six randomized controlled trials. J Am Geriatr Soc. 2002;50:1939.

Mohler ER 3rd et al. Effects of cilostazol on resting ankle pressures and exercise-induced ischemia in patients

with intermittent claudication. Vasc Med. 2001;6:151.

Soga Y et al. Efficacy of cilostazol after endovascular therapy for femoropopliteal artery disease in patients with

intermittent claudication. J Am Coll Cardiol. 2009;53:48.

Iida O et al. Cilostazol reduces restenosis after endovascular therapy in patients with femoropopliteal lesions. J

Vasc Surg. 2008;48:144.

Cruickshank JM. Phosphodiesterase III inhibitors: long-term risks and short-term benefits. Cardiovasc Drugs

Ther. 1993;7:655.

Thompson PD et al. Meta-analysis of results from eight randomized, placebo-controlled trials on the effect of

cilostazol on patients with intermittent claudication. Am J Cardiol. 2002;90:1314.

Hiatt WR et al. Long-term safety of cilostazol in patients with peripheral arterial disease: the CASTLE study

(Cilostazol: A Study in Long-term Effects). J Vasc Surg. 2008;47:330.

Samlaska CP, Winfield EA. Pentoxifylline. J Am Acad Dermatol. 1994;30:603.

Frampton JE, Brogden RN. Pentoxifylline (oxpentifylline). A review of its therapeutic efficacy in the

management of peripheral vascular and cerebrovascular disorders. Drugs Aging. 1995;7:480.

Ward A Clissold SP. Pentoxifylline: a review of its pharmacokinetic and pharmacodynamic properties, and its

therapeutic efficacy. Drugs. 1987; 34:50.

Jackson MR, Clagett GP. Antithrombotic therapy in peripheral arterial occlusive disease. Chest. 1998;114(5

Suppl):666S.

Cameron HA et al. Drug treatment of intermittent claudication: a critical analysis of the methods and findings of

published clinical trials, 1965–1985. Br J Clin Pharmacol. 1988;26:569.

Reiter M et al. Prostanoids for intermittent claudication. Cochrane Database Syst Rev. 2004;(1):CD000986.

Abramowicz M ed. L-Carnitine. Med Lett Drugs Ther. 2004;46:95.

Bagger JP et al. Effect of verapamil in intermittent claudication. A randomized, double-blind, placebo controlled,

cross-over study after individual dose-response assessment. Circulation. 1997;95:411.

Morrow DA et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med.

2012;366:1404–1413.

Bayer. Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery

Disease (COMPASS)–NCT01776424. Available at www.clinicaltrials.gov. Accessed August 25, 2015.

Daiichi Sankyo Inc. Edoxaban in peripheral artery disease (PAD). NCT01802775. Available at

www.clinicaltrials.gov. Accessed August 25, 2015.

Coffman JD. Intermittent claudication—be conservative. N EnglJ Med. 1991;325:577.

Pentecost MJ et al. Guidelines for peripheral percutaneous transluminal angioplasty of the abdominal aorta and

lower extremity vessels. A statement for health professionals from a special writing group of the Councils on

Cardiovascular Radiology, Arteriosclerosis, Cardio-Thoracic and Vascular Surgery, Clinical Cardiology, and

Epidemiology and Prevention, the American Heart Association. Circulation. 1994;89:511.

Tunis SR et al. The use of angioplasty, bypass surgery and amputation in the management of peripheral vascular

disease. N EnglJ Med. 1991;325:556.

Working Party on Thrombolysis in the Management of Limb Ischemia. Thrombolysis in the management of

lower limb peripheral arterial occlusion—a consensus document. Am J Cardiol. 1998;81:207.

Nilsson L et al. Surgical treatment versus thrombolysis in acute arterial occlusion: a randomised controlled study.

Eur J Vasc Surg. 1992;6:189.

Ouriel K et al. A comparison of thrombolytic therapy with operative revascularization in the initial treatment of

acute peripheral arterial ischemia. J Vasc Surg. 1994;19:1021.

Raynaud M. On local asphyxia and symmetrical gangrene of the extremities. In: Barlow T, trans. Selected

Monographs, 121. London: The Sydenham Society; 1888:1.

Herrick AL. Pathogenesis of Raynaud’s phenomenon. Rheumatology (Oxford). 2005;44:587.

Goundry B et al. Diagnosis and management of Raynaud’s phenomenon. BMJ. 2012;344:e289.

Prete M et al. Raynaud’s phenomenon: From molecular pathogenesis to therapy. Autoimmun Rev. 2014;13:655–

667.

Gasser P et al. Evaluation of reflex cold provocation by laser Doppler flowmetry in clinically healthy subjects

with a history of cold hands. Angiology. 1992;43:389.

Stoyneva Z et al. Current pathophysiological views on vibration-induced Raynaud’s phenomenon. Cardiovasc

Res. 2003;57:615.

123.

.

.

.

127.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

142.

143.

.

.

.

.

.

.

.

151.

.

Belch J. Raynaud’s phenomenon. Cardiovasc Res. 1997;33:25.

Wigley FM. Clinical practice. Raynaud’s phenomenon. N EnglJ Med. 2002;347:1001.

Ziegler S et al. Long-term outcome of primary Raynaud’s phenomenon and its conversion to connective tissue

disease: a 12-year retrospective patient analysis. Scand J Rheumatol. 2003;32:343.

Schapira D et al. Interferon-induced Raynaud’s syndrome. Semin Arthritis Rheum. 2002;32:157.

Franssen C et al. The influence of different β-blocking drugs on the peripheral circulation in Raynaud’s

phenomenon and in hypertension. J Clin Pharmacol. 1992;32:652.

Bakst R et al. Raynaud’s phenomenon: pathogenesis and management. J Am Acad Dermatol. 2008;59:633–653.

Suter LG et al. The incidence and natural history of Raynaud’s phenomenon in the community. Arthritis Rheum.

2005;52:1259.

Suter LG et al. Smoking, alcohol consumption, and Raynaud’s phenomenon in middle age. Am J Med.

2007;120:264–271.

Palesch YY et al. Association between cigarette and alcohol consumption and Raynaud’s phenomenon. J Clin

Epidemiol. 1999;52:321.

Freedman RR et al. Blockade of vasospastic attacks by α 2-adrenergic but not α 1-adrenergic antagonists in

idiopathic Raynaud’s disease. Circulation. 1995;92:1448.

Coffman JD, Cohen RA. Serotonergic vasoconstriction in human fingers during reflex sympathetic response to

cooling. Am J Physiol. 1988;254:H889.

Landry GJ. Current medical and surgical management of Raynaud’s syndrome. J Vasc Surg. 2013;57:1710–

1716.

Huisstede BM et al. Effectiveness of interventions for secondary Raynaud’s phenomenon: a systematic review.

Arch Phys Med Rehabil. 2011;92:1166–1180.

Stewart M, Morling JR. Oral vasodilators for primary Raynaud’s phenomenon. Cochrane Database Syst Rev.

2012;(7):CD006687.

Thompson AE, Pope JE. Calcium channel blockers for primary Raynaud’s phenomenon: a meta-analysis.

Rheumatology (Oxford). 2005;44:145.

Thompson AE et al. Calcium-channel blockers for Raynaud’s phenomenon in systemic sclerosis. Arthritis

Rheum. 2001;44:1841.

Finch MB et al. A double-blind cross-over study of nifedipine retard in patients with Raynaud’s phenomenon.

Clin Rheumatol. 1988;7:359.

Raynaud’s Treatment Study Investigators. Comparison of sustained-release nifedipine and temperature

biofeedback for treatment of primary Raynaud phenomenon. Results from a randomized clinical trial with 1-

year follow-up. Arch Intern Med. 2000;160:1101.

Leppert J et al. The effect of isradipine, a new calcium-channel antagonist, in patients with primary Raynaud’s

phenomenon: a single-blind dose-response study. Cardiovasc Drugs Ther. 1989;3:397.

La Civita L et al. Amlodipine in the treatment of Raynaud’s phenomenon. Br J Rheumatol. 1993;32:524.

Schmidt JF et al. The clinical effect of felodipine and nifedipine in Raynaud’s phenomenon. Eur J Clin

Pharmacol. 1989;37:191.

Kallenberg CG et al. Once daily felodipine in patients with primary Raynaud’s phenomenon. Eur J Clin

Pharmacol. 1991;40:313.

Wollersheim H et al. Double-blind, placebo controlled study of prazosin in Raynaud’s phenomenon. Clin

Pharmacol Ther. 1986;40:219.

Wollersheim H, Thien T. Dose-response study of prazosin in Raynaud’s phenomenon: clinical effectiveness

versus side effects. J Clin Pharmacol. 1988;28:1089.

Paterna S et al. Raynaud’s phenomenon: effects of terazosin [in Italian]. Minerva Cardioangiol. 1997;45:215.

Marasini B et al. Comparison between iloprost and alprostadil in the treatment of Raynaud’s phenomenon.

Scand J Rheumatol. 2004;33:253.

Humbert M, Cabane J. Successful treatment of systemic sclerosis digital ulcers and pulmonary arterial

hypertension with endothelin receptor antagonist bosentan. Rheumatology (Oxford). 2003;42:191.

Fries RF et al. Sildenafil in the treatment of Raynaud’s phenomenon resistant to vasodilator therapy. Circulation.

2005;112:2980.

Caglayan E et al. Phosphodiesterase type 5 inhibition is a novel therapeutic option in Raynaud disease. Arch

Intern Med. 2006;166:231.

Roustit M et al. Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud’s phenomenon:

systematic review and meta-analysis of randomized trials. Ann Rheum Dis. 2013;72:1696–1699.

.

.

.

156.

157.

.

.

.

161.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

Smith L et al. Botulinum toxin-A for the treatment of Raynaud’s Syndrome. Arch Dermatol. 2012;148:426–428.

Abou-Raya A et al. Statins: potentially useful in therapy of systemic sclerosis-related Raynaud’s phenomenon

and digital ulcers. J Rheumatol. 2008;35:1801.

Challenor VF. Angiotensin converting enzyme inhibitors in Raynaud’s phenomenon. Drugs. 1994;48:864.

Dziadzio M et al. Losartan therapy for Raynaud’s phenomenon and scleroderma: clinical and biochemical

findings in a fifteen-week, randomized, parallel group, controlled trial. Arthritis Rheum. 1999;42:2646.

Wood HM, Ernst ME. Renin-angiotensin system mediators and Raynaud’s phenomenon. Ann Pharmacother.

2006;40:1998.

Gliddon AE et al. Prevention of vascular damage in scleroderma and autoimmune Raynaud’s phenomenon: a

multicenter, randomized, double-blind, placebo-controlled trial of the angiotensin-converting enzyme inhibitor

quinapril. Arthritis Rheum. 2007;56:3837.

Coleiro B et al. Treatment of Raynaud’s phenomenon with the selective serotonin reuptake inhibitor fluoxetine.

Rheumatology (Oxford). 2001;40:1038.

Rembold CM, Ayers CR. Oral L-arginine can reverse digital necrosis in Raynaud’s phenomenon. Mol Cell

Biochem. 2003;244:139.

Muir AH et al. The use of ginkgo biloba in Raynaud’s disease: a double-blind placebo-controlled trial. Vasc

Med. 2002;7:265.

Malenfant D et al. The efficacy of complementary and alternative medicine in the treatment of Raynaud’s

phenomenon: a literature review and meta-analysis. Rheumatology (Oxford). 2009;48:791.

Obi T et al. Muscle cramp as the result of impaired GABA function—an electrophysiological and

pharmacological observation. Muscle Nerve. 1993;16:1228.

Bertolasi L et al. The influence of muscular lengthening on cramps. Ann Neurol. 1993;33:176.

Oboler SK et al. Leg symptoms in outpatient veterans. West J Med. 1991;155:256.

Naylor JR, Young JB. A general population survey of rest cramps. Age Ageing. 1994;23:418.

Haskell SG, Fiebach NH. Clinical epidemiology of nocturnal leg cramps in male veterans. Am J Med Sci.

1997;313:210.

Garrison SR et al. Nocturnal leg cramps and prescription use that precedes them: a sequence symmetry

analysis. Arch Intern Med. 2012;172:120–126.

Leclerc KM, Landry FJ. Benign nocturnal leg cramps. Current controversies over use of quinine. Postgrad Med.

1996;99:177.

Butler JV et al. Nocturnal leg cramps in older people. Postgrad Med J. 2002;78:596.

Brasi JR. Should people with nocturnal leg cramps drink tonic water and bitter lemon? Psychol Rep.

1999;84:355.

Hawke F, Burns J. New evidence for stretching for preventing nocturnal cramps. Arch Intern Med.

2012;172:1770–1771.

US Department of Health and Human Services. Drug products for the treatment and/or prevention of nocturnal

leg muscle cramps for over-the-counter human use. Fed Regis. 1994;59:43234.

Moss HK, Hermann LG. Use of quinine for relief of “night cramps” in the extremities. JAMA. 1940;115:1358.

Man-So-Hing M et al. Quinine for nocturnal leg cramps: a meta-analysis including unpublished data. J Gen

Intern Med. 1998;13:600.

Coppin RJ et al. Managing nocturnal leg cramps: calfstretching exercises and cessation of quinine treatment. Br

J Gen Pract. 2005;55:186.

US Department of Health and Human Services, US Food & Drug Administration. FDA Warns of Risks with

Unapproved Use of Malaria Drug Qualaquin.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm218383.htm. Updated July 8,

2010. Accessed August 1, 2010.

Krishna S, White NJ. Pharmacokinetics of quinine, chloroquine, and amodiaquine: clinical implications. Clin

Pharmacokinet. 1996;30:263.

Connolly PS et al. Treatment of nocturnal leg cramps: a crossover trial of quinine versus vitamin E. Arch Intern

Med. 1992;152:1877.

Baltodano N et al. Verapamil versus quinine in recumbent nocturnal leg cramps in the elderly. Arch Intern Med.

1988;148:1969.

Voon WC, Sheu SH. Diltiazem for nocturnal leg cramps. Age Ageing. 2001;30:91.

Chan P et al. Randomized, double-blind, placebo-controlled study of the safety and efficacy of vitamin B

complex in the treatment of nocturnal leg cramps in elderly patients with hypertension. J Clin Pharmacol.

.

.

1998;38:1151.

Frusso R et al. Magnesium for the treatment of nocturnal leg cramps: a crossover randomized trial. J Fam Pract.

1999;48:868.

Roffe C et al. Randomised, cross-over, placebo controlled trial of magnesium citrate in the treatment of chronic

persistent leg cramps. Med Sci Monit. 2002;8:CR326.

p. 173

Venous thromboembolism (VTE), including deep vein thrombosis (DVT)

and pulmonary embolism (PE), is caused by numerous additive risk

factors, with diagnosis based on clinical findings and objective criteria.

Case 11-1 (Questions 1–3),

Case 11-5 (Question 1)

VTE treatment includes parenteral anticoagulants (low-molecular-weight

heparins or fondaparinux) bridging to a therapeutic international

normalized ratio (INR) with warfarin, parenteral anticoagulants given

before transitioning to dabigatran or edoxaban, or as monotherapy with

rivaroxaban or apixaban.

Case 11-1 (Questions 4–6,

9), Case 11-5 (Questions 2,

3)

Unfractionated heparin is monitored with the activated partial

thromboplastin time (aPTT) test; dosing adjustments are used to

maintain the aPTT in therapeutic range, as well as monitoring for

adverse effects, including thrombocytopenia and bleeding.

Case 11-1 (Questions 7, 8,

10–12),

Case 11-2 (Question 1)

Outpatient treatment of VTE is preferred over hospitalization for patients

with DVT and low-risk PE and home circumstances that are adequate.

Case 11-3 (Questions 1, 2)

Anticoagulation prophylaxis should be used in hospitalized patients at risk

of VTE.

Case 11-4 (Question 1)

Warfarin therapy is dosed and monitored according to therapeutic

response as measured by the INR. Monitoring for adverse effects

including hemorrhage is also essential for all anticoagulants.

Case 11-5 (Questions 4–6),

Case 11-6 (Questions 5, 6),

Case 11-7 (Question 1)

Warfarin therapy is influenced by multiple factors, and patients on

warfarin require extensive and ongoing education to maintain safe and

effective anticoagulation.

Case 11-6 (Questions 1–4),

Case 11-8 (Question 1),

Case 11-13 (Question 1),

Case 11-14 (Questions 1, 2)

Warfarin and the direct oral anticoagulants (DOACs) are used for

stroke prevention in nonvalvular atrial fibrillation. Warfarin is the only

long-term oral option for stroke prevention for thrombosis prevention in

patients with artificial heart valve replacement.

Case 11-9 (Questions 1–3),

Case 11-10 (Question 1),

Case 11-11 (Question 1)

Pharmacists can play an important role in the management of

anticoagulant therapy for invasive procedures.

Cases 11-12 (Question 1)

Although the DOACs do not need monitoring to measure their efficacy,

monitoring of baseline renal function and complete blood cell counts are

necessary to ensure appropriateness of dosing and to minimize risk of

anticoagulation-related bleeding complications.

Case 11-3 (Question 1),

Case 11-5 (Questions 2, 6)

GENERAL PRINCIPLES

Thrombosis is the process involved in the formation of a fibrin blood clot. Platelets

and a series of coagulant proteins (clotting factors) contribute to clot formation. An

embolus is a small part of a clot that breaks off and is carried by blood flow to

another part of the vascular system. Damage is caused when the embolus becomes

trapped in a small vessel, causing occlusion and leading to ischemia or infarction of

the surrounding tissue. Normal clot formation maintains the integrity of the

vasculature in response to injury, but pathologic clotting can occur in many clinical

settings. Abnormal thrombotic events include venous thromboembolism (deep venous

thrombosis [DVT] and its primary complication, pulmonary embolism [PE]), as well

as stroke and other systemic manifestations of embolization of clots that form within

the heart. Anticoagulant drug therapy is aimed at preventing pathologic clot formation

in patients at risk and at preventing clot extension and/or embolization in patients

who have experienced thrombosis. This chapter emphasizes arterial and venous

thromboembolic disease and the use of the parenteral anticoagulants (unfractionated

heparin, low-molecular-weight heparins, indirect factor Xa inhibitors, and injectable

direct thrombin inhibitors) and oral agents (vitamin K antagonists, and direct oral

anticoagulants [DOACs], which include the oral direct thrombin inhibitors, and the

oral direct factor Xa inhibitors). Chapter 8, Dyslipidemias, Atherosclerosis, and

Coronary Artery Disease; Chapter 13, Acute Coronary Syndrome, and Chapter 61,

Ischemic and Hemorrhagic Stroke, provide more in-depth discussions of

thrombolytic agents and antiplatelet therapy.

p. 174

p. 175

Figure 11-1 Risk factors for thromboembolism.

Etiology of Thromboembolism

Three primary factors influence the formation of pathologic clots and are described

in a model referred to as Virchow’s triad (Fig. 11-1).

1 Abnormalities of blood flow

that cause venous stasis can result in DVT, which can progress to PE if embolization

occurs. Intracardiac stasis of blood can also result in clot formation within the heart

chambers, and embolization of intracardiac thrombi may lead to stroke or other

systemic manifestations. Abnormalities of blood vessel walls, such as those that

occur in injury or trauma to the vasculature, are a second source of thrombus

formation. The presence of foreign material within the vasculature, including

artificial heart valves and central venous catheters, is also thrombogenic and, like

vascular injury, represents the presence of an abnormal surface in contact with blood.

Finally, hypercoagulability resulting from alterations in the availability or the

integrity of blood-clotting components or naturally occurring anticoagulants also

represents a significant risk factor for thromboembolic disease.

2

Clot Formation

The intact endothelial lining of blood vessels normally repels platelets and inhibits

clot formation through secretion of numerous inhibitory substances. Damage to the

endothelium leads to exposure of circulating blood to subendothelial substances, and

this results in formation of a fibrin clot.

2

PLATELET ADHESION, ACTIVATION, AND AGGREGATION

Endothelial damage leads to exposure of blood to subendothelial collagen and

phospholipids, resulting in platelet adhesion to the surface. Von Willebrand factor

serves as the binding ligand for platelet adhesion, via the glycoprotein I (GPI)

receptor on the platelet surface. Adhered platelets become activated and release

numerous compounds, including adenosine diphosphate and thromboxane A2, which

stimulate platelet aggregation. Fibrinogen serves as the binding ligand for platelet

aggregation, via the GPIIb/IIIa receptor on the platelet surface.