Diagnosis and management of vascular Ehlers-Danlos syndrome: Experience of the UK national diagnostic service, Sheffield.

The UK National Diagnostic Service for Ehlers-Danlos Syndromes (EDS) was established in 2009 for the rare types of EDS. Vascular EDS (vEDS) is an inherited connective tissue disorder caused by pathogenic variants in the COL3A1 gene. Associated tissue fragility affects multiple organ systems, increasing the risk of blood vessel dissection and rupture, with potentially fatal consequences. The diagnosis of vEDS has improved with advances in genetic testing, however this is most often suspected following an acute event. We provide data on the clinical features of vEDS for 180 patients (full cohort) seen in our service with confirmed molecular diagnoses. Increased awareness of this rare condition will prompt genetic testing essential to confirm the diagnosis. Outcomes are improved by early diagnosis followed by appropriate management. Fragile connective tissues make invasive procedures potentially dangerous, particularly in an emergency setting. Lifestyle advice from a young age can help acceptance and understanding of the diagnosis and inform choices. There is currently limited evidence for the use of drug therapy to reduce vascular events. We report on the incidence of vascular events in 126 patients (statistical analysis cohort) in our care and the use of medication. Our retrospective data showed that those patients on a long-term angiotensin II receptor blocker and/or beta-blocker had fewer vascular events than those not on cardiac medication who received the same lifestyle and emergency care advice.

Study of Two Dose Regimens of Ticagrelor Compared With Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention for Stable Coronary Artery Disease.

BACKGROUND: Ticagrelor has superior efficacy to clopidogrel in the management of acute coronary syndromes but has not been assessed in patients undergoing percutaneous coronary intervention for stable coronary artery disease. We compared the pharmacodynamic effects of ticagrelor and clopidogrel in this stable population. METHODS: One hundred eighty aspirin-treated stable coronary artery disease patients, who were planned to undergo elective percutaneous coronary intervention in a single center, were randomized 1:1:1 to either a standard clopidogrel regimen or 1 of 2 regimens of ticagrelor, either 90 mg (T90) or 60 mg twice daily (T60), both with a 180 mg loading dose. Cellular adenosine uptake was assessed, at the time of the procedure and pre- and postdose at 1 month, by adding adenosine 1 µmol/L to aliquots of anticoagulated whole blood and mixing with a stop solution at 0, 15, 30, and 60 seconds, then measuring residual plasma adenosine concentration by high-performance liquid chromatography. Systemic plasma adenosine concentration and platelet reactivity were assessed at the same timepoints. High-sensitivity troponin T was measured pre- and 18 to 24 hours postpercutaneous coronary intervention. RESULTS: One hundred seventy-four patients underwent an invasive procedure, of whom 162 received percutaneous coronary intervention (mean age 65 years, 18% female, 21% with diabetes mellitus). No effect on in vitro adenosine uptake was seen postdose at 1 month for either ticagrelor dose compared with clopidogrel (residual adenosine at 15 seconds, mean±SD: clopidogrel 0.274±0.101 µmol/L; T90 0.278±0.134 µmol/L; T60 0.288±0.149 µmol/L; P=0.37). Similarly, no effect of ticagrelor on in vitro adenosine uptake was seen at other timepoints, nor was plasma adenosine concentration affected (all P>0.1). Both maintenance doses of ticagrelor achieved more potent and consistent platelet inhibition than clopidogrel (VerifyNow P2Y12 reaction units, 1 month, mean±SD: predose, T60: 62±47, T90: 40±38, clopidogrel 181±44; postdose, T60: 34±30, T90: 24±21, clopidogrel 159±57; all P<0.0001 for ticagrelor versus clopidogrel). High platelet reactivity was markedly less with both T60 and T90 compared with clopidogrel (VerifyNow P2Y12 reaction units>208, 1 month postdose: 0%, 0%, and 21%, respectively). Median (interquartile range) high-sensitivity troponin T increased 16.9 (6.5-46.9) ng/L for clopidogrel, 22.4 (5.5-53.8) ng/L for T60, and 17.7 (8.1-43.5) ng/L for T90 (P=0.95). There was a trend toward less dyspnea with T60 versus T90 (7.1% versus 19.0%; P=0.09). CONCLUSIONS: Maintenance therapy with T60 or T90 had no detectable effect on cellular adenosine uptake at 1 month, nor was there any effect on systemic plasma adenosine levels. Both regimens of ticagrelor achieved greater and more consistent platelet inhibition than clopidogrel but did not appear to affect troponin release after percutaneous coronary intervention. CLINICAL TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifier: NCT02327624.

Anemia, hypoalbuminemia, and renal impairment as predictors of bleeding complications in patients receiving anticoagulation therapy for nonvalvular atrial fibrillation: a secondary analysis.

OBJECTIVE: The aim of this analysis was to evaluate the roles of anemia, hypoalbuminemia, and renal impairment as independent predictors of bleeding in patients with nonvalvular atrial fibrillation (NVAF) receiving anticoagulation therapy with warfarin. METHODS: This was a previously published prospective, observational study conducted between November 1999 and July 2001. Patients with NVAF newly started on warfarin and referred to an anticoagulation clinic at a large university hospital (Northern General Hospital, Sheffield, United Kingdom), either at the time of hospital discharge or by their general practitioner, were eligible. Patients were divided into 2 groups: those aged <75 years; and those aged > or =75 years. Patients were seen at the clinic for an initial visit, and baseline information, including age, sex, employment status, medical history, and medication list, was obtained. Patients were also interviewed regarding episodes of bleeding (classified as minor bleeding events or major bleeding events) at the initial patient visit and by telephone every 4 to 6 weeks thereafter. RESULTS: A total of 402 patients (mean [SD] age, 72.3 [10.3] years [range, 34-94 years]; 224 men [55.7%], 178 women [44.3%]) were included. Follow-up was complete for all patients (mean follow-up, 19.0 [8.1] months [range, 1.0-31.0 months]). A total of 107 minor and 11 major bleeding events were reported. Hypoalbuminemia was a significant predictor of all bleeding in patients aged <75 years (adjusted odds ratio [AOR] = 2.60; 95% CI, 1.26-5.33; P = 0.01), while renal impairment was a significant predictor in patients aged > or = 75 years (AOR = 2.65; 95% CI, 1.71-6.49; P = 0.01). After stratification by bleeding type, renal impairment was a significant predictor of major bleeding in patients aged > or = 75 years (AOR = 2.93; 95% CI, 1.03-9.58; P = 0.001). Anemia was not associated with bleeding. CONCLUSION: Hypoalbuminemia and renal impairment were identified as patient-related predictive factors for bleeding, whereas anemia did not appear to increase this risk.

Risk factors for bleeding during anticoagulation of atrial fibrillation in older and younger patients in clinical practice.

BACKGROUND: The prevalence of atrial fibrillation increases with age, affecting approximately 5% of people aged >65 years and almost 10% of people aged >80 years. OBJECTIVE: The goal of this study was to identify risk factors for bleeding during warfarin treatment of nonvalvular atrial fibrillation (NNVAF) in older patients (those aged >or=75 years) compared with younger patients (those aged <75 years) in clinical practice. METHODS: All patients with NVAF newly started on warfarin at an anticoagulation clinic in a large university hospital were included in this prospective observational study. Patient details were recorded at their first visit; details of any bleeding events were recorded via telephone interview every 4 to 6 weeks for a minimum of 10 months. Patients were divided into 2 groups (ie, those >or=75 years old and those <75 years old). Logistic regression analysis was used to identify risk factors for bleeding. RESULTS: A total of 402 patients were included in the study. Group I comprised 203 patients <75 years old (mean [SD] age, 64.33 [8.33] years) and group II comprised 199 patients >or=75 years old (mean [SD] age, 80.44 [3.99] years). Follow-up ranged from 1 to 31 months (mean [SD], 19 [8.11] months). For major bleeding, number of medications was a significant risk factor in older patients (odds ratio [OR], 3.0; 95% CI, 1.2-7.8 [P = 0.02 ]) and range of the international normalized ratio (INR) was a significant risk factor in both groups. For every unit increase in the range of INR, the odds of major bleeding increased by 0.6 (OR, 1.6; 95% CI, 1.2-2.4 [P = 0.03 ]) in younger patients and by 0.4 (OR, 1.4; 95% CI, 1.07-1.99 [P = 0.04 ])in older patients. For minor bleeding, history of hypertension was the only significant risk factor in older patients (OR, 3.3; 95% CI, 1.3-8.1 [P = 0.01 ]), while history of ischemic heart disease was the only risk factor in younger patients (OR, 1.9; 95% CI, 1.1-5.4 [P = 0.04 ]). CONCLUSIONS: Bleeding pattern was similar in both age groups regarding severity, onset, anatomic site of bleeding, and INR values during the bleeding event. Risk factors for episodes of major bleeding, which are more of a clinical concern, are potentially modifiable. They include quality of anticoagulation control in both groups and number of medications in the older age group.

Hemodynamic assessment of mitral mechanical prostheses under high flow conditions: comparison between dynamic exercise and dobutamine stress.

BACKGROUND AND AIM OF THE STUDY: The study aim was to compare the effects of dobutamine stress and exercise on prosthetic mitral valve hemodynamics. METHODS: Twenty-three patients who had recently (3 +/- 1 months) undergone mechanical mitral valve implantation were studied. Hemodynamic variables, two-dimensional echocardiographic and Doppler mitral/aortic flows were recorded at rest, and then repeated during exercise and dobutamine stress. The investigations were randomized place to determine which stress would be performed first. RESULTS: Heart rates and pressure drops rose significantly from resting values. At maximum stress, exercise produced maximum and mean pressure drops which were statistically greater than with dobutamine (19.4 +/- 6.0 versus 12.8 +/- 4.7 mmHg (p < 0.001) and 10.2 +/- 3.5 versus 6.8 +/- 2.8 (p < 0.01), respectively). Exercise was associated with statistically shorter diastolic filling times and higher transvalvular diastolic flow rates. Dobutamine produced a greater augmentation in mitral effective orifice area (EOA) (p < 0.05). The slopes of pressure drop/cardiac flow were calculated for stress type and shown to be significantly lower during dobutamine administration (p = 0.03). CONCLUSION: Normally functioning mitral prostheses can generate significant increases in valvular pressure drops under high flow conditions. Physiological differences exist between dobutamine stress and exercise when assessing diastolic filling. At a given flow rate, dobutamine produces a greater augmentation in the mitral EOA and a smaller drop in transvalvular pressure.

Hemodynamic performance of the Ultracor and Carpentier-Edwards aortic prostheses using exercise and dobutamine stress echocardiography.

BACKGROUND AND AIM OF THE STUDY: The study aim was to compare the hemodynamic profiles of the aortic standard porcine Carpentier-Edwards (C-E) and Ultracor (tilting-disc) valve using exercise and dobutamine stress. METHODS: A total of 36 patients was examined, 18 for each valve type. When analyzing the data, valve types were matched for valve size, which ranged from 21 to 25 mm. All patients were analyzed within an 18-month period after implantation. Hemodynamic variables, two-dimensional echocardiography and Doppler flows were recorded at rest. These were repeated during bicycle ergometry, performed for a maximum of four, 3-min stages, with each stage increasing in workload by 20 W. After resting, patients were subjected to dobutamine stress, administered up to a maximum 40 microg/kg/min, dependent upon heart rate. RESULTS: Mean (+/- SD) resting pressure drops across the C-E and Ultracor valves were comparable (maximum drop 19.4 +/- 8.6 versus 22.9 +/- 12.2 mmHg; mean drop 9.96 +/- 3.8 versus 11.83 +/- 6.6 mmHg, respectively). During exercise, the maximum cardiac flow rate attained was approximately 400 ml/s for both valve types. At this flow rate, the maximum and mean pressure differences between valve types were 6.2 mmHg and 4.4 mmHg, respectively (p = NS). During dobutamine stress, the maximum cardiac flow attained was approximately 500 ml/s, which resulted in significant differences between valve types of 11.6 and 7.3 mmHg, for maximum and mean pressure drops, respectively. When slopes of the mean pressure drop/cardiac flow were calculated for individual valves, a difference was observed between the two valve types (p = 0.02 and p = 0.039 for dobutamine and exercise, respectively). CONCLUSION: Both prostheses demonstrated significant increases in pressure drop under stress conditions. The standard porcine C-E valve had a statistically better hemodynamic profile than the Ultracor prosthesis at higher flow rates. When a study cohort of patients is small, these differences will only be evident at optimal flow rates. The higher flow rates seem most easily obtained when using pharmacological stress.

Results of an open-label, prospective study of anticoagulant therapy for atrial fibrillation in an outpatient anticoagulation clinic.

OBJECTIVE: The goal of this study was to investigate the complications and control of warfarin treatment in patients with nonvalvular atrial fibrillation (NVAF) newly referred to an outpatient anticoagulation clinic. METHODS: This study included new patients with NVAF who were referred to an anticoagulation clinic for warfarin therapy over a recruitment period of 21 months. To reflect real-world clinical practice, patient selection for anticoagulation and patient management were left to the referring physicians, who were blinded to their patients' participation in the study. Patients were interviewed in person at the first clinic visit and then by telephone every 4 to 6 weeks. They were questioned about any bleeding or thromboembolic events. RESULTS: A total of 402 patients were included (100% of all new referrals over 21 months). The mean (SD) age was 72.3 (10.3) years, and 224 (56%) patients were men. The mean (SD) international normalized ratio (INR) was 2.4 (0.31). Patients were followed up for a mean (SD) of 19 (8.1) months (range, 1.0-31.0 months). They spent a mean (SD) 66% (18.3) of time in the target range of INR (ie, 2.0-3.0). Annual event rates were 1.7% (95% CI, 0.4%-3.0%) for major bleeding, 16.6% (95% CI, 13.0%-20.2%) for minor bleeding, 1.2% (95% CI, 0.1%-2.3%) for ischemic stroke, and 0.3% (95% CI, 0.2%-0.8%) for transient ischemic attacks. There were no cases of hemorrhagic stroke or fatal bleeding. Variability of INR and number of medications were identified as risk factors for bleeding (P = 0.03 and P = 0.001, respectively). There was no significant association between age and bleeding. CONCLUSIONS: Based on this analysis, the risks of long-term oral anticoagulation therapy in an outpatient anticoagulation clinic appear to reflect the results of clinical trials. Rates of ischemic stroke, major bleeding, and anticoagulation control were comparable. There was no age-related risk of complications.

Use of resources and cost implications of stroke prophylaxis with warfarin for patients with nonvalvular atrial fibrillation.

BACKGROUND: Patients with nonvalvular atrial fibrillation (NVAF) have often been excluded from long-term anticoagulant trials, and therefore patients in clinical practice may have different risk, compliance, and safety considerations from those usually included in such trials. OBJECTIVE: The aim of this study was to investigate the use of resources and cost implications of stroke prophylaxis with warfarin in NVAF patients in clinical practice. METHODS: New patients with NVAF referred to an anticoagulation clinic in the United Kingdom were interviewed in person at their first visit and then by telephone every 4 to 6 weeks by an investigator. They were asked about bleeding events and extra physician visits, procedures, or hospital admissions related to bleeding. They were also asked about the method and the cost of transportation to the anticoagulation clinic and the costs involved in days of work missed by the patient and caregiver. Costs of warfarin treatment consisted of the following: (1) cost of the drug, (2) cost of monitoring lie, international normalized ratio, traveling, nurse visits, work missed. postage), and (3) costs associated with complications (ie, bleeding-related physician visits, hospital admissions, related procedures). admissions, related procedures). RESULTS: A total of 402 patients were included. Mean (SD) age was 72.3 (10.3) years, and 224 patients (55.7%) were men. Mean (SD) follow-up was 19 (8.1) months (range, 1-31 months). Annual event rates were 1.7% (95% CI, 0.4-3.0) for major bleeding and 16.6% (95% CI, 13.0-20.2) for minor bleeding. The mean cost of warfarin treatment per patient per month was 11.0 pounds (95% CI, 10.2-11.6) in patients with no bleeding and 11.9 pounds (95% CI, 10.3-12.5) in patients with minor bleeding (P=NS). The cost was significantly higher in patients with major bleeding ( 299.0 pounds; 95% CI, 74.6-538.9; P<0.001). The total cost of warfarin treatment per patient per year was 159.4 pounds, and the cost to prevent 1 stroke per year was 5260.20 pounds. CONCLUSION: In clinical practice in the United Kingdom, anticoagulation with warfarin for prevention of ischemic stroke appeared to be cost-saving relative to the costs of stroke.

Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect.

BACKGROUND: Elevated urine albumin excretion (UAER) is a modifiable risk factor for renal and cardiovascular disease in type 2 diabetes. Blockade of the renin-angiotensin system lowers UAER, but whether this effect is independent of blood pressure (BP) reduction remains controversial. The MicroAlbuminuria Reduction With VALsartan (MARVAL) study was designed to evaluate the BP-independent effect of valsartan on UAER in type 2 diabetic patients with microalbuminuria. METHODS AND RESULTS: Three hundred thirty-two patients with type 2 diabetes and microalbuminuria, with or without hypertension, were randomly assigned to 80 mg/d valsartan or 5 mg/d amlodipine for 24 weeks. A target BP of 135/85 mm Hg was aimed for by dose-doubling followed by addition of bendrofluazide and doxazosin whenever needed. The primary end point was the percent change in UAER from baseline to 24 weeks. The UAER at 24 weeks was 56% (95% CI, 49.6 to 63.0) of baseline with valsartan and 92% (95% CI, 81.7 to 103.7) of baseline with amlodipine, a highly significant between-group effect (P<0.001). Valsartan lowered UAER similarly in both the hypertensive and normotensive subgroups. More patients reversed to normoalbuminuria with valsartan (29.9% versus 14.5%; P=0.001). Over the study period, BP reductions were similar between the two treatments (systolic/diastolic 11.2/6.6 mm Hg for valsartan, 11.6/6.5 mm Hg for amlodipine) and at no time point was there a between-group significant difference in BP values in either the hypertensive or the normotensive subgroup. CONCLUSIONS: For the same level of attained BP and the same degree of BP reduction, valsartan lowered UAER more effectively than amlodipine in patients with type 2 diabetes and microalbuminuria, including the subgroup with baseline normotension. This indicates a BP-independent antiproteinuric effect of valsartan.