Clinical pharmacology of higher dose eptifibatide in percutaneous coronary intervention (the PRIDE study).

This study describes the dose-exploration phase of the PRIDE trial, an investigation of the clinical pharmacology of higher dose eptifibatide in patients who underwent elective percutaneous coronary intervention (PCI). Outcomes of treatment with the platelet glycoprotein IIb/IIIa inhibitors were dependent upon proper dosing selection. In this multicenter, placebo-controlled clinical study, 127 patients were randomized 1:1:2:2 into 1 of the following treatment groups: placebo; eptifibatide as a 135 microg/kg bolus followed by a 0.75 microg/kg/min infusion; eptifibatide as a 180 microg/kg bolus with a 2.0 microg/kg/min infusion; or eptifibatide as a 250 microg/kg bolus with a 3.0 microg/kg/min infusion. Light transmission aggregometry was used to determine platelet aggregation in response to 20 microM adenosine diphosphate, and platelet receptor occupancy was also determined. Eptifibatide exhibited linear pharmacokinetics over the dose range studied. Inhibition of platelet aggregation was greater in samples collected in sodium citrate compared with those collected in D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone. The 180/2.0 dosing regimen achieved 90% inhibition of platelet aggregation immediately (5 minutes) and at steady state (8 to 24 hours). At 1 hour, mean inhibition of platelet aggregation was 80%. Eptifibatide exhibited dose-dependent pharmacodynamics that were dependent upon choice of anticoagulant. A 180 microg/kg bolus followed by a 2.0 microg/kg/min infusion at steady state achieved >80% inhibition of platelet aggregation. With the single-bolus regimen, however, there was an early loss of the inhibition of platelet aggregation before steady state was reached. Additional dose-exploration studies may further optimize eptifibatide dosing.

Impact of the Duett sealing device on quality of life and hospitalization costs for coronary diagnostic and interventional procedures: Results from the Study of Economic and Quality of Life substudy of the SEAL trial.

BACKGROUND: The Simple and Effective Arterial Closure (SEAL) trial examined the safety and effectiveness of the Duett vascular sealing device (Vascular Solutions, Minneapolis, Minn) versus manual compression after diagnostic and interventional coronary procedures. We compared quality of life and initial hospitalization costs among patients treated with the Duett device versus manual compression. METHODS: Functional status was assessed with the Duke Activity Status Index (DASI) at 7 and 30 days after intervention. General health status was assessed with the Short Form (SF-36) at 30 days after intervention. Hospitalization costs were derived from the UB92 formulation of the hospital bill. RESULTS: There was a strong trend toward higher functional status in patients receiving treatment with the Duett device at 7 days both before (P =.04) and after (P =.08) adjustment for significant covariates. This difference was significant in the diagnostic group but not in the interventional group. No significant differences in quality of life between the Duett device and manual compression at 30 days were found. There was no significant difference in total hospitalization costs between treatment arms (P =.91). For interventional patients, mean total in-hospital costs were $10,167 in the Duett group and $10,225 in the manual compression group (P =.82). For diagnostic patients, mean hospitalization costs were $7784 and $7996 for the Duett device and manual compression groups, respectively (P =.72). Trends toward reduced recovery/observation room costs with the Duett device (P =.06) were found; this difference was significant in the diagnostic group ($198 vs $279, P =.02). CONCLUSIONS: The Duett sealing device was associated with significantly higher functional status at 7 days after the procedure in addition to shortened time to hemostasis and ambulation, with no associated increase in cost.

Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: results of the GOLD (AU-Assessing Ultegra) multicenter study.

BACKGROUND: The optimal level of platelet inhibition with a glycoprotein (GP) IIb/IIIa antagonist necessary to minimize thrombotic complications in patients undergoing a percutaneous coronary intervention (PCI) is currently unknown. METHODS AND RESULTS: Five hundred patients undergoing a PCI with the planned use of a GP IIb/IIIa inhibitor had platelet inhibition measured at 10 minutes, 1 hour, 8 hours, and 24 hours after the initiation of therapy with the Ultegra Rapid Platelet Function Assay (Accumetrics). Major adverse cardiac events (MACES: composite of death, myocardial infarction, and urgent target vessel revascularization) were prospectively monitored, and the incidence correlated with the measured level of platelet function inhibition at all time points. One quarter of all patients did not achieve >/=95% inhibition 10 minutes after the bolus and experienced a significantly higher incidence of MACEs (14.4% versus 6.4%, P=0.006). Patients whose platelet function was <70% inhibited at 8 hours after the start of therapy had a MACE rate of 25% versus 8.1% for those >/=70% inhibited (P=0.009). By multivariate analysis, platelet function inhibition >/=95% at 10 minutes after the start of therapy was associated with a significant decrease in the incidence of a MACE (odds ratio 0.46, 95% CI 0.22 to 0.96, P=0.04). CONCLUSIONS: Substantial variability in the level of platelet function inhibition is achieved with GP IIb/IIIa antagonist therapy among patients undergoing PCI. The level of platelet function inhibition as measured by a point-of-care assay is an independent predictor for the risk of MACEs after PCI.

Percutaneous coronary intervention for cardiogenic shock in the SHOCK Trial Registry.

BACKGROUND: The SHOCK Registry prospectively enrolled patients with cardiogenic shock complicating acute myocardial infarction in 36 multinational centers. METHODS: Cardiogenic shock was predominantly attributable to left ventricular pump failure in 884 patients. Of these, 276 underwent percutaneous coronary intervention (PCI) after shock onset and are the subject of this report. RESULTS: The majority (78%) of patients undergoing angiography had multivessel disease. As the number of diseased arteries rose from 1 to 3, mortality rates rose from 34.2% to 51.2%. Patients who underwent PCI had lower in-hospital mortality rates than did patients treated medically (46.4% vs 78.0%, P < .001), even after adjustment for patient differences and survival bias (P = .037). Before PCI, the culprit artery was occluded (Thrombolysis In Myocardial Infarction grade 0 or 1 flow) in 76.3%. After PCI, the in-hospital mortality rate was 33.3% if reperfusion was complete (grade 3 flow), 50.0% with incomplete reperfusion (grade 2 flow), and 85.7% with absent reperfusion (grade 0 or 1 flow) (P < .001). CONCLUSIONS: This prospective, multicenter registry of patients with acute myocardial infarction complicated by cardiogenic shock is consistent with a reduction in mortality rates as the result of percutaneous coronary revascularization. Coronary artery patency was an important predictor of outcome. Measures to promote early and rapid reperfusion appear critically important in improving the otherwise poor outcome associated with cardiogenic shock.

Clinical trials of glycoprotein IIb/IIIa inhibitors.

Glycoprotein (GP) IIb/IIIa inhibitors were developed to block platelet aggregation and potentially to abolish thrombus formation. Clinical trials have demonstrated that GP IIb/IIIa inhibitors are more potent antithrombotic agents than aspirin and heparin alone. GP IIb/IIIa inhibitors reduce short- and long-term complications of percutaneous revascularization. These agents also are effective as adjuncts to various treatment strategies for the management of patients with unstable angina (UA) or non-Q-wave myocardial infarction (NQMI). Furthermore, recent clinical trials with a small number of patients suggest that GP IIb/IIIa inhibitors in combination with low-dose fibrinolytics are safe and effective for the treatment of ST segment elevation myocardial infarction. The clinical trials of GP IIb/IIIa inhibitors summarized here examined different patient populations managed under different strategies. Moreover, these agents have different indications for clinical use and varying safety profiles.

Outcome and profile of ventricular septal rupture with cardiogenic shock after myocardial infarction: a report from the SHOCK Trial Registry. SHould we emergently revascularize Occluded Coronaries in cardiogenic shocK?

OBJECTIVES: We wished to assess the profile and outcomes of patients with ventricular septal rupture (VSR) in the setting of cardiogenic shock (CS) complicating acute myocardial infarction (MI). BACKGROUND: Cardiogenic shock is often seen with VSR complicating acute MI. Despite surgical therapy, mortality in such patients is high. METHODS: We analyzed 939 patients enrolled in the SHOCK Trial Registry of CS in acute infarction, comparing 55 patients whose shock was associated with VSR with 884 patients who had predominant left ventricular failure. RESULTS: Rupture occurred a median 16 h after infarction. Patients with VSR tended to be older (p = 0.053), were more often female (p = 0.002) and less often had previous infarction (p < 0.001), diabetes mellitus (p = 0.015) or smoking history (p = 0.033). They also underwent right-heart catheterization, intra-aortic balloon pumping and bypass surgery significantly more often. Although patients with rupture had less severe coronary disease, their in-hospital mortality was higher (87% vs. 61%, p < 0.001). Surgical repair was performed in 31 patients with rupture (21 had concomitant bypass surgery); 6 (19%) survived. Of the 24 patients managed medically, only 1 survived. CONCLUSIONS: There is a high in-hospital mortality rate when CS develops as a result of VSR. Ventricular septal rupture may occur early after infarction, and women and the elderly may be more susceptible. Although the prognosis is poor, surgery remains the best therapeutic option in this setting.

Relation of coronary artery size to one-year clinical events after new device angioplasty of native coronary arteries (a New Approach to Coronary Intervention [NACI] Registry Report).

The influence of vessel size on clinical and angiographic outcomes after new device angioplasty has not been well documented. We reviewed clinical and angiographic outcomes of 2,044 patients undergoing new device angioplasty of native vessels enrolled in the New Approaches to Coronary Interventions (NACI) Registry. Quantitative angiography was performed using standard methods. Patients were divided into 3 groups according to reference vessel diameter (RVD) (<2.75, 2.75 to 3.25, and >3.25 mm). Patients with the smallest vessels had a higher incidence of diabetes (26% vs. 16%, p<0.01), multivessel disease (50% vs. 45%, p<0.01), left anterior descending coronary artery disease (61% vs. 39% p<0.01), and in general, more severe baseline lesion characteristics than patients with larger (>3.25 mm) vessels. Absolute baseline and final minimal lumen diameter (MLD) was also smaller in patients with RVD <2.75 mm despite similar final percent diameter stenosis. Although in-hospital events were similar, patients who underwent interventions in vessels <2.75 mm had an increased incidence of death (p<0.01), surgical revascularization (p<0.05), and target lesion revascularization (TLR) (p<0.01) at 1 year. Multivariate analysis by vessel size showed a stepwise increase in the risk of TLR by 1 year in patients with the smaller RVD (p = 0.0001) and the combined end point of 1 year death/Q wave-myocardial infarction/TLR (p = 0.02). Thus, despite similar early clinical events among patients undergoing new device angioplasty, patients who underwent treatment of smaller vessels had a significantly increased risk of major adverse clinical events and particularly TLR by 1 year after new device angioplasty of native coronary arteries.

Review of immediate angioplasty after fibrinolytic therapy for acute myocardial infarction: insights from the RESCUE I, RESCUE II, and other contemporary clinical experiences.

BACKGROUND: Prompt restoration of Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow improves survival in patients with acute ST-segment elevation myocardial infarction (MI). Fibrinolytic therapy fails to restore TIMI 3 flow within 90 minutes in 40% to 50% of patients. Because the results of percutaneous coronary intervention (PCI) for MI seem to be improving, a reevaluation of the role of PCI after fibrinolytic therapy for MI appears to be warranted. METHODS AND RESULTS: Data from all 9 randomized controlled trials (including new data from 4 trials) of rescue percutaneous transluminal coronary angioplasty (PTCA) versus conservative therapy after fibrinolytic therapy (1456 patients), 4 contemporary registries of PCI in this setting (977 patients), and other germane studies are reviewed. PTCA after failed fibrinolysis (TIMI 0 to 1 flow) appears to reduce early severe heart failure (3. 8% vs 11.7%, P =.04) and improve survival over 1 year in patients with moderate to large MI (92% vs 87%, P =.001) and possibly reduces early repeat MI (4.3% vs 11.3%, P =.08). Assessment of the possible benefit of PTCA for TIMI 2 flow is hampered by the small number of patients randomly assigned. Repeat MI may be decreased and left ventricular functional recovery enhanced. PTCA early after successful fibrinolysis is nearly always technically successful and may reduce repeat MI and hospital length of stay. However, it must be recalled that randomized trials from the 1980s suggested increased mortality rates with PTCA after restoration of TIMI 2 to 3 flow with fibrinolysis. Data from contemporary randomized studies of stents and glycoprotein IIb/IIIa inhibitors suggest that PCI as performed today may yield better results than those reviewed. CONCLUSIONS: These data suggest a probable benefit of rescue PTCA in several distinct scenarios and that the pivotal mid-1980s studies suggesting no benefit or harm for PTCA after fibrinolytic therapy may no longer be relevant. The role of mechanical intervention in the treatment of patients treated in these settings should be reassessed.

High-output cardiac failure related to hemodialysis arteriovenous fistula.

Among the multiple etiologies for congestive heart failure in patients with end-stage renal disease, the contribution of hemodialysis fistulas to the myocardial work load is often overlooked. We recently cared for a patient with high-output cardiac failure from an arteriovenous fistula and review the features and pathophysiology of this condition.

Inhibition of platelet aggregation with a glycoprotein IIb-IIIa antagonist does not prevent thrombin generation in patients undergoing thrombolysis for acute myocardial infarction.

Thrombin activity has been implicated as a mechanism for failed reperfusion and reocclusion following thrombolysis. Aggregating platelets provide a phospholipid surface on which prothrombin is cleaved to form thrombin. We examined markers of thrombin generation and activity in patients enrolled in a randomized, placebo-controlled, dose escalating trial of the platelet glycoprotein IIb-IIIa inhibitor eptifibatide (Integrilintrade mark) administered concomitantly with tissue plasminogen activator for the treatment of myocardial infarction. Measurements were obtained at baseline, at 90 minutes, and at 6, 12, and 24 hours after starting therapy. Eptifibatide inhibited platelet aggregation in response to 20 microM ADP. Levels of fibrinopeptide A (FPA), thrombin-antithrombin complexes (TAT), and prothrombin fragment 1.2 (F1.2) were not lower in patients treated with eptifibatide than in the control group. In the course of dose escalation, two groups of patients received the same 135 microg/kg bolus of eptifibatide, one with and one without a heparin bolus. FPA levels were dramatically lower in the heparin-treated patients. Levels of FPA, TAT, and F1.2 were not higher in patients with than in those without recurrent ischemia, or in patients without than in those with Thrombolysis in Myocardial Infarction (TIMI) grade 3 angiographic flow at 90 minutes. These data suggest that thrombin generation and activity persist following thrombolysis, despite inhibition of platelet aggregation, and that treatment with inhibitors of thrombin activity may be required even when glycoprotein IIb-IIIa inhibitors are used.

Serial troponin I measurements detect recurrent myocardial infarction after initial acute myocardial infarction.

UNLABELLED: Serial serum troponin I and CK-MB measurements were obtained for 36 patients presenting to the emergency department with a confirmed diagnosis of acute myocardial infarction (AMI). For each patient, the normalized percentage of maximum troponin I concentration (%max TropI) was plotted vs. the time from the maximum value to obtain a kinetic decay plot. The linear correlation plots of the--Log (%max TropI) vs. time were compared. Patients with uncomplicated AMI (n = 31) showed linear correlation coefficients (CC) above 0.97 (mean CC = 0.991). Patients with AMI complicated by recurrent myocardial infarction (n = 5) documented by corroborate clinical findings, electrocardiographic abnormalities and/or abnormal CK-MB results showed linear correlation coefficients (CC) less than 0.97 (mean CC = 0.763). Using a cutoff value of CC = 0.97, both patient groups were completely separated and re-infarction or extension of infarction was predicted with 100% accuracy, sensitivity and specificity. CONCLUSION: Kinetic modeling of troponin I decay in patients with AMI correctly differentiates patients with complicated vs. non-complicated courses.

A multicenter, randomized trial of percutaneous coronary intervention versus bypass surgery in high-risk unstable angina patients. The AWESOME (Veterans Affairs Cooperative Study #385, angina with extremely serious operative mortality evaluation) investigators from the Cooperative Studies Program of the Department of Veterans Affairs.

This multicenter, prospective randomized trial was designed to test the hypotheses that percutaneous coronary intervention (PCI) is a safe and effective alternative to coronary artery bypass grafting (CABG) for patients with refractory ischemia and high risk of adverse outcomes. As a comparison of revascularization strategies, the trial specifically allows surgeons and interventionists to use new techniques as they become clinically available. After 42 months of this 72-month trial, 17,624 patients have been screened and 2022 met eligibility requirements: 341 have been randomized to either CABG or PCI, and the remaining 1681 are being prospectively followed in a registry. The 3-year overall survival of patients in the registry and randomized trial is comparable. To enhance accrual into the randomized trial, site visits were conducted, a few low-accruing hospitals were put on probation and/or replaced, eligibility criteria were reviewed at annual meetings of investigators, and the accrual period was extended by 1 year. These data demonstrate that a prospective randomized trial and registry of coronary revascularization for medically refractory high-risk patients is feasible.