Luis Garza

Inflammation, infection, and atherosclerosis

Since the recent publication of 3 studies on the use of antibacterials in patients with coronary artery disease (CAD), there has been a phenomenal interest in the role of infection in the genesis of CAD. It is now generally accepted that inflammation accompanies atherosclerosis from its initiation to the evolution of end-events. Inflammation may occur in response to traditional risk factors, such as hyperlipidaemia, smoking and diabetes mellitus. There is a recent resurgence of the concept that inflammation may have an infectious basis. This concept is based on the identification of microorganisms in the atherosclerotic plaque and seropositivity. The data on eradication of the offending organism with antibiotics and prevention of atherosclerosis-related events have, however, been inconsistent. This may reflect lack of precise understanding of steps leading to atherosclerosis and the evolution of acute ischaemic events. Further work in this area may help identify subsets of patient populations within which infection may play a causative role in the genesis of CAD. Targeted therapy then may be considered logical.

Coronary artery restenosis: vascular biology and emerging therapeutic strategies.

Percutaneous coronary intervention with drug-eluting stents is currently the preferred approach to the treatment of obstructive coronary stenoses. Large, randomized trials have demonstrated a significant reduction in the incidence of restenosis after drug-eluting stent placement compared with balloon angioplasty or bare metal stents across a wide range of lesions. Furthermore, these stents have appeared to be effective in maintaining the luminal patency at follow up for up to 2–4 years. Concerns regarding the potential adverse effects of drug-eluting stents, such as aneurysm formation in arteries secondary to drug toxicity or hypersensitivity, as well as the overdependence on antiplatelet therapy for a protracted period to prevent subacute thrombosis, have been raised. However, evidence from large studies has not demonstrated any significant increase in the incidence of such adverse events. Future approaches to treating coronary stenoses involve technical modifications, such as direct stenting, accelerating endothelialization with gene delivery of nitric oxide donors, smooth muscle cell growth inhibitors after stent placement, biodegradable stents and concurrent use of local molecule delivery and oral chemotherapy. Ongoing large-scale postmarketing surveillance studies are expected to provide credible answers to the concerns regarding the safety of these stents.

Comparative Pharmacodynamic Evaluation of Eptifibatide and Abciximab in Patients with Non-ST-Segment Elevation Acute Coronary Syndromes: The TAM2 Study

Background: The importance of the relationship between clinical outcome and degree of platelet aggregation inhibition (PAI) achieved with the dosing regimens of GPIIb-IIIa inhibitors used in large trials in patients with non-ST segment elevation (NSTE) acute coronary syndromes (ACS) is increasingly appreciated. In the PURSUIT trial, eptifibatide treatment that consistently provided >80% PAI was associated with clinical benefit at 30 days and 6 months. The GUSTO IV ACS trial, however, did not show any effect of abciximab on 30-day outcomes. This difference might be due to variability of antiplatelet effects of these drugs. As previous studies found, a 12 hr abciximab infusion had <80% PAI, particularly at 6 and 12 hr. These studies did not evaluate PAI with a longer, 24-hour infusion as used in GUSTO IV ACS.Methods: We conducted a prospective study in 40 patients with NSTE ACS prior to catheterization or coronary intervention at 3 centers using the PURSUIT dose of eptifibatide (180/0.2) and the GUSTO IV dose of abciximab (0.25, 0.125). Blood samples were collected at baseline, and during the infusion at 10 min, 1 hr, 6 hr, 8 hr, 12 hr, 18 hr, and 24 hr. Measurements of ex vivo light transmission aggregometry (LTA) were performed using PPACK anticoagulant and 20 μM ADP agonist. Receptor Occupancy (RO) was also determined in a subset of patients.Results: Eptifibatide achieves higher PAI during the entire infusion period than abciximab (p < 0.01). At 10 min, average PAI with eptifibatide and abciximab was 88% and 80%, respectively, 95% and 79% at 6 hr, and 97% and 79% at 24 hr. There was also more variability in individual patient response to abciximab. Although average RO for eptifibatide was similar to that of abciximab at 10 min, 67% versus 69%, respectively, average RO was higher in the eptifibatide cohort at all subsequent timepoints. By 24 hr, average RO for eptifibatide was 86%, whereas abciximab averaged 67%.Conclusion: These data support the hypothesis that differences in clinical outcomes of large GPIIb-IIIa trials in patients with NSTE ACS may be related to the consistency and potency of antiplatelet effects of the dosing regimens used.Abbreviated abstract. We compared platelet aggregation inhibition (PAI) with the glycoprotein IIb-IIIa inhibitors eptifibatide and abciximab in patients with non–ST-segment elevation (NSTE) acute coronary syndromes (ACS), using light transmission aggregometry assays with D-phenylalanyl-L-propyl-L-arginine chloromethylketone (PPACK) as the anticoagulant and 20 μmol adenosine diphosphate (ADP) as the platelet agonist. Mean PAI with eptifibatide during the entire 24-hour infusion period was >80%, and it was significantly higher than the mean PAI achieved with abciximab (p < 0.0001). Mean PAI with abciximab was <80% at 6, 8, 12, 18, and 24 hr. Most patients in the eptifibatide arm had >80% PAI at all time points, whereas many patients treated with abciximab had <80% PAI throughout the infusion period, particularly at later times (6 hr and beyond). Mean GPIIb-IIIa receptor occupancy with eptifibatide was also higher than with abciximab. These pharmacodynamic differences may have contributed to differing clinical effects of eptifibatide and abciximab in large clinical trials in patients with NSTE ACS.

Trends in the Care of Patients With Acute Myocardial Infarction at a University-Affiliated Veterans Afffairs Medical Center:

Background: Acute cardiac care of the veterans at Veterans Administration (VA) hospitals has been thought of as poor in quality. We examined the use of life-saving, evidence-based medical therapy in patients admitted with acute myocardial infarction to the University of Arkansas for Medical Sciences-affiliated VA Medical Center in Little Rock and compared the use of this therapy with other hospitals in Arkansas and in the rest of the nation. Methods: Use of life-saving medical therapy in 117 patients admitted with acute myocardial infarction from January 2002 to December 2002 was compared with the National Registry of Myocardial Infarction database for the identical period. Results: Heparin/low-molecular-weight heparin and glycoprotein IIb/IIIa inhibitors were used in 88% and 66% of patients, respectively. Aspirin, β adrenergic-blocking agents, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) were used in 92%, 93%, 62%, and 79% of the patients, respectively. The use of these therapies was better than in similar patients in Arkansas (P < .001) and the United States as a whole (P < .01). Calcium-channel blockers were used in 16% of the patients. At a mean follow-up period of 1.5 years, use of β blockers and aspirin had decreased, whereas the use of statins and ACE inhibitors/ARBs was unchanged. Conclusion: This study shows that patients with acute myocardial infarction admitted to this university-affiliated VA Medical Center receive evidence-based life-saving medical therapy more often than in the rest Arkansas or in the entire United States. More important, patients at this federal institution continue to receive life-saving medical therapy during follow-up. Better use of evidence-based therapy may be related to affiliation of this VA Medical Center with a teaching institution where board certified cardiologists are involved in short- and long-term care of these patients.