a Cardiovascular Division, Brigham and Women's Hospital and the Department of Medicine, Harvard Medical School, USA
b Cardiovascular Division UT Southwestern Medical School, USA
* Correspondence to: C. Michael Gibson, M.S., M.D., 350 Longwood Avenue, First Floor, Boston MA, USA. Tel.: +1-617525-6884; fax: +1-888-249-5261
E-mail address: mgibson{at}timi.org
This editorial refers to "Time-to-treatment significantly affects the extent of ST-segment resolution and myocardial blush in patients with acute myocardial infarction treated by primary angioplasty"1 by G. De Luca et al. on page 1009
In this issue of the European Heart Journal, De Luca et al., demonstrate that among 1072 patients with ST-segment elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (PCI), prolonged times between symptom onset and the first balloon inflation are associated with impaired ST-segment resolution, impaired myocardial blush grades, larger infarct sizes and higher mortality.1 These data add to a growing body of literature suggesting that renewed efforts are needed to reduce symptom-to-door and door-to-balloon times in order to improve myocardial perfusion, myocardial salvage and clinical outcomes among patients undergoing primary PCI for STEMI.1
While an association between prolonged door-to-balloon times and mortality has been described previously, the association of symptom-to-door and symptom-to-balloon times has not been as well established in its association with mortality.2 The demonstration of such an association may be hampered by survival bias: those patients with prolonged symptom-to-door times may not survive to be included in analyses such as the present one.2 It is noteworthy therefore that despite being enriched with patients who survived the early hours of infarction, the present analysis still demonstrates an association of prolonged ischaemia with poorer outcomes. Prolonged symptom duration prior to fibrinolytic administration has previously been associated with impaired epicardial flow and myocardial perfusion and poorer clinical outcomes,3 and the present study demonstrates a similar association among patients undergoing primary PCI.
The association between increased duration of vessel occlusion and infarct size has been well characterised as "a wave front of necrosis" in animal models.4 The present analysis documents several key pathophysiological links with patient outcomes in STEMI which can be summarised in brief as follows: increased duration of vessel occlusion is associated with poorer perfusion on the angiogram (a dimmer or a stained myocardium) and poorer ST-segment resolutions which are both in turn associated with larger infarct sizes and worse clinical outcomes. Primary PCI restores TIMI grade 3 epicardial flow in the majority of patients, and it is important to note that the association of prolonged time-to-treatment with impaired myocardial perfusion was also confirmed in an analysis restricted to patients with post-procedural TIMI 3 flow.1
There are multiple pathological mechanisms that likely explain the association between longer duration of ischaemia and impaired myocardial perfusion, including time-dependent myonecrosis, oedema of the endothelium, myocardium, and sarcolemma, vasospasm (due to endothelial cell calcium overload and the release of vasoconstrictors), oxidative stress and re-perfusion injury, endothelial cell activation, embolisation of mature thrombo-resistant clots, and in situ formation of leucocyte aggregates in the coronary micro-circulation.5
Symptom-to-balloon times can be shortened by reducing both symptom-to-door and door-to-balloon times. Efforts to shorten door-to-balloon times have met with varied success: observational data from the National Registry of Myocardial Infarction (NRMI) 14 demonstrates that while door-to-needle times for fibrinolytic administration have fallen from 60 min to just over 30 min over the past decade, door-to-balloon times for primary PCI have dropped by only 10 min from 110 to 100 min when the intervention is performed on site.6 When inter-hospital transfer is involved, door-to-balloon times have dropped substantially from 228 to 171 min, but obviously remained quite prolonged. Indeed, when a transfer is involved, only 5% of patients in NRMI 4 achieved door-to-balloon times under 90 min.6
One emerging strategy to mitigate the impact of prolonged door-to-balloon times is the administration of pharmacological agents to open occluded arteries before PCI, in what has been termed a "pharmaco-invasive strategy" or "facilitated PCI".7,8 A variety of pharmacologic regimens are currently being evaluated for this purpose, including the administration of glycoprotein (GP) IIb/IIIa inhibitors, fibrinolytic agents, or the combination of GP IIb/IIIa inhibitors and reduced doses of fibrinolytic agents in advance of PCI. While the pharmaco-invasive strategy is intuitively appealing, few safety and efficacy data are currently available to help identify appropriate patients and to guide selection between the possible pharmacological regimens.
The other potential target for improvement lies in shortening symptom-to-door times. Unfortunately, these times have not improved in randomised trials over the past 15 years, and efforts to improve these times have met with limited success.9 In the Rapid Early Action for Coronary Treatment (REACT) study 89.4% of community survey respondents said they would use emergency medical services (EMS), yet only 23.2% of patients actually used an ambulance when they had chest pain.10 These data demonstrate the difference between what people understand is the right course of action and their actual behaviour when faced with a cardiac emergency.10 Denial of the cardiac origin of the pain remains a difficult issue to address. Patient education is one modifiable factor that may hasten patient arrival: those patients who self-prescribe ant-acids or aspirin (and who may have attributed the pain to another cause) are less likely to use EMS, while those who are familiar with heart disease and are taking nitroglycerine are more likely to use EMS.9,10 Specific educational efforts may be needed for diabetic patients who often present with atypical symptoms and were more likely to present late in the study by De Luca et al.
While prompt restoration of epicardial flow is essential in improving myocardial perfusion, it should be noted that adjunctive drugs (GP IIb/IIIa inhibitors) and devices (the Filterwire) have also been associated with improved myocardial perfusion in the setting of STEMI. It should also be noted that these drugs and devices were used infrequently in the present study.1
The present study lends further support to an intuitive and straightforward paradigm: prompt re-perfusion, whether achieved pharmacologically or through PCI, is associated with improved angiographic, electrocardiographic and clinical outcomes. We have witnessed a relentless push in the "new device" era to open arteries "better", but now is the time to emphasise the need to open them "quicker" in the setting of primary PCI. Now is the time to face the new challenge of educating both patients and providers to implement strategies to minimise delays in primary PCI.
Footnotes
References
Related articles in EHJ: