Fractional Flow Reserve-Guided PCI or Coronary Bypass Surgery for 3-Vessel Coronary Artery Disease: 3-Year Follow-Up of the FAME 3 Trial.

BACKGROUND: Previous studies comparing percutaneous coronary intervention (PCI) with coronary artery bypass grafting (CABG) in patients with multivessel coronary disease not involving the left main have shown significantly lower rates of death, myocardial infarction (MI), or stroke after CABG. These studies did not routinely use current-generation drug-eluting stents or fractional flow reserve (FFR) to guide PCI. METHODS: FAME 3 (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) is an investigator-initiated, multicenter, international, randomized trial involving patients with 3-vessel coronary artery disease (not involving the left main coronary artery) in 48 centers worldwide. Patients were randomly assigned to receive FFR-guided PCI using zotarolimus drug-eluting stents or CABG. The prespecified key secondary end point of the trial reported here is the 3-year incidence of the composite of death, MI, or stroke. RESULTS: A total of 1500 patients were randomized to FFR-guided PCI or CABG. Follow-up was achieved in >96% of patients in both groups. There was no difference in the incidence of the composite of death, MI, or stroke after FFR-guided PCI compared with CABG (12.0% versus 9.2%; hazard ratio [HR], 1.3 [95% CI, 0.98-1.83]; P=0.07). The rates of death (4.1% versus 3.9%; HR, 1.0 [95% CI, 0.6-1.7]; P=0.88) and stroke (1.6% versus 2.0%; HR, 0.8 [95% CI, 0.4-1.7]; P=0.56) were not different. MI occurred more frequently after PCI (7.0% versus 4.2%; HR, 1.7 [95% CI, 1.1-2.7]; P=0.02). CONCLUSIONS: At 3-year follow-up, there was no difference in the incidence of the composite of death, MI, or stroke after FFR-guided PCI with current-generation drug-eluting stents compared with CABG. There was a higher incidence of MI after PCI compared with CABG, with no difference in death or stroke. These results provide contemporary data to allow improved shared decision-making between physicians and patients with 3-vessel coronary artery disease. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02100722.

Biomarkers and cardiovascular events in patients with stable coronary disease in the ISCHEMIA Trials.

IMPORTANCE: Biomarkers may improve prediction of cardiovascular events for patients with stable coronary artery disease (CAD), but their importance in addition to clinical tests of inducible ischemia and CAD severity is unknown. OBJECTIVES: To evaluate the prognostic value of multiple biomarkers in stable outpatients with obstructive CAD and moderate or severe inducible ischemia. DESIGN AND SETTING: The ISCHEMIA and ISCHEMIA CKD trials randomized 5,956 participants with CAD to invasive or conservative management from July 2012 to January 2018; 1,064 participated in the biorepository. MAIN OUTCOME MEASURES: Primary outcome was cardiovascular death, myocardial infarction (MI), or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. Secondary outcome was cardiovascular death or MI. Improvements in prediction were assessed by cause-specific hazard ratios (HR) and area under the receiver operating characteristics curve (AUC) for an interquartile increase in each biomarker, controlling for other biomarkers, in a base clinical model of risk factors, left ventricular ejection fraction (LVEF) and ischemia severity. Secondary analyses were performed among patients in whom core-lab confirmed severity of CAD was ascertained by computed cardiac tomographic angiography (CCTA). EXPOSURES: Baseline levels of interleukin-6 (IL-6), high sensitivity troponin T (hsTnT), growth differentiation factor 15 (GDF-15), N-terminal pro-B-type natriuretic peptide (NT-proBNP), lipoprotein a (Lp[a]), high sensitivity C-reactive protein (hsCRP), Cystatin C, soluble CD 40 ligand (sCD40L), myeloperoxidase (MPO), and matrix metalloproteinase 3 (MMP3). RESULTS: Among 757 biorepository participants, median (IQR) follow-up was 3 (2-5) years, age was 67 (61-72) years, and 144 (19%) were female; 508 had severity of CAD by CCTA available. In an adjusted multimarker model with hsTnT, GDF-15, NT-proBNP and sCD40L, the adjusted HR for the primary outcome per interquartile increase in each biomarker was 1.58 (95% CI 1.22, 2.205), 1.60 (95% CI 1.16, 2.20), 1.61 (95% 1.22, 2.14), and 1.46 (95% 1.12, 1.90), respectively. The adjusted multimarker model also improved prediction compared with the clinical model, increasing the AUC from 0.710 to 0.792 (P < .01) and 0.714 to 0.783 (P < .01) for the primary and secondary outcomes, respectively. Similar findings were observed after adjusting for core-lab confirmed atherosclerosis severity. CONCLUSIONS AND RELEVANCE: Among ISCHEMIA biorepository participants, biomarkers of myocyte injury/distension, inflammation, and platelet activity improved cardiovascular event prediction in addition to risk factors, LVEF, and assessments of ischemia and atherosclerosis severity. These biomarkers may improve risk stratification for patients with stable CAD.

Impact of Complete Revascularization in the ISCHEMIA Trial.

BACKGROUND: Anatomic complete revascularization (ACR) and functional complete revascularization (FCR) have been associated with reduced death and myocardial infarction (MI) in some prior studies. The impact of complete revascularization (CR) in patients undergoing an invasive (INV) compared with a conservative (CON) management strategy has not been reported. OBJECTIVES: Among patients with chronic coronary disease without prior coronary artery bypass grafting randomized to INV vs CON management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial, we examined the following: 1) the outcomes of ACR and FCR compared with incomplete revascularization; and 2) the potential impact of achieving CR in all INV patients compared with CON management. METHODS: ACR and FCR in the INV group were assessed at an independent core laboratory. Multivariable-adjusted outcomes of CR were examined in INV patients. Inverse probability weighted modeling was then performed to estimate the treatment effect had CR been achieved in all INV patients compared with CON management. RESULTS: ACR and FCR were achieved in 43.4% and 58.4% of 1,824 INV patients. ACR was associated with reduced 4-year rates of cardiovascular death or MI compared with incomplete revascularization. By inverse probability weighted modeling, ACR in all 2,296 INV patients compared with 2,498 CON patients was associated with a lower 4-year rate of cardiovascular death or MI (difference -3.5; 95% CI: -7.2% to 0.0%). In comparison, the event rate difference of cardiovascular death or MI for INV minus CON in the overall ISCHEMIA trial was -2.4%. Results were similar but less pronounced with FCR. CONCLUSIONS: The outcomes of an INV strategy may be improved if CR (especially ACR) is achieved. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

Association of Residual Ischemic Disease With Clinical Outcomes After Percutaneous Coronary Intervention.

BACKGROUND: Anatomical scoring systems have been used to assess completeness of revascularization but are challenging to apply to large real-world datasets. OBJECTIVES: The aim of this study was to assess the prevalence of complete revascularization and its association with longitudinal clinical outcomes in the U.S. Department of Veterans Affairs (VA) health care system using an automatically computed anatomic complexity score. METHODS: Patients undergoing percutaneous coronary intervention (PCI) between October 1, 2007, and September 30, 2020, were identified, and the burden of prerevascularization and postrevascularization ischemic disease was quantified using the VA SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) score. The association between residual VA SYNTAX score and long-term major adverse cardiovascular events (MACE; death, myocardial infarction, repeat revascularization, and stroke) was assessed. RESULTS: A total of 57,476 veterans underwent PCI during the study period. After adjustment, the highest tertile of residual VA SYNTAX score was associated with increased hazard of MACE (HR: 2.06; 95% CI: 1.98-2.15) and death (HR: 1.50; 95% CI: 1.41-1.59) at 3 years compared to complete revascularization (residual VA SYNTAX score = 0). Hazard of 1- and 3-year MACE increased as a function of residual disease, regardless of baseline disease severity or initial presentation with acute or chronic coronary syndrome. CONCLUSIONS: Residual ischemic disease was strongly associated with long-term clinical outcomes in a contemporary national cohort of PCI patients. Automatically computed anatomic complexity scores can be used to assess the longitudinal risk for residual ischemic disease after PCI and may be implemented to improve interventional quality.

Comparison of Outcomes of Invasive or Conservative Management of Chronic Coronary Disease in Four Randomized Controlled Trials.

Revascularization and medical therapy for chronic coronary disease have both evolved significantly over the last 50 years. A total of 4 contemporary randomized controlled trials- Clinical Outcomes Utilizing Revascularization and Aggressive drug Evaluation (COURAGE), Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D), Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 (FAME 2), and International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA)-have assessed the incremental benefit of revascularization when added to secondary prevention with intensive pharmacologic and lifestyle intervention. We reviewed these 4 seminal studies with the objective of marshaling evidence to better frame how these results should apply to clinical decision making. These studies differed in study design, end points, intensity of treatment, and revascularization techniques. Nevertheless, they all demonstrate similar rates of "hard" clinical events with invasive and conservative management, and varying degrees of benefit in angina-related quality of life with revascularization. In conclusion, although controversy persists concerning the role of revascularization because of differing interpretations of the clinical trial evidence, we contend that instead of being competing management strategies, invasive and conservative approaches are complementary.

Multifaceted Intervention to Improve P2Y12 Inhibitor Adherence After Percutaneous Coronary Intervention: A Stepped Wedge Trial.

Background P2Y12 inhibitor medications are critical following percutaneous coronary intervention (PCI); however, adherence remains suboptimal. Our objective was to assess the effectiveness of a multifaceted intervention to improve P2Y12 inhibitor adherence following PCI. Methods and Results This was a modified stepped wedge trial of 52 eligible hospitals, of which 15 were randomly selected and agreed to participate (29 hospitals declined, and 8 eligible hospitals were not contacted). At each intervention hospital, patient recruitment occurred for 6 months and enrolled patients were followed up for 1 year after PCI. Three control groups were used: patients at intervention hospitals undergoing PCI (1) before the intervention period (preintervention); (2) after the intervention period (postintervention); or (3) at the 8 hospitals not contacted (concurrent controls). The intervention consisted of 4 components: (1) P2Y12 inhibitor delivered to patients' bedside after PCI; (2) education on importance of P2Y12 inhibitors; (3) automated reminder telephone calls to refill medication; and (4) outreach to patients if they delayed refilling P2Y12 inhibitor. The primary outcomes were as follows: (1) proportion of patients with delays filling P2Y12 inhibitor at hospital discharge and (2) proportion of patients who were adherent in the year after PCI using pharmacy refill data. Primary analysis compared intervention with preintervention control patients. There were 1377 (intent-to-treat) potentially eligible patients, of whom 803 (per protocol) were approached at intervention sites versus 5910 preintervention, 2807 postintervention, and 4736 concurrent control patients. In the intent-to-treat analysis, intervention patients were less likely to delay filling P2Y12 at hospital discharge (-3.4%; 98.3% CI, -1.2% to -5.6%) and more likely to be adherent to P2Y12 (4.1%; 98.3% CI, 1.0%-7.1%) at 1 year, but had more clinical events (3.2%; 98.3% CI, 2.3%-4.1%) driven by repeated PCI compared with preintervention patients. In post hoc analysis looking at myocardial infarction, stroke, and death, intervention patients had lower event rates compared with preintervention patients (-1.7%; 98.3% CI, -2.3% to -1.1%). Conclusions A 4-component intervention targeting P2Y12 inhibitor adherence was difficult to implement. The intervention produced mixed results. It improved P2Y12 adherence, but there was also an increase in repeat PCI. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01609842.

Fractional Flow Reserve-Guided PCI as Compared with Coronary Bypass Surgery.

BACKGROUND: Patients with three-vessel coronary artery disease have been found to have better outcomes with coronary-artery bypass grafting (CABG) than with percutaneous coronary intervention (PCI), but studies in which PCI is guided by measurement of fractional flow reserve (FFR) have been lacking. METHODS: In this multicenter, international, noninferiority trial, patients with three-vessel coronary artery disease were randomly assigned to undergo CABG or FFR-guided PCI with current-generation zotarolimus-eluting stents. The primary end point was the occurrence within 1 year of a major adverse cardiac or cerebrovascular event, defined as death from any cause, myocardial infarction, stroke, or repeat revascularization. Noninferiority of FFR-guided PCI to CABG was prespecified as an upper boundary of less than 1.65 for the 95% confidence interval of the hazard ratio. Secondary end points included a composite of death, myocardial infarction, or stroke; safety was also assessed. RESULTS: A total of 1500 patients underwent randomization at 48 centers. Patients assigned to undergo PCI received a mean (±SD) of 3.7±1.9 stents, and those assigned to undergo CABG received 3.4±1.0 distal anastomoses. The 1-year incidence of the composite primary end point was 10.6% among patients randomly assigned to undergo FFR-guided PCI and 6.9% among those assigned to undergo CABG (hazard ratio, 1.5; 95% confidence interval [CI], 1.1 to 2.2), findings that were not consistent with noninferiority of FFR-guided PCI (P = 0.35 for noninferiority). The incidence of death, myocardial infarction, or stroke was 7.3% in the FFR-guided PCI group and 5.2% in the CABG group (hazard ratio, 1.4; 95% CI, 0.9 to 2.1). The incidences of major bleeding, arrhythmia, and acute kidney injury were higher in the CABG group than in the FFR-guided PCI group. CONCLUSIONS: In patients with three-vessel coronary artery disease, FFR-guided PCI was not found to be noninferior to CABG with respect to the incidence of a composite of death, myocardial infarction, stroke, or repeat revascularization at 1 year. (Funded by Medtronic and Abbott Vascular; FAME 3 ClinicalTrials.gov number, NCT02100722.).

In-Stent Restenosis in Saphenous Vein Grafts (from the DIVA Trial).

Saphenous vein grafts (SVGs) have high rates of in-stent restenosis (ISR). We compared the baseline clinical and angiographic characteristics of patients and lesions that did develop ISR with those who did not develop ISR during a median follow-up of 2.7 years in the DIVA study (NCT01121224). We also examined the ISR types using the Mehran classification. ISR developed in 119 out of the 575 DIVA patients (21%), with similar incidence among patients with drug-eluting stents and bare-metal stents (BMS) (21% vs 21%, p = 0.957). Patients in the ISR group were younger (67 ± 7 vs 69 ± 8 years, p = 0.04) and less likely to have heart failure (27% vs 38%, p = 0.03) and SVG lesions with Thrombolysis In Myocardial Infarction 3 flow before the intervention (77% vs 83%, p <0.01), but had a higher number of target SVG lesions (1.33 ± 0.64 vs 1.16 ± 0.42, p <0.01), more stents implanted in the target SVG lesions (1.52 ± 0.80 vs 1.31 ± 0.66, p <0.01), and longer total stent length (31.37 ± 22.11 vs 25.64 ± 17.42 mm, p = 0.01). The incidence of diffuse ISR was similar in patients who received drug-eluting-stents and BMS (57% vs 54%, p = 0.94), but BMS patients were more likely to develop occlusive restenosis (17% vs 33%, p = 0.05).

Saphenous Vein Graft Failure: From Pathophysiology to Prevention and Treatment Strategies.

Saphenous vein grafts (SVGs) remain the most frequently used conduits in coronary artery bypass graft surgery (CABG). Despite advances in surgical techniques and pharmacotherapy, SVG failure rates remain high, often leading to repeat coronary revascularization. The no-touch SVG harvesting technique (minimal graft manipulation with preservation of vasa vasorum and nerves) reduces the risk of SVG failure, whereas the effect of the off-pump technique on SVG patency remains unclear. Use of buffered storage solutions, intraoperative graft flow measurement, careful selection of the target vessels, and physiological assessment of the native coronary circulation before CABG may also reduce the incidence of SVG failure. Perioperative aspirin and high-intensity statin administration are the cornerstones of secondary prevention after CABG. Dual antiplatelet therapy is recommended for off-pump CABG and in patients with a recent acute coronary syndrome. Intermediate (30%-60%) SVG stenoses often progress rapidly. Stenting of intermediate SVG stenoses failed to improve outcomes; hence, treatment focuses on strict control of coronary artery disease risk factors. Redo CABG is associated with higher perioperative mortality compared with percutaneous coronary intervention (PCI); hence, the latter is preferred for most patients requiring repeat revascularization after CABG. SVG PCI is limited by high rates of no-reflow and a high incidence of restenosis during follow-up. Drug-eluting and bare metal stents provide similar long-term outcomes in SVG PCI. Embolic protection devices reduce no-reflow and should be used when feasible. PCI of the corresponding native coronary artery is associated with better short- and long-term outcomes and is preferred over SVG PCI, if technically feasible.

Functional coronary angiography in symptomatic patients with no obstructive coronary artery disease.

BACKGROUND: Patients without obstructive coronary artery disease (CAD) may have epicardial or microvascular dysfunction. The purpose of this study was to characterize patterns of epicardial and microvascular dysfunction in men and women with stable and unstable angina undergoing functional coronary angiography to inform medical therapy. METHODS: 163 symptomatic patients with ≤50% diameter stenosis and fractional flow reserve (FFR) > 0.8 underwent endothelium-dependent epicardial and microvascular function after intracoronary acetylcholine (10-4  M, 81 mcg over 3 minutes). Endothelium-independent function was assessed using coronary flow reserve (CFR) and hyperemic microvascular resistance (HMR) after intravenous adenosine (140 ug/kg/min). Coronary microvascular dysfunction (CMD) was defined as CFR < 2.5, HMR ≥2, or ≤50% change in coronary blood flow with acetylcholine (CBFACH ). RESULTS: Seventy-two percent had endothelial-dependent epicardial dysfunction (response to ACH: % ∆ in coronary artery diameter and ∆%CBFACH ) and 92% had CMD. Among CMD patients, 65% had CFR < 2.5, 35% had HMR ≥2, and 60% had CBFACH change ≤50%. CFR modestly correlated with HMR (r = -0.38, p < .0001). Among patients with normal CFR, 26% had abnormal epicardial and 20% had abnormal microvascular endothelial dysfunction. Women had a lower CFR (p = .02), higher FFR (p = .03) compared to men. There were no differences in epicardial and microvascular function between patients with stable and unstable angina. CONCLUSION: In patients with no obstructive CAD: CMD is prevalent, abnormal CFR does not correlate with epicardial or microvascular endothelial dysfunction, women have lower CFR, higher FFR but similar endothelial function compared to men.

Health-Status Outcomes with Invasive or Conservative Care in Coronary Disease.

BACKGROUND: In the ISCHEMIA trial, an invasive strategy with angiographic assessment and revascularization did not reduce clinical events among patients with stable ischemic heart disease and moderate or severe ischemia. A secondary objective of the trial was to assess angina-related health status among these patients. METHODS: We assessed angina-related symptoms, function, and quality of life with the Seattle Angina Questionnaire (SAQ) at randomization, at months 1.5, 3, and 6, and every 6 months thereafter in participants who had been randomly assigned to an invasive treatment strategy (2295 participants) or a conservative strategy (2322). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate differences between the treatment groups. The primary outcome of this health-status analysis was the SAQ summary score (scores range from 0 to 100, with higher scores indicating better health status). All analyses were performed in the overall population and according to baseline angina frequency. RESULTS: At baseline, 35% of patients reported having no angina in the previous month. SAQ summary scores increased in both treatment groups, with increases at 3, 12, and 36 months that were 4.1 points (95% credible interval, 3.2 to 5.0), 4.2 points (95% credible interval, 3.3 to 5.1), and 2.9 points (95% credible interval, 2.2 to 3.7) higher with the invasive strategy than with the conservative strategy. Differences were larger among participants who had more frequent angina at baseline (8.5 vs. 0.1 points at 3 months and 5.3 vs. 1.2 points at 36 months among participants with daily or weekly angina as compared with no angina). CONCLUSIONS: In the overall trial population with moderate or severe ischemia, which included 35% of participants without angina at baseline, patients randomly assigned to the invasive strategy had greater improvement in angina-related health status than those assigned to the conservative strategy. The modest mean differences favoring the invasive strategy in the overall group reflected minimal differences among asymptomatic patients and larger differences among patients who had had angina at baseline. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Initial Invasive or Conservative Strategy for Stable Coronary Disease.

BACKGROUND: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Rationale and design of the granulocyte-macrophage colony stimulating factor in peripheral arterial disease (GPAD-3) study.

BACKGROUND: Lower extremity peripheral arterial disease (PAD) is a public health problem and many patients with PAD experience claudication despite adequate medical and/or surgical management. Mobilization of endogenous progenitor cells using Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) is a novel therapeutic option that has shown promising results in experimental models and phase I/IIA clinical trials. The GPAD-3 trial will study the effect of two successive administrations of GM-CSF at 3-month interval for improving claudication among patients with lower extremity PAD. METHODS: We plan to recruit 176 patients in this ongoing randomized, double-blind, placebo-controlled Phase IIB trial. After screening for inclusion and exclusion criteria, eligible subjects undergo a 4-week screening phase where they perform subcutaneous placebo injections thrice weekly and walk at least three times a day until they develop claudication. After the screening phase, eligible subjects undergo baseline testing and are randomized 2:1 to receive 500 µg/day of GM-CSF subcutaneously thrice weekly for three weeks or placebo injections. After 3 months, follow-up endpoint testing is performed and subjects in the GM-CSF group receive the second administration of the drug for three weeks while subjects in placebo group receive matching placebo injections. All participants undergo endpoint testing at six-month and nine-month follow-up. The primary endpoint is change in 6-min walk distance between baseline and 6-month follow-up. CONCLUSION: GPAD-3 explores a novel approach to address the need for alternative therapies that can alleviate symptoms among patients with lower extremity PAD. If successful, this study will pave the way for a pivotal Phase III trial.

Stent-Only Versus Adjunctive Balloon Angioplasty Approach for Saphenous Vein Graft Percutaneous Coronary Intervention: Insights From DIVA Trial.

BACKGROUND: Direct stenting without pre-dilation or post-dilation has been advocated for saphenous vein graft percutaneous coronary intervention to decrease the incidence of distal embolization, periprocedural myocardial infarction, and target lesion revascularization. METHODS: We performed a post hoc analysis of patients enrolled in the DIVA (Drug-Eluting Stents Versus Bare Metal Stents in Saphenous Vein Graft Angioplasty; NCT01121224) prospective, double-blind, randomized controlled trial. Patients were stratified into stent-only and balloon-stent groups. Primary end point was 12-month incidence of target vessel failure (defined as the composite of cardiac death, target vessel myocardial infarction, or target vessel revascularization). Secondary end points included all-cause death, stent thrombosis, myocardial infarction, and target lesion revascularization during follow-up. RESULTS: Of the 575 patients included in this substudy, 185 (32%) patients underwent stent-only percutaneous coronary intervention. Patients in the stent-only versus balloon-stent group had similar baseline characteristics and similar incidence of target vessel failure at 12-months (15% versus 19%; hazard ratio, 1.34 [95% CI, 0.86-2.08]; P=0.19). During long-term follow-up (median of 2.7 years), the incidence of definite stent thrombosis (1% versus 5%; hazard ratio, 9.20 [95% CI, 1.23-68.92]; P=0.0085), the composite of definite or probable stent thrombosis (5% versus 11%; hazard ratio, 2.52 [95% CI, 1.23-5.18]; P=0.009), and target vessel myocardial infarction (8% versus 14%; hazard ratio, 1.92 [95% CI, 1.08-3.40]; P=0.023) was lower in the stent-only group. Multivariable analysis showed that a higher number of years since coronary artery bypass grafting and >1 target saphenous vein graft lesions were associated with increased target vessel failure during entire follow-up, while preintervention Thrombolysis in Myocardial Infarction-3 flow was protective. CONCLUSIONS: In patients undergoing percutaneous coronary intervention of de novo saphenous vein graft lesions, there was no difference in target vessel failure at 12 months and long-term follow-up in the stent-only versus the balloon-stent group; however, the incidence of stent thrombosis was lower in the stent-only group, as was target vessel myocardial infarction. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01121224.

Medical Therapy Utilization and Long-Term Outcomes Following Percutaneous Coronary Intervention: Five-Year Results From the Veterans Affairs Clinical Assessment, Reporting, and Tracking System Program.

BACKGROUND: Optimal medical therapy is endorsed by national guidelines in the management of ischemic heart disease; however, few studies have examined its long-term utilization following percutaneous coronary intervention (PCI) and association with clinical outcomes. We sought to assess longitudinal trends in medical therapy use after PCI and its prognostic significance. METHODS AND RESULTS: From the Veteran Affairs Clinical Assessment, Reporting, and Tracking System Program, we retrospectively identified 57 900 Veteran's Affairs patients undergoing PCI from January 2005 to May 2014. Using prescription fill dates, the utilization of 4 classes of medical therapy including statins, ß-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, P2Y12 inhibitors, and their composites were assessed at discharge, 6 months, 1, 3, and 5 years post-PCI. Multivariable Cox regression models were developed to assess the association between medical therapy status and major adverse cardiovascular events, defined as all-cause mortality, rehospitalization for myocardial infarction, rehospitalization for stroke, or repeat revascularization. At discharge following PCI, 58.3% of patients received all 4 classes of medical therapy. Utilization of statins, ß-blockers, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers decreased from 89%, 84.9%, and 72.2% on discharge, respectively, to 72.7%, 67.9%, and 57.9% at 5 years. Prescription refills of P2Y12 inhibitors declined from 96.5% on discharge to 28.3% at 5 years, driven by a large decline in P2Y12 inhibitor use after 1 year. Use of each class of medical therapy, and its composite use, was associated with a significant reduction in major adverse cardiovascular events at 5 years, with the largest effect size seen by the use of statins (HR, 0.77; 95% CI, 0.75-0.79; P<0.0001) and P2Y12 inhibitors (HR, 0.82; 95% CI, 0.79-0.85; P<0.0001). CONCLUSIONS: Consistent declines in medical therapy use following PCI were observed over time, which is associated with worse outcomes. Further efforts are needed to promote long-term adherence to secondary prevention therapies after revascularization.

Improving anti-platelet therapy adherence in the Veterans Health Administration: A randomized multi-site hybrid effectiveness-implementation study protocol.

BACKGROUND: P2Y12 inhibitors are critical following percutaneous coronary intervention (PCI) with stent placement; they reduce the risk of stent thrombosis and myocardial infarction. Despite the importance of the therapy, non-adherence is common among Veterans. METHODS AND RESULTS: Our main objective is to conduct a multi-site randomized stepped wedge trial to test the effectiveness of a multi-faceted intervention to improve adherence to P2Y12 inhibitors and PCI outcomes as well as formatively evaluate and refine the intervention implementation process. The primary outcomes of the study are the proportion of patients whose P2Y12 inhibitor prescription was filled at the time of hospital discharge following PCI with stent placement as well as the proportion of patients who were adherent based on the pharmacy refill data in the year after PCI hospital discharge. We will also assess the secondary outcomes such as bleeding, myocardial infarction, stroke, and mortality among these patients, and the cost-effectiveness of the intervention. The study was conducted at Veterans Health Administration (VA) PCI sites. At each site, we enrolled patients over a 6-month period and followed them for 12 months after PCI. Additionally, we collected qualitative data to identify contextual factors and to assess barriers and facilitators to the implementation and maintenance of the intervention. CONCLUSIONS: The study will add to the current state of knowledge on improving medication adherence in patients receiving PCI with stent implantation. Moreover, the study includes an extensive examination of the implementation process and will contribute to the field of implementation science. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01609842 https://clinicaltrials.gov/ct2/show/NCT01609842?term=clopidogrel+adherence&cntry1=NA%3AUS&rank=1.

Transcatheter Aortic Valve Replacement in Patients With Aortic Stenosis and Mitral Regurgitation.

BACKGROUND: Many patients undergoing transcatheter aortic valve replacement (TAVR) for aortic stenosis also have significant mitral regurgitation (MR). We sought to understand the association of concomitant MR with TAVR clinical outcomes, as well changes in MR after TAVR. METHODS: Patients who underwent TAVR in the US Transcatheter Valve Therapy Registry from January 3, 2012, to December 31, 2013, were studied, with longer-term clinical outcomes from Center for Medicare Services data. RESULTS: Of 11,104 patients, 3,481 (31.3%) had moderate MR, and 605 (5.5%) had severe MR. At 1 year, mortality was 21.0%, 21.5%, 26.3%, and 28.0% (p < 0.0001) and heart failure (HF) rehospitalization was 13.9%, 15.8%, 20.3%, and 23.4% (p < 0.0001) in the no, mild, moderate, and severe MR patients, respectively. After adjustment for baseline differences, significant MR was associated with increased risk of 1-year mortality or HF rehospitalization, with a HR of 1.16 (95% CI, 0.99 to 1.35) for moderate MR and 1.21 (95% CI, 0.97 to 1.50) for severe MR, compared with no MR. MR improved early after TAVR grade ≥ 1 in 79% of the severe MR patients and 66% of the moderate MR patients. Patients whose baseline moderate or severe MR improved had lower mortality (p = 0.022) and HF rehospitalization (p < 0.001) compared with patients whose MR did not improve. CONCLUSIONS: Moderate or severe MR accompanying severe AS treated with TAVR is associated with increased mortality or HF rehospitalization. This increased risk may be attributable to the minority of patients whose MR does not improve, suggesting a potential role for surveillance and targeted intervention for those patients.

Should We Perform Carotid Doppler Screening Before Surgical or Transcatheter Aortic Valve Replacement?

BACKGROUND: Screening for internal carotid artery stenosis (ICAS) with Doppler ultrasound is commonly used before cardiovascular surgery. Nevertheless, the relationship between ICAS and procedure-related stroke in isolated aortic valve replacement is unclear. METHODS: We retrospectively reviewed patients with artery stenosis who underwent ICAS screening before surgical (SAVR) or transcatheter aortic valve replacement (TAVR) between January 2007 and August 2014. Logistic regression models were used to determine the relation between post-procedure stroke and total (sum of left and right ICAS) and maximal unilateral ICAS. Age, sex, history of atrial fibrillation, cerebrovascular disease and diabetes, left ventricular ejection fraction, and procedure type were considered as covariates. Two-subgroup analyses were performed in patients who underwent TAVR and SAVR, adjusting for procedure specific details. RESULTS: A total of 996 patients underwent ICAS screening before TAVR (n = 467) or SAVR (n = 529). The prevalence of at least ≥70% ICAS was 5.2% (n = 52) and incidence of 30-day stroke was 3.4% (n = 34). Eight patients who underwent carotid intervention before valve replacement and 6 patients with poor Doppler images were excluded from the final analysis. We found no statistically significant association between stroke and either the total or maximal unilateral ICAS for all patients (p = 0.13 and p = 0.39, respectively) or those undergoing TAVR (p = 0.27 and p = 0.63, respectively) or SAVR (p = 0.21 and p = 0.36, respectively). CONCLUSIONS: We found no statistically significant association between ICAS severity procedure-related stroke after aortic valve replacement. This suggests that universal carotid Doppler screening before isolated TAVR or SAVR is unnecessary.

Rationale and design of the Randomized Evaluation of patients with Stable angina Comparing Utilization of noninvasive Examinations (RESCUE) trial.

RESCUE is a phase III, randomized, controlled, multicenter, comparative efficacy study, designed to compare two diagnostic imaging/treatment paradigms that use coronary computed tomography angiography (CCTA) or single photon emission computed tomography myocardial perfusion imaging (SPECT MPI) for assisting in the diagnosis of ischemic heart disease in patients with stable angina symptoms, and guiding subsequent treatment. The study is based on the hypothesis that CCTA as a diagnostic tool is associated with no increase in cardiac risk, decreased cost, and reduced radiation exposure compared with SPECT MPI. The RESCUE trial was funded by the Agency for Healthcare Research and Quality (AHRQ) and the American College of Radiology Imaging Network (ACRIN) Fund for Imaging Innovation, began in 2011, and completed in 2014.

Does a Higher Society of Thoracic Surgeons Score Predict Outcomes in Transfemoral and Alternative Access Transcatheter Aortic Valve Replacement?

BACKGROUND: Nontransfemoral (non-TF) transcatheter aortic valve replacement (TAVR) is often associated with worse outcomes than TF TAVR. We investigated the relationship between increasing Society of Thoracic Surgeons (STS) predicted risk of mortality (PROM) score and observed mortality and morbidity in TF and non-TF TAVR groups. METHODS: We reviewed 595 patients undergoing TAVR at Emory Healthcare between 2007 and 2014. Clinical outcomes were reported for 337 TF patients (57%) and 258 non-TF patients (43%). We created 3 STS PROM score subgroups: <8%, 8%-15%, and >15%. A composite outcome of postoperative events was defined as death, stroke, renal failure, vascular complications, or new pacemaker implantation. RESULTS: TF patients were older (82.4 ± 8.0 vs 80.8 ± 8.7 years, p = 0.02), whereas the STS PROM was higher in non-TF patients (10.5% ± 5.3% vs 11.7% ± 5.7%, p = 0.01). Observed/expected mortality was less than 1.0 in all groups. The rate of the composite outcome did not differ between STS PROM subgroups in TF (p = 0.68) or non-TF TAVR (p = 0.27). One-year mortality was higher for patients with STS PROM >8% in the non-TF group; however, this difference was not observed in TF patients (p = 0.40). CONCLUSIONS: As expected, non-TF patients were at a higher risk than TF patients for procedural morbidity and death. Although no differences were observed in 30-day deaths or morbidity in different STS PROM subgroups, those undergoing non-TF TAVR at a higher STS PROM (>8%) had higher 1-year mortality. When applicable, TF TAVR remains the procedure of choice in high- or extreme-risk patients undergoing TAVR.