•Mortality at the end of the follow-up period

•

New intracranial haemorrhage

The complete search strategy identified 18,601 records and 77 records were filtered for full-text review that were narrowed down to 10 studies as per selection criteria. References searching yielded further 3 studies leading to a total of 13 studies (Figure-1).^11,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 Nine clinical trial protocols were published in various clinical trial registries, of which four were published after 2017 but no study results available for any of these ongoing trials until the period of search for this review (January 1991 till June 2022).8, 9, 10^,30, 31, 32, 33, 34, 35 All the principal investigators were contacted via email published for the details of these ongoing trials but details remained inaccessible.Fig. 1

PRISMA Flowchart of search strategy.

All the included studies were parallel-group RCTs and there are three multinational, multicenter trials.^11,19,27 Five out of 13 studies were conducted in multiple centres, 3 of which were in China, one each in the USA and Netherland.^18,22, 23, 24^,28 All the other studies were conducted in a single centre, one each in Turkey, UK, USA, Italy and Singapore.^{20,21,25,26,29} Six out of 13 studies were conducted on patients with ICH^{18,19,23,24,27,28} and the rest were conducted on patients with IVH causing obstructive hydrocephalus. Two studies out of 13 were conducted on neonates.^20,25 There were two studies conducted on patients with basal ganglia ICH^18,23 while the rest of the studies included patients with both lobar and deep supratentorial ICH/IVH.

Intraventricular hemorrhage studies involved only one type of intervention: administering fibrinolytics into the clot in the ventricle via external ventricular drain (EVD), though the choice of fibrinolytics, its dosage and protocol varied among them. Intracerberal hemorrhages studies involved two types of procedures before administering fibrinolytics into the clot. Hence there were five different sets of intervention and comparators in the included studies. For primary outcome, all-cause mortality and functional outcome with dichomatized mRS and GOS/eGOS has been anlysed while secodanry outcomes including new ICH, CNS infections, shunt-dependent hydrocephalus and time-to-clot resolution have also been assessed in each individual study (Table-1).Table 1

Characteristics of the studies.

Modified Rankin Sscale was used as an outcome of interest for risk-of-bias (ROB) assessment in 6 out of 13 studies^{11,18,19,23,27,28} while GOS was used in Akdemir et al study.²⁹ For the rest of the studies, mortality was used to assess ROB (Fig. 2). There were no imbalances in the baseline characteristics reported in all but one trial.²⁸ In Teernstra et al study,²⁸ there were significant differences in volume and location of ICH between the intervention and the control arms. The ICH was large and mostly were lobar (vs deep) in the intervention arm. Because the mRS was available only for six studies, publication bias could not be assessed with the funnel plot.Fig. 2

Overview of Risk of Bias assessment.

All the included studies reported mortality at the end of follow up (Fig. 3). In pooled analysis for IVH patients, fibrinolysis vs saline for IVH showed a reduction in the risk of death in the fibrinolysis arm [RR-0.63 (0.46, 0.85) p = 0.003]. CLEAR III trial¹¹ was the largest trial with a significant decrease in the treatment arm's mortality [RR-0.64 (0.46, 0.88) p = 0.006]. All the other trials showed statistically significant results but had wide confidence intervals due to the small sample size. In newborns with IVH, fibrinolysis vs EVD alone [RR-0.43 (0.12, 1.51) p = 0.19] and fibrinolysis vs standard care [0.65 (0.20, 2.15) p = 0.48] showed nonsignificant reduction in the risk of mortality.^20.25 In pooled analysis of ICH patients, a reduction in the risk of death in the intervention arm was noticed in fibrinolysis vs standard craniotomy [0.60 (0.40, 0.89) p = 0.01]^18,24 and fibrinolysis vs standard medical treatment [RR-0.83 (0.65, 1.05) p = 0.12].^19,23,27,28 The largest trial in this domain was MISTIE III trial that also showed comparable statistically significant results [RR-0.77 (0.55, 1.08) p = 0.07].²⁷Fig. 3

Forest plot for mortality.

Six out of 13 studies measured outcome by dichotomized mRS (Fig. 4). In the CLEAR III trial¹¹ (fibrinolysis vs saline for IVH), thw results were statistically nonsignicant for the good functional outcome [RR-1.07 (0.88, 1.30) p = 0.48]. For fibrinolysis vs standard medical treatment for ICH, the proportion of people with the favourable outcome is greater in the fibrinolysis arm [RR-1.20 (1.00, 1.44) p = 0.05].^19,23,27,28 In the CLEAR III trial (fibrinolysis vs saline for IVH),¹¹ the proportion of people with favourable outcomes measured by GOS-E is also more in the fibrinolysis arm [RR-1.24 (0.97, 1.59) p = 0.08]. In the Akdemir study²⁹ of neonates, there was statistically nonsignificant difference in the good functional outcome measured by GOS between the study arms comparing fibrinolysis vs EVD alone in IVH [RR-3.21 (0.87, 11.90) p = 0.08] and CI was wide due to small sample size (Fig. 5).Fig. 4

Forest plot for mRS.

For CNS infections/ventriculitis (Fig. 6), fibrinolysis vs saline in IVH showed reduced risk of ventriculitis in fibrinolysis arm [RR-0.59 (0.35, 1.00) p = 0.05] but for fibrinolysis vs standard medical treatment in ICH, the risk of brain infections between the study arms remained nonsignificant [RR-1.34 (0.24, 7.49) p = 0.74].^11,22,26 While for the risk of developing new hemorrhages (Fig. 7), there was nonsignificant difference in the risk of any new bleeding in the fibrinolysis vs saline in IVH [RR-1.36 (0.44, 4.23) p = 0.60] but a higher risk of new bleeding in fibrinolysis arm was noted both in Whitelaw study²⁵ of fibrinolysis vs standard care in neonates in IVH [RR-4.22 (1.31, 13.65) p = 0.02] and fibrinolysis vs standard medical treatment for ICH [RR-2.27 (1.23, 4.19) p = 0.009].^23,27 However, for fibrinolysis vs standard craniotomy in patients with ICH, there was significant reduction in the risk of bleeding in the fibrinolysis arm [RR-0.48 (0.30, 0.78) p = 0.003].^18,24Fig. 6

Forest plot for CNS infection.

For shunt-dependent hydrocephalus (Fig. 8), in fibrinolysis vs saline for IVH, the results were statistically nonsignificant between the study arms [RR-1.10 (0.77, 1.59) p = 0.59]^11,22,26 while in Akedemir study (fibrinolysis vs EVD alone for IVH), a higher risk of shunt dependent hydrocephalus in the fibrinolysis arm [RR-3.21 (0.87, 11.90) p = 0.08] was found.²⁹ Finally, in time-to-clot resolution results synthesis (Fig. 9), there was a greater daily percentage reduction of clot size in the fibrinolysis arm [SMD-0.93 days (0.39 days, 1.47 days) p = 0.0008] in fibrinolysis vs saline for IVH.^21,22 MISTIE III (fibrinolysis vs standard medical treatment for ICH) trial also reported a greater daily percentage reduction of clot size in the fibrinolysis arm [SMD-3.69% (3.40%, 3.97%) p = 0.00001].¹⁹ In CLEAR III trial, time-to-open the third and fourth ventricle was measured and in the fibrinolysis arm, there was a faster clearing of the blood with third and fourth ventricle opened sooner compared to the saline arm [SMD-0.35 days (0.17 days, 0.53 days) p = 0.0001].¹¹ Similalry, in Teernstra et al SICHPA trial and King et al study (fibrinolysis vs standard medical treatment for ICH), there was a greater significant reduction in clot size after starting treatment in the fibrinolysis arm [SMD-0.59 ml (0.11 ml, 1.06 ml) p = 0.05] and (SMD- 1.11 ml [0.03 ml, 2.20 ml] p = 0.01) respectively.^26,28Fig. 8

Forest plot for shunt dependent hydrocephalus.

There were significant variations in the ICH volumes, intervention arm, comparater sets, the choice of fibrinolytics, their dosage, and protocols of administration. While the earlier studies used Streptokinase and urokinase, the later studies used Alteplase for fibrinolysis. The studies were also carried out in different settings, diverse populations, different eligibility criteria clincal outcomes and had varied objectives. In the studies involving ICH, fibrinolysis vs standard medical care, the main aim was to determine whether local fibrinolysis is better than medical treatment in moderate volume ICH. However, in the studies of ICH for fibrinolysis vs standard craniotomy, the aim was to check whether fibrinolysis is better than craniotomy in reducing ICP and improving outcome in large volume ICH. In the studies testing ICH fibrinolysis in neonates, the main aim was to study the shunt dependency between the intervention arms. Moreover, each study used different primary outcome measures, and many of the studies were phase II or preliminary studies with a small sample size. Considering all these factors, the study results cannot be generalised to the entire population. Among all the included studies, only CLEAR III and MISTIE III trials showed no significant biases. Due to the nature of the intervention and control arms, the participants and providers could not be blinded in the MISTIE III trial. All the other included studies have high risk or unclear risks of bias in more than two domains. Especially in studies done before 2000, the study reports were preliminary and did not include a detailed methodology.^20,29

The strengths of review are its robust search strategy that it would not have missed out on any potentially eligible study and inclusion of RCTs only in review process. In terms of limitations, there were a few trial protocols published but the study results were unavaible up to date of conduct of this review period. Not including those unpublished studies carries a risk of selection bias in this review. Evaluating the funnel plot for mortality for all the studies, it was evident that there was asymmetry in the plot with a relative scarcity of small studies with negative results (those studies that showed increased mortality in the intervention arm).

Over the past three decades, there are quite a few observational studies published with focus on local fibrinolytics therapy in ICH or IVH including few systematic reviews.41, 42, 43 Predominently, the aims of all these studies and reviews, were to evaluate whether a quicker and complete clearance of the blood clots will improve clincal outcomes. To the best of our knowledge, this is the first review that has analysed the RCTs alone to study the effect of local fibrinolytics in all types of supratentorial intracranial haemorrhages including both ICH and IVH.

Guo et al⁴¹ did a network meta-analysis on different interventions on spontaneous ICH. The author included RCTs published in all the surgical modalities used for the treatment of ICH. This meta-analysis also included ten trials that used minimally invasive stereotactic puncture (MIPS) therapy in ICH. In our review, four of these trials were excluded [34–37] as per selection criteria.42, 43, 44, 45 Kim et al⁴² and Zuccarello et al⁴³ studies were excluded because participants in the intervention arm were given local fibrinolytic therapy only when there was residual clot after aspiration. Hattori et al⁴⁴ study was not included because the intervention involved stereotactic aspiration of the clot without local fibrinolytic administration while Ge et al⁴⁵ study was excluded because participants in the control arm were also given local fibrinolytic therapy for a residual clot Analogous to results of our review, Guo et al⁴¹ also found a decreased risk of mortality and increased risk of recurrent bleeding in the intervention arm in the MIPS group while on the contrary to our review, the author showed a better functional outcome in the intervention arm in the MIPS group. This is possibly because, the studies were included based on different intervention definitions (MIPS with or without local fibrinolytic therapy).

Similar to our review, Van Solinge et al¹⁵ also found a decreased risk of mortality and infection, faster clot resolution in the intervention arm (EVD + fibrinolytics), but no difference in functional outcome between the study arms. However, on the contrary, they reported decreased shunt dependency in the intervention arm. This is because more observational studies included in their review that has reported decreased shunt dependency in the intervention arm.