients with one or more risk factors, or older patients with no risk factors, or patients with 10-year CVD risk of 5% to 10%). Aspirin is not recommended in diabetic patients younger than 21 years because of the risk of Reye syndrome, and the role of aspirin in diabetic patients younger than 30 years remains largely untested. The U.S. Preventive Services Task Force has recommended aspirin use in men aged 45 to 79 years and women 55 to 79 years but has not differentiated their recommendations on the presence or absence of DM. , In contrast, the European Society of Cardiology guidelines for CV prevention do not recommend aspirin for primary prevention regardless of baseline risk, including in patients with DM (see Table 16-1 ).
Table 16-1
Summary of Recommendations Regarding the Use of Aspirin in Primary Prevention in Diabetic Individuals
| Organization | Year | Recommendation |
|---|---|---|
| American Diabetes Association | 2014 | Consider aspirin therapy (75-162 mg/day) as a primary prevention strategy in those with type 1 or type 2 DM at increased CV risk (10-year risk > 10%). This includes most men older than 50 years or women older than 60 years who have at least one additional major risk factor (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria). (Level of evidence: C) There is not sufficient evidence to recommend aspirin for primary prevention in lower-risk individuals, such as men younger than 50 years or women younger than 60 years without other major risk factors. In patients in these age groups with multiple other risk factors, clinical judgment is required. (C) |
| ADA, American Heart Association (AHA), American College of Cardiology Foundation (ACCF) | 2010 | Low-dose (75-162 mg/day) aspirin use for prevention is reasonable for adults with DM and no previous history of vascular disease who are at increased CVD risk (10-year risk of CVD events > 10%) and who are not at increased risk for bleeding (based on a history of previous GI bleeding or peptic ulcer disease or concurrent use of other medications that increase bleeding risk, such as NSAIDS or warfarin). Adults with diabetes who are at increased CVD risk include most men over age 50 years and women over age 60 years who have one or more of the following additional major risk factors: smoking, hypertension, dyslipidemia, family history of premature CVD, and albuminuria. (ACCF/AHA Class IIa, level of evidence B; ADA level of evidence C) Aspirin should not be recommended for CVD prevention for adults with DM at low CVD risk (men younger than 50 years and women younger than 60 years with no major additional CVD risk factors; 10-year CVD risk under 5%) because the potential adverse effects from bleeding offset the potential benefits. (ACCF/AHA Class III, level of evidence C; ADA level of evidence C) Low-dose (75-162 mg/day) aspirin use for prevention might be considered for those with DM at intermediate CVD risk (younger patients with one or more risk factors, or older patients with no risk factors, or patients with 10-year CVD risk of 5%-10%) until further research is available. (ACCF/AHA Class IIb, level of evidence C; ADA level of evidence E) |
| U.S. Preventive Services Task Force , | 2009 | In men aged 45-79 years, encourage aspirin use when potential CVD benefit (MIs prevented) outweighs the potential harm of GI hemorrhage (irrespective of whether the individual has DM). In women aged 55-79 years, encourage aspirin use when potential CVD benefit (ischemic strokes prevented) outweighs the potential harm of gastrointestinal hemorrhage (irrespective of whether the individual has DM). Do not encourage aspirin use for MI prevention in men younger than 45 years or for stroke prevention in women younger than 55 years (irrespective of whether the individual has DM). There is insufficient evidence to recommend the use of aspirin for primary prevention in individuals aged 80 years or older. |
| European Society of Cardiology | 2012 | Antiplatelet therapy with aspirin is not recommended for people with DM who do not have clinical evidence of atherosclerotic disease. (Level of evidence A) |
CVD = Cardiovascular disease; NSAIDs = nonsteroidal anti-inflammatory drugs.
Because trials to date have yielded inconclusive results, the net clinical benefit of aspirin in the primary prevention of CV events in diabetic patients remains an ongoing area of investigation ( Table 16-2 ). The Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D, ISRCTN48110081) study is an open-label trial that is randomizing individuals with type 1 or type 2 DM and without clinical evidence of vascular disease to aspirin with statin or statin alone to evaluate whether aspirin will reduce a first CV event. Similarly, the ongoing ASCEND (A Study of Cardiovascular Events in Diabetes) trial (clinicaltrials.gov NCT00135226) is randomizing patients with DM and without known occlusive arterial disease to 100 mg of aspirin daily versus placebo and/or supplementation with 1 g of omega-3 fatty acids daily or placebo.
Table 16-2
Ongoing Trials of Aspirin for Primary Prevention in Individuals with Type 1 or Type 2 DM
| Trial Name | Design | Population | Intervention | Outcome |
|---|---|---|---|---|
| Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D; ISRCTN48110081) |
Open label, randomized, parallel group | Approximately 5170 patients; type 1 or type 2 DM without clinical evidence of vascular disease and with an indication for statin therapy | Aspirin (100 mg/day) plus simvastatin versus simvastatin alone | CV death, MI, stroke, or CV hospitalization |
| A Study of Cardiovascular Events in Diabetes trial (ASCEND; clinicaltrials.gov NCT00135226) |
Double-blind, 2 × 2 factorial randomized design | Approximately 15,480 patients; type 1 or type 2 DM, older than 40 years, and without known history of vascular disease | Aspirin (100 mg/day) versus placebo (2 × 2: 1 g/day omega-3 ethyl esters versus placebo) | Vascular death, MI, or stroke (excluding cerebral hemorrhage) |
Aspirin in Secondary Prevention
Although the role of aspirin in primary prevention continues to be investigated, the use of aspirin in stable and unstable secondary prevention is well established. Whereas smaller studies had been suggestive, the first randomized trial that definitively demonstrated aspirin’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 aspirin at 5 weeks when compared with placebo. Subsequent trials have since demonstrated a consistent benefit for aspirin 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 aspirin, 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 nondiabetic patients, the relative benefit of antiplatelet therapy toward reducing vascular events was consistent across patient groups. For every 1000 diabetic patients treated with aspirin, it was estimated that 42 vascular events could be prevented with use of antiplatelet therapy.
Of note, it was observed in the ATC analysis that lower doses of aspirin (75 to 150 mg/day) appeared to be as efficacious as high doses of aspirin (> 150 mg/day). Furthermore, the use of lower doses of aspirin was associated with a reduced risk of bleeding complications as compared with higher doses. The evidence to support the use of lower doses of aspirin 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 aspirin 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 aspirin doses above 100 mg daily were combined with clopidogrel. More recently, the question of optimal aspirin dosage was directly addressed in a randomized clinical trial of low-dose (325 mg loading dose, 75 to 100 mg daily) versus higher-dose aspirin (325 mg loading dose, 300 to 325 mg daily) in patients with ACS. The use of higher-dose aspirin 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 aspirin after 30 days, but increased the risk of minor bleeding by 13% (HR 1.13, 95% CI 1.00-1.27, P = 0.04).
The ADA currently recommends the use of low-dose aspirin (75 to 162 mg/day) for secondary prevention of CV events (including stroke) in all diabetic patients without contraindication. Based on the strength of the data, the use of low-dose aspirin is now supported by the ACC/AHA guidelines in patients after non–ST-elevation ACS or percutaneous coronary intervention (PCI) (see also Chapter 21 ). ,
P2Y12 Receptor Antagonists
Although CV events are not always platelet mediated, platelet activation and aggregation may occur in the presence of aspirin through pathways unrelated to TXA 2 (see Fig. 16-1 ). Therefore this unmet need has prompted the development of alternate oral antiplatelet drugs to use in combination with or as a substitute for aspirin. 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 established and novel antiplatelet agents, including ticlopidine, clopidogrel, prasugrel, ticagrelor, elinogrel, and cangrelor.
Ticlopidine
Ticlopidine was the first thienopyridine to be approved for clinical use, in 1991. It is a first-generation thienopyridine that irreversibly blocks the ADP P2Y12 receptor and thereby prevents platelet activation and aggregation mediated by ADP signaling pathways. When combined with aspirin, ticlopidine has been shown to reduce the risk of CV events in patients undergoing coronary stenting as compared with aspirin monotherapy or aspirin with warfarin. However, an unfavorable safety profile (including risk of neutropenia) and slow onset of action led the way for clopidogrel to emerge shortly thereafter as the preferred thienopyridine in appropriate settings.
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