Faculty Bibliography

BACKGROUND:Guideline-directed medical therapy (GDMT) with multiple risk factor goals is recommended for patients with chronic coronary disease (CCD), yet achieving all GDMT goals is uncommon. The relative importance of these goals and timing of their attainment on cardiovascular events is uncertain. OBJECTIVES/OBJECTIVE:This study aims to describe the relationship between achieving specific GDMT goals, when they are achieved, and clinical outcomes. METHODS:This was an observational study of participants with CCD in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. The primary outcome was cardiovascular (CV) death or myocardial infarction (MI). GDMT goals were systolic blood pressure (SBP) <130 mm Hg, low-density lipoprotein cholesterol <70 mg/dL, not smoking, and antiplatelet therapy. Frequency of GDMT goals met at baseline and during follow-up is described. Bayesian joint modeling for longitudinal goal status and time-to-event analyses characterized the relative importance of specific GDMT goal attainment and timing with CV death/MI. RESULTS:All 5,179 ISCHEMIA participants were included. Among 4,914 participants with complete data on all 4 GDMT goals at baseline, 386 (9%), 2,073 (42%), 1,843 (38%), and 612 (12%) met 0-1, 2, 3, and 4 GDMT goals, respectively. The 4-year cumulative event rate for CV death/MI was highest for participants who attained no GDMT goals (24.5%; 95% credible interval [CrI]: 13.5%-42.2%) and lowest for those who attained all goals at baseline and remained at goal during follow-up (8.7%; 95% CrI: 6.7%-10.9%). SBP goal attainment was associated with a significant absolute event reduction in CV death/MI (-5.1%; 95% CrI: -11.3% to -1.0%), followed by antiplatelet therapy (-11.2%; 95% CrI: -29.1% to 0.8%), achieving low-density lipoprotein cholesterol <70 mg/dL (-2.0%; 95% CrI: -6.0% to 2.4%), and not smoking (-1.7%; 95% CrI: -9.3% to 4.2%). Ten millimeters of mercury lower SBP during follow-up was associated with 10% relative risk reduction of CV death/MI (RR [relative risk] = 0.90; 95% CrI: 0.82-0.98), after adjusting for other GDMT goals and baseline characteristics. CONCLUSIONS:Among participants with CCD, early attainment and maintenance of GDMT goals, especially SBP, were associated with fewer cardiovascular events. Compared with no GDMT goals at target, having all 4 GDMT goals at target at baseline was associated with an absolute 16% fewer CV deaths and MIs. (ISCHEMIA [International Study of Comparative Health Effectiveness With Medical and Invasive Approaches]; NCT01471522).

BACKGROUND:Guideline-directed medical therapy (GDMT) with multiple risk factor goals is recommended for patients with chronic coronary disease (CCD), yet achieving all GDMT goals is uncommon. The relative importance of these goals and timing of their attainment on cardiovascular events is uncertain. OBJECTIVES/OBJECTIVE:This study aims to describe the relationship between achieving specific GDMT goals, when they are achieved, and clinical outcomes. METHODS:This was an observational study of participants with CCD in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. The primary outcome was cardiovascular (CV) death or myocardial infarction (MI). GDMT goals were systolic blood pressure (SBP) <130 mm Hg, low-density lipoprotein cholesterol <70 mg/dL, not smoking, and antiplatelet therapy. Frequency of GDMT goals met at baseline and during follow-up is described. Bayesian joint modeling for longitudinal goal status and time-to-event analyses characterized the relative importance of specific GDMT goal attainment and timing with CV death/MI. RESULTS:All 5,179 ISCHEMIA participants were included. Among 4,914 participants with complete data on all 4 GDMT goals at baseline, 386 (9%), 2,073 (42%), 1,843 (38%), and 612 (12%) met 0-1, 2, 3, and 4 GDMT goals, respectively. The 4-year cumulative event rate for CV death/MI was highest for participants who attained no GDMT goals (24.5%; 95% credible interval [CrI]: 13.5%-42.2%) and lowest for those who attained all goals at baseline and remained at goal during follow-up (8.7%; 95% CrI: 6.7%-10.9%). SBP goal attainment was associated with a significant absolute event reduction in CV death/MI (-5.1%; 95% CrI: -11.3% to -1.0%), followed by antiplatelet therapy (-11.2%; 95% CrI: -29.1% to 0.8%), achieving low-density lipoprotein cholesterol <70 mg/dL (-2.0%; 95% CrI: -6.0% to 2.4%), and not smoking (-1.7%; 95% CrI: -9.3% to 4.2%). Ten millimeters of mercury lower SBP during follow-up was associated with 10% relative risk reduction of CV death/MI (RR [relative risk] = 0.90; 95% CrI: 0.82-0.98), after adjusting for other GDMT goals and baseline characteristics. CONCLUSIONS:Among participants with CCD, early attainment and maintenance of GDMT goals, especially SBP, were associated with fewer cardiovascular events. Compared with no GDMT goals at target, having all 4 GDMT goals at target at baseline was associated with an absolute 16% fewer CV deaths and MIs. (ISCHEMIA [International Study of Comparative Health Effectiveness With Medical and Invasive Approaches]; NCT01471522).

BACKGROUND:Guideline-directed medical therapy (GDMT) with multiple risk factor goals is recommended for patients with chronic coronary disease (CCD), yet achieving all GDMT goals is uncommon. The relative importance of these goals and timing of their attainment on cardiovascular events is uncertain. OBJECTIVES/OBJECTIVE:This study aims to describe the relationship between achieving specific GDMT goals, when they are achieved, and clinical outcomes. METHODS:This was an observational study of participants with CCD in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. The primary outcome was cardiovascular (CV) death or myocardial infarction (MI). GDMT goals were systolic blood pressure (SBP) <130 mm Hg, low-density lipoprotein cholesterol <70 mg/dL, not smoking, and antiplatelet therapy. Frequency of GDMT goals met at baseline and during follow-up is described. Bayesian joint modeling for longitudinal goal status and time-to-event analyses characterized the relative importance of specific GDMT goal attainment and timing with CV death/MI. RESULTS:All 5,179 ISCHEMIA participants were included. Among 4,914 participants with complete data on all 4 GDMT goals at baseline, 386 (9%), 2,073 (42%), 1,843 (38%), and 612 (12%) met 0-1, 2, 3, and 4 GDMT goals, respectively. The 4-year cumulative event rate for CV death/MI was highest for participants who attained no GDMT goals (24.5%; 95% credible interval [CrI]: 13.5%-42.2%) and lowest for those who attained all goals at baseline and remained at goal during follow-up (8.7%; 95% CrI: 6.7%-10.9%). SBP goal attainment was associated with a significant absolute event reduction in CV death/MI (-5.1%; 95% CrI: -11.3% to -1.0%), followed by antiplatelet therapy (-11.2%; 95% CrI: -29.1% to 0.8%), achieving low-density lipoprotein cholesterol <70 mg/dL (-2.0%; 95% CrI: -6.0% to 2.4%), and not smoking (-1.7%; 95% CrI: -9.3% to 4.2%). Ten millimeters of mercury lower SBP during follow-up was associated with 10% relative risk reduction of CV death/MI (RR [relative risk] = 0.90; 95% CrI: 0.82-0.98), after adjusting for other GDMT goals and baseline characteristics. CONCLUSIONS:Among participants with CCD, early attainment and maintenance of GDMT goals, especially SBP, were associated with fewer cardiovascular events. Compared with no GDMT goals at target, having all 4 GDMT goals at target at baseline was associated with an absolute 16% fewer CV deaths and MIs. (ISCHEMIA [International Study of Comparative Health Effectiveness With Medical and Invasive Approaches]; NCT01471522).

BACKGROUND:Guideline-directed medical therapy (GDMT) with multiple risk factor goals is recommended for patients with chronic coronary disease (CCD), yet achieving all GDMT goals is uncommon. The relative importance of these goals and timing of their attainment on cardiovascular events is uncertain. OBJECTIVES/OBJECTIVE:This study aims to describe the relationship between achieving specific GDMT goals, when they are achieved, and clinical outcomes. METHODS:This was an observational study of participants with CCD in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. The primary outcome was cardiovascular (CV) death or myocardial infarction (MI). GDMT goals were systolic blood pressure (SBP) <130 mm Hg, low-density lipoprotein cholesterol <70 mg/dL, not smoking, and antiplatelet therapy. Frequency of GDMT goals met at baseline and during follow-up is described. Bayesian joint modeling for longitudinal goal status and time-to-event analyses characterized the relative importance of specific GDMT goal attainment and timing with CV death/MI. RESULTS:All 5,179 ISCHEMIA participants were included. Among 4,914 participants with complete data on all 4 GDMT goals at baseline, 386 (9%), 2,073 (42%), 1,843 (38%), and 612 (12%) met 0-1, 2, 3, and 4 GDMT goals, respectively. The 4-year cumulative event rate for CV death/MI was highest for participants who attained no GDMT goals (24.5%; 95% credible interval [CrI]: 13.5%-42.2%) and lowest for those who attained all goals at baseline and remained at goal during follow-up (8.7%; 95% CrI: 6.7%-10.9%). SBP goal attainment was associated with a significant absolute event reduction in CV death/MI (-5.1%; 95% CrI: -11.3% to -1.0%), followed by antiplatelet therapy (-11.2%; 95% CrI: -29.1% to 0.8%), achieving low-density lipoprotein cholesterol <70 mg/dL (-2.0%; 95% CrI: -6.0% to 2.4%), and not smoking (-1.7%; 95% CrI: -9.3% to 4.2%). Ten millimeters of mercury lower SBP during follow-up was associated with 10% relative risk reduction of CV death/MI (RR [relative risk] = 0.90; 95% CrI: 0.82-0.98), after adjusting for other GDMT goals and baseline characteristics. CONCLUSIONS:Among participants with CCD, early attainment and maintenance of GDMT goals, especially SBP, were associated with fewer cardiovascular events. Compared with no GDMT goals at target, having all 4 GDMT goals at target at baseline was associated with an absolute 16% fewer CV deaths and MIs. (ISCHEMIA [International Study of Comparative Health Effectiveness With Medical and Invasive Approaches]; NCT01471522).

OBJECTIVE:Patients with peripheral artery disease (PAD) undergo lower extremity revascularization (LER) for symptomatic relief or limb salvage. Despite LER, patients remain at increased risk of platelet-mediated complications, such as major adverse cardiac and limb events (MACLEs). Platelet activity is associated with cardiovascular events, yet little is known about the dynamic nature of platelet activity over time. We, therefore, investigated the change in platelet activity over time and its association with long-term cardiovascular risk. METHODS:Patients with PAD undergoing LER were enrolled into the multicenter, prospective Platelet Activity and Cardiovascular Events study. Platelet aggregation was assessed by light transmission aggregometry to submaximal epinephrine (0.4 μmol/L) immediately before LER, and on postoperative day 1 or 2 (POD1 or POD2) and 30 (POD30). A hyperreactive platelet phenotype was defined as >60% aggregation. Patients were followed longitudinally for MACLEs, defined as the composite of death, myocardial infarction, stroke, major lower extremity amputation, or acute limb ischemia leading to reintervention. RESULTS:Among 287 patients undergoing LER, the mean age was 70 ± 11 years, 33% were female, 61% were White, and 89% were on baseline antiplatelet therapy. Platelet aggregation to submaximal epinephrine induced a bimodal response; 15.5%, 16.8%, and 16.4% of patients demonstrated a hyperreactive platelet phenotype at baseline, POD1, and POD30, respectively. Platelet aggregation increased by 18.5% (P = .001) from baseline to POD1, which subsequently returned to baseline at POD30. After a median follow-up of 19 months, MACLEs occurred in 165 patients (57%). After adjustment for demographics, clinical risk factors, procedure type, and antiplatelet therapy, platelet hyperreactivity at POD1 was associated with a significant hazard of long-term MACLE (adjusted hazard ratio, 4.61; 95% confidence interval, 2.08-10.20; P < .001). CONCLUSIONS:Among patients with severe PAD, platelet activity increases after LER. Platelet hyperreactivity to submaximal epinephrine on POD1 is associated with long-term MACLE. Platelet activity after LER may represent a modifiable biomarker associated with excess cardiovascular risk.

BACKGROUND:Lipoprotein(a) [Lp(a)] is a driver of residual cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) decrease Lp(a) with significant heterogeneity in response. We investigated contributors to the heterogeneous response. METHODS:CHOlesterol Reduction and Residual Risk in Diabetes (CHORD) was a prospective study examining lipid lowering in participants with a low-density lipoprotein cholesterol (LDL-C) >100 mg/dL with and without diabetes (DM) on lipid lowering therapy (LLT) for 30-days with evolocumab 140 mg every 14 days combined with either atorvastatin 80 mg or ezetimibe 10 mg daily. Lp(a) level was measured by immunoturbidometry, and the apolipoprotein (a) [apo(a)] isoform size was measured by denaturing agarose gel electrophoresis and western blotting. We examined the change in Lp(a) levels from baseline to 30 days. RESULTS:Among 150 participants (mean age 50 years, 58% female, 50% non-White, 17% Hispanic, 50% DM), median (interquartile range) Lp(a) was 27.5 (8-75) mg/dL at baseline and 23 (3-68) mg/dL at 30 days, leading to a 10% (0-36) median reduction (P < 0.001). Among 73 (49%) participants with Lp(a) ≥30 mg/dL at baseline, there was a 15% (3-25) median reduction in Lp(a) (P < 0.001). While baseline Lp(a) level was not correlated with change in Lp(a) (r = 0.04, P = 0.59), apo(a) size directly correlated with Lp(a) reduction (P < 0.001). After adjustment for age, sex, race/ethnicity, DM, and type of LLT, apo(a) size remained positively associated with a reduction in Lp(a) (Beta 0.95, 95% confidence interval, 0.93-0.97, P < 0.001). CONCLUSION/CONCLUSIONS:Our data demonstrate variation in Lp(a) reduction with potent LLT. Change in Lp(a) was strongly associated with apo(a) isoform size.

BACKGROUND AND AIMS/OBJECTIVE:The aim of this study was to determine the prognostic value of coronary computed tomography angiography (CCTA)-derived atherosclerotic plaque analysis in ISCHEMIA. METHODS:Atherosclerosis imaging quantitative computed tomography (AI-QCT) was performed on all available baseline CCTAs to quantify plaque volume, composition, and distribution. Multivariable Cox regression was used to examine the association between baseline risk factors (age, sex, smoking, diabetes, hypertension, ejection fraction, prior coronary disease, estimated glomerular filtration rate, and statin use), number of diseased vessels, atherosclerotic plaque characteristics determined by AI-QCT, and a composite primary outcome of cardiovascular death or myocardial infarction over a median follow-up of 3.3 (interquartile range 2.2-4.4) years. The predictive value of plaque quantification over risk factors was compared in an area under the curve (AUC) analysis. RESULTS:Analysable CCTA data were available from 3711 participants (mean age 64 years, 21% female, 79% multivessel coronary artery disease). Amongst the AI-QCT variables, total plaque volume was most strongly associated with the primary outcome (adjusted hazard ratio 1.56, 95% confidence interval 1.25-1.97 per interquartile range increase [559 mm3]; P = .001). The addition of AI-QCT plaque quantification and characterization to baseline risk factors improved the model's predictive value for the primary outcome at 6 months (AUC 0.688 vs. 0.637; P = .006), at 2 years (AUC 0.660 vs. 0.617; P = .003), and at 4 years of follow-up (AUC 0.654 vs. 0.608; P = .002). The findings were similar for the other reported outcomes. CONCLUSIONS:In ISCHEMIA, total plaque volume was associated with cardiovascular death or myocardial infarction. In this highly diseased, high-risk population, enhanced assessment of atherosclerotic burden using AI-QCT-derived measures of plaque volume and composition modestly improved event prediction.

IMPORTANCE/UNASSIGNED:In 2013, the Trial to Assess Chelation Therapy (TACT) reported that edetate disodium (EDTA)-based chelation significantly reduced cardiovascular disease (CVD) events by 18% in 1708 patients with a prior myocardial infarction (MI). OBJECTIVE/UNASSIGNED:To replicate the finding of TACT in individuals with diabetes and previous MI. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:A 2 × 2 factorial, double-masked, placebo-controlled, multicenter trial at 88 sites in the US and Canada, involving participants who were 50 years or older, had diabetes, and had experienced an MI at least 6 weeks before recruitment compared the effect of EDTA-based chelation vs placebo infusions on CVD events and compared the effect of high doses of oral multivitamins and minerals with oral placebo. This article reports on the chelation vs placebo infusion comparisons. INTERVENTIONS/UNASSIGNED:Eligible participants were randomly assigned to 40 weekly infusions of an EDTA-based chelation solution or matching placebo and to twice daily oral, high-dose multivitamin and mineral supplements or matching placebo for 60 months. This article addresses the chelation study. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary end point was the composite of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina. Median follow-up was 48 months. Primary comparisons were made from patients who received at least 1 assigned infusion. RESULTS/UNASSIGNED:Of the 959 participants (median age, 67 years [IQR, 60-72 years]; 27% females; 78% White, 10% Black, and 20% Hispanic), 483 received at least 1 chelation infusion and 476 at least 1 placebo infusion. A primary end point event occurred in 172 participants (35.6%) in the chelation group and in 170 (35.7%) in the placebo group (adjusted hazard ratio [HR], 0.93; 95% CI, 0.76-1.16; P = .53). The 5-year primary event cumulative incidence rates were 45.8% for the chelation group and 46.5% for the placebo group. CV death, MI, or stroke events occurred in 89 participants (18.4%) in the chelation group and in 94 (19.7%) in the placebo group (adjusted HR, 0.89; 95% CI, 0.66-1.19). Death from any cause occurred in 84 participants (17.4%) in the chelation group and in 84 (17.6%) in the placebo group (adjusted HR, 0.96; 95% CI, 0.71-1.30). Chelation reduced median blood lead levels from 9.03 μg/L at baseline to 3.46 μg/L at infusion 40 (P < .001). Corresponding levels in the placebo group were 9.3 μg/L and 8.7 μg/L, respectively. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Despite effectively reducing blood lead levels, EDTA chelation was not effective in reducing cardiovascular events in stable patients with coronary artery disease who have diabetes and a history of MI. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT02733185.

Platelets are key mediators of atherothrombosis, yet, limited tools exist to identify individuals with a hyperreactive platelet phenotype. In this study, we investigate the association of platelet hyperreactivity and cardiovascular events, and introduce a tool, the Platelet Reactivity ExpreSsion Score (PRESS), which integrates platelet aggregation responses and RNA sequencing. Among patients with peripheral artery disease (PAD), those with a hyperreactive platelet response (>60% aggregation) to 0.4 µM epinephrine had a higher incidence of the 30 day primary cardiovascular endpoint (37.2% vs. 15.3% in those without hyperreactivity, adjusted HR 2.76, 95% CI 1.5-5.1, p = 0.002). PRESS performs well in identifying a hyperreactive phenotype in patients with PAD (AUC [cross-validation] 0.81, 95% CI 0.68 -0.94, n = 84) and in an independent cohort of healthy participants (AUC [validation] 0.77, 95% CI 0.75 -0.79, n = 35). Following multivariable adjustment, PAD individuals with a PRESS score above the median are at higher risk for a future cardiovascular event (adjusted HR 1.90, CI 1.07-3.36; p = 0.027, n = 129, NCT02106429). This study derives and validates the ability of PRESS to discriminate platelet hyperreactivity and identify those at increased cardiovascular risk. Future studies in a larger independent cohort are warranted for further validation. The development of a platelet reactivity expression score opens the possibility for a personalized approach to antithrombotic therapy for cardiovascular risk reduction.