A. M. Lincoff

Complementary clinical benefits of coronary-artery stenting and blockade of platelet glycoprotein IIb/IIIa receptors

BACKGROUND Inhibition of the platelet glycoprotein IIb/IIIa receptor with the monoclonal-antibody fragment abciximab reduces the acute ischemic complications associated with percutaneous coronary revascularization, whereas coronary-stent implantation reduces restenosis. We conducted a trial to determine the efficacy of abciximab and stent implantation in improving long-term outcome. METHODS A total of 2399 patients were randomly assigned to stent implantation and placebo, stent implantation and abciximab, or balloon angioplasty and abciximab. The patients were followed for six months. RESULTS At six months, the incidence of the composite end point of death or myocardial infarction was 11.4 percent in the group that received a stent and placebo, as compared with 5.6 percent in the group that received a stent and abciximab (hazard ratio, 0.47; 95 percent confidence interval, 0.33 to 0.68; P<0.001) and 7.8 percent in the group assigned to balloon angioplasty and abciximab (hazard ratio, 0.67; 95 percent confidence interval, 0.49 to 0.92; P=0.01). The hazard ratio for stenting plus abciximab as compared with angioplasty plus abciximab was 0.70 (95 percent confidence interval, 0.48 to 1.04; P=0.07). The rate of repeated revascularization of the target vessel was 10.6 percent in the stent-plus-placebo group, as compared with 8.7 percent in the stent-plus-abciximab group (hazard ratio, 0.82; 95 percent confidence interval, 0.59 to 1.13; P=0.22) and 15.4 percent in the angioplasty-plus-abciximab group (hazard ratio, 1.49; 95 percent confidence interval, 1.13 to 1.97; P=0.005). The hazard ratio for stenting plus abciximab as compared with angioplasty plus abciximab was 0.55 (95 percent confidence interval, 0.41 to 0.74; P<0.001). Among patients with diabetes, the combination of abciximab and stenting was associated with a lower rate of repeated target-vessel revascularization (8.1 percent) than was stenting and placebo (16.6 percent, P=0.02) or angioplasty and abciximab (18.4 percent, P=0.008). CONCLUSIONS For coronary revascularization, abciximab and stent implantation confer complementary long-term clinical benefits.

Illusion of reperfusion. Does anyone achieve optimal reperfusion during acute myocardial infarction

Thrombolytic therapy significantly improves the natural history of acute myocardial infarction, but recent data suggest that current reperfusion strategies have yet to realize the maximum potential for reduction of mortality and salvage of ventricular function. Coronary patency rates as high as 85% assessed by angiography 90 minutes after initiation of treatment greatly overestimate the efficacy of thrombolytic regimens, as this conventional angiographic “snapshot” view does not satisfactorily reflect the dynamic processes of coronary artery recanalization and reocclusion or the adequacy of myocardial perfusion. In fact, only the unusual patient appears to achieve optimal reperfusion for acute myocardial infarction, with a substantial deterioration of benefit in many patients due to insufficiently early or rapid recanalization, incomplete patency with TEIM grade 2 flow or critical residual coronary stenoses, absence of myocardial tissue reflow despite epicardial artery patency, intermittent coronary patency, subsequent reocclusion, or reperfusion injury. Recently developed techniques to critically assess the quality of reperfusion, coupled with the introduction of novel pharmacological agents and an improved understanding of the roles and mechanisms of existing thrombolytic and adjunctive drugs, have provided the opportunity to overcome many of the present limitations of reperfusion therapy. Emerging strategies to achieve optimal reperfusion are directed at enhancement of the velocity and quality of thrombolysis, amelioration of the adverse effects of reperfusion, and use of alternative pathways to myocardial salvage.

Influence of Blockade at Specific Levels of the Coagulation Cascade on Restenosis in a Rabbit Atherosclerotic Femoral Artery Injury Model

BACKGROUND The relation among the coagulation cascade, its individual proteins, and the response to vascular injury is largely undefined. We have evaluated the effect of four probes that block specific levels of coagulation cascade on neointimal hyperplasia in the atherosclerotic rabbit arterial injury model. METHODS AND RESULTS Focal femoral atherosclerosis was induced by air-desiccation injury and hypercholesterolemic diet in 48 New Zealand White rabbits, followed by balloon angioplasty. Active-site inactivated factor VIIa (DEGR-VIIa), which blocks the binding of factor VIIa to tissue factor, was administered (n = 12 arteries) by intravenous bolus (1 mg/kg) at the time of balloon angioplasty and followed by infusion of 50 micrograms.kg-1.h-1 for 3 days; for the control (n = 13 arteries), 150 U heparin was injected as bolus and followed by infusion of saline at 50 microL.kg-1.min-1. Recombinant tissue factor pathway inhibitor (TFPI), which binds factor Xa and inhibits the tissue factor-factor VIIa complex and factor Xa, was given as a 1 mg/kg bolus followed by 15 micrograms.kg-1.min-1 infusion for 3 days (n = 17 arteries). Recombinant tick anticoagulant peptide (TAP; n = 15 arteries) and hirudin (n = 14 arteries), which block factor Xa and thrombin, respectively, were administered as a 1 mg/kg bolus followed by 5 micrograms.kg-1.min-1 infusion for 3 days. These three groups had their own controls (n = 14 arteries). There were no differences among treatment groups in preangioplasty and postangioplasty minimal luminal diameter (MLD) by angiography. The mean MLD 21 days after balloon angioplasty was significantly different between control and DEGR-VIIa-treated groups (0.74 +/- 0.25 and 1.24 +/- 0.27 mm, respectively; P = .0001) and between the TFPI-treated group and others (0.88 +/- 0.21 mm for control, 0.97 +/- 0.22 mm for hirudin-treated, 0.98 +/- 0.14 mm for TAP-treated, and 1.32 +/- 0.21 mm for TFPI-treated arteries; P = .0001 by ANOVA). By quantitative histological analysis, the ratio of neointimal cross-sectional area compared with the area of internal elastic lamina in the DEGR-VIIa-treated group was significantly less than control (0.48 +/- 0.12 versus 0.67 +/- 0.12, P = .0001), and the ratio of neointimal cross-sectional area to the area demarcated by the internal elastic lamina of the TFPI-treated group was significantly reduced compared with the other groups (0.46 +/- 0.20 for TFPI-treated, 0.67 +/- 0.15 for hirudin-treated, 0.61 +/- 0.15 for TAP-treated, and 0.64 +/- 0.13 for control groups; P = .003). CONCLUSIONS Treatment with DEGR-VIIa or TFPI for 3 days in this rabbit atherosclerotic injury model reduced angiographic restenosis and decreased neointimal hyperplasia compared with controls. These findings highlight the importance of early initiators of the extrinsic coagulation pathway, especially factor VII and tissue factor, in the response to arterial injury.

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

Background: Raised inflammatory markers are associated with worse outcome after percutaneous coronary interventions (PCI). An increase in the white blood cell (WBC) count is a non-specific response to inflammation. We hypothesised that a raised baseline WBC count would be a predictor of mortality in patients undergoing PCI. Methods: The association between preprocedural WBC count and long term mortality was studied in 7179 patients enrolled in the EPIC, EPILOG, and EPISTENT trials. The end points were the incidence of myocardial infarction at one year, and one and three year mortality. Results: There were 188 deaths and 582 myocardial infarctions at one year. While WBC count was a strong predictor of death at one year, with every increase of 1 k/μl (1×106/l) being associated with a hazard ratio (HR) of 1.109 (95% confidence interval (CI) 1.072 to 1.147, p < 0.001), there was no association with myocardial infarction at one year (HR 1.020, 95% CI 0.990 to 1.052, p = 0.195). There were a total of 406 deaths at three years with a strong association between WBC count and three year mortality (HR for every 1 k/μl increase 1.089, 95% CI 1.058 to 1.121, p < 0.001). WBC count remained a significant predictor of mortality after multivariable adjustment (HR for every 1 k/μl increase 1.100, 95% CI 1.069 to 1.131, p < 0.001). The association was significant across multiple subgroups, including diabetes, female sex, clinical presentation, and cigarette smoking. Conclusion: A raised pre-procedural WBC count in patients undergoing PCI is associated with an increased risk of long term death. These results suggest a key role for inflammation in coronary artery disease.

Clinical end point definitions after percutaneous coronary intervention and their relationship to late mortality: an assessment by attributable risk

Objectives: To explore the relative and absolute risks associated with various definitions for myocardial infarction, bleeding and revascularisation within the context of percutaneous coronary intervention (PCI). Methods: The REPLACE-2 (randomised evaluation of PCI linking Angiomax to reduced clinical events) database of patients undergoing PCI was used. Various definitions of myocardial infarction, bleeding and revascularisation were modelled by logistic regression assessing their relationship with 12-month mortality. Estimates from these models were used to calculate the “attributable fraction” for late mortality associated with each definition. Results: The most liberal definition of myocardial infarction was associated with an attributable risk of 13.7% (95% CI 3.4% to 23.0%). The most stringent definition was associated with an attributable risk of 4.6% (95% CI 0.6% to 8.6%). Restrictive definitions of bleeding such as TIMI (thrombolysis in myocardial infarction) major bleeding are associated with a high odds ratio of risk (6.1, 95% CI 2.1 to 17.7, p  =  0.001) but low attributable fraction (3.5%, 95% CI 0.9% to 6.8%). Conclusions: Stringent end point definitions may under-represent the clinical significance of adverse outcomes after PCI. Considering both the proportional and absolute risk associated with definitions may be a more useful method for evaluating clinical trial end points. This analysis supports the current definitions of ischaemic events but suggests that more liberal definitions of bleeding events may also be relevant to late mortality.

LONG-TERM MORTALITY FOLLOWING PERIOPERATIVE MYOCARDIAL INJURY IS INDEPENDENT OF MECHANISM OF TROPONIN ELEVATION

Perioperative myocardial injury detected by cardiac troponin T (cTnT) is associated with increased mortality. The mechanisms underlying perioperative cTnT elevation have however not been well described. Whether long-term mortality differs by mechanism is unknown. All patients who underwent

GENDER SPECIFIC FACTORS ASSOCIATED WITH MAJOR ADVERSE CARDIOVASCULAR EVENTS: INSIGHTS FROM ACCELERATE

It remains unknown whether the factors associated with major adverse cardiovascular events (MACE) in the contemporary setting of statin therapy for high vascular risk patients differ, according to gender. The ACCELERATE trial compared the effects of evacetrapib and placebo on MACE (cardiovascular

IMPACT OF MAJOR BLEEDING AS DEFINED BY NATIONAL CARDIOVASCULAR DATA REGISTRY ACROSS DIFFERENT BASELINE HEMOGLOBIN LEVELS IN PATIENTS UNDERGOING ELECTIVE PERCUTANEOUS CORONARY INTERVENTION

The National Cardiovascular Data Registry defines major bleeding after percutaneous coronary intervention (PCI) as an absolute drop of hemoglobin (Hb) ≥3 g/dL. We sought to study impact of this across different baseline Hb levels. 2238 patients who underwent elective PCI in our center from 2011-

Mortality at 1 year with combination platelet glycoprotein IIb/IIIa inhibition and reduced-dose fibrinolytic therapy vs. conventional fibrinolytic therapy for acute myocardial infarction. GUSTO V randomized trial

CONTEXT Among patients with acute myocardial infarction, combination reperfusion therapy with a platelet glycoprotein IIb/IIIa receptor inhibitor (abciximab) and a half dose of a plasminogen activator (reteplase) did not significantly reduce mortality at 30 days compared with a full dose of reteplase. Rates of nonfatal ischemic complications were significantly diminished. OBJECTIVE To determine if the beneficial effects of abciximab and reteplase (combination therapy) on early nonfatal complications would translate into a reduction in the risk of death by 1 year. DESIGN, SETTING, AND PATIENTS One-year follow-up of a randomized controlled trial (Global Use of Strategies To Open Coronary Arteries [GUSTO] V). Of 16 588 patients who had been treated in 820 community and referral hospitals in 20 countries between July 1999 and February 2001, mortality data were available for 16 453 (99.2%). INTERVENTION Patients were randomly assigned to receive (intravenously) a standard dose of reteplase (two 10-U boluses, 30 minutes apart) or the combination of a standard dose of abciximab (0.25 mg/kg bolus, 0.125 microg/kg per minute infusion [maximum 10 micro g/min for 12 hours]) and a half dose of reteplase (two 5-U boluses, 30 minutes apart). MAIN OUTCOME MEASURE One-year all-cause mortality rates. RESULTS All-cause mortality at 1 year occurred in 692 (8.38%) of 8260 patients in the reteplase group and 698 (8.38%) of the 8328 patients in the combination therapy group (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.90-1.11; P>.99). Reinfarction within the first 7 days occurred in 3.5% of patients in the reteplase group and 2.3% of patients in the combination therapy group, and was significantly associated with 1-year mortality (22.6% in patients with reinfarction vs 8.0% in patients without reinfarction; HR, 3.08; 95% CI, 2.53-3.75; P<.001). However, treatment assignment did not significantly influence time of mortality regardless of reinfarction status. CONCLUSION Combination therapy (abciximab and reteplase) did not reduce mortality over 1 year compared with fibrinolytic therapy with reteplase alone.