Protection Conferred by Preinfarct Angina is Manifest in the Aged Heart: Evidence from the TIMI 4 Trial.

There has been debate regarding the issue of whether ischemic preconditioning is effective in the aging and diseased heart. Therefore, we retrospectively analyzed the effect of preinfarction angina in patients less than versus greater than 60 years of age in the TIMI 4 study. Preinfarction angina was defined as an episode of typical angina pectoris that occurs prior to the time of index chest pain associated with the myocardial infarction itself. Patients who were 60 years and older had a higher rate of death and the combined endpoints of death, heart failure/shock, and/or reinfarction compared with younger patients. However, patients 60 years or older who had preinfarction angina had lower rates of the combined endpoints of death, heart failure/shock, and/or reinfarction (11%) compared with patients without angina (23%; P = 0.04). They also had lower creatine kinase (CK) values. Therefore, preinfarction angina was protective in patients 60 years or older in the TIMI 4 study.

Time to Reperfusion: The Critical Modulator in Thrombolysis and Primary Angioplasty.

Rapid achievement of reperfusion with thrombolytic therapy or primary angioplasty has made a dramatic impact an improving the survival of patients with acute myocardial infarction (MI). Restoring infarct-related artery patency early after the onset of MI minimizes infarct size, reduces the degree of left ventricular dysfunction, and improves survival. Several recent studies have confirmed the benefit of reducing time to treatment with thrombolysis (between the onset of pain to initiation of thrombolysis), and that of more rapid drug reperfusion time with more aggressive thrombolytic regimens (between initiation of thrombolytic therapy and actual achievement of reperfusion). Furthermore, these effects are additive, confirming the benefit of rapid reperfusion. For primary angioplasty, the same relationship has been observed-more rapid treatment appears to be associated with improved outcome. The "door-to-balloon" time is a major determinant of overall time to reperfusion, and as such is a crucial component of the overall strategy. Integrating the experience in trials of thrombolytic therapy and primary angioplasty, a clear relationship exists between higher rates of early reperfusion and lower mortality. Thus, time to reperfusion appears to be the critical modulator in both thrombolysis and primary angioplasty.

Time to Treatment: A Crucial Factor in Thrombolysis and Primary Angioplasty.

Time to treatment with thrombolytic therapy has been recognized as an important factor in the treatment of patients with acute myocardial infarction: By restoring infarct-related artery patency earlier, clinical outcome is improved. Of the several components of time delay between the onset of pain to opening of the artery, in-hospital time delay (i.e., the door-to-needle time) is one that physicians can control the most, with improvements being reported with the use of a myocardial infarction (MI) protocol like the one advocated by the National Heart Attack Alert Program. These same principles apply to the alternate reperfusion strategy, primary angioplasty. Indeed, while primary angioplasty has been shown to be beneficial in early clinical trials, it appears that the "door-to-balloon" time is a crucial component of the overall strategy. Thus, a growing body of evidence demonstrates that time to treatment is a crucial factor in both thrombolysis and primary angioplasty.

Hirudin in Acute Myocardial Infarction.

The central role of thrombosis in the pathogenesis of acute myocardial infarction has led to intense interest in developing more effective thrombolytic-antithrombotic regimens. Hirudin is 65 amino acid polypeptide that binds in a 1:1 relationship with thrombin, thereby inhibiting the final step in the coagulation cascade. Hirudin has several potential advantages over the current antithrombin agent heparin: It is a direct inhibitor that does not require a cofactor, it has no known inhibitors that would attentuate its anticoagulant effects, and it can inhibit clot-bound thrombin, thereby achieving an antithrombotic effect at the site of potential rethrombosis. Initial clinical trials have shown promising results: Hirudin, as compared with heparin, provided a more consistent level of anticoagulation, as gauged by the activated partial thromboplastin time. As an adjunct to thrombolytic therapy in acute myocardial infarction, hirudin improved indices of coronary reperfusion and patency. Initial results with clinical end points, including death or myocardial infarction, also have shown favorable results for hirudin compared with heparin. In the first phases of the larger phase III trials, the rate of hemorrhagic events, including intracranial hemorrhage, was higher than expected in both the hirudin and heparin arms, indicating that a safety ceiling had been reached. The TIMI 9B and GUSTO IIb trials are using lower doses of intravenous hirudin and heparin, which should allow testing of the "thrombin hypothesis": that more potent inhibition of thrombin will translate into improved clinical outcome for patients with acute MI.

Clotting for the Clinician: An Overview of Thrombosis and Antithrombotic Therapy.

The use of antithrombotic therapy has taken on central importance in the field of cardiovascular disease. Currently, anticoagulants and antiplatelet drugs are central to the treatment and the primary and secondary prevention of coronary artery disease. New insights into the "revised" coagulation cascade have highlighted new targets for intervention. In addition, the interactions between the coagulation system and platelets demonstrate ways that anticoagulants may affect platelet function and how antiplatelet agents may have anticoagulant effects. This overview will describe the present understanding of primary and secondary hemostasis, and current and future therapeutic approaches to modify these systems for therapeutic effects in cardiovascular medicine.

Optimizing the Treatment of Unstable Angina.

Unstable angina and non--Q-wave myocardial infarction (MI) are at the center of the spectrum of myocardial ischemia, which ranges from stable angina to acute Q-wave MI. In addition to clinical evaluation, cardiac specific markers such as troponin T or I can assist in early diagnosis, triage, and risk stratification. Antithrombotic therapy with aspirin and heparin have been shown to improve the outcome of patients with acute ischemic syndromes. Thrombolytic therapy does not appear to be beneficial in these syndromes. Antiischemic therapy remains an important component of the overall therapy. A strategy of early coronary angiography and revascularization leads to a similar long-term outcome as compared with a more conservative strategy of revascularization for recurrent ischemia, but the early invasive strategy is more expeditious as a large number of conservatively treated patients have recurrent ischemia. At present, many new antithrombotic agents are under active investigation, with the hope that they will lead to further improvement in the clinical outcome of patients with acute ischemic syndromes.

Thrombolytic Therapy for Acute Myocardial Infarction in Patients with Prior Coronary Bypass Surgery: Results from the Thrombolysis in Myocardial Infarction (TIMI) 4 Trial.

Little data exist on the value of intravenous thrombolysis for acute myocardial infarction in patients with previous coronary bypass surgery. The Thrombolysis In Myocardial Infarction (TIMI) 4 trial was a randomized study comparing tissue plasminogen activator, anistreplase, or a combination in patients with evolving myocardial infarction; patients with previous coronary bypass surgery were not excluded. Coronary angiography was performed 90 minutes and 18-36 hours after randomization, a myocardial perfusion scan was performed at 18-36 hours and predischarge, and a radionuclide ventriculogram was obtained predischarge. Angiographic and clinical outcome variables were determined in patients with and without a history of coronary bypass surgery. A total of 416 patients were randomized and 13 of them had previous bypass surgery; of these, 6 had an occluded vein graft as the infarct-related vessel. The incidence of TIMI grade 3 flow at 90 minutes was lower in patients with previous coronary surgery as compared with controls (42% vs. 49%), and overall patency was significantly lower (50% vs. 77%, p = 0.04). This trend persisted at 18-36 hours after randomization. Furthermore, patients with previous coronary surgery had more thrombus in their infarct-related arteries, especially with occlusion of a vein graft (83% vs. 32%, p = 0.04) and higher rates of recurrent ischemia (15% vs. 8%) and recurrent infarction (23% vs. 5%, p = 0.03) than controls. Thus, in patients with previous coronary bypass surgery intravenous thrombolysis yields results that are inferior to those achieved in patients without such a history and alternative methods of reperfusion should be considered.

Hirudin: Its Biology and Clinical Use.

Over a century has passed since the anticoagulant properties of hirudin were identified. Our understanding of this unique and promising 65 amino acid polypeptide has grown steadily, allowing clinical experience to be gained. In acute myocardial infarction, hirudin has been associated with a higher incidence of early and sustained TIMI grade 3 flow, a higher rate of infarct-related artery patency at 18-36 hours with a decreased rate of reocclusion, and a lower incidence of in-hospital death and reinfarction as compared with heparin. hirudin has also been associated with a stable level of articoagulation and an acceptable hemorrhagic complication rate when given in carefully chosen doses. In acute coronary syndromes, the initial results indicate that hirudin can improve the resolution of coronary thrombus and reduce the incidence of recurrent ischemic events. Similarly impressive reductions in thrombotic complications and ischemia have been observed in the early balloon angioplasty experience. Promising results have also been seen with hirudin in preventing deep venous thrombosis following orthopedic surgery. The favorable effects of hirudin as compared with heparin in phase II clinical trials have prompted further investigation in two large phase III trials, TIMI 9 and GUSTO 2. It is hoped that these initial results can be confirmed and that hirudin can be proved to be a safe and effective treatment for thrombotic syndromes of the venous and arterial circulatory systems.

Time as an Adjunctive Agent to Thrombolytic Therapy.

Thrombolytic therapy has dramatically reduced mortality following acute myocardial infarction (MI) with the major effect coming from early achievement of infarct-related artery patency. A major factor in achieving rapid reperfusion is early treatment with thrombolytic therapy. Recent trials have shown that mortality can be reduced if time to treatment is shortened: In the Thrombolysis in Myocardial Infarction (TIMI) 2 trial, for each hour earlier that thrombolytic therapy was started, approximately 10 lives were saved per 1000 patients treated. Thus, one must consider time as an adjunctive agent to thrombolytic therapy. There are four components of the time delay between the onset of MI and achievement of reperfusion: (1) patient delays in seeking medical attention; (2) transport delays; (3) the so-called door to needle time, the interval between the patient's arrival at the medical facility and the initiation of thrombolytic therapy; and (4) thrombolytic reperfusion time, the time between the administration of thrombolytic therapy and the achievement of roperfusion, Efforts to reduce each of these components will lead to additive benefits in improving time to reperfusion and survival of patients with acute MI.