Renate Koppensteiner

Balloon angioplasty versus stenting with nitinol stents in intermediate length superficial femoral artery lesions.

Background: Recent randomized trials investigating stent implantation compared with balloon angioplasty for treatment of superficial femoral artery (SFA) disease have given divergent results in short (mean 5 cm) and intermediate (mean 10 cm) lesions. We reinvestigated whether primary nitinol stenting is associated with a morphologic and clinical benefit when compared with percutaneous transluminal angioplasty with optional stenting (PTA) in intermediate‐length lesions. Methods: We randomly assigned 73 patients with severe claudication or chronic limb ischemia and average 8 cm long (range 3–20 cm) SFA stenosis or occlusion to primary stent implantation (n = 34) or PTA (n = 39). Restenosis >50% and clinical outcome were assessed at 3, 6, and 12 months postintervention. Results: Average length of the treated segments was 98 ± 54 mm and 71 ± 43 mm in the stent and PTA groups (P = 0.011), respectively. In the PTA group, secondary stenting was performed in 10 of 39 patients (26%) due to a suboptimal result after balloon dilation. Restenosis rates in the stent and PTA groups were 21.9% versus 55.6% (P = 0.005) at 6 months by CT‐angiography, and 2.9% versus 18.9% (P = 0.033), 18.2% versus 50.0% (P = 0.006), and 34.4% versus 61.1% (P = 0.028) at 3, 6, and 12 months by sonography, respectively. Clinically, patients in the stent group reported a significantly higher maximum walking capacity compared with the PTA group at 6 and 12 months. Conclusion: In this randomized multicenter trial, primary stenting with a self‐expanding nitinol stent for treatment of intermediate length SFA disease resulted morphologically and clinically superior midterm results compared with balloon angioplasty with optional secondary stenting.

Nitinol stent implantation in long superficial femoral artery lesions: 12-month results of the DURABILITY I study.

Purpose: To evaluate the long-term efficacy and integrity of the PROTÉGÉ EverFlex stent in superficial femoral artery (SFA) lesions in symptomatic patients with peripheral artery disease (PAD). Methods: A prospective, multicenter, nonrandomized study enrolled 151 subjects (111 men; mean age 67.8 years, range 42–93) undergoing percutaneous treatment of de novo, restenotic, or reoccluded SFA lesions between August 11, 2006, and June 26, 2007. Subjects were scheduled to receive a single stent and be evaluated through 12 months following the implant procedure. Occlusions were present in 40% of the patients. Mean lesion length was 96.4 mm (range 10–150). Results: A total of 161 stents (158 EverFlex) were implanted in the 151 patients: single stents in 93.4% (141/151) and a second stent in 6.6% (10/151). One-year follow-up information was available for 88.7% (134/151) of the study participants; of the remaining 17 subjects, 6 subjects withdrew from the study, 2 were lost to follow-up, and 9 died. Freedom from restenosis data were available for 99.3% (133/134) of the subjects who completed a 12-month follow-up visit. The mean Rutherford classification fell from 2.8±0.8 (range 1–5) at baseline to 0.6±1.1 (range 0–5) at 12 months. The mean ankle-brachial index rose from 0.6±0.2 (range 0–1.4) at baseline to 0.9±0.2 (range 0–1.2) at 12 months. The rates for freedom from >50% restenosis at 6 and 12 months were 91.3% (95% CI 84.9% to 95.2%) and 72.2% (95% CI 63.8% to 79.6%), respectively. The freedom from target lesion revascularization rate at 12 months was 79.1% (95% CI 71.2% to 85.6%). The 1-year stent fracture rate was 8.1% (95% CI 4.0% to 14.4%). Conclusion: The high freedom from >50% restenosis and low fracture rate at 12 months suggests that the PROTÉGÉ EverFlex stent offers a safe and acceptably efficacious means of treating SFA lesions in symptomatic subjects with PAD.

A prospective randomized multicenter comparison of balloon angioplasty and infrapopliteal stenting with the sirolimus-eluting stent in patients with ischemic peripheral arterial disease: 1-year results from the ACHILLES trial.

OBJECTIVES The study investigated the efficacy and safety of a balloon expandable, sirolimus-eluting stent (SES) in patients with symptomatic infrapopliteal arterial disease. BACKGROUND Results of infrapopliteal interventions using balloon angioplasty and/or bare stents are limited by a relatively high restenosis rate, which could be potentially improved by stabilizing the lesion with a SES. METHODS Two hundred patients (total lesion length 27 ± 21 mm) were randomized to infrapopliteal SES stenting or percutaneous transluminal balloon angioplasty (PTA). The primary endpoint was 1-year in-segment binary restenosis by quantitative angiography. RESULTS Ninety-nine and 101 patients (mean age 73.4 years; 64% diabetics) were randomized to SES and PTA, respectively (8 crossover bailout cases to SES). At 1 year, there were lower angiographic restenosis rates (22.4% vs. 41.9%, p = 0.019), greater vessel patency (75.0% vs. 57.1%, p =0.025), and similar death, repeat revascularization, index-limb amputation rates, and proportions of patients with improved Rutherford class for SES versus PTA. CONCLUSIONS SES implantation may offer a promising therapeutic alternative to PTA for treatment of infrapopliteal peripheral arterial disease.

Comparison of methods to evaluate clopidogrel-mediated platelet inhibition after percutaneous intervention with stent implantation

A high on-treatment residual ADP-inducible platelet reactivity in light transmission aggregometry (LTA) has been associated with an increased risk of adverse outcomes after percutaneous coronary intervention (PCI). However, LTA is weakly standardized, and results obtained in one laboratory may not be comparable to those obtained in another one. We therefore sought to determine the test correlating best with LTA to estimate clopidogrel-mediated platelet inhibition in 80 patients on dual antiplatelet therapy after elective percutaneous intervention with stent implantation. We selected the VerifyNow P2Y12 assay, the vasodilator-stimulated phosphoprotein phosphorylation assay, multiple electrode platelet aggregometry and the Impact-R for comparisons with LTA. Cut-off values for residual ADP-inducible platelet reactivity were defined according to quartiles of each assay. Sensitivities and specificities of the different platelet function tests were based on the results from LTA. The results from all four assays correlated significantly with those from LTA. The VerifyNow P2Y12 assay revealed the strongest correlation (r = 0.61, p < 0.001). Sensitivities and specificities ranged from 35% to 55%, and from 78.3% to 85%, respectively. In conclusion, although all assays correlated significantly with LTA, they need to be improved to become clinically used diagnostic tests. Further, it may be too early to define the gold standard method for assessing residual ADP-inducible platelet reactivity and generally acceptable cut-off values.

Calcium-channel blockers decrease clopidogrel-mediated platelet inhibition

Background The extent of clopidogrel-mediated platelet inhibition varies considerably from one person to the next. Numerous studies have shown that low responders have significantly more adverse events after coronary stenting than patients who respond well to antithrombotic treatment with clopidogrel. Dihydropyridine calcium-channel blockers (CCBs) inhibit the cytochrome P450 3A4 enzyme, which metabolises clopidogrel to its active form. Objective To investigate the influence of CCBs on clopidogrel-mediated platelet inhibition. Methods Adenosine-5-diphosphate (ADP)-inducible platelet reactivity was assessed by light transmission aggregometry (LTA) and the VerifyNow P2Y12 assay in 162 patients after percutaneous intervention with stent implantation. Results in the fourth quartiles of both assays were considered as high on-treatment residual ADP-inducible platelet reactivity. Results Patients with concomitant CCB therapy showed a significantly higher on-treatment platelet reactivity than patients without CCB medication (p=0.001 for both assays). Further, high on-treatment residual ADP-inducible platelet reactivity was significantly more common among patients currently taking CCBs (p=0.001 for LTA and p=0.004 for the VerifyNow P2Y12 assay). A multivariate regression analysis confirmed CCB therapy as an independent predictor of reduced clopidogrel-mediated platelet inhibition (p=0.006 for LTA and p=0.004 for the VerifyNow P2Y12 assay). Conclusion CCBs decrease clopidogrel-mediated platelet inhibition in patients undergoing angioplasty and stenting for cardiovascular disease.

Progression of Carotid Stenosis Detected by Duplex Ultrasonography Predicts Adverse Outcomes in Cardiovascular High-Risk Patients

Background and Purpose— The progression of carotid stenosis reflects the activity of atherosclerotic disease and may indicate a risk for systemic atherothrombotic complications. We investigated whether progressive carotid stenosis determined by duplex ultrasonography predicts adverse outcomes in cardiovascular high-risk patients. Methods— We prospectively studied 1065 of 1268 consecutive patients initially asymptomatic with respect to carotid disease. Carotid ultrasound investigations at baseline and after a median of 7.5 months (range, 6 to 9 months) were performed to identify patients with progressive stenosis as defined by Doppler velocity criteria. Patients were then followed up clinically for a median of 3.2 years for the occurrence of major adverse cardiovascular events (composite MACEs: myocardial infarction, percutaneous coronary or peripheral interventions, coronary or vascular surgery, amputation, stroke, and all-cause mortality). Results— We found progressive carotid stenosis in 93 patients (9%) by ultrasound and thereafter recorded 495 MACEs in 421 patients (40%) during clinical follow-up. Patients with progressive carotid stenosis had a significantly increased risk for cardiovascular events compared with patients with nonprogressive disease: adjusted hazard ratios and confidence intervals were 2.01 for composite MACEs (95% CI, 1.48 to 2.67, P<0.001), 2.38 for myocardial infarction (95% CI, 1.07 to 5.35, P=0.044), 1.59 for any coronary event (95% CI, 1.10 to 2.28, P=0.011), 2.00 for stroke (95% CI, 1.02 to 4.11, P=0.035), 2.42 for any peripheral vascular event (95% CI, 1.61 to 3.62, P<0.001), and 1.75 for cardiovascular death (95% CI, 1.03 to 2.97, P=0.039). Conclusion— Progression of carotid stenosis within a 6- to 9-month interval detected by duplex ultrasound predicts midterm clinical adverse events of atherosclerosis in high-risk patients affecting the coronary, cerebrovascular, and peripheral circulations.

Exercise training increases endothelial progenitor cells and decreases asymmetric dimethylarginine in peripheral arterial disease: A randomized controlled trial

BACKGROUND Supervised exercise training (SET) is recommended as initial treatment to improve walking capacity in peripheral arterial disease (PAD) patients with intermittent claudication. Various mechanisms by which SET yields beneficial effects are postulated, however data regarding its influence on angiogenesis are scarce. Thus, we designed a prospective randomized controlled trial to study the impact of SET on markers of angiogenesis and endothelial function in PAD. METHODS Forty PAD patients were randomized to SET on top of best medical treatment (SET+BMT) for 6 months versus best medical treatment (BMT) only. Endothelial progenitor cells (EPC) were assessed by whole-blood flow cytometry (co-expression of CD34+ CD133+ KDR+) and cell culture assays (endothelial cell-colony forming units, circulating angiogenic cells, migration assay) at baseline, 3, 6 and 12-months after inclusion. Changes of plasma levels of asymmetric dimethylarginine (ADMA), vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 (SDF-1) and maximum walking distance were determined. RESULTS EPC - measured by flow cytometric and cell culture techniques - increased significantly upon training paralleled by a significant decrease of ADMA when compared to the BMT group (p<0.05). Six months after training cessation, the beneficial effect of SET on EPC diminished, but maximum walking distance was significantly improved compared to baseline and controls (p<0.05). No significant changes were observed for VEGF and SDF-1 plasma levels in time course. CONCLUSIONS SET increases circulating EPC counts and decreases ADMA levels reflecting enhanced angiogenesis and improved endothelial function, which might contribute to cardiovascular risk reduction.

Effect of Massive Weight Loss induced by Bariatric Surgery on Serum Levels of Interleukin-18 and Monocyte-Chemoattractant-Protein-1 in Morbid Obesity

Background: Morbid obesity is associated with insulin resistance (IR), chronic inflammation and premature atherosclerosis. Since vascular inflammation may contribute to the increased risk of cardiovascular morbidity and mortality of these patients, we studied circulating Interleukin-18 (L-18) and monocyte-chemoattractant-protein-1 (MCP-1) levels in 37 patients with morbid obesity before and after significant weight loss induced by bariatric surgery and their preoperative and postoperative associations with C-reactive protein (CRP) and IR-associated factors. Methods: High sensitivity assays were used to measure concentrations of fasting CRP, IL-18 and MCP-1. Differences between patients before and after bariatric surgery were analyzed by Students paired t-test. To investigate the associations of the observed reductions of values, delta of parameters were calculated and preoperative, postoperative and delta data were tested by univariate and multivariate linear regression. Results: After a mean follow-up period of 26.5 months and a massive weight loss of 35 kg induced by bariatric surgery, circulating IL-18 levels decreased by 37% (P<0.001) and circulating MCP-1 levels by 47% (P<0.001). Multiple linear regression of delta values of IL-18 showed that only 2-hour glucose (P=0.008) remained independently and significantly associated with IL-18, whereas multiple linear regression analysis of delta values of MCP-1 revealed that only delta of HOMA-IR (P<0.001) remained independently and significantly associated with MCP-1, respectively. Conclusions: Because both biomarkers have been shown to play an important role in the development and progression of atherosclerosis, the observations presented in this study could be of clinical relevance for morbidly obese patients undergoing bariatric surgery.

Adenosine diphosphate‐inducible platelet reactivity shows a pronounced age dependency in the initial phase of antiplatelet therapy with clopidogrel

Summary.  Background: Until recently, there were hardly any data on the antiplatelet effect of clopidogrel in advanced age. Like other metabolic processes, the conversion of clopidogrel to its active metabolite may be impaired in older patients, leading to high on‐treatment residual ADP‐inducible platelet reactivity. Objective: To investigate the age dependency of clopidogrel‐mediated platelet inhibition. Patients and methods: This was a prospective observational study. We determined adenosine 5′‐diphosphate (ADP)‐inducible platelet reactivity using light transmission aggregometry (LTA) and the VerifyNow P2Y12 assay in 191 patients on dual antiplatelet therapy after angioplasty and stenting for cardiovascular disease. Results: ADP‐inducible platelet reactivity increased linearly with age after adjustment for cardiovascular risk factors, type of intervention, medication, C‐reactive protein (CRP) and renal function [using LTA 0.36% of maximal aggregation per year, 95% CI 0.08–0.64%, P = 0.013; using the VerifyNow P2Y12 assay 3.2 P2Y12 reaction units (PRU) per year, 95% CI 1.98–4.41 PRU, P < 0.001]. ADP‐inducible platelet reactivity was significantly higher in patients aged 75 years or older compared with younger patients (P = 0.003 for LTA and P < 0.001 for the VerifyNow P2Y12 assay). Further, high on‐treatment residual ADP‐inducible platelet reactivity was significantly more common among patients aged 75 years or older (P = 0.02 for LTA and P < 0.001 for the VerifyNow P2Y12 assay). Conclusion: ADP‐inducible platelet reactivity shows a pronounced age dependency in the initial phase of antiplatelet therapy with clopidogrel. The clinical implications of these findings need to be addressed in future trials.

Fetuin-A levels are increased in patients with type 2 diabetes and peripheral arterial disease

OBJECTIVE Low levels of fetuin-A, a systemic calcification inhibitor, are linked to mortality in patients on dialysis. In contrast, elevated fetuin-A is associated with cardiovascular events in non-renal patients. We investigated fetuin-A in patients with type 2 diabetes and peripheral arterial disease (PAD). RESEARCH DESIGN AND METHODS We studied fetuin-A in 76 patients with PAD and normal glucose metabolism (NGM-PAD) and in 129 patients with PAD and type 2 diabetes (type 2 diabetes–PAD). Additionally, 40 patients with diabetes without any complications (type 2 diabetes–non-PAD) were examined. RESULTS Type 2 diabetes–PAD subjects (399 ± 155 μg/ml) had significantly higher fetuin-A levels than type 2 diabetes–non-PAD subjects (247 ± 42; P < 0.001). In NGM-PAD subjects (376 ± 144), fetuin-A was significantly higher than in type 2 diabetes–non-PAD subjects (P < 0.001). Type 2 diabetes–PAD patients with mediasclerosis had lower fetuin-A than subjects without (P < 0.03). Regression analysis in type 2 diabetes–PAD subjects revealed that glycated A1C (P < 0.001) and mediasclerosis (P = 0.004) were the strongest predictors of fetuin-A. Multivariate regression revealed that a 1-SD increase in fetuin-A was associated with an odds ratio (OR) of 2.1 (95% CI 1.1–3.3; P < 0.001) for the prevalence of PAD and an OR of 1.4 (1.0–1.7, P = 0.039) for the prevalence of myocardial infarction. CONCLUSIONS In contrast to previous findings, fetuin-A was higher in type 2 diabetes–PAD patients than in type 2 diabetes–non-PAD patients. In NGM-PAD patients, fetuin-A was also higher than in type 2 diabetes–non-PAD patients. In type 2 diabetes–PAD patients, fetuin-A was inversely associated with mediasclerosis—the calcification process pathognomonic for diabetic PAD. This association persisted in multivariate regression, which is in line with the calcification inhibition in coronary heart or renal disease.