Safety and Efficacy of Low-Dose Eptifibatide for Tandem Occlusions in Acute Ischemic Stroke

Round 1

Reviewer 1 Report

Dear Authors,

This manuscript provides valuable insights into the safety and potential benefits of administering modified low-dose eptifibatide in stroke patients with tandem lesions, there are several shortcomings that should be acknowledged:

-The study's retrospective nature introduces inherent limitations, including the potential for selection bias, incomplete data, and the inability to establish causation. A prospective design would offer stronger evidence and control over confounding variables.

 - The relatively small sample size (148 patients) might limit the generalizability and statistical power of the study. Larger sample sizes are often needed to detect subtle but clinically significant effects and enhance the reliability of the findings.

 - The cohort studied appears heterogeneous, with a wide age range (23-98 years) and diverse presentations of tandem lesions. This heterogeneity may introduce variability in treatment responses and outcomes, making it challenging to draw definitive conclusions.

- The absence of randomization in treatment assignment raises concerns about potential confounding factors influencing outcomes. Randomized controlled trials (RCTs) provide a more robust framework for establishing causal relationships between interventions and outcomes.

- The manuscript does not extensively address potential confounding variables, such as comorbidities, concomitant medications, or variations in the severity of tandem lesions. These factors can impact outcomes and should be considered in the analysis.

- While the study mentions that the rates of thrombotic and hemorrhagic complications were not statistically significant, a more in-depth discussion on the nature and clinical implications of these complications, even if non-significant, would enhance the manuscript.

- The manuscript provides limited details on statistical methods and results. More information on specific statistical tests used, effect sizes, confidence intervals, and corrections for multiple comparisons would strengthen the statistical reporting.

- The unexpected finding of a significantly better neurological outcome in patients receiving eptifibatide deserves more thorough exploration and discussion. Consider additional analyses or speculations to provide a comprehensive understanding of this unexpected outcome.

- The study cohort's characteristics may not be representative of the broader stroke population. Addressing the external validity of the findings and their applicability to different patient populations is crucial.

- While the study suggests potential benefits, the need for prospective validation through well-designed clinical trials is emphasized. Prospective studies can confirm the safety and efficacy of the intervention in a more controlled setting.

Addressing these shortcomings and providing a transparent discussion of limitations will contribute to a more comprehensive and balanced presentation of the study's findings.

Thanks,

The Reviewer

Minor language correction is needed. 

Author Response

We express gratitude for pointing out the limitations of our study.

1. Limitations of our survey have already been described in the Discussion:

“We acknowledge that there are important limitations of our survey, comprising its retrospective character, relatively small number of patients assessed and a high heterogeneity of the cohort studied.”

Still, a selection bias probably played a minor role in this study, since in this retrospective analysis we included all stroke patients presenting with tandem lesions who were managed endovascularly in our hospital. This has been already described in the Materials and Methods section.

“We retrospectively evaluated results of the endovascular treatment in 148 consecutive patients….”

In order to avoid confusion, we added information about etiology of strokes:

“This survey includes both patients with strokes of atherosclerotic etiology and those presenting with artery dissections.”

We agree that a prospective study would provide much stronger evidence, and this has already been stated in Discussion:

“Still, prospective trials should unequivocally demonstrate safety and efficacy of eptifibatide or other short half-life antiplatelet agents in these challenging stroke patients. For the time being, no such data are available.”

2. We agree that our sample is relatively small, which makes detailed statistical analysis of the material difficult and not possible regarding several variable. Yet, tandem lesion strokes represent a small subgroup of strokes. Moreover, for the time being, intracranial lesions are managed in specialized centres, thus the patients cohorts available for analyses usually (except for multicentre studies) are not so big.

In the articles citied in our study: in paper 3. - 44 tandem lesion patients were managed, in paper 9. (which was a multicentre register) – 147 tandem lesion patients were managed, in paper 10. (which was a multicentre register) – 482 tandem lesion patients were managed, in paper 11. - 163 tandem lesion patients were managed, in paper 12. (which was a multicentre register) – 395 tandem lesion patients were managed, in paper 13. - 162 tandem lesion patients were managed, in paper 14. - 33 tandem lesion patients were managed, in paper 15. - 81 tandem lesion patients were managed.

In the studies focusing on epifibatide use in paper 18. - 29 tandem lesion patients were managed, in paper 19. 58 tandem lesion patients were managed, in paper 25. - 66 tandem lesion patients were managed. Thus, our material is comparable to other studies in this area, it is also, like those studies, except for multicentre ones, of retrospective design.

Nonetheless, in the Discussion, we emphasized the relatively small number of the patients assessed:

“We acknowledge that there are important limitations of our survey, comprising its retrospective character, relatively small number of patients assessed and a high heterogeneity of the cohort studied.”

3. The heterogeneity of the cohort assessed has already been discussed (point 2).

4. This survey is a retrospective analysis, not a RCT, with obvious limitation of such an analysis. A necessity of a properly designed RCT has already been mentioned. A similar message comes from all current studies on the use of epifibatide in stroke patients

“Still, prospective trials should unequivocally demonstrate safety and efficacy of eptifibatide or other short half-life antiplatelet agents in these challenging stroke patients.”

5. Since the cohort assessed was highly heterogeneous and quite small, a detailed statistical analysis was not possible. Nonetheless, we evaluated pre-interventional clinical status of both subgroups regarding such important clinical variables as: NIHSS, ASPECT score, TICI score, and necrosis volume. This analysis has already been given in the Results section.

6. There was a lower incidence of both thrombotic and hemorrhagic complications in patients receiving epifibatide (contraintuitive, since a higher bleeding rate should have been expected in patients managed with antiplatelet agent), and this information has already been given in Results:

“Of note, the frequencies of thrombotic and hemorrhagic complications were higher in patients not receiving eptifibatide, yet these differences were not statistically significant.”

also, this finding has already been discussed:

“Perhaps, these better clinical outcomes in the eptifibatide group resulted from lower rates of thrombotic and hemorrhagic complications in comparison with patients not receiving this drug (even if these differences in our material were not statistically significant). Theoretically these differences could be associated with fewer thrombotic occlusions in the cerebral microvasculature [16,20-22]. Of note, re-occlusion of the ICA or suboptimal thrombectomy are independent predictors of the intracranial bleeding in the settings of ischemic stroke [16,23]. In the study by Renu et al. it was found that the highest rate of bleeding complications occurred in the group in which stent implantation was used in combination with antiplatelet drug but there was either a suboptimal intracranial recanalization (TICI ≤2a) or there was stent thrombosis [23]. Probably, incomplete recanalization and damage to the blood-brain barrier, in combination with the antiplatelet drugs, increase the risk of intracranial bleeding [23].”

7. There is already a detailed description of statistical analysis. We added some information regarding parameters evaluated by means of parametric test:

“In order to compare preprocedural clinical characteristics of the patients, as well as the rates of severe complications in both groups, such as bleeding, thrombosis or death, the Fisher exact test was used. To compare parametric pre-interventional neurologic status (NIHSS scores, ASPECT score, TICI score, necrosis volume) and the duration of hospital stay we used the two-sample t-test; in the later case patients who died were excluded. To compare neurologic status at 30-day follow-up we categorized the patients into six ordinal groups: without neurologic symptoms (NIHSS score: 0), with mild stroke symptoms (NIHSS score: 1-4), moderate stroke symptoms (NIHSS score: 5-14), severe stroke symptoms (NIHSS score: 15-24), very severe stroke symptoms (NIHSS score: 25 and more), and those who died for any reason. Significance of the differences regarding neurologic status at the 30-day follow-up was calculated using the Mann-Whitney U test. In order to assess the correlation between the pre-procedural necrosis volume and the NIHSS score at the 30-day follow-up, the Pearson’s r coefficient was calculated. The significance of p values of all statistical tests used was set at p < 0.05.”

Also, we added information regarding statistical tests used to the tables.

8. Beneficial effect of this particular antiplatelet agent is in line with recent studies on the use of epifibatide in tandem lesion patients. There is already a discussion in the text (see point 6.).

There is also discussion on potential use of this antiplatelet agent in all tandem lesion strokes:

“Although, considering retrospective nature of this study, our results should be interpreted with caution; perhaps all stroke patients with tandem lesions should be managed with low dose eptifibatide. Indeed, such an approach was reported by Jost et al. They were giving this antiplatelet agent in all tandem lesion patients with stroke, irrespective if they were treated with stent placement or angioplasty”

Of course, as has been addressed in the point 1, RCT is a proper scientific method to evaluate clinical value of such an approach.

9. This study concerns tandem lesion strokes. This is a very special subgroup of stroke patients, with very high risk of both thrombotic and hemorrhagic complications, unfavorable clinical prognosis and, of as yet, not established optimal treatment protocol. It has already been stated in the Introduction:

“Optimal treatment strategy for acute ischemic stroke in patients presenting with so-called tandem lesions, i.e. comprising both occlusion or high grade stenosis of the extracranial segment of the internal carotid artery (ICA) coexisting with occlusion of the intracranial cerebral arteries (intracranial segments of the ICA, the middle or the anterior cerebral artery), still remains controversial’

For obvious reasons, conclusions coming from this and similar surveys cannot be extrapolated to stroke patients presenting with a single occlusions.

10. The necessity of a RCT addressing the problem of epifibatide use in tandem lesion stroke patients has already been stated. We added the message on the necessity of establishing optimal dosing of epifibatide:

“Still, prospective trials should unequivocally demonstrate safety and efficacy of eptifibatide or other short half-life antiplatelet agents in these challenging stroke patients. Such trials should also establish optimal dose of this antiplatelet agent. For the time being, no such data are available.”

and

“Yet, prospective randomized clinical trials are needed to unequivocally evaluate the clinical value of this antiplatelet agent.”

Reviewer 2 Report

I would have following comments:

1.How do you define "satisfactory cerebral flow" in patients included in the control group? There should be presented criteria of persistent stenosis or flow after PTA of extracranial carotid stenosis.

2.According to the Delphi consensus ( Goyal doi.org/10.1007/s00234-021-02735-6), 500 mg of intravenous ASA is recommended. It would be more reasonable to compare two groups of such patients with stents implanted and receiving your reduced-dose eptifibatide protocol versus the 500 mg intravenous ASA group. Can you comment on this in the discussion and provide a link to this consensus?

3.There are certainly more factors that will influence the clinical outcome, but the above protocol with a reduced dose of eptifibatide may be safe. Eptifibatide is recommended in that Delphi consensus if IV ASA is not available.

Author Response

Thank you for reviewing the manuscript. The following changes have been performed regarding your remarks and proposals.

1. Regarding the decision upon PTA/stenting of the extracranial stenosis, in order to avoid confusion, we added explanation of these criteria.

“Decision upon administration of eptifibatide was primarily associated with early stent implantation. If endovascular angioplasty of extracranial occlusion/stenosis of the ICA, using a long inflation of the balloon, resulted in satisfactory dilatation of the artery and good inflow (there should be less than 70% residual stenosis of the extracranial lesion after primary angioplasty (Fig. 1) and good inflow to the cerebral arteries.), the decision upon stent implantation was postponed until 2-7 postprocedural day.”

Importantly, such an evaluation was performed several times after revascularization, and this information is already in the text.

“In order to reveal potential reocclusion and/or bleeding control intraprocedural angiography was performed in each patient 5, 10 and 15 minutes after the stent implantation. Angiographic success of the procedure was evaluated using the modified Treatment in Cerebral Infarction score (mTICI), with the assessment of previously occluded part of cerebral circulation at the end of endovascular repair.”

2. We added commentary regarding the use of aspirin and other platelets in the Introduction:

“Yet, such a strategy is controversial in the setting of acute stroke, because of the risk of intracranial hemorrhage, which is especially high if heparin is used. Nonetheless, current guidelines also recommend antiplatelet agents in this patients, particularly intravenous aspirin, although more good quality data regarding safety profile and clinical efficacy are needed [16,17].”

3. Importantly, in the Delphi consensus by Goyal et al. epifibatide was used in the dose of 2 mg, which is known to be associated with quite a high rate of bleeding events. In our study this agent was used in a lower dose. In addition, there are known limitations of the Delphi approach, which is inferior to the RTC-based meta-analysis. Of note, the conclusion coming from this consensus document is that: “More and better data on antiplatelet management for carotid stent placement in the setting of endovascular treatment are urgently needed.”

Nonetheless, we added a commentary of alternative pharmaceutical agents aimed at improvement of clinical outcomes of tandem lesion-associated strokes:

“Of note, other antiplatelet agents, such as aspirin, clopidogrel, prasugrel or tirofiban, have also been proposed for the management in tandem lesion stroke patients. Still, evidence coming from high quality clinical trials is scarce and there is no general consensus regarding the use of these drugs in this particular subgroup of stroke patients”

With kind regards,

Marian Simka, PhD MD

Round 2

Reviewer 2 Report

I agree with your modifications.

Please read the paragraph carefully - lines 84 to 96, where there are a number of typos.

Language acceptable

Author Response

Thank you for reviewing our revised manuscript.

We corrected the questionned fragment. There were indeed many typos, we apologize for it.

best regards

Marian Simka