F. Gerry R. Fowkes

Measurement and Interpretation of the Ankle-Brachial Index A Scientific Statement From the American Heart Association

Measurement and interpretation of the ankle-brachial index : a scientific statement from the Ammerican Heart Association

Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: An intention-to-treat analysis of amputation-free and overall survival in patients randomized to a bypass surgery-first or a balloon angioplasty-first revascularization strategy

BACKGROUND A 2005 interim analysis of the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial showed that in patients with severe lower limb ischemia (SLI; rest pain, ulceration, gangrene) due to infrainguinal disease, bypass surgery (BSX)-first and balloon angioplasty (BAP)-first revascularization strategies led to similar short-term clinical outcomes, although BSX was about one-third more expensive and morbidity was higher. We have monitored patients for a further 2.5 years and now report a final intention-to-treat (ITT) analysis of amputation-free survival (AFS) and overall survival (OS). METHODS Of 452 enrolled patients in 27 United Kingdom hospitals, 228 were randomized to a BSX-first and 224 to a BAP-first revascularization strategy. All patients were monitored for 3 years and more than half for >5 years. RESULTS At the end of follow-up, 250 patients were dead (56%), 168 (38%) were alive without amputation, and 30 (7%) were alive with amputation. Four were lost to follow-up. AFS and OS did not differ between randomized treatments during the follow-up. For those patients surviving 2 years from randomization, however, BSX-first revascularization was associated with a reduced hazard ratio (HR) for subsequent AFS of 0.85 (95% confidence interval [CI], 0.5-1.07; P = .108) and for subsequent OS of 0.61 (95% CI, 0.50-0.75; P = .009) in an adjusted, time-dependent Cox proportional hazards model. For those patients who survived for 2 years after randomization, initial randomization to a BSX-first revascularization strategy was associated with an increase in subsequent restricted mean overall survival of 7.3 months (95% CI, 1.2-13.4 months, P = .02) and an increase in restricted mean AFS of 5.9 months (95% CI, 0.2-12.0 months, P = .06) during the subsequent mean follow-up of 3.1 years (range, 1-5.7 years). CONCLUSIONS Overall, there was no significant difference in AFS or OS between the two strategies. However, for those patients who survived for at least 2 years after randomization, a BSX-first revascularization strategy was associated with a significant increase in subsequent OS and a trend towards improved AFS.

Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: Analysis of amputation free and overall survival by treatment received

BACKGROUND An intention-to-treat analysis of randomized Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial data showed that initial randomization to a bypass surgery (BSX)-first strategy was associated with improvements in subsequent overall survival (OS) and amputation-free survival (AFS) of about 7 and 6 months, respectively. We describe the nature and timing of first, crossover, and reinterventions and examine AFS and OS by first treatment received. We also compare vein with prosthetic BSX and transluminal with subintimal balloon angioplasty (BAP) and examine outcomes from BSX after failed BAP. METHODS We randomly assigned 452 patients with SLI due to infrainguinal disease in 27 United Kingdom hospitals to a BSX first (n = 228) or a BAP first (n = 224) revascularization strategy. All patients have been monitored for 3 years and more than half for >5 years. We prospectively collected data on every procedure, major amputation, and death. RESULTS Patients randomized to BAP were more likely to have their assigned treatment first (94% vs 85%, P = .01, chi(2)test). BAP had a higher immediate technical failure rate of 20% vs 2.6% (P = .01, chi(2)test). By 12 weeks after randomization 9 BAP (4%) vs 23 BSX (10%) patients had not undergone revascularization; 3 BAP (1.3%) vs 13 BSX (5.8%) had undergone the opposite treatment first; and 35 BAP (15.6%) and 2 (0.9%) BSX had received the assigned treatment and then undergone the opposite treatment. BSX distal anastomoses were divided approximately equally between the above and below knee popliteal and crural arteries; most originated from the common femoral artery. About 25% of the grafts were prosthetic and >90% of vein BSX used ipsilateral great saphenous vein. Most (80%) BAP patients underwent treatment of the SFA alone (38%) or combined with the popliteal artery (42%) and crural arteries (20%). Outcome of vein BSX was better for AFS (P = 0.003) but not OS (P = 0.38, log-rank tests) than prosthetic BSX. There were no differences in outcome between approximately equal numbers of transluminal and subintimal BAP. AFS (P = 0.006) but not OS (P = 0.06, log rank test) survival was significantly worse after BSX after failed BAP than after BSX as a first revascularization attempt. CONCLUSIONS BAP was associated with a significantly higher early failure rate than BSX. Most BAP patients ultimately required surgery. BSX outcomes after failed BAP are significantly worse than for BSX performed as a first revascularization attempt. BSX with vein offers the best long term AFS and OS and, overall, BAP appears superior to prosthetic BSX.

Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: A survival prediction model to facilitate clinical decision making

BACKGROUND An intention-to-treat analysis of the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial showed that in patients with severe lower limb ischemia (SLI) due to infrainguinal disease who survived for 2 years after intervention, initial randomization to a bypass surgery (BSX)-first vs balloon angioplasty (BAP)-first revascularization strategy was associated with improvements in subsequent overall survival (OS) and amputation-free survival (AFS) of about 7 and 6 months, respectively. This study explored the value of baseline factors to estimate the likelihood of survival to 2 years for the trial cohort (Cox model) and for individual BASIL trial patients (Weibull model) as an aid to clinical decision making. METHODS Of 452 patients presenting to 27 United Kingdom hospitals, 228 were randomly assigned to a BSX-first and 224 to a BAP-first revascularization strategy. Patients were monitored for at least 3 years. Baseline factors affecting the survival of the entire cohort were examined with a multivariate Cox model. The chances of survival at 1 and 2 years for patients with given baseline characteristics were estimated with a Weibull parametric model. RESULTS At the end of follow-up, 172 patients (38%) were alive without major limb amputation of the trial leg, and 202 (45%) were alive. Baseline factors that were significant in the Cox model were BASIL randomization stratification group, below knee Bollinger angiogram score, body mass index, age, diabetes, creatinine level, and smoking status. Using these factors to define five equally sized groups, we identified patients with 2-year survival rates of 50% to 90%. The factors that contributed to the Weibull predictive model were age, presence of tissue loss, serum creatinine, number of ankle pressure measurements detectable, maximum ankle pressure measured, a history of myocardial infarction or angina, a history of stroke or transient ischemia attack, below knee Bollinger angiogram score, body mass index, and smoking status. CONCLUSIONS Patients in the BASIL trial were at high risk of amputation and death regardless of revascularization strategy. However, baseline factors can be used to stratify those risks. Furthermore, within a parametric Weibull model, certain of these factors can be used to help predict outcomes for individuals. It may thus be possible to define the clinical and anatomic (angiographic) characteristics of SLI patients who are likely-and not likely-to live for >2 years after intervention. Used appropriately in the context of the BASIL trial outcomes, this may aid clinical decision making regarding a BSX- or BAP-first revascularization strategy in SLI patients like those randomized in BASIL.

Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease.

BACKGROUND Peripheral artery disease is considered to be a manifestation of systemic atherosclerosis with associated adverse cardiovascular and limb events. Data from previous trials have suggested that patients receiving clopidogrel monotherapy had a lower risk of cardiovascular events than those receiving aspirin. We wanted to compare clopidogrel with ticagrelor, a potent antiplatelet agent, in patients with peripheral artery disease. METHODS In this double‐blind, event‐driven trial, we randomly assigned 13,885 patients with symptomatic peripheral artery disease to receive monotherapy with ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily). Patients were eligible if they had an ankle–brachial index (ABI) of 0.80 or less or had undergone previous revascularization of the lower limbs. The primary efficacy end point was a composite of adjudicated cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding. The median follow‐up was 30 months. RESULTS The median age of the patients was 66 years, and 72% were men; 43% were enrolled on the basis of the ABI and 57% on the basis of previous revascularization. The mean baseline ABI in all patients was 0.71, 76.6% of the patients had claudication, and 4.6% had critical limb ischemia. The primary efficacy end point occurred in 751 of 6930 patients (10.8%) receiving ticagrelor and in 740 of 6955 (10.6%) receiving clopidogrel (hazard ratio, 1.02; 95% confidence interval [CI], 0.92 to 1.13; P=0.65). In each group, acute limb ischemia occurred in 1.7% of the patients (hazard ratio, 1.03; 95% CI, 0.79 to 1.33; P=0.85) and major bleeding in 1.6% (hazard ratio, 1.10; 95% CI, 0.84 to 1.43; P=0.49). CONCLUSIONS In patients with symptomatic peripheral artery disease, ticagrelor was not shown to be superior to clopidogrel for the reduction of cardiovascular events. Major bleeding occurred at similar rates among the patients in the two trial groups. (Funded by AstraZeneca; EUCLID ClinicalTrials.gov number, NCT01732822.)

Association between raised inflammatory markers and cognitive decline in elderly people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study

OBJECTIVE To determine whether circulating levels of the inflammatory markers C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-α are associated with cognitive ability and estimated lifetime cognitive decline in an elderly population with type 2 diabetes. RESEARCH DESIGN AND METHODS A cross-sectional study of 1,066 men and women aged 60–75 years with type 2 diabetes and living in Lothian, Scotland (the Edinburgh Type 2 Diabetes Study), was performed. Seven cognitive tests were used to measure abilities in memory, nonverbal reasoning, information processing speed, executive function, and mental flexibility. The results were used to derive a general intelligence factor (g). A vocabulary–based test was administered as an estimate of peak prior cognitive ability. Results on the cognitive tests were assessed for statistical association with inflammatory markers measured in a venous blood sample at the time of cognitive testing. RESULTS Higher IL-6 and TNF-α levels were associated with poorer age- and sex-adjusted scores on the majority of the individual cognitive tests. They were also associated with g using standardized regression coefficients −0.074 to −0.173 (P < 0.05). After adjusting for vocabulary, education level, cardiovascular dysfunction, duration of diabetes, and glycemic control, IL-6 remained associated with three of the cognitive tests and with g. CONCLUSIONS In this representative population of people with type 2 diabetes, elevated circulating levels of inflammatory markers were associated with poorer cognitive ability. IL-6 levels were also associated with estimated lifetime cognitive decline.

PLA2G7 Genotype, Lipoprotein-Associated Phospholipase A2 Activity, and Coronary Heart Disease Risk in 10 494 Cases and 15 624 Controls of European Ancestry

Background— Higher lipoprotein-associated phospholipase A2(Lp-PLA2) activity is associated with increased risk of coronary heart disease (CHD), making Lp-PLA2 a potential therapeutic target. PLA2G7 variants associated with Lp-PLA2 activity could evaluate whether this relationship is causal. Methods and Results— A meta-analysis including a total of 12 studies (5 prospective, 4 case-control, 1 case-only, and 2 cross-sectional studies; n=26 118) was undertaken to examine the association of the following: (1) Lp-PLA2 activity versus cardiovascular biomarkers and risk factors and CHD events (2 prospective studies; n=4884); (2) PLA2G7 single-nucleotide polymorphisms and Lp-PLA2 activity (3 prospective, 2 case-control, 2 cross-sectional studies; up to n=6094); and (3) PLA2G7 single-nucleotide polymorphisms and angiographic coronary artery disease (2 case-control, 1 case-only study; n=4971 cases) and CHD events (5 prospective, 2 case-control studies; n=5523). Lp-PLA2 activity correlated with several CHD risk markers. Hazard ratios for CHD events for the top versus bottom quartile of Lp-PLA2 activity were 1.61 (95% confidence interval, 1.31 to 1.99) and 1.17 (95% confidence interval, 0.91 to 1.51) after adjustment for baseline traits. Of 7 single-nucleotide polymorphisms, rs1051931 (A379V) showed the strongest association with Lp-PLA2 activity, with VV subjects having 7.2% higher activity than AAs. Genotype was not associated with risk markers, angiographic coronary disease (odds ratio, 1.03; 95% confidence interval, 0.80 to 1.32), or CHD events (odds ratio, 0.98; 95% confidence interval, 0.82 to 1.17). Conclusions— Unlike Lp-PLA2 activity, PLA2G7 variants associated with modest effects on Lp-PLA2 activity were not associated with cardiovascular risk markers, coronary atheroma, or CHD. Larger association studies, identification of single-nucleotide polymorphisms with larger effects, or randomized trials of specific Lp-PLA2 inhibitors are needed to confirm or refute a contributory role for Lp-PLA2 in CHD.

Comparative analysis of genome-wide association studies signals for lipids, diabetes, and coronary heart disease: Cardiovascular Biomarker Genetics Collaboration

Aims To evaluate the associations of emergent genome-wide-association study-derived coronary heart disease (CHD)-associated single nucleotide polymorphisms (SNPs) with established and emerging risk factors, and the association of genome-wide-association study-derived lipid-associated SNPs with other risk factors and CHD events. Methods and results Using two case–control studies, three cross-sectional, and seven prospective studies with up to 25 000 individuals and 5794 CHD events we evaluated associations of 34 genome-wide-association study-identified SNPs with CHD risk and 16 CHD-associated risk factors or biomarkers. The Ch9p21 SNPs rs1333049 (OR 1.17; 95% confidence limits 1.11–1.24) and rs10757274 (OR 1.17; 1.09–1.26), MIA3 rs17465637 (OR 1.10; 1.04–1.15), Ch2q36 rs2943634 (OR 1.08; 1.03–1.14), APC rs383830 (OR 1.10; 1.02, 1.18), MTHFD1L rs6922269 (OR 1.10; 1.03, 1.16), CXCL12 rs501120 (OR 1.12; 1.04, 1.20), and SMAD3 rs17228212 (OR 1.11; 1.05, 1.17) were all associated with CHD risk, but not with the CHD biomarkers and risk factors measured. Among the 20 blood lipid-related SNPs, LPL rs17411031 was associated with a lower risk of CHD (OR 0.91; 0.84–0.97), an increase in Apolipoprotein AI and HDL-cholesterol, and reduced triglycerides. SORT1 rs599839 was associated with CHD risk (OR 1.20; 1.15–1.26) as well as total- and LDL-cholesterol, and apolipoprotein B. ANGPTL3 rs12042319 was associated with CHD risk (OR 1.11; 1.03, 1.19), total- and LDL-cholesterol, triglycerides, and interleukin-6. Conclusion Several SNPs predicting CHD events appear to involve pathways not currently indexed by the established or emerging risk factors; others involved changes in blood lipids including triglycerides or HDL-cholesterol as well as LDL-cholesterol. The overlapping association of SNPs with multiple risk factors and biomarkers supports the existence of shared points of regulation for these phenotypes.

Elevated Fasting Plasma Cortisol Is Associated with Ischemic Heart Disease and Its Risk Factors in People with Type 2 Diabetes: The Edinburgh Type 2 Diabetes Study

CONTEXT Increased activity of the hypothalamic-pituitary-adrenal (HPA) axis may underlie the metabolic syndrome, but whether circulating cortisol levels predict cardiovascular end points is less clear. People with type 2 diabetes are at increased cardiovascular disease risk and thus are suitable to study associations of plasma cortisol with cardiovascular risk. OBJECTIVE We aimed to assess whether altered HPA axis activity was associated with features of the metabolic syndrome and ischemic heart disease in people with type 2 diabetes. DESIGN AND SETTING We conducted a cross-sectional cohort study in the general community, including 919 men and women aged 67.9 (4.2) yr with type 2 diabetes (the Edinburgh Type 2 Diabetes Study). INTERVENTION We measured fasting morning plasma cortisol. MAIN OUTCOME MEASUREMENT Associations between cortisol levels, features of the metabolic syndrome, obesity, and ischemic heart disease were determined. RESULTS Elevated plasma cortisol levels were associated with raised fasting glucose and total cholesterol levels (P < 0.001). These findings remained significant after adjustment for potential confounding factors (P < 0.001). Elevated cortisol levels were associated with prevalent ischemic heart disease (>800 vs. <600 nmol/liter; odds ratio, 1.58; P = 0.02). This association remained significant after adjustment for duration and control of diabetes and other cardiovascular risk factors (P = 0.03). CONCLUSIONS The previously described associations between HPA axis activation and features of the metabolic syndrome are present among people with type 2 diabetes. Elevated plasma cortisol is also associated with a greater prevalence of ischemic heart disease, independent of conventional risk factors. Understanding the role of cortisol in the pathogenesis of ischemic heart disease merits further exploration.

Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: Health-related quality of life outcomes, resource utilization, and cost-effectiveness analysis

BACKGROUND The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial showed that survival in patients with severe lower limb ischemia (rest pain, tissue loss) who survived postintervention for >2 years after initial randomization to bypass surgery (BSX) vs balloon angioplasty (BAP) was associated with an improvement in subsequent amputation-free and overall survival of about 6 and 7 months, respectively. We now compare the effect on hospital costs and health-related quality of life (HRQOL) of the BSX-first and BAP-first revascularization strategies using a within-trial cost-effectiveness analysis. METHODS We measured HRQOL using the Vascular Quality of Life Questionnaire (VascuQol), the Short Form 36 (SF-36), and the EuroQol (EQ-5D) health outcome measure up to 3 years from randomization. Hospital use was measured and valued using United Kingdom National Health Service hospital costs over 3 years. Analysis was by intention-to-treat. Incremental cost-effectiveness ratios were estimated for cost per quality-adjusted life-year (QALY) gained. Uncertainty was assessed using nonparametric bootstrapping of incremental costs and incremental effects. RESULTS No significant differences in HRQOL emerged when the two treatment strategies were compared. During the first year from randomization, the mean cost of inpatient hospital treatment in patients allocated to BSX (