Massoud A. Leesar

Angiographic versus functional severity of coronary artery stenoses in the FAME study fractional flow reserve versus angiography in multivessel evaluation.

OBJECTIVES The purpose of this study was to investigate the relationship between angiographic and functional severity of coronary artery stenoses in the FAME (Fractional Flow Reserve Versus Angiography in Multivessel Evaluation) study. BACKGROUND It can be difficult to determine on the coronary angiogram which lesions cause ischemia. Revascularization of coronary stenoses that induce ischemia improves a patients functional status and outcome. For stenoses that do not induce ischemia, however, the benefit of revascularization is less clear. METHODS In the FAME study, routine measurement of the fractional flow reserve (FFR) was compared with angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease. The use of the FFR in addition to angiography significantly reduced the rate of all major adverse cardiac events at 1 year. Of the 1,414 lesions (509 patients) in the FFR-guided arm of the FAME study, 1,329 were successfully assessed by the FFR and are included in this analysis. RESULTS Before FFR measurement, these lesions were categorized into 50% to 70% (47% of all lesions), 71% to 90% (39% of all lesions), and 91% to 99% (15% of all lesions) diameter stenosis by visual assessment. In the category 50% to 70% stenosis, 35% were functionally significant (FFR <or=0.80) and 65% were not (FFR >0.80). In the category 71% to 90% stenosis, 80% were functionally significant and 20% were not. In the category of subtotal stenoses, 96% were functionally significant. Of all 509 patients with angiographically defined multivessel disease, only 235 (46%) had functional multivessel disease (>or=2 coronary arteries with an FFR <or=0.80). CONCLUSIONS Angiography is inaccurate in assessing the functional significance of a coronary stenosis when compared with the FFR, not only in the 50% to 70% category but also in the 70% to 90% angiographic severity category.

Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction: results of a multicenter, randomized, placebo-controlled trial: the Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial.

OBJECTIVES The Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial was designed to test the hypothesis that adenosine as an adjunct to thrombolysis would reduce myocardial infarct size. BACKGROUND Reperfusion therapy for acute myocardial infarction (MI) has been shown to reduce mortality, but reperfusion itself also may have deleterious effects. METHODS The AMISTAD trial was a prospective, open-label trial of thrombolysis with randomization to adenosine or placebo in 236 patients within 6 h of infarction onset. The primary end point was infarct size as determined by Tc-99 m sestamibi single-photon emission computed tomography (SPECT) imaging 6+/-1 days after enrollment based on multivariable regression modeling to adjust for covariates. Secondary end points were myocardial salvage index and a composite of in-hospital clinical outcomes (death, reinfarction, shock, congestive heart failure or stroke). RESULTS In all, 236 patients were enrolled. Final infarct size was assessed in 197 (83%) patients. There was a 33% relative reduction in infarct size (p = 0.03) with adenosine. There was a 67% relative reduction in infarct size in patients with anterior infarction (15% in the adenosine group vs. 45.5% in the placebo group) but no reduction in patients with infarcts located elsewhere (11.5% for both groups). Patients randomized to adenosine tended to reach the composite clinical end point more often than those assigned to placebo (22% vs. 16%; odds ratio, 1.43; 95% confidence interval, 0.71 to 2.89). CONCLUSIONS Many agents thought to attenuate reperfusion injury have been unsuccessful in clinical investigation. In this study, adenosine resulted in a significant reduction in infarct size. These data support the need for a large clinical outcome trial.

Correlations between fractional flow reserve and intravascular ultrasound in patients with an ambiguous left main coronary artery stenosis.

Background—Intravascular ultrasound (IVUS) is being used to assess the significance of a left main coronary artery stenosis (LMCS). However, the cutoff values of IVUS parameters at which to predict a fractional flow reserve (FFR) of 0.75 are unknown. Methods and Results—In 55 patients with an angiographically ambiguous LMCS, a pressure guidewire was used to calculate FFR, and IVUS parameters were calculated after automatic pullback. FFR averaged 0.86±0.13 (range, 0.55 to 1.0). IVUS minimum lumen diameter (MLD), minimum lumen area (MLA), cross-sectional narrowing (CSN), and area stenosis (AS) were 3.8±0.61 mm, 7.65±2.9 mm2, 59±13%, and 47±19%, respectively. Regression analysis demonstrated strong correlations between FFR and MLD (r=0.79, P<0.0001) as well as between FFR and MLA (r=0.74, P<0.0001). There were inverse, moderate correlations between FFR and CSN (r=0.69, P<0.0001), followed by those between FFR and AS (r=0.54, P<0.0001). Compared with FFR as the “gold standard,” an MLD of 2.8 mm had the highest sensitivity and specificity (93% and 98%, respectively) for determining the significance of an LMCS, followed by an MLA of 5.9 mm2 (93% and 95%, respectively). Based on an FFR <0.75 and an FFR ≥0.75, the 38-month survival and event-free survival estimates (EFSEs) were both 100% and 100% versus 90%, respectively (P=NS). Conclusions—We conclude that (1) an IVUS MLD and MLA of 2.8 mm and 5.9 mm2, respectively, strongly predict the physiological significance of an LMCS and (2) among patients with an LMCS, an FFR of 0.75 is a strong predictor of survival and EFSE.

Preconditioning of Human Myocardium With Adenosine During Coronary Angioplasty

BACKGROUND It is unknown whether adenosine can precondition human myocardium against ischemia in vivo. METHODS AND RESULTS Thirty patients were randomized to receive a 10-minute intracoronary infusion of adenosine (2 mg/min) or normal saline; 10 minutes later, they underwent percutaneous transluminal coronary angioplasty (PTCA; three 2-minute balloon inflations 5 minutes apart). In control patients, the ST-segment shift on the intracoronary ECG was significantly greater during the first inflation than during the second and third inflations, consistent with ischemic preconditioning. In contrast, in adenosine-treated patients, there were no differences in ST-segment shift during the three inflations. The ST-segment shift was significantly smaller in the adenosine-treated group compared with the control group during all three inflations. The reduction in ST-segment shift afforded by adenosine during the first inflation (-72% versus first inflation in control subjects) was greater than that afforded by ischemic preconditioning in control subjects (-52% during the third versus first inflation). Measurements of chest pain score paralleled those of ST-segment shift. Adenosine had no effect on baseline regional wall motion as determined by quantitative two-dimensional echocardiography. Thus, intracoronary infusion of adenosine before PTCA rendered the myocardium remarkably resistant to subsequent ischemia. Judging from the intracoronary ECG, the protection provided by adenosine was even superior to that provided in control subjects by the ischemia associated with the first two balloon inflations. Infusion of adenosine had no major adverse effects in patients undergoing PTCA of the left anterior descending or circumflex arteries. CONCLUSIONS Adenosine preconditions human myocardium against ischemia in vivo. Pretreatment with adenosine is remarkably effective (even more effective than ischemic preconditioning) and could be used prophylactically to attenuate ischemia in selected patients undergoing PTCA of the left anterior descending coronary artery. Whether adenosine can be safely infused into the right or the circumflex coronary artery in the presence of a temporary pacemaker remains to be established.

Delayed Preconditioning-Mimetic Action of Nitroglycerin in Patients Undergoing Coronary Angioplasty

Background—Experimental studies suggest that the cardioprotective effects of the late phase of ischemic preconditioning (PC) can be mimicked pharmacologically. However, to date, no drug has been tested with respect to its ability to elicit a late PC effect in humans. As a consequence, clinical exploitation of the powerful anti-stunning and anti-infarct actions of late PC has been elusive thus far. Methods and Results—A total of 66 patients were randomized to receive a 4-hour intravenous infusion of nitroglycerin (NTG) or normal saline; on the following day, they underwent percutaneous transluminal coronary angioplasty (three 2-minute balloon inflations 5 minutes apart). Measurements of ST-segment shifts (intracoronary and surface ECGs), regional wall motion (quantitative 2D echocardiography), and chest pain score indicated that the infusion of NTG 24 hours before angioplasty rendered the myocardium relatively resistant to ischemia and that the degree of this cardioprotective effect was comparable to that afforded by the ischemia associated with the first balloon inflation in control subjects (early phase of ischemic PC). Collateral flow (estimated from a pressure-derived index) did not differ between control and NTG-pretreated patients, indicating that the enhanced tolerance to ischemia in NTG-pretreated patients cannot be accounted for by baseline differences in collateral function. Conclusions—NTG protects human myocardium against ischemia 24 hours after its administration. To the best of our knowledge, this is the first report that a late PC effect can be recruited pharmacologically in humans. The results suggest that prophylactic administration of nitrates could be a novel approach to the protection of the ischemic myocardium in patients.

Bradykinin-induced preconditioning in patients undergoing coronary angioplasty

OBJECTIVES The purpose of this study was to determine whether administration of bradykinin reproduces the cardioprotective effects of ischemic preconditioning (PC) in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND Experimental studies suggest that activation of the bradykinin B2 receptor is an important trigger of ischemic PC. However, it is unknown whether bradykinin can precondition human myocardium against ischemia in vivo. Multicenter clinical trials have demonstrated an anti-ischemic effect of angiotensin-converting enzyme inhibitors, which has been postulated to result from potentiation of bradykinin; however, direct evidence for an anti-ischemic action of bradykinin in patients is lacking. METHODS Thirty patients were randomized to receive a 10-min intracoronary infusion of bradykinin (2.5 microg/min) or normal saline. Ten minutes later they underwent PTCA (three 2-min balloon inflations 5 min apart). RESULTS In control patients, the ST-segment shift on the intracoronary and surface electrocardiogram was significantly greater during the first inflation than during the second and third inflations, consistent with ischemic PC. In bradykinin-treated patients, the ST-segment shift during the first inflation was significantly smaller than in the control group, and there were no appreciable differences in ST-segment shift during the three inflations. Measurements of chest pain score and regional wall motion during inflation (quantitative two-dimensional echocardiography) paralleled those of ST-segment shift. Infusion of bradykinin had no hemodynamic effects and no significant adverse effects. Thus, intracoronary infusion of bradykinin before PTCA rendered the myocardium relatively resistant to subsequent ischemia, and the degree of this cardioprotective effect was comparable to that afforded by the ischemia associated with the first balloon inflation in control subjects. In a separate cohort of seven patients given the same dose of bradykinin, coronary hyperemia resolved completely within 10 min after the end of the infusion, indicating that bradykinin-induced vasodilation cannot account for the protective effects observed during the first balloon inflation. CONCLUSIONS Bradykinin preconditions human myocardium against ischemia in vivo in the absence of systemic hemodynamic changes. Pretreatment with bradykinin appears to be just as effective as ischemic PC and could be used prophylactically to attenuate ischemia in selected patients undergoing PTCA.

Thrombolysis and counterpulsation to improve survival in myocardial infarction complicated by hypotension and suspected cardiogenic shock or heart failure: results of the TACTICS Trial.

Background: Sustained hypotension, cardiogenic shock, and heart failure all imply a poor prognosis in acute myocardial infarction (MI). We assessed the benefit of adding 48 hours of intra-aortic balloon counterpulsation (IABP) to standard treatment for MI, in an international trial among hospitals without primary angioplasty capabilities.Methods: We randomized 57 patients with MI complicated by sustained hypotension, possible cardiogenic shock, or possible heart failure to receive either fibrinolytic therapy and IABP or fibrinolysis alone. The primary end point was all-cause mortality at 6 months.Results: In all, IABP was inserted in 27 of 30 assigned patients a median 30 minutes after fibrinolysis began and continued for a median 34 hours. Of the 27 patients assigned to fibrinolysis alone, 9 deteriorated such that IABP was required. The IABP group was at slightly higher risk at baseline, but the incidence of the primary end point did not differ significantly between groups (34% for combined treatment versus 43% for fibrinolysis alone; adjusted P = 0.23). Patients with Killip class III or IV showed a trend toward greater benefit from IABP (6-month mortality 39% for combined therapy versus 80% for fibrinolysis alone; P = 0.05).Conclusions: While early IABP use was not associated with a definitive survival benefit when added to fibrinolysis for patients with MI and hemodynamic compromise in this small trial, its use suggested a possible benefit for patients with the most severe heart failure or hypotension.Abbreviated Abstract. We assessed the benefit of adding 48 hours of intra-aortic balloon counterpulsation to fibrinolytic therapy among 57 patients with acute myocardial infarction complicated by sustained hypotension, possible cardiogenic shock, or possible heart failure. The primary end point, mortality at 6 months, did not differ between groups (34% for combined treatment versus 43% for fibrinolysis alone [n = 27]; adjusted P = 0.23), although patients with Killip class III or IV did show a trend toward greater benefit from IABP (39% for combined therapy versus 80% for fibrinolysis; P = 0.05).

Prediction of Hypertension Improvement After Stenting of Renal Artery Stenosis: Comparative Accuracy of Translesional Pressure Gradients, Intravascular Ultrasound, and Angiography

OBJECTIVES We investigated the comparative accuracy of renal translesional pressure gradients (TPG), intravascular ultrasound (IVUS), and angiographic parameters in predicting hypertension improvement after stenting of renal artery stenosis (RAS). BACKGROUND The degree of RAS that justifies stenting is unknown. METHODS In 62 patients with RAS, TPG (resting and hyperemic systolic gradient [HSG], fractional flow reserve, and mean gradient) were measured by a pressure guidewire; IVUS and angiographic parameters (minimum lumen area and diameter, area stenosis, and diameter stenosis) were measured by quantitative analyses. RESULTS The HSG had a larger area under the curve than most other parameters and an HSG >or=21 mm Hg had the highest sensitivity, specificity, and accuracy (82%, 84%, and 84%, respectively) in predicting hypertension improvement after stenting of RAS. The average IVUS area stenosis was markedly greater in RAS with an HSG >or=21 mm Hg versus <21 mm Hg (78% vs. 38%, respectively; p < 0.001). After stenting, hypertension improved in 84% of patients with an HSG >or=21 mm Hg (n = 36) versus 36% of patients with an HSG <21 mm Hg (n = 26) at 12 months, p < 0.01; the number of antihypertensive medications was significantly lower in patients with an HSG >or=21 mm Hg versus <21 mm Hg (2.30 +/- 0.90 vs. 3.40 +/- 0.50, respectively; p < 0.01). By multivariable analysis, HSG was the only independent predictor of hypertension improvement (odds ratio: 1.39; 95% confidence interval: 1.05 to 1.65; p = 0.013). CONCLUSIONS An HSG >or=21 mm Hg provided the highest accuracy in predicting hypertension improvement after stenting of RAS, suggesting that an HSG >or=21 mm Hg is indicative of significant RAS.

Use of fractional flow reserve versus stress perfusion scintigraphy after unstable angina: Effect on duration of hospitalization, cost, procedural characteristics, and clinical outcome

OBJECTIVES The present study sought to determine the value of fractional flow reserve (FFR) compared with stress perfusion scintigraphy (SPS) in patients with recent unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI). BACKGROUND Fractional flow reserve, an invasive index of stenosis severity, is a reliable surrogate for SPS in patients with normal left ventricular function. An FFR > or = 0.75 can distinguish patients after myocardial infarction (MI) with a positive SPS from those with a negative SPS. However, the use of FFR has not been investigated after UA/NSTEMI. METHODS Seventy patients who had recent UA/NSTEMI and an intermediate single-vessel stenosis were randomized to either SPS (n = 35) or FFR (n = 35). Patients in the SPS group were discharged if the SPS revealed no ischemia, whereas those in the FFR group were discharged if the FFR was > or = 0.75. Patients with a positive SPS and those with an FFR <0.75 underwent percutaneous transluminal coronary angioplasty. The use of FFR markedly reduced the duration and cost of hospitalization compared with SPS (11 +/- 2 h vs. 49 +/- 5 h [-77%], p < 0.001; and 1,329 US dollars +/- 44 US dollars vs. 2,113 US dollars +/- 120 US dollars, respectively, p < 0.05). There were no significant differences in procedure time, radiation exposure time, or event rates during follow-up, including death, MI, or revascularization. CONCLUSIONS These data indicate that: 1) the use of FFR in patients with recent UA/NSTEMI markedly reduces the duration and cost of hospitalization compared with SPS; and 2) these benefits are not associated with an increase in procedure time, radiation exposure time, or clinical event rates.

Optical coherence tomography compared with intravascular ultrasound and with angiography to guide coronary stent implantation (ILUMIEN III: OPTIMIZE PCI): a randomised controlled trial

BACKGROUND Percutaneous coronary intervention (PCI) is most commonly guided by angiography alone. Intravascular ultrasound (IVUS) guidance has been shown to reduce major adverse cardiovascular events (MACE) after PCI, principally by resulting in a larger postprocedure lumen than with angiographic guidance. Optical coherence tomography (OCT) provides higher resolution imaging than does IVUS, although findings from some studies suggest that it might lead to smaller luminal diameters after stent implantation. We sought to establish whether or not a novel OCT-based stent sizing strategy would result in a minimum stent area similar to or better than that achieved with IVUS guidance and better than that achieved with angiography guidance alone. METHODS In this randomised controlled trial, we recruited patients aged 18 years or older undergoing PCI from 29 hospitals in eight countries. Eligible patients had one or more target lesions located in a native coronary artery with a visually estimated reference vessel diameter of 2·25-3·50 mm and a length of less than 40 mm. We excluded patients with left main or ostial right coronary artery stenoses, bypass graft stenoses, chronic total occlusions, planned two-stent bifurcations, and in-stent restenosis. Participants were randomly assigned (1:1:1; with use of an interactive web-based system in block sizes of three, stratified by site) to OCT guidance, IVUS guidance, or angiography-guided stent implantation. We did OCT-guided PCI using a specific protocol to establish stent length, diameter, and expansion according to reference segment external elastic lamina measurements. All patients underwent final OCT imaging (operators in the IVUS and angiography groups were masked to the OCT images). The primary efficacy endpoint was post-PCI minimum stent area, measured by OCT at a masked independent core laboratory at completion of enrolment, in all randomly allocated participants who had primary outcome data. The primary safety endpoint was procedural MACE. We tested non-inferiority of OCT guidance to IVUS guidance (with a non-inferiority margin of 1·0 mm2), superiority of OCT guidance to angiography guidance, and superiority of OCT guidance to IVUS guidance, in a hierarchical manner. This trial is registered with ClinicalTrials.gov, number NCT02471586. FINDINGS Between May 13, 2015, and April 5, 2016, we randomly allocated 450 patients (158 [35%] to OCT, 146 [32%] to IVUS, and 146 [32%] to angiography), with 415 final OCT acquisitions analysed for the primary endpoint (140 [34%] in the OCT group, 135 [33%] in the IVUS group, and 140 [34%] in the angiography group). The final median minimum stent area was 5·79 mm2 (IQR 4·54-7·34) with OCT guidance, 5·89 mm2 (4·67-7·80) with IVUS guidance, and 5·49 mm2 (4·39-6·59) with angiography guidance. OCT guidance was non-inferior to IVUS guidance (one-sided 97·5% lower CI -0·70 mm2; p=0·001), but not superior (p=0·42). OCT guidance was also not superior to angiography guidance (p=0·12). We noted procedural MACE in four (3%) of 158 patients in the OCT group, one (1%) of 146 in the IVUS group, and one (1%) of 146 in the angiography group (OCT vs IVUS p=0·37; OCT vs angiography p=0·37). INTERPRETATION OCT-guided PCI using a specific reference segment external elastic lamina-based stent optimisation strategy was safe and resulted in similar minimum stent area to that of IVUS-guided PCI. These data warrant a large-scale randomised trial to establish whether or not OCT guidance results in superior clinical outcomes to angiography guidance. FUNDING St Jude Medical.