Is Anticoagulation Necessary for Severely Disabled Cardioembolic Stroke Survivors?

Round 1

Reviewer 1 Report

This retrospective study titled "Is anticoagulant necessary for severely disabled cardioembolic stroke survivors?" is treated very important problem of using anticoagulant drugs in post stroke patients with atrial fibrillation as a prevention.  Study is a kind of  observation  long-term functional outcomes of cardioembolic ischemic stroke patients with severe neurological deficits diagnosed with NVAF and  analyzing the main risk factors in four groups of patients according to kind of treatment used for secondary stroke prevention.

The paper is well written, easy to follow the scientific question. The minor remarks: in discussion you should include a little data about the frequency of stroke in Latvia and the procedure of admission are there special Stroke Units or patients are treated in Nerological Units or other. It will be also very interesting for reader. And is there was any change in anticoagulant treatment after discharge from the hospital?

Author Response

The minor remarks: in discussion you should include a little data about the frequency of stroke in Latvia and the procedure of admission are there special Stroke Units or patients are treated in Nerological Units or other. 

A paragraph has been added to address this matter.

It will be also very interesting for reader. And is there was any change in anticoagulant treatment after discharge from the hospital?

There were some/minor changes in anticoagulation treatment, but we don't consider them worth mentioning. 

Reviewer 2 Report

Relevance of this manuscript for the field:

Data are scarce with regards to the knowledge on this topic of anticoagulation in patients with severely disabled cardioembolic stroke. The intent of this manuscript was novel in trying to provide information regarding this.

Summary:

This retrospective descriptive registry study provides information on long-term neurological and functional outcomes in severely disabled cardioembolic stroke patients stratified based on secondary prevention medication.  The authors report better functional and survival outcomes in severely disabled cardioembolic ischemic stroke patients due to non-valvular atrial fibrillation who are on anticoagulation for secondary prevention and infer the need to not restrict its usage in this subgroup.

Specific Comments:

Abstract: The abstract summarizes the main results of the study well. However, the conclusions are not sustained by the presented data. Without controlling for the baseline differences in the subgroups of secondary prevention strategies studies which can potentially confound the results, to infer better functional outcomes and higher survival in patients on anticoagulation is not ideal.

Introduction: Sentence structuring and grammar of this section in sub-optimal, for instance in 43 – 44:  “The most of cardioembolic strokes are associated with atrial fibrillation (AF) – the most common form of heart arrhythmias” and 48 – 49:  “As there are increasingly better treatment options for arterial hypertension, atherosclerosis, and dyslipidemia, that could reduce the prevalence of other stroke subtypes."

44 - 45: “Its prevalence is age-dependent as below the age of 55 the prevalence of non-valvular atrial fibrillation (NVAF) is less than 0.1%, while it reaches 9% by the age of 80” and 57-58 – “However, there is no evidence of significantly better stroke outcome in patients with atrial fibrillation taking antiplatelet agents versus not taking any antithrombotic medication” The above two sentences need references.

There are several typographical errors in this section with a majority involving the use (or the lack of) of punctuations.

Methods: Methodological concerns include:

There are baseline differences in the stratified subgroups from an age standpoint (117-118) – with patients not receiving prophylaxis (secondary prevention) or being on antiplatelet therapy being significantly older (and including a higher number of patients > or = 70 years) compared to the ones getting VKA or DOACs. The adjustment for confounding was not described taking this into consideration. The results of worse outcome from a functional standpoint can potentially be ascribed to the elderly age itself within the antiplatelet and no secondary prevention groups.

Another issue is the baseline severity of the stroke, which again is worse in the patients not on any secondary prevention (or prophylaxis) and in the antiplatelet group (117-118). Once again, without adjustment for this potential confounder, it is not reasonable to attribute the better functional/neurological outcomes to either VKA or DOAC use.

Results and Discussion:  Results and discussion are described reasonably well but with the aforementioned methodological issues, this might be of limited utility especially the inferences of positive outcomes. Of note, there is no description of why there are improved outcomes in patients in whom anticoagulation was used, whether this was mainly due to reduced recurrence of Ischemic stroke or if there was another potential explanation has not been described. This discussion could be better if the results show the same pattern after adjustment at least for confounding factors like age and baseline severity of stroke. Also, generally the main findings of a study should be summarized at the beginning of the discussion section.

As with the prior sections, there are several typographical errors in these sections: examples - “propability”, “propable” “antitormbotic” “aftyer”and use of non-english terms like “exitus letalis” to name a few.  Additional comments which would be applicable to the manuscript overall would be to make sure each abbreviation is spelled after its first use and then use the abbreviation consistently.

Author Response

Specific Comments:

Abstract: The abstract summarizes the main results of the study well. However, the conclusions are not sustained by the presented data. Without controlling for the baseline differences in the subgroups of secondary prevention strategies studies which can potentially confound the results, to infer better functional outcomes and higher survival in patients on anticoagulation is not ideal.

Introduction: Sentence structuring and grammar of this section in sub-optimal, for instance in 43 – 44:  “The most of cardioembolic strokes are associated with atrial fibrillation (AF) – the most common form of heart arrhythmias” and 48 – 49:  “As there are increasingly better treatment options for arterial hypertension, atherosclerosis, and dyslipidemia, that could reduce the prevalence of other stroke subtypes."

The sentence structuring and grammar has been corrected. 

44 - 45: “Its prevalence is age-dependent as below the age of 55 the prevalence of non-valvular atrial fibrillation (NVAF) is less than 0.1%, while it reaches 9% by the age of 80” and 57-58 – “However, there is no evidence of significantly better stroke outcome in patients with atrial fibrillation taking antiplatelet agents versus not taking any antithrombotic medication” The above two sentences need references.

The references have been added. 

There are several typographical errors in this section with a majority involving the use (or the lack of) of punctuations.

The sentence structuring and grammar has been corrected. 

Methods: Methodological concerns include:

There are baseline differences in the stratified subgroups from an age standpoint (117-118) – with patients not receiving prophylaxis (secondary prevention) or being on antiplatelet therapy being significantly older (and including a higher number of patients > or = 70 years) compared to the ones getting VKA or DOACs. The adjustment for confounding was not described taking this into consideration. The results of worse outcome from a functional standpoint can potentially be ascribed to the elderly age itself within the antiplatelet and no secondary prevention groups.

Another issue is the baseline severity of the stroke, which again is worse in the patients not on any secondary prevention (or prophylaxis) and in the antiplatelet group (117-118). Once again, without adjustment for this potential confounder, it is not reasonable to attribute the better functional/neurological outcomes to either VKA or DOAC use.

I have added the description of this statistical difference in the results, but as this is a retrospective study we cannot change that these patients are indeed older than patients receiving VKA or DOACs. If it is required we can perform Cox regression analysis that would include hazards (age and NIHSS on discharge), but then we require more time to do that. 

Results and Discussion:  Results and discussion are described reasonably well but with the aforementioned methodological issues, this might be of limited utility especially the inferences of positive outcomes. Of note, there is no description of why there are improved outcomes in patients in whom anticoagulation was used, whether this was mainly due to reduced recurrence of Ischemic stroke or if there was another potential explanation has not been described. This discussion could be better if the results show the same pattern after adjustment at least for confounding factors like age and baseline severity of stroke. 

I have added the description of this statistical difference in the results, but as this is a retrospective study we cannot change that these patients are indeed older than patients receiving VKA or DOACs. If it is required we can perform Cox regression analysis that would include hazards (age and NIHSS on discharge), but then we require more time to do that. 

Also, generally the main findings of a study should be summarized at the beginning of the discussion section.

I have changed the order of paragraphs in the discussion section so it should make better sense.

As with the prior sections, there are several typographical errors in these sections: examples - “propability”, “propable” “antitormbotic” “aftyer”and use of non-english terms like “exitus letalis” to name a few.  

The typographical errors have been corrected and non-english terms have been removed

Additional comments which would be applicable to the manuscript overall would be to make sure each abbreviation is spelled after its first use and then use the abbreviation consistently.

The abbreviations are now used consistently.

Reviewer 3 Report

I think that the topic of whether to anticoagulate patients with severe deficits (mRs 4-5) from embolic stroke in the setting of atrial fibrillation is an important one. I do not recall seeing a paper on this exact topic. 

I agree that the results suggest that anticoagulation is worthwhile, even in these more severely impaired patients.

I would ask the authors why they used a "Rankin Focused Assessment-Ambulation" rather than just the modified Rankin scale, used in virtually all other stroke studies. The mRs can usually be estimated accurately by telephone. 

I am not in full agreement with the statement near the end that antiplatelet therapy is no better than no treatment. There was a small trend favoring antiplatelet therapy. I would not want to recommend no treatment. There is some data that dual antiplatelet therapy is slightly better than aspirin in patients with a fib and stroke. (Active study)

It would be helpful to include bleeding data, to understand the risk in these elderly patients.

I would also point out that bleeding rates on apixaban were only slightly higher than on aspirin in a clinical trial. 

Author Response

I would ask the authors why they used a "Rankin Focused Assessment-Ambulation" rather than just the modified Rankin scale, used in virtually all other stroke studies. The mRs can usually be estimated accurately by telephone. 

We recently made an Latvian adaptation of Rankin Focused Assessment-Ambulation and that is the main reason for using it while assessing our patients, and we believe that allows us to better distinguish patients in 0-2 mRS groups.  

I am not in full agreement with the statement near the end that antiplatelet therapy is no better than no treatment. There was a small trend favoring antiplatelet therapy. I would not want to recommend no treatment. There is some data that dual antiplatelet therapy is slightly better than aspirin in patients with a fib and stroke. (Active study)

We will change this in the paper, but comparing the no treatment and antiplatlet agents is not the goal for this paper.

It would be helpful to include bleeding data, to understand the risk in these elderly patients.

The bleeding risk in all groups was measured using HAS-BLED scale and is included in the patient characteristics table.

I would also point out that bleeding rates on apixaban were only slightly higher than on aspirin in a clinical trial. 

Our patient population included very few patients on apixaban, so we did not want to divide the NOACs separately. 

 

Round 2

Reviewer 2 Report

Thank you for working on some of the suggested changes. Without adjustment using a model like regression analysis for the baseline characteristics which are clearly different and can be confounding, it would be difficult to infer the results of the study. Irrespective of whether this is a prospective or retrospective stroke-related study, adjustment for baseline differences that can clearly play a role (and have been extensively described in stroke literature prior) in the survival and functional outcomes, like age and admission/initial NIHSS (baseline stroke severity) would be necessary. 

Author Response

Without adjustment using a model like regression analysis for the baseline characteristics which are clearly different and can be confounding, it would be difficult to infer the results of the study. Irrespective of whether this is a prospective or retrospective stroke-related study, adjustment for baseline differences that can clearly play a role (and have been extensively described in stroke literature prior) in the survival and functional outcomes, like age and admission/initial NIHSS (baseline stroke severity) would be necessary. 

 

Cox regression analyses was performed including the patient age and baseline LV-NIHSS as possible confounders. No difference was observed when comparing no-prophylaxis group and patients taking antiplatelet agents, with hazards ratio (HR) of 0,778 (p= 0,119). The HR between patients in no-prophylaxis group and patients taking VKA was 0,313 (p<0,005) and patients on DOACs 0,246 (p<0,005) that was statistically significant. So after the adjustment for confounders, the secondary prevention still showed a significant statistical importance.

Round 3

Reviewer 2 Report

Major Methodological issues:

The authors state of performing cox regression analysis taking into consideration the age and baseline NIHSS which are higher in the no-prophylaxis and antiplatelet groups and report of no difference when comparing the no-prophylaxis group and antiplatelet groups, and also report of a HR of 0.313 and 0.246 comparing patients on no-prophylaxis group with VKA and DOACs respectively which was reportedly statistically significant. Unfortunately, there was no comparison of the antiplatelet group with the VKA or DOACs after adjustment for baseline differences and as stated in the prior reviews the improved outcome from a mortality standpoint cannot be attributed to the use of VKA / DOACS compared to antiplatelet agents and rather the baseline severity of the stroke and elder age

This goes true for the functional outcome standpoint too where no analysis was performed including this adjustment for confounders - age and baseline NIHSS which are clearly different and worse in the no-prophylaxis and antiplatelet groups compared to VKA and DOACs groups.

The inferences of positive outcomes from anticoagulation with VKA or DOACs cannot be made based on the above nor can the statements, for instance, Page 8, lines 399-401 “The use of antiplatelet agents showed only slight improvement in long-term survival rate and functional outcome as……” be made. Of note, there is also no description of why there are improved outcomes in patients in whom anticoagulation was used, whether this was mainly due to reduced recurrence of Ischemic stroke or if there was another potential explanation.

Author Response

The authors state of performing cox regression analysis taking into consideration the age and baseline NIHSS which are higher in the no-prophylaxis and antiplatelet groups and report of no difference when comparing the no-prophylaxis group and antiplatelet groups, and also report of a HR of 0.313 and 0.246 comparing patients on no-prophylaxis group with VKA and DOACs respectively which was reportedly statistically significant. Unfortunately, there was no comparison of the antiplatelet group with the VKA or DOACs after adjustment for baseline differences and as stated in the prior reviews the improved outcome from a mortality standpoint cannot be attributed to the use of VKA / DOACS compared to antiplatelet agents and rather the baseline severity of the stroke and elder age

The crude probability of survival in the 682 IS patients are shown in Figure 1. The combined mortality for all treatment groups was 15,1% in 30 days, 23,8% in 90 days, 31% in 180 days and 36,8% in one year. However, these outcomes were relatively diverse among the treatment groups. In the first month after discharge, the crude probability of survival was lowest in patients that did not receive any prevention medication 63% (IQR=48-78) and patients taking antiplatelet agents 75% (IQR= 64-86). The survival was significantly higher in patients taking VKA 87%(IQR=81-93) and DOACs 92% (IQR=88-95). In 90d after discharge the crude probable survival rate in patients without secondary preventive medication was 56% (IQR=33-76), in patients on antiplatelet agents 65% (IQR=50-83), VKA 81%(IQR=72-90) and 88%(IQRS=82-94) in patients taking DOACs.

Figure 1 Cumulative survival in different treatment groups.

In 180 days the crude probability of survival in patients not taking any secondary preventive medication was 53% (IQR=31-76), 59% (IQR=41-79) in patients taking antiplatelet agents, 79% (IQR=68-89) in patients on VKA and 84% (IQR=76-92) in patients on DOACs. One year crude probability of survival of patients not taking any preventive medication was 53% (IQR=29-76), in patients taking antiplatelet agents it was 57% (IQR=37-78), 78% (IQR=68-88) of patients on VKA and 81% (IQR=72-90) in patients on DOACs.

Patients in no-prophylaxis and antiplatelet agent groups were statistically significantly older and had a higher LV-NIHSS at baseline. To compare all treatment groups cox regression analyses was performed including the patient age and baseline LV-NIHSS as possible confounders.

No difference was observed when comparing no-prophylaxis group and patients taking antiplatelet agents, with hazards ratio (HR) of 0,778 (p=0,119). The HR between patients in no-prophylaxis group and patients taking VKA was 0,313 (p<0,001) and patients on DOACs 0,246 (p<0,001) that was statistically significant.

When comparing antiplatelet group with patients taking VKA the HR was 2,485 that based on confidence interval (CI) was statistically significant. The HR between antiplatelet group and patients taking DOACs was 3,162 and was also statistically significant.

When comparing VKA and patients taking DOACs with HR of 1,272 that according to basis of CI was not statistically significant.

So after the adjustment for confounders, the secondary prevention showed a significant statistical importance, with patients taking VKA or DOACs having statistically significantly less hazards then patients on no prophylaxis of antiplatelet agents.

The inferences of positive outcomes from anticoagulation with VKA or DOACs cannot be made based on the above nor can the statements, for instance, Page 8, lines 399-401 “The use of antiplatelet agents showed only slight improvement in long-term survival rate and functional outcome as……” be made. 

The use of antiplatelet agents showed only slight improvement in long-term survival rate and functional outcome as patients without any antithrombotic treatment but this finding was not statistically significant. Therefore antiplatelet therapy should not be recommended in this patient group.

Of note, there is also no description of why there are improved outcomes in patients in whom anticoagulation was used, whether this was mainly due to reduced recurrence of Ischemic stroke or if there was another potential explanation.

The most common reason for severely disabled patients to die after a severe stroke are recurrent embolic events as IS, myocardial infarction, mesenteric thrombosis, pulmonary artery thromboembolism and complications for patient being bedbound- decubitus, pneumonia and urinary tract infections etc. [37] The usage of oral anticoagulants has proven to reduce all these types of embolic events, and this explains lower mortality rates in patients taking VKA or DOACs. [27]