Bolus and accelerated thrombolysis: experimental observations and clinical management of myocardial infarction and pulmonary embolism – Editorial
Samuel Z. Goldhaber
Experimental Observations and
Clinical Management of Myocardial
Infarction and Pulmonary Embolism
“Bolus thrombolysis” and “accelerated thrombolysis” are vague terms that imply infusion of a high concentration of fibrinolytic agent over a short duration of time. This approach was initially evaluated in an experimental model of rabbit jugular vein thrombosis. The counterintuitive finding was that venous clots continued to be lysed even after rapidly infused thrombolytic agent could no longer be detected in plasma. Though the concentration of bolus and accelerated thrombolytic regimens was much higher than with standard regimens, bolus and accelerated thrombolysis paradoxically appeared to attenuate the fibrinogenolysis observed with conventional regimens.[1]
These experimental findings generated hypotheses that led to refinements of thrombolytic dosing strategies for acute myocardial infarction. Neuhaus et al[2] initially developed an accelerated recombinant tissue plasminogen activator (rtPA) regimen for patients with myocardial infarction, which was subsequently tested in the TAPS Trial.[3] By using a 15-mg rtPA bolus, then 50 mg/30 min, followed by 35 mg/60 min, remarkably high coronary angiography patency rates were achieved at 90 min: 72% complete reperfusion, ie, Thrombolysis In Myocardial infarction (TIMI) grade 3 (normal flow), and 84% patency, ie, TIMI grade 2 (slow flow) or 3 (normal flow).[3]
Although not yet approved by the Food and Drug Administration (FDA), the majority of American critical care physicians who treat acute myocardial infarction use the “GUSTO strategy” to provide accelerated rtPA dosing. The “GUSTO regimen” – 15 mg bolus, then 0.75 mg/kg over 30 min, not to exceed 50 mg, followed by 0.5 mg/kg, up to 35 mg, over the next 60 min – is very similar to the “Neuhaus regimen.” In GUSTO, this combination of accelerated rtPA plus intravenous heparin was tested in 10,396 patients with myocardial infarction[4] and was associated with extraordinarily low 30-day mortality rate of only 6.3%. This represents a major improvement in the efficacy and safety of coronary arterial thrombolysis compared with the prolonged, often 24-h, low-to-medium concentration dosing regimens that were first used to treat myocardial infarction in the 1970s.[5,6]
An angiographic substudy[7] found a coronary artery patency rate, ie, TIMI grade 2 or 3 flow, of 81% at 90 min after initiation of treatment. The hemorrhagic stroke rate was 0.72%. Importantly, this study confirmed the “early patency hypothesis,” because patients with complete, 90-min patency of infarctrelated vessels had better residual left ventricular function 5 to 7 days after infarction and were more likely to survive at 30 days after infarction compared with patients who had delayed opening of their coronary arteries. Nevertheless, even in the bolus/accelerated rtPA group, complete reperfusion with normal coronary blood flow, ie, TIMI grade 3 flow, was achieved in only 54% of patients, indicating the need for further improvements in thrombolysis/anticoagulation regimens.
Why is bolus thrombolysis effective, and why does clot lysis persist despite no detectable drug in plasma? Initially, the high concentration of bolus rtPA overwhelms plasminogen activator inhibitor-1 (PAI-1) and renders negligible any attenuating effects of PAI-1 on rtPA activity.[8] The prolonged fibrinolysis that persists after bolus thrombolysis, in the absence of rtPA circulating in plasma, has been presumed to be due to the continuing activity of rtPA directly at the site of the thrombus.
Since 1988, Richard Prewitt’s Laboratory in Winnipeg has published important experimental studies that have improved our conceptual understanding of bolus and accelerated thrombolysis strategies in the management of pulmonary embolism and myocardial infarction. Initially, a canine model of pulmonary embolism was used to demonstrate that 15-min administration of 1 mg/kg of rtPA resulted in more rapid initial thrombolysis than a 90-min infusion, with total lysis being equivalent in both groups.[9] When 5-min and 15-min infusions of 1 mg/kg of rtPA were compared in a subsequent study,[10] Prewitt’s group found a trend toward more extensive lysis with the 15-min infusion, even though plasma levels of rtPA were about threefold higher with a 5-min infusion. These latter results demonstrated an upper limit to the relationship between rtPA concentration and thrombolysis rate, possibly due to saturation of receptors for rtPA.
The Prewitt Laboratory has more recently used a canine model of acute myocardial infarction. They found, for example, that a 15-min infusion of 0.75 mg/kg of intracoronary rtPA resulted in more rapid clot lysis than a 45-min intracoronary infusion. However, by 2 h, the 45-min group “caught up” with the 15-min group, so that overall clot lysis was similar.[11]
In this issue of Chest (see page 1146), Prewitt and colleagues used an infarct model in which they injected 300 mg of radioactive clot into the left anterior descending coronary artery. They monitored thrombolysis with a gamma camera and showed that either a bolus or 30-min infusion of intravenous rtPA results in more rapid lysis and hemodynamic improvement than a 90-min infusion. However, the final extent of clot lysis was slightly higher in the 90-min group. Importantly, a bolus of heparin (100 U/kg) was administered before rtPA, and this was followed by a continuous infusion of heparin at 10 U/kg/h. Although they did not investigate the combination of bolus plus accelerated thrombolysis, the initial rate of thrombolysis would almost certainly have been increased if a loading dose had been used.
These results underscore the utility of using an experimental model that monitors the time course of thrombolysis. The favorable results obtained in the current study with single bolus rtPA serve to heighten interest in “double bolus” rtPA, a repetitive, high concentration, short infusion thrombolysis regimen. The “double bolus” rtPA case series,[12] in which 84 patients with myocardial infarction received two, 50-mg boluses of rtPA each given 30 min apart, extends the experimental findings of Prewitt and coworkers. The theory is that after 30 min, plasma levels of rtPA should be <1% of peak levels. The double bolus strategy yielded an impressively high coronary artery patency with complete reperfusion and normal coronary blood flow, ie, TIMI-3 flow, of 8g% at 60 min and 88% at 90 min after initiation of the first bolus. There was no intracranial bleeding. Currently, a randomized controlled trial is under way to compare the strategies of double bolus with single bolus/accelerated infusion of rtPA among patients with myocardial infarction.
Results from the Prewitt Laboratory can be applied to pulmonary embolism (PE) thrombolysis as well as to coronary artery thrombolysis. As the indications for PE thrombolysis are liberalized, an increasing number of patients with PE who receive thrombolysis will have a combination of normal systemic arterial pressure and right ventricular hypokinesis on echocardiogram.[13] Among these patients, who appear at first glance to be “hemodynamically stable,” the rapidity of clot lysis may not be of paramount importance because of the available collateral blood flow through the bronchial circulation. Instead, the extent of total clot lysis, in combination with intensive heparin anticoagulation, may be the most pivotal factor in preventing recurrent PE and restoring normal right ventricular function.
Recently published PE trials from France[14] and from the USA-Italy-Canada[15] did not demonstrate improved efficacy with a reduced bolus of rtPA (0.6 mg/kg, with a maximum dose of 50 mg, administered over 15 min) compared with the FDA-approved dose of 100 mg/2 h. In fact, an overview of the two studies showed a nonsignificant trend toward improved efficacy and reduced mortality with the 2-h regimen.[16]
More importantly, reduced bolus rtPA in no way confers protection against catastrophic hemorrhagic complications. For individual patients, avoiding a plasma proteolytic state may not be strongly linked to prevention of bleeding. Because it is clear that serious bleeding, including intracranial bleeding, can occur despite administration of reduced dose bolus rtPA,[17] patients being considered for reduced dose bolus thrombolysis should be subjected to a meticulous evaluation for possible contraindications, regardless of the thrombolysis dosing regimen.
Certainly, future experimental and clinical trials will improve the efficacy and safety of currently available pulmonary artery and coronary artery thrombolysis protocols. Despite the usual caveat against extrapolating canine results to man, the Prewitt Laboratory has increased our understanding of the advantages and limitations of bolus and accelerated thrombolysis.
At the moment, increasing focus is being placed on finding the safest and most effective conjunctive anticoagulant regimen for patients undergoing coronary arterial thrombolysis, because there appears to be excessive intracranial bleeding when high doses of heparin[18] or hirudin[19] are used. However, those of us who treat acute myocardial infarction with an accelerated 90-min rtPA regimen can rest assured that we currently have available excellent experimental and clinical trials as foundations for our practice.
Associate Professor of Medicine, Harvard Medical School, Cardiovascular Division, Brigham and Women’s Hospital. Supported by the National Heart, Lung, and Blood Institute Academic Award in Systemic and Pulmonary Vascular Medicine (HL02663). Reprint requests: Dr. Goldhaber, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115
REFERENCES
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