CCCardiol CroatCardiologia CroaticaCardiol. Croat.1848-543X1848-5448Croatian Cardiac SocietyCC_2013_8_12_435-44310.15836/ccar.2013.435Review articleApplication of pharmacoinvasive strategy in primary percutaneous coronary intervention network in Western SlavoniaPrvulovicDeitiGeneral Hospital “Dr. Josip Bencevic”, Slavonski Brod, CroatiaCorrespondence to Deiti Prvulovic, Opca bolnica “Dr. Josip Bencevic”, Stampareva 42 HR-35000 Slavonski Brod, Croatia; Phone: +385-35-201-685; E-mail: deiti.prvulovic@sb.t-com-hr122013122013812435443Croatian Cardiac Society2013Croatian Cardiac SocietySUMMARY
Croatian Primary Percutaneous Intervention Network is an internationally recognized system of good organization of urgent treatment of cardiac patients. In everyday clinical practice, we have witnessed that the time required for the organization of primary percutaneous coronary intervention (pPCI), which represents the best way of reperfusion therapy in the treatment of patients with acute ST-segment elevation myocardial infarction is often too long and associated with unacceptably long delays. Pharmacoinvasive strategy encompasses a selective use of fibrinolytic therapy to be followed by prompt transportation of patients to a center capable of undertaking percutanous coronary intervention and organizing invasive treatment within 3-24 hours. Considering the organizational difficulties caused by the incapability of undertaking prompt pPCI, the application of pharmacoinvasive approach would increase the number of patients that would be provided proper and timely reperfusion therapy. Here are some practical recommendations for implementation of the pharmacoinvasive strategy in everyday clinical practice and protocol of the local organization of the pPCI network in the General Hospital “Dr. Josip Bencevic“ in Slavonski Brod, Croatia.
A man aged 60 comes to the emergency room of the County General Hospital Pozega by his own transportation vehicle at 17 hours complaining of chest pains of intensity 8/10, lasting for 40 minutes. Vital signs are stable. The 12-lead ECG recorded and interpreted within five minutes since the arrival registers segment elevation by 3-4 mm in leads V1-V4. The questions posed by the physician:
Do I need to refer the patient to the coronary care unit and administer fibrinolytic therapy to him? It will take additional 15 minutes till the start of administering alteplase.
Do I need to arrange the transportation of the patient to the catheterization lab at the hospital in Slavonski Brod? It will take another 20 minutes for the ambulance to arrive, the transportation will last for 45 minutes considering the distance of up to 43 km to get to Slavonski Brod and the patient will be admitted directly to the catheterization laboratory where the team will be prepared for primary percutaneous coronary intervention (pPCI) and it will take them about 30 minutes to get the guide wire through the occlusion in the coronary artery.
The highest quality of the treatment of patients with acute ST-segment elevation myocardial infarction (STEMI) means providing a uniform, timely, efficient and safe reperfusion therapy to the greatest number part of patients. These goals can only be achieved by well organized local network that includes a multidisciplinary team approach with a single well-defined standardized protocol, with a continuous monitoring of quality control by monitoring the time deleys and clinical outcomes.
The Croatian pPCI Network currently covers around 70% of the state territory (1), our country is ranked the high fifth with around 85% of patients with STEMI who are reperfused (2) (70% by pPCI, 15% by fibrinolytic therapy), whereas the number of treated patients increases every year. In Croatia during the year 2012, some 2.222 pPCI procedures (3) were performed which is almost 500 pPCI in 1 million of inhabitants and we are getting closer to the goal set by the initiative “Stent for life” of the European Society of Cardiology of at least 600 pPCI in one million inhabitants. Babic et al (4) have recently presented the development of the Croatian pPCI network. There is an increasing number of patients with STEMI treated by pPCI on an annual basis, the patients with more severe clinical profile are treated and the time required to perform pPCI from the moment of presentation is shorter and shorter, and in the last three years the median time is 106 minutes. All these data show that the Croatian pPCI Network is a well-organized system of care for urgent treatment of cardiac patients. Croatian cardiology successfully monitors all modern trends in interventional cardiology in the world (5). Despite all these facts, one of the primary tasks of interventional cardiologists is still improving the national pPCI network.
There are many characteristics that are emphasized as significant ones in organizing regional pPCI networks. (6) The most important among them is the involvement of an adequately equipped and trained system of emergency medical services into the prehospital diagnosis, triage and initial treatment, teleconsultation with reference invasive cardiology center, a clear written destination protocol with a precise definition of the geographical areas of responsibility for the centers capable of performing pPCI, activating intervention center by one phone call, the arrival of the pPCI team within 20 minutes from the call, in case of arrival of the patients to the intervention center, the admission of patients with STEMI directly to the catheterization lab (avoiding emergency admission units or coronary units), pPCI centers should provide the 24/7 service and be capable of performing pPCI within 60 minutes from the admission of patients with STEMI. It is particularly important to emphasize that pPCI requires many clinical, cognitive and procedural skills and that there is a link between experience (a number of procedures performed both by an institution and every operator individually) and the outcome. The 2011 American Guidelines recommend a minimum of 11 pPCI per operator and 36 pPCI procedures per institution on an annual basis (7). The most recent American guidelines mention that the volume of an institution of <200 total percutaneous coronary interventions (PCI) a year (both elective and primary ones) is the threshold of minimum performed procedures associated with poor clinical outcomes, while a higher number than that shows that there is no link between a higher annual volume and better clinical outcomes (8). The recommendation is that every operator individually should perform a minimum 50 PCI procedures a year to maintain his/her competence.
In the absence of complete joint registry that would enable us monitoring and improvement of each of these components, it is difficult to say how efficiently we can improve the quality of management of patients with STEMI within the Croatian pPCI Network. Even in ideally organized pPCI network, it will not be possible to organize the pPCI treatment for all patients with STEMI within the timeframe set by the guidelines. One of the ways to improve the quality of network is to apply pharmacoinvasive approach.
The position of the pharmacoinvasive strategy in the primary percutaneous coronary intervention networkWhat patient with STEMI is to be referred to pPCI and what patient is to be treated by pharmacoinvasive approach?
a) A simple answer: we decide on the manner of reperfusion only on the basis of the time elapsed from the onset of symptoms and on the basis of the expected pPCI delay time.
For patients who present after 3 hours after the onset of pains, and if no more than 12 hours have elapsed from the onset of symptoms till the arrival at the tertiary center, pPCI is the method of choice in any case. For patients who come to the hospital that is capable of performing pPCI the answer is simple — pPCI is the method of choice if reperfusion pPCI can be organized within 60 minutes from the first medical contact (FMC). For patients who are presented within three hours from the onset of pains at the site where the treatment with pPCI is not feasible (the hospital without pPCI treatment options, but also at other sites of entry into the medical system, for example, in the field where the emergency medical service is invited) the decision is more complex. If we assess that is takes less than two hours to the performance of reperfusion, the pPCI method is still the treatment of choice. It should be borne in mind that the time of reperfusion is considered the start of thrombolysis or the time of passage of the guide wire through the lesion responsible for STEMI. Therefore, the physician who makes the decision needs to take into account the three time periods: the time required for initiation of fibrinolytic therapy, the time of transportation and the time of entry into the hospital capable of treating pPCI till the passage of the guide wire through the responsible lesion. All the times are the indicators of good organization and quality of care for patients with STEMI, and are different for each institution and for each particular region.
b) More complicated answer: decision on the type of reperfusion therapy is made not only based on the time elapsed from the onset of symptoms and on the basis of the expected pPCI time delay, but it will be modulated by the clinical characteristics of patients.
It is logical to assume that in case of selection of reperfusion therapy we should take into account the basic clinical characteristics of patients with STEMI. Due to the development of thromboresistance, the efficacy of fibrinolytic therapy is lower if the patient arrives later after the onset of symptoms (9) (and vice versa). The younger a patient is, the greater safety of fibrinolytic therapy it will be, and vice versa, the risk of bleeding is increased in elderly patients, especially the risk of life-threatening intracranial hemorrhage (10). The importance of successful reperfusion is more important if the greater mass of myocardium is impaired (the speed of reperfusion is more important in anterior wall infarction than in other localizations).
Pinto et al (11) analyzed the data on even 192,509 patients treated from June 1994 to August 2003 in 645 hospitals in the United States of America. They calculated the PCI related delay for each hospital, so from the door-to-balloon time they deducted door-to-needle time. “PCI-related delay” theoretically represents the time interval between the time when a patient could have received fibrinolytic therapy and the time when he could have had inflated balloon in the occluded blood vessel. The authors have later used statistical models to determine the association between “PCI-related delay”, the selected type of reperfusion therapy and patient’s characteristics (age, localization of infarction, time from the onset of symptoms) and their association with hospital mortality. In this way, they set the time limit for PCI-related delay after which pPCI loses advantage over the fibrinolytic therapy, in other words, how much time we are allowed to lose to organize pPCI so that the use of this method of reperfusion would lead to lower hospital mortality than if we had used fibrinolytic therapy. The shortest “mortality balance” (less than 1 hour) is registered in patients younger than 65 years, who were presented within two hours from the onset of symptoms, and the longest one (almost three hours) in patients over 65 years of age with infarction of any other localization but the anterior one, who were presented after 2 hours from the onset of symptoms. These data clearly show that the clinical features of patients (age, length of symptoms, localization of myocardial infarction) greatly affect on how fast pPCI loses advantage over fibrinolytic therapy. Table 1 presents the data from the articles of Pinto et al11 in the way make it easier for physicians who work in the conditions where pPCI is not immediately available to make a hard decision on whether to apply fibrinolytic therapy or transport the patients for pPCI treatment.
Relationship of prehospital delay, age, and infarct location to the loss of PCI-related mortality benefit
Age
<65 years
>65 years
Localization of myocardial infarction on ECG
anterior
nonanterior
anterior
nonanterior
Symptom onset to first medical contact time
<120 min
>120 min
<120 min
>120 min
<120 min
>120 min
<120 min
>120 min
„PCI related delay“ where PCI and fibrinolytic mortality are equal (min)
40
43
58
103
107
148
168
170
PCI = percutaneous coronary intervention; min = minutes.
It should be emphasized that the highest risk patients with STEMI will mostly benefit from pPCI, that is, the patients with a diagnosis of cardiogenic shock, heart failure, or hemodynamically or arrhythmically unstable patients. The decision is easier to make that pPCI should be the therapy of choice compared to fibrinolytic therapy in this group of patients.
Does every patient whom I prescribed fibrinolytic therapy should be referred to invasive treatment?
The protocols of the studies in the pharmacoinvasive approach that are presented in this journal issue (12) show that even in the studies designed ten years ago, a major portion of patients within the same hospitalization underwent invasive treatment and revascularization, while this number is extremely high in the more recent studies. In the TRANSFER AMI (13) 89% of patients treated by fibrinlysis underwent coronarography, 93% of them in the NORDISTEMI (14) trial and in the STREAM (15) trial all the patients underwent the invasive treatment. We can say that trials answered the question as to whether early or delayed invasive treatment was indicated, not whether a routine or selective invasive approach after fibrinolytic therapy was indicated. The answer to the above question seems to be simple and it can easily be found in the most recent guidelines. The European guidelines (16) suggest routine invasive treatment for all patients treated by fibrinolytic therapy regardless of the success of the fibrinolytic therapy (Class IA), as well as the American guidelines (17) that also suggest routine coronarography for all patients treated by fibrinolysis, whereas the patients in cardiac shock and severe acute failure are advised to undergo urgent invasive treatment (class I recommendations), while for all the other patients treated by fibrinolytic therapy, the routine coronarography carries the recommendation class IIa, with the recommendation that it should be done as soon as possible, ideally within 24 hours, but not within 2 to 3 hours after the use of the fibrinolytic therapy.
When should I refer the patients treated by fibrinolytic therapy to an invasive cardiologist? What is the risk of complications during the transport?
An answer to the transportation time is specified in the guidelines: invasive treatment should be done 3-24 hours after fibrinolysis. Randomized controlled trials have evaluated the routine in comparison to the selective invasive treatment (previous trials), or early in comparison to late invasive strategy (more recent studies) and time within which an invasive treatment performed in the group of patients treated by pharmacoinvasive strategy varied from 84 min (CAPITAL AMI (18)) to 16,7 hours (GRACIA (19)), but in the vast majority of studies the invasive treatment was performed 3-6 hours after the initiation of fibrinolytic therapy, and this time seems to be optimal.
The issue as to the safety of transportation of patients with STEMI is also one of those that can modulate the decision on the type of reperfusion therapy applied and on the time required to transport patients treated by pharmacoinvasive strategy. In none of these studies on pharmacoinvasive approach12 the authors do not mention deadly outcomes during the transportation. According to the TRANSFER AMI (13) study 2.4% of patients undergoing pharmacoinvasive therapy and 3% of patients undergoing standard treatment had complications during the transportation, mainly hypotension. There are several reports on this issue in the literature. Among 2,258 patients with diagnosis of acute coronary syndrome or cardiogenic shock transported by air, 127 of them (5.6%) had one or more complications (20). The most common disorders that occur are hypotension (n=80), impairment of chest pains (n= 52), and arrhythmia (n=18), and there were no deadly incomes during the transport and the authors believe that the transportation of these potentially unstable patients is safe. This conclusion was also reached by Gachoud et al (21) that did not have any major complications during the transportation of 42 patients for pPCI. One of 300 patients with chest pains who were transported by private transport suffered cardiac arrest (22) during the transportation. Straumann et al (23) state that in a group of 68 high risk STEMI patients, among whom 17 of them had cardiogenic shock, 15 of them were resuscitated before the transportation and 8 of them were intubated during the transportation and none of them died during transportation which lasted for 55 (18 -115) minutes. Balenovic et al (24) mention the detail that 538 patients with STEMI were transported in the region of the County of Sisak and Moslavina from October 2005 to July 2012. There were 5 patients (<1%) who died during the transportation up to 70 kilometers away from Zagreb (<1%). The risk of potential complications during the transport of patients with a diagnosis of cardiogenic shock, heart failure, or hemodynamically or arrhythmically unstable patients is certainly much higher. As already noted pPCI has advantage over and should be preferred to the fibrinolytic therapy in these patients. The dilemma that physicians can have on the field is whether a patient is to be transported immediately or clinically stabilized in the first place. The data from the SHOCK (25) study is key to the recommendation of the American guidelines (17) suggesting that patients with cardiogenic shock need a transfer for revascularization with no delay, because the patients in whom medicamentous stabilization of their condition was first attempted recorded higher mortality. A total of 53% of the patients included in this trial was transported before revascularization, and 49.3% of revasculated patients had previously received fibrinolytic therapy. The transportation of patients treated with fibrinolytic therapy to the center capable of undertaking percutaneous coronary interventions performed by well-trained and equipped team do not increase the risk for patients and can be considered safe.
The attitude of the author of this article is that the transport of patients should be organized immediately after the injection of fibrinolytic therapy. Fibrinolytic drug of choice is tenecteplase as fibrin-specific agent that is administered only once, which makes it the most desirable fibrinolyc drug for prehospital usage. Regarding other drugs that are administered in a continuous infusion, the transportation may also start during the administration of fibrinolytic drug, certainly accompanied by administering antiplatelet and anticoagulant therapy.
Protocol of management of patients with STEMI in Western Slavonija
Two algorithms for transportation of STEMI patients from hospitals not having the pPCI treatment option, namely for the area covered by the University Hospital Centre Zagreb, Zagreb (26) and algorithm and the University Hospital Centre Sestre milosrdnice, Zagreb (27) have already been published in this journal. Both algorithms are practically identical and in deciding on the type of reperfusion therapy — fibrinolytic therapy is recommended in patients who were presented within 3 hours from the onset of pains, and the expected time until the opening the vessel mechanically is longer than 90 minutes. Patients with successful fibrinolysis should be directed to invasive treatment the next day, while the patients with no signs of reperfusion (elevation persistence, persistence of pains, development of complications) have indications for rescue PCI and transportation with no delay. Patients with pains lasting longer than 3 hours and less than 12 hours at the time of presentation are the candidates for pPCI and as fast transport to a tertiary center as possible.
The proposed algorithm of the approach to the patient with STEMI in Western Slavonia (Table 2) is still being developed and is subject to changes after being discussed by all the members of the multidisciplinary team involved in the management of patients with STEMI in the region of Western Slavonia. This team is composed not only of the hospital capable of performing pPCI in Slavonski Brod, but also colleagues from the county hospitals in Pozega and Nova Gradiska and emergency medical service from the whole of Western Slavonia. The aim is to create a unique protocol for the entire region which will enable the provision of adequate reperfusion therapy to as many patients with STEMI as possible, which will give clear instructions about management, but also the destination protocol to every physician regardless of the point of entry of patients with STEMI in the health care system. The postulates are that we want to develop a network where a emergency medical service with a clear destination protocol will have a crucial role in triage and transportation of patients on the field, activation of the pPCI team by one call from the field and direct admission of patients directly to the catheterization lab. In the case of presentation of patients in the hospital not capable of performing pPCI or with EMC physician, the attending physician will decide on the type of reperfusion therapy. Destination protocol is thus defined for medical emergency center. By selecting pPCI as the reperfusion strategy, the nearest hospital is skipped if it is not capable of undertaking pPCI and the patient is transported directly to the catheterization lab. The type of reperfusion strategy is decided upon by a physician based on the length of ischemia, clinical characteristics of a patient (age and localization of myocardial infarction) and the expected delay of reperfusion in case of selection of pPCI as a reperfusion therapy (transportation time and the time required to perform pPCI less the time required for initiation of fibrinolysis). pPCI method is the therapy of choice for every patient if it can be performed within a set, that is, expected pPCI time delay. If pPCI is not feasible in a given time frame for a particular patient, pharmacoinvasive strategy is applied. Regardless of the length of ischemia, pPCI is a preferable treatment method for hemodynamically or arrhythmically unstable patients. For patients in whom pharmacoinvasive strategy is the method of choice, fibrinolytic therapy should be inititated as early as possible, within 30 minutes at the latest. The immediate transportation of patients is preferred, regardless of the success of fibrinolysis, the transportation during administration of fibrinolytic therapy is also preferred, and the decision about the time of invasive treatment after fibrinolysis (rescue PCI or early invasive strategy) is to be made by the invasive cardiologist. For patients present at the hospital capable of pPCI, the protocol includes recording and interpretation of ECG within 10 minutes from the admission to the integrated emergency hospital admission department and direct entry into the catheterization lab, without passing through the coronary unit with a 30 minutes’ target time to reperfusion.
Algorithm for reperfusion strategy for patients with acute myocardial infarction with ST-segment elevation in Western Slavonia.
Diagnosis of acute myocardial infarctionwith ST-segment elevation
Time (hours):onset of pain-ECG
<3
>3-12 to undartake pPCI
Age (years)
<65
>65
Infarct location
anterior
nonanterior
anterior
nonanterior
MaximalPCI related delay* (minutes)
45
90
120
180
Reperfusion strategy
pPCI
*PCI related delay = [expected duration of transport + 30 minutes for expected time for primary PCI] – expected time for starting fibrinolitic therapy. pPCI = primary percutaneous coronary intervention.
Completion of case study
A man aged 60 who has anteroseptal myocardial ischemia lasting for 40 minutes has a maximum PCI-related delay (time after which pPCI loses its advantage over fibrinolytic therapy) of a maximum of 45 minutes.
The expected PCI-related delay for this patient at this moment is 80 minutes (20 minutes till the arrival of ambulance +45 minutes of transportation to Slavonski Brod +30 minutes to the passage of the guide wire through the occlusion -15 minutes until the start of administration of alteplase).
A physician in Pozega chooses a pharmacoinvasive strategy. The patient is explained the method of treatment and obtains a written consent to the invasive diagnostics and potentially PCI. The physician immediately organizes the transportation of a patient to the General Hospital Slavonski Brod and calling the number of attending interventional cardiologist he announces the arrival of the patient in about 65 minutes. The patient receives 300 mg acetylsalicylic acid, 600 mg of clopidogrel, 30 mg enoxaparin i.v., 15 mg of alteplase in the form of an intravenous bolus and the infusion of alteplase starts during the time of 30 minutes. In the meantime, the ambulance vehicle arrives, the patient accompanied by the complete medical team with continuous ECG monitoring is transported to Slavonski Brod. During the transportation, the second infusion of 35 mg alteplase starts during the time of 60 minutes. The transportation is carried out without complications, the patient is admitted to the Coronary Care Unit at the same time when the fibrinolytic therapy is in progress. There are no signs of heart failure, the patient is normotensive and rhythmologically stable. Chest pain is very mild, now with the intensity of 2/10, 90 minutes after the end of fibrinolytic therapy in the V3 lead where the maximum ST-segment elevation of 4 mm was registered, now the elevation is 1 mm. The attending physician in the Coronary Care Unit concludes that the reperfusion is successful, but calls the PCI team that is organized three hours after the end of fibrinolytic therapy. 95% of thrombotic stenosis of the mid anterior descending coronary artery is found, which is resolved without complications by primary stenting.
Conclusion
European and American guidelines for the treatment of STEMI recommend organizing an efficient well-organized system of management that is based on the prehospital triage and quick transportation to a referral center capable of treating pPCI. The aim is to diagnose STEMI as soon as possible and to shorten the delay time in providing reperfusion therapy to as many patients as possible. The pPCI method is undoubtedly a strategy of choice in the treatment of STEMI, but if it is feasible in the short time period of 90-120 minutes, for some patients even within 60 minutes from the moment of patient’s presentation. In our daily practice an attempt to organize pPCI for a patient with STEMI is associated with unacceptably long delays which is why pPCI loses its preferenance to the fibrinolytic therapy. The choice of reperfusion strategy should be individually tailored to each patient and to local conditions and possibilities. Implementing the pharmacoinvasive strategies in regional protocols for the management of patients with STEMI would increase the number of patients who are given proper and timely reperfusion therapy.
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