CLINICAL STUDY: MYOCARDIAL ISCHEMIA: EDITORIAL COMMENT
Coronary flow studies for risk stratification in multivessel disease
A physiologic bridge too far?*
D. Douglas Miller, MD, CM, FACC*,*
* Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA
* Reprint requests and correspondence: D. Douglas Miller, Saint Louis University, Department of Internal Medicine, FDT 12th Floor Administration, 1402 South Grand, St. Louis, Missouri 63104, USA.
In this era of intense historical reflection on the events of World War II, noted authors and film makers have transported a new generation back to the heroic acts and inglorious failures of the last struggle for Europe. Steven Spielberg’s and Tom Hanks’ Saving Private Ryan and Band of Brothers have graphically illustrated in cinema verite footage the soldiers’ perspective of combat. A noteworthy forerunner of these modern epics is the Cornelius Ryan chronicle of the World War II battle at Arnhem in Holland, A Bridge Too Far (1), which was made into a major motion picture of the same name. Located in eastern Holland nearly equidistant from the three major centers of the Intermediate Lesions: Intracoronary Flow Assessment versus 99mTc-MIBI SPECT (ILIAS) trial (2), Arnhem in 1944 was the site of a rare undamaged bridge across the Rhine River—a vital artery into the heart of Nazi Germany. At Arnhem, Allied troops suffered twice as many casualties as they did on D-Day. Operation Market-Garden illustrates the bitter result of overreaching in the pursuit of a laudable strategic goal.
Recognizing the limits of coronary angiography for functionally defining intermediate coronary stenosis severity, numerous investigators have sought a clinically valuable physiologic "bridge" to facilitate decision making regarding coronary artery disease (CAD) therapy. Each subsequent study has buttressed this "bridge" and extended our understanding of human coronary physiology, while also pointing out the inherent weakness of comparing lesion-specific physiologic end points to noninvasive imaging and angiographic data, even in the same patients. How, then, does the battle for the bridge at Arnhem inform us about the ILIAS (2) study? Has the intense competition among renowned coronary physiology investigators in the Netherlands stretched this technology beyond the limits of clinical applicability? Have the ILIAS investigators made a tactical error in the inception and execution of their ambitious study? Or is this trial a victorious assault on current diagnostic and prognostic thinking that will long influence the course of cardiology practice?
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The ILIAS mission
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The multicenter ILIAS investigator group has prospectively collected and analyzed flow wire and single-photon emission computed tomographic (SPECT) imaging data from 191 patients with multivessel disease and stable angina who were scheduled for elective percutaneous transluminal coronary angioplasty (PTCA) of the most severe angiographic stenosis. The investigators followed these patients one year for subsequent cardiac events, including myocardial infarction (MI) and death ("hard" events), and ischemia-driven coronary revascularization. Despite previous outcomes data from the Doppler Endpoints Balloon Angioplasty Trial Europe (DEBATE) study (3), a coronary flow velocity reserve (CFVR) cut point of <2.0 and the presence of a reversible SPECT perfusion defect change >1 grade defined testing abnormalities in the index artery and perfusion bed, respectively. The majority of subsequent events (16 of 19) were coronary revascularizations, of which 13 patients had myocardial ischemia documented prior to subsequent coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention (PCI).
This study enrolled sufficiently large numbers of patients for statistical validity, and it was carried out by skilled investigators blinded to the critical data elements. Two very different physiologic techniques (coronary flow wire and myocardial SPECT) were compared under nonidentical drug stress conditions (adenosine vs. dipyridamole infusion). Not surprisingly, the comparability of the two measurements was low (70%) and inconsistent with that reported in previous studies in largely single-vessel disease populations, in which good agreement ( 90%) was achieved between flow wire and SPECT data (4–10). This is likely explained by the complexities associated with multivessel coronary disease physiology, and by the fact that a direct measurement of flow enhancement during hyperemia (relative to basal index vessel flow) was compared to an imaging technique that measures flow enhancement in diverse myocardial beds using relative radiotracer uptake detected with SPECT. Neither technique provides an absolute measurement of myocardial perfusion, nor coronary blood flow enhancement. In addition, the assignment and comparability of vascular territories by flow wire and SPECT imaging is problematic, particularly in patients with multivessel disease. It is difficult to control for the effects of collateral vessels, competitive flow, differential hyperemia and other factors.
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The casualty report
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As every small skirmish or global conflict winds down to an inevitable conclusion, all combatants have one fervent with—"Don’t let me be the last casualty!" While the ILIAS trial is the first study of its size to compare these two techniques in a population of multivessel-disease patients, it has clearly been shown as early as 1995 that a normal flow wire measurement can prompt the safe deferral of a coronary intervention in stable angina patients (11). The struggle to optimize the clinical application of this novel intracoronary biomedical technology continues on several fronts. To appropriately assess whether this battle is being won, the casualty figures—major adverse cardiac events (MACE) and hard events (death or MI)—must be separated and carefully scrutinized.
The ILIAS study’s potentially most troubling new finding is that a normal SPECT in the perfusion territory of an intermediate stenosis is associated with a higher than expected MACE rate in a stable angina population, despite standard clinical interventions (i.e., risk factor modification, drugs, other factors) designed to reduce ischemia and retard disease progression. It is also of note that the MACE rate observed in ILIAS patients with normal flow enhancement was 6%, as compared to the MACE rate in patients without significant SPECT defect redistribution (11%) (Table 1). These two rates do not differ significantly from each other, but both are significantly higher than the hard event rates previously recorded with normal or near-normal myocardial SPECT (Table 2) or stress echocardiography in similar populations (averaging 1.0% per year).
How can this be explained? Clearly, the majority of events observed in ILIAS were elective coronary revascularizations. In an attempt to reduce subjectivity from clinical decision making in the study, the investigators used a proxy of ischemia as the principal determinant of the decision to perform coronary revascularization. This is consistent with recent American College of Cardiology/American Heart Association Guidelines (12), as is the use of coronary physiologic assessment to assess intermediate (30% to 70%) coronary lesions before PCI (13). Seventeen patients without a reversible SPECT defect change of >1 grade had subsequent events, again predominately coronary revascularizations.
All ILIAS patients had multivessel disease. Ischemia leading to coronary revascularization events could have occurred in the distribution of a previous PTCA vessel, or could be due to progression of CAD in other vessels. Revascularization events (n = 59 total) could have included PTCA of a restenotic or new lesion, or CABG of other vessels and/or the intermediate stenosis. The relationship of the initial physiologic studies (CFVR and SPECT) to subsequent revascularization requires further comment. Previous studies have shown that mild to moderate SPECT defects are actually more predictive of future adverse events (MI) than are severe defects (14) in patients with chest pain. It is important to understand fully the relationship of the revascularization events and other hard events to the previously identified intermediate lesions, which are prone to plaque rupture (15).
It is clearly difficult to predict from the ILIAS trial whether the intermediate lesion or the more severe PTCA lesion exerts a greater influence on future patient outcomes beyond one year. The one-year hard event rate related to intermediate lesions with normal coronary physiology was relatively low (2%), suggesting that severe lesions were the major driver of not only future revascularizations but also of MI and death. However, hard events (death or MI) related to more severe lesions are not detailed in the ILIAS study. Table 1 summarizes MACE and hard event rates in five studies (including ILIAS) using coronary physiology to make decisions on deferral of PCI in patients with intermediate lesions.
Despite these significant limitations, Kern et al. (11) and later other investigators (16–18) showed that deferring interventions on intermediate coronary stenoses with normal physiology was consistently associated with low near-term MACE rates (10%) over one to two years. The ILIAS trial extends the existing evidence in favor of an intermediate coronary stenosis "warranty" by showing a similar low event rate (6% combined MI and revascularization), and no deaths over one year after PCI deferral in a normal physiology subset of a population with exclusively multivessel coronary disease (2). The durability of this warranty depends significantly on the underlying biology of the coronary artery plaque, but it generally confers a low hard event rate of 1% to 2% annually for a term of 12 months in stable angina patients (Fig. 1).
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Figure 1 Schematic graph illustrating the cardiac "hard" event-free survival (E) without myocardial infarction or death over time (T) following a normal test (t) performed to evaluate patients with either an acute coronary syndrome (ACS) or stable coronary artery disease (CAD). The duration of the event-free "warranty" is dependent on CAD biology, with a shorter event-free survival expected following a normal test in patients with ACS (t + 1 = 6 to 12 months), compared to the extended normal post-test event-free survival in patients with stable CAD (t + 2 = 12 to 18 months). With the passage of time following a normal test, the 95% confidence intervals (CI) are significantly increased as the durability of the post-test risk prediction declines. The normal test in question could be an invasive coronary physiology study or a noninvasive stress myocardial perfusion scan.
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Supporting units
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Ever since our original 1994 report correlating coronary flow velocity with technetium-99m sestamibi myocardial SPECT imaging (5), at least 14 studies have been reported describing the relationship between catheterization laboratory-derived physiology measures of coronary stenosis severity and ischemia testing modalities (4,6–10,19–26). The list includes a previous study in the Journal of the American College of Cardiology on two-vessel coronary disease patients from several of the principal authors of the ILIAS trial (23). The ongoing Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial may provide further insights into the use of SPECT to guide CAD therapies (W. Boden, personal communication, January 16, 2002). However, outside the setting of clinical trials and despite practice guideline recommendations (12), only 60% to 70% of stable angina patients undergo ischemia testing before diagnostic coronary angiography.
Like the unpredictable weather around the Arnhem "drop zone," one cannot control for the impact of microcirculatory flow impairment (due to prior MI, acute coronary syndromes, severe hypertension, diabetes and/or ventricular hypertrophy). Nor should it be assumed that "culprit vessel" interventions based on either abnormal coronary physiology or ischemia stress testing will correct all symptoms, post-stenotic flow or myocardial perfusion abnormalities in patients with diffusely atherosclerotic arteries (27). It is now recognized, largely based on other seminal work from Dutch investigators (4,9), that abnormalities of flow (CFVR) may reflect either epicardial or microvascular CAD, but that the translesional pressure-derived index, myocardial fractional flow reserve, is not only a more reliable measure of physiologic impairment but also a marker of outcomes after PCI deferral (16,17) (Table 1).
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Epilogue
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In the ILIAS trial, as in general cardiology practice, it is clear that coronary revascularization decisions following coronary intervention in patients with multivessel disease are principally driven by other severe lesions, and not by restenosis of the index intermediate lesion. The implication that CFVR can be used electively to sample individual arterial beds for coronary intervention selection (or deferral) in patients with multivessel disease and simultaneously define future outcomes, to the exclusion of myocardial stress imaging, is contentious. By restricting their SPECT analysis to myocardial perfusion data only, the ILIAS investigators failed to take advantage of the prognostic power of several well-validated nonmyocardial functional risk markers that can be obtained during standard myocardial perfusion tomography (i.e., transiently increased tracer lung uptake, cardiac dilation, reduced ejection fraction, increased end-systolic volume, among others).
It must also be pointed out that seemingly appropriate catheterization laboratory decisions made in real time may not reflect the cumulative myocardial burden of ischemia in daily life, which may be better reflected by tomographic stress myocardial perfusion studies. Just as the Allied ground unit commanders at Arnhem made numerous seemingly correct decisions based on available information in the heat of battle, the incremental value afforded to the operation’s planners—distant general staff officers’ ability to see the bigger picture at critical junctures in the battle—was cut off by poor communications.
A seasoned warrior always favors good intelligence over random acts of heroism. So it is with defining the future risk of cardiac events in patients with known or suspected multivessel coronary disease. Experienced clinicians will continue to make the majority of their patient treatment decisions on the basis of tomographic stress imaging data (nuclear or echocardiographic), which simultaneously samples the cumulative physiologic impact of all critical and intermediate lesions and provides incremental prognostic power over the exercise, angiographic (28–31) flow, pressure or data obtained in the same population. Forcing the risk-stratification decision in multivessel disease patients into the catheterization laboratory, even in the hands of the best-equipped and most skilled of operators such as the ILIAS investigators, asks too much of an elegant technology that has other significant and useful applications. Though the mission was well conceived and well executed by leading investigators, in retrospect their goal was unachievable from the onset.
The inevitability of world peace, like the march of technology, cannot be denied. This will not be the last report on the value of intracoronary devices for the assessment of lesions’ severity, as a guide to acute intervention or future event risk. And just as the Allies eventually succeeded in crossing the Rhine and in winning the war, so too will the increasing impact of physiologic testing in the laboratory eventually become accepted as a routine adjunct to coronary angiography. However, by knowing the limits of technology, operators using this approach will benefit the majority of patients with multivessel disease by restricting themselves to making important real-time coronary lesion assessments as a guide to interventional decision making, and not using it as an index of future cardiac risk, where other more powerful and better validated approaches such as myocardial perfusion imaging are available.
Better to regroup, retrench and live to fight another day than to undertake an ill-fated campaign against insurmountable odds. After all, another monument to military hubris lies only a few kilometers to the southwest of Arnhem—in another European low-country village named Waterloo.
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Acknowledgments
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Thanks to Lynda Roepke for her expert secretarial assistance and to Morton J. Kern, MD, for his thoughtful review of the manuscript.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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All allusions to the great war aside ...
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The ILIAS mission
The casualty report