Current guidelines recommend anticoagulation (AC) for low and intermediate-risk pulmonary embolism (PE) and systemic thrombolysis (tPA) for high risk (massive) PE. How these treatment options compare with other modalities of treatment such as catheter directed thrombolysis (CDT), ultrasound assisted catheter thrombolysis (USAT), and administering lower dose of thrombolytics (LDT) is unclear. There is no study that has compared all these treatment options. We conducted a systematic review and Bayesian network meta-analysis of randomized controlled trials in patients with submassive (intermediate risk) PE. Fourteen randomized controlled trials were included, comprising 2132 patients. On Bayesian network meta-analysis, a significant decrease in mortality was noted in tPA versus AC. There was no significant difference between USAT versus CDT. For risk of major bleeding, there was no significant difference in relative risk of major bleeding between tPA versus AC and USAT versus CDT. tPA was found to have a significantly higher risk of minor bleeding and a lower risk of recurrent PE compared to AC. Systemic thrombolysis is associated with a significant reduction in mortality and recurrent PE compared to anticoagulation but an increased risk of minor bleeding. There was no difference in risk of major bleeding. Our study also shows that while the newer modalities of treatment for pulmonary embolism are promising, there is lack of data to comment on the purported advantages.
BACKGROUND: Thrombolytic therapy is usually reserved for people with clinically serious or massive pulmonary embolism (PE). Evidence suggests that thrombolytic agents may dissolve blood clots more rapidly than heparin and may reduce the death rate associated with PE. However, there are still concerns about the possible risk of adverse effects of thrombolytic therapy, such as major or minor haemorrhage. This is the fourth update of the Cochrane review first published in 2006.
OBJECTIVES: To assess the effects of thrombolytic therapy for acute pulmonary embolism.
SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 17 August 2020. We undertook reference checking to identify additional studies.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared thrombolytic therapy followed by heparin versus heparin alone, heparin plus placebo, or surgical intervention for people with acute PE (massive/submassive). We did not include trials comparing two different thrombolytic agents or different doses of the same thrombolytic drug.
DATA COLLECTION AND ANALYSIS: Two review authors (ZZ, QH) assessed the eligibility and risk of bias of trials and extracted data. We calculated effect estimates using the odds ratio (OR) with a 95% confidence interval (CI) or the mean difference (MD) with a 95% CI. The primary outcomes of interest were death, recurrence of PE and haemorrhagic events. We assessed the certainty of the evidence using GRADE criteria.
MAIN RESULTS: We identified three new studies for inclusion in this update. We included 21 trials in the review, with a total of 2401 participants. No studies compared thrombolytics versus surgical intervention. We were not able to include one study in the meta-analysis because it provided no extractable data. Most studies carried a high or unclear risk of bias related to randomisation and blinding. Meta-analysis showed that, compared to control (heparin alone or heparin plus placebo), thrombolytics plus heparin probably reduce both the odds of death (OR 0.58, 95% CI 0.38 to 0.88; 19 studies, 2319 participants; low-certainty evidence), and recurrence of PE (OR 0.54, 95% CI 0.32 to 0.91; 12 studies, 2050 participants; low-certainty evidence). Effects on mortality weakened when six studies at high risk of bias were excluded from analysis (OR 0.71, 95% CI 0.45 to 1.13; 13 studies, 2046 participants) and in the analysis of submassive PE participants (OR 0.61, 95% CI 0.37 to 1.02; 1993 participants). Effects on recurrence of PE also weakened after removing one study at high risk of bias for sensitivity analysis (OR 0.60, 95% CI 0.35 to 1.04; 11 studies, 1949 participants). We downgraded the certainty of evidence to low because of 'Risk of bias' concerns. Major haemorrhagic events were probably more common in the thrombolytics group than in the control group (OR 2.84, 95% CI 1.92 to 4.20; 15 studies, 2101 participants; moderate-certainty evidence), as were minor haemorrhagic events (OR 2.97, 95% CI 1.66 to 5.30; 13 studies,1757 participants; low-certainty evidence). We downgraded the certainty of the evidence to moderate or low because of 'Risk of bias' concerns and inconsistency. Haemorrhagic stroke may occur more often in the thrombolytics group than in the control group (OR 7.59, 95% CI 1.38 to 41.72; 2 studies, 1091 participants). Limited data indicated that thrombolytics may benefit haemodynamic outcomes, perfusion lung scanning, pulmonary angiogram assessment, echocardiograms, pulmonary hypertension, coagulation parameters, composite clinical outcomes, need for escalation and survival time to a greater extent than heparin alone. However, the heterogeneity of the studies and the small number of participants involved warrant caution when interpreting results. The length of hospital stay was shorter in the thrombolytics group than in the control group (mean difference (MD) -1.40 days, 95% CI -2.69 to -0.11; 5 studies, 368 participants). Haemodynamic decompensation may occur less in the thrombolytics group than in the control group (OR 0.36, 95% CI 0.20 to 0.66; 3 studies, 1157 participants). Quality of life was similar between the two treatment groups. None of the included studies provided data on post-thrombotic syndrome or on cost comparison.
AUTHORS' CONCLUSIONS: Low-certainty evidence suggests that thrombolytics may reduce death following acute pulmonary embolism compared with heparin (the effectiveness was mainly driven by one trial with massive PE). Thrombolytic therapy may be helpful in reducing the recurrence of pulmonary emboli but may cause more major and minor haemorrhagic events, including haemorrhagic stroke. More studies of high methodological quality are needed to assess safety and cost effectiveness of thrombolytic therapy for people with pulmonary embolism.
En una revisión sistemática, resumimos las pruebas para la seguridad y la eficacia de la trombólisis dirigida por catéter (CDT) con y sin terapia asistida por ultrasonido para el tratamiento de la embolia pulmonar submasiva y masiva (PE). El resultado primario de eficacia fue la mortalidad. Los resultados se agruparon entre los estudios con el modelo de efectos aleatorios. Veinticuatro estudios incluyeron a 700 pacientes en total; 653 recibieron tratamientos de tromboembolectomía mecánica para la EP (tasa de mortalidad, 9% [intervalo de confianza del 95% (IC), 6% -13%], P = 0,12, tasa de complicaciones menores 6% [IC del 95%, 2% -13 %]). En los estudios de trombólisis acelerada por ultrasonido (USAT), la tasa de mortalidad fue del 4% (IC del 95%, 1% -11%) y en los estudios no USAT fue del 9% (IC del 95%, 6% -13% ). Los resultados secundarios de seguridad fueron todos los eventos hemorrágicos, que ocurrieron en el 12% (IC del 95%, 7% -20%) de los estudios USAT y en el 10% (IC del 95%, 5% -20%) de los estudios no USAT. La evidencia clínica actual no demuestra que USAT sea superior a los métodos CDT.
OBJECTIVES: To evaluate the safety and efficacy of catheter-directed thrombolysis (CDT) in the treatment of acute pulmonary embolism (PE).
BACKGROUND: The use of CDT for the treatment of acute submassive and massive PE is increasing in frequency. However, its safety and efficacy have not been well elucidated.
METHODS: This study is made of two parts: one is a two-center registry of acute PE patients treated with CDT. The safety outcome evaluated was any major complication including fatal, intracranial (ICH), intraocular, or retroperitoneal hemorrhage or any overt bleeding requiring transfusion or surgical repair. The efficacy outcome was acute change in invasive pulmonary artery systolic pressure (PASP). The second part is a meta-analysis of all contemporary studies that used CDT for PE. Reported outcomes are the same as in the registry, with the addition of right ventricular to left ventricular (RV/LV) ratio change.
RESULTS: In the registry, 137 patients were included (age 59 ± 15, 50% male, 88% submassive PE). ICH occurred in two patients and major complications in 13 (9.4%). PASP decreased post procedure by 19 ± 15 mm Hg (95% CI 16-23). In the meta-analysis, 16 studies were included with 860 patients. Rate of ICH was 0.35% and the major complication rate was 4.65%, most requiring transfusion only. In-hospital mortality was 12.9% in the massive and 0.74% in the submassive group. All studies showed improvement in PASP and/or RV/LV ratio post CDT.
CONCLUSIONS: CDT is associated with a low major complication rate. Randomized studies are needed to evaluate its efficacy relative to anticoagulation alone.
BACKGROUND: The use of thrombolytic therapy in patients with intermediate-risk pulmonary embolism is controversial. To compare with anticoagulation alone, no analysis before has determined whether thrombolytic therapy is associated with improved survival or lower incidence of adverse clinical outcomes for intermediate-risk pulmonary embolism.
OBJECTIVE: This meta-analysis was performed to assess mortality benefits, bleeding and recurrent pulmonary embolism risks associated with thrombolytic therapy compared with anticoagulation in patients with intermediate-risk pulmonary embolism.
METHODS: The Web of Science, PubMed, Embase, EBSCO, and the Cochrane Library databases were searched for randomized clinical trials comparing thrombolytic therapy with anticoagulation in intermediate-risk pulmonary embolism patients (in which the mortality data were reported) from inception to August 5, 2014. Primary outcomes were all-cause mortality and major bleeding. Secondary outcomes were recurrent pulmonary embolism and minor bleeding. The pooled relative risk (RR), Mantel-Haenszel corresponding method and fixed-effect model were used to estimate the efficacy and safety of thrombolytic therapy with 95% confidence intervals.
RESULTS: Eight clinical randomized controlled trials involving 1755 patients with intermediate-risk pulmonary embolism were included. Patients treated with thrombolytics presented lower mortality than patients in the anticoagulation cohort (RR, 0.52; 95% CI, 0.28-0.97; 1.39% [12/866] vs. 2.92% [26/889]). Compared with anticoagulation, thrombolytic therapy was associated with a higher risk of major (RR, 3.35; 95% CI, 2.03-5.54; 7.80% [64/820] vs. 2.28% [19/834]) and minor (RR, 3.66; 95% CI, 2.77-4.84; 32.78% [197/601] vs. 8.94% [53/593]) bleeding. Furthermore, thrombolytic therapy was associated with a lower incidence of recurrent pulmonary embolism (RR, 0.33; 95% CI, 0.15-0.73; 0.73% [6/826] vs. 2.72% [23/846]).
CONCLUSION: Compared with anticoagulation, thrombolytic therapy in patients with intermediate-risk pulmonary embolism is associated with lower all-cause mortality and recurrent pulmonary embolism risk despite increased major and minor bleeding risks.
IMPORTANCIA: El tratamiento trombolítico puede ser beneficioso en el tratamiento de algunos pacientes con embolia pulmonar. Hasta la fecha, ningún análisis ha tenido suficiente poder estadístico para determinar si la terapia trombolítica se asocia con una mejor supervivencia, en comparación con la anticoagulación convencional.
OBJETIVO: Determinar los beneficios y los riesgos de mortalidad de sangrado asociados con la terapia trombolítica en comparación con la anticoagulación en la embolia pulmonar aguda, incluyendo el subgrupo de pacientes hemodinámicamente estables con disfunción ventricular derecha (embolia pulmonar de riesgo intermedio).
FUENTES DE INFORMACIÓN: PubMed, Cochrane Library, EMBASE, EBSCO, Web of Science, y bases de datos CINAHL desde su inicio hasta 10 de abril 2014.
SELECCIÓN DE ESTUDIOS: Los estudios elegibles eran ensayos clínicos aleatorios que compararon el tratamiento trombolítico vs terapia anticoagulante en pacientes embolia pulmonar. Se identificaron quince ensayos con 2115 personas. Ocho ensayos con 1775 pacientes especifican inclusión de pacientes con embolia pulmonar de riesgo intermedio.
EXTRACCIÓN DE DATOS Y SÍNTESIS: Dos revisores extrajeron de forma independiente los datos de primera instancia, incluyendo el número de pacientes, las características del paciente, la duración del seguimiento y los resultados.
PRINCIPALES RESULTADOS Y MEDIDAS: Los resultados primarios fueron la mortalidad por todas las causas y la hemorragia mayor. Los resultados secundarios fueron el riesgo de embolia recurrente y hemorragia intracraneal (HIC). Peto odds ratio (OR) y las estimaciones correspondientes IC del 95% se calcularon mediante un modelo de efectos fijos.
RESULTADOS: El uso de trombolíticos se asoció con una menor mortalidad por cualquier causa (OR, 0,53; IC del 95%, desde 0,32 hasta 0,88; 2,17% [23/1061] frente a 3,89% [41/1054] con anticoagulantes; número necesario a tratar [NNT ] = 59) y un mayor riesgo de hemorragia mayor (OR, 2,73; IC del 95%, 1,91-3,91; 9,24% [98/1061] frente a 3,42% [36/1054]; número necesario para dañar [NND] = 18) y ICH (OR, 4,63; IC del 95%, 1,78-12,04; 1,46% [15/1024] frente a 0,19% [2/1019]; NND = 78). La hemorragia mayor no fue significativamente mayor en los pacientes de 65 años o más jóvenes (OR, 1,25; IC del 95%, 0,50-3,14). La trombólisis se asoció con un menor riesgo de embolia pulmonar recurrente (OR, 0,40; IC del 95%, 0,22-0,74; 1,17% [12/1024] frente a 3,04% [31/1019]; NNT = 54). En los ensayos embolia pulmonar con riesgo intermedio, la trombólisis se asoció con una menor mortalidad (OR, 0,48; IC del 95%, 0,25-,92) y los eventos más importantes de sangrado (OR, 3,19; IC del 95%, 2,07-4,92).
Conclusiones y relevancia: Entre los pacientes con embolia pulmonar, incluyendo los que estaban hemodinámicamente estables con disfunción ventricular derecha, el tratamiento trombolítico se asoció con menores tasas de mortalidad por cualquier causa y un mayor riesgo de hemorragia mayor y ICH. Sin embargo, los resultados no pueden aplicarse a los pacientes con embolia pulmonar hemodinámicamente estable sin disfunción ventricular derecha.
OBJETIVO: Revisar toda la literatura disponible sobre la trombólisis dirigida por catéter acelerada por ultrasonido para las oclusiones arteriales periféricas, accidentes cerebrovasculares, trombosis venosa profunda y embolia pulmonar.
MÉTODOS: Se realizó una búsqueda sistemática de la literatura, utilizando bases de datos MEDLINE, EMBASE y Cochrane. Se identificaron un total de 77 informes centrados en la trombolisis acelerada por ultrasonido catéter entregado.
Resultados: Los estudios experimentales muestran que ultrasonidos de alta intensidad puede inducir la trombólisis, con y sin la adición de los activadores del plasminógeno, principalmente por cavitación acústica y disrupción mecánica, mientras que la baja intensidad, ondas de ultrasonido de alta frecuencia pueden realmente mejorar la trombólisis por plasmina mediada. En un total de 340 casos clínicos de diversas condiciones tromboembólicos, la trombolisis acelerada por ultrasonido dirigida por catéter estaba relacionado con la revascularización rápida y una reducción en el tiempo de tratamiento, la dosis del fármaco, el tiempo de hospitalización, y posiblemente principales complicaciones de hemorragia en comparación con la trombolisis estándar. Tasas de complicaciones reportadas, incluyendo sangrado y embolización, eran bajos.
CONCLUSIÓN: Ultrasonido mejorada trombólisis parece ser un concepto prometedor en el tratamiento de diversas afecciones tromboembólicas. La técnica ha demostrado ser segura y eficaz in vitro, in vivo y en estudios clínicos. Ensayos controlados aleatorios que están garantizados y deben esperaban antes de considerar la trombolisis acelerada por ultrasonido dirigida por catéter como un nuevo tratamiento estándar.
Current guidelines recommend anticoagulation (AC) for low and intermediate-risk pulmonary embolism (PE) and systemic thrombolysis (tPA) for high risk (massive) PE. How these treatment options compare with other modalities of treatment such as catheter directed thrombolysis (CDT), ultrasound assisted catheter thrombolysis (USAT), and administering lower dose of thrombolytics (LDT) is unclear. There is no study that has compared all these treatment options. We conducted a systematic review and Bayesian network meta-analysis of randomized controlled trials in patients with submassive (intermediate risk) PE. Fourteen randomized controlled trials were included, comprising 2132 patients. On Bayesian network meta-analysis, a significant decrease in mortality was noted in tPA versus AC. There was no significant difference between USAT versus CDT. For risk of major bleeding, there was no significant difference in relative risk of major bleeding between tPA versus AC and USAT versus CDT. tPA was found to have a significantly higher risk of minor bleeding and a lower risk of recurrent PE compared to AC. Systemic thrombolysis is associated with a significant reduction in mortality and recurrent PE compared to anticoagulation but an increased risk of minor bleeding. There was no difference in risk of major bleeding. Our study also shows that while the newer modalities of treatment for pulmonary embolism are promising, there is lack of data to comment on the purported advantages.
Pregunta de la revisión sistemática»Revisión sistemática de intervenciones
