Is Target Vessel Failure a Failure?
As with any treatment, when contemplating percutaneous coronary intervention (PCI) we must remain clear regarding our goals. In the setting of stable angina with preserved left ventricular ejection fraction, PCI delivers only 2 clinical improvements over medical therapy: patients feel better (less angina) and have fewer heart attacks (spontaneous myocardial infarction [MI]). Nevertheless, these benefits come at the price of slow but unrelenting stent failure necessitating repeat procedures, rare procedural complications, the economic cost of the stent device and implantation, and a sizable minority of asymptomatic troponin elevations of uncertain significance. Therefore, balancing the benefits and risks to each patient’s net advantage appropriately consumes much clinical attention.
As in the collaborative ILIAS registry substudy in this issue of JACC: Cardiovascular Interventions, research studies frequently use target vessel failure (TVF) as a yardstick for PCI versus medical therapy. Usually TVF includes composite cardiac death, target vessel MI (TVMI), and target vessel revascularization (TVR). At first blush this seems reasonable, but the devil lurks in the details, so let us revisit TVF and its implications for coronary flow reserve (CFR) in the fractional flow reserve (FFR) “gray zone” between 0.75 and 0.80.
TVR makes sense when comparing 2 stent devices if all patients undergo initial PCI, although an argument could be made for using the narrower notion of target lesion revascularization. However, when comparing medical therapy and PCI the traditional definition of TVR inappropriately discounts most stents. For example, among gray-zone FFR cases with reduced CFR (≤2.0) the ILIAS investigators report 5 subsequent TVR among 93 vessels treated by PCI, in contrast to 6 TVRs among 58 vessels treated medically. The difference between 5 of 93 = 5.4% (after initial PCI) and 6 of 58 = 10.3% (after initial medical therapy) appears significantly larger with initial medical therapy (per their Table 3, adjusted HR: 7.0; 95% CI: 1.3-38.2; P = 0.025).
The current concept of TVR effectively ignores the index PCI and “landmarks” the analysis from day 2 of follow-up. But what about the 93 stents originally placed in the PCI group? Accounting for all stents placed in target vessels should be (93 + 5) / 93 = 105.4% with a strategy of immediate PCI. Considering the initial PCI, far fewer stents are actually placed with a strategy of initial medical therapy (10.3% vs 105.4%)—about 10-fold less—and not the reverse, as reported in the ILIAS substudy. While the investigators are by no means the first to declare a benefit from PCI over medical therapy on the basis of this endpoint, in our opinion the fact that such Enron-style accounting of TVR has become accepted in research design and analysis makes it no less incorrect. More PCI leads to more TVR, not to less TVR. Anyone claiming the opposite is fiddling the books.
Indeed, the previous analysis holds for any study of initial PCI versus medical therapy, including recent seminal trials using low FFR or other high-risk selection criteria. However, those studies also demonstrated a benefit from greater TVR, namely less spontaneous MI. For example, in a patient-level pooled analysis of 2,400 subjects from 3 randomized trials, FFR-guided PCI instead of medical therapy for stable lesions resulted in a significant reduction in spontaneous MI from 13.4% to 8.5% after 5 years, yielding a number needed to treat of 20 to prevent 1 TVMI. Similar results were seen in the ISCHEMIA trial with a significant reduction in spontaneous MI from 10.0% to 7.1% after 5 years, yielding a comparable number needed to treat of 34, despite minority 20% use of FFR and selection criteria that included 8.5% of subjects without obstructive disease.
Conversely, with only 8 TVMIs among 412 vessels (or 1.9% during a median follow-up of almost 3 years), the ILIAS substudy of gray-zone FFR contained too few events to draw meaningful conclusions. Consequently, its depressed CFR (≤2.0) and preserved CFR (>2.0) subgroups each had even fewer infarcts, leading to wide CIs for TVMI. Does a 10-fold higher (not lower!) rate of TVR for gray-zone FFR vessels reduce TVMI? And does adding CFR distinguish or augment any PCI benefit on TVMI? These fundamental questions remain unanswered in this ILIAS substudy.
Furthermore, PCI instead of medical therapy does not reduce the risk of all-cause or cardiovascular death, as has been demonstrated in recent randomized trials. Including nonmodifiable events in a composite endpoint distorts hazard ratios toward 1 while not affecting absolute differences for TVF.
Reduced angina represents an alternative benefit from PCI, one perhaps of larger magnitude than TVMI and, given its greater frequency, possibly of more relevance to patients. This current substudy of CFR in the FFR gray zone makes no mention of symptom burden—unexpected because the ILIAS acronym contains the phrase “Angina Syndromes”—with zero data reported on physician assessment or patient questionnaires of angina severity or frequency, or number or doses of antianginal medications.
Prior work randomized patients in unblinded fashion to either PCI or medical therapy of vessels in the FFR gray zone. Paired angina assessments in 100 subjects with initial FFR of 0.75 to 0.82 and mean CFR of 2.4 (range 1.3-5.0) found significant improvements in angina frequency (adjusted P = 0.04) and quality of life (adjusted P = 0.02) after 3 months. These differences trended in the same direction after 12 months but were no longer statistically significant, perhaps caused by loss of subjects (down to 89 pairs) or restenosis. Interestingly, 76% of territories with a gray-zone FFR had no perfusion defect by cardiac magnetic resonance stress imaging.
So-called gray zone FFR values between 0.75 and 0.80 occur in 15% of vessels, and their optimal treatment remains uncertain. Two ongoing randomized trials could provide additional insights. First, the sham-controlled ORBITA-2 (A Placebo-controlled Trial of Percutaneous Coronary Intervention for the Relief of Stable Angina) trial ( NCT03742050) might consider a post hoc analysis looking for angina benefits of PCI over medical therapy in gray-zone lesions (anticipate 15% of its n = 400 cohort, so 60 total). Second, the open-label COMFORTABLE (Comparison of clinical outcomes Following percutaneous coronary intervention versus Optimal medical therapy based on gray zone fractional flow Reserve in sTABLE angina patients with intermediate coronary artery stenosis) trial ( UMIN000031526) will monitor TVMI and clinical status during 5 years of follow-up in n = 410 subjects. Unfortunately, its design includes the same “Enron accounting” of TVR and inclusion of unmodifiable cardiovascular death discussed previously. Common to both trials are small sample sizes no larger than the current n = 412 vessels from the ILIAS substudy. Given contemporary event rates, it seems almost inevitable that these trials will also be underpowered to detect a difference in TVMI and be forced to conclude that “larger studies are required” for that endpoint, although hopefully insight into angina requires fewer subjects.
The ILIAS investigators conclude from their substudy that “CFR could be used as an additional risk stratification tool to determine treatment strategies in patients with intermediate FFR.”1 We respectively note the lack of a significant impact on TVMI, no information on clinical symptoms, and a 10-fold higher rate of TVR when properly accounting for all PCI—none of which supports using CFR for additional risk stratification. In our opinion, a host of existing clinical, angiographic, and physiologic data can be used to make decisions in the gray zone, pending refinement by ongoing studies.
Figure 1 summarizes the key arguments against current TVF as an endpoint in trials comparing PCI against medical therapy: including cardiac death introduces a bias for risk ratios caused by lack of differential treatment effect; “traditional” TVR inappropriately discounts the vast majority of stents; and TVF neglects angina completely. TVF has failed—but reform is straightforward.
Visual Critique of TVF for Trials of PCI Versus Medical Therapy
This article is reproduced from JACC journals.
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