Impact of preprocedural white blood cell count on long term mortality after percutaneous coronary intervention: insights from the EPIC, EPILOG, and EPISTENT trials.

BACKGROUND: Raised inflammatory markers are associated with worse outcome after percutaneous coronary interventions (PCI). An increase in the white blood cell (WBC) count is a non-specific response to inflammation. We hypothesised that a raised baseline WBC count would be a predictor of mortality in patients undergoing PCI. METHODS: The association between preprocedural WBC count and long term mortality was studied in 7179 patients enrolled in the EPIC, EPILOG, and EPISTENT trials. The end points were the incidence of myocardial infarction at one year, and one and three year mortality. RESULTS: There were 188 deaths and 582 myocardial infarctions at one year. While WBC count was a strong predictor of death at one year, with every increase of 1 k/micro l (1x10(6)/l) being associated with a hazard ratio (HR) of 1.109 (95% confidence interval (CI) 1.072 to 1.147, p < 0.001), there was no association with myocardial infarction at one year (HR 1.020, 95% CI 0.990 to 1.052, p = 0.195). There were a total of 406 deaths at three years with a strong association between WBC count and three year mortality (HR for every 1 k/microl increase 1.089, 95% CI 1.058 to 1.121, p < 0.001). WBC count remained a significant predictor of mortality after multivariable adjustment (HR for every 1 k/micro l increase 1.100, 95% CI 1.069 to 1.131, p < 0.001). The association was significant across multiple subgroups, including diabetes, female sex, clinical presentation, and cigarette smoking. CONCLUSION: A raised pre-procedural WBC count in patients undergoing PCI is associated with an increased risk of long term death. These results suggest a key role for inflammation in coronary artery disease.

Differential effects of citrate versus PPACK anticoagulation on measured platelet inhibition by abciximab, eptifibatide and tirofiban.

BACKGROUND: High levels of glycoprotein (GP) IIb/IIIa receptor inhibition are required to prevent arterial thrombosis following percutaneous coronary intervention. Ex-vivo turbidometric platelet aggregation in citrate anticoagulated blood samples has been the primary method previously utilized to derive dose regimens for administering platelet GP IIb/IIIa inhibitors. Enhanced GP IIb/IIIa binding and inhibition of platelet aggregation for eptifibatide secondary to citrate induced reduction of ionized plasma calcium concentrations has been reported. METHODS/RESULTS: We evaluated the differential effects of citrate versus PPACK anticoagulation on turbidometric platelet inhibition in normal volunteers by eptifibatide, tirofiban or abciximab. The decrease in ionized calcium afforded by citrate was associated with enhanced in vitro platelet inhibition for all three GP IIb/IIIa inhibitors, including abciximab. The magnitude of citrate effect was greatest for eptifibatide. Both tirofiban and abciximab have similar citrate calcium chelation associated enhancement of measured platelet inhibition. CONCLUSION: Accurate assessment and comparison of platelet inhibition by GP IIb/IIIa inhibitors may require avoidance of calcium chelating anticoagulants.

The platelet function dose-response to abciximab during percutaneous coronary revascularization is variable.

The platelet function dose-response to incremental abciximab (Reopro, Eli Lilly/Centocor, Indianapolis, IN) bolus dosing during percutaneous coronary intervention (PCI) was evaluated in 85 patients using a point-of-service platelet function assay. Patients received incremental bolus doses of abciximab at 10- to 20-min intervals; platelet function was measured at 10-min intervals during dosing. The percentage of patients achieving > or = 80% inhibition of platelet function after 50%, 75%, and 100% of a standard abciximab bolus was 40%, 87%, and 95%, respectively. There were no significant associations between the platelet function dose-response to abciximab and age, weight, platelet count, hematocrit, heparin dose, peak activated clotting time, thienopyridine use prior to PCI, gender, cigarette smoking, diabetes mellitus, or clinical syndrome. This study demonstrated significant interpatient variability in platelet function dose-response to abciximab with a substantial proportion (87%) of patients achieving high-level platelet function inhibition with less than the standard abciximab bolus dose.

Leukocyte-platelet aggregation, platelet surface P-selectin, and platelet surface glycoprotein IIIa after percutaneous coronary intervention: Effects of dalteparin or unfractionated heparin in combination with abciximab.

BACKGROUND: Plaque disruption with resultant platelet activation and leukocyte-platelet aggregation is a pathophysiologic process common to both acute coronary syndromes and percutaneous coronary interventions. Unfractionated heparin is a standard antithrombotic therapy in patients with both acute coronary syndromes and in those undergoing percutaneous coronary interventions. Low-molecular-weight heparins have been reported to cause less platelet activation than unfractionated heparin. METHODS: Monocyte-platelet aggregates, neutrophil-platelet aggregates, platelet surface P-selectin, and platelet surface glycoprotein (GP) IIIa were measured serially by whole blood flow cytometry in 40 patients with unstable angina (randomly assigned to either unfractionated heparin 70 U/kg or the low-molecular-weight heparin dalteparin 60 IU/kg) undergoing coronary intervention with planned abciximab administration (in 2, one-half-dose boluses). Assays were performed at baseline, 5 minutes after administration of either type of heparin, 10 minutes after the first bolus of abciximab, 10 minutes after second bolus of abciximab, and 8 to 10 and 16 to 24 hours after administration of either heparin. RESULTS: No significant differences in clinical outcomes were observed between patients receiving either unfractionated heparin or dalteparin. The number of circulating P-selectin-positive platelets was increased by unfractionated heparin but not dalteparin, and abciximab reversed this increase. The number of circulating P-selectin-positive platelets was reduced below baseline levels in both treatment groups 8 to 10 and 16 to 24 hours after study drug administration. At 8 to 10 and 16 to 24 hours after administration of study drug, platelet degranulation in response to iso-thrombin receptor agonist peptide 1.5 mmol/L was significantly reduced by almost 50% (compared with immediately after study drug administration). Both unfractionated heparin and dalteparin significantly increased the numbers of circulating monocyte-platelet and neutrophil-platelet aggregates, which were subsequently reduced to baseline levels after administration of the second abciximab bolus and to below baseline at both 8 to 10 and 16 to 24 hours in all patients. After both unfractionated heparin and dalteparin administration, platelet surface GP IIIa expression was significantly increased compared with baseline at both 8 to 10 and 16 to 24 hours. CONCLUSIONS: Dalteparin in combination with abciximab in patients with unstable angina undergoing coronary intervention appears to be safe. Unfractionated heparin, but not dalteparin, degranulates platelets in patients with unstable angina. Both heparins increase the number of circulating monocyte-platelet and neutrophil-platelet aggregates. Abciximab therapy during coronary interventions rapidly reduces the number of degranulated platelets and leukocyte-platelet aggregates.

Intracoronary administration of recombinant human vascular endothelial growth factor to patients with coronary artery disease.

BACKGROUND: Patients with severe myocardial ischemia who are not candidates for percutaneous or surgical revascularization have few therapeutic options. Therapeutic angiogenesis in animal models with use of recombinant human vascular endothelial growth factor (rhVEGF) has resulted in successful revascularization of ischemic myocardium. This was a dose escalation trial designed to determine the safety and tolerability of intracoronary rhVEGF infusions. METHODS AND RESULTS: Patients were eligible if they had stable exertional angina, a significant reversible perfusion defect by stress myocardial perfusion study, and coronary anatomy that was suboptimal for percutaneous coronary intervention or coronary artery bypass grafting. rhVEGF was administered to a total of 15 patients by 2 sequential (eg, right and left) intracoronary infusions, each for 10 minutes, at rates of 0.005 (n = 4), 0.017 (n = 4), 0.050 (n = 4), and 0.167 mg/kg/min (n = 3). Pharmacokinetic sampling and hemodynamic monitoring were performed for 24 hours. Radionuclide myocardial perfusion imaging was performed before treatment and at 30 and 60 days after treatment. Follow-up angiograms were performed on selected patients at 60 days. The maximally tolerated intracardiac dose of rhVEGF was 0.050 mg/kg/min. Minimal hemodynamic changes were seen at 0.0050 mg/kg/min (2% +/- 7% [SD] mean decrease in systolic blood pressure from baseline to nadir systolic blood pressure), whereas at 0.167 mg/kg/min there was a 28% +/- 7% mean decrease from baseline to nadir (136 to 95 mm Hg systolic). Myocardial perfusion imaging was improved in 7 of 14 patients at 60 days. All 7 patients with follow-up angiograms had improvements in the collateral density score. CONCLUSION: rhVEGF appears well tolerated by coronary infusion at rates up to 0.050 mg/kg/min. This study provides the basis for future clinical trials to assess the clinical benefit of therapeutic angiogenesis with rhVEGF.

Low molecular weight heparin therapy for percutaneous coronary intervention: a practice in evolution.

Unfractionated heparin (UFH) remains the principal antithrombotic agent during percutaneous coronary intervention (PCI) but is associated with significant limitations including an unpredictable anticoagulation dose response, the requirement for frequent monitoring, and transient rebound hypercoagulability. Low molecular weight heparin (LMWH) represents an attractive alternative due to its predictable dose response relationship, superior antithrombotic efficacy and potential for improved clinical safety, and has been used increasingly in patients with acute coronary syndromes prior to coronary angiography. The rationale and existing data regarding the use of LMWH in PCI is summarized and reviewed. Preliminary clinical guidelines for the use of LMWH in the transition from medical stabilization of patients with acute coronary syndromes to invasive management in the catheterization laboratory are presented.

Abciximab readministration: results of the ReoPro Readministration Registry.

BACKGROUND: Platelet glycoprotein IIb/IIIa blockade with abciximab (ReoPro) improves the clinical outcomes of percutaneous coronary intervention. This registry was conducted to characterize the effects of repeated administration of abciximab during intervention. METHODS AND RESULTS: We recruited 500 consecutive patients at 22 centers in the United States who were receiving abciximab for at least a second time during percutaneous coronary intervention. Safety was measured as the incidence of hypersensitivity reactions, major bleeding, and thrombocytopenia. Efficacy was assessed as event-free clinical success. Human antichimeric antibody (HACA) responses were also characterized. There were no cases of hypersensitivity (95% upper confidence bound, 0.3%), major bleeding, or death. Clinical success was 94.4%. Thrombocytopenia occurred in 23 patients (4.6%; 95% CI, 2.8% to 6.4%), including 12 (2.4%; 95% CI, 1.1% to 3.7%) who developed profound thrombocytopenia (<20x10(9) cells/L). In 2 patients (0.4%), profound thrombocytopenia did not develop until after hospital discharge; in 4 (0.8%), profound thrombocytopenia recurred despite platelet transfusion. Before a first readministration, a positive HACA titer was present in 22 of 454 patients (4.8%); after a first readministration, an additional 82 of 432 (19.0%) became HACA-positive. HACA did not neutralize the in vitro inhibition of platelet aggregation by abciximab or correlate with clinical events. CONCLUSIONS: The results, including overall rates of thrombocytopenia, were consistent with randomized clinical trials of first abciximab treatment. However, there was a shift from mild to profound thrombocytopenia, and cases of delayed presentation and of recurrent thrombocytopenia were seen. These findings suggest that indications and guidelines for first-time use apply to retreatment, particularly the systematic monitoring for thrombocytopenia.

Initial experience with multivessel percutaneous coronary intervention during mechanical reperfusion for acute myocardial infarction.

The feasibility and safety of simultaneous multivessel percutaneous coronary intervention during mechanical reperfusion for acute myocardial infarction was analyzed in a retrospective, case-controlled study. Patients who underwent multivessel coronary intervention had a higher risk of adverse clinical outcomes through 6 months compared with matched controls in whom coronary intervention was limited to the infarct-related artery.

Abciximab suppresses the rise in levels of circulating inflammatory markers after percutaneous coronary revascularization.

BACKGROUND: Previous investigators have shown that systemic markers of inflammation may be increased in patients with acute ischemic syndromes or after percutaneous coronary revascularization and that persistent elevation in these markers is predictive of excess risk of subsequent adverse cardiac events. By virtue of its cross-reactivity with the glycoprotein IIb/IIIa, avbeta3, and alphaMbeta2 receptors, abciximab may reduce inflammatory processes. Methods and Results-- Assays for the inflammatory markers C-reactive protein, interleukin-6, and tumor necrosis factor-alpha were performed on serum samples obtained from 160 patients in a placebo-controlled, randomized trial of abciximab during angioplasty. Eighty patients each had received a placebo or abciximab bolus plus a 12-hour infusion. Serum samples were drawn at baseline (before revascularization), 24 to 48 hours after study drug administration, and 4 weeks after study drug administration. Between baseline and 24 to 48 hours, the increase in C-reactive protein was 32% less in patients receiving abciximab than placebo (P=0.025); the rise in interleukin-6 levels was 76% less in the abciximab group (P<0.001); and the rise in tumor necrosis factor-alpha levels was 100% less with abciximab therapy (P=0.112). By 4 weeks, most marker levels had returned to baseline, with no significant differences between placebo and abciximab groups. CONCLUSIONS: Systemic markers of inflammation increase in the first 24 to 48 hours after angioplasty, but the magnitude of that rise is diminished by periprocedural abciximab. Some of the long-term clinical benefit derived from this agent may be related to an anti-inflammatory effect.

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.

Enoxaparin and abciximab adjunctive pharmacotherapy during percutaneous coronary intervention.

Randomized controlled trials of patients with non-ST segment elevation acute coronary syndromes have established the superiority of enoxaparin (versus unfractionated heparin) for reducing adverse ischemic outcomes. Furthermore, adjunctive abciximab therapy during percutaneous coronary intervention (PCI) is associated with improved clinical outcomes. Since algorithms for integrating these pharmacotherapies have not been determined, patients undergoing elective PCI were enrolled into 2 distinct and separate studies conducted by the National Investigators Collaborating on Enoxaparin (NICE) study groups (NICE 1 and NICE 4 studies). Patients in NICE 1 were administered enoxaparin 1.0 mg/kg intravenously (without abciximab) and those enrolled in NICE 4 were administered a reduced dose (0.75 mg/kg) of enoxaparin in combination with standard-dose abciximab intravenously during PCI. Bleeding events and ischemic outcomes assessed in-hospital and at 30-days post-PCI were infrequent with either pharmacologic regimen. In the dose regimens studied, enoxaparin with or without abciximab appears to provide safe and effective anticoagulation during PCI. The combination of reduced-dose enoxaparin and abciximab was associated with a low incidence of adverse outcomes (bleeding or ischemic events). Additional studies may be required to establish the relative safety and efficacy of this new adjunctive pharmacologic strategy when compared with the combination of low-dose, weight-adjusted unfractionated heparin and abciximab.

Severe delayed thrombocytopenia associated with abciximab (ReoPro) therapy.

Acute thrombocytopenia associated with abciximab therapy has been well described, although the exact mechanism remains obscure. We report a case of delayed severe thrombocytopenia associated with abciximab therapy for percutaneous coronary intervention that occurred following hospital discharge. The detection of this phenomenon is important as it may portend heightened risk for severe or profound thrombocytopenia on subsequent reexposure to abciximab therapy.

Dalteparin in combination with abciximab during percutaneous coronary intervention.

BACKGROUND: Despite proved efficacy for either dalteparin or platelet glycoprotein IIb/IIIa blockade in improving clinical outcomes of patients with non-ST-segment elevation acute coronary syndromes, algorithms guiding concomitant therapy with these agents have not been devised. The purpose of this study was to assess anticoagulant effect and clinical safety for several dose regimens of dalteparin administered in combination with abciximab during percutaneous coronary intervention (PCI). METHODS AND RESULTS: Patients undergoing PCI with standard dose abciximab received dalteparin as follows: 120 IU/kg subcutaneously (SQ) to a maximum of 10,000 U if < or =8 hours before PCI (n = 3); for PCI 8-12 hours after the SQ dose, an additional 40 IU/kg intravenously (IV) was administered (n = 1); for PCI >12 hours after SQ dalteparin or with no prior dalteparin therapy, random allocation to 40 (n = 27) or 60 (n = 28) IU/kg IV during PCI was performed. Those patients who received 60 IU/kg of dalteparin IV had a lower incidence of procedural thrombosis (0% vs 11.1%, P <.01), more consistent antithrombotic effect (anti-factor Xa activity) and a similar incidence of major bleeding (3.7% vs 2.6%) compared with patients who received 40 IU/kg of intravenous dalteparin. CONCLUSIONS: Dalteparin 60 IU/kg IV appears to be safe and effective when administered in conjunction with abciximab for percutaneous coronary intervention.

Coronary perforation during percutaneous coronary intervention in the era of abciximab platelet glycoprotein IIb/IIIa blockade: an algorithm for percutaneous management.

Coronary perforation is an uncommon but potentially life-threatening complication of percutaneous coronary intervention. The use of both atheroablative technologies for coronary intervention and adjunctive platelet glycoprotein blockade pharmacology may increase the incidence of or risk for life-threatening bleeding complications following the occurrence of coronary artery perforation. The interventional database for 6,214 percutaneous coronary interventions performed between January 1995 and June 1999 was analyzed. Hospital charts and cine angiograms for all patients identified in the database as having had coronary perforation were reviewed. Coronary perforation complicated 0.58% of all procedures and was more commonly observed in patients with a history of congestive heart failure and following use of atheroablative interventional technologies (2.8%). There was no association of abciximab therapy with either the incidence of or classification for coronary perforation. Adverse clinical outcomes (death, emergency surgical exploration) were related to the angiographic classification of perforation and were more frequently observed in patients who experienced a class 3 coronary perforation. These data suggest that specific clinical and procedural demographic factors are associated with the occurrence and severity of angiographic coronary perforation. An angiographic perforation class-specific algorithm for treatment of coronary perforation is proposed.

Final results of a randomized trial comparing the NIR stent to the Palmaz-Schatz stent for narrowings in native coronary arteries.

The NIR stent is a novel second generation tubular stent that was designed to overcome some of the limitations of the earlier Palmaz-Schatz (PS) stent design. The NIR Vascular Advanced North American (NIRVANA) trial randomized 849 patients with single coronary lesions to treatment with the NIR stent or the PS stent. The study was an "equivalency" trial, designed to demonstrate that the NIR stent was not inferior to (i.e., equivalent or better than) the PS stent, for the primary end point of target vessel failure (defined as death, myocardial infarction, or target vessel revascularization) by 9 months. Successful stent delivery was achieved in 100% versus 98.8%, respectively, with a slightly lower postprocedural diameter stenosis (7% vs. 9%, p = 0.04) after NIR and PS stent placement, respectively. Major adverse cardiac events (death, myocardial infarction, repeat target lesion revascularization) were not different at 30 days (4.3% vs. 4.4%). The primary end point of target vessel failure at 9 months was seen in 16.0% of NIR versus 17.2% of PS patients, with the NIR proving to be equal or superior to the PS stent (p <0.001 by test for equivalency). Angiographic restudy in 71% of a prespecified cohort showed no significant difference in restenosis (19.3% vs 22.4%). Thus, the NIR stent showed excellent deliverability with slightly better acute angiographic results and equivalent or better 9-month target vessel failure rate when compared with the PS stent.

Final results of a randomized trial comparing the MULTI-LINK stent with the Palmaz-Schatz stent for narrowings in native coronary arteries.

The MULTI-LINK (ML) stent is a novel second generation coronary stent. The ACS MultiLink Stent Clinical Equivalence in De Novo Lesions Trial (ASCENT) randomized 1,040 patients with single, de novo native vessel lesions to treatment with the ML stent or the benchmark Palmaz-Schatz (PS) stent, to demonstrate that the ML stent was not inferior to (i.e., equivalent or better than) the PS stent in terms of target vessel failure by 9 months. Successful stent delivery was achieved in 98.8% versus 96.9% of patients, with a slightly lower postprocedural diameter stenosis (8% vs 10%, p = 0.04), and no difference in 30-day major adverse cardiac events (5.0% vs 6.5%) for the ML stent versus the PS stent. The primary end point of target vessel failure at 9 months was seen in 15.1% of ML-treated patients versus 16.7% of PS-treated patients, with the ML proving to be equal or superior to the PS stent (p <0.001 by test for equivalency). In a prespecified subset, angiographic restudy showed a nonsignificant trend for reduced ML restenosis (16.0% vs 22.1%). Thus, the ML stent showed excellent deliverability and acute results, with 9-month clinical and 6-month angiographic outcomes that were equivalent or better than the PS stent.