ARTERIAL OCCLUSIVE DISEASE

Acute Arterial Occlusion

Mesenteric Ischemia

Renal Artery Stenosis

I. General info

1. 90% occurs in lower limb
2. Sudden drop in flow occur with 75% occlusion
3. Associated with increased risk for cardiovascular events (CVA, MI, etc.) of a magnitude similar to CAD or cerebrovascular disease
4. Consider Ramipril for prevention of death in pts with with Peripheral Vascular Disease--Click HERE for more
5. Claudication is an INDEPENDENT RISK FACTOR for Abdominal Aortic Aneurysm, so may be worthwhile to screen all pts with peripheral arterial disease for AAA (Arch. Int. Med 156:2081, 1996-JW)

II. Causes

1. Atherosclerosis (same risk factors as Coronary Artery Disease)
2. Raynaud's syndrome
3. Collagen vascular disease
4. Thoracic outlet syndrome (cervical rib compressing subclavian a.)
5. Thromboemboli (including septic)

III. Presentation

1. About 2/3 of patients with PVD are asymptomatic or have atypical symptoms
2. Typical symptoms: "Intermittent Claudication" (pain in one or both legs on walking, primarily in the calves, not relieved with continued walking, relieved with rest)
3. Progresses to pain at rest
4. Subjective limb coldness
5. Pregangrenous changes

1. Pallor on elevation (in <30sec)
2. Rubor on dependency (or cyanosis if far progressed)

4. Skin ulceration
5. Gangrene

IV. Diff dx by pain location:

1. Lower back/buttock: back strain, hip arthritis
2. Thigh: lumbosacral neuritis, lumbar disk herniation, lumbar spinal stenosis, myositis
3. Calf: fallen arches, knee arthritis
4. Foot: plantar neuroma, foot strain, tight shoes, osteoporosis

V. Confirmation of diagnosis

1. Clinical exam including ankle-brachial indices usually sufficient for diagnosis (except renal or mesenteric arterial disease)
2. Imaging studies used primarily to guide revascularization interventions
   1. Arterial duplex ultrasound
   2. Conventional "digital subtraction" angiography (DSA)
   3. Magnetic resonance angiography (almost as accurate as DSA in most situations 

VI. Px

1. Reduced or absent pedal pulses
2. Thickening of nails
3. Lack of hair growth
4. Absence of superficial veins (collapsed)
5. Dermatitis around ulcers
6. "Ankle Brachial Index": ratio of systolic BP in ankle to that in arm. Should be about 1.2; <0.4 is serious disease
7. Ulcers typically located on medial foot and lateral 5th toe

1. Pre-medial malleolar ulcer: typical for VENOUS STASIS
2. Plantar foot ulcer: typical for DM

VII. Tx

1. Lifestyle
   1. Diet
   2. Exercise-may provide benefits equal to revascularization in patients with mild-moderate disease
      1. In a study in 150 pts with intermittent claudication randomized to exercise training (2x/wk supervised x 6mos) vs. angioplasty (with stenting in some cases), revascularization pts improved more rapidly but there was no sig. diff. at 6mos and 12mos in maximum walking distances or overall quality-of-life scores (Radiology 250:586, 2009-JW)
   3. Smoking cessation
   4. Treatment of Dyslipidemias
2. Meds
   1. Antithrombotics
      1. For stable PAD
         1. In a meta-analysis of 18 randomized trials involving over 5,000 pts with PAD, incidence of (CVA, MI, or cardiovascular death) was not sig. reduced by use of ASA (though there was a 12% nonsig. reduction in risk) (JAMA 301:1909, 2009-JW)
      2. After bypass surgery for PAD
         1. In a randomized, unblinded study of 831 pts undergoing LE arterial bypass surgery, ASA 325mg QD + adjusted-dose warfarin (target INR 1.4-2.8) vs. ASA alone (meds started as soon post-op as taking PO’s), over avg. 3y f/u, no sig. diff. in patency rates except for the subgroup of pts receiving prosthetic bypasses of 6mm diameter (as opposed to 8mm, the other size, 71.4% w/warfarin vs. 57.9%).  HOWEVER, sig. higher overall mortality and incidence of major hemorrhagic events in combined-therapy group (32% vs. 23%). ("VA Cooperative Study #362," J. Vasc. Surg. 35:413, 2002)
   2. Vasodilators
      1. Verapamil 120-480mg/d vs. placebo in 44pts with stable PVD increased pain-free walking distance without sig. side f/x c/w placebo (Circulation 95:411, 1997-JW)
   3. Phosphodiesterase inhibitors
      1. Pentoxifylline (Trental) 400mg TID
         1. A methylxanthine derivative
         2. Increases deformability of RBCs and WBC's and may have mild antiplatelet effects
         3. Mildly increases walking ability in patients with PVD.
      2. Cilostazol (Pletal) 100mg BID (50mg BID if taking erythromycin, diltiazem, azole antifungals, or omeprazole)

      1. A phosphodiesterase III inhibitor--may inhibit platelet aggregation and cause some vasodilation
      2. Increases exercise tolerance in pts with intermittent claudication more than placebo

         1. In a meta-analysis of 8 RCTs of 12-24wks duration of cilostazol 50-150mg BID in pts > 40yo with lower-limb PVD and stable mod-severe claudication, cilostazol was ass’d with sig. increases in maximal and pain-free walking distances (50% and 67%, respectively; both sig. greater than placebo).  Subgroup analysis showed similar benefits in men vs. women, pts > 65yo and < 65yo, and pts with and w/o DM.  Sig. improvements also noted in quality-of-life assessments.  (Am. J. Cardiol. 90:1314, 2002)

      3. More effective than pentoxifylline at increasing exercise tolerance in one randomized trial (Circ 98 suppl.1:1, 1998--Med. Lett.)
      4. May take up to 12wks for benefit to become apparent
      5. May cause HA, diarrhea, palpitations, and dizziness
      6. Ass'd with sig. increases in HDL and sig. decreases in LDL c/w placebo in one meta-analysis of 8 RCTs (Am. J. Cardiol. 90:1314, 2002, op. cit.)
      7. Contraindicated in pts with CHF--May increase risk of sudden death

   4. Cholesterol-Lowering Medications
      1. 86 pts with PVD, intermittent claudication, and tot. chol. > 220 randomized to simvastatin 40mg/d vs. placebo. X 6mos.  At 6mos, mean increases in pain-free and total walking distances were sig. greater in simvastatin group (118m and 134m vs. 26m and 11m, respectively); simvastatin group also had sig. greater increases in ABI pre- and post-exercise (Am J Med 114:359, 2003)
      2. 354 pts > 25yo with PVD and intermittent claudication (baseline tot. chol. About 210, baseline LDL about 130) randomized to atorvastatin 10mg/d, 80mg/d, or placebo.  Over 12mo f/u, 80mg atorvastatin group had sig. greater improvement in pain-free walking time than placebo (63% vs. 38%), but no sig. diff. in maximal walking time with either atorvastatin group c/w placebo.  Pts reported greater ambulatory ability on a standardized questionnaire with wither dose of atorvastatin c/w placebo.  Both atorvastatin groups, considered as one group together, had sig. lower incidence of peripheral vascular “events” than placebo group (worsening claudication, onset of rest ischemia, or peripheral revascularization). (Circ. 108:1481, 2003)
      3. 20,536 pts 40-80yo with one of the following risk factors for CAD AND baseline total cholesterol of 135 mg/dL or greater: (Baseline tot. chol. was < 5.5 mmol/L (212 mg/dL) in 7882 pts; LDL < 3.0 mmol/L (116 mg/dL) in 6888 pts):
         • Past MI or other CAD
         • Other occlusive arterial disease
         • DM (5963 pts, 3985 of whom had no CAD
         • Treated HTN if male and > 64yo (only 237 had HTN but no CAD or other occlusive arterial disease)

         Randomized into 4 groups: 40mg/d Simvastatin, Antioxidant blend (vit. E 600mg, vit. C 250mg, beta-carotene 20mg) QD, one or the other, or double-placebo . Over 6y f/u, simvastatin group vs. placebo had sig. less all-cause mortality (12.9% vs. 14.6%, RR = 0.88) over the study f/u period; also sig. less stroke and vascular events in general. The reduction in risk for vascular events was significant in various subgroups including those with vascular disease but no CAD (e.g. PVD or cerebrovascular disease) as well as in diabetics; also sig. for all subgroups of LDL level including those with LDL < 3.0 mmol/L (116 mg/dL) and those with tot. chol. < 5.0 (193 mg/dL); also sig. for all age subgroups and for men & women as subgroups. No sig. diff. in risk of vascular events between antioxidant groups and placebo (British Heart Protection Study; Lancet 360:7, 2002)

      4. In an analysis of data from the British Heart Protection Study (click link for details), of the 7,000 pts with peripheral arterial disease at baseline, simvastatin recipients had sig. lower 5y incidence of (CAD, stroke, or any revascularization) (26.4% vs. 32.7%); differences were still sig. for pts with PAD an no h/o CAD (24.7% vs. 30.5%) and those with PAD and LDL < 116 mg/dL (25.4% vs. 31.1%) (J. Vasc. Surg. 45:645, 2007--JW)

   5. Antibiotics
      1. 40 nondiabetic men (mean age 71y, over 80% smokers) with lower-limb PVD and positive Chlamydia pneumoniae serology (IgG 1:128 or greater) randomized to roxithromycin 300mg PO QD vs. placebo x 28d.  Over mean 2.7y f/u, incidence of peripheral revascularization procedures (angioplasty or bypass) and % of pts who couldn’t walk 200m w/o stopping (among those who didn’t get revascularized) were sig. lower in roxithromycin group (20% vs. 45% and 20% vs. 65%, respectively); significance persisted after adjustment for potential confounders. (Circ 105:2646, 2002)
      2. In a study in 297 pts with stable, symptomatic peripheral arterial disease randomized to rifalazil vs. placebo Qwk x 8, thre was no sig. diff. in peak treadmill walking time at 6mos or overall physical functioning ("PROVIDENCE-1" trial; Circulation 119:452, 2009-JW)
   6. Other medications
      1. In a study in 40 adults with intermittent leg claudication and evidence of superficial femoral artery stenosis randomized to ramipril 10mg/d vs. placebo x 24wks, at 24wks, ramipril group had sig. greater improvement in pain-free walking time and resting and post-exercise ABIs. (Ann. Int. Med. 144:660, 2006--JW)
      2. 40 nonsmoking nondiabetic pts aged 55-70y with lower-limb PVD randomized to IV glutathione (an anti-oxidant) BID x 5d vs. placebo.  At end of treatment, pain-free walking distance was sig. greater in the glutathione group (196 vs. 143m) and several hemodynamic measures of arterial flow were also sig. better. (Mayo Clin. Proc. 77:754, 2002)
      3. Prostacyclin Analogues shown in some uncontrolled studies to reduce pain and/or improve walking distance in patients with claudication (JACC 41:1687, 2000) but not in one RCT (JACC 41:1679, 2003)
      4. Ginkgo biloba was found in a meta-analysis of eight randomized trials to improve maximal walking distance significantly in pts with intermittent claudication (Am. J. Med. 108:276, 2000--cited in Med.  Lett. 46:14, 2004)

3. Surgery
   1. Sympathectomy
   2. Percutaneous transluminal angioplasty (PTA) with or without stenting
      1. 6mo restenosis rates 25-77% in observational studies 
      2. 279 patients w/intermittent claudication secondary to iliac disease all undergoing PTA randomized to stenting vs. stent placement only when hemodynamic results were not adequate; no significant differences for technical or clinical outcomes seen (ref?)
      3. In a Cochrane Collaboration systematic review/meta-analysis of two RCTs comparing PTA alone vs. PTA with stenting (Palmaz-type) in pts w/intermittent claudication due to femoro-popliteal disease (one study demonstrated sig. higher incidence of restenosis in the stented group!), when the data from both studies were combined in a meta-analysis, there were no significant differences in this outcome.  Neither study found significant differences in maximum walking distance between the stented and non-stented groups.  (Endovascular Stents for Intermittent Claudication.  Cochrane Database Syst Rev. 2003;(1):CD003228).
      4. Use of stents coated with drugs that inhibit intimal hyperplasia for lower-extremity PVD is under investigation
   3. Endarterectomy
   4. Bypass
   5. Bypass vs. angioplasty:
      1. In a study in 452 pts with severe limb ischemia (pain at rest or tissue loss) randomized to bypass surgery or balloon angioplasty, 30d incidence of mortality were not sig. diff; 1y incidence of (death or loss of trial leg) were not sig. diff., but incidence of requiring a second intervention was sig.  higher in angioplasty patients (26% vs. 18%) (Lancet 366:1925, 2005--JW)
   6. Intra-arterial thrombolytics
      1. Similar amputation-free survival at 6mo or 1y c/w bypass in a randomized trial in 544 pts with sx of lower-limb ischemia < 14d duration; greater incidence of major hemorrhagic complications w/urokinase (12.5% vs. 5.5%; NEJM 338:1105, 1998--JW)
      2. On subgroup analysis of the same cohort, multivariate analysis identified only length of the occlusive thrombus > 30cm as a predictor of better outcome (1y amputation-free survival) with thrombolysis than with surgery (Surgery 124:336, 1998--JW)
   7. Amputation (only indicated if highly progressed; 2-3% chance of amputation being needed secondary to op. complications!)

4. Intravascular radiation ("brachytherapy") for prevention of restenosis after percutaneous transluminal angioplasty (PTA) or bypass
   1. 17 patients aged 43-89 randomized to IR vs. no IR in conjunction with PTA of the femoropopliteal arterial system.  After 12 months, incidence of restsenosis or occlusion was significantly lower in the IR group (36.4% vs. 64.7%, odds ratio 0.56) (“Vienna-2” study, Circ. 102:2694, 2000)
   2. 120 pts with in-stent restenoses of saphenous-vein bypass grafts randomized to implantation of an Iridium-192-laden ribbon or a nonradioactive control ribbon after revascularization (PTA, atherectomy and/or stenting).  Restenosis (assessed angiographically at 6 months) was sig. lower in the IR group (21% vs. 44%).  12mo incidence of both revascularization of target vessel and a composite clinical outcome (cardiac death, Q-wave myocardial infarction, or reascularization of the target vessel) were sig. lower in IR group (17% vs. 57% and 32% vs. 63%, respectively) (NEJM 346:1194, 2002).

ACUTE ARTERIAL OCCLUSION:

1. sudden-onset, sharp, well-localized pain
2. "5 P's": pain, pallor, pulselessness, paresthesia, paralysis

RENAL ARTERY STENOSIS:

1. Diagnosis
   1. Angiography is gold standard for dx but rarely performed b/c of invasiveness
   2. Doppler ultrasonography has similar accuracy to MRA, and allows measurement of resistance to renal artery flow, which predicts response to revascularization for renal artery stenosis (NEJM 344:410, 2001)
   3. In a meta-analysis of 55 studies comparing angiography to noninvasive studies for RAS, looking at receiver operating characteristic curves, greatest area under the ROC curve (indicating overall accuracy including sensitivity + specificity) was greatest for CT angiography and MR angiography.  Captopril renal scintigraphy and ultrasonography were not as good (Ann. Int. Med. 135:401, 2001--JW)
2. Natural history:
   1. In a retrospective study of 68 pts with RAS (> 70% stenosis) who had not undergone revascularization; all had HTN. Over mean f/u 39mos, no change seen in avg. BP, though avg. # of antihypertensive drugs rose from 1.6 to 1.9; mean serum Cr. rose from 1.4 to 2.0, though only 15% of pts had deterioration of renal function (Mayo Clin. Proc. 75:437, 2000--JW)
   2. Among 477 pts with suspected renal artery stenosis b/c of resistant HTN or increase in serum Cr while on ACEIs, all of whom underwent angiography, sig. predictors of renal a. stenosis on multivariate analysis were as follows (Ann. Int. Med. 129:705, 1998--JW)

   1. Older age
   2. Female gender
   3. Signs and sx of atherosclerosis elsewhere
   4. Recent onset of HTN
   5. Smoking
   6. Abdominal bruit
   7. Elevated serum creatinine
   8. Hypercholesterolemia
   9. Normal body weight

3. Tx with revascularization
   1. 106 pts with atherosclerotic renal artery stenosis dx'd by angiography randomized to PTCA vs. no PTCA; all received meds if needed for HTN. At 3mo f/u, PTCA group required fewer meds (mean 1.9 vs. 2.5); no diff's in mean BP or mean creatinine clearance (NEJM 342:1007, 2000--JW)
   2. In a case series of 215 pts undergoing angioplasty & stenting of > 70% renal artery stenosis, improvement in BP was independently associated with female sex, high baseline mean BP, and normal renal parenchymal thickness (Circ 108:2244, 2003--abst)
   3. In a study  in 140 pts with renal artery stenosis 50% or greater and CrCl < 80 mL/min randomized to renal artery stent placement vs. medical treatment alone, incidence of (20% or greater decline in CrCl over 2y) was not sig. diff. between the two groups.  (Ann. Int. Med. 150:840, 2009-JW)