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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 2  |  Issue : 2  |  Page : 25-32

Mortality risk stratification in patients with asymptomatic carotid stenosis


1 Department of Vascular Surgery, Imperial College, London, UK; Department of Vascular Surgery, Aristotle University, Thessaloniki, Greece
2 Department of Vascular Surgery, University of Patras Medical School, Patras, Greece
3 Vascular Screening and Diagnostic Centre, Nicosia, Cyprus
4 Department of Vascular Surgery, Attikon Hospital, National and Kapodistrian University of Athens, Athens, Greece
5 Department of Informatics and Telecommunications; Engineering, University of Western Macedonia, Kozani, Greece
6 Vascular Screening and Diagnostic Centre; Department of Vascular Surgery, University of Nicosia Medical School, Nicosia, Cyprus

Date of Submission03-Feb-2019
Date of Decision08-Mar-2019
Date of Acceptance12-Mar-2019
Date of Web Publication9-Oct-2019

Correspondence Address:
Prof. Andrew Nicolaides
Vascular Screening and Diagnostic Centre, 2 Kyriacou Matsi Street, 2368 Nicosia
Cyprus
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/VIT.VIT_10_19

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  Abstract 

AIMS: The aim of this analysis was to (a) determine the long-term 5-year all-cause and cardiovascular (CV) mortality in patients with asymptomatic internal carotid artery stenosis (ACS), (b) identify risk factors that could be used in mortality risk stratification, and (c) develop a model for predicting a patient's risk of CV death within 5 years.
METHODS: This was a multicenter natural history study involving 1121 patients with ACS undergoing medical intervention alone. Proportional-hazards models were used to calculate all-cause and CV mortality using clinical and plaque texture features.
RESULTS: Totally 1121 patients with 50%–99% ICA stenosis (European Carotid Surgery Trial criteria) from the Asymptomatic Carotid Stenosis and Risk of Stroke study were included in this analysis for mortality. Mean follow-up was 48 months (range, 6–96 months). There were 213 (19%) deaths during follow-up. Average annual all-cause mortality was 4.6%. About 68.1% of all deaths were due to CV causes. Independent predictors of all-cause mortality were age, male gender, carotid stenosis >80% (NASCET criteria), diabetes, cardiac failure, left ventricular hypertrophy (LVH) on electrocardiogram (ECG), smoking, absence of antiplatelet therapy, and history of vertebrobasilar symptoms. It was also shown that age, male gender, diabetes, fibrinogen >3.6 g/L, carotid stenosis >80% (NASCET criteria), cardiac failure, absence of antiplatelet therapy, and LVH on ECG were independent risk factors for CV mortality. Receiver operating characteristic curves for the above models were 0.709 (95% confidence interval [CI], 0.659–0.754) and 0.701 (95% CI, 0.656–0.746), respectively. The CV mortality prediction model could identify several subgroups of asymptomatic patients with different risk. The highest 90%–100% predicted 5-year CV mortality carried 25 times the risk of the low-risk subgroup in which the 5-year predicted CV mortality was 4%.
CONCLUSION: Mortality risk can be taken into consideration in clinical practice, in order to identify patients with ACS who are unlikely to benefit from carotid endarterectomy. The majority of patients with ACS have a very high risk of myocardial infarction and should not be denied aggressive risk factor modification or a full cardiac investigation according to the current guidelines.

Keywords: Asymptomatic carotid stenosis, mortality, risk stratification


How to cite this article:
Giannopoulos A, Kakkos S, Griffin M B, Geroulakos G, Tsalikakis D, Nicolaides A. Mortality risk stratification in patients with asymptomatic carotid stenosis. Vasc Invest Ther 2019;2:25-32

How to cite this URL:
Giannopoulos A, Kakkos S, Griffin M B, Geroulakos G, Tsalikakis D, Nicolaides A. Mortality risk stratification in patients with asymptomatic carotid stenosis. Vasc Invest Ther [serial online] 2019 [cited 2019 Nov 19];2:25-32. Available from: http://www.vitonline.org/text.asp?2019/2/2/25/268672


  Introduction Top


Treatment of patients with asymptomatic carotid stenosis (ACS) is focused on improving stroke-free survival rates. In two large randomized controlled trials, the Asymptomatic Carotid Atherosclerosis Study in 1995[1] and the Asymptomatic Carotid Surgery Trial in 2004,[2] carotid endarterectomy (CEA) reduced the risk of stroke from about 2.0% to 1.0%/year in patients with ACS >60%.[1],[2],[3] However, in these trials, patients had a 2%–3% 30-day perioperative stroke or death risk. Medical management was left to the discretion of the local team, which by today's standards was suboptimal. Best medical therapy has improved dramatically after these trials were published. Recent reviews of cohort studies, including medically treated patients with ACS, indicate that the average annual risk of ipsilateral stroke has been reduced to approximately 1% or less.[4],[5],[6],[7] This is attributed to better medical management, including statins, antiplatelet therapy, and lifestyle changes. In addition, a recent meta-analysis of 17 studies with long-term follow-up has demonstrated that patients with ACS >50% have a 5-year cumulative all-cause mortality of 23.6% (95% confidence interval [CI]: 20.5%–26.8%).[8] The authors reported that 63% of deaths were cardiac related and that this finding translates into an average cardiac-related mortality (mainly fatal myocardial infarction [MI]) of 2.9%/year.[8]

According to the Society for Vascular Surgery (SVS) guidelines, patients with ACS ≥60% should be considered for CEA only when life expectancy is >3 years and perioperative stroke/death risk is <3%.[9] The 2017 European Society for Vascular Surgery (ESVS) guidelines as well as the American Heart Association (AHA), the American Stroke Association (ASA), and the American Academy of Neurology guidelines stress the importance of assessing life expectancy before pursuing CEA in patients with ACS, stating that candidates should have a life expectancy >5 years.[10],[11],[12],[13]

The Asymptomatic Carotid Stenosis and Risk of Stroke (ACSRS) study [14] was a multicenter natural history study involving 1121 patients with ACS undergoing vascular disease medical intervention alone. They were followed up for 6–96 months (mean: 48). A total of 59 ipsilateral cerebrovascular ischemic strokes occurred. Stenosis, degree of stenosis, history of contralateral transient ischemic attacks (TIAs) or stroke, gray-scale median, plaque area, and discrete white areas were independent predictors of stroke risk. A combination of these could stratify patients into different levels of stroke risk which was close to the observed risk. Of 923 patients with ≥70% stenosis, the predicted cumulative 5-year stroke rate was <5% in 495, 5%–9.9% in 202, 10%–19.9% in 142, and ≥20% in 84 patients.[14] A secondary objective of the ACSRS study was to determine the risk factors associated with all-cause and cardiovascular (CV) mortality other than from stroke.

An interim report on mortality in patients included in the ACSRS study was published in 2005 before data on stroke rates were available and with only 162 deaths.[15] The aim of this new analysis was to (a) determine the long-term 5-year all-cause and CV mortality in patients with asymptomatic internal carotid artery (ICA) stenosis (ACS), (b) identify risk factors that could be used in mortality risk stratification, and (c) develop a model for predicting a patient's risk of CV death within 5 years.


  Methods Top


The methodology of the ACSRS study has been previously published.[14] Only the most relevant methodology is presented here.

Patient recruitment

Newly referred patients with 50%–99% ICA stenosis in relation to the carotid bulb diameter (European Carotid Surgery Trial [ECST] method) without a history of ipsilateral cerebral or retinal ischemic (CORI) symptoms or neurological abnormality were eligible for recruitment to the study. Patients who had contralateral cerebral hemispheric or retinal or vertebrobasilar symptoms or TIA were recruited only if they were asymptomatic for at least 6 months. For patients with bilateral ACS, the side with the more severe stenosis was considered the relevant side. Patients with a limited life expectancy due to severe cardiac failure or disseminated malignancy and patients who could not attend for 6-month neurologic assessments were excluded from the study.

Baseline clinical and biochemical characteristics

As previously reported, all patients had a history taken and a physical examination by the local neurologist. Duration and severity of the following risk factors were assessed for each patient:[14] age, gender, height, weight, hypertension, diabetes, history of MI, heart failure, left ventricular hypertrophy (LVH) on electrocardiogram (ECG), smoking, hematocrit, creatinine, fasting blood cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, and fibrinogen. Furthermore, the presence of antiplatelet or statin therapy was recorded.

Duplex examination

Each patient had a bilateral carotid duplex scanning at entry to the study and every 6 months thereafter. Ultrasonographers from all centers were trained at the coordinating center in grading ICA stenosis and plaque image capture. Based on velocities and velocity ratios, both ECST and NASCET degree stenosis were calculated for every patient. Vertebral artery flow characteristics (cephalad, reversed, or absent) were also assessed.[14],[16]

Outcome measures

The primary outcome measure was any ipsilateral CORI ischemic event, including stroke (fatal or nonfatal). For every stroke, details recorded by the local neurologist and computed tomography or magnetic resonance imaging brain scan results were requested. Two coordinating center members including a neurologist made the final classification of ipsilateral strokes. Local team members diagnosed amaurosis fugax and TIAs. Among the secondary outcome measures of the ACSRS study were stroke-related, cardiac-related, vascular-related (CV), or all other deaths. The cause of death was obtained from reports by the local team, death certificates, and also from hospital and family doctor's records.

Study exit points

Follow-up ceased with the first occurrence of any of the following: the first primary outcome measure, CEA/angioplasty or stenting for the still asymptomatic artery, death from causes other than ipsilateral stroke, or loss to follow-up. Stroke, TIA, or death associated with CEA/angioplasty or stenting for the still asymptomatic study artery was not included in the event rate calculations.

Statistical analysis

Unadjusted hazard ratios of risk factors for CV mortality and all-cause mortality were first obtained with univariate Cox proportional-hazards analysis. Cox proportional-hazards models were subsequently obtained using the significant risk factors. For every patient, the predicted cumulative 5-year all-cause mortality risk was calculated from the all-cause mortality model. Receiver operating characteristic (ROC) curves for the prediction of mortality were constructed.

The predicted cumulative 5-year all-cause mortality was recoded as 0 = 0%–4%, 1 = 5%–9%, 2 = 10%–14%, 3 = 15%–24%, 4 = 25%–39%, and 5 = 40+%. This variable was used to produce six cumulative all-cause mortality curves using the observed deaths for model calibration purposes [Figure 1].
Figure 1: All-cause cumulative mortality in the six predicted 5-year mortality risk groups from Table 4 (Risk groups: 0 = 0%–4%, 1 = 5%–9%, 2 = 10%–14%, 3 = 15%–24%, 4 = 24–39, and 5 = 40+%)

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Scattergrams were produced by plotting predicted stroke risk (based on the 2010 publication)[14] against predicted mortality risk indicating the actual strokes and deaths [Figure 2] and [Figure 3].{Figure 2}
Figure 3: Scattergram of predicted 5-year stroke risk (based on 2010 publication) 14 against predicted 5-year all-cause mortality (based on Cox proportional-hazards model in Table 3) with actual deaths shown in red. Each open or closed circle represents one of the 1121 patients at baseline

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Tables were produced showing the actual (observed) strokes and deaths and death/stroke ratios in four subgroups of the predicted 5-year all-cause mortality for (a) the total cohort, (b) the low stroke risk group (<10% 5-year risk), and (c) the high stroke risk group (>10% 5-year risk).

Finally, using the independent predictors (risk factors) of the Cox proportional-hazards model for CV mortality, tables were constructed that can be used to calculate the risk of CV death in any patient from these risk factors.

Statistical analysis was performed with IBM SPSS Statistics version 20 (SPSS Inc., Chicago, IL, USA).


  Results Top


A total of 1121 patients, 39–89 years old (mean age, 70.0 years; standard deviation, 7.7; 61% men), were recruited from 1998 to 2002 to the study. Mean follow-up was 48 months (6–96 months). Baseline demographics and characteristics have been previously reported.[14]

Ipsilateral cerebrovascular events

A total of 130first ipsilateral CORI events occurred. They included 59 strokes of which 12 were fatal.

All-cause mortality

There were 213 (19%) deaths during follow-up. The causes of death are shown in [Table 1]. Life table analysis showed that the 5-year cumulative survival rate was 77%. Average annual all-cause mortality was 4.6%.
Table 1: Causes of death in asymptomatic carotid stenosis and risk of stroke

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Baseline features associated with increased mortality and independent predictors of mortality

Unadjusted hazard ratios of risk factors for CV mortality and all-cause mortality are shown in [Table 2]. Multivariate regression analysis, using Cox proportional-hazards models, showed that age, gender, carotid stenosis (<80%, >80%; NASCET criteria), diabetes, cardiac failure, LVH on ECG, smoking, antiplatelet therapy, and history of vertebrobasilar symptoms were independent predictors of all-cause mortality [Table 3]. Using this model, the predicted cumulative 5-year all-cause mortality was calculated. The area under the ROC curve for the correct prediction of mortality using the above model was 0.709. The predicted cumulative 5-year all-cause mortality was recoded as 0 = 0%–4%, 1 = 5%–9%, 2 = 10%–14%, 3 = 15%–24%, 4 = 25%–39%, and 5 = 40+%. This variable was used to produce six cumulative all-cause mortality curves using the observed deaths for model calibration purposes [Figure 1] and [Table 4].
Table 2: Unadjusted hazard ratios of risk factors for cardiovascular mortality and all-cause mortality

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Table 3: Significant risk factors (independent predictors) for 5-year all-cause mortality, using Cox proportional-hazards model

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Table 4: Recoding of predicted 5-year all-cause mortality into 6 groups for model calibration purposes

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[Figure 2] is a scattergram of predicted 5-year stroke risk (based on 2010 publication)[14] against predicted 5-year all-cause mortality [based on the Cox proportional-hazards model in [Table 3] with actual strokes shown in red. Each open or closed circle represents one of the 1121 patients at baseline. [Figure 3] is the same scattergram with actual deaths shown in red. The data from these scattergrams are summarized in [Table 5], [Table 6], [Table 7]. [Table 5] shows the actual (observed) strokes and deaths and death/stroke ratio in four subgroups of the total cohort of patients according to the predicted 5-year all-cause mortality. Both the absolute number of deaths and death/stroke ratio increase with increasing predicted mortality. [Table 6] is a similar table which includes only the subgroup of 231 patients with a predicted 5-year stroke rate of 10% or greater. [Table 7] is a similar table which includes only the subgroup of the 890 patients with a predicted 5-year stroke rate of <10%. In both subgroups [Table 6] and [Table 7], the proportion of deaths increases with increasing predicted mortality, but as expected, there is a greater increase in the death/stroke ratio in the subgroup, as shown in [Table 7].
Table 5: Actual (observed) strokes and deaths and death/stroke ratio in four subgroups of the total cohort of patients according to the predicted 5-year all-cause mortality (?2; P < 0.001)

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Table 6: Actual (observed) strokes and deaths and death/stroke ratio in four subgroups of patients according to the predicted 5-year all-cause mortality

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Table 7: Actual (observed) strokes and deaths and death/stroke ratio in four subgroups of patients according to the predicted 5-year all-cause mortality

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A second Cox proportional-hazards model was developed for predicting CV mortality [Table 8]. Using this model, the predicted cumulative 5-year CV mortality for every patient was calculated. The area under the ROC curve for the correct prediction of mortality using the above model was 0.701 (95% CI 0.656–0.746; P < 0.001). Using this model, the risk of CV death in any patient was calculated from the covariates [Table 9]. Patients with the lowest predicted 5-year CV mortality (4%) were female patients, <70 years old with ACS <80%, nondiabetic, on aspirin without cardiac failure, or LVH [Table 9]. The group of asymptomatic patients with the highest predicted 5-year CV mortality (90%–100%) were male patients, >79 years old, with a carotid stenosis >80%, diabetic with cardiac failure, and LVH not on antiplatelet therapy [Table 9].
Table 8: Significant risk factors (independent predictors) for 5-year cardiovascular mortality, using Cox proportional-hazards model

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Table 9: Predicted 5-year CV mortality based on Cox proportionate hazards model in table 8 (A) for patients <70 years, (B) patients 70-79 and (C) patients > 79 years. Predicted 5-year mortality expressed in percentages

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  Discussion Top


Our results from 1121 patients with ACS demonstrated that the average annual all-cause mortality was 4.6% with 68.1% of these deaths due to CV causes (mainly MI, heart failure, or ischemic stroke). The average annual CV mortality rate was 3.2%. These findings are similar to those from other recently published studies, indicating that in patients with ACS >50%, all-cause and CV mortality is almost three times higher than the general population of the same age.[8],[17],[18]

Large epidemiological studies, such as the Framingham and the Prospective Cardiovascular Munster Study, classify asymptomatic individuals into three risk groups, low, intermediate, and high, for CV events based on their 10-year risk.[19] Classification of individuals into one of these groups is based on whether the 10-year risk is <10% (<1%/year), 10%–20% (1%–2%/year), or >20% (>2%/year), respectively. According to our results, patients with ACS >50% are at extremely high risk.

The vast majority of the studies in patients with ACS focus on stroke risk stratification only. Considering the high mortality of these patients and ESVS, SVS, AHA, and ASA guidelines,[10],[11],[12],[13] life expectancy should be an important factor to be considered in decisions on management.

There are only three studies in the literature that developed scoring systems for mortality risk stratification in patients with ACS.[20],[21],[22] In one study, annual mortality rate of 1.2% was found in the low-risk subgroup which included 27% of the patients,[22] while in the rest of the subgroups, annual mortality rate was ≥4.0%.

Our results show that most of all-cause and CV mortality-associated risk factors are modifiable. Based on the parameters of the best Cox model [Table 8], we produced tables [Table 9] for predicting 5-year CV mortality in patients with ACS >50% (model was internally validated). From these tables, it is shown that there is a subgroup of asymptomatic patients with 90%–100% predicted 5-year CV mortality that carries 25 times the risk of the low-risk subgroup where the 5-year predicted CV mortality is 4%. The subgroup with the lowest risk consists of nondiabetic female patients, aged <70 years with <80% ACS, on aspirin, with no signs of cardiac failure, or LVH on ECG.

In patients with predicted 5-year CV mortality >40%, the death/stroke ratio is high even in those predicted to have a 5-year risk of stroke >10% [Table 5], [Table 6], [Table 7]. In fact, it appears that the majority of the patients in this subgroup die before a stroke would occur even in the presence of an unstable carotid plaque [Figure 2] and [Figure 3]. These patients should not be considered as candidates for CEA.

The risk prediction model developed is unique not only because it was derived from the ACSRS, a natural history study which included a large number of patients, but also because, in contrast to previous studies, it provided a tool for stratifying both CV mortality and stroke risk.

An interesting finding is that the predicted mortality risk is not related to the stroke risk. The predicted mortality risk remained high even in the presence of a low stroke risk group [Figure 2], [Figure 3] and [Table 5], [Table 6], [Table 7]. This means that patients with low stroke risk who will not be considered for carotid surgery because of a low-grade stenosis or a stable (e.g., echogenic or calcified) plaque should not be denied aggressive risk factor modification. They are at a very high risk of MI, and therefore, a cardiac assessment is indicated. This assessment is a unique opportunity that may never occur again in their lifetime.

A limitation of this study was that the medical management of patients was up to each physician's choice and what was considered the best medical therapy at that time. The clinician in charge was free to change therapy according to changing indications. At the beginning of the study, 84% of patients were on antiplatelet therapy and 25% on lipid-lowering therapy. Toward the end of the study, these percentages were 95% and 85%, respectively. However, very few patients were treated to a predefined target according to the current international guidelines. Furthermore, validation of the mortality prediction models was limited since this was done internally in this study. Because of the above, the Cox proportional-hazards models and the table for calculation of mortality risk need to be validated in further prospective studies with patients on best medical therapy.


  Conclusion Top


The key messages are that (a) the overall all-cause and CV mortality in patients with ACS is high, (b) mortality risk can now be calculated and taken into consideration in clinical practice, in order to identify patients with ACS who are unlikely to benefit from CEA, and (c) the majority of patients with ACS have a very high risk of MI and should not be denied aggressive risk factor modification according to current guidelines or a full cardiac investigation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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    Figures

  [Figure 1], [Figure 1], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]



 

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