Trends in use of anti-thrombotic agents and outcomes in patients with non-ST-segment elevation myocardial infarction (NSTEMI) managed with an invasive strategy.

OBJECTIVE: To analyze trends in utilization of anti-thrombotic agents (ATA) and in-hospital clinical outcomes in non-ST-elevation myocardial infarction (NSTEMI) patients managed with an invasive strategy from 2007 to 2010. METHODS & RESULTS: Using ACTION Registry(®)-GWTG™ data, we analyzed trends in use of ATA and in-hospital clinical outcomes among 64,199 NSTEMI patients managed invasively between 2007 and 2010. ATA included unfractionated heparin (UFH), low molecular weight heparin (LMWH), glycoprotein IIb/IIIa inhibitors (GPI) and bivalirudin. Although the proportion of NSTEMI patients treated with PCI within 48h of hospital arrival was similar in 2007 and 2010, percentage use of bivalirudin (13.4-27.3%; p<0.01) and UFH increased (60.0-67.5%, p<0.01), and that of GPI (62.3-41.0%; p<0.01) and LMWH (41.5-36.8%; p<0.01) declined. Excess dosing of UFH (75.9-59.3%, p<0.01), LMWH (9.6-5.2%; p<0.01) and GPI (8.9-5.9%, p<0.01) was also significantly lower in 2010 compared with 2007. Though in-hospital mortality rates were similar in 2007 and 2010 (2.3-1.9%, p=0.08), the rates of in-hospital major bleeding (8.7-6.6%, p<0.01) and non-CABG related RBC transfusion (6.3-4.6%, p<0.01) were significantly lower in 2010 compared with 2007. CONCLUSION: Compared with 2007, patients with NSTEMI, who were managed invasively in 2010 received GPI and LMWH less often and bivalirudin and UFH more frequently. There were sizeable reductions in the rates of excess dosing of UFH (though still occurred in 67% of patients), GPI and LMWH. In-hospital major bleeding complications and post-procedural RBC transfusion were lower in 2010 compared with 2007.

Creatine kinase-MB elevation after percutaneous coronary intervention predicts adverse outcomes in patients with acute coronary syndromes.

AIM: To study the relationship between outcomes and peak creatine kinase (CK)-MB levels after percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). METHODS AND RESULTS: Peak CK-MB ratios (peak CK-MB level/upper limit of normal [ULN]) after PCI were analysed in 6164 patients with NSTE ACS from four randomized trials who underwent in-hospital PCI. We excluded 696 patients with elevated CK or CK-MB levels <24h before PCI; the primary analysis included 2384 of the remaining 5468 patients (43.6%) with CK-MB levels measured <==24h after PCI. The incidence of in-hospital heart failure (0.1%, 0.8%, 3.4%, 4.1%, and 6.1%; P<0.001), arrhythmias (0.8%, 1.9%, 6.9%, 4.1%, and 7.9%; P<0.001), cardiogenic shock (0.1%, 1.3%, 2.0%, 2.3%, and 2.6%; P=0.004), and mortality through 6 months (2.1%, 2.4%, 4.9%, 4.1%, and 5.7%, P=0.005) was increased with peak CK-MB ratios of 0-1, 1-3, 3-5, 5-10, and >10xULN, respectively. The continuous peak CK-MB ratio after PCI significantly predicted adjusted 6-month mortality (risk ratio, 1.06 per unit increase above ULN; 95% confidence interval, 1.01-1.11; P=0.017). CONCLUSIONS: Greater CK-MB elevation after PCI is independently associated with adverse outcomes in NSTE ACS. These results underscore the adverse implications of elevated CK-MB levels after PCI in this high-risk population.

Monitoring and identifying antibiotic resistance mechanisms in bacteria.

Sub-therapeutic administration of antibiotics to animals is under intense scrutiny because they contribute to the dissemination of antibiotic-resistant bacteria into the food chain. Studies suggest that there is a link between the agricultural use of antibiotics and antibiotic-resistant human infections. Antibiotic-resistant organisms from animal and human wastes reenter the human and animal populations through a number of pathways including natural waters, irrigation water, drinking water, and vegetables and foods. Antibiotic usage in the United States for animal production (disease prevention and growth promotion) is estimated to be 18 million pounds annually. As much as 25 to 75% of the antibiotics administered to feedlot animals are excreted unaltered in feces. Because about 180 million dry tons of livestock and poultry waste is generated annually in the United States, it is not surprising that animal-derived antibiotic-resistant organisms are found contaminating groundwater, surface water, and food crops. It is extremely important to clearly understand the molecular mechanisms that could potentially cause lateral or horizontal gene transfer of antibiotic resistance genes among bacteria. Once the mechanisms and magnitude of resistance gene transfer are clearly understood and quantified, strategies can be instituted to reduce the potential for dissemination of these genes.

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

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

Clinical outcome of a cohort of patients eligible for therapeutic angiogenesis or transmyocardial revascularization.

BACKGROUND: Newer methods of coronary revascularization are being investigated in patients who are not candidates for coronary artery bypass grafting or percutaneous intervention. Our objective was to determine the proportion of patients eligible for newer methods of revascularization and determine their 1-year clinical outcome. METHODS: Five hundred consecutive charts and angiograms from patients undergoing diagnostic angiography for coronary artery disease from January to May of 1998 were reviewed to assess the suitability for revascularization. Patients ineligible for conventional revascularization were followed up for 1 year. RESULTS: Fifty-nine patients of the 500 studied were identified who had refractory ischemia but were not candidates for traditional revascularization. The 59 patients ineligible for traditional methods of revascularization had a rehospitalization rate of 128% (76 total hospitalizations), a 25.5% rate of myocardial infarction (15 of 59), and a mortality rate of 16.9% (10 of 59). CONCLUSIONS: The prognosis of many patients eligible for newer methods of revascularization on maximal medical therapy is poor.

Effect of lipid-lowering therapy on early mortality after acute coronary syndromes: an observational study.

BACKGROUND: Lipid-lowering agents are known to reduce long-term mortality in patients with stable coronary disease or significant risk factors. However, the effect of lipid-lowering therapy on short-term mortality immediately after an acute coronary syndrome has not been determined. We did an observational study using data from two randomised trials to investigate this issue. METHODS: We used data from the GUSTO IIb and PURSUIT trials to compare all-cause mortality among patients with acute coronary syndromes who were discharged on lipid-lowering agents (n=3653) with those who were not (n=17,156). A propensity analysis was done to adjust for presumed selection biases in the prescription of lipid-lowering agents. FINDINGS: Lipid-lowering therapy was associated with a smaller proportion of deaths at 30 days (17 [0.5%] vs 179 [1.0%], hazard ratio 0.44 [95% CI 0.27-0.73], p=0.001) and at 6 months (63 [1.7%] vs 605 [3.5%], 0.48 [0.37-0.63], p<0.0001). After adjustment for the propensity to be prescribed lipid-lowering agents and other potential confounders, prescription of a lipid-lowering agent at discharge remained associated with a reduced risk of death at 6 months (0.67 [0.48-0.95], p=0.023). INTERPRETATION: Prescription of a lipid-lowering drug at hospital discharge was independently associated with reduced short-term mortality among patients after an acute coronary syndrome.

Prognostic importance of concomitant heparin with eptifibatide in acute coronary syndromes. PURSUIT Investigators. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy.

Platelet glycoprotein IIb/IIIa inhibitors have been extensively studied in the treatment of patients with ischemic heart disease. Data regarding the use of these agents in the absence of concomitant intravenous heparin have been conflicting. We sought to determine, using propensity analysis, whether the benefit of eptifibatide, a IIb/IIIa inhibitor, in the treatment of acute coronary syndromes is affected by the concurrent administration of heparin. By trial design, patients were randomized to either eptifibatide or placebo, whereas use of intravenous heparin was left to the discretion of treating physicians. The effect of eptifibatide on the 30-day composite end point of death or myocardial infarction was studied in patients who received heparin and those who did not. Propensity analysis methods were used to control for confounding and presumed selection biases. Among 5,576 patients who were receiving heparin when the bolus dose of the study drug was administered, eptifibatide was associated with a reduced composite end point rate (13%) compared with that of placebo (14.5% vs 16.6%, p = 0.03). In contrast, among 1,441 patients who were not receiving heparin, there was no difference in 30-day event rates with eptifibatide compared with placebo (13.7% vs 13.1%, p > 0.7). After a propensity score for use of heparin was developed, however, use of heparin did not affect the reduced risk associated with eptifibatide (adjusted relative risk [RR] for heparin-eptifibatide interaction term 0.90, 95% confidence interval [CI] 0.61 to 1.32, p > 0.5), but the propensity for heparin use was a strong predictor of events (adjusted RR 1.76, 95% CI 1.42 to 2.17, p < 0.001). The use of eptifibatide independently predicted a lower risk of events (adjusted RR 0.31, 95% CI 0.10 to 0.93, p = 0.04). Thus, the apparent positive impact of heparin on the benefits of eptifibatide therapy was largely due to confounding and bias.

Shifting the open-artery hypothesis downstream: the quest for optimal reperfusion.

Successful reperfusion after acute myocardial infarction (MI) has traditionally been considered to be restoration of epicardial patency, but increasing evidence suggests that disordered microvascular function and inadequate myocardial tissue perfusion are often present despite infarct vessel patency. Thus, optimal reperfusion is being redefined to include intact microvascular flow and restored myocardial perfusion, as well as sustained epicardial patency. Coronary angiography has been used as the gold standard to define failed reperfusion, according to the Thrombolysis In Myocardial Infarction (TIMI) flow grades. However, new angiographic techniques, including the corrected TIMI frame count and myocardial blush grade, have been used to show that epicardial TIMI flow grade 3 may be an incomplete measure of reperfusion success. Furthermore, evolving noninvasive diagnostic techniques, including measurement of infarct size with cardiac marker release patterns or technetium-99m-sestamibi single-photon emission computed tomographic imaging and analysis of ST segment resolution appear to be useful complements to angiography for the assessment of myocardial tissue reperfusion. Promising adjunctive therapies that target microvascular dysfunction, including platelet glycoprotein IIb/IIIa inhibitors, and agents designed to improve tissue perfusion and attenuate reperfusion injury are being evaluated to further improve clinical outcomes after acute MI. To accelerate development of these new reperfusion regimens, an integrated approach to phase II clinical trials that incorporates multiple efficacy variables, including angiography and noninvasive biomarkers of microvascular dysfunction, should be considered. Thus, as the reperfusion era moves into the next millennium, the open-artery hypothesis is expected to shift downstream and guide efforts to further improve myocardial salvage and clinical outcomes after acute MI.

Determination of the falloff constant (k(f)) from modeling biochemical marker release: a new variable for discriminating therapies.

A new variable termed the falloff constant (k(f)) was derived from the curve fitting of serial CK-MB measurements. k(f) represents the rate constant of maximal decline in serum CK-MB and is determined from the slope of the lognormal curve at the inflection point. Physiologically, kf's magnitude reflects the balance between CK-MB's rate of release from tissue and the rate of elimination. We examined k(f) in two myocardial infarction (MI) patient sets. The first set was homogeneous and taken from the TAMI 7 study (n = 147) and included 111 patients having TIMI 2-3 flow after thrombolytic therapy and 36 patients who initially had TIMI 0-1 flow. The TIMI 0-1 patients were opened to TIMI 3 by angioplasty within 3 h. The second set consisted of 196 patients enrolled in the IMPACT-AMI study that demonstrated the efficacy of the glycoprotein (GP) IIb/IIIa antagonist eptifibatide. This second set consisted of 93 patients in the GP IIb/IIIa treatment group and 103 in the placebo group. Log-normal curve-fitting parameters including peak maximum and curve area were also compared to k(f) in the GP IIb/IIIa versus placebo set. The Wilcoxon test showed no difference between the two groups of TAMI 7 patients (p = 0.22). However, there was a highly significant difference in kf between the GP IIb/IIIa treatment group versus the placebo group (p = 0.0014). Both k(f) and peak maximum from curve fitting showed significant differences between the GP IIb/IIIa treatment group and the placebo group; however, k(f) showed a substantially lower p-value (p = 0.0014 and p = 0.023, respectively). As expected, k(f) showed no difference between the TAMI 7 groups because this was a homogeneous patient set in that they all had TIMI 3 patency status within 3 h of treatment. However, in the patient set having very different treatments, GP IIb/IIIa versus placebo, there was a highly significant difference in the kf variable. These data suggest that differences in reperfusion are reflected by kf and that this variable may represent a valuable new nonmortality end point derived from curve fitting analysis.

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

Treatment strategies for microvascular dysfunction following acute myocardial infarction.

Successful reperfusion following acute myocardial infarction is considered to be restoration of epicardial infarct vessel patency, but recent studies suggest that disrupted microvascular function and inadequate myocardial tissue perfusion are often present despite epicardial patency. New angiographic techniques, including the corrected Thrombolysis in Myocardial Infarction (TIMI) frame count and myocardial blush grade, have been used to demonstrate that restoration of downstream coronary flow and tissue perfusion may be the key links to improved clinical outcomes. Additionally, other diagnostic techniques, including infarct size measurement with cardiac marker release patterns, or (99m) Tc-sestamibi single photon emission computed tomography imaging, and analysis of ST-segment resolution have also been used to assess microvascular function and tissue perfusion. Promising adjunctive therapies that target microvascular dysfunction, including platelet glycoprotein IIb/IIIa inhibitors, anti-inflammatory agents, vasodilators, glucose-insulin-potassium, and embolization protection devices, may ameliorate microvascular dysfunction following epicardial reperfusion. However, these therapies have not yet been shown to improve clinical outcomes and are thus currently being studied together with fibrinolytics and primary angioplasty in clinical trials. Therefore, shifting the focus of reperfusion therapy to the microcirculation offers the potential to further improve myocardial salvage and clinical outcomes following acute myocardial infarction.

Clinical information determines the impact of transesophageal echocardiography on the diagnosis of infective endocarditis by the duke criteria.

BACKGROUND: Although transesophageal echocardiography (TEE) is more sensitive than transthoracic echocardiography (TTE) in detecting echocardiographic evidence of infective endocarditis (IE), the impact of TEE on the clinical diagnosis of IE has not been clearly delineated. METHODS AND RESULTS: We studied 112 patients with 114 suspected episodes of IE over a 6-year period who underwent both TTE and TEE during their diagnostic evaluation. Using the results of these studies along with clinical and microbiologic data, we attempted to determine the incremental value of TEE to the Duke Endocarditis Diagnostic Criteria. Patients were initially classified into a diagnostic category of the Duke criteria with TTE data, and then the diagnostic classification was reconsidered with TEE data. A diagnostic category reassignment occurred in 25 of 114 episodes of IE evaluated when TEE results were incorporated into the evaluation with the Duke criteria (22 patients were reclassified from possible IE to definite IE whereas 3 patients were reclassified from rejected to possible IE). Diagnostic reclassification occurred in 9 (11%) of the 80 episodes of suspected IE with native cardiac valves and 13 (34%) of 34 episodes with prosthetic cardiac valves. Most patients reclassified from possible IE to definite IE with TEE data (19 of 22) had an intermediate clinical likelihood of IE, whereas 92% of patients had negative TTE results. Pathologic examination of valvular tissue in 22 of the 114 episodes of suspected IE revealed that the positive predictive value of the Duke criteria with TEE data for diagnosis of IE was 85% in patients with native valves and 89% in patients with prosthetic valves. CONCLUSIONS: When clinical evidence of IE is present, TEE improves the sensitivity of the Duke criteria to diagnose definite IE. TEE data appears to be especially useful for the diagnostic evaluation of patients with suspected IE who have prosthetic valves.

Glycoprotein IIb/IIIa inhibitors in acute coronary syndromes.

Glycoprotein (GP) IIb/IIIa inhibitors are potent antiplatelet agents and represent an exciting breakthrough in the treatment of acute coronary syndromes. However, their safety and cost-effectiveness require further investigation, and more information on risk stratification is needed to clarify which patients benefit the most from empiric use of these agents.

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.

Direct myocardial revascularization and angiogenesis--how many patients might be eligible?

This study examines the proportion of patients with ischemic heart disease who may be candidates for the newer modalities of revascularization. A significant proportion (approximately 5%) of patients who undergo coronary angiography at tertiary referral centers may be eligible for newer methods of therapy.