On 2014 Jul 29, Shunichi Nakamura commented:

"Author Response"

Spiegel confounded the results in pulmonary embolism (PE), including massive and submassive PE, with the results in submassive PE only. Our meta-analysis selected randomized trials that enrolled patients with submassive PE only, whereas the meta-analysis published in the JAMA explored the effects of thrombolysis in patients with PE, including the massive, submassive, and non-massive types. The researchers who conducted the meta-analysis evaluated the efficacy of thrombolysis in submassive PE as a subanalysis. The number of enrolled patients in their meta-analysis was slightly larger than that enrolled in our meta-analysis (1755 patients [8 trials] vs. 1510 patients [6 trials]). The mortality risk reduction rate among the patients with submassive PE was 52% in the published met-analysis and 28% in our meta-analysis. This difference can be explained by the following reasons. We are concerned that an important selection bias might have existed in the meta-analysis published in the JAMA. First, the ULTIMA trial was designed to prove that the ultrasound-accelerated strategy was superior to anticoagulation with heparin alone in patients with submassive PE; therefore, the trial was not conducted purely to compare between thrombolysis and heparin-only therapy, and this technology is considered to influence the overall results. Second, as for the study selection, the MOPPET trial should not have been selected in their meta-analysis because its inclusion criteria were simply determined by the extent of disturbed pulmonary blood flow irrespective of the existence of RV dysfunction or myocardial injury, and this condition and submassive PE are not equivalent. Consequently, the ULTIMA and MOPPET trials influenced the overall result of their meta-analysis because of the larger risk-reduction impact of the two trials. Third, the subjects included by Goldhaber (1993) included patients with massive pulmonary embolism. The corrected number was 18 in their study, as well as in our meta-analysis. Fourth, in the meta-analysis previously published in the JAMA, although the odds ratio was calculated as an analysis method, we think that the risk ratio should be used in the meta-analysis of randomized controlled studies. Based on these issues, we believe that our article more specifically demonstrated the efficacy of thrombolytic therapy in submassive PE. Recent registry studies report that the 30-day mortality rate in patients with submassive PE was 3.0%, which is in line with our result. These results also suggest that if compared with heparin-only therapy, an adjunctive thrombolytic therapy reduces the risk of mortality in patients with submassive PE by about 30%, which is similar to the result from our meta-analysis (28%), then the size effect of this treatment is only about 1%. This could explain why the survival benefit of adjunctive thrombolytic therapy has been difficult to demonstrate in patients with submassive PE. In the two meta-analyses, a significant increase in the risk of intracranial bleeding was observed with thrombolytic therapy compared with heparin alone. Therefore, our major argument was that the harmful effects such as intracranial bleeding might be the trade-off for the benefit of a reduction in clinical deterioration, not the ineffectiveness of thrombolysis for difficult cases of submassive PE. Thus, risk stratification of patients with submassive PE is of great clinical importance. New agents also need to be developed to reduce the incidence of intracranial bleeding and replace the thrombolytic agents used in the previous studies. Moreover, we suggest the use of half-dose thrombolysis in further studies.

On 2014 Jul 24, Ryan Radecki commented:

Post-publication commentary:

"Dueling PE Meta-Analyses"

Nothing sparks controversy quite like a discussion on the utility of thrombolytics. No sooner had the wave of debate brought on by the publication of the PEITHO trial and its finding of no overall mortality benefit died down, did JAMA stoke these flames with the publication of a meta-analysis including the entirety of the literature on thrombolytic use for pulmonary embolism. Examining 16 trials, the authors found a statistically significant absolute mortality benefit of 1.12% or an NNT of 59 patients. This benefit was offset by the increase in major bleeding events observed in those given thrombolytics (9.24% vs 3.42%) with a 1.27% absolute increase in ICH.

...

http://www.emlitofnote.com/2014/07/dueling-pe-meta-analyses.html

On 2014 Jul 24, Ryan Radecki commented:

Post-publication commentary:

"Dueling PE Meta-Analyses"

Nothing sparks controversy quite like a discussion on the utility of thrombolytics. No sooner had the wave of debate brought on by the publication of the PEITHO trial and its finding of no overall mortality benefit died down, did JAMA stoke these flames with the publication of a meta-analysis including the entirety of the literature on thrombolytic use for pulmonary embolism. Examining 16 trials, the authors found a statistically significant absolute mortality benefit of 1.12% or an NNT of 59 patients. This benefit was offset by the increase in major bleeding events observed in those given thrombolytics (9.24% vs 3.42%) with a 1.27% absolute increase in ICH.

...

http://www.emlitofnote.com/2014/07/dueling-pe-meta-analyses.html

On 2014 Jul 29, Shunichi Nakamura commented:

"Author Response"

Spiegel confounded the results in pulmonary embolism (PE), including massive and submassive PE, with the results in submassive PE only. Our meta-analysis selected randomized trials that enrolled patients with submassive PE only, whereas the meta-analysis published in the JAMA explored the effects of thrombolysis in patients with PE, including the massive, submassive, and non-massive types. The researchers who conducted the meta-analysis evaluated the efficacy of thrombolysis in submassive PE as a subanalysis. The number of enrolled patients in their meta-analysis was slightly larger than that enrolled in our meta-analysis (1755 patients [8 trials] vs. 1510 patients [6 trials]). The mortality risk reduction rate among the patients with submassive PE was 52% in the published met-analysis and 28% in our meta-analysis. This difference can be explained by the following reasons. We are concerned that an important selection bias might have existed in the meta-analysis published in the JAMA. First, the ULTIMA trial was designed to prove that the ultrasound-accelerated strategy was superior to anticoagulation with heparin alone in patients with submassive PE; therefore, the trial was not conducted purely to compare between thrombolysis and heparin-only therapy, and this technology is considered to influence the overall results. Second, as for the study selection, the MOPPET trial should not have been selected in their meta-analysis because its inclusion criteria were simply determined by the extent of disturbed pulmonary blood flow irrespective of the existence of RV dysfunction or myocardial injury, and this condition and submassive PE are not equivalent. Consequently, the ULTIMA and MOPPET trials influenced the overall result of their meta-analysis because of the larger risk-reduction impact of the two trials. Third, the subjects included by Goldhaber (1993) included patients with massive pulmonary embolism. The corrected number was 18 in their study, as well as in our meta-analysis. Fourth, in the meta-analysis previously published in the JAMA, although the odds ratio was calculated as an analysis method, we think that the risk ratio should be used in the meta-analysis of randomized controlled studies. Based on these issues, we believe that our article more specifically demonstrated the efficacy of thrombolytic therapy in submassive PE. Recent registry studies report that the 30-day mortality rate in patients with submassive PE was 3.0%, which is in line with our result. These results also suggest that if compared with heparin-only therapy, an adjunctive thrombolytic therapy reduces the risk of mortality in patients with submassive PE by about 30%, which is similar to the result from our meta-analysis (28%), then the size effect of this treatment is only about 1%. This could explain why the survival benefit of adjunctive thrombolytic therapy has been difficult to demonstrate in patients with submassive PE. In the two meta-analyses, a significant increase in the risk of intracranial bleeding was observed with thrombolytic therapy compared with heparin alone. Therefore, our major argument was that the harmful effects such as intracranial bleeding might be the trade-off for the benefit of a reduction in clinical deterioration, not the ineffectiveness of thrombolysis for difficult cases of submassive PE. Thus, risk stratification of patients with submassive PE is of great clinical importance. New agents also need to be developed to reduce the incidence of intracranial bleeding and replace the thrombolytic agents used in the previous studies. Moreover, we suggest the use of half-dose thrombolysis in further studies.