Coronary Artery Lesion Lipid Content and Plaque Burden in Diabetic and Nondiabetic Patients: PROSPECT II.

BACKGROUND: Patients with diabetes have increased rates of major adverse cardiac events (MACEs). We hypothesized that this is explained by diabetes-associated differences in coronary plaque morphology and lipid content. METHODS: In PROSPECT II (Providing Regional Observations to Study Predictors of Events in the Coronary Tree), 898 patients with acute myocardial infarction with or without ST-segment elevation underwent 3-vessel quantitative coronary angiography and coregistered near-infrared spectroscopy and intravascular ultrasound imaging after successful percutaneous coronary intervention. Subsequent MACEs were adjudicated to either treated culprit lesions or untreated nonculprit lesions. This substudy stratified patients by diabetes status and assessed baseline culprit and nonculprit prevalence of high-risk plaque characteristics defined as maximum plaque burden ≥70% and maximum lipid core burden index ≥324.7. Separate covariate-adjusted multivariable models were performed to identify whether diabetes was associated with nonculprit lesion-related MACEs and high-risk plaque characteristics. RESULTS: Diabetes was present in 109 of 898 patients (12.1%). During a median 3.7-year follow-up, MACEs occurred more frequently in patients with versus without diabetes (20.1% versus 13.5% [odds ratio (OR), 1.94 (95% CI, 1.14-3.30)]), primarily attributable to increased risk of myocardial infarction related to culprit lesion restenosis (4.3% versus 1.1% [OR, 3.78 (95% CI, 1.12-12.77)]) and nonculprit lesion-related spontaneous myocardial infarction (9.3% versus 3.8% [OR, 2.74 (95% CI, 1.25-6.04)]). However, baseline prevalence of high-risk plaque characteristics was similar for patients with versus without diabetes concerning culprit (maximum plaque burden ≥70%: 90% versus 93%, P=0.34; maximum lipid core burden index ≥324.7: 66% versus 70%, P=0.49) and nonculprit lesions (maximum plaque burden ≥70%: 23% versus 22%, P=0.37; maximum lipid core burden index ≥324.7: 26% versus 24%, P=0.47). In multivariable models, diabetes was associated with MACEs in nonculprit lesions (adjusted OR, 2.47 [95% CI, 1.21-5.04]) but not with prevalence of high-risk plaque characteristics (adjusted OR, 1.21 [95% CI, 0.86-1.69]). CONCLUSIONS: Among patients with recent myocardial infarction, both treated and untreated lesions contributed to the diabetes-associated ≈2-fold increased MACE rate during the 3.7-year follow-up. Diabetes-related plaque characteristics that might underlie this increased risk were not identified by multimodality imaging. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02171065.

Predictors of 10-Year Stent-Related Adverse Outcomes after Coronary Drug-Eluting Stent Implantation: The Importance of Stent Size.

INTRODUCTION: The predictors of stent treatment failure and their importance 10 years after treatment with drug-eluting stents (DESs) have not been reported in detail. METHODS: Data were retrieved from the SORT-OUT II database encompassing 2,849 non-left main coronary lesions in 2,073 unselected all-comer patients treated with first-generation DES and followed clinically for 10 years. Stent treatment failure (STF) was defined as definite or probable stent thrombosis, target lesion revascularization (TLR), or >70% restenosis left untreated. Target lesion failure (TLF) was defined as cardiac death, target vessel myocardial infarction, or TLR. Characteristics predicting higher hazard ratios (HRs) were identified by the multivariate Cox regression analysis. RESULTS: A stent diameter ≤2.5 versus ≥3.5 mm had STF 23.3 versus 11.8% and TLF 27.9 versus 18.8%. Stent length <20 versus >40 mm had STF 13.0 versus 29.0% and TLF 18.7 versus 34.6%. In multivariate analysis, decreasing stent diameter (HR: 1.24 [3.0 mm] to 2.12 [2.25 mm], reference ≥3.5 mm) and increasing stent length (HR: 1.15 [20-30 mm] to 2.07 [>40 mm], reference <20 mm) predicted STF together with diabetes (HR: 1.31), previous revascularization (HR: 1.31), restenotic (HR: 2.25), bifurcation (HR: 1.45), and chronically occluded lesions (HR: 1.54). A predictive score (PS) was calculated for each lesion from the HRs for the predictors present. The 10-year rates of STF were 10% in lesions with a PS ≤ 1.5 and 37% in those with PS ≥ 3.5. CONCLUSIONS: Ten-year outcomes show large variations depending on the stent size and a few patient and lesion characteristics. The calculation of a PS from these unambiguous variables may be used to improve the risk estimate in individual lesions and patients.

Identification of vulnerable plaques and patients by intracoronary near-infrared spectroscopy and ultrasound (PROSPECT II): a prospective natural history study.

BACKGROUND: Near-infrared spectroscopy (NIRS) and intravascular ultrasound are promising imaging modalities to identify non-obstructive plaques likely to cause coronary-related events. We aimed to assess whether combined NIRS and intravascular ultrasound can identify high-risk plaques and patients that are at risk for future major adverse cardiac events (MACEs). METHODS: PROSPECT II is an investigator-sponsored, multicentre, prospective natural history study done at 14 university hospitals and two community hospitals in Denmark, Norway, and Sweden. We recruited patients of any age with recent (within past 4 weeks) myocardial infarction. After treatment of all flow-limiting coronary lesions, three-vessel imaging was done with a combined NIRS and intravascular ultrasound catheter. Untreated lesions (also known as non-culprit lesions) were identified by intravascular ultrasound and their lipid content was assessed by NIRS. The primary outcome was the covariate-adjusted rate of MACEs (the composite of cardiac death, myocardial infarction, unstable angina, or progressive angina) arising from untreated non-culprit lesions during follow-up. The relations between plaques with high lipid content, large plaque burden, and small lumen areas and patient-level and lesion-level events were determined. This trial is registered with ClinicalTrials.gov, NCT02171065. FINDINGS: Between June 10, 2014, and Dec 20, 2017, 3629 non-culprit lesions were characterised in 898 patients (153 [17%] women, 745 [83%] men; median age 63 [IQR 55-70] years). Median follow-up was 3·7 (IQR 3·0-4·4) years. Adverse events within 4 years occurred in 112 (13·2%, 95% CI 11·0-15·6) of 898 patients, with 66 (8·0%, 95% CI 6·2-10·0) arising from 78 untreated non-culprit lesions (mean baseline angiographic diameter stenosis 46·9% [SD 15·9]). Highly lipidic lesions (851 [24%] of 3500 lesions, present in 520 [59%] of 884 patients) were an independent predictor of patient-level non-culprit lesion-related MACEs (adjusted odds ratio 2·27, 95% CI 1·25-4·13) and non-culprit lesion-specific MACEs (7·83, 4·12-14·89). Large plaque burden (787 [22%] of 3629 lesions, present in 530 [59%] of 898 patients) was also an independent predictor of non-culprit lesion-related MACEs. Lesions with both large plaque burden by intravascular ultrasound and large lipid-rich cores by NIRS had a 4-year non-culprit lesion-related MACE rate of 7·0% (95% CI 4·0-10·0). Patients in whom one or more such lesions were identified had a 4-year non-culprit lesion-related MACE rate of 13·2% (95% CI 9·4-17·6). INTERPRETATION: Combined NIRS and intravascular ultrasound detects angiographically non-obstructive lesions with a high lipid content and large plaque burden that are at increased risk for future adverse cardiac outcomes. FUNDING: Abbott Vascular, Infraredx, and The Medicines Company.

Percutaneous Coronary Intervention for Vulnerable Coronary Atherosclerotic Plaque.

BACKGROUND: Acute coronary syndromes most commonly arise from thrombosis of lipid-rich coronary atheromas that have large plaque burden despite angiographically appearing mild. OBJECTIVES: This study sought to examine the outcomes of percutaneous coronary intervention (PCI) of non-flow-limiting vulnerable plaques. METHODS: Three-vessel imaging was performed with a combination intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) catheter after successful PCI of all flow-limiting coronary lesions in 898 patients presenting with myocardial infarction (MI). Patients with an angiographically nonobstructive stenosis not intended for PCI but with IVUS plaque burden of ≥65% were randomized to treatment of the lesion with a bioresorbable vascular scaffold (BVS) plus guideline-directed medical therapy (GDMT) versus GDMT alone. The primary powered effectiveness endpoint was the IVUS-derived minimum lumen area (MLA) at protocol-driven 25-month follow-up. The primary (nonpowered) safety endpoint was randomized target lesion failure (cardiac death, target vessel-related MI, or clinically driven target lesion revascularization) at 24 months. The secondary (nonpowered) clinical effectiveness endpoint was randomized lesion-related major adverse cardiac events (cardiac death, MI, unstable angina, or progressive angina) at latest follow-up. RESULTS: A total of 182 patients were randomized (93 BVS, 89 GDMT alone) at 15 centers. The median angiographic diameter stenosis of the randomized lesions was 41.6%; by near-infrared spectroscopy-IVUS, the median plaque burden was 73.7%, the median MLA was 2.9 mm2, and the median maximum lipid plaque content was 33.4%. Angiographic follow-up at 25 months was completed in 167 patients (91.8%), and the median clinical follow-up was 4.1 years. The follow-up MLA in BVS-treated lesions was 6.9 ± 2.6 mm2 compared with 3.0 ± 1.0 mm2 in GDMT alone-treated lesions (least square means difference: 3.9 mm2; 95% confidence interval: 3.3 to 4.5; p < 0.0001). Target lesion failure at 24 months occurred in similar rates of BVS-treated and GDMT alone-treated patients (4.3% vs. 4.5%; p = 0.96). Randomized lesion-related major adverse cardiac events occurred in 4.3% of BVS-treated patients versus 10.7% of GDMT alone-treated patients (odds ratio: 0.38; 95% confidence interval: 0.11 to 1.28; p = 0.12). CONCLUSIONS: PCI of angiographically mild lesions with large plaque burden was safe, substantially enlarged the follow-up MLA, and was associated with favorable long-term clinical outcomes, warranting the performance of an adequately powered randomized trial. (PROSPECT ABSORB [Providing Regional Observations to Study Predictors of Events in the Coronary Tree II Combined with a Randomized, Controlled, Intervention Trial]; NCT02171065).

Ten-year clinical outcome of patients treated with a drug-eluting stent in the proximal left anterior descending artery segment compared with patients stented in other non-left main coronary segments.

AIMS: The aim of the study was to determine whether patients treated with drug-eluting stents in the proximal left anterior descending artery (LAD) carried a different long-term prognosis from patients treated in other coronary artery segments. METHODS AND RESULTS: Ten-year clinical outcome expressed as all-cause mortality and major adverse cardiac events (MACE: cardiac death, acute myocardial infarction, or target vessel revascularisation) was determined for 1,479 patients with a single non-left main coronary stenosis treated with a first-generation drug-eluting stent in the SORT OUT II trial. The outcome of patients treated with stents in the proximal LAD (n=365) was compared with that of patients treated in a non-proximal LAD segment (n=1,114). Follow-up was 99.3% complete. All-cause mortality was 24.9% in the proximal LAD group vs. 26.3% in the non-proximal LAD group (p=0.60). MACE occurred less frequently in the proximal LAD group, 24.6% vs. 31.0% with a hazard ratio of 0.77 (95% confidence interval [CI]: 0.61-0.97, p=0.024). After multivariate analysis which included baseline characteristics that were unevenly distributed between the groups, the hazard ratio for MACE was 0.82 (95% CI: 0.65-1.03, p=0.09). CONCLUSIONS: Patients treated with a drug-eluting stent in the proximal LAD have similar, if not better, long-term clinical outcome compared with patients stented in other coronary artery segments.

Prognostic Usefulness of Cardiopulmonary Exercise Testing for Managing Patients With Severe Aortic Stenosis.

The approach to managing asymptomatic or questionably symptomatic patients for aortic stenosis is difficult. We aimed to determine whether cardiopulmonary exercise testing (CPET) is prognostically useful in such patients. Patients judged asymptomatic or questionably symptomatic for aortic stenosis with aortic valve area index <0.6 cm2/m2 and left ventricular ejection fraction ≥0.50 were managed conservatively provided they had either (group 1) normal peak oxygen consumption and peak oxygen pulse (>83% and >95% of the predicted values, respectively) or (group 2) subnormal peak oxygen consumption or peak oxygen pulse but with CPET data pointing to pathologies other than hemodynamic compromise from aortic stenosis. Increase in systolic blood pressure <20 mm Hg, ST depression ≥2 mm, or symptoms during the exercise test were allowed. Unexpected events included cardiac death or hospitalization with heart failure in patients who had not been recommended valve replacement. The median age of the study population (n = 101) was 75 years (interquartile range 65 to 79 years), and 67% were judged questionably symptomatic. During a follow-up at 24 ± 6 months, the rate of unexpected cardiac death and unexpected hospitalization with heart failure was 0% and 6.0%, respectively. All-cause mortality was 4.0% compared with 8.0% in the age- and gender-matched population. For group 1, 26 of 70 (37.1%) succumbed to cardiac death, or were hospitalized because of heart failure, or underwent valve replacement, and for group 2 this was 12 of 31 (38.7%). In conclusion, if CPET does not indicate a significant hemodynamic compromise because of aortic stenosis, an initially conservative strategy results in a good prognosis and an acceptable event rate.

Observed change in peak oxygen consumption after aortic valve replacement and its predictors.

OBJECTIVE: To assess the change in peak oxygen consumption (pVO2) and determine its outcome predictors after aortic valve replacement (AVR) for aortic stenosis (AS). METHODS: Patients with AS and preserved left ventricular ejection fraction who were referred for single AVR had cardiopulmonary exercise testing prior to and 9 months post-AVR. Predictors of outcome for pVO2 were determined by multivariate linear and logistic regression analyses. A significant change in pVO2 was defined as a relative change that was more than twice the coefficient of repeatability by test-retest (>10%). RESULTS: The pre-AVR characteristics of the 37 study patients included the following: median age (range) 72 (46-83) years, aortic valve area index (AVAI) 0.41 (SD 0.11) cm(2)/m(2), mean gradient (MG) 49.1 (SD 15.3) mm Hg and New York Heart Association (NYHA)≥II 27 (73%). Pre-AVR and post-AVR mean pVO2 was 18.5 and 18.4 mL/kg/m(2) (87% of the predicted), respectively, but the change from pre-AVR was heterogeneous. The relative change in pVO2 was positively associated with the preoperative MG (ß=0.50, p=0.001) and negatively associated with brain natriuretic peptide > upper level of normal according to age and gender (ß=-0.40, p=0.009). A relative increase in pVO2 exceeding 10% was found in 9 (24%), predicted by lower pre-AVR AVAI (OR 0.18; 95% CI 0.04 to 0.82, p=0.027) and lower peak O2 pulse (OR 0.94; 95% CI 0.88 to 0.99, p=0.045). Decreases in pVO2 exceeding 10% were found in 11 (30%) and predicted by lower MG (OR 0.93; 95% CI 0.86 to 0.99, p=0.033). CONCLUSIONS: Change in pVO2 was heterogeneous. Predictors of favourable and unfavourable outcomes for pVO2 were identified.

Cardiopulmonary Exercise Testing in Patients with Asymptomatic or Equivocal Symptomatic Aortic Stenosis: Feasibility, Reproducibility, Safety and Information Obtained on Exercise Physiology.

OBJECTIVE: The aim of this study was to determine the feasibility, reproducibility, safety and information obtained on exercise physiology from cardiopulmonary exercise testing (CPX) in patients with aortic stenosis. METHODS: Patients with an aortic valve area (AVA) <1.3 cm2 who were judged asymptomatic or equivocal symptomatic underwent CPX and an inert gas rebreathing test. Only those where comprehensive evaluation of CPX results indicated haemodynamic compromise from aortic stenosis were referred for valve replacement. RESULTS: The mean patient age was 72 (±9) years; an AVA index <0.6 cm2/m2 and equivocal symptomatic status were found in 90 and 70%, respectively. CPX was feasible in 130 of the 131 patients. The coefficients of repeatability by test-retest were 5.4% (pVO2) and 4.6% (peak O2 pulse). A pVO2 <83% of the expected was predicted by a lower stroke volume at exercise, lower peak heart rate and FEV1, and higher VE/VCO2, but not by AVA index. Equivocal symptomatic status and a low gradient but high valvulo-arterial impedance were associated with a lower pVO2, but not with an inability to increase stroke volume. In total, 18 patients were referred for valve replacement. At 1 year, no cardiovascular deaths had occurred. CONCLUSIONS: CPX was feasible and reproducible and provided comprehensive data on exercise physiology. A CPX-guided treatment strategy was safe up to 1 year.

Percutaneous coronary intervention without onsite cardiac surgery.

INTRODUCTION: Danish health authorities have major concerns with regard to the risk and the quality of care of percutaneous coronary intervention (PCI) without onsite cardiac surgery. We report the results of the first Danish PCI centre without onsite cardiac surgery. MATERIAL AND METHODS: A total of 245 patients underwent 254 elective PCIs during a six-month study period. The outcome measures were treatment latency, health care costs, mortality rate, major adverse cardiovascular events, symptom relief and quality-of-life at six-month follow-up. RESULTS: The median treatment latency was reduced from 28 to no days (p < 0.05) for patients with stable disease, and from seven to no days (p < 0.05) for patients with unstable disease. Health care costs were reduced by 4,246,652 DKK. The six-month mortality was 0.0% versus a predicted 0.4% New York State PCI-score in patients with stable disease, and a 1.4% observed study score versus a predicted 6.4% GRACE-score in patients with unstable disease. No patients required emergency bypass surgery. At six months, five myocardial infarctions (two periprocedural and two subacute stent thromboses), three restenoses and no in-stent restenosis had occurred, while angina was absent or reduced in 92% and quality-of-life had improved in 73% of the patients. CONCLUSION: Local PCI without onsite cardiac surgery was safe, quality of care was increased, health care costs were reduced and patient-perceived treatment effect was excellent.

A systematic review: effect of angiotensin converting enzyme inhibition on left ventricular volumes and ejection fraction in patients with a myocardial infarction and in patients with left ventricular dysfunction.

BACKGROUND AND AIM: To summarize and quantify results of echocardiographic studies examining the effect of angiotensin converting enzyme (ACE) inhibition on left ventricular remodelling in patients with acute myocardial infarction (MI) and in patients with left ventricular systolic dysfunction (LVSD). METHODS: Systematic review of the literature and meta-analysis of eligible studies providing data on end-diastolic and end-systolic volumes and left ventricular ejection fraction (LVEF) were performed. RESULTS: Data from 16 eligible studies were meta-analysed. The results of studies including patients with MI and preserved LVEF (>45%) showed no significant benefit of ACE inhibition. Results of studies/subgroups with mean LVEF < or =45% demonstrated significant differences in diastolic and systolic volumes of 3.0 (0.1, 6.0) ml and 2.25 (0.04, 4.4) ml in short-term (4-14 weeks) follow-up in favour of ACE inhibitor, p=0.041 and p=0.046 respectively. In the long-term (6-12 months) follow-up, the differences in diastolic and systolic volumes were 4.2 (0.98, 7.4) ml and 3.3 (0.9, 5.8) ml in favour of ACE inhibitor, p=0.01 and p=0.007 respectively. LVEF improved in both short and long-term follow-up, p=0.034 and p=0.021, respectively. CONCLUSION: Chronic use of ACE inhibition has a small but sustained and beneficial effect on remodelling in patients with myocardial infarction and patients with chronic left ventricular dysfunction.

Extended follow-up of patients randomly assigned in the Angiotensin-converting enzyme inhibition Post-Revascularization Study (APRES).

BACKGROUND: We hypothesized that the benefit from ramipril on cardiac events and on left ventricular end-systolic volume (ESVI) in the Angiotensin-converting enzyme inhibition Post-revascularization Study (APRES) randomized controlled trial (RCT) was associated with long-term improvement. METHODS: For the 3.2 years after the end of the RCT, we obtained information from a national database regarding date and cause of death and hospitalization for the 159 enrolled patients. RESULTS: Assignment to ramipril in the RCT resulted in a lower rate of cardiac death or hospitalization with heart failure up to the time of complete follow-up of all patients at 4.3 years (relative risk [RR], 0.28; P =.018) and up to 1.5 years after the end of the RCT (RR, 0.35; P =.042) but not up to the complete extended follow-up time at 6.9 years (RR, 0.65; P =.27). Independent predictors for risk of future cardiac death or hospitalization with heart failure were (a) left ventricular dilation (LVD) (RR, 2.84; P =.031), defined as an increase in ESVI greater than the reproducibility coefficient, and (b) composite event of acute myocardial infarction or development of heart failure or LVD (RR, 12.44; P <.001). Ramipril significantly reduced events (a) (P =.046) and (b) (P =.015) during the RCT. CONCLUSIONS: There is congruence between the beneficial effect of ramipril on LVD, acute myocardial infarction, or heart failure and the prognostic importance of these factors and on cardiac death and hospitalization with heart failure. This observation supports and reinforces conclusions from previous APRES reports that ramipril benefits non-high-risk patients after revascularization.

Effect of ramipril on postrevascularization prevalence of angina and quality of life.

BACKGROUND: The prevalence of angina after invasive revascularization is not negligible and impacts on quality of life. It has not been clarified whether potential anti-ischemic actions of angiotensin-converting enzyme inhibitors (1) may apply to non high-risk patients and (2) may reduce the prevalence of angina. We sought to test the hypothesis that ramipril, an angiotensin-converting enzyme inhibitor, may reduce the postrevascularization prevalence of angina pectoris and improve quality of life. METHODS: In the Angiotensin-converting enzyme Post-Revascularization Study (APRES), 159 patients who underwent invasive revascularization for chronic angina and who had not had heart failure, acute myocardial infarction (AMI), or severe left ventricular dysfunction were randomized to receive 10 mg of ramipril or placebo. During the 12- to 46-month follow-up, the Specific Activity Scale class, exercise tests, and SF-36 quality of life scores were serially assessed. RESULTS: The average prevalence of angina of Specific Activity Scale class II or worse was 26.6% in the ramipril group and 19.9% in the placebo group (p=0.16). The average prevalence of exercise-inducible ischemia was 30.8% in the ramipril group and 25.2% in the placebo group (p=0.39). There were no significant differences between the two treatment groups in the SF-36 quality of life scores or in the Duke treadmill score. Post-hoc power calculations revealed that the power to rule out a clinical significant benefit of ramipril on the prevalence of angina, quality of life, and Duke treadmill score was >90%. CONCLUSIONS: These data do not suggest that ramipril reduces the prevalence of angina pectoris or improves quality of life after invasive revascularization in such patients

Between observer variation is not eliminated by standardised analysis of dobutamine-atropine stress echocardiography.

AIMS: The conventional analysis of dobutamine-atropine stress echocardiography (DASE) is poorly defined and subject to considerable variation. The aim of this study was to investigate the reproducibility of strictly standardised qualitative analysis in DASE. METHODS AND RESULTS: Strict criteria for standardised DASE interpretation were defined through logistic regression analysis on categorical parameters obtained from 20 patients with coronary artery disease (CAD) and 20 healthy controls subjected to DASE. Three expert echocardiographers analysed DASE recordings from 100 consecutive patients referred for coronary angiography. Specificity for CAD and for predicting significant stenosis of a major coronary artery was 94% (95% CI: 83-100%) and 79% (95% CI: 63-96%), whereas sensitivity was 49% in both cases (95% CI: 38-60% and 37-61%). Within and between observer reproducibility was moderate to fair (kappa = 0.56 and 0.38; 95% CI: 0.40-0.72 and 0.24-0.52). In patients without prior myocardial infarction and in echogenic patients within observer reproducibility was good (kappa = 0.72 and 0.74; 95% CI: 0.52-0.92 and 0.56-0.92). CONCLUSIONS: Observer variation was not eliminated in standardised qualitative DASE interpretation based on criteria that predicted the presence of CAD with a high specificity and reproducibility was good only in certain subgroups of patients.