VIEWS & REVIEWS

New moves towards better thrombolytics

-Gill Higgins-

Conventional 90-minute patency measurements may be overestimating the therapeutic efficacy of thrombolytic agents. This calls for action in 2 directions: improvement in drug efficacy and a revision of assessment methods. Both of these issues were discussed during the XIVth Congress of the European Society of Cardiology held in Barcelona, Spain, earlier this month.

Early restoration of blood flow in the coronary artery is still believed to be the mainstay of treatment for acute MI. For this reason, researchers continue their efforts to improve early infarct coronary patency.

&tablishing measurements of optimal reperfusion

Professor Neuhaus from Kassel, Germany, conducted studies involving 939 patients with acute MI presenting within 6 hours to try to establish a measurement of optimal reperfusion. The patients were in 1 of 4 studies, each with a similar protocol but involving a different drug (one of anistreplase, urokinase, alteplase or recombinant plasminogen activator). Using angiography at 60 minutes, 90 minutes, and 48 hours, the following data using TIMI (Thrombolysis on Myocardial Infarction) grading were collected: • 75.4% had TIMI grade 11/111 flow at 90 min • 61.9% had TIMI grade III flow at 90 min • 54.7% had TIMI grade III flow at 90 min,

sustained to 48 hours • 45.5% had TIMI grade III flow at 60 and 90 min.

sustained to 48 hours.

It appears inappropriate to use the conventional 90-minute patency rate as a

sole measure of thrombolytic efficacy

If the mortality data for this cohort of patients are considered, it becomes clear that successful clinical outcome appears related to the degree of patency, the onset of patency and whether or not it is maintained [see table /].

18b1e I: Effect of patency cbaracteristies on mortality

PatInc:y cIwIIctIrI8IIca HospItal mortality at 90 min

TIMIM 7%

TlMIIIIIII 3.4%

TIMIIII 2.7%

TlMI III sustained <2%

Thus, it appears inappropriate to use the conventional 90-minute patency rate as a sole measure of thrombolytic efficacy, as such a definition includes partially perfused infarct arteries and neglects early reocclusion, reinfarction and death.

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Methods to improve current therapy must be addressed

The conclusion from the data is that perfusion should only be regarded as 'optimal' if it is complete (i.e. TIMI grade III ) during early angiography, and sustained until the control angiogram after 24 hours. This theory needs to be verified in larger clinical trials to confirm the relationship between patency and successful clinical outcome.

How can patency rates be improved? Given that early and sustained patency is the

ultimate goal of thrombolysis, methods to improve current therapy must be addressed. Professor Neuhaus suggested 3 ways to achieve this including: • greater inhibition of thrombin • prevention of platelet activation, and • improvement of current plasminogen activators.

Thrombin inhibition It was generally considered that heparin would

soon be outmoded by more specific inhibitors such as hirudin or hirulog. These latter 2 agents have the advantage of binding to thrombin directly and, therefore, may exert a greater effect.

Prevention of platelet activation Improving upon aspirin will pose a considerably

greater challenge to any competitor, Professor Neuhaus commented. However, alternatives are under development such as Centocor's c7E3 rCentoRx ') which uses specific antibodies selective for the GP IIb/llIa region of platelets. Another contender is tapostene, a chemically stable prostacyclin analogue.

Dr H Darius from the University of Mainz, Germany, presented a study which indicated that the administration of tapostene in addition to the thrombolytic agent saruplase achieved greater prevention of platelet activation and better vessel patency than saruplase + placebo.

Plasminogen activators The plasminogen activators currently in use are

all effective. However, it may be possible to improve upon the regimens of these drugs or perhaps to utilise combination therapy.

For example, clinical studies have shown that a frontloaded alteplase regimen leads to complete perfusion in 72% of patients compared with 54% of patients treated with anistreplase. In addition, the number of failed thrombolysis attempts was reduced from 30 to 15% in the front loaded alteplase group. The impact of these reductions may become clear following the results of the Global Utilisation of Streptokinase and Alteplase for Occluded Coronary Arteries (GUSTO) study.

Simple administration important In addition to requiring effective patency rates, a

thrombolytic agent should also be simple to

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6 VIEWS & REVIEWS

administer. This point was mentioned by Dr Rawles. one of the investigators of the Grampian Regional Early Anistreplase Trial (GREAT). [See Inpharma 854:12.12 Sep 1992.J Anistreplase was chosen for this study because of its ease of administration (a single bolus lasting 2-5 minutes). He made it clear that agents such as alteplase would be impractical for administration in settings out of hospital.

It appears likely that these newer agents, and the modified regimens of current

agents, will improve perfusion rates and decrease the total duration of ischaemia

Indeed. the current alteplase regimen is complicated, consisting of a bolus injection, rapid infusion and then slow infusion. lasting a total of 90-180 minutes. Three studies have been conducted to establish whether bolus alteplase alone could be effective. Unfortunately, all 3 studies concluded that the patency rates were less than satisfactory with concomitant high rates of occlusion and early intervention. It has been postulated that the short half-life of alteplase is responsible for the disappointing results.

Such pharmacokinetic properties have become a focus of new drug development. For example, Boehringer Mannheim's BM 06022 is a plasminogen activator currently in Phase II trials which has a half-life 3.3-fold greater than alteplase. Bolus administration of this drug in the clinical setting is a strong possibility.

Does the answer lie with double bolus? Although single bolus injection may be

inappropriate for alteplase, a double bolus technique has been tested by Dr JA Purvis from the Royal Victoria Hospital in Belfast, UK. He presented results of a study of 122 patients given 150mg aspirin and either alteplase 50mg as a single bolus or as a 20/50, 50/20, or 50/50mg double bolus separated by 30 minutes.

The 50/50mg dose produced optimal patency compared with the other regimens (p < 0.05) with 90% patency at 60 minutes and 93% at 90 minutes, with minimal bleeding. Thus, a happy medium may be achieved using this double bolus technique. However, its efficacy must be confirmed in comparative trials.

Adding fast-acting activators an alternative An alternative approach is to add a specific and

fast-acting activator to streptokinase. Professor Neuhaus spoke of one study performed in 1990 which compared alteplase and streptokinase versus streptokinase alone. The combined treatment produced a slight improvement in the 90 minute patency rate, but a prominent reduction in the rate of reocclusion resulting from ischaemia and reinfarction. This is in keeping with data from the Thrombolysis and Angioplasty in Myocardial Infarction-V (TAMI-V) study that combined alteplase and urokinase.

19 Sep 1992INPHARMA'"

New agents am underway In addition to developments with current drugs.

novel activators are also underway. These include recombinant plasminogen activators, e.g. BM 06022. vampire bat plasminogen activator. antibody thrombolytics and new regimens such as alteplase plus hirudin and front-loaded alteplase plus heparin.

'There's still a lot of room for improvement in early restoration of coronary flow.'

Professor Neuhaus. Germany

From research to date, it appears likely that these newer agents, and the modified regimens of current agents, will improve perfusion rates and decrease the total duration of ischaemia.

The true value and clinical importance of these changes are being tested in the GUSTO study. Almost 30,000 patients have been enrolled and the results are expected early next year.

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