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Christopher P Cannon - One of the best experts on this subject based on the ideXlab platform.

  • g protein β3 subunit polymorphism and bleeding in the Orbofiban in patients with unstable coronary syndromes thrombolysis in myocardial infarction 16 trial
    Journal of Thrombosis and Haemostasis, 2010
    Co-Authors: Andrew O Maree, Christopher P Cannon, Denis C. Shields, Dermot Cox, Ciara Vangjeli, Hani Jneid, John J Ryan, Desmond J. Fitzgerald
    Abstract:

    Summary. Background: Variability in platelet response to antiplatelet drugs is heritable. A common single base substitution (825C>T) in the G-protein beta polypeptide 3 (GNB3) gene leads to alternative splicing (41-amino-acid deletion) of the human G-protein β3 (Gβ3) subunit. This truncated protein carried by GNB3 T allele carriers is linked to coronary artery disease and implicated as a genetic marker of drug response. Large studies of Caucasians associate T allele carriage with lower platelet reactivity.Objectives: To evaluate whether the GNB3 genotype would predispose to bleeding in patients treated with a GPIIb/IIIa receptor antagonist. Methods: GNB3 genotype distribution was determined in DNA samples from patients in the Orbofiban in patients with unstable coronary syndromes–thrombolysis in myocardial infarction (OPUS–TIMI) 16 genetic sub-study. Impact of genotype on the bleeding endpoint and the composite primary endpoint of death, myocardial infarction (MI), re-hospitalization for ischemia and urgent revascularization was estimated in the treatment and placebo arm. Results: Out of 887 patients, 45.1% carried the GNB3 CC genotype, 44.5% CT and 10.4% TT. Interaction between T allele carriership and treatment for bleeding was significant (P = 0.008). This reflects the fact that GNB3 non-T carriers treated with Orbofiban had no bleeding effect compared with placebo (RR = 0.92, 95% CI 0.55–1.55) whereas T carriers did (RR = 2.62, 95% CI 1.58–4.35, P < 0.001). Interaction between T allele carriership and treatment was not significant for the primary endpoint (P = 0.18) or MI (P = 0.69). Conclusion: The GNB3 T allele significantly increased bleeding in patients treated with the platelet antagonist Orbofiban. Our findings suggest that risk of bleeding associated with an antiplatelet agent is heritable and may be dissociated from risk of thrombosis.

  • G‐protein β3 subunit polymorphism and bleeding in the Orbofiban in patients with unstable coronary syndromes–thrombolysis in myocardial infarction 16 trial
    Journal of thrombosis and haemostasis : JTH, 2010
    Co-Authors: Andrew O Maree, Christopher P Cannon, Denis C. Shields, Dermot Cox, Ciara Vangjeli, Hani Jneid, John J Ryan, Desmond J. Fitzgerald
    Abstract:

    Summary. Background: Variability in platelet response to antiplatelet drugs is heritable. A common single base substitution (825C>T) in the G-protein beta polypeptide 3 (GNB3) gene leads to alternative splicing (41-amino-acid deletion) of the human G-protein β3 (Gβ3) subunit. This truncated protein carried by GNB3 T allele carriers is linked to coronary artery disease and implicated as a genetic marker of drug response. Large studies of Caucasians associate T allele carriage with lower platelet reactivity.Objectives: To evaluate whether the GNB3 genotype would predispose to bleeding in patients treated with a GPIIb/IIIa receptor antagonist. Methods: GNB3 genotype distribution was determined in DNA samples from patients in the Orbofiban in patients with unstable coronary syndromes–thrombolysis in myocardial infarction (OPUS–TIMI) 16 genetic sub-study. Impact of genotype on the bleeding endpoint and the composite primary endpoint of death, myocardial infarction (MI), re-hospitalization for ischemia and urgent revascularization was estimated in the treatment and placebo arm. Results: Out of 887 patients, 45.1% carried the GNB3 CC genotype, 44.5% CT and 10.4% TT. Interaction between T allele carriership and treatment for bleeding was significant (P = 0.008). This reflects the fact that GNB3 non-T carriers treated with Orbofiban had no bleeding effect compared with placebo (RR = 0.92, 95% CI 0.55–1.55) whereas T carriers did (RR = 2.62, 95% CI 1.58–4.35, P 

  • drug induced thrombocytopenia and thrombosis evidence from patients receiving an oral glycoprotein iib iiia inhibitor in the Orbofiban in patients with unstable coronary syndromes opus timi 16 trial
    Journal of Thrombosis and Thrombolysis, 2006
    Co-Authors: Benjamin M. Scirica, Jacqueline Brassard, Richard A Cooper, Christopher P Cannon, Richard H. Aster, Carolyn H. Mccabe, Andrew Charlesworth, Allan M. Skene, Eugene Braunwald
    Abstract:

    Objective: To assess etiology and impact of thrombocytopenia in a large oral glycoprotein (GP) IIb/IIIa inhibitor trial.

  • Drug-induced thrombocytopenia and thrombosis: Evidence from patients receiving an oral glycoprotein IIb/IIIa inhibitor in the Orbofiban in Patients with Unstable coronary Syndromes- (OPUS-TIMI 16) trial
    Journal of Thrombosis and Thrombolysis, 2006
    Co-Authors: Benjamin M. Scirica, Jacqueline Brassard, Richard Cooper, Christopher P Cannon, Richard H. Aster, Carolyn H. Mccabe, Andrew Charlesworth, Allan M. Skene, Eugene Braunwald
    Abstract:

    Objective : To assess etiology and impact of thrombocytopenia in a large oral glycoprotein (GP) IIb/IIIa inhibitor trial. Background : Heparin is known to cause thrombocytopenia, and in some of these patients thrombosis. GP IIb/IIIa inhibitors are also associated with thrombocytopenia. Methods : The Orbofiban in Patients with Unstable Coronary Syndromes (OPUS-TIMI 16) Trial randomized 10,392 patients with ACS to the oral GP IIb/IIIa inhibitor Orbofiban or placebo. Patients were followed for a minimum of ten months. Thrombocytopenia was defined prospectively as a platelet count < 80,000. Results : Thrombocytopenia was rare in the OPUS-TIMI 16 trial (0.68% at Day 30 and 0.80% at 1 year), but more common in patients treated with Orbofiban (0.92%) compared with those treated with placebo (0.2%), p < 0.001. Patients who developed thrombocytopenia had higher rates of death (11.6% vs. 1.7%, p < 0.001), recurrent MI (12.1% vs. 2.8%, p < 0.001), intracranial hemorrhage (2.9% vs. 0.0%, p < 0.001), and major or severe bleeding (19.0% vs. 2.0%, p < 0.001) at 30 days (with similar results at one year). Conclusion : Thrombocytopenia, though uncommon, was associated with Orbofiban use and an increased risk of bleeding, but also death and MI. This study provides further evidence that drugs that lead to thrombocytopenia are, in a significant proportion of patients associated with thrombotic events.

  • association of a history of systemic hypertension with mortality thrombotic and bleeding complications following non st segment elevation acute coronary syndrome
    Journal of Clinical Hypertension, 2006
    Co-Authors: Raphaelle Dumaine, Christopher P Cannon, Carolyn H. Mccabe, Sabina A. Murphy, Elliott M. Antman, Matthew C. Southard, Robert P. Giugliano, Michael C Gibson, Hung Q Ly, Eugene Braunwald
    Abstract:

    Chronic hypertension is a well established risk factor for the development of cardiovascular disease; however, its prognostic significance after a non-ST-segment elevation acute coronary syndrome remains to be established. Data from 15,414 patients included in six randomized Thrombolysis in Myocardial Infarction (TIMI) trials (TIMI 3B, TIMI11 A, TIMI 11B, TIMI 12, the Orbofiban in Patients With Unstable Coronary Syndromes [OPUS]-TIMI 16, and the Treat Angina With Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy [TACTICS]-TIMI 18) were analyzed. A history of hypertension was present in 10,998 (71.35%) patients; comorbidities and higher TIMI risk scores were more likely in these patients. However, positive troponin and ST-segment deviations were less frequent among hypertensive patients. After multivariate analysis, the history of hypertension was associated with more adverse outcomes, specifically the composite end point of death/myocardial infarction at 30 days and 1 year (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.31–1.81; p<0.001 at 1 year) than in patients without this history. An independent relationship was also observed with mortality (OR 1.70, 95% CI 1.34–2.16; p<0.001 at 1 year), myocardial infarction (OR 1.50, 95% CI 1.23–1.82; p<0.001 at 1 year), recurrent ischemia (OR 1.24, 95% CI 1.11–1.38; p<0.001 at 1 year), and major bleeding (OR 1.45, 95% CI 1.03–2.06; p=0.036 at 30 days). It was concluded that chronic hypertension remains an independent marker for major short- and long-term cardiac adverse outcomes after non-ST-segment elevation acute coronary syndrome.

Eugene Braunwald - One of the best experts on this subject based on the ideXlab platform.

  • drug induced thrombocytopenia and thrombosis evidence from patients receiving an oral glycoprotein iib iiia inhibitor in the Orbofiban in patients with unstable coronary syndromes opus timi 16 trial
    Journal of Thrombosis and Thrombolysis, 2006
    Co-Authors: Benjamin M. Scirica, Jacqueline Brassard, Richard A Cooper, Christopher P Cannon, Richard H. Aster, Carolyn H. Mccabe, Andrew Charlesworth, Allan M. Skene, Eugene Braunwald
    Abstract:

    Objective: To assess etiology and impact of thrombocytopenia in a large oral glycoprotein (GP) IIb/IIIa inhibitor trial.

  • Drug-induced thrombocytopenia and thrombosis: Evidence from patients receiving an oral glycoprotein IIb/IIIa inhibitor in the Orbofiban in Patients with Unstable coronary Syndromes- (OPUS-TIMI 16) trial
    Journal of Thrombosis and Thrombolysis, 2006
    Co-Authors: Benjamin M. Scirica, Jacqueline Brassard, Richard Cooper, Christopher P Cannon, Richard H. Aster, Carolyn H. Mccabe, Andrew Charlesworth, Allan M. Skene, Eugene Braunwald
    Abstract:

    Objective : To assess etiology and impact of thrombocytopenia in a large oral glycoprotein (GP) IIb/IIIa inhibitor trial. Background : Heparin is known to cause thrombocytopenia, and in some of these patients thrombosis. GP IIb/IIIa inhibitors are also associated with thrombocytopenia. Methods : The Orbofiban in Patients with Unstable Coronary Syndromes (OPUS-TIMI 16) Trial randomized 10,392 patients with ACS to the oral GP IIb/IIIa inhibitor Orbofiban or placebo. Patients were followed for a minimum of ten months. Thrombocytopenia was defined prospectively as a platelet count < 80,000. Results : Thrombocytopenia was rare in the OPUS-TIMI 16 trial (0.68% at Day 30 and 0.80% at 1 year), but more common in patients treated with Orbofiban (0.92%) compared with those treated with placebo (0.2%), p < 0.001. Patients who developed thrombocytopenia had higher rates of death (11.6% vs. 1.7%, p < 0.001), recurrent MI (12.1% vs. 2.8%, p < 0.001), intracranial hemorrhage (2.9% vs. 0.0%, p < 0.001), and major or severe bleeding (19.0% vs. 2.0%, p < 0.001) at 30 days (with similar results at one year). Conclusion : Thrombocytopenia, though uncommon, was associated with Orbofiban use and an increased risk of bleeding, but also death and MI. This study provides further evidence that drugs that lead to thrombocytopenia are, in a significant proportion of patients associated with thrombotic events.

  • association of a history of systemic hypertension with mortality thrombotic and bleeding complications following non st segment elevation acute coronary syndrome
    Journal of Clinical Hypertension, 2006
    Co-Authors: Raphaelle Dumaine, Christopher P Cannon, Carolyn H. Mccabe, Sabina A. Murphy, Elliott M. Antman, Matthew C. Southard, Robert P. Giugliano, Michael C Gibson, Hung Q Ly, Eugene Braunwald
    Abstract:

    Chronic hypertension is a well established risk factor for the development of cardiovascular disease; however, its prognostic significance after a non-ST-segment elevation acute coronary syndrome remains to be established. Data from 15,414 patients included in six randomized Thrombolysis in Myocardial Infarction (TIMI) trials (TIMI 3B, TIMI11 A, TIMI 11B, TIMI 12, the Orbofiban in Patients With Unstable Coronary Syndromes [OPUS]-TIMI 16, and the Treat Angina With Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy [TACTICS]-TIMI 18) were analyzed. A history of hypertension was present in 10,998 (71.35%) patients; comorbidities and higher TIMI risk scores were more likely in these patients. However, positive troponin and ST-segment deviations were less frequent among hypertensive patients. After multivariate analysis, the history of hypertension was associated with more adverse outcomes, specifically the composite end point of death/myocardial infarction at 30 days and 1 year (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.31–1.81; p<0.001 at 1 year) than in patients without this history. An independent relationship was also observed with mortality (OR 1.70, 95% CI 1.34–2.16; p<0.001 at 1 year), myocardial infarction (OR 1.50, 95% CI 1.23–1.82; p<0.001 at 1 year), recurrent ischemia (OR 1.24, 95% CI 1.11–1.38; p<0.001 at 1 year), and major bleeding (OR 1.45, 95% CI 1.03–2.06; p=0.036 at 30 days). It was concluded that chronic hypertension remains an independent marker for major short- and long-term cardiac adverse outcomes after non-ST-segment elevation acute coronary syndrome.

  • Association of a History of Systemic Hypertension With Mortality, Thrombotic, and Bleeding Complications Following Non-ST-Segment Elevation Acute Coronary Syndrome
    Journal of clinical hypertension (Greenwich Conn.), 2006
    Co-Authors: Raphaelle Dumaine, Christopher P Cannon, Carolyn H. Mccabe, Sabina A. Murphy, C. Michael Gibson, Elliott M. Antman, Matthew C. Southard, Robert P. Giugliano, Eugene Braunwald
    Abstract:

    Chronic hypertension is a well established risk factor for the development of cardiovascular disease; however, its prognostic significance after a non-ST-segment elevation acute coronary syndrome remains to be established. Data from 15,414 patients included in six randomized Thrombolysis in Myocardial Infarction (TIMI) trials (TIMI 3B, TIMI 11A, TIMI 11B, TIMI 12, the Orbofiban in Patients With Unstable Coronary Syndromes [OPUS]-TIMI 16, and the Treat Angina With Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy [TACTICS]-TIMI 18) were analyzed. A history of hypertension was present in 10,998 (71.35%) patients; comorbidities and higher TIMI risk scores were more likely in these patients. However, positive troponin and ST-segment deviations were less frequent among hypertensive patients. After multivariate analysis, the history of hypertension was associated with more adverse outcomes, specifically the composite end point of death/myocardial infarction at 30 days and 1 year (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.31-1.81; p

  • Drug-induced thrombocytopenia and thrombosis: evidence from patients receiving an oral glycoprotein IIb/IIIa inhibitor in the Orbofiban in Patients with Unstable coronary Syndromes- (OPUS-TIMI 16) trial.
    Journal of thrombosis and thrombolysis, 2006
    Co-Authors: Benjamin M. Scirica, Richard A Cooper, Christopher P Cannon, Jacqueline A. Brassard, Richard H. Aster, Carolyn H. Mccabe, Andrew Charlesworth, Allan M. Skene, Eugene Braunwald
    Abstract:

    Objective: To assess etiology and impact of thrombocytopenia in a large oral glycoprotein (GP) IIb/IIIa inhibitor trial.

Sabina A. Murphy - One of the best experts on this subject based on the ideXlab platform.

  • association of a history of systemic hypertension with mortality thrombotic and bleeding complications following non st segment elevation acute coronary syndrome
    Journal of Clinical Hypertension, 2006
    Co-Authors: Raphaelle Dumaine, Christopher P Cannon, Carolyn H. Mccabe, Sabina A. Murphy, Elliott M. Antman, Matthew C. Southard, Robert P. Giugliano, Michael C Gibson, Hung Q Ly, Eugene Braunwald
    Abstract:

    Chronic hypertension is a well established risk factor for the development of cardiovascular disease; however, its prognostic significance after a non-ST-segment elevation acute coronary syndrome remains to be established. Data from 15,414 patients included in six randomized Thrombolysis in Myocardial Infarction (TIMI) trials (TIMI 3B, TIMI11 A, TIMI 11B, TIMI 12, the Orbofiban in Patients With Unstable Coronary Syndromes [OPUS]-TIMI 16, and the Treat Angina With Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy [TACTICS]-TIMI 18) were analyzed. A history of hypertension was present in 10,998 (71.35%) patients; comorbidities and higher TIMI risk scores were more likely in these patients. However, positive troponin and ST-segment deviations were less frequent among hypertensive patients. After multivariate analysis, the history of hypertension was associated with more adverse outcomes, specifically the composite end point of death/myocardial infarction at 30 days and 1 year (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.31–1.81; p<0.001 at 1 year) than in patients without this history. An independent relationship was also observed with mortality (OR 1.70, 95% CI 1.34–2.16; p<0.001 at 1 year), myocardial infarction (OR 1.50, 95% CI 1.23–1.82; p<0.001 at 1 year), recurrent ischemia (OR 1.24, 95% CI 1.11–1.38; p<0.001 at 1 year), and major bleeding (OR 1.45, 95% CI 1.03–2.06; p=0.036 at 30 days). It was concluded that chronic hypertension remains an independent marker for major short- and long-term cardiac adverse outcomes after non-ST-segment elevation acute coronary syndrome.

  • Statins are associated with lower risk of gastrointestinal bleeding in patients with unstable coronary syndromes: analysis of the Orbofiban in Patients with Unstable coronary Syndromes-Thrombolysis In Myocardial Infarction 16 (OPUS-TIMI 16) trial.
    American heart journal, 2006
    Co-Authors: Shaul Atar, Christopher P Cannon, Sabina A. Murphy, Salvatore Rosanio, Barry F. Uretsky, Yochai Birnbaum
    Abstract:

    Background It has recently been shown that statins increase the myocardial content of prostaglandin (PG) I 2 (prostacyclin) and PGE 2 . A systemic increase of PG production may protect the gastric mucosa and prevent gastrointestinal (GI) bleeding. We hypothesized that statins would lower the risk of GI bleeding associated with antiplatelet therapy in patients with acute coronary syndromes (ACS). Methods We retrospectively analyzed data on 10288 patients with ACS included in the OPUS-TIMI 16 trial and received aspirin and either the oral IIb/IIIa inhibitor Orbofiban or placebo. Results Inhospital GI bleeding rate was significantly lower in patients who were receiving lipid-lowering drugs before admission compared with those who were not (0.2% vs 0.6%, P = .031). Throughout 10 months of follow-up, GI bleeding occurred in 1.8% of non–statin users compared with 1.0% of statin users ( P = .001). Statin use was associated with less overall bleeding in both the Orbofiban (1.4% vs 2.4%, P = .006) and the placebo groups (0.2% vs 0.8%, P = .047). Severe and major bleeding occurred less frequently with statin use (0.8% vs 1.5%, P = .001) in both the Orbofiban (1.1% vs 2.0%, P = .006) and the placebo groups (0.1% vs 0.5%, P = .119). Logistic regression analysis showed that age >65 years, Orbofiban treatment, Killip class >1, history of cerebrovascular disease, and calcium-channel blocker use were associated with higher risk of GI bleeding, whereas statin therapy was associated with a lower risk (odds ratio 0.68, 95% CI 0.45-1.04, P = .079). Conclusions Statins may exert protective effect against GI bleeding in patients with ACS. Additional studies are warranted to explore this additional potential benefit of statins.

  • Risk factors for stroke after acute coronary syndromes in the Orbofiban in Patients with Unstable Coronary Syndromes--Thrombolysis In Myocardial Infarction (OPUS-TIMI) 16 study.
    American heart journal, 2006
    Co-Authors: Eric E. Smith, Christopher P Cannon, Sabina A. Murphy, Steven K. Feske, Lee H. Schwamm
    Abstract:

    Background Previous reports have associated acute coronary syndromes (ACSs) with cerebrovascular disease but in general have not included long-term patient follow-up or have not analyzed ischemic and hemorrhagic cerebrovascular events separately. Methods We analyzed stroke outcomes from the OPUS-TIMI 16 study, a multicenter, randomized, placebo-controlled trial. Patients were randomized to aspirin plus either Orbofiban or placebo and followed for up to 1 year. Cerebrovascular events were prospectively identified and classified by a committee of cardiologists and neurologists blinded to treatment assignment. Results During 10 months of follow-up, there were 150 (1.5%) patients with cerebrovascular events. Risk factors for ischemic stroke (n = 67) and transient ischemic attack (TIA) (n = 44) were age, prior ischemic stroke, history of hypertension, and increased heart rate. Prior ischemic stroke and history of hypertension were not risk factors for 30-day ischemic stroke or TIA. Risk factors for intracranial hemorrhage (ICH) (n = 14) were age, history of hypertension, history of TIA, and coronary angiography with evidence of coronary artery disease. Compared with placebo, treatment with Orbofiban was associated with a nonsignificant increased risk of ischemic stroke or TIA (HR 1.15, 95% CI 0.76-1.74, P = .51) and ICH (HR 1.25, 95% CI 0.39-4.00, P = .70). Conclusions The overall incidence of cerebrovascular events after ACS was highest in the first 30 days then declined; risk factors for cerebrovascular events may be different in the different periods. Orbofiban, despite no significant excess risk of ICH, was not effective in preventing ischemic stroke or TIA.

  • Association of a History of Systemic Hypertension With Mortality, Thrombotic, and Bleeding Complications Following Non-ST-Segment Elevation Acute Coronary Syndrome
    Journal of clinical hypertension (Greenwich Conn.), 2006
    Co-Authors: Raphaelle Dumaine, Christopher P Cannon, Carolyn H. Mccabe, Sabina A. Murphy, C. Michael Gibson, Elliott M. Antman, Matthew C. Southard, Robert P. Giugliano, Eugene Braunwald
    Abstract:

    Chronic hypertension is a well established risk factor for the development of cardiovascular disease; however, its prognostic significance after a non-ST-segment elevation acute coronary syndrome remains to be established. Data from 15,414 patients included in six randomized Thrombolysis in Myocardial Infarction (TIMI) trials (TIMI 3B, TIMI 11A, TIMI 11B, TIMI 12, the Orbofiban in Patients With Unstable Coronary Syndromes [OPUS]-TIMI 16, and the Treat Angina With Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy [TACTICS]-TIMI 18) were analyzed. A history of hypertension was present in 10,998 (71.35%) patients; comorbidities and higher TIMI risk scores were more likely in these patients. However, positive troponin and ST-segment deviations were less frequent among hypertensive patients. After multivariate analysis, the history of hypertension was associated with more adverse outcomes, specifically the composite end point of death/myocardial infarction at 30 days and 1 year (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.31-1.81; p

  • serum blood urea nitrogen as an independent marker of subsequent mortality among patients with acute coronary syndromes and normal to mildly reduced glomerular filtration rates
    Journal of the American College of Cardiology, 2005
    Co-Authors: Ajay J Kirtane, Christopher P Cannon, Sabina A. Murphy, David M Leder, Sushrut S Waikar, Glenn M Chertow, Duane S Pinto, Dimitrios Karmpaliotis, Andrew J Burger, Eugene Braunwald
    Abstract:

    Objectives We hypothesized that elevated blood urea nitrogen (BUN) would be associated with adverse outcomes independent of serum creatinine (sCr)-based estimates of kidney function in patients with acute coronary syndromes (ACS). Background Although lower glomerular filtration rates (GFR) have prognostic significance among patients with ACS, estimates of GFR based on sCr may perform less accurately among patients with milder kidney dysfunction. In this population in particular, BUN, which can reflect increased proximal tubular reabsorption in addition to decreased GFR, may have independent prognostic value. Methods Data were drawn from 9,420 patients with unstable coronary syndromes from Orbofiban in Patients With Unstable Coronary Syndromes-Thrombolysis In Myocardial Infarction (OPUS-TIMI)-16, a trial that excluded patients with sCr >1.6 mg/dl or estimated creatinine clearance <40 ml/min. Results Patients with elevated BUN were older, had a higher prevalence of comorbidities, and had higher heart rates, lower systolic blood pressures, and an abnormal Killip class more often on admission. In univariate analyses, as well as in stratified and multivariable analyses including sCr-based estimates of GFR as a covariate, a stepwise increase in mortality occurred with increasing BUN (multivariable hazard ratio with BUN 20 to 25 mg/dl 1.9, 95% confidence interval 1.3 to 2.6; with BUN ≥25 mg/dl 3.2 [95% confidence interval 2.2 to 4.7]) compared with BUN ≤20 mg/dl. A higher BUN was also associated with increased mortality among strata of troponin-I, B-type natriuretic peptide, and C-reactive protein concentrations. Conclusions Among patients with unstable coronary syndromes and predominantly normal or mildly reduced GFR, an elevated BUN is associated with increased mortality, independent of sCr-based estimates of GFR and other biomarkers.

Carolyn H. Mccabe - One of the best experts on this subject based on the ideXlab platform.

  • drug induced thrombocytopenia and thrombosis evidence from patients receiving an oral glycoprotein iib iiia inhibitor in the Orbofiban in patients with unstable coronary syndromes opus timi 16 trial
    Journal of Thrombosis and Thrombolysis, 2006
    Co-Authors: Benjamin M. Scirica, Jacqueline Brassard, Richard A Cooper, Christopher P Cannon, Richard H. Aster, Carolyn H. Mccabe, Andrew Charlesworth, Allan M. Skene, Eugene Braunwald
    Abstract:

    Objective: To assess etiology and impact of thrombocytopenia in a large oral glycoprotein (GP) IIb/IIIa inhibitor trial.

  • Drug-induced thrombocytopenia and thrombosis: Evidence from patients receiving an oral glycoprotein IIb/IIIa inhibitor in the Orbofiban in Patients with Unstable coronary Syndromes- (OPUS-TIMI 16) trial
    Journal of Thrombosis and Thrombolysis, 2006
    Co-Authors: Benjamin M. Scirica, Jacqueline Brassard, Richard Cooper, Christopher P Cannon, Richard H. Aster, Carolyn H. Mccabe, Andrew Charlesworth, Allan M. Skene, Eugene Braunwald
    Abstract:

    Objective : To assess etiology and impact of thrombocytopenia in a large oral glycoprotein (GP) IIb/IIIa inhibitor trial. Background : Heparin is known to cause thrombocytopenia, and in some of these patients thrombosis. GP IIb/IIIa inhibitors are also associated with thrombocytopenia. Methods : The Orbofiban in Patients with Unstable Coronary Syndromes (OPUS-TIMI 16) Trial randomized 10,392 patients with ACS to the oral GP IIb/IIIa inhibitor Orbofiban or placebo. Patients were followed for a minimum of ten months. Thrombocytopenia was defined prospectively as a platelet count < 80,000. Results : Thrombocytopenia was rare in the OPUS-TIMI 16 trial (0.68% at Day 30 and 0.80% at 1 year), but more common in patients treated with Orbofiban (0.92%) compared with those treated with placebo (0.2%), p < 0.001. Patients who developed thrombocytopenia had higher rates of death (11.6% vs. 1.7%, p < 0.001), recurrent MI (12.1% vs. 2.8%, p < 0.001), intracranial hemorrhage (2.9% vs. 0.0%, p < 0.001), and major or severe bleeding (19.0% vs. 2.0%, p < 0.001) at 30 days (with similar results at one year). Conclusion : Thrombocytopenia, though uncommon, was associated with Orbofiban use and an increased risk of bleeding, but also death and MI. This study provides further evidence that drugs that lead to thrombocytopenia are, in a significant proportion of patients associated with thrombotic events.

  • association of a history of systemic hypertension with mortality thrombotic and bleeding complications following non st segment elevation acute coronary syndrome
    Journal of Clinical Hypertension, 2006
    Co-Authors: Raphaelle Dumaine, Christopher P Cannon, Carolyn H. Mccabe, Sabina A. Murphy, Elliott M. Antman, Matthew C. Southard, Robert P. Giugliano, Michael C Gibson, Hung Q Ly, Eugene Braunwald
    Abstract:

    Chronic hypertension is a well established risk factor for the development of cardiovascular disease; however, its prognostic significance after a non-ST-segment elevation acute coronary syndrome remains to be established. Data from 15,414 patients included in six randomized Thrombolysis in Myocardial Infarction (TIMI) trials (TIMI 3B, TIMI11 A, TIMI 11B, TIMI 12, the Orbofiban in Patients With Unstable Coronary Syndromes [OPUS]-TIMI 16, and the Treat Angina With Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy [TACTICS]-TIMI 18) were analyzed. A history of hypertension was present in 10,998 (71.35%) patients; comorbidities and higher TIMI risk scores were more likely in these patients. However, positive troponin and ST-segment deviations were less frequent among hypertensive patients. After multivariate analysis, the history of hypertension was associated with more adverse outcomes, specifically the composite end point of death/myocardial infarction at 30 days and 1 year (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.31–1.81; p<0.001 at 1 year) than in patients without this history. An independent relationship was also observed with mortality (OR 1.70, 95% CI 1.34–2.16; p<0.001 at 1 year), myocardial infarction (OR 1.50, 95% CI 1.23–1.82; p<0.001 at 1 year), recurrent ischemia (OR 1.24, 95% CI 1.11–1.38; p<0.001 at 1 year), and major bleeding (OR 1.45, 95% CI 1.03–2.06; p=0.036 at 30 days). It was concluded that chronic hypertension remains an independent marker for major short- and long-term cardiac adverse outcomes after non-ST-segment elevation acute coronary syndrome.

  • Association of a History of Systemic Hypertension With Mortality, Thrombotic, and Bleeding Complications Following Non-ST-Segment Elevation Acute Coronary Syndrome
    Journal of clinical hypertension (Greenwich Conn.), 2006
    Co-Authors: Raphaelle Dumaine, Christopher P Cannon, Carolyn H. Mccabe, Sabina A. Murphy, C. Michael Gibson, Elliott M. Antman, Matthew C. Southard, Robert P. Giugliano, Eugene Braunwald
    Abstract:

    Chronic hypertension is a well established risk factor for the development of cardiovascular disease; however, its prognostic significance after a non-ST-segment elevation acute coronary syndrome remains to be established. Data from 15,414 patients included in six randomized Thrombolysis in Myocardial Infarction (TIMI) trials (TIMI 3B, TIMI 11A, TIMI 11B, TIMI 12, the Orbofiban in Patients With Unstable Coronary Syndromes [OPUS]-TIMI 16, and the Treat Angina With Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy [TACTICS]-TIMI 18) were analyzed. A history of hypertension was present in 10,998 (71.35%) patients; comorbidities and higher TIMI risk scores were more likely in these patients. However, positive troponin and ST-segment deviations were less frequent among hypertensive patients. After multivariate analysis, the history of hypertension was associated with more adverse outcomes, specifically the composite end point of death/myocardial infarction at 30 days and 1 year (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.31-1.81; p

  • Drug-induced thrombocytopenia and thrombosis: evidence from patients receiving an oral glycoprotein IIb/IIIa inhibitor in the Orbofiban in Patients with Unstable coronary Syndromes- (OPUS-TIMI 16) trial.
    Journal of thrombosis and thrombolysis, 2006
    Co-Authors: Benjamin M. Scirica, Richard A Cooper, Christopher P Cannon, Jacqueline A. Brassard, Richard H. Aster, Carolyn H. Mccabe, Andrew Charlesworth, Allan M. Skene, Eugene Braunwald
    Abstract:

    Objective: To assess etiology and impact of thrombocytopenia in a large oral glycoprotein (GP) IIb/IIIa inhibitor trial.

Desmond J. Fitzgerald - One of the best experts on this subject based on the ideXlab platform.

  • g protein β3 subunit polymorphism and bleeding in the Orbofiban in patients with unstable coronary syndromes thrombolysis in myocardial infarction 16 trial
    Journal of Thrombosis and Haemostasis, 2010
    Co-Authors: Andrew O Maree, Christopher P Cannon, Denis C. Shields, Dermot Cox, Ciara Vangjeli, Hani Jneid, John J Ryan, Desmond J. Fitzgerald
    Abstract:

    Summary. Background: Variability in platelet response to antiplatelet drugs is heritable. A common single base substitution (825C>T) in the G-protein beta polypeptide 3 (GNB3) gene leads to alternative splicing (41-amino-acid deletion) of the human G-protein β3 (Gβ3) subunit. This truncated protein carried by GNB3 T allele carriers is linked to coronary artery disease and implicated as a genetic marker of drug response. Large studies of Caucasians associate T allele carriage with lower platelet reactivity.Objectives: To evaluate whether the GNB3 genotype would predispose to bleeding in patients treated with a GPIIb/IIIa receptor antagonist. Methods: GNB3 genotype distribution was determined in DNA samples from patients in the Orbofiban in patients with unstable coronary syndromes–thrombolysis in myocardial infarction (OPUS–TIMI) 16 genetic sub-study. Impact of genotype on the bleeding endpoint and the composite primary endpoint of death, myocardial infarction (MI), re-hospitalization for ischemia and urgent revascularization was estimated in the treatment and placebo arm. Results: Out of 887 patients, 45.1% carried the GNB3 CC genotype, 44.5% CT and 10.4% TT. Interaction between T allele carriership and treatment for bleeding was significant (P = 0.008). This reflects the fact that GNB3 non-T carriers treated with Orbofiban had no bleeding effect compared with placebo (RR = 0.92, 95% CI 0.55–1.55) whereas T carriers did (RR = 2.62, 95% CI 1.58–4.35, P < 0.001). Interaction between T allele carriership and treatment was not significant for the primary endpoint (P = 0.18) or MI (P = 0.69). Conclusion: The GNB3 T allele significantly increased bleeding in patients treated with the platelet antagonist Orbofiban. Our findings suggest that risk of bleeding associated with an antiplatelet agent is heritable and may be dissociated from risk of thrombosis.

  • G‐protein β3 subunit polymorphism and bleeding in the Orbofiban in patients with unstable coronary syndromes–thrombolysis in myocardial infarction 16 trial
    Journal of thrombosis and haemostasis : JTH, 2010
    Co-Authors: Andrew O Maree, Christopher P Cannon, Denis C. Shields, Dermot Cox, Ciara Vangjeli, Hani Jneid, John J Ryan, Desmond J. Fitzgerald
    Abstract:

    Summary. Background: Variability in platelet response to antiplatelet drugs is heritable. A common single base substitution (825C>T) in the G-protein beta polypeptide 3 (GNB3) gene leads to alternative splicing (41-amino-acid deletion) of the human G-protein β3 (Gβ3) subunit. This truncated protein carried by GNB3 T allele carriers is linked to coronary artery disease and implicated as a genetic marker of drug response. Large studies of Caucasians associate T allele carriage with lower platelet reactivity.Objectives: To evaluate whether the GNB3 genotype would predispose to bleeding in patients treated with a GPIIb/IIIa receptor antagonist. Methods: GNB3 genotype distribution was determined in DNA samples from patients in the Orbofiban in patients with unstable coronary syndromes–thrombolysis in myocardial infarction (OPUS–TIMI) 16 genetic sub-study. Impact of genotype on the bleeding endpoint and the composite primary endpoint of death, myocardial infarction (MI), re-hospitalization for ischemia and urgent revascularization was estimated in the treatment and placebo arm. Results: Out of 887 patients, 45.1% carried the GNB3 CC genotype, 44.5% CT and 10.4% TT. Interaction between T allele carriership and treatment for bleeding was significant (P = 0.008). This reflects the fact that GNB3 non-T carriers treated with Orbofiban had no bleeding effect compared with placebo (RR = 0.92, 95% CI 0.55–1.55) whereas T carriers did (RR = 2.62, 95% CI 1.58–4.35, P 

  • mapping the dose effect relationship of Orbofiban from sparse data with an artificial neural network
    Journal of Pharmaceutical Sciences, 2005
    Co-Authors: Donald E. Mager, Desmond J. Fitzgerald, Dermot Cox, Jason D. Shirey, Darrell R. Abernethy
    Abstract:

    ABSTRACT: A neural network (NN) pharmacodynamic model was developed that correlates the inhibition of ex vivo platelet aggregation by Orbofiban, an oral glycoprotein IIb/IIIa antagonist, with the administered dose and patient characteristics. Data were obtained from a Phase-II dose-finding study of Orbofiban in patients presenting with acute coronary syndromes. A back-propagation NN was designed to predict drug effect measured at predose and 4 and 6 h on treatment days 1, 28, and 84 (nine responses/patient). The training set consisted of patients for whom complete response profiles were reported ( n  = 67), and remaining patients were included in the validation data set ( n  = 47). The concentration–effect relationship was described additionally using a population direct-effect inhibitory sigmoidal model, and a comparison of the predictive performances of both models was performed. The final NN reasonably described Orbofiban pharmacodynamics from sparse data sets without specifying a structural model or drug concentrations. Despite considerable inter-patient variability in response–time profiles, the population model revealed a strong correlation between drug concentration and effect and exhibited greater precision than the NN model. Although the population model showed greater precision, these results suggest that NNs may be useful for individualizing pharmacotherapy when drug concentrations are relatively unpredictable or unavailable.

  • neural network model of Orbofiban pharmacodynamics from sparse phase ii data
    Clinical Pharmacology & Therapeutics, 2005
    Co-Authors: Donald E. Mager, Desmond J. Fitzgerald, Dermot Cox, Jason D. Shirey, Darrell R. Abernethy
    Abstract:

    Background/Aims The purpose of this study was to develop a neural network (NN) pharmacodynamic (PD) model that correlates the inhibition of ex vivo platelet aggregation by Orbofiban, an oral GPIIb/IIIa antagonist, with the administered dose and patient characteristics. Methods Data were obtained from a Phase-II dose-finding study in patients presenting with acute coronary syndromes. A back-propagation NN was designed to predict drug effect measured at pre-dose and 4 and 6 hours on treatment days 1, 28, and 84 (9 responses/patient). The training set (TS) consisted of patients for whom complete response profiles were reported (n=67), and remaining patients were included in the validation data set (VS; n=47). The concentration-effect relationship was described also using a population inhibitory sigmoidal model, and a comparison of the predictive performances of both models was performed. Results The final NN reasonably described Orbofiban PD from sparse data sets (r2=0.83 & 0.61; TS & VS) without specifying a structural model or drug concentrations. Despite considerable inter-patient variability in response-time profiles, the population model revealed a strong correlation between drug concentration and effect and exhibited greater precision than the NN model. Conclusions Although the population model showed greater precision, these results suggest that NNs may be useful for predicting drug PD when plasma concentrations are relatively unpredictable or unavailable. Clinical Pharmacology & Therapeutics (2005) 77, P92–P92; doi: 10.1016/j.clpt.2004.12.244

  • Mapping the dose–effect relationship of Orbofiban from sparse data with an artificial neural network
    Journal of pharmaceutical sciences, 2005
    Co-Authors: Donald E. Mager, Desmond J. Fitzgerald, Dermot Cox, Jason D. Shirey, Darrell R. Abernethy
    Abstract:

    ABSTRACT: A neural network (NN) pharmacodynamic model was developed that correlates the inhibition of ex vivo platelet aggregation by Orbofiban, an oral glycoprotein IIb/IIIa antagonist, with the administered dose and patient characteristics. Data were obtained from a Phase-II dose-finding study of Orbofiban in patients presenting with acute coronary syndromes. A back-propagation NN was designed to predict drug effect measured at predose and 4 and 6 h on treatment days 1, 28, and 84 (nine responses/patient). The training set consisted of patients for whom complete response profiles were reported ( n  = 67), and remaining patients were included in the validation data set ( n  = 47). The concentration–effect relationship was described additionally using a population direct-effect inhibitory sigmoidal model, and a comparison of the predictive performances of both models was performed. The final NN reasonably described Orbofiban pharmacodynamics from sparse data sets without specifying a structural model or drug concentrations. Despite considerable inter-patient variability in response–time profiles, the population model revealed a strong correlation between drug concentration and effect and exhibited greater precision than the NN model. Although the population model showed greater precision, these results suggest that NNs may be useful for individualizing pharmacotherapy when drug concentrations are relatively unpredictable or unavailable.