Fibrinolytic Therapy in Clinical Practice
Authors: K. S Channer
Journal: Journal of the Royal Society of Medicine (2004)

Thrombolysis revolutionized the early management of acute myocardial infarction. The treatment was designed around the established infarction pathophysiology—rupture of a coronary artery atherosclerotic plaque triggering in-situ thrombosis which results in coronary artery occlusion. Since the landmark ISIS-2 and GISSI studies there has been an explosion of randomized controlled clinical trials aimed at further reductions of hospital mortality by pharmacological manipulations of clotting and fibrinolysis. Now, however a new phase in the early management of acute infarction is being advocated—direct disruption of the occlusion by angioplasty. This is therefore a timely book. It is written by enthusiasts and each chapter stands alone and summarizes the trial evidence. But to get a balanced view you must read the whole book.

When any new treatment is developed it has to show benefits over the current standard in order to replace it, and the alternatives are compared by means of randomized controlled trials (RCTs). However, replication of trial results in the real world is often disappointing. For example, thrombolysis within 1 hour of onset of symptoms of acute myocardial infarction reduces mortality by up to 50% but this benefit is quickly lost, declining to only 10% by 12 hours. This dramatic effect should have resulted in falling hospital mortality after the routine introduction of thrombolysis, but single-centre registry data (from Nottingham for example) show very little impact on hospital mortality through the 1990s. Now, in the 21st century, we are seeing a real reduction in mortality because of a nationally coordinated emphasis on reducing door-to-needle time with the introduction of new models of care including pre-hospital thrombolysis and chest-pain nurse specialists as part of the National Service Framework for Coronary Heart Disease. We have just got thrombolysis working well.

In this book Stephen Ellis advocates a change to direct angioplasty. The justification is a 2% absolute reduction in 30-day mortality shown in a recent meta-analysis of the few small RCTs that have been done. Other benefits include a halving of the stroke risk and a bigger reduction in reinfarction and recurrent ischaemia. Just as in thrombolysis, registry data from the USA, which record the actual results of primary angioplasty in practice, show much less benefit and even increased mortality. This is explained by the delays associated with this treatment approach, which requires clinical evaluation in the emergency room and then transfer to a cardiac catheterization laboratory, coronary angiography and the angioplasty. Since 'time is muscle', when the delay from arrival-to-balloon time exceeds 90 minutes the mortality benefits of primary angioplasty over thrombolysis are lost.

The effects of delays in thrombolysis have been addressed in another chapter which focuses on pre-hospital thrombolysis. Here a gain of 1 hour in the average time-to-thrombolysis is associated with a reduction in mortality of about 2%. However, the absolute effect depends on when the delay occurs in the natural history of infarction. A delay of 1 hour at the start of symptoms results in a 6% absolute difference in mortality, whereas a delay of 1 hour once the infarction has become established (1–3 hours after symptoms) results in only a 1% difference and the same delay after 3–6 hours, only 0.2% absolute difference.

There are no conclusions presented in this book but the data clearly show that one size does not fit all. It appears to me that patients presenting within 3 hours of the onset of infarction should have thrombolysis. Those presenting later may benefit more by a strategy of primary angioplasty, provided that services can be organized to ensure that door-to-balloon time is no longer than 90 minutes. This will be some challenge in the UK, especially given the infrastructure costs of running such a service. The book addresses other associated questions around the use of adjuvant therapy with antiplatelet drugs and anticoagulants. The good news is that aspirin, albeit a weak platelet antagonist, gives the best therapeutic results without the disadvantage of serious bleeding complications. This is good news for the UK since aspirin is very cheap.