Limitations of FFR (or any Physiologic Measurement) During STEMI: Implications for FFR-Guided Revascularization in the ACS Patient

Disclosure: Dr. Kern reports he is a consultant and speaker for St. Jude Medical and Volcano Therapeutics, and a consultant for Boston Scientific, Opsens, ACIST Medical, and Merit Medical.

A 48-year-old man comes to the emergency room with 2 hours of chest pain and electrocardiogram (ECG) showing inferior ST elevation (Figure 1). The ST-elevation myocardial infarction (STEMI) team is activated and within 60 minutes, coronary angiography shows 100% circumflex artery (CFX) occlusion and 60% right coronary artery (RCA) stenosis (Figure 2). We perform percutaneous coronary intervention (PCI) with a drug-eluting stent (DES) in the CFX. Should we proceed to also stent the RCA? Conventional wisdom (i.e. guidelines) says no, while 3 recent studies say yes. One of these 3 studies, the DANAMI3-PRIMULTI trial (just presented at the American College of Cardiology [ACC] Scientific Sessions) says yes — using fractional flow reserve (FFR) of the non-culprit artery.

Before reviewing whether or not we can use FFR in the acute coronary syndrome (ACS) patient, let’s look at the debate on the current approaches to the STEMI patient with multivessel coronary artery disease. For more than 10 years, the American Heart Association (AHA)/ACC/Society for Cardiovascular Angiography and Interventions (SCAI) STEMI and PCI guidelines on this subject were based principally on meta-analyses and several non-randomized registry studies reporting more adverse events when treating all vessels at the same time as the STEMI culprit. (Note: Shock patients did better with complete revascularization, i.e. treat all significant stenoses.) The 2013 ACC/AHA/SCAI guidelines on STEMI continue to recommend that only the culprit vessel should be treated and that treating the non-culprit lesions in the same setting is a class III (do not do, i.e. may harm) level of support. However, in the last 2 years, several studies have challenged the conventional wisdom of treating just the culprit infarct-related artery (IRA). The PRAMI¹, CvLPRIT², and PRIMULTI³ (just presented at ACC San Diego in March 2015) studies supported a more aggressive approach of complete revascularization in the STEMI patient, treating both the culprit and all significant non-infarct related artery lesions at the same time. 

One of the most interesting and perhaps controversial issues with regard to selecting the non-culprit lesions is the limitation of angiography (as in stable angina), and the role of physiology and, more specifically, FFR, for decision-making within the acute setting. For the culprit-only approach, most of the time there is little doubt about the severity of the culprit lesion, often 100% occluded or severely stenosed with evidence of thrombus. On rare occasion, the lesion may be hazy and <70% narrowed, the thrombotic obstruction having lysed and the infarction beginning to convalesce. For the acute STEMI vessel within a minimum of 4 days^4,5, FFR is not reliable because the myocardial bed supplied by the STEMI vessel is injured and infarcted with significantly, albeit transiently, reduced coronary and microvascular flow. In the culprit-only approach, the non-target vessel has little contribution to the immediate clinical decisions. 

In assessing the non-culprit lesion in anticipation of achieving appropriate complete revascularization, the question of whether FFR is useful is critical. Whether FFR can be accurate in this setting is dependent on the extent of the impairment of the non-culprit territorial injury. Said another way, the flow through the myocardial bed is critically important to obtaining an accurate FFR, and in the acute coronary syndrome, specifically the STEMI or NSTEMI, we know: 1) the myocardial bed is initially impaired with reduced flow (to variable degrees) and 2) flow improves and stabilizes over time (considered in days). 

FFR and the myocardial bed flow 

FFR, the translesional distal to aortic pressure ratio (Pd/Pa), requires maximal hyperemia to be accurate. Initial validation studies of FFR were performed in patients with stable angina with single-vessel coronary artery disease (CAD), no left ventricular hypertrophy (LVH), myocardial infarction, congestive heart failure (CHF), or valvular disease. The FFR is a measure of the percent of maximal flow across an epicardial lesion compared to flow through the same vessel in the theoretical absence of the lesion. FFR is therefore directly related to flow. For a given stenosis, the higher the flow, the lower the FFR, and vice versa. This important aspect of the FFR is at the heart of the visual functional mismatch, explaining why an angiographically severe lesion in a small diagonal branch may have a high FFR, while a mild lesion in a very large long obtuse marginal branch may have a low FFR. The artery location and size of the myocardial bed it supplies determines the flow: small territory, lower flow, higher FFR despite a “severe” lesion (Figure 3).

Complete revascularization and FFR at the time of STEMI

In the culprit-only approach for multivessel CAD, the best time to treat the non-culprit vessel after STEMI remains controversial. The “do-all” multivessel STEMI PCI approaches vary among treating all lesions at once (PRAMI study), treating the non-culprit within the week of hospitalization (CvLPRIT study), or treating the non-culprit at the time or within the week selected by FFR (PRIMULTI study). Table 1 compares these 3 studies. In PRAMI and CvLPRIT, the operators selected the non-culprit lesions based on the angiographic appearance alone. As we know from the FAME studies, it is near impossible to know if lesions <80% are physiologically significant. Recall that in the FAME 1 study, FFR-guided PCI compared to angiographic-guided PCI produced better outcomes using fewer stents and lower cost. However, the FAME patients, for the most part, had stable angina. In the subset of FAME patients with unstable angina or NSTEMI, there was no evidence for a difference of the effect of using FFR between patients with unstable angina (UA) or NSTEMI, and patients with stable angina. The guidance of PCI by FFR rather than angiography alone was associated with similar relative risk reductions of major adverse cardiac events (MACE), death, MI, and death or MI in patients with UA and NSTEMI, and patients with stable angina.⁶ It should be appreciated that the STEMI patient is different from the stable angina patient (or even the NSTEMI patient) with more intense myocardial dysfunction, heightened inflammatory and prothrombotic state, and active myocardial compensatory responses in the non-infarct territories. The NSTEMI patient likely has similar but much less intense response to myocardial injury.

The PRIMULTI study, from Denmark, used FFR to determine if stenting of the non-culprit vessel was needed. Presented at the late-breaking trial session of ACC San Diego ‘15, Dr. Thomas Engstrom, on behalf of the DANAMI 3 investigators, showed that this approach was superior to culprit-only PCI with reduced major adverse cardiac events. Unfortunately, the results of the FFR-related events were not described since the presentation was, by necessity, condensed. We must await publication of the full results. However, knowing how the FFR might function in the non-culprit vessel will help us understand the final study results and outcomes. 

During a STEMI, the extent of the culprit myocardial bed damage is unknown and the non-culprit vessel bed may or may not be impaired. In the PRIMULTI study, if the non-culprit FFR is <0.80, the lesion is considered hemodynamically significant and subsequently stented. However, if the FFR is >0.80 the lesion is deferred from immediate stenting. Does this mean the lesion is not significant? At the time of the measurement, yes. But recall the bed may be injured and several days later, if it recovers, the FFR may change to abnormal as flow increases in the stabilized, recuperating myocardial bed. We would only know this fact if we measure all non-culprit normal FFR values again several days later. The understanding of the FFR limitation in the acute infarct setting is stimulating investigators to examine other measures of coronary physiology like index of myocardial resistance or coronary flow reserve to determine exactly what the state of the myocardial bed is to accept or reject the non-ischemic FFR value. To summarize for the acute STEMI patient, in the culprit vessel, an abnormal FFR indicates the lesion is hemodynamically significant. However, if the FFR is normal, it is uncertain whether this value will change over time and become abnormal. Studies show that after 4 days, FFR corresponds to SPECT scanning results⁴ and myocardial contrast echo data⁵. 

In the non-culprit vessel, an abnormal FFR indicates lesion significance, whereas a negative FFR may be normal or may change over time. This response remains under study. Wood et al⁷ found that FFR of non-culprit stenoses during acute STEMI remained relatively stable over the subsequent 45 days and suggested that an FFR obtained in the setting of STEMI is likely a valid measurement to guide delayed revascularization decisions in patients with multivessel disease. Similarly, in NSTEMI patients in FAME⁸, the non-culprit FFR values were unchanged (for most, but not all of the patients) at 3-month follow-up measurements. The value of FFR for the non-culprit complete revascularization approach would be to stent only those vessels needing it while not over- or under-treating lesions assessed by angiography alone (Figure 4). 

I hope this brief discussion of FFR and the controversies in STEMI revascularization has been interesting and stimulated your thinking about how to use FFR in the ACS patient.

References

1. Wald DS, Morris JK, Wald NJ, Chase AJ, Edwards RJ, Hughes LO, Berry C, Oldroyd KG; PRAMI Investigators. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med. 2013 Sep 19; 369 (12): 1115-1123. 
2. Gershlick AH, Khan JN, Kelly DJ, et al. Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease. J Am Coll Cardiol. 2015; 65: 963-972. 
3. Engstrøm T. The third DANish study of optimal Acute treatment of patients with ST-segment elevation Myocardial Infarction: PRImary PCI in MULTIvessel disease. Presented at: American College of Cardiology/i2 Scientific Session; March 16, 2015; San Diego, CA.
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7. Wood DA, Poulter RS, Boone R, Lim I, Bogale N, Starovoytov A, et al. TCT-628: Stability of non culprit vessel fractional flow reserve In patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2013; 62(18_S1): B191. doi:10.1016/j.jacc.2013.08.1376.
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