באותו גיליון של ה- LANCET מתפרסמת תגובה מאד מעניינת ובוטה במידה מסוימת של Gregg W Stone מ-

Lenox Hill Heart and Vascular Institute, Cardiovascular Research Foundation למאמר הנ”ל. התגובה מובאת כאן כלשונה:

Commentary Primary angioplasty versus “earlier” thrombolysis¯¯time for a wake-up call Gregg W Stone Lenox Hill Heart and Vascular Institute, Cardiovascular Research Foundation, New York City, NY 10022, USA Available online 16 September 2002.

 See page 825 One of the longest running debates in cardiology has concerned the best reperfusion therapy in patients with evolving acute myocardial infarction (AMI).

The recognition that most cases of AMI are caused by thrombotic occlusion of a ruptured plaque resulting in diminished or absent blood flow in an epicardial coronary vessel inadequately supplied by collateral circulation[1] led to efforts to restore antegrade flow to interrupt the infarct process.

 The “wavefront phenomenon” of myonecrosis after coronary occlusion in a dog model [2] suggested that there may be a time window in human beings during which restoration of blood flow in the infarct-related artery could limit infarct size. These concepts were verified in large trials of thrombolytic therapy showing that timely reperfusion results in myocardial salvage and enhanced survival.

[3] The time from symptom onset to thrombolytic administration was related to reduced infarct size and mortality, with the greatest benefits within the first several hours after onset of the infarct. [3] From these observations arose the idioms of “time is muscle” and “the golden hour”.

The advent of percutaneous transluminal coronary angioplasty (PTCA) in 1977 provided an alternative method for the emergent recanalisation of an occluded infarct artery. Proponents of this “direct” or “primary” approach to reperfusion therapy argued that compared with thrombolytic therapy, PTCA results in higher rates of patency and TIMI-3 flow (TIMI stands for Thrombolysis In Myocardial Infarction and is a measure of epicardial blood flow in the artery; TIMI-3 is a normal flow to the heart).

 In addition, avoiding thrombolytic administration virtually eliminates the approximate 1% risk of intracranial haemorrhage inherent with systemic fibrinolysis.[4] Naysayers maintained that primary angioplasty resulted in excessive delays to treatment compared with thrombolytic therapy, was never proven beneficial in large trials, and was only available in a few hospitals.

Results from many multicentre randomised trials comparing primary angioplasty with thrombolytic therapy (streptokinase or recombinant tissue plasminogen activator) have settled this debate in the minds of all but the most die-hard “lyticists”, demonstrating reduced rates of death, reinfarction, recurrent ischaemia, unplanned revascularisation procedures, stroke, intracerebral bleeding, and earlier hospital discharge with the invasive approach.

[5] There have now been 22 such trials in which 6889 patients were randomised, demonstrating that for every 1000 patients treated with primary angioplasty rather than thrombolytic therapy, an additional 20 lives are saved, 43 reinfarctions are prevented, 10 less strokes occur, and 13 intracranial haemorrhages are avoided (meta-analysis by Ellen C Keeley, University of Texas Southwestern, and Cindy L Grines, William Beaumont Hospital in Detroit). Myocardial salvage is greater with percutaneous intervention than after thrombolytic therapy, [6] and primary angioplasty gives better results than thrombolytic therapy even in community hospitals.

 [7] Recently, primary angioplasty has been shown to reduce the composite rates of death, reinfarction, or stroke compared with tissue plasminogen activator even if patients must be transferred by ambulance for up to 3 h to reach an interventional centre.

 [8] Moreover, whereas the efficacy of pharmacological reperfusion has reached a plateau, the introduction of new devices, including coronary stents, and the optimisation of drug regimens during the angioplasty procedure has significantly improved the early safety profile and long-term results of percutaneous intervention in AMI.

 [9] Thus primary angioplasty, at experienced centres, is a superior method of reperfusion for evolving AMI. This conclusion now stands on firm evidence despite the unavoidable delays from presentation to angioplasty inherent with mobilising the team required for angiography and angioplasty, which averages nearly 2 h in the USA (60¯90 min in Europe).

[10] The mere fact that primary PTCA reduces mortality compared with thrombolysis despite these additional delays attests to the primacy of more complete reperfusion and mitigation of stroke, as well as secondary benefits from plaque stabilisation, anatomic definition, and late remodelling, as well as electrophysiological stabilisation from the open artery.

 [4] Nonetheless earlier reperfusion might further improve outcomes, [10 and 11] from which has arisen intense interest (but no proof) in so-called “facilitated angioplasty”, wherein early pharmacological reperfusion is married to definitive mechanical revascularisation. The current issue of The Lancet contains the latest salvo in the “primary PTCA versus thrombolytic therapy wars”, the well-designed and carried out CAPTIM trial.

In CAPTIM, 840 patients within 6 h of onset of myocardial infarction with acute ST-segment elevation were randomised to prehospital fibrinolysis with accelerated dosing of tissue plasminogen activator or to primary PTCA. Unfortunately, because of funding issues and slow enrolment, the trial ended before the planned recruitment of 1200 patients, the number necessary to demonstrate a 40% relative reduction in the primary 30-day composite endpoint of death, reinfarction, or disabling stroke with primary PTCA compared to early fibrinolytic administration.

 Nonetheless the results demonstrate a trend toward a 24% relative reduction in the occurrence of adverse events favouring the interventional strategy, driven by strong reductions in reinfarction and stroke (which would be expected, after all, to be largely independent of reperfusion time).

The fact that no difference in mortality was seen is not surprising given that a lower-risk population than anticipated was enrolled (3·8% mortality in the prehospital fibrinolytic group vs 7% in the Keeley and Grines meta-analysis). The survival benefit of primary angioplasty is mostly seen in high-risk patients, such as the elderly, those with anterior myocardial infarction, or shock.[4 and 12] The lack of a survival benefit in low-risk patients does not diminish the clinical relevance of fewer strokes, reinfarctions, a reduction in urgent revascularisation procedures, and the shorter hospital-stay with primary PTCA compared with tissue plasminogen activator in CAPTIM and other studies. Moreover, despite prehospital administration of fibrinolytic therapy, the difference between fibrinolytic administration and first balloon-inflation in CAPTIM was only 60 min, not much longer than the delays to PTCA in many of the earlier randomised trials; the coordination required for this study resulted in streamlining of patients’ care in the invasive arm as well, resulting in short door-to-balloon times. Thus the CAPTIM results fit nicely within the framework of our understanding of reperfusion strategies in AMI.

Of note, and perhaps the most novel finding from CAPTIM, is that prehospital thrombolysis tended to reduce the incidence of early-onset cardiogenic shock, presumably by promoting earlier reperfusion in patients prone to develop this condition. This observation adds fuel to the fire calling for facilitated primary PTCA trials. However, the additional costs and bleeding complications that will certainly accrue by adding thrombolytic therapy before primary angioplasty cannot be dismissed without evidence of overriding benefit. Moreover, four modest-sized randomised trials have thus far found facilitated PTCA either inferior to[13, 14 and 15] or no better than [16] primary PTCA alone.

 Indeed an integral component of the prehospital thrombolysis protocol in CAPTIM was immediate transfer to an interventional facility (with rescue PTCA required urgently in 26% of patients).

 Despite the fact that this strategy resulted in similar survival to primary PTCA in the low-risk cohort studied, the patients assigned to tissue plasminogen activator plus transfer in CAPTIM would probably have been better off by withholding thrombolysis for routine immediate PTCA after transport, thereby providing the full benefits of the invasive approach to every patient. Thus, until the large trials of facilitated PTCA are completed (none of which have even begun enrolling), the best therapy for most patients with evolving AMI should no longer be debated: administer antiplatelet therapy (aspirin, a thienopyridine and possibly abciximab[17]), withhold thrombolytic therapy, and transfer the patient for primary PTCA, regardless of whether the nearest catheterisation suite is three floors or 3 h away. To do less should no longer be considered standard care. Strong words, yes, but it is time for a wake-up call.

Volume 360, Issue 9336