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Oral Antiplatelet Therapy in Patients with Diabetes Mellitus and Acute Coronary Syndromes
REVIEW ARTICLES Oral Antiplatelet Therapy in Patients with Diabetes Mellitus and Acute Coronary Syndromes José Luis Ferreiro, Ángel R. Cequier, and Dominick J. Angiolillo*
Despite the use of recommended antiplatelet treatment strategies, the presence of diabetes mellitus (DM) has been consistently associated with a higher risk of recurrent ischemic events in patients suffering an acute coronary syndrome. The high prevalence of DM patients presenting with low responsiveness to standard oral antiplatelet treatment regimens contributes to these impaired outcomes. This article provides an overview of the currently available oral antiplatelet agents, focusing on limitations of these therapies in DM patients, and evaluates new antithrombotic treatment strategies that may help overcome these limitations. (Trends Cardiovasc Med 2010;20:211–217) © 2010 Elsevier Inc. All rights reserved. The prevalence of diabetes mellitus (DM), mostly at the expense of type 2 DM, is increasing worldwide, with a prediction of more than 350 million people being affected by 2030, which has led to the labeling of this disease as a “global pandemic” (Wild et al. 2004). Cardiovascular disease is the leading cause of morbidity and mortality in DM patients, José Luis Ferreiro is at the Heart Diseases Institute, Hospital Universitari de Bellvitge-IDIBELL, University of Barcelona, L’Hospitalet de Llobregat, Barcelona 08907, Spain, and the University of Florida College of Medicine–Jacksonville, Jacksonville, FL 32209, USA. Ángel R. Cequier is at the Heart Diseases Institute, Hospital Universitari de Bellvitge-IDIBELL, University of Barcelona, L’Hospitalet de Llobregat, Barcelona 08907, Spain. Dominick J. Angiolillo is at the University of Florida College of Medicine-Jacksonville, Jacksonville, FL 32209, USA. *Address correspondence to: Dominick J. Angiolillo, University of Florida College of Medicine–Jacksonville, 655 West 8th Street, Jacksonville, FL 32209, USA. Tel.: ⫹1-904-2443933; fax: ⫹1-904-244-3102; e-mail: dominick. [email protected]. © 2010 Elsevier Inc. All rights reserved. 1050-1738/$-see front matter
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due mostly to coronary artery disease (CAD) (Webster and Scott 1997). In fact, large-scale surveys have shown a prevalence of DM of approximately 30% both in patients with stable CAD and in those with acute coronary syndromes (ACS), confirming the important burden of cardiovascular disease in this population (Bartnik et al. 2004). Several metabolic and cellular abnormalities characteristic of the DM status contribute to the hyperreactive platelet phenotype observed in these patients (Figure 1) (Ferreiro and Angiolillo 2011), which contributes to the inadequate response to antiplatelet agents frequently observed in this population (Angiolillo et al. 2005, Ferreiro and Angiolillo 2011). This impaired response to antiplatelet drugs has been consistently associated with a higher risk of adverse ischemic outcomes (Ferreiro and Angiolillo 2009), a noteworthy observation given the negative impact of DM on outcomes that has been repeatedly observed in ACS (Yusuf et al. 2001).
The aim of this article is to provide an overview of the currently available oral antiplatelet agents, focusing on limitations of these therapies in DM patients, and to evaluate the most recent developments regarding new antithrombotic agents and treatment strategies that may help to overcome these limitations. • Oral Antiplatelet Drugs Two classes of oral antiplatelet agents are currently approved for treatment and prevention of recurrent ischemic events in patients with CAD: cycloxigenase-1 (COX-1) inhibitors and adenosine diphosphate (ADP) P2Y12 receptor antagonists (Anderson et al. 2011, Kushner et al. 2009). This section provides an overview of the most broadly used agents (aspirin and clopidogrel), focusing on their specific benefits and limitations in patients with DM. Aspirin Aspirin irreversibly blocks COX-1, the enzyme that catalyzes the synthesis of thromboxane A2 (TXA2) from arachidonic acid. Therefore, aspirin inhibits platelet formation of TXA2, which diminishes platelet aggregation mediated by thromboxane and the prostaglandin endoperoxide (TP) receptor pathway (Patrono et al. 2005). Routine use of aspirin for primary prevention is controversial. In fact, a consensus document suggested a restricted recommendation of low-dose (75-162 mg/day) aspirin use for primary prevention in DM patients at increased cardiovascular disease risk (men older than age 50 years and women older than age 60 years with 10-year risk of cardiovascular events ⬎10%) and who are not at increased risk of bleeding (Pignone et al. 2010). The ongoing ASCEND (A Study of Cardiovascular Events in Diabetes; NCT00135226) and ACCEPT-D (Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes; ISRCTN48110081) tri-
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Figure 1. Mechanisms contributing to platelet hyperreactivity in patients with diabetes mellitus. Numerous mechanisms contribute to platelet dysfunction observed in diabetes mellitus (DM) patients, including those due to hyperglycemia, insulin deficiency, associated metabolic conditions, and other cellular abnormalities. Hyperglycemia increases platelet reactivity by glycating platelet surface proteins (impairing membrane fluidity and, therefore, increasing platelet adhesion), activating protein kinase C (a mediator of platelet activation), inducing P-selectin (a surface adhesion protein) expression, and due to osmotic effect. Insulin deficiency is also pivotal for platelet dysfunction by different mechanisms. Some of these mechanisms have been suggested to be IRS dependent, such as the increase in intracellular calcium concentration that leads to enhanced platelet degranulation and aggregation, whereas other factors are not dependent of IRS, such as the impaired response to NO and PGI2, which also enhances platelet reactivity. Metabolic conditions frequently associated with DM status may per se play a role on platelet hyperreactivity, including obesity, dyslipidemia, and enhanced systemic inflammation. Obesity is associated with insulin resistance and contributes to platelet dysfunction, mainly in terms of adhesion and activation, due to mechanisms such as increased cytosolic calcium concentration and augmented oxidative stress. Abnormalities of lipidic profile, particularly hypertriglyceridemia, affect platelet reactivity by different mechanisms, such as inducing endothelial dysfunction. Endothelial dysfunction is another characteristic feature of DM, which enhances platelet reactivity by decreasing the production of NO and PGI2 and contributes to the prothrombotic state through an increased production of TF. DM patients present other platelet abnormalities that may increase platelet adhesion and activation, including increased expression of surface proteins (P-selectin and GP IIb/IIIa), augmented cytosolic calcium concentration, upregulation of P2Y12 signaling, increased platelet turnover, and oxidative stress, which leads to an excessive production of reactive oxygen and nitrogen species. ADP, adenosine diphosphate; Ca⫹⫹: calcium; GP, glycoprotein; IRS, insulin receptor substrate; NO, nitric oxide; PGI2, prostacycline; PKC, protein kinase C; ROS/NOS, reactive oxygen and nitrogen species; TF, tissue factor. Reproduced with permission from Ferreiro JL & Angiolillo DJ: 2011. Diabetes and anti-platelet therapy in acute coronary syndrome. Circulation 123:798-813.
als will specifically explore the benefit of aspirin for primary prevention in patients with DM. The benefit of aspirin in secondary prevention in patients with CAD or undergoing percutaneous coronary intervention (PCI) is undisputed. Aspirin must be given at an initial dose of 162325 mg followed by a daily dose of 75212
162 mg (Anderson et al. 2011, Kushner et al. 2009), which is also the recommended maintenance dose in patients with DM (Colwell 2004). The use of lowdose aspirin (75-150 mg/day) in secondary prevention has been found to be at least as effective as higher daily doses, whereas bleeding complications decrease with the lower doses (Antiplatelet Trialists’ Collab-
oration 1994, Antithrombotic Trialists’ Collaboration 2002). Because DM is an independent risk factor for presenting recurrent ischemic events, it is of particular interest to analyze antiplatelet drug efficacy in this high-risk population. Several studies have observed an association between aspirin poor responsiveness and a TCM Vol. 20, No. 7, 2010
higher risk of recurrent ischemic events (Snoep et al. 2007). The prevalence of aspirin resistance varies widely, but when using COX-1 specific assays, aspirin resistance is a very infrequent phenomenon (⬍5% of patients) (Gurbel et al. 2007). Of note, poor patient compliance is the most important factor that causes aspirin resistance (Ferreiro and Angiolillo 2011). High platelet reactivity, as measured by COX-1 nonspecific assays, is more common in patients with DM than in non-DM patients. The mechanisms associated with this phenomenon are multiple and include (1) decreased aspirinmediated protein acetylation due to hyperglycemia and poor metabolic control; (2) increased TXA2 synthesis; and (3) accelerated platelet turnover, as newly generated platelets not exposed to aspirin may continue to generate TXA2 (Ferreiro and Angiolillo 2011). Pharmacodynamic studies suggest that a twice-daily aspirin dosing regimen rather than an increase in once-daily dosing may be a strategy to optimize aspirin-induced antiplatelet effects in DM (Capodanno et al. 2011). However, whether this translates into better clinical outcomes warrants investigation. Clopidogrel Clopidogrel, a second-generation thienopyridine, is the most broadly used P2Y12 inhibitor in clinical practice. As all thienopyridines, clopidogrel is a prodrug that irreversibly blocks platelet ADP P2Y12 receptor. Clopidogrel largely replaced ticlopidine (the first thienopyridine approved for clinical use) due to its better safety profile (Bertrand et al. 2000), and it also has the advantage of achieving a faster onset of action through administration of a loading dose (Cadroy et al. 2000). The efficacy of clopidogrel for secondary prevention was evaluated in the CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trial (N ⫽ 19,185), in which the benefit of clopidogrel therapy (75 mg daily) compared with aspirin (325 mg daily) was greater (15.6% vs 17.7%; P ⫽ .042) in DM patients, whereas the reduction in the rates of ischemic outcomes in non-DM patients did not reach statistical significance (Bhatt et al. 2002). Several large-scale clinical trials have demonstrated a clear benefit of dual anTCM Vol. 20, No. 7, 2010
tiplatelet therapy (DAPT), consisting of clopidogrel in addition to aspirin, for preventing recurrent ischemic events compared with aspirin alone in the setting of ACS and/or PCI. Table 1 summarizes ACS/PCI trials comparing DAPT versus aspirin in which results are available for the DM cohorts (Mehta et al. 2001, Sabatine et al. 2005, Steinhubl et al. 2002, Yusuf et al. 2001). Accordingly, the use of this DAPT treatment regimen is endorsed by current practice guidelines (Anderson et al. 2011, Kushner et al. 2009). A relatively high percentage of patients (5%-40%) have suboptimal clopidogrel effects, which have been associated with adverse outcomes in numerous studies, underscoring the relevance of this phenomenon (Ferreiro and Angiolillo 2009). Genetic, cellular, and clinical factors have been proposed to be involved in the variability in individual response to clopidogrel. Among the latter, DM status has been repeatedly associated with impaired clopidogrel-induced platelet inhibition in both acute and maintenance phases of therapy (Ferreiro and Angiolillo 2009). Of note, DM patients at a more advanced stage, such as those requiring insulin therapy or those who have developed chronic kidney disease, have the worst response to clopidogrel (Angiolillo et al. 2006, 2010a), which may also contribute to the higher risk of atherothrombotic complications in these settings. Mechanisms intrinsic to the diabetic platelet that have been suggested to specifically contribute to clopidogrel resistance in DM patients include (1) diminished platelet response to insulin, which leads to increased platelet adhesion, aggregation, and procoagulant activity; (2) genetic polymorphisms regulating platelet signaling pathways, such as insulin receptor substrate (IRS)-1; (3) dysregulation of calcium metabolism; (4) upregulation of P2Y12 receptor signaling; (5) increased exposure to ADP; and (6) increased platelet turnover (Ferreiro and Angiolillo 2011). • Future Treatment Strategies DM is a predictor of poor responsiveness to aspirin and clopidogrel, which is associated with an increased risk of ischemic events. Several treatment strategies have been proposed to optimize platelet inhibition in patients with DM.
Modification of Aspirin and Clopidogrel Dosing Currently, the recommended maintenance dose of aspirin is 75-162 mg daily (Anderson et al. 2011, Kushner et al. 2009). In patients with DM, an increase in aspirin dose improves platelet inhibition and decreases the rate of aspirin resistance only to a certain extent (DiChiara et al. 2007). The CURRENT/OASIS-7 (Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Organization to Assess Strategies in Ischemic Syndromes) trial randomized ACS patients (N ⫽ 25,087) scheduled to undergo angiography in a 2 ⫻ 2 factorial design to high (600 mg loading dose followed by 150 mg daily for 1 week and then 75 mg/daily) or standard dose of clopidogrel (300 mg loading followed by 75 mg daily) for 1 month and in an open-label way to high (300-325 mg daily) versus low dose (75100 mg daily) of aspirin. No differences in efficacy among aspirin doses were found, whereas a trend toward a slightly higher rate of gastrointestinal bleeds in the high-dose aspirin arm was observed (0.38% vs 0.24%; P ⫽ .051) (Mehta et al. 2010). The results of this study in the DM subgroup regarding aspirin dosage are still pending. Platelet turnover is accelerated in DM patients, which may lead to an augmented proportion of nonaspirin-inhibited platelets during the daily dosing interval (Guthikonda et al. 2007). Some mechanistic studies have observed that a twice-daily dosing of aspirin may be beneficial in terms of increasing platelet inhibition in DM patients (Capodanno et al. 2011), although studies assessing the clinical impact of this strategy are lacking. The approved loading and maintenance doses for clopidogrel are 300 mg and 75 mg/daily (Anderson et al. 2011, Kushner et al. 2009), respectively, although a loading dose of 600 mg is commonly used in clinical practice. A moderate improvement in platelet inhibition with a high (150 mg) maintenance dose of clopidogrel compared to standard dosing (75 mg) in DM patients with CAD and high platelet reactivity was observed in the OPTIMUS (Optimizing Antiplatelet Therapy in Diabetes Mellitus) study (Angiolillo et al. 2007). However, the results of the CURRENT/OASIS-7 trial did not show a benefit derived 213
Results are expressed as percentage of events and association measure [95% confidence interval].
PCI patients from CLARITY Aspirin ⫹ clopidogrel vs aspirin 1,863
Use of New Agents
a
Elective PCI Aspirin ⫹ clopidogrel vs aspirin 2,116
DM, diabetes mellitus; MI, myocardial infarction; NA, not available; NSTEMI, non-ST-elevation myocardial infarction; OR, odds ratio; PCI, percutaneous coronary intervention; RR, relative risk; RRR, relative risk reduction; STEMI, ST-elevation myocardial infarction; TVR, target vessel revascularization; UA, unstable angina. Modified with permission from Ferreiro JL & Angiolillo DJ: 2011. Diabetes and anti-platelet therapy in acute coronary syndrome. Circulation 123:798-813.
6.0% vs 10.1% OR ⫽ 0.61 [0.24-1.53] 282
PCI patients from CURE Aspirin ⫹ clopidogrel vs aspirin
PCI-CURE (Mehta et al. 2001) CREDO (Steinhubl et al. 2002) PCICLARITY (Sabatine et al. 2005)
2,658
Cardiovascular death, recurrent MI, or stroke at 30 days
3.6% vs 6.2% OR ⫽ 0.54 [0.35-0.85]
% NA RRR ⫽ 11.2 [(⫺46.8)-46.2] 560 8.5% vs 11.5% RRR ⫽ 26.9% [3.9%-44.4%]
12.9% vs 16.5% RR ⫽ 0.77 [0.48-1.22] 504 4.5% vs 6.4% RR ⫽ 0.70 [0.50-0.97]
14.2% vs 16.7% RR ⫽ 0.84 [0.70-1.02] 2840 UA/NSTEMI 12,562 CURE (Yusuf et al. 2001)
Aspirin ⫹ clopidogrel vs aspirin
Cardiovascular death, nonfatal MI, or stroke at 1 year Cardiovascular death, MI, or urgent TVR at 30 days Death, MI, or stroke at 1 year
9.3% vs 11.4% RR ⫽ 0.80 [0.72-0.90]
Results in DM subgroupa N (DM) Results in overall populationa Primary endpoint Setting Study drugs N (overall) Study
Table 1. Large-scale randomized clinical trials evaluating the efficacy of standard dual-antiplatelet therapy with aspirin and clopidogrel in ACS/PCI patients in which results of the diabetes mellitus subgroup are available 214
from the high clopidogrel dose regimen in the overall population. Whereas a decrease in the rates of ischemic outcomes was observed in the PCI subgroup, the subset of patients with DM undergoing PCI did not benefit from the high clopidogrel maintenance dose (4.9% vs 5.6%; hazard ratio (HR) ⫽ 0.87 [0.66-1.15]) (Mehta et al. 2010). Although the use of a “tailored treatment”—increasing clopidogrel dosing according to the degree of responsiveness of a given patient—assessed by a platelet function assay has raised considerable interest, the GRAVITAS (Gauging Responsiveness with a VerifyNow Assay: Impact on Thrombosis and Safety) trial did not find a benefit to this strategy, which was likely due only to the modest increase in platelet inhibition achieved with a high dose of clopidogrel in addition to a low incidence of events (Price et al. 2011).
Several new agents that target the TXA2 pathway have been evaluated, including picotamide (a combined TXA2 synthase inhibitor and TP receptor blocker), ridogrel (a combined TXA2 synthase inhibitor and TP receptor blocker), ramatroban (a TP receptor inhibitor), NCX 4016 (an NO-releasing aspirin derivative), Si8886/terutroban (a TP receptor inhibitor), and EV-077 (a combined TXA2 synthase inhibitor and TP receptor blocker) (Ferreiro and Angiolillo 2011). Currently, none appear to be suitable for replacing aspirin in patients with CAD. Two novel and more potent P2Y12 receptor inhibitors (prasugrel and ticagrelor) with important pharmacological advantages over clopidogrel have been approved for clinical use, and their utilization is particularly attractive in high-risk patients, such as those with DM. Prasugrel, a third-generation thienopyridine, is a prodrug that requires hepatic metabolism to generate an active metabolite that irreversibly blocks the P2Y12 receptor. Prasugrel has a faster onset of action, greater platelet inhibition due to a more efficient conversion into its active metabolite, and less interindividual response variability compared with clopidogrel, even when used at high dose (Ferreiro and Angiolillo 2009). The greater pharmacodynamic efficacy of standard-dose TCM Vol. 20, No. 7, 2010
prasugrel (60 mg loading dose/10 mg once-daily maintenance dose) over highdose clopidogrel has also been proven in type 2 DM patients with CAD (Angiolillo et al. 2011a). A net clinical benefit of prasugrel compared to clopidogrel in patients (N ⫽ 13,608) with moderate to high-risk ACS with scheduled PCI was observed in the TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38) trial. The subset of patients with DM (n ⫽ 3146) benefited most from prasugrel in this study, as shown in a predefined subgroup analysis (Wiviott et al. 2008). Prasugrel reached a significant 30% reduction in the incidence of the primary endpoint in subjects with DM (12.2% vs 17.0%; HR ⫽ 0.70; P ⬍ .001). The risk of stent thrombosis was also reduced with prasugrel in the DM cohort (2.0% vs 3.6%; HR ⫽ 0.52 [0.33-0.84]; P ⫽ .007). Remarkably, no differences in the rates of major non-CABG-related bleeding were observed (2.6% vs 2.5%; HR ⫽ 1.06 [0.66-1.69]; P ⫽ .81). Ticagrelor is the first developed agent of the cyclopentyltriazolopyrimidines group, which directly and reversibly inhibits, through allosteric modulation, platelet ADP P2Y12 receptor signaling. Similar to prasugrel, standard-dose ticagrelor (180 mg loading dose/90 mg twice-daily maintenance dose) has a faster onset of action and provides stronger and more consistent platelet inhibition than clopidogrel (Storey et al. 2007). The PLATO (Platelet Inhibition and Patient Outcomes) trial proved the benefit of ticagrelor over clopidogrel in ACS patients (N ⫽ 18,624). In a predefined subgroup analysis of the DM cohort (n ⫽ 4662), a numerical but not significant reduction in the rates of the primary efficacy endpoint (14.1% vs 16.2%; HR ⫽ 0.88 [0.76-1.03]) was observed, which was consistent with the overall trial results (James et al. 2010). Parallel results were obtained for other efficacy endpoints, such as all-cause mortality (7.0% vs 8.7%; HR ⫽ 0.82 [0.66-1.01]), myocardial infarction (8.4% vs 9.1%; HR ⫽ 0.92 [0.75-1.13]), and stent thrombosis (1.6% vs 2.4%; HR ⫽ 0.65 [0.36-1.17]). Notably, ticagrelor showed a particular benefit in those patients with worse metabolic control (defined as HbA1c levels above the meTCM Vol. 20, No. 7, 2010
dian of 6%), in which ticagrelor significantly reduced the rates of the primary endpoint (11.4% vs 14.2%; HR ⫽ 0.80 [0.70-0.91]). Importantly, no differences in major bleeding rates were observed between the ticagrelor and clopidogrel groups (11.6% vs 11.2%; HR ⫽ 1.04; P ⫽ .43) (James et al. 2010). Other novel P2Y12 inhibitors, such as cangrelor and elinogrel, are currently under development, and their potential role in DM patients remains to be determined. Addition of a Third Antiplatelet Agent Other strategies that may improve platelet inhibition in DM patients include adding a third agent, also known as “triple therapy,” blocking platelet signaling pathways other than COX-1 and P2Y12. Cilostazol is a potent phosphodiesterase (PDE) 3 inhibitor that increases intraplatelet cyclic adenosine monophosphate concentration, leading to enhanced platelet inhibition when used in conjunction with standard DAPT (Angiolillo et al. 2011b). This effect is more pronounced in DM subjects (Angiolillo et al. 2008), in whom addition of cilostazol to standard DAPT reduces platelet reactivity to a higher extent than increasing clopidogrel maintenance dose (150 mg daily) (Ferreiro et al. 2011). These results may help explain the benefit of cilostazol in addition to DAPT in ACS/PCI patients (Biondi-Zoccai et al. 2008). However, a high frequency of side effects, mainly headache, gastrointestinal disturbances, and palpitations, has been reported (Angiolillo et al. 2008). On the contrary, addition of pentoxifylline, a nonselective PDE inhibitor, to standard DAPT in DM patients did not show any additional platelet inhibitory effects (Ueno et al. 2011). Because DM patients have increased thrombin generation, inhibiting thrombin-mediated processes, the most important inducer of platelet activation, may represent an attractive strategy in these subjects. This may be achieved by either inhibiting platelet thrombin receptors, also known as protease activated receptors (PARs), or inhibiting the coagulation cascade. Two oral thrombin receptor antagonists, which block the platelet PAR-1 receptor subtype, are currently under clinical development: vorapaxar (SCH530348) and atopaxar
(E5555) (Angiolilo et al. 2010b). Because DM subjects have increased thrombin generation (Ferreiro and Angiolillo 2011), results of ongoing clinical trials evaluating these drugs may be of special interest in this population. Novel oral anticoagulants, which include anti-factor IIa or “gatrans” (eg dabigatran) and anti-factor Xa or “xabans” (eg rivaroxaban, apixaban, and darexaban), are being investigated as adjunctive therapy in ACS (Wittkowsky 2010). The main limitation of this strategy may be the increased risk of bleeding, which led to stoppage of the APPRAISE-2 (Apixaban for Prevention of Acute Ischemic Events) trial that was designed to evaluate the safety of apixaban in addition to DAPT in ACS patients. • Conclusion Among patients with DM, there is a high prevalence of subjects with inadequate platelet inhibition using the most commonly recommended oral antiplatelet agents (aspirin and clopidogrel). This phenomenon may contribute to their increased rates of recurrent atherothrombotic events compared with those of non-DM subjects. The development of novel and more effective antithrombotic treatment strategies is warranted in such a high-risk population and may contribute to improve the clinical outcomes in DM patients. • Disclosures Dominick J. Angiolillo has received honoraria for lectures from Bristol Myers Squibb; Sanofi-Aventis; Eli Lilly and Company; Daiichi Sankyo, Inc.; consulting fees from Bristol Myers Squibb; Sanofi-Aventis; Eli Lilly and Company; Daiichi Sankyo, Inc.; The Medicines Company; Portola; Novartis; Medicure; Accumetrics; Arena Pharmaceuticals; Astra Zeneca; Merck; Evolva; Abbott Vascular; and research grants from Bristol Myers Squibb; Sanofi-Aventis; GlaxoSmithKline; Otsuka; Eli Lilly and Company; Daiichi Sankyo, Inc.; The Medicines Company; Portola; Accumetrics; Schering-Plough; AstraZeneca; and Eisai. José Luis Ferreiro has received honoraria for lectures from Eli Lilly and Company and Daiichi Sankyo, Inc. 215
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James S, Angiolillo DJ, Cornel JH, et al: 2010. 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 31:3006 –3016. Kushner FG, Hand M, Smith SC Jr, et al: 2009. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 120:2271–2306. Mehta SR, Bassand JP, Chrolavicius S, et al; CURRENT-OASIS 7 Investigators: 2010. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med 363:930 –942. Mehta SR, Yusuf S, Peters RJ, et al; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial (CURE) Investigators: 2001. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: The PCI-CURE study. Lancet 358:527–533. Patrono C, García Rodríguez LA, Landolfi R, & Baigent C: 2005. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 353:2373–2383. Pignone M, Alberts MJ, Colwell JA, et al; American Diabetes Association; American Heart Association; American College of Cardiology Foundation: 2010. Aspirin for primary prevention of cardiovascular events in people with diabetes. J Am Coll Cardiol 55:2878 –2886. Price MJ, Berger PB, Teirstein PS, et al: 2011. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: The GRAVITAS randomized trial. JAMA 305:1097–1105. Sabatine MS, Cannon CP, Gibson CM, et al; Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators: 2005. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: The PCICLARITY study. JAMA 294:1224 –1232.
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Snoep JD, Hovens MM, Eikenboom JC, et al: 2007. Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: A systematic review and meta-analysis. Arch Intern Med 167: 1593–1599. Steinhubl SR, Berger PB, Mann JT 3rd, et al; CREDO Investigators: 2002. Clopidogrel for the reduction of events during observation: Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: A randomized controlled trial. JAMA 288:2411–2420. Storey RF, Husted S, Harrington RA, et al: 2007. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol 50:1852–1856. Ueno M, Ferreiro JL, Tomasello SD, et al: 2011 Impact of pentoxifylline on platelet function profiles in patients with type 2 diabetes mellitus and coronary artery disease on dual antiplatelet therapy with aspirin and clopidogrel. JACC Cardiovasc Interv 4:905–912. Webster MW & Scott RS: 1997. What cardiologists need to know about diabetes. Lancet 350(Suppl 1):S23–S28.
Wild S, Roglic G, Green A, et al: 2004. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care 27:1047–1053. Wittkowsky AK: 2010. New oral anticoagulants: A practical guide for clinicians. J Thromb Thrombolysis 29:182–191. Wiviott SD, Braunwald E, Angiolillo DJ, et al; TRITON-TIMI 38 Investigators: 2008. 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 118:1626 –1636. Yusuf S, Zhao F, Mehta SR, et al; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators: 2001. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 345:494 –502.
PII S1050-1738(11)00064-8
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Mitogen-Activated Protein Kinase Inhibitor Regulation of Heart Function and Fibrosis in Cardiomyopathy Caused by Lamin A/C Gene Mutation Antoine Muchir,* Wei Wu, and Howard J. Worman*
Mutations in the lamin A/C gene (LMNA) encoding A-type nuclear lamins cause dilated cardiomyopathy. We have uncovered a novel connection between these mutations and hyperactivation of the extracellular signalregulated kinase 1/2 and c-jun N-terminal kinase branches of the mitogenactivated protein kinase signaling pathway in a mouse model of the disease. This discovery has identified targets that can be inhibited by drugs that improve heart function and prevent fibrosis. (Trends Cardiovasc Med 2010;20:217–221) © 2010 Elsevier Inc. All rights reserved. • LMNA Cardiomyopathy Dilated cardiomyopathy is characterized by increased myocardial mass and volAntoine Muchir, Wei Wu, and Howard J. Worman are at the Department of Medicine
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and the Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. *Address correspondence to: Howard J. Worman or Antoine Muchir, Department of Medi-
ume with thinning and stretching of the ventricular walls; this compromises cardiac contractility, ultimately resulting in poor left ventricular function (Luk et al. 2009). Genetic disorders are responsible for at least 20% of dilated cardiomyopathies (Michels et al., 1992). Causative mutations occur in genes that encode components of a wide variety of cellular structures, including the contractile apparatus, the force transduction apparatus, and the nuclear envelope (Morita et al., 2005). One such gene is LMNA encoding A-type lamins of the nuclear envelope (Bonne et al. 1999, Fatkin et al. 1999). LMNA may be the most prevalent dilated cardiomyopathy gene because mutations appear to be responsible for approximately 8% of inherited cases (Millat et al. 2011, Taylor et al. 2003). Affected individuals sometimes have associated skeletal muscular dystrophy, most frequently the Emery–Dreifuss phenotype (Bonne et al. 1999). The onset of symptoms in LMNA cardiomyopathy is variable, ranging from the first to sixth decade of life and occurring most frequently in the third decade (Ben Yaou et al. 2006). LMNA cardiomyopathy has a more aggressive course than most other inherited dilated cardiomyopathies (Pasotti et al. 2008, Taylor et al. 2003, van Berlo et al. 2005). In addition to left ventricular dilatation, affected individuals have early atrioventricular conduction block followed by ventricular arrhythmias. Arrhythmias gradually become more frequent with age, potentially leading to sudden death (Sanna et al. 2003). Although sudden death from arrhythmias may be prevented by implantation of a pacemaker and defibrillator, progressive heart failure eventually becomes resistant to treatment (Golzio et al. 2007, Meune et al. 2006, van Berlo et al. 2005). No therapies are curative, and heart transplantation is often necessary.
cine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, 10th Floor, Room 508, New York, NY 10032, USA. Tel.: 212-305-1306; fax: 212-305-6443; e-mail: [email protected] or am2434@columbia. edu. © 2010 Elsevier Inc. All rights reserved. 1050-1738/$-see front matter
217
Despite the use of recommended antiplatelet treatment strategies, the presence of diabetes mellitus (DM) has been consistently associated with a higher risk of recurrent ischemic events in patients suffering an acute coronary syndrome. The high prevalence of DM patients presenting with low responsiveness to standard oral antiplatelet treatment regimens contributes to these impaired outcomes. This article provides an overview of the currently available oral antiplatelet agents, focusing on limitations of these therapies in DM patients, and evaluates new antithrombotic treatment strategies that may help overcome these limitations. (Trends Cardiovasc Med 2010;20:211–217) © 2010 Elsevier Inc. All rights reserved. The prevalence of diabetes mellitus (DM), mostly at the expense of type 2 DM, is increasing worldwide, with a prediction of more than 350 million people being affected by 2030, which has led to the labeling of this disease as a “global pandemic” (Wild et al. 2004). Cardiovascular disease is the leading cause of morbidity and mortality in DM patients, José Luis Ferreiro is at the Heart Diseases Institute, Hospital Universitari de Bellvitge-IDIBELL, University of Barcelona, L’Hospitalet de Llobregat, Barcelona 08907, Spain, and the University of Florida College of Medicine–Jacksonville, Jacksonville, FL 32209, USA. Ángel R. Cequier is at the Heart Diseases Institute, Hospital Universitari de Bellvitge-IDIBELL, University of Barcelona, L’Hospitalet de Llobregat, Barcelona 08907, Spain. Dominick J. Angiolillo is at the University of Florida College of Medicine-Jacksonville, Jacksonville, FL 32209, USA. *Address correspondence to: Dominick J. Angiolillo, University of Florida College of Medicine–Jacksonville, 655 West 8th Street, Jacksonville, FL 32209, USA. Tel.: ⫹1-904-2443933; fax: ⫹1-904-244-3102; e-mail: dominick. [email protected]. © 2010 Elsevier Inc. All rights reserved. 1050-1738/$-see front matter
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due mostly to coronary artery disease (CAD) (Webster and Scott 1997). In fact, large-scale surveys have shown a prevalence of DM of approximately 30% both in patients with stable CAD and in those with acute coronary syndromes (ACS), confirming the important burden of cardiovascular disease in this population (Bartnik et al. 2004). Several metabolic and cellular abnormalities characteristic of the DM status contribute to the hyperreactive platelet phenotype observed in these patients (Figure 1) (Ferreiro and Angiolillo 2011), which contributes to the inadequate response to antiplatelet agents frequently observed in this population (Angiolillo et al. 2005, Ferreiro and Angiolillo 2011). This impaired response to antiplatelet drugs has been consistently associated with a higher risk of adverse ischemic outcomes (Ferreiro and Angiolillo 2009), a noteworthy observation given the negative impact of DM on outcomes that has been repeatedly observed in ACS (Yusuf et al. 2001).
The aim of this article is to provide an overview of the currently available oral antiplatelet agents, focusing on limitations of these therapies in DM patients, and to evaluate the most recent developments regarding new antithrombotic agents and treatment strategies that may help to overcome these limitations. • Oral Antiplatelet Drugs Two classes of oral antiplatelet agents are currently approved for treatment and prevention of recurrent ischemic events in patients with CAD: cycloxigenase-1 (COX-1) inhibitors and adenosine diphosphate (ADP) P2Y12 receptor antagonists (Anderson et al. 2011, Kushner et al. 2009). This section provides an overview of the most broadly used agents (aspirin and clopidogrel), focusing on their specific benefits and limitations in patients with DM. Aspirin Aspirin irreversibly blocks COX-1, the enzyme that catalyzes the synthesis of thromboxane A2 (TXA2) from arachidonic acid. Therefore, aspirin inhibits platelet formation of TXA2, which diminishes platelet aggregation mediated by thromboxane and the prostaglandin endoperoxide (TP) receptor pathway (Patrono et al. 2005). Routine use of aspirin for primary prevention is controversial. In fact, a consensus document suggested a restricted recommendation of low-dose (75-162 mg/day) aspirin use for primary prevention in DM patients at increased cardiovascular disease risk (men older than age 50 years and women older than age 60 years with 10-year risk of cardiovascular events ⬎10%) and who are not at increased risk of bleeding (Pignone et al. 2010). The ongoing ASCEND (A Study of Cardiovascular Events in Diabetes; NCT00135226) and ACCEPT-D (Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes; ISRCTN48110081) tri-
211
Figure 1. Mechanisms contributing to platelet hyperreactivity in patients with diabetes mellitus. Numerous mechanisms contribute to platelet dysfunction observed in diabetes mellitus (DM) patients, including those due to hyperglycemia, insulin deficiency, associated metabolic conditions, and other cellular abnormalities. Hyperglycemia increases platelet reactivity by glycating platelet surface proteins (impairing membrane fluidity and, therefore, increasing platelet adhesion), activating protein kinase C (a mediator of platelet activation), inducing P-selectin (a surface adhesion protein) expression, and due to osmotic effect. Insulin deficiency is also pivotal for platelet dysfunction by different mechanisms. Some of these mechanisms have been suggested to be IRS dependent, such as the increase in intracellular calcium concentration that leads to enhanced platelet degranulation and aggregation, whereas other factors are not dependent of IRS, such as the impaired response to NO and PGI2, which also enhances platelet reactivity. Metabolic conditions frequently associated with DM status may per se play a role on platelet hyperreactivity, including obesity, dyslipidemia, and enhanced systemic inflammation. Obesity is associated with insulin resistance and contributes to platelet dysfunction, mainly in terms of adhesion and activation, due to mechanisms such as increased cytosolic calcium concentration and augmented oxidative stress. Abnormalities of lipidic profile, particularly hypertriglyceridemia, affect platelet reactivity by different mechanisms, such as inducing endothelial dysfunction. Endothelial dysfunction is another characteristic feature of DM, which enhances platelet reactivity by decreasing the production of NO and PGI2 and contributes to the prothrombotic state through an increased production of TF. DM patients present other platelet abnormalities that may increase platelet adhesion and activation, including increased expression of surface proteins (P-selectin and GP IIb/IIIa), augmented cytosolic calcium concentration, upregulation of P2Y12 signaling, increased platelet turnover, and oxidative stress, which leads to an excessive production of reactive oxygen and nitrogen species. ADP, adenosine diphosphate; Ca⫹⫹: calcium; GP, glycoprotein; IRS, insulin receptor substrate; NO, nitric oxide; PGI2, prostacycline; PKC, protein kinase C; ROS/NOS, reactive oxygen and nitrogen species; TF, tissue factor. Reproduced with permission from Ferreiro JL & Angiolillo DJ: 2011. Diabetes and anti-platelet therapy in acute coronary syndrome. Circulation 123:798-813.
als will specifically explore the benefit of aspirin for primary prevention in patients with DM. The benefit of aspirin in secondary prevention in patients with CAD or undergoing percutaneous coronary intervention (PCI) is undisputed. Aspirin must be given at an initial dose of 162325 mg followed by a daily dose of 75212
162 mg (Anderson et al. 2011, Kushner et al. 2009), which is also the recommended maintenance dose in patients with DM (Colwell 2004). The use of lowdose aspirin (75-150 mg/day) in secondary prevention has been found to be at least as effective as higher daily doses, whereas bleeding complications decrease with the lower doses (Antiplatelet Trialists’ Collab-
oration 1994, Antithrombotic Trialists’ Collaboration 2002). Because DM is an independent risk factor for presenting recurrent ischemic events, it is of particular interest to analyze antiplatelet drug efficacy in this high-risk population. Several studies have observed an association between aspirin poor responsiveness and a TCM Vol. 20, No. 7, 2010
higher risk of recurrent ischemic events (Snoep et al. 2007). The prevalence of aspirin resistance varies widely, but when using COX-1 specific assays, aspirin resistance is a very infrequent phenomenon (⬍5% of patients) (Gurbel et al. 2007). Of note, poor patient compliance is the most important factor that causes aspirin resistance (Ferreiro and Angiolillo 2011). High platelet reactivity, as measured by COX-1 nonspecific assays, is more common in patients with DM than in non-DM patients. The mechanisms associated with this phenomenon are multiple and include (1) decreased aspirinmediated protein acetylation due to hyperglycemia and poor metabolic control; (2) increased TXA2 synthesis; and (3) accelerated platelet turnover, as newly generated platelets not exposed to aspirin may continue to generate TXA2 (Ferreiro and Angiolillo 2011). Pharmacodynamic studies suggest that a twice-daily aspirin dosing regimen rather than an increase in once-daily dosing may be a strategy to optimize aspirin-induced antiplatelet effects in DM (Capodanno et al. 2011). However, whether this translates into better clinical outcomes warrants investigation. Clopidogrel Clopidogrel, a second-generation thienopyridine, is the most broadly used P2Y12 inhibitor in clinical practice. As all thienopyridines, clopidogrel is a prodrug that irreversibly blocks platelet ADP P2Y12 receptor. Clopidogrel largely replaced ticlopidine (the first thienopyridine approved for clinical use) due to its better safety profile (Bertrand et al. 2000), and it also has the advantage of achieving a faster onset of action through administration of a loading dose (Cadroy et al. 2000). The efficacy of clopidogrel for secondary prevention was evaluated in the CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trial (N ⫽ 19,185), in which the benefit of clopidogrel therapy (75 mg daily) compared with aspirin (325 mg daily) was greater (15.6% vs 17.7%; P ⫽ .042) in DM patients, whereas the reduction in the rates of ischemic outcomes in non-DM patients did not reach statistical significance (Bhatt et al. 2002). Several large-scale clinical trials have demonstrated a clear benefit of dual anTCM Vol. 20, No. 7, 2010
tiplatelet therapy (DAPT), consisting of clopidogrel in addition to aspirin, for preventing recurrent ischemic events compared with aspirin alone in the setting of ACS and/or PCI. Table 1 summarizes ACS/PCI trials comparing DAPT versus aspirin in which results are available for the DM cohorts (Mehta et al. 2001, Sabatine et al. 2005, Steinhubl et al. 2002, Yusuf et al. 2001). Accordingly, the use of this DAPT treatment regimen is endorsed by current practice guidelines (Anderson et al. 2011, Kushner et al. 2009). A relatively high percentage of patients (5%-40%) have suboptimal clopidogrel effects, which have been associated with adverse outcomes in numerous studies, underscoring the relevance of this phenomenon (Ferreiro and Angiolillo 2009). Genetic, cellular, and clinical factors have been proposed to be involved in the variability in individual response to clopidogrel. Among the latter, DM status has been repeatedly associated with impaired clopidogrel-induced platelet inhibition in both acute and maintenance phases of therapy (Ferreiro and Angiolillo 2009). Of note, DM patients at a more advanced stage, such as those requiring insulin therapy or those who have developed chronic kidney disease, have the worst response to clopidogrel (Angiolillo et al. 2006, 2010a), which may also contribute to the higher risk of atherothrombotic complications in these settings. Mechanisms intrinsic to the diabetic platelet that have been suggested to specifically contribute to clopidogrel resistance in DM patients include (1) diminished platelet response to insulin, which leads to increased platelet adhesion, aggregation, and procoagulant activity; (2) genetic polymorphisms regulating platelet signaling pathways, such as insulin receptor substrate (IRS)-1; (3) dysregulation of calcium metabolism; (4) upregulation of P2Y12 receptor signaling; (5) increased exposure to ADP; and (6) increased platelet turnover (Ferreiro and Angiolillo 2011). • Future Treatment Strategies DM is a predictor of poor responsiveness to aspirin and clopidogrel, which is associated with an increased risk of ischemic events. Several treatment strategies have been proposed to optimize platelet inhibition in patients with DM.
Modification of Aspirin and Clopidogrel Dosing Currently, the recommended maintenance dose of aspirin is 75-162 mg daily (Anderson et al. 2011, Kushner et al. 2009). In patients with DM, an increase in aspirin dose improves platelet inhibition and decreases the rate of aspirin resistance only to a certain extent (DiChiara et al. 2007). The CURRENT/OASIS-7 (Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Organization to Assess Strategies in Ischemic Syndromes) trial randomized ACS patients (N ⫽ 25,087) scheduled to undergo angiography in a 2 ⫻ 2 factorial design to high (600 mg loading dose followed by 150 mg daily for 1 week and then 75 mg/daily) or standard dose of clopidogrel (300 mg loading followed by 75 mg daily) for 1 month and in an open-label way to high (300-325 mg daily) versus low dose (75100 mg daily) of aspirin. No differences in efficacy among aspirin doses were found, whereas a trend toward a slightly higher rate of gastrointestinal bleeds in the high-dose aspirin arm was observed (0.38% vs 0.24%; P ⫽ .051) (Mehta et al. 2010). The results of this study in the DM subgroup regarding aspirin dosage are still pending. Platelet turnover is accelerated in DM patients, which may lead to an augmented proportion of nonaspirin-inhibited platelets during the daily dosing interval (Guthikonda et al. 2007). Some mechanistic studies have observed that a twice-daily dosing of aspirin may be beneficial in terms of increasing platelet inhibition in DM patients (Capodanno et al. 2011), although studies assessing the clinical impact of this strategy are lacking. The approved loading and maintenance doses for clopidogrel are 300 mg and 75 mg/daily (Anderson et al. 2011, Kushner et al. 2009), respectively, although a loading dose of 600 mg is commonly used in clinical practice. A moderate improvement in platelet inhibition with a high (150 mg) maintenance dose of clopidogrel compared to standard dosing (75 mg) in DM patients with CAD and high platelet reactivity was observed in the OPTIMUS (Optimizing Antiplatelet Therapy in Diabetes Mellitus) study (Angiolillo et al. 2007). However, the results of the CURRENT/OASIS-7 trial did not show a benefit derived 213
Results are expressed as percentage of events and association measure [95% confidence interval].
PCI patients from CLARITY Aspirin ⫹ clopidogrel vs aspirin 1,863
Use of New Agents
a
Elective PCI Aspirin ⫹ clopidogrel vs aspirin 2,116
DM, diabetes mellitus; MI, myocardial infarction; NA, not available; NSTEMI, non-ST-elevation myocardial infarction; OR, odds ratio; PCI, percutaneous coronary intervention; RR, relative risk; RRR, relative risk reduction; STEMI, ST-elevation myocardial infarction; TVR, target vessel revascularization; UA, unstable angina. Modified with permission from Ferreiro JL & Angiolillo DJ: 2011. Diabetes and anti-platelet therapy in acute coronary syndrome. Circulation 123:798-813.
6.0% vs 10.1% OR ⫽ 0.61 [0.24-1.53] 282
PCI patients from CURE Aspirin ⫹ clopidogrel vs aspirin
PCI-CURE (Mehta et al. 2001) CREDO (Steinhubl et al. 2002) PCICLARITY (Sabatine et al. 2005)
2,658
Cardiovascular death, recurrent MI, or stroke at 30 days
3.6% vs 6.2% OR ⫽ 0.54 [0.35-0.85]
% NA RRR ⫽ 11.2 [(⫺46.8)-46.2] 560 8.5% vs 11.5% RRR ⫽ 26.9% [3.9%-44.4%]
12.9% vs 16.5% RR ⫽ 0.77 [0.48-1.22] 504 4.5% vs 6.4% RR ⫽ 0.70 [0.50-0.97]
14.2% vs 16.7% RR ⫽ 0.84 [0.70-1.02] 2840 UA/NSTEMI 12,562 CURE (Yusuf et al. 2001)
Aspirin ⫹ clopidogrel vs aspirin
Cardiovascular death, nonfatal MI, or stroke at 1 year Cardiovascular death, MI, or urgent TVR at 30 days Death, MI, or stroke at 1 year
9.3% vs 11.4% RR ⫽ 0.80 [0.72-0.90]
Results in DM subgroupa N (DM) Results in overall populationa Primary endpoint Setting Study drugs N (overall) Study
Table 1. Large-scale randomized clinical trials evaluating the efficacy of standard dual-antiplatelet therapy with aspirin and clopidogrel in ACS/PCI patients in which results of the diabetes mellitus subgroup are available 214
from the high clopidogrel dose regimen in the overall population. Whereas a decrease in the rates of ischemic outcomes was observed in the PCI subgroup, the subset of patients with DM undergoing PCI did not benefit from the high clopidogrel maintenance dose (4.9% vs 5.6%; hazard ratio (HR) ⫽ 0.87 [0.66-1.15]) (Mehta et al. 2010). Although the use of a “tailored treatment”—increasing clopidogrel dosing according to the degree of responsiveness of a given patient—assessed by a platelet function assay has raised considerable interest, the GRAVITAS (Gauging Responsiveness with a VerifyNow Assay: Impact on Thrombosis and Safety) trial did not find a benefit to this strategy, which was likely due only to the modest increase in platelet inhibition achieved with a high dose of clopidogrel in addition to a low incidence of events (Price et al. 2011).
Several new agents that target the TXA2 pathway have been evaluated, including picotamide (a combined TXA2 synthase inhibitor and TP receptor blocker), ridogrel (a combined TXA2 synthase inhibitor and TP receptor blocker), ramatroban (a TP receptor inhibitor), NCX 4016 (an NO-releasing aspirin derivative), Si8886/terutroban (a TP receptor inhibitor), and EV-077 (a combined TXA2 synthase inhibitor and TP receptor blocker) (Ferreiro and Angiolillo 2011). Currently, none appear to be suitable for replacing aspirin in patients with CAD. Two novel and more potent P2Y12 receptor inhibitors (prasugrel and ticagrelor) with important pharmacological advantages over clopidogrel have been approved for clinical use, and their utilization is particularly attractive in high-risk patients, such as those with DM. Prasugrel, a third-generation thienopyridine, is a prodrug that requires hepatic metabolism to generate an active metabolite that irreversibly blocks the P2Y12 receptor. Prasugrel has a faster onset of action, greater platelet inhibition due to a more efficient conversion into its active metabolite, and less interindividual response variability compared with clopidogrel, even when used at high dose (Ferreiro and Angiolillo 2009). The greater pharmacodynamic efficacy of standard-dose TCM Vol. 20, No. 7, 2010
prasugrel (60 mg loading dose/10 mg once-daily maintenance dose) over highdose clopidogrel has also been proven in type 2 DM patients with CAD (Angiolillo et al. 2011a). A net clinical benefit of prasugrel compared to clopidogrel in patients (N ⫽ 13,608) with moderate to high-risk ACS with scheduled PCI was observed in the TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38) trial. The subset of patients with DM (n ⫽ 3146) benefited most from prasugrel in this study, as shown in a predefined subgroup analysis (Wiviott et al. 2008). Prasugrel reached a significant 30% reduction in the incidence of the primary endpoint in subjects with DM (12.2% vs 17.0%; HR ⫽ 0.70; P ⬍ .001). The risk of stent thrombosis was also reduced with prasugrel in the DM cohort (2.0% vs 3.6%; HR ⫽ 0.52 [0.33-0.84]; P ⫽ .007). Remarkably, no differences in the rates of major non-CABG-related bleeding were observed (2.6% vs 2.5%; HR ⫽ 1.06 [0.66-1.69]; P ⫽ .81). Ticagrelor is the first developed agent of the cyclopentyltriazolopyrimidines group, which directly and reversibly inhibits, through allosteric modulation, platelet ADP P2Y12 receptor signaling. Similar to prasugrel, standard-dose ticagrelor (180 mg loading dose/90 mg twice-daily maintenance dose) has a faster onset of action and provides stronger and more consistent platelet inhibition than clopidogrel (Storey et al. 2007). The PLATO (Platelet Inhibition and Patient Outcomes) trial proved the benefit of ticagrelor over clopidogrel in ACS patients (N ⫽ 18,624). In a predefined subgroup analysis of the DM cohort (n ⫽ 4662), a numerical but not significant reduction in the rates of the primary efficacy endpoint (14.1% vs 16.2%; HR ⫽ 0.88 [0.76-1.03]) was observed, which was consistent with the overall trial results (James et al. 2010). Parallel results were obtained for other efficacy endpoints, such as all-cause mortality (7.0% vs 8.7%; HR ⫽ 0.82 [0.66-1.01]), myocardial infarction (8.4% vs 9.1%; HR ⫽ 0.92 [0.75-1.13]), and stent thrombosis (1.6% vs 2.4%; HR ⫽ 0.65 [0.36-1.17]). Notably, ticagrelor showed a particular benefit in those patients with worse metabolic control (defined as HbA1c levels above the meTCM Vol. 20, No. 7, 2010
dian of 6%), in which ticagrelor significantly reduced the rates of the primary endpoint (11.4% vs 14.2%; HR ⫽ 0.80 [0.70-0.91]). Importantly, no differences in major bleeding rates were observed between the ticagrelor and clopidogrel groups (11.6% vs 11.2%; HR ⫽ 1.04; P ⫽ .43) (James et al. 2010). Other novel P2Y12 inhibitors, such as cangrelor and elinogrel, are currently under development, and their potential role in DM patients remains to be determined. Addition of a Third Antiplatelet Agent Other strategies that may improve platelet inhibition in DM patients include adding a third agent, also known as “triple therapy,” blocking platelet signaling pathways other than COX-1 and P2Y12. Cilostazol is a potent phosphodiesterase (PDE) 3 inhibitor that increases intraplatelet cyclic adenosine monophosphate concentration, leading to enhanced platelet inhibition when used in conjunction with standard DAPT (Angiolillo et al. 2011b). This effect is more pronounced in DM subjects (Angiolillo et al. 2008), in whom addition of cilostazol to standard DAPT reduces platelet reactivity to a higher extent than increasing clopidogrel maintenance dose (150 mg daily) (Ferreiro et al. 2011). These results may help explain the benefit of cilostazol in addition to DAPT in ACS/PCI patients (Biondi-Zoccai et al. 2008). However, a high frequency of side effects, mainly headache, gastrointestinal disturbances, and palpitations, has been reported (Angiolillo et al. 2008). On the contrary, addition of pentoxifylline, a nonselective PDE inhibitor, to standard DAPT in DM patients did not show any additional platelet inhibitory effects (Ueno et al. 2011). Because DM patients have increased thrombin generation, inhibiting thrombin-mediated processes, the most important inducer of platelet activation, may represent an attractive strategy in these subjects. This may be achieved by either inhibiting platelet thrombin receptors, also known as protease activated receptors (PARs), or inhibiting the coagulation cascade. Two oral thrombin receptor antagonists, which block the platelet PAR-1 receptor subtype, are currently under clinical development: vorapaxar (SCH530348) and atopaxar
(E5555) (Angiolilo et al. 2010b). Because DM subjects have increased thrombin generation (Ferreiro and Angiolillo 2011), results of ongoing clinical trials evaluating these drugs may be of special interest in this population. Novel oral anticoagulants, which include anti-factor IIa or “gatrans” (eg dabigatran) and anti-factor Xa or “xabans” (eg rivaroxaban, apixaban, and darexaban), are being investigated as adjunctive therapy in ACS (Wittkowsky 2010). The main limitation of this strategy may be the increased risk of bleeding, which led to stoppage of the APPRAISE-2 (Apixaban for Prevention of Acute Ischemic Events) trial that was designed to evaluate the safety of apixaban in addition to DAPT in ACS patients. • Conclusion Among patients with DM, there is a high prevalence of subjects with inadequate platelet inhibition using the most commonly recommended oral antiplatelet agents (aspirin and clopidogrel). This phenomenon may contribute to their increased rates of recurrent atherothrombotic events compared with those of non-DM subjects. The development of novel and more effective antithrombotic treatment strategies is warranted in such a high-risk population and may contribute to improve the clinical outcomes in DM patients. • Disclosures Dominick J. Angiolillo has received honoraria for lectures from Bristol Myers Squibb; Sanofi-Aventis; Eli Lilly and Company; Daiichi Sankyo, Inc.; consulting fees from Bristol Myers Squibb; Sanofi-Aventis; Eli Lilly and Company; Daiichi Sankyo, Inc.; The Medicines Company; Portola; Novartis; Medicure; Accumetrics; Arena Pharmaceuticals; Astra Zeneca; Merck; Evolva; Abbott Vascular; and research grants from Bristol Myers Squibb; Sanofi-Aventis; GlaxoSmithKline; Otsuka; Eli Lilly and Company; Daiichi Sankyo, Inc.; The Medicines Company; Portola; Accumetrics; Schering-Plough; AstraZeneca; and Eisai. José Luis Ferreiro has received honoraria for lectures from Eli Lilly and Company and Daiichi Sankyo, Inc. 215
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PII S1050-1738(11)00064-8
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Mitogen-Activated Protein Kinase Inhibitor Regulation of Heart Function and Fibrosis in Cardiomyopathy Caused by Lamin A/C Gene Mutation Antoine Muchir,* Wei Wu, and Howard J. Worman*
Mutations in the lamin A/C gene (LMNA) encoding A-type nuclear lamins cause dilated cardiomyopathy. We have uncovered a novel connection between these mutations and hyperactivation of the extracellular signalregulated kinase 1/2 and c-jun N-terminal kinase branches of the mitogenactivated protein kinase signaling pathway in a mouse model of the disease. This discovery has identified targets that can be inhibited by drugs that improve heart function and prevent fibrosis. (Trends Cardiovasc Med 2010;20:217–221) © 2010 Elsevier Inc. All rights reserved. • LMNA Cardiomyopathy Dilated cardiomyopathy is characterized by increased myocardial mass and volAntoine Muchir, Wei Wu, and Howard J. Worman are at the Department of Medicine
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and the Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. *Address correspondence to: Howard J. Worman or Antoine Muchir, Department of Medi-
ume with thinning and stretching of the ventricular walls; this compromises cardiac contractility, ultimately resulting in poor left ventricular function (Luk et al. 2009). Genetic disorders are responsible for at least 20% of dilated cardiomyopathies (Michels et al., 1992). Causative mutations occur in genes that encode components of a wide variety of cellular structures, including the contractile apparatus, the force transduction apparatus, and the nuclear envelope (Morita et al., 2005). One such gene is LMNA encoding A-type lamins of the nuclear envelope (Bonne et al. 1999, Fatkin et al. 1999). LMNA may be the most prevalent dilated cardiomyopathy gene because mutations appear to be responsible for approximately 8% of inherited cases (Millat et al. 2011, Taylor et al. 2003). Affected individuals sometimes have associated skeletal muscular dystrophy, most frequently the Emery–Dreifuss phenotype (Bonne et al. 1999). The onset of symptoms in LMNA cardiomyopathy is variable, ranging from the first to sixth decade of life and occurring most frequently in the third decade (Ben Yaou et al. 2006). LMNA cardiomyopathy has a more aggressive course than most other inherited dilated cardiomyopathies (Pasotti et al. 2008, Taylor et al. 2003, van Berlo et al. 2005). In addition to left ventricular dilatation, affected individuals have early atrioventricular conduction block followed by ventricular arrhythmias. Arrhythmias gradually become more frequent with age, potentially leading to sudden death (Sanna et al. 2003). Although sudden death from arrhythmias may be prevented by implantation of a pacemaker and defibrillator, progressive heart failure eventually becomes resistant to treatment (Golzio et al. 2007, Meune et al. 2006, van Berlo et al. 2005). No therapies are curative, and heart transplantation is often necessary.
cine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, 10th Floor, Room 508, New York, NY 10032, USA. Tel.: 212-305-1306; fax: 212-305-6443; e-mail: [email protected] or am2434@columbia. edu. © 2010 Elsevier Inc. All rights reserved. 1050-1738/$-see front matter
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