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Biomedical subjects

Kevin P Bliden

Publications and source records attributed to Kevin P Bliden.

At least 19 recordsLinked to original sources
PubMed2006

Effect of clopidogrel with and without eptifibatide on tumor necrosis factor-alpha and C-reactive protein release after elective stenting: results from the CLEAR PLATELETS 1b study.

OBJECTIVES: This study was performed to compare the effects of antiplatelet regimens on early inflammation and cardiac marker release after elective stenting. BACKGROUND: Few data exist regarding the comparative effects of specific antiplatelet regimens on early inflammation marker release after stenting. METHODS: In a 2 x 2 factorial randomized investigation, patients undergoing stenting were treated with either clopidogrel alone (300 mg or 600 mg; n = 60) or clopidogrel with eptifibatide (n = 60). Platelet aggregation (5 and 20 muM adenosine diphosphate [ADP]), ADP-stimulated expression of active glycoprotein (GP) IIb/IIIa, and platelet-bound P-selectin, tumor necrosis factor (TNF)-alpha, C-reactive protein (CRP), and cardiac markers were measured. RESULTS: Compared with a strategy of clopidogrel alone, clopidogrel + eptifibatide reduced the release of cardiac markers. A marked reduction in platelet aggregation and active GP IIb/IIIa expression (p < or = 0.001) with clopidogrel + eptifibatide was associated with a decrease in CRP and TNF-alpha release (p < or = 0.001). CONCLUSIONS: A strategy of clopidogrel with GP IIb/IIIa blockade resulted in superior inhibition of inflammation and cardiac marker release, which was accompanied by superior platelet inhibition immediately after percutaneous coronary intervention compared with a strategy of clopidogrel alone. The mechanistic and clinical implications of attenuated periprocedural inflammation and myocardial necrosis with a strategy of GP IIb/IIIa inhibition warrant further investigation.

Aged↗
PubMed2006

Delayed thrombin-induced platelet-fibrin clot generation by clopidogrel: a new dose-related effect demonstrated by thrombelastography in patients undergoing coronary artery stenting.

BACKGROUND: We have previously demonstrated that clopidogrel reduces platelet activation and aggregation in patients undergoing stenting. However, the effect of the clopidogrel loading dose on the rate of thrombin-induced platelet-fibrin clot formation is unknown in this patient population. METHODS AND RESULTS: Using thrombelastography (TEG) we measured the time to platelet-fibrin clot formation (R), a marker of the speed of thrombin generation, in 120 patients undergoing elective coronary artery stenting treated with standard and high loading doses of clopidogrel. Platelet reactivity to adenosine diphosphate (ADP) by light transmittance aggregometry (LTA) was determined simultaneously. Measurements were made immediately before and at 24 h after clopidogrel treatment. Clopidogrel produced a prolongation in R (4.4+/-1.4 min pre vs. 5.4+/-1.7 min post, p<0.001) that directly correlated with the change in platelet aggregation (r=0.65, p<0.0001). Prolongation in R was greatest in patients treated with a high loading dose (p=0.004). CONCLUSIONS: Delayed thrombin-induced platelet-fibrin clot formation as measured by TEG is a newly reported dose-related effect of clopidogrel that may contribute to the overall antithrombotic properties of the drug in patients undergoing stenting. This effect was more marked in patients loaded with 600 mg, lending further mechanistic support for this dose of clopidogrel as a more effective antithrombotic regimen than the standard 300 mg dose. Measurement of R may serve as a new indicator of clopidogrel responsiveness.

Aged↗
PubMed2006

Prasugrel.

Clinical trials have demonstrated the superior clinical efficacy of dual antiplatelet therapy with a thienopyridine (a P2Y(12) receptor blocker) and aspirin (COX-1 inhibitor) in patients undergoing stenting as well as patients with acute coronary syndromes. However, clopidogrel treatment is associated with a wide response variability and non-responsiveness in selected patients. The latter phenomenon is linked to the occurrence of recurrent ischaemic events including stent thrombosis in the recent studies. Prasugrel is a new thienopyridine derivative that produces more potent platelet inhibition and a rapid onset of action that is associated with irreversible P2Y(12) receptor blockade. The latter properties of prasugrel may provide a superior alternative to clopidogrel, with less response variability and a decreased prevalence of non-responsiveness.

Adenosine Diphosphate↗
PubMed2006

Clopidogrel resistance: implications for coronary stenting.

Clopidogrel, in combination wih aspirin, is currently the drug of choice to prevent thrombosis after coronary stent implantation. Currently, clopidogrel is administered to the vast majority of patients without any assessment of platelet inhibition. Response variability and resistance, however, definitely occur to clopidogrel treatment. Preliminary data support the hypothesis that patients with reactive or clopidogrel nonresponsive platelets are at risk for thrombotic events. However, the magnitude of the clinical effect remains unknown and relationship between nonresponsiveness and risk of clinical events is under-investigated. Several important questions that must be answered are: A) What is the relation of clopidogrel resistance and high platelet reactivity to the occurrence of stent thrombosis, recurrent myocardial infarction, stroke and death?; B) Is there a threshold of platelet reactivity that correlates with the onset of thrombotic risk?; and C) What is the cost of administering clopidogrel to non-responsive patients? Finally, our understanding of the clinical relevance of drug resistance and high platelet reactivity should be facilitated by the use of validated point-of-service devices. The mechanisms of the response variability to clopidogrel remain incompletely defined. The contribution of intra- and extracellular pathways are under investigation.

Animals↗
PubMed2005

Neutral effect on markers of heart failure, inflammation, endothelial activation and function, and vagal tone after high-dose HMG-CoA reductase inhibition in non-diabetic patients with non-ischemic cardiomyopathy and average low-density lipoprotein level.

OBJECTIVES: This study sought to determine the effect of aggressive 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) therapy on surrogate markers in non-ischemic cardiomyopathy (NICM) patients and average low-density lipoprotein (LDL) concentrations. BACKGROUND: The effects of statins may well go beyond lipid lowering, and these pleiotropic effects may be of benefit in the treatment of heart failure. METHODS: Fifteen patients with NICM on standard maximized heart failure medication were enrolled in a randomized, double-blinded, placebo-controlled, crossover trial. Patients received 80 mg atorvastatin (ATV) or matching placebo for a 12-week treatment period with a minimum of an 8-week washout period. The following surrogate markers were evaluated: N-terminal-pro brain natriuretic peptide, high-sensitivity C-reactive protein, oxidized LDL antibody, soluble receptor tumor necrosis factor, tumor necrosis factor-alpha, circulating levels of vascular adhesion molecule-1, intercellular adhesion molecule-1, P-selectin, non-invasive endothelial function studies, and heart rate variability. RESULTS: After ATV therapy, there was a significant decrease in LDL concentration from 110 +/- 27 mg/dl to 55 +/- 18 mg/dl (p < 0.05). There were no differences between ATV and placebo with regard to the surrogate markers measured. CONCLUSIONS: Based on these findings, it seems that the administration of high-dose statins to a heart failure population with modest LDL levels and no other indication for statin therapy was neither beneficial nor detrimental as determined by surrogate marker measures. Further studies are needed to determine whether there is an appropriate patient population and optimal dose (LDL concentration) for the treatment of systolic heart failure with statin therapy.

C-Reactive Protein↗
PubMed2005

Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING Study.

OBJECTIVES: We investigated the relation of high ex vivo platelet reactivity, rapid fibrin generation, and high thrombin-induced clot strength to postdischarge ischemic events in patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: High platelet reactivity and rapid fibrin generation may affect the incidence of ischemic events after PCI. However, limited data is available to link these ex vivo markers to the occurrence of events. METHODS: We measured platelet reactivity to adenosine diphosphate (ADP) by light transmittance aggregometry (LTA) in patients undergoing PCI (n = 192). Clot strength, a measure of thrombin-induced fibrin and platelet interactions, and the time to initial fibrin generation, a marker of thrombin activity, were measured by thrombelastography. The relation of these measurements to ischemic event occurrence was prospectively examined over six months. RESULTS: A total of 100% and 84% of patients were on aspirin and clopidogrel therapy, respectively, at the time of the initial event. Posttreatment ADP-induced aggregation by LTA (63 +/- 12% vs. 56 +/- 15%, p = 0.02) and clot strength (MA) were higher (74 +/- 5 mm vs. 65 +/- 4 mm, p < 0.001) and time to initial fibrin generation was shorter (4.3 +/- 1.3 min vs. 5.9 +/- 1.5 min, p < 0.001) in patients with events (n = 38). The event rates in the highest quartiles of LTA and MA were 32% and 58%, respectively. CONCLUSIONS: High platelet reactivity and clot strength, and rapid fibrin formation are novel risk factors for ischemic events after PCI. Clot strength is more predictive than ADP-induced platelet aggregation and may explain the occurrence of events despite treatment with cyclooxygenase-1 and P2Y12 inhibitors.

Angioplasty, Balloon, Coronary↗
PubMed2005

Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study.

OBJECTIVES: We investigated whether patients who suffered subacute stent thrombosis (SAT) have higher post-treatment reactivity than those who do not encounter stent thrombosis. BACKGROUND: High post-treatment platelet reactivity has been reported after coronary stenting after clopidogrel therapy and may be an important factor in the occurrence of SAT. METHODS: We identified patients with SAT treated at two tertiary care centers over a 1.5-year period. Light transmittance aggregation induced by adenosine diphosphate (ADP) and arachidonic acid, total and activated glycoprotein (GP) IIb/IIIa after stimulation with ADP, and vasodilator-stimulated phosphoprotein phosphorylation levels to measure P2Y12 receptor inhibition were determined (n = 20) and compared with an age-matched group of patients without SAT (n = 100). High post-treatment platelet reactivity was defined as >75th percentile ADP-induced aggregation in the group without SAT. RESULTS: The SAT patients had higher mean platelet reactivity than those without SAT by all measurements (p < 0.05): 49 +/- 4% versus 33 +/- 2% for 5 micromol/l ADP-induced aggregation and 65 +/- 3% versus 51 +/- 2% for 20 micromol/l ADP-induced aggregation (p < 0.001), 69 +/- 5% versus 46 +/- 9% for P2Y12 reactivity ratio (p = 0.03), and 138 +/- 19 mean fluorescence intensity (MFI) versus 42 +/- 4 MFI for stimulated GP IIb/IIIa expression (p < 0.001). Of patients with SAT, 60% had high platelet reactivity. CONCLUSIONS: High post-treatment platelet reactivity and incomplete P2Y12 receptor inhibition are risk factors for SAT. Measures to uniformly determine platelet reactivity after coronary stenting and treatment strategies to improve P2Y12 receptor inhibition in patients with high post-treatment platelet reactivity should be further investigated.

Aged↗
PubMed2005

Overestimation of platelet aspirin resistance detection by thrombelastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation.

OBJECTIVES: This study sought to determine the prevalence of platelet aspirin resistance using methods that directly indicate the degree of platelet cyclooxygenase inhibition. BACKGROUND: Aspirin resistance in platelets may be overestimated by nonspecific laboratory measurements that do not isolate cyclooxygenase activity. METHODS: Arachidonic acid (AA)-induced light-transmittance platelet aggregation (LTA) and thrombelastography (TEG) platelet mapping were performed on the blood of healthy subjects (n = 6) before and 24 h after receiving 325 mg aspirin, and on 223 patients reporting compliance with long-term daily aspirin treatment (n = 203 undergoing percutaneous intervention [PCI] and n = 20 with a history of stent thrombosis). Aspirin resistance was defined as >20% aggregation by LTA or >50% aggregation by TEG. RESULTS: In healthy subjects, AA-induced aggregation by LTA was 82 +/- 10% before and 2 +/- 1% at 24 h after aspirin (p < 0.001), and aggregation by TEG was 86 +/- 14% before and 5 +/- 7% at 24 h after aspirin (p < 0.001). In compliant patients, AA-induced aggregation by LTA was 3 +/- 2% before PCI and 3 +/- 2% after PCI (p = NS), and aggregation by TEG was 5 +/- 9% before PCI and 6 +/- 14% after PCI (p = NS). Seven PCI patients were noncompliant, and all were aspirin sensitive after in-hospital aspirin treatment. Among 223 patients, only one patient ( approximately 0.4%) was resistant to aspirin treatment. CONCLUSIONS: Platelet aspirin resistance assessed by methods that directly indicate inhibition of cyclooxygenase is rare in compliant patients with coronary artery disease.

Adult↗
PubMed2005

The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting.

OBJECTIVES: We determined the effect of clopidogrel dosing on the incidence of nonresponsiveness (NR) and high post-treatment platelet aggregation (post-PA). BACKGROUND: We have reported NR after a 300-mg loading dose. Limited information is available on the comparative effect of a 600-mg loading dose on the incidence of NR and high post-PA. METHODS: Clopidogrel responsiveness and post-PA were measured in patients undergoing stenting (n = 190) randomly treated with either a 300-mg or a 600-mg clopidogrel load. Nonresponsiveness was defined as <10% absolute change in platelet aggregation, and high post-PA was defined as >75th percentile aggregation after 300 mg clopidogrel. RESULTS: Nonresponsiveness was lower after 600 mg compared to the 300-mg dose (8% vs. 28% and 8% vs. 32% with 5 and 20 microM ADP, respectively, p < 0.001). Among the patients with high post-PA after 300 mg clopidogrel, 62% to 65% had NR, whereas after the 600-mg dose, all of the patients with high post-PA had NR. CONCLUSIONS: A 600-mg clopidogrel loading dose reduces the incidence of NR and high post-PA as compared to a 300-mg dose. Higher dosing strategies and methods to confirm platelet inhibition should be further investigated in order to optimally use clopidogrel in patients undergoing stenting.

Adenosine Diphosphate↗
PubMed2005

Clopidogrel loading with eptifibatide to arrest the reactivity of platelets: results of the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study.

BACKGROUND: Pretreatment is not the most common strategy practiced for clopidogrel administration in elective coronary stenting. Moreover, limited information is available on the antiplatelet pharmacodynamics of a 300-mg versus a 600-mg clopidogrel loading dose, and the comparative effect of eptifibatide with these regimens is unknown. METHODS AND RESULTS: Patients undergoing elective stenting (n=120) were enrolled in a 2x2 factorial study (300 mg clopidogrel with or without eptifibatide; 600 mg clopidogrel with or without eptifibatide) (Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets [CLEAR PLATELETS] Study). Clopidogrel was administered immediately after stenting. Aggregometry and flow cytometry were used to assess platelet reactivity. Eptifibatide added a > or =2-fold increase in platelet inhibition to 600 mg clopidogrel alone at 3, 8, and 18 to 24 hours after stenting as measured by 5 micromol/L ADP-induced aggregation (P<0.001). Without eptifibatide, 600 mg clopidogrel produced better inhibition than 300 mg clopidogrel at all time points (P<0.001). Glycoprotein IIb/IIIa (GPIIb/IIIa) blockade was associated with lower cardiac marker release. Active GPIIb/IIIa expression was inhibited most in the groups treated with eptifibatide (P<0.05). CONCLUSIONS: In elective stenting without clopidogrel pretreatment, use of a GPIIb/IIIa inhibitor produces superior platelet inhibition and lower myocardial necrosis compared with high-dose (600 mg) or standard-dose (300 mg) clopidogrel loading alone. In the absence of a GPIIb/IIIa inhibitor, 600 mg clopidogrel provides better platelet inhibition than the standard 300-mg dose. These results require confirmation in a large-scale clinical trial.

Adult↗
PubMed2005

The difference between clopidogrel responsiveness and posttreatment platelet reactivity.

BACKGROUND: Aggregation is the most common measure of platelet reactivity. The relative inhibition of platelet aggregation between pretreatment and posttreatment is the most common estimate of clopidogrel responsiveness. However, patients responsive to clopidogrel may remain with highly reactive platelets and thus have increased thrombotic risk. METHODS: Platelet reactivity was determined by ADP-induced aggregation (%) in 62 patients undergoing elective coronary stenting at pretreatment and 5 days postprocedure. All patients were on aspirin (325 mg) and received 300 mg of clopidogrel immediately poststenting and 75 mg qd. Pretreatment reactivity was divided into tertiles. Based on clopidogrel drug responsiveness, nonresponders were defined as <10% relative inhibition of pretreatment aggregation, semiresponders as 10-30%, and responders as >30%. We determined the relation between clopidogrel responsiveness and platelet reactivity. RESULTS: Pretreatment reactivity tertiles by 5 microM ADP were: low (47+/-9%), moderate (64+/-4%), and high (78+/-6%). Eight patients were nonresponders, 18 were semiresponders, and 36 were responders. Clopidogrel responsiveness directly correlated with pretreatment reactivity, 86% of responders had moderate or high pretreatment reactivity, whereas 75% of nonresponders had low pretreatment reactivity. Despite being more responsive, 16% of patients with high pretreatment reactivity and 17% with moderate pretreatment reactivity remained with moderate posttreatment reactivity. CONCLUSION: Measuring clopidogrel responsiveness may overestimate the risk of stent thrombosis in nonresponders with low pretreatment reactivity and underestimate risk in those responders who remain with high posttreatment platelet reactivity. Posttreatment platelet reactivity is a better measure of thrombotic risk than responsiveness to clopidogrel.

Adenosine Diphosphate↗
PubMed2005

The platelet-related effects of tenecteplase versus alteplase versus reteplase.

Clinical studies have investigated the combination of glycoprotein (GP) IIb/IIIa inhibitors and thrombolytic agents for acute myocardial infarction. However, thrombolytic agents alone may possess direct antiplatelet properties that could affect reperfusion. Blood from 11 patients with coronary disease and five healthy subjects was incubated for 30 min with tenecteplase (4, 12, and 24 microg/ml), alteplase (1, 4, and 10 microg/ml), reteplase (1, 5, and 10 microg/ml) or control buffer. Platelet aggregation induced by 1, 20 and 50 micromol/l adenosine diphosphate (ADP), the stimulated expression of GP IIb/IIIa and P-selectin, and plasma fibrinogen levels were determined. Platelet aggregation in patients was inhibited by medium and high concentrations of alteplase when induced by 1 micromol/l ADP [1.6 +/- 0.5%, P = 0.001 and 0.9 +/- 0.2%, P = 0.002 versus 8.3 +/- 1.6% (control)] and 20 micromol/l ADP [46.9 +/- 3.9%, P = 0.001 and 46.2 +/- 4.8%, P = 0.001 versus 65.7 +/- 2.7% (control)]. High concentration tenecteplase was associated with lower aggregation by 20 micromol/l ADP (58 +/- 2.1% versus control, P = 0.033). There were no changes in GP IIb/IIIa activation or P-selectin expression in patients or healthy subjects. Platelet aggregation (1 micromol/l ADP) in healthy subjects was inhibited only by high doses of alteplase (P = 0.001). Plasma fibrinogen levels were significantly decreased after treatment with reteplase at 1 microg/ml(1.53 +/- 0.21 versus 2.65 +/- 0.31, P = .009) and 5 microg/ml(1.55 +/- 0.16 versus 2.65 +/- 0.31, P = .005). Alteplase inhibits platelet aggregation more than tenecteplase and reteplase. The attenuation of platelet aggregation by alteplase is dissociated from the expression of activated GP IIb/IIIa and P-selectin, and by fibrinogen degradation. These results suggest that alteplase exerts its antiplatelet effect independent of GP IIb/IIIa and P-selectin expressions and fibrinogen degradation. These findings may be directly relevant to the effect of alteplase on reperfusion and to future studies using combined platelet inhibitors and thrombolytic therapy.

Aged↗
PubMed2005

Resistance to antiplatelet drugs: current status and future research.

Platelet reactivity and activation are important factors during the development of atherothrombotic processes and subsequent ischaemic complications. Pharmacological agents that suppress platelet function are proved to be the most efficient in the prevention and treatment of thrombotic complications. As the activation of platelets during thrombus generation involves many complex and redundant pathways, simultaneous use of different antiplatelet drugs that are directed against different targets have been effective in reducing adverse clinical events. The main antiplatelet drugs are aspirin (which inhibits thromboxane synthesis), thienopyridines (which block P2Y12 receptors) and glycoprotein IIb/IIIa antagonists (which block glycoprotein IIb/IIIa receptors). In recent years, resistance or nonresponsiveness to antiplatelet therapy has been reported and, more importantly, are linked to the occurrence of adverse cardiovascular events. New treatment strategies to overcome nonresponsiveness are being sought. A focus on the development of simple, reproducible and user friendly point-of-care methods to determine aspirin/clopidogrel responsiveness should be undertaken to assist clinicians in tailoring antiplatelet therapy to the individual patient.

Drug Resistance, Neoplasm↗
PubMed2004

Failure of clopidogrel to reduce platelet reactivity and activation following standard dosing in elective stenting: implications for thrombotic events and restenosis.

There is no information on long-term platelet reactivity and activation following elective stenting in patients treated with clopidogrel and aspirin. We measured platelet reactivity and activation at baseline and at 2 h, 24 h, 5 days and 30 days following coronary stenting (n = 94). Patients were treated with the standard aspirin (325 mg) and clopidogrel regimen (300 mg load/75 mg qd). Reactivity was measured by aggregation (5 and 20 microM ADP) and activation was determined by the expression of total and active GP IIb/IIIa. Reactivity and activation were defined as heightened when post-stent aggregation and receptor expression exceeded baseline levels, respectively. Prolonged heightened platelet reactivity was detected by both 5 and 20 microM ADP aggregation. Using 20 microM ADP aggregation, heightened reactivity occurred in 55% of patients at 2 h, 26% at 24 h, 21% at 5 days, and 15% at 30 days post-stenting. A high frequency of heightened platelet activation was detected by both total and active GP IIb/IIIa expression. Using expression of the active GP IIb/IIIa receptor as the marker, activation was greater than baseline in 27% of patients at 2 h, 20% at 24 h, 30% at 5 days, and 22% at 30 days post-stenting. This is the first report demonstrating that a significant percentage of patients receiving standard clopidogrel and aspirin therapy for coronary stenting will have post-drug platelet reactivity and activation above baseline that persists for 30 days after the procedure. These finding suggest insufficient platelet inhibition. The clinical importance of these findings should be further investigated to establish the potential link between insufficient platelet inhibition, stent thrombosis, and restenosis.

Adenosine Diphosphate↗
PubMed2004

Platelet activation in myocardial ischemic syndromes.

Platelets play a central role in the pathogenesis of atherosclerosis and thrombosis. Platelet adhesion and aggregate formation are critical events that occur in unstable coronary syndromes. Platelet activation precedes the formation of homotypic and heterotypic aggregates. In the last 10 years, researchers have described the presence of activated platelets in the systemic circulation in various cardiovascular disease states, particularly acute coronary syndromes. This review describes the evidence for platelet activation in acute myocardial ischemic syndromes, describes the pathophysiology responsible for its occurrence, and discusses how platelet activation and reactivity may affect the use of concomitant drug therapies and patient prognosis.

Fibrinolytic Agents↗
PubMed2003

Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity.

BACKGROUND: Clopidogrel is administered to prevent stent thrombosis; however, the uniformity of platelet inhibition after treatment and the influence of pretreatment reactivity on drug response have not been described. METHODS AND RESULTS: Platelet aggregation (5 and 20 micromol/L ADP), the activation of glycoprotein IIb/IIIa (PAC-1 antibody), and the expression of P-selectin were measured in patients undergoing elective coronary stenting (n=96) at baseline and at 2 hours, 24 hours, 5 days, and 30 days after stenting. All patients received aspirin (325 mg). Clopidogrel (300 mg) was administered in the catheterization laboratory and followed by 75 mg daily. There was marked interindividual variability in drug response as measured by all markers that showed a normal distribution. Resistance, defined as baseline aggregation (%) minus posttreatment aggregation (%) < or =10% by 5 micromol/L ADP, was present in 31% and 15% of patients at 5 and 30 days, respectively. Patients with the highest pretreatment platelet reactivity remained the most reactive at 24 hours after treatment (P<0.0001). CONCLUSIONS: Interindividual variability in the platelet inhibitory response from clopidogrel occurs in patients undergoing elective coronary stenting. Patients with high pretreatment reactivity are least protected. Alternative pharmacological strategies and the association of adverse ischemic events should be investigated in these patients.

Adenosine Diphosphate↗