Faculty Bibliography

PURPOSE OF REVIEW: Stable ischemic heart disease (SIHD) is a highly prevalent condition associated with increased costs, morbidity, and mortality. Management goals of SIHD can broadly be thought of in terms of improving prognosis and/or improving symptoms. Treatment options include medical therapy as well as revascularization, either with percutaneous coronary intervention or coronary artery bypass grafting. Herein, we will review the current evidence base for treatment of SIHD as well as its challenges and discuss ongoing studies to help address some of these knowledge gaps. RECENT FINDINGS: There has been no consistent reduction in death or myocardial infarction (MI) with revascularization vs. medical therapy in patients with SIHD in contemporary trials. Angina and quality of life have been shown to be relieved more rapidly with revascularization vs. optimal medical therapy; however, the durability of these results is uncertain. There have been challenges and limitations in several of the trials addressing the optimal treatment strategy for SIHD due to potential selection bias (due to knowledge of coronary anatomy prior to randomization), patient crossover, and advances in medical therapy and revascularization strategies since trial completion. The challenges inherent to prior trials addressing the optimal management strategy for SIHD have impacted the generalizability of results to real-world cohorts. Until the results of additional ongoing trials are available, the decision for revascularization or medical therapy should be based on patients' symptoms, weighing the risks and benefits of each approach, and patient preference.

BACKGROUND: The 2014 Eighth Joint National Committee panel recommended a therapeutic target of systolic blood pressure (BP) <150 mm Hg in patients >/=60 years of age, a departure from prior recommendation of <140 mm Hg. OBJECTIVES: This study assessed the efficacy and safety of intensive BP-lowering strategies in older (age >/=65 years) hypertensive patients. METHODS: The MEDLINE, Scopus, EMBASE, and Cochrane databases were searched for all relevant randomized controlled trials from 1965 through July 1, 2016. Cardiovascular (major adverse cardiovascular events [MACE], cardiovascular mortality, stroke, myocardial infarction, and heart failure), and safety (serious adverse events and renal failure) were evaluated. Random and fixed effects analysis were used to calculate pooled relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: We identified 4 high-quality trials involving 10,857 older hypertensive patients with a mean follow-up of 3.1 years. Intensive BP lowering was associated with a 29% reduction in MACE (RR: 0.71; 95% CI: 0.60 to 0.84), 33% in cardiovascular mortality (RR: 0.67; 95% CI: 0.45 to 0.98), and 37% in heart failure (RR: 0.63; 95% CI: 0.43 to 0.99) compared with standard BP lowering. Rates of myocardial infarction and stroke did not differ between the 2 groups. There was no significant difference in the incidence of serious adverse events (RR: 1.02; 95% CI: 0.94 to 1.09) or renal failure (RR: 1.81; 95% CI: 0.86 to 3.80) between the 2 groups. The fixed effects model yielded largely similar results, except for an increase in the risk of renal failure (RR: 2.03; 95% CI: 1.30 to 3.18) with intensive BP-lowering therapy. CONCLUSIONS: In older hypertensive patients, intensive BP control (systolic BP <140 mm Hg) decreased MACE, including cardiovascular mortality and heart failure. Data on adverse events were limited, but suggested an increased risk of renal failure. When considering intensive BP control, clinicians should carefully weigh benefits against potential risks.

BACKGROUND: The optimal blood pressure (BP) target has been a matter of debate. The recent SPRINT trial showed significant benefits of a BP target of <120 mm Hg albeit with an increase in serious adverse effects related to low BP. METHODS: PUBMED, EMBASE, and CENTRAL were searched for randomized trials comparing treating to different BP targets. Trial arms were grouped into five systolic BP target categories: 1) <160 mm Hg; 2) <150 mm Hg; 3) <140 mm Hg; 4) <130 mm Hg and 5) <120 mm Hg. Efficacy outcomes of stroke, myocardial infarction, death, cardiovascular death, heart failure and safety outcomes of serious adverse effects were evaluated using a network meta-analysis. RESULTS: Seventeen trials that enrolled 55,163 patients with 204,103 patient-years of follow-up were included. There was a significant decrease in stroke (RR=0.54; 95% CI 0.29-1.00) and myocardial infarction (RR=0.68; 95% CI 0.47-1.00) with systolic BP <120 mm Hg (vs. <160 mm Hg). Sensitivity analysis using achieved systolic BP showed a 72%, 97% and 227% increase in stroke with systolic BP of <140 mm Hg, <150 mm Hg and <160 mm respectively, when compared with systolic BP <120 mm Hg. There was no difference in death, cardiovascular death or heart failure when comparing any of the BP targets. However, the point estimate favored lower BP targets (<120 mm Hg, <130 mm Hg) when compared with higher BP targets (<140 mm Hg or <150 mm Hg). BP targets of <120 mm Hg and <130 mm Hg ranked #1 and #2 respectively, as the most efficacious target. There was a significant increase in serious adverse effects with systolic BP <120 mm Hg vs. <150 mm Hg (RR=1.83; 95% CI 1.05-3.20) or vs. <140 mm Hg (RR=2.12; 95% CI 1.46-3.08). BP targets of <140 mm Hg and <150 mm Hg ranked #1 and #2 respectively, as the safest target for the outcome of serious adverse effects. Cluster plots for combined efficacy and safety showed that a systolic BP target of <130 mm Hg had optimal balance between efficacy and safety. CONCLUSIONS: In patients with hypertension, a systolic BP target of <130 mm Hg achieved optimal balance between efficacy and safety.

OBJECTIVE: To critically evaluate the efficacy of renin angiotensin system inhibitors (RASi) in patients with coronary artery disease without heart failure, compared with active controls or placebo. DESIGN: Meta-analysis of randomized trials. DATA SOURCES: PubMed, EMBASE, and CENTRAL databases until 1 May 2016. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomized trials of RASi versus placebo or active controls in patients with stable coronary artery disease without heart failure (defined as left ventricular ejection fraction >/=40% or without clinical heart failure). Each trial had to enroll at least 100 patients with coronary artery disease without heart failure, with at least one year's follow-up. Studies were excluded if they were redacted or compared use of angiotensin converting enzyme inhibitors with angiotensin receptor blockers. Outcomes were death, cardiovascular death, myocardial infarction, angina, stroke, heart failure, revascularization, incident diabetes, and drug withdrawal due to adverse effects. RESULTS: 24 trials with 198 275 patient years of follow-up were included. RASi reduced the risk of all cause mortality (rate ratio 0.84, 95% confidence interval 0.72 to 0.98), cardiovascular mortality (0.74, 0.59 to 0.94), myocardial infarction (0.82, 0.76 to 0.88), stroke (0.79, 0.70 to 0.89), angina, heart failure, and revascularization when compared with placebo but not when compared with active controls (all cause mortality, 1.05, 0.94 to 1.17; Pinteraction=0.006; cardiovascular mortality, 1.08, 0.93 to 1.25, Pinteraction<0.001; myocardial infarction, 0.99, 0.87 to 1.12, Pinteraction=0.01; stroke, 1.10, 0.93 to 1.31; Pinteraction=0.002). Bayesian meta-regression analysis showed that the effect of RASi when compared with placebo on all cause mortality and cardiovascular mortality was dependent on the control event rate, such that RASi was only beneficial in trials with high control event rates (>14.10 deaths and >7.65 cardiovascular deaths per 1000 patient years) but not in those with low control event rates. CONCLUSIONS: In patients with stable coronary artery disease without heart failure, RASi reduced cardiovascular events and death only when compared with placebo but not when compared with active controls. Even among placebo controlled trials in this study, the benefit of RASi was mainly seen in trials with higher control event rates but not in those with lower control event rates. Evidence does not support a preferred status of RASi over other active controls.

BACKGROUND: Emergent myocardial reperfusion via primary percutaneous coronary intervention is optimal care for patients presenting with ST-segment elevation myocardial infarction (STEMI). Delays in such interventions are associated with increases in mortality. With the shift in focus to contact-to-device (C2D) time as a new perfusion metric, this study was designed to examine how sex affects C2D time and mortality in STEMI patients. METHODS AND RESULTS: Clinical data on male and female STEMI patients were extracted and analyzed from the National Cardiovascular Data Registry from July 1, 2008 to December 31, 2014. A total of 102 515 patients were included in the final analytic cohort. The median C2D time in female patients with STEMI was delayed when compared to male patients (80 [65-97] versus 75 [61-90] minutes; P<0.001). The unadjusted mortality was higher in female patients when compared to male patients with STEMI (4.1% versus 2.0%; P<0.001). For every 5-minute increase in C2D time, the adjusted odds ratio for mortality was 1.04 (95% CI, 1.03-1.06) for female patients with STEMI and 1.07 (95% CI, 1.06-1.09) for male patients (P for sex by C2D interaction=0.003). CONCLUSIONS: To date, this is the largest analysis of STEMI patients that measures the impact of the new recommended C2D reperfusion metric on in-hospital mortality. Female STEMI patients have longer C2D times and increased mortality. The disparity can be improved and survival can increase in this high-risk patient cohort by decreasing systems issues that cause increased reperfusion times in female STEMI patients.

Patients with chronic kidney disease (CKD) have a high prevalence of atherosclerotic cardiovascular disease, likely reflecting the presence of traditional risk factors. A greater distinguishing feature of atherosclerotic cardiovascular disease in CKD is the severity of the disease, which is reflective of an increase in inflammatory mediators and vascular calcification secondary to hyperparathyroidism of renal origin that are unique to patients with CKD. Additional components of atherosclerotic cardiovascular disease that are prominent in patients with CKD include microvascular disease and myocardial fibrosis. Therapeutic interventions that minimize cardiovascular events related to atherosclerotic cardiovascular disease in patients with CKD, as determined by well-designed clinical trials, are limited to statins. Data are lacking regarding other available therapeutic measures primarily due to exclusion of patients with CKD from major trials studying cardiovascular disease. Data from well-designed randomized controlled trials are needed to guide clinicians who care for this high-risk population in the management of atherosclerotic cardiovascular disease to improve clinical outcomes.

Importance: Major adverse cardiovascular and cerebrovascular events (MACCE) are a significant source of perioperative morbidity and mortality following noncardiac surgery. Objective: To evaluate national trends in perioperative cardiovascular outcomes and mortality after major noncardiac surgery and to identify surgical subtypes associated with cardiovascular events using a large administrative database of United States hospital admissions. Design, Setting, Participants: Patients who underwent major noncardiac surgery from January 2004 to December 2013 were identified using the National Inpatient Sample. Main Outcomes and Measures: Perioperative MACCE (primary outcome), defined as in-hospital, all-cause death, acute myocardial infarction (AMI), or acute ischemic stroke, were evaluated over time. Results: Among 10581621 hospitalizations (mean [SD] patient age, 65.74 [12.32] years; 5975798 female patients 56.60%]) for major noncardiac surgery, perioperative MACCE occurred in 317479 hospitalizations (3.0%), corresponding to an annual incidence of approximately 150000 events after applying sample weights. Major adverse cardiovascular and cerebrovascular events occurred most frequently in patients undergoing vascular (7.7%), thoracic (6.5%), and transplant surgery (6.3%). Between 2004 and 2013, the frequency of MACCE declined from 3.1% to 2.6% (P for trend <.001; adjusted odds ratio [aOR], 0.95; 95% CI, 0.94-0.97) driven by a decline in frequency of perioperative death (aOR, 0.79; 95% CI, 0.77-0.81) and AMI (aOR, 0.87; 95% CI, 0.84-0.89) but an increase in perioperative ischemic stroke from 0.52% in 2004 to 0.77% in 2013 (P for trend <.001; aOR 1.79; CI 1.73-1.86). Conclusions and Relevance: Perioperative MACCE occurs in 1 of every 33 hospitalizations for noncardiac surgery. Despite reductions in the rate of death and AMI among patients undergoing major noncardiac surgery in the United States, perioperative ischemic stroke increased over time. Additional efforts are necessary to improve cardiovascular care in the perioperative period of patients undergoing noncardiac surgery.

In patients with previous myocardial infarction (MI), aggressive hypertension control and low-density lipoprotein cholesterol (LDL-C) reduction are important secondary prevention measures. However, residual risk remains despite aggressive treatment. Whether variability in blood pressure (BP) and LDL-C can explain this residual risk is not known. Patients enrolled in the Incremental Decrease in End Points Through Aggressive Lipid-Lowering trial with at least 1 post-baseline measurement of LDL-C and blood pressure (BP) were included. Visit-to-visit LDL-C and BP variabilities were evaluated using various measures of variability. Primary outcome was any coronary event with the secondary outcomes of any cardiovascular event (CV), MI, stroke, death, and CV death. Among the 8,658 patients included, each 1-SD (10.8 mg/dl) increase in LDL-C variability increased the risk of any coronary event (adjusted HR [HRadj] 1.07; 95% CI 1.04 to 1.11; p <0.0001), any CV event, MI, and death (HRadj 1.19; 95% CI 1.14 to 1.25; p <0.0001). Similarly, each 1-SD (7.2 mm Hg) increase in systolic BP variability increased the risk of any coronary event (HRadj 1.15; 95% CI 1.10 to 1.20; p <0.0001), any CV event, MI, stroke, death (HRadj 1.28; 95% CI 1.18 to 1.38; p <0.0001), and CV death. Compared with the group with low variability for both LDL-C and systolic BP, the group with high variability for both had a significant increase in any coronary event (HRadj 1.48; 95% CI 1.30 to 1.70), any CV event (HRadj 1.43; 95% CI 1.27 to 1.61), and MI (HRadj 1.87; 95% CI 1.46 to 2.41). In conclusions, in patients with a history of MI, variabilities in LDL-C and BP are powerful and independent predictors of CV events including death.

BACKGROUND: Although hypertension guidelines define treatment resistant hypertension as blood pressure uncontrolled by >/=3 antihypertensive medications, including a diuretic, it is unknown whether patient prognosis differs when a diuretic is included. METHODS: Participants in the Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trial were randomly assigned to first-step therapy with chlorthalidone, amlodipine, or lisinopril. At a Year 2 follow-up visit, those with average BP>/=140 mmHg systolic or >/=90 mmHg diastolic on >/=3 antihypertensive medications, or BP<140/90 mmHg on >/=4 antihypertensive medications, were identified as having apparent treatment resistant hypertension. The prevalence of treatment resistant hypertension and its association with ALLHAT primary (combined fatal coronary heart disease or nonfatal myocardial infarction) and secondary (all-cause mortality, stroke, heart failure, combined coronary heart disease, and combined cardiovascular disease) outcomes were identified for each treatment group. RESULTS: Of participants assigned to chlorthalidone, amlodipine and lisinopril, 9.6%, 11.4% and 19.7%, respectively, had treatment resistant hypertension. During mean follow-up of 2.9 years, primary outcome incidence was similar for those assigned to chlorthalidone compared to amlodipine or lisinopril (amlodipine vs. chlorthalidone adjusted HR=0.86; 95% CI 0.53-1.39; P=0.53; lisinopril vs. chlorthalidone adjusted HR=1.06; 95% CI 0.70-1.60; P=0.78). Secondary outcome risks were similar for most comparisons except coronary revascularization, which was higher with amlodipine than with chlorthalidone (HR=1.86; 95% CI 1.11-3.11; P=0.02). An as-treated analysis based on diuretic use produced similar results. CONCLUSIONS: In this study, which titrated medications to a goal, participants assigned to chlorthalidone were less likely to develop treatment resistant hypertension. However, prognoses in those with treatment resistant hypertension were similar across treatment groups. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, NCT00000542.