Reductions in sugar sales from soft drinks in the UK from 2015 to 2018.

BACKGROUND: The consumption of free sugars in the UK is more than double the guideline intake for adults and close to triple for children, with soft drinks representing a significant proportion. The aim of this study was to assess how individual soft drink companies and consumers have responded to calls to reduce sugar consumption, including the soft drink industry levy (SDIL), between 2015 and 2018. METHODS: This was an annual cross-sectional study using nutrient composition data of 7377 products collected online, paired with volume sales data for 195 brands offered by 57 companies. The main outcome measures were sales volume, sugar content and volume of sugars sold by company and category, expressed in total and per capita per day terms. RESULTS: Between 2015 and 2018, the volume of sugars sold per capita per day from soft drinks declined by 30%, equivalent to a reduction of 4.6 g per capita per day. The sales-weighted mean sugar content of soft drinks fell from 4.4 g/100 ml in 2015 to 2.9 g/100 ml in 2018. The total volume sales of soft drinks that are subject to the SDIL (i.e. contain more than 5 g/100 ml of sugar) fell by 50%, while volume sales of low- and zero-sugar (< 5 g/100 ml) drinks rose by 40%. CONCLUSION: Action by the soft drinks industry to reduce sugar in products and change their product portfolios, coupled with changes in consumer purchasing, has led to a significant reduction in the total volume and per capita sales of sugars sold in soft drinks in the UK. The rate of change accelerated between 2017 and 2018, which also implies that the implementation of the SDIL acted as an extra incentive for companies to reformulate above and beyond what was already being done as part of voluntary commitments to reformulation, or changes in sales driven by consumer preferences.

Dose selection for a direct and selective factor IXa inhibitor and its complementary reversal agent: translating pharmacokinetic and pharmacodynamic properties of the REG1 system to clinical trial design.

We performed detailed pharmacokinetic and pharmacodynamic modeling of REG1, an anticoagulation system composed of the direct factor IXa (FIXa) inhibitor pegnivacogin (RB006) and its matched active control agent anivamersen (RB007), with a focus on level of target inhibition to translate phase 1 results to phase 2 dose selection. We modeled early-phase clinical data relating weight-adjusted pegnivacogin dose and plasma concentration to prolongation of the activated partial thromboplastin time (aPTT). Using an in vitro calibration curve, percent FIXa inhibition was determined and related to aPTT prolongation and pegnivacogin dose and concentration. Similar methods were applied to relate anivamersen dose and level of reversal of pegnivacogin anticoagulation. Combined early-phase data suggested that ≥0.75 mg/kg pegnivacogin was associated with >99% inhibition of FIX activity and prolongation of plasma aPTT values ≈2.5 times above baseline, leading to selection of a 1 mg/kg dose for a phase 2a elective percutaneous coronary intervention study to achieve a high intensity of anticoagulation and minimize intersubject variability. Phase 2 validated our predictions, demonstrating 1 mg/kg pegnivacogin yielded plasma concentrations ≈25 µg/ml and >99% inhibition of FIX activity. The relationship between the anivamersen to pegnivacogin dose ratio and degree of pegnivacogin reversal was also validated. Our approach decreased the need for extensive dose-response studies, reducing the duration, complexity and cost of clinical development. The 1 mg/kg pegnivacogin dose and a range of anivamersen dose ratios are being tested in the phase 2b RADAR study (NCT00932100).

Bleeding risk with AZD6140, a reversible P2Y12 receptor antagonist, vs. clopidogrel in patients undergoing coronary artery bypass grafting in the DISPERSE2 trial.

AZD6140, the first reversible oral P2Y(12) receptor antagonist, exhibits greater and more consistent inhibition of platelet aggregation than the irreversible thienopyridine clopidogrel. As a result of its reversible effect, AZD6140 may pose less risk for bleeding when antiplatelet treatment cannot be stopped at least 5 days before coronary artery bypass graft (CABG) surgery or other invasive procedures. The Dose conflrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in NSTEMI (DISPERSE2) trial showed overall comparable bleeding rates with antiplatelet treatment with AZD6140 90 mg twice daily or 180 mg twice daily vs. clopidogrel 75 mg once daily in 984 patients with non-ST-elevation acute coronary syndromes. A post hoc exploratory analysis of bleeding outcomes in the subset of 84 patients undergoing CABG in DISPERSE2 suggests reduced risk for total bleeding (41% and 58% vs. 62%), all major bleeding (38% and 50% vs. 62%), and life-threatening bleeding (22% and 38% vs. 54%) with AZD6140 90 mg (n = 32) and 180 mg (n = 26) vs. clopidogrel (n = 26) respectively. Trends suggested that major bleeding rates were reduced with AZD6140 (combined groups) vs. clopidogrel when treatment was stopped < or = 5 days prior to surgery (39% vs. 63%, p = 0.15) but not when treatment was stopped > 5 days before surgery (50% vs. 60%). This observation is consistent with the reversible binding of AZD6140 to the P2Y(12) receptor. Further prospective studies are planned to assess the relationship between this potential clinical benefit of AZD6140 and the reversibility of its antiplatelet effects.

Effect of extended-duration thromboprophylaxis on venous thromboembolism and major bleeding among acutely ill hospitalized medical patients: a bivariate analysis.

Essentials Anticoagulants prevent venous thromboembolism but may be associated with greater bleeding risks. Bivariate analysis assumes a non-linear relationship between efficacy and safety outcomes. Extended full-dose betrixaban is favorable over standard enoxaparin in bivariate endpoint. Clinicians must weigh efficacy and safety outcomes in decision-making on thromboprophylaxis. SUMMARY: Background Among acutely ill hospitalized medical patients, extended-duration thromboprophylaxis reduces the risk of venous thromboembolism (VTE), but some pharmacologic strategies have been associated with greater risks of major bleeding, thereby offsetting the net clinical benefit (NCB). Methods To assess the risk-benefit profile of anticoagulation regimens, a previously described bivariate method that does not assume a linear risk-benefit tradeoff and can accommodate different margins for efficacy and safety was performed to simultaneously assess efficacy (symptomatic VTE) and safety (major bleeding) on the basis of data from four randomized controlled trials of extended-duration (30-46 days) versus standard-duration (6-14 days) thromboprophylaxis among 28 227 patients (EXCLAIM, ADOPT, MAGELLAN and APEX trials). Results Extended thromboprophylaxis with full-dose betrixaban (80 mg once daily) was superior in efficacy and non-inferior in safety to standard-duration enoxaparin, and showed a significantly favorable NCB, with a risk difference of - 0.51% (- 0.89% to - 0.10%) in the bivariate outcome. Extended enoxaparin was superior in efficacy and inferior in safety (bivariate outcome: 0.03% [- 0.37% to 0.43%]), whereas apixaban and rivaroxaban were non-inferior in efficacy and inferior in safety (- 0.20% [- 0.49% to 0.17%] and 0.23% [- 0.16% to 0.69%], respectively). Reduced-dose betrixaban did not show a significant difference in either efficacy or safety (0.41% [- 0.85% to 1.94%]). Conclusions In a bivariate analysis that assumes non-linear risk-benefit tradeoffs, extended prophylaxis with full-dose betrixaban was superior to standard-duration enoxaparin, whereas other regimens failed to simultaneously achieve both superiority and non-inferiority with respect to symptomatic VTE and major bleeding in the management of acutely ill hospitalized medical patients.

Dose-finding, safety, and tolerability study of an oral platelet glycoprotein IIb/IIIa inhibitor, lotrafiban, in patients with coronary or cerebral atherosclerotic disease.

BACKGROUND: Antiplatelet therapy is the mainstay of the treatment and secondary prevention of cardiovascular and cerebrovascular ischemic events. We assessed the safety, tolerability, and pharmacodynamics of lotrafiban, an oral platelet glycoprotein IIb/IIIa inhibitor, as a secondary prevention strategy in patients with cerebrovascular or cardiovascular disease. METHODS AND RESULTS: Overall, 451 patients with a recent cardiovascular or cerebrovascular acute ischemic event were randomized in a double-blind fashion to 1 of 5 dosing regimens for 12 weeks: placebo or 5, 20, 50, or 100 mg lotrafiban, both twice daily with 300 to 325 mg/d aspirin. The primary end point was the incidence and tolerability of major and minor bleeding during treatment. Secondary end points included inhibition of platelet aggregation and clinical events. The placebo and lotrafiban 5-mg groups had similarly low rates of minor and major bleeding, but the 100-mg arm was terminated early because of excess major bleeding. Protocol-defined thrombocytopenia (<100 000 platelets/microL) occurred in 5 lotrafiban-treated patients (1.4%, 95% CI 0.2% to 2.7%) and 1 placebo patient (1.1%, 95% CI 0% to 3.1%). Three lotrafiban-treated patients had a nadir platelet count <20 000/microL (0.9%, 95% CI 0% to 1.8%). Lotrafiban produced dose-dependent inhibition of platelet aggregation; 5 mg lotrafiban did not differ significantly from placebo, whereas 100 mg inhibited aggregation by nearly 100%. CONCLUSIONS: -Lotrafiban provides dose-dependent platelet inhibition when administered to a range of patients with atherosclerosis. The level of platelet inhibition appears to correlate with bleeding risk and drug tolerability.

Enhanced efficacy of eptifibatide administration in patients with acute coronary syndrome requiring in-hospital coronary artery bypass grafting. PURSUIT Investigators.

BACKGROUND: Patients with a recent episode of non-ST-segment elevation acute coronary syndrome before CABG have higher rates of operative morbidity and mortality than patients with stable coronary syndromes. The efficacy of administering eptifibatide to these patients undergoing in-hospital CABG is unknown. METHODS AND RESULTS: The Platelet Glycoprotein IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial randomized 10 948 patients to receive either eptifibatide or placebo. There were 1558 study participants who underwent in-hospital CABG: 692 received placebo, and 866 received eptifibatide. The main substudy analysis end point was death or myocardial infarction (MI) rates at the 6-month follow-up. The 30-day death or MI rates were 30. 8% and 26.1% for the placebo and eptifibatide groups, respectively (P:=0.041). The benefit of eptifibatide administration persisted through 6-months of follow-up (32.7% versus 27.6% for placebo versus eptifibatide, respectively; P:=0.029). There was a greater reduction in the 6-month death or MI rate for patients who received eptifibatide within 72 hours of CABG (33.6% versus 23.8%; P:=0.002) compared with the >72-hour group (31.6% versus 32%; P:=1.0). The incidence of major bleeding was 56.6% for placebo-treated patients versus 58.2% for eptifibatide-treated patients (P:=0.7). CONCLUSIONS: Eptifibatide administration in patients undergoing in-hospital CABG with a recent episode of a non-ST-segment elevation acute coronary syndrome results in a significant reduction in death or MI that is evident at 7 days and persists through the 6-month follow-up without a significant increase in perioperative bleeding rates.

Cost-effectiveness of platelet glycoprotein IIb/IIIa inhibition with eptifibatide in patients with non-ST-elevation acute coronary syndromes.

BACKGROUND: In the PURSUIT trial, eptifibatide significantly reduced the 30-day incidence of death and myocardial infarction relative to placebo in 9461 patients with an acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction). METHODS AND RESULTS: We conducted a 2-part prospective economic substudy of the 3522 US patients enrolled in PURSUIT: (1) an empirical intention-to-treat comparison of medical costs (hospital plus physician) up to 6 months after hospitalization and (2) a lifetime cost-effectiveness analysis. The base-case cost-effectiveness ratio was expressed as the 1996 US dollars required to add 1 life-year with eptifibatide therapy. The 2 treatment arms had equivalent resource consumption and medical costs (exclusive of the cost of the eptifibatide regimen) during the index (enrollment) hospitalization (P=0.78) and up to 6 months afterward (P=0.60). The average wholesale price of the eptifibatide regimen was $1217, but a typical hospital discounted price was $1014. The estimated life expectancy from randomization in the US patients was 15.96 years for eptifibatide and 15.85 years for placebo, an incremental difference of 0.111. The incremental cost-effectiveness ratio for eptifibatide therapy in US PURSUIT patients was $16 491 per year of life saved. This result was robust through a wide range of sensitivity analyses. The cost-utility ratio for eptifibatide (using time trade-off defined utilities) was $19 693 per added quality-adjusted life-year. CONCLUSIONS: Based on the results observed in the US PURSUIT patients, the routine addition of eptifibatide to standard care for non-ST-elevation acute coronary syndrome patients is economically attractive by conventional standards.

Benefit of glycoprotein IIb/IIIa inhibition in patients with acute coronary syndromes and troponin t-positive status: the paragon-B troponin T substudy.

BACKGROUND: Troponin T (TnT) is valuable for short- and long-term risk stratification of patients with acute coronary syndromes (ACS). It also may predict which ACS patients will benefit from glycoprotein (GP) IIb/IIIa blockade. METHODS AND RESULTS: We prospectively studied 1160 patients with non-ST-segment elevation ACS randomized in PARAGON-B to receive lamifiban, an intravenous GP IIb/IIIa antagonist, or placebo. TnT levels were obtained before study treatment began and 24 to 72 hours later; assays were performed by a blinded core laboratory. At baseline, 40.2% of patients were TnT-positive (>/=0.1 ng/mL); these patients were older and more often male or smokers. Patients positive at baseline had a significantly higher rate of the primary end point (composite of death, myocardial [re]infarction, or severe recurrent ischemia at 30 days; odds ratio, 1.5; 95% CI, 1.1 to 2.1) than those who were TnT-negative. Lamifiban was associated with significant reduction in the primary end point (from 19.4% to 11.0%, P=0.01) among TnT-positive patients but not among TnT-negative patients (11.2% for placebo versus 10.8% for lamifiban, P=0.86; P=0.08 for test of interaction between TnT status and treatment assignment). This pattern held for the end points of death alone and death or myocardial (re)infarction at 30 days. Peak TnT level at 48 hours did not differ with lamifiban treatment. CONCLUSIONS: TnT predicts poor short-term outcomes in non-ST-segment elevation ACS. Treatment benefit with lamifiban is limited almost exclusively to TnT-positive patients, reducing 30-day adverse outcomes to a rate nearly identical to that of negative patients.

Attenuation of rebound ischemia after discontinuation of heparin therapy by glycoprotein IIb/IIIa inhibition with eptifibatide in patients with acute coronary syndromes: observations from the platelet IIb/IIIa in unstable angina: receptor suppression using integrilin therapy (PURSUIT) trial.

Background- A reactivation of ischemia after the discontinuation of intravenous heparin in acute coronary syndromes has been described. The effect of glycoprotein IIb/IIIa blockade on heparin rebound is unknown. Methods and Results- Patients with acute coronary syndromes who received heparin therapy but not initial revascularization in the Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial were analyzed. Rates of death or myocardial (re)infarction while on heparin therapy and in 12-hour periods in the 2 days after heparin discontinuation were compared between eptifibatide and placebo. There was no difference between study groups in event rates during heparin infusion. In the 12 hours after heparin discontinuation, there was a 2.5-fold increase in all events, an 8-fold increase in death, and a 2-fold increase in myocardial infarction. However, in the 12 hours after heparin discontinuation, there was a significantly lower rate of events (1.68% versus 2.53%, P=0.03) and death (0.77% versus 0.21%, P=0.002) in the eptifibatide group compared with the placebo group. When only considering patients who were on study drug at the time of heparin discontinuation, the reduction in the combined end point was marginally significant, but the difference in the rate of death remained significant (0.68% versus 0.06%, P=0.004). In logistic regression analyses, the multivariate predictors of rebound events were the duration of heparin therapy, age, North American site, and lack of eptifibatide treatment. Conclusions- An increase in death or myocardial infarction occurs in the 12 hours after heparin discontinuation in patients with acute coronary syndromes. This rebound is attenuated by glycoprotein IIb/IIIa inhibition with eptifibatide.

Pharmacodynamics and pharmacokinetics of eptifibatide in patients with acute coronary syndromes: prospective analysis from PURSUIT.

BACKGROUND: Platelet deposition and aggregation are central to the pathogenesis of ischemic complications of acute coronary syndromes (ACS). Pharmacodynamic effects of the platelet glycoprotein IIb/IIIa antagonist eptifibatide have been delineated in healthy subjects but not in patients with ACS. We assessed effects of eptifibatide on ex vivo platelet aggregation in patients enrolled in the Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin (eptifibatide) Therapy (PURSUIT) trial of ACS. METHODS AND RESULTS: Patients were randomly assigned to an intravenous bolus (180 microgram/kg) and 72-hour infusion of eptifibatide (2.0 microgram/kg per minute, n=48) or placebo (n=50). We assessed correlations of plasma eptifibatide levels with receptor occupancy and inhibition of ex vivo platelet aggregation at 5 minutes and 1, 4, 24, 48, and 72 hours during treatment and 4 and 8 hours after termination of infusion. Blood was collected in buffered citrate and D-phenylalanyl-L-prolyl-L-arginine chloromethylketone anticoagulants. Although eptifibatide produced profound, prolonged inhibition of platelet aggregation during therapy, aggregation appeared to recover partially by 4 hours after the bolus. The aggregation response was greater with thrombin receptor agonist peptide versus ADP stimulation; inhibition of platelet aggregation was greater in blood samples anticoagulated with citrate versus D-phenylalanyl-L-prolyl-L-arginine chloromethylketone (PPACK). Plasma eptifibatide levels correlated significantly with receptor occupancy but not with inhibition of platelet aggregation. CONCLUSIONS: A bolus and infusion of eptifibatide inhibits platelet aggregation profoundly in patients with ACS and is followed by brief, partial recovery. These results enhance our understanding of the relation between pharmacodynamic and clinical effects of eptifibatide in such patients and may have important implications for its use in percutaneous interventions.

Management of patients with acute coronary syndromes in the United States by platelet glycoprotein IIb/IIIa inhibition. Insights from the platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression using integrilin therapy (PURSUIT) trial.

BACKGROUND: A multinational, randomized, placebo-controlled trial (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy, PURSUIT) demonstrated that the platelet glycoprotein IIb/IIIa receptor antagonist eptifibatide reduced the incidence of death or myocardial infarction among patients with acute ischemic syndromes without ST-segment elevation. Because of expected differences in practice patterns, a prospectively planned analysis of outcomes as a function of regions of the world was performed. The current study provides a detailed assessment of eptifibatide among the subgroup of patients enrolled within the United States. METHODS AND RESULTS: Patients presenting with chest pain within the previous 24 hours and ischemic ECG changes or creatine kinase-MB elevation were eligible for enrollment. Of the 10 948 patients randomized worldwide, 4035 were enrolled within the United States. Patients were allocated to placebo or eptifibatide infusion for up to 72 to 96 hours. Other medical therapies and revascularization strategies were at the discretion of the treating physician. Eptifibatide reduced the rate of the primary end point of death or myocardial infarction by 30 days from 15.4% to 11.9% (P=0.003) among patients in the United States. The treatment effect was achieved early and maintained over a period of 6 months (18.9% versus 15.2%; P=0.004). Bleeding events were more common in patients receiving eptifibatide but were predominantly associated with invasive procedures. The magnitude of clinical benefit from eptifibatide was greater among patients in the United States than elsewhere in the world. CONCLUSIONS: Platelet glycoprotein IIb/IIIa receptor blockade with eptifibatide reduces the incidence of death or myocardial infarction among patients treated for acute ischemic syndromes without ST-segment elevation within the United States.

Clinical and therapeutic profile of patients presenting with acute coronary syndromes who do not have significant coronary artery disease.The Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) Trial Investigators.

BACKGROUND: A proportion of patients who present with suspected acute coronary syndrome (ACS) are found to have insignificant coronary artery disease (CAD) during coronary angiography, but these patients have not been well characterized. METHODS AND RESULTS: Of the 5767 patients with non-ST-segment elevation ACS who were enrolled in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin (Eptifibatide) Therapy (PURSUIT) trial and who underwent in-hospital angiography, 88% had significant CAD (any stenosis >50%), 6% had mild CAD (any stenosis >0% to

Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation. Results from an international trial of 9461 patients. The PURSUIT Investigators.

BACKGROUND: Appropriate treatment policies should include an accurate estimate of a patient's baseline risk. Risk modeling to date has been underutilized in patients with acute coronary syndromes without persistent ST-segment elevation. METHODS AND RESULTS: We analyzed the relation between baseline characteristics and the 30-day incidence of death and the composite of death or myocardial (re)infarction in 9461 patients with acute coronary syndromes without persistent ST-segment elevation enrolled in the PURSUIT trial [Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin (eptifibatide) Therapy]. Variables examined included demographics, history, hemodynamic condition, and symptom duration. Risk models were created with multivariable logistic regression and validated by bootstrapping techniques. There was a 3.6% mortality rate and 11.4% infarction rate by 30 days. More than 20 significant predictors for mortality and for the composite end point were identified. The most important baseline determinants of death were age (adjusted chi(2)=95), heart rate (chi(2)=32), systolic blood pressure (chi(2)=20), ST-segment depression (chi(2)=20), signs of heart failure (chi(2)=18), and cardiac enzymes (chi(2)=15). Determinants of mortality were generally also predictive of death or myocardial (re)infarction. Differences were observed, however, in the relative prognostic importance of predictive variables for mortality alone or the composite end point; for example, sex was a more important determinant of the composite end point (chi(2)=21) than of death alone (chi(2)=10). The accuracy of the prediction of the composite end point was less than that of mortality (C-index 0.67 versus 0.81). CONCLUSIONS: The occurrence of adverse events after presentation with acute coronary syndromes is affected by multiple factors. These factors should be considered in the clinical decision-making process.

Early percutaneous coronary intervention, platelet inhibition with eptifibatide, and clinical outcomes in patients with acute coronary syndromes. PURSUIT Investigators.

BACKGROUND: Platelet glycoprotein (GP) IIb/IIIa antagonists prevent the composite end point of death or myocardial infarction (MI) in patients with acute coronary syndromes. There is uncertainty about whether this effect is confined to patients who have percutaneous coronary interventions (PCIs) and whether PCIs further prevent death or MI in patients already treated with GP IIb/IIIa antagonists. METHODS AND RESULTS: PURSUIT patients were treated with the GP IIb/IIIa antagonist eptifibatide or placebo; PCIs were performed according to physician practices. In 2253 of 9641 patients (23.4%), PCI was performed by 30 days. Early (<72 hours) PCI was performed in 1228 (12.7%). In 34 placebo patients (5.5%) and 10 treated with eptifibatide (1.7%) (P=0.001), MI preceded early PCI. In patients censored for PCI across the 30-day period, there was a significant reduction in the primary composite end point in eptifibatide patients (P=0.035). Eptifibatide reduced 30-day events in patients who had early PCI (11.6% versus 16.7%, P=0.01) and in patients who did not (14.6% versus 15.6%, P=0.23). After adjustment for PCI propensity, there was no evidence that eptifibatide treatment effect differed between patients with or without early PCI (P for interaction=0.634). PCI was not associated with a reduction of the primary composite end point but was associated with a reduced (nonspecified) composite of death or Q-wave MI. This association disappeared after adjustment for propensity for early PCI. CONCLUSIONS: Eptifibatide reduced the composite rates of death or MI in PCI patients and those managed conservatively.

Stroke in patients with acute coronary syndromes: incidence and outcomes in the platelet glycoprotein IIb/IIIa in unstable angina. Receptor suppression using integrilin therapy (PURSUIT) trial. The PURSUIT Investigators.

BACKGROUND: The incidence of stroke in patients with acute coronary syndromes has not been clearly defined because few trials in this patient population have been large enough to provide stable estimates of stroke rates. METHODS AND RESULTS: We studied the 10 948 patients with acute coronary syndromes without persistent ST-segment elevation who were randomly assigned to placebo or the platelet glycoprotein IIb/IIIa receptor inhibitor eptifibatide in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial to determine stroke rates, stroke types, clinical outcomes in patients with stroke, and independent baseline clinical predictors for nonhemorrhagic stroke. Stroke occurred in 79 (0.7%) patients, with 66 (0.6%) nonhemorrhagic, 6 intracranial hemorrhages, 3 cerebral infarctions with hemorrhagic conversion, and 4 of uncertain cause. There were no differences in stroke rates between patients who received placebo and those assigned high-dose eptifibatide (odds ratios and 95% confidence intervals 0.82 [0.59, 1.14] and 0.70 [0.49, 0.99], respectively). Of the 79 patients with stroke, 17 (22%) died within 30 days, and another 26 (32%) were disabled by hospital discharge or 30 days, whichever came first. Higher heart rate was the most important baseline clinical predictor of nonhemorrhagic stroke, followed by older age, prior anterior myocardial infarction, prior stroke or transient ischemic attack, and diabetes mellitus. These factors were used to develop a simple scoring nomogram that can predict the risk of nonhemorrhagic stroke. CONCLUSIONS: Stroke was an uncommon event in patients with acute coronary syndromes in the PURSUIT trial. These strokes are, however, associated with substantial morbidity and mortality rates. The majority of strokes were of nonhemorrhagic causes. Eptifibatide was not associated with an increase in intracranial hemorrhage, and no significant effect on nonhemorrhagic stroke was observed. We developed a useful nomogram for assigning baseline nonhemorrhagic stroke risk in this patient population.

Clinical significance of thrombocytopenia during a non-ST-elevation acute coronary syndrome. The platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression using integrilin therapy (PURSUIT) trial experience.

BACKGROUND: The significance of thrombocytopenia in patients experiencing an acute coronary syndrome (ACS) has not been examined systematically. We evaluated this condition in a large non-ST-elevation ACS clinical trial, with particular interest paid to its correlation with clinical outcomes. METHODS AND RESULTS: Patients presenting without persistent ST elevation during an ACS were randomized to receive a double-blind infusion of the platelet glycoprotein (GP) IIb/IIIa inhibitor eptifibatide or placebo in addition to other standard therapies including heparin and aspirin. The primary end point was death/nonfatal myocardial infarction (MI) at 30 days, whereas bleeding and stroke were the main safety outcomes. Thrombocytopenia (nadir platelet count <100x10(9)/L or <50% of baseline) occurred in 7.0% of enrolled patients. The time to onset was a median of 4 days in both treatment arms. Patients with thrombocytopenia were older, weighed less, were more likely nonwhite, and had more cardiac risk factors. These patients experienced significantly more bleeding events: they were more than twice as likely to experience moderate/severe bleeding after adjustment for confounders. Univariably, ischemic events (stroke, MI, and death) occurred significantly (P<0.001) more frequently in patients with thrombocytopenia; multivariable regression modeling preserved this association with death/nonfatal MI at 30 days. Neither the use of heparin or eptifibatide was found to independently increase thrombocytopenic risk. CONCLUSIONS: Although causality between thrombocytopenia and adverse clinical events could not be established definitively, thrombocytopenia was highly correlated with both bleeding and ischemic events, and the presence of this condition identified a more-at-risk patient population.

Platelet glycoprotein IIb/IIIa blockade and outcome of cardiogenic shock complicating acute coronary syndromes without persistent ST-segment elevation.

OBJECTIVES: The study examined whether antiplatelet treatment with eptifibatide affected the frequency and outcome of shock among patients in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial who had acute coronary syndromes but not persistent ST-segment elevation. BACKGROUND: Preliminary reports suggest a salutary effect of antiplatelet agents when shock complicates acute myocardial infarction. METHODS: We analyzed the impact of antiplatelet treatment with eptifibatide on the frequency and outcome of cardiogenic shock developing after enrollment. PURSUIT was a double-blind, randomized trial that examined the efficacy of eptifibatide (180 microg/kg bolus + continuous infusion of 2.0 microg/kg/min for < or =96 h) versus placebo among patients who had acute coronary syndromes but not persistent ST-segment elevation. RESULTS: Shock developed in 2.5% of the 9,449 patients at a median (25th, 75th interquartiles) of 94.0 (38, 206) h. Death by 30 days occurred in 65.8% of shock patients. Patients who had acute myocardial infarction upon enrollment had a greater incidence of shock (2.9% vs. 2.1%, p = 0.01), developed shock earlier (40.2% <48 h vs. 20.9%, p = 0.001), and had higher 30-day mortality from shock (77.2% vs. 52.7%, p = 0.001). Randomization to eptifibatide did not affect the occurrence of shock (p = 0.71, adjusted odds ratio [OR] = 0.95, 95% confidence interval [CI] = 0.72-1.25). However, shock patients treated with eptifibatide had significantly reduced adjusted odds of 30-day death (p = 0.03, adjusted OR = 0.51, 95% CI = 0.28-0.94). CONCLUSIONS: Patients with shock treated with eptifibatide had significantly reduced adjusted odds of death, suggesting a salutary effect of antiplatelet therapy on shock. This finding warrants verification in specifically designed studies.

Occurrence and clinical significance of pseudothrombocytopenia during abciximab therapy.

OBJECTIVES: This study determined the incidence of pseudothrombocytopenia during abciximab therapy administered for percutaneous coronary interventions and compared the clinical course of patients with pseudothrombocytopenia with the clinical courses of patients with thrombocytopenia and patients with normal platelet counts. BACKGROUND: Although pseudothrombocytopenia has been previously reported during therapy with abciximab, the incidence and significance of this occurrence are unknown. The failure to differentiate pseudothrombocytopenia from thrombocytopenia could lead to unnecessary interruption of abciximab infusions or to platelet transfusions. METHODS: The incidences of pseudothrombocytopenia and thrombocytopenia were determined in four large placebo-controlled abciximab trials: c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE), Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC), Evaluation of Percutaneous Transluminal Coronary Angioplasty to Improve Long-term Outcome of c7E3 GpIIb/IIIa Receptor Blockade (EPILOG) and Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT). The clinical features, bleeding complications and major clinical outcomes of patients with pseudothrombocytopenia and those with thrombocytopenia were compared with each other and with those of patients with normal platelet count. RESULTS: Pseudothrombocytopenia occurred in 2.1% (95% confidence intervals [CI]: 1.7%, 2.5%) of abciximab-treated patients and in 0.6% of placebo-treated patients (p < 0.001). Thrombocytopenia occurred in 3.7% (95% CI: 3.2%, 4.2%) of abciximab-treated patients and in 1.8% (95% CI: 1.3%, 2.3%) of placebo-treated patients (p < 0.001). Patients with thrombocytopenia had significantly higher rates of major bleeding, major decreases in hemoglobin and increased transfusion requirements of both blood and platelets compared with those without thrombocytopenia. By contrast, pseudothrombocytopenic patients did not differ from patients with normal platelet counts in any of the measures of blood loss or transfusion requirements. Thrombocytopenic patients, but not those with pseudothrombocytopenia, had increased rates of revascularization at 30 days and six months. As previously reported, there was also a higher rate of death and myocardial infarction in the thrombocytopenic patients. CONCLUSIONS: Pseudothrombocytopenia is the cause of more than one third (36.3%) of low platelet counts in patients undergoing coronary interventions who are treated with abciximab. This study demonstrates that pseudothrombocytopenia is a benign laboratory condition that does not increase bleeding, stroke, transfusion requirements or the need for repeat revascularization. It is important to recognize pseudothrombocytopenia so that the beneficial effects of abciximab are not lost by premature termination of therapy.

Percutaneous revascularization of chronic coronary occlusions: an overview.

Patients with a chronic coronary occlusion often undergo coronary angiography after weeks to months of occlusion. The published reports underestimate the extent of this problem because such patients are often arbitrarily assigned to receive medical therapy or undergo bypass surgery as a result of poor success with percutaneous revascularization and substantial restenosis. Thus, there is controversy about the role of angioplasty in this patient cohort. The goal of this overview was to evaluate the available information about angioplasty in chronic coronary occlusions. The primary indication for attempted recanalization of a chronic coronary occlusion has been symptomatic angina pectoris. Anginal status often improves after successful procedures (70% vs. 31% with a failed procedure); left ventricular function may improve; and subsequent referral for coronary artery bypass graft surgery is uncommon (3% vs. 28% in unsuccessful cases). Successful recanalization is achieved in approximately 65% of attempted procedures. Inability to cross the stenosis with a guide wire is the most common cause of procedural failure. Statistically significant predictors of procedural success include older occlusions (75% < 3 months old vs. 37% > or = 3 months old), absence of any anterograde flow through the occlusion (76% with vs. 58% without), angiographically abrupt-appearing occlusions (50% vs. 77% with tapered occlusions), presence of bridging collateral vessels (23% with vs. 71% without) and lesions > 15 mm. Procedural complications occur at a slightly lower incidence than in angioplasty of high grade subtotal stenoses. Long-term success is limited, and restenosis can be expected in > 50% of the patients. The experience with chronic total occlusions of saphenous vein bypass grafts is small, but there appear to be limited procedural success and significant procedural complications, particularly associated with distal emboli. The role of new pharmacologic agents has yet to be defined and that of new devices has been disappointing so far, but further technologic advances are on the horizon.