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25% reduction in vascular death, nonfatal MI, or
 1) Cholesterol reduction
 patients  including  those  with  PAD  to  minimize
                                                                  therapy alone.  However, major bleeding events
            cerebrovascular  accident  in  subgroups  of
 cardiovascular  events.   Thus,  ezetimibe  may
                                                                                 19
 12
 According to ACC/AHA guidelines, high-intensity
            patients  with  atherosclerotic  vascular  disease
                                                                  and  intracranial  hemorrhage  were  significantly
 prove  to be an effective  therapy when
 statin  is  recommended  for  patients  with
                                                                  increased.  Further  analysis  reported  poor
            (manifested  as  recent  ischaemic  stroke,
 co-administered  with  statin  therapy.  More
 symptomatic PAD (Target LDL-C of <70) with a
                                                                  compliance and a 30% rate of discontinuation of
            myocardial infarction, or symptomatic peripheral
 specific  studies  are  required  for  patients  with
 class I recommendation.
 8
            arterial disease).
                                                                  warfarin at follow-up.  Thus, poor adherence to
 PAD.
                                                                                        19
 a) Statin
                                                                  therapy  could  be  a  possible  reason  for  lack  of
            c) Dual anti-platelet therapy (DAPT)
 In  the  Heart  Protection  Study  Collaborative  c) PCSK9 (proprotein convertase subtil-
                                                                  efficacy in study patients.
                                                                                            19
 isin/kexin type 9) inhibitors
            In  the  CHARISMA  trial  (Clopidogrel  for  High
 Group  in  PAD  patients,  treatment  with
                                                                  b) Rivaroxaban
 In  the  FOURIER  trial  (Further  Cardiovascular
                                            and
                                                     Ischemic
            Atherothrombotic
 moderate-intensity  statin  therapy,  simvastatin
 Outcomes  Research  With  PCSK9  Inhibition  in
                                                                  The  COMPASS  trial  (Cardiovascular  Outcomes
            Stabilization,  Management,  and  Avoidance)
 reduced  peripheral  vascular  events  by  17%.  A
 9
 Subjects With Elevated Risk) patients with PAD
            DAPT  was  compared  to  single  antiplatelet
                                                                  for  People  Using  Anticoagulation  Strategies)
 recent  observational  study  also  demonstrated
 showed  a  59%  reduction  in  LDL-C  with
                                                                  demonstrated  mortality  reduction  benifit  with
            therapy  and  included  patients  with  PAD.  A
                                                          17
 that  high-intensity  statin  therapy  is  more
 evolocumab,  resulting  in  a  3.5%  absolute  risk
            post-hoc  sub-group  analysis  in  PAD  patients
                                                                  low-dose rivaroxaban in combination with aspirin
 effective in preventing limb loss than moderate
 reduction  in  cardiovascular  events  (MI,  death,
                                                                                                Major  adverse  limb
            revealed that DAPT therapy led to non-significant
                                                                  for  patients  with  PAD.
 intensity  therapy.   Besides  peripheral  vascular
                                                                                          20, 21
 10
 stroke,  hospitalization  for  unstable  angina,  and
            reduction  in  the  primary  endpoint  (rate  of  CV
                                                                  events  occurred  less  often  in  rivaroxaban  and
 complications,  statin  therapy  also  prevented
 coronary  revascularization)  compared  with  a
            death, MI, or stroke) - 7.6% in the clopidogrel plus
                                                                  aspirin combination group than aspirin alone.
                                                                                                                 20, 21
 systemic complications and reduced the rate of
 1.6% absolute risk reduction in patients without
                                                                  There  was  no  significant  increase  in  fatal
            aspirin  group  and  8.9%  in  the  placebo  plus
 all cardiovascular events :
 9
   Major  adverse  limb  events  were  also
 PAD.
 13,14
                                                                  bleeding  or  symptomatic  intracranial  bleeding
            aspirin  group  (hazard  ratio,  0.85;  95%  CI,
 coronary revascularization (30% reduction)
 reduced (acute limb ischemia, major amputation,
            0.66–1.08; P = 0.18)
                                                                  between the two treatment groups (P=0.40).
                                                                                                                 20, 21
 major coronary events (21% reduction)
 or  urgent  peripheral  revascularization  for
                                                                  The Heart Protection Study found a 22% relative
 ischemic stroke (26% reduction).
            3) Anticoagulation
 ischemia).
 13
                                                                  risk  reduction  in  the  first  major  vascular  event
            CLI
                      is
                                                            of
                                                                  with moderate-intensity statin therapy while the
 b) Ezetimibe
 2) Antiplatelet therapy
            atherothromboembolism  in  the  limbs.  Clinical
                                                                  COMPASS  trial  showed  a  28%  relative  risk
 Ezetimibe  selectively  blocks  Niemann-Pick
            evidence highlights that timely anticoagulation in
                                                                  reduction in the primary outcome with the use of
 C1-like  1  protein  (NPC1L1),  that  transports  a) Aspirin
            high  risk  patients  may  prevent  limb-related
                                                                  low-dose  rivaroxaban  and  aspirin.  HPS  and
 cholesterol  in  the  intestines  and  inhibits  lipids
 Aspirin  has been shown to be effective for
            complications  from  PAD,  as  well  as  other
                                                                  COMPASS  were  different  studies.  Mentioned
 absorption in the gastrointestinal tract.  It is a
 symptomatic PAD. CLIPS (Critical Leg Ischemia
 11
            cardiovascular morbidity and mortality.
                                                    18
                                                                  RRR values are for information only, and not for
 promising
 treatment
 option
 treat
 to
 Prevention Study) trial provides a direct evidence
                                                                  direct comparison.
                                                                                     20, 21
 hypercholesterolemia  as  it  selectively  reduces
            a) Warfarin
 regarding usefulness of low-dose aspirin (81 mg)
 low-density lipoprotein or LDL (“bad” cholesterol)
 in  366  patients  with  symptomatic  and
            The  WAVE  trial  (Warfarin  Antiplatelet  Vascular
                                                                  4) Blood Pressure management
 and
 without
 the
 affecting
 triglycerides,
 asymptomatic  PAD and  showed a  64%  relative
            Evaluation)  investigated  the  use  of  warfarin  in
                                                                  Several  prospective  and  retrospective  studies
 concentration  of  “good”  cholesterol  or  high
 risk reduction in major vascular events [ischemic
            combination  with  aspirin  for  patients  with
                                                                  have  shown  a  reduction  in  mortality  with
 density lipoproteins (HDL).
 stroke, MI, and vascular death (P=0.022)].
            symptomatic  PAD  (81.8%  of  the  total  trial
 11
 15
                                                                  Angiotensin-converting enzyme (ACE) inhibitors
            population),  subclavian  disease,  and  carotid
                                                                  and  Angiotensin  receptor  blockers  (ARBs)  over
 The  IMPROVE-IT  trial  (Improved  Reduction  of  b) Clopidogrel
            disease. The trial found no significant difference
                                                                                                           Based  on
                                                                  other  antihypertensive  agents.
                                                                                                  22,  23,  24
 The  CAPRIE  trial  (Clopidogrel  Versus  Aspirin  in
 Outcomes:  Vytorin  Efficacy  International  Trial)
                                            major
                 the
                                       of
                        occurrence
            in
                                                      adverse
                                                                  these  findings,  both  European  Society  of
 Patients at Risk for Ischemic Events) showed a
 showed  that  ezetimibe  benefits  high-risk
                               events
                                         between
            cardiovascular
                                                                  Cardiology and ACC/AHA guidelines have given a
                                                                                                              17
         Vasoclick, Edition 1  6 the   Risk  consequence  patients   receiving  combination  aspirin  and  warfarin
 class  II  recommendation  for  ACE  inhibitors  or   reduction  in  major  adverse  limb  events  along   Am Coll Cardiol 2019;73:e285–e350.   18) Hess CN, Debus ES, Nehler MR, Anand SS, Patel MR,
 doi:10.1016/j.jacc.2018.11.003  Szarek M, Capell WH, Hsia J, Beckman JA, Brodmann M,   26) Hageman D, Fokkenrood HJ, Gommans LN, van den
 ARBs or ARB for management of PAD. 22  with  cardiovascular  events.  Thus,  the  novel   Diaz R, Habertheuer P, Leeper NJ, Powell RJ, Sillesen H,   Houten MM, Teijink JA. Supervised exercise therapy
 strategy  of  rivaroxaban  and  aspirin  holds   9) Heart Protection Study Collaborative Group.   Muehlhofer E, Berkowitz SD, Haskell LP, Bauersachs RM,   versus home-based exercise therapy versus walking
 Bonaca MP. Reduction in Acute Limb Ischemia With
 Randomized trial of the effects of cholesterol-lowering
        advice for intermittent claudication. Cochrane Database
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 and improve the quality of life of PAD patients.   arterial disease and other high-risk conditions. J Vasc   VOYAGER PAD. Circulation 2021 Dec
 a) Smoking cessation  Surg 2007;45:645–654; discussion 653–654. doi:   7;144(23):1831-1841. doi:
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