15a The Heart and the Brain

Stroke is the third most common reason for death, the second for dementia, and the most common cause for permanent disability. About 25% of all strokes are caused by a cardiac source of embolism, most frequently atrial. Acute stroke should be treated in dedicated stroke units. Systemic thrombolysis with recombinant tissue plasminogen activator in a time window up to 4.5 hours or endovascular recanalization up to 6 hours is effective in decreasing permanent disability after ischaemic stroke. Secondary prevention of stroke following a cardiogenic transient ischaemic attack or stroke should mostly be performed with oral anticoagulation which is clearly superior to acetylsalicylic acid (aspirin). Antiplatelet therapy is indicated in patients with ischaemic stroke and no cardiac source of embolism. Both clopidogrel monotherapy and the combination of aspirin plus extended-release dipyridamole are superior to aspirin monotherapy. In patients with a symptomatic high-degree stenosis of the internal carotid artery, endarterectomy has a slightly lower complication rate compared to stenting and balloon angioplasty with a similar long-term outcome.

Patients with ischaemic stroke experience sudden focal neurological deficits lasting >24 hours. Mortality following ischaemic stroke is 20–30% due to brain oedema and secondary complications such as aspiration pneumonia, deep vein thrombosis, and pulmonary embolism, sepsis or heart failure. Predictors for poor outcome are: initial loss of consciousness, age >70 years, hemiplegia with forced eye deviation, prior stroke, and concomitant coronary heart disease [1].

The reduced blood flow leads to neural and glial death in the core of the infarct. The core of the stroke area is surrounded by the so-called penumbra with diminished cerebral blood flow and functional loss of neurons and glia with the potential to survive. The best strategy to rescue this tissue is recanalization. Ischaemia triggers a complex cascade of release of excitatory amino acids, Ca²⁺ influx, and release of intracellular calcium and production of free radicals. Neuroprotective therapy aiming at interrupting these processes has failed so far for treatment of human stroke [2].

The first diagnostic procedure after physical and neurological examination is computer tomography (CT) or magnetic resonance imaging (MRI) of the brain to exclude cerebral haemorrhage. Indirect signs of cerebral ischaemia can be seen in CT within 2–3 hours. Diffusion-weighted MRI shows ischaemia immediately ( Fig. 15a.1) also in areas in which CT visualizes tissue poorly e.g. the posterior fossa. CT or MR angiography or duplexsonography will identify significant stenosis or occlusion of brain-supplying arteries. Diffusion- and perfusion-weighted MRI allows identification of the penumbra and can identify patients who qualify for either systemic or local thrombolysis beyond the 4.5-hour window.

Typically, stroke due to cardiac emboli appears suddenly, mostly without further progression of deficits [3]. The clinical symptoms and signs depend on the part of the brain involved. They include motor and sensory hemiparesis, visual field deficits, dysphasia, disorientation, vertigo, ataxia, and loss of consciousness, and may be accompanied initially by palpitations or retrosternal pain. Emboli preferentially lodge

in the main trunks of the cerebral arteries or are scattered in the pial branches, much more often than in the small deep penetrating arteries. The resulting infarct is mostly a wedge–shaped, cortico-subcortical territorial infarct and rarely a deep lacune. Sometimes, multiple infarcts in one or multiple vascular territories are seen, and haemorrhagic transformation is more common than in atherothrombotic stroke. When emboli lyse, rapid recovery from a major hemispheral deficit (‘spectacular shrinking deficit’) can occur. Emboli arising from infectious endocarditis or atrial myxoma may lead to the formation of cerebrovascular aneurysm, which are usually fusiform.

Neither clinical presentation nor findings of brain imaging are specific. Therefore, cardioembolic stroke should always be suspected, when a cardiac disease or arrhythmia is found to be present and other causes of stroke have been excluded. As to the diagnosis of cardioembolic stroke, considerable disagreement exists among experts. If history and physical examination, electrocardiography, telemetry, chest X-ray, CT, or MRI of the brain show primary haemorrhage or cerebral micro- or macroangiopathy, further cardiac workup might not be needed. If clinical signs or ancillary findings indicate heart disease, a rational approach might be to perform transthoracic echocardiography (TTE), but if clinical signs or ancillary findings are normal it might be more appropriate to proceed directly to transoesophageal echocardiography (TOE) and extended monitoring for arrhythmias. Also in young patients in whom TTE has a low detection rate it might be more cost-effective to skip TTE and move directly to TOE [4].

Patients with acute stroke should be admitted to a dedicated stroke unit ( Table 15a.1). Stroke unit care decreases mortality and permanent severe disability by 20% [5, 6]. In the initial phase after a stroke, treatment aims at keeping or bringing physiological parameters into the normal range. Prospective studies showed a negative effect on outcome of too low or high blood pressure, sudden drops of blood pressure, increased blood glucose, increased temperature, fluid loss, or hypoxia. Blood pressure increases in the acute phase of stroke and returns to normal or prior levels after a few days. Therefore only very high blood pressure values exceeding 200/110mmHg should be treated [7]. The following approach is recommended although not proven by randomized trials:

The only specific therapy in acute ischaemic stroke is systemic thrombolysis with recombinant tissue plasminogen activator (rtPA) [8] ( Fig. 15a.2). Efficacy was originally demonstrated in a 3-hour time window, but recently efficacy in a 4.5-hour window has been observed [9]. The most important contraindications are cerebral bleeds, severe stroke, age >80 years, recent surgery, coagulation disorders, and blood pressure >180mmHg. Thrombolysis is effective in anterior and posterior circulation strokes. The most dangerous complication is cerebral haemorrhage which occurs in about 5% of all patients. Based on the results of diffusion-weighted and perfusion-weighted MRI some centres use thrombolysis off-label in the time window beyond 4.5 hours, when penumbra is still present. Specialized centres may alternatively perform local thrombolysis via microcatheter with urokinase or rtPA, use thrombus extraction devices, e.g. the MERCI retriever, or suction devices, e.g. PENUMBRA.

Stroke in the posterior fossa can lead to occlusive hydrocephalus requiring the insertion of a shunt by a neurosurgeon. In space-occupying cerebellar infarctions, craniectomy of the posterior fossa and resection of the ischaemic brain tissue is necessary. Malignant middle cerebral artery infarction in patients <60 years can be treated by hemicraniectomy. This procedure dramatically reduces mortality (from 80% to 30%) and shows a trend for reduced morbidity in surviving patients [10, 11]. The use of corticosteroids, haemodilution, or the systemic use of streptokinase is ineffective or even damaging.

The prevalence of a patent foramen ovale (PFO) is up to 25% in the general population. To date, epidemiologic studies have not shown thromboembolic events to occur more frequently in subjects with PFO, and therefore no special primary intervention is needed [12]. In patients with stroke of unknown cause (cryptogenic stroke), however, the prevalence of PFO is substantially higher and approximates 40% [13]. Case reports and case–control studies of cryptogenic strokes compared to strokes with known aetiology or non-stroke controls confirmed an association of PFO and stroke. Therefore, the presence of a PFO after stroke or emboli to other organs raises important questions on the management of such patients. Prospective cohort studies have shown that treatment with aspirin or anticoagulation with a vitamin K antagonist such as warfarin reduces the risk of recurrent stroke in the average patient with PFO to levels similar to those without PFO. As aspirin was as effective as anticoagulation, aspirin should be considered the treatment of choice [14]. Among patients with PFO, those with spontaneous or large right-to-left shunts, with a coinciding atrial septal aneurysm or multiple ischaemic events prior to the PFO diagnosis are at higher risk of recurrent stroke than the average PFO patient. Percutaneous device closure (PDC) becomes therefore an attractive alternative to medical treatment in such patients, but data from randomized controlled trials comparing the effect of percutaneous device closure with medical therapy are still lacking [15]. At present, general use of PDC cannot be recommended.

The evidence that oral anticoagulation prevents recurrent stroke in patients with atrial fibrillation results from the European Atrial Fibrillation Trial [16]. This randomized placebo-controlled trial showed a 68% relative risk reduction (RRR) for a recurrent stroke in patients with atrial fibrillation treated with warfarin compared to only 19% for patients receiving 300mg of aspirin per day. Numbers needed to treat are 12 per year. Therefore, oral anticoagulation in patients with atrial fibrillation is by far the most effective treatment for secondary stroke prevention. Similarly, a Cochrane analysis concluded that oral anticoagulation is more effective than aspirin for the prevention of vascular events (odds ratio (OR), 0.67; 95% confidence interval (CI), 0.50– 0.91) or recurrent stroke (OR, 0.49; 95% CI, 0.33– 0.72) [17]. As expected, the risk of major bleeding complications is increased with anticoagulation, but not the risk of intracranial bleeds. Patients with intermittent atrial fibrillation have a similar stroke risk as patients with permanent atrial fibrillation [18, 19]. The optimal international normalized ratio (INR) range for oral anticoagulation is between 2–3 [20]. INR values >4.0 lead to an increased risk of major bleeding complications particularly in the elderly [21]. The bleeding risk with anticoagulants is also increased when high blood pressure is not well controlled.

The ACTIVEW study compared the combination of aspirin and clopidogrel vs. oral anticoagulation with warfarin in patients with atrial fibrillation [22]. The study was terminated prematurely due to a significant reduction of stroke and systemic embolism in favour of warfarin. The rate of major bleeding complications was not different between the two regimens.

In conclusion, stroke patients with a cardiac source of embolism, in particular atrial fibrillation, should be treated with oral anticoagulation (INR 2–3). Patients with mechanical heart valves should be anticoagulated with an INR between 2–3.5. In patients with transient ischaemic attacks (TIAs) or minor stroke, oral anticoagulation can be initiated immediately after the exclusion of cerebral haemorrhage. Patients with contraindications or unwilling to use oral anticoagulation should receive aspirin 300mg per day.

Antiplatelet drugs are effective in secondary stroke prevention after TIAs or ischaemic stroke. This has been shown in many placebo-controlled trials and in several meta-analyses [23–25]. The RRR for non-fatal stroke achieved by antiplatelet therapy in patients with TIA or stroke is 23% (reduced from 10.8% to 8.3% in 3 years). The combined endpoint of stroke, MI, and vascular death is reduced by 17% (from 21.4% to 17.7 over 29 months).

A meta-analysis of the eleven randomized and placebo-controlled trials investigating aspirin monotherapy in secondary stroke prevention found a RRR of 13% (95% CI, 6–19%) for the combined endpoint of stroke, MI, and vascular death [26]. There is no relationship between the dose of aspirin and its efficacy in secondary stroke prevention [26, 27]. Gastrointestinal side effects and bleeding complications are, however, dose dependent and bleeding rates increase significantly beyond a daily dose of aspirin of 150mg per day [28, 29]. Therefore, the recommended dose of aspirin is 75–150mg per day.

In CAPRIE (Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events), clopidogrel monotherapy (75mg/day) was compared to ASA (325mg/day) in almost 20,000 patients with stroke, myocardial infarction, or peripheral arterial disease (PAD) [30]. The combined endpoint of stroke, myocardial infarction, and vascular death was reduced by 8.7% under clopidogrel with an ARR of 0.51% per year. The largest benefit of clopidogrel was seen in patients with PADs. The risks of gastrointestinal bleeds (1.99% vs. 2.66%) and gastrointestinal side effects (15% vs. 17.6%) were smaller with clopidogrel than with aspirin.

The MATCH (Management of ATherothrombosis with Clopidogrel in High-risk patients with recent transient ischaemic atteck or ischaemic stroke) study compared the combination of clopidogrel 75mg and aspirin 75mg per day with clopidogrel monotherapy in high-risk patients with TIA or ischaemic stroke [31]. It failed to show superiority of combination antiplatelet therapy for the combined endpoint of stroke, myocardial infarction, vascular death, and hospitalization due to a vascular event. Instead, the combination resulted in an increase of bleeding complications, and therefore is not recommended.

The CHARISMA trial (Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilization, Management, and Avoidance) was a combined primary and secondary prevention study in 15,603 patients and compared the combination of clopidogrel and aspirin with aspirin monotherapy [32]. Similar to MATCH, the study failed to show a benefit for combination therapy and displayed a higher bleeding rate under the combination. Symptomatic patients, however, appeared to derive significant benefit from dual antiplatelet therapy [33].

The combination of low-dose aspirin and extended-release dipyridamole (ER-dipyridamole) was investigated in the second European stroke prevention study (ESPS2) with 6602 patients with TIAs or stroke [34]. Patients were randomized to aspirin (25mg BID), ER-dipyridamole (200mg BID), the combination of aspirin and ER-dipyridamole, or placebo. For the primary endpoint stroke, the combination was superior to aspirin monotherapy (RRR, 23%; absolute risk reduction (ARR 3%) and placebo (RRR, 37%; ARR, 5.8%). Aspirin monotherapy lowered the risk of stroke by 18% (ARR 2.9%) and dipyridamole monotherapy by 16% (ARR 2.6%) compared to placebo. Major bleeding complications were seen more frequently with aspirin and the aspirin plus ER-dipyridamole combination, whereas dipyridamole monotherapy had a similar bleeding rate as placebo. Cardiac events occurred in similar frequency in the groups treated with dipyridamole compared to aspirin. Patients with coronary heart diseased had no increased risk of angina or MI when treated with extended-release dipyridamole [35]. The investigator-initiated, open European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) randomized 2739 patients with presumed atherothrombotic TIA or minor stroke to aspirin (30–325mg per day) or the combination of aspirin with dipyridamole and followed them for a mean period of 3.5 years. The primary endpoint was the combination of vascular death, stroke, myocardial infarction, and major bleeding complications. The event rate for the primary endpoint was 16% with aspirin monotherapy and 13% with aspirin plus dipyridamole resulting in a RRR of 20% (ARR, 1%) [36]. In the combination arm, 34% of patients terminated the trial prematurely mostly because of adverse events like headache (13% in the aspirin arm of the study). A meta-analysis of all stroke prevention trials testing aspirin monotherapy vs. aspirin plus dipyridamole showed a RRR in favour of the combination for the combined vascular endpoint by 18% (95% CI, 9–26%).

A direct comparison of clopidogrel and aspirin plus ER-dipyridamole was performed in the PRoFESS study [37]. There was no difference in efficacy across all endpoints and various subgroups of patients. Aspirin plus ER-dipyridamole resulted in more intracranial bleeds and a higher drop out rate due to headache compared with clopidogrel (5.9% vs. 0.9%). Table 15a.2 summarizes the recommendations for antithrombotic therapy from the Stroke Council of the American Heart Association ^[38].

Hypertension is the most important risk factor for stroke ( Table 15a.3; see also Chapter 13) [39]. Stroke mortality is strongly related to the level of blood pressure ( Fig. 15a.3) [40]. There are only few studies investigating the efficacy of classes of antihypertensive drugs in secondary stroke prevention. A meta-analysis comprised seven studies in 15,527 patients with TIA, ischaemic, or haemorrhagic stroke who were followed for 2–5 years [41]. Treatment with antihypertensives reduced the risk of stroke (OR, 0.76), of non-fatal stroke (OR, 0.79), of MI (OR 0.79), and the risk of all vascular events (OR 0.79). For prevention of stroke, the combination of an angiotensin-converting enzyme (ACE)-inhibitor with a diuretic seemed most effective. ACE-inhibitors and angiotensin receptor blockers are supposed to exhibit pleiotropic and protective vascular effects beyond lowering high blood pressure. Under this assumption, the Heart Outcomes Prevention Evaluation (HOPE) study compared ramipril with placebo [42]. In the subgroup of patients with TIAs or stroke as the qualifying event, ramipril resulted in a relative reduction of the combined endpoint of stroke, MI, or vascular death by 24% or an ARR of 6.3% over 5 years.

PROGRESS (Perindopril Protection Against Recurrent Stroke Study) was the first large-scale trial on secondary stroke prevention in 6105 patients who were randomized to either perindopril with or without indapamide or placebo [43]. Across the 4-year observation period, blood pressure in the treatment group was lowered on average by 9/4mmHg. The ARR for recurrent stroke was 4% and the RRR was 28%. For the combination of perindopril and indapamide, the RRR was 43% whereas the ACE inhibitor alone did not achieve the same level of blood pressure lowering and was not significantly superior to placebo.

MOSES (Morbidity and Mortality After Stroke – Eprosartan vs Nitrendipine for Secondary Prevention) included 1352 hypertensive patients who had suffered a stroke in the previous 24 months [44]. Patients were randomized to either eprosartan (600mg per day) or nitrendipin (10mg per day) on top of additional antihypertensive therapy when appropriate. Despite an identical blood pressure reduction, eprosartan was superior to nitrendipin to prevent recurrent vascular events (21% RRR). Optimal systolic blood pressure in the MOSES trial was 120–140mm Hg.

PRoFESS (Prevention Regimen For Effectively avoiding Second Strokes) randomized 20,332 patients with a recent ischaemic stroke to telmisartan 80mg/day or placebo in addition to other antihypertensive therapies, for a median follow-up of 2.4 years [45]. Mean blood pressure in the telmisartan group was lower by 3.8/2.0mmHg over the trial period. Recurrent strokes occurred in 8.7% in the telmisartan group compared to 9.2% in the placebo group, which was not significant. Initiation of telmisartan early after a stroke, and continued for a median of 2.4 years, did neither significantly lower the rate of recurrent strokes, major vascular events or new-onset diabetes.

In conclusion, all antihypertensive drugs are most likely effective in secondary stroke prevention. Beta-blockers (atenolol) show the lowest efficacy. More important than the choice of antihypertensive is the degree of blood pressure-lowering achieved. Currently recommended targets for systolic and diastolic blood pressure are 140/90mmHg in non-diabetics and 130/80mmHg in diabetics; however, even lower pressures may provide additional benefit. Achieving target blood pressure frequently requires combination therapy. Concomitant diseases (kidney failure, congestive heart failure) have to be considered. Lifestyle modification will lower blood pressure and should be recommended in addition to drug treatment.

Cardiologists and neurologists are faced in their clinical routine with patients with manifest disease of the coronary arteries and stroke or TIA. In this section we will give recommendations for the treatment of stroke patients with acute coronary syndrome and patients with coronary heart disease and an acute stroke. All these recommendations are not evidence based.

Patients with a history of ischaemic stroke who present with an acute coronary syndrome may receive thrombolysis, heparin, and/or stenting. In contrast, in patients with disabling strokes or cerebral haemorrhage, thrombolysis and standard dose heparin should be avoided. The use of clopidogrel plus aspirin after an acute coronary syndrome and/or a stent implantation carries a higher bleeding risk than monotherapy. However, the benefit of dual platelet inhibition in terms of preventing vascular events and stent thrombosis is clearly higher than with monotherapy. Patients with a cardioembolic stroke in the past who are anticoagulated and need a coronary stent might be treated for a limited time with triple therapy (aspirin, clopidogrel, and oral anticoagulation). The optimal time period when the increased rate of bleeding complications might offset the prevention of stent thrombosis is, however, not known.

In patients with atrial fibrillation receiving oral anticoagulation who suffer a cerebral haemorrhage anticoagulation should be stopped. Oral anticoagulation might be reintroduced if the expected risk of a cardioembolic stroke is higher than the risk of recurrent brain haemorrhage.

In patients with atrial fibrillation and stable coronary heart disease, cardiologists tend to combine oral anticoagulation with low-dose aspirin. The results from the two SPORTIF trials, however indicate that the combination of oral anticoagulation with ASA does not reduce the risk of vascular events but results in a significant increase in bleeding complications [46].

Two large randomized trials (North American Symptomatic Carotid Endarterectomy Trial, NASCET and European Carotid Surgery Trial, ECST) found a clear benefit for carotid endarterectomy compared to medical treatment in patients with high degree symptomatic stenosis of the internal carotid artery (ICA) [47, 48]. Taken together, the trials found an ARR of 13.5% over 5 years for the combined endpoint of stroke and death in favour of carotid endarterectomy [49]. The risk reduction was even higher in patients with an ICA stenosis >90%. In patients with an ICA stenosis of 50–69%, the 5-year ARR for the endpoint ipsilateral stroke was 4.6%. This benefit was mainly apparent in men. Patients with an ICA stenosis <50% do not benefit from carotid endarterectomy. The short-term complication rates (stroke and death) were 6.2% with an ICA stenosis >70% and 8.4% for an ICA stenosis of 50–69%. Aspirin should be given prior to, during and after carotid surgery [50]. Several studies randomized patients with significant ICA stenosis to carotid endarterectomy or balloon angioplasty with stenting ( Fig. 15a.4). Surgeons and interventional neuroradiologists had to meet defined quality standards. SPACE (Stent-protected Percutaneous Angioplasty of the Carotid vs. Endarterectomy) randomized 1200 symptomatic patients with a >50% stenosis (according to the NASCET criteria) or >70% (according to ESC criteria) within 6 months after a transient ischaemic attack or minor stroke to carotid endarterectomy or stenting [51]. The primary endpoint, ipsilateral stroke or death within 30 days, occurred in 6.84% of patients undergoing stenting and 6.34% of patients undergoing carotid endarterectomy. A post hoc subgroup analysis identified age <68 years as a factor being associated with a lower complication rate in patients treated with stenting. The complication rate of surgery was not age dependent [52]. In this study, the use of protection system did not influence the complication rate. In the SAPPHIRE study, enrolling high risk patients, complication rates were even slightly lower with carotid stenting than with carotid endarterectomy ( Table 15a.4) [53]. In contrast, the EVA-3S (Endarterectomy Versus Angioplasty in Patients with Severe Symptomatic Carotid Stenosis) was terminated prematurely after 527 patients were randomized due to a significant difference in the 30-day complication rate favouring carotid surgery (9.6% vs. 3.9%; OR, 2.5; 95% CI, 1.25–4.93) [54]. Of note, however, EVA-3S involved a considerable number of centres with very limited experience in carotid stenting which makes the interpretation of this study difficult. In addition the complication rate of surgery was much lower than observed in the SPACE study. Taken together, the results of the studies published to date show a similar and in some instances lower complication rate for endarterectomy compared to carotid stenting [55].The reported medium-time outcomes in a 2-4-year follow-up were comparable but the restenosis rate was higher after carotid stenting [56, 57]. It is likely that the success of carotid stenting (and for that matter also of carotid endarterectomy) depend heavily on the experience of a given centre.

In conclusion, symptomatic patients with significant stenosis of the ICA should preferably undergo carotid endarterectomy. In experienced centres, carotid stenting may be a valuable alternative to carotid endarterectomy. The benefit of surgery (and most likely also that of stenting) increases with the degree of stenosis between 70–95%. The benefit of surgery is highest in the first 2–4 weeks after the initial transient ischaemic attacks or minor stroke. The benefit of surgery is lower in patients with a stenosis between 50–70%, in high degree stenosis (pseudo-occlusion), in women or when surgery is performed 12 weeks or later after the initial event. The benefit of surgery is no longer present when the complication rate exceeds 6%. Patients should receive aspirin prior to, during, and after endarterectomy. Clopidogrel should be replaced by aspirin 5 days before surgery. At present, carotid stenting has a slightly higher short-term complication rate (particularly in less experienced centres) and similar medium time outcomes. The use of protection systems did not decrease the complication rate in some trials, but the favourable outcomes in SAPPHIRE suggest that the use of such devices should be preferred. The restenosis rate is higher after stenting. Whether this translates into higher long-term event rates is not yet known. The complication rate of carotid stenting is age dependent and increases beyond an age of 65–68 years. The combination of clopidogrel (75mg) plus aspirin (75–100mg) is recommended in patients after stenting for 1–3 months.

The SAVE trial in patients after MI and impaired left ventricular function as well as the SOLVD trial in stable heart failure have shown that the risk of stroke increases in parallel to the impairment of ventricular function as judged from ejection fraction [59, 60]. Most likely, left ventricular dilatation and impaired ejection fraction increases the likelihood to develop left ventricular thrombi in cardiomyopathy [61]. Impairment of left ventricular function produces atrial dilatation and stretch and therefore, produces an increased rate of atrial fibrillation depending on the severity of heart failure, which can amount to a prevalence of 49.8% in severe heart failure. In some trials the incidence of thromboembolic strokes was even higher in patients, in which atrial fibrillation was not detected. Therefore, it was subject of debate whether in patients with highly impaired left ventricular function and heart failure anticoagulation should be performed even in the presence of sinus rhythm. However, all cause mortality as well as cardiovascular endpoints are increased when patients receive warfarin therapy [62]. Therefore, in patients with sinus rhythms oral anticoagulation is not recommended unless atrial fibrillation or other striking indications are present. Even though there are arguments in favour of using platelet inhibitors like aspirin [63], there is evidence that in heart failure aspirin might interfere with the beneficial effects of ACE-inhibitors on outcome [64].

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