Textbook of Interventional Cardiovascular Pharmacology - part 9 pot

5 Drory Y, Fisman EZ, Shapira Y, et al. Ventricular arrhythmias during sexual activity in patients with coronary artery disease. Chest 1996; 109:922–924. 6 Drory Y, Shapira I, Fisman EZ, et al. Myocardial ischaemia during sexual activity in patients with coronary artery disease. Am J Cardiol 1995; 75:835–837. 7 Müller JE, Mittleman A, MacLure M, et al. Triggering myocardial infarction by sexual activity: low absolute risk and prevention by regular physical exercise. JAMA 1996; 275:1405–1409. 8 Müller J, Ahlbom A, Hulting J, et al. Sexual activity as a trigger of myocardial infarction: a case cross-over analysis in the Stockholm Heart Epidemiology Programme (SHEEP). Heart 2001; 86:387–390. 9 Solomon H, Man JW, Jackson G. Erectile dysfunction and the cardiovascular patient: endothelial dysfunction is the common denominator. Heart 2003; 89:251–254. 10 Billups KL. Endothelial dysfunction as a common link between erectile dysfunction and cardiovascular disease. Sex Health Rep 2004; 1:137–141. 11 Jackson G. Erectile dysfunction and hypertension Int J Clin Pract 2002; 56:491–492. 12 Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychological correlates: results of the Massachusetts Male Aging Study.J Urol 1994; 151:54–61. 13 Kaiser DR, Billups K, Mason C, et al. Impaired brachial artery endothelium-dependent and -independent vasodilation in men with erectile dysfunction and no other clinical cardiovas- cular disease. J Am Coll Cardiol 2004; 43 (2):179–184. 14 Snow KJ. Erectile dysfunction in patients with diabetes mellitus: advances in treatment with phosphodiesterase Type 5 inhibitors. Br J Diab Vasc Dis 2002; 2:282–287. 15 Bortolotti A, Parazzini F, Colli E, et al. The epidemiology of erectile dysfunction and its risk factors. Int J Androl 1997; 20:323–334. 16 Kirby M, Jackson G, Betteridge J, et al. Is erectile dysfunction a marker for cardiovascular disease? Int J Clin Pract 2001; 55:614–618. 17 Pritzker M. The penile stress test: a window to the heart of the man [abstract].Circulation 1999; 100:3751. 18 Solomon H, Man JW, Wierzbicki AS, et al. Relation of erectile dysfunction to angiographic coronary artery disease. Am J Cardiol 2003; 91:230–231. 19 Greenstein A, Chen J, Miller H, et al. Does severity of ischaemic coronary disease correlate with erectile function? Int J Impot Res 1997; 9:123–126. 20 Montorsi P, Montorsi F, Schulman CC. Is erectile dysfunction the ‘Tip of the Iceberg’ of a systemic vascular disorder? Eur Urol 2003; 44:352–354. 21 Kirby M, Jackson G, Simonsen U. Endothelial dysfunction links erectile dysfunction to heart disease? Int J Clin Pract 2005; 59:225–229. 22 Montrosi F, Briganti I, Salonia A, et al. Erectile dysfunction prevalence, time of onset and association with risk factors in 300 consecutive patients with acute chest pain and angio- graphically documented coronary artery disease. Eur Urol 2003; 44:360–365. 23 Virag R, Bouilly P, Frydman D. Is impotence an arterial disor- der? A study of arterial risk factors in 440 impotent men. Lancet 1985; 1:181–184. 24 Bocchio M, Desideri G, Scarpelli P, et al. Endothelial cell acti- vation in men with erectile dysfunction without cardiovascular risk factors and overt vascular damage. J Urol. 2004; 171:1601–1604. 25 Wierzbicki AS, Solomon H, Lumb PJ, et al. Asymmetric dimethyl arginine levels correlate with cardiovascular risk factors in patients with erectile dysfunction. Atherosclerosis 2006; 185:421–425. 26 Maas R, Wenske S, Zabel M, et al. Elevation of asymmetrical dimethylarginine (ADMA) and coronary artery disease in men with erectile dysfunction. Eur Urol 2005; 48:1004–1012. 27 Elesber AA, Solomon H, Lennon RJ, et al. Coronary endothe- lial dysfunction is associated with erectile dysfunction and elevated asymmetric dimethylarginine in patients with early atherosclerosis. Eur Heart J 2006; 27:824–831. 28 Vlachopoulos C, Rokkas K, Ioakeimidis N, et al. Prevalance of asymptomatic coronary artery disease in men with vasculo- genic erectile dysfunction: a prospective angiographic study. Eur Urol 2005; 48:996–1003. 29 Ponholzer A, Temml C, Obermayr R, et al. Is erectile dysfunc- tion an indicator for increased risk of coronary heart disease and stroke? Eur Urol 2005; 48:512–518. 30 Thompson IM, Tangen CM, Goodman PJ, et al. Erectile dysfunction and subsequent cardiovascular disease. JAMA 2005; 294:2996–3002. 31 Solomon H, Man J, Wierzbicki AS, et al. Erectile dysfunction: cardiovascular risk and the role of the cardiologist. Int J Clin Pract 2003; 57:96–99. 32 Jackson G, Rosen RC, Kloner RA, et al. The second Princeton consensus on sexual dysfunction and cardiac risk; new guide- lines for sexual medicine. J Sex Med 2006; 3:28–36. 33 Brock GB, McMahon CG, Chen KK, et al. Efficiency and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analysis. J Urol 2002; 168:1332–1336. 34 Porst H, Rosen R, Padma-Nathan H, et al. Efficacy and tolera- bility of vardenafil, a new selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction: the first at home clinical trial. Int J Impot Res 2001; 13:192–199. 35 Gillies HC, Roblin D, Jackson G. Coronary and systemic haemodynamic effects of sildenafil citrate: from basic science to clinical studies in patients with cardiovascular disease. Int J Cardiol 2002; 86:131–141. 36 Kloner RA, Hutter AM, Emmick JT, et al. Time course of the interaction between tadalafil and nitrates. J Am Coll Cardiol 2004; 42:1855–1860. 37 Jackson G, Martin E, McGing E, et al. Successful withdrawal of oral long-acting nitrates to facilitate phosphodiesterase Type 5 Inhibitor use in stable coronary disease patients with erectile dysfunction. J Sex Med 2005; 2:513–516. 38 Padma-Nathan H (ed). Sildenafil citrate (Viagra) and erectile dysfunction: a comprehensive four year update on efficacy, safety, and management approaches. Urology 2002; 60(2B): 1–90. 39 Mittleman MA, MacClure M, Glasser DB. Evaluation of acute risk for myocardial infarction in men treated with sildenafil citrate. Am J Cardiol 2005; 96:443–446. 40 Jackson G, Gillies H, Osterloh I. Past, present and future: a 7-year update of Viagra (sildenafil citrate). Int J Clin Pract 2005; 59: 680–691. 41 Fox KM, Thadani U, Ma PTS, et al. Sildenafil citrate does not reduce exercise tolerance in men with erectile dysfunction and chronic stable angina. Eur Heart J 2003; 24:2206–2212. 512 Erectile dysfunction 1180 Chap43 3/14/07 11:45 AM Page 512 42 Herrman HC, Chang G, Klugherz BD, et al. Haemodynamic effects of sildenafil in men with severe coronary artery disease. N Engl J Med 2000; 342:1662–1666. 43 Halcox JPJ, Nour KRA, Zalos G, et al. The effect of sildenafil on human vascular function, platelet activation and myocardial ischaemia. J Am Coll Cardiol 2002; 40:1232–1240. 44 Katz SD. Potential role of type 5 phosphodiesterase inhibition in the treatment of congestive heart failure. Congest Heart Fail 2003; 9:9–15. 45 Jackson G, Kloner RA, Costigan TM, et al. Update on clinical trials of tadalafil demonstrates no increased risk of cardiovascu- lar adverse events. J Sex Med 2004; 1:161–167. 46 Kloner RA, Jackson G, Emmick JT, et al. Interaction between phosphodiesterase 5 inhibitor, tadalafil, and two alpha block- ers, doxazosin and tamsulosin in healthy normotensive men. J Urol 2004; 172:1935–1940. 47 McMahon C. Comparison of efficacy, safety, and tolerability of on demand tadalafil and daily dosed tadalafil for the treatment of erectile dysfunction. J Sex Med 2006;2:415–424. 48 Kloner RA, Jackson G, Hutter AM, et al. Cardiovascular safety update of tadalafil: retrospective analysis of data from placebo- controlled and open-label clinical trials of tadalafil with as needed, three times-per-week or once-a-day dosing. Am J Cardiol 2006; 97:1778–1784. 49 Thadani U, Smith W, Nash S, et al. The effect of vardenafil, a potent and highly selective phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction, on the cardiovascular response to exercise in patients with coronary artery disease. J Am Coll Cardiol 2002; 40:2006–2012. 50 Nicolosi A, Glasser DB, Moreira ED, et al. Prevalence of erec- tile dysfunction and associated factors among men without concomitant diseases: a population study. Int J Impot Res 2003; 15:253–257. 51 Esposito K, Giugliano D. Obesity, the metabolic syndrome and sexual dysfunction. Int J Impot Res 2005; 17:391–398. 52 Rosen RC, Fisher W, Eardley I, et al. The multinational men’s attitudes of life events and sexuality (MALES) study; preva- lence of erectile dysfunction and related health concerns in the general population. Curr Med Res Opin 2004; 20: 607–617. 53 Bacon CG, Mittleman MA, Kawachi I, et al. Sexual function in men older than 50 years of age; results from the health profes- sionals follow-up study. Ann Intern Med 2003; 139: 161–168. 54 Blanker MH, Bosch JL, Groeneveld FP, et al. Erectile and ejac- ulatory dysfunction in a community-based sample of men 50–78 years old: prevalence, concerns and relation to sexual activity. Urology 2001; 57:763–768. 55 Blanker MH, Bohnen AM, Groeneveld FP, et al. Correlates for erectile and ejaculatory dysfunction in older Dutch men: a community-based study. J Am Geriatr Soc 2001; 49:436–442. 56 Esposito K, Giugliano F, Di Palo C, et al. Effect of lifestyle changes on erectile dysfunction in obese men: a randomized controlled trial. JAMA 2004; 291:1978–1984. 57 Shabsigh R, Kaufman JM, Steidle C, et al. Randomised study of testosterone gel as adjunctive therapy to sildenafil in hypogo- nadal men with erectile dysfunction who do not response to sildenafil alone. J Urol 2004; 172:658–663. 58 Muller M, Van Der Schouw YT, Thijssen JHH, et al. Endogenous sex hormones and cardiovascular disease in men. J Clin Endocrinol Metab 2003; 88:5076–5086. 59 Fraunfelder FW, Pomeranz HD, Egan RA. Non-arteritic ante- rior ischaemic optic neuropathy and sildenafil. Arch Ophthamol 2006; 124:733–734. References 513 1180 Chap43 3/14/07 11:45 AM Page 513 1180 Chap43 3/14/07 11:45 AM Page 514 Introduction The term “peripheral arterial disease” (PAD) covers a multitude of disorders involving arterial beds exclusive of the coronary arteries. There are numerous pathophysiologic processes that could contribute to the creation of stenoses or aneurysms of the noncoronary arterial circulation. Atherosclerosis represents the leading disease process affect- ing the aorta and its branch arteries. Patients undergoing percutaneous coronary intervention (PCI) who have PAD have been shown to have worse short- and long-term outcomes compared to patients without PAD (1–3). This chapter will cover pharmacotherapy and nonpharmacologic therapies for PAD involving lower extremities. Cardiovascular risk reduction The clinical manifestations of PAD are associated with reduction in functional capacity and quality of life, but because of the systemic nature of the atherosclerotic process there is a strong association with coronary and carotid artery disease. Consequently, patients with PAD have an increased risk of cardiovascular and cerebrovascular ischemic events [myocar- dial infarction (MI), ischemic stroke, and death] compared to the general population (4,5). In addition, these cardiovascular ischemic events are more frequent than ischemic limb events in any lower extremity PAD cohort, whether individuals present without symptoms or with atypical leg pain, classic claudication, or critical limb ischemia (6). Therefore, aggressive treatment of known risk factors for progression of atheroscle- rosis is warranted. In addition to tobacco cessation, encouragement of daily exercise and use of a low cholesterol, low salt diet, PAD patients should be offered therapies to reduce lipid levels, control blood pressure, control blood glucose in patients with diabetes mellitus, and offer other effective antiatherosclerotic strategies. A recent position paper describing antiatherosclerosis strategies includes patients with PAD, viewed as a coronary artery equivalent (7). Treatment of hyperlipidemia A meta-analysis was performed on randomized trials assess- ing lipid-lowering therapy in 698 patients with PAD who were treated with a variety of therapies, including diet, cholestyramine, probucol, and nicotinic acid, for four months to three years (8). There was a significant difference in total mortality [0.7% in the treated patients, as compared with 2.9% in the patients given placebo (p ϭ NS)], with an addi- tional reduction in disease progression, as measured by angiography and the severity of claudication. Two studies evaluated the effects of lipid-lowering therapy on clinical endpoints in the leg. The Program on the Surgical Control of the Hyperlipidemias was a randomized trial of partial ileal-bypass surgery for the treatment of hyperlipidemia in 838 patients (9). After five years, the relative risk (RR) of an abnormal ankle-brachial index value (ABI) was 0.6 (95% CI, 0.4 to 0.9, absolute risk reduction, 15% points, p Ͻ 0.01), and the RR of claudication or limb-threatening ischemia was 0.7 (95% CI, 0.2 to 0.9, absolute risk reduction, 7% points, p Ͻ 0.01), as compared with the control group. In patients with PAD, therapy with a statin not only lowers serum cholesterol levels, but also improves endothelial function, as well as other markers of atherosclerotic risk, such as serum P-selectin concentrations (10,11). In a subgroup of patients treated with simvastatin in the Scandinavian Simvastatin Survival Study, the RR of new claudication or worsening of preexisting claudication was 0.6 (95% CI, 0.4 to 0.9, absolute risk reduction, 1.3% points), as compared with patients randomly assigned to placebo (12). Several studies have revealed that statins have a beneficial effect on exercise performance in patients with claudication (13). Statins also improve endothelial function and have other 44 Peripheral arterial disease Zoran Lasic and Michael R. Jaff 1180 Chap44 3/14/07 11:46 AM Page 515 favorable metabolic effects, but the functional benefit of statins is not due to regression of atherosclerosis or gross change in limb hemodynamics. The National Cholesterol Education Program classifies patients with PAD in the group of coronary heart disease (CHD) risk equivalents. Other coronary heart equivalents include abdominal aortic aneurysm, carotid artery disease (transient ischemic attacks or stroke of carotid origin or Ͼ50% obstruction of a carotid artery), diabetes mellitus, and patients with two or more risk factors for atherosclerosis which produces the 10-year risk for CHD Ͼ20% (14). Patients with PAD and low-density lipoprotein (LDL) choles- terol (LDL-C) of 100 mg/dL or greater should be treated with a statin, but when risk is very high, an LDL cholesterol goal of less than 70 mg/dl is an appropriate therapeutic option. Factors that place patients in the category of very high risk are the presence of established cardiovascular disease (CVD) plus (i) multiple major risk factors (especially diabetes), (ii) severe and poorly controlled risk factors (especially continued ciga- rette smoking), (iii) multiple risk factors of the metabolic syndrome [especially high triglycerides, that is greater than or equal to 200 mg/dL plus non-HDL cholesterol greater than or equal to 130 mg/dL with low-HDL cholesterol (less than or equal to 40 mg/dL)], and (iv) on the basis of the PROVE IT trial (15), patients with acute coronary syndromes (16,17). Treatment of hypertension Treatment of high blood pressure is indicated to reduce the risk of cardiovascular events (18). Betablockers, which have been shown to reduce the risk of MI and death in patients with coronary atherosclerosis (19), do not adversely affect walking capacity (20,21). These agents must be offered to patients with PAD who have already suffered a MI or have established coronary artery disease. Angiotensin-converting enzyme inhibitors reduce the risk of death and nonfatal cardiovascular events in patients with coronary artery disease and left ventric- ular dysfunction (22,23). The Heart Outcomes Prevention Evaluation trial found that in patients with symptomatic PAD, ramipril, a tissue-specific ACE-inhibitor reduced the risk of MI, stroke, or vascular death by approximately 25%, a level of effi- cacy comparable to that achieved in the entire study population (24). There is currently no evidence base for the efficacy of ACE inhibitors in patients with asymptomatic PAD, and thus, the use of ACE-inhibitor medications to lower cardiovascular ischemic event rates in this population must be extrapolated from the data on symptomatic patients. However, a recent small randomized prospective placebo- controlled trial of ramipril in patients with symptomatic PAD demonstrated a statistically significant improvement in pain- free walking distance when compared with placebo (25). ACC/AHA 2005 guidelines for the management of patients with PAD recommend that antihypertensive therapy should be administered to hypertensive patients with lower extrem- ity PAD to achieve a goal of less than 140mmHg systolic over 90 mmHg diastolic (nondiabetics) or less than 130 mmHg systolic over 80 mmHg diastolic (diabetics and individuals with chronic renal disease) to reduce the risk of MI, stroke, conges- tive heart failure, and cardiovascular death (26,27). Treatment of diabetes mellitus Intensive pharmacologic treatment of diabetes is known to decrease the risk for microvascular events such as nephro- pathy and retinopathy, but there is less evidence that it decreases macrovascular disease (28,29). DCCT/EDIC trial, however, demonstrated reduction in CVD (nonfatal MI, stroke, death from CVD, confirmed angina, or the need for coronary-artery revascularization) in patients with type I diabetes assigned to intensive diabetes treatment compared with conventional treatment by 42% (p ϭ 0.02) (30). Patients with lower extremity PAD and both type 1 and type 2 diabetes should be treated to reduce their glycosylated hemoglobin (Hb A1C) to less than 7%, per the American Diabetes Association recommendation (31). Subanalysis of the UKPDS showed no evidence of a threshold effect of Hb A1C; a 1% reduction in Hb A1C was associated with a 35% reduction in microvascular endpoints, an 18% reduction in MI, and a 17% reduction in all-cause mortality. Frequent foot inspection by patients and physicians will enable early identifi- cation of foot lesions and ulcerations and facilitate prompt referral for treatment (32). Homocysteine-lowering drugs Patients with PAD have increased mortality risk from cardiovas- cular causes (4,5), which is significantly increased in the subgroup of patients with high serum homocysteine concentra- tion (33,34). Association of a low ABI and high homocysteine level could be useful for identifying patients at excess risk for cardiovascular death (34). In spite of the efficacy in lowering homocysteine level with a folic acid supplement there is no evidence that reducing homocysteine concentration is beneficial in patients with CHD and PAD (26,35). Antiplatelet and antithrombotic drugs The Antithrombotic Trialists’ Collaboration (ATC) investigated the effects of antiplatelet therapy in 287 studies involving 516 Peripheral arterial disease 1180 Chap44 3/14/07 11:46 AM Page 516 135,000 patients in comparison with antiplatelet therapy versus control and 77,000 in comparison with different antiplatelet regimens in patients at high risk of occlusive vascu- lar events (36). “Serious vascular event” (nonfatal MI, nonfatal stroke, or vascular death) was less common in patients allo- cated to antiplatelet therapy by about one quarter; nonfatal MI was reduced by one-third, nonfatal stroke by one quarter, and vascular mortality by one-sixth (with no apparent adverse effect on other deaths). Aspirin was the most commonly studied antiplatelet drug, with doses of 75 to 150 mg daily at least as effective as higher daily doses. Clopidogrel-reduced serious vascular events by 10% (4%) compared with aspirin, which was similar to the 12% (7%) reduction observed with its analog ticlopidine. Aspirin Aspirin (acetylsalicylic acid—ASA) exerts its effect primarily by irreversibly inhibiting enzyme cyclo-oxygenase that blocks platelet synthesis of thromboxane A2—a promoter of platelet aggregation (37). The benefits of ASA in reducing cardiovas- cular death, MI, and stroke in patients with CHD (36) have led to the near universal use of this medication for patients undergoing PCI. Antithrombotic effects have been shown to be present at dosages between 50 and 100 mg/day, but the optimal dose for PCI has not been firmly established. Different aspirin doses compared in the ATC meta-analysis suggest that a daily dose of 75 to 150 mg is at least as effec- tive as higher doses (Ͼ150 mg/day) and is less likely to cause gastrointestinal and bleeding complications (36). When given in combination with warfarin or thienopyri- dine class of antiplatelet agents the ASA dose is usually lowered to 80 to 100 mg based on a post hoc analysis of data from the clopidogrel in unstable angina to prevent recurrent events (CURE), which showed similar efficacy but less major bleeding with the low dose (Ͻ100 mg) of ASA (38). ASA nonresponsiveness or resistance is reported in 5% to 60% of patients (39,40). There is emerging clinical evidence that ASA resistance is associated with an increased risk of major adverse cardiovascular events. Five studies in patients with coro- nary peripheral, and/or cerebrovascular disease have reported a 1.8- to 10-fold increased risk of thrombotic events (41,42). In the Physicians’ Health Study aspirin treatment for primary prevention of PAD reduced the subsequent need for peripheral arterial surgery (43). Aspirin therapy significantly improved vascular-graft patency in 3226 patients with PAD who were treated surgically or with peripheral angioplasty during average follow-up to 19 months (43% reduction in the rate of vascular-graft occlusion: 25% in the control group as compared with 16% in the aspirin group) (44). Aspirin given as a monotherapy was as effective as the combination of aspirin and dipyridamole, sulfinpyrazone, or ticlopidine in preventing graft occlusion, without any difference between low-dose (75 to 325 mg/day) and high-dose aspirin (600 to 1500 mg/day). The ACC/AHA guidelines state that ASA in daily doses of 75 to 325 mg is recommended as a safe and effective antiplatelet therapy to reduce the risk of MI, stroke, or vascu- lar death in individuals with atherosclerotic lower extremity PAD (26). Thienopyridines Clopidogrel and ticlopidine are thienopyridine derivatives. They selectively and irreversibly inhibit the P2Y12 ADP recep- tor, which plays a critical role in platelet activation and aggregation (45). They work synergistically with ASA in provid- ing greater inhibition of platelet aggregation than either agent alone (46). The inhibition of platelet aggregation by ticlopidine and clopidogrel is present after two to three days of therapy with ticlopidine 500 mg/day or clopidogrel 75 mg/day, and platelet function recovers in five to seven days after discontin- uation owing to the synthesis of new platelets (47). Clopidogrel In the CAPRIE trial (Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events), clopidogrel reduced the risk of MI, stroke, or vascular death by 23.8% compared with aspirin in patients with PAD (48). Although this is an impressive reduc- tion in major events, the benefits of clopidogrel over aspirin were identified as a subgroup analysis rather than a primary endpoint. The Charisma trial evaluated antiplatelet treatment with aspirin alone compared with aspirin plus clopidogrel among high-risk patients with stable CVD (49). High-risk patients with established vascular disease included 37.4% with coronary disease, 27.7% with cerebrovascular disease, and 18.2% with symptomatic PAD. There was no difference in the primary endpoint of CV death, MI, or stroke between the clopidogrel plus aspirin group (6.8%) and the placebo plus aspirin group (7.3%, RR 0.93, p ϭ 0.22). The secondary endpoint of death, MI, stroke or hospitalization for ischemic event was lower in the clopidogrel plus aspirin group (16.7% vs. 17.9%, RR 0.92, p ϭ 0.04). The benefit of clopidogrel was evident in the symp- tomatic cohort (with documented CVD at enrollment) for the primary endpoint (6.9% for clopidogrel vs. 7.9% for placebo, RR 0.88, p ϭ 0.046) but not in the asymptomatic cohort (6.6% for clopidogrel vs. 5.5% for placebo, RR 1.20, p ϭ 0.20, interaction p ϭ 0.045). Severe bleeding trended higher in the clopidogrel group (1.7% vs. 1.3%, RR 1.25, p ϭ 0.09), while moderate bleeding was significantly higher in the clopidogrel group (2.1% vs. 1.3%, p Ͻ 0.001). There was no difference in intracranial hemorrhage (0.3% each). These Antiplatelet and antithrombotic drugs 517 1180 Chap44 3/14/07 11:46 AM Page 517 findings suggest that dual antiplatelet therapy may not be bene- ficial in all patients at risk for CVD, but that in patients with established CVD, dual therapy may be effective in reducing subsequent events. In the CURE study, 12,562 patients with acute coronary syndromes without ST-segment elevation have received ASA and clopidogrel 300 mg bolus, followed by 75 mg daily, versus ASA and placebo (50). The clopidogrel group had early reduc- tion [within 24 hours of treatment—9.3% vs. 11.4%, RR reduction 20% (p Ͻ 0.001) in the primary endpoint death from cardiovascular cause, nonfatal MI, or stroke], which was sustained at one year, and was observed in all patients with acute coronary syndromes regardless of their level of risk. CURE patients who underwent PCI and were randomized to clopidogrel had a 31% RR reduction in death and MI compared with placebo-treated PCI patients (51). The CREDO trial, which studied an elective population of patients who underwent PCI, showed benefits of clopidogrel (52). Patients were randomly assigned to receive a 300-mg clopidogrel loading dose (n ϭ1053) or placebo (n ϭ1063), 3 to 24 hours before PCI. Thereafter, all patients received clopidogrel, 75 mg/day, through day 28. The group loaded with clopidogrel was continued on active drug from day 28 through 12 months while the control group received placebo. Both groups received aspirin throughout the study. There was a significant 27% (p ϭ 0.02) reduction in death, MI, or stroke in patients receiving clopidogrel, suggesting that clopidogrel therapy should be continued in addition to ASA for a minimum of nine months post PCI. There was an increase in major bleeding with clopidogrel in both the CURE and CREDO trials. In CURE, those receiving clopidogrel had bleeding rates of 3.7% versus 2.7% (p ϭ0.001), most notably in those patients requiring CABG. In CREDO, there was only a trend toward more TIMI (throm- bolysis in MI) major bleeding (8.8% vs. 6.7%, p ϭ 0.07) and no excess bleedings among patients undergoing CABG. Ticlopidine Although the original stent thrombosis data were obtained with ticlopidine, its use has been virtually abandoned in the United States owing to its increased risk of neutropenia. A meta-analysis demonstrated that clopidogrel was associated with a significant reduction in the incidence of major adverse cardiac events (2.1% in the clopidogrel group and 4.04% in the ticlopidine group). After adjustment for heterogeneity in the trials, the odds ratio (OR) of having an ischemic event with clopidogrel, as compared with ticlopidine, was 0.72 (95% CI, 0.59–0.89, p ϭ 0.002). Mortality was also lower in the clopi- dogrel group compared with the ticlopidine group Ϫ0.48% versus 1.09% (OR 0.55, 95% CI, 0.37–0.82, p ϭ 0.003). The safety and tolerability of clopidogrel were superior to that of ticlopidine (53). This includes fewer rashes, gastrointestinal side effects, as well as fewer hematologic complications (neutropenia). Ticlopidine use in the United States in patients undergoing PCI is mostly reserved for those patients with allergy or intolerance of clopidogrel. Smoking cessation Smoking cessation should be encouraged because it slows the progression of PAD to critical leg ischemia and reduces the risks of MI and death from vascular causes (54). Patients with CHD who stopped smoking had a 36% reduction in crude RR of mortality compared with those who continued smoking (RR 0.64, 95% CI, 0.58–0.71) (55). While smoking cessation does not improve maximal treadmill walking distance in patients with claudication based on a meta-analysis from published data (56), smoking cessation is critical in patients with thromboangiitis obliterans, because continued use is associated with a particularly adverse outcome (57). Physician advice coupled with frequent follow-up achieves one-year smoking cessation rates of approximately 5% compared with only 0.1% in those attempting to quit smok- ing without a physician’s intervention (58). Pharmacologic interventions (nicotine replacement therapy and bupropion) should be encouraged because they achieve higher cessation rates at one year (16% and 30%, respectively) (59). Treatment for claudication Intermittent claudication decreases exercise capacity and overall functional capacity. Impaired walking ability is coupled with the inability to perform activities of daily living and results in a decrease in overall quality of life (60). Pharmacologic and nonpharmacologic measures aimed in improving mobility and consequently the quality of life is important treatment goals for patients with PAD. Exercise In patients with claudication, the most important nonpharmaco- logic treatment is a formal exercise-training program (61). An exercise program can significantly improve maximal walking time and overall walking ability (62). The optimal exercise program for improving distances walked without claudication pain involves intermittent walking to near-maximal pain over a period of at least six months based on meta-analysis from Gardner et al. (63). ACC/AHA guidelines recommend exercise training in duration for a minimum of 30 to 45 minutes, in sessions performed at least three times per week for a minimum of 12 weeks (ACC/AHA guidelines). Optimal results involve a motivated patient in a supervised setting, which represents a challenge for 518 Peripheral arterial disease 1180 Chap44 3/14/07 11:46 AM Page 518 patients and health care providers because supervised exercise- training programs are not covered by medical insurance, which makes their extensive and long-term use difficult (64). The mechanism by which exercise improves leg symptoms is uncer- tain, but it does not appear to operate through improvement of the ABI or growth of collateral vessels (65). Pharmacologic treatment for claudication Cilostazol The primary action of cilostazol is inhibition of phosphodi- esterase type 3, which increases intracellular concentrations of cyclic AMP. Cilostazol inhibits platelet aggregation, the forma- tion of arterial thrombi, and vascular smooth-muscle proliferation and causes vasodilatation (66–68). Since vasodila- tor and antiplatelet drugs do not improve claudication-limited exercise performance, the precise mechanism through which cilostazol exerts its effect in PAD is unknown. After 12 to 24 weeks of therapy patients treated with cilostazol improve maximal walking distance by 40% to 60% (69–73). In addition to improved walking capacity cilostazol improves health- related quality of life (74). Administered at the dose of 100 mg twice daily cilostazol is more effective than 50 mg twice daily (71,73). Although no trials have found a significant increase in major cardiovascular events in patients treated with cilostazol (an increased mortality was observed with other phosphodi- esterase inhibitors such as milrinone), it remains contraindicated in individuals with coexistent heart failure because of its potential adverse effect in this population. The predominant side effect of cilostazol is headache, which affects 34% of patients taking 100 mg twice daily, as compared with 14% of patients taking placebo. Pentoxifylline Mechanism of action that provides symptom relief with pentox- ifylline is poorly understood but is thought to involve red blood cell deformability as well as a reduction in fibrinogen concentra- tion, platelet adhesiveness and whole blood viscosity (75). The recommended dose of pentoxifylline is 400 mg three times daily with meals. Pentoxifylline causes a marginal but statistically signif- icant improvement in pain-free and maximal walking distance (a net benefit of 44 m in the maximal distance walked on a treadmill (95% CI, 0 14 to 0 74) based on meta-analyses of randomized, placebo-controlled, double-blind clinical trials (76). At the same time pentoxifylline does not increase the ABI at rest or after exercise (56). Pentoxifylline may be used to treat patients with intermittent claudication; however, it is likely to be of marginal clinical importance (56,77). Medical therapies whose effectiveness is not well established by evidence/opinion (Class IIb – ACC/AHA Guidelines). L-arginine Infusion of L-arginine produces systemic vasodilatation via stimulation of endogenous nitric oxide (NO) formation, which may improve vascular endothelial function and muscle blood flow in patients with PAD via the NO-cyclic GMP pathway in a dose-related manner (78). In patients with claudication, two weeks of treatment using a food bar enriched with L-arginine and a combination of other nutrients increased the pain-free walking distance 66% while the total walking distance increased 23% in the group taking two active bars per day. Improvements were not observed in the one active bar per day and placebo groups (79). L-carnitine and propionyl-L-carnitine Orally administered L-carnitine and propionyl-L-carnitine may have metabolic benefits by providing an additional source of carnitine to buffer the cellular acyl CoA pool. In this way, carnitine may enhance glucose oxidation under ischemic conditions and improve energy metabolism in the ischemic skeletal muscle. Propionyl-CoA generated from propionyl- L-carnitine may also improve oxidative metabolism through its anaphoretic actions in priming the Kreb’s cycle, secondary to succinyl-CoA production. After 180 days of treatment there was a significant improve- ment of 73 Ϯ9% (meanϮSE) in maximal walking distance in PAD patients treated with propionyl-L-carnitine compared to placebo (80). Propionyl-L-camitine has been shown to improve treadmill performance and quality of life in patients with claudication. After six months of treatment, subjects randomly assigned to propionyl-L-carnitine increased their peak walking time by 162 Ϯ 222 seconds (a 54% increase) as compared with an improvement of 75 Ϯ 191 seconds (a 25% increase) for those on placebo (p Ͻ 0.001) (81). Ginkgo biloba Ginkgo biloba extract has been reported to improve symptoms of intermittent claudication. Meta-analysis of the efficacy of Ginkgo biloba extract for intermittent claudication based on the results of eight randomized, placebo-controlled, double-blind trials found a significant difference in the increase in pain-free walking distance in favor of Ginkgo biloba (weighted mean difference: 34 m, 95% CI, 26–43 m). Though the results showed statistical superiority of Ginkgo biloba extract compared to placebo in the symptomatic treat- ment of intermittent claudication, extent of the improvement was modest and of uncertain clinical relevance (82). Exercise 519 1180 Chap44 3/14/07 11:46 AM Page 519 Prostaglandin Vasodilators decrease arteriolar tone; however, numerous controlled trials have found no convincing evidence of clinical efficacy for any of these medications in patients with claudica- tion (83). There are several potential pathophysiologic explanations for the lack of efficacy of these drugs in treating claudication. During exercise, resistance vessels dilate distal to a stenosis or occlusion in response to ischemia. Vasodilators have little effect on these already dilated vessels and may decrease resistance in unobstructed vascular beds, leading to a “steal” of blood flow away from underperfused muscles. Vasodilators can also lower systemic pressure, leading to a reduction in perfu- sion pressure. Thus, vasodilating medications do not favorably address the pathophysiology of claudication or result in a treat- ment benefit. The initial trial with oral prostaglandin beraprost showed an improvement of Ͼ50% in pain-free walking distance and maximum walking distances at six months compared to placebo (84). A US study, however, showed that administration of beraprost did not improve the pain-free walking distance or the quality-of-life measures between the treatment groups (85). Other therapies A systematic review of the literature aimed to assess the effectiveness of any type of complementary therapy for inter- mittent claudication revealed that there is no evidence of effectiveness of acupuncture, biofeedback therapy, chelation therapy, CO(2)-applications and the dietary supplements of Allium sativum (garlic), omega-3 fatty acids and Vitamin E (86). 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Recovery of platelet function after discontinuation of clopidogrel treatment in healthy volunteers. Br J Clin Pharmacol 2001; 52: 333–336. References 521 1180 Chap44 3/14/07 11:46 AM Page 521 [...]... 2,007 2,007 1,605/ 92 .5 1,601/ 93 .0 1, 393 / 1,145/ 88.0 83.1 1,347/ 1,104/ 87 .9 82.2 8 59/ 76.3 8 79/ 76.4 616/ 71.2 662/ 71.4 1, 491 1,208/ 93 .7 1,888 1, 497 / 93 .2 514 396 / 89. 0 1,033/ 852/ 89. 4 85.5 1,256/ 1,028/ 88.0 82.7 360/ 293 / 84.4 76.5 Figure 1 A Long-term outcome of patients undergoing attempted PCI of a chronic total occlusion (A ) Outcome of chronic total occlusion versus B non-chronic total occlusion... Treatment of intermittent claudication with physical training, smoking cessation, pentoxifylline, or nafronyla meta-analysis Arch Intern Med 199 9; 1 59: 337Ϫ345 Hood SC, Moher D, Barber GG Management of intermittent claudication with pentoxifylline meta-analysis of randomized controlled trials CMAJ 199 6; 155:1053–10 59 Schellong SM, Boger RH, Burchert W, et al Dose-related effect of intravenous L-arginine... acute ST-segment elevation 1180 Chap45 3/14/07 4: 59 PM Page 535 References 28 29 30 31 32 33 34 35 36 37 38 39 40 myocardial infarction: a meta-analysis of randomized trials JAMA 2005; 293 (14):17 59 1765 The CAPTURE Investigators Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study Lancet 199 7; 3 49( 9063):14 29 1435 The... claudication Eur J Vasc Endovasc Surg 199 6; 11:65– 69 Nehler MR, Hiatt WR Exercise therapy for claudication Ann Vasc Surg 199 9; 13:1 09 114 Leng GC, Fowler B, Ernst E Exercise for intermittent claudication Cochrane Database Syst Rev 2000;2:CD00 099 0 Gardner AW, Phoelman ET Exercise rehabilitation programs for the treatment of claudication pain: a meta-analysis JAMA 199 5; 274 :97 5 98 0 Regensteiner JG, Meyer TJ,... 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Gene title 768246 G6PD Glucose-6-phosphate dehydrogenase 85678 F2 Coagulation factor II 8 597 9 PLG Plasminogen 1201 89 PSG4 Pregnancy-specific beta-1-glycoprotein 4 121218 PF4 Platelet factor 4 12 792 8 HBP1 HMG-box containing protein 1 130541 PECAM1 Platelet/endothelial-cell adhesion molecule (CD31 antigen) 1318 39 FOLR1 Folate receptor 1 (adult) 135221 S100P S100 calcium-binding protein P 136821 TGFB1... nonerythrocytic 2 191 664 THBS2 Thrombospondin 2 194 804 PTTPN Phosphatidylinositol transfer protein 196 612 MMP12 Matrix metalloproteinase 1 (interstitial collagenase) 199 945 TGM2 Transglutaminase 2 (C polypeptide, protein-glutamine-gamma-glutamyltransferase) 205185 THBD Thrombomodulin 210687 AGTR1 Angiotensin receptor 1 2124 29 TF Transferrin 2126 49 HRG Histidine-rich glycoprotein 234736 GATA6 GATA-binding protein... 96 :261–268 Igawa T, Tani T, Chijiwa T, et al Potentiation of anti-platelet aggregating activity of cilostazol with vascular endothelial cells Thromb Res 199 0; 57:617–623 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 Tsuchikane E, Fukuhara A, Kobayashi T, et al Impact of cilostazol on restenosis after percutaneous coronary balloon angioplasty Circulation 199 9; 100:21–26 Dawson DL, Cutler BS, Meissner... 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The effect of vardenafil,