Paul P. Dobesh

Drug-eluting stents: A mechanical and pharmacologic approach to coronary artery disease

Coronary artery disease is the largest killer of men and women in the United States and costs the health care system billions of dollars annually. Several advances in both mechanical and pharmacologic treatment of coronary artery disease have occurred in recent decades. Mechanically, percutaneous coronary intervention is commonly used to treat coronary atherosclerosis. This approach has dramatically reduced both morbidity and mortality for patients with different levels of severity of coronary artery disease. However, percutaneous coronary intervention is limited by restenosis, which is an increase in growth of the intimal layer of the vessel wall. Despite the introduction of intracoronary stents and the addition of systemic pharmacotherapy, restenosis still affects a significant number of patients. The new technology of drug‐eluting stents combines mechanical and pharmacologic approaches to prevent restenosis. Various types of these stents exist in different stages of development; several have been shown to prevent or reduce intimal growth after stent deployment. An understanding of how this combined mechanical and pharmacologic approach reduces restenosis requires consideration of complex issues in pathophysiology and pharmacology.

Prevention of Venous Thromboembolism in Acute Medical Illness

Each year millions of patients experience a venous thromboembolic event. Due to the significant morbidity and mortality associated with venous thromboembolism (VTE), prevention is critical. Several groups, such as those undergoing orthopedic or general surgery, and patients experiencing acute myocardial infarction, are known to be at high risk for VTE. General medical patients—the medically ill—are also at risk, but they receive insufficient prophylaxis, which may be due to underestimation or lack of assessment of their risk. The American College of Chest Physicians recommends either unfractionated heparin or low‐molecular‐weight heparin to prevent VTE in these patients. The different pharmacologic profiles and dosing methods of these two groups of agents suggest that efficacy and safety may not be equivalent. Due to heterogeneity of medically ill patients and variability in clinical trials, a detailed review of the literature was performed to assist clinicians in assessing risk and choice of a regimen to prevent VTE.

Advancing the Battle Against Acute Ischemic Syndromes: A Focus on the GP IIb‐IIIa Inhibitors

Platelet aggregation and thrombus formation, resulting from disruption of a coronary artery plaque, play a critical role in the pathology of acute coronary syndromes. Currently, aspirin and heparin are administered to decrease platelet aggregation. The discovery of the platelet integrin receptor αIIbβ3, also known as the platelet glycoprotein (GP) IIb‐IIIa receptor, is a breakthrough in antiplatelet therapy. The GP IIb‐IIIa receptor is responsible for the crucial binding of fibrinogen to platelets, leading to cross‐links between platelets and further platelet aggregation. Since the introduction of abciximab, the first GP IIb‐IIIa‐receptor antagonist, several other nonantibody agents have been studied for use in percutaneous transluminal coronary angioplasty and also in stent placement, treatment of unstable angina, and myocardial infarction.

Key Articles and Guidelines Relative to Treatment of Patients with Acute Coronary Syndromes

Patients with cardiovascular disease who have acute coronary syndromes (ACS) are at risk of significant morbidity and mortality. Also, treatment of these patients in the early‐phase setting has a significant financial impact on the health care system. With the existence of numerous pharmacologic agents, abundance of major clinical trials, and several nationally recognized clinical guidelines, compiling the needed reference material to make evidence‐based decisions on the care of patients with ACS can be difficult for clinicians. To assist clinicians in this endeavor, we complied pertinent articles and guidelines that have shaped the current treatment of patients with ACS. Owing to the rapidly evolving body of evidence in the management of ACS, this compilation will require periodic updating.

Evidence for extended prophylaxis in the setting of orthopedic surgery.

Patients undergoing orthopedic surgery represent one of the highest risk groups for the development of venous thromboembolism (VTE). Evidence shows that this risk extends beyond the period in which the patient is hospitalized, especially for patients undergoing hip surgery. Clinical trials have shown that extended prophylaxis with the low‐molecular‐weight heparins is effective in reducing the rate of total VTE, and a meta‐analysis demonstrated a reduction in symptomatic VTE with extended prophylaxis after total hip replacement surgery. Based on these results, the American College of Chest Physicians gives a grade 2A recommendation for the use of extended prophylaxis after orthopedic surgery. Until recently, data evaluating the role of prophylaxis in patients undergoing hip fracture surgery were limited. Subsequently, a novel anticoagulant, fondaparinux, demonstrated significant benefit in these patients and has become the first and only agent approved by the United States Food and Drug Administration (FDA) for use in patients undergoing hip fracture surgery. Despite the limitations of the older trials, their findings supported the need to evaluate extended prophylaxis in patients undergoing hip fracture surgery. In the first well‐conducted trial of extended prophylaxis for hip fracture surgery, fondaparinux provided impressive results in reducing total and symptomatic VTE. The results of this trial have once again led to fondaparinux being the first and only agent to be granted FDA approval for the indication of extended prophylaxis in patients undergoing hip fracture surgery.

Ximelagatran: pharmacology, pharmacokinetics, and pharmacodynamics.

Thromboembolism is the largest cause of morbidity and mortality in the western world, yet oral anticoagulation is currently available only with vitamin K antagonists—most often, warfarin. Warfarin has been used for treatment of thrombotic disease for about 50 years. However, despite its widespread use, it is associated with several limitations, such as varied patient response, a narrow therapeutic window, numerous drug and food interactions, and need for frequent therapeutic monitoring. In addition, its full anticoagulant effect usually takes at least 4–5 days after the start of therapy or any dosage change, and it has a slow offset of therapy. A new oral anticoagulant, ximelagatran, has considerable advantages compared with warfarin. The agent requires no therapeutic monitoring, has a wide therapeutic window, and is not known to interact with food or drugs. The advantages ximelagatran brings to clinical practice should be a welcome addition to the options for management of thrombotic disease.

Economics of Unfractionated Heparin: Beyond Acquisition Cost

Despite numerous clinical trials demonstrating advantages of new anticoagulants, unfractionated heparin (UFH) is still used by a number of clinicians in the United States. The reason for this continued use of UFH is not superior efficacy, improved safety, or convenience, but low acquisition cost. However, several other costs associated with the use of UFH are often not considered. Appropriate economic analysis, which considers both cost and outcomes, has not demonstrated support for continued use of UFH. Its continued use based simply on lower cost is not justified by the literature.

Outcomes with Changes in Prescribing of Glycoprotein IIb/IIIa Inhibitors in PCI

Background Glycoprotein IIb/IIIa receptor antagonists have been shown to have an impact on the outcomes of death/myocardial infarction (MI) in patients undergoing percutaneous coronary intervention. At our institution, tirofiban has largely replaced abciximab in an attempt to decrease costs. Objective To assess the impact of this change on patient outcomes in the absence of head-to-head trials. Methods Medical records were reviewed and telephone follow-ups were conducted on patients receiving tirofiban (n = 83) at our facility between February and November 1999. Death/MI at 30 days and 6 months after infusion were recorded. Safety and length of stay (LOS) were also assessed. These data were compared using χ2 analysis with results obtained from a previous review of abciximab use (n = 83) collected between May 1997 and November 1998. Results There was no difference in the baseline incidence of (1) cardiovascular risk factors, (2) prior revascularization, (3) prior MI, (4) the number of vessels with atherosclerotic disease assessed by angiography, and (5) the number of vessels receiving procedures. Death/MI trended to be worse with tirofiban versus abciximab at our institution at 30 days (4.8% abciximab vs. 12% tirofiban; p = 0.163) and 6 months (6% abciximab vs. 18.1% tirofiban; p = 0.032). Bleeding and median LOS (3 d abciximab vs. 3 d tirofiban) were not different. Despite an increase in pharmacy cost, the use of abciximab provided these outcomes without an increase in total hospital cost. Conclusions The perceived economically driven change in medication selection from abciximab to tirofiban may not have been appropriate based on the negative trends seen in this review. To maintain optimal patient outcomes, this change should be reevaluated.