Effectiveness Comparisons of Drug Therapies for Postoperative Aneurysmal Subarachnoid Hemorrhage Patients: Network Meta‑analysis and systematic review

doi:10.21203/rs.3.rs-400621/v1

Objective: To compare the effectiveness of various drug interventions in improving the clinical outcome of postoperative patients after aneurysmal subarachnoid hemorrhage (aSAH) and assist in determining the drugs of definite curative effect in improving clinical prognosis.

Methods: Eligible Randomized Controlled Trials (RCTs) were searched in databases of PubMed, EMBASE, and Cochrane Library (inception to Sep 2020). Glasgow Outcome Scale (GOS) score, Extended Glasgow Outcome Scale (GOSE) score or modified Rankin Scale (mRS) score was used as the main outcome measurements to evaluate the efficacy of various drugs in improving the clinical outcomes of postoperative patients with aSAH. The network meta-analysis (NMA) was conducted based on a random-effects model, dichotomous variables were determined by using odds ratio (OR) with 95% confidence interval (CI), and a surface under the cumulative ranking curve (SUCRA) was generated to estimate the ranking probability of comparative effectiveness among different drug therapies.

Results: From the 493 of initial citation screening, forty-four RCTs (n=10626 participants) were eventually included in our analysis. Our NMA results showed that cilostazol (OR=3.35,95%CI=1.50,7.51) was the best intervention to improve the clinical outcome of patients (SUCRA=87.29%, 95%CrI 0.07-0.46). Compared with the placebo group, only two drug interventions [nimodipine (OR=1.61, 95%CI 1.01,2.57) and cilostazol (OR=3.35, 95%CI 1.50, 7.51)] achieved significant statistical significance in improving the clinical outcome of patients.

Conclusions: Both nimodipine and cilostazol have exact curative effect to improve the outcome of postoperative patients with aSAH, and cilostazol may be the best drug to improve the outcome of patients after aSAH operation. Our study provides implications for future studies that, the combination of two or more drugs with relative safety and potential benefits (e.g., nimodipine and cilostazol) may improve the clinical outcome of patients more effectively.

Neurology

Aneurysmal subarachnoid hemorrhage，Clinical outcome，Drug therapies， Network meta-analysis

Subarachnoid hemorrhage (SAH) can occur at any age, especially at 40-60 years old ¹. The global morbidity of SAH is about 6.1 per 100000 person-years²，85% of which is caused by ruptured intracranial aneurysms ³. As an extremely devastating disease, spontaneous aneurysmal Subarachnoid Hemorrhage (aSAH) has a case-fatality rate of 10.9%-27.5% ^4-7,22-28.7%^7,8 and 30.7%⁸ during hospitalization, at 30 days and at three months, respectively. Moreover, at least 10%-15% of aSAH patients have died before arriving at the hospital, missing the chance of proper rescue⁹. Even for patients who survive after operation, there remains high risks of early mortality and long-term disability ¹⁰. A one-year follow-up showed that 35% of SAH patients had a poor overall quality of life ¹¹. Another study showed 42.4% of SAH patients have poor clinical outcome(mRS=3-6)¹². It has also been indicated that since most of the data used in the existing systematic reviews have been out of date, the current mortality and prognosis of aSAH patients treated with current guidelines should be better than those reported¹⁰. Nevertheless, it is undeniable that the mortality and prognosis of the disease are still disappointing as, first, aSAH usually affects relatively young people, leading to severe disability and loss of working ability ahead of time, so the medical burden on families and society can be directly reduced with a good outcome (mRS=0-3). But several studies have shown that aSAH is still a major financial burden on health care systems in many countries ^13-15. Second, early surgical interventions (Craniotomy Clipping and Endovascular Embolization) of ruptured aneurysms can effectively reduce the incidence of rebleeding and mortality of patients. Some literature show that the early mortality rate of aSAH has decreased ^7,16-18 by approximately 25-30%^8,19, but more than 50% of the postoperative survivors still progress into a state of severe disabilities²⁰. The 10-year, 15-year and 20-year long-term mortality of the survivors remains high as 17.9%, 29.5%, and 43.6%, respectively²¹. It’s sad that successful surgical treatment did not correspond to reduce the relatively high rate of long-term poor outcome of aSAH patients, indicating that early surgical treatment is neither the endpoint nor the only treatment for patients with aSAH. Under the condition with well controlled risk of rebleeding, comprehensive postoperative management should be highlighted to improve the overall outcome of patients，in which the rational selection and application of drug therapies are especially significant. Based on the above problems, we assume the necessity of aSAH postoperative hierarchical ordering based on the effectiveness of multiple drugs. We performed a network meta-analysis (NMA) by Frequentist and Bayesian model because even without direct evidence, it could provide an overview and ranking by simultaneously comparing two or more interventions. Compared with the pairwise meta-analysis which combined the direct and indirect evaluation of therapeutic effect, the accuracy of NMA was improved ²². Therefore, out study aims to find out the best drug to improve the clinical outcome of postoperative patients with aSAH by summarizing and analyzing the existing evidence.

This review followed guidance for the conduct and reporting of systematic reviews from the Cochrane handbook²³ and the PRISMA NMA checklist²⁴. The protocol of this review was registered on PROSPERO (ID: CRD 42020219424).

Search strategy and study selection

The search strategy was designed and implemented separately by two authors. A comprehensive search of all the randomized controlled trials (RCTs) of aSAH drug treatment was conducted at PubMed, Cochrane Library, Embase from their inception to September 10, 2020. We rigorously compare the effects of two or more treatments groups or between the treatment group and the control group (placebo, inactive group) in the treatment of aSAH. Without being restricted by year and language, the Medical Subject Headings (MeSH) combined with free words followed by Boolean logical operators were conducted by using “aSAH”, “Nimodipine”, “Nicardipine”, “Magnesium”, “Milrinone”, “Statins”, “Clazosentan”, “Tirilazad”, “Fasudil”, “Cilostazol”, “methylprednisolone”, “Enoxaparin”, “Randomized controlled trials” as well as additional relevant conceptual keywords. All analyses were based on previously published research and did not require ethical approval or patient consent.

According to predefined selection criteria, two authors independently evaluated all available citations. We screened the titles and abstracts of articles obtained from the search first, and excluded articles which did not meet the inclusion criteria or were repeatedly published. For research published many times, we chose the most informative and complete manuscript. For articles that may meet the inclusion criteria, two authors (WLY, YZH) carefully read the full text to further evaluate their relevance. In addition, the references included in those articles were also evaluated to further explore the relevant research. All the citations were downloaded and managed in accordance with the prespecified standards in Endnote X9 (Thompson ISI Research Soft, Philadelphia, PA, USA). In order to ensure smooth proceeding of further analysis, it is necessary to check the accuracy and completeness of the data. Any discrepancies in search strategy and article inclusion process were resolved through discussion or arbitration by two experienced author (YC, YXJ).

Inclusion & exclusion criteria and outcome measurement

Inclusion criteria: (1) The included patients need to be diagnosed as aSAH through clear imaging characteristics and clinical manifestations, and all of patients need to be treated with coiling or clamping within 72 hours after hospitalisation; (2) Clearly reported outcome indicators; (3) At least ten aSAH patients; (4) published in English between 1980 and 2019; (5) Peer-reviewed original RCTs;

Exclusion criteria: researches that applied two or more drug interventions simultaneously;

According to the inclusion and exclusion criteria, two authors (WLY, YZH) used The Cochrane Consumers and communication Review Group’s data extraction template²⁵ to extract and organize data for qualified studies independently. We first analyzed the global data and demographic characteristics of all included studies according to the pre-customized outcome data collection form. The following relevant data were extracted by two authors (WLY, HRL) as baseline data including: name of studies, first author of article, year of publication, country and region, duration of treatment, and basic characteristics. Placebo was the designated control group (DCG) for pair-wise and network meta-analyses.

Glasgow Outcome Scale (GOS) score, Extended Glasgow Outcome Scale (GOSE) score or modified Rankin Scale (mRS) score was used as the main outcome measurements to evaluate the efficacy of various drugs in improving the clinical outcomes of postoperative patients with aSAH. Good outcome was defined as no disability or moderate disability, including GOS>3 or mRS<4 or GOSE>4. Poor outcome included severe disability, vegetative state and death (GOS≤3 or mRS≥4 or GOSE≤4). Each clinical study was followed up for at least 2 weeks.

Data abstraction and quality appraisal

In the process of extracting data, any disagreements were resolved through discussion between pairs of authors. Experienced professor (YC) was invited to judge the disagreements objectively if necessary. Data could be then entered with accuracy and unanimity.

We used Cochrane Risk of Bias tool to assess the risk of bias (ROB) of included studies²³. Seven domains of ROB were evaluated by two authors separately to define each study as of high, low, or unclear risk of bias, including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. The evaluation of ROB was carried out in software of Review Manager (Version 5.4).

Statistical analyses

The Frequentist and Bayesian network meta-analysis has stronger classification capabilities than traditional meta-analysis because it can summarize the comparisons between multiple therapies at the same time, making complex models more flexible, and generating relatively scientific interpretation in terms of causal relationships²⁶. We used minimally informative prior distributions based on random effect statistical model to integrate direct and indirect evidence and compare various drug interventions by forming a connected network. We first performed a traditional pairwise meta-analysis for each control. In terms of statistical heterogeneity, 25%, 50%, 75% I² statistic was used to evaluate the heterogeneity of each comparative test ²⁷. a random-effect based comparison-adjusted funnel plot was conducted to detect the presence of any dominant types of bias, such as publication bias, selective reporting or other biases.

We draw a network plot as a simple summary description to present all the available evidence of each treatment evidence and sequence of analyses were performed in STATA, version 16.0 (Corporation LLC, College Station, USA). We set the odds ratio (OR) as a 95% Confidence Interval (CI) for the dichotomous result.

In order to ensure that different treatment comparisons were sufficiently similar to provide valid indirect inferences, we achieved the transitivity assumption by comparing all the clinical and methodological characteristics of the included studies, such as patients and experimental designs. The hierarchical random effects were used to compare multiple drug interventions at the same time by forming a connected network, integrating direct and indirect estimates and using the methodology of multivariate meta-analysis. In the case of randomly selecting state, three parallel Markov chains were initially established to simulate the statistical models for accurate evaluate²⁸. Each chain generated 50,000 iterations, and the first 10,000 iterations were discarded to ensure that the bias of initial values were minimized when the chain reached its target distribution. The Brooks-Gelman-Rubin diagnosis method was used to assess the convergence of models by examining the history trajectory of trace plot combined with density plot²⁹. We use OpenBUGS (version 3.2.3 rev 1012) calculated treatment rank probability and the surface under the cumulative ranking curve (SUCRA) was generated to display a simple numerical statistical cumulative ranking probability plots of various interventions. SUCRA would be 1 if a treatment is certainly at the highest level or highly effective, while zero undoubtedly means that the treatment is the worst ³⁰. What’s more, we used the "node-splitting" technique ³¹ to compare the indirect evidence from the entire network with direct evidence in order to explore whether there will be a potential source inconsistence in our network. (p value > 0.05 indicates the consistency)³².

Baseline characteristics and ROB quality assessment

602 articles were initially screened through searching of databases and 13 additional articles were obtained by tracking the references from initially screened articles. Then we eliminated 165 of duplicates and other 354 articles after reading the title and abstract. Based on the full-text examination, 39 articles were excluded as 17 articles were not RCTs, 3 articles were not about treatment for aSAH or was animal experiment, 2 articles were not original research, 9 articles without relevant outcome or reported data can’t be extracted, 3 articles without a control group, and 5 articles were self-controls with different doses in the control group. Finally, 44 articles, including 13 drug interventions, and a total of 10626 patients were included in this NMA. The processing of literature selection is shown in Figure 1.

The included studies provided data published from 1986 to 2017. Table 1 summarizes the key characteristics of participants and interventions of the 44 included trials. All cases included in each study were patients with aSAH. The severity of the disease varied [Hunt-Hess grade 1-5 or World Federation of Neurological Surgeons (WFNS) grade 1-5], and each clinical study was followed up for at least 2 weeks. The duration of studies varied from 3 to 76 days. According to available data, 66.28% of patients were women. 17 RCTs consisted of 4,527 participants from Europe, followed by Asia which contained 16 RCTs with 3392 participants, 6 RCTs were comprised of participants from multiple continents, and the remaining 5 RCTs were originated from the USA and Africa.

Individual and overall study-level quality were summarized in Supplement Figure 1 and Supplement Figure 2, respectively. Within the 44 included trials, 41 trials described in detail the generation of random sequences, 38 trials described their approach of concealment, 26 studies did not describe the blind methods of participants, implementers, or outcome measurers. 38 studies have complete data, and only 5 studies may have reporting bias.

Pairwise meta‑analysis and NMA results

The funnel plot illustrated that publication bias generation relies on the distribution of some scattering spots which are asymmetrical in the inverted funnel plot (Supplementary Figure 3).

As shown in Figure 2, the network geometry was visualized to display each arm. Each treatment has its own unique node, whose size depends on their contribution to the entire network. In our NMA, comparisons between thirteen drug intervention groups were described. Magnesium (MGS) was most frequently included with 10 arms (n=1139), followed by nimodipine (NID) involving 9 arms (n=735), statins (ST) involving 6 arms (n=527), cilostazol (CTZ) involving 4 arms (n =203), clazosentan (CST) involving 4 arms (n=276), tirilazad (TZD) involving 4 arms (n=1017), fasudil (FSD) involving 3 arms (n=196), nicardipine (NCD) involving 2 arms (n=459), and erythropoietin (EPO) involving 1 arm (n=24), Omega-3 fatty acid (ω-3FA) involving 1 arm (n=55), enoxaparin (ENP) involving 1 arm (n=85), Recombinant Human Tissue-type plasminogen activator (rt-PA) involving 1 arm (n=30), methylprednisolone （MPN） involving 1 arm (n=49), among which 4 studies were direct trials.

As shown in Figure 3, a total of 2 drugs were statistically significant superior to placebo group, including NID (OR=1.61, 95%CI 1.01,2.57) and CTZ (OR=3.35, 95%CI 1.50, 7.51). In addition, the efficacy of CTZ was significantly higher than CST, ST and HPN [CST (OR=3.19, 95%Cl 1.19,8.55), ST (OR=3.58, 95%Cl 1.33,9.67), HPN (OR=4.23, 95%Cl 1.04,17.28), respectively]. The remaining NCD (OR=2.44, 95%Cl 1.50,7.51), ω-3FA (OR=2.37, 95%Cl 0.69,8.18), MPN (OR=2.15, 95%Cl 0.57,8.18), FSD (OR=1.74, 95%Cl 0.80,3.78), rt-PA (OR=1.71, 95%Cl 0.43,6.88), MGS (OR=1.43, 95%Cl 0.96,2.13), TZD (OR=1.31, 95%Cl 0.76,2.27), EPO (OR=1.21, 95%Cl 0.27,5.41), CST (OR=1.05, 95%Cl 0.60,1.85) were more likely to have a good prognosis than the placebo group (GOS>3 or mRS<4). The efficacy of ST (OR=0.94, 95%Cl 0.52,1.67) and ENP (OR=0.79, 95%Cl =0.25,2.51) may not be as good as the placebo group, but the differences were not statistically significant.

We plotted the SUCRA line to rank each drug intervention (shown in Supplement SUCRA plot and Table 2), which illustrated that compared with other 12 drug interventions, CTZ had the highest probability of improving the prognosis of aSAH patients (SUCRA=87.29%, 95%CrI 0.07-0.46) while NCD (SUCRA=78.79%, 95%CrI 0.23-1.00) and ω-3FA (SUCRA=69.99%, 95%CrI 0.07-1.00) also had a good ranking among the 13 interventions. The remaining MPN (SUCRA=65.70%, 95%CrI 0.00-1.00), FSD (SUCRA=60.51%, 95%CrI 0.07-0.92), NID (SUCRA=57.18%, 95%CrI 0.23-0.84), rt-PA (SUCRA=55.58%, 95%CrI 0.00-1.00), MGS (SUCRA=49.69%, 95%CrI 0.15-0.76), EPO (SUCRA=40.79%, 95%CrI 0.00-1.00), TZD (SUCRA=39.82%, 95%CrI 0.00-0.76), CST (SUCRA=29.19%, 95%CrI 0.00-0.69), PLB (SUCRA=22.46%, 95%CrI 0.07-0.46), ST (SUCRA=22.14%, 95%CrI 0.00-0.61) and ENP (SUCRA=20.89%, 95%CrI 0.00-0.84) had an inferior ranking. There is no statistically significant inconsistency between direct or indirect comparison detected by node-splitting approach (PLB vs. NID p value =0.343, PLB vs. MGS p value =0.638, PLB vs. FSD p value =0.430, NID vs. MGS p value =0.638, NID vs. FSD p value =0.430).

With NMA on postoperative drug treatment in patients with aSAH, we summarized the available data and concluded that CTZ is the best intervention to improve the clinical outcome of patients (SUCRA=87.29%, 95%CrI 0.07-0.46). Compared with the placebo group, only two drug interventions [NID (OR=1.61, 95%CI 1.01,2.57), CTZ (OR=3.35, 95%CI 1.50,7.51)] achieved significant statistical significance in improving the prognosis of patients.

Among our study, NID is the only drug approved by the FDA with neuroprotection and ability to improve the outcome of aSAH ^33,34. NID has been considered to work by improving brain vasospasm for a long time, however, some early critical research RCTs ^35-38 have shown seemingly contradictory results as there is a lack of correlation between the improvement of angiographic vasospasm and the improvement of outcome with NID. The potential role of NID has been re-recognized. It does not exert its effect by simply dilating the diameter of the vascular lumen. There is a special neuroprotective mechanism, which is still not fully understood. Some researchers found that NID can activate TrkB neurotrophic factor receptors to induce neuron proliferation and neuroprotective signal transduction events in the hippocampus and prefrontal cortex of mice ³⁹, which may be illustrative. Some studies have also speculated that this protective mechanism is related to the reduction of microthrombosis, inhibition of diffuse ischemia and spreading depolarizations (SD), and increase of fibrinolytic activity ^40-42. But it is clear in RCTs that it is exactly through these mechanisms instead of vasodilation that the prognosis of patients might be improved. Our study showed consistency with above results. NID did improve the prognosis of patients while it is not statistically significant for the other simple vasodilators (FSD, NCD, etc.) to be more likely to improve the prognosis, although they have reduced the frequency of cerebral vasospasm in their respective studies. It is undeniable for NID to be of prominent position clinically as the most widely used drug in aSAH patients. But unfortunately, its curative effect is mild with limited effect of improving the prognosis of postoperative patients. Brain injury after aSAH is a multimodal process including early brain injury (EBI) and delayed cerebral ischemia (DCI). The mechanism leading to DCI is not yet fully understood ⁴³. The pathophysiological processes that may be involved at this stage include cerebral vasospasm (CVS), microvascular constriction, microthrombosis, diffuse cortical ischemia, and delayed apoptosis ⁴⁴. CTZ differs from conventional platelet aggregation inhibitors as apart from microthrombosis prevention, it also has a vasodilation effect by inhibiting phosphodiesterase-3 and increasing intracellular cyclic adenosine monophosphate, which mainly functions in the DCI stage of brain injury. Since pure anti-vasospasm drugs [MGS (OR=1.43, 95%Cl 0.96,2.13), NCD (OR=2.44, 95%Cl 0.88,6.74), CST (OR=1.05, 95%Cl 0.60,1.85), FSD (OR=1.74, 95%Cl 0.80,3.78)] did not show definite prognostic improvement, the efficacy of CTZ comes most likely from its anti-microthrombosis ability. Another meta-analysis ⁴⁵ also showed the reduced risk of symptomatic vasospasm, cerebral infarction, and poor outcome in the CTZ group. However, it is not yet routinely applied to aSAH in clinical practice.

Our study is also a expand to another large-scale meta-analysis⁴⁶, which mainly studied the clinical outcome of aSAH patients treated with CVS targeted therapy. On this basis, we included anti-inflammatory, anti-oxidant, iron chelator, anti-platelet formation, and other drug RCTs for comparative analysis. This extensive and comprehensive supplement is necessary because more and more shreds of evidence, including well-designed RCTs and summarized clinical guidelines, have shown that brain injury after aSAH is a complex pathology involving multiple factors where there is no causal connection between the simple use of drugs to reduce vasospasm and a good outcome and other drugs targeted for brain damage may also play an important role in improving the effectiveness of patients' outcome.

Moreover, ENP and ST showed a tendency to be more likely to have a poor outcome than the placebo group. For the application of ENP in aSAH, it mainly works by reducing inflammation and restoring the integrity of the blood-brain barrier ⁴⁷. We found that it does not improve patient outcomes and may aggravate the patient's condition due to its potential to increase the risk of intracranial hemorrhage. For ST, they have anti-vasospasm and anti-inflammatory effects. Vasospasm is closely related to the DCI process after aSAH, but the inflammatory mechanism runs throughout the EBI and DCI brain injury process ^48-51. Several different trials ^52-55 indicated that the efficacy of statins is still controversial, although ST failed to show a good ability to improve clinical outcome in our study, given the important role of nerve inflammation in the process of aSAH and the relative safety of ST, we believe that ST still has great potential, and may be used in combination with other drugs to produce curative effect in terms of improving the prognosis of patients with significant synergistic effect. The most recent AHA/ASA guidelines ³³, published in 2012, noted that despite the lack of strong evidence of benefit, it makes sense to administer ST to prevent vasospasm in patients after aSAH. Given the controversy in current literature, more deterministic trials are needed to confirm the effect of ST on the prognosis of aSAH.

Currently, many clinically applicable drugs may play an important role in improving prognosis, but no single treatment has been proven effective in preventing complications after bleeding, and further clinical trials are needed to investigate that. From classic CVS mechanism to the DCI theory, and combined with more and more evidence supporting that the EBI after aSAH may result in significant morbidity and mortality⁹, it has been highlighted that aSAH is a complicated process of multiple factors. However, current studies mainly focus on single drug application postoperatively, and new thinking should be put forward: if single drug is not satisfactory in curative effect, we can try a combination of multiple drugs. A recent retrospective analysis⁵⁶ found a 24.36% improvement in cerebrovascular diameter in patients treated with multiple vasodilators compared with those treated with a single agent (P < 0.0001). Not only did it resolve cerebral vasospasm more effectively, but patients treated with multiple vasodilators also showed better improvement in the functional outcome at discharge (OR=0.15, 95%CI 0.04-0.55; p = 0.004) and 90-day follow-up (OR=0.20, 95% CI 0.05-0.77; p = 0.019). Studies have shown the potential benefits of multi-drug treatment strategies, but such combinations also face questions about the safety of the combined drugs and the choice of the best dose for different drugs in the multi-drug regimen, which require further study⁵⁶. Considering surgical intervention is effective to control the rebleeding, the application of CTZ may play the function of micro thrombosis to the maximum extent without worrying about the risk of rebleeding, thus remaining correspondingly secure in the combined application. Similarly, we suppose the potential combinability of ST.

At present, combined with relevant trials, review reports and our systematic review, no drugs other than NID and CTZ have a definite effect on improving the prognosis, but it cannot be denied that these drugs still potentially play an improving role in the course of the disease, among which we do not recommend routine use of CST because of its severe side effects (pulmonary edema, low blood pressure, etc.). NCD is not recommended to improve patient prognosis as it is not as effective as NID, but it can be used for patients with blood pressure management. FSD is widely used only in Japan. Its efficacy is controversial with corresponding potential in improving the prognosis of patients, and its further evaluation by RCT on a larger scale is still needed. With hemorrhage risk, routine infusion of high-dose ENP is not recommended. As glutamic acid could cause pathological SD ⁵⁷, MGS provides potential neuroprotection ^58,59 by blocking the release of glutamate, so we recommend to maintain a normal dynamic balance of serum magnesium in aSAH patients, but routine infusion of magnesium above the normal level is not needed. There is no standard use for other drugs such as ω-3FA and Tirilazad, and more research is needed to evaluate them.

Strengths and limitations

Our NMA first evaluated each therapy individually, then combined all the eligible direct and indirect evidence and compared the major interventions simultaneously in patients with aSAH, which was the greatest advantage of our study. Furthermore, the drug therapy after aSAH is complex and multifaceted with limited relevant comprehensive meta-analysis, showing the special significance of our NMA.

The limitations of our study also need to be acknowledged, and several limitations may have influenced our results. First, there was significant heterogeneity in the included studies. Due to the different severity of disease in some of the included patients, for example, 14 RCTs excluded patients with Hunt-Hess scale or WFNS grade 5, while 2 RCTS excluded patients with Hunt/Hess grade or WFNS 1-2，their prognosis could differ greatly by the severity itself, so the efficacy of some intervention measures may be misestimated. Moreover, the follow-up of outcome indicators varies from 14 days to 1 year, which may give false credibility to the prognosis assessment of patients. In view of this, people may question the original intention of our NMA. We tried to analyze the results by including RCTs with complete primary outcomes measurement, which allowed us to overcome this shortcoming by using a homogeneous end point that was easy to assess. Second, we also acknowledge that some publications may have been left out, since we only include publications in English. This can lead to language bias because studies with statistically significant results are more likely to be published in English ⁶⁰. third, due to various reasons, there are not enough RCTs for drug intervention of EPO, RT-PA, ENP, MPN and other parts, so the evidence based on its efficacy is limited, which makes it more difficult for our NMA to draw a summary conclusion.

In summary, our NMA showed that both CTZ and NID had definite efficacy in improving the prognosis of patients, while ENP and ST-based postoperative treatment of aSAH were the least effective interventions. Our study may provide strong evidence that CTZ is the best intervention for improving the prognosis of patients with aSAH in this particular population, and provide implications for future studies, which is that the combination of two or more drugs with relative safety and potential benefits (such as CTZ combined with NID) may improve the clinical outcome of patients more effectively.

aSAH: aneurysmal Subarachnoid Hemorrhage; CI: Confidence Interval; GOS: Glasgow Outcome Scale; GOSE: Extended Glasgow Outcome Scale; mRS: modified Rankin Scale; NMA: Network Meta-analysis; OR: Odds Ratio; RCTs: Randomized Controlled Trials; SUCRA: Surface Under the Cumulative Ranking curve; WFNS: World Federation of Neurological Surgeons grade; MGS: Magnesium; NID: nimodipine; ST: statins; CTZ: cilostazol; CST: clazosentan; TZD: tirilazad; FSD: fasudil; EPO: erythropoietin; NCD: nicardipine; ω-3FA: Omega-3 fatty acid; ENP: enoxaparin; rt-PA: Recombinant Human Tissue-type plasminogen activator; MPN: methylprednisolone; EBI: early brain injury; DCI: delayed cerebral ischemia; CVS: cerebral vasospasm

Acknowledgements

Not applicable.

Authors’ contributions

WLY and YZH, conceptualized the study. WLY, YC and YXJ, design of study. WLY, YZH, HRL and XLZ, literature retrieval, study selection, data extraction, statistical analyses, interpretation of the data and drafting of the initial manuscript. YC, quality evaluation. YC and YXJ, critical revision and comment for important intellectual content. all authors reviewed and approved the final manuscript.

Funding

No funding was obtained.

Availability of data and materials

All data generated or analysed during this study are included in this published article.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Øie LR, Solheim O, Majewska P, et al. Incidence and case fatality of aneurysmal subarachnoid hemorrhage admitted to hospital between 2008 and 2014 in Norway. Acta neurochirurgica. 2020;162(9):2251-2259.
Etminan N, Chang HS, Hackenberg K, et al. Worldwide Incidence of Aneurysmal Subarachnoid Hemorrhage According to Region, Time Period, Blood Pressure, and Smoking Prevalence in the Population: A Systematic Review and Meta-analysis. JAMA neurology. 2019;76(5):588-597.
Macdonald RL, Schweizer TA. Spontaneous subarachnoid haemorrhage. Lancet (London, England). 2017;389(10069):655-666.
Chan V, Lindsay P, McQuiggan J, Zagorski B, Hill MD, O'Kelly C. Declining Admission and Mortality Rates for Subarachnoid Hemorrhage in Canada Between 2004 and 2015. Stroke. 2018:Strokeaha118022332.
Lantigua H, Ortega-Gutierrez S, Schmidt JM, et al. Subarachnoid hemorrhage: who dies, and why? Crit Care. 2015;19(1):309.
Udy AA, Vladic C, Saxby ER, et al. Subarachnoid Hemorrhage Patients Admitted to Intensive Care in Australia and New Zealand: A Multicenter Cohort Analysis of In-Hospital Mortality Over 15 Years. Crit Care Med. 2017;45(2):e138-e145.
Worthington JM, Goumas C, Jalaludin B, Gattellari M. Decreasing Risk of Fatal Subarachnoid Hemorrhage and Other Epidemiological Trends in the Era of Coiling Implementation in Australia. Frontiers in neurology. 2017;8:424.
Galea JP, Dulhanty L, Patel HC. Predictors of Outcome in Aneurysmal Subarachnoid Hemorrhage Patients: Observations From a Multicenter Data Set. Stroke. 2017;48(11):2958-2963.
Daou BJ, Koduri S, Thompson BG, Chaudhary N, Pandey AS. Clinical and experimental aspects of aneurysmal subarachnoid hemorrhage. CNS neuroscience & therapeutics. 2019;25(10):1096-1112.
Roquer J, Cuadrado-Godia E, Guimaraens L, et al. Short and long-term outcome of aneurysmal subarachnoid hemorrhage patients. Neurology. 2020.
Taufique Z, May T, Meyers E, et al. Predictors of Poor Quality of Life 1 Year After Subarachnoid Hemorrhage. Neurosurgery. 2016;78(2):256-264.
Hammer A, Steiner A, Ranaie G, et al. Impact of Comorbidities and Smoking on the Outcome in Aneurysmal Subarachnoid Hemorrhage. Sci Rep. 2018;8(1):12335.
Rivero-Arias O, Gray A, Wolstenholme J. Burden of disease and costs of aneurysmal subarachnoid haemorrhage (aSAH) in the United Kingdom. Cost effectiveness and resource allocation : C/E. 2010;8:6.
Modi S, Shah K, Schultz L, Tahir R, Affan M, Varelas P. Cost of hospitalization for aneurysmal subarachnoid hemorrhage in the United States. Clinical neurology and neurosurgery. 2019;182:167-170.
Yoon S, Yoon JC, Winkler E, Liu C, Lawton MT. Nationwide Analysis of Cost Variation for Treatment of Aneurysmal Subarachnoid Hemorrhage. Stroke. 2018:Strokeaha118023079.
Nieuwkamp DJ, Setz LE, Algra A, Linn FH, de Rooij NK, Rinkel GJ. Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. The Lancet Neurology. 2009;8(7):635-642.
Mackey J, Khoury JC, Alwell K, et al. Stable incidence but declining case-fatality rates of subarachnoid hemorrhage in a population. Neurology. 2016;87(21):2192-2197.
Vergouwen MD, Jong-Tjien-Fa AV, Algra A, Rinkel GJ. Time trends in causes of death after aneurysmal subarachnoid hemorrhage: A hospital-based study. Neurology. 2016;86(1):59-63.
Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. The Lancet Neurology. 2009;8(4):355-369.
Bederson JB, Connolly ES, Jr., Batjer HH, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke. 2009;40(3):994-1025.
Nieuwkamp DJ, de Wilde A, Wermer MJ, Algra A, Rinkel GJ. Long-term outcome after aneurysmal subarachnoid hemorrhage-risks of vascular events, death from cancer and all-cause death. J Neurol. 2014;261(2):309-315.
Thorlund K, Mills EJ. Sample size and power considerations in network meta-analysis. Systematic reviews. 2012;1:41.
Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 ed: The Cochrane Collaboration. 2011.
Hutton B, Salanti G, Caldwell DM, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Annals of internal medicine. 2015;162(11):777-784.
Tarsilla M Cochrane Handbook for Systematic Reviews of Interventions. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol 5:S38. 2011.
Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. Jama. 2000;283(15):2008-2012.
Melsen WG, Bootsma MC, Rovers MM, Bonten MJ. The effects of clinical and statistical heterogeneity on the predictive values of results from meta-analyses. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2014;20(2):123-129.
Mavridis D, Salanti G. A practical introduction to multivariate meta-analysis. Statistical methods in medical research. 2013;22(2):133-158.
Brooks S, Gelman A General methods for monitoring convergence of iterative simulations. J Comput Graph Stat 7:434–455. 1998.
Page MJ, Shamseer L, Altman DG, et al. Epidemiology and Reporting Characteristics of Systematic Reviews of Biomedical Research: A Cross-Sectional Study. PLoS medicine. 2016;13(5):e1002028.
van Valkenhoef G, Dias S, Ades AE, Welton NJ. Automated generation of node-splitting models for assessment of inconsistency in network meta-analysis. Research synthesis methods. 2016;7(1):80-93.
Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. European journal of epidemiology. 2010;25(9):603-605.
Connolly ES, Jr., Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke. 2012;43(6):1711-1737.
Diringer MN, Bleck TP, Claude Hemphill J, 3rd, et al. Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society's Multidisciplinary Consensus Conference. Neurocrit Care. 2011;15(2):211-240.
Pickard JD, Murray GD, Illingworth R, et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ (Clinical research ed). 1989;298(6674):636-642.
Jan M, Buchheit F, Tremoulet M. Therapeutic trial of intravenous nimodipine in patients with established cerebral vasospasm after rupture of intracranial aneurysms. Neurosurgery. 1988;23(2):154-157.
Ohman J, Servo A, Heiskanen O. Long-term effects of nimodipine on cerebral infarcts and outcome after aneurysmal subarachnoid hemorrhage and surgery. Journal of neurosurgery. 1991;74(1):8-13.
Petruk KC, West M, Mohr G, et al. Nimodipine treatment in poor-grade aneurysm patients. Results of a multicenter double-blind placebo-controlled trial. Journal of neurosurgery. 1988;68(4):505-517.
Koskimäki J, Matsui N, Umemori J, Rantamäki T, Castrén E. Nimodipine activates TrkB neurotrophin receptors and induces neuroplastic and neuroprotective signaling events in the mouse hippocampus and prefrontal cortex. Cell Mol Neurobiol. 2015;35(2):189-196.
Macdonald RL. Origins of the Concept of Vasospasm. Stroke. 2016;47(1):e11-15.
Szabó Í, O MT, Török Z, et al. The impact of dihydropyridine derivatives on the cerebral blood flow response to somatosensory stimulation and spreading depolarization. British journal of pharmacology. 2019;176(9):1222-1234.
Carlson AP, Alchbli A, Hänggi D, Macdonald RL, Shuttleworth CW. Effect of Locally Delivered Nimodipine Microparticles on Spreading Depolarization in Aneurysmal Subarachnoid Hemorrhage. Neurocritical care. 2020.
Schneider UC, Xu R, Vajkoczy P. Inflammatory Events Following Subarachnoid Hemorrhage (SAH). Current neuropharmacology. 2018;16(9):1385-1395.
Macdonald RL. Delayed neurological deterioration after subarachnoid haemorrhage. Nature reviews Neurology. 2014;10(1):44-58.
Qureshi AI, Ishfaq A, Ishfaq MF, et al. Therapeutic Benefit of Cilostazol in Patients with Aneurysmal Subarachnoid Hemorrhage: A Meta-Analysis of Randomized and Nonrandomized Studies. Journal of vascular and interventional neurology. 2018;10(2):33-40.
Boulouis G, Labeyrie MA, Raymond J, et al. Treatment of cerebral vasospasm following aneurysmal subarachnoid haemorrhage: a systematic review and meta-analysis. European radiology. 2017;27(8):3333-3342.
Hayman EG, Patel AP, James RF, Simard JM. Heparin and Heparin-Derivatives in Post-Subarachnoid Hemorrhage Brain Injury: A Multimodal Therapy for a Multimodal Disease. Molecules (Basel, Switzerland). 2017;22(5).
de Oliveira Manoel AL, Macdonald RL. Neuroinflammation as a Target for Intervention in Subarachnoid Hemorrhage. Frontiers in neurology. 2018;9:292.
Frontera JA, Provencio JJ, Sehba FA, et al. The Role of Platelet Activation and Inflammation in Early Brain Injury Following Subarachnoid Hemorrhage. Neurocritical care. 2017;26(1):48-57.
Solar P, Mackerle Z, Joukal M, Jancalek R. Non-steroidal anti-inflammatory drugs in the pathophysiology of vasospasms and delayed cerebral ischemia following subarachnoid hemorrhage: a critical review. Neurosurg Rev. 2020.
Ďuriš K, Neuman E, Vybíhal V, et al. Early Dynamics of Interleukin-6 in Cerebrospinal Fluid after Aneurysmal Subarachnoid Hemorrhage. Journal of neurological surgery Part A, Central European neurosurgery. 2018;79(2):145-151.
Kirkpatrick PJ, Turner CL, Smith C, Hutchinson PJ, Murray GD. Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial. The Lancet Neurology. 2014;13(7):666‐675.
Tseng MY, Czosnyka M, Richards H, Pickard JD, Kirkpatrick PJ. Effects of acute treatment with pravastatin on cerebral vasospasm, autoregulation, and delayed ischemic deficits after aneurysmal subarachnoid hemorrhage: a phase II randomized placebo-controlled trial. Stroke; a journal of cerebral circulation. 2005;36(8):1627‐1632.
Garg K, Sinha S, Kale SS, et al. Role of simvastatin in prevention of vasospasm and improving functional outcome after aneurysmal sub-arachnoid hemorrhage: a prospective, randomized, double-blind, placebo-controlled pilot trial. British journal of neurosurgery. 2013;27(2):181‐186.
Wong GKC, Chan DYC, Siu DYW, et al. High-dose simvastatin for aneurysmal subarachnoid hemorrhage: Multicenter randomized controlled double-blinded clinical trial. Stroke. 2015;46(2):382-388.
Chen PR, Bulsara K, Lopez-Rivera V, et al. Use of single versus multiple vasodilator agents in the treatment of cerebral vasospasm: is more better than less? Acta neurochirurgica. 2020.
Van Harreveld A. Compounds in brain extracts causing spreading depression of cerebral cortical activity and contraction of crustacean muscle. Journal of neurochemistry. 1959;3(4):300-315.
van den Bergh WM, Algra A, van Kooten F, et al. Magnesium sulfate in aneurysmal subarachnoid hemorrhage: a randomized controlled trial. Stroke. 2005;36(5):1011-1015.
Veyna RS, Seyfried D, Burke DG, et al. Magnesium sulfate therapy after aneurysmal subarachnoid hemorrhage. Journal of neurosurgery. 2002;96(3):510-514.
Jüni P, Holenstein F, Sterne J, Bartlett C, Egger M. Direction and impact of language bias in meta-analyses of controlled trials: empirical study. International journal of epidemiology. 2002;31(1):115-123.

Table 1 Characteristics of included studies

Publication	Treatments and sample size	Endpoints	Mean age (years, ±SD)	Proportion of girls	Treatment duration	Recruiting area


Petruk, 1988	NID=72 versus PLB=82	GOS,3 months	47.1±1.0	66.9%	21d	UK
Schmid- elsaesser, 2006	NID=51 versus PLB=53	GOS,12 months	53.0±16.0	58.7%	21d	Germany
Pickard, 1989	NID=278 versus PLB=276	GOS,3 months	47.0±1.0	60.1%	21d	UK
Jan, 1988	NID=73 versus PLB=54	GOS,14 days	48.0±0.6	53.5%	7-14d	France
Ohman, 1991	NID=104 versus PLB=109	GOS,21 days	45.2±11.2	51.4%	21d	Finland
Zhao, 2011	NID=60 versus FSD=55	GOS,1 month	50.0±11.4	61.2%	14d	China
Philippon, 1986	NID=31 versus PLB=39	GOS,21 days	45.0±12.9	57.1%	21d	France
Westermaier, 2010	MGS=54 versus PLB=53	GOS,6 months	51.0±13.0	38.3%	10d	Germany
Boet, 2005	MGS=23 versus PLB=22	GOS,3 months	57.0	45.1%	14d	Hong Kong, China
Muroi, 2008	MGS=27 versus PLB=31	GOS,3 months	52.8±12.7	25.9%	12d	Switzerland
Vandenbergh, 2005	MGS=122 versus PLB=127	mRS,3 months	54.5±0.1	67.1%	14d	Netherlands
Akdemir, 2009	MGS=40 versus P=43	GOS,3 months	53.7±0.3	61.4%	10d	Turkey
Mees, 2012	MGS=606 versus PLB=597	mRS,3 months	57.0	69.7%	20d	Netherlands/Chile/UK
Wong, 2006	MGS=30 versus PLB=30	GOS,6 months	60.0±2.0	70.0%	14d	Hong Kong, China
Wong, 2010	MGS=169 versus PLB=158	mRS,6 months	57.0	63.6%	14d	Hong Kong, China
Hassan, 2011	MGS=15 versus PLB=15	GOS,3 months	49.5±0.5	70.0%	14d	Egypt
Matsuda, 2016	CTZ=74 versus PLB=74	GOS,3 months	58.5±12.0	67.6%	14d	Japan
Senbokuya, 2013	CTZ=54 versus PLB=55	GOS,3 months	60.7±12.6	62.4%	14d	Japan
Suzuki, 2011	CTZ=49 versus PLB=51	mRS,14 days	63.0±13.5	76.0%	14d	Japan
Yoshimoto, 2009	CTZ=26 versus PLB=24	mRS,1 month	59.0±1.0	74.0%	14d	Japan
Macdonald, 2008	CST=107 versus PLB=96	GOSE,3 months	51±10.5	73.9%	14d	11 countries in Europe
Macdonald, 2011	CST=764 versus PLB=383	GOSE,3 months	51.7±11.0	67.6%	14d	27 countries worldwide
Macdonald, 2012	CST=181 versus PLB=172	GOSE,3 months	53.0±1.0	70.2%	14d	27 countries worldwide
Fujimura, 2017	CST=52 versus PLB=55	GOSE,3 months	55.2±11.2	60.0%	14d	Japan/Korea
Shibuya, 1992	FSD=131 versus PLB=136	GOS,1 month	55.0±11.0	56.2%	14d	Japan
Zhao, 2006	FSD=33 versus NID=34	GOS,1 month	50.1±11.4	61.1%	14d	China
JingjianMA, 2009	FSD=32 versus NID=32	GOS,14 days	48.5±10.0	62.5%	14d	China
Tseng, 2005	ST=40 versus PLB=40	mRS,14 days	52.9±12.0	55.0%	14d	UK
Garg, 2013	ST=19 versus PLB=19	GOS,3 months	49.1±1.6	55.3%	14d	India
Naraoka, 2017	ST=54 versus PLB=54	GOS,3 months	56.5±1.5	68.5%	14d	Japan
Vergouwen, 2009	ST=16 versus PLB=16	GOS,3 months	53.5±0.5	62.5%	14d	Netherlands
Chou, 2008	ST=19 versus PLB=20	mRS,21 days	53.1±14.6	74.4%	21d	USA
Kirkpatrick, 2014	ST=379 versus PLB=403	mRS,6 months	50.0±9.7	62.7%	21d	UK/Other countries
Haley, 1993	NCD=447 versus PLB=455	GOS,3 months	49.9±14.0	63.8%	14d	USA/ Canada
Barth, 2006	NCD=12 versus PLB=12	mRS,12 months	52.5±7.1	27.0%	14d	Germany
Haley, 1995	TZD=61 versus PLB=42	GOS,3 months	50.2±14.0	61.2%	21d	Canada
Kassell, 1996	TZD=251 versus PLB=256	GOS,3 months	50.1±13.4	64.5%	10d	Europe/Australia/New Zealand
Haley, 1997	TZD=300 versus PLB=299	GOS,3 months	51.0±13.1	68.5%	10d	USA
Lanzino, 1999	TZD=405 versus PLB=414	GOS,3 months	53.0	100.0%	10d	Europe/Australia/ New Zealand/South Africa
Springborg, 2007	EPO=24 versus PLB=30	GOS,6 months	54.6±11.3	72.2%	3d	Denmark
Nakagawa, 2016	ω-3FA=55 versus PLB=45	mRS,3 months	62.2±2	52.4%	76d	Japan
Siironen, 2003	HPN=85 versus PLB=85	GOS,3 months	49.9±1.4	51.2%	10d	Finland
Etminan, 2013	rt-PA=30 versus PLB=30	GOS,3 months	56.1±10.4	63.3%	11d	Germany
Gomis, 2010	MPN=49 versus PLB=46	GOS,12 months	49.8±13.2	63.2%	21d	France

NID nimodipine, MGS magnesium, CTZ cilostazol, CST clazosentan, FSD fasudil, NCD nicardipine, TZD tirilazad, HPN heparin, ENP Enoxaparin, EPO erythropoietin, MPN methylprednisolone, ST statins, GOS Glasgow Outcome Scale, mRS Modified Rankin Scale, GOSE Glasgow Outcome Scale Extended, PLB placebo

Table 2 Efficacy of different intervention drugs compared to designated control group

TG treatment group, DCG designated control group, 95%CrI 95% credibility interval, SUCRA the surface under the cumulative ranking curve

No competing interests reported.

Effectiveness Comparisons of Drug Therapies for Postoperative Aneurysmal Subarachnoid Hemorrhage Patients: Network Meta‑analysis and systematic review

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Methods

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1