Trombólisis prehospitalaria versus intrahospitalaria para el infarto de miocardio con elevación del ST
Resumen
Antecedentes
La trombólisis temprana para los individuos que sufren un infarto de miocardio se asocia con mejores resultados de mortalidad y morbilidad. Aunque tradicionalmente la trombólisis se administra en el hospital, la trombólisis prehospitalaria se propone como una intervención efectiva para ahorrar tiempo y reducir la mortalidad y la morbilidad en los individuos con infarto de miocardio con elevación del ST (IMEST). A pesar de algunas pruebas de que la trombólisis prehospitalaria puede administrarse de forma segura, hay una escasez de datos de ensayos controlados para indicar si el momento adecuado de administración puede ser efectivo para reducir los resultados clínicos clave.
Objetivos
Evaluar la morbilidad y la mortalidad relacionadas con la trombólisis prehospitalaria versus intrahospitalaria en pacientes con IMEST.
Métodos de búsqueda
Se hicieron búsquedas de ensayos controlados aleatorios y literatura gris publicados hasta junio 2014 en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL), MEDLINE (OVID), EMBASE (OVID), dos índices de citas en Web of Science (Thomson Reuters) y Cumulative Index to Nursing and Allied Health Literature (CINAHL). También se revisaron las listas de referencias de los artículos identificados, los registros de ensayos clínicos y las fuentes de tesis inéditas. No se estableció contacto con compañías farmacéuticas para obtener ningún artículo publicado o no publicado relevante. No se aplicaron restricciones de idioma, fecha o publicación. El Grupo Cochrane de Corazón (Cochrane Heart Group) realizó la búsqueda electrónica primaria.
Criterios de selección
Se incluyeron ensayos controlados aleatorios de la trombólisis prehospitalaria versus intrahospitalaria en adultos con infarto de miocardio con elevación del ST diagnosticado por un profesional sanitario.
Obtención y análisis de los datos
Dos autores, de forma independiente, revisaron los estudios elegibles para la inclusión y realizaron la extracción de datos y las evaluaciones del "Riesgo de sesgo", resolviendo cualquier desacuerdo mediante consulta con un tercer autor. Se estableció contacto con los autores de los estudios potencialmente adecuados si se necesitaba información faltante o adicional. Se recopilaron datos de eficacia y efectos adversos de los ensayos.
Resultados principales
Se incluyeron tres ensayos con 538 participantes. Se encontraron pruebas de baja calidad que indicaron que existen dudas sobre si la trombólisis prehospitalaria reduce la mortalidad por todas las causas en individuos con IMEST en comparación con la trombólisis intrahospitalaria (cociente de riesgos 0,73; intervalo de confianza del 95%: 0,37 a 1,41). Se encontraron pruebas de alta calidad (dos ensayos, 438 participantes) de que la trombólisis prehospitalaria redujo el tiempo hasta el tratamiento trombolítico en comparación con la trombólisis intrahospitalaria. En cuanto a los eventos adversos, se encontraron pruebas de calidad moderada de que la aparición de eventos de hemorragia fue similar entre los participantes que recibieron trombólisis intrahospitalaria o prehospitalaria (dos ensayos, 438 participantes), y pruebas de baja calidad de que la aparición de fibrilación ventricular (dos ensayos, 178 participantes), accidente cerebrovascular (un ensayo, 78 participantes) y reacciones alérgicas (un ensayo, 100 participantes) también fue similar entre los participantes que recibieron trombólisis intrahospitalaria o prehospitalaria. Se consideró que los estudios incluidos presentaron un riesgo general incierto/alto de sesgo.
Conclusiones de los autores
La trombólisis prehospitalaria reduce el tiempo hasta el tratamiento, basado en los estudios realizados en países de ingresos más altos. En ámbitos en los que puede ser administrada de forma segura y correcta por personal entrenado, la trombólisis prehospitalaria puede ser una intervención apropiada. La trombólisis prehospitalaria tiene el potencial de reducir la carga de IMEST en países de ingresos bajos y medios, especialmente en los individuos que tienen un acceso limitado a la trombólisis intrahospitalaria o a intervenciones coronarias percutáneas. No se encontró ningún ensayo controlado aleatorio que evaluara la eficacia de la trombólisis prehospitalaria para el IMEST en países de ingresos bajos y medios. Los ensayos controlados aleatorios amplios, multicéntricos y de alta calidad ejecutados en países con escasos recursos aportarán pruebas adicionales sobre la eficacia y la seguridad de esta intervención. Los elaboradores de políticas locales deben considerar su infraestructura sanitaria local y las necesidades de distribución de la población. Estas consideraciones deben tenerse en cuenta al formular las guías clínicas para la trombólisis prehospitalaria.
PICO
Resumen en términos sencillos
Administración del tratamiento que elimina coágulos antes del ingreso al hospital o en el hospital para ayudar a los pacientes que sufren ataques cardíacos
La cardiopatía es la causa más común de muerte en todo el mundo según la Organización Mundial de la Salud. Un ataque cardíaco puede tratarse con un fármaco denominado trombolítico (que destruye los coágulos) o con intervención quirúrgica. Cuanto antes se administre un agente trombolítico, menos probable es la muerte o las discapacidades del individuo. Generalmente, la trombólisis se administra en un hospital; sin embargo, la administración de este tratamiento antes del ingreso al hospital, por parte de los paramédicos, puede ser una intervención efectiva que puede ahorrar tiempo y reducir la muerte y la discapacidad en los pacientes con ataques cardíacos.
El objetivo de esta revisión fue comparar el efecto de la administración prehospitalaria e intrahospitalaria del tratamiento trombolítico en la muerte por todas las causas y la discapacidad en los individuos que sufren un ataque cardíaco. Se realizó una búsqueda exhaustiva de todos los ensayos que han investigado este resultado. Dos autores trabajaron de forma independiente para asegurar que se encontraban todos los ensayos y se obtenía la información relevante de ellos. En conjunto, se encontraron tres ensayos con 538 participantes que podían incluirse en esta revisión. Se encontraron pruebas de baja calidad que indicaron que existen dudas sobre si el número de pacientes que murieron fue diferente cuando el tratamiento se administró antes del ingreso al hospital en comparación con su administración intrahospitalaria (3 ensayos). Se encontraron pruebas de alta calidad de que la administración del tratamiento antes del ingreso al hospital redujo el tiempo hasta que el individuo recibe el tratamiento trombolítico en más de 30 minutos (dos estudios), y pruebas generalmente de baja calidad de que los efectos secundarios, como reacciones alérgicas y hemorragias, fueron similares cuando el tratamiento se administró de forma prehospitalaria o intrahospitalaria. Las principales limitaciones de las pruebas fueron el incierto/alto riesgo de sesgo en los estudios y el bajo número de personas reclutadas.
Se establece la conclusión de que el tratamiento que elimina los coágulos administrado antes del ingreso al hospital reduce el tiempo hasta que el individuo recibe el tratamiento trombolítico. Las limitaciones de las pruebas encontradas deben considerarse detenidamente, especialmente en ámbitos en los que la trombólisis puede ser administrada de forma segura y correcta por personal entrenado. Se encontró que no hubo ningún ensayo que evaluara el tratamiento trombolítico prehospitalario en los países más pobres y, por lo tanto, la investigación adicional en dichos contextos proporcionará más información para asesorar sobre si la administración de este tratamiento para los ataques cardíacos es segura y efectiva.
Authors' conclusions
Summary of findings
| Pre‐hospital versus in‐hospital thrombolysis for ST‐elevation myocardial infarction | ||||||
| Participants or population: participants with ST‐elevation myocardial infarction | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Pre‐hospital versus in‐hospital thrombolysis | |||||
| All‐cause hospital mortality | 73 per 1000 | 53 per 1000 | RR 0.73 | 538 | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Follow up ranged from 15 days to 1 month | ||||||
| Pre‐hospital versus in‐hospital thrombolysis for ST‐elevation myocardial infarction | ||||||
| Participant or population: participants with ST‐elevation myocardial infarction | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Pre‐hospital versus in‐hospital thrombolysis | |||||
| Time to thrombolytic treatment [minutes] | The mean time to thrombolytic treatment [minutes] in the intervention groups was | 438 | ⊕⊕⊕⊕ | |||
| Acute myocardial infarction functional outcomes ‐ ejection fraction [percentage] | The mean acute myocardial infarction functional outcomes ‐ ejection fraction [percentage] in the intervention groups was | 416 | ⊕⊕⊝⊝ | |||
| Adverse effects ‐ ventricular Fribrillation | 25 per 1000 | 67 per 1000 | RR 2.73 | 178 | ⊕⊕⊝⊝ | |
| Adverse effects ‐ bleeding complications | 58 per 1000 | 51 per 1000 | RR 0.88 | 438 | ⊕⊕⊕⊝ | |
| Adverse effects ‐ allergic reaction | 0 per 1000 | 0 per 1000 | RR 0 | 100 | ⊕⊕⊝⊝ | |
| Adverse effects ‐ Stroke | 11 per 1000 | 23 per 1000 | RR 2.11 | 360 | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Methodological quality (e.g. no blinding in Castaigne 1989) not likely to effect this outcome, therefore not downgraded due to risk of bias | ||||||
Background
Description of the condition
The World Health Organization (WHO) reports that cardiovascular disease is the leading cause of death worldwide, with more than 80% of these deaths occurring in lower‐ and middle‐income countries (LMICs) (Mackay 2004; WHO 2011). Cardiovascular disease is responsible for more than 10% of disability‐adjusted life‐years lost in LMICs and for more than 18% of disability‐adjusted life‐years lost in high‐income countries (HICs) (Mackay 2004). ST‐segment elevation myocardial infarction (STEMI) falls under the umbrella classification of acute coronary syndromes (ACS), which also include non‐ST‐segment elevation myocardial infarction (NSTEMI) and unstable angina (Ruff 2011). A STEMI is the development of myocardial necrosis secondary to the interruption of the blood supply to an area of the myocardium identified by the presence of ST segment elevation on electrocardiography or the elevation of cardiac markers, or both. In the United States there has been a striking evolution in the epidemiology of ACS since the 1990s, with a steady decline in the incidence of STEMIs and a reciprocal incline in the incidence of NSTEMIs, as reported by Rogers 2008. In LMICs there is an increasing trend in ischaemic heart disease mortality (Mensah 2008) as these countries move through an epidemiological transition of increasing incidence and prevalence of cardiovascular disease (Gersh 2010). Acute myocardial infarction is defined as cardiac muscle death owing to prolonged lack of oxygenation (Thygesen 2007) caused by an abrupt reduction in coronary blood flow to part of the heart (Beers 2006). Symptoms of acute myocardial infarction may be more severe than those associated with angina and usually persist for longer (e.g. more than 15 to 20 minutes). Classic symptoms include chest discomfort or pain but can include other symptoms such as shortness of breath, nausea, sweating, dizziness and vomiting (Goodacre 2002; Goodacre 2003). Health costs relating to people suffering from acute myocardial infarction are diverse, with economic implications to the individual, family, healthcare system and country (IOM 2010).
Description of the intervention
STEMIs can be treated effectively using percutaneous coronary interventions (PCIs) or thrombolytic agents, or both (Bonnefoy 2009; Weaver 1993). Thrombolytic agents are enzymes that cause coronary thrombus dissolution through a cascade of effects to degrade fibrin thrombi and fibrinogen (SAMF 2010). These agents can be administered either in the pre‐hospital setting or, traditionally, in a hospital setting, and are most effective if given in the first few minutes to hours after onset of a STEMI (Beers 2006; Rawles 2003; Weaver 1993). Various thrombolytic agents are available, all with similar biological effects, efficacy and administration requirements. These include, but are not limited to, the following agents:
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streptokinase, 1.5 million units intravenously (IV) over 30 to 60 minutes;
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alteplase, 15 mg IV 0.75 mg/kg over 30 minutes followed by 0.5 mg/kg IV over 60 minutes;
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reteplase, 10 U + 10 U IV given 30 minutes apart;
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tenecteplase, single IV injection (weight dependent) (Van de Werf 2008).
A thrombolytic agent is administered either by infusion or as a single bolus dose. This distinction is important to note as bolus doses are generally easier to administer, require less resources (e.g. an infusion pump) and expertise. Treatment of STEMIs is aimed at early diagnosis and risk stratification, with relief of pain, breathlessness and anxiety coupled with immediate coronary reperfusion either with a pharmacological or mechanical intervention depending on availability and on each individual's context (O'Connor 2010). The standard of care includes anti‐ischaemic therapy (oxygen, nitroglycerin, opioids and beta‐blockers), antiplatelet therapy (Aspirin, clopidogrel) (Fox 2004; ISIS‐2 1988), antithrombin therapies (heparin and low‐molecular‐weight heparins) (Armstrong 2006) and reperfusion strategies (O'Connor 2010; Van de Werf 2008).
How the intervention might work
Effective thrombolysis for individuals with STEMI is extremely time sensitive (Sayah 2008). The earlier a thrombolytic agent is initiated the better, with greatest benefit occurring within three hours from symptom onset (Bonnefoy 2009). The goal is to initiate thrombolysis within 30 to 60 minutes after symptom onset (Antman 2008). Despite this goal, achieving this in practice is challenging (Barbagelata 2007). Pre‐hospital initiation of thrombolysis has been reported to improve time to thrombolysis and reduce mortality compared with in‐hospital thrombolysis (Antman 2008 (narrative); Björklund 2006 (cohort study); Bonnefoy 2009; Brouwer 1996; Rawles 2003 (trials); Curtis 2006 (descriptive); Morrison 2000 (review)).
Why it is important to do this review
Early thrombolysis has been associated with better mortality and morbidity outcomes (Bonnefoy 2009). Pre‐hospital thrombolysis can provide improved time to thrombolysis (Björklund 2006) and a potential reduction in mortality and morbidity compared with in‐hospital treatment (Rawles 2003). A previous systematic review by Morrison 2000 found that pre‐hospital thrombolysis for acute myocardial infarction significantly decreased all‐cause hospital mortality based on a meta‐analysis of six randomised controlled trials (RCTs). This review incorporated any new evidence and utilised the GRADE assessment, together with Cochrane Heart Group methodology. It added to current knowledge of pre‐hospital thrombolysis by considering system and infrastructure needs for the successful implementation of the models of care and ascertained gaps in current research evidence. The results of this review may guide policy makers and other healthcare stakeholders to invest in the appropriate treatment strategy and health system/service requirements for individuals with STEMI needing thrombolysis, especially in LMICs where other treatment options for STEMI are scarce or not available. This review has important implications for areas where primary angioplasty is unavailable or where pre‐hospital transport times are long, such as rural areas ‐ specifically in LMICs.
Objectives
To assess the morbidity and mortality of pre‐hospital versus in‐hospital thrombolysis for STEMI.
Methods
Criteria for considering studies for this review
Types of studies
RCTs excluding cross‐over trials.
Types of participants
Adults (16 years and older) with STEMI diagnosed by a medical healthcare provider in either the pre‐hospital or in‐hospital setting. Diagnosis of STEMI will be defined according to the included studies' criteria for STEMI but should include at least two of the following three positive indicators: the individual's history and symptoms, electrocardiogram (ECG) findings and biochemical cardiac markers (cardiac makers are not mandatory for diagnosis, but may be used in certain pre‐hospital settings).
Types of interventions
Any thrombolytic agent used to treat STEMI in pre‐hospital and in‐hospital settings.
Types of outcome measures
Primary outcomes
All‐cause hospital mortality at one month (short term) and one year (mid term).
Secondary outcomes
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Time to thrombolytic treatment, measured from symptom onset or first medical contact, or both (or as described by study authors) to the administration of a thrombolytic agent
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Adverse effects. An adverse event is defined as an event for which a causal relationship between the intervention and the event is a reasonable possibility (e.g. ventricular fibrillation, pulseless ventricular tachycardia, cardiogenic shock, inappropriate use of thrombolytics, hypotension, bradycardia, re‐infarction, bleeding, or fatal and non‐fatal stroke)
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Acute myocardial infarction functional outcomes including:
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ejection fraction, measured using an echocardiogram;
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classification of heart failure (New York Heart Association functional classification system);
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time to discharge or days in hospital, measured from admission to discharge in days
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Search methods for identification of studies
Electronic searches
In June 2014, we conducted comprehensive electronic searches for RCTs using the following key search terms ‐ thrombolysis, thrombolysis therapy, myocardial infarction, and pre‐hospital ‐ and using the Cochrane sensitivity‐precision maximising RCT filter (Lefebvre 2011), adapted for use with the following databases:
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Cochrane Central Register of Controlled Trials (CENTRAL, issue 5 of 12, September 2014, searched 5 June 2014, results: 1491);
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MEDLINE (OVID, 1946 to May Week 4 2014, searched 10 June 2014, results: 1178);
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EMBASE Classic + EMBASE (OVID, 1947 to 5 June 2014, searched 5 June 2014, results: 1196);
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Science Citation Index Expanded (SCI‐EXPANDED, 1970 to 5 June 2014) and Conference Proceedings Citation Index‐ Science (CPCI‐S, 1990 to 5 June 2014) on Web of Science (Thomson Reuters) searched 5 June 2014; results: 2489;
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CINAHL Plus with Full Text (EBSCO, 1936 to May 2014, searched 5 June 2014, results: 117).
We added no language or publication restrictions to the search strategies. The search strategies used can be found in Appendix 1.
In developing the search strategy we were assisted by the Cochrane Heart Review Group's Trials Search Co‐ordinator who conducted the main search.
Searching other resources
We searched grey literature, such as unpublished thesis sources, and the following additional databases: ProQuest Dissertations, Index to theses in Great Britain and Ireland, and DissOnline. We carried out no handsearching and contacted no pharmaceutical companies in order to identify additional studies due to operational time restraints.
We searched the reference lists of included studies and contacted the primary authors of included studies to identify additional relevant studies. We searched the following clinical trial registers: ClinicalTrials.gov (www.clinicaltrials.gov/), International Standard Randomised Controlled Trial Register (www.controlled‐trials.com/isrctn/) and the WHO International Clinical Trials Registry Platform (apps.who.int/trialsearch/).
Data collection and analysis
Selection of studies
We merged the results of the search using reference management software and removed duplicate records. Two review authors (MM and AL) independently examined titles and abstracts to remove obviously irrelevant reports and retrieved the full text of potentially relevant reports. They linked multiple reports of the same study and independently examined full‐text reports for compliance with eligibility criteria using a study eligibility form. MM and AL resolved any disagreements regarding study inclusion or exclusion with the assistance of the other author, TK. Neither author was blinded to the names of the study authors, institutions, journal of publication nor results, as this practice has uncertain benefit in protecting against bias (Higgins 2011). We created a PRISMA flow diagram (Moher 2009) to show the process of inclusion and exclusion of RCTs; potentially eligible studies that were excluded are noted in the 'Excluded studies' section.
Data extraction and management
Two review authors (MM and AL) independently extracted data from the studies using a data extraction form. We collected the following information:
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study source (name of person extracting data, study ID, report ID, review author, citation and contact details);
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eligibility (confirmation of eligibility for review as per protocol, reason for exclusion);
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methods (study aims, study design, total study duration, unit of allocation, all information required for the 'Risk of bias' tool, ethics approval);
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participants and setting (age, recruitment method, inclusion and exclusion criteria, baseline imbalances, informed consent obtained, number of participants randomised, time of first symptom onset, rural or urban setting, developing or developed country setting, subgroups measured, subgroups reported);
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interventions (group name, number randomised to group, type of medication administered, method of administration, time of medication administration, place of administration, number and explanation for any dropouts, duration of follow up, economic variables);
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outcome measures coupled with results (outcome definition/name, person measuring or reporting, all‐cause hospital mortality at 30 days and one year or longer where available, time to thrombolytic treatment, adverse effects, STEMI functional outcomes, comorbidities);
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results (continuous variables of outcome data such as measures of variability, dichotomous data such as total number of events in each arm and numbers of participants), additional notes (key conclusions of study, correspondence with authors needed, clarification of queries, ethics or stated conflicts of interest, duplicate publication, translation required);
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applicability (populations excluded, disadvantaged groups, applicability to developing countries).
We collated data from multiple reports of the same study into one data extraction form. MM collated and entered all data into Review Manager 5 (RevMan 2011). We resolved any disagreements by consensus.
Assessment of risk of bias in included studies
Two review authors (MM and AL) independently assessed the risk of bias of included studies using the Cochrane 'Risk of bias' assessment tool (six domains) (Higgins 2011), stating whether the risk of bias was low, high or unclear. The two authors independently pooled the results and discussed any differences with a third author (TK). We addressed the following bias domains: sequence generation, allocation concealment, blinding (blinding of participant and personnel, blinding of outcome assessors), incomplete outcome data, selective outcome reporting and other risks of bias. The review authors followed the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) for assessing bias. We extracted information based on the published data and contacted the authors whenever descriptions were missing or unclear.
Measures of treatment effect
Dichotomous data
Dichotomous outcomes, such as all‐cause hospital mortality, were represented as risk ratios (RR) with 95% confidence intervals (CIs). Adverse effect data were measured as proportions or rates, respectively, depending on the study data.
Continuous data
Continuous effect measures included the time from symptom onset to thrombolysis, measured as the mean difference (MD) or standardised MD between individuals receiving thrombolytic therapy in a pre‐hospital or an in‐hospital setting. Time to discharge, number of days in hospital and ejection fraction were measured as MDs or standardised MDs between groups.
Unit of analysis issues
Only RCTs were included. The authors identified no cluster RCTs or multi‐arm RCTs. Hence, the unit of analysis was at an individual level.
Dealing with missing data
We asked the authors of one RCT (the European Myocardial Infarction Project (EMIP)) to provide missing data so that the study could potentially be included in the review. Unfortunately they were unable to provide any data and the trial was excluded from the study. We performed no imputing of missing data.
Assessment of heterogeneity
We performed a visual inspection of the forest plot for heterogeneity. Heterogeneity was assessed using the Chi2 test, with a P value < 0.1 considered indicative of significant heterogeneity, and the I2 statistic. As there was reasonable clinical and methodological similarity between trials, we were able to carry out a meta‐analysis. We sought possible reasons for any substantial heterogeneity.
Assessment of reporting biases
The use of a funnel plot to explore possible reporting biases was precluded due to the limited number of included studies (< 10).
Data synthesis
As the trials were clinically and methodologically similar, we undertook a meta‐analysis. We used a fixed‐effect meta‐analysis if studies were estimating the same treatment effect (no statistical heterogeneity) and a random‐effects meta‐analysis if studies showed substantial statistical heterogeneity. We used RevMan software to perform the meta‐analysis. If we performed a meta‐analysis in the presence of high levels of heterogeneity, we sought possible explanations for this heterogeneity.
Subgroup analysis and investigation of heterogeneity
We predefined several possible subgroups for meta‐analysis:
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practitioner type: paramedic (basic versus advanced) versus physician (emergency versus cardiologist) thrombolytic administration on mortality outcome;
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HIC versus LMIC settings;
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rural versus urban settings;
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remote telemetry with consultant communication versus independent paramedic thrombolytic administration;
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automated versus manual ECG interpretation;
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different types of thrombolytic medication administered compared for mortality and adverse effects;
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anatomical location of STEMI;
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mobile intensive care units compared with primary response;
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adverse effects of pre‐hospital thrombolytic agents as administered by paramedics versus physicians.
However, we did not perform any subgroup analyses due to the limited number of included studies. The Cochrane Handbook for Systematic Reviews of Interventions recommends a minimum of 10 studies.
Sensitivity analysis
We performed sensitivity analyses in order to explore the influence of the following factors on effect size:
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fixed‐effect model versus a random‐effects model meta‐analyses;
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exclusion of trials with a high risk of bias.
Results
Description of studies
Results of the search
The electronic database searches identified 6471 titles for potential inclusion. After the removal of duplications, 4111 titles remained of which 4027 titles were found not to be relevant. We retrieved full‐text articles for the remaining 84 titles which two authors independently screened for eligibility. We included three studies, reported in six papers, met the eligibility criteria. The trial registry searches revealed 146 potentially eligible studies of which all we excluded (Figure 1). Ten trials were translated with the help of the Cochrane Heart Group.
Study flow diagram.
Included studies
See: Characteristics of included studies
We identified three RCTs (538 participants), conducted in France, USA and Germany, which examined the efficacy of pre‐hospital versus in‐hospital thrombolysis for STEMI. Castaigne 1989 used 30 U anisoylated plasminogen streptokinase activator complex (APSAC) whereas Schofer 1990 used urokinase (2 million U IV) and Weaver 1993 used alteplase 100 mg as the thrombolytic agent in both the intervention and control arms. In Castaigne 1989 and Schofer 1990 physicians in mobile care units administered the pre‐hospital thrombolytic agents whereas in Weaver 1993 paramedics administered the thrombolytic. The primary outcomes were similar across all three trials and included mortality, time intervals, angiographic data, ejection fraction and complications.
Castaigne 1989 was a two phase study conducted in the Val de Marne district close to Paris, France. The first phase comprised a simulation pilot study and an education study; the latter evaluated anaesthesiologists' hypothetical decision to correctly thrombolyse individuals with chest pain possibly due to ACS in mobile care units. A total of 294 participants were reviewed over 1 year. The second phase of the study was a RCT comparing pre‐hospital versus in‐hospital thrombolysis conducted over 2 years using 30 U APSAC injected over more than four minutes. The researchers screened 320 individuals with STEMI, and 100 were included in the trial. The intervention in both treatment groups was administered by physicians (including that in mobile care units). The main outcome for phase one of the study was diagnostic accuracy; that for the second phase was the delay between at‐home and in‐hospital injection for participants having received placebo at home.
Schofer 1990 was an RCT conducted in Germany within the mobile care unit systems of AK Altona, Stadtische Kliniken Kiel and Darmstadt. The pre‐hospital group (40 participants) received urokinase (2 million U IV) at home and placebo at hospital whereas the in‐hospital group (38 participants) received placebo at home and urokinase (2 million U IV) at hospital, both followed by 1000 U/hour of heparin at hospital. Urokinase was diluted with 20 mL of injectable water. The mobile care units were staffed with a physician and two emergency medical technicians. The following study endpoints were reported: time intervals, angiographic data and creatine kinase levels, stress test before discharge and complications.
Weaver 1993 was an RCT of pre‐hospital versus in‐hospital initiated thrombolytic therapy conducted in Seattle metropolitan area and the surrounding King County, in the USA. The trial ran from November 1988 to December 1991, and involved 19 hospitals and all paramedical systems in the Metropolitan area. The pre‐hospital‐initiated group received Aspirin 325 mg and alteplase 100 mg at home and no placebo at hospital whereas the hospital‐initiated group received no placebo at home and Aspirin 325 mg and alteplase 100 mg at hospital. A total of 360 participants were included in the study, 175 and 185 in the pre‐hospital and in‐hospital treatment arms, respectively. Pre‐hospital thrombolysis was performed by paramedics (emergency care professionals) with physician guidance. Study endpoints included diagnostic accuracy of STEMI, time to treatment, pre‐hospital and in‐hospital complications, ejection fraction and infarct size.
Excluded studies
Risk of bias in included studies
See: 'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study (Figure 2).
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
See: 'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies (Figure 3).
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Allocation
Schofer 1990, Weaver 1993 and Castaigne 1989 provided no description of random sequence generation; as a result we considered the risk of bias to be unclear. We judged the risk of bias for allocation concealment in Castaigne 1989 to be high as the allocation code was broken. We considered Schofer 1990 and Weaver 1993 to have a low risk of bias for allocation concealment.
Blinding
We considered the risk of bias for the blinding of participants and personnel, as well as for outcome assessment (detection bias), in Castaigne 1989 to be high. The authors of this study state that the mobile care unit physicians were blinded. However, the blinding is not described and the code could be broken if the physician thought it necessary. Upon arrival at hospital the code was broken as all the other physicians and assessors would have knowledge of the treatment received. In Schofer 1990, we judged the risk of bias due to the blinding of participants and personnel to be low as numbered paired ampoules containing either placebo or thrombolysis were used. For outcome assessment we judged the risk to be unclear as no description was provided. We considered the risk of bias due to blinding of participants and personnel in Weaver 1993 to be high as alteplase was administered in an open manner; we judged the risk of bias for outcome assessment to be low as the groups were unknown to the assessor.
Incomplete outcome data
We judged the risk of bias for incomplete outcome data to be high in Castaigne 1989 and Schofer 1990, and unclear in Weaver 1993. Participants in Castaigne 1989 were not assessed according to intention‐to‐treat analysis and some outcome data were not reported. In Schofer 1990 some data were excluded from analysis and some were missing. Weaver 1993 did not report whether participants were lost to follow up or withdrawn from participation.
Selective reporting
We judged Castaigne 1989 and Schofer 1990 to have a low risk of bias for selective reporting. We considered Weaver 1993 to have a high risk as some prespecified complications were not reported in the intervention group.
Other potential sources of bias
Schofer 1990 and Weaver 1993 had no indications of other sources of bias and as a result we judged this risk to be low. We judged Castaigne 1989 to have an unclear risk as the report did not include a table of baseline characteristics.
Effects of interventions
See: Summary of findings for the main comparison Pre‐hospital versus in‐hospital thrombolysis for ST‐elevation myocardial infarction; Summary of findings 2 Pre‐hospital versus in‐hospital thrombolysis for ST‐elevation myocardial infarction
Primary outcome
Mortality data were available for all three included RCTs. However, none of the studies presented the mortality data over the prespecified time periods (one month and one year); hence, no time period was used and we report the general all‐cause mortality rate.
There is low quality evidence indicating uncertainty about whether pre‐hospital compared to in‐hospital thrombolysis reduces mortality (summary of findings Table for the main comparison) (RR 0.73, 95% CI 0.37 to 1.41, three RCTs; 538 participants) (Analysis 1.1). There was no heterogeneity between studies (Chi2 = 0.29; P value = 0.86; I2 = 0%) and we therefore used a fixed‐effect model for meta‐analysis (Analysis 1.1). Further research is likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. It should be noted that the meta‐analysis included only 538 participants and thus one should interpret these results with caution. We rated the studies as having an overall unclear/high risk of bias (Figure 3).
A sensitivity analysis excluding the trial with a high risk of bias (Castaigne 1989) also found no significant difference between the pre‐hospital and in‐hospital thrombolysis groups (Analysis 3.1). Excluding Castaigne 1989, however, resulted in a shift of the pooled effect measure towards a stronger protective effect of pre‐hospital thrombolysis compared with the non‐sensitivity analysis (RR 0.68 compared with 0.73), although the difference between groups remained non‐significant.
Secondary outcomes
Time to thrombolysis
Schofer 1990 and Weaver 1993 presented data on the time from the onset of symptoms to thrombolysis. There was high‐quality evidence (summary of findings Table 2) that pre‐hospital thrombolysis reduced the mean time to thrombolysis by 38 minutes (MD ‐37.95 minutes. 95% CI ‐61.12 to ‐14.77, two RCTs; 438 participants, Analysis 2.1). We found substantial heterogeneity (Chi2 = 3.53; P value = 0.06; I2 = 72%) and we therefore conducted a random‐effects meta‐analysis. Heterogeneity was not thought to be sufficiently significant to forgo meta‐analysis as a visual inspection revealed overlapping CIs and point estimates in a similar direction. We rated these two studies as having an overall low risk of bias (Figure 2).
Acute myocardial infarction functional outcomes
All three included RCTs reported mean percentage ejection fraction. However, Castaigne 1989 presented the mean percentage ejection fraction for pre‐hospital thrombolysis (56.7%) and in‐hospital thrombolysis (53.4%) without providing the standard deviations for the measurements. We therefore conducted a meta‐analysis including Schofer 1990 and Weaver 1993 only. We found low‐quality evidence (summary of findings Table 2) that there may be no difference between the ejection fraction in pre‐hospital versus in‐hospital thrombolysis (MD ‐1.18, 95% CI ‐3.50 to 1.13, two RCTs; 416 participants, Analysis 2.2). As we found no heterogeneity (Chi2 = 0.16; P value = 0.69; I2 = 0%), we therefore used a fixed‐effect model for meta‐analysis. The low‐quality data indicate that further research is likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. We rated these two studies as having an overall low risk of bias (Figure 2).
None of the included RCTs reported data on the acute myocardial infarction functional outcomes, classification of heart failure (New York Heart Association functional classification system) and time to discharge or days in hospital, measured from admission to discharge (proposed secondary outcomes).
Adverse effects
Four adverse effects were prioritised as clinically important and incorporated in the GRADE assessment: ventricular fibrillation, stroke, allergic reaction and bleeding.
There was low‐quality evidence that there may be no difference in the occurrence of ventricular fibrillation (two RCTs), stroke (one RCT) or allergic reactions (one RCT) between groups. There was moderate‐quality evidence that was no difference in bleeding complications between groups (two RCTs, summary of findings Table 2). We downgraded the evidence due to imprecision as the confidence interval included appreciable harm and appreciable benefit (Analysis 2.3).
Discussion
Summary of main results
There is low quality evidence indicating uncertainty about whether pre‐hospital compared to in‐hospital thrombolysis reduces mortality . Additional data may change this finding (summary of findings Table for the main comparison). We rated the included studies as having an overall unclear/high risk of bias (Figure 3).
We found high‐quality evidence that the time to thrombolysis in those who were thrombolysed pre‐hospital compared with those thrombolysed in hospital was statistically significantly reduced by 38 minutes. We rated the studies included in this analysis as having an overall low risk of bias (Figure 3).
We found low‐quality evidence that there may be no difference in acute myocardial infarction functional outcomes (ejection fraction) between pre‐hospital and in‐hospital thrombolysis. We rated the relevant studies as having an overall low risk of bias (Figure 3).
There was low‐quality evidence that there may be no difference in adverse effects between pre‐hospital and in‐hospital thrombolysis (summary of findings Table 2). We rated the relevant studies as having an overall low risk of bias (Figure 3).
Overall completeness and applicability of evidence
We were able to include only three relatively small trials in this review and this influences the external validity of our findings. We were unable to obtain requested data from a potentially eligible study and therefore have excluded it (EMIP). The excluded study could have contributed to the power of the meta‐analysis to detect a difference between groups for the primary outcome. None of the included studies presented data on heart failure classification and days in hospital or time to discharge. The results of this review are applicable to HICs but less so to LMICs, as all the included trials were conducted in developed country settings. We were unable to perform subgroup analyses due to the limited number of included studies.
The findings of this review have strong external validity when generalised to HICs; however, LMICs need to take into consideration their unique health and emergency medical care systems. Local policy makers and clinical directors should consider their local health infrastructure and population distribution needs (rural compared with urban), emergency care systems and availability of the intervention compared with surgical alternatives (e.g. availability of PCI). These considerations should be taken into account when developing clinical guidelines for pre‐hospital thrombolysis.
Quality of the evidence
We used GRADE methodology to explore the quality of the evidence. The primary outcome, mortality, was supported by low‐quality evidence only, which was attributable to a high risk of methodological bias and imprecision in the point estimate. Further research is likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Secondary outcomes that were reported in the included studies were time to thrombolysis, ejection fraction and adverse effects. There was high‐quality evidence that time to thrombolysis is reduced when treatment is delivered pre‐hospital compared with in the hospital. Further research is unlikely to impact our confidence in the estimate. We rated the evidence for the outcome of ejection fraction as low quality, which we downgraded due to the risk of methodological bias and imprecision (the confidence interval includes appreciable benefit and appreciable harm). Only low‐quality evidence was available for all the adverse effect outcomes due to high levels of imprecision, with the exception of the evidence for bleeding complications, which we judged to be of moderate quality.
Potential biases in the review process
We used Cochrane methodology to conduct a comprehensive search to identify all the available trials in order to answer this review question. Data for one potentially eligible study could not be obtained as the authors did not provide the necessary data; hence, we may have omitted additional evidence that could have contributed to the results.
Agreements and disagreements with other studies or reviews
Morrison 2000 is a systematic review and meta‐analysis of pre‐hospital versus in‐hospital thrombolysis for acute myocardial infarction that assesses mortality. The study authors report a statistically significant difference in all‐cause hospital mortality in favour of pre‐hospital thrombolysis. Morrison 2000 included RCTs that assessed the efficacy of thrombolysis for both STEMI and NSTEMI. The current review specifically sought to investigate thrombolysis for STEMI as this type of therapy is not recommended for NSTEMI (O'Connor 2010). Morrison 2000 found a mean time difference of 60 minutes between pre‐hospital and in‐hospital thrombolysis for acute myocardial infarction. Our results are consistent with those of this previously published review.
Study flow diagram.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Comparison 1 Pre‐hospital versus in‐hospital thrombolysis mortality, Outcome 1 All cause hospital mortality.
Comparison 2 Pre‐hospital versus in‐hospital thrombolysis morbidity, Outcome 1 Time to thrombolytic treatment.
Comparison 2 Pre‐hospital versus in‐hospital thrombolysis morbidity, Outcome 2 Acute myocardial infarction functional outcomes.
Comparison 2 Pre‐hospital versus in‐hospital thrombolysis morbidity, Outcome 3 Adverse effects.
Comparison 3 Pre‐hospital versus in‐hospital thrombolysis: Mortality sensitivity analysis, Outcome 1 All cause hospital mortality.
| Pre‐hospital versus in‐hospital thrombolysis for ST‐elevation myocardial infarction | ||||||
| Participants or population: participants with ST‐elevation myocardial infarction | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Pre‐hospital versus in‐hospital thrombolysis | |||||
| All‐cause hospital mortality | 73 per 1000 | 53 per 1000 | RR 0.73 | 538 | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Follow up ranged from 15 days to 1 month | ||||||
| Pre‐hospital versus in‐hospital thrombolysis for ST‐elevation myocardial infarction | ||||||
| Participant or population: participants with ST‐elevation myocardial infarction | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Pre‐hospital versus in‐hospital thrombolysis | |||||
| Time to thrombolytic treatment [minutes] | The mean time to thrombolytic treatment [minutes] in the intervention groups was | 438 | ⊕⊕⊕⊕ | |||
| Acute myocardial infarction functional outcomes ‐ ejection fraction [percentage] | The mean acute myocardial infarction functional outcomes ‐ ejection fraction [percentage] in the intervention groups was | 416 | ⊕⊕⊝⊝ | |||
| Adverse effects ‐ ventricular Fribrillation | 25 per 1000 | 67 per 1000 | RR 2.73 | 178 | ⊕⊕⊝⊝ | |
| Adverse effects ‐ bleeding complications | 58 per 1000 | 51 per 1000 | RR 0.88 | 438 | ⊕⊕⊕⊝ | |
| Adverse effects ‐ allergic reaction | 0 per 1000 | 0 per 1000 | RR 0 | 100 | ⊕⊕⊝⊝ | |
| Adverse effects ‐ Stroke | 11 per 1000 | 23 per 1000 | RR 2.11 | 360 | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Methodological quality (e.g. no blinding in Castaigne 1989) not likely to effect this outcome, therefore not downgraded due to risk of bias | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All cause hospital mortality Show forest plot | 3 | 538 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.73 [0.37, 1.41] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Time to thrombolytic treatment Show forest plot | 2 | 438 | Mean Difference (IV, Random, 95% CI) | ‐37.95 [‐61.12, ‐14.77] |
| 2 Acute myocardial infarction functional outcomes Show forest plot | 2 | 416 | Mean Difference (IV, Fixed, 95% CI) | ‐1.18 [‐3.50, 1.13] |
| 2.1 Ejection Fraction [Percentage] | 2 | 416 | Mean Difference (IV, Fixed, 95% CI) | ‐1.18 [‐3.50, 1.13] |
| 3 Adverse effects Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1 Ventricullar Fribrillation | 2 | 178 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.73 [0.68, 10.86] |
| 3.2 Hypotension | 2 | 178 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.28 [0.47, 3.49] |
| 3.3 Bleeding complications | 2 | 438 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.41, 1.92] |
| 3.4 Allergic Reaction | 1 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.79 [0.19, 77.03] |
| 3.5 Intubation | 1 | 78 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.06, 14.65] |
| 3.6 Cardiac Massage | 1 | 78 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.32 [0.01, 7.55] |
| 3.7 Ventricular tachycardia | 1 | 78 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.27 [0.48, 3.31] |
| 3.8 Wrong Diagnosis | 1 | 78 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.85 [0.12, 67.97] |
| 3.9 Pulmonary Congestion | 1 | 78 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.40, 2.28] |
| 3.10 Post‐infact Angina | 1 | 78 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.14, 6.41] |
| 3.11 Bradycardia | 1 | 78 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.57 [0.15, 2.22] |
| 3.12 Reinfaction | 1 | 78 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.76 [0.22, 2.62] |
| 3.13 Percutaneous transluminal coronary angioplasty | 1 | 78 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.8 [0.44, 32.49] |
| 3.14 Coronary Artery Bypass Graft | 1 | 78 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.85 [0.12, 67.97] |
| 3.15 Stroke | 1 | 360 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.11 [0.39, 11.40] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All cause hospital mortality Show forest plot | 2 | 438 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.32, 1.41] |
