Textbook of Interventional Cardiovascular Pharmacology - part 4 pot

Although radiation therapy was successful in reducing in-stent restenosis, it failed to obtain a single-digit restenosis rate for de novo lesions, especially when coupled with stents, ei

mercury manometer at regular intervals Commercial

elec-tronic calibration manometers (such as the NETECH

DigiMano) must be sent back to the manufacturer yearly for

calibration against a mercury standard Devices that pass the

validation protocols of the American Association of Medical

Instrumentation (AAMI) will have systematic errors of more

than 5 mmHg in a substantial number of individual patients

The calibration check of a nonmercury device requires two

steps: (i) validation of the manometer in the device and

(ii) validation of the ability of the device to estimate the

pres-sure in an individual patient

For an up-to-date list of validate devices go to

http://www.bhsoc.org/bp_monitors/automatic.stm

Does the manometer in my

nonmercury device record

pressure accurately?

First, you must document whether the manometer of the device

(electronic or aneroid) registers pressure accurately Connect

the device to be tested to the reference device (mercury,

aneroid, or electronic) with a Y tube, as shown in Figure 1

The Y tube transmits pressure equally to the reference

device and the device to be tested Using the bulb connected

to the Y, pressure is increased to 300 mmHg and then

lowered by 10 mmHg Recording the pressure on each

device validates the accuracy of the aneroid or electronic

device Any device that differs by more than 3 mmHg from

the mercury or reference standard is considered to be out of

calibration and should be removed from service

Does this automated device estimate the pressure accurately enough in my patient?

The second step is to assess the error (if any) of the BP estimated by the automated device This is done by simulta-neous or by sequential readings

Simultaneous readings

This is the preferred option If the device can deflate at aconstant rate of 2 to 3 mm/sec, one can do simultaneous read-ings Record the BP by the auscultatory method as theautomated device takes the BP To be certain the automaticdevice inflates high enough to get an accurate pressure, youmust obtain the palpated systolic pressure and then ensure thatthe automatic device inflates at least 30 mm above that Thenlisten as the automatic device deflates and record the systolic anddiastolic pressure you hear After you have recorded your read-ing, record the reading from the automated device This should

be done at least three times and then analyzed as in Table 1

Sequential readings

Many devices deflate too fast or in steps, and so you must usesequential readings We recommend that this be done enoughtimes to ensure that you have a good estimate of the BPrecorded by the machine and the human observer AAMIrecommends that this be done at least five times The averagesare then calculated and compared Your local guidelines should

be used to assess whether the device is accurate enough to beused in your patient An error of more than 5 mmHg and a

180

Inflation bulb

Electronic device 186

170 (10 mm too low)

Electronic readout (6 mm too high)

To test the electronic device connect the pressure sensing input to the Y tube to the Mercury primary standard.

Raise and lower pressure in system with the bulb.

Pump air into the system until the mercury manometer reads standard say 180 Then record the pressure that the aneroid reads Do this throughout the range to be tested Aneroid should be ±3 mm Hg.

300 290 270 250 230 210 190 170 150 130 110 90 70 50 30 10

280 260 240 220 200 180 160 140 120 100 80 60 40 20 0

Figure 1

If using an electronic calibration standard, it is connected in place of the mercury manometer You should test only one device at a time.

standard deviation (SD) of more than 8 is generally considered

unacceptable Inform the patient and note this error in the

patient’s chart so others will be aware of it

To use this table in an Excel spreadsheet, you enter three

readings made by your trained observer and three made by

the device The mean error and its SD is calculated by using

Excel functions If the error is more than 5 mmHg, this device

should not be used in this patient

Failure to document these directional errors will also lead

to decisions being made on the basis of only a single BP

read-ing Another important approach is to take a home reading

and to use a systematic approach to the clinical and laboratory

evaluation of the new patient to exclude secondary causes of

high BP and to guide treatment Finally, recent advances in the

genetics of high BP need to be kept in mind while evaluating

new patients and their families

How to quickly bring blood

pressure under control in the

most difficult patient

In my experience, many cardiologists fail to recognize that

secondary causes of high BP tend to be much higher in their

referral practice and they miss important clues to secondary

causes Appendix 1 outlines a systematic approach to be

certain that one is not missing secondary causes of high BP

Blood pressure control before

and after surgery or

angiography

In contrast to older agents, which had much longer half lives, that

are used to control BP this combination of combinations uses

agents that, except for diuretics, will lead to a rapid increase in BP

if they are not given every 24 hours (Appendix 2) Therefore theagents should not be stopped on the night before or the day ofinterventional studies, as the BP may rapidly increase during orafter the study and lead to complications, including hemorrhagearound puncture sites or acute pulmonary edema

When BP control is needed during interventional dures, one can use intravenous nitrates or combinedalpha-beta blockers such as labetalol When these agents fail,

proce-I use Nipride, which proce-I have never had fail to control the BP inpatients with Cushing’s, primary aldosteronism, renal arterystenosis, pheochromocytoma, and scleroderma with malig-nant hypertension

In the postoperative state, BP control can be continuedeven if the patients are nil per os (NPO) as the medicationscan be crushed and given via a nasogastric tube

Summary

This chapter discusses some key features for BP ment and management in the office and the home andstresses the continued use of the mercury manometer asrecommended by the newest AHA guidelines A method tovalidate home and office device accuracy is detailed Finally astepwise “combination of combinations” approach to BPcontrol in the difficult patient is reviewed, which can be used

measure-in the measure-in- and outpatient settmeasure-ing

References

1 Cushman WC, Cooper KM, Horne RA, Meydrech EF Effect of back support and stethoscope head on seated blood pressure determinations Am J Hypertens 1990; 3: 240–241.

a See text on how to set up in an Excel file.

Table 1 How to test an automated blood pressure device against a trained and certified human observerusing a mercury manometer and stethescopea

2 Gerin W, Schwartz AR, Schwartz JE, et al Limitations of

current validation protocols for home blood pressure tors for individual patients Blood Press Monit 2002;

moni-7(6):313–318.

3 Pickering TG, Hall JE, Appel LJ, et al Part 1: blood pressure

measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research Hypertension 2005; 45:142–161.

4 Grim CE Evolution of diagnostic criteria for primary nism: why is it more common in “drug-resistant” hypertension today? Curr Hypertens Rep 2004; 6(6):485–492.

aldostero-5 Grim CE Management of malignant hypertension hensive Therapy 1980; 6:44–48.

Compre-6 Appel, LJ, Moore, TJ, Obarzanek, E, et al A clinical trial of the effects of dietary patterns on blood pressure DASH Collaborative Research Group N Engl J Med 1997; 336:1117–1124; May 13–16, 1998.

Appendix 1

Secondary causes of high blood

pressure (office clues)

1 Observe in the patient: cushing’s, acromegaly,

hyper–hypothyroid, neurofibromas, web neck, short4th metacarpal, café-au-lait spots, swollen feet?

2 Listen to the patient:

2.1 Family history—low K, hypertension (HTN)

preg-nancy, early stroke in men (suggests some of the newsingle gene causing high BP), etc

2.2 Medical history—low K; BP with pregnancy; birth

control pills (BCP); licorice; over the counter (OTC)phrine; renal trauma; episodes of HTN inferringpheochromocytoma, that is, headache; hyperhidrosis;

high heart rate; hypermetabolism, etc

3 Smell the patient: alcohol (EtOH), tobacco, uremia?

4 Examine the patient: fundi, bruits, left ventricular

hyper-trophy (LVH), large kidneys, radial-femoral (R-F ) pulselag, edema?

5 Labs: lytes, blood urea nitrogen (BUN)/creatinine,

urine albumin, plasma aldosterone/plasma renin ratio

to screen for excess aldosterone or mineralocorticoidproduction, or renin for renal artery stenosis (RAS) orrenin-secreting tumor

6 Patient’s education:

6.1 Teach self-BP If they do not have one, have them get

an Omron or AND device with right-sized cuff (armcircum ⬎33, use large cuff)

6.2 Instruct on self-BP measurement: Shared Care video

(sharedcareinc.com)—sit 5 minutes, take three ings, write them all down, and average the last two

read-Take BP in AM before taking treatment (RX)and any other time they feel like BP is high or theyare dizzy

6.3 Record in the book and bring in

7 Dietary approaches to stopping hypertension (DASH)

eating plan: Have the patient got the DASH Diet forHypertension Book by Thomas Moore, read it, anduse it for the 14-day test They may wish to visit blood-pressureline@yahoogroups com for support

8 Review medications

8.1 If not on a diuretic, always use hydrochlorothiazide

(HCTZ) half of 25 mg (costs $8–15/100) Havethem buy this

9 Change to a combination of combinations: Consider

stopping all other RX and begin9.1 Lotrel 2.5/10 bid, if on Norvasc, switch to

Lotrel, and9.2 Bisoprolol (BIS) 2.5/HCTZ 6.25 each AMor bid

10 Titrate to get BP control: Have patient call with BPs in

two to three days

10.1 If not at goal, increase Lotrel two AM(and two PMandBIS to two AM, two PM—do this till at Lotrel 10/20bid and BIS 10/6.25 bid

10.2 If BP not at goal in four weeks, then add Minoxidil

5 mg every morning Increase every few days byusing 5 mg AM, 5 PM, 10 mg AM, 10 PM, etc Patientneeds to be weighed daily If weight goes up, thenadd furosemide 40 bid and increase If still edema,add metolazone 10 mg every morning

10.3 Check for out eating your BP RX: 24-hour urine forNa/K/creatinine if the 24-hour sodium excretion is

⬎1500 mg a day then tell patient they are notadhering to the DASH diet

11 Diagnose drug resistant HTN, likely primary teronism (4): If aldo/renin ratio is high, then addSpironolactone 50 mg/day and may increase to

aldos-400 mg/day If gynecomastia, use Inspra 25 to 50/d.Consider adrenal computed tomography andadrenal vein aldo/cortisol with ACTH stim If thefamily history (Hx) is positive for low K then doovernight dex test for aldo/cortisol and/or genotypefor glucocorticoid remedial aldosteronism (GRA)

12 Look for other causes of HTN:

12.1 If you would do an angioplasty or an operation, doclassical renal arteriogram—not MRA or nuclear scan;the only way to exclude renal artery stenosis as acause of HTN is by selective transfemoral angiography

to get details of main and branch renal arteries.12.2 Pheochromocytoma: 24-hour urine for catechol-amines, Na, K, and creatinine

Appendix 2

How to get rapid blood pressure control in the hospital or in the clinic—the combination of

combinations approach

The following protocol has been developed and modifiedover the last 30 years and has been very successful in bring-ing BP quickly under control in the hospital and in theoutpatients’ clinic The physiological rational is based on the complex and redundant BP control systems that must beovercome to bring BP to goal The basic concept is that theBP-regulatory control systems are designed to keep the pres-sure constant Any attempt to block one system to lower thepressure activates the other systems that try to keep the pres-sure at its current set point Thus, the regimen includesdiuretics to get at the volume factor that is the key to all forms

of high BP, beta blocker (BB) or other agents to block the SNSresponse to volume depletion and BP lowering, angiotensionconverting enzyme/angiotensin receptor blocker (ACE/ARB)

1inhibition to counteract activation of this system with BP

lowering, and finally agents that act directly on the vascular

smooth muscle such as CCBs or minoxidil

1 Immediate reduction needed: very rare Nipride never

fails (5) Take BP every two minutes Infuse with pumpNipride (mix as per instructions) Double dose every twominutes till BP falls, then back down to 1/2 of last step upand adjust till at goal—usually takes about 30 minutes tostabilize Add oral agents as given in the table

2 If reduction not needed immediately: Take BP every

hour and use a stepwise increase by using a combination

of combinations In the outpatient clinic, one can use this

approach by stepping up the intensity of control everyday or two, or even every week, if the patient or familymember is measuring BP regularly

3 Volume contol: Give HCTZ 25 po q 12 hours If edema or Cr ⬎2, use furosemide 40 q 12 hours Leave orders that stress that you want the BP to

be measured every hour and you want to increase meds as given in the table, every four to six hours Alwaysimplement the DASH 1500-mg sodium diet as well (6)

4 Renin-angiotensin-aldosterone system (RAAS), calciumchannel blocker (CCB), and BB: The combination of thedrug Lotrel contains ACE and CCB, and the othercombination is BIS and HCTZ

Step 1: 1st dose at 25 HCTZ or 40 furosemide

increase other agents.

Step 5: 8 AM At goal, –HCTZ 12.5 or 25 q AM Give last dose q AM Give last dose q AM

Step 9: 8 AM At goal, watch the weight for Repeat last dose of Lotrel 10/20 q AM , BIS

increase on Minoxidil May need Minoxidil q day 10/6.25 q AM , Consider Lotrel

Note: Others to add as outpatient: Spironolactone up to 300/day Cough → ARB, Catapres if intolerant of BB.

Abbreviations: BB, beta blocker; BIS, bisoprolol; BP, blood pressure; EGFR, estimated glomerular filtration rate; HCTZ, hydrochlorothiazide.

Homocysteine is a nonprotein-building amino acid formed as

a metabolite in the methionine cycle It was first associated

with disease in 1962 (1,2) Individuals with a mutation in

cystathionine-␤-synthase (CBS) develop classical

homocystin-uria with extremely elevated plasma tHcy (⬎100 ␮mol/L) (3)

Homocystinuria is characterized by early atherosclerosis and

thromboembolism as well as mental retardation and

osteo-porosis and is ameliorated by vitamin supplementation aimed

at reducing the blood concentration of homocysteine (4)

Moderately elevated plasma homocysteine, defined as

levels between 15 and 30␮mol/L (5), has emerged as a new

risk factor for ischemic heart disease and stroke (6)

The metabolism of

homocysteine

Homocysteine is formed as an intermediary amino acid in

the methionine cycle (Fig 1) Methionine is metabolized to

s-adenosylmethionine (SAM), the methyl donor in most

methylation reactions and essential for the synthesis of

creati-nine, DNA, RNA, proteins, and phospholipids SAM is

converted by methyl donation to s-adenosylhomocysteine

(SAH), which is then hydrolyzed to homocysteine SAH is an

inhibitor of methyl group donation from SAM

Homocysteine is eliminated via the trans-sulfuration

path-way by conversion to cysteine in two steps

The vitamin B6-dependent enzyme CBS catalyzes the

first step, in which homocysteine reacts with serine to form

L-cystathionine In the second step, L-cystathionine is converted

to L-cysteine, a-ketobutyrate, and ammonia by the vitamin

B6-dependent enzyme cystathionase (7)

The trans-sulfuration pathway is present in the liver,

kidneys, small intestine, and pancreas, where it is linked to the

Continuing the folate cycle, THF reacts with serine toproduce 5,10-methylenetetrahydrofolate, a reaction catalyzed

by the vitamin B6-dependent enzyme serine/glycine ymethyltransferase

hydrox-5,10-Methylenetetrahydrofolate is then reduced to CH3THF by the vitamin B2 (riboflavin)-dependent enzyme5,10-methylenetetrahydrofolate reductase (MTHFR), usingNADPH as cosubstrate MTHFR is the key enzyme fordiverting 5,10-methylentetrahydrofolate to methylation ofhomocysteine or to DNA synthesis though the conversion ofuracil to thymidine

-Causes of elevated plasma concentrations of

homocysteine

There are a number of enzyme disorders that cause plasmatHcy elevation (8–12); the two most important are discussedlater

CBS deficiency is inherited as an autosomal recessive trait.Homozygous individuals (1 in 200,000 births) have classicalhomocystinuria with extremely high plasma tHcy The 677

C⬎ T polymorphism in MTHFR is believed to be one of themost common causes of mildly elevated plasma tHcy Thefrequency of the homozygous genotype is 11% to 15% inNorth Americans, 5% to 23% in Europeans, 11% in healthyJapanese populations, and only 2.5% in the Indian population

in New Delhi (12–14) The polymorphism induces lability in the enzyme, resulting in defect remethylation of

thermo-16

Homocysteine regulators

Torfi F Jonasson and Hans Ohlin

homocysteine and increased plasma levels The high plasma

levels of tHcy caused by the 677 C⬎ T polymorphism

respond to folate supplementation (15)

As shown in the review of the homocysteine metabolism,

vitamin B12, vitamin B6, and folate are important cofactors in

the metabolic pathways for homocysteine elimination,

and consequently, deficiencies of these vitamins are

charac-terized by elevated plasma concentrations of tHcy

Hyperhomocysteinemia is also frequently found in diseases

such as renal failure, rheumatic and auto-immune diseases,

hypothyroidism, and malignancies Several drugs are also

known to increase plasma tHcy concentrations (16–24)

Homocysteine: a risk factor

for cardiovascular disease

Many studies published during the last few decades have

suggested that hyperhomocysteinemia is a risk factor for

coronary artery disease (CAD), stroke, and thromboembolic

disease The Homocysteine Studies Collaboration

meta-analysis of 30 studies concluded that elevated tHcy is a

moderate risk factor for ischemic heart disease; a level

3␮mol/L lower reduces the risk with an odds ratio of 0.89

(95% CI⫽ 0.83–0.96) The same was true for

homocys-teine as a risk factor for stroke (odds ratio⫽ 0.81;

95%5CI⫽ 0.69–0.95) (6) A meta-analysis of 40 studies of

the MTHFR 677 C⬎ T polymorphism demonstrated a

mildly increased risk of coronary heart disease with an odds

Figure 1

Metabolism of homocysteine.

Abbreviations: BHMT, betaine homocysteine methyltransferase; CBS, cystathionine ␤-synthase;

MAT, methionine adenosine transferase;

MS, methionine synthase;

MTHFR, 5,10-methylenetetrahydrofolate reductase; SAH, s-adenosylhomocysteine; SAM, s-adenosylmethionine;

THF, tetrahydrofolate.

Effects on nitrous oxide

Homocysteine decreases the bioavailability of nitrous oxide

(NO) via a mechanism involving glutathione peroxidase (37)

Tawakol et al (38) reported that hyperhomocysteinemia is

associated with impaired endothelium-dependent

vasodila-tion in humans Homocysteine impairs the NO synthase

pathway both in cell culture (39) and in monkeys with

hyper-homocysteinemia, by increasing the levels of asymmetric

dimethylarginine (ADMA), an endogenous NO synthase

inhibitor (40) Elevation of ADMA may mediate endothelial

dysfunction during experimental hyperhomocysteinemia in

humans (41) However, Jonasson et al (42) did not find

increased ADMA levels in patients with coronary heart

disease and hyperhomocysteinemia, nor did vitamin

supple-mentation have any effect on ADMA levels in spite of

substantial plasma tHcy reduction

Effects on coagulation

Subjects with homocystinuria suffer from thromboembolic

events

Epidemiological studies indicate that elevated plasma tHcy

increases the risk of venous thromboembolism (43,44) In

homocystinuria, the presence of the factor V Leiden mutation

further increases the risk of thromboembolism (45) It has

been proposed that hyperhomocysteinemia might interfere

with the inhibition of activated factor V by activated protein C,

possibly via similar effects as those caused by the factor V

Leiden mutation (46,47) However, one in vitro study (48)

and one large clinical study failed to demonstrate an

associa-tion between hyperhomocysteinemia and activated protein C

resistance (49)

Hcy has been shown to reduce binding of tPA to its

endothelial cell receptor, annexin II, in cell cultures (50)

Animal studies have indicated that elevated plasma tHcy could

cause acquired dysfibrinogenemia, leading to the formation of

clots that are abnormally resistant to fibrinolysis (51) Elevated

plasminogen activator inhibitor and tHcy in patients with

acute coronary syndrome have been shown to be associated

with increased risk for major adverse cardiac events (MACE)

after successful percutaneous coronary intervention (PCI)

and stenting (52), whereas factor V Leiden mutation and

lipoprotein (a) were not

Inflammation

Several prospective studies have shown that markers of

inflammation, such as sensitive C-reactive protein and serum

amyloid A (S-AA), are predictors of increased risk for

myocar-dial infarction, stroke, or peripheral vascular disease (53–56)

Increases in plasma S-AA levels have previously beenreported in patients with coronary disease (57) S-AA andplasma intracellular adhesion molecule-1 were elevated inpatients with CAD and hyperhomocysteinemia, but only S-AAdecreased after vitamin supplementation (35) Homocysteineactivates nuclear factor-kB in endothelial cells, possibly viaoxidative stress (58), and increases monocyte chemoattractantprotein-1 expression in vascular smooth muscle cells (59).Additionally, it stimulates interleukin-8 expression in humanendothelial cultures (60) These inflammatory factors areknown to participate in the development of atherosclerosis.Taken together, these reports suggest an association ofelevated tHcy and low-grade inflammation in CAD

Homocysteine and smooth muscle proliferation

Proliferative effects of homocysteine have been strated in several in vitro studies Brown et al (61) found thathomocysteine activates the MAP kinase signal transductionpathway in vascular smooth muscle cells

demon-Buemi et al reported that the addition of Hcy to themedium of smooth muscle cells in tissue culture caused asignificant increase in cell proliferation and death throughapoptosis and necrosis When folic acid was added to theculture medium, homocysteine concentrations in media werereduced and the effects of Hcy on the proliferation/apopto-sis/necrosis balance of cells in culture were inhibited (62).Ozer et al (63) showed that the MAPK kinase pathway isinvolved in DNA synthesis and proliferation of vascularsmooth muscle induced by homocysteine

Carmody et al found that the addition of homocysteine to

a culture of vascular smooth muscle cells resulted in a dependent increase in DNA synthesis and cell proliferation,but vitamins B6and B12alone did not substantially inhibit theeffect of homocysteine However, the addition of folic acidresulted in significant inhibition of DNA synthesis (64).Rosiglitazone has been shown to reduce serum tHcy levels,smooth muscle proliferation, and intimal hyperplasia inSprague–Dawley rats fed a diet high in methionine (65).The results of the in vitro studies are promising withrespect to possible positive in vivo effects of vitamin supple-mentation However, the recent results of large prospectiveclinical trials of vitamin supplementation have been disap-pointing; these results are further discussed later

dose-To conclude, hyperhomocysteinemia is associated withoxidative stress, inflammation, endothelial dysfunction, anddysfunction of coagulation in animals and in humans, but vitaminsupplementation does not consistently normalize these changes

in spite of large reductions in homocysteine It still remains beseen whether homocysteine per se causes the pathologicalprocesses or whether it is simply an innocent bystander

Homocysteine and smooth muscle proliferation 179

Vitamin therapy for prevention

of cardiovascular disease

Three large-scale clinical trials of vitamin supplementation

have been published In the Vitamin Intervention for Stroke

Prevention Study (VISP), 3680 adults with nondisabling

cere-bral infarction were randomized to either a high-dose vitamin

formulation containing 25 mg pyridoxine, 0.4 mg cobalamin,

and 2.5 mg folic acid or a low-dose formulation containing

200␮g pyridoxine, 6 ␮g cobalamin, and 20 ␮g folic acid The

mean reduction of tHcy was 2␮mol/L greater in the

high-dose group than in the low-high-dose group The primary

outcome, the risk of ischemic stroke within two years, was

9.2% in the high-dose group and 8.8% in the low-dose

group (risk ratio⫽ 1.0; 95% CI ⫽ 0.8–1.3) (66)

The Norwegian Vitamin (NORVIT) trial included 3749

patients who had had an acute myocardial infarction within

seven days before the start of the trial The patients were

randomly assigned in a two-by-two factorial design to receive

one of the following four daily treatments: 0.8 mg folic acid,

0.4 mg vitamin B12, and 40 mg vitamin B6; 0.8 mg folic acid

and 0.4 mg B12; 40 mg vitamin B6; or placebo The mean

total homocysteine level was reduced by 27% in patients

given folic acid and B12, but the treatment had no significant

effect on the primary outcome, a composite of recurrent

myocardial infarction, stroke, and sudden death due to

coro-nary heart disease (risk ratio⫽ 1.08; 95% CI ⫽ 0.93–1.25)

Treatment with vitamin B6was not associated with any

signif-icant benefit In the group given folic acid, vitamin B12, and

vitamin B6, there was a trend toward an increased risk

(rela-tive risk⫽ 1.22; 95% CI ⫽ 1.00–1.50; P ⫽ 0.05) (67).

In the Heart Outcomes Prevention Evaluation 2 (HOPE-2)

study, 5522 patients aged 55 or older with vascular disease or

diabetes were randomized to treatment with either placebo

or a combination 2, 5 mg of folic acid, 50 mg vitamin B6, and

1 mg vitamin B12, for an average of five years The primary

outcome was a composite of death from cardiovascular

causes, myocardial infarction, and stroke Mean plasma

homocysteine levels decreased by 2.4␮mol/L in the

treat-ment group and increased by 0.8␮mol/L in the placebo

group The primary outcome occurred in 18.8% of patients

assigned to active therapy and in 19.8% of those assigned to

placebo (relative risk⫽ 0.95; 95% CI ⫽ 0.84–1.07;

P⫽ 0.41) (68)

The results of these three large trials are consistent and lead

to the conclusion that there is no clinical benefit from vitamin

supplementation in patients with cardiovascular disease (CVD)

As suggested by Loscalzo (69), the results indicate that either

homocysteine is not a important atherogenic determinant or the

vitamin therapy might have other adverse effects that offset its

homocysteine-lowering effects, such as cell proliferation through

synthesis of thymidine, hypermethylation of DNA, or increased

methylation potential leading to elevated levels of ADMA

Homocysteine and restenosis after percutaneous coronary intervention

Is homocysteine involved in the pathogenesis of restenosis? Anassociation between homocysteine and restenosis is notunlikely, given the fact that homocysteine appears to induceinflammation, impair endothelial function, and stimulate smoothmuscle proliferation; all these mechanisms are potentially impli-cated in the development of restenosis However, the dataregarding tHcy levels and the risk of restenosis after coronaryangioplasty are conflicting Some investigators found anincreased risk of restenosis after PCI in patients with high plasmalevels of homocysteine, especially in patients not treated withstents (70–72), whereas others did not find any increased riskeither in patients with (73–75) or without stents (76)

Homocysteine-lowering therapy and restenosis after coronary angioplasty

In the Swiss Heart Study (77), 205 patients were randomlyassigned after successful angioplasty to receive either placebo

or a combination therapy of folic acid (1 mg), vitamin B12(400␮g), vitamin B6 (10␮g) or placebo The primaryendpoint was restenosis within six months, as assessed byquantitative coronary angiography Angiographic follow-upwas achieved in 177 patients Vitamin treatment significantlydecreased plasma tHcy levels from 11.1 to 7.2␮mol/L

(P⬍ 0.001) At follow-up, the minimal luminal diameter wassignificantly larger in the treatment group, 1.7 mm versus

1.45 mm (P⫽ 0.02), and the degree of stenosis was less

severe (39.9% vs 48.2%, P⫽ 0.01) The treatment group

had a lower rate of restenosis (19.6% vs 37.6%, P⫽ 0.01)and less need for revascularization of the target lesion (10.8%

vs 22.3%, P⫽ 0.047) A difference in treatment effectbetween stented and nonstented lesions was evident In 101lesions treated with balloon angioplasty only, vitamin treat-ment reduced the rate of restenosis from 41.9% to 10.3%

(P⬍ 0.001) In 130 stented lesions, only a nonsignificant trend

to treatment effect was found; restenosis rate in the treatment

group was 20.6% versus 29.9% with placebo (P⫽ 0.32).However, the subgroups cannot readily be compared, since itwas left to the discretion of the operator whether to use stents

or not Similar results were obtained in the subgroup ofpatients with small coronary arteries (⬍3 mm) (78) Theauthors suggest that vitamin therapy might be an attractivetherapeutic alternative, especially in small coronary arteriesthat are considered less suited for stent therapy

In an extension of the original study, including 553 patients

after successful angioplasty, the clinical outcome of the

combined vitamin therapy for six months was compared to

placebo After one year, the composite endpoint (death,

nonfatal myocardial infarction, and need for revascularization)

was significantly lower in patients treated with vitamin therapy

(15.4% vs 22.8%, P⫽ 0.03), primarily due to a reduced rate

of target lesion revascularization The benefit was evident at

the end of the six months and was maintained at 12 months

after the angioplasty procedure The findings remained

unchanged after adjustment for potential confounders (78)

In contrast, the Folate After Coronary Intervention Trial

(FACIT) demonstrated adverse effects of vitamin treatment in

patients treated with coronary stenting (75) In this study, 636

patients who had undergone successful coronary stenting

with bare metal stents were randomized to either vitamin

therapy or placebo In the vitamin group, 1 mg of folic acid,

5 mg of vitamin B6and 1 mg of B12were given intravenously,

followed by oral therapy The 1, 2 mg dose of folate given

orally was slightly higher than that previously used in the Swiss

Heart Study (1 mg) The dose of B6, 48 mg, was higher than

in the previous study (10 mg), while the B12 dose, 60 ␮g,

was lower (400 ␮g) At the end of the six-month treatment,

the study endpoints (minimal luminal diameter, late loss, and

restenosis rate) were evaluated by means of quantitative

coronary angiography tHcy levels decreased significantly

from a mean of 12.2 ␮mol/L at baseline to 9.0 ␮mol/L at six

months in the folate group (P<0.001), but not in the pacebo

group At follow-up, the mean minimal diameter was smaller

in the folate group than in the placebo group (1.59 vs

1.74 mm, P⫽ 0.008) Additionally, the restenosis rate

tended to be higher in the folate group (34.5% vs 26.5%,

P⫽ 0.05) (75) Folate therapy had adverse effects on the risk

of restenosis in all subgroups except for women, patients with

diabetes, and patients with markedly elevated tHcy levels

(ⱖ15 ␮mol/L) at baseline A clinical evaluation at 250 days did

not reveal any significant difference between those patients

receiving folate and those receiving placebo with regard to

either incidence of death or rate of acute infarction in the

target vessel A trend toward more repeated target-vessel

revascularizations was observed in the folate group (15.8%

vs 10.6%, P⫽ 0.05)

The difference between the outcome of the Swiss Heart

Study and that of FACIT illustrates how difficult it is to explain

the results in terms of the biological effects of vitamin therapy

The positive results of the Swiss Heart Study seem to confirm

the classical homocysteine hypothesis, which holds that

homocysteine is an important atherosclerotic determinant and

that lowering of homocysteine with vitamin therapy might

reduce the rates of cardiovascular events However, it is more

difficult to explain the results of FACIT by an adverse effect of

low plasma homocysteine, and consequently, a less simplistic

perspective on the methionine–homocysteine metabolism

and the multiple effects of folate, B6, and B12is needed

The authors of FACIT point out that there might be adifference in the mechanisms of restenosis after balloonangioplasty and after stenting Proliferation of smooth musclecells and matrix formation are the most important mecha-nisms after stenting, whereas after balloon angioplastythrombus formation and vascular remodeling are of predom-inant importance to the process of restenosis; and the latterchanges are potentially more susceptible to homocysteinelowering Apart from lowering homocysteine, folate plays acrucial role in the synthesis of DNA via the conversion ofuracil to thymidine Thus, administration of high doses offolate might have a proliferative effect in the vessel wall.Lowering of homocysteine will also decrease the concentra-tion of SAH, which is an inhibitor of methyl donation fromSAM, and consequently, folate therapy will increase methyldonation from SAM Methylation of DNA is an epigeneticmechanism for modulating gene expression and may beinvolved in the pathogenesis of atherosclerosis (79) Thus,there are reasons to believe that folate therapy might haveadverse effects, and that the outcome of folate therapy mightdepend on a balance between the possible benefits of homo-cysteine lowering and the potential adverse effects of folate

To complicate the matter even further, folate is also capable

of improving endothelial function independently of changes inhomocysteine: 5-MTHF can directly increase NO productionand scavenge superoxide (80) Although the results ofclinical trials of homocysteine-lowering therapy havegenerally been disappointing, they have certainly helped

to raise the homocysteine hypothesis to a higher level ofcomplexity

In summary, there is abundant evidence both in vitro and

in vivo that homocysteine plays an important role in thepathogenesis of atherosclerosis, possibly by promoting oxida-tive stress, inflammation, thrombosis, and endothelialdysfunction Epidemiological studies have shown that hyper-homocysteinemia appears to be an independent risk factorfor CVD However, several studies have established thatpathological changes in hyperhomocysteinemia, such asoxidative stress and inflammation, are not always corrected

by homocysteine-lowering therapy, raising doubts as towhether mildly elevated tHcy levels in humans are noxiousper se, or whether homocysteine is simply a innocentbystander to other causative mechanisms The bystanderconcept is certainly supported by several recent large-scaleclinical trials that have failed to show any clinical benefits ofvitamin therapy in cardiovascular patients However, it is alsopossible that vitamin therapy may have adverse effects whichcounteract any possible beneficial effect of homocysteinelowering Data from the FACIT study support this notion bydemonstrating increased restenosis following vitamin therapyafter coronary stenting At present, therapy with folate, B6,and B12cannot be recommended for the prevention of CVD;

it may even be harmful in patients treated with coronarystenting The results of the Swiss Heart Study do suggest that

Homocysteine and smooth muscle proliferation 181

there may still be a case for vitamin therapy in patients treated

with balloon angioplasty without stenting However, given the

overall negative results of vitamin therapy in clinical trials, this

potential benefit must be confirmed by future studies before

vitamin therapy can be recommended for this subgroup of

patients

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The introduction of balloon angioplasty to treat coronary

atherosclerosis has created a difficult problem, namely

restenosis The interventional cardiology community and

pharmaceutical and device industries are sparing no efforts

to combat this problem, which continues to be a

formida-ble challenge Coronary stents have reduced its incidence

to 20% to 30%, a reduction of 30% to 40% (1,2) The

recent development of drug-eluting stents (DES) has

further decreased but not eliminated the problem (3)

Efforts to, therefore, overcome the challenge of

resteno-sis—including research into newer mechanisms, targets,

experimental and therapeutic agents, and clinical trials—are

still actively pursued This chapter discusses the oral agents

tested in this area, trials conducted thus far and their

results, its limitations, and future directions for this

modal-ity of treatment

Why oral agents for

restenosis?

The simplest answer is ease of administration More

impor-tantly, there are several limitations to local delivery of drugs in

the form of DES The efficacy of these new devices depends

on several variables, including the selection of an effective

drug, its solubility, diffusion characteristics, release kinetics,

arterial tissue concentration, retention, and whether the

plat-form is polymer based or nonpolymeric Local delivery of the

drug in this manner may delay rather than prevent neointima

This is supported by preclinical studies that show impaired

healing and neointimal catch-up (4) There is concern

that neointimal growth will accelerate in response to the

non-biodegradable polymer coating after complete elution ofthe drug These issues may rejuvenate investigations intosystemic therapy, particularly with those agents that haveshown positive results when administered locally, either asstandalone therapy or as an adjunct to DES Other reasonsinclude, possibility of administration of oral agents over alonger period of time, in patients with multiple stent implan-tations, the ability to withdraw the drug in case ofhypersensitivity or intolerance, and perhaps the lack of effectsassociated with DES such as subacute thrombosis, aneurysmformation, and the like

Pathology of restenosis and targets for prevention

Atherosclerosis is a progressive, inflammatory condition ofthe vessel wall leading to accumulation of lipid and othermaterials causing lesion formation and lumen encroachment(5) Balloon angioplasty fractures these lesions and helps inre-establishing the lumen patency Stents act as scaffoldingand prevent elastic recoil and vascular remodeling (6,7).Although stents are effective in reducing restenosis by elim-inating these two mechanisms, they cause restenosis byneointimal hyperplasia (NIH) Stents are associated with aprolonged, intense inflammatory state with recruitment ofleukocytes, mainly monocytes The initial events immedi-ately after stent placement result in de-endothelializationand the deposition of a layer of platelets and fibrin at theinjured site Activated platelets express adhesion moleculessuch as P-selectin and glycoprotein (GP) Ib␣, which attach tocirculating leukocytes via platelet receptors Under the influ-ence of cytokines, leukocytes bind tightly to adhesionmolecules via direct attachment to platelet receptors such as

17

Role of systemic antirestenotic drugs and

results of current clinical trials

Ron Waksman

GP Ib␣ Cytokines released from smooth muscle cells

(SMCs) and resident leukocytes induce migration of

leuko-cytes across the platelet–fibrin layer and into the tissue

Growth factors are released from platelets, leukocytes, and

SMCs, and influence the proliferation and migration of SMCs

from the media into the denuded intimal area The cell cycle

consists of resting phase, G0, G1, S phase, and M phase

Once stimulated, the cell undergoes these phases and

proliferates The resultant neointima consists of SMCs,

extracellular matrix, and macrophages recruited over several

weeks There is a shift toward fewer cellular elements with

greater production of extracellular matrix followed by

re-endothelialization of at least part of the injured vessel surface

over time The difference between restenosis that occurs as

result of balloon angioplasty and that from stent implantation

is mainly due to a longer duration and a more intense

inflam-matory response with stents Therefore, it is intriguing to

assume that targeting the release of these mediators, the

inhibition of cell cycle, and migration of SMCs would reduce

neointimal proliferation

Studies in the last two decades tested several oral agents

for their efficacy in decreasing restenosis, but only a few of

them reported beneficial effects (8,9) Table 1 lists the drugs

that failed to show consistent benefit in reducing restenosis

Although radiation therapy was successful in reducing in-stent

restenosis, it failed to obtain a single-digit restenosis rate for de

novo lesions, especially when coupled with stents, either as a

platform of the radioactive stent or as a catheter-based system.Nevertheless, the experimental work with vascularbrachytherapy guided the direction for prevention of resteno-sis The work focused primarily on antiproliferative therapyand intervention in the cell cycle Based on the current under-standing of the mechanism of restenosis, the pharmacologicalagents useful to treat restenosis are grouped into five classes:

1 anti-inflammatory and immunomodulators,

2 antiproliferative agents,

3 inhibitors of SMC migration,

4 agents promoting re-endothelialization, and

5 vitamins, antioxidants, and others

Some of these agents have more than one action Forexample, sirolimus is antiproliferative, but also carries anti-inflammatory properties and possesses immunoregulatoryfunctions Similarly, cilastozole has antiplatelet activity, but alsoinhibits SMC migration and directly inhibits intimal prolifera-tion Table 2 lists the drugs that have shown positive results inclinical trials and their mechanisms of action

Anti-inflammatory and immunomodulators

Oral agents in this category include corticosteroids, steroidal inflammatory drugs, statins, and tranilast

non-Corticosteroids

Corticosteroids are potent anti-inflammatory agents, whichalso have immunosuppressive activity Interleukins-1 and -6,secreted by activated macrophages, are powerful stimuli forSMC proliferation and hepatocyte stimulating factors induc-ing the production of acute-phase proteins includingC-reactive protein (CRP) Accordingly, preprocedural highplasma levels of CRP and its persistent elevation of plasmalevels following successful stent implantation have beenfound to predict the risk of restenosis (10,11) In the double-blind, randomized, placebo-controlled Inhibition ofMetalloproteinase in a Randomized Exercise and SymptomsStudy (IMPRESS), Versaci et al (12) tested the effect of oralprednisone on the angiographic restenosis rate after success-ful stent implantation in patients with persistent elevation ofsystemic markers of inflammation after the procedure.Eighty-three patients who underwent successful stentingwith CRP levels ⬎0.5 mg/dL 72 hours after the procedurewere randomized to receive oral prednisone or placebo for

45 days The six-month restenosis rate and late loss werelower in the prednisone-treated patients than in the

placebo-treated patients (7% vs 33%, P⫽ 0.001, and

Antiplatelet and antithrombotic drugs

Aspirin, dipyridamole, ticlopidine Thromboxane A2 receptor antagonists—vapiprost and solutroban

Omega-3 fatty acids Warfarin

Antiallergic drugs

Tranilast Growth factor antagonist

Trapidil ACE inhibotors: cilazapril, fosinopril, enalapril Nitric oxide donors

Molsidomine Antifibrotic drugs

Colchicines Lipid lowering drugs

Lovastatin, fluvastatin, simvastatin Vitamins

Tocopherol Serotonin antagonist

Ketanserin Antianginals

Calcium channel blocker and beta-blockers

Table 1 Oral agents that failed to reduce

restenosis

0.39⫾ 0.6 vs 0.85 ⫾ 0.6 mm, P ⫽ 0.001, respectively).

The IMPRESS-II MVD study comprised 95 patients; 43 of

whom received prednisone, and 52 received placebo At

18- month follow-up, major adverse cardiac events (MACE),

recurrence of angina, and target vessel failure (TVR) were

considerably lower in the prednisone group compared to

placebo (4.7% vs 34.6%, 4.7% vs 25%, and 7% vs 27%,respectively) (13)

Three other randomized, placebo-controlled studies(14–16) investigated the influence of intravenous methyl pred-nisolone before angioplasty with negative results In thesestudies, 1.0 g methyl prednisolone was infused intravenously

Pathology of restenosis and targets for prevention 187

and late loss

angina, and TVR

2 years

Marx et al (44) Significantly lower restenosis (Pioglitazone)

by inhibiting P-selectin release Kimishirado (46) Low restenosis and TLR

steine levels

Group (52)

SMC proliferation

Abbreviations: CDK, cyclin-dependent kinase; CREST, cilostazol for restenosis trial; MACE, major adverse cardiac events; ORAR, oral rapamycin to prevent restenosis; ORBIT, oral rapamune to inhibit restenosis; PPAR, peroxisome proliferator-activated receptor; PRESTO, prevention of restenosis with tranilast and its outcomes; SMC, smooth muscle cell; TLR, target lesion revascularization; tREAT, Tranilast restenosis following angioplasty trials; TVR, target vessel failure.

Table 2 Oral agents to treat coronary restenosis and the trials conducted

2 to 24 hours before planned percutaneous transluminal

coronary angioplasty (PTCA) and stenting In the M-Heart

study, the infused prednisolone was followed by an oral

pred-nisolone of 60 mg daily for one week Angiographic restudy

showed restenosis rates of 36% versus 40%, 40% versus

39%, and 17.5% versus 18.8% (P⫽ NS) compared to

placebo, in these studies, respectively It is not surprising that

these trials failed to show any benefit because restenosis is a

slow and chronic inflammatory process and a single pulse dose

of methyl prednisolone would not provide a durable effect

Nonsteroidal anti-inflammatory

agents

The proposed mechanism of action of nonsteroidal

anti-inflammatory agents (NSAIDs) includes inhibition of

prostaglandin synthesis in inflammatory cells, thus blocking

monocyte adhesion, cell differentiation, proliferation, and

angiogenesis (17) Although theoretically it is appealing to

consider NSAIDs that reduce restenosis by interfering with

the release of inflammatory substances, thus impairing

migra-tion of monocytes, data from animal experiments did not

translate into clinical reality Ebselen, a selenium-containing

NSAID with additional antioxidant properties, was tested in

80 patients undergoing PTCA and was shown to be

associ-ated with lower restenosis compared to placebo (18.6% vs

38.2%, P⬍ 0.05) (9) Experimental data in animals,

however, showed sulindac to be beneficial in reducing

steno-sis, but aspirin failed to show any benefit This could be due

to the inability of aspirin to inhibit cyclooxygenase (COX)-2

Further, sulindac has additional actions independent of COX

activity such as inhibition of proliferation, induction of

apopto-sis, inhibition of peroxisome proliferator-activated receptor

(PPAR)-␦, and increased formation of intracellular ceramide

leading to the induction of apoptosis These mechanisms

have been postulated for other NSAIDs such as aspirin and

for the new specific COX-2 inhibitors, as well The main

reasons NSAIDs are not tested in clinical trials are because of

toxicity issues and that very high doses are required to

achieve these effects in vivo

Statins

Clinical efficacy of anti-inflammatory properties has been

shown in several trials independent of their lipid-lowering

effects (18,19) Statins reduce CRP levels and it is known that

elevated CRP levels are associated with restenosis Counter

intuitively, however, several trials tested statins for restenosis

prevention and were disappointing (20–23) The only trial

that showed reduction in restenosis was the REGRESS trial

(24), which used pravastatin 40 mg once daily for a period of

two years In this study, the binary restenosis assessed at two

years was significantly lower in the pravastatin group asopposed to other trials, which assessed restenosis within sixmonths Importantly, stents were not used in this trial andpositive remodeling at the end of two years may havecontributed to better results Overall, the role of statins toprevent restenosis remains unproven

Antiproliferative drugs

Two different strategies to control neointimal proliferationafter vascular injury are proposed First is the cytostaticapproach, which aims to control the regulation and expres-sion of cell cycle-modulating proteins at any level along thepathway—modulating cell proliferation Second, the cyto-toxic approach—killing proliferating cells—has thedisadvantage of induction of necrosis, which may contribute

to vessel wall weakening Among the antiproliferative agentsproposed for this application are sirolimus and its analogeverolimus and a variety of antineoplastic drugs such as actin-omycin D, vincristine, doxorubicin, vinblastine, and the like

Sirolimus binds to an intracellular receptor protein andelevates p27 levels, which leads to inhibition of cyclin-dependent kinase (CDK) complexes, and ultimately inducescell-cycle arrest in the late G1 phase It inhibits proliferation ofboth rat and human SMCs in vitro and reduces intimal thick-ening in models of vascular injury (29,30) Sirolimus inhibits

T lymphocyte activation and proliferation, which occurs in

response to antigenic and cytokine stimulation; however, its

mechanism is distinct from that of other

immunosuppres-sants Sirolimus also inhibits antibody production In cells,

sirolimus binds to the immunophilin, FK binding protein-12

(FKBP-12), to generate an immunosuppressive complex This

complex binds to and inhibits the activation of the mammalian

target of rapamycin (mTOR), a key regulatory kinase This

inhibition suppresses cytokine-driven T-cell proliferation,

inhibiting the phase progression of the cell cycle (30,31) The

Oral Rapamune to Inhibit Restenosis (ORBIT) study was an

open-label study of 60 patients with de novo lesions treated

with bare metal stents in up to two vessels After a loading

dose of 5 mg, patients received a daily dose of 2 mg (n⫽ 30)

and 5 mg (n⫽ 30) for 30 days At six months’ follow-up, late

loss (0.6⫾ 0.5 mm vs 0.7 ⫾ 0.5 mm; P ⫽ NS), in-stent

binary restenosis (7.1% vs 6.9%; P⫽ NS), in-stent percent

volume obstruction by intravascular ultrasound (IVUS) (29%

vs 24%; P⫽ NS), and clinically driven target lesion

revascu-larization (TLR) (14.3% vs 6.9%; P⫽ NS) were similar in

2-and 5 mg groups (32)

Brito et al., in a pilot study, tested the hypothesis that oral

sirolimus is safe and effective to inhibit in-stent NIH and,

therefore, effective to prevent and treat ISR Twelve patients

(18 lesions) with high risk for ISR, including eight ISR lesions,

were incorporated One day before the procedure, patients

were given a 15 mg loading dose of oral sirolimus, followed

by 5 mg daily for 28 days, with weekly whole blood level

measurements The four- and eight-month follow-up

revealed an angiographic late loss of 0.40⫾ 0.24 and

0.67⫾ 0.45 mm (P ⬍ 0.01), respectively At 24-month

clin-ical follow-up, adverse events were one death (8.3%), two

TLR (11.1%), and four TVR (22.2%) (33)

Oral rapamycin is absorbed rapidly and concentrations peak

within one hour in the blood A loading dose of three times

the maintenance dose will achieve steady-state concentrations

within 24 hours in most patients The drug is metabolized by

cytochrome p450 system and is well tolerated In a pilot study,

Rodriguez et al (34) reported the results of the Oral

Rapamycin to Prevent Restenosis (ORAR) trial in which 34

patients undergoing coronary stent therapy were treated with

oral rapamycin (6 mg loading dose, followed by 2 mg daily) for

one month after stent implantation for de novo and restenotic

lesions At six months, angiography showed a restenosis rate

of 18.9% in de novo lesions and 50% in in-stent restenotic

lesions Interestingly, it was found that restenosis was 0% in

patients with rapamycin levels ⬎8 ␩g/mL In ORAR I,

Rodriguez et al studied 76 patients with 103 de novo lesions

treated percutaneously with bare stents who received a

load-ing dose of oral rapamycin 6 mg followed by a daily dose of

2 mg during 28 days in phase I (49 arteries in 34 patients) and

2 mg/day of oral rapamycin plus 180 mg/day of diltiazem in

phase II (54 arteries in 42 patients) In-stent restenosis in phase

I was 19% compared with 6.2% in phase II (P⫽ 0.06)

Angiographic ISR in lesions of patients with rapamycin blood

concentrations ⱖ8␩g/mL was 6.2% and with rapamycinconcentrations ⬍8 ng/mL was 22% (P ⫽ 0.041) Late loss

was also significantly lower when rapamycin concentrationswere ⱖ8 ng/mL (0.6 mm vs 1.1 mm, P ⫽ 0.031) A

Pearson’s test showed a linear correlation between follow-up

late loss and rapamycin blood concentration (r⫽⫺0.826,

P⫽ 0.008) (35)

In ORAR II, 100 patients were randomized to either oralrapamycin (6-mg loading dose given 2.7 hour before inter-vention followed by 3 mg/day for 14 days) plus diltiazem

180 mg/day or no therapy after the implantation of a coronarybare metal stent design At nine months, the in-segmentbinary restenosis was reduced by 72% (11.6% rapamycin vs

42.8% no-therapy group, P⫽ 0.001) and the in-stent binaryrestenosis was reduced by 65% (12% rapamycin vs 34.6%

no-therapy group, P⫽ 0.009) The in-segment late loss wasalso significantly reduced with oral therapy (0.66 vs 1.13 mm,

respectively; 43% reduction, P⬍ 0.001) At one year,patients in the oral rapamycin group also showed a significantlylower incidence of target vessel revascularization (TVR) (8.3%

rosiglita-Pathology of restenosis and targets for prevention 189

In their study, Choi et al conducted a prospective,

randomized, case-controlled trial involving 95 diabetic

patients with CAD who were randomly assigned to either the

control or rosiglitazone group (48 and 47 patients,

respec-tively) Eighty-three patients (45 patients with 55 lesions in the

control group, and 38 patients with 51 lesions in the

rosiglita-zone group) completed follow-up angiography The rate of

in-stent restenosis was significantly reduced in the

rosiglita-zone group compared with the control group (for stent

lesions: 17.6% vs 38.2%, P⫽ 0.030) The rosiglitazone

group had a significantly lower degree of diameter stenosis

(23.0%⫾ 23.4% vs 40.9% ⫾ 31.9%, P ⫽ 0.004)

compared with the control group (43)

In a randomized, placebo-controlled, double-blind trial,

Marx et al examined the effect of six-month pioglitazone

therapy on neointima volume after coronary stenting in

nondiabetic CAD patients Fifty nondiabetic patients after

coronary stent implantation were randomly assigned to

pioglitazone (30 mg daily; pio) or placebo (control) treatment

in addition to standard therapy and neointima volume was

assessed by IVUS at the six-month follow-up Pio treatment

significantly reduced neointima volume within the stented

segment, with 2.3⫾ 1.1 mm3/mm in the pio group versus

3.1⫾ 1.6 mm3/mm in controls (P⫽ 0.04) Total plaque

volume (adventitia–lumen area) was significantly lower at

follow-up in the pio group (11.2⫾ 3.2 mm3/mm) compared

with controls (13.2⫾ 4.2 mm3/mm; P⫽ 0.04) Moreover,

the binary restenosis rate was 3.4% in the pio group versus

32.3% in controls (P⬍ 0.01) (44)

Inhibitors of SMC migration

Cilostazole

As previously mentioned, for SMC proliferation after

coro-nary angioplasty, cell activation and cell-to-cell interaction of

platelets and leukocytes mediated by adhesion molecules are

considered to be important Coronary stenting produces the

release of an adhesion molecule, P-selectin, from α′-granule

of activated platelets P-selectin-mediated platelet–leukocyte

interaction has a crucial role in the development of stent

restenosis Cilostazol is an antiplatelet, antithrombotic,

phos-phodiesterase III inhibitor that by inhibiting P-selectin release

has inhibitory effects on SMC migration In addition, cilostazol

may directly act to inhibit intimal hyperplasia

Randomized trials conducted with cilostazol 200 mg daily

have shown that it is effective in reducing restenosis (45–47)

Douglas et al undertook the Cilostazol for Restenosis Trial

(CREST), a randomized, double-blind, placebo-controlled

trial to determine whether cilostazol would reduce

re-narrowing in patients after stent implantation in native

coronary arteries Seven hundred and five patients who had

successful coronary stent implantation received, in addition to

aspirin, cilostazol 100 mg BID or placebo for six months;clopidogrel 75 mg daily was administered to all patients for 30days Restenosis was determined by quantitative coronaryangiography at six months Restenosis, defined as ⱖ50%narrowing, occurred in 22.0% of patients in the cilostazol

group and in 34.5% of the placebo group (P⫽ 0.002), a36% relative risk reduction was observed Restenosis wassignificantly lower in cilostazol-treated diabetics (17.7% vs

37.7%, P⫽ 0.01) and in those with small vessels (23.6% vs

Vitamins, antioxidants, and other agents

Other drugs have claimed to potentially enhance healing andminimize the neointimal formation by various mechanisms.These include antioxidants with vitamins (51), probucol(52–54), antipruritic agent pemirolast (55), serotonin antago-nist sarproglate (56), and angiotensin I receptor antagonistvalsartan (57) Although individual trials failed to show anybenefit, meta analysis of calcium channel blockers (58) andbeta blockers (59) showed reduction in angiographic and clin-ical restenosis Bestehorn et al investigated the effect of oralverapamil on clinical outcome and angiographic restenosisafter percutaneous coronary intervention (PCI) Thisrandomized, double-blind trial included 700 consecutivepatients with successful PCI of a native coronary artery.Patients received the calcium channel blocker verapamil,

240 mg twice daily for six months, or placebo Late lumen loss was 0.74⫾ 0.70 mm with verapamil and0.81⫾ 0.75 mm with placebo (P ⫽ 0.11) Compared

with placebo, verapamil reduced the rate of restenosisⱖ75% [7.8% vs 13.7%; RR 0.57 (95% CI 0.35–0.92);

P⫽ 0.014] (60)

Limitations of studies with

oral agents

Table 3 summarizes the studies conducted with different oral

agents and their restenosis rates The majority of these trials

included a small number of patients, and some failed to

reproduce the same result on larger-scale trials The reasons

for failure of these trials include:

1 The long time span from balloon angioplasty to the stent

era As we previously alluded, the restenosis nisms are different between angioplasty and stenting

mecha-2 Many of the trials involved a small number of patients,many times of ⬍100 The results, therefore, were notreproducible in larger, multicenter trials such as thePRESTO trial

3 The drug dosages needed to achieve sufficient levels toinhibit restenosis are higher than therapeutic doses ortolerable doses

4 Bioavailability of the oral drugs depends on multiple factors including drug metabolism and druginteraction

5 Our understanding of the pathological mechanisms

of restenosis is constantly evolving and the targets oftherapy are changing

Limitations of studies with oral agents 191

8.9 (DCA only)

In view of the DES limitations, there is a definite role for

systemic therapy for restenosis The focus of research

involv-ing oral agents for the treatment of restenosis is changinvolv-ing

While previous trials focused on antiplatelets, anticoagulants,

lipid lowering, and concomitant potential of antianginals like

calcium channel blockers and beta-blockers, newer trials are

targeting inflammation, smooth muscle proliferation, and

inhi-bition of cell proliferation Oral agents may potentially have a

great impact on the practical application for the treatment of

restenosis The analogy of clopidogrel therapy compared to

heparin-coated stents in preventing subacute thrombosis

supports this contention At the present time, however, we

do not have the answer as to what the ideal agents of choice

are, the loading dose, maintenance dose and duration of

therapy From the available experience with oral agents,

currently we surmise that a high loading dose of an

antiprolif-erative drug followed by a tolerable maintenance dose for a

short duration will suffice Nevertheless, the dissemination

and durability of DES—and their effects now proven to four

years—have slowed enthusiasm for intensive research to

explore a systemic or oral agent to compete with DES Late

thrombosis and the high cost of DES, however, will

eventu-ally initiate continued research for new compounds to be

tested as potential substitutions for DES

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Since the introduction of coronary angioplasty, restenosis

of the target lesion has been the main limitation of this

procedure

Acute vessel recoil, chronic remodeling, and intimal

hyper-plasia were the mechanisms involved in this process (1–4)

However, after the introduction of stents in the daily

prac-tice during interventional procedures, intimal hyperplasia

became the mechanism associated in the pathophysiology of

in-stent restenosis (5–9) Therefore, its prevention should

be related with therapies that inhibit smooth muscle cell

proliferation

In recent years, drug-eluting stents (DES) (Sirolimus,

Johnson & Johnson and Paclitaxel, Boston Scientific) have been

associated with significant reduction of in-stent restenosis

among patients undergoing percutaneous coronary

interven-tions (PCI) in de novo lesions (10–17) Despite the fact that all

these devices have shown that the stent polymeric coating is a

good solution for storing drug and defining a release

mecha-nism, several publications have raised concerns about

long-term safety issues such as potential risk for late-stent

thrombosis or inducing chronic inflammation in the coronary

artery (18–22) The issue of late-stent thrombosis with DES is

clearly not going away; it is possible due to the polymer or the

delayed re-endothelialization consequent to long-term drug

release Long-term (indefinitely) dual antiplatelet therapy may

be the answer; however, such medication reduces cost

effi-cacy and may not cover the times when general surgical

procedures are needed; it is likely that the patients will have an

antiplatelet-dependent life If systemic antirestenosis agents

proved efficacious, and, therefore, antiplatelet needed, could

be reduced to the bare metal stent in a one-month period

Animal data suggest that the degree of neointimal

prolifer-ation formed after stent implantprolifer-ation is mediated by smooth

muscle cell proliferation and occurs during the first two weeks

after the initial vascular injury (24) The relative success ofnonpolymeric based drug-delivery stents using short-timerelease of medications support the concept that sustainedrelease of antiproliferative agents may not be necessary tomaintain a biological effect (25) Several preclinical studieshave demonstrated the ability of systemically administeredsirolimus or its analogs in reducing smooth muscle cell prolif-eration occurring after vascular injury (24,26–28) Systemicuse of rapamycin and its analog was associated, in animaldata, with a significant reduction in intimal hyperplasia, butonly recently, clinical studies were reported with oraladministration (29–34)

Anti-inflammatory drugs in the treatment of restenosis

In the past, several clinical studies with corticosteroids failed

to demonstrate a significant reduction in coronary restenosisafter percutaneous transluminal coronary angioplasty (35,36).However, as we mentioned previously, after balloon angio-plasty, there were other mechanisms involved in thepathophysiology of coronary restenosis (such as acute wallrecoil or chronic remodeling) that explained the negativeresults of those studies (35,36)

In contrast, in the current stent era, experimental studies indicated that a marked activation of inflammatory cells at the site of stent struts play a key role in the process of neo-intimal proliferation and restenosis (37–40) Indeed,interleukins 1 and 6 secreted by activated macrophages arepowerful stimuli for smooth muscle cell proliferation andrestenosis (41,42)

These were the rationalities for the use of corticosteroids

in clinical data in the prevention of restenosis (43)

18

Role of systemic antineoplasic drugs in the

treatment of restenosis after percutaneous

stent implantation

Alfredo E Rodriguez

Inhibition metalloproteinase

randomized exercise and

symptoms study I and II

In recent years, two multicenter experiments were conducted

with oral prednisone therapy in patients undergoing coronary

bare-metal stent implantation (44,45)

The randomized IMPRESS I study included nondiabetic

patients with single discrete de novo stenosis in patients

with C-reactive protein (CRP), elevated during 72 hours after

PCI Prednisone was given orally during 30 days after stent

deployment

The major findings of this study showed that patients

treated with oral prednisone had a significant lower major

adverse cardiac and cerebrovascular event (MACCE)

(P ⫽ 0.0063), any target vessel revascularization (P ⫽ 0.001),

and binary restenosis (P⫽ 0.001) than those allocated in the

placebo group Twelve-month event-free survival rates were

93% and 65% in patients treated with prednisone and

placebo, respectively (relative risk 0.18, 95% confidence

intervals 0.05–0.61)

The rate of six-month restenosis was 7% versus 33% and

late loss was 0.39 versus 0.85 mm (P⫽ 0.001); both were

significantly lower in oral prednisone-treated patients than in

placebo-treated patients

The following experience was reported for the same group

of investigators: In IMPRESS II, they included a

nonrandom-ized multi-vessel and multi-stent cohort of patients treated

with oral prednisone As the previous one, only patients with

elevated CRP levels 48 hours after the PCI procedure were

included In this study, they compared with similar

cohort-matched populations

Major findings of IMPRESS II were a significant reduction

of target vessel revascularization, MACCE, and

rest-enosis Event-free survival at 12 months was 93% in

prednisone-treated patients versus 69.8% in control

(P⫽ 0.006)

Both studies showed an angiographic amount of late lossaround 0.61 mm Clinical and angiographic outcome of thesetwo studies are described in Table 1

These two experiences had a potential limitation, such as ahighly selected population (nondiabetics), reference vesselsize greater than 2.8 mm and results only applied in patientswith persistently high CRP levels

However, the favorable clinical and angiographic outcomedemonstrated with both studies, taking into account that bothwere independent, non–industry-sponsored studies, offerspromising results that may be an interesting alternative

to more expensive therapies, such as DES therapy, andneeds larger controlled evaluation in more complex subsets

of patients

Systemic immunosuppressive therapies in the treatment

of restenosis: sirolimus and sirolimus analogs in

experimental and clinical data

A number of animal data supported the use of systemicimmunosuppressive therapies in reducing smooth muscle cellgrowth, the mediator of neointimal proliferation (26,37,38).Preclinical studies have demonstrated a significant reduction

of neointimal proliferation after balloon injury in the porcine

or rabbits model of restenosis, with the systemic use ofrapamycin (26)

Gallo et al (26) was the first who reported animal datashowing a significant reduction of neointimal hyperplasia withthe venous infusion of rapamycin

More recently, with sirolimus analogs such as everolimus

or with the use of nanoparticles of paclitaxel, a significant

Abbreviations : MACCE, major adverse cardiac and cerebrovascular events; TVR, target vessel revascularization.

Table 1 Clinical and angiographic follow-up of inhibition of metalloproteinase in a randomized exercise

symptoms study I and study II

reduction of neointimal hyperplasia in animal data is also

shown (24,46)

However, systemic therapy with clinical data was related

only with the use of oral rapamycin

Rapamycin (Rapamune, Wyeth-Ayerst Laboratories) is a

natural macrocyclic lactone with a potent immunosuppressive

and antiproliferative effect that was approved by the Food and

Drug Administration for the prophylaxis against renal

trans-plant rejection

The anti-inflammatory and antiproliferative effects of

rapamycin were based on its ability to inhibit the target of

rapamycin kinase, an essential component in the pathways

of the cell cycle progression (20–24,26–28)

Several nonrandomized pilot studies in de novo lesions

have been reported in recent years with the systemic use of

rapamycin

Clinical and angiographic results of the most important of

these studies are described in Table 2 As we can see in the

table, although there were some differences in the design of

these studies, there were correlative findings from those

trials, in terms of angiographic follow-up results and safety

long-term outcome data

First, there was a consistent benefit in clinical and

angio-graphic binary restenosis data As we can see in Table 2,

in-stent restenosis of the two pilot studies, which comprised

only de novo lesions, angiographic restenosis was in only a

single digit of restenosis, with a late loss of around 0.6 mm All

these numbers represent, compared to the average restenosis

rate of control arm from the more recent DES trials, a

reduc-tion of 81% of in-stent restenosis and a 42% reducreduc-tion of late

loss, and also represent a reduction of 90% of MACCE

We can obtain several lessons from these pilot trials

(30–34,47) First, the angiographic in-stent binary restenosis

was lower than 10% The ORBIT trial had 7% of in-stent

binary restenosis and 0.60 mm of late loss

This study also shows that a high maintenance dose did notimprove angiographic follow-up results and in contrast wasassociated with higher side effects

With 2 mg/day, ORBIT investigators (33) found 40% ofminor and moderate side effects, compared with 66% with

5 mg/day for 30 days

A small pilot trial from Brazil reporting 6.6% of in-stentrestenosis with 0.61 mm of late loss and with no target lesionrevascularization or any major events after two years offollow-up (47) also confirmed these positive results

Second, side effects were minor or moderate in almost allstudies and were reported among 30% to 80%, according tothe maintenance doses used in the studies At the presenttime, it is clear that one should not give a patient more than

2 or 3 mg/day as maintenance dose for more than 14 days(33) With high maintenance doses, similar final angiographicresults were obtained but with poor tolerance, as wementioned earlier in the ORBIT trial

In patients with in-stent restenosis, the first pilot trialreported negative results in a small population of inpatientspresenting restenosis after brachiterapy failure; however, ofnote, in this population, even with DES therapy, they also hadnegative results, some of them, such as those reported by theThorax Center, with high incidence of restenosis and stentthrombosis (29,48)

The only randomized controlled data in this in-stentrestenotic population were reported by the German group,the OSIRIS trial, which showed a significant reduction of clini-

cal and angiographic parameters of restenosis (P⫽ 0.005)using a loading dose of oral rapamycin of 12 mg started 48hours before the PCI procedure, followed by 2 mg/day forseven days thereafter (32) Angiographic restenosis as needed for target lesion revascularization was reduced by 50% and 40%, respectively, with the use of oral sirolimus therapy (Table 2)

Anti-inflammatory drugs in the treatment of restenosis 197

Oral rapamycin in de novo

lesions: lessons learned from

ORAR studies

Oral rapamycin to prevent

restenosis I pilot trial

From December 2001 through February 2003, 76 patients

with a clinical indication of PCI for a de novo lesion were

included in this protocol The procedures were performed in

the cardiac Catheterization Laboratories at Otamendi

Hospital in Buenos Aires, Argentina (30,34)

Among these 76 patients, 109 bare-coronary stents were

deployed in 103 de novo lesions in an equal number of major

native epicardial vessels Patients with in-stent restenosis,

bifurcation lesions, vein graft lesions, lesion length of

⬎0.20 mm, acute myocardial infarction in the previous 72

hours, poor left ventricular function (ejection fraction ⬍35%),

renal failure defined as creatinine concentration of ⬎2 mg, or

under immunosuppressive treatment were excluded from

the study

In Phase I, rapamycin was given orally as a loading dose of

6 mg followed by a daily dose of 2 mg/day for 28 days,

start-ing immediately after a successful stent deployment

In Phase II, a daily dose of 180 mg of diltiazem was

added—the diltiazem used together with oral rapamycin in

renal transplant patients has been associated with high

thera-peutic blood concentration of rapamycin and lower side

effects (11,12) (In Figure 1 we can see the study design and

patient inclusion of both phases of this pilot study.)

It has been shown that coadministration of a single dose

of diltiazem with rapamycin leads to higher rapamycin sure The mean whole blood rapamycin area under theplasma concentration in time curve increased by 60% andthe maximum concentration increased by 43%.Coadministration also decreased the renal clearance ofrapamycin, presumably by inhibiting the first-pass metabolism

expo-of rapamycin (12)

Rapamycin blood concentrations were measured in allpatients In Phase I, rapamycin blood concentration wasmeasured in all patients after the third week of treatment.However, as the immunosuppressive effect of the drug wasachieved during the first four days, in Phase II study, bloodconcentration of the drug was measured during the firstweek (7)

A lipid profile (cholesterol, high-density lipoprotein, density lipoprotein, and triglycerides) and complete bloodcount were determined before and after four weeks of treat-ment for all patients

low-Results

Table 3 presents the baseline demographic, clinical, andangiographic characteristics of the patients Mean age was 63years More than 60% of patients presented with unstableangina: 20% were diabetic, 23% had a previous AMI, andmore than 80% had class B or C lesions according to theAmerican College of Cardiology/American Heart Associationclassification

ORAR Pilot Trial

Phase I

34 pts / 49 de novo Arteries

6 mg bolus Rapamycin immediately after procedure

Oral Rapamycin 2 mg

Diltiazem 180 mg/day during 28 day

6 mg bolus Rapamycin immediately after procedure

In Phase II, after the first week of treatment, five patients

who did not reach a sufficient blood concentration of the drug

received an additional 1 mg of oral rapamycin (3 mg daily) plus

diltiazem

Hospital and 30-day results

All stents were deployed successfully One patient, who

developed subacute artery closure a few hours after the

procedure, presented the only adverse event during

hospital-ization During the first month, 19 patients (25%) had minor

side effects, six patients in Phase I (18%) and 13 in Phase II

(31%) Only three discontinued the medication (3.9%), one

in Phase I and two in Phase II The most frequent side effects

were diarrhea (7.8%) and skin rash (9.2%)

There were no changes in white cell count or cholesterol

concentration relative to baseline, whereas triglyceride

concentrations tended to be higher than atbaseline

(P⫽ 0.09) Rapamycin blood concentration was significantly

higher in Phase II than in Phase I (9.3 vs 6.2 ng/mL,

in Phase II

During the one year of follow-up including in-hospitalevents, MACCE occurred in 15 of 76 of patients (20%):13target-vessel revascularization, one repeat PCI and stenting in

a nontarget vessel, and one myocardial infarction (this patientalso had an emergency PCI after the initial procedure).Angiographic binary restenosis in the follow-up angiogramwas found in 15% (13 of 85) In-segment restenosis was

22% in Phase I versus 10% in Phase II (P⫽ 0.221), whereas

a trend to a lower in-stent restenosis in Phase II compared to

Phase I (6.2% vs.19%, P⫽ 0.066) was found

In Table 4, we can see quantitative coronary angiographydata of the 85 lesions with follow-up angiography Atfollow-up, the minimum luminal diameter (MLD) of lesions inpatients with a high rapamycin blood concentration was

Oral rapamycin in de novo lesions: lessons learned from ORAR studies 199

Source: From Ref 34.

Table 3 Baseline, clinical, and angiographic characteristics

significantly larger than in those with lower concentrations

of the drug The analysis of late loss and net gain with

rapamycin concentrations also showed a significant difference

in favor of lesions of patients with high rapamycin

concentra-tions (Table 4) Angiographic binary in-stent restenosis was

also significantly lower in the group with rapamycin high

concentrations: (6.2% vs 22%, P⫽ 0.041) As we can see in

Figure 2, Pearson’s test showed a linear correlation between

the late loss at the follow-up and rapamycin blood

concentra-tion (r ⫽ 20.826, P ⫽ 0.008) during the first week of

treatment Multivariate logistic regression analysis

identi-fied that reference vessel size (⫺2.206, P ⫽ 0.008) and

rapamycin blood concentration (⫺0.243, P ⬍ 0.036) were

the only independent predictors of angiographic restenosis atfollow-up

Constructing a receiver operating characteristic (ROC)curve, which is a quantitative analysis, it showed that arapamycin blood concentration of ⬎8 ng/mL was the propercutoff to define high blood concentration of the drug, and that

it was in agreement with the mean rapamycin blood tration in patients having no restenosis (7.9 ng/mL)

concen-In conclusion, early high concentration of sirolimus in eral blood samples was strongly associated with low late lossand an optimal angiographic follow up results

periph-Rapamycin blood concentration

Data are mean (SD) or percentage.

Abbreviation: MLD, minimum luminal diameter.

Source: From Ref 34.

Table 4 Baseline and follow-up quantitative coronary angiography data

18 16 14 12 10 8 6

Oral rapamycin to prevent

restenosis II randomized trial

Patient population and study design

After the end of the pilot Phase I and II studies, we moved

forward to a randomized trial Thus, from September 2003

to September 2004, 100 patients with severe stenosis in de

novo coronary artery were enrolled and included in the

ORAR II randomized protocol (49)

Inclusion criteria were similar to our previous pilot study

(34) Patients with clinical indication of percutaneous coronary

revascularization were randomized if they had a de novo

severe stenosis in a native coronary artery, a lesion suitable

for stent, and a reference vessel size between 2.5 and 4.0 by

visual estimation, and were a candidate for coronary bypass

surgery All the PCI procedures were performed at the

Catheterization Laboratories at Otamendi Hospital and

Sanatorio Las Lomas in Buenos Aires, Argentina

Patients were excluded if they had acute myocardial

infarction 48 hours prior to randomization, rapamycin allergy,

clopidogrel, or aspirin intolerance, significant bleeding in the

last six months, stroke or transient ischemic attack in the last

12 months, severe concomitant illness, recent major

bleed-ing requirbleed-ing transfusion, major blood dyscrasias, participation

in another trial that does not allow a follow-up angiogram,

patients with dyslipidemia of difficult treatment, patients

with thrombocitopenic disease, patients with chronic total

occlusion or in-stent restenosis lesions, and patients not

amenable to sign the inform consent allowed to a follow-up

angiogram In contrast with the previous ORAR pilot, now,

lesion length was not an exclusion criterion and multiple

stents in the same vessel as well as overlapping stent were

allowed

The protocol of this nonindustry sponsor study was

approved by the Ethics Committee of the Argentine Society

of Cardiac Angiography and Interventions and by the

Argentina National Regulatory Agency for Drug, Food, and

Medical Technology (ANMAT) During the study, an

Independent Safety Monitoring Committee adjudicated the

clinical adverse events

All eligible patients were randomized to control or oral

rapamycin group In the oral rapamycin arm, we modified the

therapeutic scheme in relation to our previous pilot studies;

patients in ORAR II received a loading dose of 6 mg, at least

two hours before stent implantation, followed by 3 mg/day

for a total of 14 days Diltiazem sustained release 180 mg/day

was added to a sirolimus regimen in order to achieve a higher

sirolimus blood concentration (21) Blood samples were

drawn to measure sirolimus blood levels and were taken at

seven days after the oral loading dose of sirolimus, according

to the second phase of our ORAR pilot trial In addition,

serum creatine, cholesterol, triglycerides, red and white

blood cells, and platelet counts were measured before and at

the end of sirolimus treatment Coronary angiography wasscheduled between six to nine months after the initial PCIprocedure

PCI was performed using standard techniques (6,30) All

100 patients received one or more identical close cell-stentdesign The same stent design was used in order to avoidpotential bias with stent selection in both groups All patientsreceived 325 mg/day of aspirin indefinitely and clopidogrel as

a loading dose of 300 mg on the day of the procedure and

75 mg/day thereafter for one month Statins were given to allpatients indefinitely

The primary endpoint of the study was to compare theangiographic binary restenosis rate and late loss determined by

an independent core laboratory blinded to treatment tion Angiographic binary restenosis was defined as ⬎50%residual stenosis in the target lesion in the follow-up angiogra-phy In patients with multilesions, lesions were countedseparately Secondary endpoints were target lesion, targetvessel revascularization, target vessel failure, and majoradverse cardiovascular events Target lesion and target vesselrevascularization were performed in the presence of angio-graphic restenosis, and symptoms and signs of myocardialischemia A major adverse cardiovascular event was defined asdeath, myocardial infarction, stroke, and target vessel revascu-larization at one year of follow-up Target vessel failure wasdefined as death, nonfatal myocardial infarction, and targetvessel revascularization, during the entire follow-up period

alloca-Results

Between September 2003 and September 2004, 100patients were randomized, 50 patients in control (55 arteriesand 59 lesions) and 50 patients in oral sirolimus arm (60arteries and 66 lesions) A total of 132 stents were deployed,

61 in control and 71 in oral sirolimus; small-stent sizes(2.5 mm) were deployed in 44.7% of the lesions

Baseline demographic, clinical, and angiographic istics between both groups are described in Table 5; treatingdiabetes was more frequent in oral sirolimus group

character-(P⫽ 0.056) Hospital and 30 days outcome in both groupswas similar During the course of treatment with oralsirolimus, 26% of the patients had side effects; however,none of them were major The most frequent side effect wasmouth ulceration (16%) Only two patients (3.9%) discon-tinued the treatment, three and eight days, respectively,after the first course of the doses Overall adverse sideeffects of ORAR I and II, ORBIT, and OSIRIS are described inTable 6

After rapamycin treatment, during the first 30 days, whiteblood counts showed a significant transient change; however, as

we found previously in the ORAR pilot trial, severe leukopeniawas not seen in any case

Oral rapamycin in de novo lesions: lessons learned from Argentina ORAR studies 201

Characteristics Oral sirolimus ⫹ Control group P value

a ACC denotes American College of Cardiology and AHA American Heart Association

Note: BMS, Standard Stent.

Abbreviations: BMS, bare metal stent; LAD, left anterior descending artery; LCX, left circumflex coronary artery; LM, left main; MVD, multiple vessel disease; RCA, right coronary artery.

Source: From Ref 49.

Table 5 Baseline demographic, clinical, and angiographic characteristics

Hospital and follow-up results of ORAR II randomized are

described in Table 7 One-year clinical follow-up was obtained

in all patients in both groups After hospital discharge during

the follow-up, there were two deaths (4%) in the control

group (both cardiac), while two patients in oral sirolimus (4%)

died during follow-up (one due to colon cancer and the other

after an elective coronary bypass surgery) After hospital

discharge, there was no documented nonfatal myocardial

infarction or stroke in both the groups

The rate of clinically driven target lesion or target vessel

revascularization was significantly lower in oral sirolimus

compared with control (Table 7) Target vessel

revasculariza-tion was 5/60 (8.3%) versus 21/55 (38%), respectively

(P⬍ 0.001), and the target lesion revascularization was 5/66

(7.6%) versus 22/59 (37.2%), respectively (P⬍ 0.001)

Target vessel failure and major adverse cardiovascular events

were also improved with oral sirolimus therapy (P⫽ 0.01

and P⫽ 0.031, respectively, Table 7)

Figure 3 shows the survival curves of freedom from targetvessel revascularization (Fig 3A) and freedom from majoradverse cardiovascular events (Fig 3A) showing significantlybetter outcome in those patients treated with oral sirolimus,that is, the numbers represent an 80% reduction of targetvessel revascularization and 55% reduction of major adversecardiovascular events compared to the control group.Baseline and follow-up angiographic data are shown in Table 8 Clinically driven or per-protocol follow-up angiography

at nine months was completed in 87% of the population (87patients and 99 vessels) At 9 months, the binary in-stentrestenosis rate per vessel was 12% for the rapamycin group

and 34.6% for the control group (P⫽ 0.015) The in-segmentanalysis showed a restenosis rate of 12% and 42.8% for the

rapamycin and control group, respectively (P⫽ 0.001) Asshown in Figure 4, the use of oral rapamycin reduced the risk

of binary restenosis by 65% within the stent and by 72% in theanalysis segment With the earlier mentioned numbers, the

Oral rapamycin in de novo lesions: lessons learned from Argentina ORAR studies 203

a Only severe side effects.

Table 6 Side effects and drug discontinuation

BMS group (n ⫽50) In-Hospital events (%)

Any major adverse cardiac

Abbreviation: BMS, bare metal stent,

Source: From Ref 49.

Table 7 Hospital and follow-up results of ORAR II

power of our study to detect differences between groups for

restenosis was 0.81 per patient and 0.94 per vessel The

in-stent restenosis pattern in five patients in the oral rapamycin

group who developed restenosis, was diffuse, but not

prolifer-ative or with total occlusion The degree of restenosis in the

control group showed that from 23 lesions with restenosis, a

significant restenosis was present in 87%, including patients

with proliferative or total closure Thus, this finding explains the

high rate of conversion to target lesion revascularization (TLR)

in control group With the oral therapy, in-stent late loss was

reduced from 1.41 mm in control versus 0.73 mm in oralrapamycin group, and in-segment from 1.13 mm in controlversus 0.66 mm in oral rapamycin group, meaning a reduction

of 48% and 43% in-stent and in-segment late loss, respectively.Multivariate analysis, (Table 9) showed that randomization tocontrol group was the only independent predictor of restenosis(odds ratio OR 6.01; 95% Confidence Interval: 2.19–16.46)

P⬍ 0.0001 As we see in Table 8, compared with the controlgroup, patients who received oral rapamycin had a significantlysmaller amount of late loss [0.66 mm in the sirolimus group vs

100 Target Vessel Revascularization

Sirolimus Group 91.4%

Months after randomization

Major Adverse Cardiovascular Events

Oral rapamycin in de novo lesions: lessons learned from Argentina oral rapamycin 205

BMS group (n ⫽50) Diameter of reference

Abbreviation: BMS, bare metal stent.

Source: From Ref 49.

Table 8 Results of quantitative coronary angiography

p: 0.0002 Late loss (mm)

Restenosis %

44% Late loss reduction

65.5% Restenosis reduction

Control Rapamycin

Figure 4

Relative reduction of late loss and binary restenosis in oral sirolimus and control group of oral rapamycin to prevent restenosis II randomized.

1.13 mm in the control group (P⫽ 0.0002)], resulting in

greater luminal dimensions and a smaller degree of stenosis at

follow-up The relative reduction in the risk of restenosis

among patients who received oral rapamycin was independent

of diabetes mellitus status, vessel location, and the length anddiameter of the lesion or stent