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Silent cerebral infarcts after cardiac catheterization: A randomized comparison of radial and femoral approaches
Transradial Angiography and Intervention
Silent cerebral infarcts after cardiac catheterization: A randomized comparison of radial and femoral approaches Martial Hamon, MD, a,b,g Janusz Lipiecki c,g Didier Carrié d,g Francesco Burzotta e,g Nicolas Durel c,g Guillaume Coutance a,g Nicolas Boudou d,g Cesare Colosimo e,g Carlo Trani e,g Nicolas Dumonteil d,g Rémy Morello a,g Fausto Viader a,g Béatrice Claise c,g and Michèle Hamon a,f,g Caen, Lille, Clermont-Ferrand, and Toulouse, France; and Roma, Italy
Background Single center studies using serial cerebral diffusion-weighted magnetic resonance imaging in patients having cardiac catheterization have suggested that cerebral microembolism might be responsible for silent cerebral infarct (SCI) as high as 15% to 22%. We evaluated in a multicenter trial the incidence of SCIs after cardiac catheterization and whether or not the choice of the arterial access site might impact this phenomenon. Methods and Results Patients were randomized to have cardiac catheterization either by Radial (n = 83) or Femoral (n = 77) arterial approaches by experimented operators. The main outcome measure was the occurrence of new cerebral infarct on serial diffusion-weighted magnetic resonance imaging. Patient and catheterization characteristics, including duration of catheterization, were similar in both groups. The risk of SCI did not differ significantly between the Femoral and Radial groups (incidence of 11.7% versus 17.5%; OR, 0.85; 95% CI, 0.62-1.16; P = .31). At multivariable analysis, the independent predictors of SCI were the patient's higher height and lower transvalvular gradient. Conclusions The high rate of SCI after cardiac catheterization of patients with aortic stenosis was confirmed, but its occurrence was not affected by the selection of Radial and Femoral access. (Am Heart J 2012;164:449-454.e1.) Acute symptomatic cerebral infarction following cardiac catheterization and percutaneous cardiovascular interventions is rare, 1-3 but unperceived asymptomatic cerebral injury could occur at an unexpectedly high rate 4-6 as detected by diffusion-weighted (DW) magnetic resonance imaging (MRI). Indeed, the high sensitivity of DW MRI suggests that this technique could allow an improved estimate of cerebral ischemic events associated with cardiovascular-catheter procedures. 7 The use of transcranial Doppler (TCD) sonography has confirmed the recording of systematic microemboli entering the middle cerebral artery during various endovascular interventions, including cardiac catheterization. 6,8-10 In the case of coronary bypass surgery, evidence indicates that From the aUniversity Hospital of Caen, Caen, France, bINSERM 744 Institut Pasteur de Lille, Lille, France, cUniversity Hospital of Clermont-Ferrand, Clermont-Ferrand, France, d University Hospital of Toulouse, Toulouse, France, ePoliclinica, Catholica University Hospital, the Sacred Heart, Roma, Italy and fINSERM U919, Cyceron, Caen, France. g For the SCIPION Investigators (Silent Cerebral Infarct and Percutaneous Cardiovascular InterventiON). See online Appendix for complete listing. NIH clinical trials registry: NCT00329979. Submitted January 21, 2012; accepted April 10, 2012. Reprint requests: Martial Hamon, MD, Recherche Clinique, Bureau 364, Centre Hospitalier
Universitaire de Caen, Avenue Côte de Nacre, 14033 Caen, Normandie, France. E-mail: [email protected] 0002-8703/$ - see front matter © 2012, Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2012.04.005
microembolism is related to cognitive impairment, based on the results of neuropsychological testing. 11 During cardiac catheterization, cerebral microembolism as detected by TCD has frequently been observed, but whether it is clinically relevant remains unknown. 7,9 However, recent studies mentioned above have suggested that some of these microemboli could be related to silent cerebral embolisms responsible for acute brain injury, as documented by DW MRI. 4 , 5-7 Nowadays, 2 vascular access sites are routinely used for percutaneous coronary intervention (PCI). Radial approach is associated with fewer local complications, 12-14 and it has been suggested that, in particular, right Radial approach avoiding to cross the aortic arch could reduce the risk of atherosclerotic plaque mobilization especially developed at this level of the aorta. 15,16 Based on these observations, we have conducted a prospective evaluation to look at the incidence of silent cerebral infarcts (SCIs) using serial DW-MRI in patients randomized either to radial or femoral access.
Methods Patients Patients with severe aortic stenosis scheduled for cardiac catheterization, because of aortic valve stenosis to assess coronary artery tree and aortic valve disease before surgery,
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have been prospectively and consecutively proposed to participate in the study. After informed consent was obtained, the patient was included. Exclusion criteria were a contraindication to MRI or inability to give written informed consent.
Study objectives and primary end point The study was designed as a prospective multicenter trial with the aim to assess the rate of DW-MRI-detected silent brain injury after cardiac catheterization and to determine if the use of Radial access, compared to Femoral, was associated with reduced risk of silent cerebral lesions. 17 The primary end point was the number of patients observed with new lesions after cardiac catheterization, as detected by DW-MRI between the 2 groups (Radial versus Femoral).
Cardiac catheterization All patients were examined clinically by a senior neurologist and assessed for any history of previous cerebral embolism. Transthoracic echocardiography, 12-lead surface electrocardiogram, and coronary angiography were performed for all patients. Cardiac catheterization was undertaken by expert interventional cardiologists using a standard Seldinger technique with 5F or 6F catheters and either by Radial or Femoral approach according to randomization assignment. All investigators were highly experimented in radial access (N70% of their procedures routinely performed by radial access during the past 3 years) and high volume operators (N300 procedures per year). Sheaths were removed immediately after the procedure in all patients. Unfractionated heparin (50 IU/kg) was recommended intravenously to all patients at the beginning of the procedure. Retrograde catheterization of the aortic valve was attempted in a right oblique projection using a long exchange guidewire (0.035 in, 260 cm length to ensure exchange of the pigtail catheter) with a left Amplatz 1 catheter or a right Judkins catheter. During attempts to cross the aortic valve, the wire was regularly withdrawn and cleaned and the catheter flushed every 2 minutes. When the pigtail catheter was placed in the left ventricle, the wire was withdrawn and the catheter vigorously aspirated and pressure measurements performed. After left ventriculography, the catheter was rapidly withdrawn from the left ventricle into the ascending aorta with simultaneous pressure measurements. Maximum and mean pressure gradients were calculated. The duration of the whole procedure and fluoroscopic time in all patients were also recorded.
Magnetic resonance imaging MRI was performed within 24 hours before and 48 hours after cardiac catheterization. MRI was performed with a 1.5 Tesla system (GE Health Care, Philips or Siemens). The imaging protocol included a DW single-shot spin echo echoplanar sequence acquired in the AP-PC plane with 24 contiguous sections (diffusion gradient b values of 0 and 1000 s/mm 2, repetition time TR 3000 to 6000 ms, echo time TE 74 to 120 ms, slice thickness 6 mm with no gap); fluid attenuated inversion recovery (FLAIR; TR/TE 8000 to 10000/120 to160 ms, TI 2200 ms); and T2-weighted turbo spin echo sequences (TR/TE 2000 to 3500/90 to 100 ms). For DW MRI, the diffusion gradients were successively and separately applied in three orthogonal directions. Trace images were then generated, and apparent diffusion coefficient maps, calculated. The offline image analysis was performed by an experimented neuroradiologist blinded
to the clinical data and the technical aspects of the angiographic cardiac procedure including the randomization. For analysis of DW-MRI (DICOM-CD provided by centers), the neuroradiologist was asked to visually determine the presence, size, number, and vascular distribution of any focal diffusion abnormalities (bright lesions) consistent with embolic lesions.
Transcranial Doppler substudy Transcranial Doppler studies for this work were performed in a subgroup of patients with the TCD 100M (Spencer Technologies, Seattle, WA), which calculates a power M-mode Doppler image concurrently with a single-gate spectrogram as previously described with a threshold of 2 MHz. 18 Microembolic signals present a unique signature or “track” in the power M-mode Doppler image, which defines them as representing emboli and facilitating exclusion of potential artifacts. High-power/highintensity, transient unidirectional signals corresponding to the definition of microembolic signature approved by the Consensus Committee of the 9th Cerebrovascular Hemodynamics Symposium were used for the analysis. 19 This analysis was performed offline by a single investigator independently, blinded to clinical and technical details of the procedure.
Statistical analysis Baseline characteristics of the study population are presented as counts and percents for categorical variables and as mean ± SD for continuous variables. The number of lesions in patients recruited has been estimated by the adjusted Wald interval at 95% in accordance with the method recommended by Agresti and Coull. 20 With small sample sizes, as recommended the midpoint of the adjusted Wald interval instead of the observed proportion was used. 21 The statistical analyses were performed using SPSS 10.0.7 program (Chicago, IL, USA). The multivariable model included all parameters with a p value less than 0.20 at univariable comparison (age, height, mean transaortic gradient and hypertension).
Sample size calculation Based on a recent publication, the Radial approach was supposed to be associated with a mean of 5.9% (95% CI, 0.01-12.5) of new lesions as detected by cerebral DW-MRI 21 in patients with aortic stenosis. In similar patients explored by Femoral approach, a 23% (95% CI, 15-31) rate of similar events was expected, as previously published. 22 With randomization 1:1, an α risk of 5% and a β risk of 20% a sample size population of 152 patients was needed to demonstrate the superiority of Radial approach associated with lower rates of SCIs compared to the conventional Femoral approach (76 patients in each arm of the study).
Randomization After informed consent signed, eligible patients were randomized 1:1 to a strategy of Radial or Femoral access, stratified by center. Randomization was performed at the catheterization laboratory before coronary angiography, by means of concealed envelopes prepared in blocks of 3 to 6 patients. No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this
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Figure 1
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Table I. Baseline characteristics of the study population (intention to treat comparison) Femoral group Radial group
Flow chart of the study population. MRI indicates, magnetic resonance imaging.
study, all study analyses, the drafting and editing of the manuscript, and its final contents.
Results A total of 165 patients were randomized to undergo left heart catheterization either by radial or femoral access. The flow chart of the study is given in Figure 1. Results are presented and analyzed by intention to treat. Among the 165 patients, 160 patients completed the protocol and were included in the final analysis: 77 to the femoral approach and 83 to the radial approach. Three patients randomized to the radial access were explored through the femoral approach (cross over) because of radial access failure. Those patients were analyzed in the radial group according to the intention to treat analysis previously mentioned. The baseline characteristics of the study population are described in Table I with no statistical difference between the two groups except for the number of catheters used which was superior in the femoral group. The primary end point of the trial, occurrence of cerebral infarct on DW-MRI after left heart catheterization, was similar in both groups with 15 patients found in the Radial group (14 per protocol) and 9 patients in the Femoral group (10 per protocol), thereby providing a mid point of the adjusted Wald interval of 18.8% for the Radial group (95% CI from 11.1% to 27.8%) and 12.7% for the Femoral group (95% CI from 6.1% to 21.0%) (Figure 2). Thus, postprocedural cerebral DW-MRI was found positive in 24 patients and 22 patients remained asymptomatic (91.6%), with no statistical difference between the incidence of cerebral infarcts observed in patients approached by the Radial access and those approached by Femoral access (12.5% vs 17.5%, P = .51 for per-protocol comparison). A periprocedural symptomatic cerebrovascular accident occurred in 2 patients
No of patients Age (y) Male (%) Smokers (%) BMI Weight (kg) Height (cm) Mean gradient (mmHg) LVEF (%) History of AF (%) History of CAD (%) History of stroke (%) Carotid Atherosclerosis (%) Hypertension (%) Hypercholesterolemia (%) Diabetes mellitus (%) Anticoagulation per catheter (%) Oral anticoagulation (%) Catheters used N3 (%) Use of 6F catheters (%) Crossing the aortic valve (%) Fluoroscopy time (mn) Procedure duration (mn)
P
77 73.4 ± 11.5 54.5 32.5 27.5 ± 4.7 76.2 ± 13.5 164 ± 8 45.8 ± 14.2 62.4 ± 12.4 22.1 11.7 3.9 24.7 75.3 46.8 36.4 76.3
83 75.5 ± 8.6 54.2 35.5 27.3 ± 4.9 74.9 ± 16.5 166 ± 8 47.9 ± 14.2 60.7 ± 12.5 16.9 12.0 4.8 19.3 78.3 54.2 27.7 88.0
.18 1.00 .99 .78 .61 .16 .36 .40 .43 1.00 1.00 .45 .71 .43 .31 .04
22.1 80.5 7.8 96.1 7.2 ± 5.6 25.3 ± 12.8
19.3 62.7 9.6 91.6 7.8 ± 4.4 24.7 ± 13.3
.92 .01 .68 .33 .49 .82
Figure 2
Percent of cerebral infarct detected by DW-MRI and their 95% CI, in the Radial access (Radial) and Femoral access (Femoral) groups of patients according to the intention to treat analysis (following the randomization plan whatever the access site finally used) and the per protocol analysis (taking in account the cross over rates: patients randomized to the Radial access and who effectively underwent left heart catheterization by the Femoral access).
whereas in the remaining patients no neurological symptoms were evident after the procedure. The univariate analysis is shown in Table II comparing patients with or without new cerebral infarct on DW-MRI.
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Table II. Comparison of clinical and procedural parameters in patients with SCI and without SCI (univariate analysis) SCI No. of patients Mean age, y Smokers (%) Male gender (%) BMI Weight (kg) Height (m) Height N1.68 m (%) Mean transaortic gradient (mmHg) LVEF (%) History of AF (%) Previous CAD disease (%) Previous stroke (%) Carotid Atherosclerosis (%) Hypertension (%) Hypercholesterolemia (%) Diabetes mellitus BMI N30 CAD on angiography Number of catheters used N3 Use of 6F catheters (%) Crossing the aortic valve (%) Fluoroscopy time (mn) Procedure duration (mn)
No SCI
P
24 77.6 ± 6.7 20.8 50.0 27.5 ± 4.5 72.0 ± 13.1 1.70 ± 0.08 75.0 41.3 ± 15.1
136 73.9 ± 10.5 34.5 55.1 27.3 ± 4.8 76.1 ± 13.4 1.65 ± 0.08 33.1 47.8 ± 13.8
.10 .19 .66 .84 .22 .002 b.001 .04
59.3 ± 15.9 29.2 12.5 0.0 25.0 58.3 41.7 25.0 33.3 50.0 75.0 4.2 95.8 8.7 ± 4.7 25.3 ± 11.7
61.9 ± 11.8 17.6 11.8 5.1 21.3 80.1 52.2 33.1 25.7 47.8 70.6 9.6 93.4 7.3 ± 5.0 24.9 ± 13
.45 .26 1.00 .38 .79 .03 .38 .48 .46 1.00 .81 .64 1.00 .23 .88
AF indicates Atrial fibrillation; BMI, body mass index; CAD, coronary artery disease.
In a substudy analysis, acute cognitive impairment was assessed in 69 individuals comparing pre and post mini mental state examination score in patients with SCI (n = 13) or without (n = 56) and no difference was detected between the 2 groups of patients (not shown, P = .88). Transcranial Doppler assessment looking at per-procedural number of high-intensity transient signals (HITS) indicated similar figures either by Radial access (56.2 ± 36.4 HITS per procedure, n = 6) or Femoral access (52.7 ± 21.7 HITS per procedure, n = 15) (P = .87), and no significant difference between the 3 patients found with positive DW-MRI post catheterization and the 18 patients with normal cerebral DW-MRI (61.3 ± 20.6 HITS vs 52.4 ± 26.8 HITS, respectively P = .59). At multivariate analysis, only the higher height of the patient (OR, 8.24; 95% CI, 2.71-25.02; P b .0001) and a lower transvalvular gradient (OR, 0.96; 95% CI, 0.93-0.99; P = .027) were associated with an increased risk of periprocedural cerebral thromboembolism as detected by DW-MRI.
Discussion The present prospective multicentre trial shows that in patients with aortic stenosis undergoing left heart catheterization, silent cerebral infarction is frequent and its occurrence is not affected by the selection of Radial or Femoral arterial access. To our knowledge, only single-
center and small studies have reported the occurrence of silent cerebral infarction following percutaneous coronary intervention and left heart catheterization. Based on previous observational data, access site selection was suggested to be relevant in influencing the occurrence of SCI. 4,15 Yet, as an incomplete Radial approach, learning curve may have influenced retrospective studies and, on the contrary, Radial approach may be associated to modified pattern of catheter frictions against the aortic arch, we designed the present study with the specific aim to investigate the possible advantage of Radial over Femoral approach in reducing silent cerebral embolism. The fact that Radial access was associated in some observational studies with lower rates of SCI compared to Femoral access can be explained by the systematic use of heparin when Radial access is used, which is rarely the case by Femoral access. In the present study, the systematic use of heparin in both arms of our randomized trial may have erased this confounding factor. We confirm that symptomatic cerebral embolism represent only the tip of the iceberg and that the incidence of DW-MRI documented cerebral infarcts was far more important and completely underestimated by clinicians. Because those SCIs have been shown to be associated with an increase incidence of symptomatic stroke, cognitive impairment, and dementia, 22 all efforts to recognize and to limit such lesion are warranted in the future. Periprocedural cerebrovascular accidents in diagnosis and therapeutic coronary interventions and left heart catheterization may be caused by multiple factors including: thrombus formation on catheters or inside catheters, thrombus on exchange wires, air embolism, and scraping debris from atheroma plaques within vessels or aorta during catheter progression or manipulation. 23-26 The fact, that symptomatic ischemic stroke occurring during PCI have been shown to be successfully treated either by thrombolysis or sometimes with some mechanical intervention may suggest a potential dominant thrombotic composition. 27-30 Material-induced contact activation can generate thrombin activation as tissue factor and fuels thrombosis. 31 Catheters or guidewires can therefore promote thrombus formation through thrombin activation and justifies either unfractionated heparin or direct thrombin inhibitor use to avoid catheter thrombosis in PCI. The overall incidence of this complication is largely unknown because it is underreported in contemporary trials of coronary intervention but might be influenced by several factors including local thromboinflammatory factors, physicochemical properties of the catheter surface, blood flow and shear stress, contrast agents, remote cellular and coagulation activation, the procedural time and the length of catheter in contact with blood. In this perspective, the height of the patient related to the length of catheter in contact with the blood stream may explained the increased risk of SCI
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among the tallest patients in our study. Indeed, as previously mentioned, catheter thrombosis is likely to be underestimated in routine and might explain the higher rate of ischemic injury when the procedures are longer. The development of new devices to protect the cerebral arteries for example in Transcatheter aorticvalve implantation where SCI have been shown to be present up to 72 to 80% of cases may serve to identify the nature of embolic materials in future assessment. 32,33 An unexpected finding was that a lower transvalvular gradient was associated with an increased risk of SCI. However, it has been demonstrated that coagulation modifications exist in the most severe aortic stenosis patients, presenting an increased risk for bleeding, namely during surgical valve replacement. 34 Therefore, primary hemostatic abnormalities may explain the relative lower risk of thromboembolic lesions observed in patients with the most severe transvalvular gradient. 34 Among the issues raised by our results, we can mention the need to inform patients and the cardiac surgeon if surgery is retained. Indeed especially in the elderly further heart catheterization can be required and if cardiac surgery requiring anticoagulation is performed, recent SCI might increase the risk of symptomatic stroke or hemorrhagic transformation. Postponing cardiac surgery and allowing recent SCIs to heal should be considered and requires further attention in future studies. On the other hand, the use of cerebral DW-MRI can also be used as a surrogate marker looking for improvements in the pharmacological environment or the technical aspects of PCI in reducing ischemic complications. 35,36
Limitations We have no midterm follow-up of the cerebral lesions allowing assessment of the evolution of those SCI. Furthermore the potential deleterious clinical impact regarding cognitive impairment or occurrence of symptomatic stroke in rather an older population remains to be determined. Because the incidence of cerebral infarcts were higher than expected in the radial arm and lower in the femoral arm, the study was underpowered. We cannot exclude a difference that came up to be potentially in favor of the Femoral approach and against our initial hypothesis, but the wide confident intervals largely overlapping between the 2 access sites are quite reassuring. However, we cannot exclude that radial access might potentially increase the rate of SCIs in patients with aortic stenosis. Refraining to cross systematically the valve is recommended in routine even for experimented and high volume operators. Larger studies are warranted to further determine the respective impact of radial versus femoral access site on the incidence of SCIs in patient who undergo standard coronary angiography or PCI.
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Conclusions Left heart catheterization in patients with severe valvular aortic stenosis carries a low risk of symptomatic cerebral ischemia but a substantial risk of cerebral embolism responsible for silent cerebral infarction as detected on DW-MRI. The impact of the arterial access site on this phenomenon seems to be unlikely. Among the independent predictors of SCIs we found the higher height of the patient and a lower transvalvular gradient. Larger trials will need to establish the clinical impact of asymptomatic cerebral ischemic lesions as well as the rate of embolization to other peripheral organs, like kidneys and bowels and their respective impact on patients' outcomes. Further studies are required to analyze this phenomenon and the relative impact of more effective antithrombotic agents or new filters able to reduce silent cerebral embolism during left heart catheterization and percutaneous cardiovascular interventions. 37
Disclosures The authors have no disclosure to declare regarding the present study. Competing interest: none.
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25. Braekken SK, Endresen K, Russel D, et al. Influence of guidewire and catheter type on the frequency of cerebral microembolic signals during left heart catheterization. Am J Cardiol 1998;82: 632-7. 26. Keeley EC, Grines CL. Scraping of aortic debris by coronary guiding catheters: a prospective evaluation of 1000 cases. J Am Coll Cardiol 1998;32:1861-5. 27. Zaidat OO, Slivka AP, Mohammad Y, et al. Intra arterial thrombolytic therapy in pericoronary angiography ischemic stroke. Stroke 2005; 36:1083-4. 28. Khatri P, Taylor RA, Palumbo V, et al. The safety and efficacy of thrombolysis for strokes after cardiac catheterization. J Am Coll Cardiol 2008;51:906-11. 29. Arnold M, Fischer U, Schroth G, et al. Intra-arterial thrombolysis of acute iatrogenic intracranial arterial occlusion attributable to neuroendovascular procedures or coronary angiography. Stroke 2008;39:1491-5. 30. Al-Mubarek N, Vitek JJ, Mousa I, et al. Immediate catheter-based neurovascular rescue for acute stroke complicating coronary procedures. Am J Cardiol 2002;90:173-6. 31. Chan My, Weitz JL, Merhi Y, et al. Catheter thrombosis and percutaneous coronary intervention: fundamental perspectives on blood, artificial surfaces and antithrombotic drugs. T Thromb Thrombolysis 2009;28:366-80. 32. Ghanem A, Müller A, Nähle CP, et al. Risk and fate of cerebral embolism after transfemoral aortic valve implantation. A prospective pilot study with diffusion-weighted magnetic resonance imaging. J Am Coll Cardiol 2010;57:18-28. 33. Kahlert P, Knipp SC, Schlamann M, et al. Silent and apparent cerebral ischemia after percutaneous transfemoral aortic valve implantation: a diffusion-weighted magnetic resonance imaging study. Circulation 2010;121:870-8. 34. Vincentelli A, Susen S, Le Tourneau T, et al. Acquired von Willebrand syndrome in aortic stenosis. N Engl J Med 2003;349:343-9. 35. Biondi A, Oppenheim C, Vivas E, et al. Cerebral aneurysms treated by Guglielmi detachable coils: Evaluation with diffusion-weighted MR Imaging. Am J Neuroradiol 2000;21:957-63. 36. Markus HS, Droste DW, Kaps M, et al. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using doppler embolic signal detection : the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial. Circulation 2005;111:2233-40. 37. Nietlispach F, Wijesinghe N, Gurvitch R, et al. An embolic deflection device for aortic valve interventions. JACC Cardiovasc Interv 2010;3: 1133-8.
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Appendix The SCIPION Investigators: Martial Hamon, Marie-rose Clergeau, Sophie Gomes, Eric Saloux, Fausto Viader, Michèle Hamon, Guillaume Coutance, Remi Sabatier, Therese Lognone, Rémy Morello, University Hospital of Caen, France; Janusz Lipiecki, Nicolas Boudou, Béatrice Claise, University Hospital of Clermont Ferrand, France; Francesco Burzotta, Cesare Colosimo, Carlo Trani, The Policlinica, Catholica University Hospital, the Sacred Heart, Roma, Italy; Didier Carrié, Nicolas Dumonteil, Nicolas Durel, University Hospital of Toulouse, France.
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Silent cerebral infarcts after cardiac catheterization: A randomized comparison of radial and femoral approaches Martial Hamon, MD, a,b,g Janusz Lipiecki c,g Didier Carrié d,g Francesco Burzotta e,g Nicolas Durel c,g Guillaume Coutance a,g Nicolas Boudou d,g Cesare Colosimo e,g Carlo Trani e,g Nicolas Dumonteil d,g Rémy Morello a,g Fausto Viader a,g Béatrice Claise c,g and Michèle Hamon a,f,g Caen, Lille, Clermont-Ferrand, and Toulouse, France; and Roma, Italy
Background Single center studies using serial cerebral diffusion-weighted magnetic resonance imaging in patients having cardiac catheterization have suggested that cerebral microembolism might be responsible for silent cerebral infarct (SCI) as high as 15% to 22%. We evaluated in a multicenter trial the incidence of SCIs after cardiac catheterization and whether or not the choice of the arterial access site might impact this phenomenon. Methods and Results Patients were randomized to have cardiac catheterization either by Radial (n = 83) or Femoral (n = 77) arterial approaches by experimented operators. The main outcome measure was the occurrence of new cerebral infarct on serial diffusion-weighted magnetic resonance imaging. Patient and catheterization characteristics, including duration of catheterization, were similar in both groups. The risk of SCI did not differ significantly between the Femoral and Radial groups (incidence of 11.7% versus 17.5%; OR, 0.85; 95% CI, 0.62-1.16; P = .31). At multivariable analysis, the independent predictors of SCI were the patient's higher height and lower transvalvular gradient. Conclusions The high rate of SCI after cardiac catheterization of patients with aortic stenosis was confirmed, but its occurrence was not affected by the selection of Radial and Femoral access. (Am Heart J 2012;164:449-454.e1.) Acute symptomatic cerebral infarction following cardiac catheterization and percutaneous cardiovascular interventions is rare, 1-3 but unperceived asymptomatic cerebral injury could occur at an unexpectedly high rate 4-6 as detected by diffusion-weighted (DW) magnetic resonance imaging (MRI). Indeed, the high sensitivity of DW MRI suggests that this technique could allow an improved estimate of cerebral ischemic events associated with cardiovascular-catheter procedures. 7 The use of transcranial Doppler (TCD) sonography has confirmed the recording of systematic microemboli entering the middle cerebral artery during various endovascular interventions, including cardiac catheterization. 6,8-10 In the case of coronary bypass surgery, evidence indicates that From the aUniversity Hospital of Caen, Caen, France, bINSERM 744 Institut Pasteur de Lille, Lille, France, cUniversity Hospital of Clermont-Ferrand, Clermont-Ferrand, France, d University Hospital of Toulouse, Toulouse, France, ePoliclinica, Catholica University Hospital, the Sacred Heart, Roma, Italy and fINSERM U919, Cyceron, Caen, France. g For the SCIPION Investigators (Silent Cerebral Infarct and Percutaneous Cardiovascular InterventiON). See online Appendix for complete listing. NIH clinical trials registry: NCT00329979. Submitted January 21, 2012; accepted April 10, 2012. Reprint requests: Martial Hamon, MD, Recherche Clinique, Bureau 364, Centre Hospitalier
Universitaire de Caen, Avenue Côte de Nacre, 14033 Caen, Normandie, France. E-mail: [email protected] 0002-8703/$ - see front matter © 2012, Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2012.04.005
microembolism is related to cognitive impairment, based on the results of neuropsychological testing. 11 During cardiac catheterization, cerebral microembolism as detected by TCD has frequently been observed, but whether it is clinically relevant remains unknown. 7,9 However, recent studies mentioned above have suggested that some of these microemboli could be related to silent cerebral embolisms responsible for acute brain injury, as documented by DW MRI. 4 , 5-7 Nowadays, 2 vascular access sites are routinely used for percutaneous coronary intervention (PCI). Radial approach is associated with fewer local complications, 12-14 and it has been suggested that, in particular, right Radial approach avoiding to cross the aortic arch could reduce the risk of atherosclerotic plaque mobilization especially developed at this level of the aorta. 15,16 Based on these observations, we have conducted a prospective evaluation to look at the incidence of silent cerebral infarcts (SCIs) using serial DW-MRI in patients randomized either to radial or femoral access.
Methods Patients Patients with severe aortic stenosis scheduled for cardiac catheterization, because of aortic valve stenosis to assess coronary artery tree and aortic valve disease before surgery,
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have been prospectively and consecutively proposed to participate in the study. After informed consent was obtained, the patient was included. Exclusion criteria were a contraindication to MRI or inability to give written informed consent.
Study objectives and primary end point The study was designed as a prospective multicenter trial with the aim to assess the rate of DW-MRI-detected silent brain injury after cardiac catheterization and to determine if the use of Radial access, compared to Femoral, was associated with reduced risk of silent cerebral lesions. 17 The primary end point was the number of patients observed with new lesions after cardiac catheterization, as detected by DW-MRI between the 2 groups (Radial versus Femoral).
Cardiac catheterization All patients were examined clinically by a senior neurologist and assessed for any history of previous cerebral embolism. Transthoracic echocardiography, 12-lead surface electrocardiogram, and coronary angiography were performed for all patients. Cardiac catheterization was undertaken by expert interventional cardiologists using a standard Seldinger technique with 5F or 6F catheters and either by Radial or Femoral approach according to randomization assignment. All investigators were highly experimented in radial access (N70% of their procedures routinely performed by radial access during the past 3 years) and high volume operators (N300 procedures per year). Sheaths were removed immediately after the procedure in all patients. Unfractionated heparin (50 IU/kg) was recommended intravenously to all patients at the beginning of the procedure. Retrograde catheterization of the aortic valve was attempted in a right oblique projection using a long exchange guidewire (0.035 in, 260 cm length to ensure exchange of the pigtail catheter) with a left Amplatz 1 catheter or a right Judkins catheter. During attempts to cross the aortic valve, the wire was regularly withdrawn and cleaned and the catheter flushed every 2 minutes. When the pigtail catheter was placed in the left ventricle, the wire was withdrawn and the catheter vigorously aspirated and pressure measurements performed. After left ventriculography, the catheter was rapidly withdrawn from the left ventricle into the ascending aorta with simultaneous pressure measurements. Maximum and mean pressure gradients were calculated. The duration of the whole procedure and fluoroscopic time in all patients were also recorded.
Magnetic resonance imaging MRI was performed within 24 hours before and 48 hours after cardiac catheterization. MRI was performed with a 1.5 Tesla system (GE Health Care, Philips or Siemens). The imaging protocol included a DW single-shot spin echo echoplanar sequence acquired in the AP-PC plane with 24 contiguous sections (diffusion gradient b values of 0 and 1000 s/mm 2, repetition time TR 3000 to 6000 ms, echo time TE 74 to 120 ms, slice thickness 6 mm with no gap); fluid attenuated inversion recovery (FLAIR; TR/TE 8000 to 10000/120 to160 ms, TI 2200 ms); and T2-weighted turbo spin echo sequences (TR/TE 2000 to 3500/90 to 100 ms). For DW MRI, the diffusion gradients were successively and separately applied in three orthogonal directions. Trace images were then generated, and apparent diffusion coefficient maps, calculated. The offline image analysis was performed by an experimented neuroradiologist blinded
to the clinical data and the technical aspects of the angiographic cardiac procedure including the randomization. For analysis of DW-MRI (DICOM-CD provided by centers), the neuroradiologist was asked to visually determine the presence, size, number, and vascular distribution of any focal diffusion abnormalities (bright lesions) consistent with embolic lesions.
Transcranial Doppler substudy Transcranial Doppler studies for this work were performed in a subgroup of patients with the TCD 100M (Spencer Technologies, Seattle, WA), which calculates a power M-mode Doppler image concurrently with a single-gate spectrogram as previously described with a threshold of 2 MHz. 18 Microembolic signals present a unique signature or “track” in the power M-mode Doppler image, which defines them as representing emboli and facilitating exclusion of potential artifacts. High-power/highintensity, transient unidirectional signals corresponding to the definition of microembolic signature approved by the Consensus Committee of the 9th Cerebrovascular Hemodynamics Symposium were used for the analysis. 19 This analysis was performed offline by a single investigator independently, blinded to clinical and technical details of the procedure.
Statistical analysis Baseline characteristics of the study population are presented as counts and percents for categorical variables and as mean ± SD for continuous variables. The number of lesions in patients recruited has been estimated by the adjusted Wald interval at 95% in accordance with the method recommended by Agresti and Coull. 20 With small sample sizes, as recommended the midpoint of the adjusted Wald interval instead of the observed proportion was used. 21 The statistical analyses were performed using SPSS 10.0.7 program (Chicago, IL, USA). The multivariable model included all parameters with a p value less than 0.20 at univariable comparison (age, height, mean transaortic gradient and hypertension).
Sample size calculation Based on a recent publication, the Radial approach was supposed to be associated with a mean of 5.9% (95% CI, 0.01-12.5) of new lesions as detected by cerebral DW-MRI 21 in patients with aortic stenosis. In similar patients explored by Femoral approach, a 23% (95% CI, 15-31) rate of similar events was expected, as previously published. 22 With randomization 1:1, an α risk of 5% and a β risk of 20% a sample size population of 152 patients was needed to demonstrate the superiority of Radial approach associated with lower rates of SCIs compared to the conventional Femoral approach (76 patients in each arm of the study).
Randomization After informed consent signed, eligible patients were randomized 1:1 to a strategy of Radial or Femoral access, stratified by center. Randomization was performed at the catheterization laboratory before coronary angiography, by means of concealed envelopes prepared in blocks of 3 to 6 patients. No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this
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Figure 1
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Table I. Baseline characteristics of the study population (intention to treat comparison) Femoral group Radial group
Flow chart of the study population. MRI indicates, magnetic resonance imaging.
study, all study analyses, the drafting and editing of the manuscript, and its final contents.
Results A total of 165 patients were randomized to undergo left heart catheterization either by radial or femoral access. The flow chart of the study is given in Figure 1. Results are presented and analyzed by intention to treat. Among the 165 patients, 160 patients completed the protocol and were included in the final analysis: 77 to the femoral approach and 83 to the radial approach. Three patients randomized to the radial access were explored through the femoral approach (cross over) because of radial access failure. Those patients were analyzed in the radial group according to the intention to treat analysis previously mentioned. The baseline characteristics of the study population are described in Table I with no statistical difference between the two groups except for the number of catheters used which was superior in the femoral group. The primary end point of the trial, occurrence of cerebral infarct on DW-MRI after left heart catheterization, was similar in both groups with 15 patients found in the Radial group (14 per protocol) and 9 patients in the Femoral group (10 per protocol), thereby providing a mid point of the adjusted Wald interval of 18.8% for the Radial group (95% CI from 11.1% to 27.8%) and 12.7% for the Femoral group (95% CI from 6.1% to 21.0%) (Figure 2). Thus, postprocedural cerebral DW-MRI was found positive in 24 patients and 22 patients remained asymptomatic (91.6%), with no statistical difference between the incidence of cerebral infarcts observed in patients approached by the Radial access and those approached by Femoral access (12.5% vs 17.5%, P = .51 for per-protocol comparison). A periprocedural symptomatic cerebrovascular accident occurred in 2 patients
No of patients Age (y) Male (%) Smokers (%) BMI Weight (kg) Height (cm) Mean gradient (mmHg) LVEF (%) History of AF (%) History of CAD (%) History of stroke (%) Carotid Atherosclerosis (%) Hypertension (%) Hypercholesterolemia (%) Diabetes mellitus (%) Anticoagulation per catheter (%) Oral anticoagulation (%) Catheters used N3 (%) Use of 6F catheters (%) Crossing the aortic valve (%) Fluoroscopy time (mn) Procedure duration (mn)
P
77 73.4 ± 11.5 54.5 32.5 27.5 ± 4.7 76.2 ± 13.5 164 ± 8 45.8 ± 14.2 62.4 ± 12.4 22.1 11.7 3.9 24.7 75.3 46.8 36.4 76.3
83 75.5 ± 8.6 54.2 35.5 27.3 ± 4.9 74.9 ± 16.5 166 ± 8 47.9 ± 14.2 60.7 ± 12.5 16.9 12.0 4.8 19.3 78.3 54.2 27.7 88.0
.18 1.00 .99 .78 .61 .16 .36 .40 .43 1.00 1.00 .45 .71 .43 .31 .04
22.1 80.5 7.8 96.1 7.2 ± 5.6 25.3 ± 12.8
19.3 62.7 9.6 91.6 7.8 ± 4.4 24.7 ± 13.3
.92 .01 .68 .33 .49 .82
Figure 2
Percent of cerebral infarct detected by DW-MRI and their 95% CI, in the Radial access (Radial) and Femoral access (Femoral) groups of patients according to the intention to treat analysis (following the randomization plan whatever the access site finally used) and the per protocol analysis (taking in account the cross over rates: patients randomized to the Radial access and who effectively underwent left heart catheterization by the Femoral access).
whereas in the remaining patients no neurological symptoms were evident after the procedure. The univariate analysis is shown in Table II comparing patients with or without new cerebral infarct on DW-MRI.
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Table II. Comparison of clinical and procedural parameters in patients with SCI and without SCI (univariate analysis) SCI No. of patients Mean age, y Smokers (%) Male gender (%) BMI Weight (kg) Height (m) Height N1.68 m (%) Mean transaortic gradient (mmHg) LVEF (%) History of AF (%) Previous CAD disease (%) Previous stroke (%) Carotid Atherosclerosis (%) Hypertension (%) Hypercholesterolemia (%) Diabetes mellitus BMI N30 CAD on angiography Number of catheters used N3 Use of 6F catheters (%) Crossing the aortic valve (%) Fluoroscopy time (mn) Procedure duration (mn)
No SCI
P
24 77.6 ± 6.7 20.8 50.0 27.5 ± 4.5 72.0 ± 13.1 1.70 ± 0.08 75.0 41.3 ± 15.1
136 73.9 ± 10.5 34.5 55.1 27.3 ± 4.8 76.1 ± 13.4 1.65 ± 0.08 33.1 47.8 ± 13.8
.10 .19 .66 .84 .22 .002 b.001 .04
59.3 ± 15.9 29.2 12.5 0.0 25.0 58.3 41.7 25.0 33.3 50.0 75.0 4.2 95.8 8.7 ± 4.7 25.3 ± 11.7
61.9 ± 11.8 17.6 11.8 5.1 21.3 80.1 52.2 33.1 25.7 47.8 70.6 9.6 93.4 7.3 ± 5.0 24.9 ± 13
.45 .26 1.00 .38 .79 .03 .38 .48 .46 1.00 .81 .64 1.00 .23 .88
AF indicates Atrial fibrillation; BMI, body mass index; CAD, coronary artery disease.
In a substudy analysis, acute cognitive impairment was assessed in 69 individuals comparing pre and post mini mental state examination score in patients with SCI (n = 13) or without (n = 56) and no difference was detected between the 2 groups of patients (not shown, P = .88). Transcranial Doppler assessment looking at per-procedural number of high-intensity transient signals (HITS) indicated similar figures either by Radial access (56.2 ± 36.4 HITS per procedure, n = 6) or Femoral access (52.7 ± 21.7 HITS per procedure, n = 15) (P = .87), and no significant difference between the 3 patients found with positive DW-MRI post catheterization and the 18 patients with normal cerebral DW-MRI (61.3 ± 20.6 HITS vs 52.4 ± 26.8 HITS, respectively P = .59). At multivariate analysis, only the higher height of the patient (OR, 8.24; 95% CI, 2.71-25.02; P b .0001) and a lower transvalvular gradient (OR, 0.96; 95% CI, 0.93-0.99; P = .027) were associated with an increased risk of periprocedural cerebral thromboembolism as detected by DW-MRI.
Discussion The present prospective multicentre trial shows that in patients with aortic stenosis undergoing left heart catheterization, silent cerebral infarction is frequent and its occurrence is not affected by the selection of Radial or Femoral arterial access. To our knowledge, only single-
center and small studies have reported the occurrence of silent cerebral infarction following percutaneous coronary intervention and left heart catheterization. Based on previous observational data, access site selection was suggested to be relevant in influencing the occurrence of SCI. 4,15 Yet, as an incomplete Radial approach, learning curve may have influenced retrospective studies and, on the contrary, Radial approach may be associated to modified pattern of catheter frictions against the aortic arch, we designed the present study with the specific aim to investigate the possible advantage of Radial over Femoral approach in reducing silent cerebral embolism. The fact that Radial access was associated in some observational studies with lower rates of SCI compared to Femoral access can be explained by the systematic use of heparin when Radial access is used, which is rarely the case by Femoral access. In the present study, the systematic use of heparin in both arms of our randomized trial may have erased this confounding factor. We confirm that symptomatic cerebral embolism represent only the tip of the iceberg and that the incidence of DW-MRI documented cerebral infarcts was far more important and completely underestimated by clinicians. Because those SCIs have been shown to be associated with an increase incidence of symptomatic stroke, cognitive impairment, and dementia, 22 all efforts to recognize and to limit such lesion are warranted in the future. Periprocedural cerebrovascular accidents in diagnosis and therapeutic coronary interventions and left heart catheterization may be caused by multiple factors including: thrombus formation on catheters or inside catheters, thrombus on exchange wires, air embolism, and scraping debris from atheroma plaques within vessels or aorta during catheter progression or manipulation. 23-26 The fact, that symptomatic ischemic stroke occurring during PCI have been shown to be successfully treated either by thrombolysis or sometimes with some mechanical intervention may suggest a potential dominant thrombotic composition. 27-30 Material-induced contact activation can generate thrombin activation as tissue factor and fuels thrombosis. 31 Catheters or guidewires can therefore promote thrombus formation through thrombin activation and justifies either unfractionated heparin or direct thrombin inhibitor use to avoid catheter thrombosis in PCI. The overall incidence of this complication is largely unknown because it is underreported in contemporary trials of coronary intervention but might be influenced by several factors including local thromboinflammatory factors, physicochemical properties of the catheter surface, blood flow and shear stress, contrast agents, remote cellular and coagulation activation, the procedural time and the length of catheter in contact with blood. In this perspective, the height of the patient related to the length of catheter in contact with the blood stream may explained the increased risk of SCI
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among the tallest patients in our study. Indeed, as previously mentioned, catheter thrombosis is likely to be underestimated in routine and might explain the higher rate of ischemic injury when the procedures are longer. The development of new devices to protect the cerebral arteries for example in Transcatheter aorticvalve implantation where SCI have been shown to be present up to 72 to 80% of cases may serve to identify the nature of embolic materials in future assessment. 32,33 An unexpected finding was that a lower transvalvular gradient was associated with an increased risk of SCI. However, it has been demonstrated that coagulation modifications exist in the most severe aortic stenosis patients, presenting an increased risk for bleeding, namely during surgical valve replacement. 34 Therefore, primary hemostatic abnormalities may explain the relative lower risk of thromboembolic lesions observed in patients with the most severe transvalvular gradient. 34 Among the issues raised by our results, we can mention the need to inform patients and the cardiac surgeon if surgery is retained. Indeed especially in the elderly further heart catheterization can be required and if cardiac surgery requiring anticoagulation is performed, recent SCI might increase the risk of symptomatic stroke or hemorrhagic transformation. Postponing cardiac surgery and allowing recent SCIs to heal should be considered and requires further attention in future studies. On the other hand, the use of cerebral DW-MRI can also be used as a surrogate marker looking for improvements in the pharmacological environment or the technical aspects of PCI in reducing ischemic complications. 35,36
Limitations We have no midterm follow-up of the cerebral lesions allowing assessment of the evolution of those SCI. Furthermore the potential deleterious clinical impact regarding cognitive impairment or occurrence of symptomatic stroke in rather an older population remains to be determined. Because the incidence of cerebral infarcts were higher than expected in the radial arm and lower in the femoral arm, the study was underpowered. We cannot exclude a difference that came up to be potentially in favor of the Femoral approach and against our initial hypothesis, but the wide confident intervals largely overlapping between the 2 access sites are quite reassuring. However, we cannot exclude that radial access might potentially increase the rate of SCIs in patients with aortic stenosis. Refraining to cross systematically the valve is recommended in routine even for experimented and high volume operators. Larger studies are warranted to further determine the respective impact of radial versus femoral access site on the incidence of SCIs in patient who undergo standard coronary angiography or PCI.
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Conclusions Left heart catheterization in patients with severe valvular aortic stenosis carries a low risk of symptomatic cerebral ischemia but a substantial risk of cerebral embolism responsible for silent cerebral infarction as detected on DW-MRI. The impact of the arterial access site on this phenomenon seems to be unlikely. Among the independent predictors of SCIs we found the higher height of the patient and a lower transvalvular gradient. Larger trials will need to establish the clinical impact of asymptomatic cerebral ischemic lesions as well as the rate of embolization to other peripheral organs, like kidneys and bowels and their respective impact on patients' outcomes. Further studies are required to analyze this phenomenon and the relative impact of more effective antithrombotic agents or new filters able to reduce silent cerebral embolism during left heart catheterization and percutaneous cardiovascular interventions. 37
Disclosures The authors have no disclosure to declare regarding the present study. Competing interest: none.
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Appendix The SCIPION Investigators: Martial Hamon, Marie-rose Clergeau, Sophie Gomes, Eric Saloux, Fausto Viader, Michèle Hamon, Guillaume Coutance, Remi Sabatier, Therese Lognone, Rémy Morello, University Hospital of Caen, France; Janusz Lipiecki, Nicolas Boudou, Béatrice Claise, University Hospital of Clermont Ferrand, France; Francesco Burzotta, Cesare Colosimo, Carlo Trani, The Policlinica, Catholica University Hospital, the Sacred Heart, Roma, Italy; Didier Carrié, Nicolas Dumonteil, Nicolas Durel, University Hospital of Toulouse, France.
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