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.
We summarize the evidence for the safety and efficacy of catheter-directed thrombolysis (CDT) with and without ultrasound-assisted therapy for treating submassive and massive pulmonary embolism (PE) in a systematic review. The primary efficacy outcome was mortality. Outcomes were pooled across studies with the random-effects model. Twenty-four studies enrolled 700 patients in total; 653 received mechanical thromboembolectomy treatments for PE (mortality rate, 9% [95% confidence interval (CI), 6%-13%], P = .12; rate of minor complications, 6% [95% CI, 2%-13%]). In the ultrasound-accelerated thrombolysis (USAT) studies, the mortality rate was 4% (95% CI, 1%-11%) and in the non-USAT studies, it was 9% (95% CI, 6%-13%). Secondary safety outcomes were all bleeding events, which occurred in 12% (95% CI, 7%-20%) of the USAT studies and in 10% (95% CI, 5%-20%) of the non-USAT studies. Current clinical evidence does not prove USAT is superior over CDT methods.
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 thrombolysis in patients with acute, intermediate-risk pulmonary embolism (PE) remains controversial. This meta-analysis compared the efficacy and safety of thrombolysis and anticoagulation treatments for intermediate-risk PE patients. Methods: Two investigators independently reviewed the literature and collected data from randomized controlled trials (RCTs) of thrombolysis for intermediate-risk PE in the PubMed, MEDLINE, EMBASE, the Cochrane Library, and Chinese Biomedical Literature Databases (CBM). Results: A total of 1,631 intermediate-risk PE patients from seven studies were included. Significant differences were not found regarding the 30-day, all-cause mortality rates between the thrombolytic and anticoagulant groups [odds ratio (OR), 0.60; 95% confident interval (CI), 0.34-1.06; P=0.08]. The rate of clinical deterioration in the thrombolytic group was lower than that in the anticoagulant group (OR, 0.27; 95% CI, 0.18-0.41; P<0.01). Recurrent PE in the thrombolytic group was also significantly lower than that in the anticoagulant group (OR, 0.34; 95% CI, 0.15-0.77; P=0.01). Comparing the thrombolytic and anticoagulation groups, the incidence of minor bleeding was significantly higher in the thrombolytic group (OR, 5.33; 95% CI, 2.85-9.97; P<0.00001), but there were no difference in the incidences of major bleeding events (OR, 2.07; 95% CI, 0.60-7.16; P=0.25). Conclusions: Thrombolytic treatment for intermediate-risk PE patients, if not contraindicated, could reduce clinical deterioration and recurrence of PE, and trends towards a decrease in all-cause, 30-day mortality. Despite thrombolytic treatment having an increased total bleeding risk, there was no difference in the incidence of major bleeding events, compared with patients receiving anticoagulation treatment.
AIM: traitement thrombolytique induit rapidement la dissolution du caillot que l'anticoagulation chez les patients présentant une embolie pulmonaire aiguë (PE), mais est associée à un risque accru d'hémorragie. Nous avons examiné les risques et les avantages de la thérapie thrombolytique dans la gestion des patients atteints de PE aiguë.
MÉTHODES ET RÉSULTATS: Nous avons systématiquement examinés études randomisées contrôlées comparant un traitement thrombolytique systémique ainsi que l'anticoagulation par anticoagulation seule chez les patients souffrant d'EP aiguë. Quinze essais impliquant 2057 patients ont été inclus dans notre méta-analyse. En comparaison avec l'héparine, un traitement thrombolytique a été associée à une réduction significative de la mortalité globale (OU; 0,59, IC 95%: 0,36 à 0,96). Cette réduction ne était pas statistiquement significative après exclusion des études, y compris PE à haut risque (OR; 0,64, IC 95%: 0,35 à 1,17). Le traitement thrombolytique a été associée à une réduction significative du critère combiné de décès ou l'escalade de traitement (OR: 0,34, IC 95%: 0,22 à 0,53), la mortalité liée au PE (OR: 0,29; IC 95%: 0,14 à 0,60) et PE récidive (OR: 0,50; IC 95%: 0,27 à 0,94). Hémorragie majeure (OU; 2,91, IC 95%: 1,95 à 4,36) et hémorragies mortelles ou intracrânienne (OR: 3,18, IC à 95%: 1.25 à 8.11) étaient significativement plus fréquents chez les patients recevant la thrombolyse.
CONCLUSIONS: Le traitement thrombolytique réduit la mortalité totale, PE récidive, et la mortalité liées PE chez les patients souffrant d'EP aiguë. La diminution de la mortalité globale est toutefois pas significative chez les patients hémodynamiquement stables avec PE aiguë. Le traitement thrombolytique est associée à une augmentation de l'hémorragie majeure et fatale ou intracrânienne.
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.
IMPORTANCE: Le traitement thrombolytique peut être bénéfique dans le traitement de certains patients souffrant d'embolie pulmonaire. À ce jour, aucune analyse n'a eu la puissance statistique suffisante pour déterminer si la thérapie thrombolytique est associée à une amélioration de la survie, par rapport à l'anticoagulation conventionnelle.
OBJECTIF: Déterminer les avantages de la mortalité et les risques hémorragiques associés à la thérapie thrombolytique par rapport à l'anticoagulation dans l'embolie pulmonaire aiguë, y compris le sous-ensemble de patients hémodynamiquement stables avec dysfonction ventriculaire droite (embolie pulmonaire à risque intermédiaire).
SOURCES DE DONNÉES: PubMed, la Cochrane Library, EMBASE, EBSCO, Web of Science, et les bases de données CINAHL de création à 10 Avril 2014.
SÉLECTION DES ÉTUDES: Les études admissibles ont été randomisés essais cliniques comparant la thérapie thrombolytique vs traitement anticoagulant chez les patients atteints d'une embolie pulmonaire. Seize essais comprenant 2115 individus ont été identifiés. Huit essais comprenant 1775 patients spécifiés inclusion des patients atteints de risque intermédiaire embolie pulmonaire.
EXTRACTION DE DONNÉES ET SYNTHÈSE: Deux auteurs ont extrait indépendamment les données au niveau du procès, y compris nombre de patients, les caractéristiques des patients, la durée du suivi, et les résultats.
LES RÉSULTATS ET MESURES PRINCIPALES: Les principaux résultats étaient la mortalité toutes causes confondues et les saignements majeurs. Les résultats secondaires étaient risque d'embolie récurrente et une hémorragie intracrânienne (ICH). Peto odds ratio (OR) et les estimations associées IC à 95% ont été calculées en utilisant un modèle à effets fixes.
RÉSULTATS: L'utilisation de thrombolytiques était associée à une plus faible mortalité toutes causes confondues (OR, 0,53; IC 95%, 0,32 à 0,88; 2,17% [23/1061] vs 3,89% [41/1054] avec des anticoagulants; nombre nécessaire à traiter [NNT ] = 59) et de plus grands risques de saignements majeurs (OR, 2,73; IC 95%, 1,91 à 3,91; 9,24% [98/1061] vs 3,42% [36/1054], le nombre nécessaire pour nuire [NNH] = 18) et ICH (OR, 4,63; IC 95%, 1,78 à 12,04; 1,46% [15/1024] vs 0,19% [2/1019]; NNH = 78). Le saignement majeur n'a pas augmenté de façon significative chez les patients de 65 ans et plus jeunes (OR, 1,25; IC 95%, 0,50 à 3,14). Thrombolyse a été associée à un risque plus faible de l'embolie pulmonaire récurrente (OR, 0,40; IC 95%, 0,22 à 0,74; 1,17% [12/1024] vs 3,04% [31/1019]; NNT = 54). In-risque intermédiaire des essais d'embolie pulmonaire, la thrombolyse a été associée à une mortalité plus faible (OR, 0,48; IC 95%, 0,25 à 0,92) et plus d'événements hémorragiques majeurs (OR, 3,19; IC à 95%, 2,07 à 4,92).
CONCLUSIONS ET PERTINENCE: Chez les patients présentant une embolie pulmonaire, y compris ceux qui étaient hémodynamiquement stables avec dysfonction ventriculaire droite, la thérapie thrombolytique a été associée à des taux inférieurs de mortalité toutes causes et des risques accrus de saignements majeurs et ICH. Cependant, les résultats peuvent ne pas appliquer aux patients présentant une embolie pulmonaire qui sont hémodynamiquement stable sans dysfonction ventriculaire droite.
CONTEXTE ET OBJECTIF: Selon US Food and Drugs Administration (FDA), 2 heures tissu recombinant activateur du plasminogène (rt-PA) infusion de 100mg est recommandé pour les patients admissibles atteints d'embolie pulmonaire aiguë (PE). Cependant, il existe des preuves impliquant qu'une dose plus faible de rt-PA peut être tout aussi efficace mais potentiellement plus sûr par rapport à rt-PA 100mg régime. L'objectif de cette revue systématique et méta-analyse est d'évaluer l'efficacité et l'innocuité d'une faible dose de rt-PA dans le traitement de PE aiguë.
Matériel et méthode: Nous avons cherché Pubmed, EMBASE, la bibliothèque Cochrane Database et CBM Littérature pour les essais contrôlés randomisés (ECR) portant sur une faible dose de rt-PA pour PE aiguë. Les résultats ont été décrits en termes de changements de tests d'image et l'échocardiographie, événements hémorragiques majeurs, décès toutes causes confondues, et la réapparition du PE.
RÉSULTATS: Cinq études (440 patients) ont été inclus, dont trois par rapport à faible dose rt-PA (0,6 mg / kg, 50mg maximum ou 50mg perfusion 2h) avec la dose standard (100mg perfusion de 2h). Il y avait plus d'événements hémorragiques majeurs en dose standard rt-PA que dans le groupe à faible dose (OR 0,33, IC à 95% de 0,12 à 0,91; P = 0,94, I (2) = 0%), alors qu'il n'y avait pas de différences statistiques récurrentes PE ou mortalité toutes causes confondues entre ces deux groupes. Deux études ont comparé une faible dose (0,6 mg / kg, au maximum 50 mg / 2 min bolus ou 10 mg en bolus, ≤40 mg / 2 h) avec de l'héparine. Il n'y avait pas de différence significative dans les grands événements hémorragiques (OR 0,73, IC à 95% 0,14 à 3,98; P = 0,72), PE récurrente ou mortalité toutes causes confondues. Aucune hétérogénéité liée à la dose n'a été trouvée pour toutes les études incluses.
CONCLUSIONS: Les résultats de cette méta-analyse ont été génératrice d'hypothèses. Sur la base des données limitées, notre examen systématique suggéré que la faible dose de rt-PA a une efficacité similaire, mais était plus sûr que la dose standard de rt-PA. En outre, par rapport à l'héparine à faible dose rt-PA n'a pas augmenté le risque de saignement majeur pour les patients de PE éligibles.
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.
