Stress Echocardiography

All SE studies were performed using either treadmill exercise or pharmacological (dobutamine-atropine) stress as described elsewhere. As per protocol heart rate lowering medications were withheld for 48 hours prior to testing. In summary, exercise stress was the preferred modality, and in patients unsuitable for exercise, dobutamine was infused in 3-minute dose increments, starting from 10 μg/kg/min and increasing to 20, 30, and 40 μg/kg/min if there were no resting wall motion abnormalities, otherwise a viability protocol was used commencing at 5 μg/kg/min. Parasternal long-axis, short-axis and apical four-chamber, two-chamber, and three-chamber images were obtained at rest and peak stress (iE33 Philips Medical Systems, Eindhoven, the Netherlands). In patients in whom the endocardial borders of two or more contiguous segments were not visualized, the ultrasound contrast agent Sonovue (Bracco, Milan, Italy) was given by intravenous bolus injection (0.3 mL) and flushed with saline. The final SE result was based on the interpretation of the expert cardiologist (R.S.)

The SEs were reported as normal (normal wall thickening at rest and stress) or ischemic (inducible WTA in one or more segments at peak stress or presence of biphasic response in patients with resting WTAs during low and high doses of dobutamine).

Coronary Angiography and FFR

Coronary angiography was performed where clinically indicated and in most cases where SE was positive for inducible ischemia. In patients with persistent symptoms and normal SE, angiography with FFR measurements may have been performed.

Coronary angiography was performed as per standard practice via either the femoral or radial approach. Coronary stenosis severity was based on visual assessment. The pressure wire (Pressure Wire Aeris, St. Jude Medical, St. Paul, MN) was calibrated and electronically equalized with the aortic pressure before being placed in the desired position distal to the lesion in the coronary artery being interrogated. Intracoronary nitroglycerin was used as per protocol before the adenosine infusion to negate the effects of any vasospasm. Intravenous adenosine was administered at a dose between 140 and 180 μg/kg/min through a large-bore intravenous line in the antecubital fossa. The resting distal coronary pressure to aortic pressure ratio (Pd/Pa) was continuously recorded throughout using the St. Jude Medical Quantien system, as calculated by dividing the mean coronary pressure measured with the pressure sensor placed distal to the stenosis by the mean aortic pressure measured through the guide catheter. At a steady state of maximal hyperemia, the nadir FFR was recorded.

FFR measurements were performed on all major epicardial arteries deemed to have intermediate stenosis (30%-80%), where the presence or absence of a severe stenosis was not evident visually. It must be noted that if SE demonstrated ischemia in a coronary territory, and quantitative angiography demonstrated < 30% stenosis, FFR would not have been clinically indicated. Conversely, on the few occasions where SE did not demonstrate ischemia in a territory, and an intermediate stenosis (30%-80%) was seen on quantitative angiography, FFR would have been performed. An FFR value of ≤0.8 was chosen as the cutoff for abnormal based on previous multicenter studies. Caffeine and all food products were withheld in patients for 12 hours before FFR measurements.

Revascularization

Revascularization was performed in vessels where FFR ≤ 0.80 (irrespective of SE results) where possible and in bystander vessels deemed to have significant stenosis and therefore viewed as needing revascularization. Where FFR was > 0.80, revascularization was not performed, irrespective of SE results.

Endpoint Definition

The principal endpoints of interest for this analysis were cardiovascular (CV) death (due to myocardial infarction [MI], cardiac arrhythmias, or heart failure) and nonfatal MI (NFMI), with patients censored at the time of event or at the last follow-up. NFMI was defined by the standard criteria of ischemic chest pain associated with an elevation of cardiac enzymes with or without electrocardiographic changes. For patients with multiple events, only the first event was considered.