Disease-a-Month 61 (2015) 356–365

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Clinical pearls in vascular medicine and anticoagulation Robert D. McBane, MD, Scott C. Litin, MD, John B. Bundrick, MD

Case 1 A 60-year-old man is evaluated for a 2-year history of slowly progressive left leg pain with walking, now limiting him to one block. With standing for 5 min, his symptoms will resolve. He has no rest pain or ulcerations on his feet. His CV risk factors include ongoing tobacco use, hypertension, and hyperlipidemia. On exam, he has a left pelvic and femoral bruit with diminished pulses in the left foot. His bedside ABI is 0.65 on the left. In addition to treating his risk factors, which of the following would you recommend? A. B. C. D. E.

Walking program CT angiography to define the location and extent of atherosclerotic disease angiography with angioplasty alone of the iliac artery angiography with stenting of the iliac artery surgical bypass of the iliac artery lesion

Discussion Peripheral artery disease (PAD) has an estimated US prevalence of 8 million. The typical presenting symptom is walking impairment due to intermittent claudication. There have been a number of studies assessing the benefits of walking programs for the treatment of intermittent claudication. In general, this intervention increases the walking distance to the onset of discomfort by more than 200 yards (179%) and the maximal walking distance by 400 yards (4 100% increase). A recent randomized controlled trial compared supervised exercise to either primary stenting or optimal medical therapy in patients with intermittent claudication due to iliac artery disease. All patients were treated with cilostazol (Pletal) regardless of randomization. In this study, improvement in the peak walking time at 6 months was nearly 2-fold greater in the supervised exercise group compared to primary stenting and nearly 6-fold greater than optimal medical therapy. Based on these combined data, the current treatment guidelines http://dx.doi.org/10.1016/j.disamonth.2015.04.006 0011-5029/& 2015 Mosby, Inc. All rights reserved.

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recommend supervised exercise for the initial treatment for all PAD patients with intermittent claudication (grade 1A). This should include either treadmill or track walking to reproduce symptoms for 30–60 min/session, 3 sessions per week for 3 months (grade 1A). Absolute indications for revascularization include rest pain or non-healing ulceration of the affected limb. Life-style limiting symptoms are a relative indication for revascularization, which should be reserved for the patients who have failed a walking program.

Pearl Although it would seem that angioplasty and stenting provides a quick and easy “fix” for patients with intermittent claudication, the evidence and guidelines support a structured walking program as the initial treatment.

References 1. Murphy TP, et al. Supervised exercise versus primary stenting for claudication resulting from aortoiliac peripheral artery disease: 6-month outcomes from the claudication: exercise versus endoluminal revascularization (CLEVER) study. Circulation. 2012;125:130–139. 2. Gardner AW, Poehlman ET. Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis. J Am Med Assoc. 1995;274(12):975–980. 3. Rooke TW, et al. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations). J Am Coll Cardiol. 2013;61:1555–1570.

Case 2 A 64-year-old man is evaluated for a 2-month history of painful ulceration involving his right lower extremity. He is sedentary but notes limited ambulation due to calf pain “for years.” He has a history of hypertension and dyslipidemia. He continues to smoke 1 pack per day. On exam, he has a left carotid and left subclavian artery bruit. His pulses are diminished bilaterally with a right femoral bruit and no palpable pulses in the right foot. Bedside ankle brachial index is 0.4 for the right leg. Which of the following lower extremities ulcers would you anticipate for this patient? (Fig.).

Discussion Identifying the mechanism of leg ulcers can be accurately achieved at the bedside with a careful history and physical examination. Ischemic ulcers due to large vessel arterial occlusive disease are typically quite painful and are localized at pressure points where the foot contacts the shoe such as the medial first or lateral fifth MTP joint, toes particularly if there is any deformity. The heels can be another pressure point where ulcerations or painful ischemic fissures can be seen. “Kissing ulcers” occur where there is contact and friction injury between the toes. A careful vascular exam will reveal pulse deficits. With limb elevation, the foot will pale in o 15 s (elevation pallor) or indeed may be pale without elevation. With dependency, the foot will become red and may be swollen (dependent rubor). The ankle brachial index is an easy and reproducible bedside confirmation of peripheral artery disease severity. This is accomplished with a blood pressure cuff and handheld Doppler device. Values less than 0.5 are considered severe. For diabetic or dialysis patients, non-compressible vessels limit the interpretation of this measure.


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Fig. Typical examples of extremity ulcers due to specific etiologies.

Panel 1 is a patient with severe venous disease. Note the hemosiderosis and dermal thickening of the intact skin. Also note the healthy red appearance of the granulation tissue in the base of the wound. Panel 3 is a patient with a small vessel arteriolar ulceration. These ulcers are quite painful and occur at unusual sites not typical of venous, large vessel arterial, or neurotrophic ulceration. Vasculitis, infection, connective tissue disease, and hypertension are in the differential diagnosis. Panel 4 is a patient with a neuropathic ulceration. These ulcers occur over the plantar aspect of the metatarsal joints of the foot, typically with foot deformity due to neuropathy. Note the associated callus. Frequently diabetes will be the underlying cause of neuropathy and large vessel arterial occlusive disease is a common accompaniment.

Pearl Ischemic ulceration due to large vessel arterial occlusive disease can be readily identified and differentiated from other causes of ulceration, by performing a careful history and physical examination supplemented by bedside ankle brachial index (ABI) assessment.

References 1. Sumpio BE, Forsythe RO, Ziegler KR, et al. Clinical implications of the angiosome model in peripheral vascular disease. J Vasc Surg. 2013;58(3):814–826. 2. O'Donnell TF Jr, et al. Management of venous leg ulcers: clinical practice guidelines of the Society for Vascular Surgery s and the American Venous Forum. J Vasc Surg. 2014;60(suppl 2): S3–S59

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3. Andrews KL, Houdek MT, Kiemele LJ. Wound management of chronic diabetic foot ulcers: from the basics to regenerative medicine. Prosthet Orthot Int. 2015;39(1):29–39.

Case 3 A 54-year-old man is seen for evaluation and management of hypertension. He uses moderate daily alcohol and is sedentary. He has a family history of hypertension. He takes chlorthalidone 50 mg once daily, amlodipine 5 mg once daily, and metoprolol 50 mg twice daily. On examination, his weight is 120 kg and height is 170 cm. His blood pressure is 160/90 in both arms. His pulse is 50 and regular. His cardiac examination reveals an S4 at the apex. Auscultation of his abdomen reveals a left renal bruit. Laboratory data: creatinine 1.5. ECG reveals left ventricular hypertrophy. CT angiography reveals 2 patent right renal arteries without stenosis. The main left renal artery has an 80% proximal stenosis. An accessory left renal artery is patent without stenosis. When counseling this patient, which of the following statements is true regarding PTRA/ stenting of his left renal artery? A. B. C. D. E.

Renal artery stenosis is the most likely cause of his hypertension PTRA/stenting is likely to improve his BP PTRA/stenting is likely to preserve his renal function His renal artery stenosis increases his risk of death from an MI PTRA/stenting is likely to improve his CV outcomes

Discussion This patient has many potential causes of hypertension apart from implicating renal artery disease. These potential causes include excess alcohol consumption, family history (implicating essential hypertension), obesity, and probable sleep apnea. While renal artery disease is in the differential diagnosis, it is not likely to be the main mechanism for hypertension in this patient. The central dilemma for those patients with known renal artery disease is determining which patient should undergo an intervention. There have been 3 major randomized trials assessing the impact of renal artery angioplasty and stenting compared to optimal medical management in these types of patients. The ASTRAL, STAR, and most recently CORAL trials were not able to show a clear improvement in hard outcomes such as renal preservation, blood pressure, renal events, cardiovascular events, or survival with renal interventions. What is clear is that renal artery disease is a strong mortality predictor with rates of 16% per year for patients with severe disease. These patients have a 2–4-fold increased rate of myocardial infarction. Currently, one should limit renal artery interventions to those patients most likely to benefit (severe stenosis, severe resistant HTN, recurrent flash pulmonary edema, and declining GFR/renal atrophy). Clinicians should recognize that patients may have incidental RAS, which may not be the cause of hypertension.

Pearl Patients may have incidental renal artery stenosis, which may not be the cause of their hypertension. Renal stenting should be reserved for compelling scenarios including severe stenosis, severe resistant HTN, recurrent flash pulmonary edema, and patients with renal artery stenosis in the setting of declining GFR/renal atrophy.


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References 1. Cooper CJ, Murphy TP, Cutlip DE, et al. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2014;370(1):13–22. 2. ASTRAL Investigators, Wheatley K, Ives N, et al. Revascularization versus medical therapy for renal-artery stenosis. N Engl J Med. 2009;361(20):1953–1962.

Case 4 A 34-year-old woman presents to the emergency department with a 3-day history of severe left leg pain and swelling. She denies recent immobility, trauma, or surgery. Oral contraceptives are her only medication. She denies dyspnea or chest pain. On exam, she has a moderately swollen and erythematous left foot and leg. Ultrasound examination of the left leg reveals extensive femoral and popliteal deep venous thrombosis. The upper extent of the thrombus was not visualized. What therapy would you advise for this patient? A. B. C. D. E.

Intravenous heparin LMW heparin Catheter-directed thrombolysis Rivaroxaban 15-mg BID for 3 weeks then 20 mg daily for 9 weeks Systemic thrombolysis

Discussion This patient has an extensive left leg DVT. The fact that the US did not demonstrate the upper extent of the thrombus means that it extends beyond the common femoral vein into the iliac system. Until proven otherwise, she has the May–Thurner syndrome resulting from left common iliac venous stenosis secondary to compression from the right common iliac artery. This is a common event accounting for up to 30% of all venous thrombotic events each year in the US. The natural history of iliofemoral venous thrombosis includes a high rate of postthrombotic syndrome (  80%) largely due to poor recanalization rates. Nearly 60% of iliofemoral DVT fail to recanalize at 6 months and nearly half will be limited by venous claudication at 5 years. For these reasons, many vascular specialists have been aggressively managing these patients with endovascular mechanical thrombectomy and thrombolytic therapy. Upon reopening the vein, residual venous stenosis is stented to reduce pressure gradients and improve patency rates. The CAVENT trial assessed the safety and efficacy of catheter-directed thrombolysis versus standard medical therapy in 209 patients with first-lifetime iliofemoral DVT. The postthrombotic syndrome was reduced and iliofemoral patency was increased, favoring thrombolysis for these patients with a number needed to treat of 7. Three patients suffered major bleeding, and 5 experienced clinically relevant non-major bleeding in the treatment arm.

Pearl Iliofemoral DVT has a dismal natural history with an increased rate of post-phlebitic syndrome, venous claudication, and DVT recurrence. Mechanical thrombectomy, thrombolysis, and stenting should be considered to relieve the proximal obstruction and reduce these dismal outcomes.

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References 1. Enden T, et al. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomized controlled trial. Lancet. 2012;379:31–38. 2. Wysokinska EM, et al. Iliac vein thrombosis: feasibility assessment of randomized controlled trials of endovascular pharmacomechanical thrombolysis. J Thromb Haemost. 2010;8:1943–1949.

Case 5 A 75-year-old man requires saturation prostate biopsies to further evaluate a rising PSA. He has a history of mechanical mitral valve prosthesis, atrial fibrillation, diabetes, and hypertension. He has no history of prior stroke or embolism. His renal function is normal. Pre-procedurally, he received bridging therapy with low-molecular-weight heparin stopped the morning prior to biopsies. How should he be managed post-procedurally? A. Restart warfarin the night of surgery. Start intravenous unfractionated heparin the following morning. B. Restart warfarin and LMWH the following morning. C. Restart LMWH the following morning, hold warfarin for 48 h to ensure hemostasis. D. Hold all anticoagulants for 3 days to allow for adequate hemostasis postoperatively. E. Restart warfarin the night of surgery, withhold heparin for 48 h postoperatively.

Discussion There are currently more than 6 million US citizens receiving chronic anticoagulant therapy. Each year approximately 10% of these require an invasive procedure. Understanding the proper periprocedural management of these patients therefore is important. The first question is whether or not the procedure can be done without anticoagulant interruption. There are a growing number of procedures that can be done with continued anticoagulant therapy. If the procedure cannot be safely done without stopping the anticoagulants, the second question is whether he requires bridging therapy with LMWH. Bridging therapy is typically restricted to those patients with high risk of thromboembolism: atrial fibrillation with prior stroke/ peripheral embolism, known intracardiac thrombus or high CHADS2 score ( Z4); mechanical heart valves in mitral position, multiple valves, non-bileaflet AVR, or AVR with other risk factors (prior stroke/peripheral embolism, known intracardiac thrombus and atrial fibrillation); venous thromboembolism within the past 3 months. LMWH can be used if the creatinine clearance is satisfactory (4 30 ml/min), otherwise, intravenous unfractionated heparin should be used. Postoperatively, it is important to allow sufficient time for hemostasis to occur. Warfarin can be restarted promptly as soon as the patient is able to take oral medications, as it takes  4–5 days to achieve a therapeutic INR. Therapeutic (full dose) heparin should be withheld for 48 h to insure adequate hemostasis. With this approach, the periprocedural thromboembolism rate is approximately 1% with bleeding rates of approximately 3%. Risk factors for major bleeding postprocedurally include history of prior bleeding, mitral valve prosthesis, active cancer, thrombocytopenia, and premature heparin initiation (r 24 h) post-procedure. Pearl Post-procedure, it is very important to be judicious with anticoagulation reinitiation. By waiting 48 h before restarting therapeutic parenteral anticoagulants, the risk of major hemorrhage can be greatly minimized.


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References 1. Baron TH, Kamath PS, McBane RD. Management of antithrombotic therapy in patients undergoing invasive procedures. N Engl J Med. 2013;368:2113–2124. 2. Tafur AJ, McBane R, Wysokinski WE, et al. Predictors of major bleeding in peri-procedural anticoagulation management. J Thromb Haemost. 2012;10:261–267.

Case 6 A 54-year-old woman requires colonoscopy screening as part of her general medical evaluation. She has been found to have microcytic anemia with positive stool studies for heme. She is receiving warfarin therapy for a history of prior large pulmonary embolism that occurred 6 months ago. There was no antecedent trauma, surgery, or immobility prior to this event, which was deemed unprovoked. Other general medical evaluation has been unrevealing. Thrombophilia testing revealed heterozygous factor V Leiden. Renal function is normal. How would you manage her warfarin therapy prior to the anticipated procedure? A. Continue warfarin but adjust the dose to target an INR of 2.0 at the time of the procedure. B. Stop warfarin 5 days prior to the procedure and allow the INR to normalize without bridging LMWH. C. Stop warfarin 5 days prior to the procedure and provide LMWH bridging therapy at the therapeutic dose. D. Stop warfarin 5 days prior to the procedure and provide LMWH bridging therapy at the prophylactic dose. E. Stop warfarin 5 days prior to the procedure, place an IVC filter and provide LMWH bridging therapy at the therapeutic dose.

Discussion Given the microcytic anemia and positive stool studies for heme, it is possibly that the patient will have a colon polyp requiring polypectomy or a lesion requiring biopsy. Given her age, she is likely no longer menstruating as a mechanism for microcytic anemia. Although you can do a diagnostic colonoscopy on warfarin, polypectomy or deep biopsy will not be feasible, and so warfarin should be stopped prior to the procedure. High-risk venous thromboembolic events are those occurring within 3 months of an anticipated procedure. For these patients we would recommend bridging therapy. For patient a VTE within 1 month of the anticipated procedure, a retrievable IVC filter could be considered, as this is the highest risk period for recurrence. This patient is 6 months out from her event, and so bridging therapy is not necessary. The factor V Leiden does not weigh into our decision making, as it is a relatively weak risk factor for VTE.

Pearl For patients chronically anticoagulated for the indication of venous thromboembolism, periprocedural bridging therapy is only required if the venous thrombotic event occurred within the prior 3 months. References 1. McBane RD, Wysokinski WE, Daniels PJ, et al. Periprocedural anticoagulation management of patients with venous thromboembolism. Arterioscler Thromb Vasc Biol. 2010;30:442–448.

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2. Wysokinski WE, McBane R 2nd. Periprocedural “bridging” management of anticoagulation. Circulation. 2012;126(4):486–490. Case 7 An 84-year-old man has a history of atrial fibrillation for 2 years. He also has a history of permanent pacemaker placement for sick sinus syndrome. His CHA2DS2-Vasc score is 3, gaining 2 points for age and 1 for hypertension. He has normal renal and liver function. He takes warfarin 5 mg daily and has consistently therapeutic INR values. He has had no bleeding or thrombotic events. What would you recommend for this patient? A. B. C. D. E.

Apixaban Dabigatran Edoxaban Rivaroxaban Continue warfarin

Discussion The era of the new oral direct factor inhibitors is firmly in place. Of the 4.4 million Americans with non-valvular atrial fibrillation, a large percentage are now receiving one of these agents. For newly diagnosed atrial fibrillation, more than 60% are given a novel anticoagulant. Of those individuals with chronic atrial fibrillation, 1 in 4 is converted to a novel anticoagulant from previous warfarin therapy. However, with well-managed warfarin , the anticipated stroke/ thromboembolic event rates should be less than 2% annually. This generally includes management oversight by a dedicated anticoagulation clinic. Although the novel anticoagulants offer many advantages including limited food and drug interactions, lack of need for monitoring, excellent efficacy, and safety profiles, the recent ACCF/AHA guidelines gave warfarin a grade 1A rating for stroke prevention in atrial fibrillation. The novel anticoagulants including dabigatran, rivaroxaban, and apixaban each received a grade 1B rating. Therefore, for the well-managed patient on warfarin therapy, there is no need to switch to a novel anticoagulant. Pearl For patients requiring anticoagulation for stroke prophylaxis in the setting of non-valvular atrial fibrillation, well-managed warfarin remains an excellent anticoagulant choice (grade 1A). Reference 1. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64(21):e1-e76.

Case 8 A 75-year-old woman is evaluated for an abdominal aortic aneurysm found at a vascular screening fair at her local supermarket. Risk factors for atherosclerosis include hypertension and hyperlipidemia. She has not smoked in the past and has no history of diabetes mellitus. The


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abdominal examination reveals an enlarged pulsatile aorta. Vascular examination reveals normal femoral, popliteal, and posterior tibial pulses. Which of the following findings should prompt surgical referral for intervention? A. B. C. D. E.

5.1 cm infrarenal abdominal aortic aneurysm Annual growth rate of 0.3 cm Accompanying left iliac artery aneurysm measuring 2.8 cm Tender aneurysm on examination Her father died of a ruptured abdominal aortic aneurysm

Discussion For patients with known or newly diagnosis abdominal aortic aneurysm (AAA), a careful history and physical examination is warranted to ensure that the aneurysm is stable. Symptoms of new abdominal or back pain, physical findings of tenderness when palpating the aorta should alert the clinician that this may be an unstable aneurysm. The physical examination can be quite helpful. Patients should lie supine with knees bent. Patients should be distracted with conversation while slowly and gently palpating the aorta. Distinguishing a tender aorta from simply discomfort on deep palpation can be difficult. A tender aorta will halt any conversation with deep palpation. In this scenario, prompt imaging (typically CT with and without contrast) and vascular surgical referral is important in the assessment. Timing of “stable” abdominal aortic aneurysm repair (either surgical or by endograft) is important and requires balancing the risk of rupture compared to the risk associated with the intervention. Currently, AAA repair is recommended at 5.5 cm. The diameter measurement should be obtained “AP” and perpendicular to the axis, which can be difficult with tortuous aorta. Other indications for repair include growth rates exceeding 0.5 cm/yr or any symptoms suggesting instability such as tenderness of the aorta on examination. Two randomized trials, showed no survival benefit associated with a policy of early elective open surgical repair compared with surveillance of small AAAs, 4.0– 5.5 cm in diameter. The iliac artery aneurysm is small and would not require surgery. Typical cutoff for iliac artery aneurysms is 3.5 cm. The family history of ruptured abdominal aortic aneurysm is not the criteria for surgery. For small aneurysms (3.0–4.0 cm), the guidelines for surveillance are every 2–3 years. For larger aneurysms (4.0–5.4), imaging should be performed every 6–12 months. The guidelines support a one-time screening for AAA in men aged 65–75 years who have never smoked but who have a first-degree relative who required repair of an AAA or died from a ruptured AAA (grade 2C). A one-time screening for AAA with abdominal ultrasonography is also recommended in men aged 65–75 years who have ever smoked (grade 1A). Screening for asymptomatic women is not recommended; however, Medicare allows for a one-time screen of women with a family history of AAA.

Pearl Indications for AAA repair include aneurysm size exceeding 5.5 cm, rapid growth defined as aneurysm growth exceeding 0.5 cm/yr, or any evidence of aneurysm instability implying contained rupture.

References 1. Rooke TW, et al. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of

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Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(14):1555–1570. 2. Lederle FA, et al. Immediate repair compared with surveillance of small abdominal aortic aneurysms. N Engl J Med. 2002;346:1437–1444. 3. The United Kingdom Small Aneurysm Trial Participants. Long-term outcomes of immediate repair compared with surveillance for small abdominal aortic aneurysm. New Engl J Med. 2002;346:1445–1452. Answers: 1-A; 2-B(2); 3-D; 4-C; 5-E; 6-B; 7-E; and 8-D.

Clinical pearls in vascular medicine and anticoagulation.

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