Textbook of Interventional Cardiovascular Pharmacology - part 8 doc

TheACC/AHA recommendations specify that ACE inhibitorsshould be initiated at very low dose and gradually uptitrated.Patients with HF should not generally be maintained on verylow doses o

who were not candidates for traditional revascularization

owing to the diffuse nature of their disease (38,39) The

stud-ies failed to account for a strong placebo effect observed in

this group and the follow-up studies failed to show efficacy

(40) The idea of using ABMSCs as potential sources of

angio-genic factors has now been tested in several trials (41–44)

Given that patients are not candidates for revascularization

injection of the cells has to be accomplished via a

transendo-cardial route with the guidance of electromechanical mapping

(EMM) using a NOGA catheter or other intramyocardial

injection catheters

The first feasibility study to assess this new methodology

enrolled eight patients with angina refractory to medical

ther-apy (42) They were assessed with functional cardiac MRI at

three months after the treatment The EF was 57% at

base-line and did not increase significantly There was an

improvement in the wall thickening (11%; P⫽ 0.004) and

wall motion (5.5%; P⫽ 0.008) of the target wall, in addition

to a decrease in hypoperfused myocardium (3.9%;

P⫽ 0.004) The EMM times approached 200 minutes Fuchs

et al study (2003) (41) was a second feasibility pilot trial of 10

patients with chronic angina secondary to nonintervenable

coronary disease but with EF above 30% (mean of 47%)

Patients received 12 injections of ABMSCs via a

transendo-cardial approach using EMM into the ischemic territory as

determined by single photon emission computer tomography

(SPECT) The outcomes assessed were EF change by

echocardiography at three months after the procedure, and achange in the size of reversible ischemia on SPECT, in addi-tion to a change in the angina score The EFs did not change.However, there was a decrease in the semi-quantitativestress scores on SPECT imaging within the injected segments

(P⬍ 0.0001) Angina score also improved in 8/10 patients.Importantly, there were no arrhythmic or procedural compli-cations The EMM time was 30 minutes

The largest study to date of 21 patients was an open-labelstudy with 14 patients who received treatment and sevenwho served as controls (44) Unlike in the pilot studies, thepatients had to have an EF of less than 40% (both pilot stud-ies enrolled patients with EFs⬎ 40%) All patients had ademonstrable reversible defect by SPECT imaging Thegroup therefore represented a high mortality and morbiditypatient population The mean of 25 million cells wereinjected (split into 15 aliquots) into the area of viability andreversible defect as determined by unipolar voltage withNOGA catheter and by prior SPECT imaging, respectively.Notably control group patients did not undergo a shamprocedure The outcomes assessed were the change incardiopulmonary exercise tolerance, echocardiographic EFand viability on SPECT at two months after treatment, inaddition to angiographic LV function and EMM at fourmonths Again, the control group did not undergo the EMMassessment at four months There was a significant decrease

in the brain natriuretic peptide (BNP) levels and improvement

MI (days) Strauer 10 Tx ⫹ 10 Ctrl 28 million IC 5–9 Decreased infarct size;

improved perfusion; improved wall motion TOPCARE-AMI 59 Tx ⫹ 11 Ctrl 200 million IC 4 Increased EF, coronary

flow, regional wall motion and decreased infarct size

Fernander-Aviles 20 Tx ⫹ 13 Ctrl 78 million IC 14 Increased EF and

wall motion BOOST 30 Tx and 30 Ctrl 2.5 billion of IC 6 Increased EF and regional

less repeat revascularization

Abbreviations: ASTAMI, autologous stem cell transplantation in acute myocardial infarction; BOOST, bone marrow transfer to enhance ST-elevation infarct regeneration; Ctrl, control; EF, ejection fraction; IC, intracoronary; N, number; Tx, treated; REPAIR-AMI, reinfusion of enriched progenitor cells and infarct remodeling in acute

myocardial infarction; TOPCARE-AMI, transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction.

Table 1 Clinical trials of cellular therapy in acute myocardial infarction

in creatinine in the treated group at two months (BNP 282

vs 565; P ⫽ 0.06; cr 1.1 vs 1.62; P ⫽ 0.03) Patients in the

treatment group had less anginal symptoms and increased

exercise capacity [metabolic equivalent units (METs) went up

from 5 to 6.7 in the treatment group and did not change in

the control group; P⫽ 0.0085] There was a 6% increase in

EF by echocardiography (P⫽ 0.027) There was a reduction

in the reversible defect by SPECT from 15% to 4.5%

(P⫽ 0.022) without a concomitant change in fixed defect

percentage (ruling out the possibility that a decrease in the

reversible defect was attributed to scar formation at the site

of the injection) There was an increase in the ischemic area

in the control group although the difference was not

statisti-cally significant The improvement in the LV function was

sustained at four months The EMM also showed increased

contractility in the injected regions (change in linear

shorten-ing 5.7 to 10.8; P⬍ 0.0005) The authors hypothesized that

the effect of ABMSCs injections was to the result of

angio-genic properties of cells and hence better contractility of the

hibernating myocardium The use of EMM to guide the

procedure was particularly useful to determine the viability of

the tissue treated The procedures were not associated with

arrhythmia or myocardial injury or high incidence of

perfora-tion The major limitation was the lack of sham procedure

control, which raises the issue of placebo effect in

interpret-ing the subjective NYHA class and exercise tolerance data

Improvement in SPECT imaging is reassuring, however

More recently, the same authors extended their patient

follow up to six and 12 months and attempted to stratify the

magnitude of improvement by progenitor cell characteristics,

that is, elucidate the potential mechanism of improvement

(43) The BNP levels increased in both groups but not as

markedly in the treatment group (BNP 507 vs 740 at 12

months; P⫽ 0.08) There was a persistent favorable

differ-ence in the NYHA class (2.7 vs 1.4; P⫽ 0.01) and exercise

tolerance (METs 7.2 vs 5.1; P⫽ 0.02) There was no longer

a difference in the EF between the two groups; however, the

size of the reversible defect on repeat SPECT scans at 12

months was markedly smaller in the treated group (11% vs

34%; P⫽ 0.01) Monocyte and early hematopoietic cell

phenotype correlated with better perfusion at six months bySPECT, particularly the monocyte lineage, suggesting theirpossible role in angiogenic factor secretion

Similar to the experience in the acute MI setting, cellulartherapy use in chronic angina patients needs validation inlarger randomized trials that would allow for sham proce-dures to control for the placebo effect In addition, althoughtransendocardial administration with NOGA catheter appears

to be an effective method of administration of cells, bothpreclinical and clinical studies are needed to establish the bestapproach that would allow for maximal cell survival andretention As recently reviewed by Thompson (45),endoventricular catheters can be subject to motion owing tocardiac cycle, interference from the subvalvular apparatus orinadequate tract formation within the myocardium by theneedle One of the possible solutions to some of these limi-tations may be a use of the injections via the coronary sinusand the great cardiac vein using the guidance of intravascularultrasound (IVUS) and an extendable nitinol needle (46) Thisapproach may also shorten the procedure times (80–90minutes as reported by Perin for EMM mapping) The results

of the trials are summarized in Table 2

Skeletal myoblast intramyocardial injection for ischemic myocardial dysfunction

In acute or chronic ischemia patients, angiogenic potential oftransplanted cells is of the greatest importance The patientswith chronic nonviable scar and myocardial dysfunction aremore likely to benefit from the cells that, either directly orindirectly (via paracrine effect) (47), improve the contractility

of the treated myocardium (9) Autologous skeletal myoblastshave been successfully expanded in vitro and implanted in themyocardia of animals Although they do not contract synchro-nously with the rest of the myocardium and do not integrateinto it, they have been shown to improve contractility

Clinical trials 445

perfusion, and regional wall motion Fuchs 10 Tx 47% 78 million TEN-EMM Decreased angina and increased perfusion Perin 14 Tx ⫹ 7 Ctrl 30% 30 million TEN-EMM Decreased angina and heart failure;

increased perfusion, EF and regional wall motion

Abbreviations: Ctrl, control; N, number; TEN-EMM, transendocardial-electromechanical mapping; Tx, treated.

Table 2 Clinical trials in cell therapy for chronic angina without revascularization options

(48,49) The major drawback has been a need for

manipula-tion in culture, need for epicardial implantamanipula-tion during an

open surgical procedure, and most importantly,

arrhythmo-genic potential of these cell islands (50)

The first clinical study enrolled 10 patients with LVEF

⬍35% and nonviable scar owing to past MI on FDG-PET

and indication for coronary artery bypass grafting (CABG)

(51) Myocytes were cultured from the patient’s autologous

vastus lateralis biopsy obtained two to three weeks before

CABG Eight hundred million myoblasts were injected via a

27-gauge needle epicardially during CABG into a scar

supplied by a nongraftable diseased vessel All patients were

given prednisone postoperatively Primary outcomes were

patient safety and ability to obtain myocytes after culture Left

ventricular EF at one, three, and six months postprocedure

was the secondary outcome Sixty percent of the expanded

cells were myogenic and 90% of them were viable The

patients had no major complications of the surgery but four

of them developed inducible VT within 11–22 days and

required automatic internal cardioverter-defibrillator (AICD)

The LVEF increased from 23% to 32% (P⫽ 0.002);

however, this increase may have been to the result of

revas-cularization alone Both nonrevascularized segments that

were transplanted with cells and those that were

revascular-ized, improved their contractility, suggesting that myoblasts

indeed improved contractility locally

Another small pilot of 12 patients undergoing CABG with

EFs between 25% and 45% and nonviable scar showed no

need for AICD implantation and improvement in EF from

mean of 35–53% at three months (P⫽ 0.002) (52) It is

unclear what contributed to this lower incidence of inducible

VT, although the use of autologous patient plasma for muscle

culture may have decreased the degree of inflammation

around skeletal myoblasts, potentially caused by culture in fetal

bovine serum The suggestion that the risk of VT can be

reduced by the use of autologous plasma is also shown in

another more recent study by Chachques et al of 20 patients(53) A smaller number of myoblasts (200 million) wereinjected than in Menasche study, and appeared equally effec-tive In contrast to the Menasche study, the scar area was alsorevascularized making it more difficult to dissect the contribu-tion of revascularization from myoblast transplant effect Themyoblast-treated areas had larger semi-quantitative improve-ment in wall motion than revascularized areas (wall motion

score index 2.6 down to 1.6; P⫽ 0.0001) The FDG-PETshowed increase in the uptake in transplanted scar areas (from

0.126 to 0.231; P⫽ 0.01) Similar change was observed in

the revascularized areas (0.170 – 0.284; P⫽ 0.014) Again,although this may imply the presence of viable myoblasts inthe scar area, a definitive proof is lacking It is possible that thisimprovement simply represents the effect of revascularization

on hibernating myocardium that was previously undetected byFDG-PET and thought to be nonviable

A small five-patient study (54) used a catheter-basedtransendocardial injection of skeletal myoblasts with EMM guid-ance and no concomitant revascularization One of the patientsdeveloped long nonsustained ventricular tachycardia (NSVT),and an AICD was placed There was a trend toward improve-ment in EF by echocardiography and LV angiography but not

by MRI Wall thickening in the injected areas showed significantimprovement over untreated segments 0.9 – 1.8 mm;

P⫽ 0.008)

The longest follow up to date of patients status tal myoblast implantation was 12 months (55) Ten patientsundergoing CABG with low EFs were treated Two patientsdeveloped NSVT in the postoperative period, necessitatingamiodarone infusion, and all subsequent patients were placed

postskele-on prophylactic amiodarpostskele-one Improvement in EF was similar

to other studies and was sustained at 12 months

In conclusion, skeletal myoblast implantations require betterinvestigation into the efficacy of implantation and the viability ofinjected myocytes by possibly obtaining the biopsy data from

Menasche 10 25 870 million TEP-CABG Increased EF and wall motion;

Complications of VT (arrhythmia) Herreros 11 36 190 million TEP-CABG Increased EF and wall

(in human serum) motion and increased viability;

no arrhythmias observed Siminiak 10 25–40 50 million TEP-CABG Increased EF and wall motion Chachques 20 28 300 million TEP-CABG Increased EF and wall motion and

(in human serum) viability; no arrhythmias

Abbreviations: Ctrl, control; EF, ejection fraction; N, number; TEP-CABG, transepicardial coronary artery bypass grafting; VT, ventricular tachycardia; TEN-EMM,

transendocardial-electromechanical mapping; Tx, treated.

Table 3 Clinical trials of cell therapy in ischemic cardiomyopathy

patients It appears that the risk of arrhythmia is substantial and

its etiology is still unclear It may be prudent that the patients

enrolled in further studies receive prophylactic AICDs which

would offer not only treatment, but also potentially better

recording and monitoring capabilities for different arrhythmias

The new EMM-guided catheters for epicardial implantation may

offer less-invasive option for implantation than open-heart

surgery One such CellFix catheter allows for possible repeat

administration of cells (56) and coadministration with angiogenic

factors to improve survival Larger safety and efficacy

random-ized trials are also needed to separate the effect of myoblast

transplant from that of revascularization Another option not yet

investigated in human trials would be the use of adult cardiac

myocytes for transplantation (57) or fetal cardiomyocytes, the

supply of which is rather scarce (58) These cells may have a

better chance of integrating with the rest of the myocardium and

being less arrhythmogenic, potentially provide enhanced

contractility The results of cell therapy trials in ischemic

myocardial dysfunction are summarized in Table 3

Angiogenesis and cytokine

clinical trials

The results of preclinical and clinical trials of angiogenic factor

protein and gene therapy were recently reviewed by Losordo

et al (59,60), and are reviewed in detail elsewhere in this

text-book Here we will discuss the issues of synergistic

coadministration of angiogenic factors and cytokine with cellular

therapy Fibroblast growth factor (FGF) Initiating

RevaScularization Trial (FIRST) of intracoronary FGF-2 protein

administration in 300 patients with coronary artery disease

(CAD) did not show any advantage over placebo and

demon-strated a substantial placebo effect (61) Similarly, a phase I trial

of VEGF-2 gene therapy by direct myocardial injection showed

no evidence of angiogenic effect by angiography (62) It is

possi-ble that the extracellular matrix or cellular vehicle is needed for

sustained and effective administration of angiogenic factors It is

also possible that the angiogenic network elaborated after an MI

is so elaborate that the administration of a single cytokine cannot

replicate it In addition, the endogenous endothelium may be

too diseased to respond to angiogenic proteins, and new

endothelial progenitor mobilization is needed for the process of

angiogenesis and vasculogenesis to take place Conversely,

transplanted cells may also demonstrate better survival and

retention when administered in their natural humoral and

struc-tural milieu rather than a suspension of cultured cells Skeletal

myoblast survival was demonstrated to be improved when

fibrin biodegradable scaffold was used (63) Other

tissue-engi-neering approaches to myocardial regeneration were recently

reviewed by Nugent and Edelman (64) Our own laboratory is

conducting preclinical trials of cardiomyoplasty for acute and

chronic MI with myotissue transplantation This technology

would provide the ultimate preservation of structure and genic milieu of the transplanted cardiomyocytes (Fig 3).Another possibility for combining cytokine treatment andcell therapy was recently tested in the Myoblast AutologousGraft in Ischemic Cardiomyopathy (MAGIC) trial (65) In thisprospective randomized trial of 27 patients undergoing stent-ing for acute MI effects of combining intracoronary infusion ofunselected peripheral blood stem cells with the administra-tion of intravenous granulocyte-colony stimulating factor(G-CSF) The hypothesis was that G-CSF would increaseendothelial progenitor/stem cell mobilization from the bonemarrow that usually occurs in the acute setting of MI (66), andthat peripheral blood could be used instead of bone marrowfor infusion The trial was stopped prematurely, however,owing to increased incidence of in-stent restenosis in thepatients treated with G-CSF This safety concern outweighedthe benefits on LVEF and exercise tolerance, in addition torecent evidence that G-CSF is capable of preventing the unfa-vorable ventricular remodeling (67)

angio-Conclusions and future directions

Cellular therapy holds great promise, especially for patientswith limited options, such as those with end-stage ischemiccardiomyopathy or refractory angina It has the potential toreduce the incidence of LV dysfunction and heart failure Theresults of small phase I trials conducted to date and summa-rized here are somewhat encouraging, but they clearly showthe need for perfecting this technology before it can be widelyapplied Similar to the early angiogenesis trials where smallphase I studies showed some promise, but larger randomizedphase II and III trials proved disappointing, we run a danger ofdisappointment with cellular therapy unless the mechanisticfoundation is elucidated first, and the technology perfectedbased on this work (68) We need more research into themechanisms of cellular therapy effects on ventricular perfor-mance, before embarking on larger randomized andappropriately controlled clinical trials One of the fundamentalissues that remains unresolved is the viability and survival ofthe injected cells that remain rather poor calling into questiontheir direct contribution to the improvement in contractility,and suggesting that possibly the paracrine effect of apoptosis ofthese cells leads to the improvement in function Manypreclinical studies to date, including our own work, haveshown this poor viability (Fig 2) Cell delivery catheter tech-nologies need to be developed further Tissue-engineeringtechnologies to construct matrix scaffolds, which would allowfor better cell survival, need to be developed The imagingtechniques to allow for cell tracking and monitoring of theirviability need to be developed further Magnetic resonanceimaging technology, allowing for gene and protein expression

Conclusions and future directions 447

imaging (69,70), would seem ideal for this purpose, in addition

to being the most sensitive and specific technique of assessing

the LV performance (wall motion, wall thickening, EF) and

perfusion in addition to viability (late enhancement)

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Management of the heart failure (HF) patient presents a

number of challenges to the interventional cardiologist These

include the pharmacologic management of heart failure and

special considerations regarding the practical aspects of

inter-vention, including the risk of intervention and the need for the

preparation before intervention (HF management,

hemody-namic support, renal function) Clinical decision-making

regarding further treatment options may be different in the

patient with HF

Pharmacotherapy in the heart

failure patient

Heart failure is a progressive syndrome, and optimal

pharma-cologic management is based on a detailed diagnosis,

determination of the etiology, characterization of the clinical

syndrome (systolic vs diastolic) and careful monitoring of the

response to pharmacologic therapy There is a need to

modify treatment in accordance with the patient’s response

Pathophysiology Drugs acting on the renin–angiotensin–

aldosterone system (RAAS) are the cornerstone of treatment

in the management of the HF patient with systolic

dysfunction Angiotensin-converting enzyme (ACE) inhibitorsinterfere with the formation of angiotensin II, both at systemicand tissue level In chronic HF, activation of therenin–angiotensin system has negative effects on themyocardium and on cardiovascular hemodynamics so thatthe preload and afterload are increased, and sodium andwater are retained (1) The increased production ofangiotensin II leads to ventricular hypertrophy, increasedmyocardial fibrosis, and apoptosis (2) Angiotensin-convertingenzyme inhibitors stop the deleterious effects of angiotensin

II, and lead to an improvement in the hemodynamic profile and a decrease in cardiac remodeling They also increase the plasma concentrations of inflammatorycytokines (e.g., bradykinin), nitric oxide, and vasodilatingprostaglandins (3)

Hemodynamic effects During treatment with ACEinhibitors, systemic vascular resistance is decreased along withthe pulmonary capillary wedge pressure and right atrialpressure (4) End-diastolic and end-systolic dimensions arereduced Long-term ACE inhibition decreasesechocardiographic left ventricle (LV) dimensions and increasesthe shortening fraction (5)

Clinical effects Angiotensin-converting enzyme inhibitorsimprove symptoms, New York Heart Association (NYHA)functional class, and exercise capacity in patients with HF.The Captopril Multicenter Research Group (6) showed thatcaptopril treatment improved the NYHA class in 61%

of patients compared with only 24% of patients takingplacebo over a 12-week period Treadmill exercise timeimproved throughout the 12 weeks of the study in 24% ofcaptopril-treated patients, but in none of the placebo-treatedpatients

Therapy with ACE inhibitors is associated with a dramaticincrease in survival in patients with NYHA class II–IV and in all

38

The heart failure patient

Basil S Lewis and Mihai Gheorghiade

patients with LV systolic dysfunction after an acute myocardial

infarction, even those without the signs or symptoms of HF

(Table 1) (7–9) After myocardial infarction, ACE inhibition

attenuates ventricular dilation, reduces the incidence and

hospitalization for HF, prevents recurrent ischemic events,

and increase survival The decreased recurrence of acute

coronary events or stroke (10) with ACE-inhibitor therapy

means that these drugs are an essential part of the

therapeu-tic armamentarium in patients undergoing intervention in the

circumstances of an acute coronary syndrome, and hence,

perhaps in more than half the patients treated in a modern

interventional center

Practical use of ACE inhibitors Based on the data frompublished trials, the 2005 American College of Cardiology/American Heart Association (ACC/AHA) guidelines (11)recommend ACE inhibitors as first-line therapy forsymptomatic HF with reduced systolic function and forasymptomatic LV dysfunction In stage C HF, they should beused in conjunction with a diuretic to maintain the sodiumbalance and prevent the development of fluid overload TheACC/AHA recommendations specify that ACE inhibitorsshould be initiated at very low dose and gradually uptitrated.Patients with HF should not generally be maintained on verylow doses of an ACE inhibitor unless these are the only doses

Study Selection criteria Patients, n Drug, dosage Results

Chronic heart failure

CONSENSUS (7) NYHA IV cardiomegaly 253 Enalapril, 20-mg 40% Reduction of overall

twice/day, mortality; significant

vs placebo improvement of

NYHA class SOLVD treatment (8) NYHA I-IV LVEF ⬍ 35% 2569 Enalapril, 10-mg 16% Reduction of overall

twice/day, mortality; fewer

vs placebo rehospitalizations for

worsening HF SOLVD prevention (9) Asymptomatic LV 4228 Enalapril, 10 -mg No differences on

dysfunction LVEF ⬍ 35% twice/day, mortality; significant

vs placebo reduction of worsening

HF and hospitalizations Postmyocardial infarction

SAVE (86) Acute MI within 3–16 days 2231 Captopril, 50-mg/ 19% Reduction of overall

LVEF ⬍ 40% no overt HF three times a day, mortality; significant

vs placebo reduction of death,

hospitalization, and recurrent myocardial infarction

AIRE (87) Acute MI within 3–10 days 2006 Ramipril, 5-mg 27% Reduction of overall

Clinical evidence of HF twice a day mortality; significant

vs placebo reduction of severe heart

failure, myocardial infarction, and stroke TRACE (88) Acute MI within 3–7 days 2606 Trandolapril, 4-mg 22% Reduction of overall

LVEF ⬍ 35% once per day, mortality; lower risk of

vs placebo cardiovascular death,

severe HF, and sudden death SMILE (89) Acute MI within 24 hrs 1556 Zofenopril 26% Reduction of overall

vs placebo mortality Abbreviations: AIRE, acute Infarction ramipril efficacy; CONSENSUS, cooperative north scandinavian enalapril survival study; HF, heart failure; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; SAVE, survival and ventricular enlargement; SMILE, survival of myocardial infarction long-term evaluation; SOLVD, studies of left ventricular dysfunction; TRACE, trandolapril cardiac evaluation study group.

Table 1 Angiotensin-converting enzyme inhibitor trials

that can be tolerated Once the appropriate dose has been

achieved, patients can be maintained on long-term therapy

with an ACE inhibitor with little difficulty Renal function and

serum potassium should be assessed within one to two

weeks of initiating therapy and every two to three months

thereafter

Adverse effects The adverse effects of ACE-inhibitor use

are related to angiotensin suppression (hypotension, increase

in serum creatinine and potassium) and bradykinin

potentiation (cough and angioedema) Initial hypotension

would usually respond to a decrease in the dose of diuretic

agent or the lowering of the ACE-inhibitor dose If

hypotension persists, the assessment of orthostatic changes in

order to properly administer ACE inhibitors may be useful

Treatment should be reassessed if the levels of creatinine are

⬎3.0 mg/dL or if serum potassium is ⬎5.5 mEq/L The

development of a cough is a major reason for the

discontinuation of the therapy, but ACE inhibitors should be

stopped only if cough is persistent, and should be replaced

with an angiotensin II receptor blocker Pregnant patients

should not be administered ACE inhibitors because of the

danger of teratogenic effects A history of angioedema or

renal failure during previous exposure to this class of drugs, or

severe hypotension with an immediate risk of cardiogenic

shock, are contraindications to the prescription of this class

of drug

Beta blockers

Pathophysiology Long-term and sustained activation of

the sympathetic nervous system in the HF patient has

detrimental effects on the cardiac function, and on the

peripheral circulation, causing vasoconstriction (12) and

possibly impairing sodium excretion by the kidney (13)

Increased levels of plasma catecholamines cause myocyte

hypertrophy and apoptosis (14–16) In the failing heart, there

is a ␤-receptor downsensitizing and uncoupling with the

intracellular signaling Sympathetic activation has shown to

be related to arrhythmogenesis and sudden death (17)

␤ blockers act by inhibiting the adverse effects of sympathetic

nervous system activation in patients with HF

Hemodynamic effects Shortly after the administration of

this class of drugs, ␤-adrenergic blockade can decrease the

ventricular contractility and impair sodium excretion,

particularly in patients whose cardiac function is already

compromised These early adverse effects may be minimized

by the use of ␤ blockers with ␣-blocking properties; inversely,

during long-term treatment, ␤ blockers can improve cardiac

performance (17,18) The administration of a ␤ blocker for a

longer period of time (three to six months) is associated with

an increase in the stroke volume and cardiac output anddecreased pulmonary wedge pressure, right atrial pressure,heart rate, and systemic vascular resistance (19) Cardiacoutput, initially reduced by short-term treatment, wasrestored or increased during long-term treatment (20,21).Left ventricular ejection fraction (LVEF) increases duringlong-term ␤-adrenergic blockade, and the magnitude ofincrease is larger than that with other treatments for HF Thisimprovement is particularly evident in HF patients who haveviable but noncontractile myocardium and has generally beenassociated with a reduction in LV systolic and diastolic dimen-sions, suggesting a favorable effect on the process ofventricular remodeling

Clinical effects A large number of randomized, blind, placebo-controlled trials have shown that the long-term use of ␤ blockers improves the clinical status in patientswith HF (22–32) (Table 2) and the ACC/AHA guidelines (11)recommend that ␤ blockers should be routinely prescribed

double-to all patients with asympdouble-tomatic LV dysfunction or stable HFcaused by LV systolic dysfunction (unless they have acontraindication or have been shown to be intolerant totreatment with these drugs) ␤ blockers should also be used

in patients with HF and preserved LV systolic function,particularly when those patients have hypertension, coronaryartery disease (CAD) and/or atrial fibrillation

␤ Blockers should be initiated at very low doses andincreased at two-week intervals to achieve the target doses.Once the target dose is achieved, patients can generally

be maintained on long-term treatment with little difficulty.Abrupt withdrawal of ␤ blockers can lead to clinicaldeterioration and should be avoided, even in hospitalizedpatients who do not require inotropic support (11) Safe andfeasible administration ␤ blockers can be initiated in all classes

of HF patients before hospital discharge, as proved in theInitiation Management Predischarge Process for Assessment

of Carvedilol Therapy for Heart Failure (IMPACT-HF) trial (33)

Adverse effects The adverse events associated with

␤ blockers may be avoided by starting treatment at very lowdoses However, treatment can be associated withcomplaints of fatigue and weakness, which usually resolve in

a few weeks Sometimes it is necessary to decrease the dose

of the ␤ blocker or diuretic Symptomatic bradycardia isanother serious adverse effect of ␤ blockers, and requires adecrease in the dose or sometimes cardiac pacing to allowthe use of this vital medication Hypotension is anotherpotential side effect; however, it is rarely seen as the therapy

is started with a very low dose (3.25 mg twice a day forcarvedilol, 1 mg for bisoprolol and 12.5 mg for extendedrelease metoprolol) The administration of ACE inhibitor anddiuretic at a different time of day than the ␤ blocker can

Pharmacotherapy in the heart failure patient 453

minimize hypotension and dizziness Patients who exhibit low

systolic blood pressure should be evaluated for orthostatic

changes In the absence of orthostatic changes, these patients

probably can safely tolerate the addition of ␤ blockers to their

ACE inhibitor and diuretic regimen Administration of ␤

blockers is contraindicated in patients with severe

bronchospasm, symptomatic bradycardia, or advanced heart

block in the absence of a pacemaker

Aldosterone antagonists

Pathophysiology In HF patients, the levels of aldosteroneare elevated, even in the presence of ACE inhibitors orangiotensin-receptor blockers (34,35) Aldosterone hasdetrimental effects in HF, such as causing potassium andmagnesium loss, sodium retention, baroreceptor dysfunction,and myocardial fibrosis; it also decreases the neuronal uptake

Chronic heart failure

MDC (22) Idiopathic cardiomyopathy 383 Metoprolol, 100 to 34% reduction of

3 times/day, vs placebo of transplantation U.S Carvedilol NYHA II–IV 1094 Carvedilol, 25 to Significant reduction

CIBIS II (90) NYHA III–IV 2647 Bisoprolol, 5 mg/day, Significant reduction

death, and hospitalization rates MERIT-HF (24) NYHA II–IV 3991 Metoprolol succinate, Significant reduction

LVEF ⬍ 40% 200 mg/day, vs placebo of mortality, sudden

death, and deaths for worsening HF BEST (91) NYHA III–IV 2708 Bucindolol, 50 to No significant

vs placebo mortality; only in

nonblack patients COPERNICUS (30) NYHA III–IV 2289 Carvedilol, 25-mg Significant reduction

reduction of 24% of composite end points in mortality and rehospitalization COMET (32) NYHA class II–IV;LVEF 3029 Carvedilol, 25-mg Hazard ratio 0.83 in

⬍ 35%; at least 1 twice/day, vs favor of carvedilol

Postmyocardial infarction

CAPRICORN (31) Acute myocardial 1959 Carvedilol, 25-mg Significant reduction

infarction within 3 to 21 twice/day, vs placebo in mortality;

reduction 3% Abbreviations: BEST, beta-blocker evaluation survival trial; CAPRICORN, carvedilol postinfarct survival control in left ventricular dysfunction; CIBIS II, Cardiac Insufficiency Bisoprolol Study II; COMET, Carvedilol or Metoprolol European Trial; COPERNICUS, carvedilol prospective randomized cumulative survival; HF, heart failure; LVEF, left ventricular ejection fraction; MDC, metoprolol in dilated cardiomyopathy; MERIT-HF, metoprolol controlled-release randomized intervention trial in congestive heart failure; NYHA, New York Heart Association.

Table 2 Major clinical trials with beta blockers

of norepinephrine, thereby enhancing the risk of cardiac

arrhythmias (36)

Clinical effects The effects of this drug class have been

demonstrated in patients with HF and postmyocardial

infarction with ventricular dysfunction ( Table 3) (37,38) The

Randomized Aldactone Evaluation Study (RALES) study was

stopped after interim analysis revealed that the aldosterone

antagonist was associated with a significant 30% relative

reduction in both mortality and hospitalization for worsening

HF The side effects of spironolactone included gynecomastia

or breast pain in 10% of men Hyperkalemia had been

thought to limit the combination of ACE inhibitors and

potassium-sparing diuretics, but with careful monitoring,

hyperkalemia was uncommon in both the placebo and

spironolactone groups (37)

The result of the RALES study has been supported by the

Eplerenone postacute myocardial infarction heart failure

effi-cacy and survival study (EPHESUS) trial results (39), but the

magnitude of improvement was smaller In this trial, most

patients were treated with ␤ blockers The mean eplerenone

dose achieved (43-mg daily) produced a significant 15%

reduc-tion in the all-cause mortality and a significant 13% reducreduc-tion in

cardiovascular deaths or hospitalizations for cardiovascular

causes The benefit was more pronounced in the group of

patients who received both ACE inhibitors/angiotensin II

recep-tor blockers and ␤ blockers, and did not exist in the patients

who received neither class of drug There was also a significant

21% reduction in the rate of sudden death from cardiac causes

The only significant complication in the eplerenone group was

the rate of serious hyperkalemia (5.5% in the eplerenone vs

in patients with moderate HF Contraindications to aldosteroneantagonists include hyperkalemia (serum potassium levels

⬎5 mEq/L) or renal insufficiency (creatinine ⬎2.5 mg/dL)

Adverse effects Renal function may deteriorate with thedecreased circulating fluid volume, especially after theaddition of another diuretic drug acting on the RAAS system,and careful monitoring of serum creatinine is essential Serumpotassium should be monitored within one week of initiationand at least every four weeks for the first three months andevery three months thereafter It should also be monitored atany dose change in spironolactone or if there is a change inconcomitant medications that affects the potassium balance.The spironolactone dose (standard 25 mg per day) should bereduced if potassium levels are ⬍5.4 mEq/L, and treatmentshould be discontinued if painful gynecomastia or seriousrenal dysfunction or hyperkalemia result

Angiotensin II receptor blockers

Pathophysiology Angiotensin-receptor blockers block theaction of angiotensin II at the receptor level, and hence, blockthe effects of angiotensin II produced in addition by the chymasepathway Current angiotensin II receptor blockers block theangiotensin II type 1 receptors (associated with hypertrophy and

Pharmacotherapy in the heart failure patient 455

Study Selection criteria Patients, n Drug, dosage Results

Chronic heart failure

RALES (92) NYHA III–IV LVEF 1663 Spironolactone, Significant reduction of all causes of

⬍ 35% Treatment with 25-mg daily, vs mortality; absolute risk reduction 11%; ACE inhibitors and loop placebo lower risk of hospitalization for worsening

Acute myocardial infarction

EPHESUS (38) AMI within 3–14 days 6642 Eplerenone, 50-mg Significant reduction of all causes of

LVEF ⬍ 40%; diabetes, daily, vs placebo mortality; absolute risk reduction 2.3%;

hospitalization for cardiovascular causes Abbreviations: ACE, angiotensin-converting enzyme; AMI, acute myocardial infarction; EPHESUS, eplerenone postacute myocardial infarction heart failure efficacy and survival study; HF, heart failure; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; RALES, randomized aldactone evaluation study.

Table 3 Trials with aldosterone-blocking drugs

remodeling) and enhance the activation of angiotensin II type 2

receptors, causing vasodilation (40) As some of the side effects

of the ACE inhibitors, such as angioedema and dry

nonproductive cough, may be bradykinin related, an angiotensin

II receptor blocker could, theoretically, provide the same

beneficial effects as an ACE inhibitor, with fewer side effects

Effects on mortality and hospitalization Table 4

summarizes the recent trials of angiotensin II receptor

blockers (41–48) In several clinical settings and controlled clinical trials of patients with chronic HF,angiotensin II receptor blockers produced hemodynamic,neurohormonal, and clinical effects similar to those obtainedwith ACE inhibitors Among symptomatic HF patients withlow LVEF enrolled in the Candesartan in Heart Failure:Assessment of Reduction in Mortality and Morbidity(CHARM-Added) trial, the addition of candesartan to arecommended dose of ACE inhibitor and other treatmentindividually reduced cardiovascular mortality and the risk of

placebo-Study Selection criteria Patients, n Drug, dosage Results

Chronic heart failure

ELITE (41) Age ⬎ 65 years 722 Losartan, 50 mg Lower rates of deaths in

NYHA II–IV LVEF daily, vs Captopril, Losartan group

ELITE II (42) Age ⬎ 60 years 3152 Losartan, 50 mg No reduction of overall

NYHA II–IV LVEF daily, vs Captopril, mortality; trend in

death and cardiac arrest

in captopril group Val-HeFT (43) NYHA II–IV LVEF 5010 Valsartan, 160 mg No reduction in overall

⬍ 0.40 LV twice/day, vs placebo mortality; reduction of

number of hospitalization CHARM-Added (47) NYHA II–IV LVEF 2548 Candesartan, 32 mg/ Absolute risk reduction

⬍ 0.40 adjunctive day vs placebo 4%; trend toward lower

(P ⫽ 0.086) CHARM-Alternative (46) NYHA II–IV LVEF 2028 Candesartan, 32 mg/ Absolute risk reduction

⬍ 0.40 Intolerance day vs placebo 7%; trend toward lower

(P ⫽ 0.11) Acute myocardial infarction

OPTIMAAL (44) Age ⬎ 50 years 5477 Losartan, 50 mg No significant difference

Acute MI with daily, vs Captopril, between the two groups; signs of HF LVEF 50 mg/3 times/day significant reduction of

Q waves VALIANT (48) Acute MI within 14,703 Valsartan, No differences in all

24 hours 10 days; 160 mg, daily vs causes of mortality signs of HF; LVEF captopril, 50 mg, 3 between valsartan and

⬍ 0.40; systolic BP times/day vs captopril, captopril; no differences

⬎100 mmHg 50 mg, 3 times/day plus in all causes of mortality

valsartan, 160 mg, daily between combined

therapy vs captopril Abbreviations: ACE, angiotensin-converting enzyme; CHARM, candesartan in heart failure: assessment of reduction in mortality and morbidity; ELITE, evaluation of losartan in the elderly; HF, heart failure; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association; OPTIMAAL, optimal trial in myocardial infarction with angiotensin II antagonist losartan; Val-HeFT, valsartan in heart failure trial; VALIANT, valsartan in acute myocardial infarction trial.

Table 4 Trials with angiotensin-receptor blocking drugs

admission to hospital for HF, and reduced the risk of each of

the secondary composite outcomes (47) The benefits of

candesartan were similar in all predefined subgroups, with no

evidence of heterogeneity of treatment effect, including

patients receiving baseline ␤-blocker treatment

Effects after myocardial infarction In patients with

evidence of LV dysfunction early after myocardial infarction,

the Valsartan in Acute Myocardial Infarction Trial (VALIANT)

(48) demonstrated that valsartan had a benefit that was not

inferior to that of ACE inhibitors without an advantage in

terms of tolerability However, the addition of an angiotensin

II receptor blocker to an ACE inhibitor did not improve the

outcomes and resulted in more side effects

Indications and use of angiotensin II receptor

blockers The ACC/AHA guidelines (11) recommend that

angiotensin II receptor blockers should be used as an

alternative first-line therapy if a patient is intolerant to ACE

inhibitors with symptomatic LV dysfunction The addition of

an angiotensin II receptor blocker is advised in the case of

persistent symptoms despite conventional therapy In the

recent ACC/AHA guidelines, the combination of an

angiotensin II receptor blocker, an ACE inhibitor, and

aldosterone is not recommended because of the

adverse effects When starting the therapy with angiotensin II

receptor blockers, it is important to begin with the

minimal dose and then double it Blood pressure, potassium,

and renal function should be assessed within two weeks

after beginning therapy For stable patients, it is reasonable

to add ␤-blocking agents before full target doses of either

ACE inhibitors or angiotensin II receptor blockers are

reached

Adverse effects The adverse effects include hypotension,

worsening renal function, and hyperkalemia The ACE

inhibitors should remain the first-choice treatment in patients

after complicated acute myocardial infarction

Diuretics

Pathophysiology Non-potassium-sparing diuretics are

the treatment of choice to reduce fluid retention and

dyspnea Acting at specific sites of nephrons, they inhibit

sodium and water reabsorption Loop diuretics act on the

loop of Henle, producing a maximal diuretic effect equivalent

to 20% to 25% of the filtered sodium load and promoting

the free water clearance Currently available loop diuretics

include furosemide, bumetanide, torsemide, and ethacrynic

acid Because of their potency, they are generally effective in

patients with advanced renal insufficiency (glomerular filtration

rates ⬍25 mI/min) (49)

Distal tubular diuretics, with the exception of metolazone,are generally six to eight times less potent than loop diuretics,and are usually reserved for hypertensive patients with mildfluid retention They are less effective as the glomerular filtra-tion rates decrease to levels ⬍25–30 mL per minute Theyare classified into potassium-wasting (thiazides, chlorthali-done, and metolazone) and potassium-sparing diuretics(triamterene, amiloride, and spironolactone, eplerenone).Potassium-wasting diuretics decrease sodium reabsorption inthe cortical segment of the ascending limb of the loop ofHenle and the distal convoluted tubule, and are associatedwith an increase in urinary potassium excretion Potassium-sparing diuretics are not potent when used alone, but may beused to avoid the potassium-wasting effects of diuretics thatact at more proximal nephron sites Thiazides and distaltubule diuretics have longer half-lives that allow them to begiven once daily or even every other day (e.g., metolazone).The plasma half-life of loop diuretics ranges from one to fourhours Once a dose of a loop diuretic has been administered,its effect dissipates before the next dose is given During thistime, the nephron avidly reabsorbs sodium, resulting inrebound sodium retention that nullifies the prior natriuresis(49) Combined diuretic therapy, using judicious doses of

diuretics, acting (i) on the loop of Henle and also on the (ii) proximal and (iii) distal tubule, invariably produces adequate

diuresis in patients resistant to individual drugs

Clinical effects Several trials have demonstrated theability of diuretics to decrease the signs of fluid retention inpatients with HF In these short-term studies, diuretic use hasled to a reduction in jugular venous pressures, pulmonarycongestion, peripheral edema, and body weight, all observedwithin days (50–52) Diuretics have been shown to improvecardiac function, symptoms, and exercise tolerance inpatients with HF Diuretics activate the neurohormonalvasoconstrictor systems that have been implicated in theprogression of the disease, increasing plasma renin activityand concentrations of angiotensin II, aldosterone, andnorepinephrine (53) Long-term diuretic use also decreasesthe circulating concentrations of the vasodilating natriureticpeptides This imbalance may partially explain thedevelopment of progressive diuretic resistance that may be afeature of advanced HF

Indications Appropriate administration of diuretics is crucialfor the success of the other drugs being used The ACC/AHAguidelines (11) recommend diuretics to be prescribed to allpatients who have an evidence of fluid retention, and that theyshould be combined with an ACE inhibitor and a ␤ blocker(and usually digoxin) Therapy is initiated with low doses, andthe dose is increased until urine output increases and weightdecreases, generally by 0.5–1.0 kg per day The treatment goal

is to eliminate the physical signs of fluid retention Once fluid

Pharmacotherapy in the heart failure patient 457

with an increased hospitalization rate; decreased exercisetime and LVEF; and increased heart rate, body weight, andcardiothoracic ratio on chest X ray.

Effects on mortality and hospitalization The DigitalisInvestigation Group (DIG) trial (60) tested the effects of digoxin

on survival in patients with HF in normal sinus rhythm The trialenrolled 7788 patients, of whom 87% had systolic dysfunction.They were randomized to a mean dose of 0.25 mg of digoxin

or placebo, with a background therapy of ACE inhibitors anddiuretic agents Before enrollment, less than 50% of thepatients were not receiving digoxin For both groups, the all-cause mortality was 35%, and the cardiovascular mortality was30% There was a trend toward a decrease in mortality caused

by HF in patients with a serum digoxin level of ⬍1 ng/mL (60)

In multivariable analysis, digoxin was associated with asignificantly higher risk of death among women, but it had nosignificant effect among men However, because serum digoxinconcentrations were measured in less than 33% of patients atone month, the trial had insufficient statistical power to testwhether the interaction between sex and digoxin therapy wasindependent of sex-based differences in serum digoxinconcentration Recent retrospective cohort analysis of thecombined PROVED and RADIANCE databases indicates that patients with a low-serum digoxin concentration(0.5–0.9 ng/mL) were no more likely to have worseningsymptoms of HF on maintenance of digoxin than those withmoderate (0.9–1.2 ng/mL) or high (⬎1.2 ng/mL) serumdigoxin concentrations (61) All serum digoxin concentrationgroups were significantly less likely to deteriorate during follow-

up study compared with the patients withdrawn from digoxin

Use of digoxin Digoxin can be used to reduce symptoms

in patients despite treatment with an ACE inhibitor and a ␤blocker In patients not taking ACE inhibitors or ␤ blockers,treatment with digoxin should not be stopped, butappropriate therapy with the neurohormonal antagonistsshould be instituted In case of atrial fibrillation with a rapidventricular rate, the ␤-blocker dose rather than the digoxindose should be increased, because higher serum digoxinconcentrations are associated with increased adverse effects.The digoxin dose should be low (0.125 mg per day), becausethis dose is shown to control the symptoms and is safe Thedrug should be used cautiously in patients who are takingmedications that can depress atrioventricular conduction andshould not be used in patients with significant sinus oratrioventricular block, unless they have a pacemaker

Adverse events The major side effects include cardiacarrhythmias (e.g., ectopic and re-entrant cardiac rhythms andheart block); gastrointestinal symptoms (e.g., anorexia,nausea, and vomiting); and neurologic complaints (e.g., visualdisturbances, disorientation, and confusion) Digitalis toxicity

retention has resolved, treatment with the diuretic should be

maintained to prevent the recurrence of volume overload The

dose should be adjusted periodically, allowing the patient to

make changes in dose if weight increases or decreases beyond

a specified range

Adverse effects Adverse effects include hypotension

and/or diminished renal perfusion, leading to the

development of prerenal azotemia or acute intrinsic renal

failure that may resolve by decreasing the diuretic dose

Hypokalemia and hypomagnesemia may increase the risk of

life-threatening ventricular arrhythmias in patients with HF,

and may contribute to the incidence of sudden death,

particularly during treatment with digoxin Usually, the use in

combination with ACE inhibitors, and if appropriate,

spironolactone will minimize potassium loss Magnesium

and/or potassium supplements can be given as needed If

hypotension or azotemia is observed, the rapidity of diuresis

could be reduced, but diuresis should be maintained until fluid

retention is eliminated Diuretics may also cause metabolic

alkalosis, carbohydrate intolerance, hyperuricemia,

hypersensitivity reactions, and acute pancreatitis It is prudent

to use the lowest dose of diuretic that helps control

congestion and perhaps use torsemide, which has a more

predictable bioavailability and may be safer than furosemide

Digitalis

Pathophysiology Digoxin exerts its effects by the

inhibition of sodium-potassium adenosine triphosphatase

(Na-K-ATPase) In the myocardium, this results in an increase

in intracellular calcium and increased myocardial contraction

(54) The inhibition of Na-K-ATPase in the vagal afferent fibers

sensitizes the cardiac baroreceptors, reducing the

sympathetic outflow from the central nervous system By

inhibiting Na-K-ATPase in the kidney, digoxin reduces the

renal tubular reabsorption of sodium, resulting in the

suppression of renin secretion from the kidneys (55,56)

These observations have led to the hypothesis that digoxin

acts in HF primarily by attenuating the activation of

neurohormonal systems and not as a positive inotropic drug

Clinical effects In HF patients, digoxin has been proven

to reduce symptoms, improve NYHA class, increase exercise

time, modestly increase LVEF, enhance cardiac output, and

decrease HF hospitalizations (56,57) The Randomized

Assessment of Digoxin on Inhibitors of the

Angiotensin-Converting Enzyme (RADIANCE) (58) and Prospective

Randomized study Of Ventricular Failure and the Efficacy of

Digoxin (PROVED) (59) trials demonstrated that these

beneficial effects are lost when digoxin is withdrawn from the

medical therapy Digoxin withdrawal has been associated

is commonly associated with serum digoxin levels ⬎2 ng/mL,

but they may occur with lower digoxin levels, especially if

hypokalemia, hypomagnesemia, or hypothyroidism are

present

Hydralazine–isosorbide dinitrate

Pathophysiology Hydralazine and isosorbide dinitrate

are effective vasodilators which may interfere with

the biochemical and molecular mechanisms responsible for

the progression of HF Combined use may interfere with the

development of nitrate tolerance (62)

Clinical benefits and effects on mortality and

hospitalization Whether used alone or in combination,

hydralazine and isosorbide dinitrate decrease the preload and

afterload, decrease mitral regurgitation, improve cardiac

output, increase exercise capacity, modestly increase LVEF,

and prolong survival in patients with HF (63,64) V-Heart

Failure Trial (HeFT) II (64) showed that enalapril had a major

benefit on survival when compared with the combination of

hydralazine–isosorbide dinitrate with enalapril in patients with

predominantly NYHA class II–III The African Americans in

Heart Failure Trial (A-HeFT) (65) showed a beneficial effect of

adding vasodilator therapy to African-American patients

already treated with ACE inhibitors, ␤ blockers, and

spironolactone There are no results with the same strategy

in other patient groups

Use of hydralazine–isosorbide dinitrate In the

ACC/AHA guidelines (11), the combined use of

hydralazine–isosorbide dinitrate may be considered as a

therapeutic option in patients with reduced LV dysfunction

already taking ACE inhibitors and ␤ blockers and with

persistent symptoms Despite the lack of data about this

vasodilator combination in patients who are intolerant of ACE

inhibitors, the combined use of hydralazine and isosorbide

dinitrate may be considered as an additive therapeutic option

in such patients However, compliance with this combination

has generally been poor because of the large number of

tablets required and the high incidence of adverse reactions

Adverse events Adverse events are few and include

headache and dizziness

Calcium antagonists

Although calcium antagonists have anti-ischemic properties

and cause systemic vasodilatation, they have not

demon-strated sustained improvement in patients with HF, and

worsening symptoms and increased mortality have beenreported, possibly because of their negative inotropic effectand reflex neurohormonal activation (66,67) Amlodipine andfelodipine appear to have less negative inotropic effects and

do not have the deleterious effects seen with first-generationdrugs in this class Amlodipine had no significant effect on themortality in the subset of patients with coronary arterydisease, as shown in the first Prospective RandomizedAmlodipine Survival Evaluation (PRAISE I) (68) Based on theavailable data, calcium antagonists are not recommended forthe treatment of HF (11) Diltiazem, verapamil, and nifedip-ine should be avoided in patients with HF with reducedsystolic function The vasculoselective agents, such asamlodipine, may be considered for the management ofhypertension in patients with LV systolic dysfunction who arealso receiving standard HF therapy

a 28% reduction in the risk of death and a 31% reduction inthe combined risk of death or hospitalization for worsening

HF in patients with advanced disease There was a trendtoward a reduction in the risk of death because of progressive

HF and the risk of sudden death The European MyocardialInfarct Amiodarone Trial (EMIAT) (73) assessed the effect ofamiodarone versus placebo in patients after myocardialinfarction with an LVEF ⬍0.40% Sudden death, however,was decreased by 35% with amiodarone, whereas the all-cause mortality was not reduced in these patients A favorableinteraction was apparent between the concomitant use of ␤blockers and cardiac mortality, independent of LV function.Because of the conflicting evidence and its known toxicity, theprophylactic use of amiodarone to prevent sudden cardiacdeath in patients with HF is not recommended in the currentACC/AHA guidelines (11) It should be used in combinationwith a ␤ blocker and an implantable cardioverter defibrillator

in patients with a history of sudden death, ventricularfibrillation, or sustained ventricular tachycardia Patients onamiodarone therapy should be monitored for the occurrence

of thyroid, ocular, pulmonary, or hepatic abnormalities.Thyroid and liver function tests, in addition to chest X-ray,should be assessed at baseline and every six months during

Pharmacotherapy in the heart failure patient 459

therapy Pulmonary function tests should be obtained at

baseline and repeated only if the findings on follow-up chest

X-ray are abnormal Patients taking amiodarone, digoxin, and

warfarin should be carefully monitored for drug interactions

Atrial fibrillation is one of the most frequent arrythmias that

HF patients experience The Atrial Fibrillation Follow-up

Investigation of Rhythm Management (AFFIRM) did not

demonstrate any benefit from rhythm control in patients with

HF or depressed LVEF (74) If indicated for the treatment of

symptomatic atrial arrhythmias, amiodarone should be used

because of its demonstrated safety in patients with HF Device

implantation rather than pharmacologic treatment is the

mainstay of preventive therapy for sudden cardiac death

among patients with HF (75)

Anticoagulation and antiplatelet drugs

Pathophysiology In large studies, the risk of

thromboem-bolism in clinically stable patients has been 1–3% per

year, including those with very low LVEF and

echocardiographic evidence of intracardiac thrombi (76,77)

Because the benefit–risk ratio is low, anticoagulation is

not justified in these patients The Warfarin and Antiplatelet

Therapy in Chronic Heart Failure (WATCH) study set

out to evaluate the role of aspirin, clopidogrel, and warfarin

to prevent major cardiovascular event and death in

patients with HF, but low enrollment in the trial precluded

definitive conclusions about efficacy In the absence of

definitive trials, it is not clear how anticoagulants should be

prescribed in patients with HF According to the ACC/AHA

guidelines (11), anticoagulation with warfarin is justified in

patients with HF and paroxysmal or chronic atrial fibrillation

and/or a previous embolic event It should not be prescribed

in patients who are in normal sinus rhythm, even with a low

LVEF Antiplatelet treatment is generally recommended in

patients with arterial disease, although the role of aspirin is

still debated

Treatment of comorbidity

A number of drugs should be avoided in HF, including

antiar-rhythmic agents, calcium channel blockers, antipsychotics,

antihistamines, corticosteriods, and nonsteroidal

anti-inflam-matory drugs Metformin and thiazolidinediones should be

used with caution in HF with diabetes Trials of statins have

generally excluded patients with symptomatic HF, but two

studies with morbidity and mortality outcomes in HF are now

under way

Anemia is a frequent finding in HF patients, and treatment

improves outcome (78) There is a growing interest in the

use of erythropoietic agents and iron supplementation to

treat anemia in HF, and outcome trials are planned Some

patients with HF also have thiamine deficiency

Patients with preserved systolic function

A few clinical trials are available to guide the management ofpatients with HF and relatively preserved LVEF (79–81) TheCHARM-preserved trial evaluated the addition of candesar-tan to the treatment regimen for patients with symptomaticmild HF and relatively preserved LVEF, significantly reducedmorbidity but did not reach the primary end point (45) In theabsence of other controlled clinical trials, the management ofthese patients is based on the control of physiologic factors(blood pressure, heart rate, blood volume, and myocardialischemia) that are known to exert important effects onventricular relaxation (11) Many patients with HF and normalLVEF are treated with ACE inhibitors, ␤ blockers, angiotensin

II receptor blockers, digitalis, and diuretics because of thepresence of comorbid conditions (i.e., atrial fibrillation, hyper-tension, diabetes mellitus, and coronary artery disease)

Special issues regarding heart failure patients in the interventional laboratory

OrthopneaWith proper pharmacotherapy and optimization of overallclinical status, most patients will be able to overcome theproblem of orthopnea for the duration of interventionalprocedure Diuretic therapy preintervention may be useful

In the very ill patient with hemodynamic compromise, andwhere intervention may lead to an improvement in cardiacfunction, supportive measure, such as intra-aortic ballooncounterpulsation, pressure monitoring, or ventilation may benecessary during the acute phase of the illness

Renal functionThe contrast load may compound renal damage, common in

HF patients, with consequent further fluid retention andworsening HF A number of adjunctive treatments arecurrently recommended in the renal patient but none guar-antee renal protection (82) The volume of contrast mediumduring intervention should be minimized and hypotensionshould be avoided

Iso-osmolar or low-osmolar contrast medium is mended, and it appears to be associated with a lower renalcomplication rate Serum creatinine level should bemeasured 24 to 48 hours after the administration of thecontrast medium Nonsteroidal anti-inflammatory drugs and

recom-diuretics should be withheld for at least 24 hours before and

after exposure to contrast medium, if possible, and adequate

hydration guaranteed Concomitant treatment with the

antioxidant N-acetylcysteine (600-mg twice daily) may reduce

the incidence of deterioration in renal function (83) but the

results of clinical trials, although promising, have not all been

consistent (84) Renal risk is compounded in the diabetic

patient, where meticulous attention to detail regarding all

these issues should be applied Biguanides (such as

metformin, which increases the acidotic load) should be

avoided where possible prior to intervention (85)

Summary and conclusions

The HF patient presents a special challenge to the interventional

cardiologist The procedure may be challenging and

compli-cated by technical difficulties regarding patient ability to undergo

the procedure and complications, such as procedurally induced

HF and renal failure On the other hand the potential benefit of

revascularization regarding survival in patients with HF owing to

coronary disease is high and rewarding

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In light of recent developments, a great deal of new material

on the acute coronary syndrome (ACS) has been published

in the last few years The data focuses on the best treatment

for the ACS patient in addition to diagnosis, prognosis, and

risk stratification (1,2) The importance of this information is

based on the prevalence of ACS and its complications (3)

Nearly 1.7 million patients are hospitalized every year in the

United States with ACS (4) Nearly 20 years ago, it was

discussed that angiographic morphology of the stenosis was

more important than the stenosis severity (5) From this

angiographic viewpoint, clinical, biochemical, and histological

information has developed for ACS patients

The ACS patient can fit into one of the three clinical

syndromes: unstable angina, non-ST segment elevation

myocardial infarction (NSTEMI), and ST-segment elevation

myocardial infarction (STEMI) These are differentiated by the

threat or degree of myocardial necrosis The chest pain

accompanying the syndromes can be constricting, squeezing,

burning, or a heavy feeling in the chest It can occur across

the chest and radiate to one or both arms and to the teeth,

cheeks, and neck It can go down the forearm to the fingers

or in the interscapular area The chest pain can be

precipi-tated by exercise, excitement, stress, cold weather, or after

meals It is often relieved by rest or sublingual nitroglycerin

Any or all of these anatomic areas can be involved

Atypical chest pain is more common in females The

females are more likely to have chest pain at rest, or sleep, or

with periods of mental stress They are more likely to have

neck and shoulder pains Fatigue, dyspnea, and nausea with

vomiting are often present (6)

Braunwald’s clinical classification of chest pain refines the

discomforts of unstable angina (7) The severity of the chest

pain is divided into three classes:

1 New onset angina pectoris or accelerated angina

pectoris but no rest pain

2 Angina pectoris at rest within the past month but not in

the past 48 hours

3 Angina at rest and within the past 48 hours

The clinical circumstances can differ:

1 Developing in the presence of an extra cardiac conditionthat intensifies ischemia

2 Angina can develop postmyocardial infarction before anytreatment or after drug treatment

3 Finally, unstable angina can develop with or without trocardiographic changes

elec-This grouping of clinical syndromes are compatible withmyocardial ischemia, and a prompt visit to the emergencydepartment is indicated Electrocardiograms in the emergencydepartment would differentiate a NSTEMI from a STEMI, thelatter suggesting a greater degree of myocardial ischemia.The usual coronary risk factors are important as well.Hypertension, cigarette smoking, diabetes, hypercholes-terolemia are the main coronary risk factors sought after inthe history taken in the emergency department

Antman developed a thrombosis in myocardial infarction(TIMI) risk score based on a database of 15,078 patients withSTEMI or new onset of complete left bundle branch block(8) The score was validated in the TIMI 9 data set Ten char-acteristics of these patients accounted for 97% of thepredictive capacity of their multivariate model These areincluded in the risk score (Table 1) Points were given fordifference parameters as listed in Table 1 The risk score had

a strong association with 30-day mortality There was agreater ⬎40-fold increase in mortality from TIMI risk score 0

to ⬎8 at 30 days (Table 1) (8) The TIMI risk score is easy toapply and can be done at the bedside

When clinical findings are added to biomarkers, these acteristics further define the high-risk patient who willespecially benefit from an aggressive strategy The patientspresenting characteristics have an impact on early decisionmaking, including transfer to a tertiary care center of the high-risk patient

char-39

The acute coronary syndrome patient

John F Moran

Biomarkers help establish the presence of myocardial

necro-sis There are nearly two dozen biomarkers currently under

study Most experience is with creatinine kinase, creatinine

kinase MB, troponin I or T, and myoglobin Others are under

study (Fig 1) (3) Two other biomarkers currently available are

C-reactive protein (CRP) and brain natriuretic peptide (BNP)

Even minor elevations of troponin I or T have had

prognos-tic importance In the tacprognos-tics TIMI 18 study, troponin levels

between 0.1 ng/mL and more than 1.5 ng/mL were found

in 60% of the 1821 patients (9) In this study, troponin

T⬎0.1 ng/mL was found in 54% of the study patients Patientswith troponins greater than 0.1 were at a significantly increasedrisk of death or recurrent ischemia at 30 days (11.7% vs 5.5%,

P ⬍ 0.001) and at six months (20.1% vs 14.2% P ⬍ 0.001).

These values were independent of age, creatinine kinase (CK)

MB, or electrocardiographic changes In the Tactics TIMI 18study, these patients with increased troponin levels benefitedfrom an early invasive strategy with upstream tirofiban––a 39%relative risk reduction of the primary end point (9) Elevatedtroponins identified high-risk patients with more complicatedcoronary artery disease with thrombus (9) No benefits of anearly aggressive strategy was seen in troponin negative patients.Higher troponin levels were associated with a greater throm-bus burden

Ohtani et al used coronary angioscopy to evaluate 62patients with ACS (10) These patients were divided intotroponin-positive and troponin-negative patients Highertroponin levels were associated with a greater thrombusburden They found that the prevalence of thrombus, largethrombus, and yellow plaques were all higher in troponin T-positive patients than in negative patients

Troponin levels are an important addition to stratify risk inthe ACS patient with history and electrocardiographicchanges However, abnormal troponins are found in otherconditions as well, notably pulmonary embolus and sepsis,when ACS patients are excluded These authors suggest that elevated troponin levels are not specific for ACS (11).This requires clinical evaluation (Table 2)

Although troponin elevation suggests necrosis, biomarkers

of myocardial ischemia are equally important modified albumin was reported to be highly sensitive for adiagnosis of ischemia in patients with chest pain presenting tothe emergency room (12) Further study needs to be done

Ischemia-on this sensitive biomarker for myocardial ischemia

Myocyte Necrosis

Hemodynamic Stress Inflammation

Troponin

hs-CRP, CD40L

BNP, NT-proBNP

Accelerated Atherosclerosis

Vascular Damage

CrCl, Cystatin C Microalbuminuria

Anterior STEMI at LBBB 1 point

Time to RX ⬎4 hours 1 point

Risk score ⫽ Total (0–14)

Abbreviations: DM, diabetes mellitus; HR, heart rate; HTN, hypertension; LBBB,

left bundle branch block; SBP, systolic blood pressure; STEMI, ST-segment

elevation myocardial infarction.

Table 1 TIMI risk score for ST-segment

elevation myocardial infarction

Transient myocardial ischemia was evaluated in 112

patients undergoing the Bruce protocol exercise stress

testing Technetium tetrofosmin scans were obtained and

BNP levels were assessed before, during, and four hours

after exercise (13) If patients had no inducible ischemia, BNP

levels were low at baseline, 43 pg/mL, and unchanged during

and after exercise However, in patients with inducible

ischemia, BNP levels rose from a median 62 to 92 pg/mL and

nearly returned to baseline at four hours postexercise

Patients with severe ischemia had median BNP levels at

baseline, 101 pg/mL and increased to 123 pg/mL These

were still elevated four hours postexercise to 115 pg/mL

Differences were based on the BNP levels Patients with no

ischemia (43 pg/mL), mild to moderate ischemia

(60–92 pg/mL), and severe ischemia (101 pg/mL) were

statis-tically different These differences were increased with

exercise stress (13)

In this study, N-terminal pro-BNP (NT-pro-BNP),

circulat-ing BNP, and N-terminal pro- atrial natriuretic peptide

(NT-pro-ANP) were measured before and after exercise

The BNP levels are as given earlier The BNP levels differed

across the ischemic categories at all three time points They

shared an approximate 25% change from the baseline BothNT-pro-BNP and NT-pro-ANP rose with ischemia but didnot differ statistically in this study (13) The difference in BNPwere more pronounced after exercise stress testing andwere categorized as mild to moderate severity on the tetros-fosmin scan scores Although coronary angiograms candemonstrate significant anatomic coronary artery disease,transient myocardial ischemia was associated with a briefrelease of BNP (13)

Ischemia results from an imbalance of oxygen supply anddemand In patients with ACS, multiple studies of atheromahave implicated inflammation as a critical part of thesyndrome Signs of inflammation in animal models and humans occur with lipid accumulation in the artery walland plaque development Plaque rupture and thrombosishave abruptly narrowed or occluded the coronary arteriesprecipitating ACS (14)

In many histologic studies, signs of inflammation occur withlipid deposition in the artery wall An atherogenic diet canresult in endothelial cells expressing surface adhesion mole-cules that would bind leukocytes Superficial vascular celladhesion molecule binds leukocytes found in atheroma, bothhuman and animal Augmented wall stress, that is, at arterialbifurcations, can promote smooth muscle cells to produceproteoglycans Proteoglycans can retain and bind lipoproteinparticles facilitating the oxidation of particles and thuspromote inflammation at that site in the artery Adherentleukocytes can penetrate the intima of the artery Once insidethe wall, monocytes scavenge lipids and become foam cells

T cells can elaborate tumor necrosis factor which wouldfurther stimulate macrophages, endothelial cells, and smooth muscle cells The activated leukocytes produce morefactors that promote smooth muscle cells and a dense extracellular matrix seen in the advanced atheroscleroticplaque Macrophages also produce tissue factor, a majorfactor in thrombosis Inflammation can lead to plaque disruption and thrombosis formation which can narrow orocclude the artery Much evidence exists that shows inflam-mation is involved in plaque developments, progression, andthrombosis (14)

Many mediators of inflammation have been identified––cytokines: IL-6, tumor necrosis factor alpha; cell adhesionmolecules: intracellular adhesion molecule-1 (ICAM-1), P-selectin; and acute phase reactants: CRP, fibrinogen, serumamyloid A, and soluble CD40 (Fig 1) (3) Myeloperoxidase is

an enzyme secreted from monocytes, neutrophils, andmacrophages A single measurement taken from patient withchest pain in the emergency department predicted the earlyrisk of myocardial infarction and the risk of major cardiac ofends in the next 30 days to six months (15)

These authors felt that myloperoxidase was good for theprediction of ACS, because it is released by leukocytes, and iselevated and active in vulnerable plaques It has also beenmechanistically associated with factors that effect plaquedevelopment and stability Myloperoxidase was independent

Myocardial ischemia

Coronary vasospasm Intracranial hemorrhage or Stroke Ingestion of sympathomimetic agents Direct myocardial damage

Cardiac contusion Direct current cardioversion Cardiac infiltrative disorders Chemotherapy

Myocarditis Pericarditis Cardiac transplantation Myocardial strain

Congestive heart failure Pulmonary embolism Pulmonary hypertension or emphysema

Strenuous exercise Chronic renal insufficiency

Table 2 Nonthrombotic causes for elevated

cardiac troponin level diagnosis

of CRP in this study (15) Renal dysfunction and abnormal

glucose metabolism were also the predictors of risk (2,3)

At this time, an important inflammatory biomarker is high

sensitivity CRP It can identify inflammation, and inflammation

predicts the prognosis in patients with ACS (16) It is possible

that CRP is a marker for atherosclerosis and not

atherothrombosis A study of 2554 patients with angina, but

not myocardial infarction, found that CRP significantly

corre-lated with the extent of coronary vascular disease But it was

a small association (r⫽ 0.02–0.08) This suggested that the

angiographic coronary artery disease and the level of CRP are

independent A high CRP and severe coronary artery disease

had the highest risk in the five-year follow up However, CRP

retained a high predictive risk for myocardial infarction or

death in the follow up regardless of the extent of coronary

artery disease There was a tenfold difference between the

lowest level and the highest level of CRP (2.5% vs 24%)

(17) This suggests that CRP is a measure of the inflamed

unstable plaque The risk for myocardial infarction or death

here was high if CRP was high and coronary artery disease

less severe In fact, this was a higher risk than the risk in those

patients who had severe coronary artery disease and a low

CRP level in this study (17)

The CRP and the inflammation it reflects play a key of role

in plaque instability Mauriello et al studied 30 autopsy cases:

16 patients dying of acute myocardial infarction within 72 hours

of symptom onset; five age-matched patients dying of cardiac

causes but who had stable angina; and nine age-matched

control cases dying of noncardiac causes who had no cardiac

history (18) Autopsies were done within 12 to 24 hours of

death Morphometric analysis showed a greater plaque area in

the acute myocardial infarction group compared with the other

two groups of patients A thrombus was found in all 16 patients

with acute myocardial infarctions that involved the culprit

artery and the infarcted myocardium The cap of the plaque

with the thrombus had ruptured in 14 cases and was attached

to plaque erosion in two cases The culprit plaque showed a

necrotic lipid core, a thin fibrous cap, and a large inflammatory

infiltrate of macrophage foam cells, CD68-positive and

CD3-positive lymphocytes In addition, the acute myocardial

infarction group had 109 vulnerable plaques per patient

compared with three or four vulnerable plaques in the other

two groups of patients There was no difference in

inflamma-tory infiltrates between the ruptured and vulnerable plaques in

the acute myocardial infarction group Even stable plaques had

more inflammation in the acute myocardial infarction group

than the plaques in the other two groups of patients The

entire coronary tree of the acute myocardial infarction patient

had three to four times the inflammatory infiltrates as the other

two groups (18) This work suggests that a diffuse

inflamma-tory process is at work in acute myocardial infarction If the

inflammatory process is diffuse, coronary blood flow could be

reduced on a global basis

Gibson et al used the technique of corrected TIMI frame

counts from the angiogram of patients with acute myocardial

infarction enrolled in the four TIMI trials (TIMI 4, 10A, 10B,and 14) (19) The number of angiographic frames that thecontrast needs to reach an anatomic landmark were counted

In all trials, the nonculprit artery frame count was 30.9⫾ 15

at 90 minutes compared with a normal frame count of

21⫾ 3.1 The nonculprit artery flow was 45% slower thannormal Abnormal nonculprit artery flow, 90 minutes afterthrombolysis in three TIMI trials, was associated with morewall-motion abnormalities and a poorer outcome (19) Therole of reinfarction is unclear but the presence of diffuseinflammation and multiple vulnerable plaques could be asignificant finding

In a comparison of thrombolysis and angioplasty, tion after thrombolysis (6.3% compared with angioplasty1.6%) worsens the patient’s outcome (20) The improvedoutcome here was driven by a reduction in the rate of rein-farction If coronary blood flow by cine frame count improved

reinfarc-in the culprit artery, the flow also improved reinfarc-in the nonculpritarteries (19) This suggests that the active inflammatory infil-trate is a dynamic phenomenon

In another study of 45 patients with ACS, the relationshipbetween plaque rupture, CRP, and prognosis was investigatedwith intravascular ultrasound (21) These 45 patients had a firstacute myocardial infarction with or without ST segment eleva-tion Intravascular ultrasound was performed in the patientsbefore any percutaneous coronary intervention and within sixhours of symptoms (21) The remaining coronary vasculaturewas examined within one month Forty-five culprit arteriesand 84 other coronary arteries were examined with intravas-cular ultrasound They found that plaque ruptures in 47% ofthe arteries at the culprit site in the acute phase of the myocar-dial infarction In addition, intravascular ultrasound revealed 17occult plaque ruptures at remote sites in 24% of the patients(21) These findings suggest that some patients with acutemyocardial infarctions have multiple plaque ruptures in othercoronary arteries and the culprit artery

The CRP levels were determined in these patients

It was higher in patients with plaque rupture (21 patients)compared with those without plaque rupture (24patients)––3.1⫾ 0.5 mg/L versus 1.9 ⫾ 0.4 mg/L (P ⫽ 0.04).

This suggests that an elevated CRP reflects an inflammatoryprocess that can lead to plaque rupture The CRP seems tohave independent predictive capacity for identifying inflamma-tion here There is also a possibility that CRP may releasefactors that further weaken the plaque’s fibrous cap and allowrupture or erosion (16)

Hong et al studied the site of plaque ruptures in patientswith three-vessel coronary artery disease utilizing intravascu-lar ultrasound They studied 206 patients scheduled forcoronary intervention: 99 patients with STEMI, 37 withNSTEMI, 22 patients with Braunwald Class IIIB unstableangina, and 48 stable angina pectoris patients (22) Plaqueruptures in the left anterior descending coronary arteriesoccurred mostly in the segments 10 to 40 mm from the ostia(83%) as did the plaques in the right coronary artery, 10 to

40 mm from the ostia (48%) The left circumflex plaque

ruptures were evenly distributed throughout the artery

Plaque ruptures follow the distribution of coronary artery

disease as seen by the intravascular ultrasound They also

occurred at branch points or high stress areas (50%)

To study the interaction between atherothrombosis and

inflammation, Monaco et al selected 40 consecutive patients

with Braunwald class IIIB unstable angina and 30 consecutive

patients with severe peripheral arterial disease (23) They

found more severe obstructive disease in the peripheral

arte-rial disease patients than in the coronary arteries of the

unstable angina patients The levels of thrombin–antithrombin

III complexes and d dimers were twice as high in peripheral

arterial disease patients as in the unstable angina patients

However, the levels of CRP and IL-6 were significantly higher

in patients with unstable angina than they were in peripheral

arterial disease patients Neutrophil activation and

myeloper-oxidase were also elevated in the unstable angina group So

more markers of thrombosis were found in the peripheral

arterial disease patients with severe ischemic disease and

more markers of inflammation in the unstable angina patients

with lesser occlusive coronary artery disease (23) The data is

graphed in Figure 2 Unstable angina had a marked up

regula-tion of inflammatory markers This suggests that the ACS may

result from a transient upregulation of inflammation rather

than the atherosclerotic burden Still it is unclear at this time

whether widespread coronary inflammation is a process thatleads to plaque rupture or is the result of plaque rupture orboth (24)

Plaque ruptures in the ACS setting are often involved with

a diffuse process Inflammation is involved in plaque growthand development in addition to complications of plaquerupture These could be considered the result of injury Well-known coronary risk factors can provide the impetus forplaque development Cigarette smoking, hypertension,hyperlipidemia, hyperglycemia, or insulin resistance arenoxious stimuli The stimuli can facilitate monocyte attach-ment to endothelial cells Eventually monocytes migrate tothe subintimal space and become foam cells to initiate plaquedevelopment

Multiple biomarkers are under study Well-studied andcommercially available biomarkers include CK-MB, troponin I

or T, CRP, and BNP, and recently, myeloperoxidase Each ofthese biomarkers is an independent predictor of death,myocardial infarction, or congestive heart failure Utilizing theopus TIMI 16 patients, Sabatine et al studied CRP, BNP, andtroponin in 450 patients These authors found a 30-day risk

of death increased in proportion to the number of thesebiomarkers that were elevated at baseline (25) They vali-dated the concept in the tactics TIMI 18 patients (26) Thesetwo trials of over 2000 patients with NSTEMI, troponin, CRP,and BNP provided independent prognostic information

60 30 10 8 6 4 2 0

240 180 120

80 70 60 50 40 30 20 10 0

250 150 50 25

20 15 10 5 0

20 15 10 5 0

15 10 5 0 –5 –10 –15 –20

Figure 2

Graphs of the differences in the coagulation cascade and circulating biomarkers and unstable angina (open bars) and peripheral arterial disease (shaded boxes).

Abbreviations: CRP, C-reactive protein; DD, D-dimer; IL, interleukin; MPXI, myeloperoxidase index; TAT, thrombin–antithrombin Source: From Ref 23.

However, in addition, there was a doubling of mortality risk

for each additional elevated biomarker (25)

Troponin assays are more sensitive than creatinine kinase

for myocardial necrosis Brain natriuretic peptide is released

from the ventricles by increased wall stress In ACS, BNP rises

rapidly, and increased levels on days 2–7 identify patients with

a poor survival (27) Mega et al in the ENTIRE TIMI 23 study

of 483 patients with STEMI evaluated CRP, BNP, and troponin

I at baseline for their prognostic value (27) Troponin I or T are

assays of myonecrosis, whereas CRP reflects the underlying

inflammation, and BNP is elevated in left ventricular overload

In this study by Mega et al., BNP was a greater indication of

mortality risk and risk assessment than either troponin or CRP

Troponin T, at the time of presentation, predicted two to three

times the increase in mortality at 30 days, whereas elevated

CRP was not predictive in the short term Patients with high

BNP had a greater mortality The ENTIRE TIMI 23 trial

showed full-dose Tenecteplase (TNK)-type tissue

plasmino-gen activator, and enoxaparin had a 30-day mortality of 4.4%,

whereas TNK and unfractionated heparin had a 30-day

mortality of 15.9% (28) These also suggest that a high BNP

identifies appropriate candidates for primary percutaneous

coronary angioplasty (27)

These data support an earlier study on the important

predic-tive value of BNP (29) The BNP levels predicted the risk of

death and nonfatal cardiac events across the spectrum of ACS

The BNP levels were supportive of other high risk factors: age

greater than 75 years; Killip class two, three, or four;

ST-segment deviation greater than 1.0 mm; new complete left

bundle branch block; troponin I, greater than 1.5 ng/mL (29)

There are differences in BNP levels according to age, body

mass, gender, and renal function (30) In the Tactics TIMI 18

study, 34% of the patients were women In that study,

women had lower CK-MB, lower TnT and TnI levels, and

higher hs-CRP and BNP levels (31)

There are also questions regarding the use of BNP and

NT-pro-BNP Richards et al made a comparison study of BNP and

NT-pro-BNP in 1049 patients with heart failure (32) They

found a correlation coefficient that was very good (r⫽ 0.90,

r2⫽ 0.81) between BNP and NT-pro-BNP The values

closely correlated and exhibited parallel changes across the

range of left ventricular ejection fractions, age, and renal

func-tion Neither marker was more influenced than the other by

age, gender, or renal function Nor was one more sensitive

than the other Brain natriuretic peptide may reflect more

rapidly hemodynamic changes But NT-pro-BNP may be

more reliable if Natrecor is used as therapy (32) In the United

States, 80% to 90% of the institutions use BNP, whereas in

Europe, it is the reverse (31) The absolute values of BNP and

NT-pro-BNP differ markedly and should not be used

inter-changedly Hospitals ought to use one or the other

These biomarkers represent a response to injury and may

reflect the degree of ischemia In a substudy of the platelet

receptor inhibition for ischemic syndrome management

(PRISM) trial, Heeschen et al found that ACS patients with low

NT-pro-BNP at baseline showed no difference in the rate ofdeath or MI between control and the Tirofiban-treated patients(33) However, a high borderline pro-BNP in ACS patients wasassociated with an increased event rate These rates tended to

be reduced by Tirofiban at 48 hours (0.5% vs 2.5% P⬍ 0.02)(33) These differences persisted up to 30 days of follow up.However, if Troponin T was negative and the NT-pro-BNPwas elevated, these patients were at high risk but received nobenefit from Tirofiban (33) If an elevated pro-BNP at baselinepersisted at 72 hours, these patients had a mortality of 9.3%compared with a negative NT-pro-BNP patients of 0.6%.Serial measurements were valuable here

Morrow et al followed unstable angina patients with BNPlevels up to four and twelve months The BNP levels greaterthan 80 pg/mL were strongly associated with poor survival(34) A persistently elevated BNP of greater than 80 pg/mLwas associated with the highest risk of death of new conges-tive heart failure If the BNP was normal at baseline andgreater than 80 pg/mL at four months, these patients had afourfold increase in the risk of death or new congestive heartfailure (34) This would suggest that BNP elevations reflect agreater ischemic burden or possibly left ventricular dysfunc-tion These data also suggest that important clinical prognosticinformation is available in serial BNP measurements In the A

to Z trial, simvastatin had no effect on the BNP levels Patients

in this trial were younger than 80 years and did not have icant renal disease In their BNP model, CRP attenuated therelationship with death or new congestive heart failure (34).The A to Z trial compared high-dose simvastatin to a lowerdose, whereas the pravastatin or atorvastatin evaluation andinfection therapy (PROVE-IT) trial compared 80 mg ofatorvastatin to 40 mg of pravastatin in patients with ACS (35)

signif-In contrast to A to Z trial, the CRP levels fell from a median

of 12.3 mg/L at baseline to 2.1 mg/L in the pravastatin groupand 1.3 mg in the atorvastatin group in the PROVE-IT TIMI

22 trial (36) The primary end point of all caused death,myocardial infarction, and unstable angina requiring hospital-ization was 26.3% in the pravastatin and 22.4% in theatorvastatin group This represents a 16% reduction in thehazard ratio, favoring atorvastatin

In the 80-mg simvastatin dose group in the A to Z trial, CRPlevels fell from 20.1 to 1.7 at four months and 1.5 at eight

months (P⬍ 0.001) (36) Higher-dose simvastatin resulted inlower CRP levels In PROVE-IT (35), A to Z (36), and MIRACLtrials (37), higher doses of statin medications resulted in lowerlow-density cholesterol (LDL) and a better outlook Higherdoses of statin also caused greater falls in CRP levels Thissuggests a role for inflammation in these ACS patients (37)

To further study the destabilized or possibly injured plaque, Toutouzas et al measured plaque temperatures in

19 patients with ACS and 23 patients with stable angina (38).Temperature differences between the plaque and the proxi-mal vessel wall were measured with a thermographycatheter Patients with ACS had greater temperature differ-ences than patients with stable angina (ACS 0.11° vs stable

angina 0.05° P⬍ 0.01) There were more plaques with

elevated temperatures in the ACS group (84.2%) than in the

stable angina group (30.4%) Moreover, patients treated with

statins had lower temperature differences in nonculprit

lesions than the untreated patients (38) The Dallas Heart

Study compared coronary artery calcifications and CRP levels

in 2726 patients with coronary risk factors (39) These

inves-tigators found a modest trend toward increasing CRP levels

and coronary calcium scores However, the relationship

between the CRP levels and coronary artery calcium scores

was not statistically significant after the analysis was adjusted

for the traditional risk factors: body mass index, estrogen, and

statin use There was a strong relationship between female

sex and body mass index (39) The CRP did not appear to be

related to atherosclerotic burden but more so to stability and

composition of the plaque (39)

The clinical setting of ACS places biomarkers in

perspec-tive If not atherosclerotic burden, then the acute event and

inflammation associated with it affect the biomarkers The

clinical presentation, the severity of inflammation with varying

degrees of ischemia, and necrosis in addition to the amount

of myocardium in jeopardy affect the degree of inflammation

and subsequently the biomarkers The coronary anatomy has

been studied by intravascular ultrasound, angioscopy,

coro-nary angiogram frame counts, plaque temperatures, and

histology at autopsy All point to a diffuse and

hemodynami-cally unstable state The value of biomarkers is their ability to

suggest the need for aggressive therapy

The ACS patient is identified by the history and physical

examination and the electrocardiogram at baseline Risk

strat-ification begins here with evaluation, such as the TIMI risk

score, as part of the history and physical Further risk

stratifi-cation is performed by an analysis of biomarkers In this

clinical setting, an elevated troponin suggests a degree of

necrosis If normal at baseline in the emergency room, serial

troponins are now performed over the next several hours

An elevated BNP could be helpful in revealing congestion or

perhaps a worsening prognosis An elevated CRP in the ACS

setting points to inflammation and leads to early

administra-tion of a high dose of statin medicaadministra-tions The data presented

here suggest that the elevation of these biomarkers worsens

prognosis Of the nearly two dozen biomarkers under study,

some will no doubt form a panel of biomarkers to help

eval-uate and stratify the risk of the ACS patients Which

biomarkers would be a part of that panel remains to be seen

The importance of the biomarkers would lie in its direct

aggressive therapy in a timely fashion A recent meta-analysis

of seven trials with 9212 patients showed that a routine

inva-sive strategy was superior to a conservative strategy that

brought patients to catheterization only if they had recurrent

symptoms (40) The benefit of the routine invasive strategy

occurred after hospital discharge During the hospitalization,

more death and myocardial infarction occurred in the routine

invasive group The use of biomarkers, glyocoprotein IIb/ IIIa

inhibitors, and antithrombins in these ACS patients needsmore research, especially in the early hospital management

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coro-30 Maisel A The coming of age of natriuretic peptides J Am Coll Cardiol 2006; 41:61–64.

31 Wiviott SD, Cannon CP, Morrow DA, et al Differential expression of cardiac biomarkers by gender in patients with unstable angina/non-ST elevation myocardial infarction Circulation 2004; 109:580–586.

32 Richards M, Nicholls MG, Espiner EA, et al Comparison of type natriuretic peptides for assessment of cardiac function and prognosis in stable ischemic heart disease J Am Coll Cardiol 2006; 47:52–60.

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selec-J Am Med Assoc 2005; 293:2908–2917.

Diabetes is extremely prevalent within the United States,

with more than 16 million confirmed cases and an additional

20 million cases of glucose intolerance As the incidence of

diabetes in this country is thought to be on the rise (1),

coro-nary artery disease (CAD) in this group, which is the principal

cause of death in this population, is expected to rise

concomi-tantly (2) Clearly reflecting these trends, in over a 20-year

period, the mortality rate in the United States from diabetes

has risen more than 30% (3)

Pathogenesis of cardiac

morbidity and mortality in

diabetics

As a result of the hyperglycemia, hyperinsulinemia,

dyslipi-demia, and hypercoagulability associated with diabetes,

diabetic patients are at particularly high risk for complications

of atherosclerosis Diabetes accelerates the natural course of

the atherosclerotic process, precipitating more diffuse disease

(4,5), increased rates of plaque ulceration and thrombosis (6),

and a doubling of the five-year mortality rate when compared

with nondiabetic CAD patients

Moreover, currently, inflammation is being implicated as a

driving force in the diabetic atherothromboembolic process

Increased concentrations of inflammatory markers such as

C-reactive protein, tumor necrosis factor-alpha, platelet-derived

soluble CD40 ligand, and upregulation of cellular adhesion

molecules have been noted in blood samples of diabetic

patients (7–10), and are a subject of great interest

Percutaneous coronary intervention and related complications

Diabetic CAD, with its impressive prevalence and severity, is thefrequent trigger of percutaneous coronary intervention (PCI)and, by extension, PCI-related complications Approximately25% of the revascularization procedures occurring in theUnited States are performed on diabetic patients (11) Diabeticpatients are known to incur higher rates of restenosis, and,interestingly, higher rates of complete occlusive restenosis, than

do nondiabetics (12) Occlusive restenosis has previously beendocumented to have markedly worse outcomes than nonoc-clusive restenosis (13) It has been theorized that occlusiverestenosis plays a large role in both the increased number oftarget vessel revascularizations (TVRs) and the overall poorerlong-term prognosis of the diabetic PCI group when comparedwith the nondiabetic PCI population (14)

Decreased reperfusion at the microvascular level might alsocontribute to the poorer prognosis of diabetic patients Recentwork in acute myocardial infarction (MI) has suggested thatdespite achieving comparable rates of thrombosis in myocardialinfarction (TIMI)-3 flow, diabetics have poorer post-PCI myocar-dial reperfusion than nondiabetics, as evidenced by reduced ST-segment resolution and myocardial blush grade (15)

Cardiovascular interventional pharmacology

in the diabetic patient

Mitchell D Weinberg and George D Dangas

identical rates of MI and mortality between the two, but have

noted increased rates of repeat revascularization in the PCI

group As a result, choosing between PCI and CABG in

nondi-abetics only requires that one weigh the risk and burden of TVR,

a risk that is believed to be diminishing in the postdrug-eluting

stent era (16–18) Deciding between PCI and CABG in

diabet-ics with multivessel disease, however, is more ambiguous

The Bypass Angioplasty Revascularization Investigation

(BARI) (19,20) revealed a significantly higher mortality in

diabetics treated with PCI than with CABG While these

find-ings were supported in two other large registries (21,22), they

were not duplicated in the BARI registry Unlike BARI, the

BARI registry was composed of those patients eligible but not

randomized and found similar outcomes in diabetics treated

with PCI or CABG (23) These findings, in conjunction with

the advent of stenting since the start of the BARI trial, call into

question the generalizability of the BARI results In a subanalysis,

the Arterial Revascularization Therapy Study (ARTS) trial

specifically studied slotted metallic stents in diabetic patients

and noted no difference in the combined endpoint of death,

nonfatal MI, or stroke, but did note increased restenosis and

TVR in the diabetes group (24,25) The recently presented

ARTS 2 data, which compared sirolimus drug eluting stent

(DES) with historical controls from the ARTS 1 trial, showed

PCI with DESs to be as good as CABG This finding is

consid-ered very significant and while the trial was nonrandomized,

the results from the diabetic subgroup analysis are being

eagerly awaited, as a greater portion of the PCI group was

diabetic than ARTS 1 (26) Thus, the current data indicates that

in the modern stent era the source of the majority of benefit

conferred by CABG to the diabetic population is a decreased

rate of restenosis-driven TVR As such, similar to nondiabetics,

before revascularizing a diabetic patient with multivessel

disease, the clinician needs to weigh the burden of an open

surgical procedure against an increased likelihood of TVR

Pharmacology

Thus, as diabetic CAD continues to warrant a great number

of PCIs and subsequent TVRs, interventional pharmacology in

this population is of great interest A number of agents which

have been studied in detail in the nondiabetic population have

been the subject of separate or substudy analysis in the

diabetic population Clearly, any pharmacological agent

effec-tive in improving PCI outcomes and reducing complications in

the diabetic population is of vital importance

Clopidogrel

In the PCI-CURE (Clopidogrel in Unstable Angina to Prevent

Recurrent Events) trial, subgroup analysis of diabetic patients

revealed only a nonsignificant trend toward benefit in theaspirin plus clopidogrel group compared with the aspirin plusplacebo group This benefit was noted to be less impressive

in diabetics when compared with nondiabetics (27) TheCredo (Clopidogrel for the Reduction of Events DuringObservation) trial studied individuals who were likely toreceive PCI and randomized them to either a loading dose ofclopidogrel followed by 12 months of clopidogrel or no load-ing dose and clopidogrel for only one month (28) There wasonly a trend toward benefit of prolonged clopidogrel therapy

in the diabetic population (relative risk reduction, RRR

⫽11%), whereas the benefit observed in the nondiabeticpopulation was significant (RRR ⫽33%) However, in a dedi-cated study among diabetics, clopidogrel was found to bemore effective than aspirin in reducing recurrent ischemicevents (29)

Platelet glycoprotein IIb/IIIa inhibitors

Platelet glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors impede thefinal common pathway of platelet activation—the bridging of GPIIb/IIIa with von Willebrand’s factor and fibrinogen—and thusinhibit direct platelet to platelet binding, platelet activation, and,ultimately, platelet-based thrombus formation Diabetics, noted

to have approximately 3X the number of platelet surface GPIIb/IIIa receptors than nondiabetics, even in the setting ofadequate glycemic control, should theoretically derive evengreater benefit from GP IIb/IIIa (30) The main PCI-relatedbenefit of IIb/IIIa inhibition was initially thought to reside inreduction of neointimal hyperplasia and, by extension, thediminution of TVR incidence Using intravascular ultrasound toquantify in-stent intimal hyperplasia, both the DiabetesAbciximab steNT Evaluation (DANTE) study, which was limited

to diabetics, and The Evaluation of ReoPro and Stenting toEliminate Restenosis (ERASER) study, which examined both 12-and 24-hour abciximab infusions in the general population, didnot reveal a reduction of in-stent intimal hyperplasia in any of the

GP IIb/IIIa inhibitor treatment groups (31,32) Thus, alternativemechanisms likely explain GP IIb/IIIa inhibitor-mediated benefit.The effects of GP IIb/IIIa inhibitors are not limited to directantiplatelet activity GP IIb/IIIa inhibitors are also thought tohave anti-inflammatory effects By suppressing CD40L, amember of the tumor necrosis-alpha family of proteins, GPIIb/IIIa inhibitors are thought to reduce platelet–leucocyteinteractions CD40L’s binding to endothelial cells has beenshown to upregulate cellular adhesion molecules (ICAM-1and VCAM-1), matrix metalloproteinases, and tissue factor, all

of which are thought to play a role in the inflammatoryresponse resulting from endothelial injury

The abciximab clinical trials, a group of prospective,randomized, double-blind trials, provided a large body of

evidence supporting the use of platelet IIb/IIIa inhibitors

during PCI in NSTE-ACS (non-ST-elevation acute coronary

syndrome) (33–37) EPILOG (Evaluation in PTCA to

Improve Long-term Outcome with abciximab GP IIb/IIIa

blockade), EPIC (The Evaluation of c7E3 for Prevention of

Ischemic Complications), EPISTENT (Evaluation of Platelet

Inhibition in STENTing), ESPRIT (The Enhanced Suppression

of the Platelet IIb/IIIa Receptor with Integrilin Therapy), and

TARGET (do Tirofiban And ReoPro Give similar Efficacy Trial)

all offered comparison of outcomes between nondiabetic

and diabetic subjects The first four of these trials noted

simi-lar benefit of GP IIb/IIIa inhibition in the diabetic and

nondiabetic population at both 30 days (endpoint of death,

MI, and urgent revascularization) and six months (death or

MI) Perhaps most compellingly, the EPISTENT trial

performed a prespecified analysis of clinical outcomes in

diabetics who were assigned to strategies of stent

implanta-tion plus placebo, stent implantaimplanta-tion plus abciximab, or

angioplasty plus abciximab (38) There was a ⬎50%

reduc-tion in death, nonfatal MI, or urgent revascularizareduc-tion rate at

six-month follow-up in diabetic patients receiving a stent and

abciximab compared with stent alone Additionally, diabetics

treated with stent plus abciximab were less likely to require

repeat TVR (8.1%) than if they were treated with stent plus

placebo (16.6%), or with angioplasty plus abciximab

(18.4%, P⫽ 0.02) This seemed to indicate that abciximab

provided additive benefit to stent implantation with

reduc-tion of TVR in the diabetic populareduc-tion, a finding which was

supported by the ADMIRAL (Abciximab before Direct

angio-plasty and stenting in Myocardial Infarction Regarding Acute

and Long-term follow-up) trial (39), but not by the EPILOG

diabetic substudy (40) or in the ESPRIT trial, which

compared integrilin plus stent with placebo plus stent in

diabetics (41) While it has been suggested that abciximab

offers a unique reduction of TVR rates as a result of its effect

on ␣v␤3 or ␣M␤2 receptors (which would explain for the

nonresult in ESPRIT), no difference was noted between

abciximab and integrillin in TARGET, making this less likely

TARGET did, however, note that abciximab was superior to

tirofiban with respect to the primary 30-day endpoint in both

diabetics and nondiabetics This is currently used to justify

the preferential use of abciximab in the PCI setting

Of note, recent interest in the anti-inflammatory effects of

GP IIb/IIIa inhibitors mentioned before has prompted

specu-lation that certain GP IIb/IIIa inhibitors are more effective than

others in reducing sCD40L (the soluble form of the protein)

In vitro work has indicated that eptifibatide and tirofiban are

possibly more effective in suppressing sCD40L than

abcix-imab (42)—a finding which was supported in one recent

small in vivo post-PCI study (43), but disputed by another

(44) Looking at other inflammatory markers, a substudy of

the EPIC trial noted the balloon angioplasty plus abciximab

group to have decreased levels of CRP and IL-6 in the

24–48-hour period than did patients with balloon angioplasty

alone (45)

Platelet glycoprotein IIb/IIIa inhibitors and clopidogrelGiven the study by Bhatt et al., which noted the superiority

of plavix to aspirin in diabetics, and the aforementioned fit of GP IIb/IIIa inhibitors, an analysis of clopidogrel incombination with abciximab, the current favorite of the GPIIb/IIIa inhibitors, in the diabetic population was warranted.The ISAR-SWEET trial (Intracoronary Stenting andAntithrombotic Regimen: Is Abciximab a Superior Way toEliminate Elevated Thrombotic Risk in Diabetics) studied theuse of abciximab in diabetic patients who were loaded with

bene-600 mg of clopidogrel before receiving bare-metal stents(46) Abciximab plus clopidogrel was not shown to signifi-cantly impact mortality or rates of MI (Fig 1), a result that wassomewhat surprising given the impressive benefit conferred

by GP IIb/IIIa inhibitors in EPISTENT As ISAR-SWEET noted

no reduction in mortality or recurrent MI but did revealtrends toward increased bleeding in those placed on concur-rent clopidogrel and abciximab therapy, it supported limitingpre-PCI antiplatelet therapy to clopidogrel and aspirin

Insulin/glucose insulin potassium infusion

Glucose insulin potassium (GIK) infusion has been suggested

by some to offer additional myocardial salvage in the setting

of an acute MI Theoretically, GIK infusion provides glycolyticfuel to both the starving ischemic myocardium before inter-vention and the reperfused myocardium after PCI It is alsothought to decrease free fatty acid (FFA) levels and toxic FFAuptake by the ischemic myocardium

Although the majority of randomized studies revealed onlyinsignificant trends toward benefit in the general population, ameta-analysis of nine such studies performed from 1965 to

1987 (two were double-blinded and seven were open)revealed a significant mortality benefit with an odds ratio (OR)

of 0.72 [95% confidence interval (CI)⫽ 0.57–0.90] (47) Inthe four most recent trials in the general population to date(48–50), only one presented a significant mortality benefit inthe GIK infusion group (51)

While the evidence for GIK infusion strategy in the generalAMI population is sparse, the diabetes mellitus insulin-glucoseinfusion in acute myocardial infarction (DIGAMI) study group,which studied GIK infusion versus conventional therapy indiabetics, noted significant mortality reductions at three monthsand one year (52) However, whether this was a metabolicbenefit of the acute GIK infusion or a result of strict glycemiccontrol was impossible to interpret The DIGAMI 2 investiga-tors aimed to resolve this question by comparing three

treatment strategies: (i) glucose–insulin infusion followed by insulin-based long-term glucose control; (ii) glucose–insulin

infusion followed by standard glucose control; and (iii) routine

management based on local practice (53) And while this design

should have been effective in isolating the source of DIGAMI 1’s

mortality benefit, DIGAMI 2 ran into considerable difficulty First,

problems with patient recruitment forced the early stoppage of

the trial Second, the established glucose targets in group 1

were never reached, and by the end of the trial glycemic

control was similar in all three groups The lack of benefit in

patients with GIK infusion in DIGAMI 2 suggests that any

bene-fit in the DIGAMI 1 treatment group was from superior

glycemic control and not the initial GIK infusion This concept

has been supported by a recent study of insulin therapy/tight

glycemic control in the critically ill, which evaluated glycemic

control in surgical and trauma patients and noted a 34%

mortal-ity reduction in the more rigorously treated group (54)

Currently, the debate as to whether the beneficial effects of

tight glycemic control with insulin regimens is because of

decreased glucotoxicity or the beneficial metabolic effects of

insulin is still ongoing As such, while there is insufficient evidence

to use intravenous insulin therapy in every case of acute MI, one

should aggressively obtain adequate glycemic control in the

diabetic acute MI patient Of note, in DIGAMI 2, only a small

percentage of patients underwent mechanical revascularization

Thus, from the interventionalist’s perspective, this debate will

remain unresolved until a randomized control trial is performed

in the setting of consistent mechanical intervention

Insulin sensitizersWhile the thiazolidindiones enhance insulin-mediated glucosetransport via binding to the peroxisome proliferator-activatingreceptor (PPAR-␥), the presence of this receptor in vascularsmooth muscle cells, inflammatory cells, and endothelial cellslikely facilitates the drug’s ability to inhibit vascular smoothmuscle cell proliferation, reduce inflammation, improvedyslipidemia, and, by extension, reduce in-stent restenosis

A number of studies using intravascular ultrasound havedemonstrated reductions of neointimal tissue proliferationafter coronary stent implantation in patients taking glitazones(55,56) Two small randomized clinical trials of the glitazonesadministered after PCI, the first by Takagi et al of troglitazone(which has since been pulled from the market) and thesecond by Choi et al of rosiglitazone, demonstrated signifi-cant reduction in restenosis (57,58) Moreover, a recent smallstudy showing decreased rates of stenosis in nondiabetics onpioglitazone therapy supports the notion that the glitazonesconfer benefit via mechanisms unrelated to glycemic control(59) Further large, prospective, randomized trials need to beconducted before glitazones are made the standard of care inthe PCI setting

Metformin, another agent with insulin-sensitizing effects,was found in retrospective analysis to have decreased rates ofdeath and MI (OR⫽ 0.29; P ⫽ 0.007 and OR ⫽ 0.31

Placebo Abciximab

Figure 1

Intracoronary stenting and antithrombotic regimen: is abciximab a superior way to eliminate elevated thrombotic risk in diabetics.

Abbreviations: MI, myocardial infarction;

NS, nonsignificant Source: Adapted from Ref 46.

P⫽ 0.002) in diabetics undergoing coronary intervention.

Interestingly, there was no difference in ischemia-driven TVR

between the metformin and nonmetformin groups—

suggesting that the mechanism of benefit from metformin was

unrelated to intimal hyperplasia The retrospective,

nonran-domized nature of this study limits it utility, and further

prospective studies are needed in this regard (60)

Heparin

The use of intravenous heparin during PCI is currently the

standard of care An indirect thrombin inhibitor, heparin

requires antithrombin-III in order to initiate thrombin

inhibi-tion While intravenous heparin is frequently used, its

limitations, which include poor bioavailability, variable dose—

response relationships, and erratic binding properties, have

prompted the study of low-molecular weight heparins

(LMWH) in the setting of PCI These agents are promising

in that they offer improved bioavailability, a steady dose–

response relationship, and possibly less bleeding While

neither agent has been explicitly studied in diabetics, they

are both regularly used in this population Most recently, the

superior yield of the new strategy of enoxaparin,

revascular-ization, and glycoprotein IIb/IIIa inhibitors (SYNERGY) trial

compared enoxaparin and unfractionated heparin in high-risk

patients with ACS intended for an invasive strategy and did

not reveal significant differences in the primary endpoints at

30 days, six months, or one year, but did note a modest

excess of bleeding (61) Subgroup analysis of diabetic patients

also noted no significant difference in rates of death or MI

between the two modes of therapy at the predetermined

follow-up periods Until there is a dedicated trial of LMWH in

diabetic patients with ACS going for invasive management,

the interventionalist needs to weigh the convenience of

administration offered by LMWH versus its accompanied

modest increased risk of bleeding

Of note, previous study has suggested that relative to

nondiabetics, diabetics are less sensitive to intravenous

heparin (62) Diabetics undergoing PCI and who have been

administered heparin in the absence of abciximab have lower

rates of ischemic events with activated clotting time (ACT) at

increased levels (63) While in diabetics placed on heparin

and abciximab elevated ACT ranges have been associated

with trends toward decreased TVR rates (64), there is strong

data from studies of diverse populations (~23% of patients

with diabetes) that when the two are used in conjunction,

lower ACT ranges (200–250 seconds) can be maintained to

decrease the incidence of bleeding without incurring

increased ischemic events (65,66) Further direct study of

diabetics exposed to varying degrees of heparinization in the

setting of GP IIb/IIIa inhibition needs to be performed to

clarify this issue

Statins and fenofibratesHigh-dose statin therapy is of particular interest in the PCI popu-lation While the mechanism of benefit is likely multifactorial, thewell-documented anti-inflammatory role of statin therapy likelyplays a large role (67) The use of high-dose statins has beencorrelated both with decreased serological measurements ofinflammation (68), and more recently with reduced unstableplaque volume in intravascular ultrasound (IVUS) studies of ACSpatients (69) Given these findings, high-dose statin therapy hasbeen the subject of great interest PROVE-IT TIMI-22 andtreating to new targets (TNT) found a significant benefit in theprimary outcome associated with high-dose statin therapy(70,71), the incremental decrease in end points through aggres-sive lipid lowering trial (IDEAL) and the A to Z trial failed to do

so (72,73) While the value of high-dose statin therapy has notdirectly been addressed in the diabetic PCI population, theTIMI-PROVE IT study showed that diabetics treated with 80 mg

of atorvastatin had an approximately 17% reduction in thecombined endpoint of death, MI, stroke, angina requiring read-mission, or revascularization at two years

Most recently, in a substudy of the Lescol InterventionPrevention Study (LIPS) trial, diabetic patients treated withaggressive lipid-reducing therapy after PCI were noted to have a51% reduced risk of future cardiovascular events at long-termfollow-up (74) Of note, there was no difference in the rate ofrestenosis between the treatment and the control groups, andthe benefit of fluvastatin in diabetics was based on reduction oflong-term complications Nevertheless, given the long-term find-ings in both of the studies, it is incumbent on the interventionalist

to begin statin therapy in diabetic patients shortly after PCI.Fenofibrates were found to slow the development of angio-graphic CAD in diabetics in the DAIS (Diabetes AtherosclerosisIntervention Study) study (75) While the diabetics undergoingPCI have yet to be evaluated, fenofibrates are being actively stud-ied in the general diabetic population The fenofibrate interventionand event lowering in diabetes (FIELD) randomized type 2diabetics to placebo or fenofibrate While there was no significantdifference in the primary endpoint of coronary heart disease(CHD)-related-death or MI, the secondary endpoint of totalcardiovascular events was significantly lower in the fenofibrategroup (76) These results were possibly confounded by the asym-metric use of statins (17% and 7% in the placebo and fenofibrategroups, respectively) and will be remedied in the action to controlcardiovascular risk in diabetes (ACCORD) trial, which willrandomize diabetics already taking statins to either fenofibrate orplacebo Fenofibrates are currently an area of interest and willeventually need evaluation in the diabetic PCI setting

Contrast-induced nephropathyContrast-induced nephropathy (CIN), defined as a serumcreatinine increase of ⬎25% relative to baseline, is associated