The Open Artery Hypothesis: Past, Present, and FutureMukesh Goel, J. Theodore Dodge Jr., MichaelRizzo, Christine McLean, Kathryn A. Ryan,William L. Daley, Christopher P. Cannon, and C. Michael GibsonCardiovascular Division of the Department of Medicine, theWest Roxbury Veteran’s Administration & Brigham andWomen’s Hospitals, Harvard Medical School, BostonMassachusetts

Journal of Thrombosis and Thrombolysis 1998;5:101–112© Kluwer Academic Publishers. Boston. Printed in the Netherlands.

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Abstract. The survival bene~t following a reperfusionstrategy, be it pharmacologic or mechanical, appears to bedue to both full and early reperfusion. While the TIMI FlowGrade classi~cation scheme has been a useful tool to assesscoronary blood flow in acute syndromes, it has several lim-itations. A newer method of assessing coronary blood _owcalled the Corrected TIMI Frame Count method has the fol-lowing advantages: (1) it is a continuous quantitative vari-able rather than a categorical qualitative variable; (2) the_ow in the non-culprit artery is not assumed to be normalas it is in the assessment of TIMI Grade 3 Flow; (3) thereis simpli~ed reporting of reperfusion ef~cacy through theuse of a single number instead of expressing the data in 2to 4 categories; (4) because a single number rather than 4categories is used to report the data, there is more ef~cientuse of the dataset by increasing the statistical power; and~nally (5) coronary _ow can be expressed in intuitiveterms (e.g. time or cm/sec for strategy A versus time orcm/sec for strategy B). This paper reviews the history of theopen artery hypothesis and recent advances in the ~eld.

The ~rst version of the open artery hypothesis wasproposed more than 50 years ago. The notion that earlyand full reperfusion should be the goal of acute revas-cularization strategies has now become the corner-stone of modern reperfusion strategies. Currently,there is a rapid expansion in both the pharmacologicand mechanical methods used to reperfuse occludedvessels in the setting of acute myocardial infarction.This article chronicles the evolution of the open arteryhypothesis and, likewise, the strategies used to openoccluded vessels, and reviews emerging ~ndings fromresearch in this rapidly changing ~eld.

Origins of the Open ArteryHypothesis

In 1941, Blumgart et al. ~rst observed that the extentof acute myocardial infarction (AMI) in dogs was re-lated to the duration of coronary artery occlusion [1],and these results were reproduced by Braunwald andMaroko in 1973 [2]. In 1977, Reimer and Jennings dis-

covered that during coronary artery occlusion in dogs,a time-dependent wavefront of cell death progressesfrom the endocardium to epicardium, which is largelycomplete by 6 hours [3]. This process was called thewavefront phenomenon of cardiac ischemia. A hypoth-esis termed the open artery hypothesis was formulatedbased upon the premise that earlier reperfusion of theinfarct-related artery would lead to greater myocar-dial salvage, which in turn would lead to better preser-vation of left ventricular (LV) function. It was furtherhypothesized that this preservation of LV functionwould ultimately improve survival. More speci~cally,this hypothesis was termed the time-dependent openartery hypothesis because it was postulated that theextent of myocardial salvage was proportional to thetime required to open the culprit artery.

Recanalization Trials and theSelection of the 90-Minute Endpoint

The time-dependent nature of myocardial salvagesparked a search for drugs that would establish my-ocardial reperfusion as early as possible in the settingof AMI. Initial human studies were termed recanal-ization trials [4]. These studies required that the in-farct-related artery ~rst be demonstrated to be oc-cluded, the thrombolytic agent was next administered,and the proportion of initially closed arteries thatopened following thrombolytic administration wasthen determined. One of the earliest recanalizationstudies was undertaken by Rentrop et al., who admin-istered intracoronary streptokinase to 17 patients whohad documented occlusion of their coronary arteries[4]. Several years later, these logistically demanding

Address for correspondence: C. Michael Gibson, M.S., M.D.,Chief of Cardiology, West Roxbury Veteran’s AdministrationHospital, 1400 VFW Parkway, West Roxbury MA, 02132.

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recanalization trials, which delayed the administrationof thrombolytic therapy until angiography was ~rstperformed, were abandoned in favor of performingwhat were termed patency trials. In these trials, thethrombolytic agent was administered immediately,without preceding angiographic documentation of ves-sel occlusion.

One question that arose was at what time followingthrombolytic administration should vessel opening beassessed. Ninety minutes was chosen as the time of theinitial “snapshot” because it was postulated that if as-sessed any earlier, the drug would not have suf~cienttime to work, and if assessed any later, it was felt thatthe body’s own endogenous thrombolytic system mightplay a role in clot lysis. While 90 minutes initially be-came the standard time point to assess thrombolytictherapy, we now know that newer reperfusion strate-gies may achieve a high degree of reperfusion evenearlier than this traditional 90-minute endpoint.

To determine if injections preceding 90 minutes af-fect this traditional endpoint, we recently examinedthe relationship between the number of injectionsprior to 90-minute angiography and patency in theTIMI 4 trial [5]. There are several reasons why earlyinjections might increase or, alternatively decrease,patency. On the one hand, injections may open vesselsand improve patency by mechanically dislodgingthrombus. However, once the material is dislodged, itmay embolize distally, causing a “no-re_ow” phenome-non [6]. The kinetic energy of an injection may increase_ow and favor patency; however, the osmolality of thecontrast may increase blood viscosity and sludging [7],and thereby reduce patency. Finally, contrast agentsdo cause a hyperemic response [7], but on the otherhand, contrast agents may also be thrombogenic [8,9].

In the TIMI 4 trial, the number of injections priorto 90-minute angiography was no different betweenoccluded (TIMI grade 0/1 _ow; 2.46 6 1.78, n 5 94) andpatent arteries (TIMI grade 2/3 _ow; 2.70 6 2.42, n 5295; P 5 0.24) [5]. In addition, the patency pro~le in pa-tients who had no injections prior to 90 minutes (TIMI0/1 5 18.3%, n 5 19; TIMI 2/3 5 81.7%, n 5 85) did notdiffer signi~cantly from that in patients who had anyinjections prior to 90 minutes (TIMI 0/1 5 26.5%, n 577; TIMI 2/3 5 73.5%, n 5 214; P 5 NS) [5]. These ob-servations are important in that they justify the judi-cious use of a limited number of “earlier snapshots” ofthe culprit artery prior to 90 minutes to ascertain justhow rapidly newer thrombolytic regimens achieve pa-tency [5].

TIMI 1 and the Early Patency Trials

The initial patency trials were performed in the mid-1980s. The ~rst Thrombolysis in Myocardial Infarction(TIMI-1) trial showed 90-minute culprit artery patencyrates of 70% and 43% for recombinant tissue plasmino-gen activator (rt-PA) and streptokinase (SK), respec-

tively [10]. This National Institutes of Health–spon-sored trial was stopped prematurely as a result of thislarge discrepancy in patency rates because it was as-sumed that this reperfusion bene~t would necessarilytranslate into a clinical bene~t. The patency rate wasde~ned as the percentage of culprit arteries that wereopen with either slow (TIMI grade 2) or normal (TIMIgrade 3) _ow. Similarly, in the European CooperativeStudy, the 90-minute patency rate for rt-PA was higher(70%) than SK (55%) [11].

At the time, it was presumed that this improved 90-minute patency pro~le for rt-PA would translate into asurvival bene~t. However, two subsequent megatrials,the second Gruppo Italiano per lo Studio DellaStreptokinasi nell Infarcto Myocardico (GISSI-2) andthe third International Study of Infarct Survival(ISIS-3), demonstrated no signi~cant difference in sur-vival in patients treated with SK, rt-PA, or APSAC[12,13]. While not supporting the increased ef~cacy ofone thrombolytic agent over another, these megatrialsdid ~nd that patients treated within 3–4 hours of theonset of symptoms had signi~cantly lower in-hospitalmortality rates, at least lending support to the notionthat earlier reperfusion is bene~cial.

Further support of the bene~ts of early reperfusioncan be found in the results of the Myocardial InfarctionTriage and Intervention (MITI) trial, which demon-strated that patients who were administered rt-PAwithin 70 minutes of symptom onset had a 1% mortal-ity compared with a 10% mortality if the thrombolyticagent was given after 70 minutes of symptom onset[14]. Of note, 40% of the patients treated within 1 hourof symptom onset showed no thallium evidence ofAMI. Similar ~ndings of improved mortality with earlytreatment were observed in the European MI Project(EMIP) trial of prehospital thrombolysis for patientsadministered APSAC within 1 hour of the onset ofsymptoms compared with the mortality in patientswho were administered APSAC after 1 hour of symp-toms [15].

While the GISSI-2 and ISIS-3 megatrials did notdemonstrate improved mortality for thrombolytic reg-imens with better patency pro~les, the dosing of rt-PAstudied in these megatrials (100 mg of rt-PA over 3hours) was soon replaced with more rapid dosing reg-imens of rt-PA that resulted in even higher patencyrates [16,17]. Neuhaus and others showed a 90-minuteangiographic patency rate of 85–90% with a more ag-gressive “front-loaded” regimen of rt-PA over 90 min-utes instead of 3 hours (15 mg IV bolus of rt-PA, fol-lowed by 50 mg IV over the next 30 minutes, then 35mg IV over next 60 minutes) [16,17]. In light of thehigher 90-minute patency rates achieved with thisfront-loaded 90-minute regimen of rt-PA, a new com-parison of the thrombolytic agents was deemed neces-sary. Furthermore, the initial megatrials administeredheparin subcutaneously as an adjunctive agent lateafter thrombolysis, and it was felt that an initial bolusof intravenous heparin might be more effective in re-

102 Goel et al.

ducing the known high rate of reocclusion following rt-PA administration.

The GUSTO Trial

The use of an aggressive front-loaded regimen of rt-PAover 90 minutes coupled with the use of an early intra-venous bolus followed by a maintenance infusion ofheparin to reduce the incidence of reocclusion providedthe rationale for the Global Utilization of Strep-tokinase and rt-PA for Occluded coronary arteries(GUSTO) trial [18,19]. The GUSTO trial demonstratedimproved survival with front-loaded rt-PA along withfull-dose IV heparin (6.3% mortality) as compared withSK along with subcutaneous heparin (7.2% mortality),SK along with IV heparin (7.4% mortality), or a com-bination of SK and rt-PA (each agent at two thirds oftheir conventional dosing) along with IV heparin (7.0%mortality) [18]. The motivation for the combinationtherapy arm was that whereas rt-PA might be moreeffective at opening arteries rapidly, SK, with itslonger half-life, might be more effective in preventingreocclusion.

The GUSTO angiographic substudy also providedimportant insight into the mechanism linking early andfull reperfusion with reduced mortality [19]. Front-loaded rt-PA administration was associated with asigni~cantly higher 90-minute culprit artery patencyrate (81% as compared with 54% for SK with subcuta-neous heparin and 60% for SK with intravenous he-parin). One question that arose was why the combina-tion arm did not fair better given that it had a patencyrate of 73%. It was in exploring the answer to thisquestion and others that the time-dependent openartery hypothesis was further re~ned. When the clini-cal outcomes of TIMI grade 2 and 3 _ows and the rateat which various thrombolytic regimens achieve TIMIgrade 2 and 3 _ows were examined, some interesting~ndings emerged.

Does TIMI 2 Flow RepresentSuccessful Reperfusion?

The GUSTO angiographic substudy demonstratedthat all open arteries are not “created equal.” The mor-tality rate of 7.4% for patients with TIMI grade 2 _ow(delayed antegrade _ow in the culprit vessel) approxi-mated that of TIMI grade 0 (an occluded vessel) orTIMI grade 1 _ow (penetration without perfusion, dyehangs up just after the stenosis; mortality 8.9%) [19].In contrast, TIMI grade 3 _ow (normal antegrade _owin the culprit vessel) was associated with nearly halfthis mortality (4.4%) [19]. A key ~nding is that the rateof TIMI grade 2 _ow did not differ signi~cantly amongthe thrombolytic regimens (25% with SK and subcuta-neous heparin regimen, 28% with SK and IV heparinregimen, 27% with rt-PA and IV heparin regimen, 35%with rt-PA and SK combination regimen, P 5 NS).

However, the rate of TIMI grade 3 _ow was highest forthe rt-PA with IV heparin regimen (54% comparedwith 29% for SK with subcutaneous heparin regimen,32% for SK with IV heparin regimen, 38% for rt-PAand SK combination regimen) [19]. A retrospectiveanalysis of four German thrombolytic trials has also in-dicated that the mortality was higher in patients withTIMI grades 0, 1, or 2 _ow compared with patientswith TIMI grade 3 _ow at 90 minutes following throm-bolysis [20].

The GUSTO trial also linked improved TIMI _owgrades with improved left ventricular ejection frac-tions (55 6 15% for TIMI grade 0, 55 6 15% for TIMIgrade 1, 56 6 15% for TIMI grade 2, and 62 6 14% forTIMI grade 3 _ow, P , 0.001 for TIMI grade 3 _owcompared with TIMI grade 0, 1, or 2 _ows) [19]. Inturn, improved left ventricular (LV) function was as-sociated with improved mortality: a 3.9% mortalitywas observed in patients with a LV ejection fraction ofmore than 45% compared with 14.7% mortality in pa-tients with a LV ejection fraction of less than 45% (P, 0.001) [19].

Some investigators have interpreted the fact thatall regimens in the GUSTO trial had nearly the same3-hour patency rate as essentially nullifying the openartery hypothesis. However, it is more likely thatreperfusion at this later time point is too late to favor-ably impact myocardial salvage and the subsequentcascade of events. In other words, the effects ofreestablishing patency may be considered to be “timedependent” [21]. Thus, it appears that the survivalbene~t with the accelerated rt-PA regimen was due tothe reestablishment of both early and full reperfusion.

Additional studies of other selected adverse eventshave raised further questions as to whether TIMIgrade 2 _ow truly represents an open artery and there-fore true reperfusion. In the second Thrombolysis trialof Eminase in Acute Myocardial infarction (TEAM-2)study, patients with TIMI grade 2 _ow had indices ofinfarct size (enzymatic peaks, time to peak activity,evolution of summed ST segments, Q waves, and Rwaves) that differed signi~cantly from patients withTIMI grade 3 _ow but did not differ signi~cantly frompatients with TIMI grades 0 or 1 _ow at 90 minutes fol-lowing thrombolysis [22]. The TEAM-3 study com-pared these TIMI _ow grades at 18–48 hours and foundthat global and segmental ejection fractions were simi-lar in the groups with TIMI-0/1 and TIMI-2 _ow butwere signi~cantly better in patients with TIMI grade 3_ow [23].

The Thrombolysis and Angioplasty in MyocardialInfarction (TAMI) 1-7 trials also found higher rates ofcongestive heart failure, recurrent ischemia, lower LVejection fractions, and a trend toward increased mor-tality in patients with TIMI grade 2 _ow as comparedwith patients with TIMI grade 3 _ow [24]. In addition,the TIMI-4 trial documented higher rates of reocclu-sion (which carries a higher mortality risk) in patientswith TIMI grade 2 _ow as compared with patients

Open Artery Hypothesis 103

with TIMI grade 3 _ow [25]. Based on the evidencestated earlier, the paradigm began to emerge that onlyTIMI grade 3 _ow truly represents an open artery (atboth an epicardial and a microvascular level) and thegoal of reperfusion strategies should be to obtain TIMIgrade 3 _ow.

Potential Role of IschemicPreconditioning in Mediating FlowFollowing Thrombolysis

One active area of research in the open artery hypoth-esis has focused on those factors associated with theachievement of higher rates of TIMI grade 3 _ow. In arecent small study by Andreotti et al., patients withpre-infarction angina (prodromal unstable angina orintermittent infarct related pain) in the setting ofacute MI were demonstrated to have smaller infarc-tions (lower peak creatine kinase and creatine kinaseMB) and a higher rate of TIMI grade 3 _ow at 90-minute angiography (86%) compared with patientswithout preinfarction angina (50%) when administeredrt-PA [26]. In addition, these patients with preinfarc-tion angina achieved earlier reperfusion (TIMI grade 3_ow; 64% at 35 minutes) compared with patients with-out preinfarction angina (0% at 35 minutes; P 5 0.006).Similar ~ndings of a lower frequency of adverse clini-cal outcomes (severe congestive heart failure, shock,or death) have been observed in patients with prein-farction angina than in patients without preinfarctionangina in the TIMI 4 trial (4% vs. 10%, respectively; P5 .03) [27]. It has been suggested that these bene~cialeffects may be due to ischemic preconditioning, whichmay result in earlier and more complete myocardialreperfusion [26,27]. Further, larger trials are needed toexplore these ~ndings because these small studiessuggest that thrombolysis may be more effective in pa-tients with preinfarction angina. A question thattherefore arises is whether primary angioplasty maybe more effective in patients without preinfarctionangina. Because coronary thrombi in patients withoutpreinfarction angina may be richer in platelets, andtherefore more resistant to thrombolytic agents, itcould also be speculated, for this reason, that primaryangioplasty may be more effective in these patients[28]. Obviously, data from larger randomized trials areneeded to explore this issue.

Current Limitations of ThrombolyticTherapy

Following treatment with front-loaded rt-PA and full-dose IV heparin, 40–47% of patients in GUSTO-I andTIMI 4 did not achieve full reperfusion (TIMI grade 3_ow) at 90-minute angiography [19,29]. Thus, thesearch for pharmacologic strategies to achieve fullreperfusion as soon as possible after thrombolytic

therapy has been intensi~ed. Newer thrombolyticagents, such as r-PA (recombinant plasminogen acti-vator), TNK (a genetically engineered mutant of rt-PA), and staphylokinase, all appear to be promisingnew agents for increasing both the speed and potencyof clot lysis, with the attendant hope of salvaging moremyocardium [30–32]. In the RAPID trial by Smallinget al., patients administered a double-bolus (10110MU) dose of r-PA achieved better 90-minute and 5- to14-day TIMI grade 3 _ows than rt-PA–treated pa-tients (63% vs. 49%, P 5 .019, and 88% vs. 71%, P ,0.001, respectively) [30]. In animal studies, Benedict etal. have observed faster and more complete recanal-ization of occluded rabbit carotid arteries with TNKthan with wild-type rt-PA [31].

Another major limitation of current thrombolytictherapy is the problem of reocclusion following suc-cessful reestablishment of patency [25]. As was shownin TIMI 4, the angiographic predictors of reocclusioninclude the presence of residual thrombus, slowerTIMI grade 2 _ow, and a tighter residual stenosis [25].New adjunctive drugs, such as antiplatelet agents(e.g., blockers of the platelet glycoprotein receptorsIIb/ IIIa), speci~c antithrombins (e.g., hirudin and hir-ulog), and thromboxane inhibitors, are being evalu-ated and appear to be promising in preventing reoc-clusion [33].

Rescue Angioplasty

If thrombolytic therapy is not effective, a “rescue” or“salvage” percutaneous transluminal coronary angio-plasty (PTCA) may be performed. Currently, theRESCUE study is the only randomized prospectivetrial to compare the outcomes of patients who undergoeither a rescue angioplasty or have no interventionperformed at all for a persistently occluded vessel fol-lowing failed thrombolysis. Only patients with their~rst anterior MI were enrolled in the study (n 5 151),which limits the generalizability of the results [34].Although there was no difference between the twogroups in the prede~ned primary endpoint of the study(left ventricular ejection fraction), Ellis et al. demon-strated a trend for a reduced incidence of the combinedendpoint of death or severe heart failure in the angio-plasty group of patients as compared with the conser-vatively managed group of patients (6% vs. 17%, P 50.05, respectively) [34]. In this trial, death and severeheart failure rates for patients treated with angio-plasty (5% and 1%, respectively) were lower than inthe conservatively managed group (10% and 7%, re-spectively). In the TIMI 4 trial, although successfulrescue angioplasty for an occluded artery at 90 min-utes resulted in a rate of TIMI grade 3 _ow that wassuperior to that of successful thrombolysis (86.5% vs.64.8%, P 5 0.002), the incidence of adverse events(death, recurrent MI, severe congestive heart failure,cardiogenic shock, or an ejection fraction ,40%) for

104 Goel et al.

rescue angioplasty was slightly worse than that of suc-cessful thrombolysis [35]. Although rescue angioplastypatients were demonstrated to have superior _owcompared with patients with successful thrombolysisin TIMI 4, this ~nding underscores the time-dependentnature of the open artery hypothesis. While the _owfollowing rescue angioplasty was superior to that fol-lowing successful thrombolysis, this superior _ow wasachieved later (at over 120 minutes after thrombolysis)than that in patients following successful thromboly-sis. This time delay may explain in part the less opti-mal outcomes for this strategy [35].

If more patients are to be identi~ed as suitable forrescue angioplasty, it is important to have reliable non-invasive markers of vessel patency. Unfortunatelyclinical symptoms, the ECG, and reperfusion arrhyth-mias are somewhat poor markers of the perfusion sta-tus of the culprit artery [36]. Newer potential markersinclude 99mTc-labeled sestamibi, continuous ST-seg-ment monitoring, and troponin or myoglobin assays[37,38]. In the future, once the technical issues sur-rounding the transpulmonary transit of sonicated mi-crospheres are resolved, it is conceivable that an in-jection may be given via the antecubital vein so thattransthoracic myocardial contrast echocardiographycan be performed to assess patency without injectingdirectly into the coronary artery.

Routine Use of Angioplasty as anAdjunctive Procedure FollowingThrombolysis

While the previous rescue angioplasty studies focusedsolely on patients with an occluded artery (TIMI grade0 or 1 _ow) following failed thrombolysis, it should benoted that the routine use of immediate adjunctivePTCA to supplement the results of thrombolysisacross all _ow categories (TIMI 0,1,2,3) has not beenshown to be any more ef~cacious than a conservativeapproach of deferred angioplasty in several large ran-domized prospective trials (39–43). Autopsy studieshave shown that the combination of thrombolytics anda mechanical intervention is limited by the heightenedpotential for bleeding into the vessel wall followingPTCA with the attendant risk of abrupt closure andrecurrent infarction. While these studies have as-sessed the ef~cacy of routine adjunctive PTCA in allTIMI _ow categories combined (TIMI 0, 1, 2, and 3),the relative bene~t of adjunctive PTCA in the sub-group of patients with suboptimal TIMI grade 2 _owhas not been assessed.

Primary Angioplasty

While the previous studies showed that the routine useof adjunctive PTCA immediately after thrombolysiswas not bene~cial, one question that naturally arose

was whether the use of angioplasty alone (primary ordirect PTCA) would be superior to the use of throm-bolytic agents alone. Direct or primary angioplasty inacute myocardial infarction has been demonstrated toachieve very high patency rates and high rates of thedesirable TIMI grade 3 _ow in angiographic trials[44–48]. The Primary Angioplasty in MyocardialInfarction (PAMI) investigators have reported a 97.1%success or patency rate (TIMI grade 2 or 3 _ow) forprimary angioplasty in acute myocardial infarction[44]. Compared with an older 3-hour dosing strategy ofrt-PA, there was a trend for patients treated with pri-mary PTCA to have a lower mortality rate than pa-tients treated with thrombolysis alone (6.5% vs 2.6%,P 5 0.06) in this trial of 395 patients [44]. Similarly, ina randomized trial of 301 patients reported by DeBoeret al., there was a reduction in mortality from 7.4% to1.9% among patients treated with primary angioplasty(P 5 0.024) [45]. Patients randomized to primary an-gioplasty also had a lower incidence of recurrent in-farction (15 patients, 10%, vs. 2 patients, 1%, P ,0.001) as well as improved left ventricular function (LVejection fraction of [LVEF] 44 6 11% vs. 50 6 11%, P, 0.001) [45]. Other smaller randomized trials, each in-volving less than 100 patients per treatment arm (an-gioplasty vs. thrombolysis), have demonstrated a non-signi~cant trend towards higher mortality but lowerrates of reinfarction in patients randomized to primaryangioplasty [46,47].

These early randomized comparisons of primaryPTCA with thrombolysis, however, were limited bythe use of either older dosing regimens of rt-PA or theuse of streptokinase rather than the more ef~caciousregimen of front-loaded rt-PA [44–47]. The trials alsoinvolved relatively small numbers of patients, and like-wise, did not involve large numbers of centers or op-erators, which limits the generalizability of the results[44–47]. Fortunately, the most recent randomized trialin this ~eld (GUSTO 2) overcame many of these limi-tations in its comparison of direct PTCA to front-loaded rt-PA in a large series of 1229 patients drawnfrom multiple international centers [48]. The primaryendpoint of the trial was the incidence of either death,reinfarction, or stroke, and these adverse events wereless frequent in the primary PTCA group comparedwith the front-loaded rt-PA group (9.6% vs. 13.7%, P 50.033). The mortality rates were only slightly lower forprimary PTCA (5.7% vs. 7.0%, P 5 NS), and the dis-crepancy in mortality was not as great as that reportedin previous smaller studies with limited multicenterenrollment.

Another advantage of the GUSTO 2 trial lies in itsuse of an independent angiographic core laboratory tocompare TIMI _ow grades rather than relying uponthe PTCA operator’s assessment. In contrast to theupper 80–90% rate of TIMI grade 3 _ow previously re-ported by angioplasty operators, only 74% of patientsachieved TIMI grade 3 _ow following angioplasty inthe GUSTO 2 substudy when the TIMI _ow was as-

Open Artery Hypothesis 105

sessed by an independent angiographic core labora-tory. This 74% rate of “normal” _ow in the artery stillcompares very favorably with the 53–60% rates ofTIMI grade 3 _ow reported in the GUSTO I and theTIMI 4 angiographic studies for front-loaded rt-PA[19,29].

Recently a nonrandomized retrospective analysis ofdata from the Myocardial Infarction Triage andIntervention (MITI) trial showed no bene~t in terms ofeither in hospital mortality (5.5% in thrombolytic ther-apy group versus 5.6% in primary angioplasty group,P 5 0.93), 1-year mortality (with adjustment for base-line characteristics), or the use of resources with pri-mary angioplasty versus thrombolytic therapy in alarge cohort of patients in the community setting (1050patients in the primary angioplasty group and 2095 pa-tients in the thrombolytic therapy group) with acutemyocardial infarction [49]. The mortality for throm-bolytic-treated patients was lower in this registrystudy than in randomized trials comparing thromboly-sis with primary PTCA. The authors cite the aggres-sive use of mechanical revascularization for failedthrombolysis and the fact that thrombolytic therapywas administered more quickly than in prior throm-bolytic trials as the reasons for the lower mortality inthis registry. The rates of success for primary angio-plasty in the MITI community hospital setting (89%)were lower than those reported in the PAMI trial(98%), and this may have accounted in part for thehigher mortality rates observed in PTCA patients.

New Device Strategies in the Settingof Acute Myocardial Infarction

While previous trials have examined the utility of con-ventional angioplasty techniques, an emerging focus ofcurrent reperfusion trials is on the use of new devicestrategies such as intracoronary stenting. With 730 pa-tients enrolled in eight trials to date [50–54], mortalityrates range from 2.9% in the largest trial of 340 pa-tients (STENTIM 1) [53] to 7% in the U.S. Multicenterexperience of only 44 patients [54]. Despite fears of anincreased risk of stent thrombosis, the overall rate ofstent thrombosis appears to be relatively low, at ap-proximately 2% [50–54]. If they are found to be supe-rior to conventional angioplasty techniques, these newdevice strategies will need to be compared with newerthrombolytic agents, such as TNK, r-PA, or staphylo-kinase.

Complexities of Choosing aRevascularization Strategy

The choice of whether to use a pharmacologic or a me-chanical reperfusion strategy in a given patient is quitecomplex, and unfortunately, the limited available ran-domized prospective trial data offer no de~nitive an-

swers. Both mechanical and pharmacologic strategiesare rapidly evolving, and their relative ef~cacy willneed to be recompared periodically. Both strategiesare a moving target, and at the present time the twoapproaches have different advantages. There is no“learning curve” in the administration of thrombolyt-ics. Newer thrombolytic agents should facilitate eveneasier dosing of these agents, including the potentialfor single-bolus administration over several seconds.In contrast, the in_uence of angioplasty operator ex-perience on clinical outcomes is quite dif~cult to deter-mine. Given the small numbers of patients treated peroperator and the relatively low event rates overall, thecon~dence intervals for this line of inquiry are quitelarge.

Thrombolytics may be effective in patients withthree-vessel disease or left main disease, whereassome of these lesions may not be approachable per-cutaneously. On the other hand, an interventional ap-proach does offer the advantage of early triage ofappropriate patients to coronary artery bypass graft-ing. Indeed, some of the bene~ts reported in primaryangioplasty trials may be due to the fact that candi-dates for coronary artery bypass grafting wereidenti~ed and revascularized (without even beingtreated by angioplasty it might be added), whereaspatients randomized to thrombolysis who did not un-dergo angiography may not have accrued the bene~tsof triage to coronary bypass grafting [45,46]. Throm-bolytics, if stored and administered in the emergencyroom, may be given rapidly 24 hours a day, whereasthere may be enormous institutional costs encoun-tered in having an in-hospital on-call team preparedto quickly perform primary angioplasty at all times.While several trials have shown high rates of normalTIMI grade 3 _ow following mechanical interventions,it is incumbent upon any institution routinely per-forming primary angioplasty to ensure that this _owis achieved quickly, preferably with a door-to-balloontime approximating that in the PAMI trial of about 60minutes. There is a trend towards a lower rate of in-tracranial bleeding with a mechanical approach, butthis comes at the cost of a higher rate of instrumentsite bleeding [48].

An important unresolved issue is whether surgicalbackup is required for primary angioplasty, andwhether a primary angioplasty strategy could be im-plemented in community hospitals without the delayinherent in transferring the patient to a tertiary carecenter. The guiding principle in selecting a reperfusionstrategy is simple, namely, the goal of achieving opti-mal blood _ow as quickly as possible. However, nu-merous variables enter into this very complicated de-cision, such as the timeliness with which cardiaccatheterization facilities would be available, the pa-tient’s hemodynamic status, the patient’s risk of in-tracranial bleeding (age, body surface area, gender),and the anatomic distribution of the infarct, to namejust a few.

106 Goel et al.

Time-Independent Open ArteryHypothesis

While all the previous trial data substantiate thebene~ts of both early and full reperfusion, whetherachieved pharmacologically or mechanically, severalobservations have raised questions as to whetherthere are bene~ts even to late reperfusion andwhether the bene~ts of reperfusion are entirely sec-ondary to myocardial salvage alone. This phenome-non is known as the “time-independent” open arteryhypothesis. For instance, a survival bene~t has beenobserved in patients with acute myocardial infarctionin whom reperfusion was achieved 6–12 hours afterthe onset of symptoms, a time when substantial my-ocardial salvage would be limited [55–58]. In the LateAssessment of Thrombolytic Ef~cacy (LATE) trial in-volving 5711 patients with acute myocardial infarc-tion, 35-day mortality for patients treated between 6and 24 hours of symptom onset was 8.9% with rt-PAversus 10.3% with placebo, a relative reduction of 14%[55]. The patients treated between 6 and 12 hours ofsymptom onset had a 35-day mortality of 8.9% withrt-PA versus 12% with placebo (a relative reductionof 25.6%) [55]. When thrombolytic agents have beenadministered more than 12 hours after the onset ofsymptoms, the results have been equivocal [55], per-haps because these agents are relatively ineffectivein establishing the infarct-related artery patencywhen clots are long-standing, a concept called throm-boresistance [56]. Another possibility is that at thislate time-point the risk of intracranial bleeding re-mains, while the potential bene~t of myocardial sal-vage is markedly attenuated. The postulated mecha-nisms by which late restoration of patency may conferbene~ts other than by salvaging ischemic myocardiuminclude (1) improved healing of the infarct and thusearly formation of a ~rm scar that reduces the riskof infarct expansion, ventricular dilatation, andaneurysm formation and favorably in_uences ven-tricular remodeling; (2) greater electrical stability; (3)restoration of myocardial function in chronic, severelyischemic, and noncontracting but viable myocardiumin the peri-infarct zone [55–58].

Newer Methods in the AngiographicAssessment of Coronary Blood Flow

Although the TIMI _ow grade classi~cation scheme[10] has been a valuable tool for comparing the ef~cacyof thrombolytic agents and in identifying patients athigher risk for adverse outcomes, there are severalproblems with this classi~cation scheme as it currentlyexists [59]. First, there is a high rate of interobservervariability in the assessment of TIMI _ow grades. Foryears it has been assumed that there are distinct cate-gories of coronary blood _ow. It has also been assumedthat the _ow observed in the nonculprit artery (the

_ow used as the “gold standard” for assessing TIMIgrade 3 _ow) is truly “normal”. Finally, as newerreperfusion strategies achieve a higher rate of TIMIgrade 3 _ow, this categorical method may have limitedstatistical power and sensitivity in distinguishing theef~cacy of different reperfusion strategies [59].

To overcome these limitations, we recently de-scribed a new, more objective and precise method ofestimating coronary blood _ow in which the number ofcineframes required for dye to reach standardized dis-tal landmarks are counted [59]. In general, cine~lm isrecorded at 30 frames per second. Therefore know-ledge of the number of frames allows a calculation ofthe time required for dye to travel the length of theartery. These frame counts were corrected for thelonger length of the left anterior descending coronaryartery (LAD) to arrive at the corrected TIMI framecount [59]. In contrast to the conventional TIMI _owgrade classi~cation scheme, the corrected TIMI framecount (CTFC) is quantitative rather than qualitative,it is objective rather than subjective, and it is a con-tinuous rather than a categorical variable.

Interobserver Variability in Assessingthe Degree to Which an Artery IsOpen

Recently, we have reported that the agreement be-tween an angiographic core lab and clinical centers isbest in determining if a culprit artery is either open orclosed (kappa value 5 0.84 6 0.05, which indicates goodagreement) [59]. In contrast, when only open arteriesare analyzed, the rate of agreement is only moderatewhen assessing TIMI grade 3 _ow (kappa value 5 0.556 0.05) and is actually poor in the assessment of TIMIgrade 2 _ow (kappa value 5 0.38 6 0.05) [59]. Even be-tween experienced angiographic core laboratoriessuch as the GUSTO core laboratory and other core lab-oratories, there can be a frequent lack of concordance.In a recent study in which the culprit artery was pre-speci~ed (which improves the rate of agreement be-tween angiographic core laboratories), the rate ofagreement between two core laboratories in the as-sessment of TIMI 2 and 3 _ow was only 83%, and threeexperienced angiographic core labs achieved perfectagreement in only 71% of the cases [60].

The reproducibility of the corrected TIMI framecount has been systematically studied in 85 evaluableconsecutive pairs of injections of the infarct-relatedartery [59]. The mean absolute value of the differencebetween two consecutive hand injections spaced apartby 1–2 minutes was 4.7 6 3.9 frames, with a range of 0to 18 frames (coef~cient of variation 5 9.0%).Reproducibility did not vary signi~cantly by infarctartery location [59]. Despite differences in the lengthof the coronary arteries, the force of injections, the di-ameter of the arteries, heart rates, cardiac output, andcatheter engagement, the standard deviation among

Open Artery Hypothesis 107

78 normal arteries was only 3.1 frames, a coef~cient ofvariation of approximately 14% [59].

Are There Really Two DistinctCategories of Coronary Blood Flow(i.e., Do TIMI Grades 2 and 3 FlowReally Exist?)

In keeping with the binary nature of clinical decisionmaking, cardiologists have a tendency to characterizecoronary blood _ow as either normal or abnormal.However, analysis of _ow data using the CTFC indi-cates that coronary blood _ow, like disease progressionor restenosis, appears to be unimodally distributed asa continuous variable. Two distinct subpopulations ofpatients with either TIMI grade 2 (slow) or 3 (normal)_ow do not in fact exist [59]. Consequently, any suchcategorical classi~cation of coronary _ow is at best ar-bitrary. In a retrospective analysis of data from theTIMI 4 trial, it appears that members of the TIMI an-giographic core laboratory frequently characterizedarteries with a TIMI frame count of .40 as havingTIMI grade 2 _ow (.1.3 seconds to reach the distallandmark) [59].

A Flawed Gold Standard of “NormalFlow”

It has also always been assumed that the _ow in thenonculprit artery in the setting of acute myocardial in-farction was “normal” with “TIMI grade 3 _ow.”However, using the corrected TIMI frame court, wehave found that following thrombolysis, the dye veloc-ity in the uninvolved bed used to gauge “normal” TIMIgrade 3 _ow is in fact not normal [59]. In the setting ofacute myocardial infarction, the mean CTFC at 90 min-utes following thrombolysis among nonculprit arteriesused to gauge normal TIMI grade 3 _ow (25.5 6 9.8)was 20% higher (i.e., _ow was 20% slower) than mini-mally diseased arteries with normal _ow in the ab-sence of acute myocardial infarction (21.0 6 3.1,P ,0.001), but returned to that of normal arterieswithin 1 day following thrombolysis (21.7 6 7.1, P 5NS). Finally, the velocity of contrast in nonculprit ar-teries may be slowed to different degrees dependingupon their anatomic location [59].

This _awed “gold standard” of _ow may lead to thepotential misclassi~cation of TIMI grade _ows in cul-prit vessels in the following way. The _ow in culprit cir-cum_ex arteries is, by de~nition, graded against the_ow in purportedly “normal” left anterior descendingarteries. However, the _ow in these nonculprit LADsarteries may be slowed to a slightly greater degreethan that in the other locations [59]. Therefore, rela-tively speaking, the majority of circum_ex arteries(92%) appear to have normal _ow. In contrast, the _owin culprit left anterior descending arteries was graded

against _ow in nonculprit circum_ex arteries that hadsustained a minimal delay in _ow. Therefore, the ma-jority of LAD arteries were assessed as having TIMI2 _ow [59] in the TIMI 4 trial. Accordingly, TIMI grade2 _ow was largely constituted by LAD culprit arteries(62.7%), and TIMI grade 3 _ow occurred predomi-nantly when either RCA or circum_ex were the culpritarteries (73.8%, P , 0.001). Consequently, it is impor-tant that any study relating clinical outcomes to theTIMI _ow grades correct for the potentially large im-balances in infarct artery location.

This reduction in basal _ow in the nonculprit arteryimplicates disordered microvascular tone as playing atleast some role in the slowed _ow following thrombol-ysis. The magnitude of the delay attributable to themicrovasculature appears to be on the order of 4–10frames (between a tenth and a third of a second). These~ndings extend those of Uren et al., who have shownby PET scanning that at 1 week following acute my-ocardial infarction, the vasodilatory response in non-culprit arteries remains reduced, which has been at-tributed to an abnormality in resistance vesselfunction [61]. In addition, Corday and others [62–64]have shown in acute coronary occlusion experimentsthat focal necrosis (microinfarcts) and regional lactatederangements occur in the nonoccluded (remote) pos-terior segments of the left and right ventricles afterocclusion of the proximal left anterior descendingartery in closed-chest dogs. In a recent study byMarjorie et al. in isolated perfused rat hearts, basalcoronary _ow in acute myocardial infarction heartswas completely normalized within 1 week, whereasmaximal coronary _ow was normalized 5 weeks afteracute myocardial infarction [65].

These ~ndings implicating the microvasculature asplaying a partial role in _ow delays are consistent withthe myocardial contrast echocardiography (MCE)studies of Ito et al., in which no relationship was ob-served between epicardial stenosis severity and theincidence of myocardial “no-re_ow” phenomenon (i.e.,no sonicated microbubbles can be demonstrated per-fusing the tissue) following successful thrombolysis[66]. The most recent results by Ito reveal that MCEno re_ow is associated with a poor recovery in leftventricular function. The left ventricular cavity wasdilated despite a patent culprit artery in patients withMCE no re_ow, whereas ventricular volumes de-creased in the convalescent stage in patients withMCE re_ow [67].

Several mechanisms have been postulated in thedevelopment of the no-re_ow phenomenon followingacute MI, such as a loss of microvasculature integrityand profound spasm of microvasculature caused bythe release of potent vasoconstrictors from activatedplatelets (e.g., serotonin), or neutrophil in~ltration andplatelet ~brin clots in the microvasculature [68–73].Free radical–mediated reperfusion injury, a potentialthreat to viable myocardium, might also be associatedwith the no-re_ow phenomenon. In a recent study by

108 Goel et al.

Grech et al., free radical levels (by coronary venousef_uent blood sampling) reached a peak between 1.5and 3.5 hours after primary angioplasty, followed bygradual decline up to 5 hours [74]. Adjunctive thera-pies, such as superoxide dismutase, catalase, adeno-sine, verapamil, and other new therapies targeted atthe microvasculature, may warrant further investiga-tions [75–78]. However, it must be emphasized thatwhile the no-re_ow phenomenon exists, the magnitudeof its contribution to _ow delays following thrombol-ysis may be relatively small and on the order of only4–10 frames based upon our experience [58]. Unpub-lished data from our laboratory demonstrate that an-gioplasty of vessels with delayed _ow followingthrombolysis does result in an improvement in _ow.Thus, both the epicardial lesion and the distal mi-crovasculature appear to play a role in _ow delays fol-lowing thrombolysis.

We have also examined the relationship betweenthe timing of culprit artery opening and subsequent_ow at 90 minutes after TNK administration for acutemyocardial infarction was examined in the TIMI 10Atrial. The coronary blood _ow was signi~cantly fasterat 90 minutes in those vessels that were open morethan 30 minutes (CTFCs of 32.6 6 17.4, n 5 55) com-pared with those open less than 30 minutes (62.1 658.5, n 5 7; P 5 0.004), and the incidence of TIMI grade3 _ow was higher in arteries that were open earlier(39.2% vs. 14.8%, P 5 0.01) [79].

Implications with Respect toStatistical Power and ClinicalEndpoints

Comparison of angiographic outcomes using a continu-ous variable such as the CTFC might be superior tousing a categorical variable, such as the TIMI _owgrade in terms of statistical power and sensitivity.Tests that are based on categories, frequencies, rank,or percentiles are considered nonparametric. If thepopulation follows a normal distribution, parametrictests are generally more statistically powerful thannonparametric tests and are more likely to detect areal treatment effect [80]. Thus, one motivation for thedevelopment of a continuous measure of coronaryblood _ow is that it might have more statistical power.

In addition, as newer reperfusion strategies are re-ported to achieve a higher incidence of TIMI grade 3_ow, a categorical scale may fail to distinguish theiref~cacies because there is a range of dye velocities thatconstitute TIMI grade 3 _ow. In other words, not allTIMI grade 3 _ow is created equally. Even if tworeperfusion strategies result in the same proportion ofTIMI grade 3 _ow, the TIMI grade 3 _ow of one strat-egy may be faster than the TIMI grade 3 _ow of theother strategy, and there may be a difference in thedye velocity between the two strategies when ana-lyzed as a continuous variable using the CTFC. For in-

stance, two new reperfusion strategies may bothachieve TIMI grade 3 _ow in 60% of patients, but TIMIgrade 3 _ow for one strategy may be a mean CTFC of30 frames and for the other strategy a mean CTFC of20 frames [59]. One critical question that naturallyarises is whether this new measure is related to clini-cal outcomes. We have recently demonstrated that thecorrected TIMI frame court is signi~cantly correlatedwith composite endpoints (death, reinfarction, shock,or LVEF ,40%) as well as mortality [82,83]. In theTIMI 4 trial, if an adverse outcome (death, recurrentMI, LVEF ,40%, or congestive heart failure/shock)was absent, the mean CTFC was signi~cantly lower(53.9 6 31.2) than in the 80 patients in which an ad-verse outcome was present (66.5 6 34.2; P 5 0.003).Similar results were observed for the relationship be-tween mortality and the CTFC following thromboly-sis. In the Restore trial (tiro~ban 1 heparin vs. he-parin alone for 36 hours in patients undergoingangioplasty for acute ischemic syndromes), the perfu-sion status of the coronary artery after angioplastywas examined in relation to mortality. The postangio-plasty _ow in survivors (CTFCs 20.4 6 16.7, n 5 1,073)was signi~cantly faster than in patients who died(CTFCs 33.4 6 27.1, n 5 10; P 5 0.017) [83].

Our angiographic core laboratory has now devel-oped a variation of this frame-counting method that al-lows the measurement of absolute velocity as an end-point in interventional trials [81]. At the completion ofthe intervention, the angioplasty wire is placed at thelandmark used for frame counting. A Kelly clamp isplaced on the PTCA guidewire as it exits the body. Thewire is then withdrawn to the ostium of the coronaryartery, and a second Kelly clamp is placed on the wireagain as it exits the body. The distance between theseclamps is the distance from the ostium of the coronaryartery to the landmark. Knowing this distance (cm)and the time (seconds 5 frames/30) required for dye totraverse this distance allows a calculation of velocity(cm/sc). The average diameter of the artery can be de-termined using quantitative angiography, and _ow canthen be calculated as velocity 3 mean cross-sectionalarea [81].

Conclusions

Recent observations bear out not only the validity ofthe open artery hypothesis but also its time-depen-dent nature as well. The survival bene~t following areperfusion strategy, be it pharmacologic or mechani-cal, appears to be due to both full and early reperfu-sion. More potent and ~brin-speci~c thrombolyticagents appear to be promising for increasing thespeed of reperfusion and salvage of myocardium, andnew device strategies appear to be promising as a me-chanical means of restoring normal antegrade _owwith little residual narrowing and little risk of abruptclosure when coupled with an optimal antithrombotic

Open Artery Hypothesis 109

regimen. In contrast to the subjective and categoricalnature of the TIMI _ow grade system, a more objec-tive method to standardize coronary blood _ow, suchas the TIMI frame count, may be desirable to comparethe ef~cacy of reperfusion strategies. This method isquantitative, objective, reproducible, and, as a contin-uous variable, it may have more statistical and dis-criminatory power to assess the relative ef~cacy ofreperfusion strategies.

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