Peripheral arterial disease (PAD) leads to obstruction of arteries, primarily caused by atherosclerosis, resulting in ischemic complications and symptoms like intermittent claudication. The prevalence of PAD is significant among older adults, affecting over 200 million people globally, with various treatment options including pharmacotherapy, lifestyle changes, and supervised exercise programs to improve symptoms and reduce complications. Management strategies emphasize risk factor optimization, such as blood pressure and lipid control, while newer agents like GLP-1 agonists and combinations of anticoagulants and antiplatelet therapies show promise in improving patient outcomes.

1. DR. Laxminarasimha Reddy
SRIHER
PERIPHERAL ARTERIAL DISEASE
(EPIDEMIOLOGY, PATHOLOGY,
TREATMENT)

2. • Peripheral artery disease (PAD) generally refers to acute or chronic
obstruction of the arteries supplying the lower or upper extremities
that, when severe, results in downstream ischemia and potentially
tissue loss.
• Causes - atherosclerosis, thrombosis, embolism, vasculitis,
fibromuscular dysplasia (FMD), or entrapment.
• Primary morbidity - limb symptoms and ischemic limb complications
(including intermittent claudication, chronic critical limb ischemia
(CLI), acute limb ischemia (ALI), and tissue loss)

3. EPIDEMIOLOGY
• Prevalance - 6% in persons 40 years and older, 15% to 20% in those
65 years and older
• Annual incidence and prevalence of PAD are 2.69% and 12.02%,
respectively
• PAD affects more than 200 million people worldwide
• men > women
• Blacks > whites (prevalence & higher rates of amputation)

4. • Prevalence of claudication:
1% to 4.5% - older than 40 years
increases with age
men > women
• Incidence of CLI - 11.08%
• Incidence of ALI - 1% to 2% per year
• The incidence of amputation - 112 to 250 per million per year.

6. ANKLE-BRACHIAL INDEX
• Ratio of SBP measured at the ankle : brachial artery.
• The normal ABI range = 1 to 1.4.
• 0.91 to 0.99 = borderline
• 0.90 or less = abnormal.
• 0.90 or lower  stenoses greater than 50%. (specificity of 83% - 99%;
sensitivity of 69% - 73%)
• The sensitivity of an ABI less than 1.0 approaches 100%.
• Patients with symptoms of leg claudication often have an ABI from -
0.5 to 0.8
• Patients with CLI usually have an ABI < 0.5.

7. • A low ABI is associated with shorter walking distance and lower speed.
• Less than 40% of patients whose ABI < 0.40 can complete a 6MWT.
• In patients with skin ulcerations an ankle SBP < 55 mm Hg  poor ulcer
healing.
• Leg BP recordings are not reliable in patients with calcified vessels
• An ABI > 1.40 = noncompressible artery (not useful confirming/
excluding PAD).
• In this case, a toe-brachial index (TBI) may be informative, with a ratio
of 0.70 or higher reflecting normal perfusion pressure.

8. PATHOPHYSIOLOGY
• Obstructive lesions  limit blood flow and O2 delivery during exercise
• Intermittent claudication results from an O2 supply demand
mismatch in the exercising muscle.
• Impairment in O2 delivery capacity + dysfunction in O2 extraction/
utilization at the muscular level  ischemic pain through activation of
local sensory receptors by accumulation of lactate or other
metabolites
Thrombosis  key role in the pathophysiology of ALI & chronic CLI
(suggesting a complex interplay between progressive atherosclerosis
and subacute thrombosis leading to worsening ischemia

9. Factors Regulating Blood Supply
• Flow through an artery perfusion pressure
1 / vascular resistance.
• Stenoses reduce flow through the artery (Poiseuille equation)
Q= ΔPπr 4 /8ηl
• ΔP is the pressure gradient across the stenosis,
• r is the radius of the residual lumen,
• η is blood viscosity,
• and l is the length of the stenosed segment.

10. • As the severity of a stenotic lesion increases, flow falls
progressively.
• BP gradient exists at rest if there is 50% stenosis
• If not, gradient is picked up during exercise when blood flow
increases.
• Metabolic demand of exercising muscle > its blood supply  local
metabolites (adenosine, NO, K+, and H2 ions) accumulate, and
peripheral resistance vessels dilate.
• Intramuscular pressure rises during exercise (may exceed the BP
distal to an occlusion)  halts blood flow.
• Flow through collateral blood vessels can meet the metabolic needs
at rest.
• But does not suffice during exercise.

12. • Peripheral atherosclerosis  reduced vasodilator capability of both conduit
and resistance vessels.
• Normally, arteries dilate in response to pharmacologic and biochemical
stimuli (Ach, serotonin, thrombin, and bradykinin) and shear stress.
• This vasodilator response (endothelial NO)  facilitates the delivery of blood
to exercising muscles in healthy persons.
• In PAD  impaired endothelium dependent vasodilation in response to flow
or pharmacologic stimuli. This prevents an increase in blood supply to
exercising muscle.
• Patients with severe limb ischemia  reduced number of perfused skin
capillaries.
• Causes of decreased capillary perfusion in CLI  reduced RBC deformability,
increased leucocyte adhesiveness, platelet aggregates, fibrinogen,
microvascular thrombosis, excessive vasoconstriction, and interstitial
edema.

13. Skeletal Muscle Structure and Metabolic Function
• EP and HPE  evidence of partial axonal denervation of skeletal muscle in legs affected by
PAD.
• Type I / oxidative / slow-twitch fibers = preserved
• Type II / glycolytic / fast-twitch fibers = lost  decreased muscle strength and reduced
exercise capacity.
• In skeletal muscle distal to PAD, the shift to anaerobic metabolism occurs earlier during
exercise and persists longer after exercise.
• Patients with claudication have increased lactate release and accumulation of acylcarnitines
during exercise and slowed O2 desaturation, indicative of ineffective oxidative metabolism.
• Mitochondrial respiratory activity
Phosphocreatine delayed in the calf muscles of PAD patients.
ATP recovery time

14. TREATMENT
• Diet modification
• weight optimization
• Exercise
• Smoking cessation
• Risk factor optimisation - hypertension and dyslipidemia.
to reduce and prevent microvascular complications, including
neuropathy and amputation.

15. Diet
• Mediterranean diet  lower risk of incident PAD
• help optimize body weight and reduce sodium  improvements in
metabolic parameters and BP
Smoking Cessation
• PAD patients who discontinue smoking have approx twice the 5-year
survival rate of those who continue to smoke.
• Pharmacologic interventions that effectively promote smoking
cessation include nicotine replacement therapy, bupropion, and
varenicline

16. GLYCEMIC CONTROL
• GLP 1 agonists (liraglutide, semaglutide) improved macrovascular
outcomes in patients with T2DM + established CV disease/ at
heightened CV risk
• Long-term glycemic control reduces microvascular disease and
complications including amputation
• LEADER trial subanalysis  reduced amputations with liraglutide in
patients with T2DM and vascular disease.
• GLP-1 agonists  particularly attractive in pts with diabetes +
concomitant PAD.

18. BLOOD PRESSURE CONTROL
• The intensity of antihypertensive treatment:
must take into consideration i) benefits of reduced risk of CV events
ii) potential to exacerbate limb symptoms.
• SPRINT trial a target SBP of 120 mm Hg or less resulted in a significant
reduction in CV events, but only few patients with PAD were included.
• ALLHAT trial  (33,357 patients, 4.3 years follow up) SBP < 120 mm Hg
and >160 mm Hg  26% higher hazard of PAD events

19. • Relationship between DBP and PAD events  72% increased hazard in
those with a DBP < 60 mmHg vs ≥ 60 mmHg (U-shaped relationship)
• HOPE (Heart Outcomes Prevention Evaluation) study  ACE inhibitor
ramipril decreased the risk for vascular death, MI/ stroke by 22%, with
44% having PAD.
• Beta blocker therapy  no significant impairment of walking capacity,
no increase of CV events /amputation

24. DYSLIPIDEMIA MANAGEMENT
• Particularly lowering of LDL cholesterol is of key importance
• Recent guidelines recommend achievement of very low LDL targets using
combination therapies
• The Heart Protection Study, (RCT of simvastatin vs placebo)  simvastatin
reduced the risk of a first acute peripheral vascular event.
• TREADMILL (Treatment of Peripheral Atherosclerotic Disease with
Moderate or Intensive Lipid Lowering) trial atorvastatin (80 mg)
increased pain-free walking distance by more than 60% vs a 38% increase
with placebo, reduction in amputations .

25. • The FOURIER trial  50% reduction MALE with evolocumab,
consistent benefit for MALE reduction with lower achieved LDL
cholesterol extending to levels < 10 mg/dL.
• Lipoprotein(a)  PAD risk and adverse outcomes, lowered by PCSK9
inhibition.
• ODYSSEY trial alirocumab vs placebo after ACS  reduction in
MALE (primarily by Lp(a) reduction rather than LDL reduction)

28. ANTIPLATELET MONOTHERAPY
• 23% reduction in vascular death, MI / stroke with antiplatelet
monotherapy, no reported benefits for MALE.
• POPA - DAD (Prevention of Progression of Arterial Disease And Diabetes)
and AAA (Aspirin for Asymptomatic Atherosclerosis) trials found no
difference in CV outcomes with long-term aspirin in asymptomatic
patients with abnormal ABI
• The CAPRIE (Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events)
trial  clopidogrel vs aspirin in reducing ischemic events in patients with
recent MI, recent ischemic stroke, or PAD. Overall, clopidogrel reduced
vascular death, myocardial infarction/ stroke by 8.7% vs aspirin.

29. • 6452 patients in the PAD subgroup clopidogrel showed greater 23.8%
relative risk reduction. However, there were numerically more
amputations with clopidogrel (52 vs 47) than aspirin.
• The EUCLID (Examining Use of Ticagrelor in PAD) trial evaluated
ticagrelor vs clopidogrel  no difference in outcome
• Platelet Inhibition and Patient Outcomes (PLATO) trial superiority for
ticagrelor vs clopidogrel for MACE in patients with ACS and PAD.
ANTIPLATELET MONOTHERAPY REDUCES CV RISK IN PATIENTS WITH
SYMPTOMATIC PAD, BUT IT IS OF UNCERTAIN BENEFIT IN THOSE WITH A
MARGINALLY LOW ABI AND NO SYMPTOMS.

30. DUAL ANTIPLATELET
THERAPY
• The CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic
Stabilization, Management, and Avoidance) trial evaluated the addition
of clopidogrel to aspirin vs aspirin alone  benefit in those with
established CV disease, particularly prior MI. No reported benefit for
MALE, there was a reduction in limb ischemic events.
• The PEGASUS-TIMI 54 trial (Prevention of Cardiovascular Events in
Patients with Prior Heart Attack Using Ticagrelor VS Placebo on a
Background of Aspirin)  addition of ticagrelor 60mg BD + aspirin vs
aspirin alone  ticagrelor resulted in a 5.2% absolute risk reduction,
significant reduction in adjudicated MALE, reduction in ALI by 35%.

32. • The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients
Intervention Study (THEMIS) studied the same regimen in patients with DM
and stable CAD (no h/o MI)  ticagrelor superior to placebo for MACE
reduction. (statistically significant, approximately 50% reduction in ALI or
major amputation)
• PRODIGY trial  prolonged DAPT after PCI, showed benefit/ lower
mortality with extended P2Y12 inhibition in those with PAD and CAD. Limb
outcomes were not reported.
• CASPAR (Clopidogrel and Acetylsalicylic Acid in Bypass Surgery for
Peripheral Artery Disease) trial  DAPT versus aspirin  did not reduce the
primary composite endpoint of graft occlusion, revascularization,
amputation, or death in patients undergoing below-knee bypass surgery
for PAD and moderate or severe bleeding was increased.

33. • Antiplatelet monotherapy for MACE reduction in PAD, but data for
MALE benefit are mixed.
• The efficacy of DAPT is supported for the reduction of MACEs and
MALEs in patients with both PAD and CAD, although there is
increased bleeding risk.
• Although DAPT is commonly used, there is paucity of RCTs to
support DAPT use for the reduction of MALEs after intervention.

34. COMBINATION ANTIPLATELET AND ANTICOAGULANT
THERAPY
• The WAVE (Warfarin Antiplatelet Vascular Evaluation) trial compared
combination antiplatelet and therapeutic vitamin K antagonist (VKA)
therapy with antiplatelet therapy alone in patients with PAD.
• Warfarin did not reduce the primary composite endpoint, but there
was a greater than 3X increase in life-threatening bleeding
• Therapeutic warfarin has been used after bypass surgery to reduce the
risk of graft thrombosis.

35. • The Dutch Bypass Oral Anticoagulants or Aspirin Study examined this
 found no benefit in limb outcomes with warfarin after infrainguinal
bypass surgery but a significant increase in hemorrhagic stroke
(Although used in patients felt to be at high risk of graft thrombosis).
• The COMPASS trial (27,359 patients) with stable atherosclerotic vascular
disease, including lower extremity PAD to rivaroxaban 2.5 BD + aspirin,
rivaroxaban 2.5 mg BD, or aspirin monotherapy  24% reduction in
MACEs for the rivaroxaban + aspirin arm vs aspirin alone, while the
rivaroxaban only arm did not show superiority.
• The benefits extended to reductions in CV death and all-cause
mortality.

36. • The benefit was accompanied by a 70% increase
in major bleeding but no statistically significant
increase in intracranial hemorrhage/fatal bleeding.
• In addition to benefits for MACEs, rivaroxaban
significantly reduced the MALEs by approx 45%.
The greatest absolute benefits observed in
patients with symptomatic PAD with a h/o prior
revascularization.

37. • The VOYAGER PAD trial  aspirin and rivaroxaban 2.5 mg BD vs aspirin
alone in a broader PAD population selected only on the basis of
symptomatic lower extremity PAD requiring intervention. In contrast to
COMPASS, only 1/3rd had CAD and 10% had a prior MI.
• Combination of aspirin and rivaroxaban 2.5 BD was superior to aspirin
alone, with a 15% relative risk reduction and 2.6% absolute risk reduction
at 3 years. There was a 43% relative increase and 0.78% absolute increase
in major bleeding at 3 years but no increase in intracranial hemorrhage or
fatal bleeding.
• Although rivaroxaban increased bleeding, there was a net benefit in both
studies with a 6:1 benefit-risk ratio in VOYAGER PAD.

38. OTHER COMBINATION THERAPIES
• The TRA2P-TIMI 50 trial  vorapaxar (antagonist of protease activated receptor 1
(PAR-1), which is the platelet receptor for thrombin) + aspirin and/or clopidogrel) in
stable patients with established atherosclerosis.
• Overall, vorapaxar reduced the risk of MI, stroke, and CV death but with an
increase in moderate or severe bleeding.
• Benefit was greatest in patients with MI or PAD, Overall harm in patients with prior
stroke.
• decreased ALI by 42%,with associated reductions in risk of graft thrombosis, stent
thrombosis, and de novo thrombosis and the greatest benefit in patients with prior
revascularization.
• Subsequent analyses  benefit of vorapaxar for MACEs was isolated to those with
concomitant CAD + PAD.

39. SUPERVISED AND HOME-BASED EXERCISE
TRAINING
• Most effective noninvasive intervention for improving limb-related symptoms.
• Postulated mechanisms of benefit  formation of collateral vessels,
improvement in endothelium-dependent vasodilation, increased the
expression of angiogenic factors, particularly in hypoxic tissue, increased
capillary density, changes in skeletal muscle structure and function, such as
increased muscle mitochondrial enzyme activity, oxidative metabolism, and
ATP production rate, and decrease in short-chain acylcarnitine concentrations,
which indicates improvement in oxidative metabolism and increased peak O2
consumption.
• increases maximal walking time by 50% to 200%.
• Each session- at least 30 mins in duration, at least thrice a week for 6 months,
and when walking is the mode of exercise.

40. • CLEVER (Claudication Exercise versus Endoluminal Revascularization)
trial in patients with iliac artery stenosis, supervised exercise training
improved mean walking time more than endovascular intervention.
However QOL was better in intervention group.
• In the ERASE (Endovascular Revascularization and Supervised
Exercise) trial, the combination of endovascular revascularization
and exercise in patients with femoropopliteal disease was superior
to exercise alone.
• Current guidelines recommend that patients with intermittent
claudication undergo supervised exercise rehabilitation as initial
therapy.

42. PHARMACOTHERAPY TO IMPROVE CLAUDICATION
• Pentoxifylline is a xanthine derivative.
decreases blood viscosity and to improve erythrocyte flexibility.
• Cilostazol is a quinolinone derivative that inhibits PDE3, thereby decreasing
degradation of cyclic AMP and increasing its concentration in platelets and blood
vessels.
Inhibits platelet aggregation and causes vasodilation in experimental animals
MOA in patients with PAD is not known.
Meta-analyses  cilostazol improves absolute claudication distance by 40% to 50% in
comparison to placebo.
Should not be used in patients with congestive heart failure because other PDE3
inhibitors decrease survival.

43. Vasodilators
• During exercise, resistance vessels distal to a stenosis dilate in response to
ischemia. Vasodilators would have minimal if any effect on these
endogenously dilated vessels but would decrease resistance in other
vessels and create a relative steal phenomenon, thereby reducing blood
flow and perfusion pressure to the affected leg.
• Moreover, in contrast to their effects on myocardial O2 consumption in
patients with CAD, vasodilators do not reduce skeletal muscle O2 demand.
Other Medical Therapies
• Serotonin (5-HT2) antagonists, alpha adrenergic antagonists, l-arginine,
carnitine derivatives, vasodilator prostaglandins, antibiotics, and
angiogenic growth factors.
• No proven benifits

44. Percutaneous Transluminal Angioplasty
• for selected patients with lifestyle-limiting claudication despite a trial of
exercise rehabilitation or pharmacotherapy.
• DCB and DES increase long-term patency and reduce the need for
recurrent revascularizations.
Peripheral Artery Surgical revascularisation
• improves symptoms in patients with disabling claudication and is
indicated to relieve rest pain and preserve limb viability in patients with
CLI that is not amenable to percutaneous interventions.
• Planning for surgical procedures requires imaging to ensure sufficient
arterial inflow to and outflow from the graft to maintain patency.
• Surgical approaches include - endarterectomy, bypass, and hybrid
approaches (endovascular and surgical).

45. Aortobifemoral bypass  Most common open surgical operation
performed in patients with aortoiliac disease
• a knitted or woven prosthesis made of Dacron or
polytetrafluoroethylene (PTFE) is anastomosed proximally to the aorta
and distally to each common femoral artery.
• At times, the iliac artery is used for the distal anastomosis to
maintain anterograde flow into at least one hypogastric artery.
• operative mortality - 4% (although high-volume centers report lower mortality rates)
• 5 year patency rates for aortobifemoral bypass grafts > 80%.

46. • Extra-anatomic surgical reconstructive procedures 
axillobifemoral bypass
iliobifemoral bypass, and
femoral-femoral bypass.
• These bypass grafts circumvent the aorta and iliac arteries and are
generally used in high-risk patients with CLI.
• 5 year patency rates
50% to 70%  axillobifemoral bypass
70% to 80%  femoral-femoral bypass grafts.
The operative mortality rate – 3 to 5% (serious comorbid conditions and advanced
atherosclerosis)

47. • Reconstructive surgery for infrainguinal arterial disease:
femoral-popliteal
femoral-tibial
femoral-peroneal artery bypass.
In situ or reversed autologous saphenous veins or synthetic grafts made
of PTFE are used as conduits.
5 primary patency rates for femoral-popliteal reconstruction:
80%  autogenous vein grafts
75%  PTFE grafts
The operative mortality rate for infrainguinal bypass operations - 2% to
3%.

48. Graft stenoses due to:
• technical errors at surgery, such as retained valve cuffs or intimal
flap or valvotome injury, from fibrous intimal hyperplasia (usually
within 6 months of surgery)
• atherosclerosis, which usually occurs within the vein graft (at least 1
to 2 years after surgery)
Graft surveillance protocols:
use of color assisted duplex ultrasonography has enabled the
identification of graft stenoses, thereby prompting graft revision and
avoiding complete graft failure.

50. THANKYOU