Reflections on the Danish Revolution

Mark C Petriea

a Department of Cardiology, Western Infirmary of Glasgow, Glasgow, UK

Felix Zijlstrab,*

b Department of Cardiology, Academic Hospital Groningen, Groningen, The Netherlands

* Corresponding author. Present address: Thorax-Centre, P.O. Box 30001, 9700RB Groningen, The Netherlands.
E-mail address: mcp1n{at}udcf.gla.ac.uk

Cardiologists have for some time accepted that primary angioplasty, at least in the best hands, results in improved outcomes in patients with ST segment elevation myocardial infarction when compared to thrombolysis. An impasse had, however, arisen in the cardiology community. Primary angioplasty was regarded as the treatment that we would like to receive, and to offer, but the results of the well conducted trials have been regarded as impossible to translate into routine clinical practice. Arguments against the routine use of primary angioplasty had centred on the assumption that these results were only achievable in high volume centres manned by high quality staff. This year two landmark publications have forced us to radically reassess the role of primary angioplasty in the management of acute myocardial infarction.

The first was a Lancet meta-analysis of 23 trials that demonstrated in the clearest terms yet the benefits of primary angioplasty.1 For every 50 patients treated, 1 life is saved. This mortality benefit is remarkable as primary angioplasty has been compared not to placebo but to a therapy, thrombolysis, with a well-documented mortality benefit of its own. Improved mortality was evident on both short- and long-term analyses. In the now vast world of clinical trials, benefit over and above efficacious therapy is notoriously difficult to demonstrate and is only rarely achieved. Patients treated with primary angioplasty also return less often with recurrent myocardial infarctions. One myocardial infarction is prevented for every 25 patients treated. Perhaps the most appealing finding for clinical cardiologists is the reduction in stroke frequency. One stroke is prevented for every 50 patients treated.

While the meta-analysis convinced us of the benefits of angioplasty in good hands, it is a second trial that has revolutionised our thinking with regards to the feasibility of providing primary angioplasty as part of our routine clinical services. This trial was included in the meta-analysis prior to its very recent formal publication.2 The Danes organised a large part of their country (62% of the population was covered) into areas covered by hospitals offering primary angioplasty. Patients were randomised to receive either primary angioplasty or thrombolysis. If the base hospital did not offer primary angioplasty, patients were transferred to one of five interventional centres. The Danes excitingly found that primary angioplasty in a "real-life" (albeit trial-based) situation produces similar benefits on almost a nationwide basis to those achieved in the earlier trials. Indeed the trial was stopped early due to a 40% relative risk reduction in the primary endpoint of death/reinfarction/disabling stroke. The reduction in the primary endpoint was driven by a marked reduction in reinfarction (although this trial was included in the Lancet meta-analysis,1 which clearly demonstrates the benefits of primary angioplasty in terms of stroke and mortality). We believe that a similar strategy of inter-hospital transfer for primary angioplasty could be applied in many parts of the world.

What are the logistical considerations?

Do we need a great expansion of cardiac catheterisation laboratories? Patients in DANAMI-2 were transported a median distance of 50 km. Eighteen percent were transferred 76–150 km. Not every hospital, therefore, needs to offer round the clock primary angioplasty. Certainly in Western Europe much of the population lives within 100 km of an interventional centre. In more isolated areas, there will be obstacles to providing such a service for which individual, local solutions will have to be found.

Do we need a large number of cardiologists skilled in the technical aspects of percutaneous intervention? As relatively few centres are required, relatively few operators can cover large areas. One of the most interesting aspects of the trial was the experience of the operators. Only two of the five interventional centres had any previous experience of primary angioplasty. All were high volume, "day-time" interventional centres. It is reassuring that operators were able to adapt their skills to primary angioplasty, as this is likely to be reflected in the experience of similar centres as they open throughout the day across the world. It should be noted that DANAMI-2 included the learning curve of these operators and still achieved rewarding results. As experienced operators achieve even better results,3 it is reasonable to anticipate that as centres become more practiced improved outcomes will follow.

Timing of primary angioplasty

The "golden hour" is well recognised in relation to thrombolysis. When primary angioplasty is employed as the reperfusion strategy, the reduction in treatment efficacy resulting in delay from symptom onset to treatment is much less striking.4 DANAMI-2 reported that patients with symptom to angioplasty time of 2 h, 2–4 h and 4 h had the same relative benefit when compared to thrombolysis.2 Patients should of course be transferred swiftly but this does allow time for the catheterisation lab team to assemble resulting in a short door to balloon time in the interventional centre.

Is there corroborating evidence?

Although DANAMI-2 is by far the largest trial involving inter-hospital transportation for primary angioplasty, there are previous trials with similar findings. Including DANAMI-2, a total 2466 patients in five trials have now been randomised to thrombolysis or inter-hospital transportation for primary angioplasty.5 These combined trials demonstrate that if 30 patients are transferred in this way, one life is saved. For every 14 patients transferred, 1 death, non-fatal re-infarction or stroke is prevented.

Can we afford not proceed with the implementation of primary angioplasty?

The answer is clearly no. If any doubt did persist in the mind of anyone involved in organising cardiological services, we need to consider two groups of patients who present not infrequently. These are patients who are not eligible for thrombolysis and patients with cardiogenic shock following a myocardial infarction. When a patient presents who is not eligible for thrombolysis, it would be difficult to justify not being able to offer either thrombolysis or primary angioplasty. The SHOCK trial demonstrated convincingly that the best management for a patient who experiences post-myocardial infarction cardiogenic shock is early revascularisation.6 For every seven patients treated, one life is saved. These two patient groups mean that every hospital must have a mechanism of action in place to access primary angioplasty. If 24-h availability of angioplasty is essential why not, by the same mechanism, provide routine primary angioplasty.

Should we delay to find out what might be the optimal combination of reperfusion strategies in acute myocardial infarction?

The role of pre- and in-hospital thrombolysis and glycoprotein IIbIIIa inhibitors in the management of acute myocardial infarction is not yet clear. Perhaps the most encouraging results so far have been achieved with abciximab administered prior to angioplasty.7 Until clear clinical benefits of these agents are demonstrated, we would urge that the maxim should be to be "safe and useful" and certainly to avoid doing harm. Aspirin should, of course, be given as early as possible.

Why is primary angioplasty better for patients with acute myocardial infarction than thrombolysis?

The answer is simply that thrombolysis works by causing fibrin-rich thrombus to break up. This is of course only the solution when this is the problem. An early pathological series of victims of acute myocardial infarctions found thrombus in only 54% of patients.8 In patients with acute myocardial infarction, a thrombectomy catheter was only able to retrieve recent thrombus in 49% of cases.9 These findings are consistent with the success rate of thrombolytic therapy in restoring TIMI 3 flow (50–60%). The catastrophe that follows plaque rupture has long been known to result in occlusion of the lumen by multiple mechanisms other than simple thrombus formation. Sometimes the lumen is obstructed by a dissected flap. Sometimes there is severe intramural haemorrhage. In other words, what is happening inside the artery is more than just occlusion by fresh thrombus. A ceiling exists under which the benefit of thrombolysis is trapped. This appears to be in the region of 60%. Primary angioplasty provides a mechanical solution that is able to tackle occlusion caused by a variety of different pathophysiological mechanisms.

DANAMI-2 demands a revolution in coronary care. While this revolution builds on the introduction of coronary care units in the 1960s, more emotionally for cardiologists this new revolution does usurp one of the jewels in the crown of evidence-based cardiology. Thrombolysis has been regarded with some reverence as the answer to the clot that is (sometimes) occluding the artery. We now know that when an occluded artery is opened by mechanical means with primary angioplasty, a better clinical result for the patient is achieved. The most appropriate strategy for patients presenting to a hospital with or without invasive facilities is clearly an interventional approach.

Guidelines should rapidly be up-dated to reflect this revolutionary trial. In the meantime, cardiologists everywhere should contact their colleagues to agree on an action plan to realise the benefits of primary angioplasty for their own populations.

References

  1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003;361:13–20.[CrossRef][Medline]
  2. The DANAMI-2 investigators. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med 2003;349:733–42.
  3. Canto JG, Every NR, Magid DJ et al. The volume of primary angioplasty procedures and survival after myocardial infarction. for the National Registry of Myocardial Infarction 2 InvestigatorsN. Engl. J. Med. 2000;342:1573–1580.[Abstract/Free Full Text]
  4. Zijlstra F. Clinical characteristics and outcome of patients with early (2 h), intermediate (2–4 h) and late (4 h) presentation treated by primary coronary angioplasty or thrombolytic therapy after acute myocardial infarction. Eur. Heart J. 2002;23:550–557.[Abstract/Free Full Text]
  5. Zijlstra F. Angioplasty vs thrombolysis for acute myocardial infarction: a quantitative overview of the effects of interhospital transportation. Eur. Heart J. 2003;24:21–23.[Free Full Text]
  6. Hochman JS, Sleeper LA, Webb JG et al. Early revascularisation in cute myocardial infarction complicated by cardiogenic shock. N. Engl. J. Med. 1999;341:625–634.[Abstract/Free Full Text]
  7. Montalescot G, Barragan P, Wittenberg O et al. Platelet gpIIbIIIa inhibition with coronary stenting for AMI: results of the ADMIRAL trial. N. Engl. J. Med. 2001;344:1895–1903.[Abstract/Free Full Text]
  8. Roberts WC, Buja LM. The frequency and significance of coronary arterial thombi and other observations in fatal acute myocardial infarction. A study of 107 necroscopy patients. Am. J. Med. 1972;52:425–443.[Medline]
  9. Murakami T, Mizuno S, Takahashi Y et al. Intracoronary aspiration thrombectomy for acute myocardial infarction. Am. J. Cardiol. 1998;82:839–844.[CrossRef][Medline]




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