Fibrinolytic therapy benefits

Fibrinolytics are not indicated in any patient with NSTE ACS, even those who have positive biochemical markers that indicate infarction. The risk of death from MI is lower in these patients, and the hemorrhagic risks of fibrinolytic therapy outweigh the benefit. 

The clear alternative to fibrinolytic therapy in the reperfusion strategy of ST-segment elevation acute myocardial infarction is primary coronary angioplasty. This therapy has a clinical benefit over the optimal thrombolytic strategy front-loaded rt-PA or tenecteplase (13). The major drawback of primary angioplasty is its limited availability and treatment delay. The... 

Any benefits of treatment with GP Ilb/IHa inhibitors must be weighed against the risks. Several studies have found an increased risk of major bleeding, which is likely to be of particular importance in patients whose absolute risk of bleeding is high, such as those receiving fibrinolytic therapy (see below for further discussion). A small excess risk of thrombocytopenia has also l n reported in some trials (37). 

Data regarding the acute benefit of /3-blockers in MI in the reperfusion era is derived mainly from the Thrombolysis in Myocardial Infarction (TIMI) II trial. In this trial, patients with ST-segment-elevation ACS were randomized to either IV metoprolol to be given as soon as possible following fibrinolytic administration followed by oral metoprolol or oral metoprolol deferred until day 6. Early administration of metoprolol was associated with a significant decrease in recurrent ischemia and early reinfarction. Patients receiving fibrinolytic therapy within 2 hours of symptom onset demonstrated the greatest benefit from early metoprolol administration. Based on the results of these trials, early administration of /8-blockers (to patients without contraindications) within the first 24 hours of hospital admission is a standard of quality patient care (see Table 16-3). 

These drugs find clinical utility in settings such as prevention of rebleeding in intracranial hemorrhages, as adjunctive therapy in hemophilia, and of course, in treatment of bleeding associated with fibrinolytic therapy. In most bleeding conditions, however, -aminocaproic acid therapy has not been shown to be of definitive benefit. In recent trials, tranexamic acid was found to reduce red cell transfusion better than -aminocaproic acid or placebo in patients undergoing liver transplantation (136). 

Pharmacoinvasive recanalization with fibrinolytic therapy to induce initial reperfusion, conjunctive pharmacological therapy with anticoagulants to enhance the rapidity and extent of lysis and subsequent timely (within 12-24 hours) PCI to prevent reocclusion and reinfarction to eliminate underlying anatomical obstruction and thrombus are particularly promising for most patients with STEMI (30,73-77). This pharmacoinvasive approach for treatment of asymptomatic patients following thrombolysis should expand the interval during which PCI can be effective well beyond the 90-minute interval within which optimal benefits are seen with primary PCI. If so, it would be attractive for patients presenting to... 

Despite the results of the PAMI and Zwolle trials, great controversy persisted regarding the relative benefit of catheter-based reperfusion versus fibrinolytic therapy for acute myocardial infarction. Primary PTCA was regarded as a reasonable alternative to fibrinol)dic therapy but was not widely employed due to logistical problems and relative paucity of data to support its clinical benefit. It took a further decade of clinical research to settle this controversy. 

More than 90% of patients achieve TIMI 3 flow with primary PCI (17,18) however, normal myocardial perfusion was attained in only -30% of patients despite TIMI 3 flow (19). Similar to thrombolytic therapy, the presence of normal epicardial and myocardial perfusion was associated with the best clinical outcomes. Among patients for whom TIMI 3 flow was restored, 1-year survival was 6.8% in the presence of normal myocardial blush, 13.2% with reduced myocardial blush, and 18.3% with absent myocardial blush (p = 0.0004) (Fig. 6.6) (19). Therefore, adjunctive aggressive pharmacotherapy (antiplatelet, antithrombotic, and fibrinolytic therapies) that could improve myocardial perfusion, further supplementing mechanical revascularization, will provide additive benefit to patients with STEMI. Furthermore, there is often a time delay from the door to balloon, which, compounded... 

In the prefibrinolytic era, antithrombins were principally administered to patients with STEMI to reduce the risks of pulmonary embolism, stroke, and reinfarction. The theoretical benefits of conjunctive use of unfractionated heparin (UFH) with a fibrinolytic include the possibility of augmentation of the initial lytic effect, reduction of the risk of reocclusion of an initially successfully reperfused infarct artery (with attendant risk of reinfarction), and reduction of the risk of early mural thrombus formation (28). Despite the logic of these arguments, clinical trials of conjunctive use of UFH with fibrinolytic therapy produced confusing results that continue to impact on clinical practice. Synthesis of a large body of information on studies with UFH leads to several conclusions ... 

Although the therapeutic benefit of coronary reperfusion—fibrinolytic therapy and primary percutaneous coronary intervention (PCI)—for the treatment of acute ST elevation myocardial infarction (STEMI) in younger patients is well established, there remains considerable debate over the appropriate choice of a reperfusion strategy for elderly patients. 

In 1994, the benefit of fibrinolytic therapy in the treatment of the elderly was brought into question by the Fibrinolytic Therapy Trialists (FTT) Collaborative Group (3). This meta-analysis included nine fibrinolytic trials incorporating over 58,600 patients. Of these patients, 17,000 were 65-74 years of age and 5754 were >75 years of age. This analysis revealed that the benefit of fibrinolytic therapy diminished with advancing age relative risk reduction (RRR) of death associated with fibrinolytic therapy was 22% in patients <55 years of age, 19% in patients 55-64 years of age, 16% in patients 65-74 years of age and only 4% in patients >75 years of age. However, while the relative effectiveness of fibrinolytic therapy diminished with advancing age, the 4% RRR translated into a 1% ARR, or NNT = 100, still a clinically important difference and similar to the 1.2% ARR in patients <55 years of age. Therefore, even small relative reductions in risk can be important when applied to groups with increased risk. 

Of the nine trials included in the FTT meta-analysis. Late Assessment of Thrombolytic Efficacy (LATE) and Estudio Multicentrico Estreptoquinasa Republicas de America del Sur (EMERAS) enrolled only patients who presented >6 hours after the onset of chest pain (8,9). Both of these studies demonstrated minimal benefit from fibrinolytic therapy as compared to the impressive reductions seen in GISSI and ISIS-2 (8.9% mortality in the t-PA group vs. 10.3% mortality in the control group in LATE and no benefit of streptokinase over control in patients presenting >12 hours after symptom onset in EMERAS). The inclusion of these two trials diluted the effects of fibrinolytic therapy in the FTT analysis. Furthermore, in the prematurely terminated APSAC Intervention Mortality Study (AIMS), only 3 of the total 502 patients were >70 years of age, raising concerns about the ability of the FTT to extrapolate these results to elderly patients (10). 

Since the original publication of the FTT, White reported unpublished data from the FTT that shows a more sustained benefit in the elderly (11). In contrast to the initial FTT analysis that included patients with factors associated with both reduced benefit and increased risk of fibrinolytic therapy (i.e., patients presenting >12 hours after the onset of symptoms as well as individuals showing ST depression or T wave... 

Further data demonstrating the long-term benefit of fibrinolytic therapy were reported by Stenestrand et al. (14). This registry enrolled every patient admitted to the coronary care unit of 64 Swedish hospitals between 1995 and 1999. Of the 50,779 admissions, 19,052 were a first-recorded admission for STEMI and 6891 patients >75 years of age received either fibrinolytic therapy or no reperfusion. In contrast to the Berger et al. analysis, fibrinolytic therapy was associated with both reductions in adjusted 30-day mortality (23% vs. 26% p = 0.02) and adjusted one-year mortality (32% vs. 36% p = 0.001). 

Numerous observational studies have confirmed the treatment benefit seen in the above RCTs of primary PCI as a reperfusion strategy in the elderly. In the previously mentioned analysis of the CCP, Berger et al. found primary PCI compared with no reperfusion was associated with significant reductions in both 30-day and 1-year mortality among patients without absolute contraindications for fibrinolytic therapy (13). Among the ideal patient subgroup, primary PCI yielded reductions in adjusted mortahty rates at 30 days and at 1 year compared with no therapy (OR 0.78,95% Cl 0.58-1.05 and OR 0.63,95% Cl 0.49-0.84). However, since this analysis used no reperfusion therapy as the comparison group, primary PCI and fibrinolytic therapy were not directly compared. 

In a separate analysis of the CCP, Berger et al. compared primary PCI directly to fibrinolytic therapy (36). The outcomes of 18,645 patients who received fibrinolytic Iherapy were compared with 2038 patients who received primary PCI. This cohort was composed of patients >65 years of age, not in cardiogenic shock, within 12 hours from symptom onset and with no contraindications to fibrinolytic therapy. Among the entire cohort, primary PCI resulted in lower crude and adjusted rates of 30-day and 1-year mortality. The benefit of PCI persisted even in those >75 years of age. 

If a fibrinolytic agent is administered, UFH is given concomitantly with alteplase, reteplase, and tenecteplase, but UFH is not administered with streptokinase because no benefit of combined therapy has been demonstrated. Rates of reinfarction are higher if UFH is not given with the fibrin-selective agents. 

A study in coronary patients has shown that fibrinogen levels are Increased over normal controls ° and that fibrinolytic activity is also decreased in these patients.The rate of degradation of fibrinogen is inhibited in rats fed an atherogenic diet. It would seem reasonable then that some control over the clinical outcome of atherosclerosis could be had by the use of fibrinolytic agents. The enzymes streptokinase and urokinase continue to be evaluated with some benefits reported in the therapy of acute Thromboembolism.Phenformin is still the only drug of interest as a fibrinolytic agent other than the enzymes and CPIB mentioned earlier. 

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