PAD screening: why? whom? when? how? - a systematic review.

An estimated 237 million people suffer from peripheral arterial disease (PAD), which is associated with high morbidity and mortality, and prevalence is still increasing. Currently, we do not have any randomized trials that compare screening to no screening specifically for PAD in the general population. Presently, PAD screening is not generally established. This systematic review gives an overview of relevant literature and guidelines. Screening usually focuses on ankle-brachial index (ABI)-measurement, which enables detection of asymptomatic and symptomatic PAD, but has limitations in diabetics. There are no sufficient data on PAD screening. Guideline recommendations are heterogeneous. While some advocate no screening until better data are available, most recommend selective screening despite insufficient data on morbidity and mortality reduction in consequence of screening. We support the only evidence-based screening strategy for PAD: combined screening for abdominal aortic aneurysm (AAA), PAD and arterial hypertension in men aged 65-74 according to the VIVA study. We additionally suggest a new simple three-step screening strategy for symptomatic PAD in all individuals aged 40 and older, who see a general practitioner: Asking one question ("Do you have pain or cramps in the legs during normal walking?") followed by physical examination (normal lower extremity pulse status?) in those, whose answer is "yes", and ABI measurement unless all pulses are normal.

Phlegmasia cerulea dolens - an uncommon but alarming manifestation of deep vein thrombosis.

In phlegmasia cerulea dolens (PCD), immediate diagnosis and prompt treatment is crucial for limb salvage. Aggressive treatment options including venous intervention, thrombolysis and/or surgical thrombectomy should be considered. Due to the lack of data, the most appropriate intervention depends upon etiology of PCD, clinical presentation and patient's bleeding risk.

One simple claudication question as first step in Peripheral Arterial Disease (PAD) screening: A meta-analysis of the association with reduced Ankle Brachial Index (ABI) in 27,945 subjects.

PURPOSE AND METHODS: A meta-analysis using data from seven German population-based cohorts was performed by the German Epidemiological consortium of Peripheral Arterial Disease (GEPArD) to investigate whether one question about claudication is more efficient for PAD screening than established questionnaires. Claudication was defined on the basis of the answer to one question asking for pain in the leg during normal walking. This simple question was compared with established questionnaires, including the Edinburgh questionnaire. The associations of claudication with continuous ABI values and decreased ABI were analyzed by linear and logistic regression analysis, respectively. The results of the studies were pooled in a random effect meta-analysis, which included data from 27,945 individuals (14,052 women, age range 20-84 years). RESULTS: Meta-analysis revealed a significant negative association between claudication and ABI, which was stronger in men (ß = -0.07; 95%CI -0.10, -0.04) than in women (ß = -0.02; 95%CI -0.02, -0.01). Likewise, the presence of claudication symptoms was related to an increased odds of a decreased ABI in both men (Odds ratio = 5.40; 95%CI 4.20, 6.96) and women (Odds ratio = 1.99; 95%CI 1.58, 2.51). CONCLUSIONS: Asking only one question about claudication was able to identify many individuals with a high likelihood of a reduced ABI with markedly higher sensitivity and only slightly reduced specificity compared to more complex questionnaires. At least in men, this question should be established as first screening step.

Drug-Coated Balloon Versus Standard Balloon for Superficial Femoral Artery In-Stent Restenosis: The Randomized Femoral Artery In-Stent Restenosis (FAIR) Trial.

BACKGROUND: Drug-coated balloon angioplasty (DCBA) was shown to be superior to standard balloon angioplasty (POBA) in terms of restenosis prevention for de novo superficial femoral artery disease. For in-stent restenosis, the benefit of DCBA over POBA remains uncertain. METHODS AND RESULTS: One hundred nineteen patients with superficial femoral artery in-stent restenosis and chronic limb ischemia were recruited over 34 months at 5 German clinical sites and prospectively randomized to either DCBA (n=62) or POBA (n=57). Mean lesion length was 82.2±68.4 mm. Thirty-four (28.6%) lesions were totally occluded; 30 (25.2%) were moderately or heavily calcified. Clinical and duplex ultrasound follow-up was conducted at 6 and 12 months. The primary end point of recurrent in-stent restenosis assessed by ultrasound at 6 months was 15.4% (8 of 52) in the DCBA and 44.7% (21 of 47) in the POBA group (P=0.002). Freedom from target lesion revascularization was 96.4% versus 81.0% (P=0.0117) at 6 months and 90.8% versus 52.6% (P<0.0001) at 12 months, respectively. At 12 months, clinical improvement by ≥1 Rutherford category without the need for target lesion revascularization was observed in 35 of 45 DCBA patients (77.8%) and 23 of 44 POBA patients (52.3%; P=0.015). No major amputation was needed. Two patients in the DCBA and 3 patients in the POBA group died. No death was procedure related. CONCLUSIONS: DCBA for superficial femoral artery in-stent restenosis is associated with less recurrent restenosis and a better clinical outcome than POBA without an apparent difference in safety. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01305070.

German multicenter real-world registry of stenting for superficial femoral artery disease: clinical results and predictive factors for revascularization.

PURPOSE: To investigate nitinol stent treatment of superficial femoral artery (SFA) lesions and the impact of different risk factors on the need for clinically driven target lesion revascularization (TLR) in a large, real-world population of claudicants. METHODS: Patients presenting with symptomatic SFA stenosis >70% were consecutively enrolled in the 13-center MARIS prospective registry (ClinicalTrials.gov identifier NCT01067885). There was no restriction on lesion length, thus leading to the inclusion of a real-world as well as high-risk patient cohort. The 998 participating patients (657 men; mean age 67.4±9.2 years) had 1050 lesions treated with the same nitinol stent type. The mean lesion length was 9.5±9.6 cm (range 0.5-44; median 8.0); more than a third of the lesions (450, 42.9%) were total occlusions. The primary endpoint was the need for clinically driven target lesion revascularization (TLR) at 12 months. RESULTS: Acute technical success was achieved in 1042 (99.2%) lesions. Restenosis occurred in 187 (23.7%) and reocclusion in 79 (10.0%) lesions at 12 months. The primary endpoint of TLR at 12 months was reached by 136 (17.2%) patients. The periprocedural complication rate was 5.4%. Independent predictors of TLR were female gender [odds ratio (OR) 0.5, 95% confidence interval (CI) 0.3 to 0.7, p<0.001] and lesion length >20 cm vs. 10 cm (OR 2.7, 95% CI 1.1 to 6.6, p=0.029) and 10-20 cm vs. 10 cm (OR 1.9, 95% CI 1.0 to 4.1, p=0.047). CONCLUSION: Stent implantation in the SFA is safe and associated with favorable acute and midterm results in a real-world setting. Lesion length and female gender were identified as independent risk factors for TLR.

Association of multiple biomarkers and classical risk factors with early carotid atherosclerosis: results from the Gutenberg Health Study.

BACKGROUND: In the Gutenberg Health Study, a random sample of the population was scanned with vascular ultrasound for early atherosclerosis. A continuous classical risk marker model (waist circumference, HbA1c, LDL/HDL ratio, pack years and pulse pressure) was compared to a model of modern biomarkers (C-reactive protein, troponin I, N-terminal pro B-type natriuretic peptide, copeptin, mid-regional pro-adrenomedullin, and asymmetric dimethylarginine) with regard to the ability of ruling out abnormal intima-media thickness (IMT), respectively, carotid plaques. METHODS: Data of the first consecutive 5,000 participants (aged 35-74 years; 2,540 men, 2,460 women) were analyzed. IMT was measured at both common carotid arteries using an edge detection system. Plaques were defined as protrusion of ≥1.5 mm in common, internal and external carotid artery. RESULTS: For classical risk factors, in comparison to a model of six modern biomarkers, regarding the variable (a) IMT>0.85 mm negative and positive predictive value (NPV and PPV) were 0.98 and 0.16 for both the classical risk factor model and the biomarker model. The second variable (b) presence of plaque could be ruled out with an NPV of 0.84 and identified with a PPV of 0.61 for classical risk factors, and 0.84 and 0.58 for biomarkers, respectively. Values were calculated using logistic regression analysis. CONCLUSION: Classical risk factors allow ruling out pathologic IMT and presence of carotid plaques in a population of primary prevention in a reliable way. Modern biomarkers performed almost equally well but did not provide further information.

Distal false lumen occlusion in aortic dissection with a homemade extra-large vascular plug: the candy-plug technique.

PURPOSE: To report a technique to create an extra-large vascular plug for occlusion of a large distal false lumen in chronic aortic dissection. TECHNIQUE: The "candy-plug" technique is demonstrated in a 58-year-old multimorbid man with a history of complicated acute type B aortic dissection and a 9-cm chronic thoracic false lumen aneurysm. The patient underwent a staged repair with a cervical debranching procedure as a first step and a thoracic endovascular aortic repair from the innominate artery to the celiac artery as a second step. To occlude the large false lumen from a distal route, a stent-graft was modified on-table with a diameter-restricting suture, giving it a wrapped candy-like shape. This plug was deployed into the false lumen, and the remaining opening was occluded with a standard vascular plug. On 3-month follow-up imaging, the thoracic false lumen aneurysm remained completely thrombosed. CONCLUSION: The candy-plug technique can facilitate complete occlusion of chronic thoracic false lumen aneurysm by prohibiting distal false lumen backflow.

Variants of Toll-like receptor 4 predict cardiac recovery in patients with dilated cardiomyopathy.

The clinical course of patients with dilated cardiomyopathy (DCM) varies from cardiac recovery to end stage heart failure. The etiology of this variability is largely unknown. In this study, we investigated the impact of coding polymorphisms of the innate immune protein Toll-like receptor 4 (TLR4) on left ventricular performance in patients with DCM. Two variants of TLR4 (rs4986790, TLR4 c.1187A→G, p.299D→G and rs4986791,TLR4 c.1487C→T, p.T399I) were investigated in 158 patients with DCM. Other reasons for heart failure were excluded by coronary angiography, myocardial biopsy, and echocardiography. Risk factors, age, gender, or treatment did not differ among the groups. At the follow-up evaluation (median 4.0-5.4 months), patients carrying the TLR4 wild type gene displayed cardiac recovery under intense medical heart failure therapy indexed by reduced left ventricular dilation, improved left ventricular ejection fraction, and reduced NT-probrain natriuretic peptide blood level when compared with the initial evaluation. In contrast, patients carrying both the rs4986790 and the rs4986791 variant showed significantly reduced improvement of left ventricular ejection fraction (p = 0.006) and left ventricular dilation (p = 0.015) at the follow-up evaluation when compared with carriers of the wild type gene under the same treatment conditions. In addition, NT-probrain natriuretic peptide level in carriers of both TLR4 variants did not change significantly at the follow up when compared with the first evaluation. Among patients with DCM, the presence of the TLR4 variants rs4986790 and rs4986791 predicts impaired cardiac recovery independently of medical treatment or cardiac risk factors.

Claudication, in contrast to angina pectoris, independently predicts mortality risk in the general population.

BACKGROUND: The aim of our analyses was to investigate whether claudication and angina pectoris, each defined and based on the answer to a single question, are predictive of future mortality. PROBANDS AND METHODS: The study population consisted of 3995 subjects selected from the population-based Study of Health In Pomerania (SHIP). Kaplan-Meier analysis and multivariable Cox proportional hazards regression analysis were used to analyze the association of angina pectoris and claudication with all-cause and cardiovascular mortality adjusted for major cardiovascular risk factors. RESULTS: At baseline, 417 individuals had symptoms of angina pectoris, and 323 had symptoms of claudication. During a median follow-up of 8.5 years, 277 individuals died. Individuals with claudication had a higher fully-adjusted all-cause mortality rate (Hazard Ratio (HR) 1.79; 95 % CI 1.34, 2.39, p < 0.001) and a higher sex- and age-adjusted cardiovascular mortality rate (HR 1.76; 95 % CI 1.03, 2.99, p = 0.038) compared to subjects without claudication. In contrast, subjects with angina pectoris had neither an elevated fully-adjusted all-cause mortality rate (HR 1.15; 95 % CI 0.82, 1.61, p = 0.413) nor sex- and age-adjusted cardiovascular mortality rate (HR 0.71; 95 % CI 0.34, 1.48, p = 0.363) compared to those without this symptom. CONCLUSIONS: Claudication, in contrast to angina pectoris, is a strong, independent predictor of all-cause mortality.

Effects of immunoadsorption and subsequent immunoglobulin G substitution on cardiopulmonary exercise capacity in patients with dilated cardiomyopathy.

BACKGROUND: Recent data indicate that cardiac antibodies play an active role in the pathogenesis of dilated cardiomyopathy (DCM) and may contribute to cardiac dysfunction in patients with DCM. The present study investigated the influence of immunoadsorption with subsequent immunoglobulin G substitution (IA/IgG) on cardiopulmonary exercise capacity in patients with DCM. METHODS: Sixty patients with DCM (New York Heart Association II-IV, left ventricular ejection fraction < or =45%) were included in this single-center university hospital-based case-control study. Patients either were treated with IA/IgG (n = 30) or were followed without IA/IgG (n = 30). At baseline and after 3 months, we compared echocardiographic assessment of left ventricular function and spiroergometric exercise parameters. RESULTS: In contrast to controls, left ventricular ejection fraction improved significantly in the IA/IgG group from 33.0% +/- 1.2% to 40.1% +/- 1.5% (P < .001). In the control group, spiroergometric exercise parameters did not change during follow-up. After 3 months, maximum achieved power increased in the treatment group from 114.2 +/- 7.4 to 141.9 +/- 7.9 W (P = .02). Total exercise time increased in the treatment group from 812 +/- 29 to 919 +/- 30 seconds (P < .05). Peak oxygen uptake (Vo(2)) increased from 17.3 +/- 0.9 to 21.8 +/- 1.0 mL min(-1) kg(-1) after IA/IgG (P < .01). Oxygen pulse (peak Vo(2)/maximum heart rate) increased in the treatment group (10.7 +/- 0.7 vs 13.6 +/- 0.7 mL beat(-1) min(-1), P < .01). The Vo(2) at the gas exchange anaerobic threshold increased after 3 months in the treatment group from 10.3 +/- 0.5 to 13.2 +/- 0.5 mL min(-1) kg(-1) (P < .001). The ventilatory response to exercise (V(E)/Vco(2) slope) decreased after IA/IgG therapy from 32.3 +/- 1.5 to 28.7 +/- 0.9 (P = .02). CONCLUSIONS: In patients with DCM, IA/IgG therapy may induce improvement in echocardiographic and cardiopulmonary exercise parameters.

Impedance cardiography versus invasive measurements of stroke volume index in patients with chronic heart failure.

We assessed the hypothesis that non-invasive measurement of stroke volume index can replace invasive measurements in patients with chronic heart failure. Non-invasive impedance cardiography (ICG) measurements together with invasive hemodynamic thermodilution (TD) measurements were performed in 13 patients with severe chronic heart failure (NYHA III-IV). Agreement between ICG and TD regarding stroke volume index was poor. Correlation between non-invasive and invasive hemodynamic measurements was low (r=0.29). In conclusion, non-invasive measurements of stroke volume index using impedance cardiography did not result in sufficient agreement with invasive thermodilution measurements in this study with patients suffering from severe chronic heart failure.

Quinaprilat: a review of its pharmacokinetics, pharmacodynamics, toxicological data and clinical application.

BACKGROUND: Quinaprilat is an ACE inhibitor for intravenous use especially in patients with arterial hypertension or chronic heart failure. In contrast to the oral prodrug quinapril, it has not been approved for clinical application. OBJECTIVE: In this review, the pharmacokinetic and pharmacodynamic profile of quinaprilat as well as toxicological data and results of preclinical and clinical studies are summarized. METHODS: In a PubMed search for the terms "quinaprilat" and "quinapril", literature relevant for this review was selected. RESULTS: Quinaprilat is a potent nonsulfhydryl selective ACE inhibitor with a short elimination half-life of 2 - 3 h, but due to slow dissociation from tissue ACE, once daily dosing is sufficient for effective ACE inhibition. Quinaprilat is excreted mainly in urine. In long-term animal studies, quinaprilat was not teratogenic, mutagenic or carcinogenic. However, due to the risk of fetal and neonatal morbidity and death, it should not be administrated in pregnancy. Quinaprilat is characterized by an excellent safety profile; adverse events occur infrequently and are rarely serious. CONCLUSION: Quinaprilat is an attractive ACE inhibitor, which potently inhibits tissue ACE.

The cardiovascular safety of tadalafil.

Tadalafil is an inhibitor of phosphodiesterase 5, approved for the treatment of erectile dysfunction. Blood pressure-lowering effects of tadalafil in healthy volunteers are minimal. In patients on a broad spectrum of antihypertensive medication, severe hypotension did not occur in combination with tadalafil; however, a combination of tadalafil with any nitric oxide donor can lead to life-threatening hypotension and is, therefore, absolutely contraindicated (at least 48 h interval after last dose of tadalafil). Combination with alpha-blocking agents, such as doxazosin, may only be considered when patients are hemodynamically stable for a longer period using the lowest dose of tadalafil and with close blood pressure monitoring. In placebo-controlled trials, severe adverse cardiovascular events were rare in tadalafil users and similar in frequency in comparison to placebo. However, as cardiovascular disease is highly prevalent in patients with erectile dysfunction, a complete diagnostic work up of these patients and potentially optimized cardiovascular treatment may be necessary before sexual intercourse can be recommended and tadalafil may be prescribed.

Haemodynamic effects of intravenous quinaprilat in comparison to sodium nitroprusside in patients with chronic heart failure.

We compared the haemodynamic effects of intravenous boluses of the ACE inhibitor quinaprilat with an intravenous infusion of sodium nitroprusside in 23 patients with chronic heart failure (NYHA Class III or IV). At the highest drug doses, sodium nitroprusside significantly increased stroke volume index (+6.63 ml/m(2), p=0.045), whereas quinaprilat induced only a minor increase (+1.79 ml/m(2), n.s.).

Hemodynamic effects of alpha1-adrenoceptor antagonist, doxazosin, in patients with chronic congestive heart failure.

PURPOSE: Non-selective alpha-adrenoceptor antagonists have not demonstrated significant beneficial effects in chronic heart failure. Previous studies with the selective alpha1-adrenoceptor antagonist, doxazosin, led to conflicting results. We assessed the hypothesis that treatment with doxazosin adjuvant to standard oral therapy results in significant increase in cardiac index in patients with chronic heart failure. METHODS: A double-blind, randomized study was conducted on 30 patients with chronic congestive heart failure (NYHA III-IV), with cardiac index<2.5 l/minxm, and/or with pulmonary capillary wedge pressure>16 mm Hg. Of the 30 patients, 15 were treated with doxazosin and 15 with placebo, both adjuvant to stable oral therapy, which included a minimum of an ACE inhibitor and a diuretic. Hemodynamic measurements were performed on days 1 and 2, and after 12 weeks on study medication. On day 1, patients were treated with 4 mg doxazosin or placebo. On day 2 and throughout the following 12 weeks, the patients were treated with 4 mg or 8 mg doxazosin/d (the latter, if 4 mg/d did not induce an increase >0.75 l/minxm in cardiac index), or with placebo. RESULTS: Six patients were treated with 4 mg doxazosin/d (group A), 9 patients with 8 mg doxazosin/d (group B), and 15 with placebo. Baseline values for the cardiac index on day 1, day 2, and after 12 weeks failed to disclose significant differences between patient groups and between the days of study. On day 1, the increase in cardiac index compared with baseline was significantly higher in group A than in the placebo group (P=0.004) and group B (P=0.001). On day 2, the increase in cardiac index compared with baseline on day 1 was significantly higher in group A than in group B (P=0.003) (with reference to alpha/3=0.0167 according to Bonferroni). This was no longer observed after 12 weeks. In the placebo group, following significant changes occurred in baseline values, heart rate was lower (P=0.023) and stroke volume index was higher after 12 weeks in comparison to day 1 (P=0.032). CONCLUSIONS: In conclusion, oral application of doxazosin supplementary to standard oral medication did not induce sustained hemodynamic benefit. Significant acute increase in cardiac index was observed in a minority (40%) of patients, whereas favorable changes in baseline hemodynamic parameters after 12 weeks occurred in the placebo group.