The effect of ticagrelor on growth of small abdominal aortic aneurysms-a randomized controlled trial.

AIMS: To evaluate if ticagrelor, an effective platelet inhibitor without known non-responders, could inhibit growth of small abdominal aortic aneurysms (AAAs). METHODS AND RESULTS: In this multi-centre randomized controlled trial, double-blinded for ticagrelor and placebo, acetylic salicylic acid naïve patients with AAA and with a maximum aortic diameter 35-49 mm were included. The primary outcome was mean reduction in log-transformed AAA volume growth rate (%) measured with magnetic resonance imaging (MRI) at 12 months compared with baseline. Secondary outcomes include AAA-diameter growth rate and intraluminal thrombus (ILT) volume enlargement rate. A total of 144 patients from eight Swedish centres were randomized (72 in each group). MRI AAA volume increase was 9.1% for the ticagrelor group and 7.5% for the placebo group (P = 0.205) based on intention-to-treat analysis, and 8.5% vs. 7.4% in a per-protocol analysis (P = 0.372). MRI diameter change was 2.5 mm vs. 1.8 mm (P = 0.113), US diameter change 2.3 mm vs. 2.2 mm (P = 0.778), and ILT volume change 12.9% vs. 10.4% (P = 0.590). CONCLUSION: In this RCT, platelet inhibition with ticagrelor did not reduce growth of small AAAs. Whether the ILT has an important pathophysiological role for AAA growth cannot be determined based on this study due to the observed lack of thrombus modulating effect of ticagrelor. TRIAL REGISTRATION: The TicAAA trial is registered at the US National Institutes of Health (ClinicalTrials.gov) #NCT02070653.

Open versus Endovascular Repair of Abdominal Aortic Aneurysm.

BACKGROUND: Elective endovascular repair of an abdominal aortic aneurysm results in lower perioperative mortality than traditional open repair, but after 4 years this survival advantage is not seen; in addition, results of two European trials have shown worse long-term outcomes with endovascular repair than with open repair. Long-term results of a study we conducted more than a decade ago to compare endovascular repair with open repair are unknown. METHODS: We randomly assigned patients with asymptomatic abdominal aortic aneurysms to either endovascular repair or open repair of the aneurysm. All the patients were candidates for either procedure. Patients were followed for up to 14 years. RESULTS: A total of 881 patients underwent randomization: 444 were assigned to endovascular repair and 437 to open repair. The primary outcome was all-cause mortality. A total of 302 patients (68.0%) in the endovascular-repair group and 306 (70.0%) in the open-repair group died (hazard ratio, 0.96; 95% confidence interval [CI], 0.82 to 1.13). During the first 4 years of follow-up, overall survival appeared to be higher with endovascular repair than with open repair; from year 4 through year 8, overall survival was higher in the open-repair group; and after 8 years, overall survival was once again higher in the endovascular-repair group (hazard ratio for death, 0.94; 95% CI, 0.74 to 1.18). None of these trends were significant. There were 12 aneurysm-related deaths (2.7%) in the endovascular-repair group and 16 (3.7%) in the open-repair group (between-group difference, -1.0 percentage point; 95% CI, -3.3 to 1.4); most deaths occurred during the perioperative period. Aneurysm rupture occurred in 7 patients (1.6%) in the endovascular-repair group, and rupture of a thoracic aneurysm occurred in 1 patient (0.2%) in the open-repair group (between-group difference, 1.3 percentage points; 95% CI, 0.1 to 2.6). Death from chronic obstructive lung disease was just over 50% more common with open repair (5.4% of patients in the endovascular-repair group and 8.2% in the open-repair group died from chronic obstructive lung disease; between-group difference, -2.8 percentage points; 95% CI, -6.2 to 0.5). More patients in the endovascular-repair group underwent secondary procedures. CONCLUSIONS: Long-term overall survival was similar among patients who underwent endovascular repair and those who underwent open repair. A difference between groups was noted in the number of patients who underwent secondary therapeutic procedures. Our results were not consistent with the findings of worse performance of endovascular repair with respect to long-term survival that was seen in the two European trials. (Funded by the Department of Veteran Affairs Office of Research and Development; OVER ClinicalTrials.gov number, NCT00094575.).

The Association of Biomarkers of Inflammation and Extracellular Matrix Degradation With the Risk of Abdominal Aortic Aneurysm: The ARIC Study.

Animal and human laboratory studies suggest that the pathogenesis of abdominal aortic aneurysms (AAAs) involves inflammation and degradation and remodeling of the extracellular matrix. This study prospectively assessed the association between biomarkers for these mechanisms and the presence of AAA during 24 years of follow-up in the Atherosclerosis Risk in Communities (ARIC) study. The ARIC prospectively identified clinically diagnosed AAAs in 15 792 men and women from baseline in 1987 to 1989 to 2011 using hospital discharge codes and death records. Additional asymptomatic AAAs were detected by an abdominal ultrasound scan in 2011 to 2013. Matrix metalloproteinase (MMP)-3, MMP-9, interleukin 6 (IL-6), N-terminal propeptide of Type III procollagen (PIIINP), and osteopontin were measured in blood samples collected between 1987 and 1992 in participants with AAA (544 clinically diagnosed AAAs and 72 ultrasound-detected AAAs) and a random sample of 723 participants selected from baseline and matched with AAAs by age, race and sex. Higher concentrations of MMP-9 and IL-6 were associated with future risk of clinically diagnosed AAA (hazard ratios [95% confidence intervals]: 1.55 [1.22-1.97] and 1.87 [1.48-2.35], respectively, comparing highest versus lowest tertiles) after multivariable adjustment ( P for trend < .001). Matrix metalloproteinase-9 was also associated with ultrasound-detected AAA. In conclusion, blood concentrations of MMP-9 and IL-6 measured in middle age predicted the risk of AAA during 24 years of follow-up.

Association of carotid atherosclerosis and stiffness with abdominal aortic aneurysm: The atherosclerosis risk in communities (ARIC) study.

BACKGROUND AND AIMS: Individuals with atherosclerosis and stiffness often have increased abdominal aortic diameters, but prospective evidence linking them to the risk of abdominal aortic aneurysm (AAA) is limited. METHODS: We prospectively examined the relationship of carotid atherosclerosis and stiffness with future risk of AAA in ARIC. At Visits 1 (1987-89) or 2 (1990-1992), we assessed carotid atherosclerosis (represented by greater carotid intima-media thickness [cIMT] or presence of atherosclerotic plaque) and lower carotid distensibility (reflected by a higher carotid Beta Index). We identified incident, clinical AAAs during follow-up through 2011 using hospital discharge codes, Medicare outpatient diagnoses, or death certificates. RESULTS: Participants' mean age at baseline was 54.2 years (SD 5.8), 45% were male and 73% white. During a median of 22.5 years of follow-up, 542 clinical AAAs were ascertained. After multivariable adjustment, the presence of carotid atherosclerotic plaque at baseline was associated with 1.31 (95% CI: 1.10-1.57; p = 0.003) times higher risk of clinical AAA. Greater cIMT and Beta Index were also associated with clinical AAA with a dose-response across quartiles (p trend for both: 0.006; hazard ratios [95% CI] for the highest vs. lowest quartiles: 1.55 [1.13-2.11] and 1.68 [1.16-2.43], respectively). The associations of cIMT and Beta Index with AAA were independent of each other. CONCLUSIONS: This prospective population-based study found that indices of greater carotid atherosclerosis and lower carotid distensibility are markers of increased AAA risk.

Identification of Acute Decompensated Heart Failure Hospitalizations Using Administrative Data.

Hospitalization for acute decompensated heart failure (ADHF) is an important outcome in clinical trials and heart failure registries; however, the optimal strategy to identify these hospitalizations using International Classification of Diseases, Ninth Revision (ICD-9) codes is uncertain. We sought to identify diagnostic codes that improve ascertainment of ADHF hospitalizations. Heart failure-related ICD-9 principal discharge codes were used to identify 2,202 hospitalizations within the Minneapolis Veterans Affairs Medical Center from 2009 to 2014. Two independent reviewers adjudicated 447 of these hospitalizations to determine the accuracy of each code. We then applied our findings to an unadjusted nationwide sample containing the same ICD-9 codes of interest, from which overall positive predictive value (PPV), sensitivity, and accuracy were calculated. Use of 428.x alone resulted in a PPV of 91.3% (95% confidence interval [CI] 91.0 to 91.7), sensitivity of 97.5% (95% CI 97.3 to 97.6), and accuracy of 89.7% (95% CI 89.4 to 90.0). Combining 428.x with 402.x1, 404.x1, 415, and 518.4 resulted in improved sensitivity (99.2%; 95% CI 99.0 to 99.3) and accuracy (90.7%; 95% CI 90.4 to 91.1) while maintaining a PPV of 91.1% (95% CI 90.7 to 91.4). Excluding chronic heart failure codes (428.22, 428.32, and 428.42) from the proposed strategy resulted in an improvement of PPV to 92.3% (95% CI 92.0 to 92.6), although sensitivity and accuracy decreased to 96.6% (95% CI 96.3 to 96.8) and 90.0% (95% CI 89.6 to 90.3), respectively. In conclusion, a combination of codes including 428.x, 402.x1, 404.x1, 415, and 518.4 improves sensitivity and overall accuracy in ascertaining ADHF events compared with 428.x alone. This strategy could be further improved by manual adjudication of chronic heart failure codes.

Lifetime Risk and Risk Factors for Abdominal Aortic Aneurysm in a 24-Year Prospective Study: The ARIC Study (Atherosclerosis Risk in Communities).

OBJECTIVE: Abdominal aortic aneurysm (AAA) is an important vascular disease in older adults, but data on lifetime risk of AAA are sparse. We examined lifetime risk of AAA in a community-based cohort and prospectively assessed the association between midlife cardiovascular risk factors and AAAs. APPROACH AND RESULTS: In ARIC study (Atherosclerosis Risk in Communities), 15 792 participants were recruited at visit 1 in 1987 to 1989 and followed up through 2013. Longitudinal smoking status was defined using smoking behavior ascertained from visit 1 (1987-1989) to visit 4 (1996-1998). We followed up participants for incident, clinical AAAs using hospital discharge diagnoses, Medicare outpatient diagnoses, or death certificates through 2011 and identified 590 incident AAAs. An abdominal ultrasound was conducted in 2011 to 2013 in 5911 surviving participants, and 75 asymptomatic AAAs were identified. We estimated the lifetime risk of AAA from the index age 45 years through 85 years of age. At age 45, the lifetime risk for AAA was 5.6% (95% confidence interval, 4.8-6.1) and was higher in men (8.2%) and current smokers (10.5%). Smokers who quit smoking between visit 1 and visit 4 had a 29% lower AAA lifetime risk compared with continuous smokers but had a higher risk than pre-visit 1 quitters. The lifetime risk of rupture or medical intervention was 1.6% (95% confidence interval, 1.2-1.8). Smoking, white race, male sex, greater height, and greater low-density lipoprotein or total cholesterol were associated with an increased risk of clinical AAA and asymptomatic AAA. CONCLUSIONS: At least 1 in 9 middle-aged current smokers developed AAA in their lifetime. Smoking cessation reduced the lifetime risk of AAA.

Long-term Cost-effectiveness in the Veterans Affairs Open vs Endovascular Repair Study of Aortic Abdominal Aneurysm: A Randomized Clinical Trial.

Importance: Because of the similarity in clinical outcomes after elective open and endovascular repair of abdominal aortic aneurysm (AAA), cost may be an important factor in choosing a procedure. Objective: To compare total and AAA-related use of health care services, costs, and cost-effectiveness between groups randomized to open or endovascular repair. Design, Setting, and Participants: This unblinded randomized clinical trial enrolled 881 patients undergoing planned elective repair of AAA who were candidates for open and endovascular repair procedures. Patients were randomized from October 15, 2002, to April 15, 2008, at 42 Veterans Affairs medical centers. Follow-up was completed on October 15, 2011, and data were analyzed from April 15, 2013, to April 15, 2016, based on intention to treat. Main Outcomes and Measures: Mean total and AAA-related health care cost per life-year and per quality-adjusted life-year (QALY). Results: A total of 881 patients (876 men [99.4%]; 5 women [0.6%]; mean [SD] age, 70 [7.8] years) were included in the analysis. After a mean of 5.2 years of follow-up, mean life-years were 4.89 in the endovascular group and 4.84 in the open repair group (P = .68), and mean QALYs were 3.72 in the endovascular group and 3.70 in the open repair group (P = .82). Total mean health care costs did not differ significantly between the 2 groups (endovascular group, $142 745; open repair group, $153 533; difference, -$10 788; 95% CI, -$29 796 to $5825; P = .25). Costs related to AAA, including the initial repair, constituted nearly 40% of total costs and did not differ significantly between the 2 groups (endovascular group, $57 501; open repair group, $57 893; difference, -$393; 95% CI, -$12 071 to $7928; P = .94). Lower costs due to shorter hospitalization for initial endovascular repair were offset by increased costs from AAA-related secondary procedures and imaging studies. The probability of endovascular repair being less costly and more effective was 56.8% when effectiveness was measured in life-years and 55.4% when effectiveness was measured in QALYs for total costs and 31.3% and 34.3%, respectively, for AAA-related costs. Conclusions and Relevance: In this multicenter randomized clinical trial with follow-up to 9 years, survival, quality of life, costs, and cost-effectiveness did not differ between elective open and endovascular repair of AAA. Trial Registration: clinicaltrials.gov Identifier: NCT00094575.

Predictors and outcomes of endoleaks in the Veterans Affairs Open Versus Endovascular Repair (OVER) Trial of Abdominal Aortic Aneurysms.

OBJECTIVE: The Veterans Affairs Open Versus Endovascular Repair (OVER) Trial of Abdominal Aortic Aneurysms study was a randomized controlled trial comparing open vs endovascular repair (EVAR) in standard-risk patients with infrarenal aortic aneurysms. The analysis reported here identifies characteristics, risk factors, and long-term outcome of endoleaks in patients treated with EVAR in the OVER cohort. METHODS: The OVER trial enrolled 881 patients, of whom 439 received successful EVAR. Logistic regression analysis was used to identify predictors for endoleaks and secondary interventions. Kaplan-Meier survival analysis, longitudinal plots, and generalized linear mixed models methods were used to describe time to endoleak detection, resolution, or death. RESULTS: During a mean follow-up of 6.2 ± 2.4 years, 135 patients (30.5%) developed 187 endoleaks. Four patients with EVAR went on to rupture; these four patients did not all have an endoleak. Mortality between patients who did and did not develop endoleaks was not significantly different. The 187 endoleaks included 12% type I, 76% type II, 3% type III, 3% type IV, and 6% indeterminate. Patient demographics and vascular risk factors were not associated with endoleak development. The presence of endoleaks resulted in an increase in aneurysm diameter over time (P < .0001). Fifty-three percent of endoleaks resolved spontaneously, and 31.9% received secondary interventions. The initial aneurysm size independently predicted a need for secondary interventions (P < .0003). Delayed type II endoleaks (detected >1 year after EVAR) were associated with aneurysm enlargement compared with the early counterpart. There was no difference in aneurysm size or length of survival between type II and other types of endoleak. CONCLUSIONS: We present one of the most comprehensive and longest follow-up analyses of patients treated with aortic endografts. Endoleaks were common and negatively affected aneurysm diameter reduction. Delayed type II endoleaks were associated with late aneurysm diameter enlargement. Endoleaks and aneurysm diameter enlargement were not associated with excess mortality compared with those without these features.

Longer Withdrawal Time Is Associated With a Reduced Incidence of Interval Cancer After Screening Colonoscopy.

BACKGROUND & AIMS: Withdrawal times and adenoma detection rates are widely used quality indicators for screening colonoscopy. More rapid withdrawal times have been associated with undetected adenomas, which can increase risk for interval colorectal cancer. METHODS: We analyzed records of 76,810 screening colonoscopies performed between 2004 and 2009, by 51 gastroenterologists practicing in Minneapolis and St Paul, MN. Colonoscopy records were linked electronically to the state cancer registry (Minnesota Cancer Surveillance System) to identify incident interval cancers that were diagnosed within 5.5 years after the screening examination. RESULTS: The physicians' mean ± SD withdrawal time was 8.6 ± 1.7 minutes and adenoma detection rates were 25% ± 9%. Longer mean withdrawal times were associated with higher adenoma detection rates (3.6% per minute; 95% confidence interval: 2.4% to 4.8%; P < .0001). We identified 78 cancers during 410,687 person-years of follow-up, for an annual rate of 0.19/1000 person-years. Physicians' mean annual withdrawal times were inversely associated with cancer incidence (P < .0001). Compared with withdrawal times ≥6 minutes, the adjusted incidence rate ratio for withdrawal times of <6 minutes was 2.3 (95% confidence interval: 1.5-3.4; P < .0001). CONCLUSIONS: Shorter mean annual withdrawal times during screening colonoscopies were independently associated with lower adenoma detection rates and increased risk of interval colorectal cancer.

Circulating Biomarkers and Abdominal Aortic Aneurysm Incidence: The Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: The pathogenesis of abdominal aortic aneurysm (AAA) is complex. Cross-sectional studies have connected circulating biomarkers with AAA, but prospective evidence is limited. METHODS AND RESULTS: In the Atherosclerosis Risk in Communities Study cohort, we measured multiple blood biomarkers of inflammation, hemostasis, thrombin generation, cardiac dysfunction, and vascular stiffness and identified incident AAAs during follow-up using hospital discharge codes. Six biomarkers (white blood cell count, fibrinogen, D-dimer, troponin T, N-terminal pro-brain natriuretic peptide, and high-sensitivity C-reactive protein) were strongly associated positively with AAA incidence. Compared with having none of these 6 biomarkers in the highest quartile, the hazard ratios of AAA for those with 1, 2, 3, or 4 to 6 biomarkers in the highest quartile were 2.2, 3.3, 4.0, and 9.9, respectively (P for trend < 0.0001) after adjustment for other risk factors. CONCLUSIONS: This prospective study found that higher concentrations of 6 biomarkers were associated with increased risk of AAA. The more markers that fell into the highest quartile, the higher the AAA risk was. Multiple positive biomarkers identify a subgroup of patients at high risk of AAA.

Costs of repair of abdominal aortic aneurysm with different devices in a multicenter randomized trial.

OBJECTIVE: Prior analysis in the Open vs Endovascular Repair Veterans Affairs (VA) Cooperative Study (CSP #498) demonstrated that survival, quality of life, and total health care costs are not significantly different between the open and endovascular methods of repair of abdominal aortic aneurysm. The device is a major cost of this method of repair, and the objective of this study was to evaluate the costs of the device, abdominal aortic aneurysm repair, and total health care costs when different endograft systems are selected for the endovascular repair (EVR). Within each selected system, EVR costs are compared with open repair costs. METHODS: The study randomized 881 patients to open (n = 437) or EVR (n = 444). Device selection was recorded before randomization; therefore, open repair controls were matched to each device cohort. Data were excluded for two low-volume devices, implanted in only 13 individuals, leaving 423 control and 431 endovascular patients: 166 Zenith (Cook Medical, Bloomington, Ind), 177 Excluder (W. L. Gore & Associates, Flagstaff, Ariz), and 88 AneuRx (Medtronic, Minneapolis, Minn). Mean device, hospitalization, and total health care costs from randomization to 2 years were compared. Health care utilization data were obtained from patients and national VA and Medicare data sources. VA costs were determined using methods previously developed by the VA Health Economics Resource Center. Non-VA costs were obtained from Medicare claims data and billing data from the patient's health care providers. RESULTS: Implant costs were 38% of initial hospitalization costs. Mean device (range, $13,600-$14,400), initial hospitalization (range, $34,800-$38,900), and total health care costs at 2 years in the endovascular (range, $72,400-$78,200) and open repair groups (range, $75,600-$82,100) were not significantly different among device systems. Differences between endovascular and corresponding open repair cohorts showed lower mean costs for EVR (range, $3200-$8300), but these were not statistically different. CONCLUSIONS: The implant costs of endovascular aneurysm repair are substantial. When evaluating total health care system expenditures, there is large individual variability in costs, and there is no significant difference at 2 years among systems or when an individual system is compared with open repair.