Thrombolytics

Characteristics of an ideal thrombolytic agent would include the following:

• Rapid acting
• High efficacy in terms of both 60-90 min. vessel patency (TIMI grade flow)
• Low incidence of adverse reactions, particularly bleeding and stroke
• Low re-occlusion rate
• Easy to administer (bolus vs. infusion)
• Simple, patient-tailored dosage regimen
• Good long-term effects on clinical outcome
• Cost-effective

Metalyse^® is the only thrombolytic that can be given as a single bolus in a simple injection over 5 to 10 seconds. This makes it ideal for pre-hospital administration.

Streptokinase is still the most frequently used thrombolytic agent in some parts of the world, because of its low acquisition costs but patients need to be hooked up to the IV bottle for administration. The large Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) I study showed that mortality results with streptokinase were significantly inferior to those produced by alteplase. Therefore alteplase became the gold standard for pharmacological reperfusion therapy until the advent of Metalyse^®, but alteplase also needs IV administration. The Assessment of the Safety of a New Thrombolytic (ASSENT)-2 study demonstrated that Metalyse^® was equivalent to alteplase in terms of mortality and gave a statistically significant safety improvement in the rate of major bleeding incidents, with the advantage of IV administration.

Reteplase, the remaining available lytic, was shown in the International Joint Efficacy Comparison of Thrombolytics (INJECT) study to be no worse than streptokinase in terms of survival benefit and is administered in two bolus doses separated by 30 min. To date, no trials have directly compared it with Metalyse^®. Because of their bolus administration and long half-lives, Metalyse^® and reteplase are the most feasible options for pre-hospital thrombolysis. However, use of double-bolus reteplase involves the inconvenience of timing the administration of the second bolus exactly 30 minutes after the first one, which may prove difficult in an emergency situation, and carries the risk of wrong dosage.

Ease of Administration

Infusion regimes with different agents

Streptokinase

Streptokinase is given intravenously as 1.5 million units in 50–250 mL of saline solution over 1 hour.

Alteplase

Alteplase is administered in three stages over 1.5 hours and the dosage adjusted for people weighting less than 65 kg. 15% of the dose is administered as an IV bolus over 1–2 minutes, followed by 50% as an infusion over 30 minutes, and the final 35% is infused over the subsequent 60 minutes.

Reteplase

Reteplase is also a double-bolus injection. A 10-unit bolus is injected intravenously as soon as possible after the onset of symptoms. 30 minutes later a second 10-unit bolus is injected.

Metalyse^® (tenecteplase)

Metalyse^® (tenecteplase) is injected intravenously over 10 seconds as a single bolus, at a weight-adjusted dose.

Fibrin specificity and systemic side effects of thrombolytics

Thrombolytic agents function by converting plasminogen into its active form plasmin, which degrades the fibrin components of a thrombus. The ideal thrombolytic would only convert plasminogen at the site of a thrombus to avoid the systemic side effects of thrombolytics with low fibrin specificity.

The first of these is the consumption of plasminogen at sites distant from the thrombus, which may lead to a reduction in the available plasminogen at the thrombus site, so that the effectiveness of thrombolysis may be compromised. This is known as the plasminogen steal effect.

The second side effect is consumption of alpha-2-antiplasmin by active plasmin at sites distant from the thrombus, which may induce a systemic lytic state, potentially increasing the risk of bleeding complications.

Metalyse^®

Due to its high fibrin-specificity, the conversion of plasminogen to plasmin by Metalyse^® is much greater in the presence of fibrin than in its absence. This decreases the systemic activation of plasminogen and the degradation of circulating fibrinogen, resulting in a modest reduction in the levels of circulating fibrinogen (5-10%) and plasminogen (10-15%) in the first 6 hours, and permits targeting of the infarct-related thrombus with minimised systemic effects.

High fibrin specificity, low plasminogen specificity

Metalyse^® has a reduced effect upon systemic coagulation factors compared to alteplase, because of its greater fibrin specificity. One study found that administration of Metalyse^® caused a 5-10% drop in fibrinogen over the first 6 hours, compared to a 40% drop after alteplase administration. The fall of plasminogen was only 10-15% after Metalyse^®, compared with a 50% drop after alteplase.

Pharmacokinetics of tenecteplase (TNK) and alteplase (rt-PA)

In the Thrombolysis In Myocardial Infarction (TIMI) 10B study, the plasma clearance of tenecteplase at single bolus doses of 30, 40 and 50 mg was compared with that of alteplase given as bolus plus 90-minute infusion (n = 159 with pharmacokinetic samples). The plasma clearance of tenecteplase ranged from 98.4±42 to 119.0±49 mL/min across the three doses, compared with 453±170 mL/min for alteplase. The plasma elimination half-life of tenecteplase ranged from 5.5±5.5 to 21.5±8.2 minutes. The corresponding half-life for t-PA is 3.5±1.4 minutes. As shown in the figure, after a single bolus of tenecteplase (at all three doses) the initial plasma concentration was higher than that of alteplase; the area under the curve for tenecteplase approximated that of alteplase.

TIMI 10B: Pharmacokinetics of TNK and rt-PA

Metalyse^® is modified on kringle-2 by substitution of one lysin, one histidine and two arginines by four alanines in positions 296-299. This mutation maps in a region that is crucial for interaction with fast-acting inhibitor plasminogen activator inhibitor 1 (PAI-1), the principal inhibitor of tissue plasminogen activator (t-PA) and urokinase, the activators of plasminogen and hence of fibrinolysis. PAI-1 is mainly produced by activated platelets.

The 80-fold higher resistance to inhibition by PAI-1 for Metalyse^® compared with alteplase adds to the easy administration of tenecteplase as a single bolus compared with front-loaded alteplase infusion.

Due to reduced plasma clearance and high PAI-1 resistance, Metalyse^® is the first thrombolytic agent that can be administered over 5-10 seconds in a single dose, thus offering clinicians the fastest administration of a thrombolytic agent to date in the treatment of heart attack. Its high fibrin-specifity permits targeting at the thrombus with minimised systemic effects.

Pre-Hospital Thrombolysis

Benefit of early thrombolysis

The amount of salvageable heart tissue is inversely related to the duration of coronary artery occlusion, up to 6 hours after the first symptoms of acute myocardial infarction (AMI), when myocardial ischaemia becomes irreversible. Boersma et al. evaluated 22 randomised trials (1983 to 1993) that compared thrombolytic treatment with placebo or control, to investigate the relationship between treatment delay and short-term mortality. For every 1000 patients treated with thrombolytic agent, 65 more will be alive at 1 month if treatment is administered in the first hour – the ‘golden hour’ – after symptom onset. 37 lives are saved for every 1000 patients treated in the 1-2 hour interval after symptom onset; 26 lives are saved for every 1000 patients treated in the 2–3 hour interval after symptom onset; 29 lives are saved for every 1000 patients treated in the 3–6 hour interval after symptom onset; and 20 lives are saved for every 1000 patients treated in the 7-12 hour interval after symptom onset.

Pharmacological reperfusion

Strategies for reducing time to treatment

Improving time to thrombolysis is critical to reduce morbidity and mortality from AMI. The time involved can be reduced by a combination of the following four strategies

• public education to shorten the delay in summoning help
• implementation of emergency department thrombolysis protocols
• use of rapid diagnostic techniques to confirm AMI
• implementation of pre-hospital thrombolysis by trained emergency-response personnel.

Many hospitals have, in recent years, improved their ‘door-to-needle’ times to a practical minimum, so further reductions in the ‘call-to-needle’ time are likely to be made by pre-hospital thrombolysis.

Absolute 35 day mortality reduction versus treatment delay

Pre-hospital thrombolysis shortens time from symptom onset to treatment

According to the WHO, in both developed and developing countries, 40 to 75% of all heart attack victims die before reaching the hospital.

A study by Pedley et al. describes the experiences in a rural district in Scotland after the closure of the coronary care facility of a small hospital. As this was expected to lead to an increase in delays to treatment, a system of pre-hospital thrombolysis delivered by paramedics that had clinical decision support from the base hospital was trialled. The authors report an impressive median ‘call-to-needle’ time of 52 minutes for patients who received pre-hospital thrombolysis, compared with 80 minutes in a cohort of urban residents and 125 minutes in a rural control group treated conventionally. Importantly, 64% of patients treated before arrival in hospital received thrombolysis within 60 minutes of medical contact, compared with 4% of the controls. This adopted policy seemed to be of low risk, caused minimal obstruction to practice, and ran smoothly over the 12 months of the study. Thus pre-hospital thrombolysis shortens time to treatment.

Composition of time delays in receiving thrombolysis

The average elapsed time from symptom onset to treatment has been 3 hours ever since the GUSTO I trial in 1993. The ASSENT-3 PLUS trial of pre-hospital Metalyse^® has broken that barrier: elapsed time from symptom onset to treatment was shorter by 47 minutes compared with the ASSENT-3 in-hospital trial. This was achieved with a 30-day mortality rate that dipped as low as 6%, even though the patients in this trial were at higher risk than those enrolled in previous ASSENT studies.

Pre-hospital thrombolysis shortens time from symptom onset to treatment

Pre-hospital vs in-hospital thrombolysis: significant reduction in all-cause mortality

Meta-analysis of six randomised controlled trials of pre-hospital versus in-hospital thrombolysis for AMI showed that pre-hospital thrombolysis was associated with a significant reduction of all-cause mortality (odds ratio 0.83; 95% CI 0.70-0.98) as well as reducing the time to thrombolysis.

Pre-hospital thrombolysis: potential for aborting acute myocardial infarction

Pre-hospital thrombolysis appears to be associated with a fourfold increase in aborted myocardial infarction (MI) compared with in-hospital treatment. In this retrospective, controlled observational study, a shorter time to treatment, a lower ST elevation, and a higher incidence of pre-infarction angina were predictors of aborted MI.¹

Aborted MI was defined as the combination of subsiding of cumulative ST segment elevation and depression to < 50% of the level at presentation, together with a rise of creatine kinase of less than twice the upper normal concentration. This study was neither prospective nor randomised. The authors stress that, as time to treatment is crucial for thrombolysis, it is ethically unjustifiable to conduct a study that assigns patients to either pre-hospital or in-hospital treatment.

1. Lamfers EJP et al. Abortion of acute ST segment elevation myocardial infarction after reperfusion: incidence, patients’ characteristics, and prognosis. Heart. 2003 May; 89(5): 496–501.

Safety in pre-hospital thrombolysis

The safety of pre-hospital thrombolysis is strongly dependent on correct diagnosis, usually by means of a standard 12-lead electrocardiogram (ECG) that can either be transmitted via telephony for interpretation by a cardiologist or interpreted onsite by specifically designed computer programs. However, once an appropriate infrastructure is in place, the benefits of pre-hospital thrombolysis are unequivocal. It has been estimated that each 30-minute delay in giving thrombolytic therapy reduces the patient’s life expectancy by an average of 1 year.

Pre-hospital vs in-hospital fibrinolysis: Significant reduction in all-cause mortality

Pre-hospital thrombolysis check-list

• Ensure that the patient’s symptoms started less than 6 hours ago, because thrombolytics like Metalyse^® are licensed for the treatment of ST-elevation MI or recent left bundle branch block within 6 hours of symptom onset.
• Ensure that the diagnosis is correct: standard 12-lead ECG is needed, which can be interpreted on-site by specially designed computer programs or transmitted via telephone to skilled cardiologists; in both cases false-positive rates are similarly low.

Contra-indications to pre-hospital thrombolysis

It is important to check that the patient has no conditions with increased bleeding risk that are contra-indicated with thrombolysis. Always follow the licence recommendations.