Acute ST-segment elevation myocardial infarction (STEMI) is one of the most common and most significant emergencies in medicine where the good organization of medical care has a decisive impact on the results of the treatment of patients. Effective, early and rapid reperfusion therapy is the most important goal in the treatment of patients with STEMI, while the good organization of the primary percutaneous coronary intervention (pPCI) network has the most important role in providing optimal health care to patients in the acute phase of myocardial infarction.

In the review article on acute coronary syndrome (ACS) published in this issue of this journal (1) authors emphasize the importance of quick transport of STEMI patients without unnecessary delay to a hospital that is capable of performing pPCI and emphasize that in everyday clinical practice it is extremely difficult to achieve the target time of 2 hours as recommended by applicable guidelines. A significant contribution to this topic is given by the authors who cite the trial of Rolland and et al (2) in which they proved that a shorter time from the onset of symptoms to pPCI is associated with reduced long-term mortality and emphasized the importance of reducing each of the components that can affect the delay in providing timely pPCI in patients with STEMI. As one of the main reasons of unnecessary delays is that the patients are admitted to the emergency departments of hospitals, instead of direct emergency medical service transportation.

Modern cardiology literature also mentions many other features that are important in organizing regional pPCI networks that allow faster access to reperfusion therapy in patients with STEMI.

The aim of this review article is to draw attention to the pharmacoinvasive approach as one of the components within a complex system of management of patients for STEMI, show the most important clinical trials on pharmacoinvasive strategy and importance of this treatment modality of STEMI in contemporary guidelines, with an attempt to cause the acceptance of the concept of pharmacoinvasive approach and its incorporation into system of organized local pPCI network to change the paradigm on universal benefit of pPCI in the treatment of all patients with STEMI, thus enabling the provision of proper and timely reperfusion therapy to as many patients as possible.

The method pPCI represents the treatment of choice for patients with STEMI. In the last ten years pPCI as a revascularization strategy has replaced the fibrinolytic therapy. The greatest challenge in organizing the pPCI network is to make it available within the time frame specified by current guidelines, which is often not feasible due to a variety of structural problems.

Strong evidence supports favoring PCI as the method of choice for achieving reperfusion in STEMI. The meta-analysis of Keeley et al (3) included 23 randomized clinical trials (RCT) on comparison of fibronolysis and pPCI in STEMI. The pPCI method compared to fibrinolytic therapy significantly reduces the overall short-term mortality (7% vs. 9%), nonfatal reinfarction (3% vs. 7%), stroke (1% vs. 2%), and the common outcome of death, nonfatal reinfarction and stroke (8% versus 14%), while better results of pPCI persisted in long-term follow-up.

In 2009, Huyn et al (4) publicized more recent meta-analysis of comparison of pPCI and fibrinolytic therapy that in addition to 23 RCT also included 32 observational studies. Observational studies include a much larger number of patients and are thus more comprehensive and more realistically represent the daily practice. The cited meta-analysis, that is, the analyzed observational studies included 180,877 patients in 23 randomized clinical trials included a total of 8140 patients. The importance of the inclusion of observational studies in this meta-analysis lies in the fact that randomized trials were conducted by top interventional cardiologists in top centers, they also include patients who are younger and have less comorbidities than patients included in the registries that also include data for patients who underwent pPCI by operators and in lower volume centers and with potentially worse outcomes. pPCI is in comparison with fibrinolytic therapy in this meta-analysis also associated with a short-term reduction in mortality, reinfarction and stroke both in RCTs and observational studies. Long-term reduction in reinfarction and mortality has been proven only in RCT, and there was no difference in long-term reduction in mortality and reinfarction between pPCI and fibrinolytic therapy in observational studies.

There are data in the literature that fibrinolytic therapy administered in the early stage of STEMI within 2 hours from the onset of pains may have better clinical results than pPCI. The study 3 ASSENT shows that approximately 25% of patients who received fibrinolytic therapy within the first hour from the onset of the discomforts did not have myocardial necrosis by measuring the values of cardiac specific enzymes, which is referred to as “aborted” myocardial infarction (5, 6). The study PRAGUE 2 reported a trend that prefers fibrinolytic therapy rather than pPCI, if it is used within 3 hours from the onset of symptoms (7), and the identical trend has been noticed in the Vienna STEMI registry (8). In-hospital mortality in patients treated with thrombolytic therapy, which is administered within 2 hours from the onset of symptoms compared to patients treated by pPCI was 5.1% versus 7.8%. The study CAPTIM in patients in whom fibrinolytic therapy was used prehospitally within 2 hours from the onset of symptoms reported a lower mortality after 30 days than in patients randomized to pPCI (2.2% vs. 5.7%) (9).

The treatment by using the method of percutaneous coronary intervention (PCI) after fibrinolytic therapy in STEMI may be performed in a variety of clinical situations. The terms used in the literature are often confusing and in case when they are not clearly defined they can make it difficult to understand the results of the trials in which they are used. It is therefore important to define these situations, their indications and how they differ from pharmacoinvasive strategy. Clinical situations that should be distinguished from the pharmacoinvasive approach include rescue PCI, facilitated PCI and delayed PCI performed after more than 24 hours following the fibrinolytic therapy, no matter whether it was done routinely or after spontaneous or documented ischemia.

Dauerman and Sobel (10) were the first who used the term “pharmacoinvasive recanalization” which is defined as a pharmacological reperfusion with fibrinolytic therapy to be followed by delayed coronary angiography and PCI. Today, pharmacoinvasive strategy is a kind of reperfusion therapy involving initial application of the full dose of fibrinolytic therapy followed by routine invasive treatment and, if necessary, PCI in the time interval from 3 to 24 hours after administration of the fibrinolytic drug.

Rescue PCI is the intervention usually performed between 60 and 120 minutes after unsuccessful fibrinolytic therapy in patients with persisting symptoms and signs of myocardial damage or occluded coronary blood vessel. There are no reliable non-invasive methods for the reliable assessment of the success of recanalization by administering fibrinolytic therapy, but the generally accepted indications for rescue PCI are ST-segment resolution by less than 50% 90 minutes after fibrinolytic therapy in the discharge where the highest elevation was initially registered and the patients who following the fibrinolytic therapy have persistent symptoms develop cardiogenic shock, hemodynamic or electrical instability. The two meta-analyses confirm the justification of PCI in these indications (11, 12).

It is particularly important to distinguish between the pharmacoinvasive approach and the so-called facilitated PCI. This term refers to a strategy where PCI was planned in advance immediately after the initial administration of pharmacological therapy aimed at improvement of coronary patency before the procedure. The administered therapy includes a full or a half-dose fibrinolytic drugs and glycoprotein IIb/IIIa inhibitors, as well as the combinations of these two classes of drugs. Numerous clinical studies have shown that despite the greater myocardial infarct related artery patency in the diagnostic coronary angiography in a group of patients who received some of these drugs before the intervention, the orderly flow through the infarcted vessel was achieved in the same incidence in patients who were randomized to facilitated PCI compared to patients randomized to pPCI. Contrary to the expectations, it was proved that this approach even harmed patients not only due to a higher risk of bleeding as expected, but also due to a significantly higher risk of ischemic complications. Keeley et al (13) have published a review including 17 clinical trials that compared the facilitated PCI versus pPCI, of which nine with glycoprotein IIb/IIIa inhibitors, six with fibrinolytic drugs and two with a combination of fibrinolytic drugs and glycoprotein IIb/IIIa inhibitors. The facilitated PCI has led to an increase in short-term mortality by 38%, reinfarction by 83%, recurrent ischemia which required urgent revascularization by 218% and an increase in major bleeding 48%. The explanations for these adverse clinical events are probably that PCI performed very soon after fibrinolysis worsens bleeding both at the injection site and intracranial hemorrhage, myocardial reperfusion injury, bleeding in the myocardium itself, while the increase in ischemic complications is explained by the evidence that fibrinolytic therapy stimulates platelet activation thereby increasing the risk of recurrent ischemia and reinfarction (14).

Significant heterogeneities exist among the presented studies. The above trials differ from each other in the final followup objectives, there is variability in therapeutic strategies and protocols, frequency of performed invasive management and PCI in the conservatively treated groups, frequency of rescue PCI, times from the early fibrinolysis to early PCI, type of administered fibrinolytic drugs, frequency of the use of GP IIb/IIIa inhibitors, and significant differences in the use of clopidogrel between invasively and conservatively treated groups of patients. There are major differences in the way of defining recurrent ischemia and different classification of clinical major bleeding.

Borgia et al (24) in a meta-analysis which included all clinical trials presented in this article, except for STREAM study, which has been published only recently conclude that early routine PCI following the fibrinolytic therapy in STEMI patients significantly reduces reinfarction and recurrent ischemia, with no major increase in bleeding and the benefits of this approach persist even after 6-12 months, and therefore they advocate early pharmacoinvasive approach for all patients who for organizational reasons cannot be treated by using the PCI method. For the differences among the trials specified above, Bogaty (25) decides to call its analysis a systematic review RCT, not a meta-analysis and very cautiously concludes that there is no evidence strong enough for reaching definitive conclusions about the optimum frequency of coronary angiography and revascularization after fibrinolysis or whether pharmacoinvasive strategy is superior to the proper selective documented ischemia-guided approach. An earlier meta-analysis of Wijeysunder et al (26) included up to five previously published RCTs, and the authors concluded that early routine invasive strategy after fibrinolytic therapy significantly reduces mortality and reinfarction, but also that the results of the meta-analysis can only generate a hypothesis that a routine invasive strategy after fibrinolytic therapy is associated with better clinical outcomes, but are not sufficient for definitive recommendations.

The systematic review of RCT in this article does not mention the incidence of major bleeding because all the mentioned studies included in the meta-analysis Borgia et al (24) show that there is no increased risk of bleeding in patients with pharmacoinvasive approach compared to the patients treated with standard therapy, identical to the conclusion reached by Wijeysunder (26).

Increased risk of ischemic and hemorrhagic complications, which discredited facilitated PCI does not exist in the studies with pharmacoinvasive approach. Timely and well-selected time when PCI was performed (in more recent studies between 3 and 6 h after administration of fibrinolysis) avoids the risk of bleeding, and the use of modern antiplatelet and anticoagulant therapy avoids the risk of reocclusion, recurrent ischemia and stent thrombosis in the prothrombotic period following the administration of fibrinolytic drugs. It is only the STREAM study where an increase in the risk of intracranial hemorrhage was recorded, but it is practically negligible after the correction of the tenecteplase dose.

The STREAM study that has been recently published and is not included in the above meta-analyses was designed according to the current European guidelines on the treatment of patients with STEMI. This trial has definitely established the pharmacoinvasive strategy and showed that pharmacoinvasive strategy consisting of fibrinolytic therapy with concomitant use of modern antiplatelet and anticoagulant therapy (administered within three hours from the onset of symptoms in patients who are unable to undergo pPCI within one hour from the first medical contact, to be followed by timely invasive treatment) is as effective as pPCI.

From July 2010 to July 2011 a total of 128 patients with STEMI were treated in the General Hospital “Dr Josip Bencevic” in Slavonski Brod. During that period, the treatment by applying the pPCI method was accessible only during the working hours in the first shift, so a pharmacoinvasive approach was introduced in the daily work due to such organizational limitations. Intra-hospital lethality in patients treated by pPCI was 3%, and in patients treated by pharmacoinvasive approach it was 5%. We concluded that in the areas where pPCI cannot be organized in acceptable timeframes, urgent PCI within 24 hours from the moment of fibrinolytic therapy is also equally safe and efficient method of reperfusion (27). In this issue of the journal we have presented a protocol of management of patients with STEMI in Western Slavonia, whereas we have implemented a pharmacoinvasive approach in this protocol in our daily work (28).

According to the most recent European (29) and American (30) guidelines on the treatment of patients with STEMI, pPCI remains the preferred method of reperfusion if it can be performed timely by experienced operators. The recommended way of triage of patients represents the involvement of the emergency medical service with direct transportation of patients to a hospital capable of treating patients applying the pPCI method.

Both guidelines in the algorithm have separate recommendations depending on whether the hospital where the patient is presented is or is not capable of performing pPCI. For patients who are presented in the hospital capable of undertaking PCI, the target time from the first medical contact, FMC to reperfusion is 60 minutes in the European, while the American guidelines allow for 90 minutes.

The differences are somewhat more significant in the case when a patient with STEMI comes to the hospital not capable of undertaking pPCI. The European guidelines introduce the categories of desirable and acceptable time to reperfusion and patients are also categorized depending on the time that has elapsed from FMC to reperfusion. Thus, the European guidelines recommend that the desirable time from FMC to pPCI is 90 minutes and acceptable up to 120 minutes, while for the patients with early presentation (time from onset of pains to FMC less than 120 minutes) the desirable time is < 60 minutes and acceptable time up to 90 minutes. For all patients in whom pPCI cannot be performed within 120 minutes undergo thrombolysis within 30 minutes from the FMC, preferably prehospitally within the first 120 minutes from the onset of symptoms. All patients treated with thrombolysis should be transported to the center capable of undertaking pPCI without delay, regardless of the success of fibrinolytic therapy (class IA), where it will be decided whether rescue PCI will be immediately performed if there are no signs of reperfusion or whether the routine angiography will be performed within the period from 3 to 24 hours if fibrinolysis was successful.

For patients who present to an institution that is not capable of performing pPCI the American guidelines introduce the concept of DIDO (door-in-door-out time) and suggest that the ≤30 minutes time is associated with lower hospital mortality. The pPCI method is a preferred method of reperfusion if it can be organized within 120 minutes. For all patients for whom the time from FMC to pPCI due to delay not to be avoided is longer than 120 minutes, the approach is identical to the European guidelines: fibrinolysis is indicated within 30 minutes from FMC. The American guidelines also recommend routine coronary angiography for all patients treated with fibrinolysis, whereas the patients in cardiac shock and severe acute failure are recommended to undergo emergency invasive treatment (class I recommendation), the term rescue PCI is no longer used and the routine coronary angiography has a class IIa recommendation for all other patients treated with fibrinolytic therapy, whereas it is recommended to be undertaken it as soon as possible, ideally within 24 hours, but not within the first 2-3 hours after the fibrinolytic therapy was performed.

The guidelines on both sides of the Atlantic Ocean clearly emphasize the principle that the proper and timely application of one of the potential forms of reperfusion therapy is more important than a choice of therapy itself.

Pharmacoinvasive strategy encompasses a good triage of patients in the field and selective use of fibrinolytic therapy for properly selected patients to be followed by prompt transportation of patients to a PCI center and organizing invasive treatment within 3-24 hours. It should be considered as a potential method of reperfusion in STEMI patients in whom fibrinolytic therapy can be initiated within three hours from the onset of pains, and the expected time to reperfusion by the pPCI method (time of passage of the guide wire through the responsible lesion) exceeds two hours. This method of reperfusion leads to a significant reduction in reinfarction and recurrent ischemia without an increased risk of bleeding and should be implemented in regional protocols for management of patients with STEMI, whereby a number of patients receiving proper and timely reprefusion therapy would increase.