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Management of Coronary Artery Disease inPatients with Diabetes Mellitus

VK Bahl, Sandeep SethDepartment of Cardiology, All India Institute of Medical Sciences, New Delhi

Diabetes mellitus (DM) is a common medical problemand a major risk factor for the development ofatherosclerotic coronary artery disease (CAD). Worldwide,more than 100 million people have DM and this figure isprojected to double in the next 20 years. In India alone, it isestimated that there are more than 20 million diabetics.1

There is no doubt that DM is going to be a major burden onthe health care system in the twenty-first century. DM isnot only associated with increased incidence and prevalenceof CAD, but diabetic patients also have a 2-fold increase inmortality after acute myocardial infarction (AMI). Theoutcome following coronary angioplasty (PTCA) andcoronary bypass grafting (CABG) is also poor. TheFramingham Heart Study data showed that patients withDM, particularly women, exhibited an increased risk ofcardiovascular events including angina, stroke,claudication, heart failure, myocardial infarction andsudden death.2 Diabetics have the same degree ofcardiovascular risk as non-diabetics who have had amyocardial infarction (MI). A number of pathophysiologicalmechanisms contribute to the development of bothmacrovascular and microvascular complications in patientswith DM. The presence of associated risk factors foratherosclerosis like obesity, advanced age, dyslipidemia andhypertension, as well as multiple metabolic abnormalitieslike hyperglycemia, hyperinsulinemia and abnormalities ofplatelet function and coagulation contribute to thecardiovascular complications.

Control of Risk Factors

In diabetics, coronary risk factors are magnified severaltimes, and these need to be strictly controlled. Smoking isan independent predictor of mortality in diabetics andcessation of smoking should be recommended for allpatients. Weight loss and increased physical activity havebeen shown to improve glycemic control, lipid profile andinsulin resistance.

Intense glycemic control is highly effective in preventingand retarding microvascular and, to some extent,

Indian Heart J 2001; 53: 147154 Editorial

macrovascular complications in both insulin-requiring DM(IRDM) and non-insulin requiring DM (NIRDM).

There is no specific trial addressing the effect of lipidlowering in diabetic patients; however, subgroup analysesfrom a number of trials with statins have shown the efficacyof this therapy. The Scandinavian Simvastatin SurvivalStudy (4S) trial, which enrolled 202 diabetic patients,indicated that simvastatin reduced five-year mortality by43% in diabetic patients with hypercholesterolemia andCAD, as compared to 29% reduction in non-diabeticpatients.3 The Cholesterol and Recurrent Events Trial(CARE) enrolled post-MI patients with average cholesterollevels. Treatment with pravastatin showed a greaterreduction in major coronary event rate during a five-yearfollow-up in patients with DM compared to non-diabetics(37% v. 29%).4 In the Long-term Intervention withPravastatin in Ischemic Disease (LIPID) study (whichenrolled 811 diabetics), pravastatin therapy showed a 19%reduction in the composite end-point of CAD-related deathand MI during 6 years of follow-up in the subgroup ofdiabetics with past history of MI or unstable angina.5 Thedata available from studies on the use of fibrate therapy islimited. The Helsinki Heart Study had suggested a trendtowards decreased coronary events in diabetic patientstreated with gemfibrozil compared to non-diabetics.6

There are a number of studies which have shown thatadequate control of blood pressure markedly reduces majorcardiovascular events. Most of the available data are fromstudies using beta-blockers and diuretics and they continueto be recommended as first-line therapy. There are sufficientdata to show that they reduce mortality and morbidity inpatients with diabetic nephropathy and in NIRDM patients.Strict control of blood pressure to a mean of 144/82 mmHghas been shown to significantly reduce strokes, diabetes-related deaths, heart failure, microvascular complicationsand visual loss in UKPDS trial.7 There is a growing amountof data coming up in support of angiotensin-convertingenzyme (ACE) inhibitors and calcium channel blockers. Therevised guidelines of the Joint National Committee (JNC)on Prevention, Detection, Evaluation and Treatment ofHigh Blood Pressure recommended a level of 130/85mmHg for diabetic patients.

Correspondence: Dr VK Bahl, Professor of Cardiology, All India Instituteof Medical Sciences, New Delhi, e-mail: [email protected]

IHJ-Editorial.p65 6/5/01, 12:09 PM147

148 Bahl et al. Management of Coronary Disease in Diabetics Indian Heart J 2001; 53: 147154

Issues in Management

Managing CAD patients with DM requires special attention.The majority of data on the management of CAD in DMare based on retrospective subgroup analysis of majorclinical trials, which on an average included 20%30%diabetic patients. Patients with DM have a number of adverseclinical, angiographic and metabolic features contributingto poor prognosis. Diabetic patients with CAD are more oftenfemale, obese and hypertensive. They usually have severeangina, history of previous MI or CABG and marked leftventricular failure. They have abnormal endothelial functionwith reduced coronary flow reserve. There is plateletactivation with increased thromboxane A2 secretion. Thelevels of fibrinogen and Factor VII are higher than normal,while antithrombin III and plasma fibrinolytic activity arelower. Angiographically, they have diffuse, extensiveinvolvement of smaller reference vessels, multivesselinvolvement, higher incidence of left main coronary arterydisease, poorer collaterals, lower ejection fraction and morethrombus formation.

Two important issues need to be considered in themanagement of CAD in patients with DMmanagementof acute myocardial infarction and coronaryrevascularization (both surgical and catheter-based).

Management of Acute Myocardial Infarction

Management strategies include the use of thrombolytics,beta-blockers, ACE inhibitors, nitrates and antiplateletagents.

Thrombolytic therapy: Diabetic patients are less likely toreceive thrombolytic therapy as they present late and/orwith atypical symptoms, perhaps due to impaired sensationof pain. There is also undue concern regarding the adverseef fects of thrombolytic agents, especially ocularcomplications. The efficacy of thrombolysis may also bereduced in DM due to enhanced platelet activity, elevatedprocoagulant activity and imparied intrinsic fibrinolysis.Despite achieving similar patency rates (70%) as non-diabetics, the mortality is higher in diabetics (17.3% v.10.2%), probably because of impaired endothelial functionand diminished myocardial flow reserve.8 Reocclusion withrecurrent ischemia was also higher in diabetics (9.2% v.5.3%) in the Global Use of Strategies To Open OccludedArteries (GUSTO) study.9 However, in spite of several factorsunfavorable for thrombolysis, they still derive substantialbenefit from it. The Fibrinolytic Therapy Trialists (FTT)Collaborative Group in an overview of 58 600 patientsincluding 4529 diabetics, showed that the absolute reduction

in the 35-day mortality after thrombolysis in patients withDM was 3.7% compared with 1.5% in non-diabetics. Indiabetic patients it fell to 13.6% following thrombolysis ascompared to 17.3% in the control group, while in the non-diabetic group, the mortality was reduced to 8.7% versus10.2% in the control group.8

The fear of increased adverse effects of thrombolytictherapy in diabetics is not borne out by the available data.The data from the FTT Collaborative Group showed nostatistically significant increase in hemorrhagic stroke inpatients with DM receiving thrombolytic therapy (0.6% v.0.4%). In the GUSTO study, the incidence of clinicallyevident ocular complications was only 0.02% and there wasno case of intraocular hemorrhage. Stroke rates werecomparable in diabetics and non-diabetics (1.9% v. 1.4%).Vitreous hemorrhage in diabetic patients was rare.8

There are some data to show the superiority of anaccelerated tissue plasminogen activator (tpa) regimen inpatients with DM. In the GUSTO-1 study, diabetics giventpa had a 30-day mortality of 8% compared to 10.2% inthe group given streptokinase (STK). The stroke rate wasnot significantly different in two groups (1.7% in the tpagroup and 1.4% in the STK group). Thus, the acceleratedtpa regimen appears to be better than STK. However, thecost-effectiveness of this regimen in our country remainsquestionable.

Post-thrombolysis strategies: Whether to follow aconservative or an invasive approach followingthrombolysis in AMI, is a matter of debate. Clinical variablescollected for the 3339 patients of the Thrombolysis InMyocardial Infarction (TIMI)-II study were analyzedretrospectively to identify predictors of clinical events at 42days, so as to identify the subgroups in which an invasiveor conservative strategy might be superior. Patients withDM had a higher mortality in the invasive compared to theconservative strategy group (14.8% v. 4.2%, p

Indian Heart J 2001; 53: 147154 Bahl et al. Management of Coronary Disease in Diabetics 149

diabetics (72.4%). Outcome at 30 days for death, MI andstroke was better for non-diabetics randomized toangioplasty versus alteplase (9.3% v. 13.2%) with a similartrend for diabetics (11.1% v. 16.7%).

Antiplatelet agents: Diabetics have increased plateletactivation and accelerated turnover of platelets. Thus,theoretically they may need higher doses or higherfrequency of aspirin administration, or need additionalantiplatelet agents like ticlopidine or clopidogrel. The subsetanalysis of the Second International Study of InfarctSurvival (ISIS-2) found no benefit of 160 mg per day ofaspirin in diabetic patients. Since this was a subgroupanalysis, it could be a chance finding but it did put a questionmark on the efficacy of low-dose aspirin in diabeticpatients.12 However, a meta-analysis of the Anti-PlateletTrialists Collaborative Group was done to determine theeffect of antiplatelet therapy on vascular events. It showeda significant benefit of aspirin therapy in DM with orwithout vascular disease, for the combined end-point ofstroke, MI or vascular death. In diabetic patients, thevascular event rate with aspirin fell to 18.5% as comparedto 22.3% in controls.13 The magnitude of this benefit wassimilar in diabetics and non-diabetics. The most widelytested antiplatelet regimen was medium-dose (75325mg/day) aspirin. Doses throughout this range seemed tohave a similar effect. There was no appreciable evidence thateither a higher aspirin dose or any other antiplateletregimen was more effective than medium-dose aspirin inpreventing vascular events.

Glycoprotein(Gp) IIb/IIIa inhibitors reduce the early andmid-term incidence of death, MI and recurrent angina inpatients with acute coronary syndrome (ACS). They havebeen found to be useful alone and in combination withthrombolytic agents such as STK and tpa. They are alsouseful during percutaneous coronary intervention (PCI).The data regarding their efficacy in diabetics are based onsubgroup analysis of some of the major trials. In the PlateletReceptor Inhibition for Ischemic Syndrome Managementin Patients Limited by Unstable Signs and Symptoms(PRISM-PLUS) study, the reduction in clinical events in thegroup receiving tirofiban plus heparin compared to heparinalone was significant in both the diabetic and non-diabeticsubgroups. The rate of death or MI at 180 days was 11.2%with tirofiban plus heparin versus 19.2% with heparinalone.14 In the PURSUIT study (10 948 patients including20% diabetics), reduction in the 30-day mortality witheptifibatide was more in diabetic patients than non-diabetics.15 A meta-analysis of 10 recent clinical trials alsoshowed that diabetics had twice the absolute reduction in

event rates as compared to non-diabetics.16

Anticoagulants: The majority of recent trials of low-molecular-weight heparins (LMWH) in ACS have showntheir superiority over unfractionated heparin (UFH) in the30-day incidence of a composite end-point of death, MI orrecurrent angina.17,18 They have been shown to be especiallyuseful in the high-risk subgroups, i.e. patients withelectrocardiographic changes, positive troponin-T and DM.The diabetic patients (n=2175) in the randomized GUSTO-IIb study (n=12142) showed a tendency towards a lowerrisk of death or reinfarction with hirudin as compared toheparin at 30 days (12.2% v. 13.9%) and 6 months (17.8%v. 20.2%). However, they had a higher incidence of majorbleeding and stroke.

Beta-blockers: Clinicians are hesitant to use beta- blockersfor diabetic patients because of their concerns regardingimpaired glucose metabolism and worsening ofdyslipidemia, and the fear that symptoms of hypoglycemiawould be masked. These concerns are only of academicinterest since the benefits outweigh the theoretical risks. Anumber of studies evaluating the effect of beta- blockers inAMI have demonstrated a two-fold reduction in the relativerisk in terms of mortality benefit after MI in diabetics ascompared to non-diabetics. With beta-blockers, thepercentage reduction in mortality was higher in diabetics(37%) compared to non-diabetics (13%). There were similartrends for reinfarction rates with a 55% reduction inpatients with DM versus 21% reduction in non-diabetics.20

From a database of 14 417 patients with chronic CADwho had been screened for participation in the BezafibrateInfarction Prevention (BIP) study, 19% had NIRDM. Thetotal mortality during a 3-year follow-up was 7.8% in thosereceiving beta-blockers compared with 14.0% in those whowere not (44% reduction). Multivariate analysis identifiedbeta-blocker therapy as a significant independentcontributor to improved survival. Within the diabeticpopulation, the main benefit associated with beta-blockertherapy was observed in older patients, in those with ahistory of MI, those with limited functional capacity, andthose at lower risk. Thus, therapy with beta-blockersappears to be associated with improved long-term survivalin the high-risk subpopulation of patients with DM andCAD.21

Angiotension-converting enzyme inhibitors: ACEinhibition in AMI improves left ventricular remodelling, thefibrinolytic balance, endothelial function andsympathovagal balance. It delays renal dysfunction andimproves glycemic control.

A retrospective analysis of the data of the GISSI-3 study



revealed a decreased 6-week mortality in diabetic patientswith lisinopril (8.7% v. 12.4%), an ef fect that wassignificantly (p


incidence of both restenosis (37.5% v. 28.3%, p


single-center EAST had 15% drug-treated diabetic patients.In these patients, the overall 8-year mortality demonstratedno statistically significant difference relative to the firstrevascularization procedure selected. In the RITA-1 trial,the predefined primary end-point of death or nonfatal MIoccurred in 17% of PTCA patients and in16% of CABGpatients (p=0.64). Diabetics did not fare any differently fromnon-diabetic patients.47

Weintraub et al.29 reported data from the EmoryUniversity showing that angiographic and clinical successrates after multivessel angioplasty were similar in diabeticsand non-diabetics. In-hospital major complications wereinfrequent (3%), with a trend towards higher death or MIin those with IRDM. The 10-year survival rate in diabeticsafter multivessel PTCA was 45% white it was 48% afterCABG. The survival in insulin-requiring diabetics was lower(31% after PTCA and 48% after CABG).29

The Northern New England Cardiovascular DiseaseStudy Group has recently reported that patients with DMtreated with percutaneous coronary intervention hadsignificantly greater mortality relative to those undergoingCABG (risk-adjusted hazard ratios [HR]=1.49; p=0.037).The risk of mortality tended to increase further amongpatients with three-vessel disease (HR=2.02; p=0.038)than among patients with two-vessel disease (HR=1.33;p=0.21).48

The St Luke database49 showed that only 42% of diabeticpatients could achieve complete revascularization bymultivessel PTCA as compared to 79% after CABG. Six-yearsurvival was 63% after PTCA and 70% after CABG. Itshowed that completeness of revascularization rather thanthe mode was predictive of late mortality.49 A majority oftrials comparing multivessel plain balloon angioplasty withCABG revealed that overall long-term survival is better withCABG and the need for repeat revascularization is less.

The Duke university database (1984 to 1990) includedpatients receiving intracoronary stents. At six years, thecardiovascular mortality was similar with tworevascularization strategies (19% after CABG and 20% afterPTCA in diabetics, and 10% and 8% in non-diabetics).50 Thebetter results with multivessel PTCA in this database wereattributed to the use of stents in some of the cases.

All these trials with multivessel angioplasty wereinitiated when stents had not really become part of routinecoronary interventions. This naturally raises the questionwhether multivessel stenting would be better than CABG. TheArterial Revascularization Therapies Study (ARTS) groupsought to answer this question.51 At one year, there was nosignificant difference in terms of the rates of death, stroke orMI between the patients undergoing multivessel stenting and

CABG, while the rate of event-free survival was better in thelatter group (73.8% v. 87.8%). However, multivariate Coxregression analysis showed that presence of DM was the keypredictor of outcome in the stented group. Therefore, evenmultivessel stenting may not solve the problems ofpercutaneous revascularization in diabetic patients.

Conclusions

The management of CAD in diabetic patients poses achallenging problem. The risk factors need to be vigorouslycontrolled with tight management of lipids and bloodpressure. Strict control of hyperglycemia should be ensured.The benefit of treating diabetics, especially withthrombolysis and ACE inhibitors, is more in terms of livessaved. Percutaneous interventions in diabetics areassociated with higher rates of in-hospital complicationsand more restenosis as compared to non-diabetics. Long-term results of CABG in diabetics are better than those withmultivessel PTCA. The availability of newer techniques ofangioplasty, better stents and the use of Gp IIb/IIIaantagonists may improve the prognosis in diabetics.Intracoronary radiation may reduce neointimalproliferation. Stents coated with antiproliferation agents likerapamycin and taxol may be useful. For patients whosevessels are not suitable for any revascularization procedure,gene therapy may provide a solution.

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Acute coronary syndrome refers to a constellation ofsymptoms that are compatible with acute myocardialischemia. It encompasses ST segment elevation, ST segmentdepression myocardial infarction, and unstable angina.Unstable angina and non-ST segment elevation myocardialinfarction (UA/NSTEMI) are components of the acutecoronary syndrome. UA and NSTEMI share commonclinical, pathophysiologic and treatment features, and thusthe 2 entities are often considered together for diagnosis andmanagement. Patients with UA/NSTEMI account for morethan 1 million hospital admissions annually in the UnitedStates, and 6%8% of patients either die or have nonfatalmyocardial infarction within the first year of diagnosis.1

Pathophysiology

The pathophysiology of UA/NSTEMI has some similaritywith that of Q wave myocardial infarction. Coronarythrombus after rupture of a vulnerable plaque plays a keyrole in the pathogenesis. Autopsy studies have demonstratedplaque rupture in approximately 60% of cases and plaqueerosion in 30%.2 The process of atherogenesis, lipidaccumulation and cellular proliferation in UA/NSTEMI isnot linear and is unpredictable. New high-grade lesionsappear in previously mildly diseased segments. In a previousstudy of patients undergoing serial angiography, 66% ofpatients presenting with myocardial infarction and totalocclusion of an artery on coronary angiography had lessthan 50% stenosis, and 97% of patients had less than 70%stenosis at the time of the initial coronary angiogrampredating the infarction.3 This unpredictable and episodicprogression is most likely a result of plaque rupture andsubsequent intracoronary thrombus. Most plaque rupturesoccur at the shoulder region (junction of the plaque capand the adjacent more normal arterial wall). Several factorscontribute to the clinical syndrome of UA/NSTEMI, namely,platelet aggregation, altered vasomotion, thrombus in thesetting of plaque erosion (endothelial cell denudation),rupture of a vulnerable plaque (related to the rich lipid core),macrophage activity and metalloproteinases.46

Classification

There is no universally accepted definition for UA/NSTEMI.It encompasses a range of different clinical presentations.These clinical variables with dif ferent prognosticimplications have been grouped under one diagnosis. In aproportion of patients admitted with a diagnosis of UA, thecondition evolves into NSTEMI during the hospital stay. Thisprocess makes interpretation of published data difficult. TheBraunwald classification7 has helped, but it is still not widelyused, as ideally should be the case (Table 1). Thisclassification was recently revised.8 Class IIIB (unstableangina with rest pain occurring within the preceding 48hours without a recent myocardial infarction) was dividedinto troponin-positive and troponin-negative groups. Therisk of cardiac death or myocardial infarction within 1month was estimated to be 15%20% in the class IIIBtroponin-positive group and less than 2% in the class IIIBtroponin-negative group. A second sample of troponin wasrecommended if the first was negative at admission. Theassociation between increased troponin levels and increasedmortality was evident in patients with normal creatinekinase-MB (CK-MB) levels. There was also a significantincrease in mortality with increasing levels of troponin. Therecent American College of Cardiology/American HeartAssociation (ACC/AHA) guidelines have stratified patientswith UA/NSTEMI into 3 categories: low, intermediateand high risk, according to the clinical information,including history and physical examination, 12-leadelectrocardiogram, and cardiac enzymes values (Table 2).This stratification is important not only for prognosticpurposes but also for treatment; different treatments maybe offered depending on the risk profile of the patient atadmission or during hospital stay.

Prognosis of Patients with Unstable Angina

Excellent predictive models are available for patients withUA/NSTEMI. Simple risk scores are available from thePlatelet Glycoprotein IIb/IIIa in Unstable Angina: ReceptorSuppression Using Integrilin Therapy (PURSUIT) data, theThrombolysis in Myocardial Infarction (TIMI) risk scorederived from TIMI IIB, and Efficacy and Safety ofSubcutaneous Enoxaparin in Non-Q-Wave Coronary Events

Percutaneous Coronary Intervention in Patientswith Unstable Angina

Mandeep Singh, David R Holmes JrDivision of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA

Indian Heart J 2001; 53: 155162 Review Article

Correspondence: Dr Mandeep Singh, Division of CardiovascularDiseases and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester,Minnesota, USA 55905, e-mail: [email protected]

IA-004.p65 6/5/01, 11:50 AM155

(ESSENCE) trials.911 The risk factors associated with ahigher risk for death or myocardial infarction in thePURSUIT trial were older age, faster heart rate, lower bloodpressure, signs of heart failure and ST depression. Anenrollment diagnosis of myocardial infarction wasassociated with a 50% increase in 30-day reinfarction.Therefore, most information about cardiac risk can beobtained at admission from patients presenting with UA/NSTEMI. The TIMI score identified that in patients with UA/NSTEMI, the following factors were associated with a higherrisk for adverse cardiac events: age 65 years or more, at least3 risk factors for coronary artery disease (such as diabetes,hypertension, family history of coronary artery disease,hypercholesterolemia and current smoking), ST segmentelevation (transient) or depression, severe anginalsymptoms (>2 anginal symptoms in past 24 hours), aspirinuse within the past 7 days, and increased values for serumcardiac markers (CK-MB fraction or cardiac-specifictroponin level). In contrast, similar scores can predictinsignificant coronary artery disease by simple nomograms.These are important because patients with minimal diseaseat coronary angiography do not seem to benefit fromglycoprotein (Gp) IIb/IIIa receptor inhibitors.11 The riskstratification and prognostication with the available scoreswould help identify patients at higher risk for adverse

156 Singh et al. Coronary Intervention in Unstable Angina Indian Heart J 2001; 53: 155162

Table 1. Classification of unstable angina

SeverityClass I New-onset, severe, or accelerated angina

Patients with angina of less than 2 months duration, severeor occurring 3 or more times per day, or angina that is distinctlymore frequent and precipitated by distinctly less exertion. Norest pain in the last 2 months

Class II Angina at rest, subacutePatients with 1 or more episodes of angina at rest during thepreceding month but not within 48 hours

Class III Angina at rest, acutePatients with 1 or more episodes of angina at rest within thepreceding 48 hours

Clinical circumstancesClass A Secondary unstable angina

A clearly identified condition extrinsic to the coronary vascularbed that has intensified myocardial ischemia, such as anemia,infection, fever, hypotension, tachyarrhythmia, thyrotoxicosis,hypoxemia due to respiratory failure

Class B Primary unstable anginaClass C Postinfarction unstable angina (within 2 weeks of documented

myocardial infarction)

Intensity of treatment1. Absence of treatment or minimal treatment2. Occurring in presence of standard therapy for chronic stable

angina (conventional doses of oral -adrenergic blockers,nitrates and calcium antagonists)

3. Occurring despite maximally tolerated doses of all 3 categoriesof oral therapy, including intravenous nitroglycerin

Data from Braunwald E7

cardiac events and would allow cardiologists to stratify thesepatients into different plans of management.

Medical Treatment

The medical management of all patients admitted with adiagnosis of UA/NSTEMI includes bed rest, aspirin,intravenously administered heparin, nitrates, and -adrenergic blockers. Angiotensin-converting enzymeinhibitors are added in patients with depressed leftventricular systolic function and diabetes mellitus.

Glycoprotein IIb/IIIa receptor inhibitors havesignificantly improved the outcome of patients presentingwith UA/NSTEMI. The 3 agents approved for clinical useare: (1) the monoclonal antibody abciximab; (2) the peptidereceptor antagonist eptifibatide; and (3) the nonpeptidereceptor antagonist tirofiban. In the Evaluation of c7E3 forthe Prevention of Ischemic Complications (EPIC) study,12

the 2099 patients who had balloon angioplasty ordirectional atherectomy had a 35% reduction in thecomposite end-points of death, nonfatal myocardialinfarction, refractory ischemia, or urgent revascularizationwithin 30 days. The benefit of abciximab persisted for up to3 years after the procedure.13 The Evaluation in PTCA toImprove Long-term Outcome with Abciximab Gp IIb/IIIablockade (EPILOG) trial14 tested the benefits of abciximabin patients at lesser risk who were given lower doses ofweight-adjusted heparin. In 2972 enrolled patients, thosewho received abciximab and low-dose heparin had a 57%reduction in the composite end-points of death, myocardialinfarction, or urgent revascularization (5.2%), comparedwith patients receiving standard heparin therapy (11.7%).In the Chimeric 7E3 Antiplatelet Therapy in UnstableAngina Refractory to Standard Treatment (CAPTURE)trial,15 patients were randomized after coronaryangiography to either placebo or abciximab. Abciximabtherapy was given for 18 to 24 hours before coronaryintervention and was continued for 1 hour after theintervention. The CAPTURE trial was prematurelyterminated because the abciximab-treated patients had asignificant reduction in the composite end-points at 30 days.Also, the progression of myocardial infarction beforecoronary intervention was significantly reduced (0.6% v.2.1%; p=0.03).

The Platelet Receptor Inhibition in Ischemic SyndromeManagement (PRISM), Platelet Receptor Inhibition inIschemic Syndrome Management in Patients Limited byUnstable Signs and Symptoms (PRISM-PLUS),16 and theRandomized Efficacy Study of Tirofiban for Outcomes andRestenosis (RESTORE) trials17 evaluated tirofiban. Among1570 patients who had percutaneous coronaryintervention (PCI) in PRISM-PLUS, there was a 42%

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reduction in the 30-day incidence of death or myocardialinfarction.16 The RESTORE trial randomized patients toeither percutaneous transluminal coronary angioplasty(PTCA) or directional atherectomy.17 In 2139 patients, thestudy showed a trend for reduction of the combined end-points of death or myocardial infarction, emergencycoronary artery bypass grafting, unplanned stentplacement for abrupt closure, and recurrent ischemiacompared with placebo at 6 months (24.1% v. 27.1%,p = 0.11).

In the Integrilin to Manage Platelet Activation to PreventCoronary Thrombosis (IMPACT-II) study,18 analysis oftreated patients showed a 24% reduction in the compositeend-points of death, myocardial infarction, orrevascularization (11.6% v. 9.1%). In patients undergoingPCI in the PURSUIT trial within 72 hours of randomization,eptifibatide resulted in a 31% reduction in death ormyocardial infarction at 30 days (17.7% v. 11.6%,p=0.01).19 Meta-analysis of 32 735 patients from 10 majorrandomized trials demonstrated a 21% reduction in theincidence of 30-day death or myocardial infarction inpatients treated with any of the given Gp IIb/IIIaantagonists.20

Abciximab is currently approved for treatment of UA/NSTEMI as an adjunct to PCI or when the intervention isplanned within 24 hours. The longer half-life of abciximabmakes it less suitable in patients likely to need coronaryartery bypass grafting. In this setting, Gp IIb/IIIa inhibitorswith a shorter half-life (eptifibatide) would be optimal.Tirofiban used in combination with heparin is approved foruse both for medical management and in conjunction withPCI. Clinical markers that put the patient in the higher-riskcategory may guide patient selection. Patients with STsegment depression or increased cardiac marker valuesderive the maximum benefit from this expensive therapy.

These trials indicate that Gp IIb/IIIa receptor inhibitorsare of benefit in patients with UA/NSTEMI, especially if PCIis planned. Treatment benefits were observed within hoursafter intervention and were sustained in the long term. Theclinical trials revealed a greater magnitude of benefit withabciximab than with the other 2 agents. The effects of twoGp IIb/IIIa inhibitors were compared in the recent DoTirofiban And Reopro Give Similar Efficacy Outcomes Trial(TARGET) (presented at the American Heart Association 2000meeting), in which 4812 patients were randomized toreceive either abciximab (n=2414) or tirofiban (n=2398).

Indian Heart J 2001; 53: 155162 Singh et al. Coronary Intervention in Unstable Angina 157

Table 2. Short-term risk of death or nonfatal myocardial infarction in patients with unstable angina*

Feature High risk (at least 1 of the following Intermediate risk (no high-risk feature Low risk (no high- or intermediate-riskfeatures must be present) but must have 1 of the following feature but may have any of the

features) following features)

History Accelerating tempo of ischemic Prior MI, peripheral or cerebrovascular symptoms in preceding 48 h disease, or CABG; prior aspirin use

Character of pain Prolonged ongoing (>20 min) rest Prolonged (>20 min) rest angina, now New-onset CCS class III or IV angina pain resolved, with moderate or high in the past 2 weeks with moderate or

likelihood of CAD high likelihood of CADRest angina (70 years related to ischemiaNew or worsening MR murmurS3 or new or worsening ralesHypotension, bradycardia, tachycardiaAge >75 year

ECG findings Angina at rest with transient ST T wave inversions >0.2 mV Normal or unchanged ECG during an segment changes >0.05 mV episode of chest discomfortBundle branch block, new or Pathologic Q waves presumed newSustained ventricular tachycardia

Cardiac markers Markedly elevated (e.g, TnT or TnI Slightly elevated (e.g. TnT >0.01 but Normal >0.1 ng/mL)

The 2 groups were matched for the baseline characteristics.Sixty-three percent had acute coronary syndrome (STsegment elevation myocardial infarction and patients withcardiogenic shock were excluded). Ninety-five percentreceived intracoronary stents. The primary end-point ofdeath, myocardial infarction, or urgent target vesselrevascularization was achieved in 7.55% of patients in thetirofiban group and in 6.01% in the abciximab group(RR=1.26, p=0.037).

The greater benefit with abciximab is possibly due toboth its longer biological half-life and its effects on non-IIb/IIIa vitronectin receptors. Dosing issues andunderestimation of platelet inhibition are possibleexplanations for the worse outcome with tirofiban than withabciximab. The current ACC/AHA guidelines recommendthat Gp IIb/IIIa inhibitors be given to patients withcontinuing ischemia or with high-risk features and topatients in whom PCI is planned.

Coronary Angioplasty in Unstable Angina

General considerations: Coronary angioplasty in asetting of unstable angina differs from that in stable anginapectoris and may be associated with increasedcomplications. Angioplasty can aggravate thrombusformation by endothelial denudation and platelet activation.The presence of an intracoronary thrombus is anindependent predictor of increased complications with PCI,especially myocardial infarction.21 The ineffectiveness ofGp IIb/IIIa inhibitors in a setting of thrombus makes thisoption less attractive.21 The setting of UA/NSTEMI also mayexacerbate the dissection at the site of plaque rupture.Vasoreactivity of the treated vessel can also be a problembecause the thrombus generates vasoactive substances.Finally, the risk of distal embolization is increased. Thesecomplications are less frequent in a setting of chronic stableangina. Recently, the introduction of intracoronary stentsand filter and thrombectomy devices, in addition toimprovement in the angioplasty equipment and operatorexperience, has led to resurgence of the concept of an earlyrevascularization strategy in this high-risk subgroup.

Combination therapy: Unfractionated heparin has longbeen the main antithrombin agent used in the managementof acute coronary syndromes. The most importantlimitation of unfractionated heparin is the variable doseresponse relationship in different patients, necessitatingfrequent monitoring of the anticoagulation status. It canalso bind to plasma proteins and endothelial cells andmay result in rebound hypercoagulability, inducethrombocytopenia, and facilitate platelet aggregation.

Low-molecular-weight heparins (LMWHs) have been

developed to address some of these limitations. These agentscan be administered subcutaneously, and no monitoring isrequired. The efficacy of LMWH has been addressed in theESSENCE and TIMI IIB trials.22,23 In the ESSENCE trial,23

3171 patients with UA/NSTEMI were randomized to eithersubcutaneous enoxaparin or unfractionated heparin.Therapy was administered for a median of 2.6 days. Theprimary end-point of death, myocardial infarction, orrecurrent angina occurred within 14 days of enrollmentin 16.6% of patients receiving enoxaparin and in 19.8% ofpatients receiving unfractionated heparin (p=0.02). Similarresults were reported in the TIMI IIB trial comparingenoxaparin and unfractionated heparin.22 The other trialswith LMWH have not demonstrated their superiority overunfractionated heparin. In the Fast RevascularizationDuring Instability in Coronary Artery Disease (FRISC II)trial,24 dalteparin was given to all patients for a minimumof 5 days. Subsequently, the patients were randomized toreceive placebo or dalteparin for up to 90 days. There was asignificant reduction in the incidence of death or myocardialinfarction at 30 days but not at 3 months (6.7% v. 8.0%).The benefits of dalteparin were limited to patients withincreased troponin T levels and those managed medically.Recently, the National Investigators Collaborating onEnoxaparin (NICE) 4, in an open-labeled study, comparedthe safety and efficacy of enoxaparin used in place ofunfractionated heparin in the setting of acute coronarysyndrome. The preliminary data compared favorably withthe previously published results. Clinical RevascularizationUsing Integrilin Simultaneously with Enoxaparin (CRUISE)is an ongoing randomized trial to address this issue. Thecurrent ACC/AHA guidelines recommend treatment witheither unfractionated heparin or with LMWH to be addedto antiplatelet therapy.

Early invasive versus conservative strategy inunstable angina (Tables 3 and 4): The 2 strategies forthe treatment of patients with UA/NSTEMI are widelydebated. In the early conservative arm, PCI is reserved forpatients who have recurrent ischemia at rest or minimalactivity or who have a strongly positive stress test despitemaximal medical therapy. The advantage of the earlyconservative treatment is that it limits the risks and costsof the invasive procedure in all patients presenting with UA/NSTEMI.

In contrast, early revascularization has several potentialadvantages that can partially offset the increased hazardof an early invasive strategy. It defines the coronaryanatomy in patients with UA/NSTEMI. Typically, less than10% have significant left main coronary artery disease,multivessel disease is present in 40% to 50%, single-vesseldisease is present in a third, and 10% to 20% have no


IA-004.p65 6/5/01, 11:51 AM158

significant disease.25 The treatment strategy can be decidedon the basis of the clinical profile and the coronary anatomy.Patients without significant coronary artery disease can beexpeditiously dismissed. The revascularization strategy isdetermined by considering several factors: the patientsclinical risk, coronary anatomy, ventricular function,severity of symptoms, co-morbidities and life expectancy.The decision for early invasive or conservative treatmentstrategies is based on the trials and registries describedbelow.

In the 1990 TIMI IIIB study, a randomized trial with a22 factorial design, an early invasive approach in patientswith unstable angina was not found to be superior to earlyconservative strategy.25 The primary end-point of death,myocardial infarction, or an abnormal exercise tolerancetest at 42 days was 16.2% in the early invasive arm andwas not significantly different from that observed in theearly conservative arm (18.1%). However, the number ofpatients rehospitalized and the number of days ofhospitalization were significantly lower in the early invasive

Table 3. Recent studies on unstable angina: features

TIMI IIIB (1994) VANQWISH (1998) OASIS (1998) Mayo Clinic (1999) FRISC II (1999)

Number of patients 1473 920 7987 7632 2433Study design 22 factorial design Randomized trial of Prospective Early invasive strategy Randomized trial

TPA v. placebo non-Q wave MI registry, studied in recent years Early invasive v.Early invasive v. Early invasive v. the relationship was compared with early conservative early conservative conservative strategy between rates of that in earlier years strategy

cardiac procedures and outcomes

Primary end-point Death, nonfatal MI, Death or nonfatal MI Death or nonfatal MI positive ETT

Time from randomizationrevascularization 1872 hours 8 days (median) 27 days

Catheterization inthe conservativegroup 64% 48% 48% v. 8.5% (7 d) 48% within 6 months

in hospitals with and without cardiac cath lab, respectively

Limitations Old study excluded Predominantly male Retrospective, single- Older patients and post-MI patients patients institution experience patients with priorNo stents or Gp Mortality in early invasive CABG excluded IIb/IIIa inhibitors strategy after CABG Revascularization

No deaths after PTCA done after 6 days

Three-vesseldisease

arm. Additionally, 64% of patients assigned to the earlyconservative arm underwent coronary angiography andalmost half underwent revascularization within 6 weeksof presentation.

The DANAMI (DANish Trial in Acute MyocardialInfarction) study26 compared an early invasive strategy ofPTCA or coronary artery bypass grafting with aconservative strategy in patients with inducible myocardialischemia who received thrombolytic therapy for firstmyocardial infarction. In 503 patients randomized to anearly invasive strategy, PTCA was performed in 266 (53%)and coronary artery bypass grafting in 147 (29.2%). In theconservative arm, only 1.6% of patients were revascularized2 months after acute myocardial infarction. At a 2.4-yearfollow-up, there was no significant difference in mortalitybetween the invasive and the conservative groups (3.6% v.4.4%). Patients assigned to an early invasive strategy had asignificant reduction in the incidence of acute myocardialinfarction (5.6% v. 10.5%; p=0.0038) and a lower incidenceof admission for unstable angina (17.9% v. 29.5%;p

myocardial infarction who were randomized to the earlyinvasive group and 1214 patients in the noninvasivegroup. Patients older than 75 years or with previouscoronary artery bypass grafting were excluded. The primaryoutcome of death or myocardial infarction at 6 months was9.5% in the invasive group and 12% in the noninvasivegroup (p=0.045). The differences were more pronouncedin men. There was a significant reduction in angina andhospital admissions in patients with unstable angina.The mortality at 1 year favored the early invasive strategy(2.2% v. 3.9%).24

The main drawback of the FRISC II study was a delay of6 days in achieving revascularization. Second, the highest-risk groups (older patients and patients who had coronaryartery bypass grafting) were excluded. In the recentlypresented Treat Angina with Aggrastat+Determine Cost ofTherapy with an Invasive or Conservative Strategy TIMI 18(TACTICS-TIMI 18) study, 2220 patients with UA/NSTEMIfrom 9 countries were randomized to routine earlycatheterization (448 hours) or an early conservativestrategy. The primary end-point of death, myocardialinfarction, or early rehospitalization for acute coronarysyndrome at 6 months was 15.9% in the early invasive armand 19.4% in the conservative group (p=0.025). Olderpatients and patients with prior bypass grafting were notexcluded. This trial extends the benefit of the early invasivegroup to early randomization and revascularization andalso to the high-risk groups excluded in the FRISC II trial.

Currently, the ACC/AHA guidelines recommend thatearly invasive treatment be considered for patients with thefollowing findings:

1. Recurrent angina or ischemia at rest or with low-levelactivities despite maximal anti-ischemic therapy

2. Recurrent angina or ischemia with symptoms ofcongestive heart failure

3. High-risk findings on noninvasive stress testing4. Depressed left ventricular function (ejection fraction

of patients with normal coronary arteries and early hospitaldismissal.

Medical management has improved, and the results ofearly PCI are encouraging. Once a patient is admitted witha diagnosis of UA/NSTEMI, risk stratification by clinical,electrocardiographic, or biochemical criteria is ofparamount importance. Patients with a low or intermediaterisk can be channeled to early dismissal, or kept underobservation in the chest pain unit. The acute ischemiapathway outlined by the ACC/AHA guidelines helps triagea patient to early coronary angiography with or withoutpercutaneous or surgical revascularization (Fig. 2). In anydecision-making, factors to be considered are the risks foran acute adverse cardiac event, life expectancy, other co-morbid diseases, the experience of the operator and theinstitution in doing PCI in the setting of UA/NSTEMI, thepatients and hospital resources, and the countrys policies.

References1. Graves EJ, Owings MF. 1996 summary: National Hospital Discharge

Survey. Vital & Health Statistics 1998; 23: 1122. Davies MJ. Stability and instability: two faces of coronary

atherosclerosis. Circulation 1996; 94: 201320203. Little WC, Constantinescu M, Applegate RJ, Kutcher MA, Burrows

MT, Kahl FR, et al. Can coronary angiography predict the site of asubsequent myocardial infarction in patients with mild-to-moderatecoronary artery disease? Circulation 1988; 78: 11571166

4. Rajavashisth TB, Xu XP, Jovinge S, Meisel S, Xu XO, Chai NN, et al.Membrane type 1 matrix metalloproteinase expression in humanatherosclerotic plaques: evidence for activation by proinflammatorymediators. Circulation 1999; 99: 31033109

5. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis ofcoronary artery disease and the acute coronary syndromes (2). NEngl J Med 1992; 326: 310318

6. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis ofcoronary artery disease and the acute coronary syndromes (1). NEngl J Med 1992; 326: 242250

7. Braunwald E. Unstable angina. A classification. Circulation 1989;80: 410414

8. Hamm CW, Braunwald E. A classification of unstable anginarevisited. Circulation 2000; 102: 118122

9. Boersma E, Pieper KS, Steyerberg EW, Wilcox RG, Chang WC, LeeKL, et al. Predictors of outcome in patients with acute coronarysyndromes without persistent ST segment elevation. Results froman international trial of 9461 patients. The PURSUIT Investigators.Circulation 2000; 101: 25572567

10. Antman EM, Cohen M, Bernink PJ, McCabe CH, Horacek T, PapuchisG, et al. The TIMI risk score for unstable angina/non-ST elevationMI: A method for prognostication and therapeutic decision making.JAMA 2000; 284: 835842

11. Roe MT, Harrington RA, Prosper DM, Pieper KS, Bhatt DL, LincoffAM, et al. Clinical and therapeutic profile of patients presenting withacute coronary syndromes who do not have significant coronaryartery disease. PURSUIT Trial Investigators. Circulation 2000; 102:11011106

12. Use of a monoclonal antibody directed against the plateletglycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. TheEPIC Investigation. N Engl J Med 1994; 330: 956961

13. Topol EJ, Ferguson JJ, Weisman HF, Tcheng JE, Ellis SG, Kleiman NS,et al. Long-term protection from myocardial ischemic events in a

randomized trial of brief integrin beta3 blockade with percutaneouscoronary intervention. EPIC Investigator Group. JAMA 1997; 278:479484

14. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparinduring percutaneous coronary revascularization. The EPILOGInvestigators. N Engl J Med 1997; 336: 16891696

15. Umans VA, Kloeg PH, Bronzwaer J. The CAPTURE trial. Lancet 1997;350: 445

16. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofibanin unstable angina and non-Q-wave myocardial infarction. PRISM-PLUS Study Investigators. N Engl J Med 1998; 338: 14881497

17. The RESTORE Investigations. Effects of platelet glycoprotein IIb/IIIablockade with tirofiban on adverse cardiac events in patients withunstable angina or acute myocardial infarction undergoing coronaryangioplasty. Circulation 1997; 196: 14451453

18. Randomised placebo-controlled trial of effect of eptifibatide oncomplications of percutaneous coronary intervention: IMPACT-II.Lancet 1997; 349: 14221428

19. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patientswith acute coronary syndromes. The PURSUIT Trial Investigators.N Engl J Med 1998;339: 436443

20. Vorchheimer DA, Badimon JJ, Fuster V. Platelet glycoprotein IIb/IIIareceptor antagonists in cardiovascular disease. JAMA 1999; 281:14071414

21. Khan MM, Ellis SG, Aguirre FV, Weisman HF, Wildermann NM, CaliffRM, et al. Does intracoronary thrombus influence the outcome ofhigh risk percutaneous transluminal coronary angioplasty? Clinicaland angiographic outcomes in a large multicenter trial. EPICInvestigators. J Am Coll Cardiol 1998; 31: 3136

22. Antman EM, McCabe CH, Gurfinkel EP, Turpie AG, Bernink PJ, SaleinD, et al. Enoxaparin prevents death and cardiac ischemic events inunstable angina/non-Q-wave myocardial infarction. Results of theThrombolysis in Myocardial Infarction (TIMI) IIB trial. Circulation1999; 100: 15931601

23. Cohen M, Demers C, Gurfinkel EP, Turpie AG, Fromell GJ, GoodmanS, et al. A comparison of low-molecular-weight heparin withunfractionated heparin for unstable coronary artery disease.ESSENCE Study Group. N Engl J Med 1997; 337: 447452

24. Wallentin L, Lagerqvist B, Husted S, Kontny F, Stahle E, Swahn E.Outcome at 1 year after an invasive compared with a non-invasivestrategy in unstable coronary artery disease: the FRISC II invasiverandomised trial. Lancet 2000; 356: 916

25. Effects of tissue plasminogen activator and a comparison of earlyinvasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction. Results of the TIMI IIIB Trial. Circulation1994; 89: 15451556

26. Madsen JK, Grande P, Saunamaki K, Thayssen P, Kassis E, Eriksen U,et al. Danish multicenter randomized study of invasive versusconservative treatment in patients with inducible ischemia afterthrombolysis in acute myocardial infarction (DANAMI). DANish Trialin Acute Myocardial Infarction. Circulation 1997; 96: 748755

27. Boden WE, ORourke RA, Crawford MH, Blaustein AS, DeedwaniaPC, Zoble RG, et al. Outcomes in patients with acute non-Q-wavemyocardial infarction randomly assigned to an invasive as comparedwith a conservative management strategy. VANQWISH TrialInvestigators. N Engl J Med 1998; 338: 17851792

28. Yusuf S, Flather M, Pogue J, Hunt D, Varigos J, Piegas L, et al.Variations between countries in invasive cardiac procedures andoutcomes in patients with suspected unstable angina or myocardialinfarction without initial ST elevation. OASIS Registry Investigators.Lancet 1998; 352: 507514

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Failed Thrombolysis: A Continuing Problem

Upendra Kaul, Ranjan KachruBatra Heart Centre, Batra Hospital and Medical Research Centre, New Delhi

Trials of thrombolysis and primary angioplasty haveshown that coronary artery patency and flowcharacteristics following thrombolytic therapy areindependent prognostic predictors of outcome in acutemyocardial infarction (AMI).15 A number of studies suggestthat patency rates with TIMI-3 flow cannot be achieved inmore than 54% of patients even with the best thrombolyticregimen.1 The timely detection of this failed reperfusion isvery important for the further rational management ofpatients with AMI. The need is to diagnose it accurately andcost-effectively, preferably using noninvasive techniques(Table 1). This has to be followed by prompt and efficientattempts to reperfuse the blocked vessels bypharmacological, catheter-based or combined strategies.

Indian Heart J 2001; 53: 163166 Review Article

after thrombolysis and primary percutaneous transluminalcoronary angioplasty (PTCA), none of the observedarrhythmias (such as accelerated idioventricular rhythm)have been shown to add independently to the predictivevalue of diagnosing reperfusion.7

Electrocardiography: Nonresolution of ST segmentchanges after thrombolysis has been shown to be a predictorof worse long-term outcome compared with a cohort withgood resolution. However, this analysis is a better predictorof successful perfusion than of failed reperfusion. Studieshave shown a variety of electrocardiographic (ECG) indicesfor reperfusion failure or success. These include 25%reduction in ST segment elevation, identified in the worstlead on the 60180 min post-thrombolytic ECG; and apost- to pre-thrombolysis maximal ST segment elevationratio or sum of post- to pre-thrombolysis ST segmentelevation ratio equal to or less than 0.5. All these indiceshave been described as having reasonable sensitivity andspecificity, irrespective of the infarct site.8,9 Continuous STsegment monitoring has also been shown to have a goodpredictive value for nonreperfusion in the GUSTO-I study,10

especially when the initial ST segment elevation is morethan 4 mm.

Biochemical markers: Of the numerous markers,creatinine kinase isoenzymes, troponin-T or I and myoglobinmeasurements have been used extensively for the earlydiagnosis of AMI. The rapid peaking of myoglobin seems tobe the earliest marker of a successful recanalization, whilstthe rate of rise of troponin-T post-thrombolysis over 3 hourshas revealed very high (94%) sensitivity as well as specificity(100%) in this situation.11 There is, however, limited evidencethat any of these markers can predict failure to achieve TIMI-3 flow at 6090 min with any degree of similar accuracy.12,13

At present, these assays are mostly reserved for post hocconfirmation rather than direct decision-making so they areof no help in the triage for patients with failed reperfusion.Early peaking of levels of these markers, while suggestingrestoration of flow, does not necessarily mean achievementof reperfusion at tissue level (restoration of microvascularreperfusion). The lack of accuracy and interpretation makestheir reliable use difficult in the setting of failed reperfusion,especially in the absence of concomitant ST segmentresolution.14

Table 1. Failed thrombolysisnoninvasive diagnosis

1. Nonresolution of chest pain

2. Nonresolution of ST segment elevation on ECG (

164 Kaul et al. Failed Thrombolysis: A Continuing Problem Indian Heart J 2001; 53: 163166

There is some evidence to suggest that patients who failto achieve detectable fibrinogenolysis followingthrombolysis could benefit from additional thrombolysis.In one small study, benefit was confined to those patientswhose fibrinogen remained at greater than 1 g/L followingtherapy with streptokinase.15 Although fibrinogen assay isnot routinely used, this measurement is potentiallyadvantageous for distinguishing patients in whomnonreperfusion is primarily due to nonfibrinogenolysisrather than due to no reflow. In such cases, furtherthrombolysis and/or intensified antiplatelet therapy is morelikely to be beneficial rather than interventional treatment.

Emerging diagnostic strategies: Even though sestamibiis accurate in assessing patency after systemic thrombolysis,the need to obtain prethrombolytic scans precludes thismethod from wide clinical application.16 The acuteassessment of microvascular perfusion by myocardialcontrast echocardiography may be the most promisingstrategy.17 Contrast agents are currently being tested inpreclinical trials and are likely to become available forclinical trial assessment shortly.18

Management of Patients in Whom Thrombolysishas Apparently Failed

Repeat thrombolysis and additional antiplatelettherapy: Readministering the thrombolytic agent is afrequently used strategy although the evidence supportingits utility is limited. Lack of attempts to prove the benefit ofthis therapy are surprising, considering the potentially largeimpact it could have in most hospitals. White et al.19 andVerheugt et al.20 showed the advantages of opening theinfarct related artery with systemic or intracoronary tissueplasminogen activator (tPA) following failure with systemicstreptokinase. Their investigations were, however, made asnonrandomized trials. In a small group of patients, stratifiedon the basis of 25% nonresolution of the ECG, Mounsey etal.15 also showed the benefit of additional intravenousalteplase in terms of improvement in the left ventricularejection fraction at 6 weeks.

Pathophysiological studies, however, fail to support thetheoretical benefit of repeat thrombolysis. Moreover, thereseems to be little benefit from repeating thrombolysis later(more than 6 hours) rather than sooner, as the limitedpositive impact of late recanalization on reperfusion can beoffset by the small but possibly deleterious effect of increasedrisk of bleeding.21 The issue of the efficacy of repeatthrombolysis can be sorted out only by a large dedicatedtrial but, in view of more recent advances in targeted

antiplatelet therapy, the role of repeat thrombolysis mayneed to be redefined.

The safety of antiplatelet therapy combined withthrombolytic therapy will be assessed in GUSTO IV. The TIMI14 trial22 has shown that a combination of abciximab anda half dose of tPA is efficacious and gives the best TIMI-3flow (72%). However, the same was not true for thecombination with streptokinase, which led to higherbleeding problems, including cerebral bleeds. Data oncombining thrombolytics and antithrombins continue tosuggest that the therapeutic window is narrow. So far,however, there are no data on the combination ofthrombolytics with glycoprotein IIb/IIIa inhibitors in asetting of rescue therapy, i.e. when thrombolysis hasfailed. For routine use, we will also need information aboutits safety, especially with the potential risk of increasedbleeding.

Role of percutaneous coronary intervention (PCI):It is clear that something needs to be done in patients withclinical signs of failed reperfusion. However, little is knownregarding the true value of the more costly rescue PCI fromthe data of trials that have already been carried out. In theTIMI IV subgroup analysis,23 no significant benefit was seenin the intervention group compared to conservativemanagement. On the other hand, observational studies byJuliard et al.24 and Kaul et al.25 have shown that rescue PCIresults compare well with the primary PCI in the samehospital. However, in their reported series, Kaul et al.25 haveused abciximab in all the patients taken up for rescue PCI.Analysis of the intervention subgroup of the GUSTO I sub-study26 has shown a trend towards improved left ventricularfunction and 30-day mortality in the PCI group comparedto conservative strategy. The outcome of these patients was,however, less favorable than that of patients in whom initialthrombolysis was successful. Failed rescue PCI in the settingof failed thrombolysis was a significant predictor of highmortality (30%).

Analysis of the TAMI 5 study27 subgroup of patients withan occluded artery post-thrombolysis showed no benefit inpatients who underwent early rather than predischarge PCI.The RESCUE trial28 compared patients with late signs (>8hours) of occlusion of the left anterior descending arterypost-thrombolysis and the results suggested improvementin the left ventricular function and composite endpoints.The relative benefits in these trials, however, have been quitemodest. The benefits could possibly be significant if catheter-based interventions are combined with the use ofglycoprotein IIb/IIIa inhibitors as has been done in the studyreported by Kaul et al.25

Although primary PCI has been shown to be superior to

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Indian Heart J 2001; 53: 163166 Kaul et al. Failed Thrombolysis: A Continuing Problem 165

thrombolysis in patients who can be taken up for theprocedure without delay, it has had very little impact onAMI treatment in a community setting, mainly because oflogistic reasons.

Referring only patients with failed reperfusion to acardiac centre with interventional facilities could probablybe both a good and realistic trade-off between additionalexpenses and resources and a significant contribution tocardiac care in the community. Whether the active researchfor signs of failed reperfusion in the early stage of AMI issuperior to the strategy of initial conservative treatmentwith predischarge risk stratification and selection for lateintervention remains to be seen. The use of intra-aorticballoon counterpulsation in a setting of failed thrombolysiscan be useful, especially in hemodynamically unstable andhigh-risk patients who need transfer for catheter-basedintervention. Data from a few trials do suggest the utility ofthis supportive procedure. A dedicated study funded by theBritish Heart Foundation, the REACT study (REscueAngioplasty versus Conservative management ofThrombolysis), has been planned to answer this importantquestion.

Newer strategies, which include intracoronarytherapeutic ultrasound or thrombectomy, could be usefulin achieving lysis of an intracoronary thrombus as well aspromoting microvascular reperfusion.2933 There is a goodtheoretical basis for these which, if proven in clinical trials,could add to the present armamentarium as adjunctiveprocedures combined with PCI.

combination of reduced doses of alteplase and abciximab.Data from the GRAPE study34 suggests that abciximab usedin anticipation of further intervention could recanalize upto 40% of the occluded vessels. It is, therefore, likely that acombination of all reperfusion methods (thrombolysis,antiplatelet agents, intracoronary interventions) could offerthe best reperfusion strategy in AMI. To this end, data fromthe SPEED trial35 advances these efforts by demonstratingthat it is safe and efficacious to perform PCI after eitherthrombolytic monotherapy or combination therapy (rPAand abciximab). The study, however, suffers from thelimitation that it is a nonrandomized comparison.

Conclusions

Failed thrombolysis continues to be a significant clinicalproblem in the management of patients with AMI. There isno proven strategy which is clearly superior and can berecommended as the treatment of choice. In the absence ofsound clinical data, however, it seems logical to recommenda careful, frequent assessment of the patients clinical statusafter instituting systemic thrombolysis. This should includefrequent 12-lead ECG control. A 90120 min recording isvery important since it could form a basis for considerationof further management, which could be PCI afteradministering Gp IIb/IIIa blockers if the option is easilyachievable.

It is likely that patients with failed thrombolysis comprisea heterogeneous group with different levels of failed lysis,microvascular no reflow or different degrees of criticalnarrowing in the target or infarct related vessel. Carefulevaluation of these factors in individual patients will resultin a more tailored and step-wise approach.

References

1. The GUSTO Investigators. An international randomized trialcomparing four thrombolytic strategies for acute myocardialinfarction. N Engl J Med 1993; 329: 673682

2. Anderson JL, Karagounis LA, Califf RM. Meta analysis of five reportedstudies on the relation of early coronary patency grades withmortality and outcomes after acute myocardial infarction. Am JCardiol 1996; 78: 18

3. Califf RM, Topol EJ, Gersh BJ. From myocardial salvage to patientsalvage in acute myocardial infarction: the role of reperfusion therapy.J Am Coll Cardiol 1989; 14: 13821388

4. Grines C, Browne KF, Marco J, Rothbaum D, Stone GW, O' Keefe J, etal. A comparison of immediate angioplasty with thrombolytictherapy for acute myocardial infarction. The Primary Angioplasty inMyocardial Infarction Study Group. N Engl J Med 1993; 328: 673679

5. Zijlstra F, de Boer MJ, Hoorntje JC, Reiffers S, Reiber JH, SuryaprantaH. A comparison of immediate angioplasty with intravenousstreptokinase in acute myocardial infarction. N Engl J Med 1993; 328:680684

Therapeutic options used in failed thrombolysis are listedin Table 2.

Table 2. Therapeutic options in failed thrombolysis

1. Repeat thrombolysis (newer agents)

2. Glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide,tirofiban)

3. Intra-aortic balloon counterpulsation (IABP)

4. Rescue PTCA

5. Combination of glycoprotein IIb/IIIa blocker and PCI

Emerging/Combined Strategies

With the advent of new, potent, targeted antiplatelet agents(abciximab, eptifibatide, etc.) there are some promising datasuggesting that they could be very useful not only as bailout measures both prior to and during intracoronaryinterventions but also as a primary adjunctive treatment.34

In the TIMI 14 study22, thrombolysis was facilitated with a

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166 Kaul et al. Failed Thrombolysis: A Continuing Problem Indian Heart J 2001; 53: 163166

6. Huskisson EC. Measurement of pain. Lancet 1974; 2: 112711317. Califf RM, O'Neil W, Stack RS, Aronson L, Mark DB, Mantell S, et al.

Failure of simple clinical measurements to predict perfusion statusafter intravenous thrombolysis. Ann Intern Med 1988; 108: 658662

8. Buszman P, Szafranek A, Kalarus Z, Gasior M. Use of changes in STsegment elevation for prediction of infarct artery recanalization inacute myocardial infarction. Eur Heart J 1995; 16: 12071214

9. Purcell IF, Newall N, Farrer M. Change in ST segment elevation 60minutes after thrombolytic initation predicts clinical outcome asaccurately as later electrocardiographic changes. Heart 1997; 78:465471

10. Klootwijk P, Langer A, Meij S, Green C, Veldkamp RF, Ross AM, et al.Noninvasive prediction of reperfusion and coronary artery patencyby continuous ST segment monitoring in the GUSTO-I trial. Eur HeartJ 1996; 17: 689698

11. Stewart JT, French JK, Theroux P, Ramanathan K, Solymoss BC,Johnson R, et al. Early noninvasive identification of failed reperfusionafter intravenous thrombolytic therapy in acute myocardialinfarction. J Am Coll Cardiol 1998; 31: 14991505

12. Lavin F, Kane M, Forde A, Ganon F, Daly K. Comparison of five cardiacmarkers in the detection of reperfusion after thrombolysis in acutemyocardial infarction. Br Heart J 1995; 73: 422427

13. Norris RM, Johnson RN, White HD, Robinson DR. Noninvasivediagnosis of infarct artery patency after acute myocardial infarctionby use of serial plasma troponin T concentrations: importance ofmeasurement of peak levels. Heart 1996; 75: 481485

14. Matetzky S, Freimark D, Chouraqui P, Novikov I, Agranat O,Robinowitz B, et al. The distinction between coronary and myocardialreperfusion after thrombolytic therapy by clinical markers ofreperfusion. J Am Coll Cardiol 1998; 32: 13261330

15. Mounsey JP, Skinner JS, Hawkins T, MacDermott AF, Furniss SS,Adams PC, et al. Rescue thrombolysis: alteplase as adjuvant treatmentafter streptokinase in acute myocardial infarction. Br Heart J 1995;74: 348353

16. Mazzota G, Protosido SK, Casati E. Myocardial scintigraphy in acutemyocardial infarction treated with systemic thrombolysis: how farare we from obtaining reliable information for rescue PTCA? Int JCardiol 1998; 29 Suppl 1: S69S73

17. Czitrom D, Karila-Cohen D, Brochet E, Juliard JM, Faraggi M, AumontMC, et al. Acute assessment of microvascular perfusion patterns bymyocardial contrast echocardiography during myocardial infarction:relation to timing and extent of functional recovery. Heart 1999; 81:1216

18. Kaul S. Myocardial contrast echocardiography in acute myocardialinfarction: time to test for routine clinical use? Heart 1999; 81: 25

19. White HD, Cross DB, Williams BF, Norris RM, Woo KS, Hamar AW, etal. Rescue thrombolysis with intracoronary tissue plasminogenactivator for failed thrombolysis with streptokinase for acutemyocardial infarction. Am J Cardiol 1995; 75: 172174

20. Vergheugt FW, Veen G, de Cock CC, Meijer A. An angiographic studyof intracoronary streptokinase versus intravenous tissueplasminogen activator after failed coronary thrombolysis withintravenous streptokinase. J Thromb Thrombolysis 1996; 3: 239243

21. Brodie BR, Stuckey TD, Wall TC, Kissling G, Hansen CJ, Muncy DB, etal. Importance of time to reperfusion for 30-day and late survival

and recovery of left ventricular function after primary angioplastyfor acute myocardial infarction. J Am Coll Cardiol 1998; 32: 13121319

22. Antman EM, Giugliano RP, Gibson CM, McCabe CH, Coussement P,Kleiman NS, et al. Abciximab facilitates the rate and extent ofthrombolysis: results of thrombolysis in myocardial infarction (TIMI)-14 trial. Circulation 1999; 99: 27202732

23. Gibson CM, Cannon CP, Greene RM, Sequeria RF, Margorien RD, LeyaF, et al. Rescue angioplasty in thrombolysis in myocardial infarction(TIMI)-4 trial. Am J Cardiol 1997; 80: 2126

24. Juliard JM, Himbert D, Cristofini P, Desportes JC, Magne M, GolmardJL, et al. A matched comparison of prehospital thrombolysis andstandby rescue angioplasty with primary angioplasty. Am J Cardiol1999; 83: 305310

25. Kaul U, Sapra R, Singh B, Sudan D, Ghose T, Dixit NS, et al. Abciximabduring rescue angioplasty after failed thrombolysis. Asian CardiovascThorac Ann 2001; 9: 3135

26. Ross AM, Lundergan CF, Rohrbeck SC, Boyle DH, van den Brand M,Buller CH, et al. Rescue angioplasty after failed thrombolysis:technical and clinical outcomes in a large thrombolysis trial.GUSTO-1 Angiographic Investigators. J Am Coll Cardiol 1998; 31:15111517

27. Ellis SG, da Silva ER, Heyndrickx G, Talley JD, Cernigliaro C, Steg G, etal. Randomized comparison of rescue angioplasty with conservativemanagement of patients with early failure of thrombolysis for acutemyocardial infarction. Circulation 1994; 90: 22802284

28. Ward SR, Sutton JM, Pieper KS, Schwaiger M, Cliff RM, Topal EJ.Effects of thrombolytic regimen, early catheterization andpredischarge angiographic variables on six-week left ventricularfunction. The TAMI Investigation. Am J Cardiol 1997; 79: 539544

29. Saito T, Taniguchi I, Nakamura S, Oka H, Mizuno Y, Noda K, et al.Pulse-spray thrombolysis in acutely obstructed coronary artery incritical situations. Cathet Cardiovasc Diagn 1997; 40: 101108

30. Topaz O, Miller G, Vetrovec GW. Transluminal extraction catheter foracute myocardial infarction. Cathet Cardiovasc Diagn 1997; 40: 291296

31. Kaplan BM, Larkin T, Safian RD, O'Neill WW, Kramer B, Hoffman M,et al. Prospective study of extraction atherectomy in patients withacute myocardial infarction. Am J Cardiol 1996; 78: 383388

32. Rosenschein U, Roth A, Rassin T, Basan S, Laniado S, Miller HI.Analysis of coronary ultrasound thrombolysis endpoints in acutemyocardial infarction (ACUTE) trial. Results of the feasibility phase.Circulation 1997; 95: 14111416

33. Yock PL, Fitzgerald PJ. Catheter-based ultrasound thrombolysis.Circulation 1997; 95: 13601362

34. van den Merkhof LF, Zijlstra F, Olsson H, Grip L, Veen G, Bar FW, et al.Abciximab in the treatment of acute myocardial infarction eligiblefor primary percutaneous coronary angioplasty. Results of theGlycoprotein Receptor Antagonist Patency Evaluation (GRAPE) pilotstudy. J Am Coll Cardiol 1999; 33: 15281532

35. Herrmann HC, Moliterno DJ, Ohman EM, Stebbins AL, Bode C, BetriuA, et al. Facilitation of early percutaneous coronary intervention afterreteplase with or without abciximab in acute myocardial infarction.Results from SPEED (GUSTO-4 Pilot) Trial. J Am Coll Cardiol 2000;36: 14891496

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A Randomized Study of the Safety and Efficacy ofReused Angioplasty Balloon Catheters

M Zubaid, CS Thomas, H Salman, I Al-Rashdan, N Hayat, A Habashi,MT Abraham, K Varghese, L Thalib

Department of Cardiology, Chest Diseases Hospital, Kuwait andDepartment of Community Medicine, Faculty of Medicine, Kuwait University

It is estimated that coronary angioplasty (PTCA) isperformed in more than one million cases worldwideannually. As the cost of equipment is substantial, severalcenters utilize previously used and resterilized ballooncatheters to perform these procedures.1 In the field ofcardiology, ablation catheters and pacemakers are also oftenreused.2,3 Although reuse of expensive materials is astandard practice in the operating room, according to themanufacturers these balloon catheters are intended forsingle use only.

Observational studies have differed in their assessmentof the safety and efficacy of reused balloon catheters.4,5

According to one observational study, the potential for costsaving is great; however, much of the costs saved in the reusestrategy are lost in treating complications.6 Therefore, ifthere were no increase in complications, cost savings wouldbe substantial.

There are no randomized controlled studies looking atthe safety and efficacy of reused balloon catheters. We

performed the first such study with the aim ofdemonstrating the safety (as judged by clinical success) andefficacy (as judged by angiographic success) of reusedballoon catheters (RC) versus new balloon catheters (NC).We also measured other relevant factors including volumeof contrast, number of balloons used and fluoroscopy time.

Methods

From February 1999 to February 2000, all patientsundergoing coronary angioplasty at our institute wereconsidered for enrollment in the study. Exclusion criteriaincluded total occlusion (Thrombolysis In MyocardialInfarction, TIMI-0 flow) of unknown duration or longerthan one month, and the presence of cardiogenic shock.Informed verbal consent was obtained from all patients. Toqualify for enrollment in the trial, the lesion had to becrossed with a guidewire and the appropriate-size balloonhad to be available (Fig. 1). Once these conditions were met,the patients were randomized to the reused balloon strategyor new balloon strategy in a ratio of 1:1. The operator wasblinded to the choice of balloon catheter. If the first

Background: To lower costs, many centers around the world utilize previously used, resterilized balloon cathetersto perform coronary angioplasty. There are no controlled trials regarding their safety and efficacy.Methods and Results: We performed the first randomized, double-blind, controlled, single-center clinical trialcomparing the safety (clinical success) and efficacy (angiographic success) of reused versus new coronaryangioplasty balloon catheters. A total of 377 procedures were included, 178 in the reused catheter arm and199 in the new catheter arm. There were no significant differences in clinical or lesion characteristics amongthe two arms. The incidence of first balloon failure in the reused catheter arm was similar to that of the newcatheter arm (12 cases [7%] v. 10 cases [5%], respectively). The angiographic success rate was also similar176 cases (98.9%) in the reused catheter arm and 196 cases (98.5%) in the new catheter arm. The number ofballoon catheters used per lesion, amount of contrast, and procedural and fluoroscopy time were similar in thetwo

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