Textbook of Interventional Cardiovascular Pharmacology - part 9 pot

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 4

5 Drory Y, Fisman EZ, Shapira Y, et al Ventricular arrhythmias

during sexual activity in patients with coronary artery disease.

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6 Drory Y, Shapira I, Fisman EZ, et al Myocardial ischaemia

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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

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9 Solomon H, Man JW, Jackson G Erectile dysfunction and the

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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

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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

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16 Kirby M, Jackson G, Betteridge J, et al Is erectile dysfunction a

marker for cardiovascular disease? Int J Clin Pract 2001;

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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 graphically documented coronary artery disease Eur Urol 2003; 44:360–365.

angio-23 Virag R, Bouilly P, Frydman D Is impotence an arterial

disor-der? A study of arterial risk factors in 440 impotent men.

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24 Bocchio M, Desideri G, Scarpelli P, et al Endothelial cell vation in men with erectile dysfunction without cardiovascular risk factors and overt vascular damage J Urol 2004; 171:1601–1604.

acti-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 lial dysfunction is associated with erectile dysfunction and elevated asymmetric dimethylarginine in patients with early atherosclerosis Eur Heart J 2006; 27:824–831.

endothe-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 tion an indicator for increased risk of coronary heart disease and stroke? Eur Urol 2005; 48:512–518.

dysfunc-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 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.

tolera-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.

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 lar adverse events J Sex Med 2004; 1:161–167.

cardiovascu-46 Kloner RA, Jackson G, Emmick JT, et al Interaction between

phosphodiesterase 5 inhibitor, tadalafil, and two alpha ers, doxazosin and tamsulosin in healthy normotensive men J Urol 2004; 172:1935–1940.

block-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 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.

placebo-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 sionals follow-up study Ann Intern Med 2003; 139: 161–168.

profes-54 Blanker MH, Bosch JL, Groeneveld FP, et al Erectile and 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.

ejac-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 rior ischaemic optic neuropathy and sildenafil Arch Ophthamol 2006; 124:733–734.

ante-References 513

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 undergoaffect-ing

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 withPAD, viewed as a coronary artery equivalent (7)

Treatment of hyperlipidemia

A meta-analysis was performed on randomized trials ing lipid-lowering therapy in 698 patients with PAD whowere treated with a variety of therapies, including diet,cholestyramine, probucol, and nicotinic acid, for four months

assess-to three years (8) There was a significant difference in assess-totalmortality [0.7% in the treated patients, as compared with2.9% in the patients given placebo (p⫽ NS)], with an addi-tional reduction in disease progression, as measured byangiography and the severity of claudication

Two studies evaluated the effects of lipid-lowering therapy

on clinical endpoints in the leg The Program on the SurgicalControl of the Hyperlipidemias was a randomized trial ofpartial ileal-bypass surgery for the treatment of hyperlipidemia

in 838 patients (9) After five years, the relative risk (RR) of anabnormal ankle-brachial index value (ABI) was 0.6 (95% CI,0.4 to 0.9, absolute risk reduction, 15% points, p⬍ 0.01),and the RR of claudication or limb-threatening ischemia was0.7 (95% CI, 0.2 to 0.9, absolute risk reduction, 7% points,

p⬍ 0.01), as compared with the control group

In patients with PAD, therapy with a statin not only lowersserum cholesterol levels, but also improves endothelialfunction, 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 theScandinavian Simvastatin Survival Study, the RR of newclaudication or worsening of preexisting claudication was 0.6(95% CI, 0.4 to 0.9, absolute risk reduction, 1.3% points), ascompared with patients randomly assigned to placebo (12).Several studies have revealed that statins have a beneficialeffect 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

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

⬎50% 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 ⬎20% (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 ity PAD to achieve a goal of less than 140 mmHg systolic over

extrem-90 mmHg diastolic (nondiabetics) or less than 130 mmHgsystolic over 80 mmHg diastolic (diabetics and individuals withchronic 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 todecrease the risk for microvascular events such as nephro-pathy and retinopathy, but there is less evidence that itdecreases macrovascular disease (28,29) DCCT/EDIC trial,however, demonstrated reduction in CVD (nonfatal MI,stroke, death from CVD, confirmed angina, or the need forcoronary-artery revascularization) in patients with type Idiabetes assigned to intensive diabetes treatment comparedwith conventional treatment by 42% (p⫽ 0.02) (30).Patients with lower extremity PAD and both type 1 and type

2 diabetes should be treated to reduce their glycosylatedhemoglobin (Hb A1C) to less than 7%, per the AmericanDiabetes Association recommendation (31) Subanalysis ofthe UKPDS showed no evidence of a threshold effect of HbA1C; 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 footinspection by patients and physicians will enable early identifi-cation of foot lesions and ulcerations and facilitate promptreferral for treatment (32)

Homocysteine-lowering drugs

Patients with PAD have increased mortality risk from cular causes (4,5), which is significantly increased in thesubgroup of patients with high serum homocysteine concentra-tion (33,34) Association of a low ABI and high homocysteinelevel could be useful for identifying patients at excess risk forcardiovascular death (34) In spite of the efficacy in loweringhomocysteine level with a folic acid supplement there is noevidence that reducing homocysteine concentration is beneficial

cardiovas-in patients with CHD and PAD (26,35)

Antiplatelet and antithrombotic drugs

The Antithrombotic Trialists’ Collaboration (ATC) investigatedthe effects of antiplatelet therapy in 287 studies involving

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 vascuvascu-lar 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 (⬎150 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 (⬍100 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 effectiveantiplatelet therapy to reduce the risk of MI, stroke, or vascu-lar death in individuals with atherosclerotic lower extremityPAD (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 andaggregation (45) They work synergistically with ASA in provid-ing greater inhibition of platelet aggregation than either agentalone (46) The inhibition of platelet aggregation by ticlopidineand clopidogrel is present after two to three days of therapywith ticlopidine 500 mg/day or clopidogrel 75 mg/day, andplatelet 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 inpatients with PAD (48) Although this is an impressive reduc-tion in major events, the benefits of clopidogrel over aspirinwere identified as a subgroup analysis rather than a primaryendpoint

The Charisma trial evaluated antiplatelet treatment withaspirin alone compared with aspirin plus clopidogrel amonghigh-risk patients with stable CVD (49) High-risk patients withestablished vascular disease included 37.4% with coronarydisease, 27.7% with cerebrovascular disease, and 18.2% withsymptomatic PAD There was no difference in the primaryendpoint of CV death, MI, or stroke between the clopidogrelplus aspirin group (6.8%) and the placebo plus aspirin group(7.3%, RR 0.93, p⫽ 0.22) The secondary endpoint of death,

MI, stroke or hospitalization for ischemic event was lower inthe clopidogrel plus aspirin group (16.7% vs 17.9%, RR 0.92,

p⫽ 0.04) The benefit of clopidogrel was evident in the tomatic cohort (with documented CVD at enrollment) for theprimary endpoint (6.9% for clopidogrel vs 7.9% for placebo,

symp-RR 0.88, p⫽ 0.046) but not in the asymptomatic cohort(6.6% for clopidogrel vs 5.5% for placebo, RR 1.20,

p⫽ 0.20, interaction p ⫽ 0.045) Severe bleeding trendedhigher in the clopidogrel group (1.7% vs 1.3%, RR 1.25,

p⫽ 0.09), while moderate bleeding was significantly higher inthe clopidogrel group (2.1% vs 1.3%, p⬍ 0.001) There was

no difference in intracranial hemorrhage (0.3% each) These

Antiplatelet and antithrombotic drugs 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⬍ 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 ⫽1053) or placebo (n ⫽1063), 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⫽ 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⫽0.001), 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⫽ 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⫽ 0.002) Mortality was also lower in the

clopi-dogrel group compared with the ticlopidine group ⫺0.48%

versus 1.09% (OR 0.55, 95% CI, 0.37–0.82, p⫽ 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 patientsundergoing PCI is mostly reserved for those patients withallergy or intolerance of clopidogrel

Smoking cessation

Smoking cessation should be encouraged because it slowsthe progression of PAD to critical leg ischemia and reducesthe risks of MI and death from vascular causes (54) Patientswith CHD who stopped smoking had a 36% reduction incrude RR of mortality compared with those who continuedsmoking (RR 0.64, 95% CI, 0.58–0.71) (55) While smokingcessation does not improve maximal treadmill walkingdistance in patients with claudication based on a meta-analysisfrom published data (56), smoking cessation is critical inpatients with thromboangiitis obliterans, because continueduse is associated with a particularly adverse outcome (57).Physician advice coupled with frequent follow-up achievesone-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) Pharmacologicinterventions (nicotine replacement therapy and bupropion)should be encouraged because they achieve higher cessationrates at one year (16% and 30%, respectively) (59)

Treatment for claudication

Intermittent claudication decreases exercise capacity andoverall functional capacity Impaired walking ability is coupledwith the inability to perform activities of daily living and results

in a decrease in overall quality of life (60) Pharmacologic andnonpharmacologic measures aimed in improving mobility andconsequently the quality of life is important treatment goalsfor patients with PAD

Exercise

In patients with claudication, the most important logic treatment is a formal exercise-training program (61) Anexercise program can significantly improve maximal walking timeand overall walking ability (62) The optimal exercise program forimproving distances walked without claudication pain involvesintermittent walking to near-maximal pain over a period of atleast six months based on meta-analysis from Gardner et al (63).ACC/AHA guidelines recommend exercise training in durationfor a minimum of 30 to 45 minutes, in sessions performed atleast three times per week for a minimum of 12 weeks(ACC/AHA guidelines) Optimal results involve a motivatedpatient in a supervised setting, which represents a challenge for

nonpharmaco-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 viastimulation of endogenous nitric oxide (NO) formation,which may improve vascular endothelial function and muscleblood flow in patients with PAD via the NO-cyclic GMPpathway in a dose-related manner (78) In patients withclaudication, two weeks of treatment using a food barenriched with L-arginine and a combination of other nutrientsincreased the pain-free walking distance 66% while the totalwalking distance increased 23% in the group taking two activebars per day Improvements were not observed in the oneactive bar per day and placebo groups (79)

L-carnitine and propionyl-L-carnitine

Orally administered L-carnitine and propionyl-L-carnitine mayhave metabolic benefits by providing an additional source ofcarnitine to buffer the cellular acyl CoA pool In this way,carnitine may enhance glucose oxidation under ischemicconditions and improve energy metabolism in the ischemicskeletal muscle Propionyl-CoA generated from propionyl-L-carnitine may also improve oxidative metabolism throughits anaphoretic actions in priming the Kreb’s cycle, secondary

to succinyl-CoA production

After 180 days of treatment there was a significant ment of 73⫾9% (mean ⫾SE) in maximal walking distance

improve-in PAD patients treated with propionyl-L-carnitine compared

to placebo (80) Propionyl-L-camitine has been shown toimprove treadmill performance and quality of life in patientswith claudication After six months of treatment, subjectsrandomly assigned to propionyl-L-carnitine increased theirpeak walking time by 162⫾ 222 seconds (a 54% increase) ascompared with an improvement of 75⫾ 191 seconds (a 25% increase) for those on placebo (p⬍ 0.001) (81)

Ginkgo biloba

Ginkgo biloba extract has been reported to improve symptoms of intermittent claudication Meta-analysis of theefficacy of Ginkgo biloba extract for intermittent claudicationbased 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 Ginkgobiloba extract compared to placebo in the symptomatic treat-ment of intermittent claudication, extent of the improvementwas modest and of uncertain clinical relevance (82)

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 ⬎50% 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)

PAD is particularly common in patients with CAD

undergo-ing PCI PCI patients affected with PAD have an increased risk

of major adverse cardiovascular events in addition to impaired

ambulatory capacity and quality of life, compared with PCI

patients without PAD PAD is undertreated, especially in

patients with asymptomatic PAD, with consideration to

phar-macologic and nonpharphar-macologic therapies Therefore it is

important to recognize PAD in PCI patients so that they can

be aggressively managed with regard to risk factor modification

using pharmacologic approach in treating hypertension,

hyperlipidemia, diabetes mellitus, and symptoms of PAD

Pharmacologic therapies should be coupled with a supervised

exercise program and smoking cessation program

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Since Andreas Grüntzig described the first percutaneous

coronary intervention (PCI) in 1978 (1), the field has

pro-gressed immeasurably in both equipment and

pharmacother-apy The overall trend with regard to the latter has been for

improved strategies aimed at inhibition of platelet aggregation

and the clotting cascade This has led to better outcomes by

reduction of the ischemic complications associated with the

procedure

The current evidence regarding the available agents in a

PCI setting is summarized in Table 2 A practical flowchart

based on our recommendations is provided in Table 3

Antiplatelet agents

Aspirin

Aspirin inhibits platelet aggregation by reducing production of

thromboxane A2 through inhibition of the enzyme

cyclo-oxygenase-1 Initial studies of aspirin often combined its

administration with dipyridamole Aspirin either with or

with-out dipyridamole was found to reduce the incidence of

coronary thrombosis during percutaneous transluminal

coro-nary angioplasty (2), and the combination was found to

reduce the incidence of Q-wave infarction compared to

placebo (3) The combination of dipyridamole and aspirin has

lost favor as the addition of dipyridamole has been found to

confer no additional benefit (4) With respect to actual dose

of aspirin used peri-PCI, there have not been any

random-ized trials looking into this issue Subgroup analysis based on

aspirin dosing (range 75 to 325 mg) of patients with non-ST

elevation myocardial infarction (NSTEMI) acute coronary

syndrome (ACS) in the Clopidogrel in Unstable Angina toPrevent Recurrent Ischemic Events (CURE) trial has demon-strated that higher doses of aspirin do not confer additionalbenefit but are conversely associated with an increased risk ofbleeding complications (5)

of agranulocytosis associated with ticlopidine (8), and its slowonset of action, ticlopidine is no longer used in most coun-tries The combination of clopidogrel and aspirin has beenproved to be as effective as aspirin and ticlopidine in theprevention of intrastent thrombosis (9)

The PCI-clopidogrel as adjunctive reperfusion therapy trialwas a randomized control trial of the use of clopidogrel inpatients treated with fibrinolysis for an ST-segment elevationmyocardial infarction (STEMI) who went on to have a PCI(10) In this trial, patients given clopidogrel prior to PCI hadbetter indices of infarct-related artery patency Thesepatients also had lower rates of preprocedural recurrentmyocardial infarction (MI) and a significantly decreasedincidence of the combined endpoint of recurrent MI, cardio-vascular death or cerebrovascular accident at 30 days.PCI-CURE studied NSTEMI patients who were randomized

to receive either placebo or a 300 mg loading dose of dogrel, followed by regular doses, with PCI carried out a

median of 6 days later (11) Those in the treatment group

had lower rates of preprocedure MI and refractory ischemia

These patients also had a significant reduction in the

combined endpoint of cardiovascular death, MI, and urgent

target vessel revascularization at 30 days, and this was

extended to the longer period of follow-up (the median

length of the latter being eight months) Clopidogrel has also

been studied among elective patients The Clopidogrel for

the Reduction of Events During Observation (CREDO) trial

found no significant benefit at 28 days from preloading

patients with clopidogrel a range of 3 to 24 hours prior to

PCI (12) In this study, clopidogrel was continued for a year,

leading to a significant decrease in the combined endpoint of

stroke, MI, and death at this time point There was also a

suggestion that there may be additional benefit from

clopi-dogrel given greater than six hours prior to PCI, with a

nonsignificant improvement in the combined endpoint

(p⫽0.51)

The three trials above all used a 300-mg loading dose

followed by 75-mg maintenance dose, yet CREDO (12)

failed to demonstrate the same shorter term benefits While

this may be because of the higher risk patients studied in

the other trials (10,11), the results relating the outcome to

the timing of clopidogrel administration may be the key In

the Atorvastatin for Reduction of MYocardial Damage during

Angioplasty-2 (ARMYDA-2) trial, comparison was made of a

300 mg to a 600 mg loading dose of clopidogrel given four to

eight hours prior to PCI (13) This trial showed a significantly

lower incidence of peri-procedural MI in the latter group

These results demonstrate the faster onset of action of the

higher loading dose of clopidogrel Kandzari et al examined

the pharmacokinetics after administration of a 600 mg dose

given at different time points (from two to three hours or

earlier) pre-PCI in elective patients (14) They found that

there was no difference, at 30 days, in the combined

endpoint of death, MI or urgent revascularization between

patients given clopidogrel two to three hours pre-PCI and

those who started it sooner These trials therefore suggest

an advantage from the higher loading dose of clopidogrel

when PCI is to be performed within eight hours

It is with respect to clopidogrel that there is a significant

point of variance in the pharmacotherapeutic management

between bare-metal stents and the newer, drug-eluting

stents In the case of the former, no benefit has been found

to a course of clopidogrel longer than one month in elective

cases, on direct comparison of a one month and six-month

course (15) With drug-eluting stents, there is a concern that

delayed endothelialization will lead to an increased risk of

stent thrombosis For this reason, trials have empirically used

longer clopidogrel regimens, three months for

sirolimus-eluting stents (16) and six months for paclitaxel-sirolimus-eluting stents

(17) While no trials are available where comparison

has been made between different lengths of treatment,

the importance of uninterrupted antiplatelet therapy is

propounded by the association between discontinuation of

clopidogrel and stent thrombosis (18,19) A longer course ofclopidogrel treatment is recommended in the ACS setting

on the basis of the PCI-CURE trial; in this study,patients with NSTEMI-ACS were given clopidogrel for up to

12 months (11)

Our own practice in terms of the length of treatment withclopidogrel is to prescribe a one month course of clopidogrelfor bare metal stents and a one year course for drug-elutingstents In the case of all ACS, a one year course is given.These practices are concordant with the current Europeanguidelines, where a month is also recommended for baremetal stents, 6–12 months for drug-eluting stents and 9–12months of clopidogrel for ACS cases (20)

Cilostazol

Cilostazol is a phosphodiesterase inhibitor that reducesplatelet aggregation, vascular smooth muscle proliferation andalso has vasodilatory effects Earlier studies comparing cilosta-zol and aspirin to ticlodipine and aspirin identified nosignificant increase in the subacute stent thrombosis rate(21–23) Indeed, the latter has been supported by compari-son of this combination to clopidogrel and aspirin (24) Tworecent trials, however, have demonstrated that a much higherproportion of patients develop subacute stent thrombosiswhen taking cilostazol as compared with ticlodipine (25,26).The data from these trials are summarized in Table 1

Glycoprotein IIb/IIIa inhibitors

Glycoprotein IIb/IIIa receptors are present on the surface ofactivated platelets Fibrinogen and von Willebrand Factor areable to cross link platelets through these receptors, leading totheir aggregation (Fig 1) Glycoprotein IIb/IIIa (Gp IIb/IIIa)inhibitors are the most potent and fastest acting anti-plateletagents available After the unfavorable results of trials with oralagents, only three commercially available drugs (all givenparenterally) are presently available in this class: abciximab(ReoPro), eptifibatide (Integrilin), and Tirofiban (Aggrastat).Abciximab use peri-PCI has been well studied in thesetting of STEMI A meta-analysis of 8 trials using abciximab inthe context of primary-PCI has demonstrated a significantreduction in mortality in the context of primary PCI at both

30 days and longer term (6 or 12 month) follow-up (27) Inthis analysis there was also a reduced reinfarction rate at 30days with abciximab and no increased risk of bleeding compli-cations Data also suggests that an early infusion (in theambulance or immediately after admission) can be beneficialwhen compared to administration at the time of the proce-dure The Chimeric 7E3 Antiplatelet Therapy in UnstableAngina REfractory to Standard Treatment (CAPTURE) trial was the first to demonstrate the benefit of abciximabamong patients with unstable angina, with a lower rate of the

combined endpoint of death, MI and urgent intervention

(driven by a lower rate of non-Q wave MI), but a higher

bleeding rate (28) In the evaluation of platelet IIb/IIIa inhibitor

for stenting (EPISTENT) trial, abciximab was shown to be of

benefit in a wider range of patients following stent

implanta-tion (elective and urgent cases), with the incidence of

bleeding reduced by the use of weight-adjusted, low-dose

heparin administration This trial showed that abciximab

reduced the incidence of the combined endpoint of

mortal-ity, MI and urgent revascularization (major adverse

cardiovascular events, MACE) EPISTENT (29) had the

merit of replicating in the era of universal stent usage the

results obtained in the earlier CAPTURE and EPIC (30) trials(which were conducted in the balloon angioplasty era).Unfortunately, no attempt was made to explore whether the

12 hour infusion shown to be more beneficial than the bolusalone in the EPIC study was still necessary when the risk ofpostprocedural abrupt occlusion was nearly abolishedthrough the use of stents

Mortality benefit for Gp IIb/IIIa inhibitors during PCI hasbeen demonstrated on meta-analysis for abciximab (31) andthis class of agents as a whole (32) These agents have alsobeen shown, on meta-analysis, to reduce rates of MI andurgent revascularization post-PCI (33)

Introduction 527

activated endothelium

RGD

dimer ic

Gp IIb/IIIa receptor

Patients with subacute stent thrombosis (%)

The first total is a comparison of ticlodipine and aspirin to cilostazol and aspirin; the second total compares the results for thienopyridines and aspirin to cilostazol and aspirin.

Table 1 A comparison of the rates of subacute stent thrombosis in trials comparingcilostazol with ticlodipine or clopidogrel

Some of the results with abciximab were duplicated using

the small molecules eptifibatide and tirofiban These are

intrinsically cheaper than abciximab which is produced using

recombinant DNA technology for its production

The enhanced suppression of platelet receptor IIb/IIIa

using integrilin therapy (ESPIRIT) trial of nonurgent PCI

demonstrated a significant reduction in the incidence of

post-PCI MI at 30 days but not death or urgent target vessel

revascularization using eptifibatide in terms of MACE (34)

However, this trial randomized patients to receive placebo in

the control arm

To date, of the Gp IIb/IIIa inhibitors, only abciximab and

tirofiban have been compared directly The Do Tirofiban and

ReoPro Give Similar Efficacy (TARGET) trial, a randomized

double-blind trial of urgent and elective PCI (excluding

patients in cardiogenic shock or with STEMI), demonstrated

that abciximab significantly reduced the incidence of MACE at

30 days compared to tirofiban (35) In further analysis it was

noted that the only point of significant difference was in the

incidence of nonfatal MI, and that the benefit of abciximab

in terms of MACE at 30 days was only present in ACS

patients No mortality benefit has been found at one year

among those patients treated with abciximab instead of

tirofiban (36) The tirofiban dosing regimen used in

the TARGET trial (10µg/kg bolus followed by 0.15µg/kg/

min infusion) has been found to be suboptimal for platelet

inhibition in one small study (37) This issue has been

addressed further in a recent observational trial which

demonstrated no difference compared to abciximab in MACE

incidence at six months when a higher tirofiban dosing

regi-men was used (25µg/kg bolus followed by 0.15µg/kg/min

infusion) (38)

The main concern with the use of Gp IIb/IIIa inhibitors

is the risk of hemorrhage and thrombocytopenia On

meta-analysis, major hemorrhage was significantly more likely

with abciximab than with either tirofiban (standard regimen)

or eptifibatide (33) The TARGET trial demonstrated

abcix-imab to predispose to thrombocytopenia when compared

to tirofiban (35) Regardless, thrombocytopenia (platelet

count ⬍20,000/µl) is rare (⬍3%) and can often be treated

conservatively, without the need for platelet transfusions

Clopidogrel use peri-PCI has gained popularity and its

interaction with Gp IIb/IIIa inhibitors has been investigated for

all three agents The intracoronary stenting and

antithrom-botic regimen–rapid early action for coronary treatment

(ISAR-REACT) trial studied low/intermediate risk patients

given clopidogrel 600 mg at least two hours before the PCI

along with aspirin, and randomized them to receive

abcix-imab or placebo (39) This trial showed that patients receiving

abciximab had a significantly higher incidence of profound

thrombocytopenia (less than 20,000 platelets per mm3) and

required more blood transfusions than the placebo group In

terms of 30 day MACE incidence, there was no difference

between the two groups This lack of benefit was further

confirmed by Claeys et al., who demonstrated that theseresults were achieved despite abciximab’s addition resulted ingreater inhibition of platelet aggregation (40) A re-evaluation

of the ISAR-REACT patients at one year continued to show alack of advantage conferred by abciximab (41) It should benoted however that these trials did not include high-riskpatients and so it may not be appropriate to extrapolate theseresults to this group which has been investigated separately inthe ISAR-REACT 2 trial

The combination of tirofiban with clopidogrel and aspirin

on the other hand, in the small (109 elective patient) troponin

in planned PTCA/stent implantation with or without tration of the glycoprotein IIb/IIIa receptor antagonist tirofibanstudy, has been shown to significantly reduce MACE inci-dence at nine months compared to clopidogrel and aspirinalone (42) This was associated with significantly lower levels

adminis-of Troponin release at 12 and 24 hours in the tiradminis-ofiban groupalthough differences that were not maintained at 48 hours Incomparison to the two abciximab/clopidogrel combinationstudies this study did use a slightly lower dose of clopidogrel[375 mg loading as opposed to the 600 mg ISAR-REACT (39)loading or 300 mg plus 150 mg loading (40)] but the influence

of this on the results is unclear

In view of the widespread use of clopidogrel peri-PCI, it isimportant to elucidate the interaction between this and GpIIb/IIIa inhibitors A lack of synergistic benefit would not

be unexpected as clopidogrel ultimately exert its effects onplatelet aggregation through the Gp IIb/IIIa receptor (43).Still, Gp IIb/IIIa antagonists do have a more potent andconsistent inhibitory action platelet aggregation thanclopidogrel

Anticoagulants

Heparin

The two forms of heparin available are unfractionated heparin(UFH) and low molecular weight heparin (LMWH) Bothexert their anticoagulant effect on the clotting cascade byenhancing the activity of antithrombin In the case of LMWHthis is by enhancing the binding of antithrombin to factor Xaand so inhibiting the function of the latter; UFH not onlyshares this effect but also enhances the inhibition of thrombinthrough antithrombin (44)

UFH is the most commonly employed anticoagulant peri-PCI UFH suffers from several shortcomings as reviewed

by Kokolis et al (45) and Rebeiz et al (8) These drawbacksinclude the variability of its anticoagulant effect necessitatingmonitoring of clotting indices, its ability to activate plateletscausing a paradoxical pro-coagulant effect, and the possibility

of inducing heparin-induced thrombocytopenia (HIT)

The main cause of debate at present with regard to UFH

centers on the amount used peri-PCI The level of

anticoag-ulation produced by UFH is measured by the activated partial

thromboplastin time and activated clotting time (ACT), the

latter being available in the cardiac catheter laboratory as a

near-patient test

A meta-analysis of earlier trials found the risk of

complica-tions associated with PCI to be closely related to the ACT,

with a target ACT of 350–375 suggested (45) Higher ACTs

were associated with increased bleeding risks ACTs above

and below this range were both associated with an increased

incidence of death, MI and urgent revascularization at 7 days

The reason for the association between ischemic

complica-tions and elevated ACTs is believed to be a consequence of

heparin’s platelet activating properties at higher doses The

trials summated in this meta-analysis were from an era prior

to the widespread adoption of stents, thienopyridines, and

Gp IIa/IIIb inhibitors A more recent meta-analysis of four

trials involving 9974 patients demonstrated different

relation-ships, most likely due to the change in practices in the interim

(46) In this meta-analysis, a lack of correlation was found

between the ACT and ischemic complications at 48 hours A

correlation was found with the total heparin dose, with doses

above 5000 units associated with increased ischemic

compli-cations With the heparin dose adjusted for weight, every

10 U/kg increase in dose, up to 90 U/kg, was associated with

a significant increase in the risk of ischemic complications

There was no significant association between ACT and rates

of major bleeding For a combination of major and minor

bleeding, increasing ACTs up to 365 were associated with an

increasing rate of major/minor bleeding but above this the

rate actually decreased When looking from a dosing point of

view, there was a relationship between increasing heparin

dose and rates of major/minor bleeding With regard to

weight-indexed dosing, there was a significant increase in the

bleeding risk with every 10 U/kg increase in dose Based on

these findings, in the context of oral and intravenous

antiplatelet therapies and stenting, the suggestion is that lower

heparin doses may not compromise efficacy and may in fact

be safer Moreover, the ACT itself may not be as useful a

marker of optimal UFH use peri-PCI compared to the actual

UFH dose given

LMWHs mainly inhibit factor Xa through antithrombin,

although they have varying degrees of associated indirect

thrombin inhibiting activity In the latter respect they share the

disadvantage of UFH of being unable to inhibit clot-associated

thrombin The advantages of LMWH over UFH include a

more predictable anticoagulant effect requiring less

monitor-ing, and reduced incidence of HIT

Of the LMWH, the most extensively studied with regard to

PCI is enoxaparin The National Investigators Collaborating

on Enoxaparin (NICE) trials examined the use of intravenous

enoxaparin peri-PCI in elective and urgent patients (47)

These trials were observational studies without a control

group: patients from other trials served as historical controlsfor comparison NICE-1 examined 828 patients treated with

1 mg/kg of intravenous enoxaparin at the time of PCI (47).Similar efficacy and safety was found to equivalent patientstreated with UFH in the previous EPISTENT trial NICE-4investigated patients treated with 0.75 mg/kg of intravenousenoxaparin and concomitant abciximab (47) The results alsocompared favorably with respect to death, infarction andurgent revascularization at 30 days as well as bleeding compli-cations on comparison to patients treated with abciximab andUFH from the EPISTENT and evaluation of PTCA to improvelong-term outcome by c7E3 GP IIb/IIIa receptor blockadetrials (48)

Among elective patients, trials have also examined thecombination of enoxaparin with eptifibatide (49,50) ortirofiban (50) and similarly found no significant differencesbetween UFH and 0.75 mg/kg intravenous enoxaparin.The above trials have investigated intravenous enoxaparin.The pharmacokinetics of enoxaparin in PCI (PEPCI)study found that anti-Xa levels, a measure of LMWH activity,were within target range two to eight hours after a dose ofsubcutaneous enoxaparin (51) Anti-Xa levels could bekept in the target range for a further two hours by an addi-tional intravenous bolus of 0.3 mg/kg The SYNERGY (52)trial of ACS patients compared UFH to an enoxaparin regi-men as suggested by the PEPCI (51) trial Among thesepatients, those who had received their last dose of subcuta-neous enoxaparin over eight hours prior to PCI were given

an additional intravenous bolus In the SYNERGY trial, nodifference in the incidence of ischemic events during PCI wasnoted between UFH and subcutaneous LMWH, and therewas an increased incidence of major bleeding in the LMWHgroup (52) The observation that an increased bleeding riskcompared to UFH was noted in this trial rather than thoseinvestigating intravenous enoxaparin may be indicative of aless predictable bioavailability of this route of administration,

or perhaps a need for dose reduction

On the whole, while not demonstrating superiority ofLMWH with regard to bleeding complications, death, infarc-tion, and urgent revascularization over UFH, the aboveresults do support its noninferiority In view of LMWH’ssimplicity of use in ACS, which makes most centers prefer it

to UFH, it is important to recognize it as an acceptable native to UFH when the patient must be treated soon aftertheir last subcutaneous dose

alter-Fondaparinux

Fondaparinux is a pure inhibitor of factor Xa, which exerts itseffect through antithrombin This compares with UFHand LMWH both of which have additional activity againstthrombin to a greater and lesser degree, respectively To dateone trial has been published investigating fondaparinux use

Introduction 529

peri-PCI Compared to UFH, no significant increase in

bleeding complications or a composite of all cause mortality,

MI, urgent revascularization, and need for bailout Gp IIb/IIIa

antagonist was demonstrated (53) Whether this agent

will have any advantage over LMWH or UFH is to be

established

Direct thrombin inhibitors

Direct thrombin inhibitors (DTIs) inhibit thrombin directly

rather than through the indirect, antithrombin-mediated

pathway utilized by UFH and LMWH Unlike heparin, they

can inhibit clot-bound thrombin and do not induce HIT

While heparin-based anticoagulation can be reversed using

protamine, there is no such agent for DTIs: this is especially

a concern for lepirudin which, unlike bivalirudin, binds to

thrombin irreversibly and so has a longer half life With

bivalirudin, the effect almost disappears after two hours

which helps planning the timely removal of arterial sheaths

Bivalirudin has been the subject of a large trial, randomized

evaluation in PCI linking angiomax to reduced clinical

events-2 (REPLACE-2), involving 6010 patients (54)

Randomization was either to UFH and Gp IIb/IIIa (abciximab

or eptifibatide) or to bivalirudin with the option of Gp IIb/IIIa

use if there were procedural or angiographic complications

Patients with unstable ischemic syndromes or acute-MI were

excluded There was no difference in the combined

endpoint of death, MI, and urgent repeat revascularization at

30 days While the latter suggested equivalence in efficacy

with UFH, a reduced incidence of major and minor bleeding

with bivalirudin suggested that it held safety advantages over

UFH At six months, the rates of death, MI, and

revascular-ization were no difference between the two groups and this

lack of difference in mortality was also present at one

year (55)

A meta-analysis of DTIs compared to UFH in ACS has

shown that there is a significant decrease in the combined

endpoint of death and MI at 30 days, with the significance

driven by the improvement in MI incidence in the former

group (56) There was no significant decrease in mortality

itself The benefit of DTIs compared to heparin was only

found in those patients undergoing early (within 72 hours)

PCI as opposed to those managed conservatively or treated

with PCI after this There was also significantly less major

bleeding in patients receiving DTIs rather than UFH These

results suggest that DTI may have increased safety and

effi-cacy for those undergoing early PCI for ACS The results

from REPLACE-2 (54) would seem to extend this benefit to

a wider group of patients and additionally suggests that a

more parsimonious use of Gp IIb/IIIa agents may be possible

The acute catheterization and urgent intervention triage

strat-egy trial has explored the use of bivalirudin in highly unstable

syndromes, also in combination with LMWH, with results just

presented The harmonizing outcomes with revascularization

and stents trial will answer the same question in STEMIpatients undergoing primary PCI

Lipid-lowering medication

In a small (81 patients) retrospective analysis, patients on lowering medication (statins, fibrates, or niacin derivatives) atthe time of PCI had a significantly lower incidence of adverseevents during the procedure, such as emboli and dissections,

lipid-as compared to those not taking such agents (57) A high-totalcholesterol, low-density lipoprotein, or ratio of low to high-density lipoprotein were also associated with increasedadverse events

A prospective trial of ACS patients undergoing PCI (119patients) showed that those on statins at the time of PCI hadsignificantly reduced incidence of peri-procedural myocardialnecrosis as determined by CK or CK-MB level (58) At sixmonths, these patients also had a lower incidence of thecombined endpoint of death, MI, target vessel revasculariza-tion, and hospital admission for unstable angina The patientswho were on statins were significantly less likely to havehyperlipidemia at the time of PCI The incidence of thecombined endpoint was not increased by patients beinghyperlipidemic at six months, or reduced by patients being onstatin therapy at six months Instead the relationship was withbeing on a statin prior to PCI, suggesting the importance ofpretreatment

he ARMYDA study of 153 low-risk elective PCI strated that pretreatment of patients with a week ofatorvastatin prior to PCI resulted in significantly less release ofmarkers of myocardial damage such as Troponin, myoglobin,and CK-MB compared to placebo (59) This was associatedwith a decrease in the rate of peri-procedural MI It is postu-lated that this effect of atorvastatin may relate to itsanti-inflammatory properties

demon-Conclusions

A summary of the discussions above regarding the varioustrials can be found in Table 2 Table 3 details our recommen-dations with regard to pharmacotherapy peri-PCI, whichincludes an attempt to offer advice in the cases where trialevidence is lacking

There is a wealth of data currently available regardingdifferent agents to use peri-PCI and yet, as with any field,there remain unanswered questions particularly concerninglong term treatment after drug eluting stents It is the task ofthe physician to tailor these therapies to the specific clinicalsituations with which they are presented In this article, aswell as reviewing the currently available evidence, we havealso provided our own recommendations for the use of the

Conclusions 531

(2) and Q-wave infarct (3) Dipyridamole No longer No longer No additional benefit when given with aspirin (4)

Ticlopidine Only if intolerant At least 250 mg bd Synergistic with aspirin in reducing platelet

to clopidogrel aggregation (6) and reducing instent restenosis (7)

Concern over associated incidence of agranulocytosis (8,9), frequent gastric intolerance and skin rashes Sequential FBC required at follow-up

Clopidogrel STEMI (10), 300 mg loading dose As effective as ticlodipine in preventing stent

NSTEMI (11), (10–12) unless PCI to be thrombosis (9) Elective PCI (12) performed within eight hours Reduced incidence of adverse hematologic reactions

in which case 600 mg compared to ticlodipine (9) recommended

Cilostazol Elective (21–25) 100 mg twice daily Possibility of increased subacute stent thrombosis

(22–26) PCI

Gp IIb/IIIa See below See below Mortality benefit in the context of PCI (32)

rates post-PCI (33) Abciximab STEMI (27), 0.25 mg/kg followed by Significant benefit (27–29) especially with respect to

unstable angina 0.125 µ g/kg/min infusion mortality (27) and reinfarction (27,28) (28),elective PCI (29) Benefit in low/intermediate Increased risk of major bleeding and thrombocytopenia

risk patients following compared to other Gp IIb/IIIa inhibitors (33) clopidogrel pretreatment

debated (39,40) Epitifibatide ACS (not including Two 180 µ g/kg boluses Studies comparing efficacy to other members of this

STEMI) (60), 10 min apart and class awaited nonurgent PCI (34) 2 µ g/kg/min infusion (34)

Tirofiban ACS (not including 25 µ g/kg bolus and Beneficial in one trial evaluating use in patients

STEMI) (61) 0.15 µ g/kg/min with non-STEMI ACS, but no benefit in another

infusion—may be more investigating patients with ACS including STEMI effective than standard Abciximab associated with more favorable regimen of 10 µ g/kg bolus outcome at 30 days (35) [no mortality benefit and 0.15 µ g/kg/min at one year (36)] This superiority may be abrogated infusion (37,38) by the higher tirofiban dosing regimen (38) UFH All PCI Dose of UFH more predictive Variable anticoagulant effect (needing monitoring),

of complications than platelet activation causing paradoxical pro-coagulant ACT value (46) effect, HIT, unable to bind clot-bound thrombin (8,44) LMWH Elective and urgent 1 mg/kg intravenous Similar efficacy to UFH with no increase in adverse

PCI (47,49,50) enoxaparin (0.75 mg/kg events (47,49,50)

if used with Gp IIb/IIIa) Unable to bind clot-bound thrombin (8,44) (47,49,50)

Fondaparinux Urgent and elective Optimal dosing still being Similar efficacy and safety to UFH (53)

DTI Elective PCI (54), Dependent on agent used Able to bind clot-bound thrombin, do not

May have benefit compared to UFH among ACS patients (56)

Lipid lowering Elective PCI (59) Dependent on agent used Pretreatment with atorvastatin associated with

Abbreviations: ACS, acute coronary syndrome; DTI, direct thrombin inhibitor; Gp IIb/IIIa, glycoprotein IIb/IIIa; HIT, heparin induced thrmobocytopenia; LMWH, low molecular weight heparin; NSTEMI, non-ST elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST elevation myocardial infarction; UFH,

Table 2 A comparison of the different drugs used peri-percutaneous coronary intervention

Drug Dose Recommendation

Pre-PCI

Aspirin 75–100 mg Start at least 48 hours before procedure Consider 250 mg

i.v if PCI to be performed sooner than this Clopidogrel 75 mg 300 mg loading dose if not already on treatment, with

600 mg loading if PCI expected to occur within eight hours

Abciximab is the preferred agent in the cases of STEMI

hypotension is recommended Agents such as midazolam with a rapid onset and offset of action are preferred

Proton pump inhibitors Low threshold in the cases of previous gastric problems

(e.g., ulcers, diaphragmatic hernias) and in the cases of microcytic anemia of unknown cause

During PCI

Heparin 50–75 mg/kg Preferred agent in the cases of chronic total occlusion

Avoid additional Recommend checking ACT after five minutes and boluses ⬎ 30 mg/kg then every hour

Target ACT of 200–250 s Keep as close as possible to 200 s if used in conjunction with Gp IIb/IIIa inhibitors

Higher target (250–300 s) recommended if filters are used Avoid routine infusion after PCI (associated with increased bleeding events with little benefit)

Enoxaparin 0.5 mg/kg i.v No additional boluses if within four to six hours of

subcutaneous injection Bivalirudin 0.75 mg/kg bolus plus Excellent alternative to heparin in elective cases

1.75 mg/kg per hour for Trial results pending for unstable syndromes the duration of PCI Adjust dose according to renal function

Not enough data in acute MI and after enoxaparin Stop after removal of intracoronary wires Remove sheath after two hours unless closure devices are used Glycoprotein Abciximab 0.25 mg/kg If infusion already started, continue same Gp IIb/IIIa

IIb/IIIa inhibitors or high dose bolus inhibitor started pre-PCI.

epitifibatide or tirofiban Low threshold for administering in the cases of thrombus

containing lesions in the context of unstable angina; no reflow/slow reflow after PCI; treatment of diffuse disease, and in diabetes mellitus

Caution (not needed or risky) for treatment of SVGs, CTO or lesions at risk of perforation

In the case of abciximab, consider withholding infusion if normal flow is obtained with a good result after stenting and the patient is fully loaded with clopidogrel

Nitrates Preferred agents: isosorbide Use intracoronarily to appropriately size the balloons and stent,

dinitrate 1–3 mg and and to prevent coronary spasm during wire/balloon manipulation nitroglycerine 100–300 µ g Not effective/contraindicated in the treatment of

secondary spasm Avoid pressure drop in no reflow/slow flow Sodium nitroprusside 40–100 µ g in three minutes Preferred agent in the cases of no reflow/slow reflow Always

selective infusion (or better subselective infusion via intracoronary catheter)

Strict BP monitoring required during administration Needs to be available for the cases of degenerate SVG or lesions containing thrombus

Table 3 Practical tips for drug administration peri-percutaneous coronary intervention

(Continued)

Conclusions 533

Adenosine 20–100 µ g Have the same indications as sodium nitroprusside

Can cause sinus arrest/AV block when high doses are used, especially in the RCA (an effect which is reversible within seconds)

Verapamil 1–2 mg Same indications as sodium nitroprusside and adenosine but

associated with more prolonged hypotension/bradycardia Post-PCI

Higher doses are advantageous only to prolong the effect in the cases of withheld doses, but are associated with increased bleeding complications with no reduction in the incidence

of thrombotic events Clopidogrel 75 mg od Continue for 28–30 days after bare metal stent insertion but

9 to 12 months in the cases of ACS

In the cases of proven resistance ( ⬍50% in vitro platelet inhibition) consider doses of 150 mg od Also consider higher dose in the cases of previous stent thrombosis

For drug-eluting stents, continue for six months (but consider stopping after two to three months for sirolimus eluting stents for simple lesion treatment) For indications outside major drug eluting/sirolimus eluting stent trials (Sirius/Taxus IV, long lesions, bifurcations, ostial, SVGs, CTO etc.) the most frequent empirical approach is to prolong treatment for 9–12 months

Where thrombosis would be catastrophic, such as in left main

or single remaining vessel intervention, a more prolonged treatment—perhaps even lifelong—can be considered until the risk of late stent thrombosis is better defined

agents, beta blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, other antihypertensives, antihyperglycemic medications

thrombo-embolic risk (cases of mechanical valve prosthesis, left ventricular thrombus, active deep vein thrombosis, high-risk atrial fibrillation), stop warfarin three to four days pre-PCI and anticoagulate with unfractionated heparin or enoxaparin Warfarin can be restarted the evening after the procedure with a loading dose

Consider the possibility of stopping clopidogrel (or aspirin) after one month in the case of nondrug eluting stents, or two to three months in drug eluting stents If the indication for warfarin

is less robust, such as AF at low embolic risk, consider stopping warfarin permanently or until double antiplatelet treatment is

no longer required

Abbreviations : ACS, acute coronary syndrome; ACT, activated clotting time; BP, blood pressure; CTO, chronic total occlusion; i.v., intravenous; MI, myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; RCA, right coronary artery; STEMI, ST-segment elevation myocardial infarction; SVGS, saphenous vein grafts.

Table 3 Practical tips for drug administration peri-percutaneous coronary intervention (Continued )

various agents available: in doing so it is hoped this will

facili-tate the decision making process

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Patients with chronic total occlusion (CTO) represent a significant

problem for interventional cardiology Interest in this group

dates back to the earliest days of the field (1–4) The presence

of a chronic total occlusion identified patients in whom the

chances of a successful procedure were decreased compared

with those patients who treated for a subtotal stenosis In

addi-tion, failure was not necessarily benign because of the potential

for coronary perforation which can lead to tamponade or

compromise of collaterals to the distal vessel which could lead

to infarction Because of these issues, the presence of a chronic

total occlusion was the most common reason for deferral of

percutaneous coronary intervention (PCI) in early studies

instead patients with chronic total occlusions were

preferen-tially treated with coronary artery bypass graft surgery (CABG)

In a more recent single-center registry series of 8004

consec-utive patients undergoing diagnostic catheterization from 1990

to 2000, a chronic total occlusion was found in 52% of patients

with significant coronary artery disease Patients with a chronic

total occlusion had more frequent hypertension and peripheral

vascular disease The ejection fraction was significantly less

53⫾ 16% versus 60 ⫾ 14% (p ⬍ 0.001), and multivessel

disease was significantly more common 66% versus 42%

(p⬍ 0.001) Twelve percent of patients had more than one

chronic total occlusion Typically, the occlusion involved the

RCA (64%) followed by the circumflex (35%) and then the

LAD (28%) In this more recent series, using multivariate

analy-sis, the presence of a chronic total occlusion remained the

strongest predictor against selection of PCI (OR 0.26, 95% CI

0.22–0.31, p⬍ 0.0001) (5)

Because of the frequency with which chronic total

occlu-sion occurs, there has been intense interest in developing and

studying new approaches These efforts have been spurred

on by the finding in multiple series that successful PCI of a

chronic occlusion is associated with a survival benefit as well

as improvement in LV function In an early study, Suero et al

(6) evaluated in-hospital and longer-term outcome in 2007

consecutive patients undergoing PCI for a CTO from 1980 to

1999 (Fig 1A and 1B) These were matched with patients

treated for a subtotal stenosis using a propensity analysis Forboth cohorts, the 10-year survival was similar —71.2% forCTO patients and 71.4% for non-CTO patients In patientswith a CTO, the outcome of the procedure was a veryimportant determinant of survival; in those patients withsuccessful CTO treatment, 10-year survival was 73.5%compared with patients with a failed procedure in whom the10-year survival was only 65.1% (p⫽ 0.001)

More recent series have also documented a survivaladvantage (7–9) Hoye et al in 874 consecutive patients with

a CTO found a five-year survival in 93.5% of patients withsuccessful revascularization versus 88.0% in these patientswith failed revascularization (p⫽ 0.02) In a Canadian registry

of 1458 patients at seven year, successful recanalization of achronic total occlusion was associated with improved survival

as well as lower rates of PCI and/or CABG (9) In addition tosurvival advantage, both regional and global left ventricularfunction is improved in patients with successful treatment of achronic total occlusion (10) This improvement may depend

on whether the patient had a prior infarction in the tion of the occlusion (11) If prior infarction resulted in frankmyocardial necrosis, then recanalization may not improve thefunction; however, many patients with chronic occlusion havepreservation of regional wall function

distribu-Despite the potential for improved outcome in patientstreated percutaneously for chronic total occlusion, in manylaboratories, these procedures are undertaken sparingly.Abbott et al (12) analyzed 2000 patients undergoing PCI infour sequential waves of patients from 1997 to 2004 In thisgroup, 5173 lesions were attempted In the first cohorttreated from 1997 to 1998, 9.6% of treated lesions werechronic total occlusions; in the last cohort from 2004, thepercentage of lesions treated that were chronic total occlu-sions had decreased to 5.7% (p⬍ 0.0001) (Fig 2).Procedural success declined from 79.7% to 71.4% duringthose same time periods Procedural success rates such asthis may be an over estimate because series of chronic total occlusion cases contain only patients in whom the

46

Pharmacologic management of patients

with CTO interventions

David R Holmes, Jr

interventional cardiologist thought that successful

recanaliza-tion was possible There are multiple reasons for the

decrease in frequency of performing procedures for CTO at

the centers, but among the most prominent are the low

success rates, procedural complexity, and time and resource

utilization In addition, recently because of the duration of

procedures, excess radiation exposure has been

docu-mented (13,14)

The most common reason for failure of a chronic total

occlusion is inability to cross with a guidewire The pathologic

basis for this has been studied (15–17) Srivatsa et al (15)

evaluated the histologic correlates of angiographic total

coro-nary artery occlusion in an autopsy series of 61 patients with

96 angiographic chronic total occlusions They analyzed theocclusion segments for histologic composition and for thepresence of neovascular channels They identified that fibro-calcific intimal plaque increased with increasing age of theocclusion and that neovascular channels were related to theextent of inflammation Micro channels particularly adventialchannels may make entry into the true lumen difficult (Fig 3).Entry into and dilatation of these advential collaterals couldresult in vessel perforation Another finding in chronic totalocclusion is a fibrotic hard cap which is sometimes calcified.These hard caps may be difficult or even impossible to cross

A final large component is collagen-rich extracellular matrix(17) The entire longitudinal picture is often underlying plaque

100 80 60 40 20

93.0 87.9 82.2 76.4 71.4

CTO

Years CTO-Success

1,491 1,208/ 1,033/ 852/ 638/ 445/

93.7 89.4 85.5 79.2 73.5 1,888 1,497/ 1,256/ 1,028/ 811/ 606/

93.2 88.0 82.7 76.6 71.9

514 396/ 360/ 293/ 221/ 171/

89.0 84.4 76.5 68.8 65.0 No./%

P=0.865 P = 0.002

CTO Matched non-CTO

CTO-success Matched-success CTO-failure

Figure 1

Long-term outcome of patients undergoing attempted PCI of a chronic total occlusion (A A ) Outcome of chronic total occlusion versus non-chronic total occlusion patients, (B B ) Outcome of successful versus unsuccessful treatment of a chronic total occlusion Successful treatment is associated with a survival advantage Abbreviation: CTO, chronic total occlusion.

Table 1 New mechanical approaches for CTO

revascularization

and then multiple layers of matrix and thrombus which build

up to form the occlusion (16)

The specific anatomy of the occlusion has a major impact

on outcome of attempted percutaneous revascularization

Correlates of decreased success rates include older age of the

occlusion, the presence of an abrupt cut off, the presence of

a large patent side branch at the site of occlusion, and the

presence of bridging collaterals There are some patients in

whom there are central intraplaque vessels (15,18,19)

These may be associated with improved success rates

These problems have led to the development and testing

of new approaches, both mechanical and pharmacologic

(Table 1) The mechanical approaches are very variableand range from new stiffer and/or coated guidewires, lasers,forward-looking ultrasound and ablative catheters In addi-tion, new guide catheter techniques and totally newapproaches such as retrograde approaches through collater-als have been tested in specialized expert centers Thesenew catheter techniques have been reviewed elsewhere andare not the scope of this chapter on pharmacology (20) Oneitem for emphasis is the use of drug-eluting stents As the fieldhas evolved, bare metal stents for chronic total occlusionwere found to be substantially superior to conventional PTCA

in reducing restenosis and reducing subsequent recurrentocclusion More recently, there has been great interest indrug-eluting stents (21–27) This has culminated in a random-ized trial which has been reported to show improvement inoutcome compared with bare metal stents (26)

Pharmacologic approaches are also evolving Some ofthese approaches are aimed at making the procedure saferand avoiding complications; others are aimed at improvinginitial success rates or preventing reocclusion or restenosis

Pharmacologic approaches

to optimize initial safety

The most important safety concerns are the potential forperforation which could result in tamponade or compromise

of collaterals which can result in infarction In current PCI practice with its reliance on drug eluting stent (DES), dualantiplatelet therapy with aspirin (ASA) and a thienopyridine(usually clopidogrel) is standard These should be used in allpatients Pre-procedure administration of the thienopyridineshould be given, if possible

IIb/IIIa platelet glycoprotein inhibitors are widely used insome institutions, particularly in the setting of complex inter-ventions However, in the setting of chronic total occlusion,these agents should not be used until the occlusion has

Pharmacologic approaches to optimize initial safety 539

Hydrophilic guidewires Tapered tip guidewires Stiff guidewires with variable stiffness (3–12 gms) New devices

Frontrunner blunt microdissection catheter Radiofrequency ablation with optical Coherence reflectometry guidance Laser guidewire

High frequency ultrasound New visualization adjuncts

Preprocedural multislice CT Forward looking ultrasound Abbreviations: CT, computed tomography; CTO, chronic

total occlusion.

successfully been crossed This minimizes the potential for

bleeding should perforation occur In addition if guidewire

perforation does occur, even if the procedure is eventually

successful and the guidewire can be seen entering the distal

vessel, IIb/IIIa agents should be avoided If crossing a

complete occlusion is achieved without complications, a

IIb/IIIa agent can then be administered particularly if the vessel

is small or has other complex features

Heparin is the standard treatment for conventional PCI

Recently, bivalirudin has been promoted extensively as an

alternative The latter has several advantages; it can be given

as a single bolus, ACTs are not measured, and the half life is

very short In the setting of chronic total occlusion, bivalirudin

has some significant disadvantages, namely although the half

life is short, it cannot be reversed; in addition, chronic total

occlusion cases are often long and would require additional

dosing of bivalirudin which can increase costs substantially

Accordingly, unfractionated heparin should remain as the

standard

Pharmacologic agents to

optimize initial success

Recognition that the usual reason for failure with chronic total

occlusions is inability to cross with a guidewire; there has

been interest in softening the occlusion This is based on a

robust experience in the treatment of peripheral arterial

occlusions with thrombolytic therapy (29–33) In that setting,

intravenous thrombolytic therapy was used initially to soften

the occluded segment and make subsequent PTA easier

and more successful The field soon migrated to using intra

arterial infusions of urokinase to decrease hemorrhagic

complications and improve success rates This has widely

been used for iliac, femoral, and poplitial occlusions The

specific dose and duration of therapy have varied, but even

for long chronic total occlusions, it has been found to be

effective although bleeding remains a problem particularly

during longer duration of occlusion; the bleeding may be in

part related to the need for heparin

Application of this concept has been expanded to the

treat-ment of coronary arterial chronic total occlusion, the aim

being the same as in the periphery to soften the occlusion and

facilitate guidewire passage (34–37) Zidar et al (36)

reported on a randomized trial of prolonged intracoronary

urohinase for chronic total occlusion of native coronary

arter-ies This study included 101 patients with an occlusion ⬎3

mo Patients were pre-treated with ASA and then given

10,000 U of IV heparin Urohinase was infused after initial

attempts at crossing the occlusion with a guidewire The

urohinase was administered for approximately eight hour

with a split dosing through the guide catheter and the infusion

catheter which were positioned proximal to the site of

occlusion One of three doses was used for a total of800,000 U, 16 million U or 3.2 million U over the eight hour.Following infusion, the patient was returned to the catheteri-zation laboratory for an additional attempt at guidewirepassage After urohinase infusion, angioplasty was successful

in 53% Patients receiving higher doses of urohinase hadmore bleeding although the numbers were too small to reachstatistical significance Follow up angiographic rates were lowbut the target vessel was patent in 91%; however, restenosisrates were high

Subsequent to this study, Abbas et al (37) reported on

85 patients who had a history of failed attempt at tion of a chronic coronary occlusion in whom at the time

recanaliza-of repeat intervention, pre-procedural intracoronary specific lytic therapy was used In this group, either weight-adjusted alteplase (tPA, Genentech, San Francisco, CA;0.025–0.05 mg/kg/hr; 2 mg/hr for weight ⱕ60 kg, 3 mg/hr forweight 61 to ⱕ80 kg, 4 mg/hr for weight 81 to ⱕ105 kg, and

fibrin-5 mg/hr for weight ⱖ105 kg) or standard dose tenecteplase(TNK) (Genentech; 0.5 mg/hr) was administered for eighthour with an infusion catheter positioned at the face of thechronic total occlusion (Fig 4) All of the occlusions weregreater than three month in duration and 62% involved theright coronary artery Despite the fact that all of the patientshad had a previous failed attempt at recanalization, the proce-dure after lytic therapy was successful in 54% Among thefailed cases, inability to cross the occlusion with a guidewirewas the most common reason for failure (97%) Proceduralcomplications were relatively infrequent and included 5% withdissections that did not result in perforation or tamponade,groin hematoma in 8%, and positive biomarkers with eleva-tion of total CK with an increase in MB fraction seen in 5%.This approach appears promising in these patients with previ-ously failed attempts and will be tested in a larger trial.Recently, there has been in the use of other pharmacologicagents to modify the chronic total occlusion and render itmore suitable for treatment (38–40) An animal model hasbeen developed for testing these new approaches In thisrabbit model, thrombin is injected into an isolated portion ofthe femoral artery After recovery, during the next two to fourmonth, the thrombus is replaced by collagen which results in

a chronic total occlusion

Using this rabbit model, a purified human grade nase was tested (39) Similar to the human situation, anover-the-wire balloon angioplasty catheter was advanced andpositioned immediately proximal to the part of occlusion Thecollagenase was administered through the central lumen for

collage-24 hour Following this, guidewire recanalization wasattempted using conventional coronary guidewires In theseries of 10 CTO treated in this way, passage of theguidewire was successful in all 10 A wire-induced dissectionwas identified in two animals; despite that the wire eventuallycrossed into the distal vessel

For this study, multiple doses of collagenase were used Theauthor studied the effect of the collagenase on subcutaneous

bruising With higher doses, there was more extensive

bruis-ing but no significant differences in hemoglobin at 24 hours

Vessel wall structure remained intact

This approach has considerable potential in the human

arena although multiple details need to be worked out

includ-ing the optimal duration of local arterial therapy This detail

has major implications for patient care Infusions for up to six

hour may be reasonably well tolerated; beyond this window,

they become increasingly complicated Prolonged heparin if

required to maintain guide and sub-selective catheter patency

may be associated with increased bleeding

Conclusions

Chronic total occlusions remain one of the last great problems

(or opportunities) for interventional cardiology Despite their

frequency, current success rates are still quite low even in

selected patients; the dominant reason for failure is inability to

cross with a guidewire New mechanical approaches continue

to be evaluated In addition to these, new pharmacologic

strate-gies are being developed to facilitate initial safe passage of the

guidewire These have the potential to improve success rates

Resolution of this problem will open up the doors for many

patients with chronic coronary artery disease to undergo a

percutaneous revascularization procedure rather than CABG

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The emergence of pharmacogenomic-guided drug

develop-ment has led to novel approaches in the effective

management of patients and ensured individualized therapy

tailored to the needs of one and all, at the right dosage and

right time The entire human genome is now completely

mapped Gene expression profiling and identification of the

single nucleotide polymorphism (SNP) will enable effective

diagnosis of various diseases, and has a role in preclinical

phases of drug development, in developing markers for

adverse drug interactions and desired pharmacologic effects

Newer drugs can be withdrawn from the drug development

pipeline should they exhibit hepatic metabolism requiring

CYP450 enzymes known to manifest SNPs resulting in

adverse drug reactions Vogel for the first time introduced the

term, pharmacogenetics, in 1959 (1), which refers to the

analysis of monogenetic variants that define an individual’s

response to a drug, and aims to deliver the right drug at right

dosage to a right patient by using DNA information The

vari-able drug response in different patients may be the result of

genetic differences in drug metabolism, drug distribution, and

drug target proteins (2) Pharmacogenetics refers to the

entire library of genes that determine drug efficacy and safety

There are approximately three billion base pairs in the human

genome that code for at least 30,000 genes Although the

majority of basepairs are identical from individual to individual,

only 0.1% of the basepairs contribute to individual

differ-ences Three consecutive basepairs form a codon that

specifies the amino acids that constitute the protein Genes

represent a series of codons that specifies a particular protein

At each gene locus, an individual carries two alleles, one

from each parent If there are two identical alleles, it isreferred to as a homozygous genotype, and if the alleles aredifferent, it is heterozygous Genetic variations usually occur

as SNPs and occur on an average of at least once every 1000basepairs, accounting to approximately three million base-pairs distributed throughout the entire genome Geneticvariations that occur at a frequency of at least 1% in thehuman population are referred to as polymorphisms Geneticpolymorphisms are inherited and monogenic; they involveone locus and have interethnic differences in frequency Raremutations occur at a frequency of less than 1% in the humanpopulation Other examples of genetic variations includeinsertion–deletion polymorphisms, tandem-repeats, defec-tive splicing, aberrant splice site, and premature stop codonpolymorphisms Pharmacogenomics, through the discovery

of new genetic targets, is expected to improve the quality oflife and control the healthcare costs by treating specificgenetic subgroups and by avoiding adverse drug reactionsand by decreasing the number of treatment failures Theevolution and the concepts of pharmacoeconomic-basedpharmacogenomics and pharmacogenetics should be widelyknown and practiced Pharmacogenomics and cheminfor-matics should become a part of the current study designs

of prospective clinical trials Pharmacogenomic and cogenetic data should be included in the investigational newdrug (IND) applications, thereby enabling the food and drug administration (FDA) to evaluate its true impact on phar-macoeconomics resulting in drastic reduction in thehealthcare expenditure worldwide Pharmacogenomicsprovides a significant paradigm shift in the management ofpatients and provides a means to increase the quality ofmedical care

pharma-47

Newer pharmacologic approaches targeting

receptors and genes

Omer M Iqbal, Debra Hoppensteadt, and Jawed Fareed

Table 1 List of genes involved in coagulation disorders

Single nucleotide

polymorphism

Pharmaceutical industries are very much interested in

phar-macogenomics as a means to reduce the costs and the time

involved in conducting the clinical trials and to improve the

efficacy of drugs tailored to the individual patient need

Although the genetic association studies are used to establish

links between polymorphic variation in the coagulation Factor

V gene and deep vein thrombosis (DVT), this approach of

“susceptibility genes” that has a crucial role in the likelihood of

developing a disease has enabled identification of other genes

(3) Variations in a drug metabolizing enzyme gene,

thiop-urine methyltransferase (TPMT), have been linked to adverse

drug reactions (4) Similarly, variants in a drug-target,

5-lipoxygenase, (ALOX5) have been linked to variations in drug

response (5) Through linkage disequilibrium (LD) or

nonran-dom association between SNPs in proximity to each other,

tens of thousands of anonymous SNPs are identified and

mapped These anonymous genes may fall either within

susceptibility genes or in noncoding DNA between genes

Through LD, the associations found that with these

anony-mous SNP markers can identify a region of the genome that

may harbor a particular susceptibility gene Through

posi-tional cloning, the gene and the SNP can be revealed

conferring the underlying associated condition or disease (6)

Numerous companies have now developed DNA

microarrays (biochips) of different genes of interest that could

be used in high-throughput sequencing in a population todetect common or uncommon genetic variants These DNA-based diagnostic microarrays, which are targeted for patientcare, must be accurate, high-throughput, reproducible, flexi-ble, and inexpensive Efforts should be made to improve thesensitivity as well as to reduce the costs of identifying poly-morphisms by direct sequencing It is important tounderstand the genetic variability in genes in relation to thesafety and efficacy of any drug The functional consequences

of nonsynonymous SNPs can be predicted by a based assessment of amino acid variation (7)

structure-Pharmacogenomics in coagulation disorders

According to the SNP Map Working Group (Nature 2001),there are 1.42 million SNPs; one SNP per 1900 bases;60,000 SNPs within exons; two exonic SNPs per gene(1/1080 bases); 93% of genetic loci contain two SNPs.Because each person is different at one in 1000–2000 bases,SNPs are responsible for human individuality A list of genesinvolved in coagulation disorders is given in Table 1

The various polymorphisms in different coagulationproteins are discussed subsequently

22040 MMP9 Matrix metalloproteinase 9 (gelatinase B, 92-Kd gelatinase, 92-Kd type IV collagenase)

26418 EDG1 Endothelial differentiation, sphingolipid G-protein-coupled receptor

40463 PDGFRB Platelet-derived growth factor (PDGF) receptor, betapolypeptide

41898 PTGDS Prostaglandin D2 synthase (21 Kd, brain)

51447 FCGR3B Fc fragment of IgG, low affinity IIIb, receptor for Z(CD16)

67654 PDGFB PDGF-betapolypeptide [Simian sarcoma viral (v-sis) oncogene homolog]

71101 PROCR Protein C receptor, endothelial (EPCR)

(Continued )

Table 1 List of genes involved in coagulation disorders (Continued )

Pharmacogenomics in coagulation disorders 545

130541 PECAM1 Platelet/endothelial-cell adhesion molecule (CD31 antigen)

136821 TGFB1 Transforming growth factor, beta 1

142556 PSG2 Pregnancy-specific beta-1-glycoprotein 2

143287 PSG11 Pregnancy-specific beta-1-glycoprotein 11

149910 SELL Selectin E (endothelial adhesion molecule 1)

180864 ICAM5 Intercellular adhesion molecule 5, telencephalin

184038 SPTBN2 Spectrin, beta, nonerythrocytic 2

194804 PTTPN Phosphatidylinositol transfer protein

196612 MMP12 Matrix metalloproteinase 1 (interstitial collagenase)

199945 TGM2 Transglutaminase 2 (C polypeptide, protein-glutamine-gamma-glutamyltransferase)

240249 APLP2 Amyloid beta (A4) precursor-like protein 2

243816 CD36 CD36 antigen (collagen type 1 receptor, thrombospondin receptor)

245242 CPB2 Carboxypeptidase B2 (Plasma, carboxypeptidase U)

261519 TNFRSF5 TNF-receptor (superfamily, member 5)

(Continued )