braunwalds PCI for AMI

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PCAT meta-analysisEvidence favoring the primary angioplastystrategy was derived from the PCAT (PrimaryCoronary Angioplasty Trialists) meta-analysis of10 randomized trials (conducted from 1989 to1996).Primary POBA significantly reduced 30-day

mortality (4.4 vs. 6.5%, P=0.02; 34% riskreduction) and the combination of death plusreinfarction (7.2 vs.11.9%, P < 0.001, 40% risk

reduction).These effects were not significantly affected by

the thrombolytic regimen. Primary angioplastywas also associated with a reduction in totalstroke (0.7 vs. 2.0%, P=0.007) and a marked

decrease in hemorrhagic stroke (0.1 vs. 1.1%, P


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PCAT AnalysisE


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What About Stents vs.

Lytics?These studies were done before the adoption ofmore advanced PCI techniques.More recent trials have compared thrombolysis

with stents and (GP) IIb/IIIa receptor inhibitors.For example, the Stent vs. Thrombolysis forOccluded Coronary Arteries in Patients with AcuteMyocardial Infarction (STOPAMI) trial comparedpatients reperfused with a stent plus abciximabwith patients receiving t-PA.Scintigraphic infarct size was significantly reduced

in the PCI group because of a larger salvageindex. In addition, the composite endpoint ofdeath, reinfarction, and stroke was lower in thestent group (8.5 vs. 23.2% at 6 months, P=0.02).


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Review by KeeleyA quantitative review by Keeley has combined the PCATanalysis with 13 more recent investigations (1997 to 2002),in which stents were used in 12 of 13 and GP IIb/IIIainhibitors in 7 of 13 trials.

Of the total group (N

= 7739), most patients (76%)randomized to thrombolytic therapy received t-PA.The summary results a significant reduction in death,

reinfarction, stroke, and hemorrhagic stroke for patientstreated with primary PCI. Major hemorrhage (5 vs. 7%,P=0.032) was the only endpoint increased in the PCIpatients.

The benefit was similar, irrespective of the thrombolyticregimen. The survival advantage for primary PCI overthrombolysis (20 lives saved for every 1000 patientstreated) is similar to the magnitude of benefit forthrombolysis compared to placebo.

Long-term (6 months) outcomes in several trials have beenpersistently favorable for the PCI patients.


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Combination Lytic & GPModification of pharmacological reperfusion using

a reduced dose lytic agent and addition of a GPIIb/IIIa inhibitor has resulted in higher TIMI-3 flow

rates.This combination therapy was tested in the

GUSTO-V and ASSENT-3 trials.Despite a decrease in early ischemic events

(including reinfarction), there was no reduction in30-day or 1-year mortality compared withstandard lytic therapy.Combination therapy also increased the risk of

hemorrhage (including intracranial) in elderly

patients.


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TIMI Flow GradesGrade 0: No perfusion. There is no antegrade flow beyondthe point of occlusion.

Grade 1: Penetration without perfusion. Contrast materialpasses beyond the area of obstruction but fails to opacify

the entire coronary bed distal to the obstruction for theduration of the cine filming sequence.Grade 2: Partial perfusion. Contrast material passes across

the obstruction and opacifies the coronary distal to theobstruction. However, the rate of entry of contrast materialinto the vessel distal to the obstruction and/or its rate ofclearance from the distal bed (or both) is perceptibly slowerthan its flow into or clearance from comparable areas notperfused by the previously occluded vessel.

Grade 3: Complete perfusion. Antegrade flow into the beddistal to the obstruction occurs as promptly as antegradeflow into the bed proximal to the obstruction, and clearanceof contrast material from the involved bed is as rapid as

clearance from an uninvolved bed in the same vessel or theopposite artery.


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TIMI Myocardial PerfusionGrade 0: minimal or no myocardial blush

Grade 1: Dye stains myocardium and stain

persists on the next injectionGrade 2: Dye enters myocardium but washes

out slowly so that the dye is stronglypersistent at the end of the injection.

Grade 3: normal entrance and exit of dye inthe myocardium.


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Advantages of the PCI

StrategySuperior Restoration of Flow

Treatment of the Inciting Pathobiology in AMI

Anatomical Definition and Risk StratificationReduction in Complications


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Superior Restoration ofFlowCritical link between early establishment of TIMI-3

flow with myocardial salvage and survival.

Primary PCI attains TIMI-3 flow in more than 90%

of patients. In contrast, less than 65% of patients receiving a lytic

agent achieve this benchmark.

Primary PCI efficacy is sustained in the late stagesof infarctionthrombolysis effectiveness declines significantly within a

few hours of symptom onset.

This discrepancy provides a theoretical basis forthe incremental improvement in outcomes withprimary PCI.


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Treatment of Inciting

PathobiologyReperfusion therapy (especially thrombolysis)

targets the thrombotic intracoronary eventthat occurs in most myocardial infarctions.

However, dynamic factors, apart fromthrombus, including plaque rupture,intramural hemorrhage, dissection, andspasm, are effectively treated with catheter-based reperfusion and may partially explainthe advantage of primary PCI overthrombolysis.


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Reocclusion occurs in 25 to 30% of patientsafter successful thrombolysis. After primaryballoon angioplasty, reocclusion ranges from 5to 16.7%

Stenting further decreases risk of reocclusion(5.1% vs. 9.3% with PTCA.)


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Anatomical Definition

and Risk StratificationAngiographic and hemodynamic data obtained at the time

of cath impart valuable decision-facilitating information andmore precise risk stratification.

Angiography defines the coronary anatomy in patients withequivocal or uninterpretable ECG changes.

After urgent coronary angiography, a subset of patients willrequire emergent coronary bypass surgery for severemultivessel or left main coronary artery disease.

Mechanical complications can also be identified duringcardiac catheterization. An additional subset of patientsexhibits spontaneous reperfusion without a significantresidual stenosis and avoids the hazards of re-perfusiontherapy, including the hemorrhagic risks of thrombolysis


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Anatomical Definition

and Risk StratificationA primary PCI strategy allows stratification of

patients into a low-risk group (age 70 years,LVEF higher than 0.45, one- or two-vesseldisease, successful angioplasty, no persistentarrhythmias) who can be discharged after 3days with reduced costs and similar survivalcompared with longer hospitalization (7 days).


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Reduction inComplications

Treatment with primary angioplasty appears toreduce infarct rupture.

In a combined meta-analysis of the GUSTO-I and

PAMI-I/II trials, primary angioplasty resulted in an86% reduction in the risk of mechanicalcomplications compared with patients undergoingthrombolysis.

There was a significant reduction in acute MR(0.31 vs. 1.73%, P < 0.001) and VSDs (0.0 vs.0.47%, P < 0.001).

In a multivariate analysis of 1375 patients,

treatment with primary angioplasty was


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Complications of

Reperfusion TherapyIntracranial hemorrhage may be fatal in half to

two thirds of patients and remains a devastatingperil of thrombolytic therapy.

In a comparative analysis, the risk of intracranialhemorrhage was found to be 1% withthrombolysis and 0.05% with PCI.

Major bleeding complications were increased with

PCI compared with thrombolysis (7 vs. 5%,P=0.032). However, these hemorrhages usuallyoccur at the access site and were found todecrease in later trials.


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Temporal Dynamics of

Reperfusion TherapyRapid reperfusion of the infarct artery leading

to myocardial salvage has remained therationale for early reperfusion.

The survival benefit of thrombolyticreperfusion therapy decreases with increasingdelay in treatment.

There is an inherent delay in initiation of

primary PCI reperfusion compared withthrombolysis.

Despite the identified advantages and trialevidence favoring a primary PCI strategy,

considerable controversy still surrounds therelative time-de endent efficac of this


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Examination of primary angioplasty (N = 27,080) in the

NRMI-2 database has revealed that the adjusted odds ofhospital mortality did not increase significantly withincreasing time from symptom onset to balloon inflation(ischemic time) but mortality did increase with a door toballoon time (treatment interval) longer than 2 hours.

One large study (N = 2635) has demonstrated increasingmajor adverse cardiac events rates with increasingpresentation delay for thrombolysis but relatively stableevent rates over time for primary angioplasty.

A mechanistic difference in reperfusion efficacy was

illustrated by the study of Schomig and associates, whodemonstrated a consistent degree of myocardial salvagewith primary PCI (stenting), despite increasing ischemictime.

Conversely, myocardial salvage achieved by thrombolysis

declines markedly with increasing ischemic time, leading toa lar er a arent advanta e from rimar PCI with later


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LOGISTIC CHALLENGE OF

EFFECTIVE REPERFUSION THERAPY.Despite analytical considerations, the selection of

reperfusion therapy remains a complex and controversialdecision. Local factors, patient risk, and temporal dynamicsmust be considered.

In facilities able to provide on-site primary PCI, expeditiousapplication clearly provides the best opportunity forsurvival.

However, only approximately 25% of U.S. hospitals have thecapacity for primary PCI.

The advantage of primary PCI and an apparent prolongedtemporal margin of benefit have created a foundation forexpanding catheter-based reperfusion by transfer tocapable centers.


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DANAMI-2The polarity of reperfusion strategy is exemplified by thefindings of two trials in this meta-analysis.

The DANAMI-2 randomized 1129 patients at referral

hospitals to on-site thrombolysis or transport for PCI (PCIdelay over thrombolysis was 67 minutes).

There was reduction in the composite endpoint of death,reinfarction, and stroke (8.5 vs. 14.2%, P=0.002), primarilybecause of less reinfarction (1.9 vs. 6.2%, P < 0.001).

Rescue PCI occurred in only 1.9%, and 4% of screenedpatients were considered unable to tolerate transport.


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CAPTIM TrialAlternatively, the CAPTIM trial (N = 840) compared theearliest possible initiation of thrombolysis with directtransport for PCI. A physician initiated thrombolysis on site.

The composite endpoint (death, reinfarction, stroke)occurred in 6.2% with PCI and 8.2% with prehospitalthrombolysis (P=0.29). In patients randomized within 2hours, there was a trend for mortality reduction (2.2 vs.5.7%, P=0.058) with prehospital thrombolysis.

Cardiogenic shock occurred less frequently withthrombolysis in this early group (1.3 vs. 5.3%, P < 0.032).

Notably, in the thrombolytic group, rescue PCI occurred in26% and, by day 30, 70% underwent PCI.


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Misc ConsiderationsOther factors should be considered with earlypresentation (shorter than 3 hours). Patientswith contraindications to thrombolysis and

those with cardiogenic shock should betransported for PCI.

Higher risk patients (e.g., anterior infarction,elderly, hemodynamic compromise) also

experience a larger benefit from catheter-based reperfusion, and the TIMI risk score canidentify this group.

Patients at higher risk for intracranialhemorrhage from thrombolysis will alsoaccrue less hazard from primary PCI.


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Patients with 2- to 3-hour or longer presentation

delays will be better served by a primary PCIstrategy if transfer and/or reperfusion can beaccomplished promptly.

Despite ACC/AHA recommendations for atreatment interval (door to balloon) of less than90 minutes, another study from NRMI-3/4 onpatients transferred for PCI has determined amedian door to balloon time of 180 minutes, withonly 4.2% treated within 90 minutes.[

Clinical trials have demonstrated the feasibility ofrapid transport for primary PCI. Early assessmentusing prehospital 12-lead electrocardiogram (ECG)acquisition can allow efficient triage and advancepreparation at the PCI center, with a considerable

reduction in the treatment interval.


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Impediments to

Widespread PCI Strategies.However, there are several impediments to

widespread application, especially in the UnitedStates, including lack of prehospital ECG

capability (10% in the United States), economicimpact on providers, organizational issues,regulatory policies involving certification,interpretation of performance metrics, and thepolitical dynamics of achieving a broad

consensus.Nevertheless, a geographic study has determined

that nearly 80% of the adult U.S. population liveswithin 60 minutes of a PCI-capable hospital.A recent AHA initiative is a step forward to

implement timely reperfusion via primary PCI in


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THROMBOLYTIC-INELIGIBLE

PATIENTS.A significant proportion (25 to 30%) of patients

presenting with ST elevation (or LBBB) infarctionwho are eligible do not receive reperfusiontherapy.In the Global Registry of Acute Coronary Surgery

(GRACE) 2084 patients presenting within 12 hoursof STEMI onset, thrombolytic were CI in 15% and,overall, 30% of eligible patients did not receivereperfusion therapy.

Correlates of the latter group included those withprior bypass surgery, diabetes, history ofcongestive failure, and age older than 75 years.

There remains a bias against thrombolysis,particularly for the elderly.

Patients with clear-cut and relativecontraindications to thrombol sis are at hi her


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PCI for Those with Lytic

CIPrimary PCI also achieved significant

myocardial salvage and a favorable 6-monthmortality in a group of patients ineligible for

thrombolysis.

Primary PCI can be applied to most higher riskpatients who are not ideal candidates forthrombolytic therapy.

The contraindications to primary angioplastyare limited to patients who cannot receiveheparin, aspirin, or thienopyridines,

documented life-threatening contrast allergy,or lack of vascular access.

PATIENTS IN CARDIOGENIC


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PATIENTS IN CARDIOGENICSHOCK.Multiple observational series of patients

undergoing balloon angioplasty in cardiogenicshock have demonstrated improvedhemodynamic status and suggested enhancedsurvival.

In contrast, thrombolysis appears less effectivewhen administered to patients in shock.Although thrombolysis may provide a survival

benefit for patients, increasing rates of PCI (28 to54%) and declining rates of lytic use (20 to 6%)

were associated with declining mortality (60 to48%, P < 0.001) for 25,311 shock patients in theNRMI database from 1995 to 2004.In this propensity-adjusted multivariable analysis,

primary PCI was associated with a significantreduction in hospital mortality (OR, 0.46; 95% CI,0.40 to 0.53).


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SHOCK TrialRandomized 302 patients to an early (within 12 hoursshock onset, 36 hours of infarction onset)revascularization strategy (PCI, 63%; bypass surgery38%) or medical stabilization (thrombolysis, 63%) with

delayed revascularization, if appropriate. IABP support was recommended (86%) in both groups.A significant survival advantage for early

revascularization was noted at 6 months and 1 yearbut not at the 30-day primary endpoint.

The 30-day mortality was significantly lower with earlyrevascularization for patients younger than 75 year.(41 vs. 57%, P < 0.05). There was no benefit for the 56patients older than 75 years, but an imbalance ofbaseline characteristics may have been present in thissmall group.


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SHOCKFurthermore, in the larger SHOCK registry, hospitalmortality was significantly lower in elderly patientsselected for early revascularization (48 vs. 81%,P=0.0003) and similar to that of younger patients (45

vs. 61%, P=0.002).With exclusion of early deaths and covariate-adjusted

modeling, the relative risk with revascularization was0.46 (95% CI, 0.28 to 0.75; P=0.002) for age of 75years and 0.76 (95% CI, 0.59 to 0.99; P=0.045) for age

younger than 75 years.Rapid reperfusion is critical for survival and a large

benefit (132 lives saved/1000 treated) is realized at 1year.

Early revascularization is clearly recommended for

patients younger than 75 years and suitable for many


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More Shocking ResultsThe survival of 82 patients undergoing PCI in

the SHOCK trial was 50% at 1 year.

One-year mortality was 38% with TIMI-3, 55%with TIMI-2, and 100% with TIMI 0-1 flow afterPCI.

The PCI success rate was 76%. Stents (34%)

and GP IIb/IIIa inhibitors (32%) were used inthe minority during the study period (1993 to1998).

A prospective registry of 96 shock patients

has indicated that the use of stents and-


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Most cardiogenic shock patients have multivesseldisease (81% in SHOCK). Survival rates for PCIand bypass surgery in the early revascularization

arm were similar, although patients undergoingbypass surgery had more extensive coronarydisease and a higher prevalence of diabetes.[

There was a trend for improved 30-day survival in

bypass surgery patients with completerevascularization (63 vs. 17%, P=0.07).

Only 13% of PCI patients underwent a multivesselprocedure, with a 1-year survival of 20%

compared with 55% with single-vessel PCI.


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Elderly +Lytics = Bad Jaeger

ShotAlthough the relative benefit of thrombolytic therapy isdiminished in the elderly, the higher overall mortalityresults in a greater absolute mortality reduction, asnoted in a meta-analysis of major trials.

Despite this evidence, age predicts failure to usereperfusion therapy.Observations from the Medicare and NRMI data bases

have indicated no benefit or possible harm for thisgroup with thrombolysis, especially in patients olderthan 75 to 80 years.

Apprehension regarding the risk of intracranialhemorrhage remains, and the cumulative risk factorsfor this complication are more common in the elderlypopulation.

Elderly patients undergoing thrombolysis have more

than a threefold risk of free wall rupture comparedwith no reperfusion or primary PCI.


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Elderly + PCI = Sexy!In contrast, Medicare patients undergoing primaryangioplasty (N = 2038) exhibited a lower 30-day(8.7 vs. 11.9%, P=0.001) and 1-year (14.4 vs.

17.6%,P=

0.001) mortality compared withthrombolysis (N = 18,645). For patients older than 75 years in the NRMI-2

registry, the combined endpoint of death andnonfatal stroke was significantly higher in patients

treated with t-PA compared with primaryangioplasty (18.4 vs. 14.6%, P=0.001).In the PCAT analysis of 10 randomized trials,

primary angioplasty was more effective inreducing 30-day mortality in patients over age 70

years compared with younger patients.


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Prior CABGMortality increased with prior CABG

Large thrombus burden in vein grafts mayalso be more resistant to lytic agents.

POBA of vein grafts assoc with higher rates ofTIMI-3 flow compared with lytics, but reducedcompared to native vessel reperfusion.


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GP 2b/3a Inhibitors with

PTCARAPPORT (ReoPro in AMI Primary PTCA

Organization Randomized Trial) assignedpeople to either placebo or abciximab while

undergoing balloon angioplasty.

Incidence of death, reinfarction, or urgent TVRwas reduced significantly at 30 days (6% vs.11%) and 6 months with reopro.


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Rescue AngioplastyLimited data regarding value of recue

angioplasty in pts who do not achievereperfusion after lytics.

Observation data showed suggested littlebenefit and high mortality in whom attemptedRA failed.

Analysis of 4 small randomized trials of RAidentified significant reduction in early severeHF, trend toward reduced mortality and 2 ofthese trials showed signif survival benefit at 1

year.


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Facilitated AngioplastySeveral trials showed adverse outcomes if

early angioplasty (compared with delayed)after lytics with more complications (bypass

surgery and bleeding), a trend for highermortality, and no difference in LV function.

PACT (Plasminogen-activator AngioplastyCompatibility Trial) pts got dose tPA hadhigher TIMI-3 flow prior to angioplasty.


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In ADMIRAL trial, reopro alone before cathresulted in TIMI-3 of only 30%.

However reopro combined with dose lyticsthe TIMI-3 flow rates were 62-77% without anincrease in major bleeding or ICH over fulldose lytics.

SPEED


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Lytics for Late

PresentationIn the NRMI data base, nearly one third ofpatients with acute infarction presented morethan 12 hours after symptom onset.

Thrombolytic therapy in this group does notsignificantly improve survival.

Guidelines restrict recommendations for

reperfusion with PCI to late presentationpatients (12 to 24 hours) with persistentischemic symptoms, heart failure, andhemodynamic or electrical instability.


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PCI for Late PresentationData from small RCTs evaluating the effect ofPCI more than 12 hours after MI are conflictingand inconclusive.

Recently, the BRAVE-2 trial (N = 365)evaluated immediate PCI in asymptomaticpatients 12 to 24 hours after symptom onset.

Scintigraphic infarct size was significantlysmaller in PCI patients (8 versus 13 percent, P< 0.001). Death, reinfarction, and stroke wereinsignificantly reduced with PCI at 30 days(4.4 versus 6.6 percent, P = 0.37).

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