Quantification of abciximab-induced platelet inhibition is assay dependent: a comparative study in patients undergoing percutaneous coronary intervention

Background The best method for measuring the degree of platelet inhibition with glycoprotein (GP) IIb-IIIa antagonists during percutaneous coronary intervention (PCI) and the optimal degree of periprocedural inhibition is uncertain. Low molecular weight heparins have been reported to cause less platelet activation than unfractionated heparin. Therefore, compared with unfractionated heparin (UHF), a low molecular weight heparin could enhance measured platelet inhibition. In this study, we compared 3 methods of measuring platelet inhibition and investigated the effects of half doses of abciximab in combination with either UFH or the low molecular weight heparin dalteparin in patients undergoing PCI with planned abciximab administration. Methods Abciximab-induced platelet inhibition was measured serially by means of 3 assays: 1) GP IIb-IIIa receptor occupancy, 2) binding of the activated GP IIb—IIIa-specific monoclonal antibody PAC1, and 3) agglutination of platelets with fibrinogen-coated beads (RPFA). Forty patients were randomly allocated to receive either UFH (70 U/kg) or dalteparin (60 IU/kg), followed by a half dose of abciximab (0.125 mg/kg) administered twice at 10-minute intervals. Assays were obtained 10 minutes after each half dose of abciximab and 8 to 10 and 24 hours after abciximab administration. Results No differences between UFH and dalteparin were observed. At each time-point measured, the mean percent platelet inhibition as determined by means of the receptor occupancy assay and PAC1 binding assay was less than the degree of inhibition determined by means of the RPFA. Conclusions The results of targeted levels of platelet inhibition cannot be extrapolated between different clinical trials of GP IIb-IIIa antagonists unless the same assay is used. Dalteparin, compared with UFH, does not enhance platelet inhibition or receptor occupancy by abciximab, as demonstrated by means of 3 separate assays. (Am Heart J 2003;145:e6.)     

Reduced inhibition by abciximab in platelets with the Pl polymorphism

Background The Pl^A2 polymorphism of the glycoprotein IIb/IIIa (fibrinogen) receptor has been associated with increased restenosis and stent thrombosis. We postulated that this allele could alter the antiplatelet effect of abciximab in patients undergoing percutaneous coronary intervention. Methods Optical platelet aggregation assays, Ultegra (Accumetrics, San Diego) rapid platelet function assays, and radiometric abciximab binding assays were performed in 66 Pl^A1/A1 and 21 Pl^A1/A2 patients undergoing percutaneous coronary interventions. The affinity of abciximab for the Pl^A1 and Pl^A2 receptors was determined with use of transfected cells. Results Compared with Pl^A1/A1 homozygotes, Pl^A1/A2 platelets were less completely inhibited after abciximab bolus (P = .002) and at 24 hours (P = .02) as assessed by the rapid platelet function assays. Optical aggregation assays confirmed that Pl^A1/A2 platelets were less completely inhibited after abciximab bolus (P = .05). The radiometric abciximab binding assay demonstrated that the Pl^A1/A2 platelets had fewer baseline fibrinogen receptors than did the Pl^A1/A1 platelets (P = .04) and more free fibrinogen receptors at 24 hours (P = .008). Cells transfected to express homozygous Pl^A1 or Pl^A2 demonstrated a nonsignificant trend (P = .12) for reduced abciximab affinity for Pl^A2. Conclusions Pl^A1/A2 platelets are less completely inhibited with abciximab, contributing to the observed interindividual variability in platelet function inhibition. Because the extent of platelet inhibition is an independent predictor for the risk of major adverse coronary events after percutaneous coronary intervention, the relative resistance of Pl^A2-positive platelets may contribute to a less favorable outcome in these patients. (Am Heart J 2002;143:76-82.)     

Pharmacodynamic profile of short-term readministration of abciximab in healthy subjects

Objective The purpose of the study was to establish a rebolus regimen for abciximab that restores pharmacologic glycoprotein (GP) IIb/IIIa receptor blockade within a short time frame (up to 48 hours) after completion of an initial treatment. Methods and Results The study was a single-center, nonrandomized, open-label dose escalation trial in healthy volunteers (n = 30). Each subject received a 0.25 mg/kg bolus and a 0.125 μg/kg per minute infusion of abciximab, followed by incremental bolus doses of the agent at 15-minute intervals up to 48 hours (10 per group) after completion of the infusion, (maximal cumulative rebolus dose of 0.25 mg/kg). Pharmacodynamic measurements (GP IIb/IIIa receptor blockade, turbidimetric and whole blood platelet aggregation with use of a rapid platelet function assay [RPFA]) were obtained at periodic intervals during and after administration of the abciximab bolus and infusion. At the time of the first rebolus, pharmacodynamic measurements were attained immediately before administration of each rebolus and 15 minutes after the last rebolus dose. In subjects who received reboluses 12 hours after infusion, a cumulative dose of 0.05 mg/kg restored >80% blockade of GP IIb/IIIa receptors and >80% inhibition of turbidimetric (5 and 20 μmol/L adenosine diphosphate) and RPFA aggregation in 10 of 10 subjects. At 24 hours after treatment, a cumulative abciximab bolus dose of 0.1 mg/kg restored >80% blockade of all 4 pharmacodynamic measurements in 10 of 10 subjects. At 48 hours after treatment, a cumulative bolus dose of 0.15 mg/kg restored >80% blockade of all 4 pharmacodynamic measurements in 10 of 10 subjects. Conclusions A fraction of the bolus of abciximab restored pharmacologic (>80%) GP IIb/IIIa receptor blockade when readministered at various postinfusion time points. These observations suggest that in the setting where acute readministration of abciximab is required less than a full bolus dose of the agent is warranted. (Am Heart J 2002;143:87-94.)     

Comparison of GP IIB/IIIA Inhibitors and Their Activity as Measured by Aggregometry, Flow Cytometry, Single Platelet Counting, and the Rapid Platelet Function Analyzer

Background: GP IIb/IIIa inhibitors have primarily been used short-term e.g., during PTCA. They failed to show clinical benefit during long-term therapy. One reason might be the absence of a method to monitor inhibitor activity. This study compared platelet aggregometry, the rapid platelet function analyzer (RPFA) test, single platelet counting, and flow cytometric determination of receptor occupancy to measure GP IIb/IIIa-receptor inhibitor activity. Methods: Increasing doses of abciximab, tirofiban, and eptifibatide were added to whole blood in vitro. Whole blood was used for the RPFA, for single platelet counting and flow cytometry. Platelet rich plasma was prepared for aggregometry. Results: The correlation between aggregometry and RPFA results was linear for abciximab and eptifibatide. Tirofiban was a stronger inhibitor with the RPFA (IC₅₀ 7.7[emsp4 ]nM) than with aggregometry (IC₅₀ 19.6[emsp4 ]nM). The single platelet counting technique showed that even supratherapeutic concentrations of all three inhibitors could not completely suppress microaggregation. Abciximab concentrations that were equipotent to tirofiban with aggregometry were less potent with regards to the inhibition of microaggregation. This difference was more pronounced with TRAP induced microaggregation than with ADP. The flow cytometric receptor occupancy test showed that occupancy was 95[emsp4 ]% with 5[emsp4 ]g/ml abciximab and almost 97[emsp4 ]% with 10[emsp4 ]g/ml. Tirofiban reached a maximum receptor occupancy of 56[emsp4 ]%, eptifibatide 64[emsp4 ]%. Conclusions: While aggregometry is time consuming the RPFA provides results fast and with little variability. There is still a discrepancy between aggregometry and RPFA results for tirofiban. The single platelet counting technique detects the inhibition of microaggregation the relevance of which for the clinical outcome is not known. The flow cytometric receptor occupancy assay is best suited for abciximab.     

Determination of platelet aggregation inhibition during percutaneous coronary intervention with the platelet function analyzer PFA-100

Background A simple device to rapidly evaluate platelet function may aid in optimizing glycoprotein IIb/IIIa inhibition during percutaneous coronary intervention (PCI). We prospectively studied platelet function in 250 patients receiving abciximab or eptifibatide during PCI. Methods and Results The platelet function analyzer PFA-100 (Dade-Behring, Deerfield, Ill) measures platelet function by determining the time to occlusion of an aperture in a biochemically active membrane as whole blood flows under high shear conditions. Platelet aggregation causes aperture occlusion, and results are reported as a closure time (CT). All patients received either abciximab or eptifibatide, along with aspirin and heparin; patients undergoing stent implantation received aspirin and a thienopyridine postprocedure. The CT was measured at baseline and 10 minutes, 4 hours, 12 hours (abciximab-only), and 24 hours after the bolus. Profound inhibition was exhibited in most patients shortly after the platelet inhibitor bolus and during the course of therapy. We observed recovery of platelet function 12 hours after discontinuation of abciximab, with a high degree of interpatient variability, and ongoing profound platelet inhibition 4 to 6 hours after the discontinuation of eptifibatide. Among patients treated with abciximab, patients who were obese recovered from platelet inhibition sooner than patients who were not obese, whereas patients who were elderly had delayed recovery compared with patients who were not elderly. Failure to achieve maximal platelet inhibition (nonclosure) at 10 minutes indicated a possible association with adverse clinical events at the 6-month follow-up examination (60% vs 20%). Conclusions PFA-100 is a rapid simple assay used as a means of assessing inhibition of platelet aggregation during PCI performed with glycoprotein IIb/IIIa inhibition. Failure to achieve nonclosure early after the initiation of abciximab therapy warrants further investigation because there may be an association with adverse cardiac events at 6-month follow-up. (Am Heart J 2002;144:151-8.)     

Bivalirudin with planned or provisional abciximab versus low-dose heparin and abciximab during percutaneous coronary revascularization: results of the Comparison of Abciximab Complications with Hirulog for Ischemic Events Trial (CACHET)

Background The direct thrombin inhibitor bivalirudin has previously been associated with better efficacy and lower hemorrhage risk than heparin during balloon angioplasty. This agent has not yet been tested with stenting or in combination with platelet glycoprotein IIb/IIIa antagonists. Methods and Results In a pilot trial, 268 patients who underwent coronary intervention were randomized in 3 sequential phases to treatment with bivalirudin (with or without abciximab) or the control regimen of low-dose weight-adjusted heparin with abciximab. Patients in the bivalirudin arms received bivalirudin (1.0 mg/kg bolus, infusion of 2.5 mg/kg/h for 4 hours) plus abciximab in phase A, bivalirudin (0.5 mg/kg bolus, infusion of 1.75 mg/kg/h for the procedure duration) plus provisional (“rescue”) abciximab in phase B, or bivalirudin (0.75 mg/kg bolus, infusion of 1.75 mg/kg/h for the procedure duration) plus provisional abciximab in phase C. Abciximab was necessitated on a provisional basis in 24% of the patients in the bivalirudin arms of phases B and C. A composite clinical endpoint of death, myocardial infarction, repeat revascularization, or major bleeding by 7 days occurred in 3.3%, 5.9%, 0, and 10.6% of the patients in the bivalirudin phase A, bivalirudin phase B, bivalirudin phase C, and heparin plus planned abciximab arms, respectively (P = .018 for the pooled bivalirudin groups versus the heparin group). Conclusion Bivalirudin with planned or provisional abciximab may be at least as safe and effective as low-dose heparin plus abciximab during percutaneous coronary intervention. (Am Heart J 2002;143:847-53.)     

Abciximab improves 6-month clinical outcome after rescue coronary angioplasty

Background Few data are available concerning the effects on clinical outcome and left ventricular function of abciximab administration in patients undergoing rescue percutaneous transluminal coronary angioplasty (PTCA) after failed thrombolysis for acute myocardial infarction. The aim of the study was to investigate such effects. Methods Eighty-nine consecutive patients referred to our laboratory from other hospitals for rescue PTCA within 24 hours from the onset of chest pain were prospectively randomized before the procedure to abciximab treatment (44 patients) or placebo (45 patients). No significant differences in baseline characteristics were observed between the 2 groups. Study end points were the occurrence of major adverse cardiac events (MACE) such as death, reinfarction, congestive heart failure, target lesion revascularization, or recurrent ischemia at 30-day and 6-month follow-up and the occurrence of periprocedural bleeding. Results Mean time from symptom onset to reperfusion was 8.5 ± 5.4 hours; rescue PTCA was successful in 96% of patients. The incidence of major, moderate, and minor bleeding was similar in the 2 groups. At 30-day follow-up, the echocardiographic left ventricular wall motion score index showed a significantly higher improvement in the abciximab group versus the placebo group (P < .001). At 6-month follow-up, the incidence of MACE was 11% in the abciximab group versus 38% in the placebo group (P = .004). Abciximab administration (P = .003) and cardiogenic shock (P = .005) were the only independent predictors of the occurrence of MACE at multivariable analysis. Conclusion Treatment with abciximab during rescue PTCA positively affects clinical outcome at 6-month follow-up without increasing periprocedural bleeding. (Am Heart J 2002;143:334-41.)     

Antiplatelet effects of angiotensin-converting enzyme inhibitors compared with aspirin and clopidogrel: a pilot study with whole-blood aggregometry

Background Although specific antiplatelet drugs are well-established and effective in atherosclerosis prevention, recent clinical trials have also shown that use of angiotensin-converting enzyme (ACE) inhibitors results in a decrease in cardiovascular events. Therefore, in this study, we sought to assess the coagulative activity of patients with cardiovascular disease grouped for treatment with either ACE inhibitors, aspirin, clopidogrel/aspirin, or none of these medications. Methods Blood samples from 303 patients with cardiovascular disease were analyzed with whole-blood aggregometry. Platelet aggregation was determined by the increase in impedance across paired electrodes in response to the aggregatory agents adenosine diphosphate (ADP) or collagen. Results As the central finding, platelet aggregation was attenuated by ACE inhibitors and by aspirin or clopidogrel/aspirin, which was indicated by a lower impedance increase compared with no medication. With ACE inhibition, platelet aggregation decreased by 33% (P = .042) after ADP induction. No significant antithrombotic effect was seen with aspirin alone (17%, P = 1.0), whereas a decrease in ADP-induced platelet aggregation was extensive with clopidogrel/aspirin (85%, P = .001). After collagen induction, platelet aggregation was reduced by 16% (P = .028) in the presence of ACE inhibitor therapy, whereas inhibition with aspirin and clopidogrel/aspirin was 23% (P = .004) and 35% (P = .026), respectively, compared with participants who were not treated. Conclusions These ex vivo data on whole-blood aggregometry provide direct evidence that ACE inhibitors decrease platelet aggregation, whereas aspirin and clopidogrel are confirmed as established antithrombotics. Pleiotropic effects of ACE inhibition on platelet function may contribute to the clinical benefit observed with this drug class on major cardiovascular end points. (Am Heart J 2003;145:343-8.)     

Glycoprotein IIb-IIIa inhibition with abciximab and postprocedural risk assessment: lessons from the evaluation of platelet IIb/IIIa inhibitor for stenting trial and implication for ad hoc use of glycoprotein IIb-IIIa antagonists

Background Angiographic features of vessels in which stents have been deployed can be used to predict the risk of postprocedural ischemic events. The purpose of this study was to compare the effects of abciximab in patients with and without high-risk postprocedure features. Methods and Results Protocol-mandated stent implantation was performed in 1586 patients in the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting trial, 783 of whom received abciximab, and was successful in 97% of the patients. High-risk features were defined as the presence of Thrombolysis In Myocardial Infarction (TIMI) flow <3, presence of thrombus or major dissection, or residual stenosis >10%. The primary endpoint was a composite of death, myocardial infarction, and urgent target vessel revascularization at 30 days. High-risk features were present in 21% of the patients. In patients without high-risk features after stent placement, abciximab reduced the primary endpoint from 9.0% to 3.9% (P <.001) compared with 16.2% to 8.6% (P = .046) in patients in whom high-risk features were present. There was no statistical evidence of interaction between abciximab treatment and the presence or absence of high-risk features. Conclusion Glycoprotein IIb-IIIa antagonism with abciximab is equally effective in prevention of a composite of ischemic events in patients with and without high-risk features after stent placement. However, patients in whom high-risk features are present after stent placement are at increased risk of ischemic cardiac events even with abciximab treatment. (Am Heart J 2002;143:594-601.)     

Pharmacodynamic profile of the direct thrombin antagonist bivalirudin given in combination with the glycoprotein IIb/IIIa antagonist eptifibatide

Background Because of the adverse characteristics associated with heparin, direct antagonists of thrombin have been investigated as anticoagulants during percutaneous coronary interventions. However, the hematologic and clinical interactions between direct thrombin antagonists and inhibitors of platelet glycoprotein IIb-IIIa are incompletely explored. Methods Forty-two patients who underwent elective percutaneous coronary intervention were randomized to receive a bivalirudin 1.0 mg/kg bolus followed by a 4-hour infusion at 2.5 mg/kg/h; a bivalirudin 0.75 mg/kg bolus followed by a 4-hour infusion at 1.75 mg/kg; or a heparin 60 U/kg bolus. All the patients also received eptifibatide, given as 2 sequential boluses of 180 μg/kg followed by a 2 μg/kg/min infusion for 18 to 24 hours, and aspirin. Results After the bolus dose of the study drug, turbidimetric platelet aggregation in response to 5 μmol/L adenosine diphosphate increased in patients assigned to heparin but not those assigned to bivalirudin. After eptifibatide, platelet aggregation was eliminated in all 3 treatment groups. The effect of heparin and the effects of both bivalirudin regimens on the formation of thrombin antithrombin complexes and prothrombin fragment 1.2 were comparable. Neither agent affected the formation of platelet-monocyte complexes or expression of CD 63 lysosomal antigen. There were no major bleeding events, and a single non-Q-wave myocardial infarction (MI) occurred in a patient treated with bivalirudin. Conclusion These findings show the feasibility of combining the direct thrombin antagonist bivalirudin with a potent antagonist of platelet glycoprotein IIb-IIIa. Clinical trials are needed to assess the safety and efficacy of this combination. (Am Heart J 2002;143:585-93.)     

Abciximab therapy improves 1-month survival rate in unselected patients with acute myocardial infarction undergoing routine infarct artery stent implantation

Background The impact of abciximab therapy on mortality in unselected patients with acute myocardial infarction (AMI) undergoing routine primary infarct-related artery (IRA) stent implantation is not yet defined, and previous randomized studies have produced conflicting results. Methods A strategy of IRA stenting alone as opposed to IRA stenting plus abciximab was compared in a series of 561 consecutive unselected patients with AMI. Abciximab tretament was strongly encouraged for all patients. The contraindication for abciximab therapy was a high risk of major bleeding as assessed by the operator before mechanical intervention. Results Of 561 patients, 348 patients underwent abciximab therapy and 213 underwent primary IRA stenting alone. The 1-month overall mortality rate was 2.9% in the abciximab group and 10.8% in the stent alone group (P < .001). The relative reduction in mortality rate was 73% for patients overall, 77% in the subset of patients aged ≤70 years (mortality rate, 1.2% vs 5.2%, P = .020), 57% in patients aged >70 years (7.7% vs 18%, P = .043), 63% in patients with cardiogenic shock (17% vs 46%, P = .022), and 77% in patients without cardiogenic shock (1.3% vs 5.6%, P = .002). Multivariate analyses on the basis of all patients, and on the subset of patients aged ≤70 years, showed that abciximab therapy was independently related to the risk of death at 1 month. No differences were seen between groups in the procedural success rate (99.1% vs 98.1%) or in the incidence rates of nonfatal reinfarction (0.3% vs 1.9%) or repeat target vessel revascularization (1.7% vs 1.9%). Conclusion The results of this study strongly support the use of abciximab therapy in nonselected patients with AMI undergoing routine IRA stent implantation. The mechanism of the clinical benefit of abciximab was not related to the patency of the IRA. (Am Heart J 2002;144:315-22.)     

Antiplatelet effects of abciximab, tirofiban and eptifibatide in patients undergoing coronary stenting

OBJECTIVES: We sought to investigate whether abciximab, tirofiban and eptifibatide achieve comparable antiplatelet effects with coronary stenting. BACKGROUND: The glycoprotein (GP) IIb/IIIa antagonists abciximab, tirofiban and eptifibatide differ in chemical structure, binding site and pharmacokinetics. METHODS: Sixty patients undergoing coronary stenting were randomly assigned to abciximab (bolus 0.25 mg/kg body weight, infusion 10 microg per min for 12 h), tirofiban (bolus 10 microg/kg, infusion 0.15 microg/kg per min for 72 h) or eptifibatide (bolus 180 microg/kg, infusion 2 microg/kg per min for 72 h). We took serial blood samples to analyze platelet function by using flow cytometry, turbidimetric aggregometry and the rapid platelet-function assay (RPFA). RESULTS: As assessed by RPFA, platelet aggregation after 2 h of infusion was reduced to 5.9 +/- 7.8% (mean +/- SD) of baseline by abciximab, to 5.0 +/- 5.4% by tirofiban and to 7.8 +/- 7.1% by eptifibatide (p = 0.42). Turbidimetric aggregometry with adenosine diphosphate stimulation yielded similar results, whereas percent inhibition of platelet aggregation after thrombin receptor stimulation was 45.8 +/- 16.8% with abciximab, 51.3 +/- 17.6% with tirofiban and 52.9 +/- 14.8% with eptifibatide (p = 0.37). Tirofiban and eptifibatide maintained their level of platelet inhibition during infusion. Flow cytometry revealed that the reduction in the monocyte-platelet interaction by abciximab, tirofiban and eptifibatide was not significantly different (20.0 +/- 21.9%, 23.8 +/- 18.2% and 21.0 +/- 19.8%, respectively; p = 0.87). CONCLUSIONS: Abciximab, tirofiban and eptifibatide, at currently recommended doses, achieved similar levels of inhibition of platelet aggregation and a similar reduction in the platelet-monocyte interaction.     

Serum glucose and lipid levels in adult congenital heart disease patients

Atherosclerosis has been correlated with known cardiovascular risk factors such as serum glucose or lipid levels. Because congenital heart disease patients tend to survive until adulthood, atherosclerosis has also become a matter of concern in these patients. One hundred fifty-eight congenital heart disease patients and 152 patients selected at random from the population were studied and compared to determine serum glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol, and triglycerides levels. Both groups had similar socioeconomic status levels and the same environmental influences. Significant differences were seen between congenital heart disease patients and the control group, after sex, age, and body mass index adjustment, in fasting plasma glucose (97.7 [94.2-101.2] vs 86.9 [83.2-90.7], P < .001), total cholesterol (171.5 [165.7-177.3] vs 199.8 [90.7-206.0], P < .001), LDL cholesterol (103.9 [98.8-108.8] vs 123.8 [118.5-129.1], P < .001), and high-density lipoprotein cholesterol (48.1 [46.2-50.0] vs 54.2 [52.1-56.2], P < .001) levels. Nonsignificant differences were seen in triglycerides concentrations. Those patients with ventricular septal defect, coarctation of the aorta, and cyanosis had the lowest total cholesterol and LDL cholesterol concentrations. Congenital heart disease patients have lower plasma cholesterol concentrations and higher serum glucose levels than noncongenital ones.     

Systemic platelet effects of contrast media: Implications for cardiologic research and clinical practice

Background Angiographic contrast media cause platelet activation and decrease aggregability in vitro. We have previously shown in vitro a significant antiplatelet effect of contrast media at the concentrations obtained locally in the coronary artery during angioplasty. It is not known, however, whether a systemic effect is present. Method Thirty patients undergoing diagnostic coronary angiography were prospectively randomized to receive the nonionic medium iohexol, ionic low-molecular-weight medium ioxaglate, or ionic high-molecular-weight medium diatrizoate. Platelet aggregability was measured before and after the investigation with whole blood electrical impedance aggregometry (WBEA) with collagen agonist and the PFA-100 (Dade, Miami, Fla) platelet function analyzer with combined shear, collagen, and adenosine diphosphate as agonists. Results With WBEA, with iohexol no difference in impedance change was seen: (medians and ranges) before, 9.8 Ω (4.8-19.2 Ω) versus after, 9.6 Ω (2-19.2 Ω) (P not significant [NS]). With ioxaglate a significant fall was seen: before, 8.6 Ω (6.4-15.2 Ω) versus after, 6.6 Ω (0-12.4 Ω) (P = .004). With diatrizoate a significant and greater fall was seen: before, 10.8 Ω (6.4-17.6 Ω) versus after, 6.6 Ω (0-10.8 Ω) (P = .002). With PFA, no difference in closure time was seen with any medium: iohexol before, 99 seconds (79-142 seconds) versus after, 142 seconds (63-128 seconds) (P NS); ioxaglate before, 120 seconds (75-258 seconds) versus after, 95 seconds (74-258 seconds) (P NS); and diatrizoate before, 114.5 seconds (65-250 seconds) versus after, 100.5 seconds (72-300 seconds) (P NS). Conclusions Ionic but not nonionic contrast media have a systemic antiplatelet effect at diagnostic angiographic doses when measured with WBEA. Such an effect has not been shown before. This may explain the observed improved clinical outcome with ionic contrast media but also might confound platelet studies in coronary angioplasty. (Am Heart J 2002; 143:e1.)     

No effect of an L-arginine-enriched medical food (HeartBars) on endothelial function and platelet aggregation in subjects with hypercholesterolemia

Background Providing l-arginine as a precursor for nitric oxide has been proposed to improve endothelial function in populations at high risk for cardiovascular events. We studied the effects of dietary l-arginine supplementation with HeartBars (a medical food rich in L-arginine, Cooke Pharma, Belmont, Calif) on flow-mediated dilation and markers of endothelial function in subjects with hypercholesterolemia. Methods We randomly assigned 47 subjects with hypercholesterolemia to receive one HeartBar containing 3.3 g l-arginine each, or a placebo bar, consumed twice daily for 2 weeks. Flow-mediated dilation, platelet aggregation studies, and soluble levels of endothelial and platelet adhesion molecules were obtained before and after the 2-week treatment period. Results Baseline and follow-up levels of l-arginine were 78.5 ± 28.2 μmol/L and 80.7 ± 26.7 μmol/L, respectively (P = .54). The HeartBar group had no improvement in flow-mediated dilation; changes in brachial artery diameter at baseline and follow-up were 5.52% ± 3.32% and 4.96% ± 2.39%, respectively. There were also no changes in the soluble levels of E-selectin and P-selectin by treatment group. Conclusions In our study, 2 weeks of HeartBar supplementation in subjects with hypercholesterolemia showed no favorable effects on endothelial or platelet function. (Am Heart J 2003;145:e15.)     

Quality of life and time trade-off utility measures in patients with coronary artery disease

Background Contemporary clinical trials commonly measure quality of life and medical costs to establish whether therapies are both effective and cost effective. Cost-effectiveness analysis, however, requires a measure of patient utility or preferences for various health states. Because utilities are not often measured directly, we sought to develop a method of translating standard quality-of-life scales into a patient utility measure.Methods Five hundred fifty-three patients enrolled in the Bypass Angioplasty Revascularization Investigation Study of Economics and Quality of Life completed a battery of quality-of-life measures and a time trade-off utility assessment an average of 7.3 years after random assignment.Results The mean time trade-off score was 8.54 (SD = 2.53) out of a maximum of 10; median score was 9.95. The distribution of scores was skewed, with 12% of patients at the highest possible score of 10. Patients with recurrent angina had significantly lower time trade-off scores than patients without angina (mean 7.03 vs 8.70, P < .05). Time trade-off scores were moderately correlated with each quality-of-life measure (Spearman coefficients 0.38-0.52). Time trade-off scores could be predicted by combinations of 4 (r² = 0.29), 5 (r² = 0.31), or 6 (r² = 0.32) variables.Conclusions Time trade-off utility scores can be inferred from commonly used quality-of-life measures. Angina significantly reduces patient utility scores. (Am Heart J 2003;145:36-41.)     

The Use of the Point of Care Helena ICHOR/Plateletworks® and the Accumetrics Ultegra® RPFA for Assessment of Platelet Function with GPIIb-IIIa Antagonists

Objective: To evaluate a newly modified rapid platelet function analysis system (ICHOR/ Plateletworks®) and to compare the results obtained with those of traditional light transmission aggregometry (LTA), and the Ultegra/RPFA® system. Background: Anti-platelet therapy is standard of care for patients as an adjunct to percutaneous coronary intervention (PCI) or for medical management of non-ST elevation acute coronary syndromes (NSTE ACS). Recent clinical trial results suggest that the three currently approved platelet GPIIb-IIIa receptor antagonists, eptifibatide, tirofiban and abciximab, may vary in extent of inhibition of platelet aggregation (IPA) at the approved doses. Thus, pharmacodynamic evaluations of these agents to determine the extent of platelet function inhibition, especially during the periprocedural time of a cardiac intervention, are necessary. A rapid measurement method as a surrogate for LTA, the current gold standard, would be ideal in order to have the option for dose monitoring or adjustment prior to or during an intervention. The Helena ICHOR/ Plateletworks® may be useful for point of care testing. Methods: Blood samples collected in D-Phe-Pro-Arg-chloromethyl ketone dihydrochloride (PPACK) anticoagulant were treated with increasing concentrations of eptifibatide, tirofiban or abciximab. LTA was carried out in conjunction with the ICHOR/Plateletworks®, using a modified method, and Accumetrics Ultegra® with RPFA cartridges. Results: This study demonstrated that platelet inhibition measured by the ICHOR/Plateletworks® mirrored the level of IPA obtained with LTA. In contrast, the Ultegra® system had less correlation when compared to LTA at inhibition levels < 90%. Conclusions: Based on these data, the ICHOR/ Plateletworks® utilized under modified guidelines may serve as a surrogate for LTA when rapid measurements are necessary.Abbreviated Abstract A rapid platelet function measurement method as a surrogate for light transmission aggregometry (LTA), the current gold standard, is ideal in order to have the option for GPIIb-IIIa antagonist dose monitoring or adjustment prior to or during a coronary intervention. A newly modified rapid platelet function analysis system (ICHOR/Plateletworks® was evaluated and compared to the results obtained with traditional light transmission aggregometry (LTA), and the Ultegra/RPFA® system. Blood samples collected in D-Phe-Pro-Arg-chloromethyl ketone dihydrochloride (PPACK) anticoagulant were treated with increasing concentrations of eptifibatide, tirofiban or abciximab. LTA was carried out in conjunction with the ICHOR/Plateletworks®, using a modified method, and Accumetrics Ultegra® with RPFA cartridges. Based on these data, the ICHOR/Plateletworks® utilized under modified guidelines may serve as a surrogate for LTA when rapid measurements are necessary.Supported in part by Helena Laboratories, Inc. and the University of Tennessee Health Science Center Vascular Biology Center of ExcellenceThis revised version was published online in May 2005 with a corrected cover date.     

An Approach to the Rational Use of Revascularization in Heart Failure Patients

The most common cause of heart failure with reduced ejection fraction (HFrEF) is coronary artery disease. A multitude of factors come into play when deciding whether a patient with HFrEF and coronary artery disease should have coronary artery bypass graft (CABG) surgery, percutaneous coronary intervention, or medical therapy alone. For candidates for percutaneous coronary intervention and CABG, evidence from large registries would suggest that patients with 2-vessel coronary artery diseases and proximal left anterior descending disease and all patients with 3-vessel coronary artery disease do better with CABG. For patients that are candidates for medical therapy with or without CABG, the results of the Surgical Treatment for Ischemic Heart Failure (STICH) trial indicate that with CABG, the reduction of mortality is not statistically significant (hazard ratio [HR], 0.86; P = 0.12). However, CABG is superior in reducing cardiovascular deaths (HR, 0.81; P = 0.05), and the combination of cardiovascular deaths and cardiovascular hospitalizations (HR, 0.74; P < 0.001). Patients undergoing CABG have an upfront risk that is eliminated by 2 years and thereafter do better. The assessment of cardiac viability or reversible ischemia does not appear to be helpful in determining which individuals will improve more with CABG. Patients with severe mitral regurgitation who undergo CABG appear to benefit from simultaneous valve repair but not from the addition of surgical ventricular reconstruction of the left ventricle, although in specific patients this might be considered. The totality of evidence would thus suggest that patients with HFrEF should be evaluated for the possibility of coronary revascularization if they are candidates for CABG.     

Influence of left ventricular size and hemodynamics on the systolic longitudinal myocardial Doppler velocity response to stress

Background Systolic myocardial Doppler velocity accurately identifies coronary artery disease. However, these velocities may be affected by age, hemodynamic responses to stress, and left ventricular cavity size. We sought to examine the influences of these variables on myocardial velocity during dobutamine stress in patients with normal wall motion. Methods One hundred seventy-nine consecutive patients with normal dobutamine echocardiograms were studied. Color myocardial tissue Doppler data were obtained at rest and peak stress, and peak systolic myocardial velocity (PSV) was measured in all basal and midventricular segments. Velocities at rest and peak stress were compared with left ventricular diastolic and systolic volumes, blood pressure, heart rate, and age by Pearson correlation and interdecile analysis by use of analysis of variance. Results The only clinical variable correlating with velocity was age; PSV showed only mild correlation with age at rest (r² = 0.01, P = .001) and peak stress (r² = 0.02, P = .001), but the normal peak velocity was significantly different between the extremes of age (<44 years and >74 years). There was very weak correlation of PSV with systolic and diastolic blood pressure (r² < 0.01), heart rate (r² < 0.01), systemic vascular resistance (r² = 0.08), and left ventricular volumes (r² < 0.01). Conclusions Peak systolic velocity during dobutamine stress is relatively independent of hemodynamic factors and left ventricular cavity size. The extremes of age may influence peak systolic Doppler velocities. These results suggest that peak systolic velocity may be a robust quantitative measure during dobutamine echocardiography across most patient subgroups. (Am Heart J 2002;143:169-75.)     

Heart rate recovery after exercise is related to the insulin resistance syndrome and heart rate variability in elderly men

Objective We investigated the associations between heart rate recovery after exercise (as a suggested measure of vagal activity), heart rate variability, and measurements of the insulin resistance syndrome. Material and Methods Seventy men aged 70 years were examined with a symptom-limited bicycle exercise test, a 24-hour heart rate variability test, and different measurements of different components of the insulin resistance syndrome. Results Heart rate recovery after exercise (mean ± SD 20 ± 9 beats during the first minute) was related to both the SD of the R-R interval and the low frequency power at the heart rate variability analyses (r = 0.39, P < .002 for both). Furthermore, heart rate recovery after exercise was related to insulin sensitivity at the hyperinsulinemic eugleucemic clamp (r = 0.28, P < .03), and to high-density lipoprotein cholesterol and exercise capacity, and inversely to obesity and insulin and glucose levels 2 hours after an oral glucose load (P < .05 for all). Heart rate recovery after exercise was not related to left ventricular mass measured by means of echocardiography or to the number of ventricular premature complexes at a 24-hour Holter recording. Conclusion Heart rate recovery 1 minute after exercise was related to measurements of 24-hour heart rate variability. Furthermore, heart rate recovery after exercise was related to several of the major components of the insulin resistance syndrome, thereby establishing a link between this syndrome and cardiac autonomic nervous activity. (Am Heart J 2002;144:666-72.)