Pre-hospital thrombolysis when compared with In-hospital thrombolysis is associated with mortality reduction and prognosis improvement in patients with suspected ST-elevation myocardial infarction
Ana Luísa Frutuoso, Ana Rita Magalhães, Bárbara Almeida, Carolina Fonseca, Catarina Machado, Diana Monteiro, Irina Rosa, João Pedro Silva, João Magalhães, Lília Monteiro, Mariana Antunes, Sofia Lopes,
Filipa Almeida, class 7
ABSTRACT
Background: Time to thrombolysis remains a key modifiable determinant of mortality in ST-elevation myocardial infarction (STEMI) 1,2,3. Despite numerous medical advances, the time from symptom onset to thrombolysis has remained at large unchanged, with a median of 2.5–3h1. A pre-hospital treatment strategy when compared with in-hospital thrombolysis may reduce time to thrombolysis with a subsequent decrease of in-hospital mortality.
Problem: There are sparse and scattered data on the impact of pre-hospital thrombolysis (PHT) in real-life patients with ST-elevation myocardial infarction (STEMI).
Aim: Evaluate treatment delays, outcome and complications in clinical trials and prospective cohort studies with real-life patients with STEMI myocardial infarction according to thrombolysis delivered on site (PHT) or in the hospital (IHT).
Methods and Results: Systematic review of clinical trials and prospective cohort studies with subsequent metanalysis. Median time from symptom onset to treatment was 113 min for PHT and 185 min for in-hospital thrombolysis. PHT group in-hospital mortality, 1-month mortality and 1-year mortality were associated with a risk ratio (IV, Random, 95% CI) of 0.70, 0.73 and 0.64, respectively, when compared with the IHT group. PHT is also associated with fewer complications; PHT reinfarction rate, ventricular fibrillation and Killip class > 1 risk ratio (IV, Random, 95% CI) were 0.88, 0.76 and 0.75, respectively, when compared with the IHT group.
KEY-WORDS: Acute Myocardial Infarction (MeSH); Pre-hospital thrombolysis (MeSH); Alteplase; Reteplase; Tecneplase; Treatment delay; Mortality (MeSH).
INTRODUCTION
Diseases of the cardiovascular system, of which acute myocardial infarction is the most serious manifestation, constitute the main cause of mortality in developed countries5.
Acute myocardial infarction (AMI) is the destruction of myocardial tissue resulting from insufficient supply of oxygen to the heart muscle 5,6. The leading cause of AMI is atherosclerosis6 which is formation of plaques in blood vessels7. Theses plaques are made of fatty substances, cholesterol, cellular waste products, calcium and fibrin that accumulate in the inner lining of the arteries7,8,9. Plaques decrease the lumen of blood vessels which consequently reduces blood flow and tissue oxygenation. The fissure or bleeding of the plaque activates the plaquetar aggregation and the coagulation cascade and thrombin, generating a thrombus that occludes the coronary artery8,10,11. The resultant death of the myocardial tissue due to lack of oxygenation constitutes an acute coronary syndromes (ACS) which could imply a cardiogenic shock (state in which the heart has been damaged so much that it is unable to supply enough blood to the organs of the body)19. The ACS encompasses three disorders of related etiology: ST-elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI) and unstable angina (UA) 5,6. The management of STEMI differs from that for UA and NSTEMI which may be considered as one clinical entity 12.
The diagnosis of acute coronary syndrome is based on three fundamental aspects: signs and symptoms, the electrocardiogram and biochemical data 12,13,14. The ST-segment variation allows distinguishing between ST-elevation myocardial infarction and non-ST elevation myocardial infarction. For this reason the initial electrocardiogram remains a pillar in the diagnosis of STEMI and one of the most important aspects in the decision of reperfusion therapy. A way to measure the severity of heart failure with myocardial infarction is a scale named Killip Classification through which patients are separated by symptoms in four categories15.
Once the STEMI consists in a total occlusion of a coronary artery with subsequent ischemia and necrosis of myocardial tissue, the treatment goal is reperfusion as soon as possible, ideally in the first 2 hours after the onset of symptoms. It can be done by mechanical methods (angioplasty) or pharmacological therapy16. The former can take place only in the hospital16. The latter consists in administering thrombolytic therapy intravenously to promote dissolution of the blood clot and thrombus and consequent opening of the coronary artery17. An earlier reperfusion reduces the short and long term mortality rate and the incidence of left ventricle dysfunction and heart failure1,2,3.
The thrombolysis consists in dissolving the fibrin clot of the thrombus that is blocking the coronary artery. This lysis of the clot is due to the action of a specific enzyme, the plasmin, derived from the proenzyme plasminogen. Since these drugs operate on plasminogen they are known as the “plasminogen activators." However, the imbalance triggered between the plasminogen-plasmin system increases possible hemorrhages, and this treatment is contra-indicated in patients with a history of cerebrovascular accident, intracranial neoplasm, suspected aortic dissection, severe uncontrolled hypertension, current use of anticoagulants, recent trauma, internal bleeding or peptic ulcer in activity12,17.
As the key factor in treating AMI is speed, the early treatment is essential in reducing the percentage of affected myocardium and thus complications and cardiovascular death. The pre-hospital thrombolytic therapy is possible and can reduce time between symptoms and reperfusion therapy. Recent studies have shown that pre-hospital thrombolytic therapy (PHT) can reduce the mortality caused by AMI between 25 and 50% 1,2,3, and other reports have raised concerns about the relative safety of PHT18.
The main objective of this study is to define if PHT is beneficial and safe in terms of morbidity and mortality for patients with ST-elevation myocardial infarction when compared with intra-hospital reperfusion therapy, either thrombolysis or mechanical reperfusion.
PARTICIPANTS AND METHODS
Study objectives and design
We performed a systematic review and meta-analysis of randomized controlled trials and cohort studies reporting outcomes of PHT versus intra-hospital reperfusion in patients with STEMI. The primary endpoints were determine if pre-hospital thrombolysis reduces early and late (1 year) cardiovascular mortality in patients with ST elevation myocardial infarction and evaluate if pre-hospital thrombolysis improves prognosis in terms of: reinfarction rates, left ventricular ejection fraction (an estimation is made of the volume of blood in the ventricle at the end of diastole and the volume of blood remaining in the ventricle at the end of systole), ventricular fibrillation rates, and killip class on admission values. The secondary endpoint evaluated was if pre-hospital thrombolysis performed by non medical teams increases complication rates. The outcomes of interest were mortality, myocardial infarction, killip class on admission values, left ventricle dysfunction and hemorrhagic complications.
Population and Sampling Methods
We performed a systematic review of randomized controlled trials and cohort studies that compared PHT with in-hospital thrombolytic therapy in adults presenting with suspected myocardial infarction with ST- elevation. The defined query was used in Medline, SCOPUS and ISI Web of Knowledge, using various combinations of the MESH terms Acute Myocardial Infarction; Pre-hospital thrombolysis; Mortality, Treatment delay, Alteplase; Reteplase and Tecneplase. Two reviewers identified articles eligible for further review by performing a screen of abstracts and titles. If a study was deemed relevant, the manuscript was obtained and reviewed according to the inclusion and exclusion criteria. The inclusion criteria consisted of: 1) only clinical trials and cohort studies, 2) studies that compare pre-hospital thrombolysis with in-hospital thrombolysis, 3) studies that use new generation thrombolytics, 4) follow-ups till 1 year, 5) cases of patients with suspect of ST segment elevation myocardial infarction, 6) comparison between pre-hospital and in-hospital treatment. The exclusion criteria are: 1) non-english studies, 2) articles with no abstract, 3) articles that don’t have full text, 4) studies that used first generation thrombolytics, 5) non related studies, 6) studies that do not compare pre-hospital thrombolysis with aspects connected to our study aim, 7) comparison between AMI and thrombolytic treatment inexistent, 8) articles that do not fulfill any of the inclusion criteria.
Study identification
We searched through for possible studies from January 1, 1990 to February 28, 2009. These dates were thought to be appropriate as the new generation thrombolytics were not used until 1990. From the search we obtained 464 articles in Medline, 692 in Scopus and 415 in ISIWeb. After this selection we restrained our articles down to 9 from Medline, 11 from Scopus and 3 from ISIWeb, using the inclusion and exclusion criteria. We read the 23 articles and included 8 (4 from Medline and 4 from Scopus) in our review (3 randomized trials, and 5 cohort studies), which directly compared the two treatment forms. From the 15 excluded, 5 articles compared pre-hospital thrombolysis with aspects not connected to our study aim (3 from ISIWeb and 2 from Scopus), 6 used first generation thrombolytics (3 from Scopus and 3 from Medline) and 4 didn’t have full text (3 from Scopus and 1 from Medline) (Flowchart 1).
Data collection methods
Two reviewers extracted independently pre-specified data elements from each study, and data was organized in four different categories: Study Sample, Study Sample Characteristics, Time to Treatment, Mortality and In-Hospital Complications. Charts were used to compile the data of each category. After creating the charts, we inserted the data in SPSS and proceeded to an initial statistic analysis. We calculated the mean values of each variable with weighted cases by number of patients on first and then with weighted cases off. The purpose of this first analysis was to give us an idea of the impact of PHT trough variable tendencies.
Variable description and study design
The following variables we created and inserted in SPSS according to the four categories: 1) Study Sample variables - PHT given by paramedics [Yes/No], Thrombolytic Type, Patients given PHT (%), Patients given IHT (%) and Total Patients; 2) Study Sample Characteristics - PHT group age, PHT female sex (%), IHT female sex (%), PHT Diabetes Mellitus (%), IHT Diabetes Mellitus (%), PHT Current Smoker (%), IHT Current Smoker (%), PHT Hypertension (%) and IHT Hypertension (%); 3) Time to Treatment and Mortality parameters - PHT Symptom onset to Treatment Time, IHT Symptom onset to Treatment Time, PHT In-Hospital Mortality (%), IHT In-Hospital Mortality, PHT 1-Month mortality (%), IHT 1-Month mortality (%), PHT 1-Year mortality (%) and IHT 1-Year mortality (%); 4) In-Hospital Complications - PHT Reinfarction rate, IHT Reinfarction rate, PHT Ventricular Fibrillation, IHT Ventricular Fibrillation, PHT Killip Class>1 on admission and IHT Killip Class>1 on admission.
Statistical analysis
Data were analyzed on an intention to treat basis. Where appropriate, data from all trials were combined using the, metanalysis software in Review Manager. All the outcome measures of this review were dichotomous. Data were combined using random effects modeling to determine a summary estimate of the relative risk and the 95% confidence interval. Heterogeneity was statistically assessed using the chi-square test (p<0.10) for all end points and the I2 statistic (Higgins 2003) for selected end points. The I2 statistic is displayed on the forest plots for all analyses.
RESULTS
Patients’ baseline characteristics
Patient’s baseline characteristics are summarized in the table below (Table 1). Patients characteristics are similar both in the pre-hospital and in-hospital groups. Still, the number of female patients in the in-hospital group is larger; the same occur for patients with diabetes mellitus. This can be associated with the larger risk of complications in these patients. In all ambulances without physicians diagnosis was established by a physician at the hospital using telemedicine (ECGs always available for the physician in the hospital).
Time until Thrombolysis
Study ID / Median Time to Thrombolysis in the PHT Group (mins) / Median Time to Thrombolysis in the IHT Group (mins) / Median Time Difference (mins)European Heart J. 2006 / 113 / 165 / 52
European Heart J. 2003 / 138 / 240 / 102
GREAT Study BMJ 1992 / 101 / 240 / 139
JAMA 1993 / 77 / 110 / 33
JAMA 2006 / 120 / 167 / 47
New Eng. J. of Med. 1993 / 130 / 190 / 60
Mean of Medians / 113 / 185 / 72
Median time from symptom onset to treatment was lower for the pre-hospital group in all studies (Table 2). In 4 of the 6 studies in which data regarding median time from symptom onset to treatment was available, the statistical analyses indicated that there was statistical significance between pre-hospital group and in-hospital group. In the remaining 2 studies the statistical analyses comparing the two groups was not performed (or at least not published in the full article).
The means of the median times from symptom onset to treatment available in the 6 studies were 113 minutes for the pre-hospital group and 185 minutes for the in-hospital group (median time difference approximately 72 minutes). This interval difference supports the finding that pre-hospital thrombolysis significantly improved time to needle for thrombolysis.
Outcomes
ID / In-Hospital Mortality (%) PHT / In-Hospital Mortality (%)IHT / 1-Month Mortality (%) PHT / 1-Month Mortality (%) IHT / 1-Year Mortality (%) PHT / 1-Year Mortality (%) IHTGreat Study 2 / 6,7 / 11,5 / - / - / - / -
New Eng. J. M. 1993 21 / 9,1 / 10,5 / 9,7 / 11,1 / - / -
JAMA 1993 20 / 5,7 / 8,1 / - / - / - / -
BMJ 2003 22 / 11 / 12 / - / - / - / -
European Heart J. 2003 23 / 7 / 13 / - / - / - / -
Circulation 2004 24 / 3,3 / 8 / - / - / 6 / 11
JAMA 2006 25 / 5,9 / 8,8 / 7,6 / 11,4 / 10,3 / 15,9
European Heart J. 2006 1 / - / - / 5,4 / 8,3 / 7,2 / 11,8
Mean / 7 / 10,3 / 7,6 / 10,3 / 7,8 / 13
Weighted Mean / 6,3 / 9,2 / 8 / 11 / 9,5 / 15
Data collected from the 8 studies included supports that pre-hospital thrombolysis is associated with lower mortality until hospital discharge, 1-month mortality and 1-year mortality (Table 3), although that difference was not always statistically significant. Our outcome measures also support those findings; in-hospital mortality, 1-month mortality and 1-year mortality in the PHT group is associated with risk ratio (IV, Random, 95% CI) of 0.70, 0.73 and 0.64, respectively, when compared with the IHT group (Figures 1, 2 and 3 respectively).