Atul Aggarwal

Suboptimal early inhibition of platelets by treatment with Tirofiban and implications for coronary interventions

Inhibition of aggregation of platelets from 15 to 60 minutes after onset of treatment with tirofiban is less than that after onset of treatment with abciximab. The suboptimal inhibition occurs during a critical interval, immediately after iatrogenic vessel injury. Further, the suboptimal inhibition is likely to be responsible, at least in part, for the greater incidence of periprocedural myocardial infarction seen in the TARGET trial after treatment with tirofiban compared with abciximab. The difference observed is a reflection of the intrinsic pharmacologic characteristics of the 2 agents. Altering pharmacodynamics by dosage adjustment leading to higher concentrations in blood of tirofiban during the first hour after treatment onset requires further study.

Increased concentrations of tirofiban in blood and their correlation with inhibition of platelet aggregation after greater bolus doses of tirofiban

P in the do Tirofiban And Reopro Give similar Efficacy outcomes Trial (TARGET) treated with abciximab compared with tirofiban had a lower 30-day incidence of the combined end point of death, myocardial infarction, and target vessel revascularization that reflected, in large part, a decrease in the incidence of periprocedural myocardial infarction.1 We have found that the extent of platelet aggregation inhibition was greater from 15 to 60 minutes after abciximab than that after the TARGET study dosage of tirofiban (10 g/kg bolus, followed by a 0.15 g/ kg/min infusion).2–4 To identify a bolus associated with maximal inhibition of platelet aggregation, we used flow cytometry to characterize the inhibitory effects of tirofiban in blood from patients with acute coronary syndromes. In subsequent studies, the average extent of inhibition of turbidometric aggregation in response to 20 M of adenosine diphosphate (ADP) was found to be 90% during the first hour when a bolus of 25 g/kg was combined with the same infusion (0.15 g/kg/min for 18 to 24 hours) employed in the TARGET study.5 In this report, we describe the concentrations of tirofiban in blood and their correlation with the inhibition of turbidometric aggregation in response to 20 M of ADP. • • • Protocols were approved by the institutional review boards of the participating institutions. All patients provided written informed consent. Eligible patients included those with an acute coronary syndrome (ischemic symptoms plus either 0.5 mm of ST-segment depression on electrocardiogram or increased troponin or creatine kinase-MB) in whom a percutaneous coronary intervention was clinically mandated and performed. Exclusion criteria included treatment with antiplatelet agents other than aspirin in the previous 14 days, thrombolytic therapy within 24 hours, renal insufficiency (creatinine 2.5 mg/dl), and contraindication to treatment with a glycoprotein IIb/IIIa inhibitor. To perform in vitro studies, blood was obtained from patients with acute coronary syndromes before coronary intervention or treatment with an antiplatelet agent other than aspirin. After anticoagulation with corn trypsin inhibitor, a specific inhibitor of coagulation factor XIIa,6 the blood was spiked with 0, 50, 100, or 150 ng/ml of tirofiban. After incubation for 15 minutes at room temperature, the capacity to bind fibrinogen in response to 1 M of ADP was determined with the use of flow cytometry. The concentration of tirofiban in blood and its associated inhibition of platelet function were assessed in a preliminary study in which patients were treated with a 10 g/kg bolus2 and in a subsequent study in which patients were treated in a sequential, open-label, nonrandomized fashion with a 20 or 25 g/kg bolus.5 Tirofiban was administered before the start of the coronary intervention, and each bolus was combined with an 18to 24-hour infusion of 0.15 g/kg/min. Patients were treated with aspirin (325 mg before the procedure and daily) and unfractionated heparin (target activated clotting time 250 seconds). Clopidogrel (300 mg initially and then 75 mg daily) was begun after the coronary intervention ( 1 hour). The concentration of tirofiban was determined by radioimmunoassay after 5, 15, 30, 45, 60, 120, and 360 minutes.7 Platelet function was assessed by light transmission aggregometry (Bio Data Corp., Helena Laboratories, Horsham, Pennsylvania), and flow cytometry before treatment and after 15, 30, 45, 60, and 120 minutes, and an additional assessment was made after 5 minutes with flow cytometry. Blood for aggregometry was anticoagulated with D-Phe-Pro-Argchloromethyl ketone (PPACK, 38 M) to avoid effects of citrate on inhibitory properties of tirofiban.8 Blood for flow cytometry was anticoagulated with corn trypsin inhibitor. Maximal turbidometric ex vivo aggregation after 4 minutes was assessed in plateletrich plasma in response to 20 M of ADP (Chronolog, Havertown, Pennsylvania). Assessment of the capacity of platelets to bind fibrinogen was performed as previously described in detail.9 Assay and fixation were performed at each site for flow cytometry. Samples were analyzed at the University of Vermont within 30 hours. As previously described,5 the primary objective was to identify a bolus dose of tirofiban that achieved a mean inhibition of platelet aggregation of 90% plus a lower bound of the 95% confidence interval of inhibition of 85% from 15 to 45 minutes after onset of treatment. The slope of the association between selected concentrations of tirofiban and the extent of From the University of Vermont, Burlington, Vermont; University of Pennsylvania Medical Center, Philadelphia, Pennsylvania; Baylor College of Medicine, Houston, Texas; Prairie Cardiovascular, Springfield, Illinois; and Merck & Company, Inc., West Point, Pennsylvania. This report was supported by Merck & Company, Inc., West Point, Pennsylvania. Dr. Schneider’s address is: University of Vermont, 208 South Park Drive, Suite 2, Colchester, Vermont 05446. E-mail: djschnei@zoo.uvm.edu. Manuscript received August 7, 2002; revised manuscript received and accepted September 24, 2002.

Incidence and Predictors of Stroke Associated With Percutaneous Coronary Intervention

Stroke is a serious complication of percutaneous coronary intervention (PCI). Clinical characteristics associated with this complication have not been well defined. Data were analyzed from the National Cardiovascular Data Registry. All patients undergoing PCI from January 1, 2004, to March 30, 2007, were included in the analysis (n = 706,782). Stroke is defined in the National Cardiovascular Data Registry as a central neurologic deficit persisting >72 hours with onset starting anytime in the cardiac catheterization laboratory until the time of hospital discharge. Periprocedural stroke developed in 0.22% of patients (n = 1,540). Patients who developed a stroke had a greater prevalence of concomitant medical illnesses and were more likely to present with an acute coronary syndrome. Patients with a stroke had a greater percentage of high-risk coronary lesions and worse PCI angiographic results. In multivariable analysis, known cerebrovascular disease, older age, acute coronary syndromes (unstable angina, ST- and non-ST-elevation myocardial infarction), and use of an intra-aortic balloon pump were factors most strongly associated with stroke. In-hospital mortality was 30% for patients who developed a stroke compared with 1% for those without stroke. In conclusion, stroke developing in association with PCI is rare but a devastating complication. Older patients and those with known cerebrovascular disease and acute coronary syndromes appear to be at the highest risk of stroke. The strong association of in-hospital stroke after PCI with acute coronary syndromes is noteworthy.

Clinical characteristics and in-hospital outcome of patients with end-stage renal disease on dialysis referred for implantable cardioverter-defibrillator implantation

BACKGROUND Little is known about the clinical profile of end-stage renal disease (ESRD) patients who undergo implantable cardioverter-defibrillator (ICD) implantation. OBJECTIVE This study sought to analyze the risk profile of ESRD patients admitted for ICD implantation. METHODS Patients undergoing first-time device implantation in National Cardiovascular Data Registry/ICD registry from 01/01/06 to 12/31/07 were analyzed (n = 164,069). Patients with ESRD (defined as those requiring dialysis) were compared with patients without ESRD. Primary outcome was in-hospital complications. Because length of hospital stay for ERSD patients was significantly longer (8 vs. 4 days), complications within 2 days of ICD implantation were also examined. The proportion of patients meeting approved indications for ICD implantation was evaluated. RESULTS ESRD patients (n = 6,851, 4.4%) had higher rates of comorbid medical conditions, major complications, and total complications, and were less likely to receive an ICD for primary prevention. ESRD patients who received ICD implantation for primary prevention were more likely to meet trial criteria. ESRD patients were less likely to receive beta-blockers and angiotensin inhibitors (P <.0001). Unadjusted in-hospital mortality was almost 5-fold among patients with ESRD (1.9% vs. 0.4%, P <.0001). Multivariable analysis confirmed that ESRD was independently associated with total in-hospital complications (odds ratio [OR] = 1.38, 95% confidence interval: 1.23 to 1.54, P <.0001), and total complications at 2 days (OR = 1.20, 95% confidence interval: 1.05 to 1.36, P = .006). CONCLUSION ESRD patients presenting for ICD implantation are sicker, and have higher rates of in-hospital complications even when accounting for overall longer length of hospital stay. Strategies to decrease complications among ESRD patients who undergo ICD implantation need exploration.

Comparison of inflammatory markers in patients with diabetes mellitus versus those without before and after coronary arterial stenting

Patients with diabetes are at increased risk for adverse events after coronary stenting, perhaps reflecting a pro-inflammatory state. To characterize the inflammatory response to coronary stenting in patients with and without diabetes, blood samples were obtained from 75 patients before stenting and 10 minutes, 1 hour, and 24 hours later. C-reactive protein (CRP, microg/ml), interleukin (IL)-6 (pg/ml), IL-1 receptor antagonist (pg/ml), and soluble CD40 ligand (ng/ml) were assayed in each sample by enzyme-linked immunosorbent assay. Concentration changes after stenting were identified by repeated-measures analysis of variance. Multivariate analysis was performed to delineate independent predictors of increased concentrations of inflammation markers. Overall, 88% of patients had acute coronary syndromes; 36% had elevated markers of cardiac injury. The preprocedural concentrations of CRP in those with diabetes were more than twice as high as those in patients without diabetes. Two independent predictors of elevated preprocedural CRP concentrations were diabetes (odds ratio 3.95, 95% confidence interval 1.17 to 13.4) and a cardiac marker-positive acute coronary syndrome (odds ratio 3.70, 95% confidence interval 1.22 to 11.2). Preprocedural concentrations of IL-6, IL-1 receptor antagonist, and soluble CD40 ligand tended to be greater in patients with diabetes. The increase in CRP after stenting was much greater for patients without diabetes compared with that in patients with diabetes such that the apparent intensity of inflammation after 24 hours was similar in those with and without diabetes. Thus, patients with and without diabetes exhibit different inflammatory responses to stenting, reflecting the lower preprocedural inflammation in those without diabetes versus those with diabetes.

Soluble CD40 ligand is an early initiator of inflammation after coronary intervention.

BackgroundThis prospective study evaluated the early increase in markers of inflammation after coronary stenting, and the predictors of early rise. Elevation of markers of inflammation after percutaneous coronary intervention correlates with an increased risk of adverse events. The role of soluble CD40 ligand (sCD40L) as a potential initiator of inflammation after stenting has not been described. MethodsSeventy-five patients were treated with heparin alone (n=25), or randomized to adjuvant treatment with eptifibatide (n=26) or abciximab (n=24) during stenting. Systemic blood was obtained before coronary stenting and at 10 min after stenting. C-reactive protein (CRP), interleukin (IL)-6, IL-1 receptor antagonist and sCD40L were determined by enzyme liberated immunosorbent assay. ResultssCD40L exhibited the greatest relative rise (35%, P=0.01 compared to concentrations before intervention) in the first 10 min after stenting. In a logistic regression model, an early increase in the concentration of sCD40L was predicted by baseline laboratory values (white blood count and sCD40L level before stenting) and procedural characteristics (number of stents and glycoprotein IIb-IIIa inhibitor assignment). ConclusionsIn conclusion, a systemic inflammatory response is detectable 10 min after coronary stent placement. The early increase in sCD40L suggests a possible role for this marker in the initiation of inflammation after coronary stenting.

Decreased platelet reactivity in blood anticoagulated with bivalirudin or enoxaparin compared with unfractionated heparin: implications for coronary intervention.

AbstractBackground: Platelet reactivity predicts complications after percutaneous coronary intervention (PCI). Accordingly, agents that suppress platelet reactivity should decrease adverse events after PCI. This study was designed to determine the effects of therapeutic concentrations of unfractionated heparin (UFH), bivalirudin, or enoxaparin alone or in combination with tirofiban on platelet reactivity. Methods: Blood taken from 13 patients with coronary artery disease was exposed to each anticoagulant alone or in combination with tirofiban ex vivo. Platelet reactivity was characterized with flow cytometry to quantify the percentage of platelets capable of binding fibrinogen (activation of glycoprotein IIb-IIIa) and expressing P-selectin in response to adenosine diphosphate (ADP, 0, 0.2, and 1 μM). Results: Platelet reactivity was greater in blood treated with UFH than in blood anticoagulated with bivalirudin with respect to both the capacity to bind fibrinogen (by 4 ± 1.8%, p = 0.01) and P-selectin expression (by 7.7 ± 0.7%, p, < 0.0001) in response to 1 μM ADP. Platelet reactivity was greater in blood treated with UFH than in blood exposed to enoxaparin with respect to P-selectin expression (by 7 ± 1.1%, p, < 0.0001) in response to 1 μM ADP. Platelet reactivity was similar in blood treated with bivalirudin or enoxaparin. Addition of tirofiban suppressed the capacity to bind fibrinogen in the presence of each anticoagulant to a similar extent. Conclusions: As platelet reactivity is greater in blood anticoagulated with UFH in comparison with blood anticoagulated with enoxaparin or bivalirudin, the use of bivalirudin or enoxaparin rather than UFH during PCI should contribute to a reduced incidence of adverse cardiac events after PCI. Abbreviated Abstract. Increased platelet reactivity presages complications after percutaneous coronary intervention (PCI). To assess effects of anticoagulants on platelet reactivity, blood was taken from 13 patients with coronary artery disease and exposed to unfractionated heparin (UFH), bivalirudin, or enoxaparin alone or in combination with tirofiban. Flow cytometry was used to quantify platelet activation. Platelet reactivity was greater in blood anticoagulated with UFH than in blood anticoagulated with bivalirudin or enoxaparin. Antiplatelet effects of tirofiban were similar with bivalirudin or enoxaparin. Lower platelet reactivity seen in blood anticoagulated with bivalirudin or enoxaparin should contribute to a reduced incidence of cardiac events after PCI.

Increase in Interleukin-6 in the First Hour after Coronary Stenting: An Early Marker of the Inflammatory Response

AbstractBackground: Inflammation after coronary stenting presages adverse outcomes after percutaneous coronary intervention (PCI). While changes in inflammatory markers have been defined 24–72 hours after PCI, potential changes during the first few hours have not. This study was designed to determine if a systemic inflammatory response could be measured within the first hour after stenting. Methods: Patients (n = 25) undergoing coronary stenting, with predominantly (n = 23) acute coronary syndromes were enrolled prospectively in this registry. Blood samples were collected before PCI, and 10 minutes, 1 hour and 18–24 hours later. No patient received a glycoprotein IIb-IIIa inhibitor. Concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), and interleukin-1 receptor antagonist (IL-1Ra) and soluble CD40 ligand (sCD40L) were measured using ELISA. Results: CRP and sCD40L did not change in the first hour after stenting. By contrast, IL-6 increased in the first hour (before = 7.6 ± 7.7 pg/ml, 1 hour = 12 ± 12 pg/ml; p < 0.001). The concentration of IL-1Ra tended to be greater after 1 hour (before = 426 ± 261 pg/ml, 1 hour = 511 ± 406 pg/ml; p = 0.11). Increase in IL-1Ra was apparent only in female subjects (p = 0.004 for the difference in trend between the two genders). A correlation was not observed between the increase in IL-6 at 1 hour and the increase in CRP at 24 hours (r = −0.21). Conclusions: In patients undergoing coronary stenting, increase in IL-6 can be detected 1 hour after PCI, and thus IL-6 may be an early initiator of the systemic inflammatory response to stenting.

EXERCISE REHABILITATION OF OLDER PATIENTS WITH CARDIOVASCULAR DISEASE

As the population of elderly patients with cardiovascular disease continues to increase, much research needs to be done with the goal of maintaining physical functioning and personal independence in this population. It is of particular importance to determine whether training programs can improve physical functioning in the most severely disabled older coronary patients. Effects of cardiac rehabilitation programs on other outcome measures, including psychosocial outcomes, lipid levels, insulin levels, and body composition require better study. Finally, the economic benefits of cardiac rehabilitation in the older coronary patients has received little attention, although early reports are promising. In summary, the older population with coronary disease is characterized by high rates of disability. Exercise training has been demonstrated to be safe and to improve strength, aerobic fitness capacity, endurance and physical function. It remains to be seen whether exercise training can reverse or prevent disability in a broad population of older patients with cardiovascular disease. If successful, cardiac rehabilitation programs will pay great medical, social, and economic dividends in this population.

Comparison of effects of abciximab versus eptifibatide on C-reactive protein, interleukin-6, and interleukin-1 receptor antagonist after coronary arterial stenting

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