Thrombolytic Regimens Research Articles

The Thrombolytic Paradox

Thrombolytic drugs do not only stimulate the plasmin system but also induce thrombin activation additionally to the preexisting hypercoagulative state in patients with acute myocardial infarction. Testing the in vitro-derived hypothesis of a plasmin-mediated activation of the contact phase of the coagulation leading to the procoagulant effect, several thrombolytic regimen have been evaluated. Paradoxical thrombin activation (referred to as “thrombolytic paradox”) was related to absence of fibrin specificity. Highly fibrin-specific drugs like tenecteplase did not cause additional thrombin activation, while non-fibrin-specific drugs like streptokinase caused a marked additional activation of the contact phase and of thrombin. It could be shown that the thrombolytic paradox was related to the extent of systemic plasmin activation confirming the hypothesis of a plasmin-mediated factor XII/kallikrein system activation as cause of the thrombolytic paradox.

Thrombolytic Therapy: State of the Art

Thrombolytic agents have become the corner stone in the treatment of acute myocardial infarction. However, the current agents are far from perfect. New thrombolytic drugs have been designed to overcome these shortcomings. Development of these agents has focused not only on increasing plasma half-life and thus allowing single-bolus administration, but also on improving fibrin specificity and resistance to plasminogen activator inhibitor. The safety and efficacy of several of these promising thrombolytic drugs have been evaluated in large-scale trials, which are discussed in the present review. Parallel to these advances, alternatives to standard thrombolytic regimens have been developed. New trials evaluating the combination of reduced-dose fibrinolytics with different regimens of antithrombotic agents will optimize future reperfusion strategies.

Techniques in dosing for thrombolysis of occluded central venous catheters

Dosing of thrombolytic agents for restoration of flow to thrombotically occluded central venous catheters has been empiric. The lowest effective dose of any agent is not known. Given that none of the dosing regimens in current use has ever been found to be toxic, this is probably not a major clinical problem as long as the regimen is highly effective. Thrombolytic regimens differ in the type of drug, dose of drug, method of administration (injection versus prolonged infusion), and duration of administration. All of these variables are important in determining the efficacy, and possibly the toxicity, of a regimen. Active research is being conducted to determine the most effective ways of using the expanding number of thrombolytic medications that are now, or soon may be, on the market.

Pharmacological versus catheter-based reperfusion: What is present state of the art?

The aim of any reperfusion therapy is quick and complete restoration of normal (TIMI-grade 3) coronary flow. At least 12 randomized studies have shown, that direct (primary) coronary angioplasty is more effective than any pharmacological approach and should be the preferred reperfusion therapy whenever available with no more than 30–60 min delay (compared with thrombolysis). Immediate knowledge of the coronary anatomy with the possibility of performing coronary bypass surgery in selected patients adds substantially to the overall benefits of the primary angioplasty strategy. Stent implantation markedly decreases the restenosis rate after primary angioplasty. The benefits of primary angioplasty are sustained in long-term follow-up. The extent of benefit from primary angioplasty is dependent on the time delay and on the operator experience, but it appears that even low-volume operators achieve similar or slightly better results than the most effective thrombolytic regimens. Thrombolysis is preferred therapy only for patients with timely access to primary angioplasty, especially when they are treated within initial 4 h of symptoms. The role of GPIIb/IIIa receptor inhibitors in conjunction with primary angioplasty or stenting is promising, but additional studies should confirm whether it is useful routinely for all patients or selectively only for the ‘extreme hypercoagulation’ situation and/or for ‘suboptimal angioplasty/stent result’.

Carotid artery dissection

Carotid artery dissection (CAD) is one of the more common causes of stroke in persons younger than 50 years. In this age group and in older persons, CAD is most often associated with trauma. Significant morbidity can be a consequence of CAD, particularly a stroke or other permanent neurologic deficit. Because stroke is the third leading cause of death in the United States, attention has focused in the past decade on understanding the phenomenon of dissection of the carotid artery. This article presents a review of the risk factors associated with CAD, the role of the nurse as a provider of care for these persons, and the approaches to prevent or limit disability related to CAD, the ultimate goal of patient care. Nurses play a crucial role in the detection of CAD and in the prevention of strokes or other neurologic disabilities through recognition of persons at risk, assessment for early signs and symptoms, and implementation of prophylactic measures. Because more than half of persons with CAD have cerebral ischemia, thrombolytic, anticoagulant, and antiplatelet regimens have evolved to limit the development of a thromboembolic event associated with dissection. The administration of these agents, the monitoring for their effectiveness, and the education of patients receiving them are fundamental aspects of care. (J Vasc Nurs 2001;19:2-9)

Thrombolytic therapy in pulmonary embolism.

Successfully utilized contemporary pulmonary embolism (PE) thrombolysis reverses right heart failure rapidly and safely. This therapeutic approach may lower mortality from PE and reduce morbidity from chronic pulmonary hypertension. PE thrombolysis remains a debatable indication because large clinical trials using survival as an endpoint have not been carried out. Instead, thrombolysis trials have been undertaken with surrogate endpoints such as reduction in clot burden, reduction in pulmonary arterial pressure, and improvement in right ventricular function. Currently, the only contemporary thrombolytic regimen for PE that is approved by the Food and Drug Administration is recombinant tissue plasminogen activator, in a dose of 100 mg/2 h. New thrombolytic agents under development for PE include reteplase, saruplase, and recombinant staphylokinase. Future clinical trials will require multicenter collaboration and focus on clinically relevant endpoints such as reduction of mortality and recurrent venous thromboembolism, under particular consideration of the risk of intracranial hemorrhage that ranges between about 1.7% in clinical trials up to approximately 3.0% in a large registry.

Thrombolysis in Pulmonary Embolism: A Debatable Indication

Successfully utilized contemporary pulmonary embolism thrombolysis reverses right heart failure rapidly and safely. This therapeutic approach may lower mortality from pulmonary embolism and reduce morbidity from chronic pulmonary hypertension. Pulmonary embolism thrombolysis remains a debatable indication because large clinical trials using survival as an endpoint have not been carried out. Instead, thrombolysis trials have been undertaken with surrogate endpoints such as reduction in clot burden, reduction in pulmonary arterial pressure, and improvement in right ventricular function. In an era where hundreds of thousands of myocardial infarction patients have participated in thrombolysis trials that focus on survival as the principal endpoint, the much smaller trials of PE thrombolysis have not been sufficiently definitive to achieve a consensus. Pharmaceutical companies have not considered this area of investigation to be a good return on investment, because PE is a much less common problem than acute coronary syndromes. No government funding agency has targeted PE thrombolysis as a priority for clinical research. Currently, the only contemporary thrombolytic regimen for pulmonary embolism that is approved by the Food and Drug Administration is tissue plasminogen activator, in a dose of 100 mg/2 h. New thrombolytic agents under development for pulmonary embolism include reteplase, saruplase, and recombinant staphylokinase. Future clinical trials will require multicenter collaboration and focus on clinically relevant endpoints such as reduction of mortality and recurrent venous thromboembolism.

Short- and long-term results after thrombolytic treatment of deep venous thrombosis

OBJECTIVESThe goal of this study was to assess the short- and long-term efficacy of different thrombolytic therapy regimens in patients with leg or pelvic deep venous thrombosis (DVT).BACKGROUNDIt is unclear whether locoregional or systemic thrombolysis is superior in treating acute leg DVT or even whether lysis is more effective than anticoagulation therapy in preventing postthrombotic syndrome.METHODSA total of 250 patients averaging 40 years of age with acute DVT were randomized into five groups to receive full heparinization (1,000 IU/h) and compression treatment, with four groups also administered locoregional tissue plasminogen activator (20 mg/day) or urokinase (100,000 IU/day) or systemic streptokinase (3,000,000 IU daily) or urokinase (5,000,000 IU daily). All groups then received anticoagulation and compression treatment for one year. Primary efficacy criteria included the change after one year in the number of closed vein segments and the occurrence of postthrombotic syndrome.RESULTSSystemic thrombolytic therapy significantly reduced the number of closed vein segments after 12 months in patients with acute DVT compared with conventional treatment (p < 0.05). Postthrombotic syndrome also occurred with less frequency in systemically treated patients versus controls (p < 0.001). High-dose thrombolysis led to better rates of complete recanalization after seven days (p < 0.01) than locoregional lysis. However, 12 patients receiving thrombolysis (9 systemic, 3 local) suffered major bleeding complications; 9 patients on systemic treatment developed pulmonary emboli.CONCLUSIONSSystemic thrombolytic treatment for acute DVT achieved a significantly better short- and long-term clinical outcome than conventional heparin/anticoagulation therapy but at the expense of a serious increase in major bleeding and pulmonary emboli. Given the inherent risks for such serious complications, systemic thrombolysis, although effective, should be used selectively in limb-threatening thrombotic situations.

Negative T waves shortly after ST-elevation acute myocardial infarction are a powerful marker for improved survival rate

Background Recent studies have reported that negative T waves in the setting of acute coronary events are associated with Thrombolysis In Myocardial Infarction flow grade 3 in the infarct-related artery and with improved parameters of ventricular function rather than with ischemia. Methods Patients enrolled in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) angiographic substudy (ie, patients with acute infarction randomly assigned to one of 4 thrombolytic regimens who then underwent coronary angiography) were included in this study if they survived at least 24 hours and had no confounding electrocardiographic factors (n = 1505). Results More patients had negative T waves develop (NT group, n = 938 [62%]) than not (PT group, n = 567 [38%]). Peak creatine kinase MB, time to thrombolysis, and randomization to accelerated alteplase were no different between the groups. Thirty days after admission, 12 patients in the NT group had died versus 25 patients in the PT group (1.3% vs. 4.4%; P <.001; odds ratio for negative T waves 0.28; 95% confidence interval 0.14-0.56). The difference persisted when only patients who survived at least 3 days were analyzed. After adjusting for relevant covariates (including presence of new Q waves in the follow-up electrocardiogram), negative T waves were an independent predictor for survival (P =.007; odds ratio for negative T waves 0.38; 95% confidence interval 0.18-0.78). Patients in the NT group were 35% more likely to have achieved patency of the infarct-related artery, although this difference was not statistically significant. Conclusions Negative T waves shortly after acute myocardial infarction treated with thrombolysis were markers for improved 30-day survival rate. This finding merits prospective testing. (Am Heart J 2000;140:385-94.)

Thrombolysis is an effective and safe therapy in stuck bileaflet mitral valves in the absence of high-risk thrombi

OBJECTIVESWe sought to evaluate the effectiveness and safety of thrombolytic therapy in stuck mitral bileaflet heart valves in the absence of high-risk thrombi.BACKGROUNDCurrent recommendations for the thrombolytic treatment of stuck prosthetic mitral valves are partially based on older valve models and inclusion of patients in whom high-risk thrombi were either ignored or not sought for. The feasibility and safety of thrombolysis in bileaflet models may be affected by the predilection of thrombi to catch the leaflet hinge.METHODSWe studied 12 consecutive patients (men/women = 5/7, age 58.8 ± 14.9 years) who experienced one or more episodes of stuck bileaflet mitral valve over a 33-month period and received thrombolytic therapy with streptokinase, urokinase or tissue-type plasminogen activator. Transesophageal echocardiography was performed in all patients. Patients with mobile or large (>5 mm) thrombi were excluded. Functional class at initial episode was I–II in 4 patients (33.3%) and III–IV in 8 patients (66.6%).RESULTSPatients receiving thrombolytic therapy achieved an overall 83.3% freedom from a repeat operation or major complications (95% confidence interval 51.6–97.9%). Minor bleeding occurred in three patients (25%) and allergic reaction in one (8.3%). Transient vague neurologic complaints, without subjective findings, occurred in four patients (33.3%). Three patients had one or more relapses within 5.2 ± 3.1 months from the previous episode, and readministration of thrombolytics was successful.CONCLUSIONSIn clinically stable patients with stuck bileaflet mitral valves and no high-risk thrombi, thrombolysis is highly successful and safe, both in the primary episode and in recurrence. The best thrombolytic regimen is yet to be established.

A contemporary approach to thrombolytic therapy for pulmonary embolism.

Successfully utilized contemporary pulmonary embolism thrombolysis reverses right heart failure rapidly and safely. This therapeutic approach may lower mortality from pulmonary embolism and reduce morbidity from chronic pulmonary hypertension. Unlike myocardial infarction thrombolysis, a 2-week 'time window' is available, during which treatment can be initiated. A high concentration of the thrombolytic agent is administered in a brief infusion lasting several hours. No special laboratory testing is needed. Currently, the only contemporary thrombolytic regimen for pulmonary embolism that is approved by the Food and Drug Administration is tissue plasminogen activator, in a dose of 100 mg/2 h. New thrombolytic agents under development for pulmonary embolism include reteplase, saruplase, and recombinant staphylokinase. Future clinical trials will require multicenter collaboration and will focus on relevant endpoints such as the reduction of mortality and recurrent venous thromboembolism.

Thrombolytic therapy in acute myocardial infarction.

Early reperfusion of thrombotically occluded coronary arteries by thrombolytic therapy has become a routine option in initial therapy of acute myocardial infarction. Many efforts have been made to improve the biological properties of thrombolytic agents in terms of fibrin specificity, plasma half-life and resistance to natural plasma inhibitors, to improve adjuvant therapy and to shorten the 'pain to reperfusion' time. Numerous randomised, multicentre trials have analysed the benefit of the various thrombolytic agents and regimens, which has enabled the creation of a 'current standard of therapy'. This review presents an update on available thrombolytic agents, their biochemical and pharmacological properties and results from clinical trials.

Combination therapy for acute myocardial infarction: Fibrinolytic therapy and glycoprotein IIb/IIIa inhibition

Reperfusion with a regimen of fibrinolytic therapy, aspirin, and unfractionated heparin is limited by a less than desirable reperfusion rate, an excessive reocclusion rate, a dose-limiting intracranial hemorrhage rate, and a competitive posture relative to direct coronary angioplasty. Only 50% to 60% of patients achieve early Thrombolysis in Myocardial Infarction grade 3 flow within 90 minutes with the most effective thrombolytic regimens. Even after initial reperfusion is achieved, transient and permanent reocclusion occurs too often and is associated with a high mortality rate. As more older patients are being treated, intracranial hemorrhage is becoming more common. Finally, the risk of bleeding and procedural failure has been high in patients who received an acute percutaneous interventional procedure shortly after treatment with fibrinolytic therapy. Early studies combining full-dose fibrinolytic treatment and glycoprotein IIb/IIIa inhibitors have been promising with regard to overcoming these limitations, but concern about bleeding has hindered this strategy. Several recent trials have evaluated full-dose abciximab with reduced-dose fibrinolytic therapy and have yielded promising results. The complementary nature of the results from different trials is striking, with substantial evidence that approximately half the conventional dose of fibrinolytic therapy combined with full-dose glycoprotein IIb/IIIa inhibition with abciximab achieves high rates of grade 3 flow and excellent clinical outcomes. This approach will now be tested in a large-scale mortality trial. (Am Heart J 2000;139:S33-S37.)

Transumbilical balloon angioplasty of subclavian artery thrombosis in a neonate

We present a case of arterial thrombosis of the upper extremity in a 1-day-old neonate. The initial response to thrombolytic and anticoagulant therapy alone was unsuccessful. Distal flow to the extremity was reestablished by combined percutaneous transluminal angioplasty of the subclavian artery using transumbilical access followed by resumption of the thrombolytic and anticoagulant regimen. Cathet. Cardiovasc. Intervent. 49:56-60, 2000.

Debate: Should the elderly receive thrombolytic therapy or primary angioplasty?

Thrombolysis and primary angioplasty are both recommended reperfusion strategies for elderly patients presenting with myocardial infarction (MI). Primary angioplasty is most beneficial in high-risk patients. While the elderly have a high absolute risk of dying or developing complications after MI, they also have an increased risk of intracranial haemorrhage if they are given thrombolytic therapy. It could therefore be reasonably argued that primary angioplasty is the reperfusion strategy of choice in the elderly. However, primary angioplasty has not been shown to have a greater relative benefit than thrombolytic therapy in the elderly. Recent data from the Fibrinolytic Therapy Trialists' (FTT) Collaborative Group show that thrombolytic therapy significantly reduces mortality compared with control treatment in patients over 75 years of age presenting within 12 h of symptom onset, with ST-segment elevation or bundle branch block. Future advances in adjunctive therapies may improve myocyte perfusion and hence the outcomes achieved by both invasive and noninvasive reperfusion strategies. Better thrombolytic regimens incorporating adjunctive agents such as bivalirudin may reduce the risk of intracranial haemorrhage. Few hospitals can provide a 24-h primary angioplasty service with door-to-balloon times consistently less than 90 min, and thrombolytic therapy is therefore a far more practical option in most instances.

A randomized trial comparing primary angioplasty with a strategy of short-acting thrombolysis and immediate planned rescue angioplasty in acute myocardial infarction: the PACT trial

OBJECTIVESThe study evaluated the efficacy and safety of a short-acting reduced-dose fibrinolytic regimen to promote early infarct-related artery (IRA) patency during the inherent delay experienced by infarct patients referred for angioplasty as the principal recanalization modality.BACKGROUNDPrevious approaches using long-acting, full-dose thrombolytic infusions rarely showed benefit, but they did increase adverse event rates.METHODSFollowing aspirin and heparin, 606 patients were randomized to a 50-mg bolus of recombinant tissue-type plasminogen activator (rt-PA) (alpha half-life 4.5 min) or to placebo followed by immediate angiography with angioplasty if needed. The end points included patency rates on catheterization laboratory (cath lab) arrival, technical results when PTCA (percutaneous transluminal coronary angioplasty) was performed, complication rates, and left ventricular (LV) function by treatment assignment and time to restored patency following angioplasty.RESULTSPatency on cath lab arrival was 61% with rt-PA (28% Thrombolysis in Myocardial Infarction trial [TIMI]-2, 33% TIMI-3), and 34% with placebo (19% TIMI-2, 15% TIMI-3) (p = 0.001). Rescue and primary PTCA restored TIMI-3 in closed arteries equally (77%, 79%). No differences were observed in stroke or major bleeding. Left ventricular function was similar in both treatment groups, but convalescent ejection fraction (EF) was highest with a patent IRA (TIMI-3) on cath lab arrival (62.4%) or when produced by angioplasty within an hour of bolus (62.5%). However, in 88% of angioplasties, the delay exceeded 1 h: convalescent EF 57.3%.CONCLUSIONSTailored thrombolytic regimens compatible with subsequent interventions lead to more frequent early recanalization (before cath arrival), which facilitates greater LV function preservation with no augmentation of adverse events.

Glycoprotein IIb/IIIa blockade and thrombolytics: Early lessons from the SPEED and GUSTO IV trials

Reperfusion with a regimen of thrombolytic therapy, aspirin, and unfractionated heparin is limited by a number of factors. Only 50% to 60% of patients achieve early thrombolysis in myocardial infarction grade-3 flow within 90 minutes with the most effective thrombolytic regimens. Even after initial reperfusion is achieved, transient and permanent reocclusion occurs too often and is associated with high mortality rates. As more older patients are treated, intracranial hemorrhage is becoming more common. Finally, the risk of bleeding and procedural failure has been high in patients who received an acute percutaneous interventional procedure shortly after treatment with thrombolytic therapy. Given the important role of platelets in the thrombotic process and the relatively weak inhibitory effect of aspirin, it is reasonable to seek agents that will provide more profound platelet inhibition. Early studies with full-dose fibrinolytic and glycoprotein IIb/IIIa inhibitors have been promising, but concern about bleeding has hindered this strategy. Several recent trials have evaluated full-dose abciximab with reduced-dose fibrinolytic therapy and have yielded promising results. (Am Heart J 1999;138:S12-S15)

Influence of time to treatment on early infarct-related artery patency after different thrombolytic regimens

Background In an in vitro model, recombinant tissue-type plasminogen activator was significantly more effective than streptokinase in dissolving 24-hour-old human blood clots. Therefore there might be a difference in the effect of time to treatment on the efficacy of these fibrinolytics with different fibrin specificity in patients with acute myocardial infarction. Methods and Results The effect of the interval between symptom onset and initiation of therapy on the efficacy of 6 different thrombolytic regimens was studied in a retrospective analysis of 6 angiographic trials with similar design. The patency of the infarct-related artery was assessed by angiography 90 minutes after initiation of thrombolysis in patients who were seen within 6 hours after symptom onset. Patency rates of patients with an interval of ≤3 hours and >3 hours between symptom onset and start of therapy were compared. There was no difference for Thrombolysis in Myocardial Infarction (TIMI) grade 3 perfusion after front-loaded alteplase (72.5% vs 76.3%) and reteplase (63.6% vs 63.2% ) between the 2 groups. In contrast, in patients treated with streptokinase (36.8% vs 27.6%, P = .09), anisoylated plasminogen streptokinase activator complex (59.5% vs 34.8%, P = .004), and urokinase (62.3% vs 41.7%, P = .03), TIMI 3 patency decreased with the increasing interval between symptom onset and initiation of therapy. Conclusions We conclude from our data that the thrombolytic efficacy of recombinant tissue-type plasminogen activator and reteplase does not decrease with the increasing interval between symptom onset and initiation of therapy. In contrast, after anisoylated plasminogen streptokinase activator complex, streptokinase, and urokinase treatment, a decrease in patency, especially TIMI-3 patency in patients treated after >3 hours after symptom onset, was observed. These results may influence the choice of the thrombolytic agent in patients who are seen >3 hours after symptom onset. (Am Heart J 1999;137:34-8.)

Advances in the medical management of acute coronary syndromes.

Many advances in the treatment of acute coronary syndromes have been realized over recent years. In ST elevation myocardial infarction, new aggressive thrombolytic regimens improve early reperfusion and improve survival. The current focus is on bolus thrombolysis, glycoprotein IIb/IIIa inhibition, and low-molecular-weight heparin as adjuncts. In unstable angina and non-ST elevation myocardial infarction, two major advances are IIb/IIIa inhibition and low-molecular-weight heparin, each of which significantly improves the outcome of patients and which have just been approved for use by the Food and Drug Administration. Following acute coronary syndromes, cholesterol lowering with statin drugs has a major effect, even in the large group of patients with average cholesterol levels. Use of clopidogrel, a more potent antiplatelet agent than aspirin, appears to decrease recurrent ischemic events, which has highlighted the potential benefits of oral IIb/IIIa inhibitors, which are much more potent antiplatelet agents. An additional focus has been on ensuring that patients actually receive the currently available medications. With a great number of new medical treatments, the outcome of patients with acute coronary syndromes has improved and will continue to improve as we enter the next millennium.

Incidence and predictors of major hemorrhagic complications from thrombolytic therapy in patients with massive pulmonary embolism

PURPOSE: The risk factors for bleeding in patients receiving recombinant tissue-type plasminogen activator for massive pulmonary embolism are not known. PATIENTS AND METHODS: The hospital records of 132 consecutive patients who received recombinant tissue-type plasminogen activator for massive pulmonary embolism were retrospectively reviewed. Bleeding was estimated by using the bleeding severity index, a method previously validated in patients receiving anticoagulants. Multivariate stepwise logistic regression was used to identify independent risk factors for bleeding. Four other definitions of bleeding in large pulmonary embolism thrombolytic trials were also used, and the agreement among these criteria was assessed. RESULTS: According to the bleeding severity index, 33 patients (25%) had one or more major bleeding complications. Hemorrhage at the venous puncture site for angiography was the most frequent complication (15 patients, 11%). Major bleeding at the catheterization site was more common at the femoral site (14 of 63 patients = 22%) than at the brachial site (1 of 63 patients = 2%; P = 0.0004). The use of the five different bleeding definitions resulted in a variation in the major bleeding rate from 3% to 43%. The kappa coefficient varied from 0.07 to 0.84, indicating poor agreement between most of the classifications. CONCLUSION: The use of the femoral vein for pulmonary angiography was the only variable significantly associated with major bleeding. Most of the differences observed in the pulmonary embolism thrombolytic trials are likely related to the differences in the definition of bleeding rather than to the thrombolytic regimen.