Accepted Manuscript

Therapeutic outcomes and thromboembolic events after treatment of acute arterialthromboembolism of the upper extremity

Hyung-Kee Kim , Heekyung Jung , Jayun Cho , Seung Huh , Jong-Min Lee , Young-Wook Kim

PII: S0890-5096(14)00611-6

DOI: 10.1016/j.avsg.2014.08.022

Reference: AVSG 2169

To appear in: Annals of Vascular Surgery

Received Date: 9 March 2014

Revised Date: 4 June 2014

Accepted Date: 21 August 2014

Please cite this article as: Kim HK, Jung H, Cho J, Huh S, Lee JM, Kim YW, Therapeutic outcomes andthromboembolic events after treatment of acute arterial thromboembolism of the upper extremity, Annalsof Vascular Surgery (2014), doi: 10.1016/j.avsg.2014.08.022.

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Therapeutic outcomes and thromboembolic events after treatment of acute arterial 1

thromboembolism of the upper extremity 2

3

Hyung-Kee Kima, Heekyung Junga, Jayun Choa, Seung Huha, Jong-Min Leeb, 4

Young-Wook Kimc 5

6

aDivision of Vascular Surgery, Department of Surgery, bDepartment of Radiology, 7

Kyungpook National University School of Medicine, Daegu, cDivision of Vascular Surgery, 8

Cardiac and Vascular Center, Samsung Medical Center, Sungkyunkwan University School of 9

Medicine, Seoul, South Korea. 10

11

12

*Corresponding author: 13

Seung Huh, M.D., Ph.D., Professor 14

Division of Vascular Surgery, Department of Surgery 15

Kyungpook National University School of Medicine 16

130, Dongduk-ro, Jung-gu, Daegu, 700-721, South Korea 17

Phone: +82-53-420-6520 18

Fax: +82-53-421-0510 19

E-mail address: shuh@knu.ac.kr 20

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Article type: Original Article 22

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Running title: Therapeutic outcomes after thromboembolism of arm 24

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Abstract 25

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Background: To investigate short- and long-term outcomes of patients with acute arterial 27

thromboembolism of upper extremity, focusing on postoperative thromboembolic events by 28

etiology. 29

Methods: Hospital records of 53 patients (average age, 70 years; males, 49%) with acute 30

arterial thromboembolism of upper extremity treated between June, 1993 and December, 31

2013 were retrospectively reviewed, evaluating patient characteristics and clinical outcomes, 32

both short- and long-term. Subjects were stratified as those with (group I, 34) and without 33

(group II, 19) atrial fibrillation as underlying cause. 34

Results: Two patients received anticoagulation alone as conservative treatment. The 35

remainder (n=51) underwent surgical revascularization. Symptoms resolved in 51 patients 36

(96%) except 2 patients with postoperative re-occlusion, and there was no need of amputation 37

in all patients. Overall inpatient mortality was 5.6% (3/53). Patients of group I suffered most 38

of the recurrent thromboembolic events (group I: 17 events, 14 patients; group II: 2 events, 2 39

patients) recorded during follow-up (mean duration, 56.8±62.2 months). Respective event-40

free survival rates at 1 year, 3 years, and 5 years differed significantly by group: 77%, 44%, 41

and 44% for group I; 100%, 100%, and 83% for group II (p=0.004). Among 14 patients with 42

recurrent embolic events in group I, half of patients were not receiving anticoagulants, 43

however, anticoagulant cessation was generally arbitrary. Overall survival rates at 1 year, 3 44

years, and 5 years were 82%, 69%, and 52% for group I and 84%, 78%, and 70% for group II 45

(p=0.21). 46

Conclusion: In this study, surgical treatment of acute arterial thromboembolism of upper 47

extremity was largely successful. Especially in patients with atrial fibrillation, adequate long-48

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term anticoagulation is indicated as prophylaxis, given the high rates of recurrent 49

thromboembolic events. 50

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Keywords: thromboembolism, upper extremity, atrial fibrillation, recurrence 52

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INTRODUCTION 73

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Acute arterial thromboembolism of upper extremity (ATUE) is implicated in a low 75

percentage (15-25%) of patients with acute limb ischemia.1-3 Standard treatment of acute 76

ATUE includes administration of heparin and balloon catheter thromboembolectomy via 77

brachial approach. More recently, thrombolysis and thromboaspiration have been reported as 78

acceptable options, based on short-term results.4-6 However, extended follow-up is another 79

matter because these patients are in the risk of recurrent thromboembolism due to the 80

potential source. 81

Whereas many follow-up studies amply detail long-term outcomes of acute arterial 82

thromboembolism of lower extremity (ATLE) (i.e., higher mortality relative to general 83

population and benefits of post-thromboembolectomy anticoagulation),7-9 similar efforts 84

addressing the upper extremity are few, assessing short-term outcomes at best.10-12 Such 85

reports are focused primarily on determining acceptable and sustained durability of surgical 86

treatment with balloon catheter; and although they do indicate a rise in mortality following 87

discharge of patients with acute ATUE, rates of recurrent embolic events in this setting are 88

not well-documented long-term. 89

The purpose of this study was to investigate short- and long-term therapeutic outcomes of 90

patients with acute ATUE, focusing on postoperative thromboembolic events by etiology. 91

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MATERIALS AND METHODS 93

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Between June, 1993 and December, 2013, 53 consecutive patients undergoing treatment for 95

acute ATUE at Kyungpook National University Hospital, Daegu, Republic of Korea, were 96

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eligible for study. The present study was initiated after obtaining approval from the 97

Institutional Review Board at our institution (IRB Number: KNUH 2013-12-036-001). 98

Informed consent for review of the medical records was exempted by the board because this 99

was a retrospective study. Patients suffering arterial trauma (including iatrogenic injury), 100

vascular access-related occlusion, and acute thrombosis of a chronic subclavian arterial 101

stenosis were excluded. 102

Fifty patients were admitted through the emergency department with acute-onset symptoms 103

such as loss of sensation, weakness, pain, paleness, lack of pulse, and remaining 3 patients 104

were consulted to our department during admission period caused by other disease. Prior to 105

December, 2002, conventional angiography was used for the diagnosis. Thereafter, computed 106

tomography angiography (CTA) or duplex ultrasonography was engaged. 107

General protocol called for intravenous heparin (3,000 to 5,000 IU as bolus injection) at time 108

of diagnosis and operative thromboembolectomy, using a Fogarty catheter. Lysis or 109

thromboaspiration were not permitted as initial interventions. Either S-shaped or longitudinal 110

skin incision was first made above the bifurcation of brachial artery. After harnessing of 111

brachial, radial, and ulnar arteries with vessel loops, transverse brachial arteriotomy was 112

performed, just proximal to the bifurcation. Bi-directional Fogarty thromboembolectomy of 113

the above three arteries then took place, and closure of the arteriotomy was achieved with 114

interrupted Prolene™ suture. The adequacy of thromboembolectomy was determined by 115

physical examination (i.e., palpation of radial artery) and hand-held Doppler device. 116

Completion angiography was not used if pulsation was restored, or if post-117

thromboembolectomy Doppler study was considered adequate. Unless contraindicated, all 118

patients subsequently were given low-molecular-weight or unfractionated heparin for 119

anticoagulation, which prior to discharge was replaced by warfarin for indefinite use as 120

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tolerated. During the first 3 months, patients visited the outpatient clinic monthly for 121

international normalized ratio (INR) testing, monitoring of clinical symptoms, and physical 122

examination (including brachial and radial pulse assessment). This regimen was then 123

conducted at 3-month intervals, adjusting warfarin dosage as needed. If clinical symptoms 124

developed or physical status declined, duplex ultrasonography was performed to check for 125

embolic recurrence or stenosis. 126

Thromboembolic origins were explored via transthoracic/esophageal echocardiography and 127

enhanced cardiac CT scanning during the perioperative period, and the carotid artery was 128

evaluated for the presence of significant stenosis through additional duplex ultrasonography 129

or prior baseline diagnostic CTA that (carotid artery was included in the field of CT scan). In 130

patients with cardiac disorder detected by electrocardiography, echocardiography, and 131

enhanced cardiac CT scanning, ATUE was attributed to cardiac etiology. Holter monitoring to 132

exclude subclinical paroxysmal atrial fibrillation (AF) and thrombophilia test for the patients 133

without a definite mechanism were not generally performed in our series. 134

This was a retrospective analysis, based on a review of patient medical records. If the patients 135

were not able to reach the hospital, anticoagulation status, details of recurrent embolic events 136

and external survival data were obtained by calling patients themselves or their family. 137

Subsequently, we evaluated the demographics and clinical manifestations of the patients on 138

admission including CHA2DS2-VASc score13 in patients with AF, as well as their in-hospital 139

and long-term clinical outcomes post-treatment. Outcomes of interest were prior 140

thromboembolic events at any site, upper-limb amputation, death, and any recurrent 141

thromboembolic events during follow-up. Recurrent thromboembolic events was defined as 142

combined macroembolization in any site and cerebral infarction (possible thromboembolic in 143

nature) during the follow-up. Event-free survival time in acute ATUE was defined as the post-144

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therapeutic interval during which objective signs of recurrent thromboembolic events were 145

absent. For evaluating basic characteristics and long-term outcomes, patients were stratified 146

as those with (group I) or without (group II) AF. 147

Student's independent t-test was applied for between-group age comparison. Given the 148

potential for skew, group comparison of symptom durations relied on the nonparametric 149

Mann-Whitney U test (also known as the Wilcoxon test for independent measures). The ten 150

categorical variables tested were subjected to chi-square analysis (if sample size was 151

adequate) or Fisher’s exact test (for smaller samplings). Overall and event-free survival rates 152

were estimated by Kaplan-Meier method, and the Log-rank test was used to compare groups. 153

The difference of recurrent embolic events according to CHA2DS2-VASc score in group I 154

was calculated by Cox regression analysis. All calculations relied on standard software (SPSS 155

v20.0; SPSS Inc, Chicago, IL, USA), with statistical significance set at p<0.05. 156

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RESULTS 158

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Patient characteristics and thromboembolic sources on admission 160

Average patient age was 70 years (range, 27-95 years), and 26 patients (49%) were male. 161

Group I patients were comparatively older. Among coexisting medical condition, congestive 162

heart failure was more common in group I and current smoker was more prevalent in group II. 163

Gender, duration of symptoms, and other coexisting medical conditions were similar for the 164

two groups (Table I). Median CHA2DS2-VASc score in group I was 5 (range, 2-8). Detailed 165

CHA2DS2-VASc score, median duration of symptoms and common associated comorbidities 166

are summarized in Table 1. 167

At the time of presentation, previous thromboembolic events were suspected by history in 24 168

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patients (45%). Prior cerebral infarction was likely in 15 patients. A history of 169

thromboembolism in other site was also elicited in remaining nine patients (lower limb, 6; 170

upper limb, 2; superior mesenteric artery [SMA], 1) (Table 1), but prior thromboembolic 171

events in aggregate did not differ by group. 172

Right arm was affected in 39 patients (74%), with left arm affected in the remaining 14 173

patients. The most proximal site of occlusion was axillary artery (18 patients, 34%), followed 174

by brachial artery (33 patients, 62%). Two patients displayed radial artery occlusion (Table 1). 175

Thirty-eight (72%) patients had ATUE of probable cardiac etiology. Among them, emboli 176

were attributable to AF in 34 patients (group I), previous myocardial infarction in 2 patients, 177

and diseased mitral valves in 2 patients (vegetation on mitral valve, 1 patient; mitral valve 178

stenosis, 1 patient). In 15 patients (28%) without detection of cardiac disorders through 179

evaluation, proximal arterial source, between ascending aorta and lesion, was implicated in 180

six patients (thoracic outlet syndrome, 2 patients; previously occluded axillofemoral graft, 2 181

patients; floating thrombus of ascending aorta, 1 patient; subclavian artery aneurysm, 1 182

patient), and vasculitis was held responsible in two patients (both systemic sclerosis). No 183

basis of thromboembolism was identified in the seven remaining patients. Forty-eight 184

subjects underwent cardiac evaluation in search of cardiac thrombus, usually by transthoracic 185

echocardiography (n=40) and/or enhanced cardiac CT (n=18). Transesophageal 186

echocardiography was performed in two patients. Ten (8 cases through echocardiography; 2 187

through CT) of these 48 patients each harbored a thrombus of cardiac chamber (21%; 9 in 188

group I; 1 in group II). 189

190

Early post-therapeutic outcomes 191

Two patients (one in each group) received anticoagulants exclusively for mild symptoms. The 192

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other 51 were treated initially by surgical thromboembolectomy (n=48) or arterial bypass 193

(n=3) under local (33/51, 65%) or general (35%) anesthesia. 194

Four (8%) of these 51 patients (1 in group I; 3 in group II) suffered re-occlusion of affected 195

arteries during in-hospital stays, necessitating repeat thromboembolectomy. One patient in 196

group I had patency restored after repeat thromboembolectomy at the time of discharge. 197

However, occlusions also recurred in three patients of group II, two of whom received an 198

anticoagulant as sole intervention. The third patient again underwent thromboembolectomy, 199

along with removal of an axillofemoral stump suspected as the thromboembolic source. None 200

of the patients required amputation. Otherwise, symptomatic relief was achieved in 51 201

patients (96%), with the exception of two post-thromboembolectomy re-occlusions after 202

treatment. 203

Within the postoperative period, three patients (5.8%) died. One in group I died from cerebral 204

infarction, and acute myocardial infarction and respiratory failure due to advanced pulmonary 205

tuberculosis was responsible in each patient in group II. 206

207

Long-term outcomes incorporating systemic embolic events 208

Mean follow-up duration was 56.8±62.2 months (median, 29.6 months; range, 1-248 months), 209

during which 19 recurrent thromboembolic events (group I, 17 (89%) in 14 patients; group II, 210

2 in 2 patients) were documented. Specifically, cerebral infarction (7 events), 211

thromboembolism of upper (4 events) and lower (3 events) extremities, and SMA embolism 212

(3 events) were recorded in group I, and each event of cerebral infarction and 213

thromboembolism of upper extremity was recorded in group II (Table 2). Of the eight 214

patients suffering cerebral infarction, seven had undergone carotid artery studies upon 215

admission for ATUE, but significant stenosis at carotid bifurcation was found in only one 216

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patient of group I (>50% stenosis bilaterally). One patient experiencing recurrent ATUE 71 217

months after initial treatment in group II (previously occluded axillofemoral graft) finally 218

required amputation. There was no significant relationship between the recurrent embolic 219

event and CHA2DS2-VASc score in group I patients (hazard ratio 0.83; 95% confidence 220

interval, 0.54-1.29; p=0.41). 221

Among 14 patients with recurrent embolic events in group I, half of patients were not 222

receiving anticoagulants when first recurrent embolic events took place. Cessation of 223

prophylaxis was arbitrary in each instance, representing independent decisions (without 224

medical advice) in six and one non-restart after a bout of gastrointestinal bleeding. Two 225

patient was given low-molecular-weight heparin during admission and five patients were 226

taking warfarin at the time of recurrent embolic events. Mean INR of these five patients was 227

1.88 (four <2.0 each; maximum of 3.43). 228

Event-free survival rates after initial therapy were 84% at 1 year, 65% at 3 years, and 58% at 229

5 years for patients overall. In subgroup analysis, respective rates were 77%, 44%, and 44% 230

for group I and 100%, 100%, and 83% for group II (p=0.004) (Fig. 1). 231

During the follow-up period, 23 patients died and 7 were lost to follow-up. Overall survival 232

rates after initial treatment were 83% at 1 year, 73% at 3 years, and 59% at 5 years (Fig. 2). 233

In subgroup analysis, respective rates were 82%, 69%, and 52% for group I and 84%, 78%, 234

and 70% for group II (p=0.21). Causes of death are indicated in Table 2. 235

236

DISCUSSION 237

Acute limb ischemia is the most common type of vascular emergency, accounting for 238

approximately 30% of such events.14 Acute ATLE is considered particularly serious, carrying 239

high rates of morbidity, amputation (10-15%), and mortality (~10%) by current reports.15-18 In 240

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contrast, the outcomes of acute ATUE demonstrated lower rates of limb loss (0-3.1%)10,18,19 241

and mortality (~6%).10,14,18 The disparity in amputation rates for upper and lower limb 242

compromise may be explained by a better developed collateral circulation in the arms.20 243

Despite the fact that episodic ATUE is not always limb-threatening, and 244

thromboembolectomy is not an absolute requirement for limb salvage, investigators are still 245

troubled by functional arm deficits, with weakness and/or claudication that may persist after 246

conservative treatment (with or without long-term anticoagulation).21,22 Hence, most vascular 247

surgeons opt for thromboembolectomy as an aggressive measure to preserve function.3,10,23 In 248

our series, two patients received anticoagulants as the sole initial therapy for mild symptoms, 249

and another two patients received anticoagulants only for early occlusion after 250

thromboembolectomy. None of these four patients required amputation, possibly due to 251

sufficient collateral blood flow and lesser demands of upper (vs. lower) limb muscle mass. 252

The relatively lower mortality rate of acute ATUE may be influenced by several factors. 253

Compared with more muscular lower limbs, reperfusion injury of the upper extremities (after 254

revascularization) expectedly is less extreme. Furthermore, upper extremity occlusions are 255

more likely to be embolic in nature, rather than a consequence thrombosis at points of pre-256

existing arterial stenosis. Some researchers also note that atherosclerotic narrowing of the 257

brachial artery seldom occurs, and associated in situ thrombosis rarely presents 258

acutely.12,20,24,25 As such, acute ATUE is usually amenable to thromboembolectomy by 259

balloon catheter under local anesthesia, without the need for major vascular bypass surgery. 260

Ueberrueck et al.14 have also emphasized that in-hospital mortality is usually a function of 261

comorbidities and cerebral or visceral embolism, rather than procedure-related complications. 262

In our series, 94% of operated patients were treated initially by thromboembolectomy via 263

brachial approach, and 65% of these were done under local anesthesia. Our in-hospital 264

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mortality rate of 5.8%, which we believe is comparable to other studies, was due to events 265

from underlying comorbidities rather than procedure-related complications. 266

Few reports have chronicled long-term outcomes of ATUE that encompass recurrent 267

thromboembolic events. However, a common finding in earlier efforts is that patients 268

undergoing upper limb thromboembolectomy were at increased risk of stroke and death, 269

compared with the population at-large.12,18,19,26 Andersen et al.19 studied a cohort (N=1377) 270

recruited nationwide over more than a decade (1990-2002), each subject status post-271

thromboembolectomy of upper extremity. By their account, 237 patients (19.1%) experienced 272

first-ever strokes after thromboembolectomy, and 20 of those patients were hospitalized for 273

the procedure when the stroke occurred. The relative risk of stroke was determined as 3.3-274

fold in males and 5-fold in females, compared with the general population. Unfortunately, no 275

other thromboembolic events were described and causes of death during the follow-up were 276

not specified. Magishi et al.18 reported event-free survival rates of 74% at 1 year and 27% at 277

3 years, with respective cumulative actuarial survival rates of 95% and 61%. In addition, 278

cerebrovascular disease was the primary comorbidity at admission and primary recurrent 279

thromboembolic pattern after operation in their series, although this study lacked 280

corroborating carotid arterial evaluations.18 281

In our patients, recurrent embolic events after ATUE were high, especially in patients with AF 282

where 1-year, 3-year, and 5-year event-free rates were 77%, 44%, 44%, respectively. Most 283

recurrent thromboembolic events involved cerebral infarction. There is no real evidence that 284

these strokes were embolic in nature and of cardiac origin, so one cannot assume a causal 285

relationship with index episodes of ATUE. However, in six of the seven affected, no 286

significant carotid arterial stenosis was detected at first presentation, which may have some 287

bearing in this context. 288

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It is well-known that without anticoagulant treatment, the risk of ischemic stroke is far higher 289

than the risk of intracranial bleeding with treatment.27,28 Moreover, in our subset of high-risk 290

patients with a history of thromboembolism and atrial fibrillation, long-term anticoagulation 291

is sanctioned to prevent recurrent embolism.29 Despite a clear mandate for anticoagulation in 292

patients with AF, many such patients are not receiving appropriate treatment.18,19,30 In our 293

series, the median CHA2DS2-VASc score was 5 and all of the patients were comprised in 294

high risk group. However, half of our patients with AF were not taking anticoagulants at the 295

times thromboembolic recurrences took place, and in anticoagulated patients suffering 296

recurrences, recommended therapeutic levels were not reached. Unfortunately, many patients 297

arbitrarily discontinued anticoagulant therapy. Follow-up monitoring of long-term 298

anticoagulation admittedly is difficult, and elderly patients who are asymptomatic after 299

treatment are inclined to become noncompliant. 300

The reported 5-year survival rate after thromboembolectomy of upper extremity has been 301

ranged from 37% to 61% and the mechanism for high long-term mortaliry was speculated 302

that most of patients with ATUE were old and displayed with multiple comorbidities.10,12,18 303

Our cohort was comparable to other studies. Importantly, the cause of mortality in patients 304

with AF was primarily due to thromboembolic events, such as cerebral infarction and SMA 305

embolism. Although Licht et al.12 followed 148 patients with acute upper limb ischemia, 306

reporting no significant survival benefit from anticoagulant therapy beyond hospital stays, 307

they failed to address late outcomes in terms of embolic events and anticoagulation status. 308

Alternatively, Mills and Porter31 found that recurrent embolization may be preventable with 309

routine anticoagulation. Our data likewise underscore that regular follow-up with adequate 310

anticoagulation is critical, especially in instances of AF. Therefore, patients should be 311

educated on these principles and their potential to impact long-term outcomes. 312

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The major limitation of this study is its retrospective nature and the small patient sampling 313

that was monitored over long a period of time. A significant number of subjects (total of 314

seven) progressively were lost to follow-up, and it was difficult to track INR values of 315

patients who were event-free, many of whom were seen at other facilities. This particular 316

limitation prohibits us from assessing the effect of adequate anticoagulation in 317

thromboembolic recurrences, and also there is a possibility to underestimate the actual 318

recurrent events due to the incomplete follow-up. In addition, although the majority of our 319

patients affected cerebral infarction during follow-up did not have significant carotid stenosis 320

at presentation, it may be difficult to have confidence that these events is mechanistically 321

related (from the same source/cause) to the index episodes of acute ATUE. 322

323

CONCLUSION 324

In this study, surgical treatment of acute ATUE was largely successful. However, the high 325

rates of thromboembolic recurrence and poor compliance we observed, especially in patients 326

with AF, indicate a need for patient education and adequate long-term anticoagulation as 327

prophylactic measure. 328

329

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Table 1. Characteristics and potential sources of acute arterial thromboembolism of upper 409

extremity 410

Characteristics Group I (n=34) Group II (n=19) P value

Age, mean (range) 73.9 (58-95) 62.9 (27-85) 0.01

Male gender 14 (41%) 12 (63%) 0.13

Symptom duration, median hour (range) 7.5 (1-240) 16.0 (2-336) 0.09

Coexisting medical condition

Hypertension 25 (74%) 10 (53%) 0.12

Smoking (current smoker) 8 (24%) 11 (58%) 0.01

Diabetes mellitus 10 (29%) 2 (11%) 0.12

Congestive heart failure 12 (35%) 2 (11%) 0.05

Ischemic heart disease 5 (15%) 4 (21%) 0.56

Renal insufficiency (s-Cr>1.5mg/dL) 2 (6%) 0 0.28

Affected side 0.20

Right side 27 12

Left side 7 7

Proximal occlusion site 0.10

Axillary artery 9 9

Brachial artery 25 9

Radial or ulnar artery 2

Suspected causes of thromboembolism

Atrial fibrillation 34

Other cardiac causes 4

Proximal artery 6

Vasculitis 2

Unknown 7

Previous thromboembolic events 17 (50%) 7 (37%) 0.36

Cerebral infarction 11 4

Embolism of lower extremity 6 0

Embolism of upper extremity 0 2

Embolism of SMA 0 1

s-Cr, serum creatinine; SMA, superior mesenteric artery 411

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Table 2. Thromboembolic events and causes of death in the aftermath of acute ATUE 415

Group I (n=34) Group II (n=19)

Recurrent embolic events 17* 2

Cerebral infarction 7 † 1

‡

Embolism of lower extremity 4 0

Embolism of upper extremity 3 1

Embolism of SMA 3 0

Under anticoagulation at recurrence 7 0

Causes of death

Cerebral infarction 4 1

Embolism of SMA 2 0

Myocardial infarction 2 1

Acute renal failure 1 0

Trauma 1 0

Pneumonia

Respiratory failure

1

0

1

1

Malignancy 2 1

Unknown 3 2

ATUE, arterial thromboembolism of upper extremity; SMA, superior mesenteric artery 416

* Three patients suffered multiple recurrent arterial embolizations. 417

† One of six patients showed >50% stenosis of carotid bifurcation bilaterally upon admission 418

for acute ATUE. 419

‡ One patient showed no significant carotid stenosis upon admission for acute ATUE. 420

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FIGURE LEGENDS 427

428

Figure 1. Event-free rates after initial therapy by group. Respective rates in patient subset 429

with atrial fibrillation (AF) marked by significant increases relative to patients without AF 430

(p=0.004). 431

432

Figure 2. Overall survival rates after treatment by group. Kaplan-Meier estimates in patient 433

subset with atrial fibrillation (AF) and without AF were similar (p=0.21). 434

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