Platelet function measurement-based strategy to reduce bleeding and waiting time in clopidogrel-treated patients undergoing coronary artery bypass graft surgery: the timing based on platelet function strategy to reduce clopidogrel-associated bleeding related to CABG (TARGET-CABG) study.

BACKGROUND: Aspirin and clopidogrel therapy is associated with a variable bleeding risk in patients undergoing coronary artery bypass graft surgery (CABG). We evaluated the role of platelet function testing in clopidogrel-treated patients undergoing CABG. METHODS AND RESULTS: One hundred eighty patients on background aspirin with/without clopidogrel therapy undergoing elective first time isolated on-pump CABG were enrolled in a prospective single-center, nonrandomized, unblinded investigation (Timing Based on Platelet Function Strategy to Reduce Clopidogrel-Associated Bleeding Related to CABG [TARGET-CABG] study) between September 2008 and January 2011. Clopidogrel responsiveness (ADP-induced platelet-fibrin clot strength [MA(ADP)]) was determined by thrombelastography; CABG was done within 1 day, 3-5 days, and >5 days in patients with an MA(ADP) >50 mm, 35-50 mm, and <35 mm, respectively. The primary end point was 24-hour chest tube drainage and key secondary end point was total number of transfused red blood cells. Equivalence was defined as ≤25% difference between groups. ANCOVA was used to adjust for confounders. Mean 24-hour chest tube drainage in clopidogrel-treated patients was 93% (95% confidence interval, 81-107%) of the amount observed in clopidogrel-naive patients, and the total amount of red blood cells transfused did not differ between groups (1.80 U versus 2.08 U, respectively, P=0.540). The total waiting period in clopidogrel-treated patients was 233 days (mean, 2.7 days per patient). CONCLUSIONS: A strategy based on preoperative platelet function testing to determine the timing of CABG in clopidogrel-treated patients was associated with the same amount of bleeding observed in clopidogrel-naive patients and ≈50% shorter waiting time than recommended in the current guidelines. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00857155.

Adenosine diphosphate-induced platelet-fibrin clot strength: a new thrombelastographic indicator of long-term poststenting ischemic events.

BACKGROUND: Poststenting ischemic events occur despite dual-antiplatelet therapy, suggesting that a "one size fits all" antithrombotic strategy has significant limitations. Ex vivo platelet function measurements may facilitate risk stratification and personalized antiplatelet therapy. METHODS: We investigated the prognostic utility of the strength of adenosine diphosphate (ADP)-induced (MA(ADP)) and thrombin-induced (MA(THROMBIN)) platelet-fibrin clots measured by thrombelastography and ADP-induced light transmittance aggregation (LTA(ADP)) in 225 serial patients after elective stenting treated with aspirin and clopidogrel. Ischemic and bleeding events were assessed over 3 years. RESULTS: Overall, 59 (26%) first ischemic events occurred. Patients with ischemic events had higher MA(ADP), MA(THROMBIN), and LTA(ADP) (P < .0001 for all comparisons). By receiver operating characteristic curve analysis, MA(ADP) >47 mm had the best predictive value of long-term ischemic events compared with other measurements (P < .0001), with an area under the curve = 0.84 (95% CI 0.78-0.89, P < .0001). The univariate Cox proportional hazards model identified MA(ADP) >47 mm, MA(THROMBIN) >69 mm, and LTA(ADP) >34% as significant independent predictors of first ischemic events at the 3-year time point, with hazard ratios of 10.3 (P < .0001), 3.8 (P < .0001), and 4.8 (P < .0001), respectively. Fifteen bleeding events occurred. Receiver operating characteristic curve and quartile analysis suggests MA(ADP)

Hypercoagulability, platelet function, inflammation and coronary artery disease acuity: results of the Thrombotic RIsk Progression (TRIP) study.

The objective of the study was to determine the relation of platelet reactivity, hypercoagulability and inflammation in various stages of coronary artery disease acuity (CAD). Thrombin-induced platelet-fibrin clot strength (MA), time to initial platelet-fibrin clot formation (R), C-reactive protein (CRP), prothrombotic factors, activated GPIIb/IIIa receptor expression and other biomarkers were studied in patients with asymptomatic stable CAD (AS), in patients undergoing PCI for stable (SA) and unstable angina (UA). MA and R were measured by thrombelastography, GPIIb/IIIa expression by flow cytometry and all other markers by fluorokine multianalyte profiling assays. An overall increase in all measurements from a clinically stable to an unstable disease state was observed. There was a distinct stepwise increment in MA [AS vs. SA (p = 0.02), SA vs. UA (p = 0.02) and AS vs. UA (p < 0.001)]. MA exhibited the strongest correlation with other prothrombotic markers (p < or = 0.02), with CRP (p < 0.001) at all levels of CAD acuity. A distinct pathophysiological state of heightened platelet function, hypercoagulability and inflammation marks the presence of unstable cardiovascular disease requiring intervention. Further studies are required to investigate the primary mechanisms linking the above processes associated with a prothrombotic state resulting in clinical destabilization of the disease.

Bivalirudin and clopidogrel with and without eptifibatide for elective stenting: effects on platelet function, thrombelastographic indexes, and their relation to periprocedural infarction results of the CLEAR PLATELETS-2 (Clopidogrel with Eptifibatide to Arrest the Reactivity of Platelets) study.

OBJECTIVES: The primary objective of this study was to compare the effect of therapy with bivalirudin alone versus bivalirudin plus eptifibatide on platelet reactivity measured by turbidometric aggregometry and thrombin-induced platelet-fibrin clot strength (TIP-FCS) measured by thrombelastography in percutaneous coronary intervention (PCI) patients. The secondary aim was to study the relation of platelet aggregation and TIP-FCS to the occurrence of periprocedural infarction. BACKGROUND: Bivalirudin is commonly administered alone to clopidogrel naïve (CN) patients and to patients on maintenance clopidogrel therapy (MT) undergoing elective stenting. The effect of adding eptifibatide to bivalirudin on platelet reactivity (PR) and TIP-FCS, and their relation to periprocedural infarction in these patients are unknown. METHODS: Patients (n = 200) stratified to clopidogrel treatment status were randomly treated with bivalirudin (n = 102) or bivalirudin plus eptifibatide (n = 98). One hundred twenty-eight CN patients were loaded with 600 mg clopidogrel immediately after stenting, and 72 MT patients were not loaded. The PR, TIP-FCS, and myonecrosis markers were serially determined. RESULTS: In CN and MT patients, bivalirudin plus eptifibatide was associated with markedly lower PR at all times (5- and 20-microM adenosine diphosphate-induced, and 15- and 25-microM thrombin receptor activator peptide-induced aggregation; p < 0.001 for all) and reduced mean TIP-FCS (p < 0.05). Patients who had a periprocedural infarction had higher mean 18-h PR (p < 0.0001) and TIP-FCS (p = 0.002). CONCLUSIONS: For elective stenting, the addition of eptifibatide to bivalirudin lowered PR to multiple agonists and the tensile strength of the TIP-FCS, 2 measurements strongly associated with periprocedural myonecrosis. Future studies of PR and TIP-FCS for elective stenting may facilitate personalized antiplatelet therapy and enhance the selection of patients for glycoprotein IIb/IIIa blockade. (Peri-Procedural Myocardial Infarction, Platelet Reactivity, Thrombin Generation, and Clot Strength: Differential Effects of Eptifibatide + Bivalirudin Versus Bivalirudin [CLEAR PLATELETS-2]; NCT00370045.

Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention: a potential antiplatelet therapeutic target.

Platelets play a central role in the genesis of post-percutaneous coronary intervention (PCI) ischemic events. High post-procedural platelet reactivity to adenosine diphosphate (HPR(ADP)) may be a risk factor for ischemic events after PCI. The study was designed to evaluate a cutpoint of platelet reactivity that is associated with the occurrence of ischemic events after PCI. Post-procedural platelet reactivity to ADP was measured by conventional aggregometry in 297 consecutive patients undergoing non-emergent PCI. Patients were prospectively followed for up to 2 years for post-discharge ischemic events. All patients had received clopidogrel and aspirin therapy at the time of aggregation measurements. Eighty-one patients (27%) suffered ischemic events. Patients with ischemic events had higher 5 microM ADP-induced platelet aggregation (46 +/- 14% vs. 30 +/- 17%, p < 0.001) and 20 microM ADP-induced platelet aggregation (60 +/- 13% vs. 43 +/- 19%, p < 0.001) compared to patients without ischemic events. Using a combined receiver operator curve analysis, cutpoints of >46% aggregation following 5 microM ADP stimulation and >59% aggregation following 20 microM ADP stimulation (HPR(ADP)) were associated with 58 and 54% of ischemic events, respectively. Multivariate Cox regression demonstrated a significant relation between event occurrence and post-procedural HPR(ADP) cutpoints (5 microM ADP, OR=3.9, and 20 microM ADP, OR=3.8, p < 0.001 for both). High post-procedural platelet reactivity to ADP is an independent risk factor for ischemic events within 2 years of non-emergent PCI. These data support a potential therapeutic target for antiplatelet therapy based on the results of an ex vivo platelet function test. The study is a step towards a personalized medicine approach to guide the intensity of antiplatelet therapy.

The effect of aspirin dosing on platelet function in diabetic and nondiabetic patients: an analysis from the aspirin-induced platelet effect (ASPECT) study.

OBJECTIVE: Diabetic patients may have a higher prevalence of platelet aspirin resistance than nondiabetic patients. Our goal was to analyze platelet aspirin responsiveness to various aspirin doses in diabetic and nondiabetic patients. RESEARCH DESIGN AND METHODS: We examined the effect of aspirin (81, 162, and 325 mg/day for 4 weeks each) on platelet aspirin responsiveness in 120 stable outpatients (30 diabetic patients and 90 nondiabetic patients) with coronary artery disease (CAD) using light transmittance aggregometry (LTA), VerifyNow, platelet function analyzer (PFA)-100, and levels of urinary 11-dehydro-thromboxane B(2) (11-dh-TxB(2)). RESULTS: In the total group, a low prevalence (0-2%) of aspirin resistance was observed with all aspirin doses as determined by arachidonic acid-induced LTA. Aspirin resistance was higher at the 81-mg dose in diabetic versus nondiabetic patients using collagen-induced LTA (27 vs. 4%, P = 0.001), VerifyNow (13 vs. 3%, P = 0.05), and urinary 11-dh-TxB(2) (37 vs. 17%, P = 0.03). Diabetic patients treated with 81 mg exhibited higher platelet function measured by VerifyNow, collagen- and ADP-induced LTA, and 11-dh-TxB(2) levels (P

Is there a doctor in the house? . . . Or the Senate? Physicians in US Congress, 1960-2004.

CONTEXT: The legislative and fiscal influences of Congress, as well as the continuing overall growth in health care spending as a portion of the gross domestic product, make congressional representation by physicians important because physicians have unique expertise in the impact of legislation on patient care and medical practice. OBJECTIVES: To describe physician representation in the US Congress between 1960 and 2004 and relate the results to past representation of physicians in Congress. DESIGN AND SETTING: A retrospective observational study of members of the US Congress from all 50 states and all represented territories, who served from January 1960 to April 2004 (including 108th Congress), using data available in public access databases and congressional biographical records. MAIN OUTCOME MEASURES: Physician representation in Congress, including occupation before taking office, state/territory of representation, sex, party affiliation, and time served. RESULTS: During the past 44 years, 25 (1.1%) of 2196 members of Congress were physicians. Physicians in Congress were more likely to be members of the Republican Party (60% vs 45.1% of all members, P = .007) and were similar to other members of Congress in mean years of service (9.2 years for physicians vs 12.3 years for all members, P = .09) and in sex distribution (4.0% female physicians vs 6.8% all female members, P = .57). Physicians in Congress represented 17 states, the Virgin Islands, and Puerto Rico. CONCLUSIONS: Physician representation in Congress is low and is in stark contrast with physician roles during the first century of the United States. However, the 8 physicians currently serving in Congress may be indicative of a shift toward more direct influence of physicians in national politics.