2022 ACC/AHA guideline for the diagnosis and management of aortic disease: A report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines.

AIM: The "2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease" provides recommendations to guide clinicians in the diagnosis, genetic evaluation and family screening, medical therapy, endovascular and surgical treatment, and long-term surveillance of patients with aortic disease across its multiple clinical presentation subsets (ie, asymptomatic, stable symptomatic, and acute aortic syndromes). METHODS: A comprehensive literature search was conducted from January 2021 to April 2021, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, CINHL Complete, and other selected databases relevant to this guideline. Additional relevant studies, published through June 2022 during the guideline writing process, were also considered by the writing committee, where appropriate. STRUCTURE: Recommendations from previously published AHA/ACC guidelines on thoracic aortic disease, peripheral artery disease, and bicuspid aortic valve disease have been updated with new evidence to guide clinicians. In addition, new recommendations addressing comprehensive care for patients with aortic disease have been developed. There is added emphasis on the role of shared decision making, especially in the management of patients with aortic disease both before and during pregnancy. The is also an increased emphasis on the importance of institutional interventional volume and multidisciplinary aortic team expertise in the care of patients with aortic disease.

Acute outcomes for the full US cohort of the FLASH mechanical thrombectomy registry in pulmonary embolism.

BACKGROUND: Evidence supporting interventional pulmonary embolism (PE) treatment is needed. AIMS: We aimed to evaluate the acute safety and effectiveness of mechanical thrombectomy for intermediate- and high-risk PE in a large real-world population. METHODS: FLASH is a multicentre, prospective registry enrolling up to 1,000 US and European PE patients treated with mechanical thrombectomy using the FlowTriever System. The primary safety endpoint is a major adverse event composite including device-related death and major bleeding at 48 hours, and intraprocedural adverse events. Acute mortality and 48-hour outcomes are reported. Multivariate regression analysed characteristics associated with pulmonary artery pressure and dyspnoea improvement. RESULTS: Among 800 patients in the full US cohort, 76.7% had intermediate-high risk PE, 7.9% had high-risk PE, and 32.1% had thrombolytic contraindications. Major adverse events occurred in 1.8% of patients. All-cause mortality was 0.3% at 48-hour follow-up and 0.8% at 30-day follow-up, with no device-related deaths. Immediate haemodynamic improvements included a 7.6 mmHg mean drop in mean pulmonary artery pressure (-23.0%; p<0.0001) and a 0.3 L/min/m2 mean increase in cardiac index (18.9%; p<0.0001) in patients with depressed baseline values. Most patients (62.6%) had no overnight intensive care unit stay post-procedure. At 48 hours, the echocardiographic right ventricle/left ventricle ratio decreased from 1.23±0.36 to 0.98±0.31 (p<0.0001 for paired values) and patients with severe dyspnoea decreased from 66.5% to 15.6% (p<0.0001).  Conclusions: Mechanical thrombectomy with the FlowTriever System demonstrates a favourable safety profile, improvements in haemodynamics and functional outcomes, and low 30-day mortality for intermediate- and high-risk PE.

2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines.

AIM: The "2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease" provides recommendations to guide clinicians in the diagnosis, genetic evaluation and family screening, medical therapy, endovascular and surgical treatment, and long-term surveillance of patients with aortic disease across its multiple clinical presentation subsets (ie, asymptomatic, stable symptomatic, and acute aortic syndromes). METHODS: A comprehensive literature search was conducted from January 2021 to April 2021, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, CINHL Complete, and other selected databases relevant to this guideline. Additional relevant studies, published through June 2022 during the guideline writing process, were also considered by the writing committee, where appropriate. Structure: Recommendations from previously published AHA/ACC guidelines on thoracic aortic disease, peripheral artery disease, and bicuspid aortic valve disease have been updated with new evidence to guide clinicians. In addition, new recommendations addressing comprehensive care for patients with aortic disease have been developed. There is added emphasis on the role of shared decision making, especially in the management of patients with aortic disease both before and during pregnancy. The is also an increased emphasis on the importance of institutional interventional volume and multidisciplinary aortic team expertise in the care of patients with aortic disease.

2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines.

AIM: The "2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease" provides recommendations to guide clinicians in the diagnosis, genetic evaluation and family screening, medical therapy, endovascular and surgical treatment, and long-term surveillance of patients with aortic disease across its multiple clinical presentation subsets (ie, asymptomatic, stable symptomatic, and acute aortic syndromes). METHODS: A comprehensive literature search was conducted from January 2021 to April 2021, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, CINHL Complete, and other selected databases relevant to this guideline. Additional relevant studies, published through June 2022 during the guideline writing process, were also considered by the writing committee, where appropriate. STRUCTURE: Recommendations from previously published AHA/ACC guidelines on thoracic aortic disease, peripheral artery disease, and bicuspid aortic valve disease have been updated with new evidence to guide clinicians. In addition, new recommendations addressing comprehensive care for patients with aortic disease have been developed. There is added emphasis on the role of shared decision making, especially in the management of patients with aortic disease both before and during pregnancy. The is also an increased emphasis on the importance of institutional interventional volume and multidisciplinary aortic team expertise in the care of patients with aortic disease.

Moderate Versus Deep Hypothermia in Type A Acute Aortic Dissection Repair: Insights from the International Registry of Acute Aortic Dissection.

BACKGROUND: The optimal strategy for cerebral protection during repair of type A acute aortic dissection has yet to be determined. We sought to determine the impact of differing degrees of hypothermia in patients undergoing acute dissection repair. METHODS: All patients in the International Registry of Acute Aortic Dissection Interventional Cohort database who underwent type A acute aortic dissection repair between 2010 and 2018 were identified. Data for operative temperature were available for 1962 patients subsequently divided into 2 groups according to lowest temperature: moderate hypothermic circulatory arrest (MHCA) (20-28°C) versus deep hypothermic circulatory arrest (DHCA) (<20°C). We then propensity matched 362 pairs of patients and analyzed operative data and short-term outcomes. RESULTS: The median lowest temperature was 25.0°C in the matched MHCA group as compared with 18.0°C in the DHCA group. For the entire cohort of 1962 patients, in-hospital mortality was 14.2% (278 deaths) but was not significantly different between DHCA and MHCA. The perioperative stroke rate was comparable between groups, before and after propensity matching. Circulatory arrest times were significantly longer in the MHCA cohort, regardless of matching. Use of antegrade or retrograde cerebral perfusion was similar in matched groups. There were no differences in 30-day survival or in other major postoperative morbidity between the 2 matched cohorts. CONCLUSIONS: A surgical strategy of MHCA + antegrade cerebral perfusion is at least as safe as DHCA during repair of acute type A aortic dissection.

Clinical Features and Outcomes of Pregnancy-Related Acute Aortic Dissection.

Importance: Women with aortopathy conditions are at risk for pregnancy-related aortic dissection, and these conditions may not be recognized until after the aortic dissection occurs. Objective: To examine the clinical characteristics, imaging features, and outcomes in women with pregnancy-related acute aortic dissection. Design, Setting, and Participants: A cohort study, comprising data from the International Registry of Acute Aortic Dissection (IRAD) (February 1, 1998, to February 28, 2018). The multicenter referral center study included 29 women with aortic dissection during pregnancy or less than 12 weeks post partum in IRAD from 1998 to 2018. Main Outcomes and Measures: Clinical features of pregnancy-related aortic dissection to be studied included underlying aortopathy, aortic size, type of aortic dissection, timing of dissection, hypertension, and previous aortic surgery. Results: A total of 29 women (mean [SD] age, 32 [6] years) had pregnancy-related aortic dissection, representing 0.3% of all aortic dissections and 1% of aortic dissection in women in the IRAD. Among women younger than 35 years, aortic dissection was related to pregnancy in 20 of 105 women (19%). Thirteen women (45%) had type A aortic dissection, and 16 women (55%) had type B. Aortic dissection onset was known in 27 women (93%): 15 during pregnancy, 4 in the first trimester, and 11 in the third trimester; 12 were post partum, occurring a mean (SD) of 12.5 (14) days post partum. At type A aortic dissection diagnosis, the mean (SD) aortic diameters were sinus of Valsalva, 54.5 (5) mm and ascending aorta, 54.7 (6) mm. At type B aortic dissection diagnosis, the mean (SD) descending aortic diameter was 32.5 (5) mm. Twenty women (69%) had an aortopathy condition or a positive family history: 13 women (65%) with Marfan syndrome, 2 women (10%) with Loeys-Dietz syndrome, 2 women (10%) with bicuspid aortic valves, 2 women (10%) with a family history of aortic disease, and 1 woman (5%) with familial thoracic aortic aneurysm. Aortopathy was not recognized until after aortic dissection in 47% of the women. Twenty-eight women (97%) survived aortic dissection hospitalization. Conclusions and Relevance: Aortic dissection complicating pregnancy is rare. Most pregnancy-related aortic dissection is due to an aortopathy often not diagnosed until after aortic dissection. In this study, type A aortic dissections were associated with a dilated aorta, and type B aortic dissections often were not. Recognition of underlying conditions and risks for aortic dissection may improve management of pregnancy in women with aortopathy.

Incident Heart Failure and Long-Term Risk for Venous Thromboembolism.

BACKGROUND: Heart failure (HF) hospitalization places patients at increased short-term risk for venous thromboembolism (VTE). Long-term risk for VTE associated with incident HF, HF subtypes, or structural heart disease is unknown. OBJECTIVES: In the ARIC (Atherosclerosis Risk In Communities) cohort, VTE risk associated with incident HF, HF subtypes, and abnormal echocardiographic measures in the absence of clinical HF was assessed. METHODS: During follow-up, ARIC identified incident HF and subcategorized HF with preserved ejection fraction or reduced ejection fraction. At the fifth clinical examination, echocardiography was performed. Physicians adjudicated incident VTE using hospital records. Adjusted Cox proportional hazards models were used to evaluate the association between HF or echocardiographic exposures and VTE. RESULTS: Over a mean of 22 years in 13,728 subjects, of whom 2,696 (20%) developed incident HF, 729 subsequent VTE events were identified. HF was associated with increased long-term risk for VTE (adjusted hazard ratio: 3.13; 95% confidence interval: 2.58 to 3.80). In 7,588 subjects followed for a mean of 10 years, the risk for VTE was similar for HF with preserved ejection fraction (adjusted hazard ratio: 4.71; 95% CI: 2.94 to 7.52) and HF with reduced ejection fraction (adjusted hazard ratio: 5.53; 95% confidence interval: 3.42 to 8.94). In 5,438 subjects without HF followed for a mean of 3.5 years, left ventricular relative wall thickness and mean left ventricular wall thickness were independent predictors of VTE. CONCLUSIONS: In this prospective population-based study, incident hospitalized HF (including both heart failure with preserved ejection fraction and reduced ejection fraction), as well as echocardiographic indicators of left ventricular remodeling, were associated with greatly increased risk for VTE, which persisted through long-term follow-up. Evidence-based strategies to prevent long-term VTE in patients with HF, beyond time of hospitalization, are needed.

Diagnosis, Treatment and Follow Up of Acute Pulmonary Embolism: Consensus Practice from the PERT Consortium.

Pulmonary embolism (PE) is a life-threatening condition and a leading cause of morbidity and mortality. There have been many advances in the field of PE in the last few years, requiring a careful assessment of their impact on patient care. However, variations in recommendations by different clinical guidelines, as well as lack of robust clinical trials, make clinical decisions challenging. The Pulmonary Embolism Response Team Consortium is an international association created to advance the diagnosis, treatment, and outcomes of patients with PE. In this consensus practice document, we provide a comprehensive review of the diagnosis, treatment, and follow-up of acute PE, including both clinical data and consensus opinion to provide guidance for clinicians caring for these patients.

Decreased mortality with local versus general anesthesia in endovascular aneurysm repair for ruptured abdominal aortic aneurysm in the Vascular Quality Initiative database.

BACKGROUND: Endovascular aneurysm repair (EVAR) is an accepted approach for patients presenting with ruptured abdominal aortic aneurysm (rAAA) and suitable anatomy. The effect of anesthesia modality on mortality outcomes in rAAA has not been well described. Using the Vascular Quality Initiative database, this study compares local anesthesia (LA) vs general anesthesia (GA) in EVAR for rAAA. METHODS: The Vascular Quality Initiative database was queried for patients presenting with rAAA managed with open surgical repair, EVAR under LA (rEVAR-LA), and EVAR under GA (rEVAR-GA) between 2003 and 2017. Patients were observed until the earlier end point of either death or 1-year follow-up. Kaplan-Meier event rates are presented at 30 days and 1 year. Cox proportional hazards regression was used to model risk of death, with adjustment for demographic and clinical factors. Additional multivariate Cox hazards analyses were used to assess effect modifiers for 1-year mortality for the different repair methods. RESULTS: A total of 3330 patients (77.4% male) met the inclusion criteria (1594 [47.9%] open surgical repair, 226 [6.8%] rEVAR-LA, and 1510 [45.3%] rEVAR-GA). Patients treated with rEVAR-LA compared with rEVAR-GA had decreased intraoperative time, number of intraoperative blood transfusions, intraoperative crystalloid administration, intensive care unit length of stay, and postoperative pulmonary complications. Mortality rates with rEVAR-LA were lower compared with rEVAR-GA at 30 days (15.5% vs 23.3%; adjusted hazard ratio [AHR], 0.70; 95% confidence interval [CI], 0.49-0.99; P = .04) and at 1 year (22.5% vs 32.3%; AHR, 0.71; 95% CI, 0.53-0.96; P = .02). Patients undergoing EVAR who were <75 years old and those without preoperative hypotension had the greatest survival benefit from LA compared with GA (both factors: AHR, 0.14 [95% CI, 0.03-0.57]; single factor: AHR, 0.57 [95% CI, 0.36-0.91]). CONCLUSIONS: This study demonstrates that rEVAR-LA for rAAA may be a safe alternative to rEVAR-GA for certain patients, with lower morbidity and improved mortality. Further prospective study is warranted to confirm mortality benefit in rEVAR-LA for rAAA.

Vascular Genetics: Presentations, Testing, and Prognostics.

PURPOSE OF REVIEW: Numerous studies have begun to unravel the genetic basis of not only aortic disease but also other forms of commonly encountered vascular diseases. The goal of this review is to provide clinicians a reference to help identify and diagnose different types of vascular disease with a genetic underpinning. RECENT FINDINGS: Ongoing studies have identified numerous genes involved in the TGF-ß signaling pathway that are also associated with thoracic aortic aneurysm and dissection, and it is possible to test for pathogenic variants in these genes in the clinical setting using commercially available genetic testing panels. Additional studies have begun to identify genetic variants associated with an increased risk of bicuspid aortic valve, abdominal aortic aneurysm, and fibromuscular dysplasia. With increased availability of low-cost genetic testing, clinicians are now able to not only definitively diagnose some vascular syndromes but also provide information on the risk of disease in other family members, as well as provide guidance in terms of family planning. As the cost of genetic testing continues to drop with the benefit of increasing insurance coverage, genetic data will increasingly become part of clinical care for many patients with vascular disease.

Efficacy and Safety of Edoxaban in Patients With Active Malignancy and Atrial Fibrillation: Analysis of the ENGAGE AF - TIMI 48 Trial.

Background Anticoagulation in patients with malignancy and atrial fibrillation is challenging because of enhanced risks for thrombosis and bleeding and the frequent need for invasive procedures. Data on direct oral antagonists in such patients are sparse. Methods and Results The ENGAGE AF - TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48) trial randomized 21 105 patients with atrial fibrillation to edoxaban or warfarin. Patients with malignancy, defined as a postrandomization new diagnosis or recurrence of remote cancer, were followed up over a median of 2.8 years. Adjusted Cox proportional hazard models were used to evaluate the safety and efficacy of edoxaban versus warfarin. Over a median of 495 days (interquartile range, 230-771 days), 1153 patients (5.5%) were diagnosed with new or recurrent malignancy, most commonly involving the gastrointestinal tract (20.6%), prostate (13.6%), and lung (11.1%). Malignancy was associated with increased risk of death (adjusted hazard ratio [HR], 3.12; 95% confidence interval [CI], 2.78-3.50) and major bleeding (adjusted HR, 2.45; 95% CI, 2.07-2.89), but not stroke/systemic embolism (adjusted HR, 1.08; 95% CI, 0.83-1.42). Relative outcomes with higher-dose edoxaban versus warfarin were consistent regardless of malignancy status for stroke/systemic embolism ( HR , 0.60 [95% CI, 0.31-1.15] for malignancy versus HR , 0.89 [95% CI, 0.76-1.05] for no malignancy; interaction P=0.25) and major bleeding ( HR , 0.98 [95% CI, 0.69-1.40] for malignancy versus HR , 0.79 [95% CI, 0.69-1.05] for no malignancy; interaction P=0.31). There was, however, a significant treatment interaction for the composite ischemic end point (ischemic stroke/systemic embolism/myocardial infarction), with greater efficacy of higher-dose edoxaban versus warfarin in patients with malignancy ( HR , 0.54; 95% CI, 0.31-0.93) compared with no malignancy ( HR , 1.02; 95% CI, 0.88-1.18; interaction P=0.026). Conclusions In patients with atrial fibrillation who develop malignancy, the efficacy and safety profile of edoxaban relative to warfarin is preserved, and it may represent a more practical alternative.

TIMI-AF score and cardiovascular events in vitamin K antagonists-naïve outpatients with atrial fibrillation.

BACKGROUND: The TIMI-AF score predicts poor outcomes in patients with atrial fibrillation (AF) and guides selection of anticoagulant therapy by identifying clinical benefit of direct oral anticoagulants (DOACs) or vitamin K antagonists (VKA). HYPOTHESIS: Our objective was to determine the ability to predict cardiovascular events according to the TIMI-AF score in a real-world population. METHODS: Retrospective observational study of VKA-naïve patients with AF was seen at a cardiology outpatient clinic in Spain between November 2012 and August 2014. We recorded adverse events (myocardial infarction, systemic embolism or stroke, major bleeding, and death). RESULTS: The study population comprised of 426 patients (50.7% men, mean age, 69 ± 14 years). The TIMI-AF score identified 372 patients (87.3%) with a low risk, 50 patients (11.7%) with an intermediate risk, and 4 patients (0.9%) with a high risk. After a mean follow-up of 423.4 ± 200.1 days, 37 patients (9%) experienced an adverse event. Patients with a TIMI-AF score ≥ 7 had a poorer cardiovascular prognosis (HR, 6.1; 95%CI, 3.2-11.7; P < 0.001). The area under the ROC curve of TIMI-AF was 0.755 (95%CI, 0.669-0.840; P < 0.001), which was greater than that of CHA2 DS2 VASc (0.641; 95%CI, 0.559-0.724; P = 0.004), HAS-BLED (0.666; 95%CI, 0.578-0.755; P < 0.001), and SAMeTT2 R2 (0.529; 95%CI, 0.422-0.636; P = 0.565). Similar results were obtained in relation to the net clinical outcome (life-threatening bleeding, disabling stroke, or all-cause mortality). CONCLUSIONS: The TIMI-AF risk score can identify patients who are at greater risk of cardiovascular events and a poor net clinical outcome with a better diagnostic yield than CHA2 DS2 VASc, HAS-BLED, and SAMeTT2 R2 .

Cardiovascular Safety of Lorcaserin in Overweight or Obese Patients.

BACKGROUND: Lorcaserin, a selective serotonin 2C receptor agonist that modulates appetite, has proven efficacy for weight management in overweight or obese patients. The cardiovascular safety and efficacy of lorcaserin are undefined. METHODS: We randomly assigned 12,000 overweight or obese patients with atherosclerotic cardiovascular disease or multiple cardiovascular risk factors to receive either lorcaserin (10 mg twice daily) or placebo. The primary safety outcome of major cardiovascular events (a composite of cardiovascular death, myocardial infarction, or stroke) was assessed at an interim analysis to exclude a noninferiority boundary of 1.4. If noninferiority was met, the primary cardiovascular efficacy outcome (a composite of major cardiovascular events, heart failure, hospitalization for unstable angina, or coronary revascularization [extended major cardiovascular events]) was assessed for superiority at the end of the trial. RESULTS: At 1 year, weight loss of at least 5% had occurred in 1986 of 5135 patients (38.7%) in the lorcaserin group and in 883 of 5083 (17.4%) in the placebo group (odds ratio, 3.01; 95% confidence interval [CI], 2.74 to 3.30; P<0.001). Patients in the lorcaserin group had slightly better values with respect to cardiac risk factors (including blood pressure, heart rate, glycemic control, and lipids) than those in the placebo group. During a median follow-up of 3.3 years, the rate of the primary safety outcome was 2.0% per year in the lorcaserin group and 2.1% per year in the placebo group (hazard ratio, 0.99; 95% CI, 0.85 to 1.14; P<0.001 for noninferiority); the rate of extended major cardiovascular events was 4.1% per year and 4.2% per year, respectively (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P=0.55). Adverse events of special interest were uncommon, and the rates were generally similar in the two groups, except for a higher number of patients with serious hypoglycemia in the lorcaserin group (13 vs. 4, P=0.04). CONCLUSIONS: In a high-risk population of overweight or obese patients, lorcaserin facilitated sustained weight loss without a higher rate of major cardiovascular events than that with placebo. (Funded by Eisai; CAMELLIA-TIMI 61 ClinicalTrials.gov number, NCT02019264 .).

Design and rationale for the Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients-Thrombolysis in Myocardial Infarction 61 (CAMELLIA-TIMI 61) trial.

OBJECTIVES: Lorcaserin, a selective serotonin 2C receptor agonist, is an effective pharmacologic weight-loss therapy that improves several cardiovascular risk factors. The long-term clinical cardiovascular and metabolic safety and efficacy in patients with elevated cardiovascular risk are unknown. RESEARCH DESIGN AND METHODS: CAMELLIA-TIMI 61 (NCT02019264) is a randomized, double-blind, placebo-controlled, multinational clinical trial designed to evaluate the safety and efficacy of lorcaserin with regard to major adverse cardiovascular events and progression to diabetes in overweight or obese patients at high cardiovascular risk. Overweight or obese patients either with established cardiovascular disease or with diabetes and at least 1 other cardiovascular risk factor were randomized in a 1:1 ratio to lorcaserin 10 mg twice daily or matching placebo. The primary safety objective is to assess for noninferiority of lorcaserin for the composite end point of cardiovascular death, myocardial infarction, or stroke (major adverse cardiovascular event [MACE]) (with noninferiority defined as the upper bound of a 1-sided 97.5% CI excluding a hazard ratio of 1.4) compared with placebo assessed at an interim analysis with 460 adjudicated events. The efficacy objectives, assessed at study completion, will evaluate the superiority of lorcaserin for the primary composite end point of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, heart failure, or any coronary revascularization (MACE+) and the key secondary end point of conversion to diabetes. Recruitment began in January 2014 and was completed in November 2015 resulting in a total population of 12,000 patients. The trial is planned to continue until at least 1,401 adjudicated MACE+ events are accrued and the median treatment duration exceeds 2.5 years. CONCLUSION: CAMELLIA-TIMI 61 is investigating the safety and efficacy of lorcaserin for MACEs and conversion to diabetes in overweight or obese patients with established cardiovascular disease or multiple cardiovascular risk factors.

Blood pressure and cardiovascular outcomes in patients with diabetes and high cardiovascular risk.

Aims: Optimal blood pressure for prevention of cardiovascular (CV) events in patients with Type 2 diabetes mellitus (T2DM) remains uncertain and there is concern for increased risk with low diastolic blood pressure (DBP). This study analysed the association between blood pressure and CV outcomes in high-risk patients with T2DM. Methods and results: Patients with T2DM and elevated CV risk were enrolled in the Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus-Thrombolysis in Myocardial Infarction 53 trial. Cardiovascular outcomes were compared in the biomarker subgroup (n = 12 175) after stratification by baseline systolic blood pressure (SBP) and DBP. Adjusted risk was calculated by blood pressure stratum using clinical covariates plus N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin-T (hsTnT). Trends were tested using linear and quadratic models. Adjusted risk of the composite endpoint of CV death, myocardial infarction (MI), or ischaemic stroke showed U-shaped relationships with baseline SBP and DBP (Pquadratic ≤ 0.01) with nadirs at SBP 130-140 or DBP 80-90 mmHg. Diastolic blood pressure <60 mmHg was associated with increased risk of MI (adjusted hazard ratio 2.30; 95% confidence interval 1.50-3.53) relative to DBP 80-90 mmHg. Adjusted odds of hsTnT concentration ≥14 ng/L showed U-shaped relationships with SBP and DBP (Pquadratic ≤ 0.01). The relationships between low DBP, elevated hsTnT, and increased MI remained after exclusion of patients with prior heart failure or NT-proBNP >median, suggesting that the relationship was not due to confounding from diagnosed or undiagnosed heart failure. Conclusions: In patients with diabetes and elevated CV risk, even after extensive adjustment for underlying disease burden, there was a persistent association for low DBP with subclinical myocardial injury and risk of MI.

Interleukin-6 and the Risk of Adverse Outcomes in Patients After an Acute Coronary Syndrome: Observations From the SOLID-TIMI 52 (Stabilization of Plaque Using Darapladib-Thrombolysis in Myocardial Infarction 52) Trial.

BACKGROUND: Interleukin-6 (IL-6) is an inflammatory cytokine implicated in plaque instability in acute coronary syndrome (ACS). We aimed to evaluate the prognostic implications of IL-6 post-ACS. METHODS AND RESULTS: IL-6 concentration was assessed at baseline in 4939 subjects in SOLID-TIMI 52 (Stabilization of Plaque Using Darapladib-Thrombolysis in Myocardial Infarction 52), a randomized trial of darapladib in patients ≤30 days from ACS. Patients were followed for a median of 2.5 years for major adverse cardiovascular events; cardiovascular death, myocardial infarction, or stroke) and cardiovascular death or heart failure hospitalization. Primary analyses were adjusted first for baseline characteristics, days from index ACS, ACS type, and randomized treatment arm. For every SD increase in IL-6, there was a 10% higher risk of major adverse cardiovascular events (adjusted hazard ratio [adj HR] 1.10, 95% confidence interval [CI] 1.01-1.19) and a 22% higher risk of cardiovascular death or heart failure (adj HR 1.22, 95% CI 1.11-1.34). Patients in the highest IL-6 quartile had a higher risk of major adverse cardiovascular events (adj HR Q4:Q1 1.57, 95% CI 1.22-2.03) and cardiovascular death or heart failure (adj HR 2.29, 95% CI 1.6-3.29). After further adjustment for biomarkers (high-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2 activity, high-sensitivity troponin I, and B-type natriuretic peptide), IL-6 remained significantly associated with the risk of major adverse cardiovascular events (adj HR Q4:Q1 1.43, 95% CI 1.09-1.88) and cardiovascular death or heart failure (adj HR 1.79, 95% CI 1.22-2.63). CONCLUSIONS: In patients after ACS, IL-6 concentration is associated with adverse cardiovascular outcomes independent of established risk predictors and biomarkers. These findings lend support to the concept of IL-6 as a potential therapeutic target in patients with unstable ischemic heart disease.

Incidence of severe renal dysfunction among individuals taking warfarin and implications for non-vitamin K oral anticoagulants.

BACKGROUND: The purpose of this study is to assess incidence and risk factors for severe renal dysfunction in patients requiring oral anticoagulation to help guide initial drug choice and provide a rational basis for interval monitoring of renal function for patients prescribed non-vitamin K oral anticoagulants. METHODS: Patients on warfarin for atrial fibrillation or venous thromboembolism were consecutively enrolled from January 2007 to December 2010. Baseline kidney function was assessed, and patients were followed to their first decline of kidney function to creatinine clearance<30 mL/min. Multivariate regression assessed independent risk factors for the primary outcome. Severe renal impairment based on baseline kidney function was assessed by Kaplan-Meier analyses. RESULTS: Of 787 patients identified, 34 were excluded for baseline CrCl <30 mL/min. The mean age was 71 years, and 74% and 31% had hypertension and diabetes mellitus, respectively. At baseline, 23% (n=174) had moderate chronic kidney disease (CKD) (CrCl 30-59mL/min), whereas 31% had mild CKD (CrCl 60-89mL/min). Severe renal impairment occurred in 92 patients (12%), 25% of which was seen within 5.3 months. Of those with baseline stage 3 CKD, 37% developed severe renal impairment. Stage 3 CKD conferred a 14-fold increased risk in the development of severe renal dysfunction (odds ratio 14.5, 95% CI 6.7-31.3, P<.001). Coronary artery disease was also associated with severe renal impairment (odds ratio 2.2, 95% CI 1.3-3.8, P=.004). CONCLUSIONS: Acute and chronic renal dysfunction is common among individuals requiring long-term anticoagulant therapy. Patients with moderate chronic kidney disease and coronary artery disease are at the highest short-term risk of developing severe renal impairment. More frequent monitoring of these patients is warranted.

A novel risk prediction score in atrial fibrillation for a net clinical outcome from the ENGAGE AF-TIMI 48 randomized clinical trial.

AIMS: The choice between initiating a non-vitamin K antagonist oral anticoagulant (NOAC) and a vitamin K antagonist (VKA) in patients with atrial fibrillation (AF) may be challenging. To assist in this decision, we developed a risk score to identify patients for whom a therapeutic benefit of NOACs over VKA is predicted. METHODS AND RESULTS: ENGAGE AF-TIMI 48 was a randomized clinical trial of edoxaban vs. warfarin in 21 105 patients with AF. Cox proportional hazard models identified factors associated with a serious net clinical outcome (NCO) of disabling stroke, life-threatening bleeding, and all-cause mortality in VKA naïve patients from the warfarin arm. These were used to develop an integer risk score. Performance was assessed by C-indices and validation by bootstrapping. Kaplan-Meier analyses were stratified by three score categories and treatment arm. Over a median of 2.7 years, 457 NCO events occurred in 2898 patients with a total person-time of 7549.5 years (6.05%/year). The risk prediction model (C = 0.693) for the NCO was translated into a 17-point integer score, with annualized event rates for the low, intermediate, and high-risk categories in the warfarin arm of 3.5%, 9.9%, and 20.8%, respectively. Therapeutic benefit of higher- and lower-dose edoxaban over warfarin was demonstrated in the high- and intermediate-risk, with equal benefit in the low-risk categories (P-interaction 0.008 and 0.014, respectively). CONCLUSION: In VKA naive patients with AF, the TIMI-AF score can assist in the prediction of a poor composite outcome and guide selection of anticoagulant therapy by identifying a differential clinical benefit with a NOAC or VKA.