Vascular Medicine

Acute Limb Ischemia and Outcomes With Vorapaxar in

Patients With Peripheral Artery Disease
Results From the Trial to Assess the Effects of Vorapaxar in Preventing
Heart Attack and Stroke in Patients With AtherosclerosisThrombolysis in
Myocardial Infarction 50 (TRA2P-TIMI 50)
Marc P. Bonaca, MD, MPH; J. Antonio Gutierrez, MD, MHS; Mark A. Creager, MD;
Benjamin M. Scirica, MD; Jeffrey Olin, MD; Sabina A. Murphy, MPH;
Eugene Braunwald, MD; David A. Morrow, MD, MPH

BackgroundPatients with peripheral artery disease (PAD) are at heightened risk of acute limb ischemia (ALI), a morbid
event that may result in limb loss. We investigated the causes, sequelae, and predictors of ALI in a contemporary
population with symptomatic PAD and whether protease-activated receptor 1 antagonism with vorapaxar reduced ALI
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overall and by type.

Methods and ResultsThe Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With
AtherosclerosisThrombolysis in Myocardial Infarction 50 (TRA2P-TIMI 50) was a randomized, double-blind, placebo-
controlled trial of vorapaxar in stable patients, including 3787 with symptomatic PAD. ALI was a prespecified adjudicated
end point using a formal definition. A total of 150 ALI events occurred in 108 patients during follow-up (placebo 3-year rate,
3.9%; 1.3% annualized). For patients with symptomatic PAD, previous peripheral revascularization, smoking, and the ankle-
brachial index were predictive of ALI. The majority of ALI events occurred as a result of surgical graft thrombosis (56%),
followed by native vessel in situ thrombosis (27%). Stent thrombosis and thromboembolism caused ALI in 13% and 5%,
respectively. Amputation occurred in 17.6% presenting with ALI. Vorapaxar reduced first ALI events by 41% (hazard ratio,
0.58; 95% confidence interval, 0.390.86; P=0.006) and total ALI events by 41% (94 versus 56 events; risk ratio, 0.59;
95% confidence interval, 0.380.93; P=0.022). The efficacy of vorapaxar was consistent across types of ALI.
ConclusionsIn selected patients with symptomatic PAD and without atrial fibrillation, ALI occurs at a rate of 1.3%/y,
is most frequently caused by acute bypass graft thrombosis or in situ thrombosis of a diseased vessel, and often results
in limb loss. Vorapaxar reduces ALI in patients with symptomatic PAD with consistency across type, including PAD
resulting from surgical graft thrombosis and in-situ thrombosis.
Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00526474.
(Circulation. 2016;133:997-1005. 10.1161/CIRCULATIONAHA.115.019355.)
Key Words:limb limb ischemia peripheral artery disease peripheral vascular diseases thrombosis

P atients with peripheral artery disease (PAD) are at height-

ened risk of major adverse cardiovascular events. This
risk is associated with the severity of disease, measured either
by the ankle-brachial index (ABI) or by symptom severity.16
Patients with PAD have been included in large, clinical tri-
als evaluating medical therapies to reduce the risk of major
adverse cardiovascular events.711 Yet, few trials that include
patients with PAD have reported limb outcomes, and those
that have generally have used a variety of outcomes and des-
ignated them as secondary or other efficacy end points.9,11,12
Currently, few medical therapies have been shown in prospec-
tive, randomized trials to reduce limb morbidity related to
atherothrombosis.13,14
Clinical Perspective on p 1005
Limb ischemic events are an important cause of morbidity
and loss of independence in patients with PAD.15,16 Similar to
acute myocardial infarction (MI) or ischemic stroke in which
acute thrombotic occlusion of an artery causes ischemia and,
unless promptly relieved, tissue death, acute limb ischemia

Received September 4, 2015; accepted January 22, 2016.

From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, MA
(M.P.B., J.A.G., B.M.S., S.A.H., E.B., D.A.M.); Dartmouth-Hitchcock Heart and Vascular Center, Geisel School of Medicine at Dartmouth, Lebanon, NH
(M.A.C.); and Wiener Cardiovascular Institute and Marie-Jose and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai School of Medicine,
New York, NY (J.O.).
Guest Editor for this article was William R. Hiatt, MD.
Correspondence to Marc P. Bonaca, MD, TIMI Study Group, Cardiovascular Division, Brigham and Womens Hospital, 75 Francis St, Boston, MA
02115. E-mail mbonaca@partners.org
2016 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.115.019355

997
 998CirculationMarch 8, 2016
(ALI) is characterized by the sudden decrease in limb perfu-
sion that threatens tissue loss and limb viability without early
reperfusion. Just as the onset of chest pain occurs with acute
MI, ALI manifests as the acute onset of limb pain often with
paresthesia, weakness, or paralysis.17
One difference between acute MI and ALI is that although
acute MI is predominantly an atherothrombotic event, ALI
has been described as having a more diverse origin, includ-
ing both embolism from the heart and proximal vessels and
in situ occlusion of native vessels, stents, or grafts.18 Although
in situ arterial occlusion may primarily be atherothrombotic,
the pathobiology of vein graft failure may be more complex,
including adverse remodeling and intimal hyperplasia of the
vessel wall after exposure to the arterial circulation, as well as
inflammation and changes in flow and shear stress predisposing
to thrombus formation. In addition, synthetic grafts may suffer
higher rates of occlusion caused by similarly complex reasons.
Therapies to modify ALI may therefore have selective benefit
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for specific types of ALI, depending on their mechanism.
The Trial to Assess the Effects of Vorapaxar in Preventing
Heart Attack and Stroke in Patients With Atherosclerosis
Thrombolysis in Myocardial Infarction 50 (TRA2P-TIMI
50) was a multinational, randomized, double-blind, placebo-
controlled trial designed to study the effects of the prote-
ase-activated receptor 1 antagonist vorapaxar on long-term
secondary prevention for reducing ischemic risk in patients
with stable atherosclerosis, including symptomatic PAD.19
On the basis of overall efficacy, vorapaxar has been approved
by the US Food and Drug Administration (FDA) in patients
with previous MI or PAD but is contraindicated in those with
a history of stroke or transient ischemic attack (TIA) resulting
from bleeding risk.20 ALI was selected as a prespecified effi-
cacy end point in the TRA2P-TIMI 50 trial with the anticipa-
tion that it would occur at a frequency similar to the frequency
of other systemic vascular events associated with significant
morbidity and that it may be modifiable through protease-acti-
vated receptor 1 antagonism. We have reported previously that
vorapaxar significantly reduced the first ALI event in patients
with symptomatic PAD.21
Because patients in TRA2P-TIMI 50 were selected for
a randomized, clinical trial, it is unknown whether the rates,
causes, treatments, and outcomes of ALI events are similar
to those reported in observational registries. In addition, it
is unknown whether protease-activated receptor 1 antago-
nism has similar efficacy for reducing all types of ALI and
for reducing both first and recurrent events. Finally, the effi-
cacy of vorapaxar for reducing ALI in patients with PAD as
described in the FDA label has not been reported. We there-
fore investigated the causes, treatments, and outcomes for ALI
as adjudicated in TRA2P-TIMI 50 and whether the efficacy
of vorapaxar was consistent across PAD type. In addition, we
evaluated the efficacy of vorapaxar for first and recurrent ALI
events and for events occurring in patients with PAD.
Methods
Study Population and Procedures
TRA 2P-TIMI 50 randomized 26449 subjects with stable athero-
sclerotic vascular disease, including coronary artery disease (recent
MI), cerebrovascular disease (recent stroke), and symptomatic PAD.
The details of the trial design have been reported previously.19,22 To
qualify for inclusion on the basis of PAD, patients had to have a his-
tory of intermittent claudication in conjunction with an ABI <0.85
or previous revascularization for limb ischemia.21 Qualifying and
follow-up ABIs were performed by trained personnel at the study
site using standardized procedures.23 Randomization was stratified
according to the qualifying diagnosis.22 Patients with MI or stroke
in the previous year who also had a history of PAD were assigned
to the MI and stroke strata, respectively; therefore, those in the PAD
stratum were free of recent systemic ischemic events.22 The primary
population for the present analysis is the population of patients who
qualified for the trial with symptomatic PAD that was prespecified for
analysis, stratified at randomization, and previously described.19,21,23
Additional analyses were performed in patients with a history of PAD
in the FDA approval population, which is a post hoc subgroup based
on the FDAs findings.20
Patients were ineligible if they had a planned revascularization
that had not yet been performed, had a history of a bleeding diathesis,
were receiving vitamin K antagonist therapy, or had active hepatobili-
ary disease.22 The trial was approved by the responsible Institutional
Review Board or Ethics Committee for each participating institution.
All patients gave written informed consent.
Eligible patients were randomized in a 1:1 fashion to receive
vorapaxar sulfate 2.5 mg daily or matching placebo and stratified
by both qualifying disease state and intention to prescribe a thi-
enopyridine. All concomitant medical therapy, including the use
of other antiplatelet agents or anticoagulants during the trial, was
managed by the local treating physician. Patients were allowed to
be enrolled while on aspirin, a thienopyridine, or their combina-
tion, as well as cilostazol and dipyridamole. Patients with an indi-
cation for anticoagulation (eg, atrial fibrillation) were not eligible
for randomization.
End Points
The primary efficacy and safety end points of TRA2P-TIMI 50 have
been described previously.22 Urgent hospitalization for vascular cause
of an ischemic nature was a prespecified composite end point that
included hospitalization for myocardial ischemia, cerebrovascular
ischemia (stroke or TIA), or ALI. As part of this composite, ALI was
prospectively ascertained and adjudicated. ALI was defined in the
Clinical End Point Committee charter as a clinical history suggesting
a rapid or sudden decrease in limb perfusion and either a new pulse
deficit with associated rest pain, pallor, paresthesias, or paralysis or
confirmation of arterial obstruction by imaging, intraoperative find-
ings, or pathological evaluation (Figure1).
All potential ALI events were reported by study sites. Sites com-
pleted an electronic case report form page indicating that a potential
ALI event had occurred. All site-reported events were submitted to
the Clinical End Point Committee for adjudication. Source docu-
mentation was collected that described the hospitalization and any
associated imaging and procedures. Efficacy end points were then
adjudicated by the Clinical End Point Committee, which comprised
trained specialists in cardiovascular medicine blinded to treatment
allocation.
Statistical Methods
The primary analysis was performed on an intention-to-treat basis
with all randomized patients in the PAD stratum. Additional anal-
yses were performed that included patients with a history of PAD
but no history of stroke or TIA as described in the FDA approval
population.24 Baseline characteristics for patients with and without
ALI were compared by use of the 2 test for categorical variables and
the Wilcoxon rank-sum test for continuous variables. Because ABI
is known to have a nonlinear association with ischemic risk, model-
ing for ABI was conducted with the use of 3 categories: low (0.5),
intermediate (>0.5< 1.3), and high (1.3).24 In addition, the relation-
ship between smoking status and incident PAD has been observed to
show a gradient of risk by category, with current and former smok-
ers being at heightened risk compared with never smokers but with
those currently smoking at the highest risk.25 Therefore, smoking
 Bonaca et al Acute Limb Ischemia and Outcomes in PAD 999

Hospitalization for acute limb ischemia patients who qualified on the basis of symptomatic PAD. An
including acute ischemia caused by:
additional 28 (15.8%) occurred in patients randomized in the
Arterial emboli MI or stroke cohorts, the majority of whom had a known his-
Arterial thrombosis
Arterial trauma from a vascular procedure
tory of PAD. Overall, 94% of events occurred in patients with
known limb disease at baseline, making this characteristic
the strongest single predictor of ALI during follow-up (unad-
AND justed hazard ratio [HR] for known PAD versus no known
Either A or B
PAD, 36.8; 95% CI, 19.868.2; P<0.001).
A. History and Exam B. Direct Conformation

Clinical history suggesting a

Baseline Characteristics in Patients Who Developed
Confirmation of arterial
rapid or sudden decrease in obstruction by imaging ALI
limb perfusion (including uulstrasound, CT,
OR The rate of first ALI event in patients enrolled on the basis
AND MRI, or conventional
angiography), surgical symptomatic PAD and randomized to placebo was 3.9% over
New pulse deficit with findings or pathology 3 years (1.3% annualized), more frequent than all stroke, isch-
associated rest pain, pallor,
parasthesias or paralysis emic stroke, and unstable angina (Figure2). Baseline char-
acteristics of patients enrolled with symptomatic PAD with
Figure 1. Trial definition of acute limb ischemia. CT indicates
computed tomography; and MRI, magnetic resonance imaging. and without ALI during follow-up are shown in Table 1. Most
patients recruited into the PAD cohort had an ABI <0.85
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(68%) and symptoms of intermittent claudication (75%).

status was categorized in these 3 groups. Baseline characteristics that
were significantly different at baseline (P<0.05) between those with Lower body weight and body mass index, smoking status,
subsequent ALI and those without ALI were considered potential hypertension, previous carotid revascularization, and previ-
predictors, with those considered to be clinically plausible predic- ous peripheral revascularization were all associated with ALI
tors of ALI selected for inclusion in a multivariable model to assess (Table 1). Median ABI was numerically lower in those who
their independence. The efficacy analyses were performed with a Cox
had ALI during follow-up (0.7; interquartile range, 0.50.9)
proportional-hazards model, with the investigational treatment allo-
cation and planned use of a thienopyridine as covariates. Cumulative compared with those who did not (0.8; interquartile range,
event rates at 3 years were calculated with the KaplanMeier method. 0.60.9); however, the difference was not statistically sig-
Safety analyses were performed among patients who received 1 nificant (P=0.12). Because ABI is known to have a nonlinear
doses of study drug and included events through 60 days after pre- relationship with ischemic risk, it was further categorized as
mature cessation of study therapy or 30 days after a final visit at
the conclusion of the trial. Total ALI events were analyzed with a
very low (0.5), intermediate (>0.5<1.3), and high (1.3),
negative binomial regression model. Incidence rate ratio and corre- with both very low and high ABI more frequent in those with
sponding 95% confidence intervals (CIs) are reported. Analyses were ALI. Baseline medical treatment was similar between groups,
performed with Stata version 12.1 (StataCorp, College Station, TX). with high use of antiplatelet therapy (96%) and statin therapy
(82%) and low use of cilostazol (11%).
Results
A total of 26449 patients were randomized in the TRA2P- Causes and Treatment of ALI
TIMI 50 trial, with 3787 qualifying with symptomatic PAD. The majority of the 150 ALI events in the PAD group occurred
Over a median of 2.5 years of follow-up, a total of 178 first as a result of surgical graft thrombosis (93, 62%), followed
and recurrent ALI events, occurring in 133 patients, met the by native vessel in situ thrombosis (37, 25%). Stent thrombo-
Clinical End Point Committee definition of ALI. The major- sis and thromboembolism were the cause of ALI in 14 (9%),
ity of these events (150, 84.3%) occurred in 108 of the 3787 and 6 (4%) cases, respectively (Figure3A). The 93 acute graft

Event Rate at 1 Year in 3,787 Patients with

Symptomatic PAD and no Recent MI or Stroke
2%
Kaplan Meier Rate at 1 Year (%)

1.9%
1.8%

1.4% Figure 2. KaplanMeier rates at 1 year for ischemic

1.3% events in patients with symptomatic peripheral
1.2%
1% artery disease (PAD; black, fatal events; red,
1.0% 1.0% systemic ischemic events; orange, limb ischemic
0.9% events). CV indicates cardiovascular; and MI,
myocardial infarction.

0%
CV Death Non-CV Death Myocardial Hospitalization Ischemic Any stroke Acute Limb Amputation
Infarction for Unstable Stroke Ischemia
Angina

Event
 1000CirculationMarch 8, 2016

Table 1. Baseline Characteristics including 16% who required amputation and 33% who
required a new surgical bypass (Figure3B). Endovascular
ALI No ALI
Variable (n=108) (n=3679) P Value therapy, including angioplasty or stent implantation with or
without thrombolysis, was used in 28%, and 5% received
Demographics
thrombolysis only. Four patients (3.7%) died during hospi-
Age, median (IQR), y 66 (5872) 66 (6073) 0.16 talization for their ALI event. The median duration of hos-
Female, % 31 29 0.64 pitalization for patients who survived to discharge was 8
White race, % 91 91 0.92 days (interquartile range, 515 days), with 34% requiring
BMI, median (IQR), kg/m2 26 (2330) 27 (2531) 0.009 admission to an intensive care unit. At discharge, 14.8% of
Weight, median (IQR), kg 74 (6386) 79 (6990) 0.009 patients either had died or were unable to return home and
Clinical characteristics%
required extended care outside of the home (eg, rehabilita-
tion or nursing home; Figure4A).
Smoking status 0.040

Current smoker 36 31
Predictors of ALI

Former smoker 56 53 For those patients randomized with symptomatic PAD,

Never smoker 7 16 future ALI was associated with baseline differences, includ-
Diabetes mellitus 39 36 0.51 ing lower body weight, hypertension, smoking status cat-
Hypertension 75 84 0.018 egory, ABI category, concomitant carotid disease, and
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Hyperlipidemia 82 88 0.11 previous peripheral revascularization. When ABI category,

smoking status category, and previous peripheral revascu-
Any coronary artery disease 53 57 0.38
larization were combined in a multivariable model to assess
Previous PCI 19 27 0.10
their independence from each other as predictors, very
Previous CABG 19 24 0.31 low and high ABI, current smoking, and previous periph-
History of stroke or TIA 9 14 0.19 eral revascularization all remained independent predictors
History of heart failure 15 10 0.11 of ALI (Table2); however, former smoking status did not
History of atrial fibrillation or flutter 5 5 0.88 (Z=1.74; P=0.082),
eGFR CrCl <60 mLmin11.73 m2 29 29 0.99
PAD details, % Outcomes After ALI
Peripheral artery revascularization, % 84 61 <0.001 In patients who survived to discharge after ALI, median follow-
up after the event was 749 days (interquartile range, 294930
Previous amputation, % 6 4 0.32
days). Over the 2 years of follow-up after their first ALI event,
Previous carotid intervention, % 18 10 0.013
11.7% had a major adverse cardiovascular event, 24.0% had
ABI <0.85, % 66 68 0.79 a recurrent ALI event, 27.0% received an amputation, 54.0%
Median ABI (IQR) 0.7 (0.50.9) 0.8 (0.60.9) 0.12 required rehospitalization, and 63.2% required a peripheral
ABI 0.50, % 23% 12% p<0.001 revascularization procedure (Figure4B). At a median of 2 years
ABI >0.50<1.30, % 72% 86% after ALI, 12.1% had died, approximately half of cardiovascu-
ABI 1.30, % 5% 2% lar causes and half of noncardiovascular causes.
Claudication (Fontaine class >1), % 75 75 0.99
Vorapaxar and ALI
Baseline medical therapy, %
In patients with symptomatic PAD, vorapaxar reduced a first
Any antiplatelet therapy 97 96 0.77
ALI event by 42% (HR, 0.58; 95% CI, 0.390.86; P=0.006).
Aspirin 85 88 0.36 The benefit of vorapaxar was not modified by planned thi-
Thienopyridine 36 37 0.88 enopyridine use (P for interaction=0.22), aspirin use (P for
Aspirin and thienopyridine therapy 27 31 0.43 interaction=0.56), or statin use (P for interaction=0.97) at
Cilostazol 9 11 0.54 baseline. The benefit of vorapaxar was consistent across all
ACEi or ARB 70 68 0.55 causes of ALI (Figure5), including the most common causes
Statin therapy 82 82 0.87
of graft thrombosis (HR, 0.63; 95% CI, 0.381.02) and in
situ thrombosis (HR, 0.39; 95% CI, 0.180.84). Of those
ABI indicates ankle-brachial index; ACEi, angiotensin-converting enzyme
with ALI, recurrent ALI events occurred in 24%, resulting in
inhibitor; ALI, acute limb ischemia; ARB, angiotensin receptor blocker; BMI, body
mass index; CABG, coronary artery bypass graft; CrCl, creatine clearance; eGFR, a total occurrence of events in patients enrolled with symp-
estimated glomerular filtration rate; IQR, interquartile range; PAD, peripheral tomatic PAD of 150. Vorapaxar reduced total ALI events by
artery disease; PCI, percutaneous coronary intervention; and TIA, transient 41% (94 versus 56 events; risk ratio, 0.59; 95% CI, 0.380.93;
ischemic attack. P=0.022).

thromboses occurred in 49 synthetic grafts, 27 vein grafts, and
17 grafts of unknown type (all unknown were femoral-popli-
teal or femoral-tibial grafts).
All patients with ALI during follow-up were hospital-
ized. The majority (60%) underwent surgical treatment,
Limb Efficacy and Safety of Vorapaxar in PAD
Patients With No Stroke/TIA
Vorapaxar has been approved by the FDA for use in patients
with PAD and no history of stroke or TIA.20 When the effi-
cacy of vorapaxar for ALI in this population was evaluated
 Bonaca et al Acute Limb Ischemia and Outcomes in PAD 1001

Causes of Acute Limb Ischemia

Surgical graft thrombosis
Peripheral stent thrombosis
6, 4%
N=150 ALI Events
14, 9%
Native vessel thrombosis Initial Treatment for Acute Limb Ischemia
Thromboembolic
Amputation Surgical Bypass Surgical Thrombectomy
Endovascular Thrombolysis only
7, 5%
N=150 ALI Events 24, 16%

42, 28%

37, 25%

93, 62%
50, 33%
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27, 18%

Figure 3. A, Acute limb ischemia (ALI) events by origin. B, Initial treatment for ALI.

(history of PAD randomized in the MI or PAD stratum with
no history of stroke/TIA, n=4677), results were consistent
with those cited above, with vorapaxar significantly reduc-
ing ALI overall consistently among all causes of PAD (2.0%
with vorapaxar versus 3.3% with placebo; Table3). Vorapaxar
increased Global Utilization of t-PA and Streptokinase for
Occluded Coronary Arteries (GUSTO) moderate or severe
bleeding (Table3). There were slightly more GUSTO severe
bleeding events with vorapaxar compared with placebo (36
versus 33; HR, 1.14; 95% CI, 0.711.83; Table3), but this
did difference not approach statistical significance. Rates of
fatal bleeds, intracranial hemorrhages, and all-cause mortal-
ity with vorapaxar were similar to those with placebo in this
subcohort.
Discussion
The results of the present study are notable in that they dem-
onstrate that in patients with symptomatic PAD receiving
intensive evidence-based therapies, including antiplatelet
(96% to 97%) and statin (82%) therapy, ALI events occur at a
frequency similar to that of ischemic stroke and MI and that
these events are associated clinically with significant morbid-
ity, including prolonged hospitalization, limb loss, reperfusion
surgery, and mortality. Importantly, these results also show
that ALI can be reduced with the protease-activated receptor
1 antagonist vorapaxar, regardless of origin. Finally, our find-
ings demonstrate that ALI can be ascertained and adjudicated
in clinical trials using objective criteria similar to those used
for commonly accepted ischemic end points such as MI and
ischemic stroke.
Outcomes With ALI
ALI is characterized as a vascular surgery emergency requiring
hospitalization and rapid intervention to prevent tissue loss.17,26
28
It is associated prolonged hospitalization and rates of limb loss
ranging from 12% to 50%, with the majority of amputations
requiring above-the-knee procedures, resulting in significant
disability.17,29 In the present study, all patients were hospitalized,

A Outcomes at Initial Hospitalization for Acute Limb Ischemia B Outcomes after ALI

80% In Hospital 80%

Median Stay 8 Days
70% (IQR 5-15) At Discharge 70%
73.1%

60% 60% 63.2%

Proportion (%)

Proportion (%)

50% 50% 54.0%

40% 40%

30% 34.0% 30%

27.0%
20% 20% 24.0%
17.6%
10% 14.8% 10% 12.1%
11.7%
0% 3.7% 0%
MACE Death Recurrent ALI Amputation Hospitalization Peripheral
Died Amputation ICU Stay Surgery Died or Revascularization
Unable to go
Event Home Event

Figure 4. A, Outcomes at initial hospitalization for acute limb ischemia (ALI). B, Outcomes after first ALI event. Median follow-up after
the event was 749 days (interquartile range, 294930 days). ICU indicates intensive care unit; and MACE, major adverse cardiovascular
events.
 1002CirculationMarch 8, 2016

Table 2. Predictors of ALI for Patients With Symptomatic PAD patients with atrial fibrillation, who are at heightened risk of
thromboembolism, was low (5%, <200), as were patients
Characteristic Z Score Adjusted HR for ALI
with heart failure (10%15%). Therefore, the identified
Previous peripheral revascularization 4.66 3.60 (2.106.18) events were more likely related to intrinsic limb disease than
P <0.001 to thromboembolism.
ABI 00.5* 4.51 2.86 (1.814.51) Within the cohort of patients with symptomatic PAD,
P <0.001 a history of previous peripheral revascularization, an ABI
ABI 1.3* 2.16 2.71 (1.096.72) 0.5 or 1.3, and current smoking were all independently
P 0.031 associated with the risk of ALI. Therefore, these clinical
characteristics may be useful to clinicians in identifying
Smoking (current) 1.99 2.17 (1.014.67)
patients at the highest risk of acute limb complications and
P 0.046
underscore the importance of smoking cessation for limb
ABI indicates ankle-brachial index; ALI, acute limb ischemia; CI, confidence outcomes.
interval; HR, hazard ratio; and PAD, peripheral artery disease.
*Compared with ABI >0.5< 1.3.
Compared with never smoker; model also includes former smoker (HR, Effect of Vorapaxar on ALI
1.93; 95% CI, 0.924.02). We have reported previously that vorapaxar reduced ALI in
this cohort of patients with symptomatic PAD.21 The pres-
ent study adds to this observation by demonstrating that the
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the majority required surgery, 16% resulted in amputation, and

15% died or were unable to return home after a median of 8 efficacy was consistent across all causes, including bypass
days in the hospital. Importantly, patients with symptomatic graft thrombosis and native vessel in situ thrombosis.
PAD were at greater risk of ALI than they were for ischemic Findings with respect to graft thrombosis are particularly
stroke or any stroke, with the risk of ALI approaching that of MI. interesting in that previous trials of thienopyridines and
Outcomes associated with ALI in the present study were similar anticoagulants have not shown consistent benefit for graft
to those reported in observational data sets.17,26,27 Therefore, both patency in trials after bypass.12,30,31 The efficacy of vora-
in clinical trials and in the community, these events occur at paxar in contrast to generally neutral findings with antico-
a frequency similar to the frequencies of other hard ischemic agulants raises the question of whether the benefit is purely
end points and are associated with significant morbidity. an antithrombotic effect or whether there are additional
actions on the vascular endothelium. This question may be
Etiologies and Predictors of ALI particularly important when considering the numeric dif-
Overall, the causes of ALI observed in the trial were similar to ferences in patients with vein graft thrombosis in whom
those in observational cohorts; however, there was 1 notable direct vascular effects may play an important role. More
difference.26 The majority of events occurred secondary to studies are required to further clarify the magnitude of and
graft thrombosis; in contradistinction, observational cohorts reasons for these observations, particularly with respect to
have demonstrated embolic causes as most frequent.26 The specific types of vascular grafts. Whether other antithrom-
most likely explanation for this difference is that because botic therapies also modify ALI as defined is unknown and
of the entry criteria for the present study, the proportion of requires future study.32,33

Vorapaxar and Acute Limb Ischemia by Etiology

N=3,787 with Symptomatic PAD

Vorapaxar Placebo
5% Overall
HR 0.58 HR 0.63
95% CI (0.39 0.86) 95% CI (0.38 1.02)
P=0.006
HR 0.39
95% CI (0.18 0.84)
KM Event Rate (%) at 3 years

HR 0.66
4% 3.9% Synthetic Graft 95% CI (0.24 1.86) HR 0.50
HR 0.63 95% CI (0.09 2.72)
95% CI (0.32 1.24)
Figure 5. Vorapaxar and acute limb
Vein Graft ischemia by type. CI indicates confidence
HR 0.38
3% 95% CI (0.14 1.07)
interval; HR, hazard ratio; KM, Kaplan
Meier, and PAD, peripheral artery
2.3% 2.3% disease.

2%
1.5%
1.3%

1%
0.5% 0.5%
0.4%
0.3%
0.1%
0%
Acute Limb Ischemia Graft Thrombosis In Situ Thrombosis Stent Thrombosis Thromboembolic
 Bonaca et al Acute Limb Ischemia and Outcomes in PAD 1003

Table 3. ALI Outcomes With Vorapaxar in Patients With Any History of PAD and No History of Stroke or TIA (FDA-
Labeled Population With PAD History)
End Point Vorapaxar (n=2313), n (%) Placebo (n=2348), n (%) HR (95% CI) P Value
Hospitalization for ALI 41 (2.0) 70 (3.3) 0.59 (0.400.86) 0.007
Graft occlusion 25 (1.2) 44 (2.1) 0.57 (0.350.94)
Synthetic graft 15 (0.7) 23 (1.1) 0.66 (0.351.27)
Vein graft 5 (0.3) 13 (0.6) 0.39 (0.141.10)
Unknown type 6 (0.3) 10 (0.5) 0.59 (0.211.62)
Native vessel in situ thrombosis 10 (0.5) 23 (1.1) 0.44 (0.210.93)
Stent thrombosis 6 (0.3) 9 (0.5) 0.68 (0.241.91)
Safety*
GUSTO moderate or severe bleed 125 (6.6%) 88 (4.5) 1.50 (1.141.98) 0.003
GUSTO severe bleed 36 (2.0) 33 (1.8) 1.14 (0.711.83)
Intracranial hemorrhage 12 (0.6) 11 (0.6) 1.14 (0.502.58)
Fatal bleed 5 (0.3) 6 (0.3) 0.86 (0.262.82)
All-cause mortality 124 (6.2) 138 (6.8) 0.95 (0.751.21) 0.68
Downloaded from http://circ.ahajournals.org/ by guest on September 17, 2017

ALI indicates acute limb ischemia; CI, confidence interval; FDA, US Food and Drug Administration; GUSTO, Global Utilization of t-PA and Streptokinase
for Occluded Coronary Arteries; HR, hazard ratio; and PAD, peripheral artery disease.
*Safety analyses performed as on-treatment in 4653 patients who received at least 1 dose of study drug.

Limitations observed within multiple etiological subgroups, includ-

ALI was a prospectively adjudicated end point that was
prespecified as a component of the composite end point of
urgent hospitalization for vascular cause of ischemic nature.
Although prospectively adjudicated, this analysis of the
details of ALI should be considered exploratory. Because
of the small numbers of the individual subsets of ALI, it
is not possible in the current data set to determine whether
differences exist in the predictors for the subtypes of ALI
(eg, in situ thrombosis versus graft thrombosis). In addi-
tion, because virtually all patients were taking aspirin, the
effect of vorapaxar monotherapy cannot be determined in the
present data set. However, because background therapy was
balanced in this randomized trial, it could not explain the
benefits seen with vorapaxar. In the description of outcomes
after ALI, it should be noted that follow-up times after ALI
events were variable, limiting the robustness of the estimates
presented, and that these data are provided for descriptive
purposes. The subgroup of patients randomized with symp-
tomatic PAD was a prespecified subgroup that was stratified
at randomization; however, subgroup analysis should gener-
ally be interpreted with caution. In addition, the FDA sub-
group presented was not prespecified and was based on the
FDA analyses and label for use in the United States. Finally,
it should be noted that the present analysis describes ALI in
a selected symptomatic population without atrial fibrillation,
recent MI, or recent stroke and therefore should not be gen-
eralized to broader populations such as those with asymp-
tomatic disease or atrial fibrillation.
Conclusions
Patients with symptomatic PAD are at a heightened risk of
ALI, facing a risk similar to that of stroke or MI. ALI is
associated with significant morbidity and warrants sepa-
rate reporting in clinical trials of antithrombotic therapies
in patients with PAD. Vorapaxar statistically significantly
reduced ALI overall, with clinically significant reductions
ing both bypass graft thrombosis and native vessel in situ
thrombosis.
Sources of Funding
This TRA2P-TIMI 50 trial was supported by a grant from Merck
and Co. Dr Bonaca was supported by a Research Career Development
Award (K12 HL083786) from the National Heart, Lung, and Blood
Institute.
Disclosures
The TIMI Study Group has received significant research grant sup-
port from Accumetrics, Amgen, AstraZeneca, Beckman Coulter,
Bristol-Myers Squibb, CV Therapeutics, Daiichi Sankyo Co Ltd,
Eli Lilly and Co, GlaxoSmithKline, Integrated Therapeutics, Merck
and Co, Nanosphere, Novartis Pharmaceuticals, Nuvelo, Ortho-
Clinical Diagnostics, Pfizer, Roche Diagnostics, Sanofi-Aventis,
Sanofi-Synthelabo, Siemens Medical Solutions, and Singulex. Dr
Bonaca has received consulting fees from Merck, AstraZeneca,
Bayer, and Roche Diagnostics. Dr Creager has received consulting
fees from Aastrom Biosciences, AstraZeneca, Baxter Healthcare,
and Genzyme. Dr Olin has received consulting fees from Merck and
Plurestem. S.A. Murphy has received consulting fees from Eli Lilly
and Amarin Pharmaceuticals. Dr Morrow has received consult-
ing fees from Beckman-Coulter, Boehringher Ingelheim, Critical
Diagnostics, Genentech, Gilead, Instrumentation Laboratory,
Merck, Roche Diagnostics, and Servier. The other authors report
no conflicts.
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Clinical Perspective
Limb ischemic events are an important cause of morbidity and limb loss in patients with symptomatic peripheral artery dis-
ease. Similar to acute myocardial infarction or ischemic stroke in which acute thrombotic occlusion of an artery causes isch-
emia and, unless promptly relieved, tissue death, acute limb ischemia (ALI) is characterized by the sudden decrease in limb
perfusion that threatens tissue loss and limb viability without early reperfusion. Currently, there are few medical therapies
available that reduce the risk of ALI in patients with symptomatic peripheral artery disease. The Trial to Assess the Effects
of Vorapaxar in Preventing Heart Attack and Stroke in Patients With AtherosclerosisThrombolysis in Myocardial Infarction
Downloaded from http://circ.ahajournals.org/ by guest on September 17, 2017

50 (TRA2P-TIMI 50) was a multinational, randomized, double-blind, placebo-controlled trial designed to study the effects
of the protease-activated receptor 1 antagonist vorapaxar on long-term secondary prevention for reducing ischemic risk in
patients with stable atherosclerosis, including symptomatic peripheral artery disease. On the basis of overall efficacy, vora-
paxar has been approved by the US Food and Drug Administration in patients with previous myocardial infarction or periph-
eral artery disease who do not have a history of stroke or transient ischemic attack. ALI was a prospectively collected and
adjudicated efficacy outcome that occurred at a frequency similar to other systemic vascular events and was associated with
significant morbidity. In this symptomatic population, ALI was most frequently caused by acute bypass graft thrombosis or
in situ thrombosis of a diseased vessel and often resulted in limb loss. Vorapaxar added to aspirin or clopidogrel significantly
reduced ALI in this population with consistency across types.
 Acute Limb Ischemia and Outcomes With Vorapaxar in Patients With Peripheral Artery
Disease: Results From the Trial to Assess the Effects of Vorapaxar in Preventing Heart
Attack and Stroke in Patients With AtherosclerosisThrombolysis in Myocardial
Infarction 50 (TRA2P-TIMI 50)
Marc P. Bonaca, J. Antonio Gutierrez, Mark A. Creager, Benjamin M. Scirica, Jeffrey Olin,
Sabina A. Murphy, Eugene Braunwald and David A. Morrow
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Circulation. 2016;133:997-1005; originally published online January 29, 2016;

doi: 10.1161/CIRCULATIONAHA.115.019355
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Copyright 2016 American Heart Association, Inc. All rights reserved.
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