Drug Development in Kidney Disease: Proceedings From a Multistakeholder Conference.

Occasional bursts of discovery and innovation have appeared during the otherwise stagnant past several decades of drug development in nephrology. Among other recent drug discoveries, the unexpected kidney benefits observed with sodium/glucose cotransporter 2 inhibitors may herald a renaissance of drug development in kidney disease. This recent progress highlights the need to further promote and stimulate research and development of promising therapies that may ameliorate the morbidity and mortality associated with kidney disease. To help identify and address barriers to drug development in nephrology, the Duke Clinical Research Institute convened a conference in April 2019 that included stakeholders from academia, industry, government agencies, and patient advocacy. From these discussions, several opportunities were identified to improve every stage of drug development for kidney disease from early discovery to implementation into practice. Key topics reviewed in this article are the utility of interconnected data and site research networks, surrogate end points, pragmatic and adaptive trial designs, the promising uses of real-world data, and methods to improve the generalizability of trial results and uptake of approved drugs for kidney-related diseases.

Exploring the potential cost-effectiveness of a novel platelet assay for guiding dual antiplatelet therapy duration in acute coronary syndrome patients following percutaneous coronary intervention.

OBJECTIVE: Duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) influences ischemic and bleeding events. Platelet expression of constant fragment of immunoglobulin, low affinity IIa, receptor (FcγRIIa) independently predicts risk of ischemic complications and is proposed as a tool to guide individualized care. METHODS: We used a Markov model to predict lifetime ischemic and bleeding events and healthcare costs in acute myocardial infarction (MI) patients treated with PCI and DAPT and to project cost-effectiveness of platelet FcγRIIa-assay-guided care (30:3 months DAPT for patients at high: low ischemic risk) versus current standard care (12 months DAPT) from the perspective of the US healthcare system. Model inputs included assay sensitivity and specificity, ischemic and bleeding event rates, and impacts on quality of life, mortality, and costs. Assay cost was $90. Sensitivity analyses were conducted over a range of plausible clinical and cost assumptions. RESULTS: Under base case assumptions, platelet FcγRIIa-assay-guided DAPT duration was projected to increase lifetime costs by $19 versus standard care, with an associated incremental cost-effectiveness ratio (ICER) of $436 per quality-adjusted life-year (QALY) gained. Assay-guided DAPT duration was consistent with high-value care (ICER < $50 000/QALY gained) over a broad range of alternative assumptions. CONCLUSION: Based on a decision-analytic model, for patients with MI treated with PCI, the additional costs of the platelet FcγRIIa assay for guiding DAPT duration would be largely offset by reductions in downstream event-related costs, and assay-guided care would be highly cost-effective by current standards. These findings require confirmation in prospective studies and in a randomized clinical trial of assay-guided versus nonassay-guided DAPT duration.

Effects on platelet function of a direct acting antagonist of coagulation factor Xa.

Because novel direct acting anticoagulants are being tested in the secondary prevention of cardiovascular events, we assessed potential effects of a direct acting antagonist of Factor Xa on platelet function. Blood from patients with known coronary artery disease who were treated with aspirin but no other antithrombotic agent was spiked in vitro with rivaroxaban alone or in combination with a direct acting P2Y12 antagonist (cangrelor). To limit cofounding effects of anticoagulants and to enable interaction between coagulation factors, blood was anticoagulated only with a specific inhibitor of Factor XIIa, corn trypsin inhibitor. Polymerization of fibrin was prevented with the peptide GPRP. Activation of platelets was determined with the use of flow cytometry in response to lipidated tissue factor, thrombin, the collagen mimetic convulxin, and adenosine diphosphate (ADP). Rivaroxaban inhibited the activation of platelets induced by tissue factor and to a lesser extent activation induced by thrombin, effects that were accentuated when combined with cangrelor. Rivaroxaban did not attenuate convulxin-induced activation of platelets; however, a limited but consistent attenuation of ADP-induced platelet activation was seen with blood anticoagulated with rivaroxaban. Effects of rivaroxaban on ADP-induced platelet activation were not mediated by thrombin, tissue factor, or platelet-leukocyte aggregation. In conclusion, rivaroxaban attenuated in vitro the activation of platelets mediated by thrombin. In light of the pivotal role of thrombin in platelet activation after rupture of an atherosclerotic plaque, rivaroxaban should attenuate platelet activation in vivo, an effect that is accentuated by combination with a P2Y12 antagonist.

Incidence rate of hospitalization and mortality in the first year following initial diagnosis of cardiac amyloidosis in the US claims databases.

OBJECTIVE: This study aimed to determine rates of hospitalization and in-hospital mortality in the first year following amyloidosis diagnosis with cardiac involvement using observational databases. METHODS: Three administrative claims databases, IBM MarketScan® Commercial Claims and Encounters (CCAE), IBM MarketScan® Multi-State Medicare Database (MDCR), and Optum's de-identified Clinformatics® Data Mart Database (Optum) were analyzed. Adults ≥18 years old, with a diagnosis of amyloidosis and evidence of cardiac involvement (i.e. heart failure, heart block, or cardiomyopathy) but no hepatic/renal failure prior to amyloidosis diagnosis were included for analysis. The primary analyses identified patients between 01-01-2010 and 31-12-2017 period. We calculated the rates of hospitalization and in-hospital mortality within 1 year after the initial diagnosis of amyloidosis. A sensitivity analysis was conducted for patients identified in Optum database during 2004-2011 period, which provided additional mortality information. RESULTS: A total of 419, 654, and 922 patients from CCAE, MDCR, and Optum were identified during 2010-2017 period, with mean age of 55.6, 77.8, and 74.2 years, respectively. Within 1 year following initial amyloidosis diagnosis, incidence rates (95% confidence interval [CI]) of hospitalization were 78.4 (66.3, 90.4), 78.6 (69.2, 87.9), and 61.2 (54.4, 68.0) per 100 person-years, rates of in-hospital mortality were 16.5 (11.8, 21.3), 8.4 (5.7, 11.0), and 17.7 (14.5, 21.0) per 100 person-years, in CCAE, MDCR, and Optum, respectively. The mortality rate from the sensitivity analysis among patients identified in Optum 2004-2011 period was higher compared with Optum 2010-2017 period. CONCLUSIONS: The results from this study indicate that amyloidosis with cardiac involvement is a condition with high rates of hospitalization and mortality in the first year after initial diagnosis. Future studies are needed to further evaluate the outcomes within the subtypes of amyloidosis and understand the risk factors associated with poor prognoses.

Randomized phase 2 trial comparing JNJ-9375, a thrombin-directed antibody, with apixaban for prevention of venous thrombosis.

BACKGROUND: JNJ-9375 is an antibody against exosite 1 on thrombin, inhibits substrate binding but not catalytic activity. OBJECTIVE: To examine the possibility that JNJ-9375 attenuates thrombosis without affecting hemostasis, we compared the efficacy and safety of JNJ-9375 and apixaban. METHODS: In this double-blind, double-dummy phase 2 trial, 308 patients undergoing knee arthroplasty were randomized to receive either a single postoperative intravenous infusion of JNJ-9375 in doses ranging from 0.3 to 1.8 mg/kg or apixaban (2.5 mg twice daily). The primary efficacy endpoint was the incidence of venous thromboembolism (assessed by mandatory unilateral venography or confirmed symptomatic events). The primary safety outcome was the composite of major, clinically relevant nonmajor, and minimal bleeding. Thrombin times were measured to assess JNJ-9375 activity. RESULTS: A total of 239 of the 308 patients (77.6%) were included in the modified intention-to-treat analysis. Of these, 238 had evaluable venograms and one had symptomatic deep-vein thrombosis confirmed by ultrasound. Despite dose-dependent thrombin time prolongation, the primary efficacy outcome occurred in 59 of 190 patients (31.1%) in the combined JNJ-9375 groups as compared with 6 of 49 patients (12.2%) given apixaban (odds ratio 3.2; two-sided 80% confidence interval 1.8-5.8; P = .011). The excess events with JNJ-9375 compared with apixaban were consistent across all JNJ-9375 dosing cohorts and there was no evidence of improved efficacy with higher JNJ-9375 doses. There were no major bleeds with JNJ-9375 or apixaban, and rates of any bleeding were similar with the highest and lowest JNJ-9375 doses. CONCLUSIONS: JNJ-9375 was safe but less effective than apixaban. This may reflect weak thrombin inhibition or inability of JNJ-9375 to attenuate the growth of thrombi that formed before drug administration.

Prognostic implications of elevated troponin in patients with suspected acute coronary syndrome but no critical epicardial coronary disease: a TACTICS-TIMI-18 substudy.

OBJECTIVES: The purpose of this study is to determine whether there is clinical significance to elevated troponin I in patients with suspected acute coronary syndromes (ACS) with non-critical angiographic coronary stenosis. BACKGROUND: Elevation of troponin in patients admitted with ACS symptoms with non-critical coronary artery disease (CAD) may result from coronary atherothrombosis not evident using standard angiography or from other ischemic and non-ischemic causes that may confer increased risk for future events. METHODS: Patients with ACS enrolled in the Treat Angina With Aggrastat and Determine Cost of Therapy With Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction (TACTICS-TIMI)-18 were included. Of 2,220 patients enrolled in the trial, 895 were eligible. Patients were divided into four groups according to troponin status on admission and presence of significant angiographic stenosis. Baseline brain natriuretic peptide (BNP) and C-reactive protein (CRP) were obtained on all patients. RESULTS: The median troponin I levels were 0.71 ng/ml in patients with CAD compared with 0.02 ng/ml in patients without CAD (p <0.0001). Troponin-positive patients with or without angiographic CAD had higher CRP and BNP levels compared with troponin-negative patients (p <0.01 for both). The rates of death or reinfarction at six months were 0% in troponin-negative patients with no CAD, 3.1% in troponin-positive patients with no CAD, 5.8% in troponin-negative patients with CAD, and 8.6% in troponin-positive patients with CAD (p=0.012). CONCLUSIONS: Elevated troponin in ACS is associated with a higher risk for death or reinfarction, even among patients who do not have significant angiographic CAD. The mechanisms conferring this adverse prognosis merit further study.

Benefits and safety of tirofiban among acute coronary syndrome patients with mild to moderate renal insufficiency: results from the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial.

BACKGROUND: The role of glycoprotein IIb/IIIa receptor antagonists for the treatment of patients with acute coronary syndrome and renal insufficiency remains undefined. METHODS AND RESULTS: Patients from the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial were stratified by creatinine clearance (CrCl) and assessed with respect to treatment assignment to tirofiban/heparin versus heparin alone for the risk of adverse outcomes and bleeding. Patients with severe renal insufficiency (defined as a serum creatinine > or = 2.5 mg/dL) were excluded from PRISM-PLUS as a whole. Patients with the lowest CrCl (< 30 mL/min) were more likely to present with high-risk clinical features. Decreasing renal function was strongly associated with adverse outcome, increasing the risk for ischemic complications at all time points examined (all P < 0.002). Irrespective of CrCl, therapy with tirofiban reduced the odds of the composite end point of death, myocardial infarction, or refractory ischemia at 48 hours (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.46 to 1.0; P=0.05), 7 days (OR, 0.68; 95% CI, 0.52 to 0.88; P= 0.003), 30 days (OR, 0.78; 95% CI, 0.63 to 0.98; P=0.03), and 6 months (OR, 0.81; 95% CI, 0.68 to 0.98; P=0.03). The risk of myocardial infarction/death was also significantly decreased to a similar magnitude at all time points examined. There was no evidence of treatment-by-CrCl interaction. The presence of declining renal function independently increased the risk for bleeding (OR, 1.57; P < 0.001 for trend across categories), as did therapy with tirofiban, but no unexpected incremental risk of bleeding due to tirofiban was observed among lowest CrCl categories. CONCLUSIONS: Among patients with mild-to-moderate renal insufficiency in PRISM-PLUS, tirofiban was well tolerated and effective in reducing ischemic acute coronary syndrome complications.

Adjunctive platelet glycoprotein IIb/IIIa receptor inhibition with tirofiban before primary angioplasty improves angiographic outcomes: results of the TIrofiban Given in the Emergency Room before Primary Angioplasty (TIGER-PA) pilot trial.

BACKGROUND: Previous work has suggested that platelet glycoprotein IIb/IIIa receptor blockade may confer benefit in the treatment of acute myocardial infarction. The TIGER-PA pilot trial was a single-center randomized study to evaluate the safety, feasibility, and utility of early tirofiban administration before planned primary angioplasty in patients presenting with acute myocardial infarction. METHODS AND RESULTS: A total of 100 patients presenting with acute myocardial infarction were randomized to either early administration of tirofiban in the emergency room or later administration in the catheterization laboratory. The primary outcome measures were initial TIMI grade flow, corrected TIMI frame counts, and TIMI grade myocardial perfusion ("blush"). Thirty-day major adverse cardiac events were also assessed. Angiographic outcomes demonstrate a significant improvement in initial TIMI grade flow, corrected TIMI frame counts, and TIMI grade myocardial perfusion when patients are given tirofiban in the emergency room before primary angioplasty. The rate of 30-day major adverse cardiac events suggests that early administration may be beneficial. CONCLUSIONS: This pilot study suggests that early administration of tirofiban improves angiographic outcomes and is safe and feasible in patients undergoing primary angioplasty for acute myocardial infarction.

Impact of different platelet glycoprotein IIb/IIIa receptor inhibitors among diabetic patients undergoing percutaneous coronary intervention: : Do Tirofiban and ReoPro Give Similar Efficacy Outcomes Trial (TARGET) 1-year follow-up.

BACKGROUND: The platelet glycoprotein IIb/IIIa receptor inhibitor abciximab, a monoclonal antibody, has been shown to improve early and late outcomes among diabetic patients undergoing percutaneous coronary intervention (PCI). It is unknown whether small-molecule agents confer similar benefits. METHODS AND RESULTS: In 18 countries, 4809 patients undergoing PCI with stent implantation were randomized to tirofiban or abciximab. At the time of enrollment, patients were stratified according to diabetes status. As compared with non-diabetic patients, patients with diabetes (n=1117) showed similar 30-day ischemic outcomes, an increased incidence of any target vessel revascularization (TVR) at 6 months (10.3% versus 7.8%; P= 0.008), and a trend toward higher 1-year mortality (2.5% versus 1.6%; P=0.056). Among diabetic patients randomized to tirofiban (n=560), the incidence of death, myocardial infarction (MI), or urgent TVR at 30 days was 6.2%, and among those randomized to abciximab (n=557) it was 5.4% (hazard ratio [HR] 1.16; P=0.540). At 6 months, the composite of death, MI, or any TVR occurred in 15.7% and in 16.9% of tirofiban and abciximab patients, respectively (HR 0.93; P=0.610). Any TVR occurred in 9.5% and 11.1%, respectively (HR 0.84; P= 0.366). The 1-year mortality was 2.1% in the tirofiban group and 2.9% in the abciximab group (HR 0.74; P= 0.436). CONCLUSIONS: Among diabetic patients undergoing PCI, tirofiban and abciximab were associated with comparable event rates, including similar rates of 6-month TVR and 1-year mortality. These findings suggest that the non-glycoprotein IIb/IIIa properties of abciximab do not translate into a discernible long-term clinical benefit among diabetic patients.

Implications of upstream glycoprotein IIb/IIIa inhibition and coronary artery stenting in the invasive management of unstable angina/non-ST-elevation myocardial infarction: a comparison of the Thrombolysis In Myocardial Infarction (TIMI) IIIB trial and the Treat angina with Aggrastat and determine Cost of Therapy with Invasive or Conservative Strategy (TACTICS)-TIMI 18 trial.

BACKGROUND: TIMI IIIB and TACTICS-TIMI 18 were 2 trials of an early invasive strategy in unstable angina (UA)/non-ST-elevation myocardial infarction (NSTEMI) that were conducted nearly a decade apart but with virtually identical enrollment criteria and designs, except that upstream glycoprotein IIb/IIIa inhibition was mandated and coronary artery stenting was routinely used in TACTICS-TIMI 18. We sought to examine the effect of these advances on clinical outcomes and the benefits of an early invasive strategy in UA/NSTEMI. METHODS AND RESULTS: Patients were stratified on the basis of their TIMI risk score into low-, intermediate-, and high-risk categories. Within each risk category, the rates of clinical outcomes and the benefit of an early invasive strategy were compared. Compared with patients in TIMI IIIB and adjusting for baseline risk, patients in TACTICS-TIMI 18 had lower rates of death, MI, or rehospitalization for acute coronary syndromes (OR, 0.62; P<0.0001). Across both trials, the benefit of an early invasive strategy was significantly greater with increasing baseline risk: OR, 1.39 in low-risk, 0.80 in intermediate-risk, and 0.57 in high-risk patients (P< or =0.004 for interactions). After adjustment for baseline risk, an early invasive strategy tended toward a more favorable result in TACTICS-TIMI 18 than in TIMI IIIB (OR, 0.79; 95% CI, 0.56 to 1.11). CONCLUSIONS: Advances in the care of patients with UA/NSTEMI, including glycoprotein IIb/IIIa inhibition and stenting, were associated with lower rates of death, MI, and rehospitalization for acute coronary syndromes and a trend toward a greater benefit of an early invasive strategy.

Elevations in troponin T and I are associated with abnormal tissue level perfusion: a TACTICS-TIMI 18 substudy. Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction.

BACKGROUND: Cardiac troponin T (cTnT) and I elevations are associated with a higher risk of adverse events, a higher incidence of multivessel disease, complex lesions, and visible thrombus in the setting of non-ST elevation (NSTE) acute coronary syndromes (ACS). Other pathophysiological mechanisms underlying troponin elevation remain unclear. METHODS AND RESULTS: We evaluated the relationship between troponin elevation and tissue level perfusion using the TIMI myocardial perfusion grade (TMPG) in 310 patients with NSTE-ACS in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction (TACTICS-TIMI) 18 trial. TMPG 0/1 ("closed" microvasculature) was observed more frequently in cTnT-positive patients both before (58.1% versus 42.1%; P=0.007) and after percutaneous coronary intervention (55.4% versus 35.6%; P=0.004). cTnT levels were higher among patients with TMPG 0/1 versus patients with TMPG 2/3 (0.50 versus 0.31 ng/mL; P=0.006). cTnT-positive patients were more likely to have thrombus (42.5% versus 29.3%), tighter stenoses (72.0% versus 64.8%), and higher rates of TIMI flow grade 0/1 (15.6% versus 7.0%; all P<0.05). TMPG 0/1 remained independently associated with cTnT elevation (odds ratio, 1.81; P=0.02), even after adjusting for epicardial TIMI flow grade, presence of thrombus, and prior myocardial infarction. TMPG 0/1 flow both before and after intervention was associated with increased risk of death or myocardial infarction at 6 months. CONCLUSIONS: Similar to what has been observed in the setting of ST-elevation myocardial infarction, abnormal tissue level perfusion is also associated with adverse outcomes in the NSTE-ACS setting. Independent of the presence of thrombus and abnormal flow in the epicardial artery, impaired tissue level perfusion is associated with a 1.8-fold increased risk of cTnT elevation.

Impact of clinical syndrome acuity on the differential response to 2 glycoprotein IIb/IIIa inhibitors in patients undergoing coronary stenting: the TARGET Trial.

BACKGROUND: Although glycoprotein IIb/IIIa inhibitors have been shown to reduce periprocedural and late ischemic events in patients undergoing stent implantation, the relative safety and efficacy of different agents in this class is less established. Also unknown is whether the acuity of the presenting clinical syndrome, which may affect the degree of platelet inhibition required or achieved, influences the response to different antiplatelet agents. METHODS AND RESULTS: A prospective, multicenter, double-blind, randomized trial was performed in which 4809 patients undergoing planned stenting were randomized to receive abciximab or tirofiban. In patients with acute coronary syndromes (ACS; n=3025), abciximab resulted in lower rates of myocardial infarction at 30 days (5.8% versus 8.5%; P=0.004) and 6 months (7.2% versus 9.8%; P=0.013), although 6-month mortality rates were identical (1.39% in both groups; P=0.99). Conversely, in patients without ACS (n=1784), myocardial infarction rates were not significantly lower with tirofiban, survival was similar, and target vessel revascularization was reduced, which translated into a trend toward enhanced 6-month event-free survival with tirofiban (89.7% versus 86.6%; P=0.056). CONCLUSIONS: In patients with ACS undergoing stent implantation, abciximab use compared with tirofiban results in greater suppression of periprocedural myonecrosis, although a survival benefit has not been demonstrated. Patients with stable coronary syndromes may have equivalent or better outcomes with tirofiban relative to abciximab, with fewer adverse hematologic and hemorrhagic events. These data raise important issues regarding the relative pharmacodynamic inhibition of platelet function required in varying clinical scenarios and have important implications for the cost-effective utilization of glycoprotein IIb/IIIa inhibitors.

Differential expression of cardiac biomarkers by gender in patients with unstable angina/non-ST-elevation myocardial infarction: a TACTICS-TIMI 18 (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18) substudy.

BACKGROUND: Diagnosis of coronary artery disease in women is more difficult because of lower specificity of symptoms and diagnostic accuracy of noninvasive testing. We sought to examine the relationship between gender and cardiac biomarkers in patients with unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI). METHODS AND RESULTS: In the TACTICS-TIMI 18, OPUS-TIMI 16, and TIMI 11 studies, baseline samples were analyzed in the Thrombolysis In Myocardial Infarction (TIMI) biomarker core laboratory. We examined the relationship between gender and elevated biomarkers. Of 1865 patients from TACTICS-TIMI 18, 34% were women. Fewer women had elevated creatine kinase-MB or troponins, whereas more had elevated high-sensitivity C-reactive protein or brain natriuretic peptide. Presence of ST-segment deviation and TIMI risk scores were not significantly different. This pattern was confirmed in TIMI 11 and OPUS-TIMI 16. The prognostic value of the markers in TACTICS-TIMI 18 was similar in women and men. When a multimarker approach was examined, a greater proportion of high-risk women were identified. Marker-positive patients of both genders had improved outcome with an invasive strategy; however, marker-negative women appeared to have improved outcomes with a conservative strategy. CONCLUSIONS: In patients with UA/NSTEMI, there was a different pattern of presenting biomarkers. Men were more likely to have elevated creatine kinase-MB and troponins, whereas women were more likely to have elevated C-reactive protein and brain natriuretic peptide. This suggests that a multimarker approach may aid the initial risk assessment of UA/NSTEMI, especially in women. Further research is necessary to elucidate whether gender-related pathophysiological differences exist in presentation with acute coronary syndromes.

Randomized COMparison of platelet inhibition with abciximab, tiRofiban and eptifibatide during percutaneous coronary intervention in acute coronary syndromes: the COMPARE trial. Comparison Of Measurements of Platelet aggregation with Aggrastat, Reopro, and Eptifibatide.

BACKGROUND: The relative anti-aggregatory effects of currently prescribed platelet glycoprotein IIb/IIIa receptor antagonists during and after percutaneous coronary intervention for acute coronary syndromes have not been established. METHODS AND RESULTS: We randomized 70 acute coronary syndrome patients undergoing percutaneous coronary intervention to receive abciximab, eptifibatide, or tirofiban at doses used in the Evaluation of Platelet IIb/IIIa Inhibitor for STENTing (EPISTENT), Platelet glycoprotein IIb/IIIa in Unstable angina Receptor Suppression Using Integrilin Therapy (PURSUIT), and Platelet Receptor Inhibition in ischemic Syndrome Management in Patients Limited by Unstable Signs and symptoms (PRISM-PLUS)/Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis (RESTORE) trials, respectively. Platelet aggregation (PA) in response to 20 micro mol/L of adenosine diphosphate was measured with turbidimetric aggregometry in both D-phenylalanyl-L-prolyl-L-arginine chloromethylketone and citrate-anticoagulated blood early (15 and 30 minutes) and late (4, 12, and 18 to 24 hours) after drug initiation. At 15 and 30 minutes, PA was significantly less inhibited by the tirofiban-RESTORE regimen compared with abciximab (P=0.028) and eptifibatide regimens (P=0.0001). The abciximab regimen, however, showed increasingly varied anti-aggregatory effects during continued infusion for > or =4 hours. Citrate exaggerated ex vivo platelet inhibition after eptifibatide and tirofiban, but had the opposite effect on abciximab. Of all regimens evaluated, the eptifibatide regimen inhibited PA most consistently throughout both the early and late periods. CONCLUSIONS: Currently recommended drug regimens to inhibit the platelet glycoprotein IIb/IIIa receptor have distinct pharmacodynamic profiles that might affect their relative efficacy in acute coronary syndromes and percutaneous coronary intervention.

A risk score to estimate the likelihood of coronary artery bypass surgery during the index hospitalization among patients with unstable angina and non-ST-segment elevation myocardial infarction.

OBJECTIVES: A simple risk score on admission to estimate the likelihood of in-hospital coronary artery bypass graft surgery (CABG) might be useful in selecting patients for early clopidogrel therapy. BACKGROUND: Routine early use of clopidogrel in patients with unstable angina (UA) and non-ST-segment elevation myocardial infarction (NSTEMI) is associated with increased risk of bleeding in patients who undergo early CABG. METHODS: The test cohort utilized to derive the score was the 2,220 patients with UA/NSTEMI enrolled in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction-18 (TACTICS-TIMI-18) trial. Patients who underwent CABG after randomization during index hospitalization were identified and were compared with patients who did not undergo in-hospital CABG. RESULTS: Overall, 362 patients (16.3%) underwent CABG during the index hospitalization. Patients with a history of prior CABG (n = 484) were significantly less likely to undergo in-hospital CABG (odds ratio [OR], 0.34). Five additional variables independently associated with CABG were identified: elevated troponin (OR, 3.9), prior stable angina (OR, 1.8), ST-segment deviation >or=0.5 mm (OR, 1.7), male gender (OR, 1.6), and history of peripheral arterial disease (OR, 1.6). A CABG risk score was generated by assigning numerical values to each of the variables based upon these odds ratios. Coronary artery bypass surgery rates increased significantly with increasing risk scores (6.2% for a risk score <3.0, 21.9% for 3 to 5, and 54.6% for >5.0). The association of the risk score with CABG was highly significant (p < 0.0001, c-statistic 0.72). The association remained significant in the validation cohorts from TIMI-11B trial and TIMI-III registry. CONCLUSIONS: Among patients with UA/NSTEMI, a novel risk score based on admission clinical variables can be used to estimate the likelihood of CABG. These data may assist in the identification of patients who might derive optimal benefit from early initiation of clopidogrel therapy.

Association of elevated B-type natriuretic peptide levels with angiographic findings among patients with unstable angina and non-ST-segment elevation myocardial infarction.

OBJECTIVES: We hypothesized that elevated B-type natriuretic peptide (BNP) levels would be associated with a greater severity of angiographic disease and a greater extent of myocardium at risk. BACKGROUND: Elevations of BNP have been associated with increased risk of adverse outcomes in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI). METHODS: Of the 2,220 patients with UA/NSTEMI enrolled in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction-18 (TACTICS-TIMI-18) trial, 276 randomized to the invasive arm had both baseline BNP levels and angiographic core laboratory data. Patients were categorized according to their baseline BNP levels as < or =80 or >80 pg/ml. RESULTS: A total of 233 patients (84%) had BNP levels >80 pg/ml, and 43 (16%) had admission BNP levels >80 pg/ml. Patients with BNP >80 pg/ml had tighter culprit vessel stenosis on quantitative coronary angiography (median stenosis 76% vs. 67%, p = 0.004) and a higher (slower) corrected TIMI frame count (median CTFC 43 vs. 30, p = 0.018) in the culprit vessel. The median BNP level was higher in patients with a left anterior descending coronary artery (LAD) versus non-LAD culprit lesion location (median BNP level 40 vs. 24 pg/ml, p = 0.005), and the culprit artery was more often the LAD in patients with BNP >80 pg/ml compared with < or =80 pg/ml (44% vs. 30%, p = 0.06). CONCLUSIONS: Among patients with UA/NSTEMI, elevated BNP levels are associated with tighter culprit stenosis, higher CTFC, and LAD involvement. These findings suggest that elevated BNP may be associated with a greater severity and extent of myocardial ischemic territory during the index event and may partly explain the association between elevated BNP and adverse outcomes.

Prospective analysis of creatine kinase muscle-brain fraction and comparison with troponin T to predict cardiac risk and benefit of an invasive strategy in patients with non-ST-elevation acute coronary syndromes.

OBJECTIVE: We sought to determine whether elevation of plasma creatine kinase muscle-brain fraction (CK-MB) would be useful to triage patients with acute coronary syndromes (ACS) to early angiography/revascularization. BACKGROUND: It is unknown whether the measurement of CK-MB is effective for triage to an aggressive management strategy. METHOD: Patients in the Treat Angina With Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy (TACTICS-TIMI) 18 study received aspirin, heparin, and tirofiban for treatment of ACS, were randomized to an invasive or a conservative strategy (angiography/revascularization between 4 and 48 h), and were followed up for a composite end point of death, myocardial infarction, or rehospitalization for ACS. Of 2,220 patients, CK-MB was elevated in 826 (37%). Of the patients with negative CK-MB, troponin T was elevated in 361 (31.2%). Event rates at 30 and 180 days were twice as high in patients with elevated CK-MB than in patients without elevated CK-MB. Both groups had similar benefit from an invasive strategy; there was no evidence of interaction between CK-MB elevation and strategy on the composite end point at 30 or 180 days. When patients were stratified according to both CK-MB and troponin status, there was evidence of a benefit in the invasive strategy among patients who were CK-negative but troponin-positive (odds ratios [95% confidence interval]: 0.13 [0.04 to 0.39] at 30 days and 0.29 [0.16 to 0.52] at 180 days). CONCLUSION: Patients with minimal amounts of recent onset myonecrosis but elevated risk as indicated by CK-MB and troponin, respectively, benefit most from invasive management. Determination of troponin levels yielded significant information regarding triage to an invasive strategy, particularly in CK-MB-negative patients.

Relationship between baseline white blood cell count and degree of coronary artery disease and mortality in patients with acute coronary syndromes: a TACTICS-TIMI 18 (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy- Thrombolysis in Myocardial Infarction 18 trial)substudy.

OBJECTIVES: This study was designed to determine the relationship between baseline white blood cell (WBC) count and angiographic and clinical outcomes in patients with unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI) and to see if WBC count was a significant predictor of outcomes independent of other biomarkers. BACKGROUND: Inflammation has been shown to play a role in atherosclerosis and acute coronary syndromes. METHODS: We evaluated the relationship between baseline WBC count, other baseline variables and biomarkers, angiographic findings, and clinical outcomes in 2,208 patients in the Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18 (TACTICS-TIMI 18) trial. RESULTS: Higher baseline WBC counts were associated with lower Thrombolysis In Myocardial Infarction (TIMI) flow grades (p = 0.0045) and TIMI myocardial perfusion grades (p = 0.03) as well as a greater extent of coronary artery disease (CAD) (p < 0.0001). A higher baseline WBC count was predictive of higher six-month mortality, ranging from 1.5% to 3.6% to 5.1% for patients with low, intermediate, and high WBC counts, respectively (p = 0.0017). In a multivariable proportional hazards model, patients with a low C-reactive protein (CRP) but an elevated WBC remained at significantly higher risk of death at six months (hazard ratio [HR] 4.3, p = 0.049), and patients with a high CRP were at even higher risk (HR 8.6, p = 0.004). conclusions: In patients with UA/NSTEMI, elevations in a simple, widely available blood test, the WBC count, were associated with impaired epicardial and myocardial perfusion, more extensive CAD, and higher six-month mortality. After adjustment for traditional risk factors and other biomarkers, assessment of two inflammatory markers, WBC count and CRP, can be used to stratify patients across an eightfold gradation of six-month mortality risk.

Evaluation of B-type natriuretic peptide for risk assessment in unstable angina/non-ST-elevation myocardial infarction: B-type natriuretic peptide and prognosis in TACTICS-TIMI 18.

OBJECTIVES: This study was designed to evaluate B-type natriuretic peptide (BNP) for risk assessment and clinical decision making over a range of cut points, alone and with cardiac troponin I (cTnI), in patients with non-ST-elevation acute coronary syndromes (ACS). BACKGROUND: B-type natriuretic peptide holds promise for risk stratification. Additional evidence regarding optimal decision limits, use in combination with troponin, and use in targeting therapy is needed before acceptance into clinical use for ACS. METHODS: We evaluated BNP at baseline in 1,676 patients with non-ST-elevation ACS randomized to early invasive versus conservative management. RESULTS: Patients with elevated BNP (>80 pg/ml; n = 320) were at higher risk of death at seven days (2.5% vs. 0.7%, p = 0.006) and six months (8.4% vs. 1.8%, p < 0.0001). The association between BNP and mortality at six months (adjusted odds ratio [OR] 3.3; 95% confidence interval [CI] 1.7 to 6.3) was independent of important clinical predictors, including cTnI and congestive heart failure (CHF). Patients with elevated BNP had a fivefold higher risk of developing new CHF by 30 days (5.9% vs. 1.0%, p < 0.0001). B-type natriuretic peptide added prognostic information to cTnI, discriminating patients at higher mortality risk among those with negative (OR 6.9; 95% CI 1.9 to 25.8) and positive (OR 4.1; 95% CI 1.9 to 9.0) baseline cTnI results. No difference was observed in the effect of invasive versus conservative management when stratified by baseline levels of BNP (p(interaction) > or = 0.6). CONCLUSIONS: Elevated BNP (>80 pg/ml) at presentation identifies patients with non-ST-elevation ACS who are at higher risk of death and CHF and adds incremental information to cTnI. Additional work is needed to identify therapies that may reduce the risk associated with increased BNP.