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Editor's Choice – The National Norwegian Carotid Study: Time from Symptom Onset to Surgery is too Long, Resulting in Additional Neurological Events

Open AccessPublished:August 25, 2017DOI:https://doi.org/10.1016/j.ejvs.2017.07.013

      Objective/Background

      The objective was to observe for 1 year all patients in Norway operated on for symptomatic carotid stenosis with respect to (i) the time from the index event to surgery and neurological events during this time; (ii) the level in the healthcare system causing delay of surgical treatment; and (iii) the possible relationship between peri-operative use of platelet inhibitors and neurological events while awaiting surgery.

      Methods

      This was a prospective national multicentre study of a consecutive series of symptomatic patients. Patients were eligible for inclusion when referred for surgery. An index event was defined as the neurological event prompting contact with the healthcare system. All 15 departments in Norway performing carotid endarterectomy (CEA) participated.

      Results

      Three hundred and seventy one patients were eligible for inclusion between 1 April 2014 and 31 March 2015, and 368 patients (99.2%) were included. Fifty-four percent of the patients contacted their general practitioner on the day of the index event. Primary healthcare referred 84.2% of the patients to hospital on the same day as examined. In hospital median time from admission to referral for vascular surgery was 3 days. Median time between referral to the operating unit and actual CEA was 5 days. Overall, 61.7% of the patients were operated on within 2 weeks of the index event. Twelve patients (3.3%) suffered a new neurological event while awaiting surgery. The percentage of patients on dual antiplatelet therapy was lower (25.0%) in this group than among the other patients (62.6%) (p = .008). The combined 30 day mortality and stroke rate was 3.8%.

      Conclusion

      This national study with almost complete inclusion and follow-up shows that the delays occur mainly at patient level and in hospital. The delay is associated with new neurological events. Dual antiplatelet therapy is associated with reduced risk of having a new neurological event before surgery.

      Keywords

      This prospective study covers > 99% of surgical treatment of symptomatic carotid stenosis in a whole nation during 1 year. This constitutes a more solid base than previous observations, even if the numbers are similar, showing that only 61.7% of patients are treated surgically within the national guidelines time limit of 2 weeks. The delays are mainly due to in hospital logistics, and also to patients not seeking medical advice immediately. The study adds to increasing evidence that dual antiplatelet therapy protects against new neurological events in symptomatic patients. The findings constitute a firm platform for implementing coordinated national improvement measures.

      Introduction

      In patients with ipsilateral carotid stenosis ≥ 50%, the stroke risk after a minor ischaemic neurological event will exceed 30% during the following 2–3 months,
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      In 2007, the UK guideline was to perform surgery within 48 hours. More recent data have shown that very early surgery might be associated with an increased peri-operative risk,
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      and in the fourth set of UK national guidelines (published in 2012), the recommendations have been amended as follows: “as soon as possible and within one week of symptoms”.
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      National clinical guideline for stroke.
      However, the documented effect of early surgery does not seem to be well implemented in everyday practice. In a Vascunet study only 6.8% of patients operated on by carotid endarterectomy (CEA; 60.1% symptomatic) had been admitted urgently.
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      Symptoms, degree of stenosis, time from symptoms to surgery, and quality of surgical treatment are the major factors to be taken into account when optimising prophylactic surgery. In addition, platelet inhibitors are shown to reduce the risk of stroke in patients with symptomatic carotid stenosis. Current guidelines advise that all patients should be on low dose aspirin while awaiting CEA, but there is increasing evidence that early commencement of dual antiplatelet therapy (DAPT) might reduce the incidence of early recurrent events.
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      Timing of carotid surgery in Norway follows the European and US guidelines. However, it is not well known to what extent these recommendations are implemented in daily practice.
      The aim of the study was to cover all carotid surgery for symptomatic disease in Norway for 1 year, to register the timing between the index event and surgery, the healthcare levels for potential delays, and the neurological events occurring during the delay, and, furthermore, to register the use of platelet inhibitors and whether this influenced the risk of such events.

      Material and Methods

      This was a prospective, national, multicentre consecutive series of symptomatic patients referred for CEA over 1 year. Patients were included when referred for surgery if they complied with the inclusion criteria (Table 1). Carotid surgery in Norway is restricted to 15 hospitals and all of them contributed with their operations. Only data related directly to the treatment were registered, that is, no personal identifiable data. The index event was defined as the most recent neurological event leading to contact with the healthcare system. There is a difference between “first event” versus “most recent event that made the patient seek medical support”. Since the focus was on the handling within the healthcare system, the latter definition of the index event was chosen. The index events were divided into four categories; amaurosis fugax, transient ischaemic attacks (TIA), minor stroke (modified Rankin Scale Score [mRSS] ≤ 2) and major stroke (mRSS > 2). In order to identify possible levels of delay, the time spans between (i) the index event; (ii) first medical examination; (iii) first examination by neurologist or vascular surgeon; (iv) referral for surgery; and (v) CEA were analysed. The use of peri-operative platelet inhibitors and anticoagulants were also registered and correlated with the incidence of new neurological events after referral for surgery. Finally, the quality of Norwegian surgical practice regarding peri-operative complications, such as peripheral nerve damage, stroke, myocardial infarction (defined as a state that rendered a classification number of the diagnosis in any of the patient journals covering the time window from the initial consultation by the general practitioner to the 30 day follow-up) and death was evaluated.
      Table 1Patient inclusion criteria.
      Inclusion criteria
      • 1.
        Referred for CEA by neurologist or vascular surgeon after clinical examination and verification of significant carotid stenosis on ipsilateral side by triplex scanning, CTA, and/or MRI.
      • 2.
        Amaurosis fugax/TIA or stroke during the previous 6 months (index event) confirmed by medical doctor. In the case of multiple neurological events, the last one was registered.
      • 3.
        Accepted by vascular surgeon for CEA
      • 4.
        Age > 18 years
      • 5.
        Able to give informed consent
      Exclusion criteria
      • 1.
        Haemorrhagic stroke
      • 2.
        Endovascular treatment (carotid artery stenting)
      Note. CEA = carotid endarterectomy; CTA = computed tomography angiography; MRI = magnetic resonance imaging; TIA = transient ischaemic attack.
      The degree of stenosis was assessed by the preferred method (ultrasound, computed tomography angiography [CTA] or magnetic resonance imaging [MRI]) at each centre. A 30 day post-operative consultation included neurological examination and assessment by a neurologist or vascular surgeon. A local investigator at each hospital was responsible for completing the case report forms (CRF). The CRFs were consecutively transferred to a custom made database via a double login procedure.

       Statistics

      Data handling, calculations, and figures were done in Excel (Microsoft, Redmond, WA, USA). Statistical analysis of the effect of platelet inhibiting drugs was done using Pearson's chi-square test (SPSS Statistics 22; IBM, Armonk, NY, USA).

       Ethics

      The study was approved by the regional ethics committee (Helse Sørøst), and all participating patients signed informed consent.

      Results

      Three hundred and seventy one patients were eligible for inclusion in the study between 1 April 2014 and 31 March 2015. Two patients declined participation, and for one patient sufficient data were not available. Hence, 368 patients were included (99.2%), and all patients underwent surgical treatment by CEA. The mean number of operations per hospital was 25 (median 23, range 6–40).
      Amaurosis fugax was the index event in 17.4% of patients (n = 64), TIA in 36.7% (n = 135), minor stroke in 39.4% (n = 145), and major stroke in 6.0% (n = 22). For two patients (0.5%) the type of index event was not reported. The degree of ipsilateral stenosis was 90–99% in 40.5% of the patients (n = 149), 70–89% in 48.9% (n = 180), and 50–69% in 10.6% of patients (n = 39).

       Time from index event to surgery

      The time from index event to surgery is shown as an accumulated percentage of patients as a function of days in Fig. 1. Median time from the index event to surgery was 11 days; 61.7% of the patients (n = 227) were operated on within the recommended 14 days and 87.8% (n = 323) within 6 weeks. The time between the five levels of healthcare is presented as accumulated percentages in Fig. 2. Fifty-four percent of the patients contacted their general practitioner on the day of the index event, and after 4 days, 80.4% of the patients had sought medical help. The primary medical contact referred 84.2% of the patients to a hospital specialist at the same day as the primary examination. Median time from hospitalisation to referral to vascular surgery was 3 days, and after 7 days 82.9% of the patients had been referred. Median time from referral to a vascular surgical unit to CEA was 5 days, and after 10 days 81.5% had been treated surgically. There was no correlation between this delay (median number of days from referral to surgery) and carotid surgical volume at each hospital (R2 = 0.133, p = .9) (Fig. 3). There was no difference in time from index event to surgery between the amaurosis fugax/TIA group of patients and the stroke group (12 days vs. 11 days, median).
      Figure 1
      Figure 1Accumulated percentage of patients as a function of days from index event to surgery. Note. IQR = interquartile range.
      Figure 2
      Figure 2Accumulated percentage of patients as a function of days between the five levels of healthcare from index event to surgery. Note. CEA = carotid endarterectomy; IQR = interquartile range.
      Figure 3
      Figure 3Relationship between delay (from referral to carotid endarterectomy) and surgical volume.

       Outcome and use of platelet inhibitors

      Twelve patients (3.3%) suffered a new neurological event between referral to surgery and CEA; eight patients had a TIA and four patients had an ipsilateral minor stroke. All the events occurred within 12 days of time of referral, and seven within 48 hours. Use of platelet inhibitors in the two groups (those who had and those who did not have a new neurological event after referral to surgery) is shown in Table 2. At the time of referral to surgery, there was no difference in the use of acetylsalicylic acid (ASA; 91.7% vs. 84.6%) between the groups, but a significantly lower proportion of the patients in the group who suffered a new neurological event were on DAPT (25.0%) compared with the group who did not (62.6%) (p = .008).
      Table 2Use of platelet inhibitory and anticoagulant drugs among the patients who had a new neurological event between referral to surgery and CEA (upper panel), and those who did not (lower panel).
      New event (n = 12/368)
      At time of index eventAt time of surgery
      ASA only9 (75.0)8 (66.7)
      Other platelet inhibitor only1 (8.3)1 (8.3)
       Dipyramidole (n)11
       Clopidogrel (n)00
      ASA + another platelet inhibitor0 (0)3 (25.0)a
       Dipyramidole (n)02
       Clopidogrel (n)01
      No platelet inhibitor2 (16.7)0 (0)
      Warfarin0 (0)0 (0)
      NOAK1 (8.3)1 (8.3)
      LMWH1 (8.3)2 (16.7)
      No new event (n = 356/368)
      ASA only155 (43.5)78 (21.9)
      Other platelet inhibitor only26 (7.3)41 (11.5)
       Dipyramidole1321
       Clopidogrel1320
      ASA + another platelet inhibitor28 (7.9)223 (62.6)a
       Dipyramidole (n)17139
       Clopidogrel (n)981
       Prasugrel (n)11
       Ticagrelor (n)12
      No platelet inhibitor147 (41.3)14 (3.9)
      Warfarin15 (4.2)17 (5.0)
      NOAK9 (2.5)13 (3.8)
      LMWH010 (2.9)
      Note. Data are n (%) unless otherwise indicated. There was a significant difference between the new event group and the no new event group in the use of dual antiplatelet therapy at the time of surgery, ap = .008 (Pearson's chi-square). ASA = acetylsalicylic acid; NOAK = non-vitamin K antagonist oral anticoagulants; LMWH = low molecular weight heparin.
      Thirteen patients (3.5%) suffered a peri-operative stroke (seven minor and six major). The combined 30 day stroke and death rate was 3.8%. The stroke/death rates are outlined in Table 3. One patient died on the fourth post-operative day, the cause of death being per-operative carotid dissection, major stroke, and cerebral herniation. Another five patients died before the scheduled follow-up; three patients died 34, 39, and 92 days after surgery, respectively, from non-stroke related causes. Two patients died on days 23 and 32, respectively, from unknown causes. There were no peri-operative myocardial infarctions. Four patients were readmitted after day 30 but before the scheduled outpatient consultation, as a result of new neurological events (one TIA, two minor strokes, and one major). Only one of these patients (one of the minor strokes) had symptoms from the ipsilateral hemisphere. Three hundred and fifty nine of 362 patients (99.2%) attended the outpatient post-operative consultation. Except for the four patients readmitted before scheduled follow-up, none had signs of new neurological events. Seven patients (1.9%) had signs of peripheral nerve injury at the follow-up consultation. Median time from CEA to follow-up consultation by a neurologist was 44 days (interquartile range 34–65 days).
      Table 3Rates of stroke/death within 30 d, subdivided according to time (d) from index event to operation.
      Days0–23–78–14> 14Total
      Operated10 (2.7)88 (23.9)129 (35.1)141 (38.3)368 (100)
      Minor stroke0 (0)1 (1.1)3 (2.3)3 (2.1)7 (1.9)
      Major stroke0 (0)2 (2.3)4 (3.1)0 (0)6 (1.6)
      Mortality0 (0)0 (0)1 (0.8)1 (0.7)2 (0.5)
      Mortality and any stroke0 (0)3. (3.4)7 (5.4)4 (2.8)14 (3.8)
      Note. Data are n (%).

      Discussion

      In this prospective national study in Norway covering carotid surgery during 1 year, the percentage of inclusion and follow-up was near complete (both 99.2%). The prospective design and the limited number of registrars (one at each hospital) confirmed that all patients eligible for inclusion were identified, and provided complete and highly reliable data. The inclusion criterion, referral to vascular surgery, is narrow and precludes assessment regarding risk of having a new neurological event in the period from index event and referral to surgery. However, it gives insights into how frequently this operation is performed, its timing, and related consequences. Furthermore, the results support a more aggressive approach to peri-operative antiplatelet therapy.

       Delays from index event to surgery

      Forty-six percent of patients did not seek medical advice on the day they had symptoms. This is in accordance with the behavior of populations elsewhere.
      • Giles M.F.
      • Flossman E.
      • Rothwell P.M.
      Patient behavior immediately after transient ischemic attack according to clinical characteristics, perception of the event, and predicted risk of stroke.
      There were also delays within hospitals, with 20% of patients not referred to vascular surgery within the first week. In the vascular surgical units, 30% of the patients had not been operated on 1 week after the referral had been received. Between referral to vascular surgery and CEA (median 5 days), 3.3% of patients suffered a new neurological event. The discussion about timing has been ongoing for a number of years and changes have been initiated in Norwegian hospitals to shorten the waiting time, but the present study confirms that there is more to be done. The general primary anticipation might be that the in hospital management is good and that the “problem” is mainly located elsewhere. However the figures partly point at hospitals, which might also be the case in other countries.
      Since the inclusion criterion in this study was referral to surgery, the incidence of new neurological events in the time period between the index event and submission of the referral to vascular surgery (median 6 days) is not known. Nor is it known if any individuals were never referred owing to new neurological events precluding surgery (i.e., major stroke) in this period. However, since the risk of new neurological events is higher the closer in time you are to the index event, it is reasonable to assume that > 3.3% had new neurological events in hospital while waiting for surgery. All the neurological events occurred before 2 weeks after referral to surgery and seven of them within 48 hours. Hence, at least five new events could have been prevented by surgery within 48 hours, which emphasizes the importance of urgent surgery for symptomatic carotid stenosis.
      Although this was a relatively small study, no indications of any increased risk associated with very early surgery were found (Table 3).
      Unfortunately, these figures are not unique. Even in areas with specialised TIA clinics, starting best medical therapy immediately, 11% of patients experience recurrent neurological events between hospital admission and surgery.
      • Ali M.
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      The present results on median time (11 days) from index event to surgery, and 38% not being operated on within 2 weeks, are almost identical to the results of the UK National Vascular Registry.
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      • et al.
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      Several studies have evaluated the delay from onset of symptoms to CEA with very similar conclusions.
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      • et al.
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      • et al.
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      • Witt A.H.
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      • Hundborg H.H.
      • Andersen G.
      Reducing delay of carotid endarterectomy in acute ischemic stroke patients: a nationwide initiative.
      The reasons vary; for example, referral delays, waiting for imaging, comorbidities, and lack of surgical theatre capacity.
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      • Guest R.V.
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      • Fraser S.C.
      • Chalmers R.T.
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      • Purkayastha D.
      • Grant S.W.
      • Smyth J.V.
      • McCollum C.N.
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      • Dyer E.
      • Lownie S.
      • Ferguson G.
      Wait times for carotid endarterectomy, London Ontario 2006-2007.
      Improvements in the care of this group of patients require better in hospital logistics, and probably also a shift of attitude among patients and colleagues, including vascular surgeons.
      It is known that patients with stroke experience less delay than patients with TIA and especially than those with amaurosis fugax. Herein, the mean time from index event to surgery was 30 days in the amaurosis fugax/TIA group and 18 days in the stroke group. However, the data were not normally distributed and there were no differences in median time (12 vs. 11 days). Hence, the study does not lend strong support to previous observations.
      All patients referred were operated on. However, the definition of “referral to CEA” does not take into account the close collaboration, beyond written communication, between neurologists and vascular surgeons. Potential CEA candidates are frequently discussed orally between the neurologist and the vascular surgeon. The neurologist's intention to refer the patient to surgery will, in some cases, be reconsidered after a joint evaluation, and the intended written referral never sent. This might explain why all referred patients went through surgery.
      Carotid artery stenting (CAS) was not included in this study for several reasons. Because CAS is not performed very often in Norway, it would probably not be possible to draw any solid conclusion regarding this subgroup. Furthermore, in Norway CAS is almost exclusively offered to patients with a higher comorbidity load, and the procedure is also associated with a higher risk of stroke. Inclusion of this subgroup may therefore have influenced the total outcome of carotid interventions even if it constituted a small number of patients. Only three CAS procedures were performed on symptomatic patients during the inclusion period.

       Effect of platelet inhibitors

      In addition to having CEA as an urgent procedure after symptom onset, patients should be started on DAPT. There is evidence that introduction of DAPT will render up to a fivefold reduction in recurrent neurological events prior to CEA.
      • Batchelder A.
      • Hunter J.
      • Cairns V.
      • Sandford R.
      • Munshi A.
      • Naylor A.R.
      Dual antiplatelet therapy prior to expedited carotid surgery reduces recurrent events prior to surgery without significantly increasing peri-operative bleeding complications.
      Even in the present small study, where only 12 patients suffered a new neurological event, there was a highly significant difference between the groups with respect to use of a platelet inhibitor other than ASA while waiting for surgery. Previous studies have shown that both clopidogrel and dipyramidole have the potential of reducing stroke incidence after TIA or stroke.
      • Batchelder A.
      • Hunter J.
      • Cairns V.
      • Sandford R.
      • Munshi A.
      • Naylor A.R.
      Dual antiplatelet therapy prior to expedited carotid surgery reduces recurrent events prior to surgery without significantly increasing peri-operative bleeding complications.
      In this study the platelet inhibitor other than ASA was dipyramidole in 2/3 of the cases and clopidogrel in 1/3. However, the cohort was not big enough to allow evaluations of the protective effect of each drug separately. As the data were not controlled for confounding variables, such as age, sex, or comorbidity, the results regarding effect of platelet inhibitors should be interpreted cautiously. Previous publications indicate that performing CEA in patients on DAPT does not increase the number of haematomas needing re-exploration.
      • Wait S.D.
      • Abla A.A.
      • Killory B.D.
      • Starke R.M.
      • Spetzler R.F.
      • Nakaji P.
      Safety of carotid endarterectomy while on clopidogrel (Plavix). Clinical article.
      However, the number of skin haematomas might increase.
      • Doig D.
      • Turner E.L.
      • Dobson J.
      • Featherstone R.L.
      • de Borst G.J.
      • Brown M.M.
      • et al.
      Incidence, impact, and predictors of cranial nerve palsy and haematoma following carotid endarterectomy in the international carotid stenting study.
      The number of patients on DAPT before surgery was quite low, indicating that this should be an improvement issue in Norway.

       Utilising carotid surgery

      The incidence of stroke in Norway is expected to be approximately 15,000 per year. Approximately 85% of strokes are due to cerebral infarction. The figures for a carotid stenosis being the source for an ischaemic embolus vary between 10% and 25%. At 15%, the estimated number of carotid related ischaemic strokes in Norway is 0.85 × 15,000 × 0.15 = 1912. However, not all major strokes are preceded by transient neurology. Stroke is preceded by a TIA in 30%, and for those having a symptomatic warning, the estimated number of carotid related events is 0.3 × 1912 = 573. In this study with complete national coverage, 371 patients were referred for CEA. Hence, it is questionable whether CEA is offered to all patients who have an indication for surgery. To optimise the use of CEA, informing the public and the health workers at all levels about its value might be just as important as the improvement of timing.

       Limitations

      The vast majority (89.3%) of patients had 70% stenosis or more on the symptomatic side. However, the degree of stenosis was not measured by any standardised method. It was estimated based on local preferences for modality (ultrasound, CTA, or MRI) during the initial examination by a neurologist, vascular surgeon, physician, and/or a radiologist. The measurements might therefore be inconsistent, but, nevertheless, they constitute part of the basis for decision making in every day practice.
      In this study, patient identifiable data were not registered. This is the main limitation of the study, and it excludes further subgroup analysis based on age, sex, and comorbidities. It also prevents drawing strong conclusions from the data showing a protective effect of pre-operative DAPT with respect to peri-operative stroke. For the same reason, a comprehensive list of causes of death cannot be presented.
      The intention was to assess the patients in the outpatient department 1 month after CEA. However, time from CEA to follow-up was longer because of existing hospital routines, but since none of the patients showed signs of new neurological events at follow-up, this deviation from the protocol had no consequence.

       Summary

      An almost complete prospective inclusion and follow-up of symptomatic patients referred for carotid surgery in Norway during 1 year showed that only 61.7% of the patients were operated on within the national guidelines of 2 weeks. The delays were mainly caused by patients not seeking medical advice immediately, and by in hospital logistics. Within 2 weeks of referral, 3.3% of the patients had new neurological events, emphasising that carotid surgery in symptomatic patients is an urgent procedure. DAPT appears to reduce the risk of neurological events before surgery, but because of very limited data on patient characteristics this finding should be interpreted cautiously.

      Acknowledgments

      We thank Arne Seternes and Erik Mulder Pettersen (former chairmen of the Norwegian Society for Vascular Surgery) and Charlotte Björk Ingul (research coordinator at Unicard) for facilitating the study. Special thanks to Tor Ivar Hansen (Norwegian University of Science and Technology, Trondheim) for programming and maintaining the database. Thanks also to the neurologists at the authors' hospitals for their contribution to the dataset.

      Conflict of Interest

      None.

      Funding

      This work was supported by the Norwegian Medical Association (Project number 14/1694 ) and by Unicard .

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