Frederik M. Zimmermann

Fractional flow reserve versus angiography for guidance of PCI in patients with multivessel coronary artery disease (FAME): 5-year follow-up of a randomised controlled trial

BACKGROUND In the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) study, fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) improved outcome compared with angiography-guided PCI for up to 2 years of follow-up. The aim in this study was to investigate whether the favourable clinical outcome with the FFR-guided PCI in the FAME study persisted over a 5-year follow-up. METHODS The FAME study was a multicentre trial done in Belgium, Denmark, Germany, the Netherlands, Sweden, the UK, and the USA. Patients (aged ≥ 18 years) with multivessel coronary artery disease were randomly assigned to undergo angiography-guided PCI or FFR-guided PCI. Before randomisation, stenoses requiring PCI were identified on the angiogram. Patients allocated to angiography-guided PCI had revascularisation of all identified stenoses. Patients allocated to FFR-guided PCI had FFR measurements of all stenotic arteries and PCI was done only if FFR was 0·80 or less. No one was masked to treatment assignment. The primary endpoint was major adverse cardiac events at 1 year, and the data for the 5-year follow-up are reported here. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00267774. FINDINGS After 5 years, major adverse cardiac events occurred in 31% of patients (154 of 496) in the angiography-guided group versus 28% (143 of 509 patients) in the FFR-guided group (relative risk 0·91, 95% CI 0·75-1·10; p=0·31). The number of stents placed per patient was significantly higher in the angiography-guided group than in the FFR-guided group (mean 2·7 [SD 1·2] vs 1·9 [1·3], p<0·0001). INTERPRETATION The results confirm the long-term safety of FFR-guided PCI in patients with multivessel disease. A strategy of FFR-guided PCI resulted in a significant decrease of major adverse cardiac events for up to 2 years after the index procedure. From 2 years to 5 years, the risks for both groups developed similarly. This clinical outcome in the FFR-guided group was achieved with a lower number of stented arteries and less resource use. These results indicate that FFR guidance of multivessel PCI should be the standard of care in most patients. FUNDING St Jude Medical, Friends of the Heart Foundation, and Medtronic.

Continuum of Vasodilator Stress From Rest to Contrast Medium to Adenosine Hyperemia for Fractional Flow Reserve Assessment

OBJECTIVES This study compared the diagnostic performance with adenosine-derived fractional flow reserve (FFR) ≤0.8 of contrast-based FFR (cFFR), resting distal pressure (Pd)/aortic pressure (Pa), and the instantaneous wave-free ratio (iFR). BACKGROUND FFR objectively identifies lesions that benefit from medical therapy versus revascularization. However, FFR requires maximal vasodilation, usually achieved with adenosine. Radiographic contrast injection causes submaximal coronary hyperemia. Therefore, intracoronary contrast could provide an easy and inexpensive tool for predicting FFR. METHODS We recruited patients undergoing routine FFR assessment and made paired, repeated measurements of all physiology metrics (Pd/Pa, iFR, cFFR, and FFR). Contrast medium and dose were per local practice, as was the dose of intracoronary adenosine. Operators were encouraged to perform both intracoronary and intravenous adenosine assessments and a final drift check to assess wire calibration. A central core lab analyzed blinded pressure tracings in a standardized fashion. RESULTS A total of 763 subjects were enrolled from 12 international centers. Contrast volume was 8 ± 2 ml per measurement, and 8 different contrast media were used. Repeated measurements of each metric showed a bias <0.005, but a lower SD (less variability) for cFFR than resting indexes. Although Pd/Pa and iFR demonstrated equivalent performance against FFR ≤0.8 (78.5% vs. 79.9% accuracy; p = 0.78; area under the receiver-operating characteristic curve: 0.875 vs. 0.881; p = 0.35), cFFR improved both metrics (85.8% accuracy and 0.930 area; p < 0.001 for each) with an optimal binary threshold of 0.83. A hybrid decision-making strategy using cFFR required adenosine less often than when based on either Pd/Pa or iFR. CONCLUSIONS cFFR provides diagnostic performance superior to that of Pd/Pa or iFR for predicting FFR. For clinical scenarios or health care systems in which adenosine is contraindicated or prohibitively expensive, cFFR offers a universal technique to simplify invasive coronary physiological assessments. Yet FFR remains the reference standard for diagnostic certainty as even cFFR reached only ∼85% agreement.

Rationale and design of the Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) 3 Trial: A comparison of fractional flow reserve–guided percutaneous coronary intervention and coronary artery bypass graft surgery in patients with multivessel coronary artery disease

UNLABELLED Guidelines recommend coronary artery bypass graft (CABG) surgery over percutaneous coronary intervention (PCI) for the treatment of 3-vessel coronary artery disease (3-VD). The inferior results of PCI demonstrated by previous large randomized trials comparing PCI and CABG might be explained by the use of suboptimal stent technology and by the lack of fractional flow reserve (FFR) guidance of PCI. TRIAL DESIGN The objective of this investigator-initiated, multicenter, randomized clinical trial is to investigate whether FFR-guided PCI with new-generation stents is noninferior to CABG in patients with 3-VD, not including the left main coronary artery. Eligible patients must have ≥50% coronary stenoses in all 3 major epicardial vessels or major side branches. Patients with a nondominant right coronary artery may be included only if the left anterior descending artery and left circumflex have ≥50% stenoses. Consecutive patients who meet all of the inclusion criteria and none of the exclusion criteria will be randomized in a 1:1 fashion to either CABG or FFR-guided PCI. Coronary artery bypass graft will be performed based on the angiogram as per clinical routine. Patients assigned to FFR-guided PCI will have FFR measured in each diseased vessel and only undergo stenting if the FFR is ≤0.80. The primary end point of the study is a composite of major adverse cardiac and cerebrovascular events, including death, myocardial infarction, repeat coronary revascularization, and stroke at 1 year. Key secondary end point will be a composite of death, myocardial infarction, and stroke at 3-year follow-up. Other secondary end points include the individual adverse events, cost-effectiveness, and quality of life at 2-year, 3-year, with up to 5-year follow-up. CONCLUSION The FAME 3 study will compare in a multicenter, randomized fashion FFR-guided PCI with contemporary drug-eluting stents to CABG in patients with 3-VD.

Fractional flow reserve and pressure-bounded coronary flow reserve to predict outcomes in coronary artery disease

Aims Fractional flow reserve (FFR) has proven to its prognostic and therapeutic value. However, the additive prognostic value of coronary flow reserve (CFR) remains unclear. This study sought to investigate the clinical utility of combined FFR and CFR measurements to predict outcomes. Methods and results Using the prospective, multicentre Interventional Cardiology Research Incooperation Society-FFR registry, a total of 2088 lesions from 1837 patients were included in this substudy. Based on baseline and hyperaemic pressure gradients, we computed physiologic limits of CFR [the so called pressure-bounded (pb) CFR] and classified lesions as low (<2) or high (≥2). The primary endpoint was major adverse cardiac events (MACE, a composite of cardiac death, myocardial infarction, and revascularization) analysed on a per-patient basis. During a median follow-up of 1.9 years (inter-quartile range: 1.0-3.0 years), MACE occurred in 5.7% of patients with FFR ≤0.80 vs. 2.8% of patients with FFR >0.80 [adjusted hazard ratio (aHR): 2.15, 95% confidence interval (CI): 1.19-3.89; P = 0.011. In contrast, the incidence of MACE did not differ between patients with pb-CFR < 2 vs. pb-CFR ≥ 2 (4.2% vs. 4.2%; aHR: 0.98, CI: 0.60 to 1.58; P = 0.92). Incorporation of FFR significantly improved model prediction of MACE (global χ2 38.8-48.1, P = 0.002). However, pb-CFR demonstrated no incremental utility to classify outcomes (global χ2 48.1-48.2, P > 0.99). Conclusions In this large, prospective registry of over 2000 coronary lesions, FFR was strongly associated with clinical outcomes. In contrast, a significant association between pb-CFR and clinical events could not be determined and adding knowledge of pb-CFR did not improve prognostication over FFR alone.

What can intracoronary pressure measurements tell us about flow reserve? : pressure-bounded coronary flow reserve and example application to the randomized DEFER trial

We propose a novel technique called pressure‐bounded coronary flow reserve (pb‐CFR) and demonstrate its application to the randomized DEFER trial.

Pressure gradient vs. flow relationships to characterize the physiology of a severely stenotic aortic valve before and after transcatheter valve implantation

Abstract Aims Echocardiography and tomographic imaging have documented dynamic changes in aortic stenosis (AS) geometry and severity during both the cardiac cycle and stress-induced increases in cardiac output. However, corresponding pressure gradient vs. flow relationships have not been described. Methods and results We recruited 16 routine transcatheter aortic valve implantations (TAVI’s) for graded dobutamine infusions both before and after implantation; 0.014″ pressure wires in the aorta and left ventricle (LV) continuously measured the transvalvular pressure gradient (ΔP) while a pulmonary artery catheter regularly assessed cardiac output by thermodilution. Before TAVI, ΔP did not display a consistent relationship with transvalvular flow (Q). Neither linear resistor (median R2 0.16) nor quadratic orifice (median R2 < 0.01) models at rest predicted stress observations; the severely stenotic valve behaved like a combination. The unitless ratio of aortic to left ventricular pressures during systolic ejection under stress conditions correlated best with post-TAVI flow improvement. After TAVI, a highly linear relationship (median R2 0.96) indicated a valid valve resistance. Conclusion Pressure loss vs. flow curves offer a fundamental fluid dynamic synthesis for describing aortic valve pathophysiology. Severe AS does not consistently behave like an orifice (as suggested by Gorlin) or a resistor, whereas TAVI devices behave like a pure resistor. During peak dobutamine, the ratio of aortic to left ventricular pressures during systolic ejection provides a ‘fractional flow reserve’ of the aortic valve that closely approximates the complex, changing fluid dynamics. Because resting assessment cannot reliably predict stress haemodynamics, ‘valvular fractional flow’ warrants study to explain exertional symptoms in patients with only moderate AS at rest.

Three-Vessel Assessment of Coronary Microvascular Dysfunction in Patients With Clinical Suspicion of Ischemia: Prospective Observational Study With the Index of Microcirculatory Resistance

Background— Difficulty directly visualizing the coronary microvasculature as opposed to the epicardial coronary artery makes its assessment challenging. The goal of this study is to measure the index of microcirculatory resistance (IMR) in all 3 major coronary vessels to identify the clinical and angiographic predictors of an abnormal IMR. Methods and Results— Ninety-three patients who underwent coronary physiological assessment in all 3 major coronary vessels were prospectively enrolled (59.8±9.4 years with 77.4% men). IMR was corrected using Yong’s formula and coronary microvascular dysfunction (CMD) was defined using vessel-specific cutoffs. A global IMR was calculated as the sum of the IMR in all 3 major epicardial vessels. Angiographic epicardial disease severity was assessed with vessel-specific and overall SYNTAX score. Median IMR and fractional flow reserve was 17.2 (Q1–Q3: 13.3–22.9) and 0.92 (0.85–0.97). The majority of patients (59.1%) had no CMD, 23.7% had 1-vessel CMD, 14.0% had 2-vessel CMD, and 3.2% had 3-vessel CMD. CMD was observed at a similar rate in the territories supplied by all 3 major coronary vessels (left anterior descending coronary artery 28.0%, left circumflex artery 19.4%, and right coronary artery 23.7%; P=0.39). Fractional flow reserve had a weak, positive correlation with IMR (&rgr;=0.16; P<0.01). The SYNTAX score had no significant correlation with IMR, both at a patient level (&rgr;=−0.002; P=0.99) and a vessel-specific level (&rgr;=−0.06; P=0.36). By multivariable ordinal logistic regression analysis, no variable was left as an independent predictor of an abnormal IMR. Conclusions— Clinical factors and epicardial coronary disease severity are not predictors of the extent of CMD. Clinical Trial Registration— URL: https://www.clinicaltrials.gov. Unique identifier: NCT01621438.

Simultaneous massive pulmonary embolism and acute myocardial infarction, associated with patent foramen ovale.

A 58-year-old man was admitted to the Catharina Hospital Eindhoven because of an out-of-hospital cardiac arrest after a period of intense pain in the left leg. 12-lead ECG showed ST-segment elevation in lead V2–V5, II, III, and AVF ( Panel B ). Emergent coronary and …

Safety and feasibility of selective intracoronary hypothermia in acute myocardial infarction.

AIMS Hypothermia reduces reperfusion injury and infarct size in animal models of acute myocardial infarction if started before reperfusion. Human studies have not confirmed benefit, probably due to insufficient myocardial cooling and adverse systemic effects. This study sought to assess the safety and feasibility of a novel method for selective, sensor-monitored intracoronary hypothermia. METHODS AND RESULTS Ten patients undergoing primary percutaneous coronary intervention (PPCI) were included. Saline at room temperature was administered distal to the culprit lesion through an inflated overthe- wire balloon (OTWB) in order to cool the endangered myocardium for 10 minutes (occlusion phase). Next, the OTWB was deflated and cooling continued with saline at 4°C for another 10 minutes (reperfusion phase). A sensor-tipped temperature wire in the distal coronary artery allowed titration of the infusion rate to achieve the desired coronary temperature (6°C below body temperature). Target coronary temperature was achieved within 27 seconds (median; IQR 21-46). Except for two patients with inferior wall infarction experiencing transient conduction disturbances, no side effects occurred. Systemic temperature remained unchanged. Finally, PPCI was performed as per routine. CONCLUSIONS Selective hypothermia of the infarct area by intracoronary infusion of saline provides a novel method to reduce coronary temperature quickly and guarantee local myocardial hypothermia. In anterior wall myocardial infarctions, the protocol appeared safe, without serious haemodynamic or systemic side effects. In inferior wall myocardial infarctions, transient conduction abnormalities of short duration occurred. Potentially, selective intracoronary delivery of hypothermia could attenuate reperfusion injury caused by traditional PPCI.

Yellow traffic lights and grey zone fractional flow reserve values: stop or go?

Traffic lights represent a type of decision common to many aspects of medicine: do (green), don’t (red), or maybe (yellow). While traffic lights remain a powerful guideline for driving safely, we have on rare occasion stopped at a green light (when a child ran into the intersection) or ran a red light (when racing to the hospital for an emergency at 2 o’clock in the morning). And how do we react to a yellow light? While perhaps befuddling to novice drivers (the formal rule demands that we stop unless unable to ‘stop safely’), with experience we all reach a common, practical answer: it depends. Wet roads, late for work, fast speed, or vehicle on your tail? Go! Lazy weekend, unfamiliar city, slow speed, or police car nearby? Stop! Fittingly, cardiology guidelines have now taken to coding their recommendations using a traffic light colour scheme: class I (recommended, green), class III (not recommended, red), and class II (with divisions IIa = should consider, yellow; and IIb = may consider, orange). Much of clinical medicine focuses on a narrow application of the guidelines in class I and class III scenarios, while—perhaps befuddling to trainees—with experience we all reach a pragmatic answer for class II options: patient preference (coupled with education and informed consent) and clinical judgement. With this analogy in mind, we turn to the article by Kang et al. in the current issue of the European Heart Journal. Their manuscript addresses the so-called ‘grey zone’ of fractional flow reserve (FFR), denoting values between 0.75–0.80. While the initial DEFER trial used an FFR < 0.75 threshold for revascularization based on a unique multitest validation before and after revascularization, the subsequent FAME family of studies, and other trials moved to an FFR <_ 0.80 threshold in a desire to avoid undertreatment. Because FFR = 0.75– 0.80 values occur in approximately 15% of lesions (about one in seven patients), their optimal treatment deserves further examination.